Maternal Smoking and Congenital Heart Defects Sadia Malik, Mario A. Cleves, Margaret A. Honein, Paul A.

Romitti, Lorenzo D. Botto, Shengping Yang, Charlotte A. Hobbs and and the National Birth Defects Prevention Study Pediatrics 2008;121;e810-e816 DOI: 10.1542/peds.2007-1519

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/121/4/e810

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2008 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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ARTICLE

Maternal Smoking and Congenital Heart Defects

Sadia Malik, MD, MPHa, Mario A. Cleves, PhDa, Margaret A. Honein, PhD, MPHb, Paul A. Romitti, PhDc, Lorenzo D. Botto, MDd, Shengping Yang, MSa, Charlotte A. Hobbs, MD, PhDa, and the National Birth Defects Prevention Study
aDepartment of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas; bNational Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia; cDepartment of Epidemiology, University of Iowa, Iowa City, Iowa; dDepartment of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah

The authors have indicated they have no nancial relationships relevant to this article to disclose.

Whats Known on This Subject

Each year, 1 million infants are prenatally exposed to maternal smoking. There is now evidence that maternal tobacco use has been linked to congenital heart defects and other congenital anomalies.

What This Study Adds

If even a fraction of congenital heart defects and other birth defects could be prevented by decreasing maternal tobacco use, this would result in improved reproductive outcomes and a tremendous savings of health care dollars.

ABSTRACT
OBJECTIVES. In a population-based case-control study, we investigated the association between congenital heart defects and maternal smoking. METHODS. The National Birth Defects Prevention Study enrolled 3067 infants with
www.pediatrics.org/cgi/doi/10.1542/ peds.2007-1519 doi:10.1542/peds.2007-1519
The ndings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention or the National Institutes of Health. Key Words smoking, pregnancy, congenital heart defects Abbreviations CHD congenital heart defect ETS environmental tobacco smoke ASDatrial septal defect NBDPSNational Birth Defects Prevention Study VSDventricular septal defect OR odds ratio CI condence interval NOSnitric oxide synthase
Accepted for publication Aug 27, 2007 Address correspondence to Charlotte A. Hobbs, MD, PhD, Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, 1120 Marshall St, Mail Slot 512-40, Little Rock, AR 72202. E-mail: hobbscharlotte@uams.edu PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2008 by the American Academy of Pediatrics

nonsyndromic congenital heart defects and their parents and 3947 infants without birth defects and their parents. Affected infants had 1 of the following defects: conotruncal, septal, anomalous pulmonary venous return, atrioventricular septal defects, and left-sided or right-sided obstructive heart defects. Mothers of case and control infants were asked if they smoked during the periconceptional period, dened as 1 month before pregnancy through the rst trimester. Maternal home and workplace exposure to tobacco smoke during the same period was also determined. Logistic regression was used to compute odds ratios and 95% condence intervals while controlling for potential confounders.
RESULTS. Case infants were more likely to be premature and have lower birth weight

than control infants. Women who smoked anytime during the month before pregnancy to the end of the rst trimester were more likely to have infants with septal heart defects than women who did not smoke during this time period. This association was stronger for mothers who reported heavier smoking during this period. This relation was independent of potential confounding factors, including prenatal vitamin use, alcohol intake, maternal age, and race or ethnicity. Women who smoked 25 cigarettes per day were more likely than nonsmoking mothers to have infants with right-sided obstructive defects. There was no increased risk of congenital heart defects with maternal exposure to environmental tobacco smoke.
CONCLUSIONS. Maternal smoking during pregnancy was associated with septal and rightsided obstructive defects. Additional investigation into the timing of tobacco exposure and genetic susceptibilities that could modify this risk will provide a more precise evidence base on which to build clinical and public health primary prevention strategies.

