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Intermittent iron supplementation for improving nutrition and development in children under 12 years of age

  1. Luz Maria De-Regil1,*,
  2. Maria Elena D Jefferds2,
  3. Allison C Sylvetsky3,
  4. Therese Dowswell4

Editorial Group: Cochrane Developmental, Psychosocial and Learning Problems Group

Published Online: 7 DEC 2011

Assessed as up-to-date: 23 OCT 2011

DOI: 10.1002/14651858.CD009085.pub2


How to Cite

De-Regil LM, Jefferds MED, Sylvetsky AC, Dowswell T. Intermittent iron supplementation for improving nutrition and development in children under 12 years of age. Cochrane Database of Systematic Reviews 2011, Issue 12. Art. No.: CD009085. DOI: 10.1002/14651858.CD009085.pub2.

Author Information

  1. 1

    Micronutrient Initiative, Ottawa, ON, Canada

  2. 2

    Centers for Disease Control and Prevention, International Micronutrient Malnutrition Prevention and Control Program, Nutrition Branch, Division of Nutrition, Physical Activity and Obesity, Atlanta, Georgia, USA

  3. 3

    Emory University, Graduate Division of Biological and Biomedical Sciences, Atlanta, Georgia, USA

  4. 4

    The University of Liverpool, Cochrane Pregnancy and Childbirth Group, Department of Women's and Children's Health, Liverpool, UK

*Luz Maria De-Regil, Micronutrient Initiative, 180 Elgin Street, Suite 1000, Ottawa, ON, K2P 2K3, Canada. lderegil@micronutrient.org.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 7 DEC 2011

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 
Summary of findings for the main comparison. Intermittent use of iron supplements versus placebo or no intervention in children younger than 12 years of age

Patient or population: children under 12 years of age
Settings: community settings
Intervention: intermittent supplementation with iron alone or with other nutrients
Comparison: placebo or no intervention

OutcomesRelative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)

Anaemia (haemoglobin below a cut-off defined by trialists, taking into account the age and altitude)

 
RR 0.51
(0.37–0.72)
1824
(10 studies)
⊕⊕⊕⊝
moderate1

Haemoglobin (g/L)MD 5.20
(2.51–7.88)
3032

 (19 studies)
⊕⊕⊝⊝
low2,3

Iron deficiency (using ferritin concentrations)RR 0.24
(0.06–0.91)

 
431
(3 studies)
⊝⊝⊝⊝
very low2,3,4

Iron status (ferritin (μg/L)MD 14.17
(3.53–24.81)
550
(5 studies)
⊕⊕⊝⊝
low2,3

Iron deficiency anaemia Not estimable0
(0 studies)
None of the trials reported on this outcome

All-cause mortalityNot estimable0
(0 studies)
None of the trials reported on this outcome

CI, confidence interval; RR, risk ratio; MD, mean difference.

*GRADE Working Group grades of evidence:
High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: We have moderate confidence in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
Very low quality: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of the effect.

1There was high statistical heterogeneity. Given the large and consistent effect (RR 0.51; 95% CI 0.37–0.72) we have refrained from downgrading even though three of the nine studies are at high risk of bias.

2 High statistical heterogeneity but results were consistent.
3 Some studies lacked blinding and clear methods of allocation.

4 Wide confidence intervals.

Note: For cluster-randomised trials the analyses only include the estimated effective sample size, after adjusting the data to account for the clustering effect.

 Summary of findings 2 Intermittent versus daily use of iron supplements in children younger than 12 years of age

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Description of the condition

Iron is an essential nutrient for all body tissues and is present in the brain of the developing fetus, where it is needed for proper formation of neural tissue (Iannoti 2006) and development of brain cells (Beard 2008). Iron deficiency, a common form of nutritional deficiency, results from long-term imbalance caused by an inadequate dietary iron intake; poor iron absorption or utilisation; increased iron requirements for growth during childhood, adolescence or pregnancy; or chronic blood losses (Moy 2006). In the later stages of iron depletion, the haemoglobin concentration decreases, resulting in a condition known as iron deficiency anaemia.

Anaemia is characterised by a reduction in the oxygen-carrying capacity of blood such that the body's needs can no longer be met. In addition to iron deficiency, other vitamin and mineral deficiencies (for example, folate, vitamin B12 and vitamin A), chronic inflammation, parasitic infections and inherited disorders of haemoglobin structure can result in all-cause anaemia (WHO 2001). Among females, anaemia is often exacerbated after beginning menstruation, especially if it occurs at an early age and the young females do not consume sufficient iron to offset menstrual losses (WHO 2001). Haemoglobin concentrations are used to diagnose anaemia, while serum ferritin, an iron storage protein, and serum transferrin, an iron transport protein, are commonly used as indicators of iron status in populations (WHO 2011a; WHO 2011b).  

Children, particularly those younger than five years, are vulnerable to iron deficiency anaemia because of their increased needs as a result of rapid growth. It is estimated that approximately 600 million preschool and school-aged children are anaemic worldwide, and it is calculated that at least half of the cases are due to iron deficiency (WHO/CDC 2008). In general, low-income countries have a higher prevalence of anaemia (WHO/CDC 2008). This association is also true in high-income countries where people of low socioeconomic status are especially susceptible to iron and other vitamin and mineral deficiencies (Cole 2010).

Consequences of iron deficiency anaemia during childhood include growth retardation, reduced school achievement, impaired motor and cognitive development, and increased morbidity from a variety of causes including diarrhoea and acute respiratory infections (WHO 2001). Specifically, iron deficiency can lead to deficits in memory and behavioural regulation as iron is required to make neurotransmitters such as dopamine, epinephrine and serotonin (Iannoti 2006; Moy 2006; Beard 2008), while impaired myelination contributes to deficits in motor function. Long-term effects of early iron deficiency include decreased work capacity and impaired cognitive and behavioural development (Lozoff 2000; Lozoff 2007). Some of these impairments are thought to be irreversible if they occur at an early age and the consequences may continue even after treatment, reinforcing the importance of prevention (Siddiqui 2004; Iannoti 2006; Lozoff 2007).

 

Description of the intervention

Mass fortification of food staples with iron; dietary diversification to increase iron intake, absorption and utilisation; and iron supplementation have been used to prevent or treat iron deficiency anaemia. Mass fortification of staple foods with iron is usually not aimed at meeting the needs of young children, with the exception of targeted complementary infant feeding programmes (WHO 2009a). Dietary diversification to improve iron status in populations at risk is also difficult because of limited food access among the most vulnerable populations, the limited quantity of food that children can consume, and the fact that the strategy requires multiple behavioural changes among children and their families. To date, there are few effective dietary diversification intervention programmes at scale (Davidsson 2003). Finally, iron supplementation, which is the provision of doses of iron alone or in combination with other micronutrients in the form of tablets, syrups or capsules, is the most widespread strategy for improving iron status in children worldwide.

The World Health Organization (WHO) recommends a supplemental provision of 2 mg of elemental iron per kilogram body weight per day for three months in children less than six years of age who were born at term. Children of school age and older should receive 30 mg of elemental iron and 250 μg (0.25 mg) of folic acid daily, particularly in populations where anaemia prevalence is greater than 40% (WHO 2001). Though the current recommendations include iron alone or with folic acid, it has been suggested that administration of additional vitamins and minerals may prevent or reverse anaemia derived from one or more nutritional deficiencies (Bhutta 2009). Daily iron supplementation has proven to be effective in increasing haemoglobin concentrations in children, especially in those who are anaemic (Gera 2007). In spite of this, in real world settings the long regimen duration, the low coverage rates and insufficient tablet distribution, and side effects associated with daily iron supplementation (for example, gastrointestinal discomfort, constipation and staining of teeth with drops or syrups) limit adherence, especially in young children (ACC/SCN 1991; Stoltzfus 2011). In older children these effects may partially be controlled with the use of slow-release iron tablets in which iron has similar bioavailability to regular iron compounds (for example, ferrous sulphate or ferrous fumarate) (Simmons 1993; Bothwell 2000), although their higher cost may be a limiting factor for wider use.

 

How the intervention might work

Oral iron supplementation on an intermittent basis (that is once, twice or three times a week on non-consecutive days) has been suggested as a more efficient preventive intervention in public health programmes than the more common daily iron supplementation scheme. The basis for this iron intermittent supplementation regimen is that the absorption is maximised by provision of iron in synchrony with the turnover of the mucosal cells (that is, intestinal cells are 'fresh' to take up iron) (Wright 1990; Berger 1997; Viteri 1997; Beaton 1999; Tavil 2003). In addition, other minerals such as zinc and copper may be more readily absorbed because they are not regularly competing with iron for absorption channels, leading to an improved micronutrient status (Baqui 2005). It has been reported that intermittent supplementation may be safer than daily supplementation because intestinal cells are less exposed to an iron-rich environment, which may cause cell damage (Casanueva 2003; Viteri 2005). Also, it has been suggested that additional iron may exacerbate malaria infection and so this reduced exposure to iron overall is particularly relevant in malaria settings as less iron is available for the parasite's growth (Ekvall 2000; NIH 2011). Though side effects may still occur with intermittent regimens, they are experienced less frequently and may be perceived as more acceptable as a result, increasing adherence to supplementation programmes (Thu 1999; Viteri 2005).

Despite the biological plausibility of this intervention to reduce anaemia, its success as a public health intervention will likely be determined by several factors such as the available resources; the existence of the appropriate policies and legislation; the production and supply of the supplements; the development of delivery systems; the development and implementation of external and internal quality control systems, and the development and implementation of strategies for information, education and communication for behaviour change among consumers. Figure 1 presents a generic logic model for micronutrient interventions that depicts the programme theory and the plausible relationships between inputs and expected changes in health and outcomes that can be adapted to the context of each setting (De-Regil 2011; WHO/CDC 2011).

 FigureFigure 1. WHO/CDC logic model for micronutrients interventions in public health (with permission from WHO)

 

Why it is important to do this review

There are currently no international recommendations on intermittent iron supplementation regimens in children. It has been reported that the provision of an iron supplement once a week is comparable to daily supplementation in improving anaemia status (Siddiqui 2004). Other authors suggest that this effect may be enhanced when iron is given twice a week (Schultink 1995; Tavil 2003; Olsen 2006).

Weekly iron and folic acid supplementation has recently been recommended by the WHO to prevent anaemia in women of reproductive age (WHO 2009b). This intervention is currently implemented at scale in many countries around the world as part of public health programmes. It could potentially be targeted to other age groups, such as young children and school-aged children, since the supplement can be provided at home and in schools or other institutional settings. However, to date, there has been no systematic assessment of the safety and effectiveness of weekly or any other intermittent iron supplementation regimen among children to inform policy makers.

This review complements the findings of two related Cochrane systematic reviews exploring the effects of intermittent regimens among menstruating women (Fernández-Gaxiola 2011) and pregnant women (Peña-Rosas 2009).

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

To assess the effects of intermittent iron supplementation, alone or in combination with other vitamins and minerals, on nutritional and developmental outcomes in children less than 12 years of age compared with daily supplementation, a placebo or no supplementation.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We included randomised and quasi-randomised studies with randomisation at either an individual or cluster level. We defined quasi-randomised trials as trials which use systematic methods to allocate participants to treatment groups, such as alternation, assignment based on date of birth or case record number (Higgins 2011). We did not include cross-over trials nor other types of evidence (for example, cohort or case-control studies) in the meta-analysis but we have considered such evidence in the discussion where relevant.

 

Types of participants

Children under the age of 12 years at the time of the trials.

We did not include studies specifically targeting premature or low birth weight infants, or children with severe infectious diseases, such as HIV, as they may metabolise iron differently and have different health and disease indicators. These topics are subject to separate Cochrane reviews (Adetifa 2009; Mills 2009).

 

Types of interventions

Oral supplements of iron, alone or with other vitamins and minerals, given on an intermittent basis and compared with a placebo or no supplementation, or compared with the same supplements provided daily.

Oral iron supplementation refers to the delivery of iron compounds directly to the oral cavity, either as a tablet, capsule, dispersible tablet or liquid. For the purpose of this review, intermittent supplementation is defined as the provision of iron supplements one, two or three times a week on non-consecutive days.

We performed the following comparisons:

  1. any intermittent iron supplementation versus no supplementation or placebo (0 to < 12 years of age);
  2. any intermittent iron supplementation versus any daily iron supplementation (0 to < 12 years of age);
  3. any intermittent iron supplementation versus no supplementation or placebo (0 to 59 months of age);
  4. any intermittent iron supplementation versus any daily iron supplementation (0 to 59 months of age);
  5. any intermittent iron supplementation versus no supplementation or placebo (5 to < 12 years of age);
  6. any intermittent iron supplementation versus any daily iron supplementation (5 to < 12 years of age).

Any intermittent or daily supplementation with iron includes the provision of iron alone, iron plus folic acid or iron plus other vitamins and minerals.

We have included studies that examined interventions where iron supplementation was combined with co-interventions such as deworming, education or other approaches only if the co-interventions were the same in both the intervention and comparison groups. 

We excluded studies examining tube feeding, parenteral nutrition or supplementary food-based interventions such as mass fortification of staple or complementary foods, home fortification with micronutrient powders, lipid-based supplements or Foodlets tablets, or biofortification.

 

Types of outcome measures

 

Primary outcomes

  1. Anaemia (haemoglobin below a cut-off defined by trialists, taking into account the age and altitude)*
  2. Haemoglobin (g/L)*
  3. Iron deficiency (as measured by trialists by using indicators of iron status, such as ferritin or transferrin)*
  4. Iron status (ferritin in μg/L)*
  5. Iron deficiency anaemia (defined by the presence of anaemia plus iron deficiency, diagnosed with an indicator of iron status selected by trialists)*
  6. All-cause mortality (number of deaths during the trial)*

* Outcomes that were included in the 'Summary of Findings' tables.

 

Secondary outcomes

  1. All-cause morbidity (number of children with at least one reported illness during the trial)
  2. Acute respiratory infection (as measured by trialists)
  3. Diarrhoea (as measured by trialists)
  4. Any other adverse side effects (as measured by trialists, such as stained teeth, headache, stomach ache, discomfort, constipation)
  5. Adherence (percentage of children who consumed more than 70% of the expected doses)
  6. Folate status (as measured by trialists)
  7. Mental development and motor skill development (children 0 to 59 months) (as assessed by trialists, including Bayley Mental Development Index (MDI), Bayley Psychomotor Development Index (PDI), Stanford-Binet Test, DENVER II Developmental Screening Test)
  8. School performance (children 60 months and older) (as measured by trialists)
  9. Physical capacity (children 60 months and older) (as measured by trialists)
  10. Height-for-age Z-scores and weight-for-age Z-scores

We planned to group the outcome time points as follows: immediately after the end of the intervention, one to six months after the end of intervention, and seven to 12 months after the end of the intervention. However, we limited our analyses to the end of the intervention as only two trials reported on continued follow-up after the end of the intervention. We have described this in Characteristics of included studies and plan to extract this information in future updates, if available.

 

Search methods for identification of studies

 

Electronic searches

We searched the following electronic databases:

Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 2), part of The Cochrane Library (searched 24 May 2011);
MEDLINE,1948 to May week 2, 2011 (searched 24 May 2011);
EMBASE, 1980 to 2011 Week 20 (searched 24 May 2011);
CINAHL, 1937 to current (searched 24 May 2011);
ICTRP (searched 24 May 2011);
POPLINE (searched 24 May 2011);
SCIELO (searched 29 June 2011);
LILACS (searched 29 June 2011);
IBECS (searched 29 June 2011);
IMBIOMED (searched 29 June 2011).

The search strategies are in Appendix 1.

We did not apply any language restrictions. For those articles written in a language other than English, we extracted the information or commissioned their translation into English.

 

Searching other resources

For assistance in identifying ongoing or unpublished studies, we contacted authors and known experts to identify any additional or unpublished data. We also contacted the Departments of Nutrition for Health and Development and regional offices of the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), the nutrition section of the United Nations Children's Fund (UNICEF), the World Food Programme (WFP), the Micronutrient Initiative (MI) and Sight and Life Foundation (3 July 2011).

We searched the International Clinical Trials Registry Platform (ICTRP) (searched 24 May 2011) for any ongoing or planned trials.

 

Data collection and analysis

 

Selection of studies

LMD screened all titles and abstracts for potential eligibility, while MEJ, TD and AS each assessed one-third of the abstracts. LMD contacted relevant institutions and searched for ongoing trials. All the authors independently assessed half of the full-text articles for inclusion according to the above mentioned criteria; each paper was therefore assessed by two review authors. We resolved any disagreement through discussion.

If studies were published only as abstracts, or the study reports contained little information on methods, we contacted the authors to obtain further details of study design and results.

 

Data extraction and management

For eligible studies, two authors independently extracted data using a form designed for this review. LMD extracted data from all the studies and the remaining authors each extracted a third. LMD entered data into the Review Manager 5 software (RevMan 2011). The same review author who extracted one-third of the data in duplicate carried out checks for accuracy. We resolved any discrepancies through discussion and documented each stage of the process.

We completed the data collection form electronically and recorded information as follows.

 
(1) Trial methods

  • Study design
  • Unit and method of allocation
  • Unit of analysis
  • Masking of participants and outcome assessors
  • Exclusion of participants after randomisation and proportion of losses at follow-up
  • Study power

 
(2) Participants

  • Location of the study
  • Sample size
  • Age
  • Sex
  • Socioeconomic status (as defined by trialists and where such information was available)
  • Baseline status of anaemia
  • Inclusion and exclusion criteria as described in the Criteria for considering studies for this review

 
(3) Intervention

  • Dose
  • Type of iron compound
  • Supplementation regimen
  • Duration of the intervention
  • Co-intervention

 
(4) Comparison group

  • Type of comparison (no intervention, placebo or daily supplementation with the same nutrients)

 
(5) Outcomes

We recorded both prespecified and non-prespecified outcomes, although we did not use the latter to underpin the conclusions of the review.

When information regarding any of the studies was unclear, we contacted authors of the original reports to provide further details. If there was insufficient information for us to be able to assess risk of bias, studies were put into the awaiting assessment section of the review until further information is published or made available to us.

 

Assessment of risk of bias in included studies

One author (LMD) assessed the risk of bias for all the included studies and the remaining authors each assessed one-third of the studies so that all the trials were assessed by two authors independently, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion or by involving a third assessor.

We reported this assessment in the 'Description of studies' and risk of bias tables. We explicitly mention when authors provided input on their trials.

 

(1) Sequence generation (checking for possible selection bias)

We have described for each included study the method used to generate the allocation sequence.

We assessed the method as:

  • low risk of bias (any truly random process, for example, random number table; computer random number generator);
  • high risk of bias (any non-random process, for example, odd or even date of birth; hospital or clinic record number);
  • unclear risk of bias.   

 

(2) Allocation concealment (checking for possible selection bias)

We have described for each included study the method used to conceal the allocation sequence and have assessed whether intervention allocation could have been foreseen in advance of or during recruitment, or changed after assignment.

We assessed the methods as:

  • low risk of bias (for example, telephone or central randomisation; consecutively numbered sealed opaque envelopes);
  • high risk of bias (open random allocation; unsealed or non-opaque envelopes);
  • unclear risk of bias.   

