parental cigarette smoking and risk for congenital anomalies of the heart, neural tube, or limb

TERATOLOGY 53:261-267 (1996)

Parental Cigarette Smoking and Risk for Congenital Anomalies of the Heart, Neural Tube, or Limb CATHY R. WASSERMAN, GARY M. SHAW, CYNTHIA D. O'MALLEY, MARIE M. TOLAROVA, AND EDWARD J. LAMMER March of Dimes Birth Defects Foundation, California Birth Defects Monitoring Program, Emeryville, California 94608 (C.R.W., G.M.S., CD.O., M.M.T.); Department of Medical Genetics, Children's Hospital, Oakland, California 94609 (E.JL.)

ABSTRACT Risks for selected congenital anomalies from parental smoking were investigated in a case-control study in California. Moth- ers of 207 infants with conotruncal heart defects, 264 infants with neural tube defects, 178 infants with limb deficiencies, and 481 live born control infants delivered in 1987-1 988 were interviewed by telephone. Modestly elevated risks were observed for conotruncal heart defects and limb deficiencies, associated primarily with both parents smoking. An odds ratio of 1.9 (95 percent confidence interval 1.2-3.1) was observed for conotruncal heart defects and an odds ratio of 1.7 (95% confidence interval 0.96-2.9) for limb deficiencies when both parents smoked compared to neither parent smoking. We did not observe increased risks associated with maternal smoking in the absence of paternal smoking, although an increased risk associated with paternal smoking in the absence of maternal smoking was observed for limb deficiencies in offspring. For conotruncal defects, the risks associated with parental smoking differed among race/ ethnic groups. Parental smoking was not associated with increased risks for neural tube defects. Observed risks did not change substantially when adjusted for maternal vitamin use, alcohol use, and gravidity. Some heterogeneity in risk was observed for phenotypic case subgroups, but data were too sparse to draw firm inferences. 0 1996 Wiley-Liss, Inc.

Cigarette smoke is recognized to be a complex mix of chemicals, including cadmium, nicotine, and carbon monoxide which have been found to be teratogenic in experimental animals, albeit by exposures likely to differ in dose from those delivered by smoking (Padman- abhan and Hameed, '90; Carmichael et al., '82; Up- shall, '72; Astrup et al., '72). In humans, maternal smoking does not appear to increase risk for all congenital anomalies, but may increase risk for specific anomalies (Werler et al., '86) Moreover, paternal smoking and involuntary maternal smoke exposures may influence risks for congenital anomalies, but have been

studied infrequently. We conducted a population-based case-control study in California to investigate the role of maternal and paternal cigarette exposures as risk factors for conotruncal heart defects, neural tube defects, and limb deficiencies.

MATERIALS AND METHODS Eligible were all live born infants and fetal deaths (n

= 344,214) delivered between January 1987 and De- cember 1988 to women residing in most California counties, and who were diagnosed within 1 year after birth with a conotruncal heart defect, neural tube defect, or limb deficiency. Cases were ascertained by staff of the California Birth Defects Monitoring Program who reviewed medical records at all hospitals and genetics centers in the surveillance area (Croen et al., '91).

Diagnostic information was reviewed by medical ge- neticists (E.J.L., M.M.T.) to determine eligibility. Eli- gible as conotruncal heart defect cases were all infants with malformations affecting aorticopulmonary septa- tion, including: tetralogy of Fallot, d-transposition of the great arteries, truncus arteriosus communis, double outlet right ventricle, pulmonary valve atresia with ventricular septa1 defect (VSD), subaortic VSD type I, and aortico-pulmonary window. Cardiac malformations were confirmed by echocardiography, cardiac catheterization, surgery, or autopsy. When multiple cardiac diagnoses were present, the primary diagnosis was determined according to a hierarchical pathoge- netic classification scheme (Clark, '90). All infants and fetuses (including elective terminations and spontaneous abortions) with diagnoses of anencephaly, spina bifida cystica, craniorhachischisis, and iniencephaly that were confirmed by autopsy, surgery report, or X

Fkceived December 11, 1995; accepted March 20,1996. Address reprint requests to C.R. Wasserman, California Birth Defects Monitoring Program, 1900 Powell St., Suite 1060, Emeryville, CA 94608.

0 1996 WILEY-LISS, INC.

262 C.R. WASSERMAN ET AL.

ray were eligible as neural tube defect cases. All infants and fetuses with longitudinal, transverse, or amniotic band limb deficiency defects of the upper andlor lower limbs that were confirmed by radiology, surgery, or autopsy reports were eligible as limb deficiency cases. Infants diagnosed with a trisomy, or Turner syn- drome (45,X) as well as neural tube defect cases of amniotic band pathogenesis (n = 2) were excluded because there were not enough cases to analyze separately.

A total of 652 control infants was randomly selected from all infants born alive during 1987-1988 who did not have a reportable birth defect prior to the first birthday and whose mothers were residents of the same California counties as case mothers.

Mothers of cases and controls were interviewed primarily over the telephone in English (91.5%) or Span- ish (8.5%). Women who only spoke other languages were excluded (22 cases and 21 controls). On average, interviews were completed 3.7 years after the date of delivery for cases (differences between case types were minimal) and 3.8 years for controls. Interviewers as- sisted each woman in defining a 4-month exposure time period from 1 month before to 3 months after the estimated date of conception. This 4-month period, re- ferred to throughout the interview, encompasses the period just before conception and the period of organo- genesis in which conotruncal defects, neural tube defects, and limb deficiencies occur. The approximately 40 minute interview elicited detailed information on direct and involuntary cigarette smoke exposures as well as potential confounders.

To assess maternal smoking, women were asked on average how many cigarettes they smoked daily over the 4-month period. To assess involuntary maternal smoke exposures during the 4-month period, they were asked whether others smoked inside their homes, near them at work or school, while they were commuting to work or school, or whether they regularly frequented (at least once/week) other locations such as friends' homes or restaurants where others smoked nearby. In- voluntary maternal smoke exposures could potentially include smoking by the infants' biological fathers. Women were also asked separately how many cigarettes per day their infants' biological fathers smoked in the 3 months before through 3 months after conception.

"he odds ratio and 95% confidence interval was used to estimate risk. Risk estimates, including those de- rived from logistic regression models, were computed using EGRET ('91). Maternal and paternal cigarette smoking were considered as polytomous variables (0, 1-19, and 2 20 cigarettes per day), but were dichoto- mized for analyses of the joint risks of maternal and paternal smoking because few parents smoked 2 20 cigarettes per day. Those variables found to be associated with each case group and maternal smoking were explored as potential covariates, and included: mater-

nal racelethnicity, gravidity, alcohol use, and vitamin use (Shaw et al., '95a,b). Risks from involuntary smoke exposures were explored among women who were non- smokers during the 4-month period.

RESULTS Interviews were completed with 207 (87% of eligible)

conotruncal case mothers, 264 (84%) neural tube defect case mothers, 178 (82%) limb deficiency case mothers, and 481 (76%) control mothers. Two to three percent of case and control mothers declined to participate, and 10-14% of case mothers and 21% of control mothers could not be located after extensive tracing.

Table 1 shows the maternal and infant characteristics of the three case groups and the controls. Mothers of conotruncal heart defect cases and limb deficiency cases were more likely to be white and less likely to be primigravida than mothers of control infants. Mothers of conotruncal heart defects cases also were more likely to be employed and to be 35 years or older, whereas mothers of limb deficiency cases were more likely to be African American. Limb and conotruncal cases were both more likely to be male. Mothers of neural tube defect cases were more likely than control mothers to be Latina, to be more than 39 years old, and to be gravida four or more.

Table 2 shows the odds ratios (ORs) and 95% confidence intervals (CIS) associated with parental smoking for all conotruncal heart defects combined as well as for the two largest diagnostic subgroups, d-transposition of the great arteries (n = 77) and tetralogy of Fallot (n = 83). For all conotruncal defects combined, slightly elevated odds ratios were observed for maternal smoking and for paternal smoking when evaluated singly. Maternal and paternal smoking were correlated, however, and risks were not elevated for maternal smoking in the absence of paternal smoking, nor vice versa, when compared with neither parent smoking. When both parents smoked, though, the risk was elevated (OR = 1.9 D.2-3.11). Slightly elevated risks were observed for involuntary maternal smoke exposures among women who did not smoke during the 4-month period. Adjustment for selected covariates did not substantially influence observed risks, except that elevated risks for maternal, paternal, and joint parental smoking were primarily due to increased risks among the offspring of Latina women. For example, among Latinas an OR of 2.9 (1.2-6.8) for all conotruncal cases was observed for maternal smoking while among whites the OR was 0.74 (0.45-1.2) (data not shown). Similar risk patterns were found for d-transposition and tetralogy of Fallot cases analyzed separately, with higher risks observed for d-transposition, but data were too sparse to draw firm conclusions.

