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Open Access Highly Accessed Research article

Quantifying circulating hypoxia-induced RNA transcripts in maternal blood to determine in utero fetal hypoxic status

Clare Whitehead1, Wan Tinn Teh2, Susan P Walker13, Cheryl Leung2, Sonali Mendis13, Luke Larmour2 and Stephen Tong1*

Author Affiliations

1 Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg 3084 VIC, Australia

2 Monash Health, Monash Medical Centre, Clayton 3168, VIC, Australia

3 Perinatal Research Centre, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg 3084, VIC, Australia

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BMC Medicine 2013, 11:256  doi:10.1186/1741-7015-11-256

Published: 9 December 2013

Abstract

Background

Hypoxia in utero can lead to stillbirth and severe perinatal injury. While current prenatal tests can identify fetuses that are hypoxic, none can determine the severity of hypoxia/acidemia. We hypothesized a hypoxic/acidemic fetus would up-regulate and release hypoxia-induced mRNA from the fetoplacental unit into the maternal circulation, where they can be sampled and quantified. Furthermore, we hypothesized the abundance of hypoxia induced mRNA in the maternal circulation would correlate with severity of fetal hypoxia/acidemia in utero. We therefore examined whether abundance of hypoxia-induced mRNA in the maternal circulation correlates with the degree of fetal hypoxia in utero.

Methods

We performed a prospective study of two cohorts: 1) longitudinal study of pregnant women undergoing an induction of labor (labor induces acute fetal hypoxia) and 2) pregnancies complicated by severe preterm growth restriction (chronic fetal hypoxia). For each cohort, we correlated hypoxia induced mRNA in the maternal blood with degree of fetal hypoxia during its final moments in utero, evidenced by umbilical artery pH or lactate levels obtained at birth. Gestational tissues and maternal bloods were sampled and mRNAs quantified by microarray and RT-PCR.

Results

Hypoxia-induced mRNAs in maternal blood rose across labor, an event that induces acute fetal hypoxia. They exhibited a precipitous increase across the second stage of labor, a particularly hypoxic event. Importantly, a hypoxia gene score (sum of the relative expression of four hypoxia-induced genes) strongly correlated with fetal acidemia at birth. Hypoxia-induced mRNAs were also increased in the blood of women carrying severely growth restricted preterm fetuses, a condition of chronic fetal hypoxia. The hypoxia gene score correlated with the severity of ultrasound Doppler velocimetry abnormalities in fetal vessels. Importantly, the hypoxia gene score (derived from mRNA abundance in maternal blood) was significantly correlated with the degree of fetal acidemia at birth in this growth restriction cohort.

Conclusions

Abundance of mRNAs coding hypoxia-induced genes circulating in maternal blood strongly correlates with degree of fetal hypoxia/acidemia. Measuring hypoxia-induced mRNA in maternal blood may form the basis of a novel non-invasive test to clinically determine the degree of fetal hypoxia/acidemia while in utero.

Keywords:
Circulating mRNA; Pregnancy; Fetal growth restriction; Fetal hypoxia; Biomarker; Diagnostics