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I 21/0 12 Gibbons L[, Ponsonby AL, D,vy.r-L A<ompanson uf pro- sVCnirc and retm[pectirc responscs n suddcn infant deaeh syndrome by csse und conrml murhers. Ani 7 Epde u,iN 1991;131:6549. 11 Marahall 7R, Havup JL. Mism n and hc e of srrong ennfuunders: uncurrelacd errnrs. Am J Fpide med 1996;143:1069-T8. 14 Holgen H, Hokfelt T; Hertzbcrg l{ Ia¢cmransr H Funetiorul and devdop,n ul snudies of shr periphrral rial chemureeepcors in me effects of nicotine and pos- sibl<.dninn w sadden Infem death wvdrvmr. Axc Na,i AcclSr+USA1995;92a515-9. 15 l.ewis KW, Rosquc EM. Deficient hyyania aw•akuting renpanse in ;nfans uf amnking mothes: pos.rble relat ship to suddcn infant death syndromc. I fNfarr 1995;12Y: 691 9. 16 Krtwr HF, Campbell GA, Fowlcr MW, Cavnn AC, Farbcr JE Matcrnal niratine adminbvation and (cml brain atam damage: a rar model with imMiotinns Por suddcn infam death syndrome. Am 7 Obuer GYancl 1981;1 a0. y4]-6. 17 Meoy RG Car.ull JL, Carbone MT, Kepy DH. Cardiores- plnturY recurdiogs 6orn iidants dYing suddanly arnf unex- pectcdly at hem> pFdiamicr 1991;93:44 0. 1 N Saycr, NM, Drncker UH. TclfoM DR, Morris JA 61fcns oS - nnc On b3QCnal mx,n5 a[roClared W,th enl dt:L,h. RrtA D'u CRJd 1995;]3:549-51. 19 \9isboq K, Henriksen T8, Hedcgaard At, tiechcr Nj. Rygc.aner Flandt gravlde samt a iodemografiske fzkmr- s M1erydnmg lor rygenphnr [Smnking cecxarion amnng pregnantwnm<nl. Uger4rfaeger 1996;ISg:3784--9. 20 Greenland S M,Weling ersd vaviablc selection in rp,d-io~ lugicanalyes.AmJA.blaH.nbh 19a9;J9:]i0-9. ? I Walter SD. Calevlariun d utribuoble risks from epidemi..- lugiral data. Inr J Epidcmlcl 1918;1:1 F6-82. 22 Wisborg K, HenriMa<n TB, Hedegaard M, S.cher N7. Snaoking habirs among Danish preZnant wromen from 1981, a 1996 in «lauon m s dodemographic und Lfesryle faetors. Acra obrru Gynerd Sca,d 1998;]]:636-J0. 23 Wisbng K, Henrikaen TB, Secher NJ. A prospeaive inoer- vcn4ion study af st9pVtng smd[mg in prcgnan[y in out'nsc an natal ore sain" Dr J pbmr GYUanu! 1999;105:1171-6. 24 SehellsNeidt J, Jorch Q Menke 3. Eftecu of heavy maternal smnking on ;nrrauterine growd+ patserns m suddcn infano dorb victims and [urviving infams. Euo J f4dimr 1998;15'F. 246-51. Call for Papers 6th European Forum on Quality Improvement in Health Care Thursday 29-Saturday 31 March 2001, Bologna, Italy For full information contact: BMA/BMJ Conference Unit, BMA House, Tavistock Square, London WC1H 9JP, UK. Tel: +44 (0) 20 7383 6409; fax: +44 (0) 20 7383 6869; email: quality@bma.org.uk; website: www.quality.bmjpg.com ww-tc. u •c/sdw<h ~ld. com

,I_d, fl.. CAJ1200,1.832U1 2[I6 Pcrinatal Epiderrdnlogicat Rescarch Unit, Deparement of Gynaeeology and Obrtetdca, Aarhus University Hospital, DK-8200 Aarhus N, Denmark K Wisborg U Kearnadel T B Hmriksen S F Olscn N I Secher t:.v.e<r.,,,dencrr~. DrWSsburR cn:ail. ,keib.~Qy..u dk A.v.r.-d 7 Ap„J 2fron A prospective study of smoking during pregnancy and SIDS Kirsten Wisborg, Ulrik Kesmodel, Tine Brink Henriksen, Sjurdur Frodi Olsen, Niels Jorgen Secher Abstract Rimr-To study the association between smoking during pregnancy and sudden infant death syndrome (SIDS) using pro- specdvely collected data, making it possi- ble to account for a number of potential confounders. Desiqn-Prospective follow up study (n = 24 986). Remalts-The overall rate of SIDS was 0.80 per 1000 live births (n = 20). Children of smokers had more than three times the risk of SIIDS compared with children of non-smokers (OR = 3.5; 95% CI 1.4-8.7), and the risk of SIDS increased with the number of cigarettes smoked per day (p < 0.05). Adjustment for parity, alcohol, and caffeine intake during pregnancy, maternal height and weight before preg- nancy, years of school, occupational sta- tus, marital status, and number of antenatal care visits did not change the results. Adjustment for mother's