Nutrition Publication

NNIW70 - Meeting Micronutrient Requirements for Health and Development

Editor(s): Z. Bhutta, R. Hurrell, I. Rosenberg. 70

The 70th Nestlé Nutrition Institute Workshop focused on the importance of nutrition in the first 1000 Days. It was addressed that maternal and fetal deficiencies can induce inadequate metabolic programming in the offspring with increased risk for non-communicable diseases later in life. In order to answer questions and lead scientific discussions, we asked world-renowned experts in the area of health science and nutrition to clarify the pathogenesis of micronutrient deficiencies in pregnancy and childhood, preventive methods and strategies, and opportunities for treatment. 

Related Articles

Global Micronutrient Deficiencies in Childhood and Impact on Growth and Survival: Challenges and Opportunities

Author(s): A. Imdad, Z. A. Bhutta

Despite numerous advances and improvements in child health, malnutrition still remains as one of the main public health challenges of the 21st century, particularly in developing countries. It undermines the survival, growth and development of children and is associated with almost 35% of all deaths in children under the age of five worldwide. An estimated 178 million children are stunted globally and an additional 19 million children have severe acute malnutrition (wasting). Many of these conditions are associated with concomitant micronutrient deficiencies and among these, Vitamin A, iron, Zinc and Iodine deficiencies are the most prevalent in childhood DALYs. Recent data on the timing of growth retardation and stunting in infants suggest that the onset is commensurate with inappropriate complementary feeding and potentially compounded by maternal undernutrition and intrauterine growth retardation, and that the first 24 months represent a critical window of opportunity for intervention. Given the wide prevalence of multiple micronutrient deficiencies in malnourished children in developing countries, the challenge is to implement intervention strategies that combine appropriate infant and young child feeding with micronutrient interventions at scale. Emerging data from community intervention trials now provide evidence that this is both tangible and can lead to alleviation of childhood undernutrition. Some of these recent findings will be discussed. 

Micronutrients in the Treatment of Stunting and Moderate Malnutrition

Author(s): M. Penny

Linear growth retardation or stunting may occur with or without low weight- for- age, but in both cases stunted or moderately malnourished children are deficient in micronutrients. Pregnancy and the first 2 years are critical periods. Dietary deficiency of zinc, iron, calcium, and vitamin A are especially common and often occur together. Zinc is essential for adequate growth, and supplements have been shown to increase intrauterine femur length and to prevent stunting. However, in general, supplements which provide a mixture of micronutrients have been more successful in preventing stunting and are simpler to take and distribute. Multiple micronutrients together with energy and macronutrients are also needed for the management of moderate malnutrition. Multiple micronutrients may be delivered as medicinal- like supplements, but may also be combined with food, for instance in milk drinks, in fortified dried cereal mixes used to supplement complementary foods or in lipid nutrition supplements. The latter also provide essential fats necessary for growth. Micronutrient powders for home fortification are effective in preventing anemia, but present combinations do not prevent stunting. Improving the diets of infant and young children is also possible, and increased intake of animal source foods can improve growth.

Zinc Requirements: Assessment and Population Needs

Author(s): K. M. Hambidge

Reliable estimates of zinc requirements have assumed greater priority as the global public health importance of preventing zinc deficiency has gained increasing recognition.  On a global public health basis our first most evident goal is reliable estimates of average population requirements. Despite expectations of rapid advances towards more simple and sophisticated strategies, estimations of zinc requirements continue to depend on a factorial approach.  Since the Dietary Reference Intakes (DRIs) were published there have been important advances in techniques for the factorial approach but also confusion of global dimensions resulting from the subsequent publication of grossly conflicting ‘international’ estimates.  The reasons for these differences have now been fully elucidated removing an obstruction to continuing progress and refinements of our knowledge base.  A key advance has been the development and validation of a model that can be simply applied to determine the inhibitory effects of phytate on zinc absorption.  Better understanding of maternal and young child zinc requirements continues to present a challenge of special importance.  

