![]() |
|
|
National Institute of Nutrition, Hanoi, Vietnam, and * The Institute of Research for Development, Research Unit "Nutrition, Food, Societies," Montpellier, France
3To whom correspondence should be addressed. E-mail: Hopnin{at}hn.vnn.vn.
| ABSTRACT |
|---|
|
|
|---|
KEY WORDS: multiple micronutrient supplementation anemia Vietnam infant growth
Undernutrition and micronutrient deficiencies, such as vitamin A, iron, and iodine, are important nutritional problems among preschool children in Vietnam (1), and a more serious problem than in many other developing countries. Although rates have improved in the last 2 decades, the prevalence of stunting remains high and was 60%, 49%, and 36% in 1985, 1990, and 2000, respectively (24). Early introduction of poor quality and inadequate amounts of complementary foods, a low rate of exclusive breast-feeding and the high frequency of diseases during early infancy may be the reasons for growth retardation (57). In rural areas of Vietnam, multiple micronutrient deficiencies are common throughout the life span and particularly in small children, such that 45% of children < 5-y old suffered from anemia in 1995 and 34% in 2000 (8,9). A major achievement in recent years has been the effective implementation of the high-dose vitamin A capsule supplementation program, which has substantially reduced the magnitude of vitamin A deficiency in the country. Nutritional blindness, which previously threatened 5000 to 7000 children a year, has been eradicated. The incidence of active xerophthalmia has fallen from 7 times above to below the WHO cutoff point that indicates a significant public health problem (10). The prevalence of subclinical vitamin A deficiency (defined as serum retinol < 0.7 µmol/L) among children aged <5 y was reduced from 14% in 1995 to 10% in 2000 (10,11).
Although the consequences of these micronutrient deficiencies during early childhood are considerable, in Vietnam, programs to resolve them are still dispersed and incomplete. Iron deficiency causes anemia and has negative effects on the motor and the mental development of young children (12). Aside from its effect on vision, vitamin A deficiency increases the risk of morbidity and mortality (13). Zinc deficiency negatively influences growth of children (14,15) and increases the risk of diarrhea and respiratory infections (16), but, as yet, there is no program aimed at controlling it. Child populations in Vietnam typically suffer simultaneously from these different micronutrient deficiencies, and yet supplementation programs for different single micronutrients are implemented in parallel, so that efforts and resources are duplicated and cost-effectiveness is reduced. Alternatives to the current single-nutrient supplementation strategies thus need to be investigated to increase effectiveness, and multiple micronutrient supplementation has been suggested as one such alternative. Several studies have been conducted to test the efficacy of multiple micronutrient supplementation in schoolchildren and adolescents. However, little is known about the efficacy of multiple micronutrient supplementation in infants, the age group mainly affected by these deficiencies. The main objective of the study was to evaluate the efficacy of multiple micronutrient supplementation for improving nutrition status of infants from micronutrient deficient populations in rural Vietnam.
| MATERIALS AND METHODS |
|---|
|
|
|---|
This study was part of the international multicenter trial carried out in 4 countries (Peru, South Africa, Indonesia, and Vietnam) and implemented according to a master protocol written with the contributions from all principal investigators in the country sites. The study began in March 2000 with a preparation phase from March to May 2000 and an intervention phase from June 2000 to January 2001. The study was conducted in 4 communes (Phu Minh, Duc Hoa, Xuan Thu, and Phu Lo) in the rural district of Socson, Hanoi City. The Scientific Committee of the National Institute of Nutrition approved the study in accordance with the guidelines of the Council for International Organizations of Medical Sciences (17). Infants aged from 6 to 12 mo were identified by a house-to-house search, and the mothers and/or caretakers were invited to participate in the study. The mothers were informed about the purpose of the study, and only infants of mothers who agreed with the informed consent were included. Additional exclusion criteria were severe wasting (weight-for-height Z-score <3 Z), fever (>39°C), premature birth (<37 wk) or low birth weight (<2500 g), and severe anemia [hemoglobin (Hb) <80 g/L]. In this randomized, double-blind, placebo-control study, subjects were randomly assigned to 4 treatment groups: daily multiple micronutrients (DMM)4; weekly multiple micronutrients (WMM); daily iron supplements (DI), and daily placebo (P). A random number selection process was used to assign children to treatment groups, with each child having a specific number that matched the numbered packages of supplements.
Intervention
The micronutrient supplement and placebo treatments, packed in identical-looking blister packs containing 7 foodlets, one for each day of the week, were developed and produced centrally as has been described previously (18). The DMM supplement contained the daily adequate intake (AI) of 15 micronutrients for young children. The WMM supplements had twice the daily AI amount of the same micronutrients. The DI supplement contained the daily AI for iron. Supplements and placebo were given 7 d/wk, with the WMM supplement given one day, followed by placebo supplements on the other 6 d. The parents of infants were requested to take their infant every day to the house of the health collaborators selected in each village/hamlet participating in the study. Treatments were numbered and were put in a plastic bag for each child and were given by the collaborators to infants each day, with one collaborator responsible for 5 to 10 infants. The commune health center workers supervised the quality of the work of the field collaborators weekly, and the National Institute of Nutrition (NIN) investigators visited the selected households twice per month.
Measurements, data, and blood sample collection
Trained NIN anthropometrists measured childrens weight and length monthly. Weight was recorded to the nearest 0.1 kg, while children were minimally clothed, with an electronic weighing scale (SECA). Length was recorded to the nearest 0.1 cm using the WHO-recommended length-measuring board for infants (Ahrtag). Venous blood was drawn from the vein in the morning between 700 and 1100 at the commune health center and was transported to the micronutrient laboratory of NIN. Blood samples were taken at baseline and at the end of the intervention.
Biochemical analysis
Hb concentration was determined in the Micronutrient Laboratory of NIN using the cyanomethemoglobin method. Blood was then centrifuged at 3000 x g for 10 min at 4°C and aliquots of plasma were placed in Eppendorf tubes. Plasma was stored at 20°C and was sent to Germany for biochemical analysis for ferritin, retinol, zinc, tocopherol, EGRAC, homocysteine, and C-reactive protein at the University of Hohenhiem, in accordance with methods indicated in the master protocol and reported elsewhere (19).
Statistical analysis
Statistical analysis of data were carried out using SAS software release 8.2 for Windows. All statistical analysis on anthropometrical and biochemical data were done after adjustment for gender and age at baseline. Means of anthropometrical indices are presented as adjusted means ± SE. Other biochemical continuous variables are presented as means (SD) except for ferritin and homocysteine, which are presented as geometric mean and 95% CI. To take into account the repeated measurement structure of the data, for each response variable a repeated measures ANOVA model was used. The compound symmetry covariance structure was chosen to model the structure of dependence of the error terms, which is equivalent to including a subject random effect in the model (multilevel model) (20). Models featuring visit, treatment group, and interaction group x visit as fixed effects were fitted using maximum likelihood estimation. Effect of treatment on the evolution of the response variables was assessed by the test of group x visit interaction term (null hypothesis of no differential evolution between the 4 groups). When relevant (i.e., "significant" F-test for visit x group effect at the chosen type I error risk level of 0.05) specific contrasts were computed to assess differential evolution between specific groups. Bonferronis correction was applied by dividing the cutoff of significance of 0.05 by the number of comparisons between groups, i.e., 6 comparisons or 0.05/6 = P < 0.0083. All the models also included gender and age at entry as covariates. The models were fitted with Proc Mixed (21) in the SAS release 8.2 for Windows. For biochemical variables that were not normally distributed (ferritin and homocysteine), statistical analysis was carried out after log transformation of data.
