Intervention Review

You have free access to this content

Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age

  1. Luz Maria De-Regil1,*,
  2. Parminder S Suchdev2,
  3. Gunn E Vist3,
  4. Silke Walleser4,
  5. Juan Pablo Peña-Rosas5

Editorial Group: Cochrane Developmental, Psychosocial and Learning Problems Group

Published Online: 7 SEP 2011

Assessed as up-to-date: 10 AUG 2011

DOI: 10.1002/14651858.CD008959.pub2

How to Cite

De-Regil LM, Suchdev PS, Vist GE, Walleser S, Peña-Rosas JP. Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age. Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No.: CD008959. DOI: 10.1002/14651858.CD008959.pub2.

Author Information

  1. 1

    Micronutrient Initiative, Ottawa, ON, Canada

  2. 2

    Emory University; Centers for Disease Control & Prevention (CDC), Pediatrics and Global Health; Nutrition Branch, Atlanta, GA, USA

  3. 3

    Norwegian Knowledge Centre for the Health Services, Prevention, Health Promotion and Organisation Unit, Oslo, Norway

  4. 4

    Independent Consultant, Geneva, Switzerland

  5. 5

    World Health Organization, Evidence and Programme Guidance, Department of Nutrition for Health and Development, Geneva, Switzerland

*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), comment added to review
  2. Published Online: 7 SEP 2011

SEARCH

 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 
Summary of findings for the main comparison. Provision of multiple micronutrient powders versus placebo or no intervention in children less than 2 years

Patient or population: children 6 to 23 months
Settings: community settings
Intervention: home fortification with multiple micronutrient powders
Comparison: placebo/no intervention

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

AnaemiaRR 0.69
(0.60 to 0.78)
1447
(6 studies)
moderate1

Iron deficiencyRR 0.49
(0.35 to 0.67)
586
(4 studies)
high2

Haemoglobin (g/L)MD 5.87

(3.25 to 8.49)
1447
(6 studies)
moderate1,3

Iron status (ferritin concentrations in ng/mL)MD 20.38

(6.27 to 34.49)
264
(2 studies)
low1,4

Weight-for-age Z-scoreMD 0

(-0.37 to 0.37)
304
(2 studies)
moderate1,5

All-cause mortality00
(0 studies)
None of the trials reported on this outcome.

CI: Confidence interval; RR: Risk ratio;

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 are moderately confident 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 effect

1One study (Adu-Afarwuah 2007) has serious risk of bias.
2 Because of the consistent and large effect of the intervention RR 0.49 (95 % CI 0.36 to 0.67), we have refrained from downgrading because of the high risk of bias in one of the four studies.
3 There was considerable statistical heterogeneity attributable to one study (Lundeen 2010). However, because of the clear conclusion and consistency in the results, assessors chose to not downgrade.
4 There was imprecision in the results.
5 There was considerable unexplained statistical heterogeneity, but given the lack of clinical significance of the different results reported in the trials (i.e. all children are within the desirable Z scores), assessors chose to not downgrade.

 Summary of findings 2 Provision of multiple micronutrient powders versus iron supplements in children less than 2 years

 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of the condition

Vitamin and mineral deficiencies affect more than two billion people worldwide (The Micronutrient Initiative 2009). Iron deficiency, which affects over half the world’s population, is the most common preventable nutritional deficiency. Together with vitamin A and zinc deficiencies, iron deficiency has the largest documented disease burden among micronutrients (WHO 2001; Black 2008; WHO 2009). There is a disproportionate burden of vitamin and mineral deficiencies in developing countries. Infants and children are the most vulnerable groups to micronutrient malnutrition given the high vitamin and mineral intake they need for rapid growth relative to the amount of food they consume (Dewey 2003). The diets of infants and young children aged six months to 23 months generally provide insufficient amounts of key micronutrients (particularly iron, vitamin A, zinc and calcium) to meet their nutritional needs, and the inclusion of animal-source foods to fill the nutrient gap may be not practical for low-income countries (PAHO 2001; WHO 2005). There are no global estimates of vitamin and mineral deficiencies specifically for children under two years, however it is calculated that 190 million preschool children are affected by vitamin A deficiency (WHO 2009) and 293 million by anaemia (WHO/CDC 2008).

Vitamin A deficiency is the leading cause of childhood blindness (WHO 2009). Iron is essential to red blood cells and is involved in several metabolic reactions; there is compelling evidence that infants aged six months to 23 months with iron-deficiency anaemia are at risk of poor cognitive, motor, social-emotional, and neurophysiologic development (Lozoff 2007). Zinc is important during periods of accelerated growth and for tissues with rapid cellular differentiation and turnover, such as the immune system and the gastrointestinal tract. Critical functions that are affected by zinc nutrition include physical growth, susceptibility to infection and neurobehavioral development (Brown 2001).

Multiple vitamin and mineral deficiencies frequently occur simultaneously, and their joint effects during the critical period from conception to two years of age can be associated with irreversible physical and cognitive consequences, increased perinatal mortality, and reduced physical work capacity and productivity (WHO 2001; Lozoff 2007; Sanghvi 2007), leading to lifelong detrimental consequences on health, productivity and economic growth. In fact, it has been estimated that nutritional risk factors, including underweight status, suboptimal breastfeeding, and vitamin and mineral deficiencies, particularly vitamin A, iron and zinc, are responsible for 3.9 million deaths (35% of total deaths) and 144 million disability-adjusted life years (DALYs) (33% of total DALYs) in children less than five years of age worldwide (WHO 2009).

 

Description of the intervention

Interventions to prevent and treat micronutrient malnutrition typically include exclusive breastfeeding during the first six months of life, dietary diversification to include foods with highly absorbable vitamins and minerals, fortification of staple and complementary foods, and provision of supplements (Bhutta 2008), with the latter being the most widespread intervention.

It has been reported that vitamin A supplementation of children between six months and five years of age significantly reduces total mortality by about 23% to 30% (Beaton 1993; Fawzi 1993; Glasizou 1993; Imdad 2010) and reduces childhood blindness by 70%. The reduction in mortality is believed to be mediated through improved vitamin A status, which may affect susceptibility to infection by an effect on the immune system (Stephensen 2001). Zinc supplementation leads to a 9% reduction in child mortality and a 23% reduction in incidence of childhood diarrhoea (WHO 2006; Brown 2009). Since adequate iron status early in life is critical for motor and cognitive development, the World Health Organization (WHO) has recommended blanket iron supplementation to all infants and children six to 24 months of age in areas where the prevalence of anaemia is 20% to 30%, or higher (INACG 1998; WHO 2001). Micronutrient interventions, particularly vitamin A and zinc supplementation of children and fortification of foods with iron and iodine, have been shown to be among the most cost-effective global development efforts (Horton 2008).

Despite the well-recognized benefits of supplementation with one, two or multiple micronutrients, implementation has been hindered by poor adherence to dosing regimens, inadequate supply, low coverage, and potential dose-related side effects and safety concerns (Sazawal 2006; Stoltzfus 2011; UNICEF 2011). In response to these operational constraints, 'home' or ‘point-of-use’ food fortification with micronutrient powders (MNP) was developed as a novel alternative to daily supplementation for delivering iron and other micronutrients with foods. MNP are single-dose packets of dry powder containing lipid-encapsulated iron and other micronutrients that can be sprinkled onto any semi-solid food (Zlotkin 2005). The lipid-encapsulation coating prevents iron from dissolving into the food and therefore prevents any change in colour, flavour or taste. Home fortification with MNP is being proposed for complementary feeding based on the rationale that 1) various vitamins and minerals can be added to the formulation in the MNP sachet; 2) the MNP sachets are lightweight and simple to store, transport and distribute; 3) MNP are easy to produce, with a relatively low production cost; 4) MNP does not affect the maintenance of usual dietary practices that facilitate the transition from exclusive breastfeeding to complementary feeding; 5) MNP are easy to use even without literacy; and 6) the potential for overdose is low (Zlotkin 2004). A drawback mentioned has been the waste disposal challenge with single-dose sachets. Because MNP products usually have higher acceptability and fewer side effects than iron drops, the approach of home fortification of foods with MNP for treating anaemia is being used in some developing countries (World Vision 2005; De Pee 2008; Dewey 2009).

The cost of increasing the number of micronutrients in the powder is minimal (the primary cost of the product is in the packaging) (De Pee 2008). Many programmes use a formulation containing 14 vitamins and minerals (Sprinkles Global Health Initiative 2010), although the formulation and the compound specifications may vary in other programmes. The efficacy of the standard 'multi-micronutrient' formulation for anaemia has been evaluated in some studies, but the potential for negative interaction among multiple micronutrients, possibly limiting their absorption and utilization, as well as the effects on other outcomes warrant further investigation.

Provision of iron in malaria-endemic areas has been a long-standing controversy due to concerns that iron therapy may exacerbate infections, in particular malaria given that the parasite requires iron for growth (Oppenheimer 2001). On the one hand, a large clinical trial of iron and folic acid supplementation in Zanzibar, an area with high rates of malaria transmission and poor malaria control at the time of the study, found that those who received iron and folic acid with or without zinc were more likely to die or need treatment in hospital for an adverse event (Sazawal 2006). On the other hand, a recent Cochrane review found that providing iron supplementation to children does not increase the risk of clinical malaria in the presence of regular surveillance of malaria and appropriate treatment (Ojukwu 2009). Because of this situation, policy makers and experts in nutrition, worldwide, have forthrightly discussed the safety of iron interventions in malaria-endemic areas in order to promote the use of safe and effective interventions (Suchdev 2009). Due to the way in which iron is absorbed and metabolized, not all forms of iron will necessarily have the same effect on susceptibility to infection. MNP may be less likely to increase the risk of infection because they are mixed with food and thus are absorbed more slowly, yielding lower peak concentrations of unbound iron in the circulation (Liyanage 2002; Dewey 2007).

From the implementation perspective, MNP programmes are currently on a national scale in several countries, such as Bangladesh, Mongolia and Haiti, and numerous countries are planning large-scale distribution for children (Hyder 2007; Menon 2007). Based on a 2009 UNICEF regional workshop in Asia, 32 programmes of home fortification with MNP have been implemented or are being planned (UNICEF 2009). However, few studies have reported operational and cost considerations, including effective distribution mechanisms (Dewey 2009; Loechl 2009). In addition, there is great variability in the formulation of MNP (for example, the number and doses of the micronutrients), producers that are manufacturing MNP, target age group of children receiving MNP, and settings in which MNP are distributed (De Pee 2008).

 

Why it is important to do this review

The WHO recommends exclusive breastfeeding until six months of age and continued breastfeeding for at least two years (PAHO 2001; WHO 2005). Intake of several vitamins and minerals after six months, including iron, zinc, calcium, selected B vitamins and (in some settings) vitamin A, remain problematic because commonly available, low-cost foods contain inadequate amounts of these nutrients. 

Various Cochrane reviews or protocols have evaluated the effects of supplementation with different vitamins and minerals in children. The effects of iron supplementation with tablets or elixirs, alone or in combination with folic acid or other micronutrients, in children less than 18 years of age living in malaria-endemic areas is evaluated by Ojukwu 2009. Published reviews have also evaluated the effects of 1) iron supplementation for improving clinical, immunologic and virologic outcomes in children infected with HIV (Adetifa 2009); 2) micronutrient supplementation in children and adults with HIV infection (Irlam 2011); 3) oral or intramuscular iron therapy for improving psychomotor development and cognitive function in children under the age of three years with iron deficiency anaemia (Martins 2001); 4) iodine supplementation for preventing iodine deficiency disorders in children (Angermayr 2004); and 5) vitamin A supplementation for preventing mortality and morbidity in children aged six months to five years (Imdad 2010). A Cochrane protocol for a review to assess the effects of any form of iron supplementation for treating iron deficiency anaemia in children (Zeng 2007) is available.

Several countries are at the stage of implementing large-scale projects with home (point-of-use) fortification of foods with MNP, so a systematic review on the effectiveness and safety of this intervention is urgently needed to help guide programmes on the effectiveness and safety, as well as on the appropriate dose, frequency and duration, of this intervention. This review is focused on nutrition, health and developmental outcomes in infants and young children whose food is fortified with multiple micronutrients, particularly iron, zinc and vitamin A, before consumption. We include the effects of this intervention on morbidity outcomes in malaria-endemic areas.

 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

To assess the effects and safety of home (point-of-use) fortification of foods with multiple micronutrient powders on nutritional, health and developmental outcomes in children under two years of age.

