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Multiple micronutrient supplementation increases the growth of Mexican infants1–4 Juan A Rivera, Teresita González-Cossío, Mario Flores, Minerva Romero, Marta Rivera, Martha M Téllez-Rojo,Jorge L Rosado, and Kenneth H Brown ABSTRACT
many studies about the effect of individual micronutrients on Background: The role of single micronutrient deficiencies in the
etiology of growth retardation has recently gained attention. How- Supplementation trials using single micronutrients show pos- ever, because multiple micronutrient deficiencies are common in itive but small effects of zinc supplementation on growth. The children in developing countries, it is possible that more than one effects are greater in stunted children and in children with low micronutrient may limit growth and, hence, the correction of a sin- serum zinc concentrations (3). The results of iron supplementa- gle deficiency may not be enough to improve growth substantially.
tion studies indicate positive effects in anemic children but Objective: The objective was to evaluate the effect of multiple
not in nonanemic children (4–7); there appear to be few or no micronutrient supplementation on the growth of children aged effects of vitamin A on growth (8–10), except in children with 8–14 mo whose diets were poor in several micronutrients.
Design: Children were randomly assigned to 1 of 2 groups. One
Multiple micronutrient deficiencies are common among chil- group received a multiple micronutrient supplement containing dren living in poverty. It is possible that more than one micronu- the recommended dietary allowance (RDA) or 1.5 times the RDA trient deficiency is responsible for limiting growth; therefore, the of vitamins A, D, E, K, C, B-1, B-6, B-12, riboflavin, niacin, correction of a single deficiency may not be enough to improve biotin, folic acid, and pantothenic acid, and iron, zinc, iodine, growth substantially. In experimental animals, an imbalance of copper, manganese, and selenium. The other group received a essential nutrients in the diet (12) or micronutrient deficiencies placebo. Supplements were administered 6 d/wk for an average of (13) produce anorexia, which may affect growth. It has been sug- 12.2 mo. Body length was measured at baseline and monthly gested that latent deficiencies of other micronutrients besides thereafter until the end of supplementation.
zinc can suppress growth after zinc repletion (14, 15).
Results: Supplemented infants initially aged < 12 mo had signi-
A multiple micronutrient supplementation trial conducted in ficantly greater length gains than did the placebo group, with a Chinese children aged 6–9 y found positive effects of supple- difference of 8.2 mm (length-for-age z score: 0.3) at the end of mentation on growth (16). Children received multiple micronu- supplementation. In contrast, differences in length gains between trients, including zinc; multiple micronutrients without zinc; or the supplemented and placebo groups initially aged ≥ 12 mo were zinc only. The greatest effects occurred after treatment with the multiple micronutrient mixture that included zinc. Notably, the Conclusions: Micronutrient deficiencies limited the growth of the
group that received multiple micronutrients without zinc had a Mexican infants studied. Improving micronutrient intakes should greater growth response than did the group that received zinc be a component of interventions to promote growth in infants liv-ing in settings where micronutrient intakes are inadequate.
Am J Clin Nutr 2001;74:657–63.
1 From the Centro de Investigación en Nutrición y Salud, Instituto Nacional de Salud Pública, Cuernavaca, Morelos, Mexico; the Departamento KEY WORDS
de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutri- growth, growth retardation, micronutrient deficiencies, Mexico, ción “Salvador Zubirán”, Mexico DF; and the Program in International Nutri- tion and Department of Nutrition, University of California, Davis, CA.
2 Preliminary results presented as an abstract at Experimental Biology 1996 (FASEB J 1996;10:A290) and in tabular form at Experimental Biology 1998.
INTRODUCTION
3 Supported by the Applied Diarrheal Disease Research Program from Harvard University (grant 184) and by the World Health Organization (pro- Growth retardation is highly prevalent among children in low-income countries (1). Infections and inadequate food 4 Address reprint requests to JA Rivera, Instituto Nacional de Salud Pub- intake are well-established causes of growth retardation; how- lica, Avenida Universidad no. 655, Colonia Santa Maria Ahuacatitlan, CP ever, the possible specific role of micronutrient deficiencies in 62508, Cuernavaca, Morelos, Mexico. E-mail: jrivera@insp.mx.
the etiology of growth retardation and other developmental and health outcomes has gained attention recently. As a result, Accepted for publication January 3, 2001.
