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28 MuLTIPLE MICRONuTRIENT NuTRITION Multiple Micronutrient Nutrition: Evidence from History to Science to Effective Programs Workshop Proceedings: 2nd World Congress of Public Health, Portugal, 2010 1 David I Thurnham Northern Ireland Centre for Food and Health, university of ulster, Coleraine, uK 06. The use of micronutrient powders (MNP) in emergency situations has given variable results; however, this may be due to the unsuitability of the biomarkers used. 07. A comprehensive guide on the use of biomarkers for Key messages 01. Multiple micronutrient (MMN) supplements have been introduced to overcome drawbacks in single micronutrient programmers is needed. 08. More experimental work is advised before programs are started. supplementation to improve diets. 09. New work on the genetic polymorphisms affecting the 02. Main nutrients of interest are vitamin A, iron, zinc, folate and vitamin B₁₂. activity of the enzyme converting β-carotene to vitamin A has shown the existence of potentially important ethnic differences. 03. Evidence for the existence of other micronutrient deficiencies is largely circumstantial and based on the knowledge that many people in developing countries 10. Most micronutrient interventions to date have been delivered using the “health” platform. exist on very poor diets. 11. Three other delivery platforms exist: market-based, 04. Randomized controlled trials in pregnant and lactating women have largely shown poor responses to MMN agriculture and social protection. However, much information is still needed for their successful implementation. supplements, compared to iron and folate. 12. The World Health Organization (WHO) is systematically 05. The poor response by women is partly due to the fact that all women routinely receive iron and folate supplements. The lack of macronutrients may also dilute any benefit from the supplements. collecting micronutrient statistics and program results to provide an international database for programmers. sIGHT AND LIFE | VOL. 26 (1) | 2012 “ Poor diets potenti ally limit human growth and development, and health is also impaired direct ly or indirect ly ” 29 30 Multiple Micronutrient Nutrition Introduction Multiple micronutrient (MMN) preparations have been introduced to overcome the inadequacies of single micronutrient interventions to improve the diet. Their use has not been entirely successful, in that the effects of MMN have not always shown the expected added benefit over single nutrients. In 2010, a symposium was organized in Portugal at the 2nd World Congress of Public Health Nutrition to examine some of the issues emerging in workers’ attempts to incorporate MMN nutrition into effective programs. In the article below, I discuss some of the highlights from the papers presented. The rationale for MMN supplementation Single nutrient intervention studies to prevent those deficiencies with the greatest public health importance, namely vitamin A and iron, have been carried out in many parts of the world. The variable responses in different populations have led researchers to speculate that they are due to other limiting dietary nutrients. This seemingly reasonable explanation is understandable, since a diet that lacks a specific nutrient is quite likely to be poor, i.e. lacking in variety and /or quantity. Vitamin E, for example, is present in almost every food we eat, as it is a component of plant and animal membranes, and serious deficiencies are rare. Vitamin A, on the other hand, is more limited in its distribution. It occurs in its precursor form, β-carotene, in green vegetables and orange /yellow fruits, and it is present in small amounts as retinol or retinyl esters in animal products, such as liver, meat, milk and eggs. If diets are poor in meat products, not only is the risk of vitamin A deficiency increased, but also the risk of other micro- and macronutrient deficiencies is raised. Animal products also supply fat to the diet, which is not only an important source of energy but also a vehicle to enhance the absorption of fat-soluble vitamins and β-carotene. Thus, the absence of animal or fish products in a diet potentially impairs the utilization of other nutrients from other foods – that is, poor diets potentially limit human growth and development, and health is also impaired directly or indirectly. Eleven papers describe the symposium proceedings.1 The first paper presents an overview of the issues discussed,2 while the second traces the evolution of thought that brings us to where we are today.3 Dr Ross4 tackles one of the thorny issues that programmers overlook – namely, the need to justify an intervention and its methodology experimentally before embarking on human trials. Dr Lietz also outlines the need for experimental work to define the genetic profile of a target population, where individual differences may influence the outcome of the intervention.5 Three papers discuss MMN interventions, in terms of the need,6 the evidence from randomized controlled studies (RCT) for the effects of MMN interventions in developing countries,7 and the use of nutritional biomarkers for program evalu- ation8 . One paper is devoted to the evidence obtained from program experience on the use of MMN powders.9 The final three papers look at the issues around how to identify appropriate “platforms” or mechanisms for the delivery of MMN (health, agriculture, market-based and social protection),10 considerations concerning efficacy, adequacy and plausibility when examining the results of MMN trials with a view to planning further implementation11 and, finally, translating research into action.12 The need for MMN supplements The term “multi-micronutrient” first appeared in the 1950s and was synonymous with essential nutrients, i.e. trace elements and vitamins.3 In the proceedings, several of the authors point out that very little is known about current MMN status in most of the countries of the developing world, with the exception of vitamin A, iron and iodine. The real needs are therefore not known; the rest of the micronutrients in MMN supplements are there “just in case.” That is, after providing nutrients to prevent nutrient deficiencies known to be present in a population, the growth and development of the recipients is not restricted by the deficiencies of other micronutrients. As a result, the major donor agencies have designed the MMN supplement to provide a mixture of nutrients that provide enough of each ingredient to meet the recommended nutrient intakes of each component, as shown in Table 1 for pregnant and lactating women,13 and for children aged six to 23 months.14 There is, however, one drawback, namely that the supplement is designed for individuals who receive adequate amounts of the macronutrients energy, protein and fat, although poor responses to MMN supplements suggest that that might not always be the case.11 “Most of the investigative work on MMN status internationally was carried out in the 1950s and 1960s” Most of the investigative work on MMN status internationally was carried out in the 1950s and 60s, after