## Abstract

BACKGROUND

There is uncertainty over whether maternal smoking is associated with birth defects. We conducted the first ever comprehensive systematic review to establish which specific malformations are associated with smoking.

METHODS

Observational studies published 1959–2010 were identified (Medline), and included if they reported the odds ratio (OR) for having a non-chromosomal birth defect among women who smoked during pregnancy compared with non-smokers. ORs adjusted for potential confounders were extracted (e.g. maternal age and alcohol), otherwise unadjusted estimates were used. One hundred and seventy-two articles were used in the meta-analyses: a total of 173 687 malformed cases and 11 674 332 unaffected controls.

RESULTS

Significant positive associations with maternal smoking were found for: cardiovascular/heart defects [OR 1.09, 95% confidence interval (CI) 1.02–1.17]; musculoskeletal defects (OR 1.16, 95% CI 1.05–1.27); limb reduction defects (OR 1.26, 95% CI 1.15–1.39); missing/extra digits (OR 1.18, 95% CI 0.99–1.41); clubfoot (OR 1.28, 95% CI 1.10–1.47); craniosynostosis (OR 1.33, 95% CI 1.03–1.73); facial defects (OR 1.19, 95% CI 1.06–1.35); eye defects (OR 1.25, 95% CI 1.11–1.40); orofacial clefts (OR 1.28, 95% CI 1.20–1.36); gastrointestinal defects (OR 1.27, 95% CI 1.18–1.36); gastroschisis (OR 1.50, 95% CI 1.28–1.76); anal atresia (OR 1.20, 95% CI 1.06–1.36); hernia (OR 1.40, 95% CI 1.23–1.59); and undescended testes (OR 1.13, 95% CI 1.02–1.25). There was a reduced risk for hypospadias (OR 0.90, 95% CI 0.85–0.95) and skin defects (OR 0.82, 0.75–0.89). For all defects combined the OR was 1.01 (0.96–1.07), due to including defects with a reduced risk and those with no association (including chromosomal defects).

CONCLUSIONS

Birth defects that are positively associated with maternal smoking should now be included in public health educational materials to encourage more women to quit before or during pregnancy.

## Introduction

Maternal smoking during pregnancy is an established risk factor for miscarriage/perinatal mortality, low birthweight, premature births and small fetuses (DiFranza and Lew, 1995; Royal College of Physicians 2010; Shah and Bracken, 2000; US Surgeon General, 2001, 2004). The biological mechanisms of how tobacco smoke affect fetal development have been examined in extensive human and laboratory studies, which show that many of the 7000 chemicals can cross the placental barrier and have a direct harmful effect on the unborn baby (BMA, 2004; Werler et al., 1985; Quinton et al., 2008; Talbot, 2008; Rogers, 2009).

Despite the risks, many women still smoke during pregnancy; 17% in England and Wales (ONS, 2006) and 14% in the USA (Tong et al., 2009). The prevalence varies considerably with maternal age and educational/professional level. In the UK, the smoking prevalence during pregnancy was 45% among those aged <20 years compared with 9% in those aged ≥35 years; and 29% in those in routine/manual work, compared with 7% classified as managerial/professional (ONS, 2006). In the USA, 20% of pregnant women aged <25 years smoked versus 9% among those aged ≥35 years (Tong et al., 2009); and it was 22% in those with <12 years of education versus 6.5% with >12 years (Williams et al., 2006).

In England and Wales, 3759 babies were born with a non-chromosomal congenital anomaly in 2008; the five most common defects were of the heart/cardiovascular system (27%), limbs (22%), urinary (17%) and genital (11%) systems, and orofacial clefts (11%) (ONS, 2010). In the USA there are >120 000 babies born with a birth defect each year (March of Dimes, 2010): an annual incidence of 3% (Parker et al., 2010).

Relatively few public health educational materials mention birth defects as a possible outcome among pregnant women who smoke, and those that do are hardly ever specific. This is probably because of uncertainty over whether congenital defects are causally associated with maternal smoking. Surprisingly, despite research studies spanning 50 years, there has never been a comprehensive systematic review of smoking and congenital defects, except for orofacial clefts (Wyszynski et al., 1997; Little et al., 2004). The purpose of our review is to establish which specific defects are associated with maternal smoking.

## Methods

We conducted a systematic literature review of English articles published 1959 to February 2010 in Medline, using the PRISMA guidelines. The keywords used were (abnormalit$or defect$ or malformation$or anomal$ or deficienc$or gastroschisis or omphalocele or atresia or cleft or craniosynostosis or clubfoot/talipes equinovarus or cryptorchidism or hypospadias or spina bifida or anencephaly or strabismus or esotropia or exotropia or polydactyly or syndactyly or adactyly or finger$ or toe$) AND (birth$ or pregnanc$or infant$ or congenital or offspring) AND (maternal or mother$or women) AND (smok$ or cigarette$or factor$ or indicator$or exposure$). References were also checked with two US Surgeon General's reports (US Surgeon General, 2004, 2010). We also examined articles in Embase, and found no additional article to those already identified using the above searches.

Any full paper when the abstract referred to maternal smoking or risk factors was obtained. A total of 9328 abstracts were examined (S.B. and A.H. independently), and 768 full papers were obtained, including those identified from article references (see Supplementary data, Flow Chart Figure). The inclusion criteria were: any observational study based on women who smoked during pregnancy (the exposure); the article reported the odds ratio (OR) or relative risk of having a defect among pregnant smokers compared with non-smokers (the outcome), whether adjusted for confounding or not, or it provided data that allowed the calculation of the OR; and there must have been a control group (usually of unaffected births).

After excluding 91 articles that contained duplicate data, there were 177 eligible articles, of which 172 were included in the analyses, covering 101 different research studies. Five articles were not included in the analyses because all controls had malformations other than the one of interest (and so could possibly dilute an association with smoking). Instead, they are summarized in the Supplementary data, table footnotes.

S.B. and A.H. extracted design characteristics and data from each paper. The ORs were sometimes adjusted for potential confounders (e.g. maternal age), either in the reported statistical analysis or by using matched controls. Unadjusted estimates were used when adjusted ORs were unavailable. Of the 101 studies, the affected cases were: live births (n = 74), only stillbirths (n = 4) or mainly live births with some stillbirths or elective abortions (n = 23). In 12 studies the comparison group included all other births unaffected by the defect of interest (i.e. those without the defect plus those with other defects, though this is unlikely to affect the ORs because the vast majority did not have an anomaly, and would only slightly dilute an effect). In one study all controls had chromosomal defects. For several disorders, such as musculoskeletal defects, orofacial clefts and gastrointestinal disorders (e.g. gastroschisis and omphalocele), diagnoses were largely made at birth (or within the first week). However, for others, such as cardiovascular defects, craniosynostosis, facial defects (e.g. of the eye), other gastrointestinal defects, and genitourinary defects, many studies ascertained affected cases up to 1 year after birth or beyond, or when diagnoses were made in infancy (including referrals for corrective treatment).

The study designs were cohort, case–control or surveys. Important study characteristics for each defect are provided in the online supplementary data: such as geographical location, year of recruitment of study subjects, time period following birth during which cases were ascertained (for defects that might not be detected at birth), and matching or confounding factors allowed for. Maternal smoking status and other characteristics were obtained by questionnaires or interviews during early pregnancy (prospectively), or shortly after birth using surveys, interviews or birth certificates (retrospectively). The 101 studies were therefore classified as prospective cohort (n = 16), prospective case–control (n = 3), retrospective case–control (n = 62) or retrospective surveys (n = 20). Several case–control studies were matched for factors such as maternal age and birth year, while others without matching reported that characteristics of cases and controls were similar.

Analyses were conducted using a random effects model, allowing for heterogeneity (REVMAN, 2008), based on adjusted ORs from each study (allowing for a range of potential confounders; see Supplementary data), and if not available, the unadjusted estimate. In addition, analyses were performed using only the adjusted estimates, and also where at least allowance was made for maternal age and alcohol use (two main potential confounders). Further subgroup analyses were restricted to studies where smoking status was collected prospectively to avoid misreporting bias, in which smokers with an affected baby might be more likely to report themselves as non-smokers. Heterogeneity between studies was assessed by a test for heterogeneity and I2 (Higgins et al., 2003). Publication bias was examined using funnel plots.

## Results

The 172 reports together contain 173 687 cases with a congenital defect and 11 674 332 unaffected controls (see reference list for all 177 eligible articles). Figure 1 and Supplementary data, Table S1 summarizes the pooled ORs from the meta-analysis for each body system or specific defect, including ORs adjusted for potential confounders. Maternal smoking is associated with a significant increased risk for defects of the cardiovascular, musculoskeletal and gastrointestinal systems, the face including orofacial clefts, and cryptorchidism. There appears to be a decreased risk for hypospadias and skin defects among smokers. There is probably no association with defects of the genitourinary, respiratory or central nervous systems (CNS).

Figure 1

Summary of the meta-analyses for maternal smoking in pregnancy and birth defects. The pooled ORs are shown for each body system and specific defects (total number of malformed cases in brackets). CI: confidence interval *Umbilical, inguinal or ventral hernia. ‘Oesophageal fistula’ is ‘oesophageal atresia/tracheoesophageal fistula’.

Figure 1

Summary of the meta-analyses for maternal smoking in pregnancy and birth defects. The pooled ORs are shown for each body system and specific defects (total number of malformed cases in brackets). CI: confidence interval *Umbilical, inguinal or ventral hernia. ‘Oesophageal fistula’ is ‘oesophageal atresia/tracheoesophageal fistula’.

### Cardiovascular/heart defects

There is a modest (9%) but significant increased risk, OR 1.09 [95% confidence interval (CI) 1.02–1.17, P = 0.009] from 25 studies (29 288 malformed cases, 2.09 million controls); Supplementary data, Table S2a and Fig. 2a. Seven studies each had significant excess risks. The pooled OR from 19 studies of heart defects only is also 1.09 (Supplementary data, Table S2b and Fig. S1); 5 were statistically significant. When we restricted the analyses to only those studies that had at least 1-year follow-up to ascertain affected cases, the pooled OR was similar: 1.10 (95% CI 1.02–1.18).

Figure 2

Forest plots for (a) cardiovascular/heart defects (Kelsey 1978 had no standard error, OR = 1.08), (b) all musculoskeletal defects (two studies had no standard error: Kelsey 1978 OR = 0.93, and Hemminki 1981 OR = 1.35), (c) limb reduction defects, (d) digit anomaly (ie polydactyly, syndactyly and adactyly), (e) clubfoot (Kelsey 1978 had no standard error, OR = 1.22; and the pooled OR excluding Shiono 1986 Kaiser is 1.35, 95% CI 1.17–1.54), and (f) craniosynostosis. Studies are ranked according to size of the odds ratio.

