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Epidemiology Unit and * Enterology and Nutrition Division, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University Songkhla, 90110 Thailand
2To whom correspondence should be addressed. E-mail: sburapat{at}medicine.psu.ac.th.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • iron supplementation • iron status • growth • schoolchildren
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–3
). The WHO recommends large-scale programs of daily iron supplementation to reduce the prevalence of anemia in high risk areas (4
). However, IDA remains common in many parts of the world, particularly among children in developing countries (5
–7
). Insufficient supply of iron tablets, low coverage of the target population and poor compliance with tablet intake are among the main reasons for the ineffectiveness of supplementation programs (8
,9
).
Administration of weekly iron as a replacement for the existing daily iron supplement programs has been discussed widely in developing countries (10
–14
) due to greater iron absorption in animal studies (15
–17
), fewer side effects in humans (15
) and potentially greater cost-effectiveness. However, field studies have yielded controversial results. Several studies have reported comparable effects between intermittent and daily iron supplementation on improvement of iron status and growth among anemic young children and adolescents (10
–12
); however, a subsequent comparative study (13
) showed significantly greater efficacy of daily over twice weekly iron supplementation in adolescents.
In Thailand, where the nature of anemia includes not only iron deficiency but also thalassemia (18
,19
), a once daily iron supplementation program has been carried out among anemic children since 1988, and a once weekly dose administered through a school-based program among primary schoolchildren will soon be implemented. It is essential to conduct a randomized controlled trial to assess the efficacy of once weekly iron supplementation before the large-scale program is launched. The main objective of this study was to compare the results of once weekly and daily iron supplementation on hemoglobin (Hb), serum ferritin (SF) and physical growth among primary schoolchildren in southern Thailand.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Data collection was carried out from June to December 1999 in a socioeconomically disadvantaged community in Songkhla Province, southern Thailand. The two (public) schools were selected because they had at least 150 pupils with a high prevalence of underweight children according to previous school records, were accessible by automobile and had teachers who were willing to cooperate in the study. These two schools were located 
35 km from the research center and had a mixture of Buddhist and Muslim students. Family occupation was mainly as rubber plantation workers. This area was free from malaria and no previous large-scale program of iron supplementation had been implemented.
The sample size was calculated to provide a power of 95% in detecting a difference at 
= 0.05 between daily and weekly supplements, and between either of these iron doses and a placebo of 1 SD in the pre- to post-treatment measurements of iron status and growth. At least 62 subjects per group were required.
An invitation letter and consent form were sent to the parents whose children were in primary school. All subjects who received parental consent had their baseline data measured. We excluded those with severe malnutrition (weight for height 
3rd percentile of the Thai reference), chronic illness such as obvious thalassemia or hemolytic disease, high iron storage (SF > 100 µg/L), physical handicaps or no baseline laboratory assessment. The children were stratified by anemic status to balance the proportion of anemic and nonanemic children across the intervention groups. Anemic children were defined as Hb < 115 g/L among children 5–11 y and Hb < 120 g/L among children 12–13 y. These cut-off levels are recommended by the WHO (20
). The children were then assigned by simple random allocation within each stratum using a computer to daily or once weekly iron supplemented or placebo groups.
Measurement of variables.
School, class, sex, age, ethnic group and socioeconomic status (parents’ education, father’s and mother’s occupations and family monthly income) data were collected via a questionnaire completed by parents before the intervention started.
At baseline and the end of the study, weight and height were measured with subjects wearing school uniforms without belts and shoes and with empty pockets using a beam balance Detecto scale and stadiometer (Detecto Scales, Brooklyn, NY) to the nearest 0.1 kg and 0.5 cm, respectively.
Before supplementation, well-trained nurses drew a 5-mL blood specimen from the cubital vein. A 2-mL portion of the blood was transferred to an EDTA-prepared tube and then stored in an ice box for subsequent Hb determination, blood morphology examination and screening for thalassemia. The remaining 3 mL of the blood was kept in a sealed plastic test tube at ambient temperature for SF assessment.
Hb level was assessed with an automated machine (Technicon H*1E system, Tarrytown, NY) using the cyanmethemoglobin method (CV = 0.6–3.4%). The One Tube Osmotic Fragility Test combined with the Dichlorophenol Indophenol Precipitation Test was used to screen for potential thalassemic disease (19
). Children with a positive One Tube Osmotic Fragility Test < 85% or Dichlorophenol Indophenol Precipitation Test had further examination of blood cell morphology by a hematologist and were excluded from the study if there was evidence of thalassemia or hemolytic diseases such as ovalocytosis, which is common in the study area (19
,21
). There was no attempt to exclude the thalassemia trait in this study. SF was assessed by the IMx assay (IMx Ferritin assay, Abbot Park, IL) using The Microparticle Enzyme Immunoassay method (CV = 4.4–6.4%). SF 20 µg/L was used to define anemia due to iron deficiency. At the end of intervention, a new 3-mL specimen of blood for Hb and SF testing was taken.
