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A multi-centre randomized\u2013controlled trial has shown that first-trimester screening followed by treatment of high-risk women with aspirin reduces the risk of pre-term pre-eclampsia. However, the biomarkers currently employed in risk prediction are only weakly associated with the outcome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a case\u2013cohort study within the Pregnancy Outcome Prediction study to analyse untargeted maternal serum metabolomics in samples from 12, 20, 28 and 36\u2009weeks of gestational age (wkGA) in women with pre-eclampsia delivering at term (n\u2009=\u2009165) and pre-term (n\u2009=\u200929), plus a random sample of the cohort (n\u2009=\u2009325). We used longitudinal linear mixed models to identify candidate metabolites at 20\/28\u2009wkGA that differed by term pre-eclampsia status. Candidates were validated using measurements at 36\u2009wkGA in the same women. We then tested the association between the 12-, 20- and 28-wkGA measurements and pre-term pre-eclampsia. We externally validated the association using 24- to 28-wkGA samples from the Born in Bradford study (25 cases and 953 controls).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified 100 metabolites that differed most at 20\/28\u2009wkGA in term pre-eclampsia. Thirty-three of these were validated (P\u2009&amp;lt;\u20090.0005) at 36\u2009wkGA. 4-Hydroxyglutamate and C-glycosyltryptophan were independently predictive at 36\u2009wkGA of term pre-eclampsia. 4-Hydroxyglutamate was also predictive (area under the receiver operating characteristic curve, 95% confidence interval) of pre-term pre-eclampsia at 12 (0.673, 0.558\u20130.787), 20 (0.731, 0.657\u20130.806) and 28\u2009wkGA (0.733, 0.627\u20130.839). The predictive ability of 4-hydroxyglutamate at 12\u2009wkGA was stronger than two existing protein biomarkers, namely PAPP-A (0.567, 0.439\u20130.695) and placenta growth factor (0.589, 0.463\u20130.714). Finally, 4-hydroxyglutamate at 24\u201328\u2009wkGA was positively associated with pre-eclampsia (term or pre-term) among women from the Born in Bradford study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>4-hydroxyglutamate is a novel biochemical predictor of pre-eclampsia that provides better first-trimester prediction of pre-term disease than currently employed protein biomarkers.<\/jats:p><\/jats:sec>","DOI":"10.1093\/ije\/dyz098","type":"journal-article","created":{"date-parts":[[2019,5,13]],"date-time":"2019-05-13T11:09:13Z","timestamp":1557745753000},"page":"301-311","source":"Crossref","is-referenced-by-count":41,"title":["4-Hydroxyglutamate is a novel predictor of pre-eclampsia"],"prefix":"10.1093","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0799-1105","authenticated-orcid":false,"given":"Ulla","family":"Sovio","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge; NIHR Cambridge Biomedical Research Centre, Cambridge, UK"},{"name":"Centre for Trophoblast Research (CTR), Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"McBride","sequence":"first","affiliation":[{"name":"NIHR Bristol Biomedical Research Centre, Bristol, UK"},{"name":"MRC Integrative Epidemiology Unit, at the University of Bristol, Bristol, UK"},{"name":"Population Health Sciences, Bristol Medical School, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela M","family":"Wood","sequence":"first","affiliation":[{"name":"Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katya L","family":"Masconi","sequence":"first","affiliation":[{"name":"Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Cook","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge; NIHR Cambridge Biomedical Research Centre, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Gaccioli","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge; NIHR Cambridge Biomedical Research Centre, Cambridge, UK"},{"name":"Centre for Trophoblast Research (CTR), Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D Stephen","family":"Charnock-Jones","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge; NIHR Cambridge Biomedical Research Centre, Cambridge, UK"},{"name":"Centre for Trophoblast Research (CTR), Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbie A","family":"Lawlor","sequence":"first","affiliation":[{"name":"NIHR Bristol Biomedical Research Centre, Bristol, UK"},{"name":"MRC Integrative Epidemiology Unit, at the University of Bristol, Bristol, UK"},{"name":"Population Health Sciences, Bristol Medical School, Bristol, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon C S","family":"Smith","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, University of Cambridge; NIHR Cambridge Biomedical Research Centre, Cambridge, UK"},{"name":"Centre for Trophoblast Research (CTR), Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,5,16]]},"reference":[{"key":"2020040317152074500_dyz098-B1","volume-title":"Pre-Eclampsia: Etiology and Clinical Practice","year":"2011"},{"key":"2020040317152074500_dyz098-B2","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1016\/S0140-6736(16)31470-2","article-title":"Global, regional, and national levels of maternal mortality, 1990\u20132015: a systematic analysis for the Global Burden of Disease Study 2015","volume":"388","year":"2016","journal-title":"Lancet"},{"key":"2020040317152074500_dyz098-B3","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s00404-004-0695-x","article-title":"Risk factors for obstetric admissions to the intensive care unit in a tertiary hospital: a case\u2013control study","volume":"272","author":"Selo-Ojeme","year":"2005","journal-title":"Arch Gynecol Obstet"},{"key":"2020040317152074500_dyz098-B4","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1016\/S0140-6736(10)62187-3","article-title":"Stillbirths: where? 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