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University of California, Davis, California and * Institute of Child Health, London, UK
2To whom correspondence should be addressed. E-mail: R.Shrimpton{at}ich.ucl.ac.uk.
The International Research on Infant Supplementation (IRIS) studies, performed in 4 developing country settings across the world and presented in this supplement, show that the use of a daily multiple micronutrient supplement during infancy is more efficacious for improving micronutrient status, anemia, and child weight growth than a daily iron supplement or a weekly multiple micronutrient supplement. Neither iron nor multiple micronutrient supplementation prevented growth faltering and, although in the pooled analysis the daily multiple micronutrient supplementation produced a small breaking effect on weight-growth faltering compared with placebo, length-growth faltering was the same in all groups. Infants receiving the daily multiple micronutrient supplement showed improved concentrations of circulating hemoglobin and of plasma ferritin, zinc, retinol, riboflavin, homocysteine, and tocopherol, whereas daily iron supplements and weekly multiple micronutrient supplements only improved hemoglobin and plasma ferritin concentrations. The morbidity data were not collected in comparable ways across countries, but in those country studies that reported morbidity, there was no difference between any supplementation group and placebo. The purpose of this article is to provide an editorial perspective on the IRIS results, discussing the internal and the external validity of the findings, together with program and research implications.
The overall biological coherence and consistency of the IRIS study results confer great plausibility to the findings. There was a significant dose–response effect between the weekly multiple micronutrient and the daily multiple micronutrient supplements for hemoglobin, plasma ferritin, zinc, retinol, homocysteine, tocopherol, and erythrocyte riboflavin concentrations. For all of these outcomes, when compared with placebo, the effect produced by weekly multiple micronutrient supplements, which contained twice the recommended daily intake taken on one day of the week (2/7), was half that produced by the daily multiple micronutrients, which contained one daily intake taken each day of the week (7/7). Similar effects were seen in weight gain where, compared with those receiving iron or placebo supplements, infants receiving the multiple micronutrient supplements for 6 mo were heavier by 180 g when taking them daily and by 90 g when taking them weekly.
The study was appropriately designed and adequately robust for testing the hypothesis that multiple micronutrient supplementation during infancy would improve growth, anemia, and micronutrient status more than iron supplementation alone or a placebo. The importance of an adequate design of research into multiple micronutrient interventions has been reviewed in relation to the IRIS trials (1). Considerable consultation and collaborative effort went into trying to ensure that the design of the IRIS studies was optimal. The use of a common protocol and of common information collection instruments with standardized questionnaires across country sites was one strong, positive design aspect. The sample size was adequate to test the growth hypothesis in the pooled sample of all 4 countries as planned and, even though deliberately underpowered at the country level, the trial still detected growth effects in one country. The centrally designed randomization procedure followed in each country proved very efficient in ensuring that there was homogeneity of the different groups across treatment arms at baseline, even though there were differences across countries in the initial conditions of the infants. Another strong point in the IRIS study design was that the interventions were double blinded. The centralized production of the foodlets in Peru ensured that supplements used in all 4 sites were the same. Because the code for identifying the blister packs containing the supplements was kept centrally, neither the subjects nor the investigators and field workers knew which treatment was which. The lack of triple blinding, with the statisticians knowing treatment groups in the data analysis, is a negative aspect, but this is somewhat offset by the data analysis being done centrally by an independent group. The central analysis of the biological samples in Germany, together with the central provision of all blood sample collection material, also adds strength to the credibility of the results produced. The detection of the dose–response effects in the clinical biochemical outcomes was made possible by the large sample size used to test the growth hypothesis. The choice to have a placebo group in the study design was also vindicated because, without this group, it would not have been possible to show that daily iron supplementation alone actually made zinc status worse. The fact that the biochemical indicators of the different multiple micronutrient supplements showed a dose–response across the multiple micronutrient supplement groups supports the field workers’ reports that the different supplements were indeed consumed, even though the delivery of the supplements was not observed or administered by members of the research team in one of the 3 sites.
