There is a compelling need for prospective, properly controlled studies in women with epilepsy (WWE) during pregnancy to improve maternal and child outcomes. The proposed investigations are pertinent to the NINDS Epilepsy Research Benchmarks and will address multiple gaps in our knowledge noted by the American Academy of Neurology guidelines. This multicenter investigation will employ a prospective, observational, parallel-group, cohort design with an established research team. The FDA requires animal testing of individual AEDs to detect risks of fetal exposure for anatomical teratogenesis (i.e., congenital malformation), but not for functional teratogenesis (i.e., cognitive and behavioral deficits). Further, the multiple human AED pregnancy registries are investigating malformations and not cognitive/behavioral outcomes. Determining the effects of fetal AED exposure on development of neuropsychological abilities requires prospective collection of potential confounding factors and testing of children years after exposure. Thus, it is not surprising that such studies are rare, and these risks for most AEDs have not been assessed. The MONEAD investigation provides a unique cohort of exposed and unexposed children who have been followed prospectively starting in pregnancy with detailed data collection including the first study to directly assess AED exposure by blood levels during pregnancy. This is critical because several commonly used AEDs undergo marked clearance changes during pregnancy with marked individual variability in these changes. Such changes could obscure “dose” relationships reducing sensitivity of detecting adverse effects. MONEAD is also collecting data on the effects of breastfeeding while taking AEDs which includes blood levels in the child to directly delineate their exposure. The collection of AED levels and other pregnancy related factors is complete. In the proposed continuation grant, the children will undergo detailed neuropsychological testing at 2-6 years/old. The results will provide clear indications of AED risks to the immature brain for the presently most commonly used AEDs, and provide sentinel data on less commonly used AEDs to direct future studies. The Specific Aims are to: determine the long-term effects of in utero AED exposure in the children of WWE on: Aim 1: cognitive outcomes (e.g., verbal IQ and other cognitive domains including creativity), Aim 2: behavioral outcomes (e.g., autism), Aim 3: cerebral lateralization, and Aim 4: determine if breastfeeding when taking AEDs adds additional risks. Hypotheses: Children exposed in utero to certain AEDs will exhibit a concentration dependent impairment in cognitive abilities, abnormal behavior, alteration of normal cerebral lateralization (verbal &lt; than non-verbal and reduced % dextrals), and continued AED exposure through breastfeeding will not add additional neurodevelopmental risk. In addition, genetic samples will be collected, which will provide a valuable resource for future pharmacogenetics studies to further delineate individual variability across patients.
|Effective start/end date||5/15/18 → 2/28/23|
- Stanford University (61869966-125439//5U01NS038455-18 REVISED)
- National Institute of Neurological Disorders and Stroke (61869966-125439//5U01NS038455-18 REVISED)