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 myelination of neural tissue (Iannoti 2006) and differentiation 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, haemoglobin concentration decreases resulting in a condition known as iron deficiency anaemia (IDA).
Anaemia is characterised by a reduction in the number of red blood cells or their oxygen-carrying capacity, such that physiological needs can no longer be met. In addition to iron deficiency, other nutritional deficiencies (for example, folic acid, vitamin B12 and vitamin A), chronic inflammation, parasitic infections and inherited disorders of haemoglobin structure can all cause anaemia (WHO 2001). Haemoglobin concentrations are used to diagnose anaemia, while serum ferritin and serum transferrin are commonly used as indicators of iron status (WHO/CDC 2007).
Children, particularly those younger than five years, are vulnerable to iron deficiency anaemia because of their increased needs resulting from rapid growth. It is estimated that 600 million pre-school and school-aged children are anaemic worldwide and it is calculated that half of the cases are due to iron deficiency (De Benoist 2008). Among females, anaemia is often exacerbated after menarche, especially if adolescents do not consume sufficient iron to offset menstrual losses (WHO 2001).
Consequences of iron deficiency anaemia during childhood include growth retardation, reduced school achievement, impaired motor and cognitive development, and increased morbidity and mortality from a variety of causes (WHO 2001). Specifically, iron deficiency can lead to deficits in memory and behavioural regulation as iron is required for enzymes needed 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 occurring at an early age and the consequences may continue even after treatment, reinforcing the importance of prevention (Siddiqui 2004; Iannoti 2006; Moy 2006).
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. However, the effectiveness of these interventions in child populations is variable. 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, 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.
Currently 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 born at term. School-age and older children should receive 30 mg of iron and 250 mg of folic acid daily, particularly in populations where anaemia prevalence is greater than 40% (WHO 2001). Though the current recommendations include only iron alone or with folic acid, it has been suggested that administration of additional micronutrients will prevent or reverse anaemia derived from one or more nutritional deficiencies (Bhutta 2009). Daily iron supplementation has proven to be effective in increasing haemoglobin concentration in children, especially in those who are anaemic (Gera 2007). In spite of this, in real world settings, the long regimen duration and side effects associated with daily iron supplementation (for example, gastrointestinal discomfort, constipation and teeth staining with drops or syrups) limit adherence, especially in young children (Mozaffari-Khosravi 2010). These effects may partially be controlled with the use of slow-release iron preparations, in which iron has similar bioavailability to regular iron compounds (for example, ferrous sulphate or ferrous fumarate) (Simmons 1993; Bothwell 2000).
How the intervention might work
Oral iron supplementation on an intermittent basis (i.e. one, two 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 because it maximises absorption by provision of iron in synchrony with the turnover of the mucosal cells (i.e. intestinal cells are 'fresh' to take up iron) (Viteri 1997; Berger 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 (Casanueva 2003; Baqui 2005). Finally, 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). This reduced exposure to iron overall is particularly relevant in malaria settings where it has been suggested that the provision of additional iron may exacerbate the infection, as less iron is available for the parasite's growth (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, which may increase adherence to supplementation programmes (Thu 1999; Viteri 2005; Casanueva 2006).
Why it is important to do this review
There are currently no international recommendations on intermittent iron supplementation regimens in children, but 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 (WIFS) is already recommended by the WHO to prevent anaemia in women of reproductive age (WHO 2009b). This intervention is currently implemented at scale in 13 countries around the world as part of public health programmes and could potentially be targeted to other age groups, such as young children and school-age children, since the supplement can be provided at home and in schools or other institutional settings. However, to date there is no systematic assessment of the safety and effectiveness of weekly or any other intermittent iron supplementation regimen among children to inform policy makers.
The proposed systematic review will complement the findings of two Cochrane systematic reviews exploring the effects of intermittent regimens among women of reproductive age (Fernández-Gaxiola 2011) and pregnant women (Peña-Rosas 2011).
To assess the effects and safety of intermittent iron supplementation, alone or in combination with other nutrients, on nutritional and developmental outcomes in children less than 12 years of age compared with daily regimen or no treatment.
