Safety and efficacy of immunosuppressants for recurrent reproductive failure: A systematic review and meta-analysis

Recurrent reproductive failure impairs women's health, and the efficacy of immunosuppressants for this condition remains uncertain. This study aimed to explore the clinical application of common immunosuppressive agents including cyclosporine A, tacrolimus, etanercept and adalimumab for recurrent reproductive failure, which covers recurrent spontaneous abortion and recurrent implantation failure after IVF/ICSI, and to assess their efficacy and safety so as to provide evidence-based references for clinical practice. We retrieved eligible randomized controlled trials and cohort studies published from January 1, 2005 to February 28, 2025 from PubMed, Web of Science, CNKI and Wanfang databases, and conducted a systematic review and meta-analysis. This study was registered on PROSPERO (ID: CRD420251057130). A total of 13 randomized controlled trials and 7 cohort studies involving 2266 patients were finally included. Meta-analysis revealed that compared with the control group, immunosuppressive therapy significantly elevated live birth rate (RR=1.33, 95%CI:1.20-1.47, P < 0.00001) and clinical pregnancy rate (RR=1.24, 95%CI:1.11-1.39, P = 0.0001), while lowering miscarriage rate (RR=0.45, 95%CI:0.37-0.54, P < 0.00001). No significant differences were found in the incidence of adverse events (RR=0.96, 95%CI:0.69-1.34, P = 0.83) and birth defect rate (RR=0.63, 95%CI:0.19-2.07, P = 0.45) between the two groups. In conclusion, the above immunosuppressive drugs can improve pregnancy outcomes in patients with recurrent reproductive failure and do not obviously increase adverse reactions and birth defects. Considering the limited quality of existing evidence and potential publication bias, the results should be interpreted cautiously, and the use of these drugs is recommended to be limited to clinical trials until verified by more large-scale and high-quality randomized studies.