Am J Clin Nutr 2001;74:657–63. Printed in USA. 2001 American Society for Clinical Nutrition only. The results suggest that deficiencies in micronutrients other sium iodide), copper (as copper gluconate), manganese (as man- than just zinc were suppressing growth.
ganese sulfate), and selenium (as selenium sulfate). The supple- The dietary intake of children in rural areas in Mexico is defi- ment also contained 1.2 times the RDA for children aged 1–3 y cient in several micronutrients. A national probabilistic survey of vitamin A (as retinyl palmitate) and 1.5 times the RDA of conducted in 1999 found that children aged < 5 y in rural Mex- ascorbic acid (extra fine), riboflavin, vitamin B-12, iron (as fer- ico had low dietary intakes of iron, vitamin A, vitamin C, and ric orthophosphate), and zinc (as zinc sulfate).
zinc relative to requirements (17). The same survey reported a The beverages were provided to the children 6 d/wk for an national prevalence of anemia of 27.2% in children aged < 5 y average of 12.2 mo under supervision of the study personnel, and almost 50% in children aged 12–23 mo. Other dietary infor- who recorded whether the supplement was consumed.
mation suggests low intakes of vitamin B-6 and riboflavin and community based studies in rural areas have found biochemical Data collection
evidence of iron, zinc, vitamin A, vitamin C, and vitamin B-12 At baseline, anthropometric measures were made, morbidity and socioeconomic (eg, education level of the parents and housing We conducted a study to evaluate the effect of multiple micronu- quality) data were collected, intakes of breast milk and comple- trient supplementation on the growth of children aged 8–14 mo liv- mentary foods were obtained by direct weighing, and information ing in a setting where the diet is poor in several micronutrients.
about the children’s appetites was ascertained. Biochemical dataon the micronutrient status of the children were unavailablebecause most of the families considered it unacceptable to draw SUBJECTS AND METHODS
blood from infants. After the baseline data were collected, allparticipating children (n = 337) were followed for an average of Study sample
12.2 ± 1.8 mo. During this time, anthropometric measures were The present study was conducted in Xoxocotla, State of made and dietary intakes were ascertained.
Morelos, a semirural setting located 90 km south of Mexico City, at an altitude of 930 m above sea level, with an estimatedpopulation of 16 800 inhabitants. Agriculture is the principal Anthropometric measures were made approximately every occupation here and the general social and economic conditions month until the end of supplementation. Weight was measured to are poor. Most streets are unpaved and there is no sewage sys- the nearest 10 g with an electronic scale (model 1583; Tanita, tem, although a water supply system is available. A study con- Tokyo) and length was measured to the nearest millimeter with a ducted in a random sample of 366 families in this community locally made wooden measuring board by 2 anthropometrists showed that 62% of the houses had dirt floors, 31% had no who were trained to take all measurements using standard tech- latrines or toilets, and 21% had no water supply into the house.
niques (22, 23). Technical errors of measurement (TEMs) at the Twenty-three percent of children aged < 5 y of age were stunted end of the standardization period were within values reported for [length-for-age or height-for-age z score < Ϫ2 of the reference carefully conducted studies such as the Fels Longitudinal Study data of the World Health Organization/National Center for Health (22). For example, the intrameasurer TEMs for the 2 anthro- Statistics/Centers for Disease Control and Prevention (WHO/ pometrists were 0.4 and 1.1 mm for length and 90 and 110 g for NCHS/CDC; 19)]. Most of the men in this region are either weight. The corresponding intermeasurer TEMs were 3.6 mm for agricultural laborers or construction workers, whereas most of length and 136 g for weight. An experienced anthropometrist the women sell agricultural products in local markets or work as visited the field every other week to supervise the measuring domestic employees in nearby cities.
