microRNA expression in the cervix during pregnancy is associated with length of gestation

Preterm birth is a leading cause of infant mortality and can lead to poor life-long health and adverse neurodevelopmental outcomes. The pathophysiologic mechanisms that precede preterm labor remain elusive, and the role that epigenetic phenomena play is largely unstudied. The objective of this study was to assess the association between microRNA (miRNA) expression levels in cervical cells obtained from swabs collected during pregnancy and the length of gestation. We analyzed cervical samples obtained between 16 and 19 weeks of gestation from 53 women in a prospective cohort from Mexico City, and followed them until delivery. Cervical miRNA was extracted and expression was quantified using the NanoString nCounter Analysis System. Linear regression models were used to examine the association between miRNA expression levels and gestational age at delivery, adjusted for maternal age, education, parity, body mass index, smoke exposure, and inflammation assessed on a Papanicolaou smear. We identified 6 miRNAs that were significantly associated with gestational age at the time of delivery, including miR-21, 30e, 142, 148b, 29b, and 223. Notably, per each doubling in miR-21 expression, gestations were 0.9 (95% CI: 0.2–1.5) days shorter on average (<i>P</i> = 0.009). Per each doubling in miR-30e, 142, 148b, 29b, and 223 expression, gestations were shorter by 1.0 to 1.6 days. The predicted targets of the miRNAs were enriched for molecules involved in DNA replication and inflammatory processes. The levels of specific miRNAs in the human cervix during pregnancy are predictive of gestational age at delivery, and should be validated in future studies as potential biomarkers of preterm birth risk.

早产是婴儿死亡的首要病因，还可引发终身健康不良及不良神经发育结局。目前，早产发生前的病理生理机制仍未阐明，表观遗传现象在此过程中所扮演的角色尚鲜有研究。本研究旨在评估妊娠期宫颈拭子采集的宫颈细胞中微小RNA（microRNA, miRNA）表达水平与妊娠时长之间的关联。我们对墨西哥城一项前瞻性队列中53名妊娠16至19周的女性的宫颈样本进行了分析，并随访至其分娩。提取宫颈miRNA，并使用NanoString nCounter分析系统对其表达量进行定量检测。采用线性回归模型检验miRNA表达水平与分娩时胎龄之间的关联，并对产妇年龄、受教育程度、产次、体重指数、吸烟暴露以及巴氏涂片（Papanicolaou smear）评估的炎症状态进行校正。我们鉴定出6种与分娩时胎龄显著相关的miRNA，包括miR-21、30e、142、148b、29b及223。值得注意的是，miR-21表达量每增加1倍，妊娠时长平均缩短0.9天（95%置信区间：0.2–1.5，P=0.009）。miR-30e、142、148b、29b及223的表达量每增加1倍，妊娠时长缩短1.0至1.6天。这些miRNA的预测靶标显著富集于参与DNA复制及炎症过程的分子。妊娠期人体宫颈内特定miRNA的表达水平可预测分娩时的胎龄，有望作为早产风险的潜在生物标志物，有待后续研究进一步验证。