Early prediction of preeclampsia in pregnancy with circulating cell-free RNA

Abstract

Liquid biopsies that measure circulating, cell-free RNA (cfRNA) offer an unprecedented opportunity to noninvasively study the development of pregnancy-related complications and to bridge gaps in clinical care. Here, we identify cfRNA transcriptomic changes across gestation and at post-partum that are associated with preeclampsia (PE), a multi-organ syndrome diagnosed after 20 weeks of gestation, using 118 samples from 42 pregnant mothers (18 normotensive (NT), 24 with PE). We find that changes in cfRNA gene expression between NT and PE mothers are most striking and stable early in gestation, suggesting that the identified cfRNA signals may correlate with PE pathogenesis. These changes also reflect our understanding of the known biology of PE, as supported by gene ontology analysis. Finally, we identify and independently validate (8 NT, 8 with PE/gestational hypertension) 11 genes, which when measured between 5-16 weeks of gestation can form a liquid biopsy test with clinically relevant specificity (88% [55-99%]) and sensitivity (100% [74-100%]) (All reported as value, [95% confidence interval]). Taken together, these results show that cfRNA measurements can form the basis of a test that would predict PE early in pregnancy, which has been an important and until now unrealized objective for obstetric care, and can help characterize the pathogenesis of PE in real time.

Differential Expression of 5’-tRNA Fragments in Circulating Preeclampsia Syncytiotrophoblast Vesicles Drives Macrophage Inflammation

“…We have corroborated perfusion-based RNA sequencing discoveries in vivo using qPCR in plasma. We overcame confounding in high-profile studies of total cell-free RNA in preeclampsia by focussing our attention exclusively on placental RNA 39,40 .…”