Molecular Regulation of Parturition: The Role of the Decidual Clock

Abstract

The timing of birth is a critical determinant of perinatal outcome. Despite intensive research, the molecular mechanisms responsible for the onset of labor both at term and preterm remain unclear. It is likely that a "parturition cascade" exists that triggers labor at term, that preterm labor results from mechanisms that either prematurely stimulate or short-circuit this cascade, and that these mechanisms involve the activation of proinflammatory pathways within the uterus. It has long been postulated that the fetoplacental unit is in control of the timing of birth through a "placental clock." We suggest that it is not a placental clock that regulates the timing of birth, but rather a "decidual clock." Here, we review the evidence in support of the endometrium/decidua as the organ primarily responsible for the timing of birth and discuss the molecular mechanisms that prime this decidual clock.

Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

Figures

Figure 1.

Proposed mechanism of labor at term. Our central hypothesis is that, in the nonpregnant state (A), the myometrium maintains a contractile phenotype and the endometrium is able to respond vigorously to an inflammatory stimulus. In early and midpregnancy (B), factors are put in place to actively suppress myometrial contractility and to alter the endometrial inflammatory response to maintain uterine quiescence and prevent pregnancy loss. As the pregnancy continues into the third trimester, there is a slow withdrawal of these effects leading to the release of biologically active inflammatory mediators (prostaglandins, cytokines, growth factors, chemokines, and reactive oxygen species) at the maternal–fetal interface and ultimately regular phasic uterine contractions and cervical change (C).

Figure 2.

Proposed molecular mechanisms underlying preterm labor. The five major molecular mechanisms thought to be responsible for preterm labor and birth are shown. All converge on a single common pathway (namely, decidual inflammation) with the release of biologically active inflammatory mediators (prostaglandins [PG], cytokines, growth factors, and chemokines) at the maternal–fetal interface leading to regular phasic uterine contractions and cervical change. CRH, corticotropin releasing hormone.

Figure 3.

Biological continuum of preterm birth. CI, cervical insufficiency; FGR, fetal growth restriction; GI, gastrointestinal; PCBs, polychlorinated biphenyl compounds; PTB, preterm birth; RPL, recurrent pregnancy loss; SIDS, sudden infant death syndrome.