techniques. Length and weight data were transformed to z scores The research team completed a census of Xoxocotla to iden- by using the WHO/NCHS/CDC reference data (19).
tify children aged 8–14 mo. A total of 337 children in this age group were enrolled after written consent was obtained fromtheir parents. The study protocol was explained in detail to each Morbidity data were collected daily at the time the supple- family and was approved by the Committee on the Use of Human ment was distributed. A checklist was used to record symptoms Subjects in Research of the National Institute of Public Health.
of diarrhea and acute respiratory infection observed by the moth-ers or caretakers during the previous 24 h. The morbidity data are Study design
The Moses-Oakford method (20) was used to randomly assign children to 1 of 2 groups in this double-blind, placebo-controlled,supplementation trial. One group received 30 mL of a beverage In a subsample of 163 children (87 in the micronutrient group containing multiple micronutrients (micronutrient group) and the and 76 in the placebo group), dietary intakes were evaluated other received 30 mL of a placebo (placebo group). The 2 bev- at baseline and 2–3 mo after the initial measurement. Dietary erages were indistinguishable, both of which contained sugar evaluations included direct weighing of all foods and beverages and artificial flavors but no protein or fat, and provided 126 kJ consumed during Ϸ12 h and a 24-h dietary recall questionnaire concerning dietary intakes during the 24 h before the direct The supplement contained the recommended dietary allowance weighing began. Data obtained from the use of both methods (RDA; 21) for children aged 1–3 y of the vitamins D (as chole- were combined to give complete 24-h dietary intakes of the chil- calciferol), E (as tocopheryl acetate), K , niacin (as nicotin- dren. A test-weighing technique was used to measure breast-milk amide), thiamine (as thiamine mononitrate), B-6 (as pyridoxine consumption during the same Ϸ12-h period of direct weighing.
hydrochloride), D-biotin, folic acid, and pantothenic acid (as Breast-milk consumption during the day was extrapolated to 24 h, D-calcium pantothenate) and of the minerals iodine (as potas- assuming that children were breast-fed during the night, by using a prediction equation derived from a study of Peruvian infants z score, which was determined monthly during supplementation, (24). The test-weighing data were not corrected for insensible and the same independent variables used in the first set, except water loss, which amounts to 0.03–0.05 g · kgϪ1 · minϪ1 (25, 26).
that the baseline length-for-age z score was used instead of base- Therefore, our values for breast-milk intake were underestimated line length. GEE models were also used to test for two-way by 1–5% (27). Energy and nutrient intakes were derived by using interactions between treatment and sex, treatment and age at a food-composition database compiled by our group that used baseline, and treatment and period of supplementation.
3 different data sources. The main source was the food-composition Probability values < 0.05 were considered statistically signifi- database of the Instituto Nacional de Ciencias Médicas y Nutri- cant for main effects and < 0.10 for interactions (32, 33). All statis- ción “Salvador Zubirán” (the Mexican database).
tical analyses were performed by using STATA (release 6.0, Stata This database was complemented with data from the US Statistical Software, Stata Corporation, College Station, TX).
Department of Agriculture (28) and from the Institute of Nutri-tion of Central America and Panama (Guatemala City,Guatemala) for nutrients or foods not available in the Mexican database. The composition of breast milk from healthy US Compliance rates relative to the total projected days of sup- women (29) was used to derive energy and nutrient intakes from plementation were 80.5% in the placebo group and 91% in the the breast milk consumed in the present study.
supplemented group (P < 0.05). Of the 337 children originallyrecruited (n = 169 in the micronutrient group and 168 in the placebo group), 18 (n = 8 in the micronutrient group and 10 in Information about the participants household characteristics the placebo group) had missing anthropometric information; (eg, type of floor, presence of toilet, and kitchen in a bedroom), therefore, 319 children (n = 161 in the micronutrient group and the possession of selected household goods (eg, radio, television, 158 in the placebo group) were included in the analysis. Baseline blender, and refrigerator), and the education level of the parents characteristics of the children, their parents, and their house- was obtained by interviewing the mothers of the participating holds by treatment group are presented in Table 1 according to
children. An indicator of housing conditions was derived by the the age of the children at baseline: < 12 mo (infants) and ≥ 12 mo.
first component obtained by principal components analysis (30).
