Fetal origins of malarial disease: cord blood cytokines as risk markers for pediatric severe malarial anemia

Abstract

Background: Severe malarial anemia (SMA) remains a major cause of pediatric illness and mortality in Sub-Saharan Africa. Here we test the hypothesis that prenatal exposures, reflected by soluble inflammatory mediators in cord blood, can condition an individual's susceptibility to SMA.

Methods: In a Tanzanian birth cohort (n = 743), we measured cord blood concentrations of tumor necrosis factor (TNF), TNF receptors I and II (TNF-RI and TNF-RII), interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-10, and interferon gamma (IFN-γ). After adjusting for conventional covariates, we calculated the hazard ratios (HR) for time to first SMA event with log(e) cytokine concentrations dichotomized at the median, by quartile, and per standard deviation (SD) increase.

Results: Low levels of TNF, TNF-RI, IL-1β, and IL-5 and high levels of TNF-RII were associated statistically significantly and respectively with approximately 3-fold, 2-fold, 8-fold, 4-fold, and 3-fold increased risks of SMA (Hb < 50 g/L). TNF, TNF-RI, and IL-1β concentrations were inversely and log-linearly associated with SMA risk; the HR (95% confidence interval [CI]) per 1-SD increase were respectively 0.81 (.65, 1.02), 0.76 (.62, .92), and 0.50 (.40, .62).

Conclusions: These data suggest that proinflammatory cytokine levels at birth are inversely associated with SMA risk and support the hypothesis that pediatric malarial disease has fetal origins.

Keywords: anemia; cord blood; cytokines; developmental programming; inflammation; malaria; risk marker.

Figure 1.

Selection of study population. Abbreviation: HIV, human immunodeficiency virus.

Figure 2.

Cumulative SMA incidence by case definition (N = 882 at baseline). Abbreviations: SMA, severe malarial anemia; WHO, World Health Organization.

Figure 3.

Risk of SMA by quartile of log(e) biomarker value after adjustment for village, sex, delivery transmission season, thalassemia, sickle cell trait, birth weight, maternal gravidity, and placental malaria status. (N = 743) Black squares and green triangles represent HR for WHO (Hb < 50 g/L) and standard (Hb <60 g/L) definitions respectively. The P values for heterogeneity are: (A) TNF (WHO: P = .0054; Standard: P = .0239), (B) TNF-RI (WHO: P = .0004; Standard: P = .0002), (C) TNF-RII (WHO: P = .0022; Standard: P = .1192), (D) IL-1β (WHO: P = .0001; Standard: P < .0001) (E) IL-5 (WHO: P = .0145; Standard: 0.0739), (F) IL-6 (WHO: P = .4209; Standard: P = .9491), (G) IL-10 (WHO: .6585; Standard: .8485), and (H) TNF/ IL-10 (WHO: P = .0487; Standard: P = .0490). Abbreviations: CI, confidence interval; HR, hazard ratio; IL, interleukin; SMA, severe malarial anemia; TNF, tumor necrosis factor; WHO, World Health Organization.

Figure 4.

Risk of standard SMA (Hb < 60 g/L) per 1-SD increase in log(e) IL-1β concentration by several participant level characteristics (N = 743). HR is adjusted for the following excluding the stratified covariate: village, sex, delivery transmission season, thalassemia, sickle cell trait, birth weight, maternal gravidity, and placental malaria status. *P values are from likelihood ratio tests. Abbreviations: CI, confidence interval; HR, hazard ratio; IL, interleukin; SD, standard deviation; SMA, severe malarial anemia.