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Statement by L. G. S. Rao, Ph.D. Bellshill Maternity Hospital Bellshill, Scotland, U.K. Regarding H.R. 4957 S. 1929 My name is Dr. L.G.S. Raor I am Senior Biochemist at Bellshill Maternity Hospital in Glasgow, Scotland. I obtained mv Ph.D. in Biochemistry from the University of Newcastle in 1966. I am the author of numerous scientific publications and have made presentations at scientific meetings in Europe andI the United States. My experience in clinical biochemistry over the past 20 years has been varied and has resulted in the development of interests in several methodological and clinical problems including perinatal medicine. Over the past several years, I have become deeply interested in the investigation of the - causes of the high incidence of low birth weight and perinatal4 mortality which is found among the poorer patients of Bellshil Maternity Fbspital. I have attempted to define in biochemica terms the risk factors associated with the "poor social condi- tions"'which are supposed to be the caus= of the poor reproduc- tive performance of these mothers. I have found, as have otheN researchers in this fiel of the poorer social gr growth ret3rdation is the has been claimed, their s of considerable practical ciencies can be correcte tion. A program of such striking reduction -.in th. nerinatal mortality and m- o' the scientific researct- Introduction - There is a widely h~ -cause of low birthweight (the "causal" hypothesis) cause the statistical ass PNM lacks the specificity significance and because causal hypothesis.

in Glasgow, Scotland. I obtained :)m the University of Newcastle in nerou s scientific publications and scientific meetings in Europe and al biochemistry over the past 20 as resulted in the development of :)dological and clinical problems . Over the past several years, I ted in the investigation of the of low birth weight and perinatal ng the poorer patients of Bellshill attemote d t o define in biochemical ziated with the "poor social condi- be the caus.e of the poor reproduc- )thers. I have found, as have other 607 researchers in this field, that the biological characteristic of the poorer social groups that is of relevance to fetal growth retardation is their poor nutritional status and not, as has been claimed, their smoking habits. This finiing could be of considerable practical iaportance because nutritional defi- ciencies can be corrxted by dietary advice or supplementa- tion. A program of such dietary intervention could lead to a striking reduction in the incidence of low birth weight and perinatal mortality and morbidity. Set forth below is a review of the scientific research supporting the above conclusion: Introduction There is a widely t~eld view that maternal smoking is a -cause of low birthweight (LBW) and perinatal mortality* (PNM) (the "causil" hypothesis). That view is challenged herein be- cause th e statistical associatio n between smoking and LBW and PNM lacks the specificity and the consistency to be of causal significance and because of evidence inconsistent with the causal hypothesis. *The term perinatal mortality includes both stillbirths and infant death within the first few weeks after birth. - 2-

608 Most of the stu9ies which favour the causal hypothesis have not corrected for factors which are already k mwn to have a marked effect on LBW and PNM. The most conspicuous fact that emerges from a scrutiny of all the studies on smoking in preg- nancy is that the so-called "effect" of smoking is seen only in the poorer underprivileged mothers and not in th e mothers who have a good family income. Low family income could lea9 to nutritional deficiencies which can caus e fetal growth retar3a- tion. Therefore, the so-called "effect" of smoking seen in only th e poorer mothers may no t b e du e to smoking itself, but due to deficiencies in maternal nutrition during pregnancy. Evidence for this has come from a recent study on the protein intake in pregnancy in Bellshill Maternity Hospital which ~ showed that among mothers with normal protein intake, there was no difference in the proportion of LBW infants between smokers and non-smokers. Other evidence a gainst the c ausal hypothesis from a review of the available literature is also presented. - Smoking in pregnancy has become such an emotioral issue that it is difficult to be unbiased in the design of the studies on this subject or in the interpretation of the results. As there is a great deal of evidence against the -3- "causal" hypothesis, o the higher incidence perinatal mortality fo, nancy. There is consic growth-retardation is m pregnancy, possibly du denoted as the "nutrit hypothesis is th e view certain type of persor. reproductive performan: -his hypothesis will b thesis. The latter tw common and are compler favour of th e "causal" in the 1979 U.S. Surge discussed in detail, t alternative hypotheses merits discussed. For a valid discuss o-° factors that are a: perinatal mortality nee

the causal hypothesis have already known to have a sost consoicuous fact that :udies on smoking in preg- of smoking is seen only in ad not in the mothers who sily income could lead to ,use fetal growth retarda- =fect" of smoking seen in ue to smoking itself, but itrition during pregnancy. -cent study on the protein Maternity Hospital which protein intake, there was BW infants between smokers 1 hypothesis from a review -esented. : such an emotion3l issue sd in the design of the he interpretation of the . o f ev idenc e aga ins t the 609 "causal" hypothesis, o ther hypotheses are required to explain the higher incidence of low birt'hweight infants and higher perinatal mortality found in sone studies o n smoking and preg- nancy. There is considerable evidence for the view that fetal growth-retardation is mediated through a reduced weight gain in pregnancy, possibly due to undernutrition. This view will be dem ted as the "nutritional" hypothesis. Another alternative hypothesis is the view that smoking is a characteristic of a certain type of person or a group of people who have a poor reproductive performance because of constitutional re3sons. This hypothesis will be denoted as the "constitutional" hypo- thesis. The latter two hypotheses have several features in common and are compleroentarx to each other. The evidence in favour of the "causal" hypothesis is presented in great detail in the 1979 U.S. Surgeon-General's report .(1) and will not be discussed in detail, but the evidence in favour of the two alternative hypotheses will be presente3 and their relative merits discussed. For a valid discussion of smoking and pregnancy, the effect of factors that are already known to affect birthweight and perinatal mortality needs a brief consideration. -4 -

