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
Objective To evaluate whether longitudinal measurements of serological
adipokines and sphingolipids can predict preeclampsia early in
gestation. Design Retrospective multi-omics discovery and longitudinal
validation. Setting Maternity units in two US hospitals. Methods A
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 and liquid
chromatography-tandem mass spectrometric assays. Main outcome measures
Interval from positive prediction to confirmative diagnosis. Results
Genomic 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. Conclusions Non-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 abstract Non-invasive longitudinal
assessment by serological evaluation of Lep and Cer ratio can predict
preeclampsia early in gestation.