No increased risks were observed for all neural tube defects from maternal or joint parental smoking, nor were risks substantially altered by adjustment for co-

PARENTAL SMOKING AND SELECTED BIRTH DEFECTS 263

TABLE 1. Maternal and infant characteristics (percent) of conotruncal heart defect cases, neural tube defect cases. limb reduction defect cases. and controls1

Conotruncal Neural tube Limb reduction Controls heart defect defect cases defect cases (n = 481) cases (n = 207) (n = 264) (n = 178)

Radethnicity Latina Non-Latina, White African American Asian Other

< 20 20-24 25-29 30-34 35-39 > 39

Employed Education

Age

< High school graduate High school graduate Some college College graduate

1 2 3 4+

Diabetes Child sex

Gravidity

28.7 57.6 2.9 5.8 4.8

9.8 26.8 33.5 22.0 6.7 0.8 55.1

23.5 29.1 30.4 16.4

27.0 26.0 22.3 21.6 4.8

23.7 65.7 3.4 3.4 3.9

7.7 24.6 34.3 22.2 10.1 0.5 64.3

19.3 31.9 31.4 17.4

22.2 24.6 27.5 24.6 9.7

33.2 58.1 2.3 4.2 2.3

9.8 21.5 37.4 21.5 6.8 1.9 54.0

26.4 29.8 30.9 12.5

22.3 19.6 23.0 32.5 7.6

24.7 62.9 6.2 2.8 3.4

12.9 27.0 30.3 20.2 7.3 1.1 52.2

25.8 33.1 28.7 11.2

20.8 28.7 18.5 29.8 6.7

Male 49.7 57.5 39.22 55.6 'May not add to 100 due to rounding or missing information for some subjects. 2Sex was unknown for 48 neural tube defect cases.

variates (Table 3). Paternal smoking showed ORs of 1.2 or less. Among non-smoking women, ORs of 1.2 were associated with involuntary smoke exposures. Analy- ses performed separately for anencephalic cases (n = 124) and spina bifida cases (n = 129) found essentially the same risks as for all neural tube defect cases combined.

Table 4 shows the risk for all limb deficiency defects in offspring to be elevated for both maternal smoking 2 20 cigarettes per day, OR = 1.5 (0.67-3.21, and paternal smoking ? 20 cigarettes per day, OR = 2.1 (1.3- 3.6). Paternal smoking showed an association in the absence of maternal smoking, but the reverse was not observed. Joint parental smoking compared to neither parent smoking also showed an elevated risk (OR = 1.7 lO.96-2.91) which was limited to those subjects for whom at least one parent smoked ? 20 cigarettes per day. Risk estimates adjusted for selected covariates did not differ substantially from crude estimates. Among non-smoking women, risks of 1.2-1.4 were associated with involuntary smoke exposure. Risks by three specific types of limb deficiency defect, longitudinal (n = 811, transverse (n = 50) and amniotic band (n = 32) are also presented and suggest some heterogeneity by

case subtype, but sparse data limit the ability to draw inferences.

DISCUSSION These results indicate parental smoking is associ-

ated with conotruncal heart defects and limb deficiency defects in offspring, but not neural tube defects. While slight to moderate increased risks were observed when either maternal or paternal smoking was evaluated without regard for the smoking of the other parent, the increases appeared to be associated with both parents smoking. When both parents' smoking habits were evaluated together, no risk associated with maternal smoking was observed when fathers did not smoke (except among longitudinal limb deficiencies). Risk associated with paternal smoking in the absence of maternal smoking was only apparent among limb deficiency defects. Of note, the risks for conotruncal defects associated with parental smoking were primarily due to increased risks among the offspring of Latina women. Although provocative, several of the comparisons presented are based on sparse data, therefore observed risks might alternatively be attributable to random variation.