The study populations chosen in the 4 countries proved to be suitable for testing the study hypotheses. The common study protocol required that the study be "population based" rather than "health center based," and be performed in an area that was reasonably accessible but that still had a sufficient degree of nutritional problems, including a high prevalence of anemia and growth faltering in infants, such that improvements could be expected as a result of the micronutrient supplements. Although the prevalences of stunting and underweight were relatively small at baseline, this is to be expected in early infancy, because growth faltering is a continuous process during the first 2 y of life, with stunting becoming progressively more prevalent from birth to 2 y of age (2). Over half of the infants were anemic at baseline and micronutrient deficiencies affected at least a quarter of infants in all sites. As hypothesized, these were multiple rather than single micronutrient deficiencies, although the micronutrients that were most deficient varied by country. Iron deficiency was most prevalent in Peru and Indonesia, zinc deficiency was most prevalent in South Africa and Peru, vitamin A deficiency was most prevalent in Vietnam and Indonesia, and riboflavin deficiency was most prevalent in Vietnam and South Africa. The causes and consequences of these interesting intercountry differences in infant nutritional status deserve attention in future studies.
There were no apparent negative consequences of taking the daily multiple micronutrient supplements. The foodlet was designed as a large tablet that could not be easily swallowed whole by infants inadvertently and that was crumbly enough to easily disperse in food or dissolve in water and was pleasantly flavored (3). In 3 sites (Indonesia, Peru, and Vietnam), the foodlets were taken under direct supervision every day; whereas in South Africa they were given by the mother, unsupervised, with weekly visits to check with the mother how the supplementation was going. There were no reported negative consequences, and there were very few dropouts during the 6-mo trial, with 90% of the infants initially randomized completing the study. In South Africa, the mothers gave the foodlet mixed with the porridge, whereas in the other 3 sites the foodlets were taken between meals as a drink by dissolving in water. The possibility of there being some effect of a food matrix, such as cornstarch porridge, on the absorption of the various micronutrients was tested in an adult simulation, with the conclusion that the effect was relatively small (4).
Considering the ubiquity of breast-feeding in these infant populations, the prevalences of low plasma retinol concentrations in infants at baseline was surprisingly high in Vietnam and Indonesia. Because the only source of vitamin A during the first 6 mo of life is likely to have been breast milk, the maternal vitamin A status was likely to have been poorer in these 2 study populations. Breast-feeding status was not included in the analysis carried out, and the lack of adequate definition of the breast-feeding status of the infants in the study makes it difficult to ascertain these linkages. The retinol content of breast milk is known to be low in mothers in Indonesia, and vitamin A capsule supplementation at birth is known to benefit the vitamin A content of breast milk and the vitamin A status of the infant (5). It seems likely that the use of large oral-dose vitamin A capsules for the mother at birth followed by infant supplementation at 6 and 14 wk through routine health service contacts as is recommended internationally (6) was either not practiced in the study site areas of Vietnam and Indonesia or was not adequate to maintain liver retinol stores.
The daily multiple micronutrient supplement was the most efficacious of the treatments tested for improving both infant anemia and micronutrient status. Although all 3 micronutrient interventions were efficacious at reducing anemia and improving iron status, the daily multiple micronutrient supplement tended to show a stronger hematinic response and to produce a higher plasma ferritin concentration than daily iron or the weekly multiple micronutrient supplements. However, perhaps the most important finding was that although the daily multiple micronutrient supplements reduced the prevalence of zinc deficiency over the 6 mo, the daily iron supplement exacerbated the problem. Whereas other studies have shown that zinc supplements alone or when given together with iron produce negative effects on iron status (7,8), the zinc in the multiple micronutrient supplements in these IRIS trials had no such effect. Another benefit was that the daily multiple micronutrient supplements improved other circulating micronutrient concentrations, such as riboflavin, retinol, and tocopherol, whereas the weekly multiple micronutrient and the daily iron had no such effect. The decrease in plasma homocysteine levels in both weekly and daily multiple micronutrient supplemented infants compared with placebo also suggests that the infants had suboptimal vitamin B-12 and/or folate status. The limited effect of the vitamin A in the micronutrient supplements on plasma retinol concentrations compared with placebo after 6 mo of intervention suggests that the periodic mass vitamin A capsule distribution programs through mass campaigns for young children aged 6 to 59 mo of age, present in all of the study countries, will have ensured that most infants received such capsules during the second semester of life. Even so, the daily multiple micronutrient supplement still produced a small but significantly greater concentration of plasma retinol than placebo, daily iron, or weekly multiple micronutrient supplementation.
