Case finding of early pregnancies at risk of preeclampsia using maternal blood leptin/ceramide ratio: multi-omics discovery and validation from a longitudinal study

Abstract

ObjectiveTo evaluate whether longitudinal measurements of serological adipokines and sphingolipids can predict preeclampsia early in gestation.DesignRetrospective multi-omics discovery and longitudinal validation.SettingMaternity units in two US hospitals.MethodsA multi-omics approach integrating genomic and lipidomic discoveries was employed to identify leptin (Lep) and ceramide (Cer) as novel PE early gestational biomarkers. The levels of placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFlt-1), Lep, and Cer in maternal sera were then determined by enzyme-linked immunosorbent (ELISA) and liquid chromatography-tandem mass spectrometric (LC/MS/MS) assays.Main outcome measuresInterval from positive prediction to confirmative diagnosis.ResultsGenomic meta-analysis compiled six PE placental cohorts with 78 PE and 95 non-PE control placentas. The Testing Cohort included sera from 7 non-PE and 8 PE women collected at confirmatory diagnosis. The Validation Cohort included sera from 20 non-PE and 20 PE women collected longitudinally through gestation. Our findings revealed a marked elevation of maternal serum Leptin/Ceramide (d18:1/25:0) ratio from early gestation (a median of 23 weeks) when comparing later PE-complicated with uncomplicated pregnancies. The maternal Lep/Cer (d18:1/25:0) ratio significantly outperformed the established sFlt-1/PlGF ratio in predicting PE for sensitivity (85% vs. 40%), positive predictive value (89% vs. 42%), and AUC (0.92 vs. 0.52) from 5 to 25 weeks of gestation.ConclusionsNon-invasive longitudinal assessment by serological evaluation of Lep/Cer (d18:1/25:0) ratio can case find early pregnancies at risk of preeclampsia, outperforming sFlt-1/PlGF ratio test.Tweetable abstractNon-invasive longitudinal assessment by serological evaluation of Lep and Cer ratio can predict preeclampsia early in gestation.