Tobacco Documents Online

1 UNITED STATES DISTRICT COURT 2 FOR THE WESTERN DISTRICT OF TEXAS 3 TEXARKANA DIVISION 4 THE STATE OF TEXAS, 5 Plaintiff, 6 v. No. 5:96CV91 7 THE AMERICAN TOBACCO COMPANY, et al., ~ 8 Defendants. 9 10 The Videotaped Oral Deposition of 11 ROBERT J. CARPENTER, JR., M.D., P.A., taken at the 12 request of the Plaintiff, pursuant to Federal Rules 13 of Civil Procedure, on Thursday, July 24, 1997, at 14 10:14 a.m., at 1301 McKinney, Suite 5100, Houston, 15 Texas, before Tara K. Taggart, Registered 16 Professional Reporter and Certified Shorthand 17 Reporter in and for the State of Texas (22385). 18 19 20 21 COURT COST: $ 22 TO BE PAID BY: Plaintiff 23 24 Certified__~~p~ 25 1 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A P P E A R A N C E S 2 3 For the Plaintiff: Provost & Umphrey, L.L.P., 4 490 Park Street, P.O. Box 4905, Beaumont, Texas 5 77704. By Robert J. Giblin and Bryan Blevins. 6 7 For Defendant Philip Morris: Shook, Hardy & Bacon, -71 8 L.L.P., One Kansas City Place, 1200 Main Street, 9 Kansas City, Missouri 64105. By Lori L. Farrar. 10 d an 11 Fulbright & Jaworski, 1301 McKinney, Suite 5100, 12 Houston, Texas 77010. By Marilyn Scanlan. 13 14 For Defendant R.J. Reynolds: Jones, Day, Reavis & 15 Pogue, 2300 Trammel Crow Center, 2001 Ross Avenue, 16 Dallas, Texas 75201. By Valerie E. Colson. 17 18 Also Present: Jerry Sorsdal 19 20 21 22 Ln ~ ~ ~ 23 m ~ 24 0~0 25 Ln 2 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 this. We'll make it -- thank you. 2 (Deposition exhibit marked, Exhibit 9.) 3 EXAMINATION BY MR. GIBLIN: 4 Q. Again, good morning, Doctor. 5 A. Good morning. 6 Q. Would you please state your name for the 7 r co d? 16 00 10 e r : : 8 A. Robert James Carpenter, Jr. 9 Q. I assume you've given a deposition before, 10 Doctor? 11 A. Yes, sir, I have. 12 Q. You know the purposes of what we're doing 13 here today? 14 A. In general, yes. 15 Q. If at any time you'd like to take a break, 16 just let me know; that's no problem. If I ask you a 17 question that doesn't make sense or isn't clear, 18 which I'm likely to do, let me know before you try 19 to answer. Okay? Ln ~ -J 20 A. I shall. ~ m 21 (Deposition exhibit marked, Exhibit 1.) ~ m co 00 22 Q. And I'll do my best to try to clean it 23 up. 24 First off, I have -- we've marked a couple 25 things here initially that we were provided. I'll 10:16:30 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 5

1 2 3 4 5 6 7 8 9 10 show you what's been marked as Exhibit 1, and I'll just ask you: Does that appear to be a true and correct copy of your report in this case? A. Yes. Q. Okay. Again, we have marked as Exhibit 2 a disclosure which indicates that there were no documents upon which you've relied in forming your opinions. Is that correct? (Deposition exhibit marked, Exhibit 2.) A. That's correct. 11 Q. Exhibit 3 is a list that you provided of 10:17:00 12 cases since 1994 where you've testified by 13 deposition or at trial. Does that appear to be a 14 complete copy of the list? 15 (Deposition exhibit marked, Exhibit 3.) 16 A. I will accept this as being true. I would 17 have to compare it with the list that I gave them 18 last week. I will assume that it is, in fact, true 19 and correct. 20 Q. Also at this time I would like to attach 21 Exhibit 9, which is the Amended Deposition Notice, 22 showing that this deposition was to begin at 10:00 10:17:30 23 a.m. 24 Doctor, when were you first contacted 25 this case? re ardin Ln r J g g N m J 6 m co KEITH & MILLER CERTIFIED REPORTERS ~ EL PASO, TEXAS 79901 (915) 533-7108

1 attorneys present, but I cannot recall who they may 2 have been. 3 Q. Okay. Where did the meeting take place, 4 Doctor? 5 A. Actually, it was at my home. I believe 6 that the 24th was a holiday or something like that, 7 and so I was at home working and told them that I 8 would be glad to meet them that particular day and 9 we met at my home, since the building where I worked 10:21:00 10 had no air conditioning in it. 11 12 13 14 15 16 17 18 19 20 21 22 23 Q. Okay. Do you know how Mr. Hlavinka got our n me? y a A. Yes, I do. I have been up against Mr. Hlavinka in several medical malpractice cases over the course of several years, and I will assume that that is how he, one, knew about me and then, two, decided to talk to me. Q. You say -- 10:21:30 A. Anything beyond that I don't know. Q. Okay. You say you've been up against him. From what standpoint? A. I was on the plaintiff side in several Ln ~ ~ cases in which he was on the defense side. m ~ 24 Q. Those cases that were tried here in Harris ~ ~ 25 County? N 9 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

-A 1 A. Well, I told him -- and then subsequently 2 several days later when there was a meeting I said 3 basically that I will serve as an expert in the 4 sense that I can tell you what I know and what I 5 don't know. I can tell you associations and disease 6 processes and such. I am certainly not a -- either 7 pharmacologist or a biochemist, and so from that 8 standpoint will not be able to help you much. But 10:19:30 9 the major issue is the specific issues of smoking, 10 One thing I was very clear both with him and then in 11 a meeting several days later with a number of 12 13 14 15 16 17 18 19 20 21 22 different attorneys for different firms, was that I was not going to sit before you or before any court and jury and say that tobacco is clean, has no potential injurious effects. That I was not and could not do, because I don't believe that. And that was understood from the very beginning. 10:20:00 Q. Okay. When was the first meeting? A The first meetin was on Januar 24th of Ln ~ . g y -i ~ this ar m ye . ~ Q. Who attended that meeting, Doctor? m %D 1~ A. I can -- I know that -- let's see. Mr. Curtis. I have cards of various people. 10:20:30 Mr. Curtis was there, I know Mr. Hlavinka was 25 there. Beyond that there were, I think, two women 23 24 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 8

1 A. I may not be able to give you an exact 2 date; it would be somewhere prior to January 22nd of 3 this year. I received a phone call from 4 Mr. Hlavinka. We discussed the case in minimal 5 rudimentary outline, and then -- in fact, it may be 6 as early as January 22, because I have a phone 10:18:00 7 conversation of about 30 minutes noted, but it may 8 have also been prior to that. So that's the best I 9 can give you, sir. 10 Q. Okay. What did Mr. Hlavinka tell you when 11 you discussed the case? 12 A. I'm not sure that I will be able to pull 13 from memory everything, but basically that there was 14 a suit against tobacco companies by the State of 15 Texas, and I said that I knew that there was a suit 16 that was either filed or going to be fil ed, and that 10:18:30 17 there had been previous suits filed by o ther 18 states. And he asked me if I would pote ntially 19 serve as a defense expert in the area of cn 20 maternal-fetal medicine, pregnancy compl ~ ications and v N m 21 such. And that was the main aspect. I cannot ~ m ~ 22 remember all of the subcomponents of tha t. 6 23 Q. During this initial discussion did you 24 tell him that, yes, you'll serve as an e xpert for 25 the tobacco companies? 10:19:00 7 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

.-s 1 I N D E X 2 WITNESS: PAGE: 3 ROBERT J. CARPENTER, JR., M.D., P.A. 4 Examination by Mr. Giblin 4 5 6 EXHIBITS: 7 1 Summmary of Expert Opinions for Texas 8 Attorney General Case 5 9 2 Documents on which Dr. Robert J. Carpenter 10 Relies in Forming his Opinions 6 11 3 List of Cases Since 1994 in which Expert Has 12 Testified by Deposition or at Trial 6 13 4 Folder with Documents 136 14 5 Documents 114 15 6 Articles 124 16 7 Condensed Transcript of Jeane A. McCarthy 117 17 8 State of Texas Expert Witnesses 126 18 9 Deposition notice 5 19 10 ACOG Technical Bulletin 68 20 11 Robbins Pathologic Basis of Disease 102 21 12 Articles 129 22 13 The Future of Children - Volume 5, Number 1 140 23 24 CORRECTIONS AND SIGNATURE PAGE 155 25 CERTIFICATION OF COURT REPORTER 156 3 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

xi 1 are. I would like to read those, because I cannot 22 Q. Okay. And that's contained in the file 23 that's been marked as Exhibit -- under your thumb? 24 A. 4. Yes, sir. 25 Q. Okay. We'll get to those -- 2 recall all of the things that he has had out, and 3 that he may have read and so -- and I certainly 4 don't have those in my possession, so I would like 5 to read what his base information that he provided, 6 and those were subsequently sent along with the two 7 different depositions. And there was also a 10:26:00 8 pediatrician whose deposition, I believe in the 9 Florida case, was sent. And that deposition, 10 likewise, is over on the side table. 11 Q. Okay. We'll cover what's in the stacks -- 12 A. Yes. 13 Q. -- in a little bit. Did you make any 14 notes, Doctor, during the meetings? 15 A. No, I did not. I did not need to. The 16 only notes -- no. I'll try to be responsive to your 17 question. No. During the meetings I did not make 18 any notes. 19 Q. Okay. You've made some notes after 20 reviewing the various depositions. Is that correct? 21 A. Yes, I have. 10:26:30 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 13 .

1 A. Okay. 2 Q. -- in a minute. Did you yourself perform 3 any type of a literature search? 4 A. No, I did not. 5 Q. Okay. So as far as the documents that are 6 stacked over there and the documents that you have 7 now looked at, those are things that have all come 8 from the tobacco companies? 9 A. Correct. I mentioned to you just before 10:27:00 10 we started the only thing -- and it's not a 11 literature search, but this is something I have in 12 my possession and have previously read parts and 13 parcels of it, and this was a book that came 14 approximately a year and a half or so ago. And I 15 got this out, and so that's provided, if you want to 16 take a look at it. 17 Q. Okay. And that's titled "The Future of 18 Children"? 19 A. Yes. 20 Q. That is a -- is that a book that you -- 21 A. Well, it's not a book. It's actually -- 22 if you want to call it a journal, it's volume 5, 10:27:30 23 number 1, spring 1995, and it's produced by the 24 Center For The Future of Children and the David and ~ , ~ 25 Lucile Packard Foundation. This particular one is r -J m ~ m 14 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 ROBERT JAMES CARPENTER, JR., M.D., P.A., 2 sworn by the Court Reporter, testified as follows: 3 EXAMINATION BY MR. GIBLIN: 4 Q. Good morning, Doctor. 5 MS. COLSON: I'm sorry. Before we get 6 started, I'd like to state on the record it's now 10:04:20 10:13:59 7 10:15 a.m.; Dr. Carpenter, counsel for defendants 10:14:00 10 30 14 : : 8 and the court reporter have been here since 9:00 10:15:00 9 this morning, the time that the deposition was 10 noticed to begin. We were not provided any 11 notification of the change or delay in the 12 schedule. 13 MR. BLEVINS: If you want to start off 14 that way, let the record also reflect that we have 15 attached as the next exhibit the Amended Notice of 16 Deposition that shows this deposition at 10:00. My 17 name's Bryan Blevins. I also confirmed this 18 deposition by time with Tom Stover, national 19 coordinator for these depositions. I also discussed 20 this deposition with Mr. Hlavinka during our 21 deposition of Dr. Arrington in Little Rock, Arkansas 10:15:30 22 Tuesday at 10:00, and that we have made our 23 apologies for the delay. Ln r 24 MR. GIBLIN: I had to let him do that, J r m 25 because I didn't do this. Let's go ahead and mark ~ m co 'i KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 4 ~

r. 22 A. That's correct. That has not been one of 23 my research areas, either actually doing it or 24 publishing it any time during my academic career. 25 Q. Do you consider yourself an expert in the 1 plaintiff review, it has been approximately 55 10:31:30 2 percent defense review. And then as I mentioned to 3 you before you started, I gave them this particular 4 set of documents last week, which is a complete 5 computerized listing of all depositions I've done, 6 as well as all trial testimony since I began any 7 reviews back in 1980. There is one other 8 classification within all these reviews which I call 9 "peer reviews," and it means reviews for either 10:32:00 10 hospitals alone or hospital attorneys and sometimes 11 in specific physician matters or sometimes in risk 12 management issues, to try to improve risk management 13 in the hospital, and specifically obstetrical 14 service. 15 Q. Okay. Have you written any articles, 16 Doctor, that deal with tobacco-related health 17 issues? 18 A. No, I have not. 19 Q. And I take it that would be the same for 20 any articles dealing with maternal smoking and 21 effects on the fetus or newborn? 10:32:30 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 18

1 that's the one. And so he apparently does 2 obstetrics on an ongoing basis, what I've been able 3 to gather from what I have read. 4 Q. Would you agree that Dr. Sachs enjoys a 10:29:00 5 very good reputation from a national perspective? 6 A. I know that he is well published and that 7 his name has been on various technical bulletins and 8 various other things. From that standpoint I would -. 9 say that he probably has a national reputation, 10 yes. 11 (Ms. Scanlan left the deposition.) 12 Q. Are you being paid -- 13 A. Yes, I am. 10:29:30 14 Q. -- for your time? 15 A. Yes, I am. 16 Q. How much are you being paid, Doctor? 17 A. $250 per hour for review and deposition, 18 and deposition preparation at 350 per hour. 19 Q. Okay. How about trial testimony? How 20 much will you charge for trial? 21 A. Trial, that will assume -- I have no idea ~ 22 where the trial will ultimately be. I am assuming J ~ 23 that if there is a trial it will be in Texarkana, ~ ~ 24 since that's where this case is filed. I charge ~ ~ 25 $2,500 a day for the workday. I will charge for 16 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 entitled, "Low Birth Weight." 2 Q. Did you say earlier that Dr. Sachs had 3 something to do with that book? 4 A. There was an article by Dr. Sachs. I 5 think he was the third author in a chapter within 6 this book, and he was specifically talking about the 7 use of current technology to monitor pregnancies 8 including ultrasound, various types of testing and 10:28:00 9 so f orth . 10 Q. Okay. You're familiar, I take it, with 11 Dr. Sachs? 12 A. I was familiar with his name from general 13 literature, which I have read in the past. I have 14 become much more aware of him with reading the 15 depositions and such since those have been 16 received. So that would be my understanding both 17 prior to and since my involvement in this case. 18 Q. What is 19 A. He's an Dr. Sachs' medical specialty? obstetrician, gynecologist. He 20 has done a Ph.D. in epidemiology, I think, the 10:28:30 21 University of Montreal. He is a maternal-fetal 22 medicine subspecialist trained, I believe, in the Ln J F-+ 23 Harvard program. He is currently on the faculty, m 24 the general faculty, at Harvard, and he is at one of 25 the hospitals, I think Beth Israel. I believe _j m ~ 15 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 travel time, expenses, and so forth, and that would 2 be at the $250 hour per rate. 10:30:00 3 Q. Okay. The case is currently set for 4 trial, I believe, in the latter part of September. 5 A. That's what I found out within the last 6 k wee . 7 Q. Okay. And I take it you do plan on 8 testifying live at the time of trial? 9 A. If I am asked to come, I will -- if I have 10 become involved in the case, if I am asked to come, 11 I will come. 12 Q. How many hours have you spent on the case 13 so far? 14 A. There are approximately 55 hours. There's 10:30:30 15 some additional minutes and stuff. Somewhere 16 between 55 and 60, and a good bit of that has been 17 in the last 10 days, pretty much the last 10 days. 10:31:00 18 Q. You've listed a number of cases here on 19 what's been marked as Exhibit 3, Doctor. I don't 20 obviously plan on going through each one of these. 21 what would be the breakdown of your expert testimony 22 from the standpoint of plaintiff versus defendant? Ln N -i ~ 23 A. In general -- I don't know what the m ~ 24 current specific number is ri ht now -- in eneral ~ m 25 g g in the past it has been approximately 45 percent m 17 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 area of tobacco-related diseases of a newborn? 2 A. I would have to say, no, I'm not. 3 Q. Do you consider yourself an expert in the 10:33:00 4 area of the maternal effects associated with a woman 5 smoking while pregnant? 6 A. Yes, I think I have a very good grasp on 7 the issues related to smoking during pregnancy and 8 specific issues related to that. I think it depends 9 on how one tries to define the word "expert." I 10 certainly cannot give you a quotation going back 20 10:33:30 11 years, 30 years, of every article published, et 12 cetera. I can't do that. I'm certainly not an 13 expert in the sense that I have done bench work as 14 we were talking about just before, measuring 15 nicotine levels, et cetera, et cetera, looking at 16 vasoconstrictive effects and things like that, I 17 have not. So that my acquisition of data over the 18 large line of time since I've been doing obstetrics, 19 for basically 20 years post residency, and then 24 10:34:00 20 years including residency, has been from both the 21 literature, meaning the journal articles, books and 22 various other treatises, plus I would say listening un J ~ 23 to lectures, which the subject could be discussed as ~ ~ 24 a component part of some presentation, but not as m N 25 primary research. Again, it's not my -- not been my 19 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 research area or research areas, since I have 2 l severa . 10:34:30 3 Q. Would you agree, Doctor, that there has ~ 4 never been a disease process studied and analyzed 5 with numerous studies that have been done more 6 closely or more in volume than smoking? 7 A. I'm not sure I can give you an affirmative 8 on that. I think that it has been very well looked 9 at by many investigators in many countries. But 10 when you say there has never been a disease process, 11 I think we can talk about malaria, we can talk about 10:35:00 12 the issues of intestinal diseases, diarrhea which 13 kills a tremendous number of people across the 14 world. We can talk about a whole host of other 15 disease processes. 16 We can even probably in this decade and 17 the decade of the '80s talk about the issues of HIV, 18 and in that particular 17-year period it may be that r. 19 HIV research and the rest far exceeds any amount of 20 either, one, expenditures or, two, publication 10:35:30 21 volume of cigarettes within the area of certainly 22 obstetrics and even perhaps multiple other areas of 23 iving you a basis for why I Ln medicine But again . , , g r ~ 24 N said no . m ~ 25 as to ~ Q. Okay. Do you have an idea Doctor , , m w KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 20 ~

1 A. Well, actually, they were filed in Harris 2 County, because the individual who filed them, 3 specifically Rock Onstad, filed them here. They 4 were actually in Texarkana against facilities in 5 Te k 10 22 00 xar ana. : : 6 Q. What took place at the first meeting? 7 A. Oh, basically we went through some of the 8 same things we discussed before, and that's pretty 9 much it. There were a number of -- we reviewed some 10 of the issues of premature labor, talked about 11 premature ruptured membranes, talked about some 12 aspects of maternal disease. I cannot recall all of 13 the specific things that were talked about from a 14 medical perspective, but we went through a lot of 10:22:30 15 medicine. Actually, if I had to categorize it as a 16 session where I did more listening or more talking, 17 I would say I did more talking. The second 18 component of that was that I did what I considered a 19 lot of teaching/education about a number of those 20 things, not knowing the specific database that the 21 individual attorneys had. There were some specific 22 questions asked at intermittent times during the 10:23:00 23 course of those discussions about specific subsets, 24 conditions and the rest. But not necessarily as Ln ~ 25 they related to smoking, per se. It was really a ~ m J 10 ~ W KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 very general and at times in-depth review of a lot 2 of different issues of maternal-fetal medicine. 3 Q. When they showed up for the meeting did 4 they bring literature or documents with them? 5 A. No, they did not. 10:23:30 6 Q. Was there a recording made -- 7 A. No, there was not. 8 Q. -- of that meeting, Doctor? 9 A. Or if there was, I am not aware of it. 10 Q. How long did the meeting last? 11 A. It was about an hour and a half. 12 Q. How did the meeting break up? What was 13 decided at the end? 14 A. People had to catch aircraft and leave 15 town. 16 Q. Well, what were the plans, I guess would 17 be a better question, when the meeting broke up? 18 A. Okay. The plans were that a number of 19 different documents would be sent, some of which are 10:24:00 20 over here on the side table, and at some later point 21 that there would be further work communication 22 involved within the case, and that's basically what Ln ~ J N 23 happened. In fact, it lay dormant for a good while, m J 24 ond the time that the Mississippi case and even be B ~ y ~ 25 then the -- what I call the national settlement, if 11 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 you will, occurred. 2 Q. Okay. The documents that were sent, were 3 they specific documents you requested, or were these 4 documents that the tobacco companies decided that 5 they would send you? 10:24:30 6 A. No. There were some information -- I told _ 7 them, one, I had a general knowledge of information w 8 concerning tobacco and its potential effect within 9 pregnancy and fetuses, and that that had been 10 gathered both from articles in journals as well as 11 books and other sources over my medical career. But 12 that I certainly did not have a library of any 13 specific articles or anything like that, which I had 14 accrued and maintained. I certainly did have a 10:25:00 15 bunch of articles, but not related to that specific 16 subject set. And so there were some articles that 17 were sent and, again, those are over there on the 18 side table. 19 Later on the -- they told me at one of the Ln ~ 20 meetings, and I don't recall which one it was, that J 21 m Dr. Sachs had been deposed in the Mississippi and ,, m 22 Florida cases, and that those depositions would be ~ 23 coming. There were a number of exhibits from 24 Dr. Sachs' deposition that I requested and I said, 10:25:30 25 you know, I would like to see what his exhibits 12 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

"N -4 1 dictate this, have it transcribed in my office or 10:37:00 2 anything like that. 3 Q. Do you know when that report was prepared? 4 A. It would have to have been prior to last 5 Wednesday, because that was when we reviewed this in 6 some detail. Other than that, I cannot give you 7 a -- I can't clarify it any more than that. 8 Q. All right. Now, you talked about the 9 meeting that you had at your home -- 10 A. Yes. 11 Q. -- with the four or five tobacco people; 12 I forgot how many. And then -- 10:37:30 13 A. Five, if I remember correctly. 14 Q. Okay. And then later some information, 15 documents, were sent to you. Correct? 16 A. Yes, sir. 17 Q. After that -- after you got the documents, 18 did you have any more face-to-face meetings with 19 anyone -- 20 A. Yes. 21 Q. -- associated with the tobacco industry? cn N ~ ~ 22 A. Yes. m 23 Q Okay When would that have been and who J ~ . . m 24 would the meeting have been with? Ln 25 A. There was a meeting, 5-21, and I think the KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 22 ---- ------~::~:

1 actual time spent with that meeting -- I have three 10:38:00 2 hours and 10 minutes here, but I think the actual 3 meeting was about two hours and 10 minutes, and then 4 I spent additional time after that with various a 5 things, which I cannot remember. That was the ~ t 6 next -- that was the next meeting after the January 7 24th meeting. Then there was a meeting on July 8 16th, which -- a week ago yesterday. And that was ~~ 9 about three hours and 15 minutes, and that, I 10:38:30 10 mentioned before, this was reviewed at that 11 particular time. 12 Q. On your report, the first time you ever 13 saw a written report, was on July the 16th? 14 A. That's correct. W* 15 Q. Okay. Prior to July -- 16 A. Oh. And I need to correct something, 17 because I did not -- I had these written down on <.A 18 little slips of paper. There was also a meeting on 19 5-30-97 for an hour and 10 minutes. Those are the 10:39:00 20 only meetings. 21 Q. Okay. Ln 22 A. Up through -- and then there was a meeting P- -j =:~f ~ ~ 23 and that was for four hours and yesterday , , v N 24 deposition preparation, reviewing many of the things m m 25 that we'll probably be talking about today. 23 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 out yesterday -- and I'll be honest and say I do not 2 remember her name -- who I found out was a physician 10:40:30 3 yesterday. And she had worked in pharmaceutical 4 research, I believe, for 15 years, doing drug 5 research. But, again, I don't remember her name. 6 Q. This was a tobacco industry employee -- 7 A. It was one of their -- 8 Q. -- that you met with? 9 A. No, it was one of their -- well, it was 10 one of their attorneys. 11 Q. Attorney for the tobacco companies? 12 A. Yes. 13 Q. Okay. 14 A. Who's also an M.D. 15 Q. Okay. What did she add to the meetings? 16 A. She was a component part of the meeting. 10:41:00 17 I'm not sure that she added to the meeting, if... 18 Q. Uh-huh. 19 A. I'll have to ask you, what do you mean by 20 added to the meeting. 21 Q. Well -- 22 A I can tell you She had -- well cn ~ . , ~ 23 specifically. She apparently had either attended N m _j ~ 24 several of the depositions; there were a number of m 25 questions that you-all had asked of other defense co 25 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 experts. A number of those questions were 2 discussed, and there were several with subcomponents 3 of those, and she had apparently written those down, 10:41:30 _., 4 and went over some of those. 5 Q. When would that have been? i 6 A. That was yesterday. _1 7 Q. Oh, yesterday? t~4 ~ 8 A. Yes. 9 Q. Okay. 10 A. Because apparently you-all have just ..~ 11 started in the last week or so the various 12 depositions. 13 Q. Uh-huh. 14 A. And you have 100 to do before the end of 15 the month? 16 Q. Uh-huh. What -- what were the questions 17 that she had written down and talked to you about 18 that we had asked earlier in the week? 10:42:00 19 A. I'm sorry; I'm not going to be able to 20 give you all of them. There were some statistical 21 questions, definitions that were asked, and they Ln 22 asked me what -- how I would respond, and I gave ~ ~ m 23 them what my definitions and understandings of ~ ~ 24 various things would be. There were a number of ~ 25 other questions that were asked concerning some of 26 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

J i 1 Q. Do you know who prepared your report, 2 Doctor? 10:44:00 3 A. I-- no, I do not. 4 Q. Okay. 5 A. I would assume that it was one or more of 6 the attorneys. 7 Q. And the first time that you saw this 8 report was July the 16th. Is that correct? 9 A. That's correct. 10 Q. When you saw it and read it did you make 11 any changes to it? 12 A. Yes, I did. 13 Q. Okay. Did you keep a copy of the draft 14 where you made changes? 15 A. No, I did not. 16 Q. What type of changes did you have to make 17 to it? 18 A. well, there were a number of different 19 words which I thought in the context of grammar were 20 not proper, there were some statements in there 10:44:30 21 which I did not -- or at least in review I did not 22 consider to be 23 appropriate - medically -- I won't say well, I'll just use appropriate. I reasonable word. And then there were ~-- 24 think that's a 25 some other words which I changed because I thought 28 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

._-.i 1 and read his deposition. So I -- that would be a 2 request, in a way, yes. 10:46:00 3 Q. Anything about -- after you read it, was 4 there anything about his testimony that had an 5 impact on your opinions in this case? 6 A. No. I think the proper answer would be 7 no but there needs to be a clarifying component f~:-l 8 , . The one thing within his deposition that I basically 9 disagreed with, which differs sharply from my 10 opinion in this particular matter, is that 10:46:30 11 Dr. Sachs' opinion, multiple places as stated in 12 both, I believe, the Mississippi as well as the 13 Florida case, was that if you are a smoker all 14 complications of pregnancy are basically related to 15 smoking, and I don't agree with that. 16 Q. Okay. Anything else -- 17 A. No. 10:47:00 18 Q. -- about that? You also -- 19 A. And he went through a lot of the 20 literature. They talked -- certainly in the 21 Mississippi case, they went through a tremendous 22 amount of statistics and epidemiology and things ~ ~ 23 like that. And I couldn't disagree with some of the m 24 things, because some of the things I think are J ~ 25 correct from the standpoint of perhaps definitions, w 30 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 processes and the rest. It was actually a quite 2 learning episode because of the volume of 10:47:30 3 epidemiology and statistics that both the attorney 4 as well as Dr. Sachs went through. 5 Q. Okay. So the disagreement that you had 6 with Dr. Sachs was that in a number of places in the 7 deposition it's your impression that he stated that 8 all pregnancy complications, if the mother smokes, " I 9 all pregnancy complications that occur are caused by 10 the smoking? Is that what you said? ~. 11 A. Yes, in basic summary. And then one other 10:48:00 12 thing; I had previously read his - - well, what I 13 found out, because I have to admit when I first read 14 it back -- received in 1993 concer ning the ACOG 15 Technical Bulletin on smoking and women, I did not 16 know that he was one of the co-aut hors, if you will, 17 of that until the deposition. But one of the 18 statements that was made within th at and after I 19 read it, his deposition, it's one of the exhibits, 20 and I pulled it from my file. He made the statement 10:48:30 21 in there that there really had been no causality 22 found, although certainly it was considered a risk Ln 23 r J certainly it was considered to be -- to have ~ factor , m ~ 24 associations made with various problems in pregnancy ~ ~ ~ 25 with cigarettes and nicotine exposure. 31 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 2 3 4 5 ~ --• . -°, 6 ~ -.~ 7 ~ 8 9 10 11 12 13 14 15 16 17 18 19 20 21 to maintain your -- both your in vitro, your chemical exposure, your environmental, your oxygen, carbon dioxide, temperature, various other things in 10:53:30 the laboratory. Well, the human is a little bit more complex than that, and so I don't think there ever will be a single study that will be able to maintain. The comment has been made in several different sources that it is purely unethical to have a randomized controlled study involving nicotine exposure and nonnicotine exposure. That would be impossible to do, and it would, in fact, be 10:54:00 unethical. So causation in that circumstance has not been proven. I think that there is a strong association, and I think that there is a -- it is a risk factor for adverse outcomes. Q. All right. Let me see if I understand the definition that you're working under here, Doctor. Ln ~ Obviously with regard to adverse pregnancy outcomes ; there are a number of things that can cause that to m ~ ~ ~ happen. Is that correct? 0° 22 A. Yes. 23 Q. Okay. Would you agree with me that 10:54:30 24 smoking -- I'm not talking about being the cause of 25 the outcome -- would you agree with me that smoking 35 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 that the impact of that specific word was not 10:45:00 2 something that I would use in the context of 3 populations. Truly semantics. ~~ 4 Q. Okay. Have you been asked to be an expert 5 witness on behalf of the tobacco company in any of 6 the state cases that are pending right now? 7 A. No, I have not been. 8 Q. So right now you're -- the only case in 9 which you're an expert for the tobacco companies is 10 the State of Texas case. Is that correct? --,, 11 A. Yes, sir. 12 Q. You mentioned Dr. Sachs' deposition which, 13 again, we'll get to those stacks here shortly. But 10:45:30 14 I take it atter you reviewed those you made some 15 notes? 16 A. Yes, I did. 17 Q. Okay. 18 A. There are several pages of notes here in 19 the blue, small folder. 20 Q. Okay. Did you request a copy of 21 Dr. Sachs' deposition? Ln ~ 22 J A. They were -- I didn't necessarily request ~ m 23 it in that exact words. I -- they told me that J N 24 F+ N it -- I think one may have been done, the other one 25 is being done. I told them that I wanted to review 29 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

--, = 3 1 Q. Okay. Was there a tape made of that 2 meeting yesterday? 3 A. No. 4 Q. Or a videotape? 5 A. No, sir. 6 Q. Okay. 7 A. Not to my knowledge. 8 Q. The meeting on 5-30, who attended that? 9 A. I'm sorry. I -- I -- there was one 10:39:30 10 meeting where there were five or six different 11 attorneys representing different firms. I know 12 Mr. Hlavinka was there, I know that Mr. Curtis was 13 there. At different times Ms. Scanlan has been 14 there, Lori Farrar, who is here today was there. 15 Carol Lindgren-Bron was there. Those are the only 16 attorney's cards I have; that's six in number. But 10:40:00 17 I don't remember which specific dates who was 18 present. Mr. Hlavinka and Mr. Curtis have been the 19 two people I think I have seen most frequently. 20 Ms. Farrar has been at several of the meetings, 21 also. 22 Q. Any of the people that you met with on the Ln ~ ~ 23 30th, do any of them have any medical training, to m ~ 24 your knowledge? m ~ 25 A. Oh. There was one young lady who I found 24 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Q. -- or epidemiology -- okay. 2 A. I think there are other people around who 3 are much more qualified than I to be able to do 4 that. 10:57:00 5 Q. Toxicology? 6 A. No. 7 Q. Pathology? 8 A. I think it would depend upon what you were 9 talking about from the standpoint of pathology. 10 However, I do not have boards in either clinical or 11 anatomic path, and therefore I would not be able to 12 sit down and discuss all of those things in the 13 sense of -- but in certain areas I know a reasonable 14 amount of pathology. But in other areas, I know a 15 very limited amount of pathology. But I will 10:57:30 16 certainly, if I am asked a question, I will give you 17 whatever my answer is, if I know anything. But I 18 certainly could not give you a treatise on many 19 areas. 20 Q. I'm sorry. I didn't mean to interrupt you. 21 A. No, I was finished. Ln r ~ 22 Q. Okay. Would the primary focus of your r m ~ 23 interest be in the area of placental pathology? ~ N F-4 24 A. Actually, not placental so much as kidney, 25 some aspects of brain pathology in the fetus and 38 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 would be a cause of an adverse pregnancy outcome? 2 Not the only cause; there may be other causes that 3 are working together. Okay? Would you agree with ~ 4 me that it's pretty well recognized that smoking can .: i .1 - ; 1 `. 5 and is in many occasions a cause -- not the only 6 cause -- but a cause of an adverse pregnancy 10:55:00 -, 7 outcome? 8 A. Yes. And I said that earlier. 9 Q. Okay. 10 A. Because a cause means that it is a risk 11 factor. One could use any number of examples, which 12 I won't do. But, yes, it is a factor in adverse 13 utcomes . o 14 Q. Okay. When did you leave Baylor? 15 A. I left Baylor June 1st, 1994. 16 Q. You're in private practice now, so to 10:55:30 17 speak? 18 A. I'll go through this -- okay. So to speak. 19 Q. So to speak? 20 A. I've always had a private practice. I'm 21 doing nothing more than I've always done, except 22 that I have no access to residents and fellows from Ln ~ ~ ~ 23 the standpoint of teaching. But other than that, m ~ 24 private practice, I've always had it, even during my r r ~ 25 multiple years on the faculty at Baylor. But in the 36 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. Yes. 2 Q. Okay. Obviously you are an expert and you 3 consider yourself an expert in the area of 4 gynecology, obstetrics and gynecology, I guess? 5 A. No, I'd have to divide that. 6 Q. Okay. 7 A. I have had training in gynecology during 8 my residency. There are many aspects of gynecology 9 right now where if I needed to I could treat women 11:01:00 10 and treat women appropriately. There are many other I 11 aspects of gynecology, such as laparoscopy, some 12 forms of procedures involving laparoscope and others 13 that I would not attempt, because I do not consider 14 myself competent. Vaginal hysterectomy, anterior, 15 posterior repairs, I haven't done that in 20-plus 16 years. And so, yes, I have boards in it and I could 17 be examined on it and I could examine other people 18 on it in an, if you will, academic way and be ~ 19 reasonably knowledgeable. But the practice of it is 11:01:30 20 a different story. Within obstetrics, yes, I Ln ~ 21 consider myself an expert within obstetrics, and I J /-+ 22 know a tremendous amount about many different m J 23 things. N ~ 24 Q. In the area of obstetrics, what would you 25 consider to be an authoritative treatise or 11:02:00 41 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

/ ;J 3.~ rl- 1 number of things. I would not go into the nursery 2 and try to take care of a small baby. I would not 3 be qualified to do so. 4 Q. And when you say a "small baby," are we 10:59:30 5 talking about a low birth weight baby or small for 6 gestational age or -- 7 A. Any baby who ends up -- I'm sorry. Any 8 baby who ends up going to special care nurseries and 9 so forth, I don't know what the current -- I won't 10 go into those. I don't know about multiple aspects 11 of current care. Ventilator care I certainly would 12 not attempt, so -- but I know a number of things 13 about neonatology and about babies post delivery, 14 but I do not know everything. 11:00:00 15 Q. Any textbooks or treatises in the area of 16 neonatology that you feel are particularly 17 authoritative? 18 A. Avery is one of the major ones that I can Ln r 19 recall. There is a textbook, Berman is at least one ~ ~ m 20 of the authors. There are several others over the ~ ~ N 21 course of time that I have seen, but those are the W 22 only two that I can recall. I was trying to pull 23 out a name, and I can't do that. 11:00:30 24 Q. Avery would be Gordon Avery. Is that 25 correct? KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 40

S-~ 1 the number of people that die every year in our 2 country due to smoking-related diseases? 3 A. Do I have an actual number in my head? 4 Q. An idea. Do you have an impression as to 5 what that number would be? 10:36:00 6 A I think it would be considerable I think .~.; . . ~ 7 that if I had to give you a number which -- you -,, 8 know, I'm not going to try to give you a number 9 because I don't know a number. 10 Q. Uh-huh. 11 A. I think it would be considerable when we 12 consider all the aspects of smoking and its impact 13 into individual people who may or may not have other .- 14 disease processes. So I think it would be ... 15 considerable. 16 Q. Uh-huh. I'm going to show you, Doctor, 17 what's been marked as Exhibit 1; you've already 10:36:30 18 identified it as a copy of your report. Did you 19 prepare that report, Doctor? 20 A. No. I reviewed it last week, I believe 21 Wednesday of last week. This was prepared from a ~ 22 discussions that tn number of the different meetings , N _j ~ 23 had been had over the whole course of time, and I m 24 J will assume going back to that first meeting of N m ~ 25 January 24th of this year. But, no, I did not 21 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

4.4 ,., `F 1 the issues in.the obstetrical component of this 2 case. 3 Q. Such as? 4 A. Oh. Issues related to -- let's see. Oh, 10:42:30 5 I think -- and I'm trying to reconstruct -- issues 6 related to the various disease processes that have 7 been seen in pregnancy, and then using three 8 different words; one, risk factor, two, association, 9 three, causation or causality, whether those 10:43:00 10 specific aspects had -- were considered to be risk 11 factors during pregnancy for adverse outcome. 12 Whether there were associations which have been 13 drawn, and whether causation or causality had been 14 attributed to those various things. 15 Q. Okay. 16 A. That was a -- and that was a significant 17 number of questions, if I remember correctly. 10:43:30 18 Q. Well, you're going to hear them here in a 19 little bit. 20 A. That's okay. 21 Q. What other questions did you talk about 22 yesterday? 23 A. Oh, God. There were some other 24 definitions. Sorry; I can't pull that from my 25 head. There were a lot of questions. 71"* 27 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

I 1 These are the people that are apparently the experts 2 in the arena of the maternal and fetal questions 3 dealing with smoking. Dr. Robert Woody. 4 A. No. ~ 5 Q. He's a pediatric neurologist. 6 A. I heard his name yesterday, but I'm not ii i i h hi f 7 aiii ar w t . m. 11:04:00 ~ 8 Q. Okay. Robert Arrington. Dr. Robert 9 Arrington? 10 A. No. Do not know him. 11 Q. Dr. Percy Luecke? 12 A. No. 13 Q. And Dr. Jack McCubbin? 14 A. No. ~ 15 Q. And I take it you have not had any 16 conversations with any of those gentlemen? 17 A. No, sir, I have not. 18 Q. Have you had any conversations, Doctor, 11:04:30 19 with any of the other tobacco company experts in 20 this case? There's -- and as you may know, there's 21 what they call their national experts, just like 22 then you have your state Ln Texas national experts , , ~ 23 ~ experts. And my question to you is: Have you ~ m a~ 24 talked with any of the national experts with -- with ~ N ~ 25 the tobacco companies? 43 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 textbook? 2 A. Oh. There are a number of different 3 books. I think Williams still stands as one of the 4 best overall texts. I think that the book that is 5 just entitled "Obstetrics," which has as some of its 11:02:30 6 authors Jennifer Niebyl, Steve Gabbe, Joe Leigh 7 Simpson -- and there is a fourth person, and I don't 8 recall who that is -- that is a very good T. V': 9 ~_ obstetrical textbook. 10 Within the area of maternal-fetal 11 medicine, probably Creasy is the standard text that 12 most of us have used, both for our own training 13 purposes over the years as well as training our 14 fellows and recommending it to our residents and/or 11:03:00 15 students who are on rotations. There are a couple 16 of other books that are -- I don't remember the name 17 of it. There is a very good book in obstetrics I 18 have seen from the UK, and I can't remember the 19 author. But there are a number of other books that 20 would likewise be very, very competent in being able 21 to teach people. 11:03:30 22 Q. Doctor, do you know any of the other 23 experts in this case for the tobacco company? Ln ~ J 24 A. Specifically, no to that question. m 25 Q. Okay. I'll give you a couple of names. ~ N Ln 42 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

2- 2 N 1.4 a 23 that information. 24 Q. Do you recall whether or not you had any 25 specific disagreements with what Dr. Speer's 1 A. No. I've talked to no one other than the 11:05:00 2 attorneys, at least the six names here, and there 3 may have been someone else. But I have not talked 4 with any of the other expert witnesses at any level 5 in this case. And the reason I said earlier from 6 the standpoint of defense, there is one person on 7 the plaintiff's experts who I know well and talk to 8 all the time, but we have not talked about this 9 case, and that's Mike Speer. He's a neonatologist 10 at TCH in Baylor. 11:05:30 11 Q. Uh-huh. 12 A. That's the only person I would talk to, 13 but not about the case. 14 Q. Have you reviewed Dr. Speer's expected 15 testimony in this case? 16 A. There was a list of the plaintiff experts, 17 and I have gone through and read those various 18 documents. I don't recall all of the things. I 19 think that predominantly he would talk about those 20 aspects of smoking he thinks is relevant for a 21 neonatal practitioner and from the standpoint of a 22 neonate, but I don't remember the exact subsets of 11:06:00 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 44

1 researchers, many scientists that have studied the 2 issue have said that the relationship between 3 maternal smoking is -- maternal smoking and low 4 birth weight is so related that the relationship is 5 a causal one? Do you agree that many people have 10:50:30 6 said that in their studies? 7 A. Not necessarily causal, and I use causal 8 in the sense that where you have good, firm data 9 that a specific factor, whatever it happens to be, 10 in and of itself with all other variables controlled 11 clearly defines an abnormality and statistically 12 ends up suggesting that that one factor, with all 13 other things controlled for, really stands out as 10:51:00 14 the factor. And so I can't agree that multiple 15 scientists -- there is a lot of discrepancy within 16 the published literature amongst multiple different 17 issues. There certainly is persistent, there are 18 consistent observations that there is an increased 19 risk of low birth weight with cigarette smoking. 20 There is also limited data that would suggest that 10:51:30 21 at least up to a certain point that there is a 22 dose-related effect, although that dose-related 23 effect does not show what you would normally trend 24 with increasing amounts of a chemical agent with 25 increasing amount of disease, there is some degree 33 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 of plateauing. 2 And then when you look at various other 3 literature, there are multiple other factors, one of 4 the most important of which is the basic issue of 10:52:00 5 the individual person who smokes and whether that 6 smoking and low birth weight, it is a component, it 7 is a risk factor, and there is that association, 8 but is it also a marker, a surrogate, if you will, 9 for other aspects of that particular person's life 10 which is confounding the basic issue of smoking? 11 And, as I said, I'm not here to say that smoking is 10:52i30 12 okay; I don't believe that. But I don't think that 13 it's a full causation statistical effect in the 14 usual causation, meaning directly related. 15 Q. If I understand your definition here that 16 you're utilizing, Doctor, for there to be causation 17 all other factors have to be eliminated and there'll 18 be one factor standing alone, which would be 10:53:00 19 smoking? 20 A. Yes. As far as trying to be a purist, 21 trying to be a scientist -- and I would hope if one Ln J 22 is a true epidemiologist that one would look for m J 23 that isolated factor of maintaining all other ~ J 24 variables. You do that in the laboratory, you do 25 that in multiple other circumstances where you try 34 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Q. Is smoking a cause of chronic obstructive 2 pulmonary disease? 3 A. Yes. 4 Q. Is smoking a cause of respiratory 5 infections such as pneumonia or influenza? 6 A. It can be associated with it, yes. ~ 7 Q. Is smoking a cause of peripheral artery 8 occlusive disease? 11:16:00 9 A. I'm not familiar with that as a specific 10 because, again, many people who have coronary artery 11 disease also have peripheral vascular disease, and 12 so it may or may not be. I won't give you a yes or 13 no on that; I'll give you a maybe. 14 Q. Okay. How about gastric or gastric 15 duodenal ulcers? ::. 16 A. As a direct cause, I don't know. Can I 17 conceptualize that it could be? Yes. And I think 11:16:30 18 there, again, going back to what we were talking ,... 19 earlier about individual personality types and those 20 other factors that lead to a disease process. It L, ~ 21 may be a contributor, but it's not one of those that ~ 22 I have in my head as a cause of gastric -- ~ w ~ 23 personality is. And, also, the Australians have 24 provided us with very elegant data concerning 25 bacteria. And so it may be a factor, but I'll have 11:17:00 48 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 usual sense of ivory tower versus the real world, 2 yeah, I guess I'm in the real world, but I've always 10:56:00 3 considered myself in the real world. 4 Q. Okay. I'm going to ask you about a couple 5 of other areas here -- 6 A. Okay. 7 Q. -- and just see if you consider yourself 8 to be an expert witness, if you will, in these 9 particular areas. This is just something we need to 10 know before we get down there at the time of trial. 11 A. Some of those questions I think we will -- 12 Q. You know, we would like to be able to know 13 where you will be going with regard to expert, if 14 you will, testimony. 15 A. Right. 10:56:30 16 Q. Do you consider yourself expert in the 17 area of epidemiology? 18 A. Simple answer: No. 19 Q. Okay. Biostatistics? 20 A. No. I have received training in it, and I 21 know a little bit about it but not an expert in , cn ~ 22 what I would consider an expert to be. ~ ~ m 23 Q. And as far as offering expert opinions on -J N 24 biostatistics -- N m 25 A. No. 37 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 then other organ systems, and especially 2 cardiovascular in the fetus. 10:58:00 3 Q. Okay. Could you give me the name of one 4 or more pathology texts or treatises, if you will, 5 that you feel are authoritative in the area of 6 pathology? 7 A. Pathology? Robbins has always been -.- in 8 fact, I was at the Baylor bookstore the other day 9 picking up a book and I saw the -- I won't call it 10 the new Robbins, because I don't know when it was 11 out, but it certainly is a textbook that I used in 10:58:30 12 medical school, and I would assume has continued to 13 be very good. There are other textbooks of 14 pathology that I have seen in the past, but I don't 15 know them. Robbins is the major one that I have 16 known. 17 Q. Okay. Do you consider yourself an expert 18 in the area of pediatric neurology? 19 A. I am not board certified in pediatrics or 20 neurology, and so I can answer a limited number of 21 questions in some areas very well, but in the 10:59:00 22 totality of pediatric neurology, no, not an expert. Ln 23 Q. Neonatology? ~ ~ 24 A. I'll give you the same answer there: I'm m -J ~ 25 not boarded, but I know a reasonable amount about a N 39 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

~ -~ 1 to put a maybe there; don't know. -4 2 Q. In your opinion is nicotine addictive? 3 A. Yes, I believe that it's addictive. , 4 Q. Did you happen to read the Houston 5 Chronicle this week, Doctor? I think it may have 6 been Tuesday? 11:17:30 7 A. I would have read the Chronicle this week. 8 Q. You have? 9 A. Yes. Several times, but... i~ 10 Q. Okay. Did you see in there -- I think it 11 may have been on the first page where the president 12 and CEO for Liggett, the Liggett Tobacco Company 13 swore, took the stand and swore and testified under 14 oath, that smoking causes lung cancer and it causes 15 emphysema and several other things and that they've 16 known for years about this but this was the first 11:18:00 17 time they've ever admitted it. Did you read that 18 ti le? a .~ r c 19 A. I did not read that article. The reason I 20 didn't read the article was because on either NBC or 21 CBS news they showed a brief clip of a component of 22 what you just stated, and that was it. Ln ~ J 23 Q. Okay. What did you think about that, when N B ~ 24 you heard that the -- or when you saw the clip of r w N 25 the president, CEO for Liggett, you know, finally 49 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 not seen those. I know that they have some internal 2 documents, because that's been on the news. But I 3 have seen none of them. 4 Q. The next area we'll talk about, just in 5 general, is categories, I guess -- 11:20:00 6 A. Okay. 7 Q. -- if you will, of adverse pregnancy 8 outcomes, if you will. And this will be a lot ~, :_-~ 9 quicker now, since I believe I understand your 10 position on these. As we talked earlier, you agree .1 11 that maternal smoking, not the -- is not the only 12 cause, but maternal smoking is a cause -- is a cause 13 of adverse pregnancy outcomes. Is that correct? 14 A. We can either say a cause or a factor, 11:20:30 15 risk factor, as long as the use of the word "cause" 16 is not rearranged or brought out as being causation ~ 17 in a true statistical sense. 18 Q. Okay. 19 A. Meaning proof beyond a shadow of a doubt. 20 So going back with what I said earlier and the rest, 21 absolutely it's a risk factor, and I think there's 11:21:00 22 association in a number of different areas. If we ~ 23 use cause as you -- if we use cause as being Ln 24 equivalent to a risk factor then I can very easily ~-a -J 25 , accept that -- N m ~ ~ w 51 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 2 Q. Okay. A. -- statement that you made. ~ 3 Q. Okay. Well, let me -- let me just tell 4 you this, Doctor: I assure you that when I say 5 6 "cause," or if I ask you is it a cause, I'm not asking whether or not there is proof beyond a shadow 11:21:30 7 of a doubt that it caused the event. Okay? U E{-1 8 9 10 11 A. Okay. Q. That's not what I'm asking you. A. I will accept that definition from this oint on . p --.-i 12 Q. Okay. But, again, I'm not asking you 13 whether or not there is proof beyond a shadow of a 14 doubt that it caused the event. Okay? 15 A Oka . y. 16 Q. What I'm asking you is: As we talked 17 earlier, there can be several causes of an adverse 18 pregnancy outcome. Correct? 11:22:00 19 A. Yes. And when we talked about -- maybe my 20 mind does not work simplistically all the time; « 21 sometimes it does. In this particular area it works Ln 22 in a little bit more complex manner. And so when we ~ ~ 23 talk about "cause," there may be some specific m ~ ~ 24 individual patients where nicotine may be the cause w Ln 25 and the cause only. But the use of the word "risk 52 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

r; 4- s~1 19 A. Yes, sir. 20 Q. I would at this time just try to get a 21 general feel for your opinions concerning smoking 22 and some diseases. Okay? 23 A. Okay. 24 MR. GIBLIN: Okay. Can we take a 25 two-minute break before we get started on this? 1 1 expected testimony is? 2 A. I can honestly say no, because I don't 3 remember all of the comments that were made. 4 Q. In your opinion is Dr. Speer a competent 5 neonatologist? 6 A. Yes, very much so. 7 Q. In your opinion is he a knowledgeable, 8 very knowledgeable, neonatologist? 9 A. Yes, he is. 11:06:30 10 Q. Do you agree that Dr. Speer enjoys a very 11 good reputation in the medical community in the area 12 of neonatology? 13 A. Certainly in this area, meaning Houston, 14 or perhaps in Texas. Absolutely. Nationally, I 15 don't know what that might be. But Mike is a good 16 doctor. 17 Q. Okay. Getting to the questions that you 18 alluded to earlier, Doctor -- 11:07:00 -- 45 KEITH & MILLER CERTIFIED REPORTERS ~ EL PASO, TEXAS 79901 (915) 533-7108

1 THE WITNESS: That's fine. 2 (A recess was taken.) 3 Q. (BY MR. GIBLIN) Doctor, again I'm just 4 going to cover 10 or 15 or so diseases and see what 11:07:30 11:13:21 5 your opinion is with regard to whether or not 11:13:30 C ~ 6 smoking is a cause of the disease. 7 A. Okay. 1 8 Q. What is your opinion on lung cancer? Is 9 smoking a cause of lung cancer? 10 A. Yes, it is a cause. 11 Q. Esophageal cancer? 12 A. Yes. 13 Q. Pancreatic cancer? 11:14:00 14 A. There are associations that have been led 15 to that, yes. 16 Q. Urinary bladder cancer? 17 A. I can honestly say I am not aware of that. 18 Q. Laryngeal -- y 19 A. So I can give you no opinion one way or 20 the other. 21 Q. Okay. And, again, when you can't give an cn ~ 22 opinion one way or the other, just tell me like you J N 23 did. Okay? m J ~ ...i 24 A. I will. N ko 25 Q. Laryngeal cancer? 46 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Within his depositions, best I can recall 2 without trying to find a specific quotation, he 3 basically changed that, said that he really thought 4 that there was causation, and that certainly differs 10:49:00 5 from what he had stated before in his other writings -;-. 6 with the technical bulletin and that was brought out -, 7 by, I believe, the defense attorneys during that 8 particular discussion, and it was discussed. 9 Q. Do you agree, Doctor, that there are 10 pregnancy complications that are associated with 11 maternal smoking? 12 A. Yes, sir, there are. 13 Q. There's no doubt about that. Correct? 14 A. I don't think there's a doubt about that. 15 That's correct. 10:49:30 16 Q. Did you also review the 1996 ACOG 17 Technical Bulletin? 18 A. If I have -- I have read that in the past; cn 19 I have not reviewed it specifically for this case. ~ N 20 Q. Okay. m ~ ~ 21 A. I usually read those when I get them, but u 22 I did not pull it, and it did not come as a -- an 23 exhibit. I think it was included as an exhibit 10:50:00 24 within Sachs' deposition, but I have not seen that. 25 Q. Doctor, would you agree that many 32 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

'-. 1 Q. Okay? I'm not interested in proof beyond 2 a shadow of a doubt. That's a burden that I don't 3 believe anyone can meet. And so I'm not questioning 4 you in that regard. Okay? 5 A. Okay. 6 Q. When I ask about a cause, it's 7 acknowledging between you and I that I know that 11:24:00 8 several things at work, each can be a cause of a 9 given event. I'm not saying that it is the only 10 cause of the event. Okay? 11 A. I agree. 12 Q. Okay. 13 A. Okay. 14 Q. With that understanding, do you agree that 15 smoking, maternal smoking, is a cause of low birth . 16 weight or small for gestational age? 11:24:30 17 A. Yes. There is clear association seen in 18 multiple different articles, yes. 19 Q. Do you agree that maternal smoking is a 20 cause for abruptio placentae? 21 A. Yes, data exists for that. Ln r ~ 22 Q. Do you agree that maternal smoking is a -i ~ m 23 cause for placenta previa? ~ ~ w ~ 24 A. Yes. 25 Q. Do you agree that maternal smoking is a 54 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

- 2 3 4 5 ~z 6 7 9 3 8 9 10 rt:, .J 11 12 13 14 15 16 17 18 19 .., 20 f 21 22 23 24 25 factors," or we can call it multifactorial risk 11:22:30 factors, because in the circumstance it's not a are multiple factors at we vast majority of single risk factor; there all different levels which haven't discussed and we on; fine. But as a factor, can if you want to later or a subset of all of those things impacting upon both the individual`who makes up the larger group, which is the statistical population, then I think that that is -- would be 11:23:00 a -- a true understanding, if you will, between -- of cause, risk factor, and so forth. Is that reasonable with you, to use it in that sense as opposed to true causation in a specific case? Q. Well, if I understand what you've told me, true causation in a specific case is essentially proof beyond a shadow of a doubt that that factor caused the event that's being looked at? A. Q. A. Trying in -- in a scientific mode, yes. Okay. And that's, again, with all other factors 11:23:30 being maintained the same. Ln F-A -J Q Again that's not -- N . , m A. We're not using that. ~ ~ w o, Q. That's not the focus of my inquiry here. A. I understand. KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 53

1 testifying under oath that it causes these things? 11:18:30 2 A. I thought it was very interesting that 3 that statement had been made. 4 Q. Did it surprise you that the statement had ~ 5 b e de? e n ma 6 A. Yes, it really did. I think those 7 associations -- and you asked me what my opinion was ;Q 8 concerning my belief. I thought it was surprising 9 that he or anybody else would say that. I think 10 it's very appropriate with respect to that 11 particular disease process, because there are some 11:19:00 12 forms which I think it is causative for. There are 13 many other forms of lung cancer which it has no 14 relationship to. But as a cause, yes. 15 Q. Uh-huh. -1 16 A. So it was surprising, yes. 17 Q. In the documents that you have been 18 provided by the tobacco companies, have they 19 provided you any of their internal memorandums and 20 the studies that they did 15, 20, 25 years ago 21 dealing with cancers being caused by smoking, 22 dealing with maternal smoking and the effects on the 11:19:30 23 fetus? Have you seen any of their internal studies Ln ~ 24 and documents? J F-~ m 25 A. No. If they have those documents, I have ~ ~ w w 50 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. Yes, there are associations. 11:14:30 2 Q. So laryngeal cancer -- smoking would be a 3 cause of laryngeal cancer? 4 A. It would be a cause, yes. 5 Q. Oral cavity cancer? 6 A. That would be in the same context. It's 7 epithelial surface that is exposed so, yes, there 8 have been associations. ~ 9 Q. Coronary heart disease? ~ 10 A. Yes. I think a very strong association, 11 if not causation there. 12 Q. So you would say that smoking would be a 13 cause of coronary heart disease? 11:15:00 14 A. Yes, and at the most minimum. If it is 15 not a cause, it is a significant contributor to 16 adverse outcomes in individuals who have coronary 17 heart disease. So it depends on how one wants to 18 take that. 19 Q. Uh-huh. 20 A. But, yes, I think it's a -- it's a cn ... 21 significant risk factor for people who have coronary 22 artery disease, and it does cause -- can be V ~ w m 23 associated with death. 24 Q. Is smoking a cause of a stroke? 25 A. Yes, it could be in some individuals. Yes.11:15:30 ~* 4 7 KEITH & MILLER CERTIFIED REPORTERS J EL PASO, TEXAS 79901 (915) 533-7108

1 cause for spontaneous abortion? 2 A. There is data that would suggest that. , : 3 The mechanism, though, certainly has not been 11:25:00 4 elucidated . 5 Q. So unknown, or some -- ~ =.. . -:, ., 6 A Well -- ~ . 7 Q. Maybe yes, maybe no? 8 A. What I can say in that circumstance, there -:~ 9 are a number of different articles which suggest 40 -r, 10 that there is an increased pregnancy loss rate in 11 patients who are smokers. Some of the actual data 12 is that it does not have the same percentage or 13 ratio of chromosomal abnormalities that we would 11:25:30 14 expect in, if you will, the general population of 15 people. And so there is an excess of nonchromosomal 16 pregnancy losses, and so that is a very distinct 17 finding. But as the ACOG Technical Bulletin talks 18 about, there is also data looking at IBF pregnancies 19 where there was not that association and then they 20 did not see a clear difference. There was an 21 increase, but it certainly was not clear. But -- 11:26:00 22 implantation and the rest. So it may be a cause. ~ 23 May be a cause. ~ N m 24 Q. Okay. Congenital limb reduction? ~ ~ 25 A. No. I'm not aware of that being anywhere w co 55 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 cry because they're hungry, cold, et cetera. What 2 behavioral problems are you talking about? I never 3 consider bad behavior in a newborn. 4 Q. Yeah, that was a bad question I asked 5 you. Forget -- 6 A. If you ask me about teenage rs, that's a 7 different issue. 8 Q. Forget the ne wborn, okay? Forget the 9 b 11 29 30 new orn. : : 10 A. Okay. 11 Q. Adolescents, teenagers. In your opinion, 12 is maternal smoking a cause of behavioral problems 13 in adolescents and teenagers? 14 A. I'll give you a no on that. I think there 15 you're talking about socioeconomic, familial and 16 environmental exposures. And beyond that, having 17 had only one nonsmoking teenager, we had relatively 18 good behavior from him until the last week of high 11:30:00 19 school. So... 20 Q. That's to be expected, though, isn't it? 21 A. Should not have been; it wasn't. But, 22 anyway, we won't discuss that. Ln N ~ 23 Q. In your opinion is maternal Doctor ~ , , m ~ 24 smoking associated with -- excuse me. Let me back ~ ~ 25 up here. N 58 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Doctor, is maternal smoking a cause of 11:30:30 2 fertility problems? 3 A. That has been reported, that decreased 4 capacity, or fecundity, if you will, it's written 5 about and stated. But statistical evaluation and 6 even reading the primary articles have not done 7 that. But, yes, that's stated. That's stated 8 within the ACOG Technical Bulletin. 9 Q. You mentioned the ACOG Technical 11:31:00 10 Bulletin. What is ACOG? 11 A. Oh, precise definition is American College 12 of Obstetricians and Gynecologists. A-C-O-G. 13 Q. And this is a national organization. Is 14 that correct? 15 A. It's a national organization which has two 16 different subsets of members. One are those 17 individuals who are considered to be full members, 18 and they are board certified individuals, and then 11:31:30 19 there is a separate subset of individuals who are 20 board eligible, and they are normally considered to 21 be, if you will, junior members of ACOG. 22 Q. Ln I take it that you are a full member of ~ -J ~ 23 ACOG? m ~ ~ 24 A. Yes. ~ 25 Q. N Is that correct? 59 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Q. In your opinion does ACOG do a good job in 2 getting the information out to its members, the 3 newest information, by way of technical bulletins 4 that come out? 5 A. It depends on what you mean "a good job." 6 There is frequently a substantial lag phase from the 7 time that, if you will, new and relatively proven 11:33:30 8 things come about and, if you will, a technical 9 bulletin updating prior data or even -- maybe even a 10 new technical bulletin or other publications, 11 because there are a multitude of different 12 publications that ACOG has. I think over the course 13 of time that, yes, that they do try to get 14 information which has -- there's a good legal term 15 I've learned over the course of time -- proved up. 16 So that they try to get information of things which 11:34:00 17 have been proved up out to the obstetricians in the 18 t coun ry. 19 20 21 22 But you brought a very specific and clean Ln ~ ~ word usage a second ago, and that is "to its ~ m members " You could be a board certified ~ . ~ obstetrician and not a member of ACOG, and you would ~ ~ 23 receive none of ACOG's publications or -- of any 24 type. And so you would have none of that educative 25 experience given to you. 11:34:30 61 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 close to being proven. There is one article in the 2 literature, and that's it. That is certainly, given 3 one of the procedures I do, chorionic villi 4 sampling, that certainly has not come out in the 5 population of patients who have had CVA, who have 11:26:30 6 been looked at because they have been indexed as TJ 7 having a limb reduction defect, as being a 8 significant factor. Maybe it will be in the future, 9 but as of this point I would consider that to be 10 unproven. 11 Q. Is maternal smoking a cause of preterm 12 delivery? 13 A. There is an excess preterm delivery rate 14 in smokers, yes. 11:27:00 15 Q. Is maternal smoking a cause of sudden 16 infant death syndrome? 17 A. Other than what I have read during the Ln J F-+ 18 last week from these various things, the suggestions m ~ 19 are that it is, but I cannot either as an w kD 20 obstetrical expert and certainly cannot from a 21 neonatology or pediatric standpoint be able to tell 22 you that there is. There is data which -- at least 11:27:30 23 in the last week which would suggest that there is 24 an excess, but talk about multitude of different 25 factors. I think that that is sub -- that may be a KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 56

! 1 A. Yes. 2 Q. How long have you been a member of ACOG, 3 D t ? oc or 4 A. I was boarded in 1980, and so within three 5 to six months or so, I would say probably 1981, 6 probable. That would be the reasonable best 11:32:00 i 7 mate. est 8 Q. What is the purpose of ACOG? 9 A. I could -- well, I think it depends on who 10 you ask, in its total complexities. I think 11 probably to some extent it -- its major purpose is, 12 in fact, educative; there is certainly a research 13 component to it. Although I'm not a politician, I 14 think that there is a political base to it, also. 15 And it's -- also serves as a forum for obstetricians 11:32:30 16 in general, and the involvement of the 17 obstetrical -- we'll use obstetrical as opposed to 18 the gynecologic component -- involvement in multiple 19 other societies, such as the American Academy of 20 Pediatrics. There are different committees that we 21 have who have AAP members. There are different 22 committees in the AAP where there are ACOG members, 11:33:00 23 and all of that is to try to come to the -- some of 24 the issues, I said again, of education and updating Ln F- ~ ~ 25 of information. m J N W 60 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Q. So the technical bulletins are, again, 2 only sent out to members of ACOG? 3 A. Right. Unless you subscribe to them as a 4 nonmember, which I'm sure people do, but they do go 5 to the members as a component part of your annual 6 dues ~ . 7 Q. What type of other materials does ACOG 8 send out in addition to technical bulletins? 9 A. Oh, they have -- if you will, it's a 10 monthly publication which basically has some 11:35:00 11 updating news about both new events, NIH or NICHD 12 data, research components. Things which may, in 13 fact, be applicable to clinical practice now that 14 has not as of this particular time been covered by 15 technical bulletins. There is a diagnosis and 16 treatment criteria sheet. It's sort of a -- and 17 that's not it's exact name, but it's close; it's 11:35:30 18 sort of a purple color right now -- where they try 19 to go through minimal diagnostic criteria and 20 minimal treatment criteria within the -- one of the 21 areas of quality assurance. There is actually Ln -,, ~ 22 another set of publications when they do come out ~ ~ 23 three, four, five pages in length on quality m ~, ~ 24 assurance areas, hysterectomies and various other c~n 25 things. 62 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 And so not everybody in -- will quickly adopt. The 11:38:30 2 way I've said it before in circumstances is 3 sometimes it's difficult to teach old dogs new 4 tricks, and some of those new tricks may be 5 appropriate; some of them may not be. 6 Q. How often do the technical bulletins come 7 out? 8 A. There is an ACOG pack which usually comes 9 out on a monthly basis. I would say that in a given 10 course of a year there are probably anywhere from 11 six to 10. So if I had to break that down, then, it 11:39:00 12 could be as frequently as every month, and it could 13 be as infrequently as every two months or so. There 14 are some months, and I'm sure that there have been 15 times when there may have been several months when 16 there was no technical bulletin, and then there were 17 two or three or four that may have come in a single 18 package. So it varies, but approximately one every 19 month to two months. 20 Q. How are these, based on your 11:39:30 21 understanding, how are these technical bulletins 22 created? 23 A. They -- there usually is a committee of 24 different individuals, with -- those with respect to 25 the obstetrician. There is a committee upon the 65 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 fetus and newborn that has both ACOG members as well 2 as AAP members, and the ACOG members certainly in 3 that particular committee would be a more dominant 4 voice. And then both the committee -- and then they 5 may bring in a specific person who is not on the 11:40:00 6 committee who may have an expertise in that 7 particular area, such as with respect to herpes 8 simplex virus. Larry Corey from Washington State, 9 Zane Brown. A number of different people who have 10 great expertise in a particular area may be invited 11 to both review and contribute toward that type of a 12 bulletin. 13 I don't know the exact role that Dr. Sachs 14 had in the ACOG Technical Bulletins on smoking and 15 OB/GYN, but his name was certainly on the back of 11:40:30 16 it. The whole committee is not listed on the back. 17 Many times the bulletin does not have any single 18 19 20 21 22 person's name listed. how they are created. So that's my understanding of I've never participated in one of those, so I don't know the ins and outs. Ln N -i Q. Do you -- ~ m ~ ~ A. They do take a long time, though, from ~ 23 the -- from conceptualization and then ultimate 24 committee meetings and then final publication and 25 distribution. 11:41:00 66 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Q. Okay. An ACOG bulletin came out in 1996, : 2 I believe -- didn't it, Doctor -- dealing with a 3 smoking and reproductive health, I think? 4 A. I think that's the term of it, yes. From 5 what I could recall and, again, this is not having a . .; 6 comparison, it had much of the information which was 7 present in that 1993 technical bulletin. But if 8 there were changes, I'm not cognizant of the exact 9 changes. 11:41:30 10 Q. Okay. You mentioned AAP, and that -- I 11 take it that that was the American Academy of 12 Pediatrics? 13 A. Yes. 14 Q. Okay. Do members of the American Academy 15 of Pediatrics receive the ACOG publications? 16 A. I would think on a general basis, no, they 17 would not. Just like I do not receive AAP -- I 18 guess they have bulletins; I don't know. But if 19 they do, before when I said that there was -- there 20 were joint committees, I gave as a specific example 11:42:00 21 standards for OB/GYN services, and there certainly 22 there was a joint committee. And I do know that Ln N ~ ~ 23 with respect to that particular book that m ~ 24 pediatricians who were members of the AAP received ~ Ln 25 it, but I would not think that that would be true m 67 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 here with regard to spontaneous abortions? 2 A. I'll be honest and say -- 3 Q. Let me back up. 4 A. -- I can't remember that as a specific 5 thing within his publication. It may have been; I 6 don't know. I got that particular book many, many 7 years ago. I went through it and looked at a lot of 8 the statistics, but I certainly don't recall those 9 statistics. 11:55:00 10 Q. I've got it right here, Doctor, if you'd 11 like to take a look at this. If you want me to just 12 read it to you... 13 A. That would be fine. 14 Q. This is from the book, "Disorders of the 15 Placenta, Fetus And Neonate: Diagnosis and Clinical 16 Significance." You got it over there? 17 A. There is a small set of that. 18 Q. I've got one here for you, Doctor. 11:55:30 19 A. Yeah. May I just see that? 20 Q. Yes, sir. 21 A. It would make it much easier, I think. 22 Thank ou 3 y . Q. es sir. , Ln N -J 24 A. Yeah. What I have does not come anywhere m ~ N 25 close to this volume. Ln -J 76 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Q. Actually, that -- the book's only about 11:56:00 2 yea big, and when you copy it that way it gets a lot 3 bigger. 4 A. I understand. 5 Q. Okay. 6 MR. BLEVINS: That's the introduction and 7 two chapters. 8 THE WITNESS: Right. 9 Q. What I'm -looking at here, Doctor, is page 10 78. It ought to be in the top right-hand -- excuse 11 me. The lower right-hand part of the page, where 12 the page numbers are. 13 A. Okay. Page 78, I have. 14 Q. 78. 15 A. Okay. 16 Q. In Naeye's book, based on the 17 collaborative perinatal study that was done he 11:56:30 18 states, "A strong association has been reported 19 between maternal cigarette smoking and spontaneous 20 abortion. The probability is strong that smoking is 21 a major cause of abortions because chromosomal 22 anomalies with major malformations are the basis for 23 the majority of abortions before 10 weeks' gestation 24 and a much smaller proportion of abortuses of 25 smokers than of nonsmokers have chromosomal 77 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

__, _, 4>: 1 substantial compounder. It may also truly be a 2 surrogate of the population of patients who are, in 3 fact, smokers. I'll let others talk about that in a 4 knowledgeable way, and I'll give you a maybe on 5 that. I can't say yes or no. 6 Q. Okay. Is maternal smoking a cause of 11:28:00 7 mental retardation? 8 A. From what I have read on that prior to and 9 during the last week or so of reading this 10 information, that is not proven. That is not proven 11:28:30 24 problems in the newborn? 11:29:00 25 A. Behavioral? Most babies defecate, pee, 11 at all. 12 Q. Okay. 13 A. I'll give you a no right now and leave it 14 to others who may be more knowledgeable to discuss 15 that with you. 16 Q. Okay. Is maternal smoking a cause of 17 cognitive deficits? Low IQs, I guess? 18 A. Very disparate data, and so I'll give you 19 the same answer as the other: I'll leave that to 20 people who work with children all the time or are 21 involved in the appropriate statistical evaluation 22 and management with those studies. 23 Q. Is maternal smoking a cause of behavioral KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 57

, 1 Q. From a national standpoint? 2 A. I think that you really have to dissect 3 this. It says 19 to 30 percent. The general figure 4 that has been used is 20 to 25 percent of pregnant 5 women smoke. Well, 20 to 25 percent is not 30 6 percent, it certainly is not 19, but it's close to 11:47:30 7 20. Now, if they divided that and said that within 8 certain ethnic populations X, then it may be 30 9 percent or 35 percent in some populations of 10 people. So I think that that is generally true, but 11 I think you have to specifically apply it. Who are 12 you talking about? Education. 13 Q. Right. 14 A. Race. Those are specific areas where it 15 changes and changes substantially. 16 Q. Page 6, I guess. The headline is 11:48:00 17 "Fertility," or the topic I guess is "Fertility." 18 A. Okay. I have that. 19 Q. You've got it? We've already touched on 20 this. I take it that you agree with the statement 21 there that, "Smoking reduces overall female 22 fertility as measured by fecundity, the probability 23 of conception for a given couple during a given 11:48:30 24 menstrual cycle. A review of published studies Ln ~ 25 reveals a consistentl nificant increased risk of si ~ y g ~ m ~ 71 ~ KEITH & MILLER CERTIFIED REPORTERS Ln 8P. EL PASO, TEXAS 79901 (915) 533-7108 C

1 abnormalities." 11:57:00 2 It further states that, "In the CPS 3 cigarette smoking" -- "smokers had more spontaneous 4 abortions than did nonsmokers. These were mainly 5 late abortions because most of the women who entered 6 the CPS did so after early abortions would have 7 taken place. The higher frequency of these late 8 abortions in CPS smokers than in nonsmokers was . 9 independent of advanced maternal age and congenital 10 malformations in the embryos, the only other factors 11:57:30 11 in the CPS that had a strong association with 12 abortions. Eleven percent of the abortions in the 13 CPS could be attributed to cigarette smoking." 14 Now, I think that's what you mentioned 15 earlier, that you had to control for the maternal 16 age, because the risk of chromosomal anomalies 17 really increases as they get older? 11:58:00 18 A. Correct. 19 Q. Is that correct? 20 A. And also the intrinsic risk of a loss of 21 pregnancy, and especially age 4.0 and above. 22 that basically Doctor So do you agree Q Ln r , , . ~ 23 Naeye had reached the same opinion that's contained ~ m ~ ~ 24 here in the 1996 technical bulletin, that smoking -- Ln 25 that smoking has this strong association with %D 78 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. That's right. I recognize that as the 2 1993 one . 3 Q. And I'll represent to you that this is a 4 technical bulletin for June of 1996 dealing with 5 smoking and women's health. 11:44:00 6 A Ok . ay. 7 Q. Okay? Obviously it's not something I've 8 drafted . :~ 9 A. I understand that. 10 Q. There's just a -- there's a few statements 11 in here I'd like to talk to you briefly about, 12 Doctor, and just see if you agree with them or you 13 disagree with them. Okay? 14 A Oka . y. 15 No, go ahead. I'm just labeling this. 11:44:30 16 It's very difficult to read the numbers at the top, 17 and I'm -- 11 45 00 : : 18 Q. Sure. You're making it a lot easier. 19 That's good. 20 A. Okay, sir. I'm sorry. I'm finished. 11:45:30 21 Q. Okay. First page, Doctor -- actually, I 22 guess it's the second page after the cover sheet. cn ~ 23 A. Right. It's labeled page 3 on the fax m 24 machine. ~ 25 Q Oka Ln N . y. 69 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. Yes. 2 Q. And that -- 3 A. That would be a relative risk factor of 4 two in that circumstance, and that is a reasonable 5 percentage. I think there was one of the things 6 within Naeye, or somebody, where they looked at 7 placental volume and indicated that there was a 8 larger placenta. And so if a larger placenta does, 9 in fact, come lower and cover the os, yes, you could 10 have placenta previa more frequently. So there was 12:02:30 11 actually a biological observation that could fit 12 with the clinical observation. So, yes, it is a 13 risk factor. 14 Q. More likely than not, does a -- would a 15 placenta previa lead to a preterm delivery? 16 A. Not necessarily. On a statistical basis 17 there is an increased risk for a preterm delivery 18 with a placenta previa because a substantial number 19 of patients with preterm -- correction. 20 A substantial number of patients with 21 placenta previa will have major bleeds prior to the 22 37th week and can end up being delivered. And so 12:03:00 23 that would be true, in general, whether you're a 24 smoker or a nonsmoker. Ln ~ J 25 Q. Okay. Next, under "Low Birth Weight," the N m J F+ ON W 82 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

I 1 for the ACOG Technical Bulletins. One specific 2 technical bulletin on group B strep infection, I 3 know that there was something similar, but how 4 similar I don't know, that was sent out to the 11:42:30 5 pedeatricians about group B strep disease. 6 Q. Uh-huh. 7 A. But that's as good an answer as I can give 8 you. 9 Q. Okay. I want to ask you just a few 10 questions. Let me get this marked. 11 (Deposition exhibit marked, Exhibit 10.) 11:43':00 12 Q. Doctor, I'll show you what's been marked 13 as Exhibit 10, and I'll just ask you, have you seen 22 technical bulletin. I will assume that the two are 23 similar. 24 Q. Actually, this is the technical bulletin 25 from May of 1993. 14 that ACOG Technical Bulletin before? 15 A. This is not in the technical bulletin 16 format. I will accept -- 17 Q. Such as this? 18 A. Correct. 19 Q. You're talking about that? Yeah. 20 A. Yeah. That's the exact format of it. 21 This would be a draft, in standard words, for that KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 11:43:30 68

1 disease, and I'm not going to list all of the other 2 thi ngs. 3 Q. Right. 4 A. I take care of rare, normal people. 5 Therefore, if I have someone who smokes -- and 6 that's infrequent to begin with -- then what I tell 7 them about cigarette smoking is that it is injurious 8 to you, you already have substantive risk factors, 12:00:00 9 and those have been gone into in detail, and that 10 cigarette smoking will increase that risk for 11 whatever proportion. I don't state specifically the 12 issue of abortion. 13 Q. I understand. Okay. Getting back to the 14 technical bulletin, ACOG Technical Bulletin, 15 D t 00 30 12 or. oc : : 16 A. Okay. 17 Q. If you would turn the page, please, from 18 the last one we talked about. What I'm going to do 19 here, Doctor, is just read to you some of these 20 statements and see if you agree with these 21 statements - 22 A. Okay. Ln r ~ ~ 23 Q. -- as being reliable and legitimate. m ~ ~ 24 A. We're on page 9 on the fax? m ~ 25 Q. Yes, sir. 80 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 the consistency -- they used the word "consistent" 2 association. That's very true. But in a lot of the 3 circumstances, that relative risk is on the order of 4 1.3 to 1.5 and you start talking to statisticians 5 and epidemiologists about, well, how sound is that 6 in an area that has many, many, many different 12:05:00 7 factors, then it may not be causation. That's what 8 we had talked about before, and so -- 9 Q. Right. 10 A. -- I'm trying not to repeat myself, 11 because I don't want to waste your time nor mine. 12 Q. No, I -- 13 A. And so "probable" means that it is not 14 causative, but there may be if you were able to do 15 that perfect study, whatever it happened to be. 16 Q. Would "probable" mean more likely than 17 not, as compared to "possible"? 18 A. I think one has to get to a difference of 12:05:30 19 semantics. 20 Q. Okay. 21 A. In the legal world "possible" is anything 22 that could happen in any circumstance. "Probable" cn ~ ~ 23 always to me is that it's more probable than not, ~ m 24 meaning 50.1 percent or more. ~ r 25 Q. Uh-huh. rn Ln 84 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. And that was the number I used, and so 2 we're going to be off one. 3 Q. Okay. Looking about a little over halfway 4 down the page, there's a statement that says, 5 "Between 19-30% of pregnant women continue to smoke 6 putting themselves and their fetuses at risk for a 11:46:00 7 number of adverse reproductive events." 8 My question to you is: Does that number 9 sound about right, with regard to your personal 10 experiences? 11 A. Personal experience, I would say no, 12 because the vast majority of patients I take care of 11:46:30 13 do not smoke. I have taken care and been involved 14 for many, many years within the Harris County 15 Hospital District for a different population of 16 people with a higher incidence of smoking within the 17 different ethnicities, and I certainly cannot 18 quantitate that, but certainly there were smoking 19 patients. So my personal experience would be that 20 would not be an appropriate figure for my personal 21 population of patients. 11:47:00 22 Q. Okay. 23 A. But I think that those figures are Ln ~ 24 probably reasonably correct, given general m 25 information. •- 70 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

! , 1 members, also. 2 Q. I take it, then, obviously the 3 publications such as the technical bulletins that 4 are sent out by ACOG to its members, that certainly ~ 5 its members can regard these publications as being 6 reliable and containing reliable information. Fair 11:37:30 7 statement? , :=a 8 A. Yes, that would be a very true statement. 9 Q. Containing information upon which they 10 should make treatment decisions with regard to their 11 own patients? 12 A. The information is there, and the 13 individual physician can use that information to 14 make decisions, hopefully positive decisions. But 15 I'm sure there are some physicians who read the 16 information and then continue practicing as they 17 have done before. I'll give you a specific example 11:38:00 18 that is true: About a third of physicians as of 19 several years ago, multiple years after a change in 20 ACOG recommendations in a technical bulletin, 21 continued to culture patients, some patients for , ~ 22 herpes simplex virus, vulvovaginal disease. Not I--- -J ~ m 23 necessary. But, still, a third of the physicians in -J ~ ~ 24 a particular survey were continuing to do that four -J 25 years or five years post a major change in policy. 64 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 I don't know, the power of the study is. 2 Q. You're familiar, Doctor, with the 3 collaborative perinatal study that was done back in 4 the '50s and '60s? 11:53:30 5 A. Try '59 through '66. They have a green 6 book, "The Women and Their Pregnancies," that was 7 published. 8 Q. Dealing with, I think it was right around 9 60,000 women or 58,000 women? 10 A. 55 to 60. Somewhere in there. 11 Q. Okay. That's a study that has been used 12 by a number of researchers, I take it, to -- and 13 statisticians to reach conclusions in a number of 11:54:00 14 different areas. Is that correct? 15 A. I think that's a correct statement. 16 Q. The data has been analyzed and reanalyzed 17 and reanalyzed many times? 18 A. I think that that's a correct statement, 19 and even analyzed in the early '90s in publications 20 specifically from Naeye that I can recall still cn ~ 21 coming out which is interesting 30 years -- almost ~ , ~ m 22 30 years later . ~ ~ 23 Ln Q. Do you recall whether or not Naeye -- you c, 24 mentioned Dr. Richard Naeye and his book. Do you 25 recall whether or not he reached the same conclusion 11:54:30 75 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

2 Q. -- what I want to cover again, just so I'm 3 clear, when you speak in terms of "causation," you 4 are saying that it has been proved -- if you say 5 that is the -- that -- let me back up here. 6 I believe you testified earlier that as 7 far as causation you regard something to cause an 8 event if it is proved beyond a shadow of a doubt 12:07:30 9 that it is the cause. Is that correct? 10 A. I think yes. May I give you one other 11 circumstance which maybe will put this in 12 perspective? 13 Q. But let me ask you, is the way I just put 14 that, is that correct? 15 A. Yes. 16 Q. Okay. Go ahead. I'm sorry. 17 A. Okay. In all of the legal work I have 18 ever done, and certainly when it comes to the point 19 of review of cases, when it com es to the point -- 20 whether that review is for the defense or the 21 plaintiff bar -- in talking about negligence and 12:08:00 22 being responsible for actions, you may have a 23 deviation in standard of care you may have a bad Ln ~ , ~ 24 outcome. But the one thing that must link all of ~ m ~ ~ 25 the elements in that issue of negligence is the ~ 86 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 issue of causation. Perhaps I have a hangup in that 2 circumstance, because I look at the data and it -- 3 whether as a scientist, but a nonmathematical 4 scientist as we've talked about, I haven't seen that 12:08:30 5 issue of causation. Association and the rest, risk 6 factors; no question about it. Do I want people to 7 smoke? No, I don't. Maybe some of my hangup and 8 perhaps is on that -- well, except for this case, 9 all of my other work in the legal area has been with 10 that causation linkage. And it may be a problem in 11 this circumstance with respect to why I go back to 12 that issue each time. And I'm not trying to beat a 12:09:00 13 dead horse. Maybe that helps, and maybe that 14 doesn't . 15 Q. I think it does. I think I understand 16 your conception of "cause." Okay? That, as we 17 talked earlier, smoking, maternal smoking, you 18 agree, is a cause -- not the only cause at work -- 19 but is a cause of adverse pregnancy outcomes. 12:09:30 20 Correct? 21 A. Yes. 22 Q. Okay. For it to be the only cause the Ln ~ , ~ 23 only cause, epidemiologically speaking or study m ~ N 24 speaking, you would have to see proof beyond a ~ 25 shadow of a doubt. Is that correct? 87 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 it is a factor, it is a component of. If you will, 2 like a pie graph. There may be 25 different things 3 in the pie graph, and smoking is one specific thing 4 in this particular area; in others it may be only 5 one of four or five different components to the pie 6 graph. But the risk factor -- I'm not trying to 7 obfuscate the current circumstance. 12:12:00 8 Q. No, you're fine, Doctor. It's -- I 9 understand what you're saying; at least I think I 10 do. But we agree, you and I agree, that smoking -- 11 smoking is a cause -- not the only cause, but 12 smoking is a cause of adverse pregnancy outcomes. 13 Correct? 14 A. I will agree with that. 15 Q. Okay. The next sentence is underneath 16 there, Doctor. It says, "Recent studies have shown 12:12:30 17 a consistent relationship between preterm premature 18 rupture of membrane, P-R-O-M, and smoking." Do you 19 agree with that? Ln r ~ 20 A. No, and I don't because from the m ~ ~ ~ 21 information I have read there is a lot of ~ 22 discordance about whether it is or is not. There 23 are papers that have tried to bring a linkage to it, 12:13:00 24 there are others that have clearly said no. When 25 you take in all of the other aspects, we cannot say 89 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 correctly you'd mentioned something with regard to 2 chromosomal analysis having to be done on the issue 3 of spontaneous abortions in your report? 4 A. No. That -- we've talked about that at 11:52:00 5 various meetings and the rest. It would be 6 true -- it is true that you can do chromosomal 7 studies on any abortus. This particular study said 8 that they did it any population of people, and that 9 there was an excess of normal karyotypes in this 10 population. Again, I have not read that specific 11 article. This particular comment has been made and 12 has been around for some period of time. I don't 13 remember from the document the exact comment that 11:52:30 14 was made, but it would basically agree that there 15 is -- it's a risk factor in that circumstance. 16 Certainly when you see a population in here, the 17 specific issue of stratification for maternal age 18 becomes a very, very significant factor, because 19 there's increasing risk for chromosome abnormalities 20 with age. And if you have controlled your study so 21 that age factor is removed and you consistently see 11:53:00 22 that difference of spontaneous losses, then one 23 would have to conclude that it is a risk factor. Ln ~ ~ 24 And if your study is powerful enough, it may even m ~ 25 conclude that it may be causal, but the latter part ~ Ln cn 74 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. Yes. Fulfilling good statistical norms. 2 Q. Okay. However, if the standard is 3 probability, not absolute proof, not proof beyond a 12:10:00 4 shadow of a doubt, if the standard is probable, 5 50.001 percent, or whatever it may be, more likely 6 than not if that's the standard, then I take it that 7 you would agree with the statement here that there's 8 a probable causal relationship between low birth 9 weight. Correct? 10 A. There is -- it is a risk factor. There is 12:10:30 11 clear association. To use the word here, there is 12 consistency of that information. But, again, it 13 leads from epidemiology and the rest; it has not 14 been proven causal. And I don't know of a way to -- 15 it certainly is not the only factor. And I guess 12:11:00 16 I'm trying to make that -- 17 Q. And if we agree -- and if we agree that 18 there are other factors that can cause the event, I 19 take it that -- what am I trying to say here? 20 A. Maybe -- maybe "cause" is not a good word cn ~ -i ~ 21 to use, because several times when you've used that m ~ 22 word the word that has hit my -- my head ~ rn 23 instantaneously, and one time before I meant to say ko 24 it and I didn't, "contributor," you could call it. 12:11:30 25 That also means it contributes, it is also a risk, 88 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 There's other information which is 2 provided on specific topics intermittently, such as 3 Cesarean section and the rest. Let's see. Oh, 11:36:00 4 there's a monthly list of those individual people 5 who have expired, and then also those who have 6 applied for membership and been granted membership, 7 and then a part of that, also, has a listing so~that 8 if you know someone on that particular list and you 9 have information which might be appropriate to the 10 American College in considering application, then 11 they have requested that information in the past. 11:36:30 12 That covers a lot of the things with ACOG. 13 Q. A lot of information. 14 A. Others -- yes, there's a lot of 15 information. There have been other things, 16 specifically books that -- or booklets, if you will, 17 that have come out over the course of time directly 18 from ACOG, such as standards of care for obstetrical 19 and gynecologic facilities, the management of 20 neonates and so forth, and that would be within 21 their realm of their technical publications, too. 11:37:00 22 It's not always as ACOG alone, such as the standards 23 for obstetrical and gynecologic facilities; that was iLn ~ ~ 24 both the AAP as well as the ACOG. So there are m ~ ~ 25 joint publications. They probably go to the AAP ~ m 63 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 spontaneous abortion? 2 A. Yes. The relative risk is increased. 3 Q. What is the relative risk here? Do you -- 4 A. The relative risk here was, all gravidas 11:58:30 5 without respect to stratification for age, was 1.5. 6 Q. What does that mean? 7 A. That would mean that you observed 50 8 percent greater incidence of spontaneous loss in 9 patients who smoked versus those who did not. 10 Q. When you counsel your patients, Doctor, do 11:59:00 11 you inform them of the risk of a spontaneous 12 abortion if they kept smoking? I'm assuming they're 13 smokers. 14 A. Okay. I don't tell them about spontaneous 15 abortion. I talk about pregnancy loss and pregnancy 16 loss most specifically in the context of weight. 17 There has to be a -- I have to make a statement 18 about this. I don't take care of normal people. 19 Okay? 11:59:30 20 Q. High risk? 21 A. I take care of high risk patients. ~ 22 Q ~ Right . . ~ ~ 5 23 A. That means the vast majority of my ~ ~ 24 patients have diabetes twins they have congenital m , , m 25 heart disease or a significant acquired heart 79 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. Yes. 2 Q. And the ACOG Technical Bulletin gave a 3.5 3 to 4.0 fold increase for smokers versus nonsmokers. 4 A. Yes. 5 Q. You indicated that was a higher number 6 than you've seen in the past. I just want to show 7 you what the 1990 Surgeon General report indicated. 12:20:30 8 It's down here, Doctor. My question is: Is the 9 Surgeon General's report of 1990 consistent with the 10 1996 ACOG Technical Bulletin? 11 A. Yes, they use the same article as their 12 reference source. 13 Q. Okay. Thank you. In your opinion does 14 that, since the Surgeon General has now utilized it, 12:21:00 15 also, does that lend more credibility, or 16 reliability, if you will, to the frequency? 17 A. I'll give you a -- it may not be 18 responsive; I hope it is, because it'll be the 19 truth. I neither believe everything I see, I don't 20 believe everything I hear, and I certainly don't 12:21:30 21 believe everything I get from the government. 22 That's a single article. Ln ~ ~ 23 I would think that if that particular m 24 number had been verified in multiple other cohorts, J J 25 that you would see not one, but you would see cn 94 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Because there are different weight classifications. 2 Whereas in the U.S. most of the time we talk about 3 Caucasian weight standards as opposed to Asian 4 weight standards, Hispanic weight standards, we talk 5 about Arizona, the Pima Indian standards. And so I 6 don't know that particular reference. That's a 12:16:00 7 very, very high number. 8 Q. Okay. 9 A. Much higher than I've ever seen. 10 Q. All right. 11 A. And I don't remember that particular 12 number being in the 1993 article. 13 Q. Let's drop down to "Perinatal Outcomes" on 14 the same page. First paragraph, Recent -- "Multiple 15 recent studies have demonstrated a clear association 16 between maternal smoking and perinatal loss. 12:16:30 17 Placenta previa, abruptio placentae, preterm 18 premature rupture of membranes were responsible for 19 most of the perinatal losses in smokers." I take 20 it, based on what you said earlier, the problem you Ln ~ 21 would have with that would be the preterm premature J ~ m 22 rupture of membranes. Is that correct? ~ ~ ~ 23 A. Only -- well, not in the context of if you w 24 talk about total losses. 25 Q. I see. 12:17:00 92 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 that this is a causative factor. There is some data 2 that shows that the risk factor, again, is greater 3 than 1. 4 But one of the other things that's been 5 very poorly studied and is becoming now a major 6 issue within obstetrics in general is the whole 7 issue of bacterial infections, ascending infections 8 specifically, bacterial vaginosis. And there has 9 not been -- and that is, in fact, a very significant 12:13:30 10 lifestyle issue. And that has not been -- that -- 11 that, I think, very potent confounder has not been 12 factored in well, and that really needs to be done. 13 And I'm sure in the next several years either the 14 National Perinatal Collaborative Group or the Texas 15 or one of the other smaller groups will look at that 16 as a specific issue. 17 Q. Okay. 18 A. Hopefully smoking data will be -- will be 19 acquired as a component part of that study. 20 Q. Okay. 12:14:00 21 A. But right now I don't think -- that 22 certainly is nowhere close to being either probable, 23 and certainly not causative. 24 Q. Okay. Let's turn the page. The first 25 paragraph, the first new paragraph. 90 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. Okay. 2 Q. It starts -- it's titled, "Pregnancy 3 Complications 12:01:00 4 A. Okay. 5 Q. It states, In the collaborative perinatal 6 study -- excuse me. "In the Collaborative Perinatal 7 Project study, abruptio placentae was 1.5 times more 8 common and was more likely to result in perinatal 9 mortality in smokers than in nonsmokers." Does that 10 make sense to you, Doctor? 11 A. The mechanism does not necessarily make 12 sense, but certainly that has been observed in 13 several different studies, and so I can accept that 12:01:30 14 as a risk factor. 15 Q. Okay. 16 A. Again, exact mechanism, that remains to be 17 determined. 18 Q. Right. Two sentences down further it 19 states, "In several recent studies, women who smoked 20 cigarettes during pregnancy had placenta previa 21 twice as often as nonsmokers." 22 A. Yes. 12:02:00 23 Q. That -- Ln 24 A. I have seen that before. ~ ~ 25 Q. You've seen that? ~ 81 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. Because preterm premature rupture of 2 membranes, if it occurs, yes, there is a 3 statistically increased risk for loss of that 4 because -- for prematurity, complications of fetus 5 prematurity. There certainly is increased risk for 6 adverse outcomes for that child if it is born as a 7 premature. Big difference between 36 weeks of 8 prematurity versus 26 weeks. I do have a problem, 9 as you stated, because that is not a clear 10 association. But from the standpoint of total 11 perinatal losses, that would be -- those are the 12:17:30 12 three major ones, besides "idiopathic preterm 13 labor." And that may be greater than the others, as 14 far as final numbers. 15 Q. Okay. I believe the rest of the technical 16 bulletin, Doctor, deals with smoking cessation, 17 getting the pregnant ladies to stop smoking. 18 A. Which is tough. 12:18:00 19 MR. GIBLIN: Okay. Let me take a break Ln 20 right now, if we could. ~ ~ 21 THE WITNESS: Okay. ~ ~ ~ 22 (A recess was taken.) ~ ~ 23 Q. (BY MR. GIBLIN) Now, Doctor, we were 24 talking earlier about the incidence of small for 12:18:30 12:19:17 25 gestational age and smoking moms versus nonsmoking. 12:19:30 12:20:00 93 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 multiple different references all citing the same. 2 That is the highest number I have seen personally in 3 looking at this information. 4 Q. Okay. 5 A. I will try to pull that article and read 6 it, because I also notice that it appears to be a 7 British publication, and -- or it is in a British 12:22:00 8 publication. Is it a British study? And if it is, 9 where did it come from? And what ethnic populations 10 and so forth are they discussing? I think that 11 that -- that's a high figure. I'll stand by that; 12 it's the highest one. But I agree, that it was in 13 the 1990 Surgeon General's report. 14 Q. Okay. 15 A. That same reference. 16 Q. Okay. 17 A. This may not be relevant, but just looking 12:22:30 12 23 1 : : 1 18 at that number, if you take a background Caucasian 19 population and the incidence of a low birth weight Ln ~ ~ ~ 6 20 which has been seen in a number of studies of plus ~ ~ 21 or minus four or five percent and then if you take ~ , m 22 a composite black population of smokers where 23 frequencies of 18 to 20 percent low birth weight 12:23:30 24 status has been seen and do simple division, you may 25 come up with a figure of about a four fold. 95 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. I'm not sure what Dr. Sachs and the other 2 individuals -- if they're using it in the sense of 3 50.1 or more, there may be, but that's still not 12:06:00 4 causation. It may be that the volume of data is 5 sufficient to think that there may, in fact, be a 6 causative effect, but you haven't proven it yet. 7 Q. Okay. 8 A. And the most interesting thing is, also, 9 in reading this and then from prior knowledge, but 10 especially going through a lot of this, given the 11 totality of all of the articles that have ever been 12 written, all of them talk about the relative risk, 13 but it still hasn't gotten down to the issue of 14 causation, because there's so many other factors. 15 And I know from my own personal experience, both 12:06:30 16 with individual patients within my private practice 17 over time, as well as patients within the county 18 system that there are so many other factors within 19 the family, within the person, their behaviors and 20 the rest that it does not come down to a simple 21 thing. And that's probably -- maybe one of the 22 reasons that if there is causation it gets clouded. 23 But it -- the numbers and association is there. 24 Q. And, again, I don't mean to beat a dead 25 horse here, but -- 12:07:00 85 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 time evaluation of carboxyhemoglobin in the fetus as 2 opposed to post delivery data. And so there -- they 3 found no conclusive evidence at all that there was 4 an impact on oxygenation of the fetus. 5 There was another comment made by Naeye -- 12:26:30 6 I believe it was Naeye; I won't state it was he -- 7 about another issue where we can have very, very, 8 very low hemoglobin, and this is specifically the Rh 9 alloimmunized patients, where some of the patients I 10 see may have hematocrits of six and eight and 10. 11 Where we know that those particular fetuses, as long 12 as there's not a major acute cord accident or when 13 we're transfusing them we create a problem from 12:27:00 14 having transfused them, we know that those very, 15 very low levels of hemoglobin and oxygen allow for 16 normal physical growth, and they allow for normal 17 cerebral development, because the outcome of those 18 pregnancies are very good. So that there's nothing 19 from the standpoint of at least Peter Soothill's 20 paper, nor the experience with severely anemic 21 fetuses which would suggest even in a smoking 22 population, as Peter looked at it, that there's an 12:27:30 23 adverse impact upon growth upon oxygenation. So now 24 it comes down to is there something else i e what Ln , . ., ~-A -J 25 other factors are involved in that issue? But it's m J 98 ko KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 not just a simple oxygenation, just as we know the 2 issue of low birth weight in smokers is not just a 3 simple issue of food intake, although that's a very 4 important variable. 5 Q. Did you say food intake? 6 A. Food intake is an important variable in 7 certain segments of the population. It is not the 12:28:00 8 only factor. 9 Q. Right. 10 A. So one can't say a smoker who has very 11 poor nutrition is going to have a small baby only 12 because they're deficient in food, as an example. 13 Again, multifactorial risk. 14 Q. With regard to the food intake, Doctor, do 15 you recall in the collaborative perinatal study that 12:28:30 16 Naeye wrote about that, you know, increasing 17 maternal weight gain did not ensure that the fetus 18 would not be small for gestational age? 19 A. Yes, that statement is made. There's also 12:29:00 20 an interesting thing from the Texas data which was 21 provided, and that is looking at the WIC program ~ 22 where they clearly saw an augmentation of fetal r 3 eight with improvement in maternal nutrition J F-+ m J ~ 24 between first, second and third trimester entrance co 25 to the WIC program. Now, that also goes back to the m 99 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 of the effect of maternal smoking on uteroplacental 2 oxygen and blood flow? 3 A. Okay. There was an article which was 4 quoted in Dr. Sachs' deposition, and specifically it 12:25:00 5 was an article by Peter Soothill who at that 6 particular time was in Charles Rodeck's department 7 at Queen Charlotte's Hospital, and he is since at 8 his own institution, which is at Bristol. 9 Peter, in that particular study, looked at 10 a population of patients having fetal blood sampling 11 for predominantly chromosomal disorders, and they 12 looked at their data from the standpoint of both 13 smokers and nonsmokers, and they found that, in 12:25:30 14 fact, there was an increased quantity of 15 carboxyhemoglobin in that smoking population 16 compared to the nonsmoking. It was about twice 17 that. They found that there was a slight increase 18 in hemoglobin content. They did not measure 19 erythropoietin, but one other study apparently has 20 measured erythropoietin and found a slight increase 21 in smokers. However, they found no change in oxygen 12:26:00 22 content, no change in oxygen characteristics, acid 23 base status stayed the same. They were not been Ln ~ 24 able to pull from -- and Peter's study is the only m ~ 25 one I know that has looked at, if you will, real J 00 97 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 issues of what was it about the person that allowed 2 them entrance at the second and the third versus the 3 first, and so those are also confounding variables. 4 But certainly augmentation of nutrition can improve 12:29:30 5 fetal weight in a number of people. Now, the 6 specific WIC I was talking about, I don't remember 7 them talking about cigarette smoking individuals 8 versus nonsmokers. But food intake is important in 9 certain segments of the population. No question 10 about it. 11 Q. Uh-huh. 12 A. But it's not the only factor, and I'm not 13 trying to make it the only factor. 14 Q. Right. What is your understanding that 15 the effect cigarette smoking may have upon the 12:30:00 16 placenta? 17 A. Oh, I think we talked about that earlier. 18 I said that there was -- I may not have said all of Ln ~ ~ 19 this. I said that there was data that suggested ~ m 20 that there was a greater surface area that the ~ ~ I--, 21 placenta has, so that the placenta is larger in its 22 major diameters. It covers a greater surface area. 23 And this data is only from having read and not from 24 having looked at the placenta. There are also 12:30:30 25 changes which have been seen in the placenta which 100 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 next topic, the ACOG bulletin states, "There is a 2 consistent association between smoking and lower 3 birth weight in the medical literature supporting a 4 probable causal relationship. This is from a 12:03:30 5 combination of pre-term deliveries of 6 appropriate-weight babies and intrauterine growth 7 retardation of term babies." Do you agree with that 8 statement, Doctor? 9 A. I think that that is a correct statement. 10 And the probable causal, that may be true in this 11 circumstance. But, again, the number of factors 12 that one has to consider is substantial on that 13 issue. But there is no question that there is a 14 negative weight differential with individuals who 12:04:00 15 smoke. 16 Q. As far as the statement about the probable 17 causal relationship, it's your position that that 18 may, in fact, be true. Is that correct? 19 A. Well, that may be true from just the Ln 20 standpoint of the statement. I find the word ~ ~ 21 choices here very interesting, and I find it G J i-+ 22 interesting because you either have a causal °i ~ 23 relationship or you do not. Statistically you've 24 either proven it or you haven't. And so in this 12:04:30 25 circumstance I think the total amount of data, and 83 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 could lead; there are a whole host of other factors. 2 Q. But, again, you don't disagree that those 3 are findings consistent with maternal smoking, that 4 being necrosis of the placenta and microinfarcts, 12:32:00 5 among the other things that you've already 6 mentioned? 7 A. Yeah. Those are findings that have been i 8 seen in excess in the population of smokers. Yes. 9 MR. GIBLIN: Let me get this marked. 12:32:30 10 (Deposition exhibit marked, Exhibit 11.) 11 Q. Doctor, I'll show you what has been marked 12 as Exhibit Number 11, which is a -- oh, the first 13 couple of pages of the "Robbins Pathology Textbook," 12:33:00 14 and then a few pages of a chapter dealing with 15 environmental and nutritional diseases. Just in 16 general, I'd like for you to look at page 381. Yes, 17 sir, and under tobacco smoking. Again, I'm just 18 going to read this and see what your thoughts are, 12:33:30 19 see if you agree with it, see if it makes sense to 20 you based on your experience and what you've read 21 and your medical training. Ln 22 It starts off, "The adverse consequences r ~ ~ 23 of cigarette smoke totally dwarf those of all the m ~ ~ 24 other pollutants combined. In the United, States w 25 almost 400,000 persons died in 1985 of various 102 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 diseases directly attributable to cigarette smoking, 2 representing 21% of all mortality." My question to 3 you is: Does -- do you agree with that? Does that 12:34:00 4 make sense to you, and is this reliable information? 5 A. I -- I know -- I do not have a personal 6 database that I can construct these numbers. I'll 7 accept these as being numbers that I don't really 8 have much qualm about, because if you take a number 9 of the issues we've already talked about today, 10 just -- well, lung cancer, anything else, given the 11 total number of deaths per year in the United 12:34:30 12 States, the 20 percent of all mortality, it may be 13 true. I think it's very important, also, again, 14 talking about is it directly contributable, or is it 15 a risk factor in consideration of other risk 16 factors? I can't disagree with this. 17 Q. If you turn the page, Doctor, there's a 18 sentence there that says, "Active Smoking and 19 Disease." It says, "Mainstream smoke that enters 12:35:00 20 the mouth with each cigarette puff is a veritable 21 quotation, Satanic brew, close quotation." Had you 22 ever seen a statement like that before? Ln ~ ~ 23 A. My -- the answer is no. What I would ~ m ~ ~ 24 consider is that whoever wrote this had a strong co 1P. 25 antitobacco bias, and also had very beautiful 103 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 know you agree with this, but I'll read it and just 2 ask you again, do you agree with it? "The unborn 3 child and the infant are also adversely influenced 4 by maternal smoking. Numerous studies have shown a 5 well-defined association between cigarette smoking 12:37:00 6 and an increased incidence of low birth weight, 7 prematurity, spontaneous abortion, stillbirths and 8 infant mortality. Furthermore, there is a 9 strong" -- "furthermore, there are strong 10 suggestions that smoking increases the likelihood of 11 some complications of pregnancy, such as abruptio 12 placentae, placenta previa and premature rupture of 13 the membranes." 14 A. Well, we've talked about that, and there 15 are many of those that that association has been 12:37:30 16 seen. 17 Q. And I take it essentially you agree with 18 that, with the exception of the premature rupture of 19 membranes? That -- 20 A. Yes. 21 Q. Okay. 22 A. We've talked about that. 23 Q. Right. You had mentioned that you've got Ln ~ J ~ m _J OD m 24 the Surgeon General reports over there. Rather than 12:38:00 25 trying to go through these page and line, my 105 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 are similar to changes in the placentas of 2 individuals who are nonsmokers and who have had 3 hypoxic conditions. So, if you will, vesidual 4 changes and both internal changes within the villus 5 and the villus vessels and so forth. I can't go 6 through a list of all of those things. Some of them 7 have been villus edema. As an example of a 8 hypoxic-associated finding within the placenta. So 12:31:00 9 there have been changes demonstrated in individuals 10 who smoke compared to individuals who do not smoke 11 at similar levels. 12 Q. Right. Smokers -- 13 A. So -- 14 Q. I'm sorry. Go ahead. 15 A. No -- so that there have been observed 16 changes. And so, again, smoking is a risk factor 17 for the placenta. 18 Q. Okay. Necrosis has been seen, 19 microinfarcts have been seen -- 12:31:30 20 A. Yes. 21 Q. -- in the placentas of smokers versus Ln ~ 22 nonsmokers. And those being two things that J F-' 23 obviously lead to the -- or that can lead to the m ~ ~ 00 24 development of an abruptio placenta? N 25 A. It's -- those would be two factors that 101 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. I don't know that as a fact, but I could 2 assume that that probably is true. I have not read 3 the frontispiece to indicate all of the various 4 people contributing toward it. 5 Q. Uh-huh. 6 A. But certainly they are a part of the 7 Surgeon General's organization, if you will. 8 Q. Just looking at the front cover, if you 9 will, Doctor, it says CDC. 10 A. CDC. 12:42:30 11 Q. Center for -- 12 A. Correct. 13 Q. The CDC, they are a group of, I guess, 14 highly qualified people in their specialties. Is 15 that a fair statement? 16 A. I think -- certainly using a far greater 17 than 50 percent, yes. 18 Q Oka Ln . y. ~ -! 19 A. Maybe 99.9 percent. They may have a bad F+ m 20 apple or two but pretty good J ~ , . ~ m 21 Q. And it could be regarded, I take it, that 22 the results of their work would be something that 23 would be reliable and could be relied upon by 12:43:00 24 physicians and general public? 25 A. I think that that statement would have to 109 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 common denominator, i.e. Ebola virus causing African 2 hemorrhagic fever in the original 1976, 1977 3 outbreak in that area, and various others. An 12:41:00 4 example, also, would be in New Mexico in the Four 5 Corners area, the outbreak of the rodent fever 6 approximately -- what -- four or five years ago now. 7 Q. Uh-huh. 8 A. Which killed a number of people because of 9 the increase in rodent population. Actually, I 10 think it was ground squirrel population because 11 their natural predators had been killed off or 12 removed. And so they investigate, evaluate and try 13 to improve health by getting to the roots of the 14 disorder. 12:41:30 15 They also maintain Ebola virus and 16 probably a number of other -- I know they do -- 17 class 4 agents within the special areas within the 18 CDC, and they use those for research, try to obtain 19 treatment, and so forth. Ln ~ ~ ~ 20 And, also, if you have an outbreak of m ~ 21 something, and you want to know, then they will test ~ 00 22 for antibodies against various things. Very good kD 23 and probably underfunded organ in our country. 12:42:00 24 Q. They participate in preparing the Surgeon 25 General's reports? KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 108

1 However, you're not comparing it necessarily to your 2 standard comparison population, which would be a 3 simultaneous black population where the relative 4 risk of low birth weight is at least 1.8 to two 5 times the Caucasian population in many different 6 studies. That may or may not be how that particular 7 figure was acquired. 8 Q. Yeah. Blacks have smaller babies, just in 9 general. Right? 10 A. Yes. 11 Q. Okay. 12 A. And that's been consistent in multiple 13 different countries. 14 Q. Right. 15 A. And parts of this country and 16 populations. But not only smaller, but if you look 17 at a true gestational age, construct it, they have a 18 higher incidence of not only low birth weight 19 babies, but pre-term babies. And that's why 20 definitions and, again, your comparison populations 21 are very critical. So I don't know if that's how 12:24:00 22 they got that number. I would hope that they didn't 12:24:30 23 get it that way, because that would not be Ln 24 appropriate use of your population statistics. ~ 25 Q. Okay. What is your understanding, Doctor, J 96 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 break here and then we'll get into your report, 2 Doctor. 3 THE WITNESS: Okay. 4 MR. GIBLIN: We'll do this, and then we'll 5 cover that briefly, and I think we're getting 12:48:00 6 close. 7 (A recess was taken.) 8 Q. (BY MR. GIBLIN) I'm going to change my 9 order up here, Doctor. 12:48:30 12:58:08 10 A. Yes, sir. 12:58:30 11 Q. At this time -- I guess I should have 12 moved those over here. I'd like for you to take a 13 look at each stack. Each stack has been marked, 14 Doctor, and we're going to try to keep them 15 together. 16 A. Okay. 17 Q. Because I'm going to end up getting a copy 18 of them 19 . A. Do you want -- 20 Q. If you could just tell me -- actually, the 21 court reporter is going to make the copy for us. cn ~ J 22 A. Okay. F-+ m 23 Q. What I'd like for you to do is just J N ~ ~ 24 identify what the documents are as you come to them, 25 and tell me what it was about that document that was KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 113

1 cigarette smoking that caused the small fetus, or 2 was it the fact that they had severe asthma, which 3 in and of itself is significantly associated with 4 small-for-dates fetuses. Those are the only two 5 people that I could even come close to saying that 6 it was certainly a risk factor, but -- in 7 identifying, going back to your very -- the earliest 8 part of this question. Nobody else. 9 Q. And that patient, the one that kept 12:46:30 10 smoking and had asthma, it could be said that 11 smoking was a cause, asthma was a cause? 12 A. Yes. And she also -- the specific patient 13 I am recalling also had a drug dependency, and 14 specifically certain barbiturates which she was 15 ingesting and nutrition was a component of her 16 particular process. And here is a very asthenic 17 person who almost looked like any of the -- let's 12:47:00 18 just call it negative food addiction problems, 19 anorexia nervosa, et cetera. And so with her, an 20 even more complex circumstance. Because I'm not 21 sure that she ate and ate properly, and all of those 22 were discussed at that particular point with her, 23 but I changed her behavior only from the standpoint 24 I would not write scrips for her medication. 25 MR. GIBLIN: Okay. Take a couple-minute 12:47:30 112 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Q. Okay. 2 A. There is a separate book which is -- in 3 fact, it has a separate component of the 1990 4 Surgeon General's report. It has Exhibit 5 on it, 5 and it is specifically pages 367 to 423. This is 13:00:30 6 chapter 8 from the book, "Smoking Cessation and 7 Reproduction," and they discuss a lot of the things 8 that we've discussed here this morning. 9 Q. Anything on those few pages that you 10 disagree with? That's a big question, huh? 11 A. Well, if we go back to the one thing that 12 we've talked about, the issue of premature rupture 13 of membranes, that would be one of those things, 13:01:00 14 since they say in there that there's -- I won't say 15 clear, but there is an association. And I'm not 16 sure that there really is, but that. In this I have 17 underlined some specific things, and also I've made Ln J 18 some notes in various parts of the margin, and so m 19 you can you can see those as they present J ~ 20 themselves. m 21 The next is what was Sachs Exhibit 14, and 22 apparently this is some of the same information from 23 the different volumes of this; that's why I put it 13:01:30 24 into this stack. The only writing that I am aware 25 of that I have done on this is at the top put 115 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Surgeon General's Reports and Exhibits, and then put 2 Dr. Sachs's name. But this is Exhibit 14 to his 3 deposition. 4 Q. And that -- 5 A. Whether this is the Mississippi or the 6 Florida deposition, I don't know. I can't tell you 7 that. 8 Q. Okay. 9 A. The next is a set of bound documents. 10 There is not an identifier as to whether this was an 13:02:00 11 exhibit or not; I suspect it is. But it's a 12 specific section from wherever the source is and it 13 talks about "Pregnancy and Infant Health." There 14 were several things in going through this that I 15 have underlined, and so it is different from all of 16 these others that have not been underlined. 17 Q. Can -- 18 A. So that is that first stack. 19 Q. Can you recall anything specific about 20 that document here, "Pregnancy and Infant Health," 21 Doctor, that you relied upon in this case? 13:02:30 22 A. Oh, I didn't rely upon it. I read it and Ln ~ 23 I'm sure I agreed and disagreed with some specific ~ m 24 components of it, but I certainly can't pull that ~ 25 from memory. N ko -Q 116 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 command of grammar and the capability to use that 12:35:30 2 grammar. 3 Q. Do you feel that based on his command of 4 the grammar that that's a pretty apt description of 5 cigarette smoke, a "Satanic brew"? 6 A. Personal, nonscientific, yeah, I think 7 that's a -- I find it noxious. 8 Q. Cigarette smoke contains something like -- 9 what -- 4,000 compounds? 12:36:00 10 A. I've seen 2,000 to 2,500, but I won't 11 disagree with 4,000. 12 Q. Okay. 13 A. I don't know what it is; it's just a 14 b h unc . 15 Q. Do you know how many of -- or have you 16 heard or have you read -- how many of the 2,000 or 17 2,500 or 4,000, whatever many it may be, how many of 18 those compounds have been determined to be cancer 19 causing? 20 A. There are a number of ones which are 21 stated to be carcinogens, yes. How many, I have no 22 idea, and I'm glad I do not have that in my brain. 12:36:30 23 Q. Again, on the right-hand side of the page, 24 Doctor at the bottom the last paragraph Again -- Ln r , , . J N 25 and these are things we've already talked about. I m _J ~ co Ln KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 104 t

1 question to you is: Do you recall the -- oh, I 2 guess conclusions, if you will, that were reached in 3 the 1990 Surgeon General report with regard to 4 maternal smoking? 5 A. I'm sorry... 6 Q. That's tough, because I can't recall them, 7 either, and I've read them repeatedly. 8 A. I -- no. 9 Q. Okay. 10 A. That whole section has got to be at least 11 30 or 40 pages, if I remember correctly, and it may 12 be longer than that. I think their basic summation 13 was get people to stop smoking while they're 14 pregnant. 15 Q. And you agree with that? 16 A. No question. Absolutely. 17 Q. All right. What is the CDC? 18 A. Center for Disease Control, and actually 19 it's no longer called the CDC. 20 Q. What - 21 A. It has new initials, and I can't recall -- 22 Center for Disease Control -- no, the initials are 23 the same, they've changed the names for the 24 initials, thanks to Mr. Reagan and Bush, I believe. 25 Q. Are there -- they're headquartered in KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 12:38:30 12:39:00 106

1 A. Requested because it was one of Sachs' 2 exhibits. 3 Q. Well, is it a reliable -- I mean, is it a 4 good study, in your opinion? The analysis, the 5 meta-analysis? 6 A. Meta-analyses can be both good and not so 7 good. There is so much information in here I'm 13:07:00 8 not -- to use the word "good," he tries to do a good 9 thing; I think in many.ways he probably has 10 accomplished such from a statistical construct -- I 11 will try to answer that question, because I don't 12 think I can, because I have never tried to do a 13 meta-analysis, and they -- you have to be as careful 14 as we have talked about confounders and 15 multifactorial analysis and such. 16 If you're doing a meta-analysis you have 17 to be very careful, also, in the articles you choose 18 that those particular articles are also comparable, 13:07:30 19 and -- or I should say the original study, study 20 design and analysis are comparable. Because 21 otherwise you get into the issue of apples and 22 oranges, and at least from what I could determine 23 from the article, he tried to do a good job of 24 sorting out those that he thought -- I think the 25 term that he used was "successfully met" his 13:08:00 120 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 criteria for analysis, and then there was another 2 term which was "did not meet," which partially met 3 his criteria so that they could be assessed, and 4 then there were a whole bunch of other articles in 5 any given area which he could not utilize in trying 6 to tabulate. So I think he tried to use appropriate 7 statistical methods. The information, though, is 8 very similar to the information which, again, we've 9 discussed this morning in many different ways, and 13:08:30 10 certainly I did not memorize 80 pages of detailed 11 data. 12 Q. Okay. 13 A. The third article, which was one of the 14 Sachs exhibits, is by Ian D. McIntosh, "Smoking and 15 Pregnancy, Attributable Risk and Public Health 16 Implications," Canadian Journal of Public Health, 17 volume 75, March/April 1984, pages 141 to 148. 18 Q. Do you agree with that article, with 13:09:00 19 whatever conclusions were reached in there? Do you 20 agree with them? 21 A. I -- it's part of the totality of 22 information which I now have been exposed to both in 23 this acute past time frame as well as in the remote 24 past. And I cannot pull specific things in my head 25 to be able to say, did this -- I don't think this 121 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. Okay. 2 Q. It states, "Smokers have a 3.5 - 4.0-fold 3 increase in small-for-gestational-age infants 12:14:30 4 compared with nonsmokers." 5 A. That's the highest relative risk I have 6 seen in any of the publications, any of the 7 tabulations. The Attorney General's -- not the 8 Attorney General's. The... 9 Q. The Surgeon General? 10 A. Surgeon General's various publications. I 11 have never seen one that high, and I don't know what 12 the reference is. That's a high figure. 13 Q. Okay. 14 A. Because most of the figures I have seen 15 have ranged from 1.4 to 1.8 in a multitude of 12:15:00 16 different studies for the small for gestational 17 age. And then one of the other things -- and again 18 going back from the standpoint of stratification, cn 19 one has to be very, very careful. What are they ~ 20 calling small for gestational age? Are they talking J 1-+ 21 about term babies who are specifically really small 22 for gestational age? Did they consider in that 23 population true population controls, meaning 24 individuals of same socioeconomic or different 12:15:30 25 socioeconomic classes and issues of ethnic origin? 91 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. But they have been admitted into evidence 2 in the Florida case as Sachs exhibits, and so I will 3 leave it at that. 4 Q. Okay. Have you read this stuff? 5 6 7 8 A. Q. A. Q. Yes. Okay. I didn't memorize it. Have you -- the Florida statistical 3:11:00 9 information, have you looked at that? 10 A. Oh, I went through all of that, and it was 11 very interesting, because it was interesting from 12 the standpoint of that they apparently have a very, 13 very good means within Florida of looking at 14 epidemiologic surveillance of their pregnant 15 population. They use their birth certificate data. 16 And I know Texas has -- I don't know how close, how 17 similar it is -- but certainly Texas has similar 13:11:30 18 birth certificates, in the sense that you can get 19 whether they have been exposed to intravenous drug 20 abuse, whether they have had cigarette smoking, 21 whether they've been a drinker. Now, how reliable 22 the data is, that's a different issue. But at least 23 the basic sheet for acquiring the information is 24 there. 25 Q. Did you review this analysis that was 123 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Q. Okay. 2 A. Then the next three are specific papers 3 which were referred to and, in fact, are exhibits 4 within Sachs' deposition; they are not labeled as 5 such here. The first would be Mary Meyer, Bruce S. 6 Jonas, James A. Tonascia, T-O-N-A-S-C-I-A, the 7 American Journal of Epidemiology, volume 103, pages 13:05:30 8 464 -- 9 Q. Anything significant in there? 10 A. -- dash 476 for 1976. It talks about 11 perinatal events associated with maternal smoking 12 during pregnancy. It goes over a lot of the similar 13 things that we've discussed. 13:06:00 14 Q. Okay. 15 A. The next article -- and I had asked for 16 these because, again, they were part of the exhibits 17 and I wanted to read them. The next is a bulletin 18 of the World Health Organization, volume 65, issue Ln ~_4 _j ~ 19 5, pages 663-737, 1987, written by M.S. Kramer, m 20 "Determinants of Low Birth Weight: Methodological ~ N m m 21 Assessment and Meta-analysis." And he covers some 22 900-plus articles that were reviewed and discussed, 23 921 publications and 895 are actually used. 13:06:30 24 Q. Was that a document that you requested, 25 Doctor? 119 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Atlanta. Is that correct? 2 A. Correct. 3 Q. Are there other branch offices around the 4 country, or is it pretty much a-- 5 A. They have epidemiology field officers who 6 are stationed in different places. I'll assume that 7 that means that they have branches in other place, 12:39:30 8 but that's not -- people are assigned different 9 places. 10 Q. What does the CDC do? What's their 11 f ti ? unc on 12 A. Oh. The Center for Disease Con trol is a 13 group of medical scientists in different 14 persuasions, both M.D. as well as Ph.D. They have 15 various degrees and training in microbiology, 16 virology, I'm sure toxicology. There are 12:40:00 17 pathologists within that, there are veterinarians. 18 They are responsible for the identification of Ln ~ 19 outbreaks -- correction. Following the v m 20 identification of outbreaks of unusual processes, ~ 21 the CDC epidemiologic field officers are frequently co co 22 called in, both within this country and without this 23 country to investigate and to try to establish 12:40:30 24 patterns of disease and to evaluate all aspects of 25 that disease process to try to come down to a final KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108 107

