Oral iron supplements for children in malaria-endemic areas

  • Review
  • Intervention

Authors


Abstract

Background

Iron-deficiency anaemia is common during childhood. Iron supplementation has been claimed to increase the risk of malaria.

Objectives

To assess the effect of iron on malaria and deaths.

Search methods

We searched The Cochrane Library, PUBMED, MEDLINE, LILACS; and trial registry databases, all up to June 2011. We scanned references of included trials.

Selection criteria

Individually and cluster randomized controlled trials conducted in hypoendemic to holoendemic malaria regions and including children below 18 years of age. We included trials comparing orally administered iron, iron with antimalarial treatment, or iron with folic acid versus placebo or no treatment. Iron fortification was excluded. Antihelminthics could be administered to either group. Additional micronutrients had to be administered equally to both groups.

Data collection and analysis

The primary outcomes were clinical (symptomatic) malaria, severe malaria, and death. Two authors independently selected the studies and extracted the data. We assessed heterogeneity and conducted subgroup analyses by the presence of anaemia at baseline, age, and malaria endemicity. We assessed risk of bias using domain-based evaluation. We performed a fixed-effect meta-analysis for all outcomes and random-effects meta-analysis for hematological outcomes. We adjusted analyses for cluster randomized trials.

Main results

Seventy-one trials (45,353 children) were included. For clinical malaria, no significant difference between iron alone and placebo was detected, (risk ratio (RR) 0.99, 95% confidence intervals (CI) 0.90 to 1.09, 13 trials). The results were similar in the subgroups of non-anaemic children and children below 2 years of age. There was no significant difference in deaths in hyper- and holoendemic areas, risk difference +1.93 per 1000 children (95% CI -1.78 to 5.64, 13 trials, 17,898 children). Iron administered for treatment of anaemia resulted in a larger increase in haemoglobin than iron given for prevention, and the benefit was similar in hyper- or holoendemic and lower endemicity settings. Iron and folic acid supplementation resulted in mixed results for severe malaria. Overall, the risk for clinical malaria was higher with iron or with iron plus folic acid in trials where services did not provide for malaria surveillance and treatment. Iron with antimalarial treatment significantly reduced malaria. Iron supplementation during an acute attack of malaria did not increase the risk for parasitological failure, (RR 0.96, 95% CI 0.74 to 1.24, three trials) or deaths.

Authors' conclusions

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.

Résumé scientifique

Oral iron supplements for children in malaria-endemic areas

Contexte

L’anémie ferriprive survient couramment au cours de l'enfance. La supplémentation en fer est supposée accroître le risque de paludisme

Objectifs

Évaluer l’effet du fer sur le paludisme et le décès.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans The Cochrane Library, PUBMED, MEDLINE, LILACS et dans des bases de données de registres d’essais cliniques jusqu’en juin 2011. Nous avons passé au crible les bibliographies des essais inclus..

Critères de sélection

Essais contrôlés randomisés individuellement et en grappes/cluster effectués dans des régions d’hypoendémie et d’holoendémie palustres et incluant des enfants âgés de moins de 18 ans. Nous avons inclus des essais comparant du fer administré par voie orale, du fer associé à un traitement antipaludique ou du fer associé à l'acide folique à un placebo ou à l’absence de traitement. L'enrichissement en fer a été exclu. Des anthelminthiques pouvaient être administrés à l’un ou l’autre groupe. Des oligoéléments supplémentaires devaient être administrés en parts égales aux deux groupes.

Recueil et analyse des données

Les critères de jugement principaux étaient le paludisme clinique (symptomatique), le paludisme grave et le décès. Deux auteurs ont sélectionné les études et extrait les données de manière indépendante. Nous avons évalué l’hétérogénéité et effectué des analyses en sous-groupe selon la présence d’une anémie à l’inclusion, l’âge et l’endémicité du paludisme. Nous avons évalué le risque de biais au moyen d’une évaluation par domaine. Nous avons procédé à une méta-analyse à effets fixes pour tous les critères de jugement et à une méta-analyse à effets aléatoires pour les critères hématologiques. Nous avons ajusté les analyses pour les essais randomisés en grappes/cluster.

Résultats principaux

Soixante et onze essais (45 353 enfants) ont été inclus. Pour ce qui est du risque d’accès palustre clinique, aucune différence significative n’a été observée entre le fer seul et le placebo (rapport de risques (RR) 0,99, intervalle de confiance (IC) à 95 % 0,90 à 1,09, 13 essais). Les résultats étaient similaires dans les sous-groupes d’enfants non anémiés et d’enfants de moins de 2 ans. Aucune différence significative n’a été notée pour ce qui est des décès dans les zones d’hyperendémie et d’holoendémie, la différence de risques étant de +1,93 pour 1 000 enfants (IC à 95 % -1,78 à 5,64, 13 essais, 17 898 enfants). Le fer administré pour le traitement de l’anémie a permis une augmentation de l’hémoglobine plus importante que le fer administré à titre de prévention et le bénéfice était similaire dans les zones d’hyperendémie ou d’holoendémie et de moindre endémicité. La supplémentation en fer et en acide folique a avait un effet variable sur le risque de paludisme grave. Globalement, le risque de d’accès palustre était plus élevé avec le fer avec ou sans acide folique dans les essais dans lesquels les services n’ont pas assuré la surveillance et le traitement du paludisme. Le fer associé au traitement antipaludique a considérablement réduit le risque de paludisme. La supplémentation en fer pendant l’accès palustre n’a pas augmenté le risque d’échec parasitologique (RR 0,96, IC à 95 % 0,74 à 1,24, trois essais) ou de décès.

Conclusions des auteurs

Le fer seul ou associé à un traitement antipaludique n’accroît pas le risque d'accès palustre ou de décès lorsque des services de surveillance régulière et de traitement du paludisme sont proposés. Il n’est pas nécessaire de faire un test de dépistage de l’anémie avant la supplémentation en fer.

Plain language summary

Iron supplements for children living in malaria-endemic countries

Children commonly develop anaemia (low haemoglobin) after birth. Anaemia is associated with several ill effects, including hindering motor development and learning skills, and impaired immunity. Children are therefore commonly given iron supplements to prevent or treat anaemia. In countries where malaria is prevalent, it has been suggested that iron supplementation increases the risk of malaria and death. The high dose of iron which is given as medicine may result in free iron circulating in the blood and is made available to the malaria parasite, promoting its growth. We aimed to assess the effects of oral iron supplementation in children living in countries where malaria is prevalent.

Iron did not increase the risk of malaria, indicated by fever and the presence of parasites in the blood. There was no increased risk of death among children treated with iron. Although it is hypothesized that iron supplementation might harm children who do not have anaemia because of the iron overload, we did not find an increased risk for malaria among non-anaemic children. When iron was administered with folic acid (a vitamin necessary for DNA synthesis) one large trial suggested there was an increased risk of severe (lethal) malaria. When iron was administered in settings of poor malaria management there was an increased risk for malaria. Iron supplementation increased haemoglobin by about 1 g/dL in areas where malaria is highly prevalent. At the end of follow-up, which varied between two weeks and six months after the end of iron supplementation, the haemoglobin gain was smaller but still present at 0.4 g/dL. Iron did not increase the risk of respiratory infections or other infections. Children given iron visited medical clinics less than children given placebo, but the rate of hospitalization was similar. The children's weight and height at the end of treatment were similar. Iron did not adversely affect the rates of cure when it was given together with antimalarial treatment in the three trials that examined this issue.

Our conclusions are that iron supplementation (without folic acid) does not adversely affect children living in malaria-endemic areas. The evidence shown in our review is limited by the lack of trials examining the relevant outcomes and the limited information available, so that we were unable to fully analyse factors that could affect our results, such as the children's baseline level of haemoglobin. Based on our review, routine iron supplementation should not be withheld from children living in countries where malaria is prevalent.

Résumé simplifié

Suppléments en fer pour les enfants vivant dans des pays d’endémie palustre

Les enfants développent couramment une anémie (faible taux d’hémoglobine) après la naissance. L’anémie est associée à plusieurs effets indésirables, notamment un retard du développement moteur et des capacités d’apprentissage, et à une diminution de l’immunité. Les enfants reçoivent donc couramment des suppléments en fer pour prévenir ou traiter l’anémie. Dans les pays dans lesquels le paludisme est fréquent, il a été suggéré qu’une supplémentation en fer augmenterait le risque de paludisme et de décès. La dose élevée de fer administrée en tant que médicament peut conduire à la circulation de fer libre dans le sang ainsi disponible pour le parasite du paludisme, pouvant favoriser sa croissance. Nous avions pour objectif d'évaluer les effets de la supplémentation en fer oral chez les enfants vivant dans des pays dans lesquels le paludisme est fréquent.

Le fer n’a pas augmenté le risque de crise de paludisme, se manifestant par une fièvre et par la présence de parasites dans le sang. Aucune augmentation du risque de décès chez les enfants traités avec du fer n’a été notée. Bien que l’hypothèse selon laquelle une supplémentation en fer pourrait nuire aux enfants non anémiés en raison de la surcharge en fer, nous n'avons trouvé aucune trace d’augmentation du risque de paludisme chez les enfants non anémiés. Lorsque le fer a été administré conjointement avec de l’acide folique (une vitamine nécessaire à la synthèse de l’ADN), un seul essai à grande échelle a suggéré que le risque de paludisme grave (mortel) était accru. Lorsque le fer a été administré dans des régions dans lesquelles la prise en charge du paludisme était insuffisante, le risque de paludisme était plus élevé. La supplémentation en fer a augmenté le taux d’hémoglobine d’environ 1 g/dl dans les régions dans lesquelles le paludisme est extrêmement répandu. À la fin du suivi, qui variait entre deux semaines et six mois après la supplémentation en fer, le gain en hémoglobine était moindre, mais toujours présent à 0,4 g/dl. Le fer n’a pas augmenté le risque d’infections respiratoires ou d’autres infections. Les enfants recevant du fer ont moins consulté les centres médicaux que les enfants recevant un placebo, mais le taux d’hospitalisation était similaire. Le poids et la taille des enfants à la fin du traitement étaient semblables. Le fer n’a eu aucune incidence négative sur les taux de guérison lorsqu’il était administré conjointement à un traitement antipaludique dans les trois essais qui ont étudié cette question.

En conclusion, la supplémentation en fer (sans acide folique) n’affecte pas les enfants vivant dans des zones d’endémie palustre. Les preuves produites dans notre revue sont limitées par le manque d’essais examinant les résultats pertinents et par les informations disponibles limitées de sorte que nous n’avons pas été en mesure d’analyser complètement les facteurs susceptibles d’affecter nos résultats, comme le taux d’hémoglobine à l’inclusion des enfants. D’après notre revue, la supplémentation systématique en fer ne doit pas être refusée aux enfants vivant dans des pays dans lesquels le paludisme prévaut.

Notes de traduction

Traduit par: French Cochrane Centre 1st November, 2011
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Summary of findings(Explanation)

Summary of findings for the main comparison. Oral iron supplements for children in malaria endemic areas
  1. 1 Data analysed with RRs and SEs, since not all trials reported raw patient numbers and data from cluster randomized trials extracted preferentially as adjusted RRs. Unadjusted raw numbers from all but one studies shown.
    2 Most of the trials had adequate allocation concealment and all but one were double-blinded. Exclusions were related to the inability to measure parasitaemia. None of the trials stopped early.
    3 Minor measured inconsistency in the analysis (I2 = 32%). Subgroup analyses by age, anaemia at baseline and iron administration schedule revealed no effects in all subgroups. Among children anaemic at baseline the RR was 1.11 (0.87, 1.43); among non-anaemic children at baseline the RR was 0.97 (0.86, 1.09).
    4 Outcome directly relevant to the question of the safety of iron supplementation and measures a clinically relevant outcome. Four trials recruited children < 2 years of age and the RR in this age group was 0.94 (0.82, 1.09).
    5 The upper value of the 95% CI is RR 1.14 overall. Although only few studies were included in the analyses of children without anaemia at baseline and children < 2 years of age, the upper RR is 1.09 for both subgroups.
    6 The funnel plot is asymmetrical with more small studies favouring control than small studies favouring iron. Thus, no publication bias in favour of iron is suspected.
    7 The outcomes reported (fever and high-grade parasitaemia or admissions for malaria) are different from the review definition for severe malaria (cerebral malaria or disease associated with the dysfunction of vital organs ).
    8 Sensitivity analyses showed an effect of allocation concealment on results: RR 0.94 (0.79, 1.11) with adequate allocation concealment and RR 1.22 (1.06, 1.40) with inadequate/unclear concealment.
    9 Results for patient subgroups (presence of anaemia at baseline and age) showed homogenous results for the subgroups assessed.
    10 The association between asymptomatic parasitaemia and clinically significant morbidity and severe malaria is unclear. The results are not directly relevant to children < 2 years of age. since only one trial was included in this age subgroup.
    11 All-cause mortality, control risk: lower and upper range of childhood mortality per 1000 in 2010 in sub-Saharan Africa, as reported in Rajaratnam et al. Lancet 2010; 375: 1988-2008.
    12 Only risk differences were analysed to allow for the inclusion of trials with no events in both study arms (ie, most of the trials included in the analysis).
    13 The major risk of bias is related to incomplete outcome assessment in most of the trials (a drop-out range of 2-62% of patients). Deaths might have occurred among the drop-outs. Most of the trials had adequate allocation concealment and all but one were double-blinded (although the latter item should not affect the outcome of mortality).
    14 No heterogeneity in the analysis (I2= 0%). Subgroup analyses by age, anaemia at baseline and iron administration schedule revealed no effects in all subgroups.
    15 Although not all deaths are related to malaria, the outcome directly assesses the study's question. The study participants consisted of children < 2 years in 6 of the 9 studies; thus this result is applicable to this age group.
    16 The upper value of the 95% CI is one death per 100 children, given a control risk of 1.5% in existing trials.
    17 The denominator refers to patient-months. The rate is expressed as admissions per patient-month.
    18 Two-thirds of the trials were adequately concealed: all were double-blind and few lost to follow-up (0.0 and 12%).
    19 Hospital admissions do not necessarily reflect the burden of malaria.

Does iron supplementation increase morbidity and mortality among children in malaria endemic areas?
Patient or population: children with or without anaemia at baseline
Settings: hypo, meso, hyper and holoendemic areas for malaria
Intervention: Oral iron supplement
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlIron
Clinical malaria
Fever (usually >37.5) with parasitaemia
Follow-up: 2-6 months
231 per 1000229 per 1000
(208 to 252)1
RR 0.99
(0.90 to 1.09)
3851
(13 studies)
⊕⊕⊕⊕
high 2,3,4,5,6
 
Clinical malaria among children without anaemia at baseline
Fever (usually >37.5) with parasitaemia
Follow-up: 2 to 6 months
361 per 1000350 per 1000
(311 to 394)1
RR 0.97
(0.86 to 1.09)
1621
(4 studies)
⊕⊕⊕⊕
high 2,3,4,5,6
 
Clinical malaria among children <2 years
fever (usually >37.5) with parasitaemia
Follow-up: 2 to 6 months
292 per 1000275 per 1000
(240 to 319)1
RR 0.94
(0.82 to 1.09)
1035
(4 studies)
⊕⊕⊕⊕
high 2,3,4,5,6
 
Severe malaria (admission for malaria or fever and high-grade parasitaemia)
Admissions for malaria (one study) or fever (>37.5 usually) with parasitaemia >5000 parasites/μL (2 studies)
Follow-up: 3 to 6 months
158 per 1000144 per 1000
(120 to 170)1
RR 0.91
(0.76 to 1.08)
1321
(4 studies)
⊕⊕⊝⊝
Low 7
 
Parasitaemia at end of treatment
Slide count with variable definitions
Follow-up: 2 to 12 months
269 per 1000293 per 1000
(263 to 328)1
RR 1.09
(0.98 to 1.22)
2291
(8 studies)
⊕⊝⊝⊝
very low 8,9,10
 
All-cause mortality in malaria hyper / holoendemic areas
Follow-up: 1.5 to 6 months
Study population11Not estimable3798
(13 studies)
⊕⊕⊝⊝
low 13,14,15,16
 
16 per 10000 per 1000
(0 to 0)12
Low11
10 per 10000 per 1000
(0 to 0)12
High11
100 per 10000 per 1000
(0 to 0)12
Hospital admissions in hyper- or holoendemic regions
Hospital admissions per child month
Follow-up: 12 to 48 weeks
52 per 100049 per 1000
(42 to 56)17
RR 0.94
(0.81 to 1.09)
14721
(4 studies)
⊕⊕⊝⊝
Low 18,19
 
*The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Oral iron with folic acid supplements for children in malaria-endemic areas

Summary of findings 2. Oral iron with folic acid supplements for children in malaria-endemic areas
  1. 1 Most children were followed up for 1 year; the maximal duration of follow-up was 18 months (until age 48 months or date of study discontinuation.
    2 Two parts of a single trial: Sazawal 2006 main study and substudy. Children in the substudy were older than those in the main study (mean age 22.5 versus 18.2 months) and probably less anaemic because children with a haemoglobin level < 7 g/dL were excluded from the substudy only.
    3 The study was discontinued for harm, when reaching a pre-defined P value of 0.2 for all-cause mortality in the main study.
    4 Significantly difference results obtained from the two parts of the trial (the main study and the substudy).
    5 The pooled results of the main study and the substudy provide a wide range between harm and benefit.
    6 Results of the main study show a large, statistically significant effect (overall, a 32% increase of cerebral malaria episodes with iron).
    7 All-cause mortality, control risk: lower and upper range of childhood mortality per 1000 in 2010 in sub-Saharan Africa, as reported in Rajaratnam et al. Lancet 2010; 375: 1988-2008.
    8 Allocation concealment adequate in 4/4 trials (an important factor for mortality assessment); all trials were double-blinded (an unimportant factor for mortality assessment); Incomplete outcome in 2/4 trials ranging from 2.6-51.5% of patients (a very important factor for mortality assessment); 2/4 stopped early and adequate adjustment for clustering in 2 cluster RCTs (an unimportant factor for mortality assessment).
    9 Pooled results compatible with benefit and harm
    10 Denominator refers to patient-months. Rate expressed as admissions per patient-month.
    11 Hospital admissions do not necessarily reflect the burden of malaria.
    12 95% CIs include small benefit and significant harm.

Does iron with folic acid supplementation increase morbidity and mortality among children in malaria-endemic areas?
Patient or population: children with or without anaemia at baseline
Settings: Hyper- and holoendemic areas for malaria
Intervention: Oral iron plus folic acid supplement
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlIron plus folic acid
Severe malaria (admissions for malaria)
Admissions to hospital
Follow-up: mean 12 months1
Results not pooledResults not pooledNot estimable17575
(2 studies2)
⊕⊕⊝⊝
low 3,4,5
 
Severe malaria (cerebral malaria)
Admissions to hospital
Follow-up: mean 12 months1
Results not pooledResults not pooledNot estimable1619
(2 studies2)
⊕⊕⊕⊝
moderate 3,4,5,6
 
All-cause mortality in hyper / holoendemic regions
Follow-up: 1.5-12 months
Study population7Not estimable17898
(4 studies)
⊕⊕⊕⊝
moderate 8,9
 
15 per 10000 per 1000
(0 to 0)
Low7
10 per 10000 per 1000
(0 to 0)
High7
100 per 10000 per 1000
(0 to 0)
Hospital admissions in hyper / holoendemic regions
Hospital admissions per child-month
Follow-up: mean 48 weeks1
9 per 10009 per 1000
(8 to 11)10
RR 1.08
(0.96 to 1.22)
191472
(1 study)
⊕⊕⊝⊝
low 3,11,12
 
*The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 Oral iron supplements with antimalarial treatment for children in malaria-endemic areas?

Summary of findings 3. Oral iron supplements with antimalarial treatment for children in malaria-endemic areas?
  1. 1 All trials were individually randomized, with adequate concealment, double-blinded and no loss to follow-up
    2 Heterogeneity is measured as P = 0.06, I2 = 64%, but all trials point in the same direction
    3 All-cause mortality, control risk: lower and upper range of childhood mortality per 1000 in 2010 in sub-Saharan Africa, as reported in Rajaratnam 2010
    4 Allocation concealment adequate and double-blinding in all trials. Incomplete outcome for mortality in 2/4 trials ranging from 2.6 to 51.5% of patients, 2/4 stopped early. There is no assurance that no deaths occurred among dropouts.
    5 Pooled results compatible with benefit and harm

Is iron supplementation with antimalarial treatment safe and beneficial for children living in malaria-endemic areas?
Patient or population: Children with or without anaemia at baseline
Settings: Hyper- or holoendemic areas for malaria
Intervention: Oral iron supplement plus antimalarial
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlIron supplementation plus antimalarial
Clinical malaria
Fever and parasitaemia
Follow-up: 3 to 12 months
413 per 1000223 per 1000
(177 to 277)
RR 0.54
(0.43 to 0.67)
728
(3 studies)
⊕⊕⊕⊕
high 1,2
 
All-cause mortality
Follow-up: 1.5 to 12 months
Study population3RR 1.05
(0.52 to 2.11)
728
(4 studies)
⊕⊕⊝⊝
low 4,5
 
39 per 100041 per 1000
(20 to 82)
Low3
10 per 100010 per 1000
(5 to 21)
High3
100 per 1000105 per 1000
(52 to 211)
*The basis for the assumed risk (eg, the median control group risk across studies) is provided in the footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 4 Oral iron supplements in the treatment of malaria

Summary of findings 4. Oral iron supplements in the treatment of malaria
  1. 1 Unclear allocation concealment, no blinding (unimportant in the assessment of mortality) and loss to follow-up ranging between 2-20% in all trials.
    2 All-cause mortality, control risk: death rate in control group (quinine treatment) among children with severe falciparum malaria of a randomized controlled trial of malaria treatment in Africa Dondorp 2010
    3 Low event rate for mortality and small number of patients evaluated overall, thus 95% CIs is compatible with both benefit and harm

Does iron supplementation increase the risk for death or treatment failure in the treatment of malaria?
Patient or population: Children with acute malaria and anaemia
Settings: Hospitalized children or those discharged from hospital with a diagnosis of malaria
Intervention: Oral iron supplements
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlIron
Parasitological failure
Slide parasite counts
Follow-up: 1-3 months
310 per 1000303 per 1000
(214 to 430)
RR 0.98
(0.69 to 1.39)
583
(3 studies)
⊕⊕⊝⊝
low 1
 
All-cause mortality
Follow-up: 1-3 months
Study population2Not estimable664
(4 studies)
⊕⊕⊝⊝
low 1,3
 
7 per 10000 per 1000
(0 to 0)
High2
100 per 10000 per 1000
(0 to 0)
*The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Childhood anaemia

Childhood anaemia is a widespread and important public health problem in sub-Saharan Africa (WHO 2008). Anaemia is defined as a low red blood cell count. It occurs due to the reduced production of red blood cells or an increased loss of these cells. Diagnosis is by examining the level of haemoglobin (the protein in red blood cells responsible for carrying oxygen). Haemoglobin levels defining anaemia in children vary according to the age group: for children between 6 and 59 months of age the cut-off value is 11 g/dL, for children aged 5 to 11 years it is 11.5 g/dL, for children aged 12 to 14 years and non-pregnant women older than 15 years it is 12 g/dL, and for adolescent males older than 15 years it is 13 g/dL (WHO 2011a). The causes of anaemia in developing countries are numerous and often multifactorial, and include micronutrient deficiencies (such as iron, vitamin A, and folate), infectious diseases (such as malaria, human immunodeficiency virus (HIV), and intestinal helminths) and haemoglobinopathies (WHO 2011a).

Iron and iron deficiency

Iron is an important mineral needed to produce haemoglobin. It is also a component of many enzymes essential for proper cell development and cell growth of the brain, muscle, and the immune system (Beard 2001). Iron is a component of the peroxidase and nitrous oxide-generating enzymes that participate in the immune response to infections and is probably involved in regulating the production and action of cytokines (mediators of immune function released during early stages of infection). Since free iron is toxic to cells it is stored as ferritin, an intracellular protein. In healthy individuals without inflammation serum ferritin correlates with total body iron stores.

A relatively large amount of iron is required to produce red blood cells (erythropoiesis) in the first few months after birth. This is usually derived from the iron stored by the foetus in the last months of pregnancy. However, by the time a child is 4 to 6 months old, these stores become marginal or depleted. A child whose diet does not provide enough iron risks developing iron-deficiency anaemia. Infants with low total body iron at birth are particularly prone to iron deficiency and this is often exacerbated by the early introduction of cereal-based weaning food from which iron absorption can be as low as 5% (FAO/WHO 2005). Iron deficiency may be worsened by chronic blood loss from the intestines as a result of intestinal parasitic infections (Stoltzfus 1997). Iron deficiency anaemia is characterized by pallor, fatigue, and weakness. Loss of appetite, strange cravings for food like eating dirt (pica), hair loss, and light-headedness, among other symptoms, can also occur. Because iron-deficiency anaemia tends to develop slowly, adaptation occurs and the disease could go unrecognised for long periods.

Iron deficiency is common and affects approximately two billion people worldwide, resulting in over 500 million cases of anaemia (WHO 2004). Globally, the most significant contributor to the onset of anaemia is iron deficiency (WHO 2008). In sub-Saharan Africa, the prevalence of iron deficiency anaemia is estimated to be around 60% overall (WHO 2004), with 40% to 50% of children under 5 years of age in developing countries being iron-deficient (UNICEF 1998). Community prevalence figures in a single study in Kenya in children under 15 years of age showed that up to 80% of them were anaemic by 11 months of age (Bloland 1999).

Based on estimates of iron deficiency anaemia as a risk factor for death, iron deficiency has been estimated to cause 726,000 deaths in the perinatal and childhood periods globally, with the greatest toll in Southeast Asia and Africa (WHO 2004; FAO/WHO 2005). Experimental and observational studies have linked iron deficiency to several adverse consequences of child development, including impairments in cognitive, emotional, and motor development (Pollitt 1993; Grantham-McGregor 2001; Gewa 2009), growth (Lawless 1994), immune function, and increased risk of infection (Berger 2000; Beard 2001). The relative risk for mental retardation associated with a 1 g/dL increase in population mean haemoglobin has been estimated at 0.78 (95% CI 0.70 to 0.86) (WHO 2004). However, these studies have been criticized for their inability to fully adjust for confounders and because they cannot establish causality (Oppenheimer 2001). Systematic reviews of randomized controlled trials (RCTs) on iron supplementation in children have demonstrated moderate improvements in mental development and intelligence scores and small or no effects on motor development or growth (Bhandari 2001; Ramakrishnan 2004; Sachdev 2005; Iannotti 2006; Sachdev 2006). Sachdev 2006 found that although iron supplementation did not improve growth overall, positive effects were present in malaria hyperendemic regions and among children above 5 years of age. The effect on mental development assessed through intelligence scores was larger for children above 7 years of age and in those who were anaemic or iron-deficient anaemic at baseline (Sachdev 2005). It should be noted that the time frame of the RCTs may have been insufficient for evaluating developmental outcomes fully.

The diagnosis of iron deficiency and iron deficiency anaemia relies mainly on the measurement of haemoglobin, iron and ferritin. The measurement of haemoglobin alone is not sufficiently sensitive (due to overlapping values in iron-sufficient and iron-deficient individuals) and it is not specific because of the numerous causes of anaemia in developing countries. Ferritin is the most commonly accepted measure of iron status (Mei 2005). However, there is a complex interaction between infection, inflammation (even if it is subclinical) and ferritin. Infection and inflammation increase ferritin, which is an acute phase reactant. The increase is proportional to the baseline ferritin levels and available iron stores (Thurnham 2010). It decreases only slowly after the resolution of infection and remains elevated in the convalescent phases of infection. Thus, in developing countries it is difficult to interpret ferritin levels and their use as a biomarker of iron deficiency may underestimate the true prevalence of iron deficiency (Nyakeriga 2004; Zimmermann 2005). Other biomarkers or combinations of biomarkers have been suggested for the assessment of iron deficiency in locations with a high prevalence of infection. These include the serum transferrin receptor, zinc protoporphyrin, transferrin saturation, and the ratio of serum transferrin receptor to serum ferritin (Lynch 2011) as well as the adjustment of ferritin to C-reactive protein or alpha1-acid glycoprotein levels, or both (Mburu 2008; Thurnham 2010). The World Health Organization (WHO) and Centers for Disease Control (CDC) recommend using concurrent measurements of haemoglobin, ferritin and transferrin receptor to assess the iron status of a group (WHO/CDC 2004, WHO 2011b). The concurrent measurement of the inflammatory markers C-reactive protein and alpha1-acid glycoprotein are recommended to facilitate the interpretation of ferritin levels. However, the exclusion of children with elevated markers of inflammation from iron deficiency assessment is not reasonable, since up to 69% of children in malaria-endemic areas might have elevated markers of inflammation (Darboe 2007).

Malaria and iron deficiency

Malaria is a leading cause of morbidity and mortality in children in sub-Saharan Africa (Breman 2001; WHO 2008). Most infections are caused by the most virulent parasite species, Plasmodium falciparum ( WHO 2008), which is transmitted to humans by the bite of an infected female anopheles mosquito. Trends and general patterns of malaria transmission vary greatly geographically and children are vulnerable to malaria from the age of approximately 3 months or earlier, when immunity acquired from the mother wanes. Malaria is an important contributor to anaemia in endemic regions through the destruction of parasitized red blood cells (haemolysis), increased clearance of infected and uninfected red blood cells by the spleen, and cytokine-induced dyserythropoiesis (abnormal production of red blood cells) (Menendez 2000; Ekvall 2003).

