Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study
Kimford J. Meador, Morris J. Cohen, David W. Loring, Ryan May, Carrie Brown, Chelsea P. Robalino, Abigail G. Matthews, Laura A. Kalayjian, Elizabeth E. Gerard, Evan Gedzelman, Patricia Penovich, Jennifer Cavitt, Sean Hwang, Maria Sam, Alison Pack, Jacqueline A. French, Jeffrey Tsai, Page B. Pennell, Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Investigator Group, Angela K. Birnbaum, Maurice L. Druzin, Richard H. Finnell, Gregory L. Holmes, Frederick T. McElrath, Lorene M. Nelson, Zachary N. Stowe, Linda Van Marter, Peter G. Wells, Mark S. Yerby, Eugene Moore, Dominic Ippolito, Julia Skinner, Lisa Davis, Nilay D. Shah, Brenda Leung, Mark Friedman, Hayley Loblein, Traci Sheer, Suzanne Strickland, Erin Latif, Yong Park, Delmaris Acosta-Cotte, Patty Ray, Kirsten Cleary, Joyce Echo, Annette Zygmunt, Camilla Casadei, M. Eileen Dolan, Kim E Ono, Donald J. Bearden, Christine Ghilian, Diane L. Teagarden, Melanee Newman, Paul C. McCabe, Michael J. Paglia, Cora Taylor, Rosemarie Delucca, Kristina Blessing, Linda Van Marter, Katrina Boyer, Ellen Hanson, Amy Young, Paige Hickey, J Strauss, Hayley Madeiros, Li Chen, Stephanie Allien, Yvonne Sheldon, Taylor Weinau, Gregory L. Barkley, Marianna Spanaki‐Varelas, Andrea Thomas, Jules E. C. Constantinou, Nazin Mahmood, Vibhangini S. Wasade, Shailaja Gaddam, Andrew Zillgitt, Taimur Anwar, Carla Sandles, Theresa Holmes, Emily L. Johnson, Gregory L. Krauss, Shari M. Lawson, Alison Pritchard, Matthew Ryan, Pam Coe, Katie Reger, Jenny Pohlman, Alisha Olson, William Schweizer, Chris Morrison, William S. MacAllister, Tobi Clements, Hima Bindu Tam Tam, Yael Cukier, Erica P. Meltzer, Jacqueline Helcer, Connie Lau, William A. Grobman, Joseph Coda
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.