Folic acid supplementation during early pregnancy, even at higher doses, is associated with improved neurodevelopmental outcomes in children, suggests new research. These findings will be presented at the American Academy of Neurology's 77th Annual Meeting, taking place April 5–9 in San Diego and online.

In a prospective, observational study of 345 children (262 born to women with epilepsy and 83 to women without epilepsy), researchers found that folic acid taken during the first trimester was linked to significantly better verbal abilities and adaptive behavior at age 6, with no evidence of negative effects at higher doses.

"Folic acid during pregnancy has been shown to reduce deformities and improve intellectual abilities in children, but the best dose of folic acid is unknown," said study author Kimford J. Meador, MD, PhD, FAAN, of Stanford University, in a press release. "Our study provides new information showing a positive connection between taking folic acid during early pregnancy and brain health outcomes in children, with no evidence of negative effects at higher doses."

Study Design and Methods

Researchers from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study recorded doses of folic acid taken by mothers during the first 12 weeks of pregnancy, and divided the children into five groups based on average dosage:

• No folic acid
• Up to 0.4 mg per day
• More than 0.4 to 1.0 mg per day
• More than 1.0 to 4.0 mg per day
• More than 4.0 mg per day.

The a priori primary neurodevelopmental outcome was the age 6 Verbal Index score (VIS), calculated by averaging results from multiple standardized tests, including the Differential Ability Scales-II Word Definitions and Verbal Similarities subtests, Expressive One-Word Picture Vocabulary Test-4, Peabody Picture Vocabulary Test-4, and Neuropsychological Assessment-2 subtests.

Behavioral outcomes were measured using the Adaptive Behavior Assessment System (ABAS-3) General Adaptive Composite Standard Score based on parent questionnaires assessing children's communication skills, social skills, and daily living skills.

Key Findings

After adjusting for potential confounders using linear regression with a stepwise selection algorithm, the researchers found:

• The adjusted least squares means for children's Verbal Index score were significantly higher in those whose mothers used folic acid in the first 12 weeks of pregnancy (107.5, 95% confidence interval [CI] = 106.5–108.5) vs those who did not (95.8, 95% CI = 86.8–104.8, P = .012).
• Similarly, adjusted least squares means for ABAS-3 scores were higher when folic acid was used in the first 12 weeks of pregnancy (102.4, 95% CI = 101.3–103.4) vs not (82.2, 95% CI = 73.9–90.5, P < .001).
• Importantly, outcomes were similar across dosage groups. Children whose mothers took low-dose folic acid (> 0–0.4 mg/day) had comparable scores to those whose mothers took high-dose folic acid (> 4.0 mg/day) for both the VIS (109.8, 95% CI = 104.7–114.9 vs 108.1, 95% CI = 105.9–110.3) and for the ABAS-3 (102.5, 95% CI = 97.3–107.8 vs 102.7, 95% CI = 100.4–105.1).

The researchers noted that the study did not look at other factors that may affect folic acid intake and absorption, such as other vitamins taken and genetics.

"While previous studies have found risks with higher doses, these findings are reassuring for people who are pregnant or planning to have children that taking a higher dose of folic acid early in pregnancy may still positively impact the brain health of their child," Dr. Meador said. "Additional studies are needed to determine the best dose of folic acid to maximize benefits and minimize risks to neurodevelopment as well as other outcomes, which could vary for different groups of women."

The study was supported by the National Institute of Neurological Disorders and Stroke and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (#U01-NS038455).