Maternal exposure to folate antagonists and susceptibility to congenital heart disease in offspring: A systematic review and meta-analysis
Analysis (6 cohort, 5 cross-sectional studies; n=1,153,383) found maternal use of folate antagonists (dihydrofolate reductase inhibitors or antiepileptics) was associated with an increased risk of congenital heart disease (OR 1.55, 95% CI 1.28–1.87; p<0.00001) vs control.
Source:
British Journal of Clinical Pharmacology
SPS commentary:
The majority of exposure occurred in the first trimester. Out of the 11 studies, 4 cohort studies and one case-control study showed statistical significance for increased odds of developing CHD versus control. Individual data for dihydrofolate reductase inhibitor (DHFRI) exposure were available from 8 studies and were included in subgroup analysis. The pooled OR for DHFRI exposure and CHD was 1.49 (1.06–2.10, I2 = 66%). The data for antiepileptic exposure was available from 7 studies, with a pooled OR for AED exposure and CHD of 1.47 (1.28–1.69, I2 = 69%).
Among the infants of women who took DHFRI during pregnancy, maternal supplementation with multivitamins containing folic acid was associated with a diminution in the risk of cardiovascular defects. However, no such reduced risk was seen for antiepileptics.
The authors acknowledge that the results of their analysis should be interpreted cautiously due to a number of limitations, including possibility of recall bias, lack of complete information on dosage and compliance, and the possibility of unaddressed confounding factors. Publication bias was noted, which could be due to heterogeneity in the study populations, study type, interventions or outcome measures.