Prenatal Dietary Folate Not Enough to Offset AEDs' Effect on Kids' Cognition

Megan Brooks

March 22, 2021

New research underscores the importance of folic acid supplementation for pregnant women with epilepsy who are taking antiepileptic drugs (AEDs).

Dietary folate alone, even in the United States, where food is fortified with folic acid, is "not sufficient" to improve cognitive outcomes for children of women who take AEDs during pregnancy, the researchers report.

"We found that dietary folate was not related to outcomes," study investigator Kimford Meador, MD, professor of neurology and neurologic sciences, Stanford University School of Medicine, Palo Alto, California, told Medscape Medical News.

"Only when the mother was taking extra folate did we see an improvement in child outcomes," he added.

The findings were published online February 23 in Epilepsy and Behavior.

Cognitive Boost

"Daily folate is recommended to women in the general populations to reduce congenital malformations," Meador said. In addition, periconceptional use of folate has been shown in previous research to improve neurodevelopmental outcomes for children of mothers with epilepsy who are taking AEDs.

Whether folate-fortified food alone, without supplements, has any effect on cognitive outcomes in this population of children has not been examined previously.

To investigate, the researchers assessed 117 children from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, a prospective, observational study of women with epilepsy who were taking one of four AEDs: carbamazepine, lamotrigine, phenytoin, or valproate.

Results showed that dietary folate from fortified food alone, without supplements, had no significant impact on IQ at age 6 years among children with prenatal exposure to AEDs.

In contrast, use of periconceptual folate supplements was significantly associated with a 10-point higher IQ at age 6 in the adjusted analyses (95% CI, 5.2 – 15.0; P < .001).

These six other nutrients from food and supplements had no significant association with IQ at age 6 years: vitamins C, D, and E, omega-3, gamma tocopherol, and vitamin B12.

Optimal Dose Unclear

The findings indicate that folates, including natural folate and folic acid, in food does not have positive cognitive effects for children of women with epilepsy who take AEDs, the researchers write.

Meador noted that the optimal dose of folic acid supplementation to provide a cognitive benefit remains unclear.

The US Centers for Disease Control and Prevention recommends 0.4 mg/d for the general population of women of childbearing age. In Europe, the recommendation is 1 mg/d.

"Higher doses are recommended if there is a personal or family history of spina bifida in prior pregnancies, but there is some concern that very high doses of folate may be detrimental," Meador said.

For women with epilepsy, he would recommend "at least 1 mg/d and not more than 4 mg/d."

Proves a Point?

Commenting on the study for Medscape Medical News, Derek Chong, MD, vice chair of neurology and director of epilepsy at Lenox Hill Hospital, New York City, said the finding that folate fortification of food alone is not adequate for women with epilepsy is "not groundbreaking" but does prove something previously thought.

"Folic acid is important for all women, but it does seem like folic acid may be even more important in the epilepsy population," said Chong, who was not involved with the research.

He cautioned that the current analysis included only four medications, three of which are not used very often anymore.

"Lamotrigine is probably the most commonly used one now. It's unfortunate that this study did not include Keppra [levetiracetam], which probably is the number one medication that we use now," Chong said.

The research was supported by the National Institutes of Health. Meador and Chong have reported no relevant financial relationships.

Epilepsy Behav. Published online February 23, 2021. Abstract

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