610 Factors that are known to affect fetal arowth: 8iological Factors The biological factor which shows the best correlation with the weight of the infant is the functional capacity of the placeita, which is determined mainly by the size of the pla- centa and the quantity and quality of th_ blood supply to the fetus. The size of the pla centa is largely determined by the height and weight of the mother. The factors that influence the quantity of blood flow are not well understood except in pathological states such as pre-eclamosia and extensive infarc- tions in the placenta. There is some evidence that uterine blood flow is under hormonal control (26). The quility of the blood supply is mainly determined by the nutritional status of the mother. It is well-known that in poorer countries with nutritional d eficiencies, the weight of the mother and the infant are both lower than that of those in the more prosperous countries (2) . Thus, maternal stature and the nutritional status during the pregnancy appear to be important factors on theoretical grounds and are, in fact, found to be so in pra c tice. The other biological factors which are known to affect birthweight are:- 1. The length of gestation, the shorter the gestational period, the smaller the baby, 2. Sex of the infant, males being slightly heavier than females (about 200g) after about 36 weeks of gesta- tion, and -5- 3. The pregnancy n lighter than lat Socio-e conon ic f actors In addition to these that there are important to influ ence birthweight status could have an in tries, probably b y affec even in some prosperous infant is related to the husband. 1hus, social c have a higher birthweig -perinatal mortality and 1 in social classes 4 ar. These socio-economic fact in their effect on perir Thus, the perinatal mort 1,000 births and was 32.0 - ~: The striking effect c appears to be mainly duc rity, low birthweight bab fact, social class has st

ws the best correlation with functional capacity of the ly by the size of the pla- of tha blcod supply to the s largely d etermined by the The factors that influence t well u nderstood except in amnsia and extensive infarc- some evidence that uterine 1 (26). The quality of the ~y the nutritional status of t in poorer countries with 3ht of the mother and the thos e i n th e mor e prosperou s tature and the nutritional to be important factors on .ct, found to be so in prac- s which are known to affect 611 3. The pregnancy number, the first chi13 being slightly lighter than later children (about 200g). Socio-econanic factors In addition to these biological factors, it is well known that there are imnortant socio-°conomic factors which are known to influ ence birthweight. It is not surprising that economic status could have an influence on birthweight in poor coun- tries, probably by affecting the nutrition of the mother, but even in some prosperous western countries the weight of the infant is related to the social a nd educatioaal status of the husband. Thus, social classes I and 2 (professional workers) have a higher birthweight„ longer gestational periods, lower -perinatal mortalit y and lower congenital deformities than those in social classes 4 and 5 (manual and unskilled workers). 'hiese socio-economic factors appear to be particularly striking in their effect o n perinatal mortality in the Unitei Kingdom. 'Ihus, the perinatal mortality in social class 1 was 9.5 per 1,000 birtl-s and was 32.0 per 1,000 in social class 5(3). The striking effect of social class on perinatal mortality appears to b e mainly due to the higher incidence of prematu- rity, low birthweight babies, and congenital abnormalities. In fact, s ocial c lass h as such a striking effect on the health of -6- Y -

612 the pooulation in certain countries (4) that there is a higher incidence of shorter mothers (449! ) in social classes 4 an9 5 comoarefl to social classes I an3 2 (?0.5$). The nunber of mothers delivered before 36 weeks gestation was twice as high for c lasses 4 and 5( 8.48 ) a s that o f I an3 2 (4.2$ ). ( See Table 1). This higher incidence of prematurity alone can ac- count for the higher perinatal problems of the social classes 4 and 5. The socio-economic differences persist even when mater- nal stature has been accouzted for (5) . It has been shown that the incidence of prematurity is associated with th e social class of the mother's father, for any given social class of the mother's husband (6). This indicated that the socio-economic status (prcbably nutritional status) of the mother when she was a child had a striking effect on her growth in chill3hoo3 and -her reproductive performance in later life. Thus, in Britain, social class appears to affect the maternal size and nutrition, and could b e a very important f actor which affects birthweight and perinatal mortality. In the United States also, similar socio-econonic factors appear to affect perinatal mortality. Thus, black populations in general and the less educate3 among the whites have a higher perinatal mortality than the better educated whites (29). In a large study on perinatal mortality conducted in Canada, the hospital status of the mother, whether private or ward patient, which is probably determine d by the educational status of the father, has been shown to be an -7- imoortant risk factor, the perinatal mortalitv than tha Thus, there are sever 'actors which affect birth :hese must be taken into ac tion between smoking and per Sone Methodoloaical consider Most studies on the sut not taken the above factor, clusions, therefore, are op Seneral's report has pointe of adjustment for differenc in the distribution of su economic status and race smoking to perinatal mortali ?he usua 1 definition of '"eighe3 less than 2500 grams zient definition, it cou1d 9estational age, the parity taken into consideratio n t o `-etal growth retardation. I

;4) that there is a higher n social classes 4 and 5 (?0.58). The number of station was twice as high of 1 an3 2 (4.2$). (See prematurity alone can ac- :ms of the social classes 4 r life. Thus, in Britain, ternal siz e an d nutrition, - which affects birthweight .ited States also, similar 'fect perinatal mortality. .: .. ~. t -- ~ . • . . id the less educated among m ortality than the better ad y o n perinata 1 mortality itus of the mother, whether ,robably determined by the has been shown to be an 613 imoortant risk factor, the private patients having a much lower perinatal mortality than that of the ward patients (21) . Thus, there are several import3-it biological ani social factors which affect birthweight and perinatal mortality and these must be taken into account when cor.sidering the associa- tion between smoking and perinatal mortality. Some Methodological considerations Most studies on the subject of smoking and pregnancy have not taken the above factors into consideration and their con- clusions, therefore, are ope n to question. The 1979 Surg eon- , General's report has pointed out that "problems arise from lack of adjustment for differences between smokers and non-smokers in the distribution of such factors as age, parity, socio- economic status and race when th e relationship of maternal smoking to perinatal mortality is under study." (1) The usua 1definition of a low-birthweight baby i s one that weighed less than 2500 grams at birth. Although it is a conve- nient definition, it co.ild be subject to serious errors. The gestational age, the parity, and the sex of the infant must be taken into consideration to obtain some degre e of validity of fetal groath retardation. It is obvious that for a small woman -8-

614 weighing 100 pounds, a 2500 gram baby born at 34 weeks is not a small baby but it is for a tall woaan weighing 160 poilds and delivering at 40 weeks of her pregnancy. In fact, the 2500 gram limit appears to be absurd in some situations as it has been shown that the perinatal morta?ity for the under 2500 gram babies increases with the increase in maternal height (7). Although it would become too cumbersome to take the mother's height and weight into consideration in defining low birth- weight, at least the gestational age, parity and sex of the in fan t shoul d b e take n int o account . An important c oncept in d efining fetal growth retardation was described by GYuenwal3 (8) and adopted in a study by Miller and co-workers (9) . According to this concept, fetal growth . -retardation is divided into two types. One is the 1ong, thin baby," which is the result of wasting that occurs during a period of days prior to birth, resulting in a low ponderal index. The second type has a general decrease in growth pro- bably extending over a period of weeks before birth, with the result that the deficits in body length and weight at birth are proportional resulting in a normal ponderal index. 'Ihe second type is described as short for dates (SHFD). The infants of the first type with the low ponderal index, have large appe- tites and will catch up within a few months with the weight of 'infants with a normal birthweight. On the other hand, the SHFD -9- infants a nd their sibling disease, suggestive off a be seen later in this pape fetal growth retardation i question of smoking ?ind pr The "Oausal" T.•lypothesis - Several studies have birthweight babies and a h be statistically a ssociate rancy. FYbwever. „there a ssoci ation i s not _-;eppr association has bee n inter -in spite of considerable e worthwhile to assess _crit this hypothesis. If maternal smoking is tion and an increase in smoking should be found }n the population. 5b~.$ve.r, effect is seen only in p upper socio-economic,group

