CME Author: Vicki Brower Study Authors: Lijuan Zhao, Lizhang Chen, et al. Target Audience and Goal Statement: Obstetricians/gynecologists, pediatricians, pulmonologists, cardiologists, family medicine specialists, internists Questions Addressed: What are the risks for fetal congenital heart defects (CHDs) associated with maternal passive smoking, and paternal active smoking in comparison to maternal active smoking? Which specific fetal heart defects are involved with parental smoking and second-hand smoke? Study Synopsis and Perspective: New data from a large meta-analysis demonstrate that paternal smoking during a mother's pregnancy is a significant and independent risk factor for congenital heart defects (CHDs) among offspring, as is secondhand smoke exposure in general. Maternal smoking is known to be a significant risk factor for CHDs in offspring. But this study indicates that maternal passive smoking and paternal smoking were also linked to greater risk for CHDs in an analysis of 125 observational studies conducted in China, involving more than 135,000 children with the birth defects, and nearly 9 million prospective mothers and fathers. The meta-analysis by Jiabi Qin of Central South University in Changsha, China, and colleagues, is also the first to examine smoking exposure at different stages of pregnancy, they wrote in the European Journal of Preventive Cardiology. Among women, smoking during pregnancy was associated with an increased risk of giving birth to a child with a congenital heart defect, but smoking before pregnancy was not associated with an increased risk. "The critical stage of fetal heart development occurs in the early stages of pregnancy," the team notes. Qin and colleagues observed that three previous reviews of smoking and congenital heart defects examined only maternal active smoking. Results from individual studies examining maternal passive smoking and paternal active smoking and CHD risk were inconsistent, thus the impetus for this study. In addition, the previous meta-analyses were largely limited to populations living in the U.S. and Europe. "In China, there were a large number of studies that assessed the risk of CHDs associated with paternal smoking," the researchers wrote. "If these Chinese documents could be included in future reviews, it will inevitably increase the statistical power, which will help to find a significant statistical difference for risk of CHDs associated with parental smoking, especially for risk estimates of CHD subtypes." A search of seven electronic databases revealed 125 studies, with 137,574 CHD cases and 8,770,837 parents. Summary risk estimates were calculated using either random-effects- or fixed-effects-modeling. The researchers conducted a sensitivity and subgroup analysis to identify potential heterogeneity moderators. The analysis revealed: Maternal active smoking (RR 1.25, 95% CI 1.16–1.34; P<0.01) and passive smoking (RR 2.24, 95% CI 1.81–2.77; P<0.01) as well as paternal active smoking (RR 1.74, 95% CI 1.48–2.06; P<0.01) were all significantly associated with CHD risk For specific CHD subtypes, maternal active smoking was significantly associated with risk of atrial septal defect (RR 1.27, 95% CI 1.02–1.59; P=0.03) and right ventricular outflow tract obstruction (RR 1.43, 95% CI 1.04–1.97; P=0.03) Overall, CHD risk associated with parental smoking increased further in analyses only including Asian populations "Our results suggest that maternal passive smoking and paternal smoking were [also] significantly associated with increased risk of CHDs in offspring, which has not been confirmed in previous meta-analyses," Qin and colleagues wrote. Study limitations cited by the researchers included a lack of information on parental smoking dosage, which prevented exploration of a dose-response effect; and the possibility of residual confounding from unmeasured and uncontrolled risk factors associated with CHD. The study population heterogeneity and the lack of available studies examining CHD subtypes were also mentioned as study limitations, as well as possible publication bias and the fact that most included trials were case-control studies. "Many factors, including maternal dietary pattern, diabetes, obesity, metabolic syndrome, alcohol consumption, viral infections and genetic background, have been reported to be associated with risk of CHDs," they wrote. "Therefore, these factors are likely to be confounding factors when evaluating the effect of parental smoking on fetal CHDs. However, restricting analysis to studies controlling confounding factors did not materially alter conclusions." "Although the role of potential bias and evidence of heterogeneity should be carefully evaluated, our study indicated that maternal active and passive smoking, and paternal active smoking, are associated with higher risk of CHDs," they concluded. Study Highlights: Explanation of Findings Congenital heart defects comprise a group of cardiovascular conditions, and are responsible for most causes of perinatal mortality, with an incidence worldwide of about 8% of live births, and 8.9% of live births in China, the authors note. While the prognoses and quality of life of infants and children born with such heart defects are improving with medical advances, the adverse effects of CHDs are lifelong. The research team also notes that observational studies have found teratogenic effects of smoking during periconception, as well as increased risk of congenital malformations, which include CHDs. With the first account of an association between maternal smoking and CHDs in neonates appearing in 1971, subsequent research has produced a range of findings that encompass negative and positive associations, and null results, as well. Reviews and meta-analyses until now have primarily focused on maternal active smoking; the impact of maternal passive smoking on CHDs, and also of paternal smoking, on offspring, has been unclear. Yet, maternal passive smoking and paternal smoking is more common than maternal active smoking, the authors note. The authors stress that previous reviews did not consider Chinese data, yet China is the world's largest producer and consumer of tobacco. There have been numerous studies on the effects of parental smoking conducted in China, but they have not been included in overall research on the subject of parental smoking and association with CHDs. The researchers identified 125 eligible studies published from 1971 to 2018, of which 84.6% were case-control studies and 13.6% used a cohort study design. Of the studies used, 50.4% were conducted in Asia, 17.6% in Europe, 30.4% in North America, 0.8% in South America, and 0.8% in Oceana. The breakdown for risk for CHDs are: an increased risk of 25% for maternal active smoking, 124% for maternal passive smoking, and 74% for paternal active smoking, compared with those with no smoking. In their study, Qin and colleagues homed in on risk for specific types of CHDs, which included atrial septal defect, atrioventricular septal defect (ASD), conotruncal heart defect, left ventricular outflow tract obstruction, right ventricular outflow tract obstruction (RVOTO), septal defect, transposition of the great arteries, tetralogy of fallot, and ventricular septal defect. Substantial heterogeneity was seen among subtypes of CV damage. Maternal active smoking was significantly associated with risk of ASD (RR=1.27, 95% CI: 1.02-1.59; P=0.03) and RVOTO (RR=1.43, 95% CI: 1.04-1.97; P=0.03). However, their review did not find statistically significant differences for risks of other CHD subtypes between comparison groups. Regarding maternal passive smoking, researchers did not analyze subtypes of CHDs in this group because the number of studies were limited for each subtype of heart damage. Similarly, regarding paternal active smoking the researchers did not review the relationship between this group and subtypes due to limited studies on each group. The team notes that the exact mechanisms involved in damage from parental smoking to offspring have not yet been determined, "and warrant further research." Some theories and preclinical research indicate hemodynamic abnormalities caused by smoking, vasoconstrictor action of nicotine possibly causing fetal hypoxia, elevated fetal blood pressure and reduced blood flow to the placenta which could impact function of muscle cells and cardiac muscles in the aorta, disruption of endothelial function and angiogenesis, and reduction of supply of essential nutrients to embryonic tissue caused by carbon monoxide and nicotine. Source