Despite the improvements in anemia and circulating micronutrient concentrations produced by the daily multiple micronutrient supplement in particular, deficiencies were still common after 6 mo of supplementation. This suggests that more micronutrients may be needed to eliminate anemia and micronutrient deficiencies in these infant populations, either through higher doses or longer duration. However, alternative interpretations include the possibilities that the cutoffs used to define anemia in infants are too high (9) and/or infectious processes were affecting nutritional status indicators (10).
The possibility of starting interventions before 6 mo of age is another consideration, because iron and zinc deficiency already affected at least a quarter of infants at the beginning of the study when they were, on average, about 8 mo old. The existence of subclinical riboflavin deficiency and of elevated homocysteine levels at baseline, suggest that breast-milk riboflavin and either vitamin B-12 or vitamin B-6 concentrations were not optimal. Micronutrient status of the mother is known to have a strong influence over the micronutrient status of the infant (11,12). Recent studies in Nepal show that antenatal anthelminthic treatment reduces severe anemia in the mothers and improved birth weight and survival rates at 6 mo of their infants (13). It would seem appropriate to develop further research that looks at a package of daily multiple micronutrient supplementation and periodic infection control measures for the mother during pregnancy and lactation, as well as the introduction of multiple micronutrient supplements before 6 mo of age in babies born low birth weight and/or whose mothers were anemic. Such an approach would be consistent with the high priority actions recommended by the WHO/UNICEF (United Nations Children’s Fund) Global Strategy for Infant and Young Child Feeding, which affirms that mothers and babies form an inseparable biological and social unit, and that the health and the nutrition of one group cannot be divorced from the health and nutrition of the other (14).
The lack of effect on growth is perhaps not surprising because few nutrient supplementation interventions during infancy have increased growth. There is considerable evidence that complementary feeding diets are more lacking in micronutrients than quantity (15); therefore, the logic of trying to increase the quality of the diet or the nutrient energy density by adding the micronutrients that are most likely to be limiting is attractive. However, the reviews of efficacy studies that have tried to increase complementary food quality have shown very limited responses (16). In addition, those well-designed and highly controlled efficacy studies that have managed to increase energy intakes through increasing complementary food consumption produced very modest weight growth effects in the order of –0.25 to +0.45 SD, and none of them managed to prevent growth faltering completely (17). The increased weight growth of +0.2 SD over 6 mo achieved by the daily multiple micronutrient supplements in these IRIS trials therefore can be considered a very reasonable achievement. One important design issue that may have limited the potential to improve infant growth in the IRIS studies is that low-birth-weight babies were excluded from the study at baseline, and inadequate infant growth is strongly linked to poor intrauterine growth (2). If low birth-weight babies had been included in the study, the growth effects of the daily multiple micronutrient supplements might have been larger.