Intervention.
All eligible children were given a single dose of 400 mg Albendazole at the beginning of the study and again 11 wk later to eliminate hookworm infection. Ferrous sulfate 300 mg tablets (60 mg elemental iron) (Government Pharmaceutical Organization, Bangkok, Thailand) were used in this study because these will be used in the real supplementation program. Placebo tablets, produced by the Faculty of Pharmacy, Prince of Songkla University, Thailand, were similar in color, shape, size and taste to the iron tablet. The tablets were placed in bottles, which were labeled only with the subject’s name. Their content was unknown to any of the project personnel. Each child received 2 bottles. The first was to be taken on Monday only. The second was to be taken for the remaining days of the week. The daily group had iron in all the bottles, whereas the once weekly group had iron in the Monday bottle and placebo in the rest. The placebo group had placebo tablets in all of the bottles. After packing, the codes were kept secret throughout the supplementation process. All oral administrations were strictly observed by either the principal investigator or the research assistant on each school day to ensure that the tablets were swallowed.
Ethical consideration.
The research proposal was approved by the Ethical Review Committee of Faculty of Medicine, Prince of Songkla University, Thailand. Children with severe IDA (Hb 80 g/L and SF 20 µg/L) were excluded from the study and treated immediately to prevent unnecessary delay. Children who had hemolytic disease or relatively high iron storage (SF >100 µg/L) were also excluded to prevent the risk of iron overload. Children who continued to have IDA at the end of the study received appropriate iron supplementation.
Data analysis.
The balance of baseline measurements across the interventions was examined. The effects of iron supplementation were analyzed on an intention-to-treat basis. The change of Hb from pre- to post-treatment was examined and compared across the interventions using Student’s paired t test and ANOVA with Bonferroni’s multiple comparison tests. Due to a problem of nonnormal distribution with SF, nonparametric statistics were used in the comparison. The Wilcoxon signed-rank test was used to see the change of SF from pre- to postintervention and the Kruskal-Wallis test was used to compare the effect across interventions. Mann-Whitney tests were performed for multiple pair-wise comparisons only when the Kruskal-Wallis test suggested a significant difference of SF among interventions. The reduction in prevalence of IDA was also compared across the interventions by using the Z-test applied to the McNemar’s 
-squares for each intervention.
Anthropometric indices used in assessing growth were weight gain, height gain, change in weight-for-age and change in height-for-age. Z-scores of weight-for-age and height-for-age were calculated using the National Center for Health Statistics growth references for weights and heights using the EPI INFO software, version 6 (Centers for Disease Control, Atlanta, GA). These constitute the international growth reference curves recommended by WHO. Anthropometric indices were compared across interventions using ANOVA. Weight and height gain were also adjusted for age using multivariate regression analysis.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Eventually, 397 primary schoolchildren, aged ranging from 6 to 13 y, participated in the study; of these, 140, 134 and 123 children were allocated to daily, weekly and placebo groups, respectively. Most of the children belonged to socioeconomically deprived families as indicated by low parental education and income. Approximately 80% of family monthly incomes were 5000 baht (125.00 US$) per month compared with the Thai national average of 12,729 baht (318.00 US$) for the same year reported by the Household Socioeconomic Survey, National Statistical Office. The prevalence of anemia was 27% but only 21.5% of these anemic children were iron deficient. Children from the two schools had similar distribution of the above-mentioned socioeconomic variables; thus, no stratification by school was used in the analysis. Baseline measurements were similarly distributed among intervention groups as summarized in Table 1
.
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). Weight gain, change of weight-for-age and change of height-for-age among intervention groups were not significantly different across the groups. The increase in height of children in the weekly group was greater than that in the other two groups, but the only significant difference was between the daily and the weekly groups (P = 0.02, Table 3
). This significance of height gain difference persisted after adjustment for age.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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During the supplementation period, the mean Hb improvement seen in the placebo group may have been due to various causes such as deworming, shift in age among children or some unknown effect of the follow-up. After allowing for the placebo effect, the net gain of Hb in the daily and weekly groups was 3.1 and 2.3 g/L, respectively, in 16 wk. The poor response to iron supplementation in these subjects may be attributable to the low prevalence of IDA or to the thalassemia trait, which exists in the southern Thai population (19
).
Our study was confined to 16 wk of supplementation. However, the real supplementation program will be implemented year round. The findings that the daily dose yielded a higher SF than the weekly dose may simply reflect a slower increase of SF. Prolonged weekly dosing may eventually lead to adequate saturation of iron in blood and in tissue.
