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Community and International Nutrition

A Multimicronutrient-Fortified Seasoning Powder Enhances the Hemoglobin, Zinc, and Iodine Status of Primary School Children in North East Thailand: A Randomized Controlled Trial of Efficacy^1,2

Pattanee Winichagoon^*, Joanne E. McKenzie, Visith Chavasit^*, Tippawan Pongcharoen^*, Sueppong Gowachirapant^*, Atitada Boonpraderm^*, Mari S. Manger^**, Karl B. Bailey^**, Emorn Wasantwisut^* and Rosalind S. Gibson^**,3

^* Institute of Nutrition, Mahidol University, Salaya, Thailand; Monash Institute of Health Services Research, Monash University, Melbourne, Australia; and ^** Department of Human Nutrition, University of Otago, Dunedin, New Zealand

³ To whom correspondence should be addressed. Email: rosalind.gibson{at}stonebow.otago.ac.nz.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Anemia and co-existing deficiencies of zinc, iron, iodine, and vitamin A occur among children in many developing countries including NE Thailand, probably contributing to impairments in growth, immune competence, and cognition. Sustainable strategies are urgently required to combat these deficiencies. We assessed the efficacy of a micronutrient-fortified seasoning powder served with a school lunch on reducing anemia and improving the micronutrient status of rural NE Thai children. Children (n = 569) aged 5.5–13.4y from 10 schools were randomly assigned to receive a seasoning powder either unfortified or fortified with zinc (5 mg), iron (5 mg), vitamin A (270 µg), and iodine (50 µg) (per serving) and incorporated into a school lunch prepared centrally and delivered 5 d/wk for 31 wk. Teachers monitored school lunch consumption. Baseline and final micronutrient status, hemoglobinopathies, and infection or inflammation were assessed from blood and urine samples. For the primary outcome, anemia (based on hemoglobin), no intervention effect was apparent (odds ratio: 1.02 95% CI: 0.69, 1.51) after adjustment for design strata. The odds of zinc (based on serum zinc) and urinary iodine deficiency in the fortified group were 0.63 (0.42, 0.94) and 0.52 (0.38, 0.71) times those in the unfortified group, respectively. Fortification had no effect on serum retinol (0.61: 0.25,1.51), ferritin (1.12: 0.43, 2.96), or mean red cell volume (1.16: 0.82, 1.64). Therefore, a micronutrient-fortified seasoning powder is a promising vehicle for improving zinc, iodine, and hemoglobin status, and its potential for incorporation into lunch programs in day care centers and schools in NE Thailand warrants investigation.

KEY WORDS: • micronutrients • fortification • children • Thailand

Micronutrient deficiencies are widespread in many developing countries, including Thailand, a country in which staple diets are predominately rice based, intakes of animal source foods are low (1), and soil iodine and zinc levels in some regions (e.g., North East Thailand) are low (2,3). Children are particularly at risk for such deficiencies as a result of excessive losses of iron, zinc, and/or vitamin A arising from infectious diseases and/or parasitic infection (4–6). Interactions between co-existing deficiencies of vitamin A and iron (7,8) and vitamin A and zinc (9,10) may also occur, which may further exacerbate some of these micronutrient deficiency states. Such deficiencies can have far-reaching health consequences, contributing to impairments in growth, neurobehavioral function, and immune competence, and increases in morbidity and mortality (11).

Several intervention programs based on single micronutrients have been launched in developing countries to alleviate deficiencies of iron, vitamin A, or iodine. These included national programs for iron and folate supplementation during pregnancy and lactation, vitamin A capsule distribution for children <5 y old and lactating women (12), and universal salt iodization (13). In some countries, community-based social marketing campaigns have also been launched to increase the intake of vitamin A–rich foods (14). However, the success of these single micronutrient interventions has been mixed. Compliance with iron-folate supplements is problematic (1,12), salt is not universally consumed (15), and community food-based programs are costly (16) and often fail to secure on-going government support. Clearly, a strategy that is sustainable, and that simultaneously targets co-existing deficiencies of iodine, vitamin A, iron, and zinc is urgently required.

