Rationale:
Folic acid supplementation during the periconceptual period has been shown to improve cognitive outcomes in children of women with epilepsy taking antiseizure medications (ASMs). The dose of folic acid necessary to provide positive cognitive outcomes is unclear. In many countries including the United States, food is fortified with folate, but no data exists on how food fortification may affect cognition in children with fetal-ASM exposure. This study evaluates the effect of dietary folic acid, separate from folic acid supplements, on age-6 years IQ in children with fetal-ASM exposure.
Method:
Data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study was retrospectively analyzed for this investigation. Assessment of nutrient intake was conducted using the Block Food Frequency Questionnaire-98. The primary outcome of this study was to assess association of maternal pre-pregnancy nutrient levels to child age-6 IQ.
Results:
Data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study was retrospectively analyzed for this investigation. Assessment of potentially confounding variables was completed, e.g., maternal age, IQ, education, race/ethnicity, seizure and epilepsy types and frequency among others. Detailed description of maternal and child screening including confounding factors is available in the original NEAD publication. Cognitive outcome of children was evaluated at the ages of 2, 3, 4.5, and 6 years by assessors who were blinded to treatment. Women were asked to estimate their food and supplement intake in the month prior to pregnancy. Assessment of nutrient intake was conducted using the Block Food Frequency Questionnaire-98 and a separate NEAD questionnaire specific to folate supplementation. The primary outcome of this study was to assess association of maternal pre-pregnancy nutrient levels to child age-6 IQ.
Results. Folate from food alone without supplement was not associated with improvement of age-6 IQ in children with fetal ASM exposure (95% CI: (-11.3 to 2.3, p= 0.194). Periconceptual folate supplement use was associated with a 10.1 point higher age-6 IQ (95% CI: 5.4 to 14.8, p < .001). Total combined folate from food plus supplement also showed that higher intake of folate was associated with 4.3 point higher age-6 IQ (95% CI: 1.9 to 6.7, p < .001). This information is depicted in Table 1. Five other nutrients from food and supplements were analyzed (Vitamin C, Vitamin D, Vitamin E, Omega 3, and Gamma Tocopherol) and had no significant association with age 6-IQ (Table 2). In the partial regression plots adjusted for maternal IQ and the unadjusted scatter plots, the association between the nutrient levels and age 6 IQ showed a negative slope for valproate compared with the other ASMs (Figure 1).
Conclusion:
Dietary content of folic acid, even in a country like the United States where food is fortified with folic acid, is not sufficient to provide improved cognitive outcomes for children of women taking ASMs during pregnancy. Folate supplementation at a level between 0.4 to 4mg daily does result in significant improvement in cognitive outcomes, specifically age-6 IQ.
Funding:
:This work was supported by the National Institutes of Health (NINDS, NICHD) [NS038455 to KJM] and NIH NINDS 2U01-NS038455 [KJM RM, PBP).
FIGURES
Figure 1