Early prediction of preeclampsia in pregnancy with cell-free RNA

Mira N Moufarrej,Sevahn K Vorperian,Ronald J Wong,Ana A Campos,Cecele C Quaintance,Rene V Sit,Michelle Tan,Angela M Detweiler,Honey Mekonen,Norma F Neff,Courtney Baruch-Gravett,James A Litch,Maurice L Druzin,Virginia D Winn,Gary M Shaw,David K Stevenson,Stephen R Quake

doi:10.1038/s41586-022-04410-z

Abstract

Liquid biopsies that measure circulating cell-free RNA (cfRNA) offer an opportunity to study the development of pregnancy-related complications in a non-invasive manner and to bridge gaps in clinical care1–4. Here we used 404 blood samples from 199 pregnant mothers to identify and validate cfRNA transcriptomic changes that are associated with preeclampsia, a multi-organ syndrome that is the second largest cause of maternal death globally5. We find that changes in cfRNA gene expression between normotensive and preeclamptic mothers are marked and stable early in gestation, well before the onset of symptoms. These changes are enriched for genes specific to neuromuscular, endothelial and immune cell types and tissues that reflect key aspects of preeclampsia physiology6–9, suggest new hypotheses for disease progression and correlate with maternal organ health. This enabled the identification and independent validation of a panel of 18 genes that when measured between 5 and 16 weeks of gestation can form the basis of a liquid biopsy test that would identify mothers at risk of preeclampsia long before clinical symptoms manifest themselves. Tests based on these observations could help predict and manage who is at risk for preeclampsia—an important objective for obstetric care10,11.

Highlights

Advances in obstetrics and neonatology have substantially mitigated many of the adverse pregnancy outcomes related to preterm birth and preeclampsia3
Gestational age at delivery to monitor maternal organ health in a non-invasive manner. These results show that cell-free RNA (cfRNA) measurements can form the basis for clinically relevant tests that would predict preeclampsia months before presentation, manage who is at risk for specific organ damage and help to characterize the pathogenesis of preeclampsia in real time
Our findings provide molecular evidence that supports the present physiological understanding of preeclampsia pathogenesis: early abnormal placentation and systemic endothelial dysfunction6

Summary

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To monitor maternal organ health in a non-invasive manner. Together, these results show that cfRNA measurements can form the basis for clinically relevant tests that would predict preeclampsia months before presentation, manage who is at risk for specific organ damage and help to characterize the pathogenesis of preeclampsia in real time. The final model performed well, with a near-perfect area under the receiver operating characteristic curve (AUROC) (0.99 [0.99–0.99]), good specificity (85% [77–91%]) and perfect sensitivity (100% [92–100%]) (Fig. 3a, Extended Data Table 3) We tested this model on validation 1 (n = 35 normotensive, 8 preeclampsia) and two other independent cohorts, which were collected at separate institutions: validation 2 (n = 61 normotensive, 28 preeclampsia) and the cohort used by Del Vecchio and colleagues (n = 8 normotensive, 5 with preeclampsia, 7 with gestational diabetes, 2 with chronic hypertension). We observed a decreased signal in hepatocyte, kidney, endothelial cell and smooth muscle signatures across gestation and an increased platelet signal before 12 weeks of gestation for preeclampsia These tissue- and cell-type-specific changes are consistent both with common preeclampsia pathogenesis and with the specific, prominent diagnoses in our cohort (for example, thrombocytopenia, proteinuria, impaired liver function and renal insufficiency)

Discussion

Methods

Code availability

Findings

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