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

Abstract

BackgroundMalaria 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 findingsWe 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.ConclusionsCurrent 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.

Effectiveness of Sulfadoxine–Pyrimethamine for Intermittent Preventive Treatment of Malaria and Adverse Birth Outcomes in Pregnant Women

“…Late initiation of ANC may lead to the late provision of IPTp-SP and insecticide-treated bed nets. As a result of the late initiation of IPTp-SP, pregnant women might be exposed to malaria in pregnancy, which may consequently lead to placental infection and adverse birth outcomes [29].…”

Poor Birth Outcomes in Malaria in Pregnancy: Recent Insights Into Mechanisms and Prevention Approaches

“…A recent study from an area of low malaria transmission reported several factors that were associated with increased odds of SGA during P. falciparum -related MiP, including symptomatic malaria and infection after 12–16 weeks' gestation ( 24 ), In addition, the risk of SGA was reported to increase by 1.13 times for every episode of infection during pregnancy ( 24 ). In contrast, in areas of high malaria transmission and particularly when pregnant women received anti-malarials in the form of intermittent preventive treatment in pregnancy (IPTp), there was no association between number of malaria episodes and SGA, suggesting that the timing of MiP may contribute to increased risk of SGA ( 25 , 26 ). Indeed, placental pigment deposition (past-chronic infection) was associated with increased risk of SGA but not LBW or preterm birth, suggesting early chronic infection (usually outside of IPTp coverage) may drive SGA and not preterm labor ( 25 , 27 ).…”

Placental Malaria

“…Malaria infection during early pregnancy leads to alterations in the vascular structure of the placenta, such as decrease of transport villi volume and increase of diffusion distance and diffusion vessel surface, which influence birth weight and gestational length [36]. Even so, Plasmodium infection mid-pregnancy has been linked increased risk of preterm birth, possibly due to the changes in angiogenic, metabolic, and inflammatory states [37].…”