Preterm Cervical Ripening in humans

Keywords:

cervical ripening, cytokines, CRH, cervical fibroblasts, HMGB1, preterm labour

G. Ekman-Ordeberg, A. Dubicke

Department of Womens and Childrens’ Health, Division of Obstetrics and Gynecology, Karolinska Institute, 171 76 Stockholm.

Correspondence at: Gunvor.Ekman-Ordeberg@ki.se

Abstract

Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity. Despite the current treatment procedures, the incidence of PTB has not changed in the past thirty years. Incomplete understanding of the biological and patophysiological mechanisms underlying preterm delivery is the major obstacle to prevent PTB. Cervical ripening is necessary for vaginal delivery and understanding of preterm cervical ripening is required for developing new treatment strategies. Several important substances such as HMGB1 and its receptors, CRH and its receptors and numerous cytokines are localized in the cervix and undergo distinct changes in labour. Other important ­molecules, such as CRH, CRH-BP, CRH-R1, CRH-R2, HMGB1, TLR2, TLR4, IL-10, IL-12, are localized in the cervical epithelium, also indicating their role in the process of cervical ripening during labour. Furthermore, CRH stimulates IL-8 secretion from both preterm and term cervical fibroblasts. Recent studies from our group show that major ­inflammatory changes occur in the cervix at labour irrespective of gestational age. This indicates that cervical ripening at both term and preterm is an inflammatory process even if no infection is present. However, preterm cervical ripening still entails some differences from term cervical ripening, for example in the down-regulation of mRNA expression of Toll-like receptors (TLR-2 and TLR-4) and IL-12, higher levels of IL-10 in cervical epithelium, and presents different secretion patterns of cervical fibroblasts. Moreover, preterm cervical ripening, like preterm delivery itself, is a multifactorial disorder with pathways which are partly different from those involved in PPROM and infected preterm labour.