age mar- ginally reduced the risk of SIDS associ- ated with smoking (OR = 3.0; 95% CI 1.2- 7.3). Conchusores--Given the prospective na- ture of the study, the number of deaths is small; however, if our resufts reflect a true association between smoking during preg- nancy and SIDS, approximately 30-40Ye of all cases of SIDS could be avoided if all pregnant women stopped smoking in a population with 30% pregnant smokers. Our study adds to earlier evidence for an association between smoldng during preg- nancy and SIDS. The strengths of the study are the possibility to adjust for a number of potential confoaandcrs and the fact that informatfon about smoking hab- its during pregnancy was prospectively collected. (Arch fkt Child 2000;83:203 20ti) Keywords: smoking; pregnancy; SIDS In industrialised countries, sudden infant death syndrome (SIDS) may account for 40% of all deaths from I month to I year of age.' The sleeping position of the infant' and the smoking habits of the mother" have been identified as possible causal factors of SIDS. Since the beginning of rhe 1990s, the medical communities in Australia and scvcral nurchcnt European ctluntries have advocated a non- prone sleeping position of infants. This was G,Ilowed by nn[able decreases in SIDS occur- rences, thus substantiating the infant's sleeping position as a causal factor." Epidemiological evidence linking SIDS with smoking derives from case control studies" " and register based studies."' While results from case control studies are prone to recall bias as a result of differential accuracy of infor- mation from case and control parents," the register based studies may be biased by insuffi- cient confounder control." Thus, there is still controversy about whether the apparent associ- ation between smoking and SIDS can be explained by differences in social factors or other lifestyle variables between smokers and non-smokers. The putative effect of smoking on SIDS may be mediated through changcs in the oxygen sensitivity of the peripheral arterial chemore- ceptors, leading to increased vulnerability to hypoxic episodes.t'." Furthermore, exposurc to nicotine may influence the maturing of car- diorespiratory control, leading to cardiac arrhytltrrtia." Finally, it has been suggested that nicotine may potentiate tbe Icthal action of certain SIDS associated bacterial toxins." The aim of the present study was therefore to evaluate the association betwecn smoking dur- ing pregnancy and SIDS, using prospectively collected data from a university ward, and making it possible to account for a number of potential confounders, including obstetric, sododemographic, and lifestyle factors. Population and methods All pregnant women booking for delivery at the Department of Obstetrics and Crynaecology, Aarhus University Hospital, from September 1989 to August 1996 were invited to parttici- pate in the study. The women were ask<d to fill in three questionnaires: the first two before the routine antenatal visit at 16 weeks of gestation, and the third before the visit at 30 weeks of gestation. Information from the first qucstionnaire was used to establish the women's medical record. It provided information on medical and obstetric history, maternal age, and smoking habits before pregnancy and during the first trimester, and alcohol intake during pregnancy-. The second questionnaire provided infor- mation on marital status, education, occupa- tional status, and caffeine intake during pregnancy. The third questionnaire was used only to register smoking habits during preg- nancy. Information about delivery was ob- tained from a birth registration form filled in by the attending midwife immediately after deliv- cry. Before data entry, all birth registration ,crcm. archdi,chi/d. m,r,

