Blood Levels of Environmental Heavy Metals are Associated with Poorer Iron Status in Ugandan Children: A Cross-Sectional Study.

BACKGROUND: Iron deficiency (ID) and environmental exposure to metals frequently co-occur among Ugandan children, but little is known about their associations, although iron and other divalent metals share the same intestinal absorption transporter, divalent metal transporter 1 (DMT1). OBJECTIVES: We examined associations between iron status and blood concentrations of lead, manganese (Mn), cobalt (Co), and cadmium, both singly and as a mixture. METHODS: We used data on sociodemographic status, iron biomarkers, and blood concentrations of heavy metals collected from a cross-sectional survey of 100 children aged 6-59 mo in Kampala, Uganda. We compared blood concentrations of metals in ID with iron-sufficient children. We examined associations between a metal mixture and iron biomarkers using multiple linear regression and weighted quintile sum regression. RESULTS: The median (interquartile range) blood Mn (µg/L) was higher in ID children defined by soluble transferrin receptor (sTfR) and ferritin (ID compared with iron-sufficient children): (sTfR [21.3 {15.1, 28.8}, 11.2 {8.6, 18.5}], ferritin [19.5 {15.0, 27.2}, 11.2 {8.8, 19.6}]; P < 0.001 for both). Similarly, the median (interquartile range) blood Co (µg/L) was higher in ID children by ferritin ([0.5 {0.4, 0.9}, 0.4 {0.3, 0.5}], P = 0.05). Based on the multiple linear regression results, higher blood Co and Mn were associated with poorer iron status (defined by all 4 iron indicators for Co and by sTfR for Mn). The weighted quintile sum regression result showed that higher blood concentrations of a metal mixture were associated with poorer iron status represented by sTfR, ferritin, and hepcidin, mainly driven by Co and Mn. CONCLUSIONS: Our study findings suggest that poorer iron status is associated with overall heavy metal burden, predominantly Co and Mn, among Ugandan children. Further prospective studies should confirm our primary findings and investigate the combined effects of coexposures to neurotoxicants on the neurodevelopment of young children.

Meningococcal vaccines and protein-energy undernutrition in children in the African meningitis belt.

BACKGROUND: Vaccines to prevent meningococcal meningitis in the African meningitis belt include PsACWY, a polysaccharide-only vaccine; and PsA-TT, a polysaccharide-protein conjugate vaccine. Protein-energy undernutrition, a condition where children do not receive enough macro- or micronutrients, is related to increased risk of infectious diseases and poor immune function. Reduced immune function could affect vaccine immunogenicity. We investigated connections between protein-energy undernutrition and vaccine immunogenicity and antibody waning to PsACWY and PsA-TT in children in the African meningitis belt. METHODS: This is a secondary analysis of data collected as part of four clinical trials testing the safety and efficacy of PsA-TT in children in Mali, Ghana, and Senegal. We identified whether anthropometric growth indices (low height-for-age, weight-for-height, or weight-for-age Z-score categories) were related to reduced vaccine-elicited antibody (measured with rabbit complement) from pre- to 1 month post-vaccination, in linear regression models. We also identified whether these growth indices were related to increased waning for vaccine-elicited antibody over time, in linear regression models. RESULTS: A total of 697 children were included in our analysis, of which 350 (50.2%) were female; the mean (SD) age was 1.0 (1.1) years, and 578 (83.0%) received PsA-TT. In linear regression models, no consistent statistical relationship was seen between pre-vaccination anthropometric Z-score categories and vaccine immunogenicity, or decline in antibody over time, for either vaccine, although children with low weight-for-height had a greater decline in antibody from 1 to 6 months post-vaccination. CONCLUSIONS: Our analysis did not find protein-energy undernutrition to be associated with immunogenicity or waning of PsACWY- or PsA-TT-elicited antibody in children living in the African meningitis belt. Future studies should consider measuring antibody titers at additional time points post-vaccination, and for longer periods of time, to determine if the rate of antibody waning over a period of several years is associated with protein-energy undernutrition.

Delayed iron does not alter cognition or behavior among children with severe malaria and iron deficiency.

