{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:24:29Z","timestamp":1787027069419,"version":"build-2736575974"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T00:00:00Z","timestamp":1630886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2019M652333"],"award-info":[{"award-number":["2019M652333"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017661","name":"China Health Promotion Foundation","doi-asserted-by":"publisher","award":["XM_2020_011_0245_09"],"award-info":[{"award-number":["XM_2020_011_0245_09"]}],"id":[{"id":"10.13039\/501100017661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To explore the therapeutic efficacy of intrauterine perfusion of cyclosporin A (CsA) in intractable recurrent spontaneous abortion (RSA) patients with endometrial alloimmune dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This is a randomized controlled trial (RCT) of patients with intractable RSA with endometrial alloimmune disorders. A total of 201 women were enrolled, all of whom had at least 3 serial abortions and endometrial alloimmune dysfunction. Participants were randomly assigned to two groups. The CsA group (\n                      <jats:italic>n<\/jats:italic>\n                      = 101) received intrauterine infusion of 250 mg CsA on the 3rd and 7th days after menstruation for 2 menstrual cycles, while the placebo group (\n                      <jats:italic>n<\/jats:italic>\n                      = 100) received placebo. The birth of healthy, deformity-free babies was the main study outcome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In total, 75 (74.26%) women in the CsA group and 59 (59.00%) women in the placebo group gave birth to healthy babies [\n                      <jats:italic>P<\/jats:italic>\n                      = 0.01,\n                      <jats:italic>OR<\/jats:italic>\n                      = 2.01; 95%\n                      <jats:italic>CI<\/jats:italic>\n                      (1.10\u223c3.65)]. Compared to the placebo group, the CsA group had dramatically lower endometrial CD56\n                      <jats:sup>+<\/jats:sup>\n                      cell and CD57\n                      <jats:sup>+<\/jats:sup>\n                      cell concentrations at the luteal phase of the second menstrual cycle (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Intrauterine perfusion of CsA was confirmed to be a promising approach for the treatment of intractable alloimmune RSA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2021.737878","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T14:55:40Z","timestamp":1630940140000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Efficacy of Intrauterine Perfusion of Cyclosporin A for Intractable Recurrent Spontaneous Abortion Patients With Endometrial Alloimmune Disorders: A Randomized Controlled Trial"],"prefix":"10.3389","volume":"12","author":[{"given":"Long","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqin","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinghui","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19039","DOI":"10.1002\/jcp.28543","article-title":"Cyclosporine A improves pregnancy outcomes in women with recurrent pregnancy loss and elevated Th1\/Th2 ratio.","volume":"234","author":"Azizi","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"B2","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.fertnstert.2004.12.018","article-title":"Evidence-based investigations and treatments of recurrent pregnancy loss.","volume":"83","author":"Christiansen","year":"2005","journal-title":"Fertil. Steril."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jri.2018.10.001","article-title":"The effect of prednisolone on endometrial uterine NK cell concentrations and pregnancy outcome in women with reproductive failure. A retrospective cohort study.","volume":"131","author":"Cooper","year":"2019","journal-title":"J. Reprod. Immunol."},{"key":"B4","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1023\/A:1021736007376","article-title":"Correlation of NK cell activation and inhibition markers with NK cytoxicity among women experiencing immunologic implantation failure after in vitro fertilization and embryo transfer.","volume":"20","author":"Coulam","year":"2003","journal-title":"J. Assist. Reprod. Genet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1093\/humupd\/dmy044","article-title":"Conventional and modern markers of endometrial receptivity: a systematic review and meta-analysis.","volume":"25","author":"Craciunas","year":"2019","journal-title":"Hum. Reprod. Update"},{"key":"B6","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1002\/cyto.b.21254","article-title":"Aberrant NK cell associated marker (CD56 and CD57) expression in chronic lymphocytic leukemia.","volume":"88","author":"Dorwal","year":"2015","journal-title":"Cytometry B Clin. Cytom."},{"key":"B7","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.tjog.2014.11.002","article-title":"Expression of markers of endoplasmic reticulum stress-induced apoptosis in the placenta of women with early and late onset severe pre-eclampsia.","volume":"54","author":"Fu","year":"2015","journal-title":"Taiwan. J. Obstet. Gynecol."},{"key":"B8","first-page":"441","article-title":"A randomized controlled trial of cyclosporine A in the treatment of refractory immune recurrent spontaneous abortion.","volume":"32","author":"Fu","year":"2016","journal-title":"Chin. J. Appl. Gynecol. Obstet."},{"key":"B9","doi-asserted-by":"crossref","first-page":"739","DOI":"10.12891\/ceog2006.2015","article-title":"Analysis of the use of cyclosporin A to treat refractory immune recurrent spontaneous abortion.","volume":"42","author":"Fu","year":"2015","journal-title":"Clin. Exp. Obstet. Gynecol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1093\/humrep\/dep470","article-title":"Cyclosporine A exposure during pregnancy in mice: effects on reproductive performance in mothers and offspring.","volume":"25","author":"Groth","year":"2010","journal-title":"Hum. Reprod."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12708","article-title":"Abnormal ratio of CD57(+) cells to CD56(+) cells in women with recurrent implantation failure.","volume":"78","author":"Jiang","year":"2017","journal-title":"Am. J. Reprod. Immunol."