Periconceptional folic acid supplementation for women with epilepsy: A systematic review of the literature

•MCMs was relatively higher in those with folic acid supplementation.•MCMs was similar between those with or without high-dose folic acid supplementation.•Periconceptional folic acid supplementation may be benefit for neurodevelopment. This study aimed to investigate whether folic acid supplementation at normal or high doses could reduce major congenital malformations and improve neurodevelopment in the offspring of women with epilepsy (WWE). The MEDLINE, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov databases were searched for observational studies reporting pregnancy outcomes and information about folic acid supplementation in WWE, with a cut-off date of December 5, 2023. Data extraction and synthesis were performed in accordance with the PRISMA guidelines. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale. A random-effects meta-analysis was conducted to obtain pooled odds ratios (ORs) and 95% confidence intervals (CI), to estimate the effect of periconceptional folic acid supplementation on pregnancy outcomes in WWE. Sensitivity analyses including only studies with WWE who took anti-seizure medications during pregnancy or studies with a sample size greater than 100 were further performed. This study was registered in PROSPEROID (no. CRD42019141820). The database search yielded 23 eligible articles. Unexpectedly, the results of subsequent meta-analysis showed that the risk of major congenital malformations was relatively higher in those with periconceptional folic acid supplementation (17463 pregnancies, OR, 1.34; 95 %CI, 1.12–1.6), and was similar between those with and without folic acid supplementation ≧ 4 mg (3822 pregnancies, OR, 0.9; 95 %CI, 0.65–1.24). Results showed that periconceptional folic acid supplementation may be beneficial for neurodevelopment but the evidence was limited. This systematic review showed no evidence of a beneficial effect of folic acid supplementation in reducing the risk of major congenital malformations, while the relative risk was slightly higher in those receiving periconceptional folic acid supplementation. Nevertheless, folic acid supplementation may improve neurobehavioral outcomes.