~y born at 34 weeks i s not a man weighinq 150 Do1n3s and gnancy. In fact, the 2500 some situations as it has !ity for the under 2500 gram e in maternal height (7) : arsome to take the mother's .on in defining low birth- ige, parity and sex of the zg fetal growth retardation idopted in a study by Miller this concept, fetal growth es. One is the "long, thin sting that occurs during a ssulting in a lo•+ ponderal ~ral decrease in growth pro- eeks before birth, with the ngth and weight at birth are oonderal index. ltie second tes (SHFD). The infants of :al index,-have large appe- !w months with the weight of On the other hand , the SHFD 615 infants a nd their siblings have a notable incidence of organic disease, suggestive of a genetic or familial pattern. It can be seen later in this paper that this tvpe of classification of fetal growth retardation is useful in the understanding of the question of smoking and pregnancy. 'lh e "Causal " !iypothesi s Several studies have reported a higher incidence of low birthweight babies and a higher rate of perinatal mortality to be statistically associated with maternaL smoking during preg- n3ncy. Fbwever, there are some studies in which. this association is not reported. Nevertheless, this statistical association has been interpreted as having causal significance, I -in soite of considerable evieience against this view. : It may be worthwhile t o asses s_critically the evidence for and against this hypothesis. If maternal s moking is,the cause of fetal growth retarda- tion and an increase in perinatal mortaLity, this effect of smoking should be found in all countries and in a1l sections of the population. [iowever, this is not found to be true. 'ihis effect is seen only in poorer social groups, but not in the upper socio-economic groups (See Table 2). Many studies have -10-

616 shown that the perinatal mortality is not significantly higher in the better-e8ucated U.S. whites, or in the upper social classes in Britain (social classes 1 an3 2). On the other hand, smoking is associated with higher perinatal mortality in only certain poorer groups such as the less educ3ted whites and blacks in the TJ.S.A. , an3 the manual and unskilled workers in Britain. This lack of consistency of the so-called "effect" of smoking i s agains t the causa l hypothesis. Fetal growth retardation is not specific to the babies of mothers who smoke in pregnancy. Other associations such as maternal stature, maternal nutrition and socio-economic status are already shown to be of causal significance. The strength of the reported statistical association bet- ween maternal smoking and perinatal mortality is much Less than that of other factors such as previous history of perinatal loss or socio-economic status. For example social class 5 (unskilled workers) in Britain shows an excess of perinatal mortality o f 400% ove r that o f social clas s 1. "Ihi s exces s i s more than ten times that which is associated with smoking (about 358)• Such a comparatively weak statistical association is not in favour of the caus3l hypothesis. The claimed dose-response relationship is often quoted as evidence f or the c obviously important different doses and ficult except by st~ co-variance. Most response relationshi other factors. How have done this and smoking, with publ: loss showing mucY mortality. In a s 50,000) by Naeye (2: affect birthweight M the mean birthweight -smokers at 37-41 M different. At 39 an subjects, at each ws wa s only 2 grams and results of this wel subjects should be v, response relationship The temporal rel dence of disease and has been cited as ev:

617 ity is not significantly higher ites, or in the upper social sses 1 and 2). On the other z higher perinatal mortality in as the less educate-i whites and anual and unskilled workers in icy of the so-called "effect" of 3othe si s - not specific to the babies of Other associations such as ition and socio-economic status 1 significance. sd statistical association bet- :al mortality is much less than previous history of perinatal For example social class 5 shows an excess of perinatal ocial class 1. This excess is h is associated with smoking :y wea k statistical association pothesi s. lationship is ofte n quoted as evidence for the causal hypothesis. In such studi,~s, it is obviously imoortant to keep other factors constant, while the different d oses and their response are compared. This is dif- ficult except by statistical methods such as by the analysis of co-variance. Most of the studies which have reported a dose response relationship have not corrected for the influence of other factors. However, a study by Mayer and associates (21) have done this and claimed a small "independent" effect of smoking, with public hospital status and previous pregnancy loss showing much stronger associations with perinatal mortality. In a study of a large number of subjects (some 50,000) by Naeye (22) where all the factors that are known to affect birthweight were taken into account, the difference in the mean birthweight o; babies of light smokers and of heavy -smokers at 37-41 weeks of gestation was not significantly different. At 39 and 40 weeks of gestation with 8454 and 10300 subjects, at each week the difference in the mean birthweight was only 2 grams and 1 gram, respectively (See Figure 1). The results of this w ell c ontrolled s tudy using large numbers of subjects should b e very reliable, but do not indicate a dose- response relationship. The t emporal relationship between the change in the inci- dence of disease and the amount of smoking in the population has been cited as evidence in the controversy regarding smoking -12 -

618 and certain diseases e.g., lung cancer. In the case of smoking and perinata 1 mortality, ther e i s a n invers e tempora 1 relation- ship. Smoking has marke3ly increased in the last thirty _vears in women, whereas perinatal mortality has markedly decreased during this pericd in most Western countries. - - . - In view of the foregoing, it is necessary to consider some alternative hypotheses to explain the higher incidence of fetal growth retardation and perinatal mortality reported in some groups of mothers who smoke during pregnancy. ' "Nutritional"hynothesis and the role of weight gain in oreg- nancv. It is well known that in poorer countries with nutritional deficiencies, the weight of the mother as well as that of the baby are lower than that of those in prosperous countris. Nutritional supplementation is known to incresse the average birthweight in these poor countries. -It is generally assutned that in prosperous western countries, such as the U.S.A. and Britain, there are no nutritional deficiencies. However, several studies have shown that it is not true for all sections of the population in these countries. Proteins, vitamins and trace elements which are essential for the normal development of the fetus are the most expensive of foods and could be defi- cient in the diet of th '_n a study in the U.S.A. , 1 ow-i ncome g roup a te 1 e income group (12) : = In third of the mothers (5 calorie intake and had a birthweight babies (13). trace metal, naanely zinc, pooulation in the U.S.A undernutrition as a ca. reflected in the higher the poorer sections of ,•K. For example,-the : 3^d 2) have an incidence the l ower s ocial c lass es litv per 1000 births (3' whereas for the lower so is 35. In the U.S.A., pe rinatal mortality i s h and the less-educated wh 'cetter-educated whites. amerges from many of th, =hat the excess of per, "'oke is not found in tl ?'»rer sections of the '~.:-077 O-x2--40

