Novel concepts on pregnancy clocks and alarms

Redundancy and synergy in human parturition

Ramkumar Menon, Elizabeth A. Bonney, Jennifer Condon, Sam Mesiano, Robert N. Taylor

Research output: Contribution to journalReview article

63 Citations (Scopus)

Abstract

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.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.

Original languageEnglish (US)
Article numberdmw022
Pages (from-to)535-560
Number of pages26
JournalHuman Reproduction Update
Volume22
Issue number5
DOIs
StatePublished - Sep 1 2016

Fingerprint

Parturition
Pregnancy
Extraembryonic Membranes
Myometrium
Pregnancy Outcome
Chorion
Uterine Contraction
Circadian Clocks
Amnion
Cell Aging
Contracts
Contraception
Extracellular Matrix
Progesterone
Rupture
Dilatation
Oxidative Stress
Animal Models
Hormones
Inflammation

Keywords

  • Aging
  • Corticosteroids
  • Endoplasmic reticulum
  • Labor and delivery
  • NK cells
  • Oxidative stress
  • p38MAPK
  • Progesterone receptors
  • Senescence
  • Unfolded proteins

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology

Cite this

Novel concepts on pregnancy clocks and alarms : Redundancy and synergy in human parturition. / Menon, Ramkumar; Bonney, Elizabeth A.; Condon, Jennifer; Mesiano, Sam; Taylor, Robert N.

In: Human Reproduction Update, Vol. 22, No. 5, dmw022, 01.09.2016, p. 535-560.

Research output: Contribution to journalReview article

Menon, Ramkumar ; Bonney, Elizabeth A. ; Condon, Jennifer ; Mesiano, Sam ; Taylor, Robert N. / Novel concepts on pregnancy clocks and alarms : Redundancy and synergy in human parturition. In: Human Reproduction Update. 2016 ; Vol. 22, No. 5. pp. 535-560.
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