In the children aged ≥ 12 mo, there were no significant differ- Only variables with factor loadings > 0.5 were maintained in the ences in any of the variables between treatment groups. In the model (ie, house and floor material and availability of piped infants, the average weight of children in the placebo group was water and a sewer system). The component explained 51.3% of 260 g less than that of children in the micronutrient group the total variance. The resulting factor scores, which have a mean (P < 0.05). However, all other variables, including baseline of 0 and an SD of 1, were used as a continuous variable [the length, age, and anthropometric indexes, were not significantly socioeconomic status (SES) score]. In addition, the factor scores were divided into tertiles, which were further used to construct a In the children aged ≥ 12 mo, the proportion of households with the kitchen in a bedroom was significantly greater in theplacebo than in the micronutrient group. No other variables were Data analysis
significantly different between treatment groups.
Baseline characteristics of the study children, their mothers, The mean dietary intake of iron ranged from 2.12 to 2.85 mg, and their families were compared between treatment groups by of zinc ranged from 2.63 to 3.13 mg, and of vitamin A from using Student’s t tests for continuous variables and chi-square tests 506 to 660 ␮g retinol equivalents in the total population. Protein for categorical variables to identify potential confounding factors.
intakes were > 20 g in all groups and energy intakes were Taking advantage of the repeated-measures design of the between 2804 and 3210 kJ/d. Differences between treatment study, we analyzed the data by using generalized estimating equations (GEEs). This technique is used for the analysis of lon- Changes in anthropometric measurements from baseline to gitudinal data that are an extension of the generalized linear the end of supplementation are presented in Table 2 by treatment
models, which were specially developed to account for the auto- group according to the age of the children at baseline. In the chil- correlation due to serial measurements (31), and allows the use dren aged ≥ 12 mo, there were no significant differences in age of time-dependent covariates, giving the regression coefficients or in the anthropometric variables between treatment groups.
the usual interpretation. The assumption of Gaussian distribution Infants in the micronutrient group were an average of 0.7 cm of the outcome variables (length and length-for-age z score) were taller (P < 0.05) and had a length-for-age z score 0.33 units supported by an exploratory analysis of the empirical distribu- higher (P < 0.05) than children in the placebo group. None of the tion of the variables. An exchangeable correlation structure that other variables differed significantly by treatment group between baseline and the end of supplementation.
Two sets of GEE models were used to test the effect of treat- A GEE model for the assessment of effects of multiple ment on length. The first set used the dependent variable length, micronutrient supplementation on linear growth was first tested which was measured monthly from the first to the last month for all ages combined (data not shown). An interaction term of supplementation, and the independent variables treatment between treatment and age was significant (P < 0.10), indicating (micronutrients or placebo), baseline length, SES score, and sex, that the effect of treatment was greater in the younger than in the which were fixed; weight-for-length z score, age, and breast- older age group. Therefore, results are presented separately for feeding status, which were measured monthly from the first to the children aged < 12 mo and for those aged ≥ 12 mo.
the last month of supplementation; and an indicator variable for Results of the use of GEEs to determine the effects of micro- the first to the fourth 3-mo periods of supplementation. The second nutrient supplementation on length are shown in Table 3 and
set of GEE models used the dependent variable length-for-age Figure 1 and on length-for-age z scores in Figure 2. The main
TABLE 1
Baseline characteristics of the children, their parents, and their households by age1
1 n in brackets.
2 x– ± SD.