ONGENITAL HEART DEFECTS (CHDs) are the most prevalent and serious of all recognized structural birth defects, occurring in 8 to 10 of every 1000 live births in the United States.13 Affected infants who survive often require repeated surgeries and lengthy hospitalizations, and many will have a lifetime of disability that imposes a signicant burden on families.4,5 In the United States, CHDs result in billions of dollars being spent each year on medical care.6 Several risk factors for CHDs have been proposed,7 including maternal smoking during pregnancy and exposure to environmental tobacco smoke (ETS; a mixture of the smoke given off by the burning end of a cigarette, pipe, or cigar and the smoke exhaled from the lungs of smokers). In the United States, an estimated 28% of reproductive-aged women smoke cigarettes, and 20% continue to smoke during pregnancy.8,9 Thus, 1 million infants are prenatally exposed to cigarette smoke by maternal smoking each year.10 There is now a growing body of evidence showing fetal susceptibility to chronic prenatal cigarette exposure affecting birth weight and congenital malformations.1113 Animal studies have shown a small increased risk of neural tube defects with tobacco exposure.14 Maternal tobacco use has been linked to intrauterine growth retardation, prematurity, perinatal mortality, and congenital malformations.1520 These malfor-

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mations include cleft lip, cleft palate, or both; limb reduction defects; clubfoot; congenital urinary tract anomalies; anal atresia; gastroschisis; central nervous system defects; and CHDs.2126 A study of orofacial clefts demonstrated that the risk associated with maternal smoking increased with the number of cigarettes smoked.27 Few epidemiologic studies have specically investigated the association between CHDs and maternal smoking. In a Swedish population-based study, unadjusted estimates revealed an increased risk of having an infant with either truncus arteriosus or atrial septal defects (ASDs) among women who smoked.28 In the Baltimore-Washington Infant Study, which included 3377 case infants with CHDs, women who were 34 years of age who smoked 1 pack of cigarettes per day were more likely to have an infant with pulmonary valve stenosis than younger, nonsmoking mothers.29 Wasserman et al30 found an increased risk of having an infant with conotruncal heart defects if both parents smoked from 1 month before pregnancy through the rst trimester. The association between CHDs and maternal workplace exposure to ETS has not been evaluated. The purpose of this study was to elucidate the association between specic subtypes of CHDs and maternal periconceptional smoking and exposure to ETS by using the infrastructure of the National Birth Defects Prevention Study (NBDPS). The NBDPS is a population-based, multicenter study that provides detailed classication of CHDs; state-of-the-art, interview-based exposure assessments; and information on multiple potential confounders and effect modiers.31 The NBDPS provides a unique opportunity to examine the association between CHD and maternal active and passive smoking. METHODS Case and Control Infant Selection Details regarding the methods of the NBDPS have been published previously.31,32 Briey, the NBDPS is an institutional review board-approved ongoing case-control study intended to identify the etiology of 30 nonsyndromic structural birth defects, including septal, conotruncal, and obstructive heart defects. Case and control infants were eligible NBDPS participants born from October 1997 through December 2002. Case infants were identied by birth defect surveillance registries in participating states with the use of uniform diagnostic criteria. NBDPS-eligible case infants were those who had no known single-gene disorder or chromosomal abnormality and were diagnosed with a CHD by echocardiogram, heart catheterization, or surgical or autopsy report before 1 year of age. Control infants were infants who had no birth defects and were randomly selected from birth certicates or hospital discharge listings in the same states and during the same time period as the case infants. Case and control mothers had to speak English or Spanish. Infants who were adopted or in foster care were ineligible.