Fortification of a suitable food vehicle with multimicronutrients for use in preexisting lunch programs in day care centers and schools has the potential to combat co-existing micronutrient deficiencies among children. A seasoning powder fortified with iodine, vitamin A, and iron to serve with instant noodles was developed in Thailand in 1995; at that time, the organoleptic acceptability, shelf life, and stability of the product were tested and confirmed (15). This fortified seasoning powder has been marketed in Thailand since 1996, but it does not include zinc and its efficacy has not been tested. Consequently, we conducted a randomized controlled trial (RCT)⁴ to investigate the efficacy of a seasoning powder fortified with iron, zinc, iodine, and vitamin A on hematological and biochemical micronutrient indices, growth, body composition, morbidity, and cognitive function of some NE Thai primary school children aged 5.5–13.4 y. The study was undertaken in 10 poor rural subdistricts of Ubon Ratchathani province, NE Thailand, a region in which the per capita income and education level are among the lowest in the country (17), and in which anemia and deficiencies of iron, zinc, iodine, and vitamin A were reported (1,2,8,10,15,17).

We hypothesized that a seasoning powder fortified with iron, zinc, vitamin A, and iodine and served once daily with noodles or rice in a school lunch program over 1 school year would reduce the prevalence of anemia, and biochemical deficiencies of iron, zinc, iodine, and vitamin A in primary school children in NE Thailand, with anemia as the primary outcome variable.

Only the biochemical results are presented here; the anthropometry and other functional health and cognitive outcomes will be reported elsewhere.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Study site and subjects. The RCT was conducted in the Trakan Phutphon district, Ubon Ratchathani province, NE Thailand between August 2002 and March 2003. The school with the largest enrollment in each of the 10 subdistricts of Trakan-Phutphon district was selected for participation in the trial for a total of 10 schools. All of the districts were of low socioeconomic status. For example, farming was the main occupation for 89% of the households in the study, and their median estimated annual household income was only US$730.00. Moreover, >80% of those identified as the head of the household or the primary care giver had received only primary school education.

The sampling frame consisted of all primary school children attending the 10 participating schools. The eligibility criteria for participation were as follows: 1) apparently healthy; 2) hemoglobin (Hb) concentration >80 g/L; 3) parental approval to participate in all aspects of the study; 4) parental agreement to avoid the use of vitamin and mineral supplements during the trial. Children with evidence of recent acute or chronic illnesses and/or Hb <80 g/L were excluded and referred to the local health center for treatment.

Each of the 10 schools selected for inclusion provided written permission for participation in the study. The school roll was obtained from each school, and within each school, children were stratified into 4 strata: girls grades 1 to 3; boys grades 1–3, girls grades 4–6, and boys grades 4–6. Fifteen children from each stratum were randomly selected. In strata with <15 children, all children were selected. To minimize correlation between participants, only one child per family was randomly selected to participate in the trial. Parents or guardians of selected children were then invited to meet with the researchers who explained the nature of the study. Informed written consent was obtained from parents and guardians who were willing to allow their child to be included. The Human Ethics Committees of Mahidol University, Thailand, and the University of Otago, New Zealand approved the study protocol.

A text file listing the children whose parents or guardians had consented to be in the study, with their sex, age, and a school code, was then sent to J.M. in New Zealand who had no involvement with the recruitment of the children. A random number was generated for each child using the statistical package STATA (18). Children within each stratum, defined by school, age (<108 mo, 108 mo) and sex, were sorted by this random number. Children in the first half were assigned to receive intervention "A," whereas those in the second half were assigned to intervention "B." Figure 1 shows the flow of participants through the trial.

View larger version (22K): [in this window] [in a new window]   FIGURE 1  Trial profile showing the number of participants randomly assigned, completing the trial, and analyzed for the primary outcome.

In the schools, children ate their respective lunches supervised by a teacher in designated groups ("A" or "B"). Compliance was monitored using a pictorial chart, in which teachers recorded whether the child ate "all," "more than half," "half," "less than half," or "none" of the school lunch; these quantities were later translated into fractions: 1.0, 0.75, 0.5, 0.25, and 0, respectively. These fractions were summed for each child for the duration of the intervention, and then divided by the corresponding number of intervention days to give the mean amount of school lunch eaten per intervention day per child. If a child was absent, the amount eaten was recorded as "none." The investigators, food preparers, teachers, outcome assessors, and children were not made aware of the intervention assignment for the duration of the study; assignments were made known only after the data analysis was completed; the effectiveness of these restrictions was not evaluated.

    Sociodemographic and anthropometric variables. Trained Thai research assistants determined the sociodemographic profile of the participants by administering a culturally appropriate pretested questionnaire at baseline; details were published earlier (19). Measurements of weight and standing height were taken at baseline and follow-up (31 wk) using standardized techniques by the same trained anthropometrist to eliminate interexaminer error (19). Technical errors of measurement for weight and height at the end of the standardization period were within the reference values set by Frisancho (20). Z-scores for height-for-age (HAZ), weight-for-age (WAZ), and weight-for-height (WHZ) (for those children <145 cm only) were calculated using the EpiInfo program (Version 6.0, CDC) and the NCHS/CDC/WHO growth reference data (Table 1) (21).

