title: The effects on malaria of treatment of iron-deficiency anaemia with oral iron in Gambian children. Breastfeeding and child cognitive development: new evidence from a large randomized trial. Lack of hemoglobin response to iron supplementation in anemic mexican preschoolers with multiple micronutrient deficiencies. Iron supplementation improves appetite and growth in anemic Kenyan primary school children. Low-dose daily iron supplementation for 12 months does not increase the prevalence of malarial infection or density of parasites in young Zanzibari children. Low dose daily iron supplementation improves iron status and appetite but not anemia, whereas quarterly anthelminthic treatment improves growth, appetite and anemia in Zanzibari preschool children. Hematological effect of supplementing anemic children with vitamin A alone and in combination with iron. Iron and zinc supplementation improves indicators of vitamin A status of Mexican preschoolers. Long-term supplementation with iron does not enhance growth in malnourished Bangladeshi children. Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria. Long-term oral supplementation with iron is not harmful for young children in a poor community of Bangladesh. Impact of iron supplementation and deworming on growth performance in preschool Beninese children Effects of iron deficiency on attention and learning processes in preschool children: Bandung, Indonesia. Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: double blind, placebo controlled study Effect of iron supplementation on cognition in Greek preschoolers Iron-deficiency anaemia and its response to oral iron: report of a study in rural Gambian children treated at home by their mothers. 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 The effect of iron deficiency and mental stimulation on Indonesian children's cognitive performance and development. Cognitive deficits in iron-deficient and iron-deficient anemic children. Zinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers. Relationship between iron deficiency and anemia in children younger than 4 years. The effect of oral iron therapy during treatment for Plasmodium falciparum malaria with sulphadoxine-pyrimethamine on Malawian children under 5 years of age. Studies in iron supplementation of preschool children. Efficacy of Daily and Weekly Iron Supplementation on Iron Status in Exclusively Breast-Fed Infants Growth performance in anemia and following iron supplementation. A comparison of iron and folate with folate alone in hematologic recovery of children treated for acute malaria.
abstract: In order to determine whether giving iron to iron-deficient children increases their susceptibility to malaria , 213 Gambian children aged between 6 months and 5 years with iron-deficiency anaemia were r and omized to receive either oral iron or placebo during the rainy season when malaria transmission is maximal . Haematological and iron measurements improved significantly in the group given iron . Regular morbidity surveys showed that fever associated with parasitaemia occurred more frequently in the iron-treated group than in the placebo group . This difference was not significant for all parasitaemias grouped together , but became significant and progressively larger for parasitaemias of ten or more positive fields per 100 high power fields ( P less than 0.025 ) , and for parasitaemias of 50 or more positive fields per 100 high power fields ( P less than 0.01 ) . Three children in the iron-treated group but none in the placebo group had more than one episode of fever and parasitaemia . Splenomegaly rates rose appreciably during the study in both groups , but in children at age 2 years the splenomegaly rate at the end of the study was significantly greater in the iron-treated group . We concluded that there is a significantly increased risk of fever associated with severe malarial parasitaemia for children with iron-deficiency anaemia given iron during the season of maximal malaria transmission in this part of The Gambia CONTEXT The evidence that breastfeeding improves cognitive development is based almost entirely on observational studies and is thus prone to confounding by subtle behavioral differences in the breastfeeding mother 's behavior or her interaction with the infant . OBJECTIVE To assess whether prolonged and exclusive breastfeeding improves children 's cognitive ability at age 6.5 years . DESIGN Cluster-r and omized trial , with enrollment from June 17 , 1996 , to December 31 , 1997 , and follow-up from December 