264 C.R. WASSERMAN ET AL. TABLE 2. Odds ratios for conotruncal heart defect cases associated with periconceptional maternal, paternal,

and involuntary maternal smoking'

Conotruncal d-Transposition of Controls heart defects2 great arteries Tetralogy of Fallot

(n) n OR 95%CI n OR 95%CI n OR 95%CI Maternal cigarettedday

0 364 147 reference 52 reference 61 reference 1-19 91 47 1.3 (0.84-2.0) 18 1.4 (0.74-2.6) 20 1.3 (0.72-2.4) 2 20 23 13 1.4 (0.65-3.0) 7 2.1 (0.79-5.6) 2 0.52 (0.08-2.4) DK 3 0 0 0


Paternal cigarettedday

Maternal and paternal smoking

Neither parent smokes 266 111 reference 41 reference 47 reference Father only smokes 90 35 0.93 (0.58-1.5) 10 0.72 (0.32-1.6) 14 0.88 (0.44-1.7) Mother only smokes 56 16 0.68 (0.36-1.3) 4 0.46 (0.14-1.4) 7 0.71 (0.28-1.7) Both parents smoke 54 43 1.9 (1.2-3.1) 21 2.5 (1.3-4.8) 14 1.5 (0.71-3.0) DK 15 2 1 1

Maternal involuntary smoke exposures3

15 reference 13 reference None 111 37 reference Home 132 55 1.3 (0.75-2.1) 20 1.1 (0.52-2.4) 20 1.3 (0.58-2.9) Work 70 39 1.7 (0.94-3.0) 8 0.85 (0.31-2.3) 24 2.9 (1.3-6.6) Any location4 246 110 1.3 (0.85-2.1) 37 1.1 (0.56-2.2) 48 1.7 (0.83-3.4)

'Maternal smoking and involuntary maternal smoking from 1 month before through 3 months after conception; paternal smoking from 3 months before through 3 months after conception. 21ncludes d-transposition of the great arteries (n = 771, tetralogy of Fallot (n = 831, double outlet right ventricle (n = 9), truncus arteriosus (n = 22), other (n = 16). 31ncludes only women who did not smoke cigarettes in the period from 1 month before through 3 months after conception. 41n addition to home and work, incudes exposures at locations frequented at least weekly by study respondents, such as a restaurant, friend or relative's home, or laundromat.

Placing our results in the context of previous findings is difficult due to variations in exposure measure- ment and in case definition and ascertainment. Previ- ous studies of smoking and congenital anomalies have been based predominantly on assessments of maternal smoking without regard for a contribution from paternal smoking. We are unaware of any study showing risks specific to joint parental smoking. An increased risk for d-transposition of the great arteries associated with parental smoking, however, has recently been reported (Lofiedo et al., '95) considering only maternal smoking, one of three studies that specifically investigated conotruncal heart defects showed an odds ratio of 1.3 for women smoking 20 cigarettes per day or less (Kelsey et al., '781, while a second reported an odds ratio of 1.9 only among women smoking 1-9 cigarettes per day (Shaw et al., '92). A third study reported no increased risk (Adams et al., '89). Findings have been mixed from other studies investigating the potential risk for cardiovascular anomalies from maternal smoking, but the proportion of anomalies in these studies that were conotruncal defects was not specified (Van den Eeden et al., '90; Fedrick et al., '71; Andrews and McGarry, '72; Evans et al., '79; Himmelberger et al.,

'78; Pradat, '92; Malloy et al., '89; Yerushalmy, '73; Christianson, '80; Shiono et al., 86; McDonald et al., '92).

Our finding of no increased risk for neural tube defects from maternal smoking concurs with results from several studies (Van den E d e n et al., '90; Andrews and McGarry, '72; Himmelberger et al., '78; Malloy et al., '89; Christianson, '80; Shiono et al., '86; Golding and Butler, '83). However, elevated risks on the order of 1.3-1.8 have also been reported (Kelsey et al., '78; Evans et al., '79 Hemminki et al., '83; Choi and Klaponski, '70; McDonald et al., '92) with two studies showing a dose response with higher risk associated with more cigarettes smoked per day (Kelsey et al., '78; Evans et al., '79). Such variability in findings might be due to chance, to differences in exposure or case ascertainment, or to temporal and geographic variations in levels of cigarette constituents, such as tar and nicotine, or the proportion of filtered cigarettes smoked (Report of the Surgeon General, '81; USDHHS, '92). In our study, 96% of smoking mothers reported using filtered cigarettes and 92% reported inhaling the smoke.