 

(3) Blinding (checking for possible performance and detection bias)

We have described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. For interventions involving the provision of iron supplements it may be possible to blind children, clinical staff and outcome assessors to group allocation by providing placebo preparations.

We assessed blinding separately for different classes of outcomes and have noted where there has been an attempt at partial blinding.

We assessed the risk of performance bias associated with blinding as:

  • low, high or unclear risk of bias for participants;
  • low, high or unclear risk of bias for personnel.

We assessed the risk of detection bias associated with blinding as:

  • low, high or unclear risk of bias for outcome assessors.

Whilst assessed separately, we combined the results into a single evaluation of risk of bias associated with blinding (Higgins 2011).

 

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We have described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We have stated whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total number of randomised participants), reasons for attrition or exclusion, where reported, and whether missing data were balanced across groups. We assessed methods as:

  • low risk of bias (less than 20% of cases lost to follow-up and balanced in numbers across intervention groups);
  • high risk of bias (20% or more cases lost to follow-up or outcome data imbalanced in numbers across intervention groups);
  • unclear risk of bias .

 

(5) Selective reporting bias

We have described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

  • low risk of bias (where it was clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);
  • high risk of bias (where not all the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
  • unclear risk of bias.

 

(6) Other sources of bias

We have described for each included study any important concerns we have about other possible sources of bias.

We assessed whether each study was free of other problems that could put it at risk of bias:

  • high risk of other bias;
  • low risk of other bias;
  • unclear risk of other bias.

 

(7) Overall risk of bias

We summarised the risk of bias at two levels: within studies (across domains) and across studies.

For the first, we made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. Attrition, lack of blinding and losses to follow-up may be particular problems in studies looking at different regimens of iron supplementation and where children are followed up over time. We explored the impact of the level of bias by undertaking sensitivity analyses, see Sensitivity analysis below.

For the assessment across studies, the main findings of the review are set out in ' Summary of findings for the main comparison and  Summary of findings 2 (SoF) prepared using GRADE profiler software (GRADEpro 2008). The primary outcomes for each comparison have been listed with estimates of relative effects along with the number of participants and studies contributing data for those outcomes. For each individual outcome, the quality of the evidence has been assessed independently by two review authors using the GRADE approach (Balshem 2010), which involves consideration of within-study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias; this results in one out of  four levels of quality (high, moderate, low or very low). This assessment was limited only to the trials included in this review and as we did not consider there was a serious risk of indirectness or publication bias we did not downgrade in these domains.

 

Measures of treatment effect

 

Dichotomous data

For dichotomous data, we have presented results as average risk ratios (RR) with 95% confidence intervals (CI). 

 

Continuous data

We present the results as mean difference (MD) with 95% confidence intervals at the end of the intervention. If trials did not provide this information but reported the mean change, we included these data as suggested by Higgins 2011. There was no need to use the standardised mean difference to combine trials as these outcomes were measured with the same methods.

 

Unit of analysis issues

 

Cluster-randomised trials

We included cluster-randomised trials in the analyses along with individually-randomised trials. Cluster-randomised trials are labelled with a (C). We obtained the intra-cluster correlation coefficient (ICC) from Hall 2002 (C) (ICC 0.0698; average cluster size (ACS): 18.55; design effect (DE) 2.22), Desai 2004 (C) (ICC 0.069; ACS: 1.5; DE 1.035) and Roschnik 2004 (C) (ICC 0.1123; ACS: 33.82; DE 4.35). We calculated the ACS from the reports and imputed the ICC from Roschnik 2004 (C) to Roschnik 2003 (C) as the study designs were very similar (ACS: 29); and from Hall 2002 (C) to Liu 1995 (C) (ACS: 27.3), Sinisterra 1997 (C) (ACS: 199.5), Yang 2004 (C) (ACS: 32), Sen 2009 (C) (ACS: 60) and Arcanjo 2011 (C) (ACS: 17.7) and then calculated each trial's effective sample size. In the case of Yang 2004 (C), the number of classes was not clear so we assumed an average cluster size of 32 based on other reports (Okebe 2011). On the other hand, Awasthi 2005 (C) reported that the sample size was calculated including a design effect of 2.0. We used this value to calculate its effective sample size and also to conduct a sensitivity analysis to examine the potential effect of clustering on the CIs of the summary estimates. As the CIs did not change significantly (5% or more), we do not report the results of the sensitivity analysis. Desai 2004 (C) and Engstrom 2008 (C) were not adjusted as the trial authors reported that the analyses accounted for the effect of clustering.

 

Studies with more than two treatment groups

For studies with more than two intervention groups (multi-arm studies), we included the directly relevant arms only. When we identified studies with various relevant arms, we combined the groups into a single pair-wise comparison (Higgins 2011) and included the disaggregated data in the corresponding subgroup category. When the control group was shared by two or more study arms, we divided the control group (events and total population) over the number of relevant subgroup categories to avoid double counting the participants. The details are described in the Characteristics of included studies tables.

 

Cross-over trials

We did not include cross-over trials.

 

Dealing with missing data

For included studies, we have noted levels of attrition in the Characteristics of included studies tables. We explored the impact of including studies with high levels of missing data in the overall assessment of treatment effect by carrying out sensitivity analysis (these same trials were assessed as being at high risk of bias, see Sensitivity analysis below).

We carried out analyses, as far as possible, on an intention-to-treat basis (ITT), that is, by attempting to include all participants randomised to each group in the analyses. If this was not possible, we performed an available case analysis in which data were analysed for every participant for whom the outcome was obtained.

 

Assessment of heterogeneity

We visually examined the forest plots from meta-analyses to look for any obvious heterogeneity among studies in terms of the size or direction of treatment effect. We used the I2 statistic, Tau2 and Chi2 test to quantify the level of heterogeneity among the trials in each analysis. If we identified moderate or substantial heterogeneity, we explored it by prespecified Subgroup analysis and investigation of heterogeneity. 

 

Assessment of reporting biases

Where we suspected reporting bias (see 'Selective reporting bias' above), we attempted to contact study authors asking them to provide missing outcome data. Where this was not possible, and the missing data were thought to introduce serious bias, we explored the impact of including such studies in the overall assessment of results by a sensitivity analysis. 

We generated funnel plots (estimated differences in treatment effects against their standard error) only for haemoglobin in comparisons one and two, and ferritin in comparison two, as sufficient studies contributed data to these outcomes. Asymmetry could be due to publication bias but it can also be due to a real relationship between trial size and effect size, such as when larger trials have lower adherence and adherence is positively related to effect size.

 

Data synthesis

We carried out statistical analysis using the Review Manager 5 software (RevMan 2011). In this review we prespecified that we would use random-effects model analyses in view of anticipated heterogeneity in the interventions, populations and methods used in different trials.

 

Subgroup analysis and investigation of heterogeneity

Where data were available, we carried out the following subgroup analysis:

  1. by dose of elemental iron per week in the intermittent group: 25 mg or less; greater than 25 mg to 75 mg; greater than 75 mg;
  2. by duration of the supplementation: 0 to three months or less; more than three months;
  3. by type of compound: ferrous sulphate; ferrous fumarate; other;
  4. by anaemia status at baseline (haemoglobin < 110 g/L or < 115 g/L for children 6 to 59 months or 5 to 11 years old, respectively, adjusted by altitude where appropriate): anaemic; non-anaemic; mixed or not reported;
  5. by intermittent supplementation regimen: one supplement a week; other intermittent regimen;
  6. by sex: males; females; mixed or not reported; and
  7. by micronutrient composition: iron alone; iron + folic acid; iron + other micronutrient; iron + multiple micronutrients.

We used the primary outcomes in subgroup analysis.

Pragmatically, we decided not to conduct subgroup analyses for those outcomes with three trials or fewer. We examined differences between subgroups by visual inspection of the subgroups’ confidence intervals; non-overlapping confidence intervals suggesting a statistically significant difference in treatment effect between the subgroups. We also used the Borenstein 2008 approach to formally investigate the differences between two or more subgroups. Analyses were conducted in Revman version 5.1.1 (RevMan 2011).

 

Sensitivity analysis

We carried out sensitivity analysis to examine the effects of removing studies at high risk of bias (studies with poor or unclear randomisation and allocation concealment, and either blinding or high or imbalanced losses to follow-up) from the analysis. We also examined the effect of different intra-cluster correlation coefficients imputed to cluster-randomised trials on the summary estimates of primary outcomes.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Description of studies

 

Results of the search

The search strategy identified 7784 references for possible inclusion, 2453 of which were duplicate references. We assessed 81 published articles in full text, three unpublished reports, one review that contained published and unpublished data, and one abstract that has not been published in full. Nine studies were published in languages other than English: Chinese (Yang 2004 (C)), Farsi (Kargarnovin 2010), French (Nguyen 2002) and Spanish (Sinisterra 1997 (C); Rivera 1998; Sotelo-Cruz 2002; Evangelista-Salazar 2004; UNICEF 2006; Avila-Jimenez 2011). Figure 2 depicts the process for assessing and selecting the studies. We included 33 trials (42 references); excluded 40 (41 references); three trials are awaiting assessment (Husseini 1999; Reid 2001; Kargarnovin 2010), and we identified one ongoing study (Zeeba Zaka-ur-Rab 2010).

 FigureFigure 2. Study flow diagram.

 

Included studies

We included 33 trials with 13,114 children; those studies which included more than two intervention arms may have been included in more than one comparison. All included trials contributed data to the review but some studies randomised participants to intervention arms that were not relevant to the comparisons we assessed. For these studies we did not include data from all groups in the analyses. We have indicated in the Characteristics of included studies tables if any randomised arms were not included.

Three of the trials had two arms providing different regimens of intermittent supplementation (Liu 1995 (C); Faqih 2006; Sen 2009 (C)). In these cases we combined the study arms for the overall comparison and included the disaggregated information in the subgroup analyses. Levels of supervision varied among trials but most of them were unsupervised. In addition, very few studies addressed the use of co-interventions such as health education to improve adherence or deworming prior to supplementation.

The sample size ranged between 60 and 1785 participants but overall tended to be small: 75% of the studies included fewer than 500 children. However, for cluster-randomised trials the analyses only included the estimated effective sample size, after adjusting the data to account for the clustering effect.

 
Settings

The studies included in the review were carried out over the last 16 years in low- and middle-income countries in Asia, Africa and Latin America: Bangladesh (Baqui 2003), Bolivia (Berger 1997; Aguayo 2000), Brazil (Da Silva 2008; Engstrom 2008 (C); Arcanjo 2011 (C)), China (Liu 1995 (C); Yang 2004 (C)), India (Awasthi 2005 (C); Sen 2009 (C)), Indonesia (Schultink 1995; Palupi 1997; Soemantri 1997), Iran (Khademloo 2009), Jordan (Faqih 2006), Kenya (Olsen 2000; Verhoef 2002; Desai 2004 (C)), Malawi (Young 2001; Roschnik 2003 (C)), Mali (Hall 2002 (C)), Mexico (Evangelista-Salazar 2004), Pakistan (Siddiqui 2004), Panama (Sinisterra 1997 (C)), Phillipines (Roschnik 2004 (C)), South Africa (Taylor 2001), Tanzania (Ekvall 2000), Thailand (Sungthong 2002), Turkey (Ermis 2002; Tavil 2003; Yurdakok 2004) and Vietnam (Thu 1999; Nguyen 2002).

 
Participants

Participant ages ranged from newborn to 19 years old. While we did not include studies specifically recruiting postmenarchal females, as these are the subject of a separate review (Fernández-Gaxiola 2011), three included studies recruited adolescents and separate data were not available for younger children (Olsen 2000; Taylor 2001; Hall 2002 (C)). Based on the age range reported in these studies, at least half of their participants fulfilled our inclusion criteria and thus we decided to retain them in the review. If the disaggregated data by age is made available to us, we will include it in future updates of the review.

In the analyses (comparisons three to six), we have set out our findings separately for studies recruiting children in these younger and older age groups. Fifteen studies included children from birth to 59 months of age only (Schultink 1995; Palupi 1997; Thu 1999; Ekvall 2000; Young 2001; Ermis 2002; Nguyen 2002; Verhoef 2002; Baqui 2003; Tavil 2003; Evangelista-Salazar 2004; Desai 2004 (C); Yurdakok 2004; Engstrom 2008 (C); Khademloo 2009) and 11 trials included only older children 60 months of age and older (Sinisterra 1997 (C); Soemantri 1997; Aguayo 2000; Taylor 2001; Sungthong 2002; Roschnik 2003 (C); Roschnik 2004 (C); Siddiqui 2004; Da Silva 2008; Sen 2009 (C); Arcanjo 2011 (C)). Seven studies included children in both age categories (Liu 1995 (C); Berger 1997; Olsen 2000; Hall 2002 (C); Yang 2004 (C); Awasthi 2005 (C); Faqih 2006). In those cases we took into account the reported average age in allocating the trial. For example, Faqih 2006 recruited children aged two to six years of age and was included in comparisons two and four (younger children), while Olsen 2000 assessed children aged four to 19 years and was included in comparisons one and five (older children).

On average, 49% of the participants were females, with a range from 37% (Tavil 2003) to 100% (Sen 2009 (C)). Seven trials included only anaemic children (Schultink 1995; Berger 1997; Verhoef 2002; Tavil 2003; Desai 2004 (C); Faqih 2006; Siddiqui 2004); three only non-anaemic (Aguayo 2000; Yang 2004 (C); Yurdakok 2004); and the rest of the trials had a baseline prevalence of anaemia ranging between 15% and 90%.

Participants socioeconomic status was not explicit in most of the studies although references to underprivileged populations were frequent.

 
Intermittent regimens, dose and type of iron compounds

Nine trials included arms where children were supplemented with iron twice a week (Liu 1995 (C); Schultink 1995; Olsen 2000; Verhoef 2002; Tavil 2003; Desai 2004 (C); Awasthi 2005 (C); Faqih 2006; Sen 2009 (C)) and in two studies children were provided with iron every other day (three times a week) (Ekvall 2000; Ermis 2002). The rest of the studies provided iron supplements once weekly.

The total weekly iron dose given to the children ranged from 7.5 to 200 mg of elemental iron per week. Evangelista-Salazar 2004 provided 7.5 mg; Nguyen 2002 gave 15 mg; two trials provided 20 mg elemental iron (Thu 1999; Baqui 2003); in two trials children received a total weekly dose of 25 mg elemental iron (Da Silva 2008; Engstrom 2008 (C)); three trials gave 30 mg (Palupi 1997; Ekvall 2000; Yang 2004 (C)); one trial (Awasthi 2005 (C)) supplemented participants with 40 mg per week and another trial with 50 mg of iron per week (Arcanjo 2011 (C)). In five trials children received 60 mg of elemental iron per week (Schultink 1995; Sinisterra 1997 (C); Young 2001; Sungthong 2002; Siddiqui 2004); in three trials children received in total a weekly dose of 65 mg (Taylor 2001; Hall 2002 (C); Roschnik 2003 (C)); in one study the dose was 108 mg (Roschnik 2004 (C)); in another study the dose was 120 mg (Olsen 2000); and in Sen 2009 (C) the total weekly dose was 200 mg of elemental iron.

Some studies reported the provision of 1 mg to 8 mg of elemental iron per kg per day (Liu 1995 (C); Berger 1997; Soemantri 1997; Aguayo 2000; Ermis 2002; Verhoef 2002; Tavil 2003; Desai 2004 (C); Yurdakok 2004; Faqih 2006). In these cases we calculated the weekly dose by using the median or average age reported in the trial and the corresponding weight according to the WHO growth charts, percentile 50.

In almost all the studies, ferrous sulphate was the source of supplemental iron. Other iron compounds tested were ferrous polymaltose (Olsen 2000); ferrous dextran (Sen 2009 (C)) and ferrous fumarate (Taylor 2001; Verhoef 2002).

Most of the studies supplemented only with iron; one study gave iron in combination with 30 mg of vitamin C (Evangelista-Salazar 2004) and five studies gave iron in combination with folic acid. In these trials the weekly dose of folic acid also varied: one trial gave 100 µg (0.1 mg) of folic acid per week (Taylor 2001; Awasthi 2005 (C)), in two the dose was 250 µg (0.25 mg) (Hall 2002 (C); Roschnik 2003 (C)), while in Sen 2009 (C) the dose was 500 µg (0.5 mg) folic acid per week . Four studies provided supplements containing multiple micronutrients (Thu 1999; Young 2001; Baqui 2003; Yang 2004 (C)).

 

Excluded studies

We excluded 40 trials (41 references) from the review. In 12 trials the evaluated population was out of the scope of this review (Beasley 2000; Kianfar 2000; Sharma 2000; Zavaleta 2000; Ahmed 2001; Februhartanty 2002; Shah 2002; Agarwal 2003; Shobha 2003; Jaleel 2004; Soekarjo 2004; Leenstra 2009). The second main reason for exclusion was that trials were not randomised (Rivera 1998; Jayatissa 1999; Perrin 2002; Sotelo-Cruz 2002; Jackson 2003; Kapur 2003; Kanal 2005; Lima 2006; UNICEF 2006; Vir 2008; Mwanakasale 2009; Azeredo 2010). We excluded eight trials because the supplements were provided as Foodlets a (a crushable tablet that may be mixed with foods) and this intervention is outside the scope of this review (Briars 2003; Hop 2005; López de Romaña 2005; Smuts 2005; Lechtig 2006; López de Romaña 2006; Wijaya-Erhardt 2007; Schümann 2009). Six trials were excluded because intermittent supplementation regimens were not compared with daily regimens or no treatment or placebo (Menendez 1997; Tee 1999; Tomashek 2001; Ahmed 2005; Risonar 2008; Avila-Jimenez 2011). We excluded Hafeez 1998 because the intermittent supplements were given on consecutive days and Lin 2001 because the nutrient tested was vitamin A. We have described these studies in the Characteristics of excluded studies tables.

 

Risk of bias in included studies

Overall, study methods were not well described in many of the included studies and this meant that assessing risk of bias was difficult (see Figure 3 and Figure 4). We attempted to contact the study authors for further clarifications and noted in the Characteristics of included studies when the information was provided by the authors.

 FigureFigure 3. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 4. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Where we assessed methods of randomisation or allocation concealment as being at high risk of bias (or unclear), and trials were either not blinded or had high or imbalanced attrition rates, we assumed that they were at high risk of bias in the sensitivity analysis looking at the impact of study quality. Using these criteria, nine studies were assessed as being at low risk of bias (Thu 1999; Aguayo 2000; Ekvall 2000; Olsen 2000; Hall 2002 (C); Sungthong 2002; Verhoef 2002; Desai 2004 (C); Arcanjo 2011 (C)). The remaining studies were either assessed as being at high risk of bias or the methods were unclear.