Figure 2

Forest plots for (a) cardiovascular/heart defects (Kelsey 1978 had no standard error, OR = 1.08), (b) all musculoskeletal defects (two studies had no standard error: Kelsey 1978 OR = 0.93, and Hemminki 1981 OR = 1.35), (c) limb reduction defects, (d) digit anomaly (ie polydactyly, syndactyly and adactyly), (e) clubfoot (Kelsey 1978 had no standard error, OR = 1.22; and the pooled OR excluding Shiono 1986 Kaiser is 1.35, 95% CI 1.17–1.54), and (f) craniosynostosis. Studies are ranked according to size of the odds ratio.

It was not clear whether any specific heart anomaly (e.g. ventricular septal defects) had a greater association with maternal smoking. The study with the largest number of affected cases (n = 3067; Malik et al., 2008) suggested that the strongest effect could be on ventricular septal defects (OR 1.34, 95% CI 1.08–1.65), and atrial septal defects (OR 1.98, 95% CI 1.53–2.57). The ORs for other types were: 1.26 (right ventricular outflow tract obstruction), 0.96 (left ventricular outflow tract obstruction) and 1.00 (conotruncal defects).

### Musculoskeletal defects and craniosynostosis

Musculoskeletal defects include a range of problems associated with the muscles, bones and limbs. There is a significant 16% increase in risk associated with maternal smoking (OR 1.16, 95% CI 1.05–1.27, P = 0.002) from 25 studies (41 159 malformed cases, 1.2 million controls); Supplementary data, Table S3 and Fig. 2b. There was evidence of heterogeneity, but this was not present in some subgroup analyses. Six studies reported evidence of a dose–response relationship (Alderman et al., 1991; Czeizel et al., 1994; Honein et al., 2001; Skelly et al., 2002; Man and Chang, 2006; Parker et al., 2009).

Eight studies of limb reduction defects (2915 malformed cases, 2.4 million controls)—the absence or severe underdevelopment of the hands or feet (transverse limb reductions), or of the radius, tibia, ulna or fibula (longitudinal limb reductions)—all reported increased risks; Supplementary data, Table S4 and Fig. 2c. Two studies each had significant results (Czeizel et al. 1994; Kallen, 2000), one with a dose–response relationship (Czeizel et al., 1994). The excess risk is 26% (OR 1.26, 95% CI 1.15–1.39, P < 0.00001), and no heterogeneity (P = 0.44, I2 = 0%).

Among six studies of digit anomalies (missing, fused or extra fingers or toes; 14 150 malformed cases, 7.6 million controls), two were each significant, and the pooled OR is 1.18 (95% CI 0.99–1.41); Supplementary data, Table S5 and Fig. 2d.

Among 12 studies of clubfoot (15 673 malformed cases, 6.6 million controls) seven were statistically significant, but one with a decreased risk. Four reported evidence of a dose–response relationship (Alderman et al., 1991; Honein et al., 2001; Skelly et al., 2002; Parker et al., 2009). The pooled excess risk is 28% (OR 1.28, 95% CI 1.10–1.47, P = 0.0009); Supplementary data, Table S6 and Fig. 2e. However, examination of the five statistically significant positive studies suggests that the effect could be greater (≥40%).

Four studies of diaphragmatic hernia did not show an association with maternal smoking; Supplementary data, Table S7 and Fig. S2. The pooled OR is 0.94 (P = 0.63).

Craniosynostosis is where sutures of the skull have fused prematurely, deforming the shape of the head. Of the five studies (1131 malformed cases, 1.4 million controls), three were each significant, with evidence of a dose–response relationship (Alderman et al., 1994; Kallen, 1999; Honein and Rasmussen, 2000); Supplementary data, Table S8 and Fig. 2f. The pooled OR is 1.33 (95% CI 1.03–1.73, P = 0.03), with no heterogeneity (P = 0.09).

### Facial defects (face, eyes or ears)

Twelve studies together show a 19% increased risk of a facial defect (OR 1.19, 95% CI 1.06–1.35, P = 0.004), excluding orofacial clefts, and seven were each significant; Supplementary data, Table S9 and Fig. 3a (5876 malformed cases, 2.6 million controls). Two reported evidence of a dose–response relationship (Chew et al., 1994; Tornqvist et al., 2002). When results for eye defects only were examined (e.g. anophthalmia, microphthalmia, esotropia, exotropia and optic nerve hypoplasia), the excess risk is 25% (OR 1.25, 95% CI 1.11–1.40, P = 0.0001); Supplementary data, Table S10 and Fig. 3b. Five of the nine studies on eye defects (4541 malformed cases, 2.3 million controls) were each significant, and one reported evidence of a dose–response relationship (Chew et al., 1994).

Figure 3

Forest plots for (a) facial defects, (b) eye defects only, and (c) cleft lip or palate. Studies are ranked according to size of the odds ratio.

Figure 3

Forest plots for (a) facial defects, (b) eye defects only, and (c) cleft lip or palate. Studies are ranked according to size of the odds ratio.

Thirty-eight studies have examined the risk of cleft lip or palate (23 441 malformed cases, 8.1 million controls), and 13 were each significant. The pooled OR is 1.28 (95% CI 1.20–1.36, P < 0.00001); Supplementary data, Table S11 and Fig. 3c. Six reported evidence of a dose–response relationship (Khoury et al., 1987; Shaw et al., 1996a; Chung et al., 2000; Honein et al., 2001; Little et al., 2004; Shi et al., 2007). The effects of cleft lip and palate were not separated because a previous systematic review (25 cohort and case–control studies) indicated that the risks are not too dissimilar: pooled ORs were 1.34 (95% CI 1.25–1.44) for cleft lip, with or without cleft palate, and 1.22 (95% CI 1.10–1.35) for cleft palate alone (Little et al.; 2004).

### Defects of the gastrointestinal system

Gastrointestinal defects include abdominal wall defects and a range of abnormalities of the pharynx, oesophagus, intestine, colon, bile ducts, gallbladder and liver. Although there are 35 studies in the meta-analysis (11 580 malformed cases, 9.7 million controls), the degree of heterogeneity was not great (P = 0.02, I2 = 36%); Supplementary data, Table S12 and Fig. 4a. One reported evidence of a dose–response relationship (Chung and Myrianthopoulos, 1975). The excess risk is 27% (OR 1.27, 95% CI 1.18–1.36, P < 0.00001); or OR = 1.22 (95% CI 1.14–1.31) excluding gastroschisis/omphalocele.

Figure 4

Forest plots for (a) all gastrointestinal defects (Kelsey 1978 had no standard error, OR = 1.55), (b) gastroschisis, (c) anal atresia, (d) umbilical/ventral/inguinal hernias, (e) all genitourinary defects, and (f) cryptorchidism. Studies are ranked according to size of the odds ratio.

Figure 4

Forest plots for (a) all gastrointestinal defects (Kelsey 1978 had no standard error, OR = 1.55), (b) gastroschisis, (c) anal atresia, (d) umbilical/ventral/inguinal hernias, (e) all genitourinary defects, and (f) cryptorchidism. Studies are ranked according to size of the odds ratio.

Five specific types of defect could be reliably examined. There is a clear association with gastroschisis, OR 1.50 (95% CI 1.28–1.76), and P < 0.00001, from 12 studies (1822 malformed cases, 2.68 million controls); Supplementary data, Table S13, Fig. 4b). All but one showed an increased risk, and five studies were each significant. The effect on omphalocele is less and not statistically significant, OR 1.19 (95% CI 0.95–1.48), and P = 0.14 from seven studies; Supplementary data, Table S14 and Fig. S3.

There is an association with anal atresia (OR 1.20, 95% CI 1.06–1.36, and P = 0.005, from seven studies (1679 malformed cases, 7.8 million controls); Supplementary data, Table S15, Fig. 4c, and umbilical/inguinal/ventral hernias, OR 1.40 (95% CI 1.23–1.59, and P < 0.00001) from four studies, 941 malformed cases and 374 086 controls; Supplementary data, Table S16, Fig. 4d. All four studies of hernias showed an increased risk. There is no evidence for oesophageal atresia/tracheoesophageal fistula, OR 0.93 (95% CI 0.81–1.07 and P = 0.32) from seven studies, Supplementary data, Table S17 and Fig. S4.

### Defects of the genitourinary system

These defects included those of the genital organs, urinary bladder, kidney, ureter and urethra. When considered together, there does not seem to be a clear association with maternal smoking, OR 1.05 (95% CI 0.98–1.12, and P = 0.20), from 40 studies, with 24 081 malformed controls and 8.2 million controls; Supplementary data, Table S18, Fig. 4e. An analysis of non-specific genitourinary defects produced an OR of 1.02 95% CI 0.91–1.14); which became 0.93 (95% CI 0.84–1.04) when based only on studies that had at least 1-year follow-up during which cases were ascertained. The OR for the genital system alone is 1.01, 95% CI 0.93–1.10, P = 0.76 (based on 32 studies; Supplementary data, Table S19 and Fig. S5).

The OR for cryptorchidism (undescended testes), based on 18 studies (8753 malformed cases, 98 627 controls) is 1.13 (95% CI 1.02–1.25, P = 0.02); Supplementary data, Table S20, Fig. 4f.

There is a reduction in risk for hypospadias (abnormal urethra), based on 15 studies (12 047 malformed cases and 1.5 million controls); OR 0.90 (95% CI 0.85–0.95, P = 0.0004), with little heterogeneity, P = 0.28 and I2 = 16%. Two of the 15 studies on hypospadias were significant (Supplementary data, Table S21 and Fig. S6).

The pooled OR is 1.15, 95% CI 0.95–1.39, for renal/urinary tract defects, which is not statistically significant (P = 0.15 from 9 studies, 3330 malformed cases and 7.7 million controls; Supplementary data, Table S22 and Fig. S7).

### Defects of the CNS

When all CNS defects were considered together, there seems to be a modest excess risk; OR 1.10 (95% CI 1.01–1.19, P = 0.02); Supplementary data, Table S23 and Fig. S8a. Seven of the 29 studies (14 739 malformed cases, 8.2 million controls) were each significant, one with a decreased risk. However, among 17 studies of spina bifida and anencephaly (the most common CNS defects) there is no evidence of an association (5910 malformed cases, 7.9 million controls); OR 0.97, 95% CI 0.86–1.10, and P = 0.66; Supplementary data, Table S24 and Fig. S8b. While it is possible that there may be an effect of maternal smoking on some CNS defects, the evidence is not sufficiently clear.

