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Medical Research Council, Parow, South Africa;
* Institute of Research for Development, Hanoi, Vietnam;
National Institute of Nutrition in Hanoi, Vietnam;
** Instituto de Investigación Nutricional, Universidad Agraria La Molina, Lima, Peru;
SEAMED-TROPMED Regional Center for Community Nutrition at the University of Indonesia, Jakarta, Indonesia;
Institute of Biological Chemistry and Nutrition at the University of Hohenheim, Stuttgart, Germany; and
UNICEF, New York City, New York
3To whom correspondence should be addressed. E-mail: marius.smuts{at}mrc.ac.za.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • iron • zinc • multiple micronutrient supplements • anemia • infant’s growth
In developing countries across the globe, the weight growth of children commonly falters between 6 and 12 mo of age (1). The timing of the growth faltering coincides with the period of dietary transition for the infant, changing from the liquid diet of breast milk to eating solid foods from the family pot. The food mixtures used to complement breast milk in this period of transition are commonly deficient in a number of micronutrients but especially in iron, zinc, and B vitamins (2–3). Furthermore, the transition diets are more commonly qualitatively deficient than quantitatively deficient (4). To test the hypothesis that correcting the multiple micronutrient deficiencies that are common during this period might help to prevent weight growth faltering, a common research protocol was developed and implemented in 4 countries across the globe, namely Indonesia, Vietnam, Peru, and South Africa, as has been described previously (5). The objectives of the common protocol were to examine the prevalence of anemia and multiple micronutrient deficiencies in infants from rural populations of these 4 selected countries and to assess the efficacy of multiple micronutrient supplementation for improving micronutrient, anemia, growth, and morbidity status. This paper presents the effects of the micronutrient supplementation on growth, anemia, and micronutrient status of the infants obtained from analysis of the pooled data set, draws conclusions, and makes recommendations for future action.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Four geographically distinct populations from 3 continents participated in the study, namely South Africa, Peru, Vietnam, and Indonesia. In each country, locations were identified where anemia and vitamin A deficiency affected at least 30% of the preschool child population and conditions were suitable for carrying out an efficacy trial. The trial was double blinded and placebo controlled, with children randomly assigned to 1 of 4 intervention groups. For each country, at least 70 infants were enrolled per intervention group (65 + 5 dropouts), with an expected total of enrollees across the 4 sites of at least 1120 infants. Infants in the study area whose families gave informed consent were included in the study using the following selection criteria: age 6–11 mo, resident in the study location, not born prematurely (<37 wk gestation), not born low birth weight (<2500 g), not severely wasted (<–3 Z-scores), not severely anemic (hemoglobin < 80 g/L), and no fever (>39°C). Infants were randomly assigned to treatment groups centrally and received identically appearing, individually numbered treatments during the course of the trial. The code was kept centrally and was only shared with the Medical Research Council in South Africa during the course of the analysis of the pooled data set.
The interventions
The foodlets used to deliver the different treatments were centrally manufactured as chewable tablets or foodlets, which were easy to break and dissolve, with the same taste, color, and flavor for all treatments in all countries. Roche Laboratories was responsible for the product formulation, and a private laboratory in Peru (Hersil SA) was responsible for the production and quality control of the supplements. Each participating family received an individually numbered blister pack containing the week’s supply of the 7 foodlets, once a week during a period of 6 mo in all 4 country sites, except South Africa where mothers are provided with one month’s supply due to logistical reasons. The 4 treatment groups were as follows: 1) multiple micronutrients each day (DMM),4 2) no micronutrients each day [placebo (P)], 3) multiple micronutrients at twice the dose of the daily foodlet for 1 d and no micronutrients the other 6 d of the week (WMM), 4) 10 mg of elemental iron each day (DI). The micronutrients included in the foodlets at a dosage of one adequate daily intake were vitamins A, D, E, K, C, B-1, B-2, B-6, and B-12, niacin, folate, iron, zinc, copper, and iodine, as described in greater detail elsewhere (6).
