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Original Investigation
June 7, 2021

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

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
JAMA Neurol. Published online June 7, 2021. doi:10.1001/jamaneurol.2021.1583
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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