Background Severe Plasmodium falciparum malaria is a major cause of death in children. The contribution of the parasite burden to the pathogenesis of severe malaria has been controversial. Methods We documented P. falciparum infection and disease in Tanzanian children followed from birth for an average of 2 years and for as long as 4 years. Results Of the 882 children in our study, 102 had severe malaria, but only 3 had more than two episodes. More than half of first episodes of severe malaria occurred after a second infection. Although parasite levels were higher on average when children had severe rather than mild disease, most children (67 of 102) had high-density infection (>2500 parasites per 200 white cells) with only mild symptoms before severe malaria, after severe malaria, or both. The incidence of severe malaria decreased considerably after infancy, whereas the incidence of high-density infection was similar among all age groups. Infections before and after episodes of severe malaria were associated with similar parasite densities. Nonuse of bed nets, placental malaria at the time of a woman’s second or subsequent delivery, high-transmission season, and absence of the sickle cell trait increased severe-malaria risk and parasite density during infections. Conclusions Resistance to severe malaria was not acquired after one or two mild infections. Although the parasite burden was higher on average during episodes of severe malaria, a high parasite burden was often insufficient to cause severe malaria even in children who later were susceptible. The diverging rates of severe disease and high-density infection after infancy, as well as the similar parasite burdens before and after severe malaria, indicate that naturally acquired resistance to severe malaria is not explained by improved control of parasite density. (Funded by the National Institute of Allergy and Infectious Diseases and others.)

IPTp does not improve overall pregnancy outcomes in Muheza, Tanzania, where SP-resistant parasites predominate and may increase the odds of fetal anemia. As parasite resistance increases in a community, the overall effect of IPTp may transition from net benefit to neutral or net harm.

Iron plus folate supplementation increases mortality and morbidity among children in areas of malaria endemicity in Africa, but the effects of supplementation on pregnant women in malaria-endemic areas remain unclear. In northeastern Tanzania, where malaria and iron deficiency are common, we found that placental malaria was less prevalent (8.5% vs. 47.3% of women; P< .0001) and less severe (median parasite density, 4.2% vs. 6.3% of placental red blood cells; P< .04) among women with iron deficiency than among women with sufficient iron stores, especially during the first pregnancy. Multivariate analysis revealed that iron deficiency (P< .0001) and multigravidity (P< .002) significantly decreased the risk of placental malaria. Interventional trials of iron and folate supplementation during pregnancy in malaria-endemic regions in Africa are urgently needed to ascertain the benefits and risks of this intervention.

Background: Placental malaria (PM) is an important cause of maternal and foetal mortality in tropical areas, and severe sequelae and mortality are related to inflammation in the placenta. Diagnosis is difficult because PM is often asymptomatic, peripheral blood smear examination detects parasitemia as few as half of PM cases, and no peripheral markers have been validated for placental inflammation.

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Inflammation during placental malaria (PM) is associated with low birth weight (LBW), especially during the first pregnancy, but the relative contribution of maternal or fetal factors that mediate this effect remains unclear and the role of gamma interferon (IFN-␥) has been controversial. We examined the relationship of maternal and cord plasma levels of IFN-␥, tumor necrosis factor alpha, interleukin-10, ferritin, and leptin to birth weight for Tanzanian women delivering in an area where there is a high rate of malaria transmission. The placental levels of inflammatory cytokines, including IFN-␥, increased significantly during PM in primigravid and multigravid women but not in secundigravid women. PM also increased maternal peripheral levels of all inflammatory markers except IFN-␥ but had strikingly little effect on cord levels of these proteins. In a multivariate analysis, placental IFN-␥ was negatively associated (P ‫؍‬ 0.01) and cord ferritin was positively associated (P < 0.0001) with birth weight in infected (PM-positive [PM ؉ ]) first-time mothers. This relationship was not observed in other mothers, consistent with the epidemiology of PM and disease. Cord leptin had a strong positive relationship with birth weight in offspring of PM-negative women (P ‫؍‬ 0.02 to P < 0.0001) but not in offspring of PM ؉ women (all differences were not significant) in the three gravidity groups. The results confirmed that placental IFN-␥ is related to LBW due to PM during first pregnancies and suggest that fetal ferritin plays a protective role. Because fetal cells are a source of placental IFN-␥ and cord ferritin, the fetal response to PM may modify the risk of LBW.

ABSTRACTPlacental infection withPlasmodium falciparumis associated with increased levels of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ), and previous studies have associated increased levels of these cytokines with low birth weight (LBW), especially for malaria-infected primigravidae. To define the contribution of TNF-α and IFN-γ networks to placental-malaria-associated LBW, we measured chemokines induced by TNF-α and IFN-γ and related them to birth weight in a birth cohort of 782 mother-infant pairs residing in an area ofP. falciparumholoendemicity in Tanzania. Among primigravidae, levels of CCL2, CXC ligand 9 (CXCL9), and CXCL13 were significantly higher during malaria infection in both the placenta and peripheral blood. Placental CXCL9 and CXCL13 levels were also higher in placental blood from secundigravidae and multigravidae. In multivariate analyses adjusted for known predictors of birth weight, malaria-infected primigravidae with placental CXCL9 levels in the lowest tertile gave birth to babies who weighed 610 g more than babies born to mothers with high CXCL9 levels. CXCL9 expression is induced by IFN-γ, and the strong association between birth weight and placental CXCL9 is consistent with previous observations relating IFN-γ to poor pregnancy outcomes.

BackgroundSevere malaria risk varies between individuals, and most of this variation remains unexplained. Here, we examined the hypothesis that cytokine profiles at birth reflect inter-individual differences that persist and influence malaria parasite density and disease severity throughout early childhood.Methods and FindingsCytokine levels (TNF-α, IFN-γ, IL-1β, IL-4, IL-5, IL-6 and IL-10) were measured at birth (cord blood; N=783) and during subsequent routine follow-up visits (peripheral blood) for children enrolled between 2002 and 2006 into a birth cohort in Muheza, Tanzania. Children underwent blood smear and clinical assessments every 2-4 weeks, and at the time of any illness. Cord blood levels of all cytokines were positively correlated with each other (Spearman’s rank correlation). Cord levels of IL-1β and TNF-α (but not other cytokines) correlated with levels of the same cytokine measured at routine visits during early life (P < 0.05). Higher cord levels of IL-1β but not TNF-α were associated with lower parasite densities during infancy (P=0.003; Generalized Estimating Equation (GEE) method), with an average ~40% reduction versus children with low cord IL-1β levels, and with decreased risk of severe malaria during follow-up (Cox regression): adjusted hazard ratio (95% CI) 0.60 (0.39-0.92), P = 0.02.ConclusionIL-1β levels at birth are related to future IL-1β levels as well as the risk of severe malaria in early life. The effect on severe malaria risk may be due in part to the effect of inflammatory cytokines to control parasite density.