=ancer. In the case of smoking 3 a n inverse tempora 1 relation- -eased in the last thirty years -tality`has markedly decreased g, it is necessary to consider :xplain the higher incidence of ?rinatal mortality reported in during pregnancy. )orer countries with nutritional mother as well as that of the those in prosperous countries. known to increase the average tries. It is generally assumed ttries, such as the U.S.A. and tional deficiencies. However, it is not true for all sections intries. Proteins, vitamins and :ial for the normal developm_nt sive of foods and could be defi- 13- cient in the diet of the mothers from 1ow-income grouns (11) . In a study in the U.S.A. , it has been shown that mothers from a low-income group ate less protein than mothers from a high income group (12). In amther study in the U.S.A. nearly a third of the mothers (53 out of 182) had a low protein-low calorie intake and had a significantly higher incidence of low birthweight babies (13). Deficiency of an extremely important trace metal, namely zinc, can occur in certain sections of the population in the U.S.A. (14). The possible importance of undernutrition as a cause of fetal growth retardation is reflected in the higher incidence of low birthweight babies in the poorer sections of the population in the U.S.A. and the U.K. For example, the upper social groups (social classes 1 and 2) have an incidence'of low birthweight of 4.5% whereas for the lower social clam es it is S.2$ (15). The perinatal morta- lity per 1000 births (3) for the upper social classes is 9.5 whereas f or the lower social c lasses (social c lass 4 and 5) i t is 35. In the U.S.A. , the incidence of low birthweight and perinatal mortality is higher for t-he babies of black mothers and the less-educate3 whites than it is for the babies of the better-educated whites. An extremely important fact that emerges from many of the studies on smoking and pregnancy is that the excess of perinatal mortality found in mothers who smoke is not found in the prosperous groups, but only in the Poorer sections of the community in the U.S.A. and the U.K. 95-077 0-82-40 -14-

620 (See Table 2) . It can be seen that perinatal mortality ratios of smokers' babies to those of non-smokers' babies, varies between 1.02 to 1.13 in seven studies in which the mothers were from the upper social groups whereas for the lower social groups the mortality ratio varied from 1.39 to 2.16. 'Shese results make it abundantly clear that the soci o-economi c status is very important in determining the incidence of perinatal mortality. A large number of studies have reported a higher incidence of low birthweight babies for mothers wh o smok e during preg- nancy since Simpson in 1957 first made this observation (See ref. 1 for further references). As mentione d before, most of these have not taken into aceount factors which affect birth- -weight such as social class. In a few studies which have taken these factors into account there is no significant difference in birthweight betwee n smokers' and non-smokers' babies (See Table 3) . Th e possible r ole of nutrition is highlighted in a recent study conducted on mothers from Bellshill Maternity Fbspital (16) . The birthweight was adjusted for the gestational parity of the mother and the sex of the infant (4). age, mothers were classified according to the social class of the husband. It was found that the mean birthweight of the upper -15- Q social classes 1, 2 z not show a signific s:nokers whereas this cant in the lower sc unskilled.) The ("SFGA" ) infant s wa s and non-smokers in 3reate r i n socia 1 clz 4). If smoking durir retardation, why doe mothers and not in o; so-called "effects" o 3nd pick on only the F The results from now the same data ca: `or or against the "c :nfants for all soci smokers and 15.2% for SFGA infants between significant (p < 0.0 _iese results that incidence of SFGA inf. other s tudies . It w _his claim with thi

: that perinatal mortality ratios of non-smokers' babies, varies :tudies in which the mothers were whereas for the lower social ried from 1.39 to 2.16. 'Shese r tha t th e soci o-economi c status ning the incidenee of perinatal have reported a higher incidence mothers who smoke during preg- `irst made this observatirn (See ). As mentioned before, most of bunt factors which affect birth- In a few studies which have taken iere i s no s ignif icant d i fference s' and non-smokers' babies (See ition is highlighted in a recent rom Bellshill Maternity Ebspital djusted for the gestational age, ie sex of the infant (4). ".he rding to the social class of the .he mean birthweight of the upper 621 social classes 1, 2 and also 3(pro_°essional an:'. technical) did not show a significant difference between smokers and non- smokers w hereas this difference w as large and highly signifi- cant in the lower social classes namely 4 and 5 (manual and unskilled.) The incids nce of sma11-`.or-gestational-age ("SFGA" ) infants was significantly different between smokers and non-smokers in only the lower social classes and was greater in social class 5 than in social class 4. (See Table 4). If smoking during pregnancy is the cause of fetal growth retardation, why does it occur only in certain groups of mothers and not in others? It can scarcely be argued that the so-called "effects" of smoking respect the upper social classes and pick on only the poor and underprivileged mothers. • The results from this study give an excellent example of how the same data can be interpreted in different ways, either for or against the "causal" hypothesis. The incidence of SFGA infants for all social classes as a whole was 6.4% for non- smokers and 15.2% for smokers. This difference in incidence of SFGA infants b etween smokers a nd non-smokers is statistically significant (p < 0.01). It would be quite easy to claim from these results that smoking was the cause of the higher incidence of SFGA infants in smokers, as has been done in many other s tudies . It would a lso be quite d i fficult to d isprove this claim with this experimental design. However, if an -16 -

622 attempt is made to make smoking the only variable between smokers and non-smokers by correcting, as far as possible,- for factors that are k nown to affect birthweight, the results are no longer in favour of the causal hypothesis, and are in fact against -the causal hypothesis. Thus, if smokers were classified according to the social class of the mothers' husband, entirely different incidences of Low birthweight are seen in the different social classes for the same amount of smoking, a nd smoking mothers from the upper socio-ecoromic groups do not show an excess of incidence of SFGA infants. If smoking d oes n ot cause fetal growth retardation in one social group, it canno t obviously b e th e cause in another ethnically same social group. _Therefore, the associat~on between the higher incidence of SFGA infants and smoking in the poorer social groups c an not b e considered t o have a causal relation- ship. A causal relationship might be claime3 if smoking were the only variable between smokers and non-smokers. Most studies on smoking and pregnancy assume that the smoking habit is the only difference between the life-style of smokers and non-smokers. z Contrary to this assumption, there is much evidence that smokers and non-smokers differ in their personality, their attitude to life and their eating and drinking habits (23). A. significant difference in the drinking habits alone could -17- account for the hic groups of smoking mo fie3 to claim that retar9ation in any c non-s moking mothers a "_he gradient in t n socio-economic str that some factor sucr associated with the tively related and °etal growth retardat nutr itiona l statu s o f cause of the higher the poore r socia 1 gro .ri11 lend itself to recently verified on Hosoital. Maternal nutritic the protei n intake i n _^.others who had a low portionately higher ir those with a normal p '-others who smoked, t

