Maternal Smoking and Congenital Heart Defects

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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 financial relationships relevant to this article to disclose.

What’s 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 out-comes 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 nonsyndromic congenital heart defects and their parents and 3947 infants without birth defects and their parents. Affected infants had ⱖ1 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, defined as 1 month before pregnancy through the first 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% confidence 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 preg-nancy to the end of the first trimester were more likely to have infants with septal heart defects than women who did not smoke during this time period. This associ-ation 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 smokedⱖ25 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 right-sided 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.

C

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.1–3Affected infants who survive often require repeated surgeries and lengthy hospitalizations, and many will have a lifetime of disability that imposes a significant burden on families.4,5In 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,7including 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, andⱕ20% continue to smoke during pregnancy.8,9Thus,1 million infants are prenatally exposed to cigarette smoke by maternal smoking each year.10There is now a growing body of evidence showing fetal susceptibility to chronic prenatal cigarette exposure affecting birth weight and congenital malformations.11–13 Animal studies have shown a small increased risk of neural tube defects with tobacco exposure.14Maternal tobacco use has been linked to intrauterine growth retardation, prematurity, perinatal mortality, and congenital malformations.15–20These

malfor-www.pediatrics.org/cgi/doi/10.1542/ peds.2007-1519

doi:10.1542/peds.2007-1519 The findings 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 ASD—atrial septal defect

NBDPS—National Birth Defects Prevention Study

VSD—ventricular septal defect OR— odds ratio

CI— confidence interval NOS—nitric 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

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mations include cleft lip, cleft palate, or both; limb re-duction defects; clubfoot; congenital urinary tract anom-alies; anal atresia; gastroschisis; central nervous system defects; and CHDs.21–26 A study of orofacial clefts dem-onstrated that the risk associated with maternal smoking increased with the number of cigarettes smoked.27

Few epidemiologic studies have specifically inves-tigated the association between CHDs and maternal smoking. In a Swedish population-based study, unad-justed 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 ⱖ34 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 al30found an increased risk of having an infant with conotruncal heart defects if both parents smoked from 1 month before pregnancy through the first trimester. The association between CHDs and ma-ternal workplace exposure to ETS has not been eval-uated.

The purpose of this study was to elucidate the asso-ciation between specific subtypes of CHDs and maternal periconceptional smoking and exposure to ETS by using the infrastructure of the National Birth Defects Preven-tion Study (NBDPS). The NBDPS is a populaPreven-tion-based, multicenter study that provides detailed classification of CHDs; state-of-the-art, interview-based exposure assess-ments; and information on multiple potential confound-ers and effect modificonfound-ers.31The 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.31,32Briefly, the NBDPS is an institu-tional 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 partici-pants born from October 1997 through December 2002. Case infants were identified 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 echocar-diogram, heart catheterization, or surgical or autopsy re-port before 1 year of age.

Control infants were infants who had no birth defects and were randomly selected from birth certificates or hospital discharge listings in the same states and during the same time period as the case infants. Case and con-trol mothers had to speak English or Spanish. Infants who were adopted or in foster care were ineligible.

Classification of Cardiac Defects

Each CHD case was reviewed by 1 of 4 NBDPS clinician case classifiers33and described as “simple,” “associated,” or “complex” on the basis of the defect’s complexity. The simple CHD category was used to describe either an isolated CHD or a well-defined single entity (eg, tetral-ogy of Fallot). The associated CHD category described case infants withⱖ2 distinct CHDs (eg, transposition of the great vessels with outflow tract obstruction). All of the CHDs that includedⱖ3 cardiac defects were consid-ered complex. Complex heart defects composed only 7.8% and did not provide sufficient power to test study hypotheses.

Cardiac defects were classified into major categories based on the anatomic lesion: (1) conotruncal, including transposition of the great arteries, tetralogy of Fallot, trun-cus 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 ste-nosis, pulmonary atresia, tricuspid atresia, and Ebstein anomaly; (4) left-sided obstructive, including aortic valve stenosis, hypoplastic left heart syndrome and vari-ants, coarctation of the aorta, and interrupted aortic arch types A and C; (5) anomalous pulmonary venous return, including total and partial anomalous pulmonary ve-nous return; and (6) atrioventricular septal defects. All of the centers collected data on eligible defects through-out 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 oc-curred 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 periconcep-tional exposures, including questions about pregnancy his-tory; 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 determin-ing those who reported smokdetermin-ing anytime from 1 month before conception through each month of pregnancy. Par-ticipants 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 preg-nancy 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 first trimester.