    Biochemical assessment. Details of the hematological and biochemical iron and retinol assessment were described earlier (19). Briefly, a complete blood count was performed via an electronic Coulter Counter (Beckman) in the Trakarn District Hospital and the Hb type determined by the Variant ß-Thalassemia Short Program (Bio-Rad Laboratories) at the Thalassemia Research Center, Mahidol University.

Serum ferritin was determined using the IMx system (Abbott Laboratories), serum C-reactive protein (CRP) using an immunoturbidimetric assay (Roche Diagnostics), serum retinol by HPLC (23), and serum zinc using flame atomic absorption spectrometry (Perkin Elmer 2690) using a standardized procedure (24). Urinary iodine concentrations were measured using a spectrophotometric assay based on the method of Benotti et al. (25).

The precision of all of the biochemical assays was checked using a pooled serum or urine sample and their accuracy established using certified reference materials or appropriate manufacturer's controls. The between-assay CV for serum ferritin, serum retinol, and serum zinc were 6.5, 5.4, and 4.1%, respectively. Corresponding between-assay CV for urinary iodine were 18.3, 5.4, and 5.5%, respectively, for low, medium, and high urinary iodine controls. For serum CRP, values for the manufacturer's controls fell within the certified ranges. For serum zinc, a certified reference material was used (Bovine Serum Reference Material 1598; National Institute of Standards and Technology); the mean value (SD, CV%) was 13.4 (0.5, 3.7%) compared with the certified value of 13.6 (range 12.6–14.5) µmol/L.

Anemia was defined a priori as Hb <115 g/L and <120 g/L for those children between 5 and 12 y old, and 12 y old, respectively (26). Vitamin A deficiency was originally defined as a serum retinol concentration < 0.87 µmol/L to be consistent with the cut-off value used in an earlier study in NE Thailand (2). However, this was changed and a serum retinol concentration < 0.70 µmol/L was used to indicate vitamin A deficiency to conform with the IVACG cut-off value (27). A second category for serum retinol 0.7 but <1.05 µmol/L was also used to indicate suboptimal vitamin A status (28). Estimates of the intervention effect were relatively unchanged with redefinition of the cut-off values. The biochemical criteria indicative of zinc deficiency (22), iodine deficiency (29), depleted iron stores, a low mean red cell volume, and a CRP level indicative of infection or inflammation, as recommended by the manufacturer (Roche Diagnostics), are specified in the footnotes in Table 2.

Logistic and proportional odds (31) ordinal regression models were used to estimate the efficacy of the intervention for binary and ordinal outcomes, respectively (Table 2).] These models were adjusted for the following design strata: age (mo), sex, and school. However, for serum ferritin concentrations indicative of depleted iron stores, there were limited events; therefore, adjustment was made only for sex and age. For the proportional odds model, the assumption of proportionality was investigated visually using the method suggested by Scott et al. (31).

At baseline, the prevalence of anemia differed between the fortified and the unfortified group. Adjusting for this imbalance, we calculated within each group the risk ratio of the proportion of children who were anemic at baseline but not at follow-up to the proportion of children who were not anemic at baseline but were at follow-up. The ratio of these risk ratios (risk ratio in the fortified group to risk ratio in the unfortified group) with 95% CI are presented (Table 3). The CI was calculated using bootstrapping; 10,000 bootstrapped data sets were created using simple random sampling with replacement. For each of these data sets, the ratio of risk ratios described above was calculated. The 2.5th and 97.5th percentiles of this distribution of ratio of risk ratios were used to produce the 95% CI.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
At baseline, a total of 569 eligible children were recruited for the study. Blood for Hb analyses, the primary outcome of this study, was obtained from 278 children in the fortified group and 275 in the unfortified group at baseline, and from 278 and 277 children, respectively, at follow-up (Fig. 1). The dropout rate was very low (<1%) and arose from relocation (Fig. 1).

The biweekly rotating lunch menu consisted of wheat noodles 3 d/week and rice for the other 2 weekdays. The median ( 1st–3rd quartiles) daily nutrient content of the school lunches was: energy 1204 (1017–1521 kJ), protein 9.9 (8.5–13.5) g, iron 1.5 (1.2–1.7) mg, zinc 1.3 (1.1–1.5) mg, and vitamin A 26 (6–64 RE).There were no important differences between the groups in the amount of school lunch eaten per day over the intervention period (143–151 d eaten, depending on the school); median fraction of school lunch eaten (1st and 3rd quartiles) per intervention day per child were 0.75 (0.66, 0.83) and 0.75 (0.68, 0.83) in the fortified and unfortified groups, respectively. This estimate included the days when children were absent from school.

