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Department of Nutrition and Program in International Nutrition, University of California, Davis;
*
Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden; and
Medicina Infantil, San Pedro Sula, Honduras
2To whom correspondence should be addressed. E-mail: kgdewey{at}ucdavis.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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110 g/L. There was no significant main effect of iron supplementation on morbidity, nor any significant interaction between iron supplementation and site, but for diarrhea (with both sites combined), there was an interaction between iron supplementation and initial Hb. Among infants with Hb < 110 g/L at 4 mo, diarrhea was less common among those given iron than in those given placebo from 4–9 mo, whereas the opposite was true among those with Hb 110 g/L (P < 0.05). We conclude that routine iron supplementation of breast-fed infants may benefit those with low Hb but may present risks for those with normal Hb.
KEY WORDS: • iron supplementation • anemia • diarrhea • breast-feeding • infant growth
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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), and in Denmark, iron supplements are recommended for infants 6–12 mo of age who do not consume at least 400 mL of iron-fortified formula per day (2
). However, the benefits and risks of iron supplementation in diverse populations have not been well documented. Iron is an essential nutrient required for infant growth and development, but it is also a potent prooxidant and its effects when given to iron-replete children have not been adequately studied. There is controversy over whether iron supplements result in increased growth (3
–5
), decreased growth (6
) or no effect on growth (7
–9
) in young children. Similarly, there is debate about the possibility that iron supplements or iron-fortified foods may increase the incidence of certain types of infections, particularly gastrointestinal infections (10
–16
). In a recent review of the relationship between iron and infectious disease, Oppenheimer (16
) pointed out that a major gap in knowledge is the effect of oral iron supplementation in breast-fed infants from nonmalarious regions.
To examine these questions, data from a randomized iron supplementation trial of breast-fed infants from 4 to 9 mo of age in Sweden and Honduras were analyzed to assess effects on growth and morbidity. The hematological results are reported elsewhere (17
). Iron status differed significantly between sites at 4 mo; nonetheless, iron supplementation significantly affected the means of all indicators of iron status at both sites. In Honduras, the prevalence of iron deficiency anemia at 9 mo [hemoglobin (Hb)3
< 110 g/L and abnormal values for at least 2 of 3 iron status indicators] was 29% in the placebo group vs. 9% in the iron-supplemented groups, whereas in Sweden, iron supplementation did not reduce the already low prevalence of iron deficiency anemia (<3%). Inclusion of two very different sites allowed us to investigate the effects of iron on growth and morbidity across a wide range in initial iron status.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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This was a randomized, double-blind, placebo-controlled iron supplementation trial conducted in two locations: San Pedro Sula, Honduras and Umeå, Sweden. In Honduras, potential subjects were identified by interviewing all mothers giving birth during February and March 1997 in the public maternity hospital. In Sweden, all parents of infants born at Umeå University Hospital between February 1997 and July 1998 who lived within 20 km of the hospital were sent a leaflet about the study and subsequently contacted by phone when their infants were 
3 mo of age. Selection criteria were as follows: 1) gestational age 37 wk; 2) birth weight > 2500 g; 3) no chronic illness; 4) maternal age 16 y; 5) infant exclusively breast-fed at 4 mo (and did not receive > 90 mL/d of formula during any period since birth); 6) mother intended to exclusively or nearly exclusively breast-feed until 6 mo (i.e., 
1 tablespoon (15 mL)/d of foods or fluids other than breast milk, and no iron-fortified foods); and 7) mother intended to continue breast-feeding to at least 9 mo. Infants with Hb < 90 g/L at any time were to have been referred to a pediatrician for iron treatment, but no such cases occurred at 4 or 6 mo. The study was approved by the Human Subjects Review Committee of the University of California, Davis, CA and the Ethical Committee of the Faculty of Medicine and Odontology at Umeå University, Sweden.
At 4 mo of age, infants were stratified by study site and sex, and randomized to three intervention groups: 1) iron supplement from 4 to 9 mo of age (Fe 4–9); 2) placebo from 4 to 6 mo and iron from 6 to 9 mo (Fe 6–9); and 3) placebo from 4 to 9 mo (Placebo). The iron supplement was a commercially available liquid formulation (Fer-In-Sol, Mead Johnson, Evansville, IN) of ferrous sulfate in a sugar solution containing 25 g/L of elemental iron. The placebo solution had a similar appearance and taste. The dose was 1 mg of elemental iron/(kg · d) (the recommended prophylactic dose), and was adjusted monthly according to each infant’s weight. The supplement or placebo was given by the mother each morning, just before or after breast-feeding and at least 1 h before or after any other food was consumed by the infant.
