Iron supplementation in anemic Zanzibari toddlers is associated with greater loss in erythrocyte iron isotope enrichment.

BACKGROUND: Heavy parasitic loads increase the risk of iron (Fe) deficiency anemia, which remains prevalent globally. Where parasites are common, understanding the influence of parasitic infections on Fe incorporation and erythropoiesis in toddlers is especially important. OBJECTIVES: The aim of this study was to identify the impacts of malarial and helminth infections on red blood cell (RBC) Fe incorporation and subsequent changes in RBC Fe isotope enrichment for 84 days postdosing in toddlers at high risk for parasitic infections. METHODS: Fe incorporation was measured in a group of Zanzibari toddlers (n = 71; 16-25 months) using a stable Fe isotopic method. At study entry, an oral stable Fe isotope was administered. Blood was collected 14 (D14) and 84 (D84) days postdosing for the assessment of Fe status indicators and RBC isotopic enrichment. Blood and stool samples were collected and screened for malaria and helminth parasites. Factors associated with changes in RBC Fe isotope enrichment were identified using regression models. RESULTS: Toddlers who had larger weight-for-age z-scores, lower total body Fe, and helminth infections (n = 26) exhibited higher RBC Fe incorporation. RBC Fe isotope enrichment decreased from D14 to D84 by -2.75 percentage points (P < 0.0001; n = 66). Greater loss in RBC Fe isotope enrichment from D14 to D84 was observed in those who received Fe supplementation, those with either helminths or both malarial and helminth infections, and in those with greater RBC Fe incorporation on D14. CONCLUSIONS: Toddlers who received Fe supplementation exhibited significantly greater losses of RBC Fe isotope enrichment over time. We speculate this greater loss of RBC Fe enrichment is indicative of increased erythropoiesis due to the provision of Fe among anemic or helminth-infected toddlers.

Effect of iron/folic Acid supplementation on the outcome of malaria episodes treated with sulfadoxine-pyrimethamine.

Folic acid supplementation may potentially alter the efficacy of sulfadoxine-pyrimethamine (SP) treatment in children with malaria. However, there is lack of evidence from randomized controlled trials and effects of folic acid supplementation on clinical efficacy of SP therapy remain moderately understood among children. In a double masked, placebo-controlled trial among preschool children in Pemba Island (Tanzania), iron and folic acid supplementation (Fe/FA) showed an increased risk of hospitalizations and death. In the present paper, we evaluated if folic acid supplementation reduced the efficacy of malaria treatment and thereby contributed to observed adverse effects. During the study, 1648 children had confirmed malarial episodes and received either sulphadoxine-pyrimethamine (SP) treatment and iron folic acid or SP treatment and placebo. These children were evaluated for recovery and incidence of hospitalization during the next 15, 30, and 140 days. Two groups did not differ in malarial episode or hospitalization rate on subsequent 15, 30, and 140 days. Altered efficacy of SP by folic acid was not observed and did not contribute to adverse events in the previous trial. This trial is registered with Controlled-trials.com ISRCTN59549825.

Effect of zinc supplementation on mortality in children aged 1-48 months: a community-based randomised placebo-controlled trial.

BACKGROUND: Studies from Asia have suggested that zinc supplementation can reduce morbidity and mortality in children, but evidence from malarious populations in Africa has been inconsistent. Our aim was to assess the effects of zinc supplementation on overall mortality in children in Pemba, Zanzibar. METHODS: We enrolled 42,546 children aged 1-36 months, contributing a total of 56,507 child-years in a randomised, double-blind, placebo-controlled trial in Pemba, Zanzibar. Randomisation was by household. 21 274 children received daily supplementation with zinc 10 mg (5 mg in children younger than 12 months) for mean 484.7 days (SD 306.6). 21,272 received placebo. The primary endpoint was overall mortality, and analysis was by intention to treat. This study is registered as an International Standard Randomised Clinical Trial, number ISRCTN59549825. FINDINGS: Overall, there was a non-significant 7% (95% CI -6% to 19%; p=0.29) reduction in the relative risk of all-cause mortality associated with zinc supplementation. INTERPRETATION: We believe that a meta-analysis of all studies of mortality and morbidity, will help to make evidence-based recommendations for the role of zinc supplementation in public health policy to improve mortality, morbidity, growth, and development in young children.

Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial.

