4-Hydroxyglutamate is a novel predictor of pre-eclampsia

Abstract

Abstract 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\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). Results We identified 100 metabolites that differed most at 20/28\u2009wkGA in term pre-eclampsia. Thirty-three of these were validated (P\u2009<\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, 0.558–0.787), 20 (0.731, 0.657–0.806) and 28\u2009wkGA (0.733, 0.627–0.839). The predictive ability of 4-hydroxyglutamate at 12\u2009wkGA 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\u2009wkGA 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.