Role of Zinc in Child Health and Survival

Author(s): R. Black, C. Fischer Walker

Zinc deficiency is a prevalent global condition with serious consequences for child health and development.  When severe it causes short stature, immune compromise, infectious disease complications and shortened life expectancy. Even less severe zinc deficiency results in important health problems. Zinc deficiency is one determinant of stunted linear growth and may impede children from reaching their developmental potential. Children with zinc deficiency are more susceptible to infections. Numerous trials comparing oral zinc supplements with placebo have been done. A recent meta-analysis found that zinc supplemented children had a 20% lower incidence of diarrhea than unsupplemented children. The benefit appears to be greatest for preschool children 12 months of age or greater and for those who were more stunted at enrollment.  Children with zinc deficiency are also more susceptible to acute lower respiratory infections (ALRI)/pneumonia. Meta-analysis of randomized controlled trials of daily or weekly zinc supplementation found a 35% reduced incidence of ALRI using specific clinical criteria for the outcome.  As with diarrhea, children who are stunted may benefit more.  Zinc deficiency may also put children at risk of more severe clinical malaria, although the data are still limited for this outcome.  Stimulated by the proven preventive effects of zinc for diarrhea and ALRI, zinc has also been tried as adjunctive treatment for diarrhea and pneumonia. The most recently published systematic review found that the duration of diarrhea is shortened by 20% by providing zinc along with oral rehydration solution. Several of these diarrhea treatment trials have also shown a reduction in the incidence of diarrhea and pneumonia in the 2-3 months following the treated diarrhea episode. An initial trial in children with severe pneumonia showed that zinc as adjunctive treatment along with antibiotics shortened the duration of the illness; however, two subsequent trials have not replicated this benefit. Several additional trials are underway to determine if there is a therapeutic benefit for pneumonia.  Large trials of zinc for treatment of diarrhea over a 1-2 year period in Bangladesh and India have shown a reduction in hospitalizations and child deaths. Additional evidence for an effect of zinc supplementation comes from preventive trials conducted in Zanzibar and Nepal. These trials along with several smaller one have been subjected to a meta-analysis. While there was no effect on child mortality in infants 1-11 months of age, preschool children 12 months old or more had an 18% reduction in all-cause mortality. Further analysis suggests that there is a reduction in diarrhea and pneumonia cause-specific mortality in these trials. Zinc deficiency is an important contributor to stunting, and increased risk for infectious diseases morbidity and mortality. 

Global Burden and Significance of Multiple Micronutrient Deficiencies in Pregnancy

Author(s): I. Darnton-Hill

Maternal mortality, low birthweight infants and childhood stunting continue to be major global public health problems, part of a recurring cycle of disadvantage.  Maternal undernutrition in particular is one of the most neglected aspects of nutrition in public health.  One possible low-cost public health intervention that might help address these problems is the antenatal provision of multiple micronutrient supplements.  If the evidence base could be established, cost-effectiveness found to be acceptable and safety ensured, supplementation could ameliorate the impact of poor nutrition and diets, high disease burdens and the socio-cultural factors contributing to these problems.   There have been good studies in over a dozen countries addressing some of these issues but with conflicting results. Consequently at least three meta-analyses have been undertaken to establish significant findings that could help guide policies and programs. They concluded that multimicronutrient supplementation improves birthweight and likely reduces the number of birthweight infants born. Supplementation with iron-folic acid or multimicronutrients also appears to have positive longer-term impacts on the health and development of the offspring.  There remain concerns about possible increased infant mortality in some populations.  Given the results of the meta-analyses, cautious scaling-up of country effectiveness trials appears justified with careful monitoring and evaluation. 

Intervention Strategies to Address Multiple Micronutrient Deficiencies in Pregnancy and Early Childhood

Author(s): A. Imdad, Z. Bhutta

Deficiencies of multiple micronutrients are prevalent among women of reproductive age and young children. This is a risk factor for increase morbidity and mortality in these women and children. Role of multiple micronutrient supplementation during an early childhood has been evaluated in randomized trials. Multiple micronutrients supplementation during pregnancy has a positive effect on birth weight and reduces prevalence of low birth weight and small for gestational age babies. It had comparable effects on prevalence of anemia regarding iron-folate supplementation. Multiple micronutrient supplementations in children have been shown to improve linear growth, weight, hemoglobin, serum zinc, serum retinol levels and motor development. Some of the most commonly used strategies to deliver multiple micronutrients include powders (e.g. Sprinkles®), crushable tablets (e.g. foodlet), etc. Multiple micronutrients supplementation during pregnancy and early childhood seems an effective way of prevention of micronutrient deficiencies and has significant protective effect against adverse outcomes related to their deficiencies. Their use on larger scale should be considered to improve the survival and decrease morbidity and mortality in children and women.  

Vitamin A Supplementation, Infectious Disease, and Child Mortality: A Summary of the Evidence

Author(s): A. Thorne-Lyman, W. Fawzi

This manuscript reviews the evidence related to the effects of vitamin A (VA) supplementation of women and children on child health and mortality. VA supplementation of  children aged 6–59 months has been well studied, and meta-analyses have consistently demonstrated effects on all-cause mortality, yet its mechanisms and the reasons for heterogeneous effects on mortality across trials continue to be debated. Recent meta-analysis of cause-specific mortality suggests beneficial effects on diarrheal mortality, with null but potentially beneficial effects also present for mortality from measles, lower respiratory infection, and meningitis. Some evidence suggests that pneumonia severity may increase with VA supplementation in this age group, particularly among well-nourished children. Maternal supplementation with VA during pregnancy has not shown benefits on neonatal mortality in large trials. A recent meta-analysis suggested that high-dose supplementation of lactating women immediately following delivery did not affect child survival. There is still uncertainty around the benefits of neonatal VA supplementation that should be resolved once the findings of ongoing trials are reported.

