Chronic histiocytic intervillositis: Insights into Immunopathogenesis and prospective treatments

Chronic histiocytic intervillositis (CHI) is a rare placental inflammatory disorder associated with adverse pregnancy outcomes, including fetal growth restriction, miscarriage, and stillbirth. Its diagnosis is made retrospectively via histopathology, limiting timely intervention. This review explores the hypothesis that CHI is an alloimmune condition resulting from aberrant maternal immune responses to paternally derived fetal antigens. Key findings from current literature include perivillous fibrin deposition and maternal mononuclear cell accumulation in the placental intervillous space, both of which disrupt maternal–fetal exchange. Additional evidence points to complement activation, particularly C4d and C5b-9 deposition, increased CD8+ T cell infiltration, and inflammasome pathway involvement, all contributing to placental insufficiency. The role of anti-HLA antibodies remains under investigation, with conflicting data on their presence and clinical significance. However, abnormal HLA class II expression on the syncytiotrophoblast in CHI may facilitate maternal alloimmune recognition and antibody production. Current treatments, including anticoagulants and immunosuppressants, show limited efficacy, and no standardised management exists. The findings underscore a critical need for prospective studies, biomarker discovery, and targeted immunomodulatory therapies. Improved understanding of CHI pathogenesis may facilitate earlier diagnosis, personalised treatment, and prevention of recurrence and primary disease in future pregnancies. • Anti-HLA antibodies may hold higher relevance in CHI versus healthy pregnancies due to HLA-II expression upregulation • Multiple immunological factors are associated with CHI, but understanding of pathophysiology is still unclear • Lack of awareness of this disorder contributes to the poor understanding of CHI pathology and therefore poor pregnancy outcomes and lack of treatment options