Abstracts

Introduction

Birth defects are the cause of high mortality and morbidity in children. It is estimated that about 5% of live births present some abnormality in their development¹1. Horovitz DDG, Llerena Jr. JC, Mattos RA. Atenção aos defeitos congênitos no Brasil: panorama atual. Cad Saúde Pública 2005; 21:1055-64.. Over the past decades, birth defects have increasingly contributed to child mortality²2. Powell-Griner E, Woolbright A. Trends in infant deaths from congenital anomalies: results from England and Wales, Scotland, Sweden and the United States. Int J Epidemiol 1990; 19:391-8.^,33. Neto PS, Zhang L, Nicoletti D, Munchen FB. Mortalidade infantil por malformações congênitas no Brasil. Rev AMRIGS 2012; 56:129-32.. In Brazil, the rate of child deaths due to birth defects rose from 9.7% in 1996 to 18.2% in 2008, representing an annual average increase of 0.71%³3. Neto PS, Zhang L, Nicoletti D, Munchen FB. Mortalidade infantil por malformações congênitas no Brasil. Rev AMRIGS 2012; 56:129-32.. This increase may be due to a better management of infections and contagious, and nutrition-related diseases, which reduced child deaths from these conditions ¹1. Horovitz DDG, Llerena Jr. JC, Mattos RA. Atenção aos defeitos congênitos no Brasil: panorama atual. Cad Saúde Pública 2005; 21:1055-64.^,33. Neto PS, Zhang L, Nicoletti D, Munchen FB. Mortalidade infantil por malformações congênitas no Brasil. Rev AMRIGS 2012; 56:129-32..

Most birth defects are of multifactorial etiology. In addition to the genetic component, their occurrence may be related to exposure of the child, even before birth, or the parents to toxic substances, including tobacco⁴4. Stillerman KP, Mattison DR, Giudice LC, Woodruff TJ. Environmental exposures and adverse pregnancy outcomes: a review of the science. Reprod Sci 2008; 15:631-50.. While this investigation was being carried out, a systematic review with 101 observational studies was published, and showed an association between maternal smoking during pregnancy and different birth defects in children ⁵5. Hackshaw A, Rodeck C, Boniface S. Maternal smoking in pregnancy and birth defects: a systematic review based on 173687 malformed cases and 11.7 million controls. Hum Reprod Updat 2011; 17:589-604.. This review, however, did not include a considerable number of relevant studies⁶6. Bird TM, 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; 44:1546-51.^,77. Bracken MB, Holford TR, White C, Kelsey JL. Role of oral contraception in congenital malformations of offspring. Int J Epidemiol 1978; 7:309-17.^,88. Cedergren MI, Selbing AJ, Källén BAJ. Risk factors for cardiovascular malformation - a study based on prospectively collected data. Scan J Work Environ Health 2002; 28:12-7.^,99. Christensen K, Olsen J, Norgaard-Pedersen B, Basso O, Stovring H, Milhollin-Johnson L, et al. Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case-control study in Denmark, 1991-1994. Am J Epidemiol 1999; 149:248-55.^,1010. DeRoo LA, Gaudino JA, Edmonds LD. Orofacial cleft malformations: associations with maternal and infant characteristics in Washington state. Birth Defects Res A Clin Mol Teratol 2003; 67: 637-42.^,1111. Dickinson KC, Meyer RE, Kotch J. Maternal smoking and the risk for clubfoot in infants. Birth Defects Res A Clin Mol Teratol 2008; 82:86-91.^,1212. Feldkamp ML, Alder SC, Carey JC. A case control population-based study investigating smoking as a risk factor for gastroschisis in Utah, 1997-2005. Birth Defects Res A Clin Mol Teratol 2008; 82: 768-75.^,1313. Ramirez D, Lammer EJ, Iovannisci DM, Laurent C, Finnell RH, Shaw GM. Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts. Cleft Palate Craniofac J 2007; 44:366-73.^,1414. Williams LJ, Correa A, Rasmussen S. Maternal lifestyle factors and risk for ventricular septal defects. Birth Defects Res A Clin Mol Teratol 2004; 70:59-64.. Moreover, defects of the abdominal wall, such as congenital diaphragmatic and inguinal hernia, gastroschisis, and omphalocele, which should be considered musculoskeletal abnormalities, according to the 10^th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10)¹⁵15. Centro Colaborador da OMS para a Classificação de Doenças em Português. Classificação estatística internacional de doenças e problemas relacionados à saúde. 10a revisão. http://www.datasus.gov.br/cid10/V2008/cid10.htm (accessed on 20/Apr/2010).
http://www.datasus.gov.br/cid10/V2008/ci... were classified as gastrointestinal defects.

