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

• Authors: Morris J. Cohen, Georgia Regents University; Kim J Meador, Emory University; Nancy Browning, EMMES Corporation; Ryan May, EMMES Corporation; Gus A. Baker, University of Liverpool; Jill Clayton-Smith, St Mary’s Hospital; Laura A. Kalayjian, University of Southern California; Andres Kanner, Rush University; Joyce D. Liporace, Riddle Health Care; Page B. Pennell, Brigham & Women's Hospital; Michael Privitera, University of Cincinnati; David W Loring, Emory University
• Journal Title: Epilepsy and Behavior
• Volume: Volume 29, Number 2
• Publisher: Elsevier | 2013-11-01, Pages 308-315
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.yebeh.2013.08.001
• Subjects: Biology, Neuroscience; Psychology, Developmental; Health Sciences, Obstetrics and Gynecology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Behavioral Sciences; Clinical Neurology; Psychiatry; Neurosciences & Neurology; Antiepileptic drugs; Child development; Behavioral neurology; Epilepsy; Pregnancy; Valproate; DEVELOPING RAT-BRAIN; SPECTRUM DISORDERS; OUTCOMES; CHILDREN; AUTISM; PREGNANCY; EPILEPSY

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.