This study investigates the risk of major congenital malformations (MCMs) in offspring exposed to antiseizure medications (ASMs) during pregnancy. The EURAP Collaborators conducted a prospective, observational, longitudinal cohort study from June 1999 to October 2022, enrolling pregnant women with epilepsy (WWE) and following their offspring until one year after birth. The study included 10,121 pregnancies exposed to ASM monotherapy, with 9,840 exposed to the eight most commonly used ASMs. MCMs were assessed at one year post-birth, and teratogenic outcomes were compared using random-effects logistic regression, adjusting for confounders and prognostic factors. Key findings include: - MCMs occurred in 9.9% of pregnancies exposed to valproate, 6.3% to phenytoin, 6.2% to phenobarbital, 5.4% to carbamazepine, 4.9% to topiramate, 3.1% to lamotrigine, 2.9% to oxcarbazepine, and 2.5% to levetiracetam. - The prevalence of MCMs decreased from 6.1% during 1998-2004 to 3.7% during 2015-2022, a significant decline that was not explained by changes in ASM exposure patterns. - Valproate, phenobarbital, and carbamazepine showed dose-dependent increases in MCM risk, while levetiracetam, lamotrigine, and oxcarbazepine had lower risks. - Parental history of MCMs was associated with a 3.4-fold increase in risk. - Folate supplementation did not reduce the risk of MCMs. The study concludes that levetiracetam, lamotrigine, and oxcarbazepine are associated with a low risk of MCMs, and the observed decline in MCM prevalence over time highlights the importance of continued monitoring and the need for further research on newer ASMs.This study investigates the risk of major congenital malformations (MCMs) in offspring exposed to antiseizure medications (ASMs) during pregnancy. The EURAP Collaborators conducted a prospective, observational, longitudinal cohort study from June 1999 to October 2022, enrolling pregnant women with epilepsy (WWE) and following their offspring until one year after birth. The study included 10,121 pregnancies exposed to ASM monotherapy, with 9,840 exposed to the eight most commonly used ASMs. MCMs were assessed at one year post-birth, and teratogenic outcomes were compared using random-effects logistic regression, adjusting for confounders and prognostic factors. Key findings include: - MCMs occurred in 9.9% of pregnancies exposed to valproate, 6.3% to phenytoin, 6.2% to phenobarbital, 5.4% to carbamazepine, 4.9% to topiramate, 3.1% to lamotrigine, 2.9% to oxcarbazepine, and 2.5% to levetiracetam. - The prevalence of MCMs decreased from 6.1% during 1998-2004 to 3.7% during 2015-2022, a significant decline that was not explained by changes in ASM exposure patterns. - Valproate, phenobarbital, and carbamazepine showed dose-dependent increases in MCM risk, while levetiracetam, lamotrigine, and oxcarbazepine had lower risks. - Parental history of MCMs was associated with a 3.4-fold increase in risk. - Folate supplementation did not reduce the risk of MCMs. The study concludes that levetiracetam, lamotrigine, and oxcarbazepine are associated with a low risk of MCMs, and the observed decline in MCM prevalence over time highlights the importance of continued monitoring and the need for further research on newer ASMs.