Neurodevelopmental Effects of Fetal Antiepileptic Drug Exposure

Abstract

Many studies investigating cognitive outcomes in children of women with epilepsy report an increased risk of mental impairment. Verbal scores on neuropsychometric measures may be selectively more involved. While a variety of factors contribute to the cognitive problems of children of women with epilepsy, antiepileptic drugs (AEDs) appear to play a major role. The mechanisms by which AEDs affect neurodevelopmental outcomes remain poorly defined. Animal models suggest that AED-induced apoptosis, altered neurotransmitter environment, and impaired synaptogenesis are some of the mechanisms responsible for cognitive and behavioral teratogenesis. AEDs that are known to induce apoptosis, such as valproate, appear to affect children’s neurodevelopment in a more severe fashion. Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains, and these appear to persist at least until the age of 6. Some studies have shown neurodevelopmental deficiencies associated to the use of phenobarbital and possibly phenytoin. So far, most of the investigations available suggest that fetal exposures to lamotrigine or levetiracetam are safer with regards to cognition when compared to other AEDs. Studies on carbamazepine show contradictory results, but most information available suggests that major poor cognitive outcomes should not be attributed to this medication. Overall, children exposed to polytherapy prenatally appear to have worse cognitive and behavioral outcomes compared with children exposed to monotherapy, and with the unexposed. There is an increase risk of neurodevelopmental deficits when polytherapy involves the use of valproate versus other agents.

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

“…attention. In line with earlier studies on older children [5,10,14,26,27,58], we found prenatal AED exposure to compromise the development of early language and social skills, as well as overall neurodevelopment at the age of seven months. However, our eye-tracker-based assessment suggests that the general speed of visuospatial orienting (or "disengagement") as well as attentional bias for faces is spared at the age of seven months in infants with prenatal AED exposure.…”

“…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].…”

Management of Adverse Effects of Mood Stabilizers

“…The estimated risk of neural tube defects, mostly spina bifida, is 0.5-1 % [33]. Studies on poor cognitive outcomes in offspring of mothers treated with CBZ show contradictory results, but most suggest that major poor cognitive outcomes should not be attributed to exposure to CBZ [34].…”

“…Lamotrigine is associated with a 10-24-fold risk of oral cleft versus the general population [44]. So far, most of the investigations available suggest that fetal exposures to LMT are safer with regard to cognition when compared with other antiepileptic drugs [34].…”

Antiepileptic Drug-Induced Apoptosis Was Prevented by L-Type Calcium Channel Activator in Cultured Rat Cortical Cells

“…For example, fetal valproate exposure causes dose-dependent reduction of cognitive abilities, and these appear to persist at least until the age of 6 [1]. Bittigau et al [2] reported that exposure to therapeutic levels of AEDs induced neuronal apoptosis in rat brains during the first 2 post-natal weeks.…”