Folic acid supplementation and prevention of adverse offspring outcomes among women with epilepsy: An observational study

OBJECTIVE: Folic acid (FA) is essential for fetal development, while the benefits and optimal dose in pregnant women with epilepsy (PWWE) remain unclear. This study explores effects of FA supplementation, dose, and initiation time on offspring outcomes in PWWE. METHODS: This multi-center cohort recruited PWWE from 58 hospitals in China. Anti-seizure medication (ASM) and FA exposures were categorized by first-trimester use. The primary outcome was a composite of preterm birth, low birth weight (LBW), major congenital anomalies (MCAs), fetal death, and neurodevelopmental delay. Logistic regression models assessed the associations between FA exposure, dose, initiation time, and adverse outcomes, adjusting for demographics and epilepsy characteristics, with stratification by maternal ASM use. Dose-response relationships were analyzed using restricted cubic splines. RESULTS: Among 1013 women with 1209 pregnancies, 952 received FA. In ASM-exposed pregnancies, FA supplementation was associated with lower risks of composite adverse offspring outcomes (adjusted odds ratio [aOR] .59, 95% confidence interval [CI] .387-.911) and fetal death (aOR .127, 95% CI .054-.296), whereas no significant differences were observed between preconception and first-trimester initiation. Compared to no supplement, supplementation with .4 mg/day protected against fetal death (aOR .185, 95% CI .078-.428); doses exceeding .4 mg/day further reduced risk of composite adverse outcomes (aOR .343, 95% CI .162-.675), and doses above 1 mg additionally showed trends toward decreased preterm birth in ASM-exposed pregnancies (aOR .338, 95% CI .104-.943). Compared with .4 mg supplementation, doses above 1 mg/day were associated with a lower risk of LBW (aOR .208, 95% CI .05-.58). SIGNIFICANCE: FA supplementation was associated with lower risks of composite adverse offspring outcomes in ASM-exposed pregnancies, specifically at doses exceeding .4 mg. No such associations were observed in pregnancies not exposed to ASMs. However, the optimal upper limit of high-dose FA supplementation requires further investigation.