Contributions to the dynamics of cervix remodeling prior to term and preterm birth

Abstract

Major clinical challenges for obstetricians and neonatologists result from early cervix remodeling and preterm birth. Complications related to cervix remodeling or delivery account for significant morbidity in newborns and peripartum mothers. Understanding morphology and structure of the cervix in pregnant women is limited mostly to the period soon before and after birth. However, evidence in rodent models supports a working hypothesis that a convergence of factors promotes a physiological inflammatory process that degrades the extracellular collagen matrix and enhances biomechanical distensibility of the cervix well before the uterus develops the contractile capabilities for labor. Contributing factors to this remodeling process include innervation, mechanical stretch, hypoxia, and proinflammatory mediators. Importantly, the softening and shift to ripening occurs while progesterone is near peak concentrations in circulation across species. Since progesterone is required to maintain pregnancy, the premise of this review is that loss of responsiveness to progesterone constitutes a common final mechanism for remodeling the mammalian cervix in preparation for birth at term. Various inputs are suggested to promote signaling between stromal cells and resident macrophages to drive proinflammatory processes that advance the soft cervix into ripening. With infection, pathophysiological processes may prematurely drive components of this remodeling mechanism and lead to preterm birth. Identification of critical molecules and pathways from studies in various rodent models hold promise for novel endpoints to assess risk and provide innovative approaches to treat preterm birth or promote the progress of ripening at term.

Keywords: cervix; extracellular matrix; macrophage; parturition; progesterone/progesterone receptor.

Figure 1.

Top. Systemic progesterone as % of pregnancy relative to term of approximately 23 days for rats, 19 days for mice, and 40 weeks for humans [42,46,139]. Bottom. Remodeling characteristics of the rodent cervix as % of term pregnancy as indicated by morphology (cell nuclei density indication of cellular hypertrophy and edema), extracellular collagen degradation (structure and cross-linked content: hydroxyproline and optical density of PSR stained collagen birefringence) [–36,140], and compliance (distensibility). Compliance is a biomechanical term that reflects the decreased slope of cervix stretch associated with disarrayed collagen fibers, elastic extension, increased water content, and increased proteoglycans [18,24]. Peak rate of change in cervix remodeling (shaded area) reflects shift from phase 1 soft to phase 2 ripening cervix [24] between 75% and 90% of pregnancy. During this transition, serum progesterone concentrations are 5- to 8-fold higher than the estrus cycle peak in nonpregnant individuals (NP). Comparable data for cervix remodeling in humans are not available before 95% of term pregnancy.

Figure 2.

Schema of a final common pathway for cervix remodeling that involves the convergence of various contributing factors to regulate local functional withdrawal of progesterone actions. (A) Based on evidence in rodent models with insights from findings in prepartum women [20], the cervix during phase 1 of remodeling with progestational support grows and softens from a nonpregnant (NP) tightly closed dense collagen cross-linked structure. Density of cell nuclei is high while macrophages in stroma are relatively low when the cervix is maximally soft. Subsequently, phase 2 ripening reflects reduced cell nuclei density and increased residency by macrophages with divergent phenotypes that are proposed to facilitate degradation of the extracellular matrix, sustain tensile strength [36], and promote distensibility [42,75,141]. (B) Multiple factors that include neural and proinflammatory stimuli are proposed to regulate the timing and pace of remodeling. Critical for phase 2 ripening is the loss of progesterone effects to sustain a soft cervix. Cells that contain genomic PRs [35,142] in the stroma, in proximity to most resident to macrophages, and possibly luminal epithelia would integrate local signals to guide phenotypic activities and prostaglandin metabolism [143]. Macrophages are a possible source for prostaglandin production. Increased prostaglandin F2α (PGF2α) production has been found to upregulate PR-A [111], a possible mechanism to induce a functional progesterone withdrawal in the cervix between about 75% and 85% of pregnancy. Conceivably, the crosstalk between stroma cells and macrophages could be mediated by paracrine signals that include proinflammatory and phagocyte-related cytokines, chemokines, hypoxia-linked molecules, as well as nitric oxide, prostaglandins, and VEGF to advance extracellular collagen matrix degradation before the uterus develops contractile capabilities for labor. Progesterone withdrawal, as possibly defined by a shift in PR-A/B isoforms in stromal cells and the actions of prostaglandins, is proposed to drive the ripening process by guiding local macrophage actions. The role of complement, local steroid metabolism, and mechanical stretch may be part of the final common pathway for the physiology of remodeling at term. Along with proinflammatory stimuli (infection) and other pathophysiological input, a threshold may be exceeded to accelerate preterm cervix remodeling and preterm birth.