There is a debate on whether iron deficiency offers protection from malaria and whether an excess of iron increases the risk for malaria or severe malaria (Oppenheimer 2001). Iron is required by many pathogens for their survival and pathogenesis (killing ability) (Beard 2001). Removal of free circulating iron seems to be an important part of the host (human) response to infection. The theory that iron deficiency may be an important defence mechanism has been termed "nutritional immunity" (Kochan 1973). The erythrocytic form of the malaria parasite requires free iron (which is lacking in an iron-deficient individual). In an observational study iron deficiency was associated with a small but significant degree of protection from episodes of clinical malaria in a cohort of young children living on the Kenyan coast (Nyakeriga 2004).

Description of the intervention

In areas where the prevalence of anaemia is 40% or more in young children, guidelines generally recommend that children of normal birthweight receive oral iron (2 mg/kg/day of elemental iron, daily, for 3 months) between the ages of 6 months and 2 years, and that children with a low birthweight receive the same amount of iron starting at 2 months (Stoltzfus 1998; INACG 1999). Iron-deficiency anaemia is treated with an oral preparation of elemental iron (3 mg/kg/day).

Several meta-analyses have previously examined the benefits and risks of iron supplementation in children (INACG 1999; Oppenheimer 2001; Gera 2002; Gera 2007; Iannotti 2006). These have shown that iron treatment increases haemoglobin and prevents anaemia. The absolute effects on haemoglobin were larger among children who were anaemic at baseline and smaller in malarial hyperendemic regions compared with non-endemic regions, and with iron-fortified food compared with oral medicinal iron (Gera 2007). An increased risk for malaria has been pointed out in several meta-analyses, mainly parasitaemia (being slide-positive for P. falciparum at the end of supplementation) (INACG 1999; Oppenheimer 2001; Gera 2002; Iannotti 2006). The effects on parasitaemia were associated with baseline rates of parasitaemia (Gera 2002). Other infections were also assessed in Gera 2002. Overall there was no difference in the incidence rate ratio for all recorded infections. Diarrhoea was more frequent in the iron-supplemented group.

Why it is important to do this review

In 2006, the results of a large RCT evaluating the effect of iron and folate supplements in a malaria-intense area of Zanzibar was published (Sazawal 2006 (C)a). The study was terminated prematurely on the recommendation of the study data safety and management board due to a higher proportion of hospitalization or death in the iron and folic acid containing groups compared with those without. A subgroup analysis revealed that the risk was limited to children who were iron-replete when iron supplementation was started. This trial heightened global concern about the routine, non-selective iron supplementation policy in areas where malaria is highly prevalent. Before this trial, the WHO guidelines for children living in malaria-endemic areas were no different than the general recommendations (WHO 2003). In 2007 a consultation convened to consider the results of this trial and the recommendations for children living in malaria-endemic areas (WHO 2007). The trial's subgroup analysis suggested that it might be necessary to screen for iron deficiency and treat only iron-deficient children. However, such a recommendation is difficult or impossible to implement. There is no consensus on the most appropriate biomarker to assess iron deficiency or monitor iron status during supplementation in regions with a high prevalence of infection (Mburu 2008; Thurnham 2010; Lynch 2011; ). Furthermore, as a public health intervention, screening of all children before iron supplementation is impractical in most malaria-endemic areas. Thus, it has become critical to examine the safety and effects of iron supplementation in malaria endemic areas considering all the available evidence.

We set to examine the complete evidence in all RCTs assessing iron supplementation for children in malaria-endemic areas. We specifically searched for outcomes related to malaria and data for all-cause mortality, which ultimately combines benefit and harm. Since iron has been claimed to harm mainly iron replete children, we aimed to explore the differential effects of iron supplementation in children anaemic at baseline and those who were not. The current update addresses several of the issues raised in commentaries (Roth 2010; Stoltzfus 2010; Suchdev 2010) and meetings following the initial publication of the review. We fully separated the intervention of iron + folic acid from the intervention of iron alone; we draw attention to the different definitions used for assessment of malaria; we assessed P. falciparum malaria separately; and we refined the stratification by anaemia at baseline and the subgroup analyses by age to address the <2 years age group.

Objectives

To evaluate the effects and safety of iron supplementation, with or without folic acid, in children living in malaria-endemic areas.

Methods

Criteria for considering studies for this review

Types of studies

RCTs that randomized individuals or clusters. Cluster-randomized trials were considered eligible only if including at least two units per study arm.

Types of participants

Children (<18 years) living in a hypoendemic, mesoendemic, hyperendemic, or holoendemic area for malaria (Hay 2004; Table 1). Studies were included if >70% of the included children lived in endemic regions and studies were excluded if it was specifically stated in the publication, or information was obtained from the authors, that the trial was conducted in an area or period without malaria activity.

Table 1. Description and location of malaria-endemic areas
  1. AFRO: WHO African Regional Office
    AMRO: WHO Americas Regional Office
    EMRO: WHO Eastern Mediterranean Regional Office
    EURO: WHO Europe Regional Office
    SEARO: WHO South East Asian Regional Office
    WPRO: WHO Western Pacific Regional Office

Area definitionParasite ratesDescriptionGeographical location
Hypoendemicity (also called designated unstable malaria)10% or fewer children aged 2 to 9 years, but may be higher for part of the yearAreas where there is little transmission and during the average year the effects upon the general population are unimportantAFRO: Chad
AMRO: Belize, Bolivia, El Salvador, Guatemala, Mexico, Nicaragua, Costa Rica, Paraguay
EMRO: Afghanistan, Iraq, Oman
EURO: Armenia, Azerbaijan, Georgia, Kyrgyzstan, Tajikistan
SEARO: Nepal
WPRO: China
Mesoendemicity (also called unstable and stable malaria)11 to 50% of children aged 2 to 9 yearsTypically found among rural communities in subtropical zones where wide geographical variations in transmission existAFRO: Angola, Botswana, Cape Verde, Chad, Eritrea, Ethiopia, Kenya (considered hyper- or holoendemic in review, as indicated in most of the trials), Mauritania, Namibia, Niger, Zambia, Zimbabwe
AMRO: Brazil, Colombia, Ecuador, Guyana, Panama, Peru, Venezuela
EMRO: Iran, Pakistan, Saudi Arabia
SEARO: Bangladesh, Bhutan, India, Indonesia, Sri Lanka, Thailand
WPRO: Malaysia
Hyperendemicity (also called stable malaria)Consistently > 50% among children aged 2 to 9 yearsAreas where transmission is intense but seasonal; immunity is insufficient in all age groupsAFRO: Angola, Benin, Burkina Faso, Cameroon, Central African Republic, Chad, Congo, Cote d'Ivoire, Equatorial Guinea, Gabon, Gambia, Ghana, Guinea, Guinea-Bissau, Liberia, Madagascar, Malawi, Mali, Mozambique, Nigeria, Sao Tome and Principe, Senegal, Sierra Leone, Togo, Uganda,Tanzania, Zambia
SEARO: Timor-Leste
WPRO: Papua New Guinea, Philippines, Solomon Islands, Vanuatu, Vietnam
Holoendemicity (also called stable malaria)Consistently > 75% among infants aged 0 to 11 monthsIntense transmission resulting in a considerable degree of immunity after early childhoodAFRO: Central African Republic, Democratic Republic of Congo, Tanzania, Uganda, Burundi, Madagascar, Malawi, Mozambique
AMRO: Dominican Republic, Suriname
EMRO: Djibouti, Somalia, Sudan, Yemen
SEARO: Myanmar
WPRO: Cambodia, Lao People's Democratic Republic

We included children with or without anaemia, malaria or parasitaemia at baseline.

Types of interventions

Intervention

  • Iron

  • Iron plus folic acid

  • Iron plus antimalarial treatment

Control

  • Placebo

  • Antimalarial (only when the intervention is iron plus anti-malarial)

Antihelminthic treatment could be added to the intervention or control arm. Iron should have been administered orally in the form of tablets or elixir (not as home or mass fortification of food or water), at any dose, duration or interval of administration. Trials that allocated other micronutrients (eg zinc, vitamin A, vitamin C) were included only if these were given to both study arms in the same dose and schedule.

The following comparisons were constructed; the first three referring to children without clinical malaria at baseline:

  • Iron versus placebo or no treatment

  • Iron plus folic acid versus placebo or no treatment

  • Iron plus antimalarial treatment or antimalarial treatment alone versus placebo or no treatment

  • Iron versus placebo or no treatment in the treatment of proven malaria

Types of outcome measures

Primary outcomes
  • Clinical malaria: uncomplicated malaria, defined as a history of fever with parasitological confirmation (WHO 2010). Cases of severe malaria could be included if they were not reported separately

  • Severe malaria: cerebral malaria or acute P. falciparum malaria with signs of severity,or evidence of vital organ dysfunction, or both (WHO 2010). If it had been defined differently, we extracted the outcome as reported in the study using its definitions

  • Death from any cause

Secondary outcomes
  • Malaria parasitaemia; any, and above a threshold, as defined in study (high-grade parasitaemia). For the comparison of iron versus placebo or no treatment in the treatment of proven malaria we assessed parasitological failure, defined as the persistence of parasitaemia after antimalarial treatment

  • Malaria parasite density, as reported in the study

  • Hospitalizations for any cause

  • Clinic visits

  • Haemoglobin levels

  • Prevalence of anaemia, as defined in the study

  • Infections other than malaria (including diarrhoea, pneumonia, sepsis, meningitis, measles, and pertussis), expressed as episodes per child-month

  • Weight, absolute values

  • Height, absolute values

We excluded studies that did not report at least one of the review-defined primary or secondary outcomes.

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).

Electronic searches

Databases

The search specialist at the Cochrane Infectious Diseases Group editorial base searched the following databases using the search terms and strategy described in Table 2: the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (June 2011); MEDLINE (1966 to June 2011); EMBASE (1980 to June 2011); and LILACS (1982 to June 2011). We also searched the metaRegister of Controlled Trials (mRCT) and International Clinical Trials Registry Platform (ICTRP) using 'iron' and 'malaria' as search terms.

Table 2. Detailed search strategies
  1. aCochrane Infectious Diseases Group Specialized Register.
    bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre 2011 ); upper case: MeSH or EMTREE heading; lower case: free text term.

Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSb
1ironironironironiron
2ferrousferrousferrousFERROUS-SULPHATEferrous
31 or 2IRON COMPOUNDSIRON COMPOUNDS1 or 21 or 2
4malaria1 or 2 or 31 or 2 or 3supplem$malaria
5anemiasupplem*supplem*3 and 4anemia
6anaemia4 and 54 and 5malariaanaemia
74 or 5 or 6malariamalariaanemia4 or 5 or 6
83 and 7anemiaanemia6 or 73 and 7
9anaemiaanaemia5 and 8
107 or 8 or 97 or 8 or 9child$
116 and 106 and 10infant$
12child*10 or 11
13infant*9 and 12
1412 or 13
1511 and 14

Searching other resources

Researchers, organizations, and pharmaceutical companies

We contacted the primary investigators of all included trials, ongoing trials and those awaiting assessment to ask for unpublished data and further trials.

Conference proceedings

We searched the proceedings of the Fourth Multilateral Initiative on Malaria Pan-African Conference (13 to 18 November 2005, Cameroon) for relevant abstracts.

Reference lists

We scanned the bibliographies of all included trials, pertinent reviews, and previous meta-analyses for additional references.

Data collection and analysis

Selection of studies

Two authors (JUO, and JO, or RS) independently inspected the abstract of each reference identified and obtained the full text of relevant articles. Both authors independently reviewed the articles and applied the inclusion criteria. If needed, the study authors were contacted to clarify the eligibility of the study. Areas of disagreement were resolved by discussion with a third author (MP or DY). Each trial was scrutinized to identify multiple publications from the same data set. We documented the justification for excluding trials from the review. Studies are named by the first author and year of publication (with the addition of a, and b, for different studies from the same author and year of publication). The addition of (C) to the trial's identification denotes that the trial was cluster randomized.

Data extraction and management

Two authors independently extracted data into a pre-piloted data extraction spreadsheet. DY extracted data from all trials and double extraction was shared between JUO, RS, and MP. Differences in the data extracted were resolved by discussion. Data were entered into RevMan 5.1 (RevMan 2011) by one author (MP or DY). Trials are labelled by first author and year of publication (a/b ending added for different trials from same author/year).

For individually randomized trials, we recorded the number of participants experiencing the event and the number analysed in each treatment group or the effect estimate reported (eg risk ratio (RR)) for dichotomous outcome measures. For count data, we recorded the number of events and the number of child-months of follow-up in each group. If the number of child-months was not reported, the product of the duration of follow-up and the number of children evaluated was used to estimate this figure. We calculated the rate ratio and standard error (SE) for each study. Zero events were replaced by 0.5. If covariate-adjusted incidence rate ratios were reported in the original studies we used these data with SEs. For continuous data, we extracted means (arithmetic or geometric) and a measure of variance (standard deviation (SD), SE, or confidence interval (CI)) and the numbers analysed in each group. SDs were computed from SEs or 95% CIs, assuming a normal distribution of the values. Haemoglobin values in g/dL were calculated by multiplying hematocrit or packed cell volume values by 0.34, when haemoglobin was not reported.

In cluster randomized trials, we recorded the unit of randomization (eg household, compound, sector, or village), the number of clusters in the trial, and the average cluster size. The statistical methods used to analyse the trial were documented along with details describing whether these methods adjusted for clustering or other covariates. We planned to extract estimates of the intracluster correlation coefficient (ICC) for each outcome. Where results have been adjusted for clustering, we extracted the treatment effect estimate and the SD or CI. If the results were not adjusted for clustering, we extracted the data reported.

Assessment of risk of bias in included studies

Two authors independently assessed the risk of bias.

For all trials we assessed:

  • generation of randomization sequence

  • allocation concealment

  • blinding: participants, investigators, or outcome assessors

  • incomplete outcome data: we recorded the number randomized and number evaluated per outcome

  • selective reporting bias

  • other biases: premature discontinuation or other

We graded the generation of randomization sequence and allocation concealment as  low, high, or unclear risk of bias, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Cochrane Handbook 2011).

For cluster randomized trials we also assessed:

  • recruitment bias

  • baseline imbalance

  • loss of clusters

  • incorrect analysis

  • comparability with individually randomized trials

Measures of treatment effect

For dichotomous data we calculated RRs and for continuous data we calculated absolute mean differences, with 95% CIs. Risk difference was computed for the outcome of all-cause mortality to allow the inclusion of the large number of studies with no deaths in both study arms in the analysis. Standardized mean differences were calculated for the outcomes of weight and height, since absolute values were combined with weight/height for age Z scores. For count data we computed rate ratios with SEs for each trial. Infectious episodes, hospitalizations and clinic visits were analysed as count data, and rate ratios per child-months are reported.

Unit of analysis issues

1. When cluster RCTs reported results as if they were individually randomized, we extracted the data reported in the trial and used estimated ICCs and design effects (DE) to adjust for clustering (Cochrane Handbook 2011). When one or more of the cluster RCTs reported RRs adjusted for clustering we computed cluster-adjusted SEs for the other trials (unadjusted SE of the log RR [SE(lnRR)] * DE0.5 = adjusted SE(lnRR)). When none of the cluster RCTs provided cluster-adjusted RRs we adjusted the sample size for clustering. We divided by the estimated DE the number of events and number evaluated for dichotomous outcomes and the number evaluated for continuous outcomes, where DE = 1 + [(average cluster size - 1) * ICC]. The derivation of the estimated ICCs and DEs is provided in Appendix 1.

2. In several outcomes a child might have experienced more than one outcome event during the trial period. For all outcomes we extracted the number of children with at least one event, except for infectious episodes other than malaria, where repeated episodes were counted.

3. Trials with several study arms could be included more than once for different comparisons. We did not include a study arm more than once in the same meta-analysis. In trials including two or more iron arms (ie different doses or different schedules), we summed up the iron groups for dichotomous outcomes, but selected for analysis the arm with the higher or more frequent dosing of iron for continuous outcomes.

Dealing with missing data

We contacted the trial authors if the available data were unclear, missing, or reported in a format that was different from the format needed.

We aimed to perform an intention-to-treat analysis where the trial authors accounted for all randomized participants; otherwise we performed a complete case analysis.

Assessment of heterogeneity

Heterogeneity in the results of the trials was assessed by visually examining the forest plot to detect non-overlapping CIs, using the Chi2 test of heterogeneity (P < 0.1 indicating statistical significance) and the I2 statistic of inconsistency (with a value > 50% denoting moderate levels of heterogeneity). When statistical heterogeneity was present we investigated the reasons for it, using subgroup analysis.

Assessment of reporting biases

A funnel plot was constructed to assess the effect of small studies for the main outcome (when including more than 10 trials).

Data synthesis

Analyses were conducted using RevMan 5.1 (RevMan 2011). Cluster RCTs were included in the main analysis after adjustment for clustering (see above). The meta-analysis was performed using the Mantel Haenszel (M-H) fixed-effect model or the generic inverse variance method (when adjustment for clustering was performed by adjusting SEs). A random-effects model was used for the outcomes of haemoglobin and anaemia, where we expected a priori heterogeneity to be displayed due to different mean baseline haemoglobin values and definitions of anaemia in different studies.

Summary of findings tables were constructed using GRADEprofiler version 3.6. We present summary of findings tables for the primary outcomes and hospital admissions.

Subgroup analysis and investigation of heterogeneity

When heterogeneity was detected, the following subgroup analyses were attempted.

  • Anaemia at baseline (ie prevention versus treatment of anaemia): mean haemoglobin of children in trial at baseline below 10 g/dL or 10 g/dL and above

  • Age groups: children aged < 2 years; children aged 2 to 5 years; and children aged > 5 years. Trials that recruited children whose ages spanned more than one subgroup were classified into the age group of most children

  • Malaria endemicity: hypoendemic or mesoendemic areas, and hyperendemic or holoendemic areas

  • Malaria management strategy: trials in which routine surveillance for malaria was conducted and treatment offered to children diagnosed with malaria as part of the trial's protocol or antimalarials were administered to both groups as part of the study intervention, and trials where such infrastructure was not available. This analysis was added after analysing the results of the review and was not part of the original review's protocol

Analyses were primarily stratified by the presence of anaemia at baseline or malaria endemicity (selected by relevance to the outcome assessed), regardless of the presence or absence of heterogeneity to address clinically relevant populations. Similarly, for the outcomes related to malaria we assessed the effects of age.

Subgroups were defined by trial (or study arm) level and not at the level of individual participants, since most trials targeted the patient subgroup of interest as the main study (eg studies were conducted on anaemic or non-anaemic children, and recruited children within a narrow age range). Moreover, studies most commonly did not present all outcomes for children subgroups. Comparisons between subgroups were performed using RevMan 5.1 (RevMan 2011).

Sensitivity analysis

We conducted sensitivity analyses by methods of allocation concealment to assess the effect of risk of bias on primary outcomes.

We restricted the analysis of malaria-related outcomes to P. falciparum. When all malaria species were assessed together, we included in this analysis trials where > 85% of malaria spp. diagnosed were P. falciparum.

We excluded studies counting multiple episodes of the outcome in individuals and studies whose outcome assessment occurred at a different point in time from that used in other studies.

Results

Description of studies

Results of the search

The last search was conducted in June 2011, resulting in a large number of publications. After the filtration of irrelevant publications and those that were clearly incompatible with the inclusion criteria, we considered in full 230 publications. Of these, 125 publications (representing 114 different studies) were excluded for the reasons detailed in the 'Characteristics of excluded studies' tables . Overall, 105 publications were included, representing 71 individual RCTs fulfilling the inclusion criteria. Two new trials were added in the current (2011) update of the review (Ayoya 2009; Gara 2010). Three additional studies are awaiting classification (Februhartanty 2002; Sazawal 2006 (C)c; Arcanjo 2011).

We made an attempt to contact the authors of all included and potentially relevant trials where the full publication did not provide enough information. We requested data primarily on malaria and all-cause mortality. Correspondence was established with 24 authors, of whom 21 were able to supply further information.

Included studies

A description of the included trials is provided in the 'Characteristics of included studies' tables. The trials were published between the years 1973 and 2010. Overall 45,353 children were recruited in included trials: 16,121 (35.5%) in 56 individually randomized trials and 29,232 in 15 cluster RCTs. The largest cluster RCT included two separate, independent cohorts: the main trial (Sazawal 2006 (C)a) and an independent substudy (Sazawal 2006 (C)b). Only two arms of this trial were included in the review (iron, folic acid and vitamin A versus vitamin A alone), totaling 15,956 children in the main study and 1619 children in the substudy (analysed as separate trials in the review). Unpublished data supplied by the authors on the outcome of malaria and death from the substudy are included in this review. Adherence was reported in 36 studies and the average overall adherence to all study drugs was good (85%).

Four trials assessed the intervention of iron during an acute attack of malaria (van Hensbroek 1995; Nwanyanwu 1996; van den Hombergh 1996; Gara 2010; ) among children < 5 years of age, all of whom were anaemic at baseline (haemoglobin range 4.1 to 9.6 g/dL).

All other trials assessed the administration of iron or iron plus folic acid for the prevention or treatment of anaemia among children without an acute illness. The mean iron supplementation dose was 2 mg/kd/day and the mean duration of treatment was 4.5 months (1.5 to 12 months). Antimalarial treatment was added to the iron arm or both study arms in five trials, anthelminthics were added to both arms in 18 trials and micronutrients were added similarly to both arms in 13 trials. One or more of the review-defined malaria-related outcomes was reported in 17 trials. Types of outcomes assessed and their definitions are described in Table 3. Severe malaria, as defined per protocol, was reported in a single trial and its substudy reporting on cerebral malaria (Sazawal 2006 (C)a; Sazawal 2006 (C)b). Twelve trials reported only or mostly (> 80%) on P. falciparum malaria (Table 3). Of the remaining trials not reporting malaria-related outcomes, 14 were conducted in hyper- or holoendemic areas for malaria and 26 were conducted in hypo- or mesoendemic settings. Nearly all trials reporting malaria-related outcomes performed regular surveillance for malaria using blood smears at baseline and during treatment (either at regular intervals or whenever febrile), and offered trial participants treatment when they were symptomatic (Table 3). Notably, no surveillance or treatment outside the hospital was offered in the main trial (Sazawal 2006 (C)a , unlike its substudy (Sazawal 2006 (C)b), where monitoring was performed and treatment was offered to children at their home. The baseline rate of malaria parasitaemia (reported in 11 of 16 trials) ranged from 0% to 70% of children (mean 45%). The mean baseline haemoglobin was lower than 10 g/dL in 13 trials (trials most commonly administering iron for the treatment of anaemia) and 10 g/dL or higher in 52 (administering iron for the prevention of anaemia). The study population consisted of children aged < 2 years in 18 trials, 2 to 5 years in 14 and > 5 years in 35 trials. The respective number of trials reporting on malaria-related outcomes in the three age groups were 7, 4, and 6.

Table 3. Studies reporting malaria as an outcome: malaria definitions, types of outcomes and methods of surveillance and treatment in the trial
  1. Time of assessment: refers to time from randomization; FU, follow-up.

Study IDClinical definitionLaboratory definitionMalaria-related outcomes reportedTime of assessmentMalaria surveillance and treatment
Adam 1997 (C)Physician's diagnosis of malariaAny parasitaemia (all malaria species, assumed most P. falciparum since trial conducted in same region as Gebresellassie 1996)Clinical malaria; any parasitaemia; malaria necessitating hospitalization (used as severe malaria); parasite density (all N events/N individuals, unadjusted for clustering)3 months to end of treatmentBlood smears for malaria obtained before, during and after treatment. Children with clinical malaria referred to local hospital and treated
Ayoya 2009Fever > 37.5°C (axillary)Any parasitaemia (P. falciparum)Clinical malaria; clinical malaria with parasitaemia ≥5000/μL (used as severe malaria); parasite density3 months to end of treatmentMalaria screening was done at baseline for all children and repeated throughout the study in children who had fever. Children infected with
P. falciparum also were treated with sulfadoxine-pyrimethamine
Berger 2000Isolated feverParasite density > 3000 (P. falciparum, P. malariae and P. ovale assessed. Over 97% were P. falciparum)Parasite index (%, used as parasitaemia); parasitaemia above 3000 (used as severe malaria) and 10,000 (%); parasite density

3 months to end of treatment

9 months to end of FU

Blood smears for malaria obtained at baseline, end of treatment (3 months) and end of FU (6 months). Chloroquine treatment given for all isolated fevers
Desai 2003Fever ≥37.5°CAny parasitaemia (P. falciparum) with fever or parasitaemia > 5000/mm3 aloneClinical malaria; any parasitaemia; hazard ratios for these; parasite density3 months to end of treatmentBlood smears at baseline and every 4 weeks. Oral quinine given for any fever with parasitaemia and cases of severe malaria referred for further treatment
Fahmida 2007Not statedNot statedPatients with "malaria" (used primarily as clinical malaria)6 months to end of treatmentNot stated
Gebresellassie 1996Fever ≥ 37.5°C with signs and symptoms suggestive of malaria and other diagnoses ruled outPresence of parasites in blood (all species, P. falciparum 88.9%)Children with at least one episode of clinical malaria; cumulative incidence of parasitaemia; parasite density > 5000 (used as severe malaria); parasite density

3 months to end of treatment

6 months to end of FU

Blood smears negative at baseline and repeated weekly. Chloroquine with or without primaquine given for any positive smear
Harvey 1989Fever and headache at the same timeAny parasitaemia (P. falciparum 67%, P. vivax 26.4%, P. malariae 6.6%)First episodes of clinically suspected malaria (used primarily as clinical malaria); any parasitaemia

4 months to end of treatment

6 months to end of FU

Blood smears for malaria obtained at 0, 6, 16 and 24 weeks. Chloroquine given for any illness reported as fever or headache, or both
Latham 1990Not assessedAny positive smear (malaria species not stated)Any positive smear; parasite density8 months - end of FUBlood smears for malaria obtained at baseline and end of treatment. Treatment not stated
Lawless 1994Child's recall of clinical illnessAny positive blood smear (malaria species not stated)Malaria is not defined (used as clinical malaria)3.5 months - end of treatmentNo blood smears at baseline or during the trial (only at end of treatment). Treatment not stated
Leenstra 2009Fever ≥ 37.5°CPositive blood smear (malaria species not stated)Episodes of clinical malaria and RRs adjusted for school; episodes of malaria parasitaemia and parasitaemia > 500 parasites/mm3 (used as severe malaria) and RRs adjusted for school, age, and baseline parasitaemia5 months to end of treatmentBlood smears for malaria at baseline (1/4 of participants positive) and monthly during the trial. No treatment offered for positive smears; symptomatic cases referred to physician
Massaga 2003History of fever in the previous 24 to 72 hours or measured temperature of ≥ 37.5°CAny level of parasitaemia (P. falciparum only)Clinical malaria as first or only episode per patient (used as clinical malaria) and episodes of clinical malaria; episodes of clinical malaria associated with parasitaemia > 5000 parasites/μL (used as severe malaria)6 months to end of treatmentBlood smears for malaria at baseline and every 2 weeks. Sulfadoxine-pyrimethamine treatment given for uncomplicated cases; complicated and severe malaria referred to the hospital
Mebrahtu 2004 (C)Not assessedAny positive smear (P. falciparum only)Parasitaemia as OR (95% CI) adjusted for repeated measurements in each child12 months - end of treatmentBlood smears for malaria at baseline and end of treatment. In addition, monthly smears from a random sample (50% of randomized). Treatment not stated
Menendez 1997Fever ≥ 37.5°CParasitaemia of any density (P. falciparum only)First or only episode of clinical malaria1 year (6 months after end of treatment)Blood smears for malaria at baseline, week 8 and for any fever. Chloroquine treatment given for clinical malaria
Nwanyanwu 1996Fever > 37.5°COver 500 asexual parasites/μL thick smear (P. falciparum only)Parasitaemia, parasite density1 month to end of treatment (all children treated for malaria)All children smear positive at baseline per study design and treated throughout the trial (trial's intervention)
Richard 2006Any fever within the previous 72 hoursP. falciparum (29%) or P. vivax (71%), any densityEpisodes of falciparum or vivax malaria, or both (used primarily as clinical malaria)7 months to end of treatmentBlood smears for malaria at baseline and whenever febrile. Treatment given for all clinical cases
Sazawal 2006 (C)aFever > 38°C andParasitaemia>1000 or history of fever and parasitaemia > 3000 or parasitaemia >10,000 parasites/mm3 regardless of fever (mostly P. falciparum)Malaria-related adverse events, defined as hospital admission or death due to malaria (used primarily as clinical malaria). RRs with 95% CI adjusted for multiple events per child and clustering; cerebral malaria (used as severe malaria)Not fixed. End of treatment about 1 year and end of FU about 18 monthsNo baseline or routine surveillance for malaria during the trial. Treatment given only if admitted to the hospital and malaria diagnosed
Sazawal 2006 (C)bFever > 38°CParasitaemia > 1000 or history of fever and parasitaemia > 3000 or parasitaemia > 10,000 parasites/mm3 regardless of fever (mostly P. falciparum)Malaria-related adverse events, defined as hospital admission or death due to malaria (used primarily as clinical malaria). RRs with 95% CI adjusted for multiple events per child and clustering; cerebral malaria (used as severe malaria)Not fixed. End of treatment about 1 year and end of FU about 18 monthsBlood smear for malaria at baseline, and at 6 and 12 months. Sulfadoxine-pyrimethamine treatment delivered to home to all slide-confirmed malaria patients or clinical disease presenting during the study
Smith 1989 (C)Fever > 37.5°C> 500 parasites/mm3 (mostly P. falciparum)Visits for clinical malaria; parasitaemia > 500; fever with parasitaemia > 5000 parasites/mm3 (used as severe malaria (all N events/N individuals, unadjusted for clustering)3 months to end of treatmentBlood smear for malaria at baseline, 2 weeks and end of treatment. No treatment at baseline; clinical malaria referred to local healthcare services
van den Hombergh 1996Not usedAny parasitaemia (P. falciparum)Parasitaemia; parasite density3 months to end of treatment (all children treated for malaria)All children smear positive at baseline per study design and treated (the trial intervention). Repeat blood smears at 2, 4, 8, 12 weeks and recurrent clinical malaria re-treated
van Hensbroek 1995Fever or history of fever in the past 48 hours with parasitaemia or parasitaemia > 5000 parasites/mm3 regardless of feverAny parasitaemia (P. falciparum)Parasitological failure1 month to end of treatment(all children treated for malaria)All children smear positive at baseline per study design and treated (trial's intervention). Repeat blood smears at 1 and 4 weeks and clinical failures treated with quinine
Verhoef 2002Axillary temperature ≥ 37.5 °CDipstick test for P. falciparumNumber of children with malaria infection (used primarily as clinical malaria)3 months to end of treatmentDipstick for P. falciparum tested at baseline, 4, 8, and 12 weeks. Confirmed with blood smear if febrile and treated with sulfadoxine-pyrimethamine, amodiaquine or halofantrine

Excluded studies

The specific reasons for exclusion are detailed in the 'Characteristics of excluded studies' tables. The major reasons for excluding RCTs were:

  • The trials were conducted in non-malaria-endemic areas, including studies in which it was explicitly stated or the authors confirmed that there was no malaria activity in the study location at the time of the trial.

