Behavioral Outcomes and Neurodevelopmental Disorders Among Children of Women With Epilepsy
Morris J. Cohen, Kimford J. Meador, David W. Loring, Abigail G. Matthews, Carrie Brown, Chelsea P. Robalino, Angela K. Birnbaum, P. Emanuela Voinescu, Laura A. Kalayjian, Elizabeth E. Gerard, Evan Gedzelman, Julie Hanna, Jennifer Cavitt, Maria Sam, Jacqueline A. French, Sean Hwang, Alison Pack, Page B. Pennell, Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Investigator Group, 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, Ryan May, Dominic Ippolito, Julia Skinner, Lisa Davis, Nilay D. Shah, Brenda Leung, Mark Friedman, Hayley Loblein, Traci Sheer, Yue Wang, N. Andrew Browning, Michelle Arias, Rebecca Ayre, Temperance Blalock, L. Hendrickson, Merin Mathew, Anjali Nair, Yinka Ogunsola, Chinh Ott, Phyllis Renehan, Sarah S. Romano, D. Schutte, Noble Shore, Vydhi Vasudevan, Steffanie H Wilson, Jamie Winestone, Thad Zajdowicz, Suzanne Strickland, Erin Latif, Yong Park, Delmaris Acosta-Cotte, Patty Ray, Kirsten Cleary, Joyce Echo, Annette Zygmunt, Camilla Casadei, Ifemoa Irobunda, Anna Chessky, Mary Eileen Dolan, Kim E Ono, Donald J. Bearden, Christine Ghilian, Diane L. Teagarden, Melanee Newman, Yvan Bamps, Emilee Wehunt, Paul C. McCabe, Michael J. Paglia, Cora Taylor, Rosemarie Delucca, Kristina Blessing, Joshua Dopko, Katrina Boyer, Ellen Hanson, Amy Young, Paige Hickey, J Strauss, Hayley Madeiros, Brian Rozumny, Li Chen, Stephanie Allien, Yvonne Sheldon, Taylor Weinau, Elizabeth Shashkova, M. Choe, Gregory L. Barkley, Marianna Spanaki‐Varelas, Andrea Thomas, Jules E. C. Constantinou, Nazin Mahmood, Vibhangini S. Wasade
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.