Human studies of neurodevelopment suggest that children exposed in utero
to certain antiepileptic drugs (AEDs) suffer a variety of brain-behavior sequelae compared to the developmental milestones of non-exposed children. These differences in neurodevelopment have been reported as developmental delays [1
], deficits in general intelligence [6
, 55], deficits in verbal intelligence [8
], additional educational needs [9
], and pervasive developmental disorders including autism [2
]. Only several of over twenty AEDs currently in clinical use, however, have been examined in studies that measure cognitive outcomes in children prenatally-exposed to AED monotherapy as an assessment of neurobehavioral teratogenesis.
Although there are limitations to many prior studies, the present literature suggests that fetal exposure to valproate and, to a lesser extent, phenobarbitol increases the risk for cognitive deficits [7
]. One limitation of some prior human studies is the lack of a prospective design beginning early during pregnancy (). Without this design, the effects of factors such as maternal seizure frequency/severity, AED blood absorption levels, pregnancy risk factors, and early home environment cannot be reliably evaluated. Second, although valproate appears to be the AED associated with greatest risk for cognitive deficits and special education needs [7
], the effects of some commonly used AEDs have not been adequately addressed, such as lamotrigine, levetiracetam, carbazepine, phenytoin, and topiramate. Third, most studies do not address differential AED effects across development, following subjects through early childhood with a longitudinal clinical and neuropsychological data collection protocol. Finally, behavioral outcome criteria in most neurobehavioral teratology studies are insufficient to determine functional deficits across a variety of human cognitive domains.
Cognitive Outcomes for Valproate Subjects Across Human Studies
In human behavioral teratology studies, cognitive function is predominately assessed by intelligence tests. Psychometric intelligence outcomes (‘IQ tests’) confer attractive experimental design advantages: IQ measures are well-standardized, sensitive to a variety of teratogens, predictive of conventional school performance, non-invasive, and facilitate comparing outcomes among studies. Despite these advantages, this strategy limits measurement of higher order cognition to convergent thinking (i.e. for a given stimulus, there is one correct response) and does not address a variety of cognitive domains.
Our ongoing prospective observational investigation entitled Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study has addressed many of the limitations in prior studies and demonstrated differential effects of AEDs on IQ . However, no prior study has addressed the effects of fetal AED exposure on an essential component of higher order cognition: the ability to generate novel ideas with fluency and flexibility. The purpose of this substudy to the NEAD investigation was to examine the differential effects of fetal exposure to AEDs on divergent thinking (i.e. for a given stimulus, there are infinite correct responses), operationalized as fluency (quantity of ideas) and originality (quality of ideas). We hypothesized widespread teratogenesis across cognitive domains and predicted that the greatest effect would be seen in the valproate exposure group, manifest as a decreased ability to generate quantity of ideas (cognitive fluency) and quality of ideas (cognitive originality).