the only variable between ng, as. far as possible, for, 3irthweight, the results are hypothesis, and are in fact Thus, if smokers were ial class of the mothers' tnces of low birthweight are ses for the same amount of )m the upper socio-economic cidence of SFGA infants.,_If th retardation in one social caus e in another-ethnically =he_association.between the and smoking in the poorer i to have a- causal, relation- z b e claimed if smoking were ers and non-s mokers. - Most ssume that the smoking ha3it ze l:ife-s_tyle of smokers and ..-. . • .._ > -. . -. _ there is much evidence that in their, personality. their and drinking habits (23). A :rinking. habits alone could 623 account for the higher incidence of SFGA infants in certain groups of smoking mothers. There`.ore, it is entirely unjusti- fie3 to claim that smoking M%as the cause of fetal growth retardation in any group of smokers, unless the smoking and non-smoking mothers are exactly comaarable in every other wav. The gradient in the incidence of SFGA infants with decrease in socio-economic status (Fig. 4) of smoking mothers indicates that some factor such as family income, which is qu3ntitatively associated with the social class gradient, is also quantita- tively related and possibly bears a causal relationship to fetal growth retardation. qince family income could affect the nutritional status of the mother, maternal nutrition may be the cause of the higher incidence of fetal gro.:th retardation in the poorer social groups. This view has the advantage that it will lend itself to experimental verification and has been recently verified on a grou p of mothers in Bellshill Maternity HosDital. Maternal nutritional status was investigated by measuring the protein intake in the third trimester o`_ pregnancy. 'Ihose mothers who had a low protein intake in pregnancy had a dispro- portionately higher incidence o f SFGA infants (438 ) comnared to those with a normal protein intake (3.4$). See Table 6. ?imong mothers who smoked, those who had a normal protein intake had -18-

624 the same lcw incidence of SFGA infants as non-smokers. This indicates that nutritional deficiency, but not smoking, is a pre-requisite for the development of fetal growth retardation. Since the majority of mothers who were delivered of SFGA infants (65 out of 95, 68%) had a low protein intake, correc- tion of this and other associated nutritional deficiencies is likely to result in a striking reduction in the incidence of low birthweight, irrespective of their smoking habits. Further evidence in favour of the nutritional hypothe- sis comes from studies on maternal weight gain during preg- nancy. It has been suggested that smoking mediated its so- called "effect" through maternal weight gain; Rush (17) and Davies and associates (18) have shown t~hat the mean weekly -weight gains were reflected in the infant's birthweight. Davies et al. reported that their results are consistent with the view that mothers' own weight gain has a greater effect on fetal growth with smoking having a very small "independent" ef fect . Other studies (19, 20) investigating the role of weight gain during pregnancy have reported an independent "effect" of smoking when weight gain was held Eiowever, when an analysis of variance was carried constant. out (21) , previous pregnancy loss and hospital status (private or public) -19 - showed a much ' ratio 97.4 and 4 and associates ( gai n i n feta l grc non-smokers and • who gained less trimesters of F retardation 'was with low weight g mothers with grea times as high amo with greater weic delivered infants of mothers wh o wer -were significantly 1070 mothers who retardation. Further evi9er pregnancy is provi: the weight gain in non-smokers and twc the first or the : who smoked during o infants in the pre

M 625 infants as non-smokers. .,This _ency, but not smoking, is a : of fetal growth retardation. who were delivered of S?GA a low protein intake, correc- d nutritional deficiencies is reduction in the incidence of :heir smoking habits. ,ur of the nutritional hypothe- nal weight gain during preg- :hat smoking mediated its so- : weight gain; a shown Rush (17) and that the mean weekly .n the infant's birthweight. ir results are consistent with t gain has a greater effect on ng a very small "independent" ) investigating the role of have reported an independent ght gain was heli constant. ariance was carried out (21). ,ital status (private or public) showed a much higher degree of statistical correlati~n (F. ratio 97.4 and 44.2 respectivel_v) tha n smoking (8.4). !iiller and associates (9) have shed some light on the role of weight gain in fetal growth retardation. They founfl in a study of 688 non-smokers and 424 smokers that there were 62 and 67 mothers who gained less than 0.5 pound per week in the last two trimesters of pregnancy. The incidence of fetal growth retardation was five times higher among non-smoking mothers with low weight gain (less than 0.5 pound'per week) than among mothers with greater weight gain. For smokers, it was three times as high among those with low weight gain than among those with greater weight gain. In th e group of 42 mothers who delivered infants with fetr~l growth retardation, the incidence of mothers who were in the lower social classes and who smoked -were significantly higher than the respective incidences a mong 1070 mothers who did not have infants with fetal growth retardation. Further e vidence for the importance of weight gain in pregnancy is provided by the work of Naeye (22). He studied the weight gain in successive pregnancies in groups of smokers, non-smokers and two groups of wois?n who smoked only in either the first or the secon-i pregnancy. Naeye found that mothers who smoked during one pregnancy but not in another had smaller infants in the pregra ncy in which they smoked irrespective of -20- 9-

626 the birth orler, and a variety of other maternal and fetal factors that are known to affect fetal- growth. _He claimed, therefore, that.smoking appears t o h ave an independent effect on fetal growth. However, close examination of his data (Table 3 of his paper) shows some interesting correlatiazs between materna_1 weigh t gain and birthweight. Since this author has recorded maternal weight gain and birthweight in both the first and second pregnancies in which smoking wa s the only variable, it is poss ible to compare the difference in maternal weight gain with the difference in birthweight between the first and second pregnancies. Such a comparison showed that the differences in weight gain between the first and second pregnancy had a highly significant correlation with the difference in birthweight between the successive pregnancies (See Fi gure 2) . Th is c learly i ndicates that'weight gain i s the factor that determines birthweight, and smoking, contrary to his claims, does not have an independent effect. Since maternal nutrition has probably the most important effect on the weight gain, these results can be considered as strong evidence in favour of the nutritional hypothesis. Constitutional Hypothesis: Smoker or Smoking? Whether low birthweight and higher perinatal mortality is due to smoking or due to the smoker (smokers' biological and -21- social characteri 45undant evidence no statistically or oerinatal morta the poorer,' undert of mothers. In ac tics, there are pr gical characterist reoroductive perfo the poorest of the tion of smokers. habits of the smok smokers (23). Yeri in favour of the " the proportion of became smokers in than those of mothe of the babies of z: indicating that cer babies, whether the `indings, the 1979 that these results a "future" smokers wae from that of the nc Yerushalmy d uring hi

