Neurodevelopmental delay in children exposed to antiepileptic drugs in utero: a critical review directed at structural study-bias

Abstract

Introduction: The general issue whether in utero exposure to antiepileptic drugs (AEDs) causes congenital malformations (teratogenicity) was raised as early as 1968. The 'congenital hydantoin syndrome' after intrauterine exposure to phenytoin (PHT) was first described in 1975. In 1984, DiLiberti proposed the label 'Fetal Valproate Syndrome' (FVS) for children with a cluster of minor congenital anomalies in the form of dysmorphic facial appearances with or without major abnormalities after intra-uterine exposure to valproate (VPA). Later, also the presence of central nervous system (CNS) dysfunction became part of the description. The question whether developmental delay, educational impairment, or behavioural disorders are also a characteristic of intrauterine exposure to AEDs and especially VPA, is of major importance to many women with epilepsy, parents and physicians involved.

Methods: Literature was searched using MEDLINE and other relevant databases: 56 studies were identified and interpreted.

Results: The identified studies do not allow definite conclusions. The possibility of neurodevelopmental delay, behavioural disorders, or learning disabilities as an outcome of in utero exposure to AEDs and especially VPA, needs to be considered seriously. The literature however does not provide evidence for a valid risk estimate. Moreover the evidence found for a specific increased risk for VPA could be structurally biased.

Discussion: The major problem in this field is the methodology and in particular the existence of important confounding factors that complicate any attempt to correlate intra-uterine exposure to AEDs with neurodevelopmental delay. We propose a number of guidelines for studies on behavioural teratogenicity.