  • The interventions were incompatible with the inclusion criteria, such as the administration of iron together with other micronutrients or the administration of iron to both trial arms.

  • Iron administered as a fortification in food or drink.

Malaria-related outcomes were reported in seven excluded RCTs, four of which were excluded due to interventions that were incompatible with the review inclusion criteria (Bates 1987; Beasley 2000; Ekvall 2000; Ouedraogo 2010), two because iron was administered as food fortification (CIGNIS 2010; Rohner 2010), and one because iron was given intra-muscularly (Oppenheimer 1986).

Risk of bias in included studies

The trial's risk of bias is detailed in the 'Risk of bias' tables and is presented graphically in Figure 1 and by study in Figure 2.

Figure 1.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies. The unclear category for incomplete outcome data represents studies that did not report this outcome, thus the relevant percentages are only those of yes or no.

Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study. The unclear category for incomplete outcome data represents studies that did not report this outcome, thus the relevant percentages are only those of yes or no.

Allocation

Twenty-nine of 71 trials (40.8%) were judged to be at low risk of bias related to allocation concealment. There was judged to be a high risk of bias from concealment in one trial that used alternate households (Smith 1989 (C)). All the remaining trials either did not describe their methods clearly or did not provide a description of them. The generation of randomization sequence was judged to be at low risk of bias in 30/71 (42.2%) trials, at high risk for bias in the one trial using alternation, and at unclear risk in all the others. Overall, the allocation procedure (both allocation concealment and generation) was considered to have a low risk of bias in 20 (28.2%) trials.

Blinding

Forty-six trials out of 71 trials (64.8%) described double-blinding or stated that the trial was double-blind, while giving no description of the blinding techniques; all of these 46 trials were considered to be at low risk of bias (see 'Risk of bias' tables). Twenty-four studies were open-labelled and considered to be at high risk of bias, and one trial in which the providers were blinded but the placebo used was saccharin was considered to be at an unclear risk of bias.

Incomplete outcome data

The reasons for excluding patients from malaria-related and haemoglobin outcome reporting was explained and related to an inability to obtain blood samples for the patients. The reasons for the exclusion of randomized children from mortality assessment was not clear and was considered to be a serious risk for bias since deaths might have occurred among the excluded children. The number of participants randomized and evaluated is provided in the 'Risk of bias' tables.

Selective reporting

We did not have access to trials' protocols to compare planned outcomes with those reported in the final publication.

Two trials specified their methods for assessing malaria throughout the trial (without defining these as study outcomes), but did not report the results per study arm (Taylor 2001; Olsen 2006). We could not contact the authors of either trial. We contacted authors of trials who did not report on malaria in their methods or result section; the authors of one trial reported that data were collected in the trial but were no longer available (Powers 1983), while the authors of 14 trials replied that malaria-related outcomes were not collected in their trials (Sarma 1977 (C); Greisen 1986 (C); Latham 1990; Idjradinata 1993; Dossa 2001a; Dossa 2001b; Hall 2002 (C); Hess 2002; Shah 2002; Baqui 2003; Zlotkin 2003; Nagpal 2004; Aggarwal 2005; Hettiarachchi 2008 (C)). Thus, selective reporting bias is unlikely with regard to the outcomes related to malaria.

Death was not defined as an outcome in all but one trial (Sazawal 2006 (C)a; Sazawal 2006 (C)b), although these results were reported in 16 trials and obtained from authors in another 14. Thus, it is not possible to discuss reporting bias in relation to the outcome of mortality.

Cluster -randomized trials

Fifteen of the included trials were cluster randomized, using households (5 five trials) or schools or /classes (10 trials) as the unit of randomization.

  • Recruitement bias: in two trials, randomizing households and preschools, it was clear that children could be born or added to the cluster after randomization (Sarma 1977 (C); Sazawal 2006 (C)a; Sazawal 2006 (C)b), one trial was at low risk of bias and none of the other trials described clearly whether children could be recruited into the trial after the clusters had been randomized.

  • Basline imbalance: two trials, in which there were baseline differences between the groups with regard to haemoglobin or iron status, were at high risk of bias (Bhatia 1993 (C); Hettiarachchi 2008 (C)). No differences in main baseline characteristics existed in any other trial.

  • Loss of clusters: one trial, randomizing schools, clearly described the fact that 2/51 schools dropped out from the control group with the reasons given, and was considered to be at low risk of bias (Roschnik 2004 (C)). Data on the loss of clusters was not provided in any other trials.

  • Incorrect analysis: only Sazawal 2006 (C)a and its substudy (Sazawal 2006 (C)b) adjusted the main outcomes for clustering. The other trials reported results per individual only and did not provide data regarding the ICC. The average cluster size could usually be calculated from the number of clusters and individuals included in the trial. Crude results reported in the publication, the DE used for adjustment, and the adjusted results used in the meta-analyses for the main outcomes are provided in Table 4 (for outcomes pooled using adjusted SEs) and Table 5 (for outcomes pooled using the effective sample size).

    Table 4. Analysis of cluster randomized trials adjusting standard errors
    1. Text in bold;results provided in publication or from authors adjusted for clustering.
      cont, control; DE, design effect used for adjustment (see methods for derivation of design effect and ICC used per outcome); Int, intervention; n, number of outcomes; N, number evaluated; OR, odds ratio; RR, risk ratio.

    Study IDOutcomen Int reportedN Int reportedn Cont reportedN Cont reportedAverage cluster sizeDEUnadjusted RR (95% CI)ln(RR)Unadjusted SE(lnRR)Adjusted SE(lnRR)/ sample size
    Adam 1997 (C)Clinical malaria7236649372Household (used 1.5)1.341.49 (1.07 to 2.08)0.400.170.20
    Adam 1997 (C)Parasitaemia127368101372Household (used 1.5)1.341.27 (1.02 to 1.58)0.240.110.13
    Adam 1997 (C)Severe malaria (necessitating hospitalization)4140532382Household (used 1.5)1.341.21 (0.78 to 1.88)0.190.220.26
    Mebrahtu 2004 (C)Parasitaemia3073071.51.34OR 0.9 (0.72 to 1.19) Converted to RR 0.980.470.280.32
    Mebrahtu 2004 (C)High-grade parasitaemia3073071.51.34OR 1.04 (0.82 to 1.34) Converted to RR 1.030.030.120.14
    Sazawal 2006 (C)aClinical malaria467795041180061.41.16 (1.00 to 1.34)0.150.07
    Sazawal 2006 (C)aSevere malaria (cerebral)795080061.41.32 (1.02 to 1.70)0.280.13
    Sazawal 2006 (C)bClinical malaria14815308041.20.46 (0.24 to0.88)-0.780.33
    Sazawal 2006 (C)bSevere malaria (cerebral)4815158041.20.26 (0.09 to 0.81)-1.350.56
    Smith 1989 (C)Clinical malaria1497889Household (used 1.5)1.341.60 (0.42 to 0.71)0.470.420.48
    Smith 1989 (C)Parasitaemia28971689Household (used 1.5)1.341.61 (0.93 to 2.76)0.470.280.32
    Smith 1989 (C)High-grade parasitaemia17971189Household (used 1.5)1.341.42 (0.70 to 2.86)0.350.130.15
    Table 5. Analysis of cluster randomized trials adjusting sample size
    1. None of the trials provided results adjusted for clustering for the outcomes reported in the table. cont, control; DE, design effect used for adjustment (see methods for derivation of design effect and ICC used per outcome); Int, intervention; n, number of outcomes; N, number evaluated.

    Study IDOutcomen Int reportedN Int reportedn Cont reportedN Cont reportedAverage cluster sizeDEn Int adjustedN Int adjustedn Cont adjustedN Cont adjusted
    Adam 1997 (C)Anaemia364368357374Household (used 1.5)1.4260263255267
    Agarwal 2003Anaemia252699348691Class (used 32)3.886518090178
    Hall 2002 (C)Anaemia273551356562202.7799199129203
    Hettiarachchi 2008 (C)Anaemia2819378181323.887502047
    Mebrahtu 2004 (C)All-cause mortality034023441.51.00103402344
    Mebrahtu 2004 (C)Anaemia1802321722721.51.4129166123194
    Roschnik 2004 (C)Anaemia125708205802293.603519657223
    Roschnik 2003 (C)Anaemia133224110203303.7036613055
    Sarma 1977 (C)Anaemia9412545253.23313814
    Sazawal 2006 (C)aAll-cause mortality149795013080061.41.00114979411307996
    Sazawal 2006 (C)bAll-cause mortality881598041.21.000488159804
    Sazawal 2006 (C)bAnaemia430873271.21.432205234
    Seshadri 1984b (C)Anaemia7422447222.95214816
  • Comparability with individually randomized trials: cluster RCTs were larger than individually randomized trials (see above); the percentage of children excluded from outcome assessment was higher (30.6% versus 15.9%) and adherence to study medications was lower (70.9% versus 89.5%). The average dose of iron used was lower in cluster RCTs (1.6 versus 2.1 mg/kg/day), and the average treatment duration was longer (5.3 versus 3.9 months), both without statistical significance. Baseline haemoglobin and the percentage of anaemic children at baseline were similar.

Other potential sources of bias

One trial was discontinued prematurely on the recommendation of the data and safety monitoring board, when reaching a predefined difference in mortality of P = 0.2.

Effects of interventions

See: Summary of findings for the main comparison Oral iron supplements for children in malaria endemic areas; Summary of findings 2 Oral iron with folic acid supplements for children in malaria-endemic areas; Summary of findings 3 Oral iron supplements with antimalarial treatment for children in malaria-endemic areas?; Summary of findings 4 Oral iron supplements in the treatment of malaria

1. Iron versus placebo/no treatment for the treatment or prevention of anaemia (52 trials; 18,841 children)

Primary outcomes
Clinical and severe malaria

Clinical malaria was defined in all trials as fever (usually > 37.5°C) and parasitaemia (any density). Overall, there was no difference between iron versus placebo / no treatment, RR 0.99 (95% CI 0.90 to 1.09, 13 trials, 5351 children), without significant heterogeneity (P = 0.11, I2 = 32%), Analysis 1.1. Despite the lack of heterogeneity, analyses were stratified by clinically relevant parameters. There were no differences between iron versus placebo / no treatment in the subgroups of children without anaemia at baseline, RR 0.97 (95% CI 0.86 to 1.09), (Analysis 1.1), and among children < 2 years, RR 0.94 (95% CI 0.82 to 1.09), (Analysis 1.2). The results were similar when analysis was restricted to P. falciparum malaria (Analysis 1.3). Three trials conducted in Kenya are included in this analysis (Latham 1990; Lawless 1994; Leenstra 2009) and for (Gebresellassie 1996), assuming a similar distribution of malaria spp. to a trial conducted in the same region around the same time where most infections were caused by P. falciparum (Adam 1997 (C)).

Seven of the 13 trials included in the analysis were at low risk of bias with respect to allocation concealment, and all but one of the trials were double-blinded. The funnel plot was asymmetric, indicating that small studies favouring iron could be missing (Figure 3). Three trials reported on episodes of malaria (Richard 2006; Leenstra 2009), or clinic visits for malaria Smith 1989 (C)) rather than patients with their first or only episode. Leenstra 2009 and Richard 2006 also administered vitamin A to both study arms. The exclusion of these trials did not affect the pooled RR for this comparison. One trial reported on children with clinical malaria only at end of follow-up, 6 months after completing iron supplementation (Menendez 1997). Its exclusion did not affect the results. The exclusion of cluster RCTs did not significantly alter the results (data not shown).

Figure 3.

Funnel plot of comparison: 1 Iron versus placebo or no treatment, outcome: 1.1 Clinical malaria (by anaemia at baseline).

Three trials reported on clinical malaria with high-grade parasitaemia and one trial reported on admissions for malaria (Adam 1997 (C)), as measures of severe malaria. Pooling of these results showed no statistically significant difference between iron and placebo/no treatment, RR 0.91 (95% CI 0.76 to 1.08) (Analysis 1.4).

Deaths

Mortality was reported in 22/52 trials (13 out of 22 trials conducted in hyper- or holoendemic settings), and in most no deaths occurred among the evaluable children. Overall, there was no difference between the iron and placebo / no treatment groups, without heterogeneity (Analysis 1.5). The absolute risk differences were -1.24 (95% CI -4.37 to 1.88) per 1000 children in hypo- or mesoendemic areas (nine trials) and 2.42 (95% CI -6.47 to 11.34) per 1000 children in hyper- or holoendemic areas (13 trials).

Secondary outcomes
Parasite prevalence and density

There was no statistically significant difference in the prevalence of parasitaemia, defined as any asymptomatic parasitaemia, RR 1.09 [(95% CI 0.98 to 1.22], eight trials, 3184 children, without significant heterogeneity (Analysis 1.6). Odds ratios were converted to RRs to allow the use of data on parasitaemia from one trial (Mebrahtu 2004 (C)). This outcome was not affected by age, anaemia at baseline or plasmodium species assessed, as for clinical malaria (Analysis 1.6; Analysis 1.7; Analysis 1.8) but only one trial assessed children aged < 2 years. Despite the lack of heterogeneity overall, there was a significant difference between trials describing adequate allocation concealment, RR 0.94 (95% CI 0.79 to 1.11) and trials with unclear or inadequate methods that showed significantly higher rate of parasitaemia with iron, RR 1.22 (95% CI 1.06 to 1.40), P = 0.02 for the subgroups' difference (Analysis 1.9). All the trials included in the comparison of parasitaemia were double-blinded. There was no statistically significant difference in the occurrence of high-density asymptomatic parasitaemia, most commonly defined as > 5000 parasites/μL, RR 1.13 (95% CI 0.93 to 1.37), five trials (Analysis 1.10). In trials continuing follow-up after the cessation of iron administration, there was a higher prevalence of parasitaemia at end of follow-up with iron, RR 1.18 (95% CI 1.03 to 1.35), four trials, 941 children (Analysis 1.11).

It was difficult to establish whether the trials reported on children with parasitaemia or on parasitaemia episodes. Gebresellassie 1996 clearly reported on cumulative incidence and Leenstra 2009 included repeated episodes. Leenstra 2009 reported incidence rate ratios with 95% CIs adjusted for age, baseline parasitaemia, and school. These were used in our analysis as relative risks. The exclusion of these trials did not affect the results.

Parasite density was reported differently in the studies, with differences referring both to the unit of measurement and the denominator (Table 6). A meta-analysis was therefore not possible and the results are shown in Table 6 for each study. Qualitatively, parasite density was higher in the iron supplemented group in four trials, lower in one and similar in one of the six trials that reported on parasite density at the end of treatment.

Table 6. Comparative malaria parasitaemia rates
  1. RBC,red blood cell; WBC, white blood cell.

Study IDInterventionUnit of measurementIronControlNo. iron

No.

Control

Favours
For prevention or treatment of anaemia
Adam 1997 (C)Iron vs placeboGeometric mean, parasites/μL15,0598225368 slides372 slidesControl
Ayoya 2009Iron vs placeboGeometric mean, parasites/μL +/- SD2733 +/- 14592648 +- 1562105 children97 childrenControl
Berger 2000Iron vs placeboGeometric mean, RBC/mm361.225.749 children with malarial index39 children with malarial indexControlor similar
Desai 2003

Iron plus antimalaria vs antimalaria

Iron vs placebo (with single-dose antimalarial treatment)

Geometric mean, parasites/mm3

1705

2569

2485

3778

129 children

127 children

127 children

108 children

Iron
Gebresellassie 1996Iron vs placeboAverage parasite density class (parasite density classified in ascending order from 1 to 10)5.25.0239 children241 childrenControl or similar
Latham 1990Iron vs placeboGeometric mean, infected RBCs/100 WBC4.81.928 children26 childrenControl
Mebrahtu 2004 (C)Iron vs placeboGeometric mean, parasites/μL (counting against 200 to 500 WBC, assuming 8000 WBC/μL

Age < 30 m 3402

Age > 30 m 2188

Age < 30 months 3422

Age > 30 months 2046

273 children (225 households)265 children (225 households)Similar
For treatment of malaria
Nwanyanwu 1996Iron daily plus antimalarial vs iron weekly plus antimalarial vs antimalarialMean, parasites/μL (counting against 300 WBC, assuming 6000 WBC/μL

4927 (daily)

2207 (weekly)

1812

77 (daily)

63 (weekly)

children

75 childrenControl
van den Hombergh 1996Iron plus antimalarial plus folic acid vs antimalarial plus folic acidGeometric mean, parasites/μL5308930248 children47 childrenIron (at baseline groups unbalanced favouring placebo)

Admissions to hospital and clinic visits

All five trials reporting on the need for hospitalization or the number of clinic visits were conducted in malaria hyper- or holoendemic areas. Overall, there was no difference between iron and placebo /no treatment (Analysis 1.12). The rate of hospitalizations was lower with iron alone compared to placebo/no treatment, rate ratio 0.81 (95% CI 0.68 to 0.98, four trials, 8775 child-months) with no heterogeneity, but not when an antimalarial treatment was given to all children (Analysis 1.12). Rates of clinic visits shown on the same graph were not significantly different.

Haemoglobin and anaemia

Analyses for haemoglobin were highly heterogenous, since individual studies' absolute magnitude of treatment effect differed and the 95% CIs were narrow. However, the heterogeneity stemmed from different magnitudes of increase in haemoglobin with iron supplementation and not in the direction of the result. Overall, mean haemoglobin at end of treatment increased by 0.87 g/dL (95% CI 0.64 to 1.09, 35 trials, 8544 children) with iron, I2 statistic = 95%, (Analysis 1.13). Children who were anaemic at baseline gained 1.59 g/dL haemoglobin (95% CI 0.93 to 2.26) with iron supplementation, while among children without anaemia at baseline the end haemoglobin was higher than control by 0.64 g/dL (95% CI 0.48 to 0.80), P =0.006 for subgroup difference. There was no significant difference in the pooled mean end haemoglobin in hypo-or mesoendemic; and hyper- or holoendemic areas (Analysis 1.14). No differences were observed between age groups, the comparison of iron versus placebo / no treatment or iron with anti-malarial versus antimalarial treatment alone; and with or without the co-administration of other multinutrients in both study groups (analyses not shown). Heterogeneity was maintained in all these subgroup analyses. The mean change of haemoglobin from the baseline at end of treatment was 0.40 g/dL (95% CI 0.22 to 0.58, 12 trials, 2595 children, I2 statistic = -78%) in hypo- or mesoendemic areas and 0.91 g/dL (95% CI 0.56 to 1.26, eight trials, 1610 children, I2 statistic = -87%) in malaria hyper- or holoendemic areas, P = 0.01 for subgroups difference (Analysis 1.15).

Anaemia at end of treatment was reported in fewer trials and the haemoglobin threshold to define anaemia varied (Analysis 1.16). In hyper- or holoendemic settings, the RR for anaemia at the end of treatment was 0.52 (95% CI 0.35 to 0.78, 13 trials, 1899 children), with similar substantial heterogeneity mainly in the magnitude of benefit.

Other outcomes

Eleven studies provided data on respiratory infections: three reported on upper respiratory infections (de Silva 2003; Nagpal 2004; Aggarwal 2005), three on lower respiratory infections (Berger 2000; Lind 2004; Berger 2006), one on pneumonia (Fahmida 2007), and four trials did not define the type of respiratory infection (Angeles 1993; Rosado 1997; Baqui 2003; Richard 2006). There was no difference between iron and placebo overall (rate ratio 0.97, 95% CI 0.91 to 1.04, 11 trials, 22,577 child-months, I2 statistic = 0%), or in the subgroups of children in hypo- or mesoendemic, hyper- or holoendemic (Analysis 1.17).

Diarrhoea was usually reported as 'infectious diarrhoea', although the symptoms could not have been well-differentiated from diarrhoea related to iron or iron/zinc supplementation. This analysis was stratified by zinc co-administration, since a higher risk with iron was observed with zinc (Analysis 1.18). But overall, there was no significant difference between iron and placebo/no treatment (rate ratio 1.07, 95% CI 0.99 to 1.16, 13 trials, 25,225 child-months, I2 statistic = 40%.

Seven trials reported on febrile episodes; three trials reported on 'other disease episodes' and one trial reported results for all infectious episodes combined (Leenstra 2009). Definitions and reporting methods were highly variable. Results are shown per outcome (Analysis 1.19). There were no significant differences between iron and placebo / no treatment, except for one trial reporting significantly more days with fever in the iron group (Dossa 2001b).

Results for height and weight were inconsistently reported as end values or as the change from baseline and absolute values or Z scores matched for age, height or weight. The analyses shown are based on absolute weight in kg and height in cm at end of treatment in all trials and weight/height for age Z scores in three trials (Berger 1997; Richard 2006; Fahmida 2007). For weight, there was no statistically significant difference between iron and placebo / no treatment at the end of treatment (Analysis 1.20), while the change from baseline favoured iron mainly in malaria hyper- or holoendemic areas (Analysis 1.21). Both analyses were heterogenous and the heterogeneity was not explained by the review-defined subgroups. Similar results were obtained for the analysis of height (Analysis 1.22), with the advantage to iron in the change from baseline analysis originating from hypo- or mesoendemic areas (Analysis 1.23).

In summary, for the comparison of iron versus placebo / no treatment in the prevention or treatment of anaemia, there was no increase in the risk of clinical malaria, clinical malaria with high-grade parasitaemia, any parasitaemia or mortality, overall, and specifically in malaria hyper- and holoendemic areas. We show the safety of iron given alone in malaria-endemic areas, with the main caveat that severe malaria (cerebral, other end organ damage and admissions to hospital) were not assessed separately in most trials. 'Summary of findings' tables are presented for these outcomes and all hospital admissions (Summary of findings for the main comparison). The quality of the evidence was graded high for clinical malaria, low for mortality and hospital admissions (mainly due to the presence of children lost to follow-up in most trials) and very low for parasitaemia (due to the indirectness of this outcome and the effect of unclear or inadequate allocation concealment on the results). With regard to secondary outcomes, iron supplementation increased haemoglobin and decreased anaemia with a large treatment effect, although the absolute magnitude of effects reported are imprecise due to substantial heterogeneity. Broadly, the benefit of iron supplementation for these haematological indices was similar to or larger in malaria hyper- and holoendemic settings than in hypo- or mesoendemic areas. We did not detect significant differences between iron-supplemented and control participants in respiratory and other infections, diarrhoeal episodes, weight or height.

2. Iron plus folic acid versus placebo for treatment or prevention of anaemia (16 trials, 26,078 children)

Primary outcomes
Clinical and severe malaria

The largest trials contributing to this analysis by far, and the only trial reporting on malaria-related outcomes were Sazawal 2006 (C)a and Sazawal 2006 (C)b. There was no routine monitoring for all clinical malaria episodes or parasitaemia in Sazawal 2006 (C)a as in other trials, and the malaria-related outcomes reported were admissions for malaria and cerebral malaria(Analysis 2.1; Analysis 2.2). The results for the main study and the substudy were significantly different, with the main study showing a higher risk for severe malaria with iron plus folic acid and the substudy showing a lower risk. The results were therefore not pooled. Children in the substudy were older than children in the main trial (mean age of 22.5 versus 18.3 months) and the baseline haemoglobin for the sub-study cohort was probably higher than that of the main study, because children with severe anaemia (haemoglobin < 7 g/dL) were excluded only from the substudy. However, the main difference, as described by the authors of the study, was that children in the substudy were monitored and offered treatment for malaria at home throughout the trial period. In the main trial, there was no organized infrastructure for the diagnosis and treatment of uncomplicated malaria.

Following this observation, we conducted a post hoc analysis pooling all trials comparing iron alone or iron plus folic acid versus placebo/no treatment subgrouped by the methods of surveillance and treatment of malaria in the trial (Analysis 2.3). In this analysis the outcome of uncomplicated malaria available form most trials was pooled with the outcome of admissions for malaria reported in Sazawal 2006 (C)a and Sazawal 2006 (C)b. In trials where surveillance and treatment of malaria were offered as part of the study, there was no significant difference between iron and control (RR 0.94, 95% CI 0.85 to 1.04). In trials where no such infrastructure was available, there was an increased risk for malaria (RR 1.16 95% CI 1.03 to 1.31), P = 0.009 for the subgroup difference.

Deaths

The pooled risk difference for mortality was +1.19 per 1000 children (95% CI -1.76 to 5.59, 4 trials, 18,107 children), with Sazawal 2006 (C)a contributing 88.1% of the weight of this analysis. Three trials were conducted in hyper- or holoendemic settings (risk difference +1.93 per 1000 children, 95% CI -1.78 to 5.64, 17,898 children). Due to the paucity of data we did not proceed with further analyses.

Secondary outcomes

Hospital admissions were reported only in Sazawal 2006 (C)a, (RR 1.08, 95% CI 0.96 to 1.22). Haemoglobin at end of treatment was significantly higher with iron and folate, mean difference 1.03 g/dL (95% CI 0.56 to 1.49), with significant heterogeneity, I2 statistic= 88% (Analysis 2.6). There were no significant differences between anaemic and non-anaemic children (Analysis 2.6) and by malaria endemicity (Analysis 2.7). These and the other review-defined subgroups did not explain heterogeneity. The RR for anaemia at end of treatment was 0.44 (0.27 to 0.70, six trials, 1,108 children), with similar effects in hypo- or mesoendemic and hyper- or holoendemic settings, Analysis 2.8. No consistent data were reported for respiratory infections, other febrile episodes and diarrhoea. There was no significant difference in the absolute end values of weight (Analysis 2.9) and height (Analysis 2.10).

The results for this comparison are summarized in 'Summary of findings 2'. The quality of the evidence was downgraded, mainly because of inconsistency between the two parts the trial, Sazawal 2006 (C)a and Sazawal 2006 (C)b, since this trial was discontinued for harm and due to the imprecision of its results. No effects are summarized for malaria-related outcomes, since the trial results were not pooled (see above).

3. Iron plus antimalarial versus placebo for treatment or prevention of anaemia (four trials, 1915 children)

Primary outcomes
Clinical malaria

Three trials reported on clinical malaria and all were individually randomized. The trials uniformly showed that the intervention was protective for clinical malaria (pooled RR 0.54, 95% CI 0.43 to 0.67, three trials, 728 children, I2 statistic= 0%) (Analysis 3.1). Severe malaria was not assessed in these trials.

Deaths

There was no difference in the risk of death for the three trials combined (RR 1.05, 95% CI 0.52 to 2.11) (Analysis 3.2).

Secondary outcomes

Both the number of hospitalizations and the number of clinic visits were significantly reduced in two trials (Analysis 3.3). Iron plus antimalaria significantly improved haemoglobin in one trial and decreased the prevalence of anaemia in two (Analysis 3.4 and Analysis 3.5). Respiratory infections, diarrhoea, and other infections were not reported in these studies.

The trials included in this comparison were four-armed trials assessing iron, placebo, iron with an antimalarial, and an antimalarial alone. The comparison of antimalarial treatment alone versus placebo showed identical results to the comparison of iron plus antimalarial versus placebo, except for the outcomes of haemoglobin / anaemia where the addition of iron conferred a higher benefit (analysis not shown). This observation strengthens the lack of effect of iron on malaria or other adverse outcome.

Results for the intervention of iron with an antimalarial are summarized in 'Summary of findings 3'. The quality of the evidence was high for clinical malaria and low for mortality due to the number of participants lost to follow-up and imprecision.

4. Iron versus control in the treatment of proven malaria (four trials, 804 children)

All four trials included in this comparison (Nwanyanwu 1996; van Hensbroek 1995; van den Hombergh 1996; Gara 2010) were individually randomized, open-label trials. The same antimalarial treatment was administered in both study arms. The studies were conducted in a hospital's outpatient clinic in Nigeria (Gara 2010), a Medical Research Council (MRC) clinic in The Gambia (van Hensbroek 1995), the outpatient and paediatric ward of a hospital in Tanzania (van den Hombergh 1996), and in an outpatient clinic in Malawi (Nwanyanwu 1996). In two trials folic acid was co-administered in both trial arms (van den Hombergh 1996; Gara 2010).

Deaths

No deaths occurred in two trials and the pooled risk difference pf the four trials was +2.66 per 1000 children (95% CI -13.34 to +18.67) (Analysis 4.1).

Parasitological failure and parasite density

Three trials reported on parasitological failure at the end of treatment. Their pooled RR showed no significant difference between iron and placebo (RR 0.96,95% CI 0.74 to 1.24, 583 patients, I2 statistic = 36%) (Analysis 4.2). Two trials reported on parasite density at the end of treatment (Nwanyanwu 1996; van den Hombergh 1996). One favoured iron and the other favoured placebo (Table 6).

The results for other secondary outcomes are based on single or two trials each. There was no significant difference in the need for hospitalization or new clinic visit (Analysis 4.3). Haemoglobin at the end of the treatment was higher by 0.32 g/dL with iron, without statistical significance (Analysis 4.4) and anaemia at the end of treatment was significantly lower with iron in one trial (Analysis 4.5). Rates of pneumonia were significantly lower with iron in one trial (Analysis 4.6).

The quality of the evidence was considered low for parasitaemia and all-cause mortality, mainly due to unclear allocation concealment in three of the four trials and loss of participations to follow-up ('Summary of findings 4').

Discussion

Summary of main results

Oral iron supplementation alone did not increase the risk for clinical malaria (RR 0.99, 95% CI 0.90 to 1.09). The results were not affected by the presence of anaemia or haemoglobin values at baseline and were similar among children in different age groups. There was no significant difference in the risk for death (absolute risk difference +2.4 per 1000 children, 95% CI -6.5 to +11.3) and hospital admissions in malarial hyper- or holoendemic areas. Data on severe malaria as a separate outcome were not available. The combination of iron and folate resulted in mixed results for malaria that were not pooled, with an increased risk of severe malaria, including cerebral malaria, in one large trial (Sazawal 2006 (C)a). Iron with an antimalarial drug significantly decreased the occurrence of clinical malaria compared to placebo or no treatment (RR 0.54, 95% CI 0.43 to 0.67), with no significant difference in mortality. When administered during an acute attack of malaria, iron administration did not adversely affect treatment failure or death.

There was a trend for an increased risk of asymptomatic parasitaemia with oral iron supplementation alone, which was statistically significant only at the end of follow-up and in trials with unclear allocation concealment methods. In all comparisons, iron supplementation increased haemoglobin significantly and decreased the prevalence of anaemia. All analyses were highly heterogenous, precluding a precise pooled estimate of effect, but the increase in haemoglobin was substantial in most individual studies and the prevalence of anaemia was reduced by 50% or more in most comparisons. We did not observe an effect of malaria activity in the region of the trial on the benefit of iron supplementation with regard to haemoglobin level and anaemia. The only variable significantly affecting this benefit was baseline anaemia, with anaemic children gaining more than those who were non-anaemic at baseline.

We did not observe a beneficial or adverse effect of iron supplementation alone on other infections, weight or height. These, as all analyses, refer to children living in developing countries where malaria has been described.

Overall completeness and applicability of evidence

The results and their quality of evidence grading are provided in the 'Summary of findings' tables.

For the intervention of iron alone or iron administered with an antimalarial drug for the prevention or treatment of anaemia, the quality of the evidence was graded as high for clinical malaria. The main limitation of this analysis was the lack of data reported separately on severe malaria, including admissions to hospital for malaria, cerebral malaria or other severe complications. However, the lack of an adverse effect on mortality in a large set of trials attests to the safety of iron supplementation in malaria-endemic locations. Despite the heterogeneity in the analyses of haemoglobin and anaemia, the beneficial effect of iron supplementation is qualitatively apparent and similar in highly endemic malarial areas compared to other settings in developing countries. Although these results pertain to all children up to 18 years of age, the main question of interest concerns young children below 2 years of age who are at highest risk from malaria. The analyses for clinical malaria and deaths included a substantial proportion of young children with no indication of an adverse effect for children below 2 years of age. We found no evidence to support the need to screen children for anaemia before treatment for safety concerns, as the supplementation effects were not dependent on the presence or absence of anaemia at baseline.

For the intervention of iron with folic acid, no consistent results were obtained. There was no information on the outcome of clinical, uncomplicated, malaria and parasitaemia. Overall, there was no statistically significant increased risk for death. A significantly increased risk for death or hospital admission was reported in a large RCT (Sazawal 2006 (C)b), but the relative contributions of the addition of folic acid and the poor infrastructure for diagnosis and surveillance of malaria to the adverse effects of iron in this trial are not clear.

Considering all trials in which oral iron was provided for the prevention or treatment of anaemia with or without folic acid, we observed an effect of the modalities used for the surveillance and treatment of malaria during the trial (ie regular examinations for parasitaemia when febrile and treatment for children diagnosed with malaria). An increased risk for any malaria-related clinical event existed when regular malaria surveillance and treatment were not available. Thus, the safety of iron supplementation is more certain when there is an adequate infrastructure for diagnosing and treating uncomplicated malaria.

Although few trials assessed iron supplementation during an acute attack of malaria, the evidence supports the safety on this intervention and indicates a benefit with regard to haematological recovery after infection.

Potential biases in the review process

Mortality data were reported in less than half of all the trials included (30/71 trials overall). Moreover, most of the trials reporting on mortality referred only to children available for analysis at end of treatment or follow-up. Deaths should be assessed among all children randomized, mainly those lost to follow-up.

There is an interest in the assessment of the effect of iron supplementation on malaria by iron status and iron-deficiency anaemia at baseline. We could not conduct a subgroup analysis by individual children's iron status or haemoglobin at baseline due to the lack of subgroup data reported in the primary trials for the outcomes of deaths and malaria. Our analyses stratified by anaemia are based on the study groups' mean haemoglobin level. Most of the studies recruited a uniform population of anaemic or non-anaemic children, thus enabling this stratification in the meta-analysis. Although this analysis could mask an adverse effect in individual iron-replete, non-anaemic children compensated by benefit in iron-deplete, anaemic children, the lack of heterogeneity in the analyses for malaria and deaths makes this possibility unlikely. This possibility is not supported by a trial-level stratified analysis restricted to trials recruiting only anaemic or non-anaemic children (data not shown). However, we could not conduct an analysis by true iron status or iron-deficiency anaemia at baseline.

There was heterogeneity with regard to the management of children identified as anaemic during the trial and after treatment. Some trials supplied iron to all children identified as anaemic below a certain threshold during the trial. After treatment, during follow-up, children who remained anaemic were all given iron per protocol, were offered the possibility of treatment, or were not addressed specifically. We could not assess the effects of this variable due to the large heterogeneity in trial protocols and poor reporting. This factor could underlie some of the unexplained heterogeneity observed in our analyses for haemoglobin and anaemia.

Much of the evidence relies on cluster randomized trials. Naturally, these were the largest trials and thus carried a large weight in the meta-analysis. However, the major outcomes assessed in these trials are probably correlated within clusters, including anaemia, iron status, malaria, and other contagious or non-contagious infectious complications. In classes or schools, the correlation between individuals may be smaller than among families, but the large cluster size increases the cluster effect. Ideally, we would want these trials to be planned and analysed accordingly. The trial should report on the unit of randomization, the average cluster size (number of children in household or class), the number of clusters and individuals randomized, the ICC for each outcome (denoting the degree of similarity between individuals in the same cluster) and an effect estimate adjusted for clustering. Unadjusted effect estimates, calculated as if the trial was individually randomized, may result in an exaggerated precision of the effect estimate, thus inflating the weight of the study in the meta-analysis. Out of the 13 cluster RCTs included in our review only Sazawal 2006 (C)a and Sazawal 2006 (C)b reported adjusted analyses for the primary outcomes. In our analyses we used estimated ICCs to adjust the weight of the cluster RCTs in the meta-analysis. We cannot be sure that the contribution of these large trials to the compiled analysis is correct. The exclusion of cluster RCTs did not significantly alter the results in all comparisons (data not shown).

The review inclusion criteria raise some considerations. We included all trials conducted in countries where malaria has been reported to occur. This does not mean that malaria was highly active or even present at all in the location and at the time of the trial. Trials reporting on malaria were certainly conducted in the setting of malarial activity. We included other, seemingly irrelevant, trials to attempt to extract malaria-related outcomes from all and to assess the effects of iron supplementation on mortality and hospital admissions in malaria-endemic areas and thus the safety of iron supplementation in these areas. So as not to dilute the effects of iron on mortality in truly malaria-endemic regions, we separated this analysis by malaria endemicity and report primarily the results restricted to trials in which malaria was active during the study. We included only oral iron supplied as a medicinal product. We did not include trials that assessed iron-fortified foods or drinks that provide lower, physiological doses of iron. Analysis of the trials identified in our systematic search but excluded from the current review for this reason reveals that only two further trials assessing iron as food fortification would have contributed to the analyses on malaria (CIGNIS 2010; Rohner 2010). Similarly, we did not include one trial assessing parenteral iron, since this is not the intervention of interest when examining the risks of routine iron supplementation in childhood (Oppenheimer 1986).

Finally, we asked Sazawal 2006 (C)a for data on malaria-related events, hospital admissions and deaths for the two arms: iron plus folic acid plus vitamin A plus zinc versus zinc plus vitamin A. These were excluded from the current version of the review since outcome data were not reported for the zinc plus vitamin A arm at the time the iron arms were stopped (and children in the iron-containing arms were reassigned to the other study arms). This will add 16,196 more children to the analyses of iron plus folic acid versus placebo treatment.

Other analyses or outcomes lacking from our review include an assessment of the effect of children's nutritional status at baseline on the results; analyses stratified by the schedule of iron supplementation (daily versus weekly); psychomotor and cognitive outcomes assessed in another Cochrane Review (Martins 2001); tuberculosis, and age/weight/height-adjusted Z scores for growth. Finally, we cannot exclude the existence of more unpublished RCTs that could contribute to the evidence on iron supplementation and malaria, such as those identified in university thesis formats (Gebresellassie 1996; Adam 1997 (C)) or others (Roschnik 2003 (C)).

Agreements and disagreements with other studies or reviews

This review was originally published in 2009, adding further debate into the conundrum of iron supplementation for children in malaria-endemic areas (Roth 2010; Stoltzfus 2010; Suchdev 2010). Before the publication of the review, based on the largest trial to date at that time (Sazawal 2006 (C)a), there was a consensus that iron supplementation harms iron-sufficient children living in malaria-endemic areas and thus it should not be prescribed in these locations without initial screening for iron deficiency (WHO 2007). The original and current update of this systematic review challenge this conclusion. Since the Sazawal 2006 (C)a trial and the current review currently form the basis for decision making, we contrast their findings.

Sazawal 2006 (C)a was by far the largest trial to date and its advantages include adequate randomization methods and double-blinding, adjustment for cluster randomization, inclusion of the relevant age group of children with the highest morbidity and mortality toll from malaria (Carneiro 2010) and the assessment of clinically relevant outcomes. This was probably the only trial to date powered to assess the effect of iron supplementation on severe malaria. It showed a significantly increased risk for the composite outcome of death or hospitalization, and for hospitalization alone, among children, mostly under 2 years of age, living in a malarial holoendemic area. The risk of death was increased, but without statistical significance. In a stratified analysis of an independent sub-study, adverse effects of iron supplementation (death or hospitalization) were observed among children who were iron-replete and non-anaemic at baseline, while among children who were iron-deficient and anaemic there were fewer adverse events with iron supplementation. Several unique features of this trial should be noted. Malaria assessment was based on hospital admissions due to malaria, unlike other trials that assessed all cases of clinical malaria or parasitaemia, or both. The trial's conclusions are based on the results at the time when the data-monitoring committee stopped the trial for harm, according to the trial's protocol. At the time of the trial, the primary healthcare system in Zanzibar was weak (prior to the Zanzibar Malaria Control Program) and the main trial's protocol did not offer children special malaria prevention, diagnosis or treatment services, unlike the design of other, smaller scale trials (see Table 3). In the substudy (Sazawal 2006 (C)b), surveillance for parasitaemia was performed and children received treatment according to the study protocol in their homes. The main trial showed that iron is harmful, while the substudy showed that iron supplementation is protective for severe malaria. The findings related to the differential effects of iron by iron status and anaemia at baseline are based on a post hoc subgroup analysis of the substudy, whose results differed significantly from the results of the main trial (Analysis 2.1).

Our review places this trial in the context of the complete evidence. It could not be combined with other studies due to its unique intervention (iron with folic acid) and outcome definitions. A compilation of all the other trials showed that oral iron supplements alone do not increase the risk for malaria or death, whether given for anaemia or to prevent anaemia. The outcome addressed in all trials was not restricted to severe malaria, but did not exclude such events from the outcome of clinical malaria reported. Neither the co-administration of folic acid nor baseline haemoglobin fully explained differences between study results in the effects of iron supplementation on malaria. Only the methods for surveillance and treatment of uncomplicated malaria explained the variability, considering all studies and the two parts the Sazawal trial. Our review shifts the emphasis of decision making prior to iron supplementation on malaria surveillance and treatment rather on than the assessment of iron status.

Authors' conclusions

Implications for practice

We did not find an increased risk of clinical malaria and parasitaemia, all-cause mortality or other infectious complications with iron supplementation alone for children living in malaria-endemic areas. Subgroup analyses did not point at an increased risk for these outcomes in hyperendemic regions, in children that were non-anaemic at baseline, and in young children below 2 years of age. Overall, iron supplementation may be associated with an increased risk of malaria in settings with no access to malaria prevention and treatment services. Conversely, the administration of iron with an anti-malarial drug confers significant protection from malaria. Iron supplementation significantly improves haemoglobin levels and reduces the prevalence of anaemia in highly malaria-endemic areas. Iron deficiency and anaemia in the long term have been shown to impair cognitive and motor development (Pollitt 1993; Grantham-McGregor 2001), growth (Lawless 1994), and immune function (Oppenheimer 2001), and contribute to childhood mortality in developing countries (WHO 2004; FAO/WHO 2005). Based on our review, iron supplementation should not be withheld from children living in malaria-endemic countries. A higher gain is achieved among anaemic children, thus baseline testing may assist decision making. However, in settings where iron deficiency and anaemia affects most children, as in some parts of sub-Saharan Africa (WHO 2004), iron supplementation should not be restricted for fear of infections or death. Malaria prevention and treatment should be offered to children regardless of iron supplementation, since these interventions reduce malaria, mortality, and anaemia (Lengeler 2004; Meremikwu 2008). Improvements in prevention and management of malaria have occurred in the last decade in sub-Saharan Africa, allowing for iron supplementation in safer setting than ever before (MDG 2011; WHO Global Malaria Programme 2010).

There are not enough data to draw conclusions on the intervention of iron with folic acid. Folic acid may interfere with the efficacy of sulfadoxine-pyrimethamine, an antimalarial drug used for intermittent preventive treatment or treatment of clinical episodes of malaria (Mulenga 2006; Metz 2007). Furthermore, there is no evidence of folate deficiency among children < 2 years old in malaria-endemic areas (Metz 2007).

Treatment of anaemia during an acute attack of malaria improves haemoglobin recovery and does not increase the risk of treatment failure or death.

Implications for research

The major remaining uncertainties are whether iron supplementation alone results in an increased risk of severe malaria, ie cerebral malaria, and deaths due to malaria (despite their being no increase in overall deaths), and whether a risk with iron supplementation alone exists in a subset of iron-replete, non-anaemic children living in highly malaria-endemic areas.

To address these questions an individual patient data (IPD) meta-analysis of existing trials might be of value. Such an analysis can look at the main outcomes that were probably collected in all or most trials, ie deaths, deaths due to malaria, cerebral malaria, and hospital admissions. An IPD will allow a better assessment of the covariates of interest than a trial-level analysis and could be performed using data in published results . These include participants' iron and haemoglobin status at baseline (most trials reported baseline assessment of one or measures of iron status and haemoglobin), and more precise age stratification to address the main group of interest, that of children between 6 months and 2 years of age.

Well-conducted observational studies assessing the effects of iron supplementation and fortification (Stoltzfus 2011) are important since RCTs measure only a limited duration of iron supplementation and may not represent the child population in need of iron supplementation, given the low risk of death observed in this review. Growth and developmental outcomes would probably be better assessed in such long-term studies.

Acknowledgements

The editorial base for the Cochrane Infectious Diseases Group is funded by the UK Department for International Development for the benefit of developing countries. Dafna Yahav received funding from the editorial base.

We acknowledge the assistance and contribution to the review of Juliana U Ojukwu (conceived the idea for the review, wrote the protocol, and contributed to the first edition of this review) ; Sarah Donegan (who advised and assisted with data analysis); Harriet G. McLehose (who assisted in the writing and final drafting of the protocol and review); Paul Garner (who assisted with the study design, analysis, and co-ordination) and Leonard Leibovici (who assisted with data analysis and interpretation).

We thank the Cochrane Infectious Diseases Group for their support of this review, without which this work could not have been performed. Special thanks to Vittoria Lutje, who designed and performed the searches. We thank Professor Jimmy Volmink, Dr Taryn Young, and Karen Essex of the South African Cochrane Centre for inviting us to meet and work on this review.

We would like to thank Professor Sunil Sazawal for supplying unpublished data for the Sazawal 2006 (C)b sub-study and Professors H.P. Sachdev and Tarun Gera for their help obtaining unpublished data for the trials included in this review. We thank all the authors who responded to our requests for further data and provided the data where available (see under 'Characteristics of included studies'). We thank the reviewers of our manuscript who raised important issues related to the analyses presented. We urge all the authors of the primary studies to correct the data used in their studies, and if necessary, add data, if available, mainly for the primary outcomes of malaria and mortality, and to point out any other inaccuracies in our analysis.

Data and analyses

Download statistical data

Comparison 1. Iron versus placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical malaria (by anaemia at baseline)13 Risk Ratio (Fixed, 95% CI)0.99 [0.90, 1.09]
1.1 Anaemia8 Risk Ratio (Fixed, 95% CI)1.02 [0.88, 1.19]
1.2 No anaemia5 Risk Ratio (Fixed, 95% CI)0.97 [0.86, 1.09]
2 Clinical malaria (by age)13 Risk Ratio (Fixed, 95% CI)0.99 [0.90, 1.09]
2.1 <2 yrs4 Risk Ratio (Fixed, 95% CI)0.94 [0.82, 1.09]
2.2 2-5 yrs3 Risk Ratio (Fixed, 95% CI)0.97 [0.75, 1.26]
2.3 >5 yrs6 Risk Ratio (Fixed, 95% CI)1.04 [0.91, 1.20]
3 Clinical malaria (P. falciparum only)8 Risk Ratio (Fixed, 95% CI)0.98 [0.87, 1.11]
4 Severe malaria (clinical malaria with high-grade parasitaemia or requiring admission)4 Risk Ratio (Fixed, 95% CI)0.91 [0.76, 1.08]
5 All-cause mortality (by location)228644Risk Difference (M-H, Fixed, 95% CI)0.00 [-0.00, 0.00]
5.1 Hypo or mesoendemic94846Risk Difference (M-H, Fixed, 95% CI)-0.00 [-0.00, 0.00]
5.2 Hyper or holoendemic133798Risk Difference (M-H, Fixed, 95% CI)0.00 [-0.01, 0.01]
6 Any parasitaemia, end of treatment (by anaemia at baseline)8 Risk Ratio (Fixed, 95% CI)1.09 [0.98, 1.22]
6.1 Anaemia5 Risk Ratio (Fixed, 95% CI)1.05 [0.92, 1.20]
6.2 No anaemia3 Risk Ratio (Fixed, 95% CI)1.17 [0.99, 1.40]
7 Any parasitaemia, end of treatment ( by age)8 Risk Ratio (Fixed, 95% CI)1.09 [0.98, 1.22]
7.1 <2 yrs1 Risk Ratio (Fixed, 95% CI)1.18 [0.89, 1.57]
7.2 2-5 yrs4 Risk Ratio (Fixed, 95% CI)1.06 [0.91, 1.23]
7.3 >5 yrs3 Risk Ratio (Fixed, 95% CI)1.12 [0.93, 1.34]
8 Any parasitaemia, end of treatment (P. falciparum only)6 Risk Ratio (Fixed, 95% CI)1.07 [0.95, 1.21]
8.1 Iron vs. placebo/no treatment5 Risk Ratio (Fixed, 95% CI)1.09 [0.96, 1.24]
8.2 Iron + antimalarial vs. antimalarial1 Risk Ratio (Fixed, 95% CI)0.87 [0.56, 1.33]
9 Any parasitaemia, end of treatment (by allocation concealment)8 Risk Ratio (Fixed, 95% CI)1.09 [0.98, 1.22]
9.1 Adequate3 Risk Ratio (Fixed, 95% CI)0.94 [0.79, 1.11]
9.2 Unclear5 Risk Ratio (Fixed, 95% CI)1.22 [1.06, 1.40]
10 High-grade parasitaemia5 Risk Ratio (Fixed, 95% CI)1.13 [0.93, 1.37]
11 Any parasitaemia, end of follow up4941Risk Ratio (M-H, Fixed, 95% CI)1.18 [1.03, 1.35]
12 Hospitalizations and clinic visits5 Risk Ratio (Fixed, 95% CI)Subtotals only
12.1 Hospitalization, iron vs. placebo4 Risk Ratio (Fixed, 95% CI)0.81 [0.68, 0.98]
12.2 Hospitalization, iron + antimalarial vs. antimalarial2 Risk Ratio (Fixed, 95% CI)1.22 [0.96, 1.57]
12.3 Clinic visit, iron vs. placebo2 Risk Ratio (Fixed, 95% CI)0.95 [0.88, 1.02]
12.4 Clinic visit, iron + antimalarial vs. antimalarial3 Risk Ratio (Fixed, 95% CI)1.02 [0.95, 1.09]
13 Haemoglobin, end of treatment (by anaemia at baseline)358544Mean Difference (IV, Random, 95% CI)0.87 [0.64, 1.09]
13.1 Anaemia112692Mean Difference (IV, Random, 95% CI)1.59 [0.93, 2.26]
13.2 No anaemia295852Mean Difference (IV, Random, 95% CI)0.64 [0.48, 0.80]
14 Haemoglobin, end of treatment (by location)358544Mean Difference (IV, Random, 95% CI)0.87 [0.64, 1.09]
14.1 Hypo or mesoendemic214335Mean Difference (IV, Random, 95% CI)0.85 [0.54, 1.16]
14.2 Hyper or holoendemic144209Mean Difference (IV, Random, 95% CI)0.90 [0.59, 1.21]
15 Haemoglobin, change from baseline, end of treatment204205Mean Difference (IV, Random, 95% CI)0.61 [0.41, 0.80]
15.1 Hypo or mesoendemic122595Mean Difference (IV, Random, 95% CI)0.40 [0.22, 0.58]
15.2 Hyper or holoendemic81610Mean Difference (IV, Random, 95% CI)0.91 [0.56, 1.26]
16 Anaemia, end of treatment (by location)245780Risk Ratio (M-H, Random, 95% CI)0.55 [0.43, 0.71]
16.1 Hypo or mesoendemic112469Risk Ratio (M-H, Random, 95% CI)0.64 [0.47, 0.86]
16.2 Hyper or holoendemic133311Risk Ratio (M-H, Random, 95% CI)0.52 [0.35, 0.78]
17 URTI/pneumonia episodes per patient-month (by location)1122577Risk Ratio (Fixed, 95% CI)0.97 [0.91, 1.04]
17.1 Hypo or mesoendemic917402Risk Ratio (Fixed, 95% CI)0.96 [0.90, 1.03]
17.2 Hyper or holoendemic25175Risk Ratio (Fixed, 95% CI)1.04 [0.86, 1.25]
18 Diarrhoeal episodes per patient-month (by location)1325225Risk Ratio (Fixed, 95% CI)1.09 [1.03, 1.14]
18.1 Hypo or mesoendemic without zinc78254Risk Ratio (Fixed, 95% CI)1.03 [0.95, 1.12]
18.2 Hypo or mesoendemic with zinc59024Risk Ratio (Fixed, 95% CI)1.16 [1.07, 1.24]
18.3 Hyper or holoendemic without zinc55643Risk Ratio (Fixed, 95% CI)0.92 [0.73, 1.16]
18.4 Hyper or holoendemic with zinc12304Risk Ratio (Fixed, 95% CI)0.99 [0.67, 1.46]
19 Infections per patient-month12 Risk Ratio (Fixed, 95% CI)Subtotals only
19.1 Fever episodes715683Risk Ratio (Fixed, 95% CI)1.03 [0.93, 1.14]
19.2 Days with fever1110Risk Ratio (Fixed, 95% CI)8.37 [1.91, 36.58]
19.3 Disease episodes other than diarrhoea or respiratory infections33096Risk Ratio (Fixed, 95% CI)1.03 [0.80, 1.33]
19.4 All disease episodes11395Risk Ratio (Fixed, 95% CI)1.15 [0.91, 1.46]
20 Weight, end value164604Std. Mean Difference (IV, Fixed, 95% CI)0.01 [-0.05, 0.07]
20.1 Hypo or mesoendemic133665Std. Mean Difference (IV, Fixed, 95% CI)0.03 [-0.03, 0.10]
20.2 Hyper or holoendemic3939Std. Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.22, 0.03]
21 Weight, change from baseline111162Std. Mean Difference (IV, Fixed, 95% CI)0.19 [0.07, 0.30]
21.1 Hypo or mesoendemic8824Std. Mean Difference (IV, Fixed, 95% CI)0.09 [-0.05, 0.23]
21.2 Hyper or holoendemic3338Std. Mean Difference (IV, Fixed, 95% CI)0.43 [0.21, 0.65]
22 Height, end value164911Std. Mean Difference (IV, Fixed, 95% CI)0.00 [-0.05, 0.06]
22.1 Hypo or mesoendemic133972Std. Mean Difference (IV, Fixed, 95% CI)0.02 [-0.04, 0.08]
22.2 Hyper or holoendemic3939Std. Mean Difference (IV, Fixed, 95% CI)-0.07 [-0.20, 0.06]
23 Height, change from baseline111162Std. Mean Difference (IV, Fixed, 95% CI)0.18 [0.06, 0.30]
23.1 Hypo or mesoendemic8824Std. Mean Difference (IV, Fixed, 95% CI)0.23 [0.09, 0.37]
23.2 Hyper or holoendemic3338Std. Mean Difference (IV, Fixed, 95% CI)0.06 [-0.16, 0.28]
Analysis 1.1.

Comparison 1 Iron versus placebo or no treatment, Outcome 1 Clinical malaria (by anaemia at baseline).

Analysis 1.2.

Comparison 1 Iron versus placebo or no treatment, Outcome 2 Clinical malaria (by age).

Analysis 1.3.

Comparison 1 Iron versus placebo or no treatment, Outcome 3 Clinical malaria (P. falciparum only).

Analysis 1.4.

Comparison 1 Iron versus placebo or no treatment, Outcome 4 Severe malaria (clinical malaria with high-grade parasitaemia or requiring admission).

Analysis 1.5.

Comparison 1 Iron versus placebo or no treatment, Outcome 5 All-cause mortality (by location).

Analysis 1.6.

Comparison 1 Iron versus placebo or no treatment, Outcome 6 Any parasitaemia, end of treatment (by anaemia at baseline).

Analysis 1.7.

Comparison 1 Iron versus placebo or no treatment, Outcome 7 Any parasitaemia, end of treatment ( by age).

Analysis 1.8.

Comparison 1 Iron versus placebo or no treatment, Outcome 8 Any parasitaemia, end of treatment (P. falciparum only).

Analysis 1.9.

Comparison 1 Iron versus placebo or no treatment, Outcome 9 Any parasitaemia, end of treatment (by allocation concealment).

Analysis 1.10.

Comparison 1 Iron versus placebo or no treatment, Outcome 10 High-grade parasitaemia.

Analysis 1.11.

Comparison 1 Iron versus placebo or no treatment, Outcome 11 Any parasitaemia, end of follow up.

Analysis 1.12.

Comparison 1 Iron versus placebo or no treatment, Outcome 12 Hospitalizations and clinic visits.

Analysis 1.13.

Comparison 1 Iron versus placebo or no treatment, Outcome 13 Haemoglobin, end of treatment (by anaemia at baseline).

Analysis 1.14.

Comparison 1 Iron versus placebo or no treatment, Outcome 14 Haemoglobin, end of treatment (by location).

Analysis 1.15.

Comparison 1 Iron versus placebo or no treatment, Outcome 15 Haemoglobin, change from baseline, end of treatment.

Analysis 1.16.

Comparison 1 Iron versus placebo or no treatment, Outcome 16 Anaemia, end of treatment (by location).

Analysis 1.17.