The lack of evidence of any effect of the micronutrients on morbidity is surprising, because other micronutrient supplementation studies have commonly shown a reduction in child morbidities. High-dose vitamin A supplements reduce the severity of infections and mortality in areas where such indices are high, but this effect is seen in older children (18) more than in infants (19). However, the infants in all treatment arms of the IRIS study will have received the periodic vitamin A capsule distribution after 6 mo of age in all study countries, so this would mask any expected effect in all treatment arms. Zinc supplements have been shown to reduce both the frequency and the severity of diarrheal and respiratory tract infections (20,21); but, again, those studies tended to be in older children and the doses were larger than those in the IRIS multiple micronutrient supplements. Zinc supplementation during infancy has been reported to reduce mortality in low-birth-weight babies (22); but, then again, low-birth-weight babies were excluded from the IRIS trials. It may also be that the effects on morbidity were not seen because these infants were still being predominantly breast-fed. However, this was not investigated, because adequate breast-feeding information was not available in the IRIS studies. The lack of impact on morbidity may be due to limitations in the method of recording infectious episodes, because field workers recorded daily whether the infant had diarrhea or acute respiratory infections or fever the day before. These data were then summarized at the weekly review with the research assistants and reported as number of days with the condition per month. This way of recording infections does not allow the separation of infectious episodes for estimating the frequency and the duration of infections. However, even with these limitations, if morbidity had been influenced, it should have resulted in some difference in the percentage of days with infections. It may also be that in these "population-based" studies rather than "health-center-based" studies, in which infants with infections and/or that were born low birth weight were excluded at baseline, those infants most likely to get infections were excluded. The lack of micronutrient effect on the circulating C-reactive protein and 
-1-acid glycoprotein concentrations is supportive of there being no effect on morbidity.
The implications of these IRIS results for programs are considerable. In the context of the Global Strategy for Infant and Young Child Feeding (14), it would seem appropriate for WHO and UNICEF to make program recommendations on the use of daily multiple micronutrient supplements instead of iron supplements for preventing iron-deficiency anemia during infancy. In all 4 country study sites, anemia was associated with multiple micronutrient deficiencies and not just iron deficiency. Furthermore, daily iron supplements failed to improve the status of other micronutrients or made it worse. The cost implications of adding multiple micronutrients in addition to that of iron are relatively small, with estimates of US$0.01–0.03 for the foodlet. These incremental costs of adding extra nutrients are very small compared with the costs of making tablets and packaging, and miniscule compared with the distribution costs (23).
In the meantime, further research should focus on large-scale effectiveness trials, perhaps in the same 4 countries, but with local production of the supplements. Such effectiveness studies should look at the communications aspects, the logistical dimensions, and the cost-effectiveness of the programs. Embedded into these effectiveness studies, further research should also investigate whether there are combined benefits from the use of multiple micronutrient supplementations, including increased doses and duration of supplementation with maternal supplementation and infant supplementation in a continuum, together with infection control measures. This research would logically be developed using the plausibility approaches suggested by Victora and colleagues (24).
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LITERATURE CITED |
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 TOP LITERATURE CITED |
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1. Gross, R. & Solomons, N. W. (2003) Multiple micronutrient deficiencies: future research needs. Food Nutr. Bull. 24(suppl.):S42-S53.[Medline]
2. Shrimpton, R., Victora, C. G., de Onis, M., Lima, R. C., Blossnes, M. & Clugston, G. (2001) Worldwide timing of growth faltering: implications for nutritional interventions. Pediatrics 107:e75.
3. Lock, G. (2003) The foodLET vehicle designed for and used in the IRIS I intervention. Food Nutr. Bull. 24(suppl.):S16-S19.[Medline]
4. Kamp, F., Jandel, D., Hoenicke, I., Pietrzk, K., Gross, R., Trugo, N.M.F. & Donangelo, C. M. (2003) Bioavailability of iron, zinc, folate and vitamin C in the IRIS multi-micronutrient supplement: effect of combination with a milk-based cornstarch porridge. Food Nutr. Bull. 24(suppl.):S20-S26.[Medline]
5. Stoltzfus, R. J., Hakimi, M., Miller, K. W., Rasmussen, K. M., Dawiesah, S., Habicht, J. P. & Dibley, M. J. (1993) High dose vitamin A supplementation of breast-feeding Indonesian mothers: effects on the vitamin A status of mother and infant. J. Nutr. 123:666-675.
6. Sommer, A. & Davidson, F. R. (2002) Assessment and control of vitamin A deficiency: the Annecy Accords. J. Nutr. 132(suppl.):2845S-2850S.
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8. Lind, T., Lonnerdal, B., Stenlund, H., Ismail, D., Seswandhana, R., Eksrom, E.-C. & Persson, L.-A. (2003) A community-based randomised controlled trial of iron and zinc supplementation in Indonesian infants: interactions between iron and zinc. Am. J. Clin. Nutr. 77:883-890.