### Defects of the respiratory system and skin

There were six studies of defects of the respiratory system, i.e. nasal passage, larynx and lungs (633 malformed cases, 415 653 controls). The OR is 1.11, 95% CI 0.95–1.30, but not significant, P = 0.18; Supplementary data, Table S25 and Fig. S9. There is a clear reduction in risk for defects of the skin (e.g. pigmentation disorders and moles) among five studies (3789 malformed cases, 386 576 controls). All showed a decreased risk and two were each significant. The pooled OR is 0.82, 95% CI 0.75–0.89 (P < 0.00001), with little heterogeneity (I2 = 0%); Supplementary data, Table S26 and Fig. S10.

### All congenital abnormalities considered together

There are 38 studies in which the OR for all birth defects combined was reported (67 716 malformed cases, 2.2 million controls). Only five were each significant, one of which had a decreased risk. The pooled OR of 1.01 (95% CI 0.96–1.07) suggests no effect; Supplementary data, Table S27 and Fig. S11. Initially, this seems inconsistent with the sections above. However, while smoking is positively associated with several disorders (and sometimes only modestly), it also appears to be protective for hypospadias and skin defects, and there is probably no effect on diaphragmatic hernia, genital defects (except cryptorchidism), and defects of the CNS, renal/urinary tract and respiratory systems. Furthermore, maternal smoking is not associated with chromosomal disorders such as Down syndrome (Rudnicka et al., 2002), but studies often include these when reporting on all abnormalities. Therefore, by examining all defects together a diluted effect is expected. By applying the pooled ORs estimated for each body system to the distribution of types of birth defects (ONS, 2010) and assuming a maternal smoking prevalence of 17% (ONS, 2006), an OR of about 1.10 is expected. This assumes that an affected case has only one defect, but there is evidence that women who smoke are more likely to have a baby with ≥2 defects: excess risks 15% (Kallen, 2000), 19% (Yushkiv et al., 2005) and 61% (Bitsko et al., 2007), compared with non-smokers. Therefore, to allow for ‘double counting’, the OR for all defects together is probably between 1.05 and 1.10. Most studies would be underpowered to detect this effect size. Furthermore, under-reporting bias in retrospective studies might be more likely to influence an OR as low as 1.05–1.10. The pooled OR among the three largest prospective studies, each with >2000 cases (Kallen 2000; Queisser-Luft et al., 2002; Morales-Suarez et al., 2006) was 1.04 (95% CI 1.01–1.07), consistent with expectation.

### Study quality, heterogeneity and publication bias

The pooled ORs where smoking status was obtained prospectively were similar to those given above, e.g. cardiovascular disease (OR 1.14 versus 1.09 based on all studies), limb reduction defects (OR 1.28 versus 1.26), gastrointestinal defects (OR 1.38 versus 1.27), gastroschisis (OR 1.65 versus 1.50) and oral clefts (OR 1.24 versus 1.28). The main concern is adjustment for confounding, another indicator of study quality. Supplementary data, Table S1 compares the pooled ORs from the main analysis with those only based on studies that allowed for potential confounders (by including them as matching variables in case–control studies, or in the statistical analysis). The ORs were similar, and those that were statistically significant remained so, indicating that the effect of confounding was minimal. Pooled ORs only from studies that allowed for at least maternal age and alcohol use (perhaps the two most important potential confounders) were also examined. The point estimates were again generally similar to those given in the sections above, e.g. cardiovascular disease (OR 1.20 versus 1.09), limb reduction defects (OR 1.30 versus 1.26), oral clefts (OR 1.40 versus 1.28), gastrointestinal defects (OR 1.30 versus 1.27), gastroschisis (OR 1.50 versus 1.50), cryptorchidism (OR 1.12 versus 1.13), hypospadias (OR 0.87 versus 0.90) and skin defects (OR 0.82 versus 0.82). Sometimes, adjusted estimates were not reported, but the authors stated that the results were similar to the unadjusted ones. Recreational drug use was not often measured, and so could not be reliably addressed.

There is some evidence that folic acid or other multivitamins could reduce the birth prevalence of defects other than of the neural tube (Czeizel, 2005), though the evidence is not consistent (Bower et al., 2006). Multivitamins would be a potential confounder if non-smoking women were more likely to use them than smokers and multivitamins were protective for many defects, because this could create a spurious association between smoking and birth defects. Few studies included in our meta-analyses adjusted for peri-conceptual multivitamin use (including folic acid), but those that did still reported an increased risk for maternal smoking (e.g. Malik et al., 2008 for cardiovascular disease, Wasserman et al., 1996 for limb reduction defects, and Van Rooij et al., 2001 and Shi et al., 2007 for orofacial clefts). Similarly, if there was a significant confounding effect of multivitamin use, looking only at studies that recruited subjects after say 1992 should produce a clear excess risk for all defects. However, when we did this, the pooled OR was only 1.06 (compared with 1.01 for all studies).

There was evidence of significant heterogeneity for some defects/body systems but not all. For cardiovascular defects and orofacial clefts, the test for heterogeneity became non-significant (P = 0.48 and P = 0.10, respectively) when the subgroup analysis was based on prospective studies only, even though the pooled estimates were not materially different from all studies. There was heterogeneity for all gastrointestinal defects considered together, but not when analysed according to specific sub-type (i.e. gastroschisis, omphalocele, anal atresia and hernias). We could not find factors that explained the heterogeneity for all musculoskeletal defects, but what is of note is that 18 out of 25 studies showed an increased risk, of which eight were each statistically significant. When examining subgroups of musculoskeletal defects the number of studies in the meta-analyses was insufficient to evaluate heterogeneity reliably (for example, digit anomalies, clubfoot, facial defects and eye defects).

Publication bias would occur if studies that found little or no association between maternal smoking and birth defects were less likely to be published, so a meta-analysis would be skewed by studies that did find an association. We examined funnel plots for all of the meta-analyses, and none indicated significant asymmetry, which is a sign of publication bias. We therefore concluded that this bias was not present to a material extent. Furthermore, the observation that most studies reported results that were not statistically significant (often interpreted to be a ‘negative’ study), provides further evidence that studies were likely to be published, regardless of what they found.

## Discussion

This first ever comprehensive systematic review of congenital birth defects shows which are associated with maternal smoking during pregnancy. There are modest effects on digit anomalies, cryptorchidism and defects of the heart and musculoskeletal system (ORs 1.09–1.19); and larger effects (ORs 1.25–1.50) on limb reduction defects, clubfoot, oral clefts and defects of the eyes and gastrointestinal system (especially gastroschisis and abdominal hernias). These defects should now be referred to by clinicians or other health professionals when providing advice to women planning a pregnancy, or early on in pregnancy.

Maternal smoking appears to have a protective effect for hypospadias and skin defects (ORs 0.82–0.90); not unexpected given that active smoking reduces the risk for some adult disorders (Wald and Hackshaw, 1996).

There is unlikely to be an effect (positive or negative) on defects of the CNS, respiratory and genitourinary (except cryptorchidism and hypospadias) systems.

It is uncertain what proportion of the study populations had ultrasound screening for malformations during pregnancy. This can influence the results when studies are based on live births only because, if widely used, ultrasound can lead to termination of pregnancy for some defects and thus reduce the prevalence at birth. However, it might increase the detection of some internal abnormalities, e.g. cardiac and renal, which could be missed at birth.

The studies were conducted or published between 1959 and 2010 with different designs, so they are expected to be of variable quality. The intention of this review was to be inclusive, and objective assessment of quality was made by subgroup analyses based on features that could be associated with bias or confounding. Women, especially those with an affected baby, could misreport their smoking status when based on self-reports (compared with blood cotinine measurements; Shipton et al., 2009), but this bias would tend to under-estimate the ORs. When the meta-analyses only included studies in which smoking status was obtained prospectively, similar pooled ORs were found. Potential confounding does not seem to be an issue; similar point estimates were found when only adjusted ORs were pooled, including allowance for both maternal age and alcohol (some individual studies made the same conclusion). Only English language articles were included in the review. However, examination of non-English language articles for a sample of the publication years did not produce additional studies. Furthermore, we examined 768 full papers and included 177 articles, so any missed studies are likely to have a negligible effect. Follow-up is an important consideration for defects that may not be readily observed at birth, because if too short, then defects could be missed and an association becomes diluted or not detected. Many studies had at least 1-year follow-up, and analysis restricted to such studies (e.g. for cardiovascular or genitourinary defects) produced almost identical pooled ORs.

Much of the literature on the harmful effects of smoking in pregnancy concentrates on other complications, such as fetal death, fetal growth restriction and prematurity. The mechanisms (Werler et al., 1985; Talbot, 2008; Rogers, 2009) are not precisely understood but are thought to include: the vasoconstrictor action of nicotine causing reduced blood flow to the placenta; carbon monoxide binding to haemoglobin so that less oxygen is available for placental and fetal tissues, leading to fetal hypoxia; disruption of vascular neogenesis; and disturbance of endothelial function in the maternal (Quinton et al., 2008) as well as, presumably, in the fetal circulations. How some or all of these mechanisms can cause a variety of congenital malformations is unknown. Abnormal morphogenesis can certainly be produced by toxins and/or hypoxia/ischemia interfering with cell proliferation or migration or both. The timing of such an insult relative to sensitive or critical periods of organogenesis, which may present only small windows of opportunity (a few days or even hours), combined with different thresholds for damage in fetal tissues, could determine which organ or system is affected. Interaction between constituents of tobacco smoke and other chemicals, particularly recreational drugs, are likely to be quite common. Some of these (e.g. cocaine and dexamphetamine) also have vasoconstrictor actions and may be important in the aetiology of gastroschisis (Morrison et al., 2005) but these data were not collected in most studies so it was not possible to examine the potential confounding effect reliably.

There are several reasons why the associations found are likely to be causal (consistent with the Bradford–Hill criteria for causality). There is biological plausibility, including laboratory experiments, and established harm in children and adults for a wide range of disorders. In many studies (i.e. the prospective ones) we can establish that the exposure (smoking) occurred before the pregnancy outcome. The ORs were statistically significant, and there was an effect after allowing for potential confounders. Although many individual studies did not have sufficient statistical power to reliably examine (and therefore report) dose–response relationships, several found evidence that the risk of the defect of interest increased with increasing cigarette consumption, for the abnormalities for which significant pooled ORs were found. There is a general consistency in the ORs estimated from studies conducted in different geographical regions (where the birth defect prevalence could vary), even though women have different lifestyle habits and medical care, either of which could affect the birth defect prevalence.

Most of the malformations associated with maternal smoking have physical and psychological morbidity for the infant and parents, often lifelong and with significant healthcare service costs for hospitalizations and length of stay (Russo and Elizhauser, 2004; Robbins et al., 2007; Wehby and Cassell, 2010). The estimated total hospital charges for treating the defects for which there are positive associations was ∼$2.1 billion in the USA in 2003 (Robbins et al., 2007). Of this, around$46 million could be crudely attributed to maternal smoking, after applying population attributable risk proportions (using our estimated ORs and the US smoking prevalence during pregnancy) to the 2003 US costs. Congenital heart defects are a common and serious birth anomaly, and infants often require several operations during their lifetime. Similarly, limb reduction defects, hand and foot anomalies, including clubfoot, and oral clefts are all visible, and despite surgical treatment (sometimes painful), may result in disability. Disorders of the gastrointestinal system also require corrective treatments.

It is worthwhile considering the use of nicotine replacement therapy (NRT) during pregnancy. It is available in several different forms (patches, gum, and spray) and has been shown to be effective in giving up smoking. There is some evidence that it is safe in pregnancy, with respect to stillbirth and fetal growth restriction, and it is being used increasingly, with the support of national guidelines (for example, in the UK). However, there is little information on congenital malformations and a cautious attitude is advisable. The view that NRT is safer than smoking is widely held but of special concern are those women who take NRT and continue to smoke as well, especially in the first trimester.

Further studies could examine in more detail the financial and other healthcare and societal costs for the defects identified here. While the risk of miscarriage and low birthweight has had some effect on smoking habits, many women still smoke just before and during pregnancy. Other research could be conducted to ascertain whether the risk of lifelong physical abnormalities to the child might encourage more women to quit, especially younger ones. In England and Wales (ONS 2008) the prevalence of a birth defect was 139.8 per 10 000 among women aged <20 years, higher than those aged 30–34 years (116.5 per 10 000). Some of this difference will be related to the much higher smoking prevalence in the younger age group (45%), acknowledging less use of peri-conceptual folic acid (because there are more unplanned pregnancies), and a much lower risk of a chromosomal defect.

In conclusion, maternal smoking in pregnancy is an important risk factor for several major birth defects. These specific defects should be included in public health educational information to encourage more women to quit smoking before or early on in pregnancy, and to particularly target younger women and those from lower socio-economic groups, in which smoking prevalence is greatest.

## Authors’ roles

A.H. had the original concept for the study, which was subsequently developed and planned by A.H. and C.R.; S.B. performed the literature searches and analyses, with A.H. All three authors were involved in interpreting the results, writing the paper and approving the final version.

## References

MM
Mulinare
J
Dooley
K
Risk factors for conotruncal cardiac defects in Atlanta
J Am Coll Cardiol
,
1989
, vol.
14
(pg.
432
-
442
)
Akre
O
Lipworth
L
Cnattingius
S
Sparen
P
Ekbom
A
Risk factor patterns for cryptorchidism and hypospadias
Epidemiology
,
1999
, vol.
10
(pg.
364
-
369
)
Alderman
BW
Takahashi
ER
LeMier
MK
Risk indicators for talipes equinovarus in Washington State, 1987–1989
Epidemiology
,
1991
, vol.
2
(pg.
289
-
292
)
Alderman
BW
CM
Greene
C
Fernbach
SK
Baron
AE
Increased risk of craniosynostosis with maternal cigarette smoking during pregnancy
Teratology
,
1994
, vol.
50

13–18
Ananijevic–Pandey
J
Jarebinski
M
Kastratovic
B
Vlajinac
H
Z
Brankovic
D
Case–control study of congenital malformations
Eur J Epidemiol
,
1992
, vol.
8
(pg.
871
-
874
)
Aro
T
Maternal diseases, alcohol consumption and smoking during pregnancy associated with reduction limb defects
Early Hum Dev
,
1983
, vol.
9
(pg.
49
-
57
)
Batra
M
Heike
CL
Phillips
RC
Weiss
NS
Geographic and occupational risk factors for ventricular septal defects: Washington State, 1987–2003
,
2007
, vol.
161
(pg.
89
-
95
)
Beard
CM
Melton
LJ
O'Fallon
WM
Noller
KL
Benson
RC
Cryptorchism and maternal estrogen exposure
Am J Epidemiol
,
1984
, vol.
120
(pg.
707
-
716
)
Beaty
TH
Wang
H
Hetmanski
JB
Fan
YT
Zeiger
JS
Liang
KY
Chiu
YF
Vanderkolk
CA
Seifert
KC
Wulfsberg
EA
, et al.  .
A case–control study of nonsyndromic oral clefts in Maryland
Ann Epidemiol
,
2001
, vol.
11
(pg.
434
-
442
)
Bell
R
Lumley
J
Alcohol consumption, cigarette smoking and fetal outcome in Victoria, 1985
Community Health Stud
,
1989
, vol.
13
(pg.
484
-
491
)
Berkowitz
GS
Lapinski
RH
Risk factors for cryptorchidism: a nested case–control study
Paediatr Perinat Epidemiol
,
1996
, vol.
10
(pg.
39
-
51
)
Biggs
ML
Baer
A
Critchlow
CW
Maternal, delivery, and perinatal characteristics associated with cryptorchidism: a population–based case–control study among births in Washington State
Epidemiology
,
2002
, vol.
13
(pg.
197
-
204
)
Bille
C
Olsen
J
Vach
W
Knudsen
VK
Olsen
SF
Rasmussen
K
Murray
JC
Andersen
AM
Christensen
K
Oral clefts and life style factors–a case–cohort study based on prospective Danish data
Eur J Epidemiol
,
2007
, vol.
22
(pg.
173
-
181
)
Bitsko
RH
Reefhuis
J
Romitti
PA
Moore
CA
Honein
MA
Periconceptional consumption of vitamins containing folic acid and risk for multiple congenital anomalies
Am J Med Genet A
,
2007
, vol.
143A
(pg.
2397
-
2405
)
Blanco Munoz
J
Lacasana
M
Borja Aburto
VH
Torres Sanchez
LE
Garcia Garcia
AM
Lopez Carrillo
L
Socioeconomic factors and the risk of anencephaly in a Mexican population: a case–control study
Public Health Rep
,
2005
, vol.
120
(pg.
39
-
45
)
Blatter
BM
Roeleveld
N
Zielhuis
GA
Gabreels
FJ
Verbeek
AL
Maternal occupational exposure during pregnancy and the risk of spina bifida
Occup Environ Med
,
1996
, vol.
53
(pg.
80
-
86
)
Botto
LD
Lynberg
MC
Erickson
JD
Congenital heart defects, maternal febrile illness, and multivitamin use: a population–based study
Epidemiology
,
2001
, vol.
12
(pg.
485
-
490
)
Bower
C
Miller
M
Payne
J
Serna
P
Folate intake and the primary prevention of non–neural birth defects
Aust N Z J Public Health
,
2006
, vol.
30
(pg.
258
-
261
)
Brouwers
MM
Feitz
WF
Roelofs
LA
Kiemeney
LA
de Gier
RP
Roeleveld
N
Eur J Pediatr
,
2007
, vol.
166
(pg.
671
-
678
)
Brouwers
MM
van der Zanden
LF
de Gier
RP
Barten
EJ
Zielhuis
GA
Feitz
WF
Roeleveld
N
Hypospadias: risk factor patterns and different phenotypes
BJU Int
,
2010
, vol.
105
(pg.
254
-
262
)
British Medical Association (BMA)
Smoking and Reproductive Life: The Impact of Smoking on Sexual, Reproductive and Child Health
,
2004
London
BMA
Butler
NR
Alberman
ED
Perinatal Problems: The second report of the 1958 British Perinatal Mortality Survey
,
1969
Edinburgh & London
E&S Livingstone Ltd
Carbone
P
Giordano
F
Nori
F
Mantovani
A
Taruscio
D
Lauria
L
Figà-Talamanca
I.
The possible role of endocrine disrupting chemicals in the aetiology of cryptorchidism and hypospadias: a population–based case–control study in rural Sicily
Int J Androl
,
2007
, vol.
30
(pg.
3
-
13
)
Cardy
AH
Barker
S
Chesney
D
Sharp
L
Maffulli
N
Miedzybrodzka
Z
Pedigree analysis and epidemiological features of idiopathic congenital talipes equinovarus in the United Kingdom: a case–control study
BMC Musculoskelet Disord
,
2007
, vol.
8
pg.
62

Carmichael
SL
Shaw
GM
Maternal life event stress and congenital anomalies
Epidemiology
,
2000
, vol.
11
(pg.
30
-
35
)
Carmichael
SL
Nelson
V
Shaw
GM
Wasserman
CR
Croen
LA
Socio–economic status and risk of conotruncal heart defects and orofacial clefts
Paediatr Perinat Epidemiol
,
2003
, vol.
17
(pg.
264
-
271
)
Carmichael
SL
Ma
C
Rasmussen
SA
Honein
MA
Lammer
EJ
Shaw
GM
Craniosynostosis and maternal smoking
Birth Defects Res
,
2008
, vol.
82
(pg.
78
-
85
)
Caton
AR
Bell
EM
Druschel
CM
Werler
MM
Mitchell
AA
Browne
ML
McNutt
LA
Romitti
PA
Olney
RS
Correa
A
Maternal hypertension, antihypertensive medication use, and the risk of severe hypospadias
Birth Defects Res
,
2008
, vol.
82
(pg.
34
-
40
)
Chambers
CD
Chen
BH
Kalla
K
Jernigan
L
Jones
KL
Novel risk factor in gastroschisis: change of paternity
Am J Med Genet A
,
2007
, vol.
143
(pg.
653
-
659
)
Chevrier
C
Bahuau
M
Perret
C
Iovannisci
DM
Nelva
A
Herman
C
Vazquez
MP
Francannet
C
Robert–Gnansia
E
Lammer
EJ
Cordier
S
Genetic susceptibilities in the association between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft
Am J Med Genet A
,
2008
, vol.
146A
(pg.
2396
-
2406
)
Chew
E
Remaley
NA
Tamboli
A
Zhao
J
Podgor
MJ
Klebanoff
M
Risk factors for esotropia and exotropia
Arch Ophthalmol
,
1994
, vol.
112
(pg.
1349
-
1355
)
Christianson
RE
The relationship between maternal smoking and the incidence of congenital anomalies
Am J Epidemiol
,
1980
, vol.
112
(pg.
684
-
695
)
Chung
CS
Myrianthopoulos
NC
Factors affecting risks of congenital malformations. I. Analysis of epidemiologic factors in congenital malformations. Report from the Collaborative Perinatal Project
Birth Defects: Orig Artic Ser
,
1975
, vol.
11
(pg.
1
-
22
)
Chung
KC
Kowalski
CP
Kim
HM
Buchman
SR
Maternal cigarette smoking during pregnancy and the risk of having a child with cleft lip/palate
Plast Reconstr Surg
,
2000
, vol.
105
(pg.
485
-
491
)
Cordier
S
Ha
MC
Ayme
S
Goujard
J
Maternal occupational exposure and congenital malformations
Scand J Work, Environ Health
,
1992
, vol.
18
(pg.
11
-
17
)
Correy
JF
Newman
NM
Collins
JA
Burrows
EA
Burrows
RF
Curran
JT
Use of prescription drugs in the first trimester and congenital malformations
Aust NZ J Obstet Gynaecol
,
1991
, vol.
31
(pg.
340
-
344
)
Croen
LA
Shaw
GM
Lammer
EJ
Risk factors for cytogenetically normal holoprosencephaly in California: a population–based case–control study
Am J Med Genet
,
2000
, vol.
90
(pg.
320
-
325
)
Czeizel
A
Vitez
M
Etiological study of omphalocele
Hum Genet
,
1981
, vol.
58
(pg.
390
-
395
)
Czeizel
A
The primary prevention of birth defects: multivitamins or folic acid?
Int J Med Sci
,
2005
, vol.
1
(pg.
50
-
61
)
Czeizel
A
Nagy
E
A recent aetiological study on facial clefting in Hungary
Acta Paediatr Hung
,
1986
, vol.
27
(pg.
145
-
166
)
Czeizel
AE
Kodaj
I
Lenz
W
Smoking during pregnancy and congenital limb deficiency
BMJ
,
1994
, vol.
308
(pg.
1473
-
1476
)
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
, vol.
12
(pg.
179
-
183
)
da Silva Costa
CM
da Gama
SGN
do Carmo Leal
M
Congenital malformations in Rio de Janeiro, Brazil: prevalence & associated factors
,
2006
, vol.
22
(pg.
2423
-
2431
)
Damgaard
IN
Jensen
TK
Nordic Cryptorchidism Study Group, Petersen JH, Skakkebaek NE, Toppari J, Main KM
Risk factors for congenital cryptorchidism in a prospective birth cohort study
PLoS ONE [Electronic Resource]
,
2008
, vol.
3
pg.
e3051

