{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T13:07:45Z","timestamp":1765544865255,"version":"3.37.3"},"reference-count":50,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2022,9,16]],"date-time":"2022-09-16T00:00:00Z","timestamp":1663286400000},"content-version":"unspecified","delay-in-days":15,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012373","name":"National Institute of Academic Anaesthesia","doi-asserted-by":"publisher","award":["NIAA19R103"],"award-info":[{"award-number":["NIAA19R103"]}],"id":[{"id":"10.13039\/100012373","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Welsh Government and European Regional Development Fund","award":["80762-CU-106"],"award-info":[{"award-number":["80762-CU-106"]}]},{"name":"Cardiff and Vale Health Board","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Maternal sepsis remains a leading cause of death in pregnancy. Physiological adaptations to pregnancy obscure early signs of sepsis and can result in delays in recognition and treatment. Identifying biomarkers that can reliably diagnose sepsis will reduce morbidity and mortality and antibiotic overuse. We have previously identified an immune-metabolic biomarker network comprising three pathways with a &gt;99% accuracy for detecting bacterial neonatal sepsis. In this prospective study, we will describe physiological parameters and novel biomarkers in two cohorts\u2014healthy pregnant women and pregnant women with suspected sepsis\u2014with the aim of mapping pathophysiological drivers and evaluating predictive biomarkers for diagnosing maternal sepsis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and analysis<\/jats:title><jats:p>Women aged over 18 with an ultrasound-confirmed pregnancy will be recruited to a pilot and two main study cohorts. The pilot will involve blood sample collection from 30 pregnant women undergoing an elective caesarean section. Cohort A will follow 100 healthy pregnant women throughout their pregnancy journey, with collection of blood samples from participants at routine time points in their pregnancy: week 12 \u2018booking\u2019, week 28 and during labour. Cohort B will follow 100 pregnant women who present with suspected sepsis in pregnancy or labour and will have at least two blood samples taken during their care pathway. Study blood samples will be collected during routine clinical blood sampling. Detailed medical history and physiological parameters at the time of blood sampling will be recorded, along with the results of routine biochemical tests, including C reactive protein, lactate and white blood cell count. In addition, study blood samples will be processed and analysed for transcriptomic, lipidomic and metabolomic analyses and both qualitative and functional immunophenotyping.<\/jats:p><\/jats:sec><jats:sec><jats:title>Ethics and dissemination<\/jats:title><jats:p>Ethical approval has been obtained from the Wales Research Ethics Committee 2 (SPON1752-19, 30 October 2019).<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration number<\/jats:title><jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05023954\">NCT05023954<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1136\/bmjopen-2022-066382","type":"journal-article","created":{"date-parts":[[2022,9,17]],"date-time":"2022-09-17T11:26:46Z","timestamp":1663414006000},"page":"e066382","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["mSep: investigating physiological and immune-metabolic biomarkers in septic and healthy pregnant women to predict feto-maternal immune health \u2013 a prospective observational cohort study protocol"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct05023954","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03777670","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05023954","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6647-9355","authenticated-orcid":false,"given":"Simran","family":"Sharma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Summia","family":"Zaher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0768-0013","authenticated-orcid":false,"given":"Patr\u00edcia R S","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke C","family":"Davies","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Edkins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Strang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1721-6532","authenticated-orcid":false,"given":"Mallinath","family":"Chakraborty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W John","family":"Watkins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Andrews","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward","family":"Parkinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicos","family":"Angelopoulos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Moet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Freya","family":"Shepherd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9807-1231","authenticated-orcid":false,"given":"Kate Megan Megan","family":"Davies","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"White","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaun","family":"Oram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate","family":"Siddall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vikki","family":"Keeping","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn","family":"Simpson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Faggian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maryanne","family":"Bray","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire","family":"Bertorelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Bell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel E","family":"Collis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James E","family":"McLaren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Labeta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie B","family":"O\u2019Donnell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Ghazal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2022,9,17]]},"reference":[{"key":"2022091704252176000_12.9.e066382.1","doi-asserted-by":"crossref","DOI":"10.1186\/s12978-017-0321-6","article-title":"Towards a consensus definition of maternal sepsis: results of a systematic review and expert consultation","volume":"14","author":"Bonet","year":"2017","journal-title":"Reprod Health"},{"key":"2022091704252176000_12.9.e066382.2","doi-asserted-by":"crossref","DOI":"10.1186\/s12978-017-0437-8","article-title":"The global maternal sepsis study and awareness campaign (GLOSS): study protocol","volume":"15","author":"Bonet","year":"2018","journal-title":"Reprod Health"},{"key":"2022091704252176000_12.9.e066382.3","doi-asserted-by":"crossref","unstructured":"Bauer M E , Bauer S , Rajala B . Maternal physiologic parameters in relationship to systemic inflammatory response syndrome criteria a systematic review and meta-analysis 2014.","DOI":"10.1097\/AOG.0000000000000423"},{"key":"2022091704252176000_12.9.e066382.4","doi-asserted-by":"crossref","first-page":"e79","DOI":"10.1055\/s-0038-1641569","article-title":"Implementing obstetric early warning systems","volume":"8","author":"Friedman","year":"2018","journal-title":"AJP Rep"},{"key":"2022091704252176000_12.9.e066382.5","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s12879-015-0813-3","article-title":"Prevalence of early-onset neonatal infection among newborns of mothers with bacterial infection or colonization: a systematic review and meta-analysis","volume":"15","author":"Chan","year":"2015","journal-title":"BMC Infect Dis"},{"key":"2022091704252176000_12.9.e066382.6","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287"},{"key":"2022091704252176000_12.9.e066382.7","doi-asserted-by":"crossref","unstructured":"Elton R , Chaudhari S . Sepsis in obstetrics. BJA Education 2015;15:259\u201364.","DOI":"10.1093\/bjaceaccp\/mku062"},{"key":"2022091704252176000_12.9.e066382.8","doi-asserted-by":"publisher","DOI":"10.4161\/viru.27135"},{"key":"2022091704252176000_12.9.e066382.9","doi-asserted-by":"crossref","unstructured":"SHARPE EE , ARENDT KW . Epidural labor analgesia and maternal fever. Clinical obstetrics and gynecology 2017;60:365\u201374.","DOI":"10.1097\/GRF.0000000000000270"},{"key":"2022091704252176000_12.9.e066382.10","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.64"},{"key":"2022091704252176000_12.9.e066382.11","doi-asserted-by":"crossref","unstructured":"Robertson S G , Petroff M S , Hunt J . Immunology of pregnancy 2015:1835\u201374.","DOI":"10.1016\/B978-0-12-397175-3.00041-7"},{"key":"2022091704252176000_12.9.e066382.12","doi-asserted-by":"crossref","unstructured":"Morelli S , Mandal M , Goldsmith LT , et al . The maternal immune system during pregnancy and its influence on fetal development. Res Rep Biol 2015:171\u201389.doi:10.2147\/RRB.S80652","DOI":"10.2147\/RRB.S80652"},{"key":"2022091704252176000_12.9.e066382.13","doi-asserted-by":"crossref","unstructured":"Abdelrahman A , Murnaghan M . Practical obstetric Multi-Professional training course. 2013;346:e8561.","DOI":"10.1136\/bmj.e8561"},{"key":"2022091704252176000_12.9.e066382.14","doi-asserted-by":"publisher","DOI":"10.3947\/ic.2014.46.1.1"},{"key":"2022091704252176000_12.9.e066382.15","doi-asserted-by":"crossref","first-page":"195","DOI":"10.4103\/2229-5151.141356","article-title":"Procalcitonin versus C-reactive protein: usefulness as biomarker of sepsis in ICU patient","volume":"4","author":"Nargis","year":"2014","journal-title":"Int J Crit Illn Inj Sci"},{"key":"2022091704252176000_12.9.e066382.16","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4314\/mmj.v28i1.4","article-title":"Point-Of-Care lactate and creatinine analysis for sick obstetric patients at Queen Elizabeth central hospital in Blantyre, Malawi: a feasibility study","volume":"28","author":"Glasmacher","year":"2016","journal-title":"Malawi Med J"},{"key":"2022091704252176000_12.9.e066382.17","doi-asserted-by":"crossref","unstructured":"McLean AS , Tang B , Huang SJ . Investigating sepsis with biomarkers. BMJ 2015;350:h254.doi:10.1136\/bmj.h254","DOI":"10.1136\/bmj.h254"},{"key":"2022091704252176000_12.9.e066382.18","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.ijoa.2018.04.010","article-title":"Sepsis in pregnancy and the puerperium","volume":"36","author":"Burlinson","year":"2018","journal-title":"Int J Obstet Anesth"},{"key":"2022091704252176000_12.9.e066382.19","doi-asserted-by":"crossref","first-page":"790","DOI":"10.3109\/14767058.2014.932765","article-title":"The white cell count in pregnancy and labour: a reference range","volume":"28","author":"Sivasankar","year":"2015","journal-title":"J Matern Fetal Neonatal Med"},{"key":"2022091704252176000_12.9.e066382.20","doi-asserted-by":"crossref","first-page":"27","DOI":"10.5468\/ogs.20206","article-title":"Role of repeat procalcitonin estimation at 48 hours for outcome in pregnancy associated sepsis: a prospective observational study","volume":"64","author":"Agarwal","year":"2021","journal-title":"Obstet Gynecol Sci"},{"key":"2022091704252176000_12.9.e066382.21","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1111\/cei.13311","article-title":"Overview of procalcitonin in