21 , 2002 , to April 27 , 2005 . SETTING Thirty-one Belarussian maternity hospitals and their affiliated polyclinics . PARTICIPANTS A total of 17,046 healthy breastfeeding infants were enrolled , of whom 13,889 ( 81.5 % ) were followed up at age 6.5 years . INTERVENTION Breastfeeding promotion intervention modeled on the Baby-Friendly Hospital Initiative by the World Health Organization and UNICEF . MAIN OUTCOME MEASURES Subtest and IQ scores on the Wechsler Abbreviated Scales of Intelligence , and teacher evaluations of academic performance in reading , writing , mathematics , and other subjects . RESULTS The experimental intervention led to a large increase in exclusive breastfeeding at age 3 months ( 43.3 % for the experimental group vs 6.4 % for the control group ; P < .001 ) and a significantly higher prevalence of any breastfeeding at all ages up to and including 12 months . The experimental group had higher means on all of the Wechsler Abbreviated Scales of Intelligence measures , with cluster-adjusted mean differences ( 95 % confidence intervals ) of + 7.5 ( + 0.8 to + 14.3 ) for verbal IQ , + 2.9 ( -3.3 to + 9.1 ) for performance IQ , and + 5.9 ( -1.0 to + 12.8 ) for full-scale IQ . Teachers ' academic ratings were significantly higher in the experimental group for both reading and writing . CONCLUSION These results , based on the largest r and omized trial ever conducted in the area of human lactation , provide strong evidence that prolonged and exclusive breastfeeding improves children 's cognitive development . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N37687716 BACKGROUND In developing countries , incomplete resolution of anemia with iron supplementation is often attributed to poor compliance or inadequate duration of supplementation , but it could result from deficiencies of other micronutrients . OBJECTIVE Our objective was to assess children 's hematologic  response to supervised , long-term iron supplementation and the relation of this response to other micronutrient deficiencies , anthropometry , morbidity , and usual dietary intake . DESIGN Rural Mexican children aged 18 - 36 mo ( n = 219 ) were supplemented for 12 mo with either 20 mg Fe , 20 mg Zn , both iron and zinc , or placebo . Children were categorized as iron-unsupplemented ( IUS ; n = 109 ) or iron supplemented ( IS ; n = 108 ) . Hemoglobin , hematocrit , mean corpuscular volume , mean cell hemoglobin , plasma concentrations of micronutrients that can affect hematopoiesis , anthropometry , and diet were assessed at 0 , 6 , and 12 mo ; morbidity was assessed biweekly . RESULTS At baseline , 70 % of children had low hemoglobin ( < /=115 g/L ) , 60 % had low hematocrit , 48 % were ferritin deficient , 10 % had deficient and 33 % had low plasma vitamin B-12 concentrations , 29 % had deficient vitamin A concentrations , and 70 % had deficient vitamin E concentrations . Iron supplementation increased ferritin from 11 + /- 14 microg/L at baseline to 31 + /- 18 microg/L after 6 mo ( P < 0.001 ) and 41 + /- 17 microg/L after 12 mo . However , anemia persisted in 30 % and 31 % of supplemented children at 6 and 12 mo , respectively , and was not significantly different between the IUS and IS groups at 12 mo . Initial plasma vitamin B-12 , height-for-age , and dietary quality predicted the hematopoietic response to iron . CONCLUSION Lack of hemoglobin response to iron was associated with indicators of chronic undernutrition and multiple micronutrient deficiencies A r and omized , double-blind , placebo-controlled iron supplementation trial was conducted in Kenya to examine the effect of iron supplements on appetite and growth in 87 primary school children .  Sustained-release ferrous sulfate ( 150 mg ) or placebo tablets were provided daily at school for 14 wk . Prior to tablet administration , baseline anthropometry , iron nutritional status ( hemoglobin and serum ferritin ) , parasitic infections and clinical indicators of morbidity were measured . A baseline appetite test was conducted twice on each child by quantitatively measuring the ad libitum consumption of a midmorning snack . In addition , each child was asked for a subjective assessment of his or her appetite . Follow-up exams and appetite tests were identical to those at baseline . Findings indicated that provision of iron supplements result ed in improved growth and improved appetite ( in terms of both energy intake of the snack and child report of appetite ) as compared with children receiving the placebo . The increased energy intake from the snack was 10 % of the daily estimated energy intake for children of this same age group living elsewhere in Kenya . Further research into the underlying physiological mechanisms may shed light on the relationship between iron nutritional status and appetite 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 duration s < or = 4 mo . We aim ed to assess the effect of low-dose , long-term iron supplementation on malaria infection using a double-blind , placebo-controlled , r and omized design , and to examine possible subgroup effects by season and child age . The study was conducted in Pemba Isl and , Zanzibar , where Plasmodium falciparum malaria has year-round high transmission . A community-based sample of 614 children 4 - 71 mo old was r and omly 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 Iron deficiency and helminth infections are two common conditions of children in developing countries . The consequences of helminth infection in young children are not well described , and the efficacy of low dose iron supplementation is not well documented in malaria-endemic setting s. A 12-mo r and omized , placebo controlled , double-blind trial of 10 mg daily iron and /or mebendazole ( 500 mg ) every 3 mo was conducted in a community-based sample of 459 Zanzibari children age 6 - 71 mo with hemoglobin > 70 g/L at baseline . The trial was design ed to examine treatment effects on growth , anemia and appetite in two age subgroups . Iron did not affect growth retardation , hemoglobin concentration or mild or moderate anemia ( hemoglobin < 110 g/L or < 90 g/L , respectively ) , but iron significantly improved serum ferritin and erythrocyte protoporphyrin .  Mebendazole significantly reduced wasting malnutrition . but only in children < 30 mo old . The adjusted odds ratios ( AORs ) for mebendazole in this age group were 0.38 ( 95 % CI : 0.16 , 0.90 ) for weight-for-height less than -1 Z-score and 0.29 ( 0.09 , 0.91 ) for small arm circumference . In children < 24 mo old , mebendazole also reduced moderate anemia ( AOR : 0.41 , 0.18 , 0.94 ) . Both iron and mebendazole improved children 's appetite , according to mothers ' report . In this study , iron 's effect on anemia was limited , likely constrained by infection , inflammation and perhaps other nutrient deficiencies . Mebendazole treatment caused unexpected and significant reductions in wasting malnutrition and anemia in very young children with light infections . We hypothesize that incident helminth infections may stimulate inflammatory immune responses in young children , with deleterious effects on protein metabolism and erythropoiesis Ninety-nine anemic children aged 1 - 8 y were divided into four groups . Each group was supplemented for 2 mo with vitamin A , iron , vitamin A plus Fe , or a placebo .  Clinical , hematological , and Fe biochemical evaluations were performed at the beginning and end of the study . Vitamin A supplementation produced significant elevations in the serum levels of retinol , blood hemoglobin , hematocrit , erythrocytes , serum Fe , and percent transferrin saturation ( % TS ) and had no effect on total Fe binding capacity ( TIBC ) or serum ferritin . Fe supplementation did not affect serum retinol . However , it improved hematological and Fe nutrition indicators , including TIBC and serum ferritin . The simultaneous administration of vitamin A and Fe result ed in a better response of serum Fe and % TS than when the supplement consisted only of vitamin A or Fe alone . Vitamin A benefits hematological condition and Fe metabolism BACKGROUND The coexistence of multiple micronutrient deficiencies is a widespread public health problem in many regions of the world . Interactions between zinc deficiency and vitamin A metabolism have been reported but no longitudinal studies have evaluated the effect of iron deficiency on vitamin A. OBJECTIVE The objective of this study was to investigate the effect of supplementation with iron , zinc , or both on vitamin A and its metabolically related proteins retinol binding protein ( RBP ) and transthyretin . DESIGN The study was a longitudinal , double-blind , placebo-controlled trial in which 219 rural Mexican children aged 18 - 36 mo were r and omly assigned to receive 20 mg Zn/d , 20 mg Fe/d , 20 mg Zn/d plus 20 mg Fe/d , or placebo . RESULTS Six months after supplementation , plasma retinol increased in all supplemented groups . Compared with placebo , zinc supplementation was associated with significantly higher plasma retinol and transthyretin but the increase in RBP was not significant . Iron supplementation significantly increased plasma retinol , RBP , and transthyretin . Supplementation with zinc plus iron significantly increased plasma retinol but not RBP or transthyretin .  Children deficient in zinc , iron , or vitamin A ( as indicated by nutrient plasma concentration ) at the beginning of the study had a significantly greater increase in retinol than did children with adequate nutrient status . CONCLUSIONS Supplementation with zinc , iron , or both improved indicators of vitamin A status . The results of this study agree with previous observations of a metabolic interaction between zinc and vitamin A and suggest an interaction between iron and vitamin A metabolism To evaluate the effect of long-term oral iron supplementation on growth , 250 children aged 6 - 71 mo were studied in a r and omized double-blind controlled trial . The intervention group received 125 mg of ferrous gluconate ( 15 mg elemental iron ) plus multivitamins ( vitamins A , D and C ) ; the comparison group received only multivitamins daily for 12 mo .  Weight ( kg ) and height ( cm ) were measured every month . Eighty three percent of the children continued the treatment for one year . The weight increment over the 12-mo period was 1.35 + /- 0.65 kg ( mean + /- SD ) in the intervention group and 1.39 + /- 0.54 kg in the comparison group . The height increments were 6.01 + /- 1.47 and 6.18 + /- 1.58 cm in the intervention and comparison groups , respectively . Mean weight and height increments did not differ ; in an analysis stratified according to different age and nutritional categories , they also did not differ between the two groups , indicating that long-term iron supplementation does not increase growth in children 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 The effect of long-term oral iron supplementation on  morbidity due to diarrhea , dysentery and respiratory infections in 349 children , aged 2 - 48 mo , living in a poor community of Bangladesh , was evaluated in this double-blind study . The treatment group received 125 mg of ferrous gluconate ( 15 mg elemental iron ) plus multivitamins and the controls received only multivitamins , daily for 15 mo . House-to-house visits were made on alternate days by trained community health workers for recording symptoms and duration of illnesses and for monitoring medicine intake . Seventy-six percent of the children continued the syrup for over 1 y. No untoward effects were noticed in either treatment group . The attack rates for diarrhea , dysentery and acute respiratory tract infections ( ARI ) were 3 , 3 and 5 episodes per child per year , respectively . Each episode of diarrhea lasted a mean of 3 d , and those of dysentery and ARI , 5 d. The two treatment groups did not differ in the number of episodes , mean duration of each episode , or total days of illnesses due to diarrhea , dysentery and ARI . However , a 49 % greater number of episodes of dysentery was observed with iron supplementation in a subset of the study children who were less than 12 mo old ( P = 0.03 ) . The results of this study suggest that long-term oral iron supplementation is not harmful for older children in a poor community . Further studies are needed to demonstrate the safety and efficacy of iron administration in young infants Objective : To assess the effects of iron and deworming on linear growth performance of preschoolers . Design : Three-month r and omized , 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 . Subjects : 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).Main outcome measures : Anthropometric parameters , hemoglobin and eggs per gram feces . Results : 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 ) . Conclusions : 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 . Sponsorship : The Nestlé Foundation ( Lausanne , Switzerl and ) .European Journal of Clinical Nutrition ( 2001 ) 55 , A double-blind clinical trial was conducted in Indonesia to assess effects of iron supplementation on performance of iron-depleted and iron-deficient anemic children in discrimination and oddity learning tasks . Half these children received elemental Fe for 8 wk ; the others received a placebo . There were significant changes from pre- to postintervention evaluations in ferritin , transferrin saturation , free erythrocyte protoporphyrin , and hemoglobin among the anemic and iron-depleted children ; no changes were observed among the placebos or any of the iron-replete children . The magnitude of hematological changes in anemic children treated with iron was small ; yet , after treatment the children 's mean ferritin , transferrin saturation , and hemoglobin values were above the cutoff points used for the definition of iron-deficiency anemia ( IDA ) . Pre- and posttreatment psychological test data show that IDA produces alterations in cognitive processes related to visual attention and concept acquisition , alterations reversed with iron treatment Abstract Objective : To measure the effects of iron supplementation and anthelmintic treatment on iron status , anaemia , growth , morbidity , and development of children aged 6–59 months . Design : Double blind , placebo controlled r and omised factorial trial of iron supplementation and anthelmintic treatment . Setting : Community in Pemba Isl and , Zanzibar . Participants : 614 preschool children aged 6–59 months . Main outcome measures : Development of language and motor skills assessed by parental interview before and after treatment in age appropriate subgroups . Results : 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 st and ard 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 . Conclusions : 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 . What is already known on this topic Iron is needed for development and functioning of the human brain Anaemic children show developmental delays , but it is not yet clear whether iron deficiency causes these deficits or whether iron supplementation can reverse them Helminth infections in schoolchildren are associated with cognitive deficits , but few studies have been made of helminth infection and early child development What this study adds Low doses of oral iron supplementation given daily improved language development in children aged 1–4 years in Zanzibar Iron supplementation improved motor development , but only in children with initial haemoglobin concentrations below 90 g/l The effects of routine anthelmintic treatment on motor and language milestones were positive , but non-significant , with our sample Objective : To examine effects of iron supplementation on vigilance , attention and conceptual learning in preschool children in Greece . Design : R and omized Double-Blind Placebo Controlled trial of iron . R and omization stratified by iron status and day care center ( DCC ) . Setting : Nine public DCCs in Athens , Greece . Subjects : In all , 49 3–4-y olds ( 21 anemic , 28 good iron status ) with birth weight not less than 2500 g , currently healthy ; benign past medical history , IQ ≥1 s.d . below the age-adjusted mean , serum Pb ≤200 ppb ( none exceeded 50 ppb ) , and height , weight and head circumference for age ≥10th percentile  . Anemia defined as : ( 1 ) pretreatment Hgb < 112 g/l and TS < 16 % and ferritin < 12 μg/L OR ( 2 ) Hgb rise of > 10 g/l ( T2–T0 ) with iron supplementation . Good iron status was defined as baseline levels of Hgb > 120 g/l and either TS > 20 % or serum ferritin > 12 μg/l . Intervention : The intervention consisted of a 2–month supplementation of 15 mg iron ( and MV ) vs placebo ( MV alone ) . Results : After iron treatment , the anemic subjects made significantly fewer errors of commission ( 14 % higher specificity , P<0.05 ) , exhibited 8 % higher accuracy ( P<0.05 ) and were significantly more efficient ( mean difference=1.09 , P<0.05 ) than those given placebo . These effects of iron were not found among preschoolers with good iron status . No effects of iron treatment were found on the Oddity Learning task . Conclusions : This study demonstrated that iron supplementation of iron-deficient anemic preschoolers results in an improvement in discrimination , specifically selective attention . Sponsorship : University of California , Davis and Nutricia Corporation Haematological and iron parameters , measured in 907 children aged from 6 months to 5 years in rural Gambia at the start of the rainy season , differed from those in American reference population s as follows : mean haemoglobin levels were much lower at ages 1 and 2 years and mean levels of mean corpuscular volume ( MCV ) were lower at all ages ( at age 1 year mean haemoglobin was 11.2 g/dl and mean MCV 68.2 fl ) ; in a sample of 249 children r and omly selected from the whole study population , mean serum iron levels were similar but mean transferrin saturation and mean serum ferritin levels were lower , especially at ages 1 - 3 years ( at age 1 year mean serum iron was 11.1 mumol/l , mean transferrin saturation 16.9 % , and geometric mean serum ferritin 8.8 ng/ml . A total of 213 children ( 23 % ) whose haemoglobin and mean corpuscular volume were both less than the 3rd percentile of the reference population received oral iron or placebo from their mothers during the rainy season when malaria transmission is maximal . Mean levels of haemoglobin , mean corpuscular volume , serum iron , transferrin saturation and serum ferritin rose in the iron-treated group and fell in the placebo group at all ages , except under 1 year for serum ferritin , to produce significant differences between the groups by the end of the study . Total iron-binding capacity showed no significant changes during the study . We concluded that oral iron given by the mother during the rainy season can be used to treat iron-deficiency anaemia in Gambian children who would otherwise become more anaemic BACKGROUND Anaemia caused by iron deficiency is common in children younger than age 5 years in eastern Africa . However , there is concern that universal supplementation of children with iron and folic acid in areas of high malaria transmission might be harmful . METHODS We did a r and omised , 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 St and ard R and omised Controlled Trial , number IS RCT N59549825 . FINDINGS The iron and folic acid-containing groups of the trial were stopped early on Aug 19 , 2003 , on the recommendation of the data and safety monitoring board . To this date , 24 076 children contributed a follow-up of 25,524 child-years . Those who received iron and folic acid with or without zinc were 12 % ( 95 % CI 2 - 23 , p=0.02 ) more likely to die or need treatment in hospital for an adverse event and 11 % ( 1 - 23 % , p=0.03 ) more likely to be admitted to hospital ; there were also 15 % ( -7 to 41 , p=0.19 ) more deaths in these groups . INTERPRETATION Routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death . In the presence of an active programme to detect and treat malaria and other infections , iron-deficient and anaemic children can benefit from supplementation . However , supplementation of those who are not iron deficient might be harmful . As such , current guidelines for universal supplementation with iron and folic acid should be revised Three studies conducted in Indonesia will be described . Soewondo ( 12 ) investigated the relation of iron deficiency and cognitive function and impact of iron supplementation on verbal intelligence , attention and concept learning among iron deficient children without anemia and iron deficient anemic children . Half of 176 children , aged 3 - 6 years , received elemental Fe for 8 weeks and the other half received  placebo . There were significant changes from pre to post intervention evaluations in ferritin , transferrin saturation , free erythrocyte protoporphyrin , and hemoglobin in the iron deficient anemic children . Pre and post treatment psychological test data showed that iron deficiency anemia produced alterations in cognitive processes related to visual attention and concept acquisition . These alterations can be reversed with iron treatment . Idjradinata ( 4 ) assessed the impact of iron supplementation on iron deficient infant 's mental and psychomotor development . Hundred twenty six subjects aged 12 to 18 month were r and omly assigned to either iron treatment or placebo intervention . After 4 months of iron supplementation , the hemoglobin , ferritin and transferrin saturation changed significantly in the iron deficient infants . A developmental delay was observed in the iron deficient anemic infants before intervention and the conditions were reversed after 4 months of iron treatment . Soemiarti ( 8) examined the effectiveness of a  training course  given to mothers of children aged 12 to 24 month on the rearing environment and consequently to the child 's development .  The subjects were 69 mothers of 20 - 35 years old . The training lasted for 21 days by giving mothers training using the program " Ibu Maju Anak Bermutu " . The rearing environment improved , also the child 's mental and psychomotor development Eighteen- to 60-month-old iron-deficient anemic children given iron therapy ( n = 25 ) and a control group matched for mother 's educational level showed no significant difference in mean mental development score at baseline . The control group 's mean score was increased significantly over baseline score at 3 and 6 months and was significantly higher than the experimental group 's mean score at 3 months . Although the experimental group demonstrated hematologic correction over 6 months , mean mental development score showed no significant improvement . Scores for an iron deficient not anemic group given iron ( n = 22 ) , despite complete hematologic correction over the six months of observation , and for its control group , did not change significantly . Baseline scores for an iron-deficient not anemic placebo group ( n = 23 ) and for its control group were not significantly different . At 3 months the control group score had increased significantly , whereas that for the experimental group had not . When experimental and control subjects were matched on baseline mental development score , the control subjects experienced increases in scores over time , further confirming an impaired ability to improve scores with repeated testing in the experimental groups . Behavioral rating data ( responsiveness to examiner , responsiveness to environment , and emotional tone ) revealed significant differences between the iron-deficient anemic group and its control group at 3 and 6 months , with the control group rated more responsive , suggesting that iron deficiency , alone or in association with anemia , may have some lasting effect on behavior and development . Group differences were also found between the mean number of occurrences of multiple stressful events . Failure to show improvement in scores in the iron-deficient anemic group may reflect the fact that those children were less testable than were children in the control group , despite repeated testings , a theory supported by the infant behavior rating data . This may be related to some irreversible behavioral deficit or to an adverse environmental milieu ( e.g. , stress ) In rural Mexico and in many developing countries micronutrient deficiencies , growth stunting , and morbidity from infectious diseases are highly prevalent in young children . We assessed the extent to which growth stunting could be reversed and the number of infectious disease episodes reduced by zinc and /or iron supplementation . In a double-blind , r and omized community trial 219 Mexican preschoolers were supplemented with either 20 mg Zn as zinc methionine , 20 mg Fe as ferrous sulfate , 20 mg Zn + 20 mg Fe , or a placebo . After 12 mo , plasma zinc increased significantly in the two zinc-treated groups , and plasma ferritin was significantly higher in the two iron-treated groups . There was no effect of treatments on growth velocity or body composition . Children in both zinc-supplemented groups had fewer episodes of disease ( zinc alone , 3.9 + /- 0.3 ; zinc+iron , 3.7 + /- 0.4 ; placebo , 4.6 + /- 0.5 ; P < 0.03 ) , including diarrhea ( zinc alone , 0.7 + /- 0.1 ; zinc+iron , 0.8 + /- 0.1 ; placebo , 1.1 + /- 0.2 ; P < 0.01 ) . Zinc and zinc+iron supplements reduced morbidity but had no effect on growth or body composition OBJECTIVE To evaluate the prevalence of anemia , iron deficiency and iron deficiency anemia in a cohort of children . METHODS A cohort study nested in a r and omized field trial . Children were recruited at birth at the maternity unit of the only public hospital in the city of São Leopoldo , southern Brazil . This study assessed  iron status ( hemoglobin and serum ferritin ) when children were 12 - 16 months old and later at the age of 3 - 4 years .  Anemia was defined as hemoglobin concentration < 11.0 g/dL ; iron deficiency as serum ferritin < 15.0 µg/L ; and iron deficiency anemia as hemoglobin concentration < 11.0 g/dL with iron deficiency . RESULTS At age 12 - 16 months , the overall prevalence of anemia , iron deficiency and iron deficiency anemia was 63.7 , 90.3 and 58.8 % , respectively . The values for age group 3 - 4 years were 38.1 , 16.1 and 7.4 % , respectively . At age 12 - 16 months , 95 % of anemia cases were associated with iron deficiency against only 19.3 % of cases at age 3 - 4 years . CONCLUSIONS Iron deficiency was the main cause of anemia in the second year of life , but not at age 3 - 4 years . Thus , we point out that anemia in preschool children may have other causes and deserves careful assessment 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 r and omized into a prospect i ve 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 result ed 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 1 . The effect of daily supplements of 20 - 30 mg inorganic iron as ferrous sulphate on the growth , activity and haematological status of preschool children was studied for 3.5 , 7 and 12 months and compared to that of children who served as controls . All children were given their daily requirements of energy and protein . In addition , they received 5 microgram cyanocobalamin and 200 microgram folic acid . 