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Epidemiology Unit and * Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, 90110, Thailand
2To whom correspondence should be addressed. E-mail: rassamee{at}ratree.psu.ac.th.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • intermittent iron supplementation • cognitive function • IQ • school performance
Intermittent vs. daily iron supplementation has been the topic of heated discussion for the last decade. Based on results from animal studies, the original argument against daily dosing was that the first dose of iron would prevent a second dose from being absorbed (1). Results from a series of studies suggest no such relation in humans (2,3). In fact, many epidemiologic studies (4–10) conducted in developing countries showed that weekly and daily iron dosing produced similar effects on subjects’ hemoglobin (Hb).3 The potential explanation is that any iron preparation, at any dosage schedule, will be sufficient to increase Hb if the dose is of adequate duration (typically 8 to 16 wk).
Few studies have compared the effects of different dosing schedules on other health consequences of iron deficiency anemia (IDA). Impairment of cognitive function is one such consequence of great concern in children (11–13). The adverse effect of a lack of iron may be explained by diminished synthesis and uptake and by degradation of the neurotransmitter (14,15). Although randomized controlled trials (RCTs) have yielded controversial results, some have reported an improvement in cognitive function scores after an appropriate duration of daily iron supplementation among anemic children (13,16,17). One of the difficulties in interpretation of these RCTs is the wide range of cognitive measurements, which may measure many different aspects of intelligence. The effect of intermittent iron supplementation on cognitive function has not been studied.
In 1997, a pilot study of 1 d/wk (weekly) iron supplementation administered through a school-based program for Thai primary schoolchildren was initiated; the program was widely expanded over the country in the following years. It is therefore important and urgent to examine the effect of intermittent iron supplementation not only on Hb but also on other health consequences. The situation of anemia in Thailand is additionally complicated because anemia includes not only iron deficiency but also thalassemia. Our previous report demonstrated that weekly iron supplementation was as effective as the 5 d/wk (daily) regimen in correcting anemia but was superior for height gain (10). In the present study, we compared changes in cognitive function as assessed by IQ, and mathematics and Thai language tests in primary school children in southern Thailand administered iron supplements weekly or daily, or placebo.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The study was designed to compare changes in IQ, language and mathematics test results among 3 groups: daily iron supplementation, weekly iron supplementation, and placebo. For 95% power and an 
of 0.05, at least 62 children were required per group to detect a difference of 1 SD. The total sample size was therefore estimated to be 186. However, for some reason, this area had not been supplemented. Due to ethical concerns, we extended the research project to all eligible children, thereby providing 
150/group. Those in the placebo group were eventually supplemented with the appropriate dose for an appropriate amount of time after the study ended. The sample size of this study therefore had >95% power.
A letter of invitation providing information and requesting consent was sent to the parents of children who were in grades 1–6. Only children with written informed parental consent were recruited into the study. Among subjects receiving parental consent, exclusion criteria were severe IDA (Hb 
80 g/L and serum ferritin (SF) 20 µg/L, severe malnutrition [weight-for-height < 3rd percentile of the Thai reference (18)], chronic illness such as thalassemia, hemolytic diseases especially those with high iron storage (SF > 100 µg/L), and physical handicaps.
Measurements of variables.
Demographic variables, sex, age, school, and class were observed directly or extracted from the school records. Information was also obtained from a parental self-reporting questionnaire, which included ethnic group and socioeconomic variables such as parents’ education in years, father’s and mother’s occupation (none, casual/farmer/seller, government officer/private) and family monthly income [ 5000 baht (125.00 US$) or > 5000 baht].
At the start and end of the study, body weight and height of children wearing school uniforms without belt and shoes and with empty pockets were measured using a beam balance Detecto scale and stadiometer (Detecto Scales) to the nearest 0.1 kg and 0.5 cm, respectively. Physical examinations were performed to detect serious illness or infection.
Hematology. Hb and SF concentrations were used to determine iron status from a single venipuncture at the start and at the end of the study. A 2-mL specimen of blood was placed into an EDTA-prepared tube for Hb, blood morphology examination, and screening for thalassemia and then stored in an ice box. The remaining 3 mL was kept in a plastic sealed test-tube at ambient temperature for SF measurement. The specimens were analyzed in the laboratory within 3 h of collection.