Davies
TW
Williams
DR
Whitaker
RH
Risk factors for undescended testis
Int J Epidemiol
,
1986
, vol.
15
(pg.
197
-
201
)
DiFranza
JR
Lew
RA
Effect of maternal cigarette smoking on pregnancy complications and sudden infant death syndrome
J Fam Pract
,
1995
, vol.
40
(pg.
385
-
394
)
Draper
ES
Rankin
J
Tonks
A
Boyd
P
Wellesley
D
Tucker
D
Budd
J
BINOCAR Management Committee
Recreational drug use: a major risk factor for gastroschisis?
Am J Epidemiol
,
2008
, vol.
167
(pg.
485
-
491
Feb 15
Ericson
A
Kallen
B
Westerholm
P
Cigarette smoking as an etiologic factor in cleft lip and palate
Am J Obstet Gynecol
,
1979
, vol.
135
(pg.
348
-
351
)
Erickson
JD
Risk factors for birth defects: data from the Atlanta Birth Defects Case–Control Study
Teratology
,
1991
, vol.
43
(pg.
41
-
51
)
Evans
DR
Newcombe
RG
Campbell
H
Maternal smoking habits and congenital malformations: a population study
Br Med J
,
1979
, vol.
2
(pg.
171
-
173
)
Fedrick
J
Alberman
ED
Goldstein
H
Possible Teratogenic Effect of Cigarette Smoking
Nature
,
1971
, vol.
231
(pg.
529
-
530
)
Felix
JF
van Dooren
MF
Klaassens
M
Hop
WC
Torfs
CP
Tibboel
D
Environmental factors in the etiology of esophageal atresia and congenital diaphragmatic hernia: results of a case–control study
Birth Defects Res
,
2008
, vol.
82
(pg.
98
-
105
)
Ferencz
C
Loffredo
CA
Correa–Villasenor
A
Genetic and Environmental Risk Factors of Major Cardiovascular Malformations: The Baltimore–Washington Infant Study 1981–1989
,
1997
Armonk, New York
Futura Publishing Co
Fernandez
MF
Olmos
B
A
López–Espinosa
MJ
Molina–Molina
JM
Fernandez
JM
Cruz
M
Olea–Serrano
F
Olea
N
Human exposure to endocrine–disrupting chemicals and prenatal risk factors for cryptorchidism and hypospadias: a nested case–control study
Environ Health Perspect
,
2007
, vol.
115

Suppl 1
(pg.
8
-
14
)
Garcia
AM
Fletcher
T
Benavides
FG
Orts
E
Parental agricultural work and selected congenital malformations
Am J Epidemiol
,
1999
, vol.
149
(pg.
64
-
74
)
Goldbaum
G
Daling
J
Milham
S
Risk factors for gastroschisis
Teratology
,
1990
, vol.
42
(pg.
397
-
403
)
Golding
J
Butler
NR
Maternal smoking and anencephaly
Br Med J Clin Res Ed
,
1983
, vol.
287
(pg.
533
-
534
)
Grewal
J
Carmichael
SL
Ma
C
Lammer
EJ
Shaw
GM
Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies
Birth Defects Res
,
2008
, vol.
82
(pg.
519
-
526
)
JE
Palomaki
GE
Holman
MS
Young maternal age and smoking during pregnancy as risk factors for gastroschisis
Teratology
,
1993
, vol.
47
(pg.
225
-
228
)
Hakim
RB
Tielsch
JM
Maternal cigarette smoking during pregnancy. A risk factor for childhood strabismus
Arch Ophthal
,
1992
, vol.
110
(pg.
1459
-
1462
)
Hearey
CD
Harris
JA
Usatin
MS
Epstein
DM
Ury
HK
Neutra
RR
Investigation of a cluster of anencephaly and spina bifida
Am J Epidemiol
,
1984
, vol.
120
(pg.
559
-
564
)
Heinonen
OP
Birth Defects and Drugs in Pregnancy
1977
Publishing Sciences Group, Inc.
Hemminki
K
Mutanen
P
Saloniemi
I
Luoma
K
Congenital malformations and maternal occupation in Finland: multivariate analysis
J Epidemiol Community Health
,
1981
, vol.
35
(pg.
5
-
10
)
Higgins
JPT
Thompson
SG
Deeks
JJ
Altman
DG
Measuring inconsistency in meta–analyses
BMJ
,
2003
, vol.
327
(pg.
557
-
560
)
Himmelberger
DU
Brown
BW
Jr.
cohen
EN
Cigarette smoking during pregnancy and the occurrence of spontaneous abortion and congenital abnormality
Am J Epidemiol
,
1978
, vol.
108
(pg.
470
-
479
)
Honein
MA
Paulozzi
LJ
Moore
CA
Family history, maternal smoking, and clubfoot: an indication of a gene–environment interaction
Am J Epidemiol
,
2000
, vol.
152
(pg.
658
-
665
)
Honein
MA
Rasmussen
SA
Further evidence for an association between maternal smoking and craniosynostosis
Teratology
,
2000
, vol.
62
(pg.
145
-
146
)
Honein
MA
Paulozzi
LJ
Watkins
ML
Maternal smoking and birth defects: validity of birth certificate data for effect estimation
Public Health Rep
,
2001
, vol.
116
(pg.
327
-
335
)
Hougland
KT
Hanna
AM
Meyers
R
Null
D
Increasing prevalence of gastroschisis in Utah
J Pediatr Surg
,
2005
, vol.
40
(pg.
535
-
540
)
Hwang
SJ
Beaty
TH
Panny
SR
Street
NA
Joseph
JM
Gordon
S
McIntosh
I
Francomano
CA
Association study of transforming growth factor alpha (TGF alpha) TaqI polymorphism and oral clefts: indication of gene–environment interaction in a population–based sample of infants with birth defects
Am J Epidemiol
,
1995
, vol.
141
(pg.
629
-
636
)
Jensen
MS
Toft
G
Thulstrup
AM
Bonde
JP
Olsen
J
Cryptorchidism according to maternal gestational smoking
Epidemiology
,
2007
, vol.
18
(pg.
220
-
225
)
Johansen
AM
Wilcox
AJ
Lie
RT
Andersen
LF
Drevon
CA
Maternal consumption of coffee and caffeine–containing beverages and oral clefts: a population–based case–control study in Norway
Am J Epidemiol
,
2009
, vol.
169
(pg.
1216
-
1222
)
Jones
ME
Swerdlow
AJ
Griffith
M
Goldacre
MJ
Prenatal risk factors for cryptorchidism: a record linkage study
Paediatr Perinat Epidemiol
,
1998
, vol.
12
(pg.
383
-
396
)
Kallen
B
Winberg
J
An epidemiological study of hypospadias in Sweden
Acta Paediatr Scand Suppl
,
1982
, vol.
293
(pg.
1
-
21
)
Kallen
K
Maternal smoking and craniosynostosis
Teratology
,
1999
, vol.
60
(pg.
146
-
150
)
Kallen
K
Multiple malformations and maternal smoking
Paediatr Perinat Epidemiol
,
2000
, vol.
14
(pg.
227
-
233
)
Kallen
K
Role of maternal smoking and maternal reproductive history in the etiology of hypospadias in the offspring
Teratology
,
2002
, vol.
66
(pg.
185
-
191
)
Kelsey
JL
Dwyer
T
Holford
TR
Bracken
MB
Maternal smoking and congenital malformations: an epidemiological study
J Epidemiol Community Health
,
1978
, vol.
32
(pg.
102
-
107
)
Khoury
MJ
Weinstein
A
Panny
S
Holtzman
NA
Lindsay
PK
Farrel
K
Eisenberg
M
Maternal cigarette smoking and oral clefts: a population–based study
Am J Public Health
,
1987
, vol.
77
(pg.
623
-
625
)
Khoury
MJ
Gomez–Farias
M
Mulinare
J
Does maternal cigarette smoking during pregnancy cause cleft lip and palate in offspring?
Am J Dis Child
,
1989
, vol.
143
(pg.
333
-
337
)
Krapels
IP
Raijmakers–Eichhorn
J
Peters
WH
Roelofs
HM
Ras
F
Steegers–Theunissen
RP
Eurocran Gene–Environment Interaction Group
The I,105V polymorphism in glutathione S–transferase P1, parental smoking and the risk for nonsyndromic cleft lip with or without cleft palate
Eur J Hum Genet
,
2008
, vol.
16
(pg.
358
-
366
)
Krauss
MJ
Morrissey
AE
Winn
HN
Amon
E
Leet
TL
Microcephaly: an epidemiologic analysis
Am J Obstet Gynecol
,
2003
, vol.
188
(pg.
1484
-
1489
discussion 9–90
Kricker
A
Elliott
JW
Forrest
JM
McCredie
J
Congenital limb reduction deformities and use of oral contraceptives
Am J Obstet Gynecol
,
1986
, vol.
155
(pg.
1072
-
1078
)
Kullander
S
Kallen
B
A Prospective Study of Smoking and Pregnancy
Acta Obstet Gynec Scand
,
1971
, vol.
50
(pg.
83
-
94
)
Kurahashi
N
Kasai
S
Shibata
T
Kakizaki
H
Nonomura
K
Sata
F
Kishi
R
Parental and neonatal risk factors for cryptorchidism
Med Sci Monit
,
2005
, vol.
11
(pg.
CR274
-
CR283
)
Kurahashi
N
Sata
F
Kasai
S
Shibata
T
Moriya
K
H
Kakizaki
H
Minakami
H
Nonomura
K
Kishi
R
Maternal genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 and the risk of hypospadias
Mol Hum Reprod
,
2005
, vol.
11
(pg.
93
-
98
)
Laumon
B
Martin
JL
Collet
P
Bertucat
I
Verney
MP
Robert
E
Exposure to organic solvents during pregnancy and oral clefts: a case–control study. [Erratum appears in Reprod Toxicol
Reprod Toxicol
,
1996
, vol.
10
(pg.
15
-
19
1996. May–Jun;10(3):vi]
Leite
IC
Koifman
S
Oral clefts, consanguinity, parental tobacco and alcohol use: a case–control study in Rio de Janeiro, Brazil
Pesqui Odontol Bras
,
2009
, vol.
23
(pg.
31
-
37
)
Li
DK
Mueller
BA
Hickok
DE
Daling
JR
Fantel
AG
Checkoway
H
Weiss
NS
Maternal smoking during pregnancy and the risk of congenital urinary tract anomalies
Am J Public Health
,
1996
, vol.
86
(pg.
249
-
253
)
Lieff
S
Olshan
AF
Werler
M
Strauss
RP
Smith
J
Mitchell
A
Maternal cigarette smoking during pregnancy and risk of oral clefts in newborns
Am J Epidemiol
,
1999
, vol.
150
(pg.
683
-
694
)
Linn
S
Schoenbaum
SC
Monson
RR
Rosner
B
Stubblefield
PG
Ryan
KJ
Lack of association between contraceptive usage and congenital malformations in offspring
Am J Obstet Gynecol
,
1983
, vol.
147
(pg.
923
-
928
)
Little
J
Cardy
A
Arslan
MT
Gilmour
M
Mossey
PA
Smoking and orofacial clefts: a United Kingdom–based case–control study
Cleft Palate Craniofac J
,
2004
, vol.
41
(pg.
381
-
386
)
Little
J
Cardy
A
Munger
RG
Tobacco smoking and oral clefts: a meta–analysis
Bull World Health Organ
,
2004
, vol.
82
(pg.
213
-
218
)
Liu
S
Liu
J
Tang
J
Ji
J
Chen
J
Liu
C
Environmental risk factors for congenital heart disease in the Shandong Peninsula, China: a hospital–based case–control study
J Epidemiol
,
2009
, vol.
19
(pg.
122
-
130
)
Lorente
C
Cordier
S
Goujard
J
Aymé
S
Bianchi
F
Calzolari
E
De Walle
HE
Knill–Jones
R
Tobacco and alcohol use during pregnancy and risk of oral clefts
Am J Public Health
,
2000
, vol.
90
(pg.
415
-
419
)
Lowe
CR
Effect of mothers' smoking habits on birth weight of their children
Br Med J
,
1959
, vol.
2
(pg.
673
-
676
)
Lubs
ML
Racial differences in maternal smoking effects on the newborn infant
Am J Obstet Gynecol
,
1973
, vol.
115
(pg.
66
-
76
)
Lumley
J
Correy
JF
Newman
NM
Curran
JT
Cigarette smoking, alcohol consumption and fetal outcome in Tasmania 1981–82
Aust N Z J Obstet Gynaecol
,
1985
, vol.
25
(pg.
33
-
40
)
Mac Bird
T
Robbins
JM
Druschel
C
Cleves
MA
Yang
S
Hobbs
CA
Demographic and environmental risk factors for gastroschisis and omphalocele in the National Birth Defects Prevention Study
J Pediatr Surg
,
2009
, vol.
44
(pg.
1546
-
1551
)
Malik
S
Cleves
MA
Honein
MA
Romitti
PA
Botto
LD
Yang
S
Hobbs
CA
Maternal smoking and congenital heart defects
Pediatrics
,
2008
, vol.
121
(pg.
e810
-
e816
)
Malloy
MH
Kleinman
JC
Bakewell
JM
Schramm
WF
Land
GH
Maternal smoking during pregnancy: no association with congenital malformations in Missouri 1980–83
Am J Public Health
,
1989
, vol.
79
(pg.
1243
-
1246
)
Man
LX
Chang
B
Maternal cigarette smoking during pregnancy increases the risk of having a child with a congenital digital anomaly
Plast Reconst Surg
,
2006
, vol.
117
(pg.
301
-
308
)
Mandiracioglu
A
Ulman
I
Luleci
E
Ulman
C
The incidence and risk factors of neural tube defects in Izmir, Turkey: a nested case–control study
Turk J Pediatr
,
2004
, vol.
46
(pg.
214
-
220
)
March of Dimes