| RESULTS |
|---|
|
|
|---|
A total of 346 infants were included in the study and were randomly assigned to the 4 groups (Fig. 1). Of these infants, 22 did not arrive for the baseline visit, and one refused blood sampling. Blood samples were obtained from 323 infants. Seventeen of these infants (5.3%) had an initial Hb concentration lower than 80 g/L [mean (SD), 69.2 ± 10.4 g/L]. They were excluded from the study and were referred to the commune health center for treatment. Five infants did not return for the final evaluation (6 mo after baseline) and were excluded from data analysis. Data analysis thus was conducted on 301 infants. All infants received >80% of the maximum dose of supplements, except for one infant in the DMM treatment group who received 77% of the maximum dose.
|
Neither gender distribution nor mean age, anthropometrical indices, or Hb concentration were statistically different among groups at baseline (Table 1). The mean length-for-age and weight-for-age Z-scores of the infants approached 1.0 compared with the National Child Health Survey (NCHS) population, and >80% of infants were anemic.
|
The anthropometric values obtained during the study period are presented in Table 2. All anthropometric indices worsened significantly from baseline to posttreatment in all 4 groups, with a significant group by month of visit interaction only for length-for-age (P = 0.001). During the study period, length-for-age growth faltering was significantly less in the DMM group than in the P or WMM groups but not significantly less than in the DI group. The prevalence of stunting was not significantly different among treatment groups at baseline or at the end of the study.
|
|
|
| DISCUSSION |
|---|
|
|
|---|
These results confirm those of the many other micronutrient supplementation trials that have shown a positive effect on growth of Vietnamese infants. For example, Ninh et al. (14) showed that daily zinc supplementation for 6 mo improved the growth of children who were already stunted. Thu et al. (22) showed that the growth of children already stunted was improved by both weekly and daily multiple micronutrient supplementation, with a multiple micronutrient supplement that only contained iron, zinc, retinol, and vitamin C. That micronutrient supplements show such an effect on growth is surprising, considering that well implemented growth promotion activities have found it difficult to improve growth of young preschool children in Vietnam, including improving complementary feeding practices (23,24).
The DMM supplement was the best treatment for improving both anemia and iron status during infancy. Those infants who received DMM had a significant increase in mean Hb level and a lower prevalence of anemia at the end of the intervention compared with the P group. The mean Hb concentration and the anemia prevalence of the other treatments (WMM and DI) were intermediate compared with DMM and P treatments but not significantly different from the placebo children. Iron stores as reflected by plasma ferritin were significantly improved in the DMM and DI groups but fell in the P and WMM groups. Although anemia rates were very high, at about 90% at the beginning of the study period when the infants averaged 8 mo of age, low iron stores were less prevalent, with <20% low ferritin values. At the end of the intervention period, no infant had low ferritin concentrations in the groups receiving daily iron, either alone (DI) or in combination with other micronutrients (DMM), whereas the prevalence of low ferritin values increased to 50% and 30% in the P and WMM groups, respectively. Other studies in children (2527), both in Vietnam and elsewhere, have shown that weekly iron supplementation, either alone or with multiple micronutrients, can be as effective as daily iron supplementation for improving iron status or reducing anemia. The WMM supplementation in this study showed an improvement in Hb concentration compared with the P group but was not able to prevent the depletion of iron stores during the second semester of life. Indeed, even in DMM, the most successful treatment group, a quarter of the children were still anemic after 6 mo of supplementation. Because the DMM supplementation was more effective than daily iron for reducing anemia in these Vietnamese infants, this suggests that the anemia is not due to iron deficiency alone but also to deficiencies of micronutrients that are contained in the multiple micronutrient supplement.