1 deposition. 2 Q. Okay. This is marked Exhibit 7, and I 3 think -- 4 A. Oh. Okay. 5 Q. Let me see if I can reconstruct this. 13:13:00 6 Would you set that down for a second, please? I 7 think this is 5 that we've kept out, and the rest is 8 7. 9 A. I apologize. 10 Q. That's no problem. 11 A. Okay. Now we're at Exhibit 6. 12 Q. Who provided those things? 13 A. The attorneys for the defense. 14 Q. Okay. 15 A. Okay. And there are actually two 16 different pages here, but they actually include the 13:13:30 17 16 -- 18 THE VIDEOGRAPHER: Put your microphone on, 19 i r. s 20 THE WITNESS: Thank you. Ln r 21 A. There are 15 papers that are referenced in J ~ m 22 here, including some of the ones that we previously J N B 0) 23 talked about today such as Naeye's, "Disorders of 24 the Placenta," chapter 5 and so forth. There were 25 two of the references which I have not been able to 13:14:00 125 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 find, specifically number 8 and number 9. I have 2 checked all of those references which I have found 3 within this information, and so they are listed that 4 way. And I don't believe that there are any 5 other -- Peter Soothill's article, I think, I 6 included and put in here, because it actually came 7 as an exhibit within Sachs, and I think several of 8 the different papers in here were papers that were 13:14:30 9 from Sachs that I just put in this since these are 10 predominantly scientific papers, as opposed to the 11 other stack of papers. 12 Q. Okay. Do all the documents or papers 13 contained there in Exhibit 6, do the conclusions 14 reached in those papers support your opinions in 15 this case? 16 A. We've talked about the issue -- because 17 most of these articles in here are some of the 18 articles talking about premature ruptured membranes, 19 they talk about low birth weight, similar to the 13:15:00 20 other documents that we've talked about today. 21 Would they 22 support it 23 dead horse 24 Q. 25 A. support it? Yeah, I think they would in the sense as -- not wanting to beat a again -- No, all I want to know -- Okay. 126 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 be modified by important contributors, and the 2 contributors is the issue of politics. And I think 3 the best example of that is the failure of the U.S. 4 Government to intervene in blood banking in the 5 early 1980s with respect to HIV, when the CDC had 6 clear and unequivocal evidence. And so, no, the 7 government does not necessarily always produce valid 12:43:30 8 data, because it is subject to political intonation 9 which is not acceptable from a medical or a 10 scientific standpoint. 11 Q. So -- 12 A. But in general, if you have their pure 13 conclusions without the political overtones, their 14 data would be quite reliable in almost all 15 circumstances. 16 Q. Do you feel that their data is reliable on 17 the issue of maternal smoking and adverse pregnancy 18 outcomes? 19 A. Within the construct of all of the things 20 that we've talked about today, the relative risks, 12:44:00 21 the associations, absence of, if you will, causation 22 in the way we've talked about it, yes, I think that 23 that data is there. They have not been the ones 24 doing most of the research; they have some of it, 25 I'm sure, but a lot of it comes from other places. 110 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 important to you, what's significant about it, and 12:59:00 2 keep on going until you're done with the stack. 3 A. Okay. Well, this first set -- and I 4 really don't think you need to duplicate it, but if 5 you want to that's your choice. 6 Q. Who provided -- you may need to put your 7 microphone on there, Doctor. 8 A. I apologize. I took that off, and should 9 h t ave no . 10 Q. If you could tell us who provided the 11 documents to you, also, that would help. 12 A. The attorneys for the defense gave these 12:59:30 13 to me at my request. They are the 1964, the 1973, 14 the 1980. There is a 1989 report of the Surgeon 15 General, also, and then the 1990 report of the 16 Surgeon General. So all of these bound volumes here 17 are those particular documents. They have not been 18 changed by me. I've made neither no additions nor 13:00:00 19 subtractions from it. 20 Q. Have you done any underlying -- 21 underlining or highlighting of any portions of the Ln ~ ~ 22 reports? ~ 23 A. That's not in my normal way of doing m ~ ~ ~ 24 things, but in these specifically I can tell you, Ln 25 no, I have not. 114 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Q. All I want to know is the discussion of 2 what they are. 3 A. The discussion of relative risk and 4 associations of various maternal outcomes is present 5 within this database. Yes. 6 Q. Okay. 7 A. Okay. 13:15:30 8 Q. You're going to get your workout here 9 today. 10 A. The last stack, which is labeled Exhibit 11 8, are a number of things. The first part is -- and 12 I will put the rubber band back on -- what I have 13 labeled State of Texas Expert Witnesses . It 14 starts -- it actually has a number 7, 3 2, 33, 43, 13:16:00 15 60, 73, and 80. And I'll not read into the record 16 what those and whose names are there. There is -- 17 Q. You mentioned earlier, Doctor, that you 18 knew one of the State of Texas experts, Dr. Michael 19 Speer. Ln N J ~ 20 A. Yes. m 21 Q. Are there any other State of Texas experts J N B OD 22 whom you know? 23 A. No, there is nobody else here that I know, 24 know in the sense of personal relationships and 13:16:30 25 personal knowledge, no. Benjamin Sachs only from 127 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 what I have read in the past in literature and only 2 in respect to the information that we've discussed 3 today. 4 Q. Okay. 5 A. The next is a set of information which 6 goes back a number of years up toward the present, 7 but not including 19 -- like '94 plus. And these 8 include -- there is a 1995-1996 Texas Health State 9 Plan, there is a Medicaid Fiscal Year 1992 Annual 13:17:00 10 Hospital Discharge Report. There is a 1990 Texas 11 Medicaid Hospital Discharge Report, 1989 of the 12 same. There is a 1991-1992 Texas State Health Plan; 13 it's labeled volume 1. There is a 1980 Data Summary 14 of a whole host of different public health issues. 13:17:30 15 There is from the Department of Health and Human 16 Services and CDC Texas 1996 Demographic Statistics. 17 There is 1987-1988 Texas Health State Plans. There 18 is a Demographic Factors Affecting Texas, a Special 19 Report of the Senate Research Center, May 1993, 20 which is included. There is 1993-94 Texas State 13:18:00 21 Health Plan. 22 There is from December 1993 from John N ~ ~ 23 Sharp's office, Medicaid, Where Does it Hurt? There m ~ 24 is a final report to the 72nd Texas legislature from N m 25 the Texas Department of Health dated February 1991. ko 128 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 documents which have been discussed within the Sachs 2 deposition. 3 Q. And they're included in the Exhibit 7 4 batch. Is that correct? 5 A. Yes. 6 Q. Okay. 7 A. The label Exhibit 7 is actually on the 8 deposition of Dr. Jeane A. McCarthy, done March 9 21st, 1997, and that was in the Florida versus the 13:04:00 10 American Tobacco Company case. I have not marked in 11 here; I may or may not have some notes over here in 12 my blue folder. 13 The next is the Sachs depositions done -- 14 the first one of which is November 22, 1996, volume 15 1, pages 1 through 262. There is a continuation of 16 that, which is volume 2, pages 263-401, March 6th, 13:04:30 17 1997. And that was entitled, Moore versus American 18 Tobacco Company. That's also in Exhibit 7. 19 The next is the State of Florida versus 20 the American Tobacco Company. It is volume 1, pages 21 1-236, and I never saw a second set or a volume 2 of 22 this. If it exists, I have not seen it. So I 13:05:00 23 will -- ~ 24 Q. You've read those depositions, Doctor? J ~ 25 A. Yes. m J F-+ ~ ~D 118 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 2 3 4 5 6 7 8 9 10 11 12 changed my mind about anything. It's a different -- a different way of looking at it, because he tries to use the epidemiologist's technique, where -- looking at attributable risk. What percentage of the population that may be exposed to a given circumstance, in this particular situation smoking, may have actually had their disease process because of smoking. And whether that is good statistical technique and the rest, again, I'm going to leave that for others to discuss. I think it's much more appropriate. Q. Okay. 13:09:30 :10:00 13 A. And then there a-e a number of other 14 things, and these were under a letterhead from, I 15 will assume, a law firm, Ness, Motley, Loadholt, 16 Richardson and Poole. Almost all of these are 17 labeled with some either Sachs or a Sachs plus a 18 number, and this is all stuff that is from -- a lot 19 of this stuff is from the Florida deposition, and 20 includes Florida vital statistics, some articles by 13:10:30 21 epidemiologists, public health people within the ~ 22 state department of public health in Florida I'm N . ~ ~ 23 not going to read all of those unless you want those m ~ 24 read as individual things. N m 25 Q. No. w 122 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 There is a 1990 Texas Survey of Postpartum Women and 2 Drug-Exposed Infants dated June 1991. There 13:18:30 3 is -- and this is from a book, apparently. The 4 Financing of Maternity Care in the United States 5 from the Alan Guttmacher Institute, and the 6 pages -- consecutive pages 59 through 73. There is 7 from the Texas Department of Health 1990-91, and 13:19:00 8 it's labeled, Expanding Knowledge, Pursuing 9 Excellence, a Collection of Published Papers by the 10 Texas Department of Public -- correction. Texas 11 Department of Health Staff. 12 There is then a report, Texas Healthy 13:19:30 13 People 2000. Health status Indicators, 1980-1993 by 14 race and ethnicity prepared by the Texas Department 15 of Health. There is a similar report, Indicators, 16 1980-1992, and that is dated September 1994. The 17 previous document is dated April 19, 1995, or at 18 least the cover letter is. And that's all of that 13:20:00 19 particular -- 20 Q. Okay. 21 A. -- Exhibit 8. Ln ~ 22 Q Oka What I'd like to do is mark this _j . y. ~ m 23 stack with another exhibit number. Leave that 8. ~ N 24 A. Okay. 6 25 Q. Mark this with the next exhibit number, 129 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 because that is some Texas specific statistics. 2 (Deposition exhibit marked, Exhibit 12.) 13:20:30 3 Q. Doctor, we have now marked as Exhibit 12 4 the various Texas specific documents on Medicaid, 5 documents from the Department of Health. My 6 question is: Were these furnished by the tobacco 7 companies to you? 8 A. Yes, they were. 9 Q. Okay. 10 A. And they have not been able to provide me 11 data which I've also asked for. I have asked for a 12 complete breakdown of statistical data based on 13:21:00 13 birth certificates with -- cross linking with all 14 neonatal and fetal death certificates, as well as 15 all birth certificates for the years 1990 to 1996, 16 with comparisons between the upper half of the birth 17 certificate and then the lower half demographic 23 24 database. Because that data has within it the Ln issues that we've talked about today ~ . ~ Q. Okay. ~ m ~ A. A multitude of different issues. N r ~ Q. A. We're going to get to that in a minute. Oh. 13:21:30 Q. Because that's in your report. I have a 25 couple more questions about that information in 130 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 So what I have seen has been relatively consistent. 2 Q. We talked earlier, briefly, about the type 3 of patients that you actually treat. 12:44:30 4 A. Yes. 5 Q. Being high risk -- high risk patients that 6 have got some rather serious problems on board 7 already before they get to you. My question to you 8 is: In your practice have you had occasion to 9 diagnose an adverse pregnancy outcome in one of your 10 patients due to the patient's refusal to quit 12:45:00 11 smoking during her pregnancy? 12 A. No, not that I can recall, even either 13 from my private practice -- either from my private 14 practice patients or within the county system, 15 because frequently you may have written down that a 16 patient smokes but, if you will, doing the 17 epidemiologic evaluation to try to determine whether 18 that is a significant cause in a significant 12:45:30 19 patient, I have not done that. I have had several 20 patients, specifically with asthma, who smoked. I 21 cannot -- and it's been a good while; a long time. 22 I believe the outcome of those pregnancies were 23 good, although the children were small. But I was 24 not -- be able to segregate out in that specific - 25 those two particular persons the issue of was it the 12:46:00 111 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 performed by Gerry Oster? 2 A. I looked at that, yes. 3 Q. Any criticisms about that? 4 A. I would have to go line by line and the 13:12:00 5 rest, and I -- 6 Q. Okay. 7 A. I don't think we need to do that. You 8 haven't asked me -- I was very surprised. You 9 haven't asked about the word "authoritative" today, 10 and just as -- I would have told you if you had 11 asked, just as books are not authoritative in 12 meaning that they are true and that God would 13 believe everything in them, neither are many papers 14 and statistical analysis. It's -- and so we can go 15 from there . 13:12:30 16 Q. And that was all stack 5? 17 A. That was Exhibit 5, correct -- oops. Yes, 18 that's Exhibit 5 which, again, is Sachs and so 19 forth. 20 Q. I think -- I'm not sure about that, 21 Doctor. If we could -- Ln ~ ~ 22 A. Oh. Did I pick up -- m J 23 Q. I think -- yes. N Ln 24 A. That was a deposition -- yeah -- no, that 25 was in stack 5, also. That was Dr. McCarthy's 124 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Q. Okay. 2 A. Now, if you really want those duplicated, 3 that's fine, because they don't -- I'm not sure you 4 need to have all of these, unless -- 5 Q. No. With regard to these documents, all 6 we're going to want attached will be the -- 7 A. The face sheets, or -- 13:03:00 8 Q. Well -- 9 A. I'll let you-all do that. I'm sorry. 10 Q. Will be the Sachs exhibit, then this other 11 bound chapter titled "Pregnancy and Infant Health," 12 then the few pages from the Surgeon General's 13 report, I guess, of 1990 that you've got glued 14 together. 15 A. Okay. 16 Q. We're not interested in the -- 17 A. Okay. 18 Q. -- actual Surgeon General reports. 19 A. I am going to move these over and out of 20 the way. 21 MS. COLSON: Here. You want me to hand 22 them to you? 13:03:30 23 THE WITNESS: That's why I took it off 24 awhile ago. Ln ~ ~ 25 A. Okay. The next set of documents are 6 _1 117 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 the Medicaid payback portion would be or anything 2 like that. Is that correct? 3 A. I have not been asked, nor do I expect to 4 be asked, nor have I done freely on my own. 5 Q. Okay. 6 A. And I won't. 7 Q. I believe we also had your file, Doctor -- 8 A. Yes. 13:27:30 9 Q. -- marked as an exhibit, marked as 10 Exhibit -- 11 A. Oh. There was one other -- there was one 12 thing in this blue file here, which actually belongs 13 in Dr. Sachs' stack, whichever number that is, 5, 14 maybe, I guess, or 6. And that was the 1993 number 15 180 ACOG Technical Bulletin, and we've discussed 16 this, basically, because the numbers are very 17 similar. 18 Q. Similar to 1996. Correct? 13:28:00 19 A. Correct. That's what I meant, similar. I 20 should have said 1996. 21 Q. Okay. And they are marked -- which ~ 22 exhibit number is that, Doctor, on the other? I,-- J ~ ~ 23 A. It's Exhibit 4. J N 24 Q. Okay. Exhibit 4, they are your two files , r J 25 two blue files that you have on this case. Is that 136 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 seeing a lot of that similar data in this data set. 2 If it -- it may be there, and I just have put in so 3 much information I don't recall. 13:24:00 4 Q. Doctor, in the Texas case do you plan on 5 testifying on the issue of damages? 6 A. No. 7 Q. Okay. 8 A. At least my understanding of damages would 9 be trying to give some type of proportionality, if 10 you will, trying to say that this weighs so much, 11 and the rest. I don't consider myself financially 12 astute enough to be able to do that. I would think 13 that actuarial statisticians would be the ones who 14 would be able to plug that data in and would be the 13:24:30 15 most appropriate group of people to do that. 16 Q. Just so we're clear on that, you don't 17 plan on devising a model or some equation that'll 18 spit out a number at the end, saying, This is what 19 Texas really spent on Medicaid due to smoking? 20 A. I'll use part of your answer as my cn ~ 21 answer. I do not plan on conceding or executing J F-+ 22 model planning. m J N 23 Q. Well, could you if you were asked? F-~ ~ 24 A. No. 25 Q. If the tobacco company said, Do it, I 133 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 mean, could you do it or would you have to defer 13:25:00 2 to -- 3 A. Oh, could I do it? Yes, I think I have 4 the statistical database, I think I have the 5 intellect and I think I have the mathematical skills 6 that would allow me to do that. And what one would 7 have to do is you've got to have good data, and you 8 have to have compartmentalization of that data. You 9 have to stratify and structure your risk factors, 10 and if one uses the attributable risk calculations 13:25:30 11 and so forth, making a basic assumption that because 12 10 percent of the population smokes and has an 13 adverse outcome that -- and making the simple 14 abstracted leap that then 10 percent of the adverse 15 outcome or a relative risk of 1.1 that 10 percent 16 then is the excess rate just because of -- yes, you 17 co ld d it on su h i l th ti l u o mp c s e ma ema ca 18 comparisons. And yeah, I could do it, and I think a 13:26:00 19 number of other people, whether physicians or 20 others, with very reasonable mathematical skills. 21 You would not need to use calculus or any of the Ln 1~ 22 other high-powered math fields. You can do it J m 23 simply. N ~ 24 Q. But you have to -- cn 25 A. But you have to make some -- you have to 134 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 incidence of preterm and low birth weight stratified 2 as far as Hispanic, black and Caucasian or, quote, 3 white/nonHispanic -- which is the way they term it 4 in here -- populations, and what you would expect in 5 that population, and the differences between 6 Caucasian -- or correction, white/nonHispanic versus 7 black, and that there, in the State of Texas, is 13:23:00 8 also significant increase incidence of preterm 9 deliveries and low birth weight among the black 10 population, for whatever the specific reasons are. 11 Q. Medicaid statisticwise, Texas is very 12 similar, based on what you've seen, to the state of 13 Florida's statistics. Is that correct? Is that 14 what you just said? 15 A. They may not be -- They're similar; they 16 may not be exactly the same. 17 Q. Right. 18 A. I said the same trends, and if I remember 19 correctly there was, like, a doubling to 2.5 fold 20 increase in the incidence of low birth weight in 13:23:30 21 general in Florida, and I think that was similar in 22 a s Tex wi t h respect to, again, white/nonHispanic N ~ ~ 23 versus black population. I don't recall seeing -- m 24 25 there was a lot of demographic data broken down by smoking in the Florida data. I don't remember -J N I , w 132 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 much more difficult than quitting illicit drugs or 2 alcohol." 3 A. I have seen that comment in other sources, 4 and I think on the basis of my limited knowledge 5 about people who undergo drug treatment programs, I 6 think that that's true. Because you asked me 7 earlier, Is it an addictive drug? Yes, it is an 8 addictive drug. Not smoking; I think nicotine. 13:33:00 9 Q. Nicotine? 10 A. Yes. 11 Q. Smoking being the delivery device for the 12 nicotine, of course? 13 A. No. Smoking being the act of the use of 14 the delivery device -- 15 Q. There you go. Ln ~ 16 A. -- the cigarette. Correct. J ~ 17 Q. Much better stated. m J 8 . hank you. N N N 19 Q. I would like to get this marked and a copy 20 of it made. 13:33:30 21 (Deposition exhibit marked, Exhibit 13.) 22 Q. Doctor, what we've done, we've marked the 23 boo k that you've provided here, "The Future of 13:34:00 24 Chi ldren," as Exhibit 13 to the deposition, and 25 we' re goin g to attach a copy of that. 140 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 correct? 2 A. Yes. Actually, it's one file. I have a 3 simple folder, and it has on the left-hand side the 4 business cards of the various attorneys I have met 5 with and talked to that I am aware of. Maybe 13:28:30 6 there's additional, and I'm -- but that's as good as 7 I can say. There is, starting from the very back, a 8 9 number of letters of transmission of various information and so forth, which will stand as 10 they -- they are September 9 -- correction. June 11 9, June 9, June 12th. There is a June 13th fax, 12 which was one of the same letters, and I have since 13 discarded the fax since the hard copy came. 13:29:00 14 There is one, June 18th. The June 18th 15 I'm sure had some of these documents present. The 16 next part is a one-page abstraction of some 17 components of the deposition testimony of Jeane 18 McCarthy done on March 21st, 1997. There is -- 19 there are a total of four pages from the two 20 different Sachs -- I should say three different 13:29:30 21 Sachs depositions; part 1, part 2 for Mississippi, 22 part 1 for Florida, and they are here. And then Ln ~ ~ ~ 23 last the front sheet of this is the time record for m _j 24 law case review that I try to maintain That is N ~ . 00 25 present inside a drop file, because that's how I 137 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 risk factors, prematurity, and so forth. 2 Q. Do you generally agree with what's 3 contained in here, in this book? 13:31:30 4 A. Many of the things in there are 5 straightforward, standard medical details of 6 medicine, which I have seen in the past and which 7 are considered to be reasonably true. That should 8 not be construed that everything that's said in 9 there -- because I don't remember everything that's 10 said in there -- that all of it is 100 percent 11 true. I don't -- I can't say that. But, yes, there 12 is a lot of information that I would consider to be 13 lid va . 14 Q. Okay. Looking at page 11, Doctor, at the 15 top it says, "While there are several things women 13:32:00 16 can do to reduce their chances of having a low birth 17 weight infant, one action stands out above all 18 others -- stop smoking cigarettes." ~ ~ ~ ~ 19 A. I would agree with that. m ~ 20 Q. Look further down on the same page. it N N m 21 states, "Smoking is not a casual activity that can 22 be easily stopped at will; it is a powerful 23 addiction. The addictive powers of nicotine are 13:32:30 24 illustrated in the results of a survey of drug 25 addicts who reported that quitting cigarettes was 139 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 whole -- the whole document. I would consider that 2 to be additive or understood that that was a factor. 3 Q. I see. I apologize. And I'm -- when I 4 read your first sentence here I thought that you 5 were making the statement that, you know, maternal 6 smoking has been reported to be associated with 7 adverse pregnancy outcomes, but that was something 8 you didn't agree with. 13:36:00 9 A. Oh, no. I agree with that. 10 Q. Okay. 11 A. I think I've stated that multiple times 12 today. 13 Q. You have. 14 A. I want everybody to stop smoking in 15 pregnancy, period. And if, in fact, cigarettes were 16 banned tomorrow by fiat of God, that would be okay 17 with me. 18 Q. I understand, Doctor. In the next 19 section, Doctor, you're talking about risk factors 13•36:30 20 for pregnant women on Medicaid? Ln ~ 21 A. Yes. ~ ~ 22 Q. And, again, you listed here as common and a ~ N 23 important risk factors in this population include N W 24 inadequate prenatal care, young maternal age, low 25 maternal weight, obesity, poor diet, abuse of 13: 37:00 142 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 premature," et cetera, et cetera, "and are not 2 counseled about" -- and smoking is included there. 3 So -- 4 Q. Okay. 5 A. -- it v ery clearly -- 6 Q. What we could have done here, I guess, 7 then, if we went back to the first sentence in your 8 report, what we could rewrite this to say is, 9 Maternal smoking during pregnancy is reported, 10 comma, and I agree, to be associated with blah, blah 11 blah. Because you agree that it is, in fact, 13:38:30 12 purported to be associated with all these things 13 that we are talking about in the report. Correct? 14 A. Yes. 15 Q. Okay. The section on demographics of 16 pregnant women on Medicaid in Texas. Now, we've 17 talked about this. I think we've already explored 18 the word "m ay" there. That was initially a problem 19 I had, because it says you may comment. But as we 20 sit here today, you're not planning on commenting 13:39:00 21 and you're - 22 A Oh if I'm rovided the information and I Ln ~ . , p ~ ~ 23 look at the data, then I'll respond to any m ~ 24 question. I don't have the information N N . Ln 25 Q. I see. 144 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. Okay. The only thing I would ask on 2 these, if I could just get those back relatively 3 soon as opposed to later, although I know that 4 technically trial is not until sometime in 5 September, but I would just like to try to keep my 6 files intact. 7 Q. She'll take care of you. 8 A. I understand that. 9 Q. I'd like to -take a look at your report, 10 Doctor. 13:34:30 11 A. Okay. 12 Q. And, again, we have pretty much covered 13 everything that you've got in here, I think, already 14 at this point in time. Again, your first 15 paragraph -- not paragraph, your first section of 16 the report -- we've got four paragraphs -- you talk 17 about, in the third paragraph, excuse me, about on 13:35:00 18 line three you talked about the common risk factors 19 for pregnant complications, and you list poor 20 reproductive history, restricted fetal growth, Ln ~ J ~ 21 maternal medical problems, various placental m J 22 problems. Wouldn't you agree that smoking should N N N 23 have been also included in there as one of the more 24 common risk factors for pregnancy complications? 25 A. I have that in the first sentence of the 13:35:30 141 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 make some very simple, basic assumptions, though, 2 which may or may not be appropriate. And, no, I 3 have not done that, and I'm not planning. I've 4 never been asked to do that. If somebody asked me 5 to do it, yeah, I'd do it, but you may have people 13:26:30 6 who would be able to do it more precisely than I -- 7 or than me. Excuse me. 8 Q. I assume that if you did that, if you were 9 asked to do that, you would generate a supplemental ? 10 report 11 A. That would be required, I believe, under 12 normal -- at least Texas rules. I don't know about 13 all of the federal rules, because there's 14 differences, but I would assume that federal rules 15 would be the same thing. 16 Q. As we sit here today -- 17 A. No. I don't plan on do ing it. 18 Q. Okay. 19 A. I have not been asked t o do it, and I 20 don't expect to be asked. I'm sorry I interrupted 13:27:00 21 your question, but I hope that -- Ln 22 Q. No, that's okay. I had to make it clear ~ ~ 23 here that as we sit here today you have not been m ~ 24 asked, nor do you plan on offering testimony on N ~ 25 damages or constructing a model to determine what 135 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 because I'm not responsible for that. 2 Q. Okay. 3 A. But, yes, I would like to have the data, 4 because I think you can only function in an 5 epidemiologic, statistical and clinical scenario of 6 looking at risk if you have data. 7 Q. Do you -- 8 A. If you have no data you can make all of 9 the allegations you want to, but it doesn't make it 10 true. 13:46:00 11 Q. Do you even know whether or not it's been 12 requested from my client, the State of Texas? 13 A. I have asked that several times. I have 14 been told, yes, it has been. I haven't seen the 15 data yet, and so -- what I was told, I believe 16 yesterday, when the last time I asked the question 17 was, that supposedly it's supposed to be given as - 18 you have a deadline of August 15th for your client Ln ~ 19 to provide the data to you so you can provide it to J m 20 other parties. I assume that's true; if it's not, N 21 then that's okay because I don't make those rules. w m 22 Q. Okay. Placental changes; we talked about 23 that. 13:46:30 24 A. Yes. 25 Q. Premature rupture of membranes; we've been 150 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 file it in the office. And then we've talked about 2 this other stuff, and I'll not go through that 13:30:00 3 unless you want me to. 4 Q. No, that's fine. Could I take a look at 5 your file for a second, please, sir? 6 A. Yes, sir. 7 Q. Thank you. 8 Doctor, you mentioned this book. 9 A. Yes. 10 Q. "The Future of Children." I take it this 11 is something that you regard as being a reliable 12 publication on the area of low birth weight. Is 13 that -- 14 A. Not necessarily. I had it 15 Q. Okay. 13:30:30 16 A. -- in my library at home. I knew where it 17 was and I knew that I had looked at it before, and 18 so over the course of the last week, and 19 specifically about 48 to 72 hours ago, I pulled it 13:31:00 20 down and went through and there were a number of 21 articles in there -- there are a significant number 22 of articles that, in fact, pertain to low birth Ln ~-4 23 weight. As I mentioned, one of the co-authors in m V 24 one section of fetal evaluation was Dr. Sachs, and N) 25 then there were a multitude of other articles about 138 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 CORRECTIONS AND SIGNATURE 2 PAGE LINE CORRECTION REASON FOR CHANGE 3 4 5 6 7 8 9 10 11 12 13 14 I, ROBERT J. CARPENTER, JR., M.D., P.A., have 15 read the foregoing deposition and hereby affix my 16 signature that same is true and correct, except as 17 noted herein. 18 19 20 ROBERT J. CARPENTER, JR., M.D., P.A. 2 SUBSCRIBED AND SWORN TO before me this the Ln N 1 ~ 22 day of -------- , 1997. N m 23 SEAL: li N w ----- ---------------- ---- Ln 24 NOTARY PUBLIC 25 (22385) 155 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 and then your percentages damages due to, quote, 2 cigarette smoking on an attributable risk basis may 3 be far, far less, even though our population, I 4 believe, is greater than the Florida population of 5 all Medicaid recipients. 6 7 8 9 10 11 12 Q. A. Q. A. Q. But -- But I don't have -- -- to determine anything like that -- You got to have data. Yeah. 3:45:00 A. Q. There is no data; that's why that was put. Do you expect to receive data, or are you 13 awaiting it? I mean -- 14 A. I'm not used to firing guns at people and 15 trying to hurt them. The only way that I could get 16 that information is for them to get the 17 information. The only way for them to get the 18 information is for your client to provide that 0 ~-A 19 information, since your client has the computers, it `' F-- m 20 has the data and it has the capabilities as „ N N 21 demonstrated by some of this department of health ~ 22 birth certificate data of being able to go into that 23 database and acquire information. It's totally 13:45:30 24 dependent on your clients to provide the 25 information. And I'll not get into that issue, 149 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. Be considered a -- 2 Q. -- risk factor for -- 3 A. A risk factor. And -- 4 Q. -- for pregnancy complications and adverse 5 pregnancy outcomes. 6 A. Correct. 7 Oh, and this is something that I'll just 8 give it to you, and I'm sure others may consider it 9 in subsequent situations. It's very interesting in 13:50:00 10 this suit -- and I won't comment about the merits of 11 whether the suit is appropriate or not in view of 12 "the settlement." That's for the lawyers to work 13 out, Congress and the President, and I am far less 14 than that. 15 However, I talked about the WIC data , and 16 it's very interesting at a time when the State of 17 Texas is suing an individual group for costs, that 18 the State of Texas is decreasing the number of 13:50:30 19 dollars being provided to the WIC program, which by 20 their own database has a major impact on positive ~ 21 pregnancy outcomes. In all of this data and all of ~ ~ ~ m 22 the stuff, that I find to be one of the most ~ N W 23 disparate factors. And I doubt seriously that any W 24 recovery of funds which would be generated from this 25 case or from the national settlement is going to be 153 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 agree that the Florida information would -- I know 2 not specifically apply, but would be generally 3 applicable to Texas? 4 A. No, I don't think so. 5 Q. Okay. 6 A. I don't think so for a very important 7 reason: If you take a look at some of the Florida 8 data, and specifically they talk about the Cuban 9 population and they talk about their Hispanic 10 population. One of the questions that -- one of at 11 least my own observations, and I think the Florida 13:42:30 12 data that I have suggested that that observation may 13 be more true than not, is that there is decreased 14 smoking within the Hispanic population. However, if 15 you take a look at Hispanic populations, not all 16 Hispanic populations are the same, and this is 17 general, and it may not be true. My thought 18 processes concerning a Cuban population with 19 certainly very heavy male smoking patterns may also 20 be true with respect to female smoking patterns. 13:43:00 21 How does that population differ from, if you will, 22 the Florida Hispanic? I don't remember truly seeing Ln ~ -j ~ 23 that segregated out, and it may have because there's m ~ 24 a lot of data there that I tried to look at. N N 25 well, in Texas my own experience both with J 147 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 Exhibit -- 2 A. 12. 3 Q. -- 12. Have you reviewed the information 4 in those various documents from the state? 5 A. I have read the information a single 6 time. As I've said several times, I have not 7 memorized it, and I probably have processed some of 8 the information, but not reviewed in the sense that 9 I normally use the word "review." To me when I 10 review something that means that I have a reasonable 13:22:00 11 understanding and comprehension of the database 12 which is enclosed in that particular -- data set. 13 Q. Okay. 14 A. I do not have that appreciation for this 15 information. There is nothing in this information 16 that I was surprised seeing, though. 17 Q. Have you utilized any of the information Ln 1~ 18 contained in Exhibit 12 to formulate some ~j 6 19 conclusions? v N 20 A. No. Because the data, I think, N is 21 duplicative, if you will, in some respects to the 22 Florida data where they have that information. I 13:22:30 23 think it's very similar. It shows the same type of 24 trending, it shows the same type of analysis. 25 Giving you a specific example, the 131 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 CERTIFICATION 2 3 I, the officer before whom the foregoing 4 deposition was taken, do hereby certify that I 5 personally recorded the testimony of the witness 6 whose testimony appears in the foregoing deposition; 7 that said deposition is a true record of the 8 testimony given by said witness; that I am neither 9 attorney for, related to, nor employed by any of the 10 parties to the action in which this deposition is 11 taken, and that I am not a relative or employee of 12 any attorney employed by the parties hereto, or 13 financially interested in the action. 14 15 16 17 18 Tara K. Taggart Certificate No. 6594 19 Expires December 31, 1997 (22385) 20 22 J N 2 3 G' m 24 25 156 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 alcohol, or illicit drugs, lack of maternal 2 education, unmarried status, short interval between 3 pregnancies, multiple partners and infections. Just 4 so we're clear here, shouldn't smoking be also added 5 to that list? 6 A. The first -- if you want to add it as a 7 separate component, yes, I have no problem with that. 8 Q. Okay. 9 A. That first sentence is applicable to all 13:37:30 10 of the things that are present within this. There 11 is not either, one, a deliberate attempt or anything 12 like that to remove smoking as a risk factor. 13 Q. I understand. 14 A. Smoking is a risk factor. But if one 15 wants to be complete and say, list everything, 16 fine. I have no objections for that being added 17 here . 18 Q. I understand Doctor and I don't mean to Ln N , , ~ 19 imply that anything was being left out of this. I N m ~ 20 didn't mean that N N . -ch, 21 A. Oh, no. I -- 22 Q. It was just the way I had read it. If -- 23 A. But go back down to page 2, the end of 13:38:00 24 that paragraph where it says, "Without prenatal care 25 patients are not advised about the signs of 143 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 A. That's why that word "may" -- because a 2 long time ago, in fact, in one of our first 3 meetings, in fact probably the first meeting -- did 4 I say February 24th? Whenever it was. January 5 24th. That issue of what available databases are 6 there? Well, the birth certificate data -- and this 13:39:30 7 is before I knew anything about the cross-linking of 8 data in the Florida case, Mississippi case, before 9 any of that, the question was asked, What 10 information do you -- would you like to have? What 11 information would be important? And so I went 12 through a whole bunch of stuff. And then I said, 13 The specific place where some of that information 14 can be acquired, although it is not going to be 15 perfect, just as the State of Florida admits their 13:40:00 16 information is not perfect, is the birth certificate 17 data. And there is linkage data available. 18 But what you have to do is you have to get 19 access to the data. The NIHC computers have Ln 20 ethnicity, they have some component of certainly 21 socioeconomic status, or at least meeting poor, n 0 22 underprivileged, however one wants to talk about 23 lack of sufficient funds for daily living, has 24 ethnic data, it has location so that you can 13:40:30 25 segregate rural versus urban individuals with 145 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 deposited into the WIC program; I'm not that naive. 13:51:00 2 But it's very interesting just thinking 3 about the politics of the circumstance, and I 4 realize this will never get to trial or anything, 5 nor do I want it to be. But it's just interesting 6 thinking about some of these issues which takes 7 us -- just the pure medical or the pure legal 8 aspects. And that's why I -- life is an interesting 9 affair . 10 Q. And do you -- 13:51:30 11 A. And I -- if you want to make it 12 nonresponsive, that's okay with me. 13 Q. Well, we know it was, so -- you know. 14 If you give me a minute or two, I may be 15 finished . 16 MR. GIBLIN: Can we take a break? 17 MS. COLSON: Sure. 18 THE WITNESS: Sounds good. 19 (A recess was taken.) 20 MR. GIBLIN: No further questions. 21 MS. COLSON: We reserve our questions. 13:52:00 13 53 59 : : 22 (The deposition concluded at 1:55 p.m.) 13:54:00 23 24 Ln ~ ~ 25 ~ m ~ 154 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 private patients and at the Harris County Hospital 2 District, Hispanic patients are much less likely to 3 smoke. Our population of Hispanic patients within 4 the total Medicaid population, I think from a 5 quantitative basis, is far greater than that of 13:43:30 6 Florida. Therefore, if you try to abstract the 7 white, black, Hispanic and then you take the total 8 Medicaid population of Texas, take those same 9 statistics and say, Gee whiz, whatever the numbers 10 are of Florida equals that of Texas, I don't think 11 that that can be done legitimately. I think there 12 would be substantially differences. 13 Q. Uh-huh. 14 A. The way to find out is at least go into 15 the databases that you have and then you can 16 quantitate. Even if you assume that all other 13:44:00 17 Florida data is valid, then you have specific ethnic 18 populations, and the demographics of those ~ ~ 19 populations. Then to be able to say, Gee whiz, this ~ ~ m 20 is the same or it's not the same. If it's the same, ~ N 21 fine. You use the same statistics, the same co 22 calculations, if you will, for recovery of damage. 23 But if it's not -- and my bias is -- this is bias 13:44:30 24 and not science -- that you'll find that Texas has a 25 far greater Hispanic, and therefore your damages, 148 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

1 a significant factor in increasing medical costs for 2 the mother, fetus, or neonate in the Texas Medicaid 3 population." What is -- what's that statement based 4 on? 5 A. Oh, the reality is I cannot technically 6 make that statement, because unless you have data as 7 I just discussed and what I have requested, even 13:48:30 8 using attributable risk, I don't know what those 9 attributable risk percentiles -- percentages might 10 be. It is -- antenatal smoking is a risk factor in 11 pregnancy. How it would come out in the Texas 12 population, I do not know. 13 Q. Okay. Going back to the first sentence. 14 You've got, "Antenatal smoking should not be 15 considered a major risk factor, pregnancy 13:49:00 16 complications and adverse pregnancy outcomes." 17 A. Well, I can't -- I can't agree with that. 18 We've talked about that, and antenatal smoking is a ~ 19 risk factor. I would delete the word "major," ~ ~ ~ 20 because major depends upon populations and other m ~ 21 factors. It is a risk factor. The word "major" N w N 22 should not be there, the word "not" should be there 23 -- should be deleted. 24 Q. So it should read, Antenatal smoking 13:49:30 25 should be considered -- 152 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

IN THE UNITED STATES DISTRICT COURT EASTERN DISTRICT OF TEXAS TEXARKANA DIVISION THE STATE OF TEXAS, Plaintiff, vs. No. 5:96CV91 THE AMERICAN TOBACCO COMPANY, et al., Defendants. Exhibits to the deposition of: ROBERT CARPENTER Taken on July 24, 1997 Volume 1 of 4 Bp Ln ~ ccxy ~ ~ m J N CJ7 Ln

1 there. Let's see. 2 A. Oh. There's one question I noticed -- or 13:47:00 3 one question you should ask, and I noticed it on 4 page 5 when I was going through this. Antenatal 5 smoking should not be considered a risk factor for 6 preterm delivery. We've talked about that this 7 morning, that it is, and I was thinking totally 8 along different lines when that -- I did not catch 9 that as a specific circumstance to change that. It 10 is a risk factor. When I was seeing that and 11 remembering -- or not remembering, when I was seeing 13:47:30 12 that and thinking about it acutely last week I was 13 thinking the issue again causation that we were 14 talking about, so and to clear that one point. 15 Because that's the only thing in going through this 16 after I have my copy that I saw that that's not Ln 17 quite precise. 18 Q. Okay. 19 A. That's on the top of page 5. 20 Q. Going to page 6, Doctor. 21 A. Okay. 13:48:00 22 Q. Under the last heading, Maternal Smoking 23 During Pregnancy and Pregnancy Complications. You 24 state in your second sentence there on the first 25 paragraph, "Maternal smoking during pregnancy is not 151 KEITH & MILLER CERTIFIED REPORTERS EL PASO, TEXAS 79901 (915) 533-7108

z HX3~ 11 8 1 81HX3 t io' 1 stosco

LIST OF CAS S SINCE 1994 IN 'WHICH EXPERT H&S TESTYFTED BY pEPOSTi'YON OR AT TRIAL Cause No. 93-02486 Johnson v. Mahafl'ey Deposition testimony 1995. Cause No. 94-7637A Rodriguez v. Brown Deposition testimony 1995. Cause No. 94-027947 Rooker v. DeBakey Deposition testimony 1995. Cause No. A-148,498 Henry v. St. Elizabeth Hospital Deposition testimony 1996. Cause No. 94-018771 Salazar v. HCHD Deposition testimony 1996. Cause No. 942-01032 Bunch v. Perinatal Services Deposition testimony 1996. Cause No. 94-32084 Mendoza v. McDonald Deposition testimony 1996. 0029203.01 5

LIST OF CAS1F'S SINCE 1994 IN WRIS`H MERT HAS TFS, IF D BY DF OSTITOr] OR AT TRIAL Robert James Curpenter, Jr., M.D. Cause No. 95-002597 Brian vs. Ortho Pharmaceutical, ct al. Deposition testimony 1996. Cause No. 94-01032 St. Louis Co. Circuit Court St. Louis Missouri Bunch v. Healthdyne Deposition and trial testimony 1996. Cause No. C-4360-91-F 332nd Judicial District Hidalgo County Cadena v. Methodist Deposition testimony 1995. Cause No. 236-158199-95 236th Tarrant County Corbell v. Huguley Medical Center Deposition testimony 1996. Cause No. 91-18066 Duru vs. Hermann Hospital Trial Testimony 1994. Cause No. 91-234 Smith vs. Mid-Century Deposition testimony 1995. Cause No. 94-002418 11th Judicial District Friday v. Hewlett Packard Trial testimony 1996; Deposition testimony 1995. Cause No. 91-59397 Gill v. Wilbourn Deposition testimony 1994. ~ 002920J.01 ~ EXHIBIT -3

LIST OF CASES SINCE 1994 IN WHICH EXPERT HAS TESTIFIED BY DEPOSITION OR AT TRIAL Cause No. A-144948 Tompkins vs. Willows Apt. Deposition testimony 1996. Cause No. 92-31965 Zumwalt v. HCHI) Deposition and trial testimony 1996. Cause No. 94-33161 Carpenter v. Abbott Laboratories Deposition testimony 1997. Cause No. 89-CV-0508 Rogers and Parker v. UTMB Deposition and trial testmony 1997. Cause No. 91-M1669 McDowell v. Cox, et al Trial testimony 1995. Cause No. 96-989 Landry v. Clement Trial testimony 1996. Cause No. 94-CI-01170 Laborde v. Thompson Deposition testimony 1997. 0029203.01 6 TOTAL P.44

L T Cause No. CI-92-5308 DeBakey v. Lucerne Deposition testimony 1994. 1C(" M L!. :f[o1:/Wq;k:l; BY DEPOSTTtON OR AT Z$IAL Cause No. 40-071-361 361 st Judicial District Brazos County Ronnie Lee and Mary Williams v. Charles Anderson, M.D. Trial testimony 1995; Deposition testimony 1995. Cause No. C 2935-94-F Hidalgo County Lucia and Carlos Mendoza v. Hugo Zapata, M.D. Trial testimony 1995. Cause No. 92-08809-M 289th JD Dallas County, Texas Tavarez v. Hewlett Packard Co. Deposition testimony 1994. Cause No. 93-09-3549-C England v. Valley Reg Mod Cntr Deposition testimony 1995. Cause No. 94-3453-4 Lay v. Scott & White Deposition testimony 1995. Cause No. 93-09-3549-C England v. Brownville Deposition testimony 1995. Cause No. 93M1478 Templeton v. Olivarez Deposition testimony 1995. Cause No. 94-1960 Prater v. Kudla Deposition and trial testimony 1995. oMszn;.o i 4 3ZU 141131 _1,

Maternal smoking during pregnancy has not been associated with local infection or chorioamnionitis, the most commonly identified cause of PROM. Also, maternal smoking during pregnancy, has little, if any, effect on the duration of gestation so that it should not be considered a risk factor for prematurity, one of the most significant complications of PROM. Placental Changes Gross observation of the placenta after birth can suggest several medical conditions that can have an adverse impact on a pregnancy or its outcome. Chronic conditions such as hypertension and severe diabetes, that can result in marked reduction of oxygen and nutrient supply to the developing fetus, may result in a small placenta relative to the size of the fetus. Examination of the placenta may reveal other pathological signs suggesting reduced blood flow to the fetus, such as placental infarcts or partial, silent abruption. Histological examination of the placenta can also suggest abnormalities that increase the risk of pregnancy complications. For example, maternal hypertension and diabetes can cause characteristic histopathological changes associated with reduced placental size. Additionally, the presence of an acute inflammatory response in placental tissue suggests infection which can adversely affect placental blood flow and/or increase the risk of chorioamnionitis and neurologic disability. Maternal smoking during pregnancy is not associated with a remarkable change in placental size or with gross abnormalities. Antenatal smoking also is not associated with significant histopathology which would suggest reduced nutrient or blood supply to the fetus. Fetal Pregnancy Complications Low Birth Weight A low birth weight (LBW) baby is less than 2,500 grams in weight. Most LBW babies are premature, being born at or before 37 weeks of gestation. Other LBW infants are born at or near term, but are small-for-gestational-age (SGA) because of intrauterine growth restriction. Low birth weight alone, unless severe, will not determine whether a neonate will require special neonatal care and incur additional medical costs. Prematurity Preterm delivery occurs at a rate of 7-12% in different populations. In this premature cohort, up to 40% of these births occur with no known risk factors. Known risk factors for prematurity include a history of premature delivery, socioeconomic status, PROM, infection, multiple gestations, oo3o721.o1 Page 4 Ln r ~ r m v N (TI l0

Robert J. Carpenter, Jr., M.D. Obstetriciare-GynecologW Maternal-Fetal Medicine Specialist Summary of Expert Opinions for Texas Attorney General Case Risk Factors for Pregnancy Complications and Adverse Pregnancy Outcomes Maternal smoking during pregnancy is reported to be associated with several adverse pregnancy outcomes for the mother and the fetus or neonate. The maternal conditions related to smoking are alleged to include an increased incidence of spontaneous abortion, placental changes, antepartum hemorrhage due to placenta previa and abruptio placenta, and premature rupture of membranes. The fetal and neonatal conditions related to smoking are alleged to include reduced or low birth weight due to prematurity and intrauterine growth restriction, as well as adverse outcomes related to fetal hypoxia. These conditions alleged to be associated with maternal smoking during pregnancy are also alleged to result in increased maternal and neonatal medical care costs for the Medicaid population in Texas. However, these pregnancy complications and adverse outcomes are known to have multiple risk factors for their occurrence, and risk factors for each mother and each fetus or neonate are unique. Also, the medical care for each mother and each fetus or neonate is determined on an individual basis after evaluation of the pregnancy history and the medical conditions present. During the course of prenatal care, high risk pregnancies are often identified. Early identification of high risk pregnancies facilitates prompt medical intervention before and after birth and reduces risks for the mother and the fetus or neonate. Among the more common risk factors for pregnancy complications and adverse outcomes are a poor reproductive history, restricted fetal growth, many maternal medical problems, and various placental problems. In addition to the known risk factors for adverse pregnancy outcomes, there are also many unknown risk factors, so that prenatal care is important for early detection of unanticipated maternal and fetal complications. The majority of newborns requiring immediate and intensive medical care are premature infants who may have many medical problems. Other infants requiring an increased level of perinatal care include a variety of other conditions, such as being small or large for gestational age, or having infections, congenital abnormalities, or sequelae from chronic or acute hypoxia. Risk Factors for Pregnant Women on Medicaid Due to their socioeconomic status, Medicaid recipients are often at increased risk for pregnancy complications and adverse outcomes. Common and important risk factors in this population include inadequate prenatal care, young maternal age, low maternal weight, obesity, poor oo;on:.o 1 Page I EXHIBIT ~ ~

BSA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-24-9Qook•Sec(a3) 90:3 boards (2] calculations (21 35:13; 4711; 51:16; 53:13, !S; behalf (1] 38:10,- 41:16 134.•10,• 148:22 84:7,• 85:4, 14, 22; 86:3. 7,• 87:1, 29:5 behavior (3) book [20] 14:13, 20, 21; 13:3, 6; 39:9; calculus [l] 134:21 5,10;110:21;151:13 causative (s] 58:3, 18; 112:23 42:4, 17; 67:23; 75:6, 24; 76:6, call 191 50:12; 84:14; 85:6; 90:1, 23 vi B h l 1 14 77 16 115 2 6 129 3 3 25 14:22 8 39 9 7 11 18 d 6 ora [ ) e a S7.•2S ; : ; : , ; : ; 138:8; 139:3; 140:23 ; ; ; ; ; : : : : 43:21; 53:1; 88:24; 112:18 cause [ ) 31:9; 50:21; 52:7, 14; 53:17; behavioral(3) book's (1) calling[1) 112:1 57:23; 58:2, 12 77:1 91:20 cavity Il) behaviors [I) booklets [ 11 Canadian (1) 47:5 8S.•19 63:16 121:16 CBS II) beGef [1) books M cancer (13) 49:21 S0.•8 12:11;19:21;42:3,16.19; 46:8,9,11,13,16,25;47:2,3, CDC (lo) believe (29) 63:16; 124:11 S: 49:14; 50:13; 103:10; 104:18 106:17, 19; 107:10, 21; 108:18; 8:16; 9:5; 13:8; 15:22, 25; 17:4; 20 4 21 25 30 12 32 7 34 12 bookstore ( l ) 39 8 cancers [1] 50 2 109:9, 10, 13; 110:3; 128:16 C ; ; : : : ; ; : ; : : : 1 enter (9) 49:3; 51:9; 54:3; 67:2; 86:6; born (1) capabilities (1] 2:15; 14:24; 106:18, 22; 107:12; 93:15; 94•19, 20, 21; 98:6: 93: 6 149.•20 109:11; 128:19; 157:8; 159:8 106:24: 111:22; 124:13; 126:4; bound [3] capability (1) CEO (2) 135:11; 136:7; 149:4; 150:15 belongs [1) 114:16; 116:9; Box 11] 117:11 104:1 capacity (1) 49:12, 25 cerebral(1) 136:12 bench I11 2:4 brain (2) 59:4 carbon (l) 98:17 Certificate (1) 19:13 38:25; 104:21 35:3 156:18 Benjamin (t) branch (l] carboxybeologlobin (2) certificate (S) 127:25 107:3 97:15; 98:1 123:15; 130:17; 143:6, 16: Berman (1) brancbes (1) carcinogens (1) 146:4, 8, 13; 149.22 40.• 19 107:7 104:21 certificates (5] besidcs Itl break (7) cardiovascular[1) 123.•18; 130:13, 14, 1S; 146:15 93:12 S:1S; 11:12; 4S:2S; 65:11; 93:19; 39:2 CERTIFICATION (2) Beth (1) 113:1; 154:16 cards (31 3:25; 156:1 15:25 breakdown 121 8:23; 24:16; 137:4 CERTIFIED [:) bias (3) 17.21; 130:12 Care(t) 157:1: 159:1 103:25; 148:23 brew (2) 129:4 Certified (3) bigger ( I ) 103:21; 104:5 care (t4] 1:16, 24; 159:23 77.•3 brief [1) 40:2, 8. 11; 63:18; 70:12, 13; certified (3) billing I 1) 49:21 79:18, 21; 80:4; 86.•23; 141:7,• 39:19; 59:18; 61:21 146:10 briefly [3) 142.•24; 143:24 certify (t] biochemist ( t] 69:11; l11:2; 113:5 career (2] 156:4 8: 7 Bristol [1) 12.•11; 18:24 Cesarean [1) biological I t) 97:8 Careful 131 63:3 82:11 British (3) 91:19; 120:13, 17 Cessation (t) Biostatictics (11 95: 7 8 Carol (t( 115:6 37:19 broke [1] 24:15 cessation (1) biostatistics ( 11 11:17 CARPENTER (s] 93:16 37:24 broken (1) 1:11; 3:3; 4:1; 155:14, 19; cetera [7)] Birth (31 132:24 157:14; 158:6; 139:14 19:12. 15; 58:1; 112:19; 144:1 15:1: 82:25: 119:20 Brown (1) Carpenter (3) chances ( I1 birth [;1) 66: 9 3:9; 4:7 5:8 139:16 33:4, 19: 34:6: 40:5; S4:1S: 83:3; Bruce (1] Case 111 CH&NGE (1] 88: 8: 9S :19. 23; 96: 4 18: 99: 2: 119: S 3:8 1SS: 2 105: 6: 123:1 S. 18; 126:19. Bryan (2) case 1391 change (71 130:13. 15, 16: 132:1, 9, 20: 2: S; 4:17 6:3, 25; 7:4, 11; 11:22, 24; 13:9; 4:11; 64:19, 25: 97:21, 22: 138:12, 2 2: 139:16: 145.6. 16: Building (21 15:17,- 16:24; 17:3, 10, 12; 27:2; 113:8; 151:9 1-96:4, 8, 13: 149:22 157:2; 159:2 29:8. 10; 30:3, 13, 21; 32:19; chauged (6) bit (6) building (!] 42.•23; 43:20; 44:5, 9, 13, 15; 28:23; 32:3; 106:23; 112:23; 27 37 17:16 19 4 21 13 13 35 9 9 13 87 10 53 15 8 116:21 118 114:18 122 1 : : : : : : , . : 52:22 : Bulletin ( I 1 ] , : ; : ; ; : : 123:2; 126:I3: 133:4; 136:25; ; : changes (15) black (7I 3:19; 31:15; 32:17; SS:17,• 39:8, 137:24; 145:8; 153:25; 158:6 28:11,14,16:67:8,9;71:15: 9S.• 2 2: 96: 3: 132.2. 7, 9, 23: 10; 68:14; 80:14; 94:2, 10; Cases (1] 100:23: 101:1. 4. 9, 16: 150:22; 148:7 Blacks ( t ) 136:15 bulletin (t91 3:11 cases 181 139:17 chapter ls) 96:8 32:6; 61:9, 10; 64:20; 65:16; 6:12: 9:14, 23, 24; 12:22: 17:18; /S:S; 102:14; 115:6; 117:11; bladder ( t ) 66:12, 17,• 67.•1, 7,• 68:2, 15, 22, 29:6; 86:19 123:24 46:16 24; 69:4; 78:24; 80:14; 83:1; casual I1I chaptcrs (1] hlah [31 93:16; 119:17 139:21 77: 7 14-r:10. 11 Bulletins [21 catch (21 characteristics (11 bktids(t) 66:14; 68:1 11:14; 131:8 97:22 ~ 82.21 bulletins (9) categories [ I I eharge [3] BLEVINS (2I 16.•7,• 61:3; 62:1, 8, 15; 64:3; 51:5 I6:20, 24, 25 ~ 4:13: 77:6 63:6. 21; 67:18 categorize I I ) Charles I1) Blel uts 121 bunch [41 10:15 97:6 m 2:5: 4: l7 12:15; 104:14; 121:4; 145:12 Caucasian [s] Charlotte's [1) J blood 131 burden [1) 92:3; 9S.•18; 96:5; 132:2, 6 97: 7 h) 972, 10: 1104 54: 2 causal(lo] checked ( t ) W blue 14) Bush [11 33:5, 7; 74:25; 83:4, 10, 17, 22; 126: 2 29:19; 118:12: 136:12, 25 106:24 88:8, 14 chemical (2] board (51 business (1] CeUSality 131 33:24: 35: 2 39:19: 39: I x, 20: 61: 21; 111: 6 137: 4 27:9, 13; 31:21 child 121 boarded (2) 39:25: 60:; - C - causation (22] 27:9, 13; 32:4; 34:13, 14, 16; 93:6; 105:3 Children [3] KEITH fi 117ILLER (925) 533-7108 From behalf to Children

fetal or uterine anomalies, hypertension or diabetes. Antenatal smoking should not be considered a risk factor for premature delivery. SGA / TUGR Major risk factors for SGA / IUGR are genetic predisposition, many maternal diseases, marked maternal malnutrition, placental conditions, fetal abnormalities, multiple gestations, and infection. SGA babies commonly reflect a chronic reduction of oxygen and nutrient delivery to the fetus. Neonates with clinically significant growth restriction have an increased risk of hypoxia and other acute complications both prior to and following birth. However, SGA infants have a lower incidence of respiratory distress syndrome unless they are very premature. Common pregnancy complications, such as pregnancy-induced hypertension or eclampsia, can result in clinically significant IUGR. Occasionally, there is no identified etiology for severe IUGR. Maternal smoking during pregnancy is rarely, if ever, the only identifiable risk factor for severe IUGR and clinically significant LBW. If antenatal smoking is the only known risk factor for a LBW baby, the reduction in birth weight is typically mild. In contrast to the above risk factors for severe IUGR, maternal smoking during pregnancy is associated with mild decrease in birth weight. Reports in the medical literature suggest that babies are generally about 200 grams smaller at birth if the mother smokes during her pregnancy. However, this mild level of growth restriction associated with antenatal smoking usually is not clinically significant, and some infants bom to smoking mothers do not have any deficit in weight accretions. Also, the literature reports linking maternal smoking with decreased birth weight may have certain weaknesses shared by many epidemiological studies, so that other risk factors for mild growth restriction may confound the results. Respiratory Distress Syndrome Respiratory distress syndrome (RDS) occurs commonly in very premature infants and requires intensive neonatal care. Infants who have intrauterine stress, such as JUGR, are less likely to develop RDS. Neonates who are born to smoking mothers and have mild IUGR tend to have a lower incidence of RDS and associated neonatal care. Maternal Smoking and Fetal Hypoxia Maternal smoking during pregnancy is alleged to result in fetal hypoxia due the effects of carbon monoxide (i.e., carboxyhemoglobin) and/or nicotine (i.e., vasoconstriction and reduced uteroplacental blood flow). However, several lines of evidence suggest that fetal hypoxia associated with maternal smoking may have little or no role in the mild weight decrease reported in the literature. The small differences in maternal oxygen saturation associated with smoking are not clinically significant, and there is little effect of maternal smoking on uteroplacental blood flow to the fetus. Also, the mild reduction in uteroplacental blood flow after smoking is not continuous oo3ona.o1 Page 5

diet, abuse of alcohol or illicit drugs, lack of maternal education, unmarried status, short interval between pregnancies, multiple partners, and infections. Often important maternal medical conditions, occuning before or after the start of pregnancy, go undiagnosed or untreated because of lack of prenatal care. These conditions include anemia, hypertension, toxemia, or diabetes. Also, without prenatal care, pregnant patients are not advised about the signs of premature labor or infection and are not counseled about diet, exercise, alcohol, drugs, or smoking. Medicaid mothers who smoke during their pregnancy may tend to be less health conscious. As a result, they may have many significant risk factors for pregnancy complications and adverse outcomes. A cluster of risk factors makes it difficult, if not impossible, to determine what contribution, if any, a specific risk factor may have in the pregnancy of a woman on Medicaid. Demographics of Pregnant Women on Medicaid in Texas Dr. Carpenter may comment on the demographics of pregnant Medicaid recipients in Texas. Texas-specific demographic data may be derived from cross-linking Texas birth certificate data with both the National Heritage Insurance Computer database and Texas death certificate data, in the event these data become available. Maternal Pregnancy Complications Spontaneous Abortion Spontaneous abortion, or miscarriage, is common and occurs in about 15-20% of pregnancies. The vast majority of spontaneous abortions occur within the first 20 weeks of gestation when the fetus is less than 500 grams. The majority of these fetuses have chromosomal abnormalities. The other spontaneous abortions that have no chromosomal abnormalities have a number ef risk factors for their occurrence, including increasing maternal age, chronic infections, chronic diseases such as hypertension and diabetes, materrial malnutrition, jendocrine abnormalities, as well as excessive exposures to alcohol, coffee, and various drugs. Unless a chromosomal analysis is completed on a spontaneously aborted fetus, the identification of a chromosomal abnormality may not be possible. Even if a chromosomal analysis is performed, the etiology of the spontaneous abortion may be difficult to identify considering the multiplicity of risk factors. Unless a large number of spontaneously aborted fetuses have a complete chromosomal analysis in the context of a well-controlled investigation, the role of maternal smoking during pregnancy, if any, on spontaneous abortion cannot be determined. Antepartum Hemorrhage (Placenta Previa and Abruptio Placenta) Two significant causes of antepartum hemorrhage are placenta previa and abruptio placenta. However, these pregnancy complications are relatively uncommon, with placenta previa occurring in less than 1% of pregnancies and abruptio placenta occurring in 1-2% of pregnancies. There are 003o•n3.01 Page 2

ASA TEXAS v. THE AIVIERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-2A-%ok•See(s8) funds (21 94:21; 110:7 71:16 H ospit al (5) 145:23; 153:24 grammar (a1 h eadquartered (1) 70.•IS ; 97:7; 128:10, 11; 148:1 furnished [ 11 28:19; 104.•1, 2, 4 106:25 h ospita l (3) 130:6 granted 111 H ealth 1171 18:10 , 13; 146:9 Future [5] 63: 6 116:13, 20,• 117:11; 119:18; h ospita ls (21 14:17 24 3:22 138:10 140:23 r 3 h 13 J6 128 8 121 12 15 17 21 1S 25 18 10 , ; ; ; future [I) g ) ap [ 89:2, 3, 6 , ; : , : , , , 25; J29:7, 11, 13, 15; J30:S h : ost [3) ; : 56:8 grasp [1] h ealth (8) 20:14 ; 102:1; 128:14 . 19:6 18:16; 67:3; 69:5; 108:13; b our (S ) -G- gravidas [1) 122:2J, 22; l28:14; 149:21 11:11 : 16:17, 18; J 7.•2; 23:19 79:4 H ealthy (1) h ours 1 7) Gabbe [l) great I1) 129:12 17:12, 14; 23:2, 3, 9, 23; 138:19 42:6 66 •10 b 2 H gain (11 . greater (9) ear ( 1 27.•18: 94:20 ousto J:14,• n [4] 2:12; 43:13; 49:4 99:17 79:8; 90:2; 93:13; 100:20, 22: b eard 13) b ub (1) gastric (3] 109.•16; 148:5, 25; 149.•4 43:6; 49:24; 104:16 115:1 0 48:14, 22 green (1) h eart (5) H uman f I1 gather (1] 7S:S 47:9, 13, 17; 79:25 128: I S 16:3 ground [1) h eavy (1 ] h uman ( I ) gathered (1) 108:10 147.'19 35:4 12:10 Group (1) h elp 121 h ungry I11 gave 161 90:14 8:8; 114:11 S8a 6:17; 18:3; 26:22; 67:20; 94:2; group (71 h elps Il) H urt (l ) 114:12 53:8; 68:2, S; 107:13; 109:13; 87:13 128:2 3 Gee 121 133:15; 153:17 b entatoc rits (1 1 h urt (l) 148:9, 19 groups (1) 98:10 149:1 5 General's [lo) 90 15 h l 3 bi h i 91:7, 8, 10; 94:9; 95:13; 108:25; : growth (4) emog o 9fi18; n 1 1 98:8, 15 ypox c 101:3 (1) 109:7; 115:4; 116:1; 117:12 83:6; 98:16, 23; 141:20 h emorrh agic ( I) b ypo>oc -associated (1 I geuerate[1] guess (171 108:2 101:8 135:9 11:16; 37:2; 41:4; S1:S; 57:17; h ereby (2 ) h ystere ctomies (1) generated (1] 67: /8; 69:22; 71:16, 17; 72:25; 1SS:1S ; 156: 4 62:24 153:24 88:15; 106:2; 109:13; 113:11; h erein (1 ) h ystere ctomy (l) gentlemen (Il 117:13; 136:14; 144:6 133:17 41:14 43:16 gULLs [1] h ereto (1 ) Gerry (1) 149:14 136:12 -I- 124:1 G h b ' uttmac er (1] erpes 1 - 1 gestation 121 129:5 64:22; 66:7 I' d (9) 77:23; 146:15 GYN [2] H igh (1) 4:6; 41:3: 69:11; 102:16; 113:12, gestational [8] 66:15; 67:21 79••20 23; 129:22; 13S:S; 141:9 40:6; 54:16; 91:16, 20, 22; gynecologic (3) hi gh (8) I' ve (23) 93:25; 96:17; 99:18 60:18; 63:19, 23 38.•18; 79:21 ; 91:11, 12; 92:7,• 16:2; 18:5; 19:18; 36:20, 21, 24; gets 121 gynecologist (1) 95:11; 111:3 37:2; 44:1; 61:15; 65:2; 66:/9: 77:2; 85: 22 15:19 hi gh-pow ered ( 1) 69:7,• 76:10, /8; 92:9; l04:10,• GIBLI\ (13] Gynecologists [ I ] 134:22 106:7,• 114.•18; 11S:J7,• 130:11; 4:3• 24; 3:3: 45:24; 46:3; 93:19, 59:12 hi gher [5 ] 131:6; 133:3; 142:11 23; 102:9; 112:25; 113:4, 8; gynecology (5] 70:16; 78:7; 92:9; 94:5; 96:18 i.e . (2) 154:16, 20 41:4,7,8,11 hi ghest [3 ) 98:24; 108:1 Giblin 12] 91:5: 95:2. 12 la u (1) 2:5; 3:4 -H- hi ghlighting 11) 121:14 ive 1291 IB F l g 7:1. 9; 19:10; 20:7 21:7, 8; 22:6; half (41 hi 114:21 ghly (l) ( l 55:18 26:20; 38:16• 18; 39:3, 24; 11:11; 14:14; 130:16, 17 109:14 id ea (a) 42:1S; 46:19, 21: 48:12. 13: halfway (t] H ispattic [ 111 16:21; 20:25; 21:4; 104:22 57:4. 13. 18; 58:14: 64:17; 68:7; 70:3 92.•4; 132:2; 147:9, 14, 15, 16, id entific ation (21 73:9; 86:10; 94:17, 133:9; 133:8; hand (I] 22; 148:2, 3, 7, 25 107:18, 20 154:14 117:21 history (1) identified [1) Given Il] hangup [21 141:20 21:18 72•13 87:1, 7 hit (I1 identifier (1) tn giien 1141 happens (11 88:22 116:10 r J 5:9; 54:9; 56:2: 61:25; 65:9; 33: 9 HIV [3) identify (11 N 70:24; 71:23: 85:10; 103:10; hard (1] 20:17, 19; 110:5 113:24 m 121:5; 122:5; 150:17; 156:8 137:13 Hlavinka (8) identifying (11 Giving Ill Hardy (1) 4:20; 7:4, 10; 8:24; 9:11, 14; 112: 7 J 131: 2S 2: 7 24:12, 18 idiopathic (l) tV giving Il] Harris (4] holiday (1) 93:12 &b 1P 20: 23 9:24; 10:1; 70:14; 148.•1 9:6 illicit (21 glad 121 Harvard 121 home (5) 140: l; 143:1 9:8; 104:22 15:23, 24 9:3,7,9;22:9;138:16 illustrated (11 glued Ill hasn't [t) honest [21 139:24 117:13 85:13 23:/: 76:2 impact 161 God 131 haven't (81 honestly 12) 21:12; 29:1; 30:5; 98:4, 23; 27:23; 124:11: 142:16 41:1 S; S3: S; 83: 24; 85:6; 87:4; 45:2; 46:17 153:20 goes 131 99 25 119 12 128 6 124:8, 9; 150:14 H ' 3 hope (a) impacting (11 53 7 ; ; : : : e s 1 1 34:21; 94:18; 96:22; 135:21 : Gordon (1 ] 15:19; 43:5; 44:9 Hopefully 11) implantatioo (2] 40:24 head (5] 90:18 SS:22; 73:3 gottea ( I ] 21:3; 27:25; 48:22; 88:22; hopefully [II Implications (1) 85:13 121:24 64:/4 121:16 Government (1] head•utg (I) horse (3) imply (U 110:4 government 121 151:22 headline (I) 85:25; 87:13; 126:23 143:19 important (10) funds to imply (915) 533-7108 KEITH & MILLER

BSA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-24-9Qoot•See(a7) 41:17 example 171 exposed (a) 47:7; 121:22; 122.•S; 123:19 fe rtility (.) 59:2; 71:22 131:22; 132:21, 2S; 137:22; 143:8,13;147:1,7,11,22: 64:17,• 67:20; 99:12; 101:7,- exposure (a1 fe rtilization [2) 148:6, 10, 17,• 149:4 108:4; 110:3; 131:25 31:25; 35:2. 11 73:1, 3 Florida's It) examples [l1 exposures Il) f el>il (8) 132:13 36:11 58:16 43:2: 97:10,• 99:22; 100:5; noW I11 exceeds(1J extent (11 130:14; 138:24; 141:20; 146:15 97:2 20:19 60.•1 J F etus I11 focus 121 Excellence (11 76:15 38:22: 53:24 129: 9 -F- fe tus(111 fold (3) except(31 18: 21; 38:23; 39:2: S0: 23; 66: J: 94:3; 9S:2S; 132:19 36:21; 87:8; 155:16 f ace [l) 93:3; 98:1, 4,• 99:17,• 112:1: Folder (1) exception (1 ] 117••7 152:2 3:13 105 18 f ace-to-face (11 f f ld : excess (61 22:18 e tuses(5) 12:9; 70:6; 98:11, 21; 112:4 o er (31 29:19; 118:12; 137.•3 55:15; 56:13, 24; 74:9; 102:8; fa cilities (31 fe ver (21 Followiog (1) 134:16 10:4; 63:19, 23 108:2, S 107:19 Excuse ( ] 1 fa ct 1221 fi at [1] follows (l) 135:7 6.•18; 7:5; 11:23; 35:12: 39:8; 142:16 4:2 excuse(4] 57:3; 60:12; 62:13; 82.•9: 83:18; fi eld [21 Food [1] 58:24; 77:10; 81:6; 141:17 85:5; 90.•9; 97:14; 109:1; 112:2; 107:3, 21 99:6 executing (i) 115:3; 119:3; 138:22; 142:15; fi dds 111 food (6) 133 21 144:11; 145:2 3 134 22 8 18 S 14 100 112 99 3 12 : Exhibit 1371 fa , ctor154) fi : gure (6) ; , , ; : : : , foregoing (3) 5:2, 21; 6:/, 5, 9, 11, 15, 21; 27.•8; 31:23: 33:9, 12, 14: 34:7, 70:20; 71:3; 91:12; 95:11, 25; 1SS:1S; 156:3, 6 13:23; 17:19: 21:17 68:11, 13; 18, 23; 33:16: 36:11, 12; 47:21; 96: 7 Forget(31 102:10, 12; 115.•4, 21; 116:2; 48:25; 51:14, 15, 21, 24; 53:3, 6, fi gures [21 S8:S, 8 118.•3, 7. 18; 124:17, 18; 125:2, 11, 16; 56:8; 73:19; 74:15, 18, 70:23; 91:14 forgot [1) 11: 126:13; 127:10; 129:21: 21, 23; 81:14; 82:3. 13; 88:10. fil e (91 22:12 130:2, 3; 131:1, 18; 136:10, 23, 15; 89:1, 6; 90:1, 2; 99:8; 13:22: 31:20,• 136:7, 12; 137:2, format [2) 24; 140:21, 24 100:12, 13; 101:16; 103:15; 25; 138.•1, S; 1S7•17 68.•16, 20 exhibit (181 112:6: 142:2; 143:12, 14; 1S1:S, fJ ed (7) Forming (I I 4:15; S.•2, 21: 6:9, 15: 32:23; 10; 152:1. 10, 15, 19, 21: 153:2, 7••16, 17; 10:1, 2. 3; 16:24 3:10 68:11: 102: /0; 116:11; 117:10; 3 fil es (3) forming 111 126:7 129:23, 25; 130:2; 136:9, fa ctored [1] 136:24, 25: 141:6 6.'7 22; 140:21 90:12 fi nal (4) forms (3] EXHIBITS (11 F actors (11 66:24; 93:14; 107:25; 128:24 41:12; 50:12, 13 3: 6 128:18 fi nancially [2) formulate (11 E hibi fa ctors 1301 133 1 156 13 13 18 x ts (1) 116:1 27:11; 34:3, 17; 48:20; 33:1, 2, Fi :1 ; : nancing [ll 1: forth [13) exhibits (3] 4, 20; 56:25; 73:16; 78:10; 80:8; 129:4 15.9; 17.•1; 40:9; 53:11; 63:20: 12: 2 3, 25: 31:19; 119: 3, 16; 83:11; 84:7,• 85:14, 18; 87:6; fi nd (8) 95:10,• 101:5: J08:19; 124:19; 120:2: 121:1-?; 123:2 88:18; 98:25; 101:25; 102:1; 32:2; 83:20, 21; 104:7: 126:1; 125: 24: 134:11: 13 7: 9: 139:1 exist [ U 103:16: 134:9; 139:1; 141:18, 148:14, 24; 153:22 forum [11 146 14 24; 142:19 23; 152:21; 153:23 fi di 2 60 15 : , n ng [ 1 : eUs(s 1'1 fa culty 131 SS:17,• 101:8 found 1111 53: 21: 118: 2' 15:23, 24; 36:25 fi ndings (:1 17.•S: 24:25; 25:2; 31:13, 22; Expanding I11 fa ilure [13 102:3, 7 97.•13, 17, 20, 21; 98:3: 126:2 129.8 110:3 fi ne (e1 Foundation [tl expect 151 Fa ir (11 46:1; 53:6; 76:/3; 89:8; 117:3; 14:25 SS:14; 132:4: 1JS:20; 136:3; 64: 6 138:4,• 143:16; 148:?1 Four ( I I 149:12 fa ir [1] fin ished (3) 108:4 expected (±1 109:15 38:21; 69:10,• 154:13 four (11I 44:14: 4S: l; 58:20 fa milial I 11 fir ing [1) 22:11; 23:23; 6?:23; 64:24; expeaditures (11 58:15 149:14 63:17,• 89: 3: 9S: 21, 25; 108: 6; 20: 20 fa miliar [61 fir m (2J 137:19; 141:16 expeacLs, I 1 ] 15:10, 12; 43:7; 48:9; 72:21; 33:8; 122:15 fourth (tl 17:1 75:2 fir ms 121 42: 7 experience (7] fa mily (1] 8:12; 24:11 frame [l] 61: 25; 70:11, 19, 85:15; 98: 20: 85:19 Fi rst (31 121:23 102:20; 147:25 Fa rrar [6) 5:24,• 69:21; 92:14 freely (1) experiences (11 2:9; 24:14, 20: 157:22; 158:21; fir st (31) 136:4 70:10 159:22 6:24; 8:18, 19; 10.•6; 21:24; frequencies I l1 Expert 141 fa x (41 23:12; 28:7,• 31:13; 49:1 J, 16; 95:23 3:7, 11, l7 127:13 69:23; 80:24; 137:11. 13 90:24, 25; 99:24; 100:3; 102:12; frequency [21 expert 1'-^3I Fe bruary (21 114:3; 116:18; 118:14; 119:5: 78: 7; 94:/6 7:19• 24; 8:3; l7:?1: 18:25; 19:3. 128:25; 145.•4 127:11; 141:14, 15, 25; 142:4: frequently (61 9, 13; 29:4. 9: 37:8, 13, 16, 21, fe cundity 121 143:6, 9: 144:7; 145:2, 3: 24:19: 6/: 6: 65:12; 82:10; 22. 23; 39:17. 22; 41:2. 3, 21; 59:4; 71:22 151:24; 152:13 107:21; 111:15 44 20 4 56 Fe deral[l] F• 1 f : ; : i cca I11 ront (2) expertice (2I 1:12 128: 9 109:8; 137:23 66:6, 10 fe deral (2] fit [1] frontispiece (1) rn experts 1121 135:13, 14 82:J1 109:3 N 26:1; 42:23; 43:1, 19, 21, 22, 23. fe el [5] Fi ve (l] J Fulbright (l) 24; 44:7, 16: /27:18, 21 39:5; 40:16; 45:21; 104:3; 22:13 N 2:11 m expired I11 110:16 fi ve (7) Fulfilling Ill 63:5 fel loN•s [21 22:11; 24:10; 62:23; 64:25; 89:5; 88:1 v Expires (I1 36:22; 42:14 95:21; 108:6 tv full 131 156:19 fe male [a Fl orida (26J 34:13; 59:17. 22 W explored I 1] 71:21; 147:20 12:22; 13:9; 30:13; 116:6; 118:9, function [21 144:17 Fe rtility [21 19; 122:19, 20, 22; 123:2, 8, 13; 107:11; 150:4 71:17 KEITH & MILLER 1915) 533-'7108 From example to function

BSA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. O7-2A-9Qook•See(49) 34:4; 99:4, 6; 100: 8; 103:13; information (64) 20:9 36:15; 69:4; 129:2; J37:10, 11, 110.•1; 114:1; 142: 23; 145:11; 12:6, 7; 13:5; 22:14; 44:23; invited [1) 14 147:6 57:10; 60:25; 61:2, 3. 14, 16; 66:10 junior (1) intportanuy It] 63:1, 9, 11, 13, 15; 64:6, 9, 12, involved 151 59:21 146: 6 13, 16; 67:6; 70:25; 88:12; 11:22; 17:10; 57:21; 70: J3; jurisdictions [1) impossible (1) 89:21; 95:3; 103:4; 115:22; 98••2S 146:20 35:12 120:7,• 121:7. 8, 22; 123:9, 23; involvement 131 jury I11 impression (21 126:3; 128:2, S; 130:25: 131:3, 1S:J7,• 60:16, 18 8:14 21:4; 31:7 S, 8. IS, 17, 2 2; 133:3; J37:9; involving [21 improve 131 18 12 4 100 108 139:12; 144:22. 24; 146 13 16 5 7 18 145:1 147 • 0, 11, 1 35:10; 41:12 -K- : ; ; : :13 , ; : , , : . ; IQs (1) improvement (11 149:16, 17, 18, 19, 23, 25 57.•17 Kaicer [3) 99: 23 infrequent ()] isolated (I] 157.•22; 158:21; 159:22 in-depth (1) 80:6 34:23 Kansas [21 11:1 infrequently (1] Israel [I) 2:8, 9 inadequate (t] 65:13 15:25 karyotyped (1) 142:24 ingesting I ll issue [351 73:21 incidence (10] 112:15 8:9; 33:2; 34.•4, 10; 58:7; 73:1; karyotypes (11 70:16; 73:4; 79:8; 93:24; 95:19; initial [ 11 74:2, 17; 80:12; 83:13; 85:13; 74:9 96:18; 105.•6; 132:1, 8. 20 7:23 86:25; 87:1, 5, 12; 90:6, 7, 10, keep 141 include (3] initially [21 16; 98: 7, 25; 99:2, 3; 110:2, 17; 28:13;1I3:14;J14:2;141:S 125:16; 128:8; 142:23 5:25; 144:18 111:25; 115:12; 119:18; 120:21; KEITH [31 included 161 initialS (3) 123:22; 126:16; 133:5; 145:5: I37:1; 139:1 32:23, 118:3; /26:6; l28:20; 106:21, 22, 24 149:23; 151:13 Keith (1) 141: 23; 144• 2 injurious [2) Issues (11 158:3 indudes I11 8••1S; 80:7 27:4 kept [31 122: 20 in9Wry It] issues 1211 79: J2; 112: 9; l2S: 7 increace191 53:24 8••9; 10:10; 11:?; 18 :12, 17,• 19:7, kidney 11 55.•21; 80.•10; 91:3; 94:3; 97:17, ins (1] 8; 20:12, 17,• 27:1. 5; 33:17; 38:24 20; 10tf:9; 132:8. 20 66:20 60:24; 73:15; 91:25; 100.1; killed (21 increased I101 inside (1) 103:9; 128:14; 130:19, 21; 154.•6 J08:8, 11 33:18; 55:10; 71:25: 73:14; 79:2: 13725 it'0 (1) kills (1) 82:17; 93:3. 5; 97.•14; 105:6 instantaneously (1) 94.•18 20:13 increaux (2) 88: 23 ivory [I) Kline (1I 78:17; 105:10 Institute I11 37:1 73:20 increasing Isl 129:5 knowing (11 33:24. 25; 74:19: 99:16; 152:1 institution (I) -J- 10.•20 i d d 8 97 e I1) Knowled n epen entItl 78:9 : intact (I] Jacl; I11 g 1298 indexed I 1 ] 141: 6 43:13 knowledge (6) 36: 6 intake 151 JA1fES (il 12:7,• 24.•7, 24; 85:9; 127.•2S; Indian (11 99••3, 5, 6, 14: 100:8 4:1 140:4 92:5 intellect Itl James (^l knowledgeable (51 indicate 111 134:5 5:8; 119:6 41:19; 45:7, 8; 57.•4, 14 109:3 interest (1) January (6) Kramer[1) indicated (31 38.•23 7:2, 6; 8:19; 21:25; 23: 6; 145:4 119:19 82:7; 9-t:5. 7 interested 131 Jaworslci ( I 1 indicates ( I I 54.•1; 117:16; 156:13 2:11 -L- 6:6 interesting ( t .; 1 Jeanc (3) Indicators 121 50:2; 75:21; 83:21, 22; 85:8; 3:16; 118:8; 137:17 L.L.P. (21 129:13, 15 99:20; 123:11; 153:9, 16; 154:2, Jennifer ( I ) 2:3, 8 individual 1131 5,8 42••6 label (1) 10:2. 21: 21:13 : 34:5: 48,19. intermittent I I] Jerry 111 118: 7 5 2: 24: 53: 7: 63 : 4; 64:1?: 72. 21; 10:22 2:18 labeled (7) 85:16, 122:24: 153:17 intermittently It] Job (3) 69:23; 119:4; 122:17; 127:10, individuals I151 63:2 157.•24; 158:19; 159:24 13; 128:13; 129:8 47:16, 25; 59:17. 18, 19; 65:24; internal 141 job (31 labeling (11 83:14; 85:2: 91:24, 100 7: 101:2. 50:19, 23; 51: l; 101:4 61:1, 5; 120:23 69:15 9, 10. 145:25: 146:4 interrupt I11 Joe (1) labor [21 industry 1=1 38:20 42: 6 10:10,• 93:13 22:21; 25:6 interrupted [t] John [1) laboratory (2) Infant131 135: 20 128:22 34:24; 35:4 116:13, 20: 117•11 interval [1) joint (31 lack 121 i f 143 2 63:25; 67:20 22 143:1: 145:23 n ant 141 56:16; 105:3• 8, /39:17 : interveue(tl , Jonas (11 ladies (11 Infants I11 110:4 119:6 93:17 129:2 intestinal I t ] Jones (31 lady 11) infants I 11 20:12 Z•14; IS7:7,• 159:7 24:25 Ln 91:3 intonation [11 Journal 121 lag [1] ~ infection I11 110:8 119:7,• 121:16 61: 6 ~ 6x: 2 intrauterine I I1 journal (2) laparoscope (11 t-A infections 141 83: 6 14:22; 19:21 41:12 ~ 48:5: 90: 7; 143:3 intravenous (tl journals ( t ) laparoscopy (I) ~ infertilit)'II( 123:19 12:10 41:11 N 72:1 intrinsic (1] JR (8) Large U1 ~ influenced I11 78: 20 1:11; 3:3; 4:1; 155:14, 19; 72:10 cn 105:.3 introduction (t] 157:14; 158:6; 159:14 large [1) influenza I,I 77: 6 Jr III 19:18 48.5 investigate 12) 5••8 larger [4] inform [ 1 I 107:23: 108:12 July (S) 53:8: 82:8; 100:21 79:11 investigators (I) 1:13; 23:7, 13, 15; 28:8 Larry [t1 June (91 66:8 KEJTN d• MILLER (915) 533-7108 From importantly to Larry

BsA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-249D6ot•s«csu mental l1l 57:7 2: 7 mortality (4) 39:23 neonatology [4) n oticed 13) 4:10; 151:2, 3 mentioned [141 81:9; 103:2, 12; 105:8 40:13, 16; 45:12; 56:21 n otification (11 14:9; 18:2; 23:10; 29:12; 59:9; mother [2) nervosa (1) 4:11 67:10,• 74:1; 75:24; 78:14; 102:6; 31:8; 152:2 112:19 n otified (11 105:23; 127:17; 138:8, 23 Motley (1) Ness 111 159:17 merits (11 122:15 122:15 N ovember (1) 153:10 M l mouth [1] 20 103 neurologist [I) 118:14 eta-ana yses 111 : 43:5 n owhere (i) 120:6 move (1) neurology (3) 90:22 Meta-analysis [ 1) 117:19 39:18, 20, 22 n oldotu (1) 119:21 moved [11 newborn (7) 104:7 meta-analysis (3] 113:12 18:21; 19:1; 57:24; 58:3, 8, 9; N umber (6) 120:5• 13, 16 MS [4) 66:1 3:22; l02:12; 137:24,• 158:9. 19; Methodological (1] 4.•S; 117:21; 154:17 21 newest [I1 159:24 20 119 M 7 61 3 : ) s ( : n umber (76) methods [1] 16:11; 24:13, 20; 157:7, 12; news (3) 8:11: 10.•9, 19; 11:18; 12:23: 121: 7 159:7, 12 49:21; 51:2; 62:11 14:23; 17:18. 24; 20:13; 21:1. 3, Memco [1] multifactoria)(3] NICHD [1) S, 7, 8, 9, 2?: 24:16; 25:24; 26:1, 108:4 53:1; 99:13; 120:15 62:11 24; 27:17; 28:18; 31:6; 35:20; Meyer [11 Multiple [1) Nicotine [1) 36:11; 39:20; 40:1, 12: 42:2. 19; 119.1 92:14 140:9 51:22; 53:9; 66:9; 70:1, 7, 8; Michael [1) multiple [19] nicotine 181 73:2, 14; 75:12, 13; 82:18, 20; 127:18 20: 22; 30:11: 33:14, 16: 34.•3, 19:15; 31:25; 35:11; 49:2; 52:24,• 83:11; 92:7, 12: 94:5, 24: 95:2, microbiology ( 11 25: 36:23; 40:10,• 53:4; 54:18; 139:23; 140:8, 12 18. 20,• 96:22; 100:5; 103:8, 11; 107:15 60:18; 64:19; 72:20, 23; 94:24; Niebyl(1) 104:20,• 108:8, 16; 122:13, 18; microinfarcts 121 95:1; 96:12; 142:11; 143:3 42:6 126:1; 127.•11, 14; 128:6; 101:19: 102: 4 multitude [6) NIH (1) 129:23, 25; 133:18; 134:19: microphone 121 56:24; 61:11; 91:15; 130:21; 62:11 136:13. 14. 22; 137:8; 138:20, 114•7: 125:18 138:25; 146.•19 A7HC [t) 21: 146:3; 133.•18 Mike (2) myself [51 145:19 n umbers (8) 44: 9; 45:15 37:3; 41:14, 21; 84:10; 133:11 Nobody I11 69••16,• 77:12; 85:23; 93:14; MILLER 121 112:8 103:6, 7; 136:16; 148:9 157:1; 159:1 i -N- nobody (1) N umerous [t) ller (1) M 127:23 l05:4 158:3 Naeye (s) nonchromosomal [1) n umerous (1) mind [ 21 7S.•20, 23, 24; 78:23; 82:6; 98:5, 55:15 20:5 S2: 20; 122:1 6; 99:16 nongenetic (t) nu rseries [1) wine[ll Naeye's [2) 73:24 40:8 84:11 77:16; 125:23 11011H)spanic 131 nu rsery (1) miniiual (31 naive [11 /32:3, 6, 22 40:1 7:4. 62:19. 20 154:1 nonmathematical [ 1 ] nu trition [4] winimum [1] name [14) 87:3 99:11, 23; l00:4; 112:IS 47:14 5:6; 9:13; 15:12; 16:7; 2S.•2, 5; nonmember (1) nu tritional [1) minus [1) 39:3; 40:23; 42:16; 43:6; 62:17; 62:4 102: IS 95:21 66:15, 18; 116:2 nonnicotine (1( w[nute 131 name's [l) 33: /1 -~- 14 130 " 154: l4 2 4:17 i : . ; ; nonrespons ve (1] winutcs (hl names [4) 154:12 oa tb 121 7: 7 17:15: 23.2. 3, 9, 19 42:25; 44:2; 106:23; 127:16 nonscientific [1) 49: l4; 50:1 miscarriage I l I National (1] 104.•6 O B (2) 72:15 90:14 nonsmoker [ 1) 66:]5; 67:21 ~ Ntissiscippi I%1 national (11) 82:24 ob esity [t) ~+ ll: 24, 12: 21; 30: l2, 21: I 16:5: 4:18; 11:25; 16:5, 9; 43:21, 22. nonsmokers (151 142:25 v 137:2/: 145:8 24; 59:13• 15; 71:1; 153:25 72:1, 13; 73:6. 24; 77••2S; 78:4, ob fuscate (1) ~' ~ Missouri [t] Nationally [1] 8;81:9,21;91:4;94:3;97:13; 89: 7 2.9 wode [t) 53:18 model [,] 133:17. 22. 135:25 modified I t I 110.• 1 mows [11 93: 2S wonitor I t ) 15: 7 mouth pq 26:15; 65:1 ?, 19 monthly [.) 62:10: 63: 4: 6S: 9 wonth5 (S1 60•S; 65:13. 14, 15, 19 Moutreal[11 13:?1 Moore(11 11x:17 uworning 171 4:4, 9: S: 4, S: 1/S: 8; 121: 9; 151: 7 Morris I t ) 45:14 natural[1) 108:11 NBC (1) 49:20 Necrosis [11 101:18 necrosis 111 102:4 needs [2] 30:7; 90:12 negative [21 83:14; 112:18 negligence [2) 86:21, 25 neonatal (31 44:21; 130:14; 146:16 Neonate [ 1) 76:1S neonate 121 44:22; 152:2 neonates (1] 63:20 neonatologist [3] 44: 9; 4S: S, 8 Neonatology [ 1) 100:8; 101:2, 22 nonsmoking [3) 58:17; 93:25; 97:16 normal [Sl 73:23; 74:9: 79:18; 80:4; 98:16; 114:23; 135:12 normally 141 33:23; 59:20; 131:9; 146:11 norms [ 11 88:1 NOTARI' (1] 1SS:24 notary (I1 159:16 note (1) 157:16 noted [3) 7:7; 153:17; 159:13 notes ta) 13:14, 16, 18, 19: 29:15, 18; 115:18; 118:11 Notice (2) 4:15; 6:21 notice (21 3:18; 95:6 objections [Il ~ 143:16 N observation 131 4' 82:11, 12; 147:12 ~ observations (.1 33:18; 147:11 observed 131 79:7,• 81:12; 101:15 obstetrical [s) 18:13; 27:1; 42:9; 56:20; 60:17; 63:18, 23 obstetrician 131 15:19: 61:22; 65:25 Obstetricians (1) 59:12 obstetrician.s (31 60:15; 61:17 Obstetrics [1) 42:5 obstetrics [9) 16:2; 19:18; 20:22; 41:4, 20, 21, 24; 42:17,• 90:6 obstructive [ 11 48:1 obtain ( l ) 108:18 hBlTtl A• ?1}I2,LER (915) 533-7108 From mental to obtain

esA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-24-9II6><-s«<s8> 26:23 VIDEOGRAPHER 11) 33:4. 19; 34:6; 40:5; 54:16; 119:18 understood 121 125:18 79:16; 83:3. 14; 88:9; 92:1, 3, 4: world (5] 8:17; 142:2 videotape (11 95:19, 23; 96:4, 18; 99:2, 17, 23: 20:14,• 37.•1, 2. 3; 84:21 unequivocal (l] 24:4 100:5; 105:6; 126:19; 132:1. 9, Wouldn't (ll 110:6 Videotaped [1) 20,• 138:12, 23; 139:17; 142:25 . 141:21 unethical (21 1:10 well-defined Il) wouldn't [1) 35:9, 13 view (1] 103:5 146:25 UN7TED (1) 153:11 WESTERN (1) write (1) 1:1 wvilli (1) 1:2 112:24 United 131 S6•'3 Wbat's (1) writing (1) 102:24; 103:11; 129:4 villus 13] 107:10 115:24 University I1] 101:4, S, 7 what's (8) writings [ 1) 15:21 virology (1) 6:1;13:11;17:19;21:1768:12: 32:5 unknown Ill 107:16 114:1; 139:2; 152:3 written (9) s5:5 virus (4) Whenever (1) 18:15; 23:13, 17; 26:3, 17; 59:4; unmarried (1] 64:22; 66:8; 108:1. IS 145:4 85:12; 111:15; 1/9:19 143: 2 vital ( U Whereas [1) wrote (2) unproven [1) 122:20 92:2 99:/6; 103:24 36:10 vitro 12] wherever (l) unusual [ 11 35:1; 73:1 J16:12 -Y- 107:20 voice [11 whichever [l) updating (3] 66:4 136:13 yea ( n 60:24; 61:9: 62:11 Volume [ 11 wbite (4) 77:2 upper (1) 3:22 132:3, 6, 22; 148:7 Yeah (9) 130:16 volume (15) whiz (2] 38:4,• 68:19, 20,• 76: J9, 24,• 96:8: urban (ll 14:22; 20:6, 21; 31:2; 76:25; 148:9, 19 102:7• 126:21; 149:10 143:23 82:7,• 85:4; 118••14, 16, 20. 21: Wbo's (1) ytah (s) Urinary [11 119:7, 18; J21:17,• 128:13 25:14 37.•2: 104: 6: 124: 24; 134:18; 46:16 volumes [21 whoever (1) 135.•S usage [1] 114.•16; 115:23 103:24 Year 11) 61: 20 vu[vovaginal (11 WIC (6) 128: 9 uses (1) 64:22 99:21, 25; 100:6; 133:15. 19; year 17) 134:10 154:1 7:3; 8:20: 14:14; 21:1. 2.5; 65:10; usual l'-1 - W - Williams It) 103:11 •14 7 1 23 ; 3 : 34 42:3 years 1 1 uteroplacental (1 ] wanted [2) WITNESS 181 9:1S; 19:11, 19. 20; 23:4: 36:25; 97:1 29:25; 119:17 3:2; 46.•1; 77:8; 93:21; 113:3; 41:16: 42:13; 49:16; 50:20: utilize [t] wanting (1) 117:23; 125:20.• IS4:18 64:19, 23: 70:14; 7S: 21. 22; 121: S 126: 22 witness (5) 76••7,• 90:13; 108:6; 128:6; utilized [2) wants [31 29:5; 37:8; 156:5. 8; 157:16 130:IS 94:14; 131:17 47.•17,• 143:15; 145:22 Witnesses (21 yesterday I1o1 utilizing (1) Washington (11 3:17; 127:13 23:8, 23; 24:2: 23:1, 3; 26:6. 7 34:16 66:8 witnesses ( t ] 27:22; 43:6: IS0:16 waste (1 ] 44:4 you'd (3) - V - 84:11 woman (1) S:1S; 74:1; 76:10 ways 1=1 19:4 you'll (21 Vaginal (1) 120:9; 121:9 Women 121 7:24; 148:24 41:14 We'll [41 75:6; 129••1 You've (61 vaginosis [ 11 5:1: 13:11. 25; 113:4 women [13) 13:19; 17:18; 71:19; 81:25; 90:8 we'll (6( 8:25; 31:13; 41:9. 10; 70:5: 71:5; 118:24: 152:14 Valerie 131 23:25; 29:13; 51:4; 60:17; 113:1. 75:9; 78:5; 81:19; 139:15; you've (17) 2:16; 157:7; 159:7 4 142:20,• 144:16 5:9; 6:7. J2; 9:20; 21:17,• 53:14,• valid 131 We're (a) women's (11 83:23; 88:21; 94:6; l02:5. 20; 110:7; 139:13: 148:17 53:23; 80:24; 117:16; 130:22 69:5 l03:23; 117:13; 132:12; 134:7; variable (:1 we're (10) won't (11) 140:23; 141:13 99:4. 6 5:12; 70:2; 98:13; 113: S, 14; 28:22; 36:12; 39:9; 40:9; 48:12; you-all [3] variables 14] 117.•6; 125:11; 133:16; 140:25; 38: 22; 98: 6: 104:10: 115:14; 25:25; 26:10; 117:9 33:10; 34:24; 73:13; 100:3 143:4 136.•6; 153:10 young [21 varies [1] We've (5] Woody Il) 24:25; 142:24 65:18 71:19; 10S•?2; 126:16; 151:6; 43:3 yourself [71 vascular [11 I 52:18 word 120) 14:2; 18:25; 19:3; 37:7, 16: 48.•11 we've (24] 19:9; 28:24; 29:1: 51:15; S2:2S: 39:17; 41:3 vasoconstrictive (1 ] 3:24; 74:4; 87:4; 103:9; 104:25; 61:20,• 83:20: 84:1; 88:11, 20, 19:16 105:14; 110:20, 22; 115:8. 12: 22; 120:8; 124.9; 131:9; 144:18: -Z- vast 13] 119:13; 121:8; I2S.•7,• 126:20; 145:1; 152:19, 21. 22 33:2: 70:12; 79.23 128:2; 130:19; 136:15; 138:1; words (5) Zanelll Ventilator (1 ] 140:22; 141:16; 144:16, 17; 27:8; 28:19, 25; 29:23; 68:21 66:9 40:11 150: 2S work [10) verified (11 Wednesday (2] 11:21; 19:13; 52:20; 54:8; 57:20; 94:24 21:21; 22:5 86:17,• 8fi9, 18: 109••12; 153:12 veritable (1 ] 103:20 week (17] 6:18; 17:6; 18:4; 21:20, 21; 23:8; workday (1) 16:25 tr ~ versus (151 26:11, 18; 49a, 7,• 56:18, 23; worked 12) ~ 17:22: 37:1: 79:9; 93:8, 25; 94:3; 57:9; 58:18; 82:22; 138:18; 9:9: 25:3 B 100:2, 8; 101:21; 118:9, 17, 19; 151:12 working 131 ~ 132:6, 23; 145:25 weeks (41 9: 7,• 3s:18; 36:3 N vesidual (i) 77:23; 93:7, 8; 146:15 workout (1) tr 101:3 weigh-c [ 1) 127.•8 Ob vessels (1] 133:10 works Il) 101:5 Weight 13] 52:21 veterinariaus [ 11 15:1; 82:25; 119:20 World (1) 107:17 weight (30] understood to Zane (915) 533-7108 KEITH & DIILLER

IIsA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-24-92ook-see(50) Laryngeal (21 I limited [4) 2:8 McCarthy's II) 46:)8, 25 laryngeal [21 47:2,3 last(22) 33:20; 38:15; 39:20; 140:4 Liodgrea-Bron [11 24:15 LINE [I) m m aiu ll) 7:21 ainly [ t] 78:4 124:25 McCubbin (1) 43:13 McIntosh (1) 6:18; 11:10; 17:5. 17; 18:4; 155:2 M ainstream (I) 121:14 21:20, 21; 22:4; 26:11; 56:18, 23; 57:9; 58:18; 80:18; 104:24; Bne (5) 19:18; 1 QS:2S; 124:4,• 141:18 m 103:19 aintain (4) McKinney (2) 1:14,• 2:11 127:10; 137:23; 138:18; 130:16; - 131:12, 22 ~ ..(ing [1] 151:8 m 35:1, 7,• 108:15; 137:24 alutaiued [2) mean [12) 25:19; 38:20,• 61:5; 79:6. 7; late 12) 78: S, 7 latter (21 link It] 86:24 linkage [31 m 12:14,• 53:21 aiotaioiug [11 34:23 84:16; 85:24; 120:3; 134:1; 143:18, 20; 149:13 Meaning ll) 17:4; 74••25 law (2) 87:10; 89:23; 14S••17 linked [ 11 m ajor (18) 8:9; 39:15; 40:18: 60:11; 64:25; 51:19 meaning (6) 122••15; 137:24 146••12 73:12; 77:21, 22; 82:21; 90:5; 19:21; 34:14; 45:13: 84:24; lawyers [ 11 liukiug [ 11 93:12; 98:12; 100:22; 1S2:1S, 91:23; 124:12 153:12 lay (11 130:13 List (11 m 19, 20, 21; 153:20 ajority 14) means (8) 18:9; 36:10,• 79••23; 84:13; 88:23; 11:23 lead (5) 3:11 list [11) m 53:2; 70:12; 77:23; 79:23 alaria (1) 107:7; 123:13; 131:10 meant (2) 48:20,• 82:15; 101:23; 102:1 leads (i) 6:11, 14, 17; 44:16; 63:4, 8; 80:1; J01:6,• 141:19; 143:5, 13 m 20:11 ale (I) 88:23; 136:19 measure Il) 88:13 leap 11) listed (5) 17:18; 66:16, 18; 126:3; 142:22 m 147.•l9 alformations [2) 97.•18 measured 121 134:14 learned [1] 61:15 learning I11 31:2 Leave (1) 129: 23 listening 121 10:16; 19:22 listing (2] 18: S; 63: 7 literature(111 11:4;14:3,11;13:13;19:21; 30:20 33:16 34 56 83 3 2 3 m m m 77.•22; 78:10 alpractice ( II 9:14 anagement (4) 18:12; 57:22: 63:19 anner (1) 52 22 71:22; 97:20 measuring [11 19:14 mechanism (4) SS:3; 73:24; 81:11. 16 Medicaid [13) 4 11 11 130 132 128 9 23 leave 161 ; ; : : : ; : : 128:1 M : arch (41 ; : ; , : : . : 133:19; 136:1; 142:20; 144••J6; 11:14: 36:14; 37:13, 19; 122:9; 123:3 live [1) 17:8 m 118:8, 16; 121:17,• 137:18 argin [I] 148:4, 8; 149:5; JS2:2 medical 1151 lectures 11) living I11 115:18 9:14; 10:14; 12:11; 15:18; 24: 23; 19:23 145:23 M arilyn (lI 39:12; 45:11; 83:3: 102:21; left-hand (1) 137 3 Loadbolt (1) 122 1 S M 2:12 k 107••13; l10:9; 139:5; 141: 21: 7 52 1 154 : : ar (1) : : ; 1 legal 15) 61:14; 84••21; 86.•17; 87:9; 154:7 location (1) 143: 24 m 129:25 ark (2) medically (I) 28••22 legiclature I11 Lori 121 4:25; 129:22 medication l11 128: 24 2:9; 24:14 m arked (27) 112:24 legitimate (1) loss (7) 5:2, 21, 24; 6:1, S, 9, 15; 13:23; medicine [7) 80:23 SS:10,• 78:20; 79:8. 15, 16; 17:19; 21:17: 68:J0, 11, 12; 7: 20; 10: l S: 11: 2: 1 S: 22: 20: 23; legitimate)y I11 92:16; 93:3 102:9. 10, 11: 113:13; 118:10; 42:11; 139:6 148 11 5 l 136 125 2 130 2 3 9 21 : ) osses ( : : ; : , ; , ; meet 131 Leigh (1) SS:16; 74:22; 92:19, 24; 93:11 140:19, 21, 22 9:8: 54:3; 121:2 42: 6 lot [:4) m arker (1) meeting 1311 lend (1) 10:14, 19; 11:1; 27:25; 30:19; 34:8 8: 2. 11, 18, 19, 21: 9:3: 10: 6; 94••ls 33:15; 51:8; 63:12. 13, 14; M ary I1) 11:3, 8, 10, 12, 17; 21:24; 22:9. length I11 69:18; 76: 7 77:2; 84:2; 85:10; 119: S 24, 25; 23:1. 3, 6. 7. 18. 22: 62: 23 89:21; 1J0:2S; 113:7.• 119:12; m aterials (1) 24:2, 8, 10; 2S:16, 17, 20.• I4S:3, Let's 15) 122:18; 132:24; 133:1; 139:12; 62: 7 21 4:25; 63:3; 90: 24; 92:13; 151:1 J47:24 M aternal (31 meetings (11) let's (3) Low [4] 144:9; 1S1:22, 25 12:20,• 13:14, 17; 21:22; 22:18: 8:22; 27:4; 112:17 1S••l; 37••17,• 82:25; 119:20 m aternal [42) 23:20; 24:20; 25:13; 66:24; 74:5; letter (21 low 1'!2) 10:12; 18:20; 19:4,• 32:11; 33:3: 145:3 129:18; 139:17 33:3, 19; 34:6; 40:5: 54:]5; 88:8; 43:2; 50:22; 51:11, 12: 54: JS, member (3) letterhead (11 4 2 9S••19, 23; 96:4, 18; 98:8, 15; 6 6 9 9 19, 22, 25, 56:11, 1S; 57:6, 16. 5 5 1 7 • 59:22; 60:2; 61:22 b 12 :1 99:2; 105: ; 12 :1 ; 132:1, , 8:J2. 23; ; 4:l7. 23; 9: ers (17) mem letters (2) 20,• 138:12, 22; 139:16; 142:24 77.•19; 78:9, 15; 87:17; 92:16; S9:16, 17, 21: 60:21. 22; 61:2. 137:8, 12 lower [4) 9fi1: 99:17. 23; J02:3; 105:4; 21: 62••2, 5; 64:1, 4. S: 66:1. 2: level 1'-1 77:11; 82:9; 83:2; 130:17 106:4; 110:17: 119:11; 127:4; 67: l4, 24 44: 4; 72:13 Lucile [ I ) 141:21; 142:5, 24, 25; 143:1 membership 121 levels (4) 14:25 m ateroal-fetal (41 63:6 19:15; 53: 4; 98:15; 101:11 Luecke (1) 7:20; 11:2; 15:21: 42:10 membrane ( l / lib 2 43 11 M I) ternit 89:18 rary ( 1 : y ( a 12:12; 138:16 lung [5) 129:4 membranes 191 lif 14 10 46 8 9 49 50 13 103 h 18 10 11 92 93 105 13 22 2 e (2) ; : , ; : ; : : m [1) at , . ; : : : , ; : 34:9; 154.•8 134:22 19; J1S:13; 126:18: 130:23 lifestyle I1) m athematica113) memorandums (1) tn ~ 90:10 J34:S, 17, 20 50:19 ' v Liggett (31 M.D. [10) m atter [1] memorize (2) tr 49:12, 25 1:11; 3:3; 4:1; 25:14: 107:14; 3030 121:10,• 123: 7 m likelihood (1) 1SS:14, 19; 157:14; 158••6; m atters (1) memorized I1) 105:10 159:14 J8:11 131: 7 ~ 6keKise 121 AI.S. (1) M ay (2) N memnry 121 ~ 13:10; 42:20 J 19:19 68:25; 128:19 7:13; 116:23 rn limb 121 35:24; 56:7 machiue (tl 69: 24 M cCarthy (3) 3:16: J18:8; 137:18 menstrual (t) 71:24 main (1) Laryngeal to menstrual (915) 533-7108 KEITH & A'IILLER

BSA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. Obriously (3] 35:19; 41:2; 69:7 obviously [3] 17:20; 64:2; 101:23 occasion [11 111:8 occasions (1) 36:5 occlusive (1] 48:8 occur (1] 31: 9 occurred (1] 12:1 occurs(t) 93:2 offering (2] 37:23; 135:24 office 14] 22:1; 128:23; 138:1; 159:16 officer (1] 156:3 officers (2] 107:5, 21 offices 121 os (11 82:9 Oster (11 124.•1 ought [1] 77:10 outbreak (3] 108:3, 3, 20 ..outbreaks [2] 107.•19, 20 outcome (11) 27:11; 35:25; 36:1, 7; 52:18; 86: 24,• 98:17; 1 J 1: 9, 22; 134:13, 15 Outcomes 111 92:13 outcomes (151 35:16, 19; 36:13; 47:16; 51:8, 13; 87.•19; 89:12; 93:6; 110:18; 127:4; 142:7; 152:16; 133:3, 21 outline (1] 7.•S outs [1) 66:20 overall (2) 17,• 143:24 1S1:2S paragraphs I11 J41:16 parcels (11 14:13 Park [1] 2:4 part 1181 17:4,• J9:24; 23:16; 62:3; 63: 7,• 74:23; 77:11; 90:19; 109:6; 112:8; 1J9:16; 121:21; 127.•I1; 133:20,• 137:16, 21, 22 partially I11 121:2 participate I11 108:24 participated 111 66:19 parties 13] 150:20,• 156:10, J2 partners (11 143:3 parts (3) 14:12; 96:15; 115:18 path [1) 07-24-99ook-See(52) 9S: 21, 23: 103:12: 109.' 17, 19 • 134:12, 14, 1S; 139:10 percentagel3) SS:12; 82:5; 122:4 percentages 121 149:1; 152:9 percentiles [1] 132:9 Percy (1] 43:11 pertect(3] 84••13; 143:IS, 16 perform (11 14:2 performed Il] J24:1 Perinatal(31 81:6; 90:14,• 92:13 permatal [91 75:3; 77:17; 81:5, 8; 92:16, 19; 93:11; 99: JS; 119: II period (3) 20:18; 74:12; 142:1 S peripheral (2) 48:7, 11 1073; 158:3 42:4,• 71:21 38:11 persistent (1) Ob (26) overtones (1) Pathologic (11 33:17 10: 7,• 23:16; 24: 23; 26: 7,• 2 7: 4, 110.•13 3:20 person (81 23; 42•2; 59:11; 62:9; 63:3; oxygen [5] pathologists (1] 34:5; 42: 7,• 44:6, )2; 66.•S; 8S.•19; 100:17; 107:12; 116:22; 123:10; 35:2; 97:2, 21, 22; 98:15 107:17 100:1; 112:17 124:22; 125:4; 130:23; 134:3; oxygenation (3] Pathology 131 person's 121 136:11; 142:9; 143:21; 144:22; 98:4, 23; 99:1 38: 7,• 39: 7,• 102:13 34:9; 66:18 151:2; 1S2:S; IS3:7 pathology (8] Personal (21 oh (2) -P- 38:9, 14, 15, 23, 23; 39:4, 6, 14 70:11; 104:6 102:12; 106:1 patient 141 personal 171 old (11 P-R-O-Af [ 1 ] J11:J6,19;112:9,12 70:9, 19, 20,• 85:15; 103:5; 65:3 89:18 patient's Ill 127:24, 2S older (1] P.A. [8) 111: !0 personality (21 78:17 1:11;3:3;4:1;133:14,19; patients (30] 48:19, 23 one-page [1) 15714; 158:6; 159:14 52:24; SS:11; 56:5; 57:2; 64.•11, personally 1'-1 137.•16 p.m. 11) 21; 70.•12, 19, 21; 79.•9, 10, 21, 95:2; IS6:S ones [6] 154:22 24; 82:19, 20,• 85:16, 17; 97:10,• persons (2) 40:18; 93:12; 104:20; 110:23; P.O. [ ( ) 98: 9; I J 1:3, S, 10, 14, 20; 102:25; 111:23 125:22; 133:13 2:4 143:25; 148:1. 2. 3 perspective (31 ongoing [1) pack I11 pattern5131 10.•14; 16:5; 86:12 16: 2 65:8 107:24; 147:19, 20 persuasions (1) Oustad [1) packageIq payback (1) 107:14 10:3 65:18 136:1 pertain (1) oops I11 Packard I11 pedeatricians I ll 138:22 124••17 14: 25 68:5 Peter 131 opinion 1161 PAGE (3) pediatric (a) 97:5, 9; 98:19, 22; 126:5 30:10, 11; 45:4, 7; 46:3, 8, !9, 3:2, 24; 155:2 39:18, 22: 43:5; 36:2/ Peter's I1) 22; 49:2; 50:7; 58:11, 23; 61:1; Page 12] pediatrician [11 97:24 78:23; 94:13; 120:4 71:16: 77:13 13:8 P6.D. (2) Opinions [2) page [261 pediatricians I11 15:20; 107:14 3:7 10 49:11; 69:21, 22, 23; 70:4; 72:7, 67:24 pharmaceutical [1] tn opinions (51 24; 77: 9, 11, 12; 80:17, 24; Pediatrics (3) 25:3 N 6:8; 30:5; 37:23; 45:21; 126:14 90:24; 92:14; 102.•16; 103:17; 60:20; 67:12, 15 v pharmacologist (11 N opposed [6] 104:23; 105:25; 139:14, 20,• pediatrics ll) 8: 7 m 53:13; 60:17; 92:3: 98:2; 126:10; 143:23; 1S1:4, 19, 20; 159.•1S, 39:19 phase(1] 141:3 16 pee (11 61:6 v OPposing 1 11 pam 1191 S7:2S N Philip [11 159:17 29:18; 62:23; 102:13, 14; peer 11) 2: 7 Oo Oral 12] 106:11; 115:5, 9; 117:12; J8:9 pbone(21 1:10; 47: S 118:1 S, 16, 20; 119: 7, 19; pending ( ll 73.6 orauges I11 121:10, 17; 125:16; 129:6; 29:6 physical I 1) 120: 22 137.•19 People 12) 98:16 order [2) PAID [1] 11:14; 129:13 physician 141 84:3; 113:9 1:22 people (39] 18:11; 25:2; 64:13; 146:10 organ (2] paid 121 8:23: 20:13; 21:1, 13; 22:11; physicians (S) 39: l: 108: 23 16:12, 16 24:19, 22; 33:5; 38:2; 41:17; 64:13, 18, 23; 109:24; 134:19 Organization [ () Pancreatic (1] 42:2J; 43:1; 47:21; 48:10; SS:IS; pick (1) 119:18 46:13 5720,• 62:4; 63:4; 66:9; 70:16; 124:22 organization 131 paper 121 71:10; 74:8; 79:18; 80:4; 87:6; picking 111 59:13, 15; 109:7 23:18; 98:20 100.5; 106:13; 107:8; 108:8; 39:9 origin U1 Papers [I] 109:4, 14; 112:5; 122:21; pie (31 91:25 129:9 133:15; 134:19; 13S:S; 140:5; 89:2, 3, 5 Original [ (] papers (10] 146:21; 149:14 Pima (11 158:5 89:23; 119:2; 124:13; J2S:21: percent(22) 92:5 original (3) 126:8,10,11,12,14 J 7:25; 18:2; 71:3, 4, S, 6. 9; Place (1] 108:2; 120:19 IS7:13 paragraph (9] a:22: 78:12; 79:8; 84:24; 88:5; 2:8 90:25; 92:14; 104:24; 141:15, Obviously to Place (915) 533-7108 KEITH & MILLER

BSA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-24-926ok-s«(sa) qualm 111 ( reality (11 referred I U 1:16, 17; 4.•2 103:8 152:5 119:3 reporter(2) quantitate 121 realize [1) reflect (11 4:8; 113:21 70.•18; 148.•16 154:4 4:14 REPORTERS 121 quantitative (1] realm 111 refusalal) 137:1; 139:1 148:5 63:21 111:10 Reports (1) quantity (1] reanalyzed [2) regard 114) 116:1 97.•14 75:16, 17 35:19; 37.13; 46:5; S4.•4; 64.•S, reports (4] Queen IU rearraoged [1) 10; 70:9; 74:1; 76:1; 86:7,• 99:14,• 105:24,• 108:25; l14:22; 117:18 97: 7 51:16 106:3; 117:5; 138:11 represent I1) question [271 REASON (1] regarded p) 69:3 5:17; 11:17; 13:17; 38.•16; 42:24; 155:2 109:21 representing 121 43:23; 58:4; 70:8; 72:17,- 83:13; reason (4) regarding [1) 24:11: 103:2 87.•6; 94:8; 100:9; 103:2; 106:1. 44:5; 49.•19; 73:25; 147:7 6:25 Reproduction 111 16; 111:7,• 111:8: 115:10; reasonable (91 Registered (1) 115:7 120:11; 130:6; 135:21; 144:24; 28.•24; 38:13; 39:25; 53:12; 60:6; 1:15 reproductive (3) 145:9; 150:16; 151:2, 3 82:4,• 131:10,• 134:20,• 146:1 related 110) 67.•3; 70:7,• 141:20 questioning [1) reasonably (31 10:25; 12:15; 19:7. 8: 27:4, 6; reputation (3) 54:3 questions (181 41:19; 70:24; 139:7 reasons 12) 30:14,• 33:4,• 34:14; 156:9 relationship 191 16.5, 9; 4S.•!1 request (S) 10.•22; 25:25; 26:1, 16, 21, 25; 85:22; 132:10 33:2, 4,• 50:14,• 83:4, 17, 23; 1:12; 29:20, 22; 30:1; 114:13 27:17, 21, 25; 37.•11: 39:21; Reavis 13) 88:8; 89:17 Requested (1) 43:2; 45:17,• 68:10,• 130:25; 2:14; 137:7,• 159:7 relationships I1) 120:1 147:10; 154:20, 21 recall (24) 127:24 requested (6) quicker (1] 9:1; 10:12; 12:20; 13:2; 32:1; relative (121 12:3, 24; 63:11; J19:24; 1S0:12: 51:9 40:19, 22; 42:8; 44:18, 24; 67:5; 79:2, 3, 4; 82:3; 84:3; 85:12; 132: 7 quickly (11 73:25; 75:20, 23, 25; 76:8; 91:5; 96:3; 110:20.• 127.•3; required (11 65:1 99:15; 106:1, 6. 21; 111:12; 134:15; 156:11 135:11 quit I11 116:19; 132:23; 133:3 relatively 141 requires I11 111: J0 recalling U1 58:17; 61:7,• 111:1; 141:2 146:11 quitting 121 112:13 relevant 121 Research (1) 139:25; 140:1 Receipt (1) 44:20,• 95:17 128:19 quotation (4) 159:23 reliability [1) research [l l) 19:10; 32:2; 103:21 receipt I1) 94:16 /8:23; 19:25: 20:1. 19: 25:4. 5; quote [21 159:17 reliable Ilo1 60:12; 62:12; l08:18; 110.•14 132: 2: 149:1 receive [4] 64:6; 80:23; 103:4; 109:23: researchers 12) quoted [t] 61:23; 67:15, 17; 149:12 110:14, 16; 1203; 123:21; 33:1; 75:12 97:4 Received (1] 138:11 reserve (1) 158:3 relied (3) 154:21 received (5) 6:7,• 109:23; 116:21 residency 13) 7.•3; 15:16; 31:14; 37:20; 67:24 Relies (1) 19:19, 20; 41:8 R.J. (11 Recent (2) 3:10 residents 121 2:14 89:16; 92:14 rely (1] 36:22: 42:14 Race I1] recent (2) 116:22 respect Ito) 71:14 81:19; 92:15 remains 11) S 0:10: 65: 24; 66: 7: 6 7: 23; 79: S; race [1) recess (41 81:16 87.•Il; /10:5; 128:2; 132:22; 129:14 46:1; 93:22; 113:7.• 154:19 remember (201 147:20 randomized (1) recipients [1] 7:22; 22:13; 23:5; 24.•17; 25:2, 5; respects 11) 35.•10 149:5 27:17,• 42:16, 18; 44:22; 45:3: 131:21 ranged (1) recognize (1) 74:13; 76:4; 92: I1; 100: 6; respiratory (t1 91:15 69:1 106:11; 132:18, 25; 139:9; 48:4 rare (11 recognized (11 147:21 respond 121 80: 4 36:4 remembering 121 26:22: 144:23 rate (5) recommendations (1) 131:11 responsible 141 17.•2; SS:10; 56:13; 72:16: 64: 20 remote Il] 86:22; 92:18; 107:18; 150:1 134:16 recommending [t] 121:23 respousivc(.) rates (2) 42:14 remove 111 13.•16; 94:18 73:3, 4 recoustruct(21 143:12 restllS) ratio Itl 27:5; 125:5 removed 12) 10:24; 20:19; 31:1; 51:20: SS:22: 55:13 record 161 74:21; J08:12 63:3; 74:5; 85:20; 87:5; 88:J3; Re 121 4:6, 14; 3:7; 127:15; 137.•23: repairs It) 93:1 S; 122: 9: 124: S: 125: 7.• 157:10,- 159:10 reach (l1 156: 7 recorded [1] 41:15 repeat (11 133:11 restricted (1) 75:13 156:5 84.•10 141:20 read 1541 recording (1) repeatedly I11 result I 11 13.•l, 3• 5: 14:12; 15:13; 16:3; 11:6 l06: 7 81:8 28:10; 30:1, 3; 31:12, 13, 19; recovery [21 Report 131 results (31 32:18, 21; 44:17; 49:4, 7, 17, 19, 148:22; 153:24 128:10, 11, 19 72:15; 109:22; 139:24 tn N 20; 56:17: 57:8; 64:13; 69:16: reducelll report 1271 retain Itl v 72:5, 6, 20. 22: 74:10; 76:12; 139: l6 6:3; 21:18, 19; 22:3; 23:12, 13; 157:17 F-+ 80:19; 89:21; 95.3; 100:23; reduces (1) 28.•l, 8; 74.•3; 94:7, 9; 95:13; retardation 121 m 102:18, 20; 104:16; 105:1; 71: 21 l06:3; 113:1; 114:14 1S; l i5:4 • 37 •7; 83:7 106:7,• 109:2; 116:22; 118:24; reduction [2) , , 117:13; 128:24.• 129:12. JS; . J retrieved [ 1) N 119:17,• 122:23, 24; 123:4; 55:24; 56:7 130:24; 135:10,- 141:9. 16; 73:3 tn 127: J5; 128:1; J31:5; 142: 4: reference(6] 144:8, 13 Return Il) m 143.•22; 132:24; 155:15; 1S9:1S 73:10, 11; 91:12: 92:6; 94:12; reported 151 159:23 reading (41 95:15 39:3; 77.•18; 139:25; 142:6; return [1) 15:14; 57:9; 59:6; 85:9 referenced (11 144:9 159:16 Reagan l11 125:21 REPORTER I1) reveals (1) 106: 24 references [31 J:2S 71:25 real 141 95:1; 12S:2S; 126:2 Reporter 13) review 1151 37:1,2,3;97:23 qualm to review (915) 533-7108 LEITH & MILLER

