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

Abstract

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 = 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.

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.

Fig 1. Flow chart for patient population.

ISTp, intermittent screening and treatment in pregnancy.

Fig 2. aRR of PTB based on malaria status and/or placental histology.

Malaria status of women at each Visit 1 (13–23 weeks), Visit 2 (28–33 weeks) or Visit 3 (34–36 weeks) were assessed. Women who had only a single positive PCR recorded over the course of pregnancy and that positive result was at Visit 1 were denoted as Only Visit 1: Malaria positive. Log-binomial regression with a log link function was used to calculate the aRR and corresponding 95% CI. RR was adjusted for treatment arm (ISTp versus IPTp), maternal age, gravidity, socioeconomic status, education status, BMI, and hemoglobin at Visit 1. aRR, adjusted relative risk; BMI, body mass index; CI, confidence interval; IPTp, intermittent preventive treatment in pregnancy; ISTp, intermittent screening and treatment in pregnancy; PTB, preterm birth.

Fig 3. Malaria before 24 weeks gestation alters the longitudinal kinetics of angiogenic, inflammatory, and metabolic mediators over the course of pregnancy.

Linear regression lines of best fit with 95% CI are represented on the graph. Malaria positive at Visit 1 (red); malaria negative at Visit 1 (black; 13 to 23 weeks gestation). Angptl3, Angiopoietin-like 3; CHI3L1, Chitinase 3-like protein-1; CI, confidence interval; CRP, C-Reactive Protein; IL18BP, Interleukin 18 Binding Protein; PlGF, placental growth factor; sEng, soluble Engdolin; sFlt-1, soluble Fms-like Tyrosine Kinase-1; sICAM-1, soluble Intercellular Adhesion Molecule-1; TNFRII, Tumor Necrosis Factor receptor II.