Does iron therapy benefit children with severe malaria-associated anaemia? A clinical trial with 12 weeks supplementation of oral iron in young children from the Turiani Division, Tanzania. Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants. Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria. A comparison of iron and folate with folate alone in hematologic recovery of children treated for acute malaria. The effect of oral iron therapy during treatment for Plasmodium falciparum malaria with sulphadoxine-pyrimethamine on Malawian children under 5 years of age. The prevention of anaemia in pregnancy in primigravidae in the guinea savanna of Nigeria. Micronutrient and iron supplementation and effective antimalarial treatment synergistically improve childhood anaemia. Effect of intermittent treatment with amodiaquine on anaemia and malarial fevers in infants in Tanzania: a randomised placebo-controlled trial. Intermittent administration of iron and sulfadoxine-pyrimethamine to control anaemia in Kenyan children: a randomised controlled trial. 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. Randomized, controlled trial of daily iron supplementation and intermittent sulfadoxine-pyrimethamine for the treatment of mild childhood anemia in western Kenya. Low-dose daily iron supplementation for 12 months does not increase the prevalence of malarial infection or density of parasites in young Zanzibari children. Management of severe malarial anaemia in Gambian children. The effect of iron therapy on malarial infection in Papua New Guinean schoolchildren. The effects of iron supplementation during pregnancy, given by traditional birth attendants, on the prevalence of anaemia and malaria. Zinc and iron supplementation and malaria, diarrhea, and respiratory infections in children in the Peruvian Amazon. Seasonal intermittent preventive treatment for the prevention of anaemia and malaria in Ghanaian children: a randomized, placebo controlled trial. Failure of twice-weekly iron supplementation to increase blood haemoglobin and serum ferritin concentrations: results of a randomized controlled trial. Bed nets for the prevention of malaria and anaemia in pregnancy. Multiple micronutrients including iron are not more effective than iron alone for improving hemoglobin and iron status of Malian school children. The effect of weekly iron and vitamin A supplementation on hemoglobin levels and iron status in adolescent schoolgirls in western Kenya. Assessment of the effect of the oral iron chelator deferiprone on asymptomatic Plasmodium falciparum parasitemia in humans. Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: double blind, placebo controlled study. Preliminary findings on iron supplementation and learning achievement of rural Indonesian children. Daily iron supplementation is more efficacious than twice weekly iron supplementation for the treatment of childhood anemia in western Kenya. Iron chelation as a chemotherapeutic strategy for falciparum malaria. Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria. Albendazole therapy and reduced decline in haemoglobin concentration during pregnancy (Sierra Leone). Comparison of artemisinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria. Seasonal intermittent preventive treatment with artesunate and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial. Comparison of artemisinin suppositories, intramuscular artesunate and intravenous quinine for the treatment of severe childhood malaria. Effect of oral supplementation with iron(III)-hydroxide polymaltose complex on the immunological profile of adolescents with varying iron status. Effect of daily iron supplementation on iron status, cell-mediated immunity, and incidence of infections in 6-36 month old Togolese children. A community randomized controlled trial of insecticide-treated bednets for the prevention of malaria and anaemia among primigravid women on the Kenyan coast. Comparative efficacy of antimalarial drugs including ACTs in the treatment of uncomplicated malaria among children under 5 years in Ghana. Iron chelation with desferrioxamine B in adults with asymptomatic Plasmodium falciparum parasitemia. Iron supplementation and physical growth of rural Indonesian children. A WHO collaborative study on iron supplementation in Burma and in Thailand. The efficacy of micronutrient supplementation in reducing the prevalence of anaemia and deficiencies of zinc and iron among adolescents in Sri Lanka. Effect of iron chelation therapy on mortality in Zambian children with cerebral malaria. Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomised placebo-controlled trial. The impact of insecticide-treated bednets on malaria and anaemia in pregnancy in Kassena-Nankana district, Ghana: a randomized controlled trial. Treatment with iron increases weight gain and psychomotor development. Effective community intervention to improve hemoglobin status in preschoolers receiving once-weekly iron supplementation. Iron supplementation improves iron status and reduces morbidity in children with or without upper respiratory tract infections: a randomized controlled study in Colombo, Sri Lanka. Iron supplementation studies among pregnant women. Decreased rate of stunting among anemic Indonesian preschool children through iron supplementation. Use of microencapsulated iron(II) fumarate sprinkles to prevent recurrence of anaemia in infants and young children at high risk. Weekly vs daily iron and folic acid supplementation in adolescent Nepalese girls. Efficacy and tolerability of four antimalarial combinations in the treatment of uncomplicated Plasmodium falciparum malaria in Senegal. Randomised trial of vitamin A supplementation in pregnant women in rural Malawi found to be anaemic on screening by HemoCue. A prospective randomized, controlled trial of intravenous versus oral iron for moderate iron deficiency anaemia of pregnancy. Chloroquine prophylaxis, iron-folic acid supplementation or case management of malaria attacks in primigravidae in western Uganda: effects on maternal parasitaemia and haemoglobin levels and on birthweight. Multivitamin-multimineral and iron supplementation did not improve appetite of young stunted and anemic Beninese children. Impact of intermittent preventive treatment with sulphadoxine-pyrimethamine targeting the transmission season on the incidence of clinical malaria in children in Mali. Impact of iron supplementation and deworming on growth performance in preschool Beninese children. Maternal vitamin A supplementation and immunity to malaria in pregnancy in Ghanaian primigravids. A randomized controlled trial of artemether/benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African children. A randomized placebo-controlled trial of iron supplementation in breastfed young infants initiated on complementary feeding: effect on haematological status. Effect of zinc supplementation on malaria and other causes of morbidity in west African children: randomised double blind placebo controlled trial. Weekly iron supplementation is as effective as 5 day per week iron supplementation in Bolivian school children living at high altitude. Once weekly is superior to daily iron supplementation on height gain but not on hematological improvement among schoolchildren in Thailand. The impact of population level deworming on the haemoglobin levels of schoolchildren in Tanga, Tanzania.
Oral iron supplementation is often routinely given to children with malaria-associated anaemia, but its contribution to recovery is controversial. A randomized clinical trial, evaluating such routine, was carried out among 100 children, who had a haemoglobin of < or = 5 g/dl and a positive blood smear for malaria parasites. All children received malaria therapy (chloroquin + fansidar) and were randomly allocated to two groups, one receiving additional oral iron treatment, the other being the control. In the 12-week follow-up period the haemoglobin level and malaria indices were measured at 2, 4, 8, and 12 weeks. There was a 100 per cent compliance during the follow-up period. In each group 20 children (40 per cent) required a blood transfusion. In the remaining 60 children, after 2 weeks the haemoglobin had risen 3.7 g/dl in the ferrous-supplemented group compared to 3.5 g/dl in the non-ferrous group. Thereafter, the increase in haemoglobin in both groups was steady. At follow-up measurements, the groups did not differ for haemoglobin levels. The mean haemoglobin at 12 weeks was 9.2 and 9.0 g/dl, respectively. It was concluded that iron supplementation did not have any effect on the rate of parasitaemia and on parasite density during the 12 weeks. However, the iron-supplemented group had a significantly increased morbidity from other causes than malaria. It appears that iron does not have an effect on the recovery of haemoglobin level in children with malaria-associated anaemia. This study provides no evidence supporting routine iron supplementation to these children. Malaria and anaemia, especially that due to iron deficiency, are two leading causes of morbidity worldwide. Little is known about the relative contribution of Plasmodium falciparum infection and iron deficiency to the aetiology of anaemia in malaria-endemic areas. We undertook a randomised comparison of different strategies for control of anaemia and malaria in infants, including an assessment of the effect of iron supplementation on malaria susceptibility.
                832 infants born at one hospital in a malaria-hyperendemic area of Tanzania between January and October, 1995, were randomly assigned to group DI, receiving daily oral iron (2 mg/kg daily) plus weekly Deltaprim (3.125 mg pyrimethamine plus 25 mg dapsone); group IP, receiving iron plus weekly placebo; group DP, receiving daily placebo plus weekly Deltaprim; or group PP. supplementation was given from 8 to 24 weeks of age, and the weekly chemoprophylaxis from 8 to 48 weeks. The frequency of severe anaemia (packed-cell volume < 25%) and malaria episodes was assessed through a combination of passive case detection and cross-sectional surveys.
                The groups that received iron supplementation had a lower frequency of severe anaemia than those that did not receive iron (0.62 vs 0.87 cases per person-year; protective efficacy 28.8% [95% CI 6.3-45.8). Iron supplementation had no effect on the frequency of malaria (0.87 vs 1.00 cases per person-year; protective efficacy 12.8% [-12.8 to 32.5]). The groups that received malaria prophylaxis had lower frequencies of both severe anaemia (0.45 vs 1.04 episodes per person-year; protective efficacy 57.3% [43.0-67.9]) and malaria (0.53 vs 1.34 episodes per person-year; protective efficacy 60.5% [48.2-69.9]) than the groups that did not receive prophylaxis. After the end of the intervention period, children who had received malaria chemoprophylaxis had higher rates of severe anaemia and malaria than non-chemoprophylaxis groups (relative risks 2.2 [1.3-3.7] and 1.8 [1.3-2.6]).
