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 and, together with vitamin A and zinc deficiencies, has the largest documented disease burden among micronutrients (Black 2008; WHO 2001; 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). Diets of infants and young children that are predominantly plant-based generally provide insufficient amounts of key micronutrients (particularly vitamin A, zinc and calcium) to meet the recommended nutrient intakes during the age range of six to 23 months and the inclusion of animal-source foods that could meet the nutrient gap increases the cost and may be not practical for the lowest income groups (PAHO 2001; WHO 2005). There are no global estimates on vitamin and mineral deficiencies specifically for children under two; however, it is calculated that 190 million preschool children are affected by vitamin A deficiency (WHO 2009) and 293 million by anaemia (WHO 2008).
Vitamin A plays a critical role in visual perception and 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 to 24 months with iron-deficiency anaemia are at risk for poorer cognitive, motor, social-emotional, and neurophysiologic development in the short and long term (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 nutriture 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, sub-optimal 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 5 years old (WHO 2009).
Description of the intervention
Interventions to prevent and/or 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 23% reduction in childhood diarrhoea incidence (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 supplementation to all infants and children six to 24 months of age in areas where the prevalence of anaemia exceeds 20% to 30% (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 micronutrient interventions, implementation has been hindered by poor adherence to supplementation dosing regimens, inadequate supply, low coverage, and potential dose-related side effects and safety concerns (Sazawal 2006).
In response to these operational constraints, 'home' or ‘point-of-use’ food fortification with micronutrient powders (MNP), for example, Sprinkles
The cost of increasing the number of micronutrients in powders is minimal (the primary cost of the product is in the packaging) (De Pee 2008) and many programs use a standard formulation containing 14 vitamins and minerals (Sprinkles Global Health Initiative 2010), although the formulation and the compound specifications may vary in some other programmes. The efficacy of the standard "multi-micronutrient" formulation for anaemia has been evaluated in some studies; however, the potential for negative interaction among micronutrients - possibly limiting their absorption and utilization - as well as the effects on other outcomes, warrants further investigation.
Provision of iron containing formulations, either supplements or MNP, 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). In 2006, the World Health Organization (WHO) consultative group issued recommendations that no children under two years of age living in malaria-endemic areas should be provided iron supplementation without appropriate screening for iron deficiency (WHO 2007a; WHO 2007b). However, a recent Cochrane review challenged the body of evidence used by the WHO to make its recommendations. The authors found that 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). The impact of this policy is unknown, but because widespread screening for iron deficiency is unlikely to be practical or affordable in developing countries, many iron supplementation programs have come to a halt. This situation has urged experts in nutrition and policy makers worldwide to forthrightly discuss 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 circulation (Liyanage 2002; Dewey 2007).
From the implementation perspective, MNP programs are currently at national scale in several countries, such as Bangladesh, Mongolia, and Haiti, and numerous countries are also 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 dose 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). Intakes 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 in improving clinical, immunologic, and virologic outcomes in children infected with HIV (Adetifa 2009); 2) micronutrient supplementation in children and adults with HIV infection (Irlam 2005); 3) oral or intramuscular iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia (Logan 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 and another one assesses the effects of supplementation with two or more micronutrients (iron, vitamin A and/or zinc) versus single micronutrient supplementation (in tablets, syrups, sprinkles) or placebo mainly for preventing acute respiratory infections, other infectious diseases and micronutrient deficiencies in young children (Fraser 2006).
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 programs on effectiveness and safety, as well as on the appropriate dose, frequency and duration of this intervention. This review will focus on nutrition, health and developmental outcomes in young children related to micronutrients, particularly iron, zinc and vitamin A. Furthermore, an effort will be made to address the morbidity outcomes of home (point-of-use) fortification of foods with MNP in malaria-endemic areas given the uncertainties and the urgent need for policy decisions on the safe delivery of iron for populations living in these settings.
To assess the effects and safety of home (point-of-use) fortification of foods with multiple micronutrient powders (MNP) on nutrition, health and developmental outcomes in children under two living in different settings.
For the purpose of this review, home fortification refers to the addition of multiple micronutrients powders to semi-liquid foods immediately before consumption and it can be done at home or in any other place where meals are to be consumed (for example, schools, wards, refugee camps).
Criteria for considering studies for this review
Types of studies
Randomised controlled trials, including both individual and cluster randomisation, and quasi-randomised trials.
Types of participants
We will include studies with infants and young children six to 23 months at the start of the intervention, as breastfeeding is the recommendation for infants from birth to six months. We intend to include apparently healthy children from the general population, although some may be at risk of malnutrition.