BsA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-2A-A2ook•See(56) 44••3; 63.•8 80.•J 129.•23; 136.•13 132.'11 114:19 Somewh ere ( 2) stacked 11) status (5) successfuUy Itl 17:15; 75:10 14:6 95:24; 97:23; 129:13; l43:2; 120:25 somewhe re [ 1) stacks (21 145:21 suddea (l) 7:2 13.•11; 29:13 stayed (11 56:15 Soothill 1 1) Statf (1) 97:23 sutficieat (2) 97:5 129:11 Steve (l1 8S:S; J43:23 Soothill's (21 stand 13) 42:6 suggest (5) 98:19; 126:3 - 49:13; 95:11; 137:9 stillbitth5 11) 33:20,• 55:2, 9,• 56:23; 98:21 Sorry 11] standard 18] 105:7 suggested 121 27:24 42:11; 68:21; 86:23; 88:2, 4, 6; stop (4) 100:19; 147.12 sorry (11 ] 96:2; 139:5 93:17,• 106:13; 139:18; 142:14 suggesting I l1 4:5; 24:9; 26:19; 38:20,• 40:7,• standards 17) mopped It) 33:12 69:20; 86:16; 101:14; 106. S; 63:18, 22: 67:21; 92:3 . 4. 5 J39:22 suggestiotss (21 117.•9; 135:20 standing (1) story I11 56:18; 105:10 Sorsdal ( 1) 34.•18 41:20 wggests It) 2:18 standpoint (20) Stover(1) 73:24 sort 121 8:8; 9:21; 16:8; 17:22; 30:25; 4:18 suing Il) 62.•16, 18 36:23; 38:9; 44:6, 21; 56:21; straightforward (l) 153:17 sorting (I ] 71:1; 72:19: 83:20,• 91 :18; 93:10,• 139:5 suit (o) 120:24 97:12; 98:19; 110:10; 112:23; stratification (3) 7.•14, 15; 133:10, 11 sound [a) 123.•12 74:17,• 79:5; 91:18 Suite 121 70: 9; 72:17,• 73: 7• 84: S Sounds (1] 154:18 source[2) 94:12; 116:12 sources (3] 12:11; 35:9; 140:3 speak (4) 36.•17, 18, 19; 86:3 spealdng (2) 87:23, 24 ataad5 (3) 33:13; 42:3; 139:17 start (2) 4:13; 84:4 started 15) 4:6; 14:10; 18:3; 26:11; 45:25 starting (1) 137: 7 starts 131 81:2; 102:22; 127:14 STATE 14) stratified (21 73:12; 132:1 stratify Il) 134:9 Street [2) 2:4, 8 strep (2) 68:2. 5 stroke (1) 47:24 strong (9) 1:14,•2:LJ suits (11 7:17 Summary (1) 128:13 summary (1) 31:11 summation [1l 106:12 Summmary (l) 3: 7 Special ( t ] 128:18 St 1:4; 157:10; 158:6; 159:10 t 9 35:14; 47:10; 77:18. 20; 78:11, 103 103 5 su pplemental I 1) special121 a el1 1 1:17; 3:17,• 7:14; 29:10; 66:8; st :24; :9 2 ; ructure (t) Su 135:9 pport [31 40:8; 108:17 118.•19: 127:13, 18, 21; 128:8, 134:9 126:14, 21, 22 specialties (11 12, 17, 20; 132:7,• 145:15: st udents I1) su pporting I1] 109:14 146:17; 150:12: 133:16, 18 42:15 83:3 specialty 111 st ate (10) st udied 131 su pposed (l) 15:18 4:6; 5:6; 29:6; 43:22: 80:11; 20:4; 33:1; 90:3 150:17 Specific 1491 98.• 6: 122• 22: 131: 4; 132• 12; st udies (l7l su pposedly (l] 8:9; 10:13, 20, 21. 23: 12:3, 13, 151:24 20.•S; 33:6; 50:20, 2 3; S 7:22; 150:17 15; 17:24; 18:11; 19:8; 24:17; st ated [11) 71:24,• 72:10; 73: 2; 74:7,• 81:13, su rface(3) 2710; 29:1; 32:2; 33:9: 44:25; 30.•11; 31:7,• 32:5; 49:22; 59:5, 7,• 19; 89:16; 91:16; 92 •1S; 95:10: 47.•7,• 100:20, 22 48: 9; 32: 23; 53:13, 15; 61:19; 93:9; 104:21; l40:17; 142.•Il 96:6; 105:4 Su rgeon (16) 64 66 63:2 17 5 20 68 1 67 t t t 26 : ; ; : ; : : : : S a emea 1 1 st udy (23) 91:9, 10; 94:7, 9. 14; 95:13; 71:14; 74:10, 17: 76:4; 89:3; 31:20; 50.•3, 4; 52:2: 64: 7, 8; 35:6, 10; 73:1; 74:7. 20, 24; 103:24; 106:3: 108:24; 109:7,• 90.•16: 100.•6; 111:24; 112:12; 70:4; 71:20; 72:22; 73:6, 8; 75:1, 3, 11; 77:17,• 81:6, 7,• 114:14, 16; 115:4; 116:1: 115:17; 116:12, 19, 23: 119:2; 75:15, 18; 79:17; 83:8, 9, 16, 20; 84.•JS; 87:23; 90.•19; 95:8; 97:9. 11712, 18 121:24: 130:1, 4; 131:25; 88:7; 99:19; 103:22; 109:15, 25; 19, 24; 99:15; 120:4, 19 su rprise (t1 132:10; 145:13: 148:17; 151.9 142:5; 152:3, 6 st uff (7) 50:4 Specifically It) st atements (5) 17••13; 122:18, 19; 123:4; 138:2; su rprised [2) 42: 24 28:20; 31:18; 69:10; 80:20. 21 143:12; 153:22 124:8; 131:16 specifically (32] ST ATES [1) su b (1) su rprising 121 10:3; 15:6; 18:13; 25:23; 32:19; /:1 S6:2S 50:8, 16 63:16; 71:11; 75:20; 79:16; St ates (3) su bcompouents (2] su rrogate(21 80:11; 90:8; 91:21; 97:4; 98•8; 102:24; 103:12; 129:4 7:12; 26:2 34:8; 57:2 111:20; 112:14; 114:24, 115:3; st ates (t0) su bject 131 su rveillance (11 126:1; 138:19; 147:2, 8 7:18; 72:10; 73:1; 77:18; 78:2; 12:16; 19:23; 110:8 123:14 Speer la) 81:5, 19: 83:l; 91:2; J39:21 su bscribe (11 Su rvey (l) 44:9; 45:4, 10; 127:19 st ationed [ 1) 62:3 129:1 Speer's [2) 107: 6 S UBSCRIBED Ill su rvey 121 44:14, 25 st atistical 1161 1SS:20 64:24; 139:24 speut (a) 26:20; 34:13; 51:17; 53:8: 57:21; su bsequentIll su spectIll cn 17:12; 23:1, 4; 133:19 59:5; 82:16; 88:1; 120:10; 121:7; 153:9 1/6:11 v spit 11) 122:8; 123:8; 124:14; 130:12; su bsequently (21 sw ore 121 N 133:18 134:4; 150:5 8:1; 13:6 49:13 m Spontaneous 121 St atistically ( i l su bset (2) S WORN (11 14 72:8; 73:22 83:23 53:6; 39:19 155:20 N spootaueous1161 st atistically 121 su bsets (3) sw ora (1) u1 55:1; 72:12, 14, 25: 73:4, 21; 33:11; 93:3 10:23; 44:22; 59:16 4:2 N 74:3, 22: 76:1; 77:19: 78:3; 79:1, 8 11 14 105 7 st atisticians 13] 75 84 13 4 133 13 su bspedalict (1) 22 sy ndrome I11 56 6 , , ; : : : ; ; : 13: :1 spring 111 St atistics (ll su bstantial [5) sy stem (2) 14: 23 128:16 S7.•1; 61:6; 82:18, 20; 83:12 83:18; 111:14 squirrel I t ) 108:10 st atistics (11] 30:22; 31:3; 76:8, 9; 96:24; su bstantially (2) 71:15; 148:12 sy stems ( 11 39:1 stack I11] 122:20; 130:1; 132:13; 146:16; su bstantive (1) 113:13; 114.•2; 115:24; 116:18; 124 •16 126:11 25 127:10 t 148.•9, 21 atisticµi e 1 80:8 b i -T- • , : : ; s s ( ) su tract ons (11 T- O-N-A-S-C-I-A (1 1 Some,where to T-O-N-A-S-C-I-A (915) 533-7108 KEITH fiMILLER

BSA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-24-9Doo><-s«(ss) place (5) 152:20 21:21; 22••3; 28:1; 129:14 proof 181 9:3; 10:6; 78:7,• 107:7,• 145:13 Pl t 3 portion (1) 136 1 preparing (1) ~ 51:19; 52:6, 13; 53:16; 54:1; acen a [ 1 : 108:24 87:24; 88:3 76:15; 92:17; 125:24 portions [1] presence (11 proper (2) l 8 14 1 p acenta 11 1 :2 J 159:16 28:20,• 30:6 54:23; 81:20; 82:8, 10, 15, 18, position (2) Present (1) properly (1) 21: 100:16• 21, 24, 25; 101:8, 51:10; 83:17 2:18 112:21 17, 24; 102.•4; 105:12 ---• positive [2) present(9) proportion (2) placentae (a) 64:14; JS3:20 9:1; 24••18; 67:7; 115:19; 127:4; 77:24; 80:11 54:20; 81:7,• 92:17; 105:12 possession l2) 128:6; 137.•1S, 25: 143:10 proportionality (11 Placental(1) 150 22 13:4,• 14:12 presentation It) 9 133:9 : post (4) :24 1 proposition (l) placental(41 19:19; 40:13; 64••2S; 98:2 President 111 146:25 38:23 24 82 7 141 21 i 1 t 133 13 d , ; : ; : l t 2 pos er or ( ) 41 15 : id prove (a) 6 p acen as( ~ 101 1 21 : P p res ent 121 9 5 1:15, 17; 86:4, 8 : , ostpartum (1) 4 :11, 2 proven (a) places 151 129:1 p reter m (131 35:14; 56:1; 57:10; 61: 7,• 83:24; 30:11; 31:6: /07:6, 9; 110:25 potent (1) 56:1 1, 13; 82:15, 17, 19; 89:17; 85:6; 88:14 Plaintiff 14) 90:11 92:1 7, 21; 93: J, 12; 132:1, 8; provide 15) 1:5. 12, 22; 2:3 potential (21 IS1: 6 130:10,• J49:18, 24; 150:19 plaintiff l5] 8:15; 12:8 p retty ( 71 provided (16) 9:22; 17:22; 18:1; 44.•16: 86:21 potent;auy (u 10:8; 17:17; 36:4; J04:4; J07:4; 4:10: S:2S; 6:11; 13:3: 14:J3; plaintiffs I11 44•7 7:18 109:2 0,• 141:12 48:24; 50:18, 19: 63:2; 99:21; power (1) p revia (sl 114:6, 10,• 125:12; 140:23; Plan ( .) 75:1 34.•23; 81:20; 82:10, 1S, 18, 21; 144:22; J33:19 128:9• 12, 21 powerful (2) 92•17,• 105:12 Provost Il) plan 171 74:24; 139:22 p reviou s (2) 2:3 17:7, 20; 133.•4, 17. 21; 135:17, powers (1) 7••17,• 119:17 PUBLIC (1) 24 139: 23 p reviou sly (31 135:24 planning 131 practice (91 14:11; 31:12; 125:22 Public (3) 133:22; 135:3; 144.•20 36:16, 20, 24; 41:19; 62:13; p riatar y 14) 121:15,16;129:10 Plans (11 85:16; 111:8, 13, 14 19:25 ; 38:22; 59:6; 72:6 public 14) 128:17 practicing l1) P rior ( I 1 109:24; 122:21, 22; 128:14 plans 1'-1 64:16 23:15 publication (7) 11:16, 18 practitioner 11) p rior 19 1 20:20; 62:10; 66:24,• 76:5; 93: 7, plateauing lt] 44:21 7:2,8; 15:17; 22:4;57:8; 61:9; 8; 138:12 34: l pre-term 121 82:21; 85:9; 146••3 publications (131 Please I ~) 83: S; 96:19 p rivate (7l 61:10, 12, 23; 62:22; 63:2 1, 23; IS7:16. 17; 139:IS precise (2] 36:16 , 20, 24; 83: /6; 11 J:13; 64:3. 5; 67:15; 75:19; 91:6 , 10; pleasc l;l 59:11; 151:17 148:1 119: 23 S: 6; 80.• 17; 125: 6 138: S precisely (I] p robabi lities (1) Published I1) plug IU I3S: 6 146:1 129:9 133:14 predators (!1 pr obabi lity (31 published (51 plaS (a) 108:11 71:22; 77:20; 88:3 16:6; 19:11: 33:16; 71:24; 75:7 19: 2 2; 9S: 20: 122:17; 128.7 predominantly [31 P robab le (1] publiuhing I 11 pneumouia ( t l 44:19; 97:11; 126:10 84:22 18.•24 48: S Pregnancies (!] pr obabl e (lol puff (1) Pogue l?I 75:6 60.•6; 83:4, 10, 16; 84:13, 16, 23; 103:20 2:15: 137: 7 159: 7 pregnancies (5) 88:4, 8; 90:22 pull (sl point Itol 13:7; 55:18; 98:18; 111:22; pr oblem (8] 7:12; 27••24: 32:22: 40:22: 95:5: I1:20: 33:21; 52:11; 56:9; 73:25; 143:3 5:16; 87:10; 92:20; 93:8; 98:13; 97:24; 116:24; 121:24 86:18, 19: 112:22; 141:14 Pregnancy [71 123:10; 143:7 144:18 pulled 121 151:14 81:2; 116:13, 20; 117:11; p roblem s (91 31:10,• 138:19 policy I 11 121:15; 151:23 31:24; 57:24; 58:2. 12; 59:2: pulmonary (1) 6-l: 25 pregnancy (ool 111:6; 112:18; 141: 21, 22 48:2 political I -, I 7:20; 12:9; 19:7; 27.•7, 11; 30:14; Pr ocedu re(t) pure 131 60:14; 110:8. 13 31:8, 9, 24; 32:10; 33:19; 36:1, 1:13 110:12; 134:7 politician I I ) 6; 51: 7, 13, S 2:18; 55:10, 16; pr ocedu res(2) Purely (t) 60:13 78:21; 79:15; 81:20; 87:19; 41:12: 56:3 35:9 politics 121 89:12; 105:11; 110:17,• 111:9, pr ocess 17) purist (t) 110:2: 154:3 11; 119:12; 141:24; 142:7, 15; 20:4, 10; 48:20; 50:11; 107:25; 34:20 pollutants I 11 144:9; 151:25; 152.•11, 15. 16; 112:16; 122:7 purple 1 t1 102: 24 153:4, 5, 21 pr ocessed Il) 62:18 tr Poole ) 11 pregnant(9) 131:7 purported (U r 122:16 19:5: 70:5; 71:4; 93:17,• 106:14; pr ocesses17) 144:12 J r poor la) 123:14; 141:19; 142:20; 144:16 8:6; 20:13: 21:14; 27:6; 31:1; purpose 12) m 99:11: 141:19: 14?: 2S: I 45: 21 Premature ( 11 107:20; 147:18 60:8, 11 poorly I t I 150:25 produce ( t ) purposes(21 ~ 90:3 r t 12 7 110 13 N 5 12 42 p ema ure [ 1 : : : : population 1441 10:10, 11; 89.•17; 92.•18, 21; produced (t) Pursuant Ul ~ 33:9; SS:14; 56:5; 57:2; 70:15, 93:1, 7,• 105.•12, 18; 115.•12; 14:23 1:12 21: 74:8• 10. 16; 91:23: 9S.•19, 126:18; 144:1 Professional I 1) Pursuing [1) 22; 96:2, 3, 5. 24; 97:10, IS; prematurity [S) 1:16 129:8 98: 2 2: 99: 7 100.• 9; 102: 8: 108: 9, 93:4, 5, 8; 105:7; 139:1 profound I11 putting ( I ) 10; 122:5; 123:15; 132:5, 10, 23; prenatal (2) 146:23 70: 6 134:l 2: 142: 23: 147: 9, 10, 14• 142:24; 143:24 program (5) 18, 21; 148: 3• 4. 8: 149:3, 4; preparation (2] 15:23; 99:21, 25; 153:19; 154.•1 152:3. 12 16:18; 23:24 programs 11) populatiuas I1:) prepare (I] 140:5 qualified (31 29:3; 71:8. 9: 95:9; 96:16, 20; 21:19 Project (I) 38:3; 40:3; 109:14 132: 4: 147:15, l6: 148:18, 19; prepared (a) 8l: 7 quality 121 62:21, 23 KEJTJi & AJJLLER (915) 533-7108 From plac:, to qualitv

as,, TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07•1A-996ok•s«css> 11:1; 16:17; 18:1, 2; 28:21; rupture 18) separate[a) 42: 7 29:25; 32:16; 66:11; 71:24; 89:18; 92:18, 22; 93:1; 105:12, 59:19; 115:2, 3; 143:7 simultaneous [1) 86.•19, 20; 123:25; 131:9, 10; 18; 113:12; 1S0:2S September 14) 96:3 137:24 ruptured 12) 17:4; 129:16; 137:10; 141:5 Sincerely (21 reviewed [)o) 10: il; 126:18 serious (1) 157:19: 159:19 10:9; 21:20; 22:5; 23:10; 29:14; rural (1) 111:6 single (6) 32:19; 44:14; 119:22; 131:3. 8 14S:2S seriously (11 35:6,• 53:3; 65:17,• 66r17,• 94.•22: reviewing 12) --.. 153:23 131:3 13.•20; 23:24 -S- serve 131 sit [51 reviews [a) 7:19,24;8:3 8:13; 38:12; 135:16, 23; 144:20 18: 7, 8, 9 Sachs [341 serves (1] situation (1) rewrite [ 1) 12:21, 24; 15:2, 4, 11, 18; 16:4; 60:15 122:6 144:8 29:12, 21; 30:11; 31:4, 6; 32:24; service (1) situations [1) Reynolds (11 66:13; 83:1; 97:4: 115:21; 18:14 153:9 2:14 117.•10; 118:1,13; 119:4; 120:i; Services (1) six [6) Rh (11 121:14; 122••17,• 123:2; 124:18; 128:16 24:10, 16; 44:2; 60:5; 63:11; 98:8 126:7, 9; 127:25; 136••13; services [t) 98:10 Richard [1) 137:20, 21; 138:24 67:21 skills 1'-1 75:24 S achs's (1) session (1) 134:3, 20 Richardson [ 1) 116:2 10:16 slight 12) 122:16 S ampling 1'-1 settlealent 13) 9737.20 Right (16) 36:4; 9730 11:25; IS3:12, 25 s6psfU 37:15: 62:3; 69:23; 71:13; 77.•8: S atanic 121 severe (1) 23:18 79:22; 80:3; 81:18; 84:9; 96:9, 103:21; 104:5 i 5 112:2 stnall-for-date.c (1) 14; 99:9; 100:14; 101:12: sa ) ng ( y severely I11 112:4 105:23 ; 132:17 S 54:9; 86:4; 89:9; 112:3; 133:18 l 3 98:20 smaU-for-gestational-age (11 right [17 1 can an [ ) shadow (8) 91:3 17: 24; 22:8; 29:6, 8; 35:17; 41:9; 2:12;16:11;24 :13 51:19; 52:6, 13; 53:16: 54:2: smaller (a) 57:13: 62:18: 69:1: 70.•9; 72:18; sc enario [1) 86:8: 87:25; 88:4 77:24; 90:15; 96:8, 16 75:8; 76:10; 90:21; 92:10; 93:20; 1S0:S Sharp's (11 smoke (12) 106:17 sc hedule [1) l28:23 70:5, 13; 71:5; 83:15; 87:7; right-han d 131 4:12 sharply (11 101:10,• 102:23; 103:19; 104:5, 77:10, I1; 104:23 sc hool [2) 30: 9 8: 148:3 Risk[11 39:12; 58:19 She'll I1) smoked 13) 121:15 sc ience (1) 141:7 79:9; 81:19,• 111:20 risk [79] 148:24 sheet 141 swoker (3) 18:11. 12; 27:8, 10; 31:22: sc ientific [31 62:/6; 69:22; 123:23; 137.•23 30:13; 82:24; 99:10 33:19; 34• 7 35:16; 36: l0; 47: 2l; 53:18; 110:10; 126:10 sheets I1) Smokers [2) S1:1S, 21, 24; 52:25; 53:1, 3. 11; Sc ientist [3) 117:7 91:2; 101:12 70: 6; 71: 25: 73:19: 74:1 S, 19, 34:21; 87:3, 4 Shook (1) smokers (21[ 23; 78:16, 20. 79:2, 3. 4, 11, 20, sc ientists [3) 2: 7 SS: l J; 36:14: S7.•3; 72:1. 12, 16; 21: 80:8. 10; 81:14: 82:3, 13, 17; 33:1, 1S; 107:1 3 Shorthand ( I ) 73:5, 22; 77:25: 78:3, 8; 79:/3; 84:3: 85:12; 87.5; 88:10• ?S: sc rips (1) 1:16 81:9; 92:19; 94:3; 95:22; 97:I3, 89: 6; 90: 2; 91: S: 93:3, S; 96: 4; 112:24 show 17) 21; 99:2; 101:21; 102:8 99:13; 101:16: 103:15: ill:S: se [tl 6:1; 21:16; 33:23; 68••12; 73:4; smokes (51 112:6: 127:4; 127:3; 134•9• 10, 10:25 94:6; 102:11 31:8; 34:5; 80:5; I11:16; 134:12 15; 139:1; 141:18, 24; 142:19• SE AL [Il showing (1) Smoking [9) 23; 143:12, 14: 149:2; 150:6: ISS:22 6:22 71:21; 103:18; IIS:6; 121:14; 151: 5, 10; 15 2: 8, 9, 10, 15, 19. se aled [11 shows (4) 139:21; 140••11, 13; 143:14; 21; 153: 2, 3 157:13 4:16; 90:2; 131:23, 24 151:22 risks II) se arch [2) sign [11 smoking [1211 110:20 14:3, 11 IS7:16 8:9; 10:23; 18:20; l9:3, 7; 20:6; Robbuis [;) se cond [9) SIGNATURE (2) 21:12; 30:13; 31:10, IS; 32:11; 3:20; 39:7, 10, 15; 102:13 10:17; 61:20; 6 9:22; 99:24; 3:24; 155:1 33:3, 19; 34:6, 10, 11, 19; 35:24, ROBER7• [sl 100:2; 118:21; 125:6: 138:5; Signature 131 25; 36:4,• 43:3; 44:20,• 43:21; l:ll; 3:3; 4:1; 155:14, 19; 151:24 158:13; IS9:1S, 16 46:6, 9; 47:2, 12, 24; 48.•1, 4. 7,- 157:14: 158:3; 159:14 se ction 171 siguature I11 49:14; S0••21, 22; 51:11, 12; Robert 161 63:3; 106:10; 116:12; 138:24; 1SS:16 34:15, 19, 22, 2S; 56:11, 15: 2:5; 3:9; 5:8; 43:3, 8 141:15; 142:19; 144:15 signed (11 S7.•6, 16, 23; 58:12, 24; 59:1; Rock 121 se gments [21 159:16 66:14; 67:3; 69:5; 70:16, 18; 4:21: 10:3 99:7; 100:9 Significance I1) 77:19, 20,• 78:3. 13, 24, 25; Rodeck's I11 se gregate121 76:16 79:11; 80:7, 10; 83:2; 87.•17,• 97: 6 111:24; 145:25 significant [15) 89:3,10,11,12,18;90:18; rodent['_I se gregated [1) 27:16; 47:13, 21; 56:8; 71:25: 92•16; 93:16, 17, 25; 97.•1, 1S; 108:5. 9 147:23 74:18; 79••2S; 90:9; 111:18; 98:21; 100:7, 15: 101:16: 102:3, role 111 se mantics [2] 114:1; 119:9; 132:8; 138•21; 17; 103:1: 105:4. 5. 10; 106:4, 66a3 29:3; 84••19 152:1 13; 110:17,• 111:11: 112:1, 10, roots [ 11 Se nate [11 significantly 111 11; 119:11; 122:6, 8; 123:20; 108:13 128:19 112:3 132:25; 133:19; 139:18: 140••8: Ross (31 se nd (21 signs [11 141:22; 142:6, 14: 143:4. 12; 2:15; 1S7:R; 159:R 12:5; 62:8 l43: 2S 144:2, 9: 147:14, 19, 20; 149:2; rotatinas [ 11 se ase [17) Simple [ll lS1:S, 25; 1.f2:10, 14. 18, 24 42: I S S.•17; 8:4; 19:13; 33:8; 37.•1; 37: J8 smoking-related (1) rubber [ I ) 38:13; 51:17; 53:12; 81:10, 12; simple [81 21:2 127:12 8S••2: 102:19; 103:4; 123:18; 8S: 20; 95:24; 99:1, 3; 134:13, societies 1;1) rud•uuentary (11 126:22; 127:24; 131:8 17; 135:1; 137:3 60:19 7:5 se ntence[9) simplex 121 socioeconomic (4) Rules I11 73:20; 89:15: 103:18; 141:25; 64:22; 66:8 S8:IS: 91:24, 25; 145:21 1:12 142:4; 143:9; 144:7,• 131:24; simplistically (1) somebody (21 rules (4) 132:13 52:20 82:6; 135:4 135:12, 13, 14: 150:21 se ntences (1) Simpson t11 someone (3) 81:18 51710 7251 hE1Tt1 8• AIILLER (915) 533-7108 From reviewed to someone

throughout the day. Finally, the growing fetus can compensate for chronic hypoxia by an increase in hemoglobin, and this is not observed in the fetuses and neonates of smoking mothers. In contrast to the mild and clinically insignificant hypoxia that may occur with maternal smoking, marked fetal hypoxia is known to result from chronic problems during gestation or acute events during labor and delivery. Risk factors for marked fetal hypoxia are frequently chronic pregnancy conditions during pregnancy such as maternal anemia, fetal blood loss, preeclampsia, toxemia, or diabetes. Severe chronic hypoxia is associated with marked IUGR and abnonnal histology of the placenta. Acute hypoxic events at birth account for the minority of cases of fetal hypoxia. Obvious acute events include cord accidents, severe antenatal hemorrhage, maternal hypotension, prolonged or intense labor, or trauma. Maternal smoking during pregnancy is not associated with the above chronic and acute conditions known to result in clinically significant fetal or neonatal hypoxia. Infants born to smoking mothers do not display signs of hypoxia that can be attributable to antenatal smoking. Apgar Scores Apgar scores provide objective information on the need to resuscitate a neonate at birth. Depressed Apgar scores are caused by many neonatal problems, including severe prematurity, marked IUGR, congenital abnormalities, and significant hypoxia. Maternal smoking during pregnancy should not be considered a factor associated with poor Apgar scores. Maternal Smoking During Pregnancy and Pregnancy Complications Antenatal smoking should not be considered a major risk factor pregnancy complications and adverse pregnancy outcomes. Maternal smoking during pregnancy is not a significant factor in increasing medical costs for the mother, fetus, or neonate in the Texas Medicaid population. Dr. Carpenter may be asked to comment on the opinions expressed by other witnesses, as well as the evidence on which they rely to the extent that these opinions relate to his areas of expertise. In addition, if individual patient records of Medicaid recipients are produced, Dr. Carpenter may testify about his review, if any, of these patient records. oo3ons.oi Page 6 -J N Ol N

BSA TEXAS v. 'I'HE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-24-9Qoolc•scc(41) L,ook-See Concordance Report 2- 37:12; 38:3, Jl; 42:20; 56:21; actions (1) 84:14; 97: 24: 111: 24: 121: 25: 86:22 20-plus [1] 125:25; 130:10; 133:12, 14; Active (1) UNIQUE WORDS: 2,439 41:15 J3S:6; 146:18; 148:19; 149:22 103:18 TOTAL OCCURRENCES: 8,949 21% (1) abnormalities 13) activity (1) NOISE WORDS: 389 103:2 55:13; 74:19; 78:1 J39:21 TOTAL WORDS IN FILE: 28,425 21st 12] abnormality I1) actual (5] J18:9; 137:18 33:11 21:3; 23:1, 2; SS:11; 117:18 SINGLE FILE CONCORDANCE - "' 22nd (1) Abortion (l) actuarial (1) 7:2 72:8 133:13 CASE SENSITIVE 24th (6) abortion (9) acute (2) 8:19; 9:6; 21:25; 23:7,• 143:4. 5 55:1; 72:25; 73:4; 77:20,• 79:1, 98:12; 121:23 PHRASE WORD LIST(S): 263-401 (t] J2, 1S; 80:12; 105:7 acutely I II JOHNSON.PHS 118:16 abortions (14) 151:12 72:13, 14; 73:21, 22; 74:3; 76:1; add (2) INCLUDES ALL TEXT -3- 77.•21, 23; 78:4, 5. 6. 8. 12 2S:15; 143:6 OCCURRENCES 30th (I] abortus II) 74: 7 added (4) 25:17, 20; 143:4, 16 DATES OFF 24:23 abortuses (1) addiction (2) 37th [ 11 7fi24 112:18; 139:23 IGNORES PL-RE NL'SIBERS 82:22 abruptio (5) addictive (5) 54:20,• 81:7; 92:17; 101:24; 49:2, 3; 139:23; J40:7, 8 POSSESSI%'E FoMIS ON -4- 10s:11 addicts [11 absence (1) l39:2S -$- 4.0-told [t] 110:21 addition [ 1) 91:2 absolute (l) 62:8 52,500(I1 42.1°k (I1 88:3 additional(3) 16: ?S 73:5 Absolutely (2) 17:13; 23:4 J37.•6 $250 (:) 45:14; J06:16 additionally [l] 16:17; 17:2 -~- absolutely (11 146:14 51:21 additions (1I -1- 5-21 (1] abstract (1) 114:18 22:25 148:6 additive (2) 1-236 (1) 5-30 (1] abstracted (1] 142:2; 146:7 118: 21 10 - 24:8 7 30 134:14 admit [ 11 :00 [ -I (1) 5- -9 abstraction (1) 31:13 4:16. ??: 6:22 23:19 137:16 admits (11 10:14 [I1 50s [I] abuse (21 I4S.•13 1:14 75:4 113:20; 142:25 admitted [2) 10:15 I11 4: 7 533-7108 121 •4; 159:4 157 academic (21 49:17,• J23:1 . 18:24; 41:18 admitting (I) 12th (I] 137: l1 5:96CV91 [4] 1:6; 157 •10; 158:9; 159:10 Academy (3) 146:8 . 60:19; 67:11, 14 Adolescents [1) 13th(11 accept (61 58:11 137: I1 -6- 6:16; 51:25; S2:10; 68:16; 81:13: adolescents [1) 15% (I1 72:15 60s (1) 103:7 58:13 I 15th III 75:4 acceptable (1) adopt [l) 150:18 I 663-737 (11 110:9 65:1 16th (?1 119:19 access [21 advanced (1I 23:8. 13: 28.8 I 6th I] ] 36:22; 145:19 78:9 17-ycarIIl 118:16 accident (11 adversc(.31 20:18 98:12 27:11; 35:16, 19; 36: J, 6, 12; 18-27.^r I II -7- accomplisbed (1] 4716; 31:7, 13; 52:17,• 70:7,• 120 •10 87 •19; 89:12; 93:6; 98:23; 72:16 9Sr (II 18 71ud (1) • accrued [I) . 102: 22: 110:17,• 111: 9; 134:13, . 73:5 128: 24 12.•14 14; 142:7,• 152:16; IS3:4 18th ! acid (1] adversely (1) 1 1 97:21 105:3 137:14 -g- 19-30.r (II 80s (I) acknowledging I1] S4: 7 advised [1) L" 143:25 ~ 70:5 20:17 ACOG [361 affair [1) v 1980-1992 l i ) 3:19; 31:14; 32:16: 55:17; 59:8 154:9 ~ 129:16 , m 1980-1993 (I ( -9- 9,10,21,23:60:2.8,22;61:1. Affecting I11 12, 22; 62:2, 7; 63:12, 18, 22. 128:18 J 129.13 900-plus(1) 24; 64:4, 20; 65:8; 66:1. 2, 14; affirmative (11 N 19S0s (Ii 119: j2 14;80:14;83:1; 67:I 1S;68:1 20: 7 W 110: S 90s I t ] , , 94:2, 10; 136:15 affixlll 1987-1988 111 75:19 ACOG's (11 155:15 128.17 9:00 (I1 61:23 African II) 1990-91 ( I [ 4:8 acquire [21 108:1 129:7 146:18: 149:23 age(171 1991-1992 I i I -A- acquired (41 40:6; S4••16; 73:12: 74:17 20, 128:12 • 145:14 79:25; 90:19; 96: 7 21; 78:9 21; 79:5; 91:17, 20 16 1993-9a i t 1 A-C-O-G (11 , acquiring (1] , , , 22; 93:25; 96:17; 99:18; 142:24 128:20 59:12 123:23 agent (11 1995-1996 111 a.m. 131 acquisition [1) 33:24 128:8 1:14; 4:7; 6:23 19: l7 agents (1] 1:55111 AAP Ixl act[I1 108:17 13-J: '? 60:21, 22: 63:24, 25; 66:2: 140:13 agree(55) Ist 111 67:10, 17. 24 action (3) 16:4: 20:3; 30.•1S; 32:9. 25; 33:3 36:15 able (231 139:17,• 156:10, 13 , 14; 3S.•23, 2S: 36:3; 45:10,• 7:1 12: 8:8; 16:2; 26:19; 35:6; , I:EITH & MILLER (915) 533-7108 Fron, S2,S00 to agree

PHILOP MvRhIS

LAW OFFtCES ATCHLEY, RUSSELL, WALDROP & HLAVINKA, L.L.P. 1710 MOORES LANE TEXARKANA,TEXAS75503 VICTOR HLAVINKA POST OFFCE BOX 5517 TEXARKANA, AR-TX 75505-5517 TELEPHONE (903) 792-8246 FACSIMILE (903) 792-5601 June 18, 1997 Dr. Robert J. Carpenter 6624 Fannin #2720 Houston, Texas 77430 . Re: Civil Action No. 5-96CV91; The State of Texas vs. The American Tobacco Company; United States District Court Eastern District of Texas, Texarkana Division Dear Bob: You may wish to review the enclosed items. Please call me at your convenience in order that we might discuss them. Thank you. VH: th Enclosure

To: Dr. Robert J. Carpenter From: Victor Hlavinka (Atchley Law) 6-13-97 18:52am p. 1 of 2 ATCHLEY, RUSSELL, WALDROP & HLAVINK/4, L.L.P. 1710 MOORES LANE - P.O. BOX 5517 TEXARKANA, AR-TX 75505-5517 TELEPHONE (903) 792-8246 FACSIMILE (903) 792-5801 PRIVILEGED AND CONFIDENTIAL. The attached information is intended only for the named addressee(s). If you are not the named addressee (or an authorized employee or agent), do not rEad the information, and note that any use or communication of this information is strictly prohibited. Please notify us of any problem by phone, and if this has reached unauthorized hands, return it to us by U.S. Mail. Thank you. To: From: Dr. Robert J. Carpenter Victor Hlavinka (Atchley Law) Date: 6-13-97 Page 1 of 2

LAW OFFICES ATCHLEY, RUSSELL, WALDROP & HLAVINKA, L.L.P. 1710 MOORES LANE VICTOR HLAVINKA TEXARKANA,TEXAS75503 POST OFFICE BOX 5517 TEXARKANA, AR-TX 75505-5517 TELEPHONE (903) 792-8246 FACSIMILE (903) 792•560 i Dr. Robert Carpenter 6624 Fannin #2720 Houston, Texas 77430 June 9, 1997 Re: Civil Action No. 5-96CV91; The State of Texas vs. The American Tobacco Company, et al - Med Ec Witness Development Dear Dr. Carpenter: I enclose excerpts from the Plaintiff's listing of proposed expert witnesses. The experts contemplated by the enclosure are those whose testimony may relate to some aspect of the case upon which you will be focusing. I also enclose a copy of the Expert Disclosure Statements that have been filed by the State in relation to each of these experts. Thank you. VH: th Enclosures Yours very truly, Victor Hlavinka V fV W U1

LAW OFFICES ATCHLEY, RUSSELL, WALDROP & HLAVINKA, L.L.P. 1710 MOORES LANE VICTOR HLAVINKA TEXARKANA, TEXAS 75503 POST OFFICE BOX 5517 TEXARKANA. AR•TX 75505-5517 TELEPHONE (903) 792-8246 FACSIMILE (9031792•5601 Dr. Robert Carpenter 6624 Fannin #2720 Houston, Texas 77430 June 9, 1997 Re : State of Tezas vs. American Tobacco Compan}; et al Dear Dr. Carpenter: I enclose copies of additional materials that may be of interest to you in your work on this case. You will note that--in most cases--these materials are excerpted from larger volumes. In the event that you should like a copy of the entire volume in any one or more of these instances, please let me know and I will get it (them) to you in due time. Please call me about these enclosures at your convenience. Thank you. Yours very truly, Victor Hlavinka VH:th Enclosures v N OD rn

c c Ak co -~-'b (~c N.. ~ '~-- -'- ?

BSA TEXAS v. THE AbMRICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-24-9(Lok•S«(aR) 66:8 Crow (3] Dear (2) de partment [3] Corners (1) 5 108 2:15; J57:8: I39:8 IS7:12; 159:12 I 97:6: 122:22: 149:21 : Coronary (1) 47:9 coronary (4) 47:13, 16, 21; 48:10 cry (1) 58:1 Cuban (2] 147:8, 18 culture (11 death (5) 47.•23; 56:16; 130:14; 146:IS, 16 deaths It1 103:11 decade (2) de de de pend (1) 38:8 pendency (i) 112:13 pendent (1) CORRECTION (1) ___ 155:2 64:21 current (5) 2036, 17 December (2) de 149:24 pends 15] correction 15) 15:7,• 17:24; 40:9, 11; 89:7 128:22; 156:19 19:8; 4fi•17,• 60:9; 61:5; 152:20 82:19; 107:19; 129:10; 132: 6; currently [21 decided 13) de posed 11) 137:10 IS:23; 17:3 9:17; 11:13; 12:4 12:21 CORRECTIONS 121 Curtis (4) decisions 131 de posited (1) 3:24; 155:1 8:23, 24; 24:12, 18 64:10, 14 IS4:J Corrections 121 CVA (1) decreased 121 D eposition (13) 159:15, 16 S6.•S 59:3; 147:13 1:10,• 3:12, 18; 4:16; 5:2. 21; 6: 9, corrections I1) cycle (1) decreasing 11) !S, 2J; 68:11; 102:10; 130:2: 159.•1S correctly 151 71:24 153:18 defecate (11 de 140:21 position (aa) 22:13; 27:17; 74•l; 106:11; -D- 57:25 4.9, 16, 18, 20, 21; 5.9; 6:13, 22; 132:19 defect (1) 12:24; 13:8, 9; 16:11, 17, 18; COST I I ) daily (1] 56:7 23:24; 29:12, 21; 30:1, 8; 31:7, 1:21 145:23 Defendant 121 17, 19; 32:24; 97.•4,• 116:3, 6; costs 121 Dallas (31 2: 7, 14 118:2, 8; 119:4; 122:19; 124:24; 152:1; 153:17 2:16; 157:9; 159:9 defendant (11 125:1: 137:17; 140: 24; 134: 22: counsel (3) damage (1] 17:22 ISS:IS; JS6:4, 6. 7. 10; 157:13; 4:7; 79:10; 159:17 148:22 Defendants ( l ) 158:5; IS9:13, 15 counseled I1) damages [51 1:8 de positions 1121 14a: 2 133:5, 8; 133:23; 148:25; 149:1 defendants I1) 4:19; 12:22; 13:7. 20; 15:13; countries 131 dash (11 4: 7 18: S; 25.24; 26:12; 32:1; 118:13, 20.•9; 72:11; 96:13 119:10 D defense (9] 24; 137:21 countr)' 171 ata 11) 7:19; 9:23; 18:2; 25:25; 32.•7; de scription II) 21:2: 61:18; 96:15; 107:4, 22, 128:13 44:6; 86:20,• 114.•12: 125:13 104:4 23; 108: 23 C data (76) 19:17 • 33:8 20; 48:24; 54:21; defer (1) de sign I11 ounty 141 9: 2S; 10.• 2; 70:14; 148:1 , , 55:2, 11, 18; 56:22: 3718; 61:9: 134:1 deficient (1) de 120:20 signated 11) countv (2) 62:12; 75:16; 83:25; 85:4; 87.•2; 99:12 146: 9 85:17 111:14 90:1, 18; 97:12: 98:2; 99.?0; deficits (1) de tail 121 couple p/i 100:19, 23; 110:8, 14, 16, 23: 57:17 22:6; 80.•9 5:24; 37:4; 42:15. 25, 71:23; 121:11; 123.•13, 22; 130:11, 12, define (1) de tailed (1) 102:13: 130: 25 18; J31:12, 20, 22; 132:24. 25; 19:9 121:10 couple-minutc I11 133:1, 14; 134:7, 8: 144:23: defines [11 de tails II) I12: 2S 145:6, 8. 17, 19, 24; 146:1, 2, 4, 33:11 139:3 course 110) 8, 11, 12, 13, 21, 23; 147:8, 12, defunidon la) De terminants (11 9:15; 10:23; 21:23; 40:21; 61:12, 24; 148:17,• 149.•9, 11, 12, 20, 34:15; 35:18; 52:10; 59:11 15; 63: 17,• 65:10 138 a 8: 140 :12 22; 150:3, 6. 8, 15. 19; 152:6: definitions ISI COURT (41 153:15, 21 26:21, 23; 27:24; 30:25; 96:20 1:1, 21 ; 3:25; 1S8:11 database (9) degree [ 1) Court 121 10:20; 103:6: 127:5; 130:18; 33:25 4.•2; 158:11 J31:11; 134:4; 146:23; 149:23; degrees I I I court (?1 1 S3: 20 107:15 4:8; 8:13: 113:21 databases (31 delay 121 s 145:5; 146:14; 148:15 co.er (. I 13:11; 46:4; 69:22: 82:9; 86 2: Date [41 4:11, 23 delete 111 109:8; 113:5; 129:18 137:6; 138:14, 16; 159:6 152:19 covered ( 2I date (1) deleted [1) 62:14; l4l:l' 7: 2 152:23 co% ersl-,] dated [4) deliberate I I I 63:1_'; CPS (SI 100:22; 119:21 128:25; 129:2, dates (11 16, 17 143:1) Delivered [1) 78: 2, 6, 8, 11. 13 24:17 158:15 Creac r' I l I David ( l l delivered (1I , 42:11 crcate(11 14:24 Day (31 82:22 deliveries 121 98:13 created ('_) 6S: 22: 66:19 credibility (11 94:15 criteria [`1 62:16. 19, 20; 121:1, 3 critical I 1 ] 96:21 criticisms I1) 124:3 cross 121 130:13; 146:12 cross-linking I11 145: 7 cross-tabulate I 11 146: 22 2:14; 137:7 159:7 da,v 1a) 9:8; 16.•25: 39:8; 155:21 days [Sl 8:2, 11: 17:17; 159:17 dead 131 85:24; 87:13; 126:23 deadline [1) 150:18 deal II] 18:16 Dealing [ 1 ] 75:8 dealing 181 18:20; 43:3; 50:21, 22; 67:2; 69:4; 72:25; 102:14 deals (1) 93:16 83:5; 132:9 delivery 191 40:13; 56:12, 13: 82:IS, 17; 98:2; 140:11, 14; 151:6 Demographic (:1 128:16, 18 demographic (2) 130:17,• 132:24 demographics [21 144: IS; 148:18 demonstrated (4) 72:11; 92:/S; 101:9; 149:21 denominator I t ) 108:] Department (71 128:15, 25; 129:7, 10, 11, 14; 130.•S 119: 20 determine 14) 111:17,• 120:22: 135:25; 149:8 determined 121 81:17,• 104:18 developed I1I 72:11 development (21 98:17; 101:24 deiiadon I1) 86:23 device [21 140:11, 14 devising [t) 133:17 diabetes (11 79:24 diagnose 11) 111:9 diagnoses 121 146:8, 9 Diagnosis [1] 76:15 diagnosis (2) 62:15: 146:11 diagnostic (1) 62:19 diatneters It) /00:22 diarrhea 11) 20: l2 dictate I1) 22: l die 111 21:1 died I 1) 102:25 liEITN A• AJ)LLER (915) 533-7108 From Corr.:rs to died

many known risk factors for these conditions, and the clinical significance of anteparturn hemorrhage for the mother or fetus depends on many unique factors in each pregnancy, including when these events occur in gestation and whether they increase the risk of premature birth. Placenta previa is the abnormally low implantation of the gestational sac in the uterus so that the placenta grows over the cervix and thus precedes the infant at birth. Risk factors for placenta previa suggest that old uterine scars exist in normal implantation sites and therefore lower implantation sites in the uterus are favored. These predisposing factors include multiparity, advancing maternal age, and previous caesarian section, as well as a tendency for repeat placenta previa in subsequent pregnancies. Placenta previa is commonly diagnosed early during pregnancy so that appropriate medical surveillance can reduce risks to mother and fetus. . Abruptio placenta is the separation of the placenta from the implantation site before delivery of the fetus. Although the primary cause of abruptio placenta is not known, the most common risk factor is chronic or pregnancy-induced hypertension. Other risk factors include increasing maternal age, increasing parity, ethnicity (more common in blacks than in Hispanics or whites), premature rupture of membranes, multiple gestations, external trauma, cocaine or alcohol abuse, uterine fibroids, and chorioamnionitis, as well as an abruption in a previous pregnancy. Abruptio placenta can be complete or partial, symptomatic or silent, and anticipated or unexpected. The course of medical treatment and outcome depend on the unique circumstances of each pregnancy. Maternal smoking is not associated with chronic or pregnancy-induced hypertension or any of the risk factors that are known to predispose for these placental complications of pregnancy. Also, as will be discussed later, maternal smoking during pregnancy, has little, if any, effect on the duration of gestation so that it should not be considered a risk factor for prematurity, one of the most significant concerns for these placental complications. Premature Rupture of Membranes Premature rupture of membranes (PROM) is the most commonly identified factor in pretenm labor. Although the cause of PROM in a pregnant woman is usually unknown, local infection or chorioamnionitis is probably present in most cases even though not diagnosed clinically. There are some other known risk factors for PROM, such as sickle cell anemia, polyhydramnios, and multifetal gestations. About 30% of pregnancies in patients with sickle cell anemia are complicated by PROM for some unknown reason. The clinical significance of PROM for the mother and fetus probably relates most importantly to the time in gestation when this condition occurs. If the pregnancy is new or at tenm, risks for the mother and fetus are minimal as long as delivery occurs soon enough to avoid chorioamnionitis. If PROM occurs before 38 weeks gestation, clinical judgement determines the appropriate course to minimize the risks of prematurity and chorioamnionitis. xamzs oi Page 3 11

To: Dr. Robert J. Carpenter From: Victor Hlavinka (Atchley Law) 6-13-97 10:52am p. 2 of 2 LAW OFFICES ATCHLEY, RUSSELL, WALDROP & HLAVIM(A, L.L.P. 1710 MOORES LM1E TEXARKANA, TEXAS 75503 VICTOR HLAVINKA POST OFFK:E BOX 5517 LicensethTexaandArkansas T ARKANA AR-T . i iELEPHONE (PW) 7928256 FACSWfILE (D0:1) 7p2590t June 12, 1997 VIA FACBIMILE 713/795-4422 Dr. Robert J. Carpenter 6624 Fannin #2720 Houston, Texas 77430 Re: Civil Action No. 5-96CV91; The State of Texas ts. The American Tobacco Company; United States District Court Eastern District of Texas, Texarkana Division Dear Bob: We have just been served with a Notice from the Plaintiff's attorneys in this case by which they seek to take your deposition on July 15. Thi © Notice came to us without any forewarning and without the usual efforts to arrive at a mutually agreeable date for the deposition. For these reasons, it is far from a certainty that your deposition will proceed on the above date. It is highly likely that we will be able to enter into discussions with the State's lawyers to bring about a rescheduling for a time that will enable everyone involved (certainly, you) to readily accommodate the deposition. i will be in further touch with you when and as the matter should become better clarified. Thank you. Yours very truly, Victor Hlavinka (DICTATED BUT NOT READ) (This docuoent is being sent directly via consXrter facsimile without signature.) VH:th

TIME RECORD FOR LAW CASE REVIEW CASE I X VS. 1 h,Wf' IV`o iUl-\ S ATTORNEY 1-I l aV I~ V~A , y~G7CtL DEFENSE: PLAINTIFF U44 - b 2'4- (p STARTING DATE I / L.. Z/ 13" I•OTALS @ $ @ $ j-gc3 -+ 92 - Sz.4 ~ Ln ~ /H R N m /HR ~ N SUM a~

BSA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07•24-9Qook-s«(42) .fl.•10,• .f4.11, 14, 19, 22, 2S; 69:12; 71:20; 72:3, 5, 18, 19, 23: 73:6; 74a4; 78:22; 80:20; 83:7 87:18; 88:7, 17,• 89:10, 14, 19; 95:12; 102:19; 103:3; 105:1, 2, 17; 106:15; 121:18, 20,• 139:2, 19: 141:22; 142:8, 9; J44:10, 11; 1471; 1S2:17 agreed 111 116:23 air (1] 9:10 aircraft [11 11:14 al (s) 1:7,• 73:20; 157:11; 158:7,• 139:11 Alan (1) 129:5 alcohol [21 140:2; 143:1 allegations (1) 150:9 alloimmunized ]1] 98:9 aUow [3] 98:15, 16; 134.•6 allowed (1] 100:1 alluded [1l 45:18 alone [31 18:10; 34:18; 63:22 Amended [2] 4:15; 6.•21 AMERICAN (4) 1:7,• 157:10: 138:7; 159:10 American 191 59:11; 60:19: 63:10; 6711, 14; ! 18:10, 17, 20; 119: 7 amongst (1] 33:16 amount [s) 20:19; 30:22; 33:25; 38:14, IS: 39:25; 41:22: 83:25 amounts ]I1 33:24 analysis [+I 74•2; 120:4, 13, 20; 121:1; 123:25; 124:14; 131:24 analyzed (31 20:4: 75:16, 19 anatomic [11 38:11 anemic (1] 98:20 Annual (11 128: 9 annual I11 62:5 anomalies (2[ 77:22; 78:16 anoreaia [ l ] 112:19 answer (1'_1 5:19; 30.•6: 37:18; 38:17: 39: 20, 24; 57.• 19: 68: 7: 103: 23: 120:11; 133:20, 21 Antenatal 131 1S1:4: 132:14, 24 antenatal [21 152:10, 18 anterior 111 41:14 antibodies [ 1 ] 108:22 autitobacco (1 ] 103:25 anybody (1 ] 30:9 anyway (1) S8.•22 anywhere(3l 55:25; 65:10; 76:24 apologies (1 ] 4:23 apologize (3) 114:8; 125:9; 142:3 apparent(11 - 72:14 apparently 191 16:1; 25:23; 26:3, 10; 43:1; 97:19; I1S:22; 123:12; 129:3 appear [21 6:2, 13 appears [z1 95:6; 156:6 apple (1] 109:20 apples l1) 120:21 applicable [a) 62:13; 143:9; 146:19: 147:3 application (1) 63:10 applied (1] 63:6 apply (21 71:11; 147:2 appreciation [1) 131:14 appropriate [14l 28:23; S0: J0; 57:21; 63: 9; 65:5: 70:20; 96:24; 121:6; 122.•11; 133:15; 135:2; 146:21: 133:11 appropriate-weight [11 83: 6 appropriately (21 41: l0• 73:11 approximately 171 14.•14; 17:14, 2S; 18:1; 65:18; 72:15; 108:6 April l-'1 121:17; 129:17 apt 111 l04:4 area (28] 7:19; 19:1, 4; 20:1, 21; 37.•17; 38: 23; 39: S, 18: 40:15; 41:3, 24; 42:10: 45:11, 13; 51:4; 32:21: 66:7, 10; 84:6; 87:9; 89:4; 100: 20, 22: 108: 3, 5: 121: S: 138:12 areas [15] 18: 23; 20:1, 22; 3 7.•S, 9: 38:13, 14, 19; 39:21; S1:22: 62:21, 24; 71:14; 75:14; 108:17 arena (I] 43:2 Arizona [1) 92: S Arkansas [11 4:21 Arrington [31 4:2/; 43:8, 9 artery 131 47:22; 48:7, 10 article (19] 15:4; 19:11; 49.•18, 19, 20; 56:1; 74:11: 92:12; 94:11, 22; 93:5; 973, S; 119:15; 120:23; 121:13. 18; 126:5 Articles [21 3:15, 21 articles (24] 12:10, 13, 15, 16: 18:15, 20; 19:21; 54:18; 55:9: 59:6; 72:6. 20, 21; 85:11; 119:22: 120:17, 18; 121:4; 122:20; 126:17, 18; 138:21, 22, 25 ascending ( t ] 90:7 Asian (1] 92:3 asking 141 32:6,9,12,16 aspect [11 7:21 aspects 1121 10:12; 21:12; 27:10,- 34.•9; 38:25; 40:10,• 41:8, 11; 44:20; 89:25; 107:24; 134:8 assessed ( 1) 121:3 Assessment 11) 119:21 assigned (1) 107:8 associated (11] 19:4; 22:21; 32:10; 47:23; 48.•6; 38:24; 112:3; 119:11; 142:6; 144:10, 12 Association (1) 87••S association (19) 27••8; 34: 7,• 35:15; 47:10; 31:22; 54:17,• SS:19; 77:18; 78:11, 2S: 83:2; 84:2; 85:23; 88:11; 92:15; 93:10; 105:5. 1S; 115:15 associations 191 8:3; 27:12; 31:24: 46:14; 47:1, 8; 50:7: 110:21; 127:4 assume (ls) S.•9; 6:18; 9:15: 16.•21; 21:24: 28.•S; 39:]2: 68: 22; 107••6: 109: 2; 122.•13; 135:8, 14; 148:16; 150:20 assuming (ZI 16:22; 79:12 assumption (11 134:11 assumptions (11 135:1 assurauce(21 62:21, 24 assure(11 52:4 asthenic (11 112 •16 asthma 141 111:20; 112:2, 10, 11 astute (1) 133:12 ate 121 112.•21 Atlauta [ 11 I07:1 attach 12] 6:20,- 140:25 attached 121 4:15; 117:6 attempt 131 40:12; 41:13; 143:11 attended (31 8:21; 24:8; 25:23 Attorney (5) 3:8: 25:11; 91:7. 8; 158:21 attorney 131 31:3; 136.•9, 12 attorney's (1] 24:16 attorneys1121 8:12;9:1;10:21;18:10;24:11; 25:10,• 28:6; 32:7,• 44.•2; 114:12: 125:13; 137:4 Attributable 11] 121:15 attributable (6) 103:1; 122:4; 134:10; 149:2; 152:8, 9 attributed (21 27.•14: 78:13 augmentation (2) 99:22; 100.•4 August (11 150:18 Australians 11) 48:23 author (2) 15:S; 42:19 authoritative (s) 39:3; 40.•17,• 41:25; 124:9. 11 authors (2) 40:20,• 42: 6 available (2) 14S:S, 17 Avenue (3) 2:13; 157:8; 159:8 Avery (3) 40:18, 24 awaiting I1) 149:13 aware (6) 11:9; 15:14; 46:17,• .SS:23; 115:24; 137:3 awhile (tl 117:24 -B- babies (tt) 40.•13: S7••2S; 83:6. 7; 91:21; 96.•8, 19 baby (6) 40:2. 4, S, 7, 8: 99:11 background (2) 72:13; 95:18 Bacon ( I1 2: 7 bacteria [ 1) 48:25 bacterial (2] 90: 7 8 band (1) 12732 Bank 121 IS7:2: 159:2 banking (1 I 110:4 banned (1 ] 142: l6 bar (I1 86:21 barbiturates [1) 112:14 base 131 13:5; 60:14; 97:23 based 131 6S: 20: 77:16: 92: 20; 102: 20; 104:3; 130:12; 132:12: 132:3 basic (7] 31:11; 34:4. 10; 106:12; 123:23; 134.•11; 133:1 basically 1131 7:13; 8:3; 10:7,• 11:22: 19:19: 30:8, 14; 32:3; 62:10; 72:3; 74:14,• 78:22; 136:16 Basis (1) 3:20 basis (9) 16: 2: 20: 23: 65:9; 67:16; 77: 22; 82:16; 140:4; 148: S; 149: 2 batch 111 118:4 Baylor (5) 36.•14, 15, 25; 39:8; 44:10 beat [31 85:24; 87:12; 126:22 Beaumont (11 2:4 beautiful (11 103:25 becomes [I] 74:18 becoming I1l agreed to becomes (915) 53 3-7108 KEI TH &>\TILLER

CONTENTS 88ZL OTLtS i Partt. Female ..................................................... 371 Pregnancy and Pregnancy Outcome .................................. 371 Introduction ................................................... 371 Pathophysiologic Framework ..................................... 371 Nonexperimental Studies ......................................... 374 Fertility and Infertility ......................................... 374 Ectopic Pregnancy and Spontaneous Abortion ...................... 375 Fetal. Neonatal, and Perinatal Mortality ........................... 376 Birthweight and Gestational Duration ............................ 379 Introduction ................................................ 379 Continued S moking .......................................... 381 Cessation Before Conception .................................. 382 Cessation After Conception ................................... 383 Birthweight ............................................. 383 Preterm Delivery ........................................ 386 Complications of Pregnancy ................................... 387 Randomized Trials of Smoking Cessation During Pregnancy ............ 387 Prevalence of Smoking and Smoking Cessation During Pregnancy and Time Trends in Prevalence and Cessation ............................... 390 nr uct .............................. 390 Prevalence of Smoking and Smoking Cessation ..................... 390 Time Trends in Smoking and Smoking Cessation ................... 393 Estimates of Attributable Risk Percent .............................. 393 Age at Natural Menopause ............................•.•.••••••••.. 396 Introduction ................................................... 396 Pathophysiologic Framework ..................................... 396 Studies of Former Smokers ....................................... 398 Part 11. Male ....................................................... 400 Introduction ..................................................... 400 Pathophysiologic Framework ........................................ 400 Sexual Activity and Performance ....................•..•.•..••••••••401 Sperm Density and Quality ......................................... 4~ Conclusions ................................................ .. ...410 References ...... ................................................ 411

_j --„ t . ...........,.....,_..,..._...._...,.. .. ,.;,. .. .............. .. .. reprinted by the U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES + ` Public Health Service From The Neakh Benefits oJSMOKING CESSATION s report of the Surgeon General 1990 pages 367-423 CHAPTER 8 SMOKING CESSATION AND REPRODUCTION CDC a.ns.w w.w m~.a E EXHIBIT S ~

68ZL 0ZLZ5 ~,.._,~-.....v W PART I. FEMALE Pregnancy and Pregnancy Outcome Introduction Since the late 1940s, cigarette smoking during pregnancy has been linked with poor pregnancy outcome (Bernhard 1949; Athayde 1948). Adverse effects of smoking on pregnancy began to receive considerable attention after publication of the results of a study of 7,499 pregnant women in San Bernardino County. CA, in which the rate of prematurity, defined as birthweight less than 2.500 g. was found to be about twice as high among smokers as among nonsmokers during pregnancy (Simpson 1957). Early reports of the Surgeon General (US DHEW 1971. 1973. 1978) concluded that maternal smoking during pregnancy retards fetal growth and is a probable cause of late fetal and infant mortality (US DHEW 1973). The 1977 Report of the Surgeon General (US DHEW 1978) concluded that smoking during pregnancy has dose-response relationships with abruptio placentae, placenta previa, bleeding during pregnancy, premature and.prolonged rupture of the membranes, and preterm delivery. The 1979 and 1980 Reports of the Surgeon General (US DHEW 1979; US DHHS 1980) comprehensively reviewed information on the association of matemal smoking with pregnancy outcome and further concluded that the risk of spontaneous abortion in- creases with the amount of smoking and that the risk of sudden infant death syndrome (SIDS) is increased by matemal smoking during pregnancy. The 1980 Report (US DHHS 1980) also indicated the possibility of a link between cigarette smoking and impaired fertility. Two earlier reports of the Surgeon General (US DHEW 1979: US DHHS 1980) concluded that mean gestational duration is not affected by maternal smoking and that data are not sufficient to support a conclusion that maternal smoking increases, decreases, or has no association with risk of congenital malformations. This Section reviews observational studies of smoking cessation and the following reproductive outcomes: fertility and infertility; ectopic pregnancy and spontaneous abortion: fetal, neonatal, and perinatal mortality; birthweight and gestational duration: and complications of pregnancy. Three randomized trials of smoking cessation and pregnancy outcome are described and discussed in detail. Information on the prevalence of smoking during pregnancy and time trends in prevalence is presented, along with estimates of the attributable risk of several pregnancy outcomes. SIDS and congenital malformations are not considered because of the limited information on smoking cessation. Pathophysiologic Framework The effects of smoking that might mediate adverse effects on the developing fetus and on fertility, fetal loss, and pregnancy complications have been reviewed in other publications (Longo 1982; Mattison 1982; US DHHS 1980). These reviews are summarized with attention to the temporal course of the relation between exposure to 371 I I

BSA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-24-9D6ot•s«t441 3.•22; 14.•18, 24; 138:10; 140:24 57:17 35:5; 52:22; 112:20 consideration [1) children [3) cognizant (1) compleadties I1) 103:15 S7••20: 111:23: 146:3 67:8 60:10 considered (12) choice (1) cohorts (1) Complications 12) 10:18; 27:10; 31:22, 23; 37•3; 114:5 94:24 81:3; 151:23 S9:J7, 20; 139:7,• JS1:S; 152:15 choices I1) cold (1) complications [I1) , 2S; 133:1 83:21 58:1 7:20,• 30:14; 31:8, 9; 32:10; 93:4; considering [11 choose Il) Collaborative (2) 103:11; 141:19, 24; 132:16; 63:10 120:17 81:6; 90:14 153:4 consistency (2) chorionic [1) collaborative (4) Component (16) 84:1; 88:12 56:3 75:3; 77:17; 81:5; 99:15 10:18; 19:24; 23:16; 27:1; 30:7,• consistent (s) . chromosomal 17) Collection (t) 34:6; 49:21; 60:13, 18; 62:5; 33: J8; 83:2; 84:1; 89:17; 94: 9; SS:13; 74:2, 6; 77:21, 2S; 78:16; 129: 9 89:1; 90:19; 112:IS; 115:3; 96:12; 102:3; 111:1 97:11 College [2) 143:7,• 145:20 consistently (2) chromosomally (1) 39:11; 63:10 components [4] 71:2S; 74:21 73••23 color I1) 62:12; 89:5; 116:24,• 137:17 coastruct (4) chromosome 11) 62:18 composite l1] 96:17; 103:6: 110:19; 120:10 74.•19 COLSON 14] 95:22 constructiug [1] chronic (1) 4: S; 117: 21; 154:17, 21 compounder (1) 133:25 48:1 Colson (6) 37:1 construed (1) Chronicle [2) 2:16; 157••7 12; 158:21; 159:7, compounds (2) J39:8 49: S, 7 12 104:9, 18 contacted (1) Cigarette [1) combination (1] comprehension (1) 6:24 104:8 83:5 131:11 contained (5) cigarette [17) combined (1) computerized [1) J3:22; 78:23; 126:13; 131: J8; 33:19: 77:19; 78:3, 13; 80:7, 10; 102:24 18:5 139:3 100:7, 13; 102:23; 103:1, 20; coming (2) computers 121 Containing ll] 104:5; 105:5; 112:1; 123:20; 12:23; 73:21 145:19; 149:19 64:y 140:16; 149: 2 comma [1] conceding (!) contaiuiog (1) cigarettes 16) 144:10 133:21 64:6 20:21; 31:25; 81:20, 139:18, 25; command (2) conception [2) contains (11 142:15 104••1, 3 71:23: 87:16 104••8 circumstance [16) commeat (7) conceptualization (t) content(2) 35:13; 53:3; SS:8; 74:13; 82:4; 35:8; 74:11, 13; 98:5; 140:3; 66:23 97:18, 22 83:11, 25; 84:22; 86:11; 87:2, 144.•19; 153:10 conceptualize (!) context[51 11; 89:7,• 112:20; 122:6; 151:9; commenting I:1) 48:17 28:19; 29:2: 47:6; 79:16; 92:23 154:3 144:20 concerning (9) continuation (t) circumstances (4) comments [1] 12:8: 26:23; 31:14; 45:21; 48:24; 1J8:1S 34:25; 65:2; 84:3; 110:15 45:3 50:8; 146:2, 3: 147:18 cootinue (2) citing [ll Commerce (2) coudude (2) 64:16; 70:5 95:1 157:2; 159:2 74:23, 2S continued (2) City [21 committee I8) concluded I1) 39:12; 64:21 2:8, 9 65:23 25; 66:3 4 6 16 24 154 22 Civil I 1) , , , , ; . 67:22 : conclusion (21 continuing lt) 64: 24 1:13 eommittecx (3) 73:13; 75:25 contributable ll) clarify [l) 60:20, 22; 67:20 conclusions (6) 103:14 22: 7 common (5) 75:13; 106:2: 110:13; 121: 19; contribute (t] clarifying (11 81:8; 108:1; 141:18, 24; 142:22 126:13; 131:19 66:11 30: 7 communication (1) coodusive ( t) coutributct(1] class (1) 11:21 98:3 88:25 108:17 community [11 Condensed I1) contributing (1) da•csec I 1) 45:11 3:16 109:4 91:23 companies [91 conditioning (1) contributor (3) classification (l) 7:14, 25; 12:4; 14:8; 25:11; 29:9: 9:10 47••1S; 48:21; 88:24 18:8 43:25; 50:18; 130:7 conditions [2] contributors (2) classifications [ 11 COMPANY 14) 10:24; 101:3 110 1 2 92:1 dean (31 1:7; 157:11; 158:7; 159:11 m 4 C confirmed (1) : , Control (3) pany 1 ) o 4:17 106:18, 22; 107:12 5: 22; 8:14; 61:19 49:12; 118:10, 18, 20 confounder(1) control [?) dear 1151 company 141 90:11 73 2 78 15 S:17,• 8:10: 54:17; 55:20, 21; 29:5; 42:23; 43:19; 133:25 confounders (1] : ; : controlled (51 86:3; 88:11; 92:15; 93:9; 110:6: comparable 12) 120:14 33:10, 13; 35:10; 73: J 7; 74:20 115:15; 133:16; 135:22; 143:4; 151:14 120:18, 20 1 confounding (2) controlling (11 compare 1 ) 34:10; J00:3 73:16 client 141 6:17 Congenital (!) controls (!) 149:18, 19; 150:12, 18 compared (6[ 53:24 91:23 tn cBents [1) 72:1; 73:5; 84:17,• 91:4; 97:16; congeoitall2] conversation (t) tr 149: 24 Clinical I 1) 101:10 comparing I11 78:9; 79:24 Congress (1) 7:7 conversations(2] v N 76:15 clinical 14) 96:1 CompaliSon (4) 153:13 consecutive (! ] 43: J6, 18 coordinator (!1 m J 38:10; 62:13; 82:12: IS0:5 67:6; 96:2, 20; 146:13 129:6 4:19 N clinicauy (1 I comparisons (3) coosequences(1] Copy [1) ~ 72:14 73:15; 130:16; 134.•18 102:22 159: J3 ~ clip 1'1 compartnweutalization [ 11 consider [21] copy (131 49:21, 24 134:8 18:25; 19:3; 21:12; 28:22; 3fi7, 6:3, 14,• 21:18; 28:13; 29: 20; clouded I11 competent (3) 16, 22; 39:17,• 41:3, 13. 21, 25; 77:2; 113:17 21; 137:13; 85:22 41:14; 42:20; 45:4 56:9; 58:3; 83:12; 91:22; J03:24; 140: J9, 25; 151:16: 158:5 co-authors 1'1 complete (4) 133:11: 139:12: 14 2: l; J S3: 8 cord (1) 31:16; 138:23 6:14; 18:4; 130:12; 143:15 considerable 131 98:12 cognitive [ll complex (3) 21:6, 11, JS Corey (l1 children to Corey (915) 533-7108 KEITH & MILLER

C.u-t. ~~.=, ( I f, (, 4, 3 - -:~ 3 4 ~ )Sz 1~_~- Eli r'A 19 ° 4 C~ rq-3 ~ -- -------- ---- ~~= --- -~ ~. ,r ~21 ~ J U- ~~{( - - - ----- - -- ---- -- U J~ C3~~~`1}) L V , V.• .-. -l/.. . _ -- -- La - - --- V~ -~rJ ~1--; ~~ rA ~ - - - S ..,,\c\L.

asa TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-24-9d.k•sKcm 119: 6 table (3) 11:20; 12:18; 13:10 tabulate (2] 121:6: 146:22 44:15; 45:1; 135:24; 137:17,• 156:5, 6, 8 testing [11 15:8 TEXARKANA (2) tabulations (1) 91: 7 Taggart (4] --~ J:3; 158:11 Texarkana (3) 10:4, 5; 16:23 1:15; 156:18: 157:21; J59:21 TEXAS 151 talces I ll 154 6 1:2, 4; 157:10; 158:7; 159:10 T : exas [59) talk [24] 9:17; 20:11, 14, 17 27:21; 44:7, 12. 19; 51:4; 52:23; 56:24; 57:3; 69:11; 79:15; 85.•l2; 92:2, 4, 24; 1:15. 17; 2:4, 12, 16,• 3:7, 17; 7:15; 29:10,• 43:22; 45:14; 90:14,• 99:20; 123:16, 17; 127:13, 18, 21; 128:8, 10, 12, 16, 17, 18, 20, 126:19; 141:16; 145:22; 147.•8, 9 talked (421 24, 25; J29: J, 7, 10, 12, 14; 130:1, 4; 132:7, 11, 22; 133:4, 10:10, ll, 13: 22:8; 26:17; 19: 135:12; 144:16,• 146.•18; 30:20; 43:24: 44:1. 3, 8: 51:J0: J47••3, 25; 148:8, 10, 24; 150:12; 52:16, 19; 72: 2: 73: J5; 74: 4; 152:2, I1; 153:17, 18; 157:2, 3, 80:18; 84:8; 87:4, 17; 100: J7,• 9; 159:2, 3, 9 103:9: 104:25: 105:14, 22; te xt [1) 110.20, 22; 1I1:2; 115:12; 42:1J 120:14; 125:23; 126:16, 20; T extbook [1) J30:19; 137:5; 138:1; 141:18; 102:13 144:17,• 150:22; 151:6; 152:18; te xtbook (41 153:15 talking (2a1 te 39:11; 40:19; 42:1, 9 xtbooks [2) 10:16, 17; 15:6; 19:14; 23:25; 39:13; 40.•15 35.• 24; 38: 9; 40:5; 48: l8; 58: 2, te xts [2] 15; 68:19; 71:12: 84:4; 86:21; 39:4; 42:4 91:20; 93:24; 100:6, 7; 103:14; T hank (s) 126:18; 142:19; 144:13; 151:14 talks 131 76:22; 94:13; 140:18 125:20: 138:7; 55:17; I16.•13: 119:10 tape I I I 24 1 th h ank (1 ] 5:1 k : Tar•a 14) 1:15; 156:18: 157:2J: IS9:?1 TCH i t th an s [I] J06:24 at'll [1] 133 J7 I I 44:10 teach 1=1 42:21; 65:3 teachiug 1'1 10:19: 36:23 th th T : eoretically [I] 146:2 ere'll [11 34:17 here's 171 Technical 1131 17: J4; 32:13; 43: 20; 63: J; 69:10: 3:19; 31:15; 32:17; 55:17; 59:8, 99:19; 151:2 9; 66:14: 68.1. 14; 80: I4: 94: 2, th ere's 1191 l0; 136:15 32:14; 43: 20; 51:21; 61: J4,• 63:4. technical 1'--,I l4; 69:10,• 70:4; 74.•J9; 85:14; 16:7: 32:6: 61:3, 8, l0; 62:1. K• 88: 7,• 98: J2, 18, 22; 103:17,• 15; 63:21; 64:3, 20: 63:6, /6. 21: 115:14; I35:13; 137:6; 147:23 67: 7 68.2. 15, 22. 24: 69.4. Th ey're (1 I 78 24 80 14 93 15 132 15 ; : : : : : tectuticaly 121 th ey're (7] 141:4; 152:5 technique 121 122:3, 9 technology I q 15: 7 (eenagerIl) 58:17 teenagers I31 58:6, 11, 13 temperature I t I 35:3 tenu (71 61: J4; 67:4; x3: 7; 91:21; 120:25; 121:2; 132:3 tenus I 11 86: 3 test I11 108: 21 Testified ( I ( 3:12 testified 141 4: ?; 6:12: 49:13; 86: 6 testifying I I 17:8. 50:1: 133:5 te.ctituony 1121 16:19: l7:'l: lX.•6; 30:4; 37:14; 58:1; 79:12; 85:2; 99:12: J06:13, 25; JJ8.3 tbey've [41 49:15, 17; 106:23; 123:21 thinkiug [5I 151:7 12, 13; 154:2, 6 third [7) I5.•5; 64:18, 23; 99:24; J00.•2; 121:13; 141:17 thoughts (11 102:18 three (11] 23:1, 9; 27: 7 9; 60:4; 62:23; 65:17; 93:12; 119:2; J37.•20; 141:18 thumb 11] 13:23 Thursday I1] J: J3 times 1141 10:22; 11:1; 24.•13; 49:9; 65: /5; 66:17; 72: J2; 75:17; 81:7; 88:21; 96:5; 131:6: J42:11; 150:13 titled (3) 14:17,• 81:2; 117:11 TOBACCO (4) 1:7; J57.•10,• 158:7; 159:10 Tobacco (4) 49:12; 1J8:10, 18, 20 tobacco [191 7:14, 25; 8:14; 12:4. 8; 14:8; 22:11, 21: 25:6, 11; 29:5, 9; 42:23; 43:19, 25; 50:18; 102:17,• 130:6; 133:25 tobacco-related (2) 18:16; 19:1 Tom (1) 4:J8 tomorrow [1) 142:16 Tonascia (1) /19:6 topic [31 71: J7,• 72: 7,• 83:1 topics [1] 63:2 total (s) 60: J0; 83:25; 92:24; 93:10; 103:11; 137••19; 148.•4, 7 totality [3) 39:22; 85:11; 121:21 totally (3) 102:23; 149:23; 151:7 toucbed [1) 71:19 tough (2) 93:18; 106: 6 tower (1) 37••1 town (1) 11:15 Toxicology [1) 38:5 toxicology [1) 107.•16 trained (1) 15:22 training 17] 24:23; 37:20; 41:7; 42:12, 13: 102:21; 107:15 Trammel [11 2:15 Trammell [2) 157:8; J59:8 transcribed (1) 22:1 Transcript [1] 3:16 transcript (2) J57:17 transfused (1) 98: l4 transfusing (1) 98:13 transmission [1) 137.•8 travel (1) 17:1 treat [31 41:9, 10; 111:3 treatise (2] 38: J8; 41: 25 treatises (3) J9:22; 39:4; 40:15 treatment (S[ 62:16, 20; 64:10; 108:19; 140:5 tremendous [3) 20:13; 30:21; 41:22 trend [1] 33:23 trending [1) 131:24 trends (l) 132:18 Trial 121 3:12; 16:21 trial [12] 6:13; 16:19, 20, 22, 23; 17:4, 8; J8:6; 37:10,• 141:4,• 154:4; 157:17 tricks (21 65:4 tries (31 19•9; 120:8; 122:2 trimester (1) 99:24 true (34) ' 6:2, 16, 18; 34:22; 5J:17,• 53:10, 13, 1S; 64:8, 18; 67:25; 71:10; 74:6: 82:23; 83:10, 18. 19; 84:2; 91:23; 96:17; 103:13; 109:2; 124:12; 139:7. 11; 140:6; 14fi13, 17, 20,• 150:10, 20,• 135:16; 156:7 Truly [1) 29:3 truly [z) 57••1; 147:22 tnfth U I 94:19 Tuesday (21 4:22; 49:6 twice (2) 41:21; 97,•16 twins [ 11 79:24 two-minute (1) 45:25 type 191 14:3; 28:16; 6/:24,• 62:7,• 66:11: 1J1:2; 131:23, 24; 133:9 types 12[ 15:8; 48:19 -U- U.S. (3) 92:2; 110••3; 158:11 lib-hub [141 21:J0,16:25:18;26:J3,16; 44:11; 47:19: 50:15; 68:6: 84:25; 100:11; J08:7,• 109:5; 148:13 UK (1) 42:18 ulcers [t) 48:15 ultimate (11 66:23 ultimately ( I ) 16:22 ultrasound (1) JS:8 Umphrey [1) 2:3 unborn [t) 103:2 underfunded (11 108:23 undergo (1) 140:5 underlined (3) 115:17,• 116:15, 16 underlining (1) 114:21 underlying [1) 114:20 underneath (1) 89:15 uoderprivileged (1) 145:22 understand (14) 34:15; 35:17,• 51:9; 53:14, 25; 69:9; 7fi4: 80:13; 87:15: 89:9; 141:8; J42:18; 143:13, 18 understanding (9) 15:16; S3: J0,• 54:14; 65:21; 66:18; 96:25: 100:14; 131:11; 133:8 understandings (1) dCE1TH & dHLLER (915) 533-7108 From table to undetstandinp,

F2'r.+el-;- 1J . 4- i ... -2 Z.- ''...• ti 5 .•a..>rl~•.,va 1G G 1~ i;,.1 ~ ---~ CL; rG C~ ~~ ., _ ... -{ l.a.." L \ ~ ~\~` CY. S n \ t J ~~.... . d '~ - C pJV':.:a:.', ` v --..... ~. . l 1 /1, p,iL1i 4-Z ~ I l, I rNN cK~CJ.~ ,; -Ii .. 4-t E IV

BSA TEXAS v. THE AMERICAN TOBACCO, DEPOSITION OF ROBERT J. CARPENTER, JR. 07-24-9t7ook-See(46) diet )1) 142:25 differ 111 147:21 difference 141 SS:20; 74:22; 84••18; 93:7 differences [3) 132:5; 135:14; 148:12 differential (11 83:14 differs 121 30:9; 32:4 difficult (31 65:3; 69:16; 140:1 dioxide (I1 35:3 direct(11 48:16 disagree (61 30:23; 69:13; 102:2; 103.•16; 104:11; 115:10 disagreed (2) 4J:3 divided (11 71: 7 DIVISION [21 1:3; 158:11 division )11 95:24 Doctor (761 4••4; 5:4, 10,• 6:24; 8:21; 9••4; 11:8; 13:14; 16:16; 17:19; 18:16; 20:3, 25; 21:16, 19; 28:2; 32:9, 25; 34:16; 35:18; 42:22; 43:18; 45:18; 46:3; 49:5; 52:4,• 58:23; 59:1; 60••3; 67:2: 68:12; 69:12, 21; 72:24; 75:2; 76:10, 18; 77:9; 78:22; 79:10; 80••1S, 19; 81:10; 83:8; 89:8, 16; 93:16, 23; 94:8; 96:25; 99:14,• 102:11; 103:17; 104:24; 109:9; l13:2, 9, 14; 114:7,• 116:21; 118:24; 119:25; 124:21; 127••17,• 130:3; 133:4; 136:7, 22; 138:8; 139:14,• dues [l) 62:6 duodenal 111 48:15 duplicate [t1 114:4 duplicated (11 117:2 duplicative (11 131:21 dwarf [1) 102:23 -E- earliest 11) 112:7 early 141 7:6; 75:19; 78:6; I10:S easier (2) 69:18; 76:21 easily (21 15:1; 42:5; 118:17 entrance (2) 99:24; 100:2 environmental (3) 35:2; 58:16; 102:IS epidemiologic (4) 107:21; 111:17; 123:14; 1S0:S epidemiological (11 72:10 epidemiologically I11 87:23 epidemiologist (1) 34:22 epidemiologist's I1) 122:3 epidemiologists (21 84:5; 122:21 Epidemiology (1) 119:7 epidemiology (7) 13:20,• 30:22; 31:3; 37:17; 38:1; 88:13; 107:5 30:9; 116:23 140:22; 141:10,• 142:18, 19; 51:24,• 139:22 ep isode (1) disagreement (1I 143:18; 151:20 Ebola (2) 31:2 31:5 d octor )t] J08:1, IS e ptbelial ( I ) disagreements (t) 4S••16 edema 111 47:7 44:25 d ocument (6) 101:7 eq uals IlI discarded [tl 74:13; I13:2S; 116:20; 119:24; Education (1) 148:10 137:13 129:17,• 142:1 71:12 eq uation 121 Discharge (21 D ocuments 131 education 131 133:17; 146:10 128:10, 11 3:9. 13, 14 10:19; 60:24; 143:2 eq uivalent (I) disclosure (11 d ocuments (291 educative/21 SJ: 24 6: 6 6: 7,• 11:4, 19; 12:2, 3. 4; 14:5, 6: 60:12; 61:24 er ythropoietin (21 discordance (11 18:4;22:13,17;44:18;30:17, effect [7) 97:19, 20 89:22 24, 25; 51:2; 113:24; J14:11, 17; 12:8; 33:22, 23; 34:13; 85:6; E sophageal (t1 discrepancy (1) 116:9; 117:3, 25; 118:1; 126:12, 97••l; 100:15 46:11 33:15 20; 130.•4, S; 131:4; 137:15 effects )51 es sentially 121 discuss (5] d oesn't (31 8:15; 18:11; 19:4, 16; 50:22 53:15; 103:17 38:12; 57:14; 58:22; 113:7 5:17,• 87:14; 130:9 eggs 11) es tablish (l) 122:10 d ogs (1) 73:2 10723 discussed (17) 65:3 eight [11 es timate (11 4:19; 7: 4, 11; 10: 8; 19: 23; 2 6: 2 d ollars I11 98: l0 60:7 32:8: 53:5; 112:22; 115••8; 118:1; 153:19 El Paso (21 et 1121 119:13, 22: 121:9; 128:2; do minant [ ) ) 157:3; 159:3 1:7; 19:11. 15; 38:1; 73:20; 136:15; 152:7 66: 3 elegant I1) 112:19; 144:1; 157:11; 158:7,• discussing l l l do rmant [1) 48:24 139:11 95:10 11: 23 dements (II et hnic 151 discussion [41 d ose-related (2) 86:25 71:8; 91:25; 95:9; 145:24; tn 7:23; 32:8; 127:1, 3 33: 22 Eleven (tl 148:17 1~ discussions 121 do ubling [31 78:12 ct hnicities (11 J 10:23; 21:22 73:18: 132:19 eligible (l) 70:17 I- Disease (51 do ubt (I1] 59:20 et m lwicity (2) 3:20; 103:19; 106:18, 22; 107:12 32:13, 14; 51:19; 52:7, 14; eliminated It) 129:14; 145:20 J di 26 88 4 53 16 54 2 86 8 87 25 34:17 sease 1 1 ; : ; : : : ; : ; : ev aluate(2) IV 8:5; 10:12: 20:4, 10. 15; 21:14; 153: 23 elucidated ( I I 107••24; 108:12 27:6; 33:25; 46:6; 47:9, 13, 17, D r 1331 55:4 ev N aluated (1) 22; 48:2, 8, ll, 20: 50:1]; 64:22: 3:9; 4:7, 21; 12••2l, 24; 15:2, 4, embryos (1) 73:21 68:3; 79:25; 80:1: 107:24, 25: J1, 18; 16:4; 29:12, 21; 30:11; 78:10 ev aluation (51 122: 7 3/:4, 6: 43:3, 8. 11. 13; 44:14, empbysema [t) 37:21; S9:S; 98:1; 111:17; diseases (7) 25; 45:4, 10; 66:13; 75:24; 83:1; 49:15 138:24 19:1; 20:12; 21:2: 45:22; 46:4; 97: 4: 116: 2; 118: 8: 124: 2S; employed 121 ev ent18) 102:15; 103:1 127:18; 136:13; 138:24 136:9, 12 52:7, 14; 53:17; 54: 9. 10; 73:19; di d d ft 2 employee 121 86 8 88 18 sor er I11 108:14 r a 1 ] 28:13; 68:21 25:6; 156:11 ev : ; : ents 131 Disorders 121 dr afted (1] Enclosed 121 62••11; 70:7,• 119:11 76:14; 125: 23 69:8 157:13; 159:13 ev erybody (21 disorders (11 dr awn Ill enclosed I11 65:1; 142:14 97:11 27:13 131:12 ev idence(31 disparate (21 dr inker I11 eod 161 98:3; 110:6; 123:1 •14; 82:22; 113:17 • 11:13; 26 57:18; 133: 23 dissect 1)1 dr 123:2J op (21 , • 133:18; 143:23 ex act 191 7:1; 29:23; 44:22; 62:17; 66:13; 71: 2 92••13; 137:25 ends 131 67:8; 68:20; 74:13; 81:16 i 33:12; 40 • 7 8 l ctinct (11 d dr ug [71 • , ex act y (1) 55:16 25:4; 112••13; 123:19; 139:24; enjoys(2) 132:16 distribution I11 140:5, 7, 8 16:4; 45:10 E XAMINATION (21 66:25 D rug-Exposed 11] ensurell) 4:3; S••3 DISTRICT (31 129:2 99:17 E xamination (1) 1:1, 2; 158:11 dr ugs (21 entered Il) 3:4 District (21 140:1; 143:1 78:5 ex amine I11 70:15; 148:2 du e [4] et;ters (11 41:17 divide ( I I 21:2; 111:10; 133:19: 149:1 103:19 entitled (3) ex amined I lI diet to examined (915) 533-7108 KEITH & MILLER

380 Perinatal mortality= fetal deaths and neonatal deaths/total births Neonatal mortality= death through 28 days in liveborn infants/live births O--O Fetal mortality= stillbirths/total births 500- 1000. 1500- 2000- 749 1249 1749 2249 BIRTHWEIGHT (g) 500- 3000- 3500- 2749 3249 3749 4000- 4249 FIGURE 1.-Perinatal, neonatal, and fetal mortality rates by birthweight in singleton white males, 1980 SOURCE: Williams and Chen (1982). V6ZL OtLtS 1 } i Birthwcight is, howevcr, a result of gestational age at birth and the rate of fetal growth. Recognition of the complex relationships among gestational duration, rate of fetal growth, birthweight, and mortality has led to attempts to classify infants according to gestational duration or joint distribution of binhweight and gcstational duration. Generally, births are categorized as pretcnn (<37 weeks gestation) and/or as small for gestational age (SGA) (<10th percentile of weight for a given gestational age). Joint classification is thought to provide a more discriminating basis for thc study ofetiologic agents. Pretenn delivery is strongly associated with increases in the risk of fetal, neonatal, and perinatal mortality and with significant childhood morbidity. Both preterm delivery and SGA increase the risk of cerebral palsy, although the risk is much greater for preterm delivery (Ellenberg and Nelson 1979). SGA is associated with increased risk of neonatal and perinatal mortality at every gestational age (Koops. Morgan. Battaglia 1982; Lubchenco, Searls, Brazie 1972); with SIDS (Buck et al. 1989); and with neurocognitive deficits, short stature, and small head circumference in childhood (Fitzhardinge and Steven 1972; Hill et al. 1984; Westwood et al. 1983; Ounsted and Taylor 1971; Harvey et al. 1982; Ounsted, Moar, Scott 1984, 1988; Fancourt et al. 1976). Continued Smoking As reviewed in previous Surgeon General's reports (US DHEW 1979; US DHHS 1980) and in other literature (Landesman-Dwyer and Emanuel 1979; Longo 1982; Werler, Pober, Holmes 1985; Kramer 1987), smoking during pregnancy decreases mean birthweight and increases the proportion of low birthweight births. Estimates vary among studies, but birthweight is reduced bv an avrrngeof.apptouimatelv 200 g and the proportion of low birthweiftht is app_roximately doubled bv gjga[stit~m_okin (Meyer, Jonas, Tonascia 1976; US DHHS 1980; US DHEW 1979; McIntosh 1984; Committee to Study the Prevention of Low Birthweight 1985; Kramer 1987). Mean birthweight decreases and the percent low birthweight increases with increasing num- ber of cigarettes stnoked daily. The relationship between cigarette smoking and decreased birthweight is considered to be causal (US DHEW 1979; US DHHS 1980. 1989). Smoking affects birthweight and the percentage of babies who are born of low birthweight by retarding fetal growth. A measure of fetal growth retardation is the probability of delivering an infant who is in the less than 10th percentile for gestational age. The relative risk of SGA is about 3.5- to 4.0-fold higher among the infants of smokers than for the infants of nonsmokers (Ounsted, Moar, Scott 1985). Preterm birth is also associated with maternal smoking, although not as strongly. Estimates of the relative ris i.ved~fore 37 weeks of gestation are typically about 1.5 for smoking during pregnancy (Committee to Study the Prevention of Low Birthweight 1985; Kramer 1987; Shiono. Klebartoff, Rhoads 1986). Mean gestational duration ~ among smokers is not sitCnificantly shorter than it is among nonsmo ers (U DREW f'tS 1979; US DHHS 1980). This finding is consistent with the observation that the risk of delivering early is greater among smokers than nonsmokers, but the percentage of 381

r cigarette smoking artd pregnancy outcome as well as ttie distinction between reversible and irreversible effects of smoking. Reversible effects would be expected to result in similar risks for never smokers and former smokers, whereas irreversible effects would be expected to lead to different risks in both current and fonner smokers compared with never smokers. Several pathways have been postulated by which tobacco smoke might adversely affect fertility (Mattison 1982) (Table 1). 'lhesc include disturbance of hypothalamic- pituitary function, interference with motility in the female reproductive tract (Chow et al. 1988). and impairment of implantation, all of which are thought to be reversible consequences of exposure to absorbed chemicals in tobacco smoke (principally nicotine). It has also been suggested that smoking results in oocyte depletion through direct toxicity (Mattison 1980), which would have irreversible consequences for fertility. Chow and col leagues (1988) postulated that altered immune function (Hersey, Prendergast, Edwards 1983) may predispose smokers to pelvic inflammatory disease, which in turn can result in permanent scarring and occlusion of the fallopian tubes. Alterations in the neuroendocrine control of ovulation have been suggested to account for increased amenorrhea reported among smokers (Pettersson, Fries, Nillius 1973); this mechanism, as an effect of smoking on fertility, would be reversible. TABLE 1.-Possible mechanisms for the effect of smoking on pregnancy and pregnancy outcome Outcome Reduced fertility Spuntanequs abonion Reduced binhweight Possible mechanism Hormonat effects Impaired tubal motility Impaired implantation Oocyte depletion Altered immunity leading to pelvic inflammatory disease Nicotine toxicity Impaired weight gain Nicotine toxicity CO toxicity Increased cyanide leading to impaired vitamin B u metabolism Hypoxia due to increased levels of CO or to vasoconstriction of umbilical anery NOTE: CO-carbon monoaide. Mechanisms for an effect of cigarette smoking on spontaneous abortion have not been clearly defined, partly because so little is known about the pathophysiologic basis for spontaneous abortion. The causes of spontaneous abortion are broadly divided into genetic and nongenetic causes (Kline 1984). Because smoking seems to have its primary impact on chromosomally normal spontaneous abortions (Kline 1984; Alber- man et al. 1976), nongenetic pathways are implicated for smoking (Table 1). 372 Most attention has been focused on the rnechanisms mediating a reduction of fetal growth among smokers (Table I). An indirect, nutritionally based mechanism in which smokers are postulated to eat less and gain less weight during pregnancy, thus delivering smallerinfants, has been prominent in discussions of fetal growth retardation in smokers (Papoz et al. 1982; Rush 1974; Meyer 1978; Davies and Abernethy 1976). This subject has been reviewed in depth in previous reports of the Surgeon General (US :Jr1EW 1979; US DHHS 1980) and more recently by other researchers (Werler, Pober. Holmes 1985). Differences in weight gain do not entirely explain fetal growth ret6,da.tion in smokers because differences in weight gain during pregnancy between smokers and nonsmokers are very small and have not been observed consistently and because a relationship between growth retardation and smoking persists after adjusting for mater- nal weight gain. In this context, however, the studies of weight gain in women who quit smoking during pregnancy are of interest. Pulkkinen (1985) found that women who quit smoking during the first trimester gained more weight than nonsmokers or continuing smokers (1.0 vs. 1.3 kg average difference, respectively). Kuzma and Kissinger (1981) also found that women who quit smoking during pregnancy gained more weight compared with women who did not smoke during pregnancy (average difference of 4.7 kg) and women who smoked throughout pregnancy (average difference of 5.6 kg). Also, women who quit smoking before the onset of pregnancy were reported to gain more weight during pregnancy than nonsmokers or smokers (1.3 kg and 0.9 kg average difference, respectively) (Anderson et al. 1984). Rush (1974) reported a reduction in weight gain of 0.12 pounds per week among continuing smokers compared with those who quit. This pattern may reflect the well-established tendency to gain weight following smoking cessation (Manley and Boland 1983; Rabkin 1984), as discussed further in Chapter 11. There are several hypotheses that attempt to explain the mechanism by which fetal growth is affected by cigarette smoking (Table 1), but cigarette smoking is believed to impact on fetal growth through intrauterine hypoxia (Longo 1977). Carbon monoxide, a component of cigarette smoke, has the ability to cross the placenta and bind with the hemoglobin in both the mother and the fetus producing carboxyhemoglobin. Car- boxyhemoglobin reduces the ability of the blood to carry adequate levels of oxygen to the fetus. Smoking is also believed to cause vasoconstriction of the umbilical arteries, and therefore, impact on placental blood flow (Lehtovirta and Forss 1978; Naeye and Tafari 1983; Longo 1982). Cigarette smoking during pregnancy decreases the availability of oxygen to the fetus by both mechanisms. These mechanisms imply a reversible effect of cigarette smoking for fetal growth because normal function would resume shortly after nicotine or CO is cleared from the system. Support for the suggestion that these effects are reversible is derived from several sources. Davies and coworkers (1979) found that 48 hours of smoking cessation late in ptegnancy increased oxygen availability to the fetus. Viinjevac and Mikov (1986) found similarly low levels of carboxyhemoglobin (COHb) in mothers and newborns when the mother was a former smoker or never smoker, mothers who smoked during pregnancy and their newborns had high levels of COHb. 373 @6ZL OTLTS

6LZL OTLTS CcL -- ~~1=~C,~ ~ -1-- 1-~ -- ~ ~ ~ . - - - --- - , -_~ 3L1 -- --- ---------- ' ~ ---- - ---- , ~~~~--~ - _ ~ - . ' '~ . \I j Gl ` \ ~;~-- - --- - - L I ~r--~-~7t-~~.~:_:~ .., ~-..----- `.J ~ ./, . r," C 7, 7.L '7I/ / i ~J-=t ,- Svn',;~-l ,) 0--."'s, °'0 * t,4: (=nv~ ,,,,!) -z • 1 , --- - - -- - -__ -. : ii ~~ ~?G,- ^-~- ~-N) ~z' `t~,,53 l I V s,.r~ s t

TABLI{ 7.-Summary of nonexperimental sludics uf smoking cessation after conception, mean increase (+) or decrease (-) in birthweight (g) according to liming of cessation Month of cessation Smoked keference 1 2 3 4 5 6 7 8 9 Unknown ttvoughuut Lowe +14 -182 (1959) Underwoud et al. -108 -152 = 30 (1967) nutler.Goldstein, +46 -(G0 Ross (1972) Andrews and -80 -170 McGarry (1972) PapozetaL +10 -70 (1982) Rush and +98 +43 +36 -90 -155 Cassano(1983) Pulkkinen -61 -225 (1985) Counsilrnan and -d0 -235 MacKay (1985) Kline. Stein. +12 -202 Hutzler (1987) MacAnhur +22 -58 -242 and Knoa (1988) NOTE: Mean inerta-or dcen:aner ve relarire ro nonunoken during pnclinanry. birthweight baby. Women who reported smoking throughout their pregnancy had a 90-percent increased risk of having a low birthwcight baby in contrast to nonsmokers. Most fetal growth occurs late in pregnancy, and the primary smoke constituents considered as candidates in mediating the effect of smoking on fetal growth (i.e.. CO and nicotine leading to intrauterine hypoxia) have short-term reversible effects. The data in Tables 6 and 7 support the conclusion that the adverse effect of smoking on birthweight occurs in the latter part of gestation, primarily during tite third trimester, and that cessation at any time during gestation is likely to mitigate the adverse effect of smoking on fetal growth. Bec use it is di tc to rsuade all r n t okers t u' smokin entir~ thV efit of du ingJi nwnber of cigarettes smoked er a c 1 t~,etaf2u411Chealth iss e. The observation that ctgarctte smo (ing rctards fetal growth in a dose-response 384 TAi3LE 8.-Summary of nonexperiniental studies of relative risk of low birthweight for smoking cessation after conception Reference Relative risk' Smoked throughout pregnancy Ceased smoking after conception Frazier et al. (1961) 1.0 1.7 Van den IIerg (1977)b 1.6 3.0 Petitti and Coleman (in press) Whites <1 mo 0.5 2.7 I-2 mo 1.0 2-3 mo 0.6 Blacks <I mo 1.4 3.8 1-2 mo 1.0 2-3 mo 1.1 Andrews and 1.3 2.0 McGany(1972) 'Compared wirh nonsmoken during pregnanc'Y• 'Whilee only. fashion supports the benefit of reducing the number of cigarettes smoked per day. Hebel, Fox, and Sexton (1988) used data from their randomized trial of smoking cessation to examine this question. These researchers found that the benefit of decreased smoking for birthweight during pregnancy was almost entirely restricted to those who achieved total cessation, perhaps because women who reduce the number of cigarettes smoked compensate by inhaling more deeply, by puffing more frequently, or by smoking the cigarette to a shorter butt length. Findings from another randomized trial support the conclusion that abstinence, not reduction, should be the goal in pregnancy (MacArthur. Newton. Knox 1987). In this latter study, the intervention led to a considerable reduction in the reported mean number of cigarettes smoked per day but almost no difference in the percentage of women who quit entirely; there was no difference in birthweight between the treatment and control groups (MacArthur. Newton, Knox 1987). Because of the social stigma associated with smoking during pregnancy, it is possible that some women in this intervention trial falsely reported a reduction in smoking; if so, this underreporting would lead to an underestimation of possible benefits of reducing cigarette consumption. Whether quitting only during the first half of pregnancy will prevent a reduction in birthweight is another important consideration. Most fetal growth takes place in the last trimester; early quitting virtually eliminates the effect of smoking on birthweight. Thus, smoking late in pregnancy may have an adverse effect on birthweight even if there is abstinence in the first trimester. Lowe (1959) found that the mean birthweight of infants of smokers who quit early in pregnancy but resumed smoking was between that of smokers throughout pregnancy and that of never smokers. Infanls of women who gave up ciearettes by the f lh.montlL4f pregnancy and who did not resum~ e sm~_ 385 96ZL OtLTS

i o. TAIiLE3.--Continued Perinatal mortality among those who smoked before pregnancy but quit during preg- 7/ nancy (15 0(b) was lower than for either nonsmokers during pregnancy (18 0/1 . , . 1.000) or smokers of 5 cigarettes or more per day throughout pregnancy (26.9/1.000). Number of Perinalal monality' Neonatal monatiry' Reference births Category Smokers Nonsmokers Smokers Nonsmokcrs hout in smokers throu f erinatal mortalit TABLI: 5 mmar of studies -S Race p y g y . u o smokers who quit in the early months of pregnancy, and pregnancy Rush and Kass 3.266 White 31.4 29.2 , nonsmokers during pregnancy (1972) Black 54.1 28.6 Matemal age Verinau- I mortalitya Fabia 6.879 <25 yr (1973) 2 16.1 12.1 Number Smoked Reference of binhs Nonsmokers Former smokers throughout pregnancy 5-34 yr 235 yr 13.2 12.6 41.7 23.0 Bullcr.Gotdstein. 21.788 32.2 1-IciB/day 31.7" 1-4ci8/day 38.5 Ross (1972) 5-9 ci8/day 31.1 5-9 cig/day 42.2 NOTE: ppd- packsJday. 10-19cig/day 28.1 10-I9cig/day 41.6 'Per 1.0(I(1; denni,iun of monaliry a, in paper cited. ' 20-30 cig/day 35.2 20-30cig/day 41.2 Adjusted for u- of infant and farher', education. 'Dcf ned in paper ciud. Andrews and 18.631 24 29e 29 'Rate based on fire demhs or fewer. McGarry (1972) Rush and Cassano 16.688 18.7 15.0i/ 26.9 (1983) TABLE 4.-Estimated relative risk of fetal plus infant mortality for maternal smoking in several birthweight groups, adjusting for maternal marital status, education, age, and parity Birthweight group (8) Estimated relative risk 95% CI 500-999 1.71 1.46-2.00 1.000-1.499 1.78 138-2.01 I.500-1.999 2.00 1.84-2.18 2.000-2 499 2.44 2.33-2.55 22.500 1.24 1.10-1.39 NOTE: FiBuret am for whirea only. CI>.confidence interval. SOURCE: M.Itoy er al. (1988). i 'Lue fetal and neonatal denhsAaal binhs x 1 A00. aWomen who quit smokin8 before the fourth nxrmh of prejnaney. 'Wornen who quit smokin8 before pn8nancy or durin8 early pretnancy. eWomen who quit amokin8 during early pretnancy. FetaL neonataL aad fxrinatal mortality are tare events. This limits the studv of their association with s f data m ' le to draw a firm conc ugon aho, r~r eh. ,aee~ation of emokin¢ cessatio with the risk of fetal neonata , or perinatal mortali . However, the limited available data are consistent with the conclusion that perinatal and neonatal mortality are lower among infants of women who quit smoking than among those women who smoke throughout pregnancy. The possibility must be considered that differences between women who quit smoking and those who continue to smoke account for the lower rate of perinatal and neonatal mortality in the studies in which this has been observed. Birthweight and Gestational Duration smoked prior to conception and who stopped before the fourth month of pregnancy as it was for never smokers. However, perinatal mortality was higher for continuing smokers than for never smokers for all categories of amount smoked. Andrews and McGarry (1972) examined mortality in the Cardiff birth survey of more than 18,631 births. PerinataJ mortality was 29 per 1,000 in those who quit smoking before pregnan- cy or in the early months of pregnancy; 29 per 1,000 in continuing smokers; and 24 per 1,000 in "nonsmokers." Rush and Cassano (1983) analyzed data from the 1970 British birth cohort, consisting of all births in Great Britain during a single week in 1970. 378 E6ZL 0tLt5 Introduction Fetal, neonatal, and perinatal mortality are the most direct measures of pregnancy outcome. Mortality is relatively uncommon, and very large samples are needed for study. This has led to the widespread study of birthweight and the percentage of births that are low birthweight (<2,500 g) as surrogates for the study of mortality. This strategy has beenjustified by the extremely strong association between birthweight and the percent of low birthweight and each of the measures ofmortality (Figure 1). Equally important is weight at birth as a determinant of infant health (McCormick 1985). 379 w, . __„.. ..............

~ !2 T Z . - - -A ~ 1 IG Z ~--i-`-`--)-- ~- .J-; 4G`/oc.-c ..~-~Lc. ° ' y- ,~ - ~" ° fL3 --T)-U- ii kl s ~ ` -j , c ,;1 - C (~3 A' *~--- --` ~=•`{a 1. ~31 ---- T- ~-~-~; ----- `~- - _ j-3--~_ , 1.. J}- -~---------- ~.:~~.~~ - --~ - ------------------- ~ - - -- ------ ~ ------ --- -- ---- - ---- ----- ~-- ,--- /C .t ~r- --- - --~ - ---~ -- -S-'-~ 51710 7277

) Prevalence of Smoking and Smoking Cessation During Pregnancy and Time Trends in Prevalence and Cessation Introduction Ideally, conclusions about the prevalence of smoking during pregnancy and trends in prevalence would be based on representative samples of pregnant women perfomied at regular intervals using the same methodology. Assessment of smoking cessation during pregnancy and time trends in smoking cessation should be based on repre- sentative samples of women who start pregnancy as smokers and who are monitored for smoking behavior throughout gestation. Available data fall short of these ideals. Furthermore, available information on smoking and smoking cessation in pregnancy is based almost exclusively on self-reported behavior. Few data on the quality of self-reponed smoking specifically in relation to pregnancy have been collected, and it is possible that the societal pressures against smoking during pregnancy would make underreporting more problematic than for other populations (Chapter 2). Similarly, pregnant smokers who admit to smoking might underreport their daily cigarette consumption, perhaps to a greater extent than nonpregnant smokers. The effect of underreporting of smoking and overreporting of cessation would make the data from former smokers more similar to that of continuing smokers with respect to their reproductive health outcomes. Also, smokers who reduce the amount of nicotine in their cigarettes by changing brands or those who reduce the number of cigarettes they smoke per day without quitting may compensate to maintain the same nicotine dose (US DHHS 1988). Prevalence of Smoking and Smoking Cessation Pertinent data on smoking during pregnancy from the 1985 National Health Interview Survey (NHIS) (NCHS 1988) are presented in Table 10. The 1985 survey focused on health promotion and disease prevention. The survey involved nearly 35,000 households and more than 90.000 persons, and the response rate was 95.7 percent. Information concerning smoking during pregnancy was obtained from all female household members aged 18 to 44 years who had had a live birth in the 5 years prior to the survey. The proportion of women who had smoked at any time during the year preceding pregnancy was 32 percent overall. Of women with less than 12 years of education. 46 percent smoked in the year preceding pregnancy, compared with 13 percent of women with 16 or more years ofeducation. Thirty percent of married women had smoked, compared with 40 percent of formerly married women. Patterns of smoking cessation or reduction were reported in detail for some demographic subgroups. Overall, 21 percent of women who smoked prior to pregnancy quit upon leaming of their pregnancy, and an additional 36 percent reduced the number of cigarettes they smoked. Cessation (but not reduction) was strongly related to education and family income. Among women with less than 12 years of education, 12 years of education, and more than 12 years of education, 15, 20, and 32 percent quit. 390 66ZL OtLTS .,~ . ~ 5 i' ._ _-I. TABLE 10.-Smoking and smoking cessation during pregnancy, summary of results of two surveys of national probability samples Percentage of pregnant women Quit upon leaming of pregnancy Smoked Reduced Educational attainment (yr) Study (yr) before pregnancy amount smoked AII <12 t2 213 National Health 32 36 21 15 20 32 Imerview Survey' (I980-1985) National 31 27 18 10 IS 22 Natality Survey6 (1980) 'NCHS (198g). 'Pnjer et a1. (19g4). respectively. The proportions for reduction in smoking were 34, 38, and 36 percent, respectively. Younger mothers were slightly more likely to quit than older mothers, and white mothers quit slightly more often than black mothers (21 vs. 18 percent). More married mothers (23 percent) than never married (19 percent) or formerly married (14 percent) mothers quit, although the proportions reducing their smoking levels were similar (36, 37, and 35 percent, respectively). Fingerhut. Kleinman, and Kendrick (1990) also reported data on smoking in whites before and during pregnancy based on the Linked Telephone Survey, which reinter- viewed 1.550 women aged 20 to 44 years who were respondents to the 1985 NHIS. This analysis confirmed the previous findings that smoking prior to pregnancy and quitting during pregnancy were strongly related to age and educational attainment. Information on amount smoked prior to pregnancy was obtained in this survey. Fifty-n` innt of women who smoked less than l_pack ror day prior to pregnancy q-uit smokin cottlplircd with 25 percent of those who smoked.l pack or moreper day, Of the w ite women who smoked prio rto pregnancy, 39 percent quit during pregnancy (27 percent when they found out they were pregnant and 12 percent later in pregnancy). This estimate of quitting during pregnancy is higher than the previous estimate of quitting from whites in this survey because it includes as quitters both women who quit upon leaming that they were pregnant and those who quit later in pregnancy. Smoking during pregnancy was also assessed in the 1980 NNS (Prager et al. 1984) (Table 10). Questionnaires were distributed to a national probability sample of married women who had had live births in 1980; the response rate was 56 percent. The restriction to married women severely compromises the generalixability of rcsults, especially for subgroups such as blacks and youth because smoking during pregnancy 391 ., ._ . ~ . ...._....~.. ._ _.._ ___-. _._ .. ~,.»..,~ ,,...._. _w. . ~.., . . ..............._.

