Abstract
Introduction: This study aimed to re-evaluate lymphocyte immunization therapy (LIT) efficacy for unexplained recurrent pregnancy loss (uRPL) to bridge the gap between restrictive international guidelines and clinical practices.
Methods: Following PRISMA 2020, PubMed/MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and Scopus databases were searched through August 4, 2025. Six randomized controlled trials involving women with uRPL and confirmed alloimmune etiology (anti-paternal cytotoxic antibodies or mixed lymphocyte reaction–blocking factor deficiency) underwent investigation. The primary outcome was the live birth rate (≥24 weeks) that was analyzed using a random-effects model (risk ratio) and the Joanna Briggs Institute quality assessment.
Results: LIT (paternal cells, pre-conception) was associated with a significantly higher probability of live birth (RR: 1.432; 95% confidence interval: 1.037–1.978; P=0.029). Statistical heterogeneity was high (78.5%). Sensitivity analysis revealed fragility, and removing three specific trials eliminated statistical significance. Finally, adverse events were primarily localized, and neonatal security was supported by reassuring birth outcomes.
Conclusion: Empirical LIT application remains unjustified. However, a significant therapeutic signal exists for optimized protocols in biomarker-screened cohorts. Overall, we advocate for a “Precision Medicine Blueprint” that prioritizes standardized protocols and strict immunologic screening.