We will attempt to collect information regarding the malaria status and any ongoing malaria treatment in the area of the trial at the time of the trials, together with information regarding malaria treatment or prevention.
Types of interventions
Multiple micronutrient powders (MNP) including at least the three micronutrients iron, zinc and vitamin A. We will consider trials where the multiple micronutrient powders have been given to whole families (added to the family meal), providing results are presented separately for our population. We will include multiple micronutrient powders given at point of care for any dose, frequency and duration.
The comparison groups will include no intervention, placebo, or treatment as usual.
Both the control and the intervention group should receive similar co-interventions.
Types of outcome measures
- Anaemia (defined as haemoglobin values < 110 g/L)
- Haemoglobin values
- Iron status (as defined by trialists)
- Growth (as measured by Weight for Age Z-scores WAZ)
- All-cause mortality
- Mental development and motor skill development (as defined by trialists, for example, it might include: Bayley Mental Development Index (MDI), Bayley Psychomotor Development Index (PDI), Stanford-Binet Test, DENVER II Developmental Screening Test)
- Linear growth (Height for Age Z-scores (HAZ))
- Serum retinol concentration
- Adverse effects (any)
- Upper respiratory tract infections
- Ear infections
- Wasting (Weight for Height Z-scores (WHZ))
- Serum zinc concentration (g/dL)
- Iron overload
For populations in malaria endemic areas we will report two additional outcomes:
- Malaria incidence
- Malaria severity
We will group outcome time points as follows: immediately post-intervention, one to five months post-intervention, six to 12 months post-intervention.
We will report other relevant outcomes reported by trial authors and label these as 'not prespecified'.
Search methods for identification of studies
We will search the following electronic databases:
Cochrane Central Register of Controlled Trials (The Cochrane Library)
African Index Medicus
Conference Proceedings Citation Index
metaRegister of Clinical Trials
Science Citation Index
WHO International Clinical Trials Registry Platform (ICTRP)
We will use the following search strategy to search MEDLINE:
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$).tw.
8 (trace adj (element$ or mineral$ or nutrient$)).tw.
10 ferric compounds/ or ferrous compounds/
11 (iron or Fe or ferric$ or ferrous$ or zinc or Zn or vit$ A or retinol$).mp.
13 food, fortified/
14 dietary supplements/
16 ((food$ 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 supplement$ or sachet$ or packet$ or powder$).tw.
21 (Sprinkles or Vita Shakti or Rahama or Anuka or Chispitas or BabyFer or Bebe Vanyan or Supplefer or Supplefem or MNP?).tw.
23 (baby or babies or infant$ or toddler$ or preschool$ or pre-school$ or child$).tw.
24 exp child/ or exp infant/
25 23 or 24
26 12 and 22 and 25
We will modify search terms as necessary when searching other databases. We will not apply any date or language restrictions, and will obtain translations of relevant data where necessary.
Searching other resources
We will search through the bibliographies of included studies and ask authors of included studies for lists of other studies that should be considered for inclusion. For assistance in identifying ongoing or unpublished studies, we will contact the Sprinkles Global Health Initiative, the In-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).
Data collection and analysis
Selection of studies
Two reviewers will independently assess identified references for potential relevance. The main author GEV will assess all references, while SW, PSS, and JPR will each assess a third. LMdR and GEV will both independently assess the relevant references for inclusion according to the above inclusion criteria. We will resolve any disagreement through discussion or, if required, we will consult one of the other authors.
If studies are published only as abstracts, or study reports contain little information on methods, we will attempt to contact the authors to obtain further details of study design and results; if there is insufficient information for us to be able to assess risk of bias, studies will await assessment until further information is published or made available to us.
Data extraction and management
We will design a form to extract data. For eligible studies, two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion. We will attempt to extract the data for children six to 23 months from those studies targeted to broader age groups. We will enter data into Review Manager (RevMan) software (RevMan 2008) and will carry out checks for accuracy.
When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). We will resolve any disagreement by discussion or by involving a third assessor.
- Sequence generation (checking for possible selection bias)
- Allocation concealment (checking for possible selection bias)
- Blinding (checking for possible performance bias and detection bias)
- Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
- Selective reporting bias (checking if expected outcomes are reported)
- Other sources of bias (such as stopping the trial early or changing methods during the trial)
We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Handbook (Higgins 2008). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we considered it was likely to impact the findings.
Measures of treatment effect
For dichotomous data, we will present results as summary risk ratio (RR) with 95% confidence intervals (CI).
For continuous data, we will use mean difference with standard deviations if outcomes were measured in the same way between trials. We will use the standardized mean difference to combine trials that measured the same outcome but used different units of measurement.
