A retrospective observational study is currently being conducted by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency on the risks to children born to fathers exposed to valproate or one of its derivatives during the three months prior to conception. The recommendations and restrictions on the use of valproate and its derivatives during pregnancy, and measures to avoid in utero exposure to medicinal products containing valproate or its derivatives remain in force and unchanged.
The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) is currently conducting a retrospective observational study (EUPAS34201) on the risks of neurodevelopmental disorders (including autistic spectrum disorders) and the risk of congenital abnormalities in children born to fathers exposed to valproate or one of its derivatives during the three months prior to conception. This study is based on Danish, Norwegian and Swedish registers (databases). It was imposed on pharmaceutical companies holding at least one marketing authorisation for valproate or its derivatives following the European Article 31 Arbitration finalised in 2018 on the use of valproate and its derivatives during pregnancy.
The preliminary results of the study suggest that the risk of neurodevelopmental disorders (but not congenital abnormalities) may be higher in children born to fathers exposed to valproate or one of its derivatives in the three months prior to conception, compared with the risks in children born to fathers exposed to lamotrigine or levetiracetam (alternative treatments to valproate) in the three months prior to conception. However, questions remain concerning different methodological parameters used in the analysis, which could have consequences for the interpretation of the study results.
The PRAC has therefore demanded that marketing authorisation holders submit further information and corrected analyses as soon as possible. These are expected from October 2023.
The EMA and the European competent authorities, including the FAMHP, will communicate on the subject once the assessment is finalised, in order to inform patients and prescribers of the conclusions and the regulatory actions recommended by the PRAC.
The ongoing assessment of the effects on the child of paternal exposure to valproate or one of its derivatives does not affect the recommendations and restrictions on the use of valproate and its derivatives during pregnancy that were made in 2018 as a result of the Article 31 Arbitration procedure. The measures adopted to avoid in utero exposure to medicinal products containing valproate or one of its derivatives remain in force and unchanged. The potential risks associated with paternal exposure to valproate or one of its derivatives were not assessed during the 2018 Article 31 Arbitration procedure.
Information for patients
• Male patients taking medicinal products containing valproate or one of its derivatives should never stop treatment under any circumstances without discussing this with their doctor. It could result in a sudden worsening of their epilepsy (with more severe or more frequent seizures) or bipolar disorder for which they have been prescribed valproate or one of its derivatives.
• Male patients taking valproate or one of its derivatives who are thinking of conceiving a child are also advised to talk to their doctor, who can discuss potential risks and alternative treatments.