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Oral iron supplements for children in malaria-endemic areas

  1. Joseph U Okebe2,
  2. Dafna Yahav3,
  3. Rana Shbita3,
  4. Mical Paul1,*

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 5 OCT 2011

Assessed as up-to-date: 29 JUN 2011

DOI: 10.1002/14651858.CD006589.pub3


How to Cite

Okebe JU, Yahav D, Shbita R, Paul M. Oral iron supplements for children in malaria-endemic areas. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD006589. DOI: 10.1002/14651858.CD006589.pub3.

Author Information

  1. 1

    Sackler Faculty of Medicine, Infectious Diseases Unit, Tel Aviv, Israel

  2. 2

    Medical Research Council Unit, Banjul, Gambia

  3. 3

    Beilinson Hospital, Rabin Medical Center, Department of Medicine E, Petah Tikva, Israel

*Mical Paul, Infectious Diseases Unit, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 49100, Israel. paulm@post.tau.ac.il. mica@zahav.net.il; MichalP2@clalit.org.il; paulm@post.tau.ac.il.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 5 OCT 2011

SEARCH

 
Characteristics of included studies [ordered by study ID]
Adam 1997 (C)

MethodsCluster 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


ParticipantsNumber 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%


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

Duration of treatment: 12 weeks

Duration of follow up: 12 months


OutcomesMain 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


NotesTrial 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

MethodsCluster 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


ParticipantsNumber 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


InterventionsElemental 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


OutcomesMain objective/outcome: Effect of iron supplementation on anaemia

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end and change)


NotesTrial 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

MethodsIndividually randomized

Trial years: April 1998 to February 1999


Participants73 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


InterventionsFerric 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial years: not stated


Participants73 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


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial years: not stated


Participants112 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


InterventionsStudy 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


OutcomesMain 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.


NotesTrial 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

MethodsIndividually randomized

Trial years: not stated


Participants80 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


InterventionsStudy 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial years: not stated


Participants218 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


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial years: not stated


Participants645 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


InterventionsType 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: March 1995 to November 1995


Participants176 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


InterventionsFerrous 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 


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial years: not stated


Participants197 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


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

Duration of treatment: 3 months

Duration of follow up: 9 months


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: March 1998 to November 1998


Participants988 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


InterventionsFerrous 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


OutcomesMain 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


NotesLocation: 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)

MethodsCluster-randomized

Trial years: not stated

Unit of randomization: 4 preschools

Average cluster size: 65.5

Adjustment for clustering: none

Methods of adjustment: not stated


Participants4 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


InterventionsIntervention 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


OutcomesMain 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)


NotesLocation: 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

MethodsIndividually randomized

Trial years: not reported


Participants460 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


InterventionsFerrous 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


OutcomesMain objective/outcome:

to evaluate the haemoglobin values after iron and folic acid supplementation

Review outcomes reported in the trial:

1. Haemoglobin (change)


NotesTrial 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

MethodsIndividually randomized

Trial years: not stated


Participants241 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


InterventionsFerrous 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial years: not stated 


Participants453 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


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

Duration of treatment: 8 weeks

Duration of follow up: 8 weeks


OutcomesMain 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.


NotesTrial 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

MethodsIndividually randomized

Trial duration: April to November 1999


Participants546 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


InterventionsFerrous 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants120 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


InterventionsIron (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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants177 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


InterventionsFerrous 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants154 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


InterventionsFerrous 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: July 1998 until March 1999


Participants800 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


InterventionsIron 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: December 2004 to June 2005


ParticipantsIn 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


InterventionsFerric 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


OutcomesMain 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).


NotesTrial 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

MethodsIndividually randomized

Trial duration: February 1994 to July 1994


Participants500 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


InterventionsFerrous 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


OutcomesMain 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.


