{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T17:08:33Z","timestamp":1758042513837,"version":"3.44.0"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2021YFC2700404"],"award-info":[{"award-number":["2021YFC2700404"]}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2022JJ30983"],"award-info":[{"award-number":["2022JJ30983"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020440","name":"Beijing Health Promotion Association","doi-asserted-by":"publisher","award":["BJHPA-2022-SHZHYXZHQNYJ-JICH-006"],"award-info":[{"award-number":["BJHPA-2022-SHZHYXZHQNYJ-JICH-006"]}],"id":[{"id":"10.13039\/100020440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Extensive research has demonstrated the detrimental effects of COVID-19 on maternal-fetal outcomes. However, few studies have examined the impact of SARS-CoV-2 infection before and during organogenesis on human embryo implantation and subsequent development. Additionally, the influence of SARS-CoV-2 on the endometrial microenvironment, which is critical for embryo implantation, remains poorly understood. This study seeks to address these gaps in knowledge.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>We prospectively enrolled 971 participants undergoing frozen-thawed embryo transfer (FET) during the final two months of 2022, coinciding with the nationwide COVID19 outbreak following the end of China\u2019s Zero-Covid policy. Patients undergoing FET during this period were at high risk of SARS-CoV-2 infection before and during organogenesis. Based on self-reported symptoms and nucleic acid testing, 520 individuals were confirmed to have SARS-CoV-2 infection, while 451 were uninfected. Consistent with existing literature, our study reinforced that SARS-CoV-2 infection negatively impacted pregnancy outcomes, as evidenced by reduced clinical pregnancy (52.69% vs. 76.50%, RR\u2009=\u200960.506, [95%CI, 0.259\u2009~\u20090.452]) and live birth rates (46.54% vs. 60.09%, RR\u2009=\u200917.865, [95%CI, 0.448\u2009~\u20090.746]), alongside an increase in obstetric complications (35.89% vs. 27.37%, RR\u2009=\u20094.380, [95%CI, 1.055\u2009~\u20092.223]). Seven fetal congenital heart defects (CHDs) were observed in the infected group versus one in uninfected population. Bioinformatic analysis of endometrial mRNA profiles showed SARS-CoV-2 infection significantly downregulated key endometrial receptivity molecules, increased natural killer cell and mast cell infiltration, and disrupted the balance of cytokine and chemokine. Moreover, our findings demonstrated that SARS-CoV-2 infection downregulated the transcriptional activity of endometrial SLC6A, a serotonin transporter, and ErbB-2, a mediator of serotonin-regulated differentiation in cardiac development. This disruption in serotonin signaling may underlie the pathogenesis of congenital heart disease.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>SARS-CoV-2 infection before and during organogenesis negatively impacts embryo implantation and development, primarily through mechanisms involving compromised endometrial receptivity and disruption of the local immune microenvironment.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0328743","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T17:24:28Z","timestamp":1757611468000},"page":"e0328743","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Influence of SARS-CoV-2 infection before and during organogenesis on embryo implantation and development outcomes: A prospective cohort observational study"],"prefix":"10.1371","volume":"20","author":[{"given":"Yanping","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zenghui","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongqing","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianghong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2656-6577","authenticated-orcid":true,"given":"Qiong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"issue":"2","key":"pone.0328743.ref001","article-title":"The effect of maternal SARS-CoV-2 infection timing on birth outcomes: a retrospective multicentre cohort study","volume":"4","author":"SN Piekos","year":"2022","journal-title":"Lancet