Clinicopathologic and molecular landscape of villitis of unknown etiology: insights from a large‐scale case–control study in PR China

Abstract Villitis of unknown etiology (VUE) is a chronic placental inflammatory lesion characterized by lymphohistiocytic infiltration and destruction of villous architecture in the absence of infection. Although VUE is well recognized for its association with fetal growth restriction and adverse pregnancy outcomes, its clinicopathologic correlates and molecular basis remain poorly understood. VUE cases were identified from the pathology database of Jinan Maternal and Child Health Hospital (2020–2023) and classified as high‐grade or low‐grade according to the Amsterdam criteria. Clinical data, maternal complications, and neonatal outcomes were collected from electronic medical records. Multivariable logistic regression was used to determine independent risk factors. RNA sequencing was performed on 28 placental samples (24 VUE and 4 controls) to identify differentially expressed genes and pathways. A total of 970 cases (381 high‐grade and 589 low‐grade) and 980 controls were included. VUE prevalence was 5.8%. Hypertensive disorders of pregnancy (HDP) were independently associated with VUE occurrence (odds ratio 1.67, 95% CI 1.28–2.19, p < 0.001). VUE placentas frequently exhibited chronic intervillositis, chronic deciduitis, and avascular villi, whereas maternal vascular malperfusion showed no significant difference from controls. High‐grade VUE was significantly associated with low‐birth‐weight, small‐for‐gestational‐age infants, and increased neonatal intensive care unit admissions, indicating a severity‐dependent impact on neonatal outcomes. Transcriptomic profiling revealed robust upregulation of interferon‐inducible, cytotoxic, and chemokine genes – most notably GBP5 , CXCL9 , and CXCL10 – with enrichment of interferon‐γ, IL‐6/JAK/STAT3, TNF‐α/NF‐κB, and antigen presentation pathways. VUE, particularly its high‐grade form, is a significant placental lesion associated with HDP, adverse neonatal outcomes, and avascular villi. Its distinct interferon‐rich molecular profile, consistent with a maternal anti‐fetal T‐cell–mediated process, underscores its clinical and biological importance. GBP5 emerges as a potential biomarker of interferon‐driven inflammation, providing new mechanistic insight and diagnostic relevance for placental immune injury.