Developing a theoretical evolutionary framework to solve the mystery of parturition initiation

Abstract

Eutherian mammals have characteristic lengths of gestation that are key for reproductive success, but relatively little is known about the processes that determine the timing of parturition, the process of birth, and how they are coordinated with fetal developmental programs. This issue remains one of biology's great unsolved mysteries and has significant clinical relevance because preterm birth is the leading cause of infant and under 5 year old child mortality worldwide. Here, we consider the evolutionary influences and potential signaling mechanisms that maintain or end pregnancy in eutherian mammals and use this knowledge to formulate general theoretical evolutionary models. These models can be tested through evolutionary species comparisons, studies of experimental manipulation of gestation period and birth timing, and human clinical studies. Understanding how gestation time and parturition are determined will shed light on this fundamental biological process and improve human health through the development of therapies to prevent preterm birth.

Keywords: eutherian mammals; evolution; evolutionary biology; medicine; parturition; pregnancy; prematurity; preterm birth.

Figure 1.. Neonatal deaths as a function of gestational age at birth for singleton pregnancies in the US in 2015.

Data reflect outcomes of 3,849,557 pregnancies demonstrating optimal survival between 38 and 40 weeks of completed gestation. This optimal survival time coincides with the peak of birth timing during pregnancy as shown by number of total live births. Drawn from data in JAMA Pediatr. 2018 Jul; 172(7): 627–634 (Ananth et al., 2018).

Figure 2.. Pregnancy-associated traits are influenced by both maternal and fetal genetics.

One framework for studying the maternal and fetal genetic effects in pregnancy is to consider the mother/fetus pair as a unit with three haplotypes, h1, h2, and h3. The maternal-fetal compound genome of pregnancy genetically contributes to maternal phenotypes (blue) through the actions of the maternal transmitted (h1, red) and non-transmitted haplotypes (h2, yellow). Fetal phenotypes are genetically determined by the maternal transmitted (h1) and the paternal transmitted (h3) haplotypes which may display parent of origin effects. The maternal environment, shaped by h1 and uniquely by h2, also influences pregnancy outcomes including pregnancy duration through maternal effects.

Figure 3.. Comparative biochemical strategies for initiating parturition in sheep, mouse, and human species.

The steroids estrogen and progesterone are conserved components, but the tissues involved and superimposed innovations, such as CRH in humans, likely result in divergence of final pathways for birth.

Figure 4.. Testable theoretical models for determining the onset of parturition in eutherian mammals.

Model one represents a fixed clock in the mother or fetus to determine when birth happens (y = 0). The precise day is determined by a physiological rate constant (r) that determines when, for a given woman, birth would occur. The time (t) is measured in months in this representation. Model two reflects a parturition inhibition signal (S_i) that must go below a threshold (th₀) for birth (B) to occur. Model three alternatively proposes a parturition stimulation signal (S_p) that must exceed a threshold for birth to occur. Model four displays that both S_i and S_p are involved in determining the timing for birth, and parturition occurs as a crossover when S_p >S_i.

Figure 5.. Muridae phylogeny and divergence times of the spiny mouse, Mongolian gerbil and house mouse with their associated pregnancy characteristics.

Image of Mongolian gerbil is from https://en.wikipedia.org/wiki/Mongolian_gerbil#/media/File:Meriones_unguiculatus_(wild).jpg, image of spiny mouse from https://commons.wikimedia.org/wiki/File:Acomys.cahirinus.cahirinus.6872.jpg, and image of house mouse from https://en.wikipedia.org/wiki/House_mouse#/media/File:Mouse_white_background.jpg.