The evidence-practice gap in immunotherapy for recurrent pregnancy loss: a critical narrative review of current treatments

Many clinicians suspect immune problems when treating women with unexplained recurrent pregnancy loss (RPL); however, we lack evidence that immunotherapy helps. Although immune tolerance is crucial for successful pregnancy, distinguishing immunologic from nonimmunologic causes of RPL continues to be a major hurdle. Apart from antiphospholipid syndrome (APS), decades of studying immune markers have yielded no reliable diagnostic tests. This diagnostic uncertainty has led to widespread off-label use of immunomodulatory treatments without strong evidence of a positive effect on pregnancy outcomes. This review examines current data on frequently used immune therapies including corticosteroids, intravenous immunoglobulin, lymphocyte immunotherapy, calcineurin inhibitors, anticoagulants, and granulocyte colony–stimulating factor. Small studies with diverse demographics and contradictory findings make up most of the information available. There are only a few high-quality randomized controlled trials, frequently demonstrating no significant treatment benefit. Designing such trials is particularly challenging because of the heterogeneous nature of RPL, which may involve patients with genetic, anatomical, endocrine, and immunologic risk factors. Ideally, such trials only include patients with similar underlying pathologies to generate robust and reliable evidence. Current evidence does not support routine use of these expensive and potentially dangerous therapies. Future progress requires identifying trustworthy biomarkers that can distinguish immune-mediated RPL from other causes to identify women who potentially could benefit from immune modulation and conducting appropriately powered randomized controlled trials in well-defined patient populations.