Potentially damaging species (reactive oxygen, nitrogen and chlorine species) arise as by-products of metabolism and as physiological mediators and signalling molecules. Levels of these species are controlled by the antioxidant defence system. Several components of this system are micronutrients (e.g. vitamins C and E) or are dependent upon dietary micronutrients (e.g. CuZn and Mn superoxide dismutase). The antioxidant defences act as a coordinated system where deficiencies in one component may affect the efficiency of the others. Oxidative stress may be an important factor in infection if micronutrients are deficient.

Nutrition is a critical determinant of the outcome of host microbe interactions through a modulation of the immune response. Besides macronutrient malnutrition, deficiencies of several macronutrients also influence immune homeostasis and thus affect infection-related morbidity and mortality. Deficiencies of micronutrients like vitamin A, iron and zinc are widely prevalent among populations living in developing countries. Besides their severe deficiencies, subclinical deficiencies are known to impair biological functions in the host, immune function being one of them. The effects of these micronutrients on various immune mechanisms are briefly reviewed in this article.

The trace element zinc is an essential micronutrient for the proper functioning of the immune system. Zinc deficiency leads to impaired function of the unspecific and specific immune response and consequently to an increased susceptibility to bacterial, viral and fungal infections. Immunological defects are not only seen in pronounced but even in marginal and moderate zinc deficiency. Lack of zinc is especially harmful for the development of the immune system, which stresses the importance of a balanced zinc level during pregnancy. However, gestational zinc deficiency due to an imbalance between intake and increased requirements is a common problem world-wide. In animals, gestational zinc deficiency results in reduced thymic and spleen size and depressed active and passive immunity in the infant. For example, depressed immunoglobulin levels, altered antibody repertoire, reduced proliferative response of lymphocytes and diminished neutrophil functions have been reported. Interestingly, immune defects caused by prenatal zinc deficiency, such as depressed antibody levels and lymphocyte proliferation, may even persist in subsequent generations and are not reversible by postnatal zinc administration. Since gestational zinc deficiency is a common problem throughout all cultures and socioeconomic levels, it might have immense consequences for the health status of the population. Based on a summary of the immunobiology of zinc, this article reviews the significance of zinc deficiency during pregnancy and the effect of gestational zinc deficiency on passive and active immunity in the infant. It provides a rational basis for both immunological laboratory investigations and field studies, such as large community-based zinc supplementation trials in pregnant women.

Micronutrient deficiency, whether clinical or subclinical, may affect growth, cognition and reproductive performance. In pregnant women moderate to severe deficiencies of iron, zinc and folic acid have been shown to increase risk of low birth weight, pregnancy complications and birth defects. Any attempt to introduce a micronutrient supplementation programme during pregnancy must be based on adequate data on the prevalence of micronutrient deficiencies, their adverse effects and the potential for reversing these through supplementation. This paper reviews parameters for assessment of iron, zinc and folic acid deficiencies in pregnancy and the available data on prevalence of these in pregnant women in South Asia. Iron deficiency and anemia affect 50 % or more of pregnant women, the prevalence of folic acid deficiency may be up to 30–50 % and there is evidence to suggest that zinc deficiency is likely to be widespread but supportive data are scarce.

Nearly 600 000 women die every year from pregnancy related conditions and the maternal mortality rates (MMR = deaths per 100 000 live births) in developing countries may be as high as 1000 compared with less than ten in industrialised countries. In the light of the striking impact of deficiencies of micronutrients such as vitamin A and zinc on immune function, morbidity and mortality in children it seems reasonable to suggest that such deficiencies might play a contributing role in the high rates of morbidity and mortality in mothers. Hitherto, there has been rather little published on the contribution of malnutrition to maternal morbidity or mortality but recent results of micronutrient supplementation show a major effect of vitamin A or beta carotene supplementation on maternal mortality in Nepal and an impressive effect of a multiple micronutrient mixture on pregnancy outcome in Tanzania. There is now data showing that subclinical mastitis, a potential risk factor for mother to child transmission of HIV by increasing levels of virus in breast milk, is influenced by maternal diet in Tanzania and feeding patterns in South Africa. Considering the massive tragedy of maternal mortality the recent data provides opportunities for new, innovative nutritional interventions for the reduction of the global burden of maternal morbidity and mortality.

