Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg 3084 VIC, Australia.
BMC Med. 2013 Dec 9;11:256. doi: 10.1186/1741-7015-11-256.
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.
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.
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.
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.
子宫内缺氧可导致胎儿死亡和严重围产期损伤。虽然目前的产前检查可以识别出缺氧的胎儿，但没有一种检查可以确定缺氧/酸中毒的严重程度。我们假设缺氧/酸中毒的胎儿会将缺氧诱导的 mRNA 从胎儿胎盘单位上调并释放到母体循环中，在那里可以对其进行采样和定量。此外，我们假设母体循环中缺氧诱导的 mRNA 的丰度与胎儿宫内缺氧/酸中毒的严重程度相关。因此，我们研究了母体循环中缺氧诱导的 mRNA 的丰度是否与胎儿宫内缺氧的程度相关。
我们进行了两项队列的前瞻性研究：1）对进行引产的孕妇进行纵向研究（引产会导致急性胎儿缺氧）；2）患有严重早产生长受限的妊娠。对于每个队列，我们将母体血液中的缺氧诱导 mRNA 与胎儿在宫内的最后时刻的缺氧程度相关联，这通过出生时获得的脐动脉 pH 值或乳酸水平来证明。采集妊娠组织和母体血液，通过微阵列和 RT-PCR 定量 mRNA。
母体血液中的缺氧诱导 mRNA 在分娩过程中逐渐升高，这是一个导致急性胎儿缺氧的事件。它们在第二产程中急剧增加，这是一个特别缺氧的事件。重要的是，缺氧基因评分（四个缺氧诱导基因的相对表达之和）与出生时的胎儿酸中毒强烈相关。在携带严重生长受限早产儿的孕妇的血液中，也增加了缺氧诱导的 mRNAs，这是胎儿慢性缺氧的一种情况。缺氧基因评分与胎儿血管中超声多普勒血流速度异常的严重程度相关。重要的是，在这个生长受限队列中，缺氧基因评分（来源于母体血液中的 mRNA 丰度）与出生时胎儿酸中毒的程度显著相关。
母体血液中循环的编码缺氧诱导基因的 mRNA 丰度与胎儿缺氧/酸中毒的程度密切相关。测量母体血液中的缺氧诱导 mRNA 可能为一种新型的非侵入性测试提供基础，以在宫内确定胎儿缺氧/酸中毒的程度。