For the purpose of this review, home fortification with multiple micronutrient powders refers to the addition of these powders containing vitamins and minerals to semi-solid foods immediately before consumption. This can be done at home or in any other place where meals are to be consumed (for example, schools or refugee camps) and thus is also referred to as point-of-use fortification.

 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials and quasi-randomised trials with either individual or cluster randomisation.

 

Types of participants

Infants and young children aged six to 23 months at the start of the intervention. Infants under six months are not included as exclusive breastfeeding is recommended from birth to six months. We intended to include apparently healthy children from the general population, although some may be at risk of having highly prevalent diseases such as malaria, diarrhoea or even undernutrition.

 

Types of interventions

Micronutrient powders (MNP) including at least the three micronutrients iron, zinc and vitamin A. We considered trials where the MNP were given to whole families (added to the family meal) provided that the results are presented separately for our population. We included MNP given at point of care for any dose, frequency and duration.

The comparison groups included no intervention, placebo or usual supplementation as follows.

  1. Home (point-of-use) fortification of foods with MNP versus no intervention or placebo.
  2. Home (point-of-use) fortification of foods with MNP versus iron only supplement.
  3. Home (point-of-use) fortification of foods with MNP versus iron and folic acid supplements.
  4. Home (point-of-use) fortification of foods with MNP versus the same multiple micronutrients as supplements.

Interventions that combined home provision of MNP for home (point-of-use) fortification with co-interventions such as education or other approaches were included only if the other co-interventions were the same in both the intervention and comparison groups. We excluded studies examining supplementary food-based interventions with lipid-based supplements, micronutrient crushable tablets, fortified complementary foods and other fortified foods.

 

Types of outcome measures

 

Primary outcomes

  1. Anaemia (defined as haemoglobin values lower than 110 g/L)
  2. Iron deficiency (as defined by trialists)
  3. Haemoglobin concentration (g/L)
  4. Iron status (as defined by trialists)
  5. Weight-for-age (Z-scores)
  6. All-cause mortality

 

Secondary outcomes

  1. Length-for-age (Z-scores)
  2. Weight-for-height (Z-scores)
  3. All-cause morbidity
  4. Side effects (such as staining of teeth, vomiting, stool discolouration, constipation, coughing)
  5. Diarrhoea
  6. Upper respiratory tract infections
  7. Ear infections
  8. Iron overload
  9. Serum retinol concentration (µmol/L)
  10. Serum zinc concentration (g/dL)
  11. Mental development and motor skill development (as defined by trialists, for example it might include the Bayley Mental Development Index, Bayley Psychomotor Development Index, Stanford-Binet Test, DENVER II Developmental Screening Test)

For populations in malaria-endemic areas we will report two additional outcomes:

  • malaria incidence;
  • malaria severity.

We presented adverse effects were presented separately for each outcome. 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 the 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 one trial reported on continued follow-up after the end of the intervention, and only for the intervention arm. We have described this in the Characteristics of included studies and plan to extract this information in future updates, if available.

We recorded other relevant outcomes reported by trial authors and labelled these as 'not prespecified'.

 

Search methods for identification of studies

 

Electronic searches

We searched the following electronic databases.

Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library). Searched 18 February 2011.
MEDLINE (1948 to week 2 February 2011). Searched 18 February 2011.
EMBASE (1980 to Week 6 2011). Searched 18 February 2011.
African Index Medicus. Searched 23 February 2011.
CINAHL (1937 to current). Searched 20 February 2011.
Conference Proceedings Citation Index - Science (1990 to 19 February 2011). Searched 21 February 2011.
LILACS. Searched 21 February 2011.
POPLINE. Searched 21 February 2011.
Science Citation Index (1970 to 19 February 2011). Searched 21 February 2011.
WHO International Clinical Trials Registry Platform (ICTRP). Searched 23 February 2011.
metaRegister of Clinical Trials. Searched 23 February 2011.
ClinicalTrials.gov. Searched 23 February 2011.

The search strategies for each database are in Appendix 1.

We did not apply any date or language restrictions, and no translation of relevant data was necessary.

 

Searching other resources

We searched through the bibliographies of included studies and asked authors of included studies for lists of other studies that should be considered for inclusion. For assistance in identifying ongoing or unpublished studies, on 25 January 2011 we contacted the Sprinkles Global Health Initiative, the Home Fortification Technical Advisory Group, the nutrition section of the United Nations Children's Fund (UNICEF), the World Food Programme (WFP), the Micronutrient Initiative (MI), the Global Alliance for Improved Nutrition (GAIN), Helen Keller International (HKI), Sight and Life Foundation, the Departments of Nutrition for Health and Development from the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC).

The International Clinical Trials Registry Platform (ICTRP) was also searched for any ongoing or planned trials (24 January 2011). We did not apply any language restrictions.

 

Data collection and analysis

 

Selection of studies

LMD screened all the titles and GEV assessed all of the selected abstracts, while SW, PSS and JPR each assessed a third. LMD and GEV both independently assessed the potentially relevant references in full text for inclusion according to the above inclusion criteria. We resolved any disagreement through discussion or, if required, we consulted one of the other review authors. Two review authors (LMD and JPR) assessed the eligibility of trials identified through other sources.

If studies were published only as abstracts, or study reports contained little information on methods, we attempted to contact the authors to obtain further details on the study design, population and intervention to properly assess the eligibility.

 

Data extraction and management

We designed a form to extract data. For eligible studies, two review authors independently extracted the data using the agreed form. Each study was extracted in duplicate. We resolved discrepancies through discussion. We attempted to extract the data for children aged six to 23 months from those studies targeted at broader age groups. We entered data into Review Manager 5 (RevMan) software (RevMan 2011) and carried out checks for accuracy.

When information regarding the methods and results was unclear, we contacted the authors of the original reports for further details. If there was insufficient information for us to be able to assess risk of bias, we placed studies under 'awaiting assessment' until further information is published or made available to us.

 

Assessment of risk of bias in included studies

Two review authors independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

  1. Sequence generation (checking for possible selection bias).
  2. Allocation concealment (checking for possible selection bias).
  3. Blinding (checking for possible performance bias and detection bias).
  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations).
  5. Selective reporting bias (checking if expected outcomes were reported).
  6. Other sources of bias (such as stopping the trial early or changing methods during the trial).

We made explicit judgements about whether studies were at high, low or unclear risk of bias according to the criteria given in the Handbook (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 the findings. We resolved any disagreement by discussion or by involving a third assessor.

The main findings of the review are set out in summary of findings (SoF) tables 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. The results are expressed as one of four levels of quality (high, moderate, low or very low). This assessment was limited only to the randomised trials included in this review.

 

Measures of treatment effect

 

Dichotomous data

For dichotomous data, we presented results as average risk ratio (RR) with 95% confidence interval (CI). 

 

Continuous data

For continuous data, we used mean difference (MD) with standard deviation if outcomes were measured in the same way between trials. There was no need to use the standardized mean difference (SMD) to combine trials that measured the same outcome but used different units of measurement.  

 

Unit of analysis issues

 

Cluster-randomised trials

We combined cluster and individually-randomised trial results. All the cluster trials reported that the sample size was calculated taking into account the effect of clustering in data. We obtained the intra-cluster correlation co-efficient (ICC) for primary outcomes from two trials (Menon 2007; Suchdev 2011). We imputed the ICCs from Suchdev 2011 to other trials that did not provide this information (Hirve 2007; Lundeen 2010), as appropriate, and calculated their effective sample size. The results of one trial (Christofides 2006) were not adjusted as the average cluster size was 1.1. Some trials reported that the sample size calculation considered a design effect of 2.0 to account for clustering and we have used this value, along with the average cluster size in each trial, to obtain a plausible range of intra-cluster correlation coefficients. We then conducted sensitivity analyses to examine the potential effect of clustering on the confidence intervals of the summary estimates. As the confidence intervals did not change significantly (5%), we do not report the results of the sensitivity analysis.

 

Studies with more than two treatment groups

For studies with more than two intervention groups (multi-arm studies), we included the directly relevant arm only (Higgins 2011). Each group was only included in the analysis once. If we came across a study that compared home (point-of-use) fortification of foods with MNP with two of our comparison possibilities, then we combined groups, where possible, to create a single pair-wise comparison (Higgins 2011).

 

Dealing with missing data

We noted levels of attrition in all the included studies. None of the included studies had high levels of attrition (all < 20%) so we did not use sensitivity analysis to explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect.

For all outcomes we carried out analyses, as far as possible, on an intention-to-treat basis. We conducted analysis using available cases and we conducted sensitivity tests (assuming worst-case scenario and assuming best-case scenario) for the four primary outcomes.

For continuous measures, where necessary, we used actual measures (no imputations).

 

Assessment of heterogeneity

We examined the forest plots from the meta-analyses to look for heterogeneity among studies. We considered the size and direction of effect and used the I² and Chi² statistics to quantify the level of heterogeneity among the trials in each analysis. If we identified substantial heterogeneity (I² between 30% and 100%), we noted this in the text and explored it by prespecified subgroup analyses. We advise caution in the interpretation of those results where there were high levels of unexplained heterogeneity.

 

Assessment of reporting biases

Where we suspected reporting bias (see 'Selective reporting bias' above), we contacted study authors asking them to provide missing outcome data or clarifications about the study design. We advise caution in the interpretation of those results where we suspected outcome reporting bias.

We planned to use funnel plots to investigate the relationship between effect size and standard error but this was not possible as we did not have enough studies to have a powered test.

 

Data synthesis

We carried out statistical analysis using RevMan (RevMan 2011). We expected there would be differences between trials in both the population and the intervention, so we used random-effects meta-analysis for combining data.

 

Subgroup analysis and investigation of heterogeneity

We planned to conduct several subgroup analyses irrespective of heterogeneity. We interpreted all subgroup analyses cautiously. The planned subgroups arose from current clinical dilemmas and uncertainties (see Background). We explored subgroup analyses on the primary outcomes based on the following criteria.

  1. By anaemic status of participants at start of intervention: anaemia defined as haemoglobin values < 110 g/L, anaemic, non-anaemic or unknown anaemic status.
  2. By iron status of participants at start of intervention: iron deficient, not iron deficient or unknown, as defined by trialists.
  3. By age of participants at the start of the intervention: six to 11 months, 12 to 17 months, 18 to 23 months.
  4. By refugee status: yes, no.
  5. By malaria status of the area at the time of the trial: yes, no, as reported by trialists.
  6. By frequency: daily versus weekly versus flexible.
  7. By duration of intervention: less than six months versus six months or more.
  8. By elemental iron content of product: less than 12.5 mg versus 12.5 mg or more.
  9. By zinc content of product: less than 5 mg versus 5 mg or more.

For the comparisons related to malaria-endemic areas, we planned to conduct a subgroup analysis by treatment and prevention of malaria but no information was available.

 

Sensitivity analysis

We carried out sensitivity analysis to examine the effects of removing studies at high risk of bias (studies with poor or unclear allocation concealment and either blinding or loss to follow-up) from the analysis and of including studies with children six to 59 months of age from which it was not possible to extract information only for children aged six to 23 months.

 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

 

Results of the search

The search strategy identified 16,374 references for possible inclusion; 5843 of which were duplicated references. Figure 1 depicts the process for assessing and selecting the studies. We included eight trials (Christofides 2006; Giovannini 2006; Sharieff 2006a; Adu-Afarwuah 2007; Hirve 2007; Menon 2007; Lundeen 2010; Suchdev 2011) and excluded 12. Two are awaiting assessment (Neufeld 2008; Bilenko 2010) and seven studies are still ongoing (Fitzsimons 2009; Jack 2008; Ribeiro Da Costa 2009; van der Kam 2010; Zavaleta 2010; Zimmermann 2010; Zlotkin 2010). All the included studies contributed data in this review.

 FigureFigure 1. Study flow diagram

 

Included studies

 
Intervention

We included eight trials; six of them (Giovannini 2006; Sharieff 2006a; Adu-Afarwuah 2007; Menon 2007; Lundeen 2010; Suchdev 2011) evaluated the effects of the provision of MNP versus no intervention or placebo (comparison 1). Two trials (Christofides 2006; Hirve 2007) compared the effects of the provision of MNP versus iron drops or syrup (comparison 2). No studies compared provision of MNP versus iron and folic acid supplements (comparison 3) or versus multiple vitamin and mineral supplements (comparison 4). The interventions lasted between two and 12 months; and one study reported a follow-up period of seven months post-end of the intervention, albeit it did not provide data for the comparison group (Menon 2007).

 
Settings

The studies included in the review were carried out over the last five years in low income countries in Asia, Africa and the Caribbean where anaemia is a public health problem (that is more than 40% of the population are affected): Cambodia (Giovannini 2006), Ghana (Christofides 2006; Adu-Afarwuah 2007), Haiti (Menon 2007), India (Hirve 2007), Kenya (Suchdev 2011), Kyrzgyz Republic (Lundeen 2010), and Pakistan (Sharieff 2006a). None of the included trials enrolled only non-anaemic children. Five of the studies were described as having been performed in malaria-endemic areas (Christofides 2006; Giovannini 2006; Adu-Afarwuah 2007; Menon 2007; Suchdev 2011). It was unclear from the reports whether malaria prevention and control programmes were in place in the study sites or whether concomitant malaria interventions were made available for study participants.

 
Participants

The participant age range was from six to 36 months. When possible, we included data only for children less than 24 months of age. All the studies included children of both sexes. The sample sizes ranged from 133 to 1869 children, however the analyses only include the estimated effective sample size after adjusting the data to account for the clustering effect.

 
Vitamin and minerals composition

In one study, MNP were formulated with 15 micronutrients (Suchdev 2011); in three trials the MNP formulation contained six micronutrients (Giovannini 2006; Sharieff 2006a; Adu-Afarwuah 2007) and in four trials the MNP provided five micronutrients (Hirve 2007; Menon 2007; Lundeen 2010). All of them provided 12.5 mg of elemental iron (as ferrous fumarate) in one of the study arms, although two trials (Christofides 2006; Hirve 2007) also tested micronized ferrous pyrophosphate as the iron compound and three dosages of elemental iron (as ferrous fumarate): 12.5 mg, 20 mg or 30 mg. The 5 mg amount of elemental zinc (as gluconate) was a constant across trials. The content of vitamin A in the MNP was 300 μg vitamin A in five trials (Christofides 2006; Giovannini 2006; Sharieff 2006a; Adu-Afarwuah 2007; Hirve 2007; Lundeen 2010) and 400 μg vitamin A in two trials (Menon 2007; Suchdev 2011). All the trials also provided folic acid as part of the MNP formulations.

See the table Characteristics of included studies for a detailed description of all the studies.

 

Excluded studies

We excluded 12 trials. Three studies assessed interventions with micronutrient powders but provided only one or two of the relevant micronutrients (Zlotkin 2003a; Zlotkin 2003b; Zlotkin 2001); two trials evaluated food-like tablets (Smuts 2005; Wijaya-Erhardt 2007); one trial assessed fortification of rice for use in childcare centre meals (Bagni 2009); another compared MNP versus multivitamin supplements (drops) but the drops did not include all three micronutrients we used as inclusion criteria: vitamin A, iron and zinc (Geltman 2009). Another trial (Ip 2009) was excluded because it did not include any of the comparisons of interest (for example, it did not compare MNP versus placebo or supplements). Other trials were excluded because the participants were in other age groups, such as two to six years of age (Chen 2008) or children three to six years of age (Sharieff 2006b), school age children five to 11 years of age (Troesch 2011) or young women (Troesch 2009).

See the Characteristics of excluded studies table for a detailed description of the studies and the reasons for exclusion.

 

Risk of bias in included studies

See the risk of bias tables included in Characteristics of included studies for an assessment of the risk of bias for each included trial and Figure 2 and Figure 3 for an overall summary of the risk of bias of all included trials. With the single exception of Adu-Afarwuah 2007, all trials were of high quality according to our pre-established criteria. We considered studies to be of high quality if they were assessed as having low risk of bias for random sequence generation, low risk of bias for allocation concealment (selection bias) and were also rated as low risk of bias for either blinding (performance or detection bias) or incomplete outcome data (attrition bias).

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

In the 'Summary of findings' tables, we present the overall quality of the evidence for each primary outcome, by comparison ( Summary of findings for the main comparison;  Summary of findings 2).

 

Allocation

We assessed seven trials as having adequate methods for generating the randomisation sequence (Christofides 2006; Giovannini 2006; Sharieff 2006a; Hirve 2007; Menon 2007; Bagni 2009; Lundeen 2010). One trial allocated the interventions randomly but not the group receiving no intervention, although it was randomly selected from the original population (Adu-Afarwuah 2007).

Five trials were randomised at cluster level (Christofides 2006; Hirve 2007; Menon 2007; Lundeen 2010; Suchdev 2011).

 

Blinding

Investigators in two trials attempted to blind participants, caregivers and staff by using placebos of similar appearance to the active treatment or coded or opaque bottles (Giovannini 2006; Sharieff 2006a).

 

Incomplete outcome data

We judged that trials with more than 20% loss to follow-up, or with imbalanced loss to follow-up in different arms of trials, were inadequate in terms of completeness of outcome data. Seven trials were judged to be at low risk of bias as the highest rate of loss to follow-up was 19% (Suchdev 2011). Adu-Afarwuah 2007 had an unclear risk of bias.

 

Selective reporting

We did not formally assess outcome reporting bias; for most of the included trials we did not have access to study protocols and assessing outcome reporting bias from published reports alone can be difficult. Additionaly, given the small number of trials, we were not able to generate funnel plots to investigate the relationship between effect size and standard error.

 

Other potential sources of bias

We have noted other concerns about studies in the notes and other risk of bias sections of the Characteristics of included studies tables.

 

Effects of interventions

See:  Summary of findings for the main comparison Provision of multiple micronutrient powders versus placebo or no intervention in children less than 2 years;  Summary of findings 2 Provision of multiple micronutrient powders versus iron supplements in children less than 2 years

In this review we have included eight trials, involving 3748 children; however in trials that had more than two treatment arms we may not have included all arms in our analyses. We have organised the summary results by the different comparisons and by primary and secondary outcomes. Most of the included studies focused on anaemia and haematological indices, and few reported on any of the other prespecified outcomes in the protocol. Because all the results showed significant heterogeneity that could not be explained by standard sensitivity analyses, including quality assessment, we used a random-effects model to analyse the results.

See the Data and analyses section for detailed results on the primary and secondary outcomes.

 

1. Home (point-of-use) fortification of foods with MNP versus no intervention or placebo

Six trials including 3182 children under two years of age examined this comparison (Giovannini 2006; Sharieff 2006a; Adu-Afarwuah 2007; Menon 2007; Lundeen 2010; Suchdev 2011).

 

Primary outcomes  

 
Anaemia (defined as haemoglobin values < 110 g/L)

All included trials evaluated this outcome. Children receiving multiple micronutrient powders were significantly less likely to have anaemia at follow-up than those children receiving no treatment or a placebo (average risk ratio (RR) 0.69; 95% confidence interval (CI) 0.60 to 0.78) ( Analysis 1.1). The risk remained almost the same after removing the one low quality trial (Adu-Afarwuah 2007) from the analysis (RR 0.69; 95% CI 0.59 to 0.80).

The visual examination of the subgroup analyses indicated that the intervention appeared equally effective in populations with different anaemia prevalence; among all infants six months to 23 months of age whether the intervention lasted two months or six or more months; and in settings described as malaria-endemic when compared with settings where malaria cases were sporadic.

 
Iron deficiency (as defined by trialists)

Four trials with 586 children (Giovannini 2006; Sharieff 2006a; Adu-Afarwuah 2007; Suchdev 2011) indicated that those children receiving MNP were significantly less likely to have iron deficiency at follow-up than those children receiving no treatment or a placebo (RR 0.49; 95% CI 0.35 to 0.67). There were no apparent differences among subgroups. The RR after removing Adu-Afarwuah 2007 from the analysis was 0.46 (95% CI 0.26 to 0.82).

 
Haemoglobin concentration (g/L)

All the six included trials evaluated this outcome. Compared to children receiving no treatment or placebo, children receiving MNP had a 5.87 g/L higher haemoglobin concentration at follow-up (mean difference (MD) 5.87 g/L; 95% CI 3.25 to 8.49). There were no obvious differences among subgroups. The mean haemoglobin difference after removing Adu-Afarwuah 2007 from the analysis was 6.14 g/L (95% CI 3.13 to 9.15).

 
Iron status (as defined by trialists)

Two trials (n = 264) (Giovannini 2006; Adu-Afarwuah 2007) provided information on ferritin concentrations. On average, children receiving multiple micronutrient powders had 20.73 ng of ferritin more per mL at follow-up than those children receiving no treatment or a placebo (mean difference (MD) 20.38 ng/mL; 95% CI 6.27 to 34.49). Both trials were included in the same subgroups. The ferritin difference after removing Adu-Afarwuah 2007 from the analysis was 13.10 ng/mL (95% CI 4.38 to 21.82).

 
Weight-for-age (Z-scores)

Two trials with 304 children (Giovannini 2006; Adu-Afarwuah 2007) in which the intervention was given for six and 12 months did not find a significant effect on weight-for-age (MD 0.00; 95% CI -0.37 to 0.37). We did not perform a subgroup analysis as both trials were very similar and were included in the same subgroup category. The Z-score difference after removing Adu-Afarwuah 2007 from the analysis was -0.17 (95% CI -0.41 to 0.07).

 
All-cause mortality

One trial (Giovannini 2006) stated that no deaths occurred over the 12 month intervention period. In one of the trials, two deaths were reported after the intervention was finalized but were judged not to be related to the study (Hirve 2007).

 

Secondary outcomes  

 
Length-for-age and weight-for-height (Z-scores)

Two trials with 304 children (Giovannini 2006; Adu-Afarwuah 2007) in which the intervention was given for six and 12 months, respectively, did not find a significant effect on length-for-age Z-scores (MD 0.04; 95% CI -0.15 to 0.23) or weight-for-height Z-scores (MD 0.44; 95% CI -0.44 to 0.52). We did not perform a subgroup analysis as both trials were very similar and were included in the same subgroup category.

 
Diarrhoea

It was not possible to pool the results due to the differences in the definitions of this indicator. In one trial (Menon 2007) children receiving MNP were on the borderline of having more diarrhoea that those who received placebo during the first month of intervention; thereafter both groups showed a similar prevalence ( Analysis 1.13). In 8.9% of the participants, recurrent diarrhoeal diseases were accompanied by recurrent respiratory infections and were more prevalent in children who received MNP than those receiving placebo but this was not statistically significant ( Analysis 1.11).

 
Recurrent diarrhoea (we did not prespecify this outcome)

One trial (Giovannini 2006) reported that seven children receiving MNP had recurrent diarrhoea (10%) versus four of the placebo group (6.4%) ( Analysis 1.14).

 
Upper respiratory tract infections

Giovannini 2006 found that upper respiratory infections were equally prevalent among those children receiving MNP (7.6%) as in those allocated to the placebo group (6.5%) ( Analysis 1.15).

 
Serum zinc concentration (g/dL)

One trial that reported this outcome (Adu-Afarwuah 2007) did not find an effect of daily provision of MNP with 5 mg of zinc for six months on children's serum zinc concentrations ( Analysis 1.16).

 
Mental development and motor skill development (as defined by trialists)

One trial (Adu-Afarwuah 2007) reported that children receiving MNP were more likely to walk independently at 12 months of age than those receiving no intervention (RR 1.58; 95% CI 1.02 to 2.46).

 
Malaria outcomes

Although four studies were conducted in settings considered as malaria-endemic, only Adu-Afarwuah 2007 reported results on the presence of positive malaria smears and found that there were no differences between the study groups ( Analysis 1.12).

 

Other outcomes

No studies reported on the outcomes we defined as all-cause morbidity, side effects, ear infections, iron overload, serum retinol concentrations or malaria incidence.

 

2. Home (point-of-use) fortification of foods with MNP versus iron supplements

Two studies including 565 children under two years of age examined this comparison (Christofides 2006; Hirve 2007).

 

Primary outcomes

 
Anaemia (defined as haemoglobin values < 110 g/L)

Hirve 2007 found that after two months of follow-up there were no statistical differences in anaemia (RR 0.89; 95% CI 0.58 to 1.39) between the children who received MNP with five nutrients and those supplemented with iron drops ( Analysis 2.1).

 
Haemoglobin concentration (g/L)

Data from the two trials showed that there was no evidence that haemoglobin concentrations were different between the groups receiving the multiple micronutrient powders or the iron supplements (RR -2.36; CI -10.30, 5.58) ( Analysis 2.2).

 

Secondary outcomes

 
Side effects

Data from the two trials showed that children receiving MNP were less likely to have stained teeth than those receiving iron syrup daily ( Analysis 2.6).

 
Diarrhoea (and vomiting)

Hirve 2007 reported that children receiving MNP were less likely to have vomiting, diarrhoea and recurrent diarrhoea than those receiving daily iron supplements (RR 0.52; 95% CI 0.38 to 0.72).

Christofides 2006 and Hirve 2007 found that differences in the mean number of episodes of diarrhoea per child between interventions were not significant ( Analysis 2.4).

 

Other outcomes

No studies reported on the outcomes we defined as iron deficiency, iron status, weight-for-age, all-cause mortality, length-for-age, weight-for-age, all-cause morbidity, upper respiratory tract infections, ear infections, iron overload, serum retinol concentration, serum zinc concentration, mental development and motor skill development, malaria incidence and malaria severity.

 

3. Home (point-of-use) fortification of foods with MNP versus iron and folic acid supplements

No studies were included in this comparison.

 

4. Home (point-of-use) fortification of foods with MNP versus same multiple micronutrients as supplements

No studies were included in this comparison.

 

Subgroup analysis

We planned to conduct a subgroup analysis for all primary outcomes in all comparisons to look for possible differences between studies by anaemia and iron status at the beginning of the intervention, age of the children, refugee and malaria-endemic settings, frequency of the provision of MNP, duration of the intervention, and iron and zinc content in the MNP formulations. As not all the trials contributed data to all the outcomes examined, and only two trials were included in comparison 2, we pragmatically decided not to conduct a subgroup analyses for those outcomes with three trials or fewer.

For several subgroup comparisons all the trials were in the same subgroup category. In the subgroup analysis we provided subtotals for each subgroup and visual examination of the forest plots suggested that there were no clear differences between groups; for most outcomes there was considerable overlap in the confidence intervals for the effects of intervention in different subgroups.

As more data become available with updates of the review, we hope to explore possible subgroup differences by carrying out formal statistical tests. In the results below, we have drawn attention to any findings in subgroups that may assist in the interpretation of 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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

We have included eight trials in this review, six of which compared groups of children receiving MNP to groups receiving no treatment or placebo. Results show that provision of MNP to infants and children under two years of age reduced anaemia by 31% at the end of the intervention, and those who received the intervention had significantly higher haemoglobin and ferritin concentrations in comparison with infants and children who did not receive the intervention or received a placebo. There were no effects on any of the growth measurements or on zinc status. The haematological effects of MNP seemed comparable to those observed with daily oral iron supplementation with drops; however, given the small number of trials evaluating the equivalence between both interventions, the results should be cautiously interpreted.

Although the real effect of an intervention is context-specific, the provision of MNP was effective in various settings including in populations with a high prevalence of anaemia (25% to 100%) and when provided for two months or for six months, or more, and to all infants and young children six to 23 months of age.

Data on side effects and morbidity are scarce and definitions for each of the outcomes were variable among trials, making it difficult to assess the overall safety of this intervention (for example, diarrhoea was reported as the average number of episodes of diarrhoea per child, longitudinal diarrhoea or number of children with at least one episode of diarrhoea). Nonetheless, none of the trials reported deaths attributable to the intervention and the pattern of disease seemed similar to that of children receiving placebo or no intervention. It is clear that a standardized approach to reporting side effects and morbidity is needed as well as improved malaria surveillance and reporting in trials conducted in malaria settings.

 

Overall completeness and applicability of evidence

The use of micronutrient powders that contain iron, zinc and vitamin A in children less than two years of age significantly reduces the prevalence of anaemia and iron deficiency in populations with high prevalence of anaemia, but there is not sufficient information to assess the effect on other health and nutrition outcomes.

Home fortification with MNP is a novel approach to increase vitamin and mineral intake that has rapidly expanded worldwide. Although doses as high as 80 mg of elemental iron per day were initially used to test the efficacy of this intervention and its equivalence to 40 mg of iron given as drops (Zlotkin 2001; Zlotkin 2003a), the widely used dose of 12.5 mg of elemental iron per sachet is based on the recommended daily dose to supplement children aged six to 23 months for iron deficiency anaemia prevention (INACG 1998; WHO 2001). Its effectiveness was confirmed by a dose response trial in which 12.5 mg of elemental iron (as encapsulated ferrous fumarate) was as effective as 20 mg and 30 mg of iron in the same form and 20 mg of elemental iron (as ferrous sulphate drops) to improve haemoglobin and ferritin concentrations of anaemic children aged six to 18 months (Hirve 2007).

Most of the evidence included in this review examines a dose of 12.5 mg of iron given on a daily basis. However, other studies suggest that providing this intervention in a flexible or intermittent regimen for two to four months, and hence a lower overall monthly dose, produces the same haematological response as daily use of MNP (Sharieff 2006b; Hyder 2007; Ip 2009). For example, it has been reported that the weekly provision of MNP containing 30 mg of elemental iron was as effective as the daily provision of MNP with 12.5 mg of elemental iron in anaemic infants six to 23 months old (Hyder 2007) and non-anaemic school-aged children (Sharieff 2006b). 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 diet and to reduce anaemia as it is supposed to maximize absorption by provision of iron in synchrony with the turnover of the mucosal cells (Berger 1997; Viteri 1997; Beaton 1999).

The lasting effect of the benefits of using MNP on haematological outcomes is still unclear. However, evidence from two studies suggests that, independently of the dosing regimen, the positive effects of MNP on anaemia prevalence may be maintained for a period of approximately six months after the end of the intervention (Menon 2007; Ip 2009).

MNP can be prepared in various formulations, but for inclusion in this review they had to contain zinc, vitamin A and iron. In the included studies these three nutrients were always accompanied by folic acid and vitamin C; in two studies also by vitamin D; and in only one case were they part of a 15 micronutrient formulation (WHO/WFP/UNICEF 2007). Leaving aside iron, only one trial evaluated the effect of this intervention on vitamin A deficiency (Suchdev 2011) and another on zinc status (Sharieff 2006a). The addition of 5 mg of elemental zinc, which is a lower dose than that recommended to treat diarrhoea (WHO/UNICEF 2004) but is sufficient to avoid competition with iron for sites of absorption, was efficacious in reducing the incidence of longitudinal diarrhoea among Pakistani infants (Sharieff 2006a). This finding was not confirmed with certainty by other trials because the incidence (and recurrence) of morbidity and side effects were not reported in a standardized way, and frequently they were under-reported.

It is difficult to assess the safety of this intervention in malaria settings. Although no deaths were reported, none of the five trials conducted in malarial areas reported malaria incidence. Only one trial (Adu-Afarwuah 2007) included data on positive malaria smears post-intervention, with no differences between children receiving MNP and those receiving no intervention.

Albeit they were not specific outcomes of this review, it is well-known that adherence and acceptability of a product are instrumental for an intervention to be implemented successfully. Overall, multiple micronutrient powders seem to be well accepted by infants, with fewer 'dislike faces', and caregivers. Formative research in Kenya shows that children eat food with MNP without problems and that the key benefits associated with this intervention are prevention of anaemia and avoidance of treatment for anaemia, such as blood transfusions (Jefferds 2010). The results of the randomised controlled trials (RCT) included in this review, along with some RCT that were excluded because of the number of nutrients, show that the acceptance of the intervention is not always translated into better adherence. High adherence (defined as consumption of four sachets or more per week) to daily provision of MNP has ranged from 32% to around 90% (Zlotkin 2001; Giovannini 2006; Geltman 2009), and the highest adherence has been observed in those trials in which children received the product on an intermittent basis (Ip 2009; Hyder 2007). This may be related to the perception of an intermittent regimen as one that produces less mental pressure and anxiety among caregivers (Ip 2009). Adherence to MNP has not always proven to be higher than daily iron supplementation with drops. Geltman 2009 found that high adherence ranged from 32% to 63% at any assessment in the participants receiving iron drops compared with 30% to 46% in those receiving MNP. This result is consistent with the findings of other trials (Zlotkin 2003a; Zlotkin 2001).  

 

Quality of the evidence

Although not all reports included detailed information on the methods followed in the studies, an effort was made to contact authors in order to obtain more data. Only one study was classified as at high risk of bias and its exclusion from the analyses in a sensitivity analysis did not affect the significance of the results and hence the review's conclusions. Blinding of mothers or caregivers, care providers and outcome assessors was not attempted in 75% of the trials although in some studies technical staff carrying out laboratory investigations were reported to be unaware of group allocation. While for some outcomes the lack of blinding is unlikely to have an impact on results (for example, anaemia), for others (for example, maternal reports on infant's side effects) lack of blinding may represent a potentially serious source of bias. Attrition was not considered a serious problem in the included studies.

When the provision of MNP was compared with a placebo, the overall quality of the evidence for iron deficiency was high whereas it was moderate for anaemia, haemoglobin concentration and growth, and low for iron status.

 

Potential biases in the review process

We were aware of the possibility of introducing bias at every stage of the review process. In this review we tried to minimize bias in a number of ways as two review authors assessed eligibility for inclusion, carried out data extraction and assessed risk of bias. Each worked independently. Nevertheless, the process of assessing risk of bias, for example, is not an exact science and includes many personal judgements. Further, the process of reviewing research studies is known to be affected by prior beliefs and attitudes. It is difficult to control for this type of bias in the reviewing process.

Since this intervention is very recent and well-known among implementing agencies, and they were contacted as part of the search strategy, we consider there is minimal risk of publication bias.

 

Agreements and disagreements with other studies or reviews

A systematic review on the efficacy and effectiveness of complementary feeding interventions carried out in developing countries evaluated various interventions that targeted children within the age range of six to 24 months (Dewey 2009). The interventions assessed included fortification of complementary foods with micronutrients (centrally processed fortified foods or home fortification products with or without additional energy). The authors restricted the evaluation of MNP specifically to anaemia prevention and included two other types of micronutrient supplements that were added to home-prepared complementary foods: crushable tablets and fat-based products. They concluded that fortification of complementary foods (either processed complementary foods or home fortification) was a feasible option in most circumstances given the cost of iron-rich foods (such as liver or meat) for complementary feeding. Home fortification requires little change in dietary practices thus allowing families to continue to use home-prepared or purchased complementary foods as the basis for the child's diet.

Our review focuses specifically on home fortification of foods with MNP, with an inclusion criterion that established three micronutrients of critical importance: iron, vitamin A and zinc, and assessed a broader spectrum of outcomes. We excluded other types of home fortification with lipid-based spreads or crushable tablets to isolate the effects of this single intervention.

An area of potential concern relates to iron interventions in areas of high malaria transmission. A technical working group convened by the US National Institutes of Health concluded that there was little evidence regarding the safety of iron-containing home fortification mixtures in malaria-endemic areas, and that there was no evidence that MNP are not safe, but recognized that no published studies have been designed to examine safety in malaria-endemic areas (NIH 2011). Our systematic review concurs with the results of this report and acknowledges the limitations of studies designed specifically to examine the safety of home fortification with multiple micronutrient powders in malaria-endemic areas on malarial outcomes. The limited evidence does not seem to suggest that there is an increased risk of mortality or morbidity associated with malaria, but ongoing trials specifically addressing this issue will help us to understand better any potential risks associated with the provision of iron through home fortification with multiple micronutrient powders.

Home fortification has been mostly targeted at infants and young children. The results of this review are only applicable to this age group. Another systematic review is underway to assess the benefits and safety of this intervention in preschool and school-age children (De-Regil 2011). The wealth of ongoing research in this area highlights the need to update the evidence appraisal when these results are available.

 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

The use of MNP for home fortification of foods is an effective intervention to reduce anaemia and iron deficiency in infants and young children. This intervention can be integrated into strategies to prevent anaemia and reduce the risk of iron deficiency in infants and children aged six to 23 months, but its benefit in reducing the risk of other vitamins and mineral deficiencies has not yet been demonstrated. It can be assumed that improving the dietary intake of vitamins and minerals in the daily diet through this mechanism is beneficial but evidence is lacking as trials have mostly focused on iron deficiency and anaemia outcomes.

In this context, the dose of 12.5 mg of elemental iron (as ferrous fumarate) along with 5 mg of zinc and 300 μg of vitamin A has proven effective and the addition of other vitamins and minerals could be considered within the recommended nutrient intake levels for this age group. Other more bioavailable iron compounds may be used but to date the evidence is limited in this age group. The use of sodium iron-ethylenediamine tetraacetic acid (FeNaEDTA or iron-EDTA) as a more bioavailable source of iron may be feasible but consideration of safe levels of iron and EDTA, a common food additive in some baby foods, is important in order to avoid their excessive intake, particularly among infants.

The provision of the sachets seems to be well accepted by mothers and caregivers. Although the evidence is limited, in comparison to iron supplements (as drops or syrups), home fortification with MNP has similar benefits on haematological outcomes but is associated with less staining of teeth and stools discolouration. If iron supplementation programmes are not in place or are not successfully implemented, the use of multiple micronutrient powders for home fortification of foods can be considered a valid option for anaemia prevention in children six to 23 months of age.

A word of caution is that as this intervention involves the use of ready to eat food as a vehicle, it would be important to assure that basic sanitation is available and food hygiene and handling is done properly with safe water. Since all the trials were performed in low resource settings where sanitation tends to be poor, behavioural and communication campaigns should promote the appropriate use of MNP in addition to the hygienic preparation of complementary foods and hand washing (World Bank 2010).

The benefits of the use of MNP as a child survival strategy or on developmental outcomes are limited. Data on the effects on malaria outcomes are also lacking and further investigation is needed in malarial settings.

 
Implications for research

The results of this systematic review have highlighted the limited evidence in some areas that merit further research.

  1. The side effects associated with home fortification with MNP in settings where infection and malnutrition are common needs to be explored in more depth, with emphasis on the harmonization of outcome definitions that will help better balance harms and benefits of this intervention in various contexts, particularly in areas with high transmission of malaria.
  2. The use of other safe and efficacious iron compounds, or their combination, in the formulation of the vitamin and mineral micronutrient powders including the safe amounts of folic acid in areas with high malaria endemicity.
  3. The effective regimen for distribution and consumption of MNP in intermittent or flexible schemes as an alternative to daily provision of MNP.
  4. The efficacy and effectiveness of home fortification with multiple micronutrient powders in additional nutritional effects (i.e. improvement of iodine status, prevention of vitamin A deficiency) but also on important functional outcomes including growth and motor and cognitive skills

 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

We would like to thank the trial authors and organizations who contributed additional data for this review. In addition, we would 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 review and, in particular, Geraldine Macdonald and Laura MacDonald, as well as Margaret Anderson who helped with the search strategy.

As part of the prepublication editorial process, this review was commented on by three peers (an editor, and two referees who are external to the editorial team) and one of the Group's statisticians.

 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 1. Provision of multiple micronutrient powders versus no intervention or placebo

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

 1 Anaemia (ALL)61447Risk Ratio (M-H, Random, 95% CI)0.69 [0.60, 0.78]

 2 Anaemia (SUBGROUPS)6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 By anaemia at baseline: anaemic
1125Risk Ratio (M-H, Random, 95% CI)0.54 [0.38, 0.76]

   2.2 By anaemia at baseline: non anaemic
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.3 By anaemia at baseline: mixed/unknown
51322Risk Ratio (M-H, Random, 95% CI)0.71 [0.64, 0.79]

   2.4 By iron status at baseline: iron deficient
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   2.5 By iron status at baseline: non iron deficient
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.6 By iron status at baseline: mixed/unknown
61447Risk Ratio (M-H, Random, 95% CI)0.69 [0.60, 0.78]

    2.7 By age at baseline: 6 to 11 months
3345Risk Ratio (M-H, Random, 95% CI)0.57 [0.43, 0.75]

    2.8 By age at baseline: 12-23 months
1126Risk Ratio (M-H, Random, 95% CI)0.54 [0.32, 0.90]

    2.9 By age at baseline: mixed/unknown
2976Risk Ratio (M-H, Random, 95% CI)0.74 [0.63, 0.86]

   2.10 By refugee status: yes
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.11 By refugee status: no
61447Risk Ratio (M-H, Random, 95% CI)0.69 [0.60, 0.78]

    2.12 By frequency: daily
51028Risk Ratio (M-H, Random, 95% CI)0.66 [0.59, 0.74]

   2.13 By frequency: weekly
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.14 By frequency: flexible
1419Risk Ratio (M-H, Random, 95% CI)0.81 [0.66, 1.00]

    2.15 By duration of the intervention: less than 6 months
3709Risk Ratio (M-H, Random, 95% CI)0.69 [0.61, 0.78]

    2.16 By duration of the intervention: 6 months or more
3738Risk Ratio (M-H, Random, 95% CI)0.66 [0.48, 0.89]

    2.17 By iron content: 12.5 mg or less
61447Risk Ratio (M-H, Random, 95% CI)0.69 [0.60, 0.78]

   2.18 By iron content:: more than 12.5 mg
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   2.19 By zinc content: less than 5 mg
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    2.20 By zinc content:: 5 mg or more
61447Risk Ratio (M-H, Random, 95% CI)0.69 [0.60, 0.78]

    2.21 By malaria status of the area at baseline: yes
4864Risk Ratio (M-H, Random, 95% CI)0.64 [0.49, 0.83]

    2.22 By malaria status of the area at baseline: no
2961Risk Ratio (M-H, Random, 95% CI)0.70 [0.63, 0.77]

 3 Iron deficiency (ALL)4586Risk Ratio (M-H, Random, 95% CI)0.49 [0.35, 0.67]

 4 Iron deficiency (SUBGROUPS)4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 By anaemia at baseline: anaemic
1125Risk Ratio (M-H, Random, 95% CI)0.27 [0.14, 0.52]

   4.2 By anaemia at baseline: non anaemic
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.3 By anaemia at baseline: mixed/unknown
3487Risk Ratio (M-H, Random, 95% CI)0.56 [0.43, 0.73]

   4.4 By iron status at baseline: iron deficient
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   4.5 By iron status at baseline: non iron deficient
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.6 By iron status at baseline: mixed/unknown
4586Risk Ratio (M-H, Random, 95% CI)0.49 [0.35, 0.67]

    4.7 By age at baseline: 6 to 11 months
3321Risk Ratio (M-H, Random, 95% CI)0.44 [0.26, 0.75]

   4.8 By age at baseline: 12-23 months
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.9 By age at baseline: mixed/unknown
1265Risk Ratio (M-H, Random, 95% CI)0.57 [0.37, 0.86]

   4.10 By refugee status: yes
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.11 By refugee status: no
4586Risk Ratio (M-H, Random, 95% CI)0.49 [0.35, 0.67]

    4.12 By frequency: daily
3321Risk Ratio (M-H, Random, 95% CI)0.44 [0.26, 0.75]

   4.13 By frequency: weekly
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.14 By frequency: flexible
1265Risk Ratio (M-H, Random, 95% CI)0.57 [0.37, 0.86]

   4.15 By duration of the intervention: less than 6 months
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.16 By duration of the intervention: 6 months or more
3321Risk Ratio (M-H, Random, 95% CI)0.44 [0.26, 0.75]

    4.17 By iron content: 12.5 mg or less
4586Risk Ratio (M-H, Random, 95% CI)0.49 [0.35, 0.67]

   4.18 By iron content:: more than 12.5 mg
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

   4.19 By zinc content: less than 5 mg
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.20 By zinc content:: 5 mg or more
4612Risk Ratio (M-H, Random, 95% CI)0.50 [0.38, 0.67]

    4.21 By malaria status of the area at baseline: yes
4586Risk Ratio (M-H, Random, 95% CI)0.49 [0.35, 0.67]

   4.22 By malaria status of the area at baseline: no
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Haemoglobin (g/L) (ALL)61447Mean Difference (IV, Random, 95% CI)5.87 [3.25, 8.49]

 6 Haemoglobin (g/L) (SUBGROUPS)6Mean Difference (IV, Random, 95% CI)Subtotals only

    6.1 By anaemia at baseline: anaemic
1125Mean Difference (IV, Random, 95% CI)7.90 [4.17, 11.63]

   6.2 By anaemia at baseline: non anaemic
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.3 By anaemia at baseline: mixed/unknown
51321Mean Difference (IV, Random, 95% CI)5.32 [2.08, 8.56]

   6.4 By iron status at baseline: iron deficient
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

   6.5 By iron status at baseline: non iron deficient
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.6 By iron status at baseline: mixed/unknown
61446Mean Difference (IV, Random, 95% CI)5.87 [3.25, 8.49]

    6.7 By age at baseline: 6 to 11 months
3345Mean Difference (IV, Random, 95% CI)6.05 [3.42, 8.68]

    6.8 By age at baseline: 12-23 months
1126Mean Difference (IV, Random, 95% CI)3.90 [-0.91, 8.71]

    6.9 By age at baseline: mixed/unknown
2975Mean Difference (IV, Random, 95% CI)6.41 [0.05, 12.78]

   6.10 By refugee status: yes
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.11 By refugee status: no
51028Mean Difference (IV, Random, 95% CI)6.66 [4.06, 9.25]

    6.12 By frequency: daily
51028Mean Difference (IV, Random, 95% CI)6.66 [4.06, 9.25]

   6.13 By frequency: weekly
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.14 By frequency: flexible
1418Mean Difference (IV, Random, 95% CI)3.0 [-0.68, 6.68]

    6.15 By duration of the intervention: less than 6 months
3709Mean Difference (IV, Random, 95% CI)6.57 [2.19, 10.95]

    6.16 By duration of the intervention: 6 months or more
2319Mean Difference (IV, Random, 95% CI)6.23 [2.72, 9.75]

    6.17 By iron content: 12.5 mg or less
61446Mean Difference (IV, Random, 95% CI)5.87 [3.25, 8.49]

   6.18 By iron content:: more than 12.5 mg
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.19 By zinc content: less than 5 mg
61446Mean Difference (IV, Random, 95% CI)5.87 [3.25, 8.49]

   6.20 By zinc content:: 5 mg or more
00Mean Difference (IV, Random, 95% CI)0.0 [0.0, 0.0]

    6.21 By malaria status of the area at baseline: yes
4863Mean Difference (IV, Random, 95% CI)4.87 [2.60, 7.14]

    6.22 By malaria status of the area at baseline: no
2961Mean Difference (IV, Random, 95% CI)8.13 [3.47, 12.79]

 7 Iron status (ferritin concentrations in μg/L) (ALL)2264Mean Difference (IV, Random, 95% CI)20.38 [6.27, 34.49]

 8 Weight-for-age (in Z-scores) (ALL)2304Mean Difference (IV, Random, 95% CI)0.00 [-0.37, 0.37]

 9 Length-for-age (in Z-scores)2304Mean Difference (IV, Random, 95% CI)0.04 [-0.15, 0.23]

 10 Weight-for-length (in Z-scores)2304Mean Difference (IV, Random, 95% CI)0.04 [-0.44, 0.52]

 11 Any cause morbidity1127Risk Ratio (M-H, Random, 95% CI)1.91 [0.60, 6.02]

 12 Malaria smears1194Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.05, 1.12]

 13 Diarrhoea (ALL)1206Risk Ratio (M-H, Random, 95% CI)1.33 [1.00, 1.78]

 14 Recurrent diarrhoea (not pre-specified)1127Risk Ratio (M-H, Random, 95% CI)1.67 [0.51, 5.42]

 15 Upper respiratory infections1127Risk Ratio (M-H, Random, 95% CI)1.19 [0.34, 4.24]

 16 Serum zinc1125Mean Difference (IV, Random, 95% CI)-0.20 [-0.95, 0.55]

 17 Walking independently1179Risk Ratio (M-H, Random, 95% CI)1.58 [1.02, 2.46]

 
Comparison 2. Provision of multiple micronutrient powders versus iron supplements

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

 1 Anaemia (ALL)1145Risk Ratio (M-H, Random, 95% CI)0.89 [0.58, 1.39]

 2 Haemoglobin (g/L) (ALL)2278Mean Difference (IV, Random, 95% CI)-2.36 [-10.30, 5.58]

 3 Diarrhoea (ALL)1262Risk Ratio (M-H, Random, 95% CI)0.52 [0.38, 0.72]

 4 Diarrhoea episodes (ALL) (not pre-specified)2389Risk Ratio (M-H, Random, 95% CI)0.46 [0.16, 1.30]

 5 Vomiting (ALL) (not pre-specified)1262Risk Ratio (M-H, Random, 95% CI)0.58 [0.35, 0.95]

 6 Staining of teeth (ALL) (not pre-specified)2395Risk Ratio (M-H, Random, 95% CI)0.37 [0.16, 0.82]

 7 Stool discolouration (ALL) (not pre-specified)2395Risk Ratio (M-H, Random, 95% CI)0.80 [0.66, 0.98]

 8 Cough (ALL) (not pre-specified)1130Risk Ratio (M-H, Random, 95% CI)0.74 [0.53, 1.03]

 9 Cold (ALL) (not pre-specified)1262Risk Ratio (M-H, Random, 95% CI)0.84 [0.73, 0.97]

 10 Fever (ALL) (not pre-specified)1262Risk Ratio (M-H, Random, 95% CI)0.59 [0.42, 0.82]

 11 Recurrent diarrhoea (3 or more episodes) (ALL) (not pre-specified)1262Risk Ratio (M-H, Random, 95% CI)0.27 [0.10, 0.73]

 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. Search strategies

CENTRAL

# 1 MeSH descriptor Micronutrients, this term only
# 2 MeSH descriptor Trace Elements, this term only
# 3 MeSH descriptor Zinc, this term only
# 4 MeSH descriptor Vitamin A, this term only
# 6 MeSH descriptor Iron, Dietary, this term only
# 7 MeSH descriptor Ferric Compounds, this term only
# 8 MeSH descriptor Ferrous Compounds, this term only
# 9 micronutrient* or micro-nutrient* or micro next nutrient*
#10 multinutrient* or multi next nutrient* or multi* nutrient*
#11 multimicronutrient* or multimicro next nutrient*
#12 multivitamin* or multi* next vitamin*
#13 multimineral* or multi* next mineral*
#14 trace NEXT (element* or mineral* or nutrient*)
#15 iron or ferric* or ferrous* or Fe or zinc or Zn or (vit* next A) or retinol*
#16 (#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 OR #15)
#17 MeSH descriptor Food, Fortified, this term only
#18 MeSH descriptor Dietary Supplements, this term only
#19 MeSH descriptor Foods, Specialized explode all trees
#20 ((food* or meal* or drink* or beverage* or diet* or snack* or breakfast* or break-fast* or lunch* or dinner*) near/5 (fortif* or enrich* or supplement*))
#21 "point of use"
#22 home near/5 fortif*
#23 (in NEXT home or at NEXT home) near/5 (fortif*)
#24 mix* or powder* or supplement* or sachet* or packet* or powder* or MNP or MNPs
#25 (#17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24)
#26 Sprinkles Or Vita NEXT Shakti or Rahama or Anuka or Chispitas or BabyFer or Bebe NEXT Vanyan or Supplfer or Supplefem
#27 (#16 AND #25)
#28 (#26 OR #27)
#29 (baby or babies or infant* or toddler* or preschool* or pre-school* or child*)
#30 MeSH descriptor Infant explode all trees
#31 child near Mesh
#32 (#29 OR #30 OR #31)
#33 (#28 AND #32)

MEDLINE

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/

9     (trace adj (element$ or mineral$ or nutrient$)).tw.

10     iron,dietary/

11     ferric compounds/ or ferrous compounds/

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

13     or/1-12

14     food, fortified/

15     dietary supplements/

16     food,specialized/

17     ((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.

18     "point of use".tw.

19     (home adj5 fortif$).tw.

20     ((in-home or at-home) adj5 fortif$).tw.

21     (mix$ or powder$ or supplement$ or sachet$ or packet$ or powder$ or MNP or MNPs).tw.

22     or/14-21

23     13 and 22

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

25     or/23-24

26     (baby or babies or infant$ or toddler$ or preschool$ or pre-school$ or child$).tw.

27     exp child/ or infant/

28     26 or 27

29     25 and 28

EMBASE

1     exp trace element/

2     vitamin mixture/

3     (trace adj (element$ or mineral$ or nutrient$)).tw.

4     iron/ or ZINC/ or retinol/

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

6     iron derivative/

7     iron intake/

8     ferric ion/ or ferrous ion/

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

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

11   (multimicronutrient$ or multi-micronutrient$).tw.

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

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

14   or/1-13

15   diet supplementation/

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) adj5 fortif$).tw.

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

21   or/15-20

22  14 and 21

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

24  22 or 23

25  exp child/

26  infant/

27 (baby or babies or infant$ or toddler$ or preschool or pre-school$ or child$).tw.

28 25 or 26 or 27

29 24 and 28

CINAHL

S28 S24 and S27

S27 S25 or S26

S26 baby or babies or infant* or toddler* or pre-school* or preschool* or child*

S25 AG Infant, Newborn: birth-1 month OR Infant: 1-23 months or Child,Preschool: 2-5 years

S24 S22 or S23

S23 (Sprinkles or Vita Shakti or Rahama or Anuka or Chispitas or BabyFer

 or Bebe Vanyan or Supplefer or Supplefem)

S22 S13 and S21

S21 S14 or S15 or S16 or S17 or S18 or S19 or S20

S20 mix* or powder* or supplement* or sachet* or packet* or powder* or MNP   or MNPs

S19 at-home N5 fortif*

S18 in-home N5 fortif*

S17 home N5 fortif*

S16 "point of use"

S15 (food* or meal* or drink* or beverage* or diet* or snack* or breakfast* or break-fast* or lunch* or dinner*) AND (fortif* or enrich* or supplement*)

S14 (MH "Food, Fortified") OR (MH "Dietary Supplements")

S13 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12

S12 iron or "Fe" or ferric* or ferrous* or zinc or "Zn" or "vit* A" or retinol*

S11 trace element* or trace mineral* or trace nutrient*

S10 (MH "Trace Elements")

S9 (MH "Ferric Compounds") OR (MH "Ferrous Compounds")

S8 multimineral* or multi-mineral*

S7 multivitamin* or multi-vitamin*

S6 (MH "Vitamin A")

S5 multimicro-nutrient* or multimicronutrient*

S4 multinutrient* or multi-nutrient* or multi* nutrient*

S3 micronutrient* or micro-nutrient*

S2 (MH "Iron") OR (MH "Iron Compounds") OR (MH "Zinc")

S1 (MH "Micronutrients")

Science Citation Index

# 12 #11 AND #10

# 11 TS= (baby or babies or infant or toddler* or pre-school* or preschool* or child*)

# 10 #1or #9

# 9 #8 SAME #7

# 8 #2 or #3

# 7 #6 OR #5 OR #4

# 6 TS=( home fortif* or at-home fortif* or  in-home fortif*)

# 5 TS= point of use

# 4 TS=((food* or meal* or drink* or  beverage* or diet* or snack* or breakfast* or break-fast* or lunch* or dinner*) SAME (fortif* or enrich* or supplement*)) 

# 3 TS=(iron or Fe or ferric* or ferrous* or zinc or Zn or vit* A or retinol*)

# 2 TS= (micronutrient* or micro-nutrient* or multinutrient* or multi-nutrient* or multi* nutrient* or multimicro-nutrient* or multimicronutrient* or multivitamin* or multi-vitamin*)

# 1 TS= (Sprinkles or Vita Shakti or Rahama or Anuka or Chispitas or BabyFer or Bebe Vanyan or  Supplefer or Supplefem)

Conference Proceedings Citation Index - Science (CPCI-S)

# 12 #11 AND #10

# 11 TS= (baby or babies or infant or toddler* or pre-school* or preschool* or child*)

# 10 #1or #9

# 9 #8 SAME #7

# 8 #2 or #3

# 7 #6 OR #5 OR #4

# 6 TS=( home fortif* or at-home fortif* or  in-home fortif*)

# 5 TS= point of use

# 4 TS=((food* or meal* or drink* or  beverage* or diet* or snack* or breakfast* or break-fast* or lunch* or dinner*) SAME (fortif* or enrich* or supplement*)) 

# 3 TS=(iron or Fe or ferric* or ferrous* or zinc or Zn or vit* A or retinol*)

# 2 TS= (micronutrient* or micro-nutrient* or multinutrient* or multi-nutrient* or multi* nutrient* or multimicro-nutrient* or multimicronutrient* or multivitamin* or multi-vitamin*)

# 1 TS= (Sprinkles or Vita Shakti or Rahama or Anuka or Chispitas or BabyFer or Bebe Vanyan or  Supplefer or Supplefem)

LILACS

micronutrient$ or multinutrien$ or micro-nutrient$ or multi-nutrient$ [Words] and home$ or fortif$ or point-of-use [Words] or sprinkles or MNP or MNPs [Words]

African Index Medicus

sprinkles OR micronutrients OR multimicronutrients OR mnp OR bebe vanyan or supplefer or vita shakti or babyfer or chispitas or anuka or rahama [Key Word]

POPline

((micronutrient* /micro-nutrient*/multinutrient/ multi-nutrient*/ multi* nutrient*) & (home fortif*/ point of use) ) /sprinkles                 

ClinicalTrials.gov

sprinkles OR "multinutrient powder" OR multimicronutrients OR mnp OR mnps | Child

metaRegister of Clinical Trials

sprinkles or multinutrients or multimicronutrients or MNP or MNPs

WHO ICTRP

Intervention: sprinkles or multinutrients  or multimicronutrients or MNP or MNPs

AND Clinical trials in children

 

 

 

 

Feedback

  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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Three queries concerning the 'Home fortification with micronutrients' review, 14 October 2013

 

Summary

Comment:
1. It was not clear to me why the numbers cited in the analysis seemed different from those given in the Hirve 2007 article [1]. For example, in analysis 2.1, N=30 in the iron supplement control group was cited yet the article flow chart described that n=83 was assigned to iron supplement (oral drop) group and 10 lost to follow up. In analysis 2.1, 30 events of diarrhea in 55 children were cited. In Table III of Hirve 2007 the mean episode per child was 1.05 which amounted to 77 events for all 73 children completed iron supplement.

2. This review also cited unpublished data from the Suchdev 2011 study. Since it was unpublished, it was not available to me to evaluate. An article by Suchdev [2] published in 2012 seemed to report on this study as Suchdev 2011 cited in this review. The actual intervention was subtly different from this review. This trial did not give MNP to every family. The MNP was marketed and sold in the selected villages so the family could buy if they wanted to. Although the authors said 93% of the intervention group received MNP at least once during the 1 year trial period, ˜40% of the control group also purchased MNP. These facts might help explaining the modest effect size of the trial.

3. The Main results section of the abstract said "No deaths were reported in the trials ....", then qualified the statement as "In one of the trials, two deaths were reported after the intervention was finalized but were judged not to be related to the study (Hirve 2007)." These statements were misleading. The second death occurred during the trial (in the 7th week of iron supplementation) not after the intervention was finalized. Deaths in clinical trials should be unambiguously and publicly reported but often were not [3]. In the Suchdev 2012 report, there were 12 deaths during the 12 months follow up period of the trial. Regardless of the causes of death, discrepancy like this might cast doubt on the completeness of unpublished data.

References:
1. Hirve S, Bhave S, Bavdekar A, Naik S, Pandit A, Schauer C, et al. Low dose 'Sprinkles' - an innovative approach to treat iron deficiency anemia in infants and young children. Indian Pediatrics 2007;44(2):91–100.
2. Suchdev PS, Ruth LJ, Woodruff BA, Mbakay C, Mandava U, Flores-Ayala R, et al. Selling Sprinkles micronutrient powder reduces anemia, iron deficiency, and vitamin A deficiency in young children in Western Kenya: a cluster-randomized controlled trial. American Journal of Clinical Nutrition 95: 1223-30, 2012.
3. Earley A, Lau J, Uhlig K. Haphazard reporting of deaths in clinical trials: a review of cases of ClinicalTrials.gov records and matched publications–a cross-sectional study. BMJ Open 2013;3:e001963.

I agree with the conflict of interest statement below:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Name: Jih-I Yeh
Email Address: jihiyeh@gms.tcu.edu.tw
Affiliation: Department of Family Medicine, Buddhist Tzu-Chi hospital & Tzu-Chi University, Hualien, Taiwan

 

Reply

Response of author team: This feedback is valid and helpful, and also, timely. The author team has recently been in discussions regarding an update this review so that it reflects the current state of the art of this intervention. The last search was conducted almost three years ago and since then a number of trials that potentially meet the inclusion criteria of this review have been published, including that of Dr Suchdev. Also, now more sophisticated statistical analysis are available for the subgroup analyses and we (those authors who will contribute to the update) would also like this review be aligned with another Cochrane review in development, Point-of-use fortification of foods with micronutrient powders containing iron in children of preschool and school age (De-Regil et al) to better inform policy making.

The editorial base of the Cochrane Developmental, Psychosocial and Learning Problems Group has accepted our plan to address the comments above whilst updating the review as described, and we hope to complete this work in 2014.

 

Contributors

Dr Jih-l Yeh (affiliation), Dr Luz de-Regil (affiliation), Joanne Wilson (Managing Editor, CDPLPG), Jane Dennis (Feedback Editor, CDPLPG)

 

What's new

  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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 10 August 2011.


DateEventDescription

5 March 2014AmendedMinor edits made to references

14 October 2013Feedback has been incorporated3 queries relating to the 'Home fortification of foods with multiple micronutrients' review and the response of the author team.



 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

All authors contributed to the development of the review.

 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Luz Maria De-Regil - none known.
Parminder S Suchdev - is the principal investigator in an effectiveness study of micronutrient powders among preschool children in Western Kenya (Suchdev 2011).
Gunn E Vist - none known.
Silke Walleser - none known.
Juan Pablo Peña-Rosas - none known.