the formation of the Interdepartmental Committee on Nutrition for National Defense (ICNND) in the United States. Nutritional surveys were conducted by the ICNND in 33 countries in which the United States had strategic interests. The survey manual for these studies outlined the main physical signs for the detection of malnutrition and described biochemical methods for the detection of hemoglobin, serum vitamins A and C, urinary riboflavin and thiamin. The results showed that micronutrient deficiencies, especially anemia and vitamin A and iron deficiencies, were highly prevalent in many countries. Dr Richard Semba,3 however, points out that there were no cross-tabulations of results, i.e. the existence MuLTIPLE MICRONuTRIENT NuTRITION SIGHT AND LIFE | VOL. 26 (1) | 2012 TABLe 1: Multi-micronutrient supplements for pregnant and lactating women Supplementary Formulation for pregnant and Micronutrient powder for children 6 –24 months of age b micronutrient lactating women a Multi-micronutrient formulation Vitamin A μg RE Vitamin D μg Nutritional anemia formulation 800 400 300 5 5 – Vitamin E mg 10 5 – Vitamin C mg 70 30 30 Vitamin B1 mg 1.4 0.5 – Vitamin B2 mg 1.4 0.5 – Niacin mg 18 6 – Vitamin B₆ mg 1.9 0.5 – Vitamin B12 μg 2.6 0.9 – Folic acid μg 400 150 c 160 c Iron mg 30 10 12.5 Zinc mg 15 4.1 5 Copper mg 2 0.56 – 65 17 – 150 90 – Selenium μg Iodine μg Amounts recommended by uNICEF/WHO/uNu for pregnant and lactating women in developing countries for 6 and 3 months respectively.13 One sachet contains 1 Recommended Nutrient Intake (RNI) in ~1 g and is consumed in one day.14 Frequency of consumption will depend on estimated child needs and programmatic feasibility for delivery. So 90 sachets for a 6 month period will provide on average 3 – 4 sachets per week or an additional intake of 50% of the RNI for each micronutrient/day. c Dietary folate equivalents a b of multiple deficiencies in individuals was not calculated. It is interesting that the nutritional information that stimulated the ICNND surveys arose from a nutritional survey in Korean army troops, which showed a high prevalence of many micronutrient deficiencies. young men are not usually the group within a community to show evidence of micronutrient deficiencies. However, at that time the army rations for the Korean troops were, no doubt, modeled on local preferences and food availability. Troops restricted to barracks would have had little opportunity to supplement their diets. History has shown that groups of people living in restricted circumstances are more susceptible to malnutrition than people eating similar diets, but without physical restriction of their movements. For example, thiamin deficiency has been reported in children living in boarding schools, prisoners in jail15 and Chinese laborers working in the tin mines of Malaya,16 while vitamin C and thiamin deficiency was found in early migrants to North America who were restricted by the long cold winter months to their cabins, with minimal food.17 Where diet is restricted through ignorance, poverty or social or environmental circumstances, quality deteriorates and the risk of dietary deficiencies increases.3 To what extent do the revelations of the 1950s apply today? It is estimated that two billion people worldwide are anemic18 and, similarly, that millions are affected by iron deficiency and deficiencies of other nutrients, such as vitamin A and zinc.6 Programs tend to focus on iron, iodine and vitamin A and, to a slightly lesser extent, on zinc and folic acid, because evidence of their deficiencies exists and they have important functional outcomes of public health concern. Semba, however, illustrates the strong circumstantial evidence for the existence of other micronutrient deficiencies in people who are extremely poor (Figure 1). The figure, based on the work of Bloem and colleagues in Indonesia, shows that, if rice is virtually the only component in the diet of poor people, it will not meet the essential requirements of most micronutrients. The composition of cooked white rice and the recommended nutrient requirements for pre-school children are shown in Table 2. They indicate that all fat-soluble vitamins and most water-soluble vitamins and minerals need to be obtained from other items in the diet. The epidemics of beriberi that spread through Asian countries with the introduction of cheap white rice in the late nineteenth and early twentieth centuries is ample evidence that rice alone will not supply sufficient thiamin to prevent deficiency in any member of the community.19 However, despite the high likelihood of the existence of micronutrient deficiencies in developing countries, there is currently little biochemical evidence for logistic reasons (invasive blood drawing, adequate laboratory facilities, the lack of a cold chain, etc.).7 31 Multiple Micronutrient Nutrition figure 1: Influence of socioeconomic status on food consumed and the risk of micronutrient deficiencies Risk of micronutrient deficiencies Relative composition of the diet n ke ic ef Be il k Ch gs M Eg Fi sh r l ga Oi Su it et Fr u Ve g Ri ce ab le s Socioeconomic status LOW Fr able ui s t Su ga r Oi l Fi sh Eg gs M il k Ch ic ke Be n ef et Ve g Ri ce NOT POOR Ve ge Fr tab ui le s t Su ga Oi r l Fi sh Eg gs Ri ce LESS POOR Ri Ve ge Fr tabl ui e s t Su ga Oi r l Fi sh HIGH ce MODERATELY POOR et Fr abl ui e s Su t ga Oi r l Ve g ce VERY POOR Ri 32 EXTREMELY POOR Diagram to illustrate the association between the relative composition of the diet and the risk of micronutrient deficiencies (with acknowledgements to Dr R Semba and the Journal of Nutrition3) VERY HIGH MuLTIPLE MICRONuTRIENT NuTRITION SIGHT AND LIFE | VOL. 26 (1) | 2012 TABLe 2: Nutrient composition of cooked, long-grain ricea and daily recommended nutrient intakes (RNI) for pre-school childrenb Energy and fat-soluble vitamins Rice Energy Vitamin A Water-soluble vitamins RNI 130 kcal 1198 kcal 0.55 MJ 5.0 MJe 0 400 – 450 (μg RE)c Carotene 0 None available 0.1 5.0 d 0 5.0 (mg) Vitamin D (μg) Thiamin RNI 0.16 0.5 – 0.6 (mg) (μg RE) Vitamin E Minerals Rice Riboflavin 0.01 0.5 – 0.6 1.5 6.0 – 8.0 1.2 4.2 –12.6 0.09 0.5 – 0.6 97 150 – 200 0 0.9 – 1.2 0 30 – 35 Zinc 0.49 2.9 – 9.6 6 17 – 22 (mg) (mg) Pyridoxine RNI (mg) (mg) Niacin (total) Iron Rice Selenium (μg) (mg) Folate (μg dietary folate equivalents) Vitamin B₁₂ (μg) Vitamin C (mg) Values shown are for 100 g 43 Values shown cover the age range from 1–6 years and allowances for low to high bioavailability in the case of zinc and iron44 c RE are retinol equivalents d mg α-tocopherol e RNI for energy is an average to cover the age range and differences between the sexes from 3.9 to 6.6 MJ/day45 a b “What may be adequate in one person or dietary environment may not be in another” MMN requirements when planning interventions The consequences of micronutrient limitations are also influenced by physiological requirements and bioavailability; what may be adequate in one person or dietary environment may not be in another. Infants, children and pregnant or lactating women have higher requirements than other groups in the population, relative to energy requirements, and thus are especially vulnerable to the effects of deficiencies when the diet is poor. However, even mild deficiencies in children may impair both physical and mental development. Seasonal factors are also extremely important in influencing the effects of a supplement on nutritional outcome and should be considered when planning an intervention. Ross argues that public health nutrition has lagged behind many of the other health sciences in embracing animal models to better understand clinical disease. She argues that human micronutrient intervention studies should be tested experimentally first, to refine the design (Table 3).4 However, the investigations outlined in Table 3 are particularly relevant to highdose, one- or two-nutrient(s) studies, such as the α-tocopherol, β-carotene (ATBC) study,20 but could equally apply to the Pemba trial, where doses akin to requirements were used.21 In the ATBC study, 20 mg β-carotene was given daily to smokers, while children in the Pemba study received 12.5 mg iron. In both, there were adverse effects of treatment. Ross believes that animal studies to pre-test and refine such interventions might have led to a better outcome.4 Both studies were done in subjects potentially exposed to high levels of inflammation: tobacco smoke in the ATBC study and endemic malaria in the Pemba trial. Inflammation alters the serum concentrations or biomarkers of many nutrients (Table 4) and is a factor which is commonly overlooked in micronutrient studies. In such cases, it is easy to assume that deficiency exists, especially when there is uncertainty concerning the dietary supply of most nutrients or sunlight irradiation, as in the case of vitamin D, or a limited knowledge of lifestyle factors. Not only do 33 34 MuLTIPLE MICRONuTRIENT NuTRITION TABLe 3: Some advantages from conducting animal studies prior to human intervention trials ⁴ Objective to investigate Potential outcome /advantage for human study Dose range > Better dose selection if only a single dose can be tested Single versus multi-nutrient > Better understanding of interactive effects; better selection of treatments to be included or not needed Variability > Better power analysis to assure adequate sample size Biomarker testing > Better biomarker selection Direct testing on tissues that are not available in human studies > Better understanding of physiological effects underpinning observed outcomes Long-term follow-up > Better understanding of potential safety and efficacy in vivo depressed concentrations of serum nutrients contribute to overestimates of those at risk of deficiency, but supplements may antagonize a potentially protective physiological mechanism. Two recent studies in malaria-endemic areas have both shown the adverse effects of iron-containing supplements: the Pemba study21 and a second in a rural area of the Handeni District in Tanzania.22 In both cases, iron was given with folic acid and, in Tanzania, 30% of children displayed sub-clinical inflammation (CRP > 8 mg/L). Inflammation is known to influence both zinc and iron metabolism and the serum concentrations of both nutrients fall substantially within the first 24 hours following the onset of infection.23 Iron was associated with adverse effects in both studies, but not the zinc supplement. Likewise, folate was probably not linked to the adverse effects, since earlier iron supplementation studies did not include folate but still increased the risk of malaria.24,25 Furthermore, inflammation is not known to have any effects on serum folate.26 Lastly, an important observation in the Tanzanian study was that the increase in malaria TABLe 4: Serum micronutrients and biomarkers influenced by inflammation Group Serum biomarker Effect of infection / inflammation Fat-soluble micronutrients Retinol a > Rapid fall in serum concentration 25-Hydroxy-cholecalciferolb > Rapid fall in serum concentration Water-soluble micronutrients Minerals Carotenoids > Low concentrations associated with inflammation Vitamin C > Rapid fall in serum concentration Vitamin B₆ > Low concentrations associated with inflammation Iron > Rapid fall in serum concentration Zinc > Rapid fall in serum concentration Selenium > Low concentrations associated with inflammation Copper > Slow rise in concentration associated Hemoglobinc > Low concentrations associated with inflammation Ferritinc > Rapid rise in serum concentration Transferrin receptorsc > Low concentrations associated with inflammation Zinc protoporphyrinc > Low concentrations associated with inflammation Ceruloplasmind > Slow rise in concentration associated with inflammation Mineral biomarkers with inflammation Retinol is an important biomarker of vitamin A status 40 25-Hydroxy-cholecalciferol is the biomarker of vitamin D status 46 c Biomarkers of iron status 41,47 d Biomarker of copper status a b sIGHT AND LIFE | Vol. 26 (1) | 2012 occurred in iron-deficient children and not in those that were replete;22 this is contrary to the findings of the Pemba study, which suggested that iron-replete children on iron supplements were more at risk from malaria. It has been suggested that the results of the Pemba trial could have been predicted,27 but they also illustrate that much more research is needed to understand the influence of nutrients on children exposed to disease and, especially, to malaria. In contrast to the two supplementation studies, a study using Sprinkles™ to supply similar amounts of iron (12.5 mg/day) in a malaria-endemic area in Kenya showed moderate reductions in anemia and no adverse effects of treatment based on hospital admissions.28 The MNP was given with food and therefore may be better managed by a child than a concentrated dose of iron, as provided by a capsule or tablet. However, it is doubtful if the use of the MNP was as regular in Kenya as it was in Pemba or Handeni, as the intervention was dependant on consumer purchases. Although almost 90% of the children had used Sprinkles™ in the period studied, over 60% only used it a little more than once a week.29 In supplementation studies, most nutrients are supplied in the form in which they are needed by the body; however, in the case of vitamin A, trials involving β-carotene have been done, especially in women of reproductive age, as vitamin A in this form is not teratogenic. However, Lietz and colleagues described some previously unexpected limitations in the enzyme converting β-carotene to retinal in this supplement. They showed that there are a number of phenotypic variations of the enzyme responsible for converting β-carotene to retinal that reduce the catalytic activity.5,30,31 The distribution of some of these enzyme variations with the poorer catalytic activity may also differ depending on ethnic origin, being more common in Asian (70%) than European/American (30%) or African (20%) populations.5 These observations reinforce the call for experimental work to precede human intervention where trials with β-carotene are involved. “People who are replete are less likely to respond to MMN supplements and the effect will dilute the overall response to an intervention