BACKGROUND: Malaria and iron deficiency (ID) in childhood are both associated with cognitive and behavioral dysfunction. The current standard of care for children with malaria and ID is concurrent antimalarial and iron therapy. Delaying iron therapy until inflammation subsides could increase iron absorption but also impair cognition. METHODS: In this study, Ugandan children 18 months to 5 years old with cerebral malaria (CM, n = 79), severe malarial anemia (SMA, n = 77), or community children (CC, n = 83) were enrolled and tested for ID. Children with ID were randomized to immediate vs. 28-day delayed iron therapy. Cognitive and neurobehavioral outcomes were assessed at baseline and 6 and 12 months (primary endpoint) after enrollment. RESULTS: All children with CM or SMA and 35 CC had ID (zinc protoporphyrin concentration ≥80 µmol/mol heme). No significant differences were seen at 12-month follow-up in overall cognitive ability, attention, associative memory, or behavioral outcomes between immediate and delayed iron treatment (mean difference (standard error of mean) ranged from -0.2 (0.39) to 0.98 (0.5), all P ≥ 0.06). CONCLUSIONS: Children with CM or SMA and ID who received immediate vs. delayed iron therapy had similar cognitive and neurobehavioral outcomes at 12-month follow-up. IMPACT: The optimal time to provide iron therapy in children with severe malaria is not known. The present study shows that delay of iron treatment to 28 days after the malaria episode, does not lead to worse cognitive or behavioral outcomes at 12-month follow-up. The study contributes new data to the ongoing discussion of how best to treat ID in children with severe malaria.

Delayed iron improves iron status without altering malaria risk in severe malarial anemia.

BACKGROUND: WHO guidelines recommend concurrent iron and antimalarial treatment in children with malaria and iron deficiency, but iron may not be well absorbed or utilized during a malaria episode. OBJECTIVES: We aimed to determine whether starting iron 28 d after antimalarial treatment in children with severe malaria and iron deficiency would improve iron status and lower malaria risk. METHODS: We conducted a randomized clinical trial on the effect of immediate compared with delayed iron treatment in Ugandan children 18 mo-5 y of age with 2 forms of severe malaria: cerebral malaria (CM; n = 79) or severe malarial anemia (SMA; n = 77). Asymptomatic community children (CC; n = 83) were enrolled as a comparison group. Children with iron deficiency, defined as zinc protoporphyrin (ZPP) ≥ 80 µmol/mol heme, were randomly assigned to receive a 3-mo course of daily oral ferrous sulfate (2 mg · kg-1 · d-1) either concurrently with antimalarial treatment (immediate arm) or 28 d after receiving antimalarial treatment (delayed arm). Children were followed for 12 mo. RESULTS: All children with CM or SMA, and 35 (42.2%) CC, were iron-deficient and were randomly assigned to immediate or delayed iron treatment. Immediate compared with delayed iron had no effect in any of the 3 study groups on the primary study outcomes (hemoglobin concentration and prevalence of ZPP ≥ 80 µmol/mol heme at 6 mo, malaria incidence over 12 mo). However, after 12 mo, children with SMA in the delayed compared with the immediate arm had a lower prevalence of iron deficiency defined by ZPP (29.4% compared with 65.6%, P = 0.006), a lower mean concentration of soluble transferrin receptor (6.1 compared with 7.8 mg/L, P = 0.03), and showed a trend toward fewer episodes of severe malaria (incidence rate ratio: 0.39; 95% CI: 0.14, 1.12). CONCLUSIONS: In children with SMA, delayed iron treatment did not increase hemoglobin concentration, but did improve long-term iron status over 12 mo without affecting malaria incidence.This trial was registered at clinicaltrials.gov as NCT01093989.

The Benefits and Risks of Iron Supplementation in Pregnancy and Childhood.

Iron deficiency is the most common micronutrient deficiency in the world and disproportionately affects pregnant women and young children. Iron deficiency has negative effects on pregnancy outcomes in women and on immune function and neurodevelopment in children. Iron supplementation programs have been successful in reducing this health burden. However, iron supplementation of iron-sufficient individuals is likely not necessary and may carry health risks for iron-sufficient and potentially some iron-deficient populations. This review considers the physiology of iron as a nutrient and how this physiology informs decision-making about weighing the benefits and risks of iron supplementation in iron-deficient, iron-sufficient, and iron-overloaded pregnant women and children.

Iron Deficiency is Prevalent among HIV-Infected Kenyan Adults and is Better Measured by Soluble Transferrin Receptor than Ferritin.