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants170 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


InterventionsIron 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants210 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


InterventionsFerrous 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


OutcomesMain objective/outcome:

The effects of iron supplementation on haemoglobin level

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end and change)


NotesTrial 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)

MethodsCluster 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


Participants12 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


InterventionsIron-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


OutcomesMain objective/outcome:

To evaluate association between anaemia and running distance

Review outcomes reported in the trial:

1. Deaths

2. Haemoglobin (end and change)


NotesTrial 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)

MethodsCluster 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


ParticipantsNumber 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


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: started June 1985


Participants318 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%


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: 1999 to 2000


Participants169 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


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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)

MethodsCluster 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


ParticipantsNumber 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


InterventionsStudy 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants126 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


InterventionsStudy 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants545 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


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants166 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


InterventionsStudy 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: winter 1996 to spring 1997


Participants523 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


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: April to November 1986


Participants55 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%


InterventionsStudy 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: March to July 1990


Participants87 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


InterventionsStudy 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: April to November 1998


Participants279 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%


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: July 1997 to May 1999


Participants680 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


InterventionsStudy 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants126 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


InterventionsStudy 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: June 1999 to May 2000


Participants291 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%


InterventionsStudy 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


OutcomesMain objective/outcome: Infections

Review outcomes reported in the trial:

1. Malaria

2. Anaemia

3. Death


NotesTrial 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)

MethodsCluster 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


Participants684 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


InterventionsStudy 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants115 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


InterventionsStudy 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: 1995


Participants832 randomized, 832 evaluated

Age: range 8 to 48 weeks

Setting: community, rural

% anaemia at baseline: not stated

% malaria at baseline: not stated


InterventionsStudy 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


OutcomesMain objective/outcome:

Haemoglobin, anaemia and iron-related outcomes

Review outcomes reported in the trial:

1. Malaria

2. Mortality

3. Anaemia

4. Hospitalizations


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants136 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


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: April 1999 to March 2000


Participants100 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


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: March to May 1995


Participants222 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


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: November 1994 to January 1996


Participants231 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%


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants299 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


InterventionsStudy 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


OutcomesMain objective/outcome:

Effect of iron ± deworming on Hb

Review outcomes reported in the trial:

1. Anaemia

2. End and change in Hb


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants80 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


InterventionsStudy 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


OutcomesMain objective/outcome:

Haematological status

Review outcomes reported in the trial:

1. Mortality

2. Haemoglobin end and change

3. End iron level


NotesTrial 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

MethodsIndividually randomized

Trial duration: February to September 1998


Participants855 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%


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants219 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


InterventionsStudy 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


OutcomesMain 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


NotesTrial 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)

MethodsCluster 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


ParticipantsNumber 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


InterventionsFerrous 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


OutcomesMain 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)


NotesTrial 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)

MethodsCluster 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


ParticipantsNumber 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


InterventionsFerrous 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


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

Review outcomes reported in the trial:

1. Anaemia

2. Death

3. Haemoglobin (end)


NotesTrial 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)

MethodsCluster 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


Participants10 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


InterventionsIron 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)


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

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end and change)


NotesTrial 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

MethodsCluster 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


Participants22,959 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


InterventionsIron 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)


OutcomesMain 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


NotesTrial 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

MethodsCluster 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


Participants3171 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


InterventionsIron 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).


OutcomesMain 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.


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants28 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


InterventionsIron 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants149 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


InterventionsIron 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


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

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end)


NotesTrial 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)

MethodsCluster 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


Participants4 preschools, 89 individuals randomized

Age: not stated

Setting: school

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

% malaria at baseline: not stated


InterventionsIron 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)


OutcomesMain objective/outcome: Anaemia

Review outcomes reported in the trial:

1. Anaemia

2. Haemoglobin (end and change)


NotesTrial 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

MethodsIndividually randomized

Trial duration: March 1998 to March 1999


Participants209 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


InterventionsFerrous 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


OutcomesMain 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


NotesTrial 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)

MethodsCluster 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


ParticipantsNumber 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


InterventionsFerrous 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


OutcomesMain objective/outcome: Hb/iron + malaria status

Review outcomes reported in the trial:

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

2. Deaths

3. Febrile disease


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants1134 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


InterventionsIron 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


OutcomesMain 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


NotesTrial 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)

MethodsCluster 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


Participants45 classes, 2163 children

Age (per study): average 12 to 15 years

Setting: school

% anaemia at baseline: not stated

% malaria at baseline: not stated


InterventionsFerrous 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


OutcomesMain objective/outcome: anaemia

Review outcomes reported in the trial:

Haemoglobin (change)


NotesTrial 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

MethodsIndividually randomized

Trial duration: not stated


Participants130 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


InterventionsFerrous 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: 1983 to 1984