Comparison 1 Iron versus placebo or no treatment, Outcome 17 URTI/pneumonia episodes per patient-month (by location).

Analysis 1.18.

Comparison 1 Iron versus placebo or no treatment, Outcome 18 Diarrhoeal episodes per patient-month (by location).

Analysis 1.19.

Comparison 1 Iron versus placebo or no treatment, Outcome 19 Infections per patient-month.

Analysis 1.20.

Comparison 1 Iron versus placebo or no treatment, Outcome 20 Weight, end value.

Analysis 1.21.

Comparison 1 Iron versus placebo or no treatment, Outcome 21 Weight, change from baseline.

Analysis 1.22.

Comparison 1 Iron versus placebo or no treatment, Outcome 22 Height, end value.

Analysis 1.23.

Comparison 1 Iron versus placebo or no treatment, Outcome 23 Height, change from baseline.

Comparison 2. Iron + folic acid versus placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Severe malaria (malaria requiring admission)2 Risk Ratio (Fixed, 95% CI)Totals not selected
2 Severe malaria (cerebral malaria)2 Risk Ratio (Fixed, 95% CI)Totals not selected
3 Clinical malaria (by malaria management, including iron + folate)15 Risk Ratio (Fixed, 95% CI)1.03 [0.95, 1.11]
3.1 Surveillance and treatment9 Risk Ratio (Fixed, 95% CI)0.94 [0.85, 1.04]
3.2 Unspecified6 Risk Ratio (Fixed, 95% CI)1.16 [1.03, 1.31]
4 All-cause mortality518107Risk Difference (M-H, Fixed, 95% CI)0.00 [-0.00, 0.01]
4.1 Hypo or mesoendemic1209Risk Difference (M-H, Fixed, 95% CI)0.0 [-0.02, 0.02]
4.2 Hyper or holoendemic417898Risk Difference (M-H, Fixed, 95% CI)0.00 [-0.00, 0.01]
5 Any hospitalization1 Risk Ratio (Fixed, 95% CI)Subtotals only
6 Haemoglobin, end of treatment (by anaemia at baseline)61140Mean Difference (IV, Random, 95% CI)1.03 [0.56, 1.49]
6.1 Anaemia4273Mean Difference (IV, Random, 95% CI)1.10 [0.30, 1.91]
6.2 No anaemia2867Mean Difference (IV, Random, 95% CI)0.95 [0.32, 1.59]
7 Haemoglobin, end of treatment (by location)72476Mean Difference (IV, Random, 95% CI)0.96 [0.62, 1.30]
7.1 Hypo or mesoendemic62392Mean Difference (IV, Random, 95% CI)1.01 [0.63, 1.38]
7.2 Hyper or holoendemic184Mean Difference (IV, Random, 95% CI)0.60 [0.06, 1.14]
8 Anaemia, end of treatment ( by location)61108Risk Ratio (M-H, Random, 95% CI)0.44 [0.27, 0.70]
8.1 Hypo or mesoendemic4557Risk Ratio (M-H, Random, 95% CI)0.44 [0.24, 0.80]
8.2 Hyper or holoendemic2551Risk Ratio (M-H, Random, 95% CI)0.38 [0.19, 0.75]
9 Weight, end value21730Std. Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.12, 0.07]
10 Height, end value21730Std. Mean Difference (IV, Fixed, 95% CI)-0.02 [-0.11, 0.08]
Analysis 2.1.

Comparison 2 Iron + folic acid versus placebo or no treatment, Outcome 1 Severe malaria (malaria requiring admission).

Analysis 2.2.

Comparison 2 Iron + folic acid versus placebo or no treatment, Outcome 2 Severe malaria (cerebral malaria).

Analysis 2.3.

Comparison 2 Iron + folic acid versus placebo or no treatment, Outcome 3 Clinical malaria (by malaria management, including iron + folate).

Analysis 2.4.

Comparison 2 Iron + folic acid versus placebo or no treatment, Outcome 4 All-cause mortality.

Analysis 2.5.

Comparison 2 Iron + folic acid versus placebo or no treatment, Outcome 5 Any hospitalization.

Analysis 2.6.

Comparison 2 Iron + folic acid versus placebo or no treatment, Outcome 6 Haemoglobin, end of treatment (by anaemia at baseline).

Analysis 2.7.

Comparison 2 Iron + folic acid versus placebo or no treatment, Outcome 7 Haemoglobin, end of treatment (by location).

Analysis 2.8.

Comparison 2 Iron + folic acid versus placebo or no treatment, Outcome 8 Anaemia, end of treatment ( by location).

Analysis 2.9.

Comparison 2 Iron + folic acid versus placebo or no treatment, Outcome 9 Weight, end value.

Analysis 2.10.

Comparison 2 Iron + folic acid versus placebo or no treatment, Outcome 10 Height, end value.

Comparison 3. Iron + antimalarial versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical malaria3728Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.43, 0.67]
2 All-cause mortality3728Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.52, 2.11]
3 Hospitalizations and clinic visits2 Risk Ratio (Fixed, 95% CI)Subtotals only
3.1 Hospitalization, iron + antimalarial vs. placebo25904Risk Ratio (Fixed, 95% CI)0.59 [0.48, 0.73]
3.2 Clinic visit, iron + antimalarial vs. placebo25904Risk Ratio (Fixed, 95% CI)0.88 [0.82, 0.95]
4 Haemoglobin at end of treatment1 Mean Difference (IV, Random, 95% CI)Totals not selected
5 Anaemia3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
5.1 Iron + antimalarial vs. placebo, end of treatment2295Risk Ratio (M-H, Random, 95% CI)0.44 [0.28, 0.70]
5.2 Iron + antimalarial vs. placebo, end of follow up1420Risk Ratio (M-H, Random, 95% CI)0.37 [0.26, 0.54]
Analysis 3.1.

Comparison 3 Iron + antimalarial versus placebo, Outcome 1 Clinical malaria.

Analysis 3.2.

Comparison 3 Iron + antimalarial versus placebo, Outcome 2 All-cause mortality.

Analysis 3.3.

Comparison 3 Iron + antimalarial versus placebo, Outcome 3 Hospitalizations and clinic visits.

Analysis 3.4.

Comparison 3 Iron + antimalarial versus placebo, Outcome 4 Haemoglobin at end of treatment.

Analysis 3.5.

Comparison 3 Iron + antimalarial versus placebo, Outcome 5 Anaemia.

Comparison 4. Iron versus control in the treatment of proven malaria
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 All-cause mortality4664Risk Difference (M-H, Fixed, 95% CI)0.00 [-0.01, 0.02]
2 Parasitological failure3583Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.74, 1.24]
3 Hospitalizations and clinic visits3 Risk Ratio (Fixed, 95% CI)Subtotals only
3.1 Hospitalization2368Risk Ratio (Fixed, 95% CI)2.00 [0.80, 5.00]
3.2 Clinic visit1273Risk Ratio (Fixed, 95% CI)0.65 [0.29, 1.46]
4 Haemoglobin at end of treatment2176Mean Difference (IV, Random, 95% CI)0.32 [-0.01, 0.64]
5 Anaemia1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
6 Infections (pneumonia)1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 4.1.

Comparison 4 Iron versus control in the treatment of proven malaria, Outcome 1 All-cause mortality.

Analysis 4.2.

Comparison 4 Iron versus control in the treatment of proven malaria, Outcome 2 Parasitological failure.

Analysis 4.3.

Comparison 4 Iron versus control in the treatment of proven malaria, Outcome 3 Hospitalizations and clinic visits.

Analysis 4.4.

Comparison 4 Iron versus control in the treatment of proven malaria, Outcome 4 Haemoglobin at end of treatment.

Analysis 4.5.

Comparison 4 Iron versus control in the treatment of proven malaria, Outcome 5 Anaemia.

Analysis 4.6.

Comparison 4 Iron versus control in the treatment of proven malaria, Outcome 6 Infections (pneumonia).

Appendices

Appendix 1. Analysis of cluster-randomized trials

Based on other trials included in the review we assumed an average cluster size of 1.5 for households and 32 for classes, when the average cluster size or number of clusters and individuals were not reported (see tables of included studies, Table 4 and Table 5 for reported and assumed cluster sizes). The DEs or intracluster correlation coefficients (ICCs) used for the different outcomes were the following:

  • Malaria (Sazawal 2006 (C)a): unadjusted RR 1.14 (CI 1.01 to 1.30) (using number of events reported and number evaluated for clinical malaria), SE (ln RR) = 0.064391; Adjusted RR 1.16 (CI 1.00 to 1.34) (reported in the publication for the same outcome), SE (in RR) = 0.074661. DE = (0.074661/0.064391)2 = 1.3444 for an average cluster size of 1.4 (households). All trials reporting on malaria-related outcomes used households as the unit of randomization and the same DE of 1.34 was used for all trials and all malaria-related outcomes.

  • Deaths (Tielsch 2006): unadjusted RR 1.04 (0.80 to 1.34), SE (ln RR) = 0.131585; Adjusted RR 1.03 (0.78 to 1.37), SE (ln RR) = 0.143692. DE = (0.143692/0.131585)2 = 1.192481 for an average cluster size of 82 (sectors), ICC = 0.002. The DE adjusted for a cluster size of 1.5 (household) was 1.001.

  • Anaemia (Kaiser 2006). We expected significant ICC between children in the same household (given their similar nutritional status and infection incidences) and a lower degree of clustering at the community level. We did not, however, find ICC estimates in the literature for these units and the cluster RCTs included in the review did not provide data allowing us to calculate DE or ICC. Ngnie-Teta 2007 reported that the degree of community-level clustering with regard to moderate to severe anaemia among Beninese and Malian children was 0.14 to 0.19. Assuncao 2007 reported an ICC of 0.07 and a DE of 2.5 in a cluster survey of all children under 6 years of age, where clusters of about 30 children comprised several households each. Kaiser 2006 reported the design effects (DE) between 1.4 and 2.4 for anaemia < 11 g/dL in three cluster surveys in Afghanistan and Mongolia (DEs between 1.4 and 2.4), allowing us to calculate ICCs between 0.093 and 0.100. We used a DE of 1.4 for trials using households as the unit of randomization and an ICC value of 0.093 to calculate the DE of trials using larger units of randomization (DE range 2.8 to 3.9). The ICC for haemoglobin, though measuring the same thing, is much smaller because it is a more precise measure. We used an ICC of 0.000 for households and 0.00271 for large clusters (school or class) based on values reported for households and the district health authority level, respectively, although these values refer to adults in England (Gulliford 1999).

  • Diarrhoea (Kaiser 2006). The pooled design effect from five observational studies in Kaiser 2006 was 3.1, for an average cluster size of 17, ICC = 0.131. The DE adjusted for a cluster size of 1.5 was calculated as 1.065.

  • Infectious episodes: a DE of 1.36 was calculated from the Sazawal 2006 (C)a study that reported both raw numbers and adjusted RR/SE.

 

What's new

Last assessed as up-to-date: 29 June 2011.

DateEventDescription
1 September 2011New search has been performedUpdated search (June 2011)
1 September 2011New citation required but conclusions have not changedNew author team; analyses significantly restructured.

History

Protocol first published: Issue 3, 2007
Review first published: Issue 3, 2009

DateEventDescription
6 August 2009AmendedError in data for graph corrected for Issue 4, 2009: Thanks to an observant reader, we identified a log conversion error for the analysis of hospitalizations and clinic visits in comparison 1. This has been corrected in issue 4, 2009.

Contributions of authors

First edition:

Juliana U Ojukwu conceived the idea for the review, wrote the protocol, identified studies for inclusion and exclusion, extracted the data, entered the data in RevMan, participated in the data analysis, and reviewed all the drafts of the first edition of this review.

Joseph Okebe wrote the protocol, identified studies for inclusion and exclusion, extracted the data, entered data in RevMan, participated in the data analysis, and reviewed all the drafts and the final review.

Dafna Yahav extracted the data from all included studies, entered data in RevMan, participated in the data analysis, and reviewed all drafts and the final review.

Mical Paul planned the data extraction, extracted the data, entered data in RevMan, participated in the data analysis, and wrote the review.

All authors agreed to the final publication.

Revised edition:

Mical Paul updated RevMan, reorganised previous data, carried out the subgroup analyses, performed the GRADE classifications, wrote the final version of the update, and revised the final manuscript.

Rana Shbita performed the search for the 2011 update and identified studies for inclusion and exclusion, extracted the data for the new studies, participated in the data analysis, and reviewed all the drafts and the final review. This work was performed in partial fulfilment of Rana Shbita's Master in epidemiology,

Dafna Yahav performed the search for the 2011 update, extracted the data for the new studies, performed the GRADE classifications, and revised the final manuscript.

All authors listed agreed to the revised publication.

Declarations of interest

All authors - none declared.

Sources of support

Internal sources

  • UK Department for International Development (DFID), UK.

    The editorial base for the Cochrane Infectious Diseases Group is funded by the UK Department for International Development (DFID) for the benefit of developing countries. Dafna Yahav received funding from the editorial base.

External sources

  • The Nuffield Foundation, Afghanistan.

    Dr Juliana U Ojukwu was awarded a Reviews for Africa Programme Fellowship (www.mrc.ac.za/cochrane/rap.htm), funded by a grant from the Nuffield Commonwealth Programme, through The Nuffield Foundation.

  • Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.

    Grant to support the 2011 update

Differences between protocol and review

Differences between the original protocol and review:

  • parasitaemia was moved from primary to secondary outcomes

  • protocol-defined secondary outcomes on iron levels, ferritin levels, total iron binding capacity (TIBC), zinc protoporphyrin concentration and zinc were removed. These outcomes were extracted but reporting was sparse

  • post hoc subgroup analyses by malaria surveillance and treatment were conducted

Differences between previous review version and 2011 update:

  • comparisons of iron versus placebo/no treatment and iron plus folic acid versus placebo/no treatment were completely separated

  • analyses of severe malaria were separated by definition of this outcome

  • trials reporting none of the review-defined outcomes were excluded

  • new trials were added and trials awaiting assessment were reclassified

  • stratification for anaemia at baseline based on mean haemoglobin in the control group rather than on the percentage of children with anaemia in the trial and subgroup analyses by anaemia at baseline were added

  • sensitivity analysis considering only P. falciparum in malaria-related outcomes were added

  • Juliana Okwuru stepped down in her role as an author

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Adam 1997 (C)

Methods

Cluster randomized

Trial years: May 1993 to October 1995

Unit of randomization: household

Number of units randomized: not stated

Average cluster size: not stated

Adjustment for clustering: none

Methods of adjustment: not stated

Participants

Number of children: 841 randomized, 738 evaluated

Age: mean 45.2 months (range 6 to 84 months)

Setting: school, rural

% anaemic at baseline: 100% (anaemia definition: Hb < 10.9 g/dL), mean haemoglobin (SD) at baseline: iron arm: 8.27 (1.2) g/dL; placebo: 8.27 (1.3) g/dL

% malaria at baseline: 12.35%

Interventions

Ferrous sulfate elixir, about 3 mg/kg/day elemental iron vs. placebo elixir

Duration of treatment: 12 weeks

Duration of follow up: 12 months

Outcomes

Main objective/outcome: Effect of iron supplementation on malaria

Review outcomes reported in the trial:

1. Clinical malaria, parasitaemia, severe malaria, parasite density

2. Anaemia

3. Hospitalization

4. Haemoglobin (end and change)

5. All infections, diarrhoea

Notes

Trial location: north-western Ethiopia, Shehdi town, and Aftit village

Malaria endemicity: mesoendemic (trial included the rainy season)

Language of publication: English

Exclusion criteria: Hb < 6 and Hb > 11, debilitating chronic disease or acute infection, new residents or about to leave the region

PhD dissertation

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number tables. Done in random permuted blocks of four households
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskSame bottles as intervention used for placebo elixir. Participants and those who supplied the medications were blinded
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk738/841 evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk742/841 evaluated

Agarwal 2003

Methods

Cluster randomized

Trial years: August 1996 to February 1999

Unit of randomization: school classes

Number of units randomized: not stated

Average cluster size: not stated

Adjustment for clustering: none

Methods of adjustment: not stated

Participants

Number of children: 3770 randomized, 2085 evaluated

Age: range 10-17 years

Setting: school, urban

% anaemic at baseline: 49.3% (anaemia definition: Hb < 12 g/dL)

% malaria at baseline: not stated

Interventions

Elemental iron tablets 100mg/ day, about 2.2 mg/kg/day elemental iron vs. elemental iron tablets 100mg/ week (arm excluded from comparisons in the review) vs. no treatment

Duration of treatment: 100 days

Duration of follow up: 115 days

Outcomes

Main objective/outcome: Effect of iron supplementation on anaemia

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end and change)

Notes

Trial location: Delhi, India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: Hb < 7 g/dl

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
High riskOpen study
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot assessed
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot assessed
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk2085 / 3770 assessed

Aggarwal 2005

Methods

Individually randomized

Trial years: April 1998 to February 1999

Participants

73 randomized, 62 evaluated

Age: mean 57.4 days (range 50 to 80 days), all were predominantly breast fed

Setting: community, urban

% anaemic at baseline: not given, baseline definition of anaemia not stated, mean haemoglobin (SD) at baseline: iron arm: 11.5 (1.3) g/dL; placebo: 11.7 (1.2) g/dL

% malaria at baseline: not stated

Interventions

Ferric ammonium citrate oral drops, about 3 mg/kg/day elemental iron vs. daily oral placebo drops

Duration of treatment: 8 weeks

Duration of follow up: 4 weeks

Outcomes

Main objective/outcome: The haematological utility of iron supplementation in predominantly breast fed term low birth weight young infants

Review outcomes reported in the trial:

1. Haemoglobin (change)

2. Weight and height

Notes

Trial location: New Delhi, India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: twins, congenital malformations, past blood transfusion, adverse neonatal events requiring hospitalization, past blood sampling (> 10 mL), receiving iron supplementation, significant current morbidity, and maternal antepartum haemorrhage

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated random numbers
Allocation concealment (selection bias)Low riskCentral, sealed and opaque envelopes
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk62/73 evaluated

Aguayo 2000

Methods

Individually randomized

Trial years: not stated

Participants

73 randomized, 64 evaluated

Age: mean 110.9 months

Setting: school, urban

% anaemic at baseline: 0% (anaemia definition: Hb < 14.4 g/dL; cut-off value recommended for pre-school children living 4000m above sea level), mean haemoglobin (SD) at baseline: iron arm: 15.66 (0.60) g/dL; placebo: 15.74 (0.63) g/dL

% malaria at baseline: not stated

Interventions

Study arms.

1. Iron: ferrous sulfate tablet, about 0.43 mg/kg/d elemental iron (3 mg/kg/week)

2. Placebo: 1 tablet/week.

Duration of treatment: 18 weeks

Duration of follow-up: 18 weeks

Outcomes

Main objective/outcome: effect of weekly iron on growth and haemoglobin status in non-anaemic children

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (change)

3. Weight and height

Notes

Trial location: outskirts of La-Paz, Bolivia

Malaria endemicity: hypoendemic

Language of publication: English

Exclusion criteria: haemoglobin < 14.4 g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable with randomly assorted digits
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk64/73 evaluated

Akenzua 1985

Methods

Individually randomized

Trial years: not stated

Participants

112 randomized, 97 evaluated

Age: range 1 to 14 years

Setting: community, rural

% anaemic at baseline: 100% (anaemia definition: packed cell volume (PCV) < 33%), mean haemoglobin 10 g/dL

% malaria at baseline: not stated

Interventions

Study arms.

1. Unsupervised administration of: ferrous fumarate tablets, about 2 mg/kg/d plus folic acid tablets 5 mg/d plus anti-malaria (single dose of 5 mg/kg chloroquine orally).

2. Unsupervised administration of ferrous fumarate syrup, about 1.5 mg/kg/d plus folic acid tablets 5 mg/d plus anti-malaria (single dose of 5 mg/kg chloroquine orally).

3. Supervised administration of ferrous fumarate tablets, about 2 mg/kg/d plus folic acid tablets 5 mg/d plus anti-malaria (single dose of 5 mg/kg chloroquine orally).

4. Proguanil hydrochloride tablets, 50 mg daily.

5. Folic acid plus chloroquine.

6. Iron intramuscularly plus chloroquine.

7. Iron intramuscularly plus chloroquine plus folic acid.

Duration of treatment: 6 weeks

Duration of follow-up: 6 weeks

Outcomes

Main objective/outcome:

To determine more accurately the extent to which folate deficiency contributes to the anaemia of childhood in the community; to find out how the prevalence of anaemia in children can be reduced by 50 % or more; to decide on a cheap and effective supplementation programme as a public health measure applicable in the community

Review outcomes reported in the trial.

1. Anaemia.

2. Haemoglobin packed cell volume change.

Notes

Trial location: Nigeria

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: haemoglobinopathies; refusal of consent

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskPrepared set of random numbers
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk97/112 evaluated

Angeles 1993

Methods

Individually randomized

Trial years: not stated

Participants

80 randomized, 76 evaluated

Age: mean 37.3 months (range 2 to 5 years)

Setting: school, urban

% anaemic at baseline: 100% (anaemia definition: Hb < 11 g/dL), mean haemoglobin (SD) at baseline: iron arm: 10.2 (0.9) g/dL; placebo arm: 10.3 (0.8) g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: hydrated ferrous sulfate powder, about 2.8 mg/kg/d elemental iron plus vitamin C 20 mg daily

2. Vitamin C 20 mg daily

Duration of treatment: 8 weeks

Duration of follow up: 8 weeks

Outcomes

Main objective/outcome:

effect of iron supplementation on growth and haematological status

Review outcomes reported in the trial.:

1. Fever, respiratory infections, diarrhoea

2. Haemoglobin status (end and change)

3. Ferritin level

4. Weight and height (end and change)

Notes

Trial location: Jakarta, Indonesia

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: acute infections

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk76/80 evaluated

Ayoya 2009

Methods

Individually randomized

Trial years: not stated

Participants

218 randomized (to 2 arms included in review), 202 evaluated

Age: 7-12 years. Mean age per study arm: iron: 8.40 (SD 1.55), no iron: 8.82 (SD 1.51)

Setting: school, urban

% anaemic at baseline: 100% (anaemia definition: Hb < 12 g/dL), mean haemoglobin (SD) at baseline: iron arm: 10.4 (1.2) g/dL; no iron arm: 10.4 (1.0) g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron plus praziquantel: ferrous sulfate tablets, 60 mg elemental iron per day 5 days / week, estimated 2 mg/kg/d elemental iron plus praziquantel tablet 40 mg at enrolment and at 4 weeks

2. Praziquantel tablet 40 mg at enrolment and at 4 weeks

Two additional study arms excluded from review compared praziquantel plus multiple micronutrients (including iron); and praziquantel plus multiple micronutrients plus iron

Duration of treatment: 12 weeks

Duration of follow-up: 12 weeks

Outcomes

Main objective/outcome:

effect of iron supplementation on haematological status

Review outcomes reported in the trial:

1. Deaths

2. Clinical malaria, severe malaria (clinical malaria and high-grade parasitaemia), parasite density

3. Anaemia

4. Haemoglobin (end)

5. Ferritin

6. Admissions

Notes

Trial location: Bamako, Mali

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: haemoglobin <7 g/dLor >12 g/dL, hookworm infection

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerized individual randomization within strata of Hb and parasite load in blocks of 4
Allocation concealment (selection bias)Low riskInvestigator recruiting patient unaware of assignment
Blinding (performance bias and detection bias)
All outcomes
High riskOnly laboratory personnel who performed hematological and biochemical determinations were blinded
Incomplete outcome data (attrition bias)
Mortality
High risk202/218 evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk202/218 evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk202/218 evaluated

Baqui 2003

Methods

Individually randomized

Trial years: not stated

Participants

645 randomized, 249 evaluated

Age (per study): 5 to 6 months at enrolment

Setting: community

None were anaemic at baseline (anaemia: Hb < 9 g/dL), mean haemoglobin 10.5 g/dL

% malaria at baseline not described

Interventions

Type of iron: ferrous sulphate capsules orally about 0.43 mg/kg/day (20 mg elemental iron weekly) plus riboflavin 1 mg/week versus zinc plus riboflavin versus ferrous sulphate plus zinc versus micronutrient mix (not used in review) vs. riboflavin alone. Duration of treatment duration: 6 months

Duration of treatment: 6 months

Duration of follow-up: 6 months

Outcomes

Main objective/outcome:

effect of iron or zinc supplementation, or both, on rates of growth during 6 months of supplementation

Review outcomes reported in the trial:

1. Deaths

2. Any infection

3. Change in haemoglobin

4. Ferritin

5. Weight and height

6. Adverse events

Notes

Trial location: Bangladesh

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: low weight-for-age, Hb < 9 g/dL, any signs of neurological disorder, physical handicap, or chronic illness affecting feeding, activity, or cognitive development

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskBlock randomization was reportedly done
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind
Incomplete outcome data (attrition bias)
Mortality
Low riskAll randomized patients included in analysis
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot relevant
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High riskData available for 249/645 participants

Berger 1997

Methods

Individually randomized

Trial duration: March 1995 to November 1995

Participants

176 randomized, 173 evaluated

Age: 3.3 to 8.3 years, 96.3% were 4 to 6.9 years. Mean age per study arm: weekly iron: 67.8 SD 7.6 months, daily iron:69.6 SD 12.2 months, placebo: 67.2 SD 9.3 months

Setting: school

100% anaemia (Hb <11 g/dL) at baseline

% malaria at baseline: not stated

Interventions

Ferrous sulfate tablet 3 to 4 mg/kg/week vs. ferrous sulfate 3 to 4 mg/kg/day 5 days a week vs. placebo once weekly

Duration of treatment duration: 16 weeks

Duration of follow up: 16 weeks 

Outcomes

Main objective/outcome:

to compare the efficacy of weekly and daily iron on haemoglobin status of anaemic children

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end and change)

3. Protoporphyrin level

4. Weight and height (end)

Notes

Trial location: La Paz, Bolivia

Malaria endemicity: hypoendemicity

Language of publication: English

Exclusion criteria: Hb > 14.4 g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren were randomized into 3 groups
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High riskData available for 173/176 participants

Berger 2000

Methods

Individually randomized

Trial years: not stated

Participants

197 randomized, 163 evaluated

Age: 6 to 36 months. Mean age per study arm: intervention: 22.8 SD 8.42 months, placebo: 24.9 SD 8.3 months

Setting: community

% Anaemia (Hb < 11 g/dL) at baseline: iron arm: 84.5% placebo arm: 79.8%, mean haemoglobin: iron arm: 9.89 SD 1.16 g/dL, placebo arm: 10.04 SD 1.06 g/dL

% malaria at baseline: iron arm: 59.3, placebo arm: 63.6

Interventions

Iron betainate tablet 2 to 3 mg/kg/day elemental iron vs. placebo

Duration of treatment: 3 months

Duration of follow up: 9 months

Outcomes

Main objective/outcome:

Impact of iron supplementation on haematological status, cell-mediated immunity and susceptibility to infections

Review outcomes reported in the trial:

1. Parasitaemia (% plasmodial index), parasitaemia > 3000, malaria density

2. Anaemia

3. Diarrhoea

4. Respiratory infections

5. Haemoglobin (end and change)

6. Ferritin, total iron binding capacity (TIBC), protoporphyrin

Notes

Trial location: sea region, Togo

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: Hb < 8 g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomized assignment of children into an intervention and placebo groups
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double blind
Incomplete outcome data (attrition bias)
Mortality
High risk163 out of 197 participants were evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk163 out of 197 participants were evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk163 out of 197 participants were analysed

Berger 2006

Methods

Individually randomized

Trial duration: March 1998 to November 1998

Participants

988 randomized. 760 to 780 (depending on outcome assessed) evaluated

Age: mean 5.9 months (range: 4 to 7 months)

Setting: community, rural

% anaemia at baseline: 54.1% (defined Hb < 11 g/dL), mean haemoglobin 10.9 g/dL

% malaria at baseline: not stated

Interventions

Ferrous sulphate syrup 10 mg/day (about 1.5 mg/kg/d elemental iron) vs. zinc vs. ferrous sulphate plus zinc vs. placebo. 100,000 IU of vitamin A was given to all infants at the start of the study.

