Abstract
The cervix is the essential gatekeeper for birth. Incomplete cervix remodeling contributes to problems with delivery at or post-term while preterm birth is a major factor in perinatal morbidity and mortality in newborns. Lack of cervix biopsies from women during the period preceding term or preterm birth have led to use of rodent models to advanced understanding of the mechanism for prepartum cervix remodeling. The critical transition from a soft cervix to a compliant prepartum lower uterine segment has only recently been recognized to occur in various mammalian species when progesterone in circulation is at or near the peak of pregnancy in preparation for birth. In rodents, characterization of ripening resembles an inflammatory process with a temporal coincidence of decreased density of cell nuclei, decline in cross-linked extracellular collagen, and increased presence of macrophages in the cervix. Although a role for inflammation in parturition and cervix remodeling is not a new concept, a comprehensive examination of literature in this review reveals that many conclusions are drawn from comparisons before and after ripening has occurred, not during the process. The present review focuses on essential phenotypes and functions of resident myeloid and possibly other immune cells to bridge the gap with evidence that specific biomarkers may assess the progress of ripening both at term and with preterm birth. Moreover, use of endpoints to determine the effectiveness of various therapeutic approaches to forestall remodeling and reduce risks for preterm birth, or facilitate ripening to promote parturition will improve the postpartum well-being of mothers and newborns.
Highlights
A role for inflammation in parturition and cervix remodeling is not a new concept, a comprehensive examination of literature in this review reveals that many conclusions are drawn from comparisons before and after ripening has occurred, not during the process
The present review focuses on essential phenotypes and functions of resident myeloid and possibly other immune cells to bridge the gap with evidence that specific biomarkers may assess the progress of ripening both at term and with preterm birth
A reduced presence of macrophages with markers associated with adhesion (CD11bhigh) and migration (CD54) were found on the day prior to birth than in mid/late gestation. These results suggest that activities by cervix macrophages are probably not related to migration, but remodeling and extracellular matrix degradation, which are important processes associated with increased biomechanical compliance in preparation for dilation and effective labor as previously described
Summary
In a survey of picrosirius-stained sections that focused on the stroma from ectocervix through endocervix in mice [39], findings provided the first indication that degradation of cross-linked collagen occurred much earlier than previously thought, more than 3 days before birth (Figure 2, top panel) This approach was used to study degradation of collagen in HSV2 infectioninduced cervix ripening and preterm birth [58]. The third component of swelling from inflammation is loss of function—clearly indicated by degradation of collagen structure and greater compliance that eliminates the barrier for birth during prepartum remodeling (described above) These morphological features characterize prepartum cervix remodeling several days before labor, which is estimated to begin, as assessed by an increase in uterus mRNA levels for contraction-associated proteins, by the afternoon of the day before birth within 19 h of appearance of the first pup in mice [62].
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