{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T06:20:02Z","timestamp":1785565202006,"version":"3.56.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"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:p>Approximately 1 in 4 pregnant women in the United States undergo labor induction. The onset and establishment of labor, particularly induced labor, is a complex and dynamic process influenced by multiple endocrine, inflammatory, and mechanical factors as well as obstetric and pharmacological interventions. The duration from labor induction to the onset of active labor remains unpredictable. Moreover, prolonged labor is associated with severe complications for the mother and her offspring, most importantly chorioamnionitis, uterine atony, and postpartum hemorrhage. While maternal immune system adaptations that are critical for the maintenance of a healthy pregnancy have been previously characterized, the role of the immune system during the establishment of labor is poorly understood. Understanding maternal immune adaptations during labor initiation can have important ramifications for predicting successful labor induction and labor complications in both induced and spontaneous types of labor. The aim of this study was to characterize labor-associated maternal immune system dynamics from labor induction to the start of active labor. Serial blood samples from fifteen participants were collected immediately prior to labor induction (baseline) and during the latent phase until the start of active labor. Using high-dimensional mass cytometry, a total of 1,059 single-cell immune features were extracted from each sample. A multivariate machine-learning method was employed to characterize the dynamic changes of the maternal immune system after labor induction until the establishment of active labor. A cross-validated linear sparse regression model (least absolute shrinkage and selection operator, LASSO) predicted the minutes since induction of labor with high accuracy (R = 0.86, p = 6.7e-15, RMSE = 277 min). Immune features most informative for the model included STAT5 signaling in central memory CD8<jats:sup>+<\/jats:sup> T cells and pro-inflammatory STAT3 signaling responses across multiple adaptive and innate immune cell subsets. Our study reports a peripheral immune signature of labor induction, and provides important insights into biological mechanisms that may ultimately predict labor induction success as well as complications, thereby facilitating clinical decision-making to improve maternal and fetal well-being.<\/jats:p>","DOI":"10.3389\/fimmu.2021.725989","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T10:24:35Z","timestamp":1631183075000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["A Peripheral Immune Signature of Labor Induction"],"prefix":"10.3389","volume":"12","author":[{"given":"Kazuo","family":"Ando","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien J.","family":"H\u00e9dou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorien","family":"Feyaerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyuan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward A.","family":"Ganio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen S.","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura S.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Verdonk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy S.","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Mari\u0107","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin S.","family":"Angst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nima","family":"Aghaeepour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David K.","family":"Stevenson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yair J.","family":"Blumenfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pervez","family":"Sultan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan","family":"Carvalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ina A.","family":"Stelzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brice","family":"Gaudilli\u00e8re","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"key":"B1","volume-title":"Inducing Labour Clinical Guideline [CG70]","year":"2008"},{"key":"B2","volume-title":"WHO Recommendations: Induction of Labour at or Beyond Term","author":"Oladapo","year":"2018"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0b013e3181b48ef5","article-title":"ACOG Practice Bulletin No. 107: Induction of Labor","volume":"114","year":"2009","journal-title":"Obstet Gynecol"},{"key":"B4","doi-asserted-by":"crossref","DOI":"10.1016\/j.ajog.2017.11.556","article-title":"Defining Failed Induction of Labor","volume":"218","author":"Grobman","year":"2018","journal-title":"Am J Obstet Gynecol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1800566","article-title":"Labor Induction Versus Expectant Management in Low-Risk Nulliparous Women","volume":"379","author":"Grobman","year":"2018","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/ppe.12068","article-title":"Obstetrical Interventions for Term First Deliveries in the US","volume":"27","author":"Ananth","year":"2013","journal-title":"Paediatr Perinat Epidemiol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"170","DOI":"10.11124\/JBISRIR-2017-003587","article-title":"Effects of Induction of Labor Prior to Post-Term in Low-Risk Pregnancies: A Systematic Review","volume":"17","author":"Rydahl","year":"2019","journal-title":"JBI Database System Rev Implement Rep"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1053\/j.semperi.2015.07.013","article-title":"Failed Induction of Labor","volume":"39","author":"Schoen","year":"2015","journal-title":"Semin Perinatol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.ajog.2020.12.1212","article-title":"Predicting