1 r f TA t3LE 9.-Sununary of birthwcight outcorne in randomized trials uf smoking cessation in pregnancy Nurnber of subjcitx Srnuking at end of pregnancy uinhwcisht (g) Reference I C I C I C Difference (g)' Donu.an(1977) 263 289 9.2 cig/day 16.4cig/day 3.172 1.184 -12 Sexton and ifebel 463 472 57.070 80.0'h, 3,278 3.186 .92 (1984) MaeAnhur. Ne..ton. 493 489 91 % 94% 3•I6t 3.130 .34 Knox (1987) NOTE: I+imerremion gruup; C~tanlrol `roup. 'Mean in lmervemlon m1nu. mean in eonval. group, but increased slightly from 14.7 to 16.4 in the control group. Mean birthweight was 3,172 g in the test group and 3,184 g in the control group. In the test group 10 percent of the infants had low binhweight (<2.500 g) compared with 9 percent in the control group. 7here were four perinatal deaths in the test group and one in the control group. None of the differences in birth outcome between the test and control groups were statistically significant. Although this trial might be regarded as evidence against a benefit of smoking cessation.during pregnancy, a number of limitations of the study must be considered. First, no'data are presented concerning the percentage of pregnant smokers who quit smoking entirely. Reducing cigarette consumption almost certainly has a smaller benefit for pregnancy outcome than complete cessation. Second, the time at which smoking behavior changed during pregnancy is unclear, data on cigarette consumption for three periods during pregnancy were obtained postnatally, and may have been affected by recall bias. Data from observational studies discussed in the previous section l4rongly suggest that smoking during the last trimester ofpregnancy is a critical mediator of reduction in fetal growth among smokers. Information from another British randomized trial (MacArthur, Newton, Knox 1987) also questions the benefit of smoking cessation during pregnancy. In this study, women who smoked at the time they were scheduled for a prenatal visit at a large hospital were assigned randomly to a control group that received routine care or to an intervention group that received supplementary health education about smoking during pregnancy. The planned intervention consisted of advice to stop smoking and information about the effects of smoking on the fetus, presented visually by a booklet or verbally by the obstetrician. There were 489 women in the control group and 493 in the intervention group. Mean birthweight for infants in the control group was 3,130 g compared with 3.164 g for the intervention group. The percentages of low birthweight and pcrinatal mortality in the two groups were not reported. The difference in mean birthweight was 388 1 / } not statistically significant as determined by the conventional 0.05 probability value and a two-sided test. In this trial, only 9 percent of the women in the intervention group quit smoking entirely, compared with 6 percent of the women in the control group. The failure of the intervention to cause smoking cessation makes this trial essentially uninformative conceming the benefit, or lack of benefit, of smoking cessation during pregnancy. In the intervention group, 28 percent of the women reduced the number of cigarettes smoked per day, compared with 19 percent of the women in the control group. The greater reduction in cigarette consumption in the intervention group, in the absence of a difference in mean birthweight between the intervention and control groups, suggests that reducing smoking does not entirely prevent the adverse effects of smoking on birthweight. The third randomized trial (Sexton and Hebei 1984) recruited women in a large metropolitan area from various sources. Smokers of at least 10 cigarettes per day at the beginning of pregnancy, who had not passed the 18th week of gestation, were randomly assigned to a control group that received routine advice or to a treatment group that received intensive, ongoing advice throughout pregnancy from specially trained profes- sional staff. There were 472 women in the control group and 463 women in the treatment group. The mean birthweight of infants bom to women in the control group was 3,186 g compared with 3,278 g for infants of women in the treatment group. ne percentage of low birthweight infants was 8.9 in the control group and 6.8 in the treatment group. 'ITtere were 1 l stillbirths in the control group and 9 in the treatment group. The difference in mean birthweight was statistically significant (pcU.05, two- tailed test): the differences in the percentages of low birthweight and in fetal mortality were not statistically significant. In this trial, 43 percent of the women in the treatment group had ceased smoking entirely by the eighth month of pregnancy, compared with 20 percent of the women in the control group. The intervention was, therefore, highly successful in causing substantial changes in smoking that exceeded changes in the comparison group. 71te investigators ruled out concomitant changes in consumption of alcohol and coffee as explanations for the increase in birthweight. Weight gain was 1.0 kg greater among the treatment group than the control group, but at least part of the difference in weight gain was a result of the higher birthweight of the infant (Sexton and Hebel 1984). Review of these three randomized trials leads to two conclusions. F'ust, to prevent entirely the adverse consequences of smoking on birthweight, it is necessary for women to cease smoking completely. Second, intensive interventions spanning the entire period of gestation may be necessary to effect large changes among the percentage of women who abstain from smoking entirely. 389 1 8 6 Z L 0 T L T S

1 Mechanisms for the effects of smoking on neonatal, perinatal, and infant mortality are poorly understotxi, although the reduction in birthweight is often considered to be the mediating process. However, smoking appears to cause a shift in the distribution of birthweiyhLwtl,hout having much effect on mean gestational age (US DHEW 1979; US DHHS 1980), and shifts in_birthweight distribution across different poPulatioqs_do_ notalwaysproducecorrespondingshiftsinmortality(Wilcox 1983; WilcoxandRussell IY a. . That gestational age is little affected by smokin , whereas birthweight is reduced at every gestational age, explains why small infants of smokers have a tter prognosis th_an small infants o nonsmokers1Yerushalmy 1971; MacMahon, Alpert, Salber 1966). Increases in perinatal mortality among smokers may result not from the reduction in birthweight, but rather from the modest increases in pretenn delivery, very low birthweight, and specific pathologic conditions such as placenta previa and abruptio placentae. liowe~ ver, this has not been addrcssed explicitly in any study. Because the smaller smokmg-related increases in less frequent, more severe outcomes parallel the - pronounced smoking-related reduction in birthweight, birthweight serves as a useful empirical marker of smoking's harmful consequences, even if it is not the direct mediator of those effects. Nonexperimental Studies Fertility and Infertility Consistent evidence indicates that smokers have lower fertility than nonsmokers (Daling et al. 1987; Howe et al. 1985: Baird and Wilcox 1985; Hartz et al. 1987), as noted in the 1989 Report of the Surgeon General (US DHHS 1989). The studies that have assessed indicators of fertility in former smokers are summarized in Table 2. Pettersson, Fries, and Nillius (1973) studied secondary amenorrhea, one mechanism for reduced fertility, and found an increased prevalence among smokers. However, prevalende among former smokers was even higher than among continuing smokers. Hammond (1961) found that irregular menstrual cycles were more common among smokers than never smokers and that former smokers were at slightly lower risk than never smokers. Howe and colleagues (1985) analyzed data on more than 4,000 women in a British cohort study, which assessed the safety of oral contraceptives. Compared with never smokers, women who smoked 20 cigarettes or more at entry into the study were twice as likely to be undelivered 5 years after ceasing contraceptive use with the intention of becoming pregnant, whereas former smokers had the same likelihood of being un- delivered as never smokers. Baird and Wilcox (1985) reported that the time period until pregnancy was the same for 31 women who quit smoking in the year prior to attempting to conceive as it was for never smokers. Daling and coworkers (1987) conducted a large case-control study in Washington State and found that, compared with never smokers, the relative risk of primary tubal infertility was 2.7 among current smokers and 1.1 among former smokers. Information 1 r.. t. :~ 1 ~:,::Y, 1 TABLE 2.-Summary of studies of fertility among smokers and former smokers Relative risk of measure of fenility' Reference Location Measure of fenility Snsokers Fonoersmokers Pettcrsson.Fries, Sweden Seeondaryunenorrhea 1.3 1.6 Nillius (1973) Howe et aI. England Not pregnant 5 yr after 2.0' 1.0 (1985) ceasing comraceptive use Baird and Wilcox Minnesota Timetopregnancy>I yr 3.4 1.0 (1985) Daling et al. Seattle Primary tubal infertility 2.7 1.0 (1987) Daling ct at. Seattle Secondary tubal infertility 1.6 1.3 (1985) •Cynpned with never amokers. 'smokcn er>2o tig/day. on secondary tubal infertility from the same study (Daling et a1.1985) revealed a smaller difference between current and former smokers. Although the study focused on prior induced abortion, data are presented that allow computadon of crude odds ratios for current and former cigarette smokers. Current smokers had a 1.6-fold increase in the risk of secondary tubal infertility, and former smokers had a 1.3-fold increase in risk. It is difficult to assess the causal effect of smoking on tubal infertility independent of the effects of sexually transmitted diseases (STDs) known to co-vary with smoking in many populations. In summary, the data suggest that impairment of fertility measured as delay in time to conception is related to smoking near the time of attempting to conceive and that smoking cessation prior to conception retums fertility to that of never smokers. Conclusions about smoking and the risk of tubal infertility cannot be drawn because of concern about uncontrolled confounding. Ectopic Pregnancy and Spontaneous Abortion Tubal (ectopic) pregnancy occurs at about the same time in the reproductive process as fetal loss. However, the mechanisms aro thought to be similar to those operating in tubal infertility and largely concern tubal motility and patency. Several reports indicate an increased risk of ectopic pregnancy in smokers (Campbell and Gray 1987; Mat- sunaga and Shiota 1980), but only Chow and associates (1988) examined the associa- tion with prior smoking in detail. In a case-control study in western Washington State, 155 cases of tubal pregnancy were compared with 456 controls who had given birth. Current smokers had an estimated 2.2-fold increased risk of ectopic pregnancy com- 37 , 375 I4 T6ZL OTLTS f

i preterni deliveries is so small that the mean would not be affected unless the shift were very large (US DHEW 1979: US DHHS 1980). Cessation Before Conception Most studies of cigarette smoking and birthweight have failed to separate ncver smokers from women who quit smoking prior to conception. MacMahon, Alpert, arid Salber (1966) first examined the association of pre-pregnancy smoking with birthweight and found no significant difference in the mean blrthwelgltt of infants whose mothers smoked before but not during pregnancy compared with never smokers. Subsequent research has confirmed the absence of an association between smoking prior to conception and reduced birthweight (Table 6). In all of these studies, smokers who quit before conception had mean birthweight values that were equivalent or higher than those of never smokers. Other studies in which infonnation on mean birthweight could not be derived (Kline. Stein, Hutzler 1987; Anderson et al. 1984; Wainright 1983), with the exception of Zabriskie (1963), have also consistently sttown no association between birthweight and smoking that ceased prior to conception. 7•rbris- kie (1963) failed, however, to adjust for smoking during pregnancy, and these results are not directly pertinent in a comparison of birthweight in never smokers and smokers who quit before conception. TABLE 6-Summary of studies of mean birthweight, by smoking status Mean birthweight (g) Reference Never smoked Smoked before but noa during pregnancy Smoked during pregnancy Cope. L.T+cuter, 3.376 3.395 3.200 Stevens (1973) Van den Berg 3.463 3.457 3.255 (1977) Rush and Cusano 3,357 3,384 NR (1983) ViSnjevae and Mikov 3.327 3.331 3.097 (1986) NOTE: NR.na repuned. In interpreting these data, misclassification of ex~osure needs to.be-coasiderud-. MacAtthur and Knox (1988) reported that wom ne who auit smekin¢ durinR Qregnancy and possibly those who ouit before orc¢aancv were more often livine with a partner who smoked. Passive smoke exposure may adversely affect the fetus (Martin and 382 ,~,.,.._._.._..__......._.... . 56ZL OTLTS Bracken 1986). Furthermore, for whatever reason, sonie women may misrepresent their smoking status, denying that they have continued smoking. thus leading to an underestimation of the benefit of smoking cessation prior to conception. More important, women whoquit smoking priorto conception differ in otherrespects from women who continue to smoke. Women who quit may have smoked fewer cigarettes per day prior to quitting. Studies of smoking cessation prior to conception have not accounted fully for other differences between women who quit and those who continue to smoke. Cessation After Conception Birthweight Table 7 summarizes nonexperimental studies in which information on mean birthweight in nonsmokers, smokers throughout pregnancy, and smokers who quit after conception could be derived. The data from each of these studies ate consistent in two important ways. First women who sm ked throu hout re nanc delivered infants who wcighed less than the infants of nons ~re econd women who quit smoking delivered infants who weighed more than the infants of smokers throughout pregnancy. In most of these studies, mean birthweight values among infants whose mothers stopped smoking were the same or higher than those of infants of nonsmokers. Table 8 summarizes nonexperimental studies estimating the relative risk of low birthweight for continuing smokers and quitters some time during pregnancy compared with nonsmokers during pregnancy. These studies aro consistent with those examining mean birthweight. Compared with nonsmokers, the risk of low birthweight is elevated among smokers throughout pregnancy, and the risk is about 1.0 for women who quit. In addition, Kleinman and Madans (1985) reported no association between the risk of low birthweight for women who quit smoking during pregnancy compared with those who had not smoked in the 12 months prior to conception among participants in the 1980 National Natality Survey (NNS). An important as ct of smoking cessation and prcgnanc o is the timin o[ cessation during pregnancy and its relation to tn weight. How early in pregnanc cessatton must occur to avoid the adverse effects o smo tng on btrthwei ht is a e issue with important implications for counse tng pregnant smo •ers._ In most of the studies examining this question, only informatton on cessation in the early months of pregnancy is presented. However, Rush and Cassano (1983) found that mean birthweight among women who quit as late as the seventh to eighth month of pregnancy was higher than for women who smoked throughout pregnancy, but lower than for nonsmokers and for women who quit earlier in gestation. MacArthur and Knox (1988) concluded ncluded that quitting any time before the 3~0th we~ek of P.,.estation increases birthweight when compared with continuin to smoke. Coopt:r (1989) assessed patterns o cigarette smo ng y trimester of pregnancy. Women who reported smoking during the "f rst trimester of pregnancy only" had a 30-percent increased risk of having a low birthweight baby, while women who rcported smoking during the "first and second trimester of pregnancy only" had a 70-percent higher risk of a low \,t Q : 30°ll^ L3w 383 1 ~ ' ° _ _ L \ Q~~ LGu% ...~. ~. . .~...~ . w...y.~ .,

had a mean birthweight identical to that of neversmokers. MacArthur and Knox (1988) also foun t tat m ants bom to womcn who quit smoking early in their pregnancy but started again before delivery had a mean birthweight value between that of smokers throughout pregnancy and those of both early quitters and never smokers. These data indicate that abstinence throughout t~_trimrster of pretnancy is necessarv to realize the full benefit of smo tng ccssation for birthweight. Pretenn Delivery Thee effect of smoking on birthweight is principally due to a reduction in size for a given gestati Lagetather than to a large decrcase in esgtional d_ufatituLCU$ I?H>iW 1979; US DHHS 1980). Thus, it would be expected that pregnancy outcome in women who quit would reflect a predomm effect on size for gestational age. Andrews and McGarry (1972) co ts der-preterm delivery as a distinct endpoint in continuing smokers and quitters; the latter group included a mixture of women who quit prior to conception and women who quit during their pregnancy. The rate of preterm delivery among nonsmokers was 6.7 per 100 compared with 7.5 per 100 for ~ f L ex-smokers and 9.2 per 100 for women who continued to smoke throughout pregnancy~\ (Andrews and McGarry 1972). Berkowitz, Holford, and Berkowitz (1982) examined the association between smok- ing during each trimester of pregnancy and the risk of preterrn delivery in a case-control Q^^r study of 175 mothers of singleton, preterm infants and 313 mothers of singleton, term infants. The risk of preterm delivery was ilncm9sed~tt~ w me t who smo e_ dJtLthe S•~. V+ third_ trimestef of pregnancyLUpeeially-itthcy-soked heavi~ly (> 10 cigarettes per day). Using data from a longitudinal study of pregnant women, Van den Berg and Oechsli (1984) re'ported rates of preterm delivery (537 weeks) among never smokers, smokers who stopped at the beginning of pregnancy, and continuing smokers for 10,947 white women whose singleton pregnancies progressed beyond 22 weeks. The rate of preterm delivery %yas 5.4 percent in never smokers, 6.8 percent in quitters, and 7.6 percent in continuing smokers. The difference in the rate of preterm delivery between never smokers and quitters was not statistically significant (p>0.05); however, the difference ~~ between never smokers and continuing smokers was significant. In a population-based case-control study of white and black women delivering singleton infants without congenital anomalies in a large urban county. Petitti and Coleman (in press) reported that the estimated relative risk of very low birthweight (<1,500 g) or of other preterm births among black and white women who quit smoking prior to the fourth month of gestation was not increased in comparison with those of nonsmokers. The estimated relative risk of very low birthweight (<1,500 g) in continu- ing smokers was 2.5 for whites and 3.1 for blacks and that of other preterm births was 2.0 for whites and 3.7 for blacks. MacArthur and Knox (1988) examined gestational duration according to smoking during pregnancy. Mean gestational len th was 1.7 da s shorter amon continuin$ smokers than nonsmokers. m a with nonsmokers, gestational periods were 0.4 days shorter or womcn wJ smokin¢ by the 6th week o prcgnancy .5 days longer 386 L6ZL OiLZS for women who quit between the 6th and 16th weeks of pregnancy, and 0.3 days longer for women who quit after the 16th week of pregnancy. Because of the limited data on the risk of preterm delivery among women who quit smoking after conception, a finn conclusion about beneft, or lack of benefit• at- tributable to smoking cessation for this pregnancy outcome cannot be drawn. Complications of Pregnancy Women who smoke during pregnancy are at increased risk of bleeding during pregnancy and of placenta previa and abruptio placentae (US DHEW 1979; US DHHS 1980; Naeye 1978; Naeye 1980). These women are probably at decreased risk of preeclampsia (US DHEW 1979; US DHHS 1980; Marcoux, Brisson, Fabia 1989). Few data on these pregnancy complications among former smokers are available. In Naeye's (1980) analysis of data from the Collaborative Perinatal Project, smoking for more than 6 years (but not short-term smoking) was found to be associated with a relative risk of 1.6 to 1.9 for abruptio placentae and a relative risk of 2.4 to 2.8 for placenta previa. Women who had stopped smoking by their first prenatal visit were not at increased risk of abruptio placentae, but were still at twofold increased risk of placenta previa if they were long-term smokers. However, the latter result was based on only 18 exposed cases. Marcoux. Brisson, and Fabia (1989) found that, compared with women who had never smoked, those who smoked at the time of conception were protected from preeclampsia (estimated relative risk (RR)=0.51), whereas women who smoked but quit prior to conception had the same risk of preeclampsia as neversmokers (RR-0.97). Women who smoked at conception but quit prior to 20 weeks' gestation were not as protected from development of preeclampsia as were continuing smokers. Because of the otherwise serious adverse effects of smoking on the fetus, this minor "benefit" of smoking during pregnancy probably has no public health consequence. Randomized Trials of Smoking Cessation During Pregnancy Three randomized trials have been conducted on pregnancy outcome in relation to advice to stop smoking (Donovan 1977; Sexton and Hebel 1984; MacArthur. Newton, Knox 1987). Table 9 summarizes the studies and birthweight results. Two other randomized trials have also been conducted on the effect of various programs on smoking cessation rates among pregnant women (Ershoff, Mullen, Quinn 1989; Windsor et al. 1985), and other trials are in progress. Information on pregnancy outcome is not available, and these studies are not reviewed. Donovan (1977) studied smokers in three matemity units in England. Women aged 35 years or younger at the start of pregnancy, who smoked more than 5 cigarettes per day, who had less than 30 weeks of gestation at the first prenatal visit, and who had no prior perinatal deaths, were randomly assigned to a control group that received usual prenatal care or to a test group that was given intense individual antismoking advice by a physician at each prenatal care unit. There were 263 women in the test group and 289 in the control group. Mean daily cigarette consumption decreased from 17.1 cigarettes per day early in pregnancy to 9.2 cigarettes perday late in pregnancy in the intervention 387

7 pared with never smokers. A I I former smokers had a 1.6-fold increase, but this increase was limited to those who had quit within the preceding 8 years. Longer durations of abstinence yielded an odd; ratio of 1.0. Concerns about the possibility of differences in sexual activity between smokers and nonsmokers and the occurrence of STDs limit the ability todraw fimi conclusions about the association of smoking with ectopic pregnancy. There is little information about former smokers, and consequently, no conclusion can be drawn. Some data suggest an association between smoking and increased risk of spontaneous abortion (US DHHS 1989). Data on smoking cessation are very sparse. Kline (1984) noted that the adverse effect of smoking observed in a case-control study of smoking and spontaneous abortion (Kline et al. 1977) was limited to current, not fonner, smokers. Alberman and colleagues (1976) found that the proportion of spontaneous abortions with abnormal karyotypes decreased with increased smoking but was identi- cal for neversmokers and women who stopped smoking prior to pregnancy (Albcnnan et al. 1976). The interpretation of this finding is uncertain. Fetal, Neonatal, and Perinatal Mortality Information linking cigarette smoking with an increased risk of the various measures of mortality used to assess pregnancy outcome has been reviewed in previous reports of the Surgeon General and other publications (US DHEW 1979; US DHHS 1980: US DH HS 1986). Table 3 provides data on perinatal and neonatal mortal ity from the earl ier reports of the Surgeon General (US DHEW 1979: US DHHS 1980) and adds informa- tion from a more recent publication on the topic (Rush and Cassano 1983). The studies ~ o~nsistent i' hi her mortality in children born to women who smoke. The high risk of mortality is indepen ent of various factors, such as educatton an social class, that are also associated with mortality. Kleinman and colleagues (1988) assessed the effect of smoking on fetal and infant mortality in 362.621 births in Missouri during 1979-1983. Using multivariate statisti- cal techniques, these investigators estimated the effects of smoking on fetal and infant mortality~among black and white primiparous and multiparous women. After adjust- ment for marital status, education, and age, fetal plus infant mortality rates were 25 to 56 percent higher in smokers for all categories of maternal race and parity. The elevations in the estimated risks of fetal plus infant mortality were statistically sig- nificant in all categories. In further analyses ofdata from the Missouri births and deaths, Malloy and coworkers (1988) showed that the relative risk of fetal plus infant mortality among whites was significantly elevated for the infants of women who smoked in all categories of low binhweight, even after adjustment for marital status, education, age, and parity (Table 4). This data set is unique in its size, consisting of more than 350,000 binh a' ven tn t e norma birthweight m ants o smokers-those that weis!he 2StX1 Q nr ~re-mortality was slgm i an y e evated for infants of mothen who smo_ ked._ - Infonnation on fetal, neonatal, and perinatal mortality in former smokers is sparse (Table 5). Butler, Goldstein, and Ross (1972) analyzed data from the British Perinatal Mortality Survey and estimated that perinatal mortality was the same for women who 376 -I'ABLE 3.-Surnmary of studies of perinatal and neonatal mortality in smokers and nonsmokers during pregnancy Perinatal monality' Neonatal monatity Number or Rereruuc binhs Category Smokers Nonsmokers Smokers Nonsmokers Yervshalnry 6.800 Whites 13.9 12.4 (1964) Blacks 22.0 23.4 Coinlock and 12,287 23.6° 15.6° Lundin (1967) Amount smoked Meyer and 51,490 <t ppd 28.0 23.0 Tonascia 21 ppJ 33.4 (1977) Soeial etasse Ramakallio 12.068 1+11 28.1° 22.44 (t978) IIIatV 25.1 t9.6 e Farmers 253d 39.0 Unknown 29.44 36.e Anaunt smoked Rush and <5 cig/day 15.9 18.7 Cassano 5-14 ci`/day 26.1 (1983) >t5 ci8/day 28.3 Butler. 21.788 41.t 32.0 17.6 13.7 Goldstein. Ross 1972) Amount smoked Andrews and 19.631 I-4 ci8/day 25 24 McGany S_9ci6/day 20 (1972) 1o-19ci8/day 32 220ci`/day 36 Race and Amount smoked Niswander 37.912 White 31.4 and Gordon I-lociglday 31.5 (t972) 211 cig/day 38.2 Black 38.5 I-I O cig/day 41.5 21I cig/day 57.4 377 Z6ZL OILTS

"fAl)1.[: 16-Sperm quality among smokers and nonsmokers Study population (number of Ratiu of measure among smokers to that among nonsmukers Raference nonsmokers/number of smokers) Spenn density % Nonnal spemt % Motile spemi Viczian Obstetricsclinic 0.82 0.90 0.77 (I968a) (smokers only) (50/120) Vogel,orovennan. Unst•rted 0.60' NS 0.87' Klaiber (39/17) (1979) Nebe and Schirren Andrologyclinic 1.01 - - (1980) (455/451) Evansetat. Subfenilitydinie - 0.92' - (1981) (43/43) Godfrey Infenility clinic - 0.94 - (1981) (74/75) Spira et al. Vafectomycandld'JIC.s 0.75' 0.94 0.93' (1981) (173/122) Infersilityclinic 0.86 0.91' 0.97 (228/292) Rodriguez•Rigau. Infenility clinic 0.95 1.00 1.00 Smidt,Steinberger (101/58) (1982) Shrrrawy muU Volunteers 0.93 0.69' 0.67' Mahrnuud((982) (20r25) Andersen. Sanezuk, Tabor (1984) Infertility clinic (86/137) 0.99 1.07 1.08 Harufelsnun Senxndonors(71/23) 0.67 0.98 0.93' ct al. (1984) Kulikausk ts, Blaustein. Fenility clinic (135/t03) 0.43' 1.00 0.78' Ablin (1985) ' Rantala and Koskimies Infenility clinic (50/60) 0.90 0.98 0.95 (1987) Vogt. I leller, Dorelti Volunteers 0.8(' 1.01 0.99 (1986) (52/150) TABLE 16-Continucd Study population (number of Ratio of nuasure among smokers to that among nonsmokers Conuncnts Reference nonsmokers/numberof smokers) Sperm density % Normal sperm %Motile sperm Comments Nodecreasein Saaranen Infertility clinic 0.81 1.00 0.97 Azoospemticc men spenndensitywith et al. (1987) (110/54) omitted increasing amuunu smoked: controls Klaiber ci al. Paid volunteers (90/60) 0.77' 0.98 0.89' were fenile men (1987) Males from infertile 032' 0.94 0.80' Dikshit. Buch, couples (43/51) Infertility clinic 0.96 0.99 1.01 Mansuri (1987) (288/219) Klaiber and Volunteers 0.93 1.02 0.97 Smokasand Droverman(1988) (21/22) nonsnmoken matched on spemt Saaranen et al. Semen dorwn 0.83 0.95 1.01 density (1989) and fertile men (32/28) Oligospennicb men Manhburn,S(oan, Infenilityelinic 0.92 0.99 0.94 omitted Hammond(1989) (294/152) (<I x 10°/mL) Rui,Oldereid, Infertilityclinic 1.17 1.05 0.96 Azoospennicrrnen Purvis(1989) (203/147) omitted EffeAdy and Krause Infertility clinic 1.13 1.06 1.12 (1987) (61/31) 'Sutistically signifieant difference (pc0.05) between smoken and nonsnwken. 'Oligospermia is a low spenn eount. 'Azoospsrmia is the absence of spenn. All subjects were fertile 10 aeoospennic` smokers omiued from analysis Oligospcmtie men omitted (<I x 10°/mL) Thompson et al. 1973; Patra, Sanyal, Biswas 1979; Biswas and Patra 1981). Some ~ studies have noted a disturbance of spermatogenesis, a decrease in the interstitium, or a destruction of the seminiferous epithelium (Larson. Haag. Silvette 1961; Larson and Silvette 1968; Essenberg. Fagan. Malerstein 1951; Viczian 1968b; Wyrobeck and . Bruce 1975; Biswas and Patra 1981; Alwachi et al. 1986; El•Sayad et a). 1987). The results may depend on the duration and dose ofexposure, as well as on the ages at which exposure takes place. Moreover, the relevance to humans of the large doses given to the animals is uncertain. None of these investigations considered spermatogenesis after exposure ended: thus, few conclusions may be drawn regarding the effect of cessation of exposure even within the limitations of the animal studies. 406 407 LOEL OZLZS

. 7 .. . ~ . ' . ~ . . . ~ ~~ . . , . . . . . . 'a Intruuuetion Age at Natural Menopause TABLE 13.--Summary of studies reporting relationship of cigarette smoking and age at natural menopause 'Rte significance of menopause extends beyond marking the end of femalc reproduc- tive potential. The age at which menopause occurs also may have implications for thc risks of osteoporotic fractures, ischemic heart disease, and cancers of the reproductive system. Thus, the effect of smoking on the age of menopause could have potentially broad health implications. In fact, an early natural menopause has been observed consistently among women who smoke cigarettes. As summarized in Table 13. the major studies addressing this topic have indicated that currently smoking women cease menstruating from I to 2 years earlier than otherwise similar nonsmokers. Expressed as relative risk, women aged 44 to 54 years who smoke become menopausal at about twice the rate of ne+er smokers (Willett et al. 1983; Bailey, Robinson, Vessey 1977; Hartz et al. 1987; Andersen, Transbol, Christiansen 1982; Baron 1990). Several features of the data suggest that this is a causal relationship. By using both cohort and cross-sectional methodology with a variety of subject populations, the results have been replicated repeatedly in studies in several areas of the United States and Europe. Dose-response effects have generally been found, with heavy smokers experiencing an even earlier menopause on average than light smokers. However, these trends have not always been assessed with formal tests of statistical significance in the reports describing the data. Several studies demonstrating this association have con- trolled for potential covariates. That premenopausal smokers may be more likely than nonsmokers to have a hysterectomy does not appear to explain the relationship (Krailo and Pike 1983). Pathophysiologic Framework There are at least three ways in which cigarette smoking could lead to an early natural menopause. Experiments with laboratory rodents indicate that the polycyclic aromatic hydrocarbons found in cigarette smoke may be directly toxic to ovarian follicles (Mattison 1980). Mattison and colleagues found that intraperitoneal injection of benzo(a)pyrene, 3-methylcholanthrene, or 7,12-dirnethylbenz(a)anthtracene led to ovarian follicular atresia (Mattison and Thorgeirsson 1978,1979; Gulyas and Mattison 1979). Earlier uncontrolled studies of prolonged exposure of mice to cigarette smoke led to similar findings (Essenberg, Fagan, Malerstein 1951), which were also seen in a later controlled study.of rats (Subbarao,1988). However, other investigators failed to find ovarian atrophy in rodents chronically exposed to cigarette smoke (Haag,larson, Weatherby 1960; Dontenwill et al. 1973a), and in most studies, parenteral nicotine or tobacco extract has had minimal effect on the ovaries of experimental animals (Essen- berg. Fagan. Malerstein 1951; Thienes 1960; Larson, Haag. Silvette 1961; Larson and Silvette 1968). The other two postulated mechanisms for premature menopause do not involve direct ovarian toxicity. Cigarette smoking may interfere with luteinizing hormone release at 396 Source and number Reference ofsubjects 1ick, Porter, Morrison 2.143 hospital patients (1977) in Boston area 1.391 hospital patients in 7 countries Daniell (1978) 500 patients B ai ley. Robinson. 733 health Vessey(1977) sceeenees McNamara et at. 1.553 general ( (978) population subjects Lindquist and 873 general population Dengtsson(1979) subjects Kaufman et al. 656 hospital (1980) Adena and C atlagher ( I 982) Willett et aI. (1983) patients 10.995 health screenees 66.663 nurses ' McKinlay. Bifano. 5.350 general McKinlay (1985) population subjects Everson et al. (1986) 261 population subjects Hiatt and Freman 5.346 HMO health (1986) screenees Stanford et d. (1987) 3.545 breast cancer screenees Brambilla and 2.565 McKinlay(1989) Covariates considered Difference in median menopausal ages' (yr) Parity, marital status. 1.7 coffeeheahtcohol, hospital service. diagnosis Same as above .31 Weight 20 None 1.3° None 0.8e Weight 1.2' Parity, ponderal index. 1.7' age first smoked, geographic region Weight,aleoholintake, 1.0 drug taking Height, weight. 1.4 diabetes. hypertension,ageof menarche. nulliparity None .7 Passive smoking 1.1 None 0.95` None 0.3 Education, income 1.5 NOTE: Hh10.kahh maintenu+a organiutim. •µedian menopcvsal age among nomnaken minus mrdian mcnopausal age amang,moken. sCanpuea by Adena and cJlagher (19g2). `Dinerenec in mean menoPauW ages. 397 .. s...M,r.¢m., ...~,...~ a..~.:.. M.w. Z 0£ L 0 T L T S .w ,..... . ..w. v,-__

with that of nonsmokers (l'sitouras, Manin, Hamtan 1982; Diokno, Brown, Herzog 1990); in a cross-sectional study of younger men, no differences were indicated ( Vogt, Flcller, Borelli 1986). Adolescent smokers are more sexually active than nonstnokcrs (Russell 1971 : Malcolm and Shcphard 1978). In contrast. Cendron and Vallery-Mas- son (1971)- in studying 70 men older than age 45, found that those who rcported smoking between ages 25 to 40 also reported being less sexually active at those ages than those who denied smoking. Overall, it appears that the relation between current cigarette smoking and the level of male sexual activity is not very strong. Among younger males, personality differences between smokers and nonsmokers may dominate any adverse physiologic effects (Russell 197I ). 11', as the aforementioned studies suggest, current smokers (or ever smokers) are similar in sexual habits to never smokers, then no differences would be expected for former smokers. Vogt, Heller, and Borelli (1986) evaluated 239 healthy male volun- teers aged 19 to 40 without genital abnormalities or diseases and taking no medications. The study results indicated that the 36 former smokers among them were comparable with both never smokers and current smokers in sexual activity (Vogt. Heller. Borelli 1986). Impotence, the inability to maintain an erection sufficient for intcrcourse, has been more extensively investigated in relation to smoking. Among treated hypertensives aged 40 to 64, cigarette smokers were more likely to report impotence, although the differences were modest and not statistically significant (Buhler et al. 1988). A statistically significant association was reported among men undergoing radiation therapy for prostatic cancer (Goldstein et al. 1984). However, in both studies, poten- tially important covariates, such as alcohol intake and age, were not considered. Two other studies of men undergoing impotence evaluation indicated a high prevalence of smoking and suggested an association between smoking with impotence (Virag. Bouilly. Frydman 1985: Condra et al. 1986). Unfortunately, neither study included a sexually functional control group, and both studies based their conclusions on ques- tionable comparisons of the smoking rate in theirclinic patients with that of the general population. Vogt. Hcller, and Borelli (1986) studied a group of young volunteers without selecting for impotence. These investigators found that smokers reported more difficulties with decreased libido and erection than nonsmokers (Vogt. Heller. Borelli 1986). This analysis did not consider fomier smokers separately. An acute effect of srnoking on sexual performance is suggested by a study of smokers monitored while viewing erotic films (Gilbert. Hagen. D'Agostino 1986). The succes- sive smoking of 2 cigarettes high in nicotine content significantly impaired the rate of penile diameterchange compared with that observed aftersntoking I cigarette orcating candy. However, the clinical relevance of these observations is unknown because frank impotence was not studied. An important clinical measurement in the evaluation of impotence is the PB1, which indicates the systolic blood pressure in the penis divided by systolic blood pressure in the arm. A low value is considered to be evidence of compromise of the penile blood supply, a factor which may interfere with erection. Several studies of men undergoing evaluation of impotence reported an association between smoking and low P81(Jacobs et al. 1983; Condra et al. 1986; Bornman and Du Plessis 1986; DePalma el al. 1987). 402 S0£L OZLTS M Among impotent diabetics, evidence of nocturnal erections was found less in smokers compared with nonsmokers, thus suggesting an increased risk of vascular compromise in smokers (Takahashl and Hlrata 1988). Howcver, other studies of impotent mcn have not reported differences between sniokers and nonsmokers in vascular measurements (Wabrek et al. 1983; Virag, Bouilly, Frydman 1985: Kaiser ct aI. 1988). Most of these investigations did not consider covariates such as alcohol u.e, although one study suggested that smoking in isolation had little effect and that an association of smoking with an abnonnal PBI may be due to the association of smoking with other arterial risk facturs (Virag. Bouilly, Frydman 1985). In niany of the studies relating smoking and impotence, the investigators did not distinquish nonsmokers as ex-smokers or never smokers. However, two investigations considered former smokers separately (Table 15). Wabrek and associates (1983) studied 120 men who were refemed to a hospital-based erectile dysfunction program. The percentage of former smokers was approximately the same among men with impaired, borderline, and normal PBI- Condra and colleagues (1986) reported on 178 patients also referred for impotence. Former smokers were not separated for analysis, but this study suggests that the PB1 for ex-smokers is more normal than in current smokers (Condra et al. 1986). However, neither study considered important covariates, such as age and alcohol use (Wabrek et al- 1983; Condra et al- 1986). Two recent investigations considered the effect of smoking cessation on impotence. Forsberg and colleagues (1979) noted that two smoking men who were impotent improved thcir functioning after smoking cessation at the same time that measures of penile blood flow improved. However, it is not clear how these two men werc selected for this study, and control subjects were lacking. Elist. Jarman, and Edson (1984) reported on the treatment of 60 impotent men- Twenty nonsmokers were treated with the vasodilator isoxsuprine, and 40 smokers were either advised to stop smoking or advised to stop smoking and also given isoxsuprine. There was no mention of randomization, and there was no untreated control group. Similar proponions im- proved whether given isoxsuprine, convinced to stop smoking, or both (Elist. Jamlan, Edson 1984)- Anlmal data have not elucidated the relation between smoking and either sexual activity or impotence. Soulairac and Soulairac (1972) studied the sexual activity of male rats given either a 0.6 mg/kg or a 1.2 mg/kg dose of nicotine subcutaneously. The sexual activity of the rats after the nicotine administration was compared with that before treatment. Sexual activity was markedly increased with the 0.6 mg/kg dose, and at 1.2 mg/kg there was trembling and twitching and no sexual behavior for 2 to 3 hours- In contrast, exposure to smoke from I cigarette has been shown to interfere with the physiology of erection in male dogs (Juenemann et al. 1987). In sumrnary, the level of sexual activity does not appear to be affected by cigarette smoking. Cigarette smoking may be associated with impaired male sexual pcrfor- mance. Among impotent men, smokers are more likely to have an underlying vascular problem. These associations have been more commonly noted in groups already at high risk of impotence, such as hypertensives and diabetics. However, these associations have not been consistently observed, and the positive findings may be due to the association of smoking with othcr factors such as alcohol use. Moreover, because the 403 _. , ^ ... .. , v. ...~. ~.... . . .. ,._ _ . .. . ..... ......_.._ _.,.Y._

i 'fABLIi 15.-Scsual pcrformancc among malc former smokers kvfercnce Studypupulabtut Fmdings Conmrenu Vugt.llcller.Ohr Voluntecrs No differences in sexual Noconsideruuun ( 19144) activity between tonner, of cuvari:nes current. and never smukcrs wahrek et al. hm{wieni patiems Proponion of fumter smokers No coroidcration (1983) similar in men with of cuvanatcs abnomtal, irnpuited. and normal Pl31 CUndr;let al. Impotent patients Indicatlonithat fomler Noconsideraiion (1986) smokers had more normal of covariates PBI thun current smokers Forsberg et al. Impotent patients Two smokers improved No controls (1979) sexual perfoOllance after smoking cessation Etist, Jannan. Edson Impotent patients Smoking cessation improved No untreated and (1984) sexual perfomsance as well cauruls as vasodilator NOTE: YBLpenVlrbrxhialinde.l studies of PBI are generated entirely in referral populations, it is unclear if these findings can be generalized. Because of limited and uncontrolled data, no conclusions can be drawn regarding sexual performance or PBI among former smokers. Sperm Density and Quality Measurements of sperm density, morphology, and motility are commonly used assessments of sperm quality (Rogers and Russell 1987). Over 20 studies have dealt with the relation of cigarette smoking to sperm density, motility, and morphology (Virr.ian 1968a; Schirren and Gey 1969; Campbell and Harrison 1979; Vogel, Brover- man, Klaiber 1979; Stekhun 1980; Nebe and Schirren 1980: Evans et al. 1981; Godfrey 1981: Rodriguez-Rigau. Smith. Steinberger 1982; Shaarawy and Mahmoud 1982: Buiatti et al. 1984; Andersen. Semczuk, Tabor 1984; Nordenson, Abramsson, Duchck 1984; Handelsman et al. 1984; Hoidas et al. 1985: Kulikauskas, Blaustein, Ablin 1985: Ablin 1986: Rantala and Koskimies 1987; Vogt, Heller, Borelli 1986; Klaiber et al. 1987; Dikshit, Buch. Mansuri 1987; Saaranen et a1.1987; Klaiber and Broverman 1988: Saaranen et al. 1989: Rui, Oldereid, Purvis 1989; Marshbum, Sloan. Hammond 1989; Oldereid et al, 1989). Table 16 summarizes the findings of those studies that reported rnean values for smokers and nonsmokers. In most studies, men smoking cigarettes had lower sperm density, al though Inany of these studies ind icated di fferences that were not statistically significant. The smokers' average sperm density was at least 80 percent that of the nonsmokers. In several studies sperm morphology ormotility was impaired 404 90£L 01LZ5 in smokers compared with nonsmokers, but this was a Icss consistent finding. Few studies have considered the spemtatic chromosomal characteristics of smokers com- pared with nonsmokers. Nordenson. Abramsson, and Duchek (1984) found smokers to have more chromosome breaks than nonsmokers, but Oldereid and coworkers (1989) reported no differences in DNA condensation as assessed by flow cytofnetry. Although differences in mean values of any of these measurements suggest an effect of smoking, the most relevant parameter may be the percentage of smokers and nonsmokers who exhibit deficiencies in sperm density, morphology, or motility. Several researchers have investigated the relative risk of azoospermia (no sperm in the ejaculate) or oligospermia (reduced number of sperm) in smokers versus nonsmokers or never smokers (Table 17). Although the range of relative risks is wide, there is a clear pattern of increased risk among smokers. However, the clinical significance of oligospermia is uncertain. Most studies have used one ejaculate per man, although the within-man coefficient of variation can be as much as 60 percent (Schenkeret a1.1988). The available information suggests that current smoking is related to low sperm density. However, these data are limited. Many studies investigated men visiting infertility clinics, limiting generalization. Moreover, if male smokers with poor sperm quality are most likely to attend these clinics, selection biases may distort the results. Also, many of these studies were relatively informal. Few of the studies accounted for potentially confounding factors such as alcohol use and age. Less than half of the studies documented that a period of sexual abstinence was required for subjects before giving the sperm sample, and few of the studies analyzed multiple semen specimens as some authorities recommend (Zaneveld and Jeyendran 1988). Most studies have a small number of subjects, and their statistical power is limited for this n;ason. In some of the studies, it is not clear whether former smokers were included in the smoker or nonsmoker group. A few studies investigated ex-smokers (Table 18). One was a case--control study of male infertility in Italy (Buiatti et al. 1984). The cases were azoospermic or oligosper- mic men being treated for infertility at the University of Florence. Controls were University outpatients who had normal sperm counts. There were no significant differences between smoking categories in the percentage of men with low sperm counts. Vogt. Heller, and Borelli (1986) evaluated 239 male volunteers. Among former smokers (those who had smoked for at least 1 year and those who had stopped smoking for at least I year). percent normal spermatozoa, percent young forms, percent old forms, and percent degenerate fortns were comparable with those of never smokers. Stekhun (1980) reported that 42 percent of former smokers had oligospermia compared with 18 percent of never smokers. Schirren and Gey (1969) reported that three men with low sperm density and motility showed substantial increases in these parameters 3 to 6 months after smoking cessation. However, there were no controls defined in this analysis. Because of the limitations of the four studies, no conclusions are possible regarding the effects of smoking cessation on sperm quality in humans. Animal studies have not been particularly informative. In sotne studies, rodents that were heavily exposed to nicotine or cigarette smoke demonstrated testicular atrophy, but this has not been a general finding (Larson. Haag. Silvette 1961; Larson and Silvette 1968; Dontenwill et al. 1973b; Essenberg. Fagan. Malerstein 1951; Thienes 1960: 405 ___._. . ~..,,.. _. . __......,.__ ...._.. __ _w .__.. _ __.._ __..

I is cunsistcntly more common among unmarried mothers (Schramnt 1980; Rush and Cassano 1983) and nearly one-half of black infants are born to unmarried mothers (NCHS 1982). The low response rate might have also affected the validity of the study. Prager and associates (1984) askcd women how many cigarettes they smoked per day before and after they found out they were pregnant. Among all married respondents, 31 percent smoked before pregnancy. Whites were more likely to smoke than blacks (32 vs. 25 percent). These investigators reported a strong association of smoking with age, with younger mothers more likely to smoke than older mothers. There were even more pronounced gradients with education. Among women with less than a high school education. 50 percent smoked before pregnancy, and this percentage diminished monotonically to 15 percent among women with 16 or more years of education. Among the women in the study (Prager et al. 1984) who smoked prior to pregnancy. 18 percent quit after realizing they were pregnant. White women were somewhat more likely to quit than black women (18 vs. 13 percent). Mothers older than 35 years of age were markedly less likely to quit; only 7 percent did. Again, education had a strong association with quitting; 10 percent of mothers with less than 12 years of education quit, and the percentage increased monotonically to 24 percent among mothers with 16 or more years of education. The patterns of cessation by amount of smoking are also of interest. Women who were smoking I to 10 cigarettes per day at the time of pregnancy recognition were far more likely to quit than women smoking 11 or more cigarettes per day (31 vs. 12 percent). Among the heavier smokers, 27 percent reduced their consumption to 10 or fewer cigarettes per day even though they did not quit. Williamson and associates (1989) used data from the Behavioral Risk Factor Surveil- lance System in 1985 and 1986 to compare smoking patterns among pregnant and nonpregnant women. Data were collected through 19,124 telephone interviews of a population-based sample of women in 26 States, with ascertainment of current preg- nancy staius, smoking history, and current smoking practices. Women pregnant at the time of interview were less likely to be current smokers than nonpregnant women (21 vs. 30 percent), but had a similar likelihood of ever having smoked (43 vs. 45 percent). The proportion of former smokers was thus greater among pregnant women (22 vs. 15 percent), largely accounting for the difference in current smoking patterns. This study (Williamson et al. 1989) suggests that if 30 percent of women pregnant at the time of the survey smoked prior to pregnancy, then 30 percent of smokers would have had to quit after becoming pregnant to account for the reported smoking rate of 21 percent. Among pregnant women who smoked, the mean number of cigarettes consumed per day was 12, compared with 20 cigarettes per day among nonpregnant women who smoked. These data suggest that smokers who do not quit upon becoming pregnant tend to reduce their cigarette consumption (Williamson at al. 1989). Patterns of smoking were generally similar across demographic subgroups, with one important exception. Among unmarried women, smoking was slightly more common in pregnant than nonpregnant women (36 vs. 34 percent), implying no change in smoking among unmarried pregnant women. The absence of pregnancy-related reduc- tion in smoking for unmarried women was due exclusively to a markedly higher smoking prevalence for white unmarried pregnant women. The results suggest that data on married mothers cannot be generalized to unmarried mothers. A number of investigators reported smoking patterns in selected populations, such as women delivering in a particular hospital or geographic region or those receiving prenatal care at a specific clinic. Table I I summarizes several of these studies. Although none are true probability samples, these studies provide an indication of the diversity of smoking and smoking cessation among different populations. The propor- tion quitting during pregnancy ranges from 6 to 49 percent. Time Trends in Smoking and Smoking Cessation Kleinman and Kopstein (1987) compared the pattern of smoking cessation during pregnancy from the similarly designed 1967 and 1980 NNS. Although there were some changes in the proportion of mothers who were married at the time of each of the two surveys.and the characteristics of nonrespondents might have varied, the surveys provide a unique opportunity to assess temporal trends in smoking and smoking cessation during pregnancy. The percentage of mothers who smoked prior to pregnancy decreased markedly during that period, from 45 to 30 percent for white mothers and 40 to 25 percent for black mothers. The percentage of white mothers who quit after pregnancy rose from I 1 to 17 percent between the two surveys, whereas the percentage of black mothers who quit decreased from 17 to 11 percent over that interval. During the interval between the surveys, the diminution of smoking during pregnancy was more pronounced for highly educated women, increasing the differential exposure to tobacco by educational status (Kleinman and Kopstein 1987). Estitnates of Attributable Risk Percent Although several measures of attributable risk are commonly used to describe the burden of disease associated with an exposure, the most recent report of the Surgeon General (US DHHS 1989) has focused on attributable risk percent, frequently termed etiologic fraction, as the most relevant measure of the likely public health impact of smoking cessation. Calculation of the attributable risk percent uses the formula as follows: R(R-I)p ARperctnr = I(RR-1)p)+1 where p is the proportion of persons with the exposure and RR is an estimate of the relative risk of the outcome in those who are exposed compared with those unexposed. At least three different studies (Meyer, Jonas, Tonascia 1976; McIntosh 1984; Kramer 1987) estimated the relative risk of several pregnancy outcomes after reviewing the research literature. Table 12 summarizes these studies and provides estimates of attributable risk for prevalences of smoking of 20, 30, 40, and 50 percent based on the relative risk estimates from the three studies. As noted earlier, demographic subgroups of women differ markedly in smoking prevalence. Of those women with less than a high school education, 50 percent smoked during pregnancy; of those women with some college education, 20 percent smoked during pregnancy (NCHS 1988). Approximate- ly 30 percent of married women and 40 percent of unmarried women smoked prior to 392 393 00EL 0ZLZ5

S N e 0 fs > r N 394 p . C W W W < rv z z 'G ~[ P tY - L TABLE 12-Summary urstudies that estimated relative risk or various pregnancy outcomes for smoking based on a"synthesis" of the literature, and attributable risk percent based on several estimates of the prevalence of smoking during pregnancy Perinatal monaliry Low binhweight Pretemt delivery q ;; a v a ~ . rv r _ ReferetK•e D RR AR% RR AR% RR AR'k Mtyer. Jonas. 0.20 1.21 ° 4 1.991, 17 1.32° 6 Tonascia 0.30 6 23 9 (1976) 0.40 8 28 11 0.50 10 33 14 Mclntosh 0.20 1.25 5 1.81 14 1.45 8 a - n 0 r1 F. N z N ~ r (198i) 0.30 7 19 12 0.40 9 24 15 0.50 11 29 ,8 Kramer 0.20 NR - 2.42 22 1.41 8 (1987) 0.30 - 30 II 40 0 - 36 14 e" ~` N N . 0.50 - 42 17 e0 ~+p, Oe .b 0 0 P P P z P Ow. P e^ P z NOTE: RR•relative ri.k: AR.wtribuublt ri.k: NR-na reponel 'Prtv.ltnce Of amuklnr. "A.enRinE anoar stwlita. .~ ~ t a g .Y y e .a .S ~ 8 a t ~. ~ _ = E T ~ E U r p € 0 z a z " E x r a f ~ f .i; .~ 2 ~ E o ~ > > ~ ~ m m ~ tn te V t: ~ ~ ~>+ c E u } ~ v ~ f v a € 'T d 7 Z o u m 3 3 . . a ° ^ g . ~ o a ,~ °' F Y P v W v G 4 : P w ? .. 7 P ^ ; 3 = n ~ L P C t C ~ .~ t s,xm° 8 x $. a u5 d 3 fY f° $~ I0£L OILtS pregnancy (NCHS 1988). The most recent estimates suggest that about 25 percent of U.S. women smoke throughout pregnancy (NCHS 1988). The relative risk estimates for perinatal mortality and preterm delivery are remarkably- c_onsistem,~ecially cpn~dering`tfiai i ie e authors conductedindependen syntheses of the literature. Estimates of the relative risk of low birthweig t~Rm 1.81 (Mclntosh 1984) to 2.42 (Kramer 1987), probably because of differences in the number of studies used to derive the estimate. For this reason, attributable risk percent for a given prevalence of smoking is more variable for low birthwcight than for perinatal mortality and prcterm delivery. Based on data that indicate that about 25 percent of U.S. women smoke throughou pregnancy, it can be estimated tTat to pe_ perinatal deathe l7 to 26 percent_ of low birt weight births and 7 to 10 rcent of reterm deliveries could be revented 6y'~ttttlln on o smoking during pregnancy. In groups with a 50-percent pfsv ence of smoking, such as women with less than a high school education, approximately 10 to I 1 percent of perinatal deaths. 29 to 42 percent of low birthweight births, and 14 to 18 percent of preterm deliveries might be prevented by elimination of smoking during pregnancy. These contributions to adverse oregnancy outcome are sizable and smok- 1- ing is2robably the mostimpottantmodifJable cause of poor prcgnancy outcome amon ~/g women in the United States (Kramer 1987). 395 ... . _ _ r..._ . . ~,:F.-. ~.».....r _ .._. .w , ~.....v,...w. ..,,. .~ ....~..W » .._. _.._.

The Collaborative Perinatal Project (27) associated smoking with term PROM but not ptzterm PROM. However, recent studies have shown a consistent rela- tionship between prLterm PROM and smoking (28, 29). Further studies controlling for differences in maternal sexual activity and in maternal genital tract pathogens are needed to assess the association between smoking and PROM. Surprisingly, a number of studies suggest that ma- ternal smoking decreases the risk of pregnancy-induced hypertension by 50%, with a dose-dependent relation- ship (30). The proposed mechanism is nicotine inhibi- tion of thrombozane A, production. Prematurity Pmmaturity has been shown in several studies to have an estimated RR of 1.2-1.5 in smokers compared with nonsmokers (5). In a prospective study of 30,596 preg- nartt women (31), preterm births (delivered at less than 37 weeks of gestation) were 20% more common in women smoking more than one pack per day while pregnant than in nonsmokers. The analysis controlled for maternal age, education, the time of initiation of prenatal care, and alcohol consumption, among other confounding variables. In a recent study attempting to characterize trxsons for higher rates of preterm births in black women compared with white women,10% of the excess risk in black women was attributed to cigarette smoking (32). Birth Weight In a large number of cpidemiologic studies, it has been shown that the mean birth weight of infants of women who smoke during pregnancy is 170-200 g less than that of infants of nonsmoktrs.'Ihis difference persists even after controlling for confounding variables such as maternal age, parity, maternal weight gain and energy intake (33), social class, level of education, and alcohol consumption. Ibe consistency of the association between smok- ing and lower birth weight supports a probable causal relationship. From the literature it is difficult to deter- mine whether this difference in birth weight is due to preterm deliveries of appropriate-weight babies or in- trauterine growth retardation of term babies. It is most likely a combination of the two. Theit is an increased rate of prtiterm deliveries among pregnant women who smoke. Smokers also have a 3.5-4.0-fold increase in small-for-gcstational-age infants compared with non- smokers (34); newborns of smokers are smaller at every gestational age. The women who stop smoking before 16 weeks of gestation have infants with birth weights similar to those of babies of women who never smoked (35). Proposed mechanisms for the decrease in birth weight include hypoxia due to carbon monoxide, pla- 4 cental vascular problems due to nicotine, decreased transfer of amino icids across the placentas of smokers, and, most recently, decreased availability of zinc. Ciga- nette smoke contains cadmiutn, which acts as a zinc antagonist. Zinc has been identified as an important alloenryme of prrgnancy, and low zinc concentrations in maternal and cord blood have been related to intrau- torine growthrrtardation (36). Reduction in birth weight after cadmium czposure has been reported in mice as well as in women with occupational exposure to cad- mium (37). Periaatal Outcomes Multiple recent studies have demonstrated a clear asso- ciation between maternal smoking and perinatal loss. Placentapttvia, abruptio placentae, andpretermPROM were responsible for most of the perinatal losses in smokers.'I'hese epidemiologic studies report an asso- ciation between smoking and perinatal mortality but do not establish a causal relationship. Most studies have not found a relationship between smoking in pregnancy and birth defeeu, childhood cancer, or long-term neurologic sequelae (38). Several studies of sudden infant death syndrome have found maternal smoking in pregnancy to be an important risk factor (39). Smoking Cessation Approximately one third of women are smokers at the time they conceive. Although a causal relationship has not been proven for all of smoking's adverse effects on fertility, it may be prudent for women attempting to become pregnant to reduce or stop smoking cigarettes. It has been estimated that if all pregnant women stopped smoking, a 10% reduction of infant and fetal deaths would be seen (40). Approximately 20% of smokers quit by the time of their first prenatal visit (S). Despite regular contact with health canrs providers who give current antismoking advice, however, only 6% give up smoking later in pregnancy (41). The most successful efforts in smoking cessation during pregnancy involve interventions that emphasize how to stop smoking and do not just provide antismok- ing advice. A prospective, randomized, controlled clin.i- cal trial of an intensive smoking reduction program with substantial patient contact and supervision (initial visit plus telephonecontact at least monthly) bas been shown to aid in smoking cessation during pregnancy and to increase birth weights (4). In a morz recent study eval- uating the efficacy of a low-cost smoking cessation pro- gram during pregnancy, initial patient education with supportive contact throughout pregnancy resulted in an improved rate of smoking cessation during the im- I'm Nw Ln ~ J ~ \r B

3 \ \ control studies have shown an approximately doubled risk of ectopic pregnancy when the mother smoked at the time of conception (11). In a multinational study of 1,108 women with confirmed ectopic pregnancies, the frequency of ectopic pregnancy was higher in smokers than in nonsmokers (OR, 2.2-4.0, depending on the subgroup) (12). The analysis was adjusted for pelvic inflammatory disease and intrauterine device use. Spontaneous Abortion Large epidemiologic studies in developed countries have demonstrated that smokeas have 1.2 to 1.8 times as many spontaneous abortions as nonsmokers. Given a background level of clinically apparent spontaneous abortions of approximately 15%, this results in a mis- carriage rate of 18-27% for smokers (6). In a large case-control study matched for maternal age, parity, obstetric history, marital status, socioeco- nomic status, and race, spontaneous abortions were 80% more common in smokers than in nonsmokers. Although no dose-dependent rrs-ponse was demon- strated in this study (13), another study has found the risk to increase with heavy smoking (14).'I'his can be contrasted with a larger prospective study of 32,000 women which found a nonsignificant ItR of only 1.2 after controlling for alcohol consumption (15). In vitro fertilization studies allow controlling for confounding variables. In such a study of 447 couples, there were no significant differences in number of eggs retrieved, fert.ilization rates, or implantation rates be- twecn smokers and nonsmokers. The incidence of spon- taneous abortion, however, was 42.1 % in smokers com- pared with 18.9% in nonsmokers (16). Kline u al evaluated 979 karyotyped spontaneous abortions (17). Spontaneous abortions of smokers were 39% more likzly to be chromosomally normal than those of nonsmokers. Tbig suggests that the mechanism is not genetic. Male Reproductive Function In a number of studies, a consistent association between smoking and impaired sperm concentration, motility, and morphology has been found (18, 19). Some evi- dence supports that cessation of smoking may improve sperm density and motility.; Effects on Pregnancy Various effects of cigarette smoking on pregnancy have been studied. They include placental changes, preg- nancy complications, and perinatal loss (Table 1). Pathophyslology Carbon monoxide and nicotine are thought to be the main ingredients in cigarette smoke responsible for adverse fetal effects. These products cause fetal by- poxia and blunt the nornZally adaptive response to the insult. Carbon monoxide has a 200 times greater affin- ity for adult hemoglobin than does oxygen and an even higher affinity for fetal hcmoglobin, resulting in a decrease in oxygen-carrying capacity. When carbon monoxide binds to fetal hemoglobin, there is also a shift of the oxygen dissociation curve to the left, resulting in greater hemoglobin-oxygen binding and decreased availability of oxygen to the tissues. 'Ibe pulmonary vascular bed serves as an effective route for drug administration; one puff of a cigarette is equal to an intravenous injection of 0.1 mg of nicotine. Nicotine's action on the adrenal gland results in in- creased levels of circulatory norepinephrine, epineph- rine, and acerylcholine, which leads to a decrease in uteroplacental perfusion. Nicotine crosses the placenta and increases blood pressure in the fetus, either directly or indinectly thrnugh the adrenal gland, and also de- creases fetal breathing (20). It may also affect the gastrointestinal, genital, urinary, and central nervous systems (21). Placental Changes Placental changes found in smokers include hypcr- trophy, a decrease in vasculosyncytial membranes, cytotrophoblastic cell proliferation, focal syncytial ne- crosis, decreased pinocytosis, and thickening of the trophoblastic basement membrane (22) as well as calci- fication (23). Many of these changes are typically seen in cases of chronic hypoxia and ischemia. 7he volume density of fetal vessels in terminal villi is decreased, signifying a loss in the exchange area of smokers' pla- centas (24). Tobacco smoke has been shown to depress active uptake of amino acids by the placenta (25). Pregnancy Complications Women who smoke during pregnancy have a higher risk of abruptio placentae, placenta previa, and prema- ture rupture of membranes (PROM). In the Collabora- tive Perinatal Project study, abruptio placentae was 1.5 times mors common and was more likely to result in perinatal mortality in smokers than in nonsmokas. Pla- cental pathologic changes found in abruptio placentae, such as decidual necrosis and large infarcts, were more common in cigarette smokers. When women stopped smoking prior to their first prenatal visit, decidual necrosis was found less fi+cquentiy and thero were 50% fewer fetal and neonatal deaths due to abruptio placen- tae (26). Historically, placenta psevia and smoking have been linked. However, because of the difficulty in clinically distinguishing placental abruption from pre- via, additional studies relying upon the ultrasound diag- nosis of placenta previa arc needed to confurn this association. .1

, 3 D j; ~ ~ t.. a I III 111 11 41 1,= la2 11 7a A :.IIgI1Iii .4 i~ ~~ ~ I I I I • i; ; I d . ; i I ~ ~~ p~ A I 1 I I t ! ~I a .. .jx. 31,: 1,; I I I 1 I 410 Chaotar 5 Prrp.ney I 6a.cw: t9)3 R.4dJ. Ch.pI.r 4. pp- 9) . 149. 4 11 51710 7324

l menopause. Like current smokers, former smokers may be more likely to be passively exposed to passive smoking than never smokers, thus possibly affecting menopausal age. These factors would tend to lead to an exaggeration of the apparent impact of fomier smoking on menopausal age (Chapter 2). Thcrefore, the results summari-r.ed above may overstate the degree to which former smoking is associated with any disturbance in menopausal age. It appears that age at menopause in fonner smokers is closer to that of never srnokers than to current smokers, and the data are consistent with a decline in the risk of early menopause with the cessation of smoking. The effect of smoking on menopausal age may be partly or wholly reversible with cessation of smokingduring the premenopausal years. However, some pertinent data are lacking. Most of the studies did not consider how long it takes after cessation of smoking for the risk of early natural menopause to decrease. No studies have verified that the women who stopped smoking had a lifetime smoking exposure similar to that of women who continued smoking. PART II. MALE Introduction Cigarette smoking has been considered to be associated with impairment of male sexual functioning, and tobacco abstinence has been recommended for men attempting to maximize sexual performance (Larson. Haag. Silvette 1961: Sterling and Kobayashi 1975; Ochsner 1971a,b). An association between smoking and impaired sexual per- formance among men has been publicized in the lay press (Reuben 1988). Although some data provide evidence for this association, they are inconclusive. Pathophysiologic Framework Three general types of mechanisms have been proposed to explain the harmful effect of cigarette smoking on sexual perfortnance, impotence, and sperm quality. First, smoking may expose the testes to compounds that arc directly toxic to the sperm- producing germinal epithelium, to early sperm forms, or to the hormone-producing Leydig cells. Tlte effects on sperm may be a manifestation of a genotoxic effect of cigarette smoke constituents (Obe and Herha 1978; DeMarini 1983). Second, smoking causes atherosclerotic peripheral vascular disease (Chapter 6); this may translate into a diminished vascular supply to the genitals,as reflected by the penile brachial index (PBI) and other vascular measurements. A diminished vascular supply to the genitals would compromise sexual perrorrnance and spermatogenesis and hor- mone production. Although atherosclerosis is often considered a fixed lesion, several studies have suggested that atherosclerotic plaques may regress with appropriate lifestyle changes (Bamdt et al. 1977: Nikkila 1980; Kramsch et 21. 1981; Chapter 6). However, no studies have been conducted on the effect of smoking cessation on regression of atherosclerotic lesions. ~ 1 Nonatherosclerotic vascular changes may also mediate the effect of smoking on genital function. The vasoconstrictive effects of nicotine in cigarette smoke may impair the complicated vascular processes involved in erection (Benowitz 1988). This may be due in part to disturbances of prostaglandin production in the vascularendothetiurn or to an enhancement of platelet aggregation noted by several investigators (Nadler. Velasco. Horton 1983; Alsteret al. 1986; Tayloret al. 1987: Lassila et al. 1988;1eremy et al. 1986: FitzGerald. Oates. Nowak 1988; Chapter6). Finally, hormonal effects of cigarette smoking could alter sexual responsiveness and spermatogenesis. Alterations in the secretion of luteinizing hormone releasing hor- mone (Moss, Riskind, Dudley 1979) or catecholamines (Patra. Sanyal, Biswas 1979;. Klaiber and Broverman 1988) are two such possibilities, but disturbances in sex hormones, particularly low testosterone or high estradiol, have been suggested more often. In general, men who smoke cigarettes have similar or higher testosterone levels than nonsmokers; thus, it is difficult to associate low testosterone with sexual dysfunc- tion among men who smoke (Briggs 1973: Shaarawy and Mahmoud 1982: Andersen. Semczuk, Tabor 1984; Handelsman et al. 1984: Deslypere and Vermeulen 1984; Vermeulen and Deslypere 1985; Vogt. Heller. Borelli 1986; Barrett-Connor and Khaw 1987; Dai et al. 1988; Lichtenstein et al. 1987; Meikle et al. 1987; Klaiber and Broverman 1988). The adrenal androgens (i.e.. androstenedione. dehydroepiandrosterone, and dehydroepiandrosterone sulfate) are elevated in male smokers (Barrett-Connor, Khaw. Yen 1986; Barrett-Connor and Khaw 1987: Dai et al. 1988). Aromatization of these hormones may explain the elevated levels of estradiot among males who currently smoke (Entrican. Mackie. Douglas 1978: LLindholm et al. 1982; Klaiber, Broverman, Dalen 1984; Barrett-Connor and Khaw 1987: Lichtenstein et al. 1987; Dai et al. 1988: Klaiber and Broverman 1988). Elevations in circutating estrogens may interfere with spermatogenesis and sexual behavior(Klaiberand Brover- man 1988); such an explanation remains speculative. Several studies have suggested that the estradiol and testosterone levels of former smokers are comparable with those of never smokers (Deslypere and Vermeulen 1984; Vogt, Heller, Borelli 1986; Barrett-Connor and Khaw 1987; Lichtenstein et al. 1987). This observation implies that smoking cessation is likely to reverse anyeffect mediated by disturbances of these hormones. Altematively, former smokers may have had a lower total dose. Androstenedione and dehydroepiandrosterone sulfate levels may be modestly higher in former smokers compared with those of never smokers (Barrett- Connor. Khaw, Yen 1986; Barrett-Connor and Khaw 1987; Lichtenstein et al. 1987). However, the relevance of these findings to sexual capabilities is unlikely to be significant. These hormones appear to have little intrinsic potency, and are important because of their capacity for conversion to more active hormones such as testosterone and estradiol (Baxter and Tyrrell 1987). Sexual Activity and Performance Surveys of ttte relationship between smoking and frequency of sexual episodes (intercourse or masturbation) have generally found smokers to be as sexually active as ttonstttokers. In two studies of elderly men, sexual activity in smokers was comparable 400 VOEL OLLTS 401

l least in rodents exposed to parenteral nicotine orcigarette smoke (Andersson et al. 1980; Andersson et al. 1984; Andersson et al. 1988; Eneroth et al. 1977a,b; Kanematsu and Sawyer 1973: Blake, Norman, Sawyer 1974: Blake 1974: Blake et al. 1972a.b; McLean. Rubel. Nikitovitch-Winer 1977). This effect appears to be due to a nicotinic effect on ncurotransmitter release. A return to a more normal function after the end of exposure to smoke or nicotine has not becn documented, but it seems likely that such a nicotinic effect on the brain would not be permanent. Therefore, it is possible that in humeuu, smoking could cause a reversible interference in the pituitary-ovarian axis, which could lead to a cessation of inenses. Several investigators found that smoking has been associated with menstrual irregularity earlier in reproductive life (Wood 1978; Pet- tersson, Fries, Nillius 1973; Brown, Vessey.Stratton 1988; Hammond 196I). Smoking has also been associated with disturbances of estradiol metabolism. Mich- novicz and colleagues (1986) found that premenopausal smokers tend to metabolize estradiol-through pathways producing more catechol-estrogen metabolites than non- smokers. This change would be expected to result in a relative antiestrogenic influence because of the lack of estrogenic potency of the catechol-estrogens compared with the estrogenic metabolites, such as estriol, which are produced in larger amounts in nonsmokers. There is also evidence that nicotine may inhibit aromatase, an enzyme important in the synthesis of estrogens (Barbieri, McShane, Ryan 1986; Barbieri, Gochberg, Ryan 1986). Again, the recovery of normal enzymatic function after cessation of smoking has not been studied. However, it is postulated that these or similar disturbances could result in enough antagonism of estrogen effect to cause an early cessation of menstrual cycling in women already in the perimcnopausal years (Baron, LaVecchia, Levi 1990) Studies of Former Smokers Former smokers experience menopause only slightly earlier than never smokers (Table 14). In a study of hospitalized women, lick, Porter, and Morrison (1977) found that formcr smokers had a median age at menopause between that of never smokers and that of women currently smoking half a pack of cigarettes per day. Kaufman and coworkers (1980) reported on hospitalized women aged 60 to 69 years. Data from 10 women who stopped smoking before age 35 indicated that the mean age at menopause was 0.2 years earlier than in never smokers, after adjustment for parity and body habitus (Kaufman et al. 1980). In a cross-sectional study of women attending a screening clinic, Adena and Gallagher (1982) found ex-smokers to have a median age of natural menopause 0.3 years earlier than never smokers. Finally. Hiatt and Fireman (1986) found among a group of enrollees in a prepaid health plan attending a screening clinic that ex-smokers reached menopause about 0.5 years earlier than never smokers. Thus, natural menopause appears to occur, at most. 6 months earlier in ex-smokers than in never smokers. Limited findings on relative risk of early menopause in fonner smokers are available (Willett et al. 1983; Baron. LaVecchia, Levi 1990). From data presented by Lindquist and Bengtsson (1979) regarding 50-year-old women, it can be calculated that compared with never smokers, former smokers had a relative risk of early menopause of 1.8 398 7 1 'CABLE 14.-Surnmary of studies of age at natural menopause among former smokers Reference Number of ex-smukers Covariates considered lick. Puner. Morrison 439 None (1977) Lindquist and ©engtsson 30 None (1979) Kauftnan el al. 10 Parity, region. (1980) Quetelet's Index Adena and Gallagher NR None (1982) Willett et at. 16.034 Age, weight. (1983) nulliparity Hiatt and Fireman 576 None (1986) NOTE: NR.not reporned. Findings Ex-smokers had menopause between those of current light smokers and never smokers Odds ratio of being menopausalfor ea-smokers vs. never smokers was 1.8 Mean age at menopause was 0.2 yr earlier among ex-smokers than among never smokers Median age of menopause was 0.3 yr earl ier among ex-smokers than among never smokers Odds ratio of being menopausa) forcurrem never smokers vsr smokers was 1.10 Mean age at menopause was 0.5 yr earlier among ea-snxtkers than among never smokers (95-percent confidence interval, (CI), 1.1-4.7). In a prospective study of American nurses, Willett and coworkers (1983) found ex-smokers to have a relative risk of early menopause of 1.1 (95-percent CI, 0.98-1.23) compared with never smokers after adjustment for age, weight, and nulliparity. In this study, those who stopped smoking in the 2 years previously retained a modest increase in risk of early menopause (RR=1.4); after a longer period of abstinence, there was no effect associated with previous smoking (Willett et al. 1983). All the investigations of smoking and menopause have relied on self-report of menstrual status and smoking history. It is unlikely that misclassification with reganl to these features would seriously distort the findings regarding cu.rent smoking, but the results for former smoking may be more susceptible to artifact. In paRicular, some of the study participants who claimed to be former smokers might actual ly have continued to s(noke, or they might have quit for health reasons related to an early natural 399 E0£L 0TLZ5 ...- - .,.,.....- -- . _._ _ .. ..._,.._. .

5 mediate postpartum period and possibly during preg- nancy (42). Birth weight was not examined. Use of a smoking cessation chart may help health care providers to track patient contacts with the goal of achieving initial smoking cessation as well as reinforcing that behavior throughout pregnancy. In the general population, approximately 65% of those who stop smoking relapse within 3 months of quitting, and another 10% relapse between 3-6 months, whereas only 3% relapse from 6-12 months (43).'Ihis suggests that women who successfully quit for the 9 months of pregnancy may have a low relapse rate. The high motivation of pregnant women may provide an excellent window of opportunity forachieving smoking cessation. Nicotine replacement therapy, in the form of cbew- ing gum or a nrdnsdetmal patch, has been demonstrated to increase the effectiveness of smoking cessation pro- grams by approximately 50% when evaluated 6 months after the intervention. Use of nicotine gum is contrain- dicated during pregnancy. The package inserts of the nansdcrmal patches suggest that pregnant women not use these therapies unless advised to do so by their doctor because nicocine is considered to be an important mediator of the adverse effects of smoking on mother and fetus. However, nicotine is not the only toxin in cigarttte smoke, and effective replacement therapy with a patch would certainly reduce fetal exposure to carbon monoxide and other toxins. It may be reasonable for an individual who smokes at least 20 cigarettes per day and is otherwise unable to discontinue or decrease her smoking to use the nicotine patch as an adjunct during pregnancy. Circulating nico- tine levels attained with this method arc no greater than, and in most cases less than, those observed in smokers of 20 or more cigarettes per day (44). In the absence of direct data concerning use of the patch during preg- nancy, it is appropriate to inform the patient about the presumed risks and benefits of this approach and to individualize therapeutic decision making. Conclusions S moking tobacco poscs seriotu health risks to all womcn. It is also associated with reproductive health problems such as lower overall fecundity, ovulatory and tubal disorders, increased pcrinatal mortality, bleeding com- plications of pregnancy, decreased mean birth weight, and higher incidences of small-for-gestational-age ba- bies, low-birth-weight babies, and preterm deliveries. The epidcmiologic studies are supported by our under- standing of the physiologic effects of cigarette smoking on pregnancy. The ultimate goal of the provider is to help a woman to stop smoking, to refrain from smoking during pregnancy, and to avoid relapse after delivery. REFERENCES I. U.S. Department of Health and Human Services. The health benefiu of smoking cessation: a report of the Surgeon Gcaeral. U.S. Department of Health and Hu- man Services publication no. (CDC)90-8416. 1990:v- vi, 245 2. Centers for Discase Control. Cigarette smoking among rsproductive-agcd wometr-Behavioral Risk Factor Sur- veillantt System, 1989. MMWR 1991;40:719-723 3. Centers for Disease Control. Cigarette smoking among adult}-UnitedStates,1988. MMWR 1991;40:757-765 4. Seatton M, Hebcl JR. A clinical trial of change in mater- nal smoking and its effect on birth weight. JAMA 1984;251:911-915 5. U.S. Department of Health and Human Services. The health benefits of smoking cessation: a report of the Surgeon GerwaL U.S. Departmentof Health and Httman Services publication no. (CDC)90-8416. 1990:371-423 6. Gindoff PR, Tidey GF. Effects of smoking on female fecundity and early pregnancy outcome. Semin Reptnd Endocrinol 1989;7:305-313 7. Howe G. Westhoff C, Vessey M. Yeates D. Effects of age, cigarette smoking, and other facton on fertility: findings in a large prospective study. BAII 1985290: 1697-1700 8. Mattison DR. Plowchalk DR Meadows MJ, Miller MM, Malek A, London S. Theeffect of smoldng on oogenesis, fertiliurion, and implantation. Semin Reptod Fadocrinol 1989;7191-304 9. Hammond EC. Smoking in relation to physical com- plaints. Arch Environ Health 1961:3:28-d6 10. MclGnhy SM. Bifano NI:., McKinlay JB. Smoking and age at menopause in women. Ann Intern Med 1985; 103:354-356 11. Chow W-H, Daling JR, Weiss NS, Voigt L.F. Maternal cigarette cmoldng and tubal pregnancy. Obsttt Gynecol 1988;71:167-170 12. Campbell O.M. Gray RH. Smoking and ectopic pneg- nancy: a multinational case-control study. ln: Rosenberg MJ, ed Smoking and reproductive bealth. Littleton, Ma.ssachusettl: PSG Publishing Co, 1987:70-75 13. Kline J. Stein ?A, Susser M, Warburton D. Smoking: a risk factor for spontaneous abortion. N Engl J Med 1977:297:793-796 14. Anokute CC. Epidemiology of spontaneous abortions: the effects of alcohol consumption and cigarette smok- ing. J Natl Med Assoc 1986;78:771-775 15. Harlap S. Shiooo PH. Aleohol, smoking, and incidence of spontaneous abortions in the first and second trimes- ter. Lancet 1980;2:173-176 16. Patflnsoo HA. Taylor P1. Partinson MH. The effect of cigarute smoking on ovarian function and early preg- nancy outcome of in vitro fertilizaaon treatment. Fertil Steril 1991;55:780-783 17. Kline 1. Levin B. Shrout P. Stein Z, Susser M. Warburton D. Maternal smoking and trisomy among spontancously 51710 7272

Contenta 5Z£L 01LZS Introduclion ............................. ........... 41`7 : i ~ Smokln6 and Birth Weight £pidemiolotJeal Studies CiBarelte Smoking and the Low-Birth-WeiBht Infant .......... 419 Evidence for a Cautal Ataoclallon Between Cipprette Smoking and Small-for-Datea Infantc .................. 420 Evidence for an Indirect Auoclatlon Between Cip- 1 relte Smoking end Small-for-Datea Infani> : .............. 424 ~ £xperlrmental Studies I I 1 Studies in Animalt Tobacco Srnoke ................................ 428 Nico/lne ..................................... 429 Carbon Monoxide ............................... 430 Polycyclk Hydrocarboas .......................... 431 Studies In Humaru Carbon IAonoxide ............................... 432 Polycyclk Hydrocarbont .......................... 433 Vilunin Bt 2 and Cyadde Detoxificatlon ............... 433 f Vltamin C .................................... 433 I Poul6le Xechanftnu ............................... 433 I Tlmint oJtAe In/fuenct ojCijmeut Smainj on Birth Weight . . ... .. .. 434 1 ... ..... ...... .. .... ......... S/te o/Action at the lYuut and CsBulai Leve! .............. 435 Sirnificance of the Auoclulon ............... . ........ 435 ~ Birth WeithtSununary .............................. 436 ( I Ciprelte SmoklnR and Fetal and Infant Mortality Introduction ...................................... 437 Spontaneout Abortlon .............. . . . . . . . . . . . . . . . . . 437 Sponlaneoue AborUon Summary ........................ 438 StlllDirth ......................................... 436 Stillbirth Summary ................................ 439 Late Fetal and Neonatal Deatht ......................... 440 Epidemlolotfcal Studies ............................. 440 Con+padsons of the Mortality Rlskr of Low- Birih-Welght Infante Born to Smokers: and Nonunokert ............ "0 Recent Studies .................................. 442 Anelyzis of Previously Reported Studies ................ 444 Factors Which intluence Perinata! Morlallty Other Than Smoklng ........................... 44S 413

CONCLUSIONS I. Women who stop smoking before becoming pregnant have infants of the same birthweight as those bom to never smokers. 2. Pregnant smokers who stop smoking at any time up to the 30th week of gestation have infants with higher birthweight than do women who smoke throughout pregnancy. Quitting in the first 3 to 4 months of pregnancy and abstaining throughout the remainder of pregnancy protect the fetus from the adverse effects of smoking on birthweight. 3. Evidence from two intervention trials suggests that reducing daily cigarette con- sumption without quitting has little or no benefit for birthweight. 4. Recent estimates of the prevalence of smoking during pregnancy, combined with an estimate of the relative risk of low birthweight outcome in smokers, suggest that 17 to 26 percent of low birthweight births could be prevented by eliminating smoking during pregnancy; in groups with a high prevalence of smoking (e.g., women with less than a high school education). 29 to 42 percent of low birth weight births might be prevented by elimination of cigarette smoking during pregnancy. 5. Approximately 30 percent of women who are cigarette smokers quit after recogni- tion of pregnancy, with greater proportions quitting among married women and especially among women with higher levels of educational attainment. 6. Smoking causes women to have natural menopause I to 2 years early. Former smokers have an age at natural menopause similar to that of never smokers. I References ABLIN, RJ. Cigarette smoking and quality of sperm. (Letter.) New York Sratt Journal of Medicine 86(2):108. February 1986. ADENA. M.A.. GALLAGHER, H.G. Cigarette smoking and the age at menopause. Annals of Human Biology 9(2):121-130. 1982. ALBERMAN. E.. CREASY. M.. ELLIOTT. M.. SPICER. C. Matemal factors associated with fetal chromosomal anomalies in spontaneous abortions. British Journal oJOhsrerrics and Gynon•olo,qy 83(3):62I-627. August 1976. ' ALSTER, P., BRANDT. R.. KOUL. B.L.. NOWAK,1., SONNENFELD. T. Effect oi •.icoline onprostacyclinformationinhumanendocardiuminrirrn. GeneralPharmacology I7(4):44I- 444, 1986. ALWACHI. S.N.. AL-KOBAISI. M.F., MAHMOUD. F.A.. ZAHID. Z.R. Possibie effect of nicotine on the spennatogenesis and testicular activity of the mature male albino mice. Journal ojBinlo,qical Scirncr Rrscorc•h 17(3):185-194, 1986. ANDERSEN. A.N., SEMCZUK. M..TABOR, A. Prolactin and pituitary-gonadal function in cigarette smoking infertile patients. Andrnl4eia 16(5):391-396, 1984. ANDERSEN. F.S., TRANSBOL.1., CHRISTIANSEN. C. Is cigarette smoking a promoter of the menopause? Ar•ra Mrdica Scondinorira 212: ( 37-( 39, 1982. ANDERSON. G.D.. BLIDNER. I.N., MCCLEMONT. S.. SINCLAIR. J.C. Determinants of size at birth in a Canadian population. American Journal of Ohsrtrrics and Gynrcolo,er 150(3):236-244,October I, 1984. ANDERSSON. K.. ENEROTH, P., FUXE, K., HARFSTRAND, A. Effects of acute intertnittent exposure to cigarette smoke on hypothalamic and preoptie catecholamine nerve terminal systems and on neuroendocrine function in the diestrous rat. Archives of Pharmacology 337:131-139. 1988. ANDERSSON. K.. FUXE, K.. ENEROTH. P.. AGNATI. L. Differential effects of mecamylamine on the nicotine induced changes in amine levels and turnover in hypothalamic dopamine and noradrenaline nerve terminal systems and in the secretion of adenohypophyseal hormones in the castrated female rat. Evidence for involvetnent of cholinergic nicotine-like receptors. Acra Physinlqtica Scondinatdco 120:489-498, 1984. ANDERSSON. K.. FUXE, K.. ENEROTH, P.. GUSTAFSSON. 1.-A., AGNATI, L.F. Mecamylamine induced blockade of nicotine induced inhibition of gonadotrophin and TSH ~ secretionandofnicotineinducedincreasesofeatecholamineturnoverintherathypothalamus. - Acra Physinlngica Scondinavica 479(Supplement):27-29. 1980. ANDREWS,1., MCGARRY.I.M. A community study of smoking in pregnancy. Journal of Obstetrics and Gynonnln,ky of the British Commonwealth 79(12):1057-1073. December 1972. ATHAYDE, E Incidencia de abortos e moninalidade nas operarias da industria de fumo. (Inquirito realizada na regiao fumageira da Bahia). Brasil-Med 62:237-239, 1948. - BAILEY. A.. ROBINSON, D.. VESSEY. M. Smoking and age of natural menopause. (Letter.) Lancn 2(8040):722. October 1, 1977. BAIRD. D.D., WILCOX. AJ. Cigarette smoking associated with delayed conception. Journal of the Amtrican Mtdira/ Associarinn 253(20):2979-2983. May 24-31,1985. BARBIERI, R.L.. GOCHBERG. 1., RYAN. KJ. Nicotine, cotinine, and anabasine inhibit aromatase in human trophoblast in vitro. Journal ejClinical lnvesrigarion 77:1727-1733. June 1986. BARBIERI. R.L. MCSHANE. P.M., RYAN. K.1. Constituents of cigarette smoke inhibit human gnnulosa cell aromatase. Fertility and Sterility 46(2):232-236, August 1986. 410 411 60£L OTLLS

MAY l g 1993 HEC-H a r c0 Uts" __ Numbor 180--Uay 1993 acog_ Technical Bulletin q4A~C_0_ A Ed ti l Aid O n uca ona to bstetrician--Gyneco/ogists Smoking and Reproductive Health Tobacco smoking is asignificantproblem among women today. It is associated with a wide variety of cancers and chronic diseases, most notably respiratory and cardio- vascvlar disorders. Women who smoke cigarettes are 12 times more likely to die from lung cancer than those who have never smoked; smoking is also responsible for 55 % of the cardiovascular deaths in women less than 65 years old (1). In addition, smoking increases the risk of oral cancer, esophageal cancer, bladder cancer, pan- creatic cancer, chronic obstructive pulmonary disease, and probably cervical cancer. L Despite these adverse effects, 26% of reproductive age women (18-44 years old) smoke, with a mean of 18 cigarettes smoked per day (2). There is a higher pieva- lenct among older women, women with less than high- school education, and black women (3). Advertising targeted at young women entering their reproductive years has successfully expanded the market for ciga- rtttcs, and the prevalence of smoking in this group is on the rise. Thc 1988 National Household Survey revealed that 10% of females 12-17 years old and 35% of females 18-25 years old reported smoking cigarettes in the month prior to the survey. Between 19-30% of pregnant women continue to smoke (2,d), placing themselves and their fetuses atrisY for a n umbcr of adverse teproductive effects. The medi- cal litcranm on smoking and reproductive health is extensive but confusing and difficult to interpret. Ani- mal data cannot always be applied to humans. Epidemiologic studies describe associations between cigarette smoking and specific out.come but cannot prove causality. Such studies may say more about the woman who smokes than smoking itself. Prospective studies, which often rely on seff-reporting of cigarette smoking, are likeiy to be biased Confounding variables such as socioeconomic status, diet, life sryle, weight, sexually transmitted diseases, and associated habits (ie, alcohol, coffee drinking, illicit drug use) must be taken into account. Prospective randomized and controlled studies are not ethically possible. Within these con- straints, this bulletin will address the effects of cigarette smoke on reproductive function and pregnancy. Epidemiology The terms relative risk (RR) and odds ratio (OR) es- timate the association between a certain event or ezpo- sure and the risk of developing a specific outcome. Relative risk is a ratio in which the incidence of disease in the exposed group is divided by the incidence of disease in the nonexposed group. It is appropriately used in cohort studies, meaning prospective or popula- tion-based studies. For caso--control studies, the OR is used. The OR is the odds of ezposure among cases divided by that among control3. When the 95% canfi- denoe interval for the RR or OR includes 1, the findings are not statistically significant (P > 0.05). Composftion of Totracco Smoke There are over 2,500 chemicals identified in tobacco smoke. Many constituents have not been evaluated for their effects on health Two of the major components that azti thought to be responsible for the adverse effects of cigarette smoke are nicotine and carbon monoxide (5). Both active and passive smoking involve the inha- lation of smoke, with systemic absorption via the pul- monary vasculaturc. Effecb on Reprodacth-e Faactloa Overall, there is evidence that women who smoke have lowered fertility (Table 1). Many mechanisms have been postulated for this effect Tobacco smoking has been implicated in disorders of ovulatory function, tuba] function, implantation physiology, oocyte deple- tion, and early pc=gnancy loss (5). Smoking also alters the characteristics of sperm, and this may affect male reproduction as welL Fecandity Smoking reduces overall female fertility as measured by fecundity, the probability of conception for a given

-2 c TABLE 1. EFFECTS OF SMOKING ON REPRODUCTION M1D PREGNANCY' Ett+c1 Relatlw Risk or t?ttw Reeuft (95% oorttld.nce trtterval) Retx.np Reproductive Increased infertility 1.3 (1.1-1.4) Howe at al. 1965 Ectopic pregnancy 22 (1.3-3.6) Campbell and Gray, 1987 Spontaneous abortlon 1.2 (0.67-2.19)r Hariap and Shlono, 1980 1.7 (1.5-32) KAne et al, 1977; Mokute, 1986 Geetatlonel Abruptlo placentae 1.5 (1.1-12) Naeye, 1980 P/aoenta previa 1.9 (12-3.0) Wiliems at al, 1991' PROM Term 1.3 (1.1-1.9) Naeye,1982 Preterrn NS (1.0-2.1) Naeye. 1982; Harger at al, 1990 cn Perinetal mortality 125 tor smoklnfl <1 pecWd ~.1 (1.13-1.39) F-' 1.56 tor srnokinp 21 padJd (1.37-1.77) Kleinman et al, 1968 m v Fe1a1 Mean birth weipM 00 0 decrease utttpb s.tudies tv vl t0 SGA Warsta 3.5 (28-4.9) Ounsted el al. 1965 Prematurity 12 (1.1-1.4) Shbrro et al. 1986 • Aear.vl.dona: nLS - na alR,rnarik vaO+d - pnrn.LRn n,qb.v ol m.mbran«, sOA ..mal ur Q..atdon.+.Q.. qt ar 95% onn+saenoe tx«v.W iner,aes 1. en. +.Ltlw n.k 1s rat st.ris8ny dprWScsnt, M+Bsr*r idk Arltl.ndxf R. I.hDertn.n E, Aianon RR. Sdn.nDum SC. Ciexwsi DFt, CIpu.Cv aroicIrq duYip pregn.ncy Ih n.tation to piaoenta previ& Am J Obstet Oyneco11o91:16526-32 couple during a given menstrual cycle. A review of published studies reveals a consistently significant in- cresscd risk of infertility in smokers compared with nonsmokers (RR or OR, 1.3-1.6) (6). The prospective Oxford Family Planning Associa- tion Study monitored 17.000 women for an average of 11.5 years (7). Time from discontinuation of contraeep•- tion to time of birth of a child was tneasured on 6,199 occasions. Fertility rates of women who smoked were approximately 30% lower than those of nonsmokers. After controlling for confounding variables such as age and last method ofbirth control, these resr.archtrs found that 10.7% of womwn smoking more than 20 cigarettes per day bad failed to have a successful pregnancy by 5 years after stopping contraception compared with 5.456 of nonsmokers. Tbe differtnee was minimal for women smoking less than 16 cigarettes per day. Tbe fertility rates of ezsmokers were not significantly different from those of women who had never smoked. Sezually transmitted diseases have been identified as a covariant of smoking in many populations. In the Oxford study, rates of pelvic inflammatory disease were higher in smokers than in n:,n;mokers: Howevcr,- the difference in pelvic inflaaunatory disease did not account for the differtncx in fertility rates in the two groups. Perhaps this is a reflection of differences in immune status related to smoking or differences in life styles of smokers. Ovulatory Dysftznctlon In animal studies, cigarette smoking has been shown to have a negative effect on ovulation. Nicotine can alter gonadotroQin release in a dose-dependent fashion, de- cre1e the lune;nirng hormone surge, inhibit the release of prolactin, and stimulate release of growth hotmone, eottisol, vasopressin, and oxytocin. Changes in the midcycle luteinizing hormone surge may explain the effect of smoking on the menstrual cycle (8). Few well-designed studies have addressed this issue in women. In 1961, Hammond studied 24,000 women and found that the frequency of abnormal vagi- nal bleeding was 67% higher in heavy smokers (those who smoked more than 21 cigarettes per day) than in nonsmokrrs (9). I,utcal estrogen production has been shown to be lower in women who smoke than in non- smokers. This may be due to effects on the hypotha- lamia-pituitary-ovatian axis or direct effects on the follicle. At least 13 studies indicate that smokers cease menstruating 1-2 years earlier than nonsmokers. This effect is dose depcndent, and the difference per%.isrc after controlling for subjects' weight (5, 10). 'Ibbal Fhnction Nicotine altet5 tubal motility in rhesus monkeys and rabbits (8). In humans, ectopic pregnancy may be a manifestation of altered tubal function. Several case- .,~

3 BARNDT, R. JR., BLANKC•NHORN, D.H.,CRAWFORD, D.W., BROOKS, S.}{. Regression and progression of early femoral atherosclerosis in treated hyperlipoproteinemic patients. Annals of Inttrnal Medicine 86:139-146, 1977. BARON. l.A. Cigarette smoking and age at natural menopause. In: Wald, N., Baron,l.A. (eds.) Smoking and Hormone-Related Disorders. Oxford: Oxford University Press. 1990, pp. 57-63. BARON,I.A., LA VECCHIA. C., LEVI, F. The antitstrogcnic effect of cigarette smoking in women. American Journal of Obstetrics and Gynecology 162(2):502-514, Febntary 1990. BARRETT-CONNOR, E., KHAW. K.-T. Cigarette smoking and increased endogenous estrogen levels in men. American Journal ofEpidemiology 126(2):187-192, 1987. BARRETT-CONNOR, E., KHAW, K.-T., YEN, S.S.C. A prospective study of dehydro- epiandrosterone sulfate, mortality, and cardiovascular disease. New England Journal of Medicine 315(24):1519-1524, 1986. BAXTER,I.D., TYRRELL, l.B. The adrenal cortex. In: Felig. P., Baxter,l.D., Broadus, A.E., Frohman, L.A. (eds.) EndocrinologyandMerobolism. Second Edition. New York: McGraw- Hill. 1987, pp. 511-573. BENOWITZ, N.L. Pharmacologic aspects of cigarette smoking and nicotine addiction. New England Journal of Medicine 319(20):1318-1330, November 17. 1988. BERKOWITZ, G.S., HOLFORD, T.R., BERKOWIT2; R.L. Effects of cigarette smoking, alcohol, coffee and tea consumption on ptetenn delivery. Early Human Development 7(3):239-250, 1982. BERNHARD, P. Sichere schaden des Zigarettenrauchens bei der Frau. (Certain injurious effects of cigarette smoking on women.) Medirinische Monataschrifi 3:58-60, 1949. BISWAS, N.M.. PATRA. P.B. Role of testosterone propionate on spermalogenesis following chronic nicotine administration in immature rats. Indian Journal of Experimenral Biology 19:604-606. July 1981. BLAKE. CA. Parallelism and divergence in luteinizing hormone and follicle-stimulating hormone release in nicotine-treated rats. Proceedings of the Societyfor Fxperintental Biology and Medicine 145:716-720, 1974. BLAKE. C.A., NORMAN. R.L., SAWYER, C.H. Localization of the inhibitory actions of estrogen and nicotine on release of luteinizing hormone in rats. Neuroendocrinology 16:22- 35. 1974. BLAKE. C.A., SCARAMUZZI. RJ., NORMAN. R.L., KANEMATSU, S.. SAWYER, C.H. Effect oT nicotine on the proesarous ovulatory surge of LH in the rat. Endocrinology 91(5):1253-1258. November 1972a. BLAKE. C.A., SCARAMUZZI. RJ., NORMAN, R.L., KANEMATSU. S., SAWYER, C.H. Nicotine delays the ovulatory surge of luteinizing hormone in the rat. Proceedings of the Socirty for Experimental Biology and Medicine 141(3):1014-1016, December 1972b. BORNMAN. M.S., DU PLESSIS, D.l. Smoking and vascular impotence. South African Medicallournal70(6):329-330, September 13,1986. BRAMBILLA. DJ.. MCKINLAY, S.M. A prospective study of factors affecting age at menopause. Journal of Clinical Epidemiology 42(11):1031-1039, 1989. BRIGGS, M.H. Cigarette smoking and infertility in men. Medical Journal of Australia 1(12):616-617, March 24. 1973. BROWN. S.. VESSEY, M.. STRATTON. I. The influence of method of contraception and cigarette smoking on menstrual patterns. British Journal of Obstetrics and Gynaecology 95:905-910, September 1988. BUCK, G.M., COOKFAIR. D.L., MICHALEK, A.M., NASCA. P.C., STANDFAST, S.1., SEV ER, L.E., KRAMER. A.A. Intrauterine growth retardation and risk of sudden infant death syndrome (SIDS). American Journal of Epidemiology 129(5):874-884, May 1989. 412 . i:::i`.. ~ ~ .._i 5.........J BUHLER, F.R., VESANEN. K., WATTERS. 1.T., BOLLI. P. Impact of smoking on heart attacks, strokes, blood pressure control, drug dose. and quality of life aspects in the Intema- tional Prospective Primary Prevention Study in Hypertension. American Heart Journal 115 ( I ):282-288, January 1988. BUTATTI, E., BARCHIELLI. A.. GEDDES. M.. NASTASI, L., KRIEBEL, D., FRANCHINI. M.. SCARSELLI, G. Risk factors in male infertility: A case-control study. Archives of Environmental Htalth 39(4):26&-270, July-August 1984. BUTLER. N.R., GOLDSTEIN, H.. ROSS, EM. Cigarette smoking in pregnancy: Its influence on birth weight and perinatal mortality. British Medicallournal2:127-130, April 15, 1972. CAMPBELL,I.M., HARRISON, K,:., Smoking and infertility. (Letter.) Medical Journal of Australia 1:342-343, Apr?1 21, 1979. CAMPBELL. O.M.. GRAY, R.H. Smoking and ectopic pregnancy: A multinational case- control study. In: Rosenberg, M:1. (ed.) Smoking and Reproductive Health. Littleton. Massachusetts: PSO Publishing, 1987, pp. 70-75. CENDRON, N., VALLERY-MASSON,1. Tabac et comportement sexuel chez 1'homme. Vie Mldicale 25:3027-3030. July 1971. CHOW. W.-H.. DALING,I.R„ WEISS, N.S.. VOIGT, L.F. Maternal cigarette smoking and tubal pregnancy. Obstetrics and Gynecology7l(2):167-170, February 1988. COMMITiEE TO STUDY THE PREVENTION OF LOW BIRTHWEIGHT. Prtvrnting [vw Birthweighr. Washington, D.C.: National Academy Press. 1985. COMSTOCK. G.W., LUNDIN. F.E. JR. Parental smoking and perinatal mortality. American Journal of Obsretrics and Gynecology 98(5):708-718, July 1. 1967. CONDRA. M.. MORALES, A., OW EN.1.A., SURRIDGE. D.H., FENEMORE. J. Prevalence and significance of tobacco smoking in impotence. Urology 27(6):495-498. June 1986. COOPER. L An Epidemiologie Assessment of Low Birth Weight and Smoking Behavior in a Black Urban Population. Doctoral Dissertation. University of Maryland. 1989. COPE, L, LANCAS'IER, P., STEVENS. L Smoking in pregnancy. Medical Journal of Australia 1:673-677, April 7, 1973. COUNSILMAN,IJ., MACKAY, E.V. Cigarette smoking by pregnant women with particular reference to their past and subsequent breast feeding behaviour. Australian and New Zralond Journal of Obsretries and Gynaecology 25(2):I01-106, May 1985. DAI, W.S., GUTAI,I.P., KULLER. LH.. CAULEY. l.A. Cigarette smoking and serum sex hormones in men. American Journal of Epidemiology 128(4):796-805, 1988. DALING. J., WEISS, N., SPADONI. L., MOORE. D.E.. VOIGT, L. Cigarette smoking and primary tubal infertility. In: Rosenberg. MJ. (ad.) Smoking and Reproductive Health. Littleton. Massachusetts: PSG Publishing. 1987, pp. 40-46. DALING, J.R.. WEISS. N.S.. VOIGT, L., SPADONI, L.R., SODERSTROM. R., MOORE. D.E., STADEL. B.V. Tubal infertility in relation to prior induced abortion. Fertility and Steriliry43(3):389-394, March 1985. DANIELL. H.W. Smoking, obesity, and the menopause. (Letter.) Lancet 2(8085):373, August 12,1978. DAVIES, D.P., ABERNETHY. M. Cigarette smoking in pregnancy: Associations with mater- nal weight gain and fetal growth.lancet 1(7956):385-387. February 21. 1976. DAVIES, J.M., LATTO, I.P., JONES, 1.G., VEALE, A., WARDROP, C.AJ. Effects of stopping smoking for 48 hours on oxygen availability from the blood: A study on pregnant worrten. British Medical Journal2J55-356, August 11. 1979. DEMARINI. D.M. Genotoxicity of tobacco smoke and tobacco smoke condensate. Mutation Research 114:59-89, 1983. DEPALMA, R.G.. EMSELLEM. H.A.. EDWARDS. C.M., DRUY. E.M., SHULT2., S.W., MILLER. H.C., BERGSRUD, D. A screening sequence for vasculogenic impotence. Journal of Vascular Surgery 5(2):228-236, February 1987. 413 OZEL 01LT5

11aur+ w-Neonatal rnwtally r.taf amon` alnata whlta b4tha In hoapltal• (by datafled birth w.laht and .p.clh.d •a..tatlon aroups: Unlted ata1.a). i_ ...._ ~ ) /'Ipre ).-htMstal eprbltfy nb per 1,000 total WAhs by eltarellt arrK dteftory. 40 30 100 eo 20 JANUARY 1 10 MARCH 31. 1950 = : 37 weeks and ow .~ • ; r 10 • 4 . . . , ~ it ~~ g~ n ~ ~ ; ~~ g9 . etu»t rretW (in ewns) souaec u.e. N.rft w.r a...t.. NdYo.d fwr« w. M..rm aww/es ftall. Iteoent 8tudles The Ontario Perinatal lfor4lity $t.iuiy (66, 67) was conducted anxmg 10 leaehinR )wnpilals during 1060 and 1961. In this retraatw- tive etudy of 51,400 prrRnaneieN a statiel.ieally siRuifxant incrrA+' in the perinat.l nwrtality rate was demondrstel for anMkrrs' in- fanle as compared with lhaee of nonemnken; the infanls of emokero e:perienred an overall relative risk of 1.27 (1'<0.0(tl). MoteYwer, the invetiRalnrn found.etalieticall~siRnifieanldux•rc.ponne relation.hip txtween eho amount of eigaretln smoked and the perinatal mortality rate (Y<0.001) (fig.7). 111 TZEL 0TLT5 20 10 0 Notaetnobr Muwwber of peetnNr d+.tha: aS! <dprp 4~ Osr der 425 ;Mel ~e.ttb O.r day 220 Total b4tM: 2R,.tlls 1"2e a9e1 (P <0.001) souactu owtrr awe.w d tws,a pe). Recently Ilutler, et at. (!6) further analyted the British I'erinat.: Mortality Study. They found a highly signifteant association betweon mitternal sewking after the fourth month of pre;nancy and "f,th late fetal and neonatal deaths. Infants of /moken had an incre.a,e in the late fetal mortality rate of 30 percent, and an increax in the neo- natal mortality rate of 26 percent, compared to the infants of non- smokers. The overall mortality ratio of late fetal plus neonatal deaths was 1.28 (I'<0.001). Oi.en the large number of women in the study, and the significant changes in emoking behavior which occurred, thoy fatnd it paesible to consider tLe eReet of a change in smoking tr. 1

HOIDAS.S.,WIf1-IAMS.A.E.,TOCIlER,1.L.,HARGREAVE,T.B. Scoringspemimorphol- ogy from fertile and infertile cigarette smokers using the scanning electron microscope and image analysis. Fertility and Sterility 43(4):595-598, April 1985. HOOK. E.B. Changes in tobacco smoking and ingrstion of alcohol and caffeinated beverages during early pregnancy: Are these consequences, in part, of feto-protective mechanisms diminishing maternal exposure to embryotoxins? In: Kelly. S.. Hook, E.B.. Janerich, D.P., Porter,l.H. (eds.) Birth Defects: Risks undConstqucncts. New York: Academic Press. 1976. pp•173-183. HOWE. G., WESTHOFF, C.. VESSEY, M., YEATES, D. Effects of age, cigarette smoking, and other factors on fenility: Findings in a large prospective study. British MedicalJournal 290:1697-1700, June 8, 1985. JACOBS,I.A., FISHK W, R., COHEN, S., GOLDMAN, A.. MULHOLLAND, S.G. A multi- disciplinary approach to the evaluation and management of male sexual dysfunction. Journal of Urology 129:35-37. January 1983. JEREMY, J.Y., MIKHAILIDIS, D.P., THOMPSON. C.S., DANDONA. P. The effect of cigarette smoke and diabetes mellitus on muscarinic stimulation of prostacyclin synthesis by the rat penis. Diabetes Research 3:467-469, 1986. JICK, H.. PORTER. J., MORRISON, A.S. Relation between smoking and age of natural menopause. Jancer I(8026):1354-1355, June 25, 1977. JUENEMANN,K.-P.,LUE,T.F.,LUO,1: A.,BENOWITZ,N.L.,ABOZEID,M.,TANAGHO, E.A. The effect of cigarette smoking on penile erection. Journal ojUrology 138:438-441, August 1987. KAISER. F.E., VIOSCA, S.P., MORLEY. I.E., MOORADIAN. A.D., DAVIS, S.S., KOREN- MAN, S.G. Impotence and aging: Clinical and hormonal factors. Journal ojtht American Geriatric Society 36:511-519, 1988. KANEMATSU. S.. SAWYER. C.H. Inhibition of the progesterone-advanced LH surge at proestrus by nicotine. Proceedings of the Society jor Experimental Biology and Medicine 143:1183-1186,1973. KAUFMAN. D.W.. SLONE. D., ROSENBERG. L, MIET1'INEN, O.S., SHAPIRO, S. Cigarette smoking and age at natural menopause. American Journal of Public Health 70(4):420-422, April 1980. KLAIBER, E.L., BROVERMAN. D.M. Dynamics of estradiol and testosterone and seminal fluid indexes in smokers and nonsmokers. Fertility and Sterility 50(4):630-634, October 1988. 1 KLAIBER, E.L., BROVERMAN. D.M., DALEN,J.E. Serum estradiol levels in male cigarette smokers. American Journal oJMrdicine 77:858-862, November 1984. KLAIBER, E.L. BROVERMAN, D.M., POKOLY. T.B., ALBERT. AJ.. HOWARD. PJ.1R., SHERER, J.F. JR. Interrelationships of cigarette smok ing, test icular varicoceles, and seminal fluid indexes. Fertility and Sterility 47(3):481--086, March 1987. KLEINMAN, J.C.. KOPSTEIN, A. Smoking during pregnancy. 1967-80. American Journal ojPublic Health 77(7):823-525, July 1987. KLEINMAN, J.C., MADANS. J.H. The effects of maternal smoking, physical stature, and educational attainment on the incidence of low birth weight. Americanlournal ojEpidemiol- ogy 121(6):843-455,June 1985. KLEINMAN,I.C.. PIERRE, M.B. JR.. MADANS,I.H., LAND. G.H., SCHRAMM, W.F. The effects of matemal smoking on fetal and infant mortality. American Journal ojEpidemiology 127(2):274-281,1988. KLINE.1. Environmental exposures and spontaneous abortion. ln: Gold. E. (ed.) The Chang- ing Risk ojDisrase in Women: An Epidemiologic Approach. Lexington, Massachusetts: D.C. Heath and Company. 1984, pp. 127-138. 416 . . r KLINE, J., STEIN, Z. HUTZLER. M. Cigarettes, alcohol and marijuana: Varying associations with birthweight. inrernationallournal o/Epidemiology 16:44-51. 1987. KLINE. 1., STEIN. Z.A., SUSSER, M.. WARBURTON. D. Smoking: A risk factor for spontaneous abortion. New England Journal ojMrdicint 297(15):793-796. October 13, 1977. KOOPS. B.L., MORGAN, L.1., BATTAGLIA. F.C. Neonatal mortality risk in relation to birth weight and gestational age: Update. Journal ojPrdiatrics 101(6):969-977. December 1982. KRAILO. M.D., PIKE. M.C. Estimation of the distribution of age at natural menopause from prevalence data. American Journal ojEpidrmiology I 17(3):356-361, 1983. KRAMER. M.S. Determinants of low birth weight: Methodological assessment and meta- analysis. Bulletin oJthe World Health Organization 65(5):663-737, 1987. KRAMSCH, D.M.. ASPEN, AJ.. ABRAMOWITZ, B.M.. KREIMENDAHL,T., HOOD. W.B. JR. Reduction orcoronary atherosclerosis by moderate conditioning exercise in monkeys on an atherogenic diet. New England Journal ojMedicinr 305(25):1483-1489. December 17, 1981. KULIKAUSKAS,V.,BLAUSTEIN,D.,ABLIN,RJ. Cigarette smoking and its possible effects on sperm. Fertility and Sterility 44(4):526-528, October 1985. KUZMA. 1.W., KISSINGER, D.G. Patterns of alcohol and cigarette use in pregnancy. Neurohehaviorol Toxicology and Teratology 3:211-221, 1981. LANDESMAN-DWYER, S.. EMANUEL, I. Smoking during pregnancy. Teratology 19(1):119-125,1979. LARSON; P.S., HAAG, H.B.. SILVEITE, H. Tobacco: E.tperimental and Clinical Studies. Baltimore: Williams and Wilkins Company. 1961. LARSON, P.S., SILVETTE, H. Tobacco: Experimental and Clinical Studies. Supplement l. Baltimore: Williams and WilkinsCompany, 1968. LASSILA, R.. SEYBERTH, H.W., HAAPANEN, A., SCHWEER, H., KOSKENVUO, M.. LAUSTIOLA, K.E. Vasoactive and atherogenic effects of cigarette smoking: A study of monozygotic twins discordant for smoking. British Mrdical Journal 297:955-957. October 15.1988. LENTOVIRTA, P.. FORSS. M. The acute effect of smoking on intervillous blood tlow of the placenta. British Journal of Obsretrics and Gynoecology 85:729-731, October 1978. LICHTENSTEIN, MJ., YARNELL, 1.W.0., ELWOOD, P.C.. BESWICK, A.D., SWEET- NAM, P.M., MARKS. V.. TEALE, D., RIAD-FAHMY, D. Sex hormones, insulin, lipids, and prevalent ischemic heart disease. American Journal ojEpidemiology 126(4):647-657, 1987. LINDHOLM,1., WINKEL, P.. BRODTHAGEN. U., GYNTELBERG. F. Coronary risk factors and plasma sex hormones. American Journal ojMtdicinr 73(5):648-651, November 1982. LINDQUIST. O., BENGTSSON, C. Menopausal age in relation to smoking. Acta Medica Scandinavico 205:73-77, 1979. LONGO. L.D. The biological effecu of carbon monoxide on the pregnant woman, fetus, and newborn infant. American Journal ojObstrtrics and Gynecology 129(1):69-103, September 1, 1977. LONGO. L.D. Some health consequences of maternal smoking: Issues without answers. In: Nyhan. W.L. and Jones, K.L. (eds.) Prenatal Diagnosis and Mechanisms ojTeratogentsis B irth Defects: Original article series, volume 18(3A). New York: Alan R. Liss, lnc.,1982, pp. 13-31. LOWE, C.R. Effect of mothers' smoking habits on birth weight of their children. British Medicollournal2(t):673-676,October10,1959. LUBCHENCO, L.O., SEARLS. D.T.. BRAZIE, I.V, Neonatal mortality rate: Relationship to birth weight and gestational age. Journal ojPediatrres 81(4):814-822. October 1972. 417 ~._....... ZI£L OTLTS

TABLE 17.-Estimated relative risk of azoospermia or oligospermia an)ong smokers versus nonsmokers or never smokers Study population (number of nonsmokers/ Reference number of smokers) Schiven and Gey Andrology, clinic (1969) (580/1377) Campbell and Fertility clinic Hartison(1979) (119/134) Stekhun Not stated (33/105) (1980) Rodriguez-Rigau, Fenilityclinic Smith. Steinberger (101/58) (1982) Ouiatti et at. Fertility clinic (1984) (80/135) Andersen. Fertility clinic Semczuk, (86/147) Tabor(1984) Ablin (1986) Not stated ((35/238) Vogt. Heller. Volunteers Borelli (1986) (52/150) t Klaiber et al. Volunteers with (1987) varicocete (1 I/9) Volunteers without varicocele (79/61) Fertility clinic with varicocele (8/21) 408 Estimated relative risk in Contrast smukers Comments Azoospemtia: 1.2 smokers vs. nonsmokers Oligospetmia: smokers 1.2 vs. nonsmokers Oligospermia 1.6' (<40 x 10°/mL); smokers vs. nonsmokers Oligospennia: current 3.2' smokers vs. never smokers Oligospermis; 0.9 (<20 x 10°/mL): current smokers vs. nonsmokers Oligospermia 1.0 (<20 x t06/mL): srnokers vs. nonsmokers Azoospermia: current ~ smokers vs. nonsmokers Oligospermis 2.9' (<40 x I0a/mL): smokers vs. nonsmokers Oligospennia (<1 x )0°/mL): current smokers vs. never smokers Azoospermia; current smokers vs. never smokers Oligospemtia (<20 x t0°/mL); current smokers vs. never smokers Oligospem,ia (<20 x 10°mL): cum nt smokers vs. never smokers Oligospermia (<20 x I0°/mL): current smokers vs. never smokers 80EL OtiLZS Oligospemtia not defined Azoospennic men omitted Oligospermia not defined TABLE 17.--Continued Study population (number of Estimated nonsmokers/ relative risk in Reference number of smokers) Contrast smokers Klaiber et al. Fertility clinic Oli ospermia (Q0 x 1.5 (1987) without varicocele 10~/ml.): current (continued) (35/30) smoken vs. never smokers Dikshit, Buch, Fertility clinic Oil ospermia (Q0 x 1.2 Mansuri (1987) (219/288) 10~mL): current smokers vs. never smokers Azoospermia: current 1.1 smokers vs. never smokers NOTE: Azoa.pcnnia is the absence of sperm: oligotpermia ls a low spenn eoun. 'Estimued mlUive risk statisticdly signincandy (pc0.05) differem from 1.0. TABLE 18.-Sperm quality among former smokers Reference Study population Schirren and Oey (1969) Andrology patients Stekhun (1980) Buiatti et al. (1984) Not stated Male panners of infertile couples 1.3 Vogt, Heller. Borelli (1986) Healthy volunteers 7.7 N07E: RR.vlrive risk. Comments Findings Commenu • Smoking cessation improved sperm No control density and motility in 3 smokers Former smokers had RR of 23 for Oligospermia not oligospennia defined No difference between current, former, and never smokers in preva)ence of azoo-/oligospermia No difference between current, former. No consideration and never smokers in sperm of covuiates morphotogy 409

U.S. DEPARTMENT OF HEALTH AND H UMAN SER V ICES. The Health Consequences of Srnoking: Nicotine Addiction. A Report of rhe Su.geon General. 1988. U.S. Department of Health and Human Services. Public Health Service. Centers for Disease Control. Center for Health Promotion and Education. Office on Smoking and Health. DHHS Publication No. (CDC) 88-8406. 1988. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Reducin,q the Healrh Conse- quences of Smoking: 25 Years of Progress. A Report of the Surgeon General. U.S. Department of Health and Human Services. Public Health Service. Centers for Disease Control. Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. DHHS Publication No. (CDC) 89-841 I, 1989. U.S. DEPARTMENT OF HEALTH. EDUCATION. AND WELFARE. The Health Conse- quences of Smoking. A Report of the Surgeon General: 1971. U.S. Department of Health. Education, and Welfare. Public Health Service. Health Services and Mental Health Ad- ministration. DHEW Publication No. (HSM) 71-7513. 1971. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The Health Conse- quences of Smoking. U.S. Department of Health, Education, and Welfare. Public Health Service. Health Services and Mental Health Administration. DHEW Publication No. (HSM) 73-8704,1973. U.S. DEPARTMENT OF HEALTH. EDUCATION. AND WELFARE. The Health Consequen- ces of Smoking. 1977-1978. U.S. Department of Health, Education, and Welfare. Public Health Service, Office of the Assistant Secretary for Health. Office on Smoking and Health. DHEW Publication No. (PHS) 79-50065, 1978. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and Health. AReporrofrheSurgeonGeneral. U.S. Department of Health. Education, and Welfare, Public Health Service. Office of the Assistant Secretary for Health, Office on Smoking and Health. DHEW Publication No. (PHS) 79-50066, 1979. VAN DEN BERG. BJ. Epidemiologie observations of prematurity: Effects of tobacco, coffee and alcohol. In: Reed, D.M., Stanley. FJ. (eds.) Epidemiology of Premarurity. Baltimore, Maryland: Urban and Schwarzenberg, 1977, pp. 157-176. VAN DEN BERG. BJ., OECHSLI, F.W. Prematurity in perinstal epidemiology. In: Bracken. M.B. (ed.). Oxford University Press, New York. 1984, pp. 69-85. VERMEULEN. A.. DESLYPERE. 1.P. Testicular endocrine function in the ageing male. Maruriras7:273-279, 1985. VICZIAN, M. Dohanyosokon vegzett ondo-vizsgalatok tapasztalaai. (Experiences with the sperm examination of smokers.) Orvosi Herilap 109:1077-1079, May 19, 1968a. VICZIAN. M. The effect ofcigarotte smoke inhalation on spermatogenesis in rats. Exprrienria 24:511-513,1968b. VIRAG, R.. BOUILLY, P.. FRYDMAN. D. Is impotence an arterial disordet? Lancet 1(8422): 181-184,1anuary 26.1985. VISNIEVAC, V., MIKOV, M. Smoking and carboxyhaemoglobin concentrations in mothers and their newborn infants. Human Toxicology 5:175-177, 1986. VOGEL, W., BROVERMAN. D.M., KLAIBER, E.L. Gonadal, behavioral and eleetro- encephalographic trorfelates of smoking. In: Remond, A.. Irard,C. (eds.) Electrophysiologi- cal Effects of Nicotine. Amsterdam: ElsevieNNonh-Hotland Biomedical Press. 1979, pp. 201-214. VOGT, H.-1., HELLER. W.-D., BORELLI, S. Sperm quality of healthy smokers, ex-smokers, and never-smokers. Fertility and Sterility 45(1):106-1 10,1anuary 1986. VOGT, H.-1., HELLER. W: D., OBE. G. Spemtatogenesis in smokers and non-smokers: An andrological and genetic study. In: Obe, G. (ed.) Mutations inMan. Berlin: Springer-Veriag, 1984, pp. 247-291. / r WABREK, A.1., SHELLEY. M.M., HOROWITZ, L.M., BASTARACHE, M.M.. GIUCA,I.E. Noninvasive penile arterial evaluation in 120 males with erectile dysfuntion. Urology 22(3): 230-234. September 1983. WAINRIGHT, R.L. Change in observed birth weight associated with change in maternal cigarette smoking. American Journal of Epidemiology 117(6):668-675, June 1983. WERLER, M.M., POBER. B.R.. HOLMES. L.B. Smoking and pregnancy. Teratology 32(3): 473-481, December 1985. WESTWOOD, M.. KRAMER. M.S., MUN2, D.. LOVETT,I.M., WATIERS, G.V. Growth and development of full-tenn nonasphyxiated small-for-gestational-age newborns: Follow- up through adolescence. Pediatrics 71(3):376-382, March 1983. WILCOX, AJ. Intrauterine growth retardation: Beyond birthweight criteria. (Editorial.) Early Human Development 8:189-193, October 1983. WILCOX, AJ., RUSSELL. I.T. Binhweight and perinatal mortality. I. On the frequency distribution of birthweight. International Journal of Epidemiology 12(3):314-318. Septem- ber 1983a. WILCOX. AJ., RUSSELL, I.T. Birthweight and perinatal mortality. 11. On weight-specific mortality. Internationallaurrtal of£pidemiology 12(3):319-325, /983b. WILLE7T, W., STAMPFER. M.J., BAIN, C.. LIPNICK. R., SPEIZER. F.E.. ROSNER, B.. CRAMER. D., HENNEKENS. C.H. Cigarette smoking, relative weight, and menopause. AmericanJournal of £pidemiology 117(6):651-658, 1983. WILLIAMS. R.L.. CHEN. P.M. California Perinatal Statistics. 1978-1980. Prepared by University of California. Santa Barbara Community and Organization Research Institute. Department of Heahh Services. State of Califomia, Maternal and Child Health Services. June 1982, p. 11. WILLIAMSON. D.F., SERDULA. M.K.. KENDRICK. J.S.. BINKIN. NJ. Comparing the prevalence of smoking in pregnant and nonpregnant women. 1985 to 1986. Journal of the American Medical Assoeiation 261(1):70-74, January 6,1989. WINDSOR,R.A.,CUTTFR,G.,MORRIS,J.,REESE,Y.,MANZELLA,B.,BARTL: TT,E.E.. SAMUELSON. C.. SPANOS. D. The effectiveness of smoking cessatio- t•:cthods for smokers in public health mstemity clinics: A randomized trial. American Journai of Public Health 75(12):1389-1392, December 1985. WOOD. C. The association of psycho-social factors and gynaecological symptoms. Australian Family Physician 7:471-478, April 1978. WYROBEK. AJ., BRUCE. W.R. Chemical induction of sperm abnormalities in mice. Proceedings of the National Academy of Science 72:4425-4429, 1975. YERUSHALMY,1. Mothei s cigarette smoking and survival of infant. American Journal of Obstetrics and Gynecology 88(4):505-518, February IS, 1964. YERUSHALMY,1. The relationship of parents' cigarette smoking to outcome of pregnancy- Impliat9ons as to the problem of inferring causation from observed associations. American JournalofEpidemiology 93(6)443-456, 197 1. ZABRISKIE. 1R. Effect of cigarette smoking during pregnancy: Study of 2000 cases. Obstetrics and Gynecology 2l (4):405-411, April 1963. ZANEVELD, LJ.D.,IEYENDRAN, R.S. Modem assessment of semen for diagnostic pur- poses. Seminars in Reproductive Endocrinology 6(4):323-336. 1988. 422 423 STEL OTLTS

J DESLYPERE. J.P., VERMEULEN. A. Leydig cell function in normal men: Effect of age. life-style, residence, diet, and activity. Journal ojClinical Endocrinology and Metabolism 59(5):955-962,1984. DIKSHIT, R.K., BUCH, J.C., MANSURI, S.M. Effect of tobacco consumption on semen quality of a population of hypofertile males. Fertility and Sterility 48(2):334-336. August 1987. DIOKNO. A.C., BROWN, M.B., HERZOG. A.R. Sexual function in the elderly. Archives of Internal Medicine 150(1):197-200, January 1990. DONOVAN, J.W. Randomised controlled triad of anti-smoking advice in pregnancy. British Journal ojPrrvenrivt and Social Medicine 31:6-12. 1977. DONTENWILL. W.. CHEVALIER, H.-1., HARKE. H.-P., LAFRENZ. U., RECKZEH. G., SCHNEIDER. B. Investigations on the effects of chronic cigarette-smoke inhalation in Syrian golden hamsters. Journal of the National Cancer Institute 51(6):1781-1807, December 1973a. DONTENWILL. W., CHEVALIER, H.-1., HARKE, H: P., LAFRENZ, U., RECKZEH, G., SCHNEIDER. B. Experimental investigations of the effect of cigarette smoke exposure on testicular function of Syrian golden hamsters. Toxicology 1:309-320, 1973b. EFFENDY. I., KRAUSE, W. Environmental risk factors in the history of male patients of an infertility clinic. Andrologia 19 (Special number):262-265,1une 1987. EL-SAYAD. H.1., GHANIM, A.E., GAMAL EL DIN. A., SWEDAN, N., EL-SHERIF, F.A. Testicular damage in rats after subcutaneous administration of cigarette smoking residues. Journal ofthe Egyptian Society ojParasitology 17(1):179-188, 1987. ELIST, J.. JARMAN, W.D., EDSON, M. Evaluating medical treatment of impotence. Urology 23(4):374-375. April 1984. ELLENBERG,I.H., NELSON. K.B. Birth weight and gestational age in children with cerebral palsy or seizure disorders. American Journal ojDiscases ojChildrtn 133(l0):1044-1048, October 1979. ENEROTH. P.. FUXE, K., GUSTAFSSON. J: A., HOKFELT, T., LOFSTROM. A.. SKETT, P.. AGNATI. L. The effect of nicotine on central catecholamine neurons and gonadotropin secretion. II. Inhibitory influence of nicotine on LH. FSH and prolactin secretion in the ovariectomiud female rat and its relation to regional changes in dopamine and noradrenaline levels and turnover. Medical Biology 55:158-166, 1977a. ENEROTH, P.. FUXE, K., GUSTAFSSON, J: A., HOKFELT. T., LOFSTRbM, A.. SKETT, P., AGNXTI, L. The effect of nicotine on central catecholamine neurons and gonadotropin sectetion. Ill. Studies on prepubertal female rats treated with pregnant mare serum gonado- tropin. Medical Biology 55:167-176, 1977b. ENTRICAN. 1., MACKIE, M., DOUGLAS, A.S. Oestrogens, myocardial infarction, and smoking. (Letter.) lnncet 2(8098):1048. November 11, 1978. ERSHOFF. D.H., AARONSON. N.K.. DANAHER, B.G., WASSERMAN. F.W. Behavionl, health, and cost outcomes of an HMO-based prenatal health education program. Public Health Rrports 98(6):536-547. November-December 1983. ERSHOFF. D.H.. MULLEN. P,D., QUINN. V.P. A randomized trial of a serialized self help smoking cessation program for pregnant women in an HMO. American Journal ojPub:ic Health 79(2):182-187, February 1989. ESSENBERG, J.M., FAGAN. L. MALERSTEIN, A.1. Chronic poisoning of the ovaries and testes of albino rats and mice by nicotine and cigarette smoke. Westernlournal ojSurgical Obstetrics and Gynecology 59:27-32, 1951. EVANS. HJ., FLETCHER, J., TORRANCE. M.. HARGREAVE, T.B. Sperm abnormalities and cigarette smoking. Lancet 1(8221):627-629, M.reh 21, 1981. 414 TT£L OTLtS . EVERSON. R.B., SANDLER. D.P., WILCOX, AJ., SCHREINEMACHERS, D., SHORE. D.L.. WEINBERG. C. Effect of passive exposure to smoking on age at natural menopause. British Medical Journal293:792, September 27. 1986. FABIA, J. Cigarettes pendant la grossesse, poids de naissance et mortalitE perinatale. Canadian MrdicolAssociationJournal 109(11):1104-1107, December 1, 1973. FANCOURT. R.. CAMPBELL S., HARVEY, D., NORMAN, A.P. Follow-up study of small-for<fates babies. British Medical Journal 1:1435-1437, June 12, 1976. FINGERHUT, L.A., KLEINMAN,I.C., K.ENDRICK, J.S. Smoking before, during, and after pregnancy. American Journal ojPublic Health 80(S):541-544. May 1990. FfiZGERALD, G.A., OATES, J.A., NOWAK. J. Cigarette smoking and hemostatic function. American Htart Journal 115(1, Part II):267-271, 1988. FfIZHARDINGE, P.M., STEVEN. EM. The small-fordate infant. I. Later growth patterns. Pediatrics 49(5):671-681, May 1972. FORSBERG. L, GUSTAVII, B., HOJERBACK, T., OLSSON. A.M. Impotence, smoking, and S-blocking drugs. Fertility and Sterility 31(5):589-59I, May 1979. FRAZIER, T.IvI., DAVIS, G.H.. GOLDSTEIN. H., GOLDBERG, I.D. Cigarette smoking and prematurity: A prospective study. American Journal of Obstetrics and Gynecology 81(5):988-996, May 1961. GILBERT, D.G.. HAGEN, R.L, D'AGOSTINO. 1.A. The effects or cigarette smoking on human sexual potency. Addictive Behaviors 11:431-434, 1986. GODFREY, B. Sperm morphology in smokers. (Letter.) Lancet t(8226):948, Apri125, 1981. GOLDSTEIN. l., FELDMAN. M.L, DECKERS. PJ., BABAYAN. R.K.. KRANF. R.J. Radia- tion-associated Impotence. Journal ojrhe American Medical Association 251(7):903-910, February 17,1984. GULYAS. BJ., MATTISON. DR. Degeneration of mouse oocytes in response to polycyclic aromatic hydrocarbons. Anatomical Record 193:863-882, 1979. HAAG. H.B., LARSON, P.S.. WEATHERBY,I.H. The effect on rats of chronic exposure to cigarette smoke. Annals ojrhe New York Academy ojScirncr 90:227-238, 1960. HAMMOND. E.C. Smoking in relation to physical complaints. Archives of Environmental Health 318-46, August 1961. HANDELSMAN. DJ., CONWAY. A.1., BOYLAN, L.M., TURTLE,I.R. Testicular function in potential sperm donors: Normal ranges and the effects of smoking and varicocele. International Journal ofAndrology 7:369-382, 1984. HARTZ, A.J., KELBER. S.. BORKOWF. H.. WILD. R., GILLIS, B.L., RIMM. A.A. The association of smoking with clinical indicators of altered sex steroids-A study of 50.145 women. Public Health Reports 102(3):254-259, May-June 1987. HARVEY. D.. PRINCE. J., BUNTON. J., PARKINSON. C.. CAMPBELL. S. Abilities of children who were small-for-gestational-age babies. Pediatrics 69(3):296-300, March 1982. HEBEL,IR., FOX. NL, SEXTON. M. Dost~response of bitth weight to various measures of rmternalsmokingduringpregrtancy. JournalojClfnicalEpidtmiology4l(5):483-489, 1988. HERSEY. P.. PRENDERGAST. D.. EDWARDS. A. Effects of cigarette smoking on the immune system. Follow-up studies in normal subjects after cessation of smoking. Medical Journal ojAustralia 2:425-429. October 29, 1983. HIATT, R.A.. FIREMAN. B.H. Smoking, menopatue, and breast cancer. Journal of the National Cancer Institute 76(5):833-838. May 1986. HILL, R.M.. VERNIAUD. W.M., DETER. R.L. TENNYSON. LM.. RETTIG, G.M., Z1ON, T.E., VORDERMAN. A.L., HELMS. P.G.. MCCULLEY. LB., HILL. LL The effects of intrauterine malnutrition on the term infant: A 14-year progressive study. Acto Paediatrica Scandinavica 73:482-487,1984. 415 t ......._,......_. ~..,...,..,. _....-.~_............_.__...__....... .............-....._.._.....___........._...... __

t/onwwM.. PW 4'' Mr ~ Nwnber of Mlanes .N~1Jr~ <2.500 anma: 1,322 1.196 74J ToW Whit: 2a.3S1 1tt,?21 fLdt+! souau: ow•..• w.•tt,.•r •r K..r lP <0.001) M). io. gjEL OILTS .ntakaIlio (76) earrietl out a ptv.l+ecllve .tudy of 11,005 .inRle t~~rllu In Fiuleud. Cigarette anwking molhrnw had algnificuilly innre infauts weil;binR le.s llwt 2,LUU grtms than did notuntokerw (1'<41.001). Itualt antl Kwa (8i), In a proepective aluily of 1,040 pregnanciro In hoaan,llas.achutietla; L)omaaala, et al. (1~), In a retroapective atudy of 1,fl14 preAnancics in Poland; and hlukhrrjee and Mukherjee (54), In a rrlrtopertire study of 2,tlB6 pregnanrir•t In India, each found a signillcantly higher ineidenoe of low-birth-weight infants .mong eiganette eninkrry. )tulkr, rt al. (Ib) hase further analysed Ilie Ilritiah Perinatal Mor- tality Stwly data. Analysis of the tlt,t)N qow.+dionnairte revef.led Uut 40.8 perernt of Ilw, somen were ciaarelle Kniekrri before prrRnancy. After tlie fmu-1l% uinnlli, Ihis ponrutar Ioad deetraxd to 27.4 )Mr- cent. (lit•en lite IarRe nuuilwr of w•nnwn iu lite atudy, and tlte eiQ• nifiraut t•hanl," in inwtkiug (rhavinr w•birit oreurred, Ituller, ot al. fuund it IMwaible tn ewieider lhu effect of a rhange in anwking IK- ha.•iur on birlh weiRhft betwrrn lhe 6eRisuwhtR of ahe pregnancy and . the fourth uNx+lh (after which .uwkLtK beharior was reportedly elaldn). 'i'1it- at4thnrw alate.l, "If Mnoking itowlf (rRlLer than lbe type of +rnnoan who Mnakea) hae • delelerimu effad on lhe fetus, it w•eultl lie reaaonable to expect the mothet~t who Ra.e ap unoking duriaq pre{,rnanKy to show differrneee In lite birth weight and peri- nafal mmtality of their offeprina rnrnnpare,l with thoan who routinu.•d to wtwkr' Their rr.ultb are presoutcd in OAure 4. The birtlt weights by Fnakins ralegnrien w-ere estiuuded by a.ing a main effect nuxlel without medialinR t•ariablea. Ilow•evrr, lbe aidlwtn reporled that wlken 11,e ninliating variables (sncial rlana, matr•ruwl aae, parity, nulcrnal height, we: of Infutt, geatatioual aRe, and (wrrinatal mortality) were allo.red Gtr, fhe treulta of Uie aualysia were very ain+ilar. The elf.rt of ciRarette unnking hefotw prelnancy w•ay in.iLnulir.nl. crntnpar.ml to that of anoking regularly after lite fouNlt nNadh of peaation. 1•6e aulhors concluded, °The tliwlina that a ehanKee in maternal smokinR habita during preRuaney had the r/feet nf ItuttinR the baby inln a Itirlh weisht and perinatal enorlalily rateotry aaaociated wi1M the new sonokins habita pninla toward some kind uf r.auan-effect relationship. ••• TLia findin6 ia further etrenRtltened by the birth weight analysia which slwwy that lite diminut.icwt in birtJt wr.iftht of lhe offspring of SttNfkinff InnIIMM IMMilfa anti is ilUleed little changed w•heu alln.ranee has been muk: for a number of ol,her.ocial and obete.trie mediating factora." IaM ®

Introduction 9ZEL 0tLt5 i ('il;nrclto emnking is a conunnn haloit amnng women of child•bearing age iii the 1'nitrd tilalra. In 10711, approximately onc-third of Amer- iun ivninen of child-IK•ariug ago tcere rigaretle smokers. The percent- age of U.S. wnweu %rltn rniokril lhroughout preguncy is nnt drflnilely konen, 6ut is presnm,dLly Imrer, prnbaLly iii the nci.-hlinrhood of 20 to 25 percent. With a large frtal IKipulatiou at IK>lrntial, but prevent- able, risk, tlto relntiouship between eigerette amnking nnd the out- come of pregitanry har Iw•cn fhe focus of crnusider.hle aud continuing rescarch. !:.•rry invesl ignlor who hes exatnined the rrlatiunFhih lus confirmed that the infauts of troutrn who riuokr during pregnancy have a lower at•eral,ro hireh wright tLan Ilse iufaula nf «'oiueu who tin nn( !"noke during prrl.•nnuc}-. Pfuch erideurr indical" flut rigarrlle smnking during lbrry;nuuury cauk•s thie rrducliat iu infnnt birth tvril;ht. 1everal int•estiy;atno-4 liat•r iIrmnli.trated (hrt tlse (e(al and ncnunlnl nsnilalily ratc ix .ignilivwdlt• hil,•Iw•r fur 16e infanlK af amnkcn tLnn for (lie infanls of nussmnukera: nther inve+tigatora have not found higher mor- talitt fnr.r~u~~lrw' influ1lit fihldirn of the.~riatinn Iw•hrrru watrrual cigarrtti• nwukiug anal rnugrnital Illnlfnl•nWtlnnS hat•c Iirmlnrcd con- flirtiul; Iraulti. 1'hr fnlluu-inl; is a rrrirtt• sit a•ea•L• prr•cinunl,v rrtxtrtrQ unJ rrcrnt afndirs ~~9hi~•h Ir•ur ou flu• r.•Inlinu+Lilw Iw•la'tro rig:urlh+ vnsoking aud QiIL ~rnt outrnnuy nf pn•gunnry. In additinn, tlic chr1i1vr Illrludes a cecic%c nf the n•Intinu..hip Ircla•Mn cigalYltr unnking usal ln4•talinn. Smokiug uld Itir16 Weight F'7~idcm inln~itel .Zlu~liu 0n.taKTTr. ti)I11KtHn .tYfl TIIr: t.nN••111aTt1•`1rr.lo/!T j\r.tNT In ID.iT, Simp+on (!M), using • trtrnalw•ctive study dr.i/.li. tIrtcr- Iniaed (het mmong 7.t:/!) q•nlnMl in Sall Ilrrunrdinn ('nw11~•. ('wlif.. (hn drlirrry of infn1iti a•eighiny: IrKt Ihan 2,.'1(Ml grnnts 1.% irr ne 417

