Human cytomegalovirus at the maternal–fetal interface: an overview of pathogenesis, defence, and interventions

Human cytomegalovirus (HCMV) is the leading infectious cause of congenital disease worldwide and a major contributor to birth defects and neurodevelopmental disorders. Vertical transmission occurs when the virus breaches the maternal-fetal interface, a complex immunological environment where the placenta is in direct contact with either the uterine lining (decidua) or maternal blood covering the syncytium. The present review synthesises current understanding of HCMV pathogenesis at this critical interface, examining viral invasion mechanisms, host immune responses, and immune evasion strategies. We outline the structural and cellular features of the placenta and decidua, highlighting key immune populations such as uterine natural killer cells and their roles in antiviral defence. The present review examines the mechanisms of HCMV dissemination across the placenta alongside placental-specific defences to infection and details on how HCMV subverts both innate and adaptive immunity to establish and maintain infection. Critical gaps in diagnostics, the limited efficacy of current antiviral therapies, and obstacles in vaccine development are reviewed, underscoring the urgent need for prevention strategies. Finally, we assess experimental models, placental explants, primary trophoblast and decidual organoids, and microfluidic placenta-on-chip systems that are advancing insights into cell-type-specific tropism, immune interactions, and mechanisms of transplacental HCMV transmission. Continued research into host-virus interactions at the maternal-fetal interface and improved model systems are critical for developing targeted prevention and treatment strategies to reduce the burden of congenital HCMV infection.