Disclaimer: Juan Pablo Pena-Rosas and Luz Maria De-Regil are full-time staff members of the World Health Organization. Parminder Singh Suchdev 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 organizations.

 

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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • Emory University, USA.
    PS works as Assistant Professor of Pediatrics for Emory University and is partially funded by the US Centers for Disease Control and Prevention (CDC), Atlanta, GA
  • Micronutrients Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.

 

External sources

  • Micronutrient Initiative (MI), Canada.
    WHO acknowledges Micronutrient Initiative (MI) for their financial support to the Micronutrients Unit for conducting systematic reviews on micronutrients interventions.
  • Global Alliance for Improved Nutrition (GAIN), Switzerland.
    WHO acknowledges the Global Alliance for Improved Nutrition (GAIN) for their financial support to the Micronutrients Unit for conducting systematic reviews on micronutrients interventions.
  • The Bill & Melinda Gates Foundation, USA.
    WHO aknowledges the financial support from The Bill & Melinda Gates Foundation for the development of systematic reviews of the evidence on the effects of nutrition 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. Feedback
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

In comparison with the protocol, this review has various differences in the following sections.

  • Type of interventions: in our protocol we stated that the comparison groups would include no intervention, placebo, or usual supplementation. We decided to list the specific comparisons in order to make them explicit for the reader. Also, for clarity we decided to specify the type of interventions that are out of the scope of this review.
  • Types of outcome measures: this section has various changes, 1) we added 'iron deficiency' as primary outcome as we have included previously iron status as a continuous variable but not a variable to diagnose the actual deficiency; 2) we moved 'all-cause mortality' from the secondary to the primary outcomes to be consistent with our objective and be able to evaluate the safety of this intervention; 3) we deleted 'growth' in one of the primary outcomes as it may refer to several indicators; we replaced it with 'weight-for-age Z-score (WAZ)' which is one of the variables to evaluate growth; 4) for the secondary outcomes, 'adverse effects (any)' was changed to 'side effects' and the definition was complemented with some examples such as staining of teeth, vomiting, fever, coughing or stool discolouration; 5) 'constipation' was included as a side effect and thus is no longer specified as an independent secondary outcome; and 6) we changed the order of the secondary outcomes proposed in the protocol to improve the legibility of the text.
  • Searching other resources: we added the International Clinical Trials Registry Platform (ICTRP) as source of data to find information about ongoing trials.
  • Assessment of risk of bias in included studies: we included a paragraph to summarize the use of the GRADE approach to generate the 'Summary of findings' tables.
  • Unit of analysis issues: in the protocol we said that we were not going to combine cluster and individually randomised trial results; however as the direction and magnitude of the effect were consistent among trials at either level of randomisation we deemed convenient to combine the results. The methods used to combine the trials are clearly described.
  • Subgroup analysis: given the small number of trials, the definition of malaria setting was changed from a four category to two categories.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  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. Feedback
  14. What's new
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
Adu-Afarwuah 2007 {published data only (unpublished sought but not used)}
  • Adu-Afarwuah S, Lartey A, Brown KH, Zlotkin S, Briend A, Dewey KG. Home fortification of complementary foods with micronutrient supplements is well accepted and has positive effects on infant iron status in Ghana. American Journal of Clinical Nutrition 2008;87:929-38.
  • Adu-Afarwuah S, Lartey A, Brown KH, Zlotkin S, Briend A, Dewey KG. Randomized comparison of 3 types of micronutrient supplements for home fortification of complementary foods in Ghana: effects on growth and motor development. American Journal of Clinical Nutrition 2007;86:412-20.
Christofides 2006 {published data only}
  • Christofides A, Asante KP, Schauer C, Sharieff W, Owusu-Agyei S, Zlotkin S. Multi-micronutrient Sprinkles including a low dose of iron provided as microencapsulated ferrous fumarate improves haematologic indices in anaemic children: a randomized clinical trial. Maternal and Child Nutrition 2006;2(3):169-80.
Giovannini 2006 {published data only}
  • Agostoni C, Giovannini M, Sala D, Usuelli M, Livio L, Francescato C, et al. Double-blind, placebo-controlled trial comparing effects of supplementation of two micronutrient Sprinkles on fatty acid status in Cambodian infants. Journal of Pediatric Gastroenterology and Nutrition 2007;44(1):136-42.
  • Giovannini M, Sala D, Usuelli M, Livio L, Francescato G, Braga M, et al. Double-blind, placebo-controlled trial comparing effects of supplementation with two different combinations of micronutrients delivered as sprinkles on growth, anemia, and iron deficiency in Cambodian infants. Journal of Pediatrics Gastroenterology and Nutrition 2006;42(3):306-12.
Hirve 2007 {published and unpublished data}
  • Hirve S, Bhave S. Re-analysis of the sprinkles study conducted by us at KEM Hospital Research Center, Pune, India. (personal communication) February 2011.
  • Hirve S, Bhave S, Bavdekar A, Naik S, Pandit A, Schauer C, et al. Low dose 'Sprinkles' - an innovative approach to treat iron deficiency anemia in infants and young children. Indian Pediatrics 2007;44(2):91-100.
Lundeen 2010 {published and unpublished data}
  • Lundeen E, Schueth T, Toktobaev N, Zlotkin S, Hyder SM, Houser R. Daily use of Sprinkles micronutrient powder for 2 months reduces anemia among children 6 to 36 months of age in the Kyrgyz Republic: a cluster-randomized trial. Food and Nutrition Bulletin 2010;31(3):446-60.
Menon 2007 {published and unpublished data}
  • Loechl CU, Menon P, Arimond M, Ruel MT, Pelto G, Habicht JP, et al. Using programme theory to assess the feasibility of delivering micronutrient Sprinkles through a food-assisted maternal and child health and nutrition programme in rural Haiti. Maternal and Child Nutrition 2009;5(1):33-48.
  • Menon P, Ruel MT, Loechl CU, Arimond M, Habicht JP, Pelto G, et al. Micronutrient Sprinkles reduce anemia among 9- to 24-mo-old children when delivered through an integrated health and nutrition program in rural Haiti. Journal of Nutrition 2007;137(4):1023-30.
Sharieff 2006a {published data only}
  • Sharieff W, Bhutta Z, Schauer C, Tomlinson G, Zlotkin S. Micronutrients (including zinc) reduce diarrhoea in children: the Pakistan Sprinkles Diarrhoea Study. Archives of Disease in Childhood 2006;91(7):573-9.
Suchdev 2011 {unpublished data only}
  • Centers for Disease Control and Prevention. Baseline data from the Nyando Integrated Child Health and Education Project - Kenya, 2007. Morbidity and Mortality Weekly Report (MMWR) 2007;56(42):1109-13.
  • Suchdev PS, Leeds IL, McFarland DA, Flores R. Is it time to change guidelines for iron supplementation in malarial areas?. Journal of Nutrition 2010;140(4):875-6.
  • Suchdev PS, Ruth L, Woodruff BA, Mbakaya C, Mandava U, Flores R, et al. Sprinkles sales reduce anemia and iron deficiency among young children in Western Kenya. (personal communication) February 2011.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  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. Feedback
  14. What's new
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
Bagni 2009 {published data only}
  • Bagni UV, Baiao MR, de Souza Santos MMA, Luiz RR, da Veiga GV. Effect of weekly rice fortification with iron on anaemia prevalence and haemoglobin concentration among children attending public daycare centres in Rio de Janeiro, Brazil [Efeito da fortificao semanel do arroz com ferro quelato sobre a frequencia de anemia e concentracao de hemoglobina em criancas de creches municipais de Rio de Janeiro, Brasil]. Cadernos de Saude Publica 2009;25(2):291-302.
Chen 2008 {published data only}
  • Chen K, Li TY, Chen L, Qu P, Liu YX. Effects of vitamin A, vitamin A plus iron and multiple micronutrient-fortified seasoning powder on preschool children in a suburb of Chongqing, China. Journal of Nutritional Science and Vitaminology 2008;54(6):440-7.
  • Chen K, Zhang X, Li TY, Chen L, Wei XP, Qu P, Liu YX. Effect of vitamin A, vitamin A plus iron and multiple micronutrient-fortified seasoning powder on infectious morbidity of preschool children. Nutrition 2011;27(4):428-34.
Geltman 2009 {published data only}
  • Geltman PL, Hironaka LK, Mehta SD, Padilla P, Rodrigues P, Meyers AF, et al. Iron supplementation of low-income infants: a randomized clinical trial of adherence with ferrous fumarate sprinkles versus ferrous sulfate drops. Journal of Pediatrics 2009;154(5):738-43.
Ip 2009 {published data only}
  • Ip H, Hyder SM, Haseen F, Rahman M, Zlotkin SH. Improved adherence and anaemia cure rates with flexible administration of micronutrient Sprinkles: a new public health approach to anaemia control. European Journal of Clinical Nutrition 2009;63(2):165-72.
Sharieff 2006b {published data only}
  • Sharieff W, Yin SA, Wu M, Yang Q, Schauer C, Tomlinson G, et al. Short-term daily or weekly administration of micronutrient Sprinkles has high compliance and does not cause iron overload in Chinese schoolchildren: a cluster-randomized trial. Public Health Nutrition 2006;9(3):336-44.
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.
Troesch 2009 {published data only}
  • Troesch B. Optimized micronutrient powder containing low levels of highly bioavailable iron and zinc together with EDTA, phytase and ascorbic acid improves the nutritional status of children. Sight and Life Magazine 2010, issue 3:9-14.
  • Troesch B, Egli I, Zeder C, Hurrell RF, de Pee S, Zimmermann MB. Optimization of a phytase-containing micronutrient powder with low amounts of highly bioavailable iron for in-home fortification of complementary foods. American Journal of Clinical Nutrition 2009;89(2):539-44.
Troesch 2011 {published data only}
  • Troesch B, van Stujivenberg ME, Smuts CM, Kruger HS, Biebinger R, Hurrell RF, et al. A micronutrient powder with low doses of highly absorbable iron and zinc reduces iron and zinc deficiency and improves weight-for-age Z-scores in South African children. Journal of Nutrition 2011;141(2):237-42.
Wijaya-Erhardt 2007 {published data only}
  • Wijaya-Erhardt M, Erhardt JG, Untoro J, Karyadi E, Wibowo L, Gross R. Effects 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.
Zlotkin 2001 {published data only}
  • Zlotkin S, Arthur P, Antwi KY, Yeung G. Treatment of anemia with microencapsulated ferrous fumarate plus ascorbic acid supplied as sprinkles to complementary (weaning) foods. American Journal of Clinical Nutrition 2001;74(6):791-5.
Zlotkin 2003a {published data only}
  • Zlotkin S, Antwi KY, Schauer C, Yeung G. Use of microencapsulated iron (II) fumarate sprinkles to prevent recurrence of anaemia in infants and young children at high risk. Bulletin of the World Health Organization 2003;81(2):108-15.
Zlotkin 2003b {published data only}
  • Zlotkin S, Arthus P, Schauer C, Antwi KY, Yeung G, Piekarz A. Home-fortification with iron and zinc Sprinkles of iron Sprinkles alone successfully treats anemia in infants and young children. Journal of Nutrition 2003;133(4):1075-80.

References to studies awaiting assessment

  1. Top of page
  2. AbstractRésumé
  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. Feedback
  14. What's new
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
Bilenko 2010 {published data only (unpublished sought but not used)}
  • Bilenko N, Belmaker I, Vardi H, Fraser D. Efficacy of multiple micronutrient supplementations on child health: study design and baseline characteristics. Israel Medical Association Journal 2010;12(6):342-7.
Neufeld 2008 {unpublished data only}
  • Aburto NJ, Ramirez-Zea M, Neufeld LM, Flores-Ayala R. The effect of nutritional supplementation on physical activity and exploratory behavior of Mexican infants aged 8-12 months. European Journal of Clinical Nutrition 2010;64(6):644-51.
  • Colchero A, Neufeld LM. Cost estimations of different types of micronutrient supplements for children and pregnant women (poster presentation). FASEB Journal 2008; Vol. 22, issue Abstract 678.21.
  • García-Guerra A, Neufeld LM, Domínguez CP, García-Feregrino R, Hernández-Cabrera A. Effect of three supplements with identical micronutrient content on anemia in Mexican children (poster presentation). FASEB Journal 2008; Vol. 22, issue Abstract 677.5.