 

Allocation

In 20 of the included trials, it was unclear how the randomisation sequence had been generated. In six studies investigators used random number tables (Thu 1999; Aguayo 2000; Verhoef 2002; Roschnik 2004 (C); Faqih 2006; Arcanjo 2011 (C)); in a further six studies computer-generated randomisation sequences were used (Ekvall 2000; Olsen 2000; Hall 2002 (C); Sungthong 2002; Desai 2004 (C); Da Silva 2008), and in two studies the groups were assigned to the treatments by drawing lots (Sinisterra 1997 (C); Sen 2009 (C)).

Eleven of the included studies used methods of concealing group allocation that we judged were low risk of bias, for example, by providing coded supplements to treatment and control groups that appeared similar to participants and to those carrying out randomisation (Berger 1997; Palupi 1997; Thu 1999; Aguayo 2000; Ekvall 2000; Olsen 2000; Taylor 2001; Nguyen 2002; Sungthong 2002; Verhoef 2002; Baqui 2003). In the remaining trials, methods were either not described or were unclear.

Eleven trials were randomised at cluster level (Liu 1995 (C); Sinisterra 1997 (C); Hall 2002 (C); Roschnik 2003 (C); Desai 2004 (C); Roschnik 2004 (C); Yang 2004 (C); Awasthi 2005 (C); Engstrom 2008 (C); Sen 2009 (C); Arcanjo 2011 (C)) and in these cases it was judged that selection bias at individual level was unlikely (low risk of bias).

 

Blinding

In 14 trials, we considered that there was low risk of bias related to blinding (Schultink 1995; Berger 1997; Palupi 1997; Thu 1999; Aguayo 2000; Ekvall 2000; Nguyen 2002; Olsen 2000; Taylor 2001; Verhoef 2002; Sungthong 2002; Baqui 2003; Yang 2004 (C); Arcanjo 2011 (C)). In the remaining trials, blinding was either not attempted or not mentioned.

 

Incomplete outcome data

While we assessed that the majority of the included trials (20 out of 33) had acceptable levels of attrition (with loss to follow-up and missing data being less than 20% and balanced across groups), in the remaining trials the levels of attrition were high or not balanced across groups. In these studies high levels of attrition were likely to represent an important source of bias and thus results are difficult to interpret; this is the case particularly if we consider that reasons for attrition may have been related to outcomes (for example, when children with side effects or those who developed anaemia were excluded from the analysis). In one trial (Baqui 2003) the dropout rate was considerably higher in one of the intervention groups (those receiving multi-micronutrients lost 41% compared to a loss of 8% to 19% in other groups) and there were further missing data for some outcomes. High levels of loss to follow-up also occurred in the studies by Engstrom 2008 (C) (20.2% attrition); Faqih 2006 (53% attrition); Young 2001 (60% attrition); Schultink 1995 (75% attrition); Sen 2009 (C) (68% missing data for some outcomes); Roschnik 2003 (C) (41.2% attrition), and Taylor 2001 (36% attrition). In one study (Da Silva 2008), 16% of participants were lost to follow up and loss was not balanced across groups; the reasons given by the authors included children developing anaemia or side effects, with no clarity about the number of children lost in each group for these reasons. In four trials losses to follow-up were not clear as the denominators were not provided (Tavil 2003; Roschnik 2004 (C); Yang 2004 (C); Khademloo 2009).

 

Selective reporting

We were not able to fully assess outcome reporting bias as we only had access to published study reports. We assessed publication bias using funnel plots only for haemoglobin (in comparisons one and two) and for ferritin (comparison two), as more than 10 trials contributed data to those outcomes. We did not find clear asymmetry that may suggest publication bias (graphs not shown). In the analyses we have ordered studies by weight so that the effect of small studies is more apparent; we have drawn attention to any results where visual inspection of the forest plot seems to suggest a more pronounced treatment effect in small as compared with larger studies.

 

Other potential sources of bias

In a study (Awasthi 2005 (C)) some children received supervised intake of the supplement; it was not clear whether this varied depending on intervention group.

There was some baseline imbalance on outcomes or other potential confounders in terms of participant characteristics in some studies (Schultink 1995; Sinisterra 1997 (C); Taylor 2001; Siddiqui 2004; Faqih 2006; Arcanjo 2011 (C)).

A potentially important source of bias was the impact of unit of randomisation; several of the included trials did not randomise at the individual level but used classes, schools or clinics as clusters for randomisation. The impact of the cluster-design effect was not clearly taken into account in most of the cluster-randomised trials (Liu 1995 (C); Sinisterra 1997 (C); Hall 2002 (C); Roschnik 2003 (C); Roschnik 2004 (C); Yang 2004 (C); Awasthi 2005 (C); Engstrom 2008 (C); Arcanjo 2011 (C)). In the Engstrom 2008 (C) trial, regression analysis was carried out to try to identify possible confounding factors but unit of analysis did not appear to be part of this analysis. We were able to obtain the ICCs for three trials (Desai 2004 (C); Roschnik 2003 (C) and Hall 2002 (C)) and we imputed the last two values to other trials to obtain their effective sample size. The summary estimates obtained from cluster trials did not differ significantly from those obtained from studies randomised at an individual level.

There are three trials awaiting assessment (Husseini 1999; Reid 2001; Kargarnovin 2010). Based on the sample size of Kargarnovin 2010 and the findings reported in the abstract, we do not consider that its temporary exclusion from the analysis will bias the results of this review. Similarly, we did not consider that the omission of the data from Reid 2001 was likely to introduce serious bias due to the small sample size. On the other hand, the effect of excluding Husseini 1999 is uncertain as the only information available is published in Beaton 1999 who obtained it by personal communication. At the end of the intervention haemoglobin concentrations were higher and anaemia prevalence was lower among those children receiving daily supplements in comparison to those children receiving intermittent supplements. As we do not have access to the primary information, it is difficult to assess the quality of the study and to adjust data by the effect of clustering, which limits any assessment of its impact on our summary estimate.

 

Effects of interventions

See:  Summary of findings for the main comparison Intermittent use of iron supplements versus placebo or no intervention in children younger than 12 years of age;  Summary of findings 2 Intermittent versus daily use of iron supplements in children younger than 12 years of age

We have included data from 33 trials; overall, these trials involved 13,114 children. This figure represents the number of children recruited to studies, in some studies we have not included data for all arms of the trials in the review comparisons. The analyses include only the estimated effective sample size, after adjusting the data to account for the clustering effect.

We have organised the summary of results by comparing supplementation regimens and by primary and secondary outcomes. Most of the included studies focused on haematological outcomes and few reported on any of the other outcomes pre-specified in the review protocol. See the Data and analyses section for detailed results on primary and secondary outcomes.

 

Comparison 1. Intermittent iron supplementation versus no supplementation or placebo (19 trials)

Nineteen trials evaluated this comparison (Berger 1997; Palupi 1997; Thu 1999; Aguayo 2000; Ekvall 2000; Olsen 2000; Taylor 2001; Ermis 2002; Hall 2002 (C); Verhoef 2002; Sungthong 2002; Baqui 2003; Roschnik 2003 (C); Evangelista-Salazar 2004; Roschnik 2004 (C); Yurdakok 2004; Yang 2004 (C); Sen 2009 (C); Arcanjo 2011 (C)). Seven of the trials met the prespecified criteria mentioned above for being at lower risk of bias (Thu 1999; Aguayo 2000; Ekvall 2000; Olsen 2000; Hall 2002 (C); Verhoef 2002; Sungthong 2002). In sensitivity analyses these trials were retained in the analysis whilst trials at higher risk of bias were temporarily removed to examine whether this had any impact on the overall pattern of results.

 

Primary outcomes

 
Anaemia

Ten trials with 1824 children provided data on anaemia following the interventions (Berger 1997; Palupi 1997; Thu 1999; Aguayo 2000; Hall 2002 (C); Verhoef 2002; Roschnik 2003 (C); Evangelista-Salazar 2004; Roschnik 2004 (C); Arcanjo 2011 (C)). Those receiving intermittent iron supplementation were significantly less likely to have anaemia at follow-up compared with children receiving no intervention (average risk ratio (RR) 0.51, 95% confidence interval (CI) 0.37 to 0.72) ( Analysis 1.1). There was variation among trials in terms of the size of the treatment effect (T2 = 0.18, I2 = 81% and Chi2 test for heterogeneity P < 0.00001). The large effect remained significant even after excluding the trials at higher risk of bias (RR 0.60; 95% CI 0.42 to 0.87).

Haemoglobin concentrations (g/L)

Nineteen studies with 3032 participants provided data on mean haemoglobin levels following the intervention (Berger 1997; Palupi 1997; Thu 1999; Aguayo 2000; Ekvall 2000; Olsen 2000; Taylor 2001; Ermis 2002; Hall 2002 (C); Verhoef 2002; Sungthong 2002; Baqui 2003; Roschnik 2003 (C); Evangelista-Salazar 2004; Roschnik 2004 (C); Yang 2004 (C); Yurdakok 2004; Sen 2009 (C); Arcanjo 2011 (C)). Those receiving intermittent iron supplements on average had higher haemoglobin (Hb) levels than those receiving no intervention or a placebo; the difference was statistically significant (mean difference (MD) 5.20, 95% CI 2.51 to 7.88) ( Analysis 1.9). There were high levels of heterogeneity among trials (T2 = 32.45, I2 = 93% and Chi2 test for heterogeneity P < 0.00001). The effect remained significant after removing the trials at high risk of bias (RR 5.02, 95% CI 2.01 to 8.03).

 
Iron deficiency

Three trials with 431 children (Verhoef 2002; Evangelista-Salazar 2004; Yang 2004 (C)) reported on this outcome. Findings suggested that children receiving intermittent supplements were at lower risk of having iron deficiency at the end of the intervention as those receiving nothing or a placebo (RR 0.24, 95% CI 0.06 to 0.91) ( Analysis 1.17). There were high levels of heterogeneity among trials (T2 = 1.01, I2 = 88% and Chi2 test for heterogeneity P < 0.0003).

Iron status measured by ferritin (μg/L)

Five trials with follow-up data for 550 participants (Ermis 2002; Sungthong 2002; Baqui 2003; Yang 2004 (C); Yurdakok 2004) reported higher mean levels of ferritin among those receiving intermittent supplements compared with those receiving no treatment (MD 14.17, 95% CI 3.53 to 24.81) ( Analysis 1.18). Only one trial (Sungthong 2002) was assessed as being at lower risk of bias.

Iron deficiency anaemia

No trials reported on this outcome.

 
All-cause mortality

No trials reported on mortality.

 

Secondary outcomes

 
All-cause morbidity

Information on all-cause morbidity was reported in one trial (Palupi 1997), with data for 194 children. There was no evidence of differences between groups ( Analysis 1.26).

 
Acute respiratory infection

No trials reported on this outcome.

 
Diarrhoea

No trials provided information on diarrhoea.

 
Any other adverse effects

One trial (Ermis 2002) reported no statistically significant difference in the total number of side effects reported by those children receiving supplements intermittently and those receiving no intervention or a placebo ( Analysis 1.27). One trial (Aguayo 2000) reported on nausea and did not find differences between groups ( Analysis 1.28).

 
Adherence

Baqui 2003 and Ekvall 2000 reported that children receiving intermittent iron supplements had similar levels of adherence to intermittent iron supplementation as those children receiving a placebo or no intervention (RR 1.04, 95% CI 0.98 to 1.09) ( Analysis 1.29).

 
Folate status (as measured by trialists)

No trials reported on this outcome.

 
Mental development and motor skill development

Baqui 2003 reported on several measures of cognitive and physical development. There was no clear evidence of difference between groups for most of these outcomes ( Analysis 1.30;  Analysis 1.31;  Analysis 1.32;  Analysis 1.34).

School performance

One study (Sungthong 2002) examined intelligence quotient (IQ), language development and mathematics performance; there were no clear differences between those receiving intermittent iron and those on no supplementation ( Analysis 1.35;  Analysis 1.36;  Analysis 1.37).

Physical capacity

One trial examined (Baqui 2003) the motor quality of children, which included seven items such as motor control and tone, and expressed the results in percentile scores. Authors found that children receiving intermittent supplementation had higher percentile scores although the clinical significance of this difference was not clear (MD 15.60, 95% CI 7.66 to 23.54) ( Analysis 1.33).

 
Height-for-age and weight-for-age Z-scores

Three trials (Palupi 1997; Thu 1999; Aguayo 2000) reported results for weight-for-age and height-for-age Z-scores for school-aged children and did not find a statistically significant effect on these outcomes ( Analysis 1.38;  Analysis 1.39).

 

Comparison 2. Intermittent iron supplementation versus daily iron supplementation (21 trials)

Twenty-one trials evaluated this comparison (Liu 1995 (C);,Schultink 1995; Berger 1997; Sinisterra 1997 (C); Soemantri 1997; Thu 1999; Young 2001; Ermis 2002; Nguyen 2002; Sungthong 2002, Tavil 2003; Desai 2004 (C); Siddiqui 2004; Yang 2004 (C); Yurdakok 2004; Awasthi 2005 (C); Faqih 2006; Da Silva 2008; Engstrom 2008 (C); Khademloo 2009; Sen 2009 (C)) and all of them contributed data to the analysis. Three of these trials were assessed as being at lower risk of bias and, where they contributed data, they were retained in the analysis when we conducted sensitivity analyses (Thu 1999; Sungthong 2002; Desai 2004 (C)).

 

Primary outcomes

 
Anaemia

Six trials with 980 participants provided data on the number of children with anaemia following the interventions (Schultink 1995; Berger 1997; Sinisterra 1997 (C); Thu 1999; Awasthi 2005 (C); Engstrom 2008 (C)). Children receiving intermittent iron supplementation had a higher risk of being anaemic at the end of the study period compared to those receiving daily iron supplementation (RR 1.23, 95% CI 1.04 to 1.47) ( Analysis 2.1). Only one trial was considered at low risk of bias (Thu 1999) and found similar results (RR 1.31, 95% CI 0.31 to 5.57).

Haemoglobin concentrations (g/L)

Nineteen trials with 2851 participants provided data on mean haemoglobin levels following the intervention (Liu 1995 (C); Schultink 1995; Berger 1997; Soemantri 1997; Thu 1999; Young 2001; Ermis 2002; Nguyen 2002; Sungthong 2002; Tavil 2003; Desai 2004 (C); Siddiqui 2004; Yang 2004 (C); Yurdakok 2004; Awasthi 2005 (C); Faqih 2006; Engstrom 2008 (C); Khademloo 2009; Sen 2009 (C)). The groups receiving intermittent iron supplements on average had 0.60 less grams of haemoglobin per litre than those receiving daily supplementation but the difference between groups was not statistically significant (95% CI -1.54 to 0.35) ( Analysis 2.9). There were high levels of heterogeneity for this outcome (T2 = 2.26, I2 = 56%, and Chi2 test for heterogeneity P = 0.001). When only those trials at lower risk of bias (Sungthong 2002; Desai 2004 (C)) were retained in the analysis, the difference between groups remained statistically non-significant (MD -0.87, 95% CI -2.77 to 1.02) (data for sensitivity analysis not shown).

 
Iron deficiency

Only one trial (Yang 2004 (C)) reported on iron deficiency and found that at the end of the intervention the number of children with iron deficiency was higher among those who received iron supplements intermittently compared to daily (RR 4.00, 95% CI 1.23 to 13.05) ( Analysis 2.17).

Iron status measured by ferritin (ng/L)

Ten trials with data for 902 participants (Liu 1995 (C); Schultink 1995; Ermis 2002; Sungthong 2002; Tavil 2003; Siddiqui 2004; Yang 2004 (C); Yurdakok 2004; Faqih 2006; Khademloo 2009) reported that ferritin values were not statistically different between those receiving iron intermittently and those receiving daily iron (MD -4.19, 95% CI -9.42 to 1.05) ( Analysis 2.18). Only one trial was at low risk of bias (Sungthong 2002) and found no differences between these two interventions. There was high heterogeneity for this outcome with considerable variation in mean values between trials; in addition, one of the studies reported exceptionally low standard errors for mean ferritin values (from which we calculated SDs) (Siddiqui 2004). We carried out a sensitivity analysis temporarily excluding this study from the meta-analysis; removing this study did not change the interpretation of results (MD - 5.20, 95% CI -10.76 to 0.35).

Iron deficiency anaemia

No trials reported data on iron deficiency anaemia.

 
All-cause mortality

No trials reported mortality by any cause.

 

Secondary outcomes

 
All-cause morbidity

Information on all-cause morbidity was reported in two trials (Desai 2004 (C); Da Silva 2008), with data for 601 children. There was no evidence of a difference between groups (RR 0.96, 95% CI 83 to 1.12) ( Analysis 2.27).

 
Acute respiratory infection

No trials reported on this outcome.

 
Diarrhoea

Two trials (Yurdakok 2004; Da Silva 2008) had data on diarrhoea and did not find differences between groups ( Analysis 2.28).

 
Any other adverse effects

Four trials (Liu 1995 (C); Ermis 2002; Desai 2004 (C); Yurdakok 2004) reported side effects among 895 children. There was no evidence of differences between intermittent and daily iron supplementation (RR 0.60, 96% CI 0.19 to 1.87) ( Analysis 2.29).

 
Adherence

Five trials involving 1130 participants reported on this outcome (Berger 1997; Desai 2004 (C); Awasthi 2005 (C); Engstrom 2008 (C); Sen 2009 (C)). There was no statistically significant difference in adherence to the interventions between groups although it tended to be higher among those children receiving intermittent iron supplements (RR 1.23, 95% CI 0.98 to 1.54) ( Analysis 2.30).

 
Folate status (as measured by trialists)

No trials reported on this outcome.

 
Mental development and motor skill development

No trials reported on this outcome.

 
School performance

One study (Sungthong 2002) examined IQ, Thai language development and mathematics performance; there were no clear differences between groups receiving intermittent iron versus no supplementation ( Analysis 2.31;  Analysis 2.32;  Analysis 2.33).

 
Physical capacity

One trial that provided weekly and twice-a-week supplementation (Sen 2009 (C)) did not find statistically significant differences in the increment of steps climbed by children receiving either intermittent or daily supplementation ( Analysis 2.26).

 
Height-for-age and weight-for-age Z-scores

Three trials reported results for height-for-age Z-scores for school-aged children and did not find an effect on this outcome ( Analysis 2.34).

 

Subgroup comparisons

There was considerable variation among trials in terms of the populations examined and the way studies were conducted, which very likely resulted in the high statistical heterogeneity observed in some outcomes. For primary outcomes, we examined subgroups to look for possible differences between studies in terms of the duration of the intervention; children's anaemia status at baseline; higher and lower weekly doses of iron; type of iron compound provided; and supplementation regimen.

For most of the outcomes very few studies contributed data, so we limited the subgroup analysis to anaemia and haemoglobin and ferritin concentrations. In the analyses we have provided overall totals along with subtotals for subgroups, and the statistics for subgroup differences.

Intermittent iron dose per week (25 mg or less; greater than 25 mg to 75 mg; greater than 75 mg)

Most of the trials provided between 25 and 75 mg of iron per week. There was some within subgroup heterogeneity and no consistent and clear differences between subgroup categories ( Analysis 1.10;  Analysis 1.19;  Analysis 2.2;  Analysis 2.10;  Analysis 2.19). It seemed that the effect of intermittent supplementation on anaemia was lost among those children receiving iron doses greater than 75 mg per week, although only two trials contributed to this subgroup ( Analysis 1.2).