s :y of other maternal and fetal sct fetal growth. . Se cl3imed, s to have an independent effect 3 examination of his data (Table nteresting correlations between .weight. Since this author has nd birthweight in both the first smoking was th e only variable, ~ difference in maternal weight and rthweight between the firstd comparison showe9 that the between the first and second nificant correlation with the +een the successive pregnancies ndicates,that weight,gaia is the :ight, and smoking, contrary to an independent effect.. Since _y th e most important effect on =s can be considered as strong tional hypothesis., - . )ker or Smoking? id higher perinatal mortality is smoker (smokers' biological and 627 social characteristics) is a real anfl important question. ?,3undant evidence is presented above to show that smoking has no statistically significant association with low birthweight or oerinatal mortality in the upper social groups, but only in the poorer, underprivileged and probably undernourished groups of mothers. In addition to these socio-economic characteris- tics, there are probably also genetic, biological and psycholo- gical characteristics of some smokers wh o will have a poor reproductive performance. It has been shown repeatedly that the poorest of the social groups have also the largest propor- tion of smokers. It is reported that the eating and drinking habits of the smokers are very different from those of non- smokers (23). Yerushalmy has (23) produced some good evidence in favour of the "ccnsti'tutional" hypothesis. He showed that the proportion of low birthweight babies born to mothers who became smokers in later pregnancies was significantly higher than those of mothers who never smoked, and was similar to that of the babies of mothers who smoked in all their pregnancies, indicating that certain types of mothers have low birthweight babies, whether they smoked or not. In commenting upon these findings, the 1979 U.S. Surgeon-General's report (1) claimed that these results are not reliable because the mean age of the "future" smokers was 19.7 years and was significantly different from that of the non-smokers which was 22.1 years. Although Yerushalmy d uring his lifetine , h ad adequately replied to this -21- -22-

® 628 type of criticism (24), his reply is not taken into account by the 1979 U.S. Surgeon-General's report 3zd may therefore be worthwhile reiterating. Figure 3 drawn from YerushaLmy's data (24) is a regression of maternal age and the incidence of the percentage of low birthweight b abies. It can be seen from the regression line the percentage of such babies at 19.7 years is 6.44% and for 22.1 years, it is 5.89%, a difference of 0.55% which is not significant by the Chi-Square test. On the other hand, the difference between the percentage of low birthweight babies of future smokers (9.5%) and non-smokers (5.3%) is significant at p<0.02. It. is also of interest that mothers who gave up smoking in later pregnancies had significantly less low birthweight babies before they gave up smoking than those S who smoked in all their pregnancies. (23) Silverman (25) set -out t o c onfirm these findings, b ut h er results were equivocal and could not either confirm or deny the findings of Yeru3halmy. Further work a1ong these lines is required to answer the question whether it is th e smoking or th e smoker that is the cause of low birthwaight and higher perinatal mortality reported in some groups of smokers. It should b e pointed out that the higher incidence of low birthweight babies does not neeessariLy result in increased perinatal mortality. Table 5 shows that the perinatal mortality rate of such babies of smoking mothers is actually -23- Lower than those of n< finding has never been hypothesis. Gruenwald's a nd Mill fetal growth retardatio n tation with a low ponder tion in length and weigh discussion of the constit babies with a low PI we non-smokers (2.3$ in nor smoking causes hypoxia to would not ezpect a highe smokers but just the opp growth retardation, namel is of much more seriou s p `,amilial pattern. Babies the latter type of growt disorder was genetic or c :'"Ie mothers of such infan ''o'ren from poor social +eight of the mothers who '-ower than that of normal, i~ hypoxi a such as altitud, normal. Under these cond

an into account by may therefore be Yerushal~ny's data incidenc e of the be s een f rom the at 19.7 years is fference of 0.55% at . On th e othe r f low birthweight iokers (5.3%) is rest that mothers ignificantly less moking than those 'lverman (25) set ts were equivocal _he findings of is required to g or the smoker higher perinatal incidence of low llt in increased the perinatal zers is actually a 629 lower than those of non-smoking mothers. This paradoxical finding has never been adequately e:cplaine9 by hypothesis. the "causal" Gruenwald's and Miller and associates' classification of fetal growth retardation into those with normal length for ges- tation with a low pon3eral index (PI) and those with retarda- tion in length and weight (SHFD) is also of relevance to the discussion of the constitutio nal hypothesis. The proportion of babies with a low PI was greater among smokers than among non-smokers (2.3% in non-smokers and 3.0% in smokers) . If smoking causes hypoxia to the fetus and other ill effect s one i would not expect a higher proportion of low PI babies among smokers but just the opposite. The other category of fetal growth retardation, namely, short for gestational age (SHFD), is of much more serious pathology, suggestive of a genetic or familial pattern. Babies of smoking mothers have an excess of the latter type of growth retardation, indicating that this disorder was g enetic or constitutional. As mentioned before, the mothers of such infants had a disproportionate number of women from poor social class. Furthermore, the placental weight of the mothers who had SHF D infants was significantly lower than that of normal, whereas in conditions which result in hypoxia such as altitude, placental weights are larger than normal. Under these conditions, it would be unjustified to -24-

630 assume that either type of fetal growth retar3ation was caused by smoking. We are still far from understan-iing the etiology of fetal growth retardation. We do not fully understand th e normal physiology of pregnancy. However, there are certain clues to the etiology of fetal growth retardation. The factors that are known to have an effect on fetal growth have been mentioned before. The quantity of blood supply to th e fetus is obviously an important .factor, and this appears to be affected by hormonal influences. Unconjugated free oestrio 1 and oestradiol appear to affect uterine perfusion (26) and an increase in bl ood volume whi ch occurs i n pregnancy. It ha s bee n show n that maternal intravascular b lood volume in pregnancy is highly ~ _correlated with fetal weight (27). As the precursors for these hormones are of fetal origin, the fetus may control its own growth potential to a large extent. 'Ihus, the vitality of the fetus which is of genetic origin probably has the most impor- tant influence on its own growth with effects of maternal and evironmental factors superimposed upon it. . In caiclusion, the evidence against the "causal" hypothesis,;2 is so considerable that alterrstive hypotheses are required to " explain th e findings of studies o n smoking and pregnancy. On '? the other hand, the evidence for the "nutritional" and "consti- y~ -25- tutiora 1" hypothesi to remain unbiased smoking during pre results. All the a i nc idence o f f etal mothers who already social problem for s,vmotom. It is alsc social problem, i.ee ted if undue attenti "!a_ch 9, 1982

rstan:9ing the etiology of fetal t fully understand the normal ,er, there are certain clues to ardation• The factors that are tal growth have been mentioned upply to the fetus is obviously s appears to be affected by e3.f=ee oestriol and oestradiol isioa (z6) and an increase in 3nancy. _ It has been shown'that olume in pregnancy is highly 1•. As the precursors for these .gainst the "causal" hypothesis , ive hypotheses are required t o o n smoking and pregnancy. On the "nutritional" and "consti- 631 tuti~ralhypothesis is far more convincing. It is important to remain unbiased and be obj s ective in desigaing stu3ies on mo{ing during pregnancy and r in the interuretation of their esults. All the available evidence sugQests that the higher incijence of fetal growth retardation aothers who alrea9 ln certain grouos of Y have a Poor reproductive performance is a social problem for which smokin g is not the cause but only a s.vmptom. It is also obvious that the soci solution of this serious al problem i,e, lack of prooe: nutrition, will be negle r ted if undue attention is given to smoking, -26-