} . i )97G

6 aborted conceptions. Am J Hum Genet 1983;35:421- 31. 43l 18. Kulikatukas V, Blaustein D, Ablin RJ. Cigarette smok- ing and its possible effects on sperm. Fertil Steril 1985; 32. 44:526-528 19. Rosenberg bJ. Does smoking affect sperm? In: Rosenberg MJ, ed. Smoking and reproductive health. 33. haleton. Massachusetts: PS G Publishing Co.1987:54-- 62 20. Manning PA, Feyerabend C. Ggarette smoldng aod fetal breathing movements. Br I Obstat Gynaecol 1976;83: 34. 262-270 21. U.S. Department of Health and Human Services. Reduc- ing the health consequences of amolzng: 25 years of progress: a report of the Surgeon Geaaal. U.S. Depart- mcnt of Health and Human Services publication no. (CDC)89-8411. 1989:71-85 22. van der Veen F, Fox H. The effects of cigarette smoking on thc human plaeenta a light and electron microscopic study. Placenta 1982;3:243-256 23. Brown HL, Miller JM Jr, Khawli 0, Gabert HA. Prema- ture placental calcification in materaal cigarette smolc- ers. Obstet Gyneeol 1988;71:914-917 24. van der Velde WJ, Copious PeerebootrrStogeman JHJ, Taffcrs PE, James J. Strocniral changes in the placenta of smoking mothers: a quantitative study. Placenta 1983 ;4:231-240 25. Rarna Sastry BV, Horst MA, Nanlnm RJ. Maternal 26. 27. 28. 29. 30. tobacco smoking and changes in amino acid uptake by human placental villi: induction of uptake systems, gammaglutamyliran.cpcptidasc and membrane fluidity. Placenta 1989;10:345-358 Nacyc RL Abruptio placentae and placenta previa: frequency, painusl mortality, and cigarette smoking. Obstet Gynecol 1980;55:701 -704 Nacyc RL. Factors that predispose to premature rupture of the fetal membranes. Obttet Gynecol 1982;60:93-98 Hadley CB, Main DM, Gabbe SG. Risk factors for prsterm premature rupture of the fetal membranes. Am J Peri nato l 1990;7:374-379 Harger JH, Hsing AW, Ttwmala RE, Gibbs RS. Mead PB. Escheabach DA, et al. Risk factors for preterm premature rupture of fetal membranes: a multicenter cac,c-control study. Am J Obstet Gynecol 1990;163:130- 137 Shiono PH, lQebanoff MA, Rhoads GG. Smoking and drinking during pregnancy. Their effects on prucrm binh. JAMA 1986:2.55:82-&t lieberman E, Ryan KJ, Monson RR. Schoenbaum SC. Risk factors accounting for racial differcnces in the rate of premana+e bitth. N Eagl J Med 1987;317:743-748 Haworth JC, Ellestad-Sayed JJ, KingJ, Dilling LA. Fetal growth retardation in eiganette-gmoldng mothers is not due to decreased maternal food intalce. Am 1 Obsut G yttecol 1980;137:719-723 Ouastod M, Mo.r VA, Scott A. Risk factors associated with small-for-dates and large-for-dates infants. Br J Obstet Gyturocol 1985;92:22b-232 35. MacArthur C, Knox PA. Smoking in pregnancy: effects of stopping at different stages. Br J Obstet Gynaecol 1988;95:551-555 36. Kuhnert BR, Kuhnert PM, Debanne S, Williams TG. The rslationship between admitmd aac, and birth weight in pregnant women who smoke. Am I Obstet Gynecol 1987;157:1247-1251 37. Webster WS. Cadmium-induced fetal growth retarda- tion in the mouse. Arch Environ Heahfi 1978:33:36-42 38. Sachs BP. Tbe effect of cmoldng on late pregnancy outeome. Semin Reprod Endocrinol 1989;7319-325 39. Rintahaha PJ, FFirvonen J. Thc epidemiology of saddea infant death syndrome in Finland in 1969-1980. Foren- sic Sci Int 1986;30:219-233 40. l4cinman JC, Pierrs MB Jr. Msdana JH, Land GH, Schramm WF. Tlx effects of maternal smoking on fetal and infant mortality. Am J Epidemiol 1988;127:274- 282 41. IumleyJ, AstboryJ. Advice forpregnancy. In: (halmcn I, FinIdn M, Keine MJNC, eds. Effective txre in pmg- nanry and childbirth. Oxford: Oxford University Press, 1989:237-254 42. Petersen 1, Handd J, Kotch J, Pododworny T, Rosen A. Stmking tsdttctioa dttring pregnancy by a program of self-help and clinical support. Obstet Gynccol 1992;79:924-930 43. U.S. Departmcat of Health and Human Services. The 44. bealsh benefits of smoking cessation: a report of the Surgeon Geaeral. U.S. DepatmentofHealth and Human Services publication no. (CDC)9Q8416. 1990:595 Benowitz NL Ntcatine teplaoerneattherapy dm9ng pR8- nancy. JAMA 1991;266:3174-3177 Marcoux S. Brisson J, F" J. The effect of cigarette smoking on the risk of prceclampsia and gestAtional hypertension. Am I Epidemiol 1989;130:954-957 This Technical Bulletin was developed utder the direction of the Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists as an educational aid to obstetricians and gyaecologists. The committee wishes to thank Susan Hcllerstein. MD, MPH, and Benjamin P. Sachs, MBBS. DPH. for their assistance in the development of this bulletin. This Tecluucal Bulletin does not define a stuwlard of cane, nor is it intended to dictate an exclusive course of management. It presents recognized methods and techniques of clinical practice foreoasidenrtion by obstetrician-gynecologists for incorporation into their practices. Variations of practice taking into account the needs of the individual padent, resources, and limitations unique to the irutitution or type of practice may be appropriate. Copyright ® May 1993 THE AMERICAN COLLE6E OF 08STETRIaMI Alm 6YMECO1.06tSTf `~ 40912th fbtrtet, SW ,23snasu M/adi.Qtaa, DC 20Q2A-2168 J N v W

, PAPOZ. L.. ESCHWEGE. E., PEQUIGNOT, G., BARRAT. J., SCHWART2; D. Maternal smoking and birth weight in relation to dietary habits. Arnrrican Journal ojObstrtrics and Gynecology 142(7):8711$76, April 1, 1982. PATRA,P.B.,SANYAL,S.,BISWAS,N.M. Possiblealpha-adrenergicinvolvementinnicotine induced alteration of spermatogenesis in rat. Andrologia l 1(4)273-278, 1979. PETITTI, D.B., COLEMAN, C. Cigarette smoking and the risk of low birth weight: A comparison in black and white women. Epidrmiology, in press. PETTERSSON, F., FRIES. H.. N1LLIUS, SJ. Epidemiology of secondary amenorrhea. I. Incidence and prevalence rates. American Journal ojObsrrtrics arrd Gynecology 117(1):80- 86, September 1, 1973. PRAGER, K.. MALIN, H., SPIEGLER, D., VAN NATTA, P., PLACEK., P.1. Smoking and drinking behavior before and during pregnancy of married mothers of live-bom infants and stillbom infants. Public Health Reports 99(2):l 17-127, March-April 1984. PULKKINEN, P. Smoking and pregnancy: The influence of maternal and gestational factors on the outcome of pregnancy and the newborn. Annales Chirurgiae rt Gynaecologiae 74(Supplement 197):55-59, 1985. RABKIN, S. Relationship between weight change and the reduction or cessation of cigarette smoking. International Journal ojObesity 8:665-673, 1984. RANTAKALLIO, P. Relationship of maternal smoking to morbidity and mortality of the child up to the age of f ve. Acta Paediatrica Scandinavico 67(5):621-631, September 1978. RANTALA. M.-L., KOSKIMIES, A.I. Semen quality of infertile couples-Comparison be- tween smokers and non-smokers. Andrologia 19(1):42r36,1anuary-February 1987, REUBEN. D. Warning: Smoking endangers your sex life. Reader's Digrsl, April 1988, pp. 98-100. RODRIGI;EZ-RJGAU. LJ_ S-Mfi}L KD_ STFII:BERGEfZ E Csgarar smokaLe aod sernen quali ry. Frrriliry a,d Srrriliry 38(l F 115-116. Jaty 19t42. ROGERS. BJ., R USSELL, L.D. Semen analysis, sperrn furscrioml abnomtaliries, and ethance- ment of semen parameters. In: Gondos, B.. Riddick, D.H. (eds.) Pathology aJln/rniliry. New York: Thieme Medical Publishers. 1987, pp. 333-352. RUI, H.. OLDEREID, N.B., PURVIS. K. ROyking og sperrniekvalitet hos menn under fertilitet- sutsedning. TidsskrNorlorgrforrn 109(5):573-575, 1989. RUSH. D. Examination of the relationship between birthweight, cigarette smoking during pregnancy and nuuemal weight gain. Journal of Obstetrics and Cynarcolugy o/rhr British Commonwealth 81:746-752, October 1974. RUSH, D., CASSANO, P. Relationship of cigarotte smoking and social class to birth weight nrrl perlnatat nuutullty amung all binh.ln Ilrataln,l-I I Aprll 1970. Juurmrl,if l:'pddrmbduAy unrl Conunrodly llruhh 37(4):249-255. Dccentbor 1983. RUSH. D.. KASS. E.H. Mutemal smoking: A reassessment of the association with pcrinatal murtulity. AmrricunJournol oJEpJdrmiolugy96(3):183-196,Scpletnbcr 1972. RUSSELL. M.A.II. Cigarette amukiny: Natural history of a dependence diaurder. Brbl.rh Jnurnal njMrdical Psychology 44(1):1-16, May 1971. SAARANEN. M., KANTOLA. M., SAARIKOSKI. S., VANHA-PERTTULA, T. Humwt seminal plasma cadmium: Comparison with fertility and smoking habita. Andrologla 21(2): 140-143, 1989. SAARANEN. M.. SUUNIU, S.. KAUHANEN, U., SAARIKOSKI. S. Cigarette slnukhtg and semen quality in men of reproductive age. Andrologla 19(6):670-676, 1987. SCfIENKER. M.B.. SAMUELS, SJ., PERKINS. C., LEWIS. E.L.. KATZ, D.F., OVER- STRE•ET, 1.W. Prospective surveillance of sperm quality In the workplace. Journal of Occ•uparional Medicine 30(4):336-344, April 1988. SCHIRREN. C.. GEY. G. Der einlluss des rauchens auf die fortp/lanzunga(llhigkeit bei mann und frau. Zritsehri/r jGr Huur• und CrsehlechtsJvankhriten 44(5):175-182, 1969. 420 VtEL OtLZS . f SCHRAMM, W. Smoking and pregnancy outcome. Missouri Medicine 77(10):619-G26, :,. October 1980. SCHWARTZ, D.. COWARD. I.. KAMINSKI. M., RUMEAU-ROUQUETTE. C. Smoking and pregnancy. Results of a prospective study of 6.989 women. Revue Europfrnnr dtrudrs CliniqursrrBiologiqurs 17:867-879,1972. SEXTON, M., HEBEL. J.R. A clinical trial of change in maternal smoking and its effect on ~ birth weight. Journal oJthe American Medical Association 251(7):911-915, February 17. : 1984. SHAARAWY, M., MAHMOUD. K.Z. Endocrine profile and semen characteristics in male smokers. Fertility and Sterility 38(2):255-257, August 1982. SHIONO. P.H., KLEBANOFF. M.A.. RHOADS, G.G. Smoking and drinking during pregnan- . cy. Journal ojrhr American Medical Association 255(1):82-86, January 3, 1986. SIMPSON. WJ. A preliminary report on cigarette smoking and the incidence of prematurity. American Journal ojObstrtrics and Gynecology 73(4):808-815, April 1957. SOULAIRAC, M.-L.. SOULAIRAC. A. Action de Is nicotine sur le comportement sexuel du I rat mJle. Comptes Rendus Soci(tf de Biologie 166:798-802, June 20, 1972. SPIRA, A., DUCOT, B., JOUANNET. P., SOUMAH, A.. FENEUX,.D., ALBERT. M. Con- sommation de tabac, d'alcool, et fertilitE masculine. INSERM 103:363-378. 1981. STANFORD, J.L., HARTGE, P., BRINTON, LA.. HOOVER. R.N., BROOKMEYER. R. Factors influencing the age at natural menopause. Journal ojChronic Diseases 40(11):995- 1002,1987. STEKHUN, F.1. (Effect of tobacco smoking on spennatogenesis indices.) Vrach Delo 7:93-94. July 1980. STERLING. T.D.. KOBAYASHI, D. A critical review of reports on the effect of smoking on sex and fertility. Journal of Ses Research 11(2):201-217, August 1975. SUBBARAO, V.V. Effects of smoking on female reproductive functions and the onset of menopause., In: Aoki, M.. Hisamichi, S.. Tominaga, S. (eds.) Smoking and Health 1987. Amsterdam: Elsevier Science Publishers. 1988, pp. 537-539. TAKAHASHI. Y., HIRATA, Y. Nocturnal penile tumescence monitoring with stamps in impotent diabetics. Diabetes Research and Clinicrrl Prtx•rkY 4: (97-201, 1988. TAYLOR, R.R., STURM. M., VANDONGEN. R., STROPHAIR. J., BEILIN, LJ. Whole blood platelet aggregation is not affected by cigarette smoking but is sex-related. Clinical and Esprrlmrnral Pharmarnluyyand Physlalaxy 14:6(rS-671, 19117. THIENES. C.H. Chronic nicotine poisoning. Annals of the New York Academy ojScirncrs 90:239-248,1960. 'I'I IUMPSON,1.1I., IRWIN. Ir.U., KANISMA'I:VII, Y., YI:RAYpANIAN, K„ Yllll, M. (Ufecll uf chrvnlc IdwOta adminlelrollun and age In male FltKhcr-344 ratx. Toxh'uloKy and Appllyd Pharmacology 26:606-620. 1973. '1'SITOURAS, P.D., MARTIN, C.L., HARMAN, S.M. Relationship of serum teaw.terune to aexual activity In haaithy elderly men. Journal rt/Grronlolopy 37(3):28g-293, 1982, UNDERWOOD. P.B., KESLER. K.F., O'LANE,I.M., CALLAOAN. D.A. Parenul smoking empirically related to pregnancy outcome. Journal ojObsrrrrics and Gynecology 29( I):1-8, January 1967. U.S. nRl'ARTMENT OP HEALT/1 AND IIUMAN SERV ICES. Thr ilrolrh Cnnsrqurnrrs n/ Smnking jor Women. A Rrporr oJthr Surgeon General. U.S. Department of Heahh atnl Human Services, Public Health Service, Office of the Assistant Secretary for Health. Office tin Smoking artd Health, 19140. U.S. DEPARTMENTOP HEALTH AND HUMAN SERVICES. RryionaJtheSrcrrtury'sTask Force on Block and Minority Health. Vol 6: Infant Mortality and Low Birthweight. U.S. Department of Health and Human Services. January 1986. 421 a

I , ,.Irnf t mnngrlaarrf f e Rrnnkrrw as amonR nrnutnu,kero. Suh"urntly, LnKo (4/i) NiNlied 2M2 wonsen in' llirtninghiim, hnRland, and dem- onctral,yl in his retrospective etudy that the infants of emokina nu,1 hern were drll%rre.l sinly slightly earlier ( 1.4 days on the average) thaut lhnne of nonainokrra, !le further noted that for Restations of 2d0 days end nrer, the Intanta of smokers were wnsistently tighter in .criQhl 1InriuQ each weck of ge.tatlon than those of the nonsmokers. This finding )ua I"n r.+nflrtned ainos, and fixure 1 lrom the hritish I'orinatal Mortality Study (1J) provides illustration of • t)tifa relationship. (iiren the nearly c.wtefant disparity present betweeR ths birth wrighla i)f I IM inlllnts of s.wtkers and nommmokers for Redations ot 200 day-s and over, but abserat prior to that t1me, and given the similar birih errights of infanla of twxrwx>kees and of woaMn who aave up ansnkinR e.rly In preltnanry and did not b*n to anroke aoin, i.nwe inferral that tlr in8uehas of anoklng epen birth weight might. lir ntainly in IIK later uxwtttu of pergn.ney. IIe wnphuiml the tentatire nature of this ronelu.wwt, sie~ca the numher of infanla with a Radation of IeM f Ioan 2M d.ya and t1W nuntlmr e/ wowrw•n who Rare up smoking carly iii We pregnancy and did not begin to emoke sain were both amall. FIEw. 1.--M.an ttletlh wNgA! br weM e/ geefMlo. aooa1 te rlnwel arnoY. b4 Q.hlt eo.t,at w«Y ak~ 12'S I ~' ~ . ~ l~.ai.es as . 76 36 37 !4 ?! 40 41 OsMaltoa M oompMted wsstu 2190 ee.u.d w wd.. .eew.M. & ry w M~ t.r.yA w !•! Y M WW o.uaN b lwdrd Mo w./w .r .y/.IW M at.11.N drW ~AM .r..h. se4NCA: a..rr. n. a. Aa.n..a, c 0. 0116 IN 9Z£L 0tLT5 42 43+ l i , Lows found that the (nfants whoae mdhert snwked throughou pregnaney, weighevl, at the average, 170 pranu 1e4m than thowr Rtwe molhen did not wnoke. In addition, he noted that the entire dislribu- lion of weights of inlanti of ernoken was shifted to the left (toRanl lower weighls) relative to that (or Uw Infanta of nona+rw+kers. 'Chis finding, too, has been conlirmed by other Investitatort Figure 2 ofien a n I I lud rat loe from Macalahon, et fal. (49). (iiven that the Infants of smokut and notisn+okere differed only dixhtly with nmMcfd to the duntioa of S.atation, Lowe obncluded thaft the lower birth weight of 4noken' infants n+uf# be atlributed to a direct reterdation of fetal Rrowth.ln other worde, on ebe basis of hi. data, the intants of smokers wron.aull-lor-datss rather than truly prrmatute. ktanJ In.esligaton have utbeeqoently conOrtned this point (It, 14. t6, ;l6, IRS, fd, dS,11.1). Ttunrher (1!), In a dudy o[ 49,897 birt hs among 114. uaral w•lre•, in the sanw Iw+pulatien stndkd hy (lnderwond, et al. (lt7r1), tatnd th.t ths Intants of anolten wer., on tbs aroraRr, de- lireteil only I day earlier thut tlwr of nonsnakers. This finding .er.wtnted fer onlr lU I+crcent of tlw dbcrepenr? In birth weight be- tRetn t hn two gronps o[ In tanta 'Che remainder of lhe st udies resulled in Ihe% iktedion of either sintilar rariatinna in gestational length or no average difference. In a recent dudy,lfulcahy, and Alurpb7 (66), rW" L-.~srneke w~M~p+ ~~~~ eW~et fJ«iwi .~hae~anal~ud t Mek of eyusttea or erora ffw day. INMlfT MfE1Gt/T ANO MRf1fTA1 SYOtt1t10 ltADfT3 10 • I • 4 2 0 4 6 a f • f 10 11 s/RTN WE/OHt (SCN.E IN trOUNCS: INYERVAI! t1f 4 O2.) ~- sOUaC[, Y.cYM...•..1 d. 091. EXNIBIT ~ Sac,1~s I ~ ®

1 fyur. 4.._.,Aw..p Mrth wNeht by met.rn}I•.mohlnt hadt (a) 6.bre eurrent W.an.ncy and (b) du.lna cu.r.nt ore.n.ncr. • 0 1-4 ti-! 10-19 40-,to NumAer et dw.tles/day b.bre ew..ry Pnsa.fty .o1Mtt: A4MM M- a.Yv. M.L Uy. Tolst bt.ll.a 21.671 E.ioexcs ioa Ax Ixaaccr Aaaocxx..rwx ar.esx CwAasrts 9r,eoaxo ANO $awl.troa-DArp Ixrarra Yeruahalmy (11J,1fi,116) has auaaNted that wnoklng is an inde: to a particular typs of reprodaeU.e outooene and thus does nolt play a eansal rob ia U» produoUoa ef .oull-for-datea infanla He has de- .ebped sa.era) lines of support for this hypothew, from an analysis of data fran the proslled.i.e In.erU6atiol of 13,ptla mothers in the Oakland Child Health and Development Study. He has emphasised that IneReeti.e randomisation and the phenomenon of se)f-seled.ion eomplieati the development of appropriate inferences with regard to eamality. Such dif$eultiee do not prevent the identifieation of eamal anoeiatiorr, but they deeund careful and critical analysis of the data. Yarwhalmy has questioned the eauaat nature of the relation- ship between cigarette emolins end small-for-datee infants because of :(a) The relationship between the smoking habit of the father and low birth weight of the Infant, (b) beha.ioral diRereneee between emokere and nonamokers, and (c) comparison of the birth weiRhts J I a woman's Infants born during the periods when aLe smoked eig+ retf.es and w•hen site did not. Yenuhalmy (114) has stated that Ihe emokint hahit of lhe father could not rea+onably be related to the birth weight of Ihe infant. From preliminary data deri.•ed from /1)e study, Iwwewr, he dcttrmined that U)ero waa an Increased itN:blenee nf Iow.birth•weight infants when the fathere smoked anQ, mnreoeer, Uure was an apparent doee- rraponse relationship as found fnr maternal smoking. liowe.er, he noted that only when both the hu.band and the wife wnwkcd was the incidena of low-birlh-weight habiea incrrasrd. 11e felt that (llene findings tupl/ortal the rotxlusiou Ihat lwakinR was a marker of tylxs of indivi4uals and uot a eawull factor for ln.r birth weighL Other inrestiKetors have aince examinwl thii r'lationship (0, 1A0), but nm/e I/nn rrnlfinlNr) sit ltwlrprndrnt .w+einlion for l.nlrrnal enNokinR. 111r acw,cialioNs Ir(.rrrn paternal /wleking and biNh wriRlit alilx•MM In IM nn inditrrl nnr. 1'alrnul .nd maternal amnkinQ he- hevinr are highly correlated and nutrnlal wlwdcinR ia ntrouttly related 1n iufant birth weitthL I)lalerwmrl, et al. ( IIIA) studied 48,!)05 women, fheir hu.han.l' amnking IMharinr, etNl Ibe rrlalion w•ilh hirlh weight (tallle 1). lf Ihe nN+lher was a newumnker, then Ihe fa(her: smoking had no ii)Auenre un Ihr bir11s weip11t of IIN, iufanL TAlLS 1.-InIdnt /ufA W.ipAt /N aul/erNa/ a.d p(erael nMokinp Anbil. re0r.m t....+N 1N ~d~ws1 cV.w4r w" Mt No.e.................. 24. !eS 1 30 0 9.541 a. 3911 0 1 te to-•-------•--..... 1.600 5, 20111 1m 3.413 5,111o T 1I lu 70 ................ 11. Il0 :1, I!MI I!r.t 10, 4O:t 3.:N11 6 >]0 ................... 1.370 ]1 I+: :1:1 1,330 :1, :IaJ ~ I N.....Is...LM aJw. s....: c.A ..w..4 r aa. Yenahalwv (ll:i) Ilninled out flint. other in.ediRalors had found marked didrn•niw hetwn•n NlMkern and nauunakers. In I)is own stndy, Iro (niuul Il1at nwl.mnkerw )anl e~adraeel.tivee nignificanlly mntw fn+plenllc Ihan d'a1 /w+nker+. 1(ut.rlrrr, a aipnificudly higher pnqr+Nia1 of Ruu/krre dr.nk eellre, herr, auil whiskey. llnwerer, he did ouf adjust fi/r Ihr?4r r.riahlra ln hia annltsia of lllr Mncialinn Irtween rignn•11r munkiug aud lu%rrr iutnnl birlh weiFht. Other in- erw/ip.(nra I1nce alen found QiRrn•nren Ir•twren wnnkers and non- Nunkem Forranlul.le.Fresier.ct al. (35) f-nmd aignincanl alirtercnrrs In Ihr dinlri6utimi of (wirily, work Linenry, education, antl l+nycho- 1)e 6IEL 0TLI5 I t11

Fllur. 1.-Asn:ent.N ol prean.nclef Wth Int.nt wlahln~ IW tMn 2.lS00 tr.ma. by c.lauetts awp&u,a cat.aorl,. NumDer of Intanta wtaht" <2.600 trama: tiotaunotea .322 <1 padt Mrd.1r 1.106 a: 1 pull W daY 793 totd &IrMr 2l,36A 1t).7L 6.581 (P <0.001) wuaco ow.r o...wrwt .r K..w tW. 6ZEL 01LTS 422 .~,.~. / ltnidakallin (76) carried out a pron(+rrtivc stwly of 11,>106 uinl;le birthy in F'iulr.uJ. Cigarette ttntoking tuntlu•rr had ei);niticently mora inhirta wcig6iug laa than 2,bUt) grawr tltan did noiuum-kera ( P<lt.p)I ). ltush uud I:ass (8B), in a prospective stu-l)• of 1,040 hregitancivs in tloston, 111ussacltit.etts; Domagala, et al. (19), in a retrosrective atudy of 1,832 pre6uancics in Poland; and Shtkhrrjrc and Atukhcrjce (5;), in a rctttitspeclivc study of 2,886 prcgnanciri in India, each found a significantly higher incidence of IoM-birtlt•weight intants among ciguetan awokeri. ltutlrr, et wl. (15) have further analyzed lite liritislt I'erinatal Ifor- tality tiltul)• tL•tta. Analysis of the 10,004 queationuaires revealetl lhnt 40.8 Iwrcent of the wonten w•ere cigarettn Piwnlrera before prrgnaucy. After Ilte f4wrth tnonth, this pet.•eulage hail decreased to •17.1 1Mr- cent. (liven tbe lurge number of w•omt•n iu Ilie atudy, and lite si);- nifiunt chau);rs in wunking behavior whirli uccurred, Ituller, et al. found it IrKsi61e ln consider lite elfec•t of n change in fntokin/; bo- havior on birtlt w•eight between tlta begiuuiug of lite pregnancy and the fowili wnnth (after which stuoking IKhevinr was rel+nrteilly sUble). 9'hc aulhnrx stated, °It wtwking itrelt (rathcr thatt Ihe type of woman who smokes) has a dektcrinat eRrct on (lie A•tns, it w•nuld t,o tea.onable to e:pect the ntathetv who gave up em,kiug during pregoNncy to sltow differences iu t1w Itirth weight and pcri- naUl tnurtality of their utispring comryur:d witlilhnsn wito contiuueil to nunlte."'1lteir results rre prexnted in li{;nre 4. The birth •roigltts by twxtkiag categoriem were estimatetl by u.ing a mrin etYP*t tnndcl wilLout malialing variaLks. Ifow•evt•r, lhe utdlWtrY rciwt•ted iluit wbat the uuvliatin); variaLle,t (social clam, mutrrnul age, parity, uulrrnul height, sc: of infattt, gestalinual atie, alul tN•ruutMl utorlality) were allowed fur, tlte results of tlto analyyis wrt.• %•rry similur. The rIG•ct of ciAarctte smoking bcfore prrgnancy w•e+ in,i);uilicant cnmliarril to that of tunoking regularly after the fotuilt uwwttth of 1,•cstation. '1'be authors concludad,'-The Qntling that a ehuuge In maternal smoking habits durinu pregnancy had the afRect uf putting llio baby iutn a birth wr.igitt and Ix•rinahtl mortality rategury awtociatnl w'ilh tltn new- amnkinl; habil.. points toward smne kiltd uf e.u+e-rlftt•t t•elaliouship. •••'1'Iti+6nding is fw•thcr strengtltened Ly fbe birth wriglit annlysis w•hit•It shows ahat tlte diminutimt ilt Lirtlt weight of Ihe oltslu•iu); of smnkin/; mnthers Itersiyls untl is imhvtl littlr 6•ltuu);e•tt wlu•n ullnu•an,•o has been mado for a uumhcr of other aocial aad obstctric tnaliating f actott" 23

f requent a mong ciga ret to smokers a s a mong none/nokers. Subacqnenl ly, IAwe (46) atudied 2,042 women in Ilinninghun, !•:nglutd, and Jem- autrate.rl in his retrospective study t}ut the iufruld of ynoking motlters were delivered uuly sJightly elrlier (1.{ days oll lhe average) than thoae of nonslnokers. Ile further noted that for gestations of 200 days and,over, ilia infanta of smoken w•ere conaistently lighter in weight rlurin/; each week of gentalion than lhoee of the nonamokers. 7'hie finding has bcen confirmed since, and figure 1 from the Hritish Periuatal ltortality Study (13) ptonWca illustration of this relatiolultip. (;iven Ille nearly constant disparity preaent between the birth we igltt s nf ilia i n fant s of smokers and nortamolce r. for geatal iou of 260 day: and over, but abseat prioe to that tlm., and given the similar birth weights of infants of nafwfokers ufd of women who gave up anulkinQ early in preRnanoy and did oot begin to nnoke again, Lowe inferred that the influence of smoking upon birth weight might lie mainly in ilia later Inon/hs of pregnancy. }L empluaiud the tentaliva nature of this conclluion, sine. the numiur of infants wi(h a 6nestation of Ino than 2t10 Ibys and the numller of wo+nen who gave up smoking early in the pregnancy uld did not begin to anfoke ag.iu were both small. ' Ftgwe 1.---Ysrn b4th w.lEht for wwk of tl+atrtlel eccofdl.g to .ate.rwal s/woh- Yme haYll: ooMnal w.k a/q/ypns.• 123 1 115 1l8 75 - -4~ .. w./~, ~° _- ~ .- fa'i~.ar.f. .~ 36 ]7 ]fa 1! 40 41 llaataUal Iw oompleted we.ks 42 43+ 2400 2150 ~ f1M 1...+ nhn Is .W1.1.w MMr M WIW= tu1/cM .a/ wd.. .ecw.Yr 1rAwa IA. wM M Y.~tl~ 3.~. ItNa. ,a ~w LcL.M/ 1. tl~. /Ir1~tlY Y.A.LIr l~r.. TA.r. .. ~ c.~yclca ~N)~~.a d./ W11r .Nlad IM Ly/.w~ ..d w.W Oc c.a1.1..M 1. 4NIW aolNlCt• saY.c. fL 1L. Aa.cft.a~ t o. U2l. Lowe found that lho infnnts whose mothers smokcd throughout prcgnnncy w•ci(;hed, nn the avernge, 170 (;rulus Icss tlhwt lllnsr+ xhoee utothcrs did not yluoku. Tn addition, lie noted that the cutiro Jistril,u- lion of weights of infants of smokers was shifted to Iho left (toward lower weights) rvlative to that for ilia infants of nonunokele. This finding, too, has heen conBruted by other invcati6ators. hi(;uro 2 oflen au illustration fronl )fucitnhoit,et al. (49). (liven that ilia infauts of smoken and nenanokero differed only slightly with respect (n ilia duration of gestation, Lowe concluded that lhe lower I/irth weight of smokers' infants ml!yt be atiriLutud to a direct retanlation of fetal growth. In other words, on tlto basis of his data, ilia infants of aulokers were amall•for-datea rather than truly premature. Many investigators )lave subsequently confirmed this point (!t, 14, LS,3S,65,78,85,11J). Iluneher (!t), in a study of 40,877 births among IfS. naval wil•es, in tito nme population studied by llndcra•aKl, et al. (lA0), found that tlro infants of ,mokers were, on ilia average, de- livered only 1 day earlier than those of nonsmokclw. 'I'his finding accounted for only 10 percent of (lie discrepancy iu birth wei(;ht Le- tween the two groups of inhnts. The remainder of llle r:tud irs rrsulted in ilia delection of cither similar variations in gMtatinnal Icngth or no avenge difRerence. In a recent study, lfulcally and Afurltlly (56), FIRw. 2.-Percuntsas didr/butlon by birth watEht of tnfants of moth.n who dld nol amoke durlnE p..Maaqr ufd of Uwse wfa amok.d l pack of ctpr.tt.a or leors per dar. 10 a 6 ~ 4 2 0 . INFANT WEIGHT AND PARFlITAL Sr<lOK1N0 HABITS A SIRTH WEIGHT (SCALE IN POUNDS: INTERVALS OF 4 02.) toU/1t0 YuY.h.w) .1 d. Nfl. . ~ 418 LZEL 0'ILTS 410

f 0 Ca1. Pelei a/ldNeowdl~.1 Dea1As : ('.nneidr.rable variation has occurred In lhe definition of the study popnlatinn among Uw dudics in which the relasionship of cigarrlte mmokinR to fetal mortality (other than abortion) and early infant mortality was examined. The most commonly idenlified study pnpula- lione have Ixcn prrinatal dcatlut, nronalal draths, and late felal plus ncnnnl a) Qra11uL 1'rri natal draUu are a oombinat ion of late fetal depths (i.e., nlillbnrn infants) and deallr occurring within the 8rbt week of life. Neonatal deatlu Include all deaths of liveborn infants within the flrst 213 days of li fo. FrtoarIotamc.L 8hversi Moet nf the earlier epidr+ninlnRical shwiks of tbe aseocial (on between cigarette smoking and Iste fetal phN neonatal mortality were reviewed in the 1071 and 1072 repnrts on the health ennlrellKnas of ImokinR (101,10L). A review of previMUJ7 unreported dudirs (B7, 78), as wr11 a.m tre:aminatinn of prrvioluly cited dudies, forms the basis of thn followinR statenxnts: The reaulls of several prnaprcii.e and telresR+edi.e stndies (ndicde a etatistically aignifiranl higlkr late fetal and/or neonatal nw+rtalitr for the infants of smnkrn rnmpared to't}nse of nonsnulkers (14. 17, tLJijt). The resulls of nllrr pe.rilxrtive and relr.>prcti.q ptlalies iden- tifiHl no aignificant diRetrnre In the mortality rates between the in- fanta of smnkers and norolmekers (W, 68. M, R6, 100, 115). If nmortalily rates were mmparrd fer those Infants of sn+okere and nensmnkers weighing leM Ihan 2I~ttt1 Rrams, /he infants of nonlanokers apparently had a coxlaidrrahl7 higher risk than did Ihnee of smokers. 'i'M rosuits of recent stluliew, coupled with a critical review of the deaign and analysis of prr.irna dudirs, and a rrr:aminatinn of e=ist- InF data, may provide at lea>tt a partial explanation of discrepancies between the resuhs of previous atLdies. t^.omp.risons of tM Mortality Risks of Low-Itirth-WriRill Infantn 11orn to Smokers and Nonsmokers The perinalal mortality riek for infants weiRllinR lese than 2;/hf1 arame appears to be lower for thene infants born to wnmcn who Rmnkn durinR pregnancy than for thoee born to nonsmokers (Iablc u• 0Z£'L OTLTS 1 f). liowever, available evidence shows that cigarette smokers' Infa tend to be arnall-for-geatalional aae rather than 6eelatinnally pre• malure. Hence, within a given birth weight group, Ule infanlr of smoken are, on the average, 6mtailonally nrore mature than lhoso of nonemokers. Data eollected by the National Cenler for i4rallh Sta- listics (10l!) dehlonulf.rate that wilhin a given birth weight gr.wp, the more geslationally mature an Infant, the lower is its mortality risk (fig. 6).'thus, the diQerenee In perinatal mottdily risks experienced by the infants of cigueUe smokers and nonsmokers, within comparable birth weight daasea, reAecta tha fae4a that the two seta of infants aro not of the aante average ge.tadonal age, and that gtotalional age is a major factor Influencing late fetal and neonatal mortality. An aceu- rate eadtnate of aanparaU.e mortality riaks for the Infants of cig- arette smokers and non.nakers reqnirea adjusfn+enl for gestational ~ For infants of cnmparalde geetational aM lower birth wright ir n..- sociated with higher mortalit7 (flg. 6). Sina ieiants of ei6aretLs emoken have, on the average, lower birth weights 1]un the Infants of nonsmokers, within /tralps of comparable gestational aqe, ei6aret.te smoken' infants should experience higher nwlrlality ratee than non- smokera' infants of similar gestational ages. In a rocent review, Meyer and Conaloek (51) provided a earo extensive discusaion of theae points. TAILS 3.-Co/%pariwa e/ fAt Oeriwalel Mat.!OrJer inJewl. wtipQiKD k,s lAaw :,600 tremb td es•okers ." Renmater. a.u...r..... 1tiWr ~~I ft" lerlV /w LM IM M.WI a.iWn N~r.a... Uader..fwd, et al. (1G0) ...................... 1!1 280 Oatarto bepaNwnest of Ilc.lli (t7) ............ 232 300 Rullaedei awd Italk. UJ) .................... 1" 13• 1LwWalUe (7e)............................. 2" fU Yenrhaloy 1 (!!tt): sa.ea weoea ............................ 11/ 202 MAne wenss. ........................... 114 as ButJer aed Atberwaa (14) .................... 9!0 284 I a4M~rW rrW..Lay,dr4dr. /fr

Flaure 6.-Neonatal mo.tally rat.s unonR sln,tla wAite blrths 1n hospitals (by det.ll.d b1Ah .elahl u+d ap.rJlwd salalron poupa: Unll.d Sta.a). 100 J/WUART I TO UARCH 31. 1950 . ~ : _ ~ ..... : : ~2aJ1 weeks ~ :% S :% % 37 weeks aid wv : 4 4 10 s : . . . t t t t t t t,. .... .. .J el ~l.i w w OtRTN 1ME/01#T (se tP+M) soUaetA u.s. nrr. w.tt• s«.hti /MtWr l:.r.. a.. N..M. ew.~ue. fta1. Recent 9tudiea T'he Ontario Perinat.l Nottality, 9tudy (66, 67) was cunducted auang 10 leaching hoepilala during 1060 and 1061. in this rrtrartuc- live study of 31,400 prcgtuncies, a statistically signiRcant increase itt the perinalal tnoMality, rate waa demonstnted for unukers' in- fants as compatrd willt thaee of nonenw+kera; tlte infants nf atunkers e:perletuyd an overall relative risk of 1.21 (1'<0.(Mtl ). Alonovcr, tha inveittiRatora found a atatidieally rigniNeant tluee-ra+POn+e relutinm,ship hetween the amount of cigarettes smoked and the perinatal mortality ryt.(P<0.001) (fig.7). F16un 7.--P.rlnatal mortality rate per 1.000 total bl.ths by clQantta smoklna category. . f 'n I a . 40 23.2 27.7 <1 pack of elprell.f yer day 33.4 Z I pack of cltarettes per day Nwnber of perinaW dealtts: 6S9 425 220 Total btrtha; 2t1,]St 1"2!! 6,981 (P <0.001) aouact: o.ts.l. o...n.,s .r tt."i tssa. Itecently IIutler, et al. (1S) further analyzed the Itritieh 1'erinatal trftort.ality Study. They found a highly significant as+ociation between maternal smoking after the fourth month of prognancy and LotL lale fetal and 'neonatal deaths. Infanti of smokurs had an incrws in the late fetal mortality r.le of 30 peroent, and an Inerease in the neo- natal mortality rate of 26 perc.nt, compared to the infantr of non- smokera. The overall mortality ratio of late fetal plus neonatal deathe was 1.2e (P<0.(101). niven the large number of women in the etudy, and the'eignificant changes in smoking behavior which occurred, they found is pouiLle,to eotuid.r the eQect, of a diango in arnoking 1 4• LV£L OtLTS y43 ../ - ~

MACARTHUR. C.. KNOX. E.G. Smoking and pregnancy: Effects of stopping at different stages. British Journal ofObsrrtrics and Gynaecology 95(6):551-555, June 1988. MACARTHUR, C.. NEWTON,I.R., KNOX, E.G. Effect of anti-smoking health education on infant size at birth: A randomized controlled trial. British Journal of Obstetrics oad Gynarcology 94:295-300. April 1987. MACMAHON, B.. ALPERT, M.. SALBER, EJ. Infant weight and parental smoking habits. AmtriconJournal oj£pidemiology 82(3):247-261. November 1966. MALCOLM, S., SHEPHARD. R.J. Personality and sexual behavior of the adolescent smoker. American Journal ojDrug and Alcohol Abuse 5(1):87-96, 1978. MALLOY. M.H., KLEINMAN, J.C., LAND, G.H., SCHRAMM, W.F. The association of maternal smoking with age and cause of infant death. American Journal ojEpidtmiology 128(l):46-55.July 1988. MANLEY. R.S., BOLAND, FJ. Side-effects and weight gain following a smoking cessation program. Addicrive Behaviors 8:375-380, 1983. MARCOUX, S.. BRISSON. J., FABIA, J. The effect of cigarette smoking on the risk of preeclampsia and gestational hypertension. American Journal ojEpidemiology 130(5):950- 957, 1989. MARSHBURN. P.B., SLOAN. CS., HAMMOND, M.G. Semen quality and association with coffee drinking, cigarette smoking, and ethanol consumption. Fertility and Sterility 52(1): 162-165. July 1989. MARTIN, T.R., BRACKEN, M.B. Association of low birth weight with passive smoke exposure in pregnancy. American Journal ojEpidemiology 124(4):633-642, 1986. MATSUNAGA. E., SHIOTA. K. Ectopic pregnancy and myoma uteri: Teratogenic effects and maternal characteristics. Teratology 21:61-69, 1980. MATTISON. D.R. Morphology of oocyte and follicle destruction by polycyclic aromatic hydrocarbons in mice. Toxicology and Applied Pharmacology 53:249-259. 1980. MATTISON. D.R. The effects of smoking on fertility from gametogenesis to implantation. Environmental Research 28(2):410-433, August 1982. MATTISON. D.R.. THORGEIRSSON, S.S. Smoking and industrial pollution, and their effects on menopause and ovarian cancer. L,ancet 1(8057):187-188, July 28, 1978. MATTISON. D.R., THORGEIRSSON, S.S. Ovarian aryl hydrocarbon hydroxylase activity and primord ial oocyte tox icity of polycycl ic aromatic hydrocarbons in m ice. CancerRrsearch 39:3471-3475, September 1979. MCCORMICK. M. The contribution of low binh weight to infant mortality and childhood morbidity. New £nglandlournal ojMtdicint 312(2):82-90. January 10, 1985. MCGARRY. J.M.. ANDREWS, J. Smoking in pregnancy and vitamin B t2 metabolism. British Medical Journal2(5805):74-77, Apri18, 1972. MCINTOSH. I.D. Smoking and pregnancy: Attributable risks and public health implications. Canadian Journal ojPublic Health 75:141-148. March-April 1984. MCLEAN, B.K., RUBEL. A.. NIK ITOVITCH -WINER, M.B. The differential effects of exposure to tobacco smoke on the secretion of luteinizing hormone and prolactin in the proestrous rat. Endocrinology 100(6):1566-1570. June 1977. MCNAMARA. P.M.. FUORTLAND, M.C., GORDON. T., KANNEL, W.B. Natural history of menopause: The Framingham Study. Journal ojConrinuing Education in Obstetrics and Gynecology 20:27-35, 1978. MEIKLE. A.W., BISHOP. D.T., STRINGHAM, ).D., FORD. M.H., WEST. D.W. Cigarette smoking alters plasma sex-steroid levels. Clinical Research 35(l):183A, 1987. MEYER. M.B. How does matemal smoking affect birth weight and matemal weight gain? Anrtrican Journal ojObsterrics and Gynecology 131(8):888-893, August 15.1979. MEYER. M.B., JONAS. B.S., TONASCIA. J.A. Perinatal events associated with maternal smoking during pregnancy. Americanlournol ofEpidemiology 103(5):464-476, 1976. 418 MEYER. M.B., TONASCIA,I.A. Maternal smoking, pregnancy complications, and perinatal mortality. American Journal ojObstetrics and Gynecology 128:494-502.1977. MICHNOVICZ. JJ., HERSHCOPF. R.J.. NAGANUMA, H., BRADLOW. H.L., FISHMAN. J. Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking. New EnglandJournol ojMedicine 315(21):1305-1309. Novem- ber 20, 1986. MOSS. R.L.. RISKIND, P., DUDLEY, C.A. Effects of LH-RH on sexual activities in animal and man. In: Colla et al. (eds.) Central Nervous System EJficts ojHypothalamir Hormones and Other Peptides. New York: Raven Press, 1979. NADLER.J.L., VELASCO,I.S.,HORTON,R. Cigarette smoking inhibits prostacyclin forma- tion. Lancet I(8336):1248-1250, June 4, 1983. NAEYE. R.L. Effects of maternal cigarette smoking on the fetus and placenta. British Journal ojObsrrtrics and Gynaecology 85(10):732-737, October 1978. NAEYE, R.L. Abruptio placentae and placenta previa: Freque.ncy, perinatal mortality, and cigarette smoking. Obstetrics and Gynecology 55(6):701-704, June 1980. NAEYE, R.L., TAFARI, N. Risk Factors in Pregnancy and Disrases ojthr Fetus and Nrwborn. Baltimore, Maryland: Williams and Wilkins, 1983. NATIONAL CENTER FOR HEALTH STATISTICS. Advancemportoffinalnatalitystatistics, 1980. Monthly Vital Statistics Report 3 1 (Supplement 8):1-S, November 30,1982. NATIONAL CENTER FOR HEALTH STATISTICS. Health promotion and disease preven- tion: United States. 1985. Vital and Health Statistics. Series 10, No. 163, Public Health Service. DHHS Publication No. (PHS) 88-1591, February 1988. NEBE. K.H., SCHIRREN, C. Statistische untersuchungen bei andrologischen patienten. Ill. Nikotin und ejakulatparameter. Andrologia 12(6):493-502, November-December 1980. NIKKILA, E.A. Is human atherosclerosis reversible? In: Miller. N.E.. Lewis, B. (eds.) Lipoproteins. Atherosclerosis and Coronary Heart Disease. Amsterdam: Elsevier/North- Holland Biomedical Press, 1980, pp. 155-164. NISWANDER,K.R.,GORDON,M. Demographiccharaeteristics. Cigarette smoking. In: The Women and Their Pregnancies. The Collaborative Perinatal Study of the National Institute of Neurological Diseases and Stroke. U.S. Department of Health. Education, and Welfare, Public Health Service. National Institutes of Health. Philadelphia: W.B. Saunders Co., 1972. pp•72-80. NORDENSON. !., ABRAMSSON. L, DUCHEK. M. Somatic chromosomal aberrations and male infertility. Human Heredity 34:240-245, 1984. OBE, G., HERHA, J. Chromosomal aberrations in heavy smokers. Human Genetics 41259- 263. 1978. OCHSNER. A. The health menace of tobacco. Medical Aspects ojHuman Sexuality 59:246- 252, November 1971 a. OCHSNER, A. Influence of smoking on sexuality and pregnancy. Midical Aspecrs ojHuman Sexuality 5(11):82-92, November 1971 b. OLDEREID, N.B.. RUI. H.. CLAUSEN, O.P.F., PURVIS. K. Cigarette smoking and human sperm quality assessed by laser-Doppler spectroscopy and DNA flow cytometry. Journal of Reproduction and Fertility 86:731-736, 1989. OUNSTED. M., MOAR. V.A., SCOTT, A. Risk factors associated with small-for-dates and large-for-dates infants. British Journal of Obstetrics and Gynaecology 92:226-232. March 1985. OUNSTED. M.. TAYLOR, M.E. The postnatal growth of children who were small-for-dates or large-for-dates at birth. Developmental Medicine and Child Neurology 13:421 -434, 1971. OUNSTED. M.K.. MOAR, V.A., SCOTT, A. Children of deviant birth weight at the age of seven years: Health, handicap, size and developmental status. Early Human Dn,rlopmtnr 9:323-340, 1984. 419 EiEL 0TLt5

1 behavior Irtween fhe IteginninR of pregnancy and llte fourth month MI late frtal and neonatal mortality. A statistically siRnifkant and d.+ee-relRtrl increass in mortality occurred among the infants of mofhers who erontimrod to amoke after the fourth month of pregitancy, as compam4l with lhe Infants of nonsmokers and Uiose of women who smoked prior to Ube pregnancy but gave up smoking by the fourth Inonth of gestation. Niswander and (lordon (8.1) reported data from' the prospective Collahor.tive f erinatal Study of (he National Inwtitute of NeuroloRi- cal Disease and Stroke. The 19,216 pregnancies reaistered at 12 uni- ver.ity hoepitals in the IlniteJ States were alenosf, equally divided bctn•ren black and while women.'I'hey found a nonsignificant im:rearn In perinatal mortality among the intants of white smokera as oompared to those of w-hite nonsawkerd; the overall erotialily ratio was 1.11 (1'>0.1). The infanta of black aaakers, howe.er, had a significantly higher mortality risk than did those of black norwrakers; the mor- tality ratio was 1.18 (1'<O.t/2). lioreo.er, a de8nits dose-response re- lationship between ciRaretles a+noked hy preanant mothers and mortality risk wasshown forblack (nfanla. Black women were noted to s,noke signilicanlly fewer cigareUe., on the acerage, titan while w-omon. ltush and Kau (8!) found, In a praepedi.e study of A,lt1A preR- nanciea followed at Ilnslon City Hospital, a nensilrnifkant increane in late frlal plus neonalal mortality rafe amonA the infants of whits wmnen who annkeil as enmparHl ln Ihnae of while nen.nnkers. Ilow- ever, the infanta of black w•nn*n who smoked had a stalietically sig- nifinnt inenase in mortality rate eompanr! to Ihe infartta nf black nibiuunnker. (i'<0.01). Thn overall mortali,y ratio fnr hl.ck women' who smoked waa 1.80. The diRerenne (n frequency of stillbirth among lhe infanta of sarxlkers and nonanwikers was Ihe primary facfor whirll cnntributed to Uie aigtnificanee of the di8enrnce in mortality rxles Analysis of Previously Reported Studies Previously repnlied studiescan lu di.ided into two Rroups: A group in which the late fetal plus neonatal mortality rates for infants born to cigarette sn.okers were aignifkantly higher than those for flie infants born to nonenwker., and a group in which no significant diRcrrneea were doleeted in the morlality rwtes for the infants hnrn to smnkers and nonsmokers. The rrsults of ae.eral studies (14, 17, !5. 0, 13. US. 84, 9t) yielded mortality rwtios ranging from 1 1R to 1.1R. The resulls of other studies (M. GS,71J.86,1tJ0, 116) yirlded mortality rwtiM ranging from l.nl tn 1.011. Rnth groups contained retrospective and prn.prcti.e sfudiro of comparable aiae. The LRo Qroupe did diRer significantly, however, with regard to control of variables other th cigarette smoking which in8uence perinalal mortality. Factors WhicJl Influence 1'er{natal Mortality Other Than 9mok;ng Dutler and Alberman (1J), on data from lhe British Perinatal Mortality Study, employed a Mgit trnneformatlon analysis of .ariance, and demonst.rafed that nlaterlul height, age, parity, social cl.a, and severe preeclampsla all had a signiflcant independent eRect, on late fetal and neonatal mortality. ILumesu-Roquetle (81) provided evi- dence Uut a pnevious stillbirth or low-birth-weight Infant signi(icantly incrr.ased Uie risk of a future etillbirth. Meyer and Comst.och (Sl) provided examples of how the dlfferrntial distribution of smoJting and other factors which aro related to perinatal mortality, in a polwlation of wolnen, ean Lisr dnts (v.g., blark w•elnr'n ha.e hiRher perinafsl mortality rates than do while women, but black women slnoke less titan whil.e women do. Nence, nonenxlkers will tend to Include more black women, and snakers more white women. This will tend to reduce any di8erenoea between the groups In nattality rstes.) Meyer and Coeletack concluded, "Comparisons of mortality rstes of emokers' and nonseaken' babie. ahould be made within .ubgrouM according to parity, socioeconomic slatus, and other appropriate risk factors, and not separated by birth welRht." In three of the tudies in which a aiRniBcantly higher mortality risk was demonatrated for Uw (nfants of smoken, adjustment for other .ariables was performed. Tba results Indicated that, after such ad- jllstment, a signifieant (ndepstldetlt association between cigarctle nnwking and infant nwKtality persisted (13 and 16, 17, 81). Of the. studies which revealed no signifkant increase in mortality risks for amokers' infants, one (115) oontrolled for race alone. Ilence, at lea.ct part of the discrr.paney in resnlta between the two groups of studie•s may he explained by a lack of control of variables ollier than smoking. Another posnible, at least partial, explanation of the discrepancy in results obtained by the two aeti of dudiea is that cigarette smoke may be more hanm(ul to the ietusea of osrtain women than othera. Several developing lines of evidence suggest that this may be the case: 1. Cigarette smoking and soeloeoonomic baekgroand. hutler, et a1. (16) noted that when data from the Hritish Perinatal Mortality Study ans Rrouped by social class of the mother's husband, the late feW plus neonatal motlality ratio for inlants of smokers and nomueoken In the upper social claeas I and II is 1.10; fJ+e mor4lity ratio for the ent ire sample was 128. Rush and Kaar (8!) reviewed the British Perinatal Mortality Study, along with ae.era) other atudiee, and noted that all have shown the stranRed association between e:eess infant mortality and clRarette smnkinR amonR the infants c! 'hoee ~M•~fa o-ri-le /71 lfe ZZ£L OtLtS

1 tiona ".ive been produeed in animais only with large doeea of nicotine (tJ, AB, 104) ; the nlevance of theee studies for humans is uncertain. SrONTAMCoUa AapeT10N SU1lY/aT Although several iaveatigators have found a significantly higher, doae-related incidenos of spontaneous abortion among cigare,tte smokers as compared to twosinoker., the l.ek of eontrol of significant variables other than eigaret.te smoking doea not permit a Rrm con- cl uaion to bn drawa about thf nature of tha r.latioaship. 8"WlrtA Epidemiologieal studies of the arociation betwean eigarette .mok- ing and stillbirth praviously raviawed ltv the 1971 and 1972 reports on the health consequenoeta of smoking (101,10d) form ths basis for tbe following st•e•......ls • Ia onf groupof rettc.peotive and prospective studies, a higher still- birth rate was found for the Infants of tskakere as compared to those of nonnookers (14, 26, 43). Ia another group of netrospective and proaieWw M.udiesy so signifleant di0ersnea was dat.etad in the still- bi rth rat& aawag the in f aats of amokus and noo.mokers (18, l0, 85, 99, !00). DiLerrroes in study ai=,a, numbers of cigarauest suwked, or the presence a ab•enoe of oontro) of variables, such as age and parity, which may influena stillbirth rates, were probably not suQieient to explain the digerertees (n results obtained. Several receat epidemiolo6ieal dudies have added to our under- standing of the relatiotnhip between cigarette smoking and stillbirth. Niawander and Gordon (GT) have reported data from 30,215 preg- nanein followed prospettively and collected between 1959 and 19tM at 12 university ho.pilals in the United States. A random sample of women wla presented to hoepital prenatal elioin were enrolled in the study. The authors reported no increase in stillbirths among white amokers as eompared with white nonsmokers. A higher incidence of stillhirths was found among black women who amoked than mong non.+mokinR blaek women, and a dcae-response relationship with rigareltn smoked was suRgnted, although the findings did nnt attain alati+tical aigniflcaner. The reailts were not adjusted for other vari- ahlea. Ruah and Kaas (8!) found, in a prospective study of 1,2t1A preRnaneiea at Ro.ton City fioepital, a nonsixnifieant increase in 43R LE£L OtLtS stillbirtha anwng wl:ite women who smoked, bul a statistically Mignifl• eant increase in stillbirths among black women who smoked ( P<O.(Yi). These findings are consistent with those previously outlined by F razier, et aI. (tS) and Underwood, el al. (90). Rumeau-Roquette (81), in a prospective study of 4,824 pregnancies in Paris, demonstrated that the risk of stillbirth was aignificantly higher for cigarette smokers than for nonsmokers (P<0.U01). The wthors also prosented evidence that a woman with either a previous stillbirth or at least one prior infant weighing less than 2,,•,00 grams at birth was significantly more likely to have a future stillborn infant than a woman without such an obstetrical hislory. After previous obstetrical history was controlled, smokera still retained a,tati.-Aically significant increased risk of subsequent stillbirth as comparod to non- smoken (P<0.U1). Of further interest was tbe finding that among women who previously had delivered only living infants, weighing over 2,500 grams, cigarette smoking had no influenoe on the stillbirth rate. Previous experimental studies were reviewed in the 1971 and 1072 reports on the health consequences of smoking (101, 1t)L). The authors demoiuitrated that exposure of pregnant rabbila to tobacco smokc and pregnant rats tc large doses of injected nicotine resulted in a signifi- eant increase in sti l lbirths (7, 8, tJ, 87). SrIuJltaT1t SUMMARY 1. The resudta of recent stadies suggest that eignrett.c smoking is naoat strong:y associated with a higher stilllsirth rate among women who I+omess less favorable socioeconomic surroundings or an unfavorable previous obstetrical history. In the United Statrs, black women have higher stilihirtlt rates tlun white women. The linding that cigarette smoking is aasociated with an even greitt.er diflerence between the still6irlh rates of the two groupec merils npecial attention. Theee findings may provide at leasl a partial explanation for Iho lack of a significant dilferenre in stillbireh rutes between smokers and nonsmokers, which sonw iuvest it;nenrv havefound. 2. The results of experiments in animals dentonvtrate thnt caxwwrc to tobacco amoke and some of its ingredients, auch as iticotine, can result in a significant increase in slill6irih rate. 439

M . i r ._ . sample of 6,Of)9 Irish mothers, concluded that although the babies Itorn to cil•errUe smokers were delivend eliR(illy earlier than thone of nonsmokers, indt•IN•ndknt of age and parity, the direct eRect of aninking in refarYiing (efal Rrow•th wasmoresiRrtificsnt '1•he folioRinR points, baned upon the rewlta from many diRerent atudicR, ran he niade abnut (he relationship between cigerrlln smoking tlnrin{; I+r.•gnant•.y and Iower infant biHh weight: 1. Women who smnke ciRarel.tes during pregnancy ha.e a higher proportion of low-hirth-wtiiRht Infants than do nonsmokers. This exe.w of low-birth-weiRht Infanta amonR elRarefte wnokers prs- dtNninanlly r.Hsada of infants who are amall-for-geetalional age rathor than R.+nlalinnally premature. 2. '1'1w, rulirr. tliHlrilwdlnn of Lirlh weigfils of the Infant.t of rica- rrUe emnkers is:hi(ted toward bwet weights compared to Ibe birih weiRhts of thelnfanb of nows.+okera 3. 7•he birth weights of the Infants of cigarette snokers aro t•on- sislentl7 lighter tha tbose of tLe infanls of nonwnoken when the birth weights of tha two eets of Infants are compared within grnsiM of similar grtatiaoal age beyond the 3llth week of gealation. The re.nlte of the studies which h..e been considered so fsr identify a relalionrhip bet.rees eiRarefle smokinR and lower infant hirih weight and illustrate some aslrods of that relationship, but do not Indicate whether Ihe awtoaiation is ea.sal or Indirect. The suerendinR two sed.ions of this chapter eonlain evaluations of the available e.i- denee which bean upon the natnree of the association between ciRar- etls smoking during pregnancy and tbe incidence of small•for-datrs infants. F.T7DENlZ 1`0! A CAL+ML AM1fK:tAt1On T1 .Rwrtlr (iloAtT.TTt .gMoitMO ANO $/[At.Lfpw-bA1ey IMrAMTf Evidenon prr.viouwl7 reviewed ln the 10'71 and 1972 rreports on the health oonsrquenoes of wrioking (101, 10l) suggpete that eirareUe aeokinR is causally associaled with the delivery of smell-for•dates infants. The followin/[ is a summaryof ehis evidence: 1. The results from all 30 studies In which the relationrhip between smoking and birth weight was examined have demonttrelyd a etr.,nR aR.ririation hefween mafernal ciR.rette smoking and delivery of low- bir/h-weight infants. (An the aeerage, the smoker has nrarly twirn the rink of delivering a low-hirih-weiRht infant ws that of a nnnninoker 1e. Lt£L OLLtS I .J, 17, t0, 98, t9,16, 4.t, 4.5, jB, 47, 49. 6'T, 68, 69, 66, 70, 7t, 73, 77,7d,10,dJ,d5,90,96,09,100,111,11d). 4. The strona association between cigarette anoking and the de- livery of amall-for-datea Infants first derrwm..trated with rnulfj from studies of tr.tros{ective design (J, 13, 17, tS. 40, 47, 49, 67, 68, 69, tld, 70.711, 73, 77, 80,85, 90, 95. P9,100,118) has been repeatedly conArmed subsequently by data f ro+n studies of prospect Le design (t0,1:6, !D, j.t, j.t, 7d, dJ,'11J). g. A strong dose-responee relationship has been established brt.roen elRarelte smoking and llte Incidence ot low-bltth-weiglat Infants (t16, 41,44,49. 100, l IJ). 4. Wheu a.arlety of known or iaaqleete4) f adnr. whlch elae exert an InAnnnce upon hltih weight heve hern rnnlrnlled for, cigarrlte amok- iug haa alwarw Iar.n drnwo to lu Itwh•prutk•utlr related to low birth Rriglrt j01,7J,7e,d-1). G. 1'Iwt awurialinn lu. IM-4•n ~Ir~wwtdrwlr.I lu many diBerruf rMin- lrirx, anrnnK diRrtent r.era and etdtutr.. atwt In diffetrut genltraphicsl srt 1 inRa (11,17, i'•S, i'9, Jr1. 0.'1.7•1.7e, >>f'),111). 0. l•rorintn auokinR t>,sea not elHw•er in intlutnre Idrlh weight it tlK nrntlkr Klt•es up /he liabit prieu• to Ilse dart of ircr preg+unt•y (ts. 7. The inf.nts of anwtkerw rapr•t3encr au reeleratnl {trow-th rsle during liut Illrl tl rnmdhs fler delltery. rwul+ered to Infants of newuatwkent Thi. MdiuK is tonitrliltle with riewinR Irirlh as fhr n- nr+cal of llte so"er s infnut fr.wn a toxie lotl1n•uee (31). Il lhda fr.wu e:hrriwrnl. In aninnls lut•e dorunrcnted that ra- Iwwtre in lolrt" iunuke or eonte of Its (nKredlrnts te.ulfs in fhr tktirerr of h+w-birth-we•i{lht u1R+hrinx (t. U, n. .o.l, 46,870. Il7). Wcertl tnrufl7 publiaird aliNlirN heve prnt•Idal atlrlilimoel sup- pnrtinR et•idrtsee for a caa.al rrL/i,Mtaiip 1.lwern eigerrlte tiIwking and p11AI1-ftw••/IatM illf.nlx T1M (1nlarin 1'r•riualal 1tl-atnlilt• Ct1MIY VY") w•.. r.yw1lM•lFl suiaifi 10 Irrt•hiua luwpitals duriuJ., 1901 aud I:MC1. "llse suflwtra of thin trt"frrfit-e Nutl-v uf W1,'..M7 Lir1ht oh•aittu- etrwlyd w Kl~nif4.nt rnerrw of inf.ulw weighiutr Irra Ihnn 1:+m 1:o*111+ suwutk ti~•en41r w~wtlrr. as raul.ernl wilh ntyumokrm (1'<t1.0111). 'virokina aa+ xigliitiraull}• deer-n•1ete.1 ln Ilw• Ix•te+•ula{.«r -of Ion•1;- uuw•irs Irriuiualiug in Ilw• tlrlivrry of a luw•Irirth-wl•i1;ht inf.nl (8a. 1). NiMw•Mnllrr alul ronlnn (P.1) hace rrrentl,r tetwrle+l deta fr.wit Ihe (`oltalwarlit•e 1`rriuatal StudC of the National inRtitlltP of KMlrO- k+gital Ilist•awt•w end ;zlmke. 14 fhin lonwlr.,4it•r ettaly of W1,:h>tt p,rg- nI1/M•M'f4 wI1M•h wele tK•arly Miudl, r dit•iAtr1 annwtR Islark aul white w•tsuN•u. fIN• atdhnrw fouud a aikuifl4•uif tlu.~••rrl.ftv) ean•t+ of Imr• bi0h-M•eight iufauta anw+ng miokcrr of Lalr qraqoe, rmtpanrl to iwnsnuokern of / loe sainr rnc•r. W i

I BirtA U'eigAl Suma+ory Cigarette Smoking and Fetal and Infant Mortality A causal a-viociation between cigarette smoking and fetal growth rctardation is sul)poeted by the following evidence: 1. Tbe retulte of all 42 atud'ee in which the relationship between amoking and birth weight was azamined have demonstral.ed a atrong as.ouation between eipretta smoking and delivery of ama11-for-datea Infanta On We average, the rnoker has nearly twtee the risk of d.lleet(ag a low-blrtb-waight Infant as that of a non.moker. 2 7bis anodation has been eooAtmed by both retrospective and proapeetive study defnpa. 6. A stroea do.e-rapooa relatioe.hlp haa been ewbliahed between eigarett..eoking and the incidaoee of bw-birLh-weight infant.a. Available evidence wiggarta that the ateet of twewkin6 upon fetal growth reaecta the number of dsarettr .moked daily during a PreguLfty, &M not the eamulative elact of eij.retle smoking which occurred before lbe pregnancy begaaa- 4. When a vatiety of known or awpeeted factors which also exert aa intluepea upon birth w.ight have been ooutrolled for, cigarette smoking has aooai.teedy b.en sbewa to be iadapetrdently related to kaw bi rtk w.i~ i. The aaaor9alSoa has beea found in many di[erent oountriea, amoo~ di[et+nt popuLtiony and la a variety of geographical "Ui&tL 6. New eadene..oggeste that if a woaua tives up smoking by the fourlh month of pragnancy, b.r risk of delivering a low-birth- weight ie [aaR i..imitar to that of a poe.enoker. T. The Il>faata of swok.rs experience a tranWnt acceleration of rrowth rate during tba t;nR 6 montha after delivery, compared to IafasiL of aoeaaiokara Tbis es,ding is compatible with viewing bitth aa tha removal o[ tb..moker'a ia[ant from a t.o:ie inAuenoe. I, I'1r rsonlte of atperltrAnta In animale have shown that exposure to tobaooo.aroke or some of ita Ingredients re.ults in the delivery .[ bw~ittJs-wwiR4~t otlspring. New evidence dama+strntes that ebronio espo.ure of rabbits to carbon mono:ide during gestation rewulta in a dowralated reduction in the birth weight of their o[spring. 9. Data from iudiea in humans have demonstrated that smokera' [stuaee are asposed directly to agents within tobacco .noke, such as earboe aoao:ide, at 1eveL ooenpanble to those which have beea shown to produce low-birth-weight otiepring in animala. 4 31% I/ 9£EL OTLZS Introduction Several previous studies of the relationship between cigarette nmok. ing and higher fetal and infant mortality among the infants of smokers havn been neviewed in lhe 1071 and 1072 rclarte on tlie'healtlt con- sequences of smoking (101, lOl). In many of these studies, the authors combined two or more categories of fetal and infant mortality. DiQer- ent mortality outcomes, such as spontaneous abortion, stillbirth, and neonatal death, are influenced by diRercnt scts of factors. Among other factors, tlie frequency of abortion is in/luenced by congenital infections, hormonal deficiencies, and cervical incompetency. In addi- tion to other factors, the froquency of slillbirth is influenced by pn- mature separatimt of tlie placenta, uterine inertia, and dystocia Along with other factors, the frequency of neonatal death is influe,icrd by grstational maturity, birth injuries, and delivery room and nureery care. Separate analysis of the relationship of cigarntte emaking to each dilferent mortality outcome, with control of the uniqne eet of facton which inAuencea it, may facilitate understanding of the relationship. Sponlmtcou. ADortiow Previous epidemioingical and experimental studies of the relation- ship between apontaneoua aboriion and cigarette smoking reviewed in the 1971 and 1072 reports on tlro health cnnsequences of smoking (101, lot) form the baeisof the follow•ingstatements: The results of several studies, both retrospective and prospective, have demonstrated a statistically aignifieant asnociation between ma- ternal eigareHe nnokinu and spmdaurnu.r alwution (4.T, 65, 70, lkl, 118). Data from some of these etudies have documented a sirong dose- response relationship between tlia numher of cigarettes smokedl and the incidence of spontaneous abnrtiona (70, 90, 118). In general, vari- ables other than eil;aretta smoking (e.g., maternal age, parity, health, desire for the pregnancy, and use of inedication), which may inlluence lhe inridcnce of spontaneous abortions, have not been controlled. The eduults of the one study, in w•hieh adjustment for the woman't desire for the pregnancy was perfnnned, indicated lhat after uuch adjuat- ment rigarctte amoking durinQ /he pregnancy retained an aesociation with sponlaneoua abortion of borderline significance (4.!). The time period dnring which cigarette smoking might exert an influcnro on the incidence of spontaneous abortions has not been deterrninal. Alxar- '•77

4 ® 'A~Nf1 VINtlOJP1Yo NiI3NtffOH 00 AN~.~~~+.- -. ... .... . ..r.N ^,SL6jTLLj 6IN1~~21~5 N ,; :•1.• f 4"91/ P- CM"" - 0:IIIO MW"N A/ AaN#2*S NaLInY " /0 0:II/O 04-n vnON Vri1 3NI/il3M ONY *NdIY•.X103 IUIY.I/ !O 1H3YYlWd30 Sfl .~~ 0 li WR1{l7I[7M U.-Iil / 4 I I I

L.ctallon /ntroduotto+. The follnwinR section ie a roview, of avsilalble evidence which bears upon any interact lros between eiRarrtt.e smok itiQ ane1 lactat inn. F:mpha- sis is rlaced u1Mn Ilte relalinnahip of riRam.tte ernoking to tlie gusntit7 of milk produrnd, to thn prrernce of conrliturn/s of ciRarrUe srnoke within lhe milk, sM to eRects upon ffie nurninR-infant meJiated through changes in either the quantity of milk available or UVe eub- etances within the milk. Bridefttolof{o.[ Strdiu Underwood, et al. (IV), in a siwly of 8,000 women from .arioia social and eronomio strata, observed adkOnite but statistically Insig- nificant tre»d toward abnre frequent inukquac7 of breast milk pro- duction among thosn smoking mothers who att.empted to norse oompared to nonamoilcrrs. 11lills (6t), in a stwly of 520 women, found that among women who Indiuted either afkein+ to nurse or no dkaire to nurse yet continued to nursu beyerud 10 days, and who had delivered their first live-born infant, the arerage period of nursing for vwU+ers who smoked was signifleai~tly shorter than for nneamokers. Noreo.er, among the 4.1 molhers who hail given up smoking during at least the Rnal 3 months of their prrgnancirs, the average length of nursing was identieal to that of the nnnsnwikers. There was no significant diflervnce between smokers and nonamoken with regard to complete inability to nurse f1eir offspring. This study is dilGcult to interpret because the author did not determine We reason(s) for the discontinustion of nursing among the women. • Eepernwenle! $tvdiu Srvdess ier Axtreu Nioot3ns Influence on the Ldation Prooess Illake and Sawyer (11) studied the innoence of subentaneously injected nirrtine (4 mg. tcdal over a 6-minute perial) upon lactation in the rat. They found that nicoline Inhibited lhe snckling-induced 131 rise In prolactin. No eRect of injectai niootine was dcmonatrat. o:ytocin secretion since milk release was not blocked. Wilson (110) examined the eRects of nicotine supplied through drinking water (0.6, 1.0, and 4.0 mg. daily) on the weight gain of nursing rats. Apparently, the nicotine had been a.ailable throughout gestation as well, because lbs authorooinmenled on a reduction in litter sire among the experimental xroups, mors or less prnportionate to the does of nicotine; hence, a prenatal etTed could noE have been dis• tinguished from a postnatal one. Average birth weight was similar for e: perimrnt al and control groupe. No 4i fTerence in weigh t gain was seen for any of tho groupe. '1'he lack of Impact on birth weight suggesb that dose was lower thaa that used in other studies. ~ Presence of NiooUne In tlw Milk Hatcher and Cr.+ahy (Z), tuilng a freig bio.asay, reported traces of nicotine In oow's milk 24 hours after We intrunuscular injection of 5.0 mg./kg. and 6 hours after the in jection of 0.6 mg /kg. Evidence foF an Effect Upon the Nursing Offspring Na/eher and Croeb7 (dtt). found that 0.6 tng./kg. nicotine injected into nursing cats had no apparent harmful edect upon Use kittena. Apparently 4.0 mg./kR. suppressed lactation. Kittens fed Use milk from the cow which Iud been Injected with 5.0 mg./kg. nicotine were also apparently unaRect.ed. Nitroeaminea Nohr (6.!) found that diefhylnitraeamine and dihutylnitroeamine, wh'n administered to laetating hamstus, were aeeociated with the development of typical traeheal papillary tumors in ltse young, aug- gesting passage of thea. oompounda in'the milk. AllhouRh diethyl- nitroeamine and dibutylnitresamine have not been identified in ciga- rette smoke, many N-nitrosaminee aro potent carcinogens, and some of them are present In eigatette.moke (J7,79). I 6roonrs tx IIo>rax. i NiooUne and/or Tobaooo Smoke Inlluenos on the Lad.ation Prcoees Emanuel (K) noted no reduction In milk prexluction among 10 wet nursca who were encoun.ged to smoke seven to 16 cigarettes daily; W I I 9fiiEL 0ZLZ5

e...ne were observed to Inhale the,.rake. Hatcher and Crosby (Jl) noted that after a mother smoked seven eigaieltra within 2 hours, it was difricult to obtain a specimen of breast milk. Perlnun, at a1. (71) found that of 55 women smokere with an adequate milk supply ai the beginning of his stwly, 11 (20 percent) of the women had an inade- quate supply at the time of discharge from the hospital. No relaion- ship was rr.ported between the number of cigarettes snaked and the likelihood of developing an inadequate milk supply.'i'he authoro' im- preeoion was that there was no grr.tar proportion with an inadequate milk supply anwmg smokera ilmn among nonsmokers, but no eor- roboraiing data wers supplied. Preeence of Nicotine (n the Milk Ilatcher and Crosby (JS) found, udna a frog bio..say, that the milk of a woman collected after she had smoked seven eigarettew in 2 hours contained approximately 0.6 .ng./liter nicotine. Emanuel (ll), using a leech bioassay, studied excretion of nicotine in the milk of wet nuraes who were encouraged to enwka for the e:perimenl After the subjects had eee~oked si: to 15 eigarettee over a 1- to 2-bour period, the author found niootins in their milk 4 to 5 hours after..aking, with a maximum conoentratioa of 0.03 asg./liter. $iedom (10) demonstrated nicotine in the milk of amolber who emoked >a0 ciganelta a day. Thompson (99') found appro:imatdy 0.1 m;./171a of nicotine Li the milk of a mother who esnoked alba cigarettes a day (phn three pipe- fub). Perlnun, at ai. (71), o.ina a Daphnia bioassay, dee+onetrated nicotine In the milk of all wosnm who emoked in tbeir study. Moreo.er, they found a direct doss-eelatiotrhip between oonoentralioa of nieotins and the number of eigarettee sewked. No coa+ment la made by the autlwra on the pos.ible inaccuracy introduced by examining only the residual milk following nursing, but it is well known that the composi- Lion of the fore milk and hind milk is diRercnt and perhaps the concentration of niootine al.o diferi E.idenoe for a Clia'scal EQeet Upon the Offspring Emanoel (t!) noted that ainong the infantn in his study, loose etoble were obser.ed only in the one whoae wet nurse had smoked 20 ciga- rettea in the previous 4 hours. IIisdonn (10) obeer.ed a cass of "nice- line poisoning" in a 6-week-old infant whose mother smokexl 20 eigs- rettes a day. The symptoms included: restlessness, vomiting, diarrhea, and taehycardia. Nicotine wu demonstrated in the milk, and the symptoms abated when smoking was stopped. dreiner (JD) also de- seribetl a case of possible nicotine poisoning in a a-week-old nurding i 1 ;a whoae mother srnoked 35 to 40 cigaret.tee a day.'I'he qmptome inetu. .omiting and looes atools. Following the curtailment of smoking, ths symptaru gradually abated over a L-day period. Perlman, et al. (71) noted no eQect of smoking on the weight gain of tlw infanta of the snwkerr (n their study. Furthermore, no untoward symptome were observed. They therefore doubted an effect of smoking on lactation. They noted that the does received by the infants was beneath the to:ia level as computed Irom adult experience, and ehie aecorded with their clinical observations. The faed that they admitted to the study only women with an app.nently adequate milk supply may have affected their resulte. The authors.y&ge.ted that perhapa the lack of eRect of smoking upon laetation might represent the development of tolerance to nioot3ne, ae both the nrotlwr and the offspring had been exposed throughout the pre{naney. VTTAMIN C Venulet (106, l08, !07), In a series of studies, demonstrated that the level of vitamin C w•as reduced in the milk of smoking mothers as eompared with nonsmokers. Ths clinical significance of this obeer.a- timn luu not been evaluated. Lsctatiow 6uaa.wyy 1. The two prrtinent epideeniological stndies eugAcatt a poeeible in- Auetxe of emoking nixn the ulehuary of milk sulqply llowever, wilh only limited numbere of women and without condrol of other potentially signilkant .ariables, no e.x0tutiona can be drawn. 2. Studies in rata have demonstrated thsi nicotine can in/erfero with suckling-induced rise In prolactin. Tlw relevance for humans is uncertain. 3. Evidence t•xists that nicotins pasats Into bteaetA milk. No clear evidenre for an acule effect upon the nursing infant is a.ailable. I'ntential ehranic eReeli have not been studied. 4. New evidena+ from expcriments with niiee auRRests that nit.ros- anunes, known Careino ,r'ena, llass thtwitCh the milk to sucklinR young. I I I " 141 £V£L OiLiS

~,

mnthe. _..ith lower socioeoonomic ststu.. Cumstock and Lundin (16) found e:oees mortality among smokers' idfants alnyodA entirely con- fined to those whose faUiers had a grammar school eduuttion or )tea. Serer.l of the etudita which rerealed no significant diRerenoe in mor- tality among the infanta of smokeet and noeusnokers were conducted in predominately middle elaam populations (L0,1IA0,1 f6). 2. CigareUe smoking atul pterioue obelatricsl e:perieeoe. 1'rter.on, et al. (7t) had rigid criteria for entry into his sludy population of 7,740 womea. }is induded only those women who pre•- .iousl7 had healthy infanta with a bitilt weight greater than 2,600 grams. lie found a significant deerease in birth weight among srnokerr' infant., but no significant Increase (. Rtortalill rate.. Aumeau- Roquette (81) found that aenong wosnea who previously had delivered only health7lnfanla weighing tnore than 9,600 graa+e, eig.ret.l.e tetok- ing was not assodal.d with aa Increased ridt of st111bir1.h; among lhou women with a previous stillbirtJt, smoking wa significantly associated with incrca..ed risk of a futant dillbirlA. 3. CigareU.e sntokittg and gMello diReresoea The consistent finding that the mortality risk for the infante of blaek smokers in higher than the risk for the Infants of white s+nokett, even when the socioeoonomio background for both is ostensibly similv, suggests that geeetio (adeis aiso snay interad with tanoiting to pro- duoe enhanced risk (d!, 09, 116). A.ailable evidence suggesta that It those women, who are already likely to have aeall infants for twsotr other than aaoitinR, smoke during pregnane7, their Intanb will be tnoslft unfavorably affected. This tneans that lhe women In the United Slales whor infants will be most affected by cigarrlte smoking are those who ha.e an unfavor- able encioeconotnio situation, ha.e a history of previously unsutxesdul prrRnancies,.nd are black Euatxzrrrat. Sivotn Studiea In Anistals Studies previously reviewed in the 1971 and 1972 reports on the health oonsequenoes of smoking (101, 10!) demonstrate that eapowre of rtibbits and r.ta to tobacco smoke and to injetiions nf large denrs of nicotine tesulted in siRnificantly increased late fetal and nronalal mortality. Astrup (t) haa reeently studied the eRect of continuous ezpnnure of ptrgnant rabbits to carbon tnono:ide on stillbirth rate*. 1{" found a siRnifiatnU7 higher, dnee-telste.l incidence of tdillhirllie and drallu within the flt+1.24 hours of life among the off.pring of Ihc expnrimental rabbits (table 4). I rAqLt 4.-rj/td e/ ererbun tMOaorutt trrn.nire of prepnant rabbi!• hirfA toripAl sad atonalal marfalitP . o..y 1 en.wt cour or.wunn ..t f. Iunn..t coub o.w t. uui~ A co~... NuoA.r ot Peepunt rabhlt.-......-.-.. I! 14 11 Tntal eumber "t b.bb ................. I Is el 123 StUl/wun .ed h.Lle+ dkd within AM 11 (.oun------------------------------ 844 (P<0.o01) $tudfu in Huasans Some investigators have e=amitteti the causes of death among the infants of smokers as compared with tltose of non,mokers. /romet.ack, et al. (17) found that infants of smokers died more frequently of as- phy:ia,atekxtasis,andimmatnrity.Kullanderand Kilkn (43) found abruptio placenlae signiAcantJy Increanrd as a cause of death among smokers' Infants. Butler and Albernun (14) found IiUle diRerence in - the death ratn fot the infants of smokers and nonemokees [ran iso- immunisatinn and malforwtationa, hut highr:r rates were found for smokers' Infant. in the Rroups in which death occurred before or dur: ing labnr, or (n which death resulted from tnassi.e pulmonary hemor. rhage, or pulmonary inftr:Eion. As the authors noted, °11+e latter three are oondit3nns known to be as.ociated with small-for-dates babies." They pointed out that disttibution of nnses of death In the smoking group eewtld be aot+ounted for alntoelt enti rel7 by t he exoeae o I low-bi rth- weiRld bahics.'i'his supports the cottehaion that the tncthanism which afRetd.s birth weight also influences mortality. StoNtl7oAlecL or t11E ANOG1A1101f The following calculation Is oRered in give some idea of the order of maRnitude of inereared latw fetal and tuonaW mortality associated w il h t igsrrl ln etnokiug durinR preirnanty. I: ( women who smnked dur- 132 ur 1l2 ~ EZEL OZLtS I

mothers with lowcr soeioeconomic status. Comstoek and Lundin (16) found e:aae mortality among amoker.' infanu almost entirely con- fined to thoee whose fathers had a grammar school education or lene. Several of the atudiee which revealed no aigniRcant digerenee in mor- tality among the infants of anokers and nonsmokers were conducted in predominately middle clam populations (g0,1/J0,116). 2 Cigaretle smoking and previous obatetricil e:perienoe. Peterson, et al. (7it) had rigid eriteria for entry into hie study population of 7,740 wotren- He ineluded only thaen women who pre- rioualy had healthy infants with a birth weight greater lhan 2,b00 grams. He found a aigniReant deeteaae In birth weight among amokere' infanta, but no cigniAeint iaereaa, in mortality ratee- Rumeau- Roquette (81) found that aaaons wmtan who pre.ioudy had delivered only healthy infanta weighing alore than 4,600 grams, cigarette aMok- ing waa not assoclated with in ineraaaed tiak of dillbirth; among those women with a previous dillbirtL, smoking wu significantly associated with increased riak of a fut.ure stillbirth. II. Cig»ette smoking and gt,netic diQereaoea The oonaistent finding that the mortality risk for the infants of black amokera ia higher thaa thi riak for the Infanta of whit. smokers, even when tJw aocioeoonomie background for both is oatenaibly similar, augaeatu that gen.tio fttetots aLo tmay intarsot with smoking to pw- duee enhattoad risk (d!, AD, 116). A.ailable evidence au#Xa.ta that if thws women, who are already likely to ha.e small infanta for reasons other than smoking, unoke during prsgdutcy, their iefantt will be ewat unfavorably affected. Thia taearts that the woman in the 1lnited States whose infants will be moet agecfed by eigarmtta anwkinR are thara who have an unfavor- able eoeioecono.aio aituation, ha.e a history of pre.ioualy unauccemful W'ettuaneie.,...d are blach. E:natKZNTAt. STontn Studies in Animals Studies previously reviewed in lhe 1071 and 1972 ref+ort-i on tlte health conaequencei of smoking (ltll,ltK) demonstrate Ihal e:pnsure of rab!>ita and r.ta to tnbaceo s+noke and to Injections of large dosca of nicotine resulted in significantly increased late fetal and neonntal mortality. Astrup (t) has recently sludied the effect of cnntinuous ealwnure of prrgnant ralibita to carlwm mono:ide on atilllpirtii rates. Ilo found a aigniAcantly higher, dnee-relatrd incidence o/ atilllsirllu and deaths within the first 24 hnurs of life among the olf+prinR of the .apsrt •I rabbits (table 4). TAaL.e 4•-E-(Jref of carbon monoride erpotine of rrcgnant rabbil, on 6irfA weigAf antl neonatal mortality a..yr 1. • ~.~ ~ou. cou. co ir i Number ef preRnant r.hbita............ 17 14 17 Total uumtier nt nabin----------------- tkllnhore and baLie, died within ent 24 110 tl 123 twun-----------------------.------ (P<0.00,) &1 Mft rl. 116 'r...L ...r..: ..uwA P. al. Sludies in flumaru Some investigalom have e:amined the causes of death among the infantt+of amokera aa compared with thoee of nonsmokers. Comstock, at al. (17) found that infants of unokers died more frequently of as• phy:ia,ateleetasia,and immaturity. Kullamler and K:Ilen (41) found abtvptio plaoentae aignificantly increased as a cause of death among .mokera' infanta. Butler and Alberman (14) found little diQertnce in the death rates for the infanta of amokers and nonsmokers fmm iso- immunisation and malformations, but higher rates were found for anwkers' infanta in the groupe in which death occurred before or dur- ing labor, or in which death residted from massive pulmonary hemor- rhage, or pulmonary infection. Aa the autLors noted, "T1ie lat.ter tiirr.e are conditiona known to be as.nciated wit)i amall-fnr-datm hahiee." T1eY pointed out that distribution of causes of death in lho smoking group could he acmwuted for almost entirely by 1 hn ezoessof low-birth- weight babies. This supports the conclusion that the mechanism which aReeta hirth weight also influcnw mortality. SION1•7CANCr. OP Tlfr: AKYM:IATNIN Tha fnllowingrnlculal ion 6 oRrrriI lo givr vqur i,leu n f tLr onlrr nf rna),ntitude of incrcascd late frtul .nd nrouulal 1norlalily n\v.w•lated with rif;aretln Nniokin}t dtu•ili); p1.-l;uunry. 1 f%cuwru w•hn Minul.•~I Jur- , :47

0 ing r/egnanc) In the Ilnited Statea had an elevation In riak of 29 per• orut for lale fetal and neonat.l mortality, as demotsalrated by I1uUer, e,t al. (16) for Jlritain, Scotland, and Wales, and if 20 pereent of prrgnant women smoked throughout the prrgnancy,' the higher risk of stillbirth and neonatal death for the infants of mothnrs who emnke cigarettes Ilurina pregnancy wnuld account for aPhrosimately 4,614 of the 87,20 stillbirth uld neonatal deaths in the United States in 11)88. LAn FrrAL Axo NeoxAru. INAr+s guYMAIT A atrong, probably eausal aaoei.llcu between dgar.tle smokins and higher late fetal and infant mortality aowna amokere' infants is supported by the followinae.idenoa: 1. Twelve retroapedl.e and proapeefl.e M,udiea have re.ealed a efa- tistieally significant nlatianhip bd..e+en eigareW amokina and an ele.ated mortality risk aeiona tha Infant. of smokers. In three of these studiea, of w6eient eise to persnit adjuetment for other risk factors, a highly aigni8eant Independent association between eawkng and mortality was establiabed. Part of the discrepancy in reenlts between these at.udie@ and tboaa ie which a aignifieant aenociation between smoking and infant awt4ality was solt dem- onslrated may be eiplained by a lack of adju.lewnt for risk faa- tora other than aarok i na. 2. Evidence is eoa.erEing to.uRged tlu! etgarette alnokinR wu.y be more harmful to the infants of aan, women than od;erst thie may also, In part, explain thi discrepancies between 0le•reaults of the d.udiee in which a significantly higher mortality risk was shown for the infants of wnoken compared to thoaa of nonanoker' and the rrsults of thoas studies in which aignifirinl diQerenoea in mortality risk were not found. 8. Within gTOUpa of similar birt]I weight., the infants of nonemokers appearto ha.e a highereartality risk than do the infants of ciga- rel.ta atrwltiera.'T11ia rawilts from the fad that the infanta of non- unoke» within sueh similar birth weight groups an on the a.erage gc.dationally les tnatnre tlun the infanls of eigarelte smokers. A.ailable evidence indicates that within groupe of sim- ilar eeatational age, infants of lower birth weight experience a higher mortality risk. Sinos the infanta of cigarette smokers are ~ a...J .~ ML.~.LIM. .f 1.1A N ~.61.o VMtW eVsfi ~rl0f MfyKr fr.~ l~. ar11W r.A.a.l Y.N.IIIr a/.47. whiN M+VVr l1.IM. fNMnaL1 NIINI.. 11/ Vfii£L OILIS j , 1 1 anall-for-geetatlonal age, one should expedd that If the infan eigar.lle amokera and nonv+wkers are oompared within aim. gedational age classes, the (nfants of oiRarette smokers would have the higher mortality rata. 4. The reaulla of recent studies ha.e documented a statistially sig- niAeYnt dose-respn/,ae relatioauhip between the number or unount qf cigarettes smoked and late fetal and neonatal mortality. ti. New data auRReat that if a wonan gives up anoking by the fourth monlh of pregnuuy, she will have the asme risk of incurring a fetal or neonatal ioas as a nonsmoker. 6. Available evidence strongly supports elguette aenokina as one cause of fetal growth relardation.'11+e causes of e:ceas deaths among llw, infants of ttnoltets are thoaa associated with amall- tor-datca Il.biey. T. 1)ata from ral+rrinwnla In animals hare demonstrated that e:po- aure to I/Aulcou lunuke or alulle of ita Inanvlienta, auch as nlcvltine or earlwn monoxide, reeulte In a sianifirant Increase In lat* fetal and or neonatal deaths. 8. The trsults of studies In humana ha.e shown that t6e fetus of a en><+kinR Inolhrr may be directly expnlyd to Wnts such as ulefinn monnxilb within lolutceq emoke, at lerels comparable to Illoee whirh have Ileen shown to produce atillbirth In experimental animala. Se: Ratio Although a number of small dudiee have found a elight, usually. statinfieally nonaiRnificanl., Inerease in tlle proportinn of female infants bnrn to,nK+kere, the Ulree largrst Mlulies of Underwood, et al. (18,505 prrgluneies), 1Tutler (16,11)1 pre4naneie.), and MaeMahon (12,155 pregnancies) have found similar infant sex ratioe among both smok- ing anll nn/latnokina mnthera, wilh lhr eallecttd aligilt e:rea" of malr amonaeach (tahle6). Srnesurp Arailallle evidence strongly Indieatre that maternal cigarette smok- InR dors not iaAlleure f he aex ratio of newborn infants. 1fO

i . TAas 8:-Proportio* ef aale infanL deli.oed to alolrirp aad now. .MOEiwp aotLra ..u.. l.r.... ~ M+1.= .N. . M a.r" /1.. r.. llsderwoee(. et al. (lOb) ................ I& 606 .61t .6111 Nosa. Butler ..d Alb.rsu (1l) .............. 11, 711 .511 .1114 Do. 1/.eNaloe, tt al. (M ................. 12. 166 .912 . e1: Do. KuU..dar.,.d xuk. Us) ............. 4 w .619 .601 Do. Rel.ke ud 11ted.rsea '(f11..-......... 3.154 .eN .617 Da Pr.al.r, et al! (W ..................... 1l trlb .41] .f06 Do. (P>0.0S) 1(le.r (!t) ............................ 1l W .502 .493 Noae. 1(t.etou. e/ al. (S) .................... 1l 116 .412 .917 Do. RaweIso(fr H at (tf) ................... La.. (1n ............................ %ta6! %M! .601 . W .631 . /lf P<0.03 No.e. Rlw.ll, et aL (p1--------------------- % talp .612 .61! De. a ahwit Women. Congenital Kalfottsution. Previous epidemiological btudiea which aiamined the relationahip between tiRaeatte unoking and congenital ealformationa wera re- viewed in tha 1971 and 1072 reports es tha health conbequenom of amolcing (101, 10t). Ra»etly, the wtlwn of the Ontario Perinatal Mortality Study (t1Q, 67.), a ratroap.diva ttadf of 61,4O0,birth., ra ported no diteraaos iA .ulfoesut.io4 rata for tha infants of tmokew.d and nonsmokers. Tbs variow.l.udies of the a..ociatioe between cigas re(te aooking and congenital eulforamtion have diQered aigni&sntly MitL regard to dudy dea'sRn, the type of population sampled, sample aisa and number of infants with >Inal[oesutioaa, the de8nition of mal- tormation, and results ( tabL 6). Previaui e:perinlsntal work was r.viewed in the 1971 and 1972 rreports on tha health ooeMequeneea of smoking (101,10R). The chick embryo haa been employed )a recent atudiaa.'1'h. direct application of nicotine to tLe ambryo re.uits ln oephalie henutanu (t8), malforma- tiona of the cervical vart.brae (93), and anomaliee of the heart (t7), depending upon does of nicotine and period of ineuhation in whieh e:po.ure oocura Anomaliea of the limbs of chicken embryns can also Ir induced hy aapowre of tsa egg to high levels of carbon monni- ide (4). 45^ ...~-J tS£L OtiLtiS 7eut.s t1-Refotiw riek of congenital mal/ormation /or in/nnte of Hparette emn!-ere anrl noannokere, compaeinp a/vilaEle ehnliea untA rrpnrrl to study de+ipn, dudy population, iample eisc, number of itlJanU witd rno(/ornlaliona, and Jr,ilrilios oJ malformation IwL.u aNa1.. Irqw. //W r VMr• afdr papalau•e a.w/J. NU rl,l W.du.. M /.dspYY ,,Y M.Uw• WMe W.WfIY1.Y W/W aN. LM1........ Sa•MM..11... elauwf pIr. bawr AL 6" a 1. Y-l.pr. aw~.. GMnMI. M.L .....ea. ........ N...Yd MMlIL ...... >pr ,f . el H.1.r. .wn .1 1»l. a..u. v..r.{.rUlo. Pn.~rMlb.... t.r.ul.., W.n r r .af uy.,. 0011, e. a.ur,. Dyb4 Ywler/M. alalM,a iplas IM- ekM 1. 1" .p rrl.l Y..W ...& A.uY rMr WI. r.l.ly eJ.aL aNW W AL .....4......... atanw.liW Mr ' 1.136 k !tl 1. N u./w. =rM N ...+. uu. ..w +.n... ~. w alalMm ob" Mf 147 u 2.36 IL.W.e...d rMp.W..... 4.M..d a.w ralY.1Y1. 4 1. MMY.. y. 1\1 e...t.y La,.r OLru tr 1.86 1. r. l. IU • a1rb.q PIr. 11.414 .MIi.M.L t10. NM~..1... ....Md 4uy 1 W6..bY •N/.'rr- N.+..•1. y. r. (W NMWdar/Y.1 .m aM..,. .Wer/. ~ ArWr/-FNr MyWtJ.rJIM MNy-n1~ ~ cr.r.r r ..L.L....,,,.r.l ......r..m Y 1. u/.). !M 1.q (ti Conyenitol Ilnl/onna[ion Sunu/lory Given the eonaidorable variation in atudy deeil,m, at.udy pnpulation, awmple aire, number of aRected infants, 4cfinifinu n( lual(nrrnalinn, and results, Iw ennclu.iuna can be drawn ahout any rclationeLip between maGernal eigaretto amoking and congouital mal(ornlation at the preaent tima 451

I habita. This would be important to know given the strong dose- rcaponse relationship which has been eetablish«i between cigarette smoking and low birth weight, and would tend to make the reproduc- tive outonmea for e=-amokers similar to those of nonanwken, and different from those of women who smoked in all pregnancies. For az-smokers, the age at which amoking began was not elicited. Hence, some of the infants of as-amok4rs may have been born before their mothers acquired tbe raoking habit. This would also tend to make the ropraluctivs a=parieuoes of a:-snwJcers more like Ihose of nonsinoken and ditaaat ftas thosa of wotrwt wLo snwkui in all pregnanciet No direct sdjusGoetit for aja, parity, and other variables was reported, altlwugb Yetvsisaimy stated tltat t6 study population was limited to the birtha that ooeurrad to woavan at age 25 years or lesa. lfe noted tbat, "In order to adjust for parity, tlrs same oomparisons were performed for Atstborn infants only. Tbe numbers were reduced oon.idarably, but tbe same tendeneiea as found above were noted " However, no data were preuatted. Primiparous births and births in teenagers are strongly aa.oeiated with tLe delivery of low-birth-weight infanta. If the prcgnabeiics which ooettrrad among future smokers included a predominanoi of very young womea and primiparoua births, t6 reproductive e:pariedcea of futttre sawkan would tend to be similar to those of wame' who smoked during all pregnancies, and di9ereat from those of nooastok.ra In the absence of anorm preeiae iwfortnatioo oa aetual tmokint be6aviotr during pregnancy and vwre rigorous adjustmcat for maternal age, tbis study does not provide a critiul teat of the bypot`esis that it is the smokint during pregnancy which is reaponsibla for tba high proportioa of small-for-dates in- fants boty to wo+oaa wbo a+mkst Brtpiswwtel $ludla 8rvorrs tx Axist.u Tobacco Smoke Several investigators have demonstrated that exposure of prefinant rats or rabbits to tobacco nnoke leada to a reduction of birth w•aght in the oQsprina, as eompared to controls (fJ, d7,117). Younacai, et a1. (117) reported data from studies in rsta which indicated Ilut some agent present in cigaretta smoke other than nicotine was reslwnsildo for the reduction in birth weight observed. The authors sugl;ested Ihat earbr-, monoxide might also not be responaible for the retardution of I I i I t fetal growth; however, the evidence presented was inadeqaate to aulkport a firm cocrlusion. llaworth and Ford (JJ) recently extended the e:per`.nenta of Younoessai. A group of pregnant rats was exposed to cigare,te tobacco snwke for 6 to 8 minutes, five times a day, from days '. :0 20 of ges- tation. These rata were compared with another group whose food intake was restricted to the amount actually consumed by lhe tobacco- esposed rats, and both were compared to a well-fed control group. The animals in both experiments were killed on the 21st day of gestation, and weights of the entire body, the liver, and the kidney of each fetus w•ert recorded. The total average fetal weight of the group exposed to tobacco smoke was significantly low•er than that of both the food-reatrieted and control groups. The fetal weights of the latter two groups were quite similar. Protein and DNA analyses were performed separately on elie entire forohraims and hindbraiiu of the fetuses and on the entire ureass. ISoth DNA and protein ivere sig- nifieuitly and proportionately reduced in the carcass and hindbraina of the animals exposed to tobacco smoke. This implies that ccll number was reduced and cell size was normal, and suggests that thc eaposure to tobacco smoke either inhibited cellular proliferation ur accelerated cellular destrudion. Nicotine Several workers have demonstrated that chronic injections of large doeus of nicotine into pregnant rats resulted in a reatuction'of birth weight of the offspring (7, B, 9, 25, 40). Other investigators havo ale- termined that tritium-IaLellal nicotine injected into prrgnant rabbits and C"-labelled niootine injected into pregnant mice ciaseod the plaoenta to the developing embryo and fetus (89, 98). Kirschbaum, et al. (41) found no significant aaite effects of small doses of nicotine, injkted intravenously into near-term sheep, on bl"l gas composition, p1I, blood prevure, or heart rate in either the ewes or their fetuses. The authors concluded that the influence of maternal smoking upon the fetus must t*sult frorn chronic effects or +.hrough the eflocts of other variables which thty did notatudy. Recently, Suzuki, et aI. (94) evaluated the e.tiort-term effects of in- jected uicotine on the cardiovascular performance, acid-base atatus, antl oxygenation of pregnant fcmale Rhesusmonkeys and their infants during eho second hnlf of gestation uaing the enothere ai their own controls. Nicotine was administered either as a single intravenotis dose of 11.5 to 1.0 mg. or as a coutinuous infusion of 100 pl;./'kg. over 41,3-e211 0-73--a Z££L OtLtS ~ 429

® ! .•: FIGURH 1.-RW/ of .clected pregp.ncy complk.- riod Noes f or .voJ<lat .nd k onunok iel raolbe n. by pd of ReaaUowal .p at dcti.cry fw A. .brvptio pl.- W.tY. A. pAO..t~ ()r7i'1.. C. p/~.tYrv NptY1. of rrabn... (PROM) SOURCB:_ ~u .l. j27). 4 ~ a." ? A ..1 i--- _ 1 a.m+ aeel 4000G aa+ 4 ,...: ... IM" . lr---TT~-T-'T II ..'M '}-~ 28 !1 ly 32 38 46 N ~MMIr•: MMY~ tA1tB 1 Aal.atd .orl.ll(y, rd ..Lli./ NNRrq aa~pllc.No.., by a.(.e..l moki.R l...1. • <I >1 f1.11s W.3f6 (11a1 f• RV+.) RMY) Rr+rJ = ..w.rr r.e.rv a~ 1... lle l+u/ AV+Mb H....Ir 11.1 f~l l~.~ ~7J/ ItiwYNwY •.l l.f 11.1 f1Jc ~rY D.rW h.1....f U1./ /lls 1M.1 ul.a ; Ry/w .f M..tw..r >~~N.r. 11A !1J l/A IN.f/ Ry/... .1 Mrtr..r O./t Y AI~W. 343 29.2 4/I 4/.16 'C.drr1 r( M.rft f.. Y.+r. 4 <0.NM1. ROURI:Rr M.fr. MJ. M d. (ft). In.t1Y Iwd (M.Y N Mf) (.Yr p.r LM. 1.1.1 klrYrl J

I [~ tlOKING HEALTH Altiuq;A' UNIVERSIFy OF J. ~ HEAUN AFFAIRS ( IUkARY MUSC--L 1 BRARY ,-a-3-2$--04 8 5 2 4 c- fHi11ur :~ report of the Surgeon General !) The Health Consequences of Smoking () The Behavioral Aspects of Smoking / f.) Education and Prevention , !i L9£L OTLtS N A+bkxor No IP/1$1 19.5,.V66 ' ~PARIMCNI QF /CAlt//, EpI1CAt/pM, yyEIFAliE c Neah sei.Jc. AW ~ ~ ~e AfsylarM Seua.rp br FMUIh S"wbp .^d 14.nh Z

e. PREGNANCY AND INFANT HEALTH. I I National Institute of Child Health and Human 99£L 0TLI9 Development

1 [.etation /wlroduotiaw TM following section Is a ro.iew of available evidence which bean upon any interaction between cii.,arette smoking and lactation. Empha- sis is plaoed upon tbe rdationsaip of cigarette smoking to the quantity of milk produced, to the presence of constituents of cigarette smoke within the milk, and to etests upon tba nursing infant mediated throufth changes in aither the quantity of etilk available or the sub- at.nces within tAe milk. g~tr.wi.Jopio.t Blt+dW Undorwood, at aL (m), in a atudY of 4A00 women from various social and eoooomie atrata, oboer.ed a definite but st.atiWtieally insig- ni8cant t{aod toward ta>ora frequent inadequuy of breast milk pro- dud.ioa aawnt those .mkilg nol1ars who atlempted to nurse compared to siounnokera - Nitla (6!), In a study of t140 woman, found that among women who indk.at.d eitber a dorire to aura or tso deairo to nurse yet continued to nursr beyond 10 days, apd who had delivered their Brst live-born Iafant, tbe average paried of aursini for rnotAen who amoked was sigaideuWy t+hodar 4+aa for taoaaewk.rs, Yoreover, among the 24 mothers who bad =i..e up .ooking duriag at laaat tha Anal s months of their pregnatade., t6o a.ersss lettgtll of nursing was identical to that of tJba aoereokas, 1'bao waa no significant diteranoa between e+nokan atsd taonassok.rs with regard to oomplete inability to nune their o[spring.ltia "y Is dilacult to interpret becausr the autlwr did not determine tlte raa.oa(s) for the dittoontinuation of nursing amoag tsa wo.w. 8.rtriswwf.180rdiu 8r[loM 1x Altttt~t. Nicotine InAuenct on the L~anlation Proaes D1ake and Sawyer (!!) studied the influence of udbcutancaisly injected nieotin. (4 mg. tolal over a tt-minule period) upon lactation in the rat 9ley found that nicotine inhibited the suckling-induced 45" ZS£L OLLiS ri*: in prulactin. No eRect of injected nicotine was demonstrated for ozytocin secretion since milk release was not blocked. 1Vilsnn (110) e:amined the efRecta of nicotine surrlieit through drinking water (0.5, 1.0, and 2.0 m6. daily) on the weighl gain of nursing rats. Apparently, the nicotine harl been available throughout gestation as well, because the autltorcommented on a reduction in litter size among tlte experimental groups, more or lcws proportionate to the dose of nicotitw; henee, a prenatal efiect could not have been dis- linguished from a postnatal one. Averagc bireh weight was similar for experimental and control groups. NodiRcrenoe in weight gain wassecn fur any of Ilte groupa 'The lack of impact on birth weight suggesta that dose wat+ lower than that used in other atudiei Presence of Nicotine in the Milk Ilatcher and Crosby (Jt ), using a frog bioassay, reportul traces of nicotine in cow's milk 2,* hours after the intramuscular injection of 6.0 mg./kt. and 5 hours after the injection of 0.5 mg./kg. Evidence for an Effect Upon the Nursing Offspring llatcher and Crosby (Jt). found that 0.S mg./kg. nicotine injected into nursing cats had no apparent harmful effect upon llte kittens. Apparently 4.0 ntg./kg. suppressed lactation. Kittens fed the milk from the cow which had been injected with 5.0 mg./kg. nicotine were also apparently unaffected. t Nitrosamines Mohr (S.!) found that diethylnitronamino and dihufyhulrneamine, when administ.ered to lactating han,sten, wero aasnciate4l with the development of typical tracheal papillary tumon in lbo ynung, sug- gesting passage of tlwte compoun.ls in'the rnilk. Although diethyl- nitrosamine and dibntytnittboamine have not been identified in ciga- rette smoke, many N-nitrnsamines are Iintent cancinogens, and some of them are present in cigarette amol•e (9T, 79). STtmars Ix IIustaxa Nicotine and/or Tol,acat Smoke Influeneo on /Iin (.actafion 1'rYteeas Emanuel (tf) notell %in rcduetinn in tuilk pr.rluclion amonb 10 wet nums who were Cncntlraged to rntoke seven to 15 cigarettes daily; 453 ,

i i I J behavior between the beginning of pregnancy and tne tounn montn on late fetal and neonatal mortality. A statistically significant and doae•relat.ed inereabe in mortality occurred among the infants of mothers who continued to smoke after the fourth monlh of pregnancy, as compared with the infants c f nonsmokers and thoee of women who amoked prior to the pregnancy but gave up smoking by the fourth tnonth of gestation. Niawander and Gordon (Q!) reported data from the prospective Collaborative Perinatal StWy of ths National ]nstitute of Neurologi- cal Disease and Stroka. The 39,215 prognaeeia registered at 12 uni- veraity hnapitala in the United Stalea wars almost equally divided between black and white•wosoan. They found a nonsignificant increase in perinatal tnortality aawng the infantA of white.nokers aa dompared to thoaa of white aonnookera; tha overall toortality ratio was 1.13 (P>0.1). The infanta of blselt wakan, however, had a significantly higher nartality r+ak thaa did thor of black aorn.wkers; the mor- tality ratio was 1.18 (P<O.tls). Moreover, a de4nite do.e-rrsponae re- lationahip betweeat eigarettee amoited by pregtuat twotbers and nwrtality risk was shown for blaeA Infada. Black women ware noted to sawke aignilinatly fewer cigarotlaay oa tLe averasa, than .•hita wo1nN6 Rush and Kar (8!) found, in a proyaeetlve study of 3,276 preg- naneies followed at Ilaaton City lfospital, a nonaigniticant increase in late fetal plua neonatal awetality rata among the infanta of white . women who airwhed as eaetpared to tbaae of white nonamokera. Itow- ever, the inlanta of Waek women who smoked had a atatist.icalty aig- niAeant increase In tawrtality rat. compared to the infants of black nuaaookers (PCO.OI). The overall mortality ratio for blaek women who raoked was 1.8t. Tbs di[erenos hs.frequeney of stillbirth among the iatanta of anwkart and nonamokera waa the primary factor which co.tributed to the aig'iAcaace of the diReranos in mortality rates. Analysis ot Previously Reported Studies Previously repotted.Wdieaean bs divided into two groups: A group in which the lata fetal plua neonatal mortality rates for infanta txtrn to eiRaretde smokers were signifieantly higher than those for the infants born to nonsmokers, and a group in which no significant diRerenoes were deteet.d in the mortality rates for the intants horn to smnkers and nonsmokers. Tbe rrwlts of several d.udier (14, 17, tS, r<t, 4.1.56, 84, D!) yielded teortal ity ratios ranging f rnm 1.38 to 1.78. The resulta of other studies (L0, 85,78, A6, 140. 115) yielded mortality ratios ranging from 1.01 to 1.1101. Roth Kroups containerl retrnsltrrtivr and prospective studies of oomparnhle airs. The two aroula di,l diffei 4t. 8V£L OTLTS signilia.nlly, however, with regard to control of variabies othor tLsn ci6wrctte unoking which influence perinatal mortality. Factors Which Influence Perinatal lfortality OUier Than Smoking lluller and Alberman (ly), on data from the British Perinatal Mortality Study, emliloyed a logit transforniation analysis of variance, and demonatrated that maternal height, age, parity, soeial class, and severo preeelampsia all lud a aignificant independent effect on late fetal and ueonatal naHality. ltu~ucau•lt~uetto (81) provided evi• d'enoe that a previous atillbirtlt or low•birth-weight infant aignifinntly increased Use risk of a future stillbirth. Aloyer and C'.omstock (Sl) provided examples of how the differcntial diatributicxt of smoking and other factors which are related to perinatal mortality, in a population of wiwnen, ean bias data (e.g., black rour.n have higher perinatal mortality rates than do white konsen, lwt black women amoke less than white women do. lfenos, nonsmokers will tend to incluJe more black women, and smokers more white w•onteu. This will tend to reduce any diQerat>ors between the groups in mortality rytes) Meyer and Comstock eoncluded, "(`,omparisons of mortality rates of smokers' and nonsmokers' babies should bo made within subgro,qps according to ltarity, socioeconomic status, and other appropriate risk factors, and uot separated by birth weigltt." In three of the studies in which a significantly higher mortality risk was demonstrated for the infants of smokers, adjustment for other variables was performed. Tbe results indicated that, after such ad- justrnent, a significant independent association between cigarette smoking and infant mortality persisted (13 and 15, 17, 81). Of the studies which revealed no significant increase in mortality risks for smokers' infants, one (115) controlled for race alone. llence, at least part of the discrepancy in results between the two groulr of studies may Ite explained by a lack of control of variablas other than smoking. Another possible, at least partial, explanation of tlw discrepancy in trMult, obtained by the two scts of dudies is that cigarette amoke may be moro harmful to the fotuafls of certain women than others. Several developing lines of evidence ui=st that this may be the case: 1. Cigarette smoking and socioeconomic hackground. Ilutler, et al. (16) noted that when data from the British Pcrinatal Mortality Study are grouped hy social elam of the mother's hushand, the late fetal plus neonatal mortality ratio for infants of smokers aod nmw;nsnkera in the npper social clas+cs I and It is 1.10; the mortality ratio for the entire sample was 1.28. Rush and Kaas (8t) reviewed the ltritish I'erina/al hfortalit.y Study, alonfi with several olher stuelies, and tinled thatAll have s,iawn the strongest asanciaiion lwtwan eseess infant jnortalify and cigarette smoking among the infants of tLoso tnJ o]an-73-•le

t 1 a 20-minuto period. The injection of nicotine in the largcr, single dose into the mother produced a rise in maternal blood pressure and a fall in maternal heart rate, and an immediate fall in both fetal blood pressure and fetal he.rt rate followed by persistent hytwtension and tachycardia in the fetua. Subsequent to the injection of 1.0 mg./kQ. nf nicotine into pregnant monkeys, in a single dose, significant changes in the arterial blood of the older fetttsrs included a fall in pit, a rise in baae deficit, and a fall In otygen tenaion. Carbon dioxide tension remained unchanged. Alieotina injected directly into the fetlu pronlpted an immediate rise in fetal blood prarura and a fall in fetal heart rate. 'Itwa reaponsea were similar to those previously uen in the mottws following a direet in f.etion of niootina The chang.ea ware morw prominent in older rather thaa in Tounpr htuses. The authors sum- marit.ed their findings by ntating tlut: (a) fetuaes In difterent grs- tatiooal et.ges an differentially reaponai.a to a given doae of nirn- tine, probably beeause of tJbla difereet stages of development of tlle autonomie nervow system; (b) diminisl+ed intervillous space per- fusion resulting from vaweonetrtetion in the uterine circulation ap- pears to be mainly responsible for the fetal aaphyxia following the injection into the mother, becauss fetal hypotenaion and bradycardia were not preceded by tha transient hypertension seen following the direct utministration of nieotine to Ula fetus; (e) the diRemluvs be- tween Ihe resulta obtained by Kirsehbaum and by Su:uki, et al. may reAeet either tha oonaiderabls dosage diffatvtoes or species diQerences; and (d) tha,dosms which the auUwn employed w+r+ much larger than thoaa which a human anothar would eb.orb from usual cigarette slnok- ing, but tbai diQerenoes in toleranea to nicotine between the Ithestls nankey and humans would imply that Uie dosages were, in fact, rnm- parabk and lhat, °Iienoet it can be envisaged that tha concentratinn of nicotine which could be reached in tbe orRanisen of a anwking reother would reduoe oxygen availability to the fetua.' 6rbon Monoxide iongo (45) has reviewed the work of several investigators a•hirh has demonstrated the tranaplacental pasaga of carbon monoxide hvw nather to fetus in animala. A recent etlNly which relatnl CO in birth weight was published by Astnlp (t). 11e found that continuolls ex- Ilosurn throut;hout gestaliml of pregnant ral>rlits to diftereW lel•els of arnbicnt carbou mnnoxide nCaultal in a statiMically siguifiraul dn.rc- r.Ltr.l reductinn in birtll .rriFllt (talde 2). Tlle actual signifir,ulre levrl was not rrlrorled. £E£L 0iLt5 Taat.te 2.-EBcel of earbon monoride espo.ure of pregn.int rabbits on birtA weigl.l 014u111 0-0 2. 4 1"wr 3. ep n.ul 0 t. h~n.. Ir u u .~...t Cb11Y CU 0116 CoI1L Numher of preanr,nt rabbita.......... 17 14 17 Tolat oumber ot habies ............... 110 dl 123 Aver.as weiaLl of l.al,ies In ar.ms..... 53. 7 51.0 44.7 tOYYe: A.Ifur. P. (e). Polycyclio !lydrocorbon. Polycyclic aromelic hy/lrocatbona (PAi/) such as Lcnzo(a)pyrene (DA1') are constituents of cigarette .moke which have hceu impli- ente.l in thegeneralion of cancers in many animal specics (Ill). No studiri presently available relate benxo(a)pyrene to a rcduetion in birUl weight of exposed oflspring. k:.idetlee suggests, however, Wat flA P does reach and erass the placenta. A ryl hydrocarllnn hydrn.ylase (AIIII) is a part of We eytoehrome P-rIS0- containing microsomal antyme system, present in many tissuea of different slbcira. This enxyme system is indueed to hydroxylate polycydic arolnntic hyllro- carbona after rxpoeure of eells to I'AI1. tieveral invcstil;alors have utilized the indncibility of Ihe enzyme syslem in deuunnstrnlte imlircclly that benxo(e)pyrelw and other Irolycyclic hyllrocarlany rcuch tlle plarxnt a and fetus. Welch, et al. (IJB) extr.nded this work by administering tlto tully- cyclic hydrocarbon, 3-methylcholanthrene (3-1IC), to rnts during late gestation. The metabolism of benzo(a)pyrene was stullieal in vivo (us- ing tritium-labellell bent.o(a)pyrene) and in vitro. A/tl1 activity was increasad in fetal livers to adult levels by prctreatmcnt with 3-AfC Sinee a relatively high dose of polycyclic hyclrncara.nu was re.luircd to stimulate enzyme aclivily in the fetos, compared to the Qoer. wllicil stimulated placental enxyme arlivity, the aatFhnrs sul:gealyd that tlle placenta may protert Ihf fcltu from exl>culuv to 1w.lyryrlir IlyIlro- earbons. Ilowever, immalority of the frtal rnxyuw+ sysirm luit:ht eIWl account for its kpp.renl rrlalive insrnaitil•ity in Iwllyryrlir hyJru- carl,one. Tllcrrfnre, an exlK..ure nf Ihe frlns to Irrrlv of IH.Iy- cyclic Ilyllra•erlwm sinlilar to lhoee rxlscriencrd by the Iuntllrr ruluuA be ruled out by tho'availablo data. iJl

I Lat. Fetal and Neonatal DcatAa Considerable variation has occurred in the definilinn of the etnily (iopulation anwng the studies in which the relationship of ci/;arelte smoking to fetal mortality (other than abortion) and early infant mortality was e:amined. The maet commonly identified study pnrula- tions have been perinatal deeths, neonatal deatlu,and late fetal phra neonatal doatlu. Perinatal deatlu ar. a combination of late fetal deaths (i.e., atillborn infants) and deaths occurring within the first werk of life. Neonatal deatly Include all deatha of liveborn infants within the firat28daysoflife. E Prowlc tas,oowar. 8rvtxM Maat of the earlier epidemiobgieal atndiee of the aseociation between cigarettaaawking and late fetal plus neonatal mortality were reviewed 1n th. 1971 and 1972 reporla on the health oonaequenoes of aooking (101, !0!). A raview of previously unreported studiei (67, 7G), as well as tft'amination of praviou.ly cited studies, fotwla tLe basir of the following atateelenb s T1.e reautts of atverel praspective and rr.trny.edive ntrwlies indieale a atatiatitally aigniReant hiRher late fetal and/or nennatal mortality for the infanta of tanokent compared to tho.e of nanaturkeri (1;, 17, t6, 41).'1'fis results of other proqreetive and rttroqwective atudiei irten- titled no significant dilfarenee in the Ir-,rtality ratea between the in- fants of t.no><ers and nonseloken (ti», Q6, 74, 86, ItaO, 115). 1f mortality raW were oontpared for thoee infaMs of anwkcra.nd nonaenoltery weighing len than $b00 jralru, lLe infants of nonsmokers apparently had aeoarirlerahly higher risk tlun did Iluroe of smokers. T1r rewilts of remet studies, eoupled with a eritieal revirr- of the design .nd analysis of previous studies, and a rrr:aminatinn of r:ist- inR data, nuy provide at least a partial explanation of disrrelurncim between the rewlta of previowu studiet Comparisons of the afoNalit,v Rieka of i.na•-Tlirfh-lYeiy ht iufnnt. 11orn to 9mokers and Nonsoinkers 'i'tvs perinatal mortality risk for infanta w-riahiug Im+ Ihnn ^_ Stxl Rrama appears to ho lower for thnre infante Irorn tn a•nmr•n %chn am"ke during preltnaney tlun (or tluae IK+ra to oonamnker.r (IaWr• 440 8EEL OILTS :f). However, available evidence shows that cil;nnette smokers' infants tend to be srnall-for-gestational age rather than gestatinnally pre- mture. 1(encr, within a given birth weight group, llie infants of amokers are, on LIin average, gestationally more matnre than thoee of nonunokert. Data collected by the National Center for llealth Sta- liatir3 (103) demonstrate that within a given birth weight group, the nwre gestationally mature an infant, the lower is its mortality risk (fig. 8). Thus, the difference in perinatal mortality risks experienced hy tlie infants of cigarntle unokera and nonsmokers, within comparable birth weight classes, reflecta the faeb that the two aets of infants are not of the same averag• gestational age, and that gestational age is a major factor influenoing late fetal and neonatal mortality. An accu- rate estimate of eom[rart+tive mortality risks for the infant& of cig- arette smokers and twnamokers requires adjudment for grstational aQa M or infants of comparable gestational agn, lower birth weight is as- sociated with higher mortality (fig. 6). Since infants ~~ cigatetta smokers have, on the average, tower birth weights than the infanLs of nonunokers, within grouts of comparable gntationa: aFe, cigarelte smokers' infants slauld experience higher mortality rates than non- smokers' infants of similar geslal.ional agea. In a recent review, Meyer and Cornstoc]t (61) provided a more e:tenaire discussion of theae points. pA pAtnp tnp~e Taa-s 3.-ComParieon of lAe per+watol erortW y Jo~J rrn 1eu fAaw 1,600 prnms, of .woakc smla .".....w..... tV%..1d .....wr ,H. Ie:Ma.... rrr Y.. YrWI a.M.n Nrr.l.n llnder«ned, el al. (100)---------------------- O.lario 1)eyr4neal ef IlealLh (I7)............ Kullander wd Kitka (43) .................... llaetrkallio (ItJ) ............................. Yenuhalmy I (1ts): Black women ........................... weue womed ........................... 6uwr .nd Allberman (14) ..................•- . a..-..+ .,m.YI .ruW r d.. edr. Ie1 260 232 300 126 tJ0 28ti 344 114 202 11t ]1e 269 2114 441

i E 1. A direct to:ic inAnrnce of constituents of cigarelte smoke upon the fetus (t, 46, 60, 6i, 117). 2. Decreascd placental perfusion (94). 3 Decreased maternal appetite and diminished maternal weight gain with secondary effects upon the fetus (C, JJ, 36, 65, 75, 99. 117). 4. A direct eQect upon the placenta (36, 67, 65, 110). S. M oxytocic effect on uterine activity (44). 6. A diaturbanceof vitamin $,g metabolism (48). 7. A disturbance of vitamin C metaboliam ( J06, I0C,107). Of the potential awh"iama, available evidence suggests that neither'decre.aed matevttal appetite and decreased maternal weight gain nor a direct aGect upon the placenta are responsible for a sig- niticant reduction in birth weight. E:iatittg evideiwa does not permit 6rm eooelusiooa eoooerniaj the rwlativa sipifxasea of the remaining merhacisma Tiwing of tAa lraifwwa of Ciyanetb Buabiwp on Birt4 1VeiyAe Several ioveaf.igaton have publiebed retulta which bear on the time period during which aapowr. to eigarette amoke most aAects fetal growUt. Low-s (4C) and Zabriskie (Ild) have ofered evidence which auRgesta that cigwrette smoking Influences fetal growtL most, during We second half of pregnancy. Ilutler, at at. (16) found that the birUi weights of infanta of women who did not smoke after the fourth month of pregnancy wer+enenUally the aatae as thoea of the infanta of aouumr>Jcera. This impliea that the inAuawoa is most probably exerted after t}* fourth month of pregnancy. Ifarriott, at aI. (36), however, found that women is lower socioeconomic classes who gave up smoking early in pregnaney tended to have interenediate weight b-bies as oom- pared with nonsmokers and parsistent wnokera, but his numbers of woman were small and the results were not statistically alviitioant. Underwood, at aL (/QO) found that ciRarwtle smoking in any sinRle trimesRar was aaaociabd with a lower birth weight of the infant, although the difference between the birth w•eiglda of infants of women who smoked only during a single trinuester and infants of non- smokers was not staJistically significant because of iunall uuuihcrn Several InvestiRators have detarte.l it nearly eonntrnt differruee 11e- tween the birth weiRhts of the infents of amnkers and nnnsulokers, delivernd during the last month of preRnanry, fnlinw-inc ftcatelinns of eomparable length (RR. 1, (!I)). Although this oheervelion is 4* S£EL OtLtS ..._..~ compatible with Lite suggealion that Lite influence of cigarette emoking upon the felus occurs prior to Lite last month of pregnauicy, it is based upon data derived from cross-sectional ratlinr than longitudin-I studies. The results of many human epideminlogicnl studiea wi66est that maternal smoking prior to pregnancy does not influance fetal weight gain (I5, t5, 46, 49,1IJ). Sils of Action at lhe Tiuive and Cellular Level The use of labelled nicotine (98) and the preparations of autoradio- grams have permitted the localization of nicotine within the tissues of the fetua and mother. Tjalve, et al. (98) found high levels of nico- tine in the reapiratory tract, adrenal, kidney, and int.cstine of 16- to 18- day mice fetuses. The use of other labelled constituents during various parts of gestation might further the understanding of how certain ingredients in cigarette smoke produce an impact upon birUk weight. Iiaworth and Ford (JJ) have reported data which suggest thnt Lite reduction of birth weight of rat fetuses caused by the -ction of the Iegredient(s) of totxceouaoke results from a reduction in cell number, but not in call aixe_ SigstilCoonu of 1Aa AuocicNon Among all women in the United Statea, cigarette smokers are nearly twice as likely to deliver low-hirW-weight infants as -re non- smokers. Assuming that 20 percent of pregnant women in llie United States smoked cigarettes through Lite entira pregnaucy (eztrzlw,lated from data on changes in smoking behavior during pregnancy collecled for the British Perin-tal•ltortality Study), taking into account the apparently different risks of delivering a am-Il-for-dstcs infsut for Caucasian and non-Caucasian women who smoke during pregnancy, and considering the number of infants with a birth weight less than 4,500 grams born to Caueaaian and non-Caucasian women, an excess of nearly 43,0p0 occurred in the 286,000 low-birih-wcight infants among the J,BQO,IXkI infants born in the 1lnited States in 19611, bceauso of the incraaasd risk among women who smoke of having small-for- datea infants. 3ince neonatal mortality I. higher for low-birth-welgth infants, with gestational age held constant, the e:oas of small-fnr-detes in fnntn among smoking mothers would imply a significant e:cess moilslity risk as well.

