Immunological Mechanisms, Immune Endotypes, and Immunotherapy in Unexplained Recurrent Pregnancy Loss: A Systematic Review
Wiku Andonotopo, Arief Setiawan, Muhammad Adrianes Bachnas, Mochammad Besari Adi Pramono, Julian Dewantiningrum, Efendi Lukas, I. Nyoman Hariyasa Sanjaya, Anak Agung Gede Putra Wiradnyana, Anak Agung Ngurah Jaya Kusuma, Khanisyah Erza Gumilar, Ernawati Darmawan, Dovy Djanas, Dudy Aldiansyah, Aloysius Suryawan, Ridwan Abdullah Putra, Theresia Monica Rahardjo, Rizna Tyrani Rumanti, Roland Frederik Lengkey, Julia Windi Gunadi, Anita Deborah Anwar, Cut Meurah Yeni, Aryani Aziz, Nuswil Bernolian, Donel Suhaimi, Agus Rusdhy Hamid, Laksmana Adi Krista Nugraha, Wibisana Andika Krista Dharma, Waskita Ekamaheswara Kasumba Andanaputra
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BSTRACT
Recurrent pregnancy loss (RPL) is an ongoing problem in reproductive medicine due to increasing awareness of the role of immunological abnormalities; however, the diagnostic value and clinical utility of immunological abnormalities in RPL are unclear. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 Statement for critical evaluation of the evidence base regarding immunological mechanisms, immune endotypes, and immunotherapies in unexplained RPL (uRPL), focusing on the available evidence for biomarker-driven management. Electronic searches were performed in PubMed/MEDLINE, Embase, Scopus, Web of Science Core Collection, Cochrane Library, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform databases from database inception to April 30, 2026. Out of the 1290 identified articles, 935 were screened at the title/abstract stage, 128 underwent full-text assessment for eligibility, and 35 articles were synthesized qualitatively. The evidence base includes systematic and scoping reviews, clinical guidelines, protocols of randomized controlled trials, observational studies, molecular investigations, qualitative studies, prediction modeling studies, and bibliometric analyses. Due to a high degree of heterogeneity in the design, population, biomarker analysis, and outcomes reporting, it was considered inappropriate to conduct a meta-analysis. Methodological quality of the articles was assessed using study design-specific appraisal tools, and the results informed the narrative synthesis. Among the articles included in the analysis, immunological abnormalities displayed significant biological diversity, limited standardization of assays, and a lack of clinical validation. Immune endotypes were suggested based on converging evidence of the mechanism, genomics, proteomics, and immune phenotyping. However, the diagnostic criteria and treatment implications of immune endotypes in uRPL are not fully characterized. In summary, the current evidence does not support empiric immunotherapy in uRPL. Instead, the findings suggest a cautious, biomarker-driven approach in which immune phenotyping is studied as a stratification approach for precision immunology studies and biomarker-stratified clinical trials.