Immunobiology of Cervix Ripening

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. The maternal immune system in mammals adapts to tolerate the differentiation of novel structures associated with the fetal allograft. Development of two interfaces protect the fetus from rejection and assault by the ecology of the external environment. The internal fetal-maternal interface, as represented by the fetal membranes, placenta, and decidua, is crucial for maintaining maternal inflammatory reactivity for surveillance and responses to pathogens. Discussion of the internal interface is elsewhere and in this special volume (1-3). However, the present review is focused on the external fetal-maternal interface consisting of an amniotic fluid buffer, in a forebag region later in pregnancy as the fetal head engages the lower uterus, and the fetal membranes as they press against the internal os of the cervix. This description of a singleton pregnancy in primates near term applies to rodents, despite anatomical differences in the uterus described below, because observations indicate a single fetal sac engages the internal os of the cervix shortly before labor. The success of this external interface to fend off the biome and virome in the vagina reflects the barrier function of the cervix to protect both the fetus and maternal host structures in the uterus. The cervix barrier function has both immunological and structural components. One part of the mate...

Combination of histochemical analyses and micro-MRI reveals regional changes of the murine cervix in preparation for labor

“…Previously, several studies have proposed that the detection of key biochemical markers can indicate premature cervical ripening (e.g. through presence of immune cells and collagenases, or markers of tissue hydration 9 , 12 , 13 , 43 , 47 ) and subsequent PTB. However, these studies mostly existed in silos, when in reality various mechanisms work together to create a ripened structure of the cervix.…”

“…Thus in this study, we aim to evaluate changes in the microstructure of different cervical sub-regions throughout gestation. Because the cervix in women and mice share many similarities (rev in 43 ), we used a well-known mouse model of pregnancy and term labor. Our study had two objectives: (1) to examine changes associated with cervical ripening and impending delivery by using micro-MRI, and (2) to visualize and quantify these regional morphological and microstructural changes in the mouse cervix by traditional histology and immunohistochemistry methods.…”

Toxicant Disruption of Immune Defenses: Potential Implications for Fetal Membranes and Pregnancy

“…The culmination of a healthy pregnancy is marked with increased prostaglandin secretion, activation of matrix metalloproteinases, and recruitment of immune cells, leading to myometrial contractions, rupture of the membranes, and cervical ripening, respectively (Vadillo-Ortega et al, 1996;Hernandez-Guerrero et al, 2000;Challis et al, 2009;Yellon, 2019). Although our understanding of the role of FM in the initiation of labor remains incomplete, it is widely accepted that they contribute to the parturition pathway.…”

Some Molecular Mechanisms of Cervical Ripening

“…(59,50) Overall, these findings raise the possibility that some balance of immune cell products guides extracellular remodeling to promote softening, ripening, and the capability to dilate. (61) During postpartum repair (Phase 4), the integrity and competence of cervical tissues are recovered to ensure a normal cervical function for subsequent pregnancies. Postpartum remodeling is characterized by decreased HA content, increased expression of genes involved in the assembly of mature collagen, synthesis of matrix proteins that promote a dense connective tissue, and inflammation.…”