Intestinal barrier disruption with Plasmodium falciparum infection in pregnancy and risk of preterm birth: a cohort studyResearch in context
Julie K. Wright,
Andrea M. Weckman,
Michelle Ngai,
Veselina Stefanova,
Kathleen Zhong,
Chloe R. McDonald,
Robyn E. Elphinstone,
Andrea L. Conroy,
Bryan A. Coburn,
Mwayi Madanitsa,
Steve M. Taylor,
Feiko O. ter Kuile,
Kevin C. Kain
Affiliations
Julie K. Wright
Sandra Rotman Centre for Global Health, MaRS Centre, Department of Medicine, University Health Network-Toronto General Hospital, University of Toronto, 101 College St TMDT 10-360A, M5G 1L7, Toronto, ON, Canada; Division of Infectious Diseases, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Andrea M. Weckman
Sandra Rotman Centre for Global Health, MaRS Centre, Department of Medicine, University Health Network-Toronto General Hospital, University of Toronto, 101 College St TMDT 10-360A, M5G 1L7, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Michelle Ngai
Sandra Rotman Centre for Global Health, MaRS Centre, Department of Medicine, University Health Network-Toronto General Hospital, University of Toronto, 101 College St TMDT 10-360A, M5G 1L7, Toronto, ON, Canada
Veselina Stefanova
Sandra Rotman Centre for Global Health, MaRS Centre, Department of Medicine, University Health Network-Toronto General Hospital, University of Toronto, 101 College St TMDT 10-360A, M5G 1L7, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Kathleen Zhong
Sandra Rotman Centre for Global Health, MaRS Centre, Department of Medicine, University Health Network-Toronto General Hospital, University of Toronto, 101 College St TMDT 10-360A, M5G 1L7, Toronto, ON, Canada
Chloe R. McDonald
Sandra Rotman Centre for Global Health, MaRS Centre, Department of Medicine, University Health Network-Toronto General Hospital, University of Toronto, 101 College St TMDT 10-360A, M5G 1L7, Toronto, ON, Canada
Robyn E. Elphinstone
Sandra Rotman Centre for Global Health, MaRS Centre, Department of Medicine, University Health Network-Toronto General Hospital, University of Toronto, 101 College St TMDT 10-360A, M5G 1L7, Toronto, ON, Canada
Andrea L. Conroy
Ryan White Center for Pediatric Infectious Diseases and Global Health, Indiana University School of Medicine, Indianapolis, USA
Bryan A. Coburn
Division of Infectious Diseases, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
Mwayi Madanitsa
Malawi University of Science and Technology, P.O Box 5196, Limbe, Thyolo, Malawi
Steve M. Taylor
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Division of Infectious Diseases and Duke Global Health Institute, Duke University, Durham, NC, USA
Feiko O. ter Kuile
Liverpool School of Tropical Medicine, Liverpool, L35QA, UK
Kevin C. Kain
Sandra Rotman Centre for Global Health, MaRS Centre, Department of Medicine, University Health Network-Toronto General Hospital, University of Toronto, 101 College St TMDT 10-360A, M5G 1L7, Toronto, ON, Canada; Division of Infectious Diseases, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Corresponding author. Sandra Rotman Centre for Global Health, MaRS Centre, Department of Medicine, University Health Network-Toronto General Hospital, University of Toronto, 101 College St TMDT 10-360A, M5G 1L7, Toronto, ON, Canada.
Summary: 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, Canadian Institutes of Health Research, Canada Research Chair program, European and Developing Countries Clinical Trials Partnership, Bill & Melinda Gates Foundation.
