TARGET-EU: Risk of adverse birth and neurodevelopmental outcomes in children born alive to fathers exposed to valproate versus levetiracetam for generalised epilepsy

This entry contains the code list used in case study 7 that is part of the broader TARGET EU project (EUPAS1000000539), which aims to advance the regulatory use of real-world data through the application of target trial emulation and estimand methodologies.

Background: Multiple studies have suggested that the intake of valproate for pregnant women during pregnancy has a negative effect on pregnancy outcomes. The evidence regarding the effect of paternal valproate exposure on offspring is much less clear, with multiple recent studies presenting contradictory results.
Therefore, new evidence is needed for regulatory decision-making, particularly regarding how methodological aspects may affect study results.

Objectives: The primary objective is to estimate the cumulative incidence of death, major congenital malformations, ADHD and autism in offspring born alive to fathers diagnosed with generalised epilepsy exposed to valproate compared to levetiracetam.

Methods: We will conduct an observational cohort study following the target trial emulation approach in combination with the estimands framework using linked electronic health records from the Valencian Health Integrated Database (García-Sempere et al, 2020), a comprehensive database of longitudinal electronic health records of the Valencia region in Spain. Eligible individuals are males of reproductive age (≥ 18 years) diagnosed with generalised epilepsy exposed to valproate or levetiracetam. In the primary analysis, the hypothetical strategy is used for treatment switch and the treatment policy strategy is used for treatment discontinuation; a principal stratum strategy is used where the principal stratum consists of those who father live births. A Poisson regression is used to estimate relative risks, weighted by the propensity score. Because of challenges in uniquely defining time-zero, the sequential trial approach is also employed.