Circulating MicroRNAs in Maternal Blood as Potential Biomarkers for Fetal Hypoxia In-Utero

Abstract

Stillbirth affects 1 in 200 pregnancies and commonly arises due to a lack of oxygen supply to the fetus. Current tests to detect fetal hypoxia in-utero lack the sensitivity to identify many babies at risk. Emerging evidence suggests that microRNAs derived from the placenta circulate in the maternal blood during pregnancy and may serve as non-invasive biomarkers for pregnancy complications. In this study, we examined the expression of miRs known to be regulated by hypoxia in two clinical settings of significant fetal hypoxia: 1) labour and 2) fetal growth restriction. Six miRs (miR 210, miR 21, miR 424, miR 199a, miR 20b, and miR 373) were differentially expressed in pregnancies complicated by fetal hypoxia. In healthy term pregnancies there was a 4.2 fold increase in miR 210 (p<0.01), 2.7 fold increase in miR 424 (p<0.05), 2.6 fold increase in miR 199a (p<0.01) and 2.3 fold increase in miR 20b (p<0.05) from prior to labour to delivery of the fetus. Furthermore, the combined expression of miR 21 and miR 20b correlated with the degree of fetal hypoxia at birth determined by umbilical cord lactate delivery (r = 0.79, p = 0.03). In pregnancies complicated by severe preterm fetal growth restriction there was upregulation of the hypoxia-regulated miRs compared to gestation-matched controls: 3.6 fold in miR 210 (p<0.01), 3.6 fold in miR 424 (p<0.05), 5.9 fold in miR 21 (p<0.01), 3.8 fold in miR 199a (p<0.01) and 3.7 fold in miR 20b (p<0.01). Interestingly, the expression of miR 373 in gestation matched controls was very low, but was very highly expressed in FGR (p<0.0001). Furthermore, the expression increased in keeping with the degree of in-utero hypoxia estimated by fetal Doppler velocimetry. We conclude quantifying hypoxia-regulated miRs in the maternal blood may identify pregnancies at risk of fetal hypoxia, enabling early intervention to improve perinatal outcomes.

MicroRNAs, immune cells and pregnancy

“…These include fetal weight restriction and low fetal birth weight (intrauterine growth retardation or IUGR), [81][82][83][84] toxin exposures such as environmental toxins, 85,86 cancer (hepatocellular carcinoma), 87 diabetes mellitus 88 and, the most heavily studied, human pre-eclampsia. 79,[89][90][91][92][93][94][95][96] Many of the pre-eclampsia studies have investigated miRNA expression using high throughput microarray, and qPCR (primarily in order to validate specific microarray findings). Previous studies have established that oxygen tension is implicated in placental development in humans and mice.…”

Progress in the understanding of the etiology and predictability of fetal growth restriction

“…Since FGFR1 mediates the functions of VEGF, it is possible that increased miRNA-424 contributes to FGR by affecting the normal vascularity in the placenta . Significantly enhanced levels of a group of hypoxia-induced miRNAs are seen in the maternal blood of women diagnosed with FGR, suggesting increased expression and secretion of these miRNAs under hypoxic conditions in the placenta during FGR pathogenesis (Whitehead et al 2013).…”

Epigenetic Programming of Cardiovascular Disease by Perinatal Hypoxia and Fetal Growth Restriction

“…Present evidence suggests that miRNAs could be transferred across the placenta [84] with important consequences on fetal and maternal physiology. In humans, circulating levels of miR-21 during gestation in the mother positively correlate with evidence of fetal hypoxia [85] and evidence from in vitro studies show the participation of miR-21 in the FGR placental vascular dysfunction [86,87]. By contrast, placental miR-126 levels negatively correlate with the FGR severity [88].…”