Systemic inflammation is associated with malaria and preterm birth in women living with HIV on antiretrovirals and co-trimoxazole

Women living with HIV (WLHIV) have an increased risk of malaria in pregnancy (MiP). It is unclear if MiP in WLHIV causes a systemic inflammatory response and increases the risk of adverse birth outcomes, especially for women receiving antiretroviral therapy (ART) and daily trimethoprim-sulfamethoxazole (TMP/SXT). We analyzed repeated plasma samples in a cohort of malaria-exposed Ugandan WLHIV receiving ART and daily TMP/SXT to examine changes in inflammatory markers across pregnancy and their association with birth outcomes. Concentrations of CHI3L1, CRP, IL-18BP, IL-6, sICAM-1, and sTNFR2 were quantified by ELISA in 1115 plasma samples collected over pregnancy from 326 women. MiP was associated with increased sTNFR2, sICAM-1 and IL-18BP concentrations across pregnancy. Women who delivered preterm had elevated concentrations of sTNFR2 and altered levels of IL-6 during pregnancy. Women with sTNFR2 concentrations in the highest quartile within 6 weeks of delivery had an increased relative risk of preterm birth. Our results indicate that despite daily TMP/SXT, MiP in WLHIV induced a systemic inflammatory response that was associated with an increased risk of preterm birth. These findings highlight the need for additional strategies to protect WLHIV from malaria infection in pregnancy to promote healthy outcomes for mother and child.