CONTENTS ~ . Ifllr+rlllCllflfl .............................................................. ~ IIi.U,rical Gln:illc•r:tliuna ........................................ 9 ~ ---- , jnnkin/, Ilirlh Wc1gIll, wul ficl:ll (iruwlh ....................11 ( Itirth Wt•il,•Il l ...................................................... 11 I •l at•c n l:t l Il:l l it,,v .................................................. 14 (;ca:llit,n ........................................................... 17 l (:rtlu•lh l f' 1 ...................................................... :f c 9 Inng-Tt•rm CruwlIl :In/l Ot'rt•Inlrnlt•nl ..................... 21 I:..I/• uf Maternal Weight (;ain ......... ..................... L1 F:••idcncc for Indircct AxwKinlit,ns liclwccn Smoking n nll Itirlh Weight ............................................. 26 Su m nutry ........................................................... 27 ~ Cit;arcllc Smoking and F'et.'ll luul Inf:lnt Mnrtality......... 28 ()ct•rvicw ........................................................... 28 ,l'pnnlancnus Alw,rlion ........................................... 30 I'crin:ILll Morlalily .............................................. 32 i ~ uf Ik:flh ..................................................36 ('nmlllic:lliuna uf Pregnancy and L:Ilwlr ................... 39 I'ntirl:unlx.i:f ....................................................... 4 1 i I'rn•lcrm Ik•livery .................................................•12 1'rc/;nancy Ulmldicali/•nr nntl 1'crinal:t) Mortality by (;twlntiun ......................................................... 43 Sudden Infanl Ikalh Syndrumt :...............•.••...•...... 44 Summ:lr}• ........................................................... 46 _. ' Islcl:llinn :tntl lirc:La 1•'t•tvlin~,• .........................•...........4g lnlraluctil,n ........................................................ 48 !•:I,i,lcminln~,•ical Stutlic•x ........................................ 48 F:xlwrifnenlul Stutlic-c ........................................... 49 Stu/Iicr in Animal.r ... . 49 I Nict,tinc ............... ................................... .49 Stutlica in llunfoln.r ....................................... 50 Nicotine :fnll Tul,acco Smnkc .......................5U ` - - - ----- ' 69£L OTLZS i I h)siuln~ic-ExlKrimcntal tilu,lic9 ................................. 52 Slwlic.r in Animals .............................................. 52 --3

VEEL OTLTS Schlede and Merker (8Q) have atudied the eflcct of benzo(a) pyrene administration on aryl hydrocarbon hydrozylaae activity in the mater- nal liver, placenta, and fetus of the rat during lhe latter half of gestation. The pregnant animala w-ere treated with large oral doses of benzo(a)pyrene 24 hours prior to sacriGce. Control rata had no detectable levela of aryl hydrocarbon hydroxylaee in their plaeentaa Treatment with benzo(a)pyrone resulted in barely det.ect.We placental levels on gestation day 13, but steadily rising values until day 15, and theo constant levels tLerwfter. No activity w•as delected in the fetusn of untreated oontrols. In the treated anisnala, the fetal enzyme activity rose steadily from the 13tb to tbe 18th day of gestation. The autlwre concluded that the stimulatory eQeet of betuto(a)pyrene treatment on aryl hydrocarbotl bydrozylass activity in the fetus demonstrates that benso ( a) pyrme readily erosses tAa rat plaoent a. ST4DfL tx IIOxAN Carbon Hoooside Smokers and their newborn infanta have signifiunlly elevated levels of carbon monoxide ss compared with nixunwkers and their infants (J1, 34, 88, 11Q). Recently, ltsribeud, at al. (5) studinl fi0 nnnsmokers and 27 cigarette sowkers and their newborns. All smokers inhakd. The authors found that t.he mean level of M content in the blood of non- tunokers was 0.211 volumes peroent eoml ired with 0.012 volumet per- oent in the blood of smokers. The values for blood samples from the umhilical cords of their newborns were 0.R82 and 0.04D volumes per- oant, resf,er3ively. Moreover, a definite dae relationtdrip was found between CO kvels and number of cigarettes emoked. 1'onneesai, et al. (116) found, in addition to elevated csrbosyhemo- jiobi.n levels among the iafants of ttmoldng nathers, signi6cant ebvation of mean capillary bemotocrib and signifkant reductinn of standard bicarbonata levels, as eompered to tlle infants of nonsmoking mothers. Since no evidenos for nicotine et{ects upon blond glucose, serum FFA levels, or urinary estecholamine., or for hypoxia was prtsa+t, they aoncludetd that the higher hernatocrit levels in tlre infants of nnoking tnothen may have represented a con,penaator,y rosprmse to the decreased oxygen-carrying capacity of the blood Que to the presence of carboxyl,enwRlobin. t.ongo (46) pointed nut that a level of 0 perexnt rarlaxl•hemnrlnl,in in the fetus is lhe equivalent of a 41 perrent derrennr in fetal idnnJ flow or fetal hemnglnllin conernfratinn. In reviewing (he rtuJiv.r ~if CO levels in human mothers snd thcir uer•bnrue, he u,edn thr fnilun•- i ing comments: "These samples were oLlained at the time of vaginal dclivery or ('esnrean section uid nuy not acenrately reflect the normal valnea of (Mllls), for scveral reasons. The nnmbor of eisnrettcs arnukid by Ihe mothera during labor may be less than their normal eonenmption and was not sl+ccified in these studies. The blood sam- rles were collerfcd at varying time pcriods following the ces+ation of amoking. Iu udditinn, rnsny nf tho anmhles were probably taken early in the da,y IMfnrr. Cnlxb levels had bnilt up tn lhe levels reached hor prolonged Ireriale of srnnkiu{. Thus artual luvels of (Cnllb)„ and (CU116), may be higlrer than tbo rclN+rtod values." Polycyclic Ifydrocarlans , The resutts of seversl stn<lies concur lbst cigarette smoking is stron{;ly associated with the induction of aryl hydrocarbon hydrox- ylase in the human placenta (18, S8, C1, 99, lt79). This finding implies that benzo(a)pyrene or other pnlyeyelie hyJrorirt,oru reanh the plaranta. To rlate, evidcnco to s,y+port the passage of Iwlycyelic hydro- carbons through the placenta to the human fetus has not been publi.%hed. Vitamin B„ and Cyanide Detoxification MeCarry and Andrews (48) determined serum vitamin B„ levels in 82G wanen at their 6rst prenatal clinic visit They found that the serum levels fnr smokers were significantly lower lhnn for nunemokers. After adjnstmeut fnr geststinnal aqe, parity, social class, hemoglobin level, hylrertcnsinn, and maternal weight, anokers still had signifi- cantly lower levels of I4,,. 7'hey also found a direct, statisticully sig- nificant dnee-n•slw,nsn rrlafionalrip between cigarettes arwke.l and serurn vitamin B„ level. They again confirmed the relatiunsl,ip be- twecn smoking aud low birth weight The authon auggested U,at the lowural vitanmiu I1„ levels reflect a disorder of cyanide detosifiutiun. Cyanide is a demonstrable ingredient in cigaretle amoke (39, 60, 61, 64,68,74,91). Vitamin C Venulct (lOS, 06, 107) has demonstreted that the vitamin C level is significantly lower in the serum of women who smoke cigarettes during pregnancy, compared to values for tl+e;r nonsmoking «+unter- wrta. PouiAle J/eeAos<iiau Thc fnllowing mcchattitms Itave Iroen (+rnpraed for the pratuction of low birth wright snd other unfavordds outcome. of preknancy following exfodLurt to ci6qretts emoke: 433

I i somatic cornl+laint scoro Let+coen smokere uul nonymukers. Iluwever, N•hen unokrrr were compared -itlr nunymokcrb of (I+e saiuc lurily, education, work history, and )roychoenmstic cnnil+l.int scurc, riguiruc sunokers still hsd a siguificsntly higher proportion of uuall infuulr than did nonsmukers. As proriously mentioued, w•heucver other (ncton known or sua()eettd to infl„ea,ce Lirtlt weight have beets controllal, cigarette antnking Das always been detnon.tratcd to have sit inde- renrlent anrl siMtil'Kant effect. ()un,tal (4'9) oftered evidena+ that the bent predictor of Ilte Irirth wright of a mother+s future oRspring was the birlh w•cigl+t of her previotu children. Ilerriott, at a1. (Jd) found prematurity rates for previous preunaneirs among unoken to be nurkedly higher then among notutr>.okers, indapebdent of pwity, height, and .ocial clase. F:vidently a woman whose preriotr infaats luve been amall lends to rnntinue to have relatively tnpaller tlun average infattls in subeequent pregnanciet The qtb.tioa ia, will thow intants be even smaller tl+.n e:L*<iHl if slta satokent doldstein, et. al. (l2,!), in a mmprehensire review, proposed a research design in which a.•otnan would serve as her own cnntrol to compare outcomes of pregnancies during whidl .he smoked with those during which abe rlirl Iwt with ctwulidrrstinn of the effect of parity on the outaw>,e, Yerualutlmy (!!t) has recently tested this tylro of rncaroh desigtt,usinRdata frorn hia(hkland t7rowth Stody.lYith information rwt (be agf, at .rhirh a woman IrFtn te smoke cigarettest, her smoking atatus durinA the pregnancy arifully.tudied, her prior repraluctive experience, and tbe outmme of her present preggnancy, the author enxnpared tlw outewrw of pregnancy during peiuds of smoking and nnn.mokinx using the woman aa her own control. As tlle author noted, "f t smoking ev.r.au the inrrea.e in low-birth-weight infants, then the inrirknce of low birth weight for infants born to frrnoking mothers durinx ehe period before they acquired the snwkinR habit, should he rolatively low. If, on t.he other hand, the high incidence of low birth weight is d+w+ to tlw+.mo.1-tr, then it dwuld be high for infan/s of futur, tNnokers alsn when (hey were born betore their mothers started to 'r'ke.w Yerushalmy tLen prorreckr) to compere the reprodudi.e e:periences of four groufw of women: (a) T'ho.e who tuooked in /wne of their pregnaneiee, (b) thoen wlto smoked in all of their pregnancies, (c) those who were snsnkinR now but preriously huf not smnked during some pregnancies (future annken), and (d) (hose whn were e:s smokers nnw hut had previously arnoketl durinR enme pregmancins. Theee oulcnmee aee shown !n flgttre E. The incidence of lo+.•birtlt- Reight infants in the pregnancies of the fntura smoker+f, be(oro they started to smnke, was similar to lhat for tvomrn who antnked in rcrry pregnancy, whirlt w•as si(,rnificantly ltigher thart that of infanla (rnln 426 T£EL OLLLS mnl hrrs ++'ho I+n.l nrccr SruukcA. l lc also nntcrl I lint c:-e+nokers, during the Iwrirwl Lcforc they qnit, y;nco Lirih tn +rlnlivcly fcw lo+v•Lirlh- Wright in(nnts; /hc inci.lrn+•u u'as sil;uiticuully lower than (or n+nthen whu sru.Jcrd .lurinl; ull uf thcir preguru+•its. lie ~ronclwled llint II+e findinl,y ce+wnt I+c rasil)• Ircnnrilcrl u'illt a ranra-cllccL basis for smnk- ing and bifth +cril;hl. I L• suid,'')(ethcr tlte cci.lrncn nppcnrs to sup)wtt tlro hylwthcsis Ihut lito higher incidence of lnw•-Lirth-w•eight infants is dun to 11K+ amul•er. nnt /he aisoldng." There are sxc.-ral enusideratious .chirlt Iimit the interpret.ations a•I+icl+ run br drr+cu fmw this study. Tho information on smoking Lehacior of Ihe women during past prrguuncies was apparently de- riced frout Ihc w•otnan'a age w•hen site began to smoke, her smoking behavior early iu Ihc ,turly pregnancy, and tlte age at which al.e had her prior prrt;uancics. '1'luu, if the wotnan reported that site began nmokiug nl a t.•ttrin age, snd that she wal still smoking al (he time of the+tudy, it +cay apparenlly inferra! (hst slte lud smoked during all of Iter ptrgnnncirs. 5iuce no queations wore specilically asked sbont actual rn+okiu); Ikltnvinr d+u•ing each previous pregnancy, it is possible that tlts w•owsn iudecd lisd uol smoked during every I+rrl,nuncy or that Ihe atnnmmt or +ray tJte uunked lud diffetel from currcul antokiiig F4ure S.--Parcant of low birth w1ght .RJte Infants by amoldnt status of thalr moth.n. or.V.das' smoUnt haEtls nencUa avbus n I Percent lar birth .r.laht Infanta l a a p han(durtn aM pntnancta) 5.3 2.529 g tior+anahar 91 210 t I ~ (hrture anwllu) SlflOher 8.9 2.076 I (during aM pretnancls) Smokar 6 0 .SL (ful+ue eu-s+noker) . t L__1 A 6 a 10 P.rc.nt I •blNarenca Is statlstkally slanltkinl (P <0.01). ••tNNu.nca /a statrstlcally alanltkant (P <0.02). /OUata, Ad.M•w b.M r.n..A.M.rr, 1. (tllt. 27

FIRU^111 •.-Awnh ptrtA wNQfit by m.t.rn" amo4ln M~ (a) b.bre current t~nancy and (b) durtr,g cur..nt ,•ry.tar,~y. Num6.r d cl~.r.tta/day /n cu.r.nt p..an.ncY, 3,4pp _ •fW th. touM rtwnth of a.u,uon ~ 3-100 c ~ E ~.200 . 1-4 20-30 1019 a-- 3,100 0 1-4 d ~ 10-19 20••Jp NunW.r e/ dpretts/My b./eh ow..nt WVy,acY sonwcti "''p''r"` ttusl.r,+.l aaL Total 1+4ihs: 21.671 Ertnwtw ro..x I>twnsvrAssocs.rtoN II._rrlrs>r Cm.arr: Srrosuwo •s• S1t1LLlo.-D.!!s Ir).Nr. Ysrvahalmy (I1d,114,116) hu ayggaged that smoking is an index to a particular type of reproducti.e outeoms and thus does not play a nusual role ia the p+oducitloll of amall-for•dates infanta. lle has de- velop.d aeveral linea of support for this hypotheais, from an analysis of data from the prospective jnveatigatian of 13,08,1 mothers in lhe Oskland Child Neakh Itnd I).veloptnent Study. lfe has emphasiud that inefled.is raudontization and the phenomenon of self•selection to u~4 ~e d•vebpnbnt of appropriate infel•rhuy with regard T Such di6eultlN do not pr,vent the identification of causal "OftiaUoN' but they demand careful and critical analysis of the data- Y.nuhalmy has yue.tioned the causal natura of lhe relation- ahip between ciRarett" smoking and small-for-dats Infants becauss of .(a) Tfie r.lationahlp between the smokinR hahit of the father and low birth weiRht of the Infant, (b) behaviora) differencea Iteta•ern enlokers and nonatnokers, and (c) con,parison of ths birth e•eights 424 OCEL OTLTS of r woinan's infants born during the perinds wh, n nlie sniuked ciga- rettrs and ttheu she did not. Ycivslialrny (114) Iia t:t.led thnt the smoking haLit u( tho father coul.l nul rcasnnably lie related to (lie birth weiRht of llie iufunt. b`rom preliwiuury datt dcrived front tlie siwly, however, lie dcterntiued (list thero wus rn ineteased incidence of lotc-birtlru•eight infetrts when tlte fethery unokert und, moreuver, tltel•o was an apliatrrnt dore- resronse relationship as found for matcrnal ,moking. IfoN•ever, lie noted tLat only when both the lutsb.ud aud the wife atnoked was the iucidrnce of lutr-bitilt•w•right bnlHti incrrstsetl. Ife felt tlut fhcse tindings utltlwrtcd (lie conclusion that swrol•ina Wau a ntu•krr of tl'i" of intlicidualy and not a atuial fut•tur for loa• bit•Ih weight. Other investigators have since e:eminetl this rela/ionship (I9, 1aC)), bot ueuo hns rnnfirtucd an indrlw,utlcpt nast+cialinu for Itatcrnul antoking. Tltc ucvnrialiat Isrtw•ern pefcrttal .wokiug and liirth tcei/;ht ahlr•ars to Ilo an indirert nue. I'aternal snd materuel iuunking bc- lut•inr nre highly mt•rrlalcd .rnd wutrrusl stunking iv 4tt•nn{;ly rclet(4l lo infaut bitih a•eil;ht. Ilutlcravv+ll, ct al. (/IJY)) studird 48s113 tvnmcn, thrir husJ)an•I.' s,unking Iw•havior, unrl the t.•latiou a•ilit I,itill wriy ht (taWe I). I( thn utnlhcr was a nnnsutokrr, thrn the fulher's awul•infi lurl nn influeuro at tltr Itiailt weight of tlir infant. TsMt.t 1.-In/oat birtA vrigAf 1y etnfernaf nn.f paternal lirnn(•ing 1 obite r~r.~4r M•/ d.r 1+•,r... ru.... a.•..•rw ~~....t_ .-.. ...... __-- ?kr W,u,c.................. Y1,1id1 n 0.547 3,3!M o 1 tn lo ................. 7. turj 3. 4KuI IrY/ 3.403 3, JAO 7 11 t..:lu ................ 14, 4:d! a, IINt 1110 10.403 3.391 a ................... 1.570 7, 1142 213 1,170 3.303 3 aw...: t'.dn....t..~ r. u+q. 1 rru.rluthur f.ll.i) I-lintr.l uut lhat utltrl• investigatorm lud found oiark.•.1 Jill'.•t.•u.•.w L•Iwr.n rtuokrtr un.1 wavunnkctx fu Itis otcn s1wlt•. Ile (.1utul ILa1 u.m,wnkrtw nw.1 ryulrrrrlrtitcs si},milicnnlly utnrn 1i1+ptrullr Ihfut .li.l +utnkrr+. lfunti~trr. aiFuillrautly higher Iar.qwuiinu of wwnkrtw Jriutk rnslrv• brrr, sud .rhi.kry. Il.ra•ercr, lie did u..t r41)ln.i fnr 16r,w t•nrinllirn iu Ilts atINI191111 of fllr ruwr•intion Irla.vu rI).tttillr .uu.kinl nud Inarr lufrnt I' ilih trriklcl. O/lirr in• vtsfiy!alat+ Itnrr alwt G.und dilfrrrnrr•tl Irdu•rcn awokrtw ami nnn- 6uwnkrr+. F.ir~•~umltlr, Vra'r.irt••rl nl. (:~i) f-111111I Rtgnlillran. .lilfrn•nrrs in Ihn lliatrihnlinn of lutril)•, u•ork hiatru•v, rdurufiuu. auJ•pst'chn- 425

I I (1a) (10I) (1I7) Rrtia.R R- LAre.oetw. J. T. TLe n1.UeneYlp at ertwW aed 1>•st, u.lal farlnr. le.ud.ko un.alMClyd drelY Ir Inta.rf. t:aaadtaR Ilydte.l A.rr1.1L.e Jnurnel1N: 114rt 1171. 11ef 2k IfMl (!!) Ilnuen. C. Ar11nw 1hnlnR.nl do .Mltaly dr'Ic.dlRe r.r 1'e.rYr7es de p..lrt. (Trr.InR..tk cllo. at akellw r,11Jhele er eYlct e~FYrl6,) (1M) ('...IMr. R..dw I Ie1.d.ww.A.lr.. J.+ f4awn. dr I'Arede.k dre ~{raw 1 1•): Helree.•e N.lurrllro 272//) : 171-17/1 Jaa 2'% 1971. U1) Nuaua. K.. tlueOoucu4 T.. CowAe-UuuftA. A. Q. Mutalta t1.u.ACw. e-. •IoRUa1wA. i1. 0. Ae.w.ore. K. iMarw.rokotle ef.r1 at wle.dlr upnn IAe frlwr a.d .wtYer tR IYe RM~ .ro.Yrf. Aarrte+r Je.rw.l at (I11) (f3) (1Mlrlrkr aed (IfRrr+loltl 111(11) : f002-11ot. ikt. 1L t011. Trata. M, (iirik R. U. Ar.}.td.mlelptle.ledl at p.rwtrrll). 1. RelallnN (lll) (Hf) ts r.nY/.R t.rart .d.re..ofJ.lrr.t...d 1*>•kae. ARxrlrRr Je+rR.l at OYdd rte. a.d Ulsre•ekq 11q (11) t MA••110. Telr. 1. f Ow TwicRCa (: H. /AM.AY. ('. P. PrnMRa T. l- t.rawrL A. J. Rusw- (llf) ntiw. Dt. I. AIIenller la rr}r+d.eU.e f.aeUe." ef .hlle rata a.re• elaled .ttY daul rFpewre to fkalw. Je.tu.l at PYrrraceloRl sad R:pe.le..wta1 TYe..pr.lk+ Ill: 1-10. 10/l (!1) TRewnsR. W. 1!. Nkrtlr.la be.Rl nt1t. Arerte.a J.araal e[ (%.1Hri.. lH) UR.aa.oar.P. R.. Hr.reLL L. lrrrrtR T» Jr. Orr.,, K. r.'rie rvU11ew- a.d (ilweedqtl l/1: ttl2-Mt. 1ttll. TiILs, It. H.wreew. ttt. r,owwrrw.ll.. C. (l. ParOe at "C-dc+11r. ard Ite rrlaYellle+ 1.1e a+ke teetwere a.d pl.aatsa Ael. PYRrmacd.Rk+ el Tealcolnldr. 20(0/ : 53W4Iv4 1tlK (10!) U.d Pvnio Ileuan Itanrct NAn.wAt. t2ewro roa HeAa.e er.nrac.. QelOYt.t MrtY a.d wr.1.a1 wC lYN aewferw-Ua1W Itlalek eeNS 1050. OrawY/.Rtes. U./1. IIe*.rtrrrt at He.ItY. Tdut.Har, ..d MeItere. P.Mk Hc.1fY lle.+ler Prblk.lte. NR 10tIR lteris 21. Ne. >t, J.II 1uE6. !3 pq, (101) •Aati P- Krawoattw. O. Tfe efeel .f ate.lllr M IYe tr..le nYb1t .ad Repert et ILe Aarlt..a Owr.l: 1011. waith1.RUe.. U.A. Deparlaewt et: Itee11Y, 1Cd.ratlea. sad welf.n, DHRw Psbucall.a 11.. (110Y) 11-16111. 1011, dM pp. U.II Porx Heaar. /to.res TYe t^.eeltY CeaeOOe.ew at tiwetlap. A Repert et tYe N.rRe+a Oe.rwl: 11•rt wa.ilaltf.w, tt.s. Ikprta.wt e[ Heallt. PLcelt•rti ad wA/)tre. DHRA P.Wkalle. Ne. (H!!M) 11r1610, 1012: 10A pp. 1111) tt,li Pu.ue ILaLrw IIef.MS ?1r Hr+ItY Ma.eq.uer..t <SrnA1.R. A Si/p at r.oY1RR te tYe e.tc+.w at pretwa.y. Arn1 e.. Jo:r..l .t 1)Ydefrta. aad or.feelqtf 011s) :2'1t1-tll Jes, 1u 10M Vw.aa.eM P. It. R.ata K. !, di.AwR J. H., C•utAUw. D. A. P.rr.tat ar.tlRR e..p/rtea111 nl.led t. prrpa.rl wkene. OY.le/rtce e.d O>•err.4iq 20(11 :1-ll JawrP 1N1. (1N) raast. t. Iro.ti f1. UYI/eY wlfaa+taf ee a.n.d.wY rY peddaRfeY N Mk t l Y f drrele0/af h.t.a Aa Kpr*ta..wlat M+dl. Aa.ala Hedkla.e Dzpert- raddtr rt dlelaetca h..Ite 20: 2a2-2l1. 10t11. •arw.er. T. NaMetrl...ledeY.r. .11ar1r1 e a p.ieep. (Cs..eq.e.eee at eltaad. C deltekwef Is ...tera) telaYle Aedd..r Medlcsaf wpr.elrw) 29 : !a-d0% lOfiO. .ee e .eeo r e ew a .eace e dd.laala d)r. t>tteale.K.. (/a aetd cwte.t la retYa.r• r11Y.) Atta PYydelecka Pele.k. 4 (4): 11s1- 1K 1964. •ewuttr. T. 11AwtaA A. tlpllw pakal. 1f1oa1e as psdoa .Ilamlel c w rleY• IGMec•1RC. ('1'YM IaOeeae .t /eY.eee rwoklRO ee IYe le.el of .Il.rta C la Yrn.a rtlR) Pedl.ttl. Pet.ta !tl(0) : tltf-Sit, Io68. / wtirll. IL M- t3oMMt. $., At...ap, A. P, CbRrtt, A. Ii. ERret et H& Ind+ellee e. IYe rrLYelhua ef Y.waelalrlr.re ted 7-mNYI. ra.er.e/Y~l.rlaneanl.ra.ewa la lYe prcyt.a.t aRd 1.1a1 r.L Caecw R#- morcN !2 (01 : Ori-0'te, May N112. 1Tw r. R M. tlAUleoR. T. 1!. OowwL 11. w, Ib~ P. J. tlRerM M. Cewrs.. A. It. lUl..lrt.rl efet:4 e[ elnr.tte ta.eUap w l1. Yldreall.• Un. of l.dJu*q.Tre.. sad IYe Nd..e/Yllel4r at LR.NY/l ~..eRs re/J.1M..lwa.antr.ar.e Yf roRtrea la Yro.a placwla. Cllalcal 1Myn r.c.lqtf and TYerepe«Ika 10(1):1r10••100. JRR.ary-Telnuery 1000. /1 ttAow. It. W. 'f1ee efeet at waeYlaR Ia perOrarf oa IYe Idaeeetal eoeH- e/e+t. Nnr 1Gwlaad ltedka J.eroa111( ITft ): f/t1-W.101Z 1rtR.rR IL t., 110ff)oARw, 17. 'AteY.rco aad TeYecce ltmoke. /tladlea la Raperlrewlat f2att•IRnge.Mrd. Net Terk Ae+dr.le Prewok 111117. 11t/ rp, Teauea.aM7. J. 10.4taRU1 .rtlM Iecrd+lrtY wrlltYt Yont YMoh IYNr ro/Yer. R1.r/ed t. Rnretf NgarrthK Arer4e.R Je.rrl .t l)Irtetrlee tad 111aF eetnttf 112(') :TfT-?JN, JRr I0k 101t (113) Trau.wAt.Mr,J.ltnlYer'o l4tarefleRewN/aRaMRar.l..le[IntaaLAw,eM- (11I) r.a Jnanul wf (tl./rlrkw Rad lltarenl.lp N1(1) : dOM1-11l1 1Wk 14 1064. 1'ranAUAt w.. J. NIR11.1l.wt r~ldrrrll.wr.Rd n.Iuwllna nf.IJd«wtnl.rd- erl pNde.cr. !r: J....q t7. 1Li.~«IY.I, ?. ( Ildlt.r.). TnYaec+ tad IIe.ItY. RIdRUikeld. C'YRNe. C. 7LRraw lOtt, m 201t-!>I& (llI) TrAuewAt.M.. J.1Ye re1.11.ri1r ef Par.wf.' ctRRre(1. rretInR te Ntce.w et pre¢uRC•1-trldtrrIloaR an to I/r preldem at lalenlaf tesra/lea fr.m alrrr.ed •Mnelell..a. Arer4.R Jwraal e[ 1t4olderlolntl O1)(A) : dd0•- Will. JrRt 1011. (111) TeuReRUf. l/. K. KAeto. A. Ha.oetw. J. G ClpretM weYlnf d.rfad INrR.aRef: Tb. NtM qMa IYe Iw..l.ertt aN .eld-trae brl..em et lYM R.w1«ww IafRwl. hr,la. Medle.l Aweec•1a11ea Jeurwal Otl(f): 101-Ie0l A wt. i 100Q (111) Touwo.aat, tl. K.. Pa.oae. J. Ita.earw. J. 0. Ma1 RrewtY retardel/o. • Ia nlr r:lrrwd Iw e/prr/lr wete drrtRR pntta.Rel. Arreetera Jourrel at (1lnletrte•. RRd flTwredaR! 1fN(11) : 12D1-1l1A. A.R. 111, 100. (1lAI ZA.uaus. J. R P.Reel of tylRretle RreY1R0 drrlaR prMt*anr7. 8twt1 of 2;000 e.AeR Qlr.Irlrfa rrd Ofaee+lryt! 21(1) : dttt04lt, Alw11 1003. I 140 1 1411 TVFL 0TLT5

.ome were observed to inhale the smoka. Hatcher and Crosby (Jt) noted that after a mother srrnoked seven citarettes within 2 hours, it was diicult to obtain a specimen of breast milk. Perlman, et a1. (71) found that of 55 women snwkers with an adequate milk supply at the beginning of hia study, 11 (20 percent) of the women had an inade- quat.e supply at the tilae of discharge from the hospital. No relation- ship was reported between the number of cigareties amoked and the likelihood of developing an fn.dequate milk supply. The authors' im- prmsion was that there wu.o greater pwpottion with an inadequate milk uipply among auaken than aaion~ nonsnwken, but no cor- roboratinr data were supplied. Pris.enes of Nicotine in tl,e Milk Hate]ter and Crosby (JI) tound, ustsr a frog bioasaay, that the milk of a wonua coll.ebd aftar she k+.d .mokad seven eigaratlea in 2 bours contained appruimaWy 0.!A mit,/litar niootine. Emaauel (lt), usint a leeck bio..aay, iudiad eseratioa of niootins in the milk of wet nurses who were encouraged to aewka for the experiment. Aftar the sub jects had amokd si: to 1` elaarettr om a 1- to 2-hour pariod, the aulhor found nicotlna Ir their milk 4 to 6 bours aft.r smoking, with a atuimusa oasamtratlat of O.OS tet,/1it.r. Disdos (10) damonatrated nicotin. in tha milk of a naetbar wAs tttaaked 9t) eipnttri a day. Thompaoa (97) touted appro:imut4ly 0.1 mg./lit.r of niootina in the milk of a motbar who tlleokrd dpa eiprattr a day (plus tbree pipe- fuls). Perlan:a, et a/. (71), osiat a D.pbaia bioassay, demonatrated nieotiat in tba milk of all wwnen who rnokad ln their study. Moreover, they found a ditrd dosa-tdatioeuhip between eoneantrstion of nicotine atsd tbe number of titarettes amoked. No comment is made by the authors on the possible inaccur.ey introduced by examining only the residual milk following nursing, but it is wdl known that the composi- tion of the fore milk and bind milk IL different and perlups the ooooantrrtion of niootine also diCers. Evideoos for a Clin'tcal Effect Upon the Offspring Eaunusl (tt) noted that among the in/ants in his study, loose stools were observed only in the one whose wet nurs had smoked 20 ciga- rettea in the previous 4 houra. IIisdom (10) observed a case of "nico- tine po'uoning" in a 6-week-old infant whoss mother smoked 20 ciga- rsttes a day. The symptotns included ; rwlesenesse, vomiting, diarrhea, and tachyeardia. Nicotine was demonstrated in lhe milk, and the symptoms abated when smoking was stopped. areiner (30) also de- scribsd a eus of possible nicotine poisoning in a S-week-old nursling whueo mother smoked 35 to 40 ciga rcltts a day. Thn eymrtoms inclwlcd vomiting auld looee stools. Following /he curtaihncnt of ainnking, ths symhtoiru graduslly abatcd over a 3-day period. Perlman, et al. (71) noted uo effect of smoking on the weight gain of the infants of tlte smokers in their atudy. hurthennore, nn unloward aymptoins were observed. They tJierelore doublat an effect of smoking on lactation. Tlicy uoted that thu dnu; receival by the infaida was bcncatlt the toxic level as computed from adult exlwerience, and this accorded with their clinical ofncrvationa. The fact tliut they adwittc•il to the study only wanen witll an apparently dequate milk snpply may have aRected their results. The authors suggested thnt perhaps lhe lack of effect of smoking upon lactation might represent flie development of tolerance to nicotine, as both the wotber alwl the oQspring had been exposed throughout lhe pregnancy. VITAMIN C Vuuilct (106, 108, 107), in a seriea of sf.aidien, dcmonetratod that the level of vitamin C K•aa reduced in ths milk of smoking noothcrs as oomfulred witll nnnamokert Tlse clinical siunificance of this olnerva- fion hss not beeu evaluated. Lnrloliox Swnmary 1. The two pertinent epidcmiolngica) aludica auggest a pamible in- Iluenee of tanoking ulw>n fhe adequacy of milk supply llntcever, with nnly limited nunnlwrsof wourntn anil N•ithunt enutrol of olhcr Iwtentially, significant t•ariabhY, nn conclusinus can Ikr drairn. 2. titudiea in rats havc tlrmnnatratrd I bat uicntiuc cru iutcrfa•u with sucklinfi•inQuced risr in proladin. '17ie relevance fnr hwusns is uncertain. 3. I•:vidence csi.rts tlut nicotine pns..ra into breast onilk. No clcar evideuce fnr nn acule clrr.-tt itIMn the nnraioig infnitt is availnble. I'ntrnl ial cLt•onic clfwrf n haci: nnt Ltti•n fituduvl. 4. New eviAPnfn frntll PXIMI'iIIMnIN N'illl n1iM nllgl„Tas tlint iiil.rns• nnlinM, knnw•n cnorinngriu, para fhrnuy,h Ilw+ milk In suckliug ynwnR. 454 _~ £S£L OTLTS _ 45~

I I Chapter 1 Smoking-Related Health Problems Unique to Women INTRODUCTION Smoking habits and attitudes among women and teenage girlt have differed in the past from the habita and attitudes among men and toenase boys. Women tended to smoke fewer ciWettea, were ieaw likely to inhale, and were more likely to smoke low "tar" and niur IJne and Nter-tlpped branda. Surveys have Jndiuted, however, that the smoking habits of women un becoming more like men's. Women are takln= up the habit at an tarller age and have become heavier amoken. Thia haa made them more vulnenble not only to lung cancer and other anoklnj-rolated dlaearea, but alLo to specific health problema that ue wilque to their ewt. For eumple, reaearch on the relationahip between cigarette aeokins and the outcome of pn.Vnancy has established that tbere .re definite rLks to both the fetus and the mother associated with ciprette amoklna during preVnancy. Moroover, women who use oral contraceptives aro at t;reater riak of cardiovascular disease If they unoke eiprettes. Yhero tr also evidenee that n{oottne li present In the breast milk of lactat- Int mothen who smoke. The following is a review of the current lnformatlon on these and other health conerquenoes of smoking unique to women. $FFECTS OP SMOKING ON THE OlfTC'QMB OP PR$CNANI:'Y there are definite health risks associated jith smoking and pn:p nancy, Including effects on birth weitht, p.linatat mortality, and long-term phyaical and Intellectual developpnent of the child. ThL section reviews each of theae aub)ecta and alio Invudea Infonnatlon about the likely mechanism of action of amojce and Ita contents on the mother and the products of conoepuon,'- Smokhs ewA Birth Weight In 1957. Simpaon published her original flndina that babies born to women who smoke during their pro`nancy weigh on lhe aveneo 200 gram+ (g) teu than the babies born to women who do not smoke

, Irr :,rul crrnccnlr:,limn (p:,rL. IK•r rnillion) in inxl,ir,•,I nir ....................................................................... 7 1 F'igurc 15. -Thc rlc1fmc nf crrrnl,cns:,tir,n nccccv:,ry lu ` offvcl llhc cffccl•r rif ckvul~.l fcl.rl carlwrxyhcrn, lnl,in concenlr:rtinrrv ...................................................... .. ?a LIST OF TABLES Table 1.-iiirlh weight under 2,5(X) grams by mal•crnal smoking h:rhil, relative and ullribuUiblc risks derived from published 4LulI1C4..•,.•....••.•••••••••••„••••,••,,,•,,,,•_, 13 Tablc 2.-Mcan birth weight of inf:rnt.s of smoking and nonsmoking mothers, Iry ulhcr hiulr,gric anrl socioccunrrmic faclors .................................................................. 15 Table 3.-Rirlh wci{ ht under 2,fi/)0 grams by maternal I smoking arul other f:rclnrt ....................................... ll f; 1 Table 4.-Sl,onlnncou. :rl,nrlinn.r I,y m:rl.crnal smoking habit and dcsidcrnlion of prcRn:rncy ..........................:12 Table 5.-('crinat.al mortality rutca per 1,(100 live I,irlhv Ur smoking and nonsmoking mcrthcrs, anrl relative riskx fnr infants of smokers by maternal aRc. I>Jrily, anrl yc:rrx rrf school ... .. . . . . ..... . .. . . .. . . .. . . .. . ..... .. ....... . .... ......... . .. .. . . . . :L1 Table 6.-Examples of prrinatal mortality by maternal smoking status related to other subgroup characteristics ........................................................ 34 Table 7.-Cause of stillbirth related to smoking hal,il..... 3f, Table 8.-Cause of neonatal death rclatcA to smoking habit .....................................................................4 Table 9.-Slillhirlhs according to cauu: in relation l.o maternal smoking during IrreRnancy ..........................:17 Table 1U.--Fcl:rl and neonatal deaths by collcd causc anrl maternal srnnkin{ h:Jril ........................................... 38 1 , r T~I I,I.-I'crinaUrl mr,rlalily :rnrl xclcclcrl prc{tnancy ~y,nyJiralion.v hy maternal .mukin{; Ievclx ................... 40 i,,IJc I'1• pcl:rI urul ni•rrnnU,I rlculhm I,y matcrnnl nrnukin/,• I nlhrr cr«Icrl cunrlitiun.r ....................................... 4 l 1i1 I' .l I'rclcrm births hy mnlernrJ smuking h:rlril, n•lati~c :rnrl :rtlrihut.•rhlc riAv, rlr•rivcrl from Iwldishcrl ~l ............................. a u~) i~•a ................................... i;,blr 11• The n•hrlirm of lhc concentrations or fetal to n,;,l,•rn:rl carlw+xyhcmrr{ Irrlrin in mothers who smoke ,hrrinl: pri•y;nancy ................................................... 72 8-6 TLEL OZLtS

• '! . . 6.-Proportiow eJ ntale inJonb d.lisered to siwokuy aad waw- nnol•inp /noGlcrs . er..r khall Arb... wA..rr r„e,,,.r„ aair. N... r.hw .w~~,. .,.. underwend, et ai. (rOt71 ................ 46, 603 .518 .{1• No... Butkr and Albennan (14) .............. 1i, 7s1 . 61e , il• be. MaeMahne, et al. (4% ................. 12, IU .313 .312 Do. Kullander vwt KUka (18) ............. A. 3A,1 .519 .801 Uo. /ieinka awd Ilenderrr '(7P).......-...- ! 16s ,{4A .617 bo. Fnai.r, el al., (ls)..................... 2.913 .47! . 60S [lb. (P>0.03) Kleer ............................. ! 068 60! .403 Now.. Herrintt, et tl. (3J) .................... 2.745 . N2 .117 IM. R.venAAt, .l al (77) ................... 7 052 . 601 .{33 P<0.06 L..~we (tq............................ ;MS .632 .929 Noeme. Ru.wA, et d. (lM ..................... !, 6Q! .613 .613 Do. I al.dv...., Cot~enlta~ Mdfa~t~tatioa. Pre.iotu epidemiologiea) stadies whklt a:anlined the telationahip between eiRatdts smoking and congenital eulforsutions were te- riewed in the 1971 and 1272 reporfe on the health aonsequenoes of smoking (101, 10a). R,eoently, the auttwts of the Ontario Perinatal ktortalit7 Study (6Q, e7), a retroapedi.e study of 51,190 bir4hs, re- ported no diterenes in malformation rate for the infants of smokers and nonsnwkets "['!le rariwr a(atdies of the aesoeiation belween eig.. rctts smoking and congenital aulformation have differed siRniflnntly with rrRard to r.udt desiKn, the type of pnpulation aampMd, sample size and number of infants with aulformations, the deflnition of inal- formation, and results (labk a). Pm.ioua a:perimental work waa reviewed in the 1471 and 1972 trports on (ha health eonuertoes of sutokinR (101,10t). The chick embr" haa been employed in reoant studirs.'T'he dired application of nicotine to tlre embryo tesulls in cephalia hematoe+us (tB), malfortna- tions of t!w cervical .ertebraa (8J), and anomalies of the heart (!7),• depr.nding upon dosa of nicotine and period of incubation in which e:posure oecurs. Anonuliea of the limbs of ehicken embryos can also be induced by e:posure of the egg to high levels of carbon mono:- ide (J). 136 Sii£L OTLTS I •[AaL d.-Itelalia ri.k eJ esltpexifal alal/onnalien Jor InJonl/ eiyard(t setokers and wateae4ers, eoMtpari/ty arailoAle ehrdi.e vw..." reDanf le seudy deriys, study p"WId". sa+Nplt ate, aurakr of .Iniliew of etalJonna(ion infanh +oilk ntalfennalie/1i, sxd de ~ . sWrA.sM. M.et r~.IrlMa a+~W ./1L !tw IN.Mr. Wlnr A.r n.a./u«.f WMA O.Y.rIM.. t.... tMf........ iM.w.lM. a1aM. 0- fLArr t Nf A 1. M 14Jn. &W&bL c.r/nA. M d. .....1.......... N...nw Arllr....... ar n a N./r..ra .t un. A.If. • 7...di.l.rd/A. Pny.ruw... (.1r1.IrMr so a Nd.. . . 1.W e. o.ww dwt. aw.w•eu... susw W. Lw- u.w I.~w n .w. N.w. «.....w w tnt. . wrd.w Lra. a.ur.aAAL ..... 4......... Malb..W.... /./fl . t,M1 LN N.6n.rr.f Lua w.r Ut/. wr 4wtr . 1./ Ne/y n, Ay...o 1n d 1.2 1 ..W Mlar w•~~ N./Y wP/W c.roA....e ' Mdr11rYy. nd1 .dW. Iua..lYl. 1. . . ' MansMrf 1.~.Y lMr /Y LM YwL ~tJ a MWr. Mr tt.er r 1.« Ih. ....YdM.1Y~ M., 4 .w. :.'( •061*01.+41. ..b...".t..~r~.I : u,,. 1. M Nw.YtMMIrI f.en fN 1.w M. i ~ ~ I I r. i s ~ A.NMri-ft, -NrMV arAlr rlbrlim- ~ c11.la.r•r..1... 1 ..N•rd rnA...... Congesilol Afal/onnnliow Suramary Oiven the considerable variation In study design, study population, wmlde size, number of aReeted infants, de8nitinn of /naiformal.ior,, and rrslllts, no cnnelNSiona can be drawn about any rrlationship between maternal cigarette smoking and congenital malformation at the prtunt time. 1» ,

in a aample of 6,090 Irish mothers, concluded th^t aithough the babiee born to cigarette amoken were delivered eiighlly earlier than those of non.amokeM independent of age and parity, the direct eflect of sn+oking in retarding fetal growth was more aitii+ificant. The following fwinta, baaed upon the results from n+any difTerent studies, can be made about the neletionship between cigarette smoking during pr•egnancy and lower infant birth weight: I. Women who amoke eigarsttes during pregnancy have a higher proportion of low-birW-weitht inf-nts than do nonsmokers. This e:cess of low•birth-weit6t infants among cigarette smoken pre- dominantly consisla of infants who an Wu))•for•gestitional age rather than gcatatioaally ptamature. 2. The entire distributiow of birth weights of the infants of eiga- rette amoltera is altifted toward lower weithL compared to the birth weightsof the infantsof nonsookacs. 1 The birt- weighta of the infants of eipretle smokers are con- sistenUy lighter than tbosa of tbe infants of nonsmolcen when the bitth weights of the two eeta of Infanta are compared within groupi of similar gastatiaeu-1 ap beyond the bbth week of test+Uan- 'I1+e rwlts of the stndies wbieh have bean ootuidered so far identify a relat+onship batw.ea cigarette smoking and lower Infant birth weight and illttstrate tloen aspeds of that relationship, but do not indieate whether the asweiatbn b eauul at Indirett. The succeeding two sections of this ebapter coetain evaltutloes of the available evi- dencs whiei been upon this natrra of the ^eso lation between cigar- etle smoking dnri,ret pt•atnaney and the Inr3denee of amall-for-dates infaata Evmawta FOR • Cavua A,eoea.ttow Ilel•rwsex Ctaaasrrs Sxottxo •ND .gleALL•!'oel-DA7eY 1MZrA11Tf Evidenee previously reviewed in the 1971 and 1072 reporta on the health oonsequencte of smokint (101, 10t).suapteats that ciAar•ette sau,king in causally associated with the delivery of small•fnr-dates lnfanli. The following is a sutnmary of this e••idenee: 1. The results from all 20 stwlies in whielt Lite relationship belween smoking and birth weight was examined have demnnUrated a strong u+ociation between maternal cigarelte smokinR and drlivery of lotr- birlh•weight infants. On the average, the smoker has nearly twice the -isk of dalivering a bw•birlh•weight infant as that of a nnnemnker 420 BZEL 0iLT5 I i (J, 13, 17, t0, M. t9, 35, 41, 43, 48, 47, 49, 67, 58, 69, 65, 70, 71, 7.1, 77,78,80,83,85,90,95,99,100,113,118). 2. The strong association bet+ceen cigarette smoking anti the de- livery of small-for•datetl infants first demonetrated witl+ multe from studity of retrorpective design (3, 13, 17, 35, 46, 47, 49, 57, 68, 59, 65, 70, 7t, 73, 77, 80, 85, 510, 95, 99, NJiO, 118) has been repeatedly confirmed sulbcquently by data from studies of prospective design (L'0, t5, t9, 4t, 43,78,83,113). 3. A strong dose•responee relationship hns been eatahlisl+ed betwcen cigarette smoking said the incidence of low-birth-weight infunta (25, 43, 4P, 49,100,11.t). 4. When it variety of knotrn or utlpectr.l frctors which Also esat u+ influence upon birth weight have been cnntrnlled for, cigarelle smnk- ing has always been shown to be iudrpeudrutly relatcd In low birth (l,I9,2S,~3,~R,71,78,8J). weight b. The acux•iation has Iw•t•n tletnnustratetl in many diRen•id roun- Irits, an+m+g+lilfrirnt raccx and cuitun•y, an+l iu diffrtrnt ),rr+);rrt.l+iruI settings (1.1, 17,=5,:9,Jl:. I1J). 0. 1'ret'IMIM UUnklng +1+My not rplMar to inllueurc k,irll+ +triF6t if the wnlher gives up Ilio hal,it I+rior fn the atatt of hrr 1+rcgnrnry (:-i. 4O.d9,11J). 7. The infrutt of sna.kers exlr•.rienre an urcelrrafed l;ro++th ratr duriug the lir,4 0 wmdlu after ilelit'ery, rompared to iofruM of nmu.tnnkrnt. This flniliug in conytatiblr w•ill+ t•ien'ing I+irili as the n•• nwcal of Ibe iunokrr i iuf:wt fnnu to toxic inllurucc (9)). K 1)rla frnn- !X(MI'It11r11fY ia animuls ILr+•r doc+uue+NN•.l 1111+t cx- lrw:urv in tnt+a.v+ vwukr ur Mnnc at ilr Ingr!((Irllt9 +euuke in Il+r drlicrrt' uf l.+tr•Lirfh-wrigLf olta+rin); (7, S. !/, :V, {O, V. 117). `).rrral trrrutlv pul.li~hwl -fn.li.w hatu I.+nt'idcd ml.lilinunl >ul+- Ix+rtinR et•iilrnre for a cuuaal nlrlinnd+it- Ia•Iw'rrn ciy;en•Ile Nnukiul; sltd wurll•for•tlrt+w iufnut.4. The (hntnri.t I'rriuatrl \I~++lnlilc `1u.lr (/JI) a:+r waulu.I.rl ntuot+g Itl Irurhinl! Iurl.ilals tlurinl; 19fal ruJ I:M"1. The uutl+rnA of Il+ir tr t tre•Iwr l it o el ud c of :d1rNIT Li+16i Jr+m.n • arrlt.( at xil;nifi.•rnl rxrr.r uf iufr111+C trelghi119 IMyI (Ik:UI '~,:•~M~ ):I•+Un~ a11Mng rigcur•Itr Nn..krr.r an r•nuyn+Irtl uilih u+r+aauoke+v (1•<U.+10I). tiaud:ing tu+r riy;nilir:uillc d.~ nlnt+rl In Il.r (K•nti•nlul;c uf I•n•1;• nrn.•ir:+ frruwiurliog in thr +I+•licrt)' of a luu'•Iri+tlrwriuld infw+t (fig. :1). Xl.rw+uid+•r nn.l (:n+vlnn (G.1) hrt'r rivtnfl~• nytnHr.l .l:~ln from Ih. ('nllrl+nr:+lit•e I'rrinrlnl 111141V at fbe \rliuurl 1+1aifutr of \r+urt• Ingi.•rl Oi-wnsrr iuul Strnle. tlt IIItM 11rv.xIMr fIt'e elu.ly of :111;!+wl I+rr}• uru.•i.-.. al+irl+ t„•+r +w•nt'1}• rrpu+llY dit•i.lr.l suu+ug hlu•k and ahite tru+nru. fl,r w+lhmr-4 fnuu.l at riguilireut ~L.~ nlslyd esa•.1s Of lou•- hirlh•trril Ll iafruts rmnu}t M+nuke+v of IrAh Kroul+s, rel/lllalcr( to uonsu+oke+r o f 1 he sn u+e rnce. 421

S9£L @ZLtiS a ,A •r PICURE 3.-O.yYemodoble .auretloe cur.ea of aupa m.terwal ud feW blood uader coolrol ud Meedy.late co.dlUo.e• le 70 ~0 ~0 ee ee 70 ae ~e 100 rq 1....1 •wtli 10 paroeel felal ead 9.4 peroe.t .etar.al IIbCO eo.ce.tntto.e. 21e meler.al a.d (.tei heeeo- Slobi oo.te.u .+n .rurd to pr.l 12 ud 16.3 per 100 .l of btood. r.eyectl..ly. A.orm.l o, co.- euyUos of S.1 Per 100 .l of blood wee erumed for bti tfe .lew ..d Its co.t.at. ..d t!e felu.. SOURCB: l.oap.L,(21) ~ Astrup, et a1. (3) carrbd out experimenlal studies on animi which may have a correlaUon with olher data based on humr atudies In this report. The investigation studied the effect of moderate CO exposul (180p.pin. and 90p.pln. CO in atmoepheric air) on feW develoP ment !n rabbits. Exposure to 180p.p.m. CO (1618 percent COH11 during pregnancy resulted In a 20 percent decrease In birth wee and a neonatal mortality rate of 35 percent as against I peruentir lhe control croup. Exposure to 90p.p.m. CO (8-9 percent COI had a kst pronounced effect. There was a negative correlatic between birth weieht and maternal COlib concentration (p<O.OS 11te authors conclude that these results lndicate that CO in tobao~ smuke might be responsible for the reduced birth wei~tl of babp~l' whose mulhensmuke during pregnancy. 12 A report from Denmark by Asmussen and )(Jeldsen (2) studied the umbilical artery as a possible model for evaluatint the vascular Injury provoked by tobacco smoking In humans. Cords from new- born children delivered by I S nonsmokin8 and 13 smoking mothers were studied In the transmission and the scanning electron micro- scope. The average weight of children born to smokers was 3,370 8 and that of children born to nonsmokerti was 3,695 8, a difference of 32S g. A difference of 123 g waa found In the we(thts of the placentas. Pronounced changes In the inUma were found In the umbilical samples from smokers. The most Important llndinp were deeenera- tlve changes In the endotheUum, such as swelline, bleedin8, contrao tion, and subsequent opening of the endothelial Junctions, with formation of-tubendotlielfa) edeie:-'1'he basement membranes were considerably thickened. The smooth muscle cells in the etxmatous wbendothelial apace often showed .acuollration. Since similu changes can be induced In arteries of anlmals by exposure to CO or perfuaion with nicotine, the authors condude that dsa.r elte smoking V harmful to the waxular endotheUum and may pro- vide some rationale for the mechanism behlnd low birth weltthts and Increased perinaW mortallty. SMOKING AND ITS EFFECTS ON CARDIOVASC'UUR DISEASE AMONG WOtI/EN.TAKING ORAL CONTRACEPTIVES Smokirt8 Is a major cause of cardiovascular dlsease amont women, and It has been found lhal the use of oral tontraoepthrea potenU- '&tee Its effect. Therefore, women who smoke and lue oral oontra- ceptlvea are at a much higher risk for cardiovascular disease and thould be encouraged to stop smoking. In a revkw by Ory (30) of the original ackntifie data that exists on the uaodation between oral contraceptives and myocardlal infarction, cigarette smoking wu found to be the most Important factor in (ncreasint the proba- bility of women less than 50 years of age having myoeardlal lnfaro• tion. Although this Increased risk Is Independent of ord oontra- oeptive tue, oral contraceptive we appean to be an added risk factor. The use of these drugs In the absence of other predisposint factors appears to have only a small effect on Inaeasine the risk .of dying from myocardlai lnfuction. ' lain (18) studied the risk of mortality associated with the use of oral contnceptives. For wdmen 40-44 who neither uoe oral oontra- .oepllves nor smoke ci8arettea, the overall mortality rate from myo- rirdial lnfarction is 7.4 ner 100,000 (Table 4). The comparable annual mortality rate among women of •thls age pibup who use ,.oral contraceplives but do not smoke Is 10.7 per 100,000. 7h1s eompara lo a rate or 62 per 100,000 for women' who take oral contraceptives and cmoke. 13 i r I

46 1 of COllb In bot)• fetal and matemal blood may also be a factor In the Increaacd incidence of low birth weight of infanta born to women who smoke. Colo, Hawkins, and Roberts (7) studies the smoking habits of a group of pregnant women and related these to the level of lblfb in the circuLting blood. A group of 222 patienls allendine antenatd dinla at a London hoapltal _were questioned about their smoking habita. Ninety-throe (42 percent) were smokers, And 129 (58 pu- een() were uotumokert. Simultaneous maternal and cord blood samples were taken at normal delivery and at Caeurean section from 28 p.tienta, .nd the COHb and fetal hemoglobin levels of the umpley were measurod. Results showed that women who smoke dutint pre8nancy have a titnlllcantly higher level of COHb in their blood than women who do not smoke (p< 0.01). The mean COHb levels were 1.2 percent (range 0 to 2.4 percent) for the non- smokera and 4.1 percent (range 0.5 to 14 percent) for the smokers. There was a po.itive correlation betwen the number of ciyueller smoked on the day of sampling And the COHb level (cortelatioa ooefticlent 0.82) (Flture 2). Nlth the exception of two patients. ptculte 2.-Mu.tw of clpnlw .or..lty u.oted per day coMpu+d wui COIn Mv.l at ll.s of ur- pllnt h 93 Vr.aaaat .or.a. Q` M.a. r.y. of COlts l.vdr for 129.or.oka9 I dl the fetal COllb levels were demonstrably higher than the re- 4ective maternal ones. The mean folr+l/matemal COlfb ratio was 1.84 to I (standard deviation t0.85). llemotlobin has a 210 tlmes Qeater affinity for carbon monoxid. (CO) than for oxygen. Il Is obvlous, therefore, that cigarette smoking during pregnancy dlmin- ihes the oxygen cartyint capacity of both fetal and maternal blood. 131s affects maternal oxygenation by Increased pulmonary venous dmisture and diminishes the oxygen available to the fetus at the tlwse level by Its efieet on fetal oxyhemoelobin dissociation. In a 1975 report by Dow, Rooney, and Spence (11), a slanifi- csntly treater rise In COHb eoncentratlon In response to smoking a :ngle cigarette was shown In pregnant women (3.9 percent Increase) a opposed to nonpregnant women (2.1 percent Increase). Thla was wore pronounced when anemia was present (5.0 percent Increase) aid appeared to be inversely related to the hemoglobin eoncentn- don. 71vee troups of women, all amoken, were selected for this sUdy. The first group consisted of 10lwrmal, pregnant women late Y the second trimester of pretrraney, with hemoyobin levels of a.er I I a per 100 milWiten (ml). Tbe second group consiated of 10 .omen also late In the second trirnester but who.e hemoglobin kvels were kss than 10 1/100 ml. Apart from anemL at the time of dmission to the dudy, these patknta were normal. The third troup consisted of 10 normal, nonpregnant women with normal hemovo- t,in levels (over 11 g/100 ml). The change in C01(b was estimated rpectrophotorttetrlcally in response to smoking the flrat cigarette ef the morn4t8, the women having rnted for at least 30 minulea. A smlpk of venous blood was withdrawn before and 2 minutes after ralokint the cigarette. The cizaretta wero of a standard size and of a'4lonantld" (i.e., not low "tar" And nicotine) variety.'Phe women ucre Instructed to take a puff every 40 seconds, Inhaling as deeply  possible, to a total of 10 puffs. In the nonpregnant tlroup, the mean rise In COlib concentration (tstandard error of inean) was 2.10.2 percent. A significantly peater increaua was found In the normal pregnant group (mean rise 3.9s0.4 percent; t=3.91; p<0.005). ille effect wu moro pro- wunced In the anemic pregnant women, who had a meaniru rise of SAi0.2 percent (t-9.9; p<0.0005). Longo (21) studied the effects of CO on oxygenation of the fetus Is utero. Results showed that the partid pressure of oxygen in fetal kood decreases in proportion to the COllb concentrations In fetal And maternal blood (Figure 3). This decrease (n oxygen tension may be a factor in the low lirth weight of infants born to women who smoke or .re exposed to severe air pollution. These tesulls suggest that significant in- deases In nlatemal and fetal COllb concentrations can significantly ftduce oxygen delivery to the fetus. I 0 1p

ing pregnancy in the United States had an clevation in riek of 2R per- «nt for late fetal and neonatal mortality, as demolullratefl by Ilutler, et sl. (15) for ilritain, Scotland, and 1V.Ies, and if 2n perrcut nf pregnant women smoked t-hroughout the pregnancy,' We higher risk of stillbirth and neonatal death for the infants of mothers who smoke cigaretteaduring pregnancy would account for arpro:ilualely 4,GtN) nf the 87,285 stillbirth and neonatal deatlu in the United States in lOGB- L4Tt r'aSAL •ND NsIM.r.L Dnatu Soxzs..r A strong, probably causal association between cigarette smoking and higher late fetal and infant snottalily ttwoag oawkers' iafanta is supported by the folbwiugevifienes: l. Twelve ret.rospeetive and praqleetive stadies have revealed a ria- tistically significant relationship between cigarette smoking and an elevated mortality risk aeoong t1,s infants of smokers.ln three of thess studiea, of sul4cient sire to permit adjustment for other risk factors, a highly significant independent arociation between smokng and mottality was establishal. Part of the discrepancy in reeults betweer tbea etuditr end those in which a signifkant aMDciatioer betweeA sOfol[ing and infant mortality was not deftt- onatrated may be explained by a lack of adju.tawlt for risk fac- tors other than smoking. 2. E.idenoa is converging to suggest that cigaretta smoking may be asore harmful to the in fanta of sosis women t.haa olhers; this may also, in part, e:plain the discrepancies between the results of the .tudies in which a signilkyatly higher mortality risk was shown for the infanta of .oaokers ooapared to those of non.nwkers and llle results of tbo.s studies in wbieh aigni6eant diQerences in mortality risk were not found , 1 Within groups of siailar bitth weight, the infants of nonsmokers appear to have a higher mortality risk than do the infants of ciga- ratte amokera. This results trom the fact tluit the infants of non- tawken within sueh similar birth weight groups aro on the average gvtationally ks mature than the infanta of cigarr.Ue seaokers. Available evidence indintrs that within grollps of sim- ilar gestational age, infants of lower birth weight experience a higher mortality risk. Since t,he infants of ciprotta smokers are ~ /4wr .. ..IriN1.11.. .t 4t. .. ....~La wa..1.r aa.ap A.r/-t 1,yu.y fr.. ta. arI1W P.r1a.1.1 Y.rf.ltl/ al.4l..alra Ma.Y/ fIMYa a Nw.wr..1/....110.1.- . I small-for-gestational ago, one should e:rect that If the infants of eigarelte smokers alld nonsulnkere are compared wit.hin similar gestational age clas.ce, llle infants of cigarette smokers wwlld have the higher mortality rate. 4. The results of recent studies have documented a statistically sig- nificant dose-response relationship between the numlicr or amount of cigarettes smoked and late fetal and neonatal moliality. B. New data suggest t11tt if a woman gives up emoking by the fourth month of pregnancy, ahu will have tlle ume risk of incurring t fetal or nconatal loss aa a nonsmoker. tZ. Available evidence strongly supfwrfe cigarette smoking as one cause of fetAl growth retardation. The causa of excess deaths amnng the infutta of unoktrs are those associated with small- for-dates babies. 7. Data from experiments in nnimals have demonstrated that expo- sure to tobacco snmke or some of its ingredients, such as nicotine or carbon monoxide, results in a aigltitkaut increase in late fetal and or neonatal deaths. 8. The results of studies ia humans have shown that the fctus of a smnking mother nlay lie directly exposed to agents such as eat4rou monoxide a•itllin tobacco anoke, at leveb eoanparable to thnse u hich have been shown to proalure stillbirth in experimental animals Sex Ratio Althnugh a numlwr of small studies have Inond a rlight, usuully statistically Ilnnsigllilicant, increase ill the prnlx+riinn of female infanta born to suulkcla, the Ihree largmt studirs o( Underwood, et al. (48,506 pregnancies), Ihltler (15,701 llreguancity), and )tac)Ifahon (12,1Sb pregnancies) have found similar infant sa: rtities among both smok- ing and urnlswnking mothers, wills the expocieJ rlight exctes of males unonRtech (trbleS). , Sufmmo+'y Available eriJence strougly indicalee Ihat maternal cigarette smok- ina doca nut iu/lurnlr Ibe sex rat io of uea•Inrn iufuds I OSEL t?1TLTS 44R

,..rw.r.. ;.:,. c_-AN*. y relallvcly larger dlfferences in the earlier weeks of pregnancy. The risk of premature rupture of inernbranes was morc than lhroe times greater for smokers than for nonsmokers unong deliveries that oo- curral before 34 weeks geatation and remained higher than the risk for norumokera through term (Figure IC). A prospective Investigation of 9,169 pregnant women was con- ducted by GouJard, et sd. (IS), and results showed a substantial Increaae !n stillbirths among smokers. A large proportion of this increase was due to abruptio placentae. T'here were 100 stillblrths, clasaified Into five categortea of cawia: vascular, abruptlo plaoen- tae, meehanlcal, mixcellaneout (typhllL. Rh, malformations, etc.), and unknown (Table 3). The abruptio placentae category exdu• dvely represented casos without toxemia, the one toxemic case being dasiified with the vaaeulu causes. The higher proportion of smoken is slgilflcant for only two of the categories: abruptio placentae (p - 0.005) and unknown eauses (p - 0.0005). Although the numbers were unall, the risk of stlllbirths by abruptio plaeentae is six tirrsea hijher among smokers. TA11IB I. lllltbtrtAa aocorUnt to nus° 1s r+t°s1ot to .s.r..t °ooktsg krtt.{ Prao-c7 LL.K7Y. fM• . wY.._ r w rr+~. IV dMT- b MI 1p1r1<_I. aouacs: 0..1..d. 1..1 r. (1 ry. c.v#..4.. N.w.( Pr..a wYW LL. od..w s..+r. w+a.+ a ss Is u u Ir 34 u $i is s IN - 7• u . - °...°s .. °.eo°I Lant-Tenn Ejjecta on Physical and Intellectual Development Three studies (6, 16, 40) report on long-term effects of smoking in pregnancy. Data from two of the sludies presented below dernon- strate an associaUon between smoking during pregnancy and im- paired physical and Intelleclual development in the offspring. Additional reports further substantiate this association (10. 11). Butler and Goldstein (6) analyzed the National Child lkvelop- mcnl Sludy, a longitudinal study of 17,000 children bom in Ilritain from Much 3 to 9, 1958. The test proeedures included a reading 0 test at lhe age of 7 years, and a mathematica tat, a reading test, and a general ability test at the age of II. At both ages the height of the child was also measured. Analyses at both ages were based on smoking habits of the mother after the fourth month ofprognancy Slatistically significant differences In height and reading .bllity between smoking categories (0, 1-9, or 10+ cigarettes dally) were found at both 7 and I I years of age. When account was taken for such factors u mother's height, age, social class as determined by father i occupatlon, number of older and younger chlldnen in the household, usd the sex of the dllld, there was a deficit of height and reading abllity In the off- spring or mothers who smoked, the extent of which Inaeaaed with the amount smoked. These results establish an association of smoking In pregnancy with later Intelkctual development, vthough the gap between chlld- ten of amokera (at all levels of smoking) and nonsmokers doea not *appear to change between the a8ea of 7 and IJ years. Smoking ln pregnancy is associated with an lmpalrment of both mental and physlcal trowth, although eomparod with other .ocial .nd blologl- eal faeton, lhe effeeta ane small. In the study by Wirtgud and Schoen (40), the net effects of various factors on length at birth and height at S yean were deterr mined In 3,707 .Ingje-born, whlte California children. Clilldren of ' smoking mothers were found to be shorter (p< 0.001) at birth and °at S years than childron of nonamoking mothers. (intellectual do- u.dopment was not measured In thL study.) In contrast to theae resulta. Hardy and Llelllla (16) found very ~ few tdgnlfkant differences ln a number of body measurernents and Intelkctual functiona up to the alDe of 7 years between children of smokers and nonsmoken. A possible explanation for this discre- pancy is that their aunpk was too small, usd a welght-matcrred con- trol group could add a bias. Whereas the Britlsh.tudy by ft'tler and Goldstein In.ohed a sample xlze of over 5,000 children, Ifanfy and Melllts based their Ilndinga on only 88 matched pairs of clilldren. Calculations by the authors of the British study show that with the imall sample used by Ifardy and Mellits thero was only about a 20 percent probability of detecting dat(stically significant differences in the heights of children born to smoking and nonsmoking mothen. CARBON MONOXIDE AND CARIIOXYHEMOGLOBIN LEVELS IN MATERNAL AND FP.TAL CIRCULATION AND THE POS- SIBLE MECHANISMS Of SMOKING EFFECTS ON PRL'GNANCY There Is evidence to show that carboiyhemoglobin (COrtb) levels ue subst.ntlally elevated In pregnant women who smoke and may result in damage to placental and fetal blood vessels. lfigher levels L 9 I

! TABLE 4. PJllmaed .nnud mortalJty r.te p.r 100.000 wom.n fros myca. dW InfuclIoe aad Ihromboeuboli.o, by ur of or•l euatr.uptl.ak ..okt.a habtu..ed .s• (In year.) Nr.cr/V/ Lf.,,11w n.o-...-h..lr- arlly N.WU Wa. N...r. Ur.. N.w.r. U..n AB_B.d.n L.s sA asA u.• u -jt.«~ 1/A 1./ 1a.1 )1.I 4A LMt 4.1 ... faA 1.1 ..1 M.rrh M IA 1.1 1..1 1A IA Nw.r,. U.... N..r..N ..s 4.1 a.. •.1 IIA •A •.1 1.. .A •.f )A •A •arl..w rw.. ..+r..d......a...,«. s......ld..,...ww1. ..r ..w r..r. b.wn....t r..+w. aouncBl s.r.AJc.(Iqn in a Iater dudy, Jaln (17) analyzed the synergistic effect of amok)n8 ard the use of ora( contnoept)vea on myocardia) infaro tion. The rrJathro risk of nonfaW myocardld (nfuction ueontt those who u.e orat contraceptives and ueoke (f estimated to be 11.7 to I(Tabie 5). The authors 1uggeat that smoking should ba considered aa another ooetraindiutloo for the prescription of oral contracept)vea. TABLB !. htk.aW Idatl.. tl.ks et w.t.W rfovrdW t.Iuctlo.. by .. of or.l ao.er.oqtt•++ ar.I e1Bar.tu makl.a, 11A1 1.11 t,.a l 4.a s .s. ..n lA] I.M y.d..MUYT.WVYhrY- W.ralY..(11)._- •IW.1 n•.L.ni r Ir.r 1. <Lratr M Vr• t 1.lMI rMan: 1no /•- 1 f et7rMlr M Mr• pURCBI J.i,A.R.(a1). Resulta of a study by Beral (4) indiute that oral contracepti.c usen who smoke have a(0 Limes treater risk of dying from can)hs vascular disease than women who neither smoke nor uss the piL Smoking by Itaelf was responsible for a 4-fold increase In the risd of dying from urdlovaacular diseases. Oral contraceptive use In thr absence of unokint a)so appnted to increaae one's risk, but the diF ferenees were not statistically significant. Mann and his colleagues also studied the relationships txlwcts vnokin6 and myocudial infarctlon in women (23, 24). Their ftnb Inp .how .n apparent but not a tlatistically rlytificunt Increase In relative risk of nonfatal myocardial infarction for nonsmokers who we oral contraceptives (2.02, with a 95 percent confidence interval of 0.5 to 8.5). In conlnst, rot smokers who use oral eontraceptiver, the relative risk was estimated to be 11.67 compared to that of the nonsmoking, nonconlraceplive user. In addltlon, these authon ra ported that the riak of nonfata) myocardial InfarcUon was related to the amount smoked. It was found that In comparison with non- smokers and ez-unoken, the relaUve risk of myocardla) Infaretlon Increa.ed significantly to 1.3 In women smoking fewer than 13 ()tarettea a day, to 4.4 In women smoking 1 S to 24 clpuettea a day, and to 11.9 )n women anokln8 2S or more d8aretta a day. , Among nonsmokers, oral contraceptive users have 2.0 (95 per ant confidence Interval, 0.5 to 8.5) tlmes the ri.k of having a myo- c.rdW Infarctlon. (Secauae the oonfidence Interval Indudea 1.0, chance variation is a poasible explanation for this finding.) Among .noken, if  woman usea oral contraoeptivea, .he has 5.4 (95 poroent confidence Inter.al, 2.0 to 14.7) Umea the risk of having a myocurdial Infarclion than If she Is a nonuser. Th4 re.ult 1a hlahly rtatlatlcally aiyilficant (p - 0.001). EFFECTS OF CICARETfE SMOKING ON LA(,'tA11ON Studies by R)cher and Ciudleelll (31), Rowan (32), and VorherT (39), further document the effects of nicotine in breaat milk on in- fanta of smoking mothers. Since nicotine has been ahown to cause aau.ea, vomitlng, diarrhea, and tachycardia (38). It la reoonuaended by the authors that lactating mothers refrain from smoking. Bradt and Herrenkohl (5) atudled the relationship between ciaa- rotte smoking and DDT In human milk. A total of 53 human milk ramptea from eastern Pennsylvania were studied. Ten of the donors were eisarette vnoken, and they donated 13 of the milk samples. Results of the study showed that smoking was one of four variables which contributed to the increaso in DDT. Mean total for the non- smoker was .101 units venus .146 units for smokers. Fout factors were identified statlatically as accounting for 54 percent of the variance on total DDT levels In human milk. These factors are: (I) number of children nursed; (2) number of eltuettea smoked daily; (3) use of nonpersistent peslicidea; and (4) diet In calories. The ro- lallonshlp between the number ot dyxtla smoked per day and the total amount of DDT in human milk wUesta either that cigarette smoke may be a source of the human body burden of DDT or that citarclte smoke may cause more DDT to be exeeted In the milk. WIIAT WOMEN KNOW AUOUT SMOKING AND PREGNANCY 7here is much infonnallon circulating in the'sclenlifle community 1

G r>I,:,r,„ ti,nwkc . ...........................................52 N ic,ilinc ...................................................... ia C:,rlw,n M„n„r"1,• ........................................... ,7 (;arlw)n Munnxidc lll,lakc nnd 1•:limin:,tinn..... •r,x I;ffccla on Fclal Crowlh nrnl I)cveluprnrml .,.1;(/ Carlw,n Monoxide F:ffccLv nn "Tixeuc Oxygenation ...................................... ..../;1 P:ff,-rln on NcwlK,rn Animtla....•,.•.••••••„•,,,•tL, f'olycvrlic Nyrlrtx•nrVw,nx.••.••.•.•.•....,••..••••••,..... t:, Stutlics in llum:rnv .............................................. 67 Tobacco Smoke ....................•........................ (i7 Carlwtn Monoxi,lc.......................................... 70 Vilamin l3uanrl Cyanide Dctoxificntion••••.••..•.,73 V it:tmin C .................................•.......,......... 74 Research 1lvutw ...................•,.............................,...... 74 Fctal Dc:tlh ........................................................7.', Neonatal ncath ................................................... 76 Spont.ana,us AIK,rlinn ...........................................77 I'rerclamlrsia........ ' ............................................... 77 Surlrlcn Infant Ik:tth Syndronxx ............................. 77 1.ung-Tcrm F ollnw-Ul . .......................................... 77 [lirth Weight anrl Placenta ................................... 7R 1•:.rlkrimcnt:tl SUulic.r ...........................................78 l.actalion and f{t•e:tat Fe-timlittK .......................•.......78 Tobacco Smoke ................................................... 79 N icoli nc ............................................................. 79 Carbon Monox idc ........................... .................... 80 Polycyclic Ilyrlrocarlrons ................•......•....,........•.• 81 Rcfcre nccs ............................................................... 82 LIST OF FIGURES Figure l.-Pcrccntagc distribution by birth weight of infants of mothers who did not smoke during pregnancy and of those who smokcYt one lw.ck or more of cigarettes pcr tl:ry .. ............... . ............................................ .. 17 Figure 2. lt:,tiu uf placcnlal weight tn birth wCighl by length of Kcatntinn nn,l maternal nmokinA cnteKnry..,., IR 8-4 I~r~ g.._blcan birth weight for week nf Qc.rl:rlinn ~n.,,nlin, tm maternal smukyng habit: control week .inglr'tnn' ............. ................. 19 1~`„rc4.- Verccnl:r{:c nf I,irtly wci(;ht-s under 2.500 {,.rume {,t n,ntornul ,<rnnkinu h,vt;l for enrly, avcrnac, nnd latc- , hirth. .............................................................0 Irrn LV~„r,. !i• Thenrelica) cumulat;iv0 mortality ri.rk according t„ :ntnking h:rbil, in rnnthcr:y of different uge, l,nrity, anJ ux ial cln`~ grnulw ............................................ 3 1 I'crccnlagc tlislrihutjnn by wecks of gestation „( birlh.q to nnnvmnkcr-rv, Amukcrm of lccv than one fr,ick ,1;,v, :tnrl nmakcrx nf one ,,pack per day or morc..... 4.1 li4ure ;,_.l`rnbability nf Ircrinalnl tlcalh for smoking antl M,nsmnkinR mulhcr.r, by Ix;rio,rl of gestational agc....... 45 t•,t;ure R.-.Risks of strlcc•lcrl pregnancy complications for .mnking and nonsmoking mothers, by ltcriotl of c,-Statirutnl age at rlclircry ....................................... 46 Ficun• 9. -Timc courw: of cnrlxrp monoxide uptake in m:ticrn:tl and fet;tl shecp cxlxxsed to varying carbon nvmoxirlc concentrations .......................................... 59 Iictm• 10.-Nurnam maternal anri fclal oxyhemoKlohin <atur.ttion curven showing c:trltpn monoxide cfft.•ct....... 62 t'icurc I1.-Tlx; lrstrt'ful pressure at which the "c}hcmofilnbin saturation is fi0 ~ tM:rccnt, f'ri0, for human maternal rnd fctnl hhwtl u•t a funt:tiun uf Irlnntl r•:rrlioxyhcnto{lk,lrin ctrnccntrttinn ............................... GI 1•4n,re 12-FcL•tl valucs uf nxy{,•cin partial ttretsurc a.m a function of cartxtxyhemnglol,in conccntrrtions during 'luaAi-slkady-slatc condilion....................................... 64 +'1:uM 13.-Thcrmr,Rr•urn from a ncar-term pregnant I,.micnt Ixforc and aflR:r smoking .......................•.....G8 LTar 1'crccnt cerlK,xyhcmoR~ol,in in mat.crnal and ft•t'l lrlood aa a funclion of carluon monoxide parllal 11-5

1 i Pneeelamp.la Previous epidemiological atudies of the relationship between cig- arette amokink and preeclampuia were reviewed in tlte 1971 nd 1972 reports on the;health oonaequencesof amolciat (101,10!) and form the baais of the following statementa: The resultii of several larao prospective and retrnapective studies indiute a staFtistinlly ti8lliReaM, lower incidence of preeclamhsia among .awkinlg women (14, j!, 1W). Tlsa results of one large hetro- apective study demonstrated i.ianifieult inverse relationship between the incidence of preeelaanpoia alld tha number of cigarettes emoked (100). When othar risk ffetora, tlvch aa parity, social rLss, maternal weight before tba prasnaaey, and 1nat.rwal waight pin dur+na the pregetane:y weFra ootttwlled, Oeoking woaea retained a aiani8cantly deereased ri* of praeeLlwptia (!1). Zba lower risk of preeelampaia for cigarette Itmokint wo...a !uu been demonstrated in Britain and Scotland (14, 11, 48, 8J), T'6a United 9tater (100, 118), Vene:uela (j!), and Sweden (43). It a lnataraal tttnoiber does de.rolop preselamp- aia, however, µ.ailahle data.uS:a.R that her infant haa a higher mor- tality risk th,Fa does aba intant of a aoa:alDok.r with pre.clampaia (11,85). Btn.a.orp 1. Arailablk evidence indieatea that Iaaternal cigarette amokeras have a yignifkantly lower riak of d..ebpint pneeelialnp.ia aa oompared to naasewk.rs. 2 If a woman whoanwke.eigaretlea during pregnancy does develop preeelaavp.ia, Aar infant 6aa a higlr.r mortality risk than the infant of', a nooaaokar with preaolatapnia. I PretltaDty BeletlttelJ (1) A.n.ainy, J. 11., OassAttoe, B. O, wa1s, A. B.. txasro, T. Y. Bms.klu4 as aa lad.p.adeat ..elatils la a raltlplt tMtrwlen analyda rpe. 14rii w.eat+t a.d aNallaa A.uleaa Jwrral .t PuNle I lealla and 14 Nan le.•s Aeelll+ 6414) :42a4.t11. Apell 1000. (1) A.tevr. P. P.IIWet4eke NIrY..lea mlrtar le1l..asae:ld-Kenaee- tr.Ue.re.. (Ptlaaleafe.l afeela et.w+se.ta ea/iaw ..nsflde ee.oe.lr.- llew..) Bla.b. 11W1nlalt.yder Lutt 12(4) : 140-100. 1072. (1) D.nuv. R. It. TA..Reet eC ral.rwal walng aa the Irtant MrIb weight. Naw l~ra4ad ll.dleel Ja.rtul 11(J00) :!OS•20r. Mar 1010. (1) 11ata., !. D.. 717YAaeula. Q P. Carbon enacrMu and a.la• a.ar)ra te.eelt ArclLes of ILarlrooaseatal 11eal1\ 21(1) : lit-dl. Ja.uar, IOTt (5) 11.ar..u., L. Y.oouk L. r.u>; J.. MAU.AS6 7., O.u, O. L'e.7aea- beslwl& de 1'ent.at .# de mera tu.e.se. (Pr..e.ce of carbos ra.o.ld. 1. Io& laloed at a eNlld bore et a amaoklnt metl+ar.) Yedeci.e tigals at f1o.esap Corperel 1(1) : 212-274. Julr-Autuat-Bettst`ser 10'70. (t) Us.t, V. A. NutrlUaul dudlee darl.l prel+.ae1. Jour.al at the Aawrt- eae Dletetle Arxlatle. 6d(1) : 121-.l20, Apr11 1011. (7) DacaR A. P.. Klwti J. It: 8tudles aa aleotlM aL.orptian derlal prd- wnes. 11. ThU eQacta of acuta 1ea.f dous an eotaer and aeoaatae. Amer4ca. Journal at ()eatetrln a.d O7ne<dlesJ 00(1) • OItLM Jw 10,10b. (8) BsoaM IL P.. LJtrsa; O. It. D., e1.0. J. t tzt+eelau.tal etsdles a. •IretlM abrorptle. Is rrta durl.t pregnancy. Ilt. tReet of asheutlaeoua I.)eello" et wll eareale dora rpen metler, tatatr and .eaaata Aarl- eea Jwrsal .f Olstetries a.d O7areotap 100(7) : Oe1-OOtI, Apr. 1. 1000. (0) DsotaK, R P. L.arlw, J. Q Vital eteea .t ehrwk nlosU.. ahwrytlo, a.d e.reele .rpoalt altue drrls prelsa.e7 ..d the arrNrt perl.d. At.erke. Jo.r.al at awt.trld aad Os.aeel.a7 110(4) : 022-M Ja.. 10. 1071. (/1) Sta.or. C. J. W. Aleohol and aleetlne pel.oelal 1. lataata (aualll.p). Uaandae\rltt .eer KlaJerPe.eslu.de 0: 332-341. 10]1. (ll) Btaat. C. A.. Bawrea, G II. Nleetl.a blaeYa I&* aaekllnt-Iaducvd ties I. elre.latlal Ore.laeUa 1. IaetaU.lR rata. Bda.o. 111(40/0) : Ol6-021. Aul.1lk 1072. (/e) auroraa, O. It. aaretta aosklut and drr.tlan at prelnaarf. A.er/e.n Jearsal .t'OldNrka asd Olaeeol.p 10J(1) : 0l2-OfO, Apr. l. 10ea (1!) Buttsa. N. IL Ataurae. t D. (tZdltees), Perlaalal Preele.a TM 9.e- a.d Report at /t+e lOO/l nrltl.h Ptrl.at.l L.rtaUt,r Sura7. Ioadam. 14 •.d S. 1JvlaeWe.r. Ud..1000. 3UOIyk (14) Bunts, N. Q.. ALJtaYaN, Il D. (Rdlter.). TAa eRaeta er asekl.e I pretna.er• CkalMer ll. fa: t4rt.alal PeNle.a illatNrlk„ Il ..d d lJ.lncrla.e. t1d' l0ft 1M. t2.ti. (IS) Buttta. N. R.. OulhatriN, It. Rees, t U. aarelte a.wklnY Is pKt- .a.e1: It. I./lue.es r birth wataft aad p.rl.atal ..11.Ut7. Brlll.a N.d1er1 Journal 2: 121-130. Apr. 10, 1971 (Il) C.or.eec.. O. W, t.urar.. l. 1111, Jr. hr..tal am.kla0 ..d perfulal r.rialllr. A.erkas Jwrnul .t Ot.r4trks and Or•rNais 00(0) : 700- 11t. Jul) 1.1007. (17) On.ra..e..0. W.lr..,.P. t., MssM 1[. B., A.aar. 1t. Low-birth welelt e.d nle.alat .wrtalll7 nt,e relaled t& sul.4rwa1 sMst;Ins a.d .o.1s aeaneok Nart Auerle.a Journal at Oa.Utrk" sad dl••co"tf l. l 1( 1) : t13-00, Bept.1.1011. (/1) Co..aT. A. 11, 1Nnca. Il, toanrar, tt, 0...s, 1L. J.oo..or, M., Muwso..ua: A. D., Ptoa, A. N., Dt; A. Pwaw., A. Pa.rw. P. J. ft.atcN. 1,1. It'aJ•:, J. A. ttdae/a at e..ll+..realal et+rwlrela.s. the aeelaAella.. .t drug*. rarelse0e.4 aW ..raal body e..atllueale 1• ran. A.nala .t the New Y.rk Ae.demr at Bctei.r.. 170: 100-17~ July 0. 1011. (10) Der.eu.a. J.. ho/tAe.u. L Y.rA.waala ala 10881 rrodae.leweJ erra teeeta.e wret.iwwanla weaN.laelwa I wad wr.d...nre\ 0 ra+v.wlhew kablet palaereA lylen. (Iltrlb wrllbt and I.eldenea ef Ir+aalarlty and eensenltal aneuwallee In w.wlrrsa at r.16.n traklnl /d.ur..) Pedl• aula Pelaka r.17(d) a20-;13Y. 1011 4= VSEL 0TLT5 • 7

09£L OtLtS ! : j (34). Since then, more than 11)0 utlclw on this relatlonshlp have led to the Zenera) acceptanos that smokers' babks ttenerally weith 130 to 230 g lees than no.pnoken' babies, and twice as many or the former welth ler than 2300 It (13). The 1973 report of 1he Heal1A Conapuencw of Jnrokbtt pressnted evldenoe to support a uuul at.otLtloe betw.ut cigarette smoking and fetal growth re- tardation (39). A strong dewruponae rolatlonshlp was also eatab- IWted in khat re)wrt, with dlfbraacee In a.itiht being ln direct pro- portfoa to tLs nusebr of tlprettar smoked. The folbwlint additional points were summarir.ed In the 1973 report to further support tlr causal association between clptette .asoklnj durlnj preVsascy an/ lower birth writht: 1. Results are conabtent In all atudlee, retrospective and pro- apecthe, from many dlf(atent eountslee, reoea, cultures, and Poaaphk settings. 2. The relationshlp between smoking and reduced birth weight In Independent of other facton that Influence birth weijht, such as raoe, parity, matenvl aize, aoetoeconoosk statue, ee: of child, and all others that have been studied. 3. If a woman dvea up smoking by the fourth month of ptat n.ney, her rWu of delivering a bw-blrth-weight baby Is dmtlar to that of a nonsmoker. Subequmt to the 1973 t.eport, additional reports have futtber ' dleattood •and oorrobonted the association between smoking In : preenancy and low birth welght (19. 2S, 33, 35). Sr.okLt; ad Perbwtd alortal/iy A atront, probably nusd, association between cigarette rmoklst and higher late felal and Infant mQrta)!ty rata amoru smokers' Infants Ii now well establhhed (38). Retrwpect7ve and prospective studies have nweakd a etatbtkally significant relatbnahip between dptette amoklnlt and an elevated mortality risk among lhe Infants of emoken. In three of these studies of sufficient du to permit ad- Justment for olher risk factors, a highly significant independent a} wcdatlon between unok•kg, and mortality wu establlshed. Patt of the discrepancy in results between these studies and those In which a dtnlflcant assodatJon between smoking and Infant mortality was not demonstrated may be explained by a lack of adjustment for risk facton other than smoklnt. The 1973 report also presented evidence Indicating that the higher relative risks occurred among populations with risk facton other than smokint being ptesenl, such as socioeconomic ttatus, aae, parity, nce, and previous pregnancy hittory. 2 3 Sinee 1973, a series of articles by Ateyer, et al. analywd data from the Ontarlo PerinatN Mortality Study of all deqle births In ten Ontario teaching hospitals In 1960-61 (26, 27, 28).'fhe study In- .olved 51,190 birtha, inciuding 701 faW deaths and 653 early neo- naW deaths, and was supplemented by clWcal records with Inter- views of mothers In lhe hoepltal. Intetv(ews with tumethotbts and attending physkluu, and autopsy rococda (29). PerlnaW tportallty rterened sisnifkantiy with amokinl; and was alw affected by such bcton as maternal age, parlty, wdoeoonomlc itatua, previous prelnancy history, hemoglobin levd, and other rlak factors (29). SmokLtl freqtsencka also varied by many of theae rhvacterist(cs. Smoking and other risk factors were crowtabulated among 52 data subgroups. In all subgroups, the mortality Increaae with amoking was dosn related, but not In a almpb. Ilnear way. The haeaaed risk of per(naW mortality associated with light smoking among youn& low-parity, nonanemie mothers wau less than 10 percent. At fhe other extreme, mothers with other rfak factors of hUlt parity, public hoepiW atatus, with ptevious bw-b(rih-welaht Infanta, or with hemoglobin less than I I t; had further Inuea.ed perlnaW mortality ru1u of 70-100 peeeent when they were smokers. The moet t+Wlfleant siak factor (mortallty ra/e of 78 per 1.000 total blrtlu) was anemla, deflned us hemoglobin of less than 8.0 It, 7be Ailta+e of ame earlier studies to find a significant Increase In pee(naW mortality with maternal smoking may be due to selection of study populations from the end of the spectrurn, where Utht smoking Ih naodated with only a rtllht lncreaae In perlnatal risk. Thtf evidence points up how population selection could Inlluence study MdinO and shows that exposuse to the effects of smoking during pregnancy ir much more danprotu for lhe babted of some women than for others. Theae findings are oorrobonted by a num- ler of dudka in which feW, neoruW, or perlnaW •mortality rates ate compared for amoklnt and nonsmokins women, contrvUlnt for the effects of various risk factors ptevioualy mentloned (1, 12, 22, 36). Additional data were published In 1976-1977 (26, 27) and re- +ealed that frequenckt of low birth weight (under 2500 t), preterm delivery (< 38 weeks), per(naW morta8ty, abruptlo plaoentae, pla- centa prevla, bfeedin8 durisu pregnanry, and prolonged and pre• euture rupture of the membranes Increard directly and~dpdfl- cantly (p< 0.00001) u the level of maternal smoking Increasr,d (Tablea I and 2). The 1976 paper used multiple repadon analyah to measure the Independent effect of amoklnt on the various risk factors. The probabilities of these complications were also com- pared (Fiaurs 1). Risks of placenta previa•and abryptlo plaeentae were higher for smokers than for nonsmokers at all gea/atlona, with 3 4 I ,

t nnd olht•r faclurs (Unlxrio data) "• .Iltukin t F'vtn, .n.l rl.... 11..th. utik, 25un /n.n.. Ilr•. hun.lml Od.l Irrtha) N.I~rnal .nv.linRI.al. Ir. A.y Snr4.r mn.....,6.~ PM.tIr. ruti 1'.r~a Lr d.Y ~ 0 <1 1. I. 11u.p.til .t.tw 1'n r.lr ~ 1 7 1 109 1 6 r w Ish 21 I u K -MnIMr'. kiRhl S6 • 103 Ia 2. < 62 i-he. 6 f Ul lt Ih 1 1 R i ' 24 l21 s/ .nrhes 4.1 1f 119 11 21 66 {7 inrhw. 3 311 6.2 10 I 1 6 24 6i1, Inrhr. 11rf-Rw..1 .riRht 17 6o /3 12 35 < 120 laur4 6.1 102 ISA 17 2t 120 111 rywn.6 / 2 9.1 95 1 6 22 U.S * Lwrl.. Se" nf thiN 113 6.1 A.7 I s 2i M.4 12 7.3 11.5 1 ~ rc.uk 52 03 12.7 16 6l1UMt'1: N.y... N p (ll11 Califurnin (;na). At an interview early in prcgnancy, information w•t, oblainel alwlut numerous factors related to the Ilregnuncy, including the wumnn's smoking hnl/itU. Plucenl.an were wciQhcal by sllecinli}' trained lkrvonncl aftcr the cord an/i attachal membranes hnll lKrn trimmed off according to F3cnirschkc's Ixmtocol, an cxlrcmely imlwK- tanl procedure to reduce vuriability of ineasuremenl. The rttudy wwt confined to black or white women who deliveral single, live inf:InLa without severe anomalies between 37 and 43 weeks' gestation anct for whom at Icast one hemoglobin value during gcstation had been teport.c~l. [3ecauac placental ratios change with gestational agc, il i.x importanl to compare values specific for weeks of gestation at the time of delivery. Rcsult.s of this study ar'c shown in Figure 2 At each gestational age from 37 through 43 wccks, the more lhc mother smoked during prcgnancy the higher is the placental ratio. Comparison of the observc<d mean wcights by smoking level showed that, >s3 exf2eclcrl, birth weights decreased as smoking level increased. Further- mure, mean placental wciRhts were the same or slighlly lower for light smokers and slightly higher for heavy smokers (over 20 cigarettes Ixr (lay) than for nonsmokers. Ratios were higher for black than for whiUr women and t,endcll to increase as maternal hemoglobin level decrc:-ed• This trend was nwsl marked in black womcn who smokcvl (7[):!). 9-IG I INFANT WEtG/tT AND PAAENTAL SMOKING /+An1TS to 8 L 6 i 0L i 4 5 6 7 8 9 tp 11 61RTN WEIGHT (SCALE IN POUNDS INTERVALS OF 4 OZ ) FI(:t/ftl': t.-I'erernlaAe distribution by birth weiKht of infanl.r of nmlhern who did not emoke durinR pregnancy and of thove who ,nNlked one ppack or more of ciltareltea per day •YK Yt-/: NrNJ+, n (/.ul Ax descrihed in nnother•ectinn of this chhpter, the atrl/nn montlxiJc pmw•nl in cigllretle smoke crnmhines with maternal anli fctal hl•mnglnbin and re:.ult.a in a reluca) currying capucity uf lhc bllxxl for '.Xcgcn anll also a reduclion of the I/remvurc at which oxygen is lk•lircrtd to the fet.•J tissues. Somewhat similar reductions of oxygen 2+aifahility for the fetus occur at high altitulle anti in cases nf maternal anemia. Unrkr these conditions, incrclses in placcntal raliu, havc also heen observed that nre in pmlN2rtion tn the elevation or to the degree of anemia (14, Nx, N11+). The las,cibilily lhal these cha'1c;cw may represent physiological rrsponses to relative fetal hypoxia, wi;.h irKrea..nl oxygen delivery by a lurger placenta and tlecrcasal oxygen 'Icmand by a emallcr fctus, has been considered (11. 88. 10,9, 202. zU.?). If this is the case, it is imtNlrtnnl to know whether a mechanism that 'niRht incrcasc the pciuil2ility of survival at a lower Ilirlh weight is ucompanicd by any long-t,erm costs in later growth and dcvclopnunl. Ce.talion The consistent finding that mcan hirth weights were lower and thc frtrtucncy of low-weight babics higher for women who smoked durinf; preRnancy than for similar nonsmnkers r2tised the obvious question of 8-17 9L£L 0tLT5

i eur .I.cl) in thc chal,lcr nn vmokin{{ and prcgnancy in The 11.^lt4 Cui. ,arnre,, of ,Crnnkinq, A RrJxni ilf Ihe Surgron Crnernl: 1!l71, whieh concluded: "Malcrnul smokinK tlurinK pregnancy excrLv a rcLar,lin influcncc on fetal rrnwth as mnnifcacd by tlrcrca.ac,l infant I,inh weight and un incrc;Lactl incidence of Ivcmnlurity, dcfinc,I l,y wt•,Kht alone" (19e)). Thre same conclusion h:ut Itecn drawn from .ul studies. In the chal>lcr on prct;nancy In The 11rn[Ih Cnn.rq,rrprrH of in 1973, a elclailccl, critical review is given uf studies Iwl,litihc,l t„ tl, A t date. The chapter vummary of lhe evidcnce lhal the a.%x„ciati,,n between maternal smoking and ralucccl birlh weight is onu nf cauv antl effect includcs the following (192): 1. ItcwulLv arc conqixt.rnl in all sludics, relro..lx.•clivc antl hroa,ectic,• from many tliffcrent countries, raccv, cullures, and gcogra/ehic ticllinK, (2, 7, 20, 22, .Y0, 31, 41, 47, 54, 62, 72, Rl, 86, 89. 11.M, 115, 11R, 11.9, 11.; 127, 137. 141-14:1, 147, 151, 152, 157, 161, 163, 164, 166, 169, 172, iRS, 192, 193. 205. 212). 2. The relationship Itclwecn smoking and raluccvl birth weight i, independent of all other factors that influence birth wei/;hl, auch i. race. Itarity, maternal si7.c, .ocirK-cnnomic st.atus, sex of child, and otlx•, factors that have IK,cn sludicvl (l, 2, 7, 217, 22, 81, 47, 54, 71, 101. ln;. 115, 118, 119, 142, 143, 1.',2, IS7, ll;{, 169, 192, 19.4). It is al~, independent of gcstntional age (2, 19, 20, 22. 54. 72. 115, 141, 157, ls.r 166, 169, 192, 206). 3. The morc the woman smokas during leregnancy, the greater th,• reduction in birth wcighl; this is a dosc-resltonse relationship (2• Y2..11. 47, 54, 89, 101, 102, 103. 115, 118, 119, 137. 142, 143, 169, 189, 192. 19.r. 206). 4. If a woman gives up smoking (luring pregnancy, her risk od delivering a low-birth-weight baby is similar to thal of a nonsmokt•r (22, 54, 101, 103, 206). To illustrate typical results of studies showing the acvociation between maternal smoking and an increased proportion of low-hirth- weight infanLs, five published studies with an aggregated totAl of almost 113,000 births in Wales, the United States, and Canada arr summarized in Table 1. In these populations, 34 to 54 percent of l1K• mothers smoked during pregnancy and on the average had twice 14 many low-birth-weight babies as the nonsmokers. Under lhew• condilions, from 21 to 39 percent of the low-birth-weight incidence in ~~ the total population could be attributed to maternal smoking (2, 20. 115, 1 J7, 142, 143). An outstanding feature of the relationship _belwecn matcrn,l smoking and hirth weight is its deliendence on the levcl of matxrnll smoking and its independence of the large variety of other factors th"t influence birth weiKhl, such as maternal size, maternal weight (C1en' age, parily, socioeconomic status, and sex of child (1, 2, 20, 22, Jl. S'' r t , I b ; ; K AF1 nlrx;; al aa cas~s v c • i ~ V > E i ~ vl ~ m l 2 - h:7 a a s d c E . : i it V.M ~ E ; I N E ~ .°. ~ r°. ~~ i PA g .8 - N . E~ 6. 5 C4 ~ = I - g a A r .- _ . .: .. ~ C ti E .4 : ~ . .~ ~~~6U~d m7~~ a I ~ i - L r I , I .~ ~

i i ZL£L OtLtS MypducUon S1nmedical Aqpects of Smoking It~ta rccumulating, in the ncicnlific lilcr:tlurc during lhc pnst dcc:uhe <Ir,{ay corrnlioratc findings t•ctxrrlcd in thc ISN,t!'v that cit;arcttc ,n,,,kinyt 1luring prcgn:rncy ha.y a vignificanl and nolvcrsr effc•cl ulN,n thr ~~t'll'1King of lhc fctux, the hcallh or the ncwlxrrn baby, aml the t,~~un ,lcvclulimcnl or lhc infant arul child. Adverse cffa•ls nn I I,r,.~n,~ncy range from incrt:nurl risk for relrrrxluctivc icttl rtality. ttrctcrm hirlh, nnrl neonatal rlcctth, to retardation in fctal ` 1?„t, th ;tv reflcctLil in birth mcnyuromt-nt.c or lower rncan lxwiy weight, I h„rlcnccl Ixxly length, anr) smaller head circumference, as u•cll as to a I n„n,lx•r or ttmldcros of ntlntttnlion in the ni•cmata) IKrirxl. 1n arlditiun, ,rc is su{;gcstivc cvirlcncc or long-term impairrncntsv in physical I ~T„~cth, dirninishcvl intellectual functiun, anJ deficiencies in ikhavioral for thct lr,thice who aurvivc the first 4 weeks (if (ifc. Il I,.,,.Inl,mcnl ci ,i,IMars that children or smoking mothers tin not catch ulr with lhc 1.,:n1; nf non:rntokin}f tnolhcrx in various lthw.cs or ilc.•clolrmcnl. ~ The prc..cnt chapter hiRhlil,.ht-s previously reported and recent slWiics on the rclalionshit>`1 between cigarette smoking and pregnancy outcome, including sections on hist.rtrical considcration.a, birth wci/;hl I rnJ fctat growth, fetnl and infant mortality, laclation and brc;>st 1I ttrdinR, aml physioingic-expcrimen1.11 titwtics. The concluding :kclion .t this chapter, entitled ltL:viatrch 1wue,s, itlentifit-s questions and arc:u aconcern that neal clurific•;ttion nnd further investigation. Itiolorkal Coneideratlone In 1957, Simpson (172) retorte_i1 thal infants lxxn to women who <nwked during their prcgnlncics were of siattificantly lower Lirtti rcight relativc to bahics Irorn to nonsmokers. During the intervening 31 - ycars, there has been increasing concern, coupled with the conduct 4 a large number of rclnlcat stwlias, nlxwt the effect of smoking during pregnancy ulon the well-being of the developing fetus anrl infant. Concern atroul the effecl.+ of cztNwurc to tobacco and cigarette <moking during pregnancy ulxtn reprixluctivc lac., maternal health, I'rt•anancy outcome, anti infant wcll-IKing rlatcs back a ccnlury. In 1M Ballantyne (9) quc:ttional what might t+c the effect of tobacco I1nisoninR ulwn anl.cnalal life. While hc did not stK•cifically mention malcrnal smoking during pregnancy, hc .ummarirxvt the opinions of a numbcr of authors writing during the latter part of the 19th century alwut the riska of spontaneous abortion for women who worked in tohacco faclories. He rcfcrrcd stxxitically to nn 1879 patxr by Decaisne from Prance amd to an 1868 rclwrt by -Kostial from Austria alwut Irmale tobacco workcrs. L3allnntync wrote that both of these authors Kere quite convinced that abortion was very frequent in womcn 8-9

I t 71, . . 1l !,, 11•Y. 1/.'f, 1.17, I;:'• I~7, l4:1, 164. !6.'l, 1.'I2, 1.'1:/). 'rhi1 (cntl i illu.vlr;,tiA in "I'iJilcx 2 fuiri :1. 'I:,Irlc 2 nhnwN rncun i,irth wcil;ht.s ror Irnbics nf .,nu+kcrm anrl nnmrnnkcrrv in wclccteil xulwlivivi/ln~ by Irirrir,gic and srx•irMrcnnumic facl,rrrv, u.ing /laln frnm the nlll~r,~xi- mntcly II1,~ttK1 white hirthv Htwlic,l from 1960 la) 1967 Iry the lierkth.t. Chilll Illwlth nnrl lkvclnlrmcnt tiLu/licn whfr.w sulrjcclA werc mcmlu.~ of the K:livcr Fnund:llinn IIcnILh i'iun. Mean I,irth w0ullLv v:,ry wilh maternal :rlZ/', lr:,rity, hr•i{;ht, wt'ight, nnrl r«KirK•c/momic aL•rlu., fn,ln ., low o( 2,!)12 grams fur lu,irics or •rnlrrking mothers who harl givcn L,ir•th to Ilrcvioll. Iflw-irirth-wcighl infnntr, LUt a hioh or 3,fi7:1 /;r:tma -f„r hallics or nonsmoking mr,lhcrx or high (lnrity. NcvcrlhclL:w, \vithin each suhgroull the cffccL of matcrnnl fcmoking on mcan birth wciQhl ix clearly seen, with smokers' infnnla weighing from 193 to 2R(i gruI'M less than nnnsmukcrs' infnntn in the rculqn+ulln shown (19•7). Tuhle a usinl; /latn from the 5(I,f1S17 hirtho or the Ontario F'crinnL•tl Mnrtnlity Study, .rhltws the incidence af low birth weight (Ixrcent under 2,!oq grams) for t.hrcc Icvcls or maternal smoking antl for subcategories /,f hospital pay status, mltthcrn height nncl wciRht, and the sex or th,• child. f k:siritc IrcrccnL•tgcs nf hirths unllcr 2,fi110 Mnma that vary frnrn 2.7 I>Lrccnl for nonvm/rkcrs who were fi}I inchcw or taller to 1•rr.R I><rct•nt for smokers ctf more than a Ictc•k IKr day who wcil;hcIl I#--,,4 than 12(! iwtunris IKfnn! llrcl,•nancy, the incre:tatA risk of having a Ir,tlty, w•cilzhinl; Icc•1 than 2,501 grams is tem;trk:tldy atallll--11IM/ut 70 IK:rvent frrr women who smoke Ic.-.+ than a Ictck uf 1'ig:lrelUn lKr day nnrl alwuwt IM percent for smukcrm of a Ir:u•k ur more I>Lr Iluy-comiwtrivl with the risk for nonsmokcra (119). The picture that cmcrgc.w from these finding% is that lrirth wcighl in affectcvl by matornal smoking inclclK:nllently an1l to a unifurm cxtcnt, rcRardless of other rlctcrmin:tnLs of birth wciAhL Comlmriwns or the Imrcent:tRc distributions uf Itirth wcighLs for smokers' nntl nunsmokcri babies show a downward shift of the whole set of wcighLq of smokers' babies by about 200 grams, as illu.tratal in Figure 1(1U•?). In other words, the dala displayed in Figure 1 corroborate lhc im(xewtion that all births arc affectod similarly by maternal smoking and negate the po.a,.ibility 'that changes in mean birth weight arc clue to cxlrenx effecta in a few caaea with other caacn unchanged. Placental Ratios Authors of a few earlier studies in which placental weights were analyzed by maternal smoking habiLs noted that thcac wcighLt were either not affected or wcrc less affccteIl by mat,crnal smoking Lh:tn were Irirlh weights (RI, R9, 125, 141, 202). A.s a result. Ixcausc of the Ilovc-rclatcd reduction in birth wcighLq with increasing numl><r of cigarettes sunl>kcrl, the ratio of l+lacenta) w1,iKhl to Ilirlh wt:iaht, or placental ratio, tcmlcd to Iu: Iargcr for smukcrx than for nonsrnokcrs• tpi1.F: 'L-Mt•tul brrlh wlvxlrl nl InL:urlN ul xmokrnK an/1 nonarwrkintt mnlhcrr, by n(her hinloair Mncl wnel/rec'onnmic ferlrrra M..e Lrd .LfLnn..•-.•i„A1 fR.) Hnn.~....1rnKmirNyml rn..t.~. yh• ~NI yr.n r•~..r. baA •:2.•'or A.e.. r...l.. r..y.K..wr7~ rriRAl .• Irrl IL. \.~1aJM ,..li• nlwa~.eL,.. IAae AipA w•A..~ Rrrlu.tr ...A.n 1.11R ... . a,,. a.~.a IIwIu/J'~ nl.r.r'rr. 4w. IA.n kiK11 .rl..d pa.lual~ v.~M t, I:I6 x.....~... ~,rs N.~..~I'~ .fIY1aIMN: Y...AIIA.I I.LM1f, M'NN' ~.«ri.rr :1,171 tnl•Kr.....4. ", /IJ.l,ul 2wl 3 301 2AR z.1 rrc >a; Kullanrier aml Kacllcn rclwlrtcrl irl:lccntal ratios of 0.171, 0.17.'i, 0.178, and 0.188, rcvpcctiveiy, for nonsmnkcrv, .nurkcrs uf Icw than 1ll riRarcttcs n/lay, lhr><~c smoking 10 to 2Q u Il:ty, anrl those smoking more lhrn 20 cigarettes per Ihty. Iuulevl on a proelpectivc awly of 6.376 1iM(tnancica in Mnlmn, Sweden (0). Wilson compared the rnliox of untrimmcvl, froah plnccnL•t wciKhln to birth wcighla for 1.895 deliveries in Shcfficld, EngIand, finllinQ u sil,•nificanlly higher ratio for bahics Iwrn to smokcre than to nnnsmokcrs. I lc sugl,•csttvl thnl the incrc:v•c miRht signify a response Iry the placenta to chronic hypoxia in the felus (202)• Wingerd, et al. have now published a clcfinitive study or this reiationship, using /lata fronl a prospective study of 7,Ot)0 pregnancies imong members or the Kaiscr Foundation Ncallh Plan in Oaklarnl, , ' 8-15 8-14 SLEL OiLIS

15U 11 5 11.0 135 115 85 is 1 37 I I 1 f 38 On 40 11 WMh o1 pMUMon 1 I 1 42 43 E:1(:lllt!•; 2.-Itatio of placenlal weight to birth weight by length of Re*,tation and maternal urx4inR caleRrwy 3UU/u•1:: r,y,..1.1 I&•n whether this might I,< clue taf :t corn.wtxlrnling reduction in the duration of Qesl.zlion if the mother smoked. In his study of 2,G42 women in Birminaham, EnRlan4l, Iwblishwl in 1959. Lowe net.cvl that the infunLq of smoking molhcrm were dclivcral only 1.4 rl:tys earlicr on the average than lhose of nonsrtwkcrs, not enough to account for the mean birth weight reduction of 170 grams (101). Su!>gcqucnt studies of mean gestation have shown similarly small differences bclwccn mean rlurulions of pregnancy for smokers and nonsmokers (2, 19, 20. 67. 72. 161, 157, 166. 20R). For cxam111c, Bunchcr, in an analysis of the 49,89? births to U.S. Navy wivcs slwlicd by Underwood, et al. (189), fourxl that the mean duration of pregnancy wa.s only 0.25 weeks shorLcr for male Ifabics nnd 0.18 weeks shorter fnr femalc babies if the mother smokcct during pregnancy (19). The finding that maternal smoking does not cause an overall downward shifl in the distribution of Kcstalional ages, such as wti' shown for Irirlh wci(;ht-r, Icads to the conclusion that the lower Irirlh wi•i/;hl nf snwki•rrv' inf:fnt-v must IK clue to adirecl rcl:tnL•tlion of fetal I;nsNth In othcr w•ords• lhr•sc infanLv are small-for-iL•ft.cs rather than I~r~ l~ rm 't•hw trulh nf lhrr rnnt•lu.iun h:1.r IKrcn dcrnrfnslrutcd by vlwlif•-' On K hn h rrn :In l.1rl h w~•i~hU tir IM•rc1•nlages of low-Irirlh-wci}{hl lrrllir•`1 I f•i(;Ultf•: 3.-Mean birth weight for week of Retatalion according to n,alrrnal smoking habit: control week xinRktona M.dr.. N k. (.w kcrc cnmlr,frecl within unila uf gcrt:tlional age. Butler nnrl Allrcrrnan, in an analy:cis of flata from the lirilish Perinatal Mort:•lily Study of 11•(IQ0 hirlhr in Great Rrit;fin in March, 1958. fouml lower mean birth w•ciRhLx for smokers' than for nunsmakcr•: babies at each week of gestation from 36 through 43, a.s shown in Figure 3(lu). Evidence of thc samc birth weight relationship is preuwenlal in Figure 4(11:!), taken frnm Mcyct s analysis of data from the Ontario F'crin:lt:fl MrlrLflily Sludy (112, 14:1). This Figure shows lhal, as one would cxlwcl, lhc prnl.rrlion nf births tfnrlcr 2,.'><ltl grams dccrcaacs :w gestation incrcascs. Il nlso ahews, within each (;cslalionnl age Rrouls, the cffecl nf maternal smoking on birth wcighl, uq the frequency r1f low-weight 6irth.i increaso directly with smoking level for term births of carly, xccrngc, anrl late time nf delivery. Fetal Growth As the low birth weight Wt.v,ciulcd with maternal smoking is independent of gcstaliunxl age and is not clue to a significant reduction in mcan Rcslalinn, it must therefore IK clue lo a realuclion in the rnt.c of fetal growth. In several studies lhe relationship between rnat.crnal smoking and other IxHly mca..urcmcnLv Iksidcs birth weight has Ixrn czamincd. Kullandcr amI K:tcllcn, in a Irro.{fectivc study of 6.376 births in Malmo, Swcxlen, found lh:fl, :f.v.lhc level of maternal smoking lncrea,.cd, the Ixxly Icn/,•th, head circumfcrcncc, and shoulder circunr ference decreased consistently for bolh male and female babies (89). N-lx , tl-t~ LLEL 01Lt 'S

wr• Il:cll:,nlym• r•nnrIuricrl liy 4l„li "W. lhrro i~ ruuc h rl ul l, lhr rr•fnn , n knrJin~ lhe evil cff,•,.tnR nic•uti.nt {n rulling Hlroirl anlr•n:,tnl lifr~, tIu•rc ~•cros lrr IK nr,:rh;ulr,w r,f rlnul,l lhnl thcm iv it vr•ry Iart,r• inf:,nlilc ninrl:rlity in Iwrtiln:,u,l Iifr, nmcrn{,• lhc• rrffrl,rint; or wrrmc•n wurkcrr in l.ul,:u•cn. 1'(K-4ild y tl,i, ,,,., r Irc due in Ircrl lrt thc infl,rcncc rrf the milk. I,ul it is murc Irrr~I,:,I,I,• th;rl it ia crn accrrunl nf crrn(;c nit:cl rlcl,ilily." I)iscu.-.%ion uf lhc Irroblcnt or smnkint; during Irrcgn:,ncy :cl lhc• Irrrr, of lhc ccnlury :yqm:crx Lo have Iwcn I,:wecl rrn empirical anecdotal rcllrrLt. Until the cnrl of the 1920'x, there wtw ;, rclxrrts on this topic in Lhc scientific literature. Thcrcaftlr, ;kvcrrl articles were Iwlrlisha3 reporting the rcrulLv or animal tilurlic.r rrn,l clinical investigations Ikrlinenl to Lhe effecta of nicotine uncl nm„kinL, (luring pregnancy upon rclrrrxluclivc loex, maternal hcallh, urri prcgnnncy outcome. In 1935, 5rmtat; anti Wallace (1Y.5) invcatil,•atAx3 the cffccl, nf cigarette smoking cluring pregnancy upon fetal heart rate. Their of>Lccrvalions were m;ulc during the Iasl 2 tnonlhe of frrrf,rnancy nn eight mothers and their fclu.cs. Their dala rrvcaled that the snwkinK of one cigarette by lhc pregnant woman generally proclua.vl an increase in the rate or the fetal heart Ix;at, and sometimes a decrew;c. They concluded that there was "a definite and real" incrca.vc in th,. fctal heart rate after the mother ce/;an to smoke a cigarette and that this w:~s frrohnlrly duc to l.ran.rlrL•rccnlal transfer of nicotine inl.o lhr• fetal circulation. In 193.5 and again in 19:3G, Camplkll (2.7, 21) rclx>rted that heavy cigarette smoking w:u prejudicial to efficient chihllrcaring nv a result of chronic nicotine poisoning. Camldx:ll warncvl that excessive smoking in certain cases wa.v clctrimcnl.:ll to maternal health. lie nol.cvl lhal, in gcncral, a woman who smoked clurinK pregnancy wa.v likely to have more difficulty rlurinK the coul•ac of pregnancy, parturition, nrrl lactation than a woman who did not smoke. In 1940. I;,wcnlxrK an<I aawciatA--A (46), in a wcll-ilesit,rnerl slurlc• investigated the effecLi of nicotine and cigarette smoke on pregnant female albino rats and their offspring. The three groups of subjcrl" included a group of animals that received inlraperitoneal or sulx:ula- neous injections of solutions of chemically pure nicotine, a second group of animals that were exfxr.aa3 to tolwcco smoke lhat afrlrroxim:rt• ed human smoking of one I>ack of cigarettes a day, and a third groulr of animals that were unlrcalal. The immediate effects on lhe animals in the two lrcatcvl t,rroulK were similar, although more severe in lhc injected group. It wa" reported that: 1. Two-thirds uf all the young of treated rnolhcrs were unrlcrwci/;hl• lhc young frrun niculinc-injcclcd rnolhcrs were morc umlcrwcight lhar, lhuvc frum nwlhcrs cxlwr.cd to lnlraccn srttokc. p. Thc on,lcrwcil,•hl {;rrwlr rcrnirinerl unrlcrwcit;ht rlirrint- the c IM.ri,Ml or ulrwvrv;,linn; many uf the ynuna or thir {;rnulr were un,le ni~c~l nnrl clicrl early. 1 ltf th,r fcmalcs injcclc!rl, 6,11.0 l,crccnl Icrnl one or more young wcuning, nnrl:3:3.3 I,<recnt Icra all of lhciryount,•. ,ltf the mnlhc-.rq cxlx,xLrl tu lnh:tcco smoke, 29 IKrccnl In.rl one or m„n• uf their ,ynunt,• 3K•furc wc:lninl,•, nncl 25 Ircrccrtl were urnlcrM•c•ighl. , f1f Ilrc rru,lhc'rx cxI«rs<•rl lo smoke prior to malin{, 2'3.:3 IKrccnl Ir>al. nr mrrrc or their young I,cfnrc weaning, and 25 IKrccnl were undcrw•cighl. ,; In IMrth {,•rnulw of lrv:rlecl molhcrv, tcmlxrrnry alcrilily, resorption ,,f %„rrng irr rrhvrr, :lnrl ulw,rlions were nolccl. ;, AItor:ctiun of malrr•n:rl I,chavior was ol>lscrvcrl, consislinfi of ,;,nnilr:rlism nnrt nct;lccl nf lhc young wa to care anrl fccrlinR. Thr findint,^c uf F:c.cnlK-r{;, cl nl. (4G), rc3xrrlcvl in 1940, raisccl nt quc+lium regarding the cffecLv of smoking (in Irrc{,rn:rnc)• ,,t,.,ruc that were not invicelil,•atal in depth until some 20 years later .Iw'n SimlKon rrpnrlwl her findings (172). {trKUILa of clridemioloytic:ll surveys anrl experimental studies aplrear- n in the literature over the past two decades owe much to ,eyinn•cmcnLs in research t.cchnulo{,ry which conlributtml to rnorc „rural.c anti rcprcwlucihlc mc-w.urcmcnts in the lalwr.rtory. For •%xmplc, nicotine cuncenlralions in minute amounLs can I,c determined rith /;:%% chromatography, uncl the dcgrcc of carlxrn monoxide .h.plarcmcnt of oxygen from hemoglobin cnn hc ncvccurcl with r••n>idcrablc precision hy I,iol,hysic:rl methodology. Use or new rrrhnalngy ha.s often permiLtlYl scienlist.. to confirm earlier irnlrrrs-• nbt.iincvl with the use of crude Irut ingenious biommays. Such •l.nfirmalion is a tribute to Ihc frcrreldion nncl Lhe dcdic•rlion of these I•NmirrinR investigators :rnd a.dutc clinicians. I Snwking, Birth Welght, and Fetal Growth IGrih Weight KibK•s born to women who smoke rluring pregnancy arc, on the I`c'rsRc, 200I{rnms lighter than I,:rbics Ixrrn to comparalrlc women who 'b, nol smoke. Since 1957, when Simpson reported this finding froni her "riginal sludy (172), it hwx becn confirmed by over 45 studies of more than half a million births (1, t, 7, 20, 22, 29-J1, Jf, 41, 47, 34. 61, 62, 71, I 89, 90, 101-103, 115. 118, 119, 12J-127, 137, 141-1 4,t, 145. 147. 151, 1%~ lS~, Igl, 16J-166, 16R, 149, IRS, 1R8, 189, 190-192, 208, 212). Rcsults "f these sludics are exlrrc.r.rcd a-s mean birlh weights of smokers' and n^namokora' babies, or alternatively, as lhc percentage of babies who `riRh Icss than a efecificvl amount, usually 2,500 grams. The meLhoJs "^'I r'c•.ull.s of 28 studies carricJ out between 1957 and 1970 were a-ltl £L£L OTLLS 1 e--11