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paternal race or ethnicity; and maternal alcohol use, heavy caffeine use (averageⱖ4 cups of coffee per day), parity, BMI, race or ethnicity, age, education, gestational diabetes or hypertension, use of lithium or folate antag-onists,34 and prepregnancy vitamin use and folic acid intake.35–37 The sources of reported folate/folic-acid in-take were diet, food supplements, and vitamin supple-ments. Mothers provided data on use of vitamins, break-fast cereals, and food supplements during the periconceptional period. Dietary intake data were as-sessed for the year preceding pregnancy.38

Statistical Analysis

The goal of this study was to assess the associations between infant CHD occurrence and maternal pericon-ceptional reports of smoking and exposure to ETS. The frequencies of smoking and exposure to ETS were inde-pendently computed for control infants, CHD case in-fants, and each CHD subtype. Smokers were divided

based on previous studies into light (1–14 cigarettes a day), medium (15–24 cigarettes a day), and heavy smok-ers (ⱖ25 cigarettes a day).39,40 Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated to evaluate these associations. We assessed the associations by computing crude ORs in global and stratified analyses and subsequently using linear logistic regression to in-clude potential confounding variables. Inclusion of po-tential 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 Mann-WhitneyU/Wilcoxon rank-sum test. Analyses were per-formed 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 in-fants) 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 pre-conceptional 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 first year of the NBDPS. In addition, 35 case and 15 control infants were excluded because they were missing information on smoking exposure. The final sample con-sisted 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.

3326 cases 3982 controls

3240 cases 3962 controls

3102 cases 3962 controls

Exclude muscular VSDs Exclude preconceptional diabetes

Exclude incomplete interviews

3067 final cases

3947 final controls

FIGURE 1

NBDPS case and control analyses.

TABLE 1 Frequencies of CHD Subtypes, National Birth Defects Prevention Study, 1997–2002

CHD Subtype Simple

(N⫽2519),n(%)

Associated (N⫽548),n(%)

Total (N⫽3067),n(%)a

Septal defects 873 (34.66) 356 (64.96) 1229 (40.07)

Ventricular septal defects, perimembranous 440 (17.47) 144 (26.28) 584 (19.04) Atrial septal defects, secundum 308 (12.23) 30 (5.47) 338 (11.02)

Conotruncal defects 646 (25.65) 103 (18.80) 749 (24.42)

Tetralogy of Fallot 312 (12.39) 3 (0.55) 315 (10.27)

Dextrotransposition of the great arteries 236 (9.37) 38 (6.93) 274 (8.93) Double-outlet right ventricle 30 (1.19) 39 (7.12) 69 (2.25) Left ventricular outflow tract obstructions 429 (17.03) 121 (22.08) 550 (17.93)

Hypoplastic left-heart syndrome 186 (7.38) 3 (0.55) 189 (6.16) Coarctation of the aorta 156 (6.19) 74 (13.50) 230 (7.50)

Aortic stenosis 81 (3.22) 25 (4.56) 106 (3.46)

Right ventricular outflow tract obstructions 416 (16.51) 131 (23.91) 547 (17.84) Pulmonic valve stenosis 299 (11.87) 87 (15.88) 386 (12.59)

Pulmonary atresia 55 (2.18) 6 (1.09) 61 (1.99)

Atrioventricular septal defect 60 (2.38) 27 (4.93) 87 (2.84) Anomalous pulmonary venous return 95 (3.77) 8 (1.46) 103 (3.36) Total anomalous pulmonary venous return 80 (3.18) 7 (1.28) 87 (2.84)

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Infant and maternal characteristics of case and control participants are presented in Table 2. There were no significant differences between case and control partici-pants with respect to maternal education, race or eth-nicity, parity, or alcohol use. However, mothers of in-fants with CHDs were more likely to beⱖ35 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 in-fants. 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 first-degree relative than controls (OR: 3.38; 95% CI: 2.39 – 4.79).

