Behavioral Outcomes and Neurodevelopmental Disorders Among Children of Women With Epilepsy
Authors: Cohen Morris J. , Meador Kimford J. , Loring David W. , Matthews Abigail G. , Brown Carrie , Robalino Chelsea P. , Birnbaum Angela K. , Voinescu Paula E. , Kalayjian Laura A. , Gerard Elizabeth E. , Gedzelman Evan R. , Hanna Julie , Cavitt Jennifer , Sam Maria C. , French Jacqueline A. , Hwang Sean T. , Pack Alison M. , Pennell Page B. ,   Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Investigator Group, Druzin Maurice , Finnell Richard , Holmes Gregory , McElrath Frederick T. , Nelson Lorene , Stowe Zachary , Van Marter Linda , Wells Peter , Yerby Mark , Moore Eugene , May Ryan , Ippolito Dominic , Skinner Julia , Davis Lisa , Shah Nilay , Leung Brenda , Friedman Mark , Loblein Hayley , Sheer Traci , Wang Yue , Browning Nancy , Arias Michelle , Ayre Rebecca , Blalock Temperance , Hendrickson Linda , Mathew Merin , Nair Anjali , Ogunsola Yinka , Ott Chinh , Zaia Renehan Phyllis , Romano Sarah , Schutte Dominic , Shore Noble , Vasudevan Vydhi , Wilson Steffanie , Winestone Jamie , Zajdowicz Thad , Strickland Suzanne , Latif Erin , Park Yong , Acosta-Cotte Delmaris , Ray Patty , Cleary Kirsten , Echo Joyce , Zygmunt Annette , Casadei Camilla , Irobunda Ifemoa , Chessky Anna , Dolan Mary , Ono Kim , Bearden Donald , Ghilian Christine , Teagarden Diane , Newman Melanee , Bamps Yvan , Wehunt Emilee , McCabe Paul , Paglia Michael , Taylor Cora , Delucca Rosemarie , Blessing Kristina , Dopko Joshua , Boyer Katrina , Hanson Ellen , Young Amy , Hickey Paige , Strauss Jolie , Madeiros Hayley , Rozumny Brian , Chen Li , Allien Stephanie , Sheldon Yvonne , Weinau Taylor , Shashkova Elizabeth , Choe Melanie , Barkley Gregory L. , Spanaki-Varelas Marianna , Thomas Andrea , Constantinou Jules , Mahmood Nazin , Wasade Vibhangini , Gaddam Shailaja , Zillgitt Andrew , Anwar Taimur , Sandles Carla , Holmes Theresa , Johnson Emily , Krauss Gregory , Lawson Shari , Pritchard Alison , Ryan Matthew , Coe Pam , Reger Katie , Pohlman Jenny , Olson Alisha , Steele Anna , Lange Hadley , Chang Patricia , Ellis Sarah , Schweizer William , Morrison Chris , MacAllister William , Clements Tobi , Riley Edward , Smith Aaron , Pleskovich Maria , Tam Hima Bindu Tam , Cukier Yael Cukier , Meltzer Erica Meltzer , Helcer Jacqueline Helcer , Lau Connie Lau , Baron Scott , Colon Olivia , Grobman William , Coda Joseph , Miller Emily , Bellinski Irena , Bachman Elizabeth , Krueger Casey , Seliger Jordan , DeWolfe Jennifer , Owen John , Thompson Matthew , Hall Cheryl , Williams Valencia , Moyana Anna , Labiner David , Maciulla James , Moon Jennifer , Darris Kayla , Bahe Alicia , Richards Scott , Privitera Michael , Flood-Schaffer Kellie , Jewell George , Mendoza Lucy , Mcelroy Becky , Serrano Enrique , Salih Yasin , Bermudez Christin , Miranda Michelle , Velez-Ruiz Naymee , Figueredo Pedro , Carns Danielle , Harcourt Scott , Ramirez Kristin , Tedesco Silva Leticia , Bagic Anto , Urban Alexandra , Gedela Satya , Patterson Christina , Jeyabalan Arundhathi , Radonovich Krestin , Sutcliffe Melissa , Beers Susan , Wiles Carrie , Duran Sabrina , Prince Dane , Alhaj Sandra , Stek Alice , Perez Sonia , Sierra Rachel , Munoz Cynthia , Miller John W. , Mao Jennie , Phatak Vaishali , Kim Michelle , Cheng-Hakimian Andrea , DeNoble Gina , Tsai Jeffrey , Anthony-Fick Erin , Steele Jennifer , Parker Lamar , Morris Melissa , Dimos Jessica , Oates Deanna , Culbreth Danielle 
Published: November 2023

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 &amp;lt; .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.