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

ImportanceWomen 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.ObjectiveTo investigate the prevalence of MCMs after prenatal exposure to 8 commonly used ASM monotherapies and changes in MCM prevalence over time.Design, Setting, and ParticipantsThis 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.ExposureMaternal use of ASMs at conception.Main Outcomes and MeasuresMCMs 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.ResultsA 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 RelevanceOf 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.