Classication of Cardiac Defects Each CHD case was reviewed by 1 of 4 NBDPS clinician case classiers33 and described as simple, associated, or complex on the basis of the defects complexity. The simple CHD category was used to describe either an isolated CHD or a well-dened single entity (eg, tetralogy of Fallot). The associated CHD category described case infants with 2 distinct CHDs (eg, transposition of the great vessels with outow tract obstruction). All of the CHDs that included 3 cardiac defects were considered complex. Complex heart defects composed only 7.8% and did not provide sufcient power to test study hypotheses. Cardiac defects were classied into major categories based on the anatomic lesion: (1) conotruncal, including transposition of the great arteries, tetralogy of Fallot, truncus arteriosus, double-outlet right ventricle, malaligned ventricular septal defects (VSDs), and interrupted aortic arch type B; (2) septal, including ASDs and VSDs; (3) right-sided obstructive, including pulmonary valve stenosis, pulmonary atresia, tricuspid atresia, and Ebstein anomaly; (4) left-sided obstructive, including aortic valve stenosis, hypoplastic left heart syndrome and variants, coarctation of the aorta, and interrupted aortic arch types A and C; (5) anomalous pulmonary venous return, including total and partial anomalous pulmonary venous return; and (6) atrioventricular septal defects. All of the centers collected data on eligible defects throughout the entire study period, with 2 exceptions. First, case infants of isolated muscular VSDs were only enrolled between October 1, 1997, and December 31, 1998, after which no additional enrollment of muscular VSDs occurred at any center. They were, therefore, excluded from our analyses. Also, one center enrolled case infants with pulmonary valve stenosis or septal defects only during part of the study period; these CHD subtypes from this center were not included in this analysis. In addition, case infants were excluded from this study if they had an additional extracardiac birth defect or were not singleton births. Data Collection As part of the NBDPS, mothers of case and control infants completed an extensive interview regarding periconceptional exposures, including questions about pregnancy history; maternal prepregnancy weight and height; pregnancy weight gain; maternal illnesses, including diabetes; tobacco and alcohol use; and vitamin supplement use and dietary intake. Maternal smoking status was assessed by determining those who reported smoking anytime from 1 month before conception through each month of pregnancy. Participants were asked to report the amount they smoked from 1 cigarette per day to 2 packs per day. Maternal home and workplace exposure to tobacco smoke and the timing of that exposure with respect to the month of pregnancy were also determined (with a dichotomous yes or no response). Unexposed mothers were those who did not smoke and were not exposed to ETS from 1 month before pregnancy through the rst trimester. Covariates of interest included infant gender, birth weight, gestational age, birth outcome, and plurality;
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3326 cases

3982 controls

Exclude preconceptional diabetes

3240 cases

3962 controls

Exclude muscular VSDs 3102 cases 3962 controls

Exclude incomplete interviews 3067 final cases 3947 final controls

based on previous studies into light (114 cigarettes a day), medium (1524 cigarettes a day), and heavy smokers (25 cigarettes a day).39,40 Odds ratios (ORs) and their 95% condence intervals (CIs) were calculated to evaluate these associations. We assessed the associations by computing crude ORs in global and stratied analyses and subsequently using linear logistic regression to include potential confounding variables. Inclusion of potential confounders was determined on the basis of the results of the bivariate analyses and previously published evidence. Maternal dietary folate and caffeine intake of case and control infants were compared using the MannWhitney U/Wilcoxon rank-sum test. Analyses were performed with SAS 9.1 software (SAS Institute Inc, Cary, NC). RESULTS From October 1997 through December 2002, 3326 women (72% of eligible participants) who had live-born singleton infants with CHDs meeting NBDPS eligibility criteria and no other congenital abnormality (case infants) and 3982 women (69% of eligible participants) who had live-born singleton infants without any birth defects (control infants) were enrolled in the NBDPS (Fig 1). Of these participants, 86 case and 20 control infants were excluded from the analyses because they had preconceptional type 1 or type 2 diabetes. In addition, 138 case infants of muscular VSDs were excluded from the analyses because they were ascertained only during the rst year of the NBDPS. In addition, 35 case and 15 control infants were excluded because they were missing information on smoking exposure. The nal sample consisted of 3067 case and 3947 control infants. In this NBDPS sample, 2519 case infants (82.1%) had a simple cardiac defect. Septal heart defects were the most common malformation (40.1%), followed by conotruncal (24.4%), right-sided obstructive (17.9%), and left-sided obstructive (17.8%) defects. The most frequent subtypes in each category are presented in Table 1.

