(A-023) Studying paternal drug exposures and offspring outcomes: feasibility assessment of large European databases

Background: Recent studies highlighted the importance of investigating the safety of paternal drug exposures with respect to offspring health. For a new PASS, TANGO, aiming to assess the risk of neurodevelopmental disorders and major congenital malformations in offspring of fathers exposed to valproate, large databases are needed for sufficient statistical power and generalizability.

Objectives: To assess the fitness for purpose of large European databases in the SIGMA Consortium for assessing the impact of paternal drug exposures on offspring health.

Methods: The assessment was conducted among 11 databases in Denmark, Finland, France, Germany, Italy, the Netherlands, Norway, Scotland, Spain, Sweden and the UK to determine 1) the availability of mother-father-offspring linkage for live and non-live birth outcomes and 2) key information pertaining to the TANGO objectives and its methodological challenges. UK assessment (CPRD) was based solely on a literature review.

Results: In CPRD, PHARMO, GePaRD (covering respectively 25%, 25%, 20% of the UK, Dutch, German populations) and population-based Nordic Registries (Sweden, Denmark, Norway, Finland) linkage of mother, father and offspring data is available but not in France, Italy, Scotland or Spain. The linkage is exact in GePaRD and Nordic Registries, while CPRD and PHARMO would rely on a probabilistic linkage. Father-offspring linkage rate for live-birth outcomes is >90% in the Nordic Registries, 66% in the CPRD, 25% of linked mother-offspring pairs in GePaRD, and 20% in PHARMO. Father-offspring linkage for non-live-birth outcomes is available in Danish and Norwegian Registries (90%), GePaRD, PHARMO and CPRD (unknown rate); not available in the Finnish and Swedish Registries. Stillbirths are recorded in all databases containing non-live birth outcomes. Spontaneous and elective abortion (if reimbursed) are available and comprehensive in GePaRD and Nordic Registries. Except for CPRD, which only captures GP prescriptions, all other databases can identify drug exposure from the first dispensing, regardless if by GP or specialist. Medical outcomes in offspring are available in all databases.

Conclusions: As a result of the feasibility assessment, GePaRD, Nordic Registries, PHARMO, and potentially CPRD are considered suitable databases to study the effects of drug paternal exposure on offspring. Due to a preferred exact father-offspring linkage, Nordic Registries and GePaRD were selected for TANGO. The mother-father-offspring linkage being a critical database feature to study effects of paternal exposure on pregnancy outcome/offspring health, the same conclusions can be drawn for any other study aiming to assess health outcomes in children of fathers exposed to drugs.