Maternal Folic Acid Supplementation and the Risk of Congenital Heart Defects in Offspring: A Meta-Analysis of Epidemiological Observational Studies

Epidemiological studies have reported conflicting results regarding the association between maternal folic acid supplementation and the risk of congenital heart defects (CHDs). However, a meta-analysis of the association between maternal folic acid supplementation and CHDs in offspring has not been conducted. We searched the MEDLINE and EMBASE databases for articles cataloged between their inceptions and October 10, 2014 and identified relevant published studies that assessed the association between maternal folate supplementation and the risk of CHDs. Study-specific relative risk estimates were pooled using random-effects or fixed-effects models. Out of the 1,606 articles found in our initial literature searches, a total of 1 randomized controlled trial, 1 cohort study, and 16 case-control studies were included in our final meta-analysis. The overall results of this meta-analysis provide evidence that maternal folate supplementation is associated with a significantly decreased risk of CHDs (RR = 0.72, 95% CI: 0.63-0.82). Statistically significant heterogeneity was detected (Q = 82.48, P < 0.001, I-2 = 79.4%). We conducted stratified and meta-regression analyses to identify the origin of the heterogeneity among the studies, and a Galbraith plot was generated to graphically assess the sources of heterogeneity. This meta-analysis provides a robust estimate of the positive association between maternal folate supplementation and a decreased risk of CHDs.