Martinez–Frias
ML
Rodriguez–Pinilla
E
Prieto
L
Prenatal exposure to salicylates and gastroschisis: a case–control study
Teratology
,
1997
, vol.
56
(pg.
241
-
243
)
McBride
ML
Van den Steen
N
Lamb
CW
Gallagher
RP
Maternal and gestational factors in cryptorchidism
Int J Epidemiol
,
1991
, vol.
20
(pg.
964
-
970
)
McDonald
Armstrong
BG
Sloan
M
Cigarette, alcohol, and coffee consumption and congenital defects
Am J Public Health
,
1992
, vol.
82
(pg.
91
-
93
)
McGlynn
KA
Graubard
BI
Klebanoff
MA
Longnecker
MP
Risk factors for cryptorchism among populations at differing risks of testicular cancer
Int J Epidemiol
,
2006
, vol.
35
(pg.
787
-
795
)
Meyer
MB
Tonascia
JA
Maternal smoking, pregnancy complications, and perinatal mortality
Am J Obstet Gynecol
,
1977
, vol.
128
(pg.
494
-
502
)
Miller
EA
Manning
SE
Rasmussen
SA
Reefhuis
J
Honein
MA
National Birth Defects Prevention Study
Maternal exposure to tobacco smoke, alcohol and caffeine, and risk of anorectal atresia: National Birth Defects Prevention Study 1997–2003
Paediatr Perinat Epidemiol
,
2009
, vol.
23
(pg.
9
-
17
)
Mitchell
LE
Murray
JC
O'Brien
S
Christensen
K
Evaluation of two putative susceptibility loci for oral clefts in the Danish population
Am J Epidemiol
,
2001
, vol.
153
(pg.
1007
-
1015
)
Mongraw–Chaffin
ML
Cohn
BA
Cohen
RD
Christianson
RE
Maternal smoking, alcohol consumption, and caffeine consumption during pregnancy in relation to a son's risk of persistent cryptorchidism: a prospective study in the Child Health and Development Studies cohort, 1959–1967
Am J Epidemiol
,
2008
, vol.
167
(pg.
257
-
261
)
Morales–Suarez–Varela
MM
Bille
C
Christensen
K
Olsen
J
Smoking habits, nicotine use, and congenital malformations
Obstet Gynecol
,
2006
, vol.
107
(pg.
51
-
57
)
Mori
M
Davies
TW
Tsukamoto
T
Kumamoto
Y
Fukuda
K
Maternal and other factors of cryptorchidism–a case–control study in Japan
Kurume Med J
,
1992
, vol.
39
(pg.
53
-
60
)
Morrison
JJ
Chitty
LS
Peebles
D
Rodeck
CH
Recreational drugs and fetal gastroschisis: maternal hair analysis in the periconceptional period and during pregnancy
Br J Obstet Gynaecol
,
2005
, vol.
112
(pg.
1022
-
1025
)
Mygind
H
Thulstrup
AM
Pedersen
L
Larsen
H
Risk of intrauterine growth retardation, malformations and other birth outcomes in children after topical use of corticosteroid in pregnancy
Acta Obstet Gynecol Scand
,
2002
, vol.
81
(pg.
234
-
239
)
Niebyl
JR
Blake
DA
Rocco
LE
Baumgardner
R
Lack of maternal metabolic, endocrine, and environmental influences in the etiology of cleft lip with or without cleft palate
Cleft Palate J
,
1985
, vol.
22

Mellits ED
(pg.
20
-
28
)
Nørgaard
M
Wogelius
P
Pedersen
L
Rothman
KJ
Sørensen
HT
Maternal use of oral contraceptives during early pregnancy and risk of hypospadias in male offspring
Urology
,
2009
, vol.
74
(pg.
583
-
587
)
Oddsberg
J
Jia
C
Nilsson
E
Ye
W
Lagergren
J
Maternal tobacco smoking, obesity, and low socioeconomic status during early pregnancy in the etiology of esophageal atresia
J Pediatr Surg
,
2008
, vol.
43
(pg.
1791
-
1795
)
Office for National Statistics (ONS)
The Information Centre

Statistics on smoking: England 2006. Office for National Statistics, 2006. http://www.ic.nhs.uk/pubs/smokingeng2006/report/file.
Office for National Statistics (National Congenital Anomaly System)
2010

Congenital anomaly statistics: notifications England and Wales 2008 (series MB3 no. 23)
Ormond
G
Nieuwenhuijsen
MJ
Nelson
P
Toledano
MB
Iszatt
N
Geneletti
S
Elliott
P
Endocrine disruptors in the workplace, hair spray, folate supplementation, and risk of hypospadias: case–control study
Environ Health Perspect
,
2009
, vol.
117
(pg.
303
-
307
)
Parikh
CR
McCall
D
Engelman
C
Schrier
RW
Congenital renal agenesis: case–control analysis of birth characteristics
Am J Kidney Dis
,
2002
(pg.
689
-
694
39
Parker
SE
Mai
CT
Strickland
MJ
Olney
RS
Rickard
R
Marengo
L
Wang
Y
Hashmi
SS
Meyer
RE
Multistate study of the epidemiology of clubfoot
Birth Defects Res
,
2009
, vol.
85
(pg.
897
-
904
)
Parker
SE
Mai
CT
Canfield
MA
Rickard
R
Wang
Y
Meyer
RE
Anderson
P
Mason
CA
Collins
JS
Kirby
RS
Correa
A
the National Birth Defects Prevention Network
Updated national birth prevalence estimates for selected birth defects in the United States, 2004–2006

