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Background  Fetuses affected by placental insufficiency do not receive adequate nutrients and oxygenation, become growth restricted and acidemic, and can demise. Preterm fetal growth restriction is a severe form of placental insufficiency with a high risk of stillbirth. We set out to identify maternal circulating mRNA transcripts that are differentially expressed in preterm pregnancies complicated by very severe placental insufficiency, in utero fetal acidemia, and are at very high risk of stillbirth.    Methods  We performed a cohort study across six hospitals in Australia and New Zealand, prospectively collecting blood from 128 pregnancies complicated by preterm fetal growth restriction (delivery < 34 weeks’ gestation) and 42 controls. RNA-sequencing was done on all samples to discover circulating mRNAs associated with preterm fetal growth restriction and fetal acidemia in utero. We used RT-PCR to validate the associations between five lead candidate biomarkers of placental insufficiency in an independent cohort from Europe (46 with preterm fetal growth restriction) and in a third cohort of pregnancies ending in stillbirth.    Results  In the Australia and New Zealand cohort, we identified five mRNAs that were highly differentially expressed among pregnancies with preterm fetal growth restriction:  NR4A2 ,  EMP1 ,  PGM5 ,  SKIL , and  UGT2B1 . Combining three yielded an area under the receiver operative curve (AUC) of 0.95. Circulating  NR4A2  and  RCBTB2  in the maternal blood were dysregulated in the presence of fetal acidemia in utero. We validated the association between preterm fetal growth restriction and circulating  EMP1 ,  NR4A2 , and  PGM5  mRNA in a cohort from Europe. Combining  EMP1  and  PGM5  identified fetal growth restriction with an AUC of 0.92. Several of these genes were differentially expressed in the presence of ultrasound parameters that reflect placental insufficiency. Circulating  NR4A2 ,  EMP1 , and  RCBTB2  mRNA were differentially regulated in another cohort destined for stillbirth, compared to ongoing pregnancies.  EMP1  mRNA appeared to have the most consistent association with placental insufficiency in all cohorts.    Conclusions  Measuring circulating mRNA offers potential as a test to identify pregnancies with severe placental insufficiency and at very high risk of stillbirth. Circulating mRNA  EMP1  may be promising as a biomarker of severe placental insufficiency.

Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth