Abstract
Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden1. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method2. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.
Highlights
1 in 12 pregnancies and is a significant cause of maternal morbidity and higher lifetime risk of cardiovascular disease[1]
By analysis of variance (ANOVA), we showed that the model was driven almost entirely by information from the cell-free RNA (cfRNA) transcripts, with body mass index (BMI), maternal age and race accounting for less than 1% of variance (Fig. 1c)
As the cfRNA signatures for gestational age demonstrated a dynamic change in transcripts as pregnancy progresses, we explored whether transcripts found in the maternal circulation during pregnancy could be linked to their tissue of origin
Summary
While other studies have looked at circulating biomarkers, a recent comprehensive review[33] concluded that more data early in pregnancy are needed to support clinical value. We have shown that novel transcript signatures from a single blood sample can (1) accurately track pregnancy progression independently of clinical factors and (2) reliably identify women at risk of developing pre-eclampsia months before presentation of the disease. Given the large sample size and diversity in our study population, it is noteworthy that race has a negligible effect on the expression patterns of gestational age estimates and pre-eclampsia risk evaluation These findings allow for the development of personalized assessments for pregnancy. An understanding of the maternal–fetal–placental transcriptome represents a vehicle by which comprehension of the biological underpinnings of maternal–fetal development can be improved and provides novel insights into interactions across the maternal–fetal dyad This holds the promise of precision therapeutic interventions that can target molecular subtypes of pre-eclampsia and preterm birth. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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