Iron deficiency (ID) and human immunodeficiency virus (HIV) infection frequently coexist. Little data exist on ID in HIV-infected individuals, partly because the iron marker ferritin is altered by inflammation common in HIV infection. We measured iron biomarkers (ferritin, soluble transferrin receptor [sTfR], hepcidin) and red cell indices (hemoglobin, mean corpuscular volume [MCV]) in newly diagnosed, antiretroviral therapy-naive, HIV-infected (N = 138) and uninfected (N = 52) Kenyan adults enrolled in a study of the immune response to malaria. We compared markers between infected and uninfected groups with t test and Wilcoxon Rank-Sum, used Spearman correlation to determine the association between iron and inflammatory markers, and applied logistic regression to determine which markers best predicted anemia. HIV-infected individuals had lower hemoglobin (P < 0.001), lower MCV (P < 0.001), higher sTfR (P = 0.003), and a greater prevalence of ID (sTfR > 8.3 mg/L) than uninfected individuals. Ferritin was elevated in HIV-infected individuals and was more strongly correlated with C-reactive protein (ρ = 0.43, P < 0.001) and hepcidin (ρ = 0.69, P < 0.001) than with hemoglobin. The best predictor of anemia in HIV-infected participants was sTfR, with a one log-unit increase in sTfR associated with a 6-fold increase in the odds of anemia (odds ratio = 6.3, 95% confidence interval: 1.8-21.8). These data suggest a significant burden of ID among treatment-naive HIV-infected Kenyan adults. Soluble transferrin receptor may be a reliable marker of ID in HIV-mediated inflammation.

Approaches for Reducing the Risk of Early-Life Iron Deficiency-Induced Brain Dysfunction in Children.

Iron deficiency is the most common micronutrient deficiency in the world. Women of reproductive age and young children are particularly vulnerable. Iron deficiency in late prenatal and early postnatal periods can lead to long-term neurobehavioral deficits, despite iron treatment. This may occur because screening and treatment of iron deficiency in children is currently focused on detection of anemia and not neurodevelopment. Anemia is the end-stage state of iron deficiency. The brain becomes iron deficient before the onset of anemia due to prioritization of the available iron to the red blood cells (RBCs) over other organs. Brain iron deficiency, independent of anemia, is responsible for the adverse neurological effects. Early diagnosis and treatment of impending brain dysfunction in the pre-anemic stage is necessary to prevent neurological deficits. The currently available hematological indices are not sensitive biomarkers of brain iron deficiency and dysfunction. Studies in non-human primate models suggest that serum proteomic and metabolomic analyses may be superior for this purpose. Maternal iron supplementation, delayed clamping or milking of the umbilical cord, and early iron supplementation improve the iron status of at-risk infants. Whether these strategies prevent iron deficiency-induced brain dysfunction has yet to be determined. The potential for oxidant stress, altered gastrointestinal microbiome and other adverse effects associated with iron supplementation cautions against indiscriminate iron supplementation of children in malaria-endemic regions and iron-sufficient populations.

Delaying the start of iron until 28 days after antimalarial treatment is associated with lower incidence of subsequent illness in children with malaria and iron deficiency.

We evaluated the incidence of all-cause and malaria-specific clinic visits during follow-up of a recent trial of iron therapy. In the main trial, Ugandan children 6-59 months with smear-confirmed malaria and iron deficiency [zinc protoporphyrin (ZPP > = 80 µmol/mol heme)] were treated for malaria and randomized to start a 27-day course of oral iron concurrently with (immediate group) or 28 days after (delayed group) antimalarial treatment. All children were followed for the same 56-day period starting at the time of antimalarial treatment (Day 0) and underwent passive and active surveillance for malaria and other morbidity for the entire follow-up period. All ill children were examined and treated by the study physician. In this secondary analysis of morbidity data from the main trial, we report that although the incidence of malaria-specific visits did not differ between the groups, children in the immediate group had a higher incidence rate ratio of all-cause sick-child visits to the clinic during the follow-up period (Incidence Rate Ratio (IRR) immediate/delayed = 1.76; 95%CI: 1.05-3.03, p = 0.033). Although these findings need to be tested in a larger trial powered for malaria-specific morbidity, these preliminary results suggest that delaying iron by 28 days in children with coexisting malaria and iron deficiency is associated with a reduced risk of subsequent all-cause illness.

Delaying Iron Therapy until 28 Days after Antimalarial Treatment Is Associated with Greater Iron Incorporation and Equivalent Hematologic Recovery after 56 Days in Children: A Randomized Controlled Trial.