FIGURE 1 NBDPS case and control analyses.

paternal race or ethnicity; and maternal alcohol use, heavy caffeine use (average 4 cups of coffee per day), parity, BMI, race or ethnicity, age, education, gestational diabetes or hypertension, use of lithium or folate antagonists,34 and prepregnancy vitamin use and folic acid intake.3537 The sources of reported folate/folic-acid intake were diet, food supplements, and vitamin supplements. Mothers provided data on use of vitamins, breakfast cereals, and food supplements during the periconceptional period. Dietary intake data were assessed for the year preceding pregnancy.38 Statistical Analysis The goal of this study was to assess the associations between infant CHD occurrence and maternal periconceptional reports of smoking and exposure to ETS. The frequencies of smoking and exposure to ETS were independently computed for control infants, CHD case infants, and each CHD subtype. Smokers were divided

TABLE 1 Frequencies of CHD Subtypes, National Birth Defects Prevention Study, 19972002
CHD Subtype Septal defects Ventricular septal defects, perimembranous Atrial septal defects, secundum Conotruncal defects Tetralogy of Fallot Dextrotransposition of the great arteries Double-outlet right ventricle Left ventricular outow tract obstructions Hypoplastic left-heart syndrome Coarctation of the aorta Aortic stenosis Right ventricular outow tract obstructions Pulmonic valve stenosis Pulmonary atresia Atrioventricular septal defect Anomalous pulmonary venous return Total anomalous pulmonary venous return
a Common

Simple (N 2519), n (%) 873 (34.66) 440 (17.47) 308 (12.23) 646 (25.65) 312 (12.39) 236 (9.37) 30 (1.19) 429 (17.03) 186 (7.38) 156 (6.19) 81 (3.22) 416 (16.51) 299 (11.87) 55 (2.18) 60 (2.38) 95 (3.77) 80 (3.18)

Associated (N 548), n (%) 356 (64.96) 144 (26.28) 30 (5.47) 103 (18.80) 3 (0.55) 38 (6.93) 39 (7.12) 121 (22.08) 3 (0.55) 74 (13.50) 25 (4.56) 131 (23.91) 87 (15.88) 6 (1.09) 27 (4.93) 8 (1.46) 7 (1.28)

Total (N 3067), n (%)a 1229 (40.07) 584 (19.04) 338 (11.02) 749 (24.42) 315 (10.27) 274 (8.93) 69 (2.25) 550 (17.93) 189 (6.16) 230 (7.50) 106 (3.46) 547 (17.84) 386 (12.59) 61 (1.99) 87 (2.84) 103 (3.36) 87 (2.84)

subtypes with 50 cases were included.

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TABLE 2 Characteristics of Case and Control Participants, National Birth Defects Prevention Study, 19972002
Variable Gender Female Male Gestational age Term or postterm (37 wk) Very preterm or preterm (37 wk) Birth weight Normal or macrosomic (2.5 kg) Low (2.5 kg) Parity Primipara Multipara Maternal age 20 y 2034 y 35 y Maternal race White, non-Hispanic Black, non-Hispanic Hispanic Others Maternal education Less than high school High school completed College education Masters degree or higher BMI, kg/m2 Underweight (18.5) Normal (18.5 and 25.0) Overweight (25.0 to 30.0) Obese (30.0) Family history of heart defectb No Yes Maternal alcohol use b1 to m3c No Yes Folic acid intake b1 to m2c No Yes Caffeine intake, mg/dd Dietary folate intake, g/dd,f
a ORs b Data

Case Participants (N 3067), n (%) 1412 (46.04) 1655 (53.96) 2494 (81.32) 570 (18.58) 2544 (82.95) 506 (16.5) 1213 (39.55) 1540 (50.21) 410 (13.37) 2227 (72.61) 430 (14.02) 1891 (61.66) 397 (12.94) 628 (20.48) 147 (4.79) 518 (16.89) 832 (27.13) 812 (26.48) 904 (29.48) 177 (5.77) 1570 (51.19) 656 (21.39) 551 (17.97) 2947 (96.24) 115 (3.76) 1904 (62.08) 1141 (37.2) 783 (25.53) 2284 (74.47) 91.2 (30.2185.4)e 460.5 (350.0598.7)e

