Maternal opioid use and hepatitis C infection disrupt the placental immune landscape and structure.

Maternal opioid use disorder (OUD) poses substantial risks to maternal and fetal health. These adverse outcomes are believed to be mediated, in part, by changes in placental structure and function; however, few studies have addressed this question. Here, we utilized flow cytometry, histology, and spatial and single-cell transcriptomics to uncover the impact of OUD on placental tissues. Given that half of individuals with chronic OUD contract hepatitis C (HCV), we further stratified our findings by maternal HCV status. Our results indicate that OUD leads to higher incidence of vascular malperfusion accompanied by increased levels of inflammatory markers and dysregulated secretion of placental development factors. Spatial transcriptomics revealed that OUD disrupts the communication between trophoblasts and immune cells important for placental vascular development. Additionally, CellChat analysis revealed aberrant vascular remodeling, neuropeptide, and chemotactic signaling across trophoblast, endothelial, and myeloid cells. Processes associated with tissue homeostasis and repair were also upregulated across trophoblasts and leukocytes. In addition, placental leukocytes were rewired toward regulatory/tissue surveillant phenotypes. Finally, frequencies and responses to ex vivo stimulation of decidual macrophages and cytolytic NK cells, critical for tissue remodeling and fetal tolerance, were decreased. Altogether, these results highlight substantial disruptions to placental health by maternal OUD.