Duration of the intervention (0 to three months; more than three months)

An almost even number of trials provided iron supplements for three months or less, or for more than three months. There was no statistical evidence that the response of haematological outcomes to intermittent supplementation differed by duration of the intervention ( Analysis 1.3;  Analysis 1.11;  Analysis 1.20;  Analysis 2.3;  Analysis 2.11;  Analysis 2.20).

Type of compound (ferrous sulphate; ferrous fumarate; other)

Most of the trials provided iron in the form of ferrous sulphate, but when other compounds were given there was no clear statistical evidence that they produced different results on haematological outcomes from those observed with ferrous sulphate ( Analysis 1.4;  Analysis 2.4;  Analysis 2.12;  Analysis 2.21). In one case haemoglobin responded better to supplementation with fumarate, but only one study contributed to this subgroup category and findings should be cautiously interpreted ( Analysis 1.21).

Anaemia status at baseline (anaemic; non-anaemic; mixed or not reported)

Intermittent supplementation appeared to be as efficacious in trials that included only anaemic children as in those studies that included populations with different degrees of anaemia ( Analysis 1.5;  Analysis 1.13;  Analysis 1.22;  Analysis 2.5;  Analysis 2.13;  Analysis 2.22). One study conducted in anaemic Bolivian children (Berger 1997) reported a very pronounced therapeutic effect on haematological outcomes and this trial contributed to the observed statistical heterogeneity; its results were consistent in terms of direction with the rest of the trials.

Intermittent regimen (one supplement a week; other intermittent regimen)

Most of the trials supplemented children on a weekly basis and in some cases only one study was included in each subgroup, which impeded the interpretation of the analyses ( Analysis 1.6;  Analysis 1.23). For the rest of the subgroup comparisons, there was no statistical evidence that the results of haematological outcomes differed when the supplements were given once, twice or three times a week ( Analysis 1.14;  Analysis 2.6;  Analysis 2.14;  Analysis 2.23).

Sex (males; females; mixed or not reported)

All but one trial included males and females, although it was possible to extract the results by sex only from Hall 2002 (C). There was no statistical evidence that in this population the positive effect of intermittent supplementation on haematological outcomes differed by sex ( Analysis 1.7;  Analysis 1.15;  Analysis 1.24;  Analysis 2.7;  Analysis 2.15;  Analysis 2.24).

Supplement's nutrient composition (iron alone; iron + folic acid; iron+other nutrient; iron + multiple micronutrients)

Most of the trials provided only iron. In the majority of the subgroup analyses there was no evidence that the provision of other nutrients in addition to iron altered the effects of intermittent supplementation on haematological outcomes ( Analysis 1.16;  Analysis 1.25;  Analysis 2.8;  Analysis 2.16;  Analysis 2.25). However, it seemed that the effect of intermittent supplementation on anaemia was higher among those children receiving iron + vitamin C ( Analysis 1.8), although this result should be interpreted cautiously as only one trial assessed the joint effect of these micronutrients.

 

Comparisons 3 to 6. Analysis by age group: children younger than 60 months versus 60 months and older

We have summarised the results of comparisons 3 to 6 in  Table 1 and  Table 2.

The visual examination of the confidence intervals suggests that the haematological effects produced by intermittent supplementation are similar between young (0 to 59 months) and older children (60 months and older), although the statistical power may be an issue in assessing the consistency among results.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Summary of main results

Available data indicate that among children less than 12 years of age, intermittent supplementation with iron (alone or in combination with other nutrients) effectively increases haemoglobin and ferritin concentrations and reduces the prevalence of anaemia compared to placebo or no intervention. Overall, this positive response does not differ between once, biweekly or three times weekly supplementation; nor does it depend on child's sex or age or the duration of the intervention.

In comparison to daily iron supplementation, children receiving intermittent iron supplementation are more likely to develop anaemia but their haemoglobin and ferritin concentrations are similar.

Adherence tends to be higher in children receiving intermittent iron supplementation compared with those receiving daily iron supplements, although the results were not statistically significant.

Information on morbidity, mortality, adverse side effects, neurocognitive and motor outcomes is scarce and therefore no clear conclusions can be drawn.

 

Overall completeness and applicability of evidence

A total of 33 randomised trials were included in this review, with data for 13,114 children included in the analysis. Seventy-five per cent of the included trials had a sample size of less than 500 children and the trials often lacked blinding and a clear description of randomisation methods. The trials were published in a wide variety of journals (and the level of quality of the journals might vary) and were mostly written in English. The diversity of publications may also reflect the range of settings in which studies were carried out: Latin America, Africa and Asia.

No studies were conducted in high-income countries and it is uncertain whether the results would be similar in those settings. On the one hand, the prevalences of anaemia and iron deficiency are lower in high income countries and there is an inverse relationship between initial iron status and response to iron supplementation. On the other hand, intermittent supplementation for children in high income countries could, however, be successful because of potentially strong institutional infrastructure and high attendance rates at schools that could support sustained high coverage and use of this intervention.

We decided to include only randomised and quasi-randomised trials in this review. Whilst randomisation reduces the risk of bias, this approach also limited the inclusion of large scale pre-post trials with no comparison groups. Such studies are more likely to be affected by external circumstances, such as famines, and it is possible that the magnitude of the effect of intermittent iron supplementation might be different under programmatic conditions.

The baseline anaemia and iron deficiency status varied across studies; most were conducted in settings with a high prevalence of anaemia. The studies included in this review largely examined this intervention for prevention as a public health strategy and not treatment of anaemia and iron deficiency as part of clinical practice. However, seven of the 33 trials included only anaemic children and subgroup analysis suggested that weekly supplementation was efficacious compared with daily supplementation. The efficacy of the intermittent supplementation schemes on haematological outcomes also seemed similar across different age groups, with few inconsistencies.

There were insufficient studies to allow us to evaluate in detail all the outcomes of interest, and by subgroups. Particularly, there were insufficient trials and a lack of comparable measures to examine mortality, morbidity, cognitive and developmental outcomes.

In addition, there was a lack of data to meaningfully examine adherence and adverse effects specifically related to intensity and frequency of dosing. These last two are critical limitations considering that these are primary justifications for the use of weekly over daily supplementation.

 

Quality of the evidence

1. Quality of the evidence across within studies. Less than one third of the trials were assessed as having a low risk of bias after considering the methods for allocating the treatment, the blinding and the attrition rates, with many studies being at high risk of bias (see Risk of bias in included studies). In most of the included trials, the methods used to randomly assign participants and conceal allocation were not described. Blinding of participants, care providers and outcome assessors was not generally attempted, although in some studies technical staff carrying out laboratory investigations were reported to be unaware of group allocation. The lack of blinding may represent a potentially serious source of bias. Attrition was also a problem in many of these studies.

2. Quality of the evidence across studies. We used the GRADE methodology for this assessment and set out the results for primary outcomes in the  Summary of findings for the main comparison and the  Summary of findings 2. We considered that indirectness or publication bias was unlikely but the quality of the trials and inconsistency (or the lack of studies) were potentially important factors in the overall assessment of the evidence. When intermittent supplementation was compared with a placebo or no intervention, the overall quality of the available evidence was found to be moderate for anaemia, whereas for haemoglobin and ferritin concentrations it was low and very low for iron deficiency. When compared with daily supplementation, the quality of the available evidence with regard to anaemia, haemoglobin and ferritin concentrations was found to be low and for iron deficiency it was very low.

 

Potential biases in the review process

There were a number of potential biases in the review process. We attempted to be as inclusive as possible in the search strategy and found publications in different languages in journals from all the continents, although the literature identified was predominantly written in English. We were also able to obtain unpublished information.

We attempted to minimise bias in several ways: two review authors independently assessed eligibility for inclusion and two review authors checked data extraction, assessments of risk of bias and data entry. However, carrying out reviews is not an exact science and may require a number of subjective judgements; it is possible that a different review team may have reached different decisions regarding assessments of eligibility and risk of bias. We would encourage readers to examine the Characteristics of included studies tables to assist in the interpretation of results.

In addition to the individual assessments of the study risk of bias, we included 'Summary of findings' tables to assess the overall quality of the evidence for primary outcomes. We attempted to produce the tables using a transparent process with two review authors independently assessing the evidence for each outcome for each quality domain and discussing any disagreements.

 

Agreements and disagreements with other studies or reviews

To our knowledge, only one meta-analysis of randomised controlled trials has been conducted on the efficacy of intermittent iron supplementation in the control of iron deficiency anaemia (Beaton 1999). It includes the results of 22 trials completed before 1999 in different age groups. In some cases authors were able to obtain the full data sets but in the rest of the cases summary statistics were collected from abstracts, final reports or directly supplied by investigators. Of the included studies, four were carried out among preschool-aged children (age range five months to five years), 10 among school-aged children and adolescents (age range three years to 21 years) and eight among pregnant women. All of the preschool and school children or adolescent trials compared once or twice a week versus daily supplementation, and most included control groups. All the studies reported results for haemoglobin; two studies in preschool children and three in schoolchildren or adolescents also measured ferritin. All the studies that Beaton 1999 included involving preschool and school-aged children were also included in this review. 

The authors found that intermittent supplementation was efficacious compared to no treatment and that it increased haemoglobin and ferritin levels and reduced anaemia. In contrast to the present review, they found that daily supplementation was more efficacious than intermittent supplementation in improving haemoglobin and ferritin levels. The authors concluded that weekly supplementation should be considered for preschool and school-aged children only in situations where there is strong assurance of supervision and high adherence.

The larger number of trials included in this Cochrane review, conducted in different settings and with different levels of supervision, suggest that intermittent supplementation is an efficacious public health intervention in children younger than 12 years of age that may be implemented in a various contexts. It may be a viable approach to consider, particularly where daily supplementation has failed, is operationally complex or unfeasible or in settings where it has not been implemented yet.

The results of the present review are only applicable to children 12 years and younger. However, other systematic review assessing the benefits and safety of this intervention in menstruating women (Fernández-Gaxiola 2011) concur with our findings. From the programme implementation perspective, a recent narrative review reports that weekly iron and folic acid supplementation has been successfully implemented in Cambodia, Egypt, India, Laos, Philippines and Vietnam, reaching over half a million menstruating women (WHO 2009).

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

 

Implications for practice

The findings from this review show that intermittent supplementation with iron (alone or in combination with other nutrients) is efficacious in improving haemoglobin concentrations and ferritin levels and reducing anaemia among children younger than 12 years of age in settings with moderate to high prevalence of anaemia. The effects of intermittent supplementation on haemoglobin and ferritin outcomes were similar to those achieved with daily supplementation although children receiving intermittent supplements were at higher risk of anaemia.

Most of the evidence in this review is derived from trials providing weekly doses between 25 and 75 mg of elemental iron, either alone, with folic acid or with other micronutrients. The positive effect of intermittent supplementation was observed in populations of males and females, with different anaemia backgrounds, and seemed not to be affected by the duration of the intervention, although a minimum of three months seems reasonable to trigger the haematological response and build some iron stores. Very few trials reported on the level of supervision or the use of a communication or education strategy to improve the use of supplements. An integrated approach with a strong behaviour change communication component that targets different audiences may be necessary to adequately support adherence and appropriate use for any supplementation regimen. Intermittent supplementation for children might be an option for countries with strong institutional infrastructures for delivery that facilitate wide and sustained coverage, for example, where school attendance is high; although it is clear that efforts should be made to also reach those children not covered by the school or health systems.

This review attempted to examine several of the primary justifications for choosing intermittent over daily supplementation, including improved adherence, reduced side effects and improved efficiency in absorption. Surprisingly, very few trials reported on these outcomes and they did not show that the children receiving supplements intermittently adhere better to the intervention or have fewer side effects that those receiving daily supplements. Clearly, more research is needed in this area. Other rationales for intermittent supplementation include diminished exposure to an iron-rich environment, which may exacerbate oxidative stress in the gut lumen and intestinal mucosal cells, as well as decreased competition with other minerals such as zinc and copper for absorption channels. Unfortunately, few trials reported on other indicators of vitamin and mineral status and therefore no conclusions can be drawn.

In summary, intermittent supplementation is efficacious at improving haemoglobin and ferritin concentrations and reducing anaemia prevalence, although children receiving daily supplements were less likely to present anaemia compared to those receiving intermittent supplements. These results suggest that in settings where daily supplementation is likely to be unsuccessful or not feasible, intermittent supplementation could be an effective public health strategy to improve iron status and reduce anaemia in children under 12 years of age.

 
Implications for research

Important research is needed at different levels before we can fully assess the effects and safety of intermittent iron supplementation regimens on anaemia, iron status and development in children less than 12 years of age. Future research should focus on the following.

  • Clinical research

  1. Examining the efficacy of intermittent iron regimens on neurocognitive and developmental outcomes and growth. In addition, attempts should be made to use comparable measures across studies, when possible.
  2. Reporting the side effects in greater detail to acknowledge not only the presence of a side effect but also its intensity and frequency.
  3. Expanding the evidence on the provision of multiple micronutrients on an intermittent basis and their effect on iron status and other indicators of vitamin and mineral status, such as retinol or zinc.
  4. Reporting comprehensively the effects of the intermittent supplementation on anaemia, haemoglobin concentrations or ferritin to better understand the clinical significance of haemoglobin changes.

  • Programme implementation

  1. Establishing the periodicity of this intervention over a year, taking into account both its biological and programmatic feasibility.
  2. Improving reporting of adherence and addressing the relevance of direct and continued supervision.
  3. Exploring the factors which may influence adherence (such as behaviour change communication (BCC)) and the types of support needed to improve adherence in supplementation interventions. BCC and supporting adherence may be important components of an effective supplementation programme but trials rarely provide detailed information about them. This limits the ability to understand the intensity of these activities needed to achieve the effects found in the trials.
  4. Examining the cost effectiveness of intermittent compared with daily supplementation, taking into account more than just the differential cost of pills.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

We would like to thank the trial authors and organisations who contributed additional information for this review and Ms Xiaoting Huo for her help in translating Yang 2004 (C) into English. Thanks are due to Deidre Thomas from the US CDC Public Health Library and Information Center and Margaret Anderson from the Cochrane Developmental, Psychosocial and Learning Problems Group (CDPLPG) for their help in devising the search strategy. We would also like to thank the staff at the editorial office of the CDPLPG for their support in the preparation of this review.

As part of the prepublication editorial process the text has been commented on by three peers (an editor and two referees who are external to the editorial team) and one of CDPLPG's statistical editors. We are grateful for their feedback.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
Comparison 1. Intermittent iron supplementation versus placebo or no intervention: children 0 - 12 years

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Anaemia (ALL)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]

 2 Anaemia (by dose of elemental iron in the intermittent group)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]

    2.1 25 mg or less/week
2157Risk Ratio (M-H, Random, 95% CI)0.15 [0.06, 0.37]

    2.2 Greater than 25 mg to 75 mg/week
61256Risk Ratio (M-H, Random, 95% CI)0.54 [0.37, 0.80]

    2.3 Greater than 75 mg/week
2411Risk Ratio (M-H, Random, 95% CI)0.71 [0.48, 1.04]

 3 Anaemia (by duration of the intervention)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]

    3.1 0 to three months
51456Risk Ratio (M-H, Random, 95% CI)0.63 [0.49, 0.82]

    3.2 More than three months
5368Risk Ratio (M-H, Random, 95% CI)0.37 [0.14, 1.02]

 4 Anaemia (by type of compound)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]

    4.1 Ferrous sulphate
91517Risk Ratio (M-H, Random, 95% CI)0.47 [0.30, 0.75]

    4.2 Ferrous fumarate
1307Risk Ratio (M-H, Random, 95% CI)0.61 [0.49, 0.74]

   4.3 Other
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Anaemia (by anaemia status at baseline)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]

    5.1 Anaemic
2424Risk Ratio (M-H, Random, 95% CI)0.30 [0.07, 1.38]

    5.2 Non-anaemic
164Risk Ratio (M-H, Random, 95% CI)0.78 [0.27, 2.31]

    5.3 Mixed/unknown
71336Risk Ratio (M-H, Random, 95% CI)0.59 [0.41, 0.85]

 6 Anaemia (by intermittent regimen)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]

    6.1 One supplement a week
91517Risk Ratio (M-H, Random, 95% CI)0.47 [0.30, 0.75]

    6.2 Other intermittent regimen
1307Risk Ratio (M-H, Random, 95% CI)0.61 [0.49, 0.74]

 7 Anaemia (by sex)101824Risk Ratio (M-H, Random, 95% CI)0.55 [0.41, 0.73]

    7.1 Girls
1248Risk Ratio (M-H, Random, 95% CI)0.75 [0.59, 0.95]

    7.2 Boys
1253Risk Ratio (M-H, Random, 95% CI)0.81 [0.66, 1.00]

    7.3 Mixed/unknown
91323Risk Ratio (M-H, Random, 95% CI)0.46 [0.30, 0.70]

 8 Anaemia (by nutrient)101824Risk Ratio (M-H, Random, 95% CI)0.51 [0.37, 0.72]

    8.1 Iron alone
61074Risk Ratio (M-H, Random, 95% CI)0.48 [0.31, 0.74]

    8.2 Iron + folic acid
2593Risk Ratio (M-H, Random, 95% CI)0.83 [0.66, 1.03]

    8.3 iron + vitamin C
150Risk Ratio (M-H, Random, 95% CI)0.06 [0.00, 0.97]

    8.4 Iron + multiple micronutrients
1107Risk Ratio (M-H, Random, 95% CI)0.16 [0.06, 0.44]

 9 Haemoglobin (ALL)193032Mean Difference (IV, Random, 95% CI)5.20 [2.51, 7.88]

 10 Haemoglobin (by by dose of elemental iron in the intermittent group)193032Mean Difference (IV, Random, 95% CI)5.20 [2.51, 7.88]

    10.1 25 mg or less/week
3324Mean Difference (IV, Random, 95% CI)8.19 [-4.01, 20.38]

    10.2 Greater than 25 mg to 75 mg/week
122059Mean Difference (IV, Random, 95% CI)5.45 [2.31, 8.58]

    10.3 Greater than 75 mg/week
4649Mean Difference (IV, Random, 95% CI)1.84 [0.25, 3.44]

 11 Haemoglobin (by duration of the intervention)193032Mean Difference (IV, Random, 95% CI)5.20 [2.51, 7.88]

    11.1 0 to three months
71616Mean Difference (IV, Random, 95% CI)5.16 [2.82, 7.51]