There was no difference among the different micronutrient supplements in their effect on other plasma micronutrient concentrations, except for tocopherol. All groups showed an increase in plasma tocopherol levels during the 6-mo trial period, but the increase in the DMM group was significantly greater than in the other groups. Whether these higher plasma tocopherol levels confer any benefit is unclear, but it suggests that the antioxidant status of the DMM group is better than that of the others. All groups showed improvement in mean vitamin A concentrations during the course of the intervention, and there was no significant interaction between time and treatment for plasma retinol levels. That the prevalence of low retinol values improved during the course of the trial in all supplement groups, including those without vitamin A, suggests that the Vietnamese vitamin A capsule program was effective in reaching most of the infants in the second semester of life in the area of the trial. About 20% of these infants had deficient plasma retinol concentrations at the beginning of the study period, which probably reflects the fact that the coverage of high-dose vitamin A capsules to mothers at or near birth is not very high and that exclusive breast-feeding during the first 6 mo is not extensively practiced. The lack of an impact of the DMM on either riboflavin or homocysteine values suggests that the folate, the B-12, and the riboflavin status of these infants were adequate or that the amount in the supplement was too low. However, the lack of impact of the DMM on plasma zinc does not mean that their zinc status is adequate, because between a third and a quarter of infants had deficient plasma zinc values at the end of the trial, with little difference across groups. This strongly suggests that the level of zinc used in the DMM supplement is not enough to treat and/or to prevent zinc deficiency in these Vietnamese infants.
The results of this trial are of relevance beyond the study area in the Red River Delta, because the nutritional status of infants included in the trial is similar to that of infants in Vietnam as a whole. At the end of the trial, when the average age of the trial children was 14 mo, the underweight rate was 32%, which compares well with the underweight rates of 35% of preschool children for Vietnam overall (4). Iron-deficiency anemia was more common in the study population than nationally, because 90% of the studied infants were affected compared with the national estimated prevalence of 34% in preschool children (9). Anemia rates are highest in infancy and then tend to decrease, and similar levels were found in another study conducted in Bac Ninh Province, where the prevalence of anemia in infants was >60% (25).
In conclusion, the DMM supplementation had the best overall performance of the micronutrient supplements tested. Only the DMM supplement reduced the rate of lengthgrowth faltering. Weightgrowth faltering was not influenced by any of the treatments tested. The DMM supplements also had the best hematinic effect. Only groups that received daily iron supplements, alone or in combination with other micronutrients, improved their iron stores, and, by the end of intervention, none of these infants had low iron stores, whereas in the other 2 groups, iron status worsened. The impact on the status of other micronutrient was less consistent, with just plasma tocopherol showing a significantly greater concentration in the DMM group compared with placebo. Zinc status was deficient in a third of infants and was not improved even in the DMM group, suggesting that the zinc dose in the DMM supplement is too small. These results are very encouraging overall and suggest that further larger scale effectiveness trials should be carried out over a longer period of intervention, looking at supplements with a greater dose of zinc.
| FOOTNOTES |
|---|
2 This study was carried out in the framework of the International Research on Infant Supplementation group (IRIS), and was funded by UNICEF. ![]()
4 Abbreviations used: AGP,
-1-acid glycoprotein; AI, adequate intake; DI, daily iron supplement; DMM, daily micronutrient supplement; EGRAC, erythrocyte glutathione reductase activity coefficient; Hb, hemoglobin; IRIS, International Research on Infant Supplementation; NIN, National Institute of Nutrition; P, placebo; WMM, weekly multiple micronutrient supplement. ![]()
| LITERATURE CITED |
|---|
|
|
|---|
1. Khoi, H. H. & Giay, T. (1994) The nutritional disorders and health status of Vietnamese community 1994 Medical Publishing House Hanoi, Vietnam.
2. Khoi, H. H. (1990) Protein Energy Nutritional Status of Some Rural Regions of Vietnam. D.Sc. dissertation 1990 University of Warsaw Warsaw, Poland.
3. Bloem, M. W., Gorstein, J. & Khoi, H. H. (1995) Vietnam: Xerophthalmia Free. National Vitamin A Deficiency and Protein-Energy Malnutrition Survey in 1994 1995 Medical Publication Hanoi, Vietnam.
4. UNICEF (2003) The State of the Worlds Children 2004 2003 UNICEF New York, NY.
5. Khoi, H. H., Khan, N. C. & Mai, L. B. (2002) Results of the National Food and Nutrition Survey 2000. Executive summary 2002 National Institute of Nutrition, Ministry of Health Hanoi, Vietnam.