The lack of a valid indicator precludes a true estimate of zinc deficiency in pregnancy in various populations. However, it is possible that mild to moderate deficiency (as assessed by available indicators) may be common in the developing world. Animal experiments indicate that zinc deficiency can result in adverse maternal and fetal consequences. Human data, particularly from prenatal zinc supplementation trials, has failed to document a consistent maternal or infant benefit on evaluated outcome measures including pregnancy induced hypertension, preterm/post-term labour, premature rupture of membranes, maternal infection, postpartum haemorrhage, perinatal mortality, congenital malformations and fetal growth and gestation. Preliminary data suggest a beneficial effect of prenatal zinc supplementation on infants’ neurobehavioural development and immune function (evaluated by diarrhoeal and ARI morbidity incidence in the first year of life). Future research should focus on these functional consequences and congenital malformations (with adequate sample sizes), and simultaneously address the safety issue, particularly in relation to micronutrient interactions. In the light of the currently available information, routine zinc supplementation can not be advocated to improve pregnancy outcome.

Increased folate intake reduces the risk of neural tube defects, other malformations and also possibly, pregnancy complications. Increasing evidence suggests that the beneficial effect of folate may be related to improved function of methionine synthase, a vitamin B12-dependent enzyme that converts homocysteine to methionine. In India, the majority of the population adheres to a vegetarian diet known to be deficient in vitamin B12. In such a population, increased folate intake may offer minimal protection against birth defects, whereas vitamin B12 administration should be considered. In this review, is described the metabolism of and interrelations between folate, vitamin B12 and homocysteine. This is followed by a brief discussion of some of the proposed mechanisms for their biological effects in relation to birth defects and pregnancy outcome.

From a public health perspective, some of the new insights into folic acid nutrition are of significance. Folate intake recommendations vary under different conditions. Intake of 350 μg is required to maintain plasma homocysteine levels, 650 μg for those with elevated plasma homocysteine, about 400 μg for women planning to become pregnant and 4000 μg for those with history of neural tube defect affected pregnancy. This raises the question whether the folate intake is adequate for the general population, particularly in the vulnerable groups or whether there is a need for scientists to take a fresh view of the requirements, recommended dietary intakes, and consider intervention measures which will have impact on the folate nutritional status. The recommendations should provide a margin of safety to allow for decreased intake, increased requirements, individual variability and bioavailability of natural food folates. The folate intake and nutriture in relation to India and other developing countries needs careful consideration to reduce anemia, neural tube defects and possibly impact on the high incidence of cardiovascular diseases.

Zinc is an essential mineral and deficiency results in abnormal immune function and higher rates of infectious diseases. Randomized controlled trials of zinc supplementation have been conducted in children in developing countries to determine effects on infectious disease morbidity and mortality. Zinc-supplemented children have been found to have lower rates of diarrhea, pneumonia and malaria in comparison with children not given zinc. Zinc used as an adjunct to fluid and dietary management of acute and persistent diarrhea has been found to reduce diarrheal duration and severity. Preliminary evidence suggests that zinc supplementation in children in poor developing country settings may also reduce infant mortality, but larger trials are needed to address this important issue. Preventive and therapeutic interventions should be implemented in developing countries where zinc deficiency is likely to be prevalent.