Criteria for considering studies for this review
Types of studies
We will include randomised, quasi-randomised and cluster-randomised controlled trials. Quasi-randomised trials are 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 2009). We will not include other types of evidence (for example, cohort or case-control studies) in this meta-analysis nor will they contribute to the results or conclusions, but we will consider such evidence in the discussion where relevant.
Types of participants
Children under the age of 12 at the time of intervention receiving any intermittent iron supplementation regimen. We will not include studies specifically targeting children with health problems, for example low birth weight infants, children with HIV or enterally fed children.
Types of interventions
Interventions of any duration involving intermittent dosage of iron alone or with other vitamins and minerals versus placebo/no intervention or versus the same supplements provided on a daily basis. For the purpose of this review, intermittent supplementation is defined as the provision of iron once, twice or three times a week on non-consecutive days.
We will include interventions that combine iron supplementation with co-interventions such as education or other approaches only if the co-interventions are the same in both the intervention and comparison groups. We will exclude studies examining supplementary food-based interventions (micronutrient powders, lipid-based supplements, fortified complementary foods and other fortified foods).
Types of outcome measures
- Anaemia: haemoglobin < 110 g/L or < 115 g/L for children 6 to 59 or 5 to 11 years old, respectively, adjusted by altitude where appropriate.
- Iron deficiency: as measured by trialists by using indicators of iron status, such as ferritin or transferrin.
- Iron deficiency anaemia: defined by the presence of anaemia plus iron deficiency, diagnosed with an indicator of iron status selected by trialists.
- Haemoglobin (g/L).
- Iron status (ferritin ug/L).
- All-cause mortality: number of events during the trial.
- All-cause morbidity: number of patients with at least one event during the trial.
- Acute respiratory infection: as measured by trialists.
- Diarrhoea: at least three evacuations of unformed faeces in 24 hours.
- Any other adverse affects: as measured by trialists, such as stained teeth, headache, stomach ache, discomfort.
- Growth impairment (stunting, underweight): less than -2 z-score for height for age or weight for age, respectively.
- Adherence: percentage of children who consumed more than 70% of the expected doses.
- Folic acid status (mg/dL).
- Mental development and motor skill development (children 0 to 59 months): as assessed by trialists; it might include Bayley Mental Development Index (MDI), Bayley Psychomotor Development Index (PDI), Stanford-Binet Test, DENVER II Developmental Screening Test, among others.
- School performance (children 60 months and older): as measured by trialists.
- Physical capacity (children 60 months and older): as measured by trialists.
We will group the outcome time points as follows: immediately post-end of the intervention, one to six months post-end of intervention, and seven to 12 months post-end of the intervention.
Search methods for identification of studies
We will search the following electronic databases without language restrictions: MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), CINAHL, POPLINE, LILACS, IBECS, Scielo, EMBASE, Science Citation Index and Biosis Previews.
We will use the following search strategy to search MEDLINE:
1 Iron/ or Anemia, Iron-Deficiency/ or Iron, Dietary/
2 Folic Acid/
4 Dietary Supplements/
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.
14 Drug Administration Schedule/
15 Dose-Response Relationship, Drug/
16 Time Factors/
17 (week$ or biweek$ or intermittent$ or alternat$).tw.
19 13 and 18
20 (iron adj3 (dose$ or dosage or administer$ or administration or frequency)).tw.
21 19 or 20
22 exp Infant/
23 exp Child/
25 (baby or babies or newborn$ or neonat$ or toddler$ or child$ or preschool$ or pre-school or schoolchild$ or boy$ or girl$ or teen$ or adolescen$ or preteen$ or youth$ or young people).tw.
27 randomized controlled trial.pt.
28 controlled clinical trial.pt.
31 drug therapy.fs.
36 exp animals/ not humans.sh.
37 35 not 36
38 21 and 26 and 37
We will not apply any language restrictions. If we find articles written in a language other than English we will commission their translation into English and put them in the awaiting assessment section of the review until translation is completed. In the event of being unable to secure a translation we will contact the editorial office of the Cochrane Developmental, Psychosocial and Learning Problems Group for support.
