Are animal models relevant to key aspects of human parturition?

Abstract

Preterm birth remains the most serious complication of pregnancy and is associated with increased rates of infant death or permanent neurodevelopmental disability. Our understanding of the regulation of parturition remains inadequate. The scientific literature, largely derived from rodent animal models, suggests two major mechanisms regulating the timing of parturition: the withdrawal of the steroid hormone progesterone and a proinflammatory response by the immune system. However, available evidence strongly suggests that parturition in the human has significantly different regulators and mediators from those in most of the animal models. Our objectives are to critically review the data and concepts that have arisen from use of animal models for parturition and to rationalize the use of a new model. Many animal models have contributed to advances in our understanding of the regulation of parturition. However, we suggest that those animals dependent on progesterone withdrawal to initiate parturition clearly have a limitation to their translation to the human. In such models, a linear sequence of events (e.g., luteolysis, progesterone withdrawal, uterine activation, parturition) gives rise to the concept of a "trigger" mechanism. Conversely, we propose that human parturition may arise from the concomitant maturation of several systems in parallel. We have termed this novel concept "modular accumulation of physiological systems" (MAPS). We also emphasize the urgency to determine the precise role of the immune system in the process of parturition in situations other than intrauterine infection. Finally, we accentuate the need to develop a nonprimate animal model whose physiology is more relevant to human parturition. We suggest that the guinea pig displays several key physiological characteristics of gestation that more closely resemble human pregnancy than do currently favored animal models. We conclude that the application of novel concepts and new models are required to advance translational research in parturition.

Endocrine immune interactions in human parturition

“…Mitchell and Taggart have suggested a model of 'modular accumulation of physiological systems' in which multiple interlinking physiological processes develop in parallel until a critical mass is achieved which results in parturition (Mitchell and Taggart, 2009). Their model also describes how the premature and inappropriate activation of some of the 'modules' could result in preterm labour thus such a concept could explain the onset of both term and preterm human labour.…”

Investigations into the mechanisms controlling parturition in cattle

“…For many mammalian species, the signal cascade leading to the initiation of parturition is still poorly understood with the information available pointing toward distinct species-specific differences (Thorburn & Challis 1979, Ló pez Bernal 2001, Zakar & Hertelendy 2007, Mitchell & Taggart 2009). So far the sheep has served as an important animal model and detailed information on the regulatory mechanisms leading to birth is available for this species (for review see Whittle et al (2001)); in the ovine fetus at the end of gestation, maturation of the hypothalamo-pituitary-adrenal (HPA) axis leads to a substantial increase in fetal cortisol, triggering in uninucleated trophoblast cells (UTC) an upregulation of cyclooxygenase 2 (COX2) and of the steroidogenic key enzyme 17a-hydroxlyase-C17, 20-lyase (CYP17).…”

Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on fetal guinea pig brain development.

“…Progesterone is present in high concentrations throughout pregnancy, and plasma concentrations increase in both the maternal and foetal circulations during late gestation in humans, nonhuman primates and guinea pigs (Gilbert Evans et al 2005, Mitchell & Taggart 2009. Levels of allopregnanolone, a major metabolite of progesterone, increase concurrently with progesterone over the course of gestation in both tissues and plasma (Gilbert Evans et al 2005).…”