To our knowledge, only two previous studies (13
,14
) have assessed intermittent iron supplementation as a blanket supplementation, that is, including both anemic and nonanemic subjects as in our study. A study of weekly iron supplementation among Tanzanian adolescents (14
) found a significantly greater increase in serum ferritin compared with a vitamin B-12 control group, but there was no significant difference in change in Hb. However, a study in Peru (13
) found that a 17-wk daily supplementation led to significantly higher Hb increases than twice weekly supplementation; however, SF and free erythrocyte protoporphyrin were similar in the two groups. It is possible that the 60 mg iron/d given to adolescents whose average weight was almost 50 kg may be too small a dose to improve Hb and correct anemia in the intermittent schedule; the actual values of SF were not shown in that paper.
Our study found no significant difference in weight gain, change of weight-for-age, or change of height-for-age among weekly, daily and placebo groups, but a significantly greater height gain among children receiving once weekly iron supplementation than that in the daily group. The patterns of height gain and change of height-for-age were consistent (i.e., worst in the daily group and best in the weekly group), but a significant difference was detected only in height gain. The lack of significance in height-for-age may be due to the lower precision of this variable. Almost 50% of our subjects had a height exceeding the limit for calculation of weight-for-height; thus, we omitted this anthropometric index.
Studies regarding the effects of daily iron deficiency upon growth have shown inconsistent results. Studies in India, Kenya and Indonesia found an improvement in growth after iron supplementation (22
–25
). Improved appetite and decreased morbidity were the explanations given in those studies for enhanced growth after iron supplementation. Studies in Mexico, Bangladesh and Thailand, however, reported no benefit of iron supplementation on growth (26
–28
). One proposed explanation is that deficiency of multiple micronutrients such as zinc and vitamin A could have limited the growth response to iron (27
). Furthermore, a report of the adverse effect of iron on weight gain in children with adequate iron status has raised concerns among public health researchers about giving supplemental iron to children (29
).
We could find only one previous study comparing weekly iron supplementation with daily dosing on growth. This study on Indonesian primary schoolchildren (10
) reported no significant differences in increases of weight-for-age, weight-for-height or height-for-age after 3 mo of weekly and daily iron supplementation among anemic schoolchildren.
Using subjects in a different age group, a study among Tanzanian adolescent girls comparing weekly iron supplementation and a vitamin B-12 control group reported a significantly greater weight gain in the weekly iron supplemented group than in the vitamin B-12 control group after 4 mo of supplementation (14
).
Iron intake in our study was observed closely, and >90% of children received complete iron supplementation. Thus, the lack of significant difference in some of the outcome measurements among the groups cannot be explained by low compliance.
The immediate goal of the iron supplementation program in Thailand is to reduce the prevalence of anemia and increase tissue iron concentration, on the assumption that this will improve the health and performance of the children. Our data suggest that the goal of iron saturation is better achieved with daily rather than weekly supplementation but the potential adverse effect on growth (height gain) should be taken into consideration.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: Hb, hemoglobin; IDA, iron deficiency anemia; SF, serum ferritin.
Manuscript received 23 July 2001. Initial review completed 31 August 2001. Revision accepted 18 December 2001.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Pollitt, E. (1997) Iron deficiency and educational deficiency. Nutr. Rev. 55:133-141.[Medline]
2.
Deinard, A. S., Gilbert, A., Dodds, M. & Egeland, B. (1981) Iron deficiency and behavioral deficits. Pediatrics 68:828-833.
3. Walter, T., Kovalskys, J. & Stekel, A. (1983) Effect of mild iron deficiency on infant mental development scores. J. Pediatr. 102:519-522.[Medline]
4. DeMayer, E. M., Dallman, P. R., Gurney, J. M., Hallberg, L., Sood, S. K. & Srikantia, S. G. (1989) Preventing and Controlling Iron Deficiency Anaemia through Primary Health Care 1989 World Health Organization Geneva, Switzerland. .
5. DeMayer, E. & Adiels-Tegman, M. (1985) The prevalence of anemia in the world. World Health Stat. Q. 38:302-316.[Medline]
6.
Looker, A. C., Dallman, P. R., Carroll, M. D., Gunter, E. W. & Johnson, C. L (1997) Prevalence of iron deficiency in the United States. J. Am. Med. Assoc. 277:973-976.
7. Cornet, M., Le Hesran, J. Y., Fievet, N., Cot, M., Personne, P., Gounoue, R., Beyeme, M. & Deloron, P. (1998) Prevalence of and risk factors for anemia in young children in southern Cameroon. Am. J. Trop. Med. Hyg. 58:606-611.[Abstract]
8. World Health Organization (1991) Iron supplementation: why are pregnant women not complying? [news]. Bull. WHO 69:130-135.[Medline]
9. Schultink, W. (1996) Iron supplementation: compliance of target groups and frequency of tablet intake. Food Nutr. Bull. 17:22-26.
