Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls

Abstract

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).

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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).

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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).

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).

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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.

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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.

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.

Supplementary data

Supplementary data are available at http://humupd.oxfordjournals.org/.

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.

Supplementary Material

Acknowledgements

References