Hb content was measured by an automated machine (Technicon H*1E system) using the cyanmethemoglobin method (19). If there was any abnormality in the reading of the RBC count from the automated machine, a standard blood smear was examined by a hematologist. The osmolarity fragility test (OF) and dichlorophenol indophenol precipitation test (DCIP) were used to screen for potential thalassemia (20). Any children with OF < 85% or positive DCIP had further examination of blood cell morphology by the hematologist. If there was evidence of thalassemia or hemolytic disease, the subject was excluded from the study. SF was assessed by the IMx assay (IMx Ferritin assay) using the microparticle enzyme immunoassay method (21).
IQ assessment.
IQ was measured by the Test of Nonverbal Intelligence, 2nd edition (TONI II) (22). TONI II is a standardized, objective, and culturally fair test measuring problem solving ability, a major aspect of intelligence. Its use was justified in this study because it measures the problem solving ability that we aimed to test (i.e., it is valid). Its correlation with the standard IQ test, WISC-R (Wechsler Intelligence Scale for Children-Revised), is 0.7 among Thai children (i.e., it is accurate) (Reungdaraganond, N., Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand, unpublished data). Its test-retest coefficient was reported to be 0.95 (i.e., it is reliable) (22). TONI II was used to measure IQ in the National Health Examination among Thai children. The results from the study therefore can be compared with the country reference. The test is easily used in the community because it does not require sophisticated equipment and it takes 5–15 min to administer (i.e., it is feasible).
Well-trained testers applied the test to all eligible children without knowledge of the children’s intervention group. Items are arranged in order of difficulty and each consists of 1 question-picture and 4 or 5 available responses but only 1 correct response. Each child began with the item indicated in the manual (depending on age) and continued until he/she made 3 incorrect responses in 5 consecutive items.
School achievement assessment. School achievement was assessed by the school examination. There are 2 semesters in each Thai school year. The scores of the first and the second semester of Thai language and mathematics tests in the academic year 1998 and the scores of Thai language and mathematics tests in the second semester of the academic year 1999 were used for the pre- and postintervention measurements, respectively. School absence was recorded daily by the researcher who administered the supplementation.
Intervention.
All children were given a single dose of 400 mg Albendazole (Government Pharmaceutical Organization) at the start of the study and 11 wk later to eliminate hookworm infection. Baseline Hb was used to identify the anemic children at Hb 115 g/L for those < 12 y old and Hb 120 g/L those 
12 y old (23). Then the interventions were assigned within each anemic and nonanemic stratum to 1 of the 3 treatment groups, daily iron supplementation, weekly iron supplementation, or placebo, by a simple random sampling technique using a computer random number generator.
Ferrous sulfate 300 mg (60 mg elemental Fe) tablets (Government Pharmaceutical Organization) were used in this study for consistency with the doses used in the real supplementation program. Placebo tablets, produced by the Faculty of Pharmaceutical Science, Prince of Songkla University, Thailand, were similar in appearance and taste to the iron tablets. The tablets were placed in packages, which were labeled only with the student’s name; their content was not known to any of the project personnel and the 2 sets of supplement packages were similar in appearance. One set was used on Monday and the other was used on the other schooldays. Packages in the first set contained ferrous sulfate for children in both the daily and weekly groups and placebo for the placebo group. The other set of packages contained ferrous sulfate for children in the daily group but placebo for the weekly and the control groups. Tablet ingestion was supervised and recorded by the researcher every school day.
Ethical considerations. The research proposal was approved by the Ethical Review Committee of Faculty of Medicine, Prince of Songkla University, Thailand.
Data analysis. The balance of baseline measurements among the intervention groups was examined. Analysis of the intervention effect was based on intention to treat. Total raw scores from the TONI II test were converted to the corresponding standardized IQ using the table provided in the manual. The change in IQ from pre- to post-treatment was examined and compared among the 3 groups using ANOVA with Bonferroni’s multiple comparison tests. School examination results were converted to Z-scores based on the distribution within the same grade and school in the same examination. Because of distributional problems with the school performance test results, nonparametric statistics were used. The Z-scores of Thai language and mathematics test results were examined using the Kruskal-Wallis test. Mann-Whitney tests were performed for multiple pair-wise comparisons when the Kruskal-Wallis test suggested significant differences among the groups (P < 0.05) (24).
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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17% of subjects had thalassemic traits. The increases in Hb did not differ between the daily and weekly supplemented groups, both of which were greater than in the placebo-treated group (Table 2). The increase in SF of the daily group was greater than that of the weekly group, which in turn was greater than that of the placebo group (Table 2).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The baseline IQ for spatial problem solving, measured by TONI II in this study (mean ± SD: 78 ± 12 points, n = 397), was relatively low compared with the mean IQ in southern rural Thai children as reported by the National Health Survey (92 ± 13 points), which used similar measurements. The low scores may reflect the socioeconomic deprivation in the study area. The mean IQ generally increased from pre- to postintervention. The increase in IQ may be the result of recall and/or learning effects.
