Maternal opioid use with and without hepatitis C infection disrupts the structure and immune landscape of the maternal-fetal interface

Maternal opioid use disorder (OUD) poses significant risks to maternal and fetal health. Adverse outcomes associated with maternal OUD are believed to be mediated, in part, by changes in placenta structure and function; however, few studies have addressed this question. Here, we utilized a combination of flow cytometry, histology, spatial and single-cell transcriptomics to uncover the impact of OUD on placental tissues. Given that nearly half of subjects with chronic OUD contract hepatitis C (HCV), we further stratified our findings by maternal HCV status. Our results indicate that maternal OUD leads to a higher incidence of vascular malperfusion accompanied by increased levels of inflammatory markers and dysregulated secretion of placental development factors. Furthermore, spatial transcriptomics revealed that maternal OUD disrupts the communication between trophoblasts and immune cells important for placental vascular development. Additionally, CellChat analysis revealed aberrant VEGF and FN1 signaling across trophoblast, endothelial, and myeloid cells. Processes associated with tissue homeostasis and repair were also downregulated across trophoblast and leukocytes. Frequencies and responses to ex-vivo stimulation of decidual macrophages and cytolytic NK cells, critical for tissue remodeling and fetal tolerance, were decreased. Finally, transcriptional analyses of placental leukocytes also indicate shifts towards more regulatory/tissue surveillant phenotypes. Altogether, these results highlight the significant disruptions to placental health by maternal OUD. One Sentence SummaryMaternal opioid use disorder {+/-} hepatitis C coinfection disrupts placental structure, immune function, and cell-cell communication.