Supplementation with high-dose folic acid appears beneficial to pregnant women with epilepsy being treated with antiseizure medications (ASMs), having been associated with a lower incidence of adverse offspring outcomes in an observational study from China.
Among ASM-exposed pregnancies, the composite of preterm birth, low birth weight (LBW), major congenital anomalies, foetal death, and neurodevelopmental delay occurred in 21.2 percent of folic-acid supplemented pregnancies vs 32.3 percent of non-supplemented pregnancies. [Epilepsia 2026;doi:10.1002/epi.70264]
Folic acid supplementation was associated with 41-percent lower odds of the composite adverse offspring outcomes (adjusted odds ratio [aOR], 0.59, 95 percent confidence interval [CI], 0.39–0.91; p=0.015), regardless of whether supplementation was initiated during the preconception or first-trimester period.
The favourable association between folic acid supplementation and adverse offspring outcomes among ASM-exposed pregnancies was driven mainly by a significantly lower rate of foetal deaths (2.4 percent vs 12.3 percent; aOR, 0.13; p<0.001). No significant effect was observed on preterm births (7.7 percent vs 10.8 percent), LBW (10 percent vs 7.7 percent), major congenital abnormalities (3.2 percent vs 1.5 percent), or neurodevelopmental delay (4.6 percent vs 3.1 percent).
“It is important to note that the observed reduction in adverse outcomes associated with folic acid supplementation specifically applies to pregnant women with epilepsy taking ASMs. For women with epilepsy who did not receive treatment during pregnancy, folic acid supplementation did not reduce the risk of any adverse outcomes,” the authors noted.
“The finding suggests that folic acid may help mitigate the risks of ASM toxicity during pregnancy,” they said. “Clinicians should inform women with epilepsy of childbearing age about the need for folic acid supplementation, particularly when taking ASMs.”
In the context of unplanned pregnancies, guidelines recommend that all women with epilepsy of reproductive age take folic acid daily continuously to ensure coverage. However, for those who are not taking folic acid, the authors emphasized that starting supplementation in the first trimester is still beneficial. “Clinicians should encourage women with unplanned pregnancies to initiate folic acid supplementation promptly upon learning they are pregnant,” they said.
Higher doses may be needed
An interesting finding was that higher folic acid doses were associated with a reduced risk of the composite adverse offspring outcomes, with supplementation at doses exceeding the recommended 0.4 mg daily conferring greater protection.
The rates of the composite adverse offspring outcome were 8.3 percent, 13.6 percent, and 22.4 percent among pregnancies that received folic acid supplementation at a daily dose of >1, >0.4 to ≤1, or >0 to ≤0.4 mg, respectively, and 25.4 percent among non-supplemented pregnancies.
Compared with no folic acid supplementation, supplementation at daily doses of >0.4 to ≤1 mg (aOR, 0.29, 95 percent CI, 0.12–0.62) or >1 mg (aOR, 0.22, 95 percent CI, 0.09–0.46) was associated with significantly reduced odds of the composite outcome.
The finding held true for ASM-exposed pregnancies. Folic acid supplementation at a daily dose of >1 mg was also associated with a substantial reduction in the odds of foetal death (aOR, 0.07, 95 percent CI, 0.00–0.37) and preterm birth (aOR, 0.34, 95 percent CI, 0.10–0.94) compared with no supplementation.
In terms of safety, “we did not observe an association between high-dose folic acid supplementation and adverse maternal health outcomes in our cohort,” the authors said.
“Nevertheless, further studies with larger sample sizes, longer follow-up, and systematic assessment of maternal adverse events are required to better evaluate the safety of high-dose folic acid supplementation in pregnant women with epilepsy,” they added.
The analyses included 1,209 pregnancies in women with epilepsy, including 851 with ASM exposure and 358 without ASM exposure. A total of 952 pregnancies were supplemented with folic acid, with 12.6 percent receiving a high dose (>1 mg/day), 10.8 percent receiving a medium dose (>0.4 to ≥1 mg/day), and 74.5 percent receiving a low dose (>0 to ≤0.4 mg/day). The dose was unrecorded in 2.1 percent of pregnancies.