{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T08:44:31Z","timestamp":1790239471587,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T00:00:00Z","timestamp":1608768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human cytomegalovirus (CMV) is a major cause of nonhereditary adverse birth outcomes, including hearing and visual loss, neurologic deficits, and intrauterine growth retardation (IUGR), and may contribute to outcomes such as stillbirth and preterm delivery. However, the mechanisms by which CMV could cause adverse birth outcomes are not fully understood. This study reviewed proposed mechanisms underlying the role of CMV in stillbirth, preterm birth, and IUGR. Targeted literature searches were performed in PubMed and Embase to identify relevant articles. Several potential mechanisms were identified from in vitro studies in which laboratory-adapted and low-passage strains of CMV and various human placental models were used. Potential mechanisms identified included impairment of trophoblast progenitor stem cell differentiation and function, impairment of extravillous trophoblast invasiveness, dysregulation of Wnt signaling pathways in cytotrophoblasts, tumor necrosis factor-\u03b1 mediated apoptosis of trophoblasts, CMV-induced cytokine changes in the placenta, inhibition of indoleamine 2,3-dioxygenase activity, and downregulation of trophoblast class I major histocompatibility complex molecules. Inherent challenges for the field remain in the identification of suitable in vivo animal models. Nonetheless, we believe that our review provides useful insights into the mechanisms by which CMV impairs placental development and function and how these changes could result in adverse birth outcomes.<\/jats:p>","DOI":"10.3390\/v13010020","type":"journal-article","created":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T22:56:45Z","timestamp":1608850605000},"page":"20","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["The Role of Congenital Cytomegalovirus Infection in Adverse Birth Outcomes: A Review of the Potential Mechanisms"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2458-2685","authenticated-orcid":false,"given":"Annete","family":"Njue","sequence":"first","affiliation":[{"name":"RTI Health Solutions, Manchester M20 2LS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Coyne","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7388-6082","authenticated-orcid":false,"given":"Andrea V.","family":"Margulis","sequence":"additional","affiliation":[{"name":"RTI Health Solutions, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5666-8622","authenticated-orcid":false,"given":"Dai","family":"Wang","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, NJ 07033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan A.","family":"Marks","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, NJ 07033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Russell","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, NJ 07033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rituparna","family":"Das","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, NJ 07033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anushua","family":"Sinha","sequence":"additional","affiliation":[{"name":"Merck &amp; Co., Inc., Kenilworth, NJ 07033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.3389\/fimmu.2019.01155","article-title":"Subversion of Immune Response by Human Cytomegalovirus","volume":"10","author":"Patro","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1093\/femsre\/fuy004","article-title":"The human cytomegalovirus terminase complex as an antiviral target: A close-up view","volume":"42","author":"Ligat","year":"2018","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_3","unstructured":"Knipe, D.M., and Howley, P.M. (2013). Cytomegaloviruses. Fields Virology, Wolters Kluwer Lippincott Williams & Wilkins. [6th ed.]."},{"key":"ref_4","first-page":"218","article-title":"Functional annotation of human cytomegalovirus gene products: An update","volume":"5","year":"2014","journal-title":"Front. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.ajog.2020.02.018","article-title":"Cytomegalovirus infection during pregnancy: State of the science","volume":"223","author":"Foulon","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2034","DOI":"10.1002\/rmv.2034","article-title":"Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis","volume":"29","author":"Zuhair","year":"2019","journal-title":"Rev. Med. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/rmv.655","article-title":"Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection","volume":"20","author":"Cannon","year":"2010","journal-title":"Rev. Med. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1542\/peds.2014-1173","article-title":"Hearing loss and congenital CMV infection: A systematic review","volume":"134","author":"Goderis","year":"2014","journal-title":"Pediatrics"},{"key":"ref_9","first-page":"1","article-title":"Diagnosis and management of CMV infection in pregnancy","volume":"1","author":"Duff","year":"2010","journal-title":"Perinatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/rmv.535","article-title":"Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection","volume":"17","author":"Kenneson","year":"2007","journal-title":"Rev. Med. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1159\/000342752","article-title":"Management of pregnancies with confirmed cytomegalovirus fetal infection","volume":"33","author":"Benoist","year":"2013","journal-title":"Fetal Diagn. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1128\/JCM.01868-16","article-title":"Testing for cytomegalovirus in pregnancy","volume":"55","author":"Saldan","year":"2017","journal-title":"J. Clin. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1111\/aji.12094","article-title":"CD8+ effector T cells at the fetal-maternal interface, balancing fetal tolerance and antiviral immunity","volume":"69","author":"Tilburgs","year":"2013","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.1016\/j.placenta.2017.04.020","article-title":"Congenital cytomegalovirus infection undermines early development and functions of the human placenta","volume":"59","author":"Pereira","year":"2017","journal-title":"Placenta"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hamilton, S.T., Scott, G., Naing, Z., Iwasenko, J., Hall, B., Graf, N., Arbuckle, S., Craig, M.E., and Rawlinson, W.D. (2012). Human cytomegalovirus-induces cytokine changes in the placenta with implications for adverse pregnancy outcomes. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052899"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1128\/JVI.02588-15","article-title":"Human cytomegalovirus modulates expression of noncanonical Wnt receptor ROR2 to alter trophoblast migration","volume":"90","author":"Ford","year":"2016","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6808","DOI":"10.1128\/JVI.74.15.6808-6820.2000","article-title":"Human cytomegalovirus infection of placental cytotrophoblasts in vitro and in utero: Implications for transmission and pathogenesis","volume":"74","author":"Fisher","year":"2000","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5134","DOI":"10.1128\/JVI.03674-14","article-title":"Human cytomegalovirus infection interferes with the maintenance and differentiation of trophoblast progenitor cells of the human placenta","volume":"89","author":"Tabata","year":"2015","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3389\/fped.2020.00013","article-title":"Congenital Cytomegalovirus Infection: A Narrative Review of the Issues in Screening and Management From a Panel of European Experts","volume":"8","author":"Lazzarotto","year":"2020","journal-title":"Front. Pediatrics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s00430-015-0411-4","article-title":"Human cytomegalovirus: Taking the strain","volume":"204","author":"Wilkinson","year":"2015","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.3390\/v6031346","article-title":"HCMV infection of human trophoblast progenitor cells of the placenta is neutralized by a human monoclonal antibody to glycoprotein B and not by antibodies to the pentamer complex","volume":"6","author":"Zydek","year":"2014","journal-title":"Viruses"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Leghmar, K., Cenac, N., Rolland, M., Martin, H., Rauwel, B., Bertrand-Michel, J., Faouder, P.L., B\u00e9nard, M., Casper, C., and Davrinche, C. (2015). Cytomegalovirus infection triggers the secretion of the PPARgamma agonists 15-hydroxyeicosatetraenoic acid (15-HETE) and 13-hydroxyoctadecadienoic acid (13-HODE) in human cytotrophoblasts and placental cultures. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132627"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.1128\/JVI.01779-09","article-title":"Activation of peroxisome proliferator-activated receptor gamma by human cytomegalovirus for de novo replication impairs migration and invasiveness of cytotrophoblasts from early placentas","volume":"84","author":"Rauwel","year":"2010","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/1743-422X-8-114","article-title":"In vitro study on human cytomegalovirus affecting early pregnancy villous EVT\u2019s invasion function","volume":"8","author":"Tao","year":"2011","journal-title":"Virol. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2831","DOI":"10.1128\/JVI.78.6.2831-2840.2004","article-title":"Human cytomegalovirus interleukin-10 downregulates metalloproteinase activity and impairs endothelial cell migration and placental cytotrophoblast invasiveness in vitro","volume":"78","author":"McDonagh","year":"2004","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Angelova, M., Zwezdaryk, K., Ferris, M., Shan, B., Morris, C.A., and Sullivan, D.E. (2012). Human cytomegalovirus infection dysregulates the canonical Wnt\/beta-catenin signaling pathway. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002959"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1016\/S0002-9440(10)64413-6","article-title":"Human cytomegalovirus-caused damage to placental trophoblasts mediated by immediate-early gene-induced tumor necrosis factor-alpha","volume":"161","author":"Chan","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/path.2025","article-title":"Ultraviolet-inactivated human cytomegalovirus induces placental syncytiotrophoblast apoptosis in a Toll-like receptor-2 and tumour necrosis factor-alpha dependent manner","volume":"210","author":"Chan","year":"2006","journal-title":"J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1016\/j.placenta.2009.09.001","article-title":"Human cytomegalovirus interacts with toll-like receptor 2 and CD14 on syncytiotrophoblasts to stimulate expression of TNFalpha mRNA and apoptosis","volume":"30","author":"Chaudhuri","year":"2009","journal-title":"Placenta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.placenta.2011.04.016","article-title":"Novel model of placental tissue explants infected by cytomegalovirus reveals different permissiveness in early and term placentae and inhibition of indoleamine 2,3-dioxygenase activity","volume":"32","author":"Lopez","year":"2011","journal-title":"Placenta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"805","DOI":"10.4049\/jimmunol.164.2.805","article-title":"Human cytomegalovirus gene products US3 and US6 down-regulate trophoblast class I MHC molecules","volume":"164","author":"Jun","year":"2000","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ydbio.2004.03.029","article-title":"The Hand1, Stra13 and Gcm1 transcription factors override FGF signaling to promote terminal differentiation of trophoblast stem cells","volume":"271","author":"Hughes","year":"2004","journal-title":"Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1095\/biolreprod.116.141861","article-title":"Function and hormonal regulation of GATA3 in human first trimester placentation","volume":"95","author":"Lee","year":"2016","journal-title":"Biol. Reprod."