The association between CHDs and maternal smoking TABLE 2 Characteristics of Case and Control Participants, National Birth Defects Prevention Study,

1997–2002

Variable Case Participants

(N⫽3067),n(%)

Control Participants (N⫽3947),n(%)

Adjusted OR (95% CI)a

Gender

Female 1412 (46.04) 1971 (49.94) Reference

Male 1655 (53.96) 1976 (50.06) 1.19 (1.08–1.31)

Gestational age

Term or postterm (ⱖ37 wk) 2494 (81.32) 3642 (92.27) Reference Very preterm or preterm (⬍37 wk) 570 (18.58) 302 (7.65) 2.67 (2.29–3.10) Birth weight

Normal or macrosomic (ⱖ2.5 kg) 2544 (82.95) 3746 (94.91) Reference

Low (⬍2.5 kg) 506 (16.5) 181 (4.59) 3.92 (3.28–4.68)

Parity

Primipara 1213 (39.55) 1568 (39.73) Reference

Multipara 1540 (50.21) 2060 (52.19) 0.98 (0.89–1.09)

Maternal age

⬍20 y 410 (13.37) 576 (14.59) Reference

20–34 y 2227 (72.61) 2930 (74.23) 1.11 (0.96–1.28)

ⱖ35 y 430 (14.02) 441 (11.17) 1.43 (1.18–1.73)

Maternal race

White, non-Hispanic 1891 (61.66) 2363 (59.87) Reference Black, non-Hispanic 397 (12.94) 468 (11.86) 0.97 (0.83–1.13)

Hispanic 628 (20.48) 910 (23.06) 0.90 (0.79–1.04)

Others 147 (4.79) 195 (4.94) 1.05 (0.84–1.32)

Maternal education

Less than high school 518 (16.89) 658 (16.67) Reference High school completed 832 (27.13) 1002 (25.39) 0.98 (0.85–1.14) College education 812 (26.48) 1066 (27.01) 0.93 (0.80–1.08) Master’s degree or higher 904 (29.48) 1213 (30.73) 0.88 (0.75–1.02) BMI, kg/m2

Underweight (⬍18.5) 177 (5.77) 228 (5.78) 1.06 (0.86–1.30) Normal (ⱖ18.5 and⬍25.0) 1570 (51.19) 2177 (55.16) Reference Overweight (ⱖ25.0 to⬍30.0) 656 (21.39) 829 (21) 1.11 (0.98–1.26) Obese (ⱖ30.0) 551 (17.97) 560 (14.19) 1.37 (1.19–1.57) Family history of heart defectb

No 2947 (96.24) 3888 (98.86) Reference

Yes 115 (3.76) 45 (1.14) 3.38 (2.39–4.79)

Maternal alcohol use b1 to m3c

No 1904 (62.08) 2399 (60.78) Reference

Yes 1141 (37.2) 1532 (38.81) 0.93 (0.85–1.03)

Folic acid intake b1 to m2c

No 783 (25.53) 1012 (25.64) Reference

Yes 2284 (74.47) 2935 (74.36) 1.00 (0.90–1.12)

Caffeine intake, mg/dd 91.2 (30.2–185.4)e 88.6 (22.6–185.2)e 0.3221

Dietary folate intake,␮g/dd,f 460.5 (350.0–598.7)e 480.9 (365.5–627.6)e 0.0001

aORs were adjusted for residence of mothers. bData show the first-degree relative.

cB1 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.

dData are from the Wilcoxon 2-sample test. eData are median (interquartile range).

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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 first 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, mother’s race or ethnicity, and maternal age. This asso-ciation was also significant for each month studied from 1 month before conception to each month in the first 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 com-pared 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 ofⱖ25 cigarettes per day was associated with right-sided obstructive defects, spe-cifically pulmonary valve stenosis.

