Recent Developments in Macrophages Imbalance and Recurrent Spontaneous Abortion.

Recurrent spontaneous abortion (RSA), defined as two or more consecutive pregnancy losses, remains a significant clinical challenge in reproductive medicine. One of the primary reasons of RSA is abnormal immunological circumstances at the interaction between mother and fetus. Emerging evidence highlights the critical role of immune dysregulation, particularly involving macrophages, in the pathogenesis of RSA. Macrophages, key immune cells in the decidua, exhibit phenotypic plasticity and can polarize into pro-inflammatory M1 or anti-inflammatory M2 subtypes, thereby influencing trophoblast invasion, placental development, and immune tolerance. How the immune system's macrophages balance impacts an embryo's development is therefore essential to study. This review elaborates on the mechanisms by which alterations in transcription factors, signaling pathways, cytokine profiles, epigenetic status, and metabolic reprogramming contribute to pregnancy loss. Such aberrations predominantly drive the polarization shift toward the M1 macrophage phenotype, characterized by an elevated M1/M2 ratio. This imbalance triggers excessive secretion of pro-inflammatory cytokines, impairs trophoblast invasion, and disrupts placental angiogenesis, thereby ultimately inducing adverse pregnancy outcomes and spontaneous abortion. By integrating findings from human studies and animal models, this review aims to provide insights into the immune mechanisms underlying RSA and highlights future research directions for improving clinical outcomes.