    11.2 More than three months
121416Mean Difference (IV, Random, 95% CI)5.13 [0.90, 9.36]

 12 Haemoglobin (by type of compound)193032Mean Difference (IV, Random, 95% CI)5.20 [2.51, 7.88]

    12.1 Ferrous sulphate
142288Mean Difference (IV, Random, 95% CI)5.57 [2.21, 8.92]

    12.2 Ferrous fumarate
2432Mean Difference (IV, Random, 95% CI)7.03 [3.36, 10.71]

    12.3 Other
3312Mean Difference (IV, Random, 95% CI)2.03 [-0.26, 4.33]

 13 Haemoglobin (by anaemia status at baseline)193032Mean Difference (IV, Random, 95% CI)5.20 [2.51, 7.88]

    13.1 Anaemic
2422Mean Difference (IV, Random, 95% CI)13.17 [3.07, 23.26]

    13.2 Non-anaemic
164Mean Difference (IV, Random, 95% CI)2.0 [-2.46, 6.46]

    13.3 Mixed/unknown
162546Mean Difference (IV, Random, 95% CI)4.35 [1.88, 6.82]

 14 Haemoglobin (by intermittent regimen)193032Mean Difference (IV, Random, 95% CI)5.15 [2.52, 7.79]

    14.1 One supplement a week
152256Mean Difference (IV, Random, 95% CI)5.61 [2.13, 9.09]

    14.2 Other intermittent regimen
5776Mean Difference (IV, Random, 95% CI)3.67 [1.05, 6.28]

 15 Haemoglobin (by sex)193032Mean Difference (IV, Random, 95% CI)5.17 [2.56, 7.77]

    15.1 Girls
1248Mean Difference (IV, Random, 95% CI)4.0 [0.83, 7.17]

    15.2 Boys
1253Mean Difference (IV, Random, 95% CI)3.70 [0.58, 6.82]

    15.3 Mixed/unknown
182531Mean Difference (IV, Random, 95% CI)5.31 [2.40, 8.22]

 16 Haemoglobin (by nutrient)193032Mean Difference (IV, Random, 95% CI)4.83 [2.25, 7.41]

    16.1 Iron alone
111699Mean Difference (IV, Random, 95% CI)4.41 [1.32, 7.50]

    16.2 Iron + folic acid
4756Mean Difference (IV, Random, 95% CI)3.36 [1.51, 5.21]

    16.3 iron + zinc
177Mean Difference (IV, Random, 95% CI)-1.60 [-8.09, 4.89]

    16.4 Iron + vitamin C
150Mean Difference (IV, Random, 95% CI)20.70 [17.51, 23.89]

    16.5 Iron + multiple micronutrients
4450Mean Difference (IV, Random, 95% CI)5.47 [0.32, 10.61]

 17 Iron deficiency (ALL)3431Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.91]

 18 Ferritin (ALL)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]

 19 Ferritin (by dose of elemental iron in the intermittent group)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]

    19.1 25 mg or less/week
1148Mean Difference (IV, Random, 95% CI)4.60 [-0.89, 10.09]

    19.2 Greater than 25 mg to 75 mg/week
4402Mean Difference (IV, Random, 95% CI)17.77 [8.21, 27.34]

   19.3 Greater than 75 mg/week
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 20 Ferritin (by duration of the supplementation)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]

    20.1 0 to three months
135Mean Difference (IV, Random, 95% CI)15.80 [-1.23, 32.83]

    20.2 More than three months
4515Mean Difference (IV, Random, 95% CI)13.82 [1.84, 25.81]

 21 Ferritin (by type of compound)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]

    21.1 Ferrous sulphate
4476Mean Difference (IV, Random, 95% CI)16.28 [4.68, 27.87]

   21.2 Ferrous fumarate
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    21.3 Other
174Mean Difference (IV, Random, 95% CI)2.46 [-14.37, 19.29]

 22 Ferritin (by anaemia status at baseline)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]

   22.1 Anaemic
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    22.2 Non-anaemic
174Mean Difference (IV, Random, 95% CI)2.46 [-14.37, 19.29]

    22.3 Mixed/unknown
4476Mean Difference (IV, Random, 95% CI)16.28 [4.68, 27.87]

 23 Ferritin (by supplementation regimen)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]

    23.1 One supplement a week
4497Mean Difference (IV, Random, 95% CI)10.14 [1.74, 18.53]

    23.2 Other intermittent regimen
153Mean Difference (IV, Random, 95% CI)27.80 [22.88, 32.72]

 24 Ferritin (by sex)5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]

   24.1 Girls
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   24.2 Boys
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    24.3 Mixed/unknown
5550Mean Difference (IV, Random, 95% CI)14.17 [3.53, 24.81]

 25 Ferritin (by nutrient)5550Mean Difference (IV, Random, 95% CI)11.41 [2.71, 20.11]

    25.1 Iron alone
4379Mean Difference (IV, Random, 95% CI)16.25 [5.41, 27.09]

   25.2 Iron + folic acid
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    25.3 Iron + zinc
153Mean Difference (IV, Random, 95% CI)5.50 [-3.91, 14.91]

    25.4 Iron + multiple micronutrients
2118Mean Difference (IV, Random, 95% CI)3.80 [-4.96, 12.56]

 26 All cause morbidity (ALL)1194Risk Ratio (M-H, Random, 95% CI)0.26 [0.03, 2.24]

 27 Any side effects (ALL)153Risk Ratio (M-H, Fixed, 95% CI)3.87 [0.19, 76.92]

 28 Nausea164Risk Ratio (M-H, Random, 95% CI)2.82 [0.12, 66.82]

 29 Adherence (ALL)2289Risk Ratio (M-H, Random, 95% CI)1.04 [0.98, 1.09]

 30 Mental development scale (ALL)1172Mean Difference (IV, Random, 95% CI)2.0 [-2.40, 6.40]

 31 Orientation engagement (ALL)1172Mean Difference (IV, Random, 95% CI)8.40 [-1.79, 18.59]

 32 Emotional regulation (ALL)1172Mean Difference (IV, Random, 95% CI)-2.5 [-11.58, 6.58]

 33 Motor quality (ALL)1172Mean Difference (IV, Random, 95% CI)15.60 [7.66, 23.54]

 34 Psychomotor development index (ALL)1172Mean Difference (IV, Random, 95% CI)6.90 [1.35, 12.45]

 35 IQ (ALL)1252Mean Difference (IV, Random, 95% CI)-3.00 [-5.96, -0.04]

 36 Thai language (ALL)1208Mean Difference (IV, Random, 95% CI)-0.30 [-0.50, -0.09]

 37 Mathematics (ALL)1233Mean Difference (IV, Random, 95% CI)-0.27 [-0.44, -0.10]

 38 WAZ3366Std. Mean Difference (IV, Random, 95% CI)-0.03 [-0.33, 0.27]

 39 HAZ3366Mean Difference (IV, Random, 95% CI)0.03 [-0.04, 0.10]

 
Comparison 2. Intermittent iron supplementation versus daily iron supplementation: children 0 - 12 years

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Anaemia (ALL)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]

 2 Anaemia (by dose of elemental iron in the intermittent group)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]

    2.1 25 mg or less/week
2404Risk Ratio (M-H, Random, 95% CI)1.20 [0.98, 1.47]

    2.2 Greater than 25 mg to 75 mg/week
4576Risk Ratio (M-H, Random, 95% CI)1.34 [0.96, 1.88]

   2.3 Intermittent group: greater than 75 mg/week
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 3 Anaemia (by duration of the supplementation)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]

    3.1 0 to three months
2172Risk Ratio (M-H, Random, 95% CI)1.24 [0.55, 2.77]

    3.2 More than three months
4808Risk Ratio (M-H, Random, 95% CI)1.23 [1.03, 1.47]

 4 Anaemia (by type of compound)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]

    4.1 Ferrous sulphate
6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]

   4.2 Ferrous fumarate
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   4.3 Other
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Anaemia (by anaemia status at baseline)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]

    5.1 Anaemic
2183Risk Ratio (M-H, Random, 95% CI)0.96 [0.50, 1.82]

   5.2 Non-anaemic
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    5.3 Mixed/unknown
4797Risk Ratio (M-H, Random, 95% CI)1.26 [1.05, 1.51]

 6 Anaemia (by supplementation regimen)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]

    6.1 One supplement a week
4549Risk Ratio (M-H, Random, 95% CI)1.18 [0.97, 1.43]

    6.2 Other intermittent regimen
2431Risk Ratio (M-H, Random, 95% CI)1.49 [1.02, 2.19]

 7 Anaemia (by sex)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]

   7.1 Girls
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   7.2 Boys
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    7.3 Mixed/unknown
6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]

 8 Anaemia (by nutrient)6980Risk Ratio (M-H, Random, 95% CI)1.23 [1.04, 1.47]

    8.1 Iron alone
4507Risk Ratio (M-H, Random, 95% CI)1.17 [0.97, 1.42]

    8.2 Iron + folic acid
1366Risk Ratio (M-H, Random, 95% CI)1.55 [1.02, 2.36]

    8.3 Iron + multiple micronutrients
1107Risk Ratio (M-H, Random, 95% CI)1.31 [0.31, 5.57]

 9 Haemoglobin (ALL)192851Mean Difference (IV, Random, 95% CI)-0.60 [-1.54, 0.35]

 10 Haemoglobin (by dose of elemental iron in the intermittent group)182751Mean Difference (IV, Random, 95% CI)-0.62 [-1.60, 0.37]

    10.1 25 mg or less/week
3536Mean Difference (IV, Random, 95% CI)-2.42 [-4.18, -0.66]

    10.2 Greater than 25 mg to 75 mg/week
132078Mean Difference (IV, Random, 95% CI)-0.58 [-1.62, 0.45]

    10.3 Greater than 75 mg/week
2137Mean Difference (IV, Random, 95% CI)1.00 [-4.68, 6.68]

 11 Haemoglobin (by duration of the supplementation)192842Mean Difference (IV, Random, 95% CI)-0.38 [-1.26, 0.50]

    11.1 0 to three months
111455Mean Difference (IV, Random, 95% CI)0.47 [-0.91, 1.84]

    11.2 More than three months
81387Mean Difference (IV, Random, 95% CI)-1.14 [-2.07, -0.22]

 12 Haemoglobin (by type of compound)192851Mean Difference (IV, Random, 95% CI)-0.60 [-1.54, 0.35]

    12.1 Ferrous sulphate
172733Mean Difference (IV, Random, 95% CI)-0.60 [-1.60, 0.40]

   12.2 Ferrous fumarate
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    12.3 Other
2118Mean Difference (IV, Random, 95% CI)-0.46 [-4.24, 3.32]

 13 Haemoglobin (by anaemia status at baseline)192851Mean Difference (IV, Random, 95% CI)-0.61 [-1.54, 0.32]

    13.1 Anaemic
7957Mean Difference (IV, Random, 95% CI)-0.76 [-2.59, 1.07]

    13.2 Non-anaemic
3166Mean Difference (IV, Random, 95% CI)0.79 [-1.42, 2.99]

    13.3 Mixed/unknown
101728Mean Difference (IV, Random, 95% CI)-0.76 [-2.00, 0.48]

 14 Haemoglobin (by supplementation regimen)192851Mean Difference (IV, Random, 95% CI)-0.70 [-1.70, 0.30]

    14.1 One supplement a week
141612Mean Difference (IV, Random, 95% CI)-0.25 [-1.57, 1.07]

    14.2 Other intermittent regimen
81239Mean Difference (IV, Random, 95% CI)-1.42 [-3.02, 0.19]

 15 Haemoglobin (by sex)192851Mean Difference (IV, Random, 95% CI)-0.60 [-1.54, 0.35]

    15.1 Girls
142Mean Difference (IV, Random, 95% CI)-2.0 [-5.43, 1.43]

   15.2 Boys
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    15.3 Mixed/unknown
182809Mean Difference (IV, Random, 95% CI)-0.53 [-1.51, 0.46]

 16 Haemoglobin (by nutrient)192851Mean Difference (IV, Random, 95% CI)-0.59 [-1.52, 0.35]

    16.1 Iron alone
152144Mean Difference (IV, Random, 95% CI)-0.51 [-1.61, 0.59]

    16.2 Iron + folic acid
2408Mean Difference (IV, Random, 95% CI)-2.26 [-4.30, -0.22]

    16.3 Iron + multiple micronutrients
3299Mean Difference (IV, Random, 95% CI)0.61 [-2.04, 3.26]

 17 Iron deficiency (ALL)176Risk Ratio (M-H, Random, 95% CI)4.0 [1.23, 13.05]

 18 Ferritin (ALL)10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]

 19 Ferritin (by dose of elemental iron in the intermittent group)9802Mean Difference (IV, Random, 95% CI)-4.34 [-10.20, 1.53]

   19.1 by dose of elemental iron in the intermittent group: 25 mg or less/week
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    19.2 by dose of elemental iron in the intermittent group: greater than 25 mg to 75 mg/week
9802Mean Difference (IV, Random, 95% CI)-4.34 [-10.20, 1.53]

   19.3 by dose of elemental iron in the intermittent group: greater than 75 mg/week
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 20 Ferritin (by duration of the supplementation)10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]

    20.1 by duration of the supplementation: 0 to three months
6442Mean Difference (IV, Random, 95% CI)-1.06 [-6.62, 4.51]

    20.2 by duration of the supplementation: more than three months
4460Mean Difference (IV, Random, 95% CI)-9.58 [-23.08, 3.93]

 21 Ferritin (by type of compound)10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]

    21.1 by type of compound: ferrous sulphate
9826Mean Difference (IV, Random, 95% CI)-3.85 [-9.28, 1.59]

   21.2 by type of compound: ferrous fumarate
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    21.3 by type of compound: other
176Mean Difference (IV, Random, 95% CI)-9.03 [-23.95, 5.89]

 22 Ferritin (by anaemia status at baseline)10902Mean Difference (IV, Random, 95% CI)-4.93 [-9.98, 0.12]

    22.1 by anaemia status at baseline: anaemic
5285Mean Difference (IV, Random, 95% CI)-2.94 [-12.23, 6.34]

    22.2 by anaemia status at baseline: non-anaemic
3167Mean Difference (IV, Random, 95% CI)-2.67 [-5.89, 0.54]

    22.3 by anaemia status at baseline: mixed/unknown
3450Mean Difference (IV, Random, 95% CI)-9.42 [-23.19, 4.35]

 23 Ferritin (by supplementation regimen)10902Mean Difference (IV, Random, 95% CI)-4.48 [-9.68, 0.71]

    23.1 by supplementation regimen: one supplement a week
7595Mean Difference (IV, Random, 95% CI)-7.34 [-16.12, 1.44]

    23.2 by supplementation regimen: other intermittent regimen
5307Mean Difference (IV, Random, 95% CI)-0.93 [-3.94, 2.08]

 24 Ferritin (by sex)10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]

   24.1 by sex: girls
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   24.2 by sex: boys
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    24.3 by sex: mixed/unknown
10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]

 25 Ferritin (by nutrient)10902Mean Difference (IV, Random, 95% CI)-4.19 [-9.42, 1.05]

    25.1 By nutrient: iron alone
9826Mean Difference (IV, Random, 95% CI)-3.85 [-9.28, 1.59]

   25.2 By nutrient: iron + folic acid
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    25.3 By nutrient: iron + multiple micronutrients
176Mean Difference (IV, Random, 95% CI)-9.03 [-23.95, 5.89]

 26 Increase in steps climbed (ALL)165Mean Difference (IV, Random, 95% CI)-5.0 [-13.34, 3.34]

 27 All cause morbidity (ALL)2599Risk Ratio (M-H, Random, 95% CI)0.96 [0.83, 1.12]

 28 Diarrhoea (ALL)2122Risk Ratio (M-H, Random, 95% CI)1.17 [0.60, 2.28]

 29 Any side effects (ALL)4895Risk Ratio (M-H, Random, 95% CI)0.60 [0.19, 1.87]

 30 Adherence (ALL)51130Risk Ratio (M-H, Random, 95% CI)1.23 [0.98, 1.54]

 31 IQ (ALL)1252Mean Difference (IV, Random, 95% CI)-3.00 [-5.96, -0.04]

 32 Thai language (ALL)1208Mean Difference (IV, Random, 95% CI)-0.30 [-0.50, -0.09]

 33 Mathematics (ALL)1233Mean Difference (IV, Random, 95% CI)-0.27 [-0.44, -0.10]

 34 HAZ3279Std. Mean Difference (IV, Random, 95% CI)-0.26 [-0.80, 0.28]

 
Comparison 3. Intermittent iron supplementation versus placebo or no intervention: children 0 - 59 months

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Anaemia (ALL)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]

 2 Anaemia (by dose of elemental iron in the intermittent group)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]

    2.1 25 mg or less/week
2157Risk Ratio (M-H, Random, 95% CI)0.15 [0.06, 0.37]

    2.2 Greater than 25 mg to 75 mg/week
2501Risk Ratio (M-H, Random, 95% CI)0.61 [0.51, 0.74]

   2.3 Greater than 75 mg/week
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 3 Anaemia (by duration of the supplementation)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]

    3.1 0 to three months
3608Risk Ratio (M-H, Random, 95% CI)0.48 [0.27, 0.85]

    3.2 More than three months
150Risk Ratio (M-H, Random, 95% CI)0.06 [0.00, 0.97]

 4 Anaemia (by type of compound)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]

    4.1 Ferrous sulphate
3351Risk Ratio (M-H, Random, 95% CI)0.26 [0.07, 1.03]

    4.2 Ferrous fumarate
1307Risk Ratio (M-H, Random, 95% CI)0.61 [0.49, 0.74]

   4.3 Other
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Anaemia (by anaemia status at baseline)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]

    5.1 Anaemic
1307Risk Ratio (M-H, Random, 95% CI)0.61 [0.49, 0.74]

   5.2 Non-anaemic
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    5.3 Mixed/unknown
3351Risk Ratio (M-H, Random, 95% CI)0.26 [0.07, 1.03]

 6 Anaemia (by intermittent regimen)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]

    6.1 One supplement a week
3351Risk Ratio (M-H, Random, 95% CI)0.26 [0.07, 1.03]

    6.2 Other intermittent regimen
1307Risk Ratio (M-H, Random, 95% CI)0.61 [0.49, 0.74]

 7 Anaemia (by sex)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]

   7.1 Girls
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   7.2 Boys
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    7.3 Mixed/unknown
4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]

 8 Anaemia (by nutrient)4658Risk Ratio (M-H, Random, 95% CI)0.43 [0.23, 0.80]

    8.1 Iron alone
2501Risk Ratio (M-H, Random, 95% CI)0.61 [0.51, 0.74]

   8.2 Iron + folic acid
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    8.3 iron + vitamin C
150Risk Ratio (M-H, Random, 95% CI)0.06 [0.00, 0.97]

    8.4 Iron + multiple micronutrients
1107Risk Ratio (M-H, Random, 95% CI)0.16 [0.06, 0.44]

 9 Haemoglobin (ALL)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]

 10 Haemoglobin (by dose of elemental iron in the intermittent group)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]

    10.1 25 mg or less/week
3324Mean Difference (IV, Random, 95% CI)8.19 [-4.01, 20.38]

    10.2 Greater than 25 mg to 75 mg/week
6930Mean Difference (IV, Random, 95% CI)5.50 [2.64, 8.36]

   10.3 Greater than 75 mg/week
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 11 Haemoglobin (by duration of the supplementation)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]

    11.1 0 to three months
4643Mean Difference (IV, Random, 95% CI)6.64 [3.01, 10.27]

