Risk of Major Congenital Malformations and Exposure to Antiseizure Medication Monotherapy
Authors: Dina Battino, Torbjörn Tomson, Erminio Bonizzoni, John Craig, Emilio Perucca, Anne Sabers, Sanjeev Thomas, Silje Alvestad, Piero Perucca, Frank Vajda, Chiara Pantaleoni, Claudia Ciaccio, Silvia Kochen, Frank Vajda, Gerhard Luef, Alejandro De Marinis, Jana Zarubova, Anne Sabers, Reetta Kälviäinen, Sofia Kasradze, Bettina Schmitz, Sanjeev V. Thomas, Nasim Tabrizi, Lilach Goldstein, Barbara Mostacci, Hideyuki Ohtani, Gordana Kiteva-Trenchevska, Eugène van Puijenbroek, Silje Alvestad, Maja Milovanović, Vladimír Šafčák, Meritxell Martinez Ferri, Torbjörn Tomson, Elisabeth Sellitto, Hsiang-Yu  Yu, Stephanie Hödl, Petr Marusic, Renata Listonova, Hana Krijtová, David Franc, Petr Busek, Michaela Kajšová, Noemi Andersen, Birthe Pedersen, Katarzyna Mieszczanek, Katarzyna Cebula, Stefan Juhl, Birgitte Forsom Sondal, Karen Nielsen, Tatiana V. Danielsen, Elsebeth Bruun Christiansen, Jakob Christensen, Ovidio Solano Cabrera, Aleksei Rakitin, Anne Kirss, Anna M. Saukkonen, Nino Gogatishvili, Dieter Dennig, Kerstin Erdmann, Christian Dippon, Bernhard Steinhoff, Lisa M. Langenbruch, Holger Lerche, Anja Herzer, Jan S. Gerdes, Elisa K. El-Allawy-Zielke, Hajo Hamer, Malgorzata Kalita, Martin Hirsch, Stephan Arnold, Hans-Beatus Straub, Rebekka Lehmann, Christiane Asenbauer, Florian Losch, Wenke Grönheit, Matthias Lindenau, Ramshekhar Menon, Jafar Mehvari Habibabadi, Maria P. Canevini, Elena Zambrelli, Katherine Turner, Michela Cecconi, Aldo Paggi, Nicoletta Foschi, Antonio Gambardella, Simone Beretta, Angela Giglio, Gaia Fanella, Lorenzo Ferri, Francesca Bisulli, Alessandra Pistelli, Pietro Pignatta, Marta Maschio, Francesca Muzzi, Maria S. Cotelli, Etsuko Yamazaki, Kiyohito Terada, Yushi Inoue, Masahiro Mizobuchi, Katsuyuki Fukushima, Masaaki Kato, Takahiro Mitsueda, Torleiv Svendsen, Erik Taubøll, Alma Sikiric, Katrine Haggag, Eline Dahl-Hansen, Ineke Hogenesch, Eylert Brodtkorb, Isabel Pires, Helena Rocha, Marta Carvalho, Ricardo Rego, Carla Bentes, Ana C. Gonçalves Franco, Sara Parreira, Halina Navumava, Ksenija Gebauer Bukurov, Juan L. Becerra  Cuñat, Clara Cabeza Alvarez, Mercedes Garces Sanchez, Gemma Sansa Fayos, David Sopelana Garay, Alvaro Sanchez Larsen, Maria D. Castro Vilanova, Lisa Gordon, Peter Mattsson, Eva Kumlien, Maria Strandberg, Avan S. Rashid, Helena Gauffin, Irene Hakansson, Maria Bograkou, Kristina Malmgren, Dominique Flügel, Stephan Rüegg, Martin Kurthen, Dilek Atakli, Önder Kemal Soylu, Janet E Graham, Alison A Hitchcock, Stefanie Gadeyne, Katherine Moreno, Hanna Jersing, Karina Als, Lone Olsen, Julie Althoen Sønderup, Pirjo Lavi, Kirsten Krämer, Siri Myklebust, Mariann Høgli Grøtte, Bibiane Moche Kamga, Laura Gargantini, Cristina Bonato, Stefania Falchi
Journal: JAMA Neurology (2024)

Importance Women with epilepsy (WWE) require treatment with antiseizure medications (ASMs) during pregnancy, which may be associated with an increased risk of major congenital malformations (MCMs) in their offspring. Objective To investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time. Design, Setting, and Participants This was a prospective, observational, longitudinal cohort study conducted from June 1999 to October 2022. Since 1999, physicians from more than 40 countries enrolled ASM-treated WWE before pregnancy outcome was known and followed up their offspring until 1 year after birth. Participants aged 14 to 55 years who were exposed to 8 of the most frequently used ASMs during pregnancy were included in this study. Data were analyzed from April to September 2023. Exposure Maternal use of ASMs at conception. Main Outcomes and Measures MCMs were assessed 1 year after birth by a committee blinded to type of exposure. Teratogenic outcomes across exposures were compared by random-effects logistic regression adjusting for potential confounders and prognostic factors. Results A total of 10 121 prospective pregnancies exposed to ASM monotherapy met eligibility criteria. Of those, 9840 were exposed to the 8 most frequently used ASMs. The 9840 pregnancies occurred in 8483 women (mean [range] age, 30.1 [14.1-55.2] years). MCMs occurred in 153 of 1549 pregnancies for valproate (9.9%; 95% CI, 8.5%-11.5%), 9 of 142 for phenytoin (6.3%; 95% CI, 3.4%-11.6%), 21 of 338 for phenobarbital (6.2%; 95% CI, 4.1%-9.3%), 121 of 2255 for carbamazepine (5.4%; 95% CI, 4.5%-6.4%), 10 of 204 for topiramate (4.9%; 95% CI, 2.7%-8.8%), 110 of 3584 for lamotrigine (3.1%; 95% CI, 2.5%-3.7%), 13 of 443 for oxcarbazepine (2.9%; 95% CI, 1.7%-5.0%), and 33 of 1325 for levetiracetam (2.5%; 95% CI, 1.8%-3.5%). For valproate, phenobarbital, and carbamazepine, there was a significant increase in the prevalence of MCMs associated with increasing dose of the ASM. Overall prevalence of MCMs decreased from 6.1% (153 of 2505) during the period 1998 to 2004 to 3.7% (76 of 2054) during the period 2015 to 2022. This decrease over time was significant in univariable logistic analysis but not after adjustment for changes in ASM exposure pattern. Conclusions and Relevance Of all ASMs with meaningful data, the lowest prevalence of MCMs was observed in offspring exposed to levetiracetam, oxcarbazepine, and lamotrigine. Prevalence of MCMs was higher with phenytoin, valproate, carbamazepine, and phenobarbital, and dose dependent for the latter 3 ASMs. The shift in exposure pattern over time with a declining exposure to valproate and carbamazepine and greater use of lamotrigine and levetiracetam was associated with a 39% decline in prevalence of MCMs, a finding that has major public health implications.