Issues and Controversies with Vitamin A in Childhood

Author(s): M. T. Murguía Peniche

Vitamin A deficiency (VAD) is common in the developing world. Vitamin A supplementation (VAS) has been used to prevent or treat VAD and  to decrease mortality  and morbidity in children.  However, there are still controversial issues in relation to the role of  universal  VAS in  different populations. Thus, studies that look at mortality outcomes reveal that VAS  decreases mortality in children &gt;6 months of age; however,  there is still controversy on  to what extent is  the decrease in mortality  due to reduction in morbidity from diarrhea and respiratory infection, other than measles. Studies in infants 1-5 months show no protective effect of VAS on mortality; whether this is secondary to environmental influences  (breastfeeding), or  interactions with DTP vaccine,  needs to be furher investigated.  Studies  with VAS in newborns have resulted in contrasting results  in countries from Africa and Asia; trials are underway to better understand this. VAS  does not have a universal  protective effect  for LRTI in children; some studies reveal an  increase in respiratory morbidity associated with VAS, specially in well nourished children; in contrast, VAS may confer some protection to  malnourished chiildren. The interaction of VAS with different vaccines is under current debate; some discussions are presented. <!--[if !supportLineBreakNewLine]--><!--[endif]-->

Influence of Inflammatory Disorders and Infection on Iron Absorption and Efficacy of Iron-Fortified Foods

Author(s): R. Hurrell

The provision of iron fortified foods is a common strategy to prevent iron deficiency however ensuring adequate iron absorption is a challenge. Iron bioavailability depends on the choice of iron compound, the presence enhancers and inhibitors of absorption in the food matrix, and the physiological state of the consumer, including iron status, other nutritional deficiencies and inflammatory disorders.  Inflammation associated with infections and inflammatory disorders would be expected to decrease iron absorption and reduce the efficacy of iron fortified foods. The decreased absorption is due to an increase in circulating hepcidin in response to inflammatory cytokines. Hepcidin degrades ferroportin and blocks the passage of iron from the intestinal cell to the plasma. This is the innate immune response to infections and aims to restrict pathogen growth by restricting iron supply. Stable isotope studies have reported women and children with chronic malaria parasitemia or febrile malaria to have increased inflammatory cytokines, increased hepcidin and much decreased iron absorption. No studies have specifically investigated the efficacy of iron fortified foods in the absence and presence of infections. In contrast, inflammation and increased hepcidin associated with adiposity in overweight have been linked to both lower iron absorption and the decreased efficacy of iron fortified foods.   

Safety of Iron Fortification and Supplementation in Malaria-Endemic Areas

Author(s): G. Brittenham

This review considers the safety of iron supplementation and fortification for the prevention and correction of iron deficiency in malaria-endemic areas, with a focus on potential means whereby provision of additional iron might heighten the risks of malaria and other infections. Iron deficiency itself may increase the risk of morbidity and mortality from malaria and other infections. The available evidence indicates that iron interventions are safe in settings without endemic malaria, and, with adequate health care, in regions with high transmission of malaria and other infections. Without regular surveillance and treatment of malaria and other infections, iron supplementation of individuals who are iron deficient seems safe but individuals who are iron replete may have an increased risk of adverse outcomes. The mechanisms responsible for harmful effects with iron supplementation have not been established. These are likely to include the effects of (i) increased amounts of absorbed iron, with the production of plasma non-transferrin-bound iron, (ii) increased amounts of iron in the gastrointestinal tract, with effects on gastrointestinal structural integrity and on gut microflora, and (iii) the complex immune effects of iron interventions. Iron fortification appears to be generally safe although more data from malaria-endemic areas are needed. 

Are Weaning Infants at Risk of Iodine Deficiency Even in Countries with Established Iodized Salt Programs?

Author(s): M. Zimmermann

Because iodine deficiency (ID) during infancy can irreversibly impair neurodevelopment and increase mortality, it is critical that dietary iodine is adequate in this vulnerable group. Lactating mothers consuming iodized salt can transfer iodine to the infant via breast milk, but during the weaning period, infants are at risk for ID for several reasons. Requirements per kg body weight for iodine and thyroid hormone during infancy are higher than at any other time in the life cycle. Experts recommend no extra salt (iodized or not) be given to infants during the first year. Cow’s milk (a major source of dietary iodine in many countries) is also not recommended for infants during the first year. Iron deficiency, a common disorder during infancy, can impair iodine metabolism and reduce thyroid hormone production. For many weaning infants in industrialized countries, iodine fortified into commercial infant foods becomes important. This has recently been demonstrated in Switzerland, where a long-standing iodized salt program provides adequate iodine to pregnant women and school-age children, but new national data suggest weaning infants not receiving iodine-containing commercial baby foods have inadequate iodine intakes. Thus, even in countries with effective iodized salt programs, infants may be at risk of iodine deficiency during weaning and may need additional dietary and/or supplemental sources of iodine during this period.  

