Prediction of preeclampsia risk in first time pregnant women: Metabolite biomarkers for a clinical test

Preeclampsia remains a leading cause of maternal and perinatal morbidity and mortality. Accurate prediction of preeclampsia risk would enable more effective, risk-based prenatal care pathways. Current risk assessment algorithms depend on clinical risk factors largely unavailable for first-time pregnant women. Delivering accurate preeclampsia risk assessment to this cohort of women, therefore requires for novel biomarkers. Here, we evaluated the relevance of metabolite biomarker candidates for their selection into a prototype rapid, quantitative Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS) based clinical screening assay. First, a library of targeted LC-MS/MS assays for metabolite biomarker candidates was developed, using a medium-throughput translational metabolomics workflow, to verify biomarker potential in the Screening-for-Pregnancy-Endpoints (SCOPE, European branch) study. A variable pre-selection step was followed by the development of multivariable prediction models for pre-defined clinical use cases, i.e., prediction of preterm preeclampsia risk and of any preeclampsia risk. Within a large set of metabolite biomarker candidates, we confirmed the potential of dilinoleoyl-glycerol and heptadecanoyl-2-hydroxysn- glycero-3-phosphocholine to effectively complement Placental Growth Factor, an established preeclampsia biomarker, for the prediction of preeclampsia risk in first-time pregnancies without overt risk factors. These metabolites will be considered for integration in a prototype rapid, quantitative LC-MS/MS assay, and subsequent validation in an independent cohort.