Participants176 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


InterventionsFerrous 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


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

Review outcomes reported in the trial:

1. Haemoglobin (end)

2. Ferritin, TIBC, protoporphyrin


NotesTrial 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

MethodsIndividually randomized

Trial years: 1996 to 1997


Participants428 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%


InterventionsFerrous 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: April to June 1993


ParticipantsIn 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


InterventionsFerrous 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: July to December 1992


Participants600 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


InterventionsSodium 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: 1998 to 2000


ParticipantsIn 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


InterventionsFerrous 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized 

Trial duration: not stated


Participants674 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


InterventionsFerrous 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


OutcomesMain 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


NotesTrial 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

MethodsIndividually randomized

Trial duration: August to December 1996


Participants312 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


InterventionsFerrous 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


OutcomesMain 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)


NotesTrial 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

MethodsIndividually randomized

Trial duration: October 1999 to March 2000


Participants437 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)


InterventionsFerrous 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)


OutcomesMain 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


NotesTrial 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

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).

OutcomesAdmissions for malaria

Cerebral malaria

Hospital admissions

Mortality

NotesData correspondence with Professor Sazawal.

 
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)13Risk Ratio (Fixed, 95% CI)0.99 [0.90, 1.09]

    1.1 Anaemia
8Risk Ratio (Fixed, 95% CI)1.02 [0.88, 1.19]

    1.2 No anaemia
5Risk Ratio (Fixed, 95% CI)0.97 [0.86, 1.09]

 2 Clinical malaria (by age)13Risk Ratio (Fixed, 95% CI)0.99 [0.90, 1.09]

    2.1 <2 yrs
4Risk Ratio (Fixed, 95% CI)0.94 [0.82, 1.09]

    2.2 2-5 yrs
3Risk Ratio (Fixed, 95% CI)0.97 [0.75, 1.26]

    2.3 >5 yrs
6Risk Ratio (Fixed, 95% CI)1.04 [0.91, 1.20]

 3 Clinical malaria (P. falciparum only)8Risk Ratio (Fixed, 95% CI)0.98 [0.87, 1.11]

 4 Severe malaria (clinical malaria with high-grade parasitaemia or requiring admission)4Risk Ratio (Fixed, 95% CI)0.91 [0.76, 1.08]

 5 All-cause mortality (by location)228644Risk Difference (M-H, Fixed, 95% CI)3.66 [-0.00, 0.00]

    5.1 Hypo or mesoendemic
94846Risk Difference (M-H, Fixed, 95% CI)-0.00 [-0.00, 0.00]

    5.2 Hyper or holoendemic
133798Risk Difference (M-H, Fixed, 95% CI)0.00 [-0.01, 0.01]

 6 Any parasitaemia, end of treatment (by anaemia at baseline)8Risk Ratio (Fixed, 95% CI)1.09 [0.98, 1.22]

    6.1 Anaemia
5Risk Ratio (Fixed, 95% CI)1.05 [0.92, 1.20]

    6.2 No anaemia
3Risk Ratio (Fixed, 95% CI)1.17 [0.99, 1.40]

 7 Any parasitaemia, end of treatment ( by age)8Risk Ratio (Fixed, 95% CI)1.09 [0.98, 1.22]

    7.1 <2 yrs
1Risk Ratio (Fixed, 95% CI)1.18 [0.89, 1.57]

    7.2 2-5 yrs
4Risk Ratio (Fixed, 95% CI)1.06 [0.91, 1.23]

    7.3 >5 yrs
3Risk Ratio (Fixed, 95% CI)1.12 [0.93, 1.34]

 8 Any parasitaemia, end of treatment (P. falciparum only)6Risk Ratio (Fixed, 95% CI)1.07 [0.95, 1.21]

    8.1 Iron vs. placebo/no treatment
5Risk Ratio (Fixed, 95% CI)1.09 [0.96, 1.24]

    8.2 Iron + antimalarial vs. antimalarial
1Risk Ratio (Fixed, 95% CI)0.87 [0.56, 1.33]

 9 Any parasitaemia, end of treatment (by allocation concealment)8Risk Ratio (Fixed, 95% CI)1.09 [0.98, 1.22]

    9.1 Adequate
3Risk Ratio (Fixed, 95% CI)0.94 [0.79, 1.11]

    9.2 Unclear
5Risk Ratio (Fixed, 95% CI)1.22 [1.06, 1.40]

 10 High-grade parasitaemia5Risk 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 visits5Risk Ratio (Fixed, 95% CI)Subtotals only

