Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study

Autoři: Robyn E. Elphinstone aff001;  Andrea M. Weckman aff001;  Chloe R. McDonald aff001;  Vanessa Tran aff001;  Kathleen Zhong aff001;  Mwayiwawo Madanitsa aff002;  Linda Kalilani-Phiri aff002;  Carole Khairallah aff003;  Steve M. Taylor aff004;  Steven R. Meshnick aff004;  Victor Mwapasa aff002;  Feiko O. ter Kuile aff003;  Andrea L. Conroy aff006;  Kevin C. Kain aff001
Působiště autorů: Sandra Rotman Centre for Global Health, University Health Network-University of Toronto, Toronto, Ontario, Canada aff001;  College of Medicine, University of Malawi, Blantyre, Malawi aff002;  Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom aff003;  Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America aff004;  Division of Infectious Diseases and Duke Global Health Institute, Duke University, Durham, North Carolina, United States of America aff005;  Department of Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America aff006
Vyšlo v časopise: Early malaria infection, dysregulation of angiogenesis, metabolism and inflammation across pregnancy, and risk of preterm birth in Malawi: A cohort study. PLoS Med 16(10): e32767. doi:10.1371/journal.pmed.1002914
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pmed.1002914



Malaria in pregnancy is associated with adverse birth outcomes. However, the underlying mechanisms remain poorly understood. Tight regulation of angiogenic, metabolic, and inflammatory pathways are essential for healthy pregnancies. We hypothesized that malaria disrupts these pathways leading to preterm birth (PTB).

Methods and findings

We conducted a secondary analysis of a randomized trial of malaria prevention in pregnancy conducted in Malawi from July 21, 2011, to March 18, 2013. We longitudinally assessed circulating mediators of angiogenic, metabolic, and inflammatory pathways during pregnancy in a cohort of HIV-negative women (n = 1,628), with a median age of 21 years [18, 25], and 562 (35%) were primigravid. Pregnancies were ultrasound dated, and samples were analyzed at 13 to 23 weeks (Visit 1), 28 to 33 weeks (Visit 2), and/or 34 to 36 weeks (Visit 3). Malaria prevalence was high; 70% (n = 1,138) had PCR-positive Plasmodium falciparum infection at least once over the course of pregnancy and/or positive placental histology. The risk of delivering preterm in the entire cohort was 20% (n = 304/1506). Women with malaria before 24 weeks gestation had a higher risk of PTB (24% versus 18%, p = 0.005; adjusted relative risk [aRR] 1.30, 95% confidence interval [CI] 1.04–1.63, p = 0.021); and those who were malaria positive only before week 24 had an even greater risk of PTB (28% versus 17%, p = 0.02; with an aRR of 1.67, 95% CI 1.20–2.30, p = 0.002). Using linear mixed-effects modeling, malaria before 24 weeks gestation was associated with altered kinetics of inflammatory (C-Reactive Protein [CRP], Chitinase 3-like protein-1 [CHI3L1], Interleukin 18 Binding Protein [IL-18BP], soluble Tumor Necrosis Factor receptor II [sTNFRII], soluble Intercellular Adhesion Molecule-1 [sICAM-1]), angiogenic (soluble Endoglin [sEng]), and metabolic mediators (Leptin, Angiopoietin-like 3 [Angptl3]) over the course of pregnancy (χ2 > 13.0, p ≤ 0.001 for each). Limitations include being underpowered to assess the impact on nonviable births, being unable to assess women who had not received any antimalarials, and, because of the exposure to antimalarials in the second trimester, there were limited numbers of malaria infections late in pregnancy.


Current interventions for the prevention of malaria in pregnancy are initiated at the first antenatal visit, usually in the second trimester. In this study, we found that many women are already malaria-infected by their first visit. Malaria infection before 24 weeks gestation was associated with dysregulation of essential regulators of angiogenesis, metabolism, and inflammation and an increased risk of PTB. Preventing malaria earlier in pregnancy may reduce placental dysfunction and thereby improve birth outcomes in malaria-endemic settings.

Klíčová slova:

Histology – Inflammation – Labor and delivery – leptin – Malaria – Pregnancy – Preterm birth – placenta


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Interní lékařství

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PLOS Medicine

2019 Číslo 10
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