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

Abstract

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.

Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation

“…These studies have been thoroughly reviewed elsewhere ( 20 ) and will not be our focus here. Recently, three groups have systematically identified (using RNA-sequencing, RNAseq) and separately validated (using RT-qPCR) changes in gene levels between matched cases and controls for spontaneous PTB ( 3 ), preeclampsia ( 4 ), and IUGR ( 5 ). The aforementioned studies all used samples from distinct collection sites for discovery and validation to increase generalizability.…”

“…Finally, Hannan et al ( 5 ) focused on identifying pregnancies with severe IUGR using whole blood sampled at the time of diagnosis. In validation, they showed that two (EMP1 and PGM5) of the five genes identified during discovery significantly differed between women carrying significantly growth-restricted fetuses and women with uncomplicated pregnancies at the same GA. Like Munchel et al ( 4 ), the ability of this test to identify pregnancy-related complications prior to symptomatic onset remains unknown.…”

“…In practice, applying such a rigid boundary can be tricky but necessary as validation metrics may otherwise prove overly positive. Concretely, building a model during discovery with a set of genes, but refining it in validation to only include a subset that showed significance again ( 5 ), falls into this paradigm. In these cases, although the individual gene changes hold, the aggregate reported statistics for the validation set are likely to be overly optimistic.…”

“…More recently, in the past 5 years, we have witnessed unprecedented leaps in the applications of this technology to monitor prenatal health following its extension to measurements of circulating RNA in whole blood or cell-free RNA (cfRNA) in plasma. Today, circulating and cfRNA measurements have been applied to predict and characterize pregnancy-related complications like spontaneous preterm birth (PTB) ( 3 ), preeclampsia ( 4 ), and intrauterine growth restriction (IUGR) ( 5 ). In contrast to cfDNA levels, cfRNA levels of specific genes change during gestation in predictable ways that map closely with their placental and fetal gene expression ( 3 , 4 , 6 – 9 ).…”

Real-World Observational Study of Glimepiride and Metformin Fixed-Dose Combination Along With Insulin in the Management of Type 2 Diabetes Mellitus: Indian Experience

“…The findings of the current study corroborate with the reported study demonstrating a strong association between age, BMI, and smoking with a prevalence of diabetes [ 23 ]. Similarly, another study from Africa showed an incidence of hypertension (71%; 95% CI 69-73), hyperlipidemia (34%), and obesity (27%), along with cataract (32%), diabetic retinopathy (15%), impaired renal function (13%), and erectile dysfunction (in men; 35%) [ 24 - 25 ]. In the current study, hypertension (64.7%) and dyslipidemia (39.1%) were the most common comorbidities observed and managed with antihypertensives and statins, respectively.…”