Pathogenesis of spontaneous preterm birth

Hemorrhage into the tissue factor-rich decidua (abruption) generates thrombin which binds to its protease-activated receptors (1 and 3) to enhance COX-2 expression triggering increased prostaglandin F2 alpha (PGF2alpha) synthesis, as well as matrix metalloproteinases (MMPs), and the potent neutrophile chemoattractant, interleukin (IL)-8. Thrombin-PAR interactions also activate the ERK1/2 MAPK pathway to inhibit decidual cell progesterone receptor (PR) expression and activity, further promoting prostaglandin, protease, and inflammatory cytokine release to cause fetal membrane rupture, cervical change, and myometrial contractions resulting in preterm birth (PTB). Changes in the vaginal microbiome can trigger an ascending genital tract infection (chorioamnionitis) resulting in increased IL-1beta production which in turn induces COX-2 (and prostaglandins), MMPs and IL-8 (with neutrophile infiltration) in the cervix, decidua, and ultimately the myometrium, and amnion-chorion. IL-1beta also activates ERK1/2 MAPK to inhibit PR expression, exacerbating prostaglandin and protease production to cause PTB with or without fetal membrane rupture. Maternal and/or fetal stress-induced and idiopathic premature activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis enhances fetal cortisol production which increases placental CRH expression to create a feed-forward loop of fetal HPA axis activation and cortisol production. CRH has direct proparturition effects and cortisol increases decidual cell production of FKBP51 which inhibits PR action to trigger the parturition cascade and cause PTB. Uterine stretch associated with polyhydramnios and multifetal gestation induces formation of myometrial gap junctions, oxytocin receptors and myosin light chain kinase, and produces amnion-chorion and cervical derived inflammatory cytokines, prostaglandins, and proteases to promote PTB. Patients may have multiple pathogenic pathways active simultaneously.