Folate supplementation in pregnant women on antiseizure medicines may improve cognitive and behavioral outcomes among children: JAMA

The management of epilepsy during pregnancy is well aided by the administration of antiseizure medications but their teratogenic potential threatens the neurodevelopment of the fetus. Historically, evidence has been shown to exist for dose-dependent effects of antiseizure medications (ASMs) on cognitive outcomes, culminating in concerns about their safe use. While folate supplementation has proven to improve pregnancy outcomes, increased doses have been surrounded by potential risks. This present study aimed at assessing verbal abilities in children of women with epilepsy (WWE) compared to healthy women (HW), in addition to examining the effects of third-trimester ASM exposures and folate use.

Between 2012 and 2016, the prospective, nonrandomized clinical trial recruited 456 pregnant women from 20 US epilepsy centers. Children were evaluated at 6 years of age between 2019 and 2022. A total of 298 children of WWE and 89 children of HW were included in the final analysis. Verbal Index Scores, calculated from multiple neuropsychological assessments, served as the main outcome measure. The study further assessed ASM blood concentrations and folate supplementation in relation to cognitive outcomes.

The key findings of the study were:

Participant Demographics:

• Children of WWE: 298 participants (mean age 6.4 ± 4.2 years), with 158 females (53.0%) and 140 males (47.0%).

• Children of HW: 89 participants, with a mean age of 6.4 ± 4.2 years, 41 females (46.1%), and 48 males (53.9%).

Verbal Abilities:

• There were no notable differences in Verbal Index Scores between children of WWE and HW (parameter estimate: −0.6; 95% CI: −3.2 to 1.9; p= 0.64).

ASM Exposure:

• Exposure-based outcomes differed depending on the ASM.

• 78% of WWE (232/298) received lamotrigine or levetiracetam, either separately or in combination, such that other ASMs could not reliably be ascertained.

Folate Supplementation:

• Folate use during the first 12 weeks of pregnancy was associated with cognitive and behavioral outcomes in favorable ways.

• Higher doses of folate did not reveal any adverse effects.

This study concludes that the verbal abilities of children of WWE are not different from those of HW, which reinforces the importance of ASM management tailored during pregnancy. Early folate supplementation holds substantial benefits for cognitive and behavioral outcomes, supporting its use as a cornerstone of prenatal care for WWE.

Reference:

Meador, K. J., Cohen, M. J., Loring, D. W., Matthews, A. G., Brown, C., Robalino, C. P., Carmack, A., Birnbaum, A. K., Voinescu, P. E., Gerard, E. E., Kalayjian, L. A., Gedzelman, E. R., Hanna, J., Cavitt, J., Sam, M., Hwang, S., Pack, A. M., French, J. A., Tsai, J. J., … Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Investigator Group. (2024). Neuropsychological outcomes in 6-year-old children of women with epilepsy: A prospective nonrandomized clinical trial. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2024.3982