Digit Health"},{"key":"pone.0328743.ref002","doi-asserted-by":"crossref","first-page":"100587","DOI":"10.1016\/j.lanepe.2023.100587","article-title":"SARS-CoV-2 variant-related abnormalities detected by prenatal MRI: a prospective case-control study","volume":"26","author":"P Kienast","year":"2023","journal-title":"Lancet Reg Health Eur"},{"key":"pone.0328743.ref003","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1056\/NEJMc2309215","article-title":"Association of SARS-CoV-2 Infection during Early Weeks of Gestation with Situs Inversus","volume":"389","author":"Y Wang","year":"2023","journal-title":"N Engl J Med"},{"issue":"1","key":"pone.0328743.ref004","doi-asserted-by":"crossref","first-page":"11422","DOI":"10.1038\/s41598-024-61778-w","article-title":"Increased risk of fetal left-right asymmetry disorders associated with maternal SARS-CoV-2 infection during the first trimester","volume":"14","author":"Y Li","year":"2024","journal-title":"Sci Rep"},{"issue":"4","key":"pone.0328743.ref005","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1111\/ppe.12812","article-title":"SARS-CoV-2 during pregnancy and associated outcomes: Results from an ongoing prospective cohort","volume":"36","author":"NM Molenaar","year":"2022","journal-title":"Paediatr Perinat Epidemiol"},{"issue":"1","key":"pone.0328743.ref006","doi-asserted-by":"crossref","DOI":"10.1136\/bmjmed-2022-000465","article-title":"Association between SARS-CoV-2 infection and newly diagnosed hypertension during pregnancy: prospective, population based cohort study","volume":"2","author":"AK \u00d6rtqvist","year":"2023","journal-title":"BMJ Med"},{"issue":"2","key":"pone.0328743.ref007","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.devcel.2021.12.022","article-title":"Early human embryonic development: Blastocyst formation to gastrulation","volume":"57","author":"J Rossant","year":"2022","journal-title":"Dev Cell"},{"issue":"10","key":"pone.0328743.ref008","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1093\/humrep\/deab183","article-title":"Single-cell RNA sequencing of SARS-CoV-2 cell entry factors in the preconceptional human endometrium","volume":"36","author":"F Vilella","year":"2021","journal-title":"Hum Reprod"},{"issue":"2","key":"pone.0328743.ref009","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.fertnstert.2020.06.026","article-title":"SARS-CoV-2 infection risk assessment in the endometrium: viral infection-related gene expression across the menstrual cycle","volume":"114","author":"I Henarejos-Castillo","year":"2020","journal-title":"Fertil Steril"},{"issue":"6","key":"pone.0328743.ref010","doi-asserted-by":"crossref","DOI":"10.1016\/j.fertnstert.2012.03.007","article-title":"Gene and protein expression signature of endometrial glandular and stromal compartments during the window of implantation","volume":"97","author":"GE Evans","year":"2012","journal-title":"Fertil Steril"},{"issue":"12","key":"pone.0328743.ref011","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1038\/s41591-022-02177-4","article-title":"A sequential re-opening of provinces for China\u2019s zero-COVID policy","volume":"29","author":"C Xu","year":"2023","journal-title":"Nat Med"},{"issue":"17","key":"pone.0328743.ref012","doi-asserted-by":"crossref","first-page":"369","DOI":"10.46234\/ccdcw2023.070","article-title":"Effectiveness of COVID-19 Vaccination Against SARS-CoV-2 Omicron Variant Infection and Symptoms - China, December 2022-February 2023","volume":"5","author":"D Fu","year":"2023","journal-title":"China CDC Wkly"},{"issue":"7","key":"pone.0328743.ref013","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2023.23219","article-title":"Association of SARS-CoV-2 Infection During Controlled Ovarian Stimulation With Oocyte- and Embryo-Related Outcomes","volume":"6","author":"F Tian","year":"2023","journal-title":"JAMA Netw Open"},{"issue":"1","key":"pone.0328743.ref014","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12958-023-01070-0","article-title":"Can biomarkers identified from the uterine fluid transcriptome be used to establish a noninvasive endometrial receptivity prediction