No association with CHDs was seen for mothers ex-posed 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 findings 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 pericon-ceptional period than control mothers. This estimated

relative risk increased with the number of cigarettes smoked. These findings are consistent with a Swedish population-based, case-control study that showed an in-creased risk of ASDs in infants of mothers who smoked (OR: 1.63; 95% CI: 1.04 –2.57) compared with non-smoking mothers.28

Our findings were based on participants in the NBDPS, which represents the largest population-based, case-trol study of major cardiovascular malformations con-ducted 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 confirma-tion of a cardiac defect and a rigorous review of abstracted medical chart data by an expert panel of clinicians maxi-mize homogeneity of case classification.

Limitations of the NBDPS and our analyses of data from this study must be considered. The sample sizes when stratified by number of cigarettes smoked were limited, reducing the power to detect dose-response relationships among some less frequent CHD pheno-types. The risk estimates were adjusted for multiple covariates. However, some residual confounding could not be excluded. Exposure to ETS was deter-mined 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 smok-ing cigarettes (and the number of cigarettes smoked) than mothers of unaffected infants.41–44 However, if such reporting bias were operating, one might expect to find a consistently decreased risk for all types of 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, 1997–2002

CHD Subtype Light Smoking Medium Smoking Heavy Smoking

No. of Case/ Control Infants

Adjusted OR (95% CI)a,b

No. of Cases/ Control Infants

Adjusted OR (95% CI)a,b

No. of Case/ Control Infants

Adjusted OR (95% CI)a,b

Conotruncal defects 100/522 1.06 (0.82–1.35) 33/204 0.84 (0.56–1.27) 8/47 0.97 (0.44–2.12) Tetralogy of Fallot 41/522 1.03 (0.71–1.48) 9/204 0.62 (0.31–1.26) 3/47 1.01 (0.30–3.38) Dextrotransposed great arteries 39/522 1.08 (0.73–1.58) 13/204 0.79 (0.42–1.48) 4/47 1.19 (0.41–3.49) Double-outlet right ventricle 8/522 1.01 (0.44–2.34) 7/204 2.15 (0.83–5.61) 1/47 1.51 (0.19–12.2) Left ventricular outflow tract obstructions 69/522 0.99 (0.74–1.32) 27/204 0.89 (0.57–1.38) 7/47 0.93 (0.38–2.26) Hypoplastic left heart syndrome 25/522 1.09 (0.69–1.72) 9/204 0.94 (0.45–1.94) 4/47 1.57 (0.46–5.40) Coarctation of the aorta 29/522 1.03 (0.67–1.57) 8/204 0.69 (0.33–1.47) 1/47 0.41 (0.06–3.09) Aortic stenosis 13/522 0.81 (0.42–1.55) 7/204 0.87 (0.38–2.02) 1/47 0.52 (0.07–4.04) Right ventricular outflow tract obstructions 79/522 1.25 (0.95–1.65) 23/204 0.93 (0.59–1.49) 13/47 2.35 (1.21–4.53) Pulmonary valve stenosis 58/458 1.24 (0.90–1.70) 17/190 0.91 (0.53–1.55) 10/45 2.31 (1.11–4.83) Septal defects 203/458 1.44 (1.18–1.76) 76/190 1.50 (1.11–2.03) 23/45 2.06 (1.20–3.54) Ventricular septal defects 93/458 1.30 (1.00–1.69) 35/190 1.33 (0.89–2.00) 10/45 1.68 (0.82–3.47) Atrial septal defects 69/458 2.02 (1.47–2.77) 22/190 1.78 (1.05–3.01) 6/45 2.35 (0.92–6.00) Atrioventricular septal defects 13/522 1.02 (0.53–1.97) 11/204 2.18 (1.04–4.55) 2/47 2.01 (0.44–9.12) Anomalous pulmonary venous return 14/522 1.19 (0.64–2.19) 7/204 1.52 (0.65–3.59) 1/47 1.10 (0.14–8.58) Total anomalous pulmonary venous return 11/522 1.05 (0.53–2.08) 7/204 1.64 (0.68–3.95) 1/47 1.19 (0.15–9.37)

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,ⱖ25 cigarettes per day.

aORs 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.