Full details of the sociodemographic and health characteristics of the children at baseline are given in Thurlow et al. (19); only selected characteristics, including age, sex, anthropometric and biochemical indices, and Hb type, are shown in Table 1. Of the children, 9.2 and 11.3% were stunted (HAZ less than –2.0), and 10.2 and 12.7% were underweight (WAZ less than –2.0) in the fortified and unfortified groups, respectively. Of the 433 children for whom WHZ scores could be calculated, 4.7% in the fortified group and 5.4% in the unfortified group were wasted (WHZ less than –2.0) at baseline. A smaller percentage of children in the fortified group had a normal Hb type (AA). Instead, a larger percentage of children in this group were heterozygous (AE), and homozygous for Hb type E (EE) compared with the unfortified group.

    Biochemical micronutrient deficiencies and anemia at follow-up. Odds ratios (OR; 95% CI) for deficiency were calculated and adjusted for age, sex, and, where possible, school. The odds of children in the fortified group being in a more severe urinary iodine deficiency category vs. a less severe category were reduced by 48%. For zinc, the intervention reduced the odds of zinc deficiency by 37%. Hence, at follow-up, children in the fortified group were significantly less likely to have a urinary iodine concentration and a serum zinc concentration in a deficient category. However, the OR for low concentrations of serum retinol, Hb, and serum ferritin, and low MCV were not significant (Table 2).

Results of additional analyses adjusting for the imbalance in baseline prevalence of anemia between the 2 groups also showed no evidence of an intervention effect. The risk ratio of the probabilities of transitioning to a nonanemic state compared with transitioning to an anemic state in the fortified group was 1.56 (95% CI 0.80, 3.28) times that of the unfortified group (Table 3).

Estimates of the effects of the intervention on the major biochemical continuous outcomes were analyzed by linear regression (Table 4). These effects were significant for Hb, serum zinc, and urinary iodine, but not for serum ferritin, MCV, or serum retinol. Further, for Hb, serum ferritin, and MCV, the intervention effect and its CI did not differ substantially between analyses with (Table 4) and without adjustment (data not shown) for Hb type. For Hb, we also tested for a potential interaction between the intervention and Hb type. There was no evidence of an interaction (P = 0.414) after adjusting for baseline Hb, school, age, and sex. The estimated intervention effect for Hb from this model in the AA, AE, and EE groups was 1.63 (0.01, 3.25), 1.28 (–0.86, 3.42), and 5.34 (–0.28, 10.95), respectively.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Hemoglobin, MCV, and serum ferritin concentrations. For the primary outcome, anemia, there was no evidence of an intervention effect, after adjustment for design strata (Table 2), or after adjustment for baseline imbalance (Table 3). However, there was some evidence of a significantly higher Hb concentration in the fortified group (Table 4). No significant improvement in serum ferritin or MCV was observed (Tables 2 and 4). These negative findings may have arisen because the level (i.e., 5 mg/serving) and/or the form of the iron fortificant may not have been adequate to significantly enhance the iron stores of the children. Certainly, the bioavailability of the iron fortificant used, H-reduced elemental iron, is poor relative to ferrous sulfate and hence may have been a limiting factor (32). H-reduced elemental iron was chosen as the fortificant because it caused fewer organoleptic problems than the more soluble iron compound ferrous sulfate, and was also less expensive (32). The absence of a positive response by serum ferritin may also be associated with the unexpectedly low prevalence of depleted iron stores (serum ferritin <12 µg/L) noted in both groups at baseline (<4%).

    Serum zinc, urinary iodine, and serum retinol concentrations. At baseline, 54% of the children had low serum zinc values and 36% had evidence of moderate iodine deficiency. Postintervention, markedly fewer children in the fortified compared with the unfortified group had such low levels. These positive results suggest that the iodine (potassium iodide) and zinc (zinc sulfate) fortificants were readily bioavailable, in the latter case perhaps because of the low phytate content of the school lunches provided (Woravimol Krittaphol; unpublished observations). Nevertheless, the prevalence of low serum zinc concentrations in the fortified group was still above the level (i.e., >20%) indicative of an elevated risk of zinc deficiency (22), whereas postintervention, the goal set by WHO/UNICEF/ICCIDD for the elimination of iodine deficiency disorders was met (29).