Objectives and outcomes
The primary objective of the trial was to test the hypothesis that improving micronutrient status would improve growth of infants at high risk of anemia in different developing country settings. The sample size was calculated based on the comparison of a drop in standardized weight for age from –0.65 to –0.95 Z for the DMM group compared with a fall from –0.65 to –1.20 Z in the P group. For a 2-group repeated measures ANOVA with 7 levels (mo 0 to 6), a sample size of 256 per group would provide the analysis with 80% power when the significance level is 5%. With an anticipated dropout of about 7%, the sample size increased to 275 children per group. A sample size of 70 children therefore was planned for each group across the 4 countries. The secondary objective of the trial was to test the hypothesis that the multiple micronutrient supplements, given either weekly or daily, are better than daily iron supplements for improving micronutrient status and for preventing the development of anemia during infancy. The sample sizes determined by the primary objective were considered sufficient to test these hypotheses.
In each study site, all information was collected using a common questionnaire and survey methodology (7). The common questionnaire used to collect information was composed of 4 components: 1) household characteristics collected at baseline, 2) monthly weight and height measurements, 3) weekly health visit form, and 4) a daily health and infant feeding questionnaire. In each study location, trained personnel measured infants’ length and weight on a monthly basis using internationally accepted methods as described in detail in the individual country papers. Blood samples were obtained from each child at baseline and at the end of the study, and all material used for blood taking and storage was the same specification across all sites and was sent from Germany. Venous blood was collected with zinc-free, 2-mL, vacuette heparin tubes with butterfly luer-lock adapters (Greiner). After centrifugation and separation of the blood locally, plasma and erythrocytes were stored at –70°C until transportation on dry ice to Germany. Hemoglobin concentrations were determined locally as specified in the country papers. The data on child health and sickness is reported elsewhere in the individual country papers.
All clinical biochemical determinations were carried out at the Micronutrient Laboratory of the Institute of Biological Chemistry and Nutrition at the University of Hohenheim, Germany, using internationally recognized methods. Plasma ferritin was measured by a standard sandwich ELISA procedure from the provider of the antibodies (DAKO). Plasma zinc and copper concentrations were analyzed by flame atomic absorption spectrophotometry according to the description of the manufacturer (Perkin Elmer). Plasma retinol, 
-tocopherol, was analyzed using reversed phase HPLC (8). Plasma homocysteine levels were measured by HPLC (9). Riboflavin status was assessed by calculating the activation coefficient of the erythrocyte glutathione reductase (EGRAC) with and without added riboflavin (10). C-reactive protein (CRP) and -1-acid glycoprotein (AGP) were measured by means of a sandwich ELISA (DAKO). Elevated CRP was considered to be a value of >12 mg/L, whereas abnormally high AGP was a concentration of >1 g/L. The status of an abnormally increased acute-phase-response marker was taken into consideration for the diagnostic assessment and interpretation of retinol, zinc, and iron status markers.
Data processing and statistical analysis
Each country team entered all collected data into a standardized spreadsheet using Statistical Package for the Social Sciences (SPSS) before sending the data files to The Biostatistics Unit of the Medical Research Council, Cape Town, South Africa, where the statistical analysis was done. Using the pooled data set, weight and height measurements were transformed into the standardized anthropometric variables, weight for age (WAZ), height for age (HAZ), and weight for height (WHZ), separately for boys and girls using ANTHRO version 1.01 developed by U.S. Centers for Disease Control in collaboration with the Nutrition Unit, WHO (11). Descriptive statistics of weight and height gain were calculated using weight/height gained (final weight/height minus the baseline weight/height) divided by months in the study (age at final date minus age at baseline). A one-way ANOVA was used for comparison of the mean weight and height gain of the 4 treatments.
For the standardized anthropometric variables, a mixed effects regression model was used with the treatment indicator, time of measurement, country indicator, and the baseline anthropometric measurement as the fixed effects covariates. The random effects model within each child was based on the time of measurement and the baseline response. A quadratic time effect in both the fixed and the random components of the model was implemented to account for the nonlinear trends. Introduction of these effects improved the model fit as assessed by the Akaike information criterion (12). The treatment by the time interaction factor was included in the model to test for a difference in slopes. This would indicate an intervention effect because the randomization ensured that the treatment groups started at the same mean baseline. Least-squares means (LSMeans) were used to estimate treatment effects and 95% confidence intervals at mo 6 based on the mean response models.
