{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:27:24Z","timestamp":1793042844220,"version":"4.5.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Embryo implantation is a complex process requiring a tightly regulated immunological dialogue at the maternal-embryonic interface. Disruptions in this dialogue, including alterations in immune cell function and cytokine production, have been implicated in implantation failure. This systematic review and meta-analysis aimed to quantitatively compare immune-related soluble mediators in the peripheral blood of women with unexplained recurrent implantation failure (RIF) and fertile controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This systematic review was conducted according to PRISMA principles. A comprehensive search was conducted across Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials. The primary outcome measure was the differential concentration of immune analytes in blood and tissue samples between women with recurrent implantation failure and fertile controls. Meta-analysis was performed for five peripheral blood cytokines (IFN-\u03b3, IL-4, TNF-\u03b1, IL-2, IL-6).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Some 12 studies reporting on 1483 patients met the final inclusion criteria for the review. The meta-analysis revealed a statistically significant difference only for Interleukin-4 (IL-4), which was lower in women with RIF compared to controls (MD -0.0298, 95% CI: -0.0436 to -0.0159, p &amp;lt; 0.0001). No significant differences were found for IFN-\u03b3, TNF-\u03b1, IL-2, or IL-6. Individual studies reported varied associations for other analytes, including lower levels of Angiopoietin-2, MMP-7, VEGF, FGF1, Glycodelin A, and MUC1, and higher levels of PDGF, TGF-\u03b2 isoforms and CCL2, IL-2 in RIF cohorts. The overall certainty of the evidence was rated as low, due to concerns about study quality and heterogeneity in RIF definitions, control group selection, and laboratory methodologies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The review highlights that immune dysregulation is associated with RIF. In particular, IL-4 may play an important role although the clinical relevance of the small, measured difference is unclear. There is a need for international consensus on RIF definition, standardised methodological protocols, and large-scale prospective studies to validate potential immune biomarkers. Currently, there is insufficient evidence to support the routine use of peripheral blood cytokine levels as diagnostic markers for RIF or to guide immunomodulatory treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:uri>https:\/\/www.crd.york.ac.uk\/prospero\/<\/jats:uri>\n                      , identifier PROSPERO 42024577277.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1627514","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T05:19:19Z","timestamp":1761542359000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Comparing the circulating immune profile of women with and without recurrent implantation failure: a systematic review and meta-analysis"],"prefix":"10.3389","volume":"16","author":[{"given":"Daxina","family":"Bhatt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousef","family":"Alebrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah","family":"Shahzad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamiya","family":"Mohiyiddeen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Mann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.rbmo.2013.08.011","article-title":"Recurrent implantation failure: definition and management","volume":"28","author":"Coughlan","year":"2014","journal-title":"Reprod BioMedicine Online."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13513","article-title":"Effectiveness comparison between endometrial receptivity array, immune profiling and the combination in treating patients with multiple implantation failure","volume":"87","author":"Jia","year":"2022","journal-title":"Am J Reprod Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.imlet.2007.09.014","article-title":"Fetal tolerance in human pregnancy\u2013a crucial balance between acceptance and limitation of trophoblast invasion","volume":"115","author":"von Rango","year":"2008","journal-title":"Immunol Lett"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23042198","article-title":"The role of interleukins in recurrent implantation failure: A comprehensive review of the literature","volume":"23","author":"Pantos","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2022.04.023","article-title":"Immune determinants of endometrial receptivity: a biological perspective","volume":"117","author":"Robertson","year":"2022","journal-title":"Fertil Steril."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/life13051097","article-title":"Immune cell functionality during decidualization and potential clinical application","volume":"13","author":"Stope","year":"2023","journal-title":"Life (Basel)."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2010.05938.x","article-title":"Inflammation and pregnancy: the role of the immune system at the implantation site","volume":"1221","author":"Mor","year":"2011","journal-title":"Ann N Y Acad Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deaa317","article-title":"Definition, diagnostic and therapeutic options in recurrent implantation failure: an international survey of clinicians and embryologists","volume":"36","author":"Cimadomo","year":"2021","journal-title":"Hum Reproduction."},{"key":"B9","doi-asserted-by":"publisher","first-page":"hoad023","DOI":"10.1093\/hropen\/hoad023","article-title":"ESHRE good practice recommendations on recurrent implantation failure","volume":"2023","author":"Cimadomo","year":"2023","journal-title":"Hum Reprod Open"},{"key":"B10","doi-asserted-by":"publisher","first-page":"R39","DOI":"10.1530\/REP-22-0150","article-title":"Immunomodulation for unexplained recurrent implantation failure: where are we now","volume":"165","author":"Genest","year":"2023","journal-title":"Reproduction."