{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:17:55Z","timestamp":1791231475988,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004160","name":"Mazandaran University of Medical Sciences","doi-asserted-by":"publisher","award":["Project number: 21925"],"award-info":[{"award-number":["Project number: 21925"]}],"id":[{"id":"10.13039\/501100004160","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Rep Immunol"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Repeated implantation failure (RIF) is often linked to immune dysregulation, particularly an elevated Th1\/Th2 ratio that impairs embryo implantation. While several immunotherapies have been used, their efficacy and safety remain unclear. This study evaluated the clinical efficacy and immunomodulatory effects of tacrolimus treatment in women with RIF exhibiting elevated Th1\/Th2 ratios.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This was a randomized, double\u2011blind, placebo\u2011controlled trial conducted between April 2024 to May 2025. A total of 153 RIF patients were screened, and 91 patients with a Th1\/Th2 ratio \u226510.3 were identified. After exclusions, 80 patients were randomized 1:1 to tacrolimus or placebo. Patients were administered tacrolimus or placebo for 16 days, beginning 2 days before embryo transfer and continuing until the pregnancy test day. The primary outcome was the clinical pregnancy rate. Live birth was prespecified as the key secondary outcome. Additional secondary outcomes included miscarriage, ongoing pregnancy, multiple gestation, changes in the Th1\/Th2 ratio, and adverse events.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Clinical pregnancy occurred in 17 of 40 patients (42.5%) in the tacrolimus group compared with 6 of 40 patients (15.0%) in the placebo group (RR = 2.83, 95% CI: 1.30\u20136.44;\n                      <jats:italic>p =<\/jats:italic>\n                      0.0125), corresponding to an absolute risk difference of 27.5% and a number needed to treat (NNT) of 4. Live birth occurred in 11 of 40 patients (27.5%) versus 3 of 40 patients (7.5%), respectively (RR = 3.67, 95% CI: 1.21\u201311.63;\n                      <jats:italic>p =<\/jats:italic>\n                      0.0367), with an absolute risk difference of 20.0% and an NNT of 5. The Th1\/Th2 ratio decreased significantly after treatment in the tacrolimus group (17.01 \u00b1 3.99 to 12.56 \u00b1 2.78,\n                      <jats:italic>p &lt;<\/jats:italic>\n                      0.0001), whereas no significant change was observed in the placebo group. No severe adverse events or treatment discontinuations occurred.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Tacrolimus treatment improved clinical pregnancy outcomes and effectively reduced elevated Th1\u2010dominant immune responses in RIF patients. These findings support the use of tacrolimus as an immunosuppressive therapy for RIF patients with elevated Th1\/Th2 ratios.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial Registration<\/jats:title>\n                    <jats:p>This trial was registered with the Iranian Registry of Clinical Trials (IRCT20231127060207N1).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/aji.70268","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T12:38:53Z","timestamp":1780922333000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Effect of Tacrolimus on Pregnancy Outcomes in Patients with Repeated Implantation Failure (RIF) and Elevated Th1\/Th2 Ratio: A Randomized, Double\u2010Blind, Placebo\u2010Controlled Trial"],"prefix":"10.1111","volume":"95","author":[{"given":"Sepideh","family":"Peivandi","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, IVF ward, Faculty of Medicine, Imam Khomeini Hospital Mazandaran University of Medical Sciences  Sari Iran"},{"name":"Sexual and Reproductive Health Research Center, Imam Khomeini Hospital Mazandaran University of Medical Sciences  Sari Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzieh","family":"Zamaniyan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, IVF ward, Faculty of Medicine, Imam Khomeini Hospital Mazandaran University of Medical Sciences  Sari Iran"},{"name":"Sexual and Reproductive Health Research Center, Imam Khomeini Hospital Mazandaran University of Medical Sciences  Sari Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maedeh","family":"Etghani","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, IVF ward, Faculty of Medicine, Imam Khomeini Hospital Mazandaran University of Medical Sciences  Sari Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5622-0294","authenticated-orcid":false,"given":"Mohammad","family":"Malekan","sequence":"additional","affiliation":[{"name":"Thalassemia Research Center, Hemoglobinopathy Institute Mazandaran University of Medical Sciences  Sari Iran"},{"name":"Department of Immunology, School of Medicine Mazandaran University of Medical Sciences  Sari Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeid","family":"Taghiloo","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Medicine Mazandaran University of Medical Sciences  Sari Iran"},{"name":"Molecular and Cell Biology Research Center Mazandaran University of Medical Sciences  Sari 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