BACKGROUND: Iron therapy begun concurrently with antimalarial treatment may not be well absorbed because of malaria-induced inflammation. Delaying the start of iron therapy may permit better iron absorption and distribution. OBJECTIVE: We compared erythrocyte iron incorporation in children who started iron supplementation concurrently with antimalarial treatment or 28 d later. We hypothesized that delayed iron supplementation would be associated with greater incorporation and better hematologic recovery. METHODS: We enrolled 100 children aged 6-59 mo with malaria and hemoglobin concentrations of 50.0-99.9 g/L who presented to Mulago Hospital, Kampala, into a randomized trial of iron therapy. All children were administered antimalarial treatment. Children with zinc protoporphyrin (ZPP) ≥80 µmol/mol heme were randomly assigned to start iron supplementation concurrently with the antimalarial treatment [immediate iron (I) group] or 28 d later [delayed iron (D) group]. All children were administered iron-stable isotope (57)Fe on day 0 and (58)Fe on day 28. We compared the percentage of iron incorporation at the start of supplementation (I group at day 0 compared with D group at day 28, aim 1) and hematologic recovery at day 56 (aim 2). RESULTS: The percentage of iron incorporation (mean ± SE) was greater at day 28 in the D group (16.5% ± 1.7%) than at day 0 in the I group (7.9% ± 0.5%; P < 0.001). On day 56, concentrations of hemoglobin and ZPP and plasma ferritin, soluble transferrin receptor (sTfR), hepcidin, and C-reactive protein did not differ between the groups. On day 28, the hemoglobin (mean ± SD) and plasma iron markers (geometric mean; 95% CI) reflected poorer iron status in the D group than in the I group at this intervening time as follows: hemoglobin (105 ± 15.9 compared with 112 ± 12.4 g/L; P = 0.04), ferritin (39.3 µg/L; 23.5, 65.7 µg/L compared with 79.9 µg/L; 58.3, 110 µg/L; P = 0.02), sTfR (8.9 mg/L; 7.4, 10.7 mg/L compared with 6.7 mg/L; 6.1, 7.5 mg/L; P = 0.01), and hepcidin (13.3 ng/mL; 8.3, 21.2 ng/mL compared with 38.8 ng/mL; 28.3, 53.3 ng/mL; P < 0.001). CONCLUSIONS: Delaying the start of iron improves incorporation but leads to equivalent hematologic recovery at day 56 in Ugandan children with malaria and anemia. These results do not demonstrate a clear, short-term benefit of delaying iron. This trial was registered at clinicaltrials.gov as NCT01754701.

Comparison of iron status 28 d after provision of antimalarial treatment with iron therapy compared with antimalarial treatment alone in Ugandan children with severe malaria.

BACKGROUND: The provision of iron with antimalarial treatment is the standard of care for concurrent iron deficiency and malaria. However, iron that is given during a malaria episode may not be well absorbed or used, particularly in children with severe malaria and profound inflammation. OBJECTIVES: We aimed to 1) determine baseline values of iron and inflammatory markers in children with severe malarial anemia (SMA), children with cerebral malaria (CM), and community children (CC) and 2) compare markers in iron-deficient children in each group who received 28 d of iron supplementation during antimalarial treatment with those in children who did not receive iron during treatment.. DESIGN: Seventy-nine children with CM, 77 children with SMA, and 83 CC who presented to Mulago Hospital, Kampala, Uganda, were enrolled in a 28-d iron-therapy study. Children with malaria received antimalarial treatment. All children with CM or SMA, as well as 35 CC, had zinc protoporphyrin (ZPP) concentrations ≥80 µmol/mol heme and were randomly assigned to receive a 28-d course of iron or no iron. We compared iron markers at day 0 among study groups (CM, SMA, and CC groups) and at day 28 between children in each group who were randomly assigned to receive iron or to not receive iron. RESULTS: At day 0, children with CM and SMA had greater values of C-reactive protein, ferritin, and hepcidin than those of CC. At day 28, interactions between study and treatment group were NS. Children in the no-iron compared with iron groups had similar mean values for hemoglobin (115 compared with 113 g/L, respectively; P = 0.73) and ZPP (124 compared with 124 µmol/mol heme, respectively; P = 0.96) but had lower median ferritin [101.0 µg/L (95% CI: 84.2, 121.0 µg/L) compared with 152.9 µg/L (128.8, 181.6 µg/L), respectively; P ≤ 0.001] and hepcidin [45.8 ng/mL (36.8, 56.9 ng/mL) compared with 83.1 ng/mL (67.6, 102.2 ng/mL), respectively; P < 0.011]. CONCLUSIONS: Severe inflammation is a characterization of children with CM and SMA. The withholding of iron from children with severe malaria is associated with lower ferritin and hepcidin at day 28 but not a lower hemoglobin concentration. This trial was registered at clinicaltrials.gov as NCT01093989.