3 Significantly different from the micronutrient group, P < 0.05 (two-tailed t test).
4 Daily intake, including breast milk.
5 Subsample for dietary study.
effect of treatment and the interaction between treatment and that had length-for-age z score as the dependent variable (data period of supplementation were significant in the children aged not shown). Results indicate that girls benefited more from sup- < 12 y for both length and length-for-age z score, indicating that the effect of supplementation on linear growth increased The magnitude of the differences in attained length between as the duration of supplementation increased in this group. In the micronutrient and placebo groups by period of supplemen- contrast, the main effect of treatment and the interaction tation, after adjustment for potential confounders, are presented between treatment and the indicator variables were not signi- separately for the 2 age subgroups in Figure 1. In the infants, ficant for length in any of the 3-mo periods of supplementa- micronutrient supplementation had a positive effect on length tion in the children aged ≥ 12 mo; however, the interaction gain, which increased from 2.6 mm at the end of the first 3-mo between treatment and period of supplementation was signifi- period to 8.3 mm at the end of the fourth 3-mo period of sup- cant for length-for-age z score only in the second and third plementation. Most of the length gain (7.9 mm) occurred during the first 3 periods of supplementation. In children aged ≥ 12 mo, During data analysis, a differential response between sexes differences between the micronutrient and placebo groups were emerged; therefore, an interaction between sex and treatment smaller and were not significant. At the end of supplementation, was formally tested and it was significant (P < 0.10) in both the children aged ≥ 12 mo in the micronutrient group were on aver- model that had length as the dependant variable and in the model age only 2.0 mm taller than the children in the placebo group.
TABLE 2
Changes in anthropometric measurements and indexes from baseline to the end of supplementation in the micronutrient and placebo groups by age
categories at baseline1
1 x– ± SD.
2 Significantly different from the micronutrient group, P < 0.05 (one-tailed t test).
overall length gain that was almost 5 mm (length-for-age z score: Results of the use of generalized estimation equations to determine the 0.19) greater than the gain in the placebo group. The effect of effect of multiple micronutrient supplementation on length by 3-mo supplementation was greater in infants than in the children aged periods of supplementation, adjusted for covariates ≥12 mo. In the younger age group, supplementation resulted in an increase in length of 8.3 mm and in the length-for-age z score of 0.3 units. In the infants, the length-for-age z score decreasedduring follow-up by Ϸ0.1 units in the micronutrient group and by Ϸ0.4 units in the placebo group. In contrast, in the children aged ≥ 12 mo, the micronutrient group gained only 2.0 mm more in length (a greater length-for-age z score of placebo group after 12 mo of supplementation.
Compared with other supplementation trials, the observed effect on the infants in the present study was not only significant but was interpreted as biologically important given that the mean baseline length-for-age z score of the study children was Ϫ1.3, that macronutrients were not administered, and that the study lasted only 1 y. For example, a well-controlled supplementary feeding trial that provided a beverage with both macronutrients and micronutrients to Guatemalan children for almost 3 y (from 3 to 36 mo of age) resulted in a cumulative effect of 2.5 cm in length 1 Micronutrient = 1, placebo = 0.
2 (34), Ϸ3 times the size of the effect observed in the present trial; however, most of the effect of supplementary feeding occurred dur- ing the first 2 y of life (35). In addition, the median length-for-age Low tertile = 1, medium and high tertiles = 0.
5 Three-month periods of supplementation.
z scores in the Guatemalan infants was less than Ϫ2 before supple-mentation (36), a value that is well below the median values in thepresent study. It is well known that the closer the z score is to 0, the The magnitude of the differences in length-for-age z scores less likely it is to detect any effect on linear growth.
between the micronutrient and placebo groups by period of sup- The effects of micronutrient supplementation on length in the plementation, after adjustment for potential confounders, are infants in the present study were greater than those shown in a presented separately for the 2 age subgroups in Figure 2. Length- meta-analysis of zinc supplementation trials (3). In contrast, the for-age z scores increased from 0.12 to 0.30 units from the first to effects on older children, although statistically significant for the fourth 3-mo periods of supplementation in the infants. As was some 3-mo periods of supplementation, were small compared with the case for length, most of the effect (0.29 units) was achieved the effects of other interventions involving supplementary feeding during the first 3 periods of supplementation. In children aged or zinc supplementation. The finding of greater effects in infants ≥12 mo, adjusted differences between treatment groups were than in older children is biologically plausible. Infants grow at smaller than those for the children aged < 12 mo. At the end of the faster rates than do older children, their micronutrient needs to fourth 3-mo period of supplementation, the adjusted differences sustain this accelerated growth are greater, and their diets are often between treatment groups were 0.10 z score units (P < 0.10).
more restricted than those of older children. As mentioned previ-ously, most of the effect of supplementary feeding occurs duringthe first year of life (35); therefore, we had expected larger effects DISCUSSION
on younger children at the time the study was designed.