    11.2 More than three months
5611Mean Difference (IV, Random, 95% CI)6.16 [-1.55, 13.87]

 12 Haemoglobin (by type of iron compound)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]

    12.1 Ferrous sulphate
7873Mean Difference (IV, Random, 95% CI)6.54 [1.44, 11.63]

    12.2 Ferrous fumarate
1307Mean Difference (IV, Random, 95% CI)8.0 [5.00, 11.00]

    12.3 Other
174Mean Difference (IV, Random, 95% CI)4.06 [-1.32, 9.44]

 13 Haemoglobin (by anaemia status at baseline)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]

    13.1 Anaemic
1307Mean Difference (IV, Random, 95% CI)8.0 [5.00, 11.00]

   13.2 Non-anaemic
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    13.3 Mixed/unknown
8947Mean Difference (IV, Random, 95% CI)6.25 [1.60, 10.90]

 14 Haemoglobin (by supplementation regimen)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]

    14.1 One supplement a week
6699Mean Difference (IV, Random, 95% CI)7.35 [0.92, 13.77]

    14.2 Other intermittent regimen
3555Mean Difference (IV, Random, 95% CI)4.68 [1.28, 8.08]

 15 Haemoglobin (by sex)91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]

   15.1 Girls
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   15.2 Boys
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    15.3 Mixed/unknown
91254Mean Difference (IV, Random, 95% CI)6.45 [2.36, 10.55]

 16 Haemoglobin (by nutrient)91254Mean Difference (IV, Random, 95% CI)6.01 [2.13, 9.89]

    16.1 Iron alone
5744Mean Difference (IV, Random, 95% CI)3.81 [1.61, 6.01]

   16.2 Iron + folic acid
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    16.3 Iron + multiple micronutrients
5510Mean Difference (IV, Random, 95% CI)8.46 [0.60, 16.32]

 17 Iron deficiency (ALL)3431Risk Ratio (M-H, Random, 95% CI)0.24 [0.06, 0.91]

 18 Ferritin (ALL)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]

 19 Ferritin (by dose of iron in the intermittent group)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]

    19.1 25 mg or less/week
1148Mean Difference (IV, Random, 95% CI)4.60 [-0.89, 10.09]

    19.2 Greater than 25 mg to 75 mg/week
3162Mean Difference (IV, Random, 95% CI)16.91 [0.99, 32.82]

   19.3 Greater than 75 mg/week
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 20 Ferritin (by duration of the supplementation)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]

    20.1 0 to three months
135Mean Difference (IV, Random, 95% CI)15.80 [-1.23, 32.83]

    20.2 More than three months
3275Mean Difference (IV, Random, 95% CI)12.34 [-6.19, 30.87]

 21 Ferritin (by type of iron compound)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]

    21.1 Ferrous sulphate
3236Mean Difference (IV, Random, 95% CI)16.12 [-1.81, 34.05]

   21.2 Ferrous fumarate
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    21.3 Other
174Mean Difference (IV, Random, 95% CI)2.46 [-14.37, 19.29]

 22 Ferritin (by anaemia status at baseline)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]

   22.1 by anaemia status at baseline: anaemic
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    22.2 by anaemia status at baseline: non-anaemic
174Mean Difference (IV, Random, 95% CI)2.46 [-14.37, 19.29]

    22.3 by anaemia status at baseline: mixed/unknown
3236Mean Difference (IV, Random, 95% CI)16.12 [-1.81, 34.05]

 23 Ferritin (by supplementation regimen)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]

    23.1 One supplement a week
3257Mean Difference (IV, Random, 95% CI)5.37 [0.39, 10.36]

    23.2 Other intermittent regimen
153Mean Difference (IV, Random, 95% CI)27.80 [22.88, 32.72]

 24 Ferritin (by sex)4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]

   24.1 Girls
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   24.2 Boys
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    24.3 Mixed/unknown
4310Mean Difference (IV, Random, 95% CI)13.15 [-2.28, 28.59]

 25 Ferritin (by nutrient)4310Mean Difference (IV, Random, 95% CI)11.15 [-1.92, 24.22]

    25.1 Iron alone
3144Mean Difference (IV, Random, 95% CI)15.70 [-2.68, 34.08]

   25.2 Iron + folic acid
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    25.3 Iron + multiple micronutrients
2166Mean Difference (IV, Random, 95% CI)4.58 [-2.27, 11.43]

 26 All cause morbidity (ALL)1194Risk Ratio (M-H, Random, 95% CI)0.26 [0.03, 2.24]

 27 Any side effects (ALL)153Risk Ratio (M-H, Random, 95% CI)3.87 [0.19, 76.92]

 28 Adherence (ALL)2289Risk Ratio (M-H, Random, 95% CI)1.04 [0.98, 1.09]

 29 Mental development scale (ALL)1172Mean Difference (IV, Random, 95% CI)2.0 [-2.40, 6.40]

 30 Orientation engagement (ALL)1172Mean Difference (IV, Random, 95% CI)8.40 [-1.79, 18.59]

 31 Emotional regulation (ALL)1172Mean Difference (IV, Random, 95% CI)-2.5 [-11.58, 6.58]

 32 Motor quality (ALL)1172Mean Difference (IV, Random, 95% CI)15.60 [7.66, 23.54]

 33 Psychomotor development index (ALL)1172Mean Difference (IV, Random, 95% CI)6.90 [1.35, 12.45]

 34 HAZ2302Mean Difference (IV, Random, 95% CI)0.04 [-0.03, 0.11]

 
Comparison 4. Intermittent iron supplementation versus daily iron supplementation: children 0 - 59 months

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Anaemia (ALL)3770Risk Ratio (M-H, Random, 95% CI)1.26 [1.05, 1.51]

 2 Haemoglobin (ALL)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]

 3 Haemoglobin (by dose of elemental iron in the intermittent group)142438Mean Difference (IV, Random, 95% CI)-0.82 [-1.82, 0.18]

    3.1 25 mg or less/week
3536Mean Difference (IV, Random, 95% CI)-2.42 [-4.18, -0.66]

    3.2 Greater than 25 mg to 75 mg/week
111902Mean Difference (IV, Random, 95% CI)-0.45 [-1.59, 0.68]

   3.3 Greater than 75 mg/week
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 4 Haemoglobin (by duration of supplementation)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]

    4.1 0 to three months
91309Mean Difference (IV, Random, 95% CI)-0.15 [-1.66, 1.36]

    4.2 More than three months
5961Mean Difference (IV, Random, 95% CI)-1.53 [-2.95, -0.11]

 5 Haemoglobin (by type of compound)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]

    5.1 Ferrous sulphate
132194Mean Difference (IV, Random, 95% CI)-0.85 [-1.91, 0.21]

   5.2 Ferrous fumarate
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    5.3 Other
176Mean Difference (IV, Random, 95% CI)1.96 [-3.05, 6.97]

 6 Haemoglobin (by anaemia status at baseline)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]

    6.1 Anaemic
5834Mean Difference (IV, Random, 95% CI)-0.57 [-2.81, 1.68]

    6.2 Non-anaemic
2113Mean Difference (IV, Random, 95% CI)1.99 [-0.72, 4.70]

    6.3 Mixed/unknown
71323Mean Difference (IV, Random, 95% CI)-1.20 [-2.22, -0.19]

 7 Haemoglobin (by supplementation regimen)142270Mean Difference (IV, Random, 95% CI)-0.72 [-1.71, 0.27]

    7.1 One supplement a week
91054Mean Difference (IV, Random, 95% CI)-0.23 [-1.67, 1.21]

    7.2 Other intermittent regimen
71216Mean Difference (IV, Random, 95% CI)-1.14 [-2.57, 0.29]

 8 Haemoglobin (by sex)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]

   8.1 Girls
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   8.2 Boys
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    8.3 Mixed/unknown
142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]

 9 Haemoglobin (by nutrient)142270Mean Difference (IV, Random, 95% CI)-0.75 [-1.80, 0.29]

    9.1 Iron alone
101490Mean Difference (IV, Random, 95% CI)-0.80 [-2.05, 0.46]

    9.2 Iron + folic acid
1366Mean Difference (IV, Random, 95% CI)-2.40 [-4.94, 0.14]

    9.3 Iron + multiple micronutrients
3414Mean Difference (IV, Random, 95% CI)0.57 [-1.84, 2.98]

 10 Iron deficiency (ALL)176Risk Ratio (M-H, Random, 95% CI)4.0 [1.23, 13.05]

 11 Ferritin (ALL)8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.59, 0.39]

 12 Ferritin (by dose of elemental iron in the intermittent subgroup)8582Mean Difference (IV, Random, 95% CI)-2.22 [-6.03, 1.59]

   12.1 25 mg or less/week
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    12.2 Greater than 25 mg to 75 mg/week
8582Mean Difference (IV, Random, 95% CI)-2.22 [-6.03, 1.59]

   12.3 Greater than 75 mg/week
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 13 Ferritin (by duration of supplementation)8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.59, 0.39]

    13.1 0 to three months
5382Mean Difference (IV, Random, 95% CI)-3.02 [-7.91, 1.87]

    13.2 More than three months
3200Mean Difference (IV, Random, 95% CI)-1.63 [-5.88, 2.62]

 14 Ferritin (by type of compound)8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.59, 0.39]

    14.1 Ferrous sulphate
7506Mean Difference (IV, Random, 95% CI)-2.69 [-6.42, 1.05]

   14.2 Ferrous fumarate
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    14.3 Other
176Mean Difference (IV, Random, 95% CI)-9.03 [-23.95, 5.89]

 15 Ferritin (by anaemia status at baseline)8582Mean Difference (IV, Random, 95% CI)-3.70 [-8.25, 0.86]

    15.1 Anaemic
4225Mean Difference (IV, Random, 95% CI)-4.47 [-15.45, 6.52]

    15.2 Non-anaemic
3167Mean Difference (IV, Random, 95% CI)-2.67 [-5.89, 0.54]

    15.3 Mixed/unknown
2190Mean Difference (IV, Random, 95% CI)-1.53 [-5.23, 2.17]

 16 Ferritin (by supplementation regimen)8582Mean Difference (IV, Random, 95% CI)-3.27 [-7.87, 1.33]

    16.1 One supplement a week
5291Mean Difference (IV, Random, 95% CI)-6.21 [-12.98, 0.55]

    16.2 Other intermittent regimen
4291Mean Difference (IV, Random, 95% CI)-0.81 [-3.89, 2.27]

 17 Ferritin (by sex)8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.58, 0.39]

   17.1 Girls
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   17.2 Boys
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    17.3 Mixed/unknown
8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.58, 0.39]

 18 Ferritin (by nutrient)8582Mean Difference (IV, Random, 95% CI)-3.10 [-6.59, 0.39]

    18.1 Iron alone
7506Mean Difference (IV, Random, 95% CI)-2.69 [-6.42, 1.05]

   18.2 Iron + folic acid
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    18.3 Iron + multiple micronutrients
176Mean Difference (IV, Random, 95% CI)-9.03 [-23.95, 5.89]

 19 All cause morbidity (ALL)1522Risk Ratio (M-H, Random, 95% CI)0.98 [0.82, 1.16]

 20 Diarrhoea (ALL)145Risk Ratio (M-H, Random, 95% CI)2.88 [0.12, 67.03]

 21 Any side effects (ALL)4895Risk Ratio (M-H, Random, 95% CI)0.60 [0.19, 1.87]

 22 Adherence (ALL)31185Risk Ratio (M-H, Random, 95% CI)1.29 [1.15, 1.45]

 23 HAZ1109Std. Mean Difference (IV, Random, 95% CI)-0.15 [-0.52, 0.23]

 24 WAZ1109Std. Mean Difference (IV, Random, 95% CI)-0.44 [-0.82, -0.06]

 
Comparison 5. Intermittent iron supplementation versus placebo or no intervention: children 5 - 12 years

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Anaemia (ALL)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]

 2 Anaemia (by dose)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]

   2.1 25 mg or less/week
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.2 Greater than 25 mg to 75 mg/week
4755Risk Ratio (M-H, Random, 95% CI)0.47 [0.21, 1.02]

    2.3 Greater than 75 mg/week
2411Risk Ratio (M-H, Random, 95% CI)0.71 [0.48, 1.04]

 3 Anaemia (by duration)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]

    3.1 0 to three months
2848Risk Ratio (M-H, Random, 95% CI)0.77 [0.67, 0.89]

    3.2 More than three months
4318Risk Ratio (M-H, Random, 95% CI)0.44 [0.16, 1.24]

 4 Anaemia (by type of compound)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]

    4.1 Ferrous sulphate
61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]

   4.2 Ferrous fumarate
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   4.3 Other
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Anaemia (by anaemia status at baseline)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]

    5.1 Anaemic
1117Risk Ratio (M-H, Random, 95% CI)0.14 [0.07, 0.27]

    5.2 Non-anaemic
164Risk Ratio (M-H, Random, 95% CI)0.78 [0.27, 2.31]

    5.3 Mixed/unknown
4985Risk Ratio (M-H, Random, 95% CI)0.73 [0.54, 0.98]

 6 Anaemia (by intermittent regimen)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]

    6.1 One supplement a week
61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]

   6.2 Other intermittent regimen
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 7 Anaemia (by sex)61166Risk Ratio (M-H, Random, 95% CI)0.59 [0.40, 0.86]

    7.1 Girls
1248Risk Ratio (M-H, Random, 95% CI)0.75 [0.59, 0.95]

    7.2 Boys
1253Risk Ratio (M-H, Random, 95% CI)0.81 [0.66, 1.00]

    7.3 Mixed/unknown
5665Risk Ratio (M-H, Random, 95% CI)0.49 [0.24, 1.01]

 8 Anaemia (by nutrient)61166Risk Ratio (M-H, Random, 95% CI)0.54 [0.33, 0.90]

    8.1 Iron alone
4573Risk Ratio (M-H, Random, 95% CI)0.39 [0.17, 0.90]

    8.2 Iron + folic acid
2593Risk Ratio (M-H, Random, 95% CI)0.83 [0.66, 1.03]

   8.3 Iron + multiple micronutrients
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 9 Haemoglobin (ALL)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]

 10 Haemoglobin (by dose of elemental iron in the intermittent group)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]

   10.1 25 mg or less/week
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    10.2 Greater than 25 mg to 75 mg/week
61129Mean Difference (IV, Random, 95% CI)5.24 [-0.78, 11.26]

    10.3 Group: greater than 75 mg/week
4649Mean Difference (IV, Random, 95% CI)1.84 [0.25, 3.44]

 11 Haemoglobin (by duration of the supplementation)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]

    11.1 0 to three months
3973Mean Difference (IV, Random, 95% CI)3.13 [1.49, 4.77]

    11.2 More than three months
7805Mean Difference (IV, Random, 95% CI)4.38 [-1.20, 9.96]

 12 Haemoglobin (by type of iron compound)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]

    12.1 Ferrous sulphate
71415Mean Difference (IV, Random, 95% CI)4.59 [-0.30, 9.47]

    12.2 Ferrous fumarate
1125Mean Difference (IV, Random, 95% CI)3.4 [-4.09, 10.89]

    12.3 Other
2238Mean Difference (IV, Random, 95% CI)1.79 [-1.25, 4.84]

 13 Haemoglobin (by anaemia status at baseline)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]

    13.1 Anaemic
1115Mean Difference (IV, Random, 95% CI)18.30 [15.55, 21.05]

    13.2 Non-anaemic
164Mean Difference (IV, Random, 95% CI)2.0 [-2.46, 6.46]

    13.3 Mixed/unknown
81599Mean Difference (IV, Random, 95% CI)2.37 [1.17, 3.57]

 14 Haemoglobin (by supplementation regimen)101868Mean Difference (IV, Random, 95% CI)4.04 [0.45, 7.62]

    14.1 One supplement a week
91647Mean Difference (IV, Random, 95% CI)4.43 [0.21, 8.65]

    14.2 Other intermittent regimen
2221Mean Difference (IV, Random, 95% CI)1.17 [-1.27, 3.61]

 15 Haemoglobin (by sex)101778Mean Difference (IV, Random, 95% CI)4.03 [0.51, 7.55]

    15.1 Girls
1248Mean Difference (IV, Random, 95% CI)4.0 [0.83, 7.17]

    15.2 Boys
1253Mean Difference (IV, Random, 95% CI)3.70 [0.58, 6.82]

    15.3 Mixed/unknown
91277Mean Difference (IV, Random, 95% CI)4.05 [-0.37, 8.46]

 16 Haemoglobin (by nutrient)101778Mean Difference (IV, Random, 95% CI)4.04 [0.30, 7.78]

    16.1 Iron alone
61022Mean Difference (IV, Random, 95% CI)4.98 [-0.71, 10.68]

    16.2 Iron + folic acid
4756Mean Difference (IV, Random, 95% CI)2.91 [0.65, 5.16]

   16.3 Iron + multiple micronutrients
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 17 Ferritin (ALL)1240Mean Difference (IV, Random, 95% CI)16.6 [11.12, 22.08]

 18 All cause morbidity (ALL)1194Risk Ratio (M-H, Random, 95% CI)0.26 [0.03, 2.24]

 19 Any side effects (ALL)153Risk Ratio (M-H, Random, 95% CI)3.87 [0.19, 76.92]

 20 Nausea164Risk Ratio (M-H, Random, 95% CI)2.82 [0.12, 66.82]

 21 IQ (ALL)1252Mean Difference (IV, Random, 95% CI)-3.00 [-5.96, -0.04]

 22 Thai language (ALL)1208Mean Difference (IV, Random, 95% CI)-0.30 [-0.50, -0.09]

 23 Mathematics (ALL)1233Mean Difference (IV, Random, 95% CI)-0.27 [-0.44, -0.10]

 24 Increase in steps climbed (ALL)160Mean Difference (IV, Random, 95% CI)8.0 [-0.72, 16.72]

 25 WAZ164Std. Mean Difference (IV, Random, 95% CI)-0.24 [-0.74, 0.25]

 26 HAZ164Mean Difference (IV, Fixed, 95% CI)-0.24 [-0.69, 0.21]

 
Comparison 6. Intermittent iron supplementation versus daily iron supplementation: children 5 - 12 years

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Anaemia (ALL)2145Risk Ratio (M-H, Random, 95% CI)0.95 [0.47, 1.91]

 2 Haemoglobin (ALL)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]

 3 Haemoglobin (by dose of elemental iron)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]

   3.1 25 mg or less/week
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Greater than 25 mg to 75 mg/week
3444Mean Difference (IV, Random, 95% CI)-1.10 [-3.01, 0.80]

    3.3 Intermittent group: greater than 75 mg/week
2137Mean Difference (IV, Random, 95% CI)1.00 [-4.68, 6.68]

 4 Haemoglobin (by duration of the supplementation)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]

    4.1 0 to three months
2155Mean Difference (IV, Random, 95% CI)0.32 [-6.54, 7.18]

    4.2 More than three months
3426Mean Difference (IV, Random, 95% CI)-0.64 [-2.12, 0.84]

 5 Haemoglobin (by type of compound)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]

    5.1 Ferrous sulphate
4539Mean Difference (IV, Random, 95% CI)0.04 [-2.63, 2.71]

   5.2 Ferrous fumarate
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    5.3 Other
142Mean Difference (IV, Random, 95% CI)-2.0 [-5.43, 1.43]