bFor 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

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heart defects and possibly across different levels of smoking; neither pattern of findings 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 al30revealed an increased risk of conotruncal mal-formations associated with paternal smoking, the NB-DPS 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 ge-netic susceptibilities that could modify the harmful effects of tobacco on the developing fetus are needed. Some indi-viduals are more susceptible to the adverse effects of to-bacco 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 deficiency defects.45–47Shaw et al48studied single nucleotide polymorphisms in the NOS3 gene among in-fants enrolled in a California population-based registry. Infants who had conotruncal defects were more likely to carry the variant alleles for NOS3 (922A⬎G), NOS3 (298G⬎T), or both and to have mothers who smoked cigarettes periconceptionally compared with control in-fants.48 The gene-environment interaction reported by Shaw et al48illustrates the importance of additional inves-tigations of the associations among CHDs, maternal smok-ing, and genetic variants that modify the effect of smoking on developing hearts.

We believe that the results of our study have impor-tant public health consequences. The US Public Health Service objectives as described in Healthy People 2010 include smoking abstinence in 98% of pregnant women by 2010.49In our study, 19% of control women reported smoking during the periconceptional period, which is consistent with national figures.50,51If even a fraction of CHDs and other birth defects could be prevented by decreasing maternal tobacco use, it would result in im-proved 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 prep-aration. We also thank William Gabello, MA, and the Uni-versity of Arkansas for Medical Sciences Office of Grants and Scientific Publications for editorial assistance during the preparation of this article. We appreciate and acknowl-edge 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.

REFERENCES

1. Cleves MA, Ghaffar S, Zhao W, Mosley BS, Hobbs CA. First-year survival of infants born with congenital heart defects in Arkansas (1993–1998): a survival analysis using registry data. Birth Defects Res Part A Clin Mol Teratol.2003;67(9):662– 668 2. Boneva RS, Botto LD, Moore CA, Yang Q, Correa A, Erickson

JD. Mortality associated with congenital heart defects in the United States: trends and racial disparities, 1979 –1997. Circu-lation.2001;103(19):2376 –2381

3. Moller JH, Allen HD, Clark EB, et al. Report of the task force on children and youth. American Heart Association.Circulation. 1993;88(5 pt 1):2479 –2486

4. Nembhard WN, Waller DK, Sever LE, Canfield MA. Patterns of first-year survival among infants with selected congenital anom-alies in Texas, 1995–1997.Teratology.2001;64(5):267–275 5. Tilford JM, Robbins JM, Hobbs CA. Improving estimates of

caregiver time cost and family impact associated with birth defects.Teratology.2001;64(suppl 1):S37–S41

6. Waitzman NJ, Romano PS, Scheffler RM. Estimates of the economic costs of birth defects.Inquiry.1994;31(2):188 –205 7. Woods SE, Raju U. Maternal smoking and the risk of congenital

birth defects: a cohort study.J Am Board Fam Pract.2001;14(5): 330 –334

8. Ebrahim SH, Floyd RL, Merritt RK 2nd, Decoufle P, Holtzman D. Trends in pregnancy-related smoking rates in the United States, 1987–1996.JAMA.2000;283(3):361–366

9. Colman GJ, Joyce T. Trends in smoking before, during, and after pregnancy in ten states.Am J Prev Med.2003;24(1):29 –35 10. Byrd RS, Howard CR. Children’s passive and prenatal exposure

to cigarette smoke.Pediatr Ann.1995;24(12):640 – 642, 4 –5 11. Koren G. Fetal toxicology of environmental tobacco smoke.

Curr Opin Pediatr.1995;7(2):128 –131

12. Jaakkola JJ, Jaakkola N, Zahlsen K. Fetal growth and length of gestation in relation to prenatal exposure to environmental tobacco smoke assessed by hair nicotine concentration.Environ Health Perspect.2001;109(6):557–561

13. Hong YC, Lee KH, Son BK, Ha EH, Moon HS, Ha M. Effects of the GSTM1 and GSTT1 polymorphisms on the relationship between maternal exposure to environmental tobacco smoke and neona-tal birth weight.J Occup Environ Med.2003;45(5):492– 498 14. Seller MJ, Bnait KS. Effects of tobacco smoke inhalation on the

developing mouse embryo and fetus.Reprod Toxicol.1995;9(5): 449 – 459

15. Khoury MJ, Gomez-Farias M, Mulinare J. Does maternal cig-arette smoking during pregnancy cause cleft lip and palate in offspring?Am J Dis Child.1989;143(3):333–337

