The effect of maternal BMI, smoking and alcohol on congenital heart diseases: a Mendelian randomization study

Background Congenital heart diseases (CHDs) remain a significant cause of infant morbidity and mortality. Epidemiological studies have explored maternal risk factors for offspring CHDs, but few have used genetic epidemiology methods to improve causal inference. Methods Three birth cohorts, including 38,662 mother/offspring pairs (N = 319 CHD cases) were included. We used Mendelian randomization (MR) analyses to explore the effects of genetically predicted maternal body mass index (BMI), smoking and alcohol on offspring CHDs. We generated genetic risk scores (GRS) using summary data from large scale genome-wide association studies and validated the strength of the genetic instrument for exposure levels during pregnancy. Logistic regression was used to estimate the odds ratio (OR) of CHD per 1 standard deviation (SD) change in GRS. Results for the three cohorts were combined using random-effects meta-analyses. We performed several sensitivity analyses including multivariable MR to check the robustness of our findings. Results The GRSs associated with the exposures during pregnancy in all three cohorts. The associations of the GRS for maternal BMI with offspring CHD (pooled OR (95% confidence interval) per 1SD higher GRS: 1.01 (0.90, 1.13)) and lifetime smoking (pooled OR: 0.97 (0.87, 1.08)) were close to the null, though with wide confidence intervals. We observed weak evidence of an increased odds of offspring CHDs with increase in the maternal GRS for alcoholic drinks per week (pooled OR: 1.09 (0.98, 1.22)). Sensitivity analyses yielded similar results. Conclusions Our results do not provide robust evidence of an effect of maternal BMI or smoking on offspring CHDs. However, results were imprecise. Our findings, including the potential effect of maternal alcohol intake on offspring CHD need to be replicated, and highlight the need for more and larger studies with maternal and offspring genotype and offspring CHD data.