                Malaria chemoprophylaxis during the first year of life was effective in prevention of malaria and anaemia but apparently impaired the development of natural immunity. Iron supplementation was effective in preventing severe anaemia without increasing susceptibility to malaria. Our findings support iron supplementation of infants to prevent iron-deficiency anaemia, even in malaria-endemic areas. Whether children with malarial anaemia should receive supplementation with iron or folic acid is uncertain. Therefore, the effects of supplementary treatment with iron or folic acid, given together with chloroquine or pyrimethamine-sulfadoxine (Fansidar), has been assessed in 600 Gambian children with uncomplicated falciparum malaria. After one month, haematological recovery was significantly better in the group treated with Fansidar than in the chloroquine-treated group (difference in mean haemoglobin level = 0.54 g/dL, P = 0.01). Children who received iron had a significantly better response than those given placebo (differences in mean haemoglobin level after one month and at dry season follow-up = 0.70 g/dL, P = 0.006, and 0.81 g/dL, P = 0.001, respectively). Iron supplementation was not associated with increased prevalence of malaria. Supplementation with folic acid did not improve the haematological response but, among children who received Fansidar, the treatment failure rate was significantly higher among those given folic acid than among those given placebo. Thus, supplementation with iron, but not folic acid, improves haematological recovery without increasing susceptibility to malaria. Concern has been raised that iron supplementation for treatment of acute malaria may worsen the severity of malaria. We compared the effect of iron and folate with folate alone on hematologic recovery in children treated for acute malaria. We randomized 82 children 6-60 months of age from Nigeria with smear-positive malaria and anemia (hematocrit < 33%) to receive iron (2 mg/kg/day) plus folate (5 mg/day) or folate alone in addition to antimalarial drugs. The mean ± SD hematocrit at baseline was 28.5% ± 2.9%. At four weeks, the mean hematocrit increased by 2.5% ± 1.6% in the iron plus folate group and by 1.4% ± 1.0% in the folate alone group (P = 0.001). Baseline hematocrit, iron supplementation, weight for height, and weekly meat intake were significant predictors of final hematocrit. The effect of iron was not significantly modified by baseline hematocrit, weekly meat intake, nutritional status, mother's education, sex, or age of the child. Iron supplementation improved hematologic recovery in children with malarial anemia. In sub-Saharan countries, although malaria and malaria-associated anaemia are major public health problems, the usefulness of supplementary iron treatment for children with malaria-associated anaemia is unknown. In a 6-week period during the 1995 rainy season, 222 Malawian children aged < 5 years, who sought treatment for malaria, had > or = 500 parasites/microliter blood and at least 5 g haemoglobin (HB)/dl blood and whose parents gave consent, were randomized into a prospective study comparing the efficacy of sulphadoxine- pyrimethamine only (SP), SP plus daily iron (SPD) and SP plus weekly iron (SPW) as treatment for malaria-associated anaemia. The patients had their HB concentrations measured on enrollment (day 0), just before antimalarial treatment, and on days 3, 7, 14, 21 and 28; 215 (96.8%) completed the 28-day study. Among the children with 5-8 g HB/dl on enrolment, HB gain by the end of the study was significantly greater than in the children with > 8 g HB/dl initially (4.1 v. 2.2 g/dl; P < 0.05), and those in the SPD group gained significantly more HB by days 21 and 28 (3.6 and 4.9 g/dl, respectively) than those in either the SPW (2.7 and 3.7 g/dl, respectively) or the S2 groups (2.6 and 3.5 g/dl, respectively); there was no difference in HB gain between the SP and SPW groups. Type of treatment had no apparent effect, at any time during the study, on HB gains in those patients who had > 8 g HB/dl on enrolment. Thus the children with 5-8 g HB/dl on enrolment benefited from daily iron therapy whereas those with > 8 g HB/dl derived no significant benefit; improvement in HB depended most on whether enrolment HB was < or = 8.0 g/dl. As treatment with an effective antimalarial drug resulted in HB gains, irrespective of treatment group or HB concentration at enrolment, the anaemia observed may be mostly related to malaria. However, as a larger proportion of the iron-treated patients failed to clear their parasitaemias than of those given SP alone, oral iron may inhibit SP action. It is therefore recommended that, for children with both malaria and malaria-associated anaemia, the malaria should first be cleared with an effective antimalarial drug, such as SP, before the anaemia, if it still persists, is treated with iron. Two hundred Hausa primigravidae at Zaria were divided into five groups in a randomized double-blind trial of antenatal oral antimalarial prophylaxis, and haematinic supplements. Group 1 received no active treatment. Groups 2 to 5 were given chloroquine 600 mg base once, followed by proguanil 100 mg per day. In addition, group 3 received iron 60 mg daily, group 4 folic acid 1 mg daily, and group 5 iron plus folic acid. Forty-five percent were anaemic (haemoglobin (Hb) less than 11.0 g dl-1) at first attendance before 24 weeks of gestation, and malaria parasitaemia (predominantly Plasmodium falciparum) was seen in 27%, of whom 60% were anaemic. The mean Hb fell during pregnancy in group 1, and seven patients in this group had to be removed from the trial and treated for severe anaemia (packed cell volume (PCV) less than 0.26). Only five patients in the other groups developed severe anaemia (P = 0.006), two of whom had malaria following failure to take treatment. Patients in group 1 had the lowest mean Hb at 28 and 36 weeks of gestation, and patients receiving antimalarials and iron (groups 3 and 5) had the highest Hb at 28 weeks, but differences were not significant, possibly due to removal from the trial of patients with severe anaemia. Anaemia (Hb less than 12.0 g dl-1) at six weeks after delivery was observed in 61% of those not receiving active treatment (group 1), in 39% of those protected against malaria but not receiving iron supplements (groups 2 and 4) and in only 18% of patients receiving both antimalarials and iron (groups 3 and 5). Folic acid had no significant effect on mean Hb. Proguanil was confirmed to be a highly effective causal prophylaxis. Prevention of malaria, without folic acid supplements, reduced the frequency of megaloblastic erythropoiesis from 56% to 25%. Folic acid supplements abolished megaloblastosis, except in three patients who were apparently not taking the treatment prescribed. Red cell folate (RCF) concentrations were higher in subjects with malaria, probably due to intracellular synthesis by plasmodia. Infants of mothers not receiving antimalarials appeared to have an erythroid hyperplasia. Maternal folate supplements raised infants' serum folate and RCF. Fourteen per cent had low birth weight (less than 2500 g), and the perinatal death rate was 11%; the greatest number were in group 1, but not significantly. A regime is proposed for the prevention of malaria, iron deficiency, folate deficiency and anaemia in pregnancy in the guinea savanna of Nigeria. The control of childhood anaemia in malaria holoendemic areas is a major public health challenge for which an optimal strategy remains to be determined. Malaria prevention may compromise the development of partial immunity. Regular micronutrient supplementation has been suggested as an alternative but its effectiveness remains unsettled. We therefore conducted a randomised placebo-controlled intervention trial with 207 Tanzanian children aged 5 months to 3 years on the efficacy of supervised supplementation of low-dose micronutrients including iron (Poly Vi-Sol with iron) three times per week, with an average attendance of >/= 90%. The mean haemoglobin (Hb) level increased by 8 g/l more in children on supplement (95% CI 3-12) during the 5-month study. All age groups benefited from the intervention including severely anaemic subjects. The mean erythrocyte cell volume (MCV) increased but Hb in children >/= 24 months improved independently of MCV and no relation was found with hookworm infection. The data therefore suggest that micronutrients other than iron also contributed to Hb improvement. In the supplement group of children who had received sulfadoxine-pyrimethamine (SP) treatment, the mean Hb level increased synergistically by 22 g/l (95% CI 13-30) compared to 7 g/l (95% CI 3-10) in those without such treatment. Supplementation did not affect malaria incidence. In conclusion, micronutrient supplementation improves childhood anaemia in malaria holoendemic areas and this effect is synergistically enhanced by temporary clearance of parasitaemia. Malaria is a major cause of infant morbidity and mortality in sub-Saharan Africa, and is often complicated by severe anaemia. Resistance of Plasmodium falciparum to most affordable antimalarial drugs is an impediment to intermittent chemotherapy. We investigated the effect of presumptive intermittent treatment with amodiaquine and daily iron supplementation in infants on malarial fevers and anaemia, in a holoendemic area of Tanzania where malaria is largely resistant to chloroquine and sulfadoxine/ pyrimethamine.
                291 infants aged 12-16 weeks who attended three clinics were randomised to receive amodiaquine, iron supplementation, amodiaquine plus iron supplementation, or placebo. Over 6 months, we gave amodiaquine three times with intervals of 60 days; oral iron supplementation was given daily. Malarial fevers and anaemia were monitored at bimonthly treatment visits and by self-reporting to health centres.
                The protective efficacy of intermittent amodiaquine treatment in prevention of malarial fevers and anaemia was 64.7% (95% CI, 42.4-77.2) and 67.0% (95% CI, 34.5-83.4), respectively. Protective efficacy was similar in the group receiving amodiaquine plus iron supplementation. Infants receiving iron supplementation only were partly protected against anaemia (protective efficacy 59.8%; 95% CI, 23.4-78.9), but not against malarial fevers. 4 months' follow-up did not show rebound morbidity. We noted no haematological or clinical adverse effects.
                Presumptive intermittent treatment for malaria with amodiaquine reduced malarial fevers and anaemia in infants, in an area with high resistance to other antimalarials. Intermittent treatment strategies for malaria in highly endemic areas could be of great benefit to public health. Iron supplementation is recommended for children at high risk of anaemia, but its benefits may not outweigh the associated risk of malaria in areas of seasonal transmission. We investigated the effect on haemoglobin concentrations of intermittent administration of iron supplements and sulfadoxine-pyrimethamine in symptom-free children under intense health surveillance.
                In a trial of two by two factorial design, 328 anaemic Kenyan children were randomly assigned either iron or placebo and sulfadoxine-pyrimethamine or placebo (82 to each group). Primary outcomes were haemological indicators of iron status and inflammation at the end of the follow-up, and occurrence of malaria attacks. Morbidity surveillance consisted of medical examinations every 4 weeks, continuous passive case detection, and visits twice a week to community health-workers. Analyses were by intention to treat.
                After 12 weeks, the groups assigned iron plus sulfadoxine-pyrimethamine, iron alone, or sulfadoxine-pyrimethamine alone had higher haemoglobin concentrations than the group assigned placebo (treatment effect adjusted for prognostic factors at baseline: 11.1 g/L [95% CI 7.5 to 14.7]; 10.7 g/L [7.1 to 14.3]; and 3.1 g/L [-0.5 to 6.7]). Administration of iron plus sulfadoxine-pyrimethamine also lowered the proportion with anaemia from 100% at baseline to 36% at 12 weeks, and of iron deficiency from 66% at baseline to 8% at 12 weeks. Survival analysis showed no evidence of substantially increased risk of malaria after iron supplementation.
                Iron supplementation gives substantial health benefits, which may outweigh possible inherent risks caused by malaria. A larger study than ours is needed to assess benefits and risks of intermittent administration of sulfadoxine-pyrimethamine in reducing the incidence of malaria attacks in areas of seasonal malaria transmission. 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.
                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.
                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.
                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. A randomized, placebo-controlled treatment trial was conducted among 546 anemic (hemoglobin concentration, 7-11 g/dL) children aged 2-36 months in an area with intense malaria transmission in western Kenya. All children used bednets and received a single dose of sulfadoxine-pyrimethamine (SP) on enrollment, followed by either intermittent preventive treatment (IPT) with SP at 4 and 8 weeks and daily iron for 12 weeks, daily iron and IPT with SP placebo, IPT and daily iron placebo, or daily iron placebo and IPT with SP placebo (double placebo). The mean hemoglobin concentration at 12 weeks, compared with that for the double-placebo group, was 1.14 g/dL (95% confidence interval [CI], 0.82-1.47 g/dL) greater for the IPT+iron group, 0.79 g/dL (95% CI, 0.46-1.10 g/dL) greater for the iron group, and 0.17 g/dL (95% CI, -0.15-0.49 g/dL) greater for the IPT group. IPT reduced the incidence of malaria parasitemia and clinic visits, but iron did not. The combination of IPT and iron supplementation was most effective in the treatment of mild anemia. Although IPT prevented malaria, the hematological benefit it added to that of a single dose of SP and bednet use was modest. Conflicting evidence exists on the possible role of iron supplementation in the predisposition to malaria infection or the enhancement of its clinical severity. Where anemia prevalence is >40%, current guidelines are to provide low-dose daily iron to young children for up to 18 mo. Earlier studies used doses higher than the current guidelines, intermittent doses, or have supplemented for durations < or = 4 mo. We aimed to assess the effect of low-dose, long-term iron supplementation on malaria infection using a double-blind, placebo-controlled, randomized design, and to examine possible subgroup effects by season and child age. The study was conducted in Pemba Island, Zanzibar, where Plasmodium falciparum malaria has year-round high transmission. A community-based sample of 614 children 4-71 mo old was randomly allocated to 10 mg/d iron or placebo for 12 mo. Outcome measures were the prevalence and density of malaria infection, which was assessed by blood films at monthly intervals. At baseline, 94.4% were anemic (hemoglobin < 110 g/L), 48.1% were stunted (height-for-age Z-score less than -2) and >80% had malaria-positive blood films. No significant differences in malariometric indices were observed between children in the iron-supplemented and placebo groups. Parasite density was higher in certain months and in younger children, but iron supplementation was not associated with any malarial infection outcome in any season or age subgroup. We conclude that in this environment of high malaria transmission, daily oral low-dose supplementation of iron for 12 mo did not affect the prevalence of malaria infection or parasite density. The optimum management of children with severe malarial anaemia is still uncertain. Hence, we have undertaken a study to determine whether iron treatment is as effective at restoring haemoglobin levels one month after presentation as blood transfusion without iron treatment in children with moderately severe malarial anaemia. Two hundred and eighty-seven children with a packed cell volume (PCV) < 15% and malaria infection were recruited into the study; 173 children were assigned to receive blood transfusion because they had a PCV < 12% and/or signs of respiratory distress and the remaining 114 children were allocated at random to receive either blood transfusion (58) or treatment with oral iron (56) for 28 d. Twenty-four children died, 23 in the most severely anaemic group. Fifteen children (65%) died before transfusion was given and most deaths occurred within the first 4 h of admission. One child died in the iron treatment group and 10 subsequently required transfusion. Among the severely anaemic children, those with respiratory distress were at greater risk of death than those without respiratory distress. After 28 d, haematological restoration was significantly better in children who had received iron than in those treated by blood transfusion (P = 0.02). Children who received malaria chemoprophylaxis after discharge from hospital had fewer episodes of malaria and subsequent admissions to a hospital or health centre than those who did not. Children with severe anaemia and clinical signs of respiratory distress must be identified quickly and transfused as soon as possible. However, for less severely anaemic children who are clinically stable, iron therapy offers an alternative to transfusion provided such children can be kept under surveillance and transfused subsequently should this become necessary. The effect of iron therapy on malarial infection was investigated in Papua New Guinea, where malaria is endemic. Prepubescent schoolchildren with hemoglobin levels of 8-12 g/dl were randomly assigned to receive either 200 mg ferrous sulfate or a placebo twice daily for 16 weeks. Iron status and malarial infection were assessed at baseline, after 6 and 16 weeks of therapy, and 8 weeks after therapy was discontinued. Iron status was significantly improved by the treatment. The treatment did not significantly affect parasite rate, parasite density, or levels of anti-malarial IgG. No changes in spleen size were observed in either group. Furthermore, there was no significant difference between the groups in reported episodes of suspected malaria during the therapy. These results suggest that, in malaria endemic areas, oral treatment for iron deficiency can be carried out in semi-immune or immune schoolchildren without adverse consequences. A randomized, double-blind, placebo-controlled community-based trial of oral iron supplementation (200 mg ferrous sulphate daily) administered to multigravid pregnant women by traditional birth attendants (TBAs) was carried out in a rural area of The Gambia. Iron supplementation led to a significant reduction in the prevalence of anaemia and of iron deficiency. Iron supplementation was not accompanied by increased susceptibility to malaria infection; there was no difference in the prevalence and severity of peripheral blood or placental malaria infection between the 2 groups of women. The birth weight of children born to women who received iron prophylaxis was increased by an average of 56 g. It is concluded that oral iron prophylaxis can be successfully delivered through TBAs integrated into a primary health care programme. This simple intervention can produce significant beneficial effects on the health of the mother without inducing increased susceptibility to malaria and has the potential for reducing perinatal mortality by increasing birth weight. Iron and zinc deficiencies are common in developing countries and supplementation is one way of reversing these deficiencies. The objective of this randomized, placebo-controlled clinical trial was to identify the effect of daily supplementation with iron, zinc, and iron plus zinc on the morbidity experience of 855 children 0.5-15 years of age in Peru. Single nutrient supplementation with zinc reduced diarrhea morbidity by 23% in all children. In older children (more than five years of age), iron supplementation increased morbidity due to Plasmodium vivax and diarrhea. In younger children, iron combined with zinc provided protection against P. vivax malaria, but also interfered with some of the diarrhea protection associated with zinc supplementation. No statistically significant effect was observed of either supplement on incidence of respiratory infection or anthropometric indices. Iron and zinc deficiencies should be remedied, and combined supplementation may be a good option, particularly in younger children in P. vivax malaria-endemic areas, although local endemicity and species-specific prevalence should be considered carefully when designing any supplementation program involving iron in a malaria-endemic area. Malaria and anaemia are the leading causes of morbidity and mortality in children in sub-Saharan Africa. We have investigated the effect of intermittent preventive treatment with sulphadoxine-pyrimethamine or artesunate plus amodiaquine on anaemia and malaria in children in an area of intense, prolonged, seasonal malaria transmission in Ghana.
                2451 children aged 3-59 months from 30 villages were individually randomised to receive placebo or artesunate plus amodiaquine (AS+AQ) monthly or bimonthly, or sulphadoxine-pyrimethamine (SP) bimonthly over a period of six months. The primary outcome measures were episodes of anaemia (Hb<8.0 g/dl) or malaria detected through passive surveillance.
                Monthly artesunate plus amodiaquine reduced the incidence of malaria by 69% (95% CI: 63%, 74%) and anaemia by 45% (95% CI: 25%,60%), bimonthly sulphadoxine-pyrimethamine reduced the incidence of malaria by 24% (95% CI: 14%,33%) and anaemia by 30% (95% CI: 6%, 49%) and bimonthly artesunate plus amodiaquine reduced the incidence of malaria by 17% (95% CI: 6%, 27%) and anaemia by 32% (95% CI: 7%, 50%) compared to placebo. There were no statistically significant reductions in the episodes of all cause or malaria specific hospital admissions in any of the intervention groups compared to the placebo group. There was no significant increase in the incidence of clinical malaria in the post intervention period in children who were >1 year old when they received IPTc compared to the placebo group. However the incidence of malaria in the post intervention period was higher in children who were <1 year old when they received AS+AQ monthly compared to the placebo group.
                IPTc is safe and efficacious in reducing the burden of malaria in an area of Ghana with a prolonged, intense malaria transmission season.
                ClinicalTrials.gov NCT00119132. In order to increase the intestinal absorption of iron whilst simultaneously minimising the side-effects and thus increasing compliance, once- or twice-weekly, instead of daily, iron supplementation has been widely recommended. In a randomized, placebo-controlled, double-blind study in western Kenya, a tablet of ferrous dextran (containing 60 mg elemental iron) or an identical-looking placebo tablet was provided twice-weekly for 12 months to each child or adult investigated. At baseline each subject had a moderately low blood concentration of haemoglobin (Hb). Initial Hb and serum ferritin (SF) concentrations were determined and each subject was tested for malarial and helminth infection and treated, if necessary, with the appropriate anthelminthic drug(s). Overall, 200 children (aged 4-15 years) and 129 adults (aged 16-63 years) completed the 12-month study. At baseline, 47.5% of the children and 58.1% of the adults were anaemic, hookworm (detected in 60.0% of the children and 69.9% of the adults) was the most common helminth infection, and malaria was endemic. The results of bivariate analyses indicated that twice-weekly iron supplementation had no significant effect on blood Hb or SF concentrations, either in the children or the adults investigated. The results were confirmed in multiple linear-regression analyses, which revealed that the predictors of the final Hb concentration in the children investigated were age and infection, after enrollment, with Ascaris lumbricoides. Gender and the serum concentration of alpha-1-antichymotrypsin (ACT) at final follow-up were predictors of the final SF concentration in the children. In adults, the predictors of the final Hb concentration were gender and HIV infection, and the predictors of the final SF concentration were age and the serum concentration of ACT at the final follow-up. Twice-weekly iron supplementation did not increase Hb or iron stores in children or adults. Since compliance appeared to be high, this lack of effect may be the result of an inadequate dose of iron or of subjects who have deficiencies in micronutrients other than iron. A prospective comparison of the antimalarial efficacy of bed nets was conducted with 341 pregnant women living in a mesoendemic malarious area of the Thai-Burmese border. Women in 3 adjacent study sites were allocated at random to receive either a single size permethrin-impregnated bed net (PIB), a non-impregnated bed net (NIB), or to a control group who used either their own family size non-impregnated bed net (FNIB) or no net. In one study site, but not the other 2, PIB significantly reduced parasite densities and, together with FNIB, reduced the incidence of malaria in pregnancy from 56% to 33% (relative risk = 1.67, confidence interval = 1.07-2.61, P = 0.03, allowing for parity). Anaemia proved a more sensitive marker of bed net antimalarial efficacy than parasite rates. The incidence of anaemia (haematocrit < 30%) at all study sites was significantly lower at delivery in the PIB (27%) and FNIB groups (21%) than in the NIB group (41%) or those using no net (56%). This suggests that a significant proportion of the malaria in pregnancy in this mesoendemic area was sub-patent. Both patent Plasmodium falciparum parasitaemia and anaemia were associated with a reduction in birth weight. Infant mortality was high (16%) and strongly associated with prematurity, low birth weight and maternal anaemia. PIB were well tolerated and had no apparent adverse effect on the pregnancy or infant development. Although the overall effect of bed nets on patent parasitaemia was marginal, they were associated with a significant reduction in maternal malaria-associated anaemia.(ABSTRACT TRUNCATED AT 250 WORDS) Iron deficiency and anemia remain among the most important global public health problems facing school children. Helminth infections often peak at school age and aggravate nutritional risks. We conducted a 12-wk randomized controlled trial in 406 Malian anemic schoolchildren infected with Schistosoma hematobium to examine the effects of 2 doses of praziquantel (P) (40 mg/kg body weight), P + 60 mg/d iron (Fe), and/or a multiple micronutrient supplement (MM) that included 18 mg/d Fe. Supplements were administered to the children each school day (5 d/wk) throughout the study. Changes in hemoglobin (Hb), serum ferritin (SF), and serum transferrin receptors (s-TfR) were followed. We also examined interactions between Fe and MM supplements on Hb and SF concentrations and malaria incidence. The effects of Fe on Hb and SF concentrations were greater than the effects of P alone and MM with or without added Fe at 6 and 12 wk (P < 0.001). In all groups, s-TfR decreased at 6 and 12 wk compared with baseline. The decrease was most pronounced in the P + Fe group compared with the other 3 groups at wk 6 (P = 0.05). Fe and MM interacted negatively at wk 6 and 12 to affect Hb (beta = -0.43, 95% CI = -0.77, -0.09; P = 0.01 and beta = -0.47, 95% CI = -0.83, -0.11; P = 0.01, respectively) and SF (beta = -0.42, 95% CI = -25.60, 12.31; P < 0.001, and beta = -0.37, 95% CI = -0.63, -0.12; P = 0.004, respectively). Malaria incidence was higher in the groups treated with added Fe (relative risk: 1.66; 95% CI: 0.75, 3.67). In this context, MM with added iron were not more effective than Fe without MM. Fe supplementation of schoolchildren with 60 mg/d for anemia control should be considered carefully. Iron deficiency anemia is a major public health problem in developing countries and may affect school performance and physical work capacity in nonpregnant adolescents, and may increase the risk of anemia during subsequent teenage pregnancies. We assessed the effect of weekly iron (120 mg elemental iron) and vitamin A (25 000 IU) supplementation on hemoglobin, iron status and malaria and nonmalaria morbidity in adolescent schoolgirls.
                A total of 279 schoolgirls aged 12-18 years from public primary schools in Kisumu, western Kenya. Double-blind randomized placebo-controlled trial using a factorial design.
                Five months of iron supplementation was associated with a 0.52 g dl(-1) (0.21, 0.82) greater increase in hemoglobin relative to iron placebo. The effect was only observed in girls with iron deficiency on enrollment (1.34 g dl(-1) (0.79, 1.88)), but not in iron-replete girls (-0.20 g dl(-1) (-0.59, 0.18)). Similar differences in treatment effect were seen between menstruating and nonmenstruating girls. The effect of iron was independent of vitamin A. The baseline prevalence of vitamin A deficiency was low (6.7%) and no sustained increase in hemoglobin was seen with weekly vitamin A (-0.07 g dl(-1) (-0.38, 0.25)). Incidence of malaria parasitemia was higher in the iron than iron-placebo groups (Rate ratio 1.33 (0.94, 1.88)).
                Weekly iron supplementation results in substantial increases in hemoglobin concentration in adolescent schoolgirls in western Kenya, which may outweigh possible risks caused by malaria, but only in iron-deficient or menstruating girls and not in iron-replete and nonmenstruating girls. While the parenteral iron-chelating agent desferrioxamine B has anti-malarial activity in humans, the usefulness of an orally active chelator for this indication has not been investigated previously in vivo. We conducted a prospective, double-blind, placebo-controlled, cross-over trial of deferiprone (L1; CP20; 1,2-dimethyl-3-hydroxypyridin-4-one) in 25 adult Zambians with asymptomatic Plasmodium falciparum parasitemia. Deferiprone was administered daily for three or four days in divided doses of 75 or 100 mg/kg of body weight, dosages that are effective for treating iron overload. No reduction in asexual intra-erythrocytic parasites was observed during or after deferiprone treatment. The mean peak plasma concentration of deferiprone (108.9 +/- 24.9 micromol/L) achieved was within the range demonstrated to inhibit the growth of P. falciparum in vitro, but the systemic exposure as determined by the 24-hr plasma concentration-time curve would not be predicted inhibit growth in vivo. No evidence of deferiprone-associated hematological toxicity was noted in this short-term study of these subjects, all of whom had clinical evidence of normal body iron stores. Because of the risk of neutropenia and other adverse effects with higher doses or prolonged use of the chelator, additional trials of deferiprone as a sole anti-malarial agent would not seem to be justified. In contrast, further efforts are needed to develop other orally active iron-chelating agents specifically for their anti-malarial action. To measure the effects of iron supplementation and anthelmintic treatment on iron status, anaemia, growth, morbidity, and development of children aged 6-59 months.
                Double blind, placebo controlled randomised factorial trial of iron supplementation and anthelmintic treatment.
                Community in Pemba Island, Zanzibar.
                614 preschool children aged 6-59 months.
                Development of language and motor skills assessed by parental interview before and after treatment in age appropriate subgroups.
                Before intervention, anaemia was prevalent and severe, and geohelminth infections were prevalent and light-Plasmodium falciparum infection was nearly universal. Iron supplementation significantly improved iron status, but not haemoglobin status. Iron supplementation improved language development by 0.8 (95% confidence interval 0.2 to 1.4) points on the 20 point scale. Iron supplementation also improved motor development, but this effect was modified by baseline haemoglobin concentrations (P=0.015 for interaction term) and was apparent only in children with baseline haemoglobin concentrations <90 g/l. In children with a baseline haemoglobin concentration of 68 g/l (one standard deviation below the mean value), iron treatment increased scores by 1.1 (0.1 to 2.1) points on the 18 point motor scale. Mebendazole significantly reduced the number and severity of infections caused by Ascaris lumbricoides and Trichuris trichiura, but not by hookworms. Mebendazole increased development scores by 0.4 (-0.3 to 1.1) points on the motor scale and 0.3 (-0.3 to 0.9) points on the language scale.
                Iron supplementation improved motor and language development of preschool children in rural Africa. The effects of iron on motor development were limited to children with more severe anaemia (baseline haemoglobin concentration <90 g/l). Mebendazole had a positive effect on motor and language development, but this was not statistically significant. The effects of oral iron supplementation on blood iron levels and learning achievement in 130 rural Indonesian school children were assessed in this double-blind study. The children were classified into anemic and nonanemic groups according to their initial hemoglobin and transferrin saturation levels and were randomly assigned to either iron or placebo treatment for 3 mo. Hematological, anthropometric, and learning-achievement data were collected before (T1) and after (T2) the treatment period and 3 mo later. The means and standard deviations suggest that supplementation with 10 mg ferrous sulfate per kilogram body weight per day for 3 mo resulted in an apparent improvement in anemic subjects' hematological status and learning-achievement scores. No tests of statistical comparisons are reported. A recent meta-analysis of 14 clinical trials indicated that daily compared with intermittent iron supplementation resulted in significantly greater hematological improvement in pregnant women. No such definitive beneficial effect was demonstrated in preschool children. We compared the efficacy of daily and twice weekly iron supplementation for 6 wk under supervised and unsupervised conditions in the treatment of mild and moderate anemia [hemoglobin (Hb) 50-109 g/L] in children aged 2-59 mo living in a malaria-endemic area of western Kenya. The study was a cluster-randomized trial using a factorial design; participants were aware of the treatment assigned. All children (n = 1049) were administered a single dose of sulfadoxine-pyrimethamine at enrollment followed by 6 wk of daily supervised iron supplementation [3-6 mg/(kg.d)], twice weekly supervised iron supplementation [6-12 mg/(kg.wk)], daily unsupervised iron supplementation, or twice weekly unsupervised iron supplementation. In the supervised groups, Hb concentrations at 6 and 12 wk (6 wk postsupplementation) were significantly higher in children given iron daily rather than twice weekly [mean (95% CI) difference at 6-wk: 4.2 g/L (2.1, 6.4); 12-wk: 4.4 g/L (1.8, 7.0)]. Among the unsupervised groups, Hb concentrations were not different at 6 wk [mean (95% CI) difference: 0.86 g/L (-1.4, 3.1)], but significantly higher at 12 wk for those assigned daily iron [mean (95% CI) difference: 3.4 g/L (0.79, 6.0), P = 0.02]. In this malarious area and after initial antimalarial treatment, 6 wk of daily iron supplementation results in better hematological responses than twice weekly iron supplementation in the treatment of anemia in preschool children, regardless of whether adherence can be ensured. To examine the effect of iron chelation against human malaria, 37 Zambians with asymptomatic Plasmodium falciparum infections were randomly assigned to 72-hr infusions of desferrioxamine B or placebo. Mean concentrations of ring forms decreased significantly with desferrioxamine B (P < 0.001) but not with a placebo. Over seven days of observation, mean parasite concentrations remained at the initial levels in six individuals originally given placebo, but decreased promptly with administration of desferrioxamine B (P = 0.001). Mean parasitemia was significantly lower for up to four weeks in 16 subjects treated with desferrioxamine B when compared with the eight who had received placebo only (P = 0.027). We conclude that iron chelation has antiplasmodial activity and may offer a new therapeutic strategy for falciparum malaria. Cerebral malaria is a severe complication of Plasmodium falciparum infection in children, with a mortality rate of 15 to 50 percent despite antimalarial therapy.
                To determine whether combining iron chelation with quinine therapy speeds the recovery of consciousness, we conducted a randomized, double-blind, placebo-controlled trial of the iron chelator deferoxamine in 83 Zambian children with cerebral malaria. To be enrolled, patients had to be less than six years old, have P. falciparum parasitemia, have normal cerebrospinal fluid without evidence of bacterial infection, and be in a coma from which they could not be aroused. Deferoxamine (100 mg per kilogram of body weight per day, infused intravenously for 72 hours) or placebo was added to standard therapy with quinine and sulfadoxine-pyrimethamine. The time to the recovery of full consciousness, time to parasite clearance, and mortality were examined with Cox proportional-hazards regression analysis.
                The rate of recovery of full consciousness among the 42 patients given deferoxamine was 1.3 times that among the 41 given placebo (95 percent confidence interval, 0.7 to 2.3); the median time to recovery was 20.2 hours in the deferoxamine group and 43.1 hours in the placebo group (P = 0.38). Among 50 patients with deep coma, the rate of recovery of full consciousness was increased 2.2-fold with deferoxamine (95 percent confidence interval, 1.1 to 4.7), decreasing the median recovery time from 68.2 to 24.1 hours (P = 0.03). Among 69 patients for whom data on parasite clearance were available, the rate of clearance with deferoxamine was 2.0 times that with placebo (95 percent confidence interval, 1.2 to 3.6). Among all 83 patients, mortality was 17 percent in the deferoxamine group and 22 percent in the placebo group (P = 0.52).
                Iron chelation therapy may hasten the clearance of parasitemia and enhance recovery from deep coma in cerebral malaria. WHO recommends that anthelmintic treatment be included in strategies to improve maternal nutrition in areas where hookworms are endemic and anaemia is prevalent. At present, few countries have adopted this recommendation, partly owing to the lack of data to support the adverse effects of hookworms on maternal health. A longitudinal study was conducted on 125 women in Sierra Leone (in 1995/96) to measure the impact of single-dose albendazole (400 mg) and daily iron-folate supplements (36 mg iron and 5 mg folate) on haemoglobin and serum ferritin concentration during pregnancy. Women who received both albendazole and iron-folate supplements experienced no significant change (P > 0.05) in the prevalence of anaemia and iron-deficiency anaemia between the first and third trimesters. These prevalence levels significantly increased (P < 0.05) in women who received either albendazole or iron-folate supplements or neither. After controlling for baseline haemoglobin concentration and season, the mean decline in haemoglobin concentration between the first and third trimester in women who received albendazole was 6.6 g/L less than in women who received the control (P = 0.0034). The corresponding value for iron-folate supplements was 13.7 g/L haemoglobin (P < 0.001). The effects of albendazole and iron-folate supplements were additive. These findings lend support to WHO's recommendation for anthelmintic treatment during pregnancy. Seventy-nine comatose cerebral malaria patients given standard supportive treatment were randomized to receive specific antimalarial chemotherapy of intravenous quinine, intravenous artesunate, or artemisinin suppositories. Artesunate and artemisinin reduced peripheral asexual parasitaemia significantly more rapidly than quinine (90% clearance time 16 h, 18.9 h and 34.5 h respectively), but did not significantly reduce the duration of coma or mortality. The rapid lowering of peripheral parasitaemia may not ameliorate complications already present. These results demonstrate that artemisinin suppositories are as effective as artesunate and quinine given intravenously, and have economic and practical advantages for the treatment of severe malaria in areas remote from major medical centres. However, large numbers of patients will need to be studied if differences in mortality between the 3 treatment groups are to be demonstrated. In the Sahel and sub-Sahelian regions of Africa, malaria transmission is highly seasonal. During a short period of high malaria transmission, mortality and morbidity are high in children under age 5 years. We assessed the efficacy of seasonal intermittent preventive treatment-a full dose of antimalarial treatment given at defined times without previous testing for malaria infection.
                We did a randomised, placebo-controlled, double-blind trial of the effect of intermittent preventive treatment on morbidity from malaria in three health-care centres in Niakhar, a rural area of Senegal. 1136 children aged 2-59 months received either one dose of artesunate plus one dose of sulfadoxine-pyrimethamine or two placebos on three occasions during the malaria transmission season. The primary outcome was a first or single episode of clinical malaria detected through active or passive case detection. Primary analysis was by intention-to-treat. This study is registered with , number NCT00132561.
                During 13 weeks of follow-up, the intervention led to an 86% (95% CI 80-90) reduction in the occurrence of clinical episodes of malaria. With passive case detection, protective efficacy against malaria was 86% (77-92), and when detected actively was 86% (78-91). The incidence of malaria in children on active drugs was 308 episodes per 1000 person-years at risk, whereas in those on placebo it was 2250 episodes per 1000 person-years at risk. 13 children were not included in the intention-to-treat analysis, which was restricted to children who received a first dose of antimalarial or placebo. There was an increase in vomiting in children who received the active drugs, but generally the intervention was well tolerated.
                Intermittent preventive treatment could be highly effective for prevention of malaria in children under 5 years of age living in areas of seasonal malaria infection. Severe malaria remains a major cause of mortality and morbidity for children living in many tropical regions. With the emergence of strains of Plasmodium falciparum resistant to both chloroquine and quinine, alternative antimalarial agents are required. The artemisinin group of compounds are rapidly effective in severe disease when given by intramuscular or intravenous injection. However, these routes of administration are not always available in rural areas. In an open, randomized comparison 109 Vietnamese children, aged between 3 months and 14 years, with severe P.falciparum malaria, were allocated at random to receive artemisinin suppositories followed by mefloquine (n = 37), intramuscular artesunate followed by mefloquine (n = 37), or intravenous quinine followed by pyrimethamine/sulfadoxine (n = 35). There were 9 deaths: 2 artemisinin, 4 artesunate and 5 quinine-treated children. There was no difference in fever clearance time, coma recovery, or length of hospital stay among the 3 groups. However, parasite clearance times were significantly faster in artemisinin and artesunate-treated patients than in those who received quinine (P < 0.0001). Both artemisinin and artesunate were very well tolerated, but children receiving these drugs had lower peripheral reticulocyte counts by day 5 of treatment than those in the quinine group (P = 0.011). No other adverse effect or toxicity was found. There was no treatment failure in these 2 groups, but 4 patients in the quinine group failed to clear their parasites within 7 d of starting treatment and required alternative antimalarial therapy. Artemisinin suppositories are easy to administer, cheap, and very effective for treating children with severe malaria. In rural areas where medical facilities are lacking these drugs will allow antimalarial therapy to be instituted earlier in the course of the disease and may therefore save lives. To assess the effects of iron supplementation on immunological parameters of adolescents with varying iron status.
                Adolescents of both sexes with varying iron status were allocated to four treatment groups by using inclusion criteria. Three of the four groups received iron(III)-hydroxide polymaltose complex (IPC, Maltofer) containing 100 mg of iron 6 days a week for 8 months. The fourth group was given a placebo. Immunological parameters were assessed at baseline and after 4 and 8 months of supplementation.
                Increases from baseline to 4 months and from 4 to 8 months of supplementation were observed for Bactericidal Capacity of Neutrophils (BCA), NitroBlue Tetrazolium Reduction Test (NBT), and phytohaemagglutinin (PHA) in all three supplemented groups. No increase was found in the control placebo group except for PHA. No side effects were noted in any participants.
                IPC supplementation for eight months led to significant improvements of immunological parameters in iron deficient adolescents with and without anemia. To assess the impact of a daily oral iron supplementation on hematological status, cell-mediated immunity and susceptibility to infections in children living in an environment where iron deficiency, malaria and other infections are frequent.
                Randomized, double-blind iron supplementation including a placebo group.
                A village in Togo, West Africa.
                Of the 229 6-36-month-old children of both sexes recruited, 197 with hemoglobin concentration >/=80 g/l were included and 163 completed the study.
                Children received daily a placebo (n=79) or a dose of 2-3 mg of elemental iron per kg of body weight (n=84) for 3 months. Hematological, nutritional and immune status were assessed at the beginning and at the end of the supplementation period, and 6 months later. Morbidity was recorded throughout the study.
                Iron supplementation had a significant and positive effect on iron status of children and no impact on the incidence of infections, especially malaria. Its probable effect on immune status was masked by interference of infections and their treatment, which contributed to improve hematological and immune status in both groups.
                According to the negative consequences of anemia and iron deficiency on global child development, control of iron deficiency by oral iron supplementation in young children has to be conducted, associated with prophylaxis and treatment of malaria and repeated deworming.
                Program supported by IRD. European Journal of Clinical Nutrition (2000) 54, 29-35 The effectiveness of insecticide-treated bednets (ITBN) in preventing malaria and anaemia among primigravidae living in Kilifi District, Kenya, was assessed by a randomized controlled trial between September 1994 and November 1995. All residents within 28 community clusters received ITBN in July 1993, whilst residents of another 28 clusters served as contemporaneous controls. All resident primigravid women with singleton pregnancies attending antenatal care at Kilifi District Hospital were eligible for recruitment. 503 primigravidae were recruited. 91.4% were anaemic antenatally (Hb < 11 g/dl): 91.0% from the intervention arm and 92.0% from the control arm. Severe anaemia (Hb < 7 g/dl) was found among 15.1% of intervention women and 20.1% of control women (P = 0.28). No significant differences were observed in reports of febrile illness or the presence of chloroquine in the serum or peripheral parasitaemia during the third trimester between the two groups. In the women delivering in hospital (n = 130), there was no association between placental malaria infection and the intervention: 77.4% of placentas from control women had evidence of past or active infection, compared with 72.0% of placentas from intervention women (P = 0.76). Similarly, in the women delivering in hospital, ITBN did not improve birth weight, and there were no differences in perinatal mortality between the two study groups. Despite ITBN having a great impact on paediatric severe malaria and mortality in this transmission setting, there was very little impact of ITBN on the morbidity associated with malaria infection in primigravidae. Alternative strategies are required to tackle this continued public health problem for pregnant women living in endemic areas similar to the Kenyan Coast. The emergence and spread of Plasmodium falciparum resistance to commonly used antimalarials such as chloroquine and sulphadoxine/pyrimethamine poses major challenges to malaria control in sub-Saharan Africa. We undertook a study on the efficacy of some antimalarial drugs in 2003 with the view of supporting the National Malaria Control Programme in the review of the antimalarial drug treatment policy in Ghana. Children aged 6-59 months with signs/symptoms of uncomplicated malaria including axillary temperature > or =37.5 degrees C; mono infection with P. falciparum; and parent's willingness to give consent, were randomized into four treatment groups and followed up for a maximum of 28 days. The treatment groups were chloroquine (CHQ), sulphadoxine/pyrimethamine (SP), amodiaquine+artesunate (ADQ+ART) combination, and artemether+lumefantrine (Coartem) combination. Clinical evaluation of 168 children studied showed that cumulative pcr-corrected cure rates on day 28 were 100% for ADQ+ART; 97.5% for coartem, 60% for SP and 25% for CHQ. The artemisinin-based combinations effected rapid fever and parasite clearance. Prevalence of gametocytaemia was highest in the SP group whilst the CHQ group did not show any significant changes in haemoglobin levels during the follow-up period. The findings are in agreement with current recommendations for using artemisinin-based combinations for treating uncomplicated malaria in areas of high CHQ failure such as Ghana. To determine if iron chelation therapy has activity against human malaria, we administered desferrioxamine B in amounts of 100 mg/kg per day by continuous 72-hour subcutaneous infusions to 28 volunteers with asymptomatic Plasmodium falciparum infection in a randomized, double-blind, placebo-controlled crossover trial. Peripheral blood concentrations of P falciparum ring forms were determined at 12-hour intervals in all subjects and serum concentrations of desferrioxamine B + ferrioxamine (the iron complex of desferrioxamine B) were measured in 26 subjects. Geometric mean concentrations of asexual intraerythrocytic parasites decreased with both chelator and placebo treatment, but the decrement with desferrioxamine B was significantly greater than that with placebo (P less than .006) during both the initial and crossover periods. Compared with placebo, desferrioxamine B treatment was associated with an almost 10-fold enhancement of the rate of parasite clearance during both phases of the trial (P less than .007). Mean +/- SEM steady state concentrations of desferrioxamine B + ferrioxamine were 6.90 +/- 0.60 mumol/L at 36 hours and 7.72 +/- 0.68 mumol/L at 72 hours; in vitro, the ID50 has been reported to be approximately 4 to 20 mumol/L. No drug toxicity was detected. Parasitemia recurred in 19 of 24 participants followed-up over 1 to 6 months. We conclude that desferrioxamine B enhances the clearance of P falciparum parasitemia and that iron chelation may provide a new strategy to be developed for the treatment of malaria. The effect of oral iron supplementation on blood Fe levels and physical growth in 119 rural Indonesian school children was assessed in this double-blind study. The children were classified into anemic and normal groups according to their initial hemoglobin and transferrin saturation levels and were randomly assigned to either Fe or placebo treatment for 12 wk. Hematological, anthropometric, and morbidity data were collected before and after the treatment period. Before treatment, anemic subjects were smaller and had higher morbidity than normal subjects. Treatment with 10 mg ferrous sulfate.kg-1.d-1 for 12 wk resulted in a significant improvement in anemic subjects' hematological status, growth velocity, and level or morbidity. Studies on the treatment and prevention of iron deficiency anemia, in pregnant and nonpregnant women and in men, were conducted in Thailand and Burma. The effects of the dose of Fe, duration of Fe administration, additional supplementation with folate, mode of supplement delivery (either supervised or unsupervised), and the presence of Hb(AE) were studied. The frequency and severity of side effects were also recorded. Fe administration resulted in an increase in hemoglobin concentration in all anemic individuals but approximately 20% failed to reach normality. The length of administration and the dose influenced the results. Frequency and severity of side effects increased with the dose of Fe administered. Folate supplementation did not affect the results. It appears possible to integrate a program of prevention and treatment of Fe deficiency anemia in a primary health-care system but the constraints and limitations of achievable results should be recognized. To determine the effectiveness of combined iron and zinc over the iron or zinc-only supplementation in correcting deficiency and possible interactive effects in a group of adolescent school children.
                Schoolchildren (n=821) of 12-16 years of age were randomized into four groups and supplemented with iron (50 mg/day), zinc (14 mg/day), iron+zinc or placebo capsules 5 days per week for 24 weeks. Anthropometry, and haemoglobin (Hb), serum zinc (SZn) and serum ferritin (SF) concentrations were determined before and after the intervention.
                There were no significant effects between-groups in their weight, height and Hb concentrations with the intervention when compared with the placebo group. Iron-only and combination-supplemented groups had reached mean SF concentrations of 55.1 microg/l with no difference between them (P=0.99). The zinc-only group had a mean change of 4.3 micromol//l whereas the combine-supplemented group had a mean change of 4.0 micromol/l (P=0.82). The prevalence of anaemia was found to be 70.3% in the iron group at baseline; this was reduced to 14.5% after the supplementation. In the combine-supplemented group anaemia, prevalence was reduced from 64.8 to 19.3%.
                Zinc alone or in combination with iron has not shown a significant improvement in growth in adolescence. Severe and moderate forms of anaemia were successfully treated in children who received iron supplementation. Initial high prevalence of low SZn and iron stores was significantly improved with micronutrient supplementation. To examine the effect of iron chelation on mortality in cerebral malaria, we enrolled 352 children in a trial of deferoxamine in addition to standard quinine therapy at 2 centres in Zambia, one rural and one urban. Entrance criteria included age < 6 years, Plasmodium falciparum parasitaemia, normal cerebral spinal fluid, and unrousable coma. Deferoxamine (100 mg/kg/d infused for a total of 72 h) or placebo was added to a 7 d regimen of quinine that included a loading dose. Mortality overall was 18.3% (32/175) in the deferoxamine group and 10.7% (19/177) in the placebo group (adjusted odds ratio 1.8; 95% confidence interval 0.9-3.6; P = 0.074). At the rural study site, mortality was 15.4% (18/117) with deferoxamine compared to 12.7% (15/118) with placebo (P = 0.78, adjusted for covariates). At the urban site, mortality was 24.1% (14/58) with deferoxamine and 6.8% (4/59) with placebo (P = 0.061, adjusted for covariates). Among survivors, there was a non-significant trend to faster recovery from coma in the deferoxamine group (adjusted odds ratio 1.2; 95% confidence interval 0.97-1.6; P = 0.089). Hepatomegaly was significantly associated with higher mortality, while splenomegaly was associated with lower mortality. This study did not provide evidence for a beneficial effect on mortality in children with cerebral malaria when deferoxamine was added to quinine, given in a regimen that included a loading dose. In areas of endemic transmission, malaria in pregnancy is associated with severe maternal anaemia and low-birthweight babies. We studied the efficacy of intermittent treatment doses of sulphadoxine-pyrimethamine in preventing malaria and severe anaemia in pregnancy in a double-blind placebo-controlled trial among primigravid women living in Kilifi District, Kenya.
                Between January, 1996, and April, 1997, 1264 primigravid women were recruited when they attended for antenatal care, and randomly assigned sulphadoxine-pyrimethamine (640) or placebo (624). Women received one, two, or three doses of study medication depending on the duration of gestation at enrolment. Primary outcome measures were severe anaemia (haemoglobin <8 g/dL) and malaria parasitaemia, assessed at 34 weeks of gestation. Analyses were based on intention to treat among women who had study blood tests at 34 weeks.
                30 (5.3%) of 567 women in the sulphadoxine-pyrimethamine group and 199 (35.3%) of 564 in the placebo group had peripheral parasitaemia (protective efficacy 85% [95% CI 78-90], p<0.0001). 82 (14.5%) and 134 (23.7%) had severe anaemia (protective efficacy 39% [22-52], p<0.0001). Even women who booked late and received only one dose of sulphadoxine-pyrimethamine benefited significantly from the intervention. The effects were seen both in women who owned insecticide-treated bednets and in women who did not.
                Intermittent presumptive treatment with sulphadoxine-pyrimethamine is an effective, practicable strategy to decrease the risk of severe anaemia in primigravidae living in malarious areas. The impact of insecticide-treated bednet use on malaria and anaemia in pregnancy was assessed, as a supplementary study, in a major WHO/TDR-supported bednet trial in northern Ghana between July 1994 and April 1995. The study area was divided into 96 clusters of compounds, with 48 clusters being randomly allocated to intervention. All pregnant women were included in the study but the focus was on primigravidae and secundigravidae. 1961 pregnant women were recruited into the study--1033 (52.7%) in the treated bednet group and 928 (47.3%) in the no net group. 1806 (92.1%) had blood taken for malaria microscopy and haemoglobin determination in the third trimester. Pregnancy outcomes were reported for 847 women. The characteristics of women in intervention and control groups were comparable. The odds ratios, with 95% confidence interval (CI), for different study endpoints were, for Plasmodium falciparum parasitaemia--0.89 (0.73, 1.08), for anaemia--0.88 (0.70, 1.09), for low birthweight (LBW)--0.87 (0.63, 1.19), indicating no benefit for treated bednet use. Effective net use by parity varied from 42% in primigravidae to 63% in multigravidae, in spite of free nets and insecticide impregnation. The main reasons for not using a net were warm weather and perceived absence of mosquito biting. Chloroquine use in pregnancy was low and comparable in both groups. Implications of findings for malaria control in pregnancy and further research are discussed. Previous work at this hospital and elsewhere has shown that anaemia in toddlers is common and is associated with psychomotor delay. It seemed unclear, however, whether this association was cause and effect or merely due to the same underprivileged environment. A double blind randomised intervention study was, therefore, performed. After an initial assessment 97 children with anaemia (haemoglobin 8-11 g/dl) aged 17-19 months received either iron and vitamin C or vitamin C only (control group) for two months and were then reassessed. The children who received the iron had an increased rate of weight gain and more of them achieved the expected rate of development. While iron deficiency anaemia is unlikely to be the only factor in the slower development of children living in underprivileged circumstances, it can at least be easily identified and treated. Routine child health surveillance in such areas should include a haemoglobin determination. The effect of weekly iron supplementation with and without deworming on hemoglobin was investigated in a double-masked, placebo-controlled field trial. Subjects were 289 preschoolers who were randomly divided into three groups. Groups 1 and 2 received 30 mg Fe once weekly and group 3 received a placebo. Group 1 additionally received anthelminthic treatment. Supplements were administered by the mothers, who were educated about iron deficiency beforehand. In the iron-supplemented groups prevalence of anemia decreased from 37.2% to 16.2% (P < 0.001). Hemoglobin increased by an average of 6.9 +/- 9.8 g/L in the two iron-supplemented groups (n = 191), which was greater (P < 0.001) than the increase of 1.9 +/- 8.0 g/L in the placebo group. None of the subjects had hookworm, and anthelminthic treatment did not have an additional effect. Iron supplements administered once weekly by mothers reduced anemia without major involvement of health staff. Iron deficiency anemia and recurrent infections are common among children of low socioeconomic status.
                The objective was to evaluate the effects of iron supplementation on iron status and morbidity in children with or without infection.
                Children aged 5-10 y were recruited for a randomized, controlled, double-blind study from outpatients attending the Children's Hospital, Colombo, Sri Lanka. Clinical, inflammatory, nutritional, and iron statuses were determined at baseline and after the intervention. Children with a history of recurrent upper respiratory tract infections (URTIs) and with laboratory and clinical evidence of a current URTI constituted the infection group (n = 179), and children without infection constituted the control group (n = 184). Subjects in both groups were supplemented with ferrous sulfate (60 mg Fe) or placebo once daily for 8 wk. Morbidity from URTIs, the number of gastrointestinal infections, and compliance were recorded every 2 wk.
                The overall prevalence of anemia was 52.6%. Iron supplementation significantly improved iron status by increasing hemoglobin (P < 0.001) and serum ferritin (P < 0.001) concentrations from baseline values in the children with or without infection. There was no significant improvement in iron status in the children who received placebo. In both the infection group and the control group, the mean number of URTI episodes and the total number of days sick with an URTI during the period of intervention were significantly lower (P < 0.005 and P < 0.001, respectively) in the children who received iron supplements than in those who received placebo.
                Iron supplementation significantly improves iron status and reduces morbidity from URTIs in children with or without infection. The effect of iron supplementation alone or in combination with ascorbic acid as a preventive and or corrective measure against anemia were tested using pregnant women seeking pre-natal consultation at various health centers in Greater Manila Area. One tablet containing 65 mg iron alone or in combination with ascorbic acid per day during a supplementation period which varied from 16.5 to 17.8 weeks maintained initial hemoglobin and hematocrit levels in non-anemic women. Three tablets of the same iron preparation (total of 195 mg iron) daily resulted in significant increases in hemoglobin and hematocrit in anemic women. Ascorbic acid had no apparent beneficial effect. Considering the positive response to iron treatment, it is recommended that a nationwide program of iron supplementation of pregnant Filipinos be undertaken. Effects of iron supplementation on growth and hematological status of Indonesian anemic preschool children with low weight-for-age were investigated. A treatment group (n = 39) received daily supplements of 30 mg Fe and 20 mg vitamin C, whereas a control group (n = 37) received 20 mg vitamin C only for a period of 2 mo. Supplement allocation was double blind. At the start and finish of the study, body weight, height, food intake, and hemoglobin and serum ferritin concentrations were determined. Only the treatment group showed a significant increase in all hematological values (P < 0.001). Height and weight of all children increased (P < 0.01). Increases in height and height-for-age Z score in the treatment group were larger (P = 0.001) than the increase in the control group. The positive effect of iron supplementation on linear growth was not caused by increased food intake, but seems to be influenced by decreased morbidity. Iron supplementation may be a relatively inexpensive way to help decrease the high prevalence of stunting. To compare the effectiveness of microencapsulated iron(II) fumarate sprinkles (with and without vitamin A), iron(II) sulfate drops, and placebo sprinkles in preventing recurrence of anaemia and to determine the long-term haematological outcomes in children at high risk of recurrence of anaemia 12 months after the end of supplementation.
                A prospective, randomized, placebo-controlled design was used to study 437 Ghanaian children aged 8-20 months who were not anaemic (haemoglobin > or = 100 g/l). Four groups were given microencapsulated iron(II) fumarate sprinkles, microencapsulated iron(II) fumarate sprinkles with vitamin A, iron(II) sulfate drops or placebo sprinkles daily for six months. Primary outcome measures were change in haemoglobin and anaemic status at baseline and study end. Non-anaemic children at the end of the supplementation period were reassessed 12 months after supplementation ended.
                Overall, 324 children completed the supplementation period. Among the four groups, no significant changes were seen in mean haemoglobin, ferritin or serum retinol values from baseline to the end of the supplementation period. During the trial, 82.4% (267/324) of children maintained their non-anaemic status. Sprinkles were well accepted without complications. At 12 months post-supplementation, 77.1% (162/210) of children with no intervention remained non-anaemic. This proportion was similar for children among the four groups.
                In most children previously treated for anaemia, further supplementation was not needed to maintain their non-anaemic status. These results may have important implications for community intervention programmes in which initial high-dose treatment is needed because of a high prevalence of anaemia. To compare the effectiveness of weekly vs daily iron and folic acid supplementation for control of anemia in adolescent Nepalese girls.
                Randomized controlled trial.
                A Government Girl School in Dharan, Nepal, an urban foothill town that is 305 m above sea level.
                Consecutive healthy adolescent girls (n = 209, median age 15 years) randomized to 3 groups matched for age, anthropometry, and personal and sociodemographic characteristics. Of 209 subjects, 181 completed the trial. Two girls had adverse reactions to treatment and were excluded.
                Group A (n = 70) received a 350-mg ferrous sulfate and 1.5-mg folic acid combination once daily for 90 to 100 days. Group B (n = 67) received the tablet under supervision once a week for 14 weeks. Group C (n = 72) did not receive any drugs.
                Presupplementation and postsupplementation differences in prevalence of anemia and change in hematocrit.
                Prevalence of anemia (defined as hematocrit <36%) declined from 68.6% and 70.1% in groups A and B to 20% and 13.4%, respectively, postsupplementation (P<.001), whereas the prevalence in group C changed little (68.1% to 65.3%, P =.81). There was a significant rise in the mean hematocrit of both supplemented groups (group A, 32.9% +/- 3.5% to 41.0% +/- 5.6%, P<.001; group B, 33.2% +/- 3.6% to 40.4% +/- 4.9%, P<.001) but no appreciable change in controls (34.2% +/- 2.9% to 34.1% +/- 3.3%, P =.91). Net change in mean hematocrit in both the supplementation groups was comparable (P =.57).
                The prevalence of anemia in adolescent Nepalese girls is high. Supervised iron and folic acid therapy once a week is an effective alternative to daily administration and helps lower the prevalence of anemia in adolescent girls. In view of the high level of chloroquine resistance in many countries, WHO has recommended the use of combination therapy with artemisinin derivatives in the treatment of uncomplicated malaria due to Plasmodium falciparum. Four antimalarial drug combinations, artesunate plus amodiaquine (Arsucam), artesunate plus mefloquine (Artequin), artemether plus lumefantrine (Coartem; four doses and six doses), and amodiaquine plus sulphadoxine-pyrimethamine, were studied in five health districts in Senegal.
                This is a descriptive, analytical, open, randomized study to evaluate the efficacy and tolerability of these four antimalarial combinations in the treatment of uncomplicated falciparum malaria using the 2002 WHO protocol.
                All drug combinations demonstrated good efficacy. On day 28, all combinations resulted in an excellent clinical and parasitological response rate of 100% after correction for PCR results, except for the four-dose artemether-lumefantrine regimen (96.4%). Follow-up of approximately 10% of each treatment group on day 42 demonstrated an efficacy of 100%.The combinations were well tolerated clinically and biologically. No unexpected side-effect was observed and all side-effects disappeared at the end of treatment. No serious side-effect requiring premature termination of treatment was observed.
                The four combinations are effective and well-tolerated. To assess the effects of vitamin A supplementation in women with anaemia during pregnancy.
                Single-centre randomised controlled trial.
                Rural community in southern Malawi, central Africa.
                Seven hundred women with singleton pregnancies at 12-24 weeks measured by ultrasound scan and with haemoglobin <11.0 g/dl by HemoCue screening method. Analysis was by intention to treat. All received iron and folate, and sulphadoxine/pyrimethamine for antimalarial prophylaxis.
                Women were randomised to receive oral supplementation with daily 5000 or 10,000 iu vitamin A, or placebo.
                Anaemia, as assessed by Coulter counter, severe anaemia, iron status and indices of infection.
                Vitamin A deficiency was, in this rural population, less common than predicted. Vitamin A supplementation had no significant impact on anaemia, severe anaemia, iron status and indices of infection. Vitamin A stores were less likely to be depleted at the end of pregnancy in supplemented groups.
                Vitamin A supplementation programmes to reduce anaemia should not be implemented in similar antenatal populations in rural sub-Saharan Africa unless evidence emerges of positive benefit on substantive clinical outcomes. Introducing public health interventions of unknown benefit and with unclear biological mechanisms can divert scarce resources from clinical and social interventions more likely to impact maternal mortality. Iron deficiency anaemia is the most common deficiency disorder in the world, affecting more than one billion people, with pregnant women at particular risk.
                We conducted a single site, prospective, nonblinded randomized-controlled trial to compare the efficacy, safety, tolerability and compliance of standard oral daily iron versus intravenous iron.
                We prospectively screened 2654 pregnant women between March 2007 and January 2009 with a full blood count and iron studies, of which 461 (18%) had moderate IDA. Two hundred women matched for haemoglobin concentration and serum ferritin level were recruited.
                Patients were randomized to daily oral ferrous sulphate 250 mg (elemental iron 80 mg) with or without a single intravenous iron polymaltose infusion.
                Prior to delivery, the intravenous plus oral iron arm was superior to the oral iron only arm as measured by the increase in haemoglobin level (mean of 19.5 g/L vs. 12 g/L; P < 0.001); the increase in mean serum ferritin level (222 microg/L vs. 18 ug/L; P < 0.001); and the percentage of mothers with ferritin levels below 30 microg/L (4.5% vs. 79%; P < 0.001). A single dose of intravenous iron polymaltose was well tolerated without significant side effects.
                Our data indicate that intravenous iron polymaltose is safe and leads to improved efficacy and iron stores compared to oral iron alone in pregnancy-related IDA. The effects of weekly chloroquine prophylaxis, daily iron-weekly folic acid supplementation or passive case management on maternal haemoglobin and parasitaemia and on birthweight were examined in primigravidae in a randomized, double-blind placebo-controlled intervention trial in 1996-98 in Hoima District, western Uganda. Iron-folic acid supplementation significantly increased mean birthweight as compared to case management (P = 0.03). Low birthweight (< 2.5 kg) occurred in 2% of babies of women receiving chloroquine prophylaxis for > or = 8 weeks and in 9% in the case management group (RR = 0.36, 95% CI 0.13-1.00, P = 0.009). Parasitaemia at enrolment significantly correlated with low birthweight in the case management group as compared to the intervention groups (P = 0.02). Women in the case management group who were parasitaemia and had haemoglobin levels < 100 g/L at delivery had babies with lower mean birthweight as compared to babies in the other groups (P = 0.04). Low haemoglobin level at enrolment, irrespective of parasitaemia status, was a predictor of low birthweight in the case management group only (P = 0.04). Chloroquine prophylaxis and iron-folic acid supplementation significantly increased maternal haemoglobin levels during pregnancy as compared to case management (P = 0.01 and 0.007, respectively) and the increase correlated to the duration of the intervention. In developing countries, low food intake is often reported in children < 5 y old. Reduced appetite may be a contributing factor. We investigated whether a combination of a multivitamin-multimineral supplement and additional iron treatment improved appetite and growth of 18- to 30-mo-old stunted and anemic Beninese children. The study was placebo-controlled using VITALIA tablets (11 vitamins and 10 minerals) and ferrous fumarate tablets (66 mg of iron). One hundred fifty stunted (height-for-age Z score < -2) and anemic children (hemoglobin < 110 g/L) were randomly assigned to one of four groups: group 1, multivitamin-multimineral plus iron; group 2, multivitamin-multimineral plus placebo; group 3, placebo plus placebo; and group 4, placebo plus iron. Supplementation was daily and supervised for 6 wk. Appetite, knee-heel length, dietary intakes and morbidity were assessed before and after supplementation. Length, weight, arm circumference and hemoglobin concentration were assessed before, just after supplementation and 4 mo after the intervention. Appetite was assessed by means of an appetite test using a test food, riz-au-gras, eaten ad libitum after an overnight fast. Dietary intakes were assessed during three consecutive days in a subsample by means of the observed weighed record method. Energy intake from the habitual breakfast was significantly correlated with that from the test food (r = 0.49, n = 38, P = 0.002). There were no differences among groups in changes in appetite and growth performance. The habitual diet of the children was monotonous and contained only small amounts of animal products. The morbidity status of the children was comparable in all study groups, before as well as after supplementation. We conclude that the 6-wk multivitamin-multimineral supplementation with additional iron treatment failed to improve the appetite and growth of the children. Recent studies have shown that intermittent preventive malaria treatment (IPT) in infants in areas of stable malaria transmission reduces malaria and severe anaemia incidence. However in most areas malaria morbidity and mortality remain high in older children.
                To evaluate the effect of seasonal IPT with sulphadoxine pyrimethamine (SP) on incidence of malaria disease in area of seasonal transmission, 262 children 6 months-10 years in Kambila, Mali were randomized to receive either IPT with SP twice at eight weeks interval or no IPT during the transmission season of 2002 and were followed up for 12 months. Subjects were also followed during the subsequent transmission season in 2003 to assess possible rebound effect. Clinical malaria cases were treated with SP and followed to assess the in vivo response during both periods.
                The incidence rate of malaria disease per 1,000 person-months during the first 12 months was 3.2 episodes in the treatment group vs. 5.8 episodes in the control group with age-adjusted Protective Efficacy (PE) of 42.5%; [95% CI 28.6%-53.8%]. When the first 16 weeks of follow up is considered age-adjusted PE was 67.5% [95% CI 55.3% - 76.6%]. During the subsequent transmission season, the incidence of clinical malaria per 1000 persons-days was similar between the two groups (23.0 vs 21.5 episodes, age-adjusted IRR = 1.07 [95% CI, 0.90-1.27]). No significant difference was detected in in vivo response between the groups during both periods.
                Two malaria intermittent treatments targeting the peak transmission season reduced the annual incidence rate of clinical malaria by 42.5% in an area with intense seasonal transmission. This simple strategy is likely to be one of the most effectives in reducing malaria burden in such areas.
                Clinicaltrials.gov NCT00623155. To assess the effects of iron and deworming on linear growth performance of preschoolers.
                Three-month randomized, double-blind and placebo-controlled trial. The children were allocated to four treatments: iron (60 mg elemental iron/day) + albendazole (200 mg/day for 3 consecutive days, repeated 1 month later), iron + albendazole-placebo, albendazole + iron-placebo or placebos. The supplementation was supervised.
                A group of 177 children aged 3-5 y was selected from low-income households in a rural area in southern Bénin. A complete data set was analysed for 140 subjects. Many children were stunted (58% had height-for-age Z-score <-2), none were wasted (2% had weight-for-height Z-score < -2) and 76% were anemic (Hb < 110 g/l).
                Anthropometric parameters, hemoglobin and eggs per gram feces.