program” Factors affecting MMN delivery The objective of the paper by Neufeld and Cameron6 was to review the information from dietary intake, serum biomarkers and formal and informal health systems that can be used to identify the need for and assist in designing micronutrient programs. Multiple Micronutrient Nutrition They point out that most biomarkers identify deficiency and cannot be used to assess whether intakes are optimized or in excess. The inability to assess whether iron intakes are optimal from iron biomarkers is particularly well illustrated in communities where hemoglobinopathies are common (see below). The authors recognized the confounding effects of inflammation on ferritin, but failed to note that several other important micronutrients are affected by inflammation or that depression of serum vitamin concentrations through inflammation can lead to overestimations of nutrient deficiencies (Table 4). People who are replete are less likely to respond to MMN supplements and the effect will dilute the overall response to an intervention program. In the case of diet, they recognize that there are many ways to calculate nutrient intake (information from consumers, wholesalers, importers, etc.) but that bioavailability is more difficult to estimate, as uptake by the body depends on multiple factors. So, in the case of iron, there are facilitators and inhibitors (vitamin C and phytate, respectively) and the type of iron used will also influence bioavailability. However, dietary data are particularly scarce for those regions of the world with higher vulnerability to micronutrient deficiencies: the authors only found published data for five countries in Africa, four in South and Central America and four in South East Asia. Hemoglobinopathies also influence iron metabolism.32 Thalassemia mutations are extremely common in South East Asia and the Middle East: up to 25% of Thai people are carriers of α-thalassemia; there are regions of Thailand, Laos and Cambodia where up to 60% of people are carriers of hemoglobin E (HbE);33 and there are many millions of people in China who are carriers of the α- and β-thalassemia gene.34 People who carry the homozygote or compound heterozygotes (HbE/βthalassemia) of these genes display ineffective erythropoiesis, which stimulates iron absorption even if stores are adequate, and have an increased risk of iron excess. Recent work with heterozygotes of these conditions suggests that some may also display similar, although milder, characteristics32 and a higher risk of anemia.33 In heterozygotes for α- or β-thalassemia, iron utilization is lower than in controls and iron absorption is not appropriately regulated, despite modestly higher concentrations of serum ferritin and storage iron. In the compound heterozygote (HbE/β-thalassemia), iron utilization was depressed, iron absorption and body iron stores were markedly higher and additional dietary iron would not be beneficial, despite the presence of anemia. In people carrying the HbE trait (heterozygotes), the most common hemoglobinopathy in Thailand, iron utilization and absorption did not differ from that of the controls. Thus, in regions where there is a high prevalence of these traits, particularly the thalassemias, iron should be targeted at groups vulnerable to iron deficiency (women and children). If food fortification with iron is used, iron stores should be moni- 35 36 MuLTIPLE MICRONuTRIENT NuTRITION TABLe 5: Population biomarkers for nutrients vitamin A, iron, zinc, folate and vitamin B12 Nutrient Measurement of statusa Vitamin A > Serum retinol and history of night blindness > Supported by dose response test in subsample if possible Iron > Hemoglobin and serum ferritin > Supported by serum transferrin receptors and zinc protoporphyrin > Supported by indicators of underlying infection to interpret serum ferritin Folate > Serum folate and red blood cell folate Vitamin B12 > Serum B12 a Dietary intake should be determined as an indicator of nutrient deficiency and underlying infection should be measured using the acute phase proteins, serum C-reactive protein and α1-acid glycoprotein.40,41 See also Table 4 for influence of inflammation on biomarkers. tored in groups with a low iron turnover, such as men or postmenopausal women, to detect excessive exposure, if present.32 Knowledge of other programs ongoing within countries and of global data resources may help to design context-appropriate interventions to improve micronutrient status. Within-country programs may also provide access to pre-existing structures within countries. There are also national and other sources of data available from WHO and uNICEF, such as Multiple Indicator Cluster Survey (MICS) reports to assist in planning trials and Vitamin and Mineral Nutrition Information System (VMNIS),12 Department of Health Surveys (DHS), reports from ministries and non-governmental organizations and peer-reviewed literature. (See also the paper on WHO activities in this supplement.)12 These provide data of varying quality and usefulness, but should be used to identify the need and its location within country. They emphasized that monitoring and evaluation systems should be in place to detect changes in micronutrient status over time. Consistent collection and reporting of such information would allow for more accurate mapping of nutritional shortfalls and provide information on whether existing interventions are meeting the required need.6 Where are we now? The objectives of the review by Christian and Tielsch were, first, to show the role of statistical methods to demonstrate the efficacy of nutritional intervention in the developing world and, secondly, to summarize some of the evidence for the beneficial impacts of MMN supplements in pregnant women and young children on a number of outcomes.7 A randomized control trial (RCT) is considered the gold standard to evaluate the efficacy of a nutritional intervention. The key characteristic is the concept of comparing like with like. That is, the intervention and control groups should have the same degree of risk for the outcome being examined. Ideally, neither the investigators nor the subjects will be aware of who is receiving which treatment, to avoid introducing bias. In addition, subjects are randomly allocated to the treatment groups, which can be at the level of the individual or, in large trials, at a village or community level. However, comparability, blinding and randomization alone are not sufficient to guarantee a satisfactory result, since factors specific to a community (infections such as malaria, exposures such as arsenic, aflatoxin or genetic conditions such as hemoglobinopathies) may obscure any differences in the outcome of the intervention. There is therefore also a need to replicate RCTs under different settings. Data from RCTs are analyzed by metaanalysis or systematic reviews to provide an average effect for the outcome of interest. In the case of systematic reviews, the data included will be restricted to only those studies that meet defined criteria.7 “The impact on birth weight was larger in women with a higher BMI and there was also an increase in large-for-gestational-age births” In the last decade, there has been a global interest in establishing the efficacy of the united Nations International Multiple Micronutrient Preparation (uNIMAPP) formulation of 15 micronutrients for pregnancy (Table 1).13 Meta-analyses of the effects of antenatal MMN supplements in 12 RCTs35,36 revealed a small but significant increase in birth weight (22.4 g, 95% CI 8.3, 36.4) and an 11% reduction in low birth weight (CI 3,19). There were no significant effects on preterm births or prenatal mortality. The uNIMAPP preparation was tested in nine of the trials. However, the fact that all trials were largely conducted using the standard sIGHT AND LIFE | Vol. 26 (1) | 2012 of care of iron-folic acid as the control groups probably accounts for the small effects. That is, folate and iron deficiencies are the major micronutrient deficiencies in pregnant women in developing countries and the addition of other micronutrients had little impact on birth outcomes. However, an important observation was that the impact on birth weight was larger in women with a higher BMI. There was also an increase in large-for-gestationalage births.35 Habicht and Pelto suggest that the latter observations may indicate that many women were also deficient in one or more macronutrients and therefore could not benefit fully from the supplement.11 In children, MMN as supplements, powders or fortified readyto use foods are being used to address MMN deficiencies in developing countries. Outcomes of interest range from birth weight to child growth, infant morbidity, mortality and nutrient status and cognitive function. Christian and Tielsch reported that comparisons of height/length or weight for those receiving three or more micronutrients, compared to fewer micronutrients, found small effects of 0.13 cm (0.06, 0.21) and 0.14 g (0.03, 0.25) respectively. There was little evidence of effects on morbidity or cognitive function7 and other workers also report that evidence for the effectiveness of micronutrient supplements given as powders (MNP) in large-scale programs on these outcomes is scarce.9 The efficacy of MNP in the treatment of anemia in moderately anemic children and well-controlled trials has been clearly demonstrated.37 Nevertheless, information about the impact of MNP in large-scale programs is scarce. The aim of the paper by Rah and colleagues was to briefly review experience and data collected during impact evaluation in recent large-scale MNP programs. More than 80 MNP programs have been carried out at sub-national or pilot scale, targeting children under five years of age and conducted in many different countries across several regions. Most programs have been implemented either in refugee camps or as part of an emergency response. They report that consumption of 90 sachets by a child within a flexible time-frame of 90 to 180 days is considered sufficient to improve micronutrient intake to approach recommended levels (Table 1). The recommendation of 60 doses over two to four months is efficacious in reducing anemia; however, these results were obtained under controlled conditions. The joint statement recommended 15 micronutrients38 and, in general, that composition was maintained in the MNP in different studies, except where there were known to be other components in the diet or environment that might compete (malaria, tannins and phytic acid) or lead to an excess (on-going supplementation programs, fortified foods, e.g., vitamin A in oil, etc.) when small changes were made. Examples of the changes made to maintain the availability of the MNP contents are provided by the authors.9 Multiple Micronutrient Nutrition “Because anemia is influenced by so many factors, hemoglobin may not be the most appropriate biomarker to use” The impact of MNP (MixMe™) is reported in a number of refugee camps. The main outcome assessed was hemoglobin concentration, as a proxy indicator of micronutrient deficiencies, and anthropometric measurements and morbidity in the prior two weeks, to assess nutritional status and health. In all cases, prevalences of anemia were high (> 45%) at the start but, after the introduction of MNP, some results increased, some fell and others did not change. There was mostly a small positive effect of MNP on stunting and, in one camp, there was evidence that the cumulative incidence of diarrhea fell over three years. Subjects were mostly used as their own controls in these evaluations, so other changes could have taken place to negate any impact of MNP. The authors recognized these considerations as important and suggested that, because anemia is influenced by so many factors, it may not be the most appropriate biomarker to use.9 Biomarkers of program impact evaluation in developing countries Wasantwisut and Neufeld8 outlined the activities of the program group within the Biomarkers of Nutrition for Development (BOND) initiative. In countries where micronutrient deficiencies are prevalent, the programs in place require biomarkers of exposure and status to monitor programs and evaluate impact. The goal of BOND is to provide guidance for the selection and interpretation of biomarkers that meet ranges of interests among food and nutrition stakeholders.39 The BOND group has focused on five micronutrients: iron, zinc, vitamin A, folate and vitamin B12. Although the focus of the working groups was at the population level, the individual use and interpretation of appropriate biomarkers was also discussed (Table 5). The authors also pointed out that biomarkers of micronutrients within a program context are not enough; there is a need to include proxy measures of factors that influence micronutrient utilization or metabolism, e.g., growth, dietary intake (of both nutrients and inhibitory factors like phytate) and infection rates. Biomarkers of iron, vitamin A and zinc are strongly influenced by inflammation,40,41 (Table 4) but there is no evidence for any effects on folate or vitamin B12.26 The information is needed so that program managers have a clear understanding of the situation to effectively plan and implement programs. Finally, the group suggested that program managers would benefit from specific information related to the use of biomarkers, e.g., sample size, timing and frequency of measurements to meet specific program 37 38 MuLTIPLE MICRONuTRIENT NuTRITION TABLe 6: Methods of delivery of MMN Platform of program delivery Methods Health > Tablets or syrups > Fortification > Micronutrients commercially incorporated in foods > Bio-fortification > Home fortification e.g. MNP > Diet modification Agriculture > Promote consumption of bio-fortified crops; homestead food production (HFP) generally limited in scale; HFP targeted at women to increase household availability as well as generating income from sale of crops. Market based > In many setting delivery has been through the private sector in retail markets; promotion of staple foods as well as fortified complementary foods; uncertainty as to whether can reach the poorest people. Social protection of individuals and households > CCTs (conditional cash