16. Secker-Walker RH, Vacek PM. Relationships between cigarette smoking during pregnancy, gestational age, maternal weight gain, and infant birthweight.Addict Behav.2003;28(1):55– 66 17. Misra DP, Nguyen RH. Environmental tobacco smoke and low

birth weight: a hazard in the workplace?Environ Health Per-spect.1999;107(suppl 6):897–904

18. Dejin-Karlsson E, Hanson BS, Ostergren PO, Sjoberg NO, Mar-sal K. Does passive smoking in early pregnancy increase the risk of small-for-gestational-age infants?Am J Public Health. 1998;88(10):1523–1527

19. English PB, Eskenazi B. Reinterpreting the effects of maternal smoking on infant birthweight and perinatal mortality: a mul-tivariate approach to birthweight standardization.Int J Epide-miol.1992;21(6):1097–1105

20. Nielsen A, Hannibal CG, Lindekilde BE, et al. Maternal smok-ing predicts the risk of spontaneous abortion.Acta Obstet Gynecol Scand.2006;85(9):1057–1065

21. Ericson A, Kallen B, Westerholm P. Cigarette smoking as an etiologic factor in cleft lip and palate. Am J Obstet Gynecol. 1979;135(3):348 –351

(7)

Congen-ital heart defects and abnormal maternal biomarkers of methi-onine and homocysteine metabolism.Am J Clin Nutr. 2005; 81(1):147–153

23. Honein MA, Paulozzi LJ, Moore CA. Family history, maternal smoking, and clubfoot: an indication of a gene-environment interaction.Am J Epidemiol.2000;152(7):658 – 665

24. Honein MA, Paulozzi LJ, Watkins ML. Maternal smoking and birth defects: validity of birth certificate data for effect estima-tion.Public Health Rep.2001;116(4):327–335

25. Li DK, Mueller BA, Hickok DE, et al. Maternal smoking during pregnancy and the risk of congenital urinary tract anomalies. Am J Public Health.1996;86(2):249 –253

26. Yuan P, Okazaki I, Kuroki Y. Anal atresia: effect of smoking and drinking habits during pregnancy.Jpn J Hum Genet.1995; 40(4):327–332

27. Chung KC, Kowalski CP, Kim HM, Buchman SR. Maternal cig-arette smoking during pregnancy and the risk of having a child with cleft lip/palate.Plast Reconstr Surg.2000;105(2):485– 491 28. Ka¨lle´n K. Maternal smoking and congenital heart defects.Eur

J Epidemiol.1999;15(8):731–737

29. Ferencz C, Loffredo C, Correa-Villasenor A, Wilson PD.Genetic and Environmental Risk Factors of Major Cardiovascular Malformations: The Baltimore-Washington Infant Study 1981–1989. Armonk, NY: Futura Publishing Co, Inc; 1997

30. Wasserman CR, Shaw GM, O’Malley CD, Tolarova MM, Lam-mer EJ. Parental cigarette smoking and risk for congenital anomalies of the heart, neural tube, or limb.Teratology.1996; 53(4):261–267

31. Yoon PW, Rasmussen SA, Lynberg MC, et al. The National Birth Defects Prevention Study. Public Health Rep. 2001; 116(suppl 1):32– 40

32. Rasmussen SA, Olney RS, Holmes LB, Lin AE, Keppler-Noreuil KM, Moore CA. Guidelines for case classification for the Na-tional Birth Defects Prevention Study.Birth Defects Res Part A Clin Mol Teratol.2003;67(3):193–201

33. Botto LD, Lin AE, Riehle-Colarusso T, Malik S, Correa A, National Birth Defects Prevention Study. Seeking causes: Clas-sifying and evaluating cogenital heart defects in etiologic stud-ies.Birth Defects Res A Clin Mol Teratol.2007;79(10):714 –727 34. Herna´ndez-Dı´az S, Werler MM, Walker AM, Mitchell AA. Folic

acid antagonists during pregnancy and the risk of birth defects. N Engl J Med.2000;343(22):1608 –1614