Current Challenges in Meeting Global Iodine Requirements

Author(s): C. Eastman and P. Jooste

Iodine deficiency is a global problem of immense magnitude, afflicting 2 billion of the world’s population. The adverse effects of iodine deficiency in humans, collectively termed iodine deficiency disorders or IDD, result from decreased thyroid hormone production and action and vary in severity from thyroid enlargement (goitre) to severe, irreversible brain damage, termed endemic cretinism. Thyroid hormone is essential throughout life, but it is critical for normal brain development in the fetus and throughout childhood. During pregnancy maternal thyroid hormone production must increase by 25-50% to meet maternal-fetal requirements. The principal sources of iodine in the diet include milk and dairy products, seafoods and foods with added iodized salt. Vegetables, fruits and cereals are generally poor sources of iodine because most of our soils and water supplies are deficient in iodine. The accepted solution to the problem is Universal Salt Iodization (USI) where all salt for human and animal consumption is iodized at a level of 20 to 40 ug/g. In principle, mandatory fortification represents the most effective public health strategy where safety and efficacy can be assured and there is a demonstrated need for the nutrient in the population. Voluntary fortification of salt and other foods has many limitations and few benefits. Iodine supplementation is a useful, but an expensive, inefficient and unsustainable strategy for preventing iodine deficiency. The current worldwide push to decrease salt intake to prevent cardiovascular disease presents an entirely new challenge in addressing iodine deficiency in both developing and developed countries.  

Folate and Vitamin B12: Function and Importance in Cognitive Development

Author(s): A. Troen

The importance of the B-vitamins folate and vitamin B12 for healthy neurological development and function is unquestioned. Folate and vitamin B12 are required for biological methylation and DNA synthesis. Vitamin B12 also participates in the mitochondrial catabolism of odd chain fatty acids and some amino acids.  Inborn errors of their metabolism and severe nutritional deficiencies cause serious neurological and hematological pathology. Poor folate and vitamin B12 status short of clinical deficiency is associated with increased risk of cognitive impairment, depression, Alzheimer's disease and stroke among older adults and increased risk of neural tube defects among children born to mothers with low folate status. Folate supplementation and food fortification is known to reduce incident neural tube defects, and B-vitamin supplementation may have cognitive benefit in older adults. Less is known about folate and vitamin B12 requirements for optimal brain development and long-term cognitive health in newborns, children and adolescents. While increasing sub-optimal nutritional status has observed benefits, the long-term effects of high folate intake are uncertain. Several observations of unfavorable health indicators in children and adults exposed to high folic acid intake make it imperative to achieve a more precise  definition of folate and B12 requirements for brain development and function.  

Pros and Cons of Increasing Folic Acid and Vitamin B12 Intake by Fortification

Author(s): L. Allen

There is no doubt that folic acid fortification can be effective for reducing the incidence of neural tube defects (NTDs). The degree of efficacy depends on both the level of folate depletion and other, yet to be fully characterized, genetic and/or environmental factors. This article summarizes briefly data on NTD reduction and other benefits of folic acid fortification as these have been reviewed in more detail elsewhere. More attention is drawn to questions that have been raised about the possible adverse effects of folic acid fortification including the incidence of colorectal cancer and immune function. The main question addressed here is whether folic acid fortification can exacerbate the adverse effects of vitamin B12 deficiency. Most analyses of this question have been conducted in wealthier countries based on data from elderly populations – which have the highest prevalence of vitamin B12 deficiency. However, of potentially greater concern is the increasingly common practice of folic acid fortification in developing countries, where folate status is probably often adequate even prior to fortification, and vitamin B12 depletion or deficiency is common. To add to this information, data from a group of Chilean elderly with a range of vitamin B12 status and exposed to high levels of folic acid fortification will be presented.

Discussion on Micronutrient Requirements

Author(s): Noel W. Solomons

Discussion on Zinc in Maternal and Child Health

Author(s): Emorn Wasantwisut

Discussion on Vitamin A Supplementation in Childhood

Author(s): Jatinder Bhatia

Discussion on Folate and Vitamin B12Importance in Cognitive Development

Author(s): Irwin H. Rosenberg

Discussion on Vitamin B12 and Folic Acid Fortification

Author(s): Irwin H. Rosenberg