Each child had 2 measurements for each clinical biochemistry variable, at baseline (pre) and 6 mo (post). The variables analyzed were AGP, CRP, ferritin, hemoglobin, homocysteine, retinol, riboflavin, tocopherol, and zinc. Individual pre-post differences were also calculated, which represent changes from baseline. A logarithmic transformation was used for ferritin, and this transformed scale was used for all inferences on this variable. The mean and SD of the clinical biochemistry variables and prepost difference, as well as the 95% confidence intervals, were calculated. Significant changes within groups are reported based on the paired t test. The experimental analysis of the clinical biochemistry variables was also done using analysis of covariance. The biochemistry measurement at 6 mo was modeled with the factors for treatment and country, and the baseline value used as the subject-level covariate in the linear regression model. In the model development, the interaction term between the baseline response and the treatment indicator was investigated. However, because this interaction term was not significant in any of the models, the main effects analysis of covariance model is reported for all the clinical biochemistry variables. LSMeans were used to estimate the treatment effects and 95% confidence intervals at mo 6 based on the mean response model. For the P, WMM, and DMM groups, tests for linear and quadratic dose effects of the 0, 2, and 7 RDA doses were done for biochemical measurements using the LSMeans.
The effect of the various micronutrient supplements on the levels of micronutrient deficiency and anemia were also investigated. Deficient levels of the various clinical biochemical indicators measured were considered to be <110 g/L for hemoglobin, <20 mg/L for plasma ferritin, <0.7 µmol/L for plasma retinol, <10.7 µmol/L for plasma zinc, and an EGRAC >1.4 for riboflavin. Significant changes within groups in levels of deficiency are reported based on the McNemar test.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Failure to detect an effect of the different micronutrient treatments on length growth was not due to differences in the quality of anthropometric measurement across sites. In each site, experienced anthropometrists, using adequate equipment, made the measurements in accordance with predetermined procedures. The quality of the anthropometric data was checked by examining the SD of the mean value of the Z-score for height for age, weight for age, and height for age, as recommended internationally (13). The values obtained within groups during pre- and post-trial measurements are very acceptable, with the SD being 0.81–1.08 for the length for age, 0.93–1.05 for the weight for age, and 0.87–1.02 for weight for length Z-scores. These values are either lower than or within those considered to be acceptable internationally.
Whether giving complementary food, rather than just micronutrients, would have been more effective in preventing growth faltering is open to speculation. It might be that the lack of growth impact was because the infant diets were inadequate in energy, because no extra complementary foods were provided to families, nor was any orientation provided to mothers to provide more complementary food. However, evidence from both program evaluations and well-controlled experimental trials, shows that even when complementary food intakes are improved, there may be some small impact on weight growth but very little or no impact on length growth (2–3,14–16).
The foodlets, and especially the DMM supplements, were successful in improving infant anemia and micronutrient status. The DMM was superior to the WMM and the DI supplementation treatments on a number of counts. First, and perhaps most importantly, DMM was as good if not better than the DI supplement and the WMM supplement for improving iron status and reducing anemia. The study confirms the review of Beaton and McCabe (17), which found that DI supplementation is more efficacious than weekly supplementation for controlling anemia during periods of rapid growth. It is logical that the DMM would be better than the DI for controlling anemia, because anemia is not just caused by iron deficiency but by a lack of other components of the multiple micronutrient supplements, such as riboflavin, folic acid, vitamin C, and vitamin A, which are all known to favor iron absorption and/or hematopoiesis (18–19). Second, the DMM improved circulating concentrations of other nutrients, perhaps most importantly, zinc, but also tocopherol and riboflavin. Third, the DMM and the WMM improved B vitamin status of these infants, as evidenced by reduced plasma homocysteine concentrations. Homocystinemia is associated with deficiencies of folate, vitamin B-12, vitamin B-6, or riboflavin. Because the multiple micronutrient supplements contain all of these nutrients, the improvement could be due to any of them. Folate deficiency is less likely than B-12 deficiency in breast-fed infants, because breast milk folate content is protected by depleting maternal folate reserves (20), whereas breast milk B-12 levels are known to be poor when maternal intake of animal source foods is limited (21). The limited impact of the DMM and the WMM on vitamin A status of the infants is a testament, on one hand, to the protective benefits of breast milk for vitamin A status and, on the other hand, to the massive dose capsule campaigns carried out in all 4 countries, which attempt to reach all children aged 6–59 mo at least twice a year. Even so, there was still an effect of the DMM treatment on plasma retinol. Unfortunately, biochemical markers for other water-soluble vitamins contained in the multiple micronutrient supplements, such as thiamine, vitamin B-6, and vitamin C, were not measured, so it is not possible to assess whether the status of these micronutrients was also improved.
