Maternal Blood Test May Reveal Severity of Fetal Hypoxia

Jenni Laidman

December 18, 2013

A maternal blood test measuring messenger RNA (mRNA) expression of hypoxia-induced genes may provide a noninvasive method to monitor the severity of fetal hypoxia/acidemia during pregnancy, according to research published online December 9 in BMC Medicine.

Clare Whitehead, MBChB, from the Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Victoria, Australia, and colleagues correlated mRNA expression of hypoxia-related genes in maternal blood to lactate levels in umbilical arterial cord blood in 2 studies: one that sampled maternal blood during induced labor as a measure of acute hypoxia, and a second that sampled maternal blood during pregnancy among women with severe fetal growth restriction (FGR) as a measure of chronic hypoxia.

The researchers developed a hypoxia gene expression score that showed a highly significant correlation between hypoxia gene expression in maternal blood at the moment of birth and fetal lactate concentrations (r, 0.81; P < .0001).

In the induced labor study, maternal blood samples were taken from 30 women before induction, at the start of uterine contractions, at the beginning of second-stage labor, and at delivery. Immediately after birth, researchers tested umbilical cord blood lactate levels; lactate levels higher than 6 mmol/L were considered hypoxic. Mothers in the hypoxic cohort were matched by gestation, parity, and maternal characteristics to mothers whose umbilical cord blood did not indicate hypoxia.

Genome-wide microarray analysis of both fetal and maternal blood taken at the moment of birth revealed an overrepresentation of hypoxia-associated pathways in the hypoxia cohort compared with samples from mothers and infants in the control group. Similarly, quantitative real-time reverse-transcription polymerase chain reaction (PCR) showed upregulation of 4 hypoxia-induced transcripts in both fetal and maternal blood from the hypoxic cohort compared with the control cohort. The up-regulated genes are hypoxia inducible factor 1α (Hif1α), Hif2α, adrenomedullin (Adm), and lactate dehydrogenase A (LdhA). The investigators also found that the same genes were upregulated in placental tissue in the hypoxia cohort compared with that of the control cohort.

By summing the relative expression of Hif1α, Hif2α, Adm, and LdhA, Dr. Whitehead and colleagues developed a hypoxia gene expression score that found a significant correlation between maternal hypoxia gene expression and fetal acidemia.

In the second study looking at chronic hypoxia, researchers compared blood samples from 20 women carrying severely growth-restricted fetuses with 30 control patients who had normal-growth fetuses delivered at term without complications. The 2 groups were matched by gestation, parity, and maternal characteristics. In addition, researchers collected placental samples from 8 preterm infants of appropriate growth, without hypertensive disease and without histological evidence of chorioamnionitis. The researchers included only FGR placenta samples from infants delivered via caesarean section to avoid any complication from the acute hypoxia of labor.

Microarray analysis of maternal blood mRNA showed overrepresentation of hypoxia pathways in the FGR cohort compared with the control cohort. PCR confirmed that Hif1α, Hif2α, Adm, and LdhA were significantly upregulated in maternal blood in the FGR cohort and in FGR placentas compared with gestation-matched preterm placentas not complicated by FGR and placentas from healthy term pregnancies.

Researchers found a strong correlation (r, 0.76; P = .008) between hypoxia gene expression score in maternal blood samples of the FGR cohort on the day of delivery with fetal acidemia as determined by umbilical pH at birth.

Fetal acidemia is associated with perinatal death or complications, the authors note. For example, a previous study of 604 neonates delivered at 33 or fewer weeks' gestation showed that an umbilical cord pH of 7.20 or less was associated with a likelihood ratio for fetal death of 4.2.

"Therefore, a non-invasive test that can estimate fetal acidemic status could help clinicians' better time delivery," the authors write.

This research was supported by the National Health and Medical Research Council, the Viertel Charitable Foundation, the Royal Australian and New Zealand College of Obstetricians and Gynecologists (Arthur Wilson Fellowship, Luke Proposch Perinatal Scholarship), and ANZ Trustees. The authors have disclosed no relevant financial relationships.

BMC Med. Published online December 11, 2013. Full text

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