Up to 2-fold increased risks for limb deficiency defects associated with maternal smoking have been re-


TABLE 3. Odds ratios for neural tube defect cases associated with periconceptional maternal, paternal, and involuntary maternal smoking'

Controls Neural tube defects' Anencephaly Spina bifida (n) n OR 95% CI n OR 95%CI n OR 95%CI

Maternal cigaretteidday 0 364 213 reference 99 reference 105 reference 1-19 91 36 0.68 (0.43-1.0) 19 0.77 (0.43-1.4) 16 0.61 (0.33-1.1) 2 20 23 14 1.0 (0.49-2.2) 5 0.80 (0.26-2.3) 8 1.2 (0.48-2.9) DK 3 1 1 0


Paternal cigaretteidday

Maternal and paternal smoking

71 reference 75 reference Neither parent smokes 266 152 reference Father only smokes 90 59 1.1 (0.76-1.7) 28 1.2 (0.69-2.0) 28 1.1 (0.65-1.9) Mother only smokes 56 18 0.56 (0.30-1.0) 10 0.67 (0.30-1.4) 8 0.51 (0.21-1.2) Both parents smoke 54 32 1.0 (0.62-1.7) 14 0.97 (0.48-1.9) 16 1.1 (0.54-2.0) DK 15 3 1 2


None 111 55 reference 27 reference 25 reference Home 132 81 1.2 (0.79-1.9) 41 1.3 (0.71-2.3) 36 1.2 (0.66-2.2) Work 70 39 1.2 (0.67-2.0) 12 0.70 (0.31-1.6) 25 1.6 (0.81-3.1) Any location* 246 151 1.2 (0.83-1.9) 69 1.2 (0.68-2.0) 75 1.4 (0.79-2.3)

'Maternal smoking and involuntary maternal smoking from 1 month before through 3 months after conception; paternal smoking from 3 months before through 3 months after conception. 21ncludes anencephaly (n = 1241, spina bifida (n = 129), and other neural tube defect cases (n = 11). 31ncludes only women who did not smoke cigarettes in the period from 1 month before through 3 months after conception. *In addition to home and work, includes exposures at locations frequented at least weekly by study respondents, such as a restaurant, friend or relative's home, or laundromat.

ported previously (Kallen, '89; An>, '83; Czeizel et al., '94; Stoll et al., '92). While our data show a slightly increased risk associated with maternal smoking 2 20 cigarettes per day, we did not observe an increased risk from maternal smoking in the absence of paternal smoking, and attribute the observed increase to both an association with joint parental smoking as well as an increased risk from paternal smoking among parents who both smoke. No previous study of limb anomalies investigated paternal smoking, and an elevated risk for limb deficiencies in offspring associated with paternal smoking in the absence of maternal smoking has not been reported. While two studies have looked at the potential association between paternal smoking and congenital anomalies, neither specifically investigated limb deficiency defects (Zhang et al., '92; Savitz et al., '91).

The increased risks for conotruncal and limb deficiency defects found when both parents smoked, but not when mothers only smoked are curious. Such differences might be explained by differences in smoking behaviors which may vary according to whether only one or both parents smoke. These differences could influence fetal exposure to a potential teratogen found in cigarette smoke. For example, in couples where only one parent smokes, the smoker may smoke fewer cig-

arettes, lighter yield cigarettes (of tar, nicotine, carbon monoxide, or other potential teratogen), different types of cigarettes (mentholated vs. non-mentholated), less of the cigarette itself, and/or be in contact with cigarette smoke less than in couples where both parents smoke. While we did collect information on some of these characteristics, our numbers are too sparse to draw conclusions about their influences. Variations in behaviors or exposures not directly associated with smoking, but that are more common among parents who smoke, might also account for the differences in risk observed if they were related to these anomalies.

Similar variations in exposures might also explain the race/ethnic differences in risk that we observed for conotruncal defects. To our knowledge, such race/ethnic specific differences have not been reported previously. Alternatively, differences in genetic susceptibil- ity could account for the racelethnic differences.

Unlike many previous studies, this study has the advantages of being population based with complete case ascertainment, quantitative exposure information for both parents during the relevant embryologic peri- ods, and information on potential covariates. Neverthe- less, chance and undetected biases provide alternative explanations for the observed results. Many elevated risk estimates had associated confidence intervals

266 C.R. WASSERMAN ET AL.

TABLE 4. Odds ratios for limb reduction defect cases associated with ericonceptional maternal, paternal, and involuntary maternal smoking P Limb reduction

Controls defects' Longitudinal Transverse Amniotic band (n) n OR 95%CI n OR 95%CI n OR 95%CI n OR 95%CI

Maternal cigarettedday 0 1-19 2 20 DK

0 1-19 2 20 DK

Maternal and

Paternal cigarettedday

paternal smoking Neither parent smokes Father only smokes Mother only smokes Both parents smoke DK