Decline in childhood iron deficiency after interruption of malaria transmission in highland Kenya.

BACKGROUND: Achieving optimal iron status in children in malaria-endemic areas may increase the risk of malaria. Malaria itself may contribute to iron deficiency, but the impact of an interruption in malaria transmission on the prevalence of iron deficiency is unknown. OBJECTIVES: We aimed to determine whether 1) iron status improved in children living in 2 Kenyan villages with a documented cessation in malaria transmission and 2) changes in iron status correlated with changes in hemoglobin. DESIGN: We measured iron [hemoglobin, ferritin, soluble transferrin receptor (sTfR)] and inflammatory [C-reactive protein (CRP)] markers in paired plasma samples from 190 children aged 4-59 mo at the beginning (May 2007) and end (July 2008) of a documented 12-mo period of interruption in malaria transmission in 2 highland areas in Kenya with unstable malaria transmission and ongoing malaria surveillance. RESULTS: Between May 2007 and July 2008, mean (±SD) hemoglobin increased from 10.8 ± 1.6 to 11.6 ± 1.6 g/dL. Median (25th, 75th percentile) ferritin increased from 17.0 (9.7, 25.6) to 22.6 (13.4, 34.7) µg/L (P < 0.001), whereas median sTfR decreased from 32.4 (26.3, 43.2) to 27.7 (22.1, 36.0) nmol/L (P < 0.001). Median CRP was low (<1 mg/L in both years) and did not change significantly. Iron deficiency prevalence (ferritin <12 µg/L, or <30 µg/L if CRP ≥10 mg/L) decreased from 35.9% (95% CI: 28.9%, 43.0%) to 24.9% (18.5%, 31.2%) (P = 0.005). The prevalence of iron deficiency with anemia (hemoglobin <11.0 g/dL) declined from 27.2% (20.7%, 33.8%) to 12.2% (7.4%, 17.1%) (P < 0.001). Improvement in iron status correlated with an increase in hemoglobin and was greater than explained by physiologic changes expected with age. CONCLUSIONS: In this area of unstable malaria transmission, the prevalence of iron deficiency in children decreased significantly after the interruption of malaria transmission and was correlated with an increase in hemoglobin. These findings suggest that malaria elimination strategies themselves may be an effective way to address iron deficiency in malaria-endemic areas.

Assessment of iron status in US pregnant women from the National Health and Nutrition Examination Survey (NHANES), 1999-2006.

BACKGROUND: Total body iron calculated from serum ferritin and soluble transferrin receptor concentrations allows for the evaluation of the full range of iron status. OBJECTIVE: We described the distribution of total body iron and the prevalence of iron deficiency (ID) on the basis of total body iron in US pregnant women. DESIGN: We examined data from the National Health and Nutrition Examination Survey (NHANES) in 1999-2006 for 1171 pregnant women. RESULTS: ID prevalence (±SE) in US pregnant women, which was defined as total body iron <0 mg/kg, was 18.0 ± 1.4%. Pregnant women in the first trimester had a higher mean total body iron than did pregnant women in the second or third trimesters. ID prevalence in pregnant women increased significantly with each trimester (6.9 ± 2.2%, 14.3 ± 2.1%, and 29.5 ± 2.7% in the first, second, and third trimesters, respectively). Pregnant women with parity ≥2 had the lowest mean total body iron and the highest prevalence of ID compared with values for pregnant women with parity of 0 or 1. The ID prevalence in non-Hispanic white pregnant women was significantly lower than in Mexican American or non-Hispanic black pregnant women. The mean total body iron and the prevalence of ID did not differ by educational level or by family income. CONCLUSIONS: To our knowledge, these are the first data on total body iron distributions for a representative sample of US pregnant women. Low total body iron is more prevalent in pregnant women in the second or third trimesters, in Mexican American pregnant women, in non-Hispanic black pregnant women, and in women with parity ≥2.