BACKGROUND: Anaemia caused by iron deficiency is common in children younger than age 5 years in eastern Africa. However, there is concern that universal supplementation of children with iron and folic acid in areas of high malaria transmission might be harmful. METHODS: We did a randomised, placebo-controlled trial, of children aged 1-35 months and living in Pemba, Zanzibar. We assigned children to daily oral supplementation with: iron (12.5 mg) and folic acid (50 mug; n=7950), iron, folic acid, and zinc (n=8120), or placebo (n=8006); children aged 1-11 months received half the dose. Our primary endpoints were all-cause mortality and admission to hospital. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59549825. FINDINGS: The iron and folic acid-containing groups of the trial were stopped early on Aug 19, 2003, on the recommendation of the data and safety monitoring board. To this date, 24 076 children contributed a follow-up of 25,524 child-years. Those who received iron and folic acid with or without zinc were 12% (95% CI 2-23, p=0.02) more likely to die or need treatment in hospital for an adverse event and 11% (1-23%, p=0.03) more likely to be admitted to hospital; there were also 15% (-7 to 41, p=0.19) more deaths in these groups. INTERPRETATION: Routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. In the presence of an active programme to detect and treat malaria and other infections, iron-deficient and anaemic children can benefit from supplementation. However, supplementation of those who are not iron deficient might be harmful. As such, current guidelines for universal supplementation with iron and folic acid should be revised.

Short-term effects of vitamin A and antimalarial treatment on erythropoiesis in severely anemic Zanzibari preschool children.

BACKGROUND: The pathophysiology of anemia in coastal East Africa is complex. Impaired erythropoietin production is one possible mechanism. Plasmodium falciparum malaria has been found to blunt erythropoietin production, whereas vitamin A stimulates erythropoietin production in vitro. OBJECTIVE: We investigated the 72-h effects of vitamin A and the antimalarial drug sulfadoxine pyramethamine (SP) on erythropoietin production in severely anemic (hemoglobin < or = 70 g/L) preschool children in Zanzibar, a region of known vitamin A deficiency. We hypothesized that both treatments would stimulate erythropoietin production directly, within 72 h, before a change in hemoglobin would occur. DESIGN: One hundred forty-one severely anemic children were identified during the baseline assessment of a morbidity substudy of a community-based micronutrient supplementation trial. All severely anemic children were randomly assigned to receive either vitamin A (100,000 or 200,000 IU depending on age) or SP at baseline; 72 h later they received the opposite treatment plus daily hematinic syrup for 90 d. Erythropoietic and parasitic indicators were assessed at baseline and again after 72 h. RESULTS: After 72 h, SP reduced the malaria parasite density (by 5029 parasites/microL; P < 0.001), CRP concentrations (by 10.6 mg/L; P = 0.001), and the proportion of children infected with malaria (by 32.4%; P < 0.001). Vitamin A reduced CRP (by 9.6 mg/L; P = 0.011), serum ferritin (by 18.1 microg/L; P = 0.042), and erythropoietin (by 194.7 mIU/mL; P = 0.011) concentrations and increased the reticulocyte production index (by 0.40; P = 0.041). CONCLUSIONS: Contrary to our hypothesis, vitamin A significantly decreased erythropoietin concentration. The most important effect of both vitamin A and SP was the rapid reduction of inflammation. Vitamin A also mobilized iron from stores and stimulated the production of new erythrocytes.

Evaluation of the efficacy of pyrantel-oxantel for the treatment of soil-transmitted nematode infections.

A randomized controlled trial comparing the efficacy of pyrantel-oxantel (10 mg/kg) with mebendazole (500 mg) was performed on 1329 schoolchildren aged 6-9 years on Pemba Island in September-October 2000 to evaluate alternative single-dose drugs for regular treatment of intestinal nematode infections. Both mebendazole and pyrantel-oxantel were very effective in eliminating Ascaris lumbricoides infection, inducing cure rates of more than 96% and reducing the mean egg counts by more than 95%. Both drugs had a moderate efficacy against Trichuris trichiura infection, but pyrantel-oxantel had a higher cure rate (31.5% vs. 23.3%, P < 0.01), though the reductions in egg counts did not differ significantly and were more than 80%. Pyrantel-oxantel and mebendazole had a similar, poor efficacy in curing hookworm infections and had a moderate effect in reducing the egg counts by 67% and 68%, respectively. Pyrantel-oxantel (10 mg/kg) offers a valuable alternative to mebendazole as a single-dose treatment for the control of intestinal nematode infections in children in endemic areas of sub-Saharan Africa, due to its comparable efficacy, its low cost and its suitability for use in young children.