Effects of iron supplementation and placebo on cognitive function. Several studies of daily iron supplementation reported an improvement in IQ and school performance including mathematics and language ability among children with iron depletion (25) and children with iron deficiency anemia (13,16,26). However, the studies conducted in Thailand, that of Pollitt et al. (27), and the current study, consistently reported no improvement in cognitive function due to iron supplementation.
Particular features of the ecological and population setting such as deficiencies in many nutrients and a deprived environment can contribute to poor cognitive function, which is likely not correctable by iron supplementation per se. Long-lasting effects of iron deficiency on cognitive function among Thai children, which are difficult to measure, may require a longer duration of appropriate intervention to improve outcomes.
Because increases in Hb and serum ferritin were observed directly and confirmed in dose-response relations with iron supplementation, the lack of improvement in the outcome parameters was not the result of improper supplementation or compliance problems.
Weekly and daily iron supplementation differentially affect IQ but not school performance. Unexpectedly, a greater improvement in IQ score occurred in children who received weekly than in those receiving daily supplementation. This is not likely to be by chance because the sample size was relatively large and range estimates of the difference were narrow.
We propose 2 potential explanations for this finding. The first mechanism is a direct effect of high iron storage on cognitive function, which may lead to oxidative stress. The other is an indirect effect on cognitive function due to a reduction in the absorption or redistribution of other nutrients after iron supplementation. These mechanisms, however, require further specific research for support.
School-based daily iron supplementation may present risks of high iron storage for those with normal iron status; this may constitute a large proportion of the population. Children who received daily iron in this study had higher iron storage than the weekly group. This is reflected in higher SF levels, although these did not reach the level of iron excess. Our previous observational study found significantly lower mathematics test scores among children with a combination of high serum ferritin and high Hb concentrations (28). High iron is also a risk factor for brain degenerative disease (29) and some psychiatric illnesses that may respond to a specific iron chelator (30). A randomized, controlled trial (31) of iron supplementation in low-birth-weight infants did not find any advantage on developmental outcome associated with elevated iron intake.
Low plasma copper, zinc, and vitamin A were reported as adverse outcomes of supplementation with high levels of iron (31–33). Deficiencies in other nutrients, particularly zinc, are associated with delayed cognitive development (34–37).
The concern raised by our findings is the potentially adverse effects of universal daily iron supplementation on cognitive function among schoolchildren. Other negative health consequences of routine daily iron supplementation were also reported. Nonanemic pregnant Mexican women who received 60 mg iron/d had an increased risk of low birth weight and premature birth compared with those who were supplemented with 120 mg iron intermittently (33). Daily iron supplementation in iron-replete children can adversely affect growth (10,38,39). Our previous report (10) showed that the increase in height of children in the weekly supplementation group was greater than that in the daily and placebo groups.
Weekly iron supplementation is another option to improve nutrition in the community. However, the long-term effect of this dose on cognitive function and other health consequences should also be monitored and assessed, and those findings should be tested further in large-scale trials. More research is required to identify the most effective way to improve cognitive function, particularly in deprived children.
The strength of this study is in its double-blind, randomized, controlled design. The intervention was conducted under close supervision and the compliance was high. The IQ test used is valid, accurate, and reliable. The school-based setting is similar to the actual country program and there was good participation by the children and teachers. Two limitations of the study were found. First, the school examination results may not be sufficiently sensitive or may require longer study duration to detect the effect of different doses of iron on school performance. Longer supplementation, however, may lead to an overdose in iron-replete children and a delay in treating the placebo control group. The duration of the study was therefore restricted because of these ethical considerations. Second, although the prevalence of hemoglobinopathy was high in the study area, we did not collect data on Hb typing because of resource constraints. This limited our study among thalassemic children but did not affect the validity of the findings.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: DCIP, dichlorophenol indophenol precipitation test; Hb, hemoglobin; IDA, iron deficiency anemia; IQ, intelligence quotient; OF, osmolarity fragility test; RCT, randomized controlled trial; SF, serum ferritin; TONI II, Test of Nonverbal Intelligence 2nd ed.; WISC-R, Wechsler Intelligence Scale for Children-Revised; Z-score, standardized score.
Manuscript received 22 October 2003. Initial review completed 17 February 2004. Revision accepted 1 July 2004.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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