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Observational Study
. 2024 Jan 1;81(1):19-29.
doi: 10.1001/jamaneurol.2023.4315.

Behavioral Outcomes and Neurodevelopmental Disorders Among Children of Women With Epilepsy

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

Behavioral Outcomes and Neurodevelopmental Disorders Among Children of Women With Epilepsy

Morris J Cohen et al. JAMA Neurol. .

Abstract

Importance: The association of fetal exposure to antiseizure medications (ASMs) with outcomes in childhood are not well delineated.

Objective: To examine the association of fetal ASM exposure with subsequent adaptive, behavioral or emotional, and neurodevelopmental disorder outcomes at 2, 3, and 4.5 years of age.

Design, setting, and participants: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational cohort study conducted at 20 epilepsy centers in the US. A total of 456 pregnant women with epilepsy or without epilepsy were enrolled from December 19, 2012, to January 13, 2016. Children of enrolled women were followed up with formal assessments at 2, 3, 4.5, and 6 years of age. Statistical analysis took place from August 2022 to May 2023.

Exposures: Exposures included mother's epilepsy status as well as mother's ASM blood concentration in the third trimester (for children of women with epilepsy). Women with epilepsy were enrolled regardless of ASM regimen.

Main outcomes and measures: The primary outcome was the Adaptive Behavior Assessment System, Third Edition (ABAS-3) General Adaptive Composite (GAC) score among children at 4.5 years of age. Children of women with epilepsy and children of women without epilepsy were compared, and the associations of ASM exposures with outcomes among exposed children were assessed. Secondary outcomes involved similar analyses of other related measures.

Results: Primary analysis included 302 children of women with epilepsy (143 boys [47.4%]) and 84 children of women without epilepsy (45 boys [53.6%]). Overall adaptive functioning (ABAS-3 GAC score at 4.5 years) did not significantly differ between children of women with epilepsy and children of women without epilepsy (parameter estimate [PE], 0.4 [95% CI, -2.5 to 3.4]; P = .77). However, in adjusted analyses, a significant decrease in functioning was seen with increasing third-trimester maximum ASM blood concentrations (PE, -7.8 [95% CI, -12.6 to -3.1]; P = .001). This decrease in functioning was evident for levetiracetam (PE, -18.9 [95% CI, -26.8 to -10.9]; P < .001) and lamotrigine (PE, -12.0 [95% CI, -23.7 to -0.3]; P = .04), the ASMs with sample sizes large enough for analysis. Results were similar with third-trimester maximum daily dose.