Unit of analysis issues
Because we suspect that behaviour may be affected by different interactions, with different delivery personnel and with different delivery methods, we will not combine cluster and individually randomized trial results. We plan to present separate subgroups from cluster-randomized trials in the analyses next to individually randomized trials. If we identify any such trials, we will adjust the standard error of the effect estimate from cluster trials using the methods described in the Cochrane Handbook (Higgins 2008). We will carry out meta-analyses using the generic inverse-variance method available in RevMan (RevMan 2008). We will use an estimate of the intra-cluster correlation co-efficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources are used, we will report this and conduct sensitivity analyses to investigate the effect of variation on the ICC.
Studies with more than two treatment groups
For studies with more than two intervention groups (multi-arm studies), we will include the directly relevant arm only (Higgins 2008). Each group will only be included in the analysis once. If we come across a study that compares home (point-of-use) fortification of foods with MNP with two of our comparison possibilities, then we will, where possible, combine groups to create a single pair-wise comparison or use the methods set out in the Cochrane Handbook to avoid double-counting study participants (Higgins 2008).
Dealing with missing data
For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.
For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis. We will conduct analysis using available cases, and we will conduct sensitivity tests (assuming worst-case scenario and assuming best-case scenario) for the four primary outcomes.
For continuous measures where necessary, we will use actual measures (no imputations).
Assessment of heterogeneity
We will examine the forest plots from meta-analysis to look for heterogeneity among studies. We will consider the size and direction of effect and consult with the I² and Chi-square statistics to quantify the level of heterogeneity among the trials in each analysis. If we identify substantial or considerable heterogeneity (I² between 30 and 60% or between 50 and 100%), we will note this in the text and explore it by prespecified subgroup analysis. We will advise caution in the interpretation of those results where there are high levels of unexplained heterogeneity.
Assessment of reporting biases
Where we suspect reporting bias (see 'Selective reporting bias' above), we will attempt to contact study authors asking them to provide missing outcome data. We will advise caution in the interpretation of those results where we suspect outcome reporting bias.
We will use funnel plots to investigate the relationship between effect size and standard error when possible.
We will carry out statistical analysis using RevMan software (RevMan 2008). We expect there to be differences between trial differences in both population and intervention so we will use random-effects meta-analysis for combining data.
Subgroup analysis and investigation of heterogeneity
We are planning to conduct several subgroup analyses irrespective of heterogeneity. We will interpret all subgroup analyses cautiously. The planned subgroups have arisen from current clinical dilemmas and uncertainties (see Background). We will explore subgroup analyses on the primary outcomes based on the following criteria.
- By anaemic status at start of intervention (anaemia defined as haemoglobin values < 110 g/L, anaemic, non-anaemic or unknown anaemic status)
- By iron status at start of intervention (iron deficient, not iron deficient or unknown as defined by trialists)
- By age of children at the start of the intervention: six to 11 months, 12 to 17 months, 18 to 23 months
- By refugee status (yes, no)
- By malaria status of the area at the time of the trial (as defined by trialists; if not, we will use four categories: no malaria, malaria all year, malaria all year with peak seasons, only seasonal malaria)
- By frequency: daily versus weekly versus flexible
- By duration of intervention: less than six months versus six months or more
- By iron content of product: less than 12.5 mg versus 12.5 mg or more
- By zinc content of product: less than 5.0 mg versus 5.0 mg or more
For the comparisons related to malaria-endemic areas, we will conduct a subgroup analysis by treatment and prevention of malaria.
We will carry out sensitivity analysis to examine the effects of removing studies at high risk of bias (studies with poor or unclear allocation concealment) from the analysis and of including studies with children six to 59 months from which it is not possible to extract information only for children six to 23 months. If future updates of the review include cluster trials, we will carry out sensitivity analysis using a range of intracluster correlation values.
We thank the following for partial financial support to the Micronutrients Unit for this work: the Government of Luxembourg, the Micronutrient Initiative (MI) and the Global Alliance for Improved Nutrition (GAIN) .
Protocol first published: Issue 1, 2011
Contributions of authors
All authors contributed to the development of the protocol. PSS, LMR and JPR drafted the background sections. GEV and JPR drafted the methods and all authors contributed to the finalization of the protocol.
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.
Declarations of interest
GE Vist, LM De-Regil, SWalleser, JP Peña-Rosas - None known
PS Suchdev - Principal investigator in an effectiveness study of micronutrient Sprinkles among pre-school children in Western Kenya. Author of a study cited in this review (Suchdev 2009).
Sources of support
- 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.
- Micronutrient Initiative, Canada.WHO acknowledges Micronutrient Initiative for their financial support to the Micronutrients Unit for conducting systematic reviews on MNP 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.