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

Background: 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=1628), with a median age of 21 years [18, 25] and 562 (35%) were primigravid. Pregnancies were ultrasound dated and samples were analyzed at 13-23 weeks (Visit 1), 28-33 weeks (Visit 2), and/or 34-36 weeks (Visit 3). Malaria prevalence was high; 70% (n=1138) 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% vs 18%, p=0.005; adjusted relative risk (aRR) 1.30, 95% 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% vs 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 (CRP, CHI3L1, IL-18BP sTNFRII,), angiogenic (sICAM-1, sEndoglin), and metabolic mediators (Leptin, Angptl3) over the course of pregnancy (χ2 >13.0, p≤0.001 for each). Limitations include being underpowered to assess the impact on non-viable births, being unable to assess women who had not received any anti-malarials, and due to the exposure to antimalarials in the second trimester there were limited numbers of malaria infections late in pregnancy. Conclusions: 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