Abstracts

Rationale: As a group, children of women with epilepsy are at risk for reduced cognitive outcomes. Animal studies have demonstrated that in utero exposure to some antiepileptic drugs (AEDs) can produce behavioral deficits at dosages lower than required for structural malformations. Although prior studies have suggested a similar risk in humans for some AEDs, the cognitive effects of fetal AED exposure in humans remain uncertain. Methods: The NEAD Study is an ongoing prospective observational multicenter study in the USA and UK, which has enrolled pregnant women with epilepsy on AED monotherapy from 1999 to 2004. The purpose of the investigation is to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). This report focuses on cognitive outcomes in 258 children at 3 years/old. Cognitive outcomes were evaluated by assessors (blinded to AED) using Mental Developmental Index of Bayley Scales of Infant Development-2nd edition (conducted 24-27 months/old) and Differential Ability Scales (conducted 36-39 months/old). Primary analysis used children who completed age 2 or 3 testing. Linear regression models were used to examine IQ group differences, adjusting for covariates: AED, maternal IQ, pregnancy average AED dose, AED/dose and AED/maternal IQ interactions, maternal and gestational age, and preconception folate. The effects of multiple additional covariates were also examined. Results: Children exposed in utero to valproate had significantly lower IQ than each of the other AEDs. Mean IQs adjusted for maternal IQ, age, AED dose, gestational age and folate were: valproate = 89, carbamazepine = 98 (95% Confidence Intervals for difference vs. valproate 2.84:5.43; p=.009), lamotrigine = 102 (6.38:18.60; p=.003), phenytoin = 97 (0.19:15.51; p=.04). Dose dependent effects were found for valproate, but not for other AEDs. Maternal IQ was correlated to child IQ for each AED except valproate. Conclusions: These findings suggest that in utero valproate exposure is more likely than other commonly used AEDs to impair cognitive development. Since valproate appears to pose a greater risk to the unborn child for both cognitive and structural teratogenesis, we recommend that it not be used as the drug of first choice in women of child bearing potential. Additional studies are needed to define risks for other AEDs and to disclose underlying mechanisms.