A Noninvasive Molecular Clock for Fetal Development Predicts Gestational Age and Preterm Delivery

Abstract

We performed a high time-resolution, longitudinal study of normal pregnancy development by measuring cell-free RNA (cfRNA) in blood from women during each week of pregnancy. Analysis of tissue-specific transcripts in these samples enabled us to follow fetal and placental development with high resolution and sensitivity, and also to detect gene-specific responses of the maternal immune system to pregnancy. We established a "clock" for normal pregnancy development and enabled a direct molecular approach to determine expected delivery dates with comparable accuracy to ultrasound, creating the basis for a portable, inexpensive fetal dating method. We also identified a related gene set that accurately discriminated women at risk for spontaneous preterm delivery up to two months in advance of labor, forming the basis of a potential screening test for risk of preterm delivery.

Influenza-Induced Interferon Lambda Response Is Associated With Longer Time to Delivery Among Pregnant Kenyan Women

“…Our study provides insight into potential immune mechanisms that could drive preterm birth, but did not identify a clear biomarker for preterm birth akin to the signature recently identified using analysis of cell-free DNA (31). In fact, it will be important to validate such signatures in cohorts drawn from a range of geographic areas, with a particular focus on Africa and Asia where preterm birth is most prevalent.…”

“…Consistent with the idea that preterm birth is an inflammatory state, monocytes from women with a history of preterm birth demonstrated enhanced inflammatory responses in response to stimulation in vitro (30). More recently, significant progress was made in identifying signatures predictive of preterm birth and delivery timing using cell-free RNA in the blood (31,32). The studies performed to date have varied in the specific gene signatures identified, and in fact, there has been very poor agreement between studies in the genes identified (33).…”

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 are associated with gestational duration

“…eQTL results from the GTEx and GEUVADIS data bases for skin tissue and lymphoblastoid cell lines, respectively, support this suggestion. However, to fully investigate this hypothesis, larger sample sizes and further functional follow-up experiments are needed, including fine-mapping of the locus and characterization of pro-inflammatory cytokine signalling shortly before parturition e.g., through non-invasive techniques allowing quantification of cell-free fetal RNA 39,40 and measurement of cytokine levels.…”