! (!t) B.eaa, R LAaawaata, l. T. Tb. relalloaablp ot anleaalal tad pool• ualat faelur. lo wddra unralw.lrd d.•alb In lufaarp. l'uudlra )Ldlc.l AeanrlallnrJ..uraAlD(: 111C itlt. )lay 3k 1144 . (fJ) Araumm, l). AeNl.sa 1'ratnRrae du eulfe/e d& nlcn(Ine eur 1'enJ.rf..o de pptwlrt. (Tera/uteak aellua ut alea/lae ull.lul. .w elJtk roul.rye.) ('neap/r. Reedua 1Ir1.d.rradalrra Ae. R.aaerr de 1'Aradaaile J.•r SHeaee.; 11: Bcl eace. Na I u rrlleo 272 (1) : al]-470, J a a. Y.t 1071. 8utunl, K., Ilmrauryl, T.. ('owaa-Ilaalnu. A. (:., 1Juu..ra llLUUru, R.• )JouaaluA. I1. O., AaAUrwaa, K. I`barnatolWttc rR.r/w At ulrntlae ulea Ike fe/ua aad taa/ber Is Iko Rbewe aw.akH• Amerfcaa Jnunul f.t (WrtHrk.aaA AfareMwRt 1111N) : 1002-1101. 14e. 13, 1071. (DS) Traatk 11., f>aeje. R Y. Aa MiIderaiMaRfe afudT At hre+wlurllf. I. Rtlallna 1.a aoeklaR, heart ealume,.o.plyawll. aad IslayW4uoir. Arer(na PAUaal ot06NNrknta/afaae.iap 1lq(A1:36N-110. re4L 1, 1000. (N/ Tr/eatn. (`. It., (nw1u1M, (; P., lhel.+aa r. J_ t raaM A. ]., ru.c.- (l0I) Wrl.rM• n. kt.• Oouur• n., Ai.eA.u. A. 1'. (`oMMer. A. II. RRect At earyme IuduNlno nu Ib& auelalwlbua i.f Irurn(.yprreue aad ]•ntlhilU• aroaowt/hllaminwenl.euurv bi Ibe Iirrtiuol eiwl felul nl. (`encrr Ite. aeanrh 011-D7K blaf !Ol2. (100) \V•ru•u, Il. It.. IlAaelaoe• Y. 1C.• llouul, tl. W.. rorrLen, r. J.. rIaart., N., Coaaer, A. H. Allsulalnrl• eReel of clRa.etle amoklne oa the hldrorll.• tlnn At !,4-IwnLhyteae aad Ihe N-demelhtlalloa of l-nNhyl•~•a oeo ulellitlanllanaanl.euteae I.y Mtfua. In humae placrnt.. 111a1ey1 Itiiar• satoloRy am1 •rkeralieaUca le(1) :10t1-1(O. ].uuart-February 1000. (1/1) 11'luoa, K. \V• The efeel at awoklne la Irregmuaey ua lhe hlaoeatal aatti- ekal, New %alalul AI«Iltal Jnurua174141G) : sAl-3116, 1012 (!l/) N'iMN4 C 1, IIa1PyAaM, U. 'lrlweee aad I`nbateo 9.eke. Atudle. Is RrpeNraeefal f7anNtrnReaerl~ New York. Atadeiuk rrru, 1007. 730 lys. (llt) YnuaMALwt. l. lahale with lnw4dr(k weltbt bura Lefora tkelr reolken atarled /e aarak* elpretles• Aavr(eaa Jaurfal at O1rtNrfn aad dlme- teladp 11211) : 271-yJN, Jaa• 10, 1072. 3•e11u111ALUT. J• ktalher'r elttare/le aaeaklaA and aunlral of IufanL Aeer1- r1aa., Y• J. Allentlaaa Ia r+rndrMLa trart)awa at whlle rele awr elaltd wllk Ia11J hpiwra ta ta/er/lae. Jwrwal af rbaerarNnlu' oad (113) Rcptrlaa/a1 '1'1saapealkw llt: 1-1R 10M, (!7) T.arPaaM, W. 11, NkMl..la ta.rall IuUk. Aaiwiewa Jwr.al af Ol../etrtes (11J) a ad O f arc.l+fs 28: IIM2-tltl. I OSi (01) TaZL.e, 11., HarO.on. E, >lt.krtrntllr, C. lI. PawRe at "C-alcwlne and Ita U%eleball/ea Wa.lea taMmanwaad Idateatae. Acla IMrarwur.InRka et Taaleetntk+ y(dl : tVOdIM, 1tNK (b) uatMrawem, r. n.. llearit r. 1-. /.Alntt>L T.. Jr.. llaraeq K. \. Tiw r. Llln.- rialp at anaklaR la fka au(taare at peRaaaer. Aaserlera Jnunul at ObNa(rke aad (11•aer.doR2 t11:) : 210-n4, Jaa. 14. i0L1 (!w) ilarxaweaq P. n. Kt~aLOt K. r. (Yt...11. J. lt., t•Ar.L.a... 1). A. r.rra/al rwklat ewarledll re•la1e.1 ta Iv.itaaary autt.are. (Na1Mrlea aw1 f1,weemMtf 2111(1) :1A Jaarnar7 10lT. 1101) 11.R, Prnalc IleA/aM tlnataIL 91r II.~allb ISwuwqrearw .if VwnklnL. A 111ersrt at Ibo n.r*rw l)t.rrrl : 1011. \\'ahlaa(•al. Ir.M. Irryrrlw.vil At Iteatlk, rArea/1M aaw \t'elfar.. I)III:W rahlleal/na An. 111N]1) i1-lG1% 1071, 40/1 A, (l01) U.OL hraLrr NeALtM Aselcs 11. Heallb (`aeapurwrea at Amnl•Inlt. A Il.part of tlu f4rrNeoa (Iewen.l: 1611 \t'aakla/e1na, II.A. Ittlarlas.•nl nt Nealtk. Rolacrllna, aad Wdflra, r1/1R\I' Pwdkal/oa Na. /11A?I) Ti-tt14. lVTt, iHl lp, (1/.1) U.L Pu" Hturar Aoaaca NA»arAL l`tsrra rroa Ib.u.rM ArAtIe.IM NtltAt at birlk aad aar.leal af Ike ataMara-Ualled AlalM Hrl1 10t\0. waaklrytlm U.N. flrprlrae./ at I/eallk. Y/lueallnr, aud lYelfare• ruhlk Health Aertlee P+blka/lael Nn. 1(104 Aer(ea 21. NA. 11, Jul), 1DK'., 11 pp. (!0{) VAU. P.. Ktarluatx, A. Tbo eRM af alrollao aa the feaale relJJt aad dwotepla( foe(aa. As eepnlareaf.l aludf. Aaula NeJle/uae Eeherl- aeoalallaat nwaalea 1lraalae'.D:2AQ-211• )YSt. VeaoAaY. r. Naalprlwa nlednl.oeM watarlar e u prlarty• (C.en.reluencw (1N) 41471 e[ Hlarla C/eAtlewel la e.oiera) Polable ArcWwu. lledpefas wow.Nrwl 20 : 30940..'. 101'rt Vsatnst. r- I.AUaa, 11. IILy/ek w11anIaf e w narsaAaeh aalf pndAaalck dalalaala drwu 121rfa.eta IlaOaeaef at lehacre awnke aa a.rnrhle ae/d e.alaal Ia .na/kea• m11k.) ANa rblalnletlea fWoak. d(d) :1.l1- ILA 1061. VRa/sli.T, r., I)aMtaA A. \Vpltw halewlo fllnalu aa Melmn M•Ilannlnl e w mleku Kdd.yin. (The IaAuenee At Idaree aarnkln/t m' Ihe le.rl ot tllamln 1: 1a buaua imllk.) reJlalr(a rnleka Jt/101 :R11-N17. 1W/S. I tea Journal at (Asatelrlrw aad praecelnq Af1M : bOG-O1N, PrL. 14 11114141. YnuaMALUr, J. ></a11a/kaI tnalidee.fla.a and e.aluallna at eplderalolnel• eal eeldenoe. !a: Jaaaea, Q., Rorwa/hal, T, (Rdllor.)• ToLatco aad Health. dprlat;Aeld, (Sarlea C'. Tlwruti 100', IML *-W230. (11S) YaYUan.LU V, J. Tbe rNat/.rufblp nr parral.• elsarelte uaoklne la ouleeme ot pretamaes-Iaq-lleallaaa aa ta tbo praWen of laferrlnt eaulalNwe frem a4Nr.ed aaanelallana, Aarer(raa Jaur+ral at I4•ldtWle4Kr 0;1(0) :4I11- 404 Jaao 2071. (llt) YnureaaAt, k1. K, KAe/c~ A, NAwoaru, J. C. Clprelle asoklne tIuMae (117) nr'tt+loaes: Tko efraet upea Itw Mraafecrlt arwl arld-Ir.,. Irlnc•e of tba neerl.urn lafaat. Caaadlaa )yedital A..nelallon Z.wraat fNl(0) : 107-'0Q AuR. > 100d iouaoasat, kl• K. Per.naa, J- Iiawnatu. J. Q, Pelal Rrnwlh retarAallea Ia rala oalw•ed tn elAaeNle.arke durlnR lirry(aancf. Asnetlean ]oureal At OlnlNrlal aud Ataea•atrtiT 1u1(A) :/"J17-1_tA AuR. 15. /llOp, (118) t.ruatle, J• lt. RReet af tlplntla ernblat durlna pretnancr. BtuJ>• of 1;000 eaaes. Olrtetrfa aad 0ra•tolalv Aprll 104L '463 46' LS£L OtLtS

I r,nd dewide•ratiun elf prcgnaney .... ............ e; ttabtt .N..nt.n..... .t-, - trr IIIp treRnanrr. nw,uw..i.. 14-Ltiri rnL s.n.4.•.. N..w,m.len Tntaf .pnntan,.w. .Iwtinn. 91 7 2 1 -11 PrtRn.nrr .v.nt..l 7.e {q 1 pn 1'rrl[n._r un..nlr .l 16o 111 t.11 sc7uRrr Kat.n.k.•1(/ot percent), but the increased risk of spontaneous aborlion was seen among smoken: whether or not the pregnancy was wanted (tT9). The mclhaul for slwlyinR spontaneous abortions that may be th,• least subject to error if carefully done is the traditional, retrarix.•ctive, case-control approach, used recently by Kline and coworkers (A7). In their study a log-linear analysis was used to test the hypothesis that maternal smoking is associated with spontaneous abortion, controllinR for confounding variables such as agc, number of previous spontaneous ahortions, induced ahortions, and live births. Of the cases uf spontane- ous abortion, 41 percent were smokers compartrt with 28 percent of the controls, giving an odds ratio of 1.8. This Ieada to the conclusion that smoking during pregnancy is a risk factor for spontaneous abortion. Perinatal Mortality Most of the cpidemiological studies about which questions of causality have arisen have usal porinaltal death (late fetal and early nconatal), neonatal death, or combinations of these as their outcome variable. Ascertainmcnt and recordkeeping may start at 20 wecks, at 28 wecks, or at the time of registration. These differenecs in definition anti desif,.n affecl the study results but are not fundamental to the baaic questions raiac.l in the 1973 report and by other authors. Progress toward resolving these questions has been made since the 1973 report through new studies and analyses in which attention is paid not only to differences in the number of cigarettes smoked but also to other characteristics of the atudy populations. A table from Fabia's study of a 10 i>ercent random sample of registered births in Quebec in 1970-71 illustrates this approach (Table 5). Within subgroul's of the population by matk-rnal age, llarity, and years of school, the relative Ixrinatal mortality risk for smoking versus nonsmoking mothers varies from 1.00 to 1.81 for categories with at least 10 dcaths (67). Table G(117) shows examples of a number of studies in which tX81 F 5.-1'erinat.l mortality ralen per 1.(M10 live hirths tlrnokinX and nonsmokinA motherti and relativt ,Hkn for lnfant* of Amokers by maiernal aRe, parity, and years of achcwl (10 % random aamplc of medical certifica(es of birthR in ()uelxc In 1970-71) .....~LVkIN I,fnn G.. IwUM TM.1 LLIl. (Friwt.1 .k.1r t.r c.,.a..: nnw.nv.6n A.Ltne .:.4 Nnn.~krn anv.l,m er 1.fM, 121 1111 1 v u t,717 126 112 1m 1S7 2.1n 417 , 11t1 ( 2.711111 142 2 IR 7 132 a.9'e 111 112 1 M ~ Will 21.R YC1 Irr . ...a 1 ~ 1./n0 145 IR e 170 .u 3.043 126 11.7 154 1 t.• 1.170 las f R91 (066) CrM4.MG.nb..+thw h..lJ.. I.rol Nu.. I re.av etr. (.4ulr IWr•Rrr-r.rk j ten irrinatal mortality rates by maternal smoking are shown within .•ytel,rories of other relevunt factors. Thene studies show that pc:rinat;el nwtrtality ratce vary with maternal smokinR level anc' also with tlu ..thcr faclurs ehown. The general stnl.emcnt can be mnelc that the •tt•lrimental effect of maternal smokina on fetal survival iR Rrcntcr in taoup.i of women who already have a higher risk of Ix:rinntnl luss for .ahcr reasons. Women ehnrnctcriaal I/y low social elaxv, low level of tducation, {css than optimum matcrnnl 11{;c, or lxinQ black have higher ri.ks of pcrinatn) mortality than their count.crpart., and their relative mrrrx+c in risk duc to maternal smoking is enhanced. Studics in which tlit- lwpulation, by design or by chance, inclwh,.h mainly or only women vithout other reproductive risk factors show the smallest differences Ia'tween the risks of smokers anll nonsmokers (Yf, .10, 47, 1y7. 155, 169, .'K) A scri(!s of articles by Mcycr, et alL reports analyses of dat.t from the t)ntario Perinatal Mortality Study of all single births in 10 Ont:lrio +e•aching hospitals in 19G(1-61, including 51,490 births, 701 fetal deaths, an'1 655 neonatal deaths (115, 116, 117). t: or the Ontario stwSy, '1'0nsored and supportcd by the Maternal and Child Health [Sranch of the Ontario Department (of ilcalth (1a 14.1), detailed data were 8-32 { 8-aJ i'i8£L OtLi f5

I (tI) Doware. O. l:. OrarrAr. W. t deaokl.d ud pr.a.aael. A atallatleal rfudy .t 11.11111,11 tniksta Gllfor.la Yedkloe 1W(Y): 1111. tlarr4 ItMti. (tl) DurtuS U. Y, tJ.uOu.uraar, 1. Tt.e IaNde.ar at pr.eelamptk toa.erla 1o erotere awd reauaekere, lAaavt 1(7f380) : 1Ui-llp6. Yaf 11. 1062. (t!) 111rarua, W. Otrr W Verkeea.a. r.. NlcoUa Is der tTaueerllek saah YJpretteadeauea (O. I!•e 1Meaek+ at aleotlae Is IueeN mllk tol• lewl.d lfae sae at elpr.t/a.) ZeLadkelh tYr I[IederYWkusde 62: /1- 41k 10.11. (tJ) luearsrae, J. U, lbtwtq J. r, Parta., A. R. '1'ke eteeli at koll.. sad ettarette wike ar perp.asl tefaala alklae r.lr arl 141r uR.yrl.da Jour.al el Lb.wIMJ ad qlakal Madklas 25: 706-111, 1048. (:O )ltaatoa. J.. Ataeaaat, : D, OarwM. 1L Nrrlw Irralep.k etted of dpr.tte ea.eklad.:Katara 221: L2Li10, Jr.e 23, IIt7t. (Itl) fluam, T. Y, nart., a H, Oae+enr. 11. Oae...at, 1. D. Clpretle .reklaR asd pee.a/rrl/): A pnelwdl.e WW. A.erleas Je.r.al et Otrletr4cft asd Ofs6M.tif t1(t) : ML411111. Ma)12i1. (fit) Oau.r. R. R WYeei at' deatias as dttelt ata4rsa Atellras at Path.lap il : 02-a07. Dravea4t• 1wtK (t7) Oturt, tl. It. NkWlaa s.d ardtatesr/a. Aa e>hertaastal ./udl. Patkel- eitla e( Mlerobt.l.tl&17(.f) : 2t3-M 1e71. (t/) Oot..ruu, H, Oataaer, L D, haatttll T. M, DASt, O. Q Clpr.tle sr.tl.t asd preralartll. Jwn.al ef tlr AareHttia O.leutntl.k Aaef t4allo.N: W1-LMt,Jawerll0& (bl OeuJ.aa, J, Ihrat.w G. 1t..Aa., P. CaneteNellduea Ma/er.ellu et peldn dr, salwea.ee. Iltal.r.al eMr.eler4slrs ard Wrl>, avkf.1.) Iterue dr 1'ra//r4es 101YM, Nulyderr'sl ): f.t. fbit t>Q \.r. 1. 1f0p. (JI) O.u.nti 1. NIkNl..ertsltls.d. W.6aeNet 6N rlrew lltiedllad. (Nleo/l.e IrdwlaR u/wrrwl Is a Ln..l fe.Jlrt Isfarl.) Jet.rlruM frr Kl.der- Iralk.wlr I Iu: 131-12.. 111131 (31) IIAw.w, N'» Jr, Ne,t.n, lt. IL 1.. Oaseu. L Ilrekla= e.d preR*a.e7: 1•er/.r .urwaWr Is Wuad durlaR tpr+lalles awl at Lrw. fMrlNrke aad OYr....lu[) INI2/ : _'l1-2t7.ll.y/e.rker 1061. /!tl ll.n•ur^ N. A, /:ae.ar, H.'TM e1lselttallaw at sleNls I. IUe nllk. Jo.nul at 1'L.raanrallnl a.d Italerts,eaal TMraM 22(Il: 14 IRJ'1. (1.1) Ilawonu, J. l1~ ftem. J. D. Cesparlem at tb eteeia at a+alerwel ueder- rulritlw sad ea/rawrv le al prr/te reie.s 1ha.vtlslar Arwlk at Ib rat trlua Arerleaa Jwrwal et tlWelr4aa asd O).est.dl 112(/) : 003- llbAL Yar. 1, 157% (Jj) llLaow. 11. J. Tlu efeets at saeklag d.rltt; pretae•es: A rertew with a Irrrlww. v.w %tilasd 1JrJ1..l Jeur.al lil: WQ-fiJA, Nere.J.er 111141 (L') lir.awrr, A, IUty..rtM W. Z, tlmpt, r. 1. Clytr+tla.meklwd 1n pretR- sa rh. 1Aar.i 1: 711-M A pr. 14. 1 M2. (u/ JAa.r.aw. 1•. A.. fLrnws, lC. Plteel e[ da.i/sA dvtsd PrKeasH aft lke letM Mat"la asd delarety. A.salr Paedlalr/ae Iesstae ta: 1it-2Q. 1KL (t7) Jousa.r, n. 4 RtteaasS. J. W. N-Nttseaa,lw Is rwtta eesde.aate treo errer.l rarlMkw at /aL.ero. Jerr.al at /he Na/M.al Caser. ls- ruWe ~ALI : /MIA-t1t17. Juwr 1t/72. (AJ l Juouur. ]/. R. IL.us w"%tal UdnaJlaaea at 2.1•kesspfre•. durlwd rerl2 Rr.lalle. atil al IPe.. 7W.la.lq) asd AMdkd 1•kansawlodt tA/t) : tMl'1•41q llarrt, 11110111. (!1) Kanu. (`• 11. 'Ptwu. 1•. tl. Meeauwt.est at Ik. lNal eaa.ke Ia.u1wA tre. a Ler.ls; rltRarMla 9Wre.. 100(/0): 1/1-2l. Apr. 0. 1001), 4e SSEL OiLTS (1~) ~Ma J. i, asostr~ R. r. etudlee es slcetlN alror9ll0a durlJj QreYnea.7• 1. 1.L1.. for prrlte.at sod eo.pretnaat r.t.. Anerlcaa Jour.el at Ob- .telrtee sad Osuetolely 00(4): 60Y-a1t, Ju.e ltl, It101 CilaeCY.AUY. T. lt., Du.r., P. V, Jr, Dur=ttalt. O. R, I11. Sosu aeute eCeete at aswt/sA Is rkeep asd tkNr tetueta OYetetrln and Olseeelop 20/ ll : 027-tYW A pr11 1570. (/t) Kuick e. latauese/a dd kaWto de trsar wEre at ea+bar.ao, perto t reNea (111 U~l seNde. (L'teot at ltw e.wklsg luWt os laet...cf. dellrery, and tfe aewAorw.) RerlNa d. O4atetNefa y Olnecetegta de Vea.eaayala 21(4) : IDS-N1, lt!•7. XtnIastnf, t., Klusa. !t. A preep.etir..tud) of st.oklsg asd pnf+usef. Aeta /11mile1Nda et Oysec.tetk. frasdleartaa 80(l) :!J-04, 1071. ruraq D, Lwaua, P. A. atndles es kura& ptea.ature t,lrtka 1t. fs rlre efeM.t awklaA sad Is rllre eleaK of akNlae as kuaeas erierl.e ee.lrati111t1. A.wteas Je.r.al e[ iXaletrtes a.d O1isseliteA1' n(11) : 113-411, Oe1.1.10ti3. (It) Lolte4 L D. Grtw taesetlda' /n t1e ptKsast tet>ter asd letrut asd Its eaelnftAe aew.t tke plaeeala. Assale ef /w 11ew Yerk Acade.7 et 8c4wne 174 (11 : l13-211, Oci A, totfl (M) LowR a It. Ittteet at e)eliere' sueWst baklta eM birth welgkt e[ tlwlr e.lldreu stfllw lledlr,al Jettrsal 2: ti7f-a7f, Oct 10.1900. (J7) Mctbtrua i. L, Irtroy O. !. 1CleeU ef ea.oklaA as selected dl.leal (N) (4111) eletetrle tatl.ra OlrMrta asd Of, ~tatU 26(4), /70-t70, OeloMr 10w MaOA.ar, J. LL, Arsawik J. 5e.ek1.A 14 peepaact esd rltaealn D. raetakeltsk RrftW Medical Jeur.al 2: 74-77, Apr. A, 1p72. MaeMAeutt, D, Atasar, 1t., 1)auat,, lL J. I'.tast wddYt asd parental rekl.d kaklta, Ata.e4ees Je.r.al at lp/denlet.Rr S2(t): 217-2e1, Nereoker lOtiO. (l1) Maerat, 4 D. 1MtellstR Is prepanet: TfU at plaPed l1 cerboak aebi. drw tfew Leal.ad MMkal le.r.al 43: fa01-d00. Brptenber IOM. (il) Ytrss, M, s, Gutnac.. A. W. Ma/etwal Hprette s.eklst and perlsatal ametalltt. A.erleas Jalr.al at lplde~l.lep N(1) : 1-Iq Jul2 1072. (l!) Mw, O. A. TMaeee aseklst: {s.e h1s/e et Ita kleloale karerda. Okle I)tat. Madle.l Jwrwal 44(12): 11t16-1174 t1.ee.4er 1256. (q) Me.a6 U, Ata.es, l. CatelseAeak aetlrltf at allpkalle Iltroaaslae..Ia tlu .e/Mth taUk /a Ib etqtlatr at 111lrlea Oetde% hankter.. Praceed- lap at W t)ee/etP ter lapeettawta! pla/ap asd MeAteSw 1360). 1001-1000, Marth, 11a71. (ld) Ho..aant; !, Mu..ks/a; IQ N. A etudf et p.e.utara Wrtka. ladla (W) (N) le.rsal at Pedlatrta Y(2t10/ : 2lp.tOt; (leleber 1071. Mtn.a.e+r, 11„ Kr,t.rk l. 1. lSert ef ade, parllf, sad elpnlte ea.ekle= ." o.le.+..t lmPxtf. Asurteas Jwr.al at l>•aletMn aad Of"calotTT 101(d):A14i/0,Ju11l0,106i Hut.da.*. 1L, lttrwr, l. Malersal soklst; aad lke f1.IsA at daltrcrr. JMrYl at the tMa\ Medleal Aaarelatlew 110(1) : lt111-17T, Apr. 1 l012 , . (11) Mlttaaar. It., Mosr.r, J. Masrt., •. Ptacealal ekasA.e aad a.tereal wdNt 1. eaeklat; aad sea.neklud awtAerL Asurteas Jesrnal at Os- .tNrks a u 0,112,0081647 101(e ): 7111.701. Mae. 1. 1P74 (N) Muueo.. D. l Itlrlk wNAkt aad oa+ekla:. Nekr.ekAt tltat. M.dlcal leue~ sal ~A(11) : tl0l ~ Norerket 111161 (N) Musesr, J. r, Mut.aA.r. R.?ha.Reet etap, Mrlls. aM elA.wlte a.ek. tat e" kakf wNd\t A.et/eas Jwrsal at Ol+etetAe. ay llf.+cotot7 111(1) : l3.2a tlept, 1. 1171. .~

i l 1 1 ) ;I. ~! ratio of plnc•cnL•c weight to I,irlh wciKhl Incrcn:" with incrL. nK levels or maternal smoking. This increase ni:cy siKnify 1, r•cltlronsc to reduced nxyKon availability due to carl)un monnxidc an,l may have eomc survivnl value for lhc fclu.v. 4. There i.r no overall reduction in the rlurallnn o( gcslnUnn wilh maternal smokinl;, imlic:rlinQ lhnt the lower birth weight or Hmnker'• infanlv is due to retardation of fetal fzruwth. 5. The paltcrn of fetal growth r•clarrlalion that nccurrv with m:tlc•rnal smoking is a rlccrcn.vc in all rlimcnsionv: lxHly length, chcYl circumft-.r encc, and head circumference are smaller if the mnlhcr xmoktnSmnkcr9' Iral>icv are short for c1aLn a-Y well a.Y light and do nol cxhiLit reduction in /xonclcral index. 6. Sturlicv of IonK-lcrm I,rrowth and rlcvclolrmcnl give evidence thal amoking rlurinK lrrrxnuncy may uffccl physical Qrowlh, mental development, and behavioral charact.crislics of children al laut up to the age of i l. 7. Overwhelming evidence inrlicates that mat•crnal smoking during pregnancy affecLr fetal growth rate dircctly, that fctal growth rate is not due to characlcrislica of the smoker rather lhan to lhc smoking nar mediated by reduced malcrnal afqKaitc, eating, and wcil;hl gain. ClgareHe Smoking and Fetal and Infant Mprtallty Overview In conlrauvt with the slrong, con.vi4t.enl relationship of matcrnal smoking to ralucecl birth weight, the rclalion.hifi of maternal .rmokinK to pcrinatal mortality ha,. lwvn marked hy variation in the level of increased risk for women who smoke. This has lal to ctnlrovcr-+y n.v to whether there truly are lethal cffcct-v for the fclug or neonate cauK4l by maternal smoking. Earlicr cfriclcmiulc4,rical Ylurlics of lhc av.vocialinn Ir<lwcen matcrnal cigarette smoking and I,Lrinatal mortalily (fctsrl dcnlhx, nconat:rl deaths, or Ircrinal:rl dculh.r) were reviewed in the 1971. 1972, and 1973 reports on TLc Hrnllh Conraynenr.s of Smnkinq (190-192). The 1971 rcfwrl gave details of 12 slwlit..~s of maternal snx>king and lhc incidence of slontancous ubortion, slillbirth, and neonatal death (20, 41, 54, X7. 101. 141. 1.51, 164, 166, 188. frM, 212). The incrcmv-vl risk of loew among smokers varial from elurly to study. Inconsistencies between studies were cleacrilxxi, and it was noted that both smoking habits nnJ pcrinatal lovs were influcncal I,y such factors as social class, matcrnal a{ c, an~l Irarily. Itush and Ka.w reviewed the English language lilc•ralun• in 1972 unrl found rclwsrt.v of 12.388 pcrinatal deaths ancl alm,rtr+in+ w,tlr a rnvan cxcr:cr IK•rinal:cl hr.v fur srnctkcrrv of :l4.4 Ikrccnl• Whrn• rol-rW.l, c•xci•.m hi\v w:w higher amonlz the txxtr anrl arnon/; I,I:rrkv Thc•,r rlu,ly or IJ:u•k anil white wurncn in 13uYtun showed cxcc-~< 8-'2R ,1 mortalily risks of 86 percent for black smokers anrl I1 Ixrc, for w hitc amokcrs (16.Y). the 1973 report (192) summarizccl studies lhat were published up to lhlt rlatc and contained a critical analysis of known reasnns for cariabililIIn1 incrc.a.adc hcrinatal Icht. Much of lhcl c+rtrovcr.ry atxwt ,mnkinR ncethcr maternal smoking clicl or did not causc .fclal or neonatal loss n•ntcrcl around the ha.rically irrelevant iwucg of whclhcr slwlics were „I,r~cl,cclivc" or "rxaroslLclivc° (usually rcfcrrinK to the time at which .m„king information was olrtainal rnlhcr than to whether the study M„ I,:1!wd on a cohnrl or Irirths or on a scl of cases anrl controls), nncl „n u•hclhcr or not the rlirrcrrnccs were "atalislicully sif{nificanl." (•I;,,.ificalion or the slwlics rcvicwwl in the 1973 report according to <Iatistical significance revealed that sludics in which the higher rates „f mort,dily for lhc infanLs of smokcnt coml>.lrcvl with nonsmokers a significant level (usually Ir <0.0.5 or smallcr) (2/), 22. an• 56, 124. 142, 10, 11;.5, 1Xr1) har) mortalily rulios (smoker ratj:: nonsmnkcr rate) that ranged from 1.38 to 1.78, whereas studies in rhich significant Icvcls were not reached (41. 141, 151, 155, 166, 18.`1, .~);) had morL•tlily r.tlicrt that ranged from 1.01 to 1.06. Both groutxs rontainccl retriwixxtivc and {irayicctivc studics of comparable sizc. Statiaticnl significance obviously dcpenrkvl upon thc combined cffccts .f the risk ratio and the sizc of the study. A further source of rnnlrnvcmy in this nuttcr wa.t the fact that when one compares ncnnatal death rates for Inw-lrirth-wciRht babies only, the low-weight hahics of smokers hnvc lower death rat,es than those of nonsmokers. This apparently paradoxical relationship is partly due to the rclaliv4zly Rrrotcr maturity of the under-2,500-Rrnm smokers' Labics. It is also duc to the fact that mntcrnnl smoking affects birlh weight more amngly than it cloc.r neonatal morLtlity. Because the denominators of Ihc+c rates include only babies under 2,500grams, the downward shift nf hirth weight wilh matj--rnnl smoking inflat•es the denominators and lnwrn neonatal murlatlily rnlca fur smokers. Numcrntory include a majnrity or low-birth wcighl habics, whether or not the mother %mokes. This maltcr is rliaeusacvl mnrc fully in the 1973 report (192) and in the commentary Iry Meyer anti t.omstock (114). In the 1973 rcfwrl, nnalysi.a of rexvons for variability between sturlics include<I two imfxnrtanl IainLa. First wa.q the olacrvation that other rmpw'lanl variablas might influcncc the resulta if they were unequally dislributal in comparison Rroufxv of smokers and nonsmokers. A Iotislic transformation analysis of variance appliLd to data from the liritish pcrinal•al Mortality Study demonstrated that in addition to matcrnal smoking, materna) hciKhl, age, parity, social class, N-rt lkevc,c hrecclamltsia had significant inclclxndcnl effects on late fetal and nrnnatal mortality (Figurc 5). Meyer ancl Comstock (114) provid1xt cimrnples of how the differential distribution of smoking and other i

. 1 F: 17 I' l hl th b t l kl h rn .- crm r n y mx crna Hmo nR abll, rel.tl1.e an(I allrihulahlc riHkm, derived from publlNl)od nl lldien i t•Irl~r,. 1.. IrnA.~ IfYI H.'Ir11Y. Iull rrr rY $Iwly Ilr.yvl..nl bdd IrnM Aitnl„I~Iy Rm.ir-N,.n. rn~. ~ rM N- wmrni,'n G"rn .nrL .. I r a• 1 Canldf (2) IGS 67 92 17n ' r ~ rr, Ga•d nnWrl211l Maetrod (47) .274 Lt2 4 7 77 69 Int 1/ 147 tl 1 1104 b r run r,.. Onl.nu••• C.Idlrnu (Tn7) .CtS 7./ 101 . II 136 / # rw. O . rnn• WAltr .412 59 6! 1 10 O / Nl.rY tll 1].1 16.7 1.25 A r.u •C..d.ff ..W 1)a..rA.1. .R fwr < il .eeka AM.11.e.r r.rlor < 71 ...da ••rr.Irn.f1.1.L1..R....A.r1.- ' -rfrJwa •••IJyrhl.rl.r/. /m..J !nr .ryrW Arta earlier weeks, remaining higher until term. Separate calculalions for fetal and neonatal deaths (not shown) indicated a fetal death pattcrn very similar to the one shown for pcrinat.al deaths. Neonatal dcalhs appeared to (x duc solely to an increased risk of early delivery amonR sn)okcrs' babies, rather than to diffcrencrs in survival between smokers' and nonsmokcrs' babies of the same gestational age. A similar approach wa.q applied to the risk of abruptio placcntac. placenta previa, and premature rupture of membranes for smokers arrl nonsmokcrs, as shown in Figurc 8. All o- these complications are morc frequent in smokers than in nonsmokers throughout gestation, hul again the biggest differences occur in the wocks of pregnancy from M to 32 or 34 weeks (11h). The rclalionnhifu between maternal amokinR. these comlrlicalinnn, early fetal Ilcalh, and pr•etcrtn delivery accoml>a- nial by neonatal Ilenlh are apparent from the stalislieal a_wocialion., between them anfl from thc similar time patterns they share. Sudden Infant Death Syndrome Maternal smoking habits have hcen ascertained in several studies nf the sudden infant /lcalh syndrome (SIDS). In all of these, a positil•c aqaociation has been found between maternal smoking during preR- nancy and the incidcncc of .uddcn infant /lcath. Steele and Langworth• in a study of 80 ca..cn, each with two matched controls, which wcr* traced back to the Ontario I'crinntal Mortality Study population of 1Jtilt•61, found thal +uddcn infant deaths were strongly associated wilh the frc(lucncy nf maternal smoking durinK pregnancy (p<0.0Q!) arwl alsu with the level uf malcrnnl smoking. Thirty-nine Ir<rccnl of lhc cx4c.r were nonsmokers vcr.wY (iq Ilcrccnt of controls; 36 percent of lhe /tllw IWna I/)IM U1./1,1 La.rw.l/. n caa1.1 wli.l.a).I /y y. r l wl ~L.r (,... ~ w. -- . ~~ .v i. n u A w u. (J 31.14}. 1y 1.3 PI(:11111': 7.-1'rohability of prrinatal death for smoking and n~mnkinR molhers, by period of Re!Ilational age. Iiary show 95 prrecnt confidence intervalK ?.11 Y1: M.~n.M M 11I-1 ,;Iq:qand 271M'rccnl of the controls smoked Ic`a lhan a pack I+cr day; 21 1.•rc•cnl of the carcm and 10 Ixrrcnl nf the controls smoked a pack IKr .Iav• nr more. The hul/its of the remaining I to 2 Ilcrccnl of mothers terr unknown (!xu). 13cr{,•man und Wiesner nutcml the cffccts of rAlrx.urr to cigartllc snmkc (pa.cvivc smoking) un infant.v, including Ihl• increased fralucncy of respiratory infections in the infants nf •nMlkinR molhcrr, und ntnlctil their imllresnion that the amount of >rnnkinK necme.l unusuully heavy at meetings nf llnrcntr who hnfl lunl rhildren to SIDS. The rwlhore alu/licd .r,Ci fnmiliew who lost Irullics tu the wlklcn infanl death syndrome nn/l Rfi control families. They rclMoru.l that a higher Ilrolmrlinn of SIUS rnnthcrs smoked durinK Irrcl,rnancy than contrvls (61 pcrrl•nl vcnus 42 (Krccnt), mnre smoked after pn•f;nancy (59 percent vcrNu>a 42 IKrccnl), and SIDS mothers srnukc/l a •iRnificantly greater numlKr nf cigarettes than controls. These authors ifwlicalc that cxlmsurY: to ci{;arcllc.rnokc (luiasivc smoking) appears to 1•nhancx the risk for S11)S for rcw.ons nol ycl known (1.',). ltowcvcr, Khclhcr prcnatal or Ixrslnatad cxluxsurc is more imlxrrtanl cannot !x ,k•tcrminal. Nacyc, et al., in their analysis of 125 SIDS victims from the I'opulalion of the Cu1l:11Mrralive I'crinatal Project of the NIN<'DS, 't°lpl: "Thc gestations that Iu•olluccll the SIDS victims were characlcrizcd by a greater frcrlucncy of mothers who afnukcd riRarclles and had arncrniu" than wa.v true for the whole population of '7.721 infanl., or for a set of 376 controls matched on imlx,rtant factors 9-44 06£L 0ZLj5 1 8-45

3 1 7!7) ~~nir nf Ihr.4,• vtii,licv h:,w! ,hnwn nn irtvl•rW. c l((arlttl ~ :w lh,• niiml, ~ 1'r~Y' Vln,~kl•, 1 1 i`n,'rciw,I ( I/,i~` 1 /+0)11 1)'r l:t l fr , 'mir' lht: I{rili.h Mnrl:,lily tilurly worc rrs..v-lalnrl:rlld I,y I,:rrilYt st'vl•rily nf Lr..,. via, an,l nc,lcrn:,l mmoking st.•,tus. tirtnnkrrs h;,,l 1„N,,r I' I,•rarlcs of I,rcccl:unlwia than nonsmokcr:rv• whclhrrr th,•t• ac or mullilr,,rac (•l,/). Anilrcw.r tutJ McGnrry shr,wc,l th:,l rclationshili Ixlwecn cignrctt.c vrnoking :,nd I,reccl:,n,1 ,ti,. l inrlclkndenl (of nrx•ial chww, m:tlrrnnl weight IKforc I,r•I,,n:,n,, maternal wci{ ht Qnin during pregnancy (2). ))cs1,ill. ll,,1 effect uf smoking on the incidence of hylKrt,cnsinn in I~rlKn;,r~,.t tl is a greatly incrcascvl risk of (tc:rinatal mortality if lul•,v.laml^,:, • hypertension does develop in at smoker (2, 42, 184). k•vi.ral have suggested thal this ncgalivc nsvncintion may IK! rlur• hy(wlcnsivc cffccl of thiocyanate, which is ,Icrivpl from Ili,. present in cif,rarettc snx,kc and regularly found in the hlr~wl „f;,,,,.1 (2.146). Preterm Delivery Previous scctions of this chapter have inllicllctil that lhe shifl of the diaril,ulirm of I,irlh wciRhL•r with maternal .rmnkini: ,. . accompanied hy a similsr dnwnward ahifl of gt..wUttinmtl :rl;r•.. rir, •., other hanrl, xhunol:,nl cvirlcncc hu. 1><rn I,rcx;nl.cvl that :, rclntcd incr'c:wc in prcl.crm delivery I,L•tys nn imlw,rt:u,l r.l,• ,,, ••. increased risk ur nCr,nAtal lle:tth for the infnntv of .mr,kl•r.. lion of this ulqr.tmnl Icrradox is f„uml hy exuminali•m .4 distribution by gc.rt:,liunal nRc of birlhs ln non:,mokcrx, light and heavy smokcrx wa shown in Figure 6, plotted on n xcrnilorlz:,rnrh•• scalc to emphasize relative lliffcrenccs in the carly wiv•k.. Th• r• littlc difference hetwttn the means of thcu: curves I,ccatux• th,•.r• majority of births occur strmuml term in nll groul>l,. There is. significant and d/ticc-rcl:tto-41 increase in the prolN,rtiuns oif I•r +• ~ habicn horn to women who smokc. Tha.c I,r•clcrm dclivi•ril•s :u•r.wni '' a small proportion of t.ntal births bul for n large l,rolo,rlimn ••f ' dcath. (112). Pul,lishal studies in which the percent of births occurring term ha.. bcen related to maternal smoking have con`isll•nllr higher rates for smokers than for nonemokcr.. Some c.N:,mld'" '° shown in Table 13. In four studies where all I,irths nni1 l,crin:rt:,l'I'':'r••' ar' t" I were inclwkvl, the risk of early dclivcry incrca•aal from l,crcent if the mother emoked, and 11 to 14 In:rcent of o,ll hirthn could lxt attributed to maternal emoklnA (i', pn. rti lower relative and nttributablc risks fnund In Ycrushalmy'.r Mlu'IS t" may have rcvultwl from selection of particular births to IK Nlull"•I from the exclusion of fetal ,lcttlhs. Annlysis of the Ontario `tl"'1` ~ 0 ~ 0 Goo •oo 40 C. to 0 ion to .c 0.2 0.1 20 24 t• 32 ss 40 .+. GESTATION, WEEKl Ilr,l'kf: 6.-1'errentaRe disfribution by weeks of geatation of nnnsmnkem rvnokera of IeAs than one pack per day, ap-~' ..d.r.,if nne pack per day or tnore . ..+.... vof urn .• I rat,•v nf rlclivcry (reforc 38 weeks or 77 pcr 1.000 hirlhs for -••t.-r..!r2 per 1,(X1) for light smokers, and 116 per 1,000 for ceavy r•. aflr•r ndjustmcnt for lhc effects of other maternal factors i1tnAnrt l'omplicalions and 1'erinalal Mortality by Gestation :,n4 Trln:,.w•i:t (11c) havc related the cxccs•M fetal anrl neonatal •..,l,t} nf xmnkerr' infanLt and the excess incidence of pregnancy amonfi women who smoke I.o the gestational age of nr,•. using a lifc-t:d,lc approach. A starting population of all ulrru at 20 weeks wa.s ux•d to calculate the probabilities "'A 'k•ath, live rlclivcry followed by survival or dcath, or the "'''" nt+• fir n eomplicntion followed I,y fetal death or dullvory. At 28 """ IlM• nc>rt Imint dcfinaJ by the data), the population at risk ~,'k't th'„c remaining in ulrt,o at that point. Figure 7 shows the risk ~:'r"ut.,l dcuth during each poriod of Restational ago atarting at 20 '"t' kiAs for smokers' Infants were aignificantl y grualer in the 1 e-,2 68£L OZLZS

, C on Monoxido Uptake and Etimination Te dclcrminc the rate at which ItIrxxl carlxrxyhcrno{;lul,in concenlry lions in the mother nnd the fclus rhnngc in rcr(rnnsc lo cx(xr.rurc tnx given r•onccnlrntinn uf errrlxwn monnzirlc in Lhc stir, I.rmgu anrl llill (,;I exposed pregnant sheep with catheters chronically inypl;rrrli.,l in rn:ttcrn:rl unrl fctJrl Irlrxxl vc ~ecls to inspirol CO cnncenlr:rliun. „f ;qt t, 300 Irlrrn. Figurc 9 summarizc.a tht: rt..~ulLv for changes in rnal.crn:rl ;,ryl fetal c:trlxrxyhemoRlulrin cnncrnlrulions. It also compares the cxlx•ri. mental rc..ulLs wilh Irrc<liclions made using u mathematical morlcl. At all levels of carlion monoxitlc exlxxwrc, the mal.crnal carlxrxyhemNln, bin conccnlralion incrcn.nwl rclalivcly rnlurlly during the firsl 2 t„ ~ hours. It then conlinual to increase more slowly over the next f,,t hours, rcachinK a rclalivcly constant kvcl in 7 to 8 hourv. The chanar in maternal carixixyhcmtglohin concentration rescmldetl a simpL exponcnlial Irroccw-q with a half-limc of 25 houri. The increase in fctal curlxixyhcmogltdrin concentrations IeQ~,~l Ix:hintl maternal cnnccnlntlion.a (.9:). During lhc first hour trf cxlxKUn., fetal carlroxyhcmnf;lohin t.+neenlralionN showed liltlc change. Uurinl the following 4 to 5 hours they incrt:u.wvl, hut aLrt relatively slow r:rlr a.% comlrart4l with the rate of thc carly carlwtx,vht•nwglulrin rise in Ux• mother. fly 5 to 6 hmrrn, Ra:tl carlrrxyhcnxiglubin triualtsl maternal concenlralions, nft.cr which the vstluL-4 continutvl ttr incre:~.c: alowly Gr 24 hours or more. Only aftcr 36 tn 48 hours tiitl the fetal lrlucxl attain final stcady-ataLc cnrbuzyht:mo/;lolrin concentrations. The time bK fctal cartxrxyhcmo~,•lubin concentration to rt•atch half iL+ final vulrx• was aboul 7 hours. At t.nuililrrium, ftairl carlxixyhemogluhin t,rncentra• tion exccelet) the m:tl.crnnl conccntralion by ;tixrut 5R Iwrccnl. Ilill, r•t al. (7Y) Lhcn uvcvl rt malhcmalic:rl mtxlcl to calculate lht: lheurclical rclutions of fctal-lo-mutcrnal c:rrlmxyhcmoglrrhin conccnlr.ttinns in humans. AllhouQh slightly different in ximc dcUtil.r, the Irrtxlicttrl uptake and climinalion curves in pregnant women after cxlKrsurt: ln several inapiral carlxrn monoxide concentrations were strikinglv similar to the experimental resulla in animals. The mechanism by which carlxm monoxide crosvcy the Irlarenta from maternal to fctal bltxxl clearly is hy diffuunn. LonRo, ct aI. (90) shnwcd in sheep nnd tlo{,•n that the half-timc for carlxm monoxide to diffur acro`s the pl:tcent.:t is nlaul 2 hours. These workers (98) als" rlcrnonstralcd that thc rrsislant•t- to diffusion in the Id:tcent:t iv due t•qu:tlly lu lhc IrL•tct•nl:rl rncmlhr:tncs iKr se and to the rcl:ttic*C n•.raanrr :rffonlr•rl Ioy (lie cht•niir:tl cr+mbinalinn of carlrun rnonuxiJc with ht•mn/;l-drin. f 41 c Y ` FIf:UI2E 9.-Time eourne of carbon monoxide uptake in malernal and fetal sheep expo+ed to varyinA carbon nwnoxide concenlrations. The experimental rexults for lhe ewe (0) and fetal lamb (0) are llre mean values (t SEM) of 9 to 11 sludies at each Inspired carbon atonoxide level, excepl in lhe case.of 300 ppm, at which only three aadies were performed. The lheoreticat predktions of the chanRes in ^ralernal and fetal carboxyhemuitlobin levels for lhe ewe and lamb are 'ho*n by lhe solid and inlerrupted lines, respectively . s o u ra c e: t..... t. e. r. n. p_;,8 L6EL 0tLI5 I p. MI

) , ti ,u. n,n .ugg,.l unl:r.•.,.,,.It• ,IIcrls ,lI III;,I.o--r'r1:,1 xltlnklnR rlurin n•gn:Inrv nn lllc chil,l's lunl;-ttirm growth, inlwalcctual rlcvcl,., ..,cnl, nnd IK-h;rviunll ch,iraclc•rislic_-4. Although lhc~ chring(•, nrc tlifficult lti slwly I,crauu_- uf the va.rl cnnytlcxily /lf IMIyYII,Ic nnlcccdcnl and cnnfuuuiliny,• v:Irialolcn• high prirlrily ehrlulil IK. obtaining cnnclu.ivc answcrv ;ilwlul the role nf fctai cxl,osurr: U, mal.crnal snloking in lhcxc cnruliliouls. Thc futa that the din•cli,,,, „f olr..crvcrl ,liffcrcncc•-4 in ;1 variety uf rliffcrcnl vtwlicv is lhc xnmc n,l,l.v to the urgency of lhiy rlucYtiun. R.ole of Maternal Weight Gain In lhc search for mechanisms thmugh which maternal smnkinK reduces hirlh wcighl, the rlucwlion h;uv Iiccn uskc~l whether it might Ix an indirect result of n.Vltu.Vl n1rlletitc, Icm intake of faNl, anrl lower maternal weight gain. Scvcr,il carly studies rclarrl.cil no diffcn-nc~r Ex;lwcen smoking nnri nonxmoking women in intakc of fcxi»I or in weight gain and concluded that the effect of mntcrnxl smoking „n birth weight was not mwllalicol in this way (R, 5;, 76, 1r71, 141, Y1?). Iicccnlly the qucslion hn.q lKrn raim-4l again by Itush in a stwly of births to 160 women of whom 41 smoked throughout 11rcRnancy. Ilis evidence shuwcvl that the mean weekly weight gain wtLn rcfleclcvl in the infant's weight at hirth (167). In a sulau.vlucnt sludy. I)avics, et al. cxamins.vl the intcrn:latinnxhii.v of cigarette smoking in prc{;nnncy, maternal weight gtrin, antl fctal gmwth. Il,y analyvis of covariance rrf 480 molhcr-infanl paira from the t.Ital of 1.159 includca) in the aturlJI •, these authors aUrted: "Correction of Ilirlh wcighLt within smokin/; grouµp to a common mcan maternal weight grtin nlqicurn to remove moRt of the differences Irclwecn infantA of nonenxlkcra and hcuvy smokers, although tti•chnicully lhi-.wc corrocl.etl means are still stirtinli- cally heterogeneous." That is, the effect of anxrking on birth weight was still ol>_vcrvcd although diminished by these procedures. From this the authors concluded that "a large part of the effect of maternal smoking is mediated through maternal wciRhl gain with only a very small additional direct effect on the fclus. This suggcwts that increasing weight gain in smoking mothcrs might prevent some of the harmful cffccL% of smoking on fetal growth." However, the alternative explanation that lower matcrnal weight gain and fetal growth retardation are both inrlc/mnflently related to cigarette smoking in pregnancy iv a11sr1 menlinnwl (.4{). Other studies have not corroborated these findings. Mau rcflort-,% reaulls of the German pnlvlx-Ttivc study in which 6,2W pregnant women were examined every monlh from the first trimester to delivery and the children followed for u11 to three years. Smoking was classified as t10nC, 1 to 5, 6 to 10, or more than 10 cigarettes (xr day. No si},•nificanl :uux'ialion was fuund Ixawcen smoking halril and weight gain. On lhc other hnnrl, there wu") n clwtc correlation between the nJjml,cr uf small-for-dalcs Ilnhfcs an<I thc cmokinfi h:11,i1 in a :' routl nf Nnrncn with normal weight gain (10 to 15 kg). The Ilrolloruons of t,.bir.% IKllIw the tenth percentile were 7.7 percenl for nonsmokcrs, 8.4 nt .t 1 tn 5 ciRarettc9, 12.5 percenl at 6 to 10, and 17.6 Ilercenl nt Ip cigxrcttcr 1Mr day. These babies hail a general retardation uf length, nnd head circumference rather thnn ufllx!nrinR n,,,lnnurishcrl (1u7). These finding?t nrc in agreement with lhc sturlics , fNtilh.r rrnrl Hnsaancin, who round that the effects of smoking on arnlc(ll rlid not al,l,cnr In (IC rclaletl to Ix)or maternal nutrition. ,,,•i{ ht gains rlurin/,• the last two trimcsl.crs of Irn:Knancy wcrc I <ignific•nntly dim•mnl in smoking :Ind non.mrrking mothcrx and .,,n, ;11.,1u the mcan weight 1,•ains recommenrlcvl by the National llru•:rn'h tinlnt•il (11•Y). if,•v,•r invcsligatwl the relationship of maternal smoking to m:dr•rnal weight gain and to birlh weight, using rL•ila from the 31,788 F;nl;lish-SiKakinf,• Crrnarlinn-Iarn women includiprl in lhr• I'crinntal Mortality Study (11.7, 142, 14.Y). As cxlKx:t.al, hirth r,.ight rlistrilwlinna shifted downward as maternal smoking level in,n;c•pl. Mat.crnal weight-gain distribulions, on the other hand, were Ihc clmc for smokers and non..mokcrs. Furthcrmore, the I,rolwrtion of infanls weighing Icma than 2,50O grams increased with cach level of Anvokinl; (nonc, less than it llnck, nnd more than 1 pack per day) within r•arh maternal weight-gain group from lav than 5{xwnds to nlclrc than tn Inund+. This evidence supports u direct effcrl of maternal smoking ron birth weight rather than one mcvlial.ed through calinK. Evaluation nf Rueh's study (162) Is difficult hecauec of amall numlifcrn and frccauee nf Ixlpulntinn-aclcctlon factors thnt led to large diffcrences txlwecn snwlkcn and nonsmokcrs in aRc, parity, marital slntus, and education. The slurly population of f)nvic-i, cl nl. (.74) is more homogeneous arul r.mLYln.a 450 smokers, but Iwolh studies aharc a common problem in inlcrprctalion. Meyer IroinLi out that an incvil:ddc correlation exicLw L-Iw•ccn matcrnal weight gain und hirth weight insofar its Iwth inrn:asc with gestational a", nerc-•.aitalinR careful control of this factor. Furthermore, lhe facl that fetal weight is an incrcasingly impnrLinl component nf matcrna) weight gain towards term (51 Ioerccnt 1,<lwcrn 30 and 40 weeks) nnd nccounLs for a larger prulxrrtinn of a low-weight gain than of a high-weight gain ensures a considerable 'kRrec of correlation Irclween the two values. The samc baby is weighed twice, once while growing in ulero and contributing to mal.crnal weight gain, aml again at birth. In this way the mother gains keiKhl because the I,al,y is growin/,•, and not vice versa. Meyer rnncludts that efforts to prevenl or reduce smoking (luring prcgnanr.y 'hould have grcal.cr benefits for mother and child than would cfforts to increasc food intnkc among women who smoke (11.?). 8-'Lt w-n

! fnrt _AiI Ijia4 tL•iLa. I•'..r ~xanilJc, m n•IwtrtA:d in tlic il:I l:r fr,.,,r ll,, 0,IL•i. iivv I'crinaIal tilut Iy a lhr NIN(:I)ti (I!li'J I:)(;(',), Vti mnrlnlily r.it.•~ wcrc hit;ht•r f.-r Wark thiui f.ir white I~al,icx, whilc whilc wnmcn wivc rrnorr nfli•n srn.,kvrv irnel ymuk,.vl more cijz„rc(4., than lilnck w4im(•n (1.17). ti.rIc.-ti.in or hirlh.r rin lhc Iuu%iH or Nrn„kin~ alunc wuuld Lcnd to inclu(lc more nonrm.,kcra who wcrY: Ill;r('k nnil st high risk and more smrrkurH who were whils iind rnl Iiar<icully (nw ri~k thereby minimizing the irlqurrcnt cffects of maternal ;~rn.,kin~ ,inpcrinalal loss. ln three rviwrrLol sludics in which adjustment for uther factors was carried oul, it significant indcix:nilcnl a&-;ocialiun IKIwcvn ciQarcllc smoking and infnnl mortality lx:rqivlwl (20, 22, Ja, !r9) ()f the studies that revcalcvl no aignificrnl incrc:wc in mortality riHks G,r smokers' infant.v, one (2t)7) cnnlrollal for race alone. "Hencc, at k;t~t part of the discrepancy in renulLv Iklwcc:n Lhc two Kroulls of etu,l may bc cxplainal by a lack of rnnlrol of vurialrlc.a other than nmokinK • (192). The accond imlx>rtant Ixrinl Irrescnted in the 1973 rclK)rl was lhc suggestion that cigarette smoking might bc more harmful to lhe fetuses of certain women than of olhers. Analyaia of cI:,La I,y socioeconomic al.alun (2, 22, 211), race (137. 11;.7, 1XX, 206. 21)f), Irrcviuus obstetrical cx(K:ricncc (22. 1;I, 111.'1), and maternal agc (20) indicatkrl that the increased pc:rinaL•il mortsrlily risk wc+ncial.eJ with maternnl smoking varial considcralrly with lh~..wc other factora (1-92). Spontaneous Abortion The results of aevcral p:Lal slwlic,3 have dcmonslralal a st.atislicallr significant asaoriation Ixlwecn maternal cigarette smoking anrl spontaneous abortion (74. 89, 141, 147. lRR, 212). Data from some of lhe.e studies have documented a.LronR davc-resltt,n..c rcl:rlionship between the number of cigarettes smoked and the incidence or spontaneous alKorlion (147. 188. 212). Spontaneous abortions are difficult to study liecauu: of problems in a.acertrinment. The m~nt comptet.e ascertainment is prxaailric when the mnlher's history of I~:«t spontaneous alxirlionn is u.ved, despite prol,lcmn of recall. Diffcrcnrc• in rates liclwcen smokcrs and nonsmokcrni are larg~..•s1 when thi% method is use+l (141, 212). In prospective eLudics, many carl)• spontancous alrorlionm will he missed, and bias will occur if one {tmul' t.ende to register earlier lhnn the other. Nevertheless, higher ralcs or spontaneous abortion are also reported among amoking nwthore in prospective sludlee (N9). The slwly by Kullander ttnd Kacllun counU'1 sliontancous abortions through the eighth month of gcatalinn a^'I noted that the largest incrc:Lse: wa.q among smoking women whrX%C pregnancies were unwanted. Although lhi.r was a prospective elu'IF• wilh smukin); ilala culluclcrl rclxalcdly during lrrcnal:il care. lhc method of analysis war rclru.vleclivc. Itcarrangcmcnt of their l:rhlc t" t:. .._.1 a..l . I ~ F o A a ~ ~ mrL. _J a 1 . I . ~ a ~ ( o .~ w <•: • e a ° 33 D N 001 ~ . , ~~a FICIIRE S.-Theorelical cumulalive mortrlity riak according to 'b+okiag habit, in mothers of different aRe, parity, and social claee Rroups aIasrr.. wrw. w a tM 4'loin incidence ratcs of slt<,nt;rncnus alxirlion for suh{,'roups of '^'°kers and nonamokcra l,•ivca rntes and relative risks of Klqntancuuy rl'Orlion by dcsidcrulion of pregnancy (Tahlc 4). More of lhc srnokcrrv' th1n nonsmokcrs' prcgnancii,.y were unwunl.cvt (19 (xrccnl versus 13 8-711 £8£L 0ILi5 ' 8-JI A

E 0 E 0 x 1 5 S r 5 m 0 15 Public Hospital Status 0 3a-Df 40-41 4z+ WEEKS of GESTATION FIGURE 4.-Percentage of birth weights under 2,500 RrunK h, maternal emokinR kve) for early, average, and late-Irrm hirths Private hospital atatue and public hospltA{ statua (flar* NhoM 45 percent confidence intervals) Other studies have corrol,orated thsc findings (.1j, 67. Rl, 111). It:,nt% and Mellita compared the birth measurements and suhsc•rlucnt ylrouth of 88 pairs of neonates from the pofwlalion of the G,II:Jirr:rti,r• Perinalal Study of lhe National institute of Ncurah+Ric:,l :111-1 Communicative Disorders and Slroke (NINCDS) (137). Women `"'h" reported smoking 10 or more cigarettes a (lay and whose childn•n hml eurvived and been examined al age 7 were mal•ched by r:,cc• :,a.^•. educalional background, sex of child, and delivery date with N'linw'n who did not smoke any cigarclles during pregnancy and N'hl•K' children were examined at age 7, At birth, the smokers' babica .+•ciKhr`I an average of 250 grams less (p<0.001), were 1.34 centimeters .rhoru'r (p<0.Wl), and had head circumferences 0.32 cenlirneters smatlcr thnn babics of nunYmokinf{ mothers (67). ln a study of 1.159 infanLr N'h""'• molhcr.+' smoking h:d,i4+ were aaccrtnined early in )+rcylnancy. 1)n~'i"` 8-:7(1 1 (nunrl lh(. f:uuilinr Kr:,rlu•nl of rlrrr~nrin~ rnr;in 1, "t r, wr,rkcr+ ~~.xfi~, N•ith inrrcavinf,• smokinf; level. When lhc~c infant.v r: ~`~un,l xl i Ir, 14 d+ry.v „f awc, n similar firurlicnt wa.v frwnrl for Iwwly ~fi ~nJ hc:ul cin•umfcrcncc or Ix,lh malc nnrl fcm:rlc 1,11,ic.v ,-,,. ~ml ~~th~'r xt~Irli~'" (•Y.?. I17, 214) inrlic:,tc that mnt.crn:,l >lmnkin{~ ,,rrnll rr nl: tinn uf fcl,l f r<,wlh. tn Il:r•~:,n,'in, nnrl cr,wrrrk,•rv have rlcvcritKrl two ly/,en or fcUil in term Ir,,Lics. One is churncU!rizrvl I,y nn r:rtin or lrirth weight lo cruwn-hccl Icnf;th, thc thin inrlcx hul with norrnal Icn{;lh. Thc uthcr is r,".,t l,y :,bnnrrnally shr,rl crY,wn-hccl lcn{,•th for fet.al arc, the r,•„r•r:rlly xmallcr than cxlx•ctcai in all mc».aurcment.s (118). 1.11? uncomf,)ica lal term (ircf;nnncica indical.c•c( lhat <nurkrrl cif;areltc.r rluring pregnancy were more likely to „ith short Swwly lcng•ths for,Litca, whereas mothers who t' Ina• weight f;sun in the (tlat two trlmestcr:s were more I.:r6ir, u•ith low fwmrlcrnl inrlicca (1l9). t,•o,c•Trrm Growth and Ihvelopment ,•. •4, r,-r n,d there arc long-term rnn.atYlucnccv of the fctal growth :ss+x'iat,.•rI with m:+lcrnnl i<moking during pregnancy ia of I:r,•at4•r cunirrn than nrY mca..urLment•U at the time of birth. ,• r•, irk•nrc that children of emoking mothers have mcn.vurahlc ,ew< in phyxir,l }m,wlh, intellectual development, nnd emulion- .•b-pwent th:,t are inr(clx:ndenl of other known prc•rlialK,sin(; m:,tch,~l-l+xir alurly of Ifnr,ly nnd Mcllits cumlxrrwl f,hyvical ~ m nt~ and intellectual function in children of smokers and •• 4.•r• thrnof;h age 7. Among ri}t pairrv, allhuu(,rh lhc h:rbics of r«,•r,• Cdl f,•rama lighl•cr and I to 2 cm shorter rtt birth an+! still • ihcu, their cuunlcrf,nrL+ al one ycar, the authors rclwirlcd that •,.,• ,r,.if;nificnnt diffcr•encc in either lrhysicul rnca•curcmcnl.v or •'1cd fanrliun at 4 a,nrl 7 years (67). li should I,c nutw(, howcvcr, :r- hir•cr• a:,lixtical.vif,rnificancc from such numhcrx nf cnsc:., lhe Iv•tu-,rn them nwat 1u; very strong. In Nanly anti Mcllils' "f tlK' tW pairx or chihlren matchea( for rncc, rlat.c of rlclivcry, :,r,• and iaucalir,n, and sex of child, mcan values for the n'If rum.mnkcrs were larger than lhnsc of smokers at all n[;es ~i rn'':1-1urvmcnl+ lhrnuf;h ngt; 7, inclwlinA bor(y wcight, txxly hcarl cireumfcr+ence. At age 1 year, 96 (,crcenl of '•'n^k,•ri habicA and 90 (Krcenl of smokers' babies had norrnal "'fwa:d slalu.. At nge 4, nonsmokers' babies hail slightly higher the Stanfnnl-Ilincl inlclliKencc I,r;st, and al age I they lcstti•d '''r '•n :1lt of the test.s re(,orlcd except for the Wide Range ~'"•mvnt Test suhlesl for arithmclic. An additional set of 55 hairr `'1'I^'n „f srnokcn anrl nonsmokers who were matchal on birth 8-21 8L£L OiLiS

f 1 1Q.-Pelal rlnll nron;llal dc;tlhN by t/Nltd cHUVC aad malcrn:tl Mmllkinl habil (1:nK1iNh clrcakin~ rh„Ih rru in..r.,.l M:. .l l nl.....,1. l N.•n.m.•4.~. .,w.,4, . L .. .m,4, . r.,.. ~.l 1• ~ Fe1.l ,4.Ikw Un4m•.n 75 I2S n1/ l1/l M.unn..lr,n. 1( Y/ :u 1 In 7 'I.." Ilfn.,J) lK J~.~•u. I I IS II'l 11 N~ Ann.u IR 2tl 17 / 114 Mal.+nd ..~.e 11 4. 117 11.1 AII nlM•r1 N Il Ni 1.1 NS Tol.l 17:1 2t1 lra7.! q I - , Nelwlal.l ,kath. Un`b., u 51 Sn5 .OS 0 fill H$ 111.1fn.wat6n. 22 14 2t f 0.1 He.dytie durur 7 11 7.0 0/ Aey.raury dirr'ruHy ~t [t M.0 130 v+...t"'ity .1... Maerw.l e.u.e 33 2 as 4 aaa 12 ss fe .m, NS All et4s It It 17.1 •I/ Nt TM.1 17M Ztl IYl] >f.t< 0a TM.1 Ai.tll. I5,7M1 lt;.p ~ 1 r..Iw J.n...l r.w~ .ii qr.wr 4wd r..,JI y p,11r.i. w1 r+n...re 4.L..v .ri.w .rl r+u,~a._ ]OUNCr. N.rw.N.N I1Nt ~ For fetal dcalhs, the L•trgLwt csttA•gury nf l•nMkvl cnuv, wra.i "un• known." and by far lhc largest nnll nx.vl aignificant slnuking-rclut(•I difference fcll in this catcl;l/ry (I) -0.lK1C3). Snx)kers ul.wt shnwwl mlm• than expected fetal /lc:tlh.r Iluc to anoxin und maternal cau..cs :url fewcr dcalhs than cxlKctA.vl due lo malformations. In other ca(.c{ r/ril> only minor mortality rlll(: Iliffcrrnct_y were found IKlwc(:n the lw,- gruulrs. For nconaL•tl deaths the lurg(..~al c:wac or dculh category wa "unknown," hut here thcre w:s no exccxa for arrNtkcra' infnnta. Mn.t 4 the smnkinK-rclaU.vl cxt.rm of neonatal dcaths was among lh/-' attributable to prematurity alonc (p-0.005), with additionatl numlN•r+ in the rclntc(i category of "respiratory difficulty." Uiffcrcna-5 between observed and expccl.cll dcath•m in other ail.egorics M'cn' negligible. The tentative conclu.ion to be drawn from thcac findings is that many of the excess fetal (Ieaths as.c)cial.al with maternal ..mokinR,k' not have any recoanis.ablo pathology llut occur from olharwi,r unknown causca. A el(=nlflcanl excc..a alan occura m a result nf antcltarlum hemorrhage or abruhlio placonlac. The oxcccy ncnnat'," dcalhs amung the infant.s of .mukcr% alll><aro.4i to Itt: duc ('' fin•malunty and tu n•Ial1ml rr.rl/iratury Ilrol/lcros. In other wonly, tlt("r• WNW- k}Ih, „rcurrcrl in hahic.r whu were Ix/rn Ilrclcrm, Iwl were wi evidence that rn:llcl. . ,lth~•r 1'~lfl„lu/ry There is nn convincing ,m„kir,g Incrc:c`w=, the incidence of ccmgcnilal malfnrrnati/ln.. RcvulLr f I„IIdisht•lI stwlic.v, revicwcvl in the 1973 rcixlrl, .hnw relative rivk.v f rsIl,,,kl•r.r vcr4uo nnncmltkcm ranging from 0.31 t.o l.•'>r) ( L')Y). l•nmplirallnnN af I'reRnancy and ljtlxir Iqr,.r~alinnx from the Ontario study un/l othcr rlata shnw(,til thal M rn,,n w•h,/ smoked during 11r1•gnancy had cxcc.ti fat:t) llt•;tlh.r either i~n,.~lllainlYl ur utlrillulcll l) antlxia an/l excms nc(ln:tlal llcalhs duc to I,rl,nl:llurc delivery. These finrlin{,w suggcstAxl that maternal smoking ~ht inrrra:+c the risk rtf ccrL•tin pregnancy complications thal were it, turn, to these cuu:w% of Iterin:tUll I(>ti.. A direct relationship maU;rnul .mrlking level and the incidence of I/laccnta prcvia, .I,r,Iplin Idan-nUtc, Itl(.rrling during Irrcgnancy, and prcmnlurc rvltlurc ;,. •ld/r:Inca had IKen rclxlrlal Itrcviuurly (2. :11. R•1, 115, t•n,l(•rr•axl, cl ul., fuund higher raha for smokcrs than for nonsmokcry „f bhrvling, nbrul/lio Irluccnlnc, nnd placenta previa co:nhincd, and of I.n malurc rupture of inemhrunes in three Rroul>w of women with .liffcn•nl vociol.rnnomic and racial huckgr»unda (1NR). In a large study ,d hirlhs lu U.S. Navy wivca, the same complicnliona increwacvl with m:dcrnal .muking. In the latter slully, the incidence of prenlalurc ruplum af mcmhr:tnes incre:wcJ within four levels of maternal •nwlkinl: fmm none to 31+ ci/;arcltes Iwr elay (IRn). Kullandcr anll li:u•llcn found a aignificnnl incrclse- in the frwlucncy of ahrulltio Id:n•cntac nmung children (IyinR IM:fnrc the age of 1 week (R9). Anlhrr•s and McCarty f(luntl incrcawtl inci/lencc of abrultlio IAaccnlac anll other forms of uccilk:nUtl nnlellurlum hemorrhaQe to !>,e :m.nciatktil silh maternal smoking. They aL•Iled that this wru lhoul;hl to lie the cau.c of premature delivery in 1.2 Iwrrcnl of .mukcra comparwl with IMIY 0.5 IKreenl of nonsmokers. The incidence of accillent•rl hemor- rhaRc.pecific for lurrity was higher for mmoikcrm than for nnnsrnokccr M all parities, rbtinR tn 3.16 Ikrccnt of amukcra who were para 4 or mnrc (2). Similarly, Ruaacll, et al. found an increase in vaginal hlerrlinl; during early prcgnancy umonl; women who.mokal (Ir:.S). In the study h}' Cnujar(l, cl al., a.1 Itrtviuusly notal, a large prof,ortion of the incrrase in stillbirlh.s amnnQ.mokcrs wit.m caused by ahruplio placcntac (+.1). Naeye reviewed the clinical and p(><lmortam material from the 1,897 fetal and infant deaths in the Collaborative f'crinalal Project of the NINCDS (137) an(I reported an a.tiaocialion between pcrina(al nwrlality rates cauned by abruplio placentac and number of cigarettes "mokcd by tho mother (1J1). Abruptlo rlacontao waa the underlying eaulle idenlified in 11 percent of nll the deaths !n thia large study (lYa). The Ontario data corroborated these findings, as shown in Table 11. Increasing levels of smoking resulted in a highly aiRnificnnl increase in the risks of placental ahrultliona, f/lacenta previa, bla.ding, and 8-:IH L8£L OtLtiS

.4* _~

f J I Preetlarnpal. 1'revious epidemioloRical stuiiies of th. relationship belween cig- areUe smnking and preerlampeia were revie.rerl in the 1071 and 1074 FePort° on the health oon.equencee of smoking (101,101) and form the baais of tlle foilow•in6st.at.ernents: The rrsults of severxl large i.roepet•tive and relroepective studies Indicate a statistically sianifx•ant lower incidence of proeclampeia among smokinR women (14, 43, 100). The results of one large retro- slxxtive study demonatraied a siRnificant inverse relationship between the incidenre of prreclampeia and the aumbef of eigarettes smoked (NA0). Whrw other risk factore, weh sn patity, social class, maternal weight before the pregnancy, and Inaternal weight gain during the prrgnancy were cont.n,lled, smoking wtMnen lelaitMd a siRnifxantly drerrased risk of preeclalepeia (!1).'Ibs lower risk of preeclampeia for eigaretfe emoking wonka ha" been dnnwntrded In Britain anJ Scotland (14, !I, 46, d1), The United 8tat" (lOn, 118), Venezuela ( jt), and Sweden (0). If a er.larnal slsoker does d.eelop prwJamp- sia, however, available data algArd that her infant has a hiRher Irar- talitr risk than does the Infant of a sow.moker with preeclampeia (11,85). Bu+wae,Ir 1. Availahlo evidence indicatee that maternal cigarette anokers have a sipnificanlly lower risk of developinR•preeclampaia as eYlmparrd to nonanokers. : 2. I f a women who snmkrs cipretks during prrgnancy doe. develop preeclampaia, her Infant has a higher nwrtality risk thin the infantof a nonsmoker with pr.eclunpeia. (1) Pregnancy References A.ea.AVwv. J. L. Otusw.ea.. B. O. ela•_, H. B., hAUak 'P. M. Bmeals aa aa la/ep~Me.t vaA.W /s a m.ltlpto r.arr..lea ..ay.lo vpe birth weteat.d eedatMa Anerkea J.er.al K AAtk Ilr.lth ..d ta. Natl..•. He.HL se (1) :C1116M&Aprtl 19011. tl) A.*sve. r. 4ataNeel.eM wlrhvaM ada.leer 1<oalrw.ea..ld-Renrew. tr.ll..ea (Yslhal.vevl efoets.t.rdente e.rbeu a.esalde eewerwtrn. t/..a ) Btaw4/W.a.Itwwe A.r twtt S2(4) : 11e_I tfQ 1e71 (!) BAnsT. 1t. R. TM etreet of ort.rrl rsal.a eN ll.e I.faM birth welaht. New Lesla.d Medle.1 loera.l tl(Jtle) : 2Y.t-201. Mol riM10. 141 I (4) B,.es. s. a. TeMAaosu. (I P. 0111,41011 asea.ttl..d arlaa e.arf• t;..o.tt Ardlres at r..Ir..oNt4t flr.ltl 2411) : L1-el. Ja.wrf Ir (S) BaauaaW 1., taoav.. 11. tAtr.a, l, MAUMA.. T. (Lu. O. floa>.r.. , e.la.t. A.I'eefaal aJ do nera hre..e. (Pn.r.c..t r.rfo" a+owslde 1s tb tae.d .[ a el+Ild Mra .[ a e.oalwa ..tier.) Medret.e 1.eaele et 1)or.aa. Corp.rat f(J): s1!-l74. J.If-Aa;v.t.eepte.eer lY?o. (t) Ba.l, V. A. Nrtrltl..al .tedles hrtae preta..ef. Jwrrl .[ the Asorl- r.w tMetrtk Ar..rlaltea fdM s 1t2t-124 ApMl 1171. (7) Beeam B, r. Rrft J. fi atrdl.a as akN1M alwerptlM dorls prea- Ya). II. '1'% eR Kt! .f aeide beavy 4O.N M Mther a./ nloYtr.. Arerk.s J..r.al .t O<t.tetrta ad Ol.eoet.fJ 96(1) : li1a-822, Jus. 10.1fM. (1) B.oaM L t. tttn; O. L b. >Tr.e. J. X laperlee.lal Medt.s ee .k.t1 ae abew7tlee la rsla o0edaR perttaa ael. 111. tJfaet .t .vbrata.eoaa LJeetlwn .t w.ar efnale do.r..poe rotlwr. fete., aad aeoeatr. A.rerl- e.s J..r.al.t OB.telrtti! #ad 07aeeMotif f0f1(i) : tIG7-M Apr. 1. f0A11. (9) Beettta4 R t„ MaavtR, l. g, yltal efeeta et ehreak ak./tar ae.erptlee aed eYroek 1.1}.ak .t..am lwtag /ro. aaeef awA tae arrds prMed. Artkaa Jsernal .t r)Mtotrkt a.d 07aseel•117 110(1) : t22.-07J, Jasa 16,1f71. (11) Br..r. 4 J. W. AlaMrt a.d aicMlee p.t.aa1.B la lahata (wekllaa). Maa.d.Arln v..r 1cWerteeor4.aA..: ttl3 11, 1/tf. (11) Bu.tz a A. ILwvm C H. NlaUae bIeeLa tb ..ettlat;-l.deced rl.. Is dreoi.tlas pnlaetla la IaelatlsA nta Bdse. 1t1(sOH) :41.-tt1. A.R. 1a lflti tff) Bewoaa, ll 1l. Olpretq.w.tlaA aad deratlr et t+rt>rad. A..erk.a Joera.l .[ OblNHea ad Ola.rNep 1tq(t) : Nt-OW Apr. -l. 190. (1!) Bottsa. N. IL Ausara.. L U. (EAIw.), hortaatal [roNea.a'rie Bec- ..d 1Lywt at w 1t1t111 Brttw Pertrl,l Mertauti rar,er. lmd... 19a a.d !l IJ.I.RSIe.e. Ue..1elN.1N6 fy. (11) Brrrta. N. 1L. Araeerau. Ia /1. (fAdltsn). t4 ett.et..t wrotLR Is p.+eraey. taapter a/.: 14etaetal lroMewa LAIaMrsa, a o.d S. 11.faa.l•ar.1.tL. I l1eR p. t3" (!i) Bvrv.a, N. R. O.u.rw.. H. tiew a M. Clttantte raealai la pr.t- sa.a: Its 1a/re.cw rr MNa wrtRat aa/ pert.alal teortallty. Br/U.a M.dk+1 Je.raal 2: 12i-Lt& Apr. 19. 11012. (!f) Cevnvet. O. M. LuMrt, p. IrE. Jr. tere.tal a.wtlat and peeteatAl .rortallll. Aa.r.k.a Jeeraal ol tlMtetrks aN Olratptl twl(tt): 7n6- tta Jel, 1.1t1lt. (fl) aree+ca. O. w„ B.AU. t.1t. Matea, M. B. Ae.aT.1t. te+r-btrtr wrlebt aw tneeatst ..rtallty rab related le oal.r.al ..eklett a.d mw4.- er.aa.k .lat.a Aoe+kaa J.enal et OrMetrla sad Ofareotop 111(t):fM Bed-1.1tt11. (111) Cs.vn. A. H. wa.ew. It. Rewnra.. !. Ctane. 1t., JAea..e.. M.. Mv.wAVas. A. b. remt. A. W. Bve. A. 1%t..ws, A., rev~ P. J. 1hN...s. 7/. ttiwr. J. A. RRerta at Mrlr.smeatal eMrlral. M tae .rlat+dlM ef Qwy% e+Ma.Rr.ti aad aor.ul bdl ce..lltur.l. Is raa. Aasaln at the New l.rt Aerr>"f at /lrtrseea 1ff; 1St1-lt; Jw11 IL tett. (1t) 1?sMAUt1. 3. 11orAUta. 1. Ue•Aeweal. Nf! wet;t erodrrd.wel oras r•wter. w3,4rl.sw.ala wr.nwlaatwa I wd wr./as.Jch a rwwerwdkew k.Met IMl.efea lr/e.. (}Ilrth wel.at sad Lr/dr.ee et pr..aat.rllf ••d ew.a..llal saerall.. la ...A.ra. ot ..lt.eee aslola= telueaa) rrdl- atrta rew. r..7(e) :max 1tm 1e1 6C£L OTLTS

"N ~

R l POl (..wF1qu FICUItF; 10.-Iluman maternal and fetal ozyhemoRlobin naluralinn curves showing carbon monozide effecl. 'ibe effect of varyinR concentrationa of carhoxyhemnRlohln [IIbCO[ Ia nkulaled by IAe method of RouAhton and I)arling (1911).'i'he oxyhemoglobin wlura- (ion (IIbO,] le that percentage of hemogtobin not bound ae carbozy hemoxl.)bin anuacr. 1.,,., t. o. l.n in the fetal desecnrling nnrta decrcasel from a control vnlue of alKwt 20.0 torr to 15.5 torr at 10 ix:rccnl fct,tI carlmxyhemoglnlrin conccntr.l- tion. (The regrevion equation for this rvlalinn was Pcn-Z0.1-0./ [HbCOr), (R--0.094).) This figure also shows the relation of oxygrn tension of the inferior vena cava below the ductus venosus to carboxyhemoglobin concentration in the fetus. At 10 percent cariwxy hcmoglobin concentration, inferior vena cava oxygen tension dc- creased from a control value of aboul 16.0 to 12.5 t.orr. (The regression equation for this relation was Paa--0.3 [HbCOr),(It--.ODfi).) As noted aiwvc, the fclus, which normally has a relatively k,w oxygen tension in relation to that of the adult, is particularly vulnerable to these rlecrement.a in blood oxygen tension with incrca.101 carhvxyhcmo{llobin concentration. In the above-mentioned study (.97). 57 percent of the fcluses died when fetal carloxyhemoRlubin vnlucK incrcascd :rlxrvc 15 lKrccnl for 30 minutes or longer (5 of I I liied at 100 ppm. and :1 of 3 died at 300 Ilprn). These deaths presumably rcyuIl.al frorn hyixrxia uf vilal tisvucs. Probably two major rca.vons accuunl for 8-62 1 I I 10 20 30 ~O [H6C0] FIGIIRR II.-The partial pretwure at which the oxyhemoalohin /aturalion ie SO percent. 1'S0, for human maternal and fetal bllwd aH a function of blood carhoxyhemoRlobin concentration u y'M'/: 1..0t L tl. l ool Ihia. Firsl., in the arlull, clevution of carlw,xyhcmoglobin cnnccnlralinn te 15 to 2(1 percent results in a 6 to 10 torr dcrrc1ac in venous I'v, %:ducs. Although this Ilecreasc is sul>,vtantial, the resultant oxygcn l.vti;rl prrx.ures prnbably remain well alrove critical values for maintaining liruc oxygen delivery (178). In cnntrua, the fetus with normal artcrial nnd vcnous Pta values probaldy close to the critical lcvcls would develop tissue hylaxia or anoxia with substantial -ken:ascs in oxygen tension. Furthcrmore, adult subjects and animals subjKtal to carhnn monoxide hy/w+xi:r show incrcwaes in canliac output (6) and presumably coronary and tissue blood flow. Apparently such enmpensatory adjustmcnla are not uv:rilalrlc to the fetus to any great cstcnl. The decreases in Idr><al oxygen tension mc:u.urcrl exilcrimcntal- II' followed those 11r1.VI1ctCYI, as.urning no increase in tis,;uc 61ua1 flllN•. In addition, the fetus probably cannot increase it-1 cartliac oulllul xiRnificanlly, as the output normally is alKrut. two to three lirnc.r that nf lhc adull on a per weight basis (1,4). Thus, the fetus probably normally "1Kralcs near thclKak nf its cardiac function curve. In an attcmpL to determine to what extent the fetus in p,rcn, rMponcis to carbon monoxide hyiaxia us compared with hylxlxia inAuccd by the mother breathing air or gas with a low oxygen cllntenl. 66EL OTLIS

I i (q) NatL. J. i. Coe"p1e:N e7anlde 1e oolieeled elpretle Atrlr.ete of 20th T.Lese. CLe.l.ta' Rexarch Grler..co. No.. 1-4. 100/, Wle.lo.- Sa leem. N.ll. l 0K pp.111-2T. Neasr, O. W, Wr..aa. J. Ottcsa.. H. V. Ar71 htdroeer4oa hfdrotfla.• aeUvllt la huau• plaeMla trese elttar.tle sa.eklag and wparokl.f w..ea C..eer Reetaref 20(ltl) : 17p•-1700. Ocloher 1000. (f!) Nsweo>+; J. R.. Noara.. Y. KJtt. Q 1L Vapor ptuae aaayels of leb.o e. ee.okt Taftaece tlefe.a f: 1(13-110. J.ll 23. l0118. (f!) Nuwaata. K. R-, Oowr. U. itecllo. 1. 11r"r.phk ehar.Nerlalld pwe.lte sa.ellsA. l.: 'ffa Ael.r 11161, Their Prelaaselae. '11e Co1- taDeesure P.Ma.w 11hb er tfw Natsert LMltul: et Neurolagteal 1%.- e.w eed bteeka ftWdetNl.. w. L lee.dee. C.. 1072 pp. 72-110. (d)) Neer.r V. Ntlwewq J. 1<„ lYatt, Q N. RreYl.ti aaaehUwe ter the uati'.M ef tM e.w RYIw et dpw/M u.ekw T.Meeo tlete.a 11: 2111-221.114L (U) O'l.awft, J. M. MON bh1 M.els ef rt.rrl dfr.lls wkt.j. OMtehiee a.d O2se.lea 11!(f) f 1t1-1sl,A.Ovetlw. (p) O:eraw iktaatYf11WO M Hsat.tt. 11awM IMMrt et the Perlutal lten lalel2 IurU IR !M 11iaNtedls TertlttlR H4t.la l1w+.la. aaade. ONarte D.porttlar+l at d..ll!~. OMar/o fretrtat Uertalllf St.dl rAsm.Iltee. r+l l. 110111. !11 M. (tt7) O.r.w Os..rlllmtar HluuVt. tl.pplw.t t. t11 tiece.d leperl ef Ike Pre4.ala1 MeetaUl) !tW W'f'a. U./w./il't'Mevat li..pltaIa Terao- I.v a.a4. (faler4e Dyrrtaart et HrpK, l7Marte lvtl.alat fllertallt7 Bl.df Ce.uNttet..OL 11,19t1, A, Ob-Ytl (OJ) Otr.utt J. l, Aa.reat, k flerq M. i/re a~M.rte.t W puw at dprMta reta A..llllt.l Qe.ldrf 1ti(!) : t11-l10. l.Me.arf 1fOl (I1) Oerertal 1f. Mateetil a.alrfl.t et taMal powlf Yt .aa O..M.tremawlat MNk(r tul CYIY IL.rNep T: d7a1-M1, Ot1.Mr 114L (70) l.f.r..al, it, watuptft D. (1peettrilt.1.R «! Na! t..eeL.tle prew p.1U. trMedlnlas e. tlli t1ffirwMW.. (QtMretN relLtt aN aMn !Na Oe.e.e.tlw t+eospaV•• aMt •t 4.111 ttnpr.el.&) 111untld- d.p. M(2!) : 1011-101; Ma) f0. 1R?1. Ilattaw. N.'ffe ae.etles et elcettaM (71) hrta.at. IL d, Dultrtatr.K A. U. 1. M..et nIIL.ed.el.e te.. eltnr.tte r.etl.ti. Je.rrl et tho Aa.erfe. Mdle.l Aardatlr 12A(iJ) : 1MI6-NM tie..2A Ittlt (71) P.e.aer, W. P. Merrl; L N., Ranltwsti DA T. RtaeLleK eed pr+ .et.r4y. A peotl.l..r7 reYwt harN es et+y et 1.146 a.eadasa drletrla .M Oly.et+t! U101 1 77L"* Deee.her 1tdR. (7J) Pa*erott, P. MeYel.eAa iM.e.ettllttyar at Nkd.& IItK.led eel trl- .ebly~.k~Wt/eWa ll0ata.L (Narstd eUMe.i 6116042 ef wt1.K smehl.t< W ~.eeNe{fbl+ANelrte.l erdltloa) Redd-Medtdr.k 1+wtltt ! (...ew 1.11. (71) P.nlrIL IL J. Hn..K M. i R..e ee.pe.e.la at It.e tae pluse et atpe.lle n.d& A../7Uee1 ('>aewletr7 !11(12) : !10lr200l1, Ilec..JS.r lltll (7i) P.ir.e.a T. HwurA A. A el.b 1• heree aalepertu. Mu1r111en. Je.r+rl et R.pe+d.ell" Mdklee t(0) : 2117-1i/. fl.e.weer 1971. (70) 11...ateta.M P. Ore.p..l RINt I. f.ew 111Mh WNRhI Ltade and Trrln.. tal Moetalltt. A pr+yae~lre elnll ef llw Nelqlleal thar.eterlalln and eeH..c-le etreasi.talet. et relhera I. 12,t1(p drllverl.a In Nnrttt Halad 1M1. A dlrerta.lnaet luaetlr aullala.' Aeta Paed/elrtea 11aawYae rlv ( A.plle..et lOf ): f OM 71 tIR 4f 9SEL OILTS 1 1 (77) Raves.aot_t. It. T., 12wlwaKt. 31. 1., Nu.t1eT. 1). J.. T.acwaa., 11. tl<eelS ot .rruklut ulrul rrVraluNl.wi. ArKrlrae Jouraal of /M..lelrln aud (:1 uea..1.KJ INII':) :'101-2tl1. lLy.t. 19. lUOtl. (11) 11.,NrR H'. A.. Ilc.rtaww, 11. 1toaMclut erd preerarurlly In I1.e presence ut o/her rerlaWea Ate61r.• at Earlroewetal 1leallh L'(Ol : 000-d0l, Ituy 11N1t1. 1111u.etd, J. IV., 1olt.ao., D. ! llethod tor IAe delermloallon of N-altro. wwlets tn lolreeo.uuokt sawwkuralr. Juur.al of the Nallonal (a.cer 1nMlllofe IN(tl) : 11N1-11W,Juae 1072. (/1) ltoerwee:r, 1'. •1'wh.•r .elhl•r. 1lrruwiwl ran• hhrtrr Whahp'tw 1 h'n h'M1.r r'kl•IM•d. (Ma.nhlMt 1.1 Ilurtltee n•1unem durlnt 1.rMgsaael• aed Ile IaOue.ee e. tbe .wtYer, 1he felue aed tb .ewkor..) /iarrtueh 1Y(2) :tt7-.'/0, 1f106. (11) 1tuuR.u.ltoupuer.~ C.. OsuJaly J, K.wtr.a, l1., Ileaw.ata D. 11ur1011/e 1wrleatale e. rtlallu" aeee In a.ttttrd..ta oWetrle.ua et 1'uratte du lalre. (1'erlqd/el ruN.lll1' 1n relatlNt te eMtelrk a.leeedenta aud folrreee uu1e.) Paper ptr.eeled at Ihe'Phlyd 4lreqoe. CauArer at /'Yrt4n1a1 Lrdlela, L.aae.r, Apr. 111-22. 1.7t, e pp (t't) Ituatr, D., KAeK E ll. Lalenul eaehl.7: A wlwesaet ot t`e auoNa. Ilen wllh pertlulal norlalllt. Asmerk'a. Jeurtul e[ iLplderlole" M/J) : 1111-100. se1Nr.4r 107Y Ruaasat„ C. S.. Tattaa. )1., )..w, G R lleietlng 1e prrtaanes. gualtraal blood pteewre, pmeesuef auleeex, 1rbf weltOt aad crewtlti a.d othec relaled faelen. A t.eaetrNlre eluds. nt111e4 Je.r.al at Preve.tl.e ad Snelel Ldlel.e 22(!) : 11R-120. Jult Itltll (1{) Ruaaeltti C. Il, T.amb R, Laasuor, R. N. tieae eReNe of aeohlnt 1e pretma.es. Jeur..1 ef O4etetefcy ad 07.eoolep.t the 1lrutak L•o.aa., w+rllfa 7! : 74f-7K Oetabor 1tIK (U) Davq, 1. l, Rer., t. RLeets ef weklaJ /N pret.aec2: A ooatlorleJ rctr.epeetle, elry. O6elMrlee aad Ottmet+bolt7 D0(J) : l13-i10. 8epte.- Irr I11tt. (W) /)olttese. i, I1n.eq, if. ). Mirett at btaan(a)p7rese tre.lo.eel a. the txwsn(a)ptremoe hldreailaae aNlv/ly la lulersal liver. pl.eenla, sad telua ot IKe nt durllt7 de) 1! is d.2 12 et geetatlea Nauare-tievld" her7'e Archlres et 1'W roaedeltt M(l): AO-ltltl. Ike. 21. 1071. (f7) icusar.ca, Y. J. (yprMte rrek/eR /N prrsu.e2. New 7erti Alal. Jeurrel uf ]ledklee 41: 1tllb-1R1A, f1et. 1. 1011. (lp) S.vrerrA. V. Ru1 terltaula dl erlde dl tarlwle ntl sanaow Nrcdaab 11 ttMlaall tuaufrtel. (l'ar4n, re..alde eoelewt 1e the flnod NrcrNellnd In prrttru.l at.nkera) Arefiteb dl OelNrfets e OLesoYKta ?!(1) : IU? !ri1i Ma2-Ju.e 104L prtl..Mawlallo. (") Meee; a. 1/.1 YAaaq S Iderl/tleatlan at dru¢s 1e 1\e W.elneret aN 1e Iht Maamaa. Wer/ae aeerrtlea arl ar/ee ut Ihe prrtnaat ratd.ll. Jeunlal et 1'har.utolop uu) )C:IMNmealal Therepeullee 17t1(1) 1 •S-1t1, f011. (>r) AluraOM, IV. J. A prellnllrar) repnrt an e1gaM1w asoklnA and /be laeld..ee .t preeaturlty. Aeerlea. Jwr.al ef Ole/NMee aad O)ee- - rrdnq 7~(~) : Mtrt-N/tl AprN 1~Or. (p1) Areau. A. W.. RiNoru. t1'. R A rn.IdeM epfuneeh fe Ibe quanll/allve asal).1e et Ih. r1.4.llle r.wnlr.nenlm of elltarellr lawnke. )'alMr l.reru/M at Ihe 1Wh Tal.aete 1'han4lr 1bwsirrh Cwlterr.er. ltalel.h, N.t7„ 1066/. reb-e11 0 -13--11 I

1 FIGIIIiE A.-Riake of aeiected pregnancy complications for amok• Ing and nonar»okinR motherti by period of Restational aae at delivery. A-abruptio placentae; li-plarenta previa; C-admiKyinn diaRnolti% rupture of inemhraner only RNNRl7: M a ./N.l (!:M). Rhcarl, t.rrrunrenlinti• un slwlics published to dat.c which demonstrate an incrl :w.erl incidcncc of maternal cigarette smoking in SII)S, states: "It is nuw...i•Icur that maternal cigurcltc smokine contributes lo an infant's risk uf iIyinR from SI bS" (!59), Summary l. The risk of slmnt:tncous aliorlion, of fetal dcath, and of ncon'rUl death incrca.eas directly with increasing levels of maternal smokinR during pregnancy. Y. puhilNhai tilwlhla nf en+uklna durln{t Ilru(inatu+y xhuw a rnn)(o nI pcrlnalal morlqllly rlNk ralloe (smokars vorsus nonamnkura) from x 10'"• of 1.01 to a high or 2.42, Il. Caunos of varhtlrllll~' Iwtwoun rlAk rullne In tllrforunt Itu'IF pnpulatlons havo Iwen uxi~lKlnwl by rqnonl analYaox. ThoY Includo: r (a) tsck of cnmltarublli'-y Ixawccn smokcrs anll nrrnsmnkl vith rc,t,ect to other imlarrtnnl varialrlcs that influence IKrtnalall nu,rtnlily, nuch iu+ race, saciocconomic sL-ilur<, age, lulrity, unrl nthcrs• (1,) lntcruction between the cffect.i or maternal smnkinR nnrl lhcnc nlhcr vnrinhlc,r, which makes m:ltcrnal smnkin{,• more dangcrou+ for the fetus in sornc pregnancies than in olhem. ~, vluJics fuiling to take nr.counl of these other varialiles may vhuw "n,,.u:dly high or unusu:llly luw risk ralios, flin nnr large study, the lurin:ltnl murtnlily risk incrc:i..cll by 20 I,,.nrnl for lhe inf:tnLs of nmukcrs nf Ics.v than a pack Ikr day and Iry 3.5 I.(.n•,•nt fur Amokcrr nf :t pack IK:r day or morc, compared with n„nsmrlkl'ra, nflcr simuttanemis adjustment to balance the cffccl_r of r,lri:lbltw other than smokinte. These inrrcwaes are similnr to thrr,ec of rdhl•r large sturlicA with nplrroirri:tlc cuntrr+l of other variables. r. Fart:A+ ~Iratlts of srnrrkl rs' inf:tnLs are found mainl}• in thc crxlcll ,•sllc/;urics or "unknown" unll "unuxiu" for fctal llc:llhs, anll in Ihl• categories of "prematurity alonc" und "respiratory difficulty" for ntrlnatul deaths. This finlling indicntc.s that the exccns deaths result Mlt from nbnormnliliiw of the fetun or neonate, hut from IrrolrlcrnA n•Int-l to the pregnancy. 7. (nrrctt•vinl,• levels of maternal emokinA renull in a highly siRnificanl incr+enKC in the risks of placental abrulrlion., placenta pn't•i:t, blecding early or Iat•t: in Irrey:n:tncy, premature and I,rrlbinl;cll rupture of mrmbranea, nnd prclcrm rlclivcry-ali of which carry high ri:ks or pcrinal.ttl (os.a. R. Although there is little effect of matcrnal smokinff on mean gl+lation, the prolxtrtion of fctal deaths and live Irirth.v that cx•cur IrRnr term increases directly with maternal smokinl,• level. Up to 14 Ir•nrnl of nll prctcrm deliveries in lhc United Sl,llcs m:ly lie altributablc to maternal smrrking. 9. AcconlinR to the resull.s nf nne large slwly, the most vi);nific:lnl diffcrencc IKlwccn smokers' unri nonsrnokcrs' risk of IKrinatal mnrtalily and Itregnancy cmnlrliculions occurs nl the gestational x);ca from 20 weeks I.n 32 or 36 weeks. 10. These findings lend to the cnnclu.ion that maternal srnoking can Ir a direct cause of fctal or nchn:d:tl death in an otherwise normal infrlnt. The immcrliat.•c cause of rnnSt mmoking-rclatcvi fctal deaths is hrnltahly anoxia, which can bc attributed to placental complications wilh antcparlum bleeding in 30 percent or more of the cases. In other rl+es, the oxygen supply may nimltly fnil from reducoal carrying ralwelty anti rwiucwi unll>tulina prmuror fdr oxyRrn oauwd by thn IotMhnoo of tsarbon mortoxitle In n)qtcrnal Knd fot.al Illo«xl. Nqonatbl ,Isatha oocuc as a rcrult of thc Incrrnalyl riak of carly tiullvory among Imok.rw, which may I,u aooontinrlly 'roiatal to b)ouciing oariy In PMRnancy and hromatylv, ruplurv uf mombrtina. I e-<a I ~ e--4l

! inc r in Ll-l rpincl l,rinc and nurcpincphrine cnncenlralioM cur, , cd with lucinjcclion valuex. Thc aulhon concludcd lhat the uterine vavcul:,r rcslanxc ln nicotine w:ta mc:lialed by the rclca,k of calcchol::mincv within lhc matcrn::l circulation. Scvcr.il invcatiKnlnrx have awlial nicotine effccLs on the fcl:tl ,yn,l ncwl,urn central ncrvoun Ryntcm. Iludnnn, cl al. (77) injuctevl 1 mR nf nicotine IKr kg Ixxly weight twice :Iaily in raLv :IurinR the cuur,u. „f a 21-day pregnancy and nltcnq:lcd tn ax9csa nicolinc effc•t•tx un thc developing brain frmm bch:wiora) resl+onnes. They comlanrwl ncizur,. activity between the nffnl:rinR of nicolinc-lrcata) anti untrcabrl animals. Such clectrol:hysioloRical data have hecn shown to prnvi,k useful information on brain mnturation paltcrns. Although convul.rive ecizures rcpresenl a fundumenlslly rutlholoKic phenomenon, when uk.,l experiment:tlly they offer a mearure of interaction occurring fxlwe"n inhibitory and excitalory nystents of the central nervous nystem that manifcs4s a.s ovcrl motor activity. The researchers utilizcvl th,. electroshock seizure thresholrl nt+ a specific index of euhcortical brain maturation, showing it ln he markedly effected in nicoline-trcah.,l animals. In control ncwlx,rn raLv, the eleclrr>Fhnck seizure thre.hol,l dccrcacol slowly fmm:l::y 10 torlay 18 and rcmuina) at this level unlil :Iay 24, the L•ccl d::y of testing. On the other hand, in the offsprinR from nicolinc-lrclt.c4l mothers, the cl:.rtr.vhrx•k acizurc threshold incrcae,.I from days 10 tn 14, then drrqqx..l Ixluw control values on day Ifi :uwl cunlinual ln decreaw! until d:ty 24. The differencey in cleclnshoK•k scizure threshol:ls in:licate that nientine inducv.vl a transitory effert on the development nf .cizurr nctivily, most likely involving sulicnrtic:d inhibitory and excit::tnry Inithwaya. Hudsnn, et nl. (7:) nlw) uliliu-d maximal clectro.ahnck .cizun• paltsrns 1a a aixrific infk:x of the whole Lrun malurttiom and cortical dcvclopmcnL They showed that nn day 26, the duration ur flexinn w:.t shorter and the :htrulinn of extension longer in offspring of nicutinc• treated ruLs than in their t.:rrcnporwllnR cnntrol.. These rcax:nset~s returned t.o control Icvcls within 3.'1 days. The reslxmsca intlicalc increased brain cxcitahility, which at this age may indicate immnturil' %• or olhcr dislurlwlnitiw of central nervous system maturation. Thus. nicotine administration :luring gestation I:rolongf-rl the normal mntu• ralional timet.nblc for excitatory and inhibitory ayst.emn, either cev delaying the :Icvelopmcnt of excilvlinn or acccleralin{; lhe devcloM~ ment of inhibition. Although lhcwe slx.rific clectrrcanvul.ivc reslx,n.r~ normalize with increasing nQe, even transient abnormalities nccurrinR (luring critical maturational pcriods may havc functional rclKrcucaionx because of the complexity nf evcnLv takin); place during centr.:l ncrvous system rlevclnpment. In,lecd, these authors lwinl nul thal continuing studies on lhe effecLx uf endnl;ennus anti exo/;en::us faclorx al on central ncrvous systcm development reveal that alterations critical I,crio,is of prcnalal and Ixi.rlnatal Lruin maluratiun, thuuKh r imrncvlial.cly nhscrvahlc, nn: fnYlucntly msnifezl in the o f ,I,crific funclions or when a nlxcialiu4l demand i. lilaced nn .nc ,~i,,olinc admini.rlrulion durinl,• gestation uLrn may nffcct ncwlx:rn h„motur funclion. Marlin and Ikckcr (!nr) noted that young ratA 1n•Hl''i1 IKrfnrmw) 1eKr well than control nnimalv on fixcd-rr;io, ,;,rial~lc i1i'Kriminulinn, nnd cliscriminulinn revcrsal. t•I;,,,.,;ic:tlly. il hmr IKC•n hcld lhal utriw:n monnxidc cxlxr.lurc resulting in „iKnificant Ipiulol,•ic effcrLs on lhc human organism is praluccd n,ainlc It}• Iwiisnninl,• with relatively high arnccnlralions of bl,xHI ;:vl,,,N)'Lc:n"/;kohin. 1)uring the I:asl tlera:lc, it has I,ccn npl:rcciat,cd Ih:1t cvett rec-Ialivrly Inw rtrlxixyhcmnglnbin concentrations, for 4 l,t 5 IKrcYrnl, can result in demonstrable disturbances of aa:l nlhc•r fdncliuns (26). IAm{,ro (97) recently has numcrous uam.-cLv of cnrlx:n monoxide cxlx,surc in the I,r,•I;nonl m:dhcr, the felus, and the newlxrrn infant. Those .turlics hri~i.l frum nnimul exlxrimcnLt may I:c considcrc<I from the -lyn,llx:inl of the rate of huildup or climinalion of carlx,n monoxi,le fr,-nt lbc prcl;n:tnl mnlhcr an:i fclus, fcL•tl to maternal carlx,xyhcmo- cbAsin con:Ynlraliuna tuuler xlc:uly-slalc con:litinns, and the cffccLa of ,:virin n:nnnxidc on the fctus iii nlrrr,. For ol,vious ethical nnd I,rhniral rcnwms, auQica of maternal and fetal cnrlxm monoxide r%rh::nl;c nrc intlxitaildc in human IKinl,•e, stnd much of our knowledge 4 thc..c relnlinns arc basterl on animal sludic•. Ilkxrl carlmxyhemnRlohin concentration (III,CO) usually is expressed as IK-rcent saturation: IHbCO] blood CO content x 100 LL blood CO capacity The terms "Itercenl saturntion" and "carlroxyhemoglobin concenlra- I'ren" are uscvl intcrchangcahly. Both imply the percentage of I+emnRlohin combined with carbon monoxide. Douglas, el al. (ay) firvt •I+nk•e:l that the amount of Idual atrhoxyhemoglobin concentration in n•lalion to oxyhemoRlnhin concentration resulted not only from the rAlin of the I,arlial 1trc.raure of carlwn monozide. Poo, to the partial IKtswre of oxygen, Po2, but in addition, from the relative affinity of IK"lohin for carbon monoxide as compared with oxygen, a factor txlKcssed by the symbol M. IHbCOI ~ Pco x M IHGO, ) P04 8-56 96EL OTLTS 1 8 57

lhc .•I•lir aud y wnm pn•Iimin:u;V, lu-wt•v,•r, nn~l furlh,•r iLtty uh ncc. . tu cv:,lu:tti• lhc implicrnlions fur the health „( inf,uiLv. l'ilrrmin C. Vcnulct nn,l U:tnyx•r. (1.'1.;• Ilr/i) clcrnunstrac,l in u- rit, of slwlicx that the level or viliunin C w:t.-4 ralucwl in lhc rnilk ,f nrn,iking m„thcrs mr ,•nnolr•trwl with nnnvmnkr•r.. The clini,al signifi. cance or this oI.•krvaliiin Ict.v nnl been cvalual.cd. Physlologlc-Experlmenlal Studies Sludie" in Animale ToAnccn Sru,,lrr Scvcrnl int•cvlignlnrx hqvo ,Iemunxlrrttal that cxlwieure of prounnnl rats or rnld,il.a lu Utlutccn nmukc IcatN lo it ralucli„n of I,irth wulizht in the offslving, u.r t.oml,art_rl t.o cuntrulx (j7, lGx, 211). Alyiarcnlh F-mcnlKr/;, et :tl. (4r,) were the firxl ttt elwly the cffccLv of t•Illctrt•ll,• smoke on pregnant anim:tlv. Tht:•u: aulhorn rrlxtrltv) lhat in fcmulc r:,l, exlxntctl to smoke fn,m t•ifi:uxate" the incitknc•t: or al.crilily, rcal,,<orl, lion of lhc young in „hv,t, nlwvliunr, nnd ncwlxtrn tlc:tlhx prior 1„ weaning incrca-vctl significantly :u comlutre.vl to controls. Wagner, cl :tl. (197) rclxtrtLvl lhnl, in alltino mice cxlx.vtvl to tohacco smokc, matxrnal wciRhl { ain during pnr/,•nancy w:w significantly Icta than in cr,nln,l animnla. Sh,Kneek (l4x) exlwpi-4.l r:tLl,iLa to trdxtccn smoke for 'wvcr,tl Rcncrnlinns. The original thx: weighed 3.5 kg. A fcmalc or the fir.t generation wcight.vl 2R k/,•, that from the rv.roml generation w•t•ight.l only 1.5 k{,•, and all atlemltLs to I,r•etrl the doe were either tG,L•tll.% unsuccessful or resullt.vl in slilll,irlhs or ntvtnatal deaths. Of course, factors other than rarhon mx>noxiJc in lnbaccn smoke may also cause fetal growth rctnnhttion. 1 ounowxi, et al. (211) rcfxtrloo.l data from sludics in raLs which indica4crl lhaL some agent prc-•xnl in cigarette smoke other than nicolinc was nslronsihlc for the reduction in birth weight ol,<vcrvel. The-sc workers cxlxuu•tl rats to several lylxa of smoke, including the nmokc of tohaoco Icaf, nmokc from Icllu<r• leaves plus nicotinc, and rmoke from lettuce leaves alone. The Ixxl%' weight of rat fcluaer cxlxxsed to lettuce leaf smoke decrcaral 9 percent, Ix>.(y wciRhl of the fclu." cxlxtecd to lettuce leaf smoke plus nicolinc dccresuctl alioul 12 Ixrccnl., and body weight of fctu.'A•~ exiwsed to tobacco smoke decrcasal about 17 percent. The rclxtrtcvl carlwxyhemoRlobin concentrations varit•tl from 2 to 8 Ix:r•ct:nl in sdl animals, but the data were nol given. Although the authors suQgcstA4t lhal carlwn monoxide might not. Ix! responsible for the rctan)aliun 'If fclal Rrowth, the evidence presented was inadequate to eultfxtrt a firm conclusion. 1n an atlcrnlrl to dcl.crrninc whether the dcerrasc in fctnl wcighl% of smukinR molhcrv results from smoking ltcr sc nr from decrctLsal fa"I inUikc, llaworlh and P'unl (6!1) compared fetal body nnd organ wciKhL` 7 I in I~n.Rrrnnl rnLx crlwwt•,l ln lnh:tccn smoke for (i to H minulr n~Ilty, frmrn tL•tya 1 to 2(1 or {tcvlntinn. Thcsc rnLr were cnrnl..,rcll „i1h un"thcr ft•ruul, whu•a: frxxl intake was re+lriclc+l t» the amount "rtnully ~~~nvumt~I hy lhc lulutcco-i-xlx>vtvl raLi, nn,l I,oth were r ml,;trtrl to n wcll-ftrl cnrtlrnl group. The animals in Iw,lh cxlrcrimcnLY M,.r,• killed on lht• 'llst tlay or gc+L•tlinn, and wciRhLv of the entire I~ tl,t• liver• nn,l the ki,lncy or each fclus were rcc„nlal. The tulal ~% .vr,%g( . fclnl wci{;hl of the group exlxwaxl tn t<donccu smoke w;Vr ,~nific,tnlly lower than lh:tl t,f Ix,lh the forxl-rn•.rlriclal and atnlrml Thi• fclal wci/;hLv or the Inltcr two gmulxt were tluitc similar. ly„~i•in und ItNA unnlywcw were Ix:rfurmcd wclrnrntcly on the entire f„n•bruin.r nnd hindltruinn or lhc feluxcw nnrl on the entiro carca-u. 1G.1h I/NA :trt1l Irrnlt•in were xignificnntly nnd lu•nlxtrlinn:tlcly rcvlucc,l In 11i,. t.art;t•Vr nntl hinilln;tin:t or the nnimuls cxlx,-L-tl ln lul,acco smokc. this iml~lit•~t th:tl eeII nmtdx•r w:t.r reduced nnrl cell ni-r.c was normul, -„ya.,•aing that the c•xlxnurc to lnlr.tcco smoke either inhih;tcvl cellular •'•-r:tlinn or nrrrh•r;tlrol ct•Ilul:tr drstrurtinn. ;tnpilht•r xlwly or smoking In nnim:tla thal is tluulal for its rcl:ttivcly rn.K;ttivc rc.ulLr is lhnl of Kirachlr.wm, et al. (x,). Thwc rcacarchcr. ,llcml,ttrl ht simulate mutcrnnl smoking in 12 ncar-;.crm pregnant ,het•p hy having lhc ewe innltirc ciQarcllc emokc Ix:riodic:tlly so that 8 in g ci/ amtl~w were consumed in one hour. The nuthorq rrlxtrtal only minor ch:utRt•s in maternal and fctal bhxxl prm-turca, heart ralcw, antl Ikwl R:t%(•s. Iluwcvcr, nn the It:,.aix of the hlnotl carlton monoxide r„ntt•nts (:tnrl assuming n nurmal hhxxl hemogIobin concentratinn), one ran calcuL•tte that the maternal blaxl mtrlxtxyhcmoRlohin conecnlra- ti„n durinl; smoking equnlcd only 0.6 Ixrcenl, n conccntrnlion not -i/;nificanlly greater than that nbluincyl under normal control contli- ti"na in mtwl rclxorl+ (99). Thu., one muaL conclude that in facl the rarl,nx}•hemnglul,in conccntralion.r did nnl xpproach tho,%c levels scrn rtrn in nnc-Itack-n-day smnkcra. - In one of lhc few slutlii.s on simuhtt•crl marijunna srnukina in anim:J.r. Sinkcr, cl nl. (17.Y) rrlxtrte.) lhnl in Rvinca IriQn exlro.vcd to mxrijuanu amoke the maternal hr.trl rate increasal during the "•<mnkinR" Ix:ritxl, and lhc maternal clectrt,<nccphaloRram changed to a paltcrn of Inw-freflucncy and high-nm(diludc nclivily. The fetal ek<trtxncephaloKnam ch:tngcxl to n Inw-frc+lucncy, hil;h-vollal;c u•tit•ity pattern during lhc amok inR Itcrial; after cessation of maternal snakinR, it ch:tnl;t.rl to u luwcr•wtltal;c und higher-frequency activity. Niralin. 1'nllnwinR the studies of Fascnlrcr/,•, ct nI. (4b), several workers have 'kmonalratlcd lhnl chronic injections of large do,.ca of nicotine into 1'rcRnanl raLs result in a reduction of Irirth weight of lhc off.prinr (11- 1,1, js R4. 122). For example, (icckcr, et nI. (12) dcnwnstratc.l lhul the fcluscs of mothers who received nicotine not only weighed less for 8-52 V6£L OTLTS

i r -.,rrnin.v Mrolhr:iniI Allhrrff (1_'1) founrl thalrliclhylnilrq,y;rrhinc unJ .rulylnitrir.:uninc, whcn :ulrnirri.tr•rcrl t.t, Iactaling hamxlcn wcrc rc..rrci:rtc•rl with the Jcvcbrlrmcnl. or typical lrachcnl hal~illu~ lumnrv in the yuun~, ru{ y cvlinf; Ir:c-.val;c rrf thrsvc cnmlKiun,ls in the milk. Allhnul;h rliclhy(uilrnn:rminc and rlil,ul.ylnilrrxvaminc havc ru,t Irccn irlcnlificrl in cig:rrcllc vnu,ke• many N-nilrrrrnmincs nrc I,,,14•rrt cnrcinogcns, and wirnc rrf them nrc Irrc.cnt in cigarcllc rmnkc (x,, 1611) Slurfir.. irr llumn,r.v Nicotine and Tobacco Smoke In)(rrrnrr nn !!rr Lrtrlnlioa 1'rrrrs.r. F:mnnucl (4.5) nntrvl no rcvluclion in milk Irraluclion among 10 wet numex who were encouraged to sm,rkc 7 to 15 cigarrclli:s daily: some were ulrrcrvcvl to inhale the Ymokt•. Halchcr and Crosby (r,R) nol.a) lh:tl after a mother smoked srvrn cigarettes within 2 hours, it w;u difficult to olrtain a specimcn of hrri.,t milk. f'crlman, cl al. (/49) found lhal, of 55 women smnkt:r.rv with an adcvlualc milk sulrl,l,y at the Ircgrinning of hir<aludy, ll (201Krccnt) had nn in:ulcyuatc Rulqrl,y at the lirtx: of discharge from the hospital. Nn relationship was rclwrrl.cvl IKlwcrn the numlwr of ciRnrrlt.e+ smnkc,l anrl the IikclihrtMl nf dcvclolring nn inndctluntc milk supply. Thc aulhnn' imlrrc`vion was that there was no greater I,rolrorlion with an instJcquat.c milk nulqrl,v among smokers than among nonanwkcrs. Iwt nr, cv,rrolNrraling r1:tL•t were supplied. Thoml.aon (186) relates the f:u•l that a young primil,ara whr, consumed 14 ciQarctLes secreted only afI rc of milk obtained at two pumpin{,•.. He sL'tbes that nllhouRh thc cvirlcncc is mrnimal, he has yet to nl,ncrvc a patient avcra~,~inK eight or more ciRarcll.cs rlail,v whose lactation was adequate at 3 month6 postpartu m. Pr..sence oJNirolinc in Ibr Afilk. Usinqa frog I,ioasany, Hatcher nrwl Crosby (68) found that the milk of a woman collcctk4l aftcr shc had smoked seven ciKurcll.a.s in 2 hours containad approximately 0.6 mg/liter nicotine. Emanuel (LS), using a leech bioasQay, sludial excretion of nicotine in the milk of wet nurses who were encouraged to smoke for the expcriment_ After the subjects had smoked 6 to IS cigarettes over a 1- to 2-hour pcriod, the author found nicotine in their milk 4 to 5 hours aftcr vmokinR, with a maximum concentration of 0.0,1 ml{rlilcr. I3isdom (16) dcmonslrated nicotine in the milk of a mother who smoked 20 cigarettes a<lay. Thompson (186) found approximatclY 0.1 mQ/lit.er of nicotine in the milk of a mother who smoked nine ciRarcllcs a rlay and altcmpt.al three "piresful." 1'crlman, et al. (119). using a Daphnia bioassay, dcmonstrat.erl nicotine in the milk of all women in their study who smoked. Moreover, they found a direct rl08C, relationship IKlwcrn concentrations of nicotine and the number of ciKarcltc.r smoked. No comment was rn:ulc by the authors on the Ix>nsilrle inaccuracy inlrorluced hy examining only the residual milk fdlnwlnR nurVin{, Irul it ir wcll knrrwn that the comlwwitinn of lF c Milk And lhc hind milk is rliffcrcnt, an,l 1><rh:ycv tile c•unc•cntr:rli. nwr,tinc slsa diffcrs. Thr,sc inReninus hinn-uy mclhalv have now l,ccn rclrl:tccrl Iry m„Ir•rn lc•chnnlngy. Fcrgusun, cl al. (Sa) mcwaurcrl Iry kn.r chrrrrnntng- rrl ht nirnlirx in a total nf 34 sumlrlcn of humnn milk frnm ICi rlonnr.v. ~„ nir•,rtinc f><nkY were found in the chrrrmnlugramx nf lhc xix rlunrrrv hr~ ot,n nrrnsmokcrs. The average nicotine content for the nlhcr M .inrl lr.~ tt;c. !)1 IutrL. IK•r Irilliun (Irfrlt), ranging frum '1) to 512 Iqdr. (4y.,1114, thc hnrnldinl,• w:cv rlunc r:tnrlrrmly, the nulhnr.rv cuulrl nnl ,rnl:dr thc rtmuunl uf snurkinf,• with the cnnccntr:ttirm rrf nicotine in nrrlk A„-r.11-plsrnnrrl Irh:trnt:u•nkinclic• slurly is ncr'rlwl lo rlctcrrninc lhe r.,t,.,,f nicrdinc•ccrcliun aml rnr„lifyinl,• fnctnrv. f;rilrnrr frrr n tli,rirnf /•,'ffrrl lllwur the l)JJcprirrg. F:m:uruc•1 (I,S) m lr+l Ilcrl, amung the infanLs in his slurly. IrK.vc slrrrls wcrc nlscrvcrl ~; irn Ihr'rrnr• inf:tnl whuae wcl num, h:rd .nxikcrl 21) cig:trcllc.. in lhc ..1r.. .I nuurs. ltiwlum ( l,t) uloocrvcvl st c:uc: nf "nicutinc lariwrninl;" in a/:reck-old infant whose mother smoked 20 cigarettes a rlay. The ~mptum. includr.rl r•aellc:c.nc.s., vomilinK, rlinrncen, nnd Llchycardia. %ir„tinc was dcmanslrsttcd in the milk, and the symldorns abat.crl +Ir'n smoking was slolrlKJ. Greiner (Q) also dc:scrilKrl a ca.-c of L.:<ihlc nicotine Iwriwming in a 3-wetik-cold nursling whrxec mother nnkrrl 15 to 40 cil,•rrn:I t,cr it day. The rymplnmi firadually :tlratcrl uvcr j1-d:r}• (Krial. /'crlrn:ut, cl al. (16!r) noted no effect of smoking nn lhc v,•irhl gain of the infnnLv of lhc amnkcn in thcir study. F'urlhcrmnrc, nr untoward symptoms were olacrvt.d. They therefore dnuhlal an .fG.•l of smoking on htctation. They noted lhnl the du.c received liy the infanh was hcncnlh the toxic level as computed front adull r•XIr•ricncc, nnd this wa.s in accurtil with their clinical ol.krv:rlinns. Thc r fart that they studied only women with an npparenlly atdcyu:rtc milk I •uly4•v may hnvc affcrtcvl lhrir results. Thc authors suggested that L•rhapa the lack of effect of smoking ulwm lactation rnil;hl rcpreknl the rkvclnpmcnt of tolerance to nicotine, str Iroth the molhcr and the ,df.(KinR harl been exltct.vcd lhrou);huul the pregnancy. Fcrl,rusnn, ct al. 01) notcd that all infanLti ubservcrl in their study were meyrnldorn:tlic, tith normal fecclinK halriLt nnd I,ch;tvior. While all authors refer to the I+rence or alretence of immcilialc toxic efft.•cL., no evaluation of subtle 'fftYLi hai been done. Such cffccL+ may develop us a cnnscvlucnco of thc• infant's doublc cx/wrsurc, through milk ingestion and inhalation from a'•srnokinR" environment. nUY'. [3radt and Hcrrcnkohl (18) mcnvured DDT content in human milk samplca from 10 donors and. found that the results were r"r*elals.ld with lhe numl,cr of cigarettes smoked Ix:r day. This 'ORRuts either that cigarette smoke may be a source of the human I"dY burden of DUT or that it may cause more DDT to I,c excreted in e-:•41 1 1-51 £6EL OTLIS

