First Trimester Circulating MicroRNA Biomarkers Predictive of Subsequent Preterm Delivery and Cervical Shortening (original) (raw)

Preterm birth (PTB) is the leading cause of infant death and disability worldwide. The onset of preterm uterine contractions is preceded by asymptomatic cervical remodelling and ripening, which can be seen on trans-vaginal ultrasound as cervical shortening. This study aimed to identify plasma miRNA biomarkers that predict preterm birth and/or cervical shortening. We collected serial plasma samples from pregnant women prospectively from 12 to 22 weeks gestation. The nCounter miRNA assay was used to identify differentially expressed miRNAs associated with spontaneous PTB and/ or cervical shortening (n = 16 term no short, n = 13 preterm, n = 24 short). Predictive values of the miRNA biomarkers were confirmed in an independent validation cohort consisting of 96 women who delivered at term, 14 preterm and 21 early cervical shortening at <20 weeks gestation. Nine miRNAs (hsa-let-7a-5p, hsa-miR-374a-5p, hsa-miR-15b-5p, hsa-miR-19b-3p, hsa-miR-23a-3p, hsa-miR-93-5p, hsa-miR-150-5p, hsa-miR-185-5p and hsa-miR-191-5p) were differentially expressed (P < 0.001) in women subsequently experiencing PTB or cervical shortening. Hsa-miR-150-5p had the strongest ability to predict PTB (AUC = 0.8725) and cervical shortening (AUC = 0.8514). Plasma miRNAs in the first trimester can predict PTB and cervical shortening in women at risk of preterm delivery. This is a key period in pregnancy when early identification of PTB risk allows time to deliver outcome-modifying interventions. Preterm birth (PTB) before 37 weeks of gestation is a complex clinical syndrome with multiple aetiologies 1. It is the leading cause of mortality in children under five years-old worldwide, accounting for more than 1 million deaths per year 2. The onset of labour, both term and preterm, is diagnosed clinically by uterine contractions, but is preceded by cervical remodelling which occurs over many weeks 3. Cervical ripening is associated with an inflammatory signature, including up-regulation of prostaglandins, chemokines and cytokines, inflammatory cell infiltration and increased matrix metalloproteinase activity 4. Cervical remodelling can be observed on trans-vaginal ultrasound (TVUS) as shortening of the cervix. Shortened cervical length (CL) is a risk factor for spontaneous preterm labour (PTL) in both low-and high-risk pregnancies 5. It has been reported that ultrasound measurement of CL at 19-24 weeks detects most PTL <28 weeks and 50% of PTL <37 weeks gestation 5. This is clinically useful in populations already identified as being at high risk of PTL, since interventions (cervical cerclage or progesterone) can reduce the risk of PTB. However, CL measurements using TVUS is not routinely offered to low-risk pregnancies where 60% of all low-risk pregnancies with short cervix at 22-24 weeks deliver <28 weeks of gestation and 90% <32 weeks 6. It has been suggested that universal CL measurement should be introduced into maternity care for all women for the prediction of PTL 7,8 .