Rethinking Evidence Generation for Vaccine Safety in Pregnancy: Beyond Randomized Trials Across the Immunization...

Maternal immunization protects pregnant individuals and infants. However, evidence on vaccine safety during pregnancy remains variable across vaccine products and maternal, fetal, neonatal, and infant outcomes. Debate has often focused on whether pregnant individuals should be included in randomized controlled trials, overlooking the complementary roles of other study designs. Trials are indispensable for assessing immunogenicity, reactogenicity, efficacy, and common short-term outcomes, but are rarely powered to exclude modest increases in uncommon obstetric, congenital, neonatal, or delayed childhood outcomes. This Perspective examines a coordinated approach to maternal vaccine safety assessment before and after authorization, including randomized trials, spontaneous reporting, pregnancy vaccine exposure registries, linked maternal-infant databases, near-real-time surveillance, and international research networks. Lessons from influenza, pertussis, COVID-19, and maternal respiratory syncytial virus vaccination show why authorization should initiate sustained pregnancy-specific safety monitoring. We discuss the limitations of real-world evidence, including confounding, healthy-vaccinee effects, gestational timing, conditioning on live birth, outcome misclassification, and background rate estimation, as well as methods to strengthen causal interpretation. Regulators and vaccine developers should prespecify pregnancy-specific post-authorization studies, harmonize outcome definitions and exposure windows, and distinguish the absence of a detected signal from the exclusion of a clinically relevant risk. Coordinated surveillance is essential to provide timely, precise, and clinically meaningful evidence for pregnant individuals and their children.