tool? A proof-of-concept study","volume":"21","author":"A He","year":"2023","journal-title":"Reprod Biol Endocrinol"},{"issue":"7","key":"pone.0328743.ref015","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","author":"AM Newman","year":"2019","journal-title":"Nat Biotechnol"},{"issue":"3","key":"pone.0328743.ref016","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/nrmicro775","article-title":"SARS--beginning to understand a new virus","volume":"1","author":"K Stadler","year":"2003","journal-title":"Nat Rev Microbiol"},{"issue":"11","key":"pone.0328743.ref017","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1038\/s41422-021-00575-w","article-title":"Tracing the origins of SARS-CoV-2: lessons learned from the past","volume":"31","author":"Q Wang","year":"2021","journal-title":"Cell Res"},{"issue":"3","key":"pone.0328743.ref018","article-title":"A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS","volume":"182","author":"L Dai","year":"2020","journal-title":"Cell"},{"issue":"1","key":"pone.0328743.ref019","doi-asserted-by":"crossref","DOI":"10.1136\/bmjgh-2022-009495","article-title":"Adverse maternal, fetal, and newborn outcomes among pregnant women with SARS-CoV-2 infection: an individual participant data meta-analysis","volume":"8","author":"ER Smith","year":"2023","journal-title":"BMJ Glob Health"},{"issue":"1","key":"pone.0328743.ref020","doi-asserted-by":"crossref","first-page":"10077","DOI":"10.1038\/s41598-017-10098-3","article-title":"Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptomic biomarkers","volume":"7","author":"S Altm\u00e4e","year":"2017","journal-title":"Sci Rep"},{"key":"pone.0328743.ref021","doi-asserted-by":"crossref","first-page":"861245","DOI":"10.3389\/fimmu.2022.861245","article-title":"The Inflammatory Cytokine Imbalance for Miscarriage, Pregnancy Loss and COVID-19 Pneumonia","volume":"13","author":"F Vesce","year":"2022","journal-title":"Front Immunol"},{"issue":"1","key":"pone.0328743.ref022","doi-asserted-by":"crossref","first-page":"3410","DOI":"10.1038\/s41467-020-17240-2","article-title":"Immunological and inflammatory profiles in mild and severe cases of COVID-19","volume":"11","author":"J-W Song","year":"2020","journal-title":"Nat Commun"},{"issue":"3","key":"pone.0328743.ref023","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1093\/humupd\/dmq053","article-title":"The role of mast cells and their mediators in reproduction, pregnancy and labour","volume":"17","author":"FM Menzies","year":"2011","journal-title":"Hum Reprod Update"},{"issue":"1","key":"pone.0328743.ref024","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/s41392-021-00849-0","article-title":"SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar epithelial inflammation and lung injury","volume":"6","author":"M-L Wu","year":"2021","journal-title":"Signal Transduct Target Ther"},{"issue":"6","key":"pone.0328743.ref025","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1093\/humupd\/dmi023","article-title":"Cytokines, chemokines and growth factors in endometrium related to implantation","volume":"11","author":"E Dimitriadis","year":"2005","journal-title":"Hum Reprod Update"},{"issue":"2","key":"pone.0328743.ref026","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/icb.2010.95","article-title":"Expression of chemokine decoy receptors and their ligands at the porcine maternal-fetal interface","volume":"89","author":"JM Wessels","year":"2011","journal-title":"Immunol Cell Biol"},{"issue":"6","key":"pone.0328743.ref027","doi-asserted-by":"crossref","first-page":"514","DOI":"10.3390\/v11060514","article-title":"Mast Cells and Natural Killer Cells-A Potentially Critical Interaction","volume":"11","author":"L Portales-Cervantes","year":"2019","journal-title":"Viruses"},{"issue":"3","key":"pone.0328743.ref028","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1093\/qjmed\/hcac234","article-title":"MIF is a common genetic determinant of COVID-19 symptomatic infection and severity","volume":"116","author":"JJ Shin","year":"2023","journal-title":"QJM"},{"issue":"7","key":"pone.0328743.ref029","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/s41590-021-00937-x","article-title":"TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines","volume":"22","author":"M