    12.1 Hospitalization, iron vs. placebo
4Risk Ratio (Fixed, 95% CI)0.81 [0.68, 0.98]

    12.2 Hospitalization, iron + antimalarial vs. antimalarial
2Risk Ratio (Fixed, 95% CI)1.22 [0.96, 1.57]

    12.3 Clinic visit, iron vs. placebo
2Risk Ratio (Fixed, 95% CI)0.95 [0.88, 1.02]

    12.4 Clinic visit, iron + antimalarial vs. antimalarial
3Risk 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 Anaemia
112692Mean Difference (IV, Random, 95% CI)1.59 [0.93, 2.26]

    13.2 No anaemia
295852Mean 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 mesoendemic
214335Mean Difference (IV, Random, 95% CI)0.85 [0.54, 1.16]

    14.2 Hyper or holoendemic
144209Mean 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 mesoendemic
122595Mean Difference (IV, Random, 95% CI)0.40 [0.22, 0.58]

    15.2 Hyper or holoendemic
81610Mean 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 mesoendemic
112469Risk Ratio (M-H, Random, 95% CI)0.64 [0.47, 0.86]

    16.2 Hyper or holoendemic
133311Risk 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 mesoendemic
917402Risk Ratio (Fixed, 95% CI)0.96 [0.90, 1.03]

    17.2 Hyper or holoendemic
25175Risk 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 zinc
78254Risk Ratio (Fixed, 95% CI)1.03 [0.95, 1.12]

    18.2 Hypo or mesoendemic with zinc
59024Risk Ratio (Fixed, 95% CI)1.16 [1.07, 1.24]

    18.3 Hyper or holoendemic without zinc
55643Risk Ratio (Fixed, 95% CI)0.92 [0.73, 1.16]

    18.4 Hyper or holoendemic with zinc
12304Risk Ratio (Fixed, 95% CI)0.99 [0.67, 1.46]

 19 Infections per patient-month12Risk Ratio (Fixed, 95% CI)Subtotals only

    19.1 Fever episodes
715683Risk Ratio (Fixed, 95% CI)1.03 [0.93, 1.14]

    19.2 Days with fever
1110Risk Ratio (Fixed, 95% CI)8.37 [1.91, 36.58]

    19.3 Disease episodes other than diarrhoea or respiratory infections
33096Risk Ratio (Fixed, 95% CI)1.03 [0.80, 1.33]

    19.4 All disease episodes
11395Risk 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 mesoendemic
133665Std. Mean Difference (IV, Fixed, 95% CI)0.03 [-0.03, 0.10]

    20.2 Hyper or holoendemic
3939Std. 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 mesoendemic
8824Std. Mean Difference (IV, Fixed, 95% CI)0.09 [-0.05, 0.23]

    21.2 Hyper or holoendemic
3338Std. 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 mesoendemic
133972Std. Mean Difference (IV, Fixed, 95% CI)0.02 [-0.04, 0.08]

    22.2 Hyper or holoendemic
3939Std. 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 mesoendemic
8824Std. Mean Difference (IV, Fixed, 95% CI)0.23 [0.09, 0.37]

    23.2 Hyper or holoendemic
3338Std. Mean Difference (IV, Fixed, 95% CI)0.06 [-0.16, 0.28]

 
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)2Risk Ratio (Fixed, 95% CI)Totals not selected

 2 Severe malaria (cerebral malaria)2Risk Ratio (Fixed, 95% CI)Totals not selected

 3 Clinical malaria (by malaria management, including iron + folate)15Risk Ratio (Fixed, 95% CI)1.03 [0.95, 1.11]

    3.1 Surveillance and treatment
9Risk Ratio (Fixed, 95% CI)0.94 [0.85, 1.04]

    3.2 Unspecified
6Risk 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 mesoendemic
1209Risk Difference (M-H, Fixed, 95% CI)0.0 [-0.02, 0.02]

    4.2 Hyper or holoendemic
417898Risk Difference (M-H, Fixed, 95% CI)0.00 [-0.00, 0.01]

 5 Any hospitalization1Risk 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 Anaemia
4273Mean Difference (IV, Random, 95% CI)1.10 [0.30, 1.91]

