EURAP & Development: Study Protocol of a Dutch Prospective Observational Study into Fetal Antiepileptic Drug Exposure and Long-term Neurocognitive, Behavioral and Family Outcomes

Abstract

Background: Children exposed to antiepileptic drugs (AEDs) in utero are at higher risk for congenital malformations. Less is known about the long-term association with neurocognition and behavior. Research into family factors related to long-term developmental outcomes of children of women with epilepsy is also rare. We present a protocol to investigate the neurocognitive and behavioral development in children of mothers with epilepsy from a family perspective. Methods: This is a prospective observational longitudinal study, of children exposed in utero to monotherapy carbamazepine, lamotrigine, valproate or levetiracetam whose mother were previously included in the European Registry of Antiepileptic Drugs and Pregnancy (EURAP-NL) database. Children are tested at age six or seven years (T1) and at eight or nine years (T2). Children, mothers and fathers are asked to undergo neuropsychological assessments and to complete questionnaires on behavioral functioning and distinct family factors. Discussion: This study contributes to future counseling of women with epilepsy who have children or wishes to start a family. Strengths are the inclusion of levetiracetam, the longitudinal design, and alongside neurocognition, the inclusion of differential behavioral and family outcome measures. Anticipated limitations are discussed.

Neurocognition after prenatal levetiracetam, lamotrigine, carbamazepine or valproate exposure

“…We collaborated with the European Registry of Antiepileptic Drugs and Pregnancy (EURAP) to design the Dutch EURAP & Development study [15]. EURAP & Development is a prospective observational study of children of mothers with epilepsy, with assessors blinded to drug exposures.…”

“…EURAP & Development is a prospective observational study of children of mothers with epilepsy, with assessors blinded to drug exposures. The current study is part of a larger longitudinal study in which long-term effects of prenatal exposure to AEDs on neurocognitive and behavioral development are investigated from a family perspective [15].…”

Behavioral problems in children of mothers with epilepsy prenatally exposed to valproate, carbamazepine, lamotrigine, or levetiracetam monotherapy

“…18 Participants were children of mothers with epilepsy identified from the EURAP-NL database in The Netherlands, a national, single center pregnancy register that investigates the prevalence of major congenital malformations following prenatal exposure to AEDs. The current study is part of a larger longitudinal study in which long-term effects of prenatal exposure to AEDs on neurocognitive and behavioral development are investigated from a family perspective.…”

“…The current study is part of a larger longitudinal study in which long-term effects of prenatal exposure to AEDs on neurocognitive and behavioral development are investigated from a family perspective. 18 Participants were children of mothers with epilepsy identified from the EURAP-NL database in The Netherlands, a national, single center pregnancy register that investigates the prevalence of major congenital malformations following prenatal exposure to AEDs. Women are enrolled by the EURAP-NL center through self-referral or by their health professional.…”

“…3,7,9 Symptoms of childhood psychiatric disorders have rarely been examined. 18 Systematic screening will provide more insight into the behavioral development of exposed children. Controlling for potential confounders, such as epilepsy-and pregnancy-related factors (eg, prenatal alcohol or nicotine exposure, folate use, and breast-feeding), as well as more genetic and environmental components such as parental behavioral problems and educational level, is also important.…”