This review summarizes the results of published, randomized clinical trials that have examined the impact of administration of micronutrients, singly or in combination to infants, preschool and school children on linear growth. Supplementation of single micronutrients resulted in small or no benefits on linear growth. A meta-analysis of zinc supplementation trials confirmed that zinc has a significant but small impact (0.22 SD units) on length gain in children 0–13 years of age. however, a recent study reported a substantially greater benefit (>1 sd) in stunted and non-stunted breast-fed infants 6–12 months of age. With iron supplementation, a beneficial effect was found only in anemic children. Vitamin A supplementation trials have reported little or no benefit on linear growth. Data currently available suggest some impact in children with clinical or biochemical vitamin A deficiency, but this issue needs confirmation. Few studies could be identified where a combination of micronutrients was given as a supplement or as fortified food; in the latter set of studies energy availability was assured. The impact on length without multiple micronutrient supplementation was no greater than that observed with single micronutrients. In conclusion, zinc and iron seem to have a modest effect on linear growth in deficient populations. Vitamin A is unlikely to have an important effect on linear growth. Limited available evidence does not allow us to conclude whether a combination of micronutrients, with or without additional food, would have a greater impact than that seen with zinc alone.

Cognition is a field of thought processes by which an individual processes information through skills of perception, thinking, memory, learning and attention. Zinc deficiency may affect cognitive development by alterations in attention, activity, neuropsychological behavior and motor development. The exact mechanisms are not clear but it appears that zinc is essential for neurogenesis, neuronal migration, synaptogenesis and its deficiency could interfere with neurotransmission and subsequent neuropsychological behavior. Studies in animals show that zinc deficiency during the time of rapid brain growth, or during the juvenile and adolescent period affects cognitive development by decreasing activity, increasing emotional behavior, impairing memory and the capacity to learn. Evidence from human studies is limited. Low maternal intakes of zinc during pregnancy and lactation were found to be associated with less focused attention in neonates and decreased motor functions at 6 months of age. Zinc supplementation resulted in better motor development and more playfulness in low birth weight infants and increased vigorous and functional activity in infants and toddlers. In older school going children the data is controversial but there is some evidence of improved neuropsychological functions with zinc supplementation. Additional research is required to determine the exact biological mechanisms, the critical periods, the threshold of severity and the long-term effects of zinc deprivation on cognitive development.

Earlier studies show that in iron deficiency with anaemia and in latent iron deficiency neurotransmitters are altered. The changes induced in the fetal brain are irreversible on rehabilitation. The important alterations in glutamate metabolism in latent iron deficiency stimulated studies on gamma aminobutyric acid and glutaminate receptors. It was observed that binding of 3H-muscimol at pH 7.5 and 1 mg protein/assay increased significantly in synaptic vesicular membranes and under similar conditions 3H-glutamate binding showed reduction. Thus iron deficiency played a role in both excitatory and inhibitory neurotransmitter receptors. To elucidate the role of body iron status on the brain, anaemic children with thalassemia and iron deficiency were subjected to ‘magnetic resonance spectroscopy’ of globus pallidus, caudate and dentate nuclei and there was no change in iron content. The concentrations of creatinine and aspartate increased, with lowering of choline content. The findings were similar in thalassemia as well as iron deficiency anaemia, suggesting that in anaemia changes operate through reduced oxygen availability.

Role of micronutrients namely vitamin A, zinc and folate, as adjunct therapy of illness episodes in children in developing countries have been discussed in the light of health policy. Apart from a selective review, attempts have been made to statistically combine results of several studies to address policy issues. In children, vitamin A supplementation during illness has (a) a profound effect in reducing mortality in measles, (b) possibly a significant effect in reducing persistent diarrhea episodes in children with acute diarrhea, and (c) no benefit in pneumonia.

