Preterm birth (PTB), defined as delivery before 37 completed weeks of gestation, remains a major challenge in obstetric care due to its significant contribution to neonatal morbidity and mortality. PTB can be categorized into spontaneous preterm birth, resulting from spontaneous preterm labor or preterm premature rupture of membranes, and iatrogenic preterm birth, medically indicated due to conditions such as preeclampsia, fetal growth restriction, or placental abruption. While the underlying mechanisms differ, both pathways ultimately lead to early delivery, posing risks to neonatal health. Despite extensive research, the exact mechanisms leading to PTB remain unclear. The pathogenesis of PTB is related, at least in part, to a complex set of biochemical processes that lead to an untimely degradation of the ECM of the fetal membranes [1,2]. In this respect, one of the most intriguing fields of investigation concerns the contribution of miRNAs, small non-coding RNAs that modulate gene expression at the post-transcriptional level, to biological processes relevant to maintaining pregnancy. Changes in the miRNA expression profile in the chorioamniotic membrane, a critical structure for fetal protection and development, have recently been implicated more and more in the pathogenesis of PTB [3].

The chorioamniotic membrane, having the chorion and amnion as constituent layers, offers a multi-functional impact on protection from pathogens, homeostasis of the amniotic fluid, and the processes of inflammatory reactions. However, external and internal stressors such as infections, inflammation, oxidative stress, and mechanical stretch disrupt this tissue equilibrium to cause aberrant expression of miRNAs. These alterations might affect key pathways related to inflammation, extracellular matrix remodeling, and apoptosis in the onset of labor [[4], [5], [6]].

Expression of miRNAs in the fetal membrane has been linked with preeclampsia (miR-210), chorioamnionitis (miR-223, miR-338, and miR-214), and spontaneous preterm birth (miR-199a, miR-202, and miR-214), all causes of preterm labor. Despite these findings, considerable gaps in knowledge still exist on how post-transcriptional regulation, particularly within the amnion and chorion, controls PTB [7].

As seen in the Figure. 1, the present review discusses the factors involved in the fetal membrane that affect miRNA expression patterns, particularly those relevant to preterm labor (Table 1, Table 2). While the primary focus is the chorioamniotic membrane, we have also incorporated relevant findings from placental studies to provide a more integrative and comprehensive perspective. Both tissues engage in bidirectional paracrine signaling, and express overlapping sets of regulatory miRNAs that contribute to pregnancy maintenance and its complications [8]. The interplay of these factors with the regulatory networks mediated by miRNAs will convey the understanding of molecular mechanisms of preterm labor and possibly highlight new biomarkers or therapeutic targets to improve maternal-fetal outcomes.