The purpose of this systematic review is to investigate maternal smoking during pregnancy and birth defects in children. The possible dose-response relation in that association was also studied.

Methods

A systematic review with meta-analysis was conducted. The procedures for the review and reporting of the results were based on the recommendations by MOOSE (Meta-analysis of Observational Studies in Epidemiology) ¹⁶16. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000; 283:2008-12.. The protocol for the review was assessed and approved by a panel that included two experts in Pediatrics and one in Epidemiology, in 2010.

Studies that investigated the association between maternal smoking during pregnancy and birth defects in children were considered eligible for the review. Studies that contemplated the association between maternal smoking and chromosomal abnormalities were ruled out.

The electronic search of the studies was made on databases Ovid MEDLINE (1950 until April 2010), SciELO, and LILACS. The strategy to search potentially relevant studies for the review on the databse Ovid MEDLINE is composed of two parts (Figure 1): the first (from line #1 to line #4) is the search strategy to identify studies on maternal smoking, and the secons part (from line #5 to line #20) is the strategy to find birth-defects-related studies. The bibliographic references of articles whose full text was obtained were reviewed, in order to identify additional studies. The Google Translator (https://translate.google.com.br/) was used to translate two articles, one in Lithuanian and other in French.

Study selection was independently made by four investigators (two teams of two). Selection process was made in two stages: in the first, the title and abstract of the articles identified during the electronic search were reviewed to select potential studies for this review. The full text of articles was obtained for which information from the title and the abstract met the inclusion criteria, or in cases where there was not enough information to decide about their inclusion. In the second stage, the articles were read in full for a final selection of the studies, with the inclusion and exclusion criteria being checked. Discrepancies among the investigators were resolved by consensus. Data extraction was performed by four investigators using a standard form. The extracted data were checked by the investigators.

Meta-analysis was performed using the software Stata, version 11.0 (Stata Corp., College Station, United States). A random effects model was applied. The association between maternal smoking during pregnancy and the presence of any kind of birth defects in children was evaluated by means of odds ratios (OR) and 95% confidence intervals (95%CI). When the original studies indicated the presence of more than one defect, the results of each defect were combined to obtain data of any type of defect. Whenever possible, adjusted OR was used.

The pre-defined sub-group analyses were performed to investigate the association between maternal smoking during pregnancy and birth defects in children, according to the organ systems involved. The classification of birth defects was based on the ICD-10. The pre-defined sub-group analyses were also used to assess the potential influence of the following methodological aspects in the results of the meta-analyses: design of the investigation (prospective vs. retrospective); size of the sample (cases) (≤ 200; 200-1,000; 1,000-5,000; > 5,000); adjustment/matching of confounding factors, including age of the mother (yes vs. no). Two post hoc subgroup analyses were performed to assess the potential impact of exposure definition (maternal smoking), and the period of exposure during pregnancy in the meta-analysis results. To investigate the dose-response relation between maternal smoking during pregnancy and birth defects in children, the analysis was stratified in three categories according to the number of cigarettes smoked per day (1-9, 10-19 and > 20).

Heterogeneity of results among the studies was assessed through the I²2. Powell-Griner E, Woolbright A. Trends in infant deaths from congenital anomalies: results from England and Wales, Scotland, Sweden and the United States. Int J Epidemiol 1990; 19:391-8. statistic. I²2. Powell-Griner E, Woolbright A. Trends in infant deaths from congenital anomalies: results from England and Wales, Scotland, Sweden and the United States. Int J Epidemiol 1990; 19:391-8. > 75% indicates significant heterogeneity¹⁷17. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003; 327:557-60.. Possible causes for heterogeneity were examined through the above mentioned sub-group analyses. The publication bias was investigated with the use of the funnel plot and the Egger test¹⁷17. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003; 327:557-60..

