Unintended Pregnancies and Breastfeeding Studies during Central Nervous System Drug Development: How Are they Handled, Is There Room for Improvement?: Maintaining the Gap: Pregnancy and Breastfeeding in CNS Clinical Trials.

Pregnant and breastfeeding individuals are routinely excluded from clinical drug development, creating persistent evidence gaps in pharmacology, safety, and dosing. Despite mandatory contraception and pregnancy testing, unintended pregnancies occur, particularly during the development of central nervous system (CNS) medicines used by women of reproductive age. Once exposure to an investigational medicinal product (IMP) has occurred, these pregnancies may provide valuable prospective human data; however, treatment or trial participation is often discontinued and follow-up may be incomplete. This study assessed how unintended pregnancies and breastfeeding data were reported, managed, and evaluated in clinical trials supporting marketing authorization applications (MAAs) for CNS products. We reviewed 35 MAAs for centrally authorized CNS products submitted to the European Medicines Agency between 2012 and 2022. Pregnancy frequency, IMP exposure, pregnancy outcomes, breastfeeding data and regulatory comments were extracted from MAA dossiers, Day 120 Lists of Questions and Summaries of Product Characteristics. Overall, 451 pregnancies were identified, including 343 with IMP exposure. Of these, 108 occurred in pivotal phase 3 trials, resulting in 39 live births, 23 elective terminations, 17 spontaneous pregnancy losses, and 29 unknown or ongoing outcomes. Regulators raised 19 pregnancy-related and six breastfeeding-related concerns. Only one dossier included a dedicated human lactation study. Pregnancy reporting varied substantially in location, format and case-level detail, while 27% of pivotal IMP-exposed pregnancies had unknown or ongoing outcomes at assessment. More structured reporting and follow-up, including relevant exposure and pharmacokinetic data where feasible, could strengthen clinical pharmacology and regulatory evidence and support more informative product information.