The neuroendocrine processes linking stress to prematurity are mediated by placental CRH (reviewed by Wadhwa et al. ). Placental CRH is responsive to stress. In vitro studies of human placental cells have shown that CRH is released from cultured human placental cells in a dose-response manner in response to all the major biological effectors of stress, including cortisol, catecholamines, oxytocin, angiotension II, and IL-1. In vivo studies have also found significant correlations between maternal psychosocial stress and the levels of CRH, ACTH, and cortisol in maternal plasma. Several studies have related early increases in maternal plasma CRH levels to the timing of birth. Hobel and colleagues (1999) conducted serial assessments of CRH levels over the course of gestation and found that women delivering preterm had significantly elevated CRH levels compared with those in women delivering at term, as well as a significantly accelerated rate of increase in CRH levels over the course of their gestations. In addition, they found that maternal psychosocial stress levels at midgestation significantly predicted the magnitude of increase in maternal CRH levels between midgestation and later times of gestation.
These data suggest that the relationship between maternal psychological stress and prematurity may be mediated by prematurely increased levels of expression of placental CRH. As discussed earlier in this chapter, in term parturition placental CRH activation is largely driven by the fetal HPA axis in a forward-feedback loop upon fetal maturation. In preterm parturition it may be the maternal HPA axis (as well as the sympathoadrenal-medullary [SAM] system) that drives placental CRH expression (Wadhwa et al., 2001). Maternal stress results in increased levels of biological effectors of stress, including cortisol and epinephrine, which could activate placental CRH gene expression. Placental CRH, in turn, can stimulate fetal secretion of cortisol and DHEA-S (by activation of the fetal HPA axis) and placental release of estriol and prostaglandins, thereby precipitating preterm delivery (reviewed by Hobel et al., 1998).
Stress can also alter neuroendocrine modulation of immune function, leading to increased susceptibility to intra-amniotic infection or inflammation. Extensive interconnections exist among the SAM system, the HPA axis, and the immune system. Under physiological conditions, the SAM system and the HPA axis suppress the body’s immunoinflammatory responses. A negative-feedback loop exists between the HPA axis and the immune system; proinflammatory cytokines (e.g., IL-1β, TNF-α, and IL-6) stimulate the HPA axis, resulting in the secretion of glucocorticoids. These