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13563","article-title":"Immune alterations in recurrent implantation failure","volume":"89","author":"Mukherjee","year":"2023","journal-title":"Am J Reprod Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2019.10.014","article-title":"How common is real repeated implantation failure? An indirect estimate of the prevalence","volume":"40","author":"Busnelli","year":"2020","journal-title":"Reprod BioMed Online."},{"key":"B13","doi-asserted-by":"publisher","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"Bmj"},{"key":"B14","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/1471-2288-5-13","article-title":"Estimating the mean and variance from the median, range, and the size of a sample","volume":"5","author":"Hozo","year":"2005","journal-title":"BMC Med Res Methodol"},{"key":"B15","article-title":"Chapter 6: Choosing effect measures and computing estimates of effect","volume-title":"Cochrane Handbook for Systematic Reviews of Interventions version 6.5","year":"2024"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"GRADE: an emerging consensus on rating quality of evidence and strength of recommendations","volume":"336","author":"Guyatt","year":"2008","journal-title":"Bmj."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2016-011458","article-title":"Development of a critical appraisal tool to assess the quality of cross-sectional studies (AXIS)","volume":"6","author":"Downes","year":"2016","journal-title":"BMJ Open"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.52711\/0974-360X.2021.00360","article-title":"The association between Angiopoietin-2 and the risk of recurrent implantation failure","volume":"14","author":"Abdulhaleem","year":"2021","journal-title":"Res J Pharm Technol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1017\/S0967199421000113","article-title":"Circulating MMP-7 and VEGF as potential predictive biomarkers for recurrent implantation failures","volume":"29","author":"Benkhalifa","year":"2021","journal-title":"Zygote."},{"key":"B20","doi-asserted-by":"publisher","first-page":"103735","DOI":"10.1016\/j.jri.2022.103735","article-title":"Immunophenotyping of peripheral blood monocytes could help identify a baseline pro-inflammatory profile in women with recurrent reproductive failure","volume":"154","author":"Comins-Boo","year":"2022","journal-title":"J Reprod Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"949123","DOI":"10.3389\/fendo.2022.949123","article-title":"Alterations of cytokine profiles in patients with recurrent implantation failure","volume":"13","author":"Guo","year":"2022","journal-title":"Front Endocrinol (Lausanne)."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2015.08.009","article-title":"The pro-inflammatory and anti-inflammatory cytokine profile in peripheral blood of women with recurrent implantation failure","volume":"31","author":"Liang","year":"2015","journal-title":"Reprod BioMed Online."},{"key":"B23","doi-asserted-by":"publisher","first-page":"104209","DOI":"10.1016\/j.jri.2024.104209","article-title":"Recurrent implantation failure and inflammatory markers in serum and follicle fluid of women undergoing assisted reproduction","volume":"162","author":"Nenonen","year":"2024","journal-title":"J Reprod Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.4103\/jhrs.jhrs_68_24","article-title":"Association of Fibroblast Growth Factor-1 Promoter Polymorphism and its Serum Concentrations with Repeated Implantation Failure after In vitro Fertilisation: A Cross-sectional Study","volume":"17","author":"Kharamani","year":"2024","journal-title":"J Hum Reprod Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s10815-017-0992-5","article-title":"Chemokine (C-C motif) ligand-2 (CCL2) and oxidative stress markers in recurrent pregnancy loss and repeated implantation failure","volume":"34","author":"Naml\u0131 Kalem","year":"2017","journal-title":"J Assist Reprod Genet"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2017.5334","article-title":"Increased levels of CCR7(lo)PD-1(hi) CXCR5(+) CD4(+) T cells, and associated factors Bcl-6, CXCR5, IL-21 and IL-6 contribute to repeated implantation failure","volume":"14","author":"Gong","year":"2017","journal-title":"Exp Ther Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1016\/j.fertnstert.2015.01.025","article-title":"Role of Mucin 1 and Glycodelin A in recurrent implantation failure","volume":"103","author":"Bastu","year":"2015","journal-title":"Fertil Steril."},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.15296\/ijwhr.2017.19","article-title":"Uterine and serum glycodelin concentration in recurrent implantation failure versus normal fertile women on implantation window","volume":"5","author":"Taheripanah","year":"2017","journal-title":"Int J Women\u2019s Health Reprod Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deg139","article-title":"Analysis of intra-uterine cytokine concentration and matrix-metalloproteinase activity in women with recurrent failed embryo transfer","volume":"18","author":"Inagaki","year":"2003","journal-title":"Hum Reprod"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1523871","article-title":"Endometrial immune profiling and precision therapy increase live birth rate after embryo transfer: a randomised controlled trial","volume":"16","author":"L\u00e9d\u00e9e","year":"2025","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"104827","DOI":"10.1016\/j.rbmo.2025.104827","article-title":"Resolving recurrent implantation failure","volume":"50","author":"Macklon","year":"2025","journal-title":"Reprod BioMed Online."}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1627514\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T05:19:20Z","timestamp":1761542360000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1627514\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,27]]},"references-count":31,"alternative-id":["10.3389\/fimmu.2025.1627514"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1627514","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,27]]},"article-number":"1627514"}}