Results

Out of the 1,043 citations identified by the electronic search, 129 studies were selected. Fifty-nine additional studies were included, found in reviews of original articles and from the systematic review. Therefore, a total of 188 studies (153 projects or independent databases) ⁶6. Bird TM, 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; 44:1546-51.^,77. Bracken MB, Holford TR, White C, Kelsey JL. Role of oral contraception in congenital malformations of offspring. Int J Epidemiol 1978; 7:309-17.^,88. Cedergren MI, Selbing AJ, Källén BAJ. Risk factors for cardiovascular malformation - a study based on prospectively collected data. Scan J Work Environ Health 2002; 28:12-7.^,99. Christensen K, Olsen J, Norgaard-Pedersen B, Basso O, Stovring H, Milhollin-Johnson L, et al. Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case-control study in Denmark, 1991-1994. Am J Epidemiol 1999; 149:248-55.^,1010. DeRoo LA, Gaudino JA, Edmonds LD. Orofacial cleft malformations: associations with maternal and infant characteristics in Washington state. Birth Defects Res A Clin Mol Teratol 2003; 67: 637-42.^,1111. Dickinson KC, Meyer RE, Kotch J. Maternal smoking and the risk for clubfoot in infants. Birth Defects Res A Clin Mol Teratol 2008; 82:86-91.^,1212. Feldkamp ML, Alder SC, Carey JC. A case control population-based study investigating smoking as a risk factor for gastroschisis in Utah, 1997-2005. Birth Defects Res A Clin Mol Teratol 2008; 82: 768-75.^{, 13}13. Ramirez D, Lammer EJ, Iovannisci DM, Laurent C, Finnell RH, Shaw GM. Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts. Cleft Palate Craniofac J 2007; 44:366-73.^,1414. 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Anal atresia: effect of smoking and drinking habits during pregnancy. Jpn J Hum Genet 1995; 40:327-32.^,196196. Zeiger JS, Beaty TH, Hetmanski JB, Wang H, Scott AF, Kasch L, et al. Genetic and environmental risk factors for sagittal craniosynostosis. J Craniofac Surg 2002; 13:602-6. with a total of 13,564,914 subjects (192,655 birth defect cases, and 13,372,259 controls with no defects) were included in this review (Figure 2). Twenty-nine were prospective studies (cohort, or nested-case control studies), and 159 were retrospective (case-control, or cross-sectional studies). The overall characteristics of the 188 studies included are shown in Table 1.

Table 2 presents individual and combined results of the 188 studies about the association between maternal smoking during pregnancy and birth defect of any type in children. The meta-analysis of the 188 studies showed that children of smoking mother had a higher chance of presenting any type of birth defects (OR: 1.18; 95%CI: 1.14-1.22; p < 0.001; I²2. Powell-Griner E, Woolbright A. Trends in infant deaths from congenital anomalies: results from England and Wales, Scotland, Sweden and the United States. Int J Epidemiol 1990; 19:391-8.: 77.2%).

In the sub-group analyses, according to the organ systems involved, there were significant positive associations between maternal smoking and defects in the cardiovascular system (OR: 1.11; 95%CI: 1.03-1.19), digestive system (OR: 1.18; 95%CI: 1.07-1.30), musculoskeletal system (OR: 1.27; 95%CI: 1.16-139), and face and neck (OR: 1.28; 95%CI: 1.19-1.37) (Figure 3). Other subgroup analyses showed that retrospective studies and those with smaller sample size (≤ 1.000 cases) has higher combined OR values. Using or not adjustment/matching in the original studies to control confounding factors, particularly the age of the mother did not significantly affect the meta-analysis results (Table 3). Two post hoc sub-group analyses were performed to assess the potential impact of the definition of maternal smoking, and the period of pregnancy the pregnant mother was exposed to smoking in the meta-analysis results. There was no statistically significant difference between studies in which maternal smoking during pregnancy was explicitly defined as daily smoking (n = 91; OR: 1.21; 95%CI: 1.16-1.26) and those studies with no clear definition (n = 97; OR: 1.17; 95%CI: 1.11-1.23) (χ² = 1.0; p = 0.32). In addition, there was no statistically significant difference between studies in which exposure to smoking occurred in the first quarter of the pregnancy (n = 80; OR: 1.22; 95%CI: 1.17-1.29) and those studies with no clear definition (n = 108; OR: 1.16; 95%CI: 1.10-1.21) (χ² = 2.1; p = 0.15).

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Maternal cigarette smoking during pregnancy increases the risk of having a child with a congenital digital anomaly. Plast Reconst Surg 2006; 117:301-8.^,119119. McDonald AD, Armstrong BG, Sloan M. Cigarette, alcohol, and coffee consumption and congenital defects. Am J Public Health 1992; 82:91-3.^,121121. 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; 23:9-17.^{, 122}122. Miller EA, Rasmussen SA, Siega-Riz AM, Frías JL, Honein MA. Risk factors for non-syndromic holoprosencephaly in the national birth defects prevention study. Am J Med Genet C Semin Med Genet 2010; 154C:62-72.^,123123. 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; 153:1007-15.^,124124. Morales-Suárez-Varela MM, Bille C, Christensen K, Olsen J. Smoking habits, nicotine use, and congenital malformations. Obstet Gynecol 2006; 107:51-7.^,132132. 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; 43:1791-5.^,135135. Parker SE, Mai CT, Strickland MJ, Olney RS, Rickard R, Marengo L, et al. Multistate study of the epidemiology of clubfoot. Birth Defects Res A Clin Mol Teratol 2009; 85:897-904.^,144144. 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; 166:775-85.^,150150. Shaw GM, Wasserman CR, Lammer EJ, O'Malley CD, Murray JC, Basart AM, et al. Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants. Am J Hum Genet 1996; 58:551-61.^,151151. Shaw GM, Velie EM, Morland KB. Parental recreational drug use and risk for neural tube defects. Am J Epidemiol 1996; 144:1155-60.^,157157. Slickers JE, Olshan AF, Siega-Riz AM, Honein MA, Aylsworth AS. 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; 168:1259-67.^,163163. 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. Matern Child Health J 2008; 12:394-401.^,169169. Tikkanen J, Heinonen OP. Maternal exposure to chemical and physical factors during pregnancy and cardiovascular malformations in the offspring. Teratology 1991; 43:591-600.^,172172. Tornqvist K, Ericsson A, Kallen B. Optic nerve hypoplasia: risk factors and epidemiology. Acta Ophthalmol Scand 2002; 80:300-4.^,173173. 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Use of US birth certificate data to estimate the risk of maternal cigarette smoking for oral clefting. Cleft Palate Craniofac J 2002; 39:188-92. with a total of 12,137,944 subjects (103,107 cases) contributed their data to the analysis, of which 11 were prospective studies. The power of association between maternal smoking and defects measured by OR (95%CI) is significantly related with the daily amount of cigarettes smoked (χ² = 12.1; p = 0.002). Post hoc sub-group analyses were performed according to the design of the investigation, control of confounders, and size of the sample (cases). The statistically significant dose-response relation was seen in sub-groups of studies that had controlled confounder factors and in studies where the number of cases ranged between 200 and 5,000 (Table 4). The design of the investigation did not substantially affect the results of the dose-response relation.

The cumulative meta-analysis showed a statistically significant association between maternal smoking during pregnancy and birth defects in children when 40 studies published until 1990, with a total of 26,827 were included in the analysis (OR: 1.09; 95%CI: 1.001-1.19; p = 0.035). The OR (95%CI) and the p value were respectively 1.16 (1.10-1.23) and < 0.001, when 87 studies published until 2000, with a total of 95,556 cases were included in the meta-analysis. The result of the meta-analysis remained almost unchanged when 101 studies (97,099 cases) published between 2001 and 2010 were included (Figure 5).

In the funnel plot (Figure 6), a slight asymmetry in the lower left corner was observed due to lack of studies, which suggested that studies with small samples demonstrating protective effects of maternal smoking against defects in children had not been published. The Egger test also showed evidence of the "small studies" effect, which suggests the presence of publication bias (p < 0.001).

Discussion

This systematic review with meta-analysis has shown that children of mothers who smoked during pregnancy are at a higher risk of presenting birth defects of any type. Significant associations between maternal smoking during pregnancy and birth defects of the cardiovascular, digestive, musculoskeletal systems and of the face and neck were evidenced. Positive associations were also observed between maternal smoking and birth defects of the respiratory, nervous, and urogenital systems; however, these associations were not statistically significant.