6. Hop, L. T. (1995) Longitudinal Observation of Physical Growth of Vietnamese Children from Birth to 10 Years in Vietnam Conditions. MSc Thesis 1995 SEAMEO-TROPMED, University of Indonesia Jakarta, Indonesia.
7. Hop, L. T., Gross, R., Giay, T., Schultink, W., Thuan, B.T.N. & Sastroamidjojo, S. (1997) Longitudinal observation of growth of Vietnamese children in Hanoi, Vietnam from birth to 10 years of age. Eur. J. Clin. Nutr. 51:164-171.[Medline]
8. Ninh, N. X., Khan, N. C. & Khoi, H. H. (2001) Khoi, H. H. Ninh, N. X. Khan, N. C. Lam, N. T. eds. Micronutrient deficiencies and strategies for their control in Vietnam. In: 20 Years of Prevention and Control of Micronutrient Deficiency in Vietnam 2001:24-33 Medical Publishing House Hanoi, Vietnam. .
9. Khanh, N. C., Dien, D. N. & Tan, T. M. (2001) Anemia in Vietnamese children in 1997. Khoi, H. H. Ninh, N. X. Khan, N. C. Lam, N. T. eds. 20 Years of Prevention and Control of Micronutrient Deficiency in Vietnam 2001:113-121 Medical Publishing House Hanoi, Vietnam. .
10. Khoi, H. H., Khan, N. C. & Giay, T. (2001) Progress of vitamin A deficiency control program in Vietnam. Khoi, H. H. Ninh, N. X. Khan, N. C. Lam, N. T. eds. 20 Years of Prevention and Control of Micronutrient Deficiency in Vietnam 2001:4-23 Medical Publishing House Hanoi, Vietnam. .
11. Ninh, N. X., Quyen, D. T. & Thu, N. N. (2001) Sub-clinical vitamin A deficiency and some related factors among children and lactating mothers in Red River Delta provinces. Khoi, H. H. Ninh, N. X. Khan, N. C. Lam, N. T. eds. 20 Years of Prevention and Control of Micronutrient Deficiency in Vietnam 2001:123-130 Medical Publishing House Hanoi, Vietnam. .
12. Latham, M. C., Stephenson, L. S., Kinoti, S. M., Zaman, M. S. & Kurz, K. M. (1990) Improvements in growth following iron supplementation in young Kenyan Children. Nutrition 6:159-165.[Medline]
13. Rahmathullah, L., Underwood, B. D., Thulasiraj, R. D. & Milton, R. C. (1990) Diarrhea and respiratory infections and growth are not affected by a weekly low dose vitamin A supplement: A controlled field trial in children in Southern India. Am. J. Clin. Nutr. 54:568-577.
14. Ninh, N. X., Thissen, J. P., Collette, L., Gerard, G., Khoi, H. H. & Ketelslegers, J. M. (1996) Zinc supplementation increases growth and circulating insulin-like growth factor I in growth retarded Vietnamese children. Am. J. Clin. Nutr. 63:514-519.
15. Brown, K. H., Peerson, J. M. & Allen, L. H. (1998) Effect of zinc supplementation on childrens growth: a meta analysis of intervention trails. Bibl. Nut. Dieta 54:76-83.
16. Castillo-Duran, C., Heresi, G., Fishbierg, M. & Uauy, R. (1987) Controlled trial of zinc supplementation during recovery from malnutrition: effect on growth and immune function. Am. J. Clin. Nutr. 45:602-608.
17. Council for International Organizations of Medical Sciences (2002) International Ethical Guidelines for Biomedical Research Involving Human Subjects 2002 CIOMS/WHO Geneva, Switzerland.