},{"key":"ref_34","first-page":"383","article-title":"Cytomegalovirus infection in the human placenta: Maternal immunity and developmentally regulated receptors on trophoblasts converge","volume":"325","author":"Pereira","year":"2008","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s00281-014-0449-1","article-title":"Models of vertical cytomegalovirus (CMV) transmission and pathogenesis","volume":"36","author":"Weisblum","year":"2014","journal-title":"Semin. Immunopathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.tim.2005.02.009","article-title":"Insights into viral transmission at the uterine-placental interface","volume":"13","author":"Pereira","year":"2005","journal-title":"Trends Microbiol."},{"key":"ref_37","first-page":"190","article-title":"Human placental trophoblast invasion and differentiation: A particular focus on Wnt signaling","volume":"4","author":"Pollheimer","year":"2013","journal-title":"Front. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"68","DOI":"10.4161\/org.4.2.5851","article-title":"Wnt signal transduction pathways","volume":"4","author":"Komiya","year":"2008","journal-title":"Organogenesis"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.placenta.2010.07.011","article-title":"Wnt signalling in implantation, decidualisation and placental differentiation\u2014Review","volume":"31","author":"Sonderegger","year":"2010","journal-title":"Placenta"},{"key":"ref_40","first-page":"579279","article-title":"Major histocompatibility complex I mediates immunological tolerance of the trophoblast during pregnancy and may mediate rejection during parturition","volume":"2014","author":"Dabrowska","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1093\/infdis\/jiu019","article-title":"Intrauterine growth restriction caused by underlying congenital cytomegalovirus infection","volume":"209","author":"Pereira","year":"2014","journal-title":"J. Infect. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4137\/CMRH.S974","article-title":"In vitro models using the human placenta to study fetal exposure to drugs","volume":"2","author":"Kovo","year":"2008","journal-title":"Clin. Med. Reprod. Health"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"814","DOI":"10.2174\/138920111795470976","article-title":"Application of human placental villous tissue explants to study ABC transporter mediated efflux of 2,4-dinitrophenyl-S-glutathione","volume":"12","author":"Vaidya","year":"2011","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2880","DOI":"10.3389\/fimmu.2018.02880","article-title":"Cross-Reactivity of Virus-Specific CD8+ T Cells Against Allogeneic HLA-C: Possible Implications for Pregnancy Outcome","volume":"9","author":"Anholts","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1093\/ilar.47.1.49","article-title":"Nonhuman primate models of intrauterine cytomegalovirus infection","volume":"47","author":"Barry","year":"2006","journal-title":"ILAR J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13204","DOI":"10.1128\/JVI.05749-11","article-title":"Modeling of human cytomegalovirus maternal-fetal transmission in a novel decidual organ culture","volume":"85","author":"Weisblum","year":"2011","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.coviro.2017.08.005","article-title":"Rhesus monkeys for a nonhuman primate model of cytomegalovirus infections","volume":"25","author":"Itell","year":"2017","journal-title":"Curr. Opin. Virol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Grimm, D. (2019, November 01). Record Number of Monkeys Being Used in U.S. Research. Available online: https:\/\/www.sciencemag.org\/news\/2018\/11\/record-number-monkeys-being-used-us-research.","DOI":"10.1126\/science.aav9290"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Grimm, D. (2020, August 18). 2020 U.S. Spending Bill Restricts Some Animal Research, Pushes for Lab Animal Retirement. Available online: https:\/\/www.sciencemag.org\/news\/2019\/12\/2020-us-spending-bill-restricts-some-animal-research-pushes-lab-animal-retirement.","DOI":"10.1126\/science.aba6454"},{"key":"ref_50","unstructured":"Reardon, S. (2020, August 18). Trump Administration Halts Fetal-Tissue Research by Government Scientists. Available online: https:\/\/www.nature.com\/articles\/d41586-019-01783-6."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1093\/infdis\/jiy327","article-title":"Human cytomegalovirus enhances placental susceptibility and replication of human immunodeficiency virus type 1 (HIV-1), which may facilitate in utero HIV-1 transmission","volume":"218","author":"Johnson","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"639","DOI":"10.5858\/arpa.2017-0421-RS","article-title":"Placental cytomegalovirus infection","volume":"143","author":"Lindholm","year":"2019","journal-title":"Arch. Pathol. Lab. Med."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/1\/20\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:45:29Z","timestamp":1760179529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/1\/20"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,24]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["v13010020"],"URL":"https:\/\/doi.org\/10.3390\/v13010020","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,24]]}}}