Fetal growth restriction (FGR) is a leading cause of perinatal mortality, yet no reliable screening test exists. Placental specific mRNA in the maternal circulation may reflect changes in the placental transcriptome and could be novel biomarkers for placental function. Identifying genes that are very highly expressed in placenta (relative to all other tissues) may therefore be a promising strategy to identify biomarkers of FGR. This approach would also bias detection of transcripts that are mainly placentally derived rather than maternal, making them ideal biomarkers. Therefore we sought to identify placental specific RNA detectable in the maternal circulation and examine whether they are differentially expressed in severe preterm FGR.
Using in silico analysis of microarray repository data, we identified 137 genes that were very highly expressed in the placenta relative to other tissues. The expression of these 137 genes in the maternal blood from pregnancies complicated by severe preterm FGR and preterm controls was then analysed using microarray. We found all 137 genes were detectable in the maternal blood and were globally dysregulated with preterm FGR: 64 genes (46%) had a ≥1.5 fold differential expression compared to controls. Eight of these genes (ERVWE-1, PSG1, PLAC4, TAC3, PLAC3, CRH, CSH1 and KISS1) were then validated by RT-PCR and confirmed to be significantly increased in both maternal blood and placenta in a larger cohort of severe FGR compared to controls. Finally, in situ hybridization confirmed PAPPA2 and ERVWE-1 localised to the syncytiotrophoblast in the placenta, the likely source of free RNA in the maternal circulation.
In conclusion, we found global differential expression of placental specific mRNA in the maternal blood in pregnancies complicated by severe preterm FGR. Therefore placental specific mRNA in maternal blood may represent a new class of biomarker for preterm FGR, and reduce the risk of stillbirth in these pregnancies.