Intrauterine inflammatory activation, functional progesterone withdrawal, and the timing of term and preterm birth

The central role of inflammatory processes in labour and delivery is now well-recognised. However, the biomolecular, immunological and endocrine mechanisms involved in the labour process, and the clinical manifestations of inflammation in pregnancy, are complex, variable and modulated by factors such as aetiology, ethnicity and gestational age. In this review, evidence is presented of the pivotal relationship between progesterone and inflammation in pregnancy in terms of determining the timing of labour and delivery. The maternal inflammatory burden increases with advancing gestational age in response to endocrine, maturational, physical, metabolic and biochemical drivers, leading to functional progesterone withdrawal necessary for labour and delivery. Variability in the nature, timing and magnitude of these drivers influence the timing of delivery and the likelihood of preterm birth. Pathological inflammatory insults in pregnancy, such as infection, oxidative stress, senescence and maternal allograft rejection, can precipitate preterm birth, often involving common signalling pathways. Intrauterine infection is an important cause of early preterm birth, associated with delivery of the infants at greatest risk of death and disability; however, most preterm deliveries with intrauterine inflammatory activation are not infection-associated. This observation has important diagnostic and therapeutic implications and challenges. The key differences and similarities between infection-associated and sterile inflammation in this context are highlighted, and the clinical implications and significance of these processes and how they might be exploited are discussed.