Control Participants (N 3947), n (%) 1971 (49.94) 1976 (50.06) 3642 (92.27) 302 (7.65) 3746 (94.91) 181 (4.59) 1568 (39.73) 2060 (52.19) 576 (14.59) 2930 (74.23) 441 (11.17) 2363 (59.87) 468 (11.86) 910 (23.06) 195 (4.94) 658 (16.67) 1002 (25.39) 1066 (27.01) 1213 (30.73) 228 (5.78) 2177 (55.16) 829 (21) 560 (14.19) 3888 (98.86) 45 (1.14) 2399 (60.78) 1532 (38.81) 1012 (25.64) 2935 (74.36) 88.6 (22.6185.2)e 480.9 (365.5627.6)e

Adjusted OR (95% CI)a

Reference 1.19 (1.081.31) Reference 2.67 (2.293.10) Reference 3.92 (3.284.68) Reference 0.98 (0.891.09) Reference 1.11 (0.961.28) 1.43 (1.181.73) Reference 0.97 (0.831.13) 0.90 (0.791.04) 1.05 (0.841.32) Reference 0.98 (0.851.14) 0.93 (0.801.08) 0.88 (0.751.02) 1.06 (0.861.30) Reference 1.11 (0.981.26) 1.37 (1.191.57) Reference 3.38 (2.394.79) Reference 0.93 (0.851.03) Reference 1.00 (0.901.12) 0.3221 0.0001

were adjusted for residence of mothers. show the rst-degree relative. c B1 to M3 is for 1 month before conception through 3 months after conception; B1 to M2 is 1 month before conception through 2 months after conception. d Data are from the Wilcoxon 2-sample test. e Data are median (interquartile range). f Dietary folate intake is energy-adjusted intake in dietary folate equivalents.

Infant and maternal characteristics of case and control participants are presented in Table 2. There were no signicant differences between case and control participants with respect to maternal education, race or ethnicity, parity, or alcohol use. However, mothers of infants with CHDs were more likely to be 35 years of age (OR: 1.43; 95% CI: 1.18 1.73) and obese (OR: 1.37; 95% CI: 1.19 1.57) and to have a lower dietary folate intake during the index pregnancy (460.5 g dietary folate equivalents) compared with mothers of control