2n.t 'Ns6l: /,5lDS u uNin,r tu,nlnkln3leabin dunn, Pre,enunn~ und admr 8lesrvle am+ ,n[iadrn,r~'raPlu. Jar tan Jn) rvr,,, Numher ul antcnacal .arc cians Sea ui me chiL1 htatcrnal vge (v) Marital sraus YCersJtcdVCVlIOn oc<upatinnal stalus during prcgnanq CaReine inoke during pregnancy (mdday) AImM+I intekc during Vrcgnancy (dnnlWweek) Mmher z height (cm) MotMr's Greprc8nanq wcighs (kg) Trcl.,,,1 a l:b SInS k. 0 17536 % -_ 1-9 )249 5 1 5i 4201 I r,~ p,i,,,ip„n- 12750 1.1 0 T9 Multiproue 12236 In 0.a2 1-9 9336 0 81, 10+ 13401 0.81 Nitwng 2249 041 Male 12834 0.78 F.male 12152 0.81 15-24 4633 IU 2.16 35-50 20353 Ir/ 0.49 CohabianF 20176 11 069 Single 916 2.19 Missmg 3894 1.03 <IO 7520 I 06 104 10502 0.4a Mixsing w"ortting 695R 11961 1 nl 094 unemplvyeA 3853 0 52 Sludent 1895 053 Missin8 7277 0.96 <!00 2107 0.66 400. 64U7 0.94 .Nissing 6472 0.93 0 16539 0.91 -2 55E1 0.)6 3• 2298 0.a7 \llumg 568 1.76 <166 8447 0.]1 166-170 6149 061 171+ 7955 191 Miasina 435 7 30 <50 1153 LY) 50-59 0443 0.85 60-09 9104 0.66 70. 4792 0.63 btissing 494 2.02 forms were manually checked and compared with the medical records by a research midwife who also registered all complications during the first days after delivery. Information about deaths during The first year of life was obtained from the Registry of Causcs of Death, administered by the Danish National Board ofHealth, and from the Danish Civil Registration System, administered by the Danish government. Furthertnore, we re- viewed the hospital records ofall cases of death before one year of life to validate the cause of death. The International Classification of Dis- eases, 8th Revision (ICD-8) was used in Den- mark to classify causes of death through 1993, and from January 1994 the 10th Revision (1CD-10) was used. SIDS Svas defincd as death ICD-8 code 795-80 and ICD-IU code R95.9. The medical records of the children with SIDS were manually checked to ensure Ihal the diag- nosis was correct The study population was restricted to Dan- ish speaking women who completed the first questionnaire and carried their pregnancy to a live birth of a single child (n = 24 986). This number corresponds approximately to 90% of all Danish speaking women booking fnr defroerv during the study period. l'he second quorionnaire was completed by 18 517 (74'K,) u-omcr., and The third by 16 43(i (6n %). infor- nlauon about birth weight and gestauonal age ar dch~crv uas missing in 87 and four cascs, nsprclivdy. The women were defined as smokers if they smoked one or more cigarettes per day when 16 or 30 weeks pregnant. Only minimal changes in smoking habits appear after 16 weeks of gestatiun.' Smoking was analysed in two categories (smokers versus non-smokers), and also in ordered categories. 0, 1-9, and 10 or more cigarettes per day. STATISTICAL ANALYSIS The association between smoking during preg- nancy and SIDS is presented as odds ratios (OR) with 95% confidence intervals (CI). Potential confounding variables were catego- rised as in table 1. They were evaluated in logistic regression analyses, and if they changed The measure of association between smoking and 51D5 by more than 10% they remained in the linal model."' All covariates were entered as ordinal, creating a number of dummy variables equal to the number of categories minus one- To take into account the time of death after delivery, all measures of association were evaluated in a Cox regression analysis. How- ever, as the results were similar to those from logistic regression analyses, Ihey are not presented. Difl'erences in mean birth weight were evaluated by analysis of variance. The attributable fraction (AF) was calculated from the following formula": AF_- proporuon nf e~osed in d+c ponulation .;OR -- 1/ prornnion ot expoxd in The popnlatl6n x(OR- 1) + I The study was approved by the regional eth- ics committee and by the Danish National Board of Health. Results The study group consisted of 24 986 live born children. In 7450 (30%) pregnancies the