pregnancy and in pre-eclampsia","volume":"198","author":"Mangogna","year":"2019","journal-title":"Clin Exp Immunol"},{"key":"2022091704252176000_12.9.e066382.22","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1055\/s-2008-1078761","article-title":"Fetal heart rate monitoring patterns in women with amniotic fluid proteomic profiles indicative of inflammation","volume":"25","author":"Buhimschi","year":"2008","journal-title":"Am J Perinatol"},{"key":"2022091704252176000_12.9.e066382.23","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1272\/jnms.75.106","article-title":"Fetal heart rate monitoring as a predictor of histopathologic chorioamnionitis in the third trimester","volume":"75","author":"Miyake","year":"2008","journal-title":"J Nippon Med Sch"},{"key":"2022091704252176000_12.9.e066382.24","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1097\/CCM.0000000000003225","article-title":"Surviving sepsis campaign","volume":"46","author":"Coopersmith","year":"2018","journal-title":"Crit Care Med"},{"key":"2022091704252176000_12.9.e066382.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)04234-3"},{"key":"2022091704252176000_12.9.e066382.26","doi-asserted-by":"crossref","unstructured":"Sinha P , Otify M . Genital tract sepsis: early diagnosis. management and prevention 2012.","DOI":"10.1111\/j.1744-4667.2011.00083.x"},{"key":"2022091704252176000_12.9.e066382.27","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf7165"},{"key":"2022091704252176000_12.9.e066382.28","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/j.1365-2249.2008.03714.x","article-title":"Allergy and the cardiovascular system","volume":"153 Suppl 1","author":"Triggiani","year":"2008","journal-title":"Clin Exp Immunol"},{"key":"2022091704252176000_12.9.e066382.29","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph110807993"},{"key":"2022091704252176000_12.9.e066382.30","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01781-14"},{"key":"2022091704252176000_12.9.e066382.31","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(99)00077-1"},{"key":"2022091704252176000_12.9.e066382.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.lab.2005.10.005"},{"key":"2022091704252176000_12.9.e066382.33","doi-asserted-by":"publisher","DOI":"10.1039\/b707122c"},{"key":"2022091704252176000_12.9.e066382.34","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.ymeth.2013.03.032","article-title":"Transcriptional profiling technology for studying vaccine responses: an untapped goldmine","volume":"60","author":"Flanagan","year":"2013","journal-title":"Methods"},{"key":"2022091704252176000_12.9.e066382.35","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5649"},{"key":"2022091704252176000_12.9.e066382.36","doi-asserted-by":"crossref","unstructured":"Chakraborty M , Rodrigues PRS , Watkins WJ , et al . nSeP: immune and metabolic biomarkers for early detection of neonatal sepsis\u2014protocol for a prospective multicohort study. BMJ Open 2021;11:e050100.doi:10.1136\/bmjopen-2021-050100","DOI":"10.1136\/bmjopen-2021-050100"},{"key":"2022091704252176000_12.9.e066382.37","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2019.02863","article-title":"The cellular transcriptome in the maternal circulation during normal pregnancy: a longitudinal study","volume":"10","author":"Gomez-Lopez","year":"2019","journal-title":"Front Immunol"},{"key":"2022091704252176000_12.9.e066382.38","doi-asserted-by":"publisher","DOI":"10.2310\/JIM.0b013e31821b8755"},{"key":"2022091704252176000_12.9.e066382.39","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.copsyc.2015.03.007","article-title":"Current directions in stress and human immune function","volume":"5","author":"Morey","year":"2015","journal-title":"Curr Opin Psychol"},{"key":"2022091704252176000_12.9.e066382.40","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2022091704252176000_12.9.e066382.41","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"2022091704252176000_12.9.e066382.42","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2022091704252176000_12.9.e066382.43","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1012491"},{"key":"2022091704252176000_12.9.e066382.44","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3252"},{"key":"2022091704252176000_12.9.e066382.45","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1147"},{"key":"2022091704252176000_12.9.e066382.46","doi-asserted-by":"publisher","DOI":"10.1186\/1752-0509-4-117"},{"key":"2022091704252176000_12.9.e066382.47","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2008.55"},{"key":"2022091704252176000_12.9.e066382.48","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1003"},{"key":"2022091704252176000_12.9.e066382.49","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv1351"},{"key":"2022091704252176000_12.9.e066382.50","doi-asserted-by":"publisher","DOI":"10.3390\/cancers4041180"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2022-066382","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,17]],"date-time":"2022-09-17T11:27:22Z","timestamp":1663414042000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2022-066382"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9]]},"references-count":50,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9,17]]},"published-print":{"date-parts":[[2022,9]]}},"alternative-id":["10.1136\/bmjopen-2022-066382"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2022-066382","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"type":"print","value":"2044-6055"},{"type":"electronic","value":"2044-6055"}],"subject":[],"published":{"date-parts":[[2022,9]]}}}