Heparin prevents inflammation-induced pregnancy loss in mice through its anti-inflammatory effects.

Excessive inflammation at the feto-maternal interface is a major contributor to adverse pregnancy outcomes, including miscarriage and preterm birth. Heparin, which is widely used as an anticoagulant, has also been recognized as possessing anti-inflammatory properties; however, its role in inflammation-driven pregnancy complications remains unclear. In this study, we examined whether unfractionated heparin (UFH) prevents inflammation-induced miscarriage and preterm birth in mice. Lipopolysaccharide (LPS)-induced murine models were used to mimic inflammation-driven pregnancy complications. Pregnant C57BL/6 mice were administered LPS to induce miscarriage or preterm birth, with or without UFH treatment. Immunological, histological, and ex vivo analyses were performed to evaluate inflammatory responses and tissue integrity at the feto-maternal interface. UFH markedly reduced both miscarriage rates and the incidence of preterm birth. It decreased the M1/M2 macrophage ratio and suppressed the production of proinflammatory cytokines, including interleukin-12 (IL-12) and tumor necrosis factor-alpha. UFH also reduced interferon-gamma production by T and natural killer T cells, and downregulated Tbx21 expression in decidual tissues, indicating the attenuation of a proinflammatory immune environment. These protective effects were observed without substantial changes in coagulation parameters. Ex vivo experiments further showed that UFH directly suppressed LPS-induced IL-12 production by decidual macrophages. Collectively, these findings indicate that UFH prevents inflammation-induced miscarriage and preterm birth by modulating immune responses at the feto-maternal interface, independent of its anticoagulant activity.