Cesarean Delivery for Failure to Progress as an Outcome of Labor Induction in Term Singleton Pregnancy","volume":"224","author":"Kamel","year":"2021","journal-title":"Am J Obstet Gynecol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(89)90172-5","article-title":"Infection and Labor. III. Interleukin-1: A Signal for the Onset of Parturition","volume":"160","author":"Romero","year":"1989","journal-title":"Am J Obstet Gynecol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1177\/1933719112446084","article-title":"Physiologic Uterine Inflammation and Labor Onset: Integration of Endocrine and Mechanical Signals","volume":"20","author":"Shynlova","year":"2013","journal-title":"Reprod Sci"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2014.46","article-title":"Immune Cells in Term and Preterm Labor","volume":"11","author":"Gomez-Lopez","year":"2014","journal-title":"Cell Mol Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/me.2009-0016","article-title":"Minireview: Fetal-Maternal Hormonal Signaling in Pregnancy and Labor","volume":"23","author":"Mendelson","year":"2009","journal-title":"Mol Endocrinol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nm0595-460","article-title":"A Placental Clock Controlling the Length of Human Pregnancy","volume":"1","author":"McLean","year":"1995","journal-title":"Nat Med"},{"key":"B15","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1055\/s-2006-956771","article-title":"Myometrial Progesterone Responsiveness","volume":"25","author":"Mesiano","year":"2007","journal-title":"Semin Reprod Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2018.11.003","article-title":"Fetal Membrane Architecture, Aging and Inflammation in Pregnancy and Parturition","volume":"79","author":"Menon","year":"2019","journal-title":"Placenta"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199908263410906","article-title":"The Control of Labor","volume":"341","author":"Norwitz","year":"1999","journal-title":"N Engl J Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2826.2008.01668.x","article-title":"Cytokine Networks and the Regulation of Uterine Function in Pregnancy and Parturition","volume":"20","author":"Orsi","year":"2008","journal-title":"J Neuroendocrinol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1186\/s12916-016-0632-4","article-title":"Modeling Hormonal and Inflammatory Contributions to Preterm and Term Labor Using Uterine Temporal Transcriptomics","volume":"14","author":"Migale","year":"2016","journal-title":"BMC Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-16-0157","article-title":"Myometrial Cytokines and Their Role in the Onset of Labour","volume":"231","author":"Sivarajasingam","year":"2016","journal-title":"J Endocrinol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"8","DOI":"10.7554\/eLife.52004","article-title":"Single Cell Transcriptional Signatures of the Human Placenta in Term and Preterm Parturition","volume":"12","author":"Pique-Regi","year":"2019","journal-title":"Elife"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.13160","article-title":"Immunophenotyping and Activation Status of Maternal Peripheral Blood Leukocytes During Pregnancy and Labour, Both Term and Preterm","volume":"21","author":"Zhang","year":"2017","journal-title":"J Cell Mol Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gap054","article-title":"Leukocytes are Primed in Peripheral Blood for Activation During Term and Preterm Labour","volume":"15","author":"Yuan","year":"2009","journal-title":"Mol Hum Reprod"},{"key":"B24","doi-asserted-by":"publisher","first-page":"eaan2946","DOI":"10.1126\/sciimmunol.aan2946","article-title":"An Immune Clock of Human Pregnancy","volume":"2","author":"Aghaeepour","year":"2017","journal-title":"Sci Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1093\/bioinformatics\/bty537","article-title":"Multiomics Modeling of the Immunome, Transcriptome, Microbiome, Proteome and Metabolome Adaptations During Human Pregnancy","volume":"35","author":"Ghaemi","year":"2019","journal-title":"Bioinformatics"},{"key":"B26","doi-asserted-by":"publisher","first-page":"eabd9898","DOI":"10.1126\/scitranslmed.abd9898","article-title":"Integrated Trajectories of the Maternal Metabolome, Proteome, and Immunome Predict Labor Onset","volume":"13","author":"Stelzer","year":"2021","journal-title":"Sci Transl Med"},{"key":"B27","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1007\/s00281-019-00772-1","article-title":"Multiomic Immune Clockworks of Pregnancy","volume":"42","author":"Peterson","year":"2020","journal-title":"Semin Immunopathol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01305","article-title":"Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia","volume":"10","author":"Han","year":"2019","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.clp.2010.02.003","article-title":"Diagnosis and Management of Clinical Chorioamnionitis","volume":"37","author":"Tita","year":"2010","journal-title":"Clin Perinatol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0b013e3182704880","article-title":"Preventing the First Cesarean Delivery: Summary of a Joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, and American College of Obstetricians and Gynecologists Workshop","volume":"120","author":"Spong","year":"2012","journal-title":"Obstet Gynecol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"11565","DOI":"10.1038\/ncomms11565","article-title":"Molecular Evidence of Functional Progesterone Withdrawal in Human Myometrium","volume":"7","author":"Nadeem","year":"2016","journal-title":"Nat Commun"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1177\/1933719117716775","article-title":"Control of Progesterone Receptor-A Transrepressive Activity in Myometrial Cells: Implications for the Control of Human