{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T19:19:25Z","timestamp":1793992765329,"version":"4.8.0"},"reference-count":55,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T00:00:00Z","timestamp":1764979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background\/Objectives: Recurrent pregnancy loss (RPL) is one of the most challenging conditions in reproductive medicine, particularly when no identifiable cause can be determined after diagnostic evaluation. Although the role of immunological dysregulation has been hypothesized, the implementation of immunotherapies in clinical practice is controversial due to inconsistent findings and methodological heterogeneity across studies. This systematic review aims to provide an overview of the main characteristics of existing research on the role of immunological interventions in relation to In Vitro Fertilization (IVF) outcomes in women with RPL. Given the marked inter-individual variability in immunological mechanisms among affected women, evaluating these treatments may help identify future directions for personalized reproductive medicine. Methods: A comprehensive bibliographic search was systematically conducted from inception to October 2025 across databases, including Medline, Embase, Scopus, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. Studies were included if they evaluated the efficacy of immunological treatments in women with unexplained RPL, comparing IVF outcomes between case and control groups. Results: Six cohort studies were included, four retrospective and two prospective. The immunological treatments investigated were granulocyte colony-stimulating factor (G-CSF), intravenous intralipid (with or without prednisolone), and lymphocyte immunization therapy (LIT). Despite some promising results, particularly for G-CSF and LIT, the studies were limited by small sample sizes, heterogeneous diagnostic criteria for RPL, and inconsistent treatment protocols. Furthermore, not all IVF outcomes, such as implantation and biochemical pregnancy rates, were reported. Conclusions: Current evidence is insufficient to support the use of immunotherapy in clinical practice for improving IVF outcomes in women with unexplained RPL. The variability in study design, patient selection, and immunotherapy regimens hinders the ability to draw firm conclusions. Well-designed randomized controlled trials with standardized definitions and outcome measures are needed to determine whether and for whom immunological treatments may offer clinical benefit.<\/jats:p>","DOI":"10.3390\/jpm15120606","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T15:30:07Z","timestamp":1765207807000},"page":"606","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Immunotherapy and IVF Outcomes in Unexplained Recurrent Pregnancy Loss: A Systematic Review with Implications for Personalized Reproductive Medicine"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1818-0105","authenticated-orcid":false,"given":"Giosu\u00e8 Giordano","family":"Incognito","sequence":"first","affiliation":[{"name":"Obstetrics and Gynecology Unit, Maternal Child Department, ARNAS Garibaldi Nesima, 95122 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0864-2801","authenticated-orcid":false,"given":"Carla","family":"Ettore","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Unit, Maternal Child Department, ARNAS Garibaldi Nesima, 95122 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"D\u2019Asta","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Unit, Maternal Child Department, ARNAS Garibaldi Nesima, 95122 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferdinando Antonio","family":"Gulino","sequence":"additional","affiliation":[{"name":"Unit of Gynecology and Obstetrics, Department of Human Pathology of Adults and Developmental Age, \u201cG. Martino\u201d University Hospital, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Foti","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, AOU Policlinico \u201cG. Rodolico\u201d-San Marco, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6123-1628","authenticated-orcid":false,"given":"Roberto","family":"Tozzi","sequence":"additional","affiliation":[{"name":"Unit of Gynecology and Obstetrics, Department of Women and Children\u2019s Health, University of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orazio","family":"De Tommasi","sequence":"additional","affiliation":[{"name":"Unit of Gynecology and Obstetrics, Department of Women and Children\u2019s Health, University of Padua, 35128 Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7482-3833","authenticated-orcid":false,"given":"Pierluigi","family":"Chieppa","sequence":"additional","affiliation":[{"name":"Gynecology and Obstetrics 1, Department of Surgical Sciences, A.O.U. City of Health and Science of Turin, S. Anna Hospital, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9644-7919","authenticated-orcid":false,"given":"Stefano","family":"Di Michele","sequence":"additional","affiliation":[{"name":"Division of Obstetrics and Gynecology, Department of Surgical Sciences, University of Cagliari, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Ettore","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Unit, Maternal Child Department, ARNAS Garibaldi Nesima, 95122 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"ESHRE Guideline Group on RPL, Atik, R.B., Christiansen, O.B., Elson, J., Kolte, A.M., Lewis, S., Middeldorp, S., Mcheik, S., Peramo, B., and Quenby, S. (2023). 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