Neuropeptide Pathways Controlling the Timing of Birth

The mechanisms regulating gestation length and birth differ markedly between species. In many mammals, corticotropin releasing hormone (CRH) plays a central role in the processes that trigger the progression from uterine quiescence to active labor. This results in processes being well coordinated with the maturation of the fetus and ensures sufficient maturation of fetal organ systems for successful extra-uterine life. In many mammalian species, CRH release and stimulation of the fetal hypothalamic-pituitary-adrenal (HPA) axis, with a consequent rise in cortisol levels, triggers the initiation of labor and birth. The onset of labor in women differs markedly, with initiation processes begun by rising levels of CRH produced by the syncytiotrophoblast of the placenta. This “placental clock” mechanism leads to increased production of estrogens toward term and a rise in the expression of contraction-associated proteins. A premature rise in CRH production leads to preterm labor in some instances; however, many cases of early preterm labor are started independently of these mechanisms and involve intra-uterine infection and inflammation. Oxytocin is a maternal signal triggering labor once the uterine tissues are adequately prepared, and has a role in setting the time of day that labor is initiated. Myometrial stimulation by oxytocin is also important in the final stages of birth for expulsion of the fetus, separation of the placenta, and for reducing postpartum bleeding. Synthetic oxytocin may be used to promote uterine contractions for the augmentation of labor. Recent observations therefore suggest that CRH and oxytocin have key roles in controlling the onset of labor in women, whereas early preterm birth is controlled differently, involving poorly understood inflammatory mechanisms.