9. Domellof, M., Dewey, K. G., Lonnerdal, B., Cohen, R. J. & Hernell, O. (2002) The diagnostic criteria for iron deficiency in infants should be reevaluated. J. Nutr. 132:3680-3686.
10. Stoltzfus, R. J., Chway, H. M., Montressor, A., Tielsch, J. M., Jape, J. K., Albonoico, M. & Savioli, L. (2003) Low dose daily iron supplementation improves iron status and appetite but not anemia in Zanzibar preschool children. J. Nutr. 134:348-356.
11. Dijkhuizen, M. A., Wieringa, F. T., West, C. E., Muherdiyantiningsih, & Muhilal, (2001) Concurrent micronutrient deficiencies in lactating mothers and their infants in Indonesia. Am. J. Clin. Nutr. 73:786-791.
12. de Pee, S., Bloem, M. W., Sari, M., Kiess, L., Yip, R. & Kosen, S. (2002) The high prevalence of low haemoglobin concentration among Indonesian infants aged 3–5 months is related to maternal anemia. J. Nutr. 132:2215-2221.
13. Christian, P., Khatry, S. K. & West, K. P. (2004) Antenatal anthelminthic treatment, birth weight, and infant survival in rural Nepal. Lancet 364:981-983.[Medline]
14. WHO/UNICEF (2003) Global Strategy for Infant and Young Child Feeding 2003 World Health Organization Geneva, Switzerland.
15. Lutter, C. K. & Rivera, J. A. (2003) Nutritional status of infants and young children and characteristics of their diets. J. Nutr. 133(suppl.):2941S-2949S.
16. Rivera, J. A., Hotz, C., Gonzalez-Cossio, T., Neufield, L. & Garcia-Guerra, A. (2003) The effect of micronutrient deficiencies on child growth: a review of results from community-based supplementation trials. J. Nutr. 133:4010S-4020S.
17. Caulfield, L. E., Huffman, S. L. & Piwoz, E. G. (1999) Interventions to improve intake of complementary foods by infants 6 to 12 months of age in developing countries: impact on growth and on the prevalence of malnutrition and potential contribution to child survival. Food Nutr. Bull. 20:183-200.
18. Beaton, G. H., Martorell, R., Aronson, K. J., Edmonston, B., McCabe, G., Ross, A. C. & Harvey, B. (1993) Effectiveness of Vitamin A Supplementation in the Control of Young Child Morbidity and Mortality in Developing Countries. ACC/SCN State of the Art Series Nutrition Policy Discussion Paper No. 13 1993 United Nations Administrative Committee on Coordination/Subcommittee on Nutrition Geneva, Switzerland.
19. WHO/CHD Immunisation-Linked Vitamin A Supplement Study Group (1998) Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy. Lancet 352:1257-1263.[Medline]
20. Zinc Investigators Collaborative Group (1999) Prevention of diarrhoea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomised controlled trials. J. Pediatr. 135:689-697.[Medline]
21. The Zinc Investigators Collaborative Group (2000) Therapeutic effects of oral zinc in acute and persistent diarrhoea in children in developing countries: pooled analysis of randomised controlled trials. Am. J. Clin. Nutr. 72:1516-1522.
22. Sazawal, S., Black, R. E., Menon, V. P., Dinghra, P., Caulfield, L. E., Dhingra, U. & Bagati, A. (2001) Zinc supplementation in infants born small for gestational age reduces mortality: a prospective, randomised controlled trial. Pediatrics 108:1280-1286.
23. Nestel, P., Briend, A., de Benoist, B., Decker, E., Ferguson, E., Fontaine, O., Micardi, A. & Nalubola, R. J. (2003) Complementary food supplements to achieve micronutrient adequacy for infants and young children. J. Pediatr. Gastroenterol. Nutr. 36:316-328.[Medline]
24. Habicht, J. P., Victora, C. G. & Vaughan, J. P. (1999) Evaluation designs for adequacy, plausibility and probability of public health programme performance and impact. Int. J. Epidemiol. 28:10-18.
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