4-Hydroxyglutamate is a novel predictor of pre-eclampsia.

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McBride, Nancy 
Wood, Angela M 
Masconi, Katya L 
Cook, Emma 

BACKGROUND: Pre-term pre-eclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide. A multi-centre randomized-controlled 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. METHODS: We conducted a case-cohort study within the Pregnancy Outcome Prediction study to analyse untargeted maternal serum metabolomics in samples from 12, 20, 28 and 36 weeks of gestational age (wkGA) in women with pre-eclampsia delivering at term (n = 165) and pre-term (n = 29), plus a random sample of the cohort (n = 325). We used longitudinal linear mixed models to identify candidate metabolites at 20/28 wkGA that differed by term pre-eclampsia status. Candidates were validated using measurements at 36 wkGA 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). RESULTS: We identified 100 metabolites that differed most at 20/28 wkGA in term pre-eclampsia. Thirty-three of these were validated (P < 0.0005) at 36 wkGA. 4-Hydroxyglutamate and C-glycosyltryptophan were independently predictive at 36 wkGA 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, 0.558-0.787), 20 (0.731, 0.657-0.806) and 28 wkGA (0.733, 0.627-0.839). The predictive ability of 4-hydroxyglutamate at 12 wkGA was stronger than two existing protein biomarkers, namely PAPP-A (0.567, 0.439-0.695) and placenta growth factor (0.589, 0.463-0.714). Finally, 4-hydroxyglutamate at 24-28 wkGA was positively associated with pre-eclampsia (term or pre-term) among women from the Born in Bradford study. CONCLUSIONS: 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.

Metabolomics, cohort study, pre-eclampsia, pregnancy, risk prediction, Adult, Area Under Curve, Biomarkers, Case-Control Studies, Female, Gestational Age, Glutethimide, Humans, Metabolomics, Pre-Eclampsia, Predictive Value of Tests, Pregnancy, Pregnancy Outcome, Pregnancy Trimester, Third, Pregnancy, High-Risk, ROC Curve, Risk Adjustment
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Int J Epidemiol
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Oxford University Press (OUP)
All rights reserved
Medical Research Council (G1100221)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Medical Research Council (MR/K014811/1)
British Heart Foundation (None)
British Heart Foundation (RG/18/13/33946)
Medical Research Council (G0701619)
The work was supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (Women’s Health theme), the Medical Research Council (United Kingdom; G1100221 to GCSS and DSC-J, MR/K014811/1 to AMW, MR/N024397/1 to DAL), the Wellcome Trust (WT101597MA), National Institutes of Health (R01 DK10324), the European Research Council (669545), the NIHR Blood and Transplant Research Unit (NIHR BTRU-2014-10024, which funded KLM), and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol, which funds NM PhD studentship. NM and DAL work in a unit that receives support from the MRC (MC_UU_00011/6) and University of Bristol.