Table 1. Incidence of Certain Characteristico in Primiparae • 9SIB09E0 S7omen below 62 inchea 157.5 cm.) per cont) I and II 4.2 20.6 IIIa ' 6.5 32.9 IIIb 6.5 38.1 IV and Y 8.4 .. 44.0 m P:7tIN4TAL if01rPALITY IN RI•:LATION TO S710KIpC. Perinatal loss/1000 1. Britiah Perinatal aortality Survey c.,..4 .,1 nl ...... 'I b Husbznd'e Social Clnss. Husband'a Social Class Deliverr:d at 36 aeeke or earlier (per cent) lJon= u!wkero ~ ~:..,. ;: okers Non-Smokers Smokprs Ratio Re fc.wu

NU Table 2, P:3tIN!ITAL J.IORPALITY IN RI:LATION TO SJIOKINC. Perinatal losn 1000 1. British Perinatal aortality Survey Social Class 1 and 2 eutlor et al. (1968) 2. Boston City Hoapital Rush and Kass (1972 Vhite 3. U.S. Collaborative Pprinatal Survey Nie-rander and Cordon (1972) ilhite 4. Comatock et nl. (1971) Hon-Smokr•rr; ;:~okers Non-Smokers Smokers Ratio Rqc......u -nr...~w .,.~.. " 11,145 4660 25.8 26.3 1.02 2_8 513 892 29.2 31.4 1.08 8,521 . 11.369 ~ 31.4 35.5 1.13 3e (Fathers education 9+ years) 7.646 4,641 29.2 31.4 1.12 31 5. Un]ervood et al. (1969) 24,865 23,629 19.7 20.8 1.05 31 6. an:t-iXallio (1969) (NorthFrn Finland) 8,898 2,368 23.2 23.4 1.08 ;; 7. Fabia (197%) (Cannda) • (':nt rnul ati^q 25-3•1) 3,192 2,962 12.6 13.2 1.05 34 1SL809E0 ' . .40

m TRh1e .(Go..m) 1. Britinh Pnrinatal a.brtality Sarv^y 44Ir11 N!:VR_ SP.O"1Pf A 1fI :11i;P. °•'.i?I11.1TAb !iOFPALTTY IN 5'i01^:RS .• m Pe.r.inatal 1oa4 1000 ;Jon-SMokr.rs Smol;rrs R1tio Sooial Clacsos 3, 4 and 5 Butler et al. (1968) 33.5 2. Rush and Kass (1972) Dlack J 28.6 3. Comstock et al. (1971) IYhite C 8 yearo ed•scation' 17.6 4. Fabia (1977) • flhite>35 Years 23.6 46.6 1.39 28 54.1 1.89 29 38.0 2.16 yJ 41.7 1.91 34 TADLE BIRTBWEIGFfP ACCORDING TO SOCIAL CLASS AND SMOXING (X•,.. /q7y, ~(. 46) NON-SMOKERS Social Class n Birt+weiqht 9 - iSD . S.F.D;• 'n t SMOKERS n Rirthw9iqht S.F.D. 9 ± 1SD n •

Social Clacsos 3, 4 and 5 33.5 4o.b l.Jy Butler at al. (1968) - 1 2. Rnsh and Bass (1972) Dlack 28.6 ' 54.1 1.89 3. Coastock et al. (1971) S7hite < 8 yearo oducation• ., . - 17.6 38.0 2.16 4. Fabia (1977) dhite>35 Years 23.6 41.7 1.81 TADLE 4. SIRTHWEIGRT ACCORDING TO SOCIAL CLASS AND SMOKING Cnern /~ao~ /97y, 6SI809E0 NON-SMOKERS Social Class n Dirthweight S.F.D: g ± 1SD n • 1. 74 3504 ± 450 4 2. 226 3471 ± 502 ~13 3. 496 3375 ± 528 32 4. 657 3452 ± 512 42 5. 168 3396 ± 548 14 SMOKERS iq ;t 3 4 Rirthweight S.F.D. + g - 1SD n 5.40 '" 25 3398 ± 416 5.75 74 3352 ± 564 5 6.45 233 3259 ± 527 ' 18 8.46•e 626 3178 ± 496* 95 7.14 . 271 3101 ± 566* 69 • Significant difference between smokers and non-smokers p < 0.001 S.F.D. - Small for the gestational age, parity and sex of infant. 6.75 7.27 15.17* 25.46•

TABLE :':3 Perinatal deaths among all infants and emone lov- birthneight infants bjmothor's smolcing stntus i.n ~~ four larRo studies Per cent L.B.T7, Infants Perinatal deatha/10C0 ® IM 6m Table f.L Incidence of T.ow birthwciEht (LBW) according to protein intake in is+nokere and non-amokera LBP! Infants 1lon Smokor Smoker 187.5 269.0 287.5 343.6 268.5 2a+.5 113.9 218.3 113.8 201.6 1'i All Infants TI f l~on Investitator o, o S Yoar Birt is Smokor Non-smokor ; Smokoz+ molcer Underwood 4 Assooiatos (30 1967 48505 8.9 5.7 20.5 19.7 Rantakallio (310 1969 ]1931 6.1 „ 3.5 23.4 23.2 Butler & Colleagues (zQ) 1969 1699t,. 9.3 5.4. 44.8 32.4 Yerushalmy 1971 {'rhite 9793 6.+ 3.2 11.3 11.0 Black 3290 12.3 5.8 21.5 17.1 • Neonatal deaths only Non-emokere Light emokera NediuA-emokere .. Heavy emokere Total