In this systematic review a statistically significant dose-response relation was alsou found between maternal smoking during pregnancy and the risk of birth defects in children; this means, the higher the number of cigarettes a day smoked by the mother, the higher the risk of having babies with some type of birth defects. It was also observed that all the three daily doses of cigarette-smoking were significantly associated with higher risk of birth defects compared to non-smoking, suggesting that the regular use of cigarettes by the pregnant woman, even in small amounts, may cause adverse impact in the development of the fetus.

The mechanisms of action of tobacco in the increase of abnormalities in babies are not accurately understood. It is believed that the vasoconstrictor effect of nicotine may reduce the uterine and placental blood flow¹⁹⁷197. Leopércio W, Gigliotti A. Tabagismo e suas peculiaridades durante a gestação: uma revisão crítica. J Bras Pneumol 2004; 30:176-85.. Carbon monoxide binds to the hemoglobin in such a way that less oxygen is available for the placenta. In addition, the endothelial injury caused by tobacco increases the rupture of blood vessels from neovascularization of the placenta, leading to a decrease in the blood flow to the fetus, causing hypoxia which will likely result in abnormal fetal morphogenesis¹⁹⁸198. Quinton AE, Cook CM, Peek MJ. The relationship between cigarette smoking, endothelial function and intrauterine growth restriction in human pregnancy. BJQG 2008; 115:780-4.. Therefore, exposure to toxins in tandem with hypoxia and cellular ischemia results in abnormal cellular proliferation.

Approximately one third of Brazilian adults were smokers by the end of the 1990s; there was, however, a reduction of about 50% (from 34% to 18.2%) in the prevalence of smokers in this population between 1989 and 2008¹⁹⁹199. Szklo AS, de Almeida LM, Figueiredo VC, Autran M, Malta D, Caixeta R, et al. Snapshot of the striking decrease in cigarette smoking prevalence in Brazil between 1989 and 2008. Prev Med 2012; 54:162-7.. A number of factors account for this reduction, including anti-tobacco policies and availability of smoking-cessation treatments. Smoking during pregnancy is of particular concern, as it is associated with many maternal-fetal outcomes, such as low-weight at birth, premature deliveries, perinatal deaths, and birth defects²⁰⁰200. Salihu HM, Wilson RE. Epidemiology of parental smoking and perinatal outcomes. Early Hum Dev 2007; 83:713-20.^,201201. Zhang L, González-Chica DA, Cesar JA, Mendoza-Sassi RA, Beskow B, Larentis N, et al. Tabagismo materno durante a gestação e medidas antropométricas do recém-nascido: um estudo de base populacional no extremo sul do Brasil. Cad Saúde Pública 2011; 27:1768-76.. In countries such as the United States and Canada, where anti-tobacco governmental policies are aggressive, and strong investments are made to control smoking during pregnancy, the prevalence of maternal smoking during pregnancy is currently around 10 to 12%²⁰²202. Tong VT, Dietz PM, Morrow B, D'Angelo DV, Farr SL, Rockhill KM, et al. Trends in smoking before, during, and after pregnancy: Pregnancy Risk Assessment Monitoring System, United States, 40 sites, 2000-2010. MMWR Surveill Summ 2013; 62:1-19.^,203203. Ontario Tobacco Research Unit. Indicators of smoke-free Ontario progress. Toronto: Ontario Tobacco Research Unit; 2010.. A recent study carried out in nine countries, including Latin America (Argentina, Brazil, Ecuador, Guatemala and Uruguay), Asia (India and Pakistan), and Africa (Democratic Republic of Congo and Zambia) showed higher prevalence of maternal smoking during pregnancy in Uruguay (18.3%), followed by Argentina (10.3%) and Brazil (6.1%)²⁰⁴204. Bloch M, Althabe F, Onyamboko M, Kaseba-Sata C, Castilla EE, Freire S, et al. Tobacco use and secondhand smoke exposure during pregnancy: an investigative survey of women in 9 developing nations. Am J Public Health 2008; 98:1833-40.. However, some local studies made in Brazil have shown a prevalence of active smoking of around 20% among pregnant women²⁰¹201. Zhang L, González-Chica DA, Cesar JA, Mendoza-Sassi RA, Beskow B, Larentis N, et al. Tabagismo materno durante a gestação e medidas antropométricas do recém-nascido: um estudo de base populacional no extremo sul do Brasil. Cad Saúde Pública 2011; 27:1768-76.^,205205. Reis LG, da Silva CF, Trindade A, Abrahão M, da Silva VA. Quem são as mulheres tabagistas que param de fumar na gestação? Rev Bras Saúde Matern Infant 2008; 8:217-21., a proportion much higher than the reported in this international multicentric study. These data point the need for yet stronger actions against tobacco-use during pregnancy in Latin America, including Brazil.

