Antiepileptic drugs and neurodevelopment

Abstract

Clinical studies have documented the teratogenic potential of antiepileptic drugs (AEDs). More recent cohort studies have been trying to sort out which AEDs impose the highest risk of teratogenicity. Currently, there is evidence demonstrating an increased risk of major congenital malformations (MCMs) for valproate, phenobarbital, and polytherapy during pregnancy. Based on the current data from multiple studies, the risk for valproate is the highest. Additional studies are needed to fully delineate if differences exist for other AEDs, especially the newer AEDs. However, although MCMs are easy to recognize and have been shown to be more common after in utero exposure to AEDs, there are insufficient data regarding their long-term effects on cognition and behavior in exposed children. Although most children born to women with epilepsy are healthy, in recent years there has been increasing awareness of the long-term effects of in utero exposure to AEDs. Recent discovery of neuronal apoptosis following in utero AED exposure in animals during a period that corresponds to the third trimester and early infancy in humans raises further concerns. Prospective clinical studies seem necessary in order to better understand the long-term neurodevelopmental effects of in utero exposure to AEDs.

Antiepileptic Drug-Induced Neuronal Cell Death in the Immature Brain: Effects of Carbamazepine, Topiramate, and Levetiracetam as Monotherapy versus Polytherapy

“…Exposure to antiepileptic drugs (AEDs) during a critical period in brain development causes long-term detrimental effects on cognitive and behavioral outcomes (Lauer et al, 1987;Glauser, 2004;Wolansky and Azcurra, 2005;Motamedi and Meador, 2006). One mechanism underlying adverse outcomes of AED exposure may be neuronal apoptosis during late gestation and the perinatal period.…”

“…Of particular clinical relevance is the observation that when two AEDs are combined, cell death may be substantial even when each drug is given in a dose subthreshold for causing cell death by itself (Bittigau et al, 2002). Drug combinations are problematic clinically, especially during pregnancy and early childhood; polytherapy causes more adverse effects on cognition compared with monotherapy (Adab et al, 2004;Motamedi and Meador, 2006). Because AEDs are often given in combination, it is crucial to determine whether certain drug combinations minimize or avoid developmental proapoptotic actions.…”

Long‐term antiepileptic drug administration during early life inhibits hippocampal neurogenesis in the developing brain

“…Ample evidence from both clinical and animal studies indicates that many commonly used AEDs interfere with fetal brain development (Faiella et al,2000; Marsh et al,2006; Ornoy,2006). There exists, however, only a small body of literature that describes the effects of AED exposure during infancy and early childhood, and animal models have not been extensively developed (Kaindl et al,2006; Motamedi and Meador,2006). The limited clinical data are in agreement that some AEDs—especially phenobarbital (PB) and benzodiazepines—can affect cognition significantly in young patients (Bourgeois,2004; Loring and Meador,2004; Marsh et al,2006; Kothare and Kaleyias,2007).…”

Pregnancy Outcome in Maternal Crigler-Najjar Syndrome Type II: A Case Report and Systematic Review of the Literature

“…We were aware of the controversial findings regarding the teratogenic risk in phenobarbital treatment [36] , but all studies refer to therapy of epileptic women in pregnancy who frequently take more than one drug. An increased risk for major congenital malformations has been reported by some authors [37][38][39] , though a recent case-time-control study [40] found only borderline or no statistically significant associations between congenital abnormalities and antiepileptic drugs. Although some authors found negative effects (e.g.…”