Searching other resources
For assistance in identifying ongoing or unpublished studies, we will contact authors and known experts to identify any additional or unpublished data. We will also contact 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), Helen Keller International (HKI) and Sight and Life Foundation.
We will search the international clinical trials registry platform (ICTRP) and the metaRegister of Controlled Trials (mRCT) for any ongoing or planned trials.
Data collection and analysis
Selection of studies
LMR will screen for potential eligibility all titles and abstracts, while MEJ, TD and AS will each assess one-third. One review author (LMR) will search the additional sources. All the authors will independently assess half of the full-text articles for inclusion according to the above mentioned criteria; each paper will be assessed in duplicate. We will resolve any disagreement through discussion.
If studies were published only as abstracts, or study reports contain little information on methods, we will attempt to contact the authors to obtain further details of study design and results.
Data extraction and management
For eligible studies, two authors (from AS, MEJ and TD) will independently extract data using a form designed for this review. One author (LMR) will extract data from all the studies and enter data into the Review Manager software (RevMan 2008). The review author who extracted in duplicate one-third of the data will carry out checks for accuracy. We will resolve any discrepancies through discussion and document all the processes.
We will complete the data collection form electronically and will record information as follows.
(1) Trial methods
- Study design
- Unit and method of allocation
- Unit of analysis
- Masking of participants and outcomes
- Exclusion of participants after randomisation and proportion of losses at follow up
- Study power
- Location of the study
- Sample size
- Socio-economic status (as defined by trialists and where such information is available)
- Baseline status of anaemia
- Inclusion and exclusion criteria as described in the Criteria for considering studies for this review
- Type of iron compound
- Supplementation regimen
- Duration of the intervention
(4) Comparison group
- No intervention
- Provision of same nutrients in both intervention and comparison group
- Primary and secondary outcomes outlined in the Types of outcome measures section
We will record both prespecified and non-prespecified outcomes, although we will not use the latter to underpin the conclusions of the review.
When information regarding any of the studies is unclear, we will attempt to contact authors of the original reports to provide further details. If there is insufficient information for us to be able to assess risk of bias, studies will await assessment until further information is published, or made available to us.
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). We will resolve any disagreement by discussion or by involving a third assessor.
(1) Sequence generation (checking for possible selection bias)
We will describe for each included study the method used to generate the allocation sequence.
We will assess 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 will describe for each included study the method used to conceal the allocation sequence and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We will assess 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, alternation; date of birth);
- unclear risk of bias.
(3) Blinding (checking for possible performance and detection bias)
We will describe 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 women, clinical staff and outcome assessors to group allocation by providing placebo preparations.
We will assess blinding separately for different classes of outcomes, and we will indicate where there has been an attempt at partial blinding.
We will assess 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 will assess the risk of detection bias associated with blinding as:
- low, high or unclear risk of bias for outcome assessors.
Whilst assessed separately, we will combine the results into a single evaluation of risk of bias associated with blinding (Higgins 2009).
(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake. We will assess 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);
- risk of bias unclear.
(5) Selective reporting bias
We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We will assess the methods as:
- low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
- high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are 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);
- risk of bias unclear.
(6) Other sources of bias
We will describe for each included study any important concerns we have about other possible sources of bias.
We will assess whether each study was free of other problems that could put it at risk of bias:
(7) Overall risk of bias
We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2009). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings.
Attrition and lack of blinding may be a particular problem in studies looking at different regimens of iron supplementation and where children are followed up over time. We will explore the impact of the level of bias through undertaking sensitivity analyses - see 'Sensitivity analysis' below.
Measures of treatment effect
For dichotomous data, we will present results as summary risk ratios (RR) with 95% confidence intervals (CIs).
For continuous data, we will use the mean difference (MD) (with 95% CIs) if outcomes are measured in the same way between trials. We will use the standardised mean difference (SMD) to combine trials that measure the same outcome (for example, serum folate levels) but use different methods.
Unit of analysis issues
We will include cluster-randomised trials in the analyses along with individually-randomised trials. We will adjust the standard error of the effect estimate from cluster trials using the methods described in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2009). We will carry out meta-analyses using the generic inverse-variance method available in RevMan (RevMan 2008). We will use an estimate of the intra-cluster correlation co-efficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources are used, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC.
