Intestinal barrier disruption with Plasmodium falciparum infection in pregnancy and risk of preterm birth: a cohort study

BACKGROUND: Malaria in early pregnancy is a risk factor for preterm birth and is associated with sustained inflammation and dysregulated angiogenesis across gestation. This study investigated whether malaria is associated with increased gut leak and whether this contributes to systemic inflammation, altered angiogenesis, and preterm birth. METHODS: We quantified plasma concentrations of gut leak markers, soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP) from 1339 HIV-negative pregnant Malawians at <24 weeks gestational age. We assessed the relationship of sCD14 and LBP concentrations with markers of inflammation, angiogenesis, and L-arginine bioavailability and compared them between participants with and without malaria, and with and without preterm birth. FINDINGS: Plasma concentrations of sCD14 and LBP were significantly higher in participants with malaria and were associated with parasite burden (p < 0.0001, both analyses and analytes). The odds ratio for preterm birth associated with one log sCD14 was 2.67 (1.33 to 5.35, p = 0.006) and 1.63 (1.07–2.47, p = 0.023) for LBP. Both gut leak analytes were positively associated with increases in proinflammatory cytokines CRP, sTNFR2, IL18-BP, CHI3L1 and Angptl3 (p < 0.05, all analytes) and sCD14 was significantly associated with angiogenic proteins Angpt-2, sENG and the sFLT:PlGF ratio (p < 0.05, all analytes). sCD14 was negatively associated with L-arginine bioavailability (p < 0.001). INTERPRETATION: Malaria in early pregnancy is associated with intestinal barrier dysfunction, which is linked to an increased risk of preterm birth. FUNDING: Open Philanthropy, 10.13039/501100000024Canadian Institutes of Health Research, Canada Research Chair program, 10.13039/501100001713European and Developing Countries Clinical Trials Partnership, 10.13039/100000865Bill & Melinda Gates Foundation.