(BSPOT21) Changes in adverse event reporting of neurodevelopmental disorders after maternal valproate exposure, following a major scientific publication and regulatory decisions, a contribution of the ConcePTION project

Background: Understanding how publications and regulations regarding neurodevelopmental disorders (NDDs) and valproate (VPA) exposure during pregnancy affect the quantity and characteristics of Individual Case Safety Reports (ICSRs) submitted to pharmacovigilance centres is crucial for accurately interpreting quantitative approaches in signal detection.

Objectives: To assess alterations in the outcome measures of signal detection methods, specifically disproportionality and clustering of events, subsequent to scientific publications and regulatory decisions concerning maternal VPA exposure and NDDs in the offspring.

Methods: Observational study in VigiBase, the WHO global database of ICSRs, using reports dated between January 1, 2000, and May 1, 2023. Changes in disproportionality and ICSRs clustering based on reported events, involving VPA exposure during pregnancy and NDDs in the offspring were studied, focusing in particular on significant events i.e. a major publication and regulatory decisions by the European Medicines Agency. Carbamazepine and lamotrigine, drugs for which there are currently no safety signals regarding NDDs, were used as controls in this research.
For VPA and events related to NDDs, crude reporting odds ratios and 95% confidence intervals were calculated. For cluster analysis the vigiGroup method was used, performing a repeated mixture-model-based cluster analysis using a latent class model for reports with conditionally independent binomial distributions for the reported events.
Clusters were randomised and assessed by three qualified assessors for reviewing and rating the meaningful clusters. Time trend graphs were used to visually study any changes in the reporting behaviour following the events that received public attention.

Results: The total number of pregnancy reports after the exclusions was 275.402. There was a clear increase of the number and diversity of reported NDDs for VPA as compared to the controls. The most frequently reported event was Autism Spectrum Disorder. Although the major scientific publication on VPA associated NDDs seemed to have an impact on both the absolute number of reports and disproportionality, the effect of regulatory decisions was less clear. Cluster analysis showed a more diverse pattern of reported events over time.

Conclusions: Our study revealed a general increase in reporting and awareness of events related to NDDs and VPA exposure during pregnancy and a more diverse way of reporting over time.