Parturition","volume":"25","author":"Patel","year":"2018","journal-title":"Reprod Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-4023","article-title":"Pulsatile Interleukin-6 Leads CRH Secretion and is Associated With Myometrial Contractility During the Active Phase of Term Human Labor","volume":"98","author":"Papatheodorou","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-225664","article-title":"Signal Transducer and Activator of Transcription-3 (Stat3) Plays a Critical Role in Implantation via Progesterone Receptor in Uterus","volume":"27","author":"Lee","year":"2013","journal-title":"FASEB J"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2010.12.008","article-title":"Novel Role of Signal Transducer and Activator of Transcription 3 as a Progesterone Receptor Coactivator in Breast Cancer","volume":"76","author":"Proietti","year":"2011","journal-title":"Steroids"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2009.08.002","article-title":"Placental Blood Leukocytes are Functional and Phenotypically Different Than Peripheral Leukocytes During Human Labor","volume":"84","author":"Vega-Sanchez","year":"2010","journal-title":"J Reprod Immunol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/j.1749-6632.2009.04911.x","article-title":"Signal Transducer and Activator of Transcription-3, Inflammation, and Cancer: How Intimate is the Relationship","volume":"1171","author":"Aggarwal","year":"2009","journal-title":"Ann N Y Acad Sci"},{"key":"B38","doi-asserted-by":"publisher","first-page":"3996","DOI":"10.1210\/en.2010-0063","article-title":"Interleukin-6 is an Essential Determinant of on-Time Parturition in the Mouse","volume":"151","author":"Robertson","year":"2010","journal-title":"Endocrinology"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/aogs.12708","article-title":"Role of SOCS3 in the Jak\/stat3 Pathway in the Human Placenta: Different Mechanisms for Preterm and Term Labor","volume":"94","author":"Zhou","year":"2015","journal-title":"Acta Obstet Gynecol Scand"},{"key":"B40","doi-asserted-by":"publisher","first-page":"ra106","DOI":"10.1126\/scisignal.aac6151","article-title":"Phosphorylation of STAT3 Mediates the Induction of Cyclooxygenase-2 by Cortisol in the Human Amnion at Parturition","volume":"8","author":"Wang","year":"2015","journal-title":"Sci Signal"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1159\/000433429","article-title":"Definition of Failed Induction of Labor and Its Predictive Factors: Two Unsolved Issues of an Everyday Clinical Situation","volume":"38","author":"Ba\u00f1os","year":"2015","journal-title":"Fetal Diagn Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0412.2002.810306.x","article-title":"Risk Factors and Outcome of Failure to Progress During the First Stage of Labor: A Population-Based Study","volume":"81","author":"Sheiner","year":"2002","journal-title":"Acta Obstet Gynecol Scand"},{"key":"B43","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1097\/AOG.0000000000004257","article-title":"Incidence of and Risk Factors for Failed Induction of Labor Using a Contemporary Definition","volume":"137","author":"Freret","year":"2021","journal-title":"Obstet Gynecol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3109\/14767058.2012.703718","article-title":"Risk Factors for Failed Induction in Nulliparous Women","volume":"25","author":"Frederiks","year":"2012","journal-title":"J Maternal-Fetal Neonatal Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2017.11.603","article-title":"A Validated Calculator to Estimate Risk of Cesarean After an Induction of Labor With an Unfavorable Cervix","volume":"218","author":"Levine","year":"2018","journal-title":"Am J Obstet Gynecol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0000000000003696","article-title":"Risk Calculator to Predict Cesarean Delivery Among Women Undergoing Induction of Labor","volume":"135","author":"Rossi","year":"2020","journal-title":"Obstet Gynecol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0000000000004039","article-title":"Externally Validated Prediction Model of Vaginal Delivery After Preterm Induction With Unfavorable Cervix","volume":"136","author":"Kawakita","year":"2020","journal-title":"Obstet Gynecol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"CD010762","DOI":"10.1002\/14651858.CD010762.pub2","article-title":"Methods for Assessing Pre-Induction Cervical Ripening","author":"Ezebialu","year":"2015","journal-title":"Cochrane Database Syst Rev"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22271","article-title":"Normalization of Mass Cytometry Data With Bead Standards","author":"Finck","year":"2013","journal-title":"Cytometry"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.020","article-title":"Palladium-Based Mass Tag Cell Barcoding With a Doublet-Filtering Scheme and Single-Cell Deconvolution Algorithm","volume":"10","author":"Zunder","year":"2015","journal-title":"Nat Protoc"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/s42256-020-00232-8","article-title":"Integration of Mechanistic Immunological Knowledge Into a Machine Learning Pipeline Improves Predictions","volume":"2","author":"Culos","year":"2020","journal-title":"Nat Mach Intell"},{"key":"B52","article-title":"Visualizing Data Using T-SNE","volume":"9","author":"van der Maaten","year":"2008","journal-title":"J Machine-Learning Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.725989\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T10:24:44Z","timestamp":1631183084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.725989\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,9]]},"references-count":52,"alternative-id":["10.3389\/fimmu.2021.725989"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.725989","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,9]]},"article-number":"725989"}}