Recurrent pregnancy loss and targeted immunotherapy: Mechanistic insights and the role of biologic disease-modifying anti-rheumatic drugs

Recurrent pregnancy loss (RPL) is a complex condition with heterogeneous etiologies, increasingly recognized to involve immune dysregulation. In a subset of women with unexplained RPL, abnormal maternal immune activation-characterized by an imbalance of proinflammatory cytokines, Th1/Th2 dysregulation, and impaired maternal-fetal tolerance-may contribute to pregnancy failure. Biologic disease-modifying anti-rheumatic drugs (bDMARDs), particularly tumor necrosis factor inhibitors (TNFi), are established therapies for autoimmune diseases and are increasingly proposed as immunomodulatory agents in immune-mediated RPL due to shared pathogenic pathways. This review summarizes the biological rationale, clinical evidence, and safety data for bDMARD use in RPL. Although high-quality randomized controlled trials are lacking, small studies with TNFi-including adalimumab, etanercept, and certolizumab pegol-have reported improved pregnancy outcomes in selected populations. Accumulating evidence from pregnancy registries and observational cohorts, particularly in women with rheumatic diseases, suggests that TNFi, especially certolizumab pegol, due to minimal placental transfer can be used during pregnancy and lactation without increasing the risk of major congenital malformations or serious neonatal complications. Data on non-TNFi bDMARDs are limited but do not indicate major safety concerns. Maintaining adequate disease control during pregnancy appears critical for optimizing maternal and fetal outcomes. While bDMARDs represent a promising therapeutic strategy for immune-mediated RPL, their use should currently be confined to carefully selected patients under specialist supervision or within research settings, pending further evidence from large-scale prospective studies.