Hypoxia-inducible factors (HIFs) in early pregnancy: implications for miscarriage

Abstract Miscarriage poses a significant threat to both maternal and fetal health. Its etiology remains unknown, and there are no established effective identification or prevention strategies. A low oxygen environment in early pregnancy is a physiological necessity for embryonic and placental growth. Hypoxia-inducible factors (HIFs) are a family of classic hypoxia signaling molecules, whose expression level may fluctuate abnormally because of imbalance in oxygen levels. Its unusual fluctuations initiate multiple signaling pathways at the maternal–fetal interface and modulate a range of phenotypic changes, including proliferation, differentiation, migration, invasion, angiogenesis, endometrial decidualization, and immune tolerance. Notably, aberrant regulation of these processes may lead to miscarriage. This review aims to clarify how HIF-1α mediates the aberrant regulation of biological processes, including autophagy, metabolic reprogramming, immunity, epigenetics, and angiogenesis, and how these effects impact trophoblasts and other cells at the maternal-fetal interface. These findings provide new insights into potential therapeutic and preventive strategies for miscarriage.