Progesterone regulation of cervix ripening in preterm and term birth in mice.

In brief: With an automated image analysis approach using artificial intelligence and machine learning, cytoarchitectural and spatial characteristics of prepartum cervix remodeling occur before term and preterm birth with loss of response to progesterone. Evaluation of local features of inflammation associated with prepartum cervix remodeling may distinguish pathophysiological from physiological processes to reduce risk of adverse pregnancy outcomes. Abstract: The cervix functions as a gatekeeper barrier to maintain pregnancy and virtually vanishes for birth. Cervix remodeling occurs well before term while progesterone (P4) is at or near peak in maternal circulation. The inflammatory ripening process is associated with reduced cell nuclei (CN) density, increased density of resident macrophages (Mφs), and reduced cross-linked collagen in stroma. Whether a functional or actual loss of response to P4 regulates cytomorphological characteristics associated with prepartum ripening at term was the focus of the present study. In a murine model, ovariectomy on pregnancy day 16 produced preterm birth (<24 h, Ovx) in mice with an oil-filled implant, while P4 treatment (Ovx + P4) and controls (PP) birthed at term. Cytoarchitecture of cervix remodeling (reduced CN/area and cross-linked collagen degradation) was advanced in Ovx compared to control mice, but forestalled by sustained plasma P4 in Ovx + P4 mice. Loss of response to P4 was also evident at term by increased resident Mφs in controls and Ovx + P4 PP mice from initial responses. By contrast, births were delayed or did not occur in ovary-intact mice given P4. Adverse pregnancy outcomes and dystocia were associated with arrest of prepartum cervix ripening. A novel spatial morphometric approach found Mφ-stain area/Mφ/CN increased during prepartum ripening versus that on preterm or term birth. This biomarker for local inflammation was blocked in intact + P4 mice. Mφ area, as indicative of alternative activation versus smaller-sized inflammatory phenotypes, collectively suggests loss of prepartum cervix P4 responses in the final common pathway for term and preterm parturition.