First-Trimester Serum Targeted Metabolomics for Eicosanoids Reveals Predictive Potential and Preventive Targets for Severe Preeclampsia: A Nested Prospective Cohort Study

Abstract Background: The metabolic profiles of eicosanoids before the clinical onset of preeclampsia remain incompletely understood. This study aimed to use a targeted metabolomic approach to identify eicosanoid metabolites in first-trimester blood samples and assess their potential to predict severe preeclampsia. Methods: We carried out a nested case-control study focusing on eicosanoid metabolites within a prospective cohort of 5,809 pregnant women. The study analyzed 45 participants who subsequently developed severe preeclampsia and 41 controls with uncomplicated pregnancies. Metabolomic data were examined, and the predictive performance of these metabolites was evaluated using receiver operating characteristic (ROC) curves. Results: Among 40 eicosanoids metabolites quantified, the levels of 10 metabolites differed statistically between groups. Further analysis revealed an increased activation of cyclooxygenase (COX) and 12/15-lipoxygenase (LOX) pathways, alongside a compromised cytochrome P450 (CYP450) pathway, as the underlying mechanisms in the altered eicosanoid metabolomics preceding the clinical onset of severe preeclampsia. Notably, ratios of metabolites indicating a shift from heightened (COX and 12/15-LOX) to compromised (CYP450) pathways demonstrated clinically relevant predictive potential: the performance of the Fetal Medicine Foundation first-trimester preeclampsia screening algorithms (area under curve [AUC] = 0.77, 95% confidence interval [CI]: 0.67 to 0.87) was significantly improved by incorporating these ratios, with the highest increment achieved by the 14-hydroxy-docosahexaenoic acid/19,20-epoxydocosapentaenoic acid ratio (AUC = 0.87, 95% CI: 0.80 to 0.94; ΔAUC = 0.10, 95% CI: 0.03 to 0.18, P = 0.008). Conclusions: Our findings revealed novel prediction models for severe preeclampsia based on first-trimester eicosanoid metabolomics, and provide mechanistic evidence supporting early aspirin use for COX pathway inhibition and suggest that rebalancing the 12/15-LOX and CYP450 pathways may be a potential strategy for preventing severe preeclampsia. Trial registration: Chinese Clinical Trial Registry Identifier: ChiCTR-EOC-15007644