The improved micronutrient status due to the multiple micronutrient supplements will likely contribute to improving other child development outcomes beyond growth. Iron deficiency and anemia during infancy are known to produce cerebral changes in early life that compromise cognitive function in early and late development (22). Zinc deficiency is postulated to be a cause of stunting (23), and zinc supplementation trials have shown growth effects in young children, primarily in those already stunted (24–28). Zinc deficiency greatly increases the risk of young child morbidity and mortality (29), and zinc supplementation can have a dramatic impact on infections common in childhood (30–31). The lack of impact of any of the micronutrient supplement treatments on either AGP or CRP concentrations suggests that there was no effect of these interventions on infection rates or response to infections. Whether the multiple micronutrient supplements that contained zinc used in the IRIS trials had an effect on infant health is discussed further in the individual country papers; but, because definitions and reporting methods for morbidity differed across sites, morbidity was not included in this pooled data analysis.
A higher dose of the multiple micronutrients, and especially of iron and zinc, would likely have caused a greater improvement in micronutrient status and reduction in anemia in the infants studied. At the end of the trial, between a third and a quarter of the infants were still either iron and/or zinc deficient and/or anemic. The weekly and the daily multiple micronutrient supplements showed dose–response relationships for most biochemical outcomes, such that if a higher daily dose were used, it should be possible to eliminate anemia and/or iron and zinc deficiency states during 6 mo of supplementation. The level of nutrients contemplated for use in the foodlets were based on those recommended daily intakes in Canada and the United States (6), and were developed to prevent deficiency developing and not to reverse deficiencies already installed. In the IRIS trial, at least half of the infants were anemic at baseline. Furthermore, the levels of infection in developing country settings are considerably greater than in the United States and Canada, which will increase needs for all nutrients. There was no evidence from the study of any negative effects of the foodlets. Furthermore, there was no negative interaction observed between zinc intake and iron status in the multiple micronutrient supplement foodlets, as has been reported for joint iron and zinc supplementation given as syrups (32–33). Future experimentation with the development of foodlets should consider ways of delivering a higher dosage of nutrients. Regardless of these further trials to further refine the type of multiple micronutrient supplements to be used, it would seem important to now take the positive results of this efficacy trial and subject the foodlets to larger-scale effectiveness trials.
In conclusion, DMM supplementation through foodlets given to infants during the second semester of life was successful in reducing the degree of weight growth faltering in the 4 countries IRIS pooled data analysis. Weight growth faltering still occurred, however, and there was no protective effect on stunting in infancy. Daily micronutrient supplementation through foodlets was more effective than weekly supplementation in reducing anemia and in improving nutrient status. The prevalence of multiple micronutrient deficiencies in the pooled sample was high, with anemia affecting the majority, and was not fully controlled in the supplemented infant population even after 6 mo of treatment. These very positive results indicate the need for larger effectiveness trials to examine how to deliver foodlets at program scale and how to estimate cost benefits. Consideration should also be given to increasing the doses of micronutrients delivered in the foodlets.
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FOOTNOTES |
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2 Supported by UNICEF, New York, NY.
4 Abbreviations used: AGP, -1-acid glycoprotein; CRP, C-reactive protein; DI, daily iron supplement; DMM, daily multiple micronutrient supplement; EGRAC, erythrocyte glutathione reductase activity coefficient; HAZ, height-for-age Z-score; IRIS, International Research on Infant Supplementation; LSmeans, Least-squares means; P, placebo; WAZ, weight-for-age Z-score; WHZ, weight-for-height Z-score; WMM, weekly multiple micronutrient supplement.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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