Maternal Inflammation During Pregnancy and Cord Blood Metabolomic Signatures in the Context of HIV Exposure.

Background/Objectives: Pregnant people with HIV (PWH) are more likely to experience systemic inflammation than pregnant people without HIV (PWoH), which may contribute to adverse outcomes in HIV-exposed uninfected (HEU) infants; however, the underlying mechanisms are not well studied. This study examined associations between maternal inflammatory markers during pregnancy and cord blood inflammatory markers and metabolomic signatures. Methods: Between 2011 and 2025, pregnant PWH and PWoH were enrolled at 24-28 weeks of gestational age. Maternal plasma was analyzed for inflammatory markers [interleukin (IL)-6, high-sensitivity C-reactive protein (hsCRP), soluble TNF-α receptor 1 (sTNFR1) and 2 (sTNFR2), soluble CD163 (sCD163), soluble CD14 (sCD14)]. At delivery, cord blood was collected for measurement of IL-6, TNF-α, IFN-γ, and IL-10 and for targeted metabolomics by ultra-performance liquid chromatography-mass spectrometry. Spearman correlation, linear regression, and weighted correlation network analysis (WGCNA) were used to evaluate associations, stratified by HIV exposure. Results: This study included 22 PWH and 47 PWoH and their infants. Among HEU infants, but not HUU infants, maternal IL-6 correlated with cord blood TNFα (r = 0.443, p < 0.05) and maternal sTNFR1 correlated with both cord blood TNFα (r = 0.617, p < 0.05) and IFNγ (r = -0.517, p < 0.05). WGCNA identified five metabolomic modules. In the HEU group, naternal sCD14 was positively associated with a metabolomic module characterized by lysophosphotidylecholines in the HEU group. Conclusions: We identified distinct patterns in the relationships between maternal inflammation and infant immune-metabolic profiles by HIV exposure status. These findings suggest that HIV infection, even with viral suppression, may alter the maternal-fetal inflammatory interface and influence early metabolic programming.