    6.2 No anaemia
2867Mean 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 mesoendemic
62392Mean Difference (IV, Random, 95% CI)1.01 [0.63, 1.38]

    7.2 Hyper or holoendemic
184Mean 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 mesoendemic
4557Risk Ratio (M-H, Random, 95% CI)0.44 [0.24, 0.80]

    8.2 Hyper or holoendemic
2551Risk 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]

 
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 visits2Risk Ratio (Fixed, 95% CI)Subtotals only

    3.1 Hospitalization, iron + antimalarial vs. placebo
25904Risk Ratio (Fixed, 95% CI)0.59 [0.48, 0.73]

    3.2 Clinic visit, iron + antimalarial vs. placebo
25904Risk Ratio (Fixed, 95% CI)0.88 [0.82, 0.95]

 4 Haemoglobin at end of treatment1Mean Difference (IV, Random, 95% CI)Totals not selected

 5 Anaemia3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    5.1 Iron + antimalarial vs. placebo, end of treatment
2295Risk Ratio (M-H, Random, 95% CI)0.44 [0.28, 0.70]

    5.2 Iron + antimalarial vs. placebo, end of follow up
1420Risk Ratio (M-H, Random, 95% CI)0.37 [0.26, 0.54]

 
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 visits3Risk Ratio (Fixed, 95% CI)Subtotals only

    3.1 Hospitalization
2368Risk Ratio (Fixed, 95% CI)2.00 [0.80, 5.00]

    3.2 Clinic visit
1273Risk 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 Anaemia1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 6 Infections (pneumonia)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Summary of findings for the main comparison. Oral iron supplements for children in malaria endemic areas

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)
⊕⊕⊕⊕
high2,3,4,5,6

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)
⊕⊕⊕⊕
high2,3,4,5,6

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)
⊕⊕⊕⊕
high2,3,4,5,6

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)
⊕⊕⊝⊝
Low7

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 low8,9,10

All-cause mortality in malaria hyper / holoendemic areas
Follow-up: 1.5 to 6 months
Study population11Not estimable3798
(13 studies)
⊕⊕⊝⊝
low13,14,15,16

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)
⊕⊕⊝⊝
Low18,19

*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.

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

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)
⊕⊕⊝⊝
low3,4,5

Severe malaria (cerebral malaria)
Admissions to hospital
Follow-up: mean 12 months1
Results not pooledResults not pooledNot estimable1619
(2 studies2)
⊕⊕⊕⊝
moderate3,4,5,6

All-cause mortality in hyper / holoendemic regions
Follow-up: 1.5-12 months
Study population7Not estimable17898
(4 studies)
⊕⊕⊕⊝
moderate8,9

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)
⊕⊕⊝⊝
low3,11,12

*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.

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

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)
⊕⊕⊕⊕
high1,2

All-cause mortality
Follow-up: 1.5 to 12 months
Study population3RR 1.05
(0.52 to 2.11)
728
(4 studies)
⊕⊕⊝⊝
low4,5

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.

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

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)
⊕⊕⊝⊝
low1

All-cause mortality
Follow-up: 1-3 months
Study population2Not estimable664
(4 studies)
⊕⊕⊝⊝
low1,3

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.

 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
 
Table 1. Description and location of malaria-endemic areas

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

 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
 
Table 2. Detailed search strategies

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

 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.
 
Table 3. Studies reporting malaria as an outcome: malaria definitions, types of outcomes and methods of surveillance and treatment in the trial

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 density3 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 density3 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 parasitaemia4 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

 Time of assessment: refers to time from randomization; FU, follow-up.
 
Table 4. Analysis of cluster randomized trials adjusting standard errors

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

 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.
 
Table 5. Analysis of cluster randomized trials adjusting sample size

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

 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.
 
Table 6. Comparative malaria parasitaemia rates

Study IDInterventionUnit of measurementIronControlNo. ironNo.

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 2003Iron plus antimalaria vs antimalaria

Iron vs placebo (with single-dose antimalarial treatment)
Geometric mean, parasites/mm31705

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/μLAge < 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/μL4927 (daily)

2207 (weekly)
181277 (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)

 RBC,red blood cell; WBC, white blood cell.