Declining malformation rates with changed antiepileptic drug prescribing: An observational study

Objective Changes in prescribing patterns of antiepileptic drugs (AEDs) in pregnant women with epilepsy would be expected to affect the risk of major congenital malformations (MCMs). To test this hypothesis, we analyzed data from an international pregnancy registry (EURAP). Methods EURAP is an observational prospective cohort study designed to determine the risk of MCMs after prenatal exposure to AEDs. The Cochrane-Armitage linear trend analysis was used to assess changes in AED treatment, prevalence of MCMs, and occurrence of generalized tonic-clonic seizures (GTCs) over 3 time periods: 2000–2005 (n = 4,760), 2006–2009 (n = 3,599), and 2010–2013 (n = 2,949). Results There were pronounced changes in the use of specific AEDs over time, with a decrease in the use of valproic acid and carbamazepine and an increase in the use of lamotrigine and levetiracetam. The prevalence of MCMs with monotherapy exposure decreased from 6.0% in 2000–2005 to 4.4% in 2010–2013. The change over time in MCM frequency after monotherapy exposure showed a significant linear trend in the crude analysis (p = 0.0087), which was no longer present after adjustment for changes in AED treatment (p = 0.9923). There was no indication of an increase over time in occurrence of GTCs during pregnancy. Conclusions There have been major changes in AED prescription patterns over the years covered by the study. In parallel, we observed a significant 27% decrease in the prevalence of MCMs. The results of adjusting the trend analysis for MCMs for changes in AED treatment suggest that changes in prescription patterns played a major role in the reduction of teratogenic events. Fil: Tomson, Torbjörn. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Battino, Dina. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Thomas, Sanjeev V.. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Vajda, Frank. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Kochen, Sara Silvia. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic; Argentina. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina Fil: Craig, John. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Binozzoni, Erminio. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Lindhout, Dick. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Perucca, Emilio. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia Fil: Sabers, Anne. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia