title: Is maternal smoking during pregnancy associated with an increased risk of congenital heart defects among offspring? A systematic review and meta-analysis of observational studies.
abstract: OBJECTIVE
  To investigate the association between maternal smoking during pregnancy and risk of congenital heart defects (CHDs) among offspring.
  
  
  METHODS
  PubMed, EMBASE, and Web of Science were searched for eligible studies. The outcomes of interest included risk of any CHD and nine subtypes. We summarized study characteristics and used a random-effects model in meta-analysis, and a two-stage dose-response model was utilized to assess the association between smoking consumption and risk. Statistical heterogeneity was assessed by a chi-squared test of the Cochrane Q statistic and I-squared value. Publication bias was assessed by funnel plots and Egger's test, and trim and fill method was utilized when publication bias existed.
  
  
  RESULTS
  Forty-three observational epidemiologic studies were included. The pooled risk ratio (RR) of any CHD was 1.11 (95% CI: 1.04, 1.18), but it exhibited substantial statistical heterogeneity (p < 0.001, I2=69.0%). In sensitivity analysis, we observed significant associations for atrial septal defect (ASD) and marginally significant associations for septal defects (SPD). The two-stage dose-response analysis showed evidence to support that higher levels of tobacco smoke was associated with an increased risk of septal defects, particularly for ASD and VSD (ventricular septal defect).
  
  
  CONCLUSIONS
  Our study presents evidence to support the cardiovascular teratogenic effect of maternal smoking during pregnancy, and their offspring may suffer from approximately a 10% relative increase in the risk of CHDs on average.
authors.affiliation: a Department of Epidemiology , University of North Carolina at Chapel Hill Gillings School of Global Public Health , Chapel Hill , NC , USA.
authors.forename: Dongyu
authors.initials: D
authors.lastname: Zhang
authors.affiliation: b Department of Health , Zhuhai Maternity and Child Health Hospital , Zhuhai , Guangdong , China.
authors.forename: Hao
authors.initials: H
authors.lastname: Cui
authors.affiliation: c Department of Epidemiology and.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: d Department of Health Policy and Management , Johns Hopkins University Bloomberg School of Public Health , Baltimore , MD , USA.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Huang
authors.affiliation: e National Office for Maternal and Child Health Surveillance of China, West China Second Hospital, Sichuan University , Chengdu , Sichuan , China , and.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: f National Center for Birth Defects Monitoring of China, West China Second Hospital, Sichuan University , Chengdu , Sichuan , China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
mesh_terms: D016009:Chi-Square Distribution; D005260:Female; D006330:Heart Defects, Congenital / Q000209:etiology*; D006801:Humans; D007231:Infant, Newborn; D064887:Observational Studies as Topic; D016017:Odds Ratio; D011247:Pregnancy; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*
keywords: Cardiovascular disease; child health; smoking; systematic review