transfers) provide monetary transfers conditional on compliance with a number of criteria e.g. attend preventive health services, maintain school-age children at school. > SFPs (school feeding programs) can be a vehicle for MMN interventions and particularly effective at reaching girls. However, they fail to reach children in the critical window of pregnancy to 24 months. objectives. Capacity development for in-country processing of samples is also required. The group considered that there was a good case for the development of a guide to encompass this information, to assist program managers to plan and implement programs. Identify ing potential programs and platforms to deliver MMN interventions to at-risk populations The paper by Olney and colleagues discussed the types of MMN intervention programs available and those that might be used more effectively to improve status.10 They identified four broad types of delivery platform (health, agriculture, market-based and social protection) (Table 6), seven performance criteria and four program elements. They discussed the critical knowledge gaps and highlighted what was needed to improve the effectiveness of current intervention methods in at-risk populations. The Health platform has been widely used to promote MMN interventions and, together with messages to promote behavioral change, has been well accepted and appropriately utilized in many countries. There has been high coverage, excellent compliance and a positive impact in reducing some micronutrient deficiencies. Programs are well targeted at women and children. However, the potential to deliver MMN intervention is largely dependent on the reliability and consistency of supplies, and inputs, well-trained health staff and sustainability may well depend on services of beneficiaries. In developing countries, these are often critical constraints. The agriculture platform is particularly suitable for promotion of the production and intake of micronutrient-rich foods, including biofortified crops. Programs have generally been successful in promoting increased intake of micronutrient-rich foods, but have been criticized for their low coverage. However, it was pointed out that the Helen Keller International (HKI) program to promote homestead food production was reported to have improved food security in five million vulnerable Bangladeshi people. Market-based programs are gaining increased attention, as it is hoped that consumer demand for the MN-rich products will promote sustainability and increase health and welfare.10 However, there is concern that a marketing approach will not reach the very poor. The marketing of Sprinkles™ in Kenya29 has shown that sellers have to be well trained to convey the right messages to consumers and must be regularly encouraged to buy stocks by inducements. Tracking of sales and use by the local population in the Kenyan study suggested that only 33% of households had purchased Sprinkles™ at the time of the visits but, although 90% of children had used MNP at some time, consumption was only ~1 sachet per week. Both increased consumer awareness of the product and a perceived benefit to the children may be needed to increase the effectiveness of a market-based approach. Olney and colleagues discussed two social protection platforms. The first, conditional cash transfer programs, have been praised for their remarkable impact on reducing poverty, food insecurity and, in some cases, gender inequalities, although they have only had a variable impact on micronutrient status.10,42 Other workers have pointed out that more research on beliefs around traditional and modern biomedical practices, socio- sIGHT AND LIFE | Vol. 26 (1) | 2012 cultural norms, gender relations and the everyday experience of poverty in many dimensions are needed to obtain a better understanding of the many influences on health care decisions, before these programs can be used to impact on micronutrient status.42 The second platform discussed was the school-feeding program as a means of intervention. The programs are popular because of the logistic simplicity of targeting schools and reaching girls before pregnancy (Table 6). The programs are not necessarily independent, since a condition of receiving a cash donation may be to ensure that girls attend school to a certain age. Multiple Micronutrient Nutrition by baseline birth weight values. They argued that present standards for implementing and interpreting RCT in nutrition needed to be re-examined. They considered that the current approach to efficacy studies did not enable the adequacy of the dose and the plausibility of the results to be assessed and they called for modifications to include intermediary behavioral and biological steps between intervention and biological outcomes. As ethical considerations will restrict much alteration in the design of human intervention studies, the request translated into a need for more experimental work to precede the human interventions. “Governments must have the political “Individuals who are replete do not will to make long-term investments in the provision of effective MMN programs for pregnant and lactating women and young children” The authors concluded that each of the systems described has the potential to deliver MMN interventions, but that much still needs to be done. Key strengths include good targeting of poor populations and, in some cases, women and children under two years of age. However, all of the programs were found to have weaknesses which should be addressed. Sustainability was believed to be most likely achieved through agricultural and/or market-based platforms and profits could potentially feed back into the system to reach the poorest of the poor. Finally, governments have to be encouraged and have the political will to make long-term investments in the provision of effective MMN programs for pregnant and lactating women and young children. Is more research needed? In the last paper in the proceedings, Habicht and Pelto questioned whether there had been sufficient scientific scrutiny of the results of RCT to justify their implementation without further research. They pointed out that the efficacy of MMN supplementation had been established by state-of-the-art RCT and that these trials had also provided strong evidence of widespread deficiencies. However, the magnitude of the impact of the trials intended to demonstrate a health benefit had generally been inadequate. The authors gave as an example the small benefits to birth weight obtained by MMN supplementation of pregnant women, where the mean added weight gain by the infants of the supplemented mothers was only 22 g.35 The authors recognized that the controls were also being supplemented with iron and folate, so any effect from the comparison of the two groups was due to the other micronutrients in the supplement. Even so, the impact of the MMN was not related to the presumed need of the infants judged respond to additional micronutrients and will clearly dilute the impact of the intervention” Adequacy and plausibility of response The authors argued that RCT, which compared MMN against iron and folate and did not contain a third group that received no intervention, was most likely to underestimate the added benefit of the other micronutrients. The danger of such a result was that the magnitude of results might not be sufficiently large to demonstrate a public health benefit for MMN. The benefit must be weighed against all the other costs of implementing the program and had to be adequate for policy considerations. The benefit or response to the MMN supplement would also be diluted by the fact that, in any population with endemic undernutrition, there will always be individuals who were not deficient. Individuals who are replete do not respond to additional micronutrients; clearly, these individuals will dilute the impact of the intervention. Other factors can also dilute the response, such as the lack of fat to enable the absorption of fat-soluble vitamins or genetic factors that impair the response to the added micronutrients. Thus, assessment of the potential to respond to an intervention requires knowledge of many factors. However, a partial solution may be to include a group of nutritionally replete individuals in the study, who are exposed to the same environmental circumstances to provide a “replete normal response.” As well as assessing the adequacy of the response, the plausibility of the results must also be interpreted. The authors argued that, where results were counter-intuitive, they should be followed up to identify the factors to explain them. They suggested that the absence of a dose response in relation to a baseline deficiency may occur because the supplement cannot be used by the people receiving the intervention. Food is not supplied in MMN trials and limitations in dietary protein and energy are very likely to diminish any response to MMN. 39 40 Multiple Micronutrient Nutrition Finally, the authors pointed out that failure to properly account for adequacy and plausibility following efficacy studies can impact on implementation. There is already evidence from the limited impact documented from the MMN efficacy trials that donors are losing interest in MMN interventions. To meet this challenge, the efficacy trial findings should be put into the context of what is already known about the essentiality of micronutrients for performance, health and survival. However, efficacy research must also be expanded and better linked to program development and implementation. The authors argued that more research is needed on the factors influencing the program impact pathway. They pointed out that understanding the relative merits of the different pathways will become overridingly important when a variety of program platforms (health, agriculture, market-based and social protection)10 are tested as potential delivery mechanisms for MMN. Translating research into action For the WHO, research is defined as the development of knowledge with the aim of understanding health challenges and mounting an improved response to them. In 2009, the WHO adopted a new process by which recommendations for safe and effective micronutrient intervention were developed, ensuring the use of best practices and available evidence. Pena-Rosas and colleagues12 outlined the steps involved, leading to the methodology to assess overall evidence quality and strength. Guidelines were being developed for iron and vitamin A supplementation, home fortification with MNP and the fortification of staple foods. The paper focused on the process currently being followed by the WHO Department of Nutrition for Health and Development to produce global guidelines on safe and effective nutrition interventions, especially in respect of micronutrients. “Appeals were made for all interventions to be monitored and reported so that others can benefit from the collective experience” cases, specific evidence that suggests that other micronutrient deficiencies co-exist. Unfortunately, randomized controlled trials of MMN in pregnant and lactating women have demonstrated only small benefits and several speakers discussed the reasons for this limited effectiveness. MNPs have been shown to be effective under controlled conditions, but their use in emergency situations produced inconsistent results. Speakers discussed the limited usefulness of some biomarkers and indicated that better biomarkers were needed for those working in the field. An appeal was made for more experimental work to precede micronutrient intervention programs, to gather appropriate background information in target populations to improve effectiveness and reduce the risk of tragedies. It was also pointed out that most programs to date had approached intervention from a health perspective. Three other options were presented, namely agricultural, market-based and social protection schemes. The authors noted some successes, but also that a lot more information was needed on biomedical practices, sociocultural norms, gender relations and everyday experience of poverty before some of these platforms could be adapted for MMN interventions. Finally, it was pointed out that the WHO is collecting information on intervention programs. The data is available to assist researchers, but appeals were made for all interventions to be monitored and reported so that others can benefit from the collective experience. Editor’s note: Workshop Proceedings: 2nd World Congress of Public Health, Portugal, 2010: Evidence in Multiple Micronutrient Nutrition: From History to Science to Effective Programs can be obtained from Sight and Life upon request. Correspondence: David I Thurnham, 46 High Street, Little Wilbraham, Cambridge, CB21 5JY, UK E-mail: [email protected] References 01.Kraemer K, Semba RD, Neuhouse M. Multiple micronutrient nutrition: Evidence from history to science to effective programs. J Nutr 2012; 142:136–209. Conclusions A workshop on MMN interventions was held in Lisbon, Portugal in 2010. The objective was to discuss the successes and shortcomings of the programs in developing countries that aim to provide up to one recommended nutrient intake (RNI) per day of the major micronutrients to women of reproductive age and young children. Vitamin A, iron and iodine deficiencies are known to affect many millions of women and children in developing countries, but there is also circumstantial and, in some 02.Kraemer K, de Pee S, Badham J. Evidence in multiple micronutrient nutrition: from history to science to effective programs. J Nutr 2012; 142:138S–142S. 03.Semba RD. The historical evolution of thought regarding multiple micronutrient nutrition. J Nutr 2012; 142:143S–156S. 04.Ross AC. Use of laboratory studies for the design, explanation, and validation of human micronutrient intervention studies. J Nutr 2012; 142:157S–160S. 05.Lietz G, Oxley A, Leung WC et al. Single nucleotide polymorphisms Multiple Micronutrient Nutrition sIGHT AND LIFE | Vol. 26 (1) | 2012 upstream from the ß-carotene 15,15'-monoxygenase gene influence 22.Veenemans J, Milligan P, Prentice AM et al. Effect of supplementa- provitamin A conversion efficiency in female volunteers. J Nutr tion with zinc and other micronutrients on malaria in Tanzanian 2012; 142:161S–165S. children: A randomised trial. PLoS Med 2011; 8:e1001125. 