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Clinical Trial
. 2025 Jan 1;82(1):30-39.
doi: 10.1001/jamaneurol.2024.3982.

Neuropsychological Outcomes in 6-Year-Old Children of Women With Epilepsy: A Prospective Nonrandomized Clinical Trial

Kimford J Meador  1 , Morris J Cohen  2 , David W Loring  3 , Abigail G Matthews  4 , Carrie Brown  4 , Chelsea P Robalino  4 , Andrea Carmack  4 , Angela K Birnbaum  5 , Paula E Voinescu  6 , Elizabeth E Gerard  7 , Laura A Kalayjian  8 , Evan R Gedzelman  3 , Julie Hanna  9 , Jennifer Cavitt  10 , Maria Sam  11 , Sean Hwang  12 , Alison M Pack  13 , Jacqueline A French  14 , Jeffrey J Tsai  15 , Cora Taylor  16 , Page B Pennell  17 ; Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Investigator Group
Affiliations
Clinical Trial

Neuropsychological Outcomes in 6-Year-Old Children of Women With Epilepsy: A Prospective Nonrandomized Clinical Trial

Kimford J Meador et al. JAMA Neurol. .

Abstract

Importance: Antiseizure medications (ASMs) are potential teratogens commonly prescribed for multiple indications. ASM fetal exposure can impair neurodevelopment. Folate improves pregnancy outcomes, but higher doses may pose risks.

Objectives: To compare the outcomes of 6-year-old children of women with epilepsy (WWE) vs those of healthy women (HW), and assess the association of outcomes to third-trimester ASM exposures.

Design, setting, and participants: After informed consent, pregnant WWE and HW were enrolled from 2012 through 2016 in this prospective, multicenter, nonrandomized clinical trial. Children were assessed at 6 years of age (2019-2022). Participants were recruited from 20 US epilepsy centers. Study data were analyzed from August 2023 to August 2024.

Exposures: Fetal ASM exposures.

Main outcomes and measures: The a priori main neurodevelopmental outcome was the blindly assessed Verbal Index Score in 6-year-old children. The Verbal Index Score is calculated as the mean of the scores from the Word Definitions and Verbal Similarities subtests from the Differential Ability Scales, Expressive One-Word Picture Vocabulary Test, Phonological Processing, Comprehension of Instructions, and Sentence Repetition subtests from the Neuropsychological Assessment and Peabody Picture Vocabulary Test. The 2 primary analyses (1) compared children of WWE and HW using linear regression and (2) examined the outcomes of fetal exposure via ASM blood concentrations. Analyses were adjusted for multiple potential confounding factors. Other outcomes and folate exposure-related outcomes were assessed.

Results: A total of 1123 pregnant women were screened, and 456 were enrolled (426 did not meet criteria, and 241 chose not to participate). A total of 298 children of WWE (mean [SD] age, 6.4 [4.2] years; 158 female [53.0%]; 140 male [47.0%]) vs 89 children of HW (mean [SD] age, 6.4 [4.2] years; 41 female [46.1%]; 48 male [53.9%]) did not differ on Verbal Index Score (parameter estimate, -0.6; 95% CI, -3.2 to 1.9; P = .64). Exposure-dependent outcomes differed across ASMs. Assessment of other ASMs was limited because 232 of 298 WWE (78%) were taking lamotrigine or levetiracetam alone or in combination. Folate supplementation during the first 12 weeks of pregnancy had positive associations with cognition and behavior with no signal for risks at higher folate doses.

Conclusions and relevance: Results of this prospective nonrandomized clinical trial suggest that verbal abilities in children of WWE vs HW did not differ. Exposure-dependent outcomes of ASMs highlight the importance of dosing high enough to protect the mother and fetus from seizures but low enough to protect the fetus. Folate supplementation early in pregnancy including higher doses was associated with improved cognitive and behavioral outcomes. Additional research is needed for ASMs with inadequate information on fetal exposure risks.

