Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study

Abstract

Importance: The neurodevelopmental risks of fetal exposure are uncertain for many antiseizure medications (ASMs).

Objective: To compare children at 2 years of age who were born to women with epilepsy (WWE) vs healthy women and assess the association of maximum ASM exposure in the third trimester and subsequent cognitive abilities among children of WWE.

Design, setting, and participants: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicenter investigation of pregnancy outcomes that enrolled women from December 19, 2012, to January 13, 2016, at 20 US epilepsy centers. Children are followed up from birth to 6 years of age, with assessment at 2 years of age for this study. Of 1123 pregnant women assessed, 456 were enrolled; 426 did not meet criteria, and 241 chose not to participate. Data were analyzed from February 20 to December 4, 2020.

Main outcomes and measures: Language domain score according to the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), which incorporates 5 domain scores (language, motor, cognitive, social-emotional, and general adaptive), and association between BSID-III language domain and ASM blood levels in the third trimester in children of WWE. Analyses were adjusted for multiple potential confounding factors, and measures of ASM exposure were assessed.

Results: The BSID-III assessments were analyzed in 292 children of WWE (median age, 2.1 [range, 1.9-2.5] years; 155 female [53.1%] and 137 male [46.9%]) and 90 children of healthy women (median age, 2.1 [range, 2.0-2.4] years; 43 female [47.8%] and 47 male [52.2%]). No differences were found between groups on the primary outcome of language domain (-0.5; 95% CI, -4.1 to 3.2). None of the other 4 BSID-III domains differed between children of WWE vs healthy women. Most WWE were taking lamotrigine and/or levetiracetam. Exposure to ASMs in children of WWE showed no association with the language domain. However, secondary analyses revealed that higher maximum observed ASM levels in the third trimester were associated with lower BSID-III scores for the motor domain (-5.6; 95% CI, -10.7 to -0.5), and higher maximum ASM doses in the third trimester were associated with lower scores in the general adaptive domain (-1.4; 95% CI, -2.8 to -0.05).

Conclusions and relevance: Outcomes of children at 2 years of age did not differ between children of WWE taking ASMs and children of healthy women.