In contrast, at baseline, the prevalence of vitamin A deficiency was very low (3%), although 19% of the children had suboptimal vitamin A status (i.e., serum retinol 0.70 and <1.05 µmol/L). Further, there was no significant intervention effect for vitamin A. The absence of a treatment effect on serum retinol in our study was probably associated with the known instability of retinyl palmitate in dry matrices (33). Pretests showed some loss of retinyl palmitate when the seasoning powder was steamed with the rice, a necessary step to ensure homogeneity of the fortificant mix. Less loss occurred, however, during the preparation of the noodle lunches served 3 times/wk because the seasoning powder was added after the noodles were cooked.

In this study, a reduction in the prevalence of anemia, low MCV, zinc, iodine, and vitamin A deficiencies, and suboptimal vitamin A status was apparent in both groups. This trend is probably associated in part with the improved dietary quality of the school lunch that both groups consumed during the 31-wk trial. Certainly, the unfortified school lunches provided nearly 30% of the mean daily intakes of zinc and iron, based on 24-h recall data collected on a subsample of the children at baseline.

Fortified seasoning powder has several advantages as a food vehicle. For commercial purposes, it was packaged in a single-serving size sachet to avoid potential overdose and to protect it from light, air, and moisture in an effort to ensure a long shelf life. The seasoning powder can then be incorporated into noodle dishes without any additional cooking before consumption, thus avoiding losses due to thermal instability and/or leaching. Finally, it is an ideal vehicle for incorporation into preexisting lunch programs in day-care centers and schools because it avoids the necessity of costly social marketing campaigns. Nevertheless, based on our biochemical results, some modifications to the levels of the fortificants in the seasoning powder are required, particularly the hydrogen-reduced iron and the retinyl palmitate to take into account the poor absorption of hydrogen-reduced iron relative to ferrous sulfate and the instability of retinyl palmitate in dry mixes. In addition, a method must be devised whereby the seasoning powder can be incorporated into rice after steaming without compromising the homogeneity of the mixture. This will allow the seasoning powder to be incorporated into both noodle and rice dishes after cooking, thus enhancing the dietary variety of a day-care or school lunch program. A protective packaging for the seasoning powder for bulk cooking must also be used. Finally, a pragmatic trial must be undertaken to assess whether providing the fortified seasoning powder in the existing lunch programs in day-care centers and schools in NE Thailand is an effective public health strategy. Its cost effectiveness also must be established.

This trial has many strengths. In particular, the low attrition rate for the primary outcome in both the fortified and unfortified group (2%) strengthens the internal validity, and the random selection of children for inclusion in the study with a high response rate (95%) strengthens the external validity. However, care should be taken when interpreting some of the exploratory results due to the multiplicity of the analyses.

In summary, our trial confirmed that a micronutrient-fortified seasoning powder served once daily for 31 wk can improve zinc and iodine status of NE Thai primary school children. Moreover, because of the strengths of this trial, our results can probably be generalized to children living in similar socioeconomic districts in NE Thailand. Nevertheless, based on our biochemical results, when used in a day-care or school lunch program, it may be necessary to increase the levels of all of the fortificants, possibly to one half of the Thai Recommended Dietary Intake (34) if the seasoning powder is to be served only once a day in these programs. However, the efficacy of any increase in the level of fortificants would have to be established.

	ACKNOWLEDGMENTS

 
We thank Arporn Sriphrapradang for the urinary iodine analysis, Dr. Pranee Fucharoen for the analysis and interpretation of the hemoglobinopathy data, and Dr. Ian L. Gibson for his support during the project.

	FOOTNOTES

 
¹ Presented at the International Zinc Nutrition Consultative Group (IZiNCG) Symposium, November 2004, Lima, Peru [Winichagoon P, Pongcharoen T, Manger MS, McKenzie J, Gorwachirapan S, Boonpraderm A, Chavasit V, Cook R, Bailey K, Ryan B, Gibson RS. Efficacy of micronutrient fortified seasoning powder in Thai primary school children. p. 8; 2004].

² Supported by the Micronutrient Initiative Fund, the University of Otago Research Fund, and the Institute of Nutrition, Mahidol University.

⁴ Abbreviations used: AA, normal Hb type; AE, heterozygous for Hb type E, CRP, C-reactive protein; EE, homozygous for Hb type EE; HAZ, height-for-age Z-score; Hb, hemoglobin; IVACG, International Vitamin A Consultative Group; MCV, mean red cell volume; RCT, randomized controlled trial; RE, retinol equivalents; WAZ, weight-for-age Z-score; WHZ-score, weight-for-height Z-score.

Manuscript received 18 October 2005. Initial review completed 3 January 2006. Revision accepted 16 March 2006.

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