infants (480.9 g dietary folate equivalents; P .0001). Infants with CHDs were more likely to be premature (OR: 2.67; 95% CI: 2.29 3.10) and more likely to be male (OR: 1.19; 95% CI: 1.08 1.31) than control infants. Infants with CHDs were more likely to be born with low birth weight than control infants (OR: 3.92; 95% CI: 3.28 4.68). Infants with CHDs were also more likely to have a family history of CHD in a rst-degree relative than controls (OR: 3.38; 95% CI: 2.39 4.79). The association between CHDs and maternal smoking
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TABLE 3 Reported Maternal Smoking by Highest Level of Reported Smoking in the Periconceptional Period From 1 Month Before Pregnancy Through the End of the First Trimester, National Birth Defects Prevention Study, 19972002
CHD Subtype Light Smoking No. of Case/ Control Infants Conotruncal defects Tetralogy of Fallot Dextrotransposed great arteries Double-outlet right ventricle Left ventricular outow tract obstructions Hypoplastic left heart syndrome Coarctation of the aorta Aortic stenosis Right ventricular outow tract obstructions Pulmonary valve stenosis Septal defects Ventricular septal defects Atrial septal defects Atrioventricular septal defects Anomalous pulmonary venous return Total anomalous pulmonary venous return 100/522 41/522 39/522 8/522 69/522 25/522 29/522 13/522 79/522 58/458 203/458 93/458 69/458 13/522 14/522 11/522 Adjusted OR (95% CI)a,b 1.06 (0.821.35) 1.03 (0.711.48) 1.08 (0.731.58) 1.01 (0.442.34) 0.99 (0.741.32) 1.09 (0.691.72) 1.03 (0.671.57) 0.81 (0.421.55) 1.25 (0.951.65) 1.24 (0.901.70) 1.44 (1.181.76) 1.30 (1.001.69) 2.02 (1.472.77) 1.02 (0.531.97) 1.19 (0.642.19) 1.05 (0.532.08) Medium Smoking No. of Cases/ Control Infants 33/204 9/204 13/204 7/204 27/204 9/204 8/204 7/204 23/204 17/190 76/190 35/190 22/190 11/204 7/204 7/204 Adjusted OR (95% CI)a,b 0.84 (0.561.27) 0.62 (0.311.26) 0.79 (0.421.48) 2.15 (0.835.61) 0.89 (0.571.38) 0.94 (0.451.94) 0.69 (0.331.47) 0.87 (0.382.02) 0.93 (0.591.49) 0.91 (0.531.55) 1.50 (1.112.03) 1.33 (0.892.00) 1.78 (1.053.01) 2.18 (1.044.55) 1.52 (0.653.59) 1.64 (0.683.95) Heavy Smoking No. of Case/ Control Infants 8/47 3/47 4/47 1/47 7/47 4/47 1/47 1/47 13/47 10/45 23/45 10/45 6/45 2/47 1/47 1/47 Adjusted OR (95% CI)a,b 0.97 (0.442.12) 1.01 (0.303.38) 1.19 (0.413.49) 1.51 (0.1912.2) 0.93 (0.382.26) 1.57 (0.465.40) 0.41 (0.063.09) 0.52 (0.074.04) 2.35 (1.214.53) 2.31 (1.114.83) 2.06 (1.203.54) 1.68 (0.823.47) 2.35 (0.926.00) 2.01 (0.449.12) 1.10 (0.148.58) 1.19 (0.159.37)

Smoking levels are as follows: light, less than half a pack per day, 1 to 14 cigarettes per day; medium, 1 pack per day, 15 to 24 cigarettes per day; heavy, 25 cigarettes per day. a ORs were adjusted for infant gender, maternal age, race, BMI, drinking from 1 month before through 3 months after conception, folic acid intake from 1 month before through 2 months after conception, dietary folate intake in dietary folate equivalents (energy adjusted), caffeine intake, family history of heart defect, and residence of mothers. b For CI, the number of control infants was lower for septal and right heart obstructive defects, because 1 center enrolled case infants with pulmonary valve stenosis or septal defects only during part of the study period; case and control subjects from this center were not included for these CHD subtypes.

was analyzed for each group of heart defect subtypes (Table 3). Women who had infants with septal heart defects were more likely than women who had infants without birth defects to have reported smoking at some time during the month before pregnancy through the end of the rst trimester. This association was seen with both ASDs and VSDs and was independent of potential confounding factors, such as prepregnancy vitamin use, folic acid intake, alcohol intake, family history of CHD, mothers race or ethnicity, and maternal age. This association was also signicant for each month studied from 1 month before conception to each month in the rst trimester and for septal heart defects that were isolated as well as associated with a second heart defect (data not shown). There was a stronger association for septal defects in infants exposed to medium and heavy smoking compared with light smoking exposure (OR for septal defects in heavy smokers: 2.06; 95% CI: 1.20 3.54). A maternal history of smoking an average of 25 cigarettes per day was associated with right-sided obstructive defects, specically pulmonary valve stenosis. No association with CHDs was seen for mothers exposed to ETS at home or in the workplace. There was no increase in ORs among mothers who smoked and were also exposed to others who smoked compared with mothers who smoked but were not exposed to smoke from others (data not shown). DISCUSSION The ndings of this population-based, case-control study suggest that mothers who had infants with septal heart defects were more likely to have smoked in the periconceptional period than control mothers. This estimated
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relative risk increased with the number of cigarettes smoked. These ndings are consistent with a Swedish population-based, case-control study that showed an increased risk of ASDs in infants of mothers who smoked (OR: 1.63; 95% CI: 1.04 2.57) compared with nonsmoking mothers.28 Our ndings were based on participants in the NBDPS, which represents the largest population-based, case-control study of major cardiovascular malformations conducted in the United States. To date, 7864 women who have had infants with CHDs have been interviewed, and 6768 control mothers have been interviewed; the NBDPS is ongoing at 9 sites. The NBDPS uses a structured maternal questionnaire to provide detailed information regarding lifestyle exposures. Uniform criteria for clinical conrmation of a cardiac defect and a rigorous review of abstracted medical chart data by an expert panel of clinicians maximize homogeneity of case classication. Limitations of the NBDPS and our analyses of data from this study must be considered. The sample sizes when stratied by number of cigarettes smoked were limited, reducing the power to detect dose-response relationships among some less frequent CHD phenotypes. The risk estimates were adjusted for multiple covariates. However, some residual confounding could not be excluded. Exposure to ETS was determined by maternal self-reports, without independent biochemical validation. Associations such as those found in this study could also arise if mothers of affected infants are more likely to underreport smoking cigarettes (and the number of cigarettes smoked) than mothers of unaffected infants.4144 However, if such reporting bias were operating, one might expect to nd a consistently decreased risk for all types of