Zheng","year":"2021","journal-title":"Nat Immunol"},{"issue":"2","key":"pone.0328743.ref030","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1093\/humupd\/dmu053","article-title":"Estrogen receptor \u03b2: the guardian of the endometrium","volume":"21","author":"DK Hapangama","year":"2015","journal-title":"Hum Reprod Update"},{"issue":"12","key":"pone.0328743.ref031","doi-asserted-by":"crossref","first-page":"103487","DOI":"10.1016\/j.isci.2021.103487","article-title":"The role of epithelial progesterone receptor isoforms in embryo implantation","volume":"24","author":"R Li","year":"2021","journal-title":"iScience"},{"issue":"8","key":"pone.0328743.ref032","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S1050-1738(01)00135-9","article-title":"A novel role for serotonin in heart","volume":"11","author":"CG Nebigil","year":"2001","journal-title":"Trends Cardiovasc Med"},{"issue":"3","key":"pone.0328743.ref033","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1365-2885.2008.00944.x","article-title":"Serotonin: a review","volume":"31","author":"LF Mohammad-Zadeh","year":"2008","journal-title":"J Vet Pharmacol Ther"},{"issue":"4","key":"pone.0328743.ref034","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1007\/s11065-010-9148-4","article-title":"The basics of brain development","volume":"20","author":"J Stiles","year":"2010","journal-title":"Neuropsychol Rev"},{"key":"pone.0328743.ref035","doi-asserted-by":"crossref","first-page":"9508","DOI":"10.1073\/pnas.97.17.9508","article-title":"Serotonin 2B receptor is required for heart development","volume":"97","author":"CG Nebigil","year":"2000","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"22","key":"pone.0328743.ref036","doi-asserted-by":"crossref","first-page":"4851","DOI":"10.1016\/j.cell.2023.09.013","article-title":"Serotonin reduction in post-acute sequelae of viral infection","volume":"186","author":"AC Wong","year":"2023","journal-title":"Cell"},{"issue":"4","key":"pone.0328743.ref037","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1210\/en.2017-03025","article-title":"Pathway of Maternal Serotonin to the Human Embryo and Fetus","volume":"159","author":"HJ Kliman","year":"2018","journal-title":"Endocrinology"},{"issue":"6","key":"pone.0328743.ref038","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.fertnstert.2022.10.034","article-title":"COVID-19 and the endometrium: inflammation as understanding","volume":"118","author":"R Weinerman","year":"2022","journal-title":"Fertil Steril"},{"issue":"3","key":"pone.0328743.ref039","doi-asserted-by":"crossref","first-page":"109841","DOI":"10.1016\/j.celrep.2021.109841","article-title":"The N-terminal domain of SARS-CoV-2 nsp1 plays key roles in suppression of cellular gene expression and preservation of viral gene expression","volume":"37","author":"AS Mendez","year":"2021","journal-title":"Cell Rep"},{"issue":"1","key":"pone.0328743.ref040","doi-asserted-by":"crossref","first-page":"21779","DOI":"10.1038\/s41598-022-26457-8","article-title":"COVID-19 plasma exosomes promote proinflammatory immune responses in peripheral blood mononuclear cells","volume":"12","author":"L Chen","year":"2022","journal-title":"Sci Rep"},{"issue":"1","key":"pone.0328743.ref041","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41421-022-00510-2","article-title":"Extracellular vesicles mediate antibody-resistant transmission of SARS-CoV-2","volume":"9","author":"B Xia","year":"2023","journal-title":"Cell Discov"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0328743","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T17:24:35Z","timestamp":1757611475000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0328743"}},"subtitle":[],"editor":[{"given":"Ayman A","family":"Swelum","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,9,11]]},"references-count":41,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9,11]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0328743","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2025,9,11]]}}}