There are a number of resources available to facilitate smoking cessation, such as anti-smoking patches, and anti-anxiety agents like bupropion¹⁹⁷197. Leopércio W, Gigliotti A. Tabagismo e suas peculiaridades durante a gestação: uma revisão crítica. J Bras Pneumol 2004; 30:176-85.. These may be used prior to the patient become pregnant. For this reason, we stress the importance of pre-pregnancy counseling.

A systematic review has also shown an association between maternal smoking during pregnancy and birth defects in children⁵5. Hackshaw A, Rodeck C, Boniface S. Maternal smoking in pregnancy and birth defects: a systematic review based on 173687 malformed cases and 11.7 million controls. Hum Reprod Updat 2011; 17:589-604.. Compared to that review, this one has included 20 additional studies⁶6. Bird TM, 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; 44:1546-51.^,77. Bracken MB, Holford TR, White C, Kelsey JL. Role of oral contraception in congenital malformations of offspring. Int J Epidemiol 1978; 7:309-17.^,88. Cedergren MI, Selbing AJ, Källén BAJ. Risk factors for cardiovascular malformation - a study based on prospectively collected data. Scan J Work Environ Health 2002; 28:12-7.^,99. Christensen K, Olsen J, Norgaard-Pedersen B, Basso O, Stovring H, Milhollin-Johnson L, et al. Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case-control study in Denmark, 1991-1994. Am J Epidemiol 1999; 149:248-55.^,1010. DeRoo LA, Gaudino JA, Edmonds LD. Orofacial cleft malformations: associations with maternal and infant characteristics in Washington state. Birth Defects Res A Clin Mol Teratol 2003; 67: 637-42.^,1111. Dickinson KC, Meyer RE, Kotch J. Maternal smoking and the risk for clubfoot in infants. Birth Defects Res A Clin Mol Teratol 2008; 82:86-91.^,1212. Feldkamp ML, Alder SC, Carey JC. A case control population-based study investigating smoking as a risk factor for gastroschisis in Utah, 1997-2005. Birth Defects Res A Clin Mol Teratol 2008; 82: 768-75.^,1313. Ramirez D, Lammer EJ, Iovannisci DM, Laurent C, Finnell RH, Shaw GM. Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts. Cleft Palate Craniofac J 2007; 44:366-73.^,1414. Williams LJ, Correa A, Rasmussen S. Maternal lifestyle factors and risk for ventricular septal defects. Birth Defects Res A Clin Mol Teratol 2004; 70:59-64.^,2424. Bailey RR. The effect of maternal smoking on the infant birth weight. N Z Med J 1970; 71:293-4.^,4343. Carmichael SL, Shaw GM, Laurent C, Lammer EJ, Olney RS. Hypospadias and maternal exposures to cigarette smoke. Pediatr Perinat Epidemiol 2005; 19:406-12.^,7979. Hobbs CA, James SJ, Jernigan S, Melnyk S, Lu Y, Malik S, et al. Congenital heart defects, maternal homocysteine smoking, and the 677 C>T polymorphism in the methylenetetrahydroflate reductase gene: evaluating gene-environment interactions. Am J Obstet Gynecol 2006; 194:218-24.^,8383. Honein MA, Rasmussen SA, Reefhuis J, Romitti PA, Lammer EJ, Sun L, et al. Maternal smoking and environmental tobacco smoke exposure and the risk of orofacial clefts. Epidemiology 2007; 18:226-33.^,9595. Kuciene R, Dulskiene V. Maternal socioeconomic and lifestyle factors during pregnancy and the risk of congenital heart defects. Medicina (Kaunas) 2009; 45:904-9.^,9999. Lam PK, Torfs CP. Interaction between maternal smoking and malnutrition in infant risk of gastroschisis. Birth Defects Res A Clin Mol Teratol 2006; 76:182-6.^,102102. Li Z, Ren A, Zhang L, Guo Z, Li Z. A population-based case-control study of risk factors for neural tube defects in four high-prevalence areas of Shanxi province, China. Paediatr Perinat Epidemiol 2006; 20:43-53.^,103103. Lie RT, Wilcox AJ, Taylor J, Gjessing HK, Saugstad OD, Aabyholm F, et al. Maternal smoking and oral clefts. Epidemiology 2008; 19:606-15.^,122122. Miller EA, Rasmussen SA, Siega-Riz AM, Frías JL, Honein MA. Risk factors for non-syndromic holoprosencephaly in the national birth defects prevention study. Am J Med Genet C Semin Med Genet 2010; 154C:62-72.^{, 125}125. Morgana LM, 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; 167:257-61.^,188188. Werler MM, Bosco JLF, Shapira SK. Maternal vasoactive exposures, amniotic bands, and terminal transverse limb defects. Birth Defects Res A Clin Mol Teratol 2009; 85:52-7. that have added about 10,000 cases of defects, and 800,000 of controls. Another difference between the two reviews is that 19 studies about abdominal wall defects were included in the meta-analysis of the gastro-intestinal system in the previous review, whereas these defects were classified as pertaining to the musculoskeletal system in this review. Despite these methodological differences, the results of these two reviews were similar in regards to the association between maternal smoking during pregnancy and defects of the cardiovascular, respiratory, digestive, nervous, urogenital and musculoskeletal systems. The meta-analysis from the previous review included 38 studies in which all defects were combined together did not show significant association between maternal smoking and birth defects (OR: 1.01; 95%CI: 0.96-1.07). The meta-analysis of the current review has included all the 188 studies in which the defects were both combined or of a particular type, and evidenced a statistically significant association between maternal smoking during pregnancy and the risk of any type of birth defect in children (OR: 1.18; 95%CI: 1.14-1.22).