mother was categorised as a smoker and in 17 536 (70%) pregnancies as a non-smoker. Among dtosc categorised as non-smokers, 2642 (15%) had smoked before pregnancy but stopped during the first Irimesrer. Among smokers, 3249 (44%) smoked 1-9 cigarettes per day, and 4201 (56%) 10 or more cigarettes per day. The mean number of cigarettes smoked per day was 9 (5). The overall rate of S1DS was 0.80 per 1000 live births (n = 20). The median age at death among children who died from SIDS was 69 days (25% percentile 40 days; 75% percentile 109 days). The mean age at death was 27 days (95%, CI -l5 to 69 days) less among children born to women who had smoked during preg- nancy compared widt children of non-smokers. The crude analysis showed that children of smokers had more than three times the risk of SIDS than children of non-smokers (table 2). The risk of SIDS increased with the number of cigarettes smoked per day (test for trend p < 0,05; table 2). Adjusvncnt for parity, alco- hol, and caffeine intake during pregnancy, maternal height and weight before pregnancy, vears of school, occupational status, marital status, and number of antcnatal care visits did not c:hange the results. Adiustmcnt for moth- er's agr reduced the risk of SIDS associated weov.archd;.ehdd ro.,,

Sronkiu,¢ dmi,yF pn.Ynon y mr.f SlD.S 'f 67r Z Crude anrf adiu<red OX nJ Sll).S' on nrviiieg r.r diJ L•nvu caagnrtes rrf.mrnking 6ublr, drod.g yregnuncv Thr.,f nu M, teid, SfDS' Y„ AJisurcd' OX (95;i C!) Nnn-smnkcsfroml6wneksgesution 1F53(i 8 0.5 Reforcnce Smokxas 71511 12 1.6 3.5 (1.4-g.1) I-9 ogarenes'dar . 3249 5 I.5 3.1(I.l 10, 3. 10• agarcavNday 4'LUl 7 1.7 3.7 (1.)-10.1) •Adiusced for maternal age. with smoking (table 2). Mean birth weight was 323 g (95% CI 81 to 566 g) lower among chil- dren who died from SIDS than among surviv- ing children. Adjustment for birth weight and gestational age at birth also reduced the risk of SIDS associated with smoking (OR = 2.9; 95% CI 1.2 to 7.2). Conclusions were not changed after adjustment for maternal age, birth weight, and gestational age at birth. Discussion In this prospective study of smoking during pregnancy and SIDS, children of women who smoked during pregnancy had an increased risk of SIDS compared with children born to women who had not smoked during preg- nancy. Despite a small numbrer of cases and controlling for possible confounders the associ- ation was statistically significant. The risk of SIDS increased with the number of cigarettes smoked per day during pregnancy. Information about smoking habits during pregnancy was obtained from a self adminis- cered questionnaire completed by the pregnant women at 16 and 30 weeks of gestation. Because the data were collected prospectively, information about smoking could not be biased by the parents' knowledge about the deafi of their child. With only 20 cases, it was not meaningful to assess any differential effect between smoking at weeks 16 and 30. Further- more, among 8607 women (34%) information was missing about smoking habits at 30 weeks of gestation. In our population 30-40% of the smokers stopped smoking in early pregnancy, but after the first trimester very few stopped smoking."- 2' Thus, smoking habits at 16 weeks of gestation are a valid measure of smoking habits throughout pregnancy. Women who stopped smoking before 16 weeks of gestation were categotised as non- smokers in the present study. However, if exposure in early pregnancy is associated with an increased risk of SIDS, compared with no exposure during the entire pregnancy, our result is an underestimation of the true associ- ation between smoking during pregnancy and SIDS. Owing to careful prospective collection of information about maternal lifestyle, and sociodemugraphic and obstetric factors, we could adjust for a variety of potential con- founders. Adjustment for maternal age margin- ally