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In American journal of obstetrics & gynecology MFM

BACKGROUND : Preterm birth remains a major public health issue affecting 10% of all pregnancies and increases risks of neonatal morbidity and mortality. Approximately 50-60% of preterm births are spontaneous, resulting from preterm premature rupture of membranes or preterm labor. The pathogenesis of spontaneous preterm birth is incompletely understood, and prediction of preterm birth remains elusive. Accurate prediction of preterm birth would reduce infant morbidity and mortality through targeted patient referral to hospitals equipped to care for preterm infants. Two prior studies have analyzed cervical microRNA (miRNA) in association with spontaneous preterm birth and the length of gestation, but the extent to which miRNA serve as predictive biomarkers remains unknown.

OBJECTIVE(S) : We sought to examine associations between cervical miRNA expression and spontaneous preterm birth, with the specific goal of identifying a subset of miRNA that predict spontaneous preterm birth.

STUDY DESIGN : We performed a prospective, nested, case-control study of 25 cases with spontaneous preterm birth and 49 term controls. Controls were matched to cases 2:1 based on age, parity, and self-identified race. Cervical swabs were collected at a mean gestational age of 17.1 (4.8) weeks of gestation, and miRNA were analyzed using a quantitative polymerase chain reaction array. Normalized miRNA expression was compared between cases and controls, and a false discovery rate of 0.2 was applied to account for multiple comparisons. Histopathologic analysis of slides of cervical swab samples was performed to quantify leukocyte burden for adjustment in conditional regression models. We explored the use of Relief-based unsupervised identification of top miRNA and support vector machines to predict spontaneous preterm birth. We performed miRNA enrichment analysis to explore potential biologic targets and pathways in which upregulated miRNA might be involved.

RESULTS : Of the 754 miRNA on the PCR array, 346 were detected in at least 75% of participants' cervical swabs. Average cervical miRNA expression was significantly higher in cases of spontaneous preterm birth than controls (P=0.01). There were 95 individual miRNA significantly upregulated (>2-fold change) in cases of subsequent spontaneous preterm birth compared with term controls (P<0.05 and q<0.2). Notably, miR-143, miR-30e-3p, and miR-199b were all significantly upregulated, which is consistent with the one prior study of cervical miRNA and spontaneous preterm birth. A Relief-based, novel variable (feature) selection machine learning approach had low to moderate prediction accuracy with an area under the receiver operator curve of 0.71. Enrichment analysis revealed that identified miRNA may modulate inflammatory cell signaling.

CONCLUSION(S) : In this prospective nested case-control study of cervical miRNA expression and spontaneous preterm birth, we identified a global increase in miRNA expression and up-regulation of 95 distinct miRNA in association with subsequent spontaneous preterm birth. Larger and more diverse studies are required to determine the ability of miRNA to accurately predict spontaneous preterm birth, as well as mechanistic work to facilitate development of novel therapeutic interventions to prevent spontaneous preterm birth.

Burris Heather H, Gerson Kristin D, Woodward Alexa, Redhunt Allyson, Ledyard Rachel, Brennan Kasey, Baccarelli Andrea A, Hecht Jonathan L, Collier Ai-Ris Y, Hacker Michele R


Cervix, epigenomics, miRNA, microRNA, non-coding RNA, pregnancy, preterm birth, spontaneous preterm birth