Birth Defects Res A Clin Mol Teratol 2010 Sep 28. http://www.cdc.gov/ncbddd/features/birthdefects-keyfindings.html.
Pierik
FH
Burdorf
A
Deddens
JA
Juttmann
RE
Weber
RF
Maternal and paternal risk factors for cryptorchidism and hypospadias: a case–control study in newborn boys
Environ Health Perspect
,
2004
, vol.
112
(pg.
1570
-
1576
)
Porter
MP
Faizan
MK
RW
Mueller
BA
Hypospadias in Washington State: maternal risk factors and prevalence trends
Pediatrics
,
2005
, vol.
115
(pg.
e495
-
499
)
Preiksa
RT
Zilaitiene
B
Matulevicius
V
Skakkebaek
NE
Petersen
JH
Jorgensen
N
Toppari
J
Higher than expected prevalence of congenital cryptorchidism in Lithuania: a study of 1204 boys at birth and 1 year follow–up
Hum Reprod
,
2005
, vol.
20
(pg.
1928
-
1932
)

PRISMA guidelines for reporting meta–analyses of observational studies – http://www.prisma-statement.org/
Quinton
AE
Cook
CM
Peek
MJ
The relationship between cigarette smoking, endothelial function and intrauterine growth restriction in human pregnancy
BJOG
,
2008
, vol.
115
(pg.
780
-
784
)
Queisser–Luft
A
Stolz
G
Wiesel
A
Schlaefer
K
Spranger
J
Malformations in newborn: results based on 30,940 infants and fetuses from the Mainz congenital birth defect monitoring system (1990–1998)
Arch Gynecol Obstet
,
2002
, vol.
266
(pg.
163
-
167
)
Rantakallio
P
Relationship of maternal smoking to morbidity and mortality of the child up to the age of five
Acta Paediatr Scand
,
1978
, vol.
67
(pg.
621
-
631
)
Reefhuis
J
de Walle
HE
Cornel
MC
Maternal smoking and deformities of the foot: results of the EUROCAT Study
Am J Public Health
,
1998
, vol.
88
(pg.
1554
-
1555
European Registries of Congenital Anomalies
REVMAN
2008

Review Manager (RevMan) [Computer program]. Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration
Robbins
JM
Bird
TM
Tilford
JM
Cleves
MA
Hobbs
CA
Hospital stays, hospital charges, and in–hospital deaths among infats with selected birth defects – United States, 2003
Morb Mortal Wkly Rep
,
2007
, vol.
56
(pg.
25
-
29
)
Robitaille
J
Carmichael
SL
Shaw
GM
Olney
RS
National Birth Defects Prevention S
Maternal nutrient intake and risks for transverse and longitudinal limb deficiencies: data from the National Birth Defects Prevention Study, 1997–2003
Birth Defects Res
,
2009
, vol.
85
(pg.
773
-
779
)
Rodriguez–Pinilla
E
Mejias
C
Prieto–Merino
D
Fernandez
P
Martinez–Frias
ML
Group
EW
Risk of hypospadias in newborn infants exposed to valproic acid during the first trimester of pregnancy: a case–control study in Spain
Drug Safety
,
2008
, vol.
31
(pg.
537
-
543
)
Rogers
JM
Tobacco and pregnancy
Reprod Toxicol
,
2009
, vol.
28
(pg.
152
-
160
)
Romitti
PA
Sun
L
Honein
MA
Reefhuis
J
Correa
A
Rasmussen
SA
Maternal periconceptional alcohol consumption and risk of orofacial clefts
Am J Epidemiol
,
2007
, vol.
166
(pg.
775
-
785
)
Britton
J
Edwards
R
Royal College of Physicians
Effects of maternal active and passive smoking on fetal and reproductive health

In: Passive smoking and children. A report by the Tobacco Advisory Group of the Royal College of Physicians, Chapter 3, 40–76. Eds. Royal College of Physicians 2010
Rudnicka
A
Wald
NJ
Huttly
W
Hackshaw
AK
Influence of maternal smoking on the birth prevalence of Down syndrome and on second trimester screening performance
Prenat Diagn
,
2002
, vol.
22
(pg.
893
-
897
)
Russo
C. A
(Thomson Medstat) and Elixhauser, A. (AHRQ)
Hospitalizations for Birth Defects, 2004

HCUP Statistical Brief #24. January 2007. U.S. Agency for Healthcare Research and Quality, Rockville, MD. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb24.pdf.
Salemi
JL
Pierre
M
Tanner
JP
Kornosky
JL
Hauser
KW
Kirby
RS
Carver
JD
Maternal nativity as a risk factor for gastroschisis: a population–based study
Birth Defects Res
,
2009
, vol.
85
(pg.
890
-
896
)
Saxen
I
Cleft lip and palate in Finland: parental histories, course of pregnancy and selected environmental factors
Int J Epidemiol
,
1974
, vol.
3
(pg.
263
-
270
)
Schmidt
RJ
Romitti
PA
Burns
TL
Browne
ML
Druschel
CM
Olney
RS
Maternal caffeine consumption and risk of neural tube defects
Birth Defects Res
,
2009
, vol.
85
(pg.
879
-
889
)
Seidman
DS
P
Gale
R
Effect of maternal smoking and age on congenital anomalies
Obstet Gynecol
,
1990
, vol.
76
(pg.
1046
-
1050
)
Shah
NR
Bracken
MB
A systematic review and meta–analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery
Am J Obstet Gynecol
,
2000
, vol.
182
(pg.
465
-
472
)
Shaw
GM
Malcoe
LH
Swan
SH
Cummins
SK
Schulman
J
Congenital cardiac anomalies relative to selected maternal exposures and conditions during early pregnancy
Eur J Epidemiol
,
1992
, vol.
8
(pg.
757
-
760
)
Shaw
GM
Wasserman
CR
Lammer
EJ
O'Malley
CD
Murray
JC
Basart
AM
Tolarova
MM
Orofacial clefts, parental cigarette smoking, and transforming growth factor–alpha gene variants
Am J Hum Genet
,
1996
, vol.
58
(pg.
551
-
561
)
Shaw
GM
Velie
EM
Morland
KB
Parental recreational drug use and risk for neural tube defects
Am J Epidemiol
,
1996
, vol.
144
(pg.
1155
-
1160
)
Shaw
GM
Wasserman
CR
O'Malley
CD
Nelson
V
Jackson
RJ
Maternal pesticide exposure from multiple sources and selected congenital anomalies
Epidemiology
,
1999
, vol.
10
(pg.
60
-
66
)
Shaw
GM
Croen
LA
Todoroff
K
Tolarova
MM
Periconceptional intake of vitamin supplements and risk of multiple congenital anomalies
Am J Med Genet
,
2000
, vol.
93
(pg.
188
-
193
)
Shi
M
Christensen
K
Weinberg
CR
Romitti
P
Bathum
L
A
Morris
RW
Lovett
M
Murray
JC
Orofacial cleft risk is increased with maternal smoking and specific detoxification–gene variants
Am J Hum Genet
,
2007
, vol.
80
(pg.
76
-
90
)
Shiono
PH
Klebanoff
MA
Berendes
HW
Congenital malformations and maternal smoking during pregnancy
Teratology
,
1986
, vol.
34
(pg.
65
-
71
)
Shipton
D
Tappin
DM
T
Crossley
JA
Aitken
DA
Chalmers
J
Reliability of self reported smoking status by pregnant women for estimating smoking prevalence: a retrospective, cross sectional study
BMJ
,
2009
, vol.
339

b4347 .
Skelly
AC
Holt
VL
Mosca
VS
Alderman
BW
Talipes equinovarus and maternal smoking: a population–based case–control study in Washington state
Teratology
,
2002
, vol.
66
(pg.
91
-
100
)
Slickers
JE
Olshan
AF
Siega–Riz
AM
Honein
MA
Aylsworth
AS
National Birth Defects Prevention Study
Maternal body mass index and lifestyle exposures and the risk of bilateral renal agenesis or hypoplasia: the National Birth Defects Prevention Study
Am J Epidemiol
,
2008
, vol.
168
(pg.
1259
-
1267
)
Smedts
HP
de Vries
JH
Rakhshandehroo
M
Wildhagen
MF
Verkleij–Hagoort
AC
Steegers
EA
Steegers–Theunissen RP
High maternal vitamin E intake by diet or supplements is associated with congenital heart defects in the offspring
BJOG: An International Journal of Obstetrics & Gynaecology
,
2009
, vol.
116
(pg.
416
-
423
)
Sorensen
HT
Norgard
B
Pedersen
L
Larsen
H
Johnsen
SP
Maternal smoking and risk of hypertrophic infantile pyloric stenosis: 10 year population based cohort study
BMJ
,
2002
, vol.
325
(pg.
1011
-
1012
)
Steinberger
EK
Ferencz
C
Loffredo
CA
Infants with single ventricle: a population–based epidemiological study
Teratology
,
2002
, vol.
65
(pg.
106
-
115
)
Stoll
C
Alembik
Y
Roth
MP
Dott
B
Risk factors in congenital anal atresias
Ann Genet
,
1997
, vol.
40
(pg.
197
-
204
)
Stoll
C
Alembik
Y
Dott
B
Roth
MP
Risk factors in congenital abdominal wall defects (omphalocele and gastroschisi): a study in a series of 265,858 consecutive births
Ann Genet
,
2001
, vol.
44
(pg.
201
-
208
)
Suarez
L
Felkner
M
Brender
JD
Canfield
M
Hendricks
K
Maternal exposures to cigarette smoke, alcohol, and street drugs and neural tube defect occurrence in offspring
Maternal Child Health J
,
2008
, vol.
12
(pg.
394
-
401
)
Szendrey
T
Danyi
G
Czeizel
A
Etiological study on isolated esophageal atresia
Hum Genet
,
1985
, vol.
70
(pg.
51
-
8
)
Talbot
P
In vitro assessment of reproductive toxicity of tobacco smoke and its constituents
Birth Defects Res C Embryo Today
,
2008
, vol.
84
(pg.
61
-
72
)
Tamura
T
Munger
RG
Corcoran
C
Bacayao
JY
Nepomuceno
B
Solon
F
Plasma zinc concentrations of mothers and the risk of nonsyndromic oral clefts in their children: a case–control study in the Philippines
Birth Defects Res
,
2005
, vol.
73
(pg.
612
-
616
)
Targett
CS
Ratten
GJ
Abell
DA
Beischer
NA
The Influence of Smoking on Intrauterine Fetal Growth and on Maternal Oestriol Excretion
Aust N Z J Obstet Gynecol
,
1977
, vol.
17
(pg.
126
-
130
)
Tata
LJ
Lewis
SA
McKeever
TM
Smith
CJ
Doyle
P
Smeeth
L
Gibson
JE
Hubbard
RB
Effect of maternal asthma, exacerbations and asthma medication use on congenital malformations in offspring: a UK population–based study
Thorax
,
2008
, vol.
63
(pg.
981
-
987
)
The
NS
Honein
MA
Caton
AR
Moore
CA
Siega–Riz
AM
Druschel
CM
Risk factors for isolated biliary atresia, National Birth Defects Prevention Study, 1997–2002
Am J Med Genet A
,
2007
, vol.
143A
(pg.
2274
-
2284
)
Tikkanen
J
Heinonen
OP
Maternal exposure to chemical and physical factors during pregnancy and cardiovascular malformations in the offspring
Teratology
,
1991
, vol.
43
(pg.
591
-
600
)
Torfs
CP
Velie
EM
Oechsli
FW
Bateson
TF
Curry
CJ
A population–based study of gastroschisis: demographic, pregnancy, and lifestyle risk factors
Teratology
,
1994
, vol.
50
(pg.
44
-
53
)
Tornqvist
K
Ericsson
A
Kallen
B
Optic nerve hypoplasia: Risk factors and epidemiology
Acta Ophthalmol Scand
,
2002
, vol.
80
(pg.
300
-
304
)
Tong
VT
Jones
JR
Dietz
PM
D'Angelo
D
Bombard
JM
Trends in smoking before, during, and after pregnancy – Pregnancy Risk Assessment Monitoring System (PRAMS), United States, 31 sites, 2000–2005
Morbidity and mortality weekly report. Centers for Disease Control and Prevention
,
2009
, vol.
29