Yoar vnderuood la Assooiatos(3e) 1967 Rantakallio (3.0 1969 Butler k Colleaguea (sv) 1969 Yeruatwlmye (Zg) 1971 1'fhite Black Number of pregnancies Bi-rt ia Smoker 48505 8.9 11931 16994. 9.3 Non-amokor Smokor Smoker Smohor Smoker 5.7 i 20.5 19.7 187.5 269.0 3.5 ! 23.4 23.2 ; 287.5 " 343.6 5.4 i * 44.8 32.4 268.5 ...2%.5 3.2 1i.3 11.0 113.9 .218.3 5.8 21.5 17.1 113.8 201.6 Table fl Incidence of Low birthweiFht (LBW) according to protein intake in smokers and non-smokers Non-smokera Light smokers Medium-smokere . 470 189 LBW in normal protein 16 out of 422 . 4 out of 173 intake 3.78 % 2.3 % LBYI in low protein 12 out of 47 9 out of 18 intake 25.5 % 50 % Heavy smokers Total 224 127 1010 6 out of 175 4 out of 95 30 out of 865 3.4 % 4.2 % 3•4 % 36 out of 48 18 out of 32 65 out of 145 54 % 56.2 % 44.8 % LBW in all smokers: Normal protein: 14 out of 540 = 3.81 % Low protein: 53 out of 98 = 54 % All LBW infants with low protein: 65 out of 95 ='68 % Light smokers (less than 10 cigarettes a day); Medium smokers (10-19 cigarettes a day) Heavy smokers (20 or more cigarettes a day) I9IB09E0

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Y.an, G. Laz Meyer, M.B. Meyer, M.B. : dm. J. Epider Naeye, R.L. 7eruehalmy ; 7erusbalmy ;

i40 641 References 1. 2. 3. T H 4. 5. ~ ~ as ~ 6. ~ ~ 7. 8. y 9. ~ ~ 0 10 . N ~ ~ L 11. K + 12 a r . a 13. 0 • a 14. . ~ M V ,n 15. ! `y 16, 0 O• 17. 18. - q 3 ~ 19=. 20. 21.  f 22. 23, g 11 ~~nX/*•9 na~ ~ 24. U.S. Surgeon-General's Report on Smoking and Health 1979. Birch, H.G. & Gussow, J.D. in Disadvantaged Children: Health, Nutrition and School failure. Grnne & Stratton. New York and London. 1970. Chamberlain, R., Chamberlain G., Howlet, B. & Claireux, A. on British Births, 1970. London. Heineman, 1975. Thomson, A.M. Billewicz, W.Z. & Hytten, F.E. The Assessment of fetal growth. Brit. J. Obstet. Gynaecol. M, 903 Illsley R. & Kincaid J.C., in Perinatal Mortality Livingstone, Edinburgh, p. 270. 1963. Drillien, C.M. Brit. J. Obstet. Gynaecol. 6, j161. 1957 Hickey, R.T., Clelland, R.C. & Bowers, E.J. (1978). Am. J. Obstet. Gynaecol. 131, 803-811, 1978 Gruenwald, P: Biol. Neonate 5, =, 1963 Miller, H.C. Hassanein, g., & Hensleigh, P.d. Aa. J. Obstet. Gynaecol. 12 , 55 1976 U.S. Surgeon-General'asreport on Smoking and Health, 1973. Morris J.N. Lancet 1,87, 1979 Johnson, W.C. Am. J. Obstet. Gynaecol. 128, 29. 1977 Crosby, W.M., Metcoft, J. Costiloe, J.P. Marnesh, M., Sandstead, H.H., Hacob, R.A. McLair, P.E., Jacobson, G. Reid,`W., Burns, G. Am. J. Obstet. Gynaecol. 128, 22,,1977 Weisman S. Dan. Med. Bull. 21. 146, 1976 Morris, J.N. & Pharoah, P.O.D. Lancet, ii, 252. 1979 Rao, L.G.S. Lancet 1. 976. 1979 Rush. D. Brit. J. Obstet. Gynaecol. 81, 746, 1974 Davies, D.P., Gray, O.P., Elwood, P.C. & lbernethy, M. Lancet 1, 385, 1976. Man, G. Lancet 1. May 1 1976. Meyer, M.B. Am. J. Obstet. Gynaecol. =, 888 197 Meyer, M.B. Jones, B.J. & Tonascia, J.d. Am. J. Epidemiol. 10, 464 1976 8 Naeye, R.L. Brit. J. Obstet. Gyaaecol. §J, 732, 1978 Yerushalmy J. Am.J. Obstet. Gynaecol. }12, 277, 1971 Yerushalmy ;. Am.J. Obstet. Gynaecol. 571, 1971

642 25. Silverman, D. lm.J. Epidemiol. Ia, 513, 1977 26. Sallam, A.P. Rosenfeld, C.R., & Baltaghia F.C. Am.J. Obstet. Gynaecol. =, 1045, 1973 27. Arias, F. Am. J. Obstet. Gynaecol. =, 610, 1975 28. Butler, 1(.B. & llbe:man, E.D. Editors in Perinatal Problems Livingstone, Edinburgh, 1969. 29. Rush, D. & lass, E.H., im. J. Epidemiol. s6_, 183, 1972 30. Hisvnader, K.R. & Gordon, M. in Women and their pregnancies Ool. 1 Phaldelphia. 1972. 3l. Cornstock, G.W. Shah, F.g. & Meyer, M.B. Gynaecol. jU, 53, 1971 Pabia, J. Canad. Med. laen. J. I„SO, 1104, 1973 Moser, B.J. Hollingxorth, D.R. & Carlson J.W. & Lemotte, L.- Lmm.J. Obstet. Gynaecol. =, 1080, 1974 32. IInderxood, P.B., %es3er, S.F. O'Lane, J.PI. & Callagan, D.A. Obstet. Gyaaecol. 22, 1, 1969 33. Rantal'llia, P. Acta Pediat. Scand. 9upp1. 193 S4. 35. 36. Spellacy, W.P. Buhi, W.C. & Birk. S.A. Am. J. Obstet. Gynaecol. ?~, 232. 1977 37. Am. J. Obstet. N Alvear J. & Brooks, O.G. Lancet 1. 1158, 1977 a 4 I am Dr. Jay Ro of Pharmacology at t phia. I also have s Council, NIH study s companies and labora cn the consulting st~ My current acti• 4irect laboratory exl responsibilities for "oard for the Journa: vascular Pharmacologj The professional :,-.erican Society of F c]he Society for Exper ':):1eae of Clinical F _:;:lege of Cardiology sad the Gercntologica I have been aske cefore Congress, HR 4 -z the scientific poi My primary conce 'n_.:re of Section 2. =-e to mind: -• To what exte 3sscc.ated with aqing