decreased the risk of S1DS associated with smoking. However, maternal age may represent a proxy for other factors associated with smok- ing and the occurrence of SIDS, for example, attitudes towards childcare. It is possible that controlling for those factors would further decrease the risk of SIDS associated with 205 smoking. Furthermorc, information about so- cioeconomic markers was missing in one third of all women which may constrain the possibility to fully adjust for these factors. We did not have information on smoking by the mothers after delivery. However, this is likely to be closely associated with smoking habits during pregnancy. For outcomes as- sessed shortly after birth, any attempt to discriminate between effects of maternal smoking during pregnancy or after birth remains speculative. It is therefore possible that the association identified in this study may be caused by smoking exposure after delivery. Unlike Schellscheidt and coworkers" we found that SIDS children had a lower mean birth weight than with surviving infants, Some children might be more vulnerable to tobacco exposure in utero, but it is also possible that women whose children died from SIDS smoked more than they actually reported, or smoked differently from mothers with surviv- ing infants. Biochemical measures of tobacco exposure could throw light on this problem. The risk of SIDS was marginally reduced after adjustment for birth weight. Thus our result may indicate that smoking increases the risk of SIDS in addition to its effect on birth weight and preterm delivery. Our study adds to earlier evidence for an association between smoking during pregnancy and SIDS. The study i strengths are the possi- bility to adjust for a number of potential confounders and the fact that information about smoking habits during pregnancy was prospectively collected. Given the prospective nature of the study, the number of deaths is small: however, if the association between maternal smoking and SIDS found in this and previous studies reflects a causal relation, approximately 30-40°% o of all cases of SIDS could be avoided if all pregnant women stopped smoking in a population with 30% pregnant smokers. I Willinger M. SIDS prevennon. Prdlmr Ann 1995;24:358- 64. 2 Oy<n N, Marknlad T, Skaervas R, a N. Combincd effetts of sleeping position and prenatal risk factors in sudden in6ns death syndmme the Nordic 6pidemiologicd SIDS Study. P!d'uvirs 199];100:61 }21. 3 Haglund B, Cnatrfogius 5. Cipreae smokfrsg as a r'sk fac- tor for sudden irdant deaN syndrome: a popsdarion-bescd rmdy. Am ] Publu HeNih 1990;g0:29-32. 4 Malloy MH, Kleinman JC, tnnd GH, Schramm WF. The sociation of maternal smoking vi+h age and cause of /nfant death. A,n 9 £prdaniof 1986;12g:46-55. 5 Schnendorf KC, 14ely Jt- Rdanonsbip of suddcn infanr deada syndrome tu maternal smoking during and after pregnancy lkdfaMa 1992;90:905-8. 6 Malloy MH, HoRman HJ, Peter.on DR. Sudden infant death ayndrome and mate•rnal smoking. A,e) fi,blic Haald, 1992i112:136o-2. 7 fbnaonhy At., Dwyxr T, Kasl SV, Cochrane JA. The Tasma- nian SIDS CascControl Smdy: umvariable and mulnvari- ahlc risk factor analysis-lhnfian Prnbna Fpidnnid 1995;9: 256-'/2. a Blair PS, Fleming Pl, Bansley D, er al. Smoking and the ,udden infant death s.ndrome. resuln 5om 1993-5 se-conrmi studr for confWential inquiry intn uiltbirrlu and dcmhr m infancy.0on6dential Hnqulry into Srillbirths and [Xaahs Regional Coordinarors and Researchers. DA17 1996;313195-9 e l-ewak N, .an den Berg DJ, Beckwhh JD. Sudden infant death ayndromc dsk fecrers- Prospecti.r dutn re+,eu-. Clin ftdlnr. (Phdu) 1939;18:4V4-ll. 11/ Hilcy CM, Mnrley CJ. bvaluatiun ( governmenrk ca - paign to reduce risk n( mr death. BMJ 1994;3a9:7U3-41n I I Mhchell E4. Furd Rf. St.+vart AW, er a(. Smoking and the •udArn m(.n, Jr:nh syndrnma fbLsv:r. 19V3:91:g936. amm,.u,rhdi,cluld.cerw