Duration of treatment: 6 months

Duration of follow up: 6 months

Outcomes

Main objective/outcome:

to evaluate the effect of combined iron–zinc supplementation on micronutrient status, growth and morbidity

Review outcomes reported in the trial:

1. Anaemia

2. Any infection

3. Respiratory infections

4. Diarrhoea

5. Haemoglobin (end and change)

6. Ferritin, zinc, TIBC

7. Weight and height

Notes

Location: district of Que Vo, 50 km northwest of Hanoi in the Red River Delta in Vietnam

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: chronic or acute illness, severe malnutrition or congenital abnormality, Hb < 7 g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk864/988 participants were evaluated

Bhatia 1993 (C)

Methods

Cluster-randomized

Trial years: not stated

Unit of randomization: 4 preschools

Average cluster size: 65.5

Adjustment for clustering: none

Methods of adjustment: not stated

Participants

4 pre-schools randomized (262 participants), 156 participants evaluated

Age: 3 to 5 years. Mean age per study arm:

iIron anaemic: 46.8 months

Iron non-anaemia: 58.3 months

Placebo anaemic: 46.2 months

Placebo non-anaemic: 49.6 months

Malaria endemicity: mesoendemicity

Setting: preschool

% Anaemia (Hb < 11 g/dL; Hb 7 to 10 moderate anaemia) at baseline: iron anaemic:100%, iron non-anaemia: 0.0%, placebo anaemic:100.0%, placebo non-anaemic: 0.0%, mean haemoglobin: iron anaemic: 9.2 SE 0.1, iron non-anaemia: 11.6 SE 0.1, placebo anaemic: 9.4 SE 8.1, placebo non-anaemic: 11.5 SE -0.2

% malaria at baseline: not stated

Interventions

Intervention arm:

Iron 40 mg elemental iron per day (3 mg/kg/day) for anaemic children vs. iron for non-anaemic children vs. placebo for anaemic children vs. placebo for non-anaemic children

Duration of treatment: 6 months

Duration of follow up: 6 months

Outcomes

Main objective/outcome:

1. To determine the growth status of moderately anaemic and non-anaemic (normal) young children living under similar environmental conditions

2. To evaluate the growth status of anaemic and normal children before and after supplementation with iron

Review outcomes reported in the trial:

1. Haemoglobin level (end and change)

2. Weight and height (end)

Notes

Location: Baroda City, India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: mild anaemia Hb <10.1 to 10.9 g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk2 out of 4 classes were randomly selected for treatment
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
High riskControl different from intervention
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNo description
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk156 out of 262 participants were evaluated

Charoenlarp 1973

Methods

Individually randomized

Trial years: not reported

Participants

460 randomized, 437 evaluated

Age: 5 to 14 years

Setting: school, rural

Mean haematocrit at baseline: placebo: 36.3 SD 2.7%, iron: 36.4 SD 2.6%, folic acid: 36.2 SD 2.6%, iron plus folic acid: 36.8 SD 2.4% months

% anaemia at baseline: 52%

% malaria at baseline: not stated

Interventions

Ferrous gluconate tablet once daily 5 days a week (about 1.1 mg/kd/d) vs. placebo vs. ferrous gluconate plus folic acid 10 mg once daily 5 days a week vs. folic acid

Duration of treatment: 3 months

Duration of follow-up: 3 months

Outcomes

Main objective/outcome:

to evaluate the haemoglobin values after iron and folic acid supplementation

Review outcomes reported in the trial:

1. Haemoglobin (change)

Notes

Trial location: Thailand

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: haematocrit levels within 3 SD of the initial mean values

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk437 out of 460 children evaluated

Chwang 1988

Methods

Individually randomized

Trial years: not stated

Participants

241 participants randomized and evaluated

Age range 8.2 to 13.5 years

Setting: community

Participants were stratified by anaemia status into 2 intervention groups, mean Hb for anaemic group was 9.7 g/dL and the non-anaemic group was 13.25 g/dL

% malaria at baseline: not stated

Interventions

Ferrous sulphate tablets 10 mg/day (2 mg/kg/day elemental iron) vs. saccharin + tapioca (placebo)

Duration of treatment: 12 weeks

Duration of follow up: 12 weeks

Outcomes

Main objective/outcome:

effect of oral iron on blood iron levels and growth

Review outcomes reported in the trial:

1. Haemoglobin (end)

2. Iron levels (end), TIBC

3. Weight and height (change, absolute values)

Notes

Trial location: 3 villages in subdistrict of Kalibawang in central Java, Indonesia

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: Hb 11.1 to 11.9 g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind but method not described
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskAll participants evaluated

de Silva 2003

Methods

Individually randomized

Trial years: not stated 

Participants

453 randomized, 363 evaluated

Age: 5 to 10 years

Setting: hospital

% anaemia (Hb < 11.5 g/dL) at baseline: 52.6%, mean haemoglobin 11.4 g/dL

% malaria at baseline: not reported

Interventions

Ferrous sulfate 60 mg/day elemental iron (3 mg/kg/day) vs. placebo

Duration of treatment: 8 weeks

Duration of follow up: 8 weeks

Outcomes

Main objective/outcome:

to evaluate the effects of iron supplementation on iron status and morbidity in children with or without infection

Review outcomes reported in the trial,

1. Anaemia (end).

2. Diarrhoea, respiratory infections.

3. Haemoglobin (change).

4. Ferritin.

5. Adverse events.

Notes

Trial location: 1 village in Sri Lanka

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: Hb < 7 g/dL, severe malnutrition, asthma, chronic diarrhoea 

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren were stratified by age and sex and were randomly assigned to receive iron or placebo on a 3:1 basis within each stratum
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High riskIn all 363 out of 453 participants evaluated

Desai 2003

Methods

Individually randomized

Trial duration: April to November 1999

Participants

546 randomized, 491 evaluated

Age range 2 to 36 months, mean for all groups= 11.6 months

Setting: community

100% anaemic at baseline (defined as Hb < 11 g/dL), mean haemoglobin 9.5 g/dL

20% to 28% malaria prevalence at baseline

Interventions

Ferrous sulfate suspension (40 mg/ml) 3 to 6 mg/kg/day elemental iron plus sulfadoxine-pyrimethamine 25/2.25 mg as a single dose at baseline, week 4 and 8 (IPT) vs. IPT vs. ferrous sulfate + sulfadoxine-pyrimethamine 25/2.25 mg as a single dose at baseline vs. placebo plus sulfadoxine-pyrimethamine 25/2.25 mg as a single dose at baseline

Duration of treatment: 8 weeks

Duration of follow-up: 24 weeks

Outcomes

Main objective/outcome: 

The efficacy of single and combined therapy with iron supplementation and IPT with SP in improving haemoglobin concentrations among anaemic preschool children

Review outcomes reported in the trial:

1. Deaths

2. Clinical malaria, parasitaemia, malaria density

3. Anaemia

4. Haemoglobin (end)

5. Clinic visits

Notes

Trial location: 15 villages in Asembo, Bondo district, Western Kenya

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: parasite count > 20,000, sickle cell disease

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number listing generated independently before the study
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind
Incomplete outcome data (attrition bias)
Mortality
High risk491/554 participants evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk8 were excluded before the first dose of interventions, 55 were lost to follow up, 13 died by week 24. 491/554 participants evaluated.
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk428/554 participants evaluated

Devaki 2007

Methods

Individually randomized

Trial duration: not stated

Participants

120 randomized, 115 evaluated

Age range: 15 to 18 years

Setting: school, urban

Four study groups. Haemoglobin at baseline: 1) placebo mean 13.6 SD 0.2 2) iron: mean 13.5 SD 0.23) iron supplementation for iron deficient children: mean 12.5 SD 0.2 4) iron supplementation for children with iron-deficiency anaemia (100% anaemic at baseline) mean 10.0 SD 0.2. Anaemia defined as Hb < 11 g/dL for boys, < 10.5 g/dL for girls and transferrin saturation < 16% for both sexes.

% malaria at baseline: not stated

Interventions

Iron (III)-hydroxide polymaltose complex 100 mg/day, 6 days a week (about 2.2 mg/kd/day elemental iron) vs. placebo vs. iron for iron deficient children vs. iron for iron deficient anaemic children

Duration of treatment: 8 months

Duration of follow up: 8 months

Outcomes

Main objective/outcome:

To evaluate the effects of iron supplementation on immunological parameters

Review outcomes reported in the trial:

1. Haemoglobin (end)

2. Ferritin, TIBC

3. Adverse effects

Notes

Trial location: Tirupati (Andhra Pradesh State), South India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: haemoglobin per group

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk115 out of 120 children evaluated (2 and 3 drop-outs in the ID and IDA groups)

Dossa 2001a

Methods

Individually randomized

Trial duration: not stated

Participants

177 participants randomized

Age range 3 to 5 years. Mean 46 months.

Setting: community, rural

76% anaemic at baseline, mean haemoglobin 10.5 g/dL

% malaria at baseline: not stated

Interventions

Ferrous sulphate 60 mg/day elemental iron (about 4.6 mg/kg/d) plus albendazole 200 mg/day for 3 days; 1 month later same dose vs. ferrous sulphate plus placebo plus albendazole plus placebo vs. placebo plus placebo

Duration of treatment: 3 months

Duration of follow-up: 10 months

Outcomes

Main objective/outcome:

The effects of iron and deworming treatments on appetite and physical growth performance in preschool children

Review outcomes reported in the trial:

1. Deaths

2. Haemoglobin (end and change)

3. Weight and height

Notes

Trial location: Agblangandan, south Benin 10 km from Cotonou, Benin

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren were selected and randomly assigned to 4 treatment groups
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
Mortality
High risk138/177 participants evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk138/177 participants evaluated

Dossa 2001b

Methods

Individually randomized

Trial duration: not stated

Participants

154 participants randomized, but only 76 in the relevant intervention groups, 74 were evaluated

Age range 3 to 30 months, mean 22 months

Setting: community

100% anaemic at baseline, mean haemoglobin 9.5 g/dL

% malaria at baseline: not stated

Interventions

Ferrous fumarate 66 mg/day elemental iron (about 7.3 mg/kg/d) vs. placebo (Seresta forte). Both arms received mebendazole 200 mg/d for 3 days

Duration of treatment duration: 6 weeks

Duration of follow up: 5.5 months

Outcomes

Main objective/outcome:

The effects of iron and deworming treatments on physical growth performance, haemoglobin level, and intestinal helminth egg loads in preschool children

Review outcomes reported in the trial:

1. Deaths

2. Haemoglobin (end and change)

3. Fever, diarrhoea

4. Weight and height change

Notes

Trial location: Ze, south Benin 50 km from Cotonou, Benin

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers
Allocation concealment (selection bias)Low riskA researcher not involved in the trial allocated children by the randomization code
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, placebo used
Incomplete outcome data (attrition bias)
Mortality
High risk74/76 participants evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk74/76 participants evaluated

Fahmida 2007

Methods

Individually randomized

Trial duration: July 1998 until March 1999

Participants

800 participants randomized, but only 392 in the relevant intervention groups. All were evaluated

Age range 3 to 6 months, mean 5.1 ± 1.1 months

Setting: community

83% anaemic at baseline, mean haemoglobin 9.6 g/dL

% malaria at baseline: not stated

Interventions

Iron sulfate syrup 10 mg/day (about 2 mg/kg/day elemental iron) plus zinc sulfate vs. zinc sulfate vs. iron plus zinc plus vitamin (not used in review) vs. placebo (not used in review)

Duration of treatment duration: 6 months

Duration of follow-up: 12 months

Outcomes

Main objective/outcome:

To investigate the effect of supplementation on improving infants' micronutrient status and linear growth

Review outcomes reported in the trial:

1. Clinical malaria

2. Deaths

3. Anaemia

4. Fever, diarrhoea, pneumonia

5. Haemoglobin (end and change)

6. Ferritin, TIBC

7. Weight and height (end)

Notes

Trial location: East Lombok, West Nusa Tenggara, Indonesia

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: congenital abnormalities, Hb < 6 g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAllocation to supplementation groups was conducted using systematic random sampling in each sex group. The randomization of the subjects in the study was done, firstly, by assigning to each intervention group codes A to D ( randomly assigned to placebo; zinc; zinc plus iron; and zinc plus iron plus vitamin A groups, respectively), then each child was randomly assigned to each A to D category using systematic random sampling
Allocation concealment (selection bias)Low riskCentral
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind
Incomplete outcome data (attrition bias)
Mortality
Low riskAll participants evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk314/392 participants evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk308/392 participants evaluated

Gara 2010

Methods

Individually randomized

Trial duration: December 2004 to June 2005

Participants

In total 82 participants randomized, 80 evaluated

Age: 6 to 60 months; Age per study group: iron plus folate: mean 26.78 (SD 17.8), folate: mean 32.5 (SD 17.4) months

Setting: hospital / community

100% anaemic (haematocrit < 33%) at baseline, mean haematocrit (%): iron plus folate 28.4 (SD 3.2), folate: 28.5 (SD 2.7)

% malaria at baseline: 100% with clinical malaria

Interventions

Ferric ammonium citrate syrup 2 mg/kg/day plus folic acid 5 mg/day vs. folic acid 5 mg/day. All children received antimalaria treatment with chloroquine and sulfadoxine-pyrimethamine

Duration of treatment duration: 1 month

Duration of follow-up: 1 month

Outcomes

Main objective/outcome:

To test the hypothesis that iron with folate is more effective than folate alone in the haematological recovery of children with malarial anaemia

Review outcomes reported in the trial.

1. Deaths.

2. Admissions.

3. Anaemia.

4. Haemoglobin (end and change).

Notes

Trial location: Jos, Nigeria

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: Severe malaria, associated illness requiring admission

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskLottery method in blocks of 20
Allocation concealment (selection bias)Low riskOpaque envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskOpen study
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk80/82 patients evaluated

Gebresellassie 1996

Methods

Individually randomized

Trial duration: February 1994 to July 1994

Participants

500 participants randomized, 480 evaluated

Age range 5 to 14 years, mean 10.3 years

Setting: school

91% anaemic (Hb < 12 g/dL) at baseline, mean haemoglobin 9.5 g/dL

% malaria at baseline: 98% with ≥1 episodes) of malaria attack in the past 14 days; negative malaria smears on initial screening for all

Interventions

Ferrous sulphate 60 mg/day elemental iron (about 2.5 mg/kg/day) vs. placebo

Duration of treatment duration: 3 months

Duration of follow-up: 6 months

Outcomes

Main objective/outcome:

To assess the effect of oral iron on host susceptibility to malaria infection in children with mild to moderate iron deficiency anaemia

Review outcomes reported in the trial:

1. Clinical malaria, cumulative incidence of parasitaemia, parasite density, parasitaemia > 5000/μl

2. Deaths.

3. Anaemia.

4. Haemoglobin (end).

5. Ferritin.

Notes

Trial location: Northwest Ethiopia, Beles Valley (Pawe), Ethiopia

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: Hb > 12 or < 5, serum ferritin > 12, positive malaria smears on initial screening, concurrent major illnesses; no iron supplementation past 6 m, < 12 m residence in the area

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated list of random numbers
Allocation concealment (selection bias)Low riskCentral procedure
Blinding (performance bias and detection bias)
All outcomes
Low riskField workers, technicians, parents and children blinded. Placebo used in coded bottles
Incomplete outcome data (attrition bias)
Mortality
High risk480 out of 500 were evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk480 out of 500 were evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk480 out of 500 were evaluated

Gopaldas 1983

Methods

Individually randomized

Trial duration: not stated

Participants

170 participants randomized (90 participants for 5 to 9 year age group and 80 participants for 10 to 13 year age group)

Age range: 5 to 9 years and 10 to 13 years (results reported separately for these age groups)

Setting: school, urban

Anaemic at baseline: 93% (Indian definition), 94% (WHO definition) for 5 to 9 year olds; (WHO definition: Hb < 12 g/dL, Indian definition: Hb < 11 g/dL), mean haemoglobin 9.6 g/dL

Malaria at baseline: not stated

Interventions

Iron 20 mg/day elemental iron (about 0.7 mg/kg/day) plus folic acid 100 mg/day vs. placebo vs. iron plus folic acid plus mebendazole 100 mg BID for 3 days (not used in review) vs. iron plus folic acid plus mebendazole 100 mg BID for 3 days (not used in review) plus vitamin A vs. mebendazole plus tinidazole 50 mg/kg for 3 days (not used in review)

Duration of treatment: 4 months

Duration of follow-up: 12 months

Outcomes

Main objective/outcome:

To evaluate the feasibility, efficiency, nutritional impact, and cost of delivering differential packages of health and nutrient inputs for 2 school terms

Review outcomes reported in the trial:

1. Haemoglobin (end)

Notes

Trial location: Baroda, India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: boys, income, no consent, participation in another nutritional programme, age unknown

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskIntention-to-treat analysis

Gopaldas 1985

Methods

Individually randomized

Trial duration: not stated

Participants

210 participants randomized

Age range: 8 to 15 years

Setting: school, rural

Hb at baseline: 10.78 SD 0.15 g/dL

% malaria at baseline: not stated

Interventions

Ferrous sulphate 30 mg/day elemental iron vs. ferrous sulfate 40 mg/day elemental iron (1 to 1.3 mg/kd/day) vs. placebo

Duration of treatment: 2 months

Duration of follow-up: 4 months

Outcomes

Main objective/outcome:

The effects of iron supplementation on haemoglobin level

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end and change)

Notes

Trial location: Baroda, Balwadi children, India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStratified by age and randomized
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
High riskPatient blinded ("the study was blind. Investigators recognized drugs only by their colour and the children did not know what they are receiving"). Intervention tablets were sugar coated.
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskIntention-to-treat analysis

Greisen 1986 (C)

Methods

Cluster randomized

Trial duration: May to June 1981

Unit of randomization: 12 school classes

Average cluster size: 38.7

Adjustment for clustering: none

Methods of adjustment: none

Participants

12 school classes were divided in 2 equal groups according to their listing on the class registers yielding 24 groups, overall 464 children

Age range: 5 to 15 years

Setting: school, rural

28% anaemic at baseline (Hb < 12 g/dL), mean haemoglobin 12.4 g/dL

% malaria at baseline: not stated

Interventions

Iron-fumarate 66 mg/day on school days (about 2 mg/kd/day elemental iron) plus placebo vs. iron-fumarate plus chloroquine 300 mg at baseline and 28 days plus tetrachlorethylene liquid 2.5 ml at baseline vs. iron-fumarate plus chloroquine vs. iron-fumarate plus tetrachloroethylene

Duration of treatment: 6 weeks

Duration of follow-up: 6 weeks

Outcomes

Main objective/outcome:

To evaluate association between anaemia and running distance

Review outcomes reported in the trial:

1. Deaths

2. Haemoglobin (end and change)

Notes

Trial location: Namwala township in the great plains of the Kafue river, Zambia

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: acute illness, increased reticulocyte count

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers (12 school classes were divided in 2 equal groups according to their listing on the class registers, yielding 24 groups)
Allocation concealment (selection bias)Low riskCentral procedure (at the pharmacy)
Blinding (performance bias and detection bias)
All outcomes
Low riskOpen
Incomplete outcome data (attrition bias)
Mortality
High risk225 out of 464 were evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk225 out of 464 were evaluated

Hall 2002 (C)

Methods

Cluster randomized

Trial duration: started January 2000

Unit of randomization: school

Number of units randomized: 60 schools

Average cluster size: authors statement: "We did not look at size of school or sub-district. But since they were all community schools, they were all small rural schools".

Adjustment for clustering: not mentioned

Methods of adjustment: no adjustment method was used

Participants

Number of children: 1201 randomized, 1113 evaluated

Age range: mean 11.4 years range (6 to 19 years)

Setting: school; rural

% anaemic at baseline: 55.8% (anaemia definition: age 5 to 11.99 years Hb <11.5 g/dL; age 12 to 14.99 years Hb < 12 g/dL; > 15 years - boys Hb < 13 g/dL, girls Hb < 12 g/dL), mean haemoglobin 10.5 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: ferrous sulphate tablets, about 0.25 mg/kg/d elemental iron plus folic acid plus albendazole.

2. Control: albendazole only.

All children received vitamin A before intervention

Duration of treatment: 10 weeks

Duration of follow-up: 2 weeks after end of treatment, 14 to 16 weeks from baseline survey weeks

Outcomes

Main objective/outcome:

To assess the effect of weekly iron on haemoglobin status

Review outcomes reported in the trial:

1. Deaths

2. Prevalence of anaemia

3. Haemoglobin (end and change)

4. Growth parameters

5. Adverse events

Notes

Trial location: Kolondieba district in Sikasso region of south eastern Mali

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: severe anaemia (haemoglobin < 8 g/dL)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table
Allocation concealment (selection bias)Unclear riskNor reported
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
High risk1113 out of 1201 were evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNor reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk1113 out of 1201 were evaluated

Harvey 1989

Methods

Individually randomized

Trial duration: started June 1985

Participants

318 randomized, up to 298 evaluated for malaria outcomes, 318 evaluated for haemoglobin

Age: mean 9.7 years (range 8 to 12 years)

Setting: school, rural

% anaemic at baseline: 92% (anaemia definition: Hb < 12 g/dL), mean haemoglobin 10.7 g/dL

% malaria at baseline: 70.5%

Interventions

Study arms:

1. Iron: ferrous sulphate tablets, about 3.8 mg/kg/d elemental iron

2. Placebo: 75% cellulose, 25% lactose tablets

Duration of treatment: 16 weeks

Duration of follow-up: 24 weeks

Outcomes

Main objective/outcome:

To investigate the effects of iron therapy and changes in iron status on malarial infection in children with mild to moderate iron deficiency and some immunity to malaria

Review outcomes reported in the trial:

1. Malaria (clinical and uncomplicated)

2. Haemoglobin (end and change)

3. Adherence

Notes

Trial location: north coast,, Madang, Papua New Guinea

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: Hb < 8 g/dL or > 12 g/dL, signs of puberty

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskOf 318 patients authors formed 156 matched pairs based on Hb, age and oval-shaped RBC. Members of each pair were randomized to either iron or placebo
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk298 and 279 children analysed at 16 weeks and 24 weeks respectively
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskIntention-to-treat

Hess 2002

Methods

Individually randomized

Trial duration: 1999 to 2000

Participants

169 randomized, 166 evaluated

Age: mean 8.5 years (range 5 to 14 years)

Setting: school, rural

% anaemic at baseline:

Iron arm: 84%; placebo arm: 85% (anaemia definition: Hb < 12 g/dL in age 12 years and above and Hb < 11.5 g/dL in age 5 to 11 years), mean haemoglobin 10.9 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: ferrous sulphate tablets, about 1 mg/kg/d elemental iron plus albendazole single dose (400 mg) at baseline.

2. Placebo: identical looking tablets plus albendazole single dose (400 mg) at baseline

Half received a single dose of iodinized poppy seed oil containing 200 mg

Duration of treatment: 16 weeks

Duration of follow-up: 20 weeks

Outcomes

Main objective/outcome:

To investigate change in response to iodine after iron supplementation

Review outcomes reported in the trial:

1. Prevalence of anaemia

2. Haemoglobin (end and change)

3. Ferritin (end)

4. Zinc (end)

5. TIBC

6. Growth parameters

Notes

Trial location: Danané health district, an area of endemic goitre in the mountains of western Côte d'Ivoire

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: Hb < 8 g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk166/169 evaluated

Hettiarachchi 2008 (C)

Methods

Cluster randomized

Trial duration: not stated

Unit of randomization: class

Number of units randomized: not stated

Average cluster size: not stated

Adjustment for clustering: not mentioned

Methods of adjustment: no adjustment method was stated

Participants

Number of children: 821 randomized, 774 evaluated

Age: mean 13.5 years (range 12 to 16 years)

Setting: school, urban and rural

% anaemic at baseline: 57.1% (anaemia definition: Hb < 12 g/dL), mean haemoglobin 11.6 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: ferrous fumarate capsules, about 1.3 mg/kg/d elemental iron

2. Zinc: zinc sulphate, 14 mg per day

3. Iron + zinc: same doses as above

4. Placebo: anhydrous lactose

All arms received mebendazole tablets 500 mg single dose 2 weeks before study

Duration of treatment: 6 months

Duration of follow-up: 6 months

Outcomes

Main objective/outcome:

To assess efficacy of iron and zinc in improving anthropometry, Hb, Zinc and ferritin

Review outcomes reported in the trial:

1. Prevalence of anaemia

2. Haemoglobin (end and change)

3. Ferritin (end)

4. Growth parameters (end)

Notes

Trial location: Galle district, Sri Lanka

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: haemoglobin < 8 g/dL, acute or chronic disease, inflammatory conditions, drug consumption other than paracetamol or antihistamines, currently on nutritional supplementation, donated or received blood the last 4 months

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk774/821 evaluated

Idjradinata 1993

Methods

Individually randomized

Trial duration: not stated

Participants

126 randomized, 119 evaluated

Age: mean 14.4 months (range 12 to 18 months)

Setting: community, urban

% anaemic at baseline: 40% iron-deficiency anaemia ( Hb 10.5 g/dL or less, transferrin saturation 10% or less and ferritin 12 μg/L or less), mean haemoglobin 11.5 g/dL

% malaria at baseline: not stated

Interventions

Study arms.

1. Iron for iron-deficiency anaemia: ferrous sulphate syrup, about 3 mg/kg/day elemental iron

2. Iron for iron-deficient without anaemia: same as above

3. Iron for iron-sufficient: same as above

4. Placebo for iron-deficiency anaemia: similar in appearance and taste syrup

5. Placebo for iron-deficient without anaemia: same as above

6. Placebo for iron-sufficient: same as above

Duration of treatment: 4 months

Duration of follow-up: 4 months

Outcomes

Main objective/outcome:

To investigate effects of iron supplementation on mental and motor development of iron deficient infants

Review outcomes reported in the trial:

1. Haemoglobin (end)

2. Prevalence of anaemia

3. Infection episodes

4. Ferritin (end)

5. TIBC (end)

6. Growth parameters (end and change)

Notes

Trial location: Bandung, Indonesia

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria:

Included: birthweight > 2500 g, singleton, no major congenital anomalies or perinatal complications, no jaundice treated with phototherapy, no hospital admission or supplementation with micronutrients during the 6 months before trial, no neuromotor delay, no chronic illness or folic acid deficiency, Hb 8 g/dL or more, no signs of abnormal Hb or thalassaemia, weight, height, and head circumference within 2SD

Excluded: Hb between 10.5 to 12 g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers separately for each iron status class (iron deficiency anaemia and iron deficiency, iron sufficiency)
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk119/126 evaluated

Kapur 2003

Methods

Individually randomized

Trial duration: not stated

Participants

545 randomized, 451 consented and actually included, 232 evaluated

Age: mean 20.6 months (range 9 to 36 months)

Setting: community, urban

% anaemic at baseline: 57.3% (anaemia definition: Hb < 11 g/dL), mean haemoglobin 10.6 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Nutrition education only: formal meetings with mothers

2. Iron: ferium, about 0.35 mg/kg/d elemental iron

3. Nutrition education plus iron: ferium, about 0.35 mg/kg/day

4. Placebo: sugar syrup weekly

Duration of treatment: 8 weeks

Duration of follow up:16 weeks

Outcomes

Main objective/outcome:

To compare the effect of nutrition education and/or iron on iron status

Review outcomes reported in the trial:

1. Haemoglobin (end and change)

2. Ferritin (end)

3. Adverse events

Notes

Trial location: Delhi, India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table
Allocation concealment (selection bias)Low riskSealed envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk232 out of 545 evaluated

Kashyap 1987

Methods

Individually randomized

Trial duration: not stated

Participants

166 randomized, 166 evaluated

Age: range 8 to 15 years

Setting: school, urban

% anaemic at baseline: 70% (anaemia definition: Hb < 11 g/dL), mean haemoglobin 10.3 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: ferrous sulphate tablets, about 1.7 mg/kg/d elemental iron

2. Placebo: sugar tablets

Duration of treatment: 120 days of active supplementation during 8-month period

Duration of follow-up: end of treatment, 4 months after the end of treatment

Outcomes

Main objective/outcome:

To evaluate the effect of iron supplementation on cognitive function

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end)

3. Iron (end)

4. Ferritin (end)

Notes

Trial location: Baroda, India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: boys, a level of family income exceeding a certain cut-off

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk83 matched pairs, 1 subject from each pair was randomly assigned to either iron or placebo
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskIntention-to-treat

Kianfar 1999

Methods

Individually randomized

Trial duration: winter 1996 to spring 1997

Participants

523 randomized, 523 evaluated

Age: mean 16.3 years

Setting: school, urban

% anaemic at baseline: 50% (anaemia definition: Hb < 12 g/dL in Rashat and < 12.7 g/dL in Zahedan (adjusted for altitude)), mean haemoglobin 12.5 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Daily iron for anaemic: ferrous sulphate tablets, about 1 mg/kg/d elemental iron

2. Daily iron for non anaemic: same as above

3. Twice weekly iron for anaemic: ferrous sulphate tablets, about 0.3 mg/kg/d

4. Twice weekly iron for non anaemic: same as above

5. Once weekly iron for anaemic: ferrous sulphate tablets, about 0.15 mg/kg/d

6. Once weekly iron for non anaemic: same as above

7. Control anaemic: no treatment

8. Control non anaemic: no treatment

Duration of treatment: 3 months

Duration of follow up: 3 months

Outcomes

Main objective/outcome:

To determine effects of daily and intermittent iron on haemoglobin

Review outcomes reported in the trial:

1. Prevalence of anaemia

2. Adherence

3. Haemoglobin (change)

4. Ferritin (end)

5. Adverse events

Notes

Trial location: Zahedan and Rashat (capitals of Sistan-Baluchestan and Gilan provinces), Iran)

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskAnalysis by intention-to-treat

Latham 1990

Methods

Individually randomized

Trial duration: April to November 1986

Participants

55 randomized, 54 evaluated

Age: mean 8 years

Setting: school

% anaemic at baseline: not stated (anaemia definition: Hb < 12 g/dL), mean haemoglobin (SE): iron arm: 11.6 (0.18) g/dL; placebo arm: 11.5 (0.18) g/dL

% malaria at baseline: iron arm: 76%, placebo arm: 46%

Interventions

Study arms:

1. Iron: ferrous sulphate tablets, about 2.85 mg/kg/d elemental iron

2. Placebo: saccharin tablets

All groups received albendazole tablets 400 mg single dose once after 32 weeks

Duration of treatment: 15 weeks

Duration of follow up: 32 weeks

Outcomes

Main objective/outcome:

To determine whether iron given to school children in Kenya improves growth

Review outcomes reported in the trial:

1. Uncomplicated malaria

2. Death

3. Malaria density

4. Haemoglobin (end and change)

5. Growth parameters (end and change)

Notes

Trial location: Kwale district, Coast Province, south of Mombasa, Kenya

Malaria endemicity: holoendemic, undertaken during rainy season

Language of publication: English

Exclusion criteria: haematuria and proteinuria (indicative of Schistosoma haematobium), absence on the day of first examination, serious disease or malnutrition, Hb < 8 g/dL, heavy infections with hookworms (> 10,000 eggs per gram stool), and refusal to participate

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren were paired by gender within the Hb rankings, from each pair one was randomly assigned to placebo and the other to iron
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear riskSaccharin used as placebo
Incomplete outcome data (attrition bias)
Mortality
High risk54 out of 55 evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk54 out of 55 evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk54 out of 55 evaluated

Lawless 1994

Methods

Individually randomized

Trial duration: March to July 1990

Participants

87 randomized, 86 evaluated

Age: mean 8.7 years (range 6 to 11 years)

Setting: school, rural

% anaemia at baseline: 75.5% (anaemia definition: Hb < 12 g/dL), mean haemoglobin 11.1 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: ferrous sulphate sustained release capsules, about 1.4 mg/kg/d elemental iron

2. Placebo: identical placebo capsules

Duration of treatment: 14 weeks

Duration of follow up: 14 weeks

Outcomes

Main objective/outcome:

To determine effects of iron given to school children in Kenya on appetite and growth

Review outcomes reported in the trial:

1. Clinical malaria

2. Diarrhoea

3. Haemoglobin (end and change)

4. Ferritin (end)

5. Growth parameters (change)

Notes

Trial location: Coast Province, Shamu village, Kenya

Malaria endemicity: holoendemic

Language of publication: English

Exclusion criteria: Hb < 8 g/dL, heavy hookworm infection (>10,000 eggs/gram faeces), hematuria

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk86/87 evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk86/87 evaluated

Leenstra 2009

Methods

Individually randomized

Trial duration: April to November 1998

Participants

279 randomized, 279 evaluated

Age: mean 13.8 years (range 12 to 18 years)

Setting: school, urban

% anaemia at baseline: 30.5% (anaemia definition: Hb < 12 g/dL), mean haemoglobin 12.8 g/dL

% malaria at baseline: 25.4%

Interventions

Study arms:

1. Iron plus vitamin A: ferrous sulphate tablets weekly, about 0.4 mg/kg/d elemental iron + vitamin A capsule 25,000U per week

2. Iron only: same as above

3. Vitamin A only: same dosage as above

4.Placebo

Duration of treatment: 5 months

Duration of follow-up: 5 months

Outcomes

Main objective/outcome:

To determine effects of iron and vitamin A on haemoglobin, iron status, malaria, and other morbidities in schoolgirls

Review outcomes reported in the trial:

1. Clinical malaria

2. Severe malaria

3. Infections

4. Adverse events

Notes

Trial location: Kisumu City, on shores of lake Victoria, Nyanza province, western Kenya

Malaria endemicity: mesoendemic, undertaken during rainy season

Language of publication: English

Exclusion criteria: Hb < 7 g/dL, severe vitamin A deficiency (xerophthalmia), pregnancy, concomitant disease requiring hospitalization

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Low riskIntention-to-treat
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Unclear riskNot evaluated

Lind 2004

Methods

Individually randomized

Trial duration: July 1997 to May 1999

Participants

680 randomized, 680 evaluated for mortality, 549 evaluated for anaemia

Age: mean 6.2 months

Setting: community, rural

% anaemia at baseline: 41% (anaemia definition: Hb < 11 g/dL), mean haemoglobin 11.4 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Placebo: syrup

2. Iron: ferrous sulphate syrup daily, about 1.7 mg/kg/d elemental iron

3. Zinc: zinc syrup 10 mg once a day

4. Iron plus zinc: same doses as above

Each dose of all supplements included 30 mg ascorbic acid

Duration of treatment: 6 months

Duration of follow up: 6 months

Outcomes

Main objective/outcome:

To determine effect of iron, zinc or both on growth, psychomotor development and incidence of infectious diseases

Review outcomes reported in the trial:

1. Anaemia prevalence

2. Death

3. Total infections

4. Diarrhoea

5. Pneumonia

6. Haemoglobin (end)

7. Ferritin (end)

8. Growth parameters (end)

9. Adverse effects

8. TIBC (end)

Notes

Trial location: Purworejo, central Java, Indonesia

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: metabolic or neurologic disorders; physical handicaps affecting development, feeding, or activity;severe or protracted illness; Hb < 9 g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPlanned and generated by an independent statistician and was performed in blocks of 20; randomization list
Allocation concealment (selection bias)Low riskPlanned and generated by an independent statistician and was performed in blocks of 20; randomization list
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind (researchers and participants blinded)
Incomplete outcome data (attrition bias)
Mortality
Low riskAnalysis by intention-to-treat
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk549/680 evaluated

Majumdar 2003

Methods

Individually randomized

Trial duration: not stated

Participants

126 randomized, 100 evaluated

Age: range 6 to 24 months

Setting: community, urban

% anaemia at baseline: 0% (anaemia definition: Hb < 11 g/dL), mean haemoglobin 13.9 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: iron syrup daily, about 2 mg/kg/d elemental iron

2. Placebo: identical placebo

Duration of treatment: 4 months

Duration of follow-up: 4 months

Outcomes

Main objective/outcome:

Effect of iron therapy on growth and Hb status

Review outcomes reported in the trial:

1. Haemoglobin (end and change)

2. Ferritin (end)

3. Weight and height (change)

Notes

Trial location: New Delhi, India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: major congenital anomaly, prenatal complication, hospital admission or iron supplementation during the months before enrolment, chronic illness, anaemia other than iron deficiency, recent blood transfusion

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Low riskConsecutively numbered bottles with code known only to the nurse
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk100/126 evaluated

Massaga 2003

Methods

Individually randomized

Trial duration: June 1999 to May 2000

Participants

291 randomized, 291 evaluated

Age: mean 14.3 weeks

Setting: community, rural

% anaemia at baseline: 0% (anaemia definition: PCV < 24%), mean haemoglobin 9.9 g/dL

% malaria at baseline: mean 31.5%

Interventions

Study arms:

1. Iron: ferric ammonium citrate suspension daily, about 7.5 mg/kg/d elemental iron

2. Placebo oral suspension

3. Iron as described above + amodiaquine oral suspension 25 mg/kg once every 2 months (overall three doses).

4. Amodiaquine only as described above.

Duration of treatment: 6 months

Duration of follow-up: 10 months

Outcomes

Main objective/outcome: Infections

Review outcomes reported in the trial:

1. Malaria

2. Anaemia

3. Death

Notes

Trial location: Muheza district, north-eastern Tanzania

Malaria endemicity: holoendemic

Language of publication: English

Exclusion criteria: infants with congenital malformation, conditions that needed hospital treatment, fever within preceding 2 weeks, packed cell volume < 24%, participants on chemoprophylaxis

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated
Allocation concealment (selection bias)Low riskCentral
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
Low riskIntention-to-treat
Incomplete outcome data (attrition bias)
Malaria
Low riskIntention-to-treat
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskIntention-to-treat

Mebrahtu 2004 (C)

Methods

Cluster randomized

Trial duration: 1996 to 1997

Unit of randomization: household

Number of units randomized: 451 households

Average cluster size: 1.5 children per household

Adjustment for clustering: yes

Methods of adjustment: generalized estimating equation approach was used to account for repeated measurements in children

Participants

684 children randomized, 684 evaluated for mortality, 614 evaluated for malaria, 459 evaluated for anaemia

Age: mean 33.4 months (range 4 to 71 months)

Setting: community, rural

% anaemia at baseline: 94.40% (anaemia definition: Hb < 11 g/dL), mean haemoglobin 8.7 g/dL

% malaria at baseline: not stated

Interventions

Study arms.

1. Iron: ferrous sulphate syrup daily, about 1 mg/kg/d elemental iron.

2. Placebo syrup.

Randomization was also done by child to oral mebendazole 500 mg every 3 months; vs. placebo

Duration of treatment: 12 months

Duration of follow-up: 12 months

Outcomes

Main objective/outcome:

To assess the effect of low-dose, long-term iron supplementation on malaria infection

Review outcomes reported in the trial:

1. Malaria (any malaria, severe malaria)

2. Mortality

3. Haemoglobin (end)

4. Ferritin (end)

Notes

Trial location: Pemba Island, Tanzania

Malaria endemicity: holoendemic

Language of publication: English

Exclusion criteria: severe anaemia (Hb < 7 g/dL)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description
Allocation concealment (selection bias)Low riskPharmacy, sealed envelopes
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
Low riskIntention-to-treat
Incomplete outcome data (attrition bias)
Malaria
High risk614/684 evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk459/684 evaluated

Mejia 1988

Methods

Individually randomized

Trial duration: not stated

Participants

115 randomized, 99 evaluated

Age: range 1 to 8 years

Setting: community, rural and urban

% anaemia at baseline: 100% (anaemia definition: haematocrit < 1.5 SD below the value for age and place), mean haemoglobin 10.4 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: ferrous sulphate syrup, about 3 mg/kg/d elemental iron

2. Vitamin A syrup 10,000 IU/d

3. Iron plus vitamin A as described above

4. Placebo syrup

Duration of treatment: 2 months

Duration of follow-up: 2 months

Outcomes

Main objective/outcome:

Effect of vitamin A ± iron on haematological status

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end and change)

3. Ferritin (end)

Notes

Trial location: Guatemala Cty and smaller cities, Guatemala

Malaria endemicity: hypoendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe children names were randomly drawn as in a raffle and assigned sequentially to groups I-IV
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk99/115 evaluated

Menendez 1997

Methods

Individually randomized

Trial duration: 1995

Participants

832 randomized, 832 evaluated

Age: range 8 to 48 weeks

Setting: community, rural

% anaemia at baseline: not stated

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: ferrous glycine sulphate syrup daily, about 2 mg/kg/d elemental iron

2. Placebo syrup

3. Iron (same as above) plus pyrimethamine plus dapsone (Deltaprim) syrup 3.125 mg plus 25 mg once weekly

4. Pyrimethamine plus dapsone (Deltaprim) alone, as described above

Duration of treatment: iron; 16 weeks, antimalarial; 40 weeks

Duration of follow-up: 1 year

Outcomes

Main objective/outcome:

Haemoglobin, anaemia and iron-related outcomes

Review outcomes reported in the trial:

1. Malaria

2. Mortality

3. Anaemia

4. Hospitalizations

Notes

Trial location: Ifakara, Kilombero District, Morogoro Region, south-eastern Tanzania

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: packed cell volume < 25%

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequential numbers of a randomization code
Allocation concealment (selection bias)Low riskRandomization code kept by an independent monitor - central
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double blind
Incomplete outcome data (attrition bias)
Mortality
Low riskIntention-to-treat
Incomplete outcome data (attrition bias)
Malaria
Low riskIntention-to-treat
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskIntention-to-treat

Mwanri 2000

Methods

Individually randomized

Trial duration: not stated

Participants

136 randomized, 135 evaluated

Age: mean 10.8 (range 9 to 12 years)

Setting: school, rural     

% anaemia: at baseline: 100% (anaemia definition: Hb < 12 g/dL), mean haemoglobin 10.5 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: ferrous sulphate tablets thrice weekly, about 0.65mg/kg/d elemental iron

2. Vitamin A (retinyl acetate) 5000 IU thrice weekly

3. Iron plus vitamin A (both as described above)

4. Placebo tablets

All subjects were dewormed for helminthiasis 2 weeks before baseline survey

Duration of treatment: 3 months

Duration of follow-up: 3 months

Outcomes

Main objective/outcome:

Effects of dietary supplements on anaemia and growth

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (change)

3. Weight and height changes

Notes

Trial location: Bagamoyo District, coastal area of Tanzania

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: chronic illnesses, physical impairments, severe anaemia (Hb < 8 g/dL)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe RAND function of Excel was used to implement randomization
Allocation concealment (selection bias)Low riskPharmacy
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk135/136 evaluated

Nagpal 2004

Methods

Individually randomized

Trial duration: April 1999 to March 2000

Participants

100 randomized, 71 evaluated

Age: mean 5.25 months (range 4 to 6 months)

Setting: community, urban

% anaemia at baseline: not stated (anaemia definition Hb < 11 g/dL), mean haemoglobin 11.2 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: ferric ammonium citrate drops daily, about 2 mg/kg/day elemental iron

2. Placebo: identical solution

Duration of treatment: 8 weeks

Duration of follow-up: 8 weeks

Outcomes

Main objective/outcome:

Haematological utility of iron supplementation in predominantly breast fed young infants

Review outcomes reported in the trial:

1. Haemoglobin (end and change)

2. Ferritin (end)

3. Weight and height changes

Notes

Trial location: New Delhi, India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: birthweight < 2500 g, gestational age < 37 weeks, twins, congenital malformation, history of blood transfusion, blood sampling (> 10 ml) prior to recruitment, infants already receiving iron supplementation, adverse neonatal events requiring admission to the special newborn care nursery, and those with significant current morbidity.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random numbers
Allocation concealment (selection bias)Low riskRandomization sequence was sealed in an opaque envelope at a central place
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Unclear risk71/100 evaluated

Nwanyanwu 1996

Methods

Individually randomized

Trial duration: March to May 1995

Participants

222 randomized, 215 evaluated for mortality and malaria, 143 evaluated for haemoglobin change

Age: mean 26 months

Setting: community, urban

% anaemia: at baseline: not stated (anaemia definition: Hb < 8 g/dL), mean haemoglobin 8.9 g/dL

% malaria at baseline: 100% with clinical malaria

Interventions

Study arms.

1. Sulphadoxine-pyrimethamine 0.5 tablet once daily for children aged < 4 years, 1 tablet once daily for children aged 4 to 5 years. Each tablet contained sulphadoxine 500 mg and pyrimethamine 25 mg.

1. Daily iron: ferrous sulphate syrup daily, about 6 mg/kg/d elemental iron plus sulphadoxine-pyrimethamine tablets as described above

2. Weekly iron: ferrous sulphate syrup weekly, about 0.85 mg/kg/d elemental iron plus sulphadoxine-pyrimethamine tablets as described above

Duration of treatment: 4 weeks

Duration of follow-up: 4 weeks

Outcomes

Main objective/outcome:

To determine whether oral iron supplementation enhances haematological recovery in young children with malaria treated with SP

Review outcomes reported in the trial:

1. Malaria

2. Death

3. Haemoglobin change

Notes

Trial location: city of Matiki, Malawi

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: hospitalization, Hb < 5 g/dL, refused consent, urine positive for 4-aminoquinolines or sulphonamides

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
High risk215/222 evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk215/222 evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk143/222 evaluated

Olsen 2006

Methods

Individually randomized

Trial duration: November 1994 to January 1996

Participants

231 children randomized, 231 evaluated for mortality, 200 for haemoglobin end and change

Age: mean 8.7 years

Setting: community

% anaemia at baseline: 47.8% (anaemia definition: Hb < 11 g/dL for children aged < 5 years, < 11.5 g/dL for children aged 5 to 11 years, < 12 g/dL for children aged 12 to 13 years and for girls > 13 years, and < 13 g/dL for boys > 13 years), mean haemoglobin 11.5 g/dL

% malaria at baseline: 60.6%

Interventions

Study arms:

1. Iron: ferrous dextran tablets twice weekly, about 0.7 mg/kg/d elemental iron

2. Placebo tablets twice weekly

Duration of treatment: 12 months

Duration of follow-up: 12 months

Outcomes

Main objective/outcome:

Effect of 12 months of twice weekly iron supplementation on haemoglobin and ferritin

Review outcomes reported in the trial:

1. Death

2. End and change in Hb

Notes

Trial location: Kisumu district of Nyanza province, Kenya

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: Hb<8g/dL, pregnancy and refusal to participate

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated
Allocation concealment (selection bias)Low riskSealed envelopes kept in a central location
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
Low riskIntention-to-treat analysis
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Unclear risk200/231 evaluated

Palupi 1997

Methods

Individually randomized

Trial duration: not stated

Participants

299 randomized

Age: mean 3.5 years (range 2 to 5 years)

Setting: community, rural

% anaemia at baseline: 36.7% (anaemia definition: Hb < 11 g/dL), mean haemoglobin 11.3 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: ferrous sulphate syrup weekly, about 0.35 mg/kg/d elemental iron plus a single dose of albendazole (400 mg) a week before commencing supplements.

2. Iron only (as described above)

3. Placebo syrup

Duration of treatment: 9 weeks

Duration of follow up: 9 weeks

Outcomes

Main objective/outcome:

Effect of iron ± deworming on Hb

Review outcomes reported in the trial:

1. Anaemia

2. End and change in Hb

Notes

Trial location: Indonesia

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk289/299 evaluated

Powers 1983

Methods

Individually randomized

Trial duration: not stated

Participants

80 randomized, 40 evaluated

Age: range 4 to 12 years

Setting: community, rural

% anaemia: at baseline: not stated, mean haemoglobin 11.1 g/dL

% malaria at baseline: not stated

Interventions

Study arms.

1. Iron: ferrous sulphate syrup daily, about 2 mg/kg/d elemental iron plus chloroquine tablets 6 days before the supplementation and thereafter weekly.

2. Iron (as described above) plus riboflavin.

3. Placebo (lactose tablets) plus chloroquine tablets 6 days before the supplementation and thereafter weekly.

Duration of treatment: 6 weeks

Duration of follow-up: 6 weeks

Outcomes

Main objective/outcome:

Haematological status

Review outcomes reported in the trial:

1. Mortality

2. Haemoglobin end and change

3. End iron level

Notes

Trial location: Keneba village, Gambia

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Low riskSealed envelopes
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
High riskAuthors only stated that there were 'no deaths' in the study, denominator derived from the Hb outcome - for which 40 out of 80 children were evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High riskIn all 40/80 evaluated

Richard 2006

Methods

Individually randomized

Trial duration: February to September 1998

Participants

855 randomized, 836 evaluated for malaria, 748 evaluated for mortality and haemoglobin

Age: range 0.5 to 15 years

Setting: school, rural

% anaemia at baseline: 46.4% (anaemia definition: Hb < 11 g/dL for age < 5 years, Hb < 11.5 g/dL for age 5 to 11 years, and Hb < 12 g/dL for age > 11 years), mean haemoglobin 11.4 g/dL

% malaria at baseline: 5%

Interventions

Study arms:

1. Iron: iron sulphate syrup daily, about 0.75 mg/kg/day elemental iron

2. Iron (as described above) plus zinc 20 mg/day

3. Zinc only (20 mg/d)

4. Placebo syrup

Duration of treatment: 7 months

Duration of follow-up: 7 months

Outcomes

Main objective/outcome:

Effect of daily iron and/or zinc on morbidity - malaria, diarrhoea, and respiratory infections

Review outcomes reported in the trial:

1. Mortality

2. Malaria

3. End haemoglobin

Notes

Trial location: Santa Clara Village, Peru

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: chronic illness (congenital diseases or major illness requiring medical care or medication, or both, determined by the physician at baseline evaluation) or severe malnutrition

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskTriple blinded: participants, study personnel, and data analyst all blinded
Incomplete outcome data (attrition bias)
Mortality
High risk748/855 evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk836/855 evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk748/855 evaluated

Rosado 1997

Methods

Individually randomized

Trial duration: not stated

Participants

219 randomized, 194 evaluated

Age: mean 28.4 months (range 18 to 36 months)

Setting: community, rural

% anaemia at baseline: not stated (anaemia definition: Hb < 11.5 g/dL), mean haemoglobin 10.8 g/dL

% malaria at baseline: not stated

Interventions

Study arms:

1. Iron: ferrous sulphate syrup 5 days a week, about 1.8 mg/kg/d elemental iron

2. Zinc: zinc methionine, 20 mg elemental zinc daily 5 days per week

3. Iron plus zinc (administration as described above)

4. Placebo

Duration of treatment: 12 months

Duration of follow up: 12 months

Outcomes

Main objective/outcome:

To assess the extent to which growth stunting could be reversed and the number of infectious episodes reduced by zinc or iron, or both

Review outcomes reported in the trial:

1. Anaemia

2. End haemoglobin

3. End iron levels, end ferritin

4. Weight and height

5. Infections - diarrhoea and respiratory tract infections

Notes

Trial location: Valley of Solis, Mexico

Malaria endemicity: hypoendemic

Language of publication: English

Exclusion criteria: not stated; included only growth-stunted children

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk194/219 evaluated

Roschnik 2003 (C)

Methods

Cluster randomized

Trial duration: February to September 2002

Unit of randomization: schools

Number of units randomized: 40 schools

Average cluster size: 29

Adjustment for clustering: none

Methods of adjustment: not stated

Participants

Number of children: 40 schools, 1160 were tested for haemoglobin at baseline. Number randomized not stated

Age: 7 to 8 years and 10 to 12 years

Setting: school, rural

% anaemic at baseline: 54%, mean Hb 11.8 g/dL

% malaria at baseline: no or little malaria, not reported further

Interventions

Ferrous sulfate tablets 65 mg/week elemental iron (about 0.3 mg/kd/d) + folic acid 0.25 mg / week vs. no treatment. In addition all children received praziquantel 600 mg once, 1 week before the beginning of the trial

Duration of treatment: 3.5 months

Duration of follow-up: 4.5 months

Outcomes

Main objective/outcome: to evaluate the effectiveness of weekly school-based iron supplementation: its impact on mean haemoglobin concentration and anaemia prevalence, on school attendance, performance, drop-out, and repetition rates

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end)

Notes

Trial location: Mangochi District in Malawi, upland and coastal areas

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table (inside each class 33% of children were selected for the trial - started from a random number and taking every third trial from this number on)
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
Low riskAll participants evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskAll participants evaluated

Roschnik 2004 (C)

Methods

Cluster randomized

Trial duration: July 2001

Unit of randomization: schools

Number of units randomized: 51 schools

Average cluster size: 29

Adjustment for clustering: none

Methods of adjustment: not stated

Participants

Number of children: 51 schools, 1510 individuals randomized

Age: 7 to 8 years and 10 to 12 years, mean 9.2 years

Setting: school, rural

% anaemic at baseline: 17% (anaemia defined by age 5 to11.9 Hb<11.5g/dL, age 12 to 14.9 Hb < 12 g/dL), mean Hb 12.5 g/dL

% malaria at baseline: no or little malaria, not reported further

Interventions

Ferrous sulfate tablets 108 mg/week elemental iron (about 0.57 mg/kd/day) vs. no treatment

Duration of treatment: 2.5 months

Duration of follow-up: about 5.3 months

Outcomes

Main objective/outcome: Effect of weekly iron supplementation on haemoglobin levels

Review outcomes reported in the trial:

1. Anaemia

2. Death

3. Haemoglobin (end)

Notes

Trial location: Islands of Iloilo and Guimaras in the west Visayas region of the Philippines

Malaria endemicity: hypoendemic (originally hyperendemic, but author wrote that little malaria in the specific area)

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table (inside each class 33% of children were selected for the trial - started from a random number and taking every third trial from this number on)
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
Low riskAll participants evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskAll participants evaluated

Sarma 1977 (C)

Methods

Cluster randomized

Trial years: not stated

Unit of randomization: preschools

Number of units randomized: 10

Average cluster size: 25

Adjustment for clustering: none

Methods of adjustment: none

Participants

10 preschools, 255 individuals randomized

Age: 2 to 6 years

Setting: school

% anaemia at baseline: 54% (anaemia defined as Hb < 11 g/dL). Mean haemoglobin 110.8 g/dL

% malaria at baseline: not stated

Interventions

Iron tablets (formulation not stated) 20 mg/day elemental iron (about 1.3 mg/kg/d) + folic acid 100 μg/day vs. no treatment

Duration of treatment: 12 months on school days (the school year included only 265 days)

Duration of follow up: 12 months (1school year)

Outcomes

Main objective/outcome: effectiveness of iron and folate given by teachers

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end and change)

Notes

Trial location: India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
High riskOpen study
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk89/255 individuals evaluated

Sazawal 2006 (C)a

Methods

Cluster randomized trial

Unit of randomization: households

Number of units randomized: 22,959

Average cluster size: 1.4

Adjustment for clustering: was performed for adverse events (episodes of infection) and admissions. For mortality and cause-specific mortality adjustment for clustering is not reported.

Methods of adjustment: for analysis of adverse events and admissions, Anderson Gill time-to-event survival methods in Cox regression with robust estimation of standard error to account for multiple events per child or within household were used (SAS version 9.0, STATA version 8.2). For total mortality and cause-specific mortality, Cox regression with exact handling for ties was used.

Trial duration: January 2002 to August 2003

Participants

22,959 units and 32,155 individuals; 15,956 in the 2 arms relevant for this review

Age: 1 to 35 months, mean about 18 months

Setting: community

% anaemic at baseline: not stated

% malaria at baseline: not stated

Interventions

Iron tablets (preparation not stated) dissolved in water or breast milk 12.5 mg/d plus folic acid 50 μg/day plus vitamin A; versus placebo plus vitamin A; versus iron plus folic acid plus zinc 10 mg/d plus vitamin A (not used in this review); versus zinc plus vitamin A. Children aged 1 to 11 months received a half dose of iron.

Duration of treatment: not fixed; from < 3 months to maximum of 18 months of age (until the age of 48 months or the discontinuation of the study ). Most participants received the intervention for about 12 months.

Duration of follow-up: not fixed. Maximum of 18 months (until age 48 months or study discontinuation)

Outcomes

Main objective/outcome: Composite of death or hospital admission (looking very specifically at malaria)

Review outcomes reported in the trial:

1. Clinical malaria, severe malaria

2. Deaths

3. Hospitalization

4. Any infection, diarrhoea

Notes

Trial location: Tanzania

Malaria endemicity: holoendemic

Language of publication: English

Exclusion criteria: none

Comparison relevant to this review (iron + folic) stopped at interim analysis based on recommendation from the data and safety monitoring board. The board received data from the main trial every month and established at the beginning of the trial that it would do further analysis of the data when the difference in mortality between any 2 groups reached a P value of 0.2 or less. Stopping rules not defined in publication. No statement on sample size and analysis adjustment for interim monthly monitoring and truncation.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAllocation sequence generated at the WHO controlled by computer (page 136). Permuted in blocks of 16
Allocation concealment (selection bias)Low riskLabelled the strips of supplements with 16 letter codes- 4 for each of the groups. This letter code was hidden in the batch number on each strip of tablets
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind. Strips of supplements coded with 16 letter codes
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNumber evaluated not specifically stated in article; assumed to be all participants randomized
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNumber evaluated not specifically stated in article; assumed to be all participants randomized
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Unclear riskEvaluated only children in a sub-study: 635/15,956 children in the 2 arms relevant for this review

Sazawal 2006 (C)b

Methods

Cluster randomized trial (independent substudy of Sazawal 2006 (C)a

Unit of randomization: households

Number of units randomized: 2818 before exclusion of anaemic children

Average cluster size: 1.2

Adjustment for clustering was performed for adverse events (episodes of infection) and admissions. For mortality and cause-specific mortality, adjustment for clustering is not reported.

Methods of adjustment for the analysis of adverse events and admissions, Anderson Gill time-to-event survival methods in Cox regression with robust estimation of SE to account for multiple events per child or within household were used (SAS version 9.0, STATA version 8.2). For total mortality and cause-specific mortality, Cox regression with exact handling for ties was used.

Trial duration: March to November 2002

Participants

3171 individuals; 1619 in the 2 arms relevant for this review

Age: 1 to 35 months, mean about 22.5 months

Setting: community

% anaemic at baseline: 57% (mean Hb 9.7 g/dL)

% malaria at baseline: not stated

Interventions

Iron tablets (preparation not stated) dissolved in water or breast milk 12.5 mg/d plus folic acid 50 μg/d plus vitamin A; versus placebo plus vitamin A; versus iron plus folic acid plus zinc 10 mg/d plus vitamin A (not used in review); versus zinc plus vitamin A. Children aged 1 to 11 months received a half dose of iron.

Duration of treatment: not fixed from < 3 months to a maximum of 18 months (until the participants were aged 48 months or the discontinuation of the study). Most received the intervention for about 12 months.

Duration of follow-up: not fixed. Maximum 18 months (until the participants were aged 48 months or the discontinuation of the study).

Outcomes

Main objective/outcome: to make a composite of death or hospital admission (looking very specifically at malaria)

Review outcomes reported in the trial.

1. Clinical malaria, severe malaria.

2. Deaths.

3. Anaemia.

Notes

Trial location: Tanzania

Malaria endemicity: holoendemic

Language of publication: English

Exclusion criteria: Hb <7 g/dL

This was a separate, independent, substudy of the bigger Sazawal 2006 (C)a trial. Separate households were randomized to the substudy, where children had baseline blood samples, anaemic children excluded (Hb < 7 g/dL), half-yearly surveillance for malaria and clinical infections performed, and treatment for malaria offered throughout the trial.

