Point-of-use fortification of foods with micronutrient powders containing iron in children of preschool and school age

  • Protocol
  • Intervention


  • Luz Maria De-Regil,

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

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  • Maria Elena D Jefferds,

    1. 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
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  • Juan Pablo Peña-Rosas

    1. World Health Organization, Evidence and Programme Guidance, Department of Nutrition for Health and Development, Geneva, Switzerland
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This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of point-of-use fortification of foods with micronutrient powders containing iron alone or in combination with other vitamins and minerals on nutrition, health and development among children of preschool and school age (24 months to 12 years old) compared with no intervention, a placebo or iron-containing supplements.

For the purpose of this review, point-of-use fortification of foods with micronutrient powders refers to the addition of iron alone or in combination with other vitamins and minerals in powder form to energy-containing foods (that may or may not be in semi-solid form) at home or in any other place where meals are to be consumed, such as schools, nurseries and refugee camps. Micronutrient powders can be added to foods either during or after cooking or immediately before consumption without the explicit purpose of improving the flavour.


Description of the condition

Vitamin and mineral deficiencies are highly prevalent among children of preschool and school age (usually 24 to 59 months of age and 5 to 12 years of age, respectively), limiting their health and daily performance. In addition to anaemia, frequently reported micronutrient deficiencies in these age groups are those of iron, vitamin A, zinc and iodine.

Anaemia is a condition characterised by a reduction in the body's oxygen-carrying capacity. It is estimated that over 1.6 billion people, or a quarter of the world's population, are anaemic. The prevalence of anaemia is highest (47.4%) among preschool-age children and over 25% of school-age children. Most anaemia occurs in low- and middle-income countries, particularly in Asia, Africa and South America (WHO/CDC 2008).

Causes of anaemia include, iron, folate, vitamin B12 and vitamin A deficiencies, chronic inflammation, parasitic infestations and inherited blood disorders (WHO 2001; Jimenez 2010). Around half of this burden worldwide is assumed to be due to iron deficiency in malaria-endemic areas and more than half (about 60%) in malaria-free areas (Rastogi 2002; Stoltzfus 2004; WHO 2009a). Iron deficiency can be caused by chronic poor dietary iron intake (in quantity and quality), together with increased iron requirements resulting from growth and from losses due to intestinal parasitic infestations and menstruation in postmenarchal girls (WHO 2001). Anaemia in children is diagnosed when the haemoglobin (Hb) concentration in the blood is below a predefined cut-off value, which varies with age and the residential elevation (WHO 2011a). Iron deficiency anaemia is diagnosed by the combined presence of anaemia and iron deficiency, measured by ferritin or any other biomarker of iron status such as serum transferrin receptors or zinc protoporphyrin (WHO 2011b).

Iron deficiency anaemia in children of preschool and school age is associated with considerable morbidity. This condition appears to be associated with potentially irreversible impairment of cognitive development in preschool-age children and with reduced learning and educational performance in school-age children (Lozoff 2007). Iron deficiency has been estimated to contribute to 0.2% of deaths in children under five years, and every year approximately 2.2 million years are lost due to iron-induced disability worldwide (measured in disability adjusted life years (DALYs), a measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death) (Stoltzfus 2004; Black 2008; WHO 2009a).

On the other hand, vitamin A deficiency, the leading cause of childhood blindness and an important contributor to young child mortality (WHO 2009a), affects an estimated 190 million preschool-age children, mostly from the World Health Organization (WHO) regions of Africa and South-East Asia (WHO 2009b). Zinc deficiency may impair physical growth, increase susceptibility to infection and affect neurobehavioural development (Brown 2009). Some authors have estimated that zinc deficiency is responsible for about 4% of child mortality (Black 2008) and that supplementing children with this nutrient may help reduce deaths related to diarrhoea and pneumonia (Yakoob 2011). Iodine deficiency affects more than one-third of school-age children worldwide and results in developmental delays and other health problems (Andersson 2005). Vitamin D deficiency and folate insufficiency may also be a concern during childhood. Vitamin D has a key role in bone metabolism (Winzenberg 2011) while adequate folate and folic acid intake is particularly important for pubescent girls who are capable of reproduction, as poor maternal folate status around the time of conception increases the risk of neural tube and other defects at birth (Mulinare 1988). Unfortunately, to date there are insufficient data to estimate the global magnitude of inadequate folate or vitamin D status among any populations, including children.

In low-income countries, some nutritional risk factors increase the incidence or severity of infectious diseases and contribute to a high number of deaths and loss of healthy years. Micronutrient deficiencies (iron, vitamin A and zinc) in combination with childhood underweight and suboptimal breastfeeding cause 7% of deaths and 10% of total disease burden (WHO 2009a). In 2010, globally, an estimated 27% (171 million) of children younger than five years were stunted and 16% (104 million) were underweight. Africa and Asia have more severe burdens of undernutrition, but the problem persists in some Latin American countries (Lutter 2011). Underweight and undernutrition particularly increase child death and disability. Due to overlapping effects, these risk factors are responsible for an estimated 3.9 million deaths (35% of total deaths) and 33% of total DALYs in children less than five years old. Their combined contribution to specific causes of death is highest for diarrhoeal diseases (73%) and close to 50% for pneumonia, measles and severe neonatal infections (WHO 2009a).

Description of the intervention

Public health strategies to address micronutrient malnutrition include prevention of parasitic infestations and other infections, dietary diversification to improve the consumption of foods with highly absorbable vitamins and minerals, fortification of staple foods, provision of supplementary foods and provision of supplements in the form of pills and tablets (Bhutta 2008), with the latter being a widespread intervention.

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. Children of school age and older should receive 30 mg of iron and 250 μg (0.25 mg) of folic acid daily, particularly in populations where anaemia prevalence is greater than 40% (WHO 2001). The intermittent use of iron supplements has also recently been recommended as a public health strategy for these age groups in settings where anaemia prevalence is higher than 20% (WHO 2011c). Both supplementation regimens have proven to be effective in reducing the risk of having anaemia and iron deficiency (Gera 2007; De-Regil 2011a). Though the current recommendations only include iron alone or with folic acid, it has been suggested that administration of additional micronutrients may prevent or reverse anaemia derived from other nutritional deficiencies (Bhutta 2008) and also have positive effects on length or height and weight, serum zinc, serum retinol and motor development (Allen 2009). However, the long regimen duration and side effects associated with daily iron supplementation (for example, gastrointestinal discomfort, constipation and teeth staining with drops or syrups) and the still reduced implementation of large-scale intermittent supplementation have limited the use of vitamin and mineral supplements and led to the development of new approaches to provide iron and other nutrients.

Point-of-use fortification of foods with micronutrient powders has been proposed as an alternative to oral supplements and central fortified foods to provide micronutrients to different age groups ((Zlotkin 2001; Zlotkin 2005). It refers to the addition of vitamins and minerals in powder form to energy-containing foods at home or in any other place where meals are to be consumed, such as schools, nurseries and refugee camps. Micronutrient powders can be added to foods either during or after cooking or immediately before consumption without the explicit purpose of improving the flavour or colour. In some cases point-of-use fortification is also known as home fortification.

Point-of-use fortification with micronutrient powders could be described as a hybrid intervention between mass fortification of staple foods or condiments and targeted vitamin and mineral supplementation. The uniqueness of this intervention results from the mixture of advantages and disadvantages inherited from both parent interventions. Point-of-use fortification is similar to mass fortification because the vitamins and minerals are added to foods or condiments regularly consumed and usually does not require additional changes to dietary intake behaviours. Point-of-use fortification entails the fortification of foods immediately before consumption at home or at another point of use such as schools or child care facilities and there is no long-term interaction between micronutrients and food that can diminish their shelf life. In mass fortification, conversely, micronutrients are added to staple foods or condiments during industrial processing and are more prone to the potential undesirable chemical interactions over time which affect the food sensory properties as well as the bioavailability of some micronutrients.

Like micronutrient supplementation, point-of-use fortification with micronutrient powders is targeted to specific populations so that the number and amount of micronutrients can be tailored to meet the target groups' needs without increasing the risk of overload among other population groups. Also typical of vitamin and mineral supplementation, point-of-use fortification allows for flexibility in the provision regimen (for example, daily, intermittently) (Hyder 2007), and can be adapted according to the selected delivery channel (for example, health or school systems or social protection programmes) or context.

Both micronutrient supplementation and point-of-use fortification of foods with micronutrient powders require an active participation from the target population in order to achieve high coverage and regular and appropriate use. However, in comparison to supplementation, the addition of micronutrient powders to the food or meal may result in a higher acceptance among children and caregivers as a result of the lower number of side effects (Zlotkin 2005) and tastelessness of the product when prepared correctly. It is still unclear whether the absorption of micronutrient powders mimics that of supplements or that of mass fortification.

Point-of-use fortification of foods with micronutrient powders containing at least iron, vitamin A and zinc is recommended to improve iron status and reduce anaemia among infants and children aged 6 to 23 months of age (WHO 2011d).

How the intervention might work

Micronutrient powders were initially conceived as a way to deliver a novel iron compound, encapsulated ferrous fumarate, which is an iron salt covered by a thin lipid layer aimed at preventing the interaction of iron with foods. The encapsulation minimises changes caused by iron to the taste or colour in the added food (Liyanage 2002). However, other iron compounds have also been tested. Micronised ferric pyrophosphate has produced a similar haematological response in 6 to 23-month old children in comparison to encapsulated ferrous fumarate but it is still too expensive to be extensively used in community interventions (Christofides 2006; Hirve 2007). More recently sodium iron EDTA has been proposed as a more efficacious fortificant that, given in a low dose, could produce similar effects on haemoglobin as those observed with ferrous sulphate among school-age children, particularly when added to cereal-based foods that are rich in inhibitors of iron absorption (Troesch 2010). Independently of the source, the iron is frequently accompanied with other micronutrients such as zinc, vitamin A, vitamin C, vitamin D or folic acid, and in some cases micronutrient powder formulations may include up to 15 vitamins and minerals. These formulations are currently developed by various manufacturers (De Pee 2008; de Pee 2009). From the packaging perspective, micronutrient powders were initially delivered in single-dose sachets, which are lightweight, simple to store and transport, and allow easier dosage control (De Pee 2008; SGHI 2008), although the disposal of non-degradable sachets has raised some environmental concerns. Currently the package of the micronutrient powders has been broadened to the use of bulk packs from which powders are added over the meals by using measuring spoons.

The use of micronutrient powders by children aged 6 to 23 months has been reported to reduce the risk of having anaemia and iron deficiency in settings where anaemia prevalence is higher than 20%; an effect apparently similar to that achieved by oral iron and folic acid supplements (Dewey 2009; De-Regil 2011b). Although most of the trials have examined the provision of micronutrient powders on a daily basis, other studies suggest that providing this intervention in a flexible or intermittent regimen, and hence a lower overall monthly dose, produces the same haematological response as daily use of micronutrient powders (Sharieff 2006; Hyder 2007; Ip 2009). The intermittent provision of iron was proposed more than 25 years ago as a feasible public health strategy to supplement children's and women's diets and to reduce anaemia, as it is supposed to maximise absorption by provision of iron in synchrony with the turnover of the mucosal cells (Berger 1997; Viteri 1997; Beaton 1999).

An important consideration when providing supplemental iron to children is the presence of malaria (Okabe 2011). Approximately 40% of the world population is exposed to the parasite and it is endemic in over 100 countries (WHO 2009a; WHO 2010a). In 2008, malaria accounted for 8% of deaths of children under five globally and for 27% of deaths of children under five in Africa (WHO 2010b). Of all the complications associated with malaria, severe anaemia is the most common and causes the highest number of malaria-related deaths. Although the mechanisms by which additional iron can benefit the parasite are far from clear (Prentice 2007), it has been hypothesised that the provision of iron along with foods or low doses of iron, either as encapsulated ferrous fumarate or sodium iron EDTA, might help to prevent anaemia at the time of infection if it reduces the amount of free iron (non-transferrin-bound iron) available to the parasite (Hurrell 2010).

In addition to malaria, another safety concern related to the use of micronutrient powders is their possible effect on diarrhoea. Some trials have reported an increase in the number of episodes after initiating the intervention, followed by a decrease in the frequency of liquid stools after few days (De-Regil 2011b). As a preventive measure, some organisations have advocated the widespread distribution of information on the prompt detection and treatment of diarrhoea (WFP/DSM 2010). Despite these possible caveats, the use of micronutrient powders has been considered by some as one of the most cost-effective strategies to prevent vitamin and mineral malnutrition (Horton 2010).

Why it is important to do this review

The use of micronutrient powders for home or point-of-use fortification of complementary foods among infants and young children aged 6 to 23 months of age has been shown to be effective in reducing anaemia and iron deficiency in young children. The initial success of this intervention has encouraged its use in other vulnerable populations such as children of preschool and school age, as the distribution of micronutrient powders can potentially build on existing school feeding programmes. Currently this intervention has been pilot-tested in over 40 countries for various population groups (often children 6 to 59 months of age (UNICEF/CDC 2010)), but its large-scale use is as yet limited. To date, there is no systematic assessment of the effects of micronutrient powders provision among preschool and school-aged children to inform policy-making.

This review will complement the findings of other systematic reviews that explore the effects of home fortification with multiple micronutrient powders in children less than two years of age (De-Regil 2011b) and among pregnant women (Suchdev 2011).


To assess the effects of point-of-use fortification of foods with micronutrient powders containing iron alone or in combination with other vitamins and minerals on nutrition, health and development among children of preschool and school age (24 months to 12 years old) compared with no intervention, a placebo or iron-containing supplements.

For the purpose of this review, point-of-use fortification of foods with micronutrient powders refers to the addition of iron alone or in combination with other vitamins and minerals in powder form to energy-containing foods (that may or may not be in semi-solid form) at home or in any other place where meals are to be consumed, such as schools, nurseries and refugee camps. Micronutrient powders can be added to foods either during or after cooking or immediately before consumption without the explicit purpose of improving the flavour.


Criteria for considering studies for this review

Types of studies

Randomised trials and quasi-randomised controlled trials with randomisation at either individual or cluster level. 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 2011). We will include the first period of randomised cross-over trials. We will not include other types of evidence (for example, cohort or case-control studies) in this review but we will consider such evidence in the discussion where relevant.

Types of participants

We will include studies aimed at healthy children aged 24 months to 12 years at the time of receiving the intervention with the micronutrient powders. We will not include studies specifically targeting children with health problems, children with HIV or enterally fed children.

We will include studies for which results for children between 24 months and 12 years of age can be extracted separately, or in which more than half of the participants fulfil this criterion. (We will perform sensitivity analyses if marginal decisions are made).

Types of interventions

Interventions involving the provision of micronutrient powders for point-of-use fortification given at point-of-use at any dose, frequency and duration.The comparison groups include no intervention, placebo or usual supplementation. Specifically, we are going to assess the evidence on the following comparisons.

  1. Point-of-use fortification of foods with micronutrient powders versus no intervention/placebo

  2. Point-of-use fortification of foods with micronutrient powders versus iron-only supplement

  3. Point-of-use fortification of foods with micronutrient powders versus iron and folic acid supplements

  4. Point-of-use fortification of foods with micronutrient powders versus same micronutrients in supplements

We will include interventions that combine micronutrient powders along with co-interventions such as education, vitamin A supplementation programmes, zinc for the treatment of diarrhoea 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 (lipid-based supplements, chewable tablets, fortified complementary foods and other fortified foods).

Types of outcome measures

Primary outcomes
  1. Anaemia (defined as haemoglobin lower than 110 g/L for children 24 to 59 months and lower than 115 g/L for children 5 to 11.9 years old, adjusted by altitude where appropriate)*

  2. Haemoglobin (g/L)*

  3. Iron deficiency (as defined by using ferritin concentrations < 15 µg/L)*

  4. Ferritin (μg/L)*

  5. All-cause mortality (number of deaths during the trial)*

  6. Diarrhoea (three liquid stools or more per day)*

* These outcomes were considered critical for decision making by a panel of experts and are intended to be included in 'Summary of findings' tables in the completed review (Guyatt 2011; Pena-Rosas 2012).

Secondary outcomes
  1. Iron deficiency anaemia (defined by the presence of anaemia plus iron deficiency, diagnosed with an indicator of iron status selected by trialists)

  2. Cognitive development and school performance (as defined by trialists)

  3. Motor development and physical capacity (as defined by trialists)

  4. All-cause morbidity (number of patients with at least one episode of any disease during the trial)

  5. Acute respiratory infection (as defined by trialists, they may include pneumonia, bronchiolitis or bronchitis)

  6. Adverse affects (any, as defined by trialists)

  7. Growth (Z-score height for age)

  8. Growth (Z-score weight for age)

  9. Growth (Z-score weight for height)

  10. Adherence (percentage of children who consumed more than 70% of the expected doses over the intervention period)

  11. Red blood cell folate (mg/dL)

  12. Serum/plasma retinol (mmol/L)

  13. Serum/plasma zinc concentrations (unit)

We will group the outcome time points as follows: immediately post end of the intervention, one to six months post end of intervention, seven to 12 months after the end of the intervention.

Search methods for identification of studies

Electronic searches

We will search the following electronic databases without language restrictions: the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, CINAHL, POPLINE, LILACS, IBECS, Scielo, Science Citation Index and Biosis Previews.

We will search for theses using WorldCat, Networked Digital Library of Theses and Dissertations, DART-Europe E-theses Portal, Australasian Digital Theses Program, Theses Canada Portal and ProQuest-Dissertations and Theses.

We will identify planned or ongoing trials in the International Clinical Trials Registry Platform (ICTRP) and the metaRegister of Controlled Trials (mRCT).

We will use the following search strategy to search MEDLINE and adapt it as required for other electronic databases.

  1. micronutrients/

  2. iron/ or zinc/ or vitamin A/

  3. (micronutrient$ or micro-nutrient$).tw.

  4. (multinutrient$ or multi-nutrient$ or multi$ nutrient$).tw.

  5. (multimicro-nutrient$ or multimicronutrient$).tw.

  6. (multivitamin$ or multi-vitamin$).tw.

  7. (multimineral$ or multi-mineral$).tw.

  8. Trace Elements/ or (trace adj (element$ or mineral$ or nutrient$)).tw.

  9. iron,dietary/

  10. ferric compounds/ or ferrous compounds/

  11. (iron or Fe or ferric$ or ferrous$ or zinc or Zn or vit$ A or retinol$).mp.

  12. or/1-11

  13. food, fortified/

  14. dietary supplements/

  15. food,specialized/

  16. ((food$ or meal$ or drink$ or beverage$ or diet$ or snack$ or breakfast$ or break-fast$ or lunch$ or dinner$) adj5 (fortif$ or enrich$ or supplement$)).tw.

  17. "point-of-use".tw.

  18. (home adj5 fortif$).tw.

  19. ((in-home or at-home or school or child care or nursery) adj5 fortif$).tw.

  20. (mix$ or powder$ or supplement$ or sachet$ or packet$ or powder$).tw.

  21. (Sprinkles or Vita Shakti or Rahama or Anuka or Chispitas or BabyFer or Bebe Vanyan or Supplefer or Supplefem or MNP or MNPs).tw.

  22. or/13-20

  23. 12 AND 22

  24. 21 OR 23

  25. (baby or babies or infant$ or toddler$ or preschool$ or pre-school$ or child$ or schoolage$ or schoolage$ or schoolchild$ or school-child$ ).tw.

  26. exp child/ or exp infant

  27. 25 OR 26    

  28. 24 and 27

MNP formulations were introduced after 2000, therefore we will limit searches by publication year (from 2000 to current date). We will not apply language restrictions and 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, at which point we will assess them for eligibility according to the identified inclusion/exclusion criteria. 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

We will contact authors and known experts for assistance in identifying ongoing or unpublished data. We will also contact the Departments of Nutrition for Health and Development and regional offices from the World Health Organization (WHO) and the Nutrition and Infant and Young Child Feeding sections of the Centers for Disease Control and Prevention (CDC), the United Nations Children's Fund (UNICEF), the World Food Programme (WFP), the Micronutrient Initiative (MI), Helen Keller International (HKI), Home Fortification Technical Advisory Group (HFTAG), the Global Alliance for Improved Nutrition (GAIN) and Sight and Life.