                No significant difference in changes in anthropometric parameters was observed between study groups, and also not in a sub-sample of stunted and anemic subjects. Changes in hemoglobin were highest in the iron-treated subjects at the end of the 3-month intervention period (P = 0.032). The difference between the iron and the placebo groups remained significant even 7 months later (P = 0.022). The difference was 5 g/l in both periods. Ascaris lumbricoides and hookworm infections decreased significantly in albendazole-treated subjects (P < 0.05).
                In addition to recurrent parasitic infection burden, the children may have multiple micronutrient deficiencies. Therefore, it may be interesting to study appetite and food intake of young toddlers in relation to health and linear growth performance in poor environments. Vitamin A supplementation is believed to enhance immune responses to infection but few studies have assessed its effects on anti-malarial immunity, especially during pregnancy when women are at increased risk from both vitamin A deficiency and pregnancy-associated malaria. The pathological effects of malaria in pregnancy are believed to be due to the sequestration of parasites in the placenta mediated via binding of variant surface antigens (VSA) expressed on the surface of P. falciparum infected red blood cells to placental chondroitin sulphate A (CSA).
                We conducted a randomized double-blind controlled trial of vitamin A supplementation in 98 primigravid Ghanaian women to investigate the effects of vitamin A supplementation on levels of IgG antibodies binding to VSA of a clinical, P. falciparum placental isolate and to two isolates selected (or not) for adherence to CSA in vitro (anti-VSACSA IgG or anti-VSA IgG). Placental malarial infection was determined by placental blood smear and histology.
                Vitamin A supplementation was non-significantly associated with a decreased risk of active or chronic-active placental malarial infection compared to past, resolved infection at delivery, as determined by histology (OR=0.42, P=0.13--adjusted for level of education). After adjustment for differences in baseline values, levels of anti-VSACSA IgG to a placental, CSA-adherent isolate (EJ-24) but not to two isolates selected for CSA-adhesion in vitro (FCR3CSA and BusuaCSA), were significantly lower in women receiving vitamin A supplementation than in women receiving placebo (P=0.002). There was no apparent effect of vitamin A supplementation to levels of Ab to non-CSA-adherent parasite isolates.
                The data suggest that the reduction in the levels of anti-VSACSA antibodies to the known placental malaria isolate may reflect reduced intensity or duration of placental parasitaemia in women receiving vitamin A supplementation. These observations are of potential public health significance and deserve further investigation. We report here the results of a randomized double blind trial comparing coartemether (CGP56697), a combination of artemether and benflumetol, with pyrimethamine/sulfadoxine (P/S). Two hundred eighty-seven children 1-5 years of age with uncomplicated falciparum malaria were enrolled at two centers in The Gambia between July 1996 and December 1996. Following treatment, children were visited at home every 24 hr until a blood film free of asexual parasites was obtained. Genotyping of parasites was used to distinguish recrudescence from new infections. Three days after the start of treatment, 133 (100%) of the CGP56697-treated children compared with 128 (93.4%) of children treated with P/S had cleared their parasites (P = 0.003). The day 15 cure rate was 93.3% for CGP56697 and 97.7% for P/S (P = 0.13). Within the third and fourth week after initiation of therapy, 20 children treated with CGP56697 and one of the P/S-treated children returned with second malaria episodes (P < 0.0001). Genotyping suggested that the majority (19 of 23 [82.6%]) of these second episodes were due to new infections, supporting the World Health Organization recommendation that longer follow-up is not relevant for the assessment of drug efficacy. At the two-week follow-up, 28.9% of the P/S treated children but none of the CGP56697-treated children carried gametocytes (P < 0.0001). This study showed that CGP56697 is safe in African children with acute uncomplicated falciparum malaria, clears parasites more rapidly than P/S, and results in fewer gametocyte carriers. More frequent new infections within the third and fourth week following treatment with CGP56697 than treatment with P/S are likely to be due to the short prophylactic effect of CGP56697. To combat iron deficiency manifesting around six months of age, iron-fortified complementary feeding has been recommended. In developing countries, in view of the poor bioavailability of iron from predominantly cereal-based diets and the high cost of fortification, medicinal iron supplementation is an alternative intervention. This double-blind randomized placebo-controlled trial was conducted from April 1999 to March 2000 in the Out-patient Department of a tertiary hospital in New Delhi, India, to evaluate the haematological effects of medicinal iron supplementation to breastfed young infants initiated on complementary feeding. One hundred healthy non-low birth-weight, predominantly breastfed infants aged 4-6 months were randomized into two groups to receive either iron (2 mg/kg/day) (IS group; n=49) or placebo drops (P group; n=51) beginning with the initiation of home-based non-fortified complementary feeding. Haematological parameters and anthropometry of mothers and infants were measured at baseline and repeated for infants after four and eight weeks of recruitment. Seventy-one subjects (35 in the IS group and the 36 in P group) came for the first follow-up, and of these, 43 (19 in the IS group and 24 in the P group) reported for the second visit. The adjusted (for maternal and baseline infant ferritin) serum ferritin levels were significantly higher in the IS group at both the follow-ups (p=0.006). The adjusted (for maternal ferritin and baseline infant ferritin) change in haemoglobin was significantly higher only at the second follow-up (0.7 g/dL; 95% confidence interval [CI] 0.3-1.0 g/dL). The adjusted rise in haemoglobin was higher in initially anaemic infants (at second follow-up by 1 g/dL; 95% CI 0.5-1.6 g/dL). Medicinal iron supplementation, at the time of initiating complementary feeding, to breastfed young infants resulted in an elevation of serum ferritin and haemoglobin. The response was higher in initially anaemic infants. From a programmatic perspective, evidence needs to be generated on the relative merits of selective (anaemic) versus general supplementation and daily versus weekly supplementation. To study the effects of zinc supplementation on malaria and other causes of morbidity in young children living in an area holoendemic for malaria in west Africa.
                Randomised, double blind, placebo controlled efficacy trial.
                18 villages in rural northwestern Burkina Faso.
                709 children were enrolled; 685 completed the trial.
                Supplementation with zinc (12.5 mg zinc sulphate) or placebo daily for six days a week for six months.
                The primary outcome was the incidence of symptomatic falciparum malaria. Secondary outcomes were the severity of malaria episodes, prevalence of malaria parasite, mean parasite densities, mean packed cell volume, prevalence of other morbidity, and all cause mortality.
                The mean number of malaria episodes per child (defined as a temperature >/=37.5 degrees C with >/=5000 parasites/microliter) was 1.7, 99.7% due to infection with Plasmodium falciparum. No difference was found between the zinc and placebo groups in the incidence of falciparum malaria (relative risk 0.98, 95% confidence interval 0.86 to 1.11), mean temperature, and mean parasite densities during malaria episodes, nor in malaria parasite rates, mean parasite densities, and mean packed cell volume during cross sectional surveys. Zinc supplementation was significantly associated with a reduced prevalence of diarrhoea (0.87, 0.79 to 0.95). All cause mortality was non-significantly lower in children given zinc compared with those given placebo (5 v 12, P=0.1).
                Zinc supplementation has no effect on morbidity from falciparum malaria in children in rural west Africa, but it does reduce morbidity associated with diarrhoea. To compare the efficacy of a daily and a weekly iron supplementation on the hematological status of anemic children living at high altitude.
                Double blind iron supplementation trial including a placebo control group.
                A socioeconomically disadvantaged district of La Paz, Bolivia (altitude of 4000 m).
                Anemic (hemoglobin concentration < or = 144 g/L), 3.3-8.3 y old children of both sexes.
                Children received a placebo (n = 57) or a dose of 3-4 mg of elemental iron per kg body weight (FeSO4 tablets) 1 d per week (n = 58) or 5 d per week (n = 58) for 16 weeks.
                Hemoglobin and zinc erythrocyte protoporphyrin concentrations improved significantly in supplemented groups but not in the placebo group. Changes in hemoglobin during the study were not significantly different between supplemented groups (weekly group: 15.2 +/- 6.9 g/L and daily group: 18.6 +/- 11.1 g/L) but were different from the placebo group (0.5 +/- 7.1 g/L, P < 0.001). At the end of the supplementation period, the hemoglobin distribution was Gaussian, and similar in both supplemented groups. Adjusting for the initial hemoglobin concentration, final hemoglobin and its changes were similar in both supplemented groups.
                Weekly iron supplementation is as efficacious as daily iron supplementation in improving iron status and correcting moderate iron deficiency anemia in Bolivian school children living at high altitude.
                Program supported in part by ORSTROM, the French Ministry of Foreign Affairs and the National Secretary's Office of Health, Bolivia. Intermittent iron supplementation has been suggested as a replacement for daily iron supplements for reducing anemia in developing countries. The effects of once weekly and daily iron supplementation on hemoglobin (Hb), serum ferritin (SF), prevalence of anemia, weight and height are compared in this study. Primary schoolchildren (n = 397) from two selected schools in the Hat Yai rural area, southern Thailand, were recruited in 1999. All children received Albendazole and then randomly received ferrous sulfate (300 mg/tablet) either daily or weekly, or a placebo for 16 wk. The average increase in Hb was not significantly different between the daily (mean +/- SD; 6.5 +/- 6.0 g/L) and weekly (5.7 +/- 6.3 g/L) groups. However, the average increase in SF was greater (P < 0.01) in the daily (mean +/- SD; 39.8 +/- 30.3 microg/L) than the weekly (13.4 +/- 17.3 microg/L) group. All cases of iron deficiency anemia were abolished in both daily and weekly groups, whereas no reduction in prevalence occurred in the placebo group. Height gain was greater in children who received weekly (mean +/- SD; 2.6 +/- 0.9 cm) than in those who received daily iron (mean +/- SD; 2.3 +/- 0.8 cm), (P < 0.01). Weight gain, weight-for-age and height-for-age were not significantly different among the intervention groups. It is concluded that a weekly iron dose is more effective than a daily dose in height gain but not in hematological improvement over 16 wk of supplementation. The impact of albendazole (400 mg) and praziquantel (40 mg/kg body weight) treatment of schoolchildren was compared with placebo according to the presence of anaemia (haemoglobin concentration < 11. 0 g/dl) and heavy (> 5000 epg) or light (< 5000 epg) hookworm egg load. The study was conducted in rural Tanga. Medication was administered in September 1994 and children were followed-up in January 1995. Overall, anthelminthic treatment reduced the fall in haemoglobin concentration compared with that observed in the placebo group (- 0.11 g/dl vs. - 0.35 g/dl; P = 0.02). Anthelminthic treatment was of greatest benefit to the 9% of children with both anaemia and heavy hookworm egg load (+ 0.67 g/dl vs. - 0.67 g/dl) and was also of significant benefit to the 38% of children with anaemia and light hookworm egg load (+ 0.07 g/dl vs. - 0.21 g/dl). It was of no significant benefit to children who were not anaemic. This study suggests that single-dose anthelminthic treatment distributed in schools in this area achieves haematological benefits in nearly half of children infected with S. haematobium and geohelminths (37% of total population).
Iron alone or with antimalaria treatment does not increase the risk of clinical malaria or death when regular malaria surveillance and treatment services are provided. There is no need to screen for anaemia prior to iron supplementation.