Elsevier

Epilepsy & Behavior

Volume 29, Issue 2, November 2013, Pages 308-315
Epilepsy & Behavior

Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6 years

https://doi.org/10.1016/j.yebeh.2013.08.001Get rights and content

Highlights

  • Fetal valproate exposure can significantly lower adaptive functioning especially at higher dosages.

  • Children of mothers who took valproate during pregnancy are at significantly greater risk for a diagnosis of ADHD.

  • Mothers who reported maternal folate use endorsed fewer physical complaints and atypical behaviors in their children.

Abstract

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate). In this report, we examine fetal AED exposure effects on adaptive and emotional/behavioral functioning at 6 years of age in 195 children (including three sets of twins) whose parent (in most cases, the mother) completed at least one of the rating scales. Adjusted mean scores for the four AED groups were in the low average to average range for parent ratings of adaptive functioning on the Adaptive Behavior Assessment System—Second Edition (ABAS-II) and for parent and teacher ratings of emotional/behavioral functioning on the Behavior Assessment System for Children (BASC). However, children whose mothers took valproate during pregnancy had significantly lower General Adaptive Composite scores than the lamotrigine and phenytoin groups. Further, a significant dose-related performance decline in parental ratings of adaptive functioning was seen for both valproate and phenytoin. Children whose mothers took valproate were also rated by their parents as exhibiting significantly more atypical behaviors and inattention than those in the lamotrigine and phenytoin groups. Based upon BASC parent and teacher ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of ADHD. The increased likelihood of difficulty with adaptive functioning and ADHD with fetal valproate exposure should be communicated to women with epilepsy who require antiepileptic medication. Finally, additional research is needed to confirm these findings in larger prospective study samples, examine potential risks associated with other AEDs, better define the risks to the neonate that are associated with AEDs for treatment of seizures, and understand the underlying mechanisms of adverse AED effects on the immature brain.

Introduction

Animal studies have demonstrated that fetal exposure to some antiepileptic drugs (AEDs) at doses lower than those that result in structural malformations can produce cognitive and behavioral deficits, alter neurochemistry, and reduce brain weight [1], [2]. Further, AEDs including clonazepam, diazepam, phenobarbital, phenytoin, vigabatrin, and valproate can produce widespread neuronal apoptosis similar to alcohol in the immature rat brain [3], [4], [5], [6], [7], [8], [9]. This effect is dose-dependent, occurs at therapeutically relevant blood levels, requires only relatively brief exposure (single injection), and has been related to reduced expression of neurotrophins and levels of protein kinases that promote neuronal growth and survival.

These observations suggest that certain AEDs might produce similar adverse effects in children exposed in utero or in the neonatal period. In fact, several AEDs have been associated with reduced cognitive abilities (e.g., IQ) in children exposed in utero [10], [11], [12], [13], [14]. Further, in the NEAD follow-up study at 3 years of age [13], fetal valproate exposure was also shown to significantly impair verbal as well as nonverbal abilities, whereas carbamazepine significantly impacted only verbal abilities. In addition, there were dose-dependent relationships between both lower verbal and nonverbal abilities and valproate and between lower verbal abilities and carbamazepine. Six-year cognitive outcomes recently reported by the NEAD study group [15] indicated that children with fetal valproate exposure continued to exhibit significantly lower IQ than children exposed to carbamazepine, lamotrigine, or phenytoin. In addition, valproate-exposed children performed more poorly than children exposed to the other three AEDs on measures of linguistic functioning and learning/memory. Only a higher valproate dose continued to be negatively associated with performance on measures of intelligence, linguistic functions, nonverbal abilities, learning/memory, and executive functions. Finally, children exposed to preconception folate exhibited higher mean IQ scores.

Previously, we reported [16] a significant dose-related performance decline in motor function for children whose mothers took valproate or carbamazepine during pregnancy. A similar decline in adaptive functioning was reported by parents in the valproate group, and a trend in the same direction was also noted for the carbamazepine group. On the basis of parent ratings of attention span and hyperactivity, the children of mothers who took valproate during pregnancy appeared to be at a significantly greater risk for attention-deficit/hyperactivity disorder (ADHD). In this report, we examine the effects of fetal AED exposure on adaptive and emotional/behavioral functioning at 6 years of age (the final time point of the study) in children of women with epilepsy.

Section snippets

Design

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is a prospective observational investigation with blinded assessments that examined the possible cognitive and behavioral teratogenesis of AEDs. Pregnant women with epilepsy on one of four AED monotherapies (i.e., carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled from October 1999 through February 2004 across 25 epilepsy centers in the USA and UK. During the enrollment period, no other AEDs were being prescribed

Results

The primary analysis included 192 mothers and 195 children (including 3 sets of twins). Baseline maternal characteristics are depicted in Table 1. This table also shows a comparison of baseline characteristics in these mothers with the 113 mothers of children who were excluded from the analysis because of missing data. Mothers who were excluded from the analysis did not differ statistically on any of these characteristics from those who were included in the analysis.

Discussion

The NEAD study is the largest prospective investigation of cognitive and behavioral outcomes following fetal exposure to valproate, carbamazepine, lamotrigine, and phenytoin. The study seeks to determine if differential long-term neurodevelopmental effects exist across these four commonly used AEDs. In this report, we examined the effects of fetal AED exposure on adaptive and emotional/behavioral functioning at 6 years of age (the end point of the study) in children of women with epilepsy.

The

Funding

This work was supported by the National Institutes of Health [2RO1-NS038455 to K.M., R01NS050659 to N.B.] and the United Kingdom Epilepsy Research Foundation [RB219738 to G.B.].

Acknowledgments

The investigators would like to thank the children and families who have given their time to participate in the NEAD study.

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