Periconceptional Folic Acid Supplementation Decreases Risk of Preterm Birth in Epilepsy

Silje Alvestad, MD, PhD

Findings from the prospective Norwegian Mother and Child Cohort Study (MoBA) showed that among women with epilepsy on an antiseizure medication (ASM), periconceptional folic acid supplementation was associated with a lower risk of preterm birth. All told, there was a 3-fold increase in the risk among those who did not undergo supplementation vs those who did.¹

To evaluate whether folic acid supplementation was associated with primary outcomes such as preterm birth (gestational age <37 weeks at birth), small for gestational age (SGA), and preeclampsia, investigators evaluated 100,105 singleton pregnancies from 1999-2008. In 764 of these pregnancies, the mother had a diagnosis of epilepsy; 316 mothers were exposed to ASM during pregnancy and 358 were not.

Folate has been shown to be essential for DNA synthesis, and the demand for folate increases during pregnancy due to uterine, placental, and fetal growth, the investigators noted. Led by Silje Alvestad, MD, PhD, postdoctoral fellow, University of Bergen, group defined the main exposure of periconceptional folic acid supplementation as intake between 4 weeks before pregnancy and 12 weeks into pregnancy.

Among those with epilepsy on an ASM, the mean gestational age at birth was 279 days (SD, 11.8) in pregnancies with periconceptional folic acid supplementation, compared with 272 days (SD, 19.8) for those without periconceptional folic acid (P <.001). In contrast, the mean gestational age at birth was similar in those with epilepsy without ASM and those without epilepsy, regardless of folic acid supplementation.

"Our study supports the recommendation that ASM-treated women with epilepsy with a potential to become pregnancy should use daily folic acid supplement," Alvestad et al wrote. "The optimal dose of folic acid remains unknown and likely varies between ASMs and between individual women. A broad scope of studies on even larger populations are essential to assess the risks and benefits of folic acid for individual ASMs, also taking genetic variations in folate metabolism into account."

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In total, 5% of the pregnancies among those with epilepsy with an ASM resulted in preterm birth for the mothers who had used folic acid supplementation periconceptionally, compared with 14% when they had not (adjusted odds ratio [aOR], 3.3; 95% CI, 1.2-9.2). Similar to previous findings, those with epilepsy not on an ASM and those without epilepsy did not demonstrate any association between folic acid supplementation and preterm birth.

Folic acid supplementation did not influence the risk of SGA. In comparison, 14% of the women without periconceptional folic acid developed SGA compared with 9% on the study treatment (aOR, 1.3; 95% CI, 0.5-3.6). For those with epilepsy who did not receive ASM, the risk of SGA was the same with (7%) and without (7%) periconceptional folic acid (aOR, 0.9; 95% CI, 0.4-2.5). Similar to SGA, there was no association between periconceptional folic acid supplement and the risk of preeclampsia, neither in women with epilepsy using ASM, not using ASM, nor in the group without epilepsy.

For ASM-treated women who used folic acid supplementation periconceptionally, the risk of preterm birth did not differ regardless of the presence of epilepsy (aOR, 0.9; 95% CI, 0.5-1.6). In contrast, ASM-treated women who did not start the supplementation until the second or third trimester had an increased risk of preterm birth compared with women without epilepsy (aOR, 2.6; 95% CI, 1.1-6.5). Notably, an even higher risk of preterm birth was observed for ASM-treated women who did not take folic acid supplement at all during pregnancy (n = 16) compared with women without epilepsy who did not take folic acid (aOR, 9.4; 95% CI, 2.6-34.8).

The use of ASMs have been shown to not have an impact on the neurodevelopment of children, according to findings from the critical MODEAD study (NCT01730170). Overall, that study found no significant differences between children of women with epilepsy vs healthy women for the primary language domain outcome on the Bayley Scales of Infant and Toddler Development, Third Edition. In the full model, significant factors such as higher maternal IQ (0.3 [95% CI, 0.1-0.4]), birth weight (3.0 [95% CI, 0.3-5.6]) and female child sex (6.4 [95% CI, 3.3-9.4]) were associated with higher language domain scores.

REFERENCE
1. Alvestad S, Husebye ES, Christensen J, et al. Folic acid and risk of preterm birth, preeclampsia and fetal growth restriction among women with epilepsy: a prospective cohort study. Neurology. Published May 16, 2022. doi:10.1212/WNL.0000000000200669
2. Meador J, Cohen MJ, Loring DW, et al. 2-year-old cognitive outcomes in children of pregnant women with epilepsy in the maternal outcomes and neurodevelopmental effects of antiepileptic drugs study. JAMA Neurol. published online June 7, 2021. doi: 10.1001/jamaneurol.2021.1583