Authors :
Presenting Author: Yutong Fu, MS – West China Hospital of Sichuan University
Fanfan Shi, MPH – Department of Clinical Research and Management, Center of Biostatistics, Design, Measurement and Evaluation (CBDME), West China Hospital, Sichuan University, Chengdu, Sichuan, China
Lei Chen, MD – West China Hospital of Sichuan University
Rationale:
Folic acid is essential for fetal development, and 0.4 mg/day is commonly recommended during the periconceptional period. However, the benefits and optimal dosage in women with epilepsy (WWE), especially those on antiseizure medications (ASMs), remain unclear. This study aims to explore effects of folic acid supplementation and dosage on offspring outcomes in WWE.
Methods:
This multicenter ambispective cohort study recruited Pregnant WWE from 50 hospitals in China. Antiseizure medication (ASM) exposure and folic acid supplementation were categorized by first-trimester use and dosage. The primary outcome was a composite of preterm birth, low birth weight, major congenital malformation, fetal death and neurodevelopmental delay. Logistic regression models assessed the associations between folic acid exposure, dosage, and adverse outcomes, adjusting for demographic and epilepsy characteristics, with stratification by maternal ASM use. Dose-response relationships were analyzed using restricted cubic splines. Results:
Among 934 women with 1,110 pregnancies, 865 received folic acid. In ASM-exposed pregnancies, folic acid supplementation was associated with a lower risk of composite adverse offspring outcomes (adjusted odds ratio [aOR] 0.599, 95% confidence interval [CI] 0.359~0.999), fetal death (aOR 0.015, 95% CI 0.001~0.090), and preterm birth (aOR 0.465, 95% CI 0.232~0.988). No significant associations were observed in pregnancies not exposed to ASMs. Exploratory analysis indicated that, within the levetiracetam and oxcarbazepine monotherapy subgroups, folic acid was associated with a reduced risk of composite adverse outcomes and preterm birth. A higher folic acid dose ( >1.0 mg) was associated with a lower risk of composite adverse offspring outcomes compared to no supplementation (aOR 0.302, 95% CI 0.126~0.643), and a lower risk of low birth weight (aOR 0.276, 95% CI 0.066~0.769) compared to lower doses ( >0 to 0.4mg), whereas no protective effects were observed for congenital malformations or neurodevelopmental outcomes.
Conclusions:
Folic acid supplementation was associated with a reduced risk of composite adverse offspring outcomes in ASM-treated pregnancies, specifically at doses exceeding 0.4 mg. No such associations were observed in pregnancies not exposed to ASMs. However, the optimal upper limit of high-dose folic acid supplementation requires further investigation.
Funding:
This work was financially supported by Sichuan Science and Technology Program Grant/Award Number: 2024ZDZX0018.