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heart defects and possibly across different levels of smoking; neither pattern of ndings was observed in this study. Also, questionnaire items used to identify women exposed to ETS did not include questions about the amount of smoke exposure in the home, workplace, or both. Although a study by Wasserman et al30 revealed an increased risk of conotruncal malformations associated with paternal smoking, the NBDPS questionnaire did not include separate items for paternal smoking, because the items regarding passive smoking did not require the respondent to indicate who smoked. Future studies identifying both maternal and fetal genetic susceptibilities that could modify the harmful effects of tobacco on the developing fetus are needed. Some individuals are more susceptible to the adverse effects of tobacco exposure than others. Genetic polymorphisms in the nitric oxide synthase (NOS) gene are associated with birth defects including cleft lip, cleft palate, or both; gastroschisis; and limb deciency defects.4547 Shaw et al48 studied single nucleotide polymorphisms in the NOS3 gene among infants enrolled in a California population-based registry. Infants who had conotruncal defects were more likely to carry the variant alleles for NOS3 (922AG), NOS3 (298GT), or both and to have mothers who smoked cigarettes periconceptionally compared with control infants.48 The gene-environment interaction reported by Shaw et al48 illustrates the importance of additional investigations of the associations among CHDs, maternal smoking, and genetic variants that modify the effect of smoking on developing hearts. We believe that the results of our study have important public health consequences. The US Public Health Service objectives as described in Healthy People 2010 include smoking abstinence in 98% of pregnant women by 2010.49 In our study, 19% of control women reported smoking during the periconceptional period, which is consistent with national gures.50,51 If even a fraction of CHDs and other birth defects could be prevented by decreasing maternal tobacco use, it would result in improved reproductive outcomes and a saving of millions of health care dollars.6 ACKNOWLEDGMENTS This project was supported by cooperative agreement No. U50/CCU613236 from the Centers for Disease Control and Prevention and by a grant from the National Institute of Child Health and Human Development No. 1R03HD05 0663-01A1. We thank Cynthia Bond, MA, and Connie Whitehead, CDC Editor, for assisting with the editing and article preparation. We also thank William Gabello, MA, and the University of Arkansas for Medical Sciences Ofce of Grants and Scientic Publications for editorial assistance during the preparation of this article. We appreciate and acknowledge the generous participation of the many study families who made this work possible. We also thank the staff and scientists at all of the participating sites of the National Birth Defects Prevention Study.

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Maternal Smoking and Congenital Heart Defects Sadia Malik, Mario A. Cleves, Margaret A. Honein, Paul A. Romitti, Lorenzo D. Botto, Shengping Yang, Charlotte A. Hobbs and and the National Birth Defects Prevention Study Pediatrics 2008;121;e810-e816 DOI: 10.1542/peds.2007-1519
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