Data collection and analysis

Selection of studies

Each author will screen titles and abstracts independently. Luz Maria De-Regil (LMD) will screen all titles and abstract sfor potential eligibility while Maria Elena Jefferds (MEJ) and Juan Pablo Pena-Rosas (JPPR) will assess half each. One review author (LMD) will search the additional sources. Each review author will independently assess two-thirds of the full-text articles for inclusion according to the above criteria; we will assess each paper in duplicate. We will resolve any disagreement through discussion.

If studies are 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 will independently extract data using a form designed for this review. MEJ will extract data from half of the studies and JPPR will extract data from the other half. LMD will extract data from all the studies. LMD will enter data into Review Manager 5 software (RevMan 2011) and the review author who extracted the data in duplicate will check LMD's data entry for accuracy. We will resolve any discrepancies through discussion and document the process.

We will complete the data collection form electronically and will record information as follows.

(1) Trial methods

  • Study design

  • Unit and method of allocation

  • Method of sequence generation

  • Masking of participants, personnel and outcome assessors

(2) Participants

  • Location of the study

  • Sample size

  • Age

  • Sex

  • Socioeconomic status (as defined by trialists and where such information is available)

  • Baseline prevalence of anaemia

  • Baseline prevalence of soil helminths

  • Inclusion and exclusion criteria

(3) Intervention

  • Dose

  • Type of iron compound

  • Provision of micronutrient powders regimen

  • Duration of the intervention

  • Co-intervention

(4) Comparison group

  • No intervention

  • Placebo

  • Provision of iron supplements

(5) Outcomes

  • Primary and secondary outcomes outlined in the Types of outcome measures section

  • Exclusion of participants after randomisation and proportion of losses at follow-up

We will record both prespecified and non-prespecified outcomes, although the latter will not be used 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 2011). We will resolve any disagreement by discussion or by involving a third assessor.

(1) Random sequence generation (checking for selection bias)

We will describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it produces comparable groups.

  • 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 the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment.

  • 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 of participants and personnel (checking for possible performance bias)

We will describe all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received.

We will assess the risk of performance bias associated with blinding as follows.

  • Low, high or unclear risk of bias for participants.

  • Low, high or unclear risk of bias for personnel.

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

(4) Blinding of outcome assessment (checking for possible detection bias)

We will describe all measures used, if any, to blind outcome assessors from knowledge as to which intervention a participant received.

  • Low risk of bias (blinding).

  • High risk of bias (for example, no blinding of outcome assessment where measurement is likely to be influenced by lack of blinding, or where blinding could have been broken).

  • Unclear risk of bias (where insufficient information was provided to permit judgement).

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

Outcomes in each included study will be assessed as follows.

  • Low risk of bias: either there was no missing outcome data or the missing outcome data were unlikely to bias the results based on the following considerations: study authors provided transparent documentation of participant flow throughout the study, the proportion of missing data was similar in the intervention and control groups, the reasons for missing data were provided and balanced across intervention and control groups, the reasons for missing data were not likely to bias the results (for example, moving house).

  • High risk of bias: if missing outcome data were likely to bias the results. Studies will also receive this rating if an 'as-treated (per protocol)' analysis is performed with substantial differences between the intervention received and that assigned at randomisation, or if potentially inappropriate methods for imputation have been used.

  • Unclear risk of bias.

(6) Reporting bias

We will state how the possibility of selective outcome reporting was examined and what was found.

  • Low risk of bias (where it is 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 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).

  • Unclear risk of bias.

(7) Other sources of bias

We will assess if the study is free of other potential bias as follows.

  • Low risk of bias (where there is similarity between outcome measure at baseline, similarity between potential confounding variables at baseline, or adequate protection of study arms against contamination).

  • High risk of bias (where there is no similarity between outcome measure at baseline, similarity between potential confounding variables at baseline, or adequate protection of study arms against contamination).