 6 Haemoglobin (by baseline prevalence of anaemia)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]

    6.1 Anaemic
3271Mean Difference (IV, Random, 95% CI)0.37 [-3.44, 4.17]

   6.2 Non-anaemic
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.3 Mixed/unknown
2310Mean Difference (IV, Random, 95% CI)-1.22 [-3.08, 0.63]

 7 Haemoglobin (by supplementation regimen)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]

    7.1 by supplementation regimen: one supplement a week
5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]

   7.2 by supplementation regimen: other intermittent regimen
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 8 Haemoglobin (by sex)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]

    8.1 Girls
142Mean Difference (IV, Random, 95% CI)-2.0 [-5.43, 1.43]

   8.2 Boys
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    8.3 Mixed/unknown
4539Mean Difference (IV, Random, 95% CI)0.04 [-2.63, 2.71]

 9 Haemoglobin (by nutrient)5581Mean Difference (IV, Random, 95% CI)-0.31 [-2.59, 1.97]

    9.1 Iron alone
4539Mean Difference (IV, Random, 95% CI)0.04 [-2.63, 2.71]

    9.2 Iron + folic acid
142Mean Difference (IV, Random, 95% CI)-2.0 [-5.43, 1.43]

   9.3 By nutrient: iron + multiple micronutrients
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

 10 Ferritin (ALL)2320Mean Difference (IV, Random, 95% CI)-11.57 [-38.75, 15.61]

 11 All cause morbidity (ALL)177Risk Ratio (M-H, Random, 95% CI)0.92 [0.68, 1.24]

 12 Diarrhoea (ALL)177Risk Ratio (M-H, Random, 95% CI)1.12 [0.56, 2.22]

 13 Adherence (ALL)2245Risk Ratio (M-H, Random, 95% CI)1.29 [0.44, 3.75]

 14 IQ (ALL)1252Mean Difference (IV, Random, 95% CI)-3.00 [-5.96, -0.04]

 15 Thai language (ALL)1208Mean Difference (IV, Random, 95% CI)-0.30 [-0.50, -0.09]

 16 Mathematics (ALL)1233Mean Difference (IV, Random, 95% CI)-0.27 [-0.44, -0.10]

 17 Increase in steps climbed (ALL)165Mean Difference (IV, Random, 95% CI)-5.0 [-13.34, 3.34]

 18 HAZ2170Std. Mean Difference (IV, Random, 95% CI)-0.32 [-1.26, 0.63]

 19 WAZ2170Std. Mean Difference (IV, Random, 95% CI)0.09 [-0.21, 0.39]

 20 WAZ2302Std. Mean Difference (IV, Random, 95% CI)0.04 [-0.34, 0.41]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Appendix 1. Search strategies

CENTRAL

#1MeSH descriptor Iron, this term only
#2MeSH descriptor Iron, Dietary, this term only
#3MeSH descriptor Anemia, Iron-Deficiency, this term only
#4MeSH descriptor Folic Acid, this term only
#5MeSH descriptor Dietary Supplements, this term only
#6MeSH descriptor Trace Elements, this term only
#7iron*
#8folic* or folate* or folvite* or folacin* or pteroylglutamic*
#9diet* NEAR/3 supplement*
#10micro-nutrient* or micronutrient* or multi-nutrient* or multinutrient*
#11MeSH descriptor Ferric Compounds, this term only
#12MeSH descriptor Ferrous Compounds, this term only
#13ferrous* or ferric* or fe
#14MeSH descriptor Micronutrients, this term only
#15(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14)
#16MeSH descriptor Drug Administration Schedule, this term only
#17MeSH descriptor Dose-Response Relationship, Drug explode all trees
#18MeSH descriptor Time Factors, this term only
#19week* or biweek* or bi NEXT week* or intermittent* or alternat*
#20(#16 OR #17 OR #18 OR #19)
#21(#15 AND #20)
#22(iron NEAR/3 (dose* or dosage or administer* or administration or frequency))
#23(#21 OR #22)
#24 (baby or babies or newborn* or neonat* or toddler* or child* or preschool* or schoolchild* or boy* or girl* or pre-school* or teen* or adolescen* or preteen* or youth* or young person* or young people)
#25(#23 AND #24)

MEDLINE

1 Iron/ or Anemia, Iron-Deficiency/ or Iron, Dietary/
2 Folic Acid/
3 micronutrients/
4 Dietary Supplements/
5 iron$.tw.
6 (folic$ or folate$ or folvite$ or folacin$ or pteroylglutamic$).tw.
7 Trace Elements/
8 (diet$ adj3 supplement$).tw.
9 (micro-nutrient$ or micronutrient$ or multi-nutrient$ or multinutrient$).tw.
10 Ferric Compounds/
11 Ferrous Compounds/
12 (ferrous$ or ferric$ or fe).tw.
13 or/1-12
14 Drug Administration Schedule/
15 Dose-Response Relationship, Drug/
16 Time Factors/
17 (week$ or biweek$ or bi-week$ or intermittent$ or alternat$).tw.
18 or/14-17
19 13 and 18
20 (iron adj3 (dose$ or dosage or administer$ or administration or frequency)).tw.
21 19 or 20
22 exp Infant/
23 exp Child/
24 Adolescent/
25 (baby or babies or newborn$ or neonat$ or toddler$ or child$ or preschool$ or schoolchild$ or boy$ or girl$ or pre-school$ or teen$ or adolescen$ or preteen$ or youth$ or young person$ or young people).tw.
26 or/22-25
27 randomized controlled trial.pt.
28 controlled clinical trial.pt.
29 randomi#ed.ab.
30 placebo$.ab.
31 drug therapy.fs.
32 randomly.ab.
33 trial.ab.
34 groups.ab.
35 or/27-34
36 exp animals/ not humans.sh.
37 35 not 36
38 21 and 26 and 37

EMBASE

1 iron/
2 iron intake/
3 iron deficiency anemia/
4 folic acid/
5 exp trace element/
6 diet supplementation/
7 iron$.tw.
8 (folic$ or folate$ or folvite$ or folacin$ or pteroylglutamic$).tw.
9 (diet$ adj3 supplement$).tw.
10 (micro-nutrient$ or micronutrient$ or multi-nutrient$ or multinutrient$).tw.
11 ferric ion/
12 ferrous ion/
13 or/1-12
14 drug administration/
15 drug dose regimen/
16 time/
17 (week$ or biweek$ or bi-week$ or intermittent$ or alternat$).tw.
18 or/14-17
19 13 and 18
20 (iron adj3 (dose$ or dosage or administer$ or administration or frequency)).tw.
21 19 or 20
22 exp infant/
23 exp child/
24 adolescent/
25 (baby or babies or newborn$ or neonat$ or toddler$ or child$ or preschool$ or schoolchild$ or boy$ or girl$ or pre-school$ or teen$ or adolescen$ or preteen$ or youth$ or young person$ or young people).tw.
26 or/22-25
27 21 and 26
28 exp Clinical trial/
29 Randomization/
30 Single blind procedure/
31 Double blind procedure/
32 Crossover procedure/
33 Placebo/
34 Randomi#ed.tw.
35 RCT.tw.
36 (random$ adj3 (allocat$ or assign$)).tw.
37 randomly.ab.
38 groups.ab.
39 trial.ab.
40 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
41 Placebo$.tw.
42 prospective study/
43 (crossover or cross-over).tw.
44 prospective.tw.
45 or/28-44
46 27 and 45

CINAHL

S43 S24 and S42
S42 S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 or S33 or S34 or
S35 or S36 or S37 or S38 or S39 or S40 or S41
S41 (MH "Evaluation Research") OR (MH "Summative Evaluation Research") OR
(MH "Program Evaluation")
S40 (MH "Treatment Outcomes")
S39 (MH "Comparative Studies")
S38 TI (evaluat* study or evaluat* research) or AB (evaluat* study or
evaluat* research) or TI (effectiv* study or effectiv* research) or AB
(effectiv* study or effectiv* research) OR TI (prospectiv* study or
prospectiv* research) or AB(prospectiv* study or prospectiv* research) or
TI (follow-up study or follow-up research) or AB (follow-up study or follow-up research)
S37 placebo*
S36 crossover* or "cross over*"
S35 (MH "Crossover Design")
S34 (tripl* N3 mask*) or (tripl* N3 blind*)
S33 (trebl* N3 mask*) or (trebl* N3 blind*)
S32 (doubl* N3 mask*) or (doubl* N3 blind*)
S31 (singl* N3 mask*) or (singl* N3 blind*)
S30 (clinic* N3 trial*) or (control* N3 trial*)
S29 (random* N3 allocat*) or (random* N3 assign*)
S28 randomis* or randomiz*
S27 (MH "Meta Analysis")
S26 (MH "Clinical Trials+")
S25 MH random assignment
S24 S19 and S23
S23 S20 or S21 or S22
S22 baby or babies or newborn* or neonat* or toddler* or child or preschool* or schoolchild* or boy* or girl* or pre-school* or teen* or adolescen* or preteen* or youth* or young person* or young people
S21 AG adolescent
S20 AG infant or child
S19 S17 or S18
S18 (iron N3 dose*) or (iron N3 dosage) or (iron N3 administer*) or (iron N3 administration) or (iron N3 frequency)
S17 S11 and S16
S16 S12 or S13 or S14 or S15
S15 (week* or biweek* or bi-week*or bi week* or intermittent* or alternat*)
S14 (MH "Time Factors")
S13 (MH "Dose-Response Relationship, Drug")
S12 (MH "Drug Administration Schedule")
S11 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10
S10 micro-nutrient* or micronutrient* or micro nutrient* multi-nutrient* or multinutrient* or multi nutrient*
S9 ferrous* or ferric* or "fe"
S8 diet* N3 supplement*
S7 folic* or folate* or folvite* or folacin* or pteroylglutamic*
S6 iron*
S5 (MH "Micronutrients")
S4 (MH "Trace Elements")
S3 (MH "Dietary Supplements")
S2 (MH "Folic Acid")
S1 (MH "Iron") OR (MH "Anemia, Iron Deficiency") OR (MH "Iron Compounds") OR (MH "Ferric Compounds") OR (MH "Ferrous Compounds")

POPLINE

(iron* /folic* / folate* /supplement*/micronutrient*/micro-nutrient*) & (week* /bi-week* / bi week* / biweek* / intermittent / alternat*)

ICTRP

Intervention: iron or folic or folate or micronutrient*
limited to Clinical trials in children

IMBIOMED

Intervention: suplementacion hierro

LILACS

Intervention: suplementacion hierro

IBECS

Intervention: suplementacion hierro

Scielo

Intervention: suplementacion hierro

 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

All four review authors contributed to drafting the text of the review, commented on the drafts and approved the final version.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Luz Maria De-Regil - none known.
Maria Elena D Jefferds - none known.
Allison C Sylvetsky - none known.
Therese Dowswell - none known.

Disclaimer: Luz Maria De-Regil is a full-time staff member of the World Health Organization (WHO), Allison C Sylvetsky did a 6-week internship at WHO (summer 2010), and Therese Dowswell has received financial support from the WHO for her work on this review. Maria Elena Jefferds is a full-time staff member of the US Centers for Disease Control and Prevention. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the official position, decisions, policy or views of these Organisations.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms
 

Internal sources

  • Centers for Disease Control and Prevention (CDC), Division of Nutrition, Physical Activity, and Obesity, USA.
  • Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.

 

External sources

  • Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.
    Dr Therese Dowswell received partial financial support for her work on this review.
  • Government of Luxembourg, Luxembourg.
    WHO acknowledges the Government of Luxembourg for their financial support to the Micronutrients Unit for conducting systematic reviews on micronutrient interventions

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

We added a description of the methodology followed to produce the 'Summary of findings' tables in the 'Assessment of risk of bias in included studies' section.

We made the following changes to the outcomes section:

  • we modified the order of the primary outcomes so that the effects of the same indicator, presented either as a continuous or as a dichotomous variable, could be assessed together (for example, anaemia and haemoglobin concentrations);
  • since there are no official cut-offs for children younger than 6 months, we changed the definition of anaemia from "haemoglobin < 110 g/L or < 115 g/L for children 6 to 59 months or 5 to 11 years old, respectively, adjusted by altitude where appropriate" to "haemoglobin below a cut-off defined by trialists, taking into account the age group and altitude";
  • for our secondary outcome 'all-cause morbidity', we replaced 'at least one event' with 'at least one reported illness' to make it clearer;
  • we renamed our secondary outcome 'folic acid status' as 'folate status' and replaced the units with 'as measured by trialists'. Folate may be measured in serum, plasma or red blood cells and the most frequently used units may vary.
  • as the duration of the trials was mostly short, we changed the definition of our secondary outcome 'growth impairment (stunting and wasting)' to 'height-for-age and weight-for-age Z-scores' and moved this to the end of our list of outcomes.

 

Index terms

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Index terms

Medical Subject Headings (MeSH)

*Dietary Supplements; Anemia, Iron-Deficiency [blood; complications; *drug therapy]; Child Development [*drug effects]; Child Nutritional Physiological Phenomena [drug effects]; Drug Administration Schedule; Hemoglobin A, Glycosylated [metabolism]; Iron, Dietary [*administration & dosage]; Randomized Controlled Trials as Topic; Trace Elements [administration & dosage]; Vitamins [administration & dosage]