References to ongoing studies

  1. Top of page
  2. AbstractRésumé
  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. Feedback
  14. What's new
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
Fitzsimons 2009 {unpublished data only}
  • International Clinical Trials Registry Platform, World Health Organization. Early Childhood Development: A cluster-randomized controlled trial to Identify successful interventions and the mechanisms behind them. http://apps.who.int/trialsearch/Trial.aspx?TrialID=ISRCTN18991160 (accessed 23 January 2011).
Jack 2008 {unpublished data only}
  • International Clinical Trials Registry Platform, World Health Organization. Combating anaemia and micronutrient deficiencies among young children in rural Cambodia through in-home multiple micronutrient fortification and nutrition education compared with nutrition education alone. http://apps.who.int/trialsearch/Trial.aspx?TrialID=ACTRN12608000069358 (accessed 24 January 2011).
Ribeiro Da Costa 2009 {unpublished data only}
  • International Clinical Trials Registry Platform, World Health Organization. The impact of the use of zinc supplementation and other micronutrients on the occurence of diarrhea diseases and respiratory infections in children of daycare centers. http://apps.who.int/trialsearch/Trial.aspx?TrialID=NCT00967551 (accessed 24 January 2011).
van der Kam 2010 {published data only}
  • Kam van der S. Effectiveness of nutritional supplementation in preventing malnutrition in children with infection. NIH ClinicalTrials.gov Register NCT01154803 2010.
Zavaleta 2010 {unpublished data only}
  • International Clinical Trials Registry Platform, World Health Organization. Efficacy of the nutritional supplement sprinkles with zinc and micronutrients on anaemia and acute diarrhoea in Peruvian children. http://apps.who.int/trialsearch/Trial.aspx?TrialID=ISRCTN39244429 (accessed 24 January 2011). [: Identifier ISRCTN39244429]
Zimmermann 2010 {unpublished data only}
  • International Clinical trials Registry Platform, World Health Organization. The Effect of iron fortification of complementary foods on iron status and infant gut microbiota in Kenya. Available at http://apps.who.int/trialsearch/Trial.aspx?TrialID=NCT01111864 (accessed 24 January 2011).
Zlotkin 2010 {unpublished data only}
  • International Clinical Trials Registry Platform, World Health Organization. Seasonal Impact of iron fortification on malaria incidence in Ghanaian children. Available at http://apps.who.int/trialsearch/Trial.aspx?TrialID=NCT01001871 (accessed 24 January 2011).

Additional references

  1. Top of page
  2. AbstractRésumé
  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. Feedback
  14. What's new
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. References to ongoing studies
  24. Additional references
Adetifa 2009
Angermayr 2004
  • Angermayr L, Clar C. Iodine supplementation for preventing iodine deficiency disorders in children. Cochrane Database of Systematic Reviews 2004, Issue 2. [DOI: 10.1002/14651858.CD003819.pub2]
Balshem 2010
Beaton 1993
  • Beaton G, Martorell R, Aronson K, Edmonston B, McCabe G, Ross CA, et al. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. UN, ACC/SCN State-of-the-art Series. Nutrition Policy Discussion Paper 1993, issue 13.
Beaton 1999
  • Beaton GH, McCabe GP. Efficacy of intermittent iron supplementation in the control of iron deficiency anaemia in developing countries. The Micronutrient Initiative. Ottawa: The Micronutrient Initiative, 1999.
Berger 1997
  • Berger J, Aguayo VM, Tellez W, Lujan 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.
Bhutta 2008
Black 2008
  • Black RE, Allen LH, Bhutta ZA, Caulfield LE, De Onis M, Ezzati M, et al. Maternal and child undernutrition: global and regional exposures and health consequences. Lancet 2008;371(9608):243-60.
Brown 2001
  • Brown KH, Wuehler SE, Peerson JM. The importance of zinc in human nutrition and estimation of the global prevalence of zinc deficiency. Food and Nutrition Bulletin 2001;22(2):113-25.
Brown 2009
  • Brown KH, Baker SK, IZiNCG Steering Committee (International Zinc Nutrition Consultative Group). Galvanizing action: conclusions and next steps for mainstreaming zinc interventions in public health programs. Food and Nutrition Bulletin 2009;30 Suppl(1):179-84.
De Pee 2008
  • De Pee S, Kraemer K, van den Briel T, Boy E, Grasset C, Moench-Pfanner R, et al. Quality criteria for micronutrient powder products: report of a meeting organized by the World Food Programme and Sprinkles Global Health Initiative. Food and Nutrition Bulletin 2008;29(3):232-41.
De-Regil 2011
  • De-Regil LM, Jefferds MED, Pena-Rosas JP. Home fortification with multiple micronutrient powders for preschool and school age children. Cochrane Database of Systematic Reviews To be published.
Dewey 2003
  • Dewey KG, Brown KH. Update on technical issues concerning complementary feeding of young children in developing countries and implications for intervention programs. Food and Nutrition Bulletin 2003;24(1):5-28.
Dewey 2007
Dewey 2009
Fawzi 1993
  • Fawzi WW, Chalmers TC, Herrera MG, Mosteller F. Vitamin A supplementation and child mortality. A meta-analysis. JAMA 1993;269(7):898-903.
Glasizou 1993
GRADEpro 2008
  • Brozek J, Oxman A, Schünemann H. GRADEpro Version 3.2 for Windows. Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group, 2008.
Higgins 2011
  • Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Horton 2008
  • Horton S, Alderman H, Rivera JA. Copenhagen Consensus 2008 Challenge Paper: Hunger and Malnutrition. http://www.copenhagenconsensus.com/Admin/Public/Download.aspx?file=Files%2fFiler%2fCC08%2fPapers%2fOfficial+papers%2fCopenhagen_Consensus_2008_-_hunger_and_malnutrition.pdf 2008:1-40.
Hyder 2007
  • Hyder SMZ, Haseen F, Rahman M, Tondeur M, Zlotkin SH. Effect of daily versus once-weekly home fortification with micronutrient Sprinkles on hemoglobin and iron status among young children in rural Bangladesh. Food Nutrition Bulletin 2007;28(2):156-64.
Imdad 2010
  • Imdad A, Herzer K, Mayo-Wilson E, Yakoob MY, Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in children from 6 months to 5 years of age. Cochrane Database of Systematic Reviews 2010, Issue 12. [DOI: 10.1002/14651858.CD008524.pub2]
INACG 1998
  • International Nutritional Anemia Consultative Group (INACG). Guidelines for iron supplementation to prevent iron deficiency anemia. In: Stoltzfus RJ, Dreyfuss ML editor(s). Guidelines for the Use of Iron Supplements to Prevent and Treat Iron Deficiency Anemia. Washington DC: ILSI Press, 1998.
Irlam 2011
Jefferds 2010
  • Jefferds ME, Ogange L, Owuor M, Cruz K, Person B, Obure A, et al. Formative research exploring acceptability, utilization, and promotion in order to develop a micronutrient powder (Sprinkles) intervention among Luo families in western Kenya. Food and Nutrition Bulletin 2010;31 Suppl(2):179-85.
Liyanage 2002
  • Liyanage C, Zlotkin S. Bioavailability of iron from micro-encapsulated iron sprinkle supplement. Food and Nutrition Bulletin 2002;23 Suppl(3):133-7.
Loechl 2009
Lozoff 2007
  • Lozoff B. Iron deficiency and child development. Food and Nutrition Bulletin 2007;28 Suppl(4):560-71.
Martins 2001
Menon 2007
  • Menon P, Ruel MT, Loechl CU, Arimond M, Habicht JP, Pelto G, et al. Micronutrient Sprinkles reduce anemia among 9- to 24-mo-old children when delivered through an integrated health and nutrition program in rural Haiti. Journal of Nutrition 2007;137(4):1023-30.
NIH 2011
  • National Insititutes of Health, Iron and Malaria Technical Working Group. Chapter 3: Interventions. In: Raiten D, Namaste S, Brabin B editor(s). Considerations for the Safe and Effective Use of Iron Interventions. Bethesda: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), 2011 (in press):16-51.
Ojukwu 2009
Oppenheimer 2001
  • Oppenheimer SJ. Iron and its relation to immunity and infectious disease. Journal of Nutrition 2001;131 Suppl 2:616-33.
PAHO 2001
  • PAHO/WHO. Guiding Principles for Complementary Feeding of the Breastfed Child. Washington DC: Pan American Health Organization, 2001.
RevMan 2011
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
Sanghvi 2007
  • Sanghvi T, Ross J, Heymann H. Why is reducing vitamin and mineral deficiencies critical for development? The links between VMD and survival, health, education and productivity. Food and Nutrition Bulletin 2007;28 Suppl 1:167-73.
Sazawal 2006
  • Sazawal S, Black RE, Ramsan M, Chwaya HM, Stoltzfus RJ, Dutta A, et al. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomized, placebo-controlled trial. Lancet 2006;367(9505):133-43.
Sprinkles Global Health Initiative 2010
  • Sprinkles Global Health Initiative. Product Information. Standard Formulations. http://www.sghi.org/ (accessed 20 May 2010).
Stephensen 2001
Stoltzfus 2011
Suchdev 2009
The Micronutrient Initiative 2009
  • Micronutrient Initiative, Flour Fortification Initiative, USAID, GAIN, WHO, The World Bank, UNICEF. Investing in the Future: A United Call to Action on Vitamin and Mineral Deficiencies: Global Report 2009. Ottawa, Canada: The Micronutrient Initiative, 2009. [: ISBN: 978-1-894217-31-6]
UNICEF 2009
  • UNICEF. Workshop Report on Scaling up the use of Multiple Micronutrient Powders to improve the quality of complementary foods for young children in Asia. Summary, outcomes, conclusions and next steps; 2009 28 Apr-1 May, Bangkok, Thailand. Bangkok: UNICEF, 2009.
UNICEF 2011
  • UNICEF 2011. The state of the world's children 2011: Adolescence An Age of Opportunity. New York: United Nations Children’s Fund, 2011.
Viteri 1997
  • Viteri FE. Iron supplementation for the control of iron deficiency in populations at risk. Nutrition Reviews 1997;55(6):195-209.
WHO 2001
  • World Health Organization, UNICEF, UNU. Iron Deficiency Anaemia Assessment, Prevention and Control: a Guide for Programme Managers. Geneva: World Health Organization, 2001.
WHO 2005
  • World Health Organization. Guiding Principles for Feeding Non-Breastfed Children 6-24 Months of Age. Geneva: World Health Organization, 2005.
WHO 2006
  • World Health Organization. Workshop to review the results of studies evaluating the impact of zinc supplementation on childhood mortality and severe morbidity: conclusions and next steps; 2006 15-16 Sept, Geneva, Switzerland. Geneva: World Health Organization, 2007, issue http://www.who.int/child_adolescent_health/documents/pdfs/zinc_mortality_workshop_2007.pdf.
WHO 2009
  • World Health Organization. Global Health Risks: Mortality and Burden of Disease Attributable to Selected Major Risks. Geneva: World Health Organization, 2009.
WHO/CDC 2008
  • World Health Organization, Centers for Disease Control and Prevention. Worldwide prevalence of anaemia 1993-2005: WHO global database on anaemia. World Health Organization, 2008. Available from http://whqlibdoc.who.int/publications/2008/9789241596657_eng.pdf.
WHO/UNICEF 2004
  • World Health Organization/UNICEF. Clinical management of acute diarrhoea. Geneva: World Health Organization, 2004.
WHO/WFP/UNICEF 2007
  • World Health Organization, World Food Programme, UNICEF. Preventing and controlling micronutrient deficiencies in populations affected by an emergency. Geneva: World Health Organization, 2007.
World Bank 2010
  • World Bank, UNICEF, WHO, WFP. Scaling Up Nutrition: A Framework For Action. Policy Brief. Food and Nutrition Bulletin 2010;31(1):178-86.
World Vision 2005
  • World Vision Mongolia. Effectiveness of home-based fortification of complementary foods with Sprinkles in an integrated nutrition program to address rickets and anemia. Ulannbaatar 2005.
Zeng 2007
  • Zeng X, Wu T. Iron supplementation for iron deficiency anemia in children. Cochrane Database of Systematic Reviews 2007, Issue 2. [DOI: 10.1002/14651858.CD006465]
Zlotkin 2004
  • Zlotkin SH, Tondeur M. Specific strategies to address micronutrient deficiencies in the young child: supplementation and home fortification. In: Pettifor J, Zlotkin S editor(s). Micronutrient Deficiencies During the Weaning Period and the First Years of Life. Nestlé Nutrition Workshops Series Pediatric Program. Vol. 54, Basel: Nestec Ltd, 2004:233-48.
Zlotkin 2005