06.Neufeld LM, Cameron BM. Identifying nutritional need for multiple micronutrient interventions. J Nutr 2012; 142:166S–172S. 07.Christian P, Tielsch JM. Evidence for multiple micronutrient effects based on randomized controlled trials and meta-analyses in developing countries. J Nutr 2012; 142:173S–177S. 08.Wasantwisut E, Neufeld LM. Use of nutritional biomarkers in program evaluation in the context of developing countries. J Nutr 2012; 142:186S-190S. 09.Rah JH, de Pee S, Kraemer K et al. Program experience with micronutrient powders and current evidence. J Nutr 2012; 142:191S–196S. 10.Olney DK, Rawat R, Ruel MT. Identifying potential programs and doi:10.1371/journal.pmed.1001125. 23.Beisel WR. Trace elements in infectious processes. Med Clin North Am 1976; 60:831–849. 24.Smith AW, Hendrickse RG, Harrison C et al. The effects on malaria of treatment of iron-deficiency anaemia with oral iron in Gambian children. Ann Trop Paed 1989; 9:17–23. 25.Oppenheimer SJ, Gibson FD, MacFarlane SBJ et al. Iron supplementation increases prevalence and effects of malaria: report on clinical studies in Papua New Guinea. Trans R Soc Trop Med Hyg 1986; 80:603–612. 26.Galloway P, McMillan DC, Sattar N. Effect of the inflammatory platforms to deliver multiple micronutrient interventions. J Nutr response on trace element and vitamin status. Ann Clin Biochem 2012; 142:178S–185S. 2000; 37:289–297. 11.Habicht JP, Pelto GH. Multiple micronutrient interventions are efficacious, but research on adequacy, plausibility, and implementation needs attention. J Nutr 2012; 142:205S–209S. 12.Pena-Rosas JP, De-Regil LM, Rogers LM et al. Translating research 27.Oppenheimer SJ. Comments on background papers related to iron, folate, malaria and other infections. Food Nutr Bull 2007; 28:S550–S509. 28.Suchdev PS. Nyando integrated child health and education project. into action: WHO evidence-informed guidelines for safe and effec- 2009. Nairobi, 4th Africa Nutritional Epidemiology Conference tive micronutrient interventions. J Nutr 2012; 142:197S–204S. <http://imtf.org/blog/2010/10/29/ANEC%204%20Nairobi%20 13.UNICEF/UNU/WHO. Composition of a multi-micronutrient supplement to be used in pilot programmes among preg- Declaration>. 29.Suchdev PS, Ruth L, Obure A et al. 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Encyclopedia of Human Nutrition. 2nd ed. Oxford: Elsevier; 2005. 269–278. 20.Rowe PM. Beta-carotene takes a collective beating. Lancet 1996; 347:249. 21.Sazawal S, Black RE, Ramsan M et al. Effects of routine prophylactic 34.Angostiniosis M, Modell B. Global epidemiology of hemoglobin disorders. Ann N Y Acad Sci 1989; 850:251–269. 35.Fall CH, Fisher DJ, Osmond C et al. Multiple micronutrient supplementation during pregnancy in low-income countries: a metaanalysis of effects on birth size and length of gestation. Food Nutr Bull 2009; 30:S533–S546. supplementation with iron and folic acid on admission to hospital 36.Ronsmans C, Fisher DJ, Osmond C et al. Multiple micronutrient and mortality in preschool children in a high malaria transmission supplementation during pregnancy in low-income countries: a setting: community-based, randomised, placebo-controlled trial. meta-analysis of effects on stillbirths and on early and late neonatal Lancet 2006; 367:133–143. mortality. Food Nutr Bull 2009; 30:S547–S555. 41 42 MuLTIPLE MICRONuTRIENT NuTRITION | OPINION 1 37. De-Regil LM, Suchdev PS, Vist GE et al. Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age. Cochrane Database Syst Rev 2011; 9:CD008959. 38. WHO/WFP/UNICEF. Preventing and controlling micronutrient deficiencies in populations affected by an emergency. 2010. Internet, http://www.who.int/nutrition/publications/WHO_WFP_UNICEFstatement.pdf. 39. Raiten DJ, Namaste S, Brabin B et al. Executive summary--Biomarkers of Nutrition for Development: Building a Consensus. Am J Clin Nutr 2011; 94:633S-650S. 40. Thurnham DI, McCabe GP, Northrop-Clewes CA et al. Effect of subclinical infection on plasma retinol concentrations and assessment of prevalence of vitamin A deficiency: meta-analysis. Lancet 2003; 362:2052-2058. 41. Thurnham DI, McCabe LD, Haldar S et al. Adjusting plasma ferritin concentrations to remove the effects of subclinical inflammation in the assessment of iron deficiency: a meta-analysis. Am J Clin Nutr 2010; 92:546-555. 42. Adato M, Roopnaraine T, Becker E. Understanding use of health qualitative research in Latin America and Turkey. Soc Sci Med 2011; 72:1921-1929. 43. National nutrition database for standard reference. [Release 24]. 2011. http://www.ars.usda.gov/bhnrc/ndl, United States Department of Agriculture. 44. FAO/WHO. Vitamin and mineral requirements in human nutrition. 2ed. 2004. http://www.who.int/nutrition/publications/ micronutrients/9241546123/en/index.html, Geneva: World Health Organisation, 2004. 45. FAO/WHO/UNU. Human energy requirements Report of a Joint FAO/ WHO/UNU Expert Consultation. http://www.fao.org/docrep/007/ y5686e/y5686e06.htm#bm06.4, Geneva: World Health Organisation, 2001. 46. Reid D, Toole BJ, Knox S et al. 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Shibani Ghosh and Jeffrey B Blumberg Friedman School of Nutrition Science and Policy Tufts university, Boston, MA, uSA In Response to: Evidence in Multiple Micronutrient Nutrition: From History to Science to Effective Programs David I Thurnham Northern Ireland Centre for Food and Health university of ulster, Coleraine, uK Despite substantial evidence collected for over a hundred years concerning the impact of micronutrient deficiencies on health, and some notable successes, such as the fortification of staple foods in North America and Europe, efforts to control micronutrient deficiency disorders only gained prominence in the international nutrition community at the beginning of the 1980s.1, 2 This situation has been attributed to the hidden nature of the ef- fects of complex micronutrient disorders; the slow generation of a suitable evidence base; and the emphasis on treating clinical manifestations of malnutrition associated with specific macroand micronutrients with supplementation or fortification.1 We now have a greater understanding of common multiple and concurrent deficiencies, but we continue to debate important issues regarding the need for basic and applied research, along with the ways to identify the most effective approaches to program implementation.3 In this issue of Sight and Life magazine, Dr David Thurnham provides a comprehensive overview of a workshop held during the 2nd World Congress of Public Nutrition in September 2010 in Portugal that examined the current knowledge, gaps and future needs concerning multiple micronutrient (MMN) programs.4 It is clear that we must soon address several crucial areas to generate an actionable evidence base for MMN and more quickly translate this into effective policies and programs. For example, on a translational level, we need to understand the role of inflammation and infection in altering MMN needs and utilization and the factors that affect the targeting and delivery of MMN