18. Lock, G. (2003) The foodLET vehicle designed for and used in the IRIS 1 interventions. Food Nutr. Bull. 24:S16-S19.[Medline]
19. Smuts, C. M., Benadé, A.J.S., Berger, J., Hop, L. T., López de Romaña, G., Untoro, J., Karyadi, E., Erhardt, J. & Gross, R. (2003) IRIS I: a foodlet-based multiple-micronutrient intervention in 6- to 12-month-old infants at high risk of micronutrient malnutrition in four contrasting populations: description of a multicenter field trial. Food Nutr. Bull. 24:S27-S33.[Medline]
20. Diggle, P. J., Liang, K. Y. & Zeger, S. L. (1994) Analysis of Longitudinal Data 1994 Clarenton Press Oxford, UK.
21. Littell, L., Milliken, G. A., Stroup, W. W. & Wolfinger, R. D. (1996) SAS System for Mixed Models 1996 SAS Institute Inc Cary, NC.
22. Thu, B., Schultink, W., Dillon, D., Gross, R., Leswara, N. D. & Khoi, H. H. (1999) Effect of daily and weekly nutrient supplementation on micronutrient deficiencies and growth of young Vietnamese children. Am. J. Clin. Nutr. 69:80-86.
23. Schroeder, D. G., Pachon, H., Dearden, K. A., Kwon, C. B., Ha, T. T., Lang, T. T. & Marsh, D. R. (2002) An integrated child nutrition intervention improved growth of younger, more malnourished children in northern Viet Nam. Food Nutr. Bull. 23:53-61.
24. Pachon, H., Schroeder, D. G., Marsh, D. R., Dearden, K. A., Ha, T. T. & Lang, T. T. (2002) Effect of an integrated child nutrition intervention on the complementary food intake of young children in rural north Viet Nam. Food Nutr. Bull. 23:62-69.[Medline]
25. Ninh, N. X., Berger, J., Quyen, D. T., Khan, N. C., Traissac, P. & Khoi, H. H. (2002) Efficacité de la supplémentation en fer quotidienne et hebdomadaire pour le contrôle de lanémie chez le nourrisson en milieu rural au Viêt Nam. Cahiers detudes et de recherches francophone/Santé, vol. 12, no. 1 2002:31-37 JanvierFévrier 2002.
26. Schultink, W., Gross, R., Karyadi, D. & Matulessi, P. (1995) Effect of daily vs twice weekly iron supplementation in Indonesian preschool children with low iron status. Am. J. Clin. Nutr. 61:111-115.
27. Berger, J., Aguayo, V., San Miguel, J. L., Tellez, W., Lujan, C. & Traissac, P. (1997) Weekly iron supplementation is as effective as 5 day-per week iron supplementation in Bolivian school children living at high altitude. Eur. J. Clin. Nutr. 51:381-386.[Medline]
This article has been cited by other articles:
![]() |
S. Adu-Afarwuah, A. Lartey, K. H Brown, S. Zlotkin, A. Briend, and K. G Dewey Home fortification of complementary foods with micronutrient supplements is well accepted and has positive effects on infant iron status in Ghana Am. J. Clinical Nutrition, April 1, 2008; 87(4): 929 - 938. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. Adu-Afarwuah, A. Lartey, K. H Brown, S. Zlotkin, A. Briend, and K. G Dewey Randomized comparison of 3 types of micronutrient supplements for home fortification of complementary foods in Ghana: effects on growth and motor development Am. J. Clinical Nutrition, August 1, 2007; 86(2): 412 - 420. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. T. Howard, S. de Pee, M. Sari, M. W. Bloem, and R. D. Semba Association of diarrhea with anemia among children under age five living in rural areas of Indonesia J Trop Pediatr, August 1, 2007; 53(4): 238 - 244. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. F. Walker, K. Kordas, R. J Stoltzfus, and R. E Black Interactive effects of iron and zinc on biochemical and functional outcomes in supplementation trials Am. J. Clinical Nutrition, July 1, 2005; 82(1): 5 - 12. [Abstract] [Full Text] [PDF] |
||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||