},{"key":"B12","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/humupd\/dmg013","article-title":"A. review of immune cells and molecules in women with recurrent miscarriage.","volume":"9","author":"Laird","year":"2003","journal-title":"Hum. Reprod. Update"},{"key":"B13","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.jri.2016.04.290","article-title":"Standardisation of uterine natural killer (uNK) cell measurements in the endometrium of women with recurrent reproductive failure.","volume":"116","author":"Lash","year":"2016","journal-title":"J. Reprod. Immunol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1111\/aji.12483","article-title":"The uterine immune profile may help women with repeated unexplained embryo implantation failure after in vitro fertilization.","volume":"75","author":"L\u00e9d\u00e9e","year":"2016","journal-title":"Am. J. Reprod. Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3865","DOI":"10.1182\/blood-2010-04-282301","article-title":"CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset.","volume":"116","author":"Lopez-Verg\u00e8s","year":"2010","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","first-page":"2074","DOI":"10.1002\/eji.201344072","article-title":"NK cells gain higher IFN-\u03b3 competence during terminal differentiation","volume":"44","author":"Luetke-Eversloh","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"B16","doi-asserted-by":"crossref","DOI":"10.1016\/S0016-5085(12)60561-7","article-title":"PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immuno-modulators and biologic therapy.","volume":"142","author":"Mahadevan","year":"2012","journal-title":"Gastroenterology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1016\/j.fertnstert.2007.01.028","article-title":"Normal percentage of CD56bright natural killer cells in young patients with a history of repeated unexplained implantation failure after in vitro fertilization cycles.","volume":"88","author":"Matteo","year":"2007","journal-title":"Fertil. Steril."},{"key":"B18","doi-asserted-by":"publisher","first-page":"625","DOI":"10.29252\/ijrm.14.10.625","article-title":"Effects of autologous platelet-rich plasma on implantation and pregnancy in repeated implantation failure: a pilot study.","volume":"14","author":"Nazari","year":"2016","journal-title":"Int. J. Reprod. Biomed."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.3109\/14767058.2011.634461","article-title":"Pregnancy outcomes after kidney transplantation-immunosuppressive therapy comparison.","volume":"25","author":"Perales-Puchalt","year":"2012","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"B20","doi-asserted-by":"crossref","DOI":"10.1002\/14651858.CD000112.pub2","article-title":"Immunotherapy for recurrent miscarriage.","volume":"19","author":"Porter","year":"2006","journal-title":"Cochrane Database Syst. Rev."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2386","DOI":"10.1093\/humrep\/14.9.2386","article-title":"Pre-implantation endometrial leukocytes in women with recurrent miscarriage.","volume":"14","author":"Quenby","year":"1999","journal-title":"Hum. Reprod."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1799","DOI":"10.4049\/jimmunol.1002679","article-title":"Spontaneous pregnancy loss mediated by abnormal maternal inflammation in rats is linked to deficient uteroplacental perfusion.","volume":"186","author":"Renaud","year":"2011","journal-title":"J. Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.jri.2011.03.013","article-title":"The distribution of immune cells and macrophages in the endometrium of women with recurrent reproductive failure I: techniques.","volume":"91","author":"Russell","year":"2011","journal-title":"J. Reprod. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1093\/humupd\/dmt056","article-title":"Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis.","volume":"20","author":"Seshadri","year":"2014","journal-title":"Hum. Reprod. Update"},{"key":"B25","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1055\/s-0033-1363550","article-title":"Embryo selection with preimplantation chromosomal screening in patients with recurrent pregnancy loss.","volume":"32","author":"Shahine","year":"2014","journal-title":"Semin. Reprod. Med."},{"key":"B26","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/S0015-0282(03)00611-3","article-title":"Differences in number and activity of peripheral natural killer cells in primary versus secondary recurrent miscarriage.","volume":"80","author":"Shakhar","year":"2003","journal-title":"Fertil. Steril."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2208","DOI":"10.1093\/humrep\/dem141","article-title":"Prognostic value of the measurement of uterine natural killer cells in the endometrium of women with recurrent miscarriage.","volume":"22","author":"Tuckerman","year":"2007","journal-title":"Hum. Reprod."},{"key":"B28","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.jri.2010.07.001","article-title":"Uterine natural killer cells in peri-implantation endometrium from women with repeated implantation failure after IVF.","volume":"87","author":"Tuckerman","year":"2010","journal-title":"J. Reprod. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1189\/jlb.0708395","article-title":"Embryonic implantation: cytokines, adhesion molecules, and immune cells in establishing an implantation environment.","volume":"85","author":"van Mourik","year":"2009","journal-title":"J. Leukoc. Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1093\/oxfordjournals.humrep.a019439","article-title":"Immunohistochemical evidence for increased numbers of \u2018classic\u2019 CD57+ natural killer cells in the endometrium of women suffering spontaneous early pregnancy loss.","volume":"11","author":"Vassiliadou","year":"1996","journal-title":"Hum. Reprod."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12766","article-title":"Successful treatment with intrauterine delivery of dexamethasone for repeated implantation failure.","volume":"78","author":"Zhang","year":"2017","journal-title":"Am. J. Reprod. Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1530\/rep-07-0063","article-title":"Cyclosporin A improves murine pregnancy outcome in abortion-prone matings: involvement of CD80\/86 and CD28\/CTLA-4.","volume":"135","author":"Zhou","year":"2008","journal-title":"Reproduction"}],"updated-by":[{"DOI":"10.3389\/fphys.2021.774213","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T00:00:00Z","timestamp":1633996800000}}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.737878\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,8]],"date-time":"2023-01-08T13:37:30Z","timestamp":1673185050000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.737878\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,6]]},"references-count":33,"alternative-id":["10.3389\/fphys.2021.737878"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.737878","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,6]]},"article-number":"737878"}}