Use of large dose vitamin A is recommended during measles episodes but not in non-measles pneumonia. Its use in acute diarrhea is debatable but recommended in persistent diarrhea and in severe malnutrition as a component of a micronutrient mixture. Large dose vitamin A supplementation should be used with caution in young infants as there are unresolved concerns about its safety particularly, bulging fontanelle observed in infants when co-administered at immunization. In children, zinc supplementation during illness, (a) had a marked effect in reducing prolonged episodes and a modest effect on episode duration in acute diarrhea, (b) resulted in reduced rate of treatment failure and death in persistent diarrhea, (c) had no effect in measles and non-measles pneumonia, and (d) probably had a detrimental effect of increasing death rate when a large dose was used in severely malnourished children. The desirability of routine zinc supplementation therapy of undernourished children with acute diarrhea should be assessed further. Concerning policy, zinc supplementation as a component of a micronutrient mixture is recommended in the rehabilitation of severely malnourished children and in persistent diarrhea. However, recommendation for its routine use in all cases of acute diarrhea in children needs additional studies on effectiveness, cost, operations and safety. In two randomized controlled trials folate has been evaluated in acute and persistent diarrhea and found to have no beneficial effect. Folate is not recommended as adjunct therapy of diarrhea. Role of folate in preventing severe disease and/or death deserves further evaluation.

Both cereal staples and household diets can be manipulated to enhance the content of micronutrients and/or alter the levels of absorption modifiers to improve micronutrient bioavailability. Strategies described range from plant breeding, use of fertilizers and genetic engineering to changes in food preparation and processing methods at the household level involving soaking, fermentation and germination. The impact of five household strategies designed to enhance the content and bioavailability of iron, zinc and calcium in a representative daily menu for rural Malawian preschool children has been calculated using food composition data. In the five strategies, relishes based on small dried fish replaced plant-based relishes, maize-based porridges prepared with maize flour soaked to reduce its hexa (IP-6)- and penta (IP-5)-inositol phosphate content replaced conventional porridges; and a pumpkin-leaf relish replaced sweet potato to increase the retinol content of the daily menu. Comparison of the calculated energy, nutrient, and phytate content, and [phytate]:[zinc] molar ratios of the five modified menus compared with the unmodified menu emphasizes that to ensure that the estimated requirements for iron and zinc are met, the optimal strategy includes dried fish relish twice daily together with porridges prepared using soaked (or fermented) maize flour to reduce their hexa- and penta-inositol phosphate content. Implementation of these household strategies has the potential to increase the bioavailability of iron and zinc in rural Malawian diets from low to high.

Fortification of salt with iron has been developed by the National Institute of Nutrition (NIN) as a strategy for the control of iron deficiency anaemia (IDA) in India, similar to iodization of salt for control of iodine deficiency disorders (IDD). Stability of the iron fortified salt (IFS), its bioavailability and organoleptic evaluation of food items containing the IFS have been demonstrated. Acceptability and effectiveness of the IFS in school children and in multicentric community trials have been demonstrated. With the introduction of universal iodization of salt as a national policy in 1988, NIN has developed a formulation for double fortification (DFS) of salt with iodine and iron. The stability of the nutrients under laboratory conditions along with their bioavailability were found to be good but varying with the quality of salt used. The DFS has been evaluated in controlled trials in tribal communities and in residential school children. The findings of these studies are discussed. Overall, in these trials, DFS effectively controlled iodine deficiency but a clear impact on reducing anaemia was not demonstrated. In residential schoolchildren, increased urinary excretion of iodine as well as reduced anaemia were observed. The quality of salt has been found to be an important determinant of the stability of iodine in DFS. Further evaluation of this potentially important intervention is in progress.