! j . r; fi.-1•:xnrnplc, uf K•rinal:,l rnnrLalily hy mat/•rnal Kntuki^ r;laluH rcIII1,Yl 1,r olhcr Nul>gruup characleri4licM R ti,u.ly I^Iw1. ..M N.. ..1 I..r,h. I'rnn.l.l a n..,n,Vl -! N- .._ - ._._ \nr.L. n ,.6•R.vy N..w. vnLrn Cm.L. n H.LI.,. ny. Hnl,.h 1•rnn•l.l M...Lley Survey, /:nRlsml. .H I I,11'. l,rln S.-l rl.. 12 Ih,~h/ r. R a,i Lrlha S1.'. u,s 1,r. 114 W.•h-nRlnn ('n M.ryl.ml• .Mta 7 4411 IR/1 1'aIM~.'. ~Iwa..n 14 41 IRII 112 A yr.n 17RI JRM _ 214 NoAbtrn Finland, .hile ePM tsw 212 Z11 . 1,/( Ghrorwi., n.iMle te u(,i. P~ n..Llk ti.w tlM7 1.M wAite 11 0/ 11 3f l.21/ 1.071 HLr1 17.1/ 21 AI 124 Hrwlnn c:ily /~ 1•n•n.Ul fhnr SW I= /92 [iR Wh,4 Hl.ri 292 ac J1/ u1 11111 1os G~Idw.G.r I4rinW S,,r1y, 12 (LC ,en,en Il.rt .al rq,. .,rt4.,,l.p 11.121 1111a/ Whi1.• 214 I 10 SIS Iru u. 311.2 lu 1.M2 P• IT Nl.r4 1t S I le 41.5 I,N II. 57.1 149 Qu.I.r. Ins on,r.k nl ],l12 ?,fR7 M.ar..l Re reRutr.ad b,r1Y. <2S 121 161 I 17 2S 31 12 a 11.2 1 1ti 35. 2:I.o 417 IAI •R.W d rrld.l -lr rr IY W y IN....W..ly lOUM:C. Mey«. M.11. (IIIt - collccled from routine records, and from interviews with mothcrs. ancalhetiata, and attending physicians, and from auto)>sy r•ccor.b• Results related perinatal mortnlily to social, clemogrnl/hlc, and phyia'I maternal factors, prenatal carc, histories of prior prcKnnnciL"s complications of pregnancy, details of ancvthcvia, delivery, hospilal cour•sc, and survival of the infant up to 8 days. The intcrvicws ^f >r ~,lhcr• inc•lullc•rI tlw•sliunn nn tlu• nlaximum amnunl smc,kc•. nl IR'l'n'y, cxl,rc~r4rl :IV tr.lck:r/ (~ I,cr rl:ly (1GY. 16•1). Thc large r,f Ihl. y:Ind the richncs.r or iL. nv;til:Illlc infnrmalion Ilrot•i,lcle :t rcvwrc•e for sorting nul curnlll,•x inlrrrcl:llil,n.hitw Ixlwecn n,;,l,•rnal smoking, ulhcr f:rclnrr, :tnrl IKrino,l:tl luw. In the firrrvl arlic•le „f Ihc u'ri''v, lhc Iliffcrenti:ll risk (+f .mrrkin{; Ila.cvl nn maternal wlu demonstrated Ily extensive crcKe-1:11wL•tlinn of /,•rin:rlal rnrirt:tlit,v r:,tcs for :1 Ic•vcl-4 or sm„kinQ (nr,no. Ic.. than a tr•t I I,;u•k or nrnn• Ix•r,L•ty) within .',2.rul,l,•rrull,v u( other Inalcrnal ,:,rial+h'`• Ilisk r.tlinx fnr light srnnkcr.t compared with nonsrnokcrs II «.L,1 cr,•c.w rlc:tlh ri.k% or Icvs than 1(1 I,c:rccnl for w„men or young I„W I,:Irity. and normal hcmuglullin. At the other extrcl7x, rll„(hc•n, or high p:trill'. public hcwlrital sL•Ilus, with previous Ilrcmalurc In(allts, or with hemoglobin under 11 grams anrl who wcrn heavy ,Ilt„I;t.r, (une Iclck or mur•c IKr day) h:ul incrc:wcvl pcrinatal mortality r,f 711 ln 1O/1 Irrc•c•nt. Itisks for light nmokcr7s who ha,l other ..Irnl risk Gu•Ira. :Inrl for heavy snu,kc•rx with uthcrw•ise gINMI I,n,~ll„sia fcll Ilclw'crn lhcsc exlrcmcs when comparal with nonsmok- ,•n. Thc•4: rclatiunxhilw show how sdection of it slully population from „n,• cnd or thc tither or this sluvclrum nf smokinR-aasociatcxl risk levels w"ouLl influence the relative risk founrl for smoking when no adjuslmcnt is matlc for these other factors (11T). Other studies in rhich similar crnisv-1:11wL•Itions havc IKCn msalc IKlwccn maternal =mukinR level and wki(cconermic Icvcl, mltt.crnal aKc, Ir,trily. I,rcviuu.r pn•{lnancy hislnry, and olhcr such f•rctors have corrolloralcd thcsc firutingr (2.22.29.47.11)2. lY,!)). iteeau.tc of IMIR.iblc intcruclions Ir<lwccn maternal smoking and thc olhcr indclKndcnt varinhlt.x. Meyer, et al. undcrtc,,,k further analysis rrf the Ontario ,lat:l to define and mcw.urc the inrlc/,cn,lcnt cffect or maternal smoking on the risk of Iwrinatnl mortality. h'or this a multiplc rcgrccvion an.llyais wits uscrl to compare the relative imlartancc of nmoking and other f:tclnrs in their influence (in pcrin:IL•tl mnrtality and on the frcjucnry nf low I,irthwcighl, or I+rcl.crm dclivcry, anrl of ItL•Icv:nl:ll cumldic:ttirms (115). When the r:tt.cs of Irrinatal mortality by smoking were suljusl.ecl for the effects of all other fact•on, pcrinatal mortality rates per thousand births were 2-:1.5 for non.moken, 28.2 fnr smokcrs or Icaa than a pack pcr clay, and 31.8 for smokers of a lutck or more per duy. In other wonls, light smoking incrcased the risk by 20 percent and heavy smoking increased it by 35 Irrcenl. This is a highly significanl, close-related, independent effect, but it Ie lou strong than lho rcllttionnhtp lo porinatal mortality of 11Mpltal pay atatus (a 5.5 Ircrconl increase for public etatus mothers), Rc'parity diffcrencea, or a history of previous pregnancy loss (190 Ilcrcenl greater risk if there is .a I)rcvious loss compared with Primiparity or with a previous pregnancy with no fetal or neonatal I'n') (11S). I I I A-:11 a, S8£L OZLTS J 8 -

1 1'.- .d .t.lll.rlh ........... ......,,. ,.. ..,utlNtttK U1(ult rrta,c.laAe ilwwknn A i tAg I g g_-Cauae of neonatal death related to amokinK habil here.ty. I.n.k,.ra N„MeN1'M y,~,`rn~~ Nnnrww.Aen M\t:/..t Al.r.,r nOt r) 025 MrlfnUl h)~W(~NMN 0.! _ 1117 .-rl~,), la^ "/kr uw 11 O IAffwuI( lal.wr orn ntn ' .A~ .Jf.r~l.lw -r nnt A.lryrnunl Mnrw.Aatte 0 11 O;p n 11 C frml.l /wrl/.rlwat... 6.12 n27 tr•wr Ortl /l.rl~,alfl~r di.rase 01.1 Om InfrflbN onl n111 Awnu (.Iltww! d.r..u. r.u..rl 021 0 aw~J.lr n 1n fltlrr c.ux .blll«rt\ - 002 O.tl Y.n•r.4•d ,111flrrlh (.itArwt .J..irwu r.wr) 0.2! 0 D . 1.10 Tctal Ldlhrtha 1.10 154 E a.1.....J IA SQUIt(:E A..tns•J (f1 :~ f SnY.~en O.lt 031 o t! n 12 00! _ nm 614 012 1 40 ause of Death t lIt1.F 9•-Stillhirtht acrnrdinA to cause in relation to maternal C smoking during pregnancy The weight of evidence I/rc.•.cntal in this chapter clearly indicates lhat maternal smoking Ihr<s incrca,9e the risk of slrontancous alartirln, carly and late fcta) ticath, antl early nconlt.nl dcnth. This being u>, it i.s atlpropriatc Lo attempt to identify mechanisms of action and inlcrnk. diate llathwayx Ilctwecn the cigirctt.c smoke nnd the futal event. Clue, to these mechaniama might he foun/l if certain causes of de;tth showed an cxcra.s among the infunts of smoking molhcrs. Several nuthcxs have reported cause-specific mortality rates for the infants of smokers nnd nonsmokers. Andrews and McGarry (2) relxlrted atillhirlh rawa of 1.30 per 100 births for nonsmokcrs and 1.54 p_r 100 for smokers, among which 0.11 and 0.39 were due to anwpartum hemorrhage for nonsmokers and smokers respectively. For neonatal dcathr, causcs showing excess rates for infants of smoking mothers were "immaturi- ty (no other cause)," "rcnpirat.ory distress syndrome," and "pncumo- nia," with overall rates of 1.10 anti 1.40 for nonsmokers, and emokcr., respectively (Tahlcs 7 and 8). Comstock, et al. (30) compared olJscrved neonat.al deaths of smokers' babies with numbers of deaths expectad at nonsmoker rates. Out of 100 total observed deaths, smokers' infant.t had excesses of 17 due to immaturily, 15 due to asphyxia and atelect.a,is, and 7 due to birth injuries, with deficiencies of -7 due to congenital defecta and -4 due to "other," leaving a net excess of +28. In Lhe prospective study of 9.169 pregnancies carried out by Coujard, et al. (68), causes of stillbirth that increased significantly with maternal smoking were "abruptio placentac" (p-.005) and "unknown cause" (p-0.0005). Overall differences in stillbirth ratcs showed an excess for smokers nt a significance level of p-0.0U01 (Table 9). ( 4du;ru. ~ NruJ.•r wr JvG.rrcr+ t nf .n.i- fww,(..n.u. .,lh r.r wAh. I ~ . .r ~,1~. . . I .....kr . . ..................... 1, ttis t•.ya.. rJr.allar .................. 1] Mn p~nmS v..W.nl rw.. .................... 11 1.5•2 ~ • ..Il.r.+w btl-Miq k. ..M..w.lrwl ................. '.-1r...we ..................•..• U ]2 ,.ti ]51 P-00tln0 '...N /./..,r ..( ..s• .~ 4 S - L,r Im 3'f• v-naool ..L,h. .... ........................ fna 1211 •.r. r... n•h.fr 6ft....er /. w wr•H.rM. +r rr. C(a4 11et'cr and Tona.vcia (!Ir) have unalyu.rl fetall and neonatal deaths 'nlm the Ontario Perinatal Mortality Study (142. 14:J) to idcntify rau.cs of death that shuw nn cxccsa if the mother smokes anti to t'lxminc the relationship uf lh4•+e dcsths to complications of pregnancy 3nd lalar. Fetal and neonatal deatths hy calexl cause emt maternal =moking habit are shown in Tallle 10. For each cause the ohscrved numbcrs for smokers were compared with the number expected at "In.nwker rates. The differences t>tlwecn observed and expectwf numbers indicate the number of deaths in each category altributalde I" Atitlernal smoking. Significance levels' of the differences bcl.t' __n 'n+okcr and nonsmoker rates, Lascd on the null hypothesis of no 'lif fcrence, are shown for ll values of 0.06 or•Icss. t 8-36 98£L OILtS 1 • e-:t7

} . , _ . . . ~ . . 1 . .1 t.......t L...::1. 1 Evid, or Indirrct AK-ctx•inuonr liclwecp Smoking and turth We•igh. Ycrushalmy ha.r vu{;l;cnt-l thul .mokinK la nn Irnlcx to a pnrtlcular tY3K or rcltrvxluctivc (1ult•nmc nml dhwx nnl Idaiy a cauxal role in the praluction of vnnll-for-+I:tt,cv inf:tnLv (2r6•2l1x). The line of renwtninK and evidence ltrcrcnlcYl t)y Ycruxhalmy and thc rc~lw~nkw Ln it :,rt, discusqcvl in dctail in the 1J7:3 rclHrrl on Thc Ilrnllh (w,»xrq„r„r,., ,/ $moking (1!l•1). The IiroLlcros inherent in Ycrush:tlmy's sLwly, in which hc found u higher lx•rccnt.'tgc of low birth wci9hLv amnn3; 214 nonsmokers who later IK•~:amc smokcr, than among nonsmt+kcrs who did nol takc il ult, have ltcen dc.wcrilxd. The most serious of Lhee problems is the hias intralucxvl by the study tle-Rign "ulling in significantly younger aM for the "fulure amokcr" group (mean age 19.70±0.15) than for his nonsmokers (22-10±0.04); the doubly rctrm, apeclive nature of lho Informalion Rathoral(womon being a.aked alwwl amokinR habits at the time of Itrevinua pregnancies); and lack of control for other imlxtrtanl factora influoncing birth wciRht, such ar primiparity and sex of child. Silverman addr•c,~sml the question of whether the smoker rnlhcr than the smoking wa., responsible for increased frequency of low Itirth weight by comparing lutirs of births to the same worrian, using data from the 1963 private ccnsus of the population of Washinaton Gtunty, Maryland (28). In this ccnsus nll mcmbcrs of lhe houscholtl were listed with birth dates, and all members were asked whcthcr and how much they smoked and when lhcy had aLarted. Uaing these data, Silverman constructed a population of Imira of hirth.s that occurretl durinR the I7- year period prior to lhc census date of July 15, 1963. Assuming that the mothers did not stop smokinR durinR pregnancy and that the age or starting was accurately rcitortal, shc was able to compare birth weights in first and second births of 143 women who smokat during the second pregnancy, but not during the first, wilh corresponding birth weights from 392 women who smoked during neither pregnancy and 491 women who smoked during both pregnancies. The many problems inherent in this slwly were fac~.vl, and adjustments were made insofar as possible. For examltle, as in Yerushalmy's stutly, significantly more of lhc future smokers (44.8 percent) were under ZO years of age at the time of the first aludy birth, comparcvl with 7.d.5 percent of the continuing nonsmokers. Young, primiparous mothcrs are known to have lighter babies than older mothers with higher parity. When wcighLs were compared specific for maternal age and sc:t of child, the mean birlh weight for lhc first memlx:r of the birth I+air was lower in four out of six comparisons and higher in two. With simultaneous adjustment for the effecty of infanl st:x, rnatcrnal agc. and birth ortlcr, there were no sif,rnificanl differences in mean birtIt weight tliffcrcncc among pairs in which the mother smoked during Itulh Itrcl,•nancics and paim in which the mother smoked during lhe .,n,l pregnancy of the Iinlr, Itul not tho flra. Comparison .- the tr,can birth weights for lhc firsl inf:tnLa in each pair .rhowlY3 that futurr xrnokcrs had hahica who weighed ILx+ than those or womcn whtt ,lid nnt l3kc up smoking and more than those of women who were pIr~.mnkcrs nnd crnntinue,) to smoke. Silverman cnnclu~lcvl: "Thcse f,r„ling% neither confirm nor deny the hylwtthc•ris that the smoker ryth,•r than the smoking Iw_r ac causes a reduction in birthwci{ ht" tl:11. f:%i,lcncc fnr it direct effect of maternal smoking on fctal t,*rowth :w I,rt.4nltyl in this chapter is extremely stronl;. Furthermorr, the I,ioln,icai cffecLs or carlxm muntixitlc, nicvdinc, and other known ,,,ntlwencnts or cigarette srnnke unt compatible with the findinp. from cpwlrmiulogic aludica. Therefnre, there .rcrma little value in arguing thnl this din-cl effect tltvx not exiat. On the other hnnd, smokers arc to wane exlent relf-sc•leclcvl, ltnd cnml+arison% of "smoker." and "non- L~ in a ltnlwlalinn ruvt'al differences IKtwLxen l.hc•m. These may t, rclaterl to calendar limu lrcmis. Itecr group influcnce, cultural arxl rthnir h:u•kgrr>untl, aociatl e/tts., or personality type. Because the mlatinnchip IKtwtVn maternal smoking ant) hirth weight is tw qlronK, tht+c diffcrcnccs tln nel oltscuro it. More prublcrru nrise fmm lack of adjustmcnt fttr diffcrenccs Itelwttn snutkcrs and nonsmokers in the di+tribulion of such factors na ngc, p7rity, aociocconomic sLllus, antl rxc w•hcn the relationship nf maternal amoking to lwrinalal mortality is untkrslutly; these is.ucs are tliscu`vwl in dcLlil in another section of thi.chapter. In nddition, attenllon should be paid to the fxxavibilily that 1vi}•ehologica) makeup and alrength of addiction to cigarette smoking may have an independent influence on some of the outcomes I,cing .twlivYl. Future studies should not only ndjust for independent factors that influence whether or not a woman 1>w•comcy u smoker and smukcs during pregnancy but shot:ld also distinguish Iktwecn the cffccLv of a Irrsnnalily type that ndupLq rmnking and the physical effccLv of lhc "moke on mother, ltlaccnta, rtntl fvlux. S.aaury I. Babies born to women who smnkc during pregnancy are on the average 200 grams lighter than babies born to comparable women who do not smoke. The whole tlislrihution or hirlh weights of smokers' habics is shifted downward, antl twice Jts many of these babies weigh kft than 2,500 grams compared with bahics of nonsmokers. There is +bundant evidence that mnlernal smoking is a direct cause of the reduction in birth weight. Z. Birth weight is affected by matcrnal smoking independently and t~ a uniform exl.ent, rc/;:trtllcxi of other determinants of birth wei/,•ht. The more the mothcr srnokes, the greater the reduction in birth wcighl of the baby. 8-2G 1 8-Y'I

) r r I age, btrl funl n.hnrlr•r ,•n-wn-runtp Icnl;lh, n nm:tll,•r tr:tnYVC, ht.,,,I rli:trnclcr, Ic,,4 us4ifir•nlmn of fon•litnl, Iwrncs, .hurt.cr vilrntx.;,c antl shorter claw IcnKth in relation tu fetal u{ c. Niehinruru aml Nnkej (1aiJ) rcjwrrlcvl numcrutw malfnrrn:tlirrns, Irurlicul:trly uf the skclct4l syacm rrf fctul mice (strnin S) whiwc rnnthcr9 rcrcivcd injcctinn., of nicotine. These dcvclolrmcnLrl annmulics inclurlcvl Jclayctl nvlAY,gencsi~ anrl mnlfrtrm:tllun ,if major juinLs, (Nrlyrlnctyly, symlaclyly, .I,inal curvaturc, clc. Thc critical Ikrir„1 for Itnwlucing, ltxsc: ul,norrnalitiL, was longer than fur many other drugs tcsttxl, ext.cnrling from the fith through the 14th clay of gesLlliun. In a sulr.vcqucnt study, Geller (S7) showed that rloscs of nicolinc, about 15 Itcrccnl of that uswl Iry Nishimura aml Nnkai, resultcvl in no fetal abnormalities. Lantlaucr(~!) also noted multiple congenital abnormalities in white leghorn chicks in which the cgkm were injcclcYl with varying concentrations of nicolinc sulfate at several stagcs of inculwtion. The prcrlominnnt lesion notcvl was shortening anr) LwistinQ, of the nock, secondary to abnorm:.' dcvclnpmcnl of the cervical spine. Several groula have shown lhal nicotine administration to Nregnant rats resulted in ltrolongcvl gestation (11, 11, 75, 79). For in.stancc, in Sprague-Dawley rril.s receiving d:uly injections of 3 mg of nicotine pcr kg of Lcxly weight throughout the 21 daya of gestation, the onset of lahor was delayed I duy in 40 1><rccnt, rklayal 2 days in another 40 pcrcent, and the remainrlcr delivered on thc third day (13). Maternal weight gain in nicotinc-lrenl.ivl rats ia also significantly less (12, 78, 79). Damage to the Idaccntal capillaries of nicolinc-trcalcvl dogs was rcfxrrted by Fischer (52)• That nicotine dcfinit<rly croRse.w the placenta into the fclus has Ircrn demonstrated by a numlu;r nf workers (i;6, 187). Nicotine and itn metabolic praluct, cotininc, are also found in amniotic fluirl (194). The question of the rate at which nicotine and its mclalx,lilcs cros_s the placenta is nf somc interest. Tjalvc, cl al. (187) showcvl that, following maternal injection of C"-Ial,<Icvl nicrntinc, radioactivity aplx;an.l rather quickly in the placenta and fcla lissucs, reaching a I,cak in lwlh in about 30 minutes. In alurlics of rhesus monkcys with catheters in maternal anri fetal Idocxl vessels and amniotic fluiri. Suzuki, cl nl. (1X4) mca,sura) nicotine levels following a single injection of 0.5 to 1.0 mIC '11-nicolinc into the maternal circulation. The decres~sc in maternal nicotine concentration was a double cx fwncnlial pr(xx.ss. Initially there was a rapid decrease as nicolinc tx~camc dislributAVl in various maternal bocly conyrarlntents. Then there was a slow decre:sc duc to lhe metal,olism of nicotine and its crossing the placenta. Fetal nicotine concentration incrca.sc•d rapidly; then a plalaau devclolerl, followcd I'Y a slow rlccrc:~sc as nicotine was mclal>rrlir.ed and re-entered lhc maternal circulation. It was noted that the fclal adrenal I;lands, hcar,• and kidneys lcnrlcJ tu accurnulatc the nicotine. 3_54 S6ZrL OtLtS I pp' Whilc the fctal liver rnet:tlxdi•r.cr nicotine (Irrcvurn:tlJy hc (hiut rn:ttcrnnl livcr (/xr) it is Icvv efficient ) •li . un , n,jcrr~+"nrnl fr:u `4,Ih:,nrl+kc, cl nl. (17fr) rluuntitutcvl Ihiv relation by mcresurinK the f„rrnatiun uf I:t1KIcrI cnlininc nflcr incubalinn of C"-InIwIcYI nicrrlinc „ilh Ijv~•r slircv from fetal :rn4 ncwlxrrn mice. These workcrv shrrwcvl an Mlrn,r.l Iincar incrc:crt: In lhc rate of m(.-Ltlx)Ii+m rrf nicotine from aloul I rlay Itrinr lrr Irirth, which ix mrrrnally 19 days in the vlr:tin nf unlil n K'r•ek following Irirlh. Thr• t•ffr''•4v of nic.rlinc rin the fetal cirruhrtirrm My vary urmcwh:tl. iv amiL•tr to nccl,vlchnlinc in its action un Ix,lh symp:tthclic nmI i,ar;t•.vntp:tlhclic {;nnglia, on rkclcL•tl musclcs, n.s wcll n.s on thc ,.•nlr:tl ncr.•au,v syatr•rn. It acts at all three sitcs, first alirnulalin{,•• thcn k.l,r,•!kang thcm. Minute rlrrcs rrf nicutinc stirnuL•rlc thc chcntorccc•Ir- „f lhc carulirl :tnd ;wrtic INMIICs, c•ausinl,• reflex hylkrtcnsirrn, ;;adiac :uYy'Icr:rlion, ttnrl incr•u:r.cv) respiratory ralc. Nicrrtinc also i•Irinr•lthrinc frnnt the arlrenal mcvlulln, (hcrcl,v IrrrMluc•inl; ,•Ir„ca~ulnr chanl;c•v. 't'hus, nit•utine can Irnalucc tvirluly tiiffr•rin/; ,•ff~rlra, rlclknrlinK un the rlrnurgc nnrl the particular eitc that in rnonl wn--titivc lo sLimuLalirrn or rlclrrerzsinn. tiuzuki, et uI. (IXI) rlwlletil the effects of nicutine injection on henrl rylr anrl arterial bl«xl pre:cwrc in rhesus monkeys. Following infusion ,.f nicatinc into the mother for 20 minulr_w(nl a rate of 1W rn{;/k{, for a 1„Ial ncttcrn:J close rrf 2 mg/kg), maternal nrl.i:ri::' lrrc.s.surc rvxu: arHl heart rate fcll Iry :du,ut 15 IKn•cnl. Changcs in '.drr,Ml pressure nn,l Irart rate of the fetus were less marked anrl more vari:tlrlc th:,n lho-te -d lhi• mother. There wns rrlalivcly slight hylwdcn.ion anrl an irregular .k•la)•c.l lachycanliu. M•rtun! fcUuK.•s (greater than 120 (lays y;r•aatiun) alsn dcvclolKVl si);nifiranl acidrwis, hylKrcarbia, nnd hyIxrxi:t. Oit thc --lhcr hand, Kir•.schb:wm, cl ul. (x5) showed no significant changes in frlal hirxwl (rrcssurc or umlrilical Irl«wI flow fullctu•inl; injection uf :i mJ!•kR nicotine Lrrtral.c into a Irrv{tn:rnt sheep. Ilowcvcr, these m•Calivc findinR.s may have rt•+ullcd from the ewes being uncvthclirAd sith thc fclu.ses exlerinrizwl, an cxlKrimcntal condition resulting in altcresl cardiovascular reslKrn.stw. Suzuki, ct al. (lsl) also administ.en:d nicotinc directly to lhc fetus irr rrMnr. The fetal Itlocxt prc..urc immcdiatcly rose anrl heart rate dccrr•:r.acd, lwtlh values returning to control valucs within 10 minutes. The fetal reslxmscw showed a "iKnificanl age dclKndcncy. The changes were more markal in thc nklcr fetuses in contrast to the younger fetuses, despite a larger tlrnc for lhc latt.cr. Thcsc differences in reslxrnsc of the fetuses as a funcliun of Restationnl age imply diffcrenres in the rlCvclultrncnl of the sulonomic nervous syslcm, with the morc mature fetuses txin{{ rnorr -vnsilivc lhan Ics.s maturc oncs. In a prclirninary study. Itcsnik, et al. (158) refxrrl that injection of I ln 1.5 mg/min of nicotine rwlucc.yl uterine bioal flow 4O percent in hreRnanl sheep. This decreased flow was associalal with a twofold

t' Ir:rl farlr rY :ur inv rlvr l in Irrulrrn);irt{ /;r' l:rli n:rl Icrr~llt i I:rl. •rry nnirrtnl+.' ~ (Ai tiincc ni,ullnc rrt,rlulnlcv ncun,lngicnl funcliun in :ulult.r hl ncvcr:rl :rn•:rs (rrrtlnrl rtr•rvnuv syarnt, .kclclnl•mu.rul:rr, g:rngli:r, nnl ttn f,+rllr)• hnw• Jrw•x it mrwlify,I,•v,•Irquncnl :rnrl fun(lirrn? 67. Trt wh:rl crlcnl rliK•m lhc cffccl of nicntinc rrn n,rnrrl„l;i,•,I func•linn cunlriltrtl,• ln hy)x•rkinclic vyntlrnntc in chilrlrcn? (iR. Wh:rl is lhc iMrlcnli:rl f,.r niculinc rncl.alwrlilcv I,cing c:rr, inul;,.rti, in curnlrin:rlirrn willr IKVtr.r(n)Iryrcnc? Carlxtn Monoxide 69. To what extent nrc emlrryonic, fctLl, or ncwlxtrn lixvucs mnrc ~ less scn.silivc to the effecLv uf carlKtn monoxide lhxn lhavc of arlulLe? 70. flow rlrx.•" cxlxtsurc to carbon monoxide physiologically affc~;l lhc dcvclultin); fclus or ncwlKrrn? 71. To what cxlenl rlo tlncu:-rc••ylxtnec rclalionshilvt exist for varinux carboxyhemoglobin concentrations? 72. Uocs a"lhrcahold" Icvcl result in advcrsc effccLv? 73. Uocs the fetus adapt to low CO conct:nlralions, and if so, by what m, hanism? 74. To what extent does CO affecl oxygen consumption by the fetus or by individual organs? 75. /Iow dcxs the dLrrctu.c in Irlrrr>,I oxygen tension physiologicnlly affect oxygen availability to the fctal brnin, hcarl, and other vital organs? 76. To what extent do dccrc:uvcs in the mean partial lue:wures of capillary oxygen affecl cellular respiration? 77. llow does incrctwcvl crrlKtxyhcrrwgloltin concentration afferl lissuc oxygenation? 78. To what extent atrc the patterns of growth, rlcvcloltmenl, anrl maturation of the central nervous systcm and other organ syalcrnc interrelated and affcx:tcvl by chronic low-level carlrnn monoxide ex Ixosu rc? 79. How doc.i carlxtn monoxide affccl developing ncurobL•lsLti? 80. To what extent does carbon monoxide incrcn-u the risk of prematurity or arlverscly affecl the rate of infanl growth? 81. To what extent rlocs the inl.crfcr•cncc with fclal oxygenation result in problems such as mental retarrlulion, cerebral Iutlsy, and perhaps sul,clinical ncuroloRic, intclleclual, or IKhavioral dcficiL.? 82. Can malificalions significantly tlccrraec carLon monoxide Icvcls in luhaccn smokc? li:l. 1)o lltc carlwtn rnnnuxirlc cunccnlrslions encountered in asyrx•ia- liun willt rn:rlcrnal smtrkinf; :ulvcrscly affccl the infanl'.r Ithyviearl or Irsychomulnr tlt•veIrtlrnu•nl? . I m Wl,al :u•r lhe lrK:rl :tnrl rr-l;ul:rlnry r'nnsiJ,•r:,l i, n.v ,•„nrrrnin• ^c~cirnum cxrlwrm mipnoxiJc cxlurvurc nll,rwr•rl frrr Irn•);n:tnl wnmr. I ~~,alrrrn infunL4? ('nl}rvcllc Ilydn,<•arlwrny K• Tu wlurl t•xlcrtl rla:. Ik•n•r•n(n)Ityrt•nc crvrsv lhr• Irlaccnlu ruul tvtlt•r Ihr fr•U~s? What (4 iLs divlrilrulirrn in the fclal ur/;:tnm nnrl lis.ucs? l; To whal (-xtt:nl rlrr the Ix•nyar(n)Irymnc cunrcnlralirrns cncnun• lo•rol irt vmnkin{; rnrdllcrv nffccl the {;mw1•ft nnrl rlcvcln)rmcnl of the (rlal hrain aurl ulhtrr ur{ :rn•r? gsTn what exlcnt rlrKs Ircnzr,(n)Ityrcnc have long term cffccL. rtn Ihc &•v(•Inlrin{; embryo and fcluv; that i•r, to what extent nrc fcluscs srt c . 1),,.~41 xuhjccl to the L•tlcr dcvclulrmenl uf ncolrlswms or maliKnun- N-xll I 8-x t 2OVL OiLT `S

, Etf on Fetal Growlh and Development Only a fcw ;rlurli,:v Icrvc ryw,rtcrl lhc cffccls nf crrrlr,m monnxi,le nn fcta•rl }Lrnwlh :,nrl dr•vclryrnicnt. Wcll. (!r)()) cxlwncd Irrcgn:rnt r,,L` ~~ 1.5 Ix:rc,•nt (I5INN) lyun) ('O fnr 5 to K rninules 1(1 limcY on ;tllcrn;,4, ,Iayx during the Y1•.L•,y Irrc{ nnncy. This resullcrl in mal,•rn;,l uncr,n, acinusncxs and :rlxrrliun or uliwrrlrtion of mnsl fcluse.r. Thc .urvi newlx,rnn failed Ur { row normally. Similar cxlr.xure tu 5; xNl I,I"n nffectal only a ratnnll Ik•rccnta);c uf animals. Thi. Irricf rclwirt Int•k, rlu:,ntitalivc rl:,lu on the numlwr nf cx)Krimcnla,l animals :rn,l numl„•r und weight nf lhe fctu.cr. Williams nnri Smith (ln!) exlxr.url raLr t„ 0.34 Ix:rccnl (3,4(1(1 lyrm) c:rrlxm monoxide for 1 hour d:,ily for ~ months. Peak rrrlxrxyhcmogluhin concentr.ttinns in lheK unimal, varicrl from 60 to 70 Ix:rcent. ArnonQ xcvcn fcmalc animals, only nrk- half the control numix:r or known I,re~,•nxncicn occurred. Thc numlkr of young fxr liltor w,a rcvlucal nnrl only 2 out of 13 newlx,rns aurvive.1 to weaning age. No 1rrcgnunciL-+ n..aultud in five femnlcs exixvtvl for 150 days. Astrup, ct al. (5) rclxirtc:4i qunntitalivc d:rla on fclal wcight.x following extx.vurc of Irrcgm,nl r.rhhiLv to carlxm monoxirlc continu• ously for 30 day.. Exlxxsurx; to 90 I+pm rcyulte) in maternal carl,oxyhcmnglobin conccntratinnn of 9 to 10 lKrccnt. Birlh wci/;ht.u decreased 11 lrcrccnt from 57.7 to 51.0 g, and ncona,tnl mortslilt• increased t.o 10.0 txrrenl fmm it control value uf 4.5 Irercent. Morlalilt• of the young rabbils during the following 21 rlays incrcrLCwl to r, percent from a control value of 13 lx:rrocnt. Pollowing cxlxxeurc to 1fV) ppm CO, with resulting maternal carloxyhcmngh,hin concentrations of 16 to 18 percent, birth wci{lhls rlccrra.arl 20 Ixrcx:nl from 53.7 to 44.7 g, and nconatal mortality wn.a 3,5 Ix;rti'c:nt r•rmlxrred with I lrcrrx;nl for llx• controls. Three of ai:ventixn newlx>rns in this l,mrulr had lirnh deformities. Mortality during the following 21 days was 27 Ix:rccnt, the same value a.s for the controls. 1'echlcr anrl Annau (48) exlx..cd prnf;nnnt Lnn/;-F:vana raLs Ln 15t) ppm CO throughout Kcantion. Thc newlx,rna of the CO cxlx,,sal ral: wciRhLd slightly less nl hirth thnn cuntrnls (5.55 (±(1.0.5 SI:M)g vcrcus 5.74 [±0.06Jl;). During the newlxx•n hcrial this diffcrt:nce incrc:LVCVI• fly day 21, the wcighLs were alxwt 42 (± 1) and 46 ( ± 1)Q, respectively. Behavioral tests discloacxl Iess spontaneous and 1..Mpa-ntimulatcrl activity as compared with controls. Garvey and Longo (.56) exfw•1 pregnant Long-Evans raLs to 30 or 90 ppm CO throughout gestation. Although fclal total hu,ly weight was unaffectcd hy thesc conccn(rs- tions, the brain weighl-s incrr:Lay1 14 txrccnl and lung weight recrcarcd 24 percent in thosc fctuscy cxtx>rcrl to 90 ppm CU. This br:rin enlarKement was attributed to an incre:LVCd water content as the cunccntr.rliunn of brain protcin, 1)NA, nnrcpinephrinc, anrl scrotonin were dccrcavr•rl, as wav lhc brain wcl-dry weight ralio. Schwctz, et al• (l7u) rc/Mrrlcrl that mir•e anrl r.,l,lril fetuses cxlxrsal to 2.50 Irpm CO 8 -60 86FL OtLtS fmm days 6 to Ifi nf Irrcgn:,ncy (mice) nnrl rlay. 6 ln IR nf Isrc, •y tral,bi4~1 rlcvclnlx:d minnr skclMal nltcr:,linnr. Garbon Monoxide Effects on Tissue Oxygenation ~,,,.rl mcchanivms Irrulr.rl,ly account for the cffccLv of carlx,n xr„nnsidc nn developing ti--euc. Unrluuhlcrlly the mo.rt imlxirl:rnt of rh~.,• ic the intcrfcrcncc with li-,auc oxygenation (In, 5:!). Claude 1G.rrl;,nl in 1957 fir•.al olwwrv,vl that c:,rlxrn monoxide decreases the ,-;,I,;u•il}' nf h11xxl tn tr:,nslw,rl oxygen by cnmlxain{t with it for h,.n1„9I„Lin. C:rrlxm monoxide hinrlin~,• ln hcmnl;lohin increases thc affinily of thc remaining hcrnrrglul,in (hil,•urc• 10:rnd 1I). Thi. .hdt ~~f the nxyhcrnnl;lul,in :r:rturation curve ln the left means that thc „,,.gn•n tension or bhwwl must Arrc+LYe ln lower than normal w,lucx Lfr,n it given mmount of oxygen will rclcrL•ue from hemnl;lohin. Thie n+:t!' !x' Irnrtieul;rrly aif;mficant for the fetus IKcausc the oxygen ,I prcxqurr• in iL-4 w•lerinl hhxxl ix normally rclulivr•I}' luw, nlM,u( :'O r„ :ql lurr a.. cnmluvcrl to adult valuca of ahnut 100 tnrr. Carlxrn r,Nrnosidc nlsn intcrferra with oxygen lranslmrl by dislrlacinR ox)•f cn fnwm thc hcmnglnhin in nrLcrial binrx(, thus rlccrc:uinl,• the hlrxxl „%tf;cn transport capacity. To the pregnant woman these cffccty on W,-rl oxygenation lxxae n slrccial threat. Not only is her oxygen ,"nsumlrtinn incrr:Lacvl 15 to 25 percent rluring pregnancy (l511), hut her IJ,.1 nxy{;cn capacity is rlccrc:L.LrI 20 to 30 Ircrccnl or morc Ix.r:ruse of the Jerrc:La4yl concentration of hcmnglol,in. Thc woman with a >if;nificant anemia facLw nn even more .revere compromise of her ..%cI!cn delivery. acrohic metalx,lic processes depend upon the maintenance of tissue oryQcn partial pressure alxwe some critical level, which varies amunl; ,liffcrcnl tissues. Intracellular ga.. Lcnsions are difficult, if not imlx.s.ihle, to mea.urc directly. However, changes in capillary f'cn ralueY rcflecl tissue oxygen tensions, other things tx:ing equal. In ll,c xh".nce of arteriovenous shunta, the I'rn of venous blood r(raining a tiv.ue equals the 1'oe at the venous end of iLs capillaries. Thus, venous 1'mroughly indicates the aricluacy of tissue oxygenation. longo (94) and Longo and Hill (97) have examined thc changes in maternal and fctal oxygen Lension in re-4lanx to various carboxyhem- "Mtlolrin concentrations in sheep with catheters chronica'ly implant«d in matcrnal and fetal vewls. Figurc 12 shows the rbx^easing oxygen l1'rlial prcasures in lhc fetal desccnding aorta and infcrior vena crva "clow the ductus venosus a-s the concentration of carhoxyhemoglohin rncrcaaes (97). In contrast to the adult, whose arterial oxygen tension remains relatively unaffccted by changes in carboxyhemoglobin Mnccnlrxtions, the fetus has art..crial oxygen tensions w:,: ', are pIrticularly sensitive to incrcases in mat•ernal or fetal carboxyhcrno- globin concentrations. In the illustration, the oxygen partial pmssurc 8-6 1

i TA ; II.-I'/•rinal:J m.nrlalily nncl N•1trlc•d prcKnnncy ceml/lic•:Iliun4 I/y ncllc•nul) nmotkinK Icvelx tinuiinR 4vr1 /lw\. Lv .l.yl fI /.rb+ I.•. I JYin bA.I /..th.l i ./tf..T! a (D41'ul il (ISt]t I. 1R:W1 1..Ih.) 1u.th.l 4.th./ ~ r.nn.l.l nr,.lddr Y1.1 2/1 n YI / 27 NI AhrvVla law•nt.. rl.-nt. f..." fl Is / a4 EnR a 2 2M9 Ll 1 /7.11 2h 6/ ~ kalinR ,IurinR I16 S 141.4 IM I 20191 MKtiM) Rulaunr of n.emlr.n >/n hnun ,•. IS11 21.1 1511 In9 91 ~ Rul.lune n( ,ne.nlr.n e. .lD t ~.2 IR 0 l5 71 enly •l .dwir.ie. . ~ .V qu..e (w ln.&. 1r<oWn01 SoUIWf: M.y..• M fl Ulq prolongecl rupture of membranes- all of which carry hil;h risks coi {xrinatal loss. Fctal ancl nalnuL•11 deaths from the Ontarin stuJy wen• analyzed (ili;) to la/k for smf/king-rclatcvl excesses Ilf v:lri,K/s complications of I/rc/;nancy and Inlx,r among those ccxh.Yl by tiK• original Ontario Pcrin:Ital Ml/rtality Study (142). Results are shown in Table 12. Mcmt tliagnowi.w showed no ruwnci:ltion with cxcrxq morlaiitc for smokcrs' Iwbich, but a few .t.xxl out a/_v highly significant. As ahow•r. in Table 10, the net excess nf fetal /lcuth.s for smoking mothers was 63. Table 12 shows that thc.'ac dcnth.r were ntrongly as.aocint.cvl with b1ee11inR Iluring prr{,rnancy, either before (11-0.01) or after (p-0.00fYl) 20 weekn' gcatatiun, with 88 Ikrcent of the total exc•oems fallinK in these categories. In other coJcoil cutcl,*oric.r, a eil,rnificant excess of fetal deaths occurrrvl among smoking mothers with abruplio pluccntac (p-0.001) or other oiMlctrical I/r•nlllems. Analysis of coJcal complica- tions of laix/r showed an exct-m-t of 32 fctal deaths codt,•d as ubruptin placentac and 8 codt..l a,s plau:cnta lur:vin. Fourteen more than cxpcctcvl had prolonged rupture of mcmbrnncs. Similar comparisons were made for neonatal deaths (Table 8). For these, the net exccss among smoking mothers was 40. Among women who had vaginal bleeding (xforc 20 weeks' gestation, there were 41 more neonatal deaths observed than exi/ectG.v1, accounting for the tutal difference (1)-0.0001). Other categories that showed sil;nificant increases of srnokinl;-a.v.sociattivl neonatal deaths are the adrnission status of rupture of membranes only, other obstetric compiications. and duration of rupture of membranes over 48 hours, with 19 morc nconat:tl dcathY than cxix:cled in the latter group (116). 1 -Felal and ntrmnlnl dc•nlhN hy mnlernnl nrnokink I 1 12 • 1JL 14 other cndcd conditions (Ontario 1'crinatal Mortality Study data. (:anadian•born, 1•:nRliKh•npeakinR women. N- 31,7R9 birihn, 411 perinatal deathn) ~- r,,,{,.1 ..rlit.w~ p. `.n I. ..ul • ~.... t...4.( dminr I0"M.Kr .« w f... 2„ ...1. t+n 71 ...a. IMaA. w/ ....ken' h.lw. f)tw•rval<.Iralnl .bf Lanr.+' Frlal rf N...utal F 1 1'.1 N s. 2R S N 3 .n9 M~ n7 NS /11S nml 2S N3. •21 NR. S9 NS. -/9 NS. all NS n/ NS 130 nr4 1G.11 nlK t0 001 122 NC 13 7 NS 21 N\ al y5 I/a N.N. 19/ Ool M.S nnt I 7 N S. SN N.S. 1.7 NS. 2A NR. S/ NS 217 Onl 111 olnnl 722 nm1Y 33 NS Ia2 NS 222 NS 79 Nt. tt NS 1121 nnrl 62 NS n 7 N.S. 19 N S •2/ NS. IIt N9 /11 N C 7.1 N.S 49 NC. Jl0 0.06 %.% -V.fy..fvW 'ru.4 - r..rJq n.4. •r.Jr M1...1 fn...N .*..w Iw•1+.. w11 \n.il..:.+f r.\fr...n.r 1n..e...wi.n .wA r+.w...\.n w rr: o,.:..A rn,. Mepe.. M f/. U HA The conclusion may I/c dr,lwn that maternal smoking increases lhc risk of fetal nnd neonatal /k:lth at luL-;t partly by increasing the incidence of these complications. The mechanisms of action of various n"mllnncnLs of cigarette smoke in bringing nlxlut these events arc 'lixusscd in anothcr sc'elion of this chapter. WeeclampNa 11 has heen a consistent finding in almost all published studies that the incidence of preeclampsia and toxcmia, however definocl, is negatively ao4Incialcd with maternal smoking (2, 111, .Y1• 42. 74, 89, 101, 146, 164. A x_tr~ I u .t

1 14.-'fhc rclnlilln o( Ihc cuncrnlralionM of fcl:ll t/( m7lcrn:ll c:trlklxyht•mogluhin in tnothcrn who aln"kr during pregnancy I rar/..a.A.nwy;La«n u.1...71r,,,.,pN«n r..1.ny/r~n,.~LJu n.nr.~nlr.l..n . nlrrlw.n r.ln. 7S/ /1 1 " rn) tN ti};M:slq' s2(rn751• 14t021' .lll_11M1•• :1 ([ t I Ili.(•• 117( ! 11 1/) 5Q=0w) l71211L1) 07( e0M) •(711 7q:011 6,4217 1171:11 151 Ix) 6J(a0Tt1 6.7(zO.YAI nn_n(R) 1M) 24([11:101 211:a71) 1:6'inlM) 73 wt 11,11, •/ l..r wr n..ee nRv.IN 1\. w 4- p\v "llwt r nw. ry.nlv. I Y.241n (.w M.N....r. 117.4.6.1 b.... t nlal_) .rl lM rd:../ //11~ Y 411• t in~•rt l Sn11R•[E L.y.l•U (.n tam 1211/ carl,r,xyhcmoglubin. Fil,+urc I I shows the change in the oxygen l,:Irti:ll prcceurc cnrrosiandint; to ."Ill iM:rrcnl oxyhemoglobin .:ttur:llinn, tiv• 1'f7U, for maternal and fcln) i,kxKl u.. u function of blrxxl tarlx7xyh(•nr. globin concentration. Fur instr•Incc, at 10 l7cra:nl carlwlxyhcmnglu6in cwlccnlratiun, the i7o for mxlurn:ll I,1cNx1 /lurrcmxx to 21.t1 lnrr frrrm a control value of 2G.Cs tnrr. Al lhis same cmlx/xyhcmr,glnl,in tr,ncrntr.l• lion, the fct;ll P50 Ilccrc:4ecs to 17.3 lorr from n normal valuc or 2(l;r, torr. In a theoretical analysis of the effir.ta or clcvallc/l I,I/MM) carlwlr% hrnl- oKlobin on fetal nxyl;cnation, i.unl;u, et ul. (J:J, 93) have shown 1hal either markedly incrrst_wcll ti;wuc hlrMrl flow or cnnsilQ:r:thly nyiurl.l oxygen tensions are the Ilricc lh:(l must lK: puill to mnintnin nnrm:d oxygen dclivcry. The uI,IKx part of Figurc 15 shows the I,m-flictl.l decrease in oxygen tension as carlloxyhcrrwglubin cnnccntrntinns increase. The lower 17ortiun ohows the comi><nvatory or eYluiv:Il(•nt change in fetal blond flow necessary to maintain a stc:uly-xtalc nxy1;1'n exchange in the placenta, assuming no drnl/ in umhilicnl artery nxyu/•n tension. A 10 l7crccnt carlroxyhcmoglohin concentration woul(1 1.• cquivnlcnl to a drastic rtvluclion in ldood fluw. Fctnl hhxwl (lnw wuuld have t.n increase 62 Ix:rr,cnl (from 3.ri0 to 570 mI/mit)) to rnaint:+in normal oxygen exchange. Iligher (evcl.r of fl:t.•+l cartwxyhctno/;lobin require even more /lr.unalic camlwnwlliun.r. Ilowever, it st•r'n'' doubtful that much, if :uly, corn/Knsalory incrc:ts/: in 1,IocN1 flow (xrtlr` in thc pnwcncc uf r.vla,n monoxide in lhc fctu+ (97). Thcrcforc. li'c s i~LCO.) a n e s im6ca 1 w ,s t'l(a)rtP: 15.-The degree of cnmpcnwlion necec`ary to orfel thr rff.cla of elevated fetal rarlwxyhemnglobin cnncentrntiun.. Upl>ti•r prwllnn: Ikcreane in umbilical artery I'Inantr umbilical vein (placental .ad<apillary) I'm neceN:ary to muinlain normal oxygen exchange arrlm. lhe placcnla in the preeence of increaring amount of fetal ruhnx)hcnu,Abhin. Lnwer portion: Increar.e in fetal bLxx1 flow (tlf) •hirh ,ould he required to maintain the normal (3„ exchange in the plarcnla Kilh no change in umbilical artery I'/a .. r' M',: 1.y..• 1. 11 1o11 Aangcq in 1'la values I,rutL:lbty illustrate thc i,/ riro situntion morc 4K•h• th:ln du the trluivstlcnt ch:lnl;cv in hlrxul flow. 1'ilnnli,l R,rnud C(Krttillr lJrlotifirnlinu M%{i:vey and Andrews ( l11)) delcrmincvl serum vitamin Ilu Icvcl. in v2li •' men at their first prcnat;d ciinic visit. They found that the scrun+ f'Ir•ls for smokers were sif;nificnnlly lower thun for nonsmokers. Aftcr a'1)u.tmcnl for gestational nuc, parity, social cl.•ws, hemoKlubin levcl. I'llrrtcnsion, un/l maternal weight, am/lkcrs still haJ sil,rnificanlly I"a'cr levels or ti,:. They nlso founO a 4ircet, statislically sil,•nificanl 'I'"c•respon..e rclalionship lKtwccn ci);:Ircttcs smoked and scrum titamin Uu level. They again confirmed the relationship txtwern 'RU1kinR and low birth weight. The authors suggested that lhc lower 1 8-7'l / H-7a i~Ofi~L OtLt /'S

._ .. __. :?~.r_.. ...._..._ , .~ . Ness, Motley, Loadholt, Richardson & Poole 1 S1 Mrrting Street, Suite 600 Charleston, SC 29401 (803) 720-9000 Far (803) 577-7513 , T 'r.c ori,vinal ,_ will Ywill not be mailed to you. C o0p~( YOU SHOULD RECEIVE __~, PAGE(S), INCLUDING THIS COVE.:Z SHEET. IF YO U DO NOT RECF1 VE ALL THE PAGES, PLEASE CALL (803) 720-9000. ;ZrtofTrtt+uTTT rtJTE it•is facslnlle tr.wnetslon cwtatnt leQally privfleted ond confl6entlet• eniorwa lon 1nteq dcd snly 1or the u.e of the Irdivtduel or .ntlty nae.cd above. If Me reeder of thls .cuaae Ic not the Intended rKSpt.nt, you .r-e hereay notltIed t!+at .ny dloeem/rwtton, dlsctoture, dlstrltution or copyieq of thts trencaieslon Is strictly prolflDlted. If you Mve received tfifs comnricetlon In error, ylese Imrdlately notlfy vs by utey+one .rd rcturn the oripieul eessape to vic et the ebove a6aresf YJ1 the U.S. Deatsl fervice. FAX TRANSMISSION COVER SHEET C3I 4-~ 7[; Ci Q 1 ~' ~ ----~ - - J N W

4 Lac n and Breast Feeding Inan..,uctiun In IJll2, It:rll:rtync (.'/) liugl;cvlul the IMr4-silrilily or rlclrimcnl:rl effc,,lr of breast fccrling on Ir:rlricr wht.•rc molhcrs worked in Inh:rccu fur•t,rr In the inlcrvcnin{ yc:trr, rluc:rtinns have been raised cun•erning, lh,. {nlcncliun IKlwccn ril;:rrcLlc nrnnking and I:rcL•rlinn, as will ns lh,• relationship of ciKnruttc rrmok.nK to the rluantily or milk Irrvwlrtc,.,I. (, the Irresencc or conalitucntn of cil;arolt.c smoke wilhin Lite milk, nn,l effecl.i ulKrn the nuninK Infnnt mtslialt41 lhruugh chnnKt:.r in eilher lh,. tluanlily of milk avaihrhlc or the eulrtUtnccn within the milk. Epidemiological Studiee Unrlcrwoal, cl aI. (1xX), in a slutly of 2,000 women from vnrioux uKial and economic slrata, o6rcrvcv1 a tn_ntl, though stntislically insignifi. cant, loward more frwlucnl innrlaluncy of I-rt:ast milk prolucli,rn among those smoking mulhcrs who altempt.wl In nurec, as cumlrnral to nonsmnkcrs. They conclwltil that smoking tkxs not int.crfcrr with brcasl fccvlinK to any siKnificnnl degree. Iluwevcr, this study, I-M-tl,rn interviews of Iruerikral wnmcn, was not designed to analyze the effect of smoking on Irrcaal fecvling and Irrti:vt•nLq only percentile re`uILt. Na data are provirltvl to IKrmil it rcanaly.ris to determine the validity of their conclusions. 1'crlman, et al. (149) also prrsent ant.•t.r1oU-I rlaUt. They fuunl that in their Iwstfrnrlum IwtruL•ttion practically all rmokinR women startal in consume cigart:tles within two days after delivery. Although they collected milk between the fourth and ninth Ixxstpartum days to determine nicotine conl.cnl, they do not report and compare actual amounts of milk accrct.ed by lxrth smokt:re and nonsmokers. They nott4l that of the 55 nmokinQ, IactAling muthcr.n, 11 failed to have enough breast milk for the ncetli of their babies. No comparative sludy was done in a nonsmoking but othcrwinc c+tuivalcnt population. Mills (120) studied the nursina Iwlttrna of 520 women giving birth to their finl live-born infant. Among the molhcn nursing lhcir bnbic• for a minimum of 2 mtrntha and IKyonrl, the mean nurainK period w1c significantly shorter for smoken than for nonsmokers. Morcovcr, among the 24 mothen who hail given up smoking durinR at, least the final 3 months of their preRnancics, the avcrngc length of nursing was idcntical to that, of the nonsmokcrs. Thcre was no significant diffcFencc between smokers anti nonsmokerx with regard to complete inability to nurw: their offspring. This study is difficult to inl.i:rpn't IK•r:rux• lh(- :rulhor tlirl not determine the m-:uon(s) for the discuntinua• linn of nur.rnl; nrnnn{; the women. tiurv,•)r of I:rrt;,•r Lolrul:rliun or women, vnwkcrv and nunsrnokcrs. are nr•r•dr.I to rlrlcrminc accurttcly the cfft.•cl of smoking on milk I POVluclinn and to corrcl:rlc amnunt and pattern of smr~kinK wi'~ ty,~nlrnlinn of nicotine in milk throughout the l:tct.utinl; cycle. f.~prrlrrKnla) Studiee :hulir„ i,r /tnirnnls N,cotlne fMn"r.r,cr r,n Ibr InHn-inn I'r+r•r,u, ttlnkc unrl Suwycr (17) sturliect the rnflru'r i I) lulwlnnlnclnlicnn in llht, rrnt`rThcy fmun (trthlah n irrtinc nrinult• IN 'r rnhibittrl the aucklinl;-inluceJ rise in pnrL•tctin. No cffect of inject.crl ~i,,dint tt'r~ th'rnunrlrnlt.vi for nxyltxin secretion cint•c milk rclcn.w: ,,;tc not Idnrkcrl. In cs.w:nt•c, lhewc finlin),m rugl;csl that nitx,tinc can it m:tlfuncliun in milk Itrtrrluclion but not in its rclc:Lu rrN.,•h:tniam. This lrht•nomt•nun was examintxl by Tcrkcl, et nl. (1)14) in •rrm+ nf Irrrlt4 . survival. Most or lhtnt: pupn Ixrrn to females oven a Lr~+ or nicttlint• lhnrl;huut Irn't,rnancy anl IacUrlion dicrl of ,tanation Ireforc weaning. Their mothers' mammary glands containcrl trrc lilllc rnilk, and IrL•tsmn pruL•tclin Icvcls were very low. The nKrh:rnism by whit•h nicotine may afft.•ct prolnctin rclcasoc is not yet rlarif itvl. Ilatchcr and Crosby (Gx) found that, injection of 4.0 mg/kg nicotine inlo nur.ing c:tL+ sulrprt.:ti•al L'tcUtlion for ru:vcral hours. This was also .drt•n•td in it cnw. lCil.ann (!M.') examined the cfft.•cLa of nicotine supplied through .IrinkinR wal.cr (0.5, 1.0, anti 2.0 mg rlaily) on the weight gain of naning rats. Apparinlly, the nit.•olinc had I,--cn available thmu/;huut Ktrtation as well. I>Lrau.c the nulhor cnmmcnl.txl on a raluction in lillcr eizc among the exlKrimt:nUtl grtwl-a, more or less Irrol,ortinnale it, the dosc of nicotinc: hence, a pren:tUtl cfft.•cl could not have been •Iislingui.hetl from a IxwtnaUtl one. Average birth weight was similar 6rrcxlKrimcnUtl anti control ),-ruups. No diffcrencc in weight gain w:ts ,rn for any of the gruulrn. The lack of impact on birlh wci{;hl nul;y;csLc that the dr.rc was lower than that tiactl in other studies. Inrlccvl, (icckcr nrwl Marlin (1.7) olrrcrvtrl it xit,~nifitanl tlccrcn:rc in weight in the Affrpring of rnt.a receiving 3.0 mg/kg twice daily during gestation. If the trrnlmenl conlinuwl throughout the nur:aing t>Lriol, Lite young had " Irnnrcr survival chance than when exposed only in rtlrro or when 1uLjtrlerl tlaily to hylwrxic strc•-t in a.•yrecial environmental ch:rmlKr. Prrn.ncr. of Nirnline in the Itlilk nnd ila FJJrrf Upnn the Nrrrxirrq tllftpring. Nalchcr and (:mslry (lix), usinR a frog biu:t.•tcay, rcllOrtAVl lrzres of nicotine in cuw'a milk 24 hours after the intramuscular injcctinn of 5.0 mg/kg. They also rclw,rtetl that 0.5 mg/kg nicotine injcclcd into nursing caLv hail no aplr:trent harmful cfftxl ufron the tdlt'n+. Kittens ferl the milk from Lite cow that had I,<•en injcclal with '0 mR/kg nicotine were apparently unaffected. I 8 -SI) 8-dtl Z6£L OTLtS

I 1 rhil, 1r4•n H,itl, nnrnt:rl nrurnlnt ir•al slaluv :rrul luwcr `" Ac"r,y fry s' ,-hilrln•n rui li ~ ul or H tr sLa or intrllcclu:rl funclinn. Thu f,~l lh;rl (r•w n( llii•vc li(f~ rr•nres n,elrc.l "~l:rlixlic:rl Ki{tnificancc",I„cx flal't rulc nut thc Iwrwil,ility that h:rrmful Irrnl,r-tcrm cffcctH may cxixt (~k L•~). • In thc (arlifnrni;r nlurly by WingcrJ anti Schrxn (204), lhc net cff<.rt of vnrinuv (:rctr+r~ un lcngth at. Irirlh and height at 5 y,•„rH w, rlclcrmincrl in :1•707 sinQlc-Ixrrn, whilc, California children. Chil,Ircn „f smoking molhcrs were found to be shorter (1)<0.001) at I,irlh an,l at f, years than children of nonsmoking molherx. (lntclleclual <levelolnnent was not mcnsurcrl in this atudy.) In a prcr.rhect'+vc slwly of chih{n:n of low birth.wciKht, 1)unn an,l coworkerv analyzccl growth with respect to maternal smoking habitn of 81 who were "amnll-for-<Iatcs," 99 "truly prematurc;" and 146 contrn(, of full birth weight. At 6'/s years of age, the children of nnnsmoking mothers had it slightly Rn:utcr mean height and weight in all lhrcr cateKorics. The mean wrciul class of the i~moking mothers was lowcr than that of the non.rmoken, but within the two lowest social clatu~ I V and V (77 percent of all aubjccts), the nonsmokers' children ha,l a greater mean height and weight than their eounlcrfutrt.l whaw mothers smokcvl. Statistically significant differences in favor of nonsmokers' children were <Icmonslrulslc with reganl to wciqht Rain and growth in length/weight at I to 4 years and with regard to actual height at 4 and 6'/z years and weight at 6'/z year. in the full birth weight controls (4.1). There was no evidence that the children of smoking women "caught up" in Rrnwth with the nonsmokera' children• a concept poatulatal by Rusrtt:ll, et al. (164) but not corroborated M- othcr studies. Dunn also evnluntcxl the ncurological, intclleclual, and behavioral atatus of these children at age 7 and nnalyac<I the rcaulta according In the mothers' smoking habits <lurinA pregnancy. Neurological abnor- malities, including minimal ccrchral dysfunction and abnormal or borderline cncephah+gams, were slightly more common amonR children of smoking women, although this differrnce was not quite statistically si"ificant. In a batttry of psychological tests, the mean scort.~s of children of nonsmoking molhcrs were bcllcr than those of smokers' children in 45 out of 48 corrclations, and the difference v++}% significant in 14 of these. Faclnrial analysis of variance suggested that these differences could be only partially attributed to the siightl}' lower social status of smokers' children. Some significant differences In favor of nonvmukcr:v' children were also dcmonstrat.ed with rrspect Le behavior ratingY and school Irlac<:mcnt (44). Thcse results are vcry similar to those of Ifarnly anti Mcllits in that the direction of thr differences is almovt always in favor of the nonsmokers' child. {'crhlll1i more attention should lrc paid to these lutllcrns and less to the qucstion 6LEL OTLTS 1 C of •',lntiAtic:kl siRnificnncc," which is rlifficull Ur :u•lucvc wclr 'mxll nunrlwr+. Uunn cnnclwlcv that ".w,rnc xlil;hl rlirccl r. ..j;urt cffcct on ftxU'1 brain rlcvcloq+rncnt urul aulr.acyucnl inlclligcncc unil l,,.l,avinur cannot be cxclurlivl" (44). Cmrll numlk-~ anti Ixrlrrnlalinn acli~:tir,n f:<c.Urrr are not a IrrnLlc•m in Ihr lung'tudinul fullow-ulr of the IKrlruL•iliun urigin:rlly inclullcrl in (lie ltritiAh I'crinaUrl Mnrlnlity 4;lwl,y, cr,mpriring nlqrrurirnstlcly 17,txxl I,rrlh~, an c~limnlcrl 9H 1Krcenl nf ull hirlha in h:ngl:rncl. Sn,ll:rnrl, ruvl lCalcsduring the week of March 3 tn'J, 1959. Th<•u: chilrlrcn have Iwcn trac<+1 nnrl sludicr( again nt ttgc 7 and at u{;c It, in rlescrilK their Ir•hn,inr, their health, their 1-hy.ricrtl <levt•lol,mcnt, their cclucnlinnal .tnn<I:rrda, and their hnmc cnvircinmcnt. At nRcn 7 anti 11 ycals, I,h3 •acal anti mental retardation due to smoking in pregnancy wore („un,l, and this deficit incrcuswl with the numl,<r of cigarettes emokucl Juring prrgnancy. Children whose mothcrs smukc<1 10 or more rig„rcttca a d:ty rluring lrrcRnuncy were on average 1.0 ccnlimctcr•x '•••rtr•r and between 3 to 5 rnupths m-latrrlc<l in recling, malhcm:,lie., am1 gencral•ahility, as comptumd with the offril-rinA of nonsmokers. After allowing for asaociut<41 social and biological faclorv, all of thcr:e diffcrcnces are highly significant (p<0.001x.?.1, JR, j.!• 204). Recently an association has been rrlarl.cd between maternal .mnkin{; and hyfierkineaia in chihlren. Denwn and coltcay,rucs rnatcl,crl rsch of zIl conecc.utivc mclhyl-Ithcni<latc-scnsitivc casc.g with a nonh,vlrcrkinctic dy.lcxic child anti also with a normal control by scx, agc within six montha, and rucinl cla.m+. Mean birth wcil;ht, were .imilar for the three f,-rnulr.r. Mothcn of hyperkinetic children tended In lie younger, and sianificnntly more of their children were finl-lburn. Oulatanding anti highly ai{;nifiatnl <liffercncct were found in rnalcrnnl riR:rrcttc consumption. Mnthcrr of hypcrkinctic children cnnaurncrl mnrc cigarettes during Use study pregnancy (p<0.(l5), had higher maximum consumption during that pregnancy (p<0.01), and cnn- wmwl more at the time of questioning (Ir<0.001). The Irresent mean ronsumption by mothers of hyfKrkinctic children was z1.3 ci{ aretl,cs frrday, more than three times the average for the two control I,rroults. Only four mothers of hylrcrkinctic children had not smokerl during prcRnancy, and all or thcsc relxrrtwl complicated deliveries. Of smokcrs, 11 with complicatiyl pr•cgnuncics hail a mean consumption or 13.4 cigarettes daily, anti 5 with various complications smoked an avcragc of 28 cigarettes daily throughout pregnancy. The role of anoxia as a possible cause or hylrcrkinetic discase anti the hylwxic cifccls of carbon nwnoxidc anti or smoking-related complications of pregnancy anti labor are diacumuvl in the study. The authory conclude: "These findings are consistent with the hypothesis that smoking during pregnancy is an imfartnnt cau:w of the hy fxrkinclic syn<lrumc" (96). 8-M

l s -A rr:l..,•,I ,cVlC~'Ir r:rrr~int, r:,l,:,rily n( llrc LLl,rHl,Inr• tn llu: I,rl•w.nti A:1 n„lr,l rlv•wh,v',• in Il,iv rh:l{,lcr, rrtnlhorM whu xttSl,kl. hi};hcr inai,Ir•nr•r uf ,•„ml,Iiraliunv vul•.h av :lI,ru ,tin I resultiny; slilll,irllt, (,I:urIVIL•1 I,rcvia, :Inrl other c;,,,S,., , f wr, ,luring {nc~:n:uu•y x.7, lul• 102. 1fi, I1G, I.V!r).'(h,• illr, I I" {,rcrnalurc rul,lun: nf tile fcL•11 rncmlrrancs :11.,, n•. '. whilc• thc inc•i,lcnce of the hylx•rlensive ,liu,r,lerx „f Irl I' rlccrcn.c. (Y. 211, N':, 1rl.',, l.'0). Unfurlun:llcly, lhc lhcxc rlisurrlcrs is nul knr,wn. It c:ln IK Ixlslulat.cvl t I,I:,crnia m:ly f„11„w al,:L.m of utcrinc vc`ulv such :cK, !ho r,'I arlrri/rlcw kc•I,nrl:lry ln nic•ulinc aml other cnm{xiun/19. It is „f i„,, .r lhal :If,rul,tin I,I:IccnL•rc :mrl ulhcr /li.+,r,lcrs c/ccur m,+rc frc•,t,,,.,,ll} wumcn wh/a.c pregnancies are cuml,licalt.vl by tile h}.Iw•rl, n. /liurnlcrw or pregnancy. On thc alhcr hand, thc IIly:rc.wc,I iru•i16•,1,• . hy{,crtcnvicc IliWrrrlcrn among Ivcgnunl women who xnu,kc rr,;l, r,. from lhc vn.uxlilaling nelion uf the lhiucynnule {Iru.enl in smoke. Cnr•lr,n Rfonujidr Although there arc few •rtullicr of c:lrix,m monnxi/lc efft.rLc I,rcl;nnncy, lhvnc rr{xirL•1 <,f maternal unll fct'd blrxHl r.lrlw,x%,lu•,r,,,ci. i,in cunccntraliuns rlurin}; m:lternal .moking will l/c wln.illor~•,I in it. . !4)cliun. Thc blrxxl carl,nxyhcmo};lullin cnnccnlralirm uf norrnsll nnnwm,l,•,• I,rcl;nant women, I Illd:p. 1, normally is 0.5 lu 1.0 fKrccnl w•hih• Ih:,r • the fclus is ulxwl 10 (n 211 Ix:rccnt hi};hcr, that is, ll•t'i U, 1.2 Ix•n. . F'igurc 14 rlcllicL+ lhcacsuly-vL•rl.c fcl:rl unrl maternal carlw,x~•h,•rrn.ci•. llin concentrations :w a function nf the c.arlx)n nwnosillc rnnr/•ntr:,l,. Several studies have rc{x,rlcd carlxrxyhcrnul;ltrhin canccnlrali..n• lhc blw.xt of imokiny,• muthcr.l anll their ncwlxrrn. (Tnblc 14). fctal carlxrxyhemoy(lubin conccnlralions r.lngc fnrm 2 to {0 1.•r.- and matcrnat concentrations range from 2 to 14 pcrccnl. Thc:w• 1.1 samldcs, ohtainc•It at the time of vaginal delivery or (',c..w:lrc:ln s•,'tl^r lrrobalrly fail to reflect :Iccuratcly the normal values nf carlnc~hl u" Rlobin. For invt.,kncc, the numlKr of ciRarcltc..~ smoked Ilurin}; I:d•+ nri{;hl have lx-•en I~~1 than the number normally conxumlyl: samples were collcctcJ at varying limc intervals fnll-0 n}; tt" ccmation of smokina, nnd many aamlrtcs were I/robably l:lkl•n in tl. morning hefure the carlxrxyhemu};lollin concentrations hnrl built ul"• lhc values reached aflcr prolonged tw:ri(xis nf :cmnkin{,r. Thcrcff'ri'• tM avcr:µ,c vsllucs for nurm:rl smoking mnthcrw anll their fclusc~ 0•ul•I I• w4•11 alx,vc thc runrl•nlraliuns relxrrlcll in rnalcrtull anll f"l"I 1'I"" Usin}; a ncllhcrn:rlical rnrxlal, Ilill, cl al. (7•Y) ealruL'lll•1 tl" thl•nrrtlc:,I n•latinnN uf fctal :Inll rn:rl.i•rnaV c:lrlxrxyhcmngInhin c"n'o f" -70 £OVL OILTS , I .• 40 Cot,P-1°O r--~ r oo1 w ,00 007 003 oo. 005 oor 007 f CoL,..H.1 • }p,111E It.-1'crcenl earlxrxyhcmnRlnhin lm matcrnnl and fclnl tunrlinn nf rarlNm monoxide parlial prcwure arKl ~.nrrali,.n (p:lr(,l per millinn) in inxpind air. These carlxrxyhemo- rtb,,, rnnrrntraiione were rnlculated from the llald:rne rrlalion .r..rinr for the c.rlKrn nKlnoxide effect on the oxyhcmouloLin .AtYftld,n rYr% '['M ,n huncln ruLjlv-L+. 1)urin}g c:+rl)on mon/+ridc uplakc, fcl:ll lu rn,.};IuLin couu•c•nlraliunn wnu1/I lag Ix hin,l lhc malcrn;ll - ratnmx f„r the first few hours. After 14 to 21 hours they M•oul,l n,:ll,•rn:J r:lrlw/xyhcmnghd,in cnncenlrnliuns. F:vcnlu:llly lhc would c<luilillr.llc sit cnnc•enlr:rlinns 10 to 15 •,t high/•r lhan the maternal cnnlcnlratiunx, During the washout - f,•t:d r:lrlxln m,mnxillc climinalion wuuhl lag IK:hind thc •,al 1•limin:lli/m and the carlxrxyhcmr+{;hrbin concentration in lhc A••uld 1,•.i};nificanlly l,n'cntcr than that of the mother. The tirrrc 1•, rrarh unc-h:tlf uf the fin:d value wnuld average alx,ut 2 tile molhcr and 7 hnum for tile fetus. The pattern of carlx,n uplakc and elimination in lhis theoretical analysis (7.'1) is t., that of tile cxlx:rimenLnl rrsulLb in shtxp (97)• ''1••n nwnnxillc markc/lly ahifLv tile oxyhcmoglobin saluraliun t•• tile Icfl :Ind allctr tile shapc uf (lie curve toward a more G,rm. Fi};ure 111 xhows thi.r cf fc•ct for several concentr•Itiunw nullernal anll fetal earlxrxyhemuKlulrin (93). The oxyhr:rno- r''n •:Itur:liinn is for lhul lx:r•ccnL•ly;c nf hemoglobin nul bound tuy

Section 6. PREGNANCY AND INFANT ~ HEALTH

~ . ._ ._ .. _. , pn ly avarLrlrlc n•I;rl+• IK•nr.~(Y)Iryrcnc to u rctlucliun in Li W+•r nf crlKr:a.•rl rrffxlrrin{. Evidence qug/,caLv, however, lhul llnF rioc•v reach nn<I crvc.ur (lie Id:+ccnht. Aryl hytlrocarlxm hytlroxyla., (AlllI) is it part nf thc cytochrti+mc f'-4CiU-cnnl.iininQ micrr>x+mzl enzyme system Irrc.%enl in many lix.uc•n nf rliffcrrnl nlw~ica. Thic enzyme eyelcm in induced to hyrln+xylnt.c Ix+lycyclic nromnlic hyrlr,x.nn hono nftcr cxlX+auru of cclln to I'A Il. `3cvcrnl inveslitrnlnrn have utili;pl the inducil+ilily of the enzyme syvlcrn to rlctnonqlrntc indirectly lh;rl Ixnao(n)Iryrcnc untl other Iw+lycyclic hyrlmcnrlxrnv rcnch lhc Irlnccnl;r anrl fetus. Welch, cl al. (1'19) exten4crl lhir work I+y arlrnini.rtcrinR lhc polycyclic hyrlrr,cnr•I+nn, 3-mclhylchrdunlhrcnc (.3-MC) ln ratn rlurink late Rcst.atinn. The rr>Llalx+linm of I+cn~.+(n)I+yrcnc wa.c stwlicrl in r•irr, using lrilium-Ial+clerl I+cnzn(n)I,yrcnc, untl in uifro. AHH uclivily w;cc incrcascvl in fcL•tl livcn to adult Icvcln by prclrcalmenl with :l-MC. Since a relatively high r(nvc of IK>lycyclic hydrocarlxm was n.vluircrl to stimulate enzyme activity in the fclus, compar•cr) to the dosc which nlimuL•tlcd I+laccntatl enzyme activity, the aulhon xugacstcvl that the placcnla may I+rotect the fclua fmm exlwnun: to Ix+lycyclic hyrlr•ucar, (x+ns. Howevcr, immaturity of the fetal enzyme nysl.cm might alw, account for it.i apl+un:nl relative insensitivity to (Krlycyclic hydn+c:v- twns. Thcr•cforc, an cxlMwurL of the fctu.v to levels r+f Ir,+lycyclic hydrocarlwn similar to lhr..c exl+cricncal hy the molhcr cannot IK ruled out by the avaihtblc data. NclKrl, et al. (1-7-1) anrl Pclknnen, et ul. (148) alxt correlated the aclivily of this cnzymc, which wnn readily induced in placental liauc with matcrnnl smoking. Schlede and Mcrkcr (1B7) have studied the effect of bcmn(n)l+yrrnc administration on aryl hydnxarlron hydrozylnvc nclivily in the matxrnal liver, placenta, anrl fclu.r of the rat during the latter half ur gestation. The pregnant unimals were treated with large oral thx,cs of benzo(n)pyrcnc 34 hnurs prior to sacrifice. Control raLi hail no detectable lcvcls of aryl hytlnocarhon hydrozylau: in their plarenlnc. Treatment with henzo(n)pyrcnc resullcvl in hnrrly detectable placcnlal levels at Ac.vlaliun (lay 13, but steadily rising values until day 15. and then constant levels lhcnrxftcr. No activity was detected in the fclusc+ of untrcatcrl controls. In the treated animals, the fctnl enzyme activity rosc steadily from the 131h to the 18th day of gestation. The authnr. concluded that the slimuL•tlory effect of benzo(a)pyrene treatment on aryl hydrocarbon hytlroxylasc activity in lhc fetus dcmonalrales that lxnzu(n)Iryrcnc rcadily crossca the rat placenta. The placcnt.1 i+ involvcrl in complex hormonal interrelations between mother an+1 fclus, and oxidative enzyme pathways in the placenta arc imlw+rtanl in maintaining hormonal balance for normal fetal dcvclopmcnt. Thc hydroxylation of polycyclic hydrocurlx+ns anrl the active tr,tnslwrt uf various comlwunrls by lrul+hublayl cclls may shurc common cniynu ,tacnr`• Thu.r, lhc lnduclion rrf various enzymes hy maternal sm tcrfcrc with the lrtntlw+rl systems. in Thc cffcct or matxrnul admini.rlralinn of I,enzn(n)l+yrenc ns u Jtn•innRcnie risk fnr progeny waa cxamincrl I+y Nikonovu (1.75). Lr•.Knnnl mia: (Mlrninn A nn,l' nc on the 1Hlh orclOllhWlnh I t.nlulion, f,•ithcr or f mg Ircn~.rr(n)1 y Y of K' In Lrth sl~rnin.r, the nrf.rl+rin{,•, when cxumintvl 1 ycnr Inlcr, nhowcrl +t M;trktYllY higher inciduncc of ncv+l+luvms nf lhc lun{n, livcr, unrl nrtn+nrar~' (;land.r. ~I~ics In Ilumann f,J.u ru Srnr~t rt itn,l Wnlhtce (175) fir.vl relK+rltvl nn incr•c-wte in fetal henrl rate ,luring mntcrnul smoking. Thc•ac tuwlhura concluded thal lhc rc.ponsc ,,;c, ~.rnnrlnry to the (ut:cvnl,•c of nicotine ncn>.v the placcnln, although ~.- ,t:r± not dt munaralcrl. I lcllman, et nl. (:r1) stuJial acvcral factorY ,,i„•lurl; the fetnl heart rate. Thesc worken+ asked habitual smokers n„t to smnkc fnr 24 hour., then to smoke one to two cigarettes. tt.hirally, a gradually incrcasing maternal lachycanlia devclolxd ,6lhin :I minul•a of the on..cl uf smoking. Fctal trchycanlia with a flatU•ning uf llrc normal IKat-lo-I+cal variation occurred in about 3.5 in ennlrm.l, a.irnilar ro.q+onsc ler maternal atropinc injection minutcsM .IMI not occur fur about 12 minul.c..•.. The nulhnrs rcporl.cvl shnrl burots rrf fetal lachycnnlin during the limc lhal the mother was being given tlk• cigarctlc, hul I>Lforc the lighting af the cigarette. They callcvl this xn "anlicilutlnry n..wla+nnu" anrl concluded that it prnlmhly rc.ultal fnim some vnaomolnr chnnQc in the uterine placcnLll vcrncla. Clocrcn, r•t al. (2S) rcpnrln( that in 71 prcananl women studicyl during thc In.rl h;df nf pregnancy fetal Ltichyatnlia usually fallnwcd maternal :nrrkinR, and in two-lhinl+ of the cn.c:s thc fetal heart rate showed a 6m of hcal-lo-Ircal variability. Rcrenl reports indicate that "I+rrnlhinR" movements by the fclu.r arc a normal curnlwrncnl uf intrauterine development. 13o1h the I-rnlrnrlion of limc the fclus makes breathing movements antl lhc rharactcr of these movcmcnL+ rtpl><xr to reflccl fetal condition. In Krrmcn with normal Irrcgnnncics, cignrctl.c emoking abruptly and xiKnific•rnlly dh-crcu.wil the pr•nl+nrtion of time that the fclus marlc In•alhiniz muvcmenLe lu fi0 lxrccnl frum a control value of 6a percent (:x, hl.',). These acute changc+ may not result from nicotine or carbon monoxirlc, howcvcr, sincc marked dccrm~tcs in breathing fniled t.u ncur in the feluxs of women who smoked non-nicotine cigarcllcs IUIj). These changes in fctal heart rate and breathing movcrncnts can rrsull dircclly from effc•cLs on lhc fclus I+cr sc, or indirectly frum rffccLc on lhc placental circulation, or both. Flnlrcrman (see Longo (9e)) vxtil thermography to assess ulcno-placcntal blood flow. In this 8-66 1 8-67

< ~

Check Request I~orm Pnyce: 13cnjanun & Vickie Sachs Charitable Fund JJatc rtequeslcd: 12/3/9G Mai1 Check To:James Brcznay Associate Director, Endowment, CJP, 126 riigh Street, Boston, Mass 02110 Campbell Requested 13y:Deana Client f/ File Naine Accouut// Olrce Croup Description A nt 053700 MS Attorney General CI1S TOB Deposition preparution 7000.00 053700 MS Attorney General CHS T013 Deposition on 11/22/96 4500.00 p;\aoctg\furvulchcJ:.fi m PZt', 0tI- TS Total Check ~ 11500_ 00

I 1 0 .•n fcl:J J,•aUi a~: H i:,lr I with rn:,lcrnt,l vrnnking :tnd Iilaccn~l I,- li„ns Iw ~ • I I I •f l • l il i l r, , „ r ~ ty c:in u ntun ur n); of ;uty I trcgna nt willt.il;n.,,f lilccrlin); a(lcr'1,O wt•ckv„f Irrcy;nancy? y 14. (::ut these rA•:,lltv Iw I,rcvt•ntt,I by cccvaliun of ~nt~,kinK. KulyrlcrncnL< uf vitaminr unrl fr1lic ucirl, unrl ulhcr lrcattnenl t rnainlain ft•t:tl nxV{;cnali,rn? Neonatal Ucalh 15. I)r, availal,lc rl:,la stLv cunfirm lhc cvi,lcncc lh:tl rn;tl,k.rn,jl srnokin{ Icads to nt•onrtt:tl dc:tlh uf otherwise normal I,;,lhies increasing the occurrence of I,rctcrrn birlh? I~t 16. What l+rolx,rtion of I,rct,crrn deliveries of smoking mnlhcrg i, associalel with a hivtury nf bleeding curly in pregnancy? 17. What prolKtrliun uf. l,rctcrm deliveries of smoking molhcrr, i„ ussociaLcxl with premature rultturc nf membranes? 18. What is the relationship of maternal MmokinR to the inculcnco nf l,lccyling carly in ItrcKn,tncy antl nf l,rcn•utlure rultluru of mcmhr.tnt„ whether or not there is n Itrclerrn delivery unQ whether or not there ix n fclal or ncon:tl:tl tlcath? 19. Through investigation uf charactcrislic.s such t!a age, Itaril)•. socitxcnm,rnic status, anJ rrl,r,wluclivc hislnry, is it lxnsil,lc to idenlift worncrt who will IK at Itarlicularly high risk of larl,•nancy cnrnl,licas lions :tnrl I,rcgn:tncy loss if they vrmrkc? 20. Iksi,lcs the warning sign uf I,lcwlin/;, what other mc:uvurcmcnlc will help to identify the woman who must stop smoking in order ln mainlain the pregnancy? 21. Will measurement of /cvcls of r~trlwrxyhcmuf;lol,in, vitamin C• vitamin 13r:, fnlic ucitl, :tnrl ulhcr rwlicti•s help to elucidate the mechanisms Ic:tdinl; lo I,kwling :uul to prcrnaturc nrldur+c of mcmhranes among smnkin); mothers? 'L2. Is there evidence that the tensile strength of fct:tl membranes i~ reduced if the mnlhcrsrnukcs? 23. Is there evidence lh:tl mmniulic fluirl infecliun plays a part in lhc smokinR-rclalcvl increase in thc incidence of lucmalure rupture of the membranes? 24. Will elucidation of the mechanisms whereby maternal smokinR causes complications of Irrcl{nancy, early delivery, and neonatal death help to persuade pregnanl women to at.op smoking-particularly if they have bleeding early or latc in prcRnuncy-and to f>t:rsusile obstetricians that cessation of maternal smoking is of crucisl imlrortance for a successful pregnancy? 25. Will monitoring of exhaled CU Icvcls in all prenatal care clinic:, help to reverse the recent trend t.uwarJ more frcqucnl.and hcavicr smoking among young women? s-7c 90i,L OZLZS i I epi,t,laneous Al"'rlion ~ % l-;tn the incrca.acrl incidence of :,Iw,ntancuuv ulNtrtinn w.... n~lrrn;j smoking lie confirmed I,y furlhcr sludicn, allrrwinK for n~,t,urcrncnl of ,h>k•reslxu,sc rclalinnshilrs anrl an uccurat,c estimate f ri- k ratin9? ,; Cnn the mtx Ituni.rrn+ uf uctinn l,c workal out, using the s:tmc ,l ruarh av hn~ I,ccn rlnnc fur Ikrin:tlul mortality? .-4 Tn uh:tl cstcnl is :t previous RlKrnlancous alwrtiun In n smoker r l,l~•d lu a.rul,s<tlucnt unL•tvural,lc oulcomc nf I,rc•{ nancy if lhc M„nt:,n rnntinucs lu rrnnkc? ~t I; there an uvcrall increwse in lhc risk of slxml.:tncuus alKrrlion a.x t r,.,ult of malcrn:tl Kmt,king, ur Is the incrruscd rink confined to .,,nu•n nlrrntly nt risk for other rctt4m.v? ur tt'hnt is the mcrh:tnism linking smoking durinK Irrc/,rnuncy to n r„luccd incirk•ncc of pnti•c•Iaml,si:t nnrl luxcmia? :IL ('r~ubl cnrn)wrncnls nf lhis me-rhnnixm, if unrlcrvlrxx!, Iu' 111114441 so -h:d lhc risk nf Irrct•cl:tny,.ia cuukl Irc rcrlutwrl wilhoul incurring the r„{,<;,scrK•i:tlCrl with snu,king? •udden Infanl Death Syndrome :12. Ikr existing rlatl:t st•t-v with Iw,anaL•tl fnlluw-ul, cr,nfirm lhc j.mx•i:dinn uf maternal smoking with atn incrcu.al risk of SIhSi al. Do the smoking mothers of SIUS victims have other sil;ns uf unpairmcnl of their oxygen supply system such :t.s ancrnia, heart. :muhlc, irnlrairerl I,ulmunary funcliun, or high :tllilwlc rcxitlcncc, a.r :ndir:rlt.l in l,rcn:tlal records? :11. Ik, the smoking mnlhcrx of SII)S viclints have early or late Idrr.lin);, prcrnulurc ruldurc uf lhc mcntl,r:tncx, al,rupliu I,L'tccnlac, or IK,•tt•rm delivery? lnnit-Term Follow-llp 15. Can .rluQics with long-tcrm follow-up nf l,n-owlh anrl development wknlify gruulM with smr,king-rclaled impairment of a serious nature "`nhlxral to very slight chnnges in overall means? 16. Could case-control slurlics using prospective long-term follow•ul, '13t& (such as that from lhc f3rilish I'crin•rlal Mortality Slutly) identify malernal smoking Iti'tllcrns unrl other prenatal factors associated with thc problcros of physical, inlcllcclual, and cmutinnal tlcvclol,mcnt of thc childrenl

vil ., Itir Iv% .•Is rrflrrl :r di.unl,•r nf ry:utirlt rlcl~rxi(i^:,lic>n. (;y;cni4 i. :. _ mr,nstr:rldc int;rr,lit•nl in ,-ig:,nalc sntukc (Xa, 1~fY, l a~ 1:1X. It~ 1.53. Vilnrrtin (' uc•nulc•l crnrl Ih,n,y4r (11L;. 11)r;) h:cvc rlcmnnar:tlcrl lhnl th,• vil:,rr,in r. Icvcl is .ignificnnlly Ir,wcr in lhc .crurn of wnmcn wiu, sntIk, cigarettes tluring Irrcgnanc•y, cnrnl,nrccl to values for their nnnxny,kint caunlc•rlr:trLs. Research Issues NutricnLv antl oxy{;c!n Irrovitkvl by the maternal circulalic,n essential lcr normal fctal I,mrwlh nnrl development. Il may I,, anlicilralal lhal wunrn nltcrtlions may Irc lrrwluca) in lhc c)cvclul,ial• fclus when lhc nutrients are accomlatniwl by toxins in the inh:rlrrl smoke of burning lolr;tcco anrl Ir:tltcr anc) when cariwrn munuxi,lc i, mixed with the oxygen. sC+mc of the nl>servcrl altcratinns may I• considered innocuous in lhemscaves, Irul the evidence ht date justific, high lrrirtrily inveslil;atirm tn dct.erminc whether they are inclicalcuxr,f pruccs.cc.r that :tr•c fundamentally rL•rngcrous to either the immcvli:tl.c,.. Iong-tcrm health of the fclus and thc child. A numlrcr of imlr,rLtnl rlucntlinns relating to l)x; Iros,rilrlc I,iuloLric:d cffccl+ of tcilwcco emukc nncl iLs constituents on the fetus in rder.m antl the ncwlKrrn infnnl remain unnnswcral. The ethical ir;.uc of cx fxri- mcnl. in Irrcl,rnanl human aul,jcrls nncl ncwlxtrn infanLv nfftrl, furthcr rescarch. The Irrolrlcros u( such slwlic.s are nbvious hut will n.rl lrc rrxo)vwl in llrc fnrescralrlc future. Mnlhcmnlicnl mcwlcls, whih• usoful, require considcr.tldc daln lra_vc.4l nn human or nnimal sludic,- Malcls, in addilion. Ixwacx..crioux limitations and restrictions Ik•caux• any malhemalical nkrtraction cncnmlcts.xxs only n very minutc Iwrrlinn of the finite world or a given problem. Thus, futurc progrrcxr in rKrr undcrslandinQ of the cffccLs of tobacco ltroclucLs in thcsc nrca. r-l investigation will require alrprolrriat.c animal studi`s with cxlr.tlx,la• Lion to humans. The research objectives are (1) to idcnlify risk of pcrinatstl Ioca trr damage in women who smoke during prcgnancy, and (2) to clcfinc lhc• effects on the fetus and the new-lwrn infanl resulting from rnxl.crnll- ly•inhalcd tcil,acco smoke. In conxirlcring lhc cpiclcrniologic, Irinlogic, and Irharmacnlul;ic f:tccL' of lhc Itrul,lem of c•igarcllc snmkin{t ancl it.r irnlrael on fclnl :cnd infant wr•II-IKring, thc (ullowing arcas of slucly are suggested: FrU1 I)ealh lDo availalrlc data .rcls cnn(irrn the evidence that ...lcrnal ,m„kinR rnay lead tn :rnnsic death in ulrprr uf a ncrrrnal fcl,:. In an un,r,ml,licalrrl Irrcgnnnc•y? ., l•;,n thc risk of rtu•h u dcath Ia• culc•ulalctl in tcrrn.-% nf thc molhcr'.r r„I,:,, ily lo nff:~cl (hc hylwrxic arcrt.r uf smnkin{; Iry euch rnoclutnismv tcr ~s,.rc.:tcin{,• hcmu/;lrrhin or cemalcK•rit; incrc:~eml; c:,rrliac oullrul: incn•:t-Sing I'L•tccntnl r:tlie, surf:u•c nrt:a, ancl arca nf :ttt:tchrncnt: or Iry ,.thcr ntcrh:rni:cmr? :l. Are thcrc indications in existing cl:tt:c `cl: that anoxic fclnl rlcath.r ,,~urnrl in .vrnnkinl; rnuthars wilh, for cxnmplc, :tncmia, Iwxrr c:trrliac f,rn;linn• Ixwrr lru)mnnary funcliun, pcwrr general hcalth• unfavnrtl,lc (nhk•r), or low :aK•icK•c•onnmic elatus? J, I)o thccc clc•alh. «•rur nurrc frrvluc•nlly in nwlhcrs whu, IK;sidev I,.inl; hcat~)• smukcr., arc• anc•rnir or live at high :tllitwlcs? '. It•r Iht-sc fh•alhv rxrur Intc•r in Irrc•gmancl- when lht•rrr is Ic.. n•"•rt c• •.,I.:n 11 ' V lo sulqrly ux)'I;cn IK•c:tura: uf Llhc grralcr usyl;cn rlcm:uul uf thc• Iargcr fclu., (lie rvrluction of the placental ratio, and thc reaching 4 lhc natural IintiLa crf incrcnx! of hcmnlocril :tnd cnrliac crutlrut? 6, Can pregnant wnntcn :tt Irarlic•trL•tr risk nf annxic fctal cicath if IM•}• smnkc IK• iclcnlifitxl prnslK-t•livcly by measurement nf cxhaicrl (() and rarlrnxyltemcrgluhin• rc•L•tling theve Ievels to hem:tttK•rit, c:cr,li:tc .udput, nnrl ulhcr texlx nf rcwcrvc• calr:u•ity to incrclac oxygen .ulrlrly tn thcfctus' 7. ('•nn pregnnnt wnmen nt parliculnr risk nf nnnxic fctnl ,Icalh if thcv r<mcrkc hc: iclenlificrl Iry use of exercise testing clurinu I,rcn;tl:,l rarc? R. 1)o avaihtldc rL•tlu rccLa confirm the evidence that rn:tlcrn:tl ,mrrking during lrrc/;nancy causes fetal clcath Iry incrc:Leinl,• the incidcncc of uhrulctiu Irlaccntnc, ulhcr antepartum I,Iccvlinl;, an,l relatcvl rnmlrlie:tlinnx? 9. Do avniL•tldc dal:t scLs confirm the evidcncc lhal (lie alK,vc• cnmplicalinn.r oc•cur more frcrlucntly among w•onun with other risk factnn such :tt low w><ictt--cunomic aUttu.r, oldcr age, higher Irarily, unfavorablc previous pregnancy history, nnd more frcetucnlly lhc rnurc thc molhcr.mukcs? 10. Arc the higher incidcncc:a crf Irlnccnl:tl complications and fctal rk:athx among women whu smoke duc lu Iwxrrcr dict and lower Icvcls ,rf t•itamin C, vit.min l3u, folic acid, amI other sulbtances that help to maintain tissue inlc{,rrily? II. Is there a rclationahilr Iretwcrn the incrciscd incidence of vag-inal Irkr,ling in the al,ovc ca.KS and the Ir.tlholol,•ical changes in placcntal I'loocl vessels from smoking women oli.crvcd by Asrnus.aun? 12. If there is a ti•cncrali•r.wl cffccl of smoking on the integrity of ltlar>,I vcssc•I lininy,ry :tnd other tissues, what role does this Irlay in thc hlcnling anti ahruptio plneenlae olrservcsl in such cascs? 8-74 SObL OtLZS 1 11 ...

, ...._.. _..:~'._. OW7. Benjamin P. Sachs, .-4f.D. 2jS Dudley Street Brookline, MA 02146 617-667-2286 INVOICE Chartes W. Patrick. Jr. Ness, Motley, Loadholt, Richardson & Poole 151 Meeting ST. POB 1137 Charleston SC. 29402 re: Mississippi Tobacco Litigation Itemued Account meaing 10/24 6 hours preparation for meeting 3 hours preparation for deposition : 5 hours review of Mississippi data dcpositions Peto & Pratzker S 7000 +~k¢se make check payszbte to Benjxnin & Viclae Sachs Chon'table Fund, and send to the °f Janea Bremay Associate Director Endowrnent : CJP 126 Hi h ST g . Afl* 02.110 Pdy.:. OW ® ~ ~ N 01

M Benjamin P. Sachs, M.D. 255 Dudley Street Brookline, MA 02146 617-667-2286 INVOICE 11/25/96 Charles W. Patrick. Jr. Ness, Motley, Loadholt, Richardsoo & Poole 151 Meeting ST. POB 1137 Charleston SC. 29402 re: 14ississippi Tobacco LitYgation Itemized Account Deposition 11/2J 96 9hours ( incl travel time ) S 4500 Please make check payable to attentiou of Janes Breznay Assocr Boston Mass 02110 iMI-10wi FSidc~l'ferii~-~ d send to 726 tligh ST.

Research Approaches Recommendations for Human Studies Recommendations for Behavioral Studies Rearnunendations for Clinical Studies General Studies Placental Studies Autopsy Studies Breast-Feeding Studies Recommendations for Physiologic-Pharmacologic Studies Tobacco Smoke Nicotine Carbon Monoxide Polycyclic Aromatic Hydrocarbons Other Substances Priorities for Research Recommendations Summary Ref crences 256 e

r Itir V,•ir;hl and I'I:,ct'nl:t :17. Tn wh:rl cxlt•nt ,hKr.r lh,• n•Ju+•li,rn if I+irlh wt•il;hl or nmuki,n, I+al,ir•s ml+'twcnl n I+hy:rir,lngic:r) :ulnt+Urliun ln r~~lurcrl ++xyK~ n av:rital+ilily. 38. Wh:rl nrt• thc cuml,in(-4l cff(xLv on I+irlh wt•Il;hl or mnlcrn:,l srnr,king, :urcmi:r, nnrl high nllilurk•? ;1!). Wh:ll nrc lhc cnrnl+intYl t•ffccLc u( m:rtcrn:rl rrnr+king, :Int•rni;,• i,ryt high :+Ililu+lre on weight, sh:yK, :Irttu nnrl silc or nll:rchmcnl, :,nl I+I:tccnl:rl-fcl:rl r.rlin? 4(1. Ilnw urc lhcse rclalionxhil>y uffccU-rl hy olhcr m,ylcrn;,l nnlcccrlcnl fuclors, such rw :l(;c, wx:irx.-a,nurnic alalus, and prcvino, hi-U+ry? 41. Is the incrca.•ttxl incidence of I,L•Iccnta previa with matcrn:+I smoking and high altitude rcl:lU.c) to an adaptive increase in Ih,. I+IaccnL•rl site of attachment? 42. To what extent do I,IalcanUtl chnnKav with maternal xmokin~ represent I+h,y.iolo/,.ic:ll urL•Il,lalions Ur hyt,nxic antl other slrc~acw? 43. To whal cxU-nl do placental changes represent I,alhnlngic;,l effects of smoking :urd wh:rt is their role in unfuvuraUle I,rcl,•nan,•t. ou lconres? Experimental tiludiiew 44. ('an cxlx_rimcnL•ll elurlics of extx>Rurc to cigarette .rmnke or In the corntx,ncntn of ci/,•ar•ettc amokc elucidate the mechanism of rr.lutrrl birth weight? 45. Ix the mmoking-a-%-ux:in/.,-til rc+luction of fotal Rrowlh due U+ a rt_vtuclion in the r.ltc or miUrris resulting in a decretutvl nurnl,cr nf cclls? 46. Is the •rrnnkinR-rucsocintel reduction of fcUrl growth rate duc lna dccrcnsctl nurnlxr or cclln in some I,arL0 of the Ixxly but not in nlhcrs: 47. 1s the xmnkinK-aqvncial.cd raluclion of fetal growth ralr accnmt,anical by deficiencies in learning abilily, emotional rlcvctnl• ment, or physical growth? lAclation and ItreaHt 1''eeding 48. Doc-,s smoking inhibit milk prtxluction in humans? This qucslinn could he approached through et,irlemiolo{,rical and ext,criment;"l studies. Survcys or a large Ix,lrul:rlion of smoking and nonvmoking wnrru•n are rleviral+lc to correlate the numlx•r of cigarettes cunsumt4l and Ih+ I:,It, rn nf .rnokin} wilh the :Irnnunt or milk t,rrxluccd :uul lhr runr+•nlr:+tu,n -+f nirulint• :tnd ulht•r ronailucrtLv of sntukc in ,nitk Ilirnu1zl+nul lhr I:,rl:,l,nn ry,•It•. 4:1 m,w ~I,.,•v n,r,-lin,• :+fft•vl I+rr+l:,ctin rchwsc, arul can lhis Irht•numcnnn lie rrvcrsc+l? Alq+r,q,ri:rlc cxl+crimcnl:ll animal rcvc:'rch roul(I provirlc the hrnls for un+lcrstnmling mcchoni.rm(.r) or acli. nJ lhr malN+ing of nl,t,rnprialc interventions. soIlow much nicotine is excreted in hrcn.l milk inl;cst.cvl by the nur.ing infant? A wcll-I,lannt.il phurmacokinclic study should lie rlnnc intnlvinQ the mothcr-infanl rlynd. ,,I. Is il Ix,.•oihlc to determine the cnmtdt•tc lunfilc of nlh+•r rf+ni1,,,ncnLs or ci/,•:trrlU: smukc in breast milk? The anvwt:r ln thi.v ,li,t•slinn will Ix:rmil the irlenlificulion of I+nlentiul c:lrcinu{ trnic a{;enLr an,l thcir rle/,•ree or ingestion I,y the infanLe. 52. I)ucs the inler:lcliun Iwlwecn nicr,linc nn+I nther rlrut,R cxcrcU•1I in hrc;Lal milk nfferl llrc I,hyaiulol,ry or the inf:tnL.? The (,resenc•c or III1T and I,en:a>(n)t,yrcnt!, indurt'rs of the activity nf rlrug-mclalx,lizing ,•nrl•mcs, rna,v cnuw: unexlrcterl, •rul,llc airlc effccla in the growing inf:rnt which may rnanifcsl :Il a InU•r date. r•o timnkc SI• To what extent drxs maternal smoking in humant affect malcrnal and fetal bhxxi t•:rUxholaminc concentrations? 64. To what extent drx•s matcrnal smoking rJfecl uterine arr,l pl:rrcnUll bkxxl flow? f.5. To what extent drxw maternal srnnking nfftxt fclal heart ratc. Ln•:rlhinkr t41ttern, ekrtra:neephulu{;rnl,hic activity, or nlhcr t,:rramc- lt•n th:ll can Iw munilurwl (that i.r, dr.vc-rc:.qxm.c rclaCon.hilr)' fiG. To whut extent duc.a smnking murijuana differ :n iLo cffccL; on lhc mother nnrl fclus aa compared with smoking toI,;rcco in cil;:rrclles? 57. To what extent arc there inlcracliona I,elwern the cffects of the major (and pcrhutn minor) cnmlx>nenl.q or tobncco srnokc? fiR. How can cffurt.% to actively disctwraRc Rmuking rlurin/ l,rcl,nan- cn cc madc more effective? 59. To what extent will smoking withdrawal during pregnancy result in chanRcq in infanl wcighl, perimlUt) morUllily, an+I lunl;-txrm sertuclac? Nirotine , !',0. Flow does nicotine :Iffcct ganglionic tlcvcloluncnl in the crnl,ryu f An4 fclus? 61. What is the rclnliun.hil, I,etwccn rlcvch+l,rncnl of essential ~ hypcrl.cnsion ami nicotine imprint on fetal development? I 62. boc•'n nicotine accumulation in the fctal adrenal /;Innrl.r, heart. J xnd kidneys mwlify development or lhcsc organs? I 63. Whal is the effcrl of nicotine on the hormonal syslcrns or lhc adrenal ami those or/,ans regulating ndrenul function? 64. To what extent is nicotine accumulation in lh.• fclal kirlnt•y invulvecl in a lx,v.ril,lc antidiuretic hormone abnormality or other Complications in later dcvclupmcnl? u ~.. I Y 141

S S ~ 1 ~..... _.~ . .. . ~. l , 70 1. /. 17 lo o~-- 0 /.,.1 b......~..~ ..... r..d /vc 7 • • a lo 12 Y 1~ (Nbcol] N FIGURF: 12.-Fetal values of oxygen partial pressure aa a function of carboxyhemoglobin concentrations during quasi.aleady-atak eondi• lions. Fetal infcrbr vena caval oxygen Ienttion is a function of both maternal and fetal carhtrxyhemoRlohin concentrations. The oxygen partial presMure of fetal arterial blood Ia chkfly a function of maternal carboxyhemoRlobin concentrations. During steady-stale conditions, how•ever, it will alao be related to the fetal carboxyhemo- glohin concentration level. Each point represents the meatn ±tiI:M (vertical bars) of 6 to 20 determinations at each kvel of blood carboxyhemoRlobin sou.cc. t..1..~ i. u. (.n LonRo, et al. (loo) mcaaurn( the canliac output and dislriltution of blood flows to various organs of the fetus. Thcsc investigators usal chronically-calhel.eri7,cx) fetal lambs in near-Lerm pregnant sheep arnl mca.~ured blood fluw using rudioactivo-labek.~d microspher•cs. They found t.hat the fetal reslion..c to carbon monoxide induced hypoxia was imlislinguishah(c from its response to so-callwl hypoxic hypoxia. Under bolh sets of conditions, the output of the fetal heart showed no significant increase during hypoxia, a compcnsat.ory adjustment that occurs in adults in an att.cmpt to maintain atlcquat,c lis..uc oxygen- ation. On the other hand, the fclus /lcrnonstral.ctl a rctlistributiun of iLa pcriphcra( circulation such that IdaN( flow incrca.vcd somewhat to lhc brain, heart, and adrenal glands. Presumably this increased fluW T 1 I ,,currrl in an effort UI nutinUtin oxygcnutinn tlf lhrr+c ". ,;Il" nrRAn." rinslicrR and Mycr.r (.S/), sn) studied the cffccl4 nf CO cxln.urc on n,•nr-tcrm IortY.'nant monkeys and their fcluvcs. When they cx1N)u-./1 ,cIIICIC•anwthCtlZlY1 nnimn(s tal 0.1 tn 0.3 Ibercunl cnrlwlm monnxi/Ic, rl.adting mnlcrnnl rarlwtxyht:mngItAlin ctlnccnlrnlinns were ;,l,lwl li/l rl.,•nl• Uurin},• the I. lt, :1-htlur slullies, fclnl IdtM,ts O7 crlntcnl .w) tn Icm lhnn'l tn(/l/l!1 m( hhMr,l, (rttm cnnlrnl valucs af 9 ln 15 ntl (IX1 1111 IIIIKr,l. Ft•t:t( heart rates tlerrcaxtrl in Ilrniwlrtiun to the IIIIwMI ,~t4cn v:,lt,cs. Thew! fcluscr alwt tlcvchqa.vl .evcrc ncidusis (111) Ic.Nr Ihan i.115), hy(Krcnrllin (I',.M-70 Utrr or &-rc:ttcr), hylwd.cnsiun, and •1nKanliug-rn(thic clutnl;c..w, such ns T-wavc flattening und invcrsion t.:dl. Ellecls on Newborn Animals r:., ,•fftrl I/f en tln nttcht/rn surriv;tl has Ix•un sltnlic/l I1y set•1•r:,l Smilh, el al. (174) exlityuvl ralv to rnixlures uf ilhiminaling uw, in,tir with carbon monoxide cnnccntralinns calual!n{; 0.47 Ilcrccnt. For 1 nea•Iwlrn raL., 12 to 49 hours oh(, cxlwmetil to cnrlNm monnxillc, the atrratzc survivnl time wat.v nl,ctut 195 minutew, in contrast to nn average :un•ica( time of alwntt 36 minutes in mature animals. McCralh nnd Jargcr (111) noted lhat 50 Ilcn:cnt of newly hntchwl chicks could withstand cxlw>4urc to I(wrccnt (1U,t100 (1(rm) cnrlKm monoxide for alw/ul 32 minutes. This initud resisl:tnt.•c to curlan monoxide tlccrcaued rapidly. Ry day 1, mean survival time dccrc:wed to alloul 10 rninutc., bc rlay / it wus 6 minuU:s, nnd by t(:ty 8 it wn. 4 minul.cs, where it n•mninal for al( nRt_•v lcstal u(t tn 21 days. Suhscvlucnlly Jaeger and McGrath (RO) showed that dccrta.ving the IxNly tcmlwr.tlurc incrcasctl the time to (ast gwqt from a mean value of 9.8 ± 0.5 min :tl 40°C tu 211.7 ± 0.1 at a0°C. They now4l that hylxtlhcrmia caused markedly reduced heart and resltiralory rttar and suggcwtctl that iLi major IKncfit was a reduction in cncrRy-n.rluirin{,• functions. In an attempt to devclolr an animal mttirl for hyl,crkinosis, ('ult•cr arrl Norton (•rY) and Nnrtnn, cl al. (/as) exlwoccd .'r•tlay-tlld Sllra/;uc- Dawky rats to 1 Ilercent (10.(XX) ppm) CO until breathing ce:cec(l fur 20 x•cuntls. This required u(rlut 2 houray ily(Kr.tctivily w:Lx ftrescnl when the rata were tcatctl ut 4 tu R wcrkn nf aQc, but not when they were tested al 3 to 5 tnunths of nQe. lncidental(y, a similar ty(x of hTpcraclivc behavior devclulletl following X-irraclialion nnd ltilutcntl xtcn.~otaxic lesions of the {llubus Ir.r((itlus (la9). f Wycyctic Il yd roca rbau s 1'olycyclic aromalic hydrocarlmns (f'A 1() such a. hcnxo(n)Ilyrcnc (ltal') are constituents of ciaarctl.c srnokc which have been implicatrtl in the Rencration of cancers in many nnimal spccics (2w). No studies / e- '/6f 8-f.5 001iL OtLTS

TABLE 12.-Summary of dudle. tlul cstlltuted relatlve r{sk of varlous P".aec7 erlcaree for aoeltat bued oa a"ayathcth° at ILt 1lttratrre, aad atlributabk risk oercenl baxd ae several eslinulea ef lie Prtvakect of smoklet durlt.t prerlancy i lQrwrdnswry ta.bi.A+.ytr n~k.~.drl~.~y Rl ARL RR 11.20 1.2/, 1 1.90 0.20 ~ 0.10 1 0.30 to 0.20 1.22 ! 1.11 0.20 1 0.10 9 0.30 I 1 0.10 NR - 2.42 0.30 - 0.10 - 0.30 - MpTi RR-.yI.. w: Aarr,.J6 AZ lir q...l ti....r.. r.r.r.. 'A...aYr s.r wdl.. ARS RR ARS 11 1.)t 6 22 9 21 11 )2 14 II 1.4! / t9 12 24 13 M 1/ 21 1.41 1 30 tt 36 I. /t 17 petnancy (NCffS 19b8). The most retent estimates wuest that about 25 percent of U.S. women smoke duouthout prevnrrcy (NCIIS 1968). The rclative risk eatimata for perinua) mortality and prdum delivery ate remu! ably oomiuenl, etpocially eootidering that these wlhors conducted independnr tyntheses a/ the lilertture. Estimates of the eelalive risk of low birthweight ranged from 1.l1 (Aktnloth 1961) to 2.42 (Kruner 19H7), probably because of diffetences in the number of studies used to derive the estimate. fcr this rta.otl. attr(bulabk risk percent fa a given pevaknoe of smoking is more vRriabk fa low birthweight than for perinatal arortality and preWm delivery. Based on dau Uw Indicate UW about 23 percent of U.S. women smoke Ilvou6houl pretnancy, it can be estimated that 3 to 6 percent of perinual duths, 1? to 26 percent of low birthweight birtht, and I to 10 percent of preterm deliveries could be prevtmed by eliminuion of ImoRing dur(nt pegnaney. In SIVupt with a 30-peroent pevdenct of tmoking, such as women with less than a high school edueation, approsimately 10 to I I percent of yerinatal deaths, 29 to 42 percent of bw birthweight binlu, and 141o It percent of preterm deliveries might be prevented by elimination of smoking during Orcen.ncy. Thete contribulions to advene PIeW+ry outcome we si:1We, u,d srnok- int is probably the moal important mudifiable cause of poor pregnancy outewoe unon& women in the United Sutet (Kramer 19lt7). 393

I L tai g _.. I i A  ® E ® M 0 a 0 TAef.$ 7.-8.aary af.o.expe.(.eaa! audles of as.ottlot cef.Nb..fier ca.ceyrlo., .e.n Irenase (+) .r decreaae (-) in blrthweighl (Z) .arordlnt to uolng ef oraYtiote 1,40" of oeralp. R`k~ 1 2 ) e S e 7 ! l~ Il"ql U+dnroud a d (1P671 -101 S.dn. QolAud, W Rou 11.72) t1&k..u. II")1 -p -41 •11 -112 .10 .U •!e -90 Ca-W...rd -40 164M/t.y (1 N!) Kline. S.rl^. 11r.1s (1q71 4.rAn)rr .22 r/ Ic.e. 11OU1 -32 s~ore s..~ 4...,.,.o.......~n........,....,l,a„~„~~. s....d Wfi~ d.u.eta .12 -112 -2J0 -1W =170 -)D -2j1 -2J! -X2 -2u2 binhweithl baby. Women who /epont,ll smotint duoughoul their pregnancy had e 94percenl Y+cressed risk of having a Iow, birtAweiW baby In coayrast to rorimokem Mou feul growth occurs IaWe in preenancy, and the primary yllof<c conuilueur considaed as candidates in mediating the effocl of smoking on feW growth (i.e.. CO and nicoline kading to intnuler(ne 6yposia) have short-tcrm n:versibk effects. The data in Tabka 6 and 7 wpqorl the conclusion the tlx.dvpse effect of smokins a. binhwcitlu occurs In the luw pnt of jeuation, primarily during (he th'ad trimeskr, and Ihat cessation at any time during gesW ion is likely to mititak the adverse effep of smoking on feul growth. Because it is difficult to persuade a11 prejn.ry smokers to quit srnotinj enlieely, the bcnefil of reducing the number of cigarettes smoked per day becomes a public health issue. The observation that ci6arette smoking Rtards feUl growth in a dotc...esyonx 394 PtVL OtLTS tA!(,E l.--Sus.ary of no.azperlsrenlal uudks.f relatlve rWt of low bfri.wel&ll (or i.eklwj nssaUoa aner eewoeP/lo. c....d s..aw .hr careMia. Rsnmia ri.l,' s.a..a i.wtlor 1Rl'r^ry F.uis r d. 11941) IA 1.7 Vr A. Oat 1 H77)' 1.6 1.0 luial ad C.ia.r /in pmul 1H111rer <1 .e 0.3 1.7 1-2 r 1.0 L-7r 0.6 N.r1a <I.r 1.4 71 1-2.. 1.0 2-I .r 1.1 A../Rw rd L7 2.0 YoC,rry (1172) 'G..O..d..I6 lqrr.r,. ® W fauLic. suppotu the benefit of reducing the number of cipreltes rrnokcd per day. Nebd. Fos, .nd Season (19t!) used data from their rVldorn(2r,d trial of smoking crisatios to eAamine Ih1s Qacitiat. These researchers foa+d that the benefit of docrraaed smoking fa birthwcight durint pretnancy, wwas almost entirely restriclcd to ANe who rhieved taW assuion. per(u,ps because women who reduce the number of eipeellu smoked compem.le by inhaling nare deeqlr, by puffin[ mae frequently. or by smoking the eiprate to a shorter bun length. Fmdings flarn leother rsudaniud trial supqat the oonclusion that absnrnce. not redndion. should be the goal 'x: pregnancy (MrArthur. Newwl. Knot 19II7). In this l.tter study. the intervention led so a cauidest.bk reduaion In the reported me.n number of cigarettes smoked per day but ai+wat no difference In the penentage of women who quit entirely: there was no difference in binhweiaht between the Ueatment and contro( groupa (MacArthur. Newsoe. Knot 19R7). Because of the social sligm. usoeined with smokinj durint DRtnancy it (s possibk that some women in this Intervention Mial fslscly reported a wduction in unoking: if so. this underxportinj would lead b an underestimation of pouible benefiu of reduelng cigarette tansurnytion. Whether quitting only during the fint hdf of pregnancy will prevent a reduction in birtAweighl is untlw Important eonsider.tian. Maa1 fctlal trowth takes place in the Lsl trimcster, ear(y quittiet virtually eliminata the effect of smokint an binhweitht. 17uu, smokInt lale in pregnancy may have an adverse effect on birthwtith/ even if there is abstinence In the first trimester. Lowe (1939) round thr the mean birthwcitht of infuus of smolen who quit urly in pegnaney but resumed smolcing was between that of smokers throughout prepuncy and Ihsl of never smoters. Infants of women who gave up ciyuetw by the fifth monlh of pregnurcy and who did not Ics umc smoking ses t

F-IGURC I.-FlrinaW, noonatal,.nd fe'W mostality rttef by birthweight In singleton white malr:g. 1930 SOUItCti• wYlia.r ..d Cle. (Ntl2). ESVL OZLZS (iinhwclght Is, however, a result of gcsutioaul age at binh and the rate of fcLLl growth. ilecognilion of the compks retalionshipa among ResUllonal duration. nte of (eul Prrth, blrthweight, and mortality has kd to attempts to classify infants according iu pstrional duration or joint distribution of birthweigN and aestational duration. Gnerally, births are categor(zcd u preterm (<77 weeks gestation) and/or u small for putiona) age (SGA) (<101h percentile of weight for a given gestation.l ate). loint dauiflcalion Is thought to provide a more discriminuing basis for the study of etiologic dor". Itcuum delivery Is suongly auociated with increases in the risk of fetal. nconaul, a.d perinaW moau)ity nd with signiflcard chi{dhOOd morbidity. Both pftlerm ldivery and SCA increase the risk of cerebral p.lsy. although the risk Is much grcaur br prelene delivery (f7lenbert and Nelwn 1979). SGA is utocired with Increased sisk of noonud .nd perinalul nsorulily at every geuatbnal age (Koops. Morgan. Sauaglia 1982; LLbclrcneo, Seuts. Brazie 1972): with SIDS (Buck ef d. 19g9); and widt aeurocognitlve deficiu, drort stature, and small head circumference in childhood (Fitthudinge and Steven 1972; Hill et d. 19gAI; Westwood et d. 1993- Ounited and Taylor 1971; llnvey el al. 1922. OunNed, Morr, Scott 1994. 1988. Fancourt ct at. 1976). CauiaredSatollnt As reviewed In previous Surgeon Genent's reports (US bHEW 1979; US DIIHS 191[/) and In other Iitcrature (l.andesnum-Dwyer and Emanuel 1979: Longo 1912; Werln, fbbcr, Hdmef 1985: Krumer 19g7), smokint during pregnancy decR+es mean birthweigN and Mcreases the propation of low birAweigN births. Estimates vary anong sludies, but binhwcight Is redaced by an average of approaimauly 200 g, and the praponion of low birthweigN Is approsimalely doublod by cigarette imoking (Mcyer, lonu, Tonucla 1976; US DIIHS 1980. US OHEW 1979; McInlosh 1994; Conunittee to Study the Prevention of Low Binhweight 150113; Kr.mer 19g7). Mean "weigN decreases ud the percent bw binhweighl increasn with Increasing num- ber of eipreues uroked daily. The relationship between eigarctte smoking and dareued birthweight is considered to be uusal (US DHEW 1979; US OHIIS 1980. 1919). Smoking affects birthweigN ud the percentage of babies who are born of low birthweitht by rWrdinj feul growth. A measwe of (dal growth teuntation is the p+obability of delivering an Infant who is in the less than 10th percentile for gestational age. The relative risk of SGA is about 3.3- to 1.4fold hither arrwng the Infants of smuken than for Ihe infants of nonsnKSkens (Ounsted. Mou, Scott 19g3). fiesesm birth Is also associatod with malemal smoking, dthouth not as strongly. Estimates of the relative risk of delivering before 37 weeks of gestalon oe typically about 1.5 fow smoking during fxegnancy (Cormnitlee to Study the Prevemion of Low Birthwcight 1993. Knmer 19117: Shiono, Kleb.nolT, Rhoads 19g6). Mean gesutional dvatian anrmg smokern is not significanMly shoner than It is among nonsmakers (US DIIEW 1979: US OHlIS 19g0). This finding is consistent with the observation thal the risk of delivering early Is greater amo+g snwken than nonsmoken, but dhe percentage of 311

I I a Mechanisms for ihc effecu of smokint on neonaW, pertnatal. and infant nwnallry are poorly undentood. although the reduction in binhwciyr Is often considcrnllo hr the mediating poceu. However, smdcing appears to cause a shift in the disuiEutios of binhweilht without having much effect on mean gestaliona) aje (US DHEW I979, US DHHS 1980). ud shifu in binhweilht distribution acrou different popuitlions de not al ways produce corresponding shi fta in monaliry ( W iko. 19/3; W ikoa And Ruud I9aJa,h). T1w teswional age is link affectcd by smoking, whereas birlhweitM is neduced r every liestuional age. esplains why smdl (nfrW of smoken have a better ptoRnorY than small infants ot nonsrnoten ( Yerush.lmy 1971; MaeMalroa. Alpesl, Salher 1966). Increases in perinaw mona)ity, anson& tnqken may reauh not fraa the tedudiom in binhweight. but rnher frorn the modest increases In pmerm delirery. very low Airthweitht, and specific pnhobt)c conditiom we ar QLcraMa [rey ._ And X.rp pliiocnuc. Howcver. lfiii Tias not been iddrei.ed eaplkilly iy any ssudy. 8«awe tlr smaller unokint•re(ated increases in ku frequent, more severe owcarees p.rdkl 11114 pronounced smoking-related reduction in pinhweitht, biMweigM serves u a wehi empirical martier of snwking's harmful oonsequences, evr, If it is not t!rc diree mediator of tlqse effau. No.eaperise.W Str/ks Fertility and Infertility Consisteru evidence indicaaea that smoken have lower fertility than nonsmoker (b.linR et ai. 19l7; Howe et al. 1985: Baird and Wikos 19113: Hartz d al. 19t7), aa noted in the 19l9 Repon of the Surileun Geoerd (US DI()(S 1989). T'he studies tlta have assessed indicyon of fwiliry in ftssner smoken are arrrnariuE (n Tabk 2. Pttwsson, Frirs, rd Nillius (1973) studied secondary amerqnhea, one meehaniss for reduced fertility, and found an inneased prevalence ansorr< smolen. Howeva, prevalence u" fomrcr unolen was even hij6er than amo.ll condnaing smohcra Hammond (1961) found ehat irregular mcnsuoa) cycles were more earruens r" smokers than never smokers And IAat former smoken were at slightly lower risk that never srnoken. Howe and colkatua (1995) aanalyzed dau on nsore than tI,000 women in a British cohort uudy, which auesaed the ufety of oral eorur.eeptives. Conpued with new smoken, women who smoted 20 cipreuea or more at entry into the ssudy w<re twia as likely to be undclivered 3 yun afkn eeising contraceptive use with the inlentio, ef becoming pregnant, whereas former snwAen had the same likelihood of being trw delivered as never smotert Baird And Wikos (1995) reqorsad that the tlme period a.el Iregnancy was the same for 31 women who quit smoking in the year pr'ar to ukrnptiq to currceive as it was for never smuken. baiint and coworkers (1917) econducted a large case-control study in Washintbu Stutc and found rhat, compared with never smokcn, the relative risk of primary lubal infendiry was 2.7 among current unoken And 1. 1 amrarj fomser smoken. InfarnWie. 774 OtbL OZLIS L ' 3 S..&. S.ca.Ary rr.«r*" 1.3 1.6 FftIrd Nut pepm S„afltr 2D~ 1.0 Mi..raa. CONMC cw--*M^'a +k TL.ebreprrr>lyr l.4 1.0 S.ra. Ninu~ WI Y.MYky 2.) 1.0 3rir S.c+drywbdLMY+y tI 1.3 a. secardary tubd infertility from the aame study (balint et al.19lS) teveakd a s+nalkr, diRe+ewrce between earrent And former m+oken. Although the awdy focused aw pTia Lduoed abortion, data ae prewMed dW allow oornprration of eude odds ratioa fae evRat sd farmet eiRneu aewA,en. CLrnent snmoken had a I b-fold Yscreue In the rYk of seoonduy twb.l idertility, rd faemer smoken had a 1.3-fotd ineteaoe in risk. It 4 difficuh to asaeu the causal effed of stswt)nj oa tatb.l l.frytllity Indepeadert af t>te effecv of aexu.lly tr.sminod diwan (STU.1 tnown to odv.ry whh amold.R in -y oooulmissrus. 1s wnrnry, the dau suuat du1 ie+p.lnttcnt of fertility seaaured as delay In time to oo>toeption ia relred fo sewkinR nnr the time of aqe,nptint to conceive and dut st.oking ceasation priow to oonocpio. teetrna fertility to fhu of never amokaa. Ca.clutiona about srnokittR And the sisk of wbal i.fenility casot be dnwn bec.uae of co.cer..bout uneo.ervlkd omfouwdi.s. Ecxroic PreVnrrcy and Spontaneous Ahanioa Tub.l (ocsopk) pretn+ncy oaan as nbax Ihe ume time In the reproductive process u kul loss. Howe.er. the medueisnr .re thought to be similar to thae oqerting M lusal infertility and largely eenoen tnbd motilay, uAnd puency. Several reports indicate aa hrctuscd risk of eelopk pretnassey ie amoters (Campbell .nd Cny 1987. Mu- wnap And Shiou 19l0). but only Chow And associnea (19d!) eaamined the assocla tion with prior wnoldns in detail. In a case-oanuol study in western Washington