Macrophage Switching in Pregnancy: Regulatory Mechanisms Governing Term Labour and Preterm Birth

ABSTRACT Macrophages play a pivotal role in the immune adaptations required for pregnancy, influencing both term and preterm labour (PTL) through their activation and polarisation. These immune cells originate from the yolk sac, foetal liver, and bone marrow, differentiating into diverse subtypes, including pro‐inflammatory (M1) and anti‐inflammatory (M2) macrophages. The dynamic transition between these states, termed macrophage switching, is crucial for maintaining pregnancy and orchestrating labour. This switch is tightly regulated by hormones, cytokines and immune signals, ensuring a controlled inflammatory response at term whilst preventing pathological inflammation leading to preterm birth. During term labour, macrophages accumulate in the cervix, decidua and myometrium, responding to signals from placental aging, foetal lung maturation and endocrine changes. They secrete pro‐inflammatory cytokines (TNF‐α, IL‐1β and IL‐6), matrix metalloproteinases (MMPs) and prostaglandins, promoting uterine contractions and cervical remodelling. The sources of these macrophages include maternal monocytes recruited from circulation and resident decidual macrophages (DMs). In contrast, PTL often arises from dysregulated macrophage activation due to infection, sterile inflammation, or stress signals, triggering an early pro‐inflammatory shift. Premature M1 dominance leads to excessive inflammation, extracellular matrix degradation and foetal membrane rupture. Understanding the mechanisms regulating macrophage switching in PTL, including TLR signalling and hormonal modulation, may uncover therapeutic targets and suitable interventions. This review explores the origins, activation, and functional switching of macrophages in term and preterm labor, emphasising their regulatory mechanisms and potential interventions to prevent preterm birth.