Comparison relevant to this review (iron plus folic) stopped at interim analysis based on recommendation from the data and safety monitoring board. The board received data from the main trial every month and established at the beginning of the trial that it would do further analysis of the data when the difference in mortality between any 2 groups reached a P value of 0.2 or less. Stopping rules not defined in publication. No statement on sample size and analysis adjustment for interim monthly monitoring and truncation.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAllocation sequence generated at the WHO controlled by computer (page 136). Permuted in blocks of 16
Allocation concealment (selection bias)Low riskLabelled the strips of supplements with 16 letter codes- 4 for each of the groups. This letter code was hidden in the batch number on each strip of tablets
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind. Strips of supplements coded with 16 letter codes
Incomplete outcome data (attrition bias)
Mortality
Low riskNumber evaluated not specifically stated in article; assumed to be all participants randomized
Incomplete outcome data (attrition bias)
Malaria
Low riskNumber evaluated not specifically stated in article; assumed to be all participants randomized
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskEvaluated only children in a sub-study: 635/15,956 children in the 2 arms relevant for this review

Seshadri 1982b

Methods

Individually randomized

Trial duration: not stated

Participants

28 randomized (14 pairs of boys)

Age (per study): 5 to 6 years

Setting: school

% anaemia at baseline: 100% (defined as Hb <10.5 g/dL). Mean haemoglobin about 9.7 g/dL.

% malaria at baseline: not stated

Interventions

Iron tablets (preparation not stated) 40 mg/day elemental iron (about 1 mg/kg/d) plus folic acid 0.2 mg/day vs. placebo. All received a 3-day course of mebendazole at start of treatment

Duration of treatment: 2 months

Duration of follow-up: 2 months

Outcomes

Main objective/outcome: to evaluate the effect of iron plus folate on cognitive test performance

Review outcomes reported in the trial:

1. Haemoglobin (end and change)

Notes

Trial location: India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: malnourished children (weight for age < 60% of standard), Hb > 10.5 g/dL or < 8 g/dL, RBC morphology other than hypochromic-microcytic, IQ test ( < 70 or > 100

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk14 pairs of boys matched for growth measures, Hb, IQ and parents income and education. One child from each pair was randomly assigned to a group by coin toss
Allocation concealment (selection bias)Unclear riskOne child from each pair was randomly assigned to the intervention group by coin toss and the other to placebo
Blinding (performance bias and detection bias)
All outcomes
Low riskStated as double blind, placebo used
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskAll participants evaluated

Seshadri 1984a

Methods

Individually randomized

Trial duration: not stated

Participants

149 randomized

Age: 4 to 8 years (stratified to 2 groups: 4 to 6 years and 6 to 8 years)

Setting: school

% anaemia at baseline: 61% of iron group and 59% of control group (Hb < 11 g/dL), mean Hb 10.3 g/dL

% malaria at baseline: not stated

Interventions

Iron tablets, preparation not stated, 20 mg/day elemental iron (about 1 mg/kg/d) + folic acid 0.1 mg/day vs. no treatment

Duration of treatment: 2 months

Duration of follow up: 2 months

Outcomes

Main objective/outcome: to evaluate haemoglobin status after iron plus folate supplementation

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end)

Notes

Trial location: India

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: income category

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk10 to 12 children within each of the year age groups were randomly allotted to the control group and the rest to the experimental group
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
High riskOpen trial
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskAll participants evaluated

Seshadri 1984b (C)

Methods

Cluster randomized

Unit of randomization: preschools

Number of units randomized: 22,959

Average cluster size: 22

Adjustment for clustering: none

Methods of adjustment: none

Trial duration: not stated

Participants

4 preschools, 89 individuals randomized

Age: not stated

Setting: school

% anaemic at baseline: 73%, mean Hb 10.3 g/dL

% malaria at baseline: not stated

Interventions

Iron tablets (preparation not stated) 20 mg/day elemental (about 1 mg/kg/d) + folic acid 0.1 mg/day vs. placebo

Duration of treatment: 4 months (2 different periods of 60 days in 1 school year)

Duration of follow up: 12 months follow up after net 120 days of treatment (3 months after end of treatment only in intervention group)

Outcomes

Main objective/outcome: Anaemia

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end and change)

Notes

Trial location: India

Malaria endemicity: mesoendemic

Language of publication: English

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
High riskOpen, but placebo used
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskAll participants evaluated

Shah 2002

Methods

Individually randomized

Trial duration: March 1998 to March 1999

Participants

209 randomized

Age: 11 to 18 years, mean of about 15 years

Setting: school

% anaemia at baseline: 68.8% (haematocrit < 36%), mean baseline haematocrit about 33%

% malaria at baseline: not stated

Interventions

Ferrous sulphate tablets 350 mg/day (about 1 mg/kg/d elemental iron) plus folic acid 1.5 mg/day vs. iron 350 mg/week plus folic acid vs. no treatment

Treatment duration: about 3.5 months

Duration of follow-up: about 4 months

Outcomes

Main objective/outcome: to compare daily vs. weekly iron plus folate for control of anaemia and Hb status in girls

Review outcomes reported in the trial:

1. Deaths

2. Anaemia

3. Haemoglobin (end and change) 

4. Adverse events

Notes

Trial location: Nepal

Malaria endemicity: hypoendemic

Language of publication: English

Exclusion criteria: male sex, chronic illness, long-term allopathic or indigenous drug treatments, hospitalization for severe illness in the past 2 weeks

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated numbers
Allocation concealment (selection bias)Low riskSealed envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskAll participants evaluated

Smith 1989 (C)

Methods

Cluster randomized

Trial duration: July to August 1983

Unit of randomization: household

Number of units randomized: not stated

Average cluster size: not stated

Adjustment for clustering: none

Methods of adjustment: not stated

Participants

Number of participants: 213 children

Age: 6 months to 5 years, mean about 2.7 years

Setting: community

% anaemic at baseline: 100% (defined as Hb < 11.1 g/dL and mean corpuscular volume < 70 (less than the third percentile by age)), mean Hb 9.3 g/dL

% malaria at baseline: not stated

Interventions

Ferrous sulphate elixir of crushed tablets in orange juice 3 to 6 mg/kg/d elemental iron versus orange juice (placebo)

Duration of treatment: 12 weeks

Duration of follow-up: 13 weeks

Outcomes

Main objective/outcome: Hb/iron + malaria status

Review outcomes reported in the trial:

1. Clinical malaria, parasitaemia, parasitaemia > 5000/μL

2. Deaths

3. Febrile disease

Notes

Trial location: Gambia

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: Hb < g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskThe first compound on the compound list for each village was randomly assigned and compounds were assigned alternately thereafter 
Allocation concealment (selection bias)High riskAlternation
Blinding (performance bias and detection bias)
All outcomes
Low riskParents, field workers, and study investigator blinded
Incomplete outcome data (attrition bias)
Mortality
Low riskAll participants evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk186/213 participants evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Unclear riskNot reported

Smuts 2005

Methods

Individually randomized

Trial duration: not stated

Participants

1134 randomized

Age: 6 to 11 months, mean 8.7 months

Setting: community

% anaemia at baseline: 64.9% and 58.6% (defined Hb < 11 g/dL) in iron and placebo groups, respectively. Mean Hb 10.7 g/dL

% malaria at baseline: not stated

Interventions

Iron as chewable tablets or foodlets 10 mg/day elemental iron (about 1 mg/kg/day)

Duration of treatment duration: 6 months

Duration of follow-up: 6 months

Outcomes

Main objective/outcome: to test the hypothesis that improving micronutrient status would improve growth of infants at high risk for anaemia

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end and change)

3. Weight and height

Notes

Trial location: Vietnam, South Africa, Peru, Indonesia

Malaria endemicity: meso- and hyperendemic

Language of publication: English

Exclusion criteria: birth < 37 weeks or < 2500 g, severe wasting (> -3 Z-score), Hb < 8, fever > 39°C

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Low riskCentrally
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low risk481/571 participants evaluated

Soekarjo 2004 (C)

Methods

Cluster randomized

Unit of randomization: classes in school

Average cluster size: 48

Adjustment for clustering: none

Methods of adjustment: not stated

Trial duration: October 1996 to May 1997

Participants

45 classes, 2163 children

Age (per study): average 12 to 15 years

Setting: school

% anaemia at baseline: not stated

% malaria at baseline: not stated

Interventions

Ferrous sulphate tablets 60 mg elemental iron weekly (about 0.2 mg/kg/day) plus folic acid 250 μg x 1/week plus vitamin A 10,000 U x 1/week vs. vitamin A

Duration of treatment: 14 weeks

Duration of follow-up: 14 week

Outcomes

Main objective/outcome: anaemia

Review outcomes reported in the trial:

Haemoglobin (change)

Notes

Trial location: Indonesia

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk2012/2163 participants evaluated

Soemantri 1989

Methods

Individually randomized

Trial duration: not stated

Participants

130 randomized

Age: mean 10.4 ± 1.6 (anaemic children) and mean 10.5 ± 1.5 (non-anaemic children)

Setting: school

% anaemia: at baseline: study stratified by anaemia, mean haemoglobin about 9.7 in anaemic group and 13.3 in non-anaemic group (Hb < 11 g/dL)

% malaria at baseline: not stated

Interventions

Ferrous sulphate tablets 2 mg/kg/d elemental iron vs. saccharin plus tapioca (control). Pyrantel pamoate (Pyrantel embonate) was given to all parasite-positive children before randomization.

Duration of treatment: 3 months

Duration of follow-up: 6 months

Outcomes

Main objective/outcome: Effect of iron on learning achievement of iron deficient anaemic children

Review outcomes reported in the trial:

1. Haemoglobin (end and change)

2. TIBC

Notes

Trial location: Indonesia

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: < 80th percentile of weight and height or mid-arm circumference < 85th percentile of Indonesian growth standards, positive parasite egg count by stool examination after deworming treatment, acute or chronic illness, clinical signs of malnutrition, physical handicaps, mental retardation, neurological dysfunction, or haematological disorders, IQ < 75, acute or severe morbidity, Hb 11.1 to 11.9 g/dL and saturation 13% to 19%

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind (placebo had same size and colour as study drug)
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskAll participants evaluated

Soewondo 1989

Methods

Individually randomized

Trial duration: 1983 to 1984

Participants

176 randomized

Age: preschool children

Setting: school

% anaemia: at baseline: stratified by haemoglobin and iron status. Mean haemoglobin 10.6 g/dL for iron deficient and anaemic children, 11.7 for iron deficient and 12.3 for iron replete children

% malaria at baseline: not stated

Interventions

Ferrous sulphate syrup 50 mg/day elemental iron (about 3 mg/kg/day) vs. placebo

Duration of treatment: 2 months

Duration of follow-up: 2 months

Outcomes

Main objective/outcome: effects of iron supplementation on performance in learning tasks

Review outcomes reported in the trial:

1. Haemoglobin (end)

2. Ferritin, TIBC, protoporphyrin

Notes

Trial location: Indonesia

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: not stated

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, placebo used
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskAll participants evaluated

Taylor 2001

Methods

Individually randomized

Trial years: 1996 to 1997

Participants

428 randomized

Age: 6-15 years

Setting: school

% anaemia at baseline: 33.5% (defined as Hb < 12 g/dL), mean haemoglobin 12.3 g/dL

% malaria at baseline: 5%

Interventions

Ferrous fumarate 200 mg tabs containing 65 mg elemental iron (about 0.3 mg/kg/d) plus 100 μg folate once weekly plus albendazole 400 mg/day plus praziquantel 40 mg/kg/day for 3 days vs. placebo plus albendazole plus praziquantel for 3 days vs. placebo plus albendazole plus praziquantel single dose vs. ferrous fumarate plus antihelminthic placebo vs. placebo all

Duration of treatment: iron for 10 weeks, anthelminthics at 6 and 12 months

Duration of follow-up: 12 months

Outcomes

Main objective/outcome: to determine whether different combinations of antihelminthics and iron would improve nutritional and health status

Review outcomes reported in the trial:

1. Haemoglobin (end and change)

Notes

Trial location: South Africa

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: girls post-puberty

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, placebo used
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk275/428 participants evaluated

van den Hombergh 1996

Methods

Individually randomized

Trial duration: April to June 1993

Participants

In total 100 randomized

Age: < 30 months

Setting: hospital/community

% anaemia at baseline: 100% (defined as Hb < 5 g/dL), randomization stratified by receipt of blood products, mean Hb 4.1 g/dL

% malaria at baseline: 100% with clinical malaria

Interventions

Ferrous fumarate tablets 200 mg/day (65 mg elemental iron, about 4 mg/kg/day plus folic acid 100 μg) vs. folic acid. In addition all children received quinine sulphate treatment for malaria

Duration of treatment: 3 months

Duration of follow-up: 3 months

Outcomes

Main objective/outcome: adverse effect of iron treatment on malaria infection

Review outcomes reported in the trial:

1. Malaria parasitaemia, parasite density

2. Deaths

3. Anaemia

4. Haemoglobin (end)

5. Clinic visits

6. Pneumonia

7. Weight

Notes

Trial location: Tanzania

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: cerebral malaria, non-falciparum malaria, sickle cell anaemia, and children meeting the criteria in whom malarial anaemia was not the main medical problem (eg meningitis, measles)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description
Allocation concealment (selection bias)Unclear riskNo description
Blinding (performance bias and detection bias)
All outcomes
High riskOpen
Incomplete outcome data (attrition bias)
Mortality
High risk96/100 participants evaluated
Incomplete outcome data (attrition bias)
Malaria
High risk94/100 participants evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Low riskAll participants evaluated

van Hensbroek 1995

Methods

Individually randomized

Trial duration: July to December 1992

Participants

600 randomized

Age: 6 months to 9 years

Setting: hospital/community

% anaemia at baseline: 74% (defined as Hb < 11 g/dL), mean Hb 9.6 g/dL

% malaria at baseline: 100% with clinical malaria

Interventions

Sodium iron edetate syrup, 27.5 mg x 3/days elemental iron for children < 20 kg, 41.25 mg x 3/days elemental iron for children > 20 kg (about 6 mg/kg/d elemental iron) plus sulfadoxine-pyrimethamine single dose vs. placebo plus sulfadoxine-pyrimethamine; vs. placebo plus chloroquine; versus folic acid plus chloroquine (not used for this review) vs. folic acid plus sulfadoxine-pyrimethamine (not used for this review)

Duration of treatment: 1 month

Duration of follow-up: 4 months after end of rainy season

Outcomes

Main objective/outcome: The effect of iron or folic acid plus antimalarial on malarial anaemia

Review outcomes reported in the trial:

1. Malaria parasitaemia

2. Deaths

3. Haemoglobin (change)

Notes

Trial location: The Gambia

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: severe underlying disease or complicated malaria that required hospital admission, non-falciparum malaria or less than 5 parasites per high power field

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskChildren were allocated at random to receive either chloroquine or Fansidar as antimalarial treatment and iron, folic acid or placebo as supplementation
Blinding (performance bias and detection bias)
All outcomes
High risk 
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNumber randomized not reported per group

Verhoef 2002

Methods

Individually randomized

Trial duration: 1998 to 2000

Participants

In total 328 randomized

Age: 2 to 36 months, mean about 18 months  

Setting: community

% anaemia at baseline: 72% in this age group from an earlier survey (defined as Hb < 11 g/dL), mean Hb 9.6 g/dL

% malaria at baseline: as indicated by a dipstick test result, 31% in this age group from an earlier survey

Interventions

Ferrous fumarate suspension 6 mg/kg/week elemental iron (about 0.86 mg/kg/d) given in two doses (twice a week) plus sulfadoxine/pyrimethamine 25/1.25 mg/kg once every 4 weeks vs. ferrous fumarate plus placebo; vs. sulfadoxine-pyrimethamine plus placebo vs. placebo

Duration of treatment: 3 months

Duration of follow-up: 3 months

Outcomes

Main objective/outcome: effect of intermittent iron and sulfadoxine-pyrimethamine on Hb in symptom-free children

Review outcomes reported in the trial:

1. Clinical malaria

2. Anaemia

3. Haemoglobin (end)

Notes

Trial location: Kenya

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: Hb < 6 or >11 g/dL, axillary temp > 37.5 °C, symptoms suggestive of malaria or anaemia, or any systemic illness occurring in combination with a blood dipstick test result indicating current or recent malaria infection

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTables with randomized permutations
Allocation concealment (selection bias)Low riskThe order of children listed was concealed from the person generating the allocation schedule
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind: field investigators, participants
Incomplete outcome data (attrition bias)
Mortality
Low riskAll participants evaluated
Incomplete outcome data (attrition bias)
Malaria
Low riskAll participants evaluated
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk307/328 participants evaluated

Wasantwisut 2006

Methods

Individually randomized 

Trial duration: not stated

Participants

674 randomized, 256 evaluated for review outcomes

Age: 4 to 6 months, mean 4.5 months

Setting: community

% anaemia at baseline: 30% (defined as Hb < 11 g/dL, mean haemoglobin 11.5 g/dL

% malaria at baseline: not reported

Interventions

Ferrous sulphate syrup 10 mg/day (about 1.5 mg/kg/d) vs. placebo vs. ferrous sulphate + zinc sulphate 10 mg/day vs. zinc. In addition all supplements contained vitamin C and each subject received vitamin A at the beginning of trial.

Duration of treatment: 6 months

Duration of follow-up: 6 months

Outcomes

Main objective/outcome: to test the hypothesis that supplementation of iron or zinc alone, or iron and zinc combined, can improve iron and zinc status and growth of infants

Review outcomes reported in the trial:

1. Anaemia

2. Deaths

3. Haemoglobin (end)

4. Ferritin, zinc

5. Weight and height

6. Adverse events

Notes

Trial location: Thailand

Malaria endemicity:  holoendemic

Language of publication: English

Exclusion criteria: congenital abnormalities, Hb < 8.0 g/dL, chronic illnesses, or children who were bottle fed

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers
Allocation concealment (selection bias)Low riskThe randomization was done by a statistician who was not involved in the study
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, placebo used
Incomplete outcome data (attrition bias)
Mortality
High risk256/674 participants evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk256/674 participants evaluated

Zavaleta 2000

Methods

Individually randomized

Trial duration: August to December 1996

Participants

312 randomized

Age: 12 to 18 years

Setting: school

% anaemia at baseline: 15.4%, 18.5% and 19.8% across groups (defined as Hb < 12 g/dL), mean haemoglobin 12.7 g/dL

% malaria at baseline: not stated

Interventions

Ferrous sulphate tablets 60 mg/day plus elemental iron (about 0.63 mg/kg/d) on school days vs. ferrous sulphate tablets 60 mg twice weekly plus placebo on other school days vs. placebo

Duration of treatment: 17 weeks

Duration of follow-up: 17 weeks

Outcomes

Main objective/outcome: to assess the feasibility, efficacy, and acceptability of reducing anaemia in adolescent girls attending public school using daily or intermittent iron supplementation

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end)

Notes

Trial location: Peru

Malaria endemicity: mesoendemic

Language of publication: English

Exclusion criteria: irregular menstruation in the preceding 3 months, any multivitamin-mineral supplement in the last 6 months, Hb < 8 g/dL

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAssigned at random
Allocation concealment (selection bias)Unclear riskDistributed in coded blister packages
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind, placebo used
Incomplete outcome data (attrition bias)
Mortality
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
Unclear risk296/312 participants evaluated

Zlotkin 2003

Methods

Individually randomized

Trial duration: October 1999 to March 2000

Participants

437 randomized, 165 evaluated

Age: mean 16.5+/-3.9 months and 15.2 +/- 4.1 months for iron vs. placebo

Setting: community

% anaemia at baseline: 0% (defined as Hb < 10 g/dL), mean haemoglobin 12.7 g/dL

% malaria at baseline: 62.3% (202/324 children who completed the intervention)

Interventions

Ferrous sulphate drops 12.5 mg/day elemental iron (about 1.25 mg/kd/d) vs. placebo sachets sprinkled on food vs. iron fumarate sprinkles (not used in review) vs. iron fumarate sprinkles plus vitamin A (not used in this review)

Duration of treatment: 6 months

Duration of follow-up: 18 months (only children who were not anaemic at the end of supplementation were followed-up for the additional period of time)

Outcomes

Main objective/outcome: to compare the efficacy of microencapsulated iron fumarate sprinkles ± Vit A with iron sulphate drops with placebo in preventing recurrent anaemia and to determine the long-term haematological outcome

Review outcomes reported in the trial:

1. Anaemia

2. Deaths

3. Haemoglobin (end and change)

4. Ferritin

Notes

Trial location: Ghana

Malaria endemicity: hyperendemic

Language of publication: English

Exclusion criteria: Hb < 10 g/dL, age 8 to 20 months, only breast feeding children

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated
Allocation concealment (selection bias)Low riskSealed opaque envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskOpen trial, intervention and control arms different
Incomplete outcome data (attrition bias)
Mortality
Low riskAll participants were evaluated
Incomplete outcome data (attrition bias)
Malaria
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Haemoglobin or anaemia
High risk165/220 participants evaluated

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    Fe = iron
    RCT = randomized controlled trial
    Vit C = vitamin C

Abdelrazik 2007Non-RCT
Adu-Afarwuah 2008Fortification of food or drink
Ahmed 2001Study not in children (participants' age 14-19 years and results for children not separated)
Anand 2007Fortification of food or drink
Angeles-Agdeppa 1997Incompatible intervention (iron + other micronutrients)
Anonymous 2006Editorial (non-RCT)
Arcanjo 2008Fortification of food or drink
Asibey-Berko 2007Fortification of food or drink
Assunçăo 2007Fortification of food or drink
Aukett 1986Non-endemic areas: England
Baird 1997Non-RCT
Barclay 1991Non-endemic areas
Bates 1987Incompatible intervention (iron + other micronutrients) iron + vit C + riboflavin vs. placebo
Bates 1994Incompatible intervention (Iron + other micronutrients) iron+ multivitamin tablet
Beasley 2000Incompatible intervention (iron + other micronutrients: iron vs. B12)
Bender-Götze 1980RCT conducted in non-endemic area: Germany
Berger 1992Non-RCT
Boivin 1993None of the reported outcomes relevant / usable for the review
Bojang 1997RCT, blood transfusion vs. iron (parenteral administration of iron)
Bradfield 1968Non-RCT
Bruner 1996Non-endemic areas
Brunser 1993Non-endemic area (Chile), iron administered as fortification of milk
Carter 2005RCT, all groups received iron
Chandramohan 2005RCT, all groups received iron
CIGNIS 2010Incompatible intervention (Iron + other micronutrients). Comparison between basal and rich fortification including multiple vitamins + iron
Cusick 2005RCT, all groups received iron
Deinard 1986 Non-endemic area: Minnesota, USA
Desai 2004Dose comparison, all groups given iron
Dewey 2002Non-endermic area; Sweden, Honduras
Dijkhuizen 2001Stated specifically in study that the area is malaria-free
Diouf 2002Non-RCT (correspondence)
Domelloff 2001Neither Honduras nor Sweden mentioned in our malaria-endemic areas table
Ekvall 2000Incompatible intervention (iron + other micronutrients: multivitamins vs. promethazine hydrochloride)
Engstrom 2008Cluster-randomized trial. Inclusion criteria of children in control clusters (no iron for 6 months) differed systematically from those of iron-supplementation clusters (no iron for 1 month)
Fuerth 1972Non-endemic area: California
Giovannini 2006Fortification of food or drink
Gomber 1998All children were given iron supplementation
Greisen 1986Non-RCT
Hathirat 1992Stated specifically in study that the area is malaria-free
Heywood 1989RCT, parenteral iron
Hirve 2007Fortification of food or drink
Honig 1978RCT with intramuscular iron
Hussen 1985Non-endemic area: Egypt. Not known whether RCT
Hyder 2007Fortification of food or drink
Ip 2009Fortification of food or drink
Isager 1974Non RCT (review article)
ISRCTN21782274According to correspondence with authors, the trial used iron fortified biscuits
ISRCTN85737357No relevant outcome. In correspondence with author, the study was not adequately completed, therefore results will not be analysed.
ISRCTN88523834Randomization to antimalaria treatment. All children received iron
Jacobi 1972Non-RCT
Kanani 2000Cluster-RCT with less than 2 units per arm
Kleinschmidt 1965Non-RCT
Kurz 1985Non-RCT
le Cessie 2002Non-RCT
Le Huong 2007Fortification of food or drink
Lima 2006Non-RCT
Liu 1995Comparison of different iron administration schedules. No placebo group
Liu 1996Dose comparison, all groups given iron
Lozoff 1982Incompatible intervention (iron + other micronutrients)
Lozoff 1996None of the reported outcomes relevant / usable for the review
Lozoff 2003Non-endemic areas
Lutter 2008Fortification of food or drink
Maldonado 2007Fortification of food or drink
Mamiro 2001Non RCT (cross-sectional survey)
Migasena 1972Stated specifically in study that the area is malaria-free
Mitra 1997Stated specifically in study that the area is malaria-free
Morales 2008Fortification of food or drink
Morley 1999Non-endemic areas: England
Mozaffari-Khosravi 2010Incompatible intervention (dose of iron administered was 0.08 mg/kg/day, too low for consideration as supplementation
Murray 1978RCT, adults
Muñoz 2000The supplements used were a part of a beverage
Mwanakasale 2009Incompatible intervention (iron vs. vitamin C)
Naghii 2007Fortification of food or drink
Nchito 2004No relevant outcome (study assessed geophagy as outcome)
NCT00213161Fortification of food or drink
NCT00301054No relevant outcome. The pharmaceutical company which supplied the drugs, placebo and drug blinding codes did not provide the investigators with the codes (author correspondence). The authors stated that "Should the drug company come forth with the codes we will certainly share the results with you".
Nguyen 2002Incompatible interventions: group 1 placebo, group 2 iron, group 3 daily iron, group 4 weekly iron. Only groups 3 and 4 were assigned randomly
Oppenheimer 1986RCT, parenteral iron
Oski 1978RCT, parenteral iron
Oski 1983Non-randomized trial
Ouedraogo 2010Incompatible intervention (Iron + other micronutrients). Intervention included iron, zinc, vitamin A, vitamin C and iodinedes MM
Parks 1989Non endemic area: Birmingham
Pereira 1978Non-RCT
Perrone 1999Non endemic area: Italy
Rahimy 2007Non-RCT
Rahman 1999Stated specifically in study that the area is malaria-free
Rico 2006None of the reported outcomes relevant / usable for the review
Rohner 2010Fortification of food or drink (iron fortified biscuits)
Salinas-Pielago 1998Fortification of food or drink. Iron fortified biscuits
Sankar 2009Non-endemic areas. Study conducted within a neonatal unit in India, with no exposure to malaria
Sarker 2008Non-endemic areas. Author stated in correspondence that area not endemic for malaria
Sarma 2006Fortification of food or drink
Schellenberg 2001RCT, all groups received iron
Schellenberg 2004Dose comparison, all groups given iron
Schultink 1995All groups given iron (dose, schedule, or other comparisons)
Schumann 2009Fortification of food or drink
Schumann 2009aNon-endemic areas. Author stated in correspondence that area not endemic for malaria
Seshadri 1982aNone of the reported outcomes relevant / usable for the review
Sharma 2000All groups given iron (dose, schedule, or other comparisons)
Singla 1982Incompatible intervention (iron + other micronutrients: iron + FA + B12 vs. placebo)
Sungthong 2002Stated specifically in study that the area is malaria-free
Tee 1999Stated specifically in study that the area is malaria-free
Thibault 1993Non-endemic area: France
Thu 1999Incompatible intervention (iron + other micronutrients: iron + zinc + retinol + vitamin C vs. placebo)
Tielsch 2006Non-endemic area, according to correspondence with the author
Tomashek 2001RCT, all groups received iron
Troesch 2011Non-endemic areas. Stated specifically that the area is malaria-free. Intervention consisted of multiple micronutrients
van Stuijvenberg 2008Fortification of food or drink
Vaughan 1977None of the reported outcomes relevant/ usable for the review
Walter 1986Non-RCT
Wegmüller 2006Fortification of food: iodized salt fortified with 3 mg Fe/g vs. iodized salt
Williams 1999Non-endemic areas: England
Yalcin 2000Non-endemic area
Yang 2004Non-endemic area

Characteristics of studies awaiting assessment [ordered by study ID]

Arcanjo 2011

MethodsCluster randomized, placebo-controlled double-blind trial
ParticipantsPreschool children, 5 years old, living in the north-east of Brazil
InterventionsWeekly iron supplementation with ferrous sulphate heptahydrate compared with placebo
OutcomesHaemoglobin / anaemia
NotesAwaiting correspondence regarding malaria activity

Februhartanty 2002

MethodsRandomized trial
ParticipantsPostmenarcheal female adolescent students in Kupang, East Nusa Tenggara, Indonesia
InterventionsWeekly iron vs. iron for four consecutive days during the menstruation cycle vs. placebo
OutcomesHaemoglobin
NotesAwaiting correspondence regarding malaria activity

Sazawal 2006 (C)c

MethodsCluster randomized controlled trial, double-blind, placebo controlled
ParticipantsChildren aged 1 to 35 months living in Pemba, Zanzibar
InterventionsIn the current version of the review we included two arms of this trial: iron- folic acid-vitamin A vs. placebo-vitamin A, up until the time the iron arms were stopped based on the safety committee decision. Depending on data availability, we plan to add results from the iron-folic acid plus vitamin A and zinc; vs. zinc-vitamin A arms at the time the iron arms were stopped (and the children receiving iron were transferred to the respective study arms without iron supplementation).
Outcomes

Admissions for malaria

Cerebral malaria

Hospital admissions

Mortality

NotesData correspondence with Professor Sazawal.