2 . Fe supplementation increased the haemoglobin , serum Fe and percentage saturation of transferrin and reduced the unsaturated Fe-binding capacity significantly compared to corresponding values for the controls . 3 . Height and activity were unaffected by Fe supplements . 4 . Of the children 45 % had haemoglobin values below 110 g/l at the end of 7 - 12 months of Fe supplementation Iron deficiency anemia ( IDA ) remains the most prevalent nutritional deficiency in infants worldwide . The purpose of this study was to determine the efficacy of daily and weekly iron supplementation for 3 months to improve the iron status in 4-month-old , exclusively breast-fed healthy infants . Infants 4 months of age were eligible for the open , r and omized controlled trial if their mothers intended to continue exclusive breast-feeding until the infants were 6 months of age . Infants or mothers with iron deficiency ( ID ) or IDA on admission were excluded . The infants ( n = 79 ) were r and omly assigned to three groups , the first group receiving daily ( 1 mg/kg daily ) , the second group weekly ( 7 mg/kg weekly ) , and the third group no iron supplementation .  Anthropometric measurements were taken on admission and at 6 and 7 months of age . Iron status was analyzed on admission and monthly for 3 months . Both hematologic parameters and anthropometric measurements were found to be similar among the three groups during the study period . Seven infants ( 31.8 % ) in the control group , six ( 26.0 % ) in the daily group , and three ( 13.6 % ) in the weekly group developed ID or IDA ( P > 0.05 ) . Infants whose mothers had ID or IDA during the study period were more likely to develop ID or IDA independently from iron supplementation . Serum ferritin levels decreased between 4 and 6 months of age in the control and daily groups ; the weekly group showed no such decrease . In all groups , the mean levels of serum ferritin were significantly increased from 6 months to 7 months of age during the weaning period . In this study , which had a limited number of cases , weekly or daily iron supplementation was not found to decrease the likelihood of IDA . In conclusion , exclusively breast-fed infants with maternal IDA appeared to be at increased risk of developing IDA The growth status of anemic ( n = 117 , Hb 7 - 10 g/dl ) and normal ( n = 53 , H > or = 11 g/dl ) children 3 - 5 years of age living under similar environmental and socio-economic conditions was evaluated . The dietary intake was assessed on a r and om sub sample of the anemic and normal children . The anemic children had a poorer growth status than normal children as indicated by their significantly ( p < 0.001 ) lower body weight , height and weight for age and significantly ( p < 0.001 ) larger number in Grade s II and III malnutrition . Iron supplementation ( 40 mg elemental iron/day ) for six months produced a significant ( p < 0.001 ) increase in Hb levels of both groups ( 1.6 g/dl in the anemic and 0.8 g/dl in the non-anemic ) compared to their respective controls who received sugar placebos . The growth performance of the anemic children supplemented with iron was superior to that of anemic placebo treated children as indicated by a better weight gain and a significantly higher weight for height ( p < 0.05 ) . Weight for age was a good differentiator of the anemic from normal while weight for height was a good indicator of the impact of iron  supplements on growth 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 r and omized 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
target: Limited evidence suggested that iron supplementation produced a small improvement in cognitive development but had no effect on physical growth .
  CONCLUSIONS : In 2 to 5 year olds , daily iron supplementation increases hemoglobin and ferritin .
  There is a concerning lack of data on the effect of iron supplementation on clinical ly important outcomes including anemia , ID anemia , ID , and cognitive development .
background: BACKGROUND AND OBJECTIVES : Iron deficiency ( ID ) is the most common cause of anemia worldwide .
  The prevalence is highest among preschool-aged children .
  Iron is widely administered to children with or at risk for ID , but evidence of benefit among 2- to 5-year-old children has not been evaluated by systematic review .
  We summarize the evidence for the benefit and safety of daily iron supplementation with regard to hematologic , growth , and cognitive parameters in 2 to 5 year olds .