SS–4
Torp–Pedersen
T
Boyd
HA
Poulsen
G
Haargaard
B
Wohlfahrt
J
Holmes
JM
Melbye
M
In–utero exposure to smoking, alcohol, coffee, and tea and risk of strabismus
Am J Epidemiol
,
2010
, vol.
171
(pg.
868
-
875
)
Tuohy
PG
Counsell
AM
Geddis
DC
The Plunket National Child Health Study: birth defects and sociodemographic factors
N Z Med J
,
1993
, vol.
106
(pg.
489
-
492
)
Tuthill
DP
Stewart
JH
Coles
EC
Andrews
J
Cartlidge
PH
Maternal cigarette smoking and pregnancy outcome
Paediatr Perinat Epidemiol
,
1999
, vol.
13
(pg.
245
-
253
)
Underwood
P
Hester
LL
Laffitte
T
Jr.
Gregg
KV
The relationship of smoking to the outcome of pregnancy
Am J Obstet Gynecol
,
1965
, vol.
91
(pg.
270
-
276
)
US Surgeon General
Department of Health and Human Services, Women and smoking
2001
Rockville
DHHS

A report of the US Surgeon General
US Surgeon General
Department of Health and Human Services, The health consequences of smoking
2004
Rockville
DHHS

A report of the US Surgeon General
US Surgeon General
U.S. Department of Health and Human Services
2010

How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking–Attributable Disease. A Report of the Surgeon General. Public Health Service. Office of the Surgeon General
van den Boogaard
MJ
de Costa
D
Krapels
IP
Liu
F
van Duijn
C
Sinke
RJ
Lindhout
D
Steegers–Theunissen
RP
The MSX1 allele 4 homozygous child exposed to smoking at periconception is most sensitive in developing nonsyndromic orofacial clefts
Hum Genet
,
2008
, vol.
124
(pg.
525
-
534
)
Van den Eeden
SK
Karagas
MR
Daling
JR
Vaughan
TL
A case–control study of maternal smoking and congenital malformations
Paediatr Perinat Epidemiol
,
1990
, vol.
4
(pg.
147
-
155
)
van Rooij
IA
Wegerif
MJ
Roelofs
HM
Peters
WH
Kuijpers–Jagtman
AM
Zielhuis
GA
Merkus
HM
Steegers–Theunissen
RP
Smoking, genetic polymorphisms in biotransformation enzymes, and nonsyndromic oral clefting: a gene–environment interaction
Epidemiology
,
2001
, vol.
12
(pg.
502
-
507
)
van Rooij
IA
Groenen
PM
van Drongelen
M
Te Morsche
RH
Peters
WH
Steegers–Theunissen
RP
Orofacial clefts and spina bifida: N–acetyltransferase phenotype, maternal smoking, and medication use
Teratology
,
2002
, vol.
66
(pg.
260
-
266
)
Verkerk
PH
Buitendijk
SE
Verloove–Vanhorick
SP
Differential misclassification of alcohol and cigarette consumption by pregnancy outcome
Int J Epidemiol
,
1994
, vol.
23
(pg.
1218
-
1225
)
Virtanen
HE
Tapanainen
AE
Kaleva
MM
Suomi
AM
Main
KM
Skakkebaek
NE
Toppari
J
Mild gestational diabetes as a risk factor for congenital cryptorchidism
J Clin Endocrinol Metab
,
2006
, vol.
91
(pg.
4862
-
4865
)
Vogt
G
Horvath–Puho
E
Czeizel
AE
A population–based case–control study of isolated primary congenital glaucoma
Am J Med Genet A
,
2006
, vol.
140
(pg.
1148
-
1155
)
Wang
W
Guan
P
Xu
W
Zhou
B
Risk factors for oral clefts: a population–based case–control study in Shenyang, China
Paediatr Perinat Epidemiol
,
2009
, vol.
23
(pg.
310
-
320
)
Wasserman
CR
Shaw
GM
O'Malley
CD
Tolarova
MM
Lammer
EJ
Parental cigarette smoking and risk for congenital anomalies of the heart, neural tube, or limb
Teratology
,
1996
, vol.
53
(pg.
261
-
267
)
Watkins
ML
Scanlon
KS
Mulinare
J
Khoury
MJ
Is maternal obesity a risk factor for anencephaly and spina bifida?
Epidemiology
,
1996
, vol.
7
(pg.
507
-
512
)
Watkins
ML
Rasmussen
SA
Honein
MA
Botto
LD
Moore
CA
Maternal obesity and risk for birth defects
Pediatrics
,
2003
, vol.
111
(pg.
1152
-
1158
)
Werler
MM
Mitchell
AA
Shapiro
S
Werler
MM
Mitchell
AA
Shapiro
S
Demographic, reproductive, medical, and environmental factors in relation to gastroschisis
Teratology
,
1992
, vol.
45
(pg.
353
-
360
)
Werler
MM
Bower
C
Payne
J
Serna
P
Findings on potential teratogens from a case–control study in Western Australia
Aust N Z J Obstet Gynaecol
,
2003
, vol.
43
(pg.
443
-
447
)
Werler
MM
Sheehan
JE
Mitchell
AA
Association of vasoconstrictive exposures with risks of gastroschisis and small intestinal atresia
Epidemiology
,
2003
, vol.
14
(pg.
349
-
354
)
Werler
MM
Mitchell
AA
Moore
CA
Honein
MA
National Birth Defects Prevention Study
Is there epidemiologic evidence to support vascular disruption as a pathogenesis of gastroschisis?
Am J Med Genet A
,
2009
, vol.
149A
(pg.
1399
-
1406
)
Werler
MM
Starr
JR
Cloonan
YK
Speltz
ML
Hemifacial microsomia: from gestation to childhood
J Craniofac Surg
,
2009
, vol.
20

Suppl 1
(pg.
664
-
669
)
Wong–Gibbons
DL
Romitti
PA
Sun
L
Moore
CA
Reefhuis
J
Bell
EM
Olshan
AF
Maternal periconceptional exposure to cigarette smoking and alcohol and esophageal atresia +/– tracheo–esophageal fistula
Birth Defects Res
,
2008
, vol.
82
(pg.
776
-
784
)
Woods
SE
Raju
U
Maternal smoking and the risk of congenital birth defects: a cohort study
J Am Board Fam Pract
,
2001
, vol.
14
(pg.
330
-
334
)
Wald
NJ
Hackshaw
AK
Doll
R
Crofton
J
Cigarette smoking: an epidemiological overview
Tobacco and Health
,
1996
, vol.
52
(pg.
3
-
11
British Medical Bulletin
Wehby
GL
Cassell
CH
The impact of orofacial clefts on quality of life and healthcare use and costs
Oral Dis
,
2010
, vol.
16
(pg.
3
-
10
)
Werler
MM
Pober
BR
Holmes
LB
Smoking and pregnancy
Teratology
,
1985
, vol.
32
(pg.
473
-
481
)
Williams
L
Morrow
B
Shulman
H
Stephens
R
D'Angelo
D
Fowler
CI
PRAMS 2002 Surveillance Report
Atlanta, GA
Division of Reproductive Health

National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, 2006. http://www.cdc.gov/PRAMS/Reports.htm.
Wyszynski
DF
Duffy
DL
Beaty
TH
Maternal cigarette smoking and oral clefts: a meta–analysis
Cleft Palate Craniofac J
,
1997
, vol.
34
(pg.
206
-
210
)
Yushkiv
N
Honein
MA
Moore
CA
Reported multivitamin consumption and the occurrence of multiple congenital anomalies
Am J Med Genetics
,
2005
, vol.
136A
(pg.
1
-
7
)
Wyszynski
DF
Wu
T
Use of US birth certificate data to estimate the risk of maternal cigarette smoking for oral clefting
Cleft Palate Craniofac J
,
2002
, vol.
39
(pg.
188
-
192
)
Yerushalmy
J
The relationship of parents' cigarette smoking to outcome of pregnancy – implications as to the problem of inferring causation from the observed associations
Am J Epidemiol
,
1971
, vol.
93
(pg.
443
-
456
)
Yerushalmy
J
Congenital heart disease and maternal smoking habits
Nature
,
1973
, vol.
242
(pg.
262
-
263
)
Yuan
P
Okazaki
I
Kuroki
Y
Anal atresia: effect of smoking and drinking habits during pregnancy
Jpn J Hum Genet
,
1995
, vol.
40
(pg.
327
-
332
)
Zeiger
JS
Beaty
TH
Hetmanski
JB
Wang
H
Scott
AF
Kasch
L
Raymond
G
Jabs
EW
VanderKolk
C
Genetic and environmental risk factors for sagittal craniosynostosis
J Craniofac Surg
,
2002
, vol.
13
(pg.
602
-
606
)
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