Conclusions and relevance: This study suggests that adaptive functioning of children of women with epilepsy taking commonly used ASMs did not significantly differ from that of children of women without epilepsy, but there was an exposure-dependent association of ASMs with functioning. Thus, psychiatric or psychological screening and referral of women with epilepsy and their offspring are recommended when appropriate. Additional research is needed to confirm these findings.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cohen reported receiving personal fees from Stanford University during the conduct of the study; in addition, Dr Cohen had a patent with royalties paid from Multi Health System Inc as author of the Children’s Memory Scale. Dr Meador reported receiving grants from the National Institutes of Health (NIH), Eisai Inc, and Sunovion Pharmaceuticals; 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, and Vivus Pharmaceuticals outside the submitted work. Dr Loring reported receiving active research support from the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health; he is a consultant for NeuroPace, Inc; he receives book royalties from Oxford University Press and an editorial stipend from Epilepsia and Neuropsychology Review; he is an employee of Emory University and derives clinical income from neuropsychological patient evaluations. Dr Birnbaum reported receiving grants from UCB Pharma, Vireo Health, HealthPartners Institute, Veloxis Pharmaceuticals, the NIH, and the University of Minnesota outside the submitted work; in addition, Dr Birnbaum reported receiving grant support, paid to her institution, from the National Institutes of Health, UCB Pharma–Small Grant, Health Partners Institute–Small Grant, 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. Dr Voinescu reported receiving personal fees from Physicians’ Education Resource, Neurodiem, and StonyBrook University outside the submitted work and serving as board chairperson for My Epilepsy Story and as a member of the scientific advisory board of the North American AED Pregnancy Registry. Dr Gerard reported receiving research support from Sage Pharmaceuticals, Sunovion Pharmaceuticals, Xenon Pharmaceuticals, and Eisai/Stanford; speaker honoraria from Greenwich Pharmaceuticals and UCB Pharma; travel funds from UCB Pharma; and honoraria from Neurology Week. She also serves on an advisory board for Xenon Pharmaceuticals and receives royalties from UptoDate, Inc. Dr Cavitt reported receiving research support from GW Pharmaceuticals. She also receives support for advisory board consulting for Jazz Pharmaceuticals. Dr Sam reported serving on the advisory board for Aquesti outside the submitted work. Dr French reported receiving personal fees from the Epilepsy Foundation; receiving New York University salary support for consulting work and/or attending scientific advisory boards on behalf of the Epilepsy Study Consortium for Aeonian/Aeovian, Agrithera Inc, Alterity Therapeutics Limited, Anavex, Angelini Pharma S.p.A, Arkin Holdings, Arvelle Therapeutics Inc, Athenen Therapeutics/Carnot Pharma, Autifony Therapeutics Limited, Baergic Bio, Beacon Biosignals Inc, Biogen, Biohaven Pharmaceuticals, BioMarin Pharmaceutical Inc, BioXcel Therapeutics, Bloom Science Inc, BridgeBio Pharma Inc, Bright Minds, Cerecin, iQuire, Camp4 Therapeutics Corp, Cerebral Therapeutics, Cerevel, Clinical Education Alliance, Coda Biotherapeutics, Cognizance Biomarkers, Corlieve Therapeutics, Crossject, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epalex, Epihunter, Epiminder, Epitel Inc, Equilibre BioPharmaceuticals, Genentech Inc, Greenwich Biosciences, Grin Therapeutics, GW Pharma, Janssen Pharmaceutica, Jazz Pharmaceuticals, Knopp Biosciences, Korro Bio Inc, Lipocine, LivaNova, Longboard Pharmaceuticals, Lundbeck, Marinus, Merck, Modulight.bio, NeuCyte Inc, Neumirna Therapeutics, Neurelis, Neurocrine, Neuroelectrics USA Corp, Neuronetics Inc, Neuropace, NeuroPro Therapeutics, Nxgen Medicine Inc, Ono Pharmaceutical Co, Otsuka Pharmaceutical Development, Ovid Therapeutics Inc, Paladin Labs Inc, Passage Bio, Pfizer, Praxis, PureTech LTY Inc, Rafa Laboratories Ltd, Rapport Therapeutics Inc, Receptor Holdings Inc, Sage Therapeutics Inc, SK Life Sciences, Sofinnova, Stoke, Supernus, Synergia Medical, Takeda, Third Rock Ventures LLC, UCB Inc, Ventus Therapeutics, Vida Ventures Management, Xenon, Xeris, Zogenix, Legal Therapeutics, and Zynerba; receiving grants from Eisai, the Andrews Foundation, Pfizer, SK Life Sciences, UCB, FACES, and GW/Jazz; and travel support from the Cerebral, Rappaport, Stroke, Epilepsy Study Consortium, Angelini Pharma, Biohaven Pharmaceuticals, Cerebral Therapeutics, Cerevel, Clinical Education Alliance, Neurelis, Neurocrine, Praxis, Takeda, and Xenon outside the submitted work. Dr Pack reported receiving funding from NIH, royalties from Up to Date, and travel reimbursement for AAN and ABPN activities. Dr Pennell reported receiving grants from NIH, personal fees from NIH for grant reviews, personal fees from AES as speaking honoraria, personal fees from 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. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Adaptive Behavior Assessment System, Third Edition (ABAS-3), General Adaptive Composite (GAC) Scores at 4.5 Years of Age for Children of Women With Epilepsy (WWE) vs Women Without Epilepsy (WWoE), and ABAS-3 GAC Scores at 4.5 Years of Age vs Third-Trimester Maximum Observed Ratio Antiseizure Medication (ASM) Concentrations for Children of WWE
A, Box plots for children’s ABAS-3 GAC scores at 4.5 years of age for children of WWE and WWoE. Children with imputed scores were excluded (imputation population, n = 326). B, Scatterplot with fitted linear regression line for ABAS-3 GAC scores at 4.5 years of age vs third-trimester maximum observed ratio of ASM concentration for children of WWE with third-trimester blood levels. Children with imputed scores were excluded (imputation population, n = 229). Sample sizes for individual ASM regimens included in the full imputation population (n = 271) include the following: lamotrigine = 98, levetiracetam = 77, oxcarbazepine = 14, carbamazepine = 10, zonisamide = 10, topiramate = 4, lacosamide = 2, valproate = 2, gabapentin = 1, phenobarbital = 1, lamotrigine plus levetiracetam = 25, lacosamide plus levetiracetam = 5, and other polytherapy = 22 (see eTable 3 in Supplement 1 for a list of other polytherapy regimens with ≤3 children with mothers taking a regimen).
Figure 2.
Figure 2.. Association Between Adaptive Behavior Assessment System, Third Edition (ABAS-3) General Adaptive Composite (GAC) Scores and Third-Trimester Maximum Observed Ratio of Antiseizure Medication (ASM) Concentration for Children of Women With Epilepsy by Mother’s ASM Category
Scatterplot with fitted linear regression line for ABAS-3 GAC score at 4.5 years of age vs third-trimester maximum observed ratio of ASM concentration for children of women with epilepsy with third-trimester blood levels for lamotrigine (A), levetiracetam (B), other monotherapy (C), lamotrigine plus levetiracetam (D), and other polytherapy (E). The completers population (n = 229) included sample sizes, parameter estimates (PEs), 95% CIs, and P values from a multiple linear regression model that included the mother’s third-trimester maximum observed ratio of ASM concentration, ASM category, and their interaction, adjusting for mother’s IQ, educational level, age at enrollment, smoking during pregnancy, postbirth mean anxiety score, McMaster Family Assessment Device problematic family functioning at child’s 2-year visit, and child’s sex and small-for-gestational-age status. A total of 12 children were excluded from the adjusted analysis due to missing covariates.
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References

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