The cumulative meta-analysis of this current review shows that there was already evidence of the association between maternal smoking during pregnancy and birth defects in children by analyzing the results of 40 studies published until 1990 that included a total of 26,827 cases of defects (OR = 1.09; p = 0.035). The evidence of the association became more robust with the results of 87 studies published until 2000, with a total of 95,556 cases (OR = 1.16; p < 0.0001). Between 2000 and 2010, more than 100 studies were carried out with some 100,000 cases of defects; the inclusion of these studies, however, did not change significantly the results of the meta-analysis. These data indicate that findings about the association between maternal smoking during pregnancy and birth defects in children are convincing, and there is no need of further epidemiological studies to investigate this association.

Some methodological studies should be considered in interpreting the results of this systematic review. The heterogeneity of the results of the studies included in this review is to be expected, considering the differences in the research design, type of defect and method used for diagnosis, definition of maternal smoking and control of the effect of confounders. Some of the confounding factors were investigated through subgroup analyses, whose results suggest that the type of defect, the design of the research and the size of the sample are possible causes of heterogeneity. The quality of the studies included was not assessed individually due to limitations of the tools currently available²⁰⁶206. Sanderson S, Iain D, Tatt ID, Higgins JPT. Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. Int J Epidemiol 2007; 36:666-76.; however, the potential influences of the methodological aspects of the studies (research design, sample size, control of the effect of confounders, and definition of exposure) in the results of the meta-analysis were investigated through the sub-group analyses. The influence of passive smoking in the association between maternal smoking during pregnancy and birth defects in children was not investigated due to lack of information in most of the original studies. Future studies should address this issue. The funnel plot and the Egger test suggest the presence of publication bias, due to non-publication of small studies that would demonstrate the protective effect of maternal smoking against defects in children. We believe that the number of this type of study is limited, and the lack of data from these studies does not significantly affect the results of the meta-analysis.

We conclude, from this systematic review with meta-analysis, that maternal smoking during pregnancy is associated with a higher risk of birth defects in children, and that this is a dose-dependent association.

References

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