<p class="first" id="d6433670e241">The signals and mechanisms that synchronize the
timing of human parturition remain
a mystery and a better understanding of these processes is essential to avert adverse
pregnancy outcomes. Although our insights into human labor initiation have been informed
by studies in animal models, the timing of parturition relative to fetal maturation
varies among viviparous species, indicative of phylogenetically different clocks and
alarms; but what is clear is that important common pathways must converge to control
the birth process. For example, in all species, parturition involves the transition
of the myometrium from a relaxed to a highly excitable state, where the muscle rhythmically
and forcefully contracts, softening the cervical extracellular matrix to allow distensibility
and dilatation and thus a shearing of the fetal membranes to facilitate their rupture.
We review a number of theories promulgated to explain how a variety of different timing
mechanisms, including fetal membrane cell senescence, circadian endocrine clocks,
and inflammatory and mechanical factors, are coordinated as initiators and effectors
of parturition. Many of these factors have been independently described with a focus
on specific tissue compartments.
</p><p id="d6433670e243">In this review, we put forth the core hypothesis that fetal
membrane (amnion and chorion)
senescence is the initiator of a coordinated, redundant signal cascade leading to
parturition. Whether modified by oxidative stress or other factors, this process constitutes
a counting device, i.e. a clock, that measures maturation of the fetal organ systems
and the production of hormones and other soluble mediators (including alarmins) and
that promotes inflammation and orchestrates an immune cascade to propagate signals
across different uterine compartments. This mechanism in turn sensitizes decidual
responsiveness and eventually promotes functional progesterone withdrawal in the myometrium,
leading to increased myometrial cell contraction and the triggering of parturition.
Linkage of these processes allows convergence and integration of the gestational clocks
and alarms, prompting a timely and safe birth. In summary, we provide a comprehensive
synthesis of the mediators that contribute to the timing of human labor. Integrating
these concepts will provide a better understanding of human parturition and ultimately
improve pregnancy outcomes.