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Epilepsy and Seizures

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

Educational Objective
To determine whether fetal antiseizure medication exposure in the third trimester of pregnancy affected neurodevelopment and cognitive outcomes in children at 2 years of age.

1 Credit CME

JAMA Neurology

Published Online: June 7, 2021

Original Investigation

Article Information and Disclosures

Kimford J. Meador, MD¹;

Morris J. Cohen, EdD²;

David W. Loring, PhD³;

Ryan C. May, PhD⁴;

Carrie Brown, MS⁴;

Chelsea P. Robalino, MStat⁴;

Abigail G. Matthews, PhD⁴;

Laura A. Kalayjian, MD⁵;

Elizabeth E. Gerard, MD⁶;

Evan R. Gedzelman, MD³;

Patricia E. Penovich, MD⁷;

Jennifer Cavitt, MD⁸;

Sean Hwang, MD⁹;

Maria Sam, MD¹⁰;

Alison M. Pack, MD¹¹;

Jacqueline French, MD¹²;

Jeffrey J. Tsai, MD¹³;

Page B. Pennell, MD¹⁴;

for the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Investigator Group

Author Affiliations

¹Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, California
²Pediatric Neuropsychology International, Augusta, Georgia
³Department of Neurology, Emory University, Atlanta, Georgia
⁴Emmes Company, Rockville, Maryland
⁵Department of Neurology, University of Southern California, Los Angeles
⁶Department of Neurology, Northwestern University, Evanston, Illinois
⁷Minnesota Epilepsy Group, St Paul, Minnesota
⁸Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio
⁹Northwell Health, Manhasset, New York
¹⁰Department of Neurology, Wake Forest University, Winston-Salem, North Carolina
¹¹Department of Neurology, Columbia University, New York, New York
¹²Department of Neurology, New York University, New York
¹³Department of Neurology, University of Washington, Seattle
¹⁴Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Investigator Groupfor the

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Key Points

Question What is the association between fetal exposure to antiseizure medication (ASM) and subsequent cognitive abilities of the child?

Findings This multicenter cohort study found no differences in 2-year-old children of women with epilepsy vs healthy women on the primary outcome of language domain scores of the Bayley Scales of Infant and Toddler Development, Third Edition. However, secondary analyses revealed that higher ASM levels and doses in the third trimester were associated with lower scores for other domains.

Meaning Overall, in this study, outcomes at 2 years of age did not differ by ASM exposures.

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

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Article Information

Accepted for Publication: March 27, 2021.

Published Online: June 7, 2021. doi:10.1001/jamaneurol.2021.1583

Corresponding Author: Kimford J. Meador, MD, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 213 Quarry Rd, Mail Code 5979, Palo Alto, CA 94304 (kmeador@stanford.edu).

Author Contributions: Drs Meador and May had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Meador, Cohen, Loring, May, Brown, French, Pennell.

Acquisition, analysis, or interpretation of data: Meador, Cohen, May, Robalino, Matthews, Kalayjian, Gerard, Gedzelman, Penovich, Cavitt, Hwang, Sam, Pack, French, Tsai, Pennell.

Drafting of the manuscript: Meador, May, Brown, Robalino.

Critical revision of the manuscript for important intellectual content: Meador, Cohen, Loring, Brown, Robalino, Matthews, Kalayjian, Gerard, Gedzelman, Penovich, Cavitt, Hwang, Sam, Pack, French, Tsai, Pennell.

Statistical analysis: May, Brown, Robalino, Matthews, Tsai.

Obtained funding: Meador, Loring, Pennell.

Administrative, technical, or material support: Meador, Loring, Gerard, Pack, Pennell.

Supervision: Meador, May, Matthews, Gerard, Sam, Pack, Pennell.

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.

Funding/Support: This work was supported by grants U01-NS038455 (Drs Meador and Pennell), U01-NS050659 (Dr May), and 2U01-NS038455 (Drs Meador, Pennell, and May) from the NINDS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the NIH.

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: A complete list of the members of the MONEAD Investigator Group appears in Supplement 2.

Additional Contributions: The investigators thank the children and families who have given their time to participate in the MONEAD Study. The authors thank the members of the MONEAD Investigator Group for their contributions.

AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
1.00 credit toward the CME of the American Board of Surgery’s Continuous Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.