Administration of a multiple micronutrient supplement 6 d/wk Moreover, it is possible that the effects of supplementation for Ϸ12 mo to children aged 8–14 mo at baseline resulted in an would have been greater if the infants had been admitted to the FIGURE 1. Differences in length between the micronutrient and placebo groups (micronutrient Ϫ placebo) adjusted for length at baseline, weight-
for-length z score at baseline, monthly breast-feeding status, sex, and socioeconomic status. *Significantly different from 0, P < 0.05.
FIGURE 2. Differences in length-for-age z scores between the micronutrient and placebo groups (micronutrient Ϫ placebo) adjusted for length-
for-age z score at baseline, weight-for-length z score at baseline, monthly breast-feeding status, sex, and socioeconomic status. *Significantly differ-ent from 0, P < 0.05.
study at a younger age. The mean length of our study children at the children in the present study. However, the mean total protein baseline was already 1.3 SDs below the reference mean. The intake was 30–40% greater than recommended amounts (21) and mean length in the placebo group 1 y later was 0.25 SDs lower.
human and cow milk were the main protein sources, indicating Therefore, potentially, a greater effect could have been achieved that the protein consumed was generally of high quality. In con- in younger children. We did not include children aged < 8 mo trast, iron and zinc intakes were well below recommendations because we were also interested in evaluating the effects of sup- (21). Our results corroborate that micronutrients were a limiting plementation on appetite and behavior, which were considered dietary factor in the population studied.
easier to evaluate at older ages. Future studies should start sup- The finding that girls benefited more from supplementation than did boys, based on the effects of the interaction between sex It is highly likely that the differences in linear growth between and treatment on length, should be interpreted with caution the micronutrient and the placebo groups was due to supplementa- because sex was an unplanned comparison. Moreover, many vari- tion because our study was randomized and double-blind, the ables, including length-for-age z score, were significantly differ- supplements were administered to all children 6 d/wk under super- ent between treatment groups within sexes at baseline because vision, and the supplements were well accepted as reflected by the randomization was not stratified by sex. We recommend that high compliance rate; on average, the supplements were consumed future studies investigate this association.
on 86% of the scheduled days. Because the anthropometric indexes Breast-feeding was negatively associated with linear growth at baseline, most of the anthropometric measures made during the in this analysis, however, this finding may have been due to neg- study period, and other characteristics of the children and their ative confounding. In poor rural and semirural settings in Mex- families at baseline were similar between treatment groups, we ico, such as the site in the present study, more educated women considered randomization to have been effective (Table 1).
and those who work out of home tend to breast-feed less but live Our results indicate that growth was stimulated in the infants in in better conditions, which in turn is associated with better the first 3 mo of supplementation and continuation of supplemen- growth. In addition, anthropometric measures tend to be smaller tation yielded ongoing positive effects on growth for at least in breast-fed than in bottle-fed infants (40).
9 mo. Additional studies are needed to measure growth responses The results of our study show that micronutrients are a limit- when supplementation is begun at younger ages and continued for ing factor for the growth of infants in Mexico and that public health interventions aimed at improving the nutritional status We had hypothesized that children who were more stunted at and growth of infants and young children should consider baseline would benefit more from supplementation than would improvements in micronutrient intakes as an essential compo- less-stunted children, as was observed in a zinc supplementation nent. In addition, infants should be targeted in interventions trial in Guatemalan children (37). However, the interaction aimed at promoting growth through improvements in micronu- between degree of initial stunting and treatment was not signifi- cant. It is possible that the lack of an interaction between treat-ment and the degree of stunting was because the degree of stunting REFERENCES
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