  • Unclear risk of bias.

(8) Overall risk of bias

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

For the first, we will assess the likely magnitude and direction of the bias in each of the above mentioned domains and whether we consider they will likely impact on the findings. We will consider studies at high risk of bias if they have poor or unclear allocation concealment and either inadequate blinding or high/imbalanced losses to follow-up. We will explore the impact of the level of bias through a Sensitivity analysis.

For the assessment across studies, we will set out the main findings of the review in 'Summary of findings' (SoF) tables prepared using GRADE profiler software (GRADEpro 2008). We will list the primary outcomes for each comparison with estimates of relative effects along with the number of participants and studies contributing data for those outcomes. For each individual outcome, we will assess the quality of the evidence 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 and results in one out of four levels of quality (high, moderate, low or very low). This assessment will be limited only to the trials included in this review.

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results as risk ratio (RR) with 95% confidence intervals (95% CI).

Continuous data

For continuous data, we will use the mean difference (MD) with 95% CI if outcomes were measured in the same way between trials. Where some studies have reported endpoint data and other have reported change from baseline data (with errors) we will combine these in the meta-analysis if the outcomes have been reported using the same scale.

We will use the standardised mean difference (SMD with 95% CI) to combine trials that measure the same outcome but using different measurement methods.


For rates, if they represent events that could have occurred more than once per participant, we will report the rate difference using the methodologies described in Deeks 2011.

Unit of analysis issues

Cluster-randomised trials

We will include cluster-randomised trials in the analysis, along with individually randomised trials. To take account of design effect we will adjust their sample sizes using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If possible we will use an estimate of the intra-cluster correlation coefficient (ICC) derived either from the trial or another source. If ICCs from other sources are used, we will report this and will conduct sensitivity analyses to examine the impact of variation in the ICC. If both cluster and individually randomised trials are identified, we will synthesise the relevant information provided there is little heterogeneity between study designs, and we consider interaction between the effect of intervention and choice of randomisation unit is unlikely (Higgins 2011).

Studies with more than two treatment groups

For studies with more than two intervention groups (multi-arm studies), we will include the directly relevant arms only. If we identify studies with various relevant arms, we will combine the groups into a single pair-wise comparison (Higgins 2011) and include the disaggregated data in the corresponding subgroup category. If the control group is shared by two or more study arms, we will divide the control group (events and total population) over the number of relevant subgroup categories to avoid double counting the participants. We will describe the details in the 'Characteristics of included studies' tables.

Cross-over trials

We will only inlcude the first period of a randomised cross-over trial prior to the wash-out period or to a change in the sequence of treatments. We will treat them as parallel randomised controlled trials.

Dealing with missing data

Missing individuals

We will note dropout for each included study. We will note attrition on the risk of bias form and include it in the 'Risk of bias' summary. We will conduct analysis on an available case analysis basis: we will include data from those participants whose results are known. We will consider variation in the degree of missing data as a potential source of heterogeneity.

We will attempt to include all participants randomised to each group in the analyses. If a study reports outcomes only for participants completing the trial or only for participants who followed the protocol, we will contact the authors and ask them to provide additional information to permit analyses according to intention-to-treat principles. If this is not possible, we will perform an available case analysis and we will discuss the extent to which the missing data could alter the results/conclusions of the review. We will assess the sensitivity of any primary meta-analyses to missing data using the strategy recommended by Higgins 2011.

Missing data

Where key data (for example, standard deviations) are missing from the report, we will attempt to contact corresponding authors (or other authors if necessary) of included studies to request unreported data. If this information is not achievable, we will not impute it and will note that the study did not provide data for that particular outcome.

Assessment of heterogeneity

We will assess the methodological heterogeneity by examining the methodological characteristics and risk of bias of the studies, and clinical heterogeneity by examining the similarity between the types of participants, the interventions and the outcomes.

For statistical heterogeneity, we will examine the forest plots from meta-analyses to look for heterogeneity among studies and use the I2 statistic, Tau2 and Chi2 test to quantify the level of heterogeneity among the trials in each analysis. If we identify moderate or substantial heterogeneity we will explore it by prespecified subgroup analysis.

