Abstract
Background and ObjectivesNeurodevelopmental effects of fetal antiseizure medication (ASM) exposure on creativity and executive functions are poorly understood. We previously found fetal valproate exposure to adversely affect measures of creativity and executive functions. In this study, we examine fetal exposure of newer ASMs on these functions in children of women with epilepsy (WWE) compared with children of healthy women (HW).MethodsThe Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a multicenter NIH-funded prospective observational cohort study of WWE and HW enrolled in pregnancy and their offsprings. This report examines blindly assessed creativity and executive functions in 4.5-year-old children of WWE vs HW. In addition, exposure-dependent ASM effects during the third trimester were examined in children of WWE, using a ratio of maximum observed ASM concentrations and ratio of defined daily dose (ratio DDD). For polytherapy, ratios were summed across ASMs. Linear regression models adjusted for multiple potential confounding factors were conducted for all analyses. The primary outcome for 4.5-year-old children was the Torrance Test of Creative Thinking - Figural Creativity Index. Secondary outcomes included the Global Executive Composite Score from the Behavior Rating Inventory of Executive Function - Preschool Version and subscales and other indexes of both measures.ResultsThe primary analysis included 251 children of WWE and 73 of HW. No differences in creativity or executive function were found between children of WWE vs HW. No ASM exposure-dependent effects were found for the creativity measures, but exposure-dependent effects for executive function were present for ratio ASM concentration and ratio DDD.DiscussionOur findings at 4.5 years show no differences in creative thinking between children of WWE vs HW (-3.2 [-9.0 to 2.7], p = 0.286) or associations with fetal exposure to ASMs (-2.6 [-11.0 to 5.7], p = 0.530). Secondary analyses revealed fetal exposure-dependent effects for executive function in children of WWE (7.0 [2.9-11.2], p = 0.001), which are most marked for levetiracetam (12.9 [4.2-21.6], p = 0.004). Our findings suggest that even for relatively safe ASMs, dosing needs to be adjusted to concentrations that prevent seizures, but balance risks to the fetus that high concentrations may pose.
| Original language | English (US) |
|---|---|
| Article number | e209448 |
| Journal | Neurology |
| Volume | 102 |
| Issue number | 12 |
| DOIs | |
| State | Published - May 29 2024 |
Funding
K.J. Meador has received research support from the NIH, Eisai, and Medtronic Inc. The Epilepsy Study Consortium pays his university for his research consultant time related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals. In addition, K.J. Meador is Co-I and Director of Cognitive Core of the Human Epilepsy Project for the Epilepsy Study Consortium, and is on the editorial boards for Neurology, Cognitive & Behavioral Neurology, Epilepsy & Behavior, and Epilepsy & Behavior Case Reports. M.J. Cohen receives royalties from Multi Health Systems, Inc. as author of the Children's Memory Scale. D.W. Loring receives research support from the NIH, is a consultant for Medtronic, serves on the editorial boards for Neuropsychology Review and Epilepsia for which he receives editorial stipends, and is on the editorial board for Archives of Clinical Neuropsychology. A.K. Birnbaum reports receiving grant support, paid to her institution, from Supernus Pharmaceuticals and Veloxis Pharmaceuticals, holding patent US9770407B2 on parenteral carbamazepine formulation, licensed to Lundbeck, and patent EP12150783A on novel parenteral carbamazepine formulations, licensed to Lundbeck. P.E. Voinescu received speaking honoraria from Physicians' Education Resource and from Philippines League Against Epilepsy. E.E. Gerard has served as site-PI for clinical trials sponsored by Xenon and Sunovion pharmaceuticals as well as a trial sponsored by Eisai and Stanford University, and has been reimbursed for lectures given to GW Pharmaceuticals Staff and Neurology Week. J. Cavitt received research support from National Institute of Neurological Disorders and Stroke (MONEAD) and from GW Pharmaceuticals, and advisory board fees from Jazz Pharmaceuticals. M. Sam has received advisory board consulting fees for Aquestive. S. Hwang reports no disclosures. A.M. Pack reports funding from NIH, royalties from Up to Date, and travel reimbursement for AAN and ABPN activities. J.J. Tsai reports grant from Institute of Translational Health Sciences (funded by the National Center for Advancing Translational Sciences of the NIH), and has served as site-PI for clinical trials sponsored by Xenon. P.B. Pennell reports grants from NIH, personal fees from NIH for Grant reviews, personal fees from AES and the AAN as speaking honoraria, personal fees from Medical Schools for speaking honoraria and travel, and personal fees from UpToDate, Inc. for royalties outside the submitted work. The other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures. Funded by NIH, National Institute of Neurological Disorders and Stroke/NICHD U01-NS038455; ClinicalTrials.gov number NCT01730170. The authors acknowledge Eugene Moore and Jordan Seliger for their administrative assistance throughout the MONEAD trial. They thank the patients, subjects, families, and research staff that made this work possible. See online supplemental materials for other members of the MONEAD Investigator Group (eAppendix 1).
ASJC Scopus subject areas
- Clinical Neurology