Compartment-specific soluble immune profiles associated with preterm birth, perinatal death, and low birthweight in pregnant individuals living with HIV.

Human immunodeficiency virus (HIV) infection in pregnancy is associated with preterm birth (PTB), low birthweight (LBW), and perinatal death (PND). Although antiretroviral therapy (ART) suppresses viral load it does not prevent HIV-associated adverse pregnancy outcomes or resolve inflammation. As circulating maternal immune factors may not fully capture maternal-fetal interface immune dysregulation, this observational cohort study aimed to identify localized and systemic immune factors associated with PTB, LBW and PND in ART-treated pregnant people living with HIV (PPLWH). We enrolled 118 PPLWH in Kinshasa, Democratic Republic of the Congo, during the second or third trimester. We collected maternal peripheral plasma (at enrollment, 1-3 days post-delivery, and postpartum) alongside umbilical cord and placental plasma at delivery. Concentrations of 45 immune factors were measured via LegendPlex and ELISAs and associations analyzed using Kruskal-Wallis tests with Dunn's correction or Mann-Whitney tests. Placental plasma exhibited the highest overall concentrations of immune factors, highlighting a distinct localized microenvironment. Among 118 pregnancies, 35 (30%) resulted in PTB, 10 (9%) in PND, and 9 (8%) in LBW. Compared to term births, PTB was associated with higher levels of the chemokines CCL20, CXCL9, and CXCL10 in cord and/or postdelivery plasma (p<0.01), while placental CCL20 levels were lower (p<0.05). Compared to live births, PND was associated with higher postdelivery CXCL1, cord IL-8, placental MPO and NGAL (p<0.05); higher postdelivery CXCL5 (p<0.01); and higher S100A8/A9 levels in cord and postdelivery plasma (p<0.01 and p<0.001, respectively). Finally, LBW was associated with higher enrollment IL-18 and S100A8/A9 levels (p<0.05 and p<0.01, respectively); as well as higher SAA levels in postdelivery and postpartum plasma (p<0.05). In ART-treated PPLWH, distinct adverse birth outcomes are driven by time- and compartment-specific immune pathways. PTB is associated with localized T-cell chemokine responses, PND with neutrophil recruitment and activation, and LBW with pro-inflammatory cytokine and acute-phase protein responses. These pathways provide mechanistic insights into pregnancy complications in PPLWH and highlight potential compartment-specific biomarkers for risk stratification.