Trial registration: ClinicalTrials.gov Identifier: NCT01730170.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Meador reported receiving research support from the National Institutes of Health (NIH), Eisai Co, Ltd, and Sunovion Pharmaceuticals Inc; travel support from Eisai Co, Ltd; and consulting for Eisai Co, Ltd, GW Pharmaceuticals, NeuroPace, Novartis AG, Supernus Pharmaceuticals, Inc, Upsher-Smith Laboratories, LLC, UCB SA, and VIVUS Inc, with fees paid to the university by The Epilepsy Study Consortium. Dr Loring reports receiving support for research from the National Institute of Mental Health (NIMH) and National Institute of Neurological Disorders and Stroke (NINDS), consulting for NeuroPace, receiving editorial stipends from Epilepsia and Neuropsychology Review, and receiving book royalties from Oxford University Press. Dr Gerard reported receiving research support from Sage Therapeutics, Inc, Sunovion Pharmaceuticals Inc, and Xenon Pharmaceuticals Inc; speaker fees from GW Pharmaceuticals and UCB SA; and travel funds from UCB SA. Dr Penovich reported receiving support for advisory and speakers bureau for Neurelis, Inc, SK Biopharmaceuticals, and UCB SA, and for advisory work for LVIS Corporation and Engage Therapeutics, Inc. Dr Cavitt reported receiving research support from the NINDS (MONEAD) and from GW Pharmaceuticals. Dr Sam reported receiving advisory board consulting fees for Aquestive Therapeutics. Dr Pack reported receiving royalties for the website UpToDate. Dr French reported receiving salary support at New York University from the Epilepsy Foundation and for consulting work and/or attending on behalf of the Epilepsy Study Consortium for Adamas Pharmaceuticals, Inc, Aeonian/Aeovian, Anavex Life Sciences Corp, Arvelle Therapeutics, Athenen Therapeutics/Carnot Pharma, Axovant Sciences, Baergic Bio, Inc, Biogen Inc, Biomotiv/Koutif, BioXcel Therapeutics, Inc, Blackfynn, Bloom Science, Bridge Valley Ventures LLP, Cavion, Cerebral Therapeutics, Cerevel Therapeutics, Crossject, CuroNZ Limited, Eisai Co, Ltd, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Inc, Engrail Therapeutics, Epiminder, Epitel, Inc, Fortress Biotech Inc, Greenwich Biosciences, GW Pharmaceuticals, Idorsia Pharmaceuticals Ltd, Ionis Inc, Janssen Global Services, LLC, Johnson & Johnson Services, Inc, Knopp Biosciences, H Lundbeck A/S, Marinus, Mend Neuroscience, Merck, NeuCyte, Inc, Neurelis, Inc, Neurocrine, Novartis AG, Otsuka Pharmaceutical Development, Ovid Therapeutics Inc, Passage Bio, Inc, Pfizer Inc, Praxis, Redpin Therapeutics, Inc, Sage Therapeutics, Inc, Shire plc, SK Life Sciences, Inc, Sofinnova, SpringWorks Therapeutics, Inc, Stoke Therapeutics, Sunovion Pharmaceuticals Inc, Supernus Pharmaceuticals, Inc, Takeda Pharmaceutical Company Limited, UCB SA, West Therapeutic Development, LLC, Xenon Pharmaceuticals Inc, Xeris Pharmaceuticals, Inc, Zogenix, Inc, and Zynerba Pharmaceuticals, Inc; receiving research grants from Biogen Inc, Cavion, Eisai Co, Ltd, Engage Therapeutics, Inc, GW Pharmaceuticals, H Lundbeck A/S, Neurelis, Inc, Ovid Therapeutics, Inc, Pfizer Inc, SK Life Sciences, Inc, Sunovion Pharmaceuticals Inc, UCB SA, Xenon Pharmceuticals Inc, Zogenix, Inc, the Epilepsy Research Foundation, the Epilepsy Study Consortium, and the NINDS; serving on the editorial board of Lancet Neurology and Neurology Today; serving as chief medical/innovation officer for the Epilepsy Foundation, for which New York University receives salary support; and receiving travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Adamas Pharmaceuticals, Inc, Arvelle Therapeutics, Inc, Axovant Sciences, Biogen Inc, Blackfynn, Cerevel Therapeutics, Crossject, CuroNZ Limited, Eisai Co, Ltd, Engage Therapeutics, Inc, Idorsia Pharmaceuticals Ltd, H Lundbeck A/S, NeuCyte, Inc, Neurelis, Inc, Novartis AG, Otsuka Pharmaceutical Development, Ovid Therapeutics Inc, Pfizer Inc, Redpin Therapeutics, Inc, Sage Therapeutics, SK Life Sciences, Inc, Sunovion Pharmaceuticals Inc, Takeda Pharmaceutical Company Limited, UCB SA, Xenon Pharmaceuticals Inc, and Zogenix, Inc. Dr Tsai reported receiving research support from the NIH, SK Life Sciences, Inc, and Xenon Pharmaceuticals Inc. Dr Pennell reported receiving grants from the NIH during the conduct of the study, personal fees from the NIH for grant reviews, personal fees from the American Epilepsy Society and the American Academy of Neurology as speaking honoraria, personal fees from Medical Schools for speaking honoraria and travel, and personal fees from UpToDate for royalties outside the submitted work. No other disclosures were reported.

Figures

Figure.. Ratios of Antiseizure Medication (ASM) Blood Level (ABL) and Defined Daily Dose (DDD) of ASM

Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), domain scores vs maximum observed ratios of ABL and DDD during the third trimester by the mother’s ASM group at time of maximum observed level.