Trial registration: ClinicalTrials.gov Identifier: NCT01730170.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Meador reported grants from the National Institutes of Health (NIH), VA, Eisai, and Medtronics during the conduct of the study; in addition, the Epilepsy Study Consortium pays Dr Meador’s university for his research consultant time related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, UCB Pharma, Vivus Pharmaceuticals, and Xenon Pharmaceuticals outside the submitted work. Dr Cohen reported receiving personal fees from Stanford University during the conduct of the study; in addition, Dr Cohen reported having a patent for author royalties with royalties paid from Mental Health System Inc as author of the Children's Memory Scale. Dr Matthews reported receiving grants from The Emmes Company for providing CRO services during the conduct of the study. Dr Loring reported receiving active research support from the NIH, receiving an editorial stipend from Epilepsia and Neuropsychology Review, being President of the Neuropsychological Society, being an employee of Emory University, and deriving clinical income from neuropsychological patient evaluations. Dr Brown reported receiving a salary from the National Institute of Neurological Disorders and Stroke (NINDS) covered by Emmes, which received funding from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study. Dr Robalino reported receiving a salary from NINDS, which was covered by Emmes and a NINDS grant subaward to provide CRO services during the conduct of the study. Dr Birnbaum reported receiving grants from the NIH, UCB Pharma, and Vireo Health outside the submitted work. Dr Voinescu reported receiving grants from the NIH during the conduct of the study; personal fees from Philippines League Against Epilepsy and Physicians' Education Resource outside the submitted work; and serving as member of the scientific advisory board for North American AED Pregnancy Registry and board chair of My Epilepsy Story. Dr Gerard reported receiving grants from NIH/NINDS during the conduct of the study, advisory board fees from Xenon, funds from Eisai/Stanford Research, and royalties from UpToDate outside the submitted work. Dr Kalayjian reported receiving grants from the NIH during the conduct of the study. Dr Cavitt reported grants from the NIH/NINDS during the conduct of the study and advisory board fees from Jazz Pharmaceuticals outside the submitted work. Dr Sam reported receiving grants from the NIH during the conduct of the study. Dr Pack reported receiving funding from the NIH, royalties from Up to Date, and travel reimbursement for AAN and ABPN activities. Dr French reported receiving grants from Epilepsy Study Consortium/Epilepsy Foundation funded by UCB; consulting fees from UCB on Acadia Pharmaceuticals, Access Industries, Acuta Capital Partners, AFASCI Inc, Agrithera Inc, Alterity Therapeutics Limited, Angelini Pharma, Arvelle Therapeutics, Autifony Therapeutics, Axonis, Baergic Bio, Beacon Biosignals, Biogen, Biohaven Pharmaceuticals, BioMarin Pharmaceutical, Bloom Science, BridgeBio Pharma, Bright Minds Biosciences, Camp4 Therapeutics Corporation, Capsida Biotherapeutics, Cerebral Therapeutics, Cerecin, Cerevel, Ceribell, Clinical Education Alliance, Coda Biotherapeutics, Cognizance Biomarkers, Cowen and Company, Crossject, EcoR1 Capital, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Epitel, Equilibre BioPharmaceuticals, Genentech, Greenwich Biosciences, Grin Therapeutics, GW Pharma, iQure Pharma, IQVIA RDS, Janssen Pharmaceutica, Jazz Pharmaceuticals, Knopp Biosciences, Korro Bio, Leal Therapeutics, Lipocine, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus, Modulight.bio, Neumirna Therapeutics, Neurelis, Neurocrine, Neuroelectrics USA Corporation, Neurona Therapeutics, Neuronetics, Neuropace, NeuroPro Therapeutics, Neuroventis, Ono Pharmaceutical Co, Otsuka Pharmaceutical Development, Ovid Therapeutics, Paladin Labs, Pfizer, Praxis, PureTech LTY, Rafa Laboratories, Rapport Therapeutics, Receptor Holdings, Rivervest Venture Partners, Sage Therapeutics, SK Life Sciences, Stoke, Supernus, Takeda, Taysha Gene Therapies, Third Rock Ventures, Ventus Therapeutics, Vida Ventures Management, Xenon, and Zogenix; nonfinancial support/travel fees from Angelini Pharma, Biohaven Pharmaceuticals, Cerebral Therapeutics, Clinical Education Alliance, Cowen and Company, Longboard Pharmaceuticals, Neumirna Therapeutics, Neurelis, Neurocrine, Neuropace, Praxis, Rapport Therapeutics, SK Life Sciences, Takeda, and Xenon; serving as president for Epilepsy Study Consortium Inc, which provides travel reimbursement and salary support to NYU and is funded by Andrews Foundation, Eisai, Engage, Lundbeck, Pfizer, SK Life Science, Sunovion, UCB, Vogelstein Foundation; serving as chief medical/innovation officer for Epilepsy Foundation, which provides travel reimbursement; receiving grants from GW/FACES/One8Foundation and grants from NINDS outside the submitted work; and serving on the editorial board of Lancet Neurology and Neurology Today. Dr Tsai reported receiving grants from NIH during the conduct of the study and clinical trial agreement from Xenon Pharmaceuticals outside the submitted work. Dr Pennell reported receiving grants from the NIH, in addition, Dr Pennell reported having a patent for UpToDate Inc with royalties paid from University of Pittsburgh School of Medicine for contributing author. No other disclosures were reported.

References

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