MeSH check words

Child; Child, Preschool; Female; Humans; Male

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé摘要
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
Aguayo 2000 {published data only}
  • Aguayo VM. School-administered weekly iron supplementation - effect on the growth and hemoglobin status of non-anemic Bolivian school-age children. A randomized placebo-controlled trial. European Journal of Nutrition 2000;39(6):263-9.
Arcanjo 2011 (C) {published data only}
  • Arcanjo FPN, Arcanjo CC, Amancio OMS, Braga JAP, Leite AJM. Weekly iron supplementation for the prevention of anemia in pre-school children: a randomized, double-blind, placebo-controlled trial. Journal of Tropical Pediatrics 2011 Feb 1 [Epub ahead of print].
Awasthi 2005 (C) {published data only}
  • Awasthi S, Verma T, Vir S. Effectiveness of biweekly versus daily iron-folic acid administration on anaemia status in preschool children. Journal of Tropical Pediatrics 2005;51(2):67-71.
Baqui 2003 {published data only}
  • Baqui AH, Walker CL, Zaman K, El Arifeen S, Chowdhury HR, Wahed MA, et al. Weekly iron supplementation does not block increases in serum zinc due to weekly zinc supplementation in Bangladeshi infants. Journal of Nutrition 2005;135(9):2187-91.
  • Baqui AH, Zaman K, Persson LA, El Arifeen S, Yunus M, Begum N, et al. Simultaneous weekly supplementation of iron and zinc is associated with lower morbidity due to diarrhea and acute lower respiratory infection in Bangladeshi infants. Journal of Nutrition 2003;133(12):4150-7.
  • Black MM, Baqui AH, Zaman K, Ake Persson L, El Arifeen S, Le K, et al. Iron and zinc supplementation promote motor development and exploratory behavior among Bangladeshi infants. American Journal of Clinical Nutrition 2004;80(4):903-10.
  • Fischer Walker CL, Baqui AH, Ahmed S, Zaman K, El Arifeen S, Begum N, et al. Low-dose weekly supplementation of iron and/or zinc does not affect growth among Bangladeshi infants. European Journal of Clinical Nutrition 2009;63(1):87-92.
Berger 1997 {published data only}
  • Berger J, Aguayo VM, Téllez W, Luján C, Traissac P, San Miguel JL. Weekly iron supplementation is as effective as 5 day per week iron supplementation in Bolivian school children living at high altitude. European Journal of Clinical Nutrition 1997;51(6):381-6.
Da Silva 2008 {published and unpublished data}
Desai 2004 (C) {published data only}
  • Desai MR, Dhar R, Rosen DH,  Kariuki SK, Shi YP, Kager PA, et al. Daily iron supplementation is more efficacious than twice weekly iron supplementation for the treatment of childhood anemia in western Kenya. Journal of Nutrition 2004;134(5):1167-74.
Ekvall 2000 {published data only}
Engstrom 2008 (C) {published data only}
  • Engstrom EM, Castro IR, Portela M, Cardoso LO, Monteiro CA. Effectiveness of daily and weekly iron supplementation in the prevention of anemia in infants. Revista de Saúde Pública 2008;42(5):786-95.
Ermis 2002 {published data only}
  • Ermis B, Demirel F, Demircan N, Gurel A. Effects of three different iron supplementations in term healthy infants after 5 months of life. Journal of Tropical Pediatrics 2002;48(5):280-4.
Evangelista-Salazar 2004 {published data only}
  • Evangelista-Salazar E. Evaluation of the preventive effect of the intermittent provision of iron and vitamin C on the reduction of the iron and neurodevelopment in infants [Evaluacion del efecto preventivo de la administracion intermitente de hierro y vitamina C sobre la disminucion de la reserva de hierro y el neurodesarrollo en lactantes]. Doctoral Thesis. Universidad de Colima, Mexico 2004.
  • Martínez H, Evangelista Salazar JJ, Avila Jiménez L. Iron supplementation for preventing anaemia in infants [Suplementación con hierro para prevenir anemia en la primera infancia]. In: Luis Durán Arenas, Onofre Muñoz Hernández editor(s). La traducción del conocimiento. del resultado de la investigación a la aplicación de los servicios de salud. México, D.F: CAMS, 2006:71-86.
Faqih 2006 {published data only}
  • Faqih AM, Kakish SB, Izzat M. Effectiveness of intermittent iron treatment of two- to six-year-old Jordanian children with iron-deficiency anemia. Food and Nutrition Bulletin 2006;27(3):220-7.
Hall 2002 (C) {published and unpublished data}
  • Hall A, Roschnik N, Ouattara F, Toure I, Maiga F, Sacko M, et al. A randomised trial in Mali of the effectiveness of weekly iron supplements given by teachers on the haemoglobin concentrations of schoolchildren. Public Health Nutrition 2002;5(3):413-8.
Khademloo 2009 {published data only}
  • Khademloo M, Karami H, Ajami A, Yasari M. Comparison of the effectiveness of weekly and daily iron supplementation in 6- to 24-months-old babies in urban health centers of Sari, Iran. Pakistan Journal of Biological Sciences 2009;12(2):195-7.
Liu 1995 (C) {published data only}
  • Liu X-N, Kang J, Zhao L, Viteri FE. Intermittent iron supplementation in Chinese pre-schoolchildren is efficient and safe. Food and Nutrition Bulletin 1995;16(2):139-46.
  • Liu XNA, Liu PY. The effectiveness of weekly iron supplementation regimen in improving the iron status of Chinese children and pregnant women. Biomedical and Environmental Sciences 1996;9(2-3):341-7.
Nguyen 2002 {published data only}
  • Nguyen XN, Berger J, Dao TQ, Nguyen CK, Traissac P, Ha HK. Efficacy of daily and weekly iron supplementation for the control of iron deficiency anaemia in infants in rural Vietnam [Efficacite de la supplementation en fer quotidienne et hebdomadaire pour le controle de l'anemie chez le nourrisson en milieu rural au Vietnam]. Santé (Montrouge, France) 2002;12(1):31-7.
Olsen 2000 {published data only}
  • Olsen A, Nawiri J, Friis H. The impact of iron supplementation on reinfection with intestinal helminths and Schistosoma mansoni in western Kenya. Transactions of the Royal Society of Tropical Medicine Hygene 2000;94(5):493-9.
  • Olsen A, Nawiri J, Magnussen P, Krarup H, Friis H. Failure of twice-weekly iron supplementation to increase blood haemoglobin and serum ferritin concentrations: results of a randomized controlled trial. Annals of Tropical Medicine and Parasitology 2006;100(3):251-63.
Palupi 1997 {published data only}
  • Palupi L, Schultink W, Achadi E, Gross R. Effective community intervention to improve hemoglobin status in preschoolers receiving once-weekly iron supplementation. American Journal of Clinical Nutrition 1997;65(4):1057-61.
Roschnik 2003 (C) {unpublished data only}
  • Roschnik N, Phiri V, Mukaka M. The impact of weekly school-based iron supplementation. Mangochi District, Malawi (Report). Save the Children, USA February 2003.
Roschnik 2004 (C) {published and unpublished data}
Schultink 1995 {published data only}
  • Schultink W, Gross R, Gliwitzki M, Karyadi D, Matulessi P. Effect of daily vs twice weekly iron supplementation in Indonesian preschool children with low iron status. American Journal of Clinical Nutrition 1995;61(1):111-5.
Sen 2009 (C) {published and unpublished data}
  • Sen A, Kanani SJ. Impact of iron-folic acid supplementation on cognitive abilities of school girls in Vadodara. Indian Pediatrics 2009;46(2):137-43.
  • Sen A, Kanani SJ. Physical work capacity of young underprivileged school girls impact of daily vs intermittent iron folic acid supplementation: a randomized controlled trial. Indian Pediatrics 2009;46(10):849-54.
Siddiqui 2004 {published data only}
  • Siddiqui IA, Jaleel A, Rahman MA. Preventive strategy to control iron deficiency anemia in children and adults. Journal of the Pakistan Medical Association 2003;53(4):131-3.
  • Siddiqui IA, Rahman MA, Jaleel A. Efficacy of daily vs. weekly supplementation of iron in schoolchildren with low iron status. Journal of Tropical Pediatrics 2004;5:276-8.
Sinisterra 1997 (C) {published data only}
  • Sinisterra OT, Valdes VE, Valverde C. Effect of supplementation with iron salts and knowledge, attitudes and practices in relation to anaemia among schoolchildren in the province of Cocle, Ministry of Health, Republic of Panama (report). [Efecto de la suplementacion con sales de hierro y de conocimientos, actitudes y practicas en relacion a la anemia en escolares de la provincia de Cocle, Republica de Panama: reporte]. Vol. DCE/18, Panama: INCAP, Ministry of Health, Republic of Panama, 1997.
Soemantri 1997 {published data only}
  • Soemantri AG, Hapsari DE, Susanto JC, Rohadi W, Tamam M, Irawan PW, et al. Daily and weekly iron supplementation and physical growth of school age Indonesian children. Southeast Asian Journal of Tropical Medicine and Public Health 1997;28 Suppl 2:69-74.
Sungthong 2002 {published data only}
  • Sungthong R, Mo-Suwan L, Chongsuvivatwong V, Geater AF. Once weekly is superior to daily iron supplementation on height gain but not on hematological improvement among schoolchildren in Thailand. Journal of Nutrition 2002;132(3):418-22.
  • Sungthong R, Mo-suwan L, Chongsuvivatwong V, Geater AF. Once-weekly and 5-days a week iron supplementation differentially affect cognitive function but not school performance in Thai children. Journal of Nutrition 2004;134(9):2349-54.
Tavil 2003 {published data only}
  • Tavil B, Sipahi T, Gökçe H, Akar N. Effect of twice weekly versus daily iron treatment in Turkish children with iron deficiency anemia. Pediatric Hematology and Oncology 2003;20(4):319-26.
Taylor 2001 {published data only}
  • Taylor M, Jinabhai CC, Couper I, Kleinschmidt I, Jogessar VB. The effect of different anthelmintic treatment regimens combined with iron supplementation on the nutritional status of schoolchildren in KwaZulu-Natal, South Africa: a randomized controlled trial. Transactions of the Royal Society of Tropical Medicine and Hygiene 2001;95(2):211-6.
Thu 1999 {published data only}
  • Thu BD, Schultink W, Dillon D, Gross R, Leswara ND, Khoi HH. Effect of daily and weekly micronutrient supplementation on micronutrient deficiencies and growth in young Vietnamese children. American Journal of Clinical Nutrition 1999;69(1):80-6.
Verhoef 2002 {published data only}
  • Verhoef H, West CE, Kraaijenhagen R, Nzyuko SM, King R, Mbandi MM. Malarial anemia leads to adequately increased erythropoiesis in asymptomatic Kenyan children. Blood 2002;15(00(10)):489-94.
  • Verhoef H, West CE, Nzyuko SM, de Vogel S, van der Valk R, Wanga MA, et al. Intermittent administration of iron and sulfadoxine-pyrimethamine to control anaemia in Kenyan children: a randomised controlled trial. Lancet 2002;21(360(9337)):908-14.
Yang 2004 (C) {published data only}
  • Yang Q, Yin S, Zhao X, An J. Effect of daily or once weekly iron supplementation on growth and iron status of preschool children. Wei sheng yan jiu = Journal of Hygiene Research 2004;33(2):205-7.
Young 2001 {published data only}
  • Young MW. The effectiveness of weekly iron and vitamin supplementation of Malawian preschool children. South African Medical Journal = Suid-Afrikaanse tydskrif vir geneeskunde 2001;91(1):49-50.
Yurdakok 2004 {published data only}
  • Yurdakök K, Temiz F, Yalçin SS, Gümrük F. Efficacy of daily and weekly iron supplementation on iron status in exclusively breast-fed infants. Journal of Pediatric Hematology/Oncology 2004;26(5):284-8.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé摘要
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
Agarwal 2003 {published data only}
  • Agarwal KN, Gomber S, Bisht H, Som M. Anemia prophylaxis in adolescent school girls by weekly or daily iron-folate supplementation. Indian Pediatrics 2003;40(4):296-301.
Ahmed 2001 {published data only}
  • Ahmed F, Khan MR, Jackson AA. Concomitant supplemental vitamin A enhances the response to weekly supplemental iron and folic acid in anemic teenagers in urban Bangladesh. American Journal of Clinical Nutrition 2001;74(1):108-15.
Ahmed 2005 {published data only}
  • Ahmed F, Khan MR, Akhtaruzzaman M, Karim R, Marks GC, Banu CP, et al. Efficacy of twice-weekly multiple micronutrient supplementation for improving the hemoglobin and micronutrient status of anemic adolescent schoolgirls in Bangladesh. American Journal of Clinical Nutrition 2005;82(4):829-35.
Avila-Jimenez 2011 {unpublished data only}
  • Ávila Jiménez L, Méndez, Villalpando-Hernández S, Martínez-Salgado H. Preventive iron supplementation and nutritional status of infants measured by anthropometry assigned to IMSS obligatory regimen [Suplementación preventiva con hierro y estado nutricio medido por antropometría de lactantes del régimen obligatorio del IMSS]. Unpublished article sent by Dr Homero Martinez.
  • Ávila-Jiménez L, Méndez I, Villalpando-Hernández S, Martínez-Salgado H. Effect of iron supplementation on growth velocity in infants [Efecto de una suplementación con hierro sobre la velocidad de crecimiento en lactantes]. Unpublished article sent by Dr Homero Martinez.
Azeredo 2010 {published data only}
  • Azeredo CM, Cotta RM, Sant'Ana LF, Franceschini Sdo C, Ribeiro Rde C, Lamounier JA, et al. Greater effectiveness of daily iron supplementation scheme in infants [Efectividad superior del esquema diario de suplementación de hierro en lactantes]. Revista de Saúde Pública  2010;44(2):230-9.
Beasley 2000 {published data only}
Briars 2003 {published data only}
  • Adank C, Green TJ, Skeaff CM, Briars B. Weekly high-dose folic acid supplementation is effective in lowering serum homocysteine concentrations in women. Annals of Nutrition and Metabolism 2003;47(2):55-9.
Februhartanty 2002 {published data only}
Hafeez 1998 {published data only}
  • Hafeez A, Ahmad P. Iron deficiency anaemia: continuous versus intermittent treatment in anaemic children. Journal of the Pakistan Medical Association 1998;48(9):269-72.
Hop 2005 {published data only}
  • Hop LT, Berger J. Multiple micronutrient supplementation improves anemia, micronutrient nutrient status, and growth of Vietnamese infants: double-blind, randomized, placebo-controlled trial. Journal of Nutrition 2005;135(3):660s-5s.
Jackson 2003 {published data only}
  • Jackson RT, Al-Mousa Z, Al-Raqua M, Prakash P. Effect of short-term weekly supplementation on anemia and symptoms in adolescent Kuwaiti girls. Kuwait Medical Journal 2003;35(4):275-80.
Jaleel 2004 {published data only}
Jayatissa 1999 {published data only}
  • Jayatissa R, Piyasena P. Adolescent schoolgirls: daily or weekly iron supplementation. Food and Nutrition Bulletin 1999;20(4):429-34.
Kanal 2005 {published data only}
  • Kanal K, Busch-Hallen J, Cavalli-Sforza T, Crape B, Smitasiri S, Cambodian Weekly Iron-Folic Acid Program Team. Weekly iron-folic acid supplements to prevent anemia among Cambodian women in three settings: process and outcomes of social marketing and community mobilization. Nutrition Reviews 2005;63(12 Pt 2):S126-33.
Kapur 2003 {published data only}
  • Kapur D, Sharma S, Agarwal KN. Effectiveness of nutrition education, iron supplementation or both on iron status in children. Indian Pediatrics 2003;40(12):1131-44.
Kianfar 2000 {published data only}
  • Kianfar H, Kimiagar M, Ghaffarpour M. Effect of daily and intermittent iron supplementation on iron status of high school girls. International Journal for Vitamin and Nutrition Research 2000;70(4):172-7.
Lechtig 2006 {published data only}
  • Lechtig A, Gross R, Vivanco OA, Gross U, López de Romaña D. Lessons learned from the scaling-up of a weekly multimicronutrient supplementation program in the integrated food security program (PISA). Food and Nutrition Bulletin 2006;27 Suppl Peru(4):160-5.
Leenstra 2009 {published data only}
  • Leenstra T, Kariuki SK, Kurtis JD, Oloo AJ, Kager PA, Ter Kuile FO. The effect of weekly iron and vitamin A supplementation on hemoglobin levels and iron status in adolescent schoolgirls in western Kenya. European Journal of Clinical Nutrition 2009;63(2):173-82.
Lima 2006 {published data only}
  • Lima AC, Lima MC, Guerra MQF, Romani SAM, Eickmann SH, Lira PIC. Impact of weekly treatment with ferrous sulfate on hemoglobin level, morbidity and nutritional status of anemic infants. Jornal de Pediatria 2006;82(6):452-7.
Lin 2001 {published data only}
  • Lin X, Tang Y, Long Z. Effects of vitamin A and iron supplementation on the improvement of iron status and immunological function in preschool children. Chinese Journal of Preventive Medicine - Zhonghua Yu Fang Yi Xue Za Zhi 2001;35(6):374-7.
López de Romaña 2005 {published data only}
  • López de Romaña G, Cusirramos S, López de Romaña D, Gross R. Efficacy of multiple micronutrient supplementation for improving anemia, micronutrient status, growth, and morbidity of Peruvian infants. Journal of Nutrition 2005;135(3):646s-52s.
López de Romaña 2006 {published data only}
  • López de Romaña D, Verona S, Vivanco OA, Gross R. Protective effect of multimicronutrient supplementation against anemia among children, women, and adolescent girls in lower-income areas of Chiclayo, Peru. Food and Nutrition Bulletin 2006;27 Suppl Peru(4):S143-50.
Menendez 1997 {published data only}
  • Menendez C, Kahigwa E, Hirt R, Vounatsou P, Aponte JJ, Font F, et al. Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants. Lancet 1997;350(9081):844-50.
Mwanakasale 2009 {published data only}
  • Mwanakasale V, Siziya S, Mwansa J, Koukounari A, Fenwick A. Impact of iron supplementation on schistosomiasis control in Zambian school children in a highly endemic area. Malawi Medical Journal 2009;21(1):12-8.
Perrin 2002 {published data only}
  • Perrin E, Rothman R, Coyne-Beasley T, Ford C, Bordley WC. Is weekly iron and folic acid supplementation as effective as daily supplementation for decreasing incidence of anemia in adolescent girls?. Archives of Pediatrics and Adolescent Medicine 2002;156(2):128-30.
Risonar 2008 {published data only}
  • Risonar MG, Tengco LW, Rayco-Solon P, Solon FS. The effect of a school-based weekly iron supplementation delivery system among anemic schoolchildren in the Philippines. European Journal of Clinical Nutrition 2008;62(8):991-6.
Rivera 1998 {published data only}
  • Rivera G, De Thomson M. Effect of ferrous salts supplementation on iron status of schoolchildren, Chiriqui, Panama, 1995-1997 [Efecto de la suplementacion con sales ferrosas en el estado nutricional de hierro de escolares, Chiriqui, Panama, 1995-1997]. Panama: Ministry of Health, Republic of Panama, 1998.
Schümann 2009 {published data only}
  • Schümann K, Longfils, P, Monchy D, von Xylander S, Weinheimer H,  Solomons NW. Efficacy and safety of twice-weekly administration of three RDAs of iron and folic acid with and without complement of 14 essential micronutrients at one or two RDAs: a placebo-controlled intervention trial in anemic Cambodian infants 6 to 24 months of age. European Journal of Clinical Nutrition 2009;63(3):355-68.
Shah 2002 {published data only}
  • Shah BK, Gupta P. Weekly vs daily iron and folic acid supplementation in adolescent Nepalese girls. Archives of Pediatrics and Adolescent Medicine 2002;156(2):131-5.
Sharma 2000 {published data only}
  • Sharma A, Prasad K, Rao KV. Identification of an appropriate strategy to control anemia in adolescent girls of poor communities. Indian Pediatrics 2000;37(3):261-7.
Shobha 2003 {published data only}
  • Shobha S, Sharada D. Efficacy of twice weekly iron supplementation in anemic adolescent girls. Indian Pediatrics 2003;40(12):1186-90.
Smuts 2005 {published data only}
  • Smuts CM, Dhansay MA, Faber M, van Stuijvenberg ME, Swanevelder S, Gross R, et al. Efficacy of multiple micronutrient supplementation for improving anemia, micronutrient status, and growth in South African infants. Journal of Nutrition 2005;135(3):653s-9s.
Soekarjo 2004 {published data only}
  • Soekarjo DD, Pee S de, Kusin JA, Schreurs WH. Schultink W, Muhilal, et al. Effectiveness of weekly vitamin A (10,000 IU) and iron (60 mg) supplementation for adolescent boys and girls through schools in rural and urban East Java, Indonesia. European Journal of Clinical Nutrition 2004;58(6):927-37.
Sotelo-Cruz 2002 {published data only}
  • Sotelo-Cruz N, Gómez-Rivera N, Ferrá-Fragoso S, Pereyda-Galaz DE. Ferrous sulfate weekly dose for iron deficiency in preschool children. Gaceta Médica de México 2002;138(3):225-30.
Tee 1999 {published data only}
  • Tee ES, Kandiah M, Awin N, Chong SM, Satgunasingam N, Kamarudin L, et al. School-administered weekly iron-folate supplements improve hemoglobin and ferritin concentrations in Malaysian adolescent girls. American Journal of Clinical Nutrition 1999;69(6):1249-56.
Tomashek 2001 {published data only}
  • Tomashek KM, Woodruff BA, Gotway CA, Bloland P, Mbaruku G. Randomized intervention study comparing several regimens for the treatment of moderate anemia among refugee children in Kigoma Region,Tanzania. American Journal Tropical Medicine and Hygiene 2001;64(3-4):164-71.
UNICEF 2006 {published data only}
  • Ministry of Health Panama, UNICEF, PAHO. [Situacion de deficiencia de hierro y anemia]. Status of iron deficiency and anaemia. Panama: UNICEF, 2006.
Vir 2008 {published data only}
  • Vir SC, Singh N, Nigam AK, Jain R. Weekly iron and folic acid supplementation with counselling reduces anemia in adolescent girls: a large-scale effectiveness study in Uttar Pradesh, India. Food and Nutrition Bulletin 2008;29(3):186-94.
Wijaya-Erhardt 2007 {published data only}
  • Wijaya-Erhardt M, Erhardt JG, Untoro J, Karyadi E, Wibowo L, Gross R. Effect of daily or weekly multiple-micronutrient and iron foodlike tablets on body iron stores of Indonesian infants aged 6-12 mo: a double-blind, randomized, placebo-controlled trial. American Journal of Clinical Nutrition 2007;86(6):1680-6.
Zavaleta 2000 {published data only}
  • Zavaleta N, Respicio G, Garcia T. Efficacy and acceptability of two iron supplementation schedules in adolescent school girls in Lima, Peru. Journal of Nutrition 2000;130(2):462s-4s.

References to studies awaiting assessment

  1. Top of page
  2. AbstractRésumé摘要
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
Husseini 1999 {unpublished data only}
  • Husseini T. Bagor, Indonesia Trial. Information included in Beaton 1999.
Kargarnovin 2010 {published data only}
  • Kargarnovin Z, Tamkins A, Jalaly M, Salavan K, Pam L. Effects of daily versus weekly iron therapy in infants between 6-24 months for iron deficiency anemia. Journal of Nursing and Midwifery 2010;20(69):48.
Reid 2001 {published data only}
  • Reid ED, Lopez P, Galaviz IA, Isoard F, Rosado JL, Allen LH. Hematological and biochemical responses of rural Mexican preschoolers to iron alone or iron plus micronutrients. FASEB Journal. 2001; Vol. 15:A731.

References to ongoing studies

  1. Top of page
  2. AbstractRésumé摘要
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
Zeeba Zaka-ur-Rab 2010 {published data only}
  • Dr. Zeeba Zaka-ur-Rab. A clinical trial to compare the effects of daily versus intermittent iron supplementation on markers of oxidative stress and anti-oxidant status in children with iron deficiency anemia . The Clinical Trials Registry- India (CTRI).

Additional references

  1. Top of page
  2. AbstractRésumé摘要
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to studies awaiting assessment
  21. References to ongoing studies
  22. Additional references
ACC/SCN 1991
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Adetifa 2009
Balshem 2010
Baqui 2005
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Beard 2008
Beaton 1999
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Bhutta 2009
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Okebe 2011
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Peña-Rosas 2009
RevMan 2011
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Stoltzfus 2011
Thu 1999
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WHO 2001
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WHO 2009
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WHO 2009a
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WHO 2011a
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