Taking folic acid early in pregnancy was associated with better neuropsychological outcomes in the offspring at age 6 years, including improved verbal skills and behavior, new research suggests.
The study, which included women with and without epilepsy, found no evidence of negative cognitive or behavioral outcomes, even with higher doses of folic acid.
“The study provides evidence that folic acid taken in pregnancy, by women with epilepsy and healthy controls, improves neurodevelopmental outcomes” in their children, lead study author Kimford J. Meador, MD, professor of neurology and neurological sciences, Stanford University, Palo Alto, California, told Medscape Medical News.
The findings were presented on April 8 at the American Academy of Neurology (AAN) 2025 Annual Meeting.
‘Best Guesses’
Taking folic acid supplements in pregnancy is known to reduce neural tube defects and cardiac malformations. However, noted Meador, it’s unclear if folic acid reduces such malformations in the offspring of women taking antiseizure medications (ASMs) for psychiatric conditions or epilepsy.
Concerns have also been raised over possible risks for heart issues and behavioral issues in children exposed to higher doses of folic acid in utero.
Meador generally recommends 0.4 mg/d of folic acid for healthy women with no risk factors and 0.8 or 1 mg/d for women with epilepsy. ASMs can interfere with folate absorption, he said.
But these are “best guesses and not evidence-based medicine,” he said. “We really don’t know what is the best dose of folic acid.”
The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a long-term prospective, observational investigation that enrolled women with epilepsy and healthy women during pregnancy at 20 US sites. The current analysis included 262 6-year-olds who were born to women with epilepsy and 83 born to those without the condition.
Researchers divided the children into groups based on the mother’s average prenatal folic acid dosage in the first 12 weeks of pregnancy: None; up to 0.4 mg/d; > 0.4-1.0 mg/d; > 1-4 mg/d; and > 4 mg/d.
The study adjusted for numerous factors including maternal intelligence quotient and education level, epilepsy medications, and pregnancy complications.
Investigators chose the Verbal Index Score (VIS) of children at age 6 years as the primary neurodevelopmental outcome because there is some evidence to suggest language abilities may be sensitive to the effects of prenatal ASM use.
Significant Benefits
The least square (LS) mean VIS score for the general population is 100; a score below 70 is considered partially impaired, said Meador.
Investigators found that VIS scores were significantly higher in those with any prenatal folic acid exposure (P = .008). The offspring of women not taking folic acid had an LS means of 90.0 vs 109.8 for those taking 0-0.4 mg/d, 109.5 for those taking > 0.4-1.0 mg/d; 105.5 for those taking 1.0-4.0 mg/d, and 108.1 for those taking > 4.0 mg per d.
The main behavioral outcome was the Adaptive Behavior Assessment System (ABAS-3) General Adaptive Composite Standard Score. Through questionnaires, parents evaluated their child’s behavior, social interactions, and daily living skills.
The adjusted LS means for ABAS-3 were higher when folic acid was used (P < .001). The LS means were 82.3 for the offspring of women not taking folic acid vs 102.5 for those taking 0-0.4 mg/d, 102.9 for those taking > 0.4-1.0 mg/d, 101.8 for those taking 1.0-4.0 mg/d; and 102.7 for those taking > 4.0 mg/d.
The benefits of folic acid supplementation in early pregnancy were found in the offspring regardless of the mother’s epilepsy status.
Findings Offer ‘Impactful Clarity’
Meador stressed the outcomes were similar for the various doses. “All the way up to, and over 4 mg, we don’t see any difference; there’s not even a suggestion of a difference” in behavior problems among the kids, he said.
While the findings don’t mean there are no possible risks related to higher folic acid doses “we’re not seeing it in this cohort,” Meador added.
While the study looked at folic acid supplementation in the first 12 weeks of pregnancy, Meador recommends women start taking the supplement before pregnancy, adding that he starts his female patients on folic acid when he first prescribes an ASM.
Research suggests there are no additional neurodevelopmental benefits for children of moms taking supplements beyond the first 12 weeks of pregnancy, he said.
A limitation of the study was that it didn’t look at factors such as intake of vitamins beside B-9 and genetics, that may also affect folic acid intake and absorption. Also, the group of women not taking folic acid supplements during pregnancy was very small.
The findings offer “impactful clarity on some of the existing controversies about folate supplementation during pregnancy,” said Linda M. Selwa, MD, professor and associate chair for clinical activities and codirector, Epilepsy Division, Department of Neurology, University of Michigan, Ann Arbor, Michigan, who was not part of the study and commented on the results for Medscape Medical News.
“This report of verbal and behavioral benefits from early folic acid supplementation at any dose in pregnant mothers will be immediately useful in counseling our pregnant patients,” Selwa said.
This study was supported by the National Institutes of Health (NIH) — from the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Child Health and Human Development (NICHD). Meador received NIH grants (from NIAAA, /NINDS), Veterans Administration Office of Research and Development, and NIMH. Selwa had no relevant conflicts of Interest.