35. McDonald SD, Perkins SL, Jodouin CA, Walker MC. Folate levels in pregnant women who smoke: an important gene/environment in-teraction.Am J Obstet Gynecol.2002;187(3):620–625

36. David SP, Eaton CB. Comment on “The public health implica-tions of smoking-induced decreased serum and red blood cell folate levels.” Nicotine Tob Res.2003;5(3):397–399

37. Ortega RM, Requejo AM, Lopez-Sobaler AM, et al. Smoking and passive smoking as conditioners of folate status in young women.J Am Coll Nutr.2004;23(4):365–371

38. Willett WC, Sampson L, Stampfer MJ, et al. Reproducibility and validity of a semiquantitative food frequency question-naire.Am J Epidemiol.1985;122(1):51– 65

39. Michael YL, Colditz GA, Coakley E, Kawachi I. Health behaviors, social networks, and healthy aging: cross-sectional evidence from the Nurses’ Health Study.Qual Life Res.1999;8(8):711–722 40. Honein MA, Rasmussen SA, Reefhuis J, et al. Maternal

smok-ing and environmental tobacco smoke exposure and the risk of orofacial clefts.Epidemiology.2007;18(2):226 –233

41. Czeizel AE, Petik D, Puho E. Smoking and alcohol drinking during pregnancy: the reliability of retrospective maternal self-reported information. Cent Eur J Public Health. 2004;12(4): 179 –183

42. Khoury MJ, James LM, Erickson JD. On the use of affected controls to address recall bias in case-control studies of birth defects.Teratology.1994;49(4):273–281

43. Lieff S, Olshan AF, Werler M, Savitz DA, Mitchell AA. Selec-tion bias and the use of controls with malformaSelec-tions in case-control studies of birth defects. Epidemiology. 1999;10(3): 238 –241

44. Swan SH, Shaw GM, Schulman J. Reporting and selection bias in case-control studies of congenital malformations. Epidemiol-ogy.1992;3(4):356 –363

45. Torfs CP, Christianson RE, Iovannisci DM, Shaw GM, Lammer EJ. Selected gene polymorphisms and their interaction with maternal smoking, as risk factors for gastroschisis.Birth Defects Res Part A Clin Mol Teratol.2006;76(10):723–730

46. Carmichael SL, Shaw GM, Yang W, Iovannisci DM, Lammer E. Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake.Am J Med Genet.2006;140(8): 1915–1922

47. Shaw GM, Iovannisci DM, Yang W, et al. Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts.Am J Epidemiol. 2005;162(12):1207–1214

48. Shaw GM, Iovannisci DM, Yang W, et al. Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes.Am J Med Genet.2005;138(1):21–26

49. US Department of Health and Human Services.Healthy People 2010: Understanding and Improving Health. 2nd ed. Washington, DC: US Government Printing Office; 2000

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DOI: 10.1542/peds.2007-1519

2008;121;e810

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Sadia Malik, Mario A. Cleves, Margaret A. Honein, Paul A. Romitti, Lorenzo D.

Maternal Smoking and Congenital Heart Defects

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Figure

FIGURE 1NBDPS case and control analyses.

FIGURE 1NBDPS

case and control analyses. p.3
TABLE 1Frequencies of CHD Subtypes, National Birth Defects Prevention Study, 1997–2002

TABLE 1Frequencies

of CHD Subtypes, National Birth Defects Prevention Study, 1997–2002 p.3
TABLE 2Characteristics of Case and Control Participants, National Birth Defects Prevention Study,1997–2002

TABLE 2Characteristics

of Case and Control Participants, National Birth Defects Prevention Study,1997–2002 p.4
TABLE 3Reported Maternal Smoking by Highest Level of Reported Smoking in the Periconceptional Period From 1 Month Before PregnancyThrough the End of the First Trimester, National Birth Defects Prevention Study, 1997–2002

TABLE 3Reported

Maternal Smoking by Highest Level of Reported Smoking in the Periconceptional Period From 1 Month Before PregnancyThrough the End of the First Trimester, National Birth Defects Prevention Study, 1997–2002 p.5