If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs; where we pool results from individually and cluster-randomised trials we will make this clear to readers in the presentation of results. If there is heterogeneity between study designs we will set out results for the individually randomised trials and cluster trials separately and provide subtotals only.
Studies with more than two treatment groups
For studies with more than two intervention groups (multi-arm studies) we will combine groups to create a single pair-wise comparison (Higgins 2009).
We will not include cross-over trials.
Dealing with missing data
For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.
We will carry out analyses, as far as possible, on an intention-to-treat basis (ITT), i.e. by attempting to include all participants randomised to each group in the analyses. If it is not possible or we are comparing daily versus intermittent supplementation, we will perform an available case analysis in which data are analysed for every participant for whom the outcome was obtained.
Assessment of heterogeneity
We will examine the forest plots from meta-analyses to look for heterogeneity among studies, and will use the I
Assessment of reporting biases
Where we suspect reporting bias (see 'Selective reporting bias' above), we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.
We will draw funnel plots (estimated differences in treatment effects against their standard error) if we find sufficient studies. Asymmetry could be due to publication bias, but can also be due to a real relationship between trial size and effect size, such as when larger trials have lower compliance, and compliance is positively related to effect size. In the event that we find such a relationship, we will examine clinical variation of the studies (Higgins 2009). As a direct test for publication bias, we will compare results extracted from published journal reports with results obtained from other sources (including correspondence).
We will carry out statistical analysis using the Review Manager software (RevMan 2008). In this review we will use random-effects analyses in view of anticipated heterogeneity in the interventions, populations and methods used in different trials.
In the analysis we will divide the population into two age groups: 0 to 59 months and 60 months and older.
We will perform the following comparisons:
- any intermittent iron supplementation versus no supplementation/placebo; and
- any intermittent iron supplementation versus any daily iron supplementation.
Any intermittent/daily supplementation with iron includes the provision of iron alone, iron plus folic acid or iron plus other vitamins and minerals.
Subgroup analysis and investigation of heterogeneity
Where data are available we will carry out subgroup analysis:
- 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;
- by duration of the supplementation: 0 to three months; more than three months;
- by type of compound: ferrous sulphate; ferrous fumarate; other;
- by anaemia status at baseline (haemoglobin < 110 g/L or < 115 g/L for children 6 to 59 or 5 to 11 years old, respectively, adjusted by altitude where appropriate): anaemic; non-anaemic; mixed/not reported;
- by intermittent supplementation regimen: one supplement a week; other intermittent regimen;
- by sex: boys; girls; mixed/not reported; and
- by micronutrients: iron alone; iron + folic acid; iron + multiple micronutrients.
We will use the primary outcomes in subgroup analysis.
We will examine differences between subgroups by inspection of the subgroups’ confidence intervals; non-overlapping confidence intervals suggesting a statistically significant difference in treatment effect between the subgroups. If we suspect differences between subgroups we will seek statistical advice on carrying out and interpreting a formal approach to explore subgroup differences such as that suggested by Borenstein 2009.
We will carry out sensitivity analysis to examine the effects of removing studies at high risk of bias (studies with poor or unclear allocation concealment or high levels of attrition) from the analysis. If cluster trials are included we will carry out sensitivity analysis using a range of intra-cluster correlation values.
We would like to thank Deidre Thomas from the US CDC Public Health Library and Information Center for help in devising the search strategy. We would also like to thank the staff at the editorial office of the Cochrane Developmental, Psychosocial and Learning Problems Group for their support in the preparation of this protocol.
As part of the pre-publication 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.
Protocol first published: Issue 4, 2011
Contributions of authors
All four review authors contributed to drafting the text of the protocol and commenting on drafts.
Disclaimer: Luz Maria De-Regil is a full-time staff member of the World Health Organization (WHO) 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 organizations.
Declarations of interest
Allison C Sylvetsky - none known
Maria Elena D Jefferds - none known
Luz Maria De-Regil - none known
Therese Dowswell - none known
Sources of support
- US Centers for Disease Control and Prevention (CDC), USA.
- Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.
- 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