10. Soemantri, A. G., Hapsari, D.E.A.H., Susanto, J. C., Rohadi, W., Tamam, M., Irawan, P. W. & Sugianto, A. (1997) Daily and weekly iron supplementation and physical growth of school age Indonesian children. Southeast Asian J. Trop. Med. Public Health. l 2:69-74.
11. Berger, J., Aguayo, V. M., Tellez, W., Lujan, C., Traissac, P. & San Miguel, J. L. (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]
12.
Schultink, W., Gross, R., Gliwitzki, M., 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.
13. Zavaleta, N., Respicio, G. & Garcia, T. (2000) Efficacy and acceptability of two iron supplementation schedules in adolescent school girls in Lima, Peru. J. Nutr. 130:462S-464S.
14. Beasley, N. M., Tomkins, A. M., Hall, A., Lorri, W., Kihamia, C. M. & Bundy, D. A. (2000) The impact of weekly iron supplementation on the iron status and growth of adolescent girls in Tanzania. Trop. Med. Int. Health 5:794-799.[Medline]
15. Liu, X. N. & Liu, P. Y. (1996) The effectiveness of weekly iron supplementation regimen in improving the iron status of Chinese children and pregnant women. Biomed. Environ. Sci. 9:341-347.[Medline]
16. Benito, P., House, W. & Miller, D. (1997) Influence of iron supplementation frequency on absorption efficiency and mucosal ferritin in anaemic rats. Br. J. Nutr. 78:469-477.[Medline]
17. Viteri, F. E, Xunian, L., Tolmei, K. & Martin, A. (1995) True absorption and retention of supplemental iron is more efficient when iron is administered every three days rather than daily to iron normal and iron deficient rats. J. Nutr. 125:82-91.
18.
Linpisarn, S., Tienboon, P., Promtet, N., Putsyainunt, P., Santawanpat, S. & Fuchs, G. J. (1996) Iron deficiency and anaemia in children with a high prevalence of haemoglobinopathies: implications for screening. Int. J. Epidemiol. 25:1262-1266.
19. Nopparatana, C., Fukumaki, Y. & Pornpatkul, M. (1996) Thalassemia in the South of Thailand: Prenatal and Postnatal Diagnosis 1996 Report Prince of Songkla University, Thailand. .
20. Stoltzfus, R. & Dreyfuss, M. (1998) Guidelines for the Use of Iron Supplements to Prevent and Treat Iron Deficiency Anemia 1998 ILSI Washington, DC. .
21. Ganesan, J., George, R. & Lie-Injo, L. E. (1976) Abnormal haemoglobins and hereditary ovalocytosis in the Ulu Jempul district of Kuala Pilah, West Malaysia. Southeast Asian J. Trop. Med. Public Health 7:430-433.[Medline]
22. Kanani, S. J. & Poojara., R. H. (2000) Supplementation with iron and folic acid enhances growth in adolescent Indian girls. J. Nutr. 130:452S-455S.[Medline]
23. Lawless, J. W., Latham, M. C., Stephenson, L. S., Kinoti, S. N. & Pertet, A. M. (1994) Iron supplementation improves appetite and growth in anemic Kenyan primary school children. J. Nutr. 124:645-654.
24.
Chwang, L. C., Soemantri, A. G. & Pollitt, E. (1988) Iron supplementation and physical growth of rural Indonesian children. Am. J. Clin. Nutr. 47:496-501.
25.
Angeles, I. T., Schultink, W. J., Matulessi, P., Gross, R. & Sastroamidjojo, S. (1993) Decreased rate of stunting among anemic Indonesian preschool children through iron supplementation. Am. J. Clin. Nutr. 58:339-342.
26.
Rosado, J. L., Lopez, P., Munoz, E., Martinez, H. & Allen, L. H. (1997) Zinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers. Am. J. Clin. Nutr. 65:13-19.
27.
Rahman, M. M., Akramuzzaman, S. M., Mitra, A. K., Fuchs, G. J. & Mahalanabis, D. (1999) Long-term supplementation with iron does not enhance growth in malnourished Bangladeshi children. J. Nutr. 129:1319-1322.
28. Migasena, P., Thurnham, D. I., Jintakanon, K. & Pongpaew, P. (1972) Anemia in Thai children: the effect of iron supplement on haemoglobin and growth. Southeast Asian J. Trop. Med. Public Health 3:255-261.[Medline]
29. Idjradinata, P., Watkins, W. E. & Pollitt, E. (1994) Adverse effect of iron supplementation on weight gain of iron-replete young children. Lancet 343:1252-1254.[Medline]
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