Developmental effects of antiepileptic drugs and the need for improved regulations

Abstract

Antiepileptic drugs (AEDs) are among the most common teratogenic drugs prescribed to women of childbearing age. AEDs can induce both anatomical (malformations) and behavioral (cognitive/behavioral deficits) teratogenicity. Only in the last decade have we begun to truly discriminate differential AED developmental effects. Fetal valproate exposure carries a special risk for both anatomical and behavioral teratogenic abnormalities, but the mechanisms and reasons for individual variability are unknown. Intermediate anatomical risks exist for phenobarbital and topiramate. Several AEDs (e.g., lamotrigine and levetiracetam) appear to possess low risks for both anatomical and behavioral teratogenesis. Despite advances in the past decade, our knowledge of the teratogenic risks for most AEDs and the underlying mechanisms remain inadequate. Further, the long-term effects of AEDs in neonates and older children remain uncertain. The pace of progress is slow given the lifelong consequences of diminished developmental outcomes, exposing children unnecessarily to potential adverse effects. It is imperative that new approaches be employed to determine risks more expediently. Our recommendations include a national reporting system for congenital malformations, federal funding of the North American AED Pregnancy Registry, routine meta-analyses of cohort studies to detect teratogenic signals, monitoring of AED prescription practices for women, routine preclinical testing of all new AEDs for neurodevelopmental effects, more specific Food and Drug Administration requirements to establish differential AED cognitive effects in children, and improved funding of basic and clinical research to fully delineate risks and underlying mechanisms for AED-induced anatomical and behavioral teratogenesis.

Initial Treatment for Nonsyndromic Early-Life Epilepsy: An Unexpected Consensus

“…This is particularly true for phenobarbital, for which animal data demonstrate abnormal neuronal apoptosis and human clinical data suggest potential for long-term developmental consequences of early-life exposure. 8,9,20 It is possible that selecting an alternative to phenobarbital might result in improved developmental outcomes. Data from animal models suggest that other medications, including topiramate and levetiracetam, may not induce such deleterious effects and may, therefore, be preferable for use in early-life epilepsies.…”

“…5,6 Although there are legitimate concerns about the effect of antiseizure medications on the developmental trajectory of the young child’s brain, 7–9 failure to control early-life seizures may be associated with adverse neurodevelopmental outcomes. 10 More than 20 antiseizure medications are now available, but there are few data to suggest that one antiseizure medication is more effective than another.…”

How can we overcome neuropsychological adverse effects of antiepileptic drugs?

“…Important exceptions are the potentially lifelong consequences of in utero exposition to AEDs or of antiepileptic pharmacotherapy for the cognitive development in children with epilepsy [9].…”

Evidence for spared attention to faces in 7-month-old infants after prenatal exposure to antiepileptic drugs

“…Recent data suggest that the effects on structural and functional teratogenesis vary widely between AEDs [6], with most data available on the effects of valproate, carbamazepine, lamotrigine, and phenytoin. In particular, prenatal valproate exposure relates to a relatively higher risk of major malformations, cognitive impairment, and autism spectrum disorders [6][7][8][9]. Comparisons between AEDs suggest that in utero valproate exposure in six-year-old children is associated with an IQ that is 8 to 11 points lower compared with children with in utero exposure to lamotrigine, carbamazepine, or phenytoin [10].…”

“…Besides the need for assessing the general effects of AED exposure on early development [7,9,10,[25][26][27], it has become important to assess changes in specific cognitive processes, and in particular, those related to visual functions. Recent developments in eye-tracking-based testing of infant cognition [28][29][30] have opened new possibilities for automated testing of infants' visual acuity, visuospatial orienting (gaze shifts to a novel visual stimulus), and attention to salient social stimuli, such as faces [31][32][33][34][35].…”