None Home Work Anv location4

364 91 23 3

322 94 50 15

266 90 56 54 15

111 132 70

246

129 reference 57 reference 39 reference 23 reference 34 1.1 (0.66-1.7) 19 1.3 (0.73-2.4) 8 0.82 (0.34-1.9) 5 0.87 (0.28-2.5) 12 1.5 (0.67-3.2) 5 1.4 (0.44-4.1) 3 1.2 (0.28-4.5) 4 2.8 (0.74-9.4) 3 0 0 2

103 reference 54 reference 29 reference 15 reference 36 1.2 (0.75-1.9) 9 0.57 (0.25-1.3) 11 1.3 (0.59-2.8) 13 3.0 (1.3-6.9) 34 2.1 (1.3-3.6) 17 2.0 (1.0-3.9) 9 2.0 (0.82-4.7) 4 1.7 (0.46-5.8) 5 1 1 2

86 reference 42 reference 26 reference 13 reference 41 1.4 (0.88-2.2) 14 0.99 (0.49-2.0) 12 1.4 (0.62-3.0) 10 2.3 (0.89-5.8) 17 0.94 (0.50-1.8) 12 1.4 (0.63-2.9) 3 0.55 (0.13-2.0) 2 0.73 (0.11-3.6) 29 1.7 (0.96-2.9) 12 1.4 (0.65-3.0) 8 1.5 (0.60-3.8) 7 2.7 (0.91-7.6) 5 1 1 2

35 reference 15 reference 10 reference 9 reference 53 1.3 (0.75-2.2) 24 1.4 (0.64-2.9) 16 1.4 (0.55-3.3) 6 0.56 (0.17-1.8) 30 1.4 (0.74-2.5) 13 1.4 (0.57-3.3) 9 1.4 (0.50-4.0) 4 0.70 (0.17-2.6) 93 1.2 (0.75-1.9) 41 1.2 (0.63-2.4) 29 1.3 (0.59-3.01 14 0.70 (0.28-1.8)

'Maternal smoking and involuntary maternal smoking from 1 month before through 3 months after conception; paternal smoking from 3 months before through 3 months after conception. 'Includes longitudinal limb reductions (n = 811, transverse reductions (n = 501, amniotic band reductions (n = 34), and 13 limbs of known syndromic etiology (includes chromosomal abnormalities, autosomal dominant, and autosomal recessive disorders). 31ncludes only women who did not smoke cigarettes in the period from 1 month before through 3 months after conception. 41n addition to home and work, includes exposures at locations frequented at least weekly by study respondents, such as a restaurant, friend or relative's home, or laundromat.

which included 1.0. Given the response rate, selection bias may have been introduced if disproportionately fewer of the eligible control mothers who smoked chose to participate in the study compared to the case mothers who chose to participate. Alternately, falsely elevated odds ratios could have resulted from recall bias due to control mothers underreporting, or case mothers overreporting, their own or their partner's smoking behaviors. The proportion of control mothers who reported smoking in this study (23.7%) was similar to that in other studies (Windham et al., '92; Fox et al., '94) suggesting that disproportional non-participation by smoking controls, or underreporting by control mothers, were unlikely explanations for the observed results. While overreporting by case mothers was possible, reasons why non-smoking case mothers would report that they or their non-smoking partners smoked are not obvious. Moreover, women's reporting of their partners' smoking in the first trimester has been shown to be relatively reliable (Hatch et al., 1991). Etiologic heterogeneity within the studied case groups may also have biased our results leading to underesti- mates of risk (assuming these etiologies were unre- lated to parental smoking).

Despite numerous public health warnings of its potential adverse fetal effects, cigarette smoking contin- ues to be common among pregnant women, with almost 1 in 4 women smoking during early pregnancy. In addition to the known increased risk for adverse reproductive outcomes, such as intrauterine growth retar- dation, this study indicates parental smoking may also modestly increase the risk of delivering infants with conotruncal heart defects or limb deficiency defects. Replication of these analyses in a study with greater power to detect low increased risks and additional in- vestigation of joint parental smoking and potential racelethnic differences in risk, could extend the findings of this study.

ACKNOWLEDGMENTS This work was partially supported by the Cigarette

and Tobacco Surtax Fund of California Tobacco-Re- lated Disease Research Program, University of Califor- nia, 1RT466.

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