Using a highly fortified food is the most attractive option to bringing missing nutrients to vulnerable groups. The recent development of a highly nutrient-dense spread (HNDS) for the treatment of malnourished children may have some relevance for other high-risk groups. Traditionally, severely malnourished children are fed for 3–4 weeks during their recovery with adapted milk feeds prepared by mixing dried skimmed milk, oil and sugar with a vitamin and mineral complex. This approach, however, is difficult to implement, since these feeds are excellent growth media for bacteria, and they must be prepared and fed under close supervision. This constraint led to the development of a HNDS, which is obtained by replacing part of the dried skimmed milk with a mixture of groundnut butter and powdered lactoserum. This spread can be eaten without dilution with water and preliminary trials showed that children preferred this HNDS to traditional liquid diets. In HNDS all powdered ingredients are embedded in fat which protects vitamins against oxidation and increases the shelf life of this product. Spreads also have a very low humidity and bacteria do not grow in it. Attempts to use spreads to supplement other vulnerable groups such as moderately malnourished children and pregnant women are discussed.

A potential risk of interactions between micronutrients affecting absorption and bioavailability has to be considered in any supplementation or fortification strategy. At levels of essential micronutrients present in foods, most micronutrients appear to utilise specific absorptive mechanisms and not be vulnerable to interactions. In aqueous solutions and at higher intake levels competition between elements with similar chemical characteristics and uptake by non-regulated processes can take place. These interactions have clearly been demonstrated in experimental absorption studies and to some extent have been confirmed in supplementation studies. Negative effects of iron supplementation on indices of zinc and copper status and of zinc supplementation on iron and copper status have been reported. In contrast, the negative effect of calcium on iron absorption has not been confirmed in long-term supplementation studies. Ascorbic acid has a strong iron absorption promoting potential and in iron deficient populations ascorbic acid supplementation improves iron status. Thus, ascorbic acid supplements or an increased intake of ascorbic acid rich foods could have important public health implications, especially in populations subsisting on a mainly plant food based diet. The effect of poor status of a given micronutrient on absorption and utilisation of other micronutrients should also be considered while developing strategies to improve micronutrient status in a population. Awareness of these interactions, combined with a balanced evaluation of the dietary intake of the population with regard to absorption promoting and inhibiting substances and the risk for multiple deficiencies, could lead to more effective strategies to improve micronutrient status.

Strategies such as dietary diversification and food fortification have yielded significant results in controlling iron deficiency anaemia in developed countries. Reducing the prevalence of iron deficiency anaemia in developing countries is still a matter of importance. The major factors responsible for iron deficiency anaemia in the vulnerable segments of developing countries are reduced intake and poor bioavailability of dietary iron. Dietary diversification and food-based approaches pose considerable challenges before they can be implemented on a wide scale. Anaemia control programmes based on the administration of prophylactic doses of iron and folic acid tablets have been widely implemented. As the programmes were not effective in countries such as India, the dosage of iron was increased. The role of excess iron in causing intestinal oxidative stress has drawn attention to other approaches of iron supplementation. Prophylactic administration of iron along with antioxidants like vitamins E and C or foods rich in these vitamins is one such strategy. To reduce the intestinal oxidative stress, intermittent supplementation of iron is being considered. The potential benefits and shortcomings of these approaches are reviewed.

Vitamins and minerals, referred to collectively as micronutrients, have important influences on the health of pregnant women and the growing fetus. Iron deficiency results in anemia which may increase the risk of death from hemorrhage during delivery, but its effects on fetal development and birth outcomes is still unclear. Folic acid deficiency can lead to hematological consequences, pregnancy complications and congenital malformations, but again the association with other birth outcomes is equivocal. Zinc deficiency has been associated in some, but not all studies with complications of pregnancy and delivery, as well as with growth retardation, congenital abnormalities and retarded neurobehavioral and immunological development in the fetus. Iodine deficiency during pregnancy results in cretinism and possible fetal wastage and preterm delivery. Deficiency of other minerals such as magnesium, selenium, copper, and calcium have also been associated with complications of pregnancy, childbirth or fetal development. Deficiencies of vitamins other than folate may likewise be related to such complications; and vitamin A or β-carotene supplements in pregnancy reduced maternal mortality by 50 % in a controlled trial in Nepal. Additional research is need on the prevalence of such deficiencies and their consequences and on cost-effective public health interventions for their control.