We will advise caution in the interpretation of analyses with high degrees of heterogeneity.

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. 

If more than 10 trials contribute data to the primary outcomes, we will present a funnel plot to evaluate asymmetry and hence a possible indication of publication bias for primary outcomes. Any identified asymmetry could be due to publication bias, but can also be possibly attributable to a real relationship between trial size and effect size (for example, larger trials may have poorer patient supervision and thus compliance to supplementation, which may in turn influence effect size). In such a case, we will include in the discussion a section on the possible causes of the observed asymmetry, including descriptions of reported compliance in the larger as compared with smaller studies. Finally, for the primary outcomes, we will conduct sensitivity analysis for publication bias by comparing results of published versus unpublished studies.

Data synthesis

We will conduct meta-analysis to obtain an overall estimate of the effect of treatment when more than one study has examined similar interventions using similar methods, been conducted in similar populations, and measured similar (comparable) outcomes. We will carry out meta-analysis using the generic inverse-variance method in RevMan 2011.

We will account for heterogeneity using a random-effects meta-analysis for combining data, as we anticipate that there may be natural heterogeneity between studies attributable to the different doses, durations, populations and implementation/delivery strategies.

Where different studies have reported the same outcomes using both continuous and dichotomous measures, we will re-express odds ratios as standardised mean differences or vice versa and combine the results using the generic inverse-variance method, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011).

Subgroup analysis and investigation of heterogeneity

Where data are available we will carry out the following subgroup analyses:

  1. by anaemic status of participants at start of intervention (anaemia defined as haemoglobin values < 110 or < 115 g/L, adjusted by altitude if appropriate): anaemic, non-anaemic, mixed/unknown;

  2. by age of children at the start of the intervention: 24 to 59 months, 60 months and older;

  3. by refugee status: yes, no;

  4. by malaria status of the study site at the time of the trial: yes, no, not reported;

  5. by frequency: daily, weekly, flexible;

  6. by duration of intervention: less than three months, three months or more;

  7. by iron content of product: 12.5 mg or less, more than 12.5 mg;

  8. by type of iron compound: as reported by the trialists;

  9. by number of nutrients accompanying iron: 1 to 4, 5 to 9, 10 to 15.

We will use the primary outcomes in subgroup analysis.

We will not conduct a subgroup analyses in those outcomes with three or fewer trials. We will explore the forest plots visually and identify where confidence intervals do not overlap to identify differences between subgroup categories. We will also formally investigate differences between two or more subgroups (Borenstein 2008).

Sensitivity analysis

We will carry out sensitivity analysis to examine:

  1. the effects of removing studies at high risk of bias (studies with poor or unclear allocation concealment and either blinding or high/imbalanced loss to follow-up) from the analysis;

  2. the effects of different intra-cluster correlation values for cluster studies (if these are included);

  3. studies with mixed populations in which marginal decisions were made.


We would also like to thank the staff at the editorial office of the Developmental, Psychosocial and Learning Problems Group (CDPLPG) 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.

Contributions of authors

LMD drafted the background section. LMD and JPR drafted the methods section and MEJ provided feedback on the draft. All authors contributed to the finalisation of the protocol.

Declarations of interest

  • Luz Maria De-Regil - none known.

  • Maria Elena D Jefferds - co-investigator on a cluster-randomised trial including micronutrient powders targeted at children aged 6 to 35 months (trial registered at clinicaltrials.gov, identifier NCT01088958) and technical advisor in various countries implementing programmes with micronutrient powders.

  • Juan Pablo Peña-Rosas - none known.

Disclaimer: Luz Maria De-Regil and Juan Pablo Pena-Rosas are full-time staff members of the World Health Organization. Maria Elena del Socorro Jefferds is a staff member of the US Centers for Disease Control and Prevention (CDC). 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

Internal sources

  • Centers for Disease Control and Prevention (CDC), USA.

    MEJ works at the International Micronutrient Malnutrition Prevention and Control Program (IMMPaCt)

  • Evidence and Programme Guidance Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.

    LMD and JPPR are staff of the Department of Nutrition for Health and Development at the World Health Organization.

External sources

  • No sources of support supplied