Between 4 and 6 mo, the mothers were asked to continue exclusive breast-feeding but were permitted to give "taste portions" (1 tablespoon (15 mL)/d) of foods with little or no iron. Adherence to this request was assessed by interview at each monthly visit, and was reportedly high. Between 6 and 9 mo, the mothers continued breast-feeding and gave complementary foods at their own discretion. No attempt was made by the investigators to influence the choice of foods or the extent of breast-feeding.
As explained elsewhere (17
), the minimum target sample size was 60 infants/treatment group, or 30/group in each site, based on detecting a difference in hemoglobin concentration of 5 g/L among treatment groups in the pooled data. This assumed that any differences between sites in the response to iron supplementation would be due to initial iron status, which could be adjusted for in the data analysis.
Data collection.
Blood samples were collected by venipuncture at 4, 6 and 9 mo of age and analyzed for Hb, various indices of iron status (plasma ferritin, erythrocyte zinc protoporphyrin, mean corpuscular volume and plasma transferrin receptor), and C-reactive protein, as described (17
). Birth weight was measured by the study team in Honduras and recorded from medical charts in Sweden. Each month from 4 to 9 mo, infant weight was measured on an electronic scale (to the nearest 10 g), length was measured on a recumbent length board (to the nearest 0.1 cm) and head circumference was measured using a tape measure (to the nearest mm). In Honduras, one individual (RJC) performed all of the measurements; in Sweden, two trained nurses performed measurements after completing a standardization procedure to ensure that the interobserver variability was within tolerable limits. Nutrient intake from complementary foods was assessed between 6 and 9 mo, as described (17
). Morbidity data were collected by providing a daily calendar for mothers to record the infant’s stool frequency and consistency and any symptoms of illness (cough, fever, nasal congestion or discharge, diarrhea, vomiting or skin rash) or diagnoses made by a health care provider (e.g., otitis media). The records were reviewed with the mothers every 2 wk. Diarrhea was defined as >3 abnormally loose stools per day.
Compliance with the intervention was monitored by asking the mothers to keep a daily checklist indicating whether the drops were given, and by collecting the used bottles each month and measuring the amount of fluid remaining. Subjects who received the study drops <75% of the days during either of the age intervals (4–6 mo or 6–9 mo) were considered "noncompliant." Noncompliers were included in all statistical analyses according to the "intention to treat" principle.
Data analysis.
Data were analyzed by using SAS-PC software (18
). Because the study was designed based on pooling data from the two sites (Honduras and Sweden), initial analyses were performed to determine whether there were any significant interactions between treatment group and site, or between treatment group and initial Hb (< or 110 g/L) or ferritin (< or 50 µg/L). We could not use the typical cut-off value for low ferritin (<12 µg/L) because there were only 4 infants with values below this level at 4 mo. Therefore, we chose a cut-off value based on the 25th percentile for the combined sites at 4 mo (<50 µg/L). These two variables (Hb < 110 g/L and ferritin < 50 µg/L at 4 mo) both significantly predicted the likelihood of Hb < 110 g/L at 9 mo in the placebo group [relative risk of 2.1 for the Hb cut-off value (P = 0.01) and relative risk of 2.2 for the ferritin cut-off value (P = 0.004)]. Based on this, we used them as proxies for low initial iron status in these analyses.
When warranted, subsequent analyses were conducted to examine the effects of iron supplementation within each site or within categories of initial Hb or ferritin. The three-way interactions of treatment group, site and initial Hb or ferritin were also of interest, but could not be examined because in one of the treatment groups (Fe 4–9) in Sweden, there were no infants with low initial Hb (and only 3 with ferritin < 50 µg/L). Therefore, the treatment group by initial Hb or ferritin interactions were examined separately within Honduras. Differences with P-values < 0.05 were considered significant.
For growth, gains in weight, length and head circumference were calculated by dividing the absolute change by the actual number of days between measurements for each infant, and then multiplying by the standard interval length (60 d for 4–6 mo, 90 d for 6–9 mo, 150 d for 4–9 mo). Group comparisons were performed by ANOVA, with Fisher’s least-squares means test to determine differences between pairs of treatment groups. The independent variables for the pooled analyses included treatment group, site (Honduras vs. Sweden), maternal height and baseline growth status (weight, length or head circumference), as well as the interaction terms described above. The same models were used for the within-site analyses, but without the variable for site.
Morbidity variables were created by calculating the percentage of days with each symptom of illness. Because these variables were highly skewed (many cases with no illness) and could not be normalized with any transformation, dichotomous variables for the presence or absence of illness in each age interval were then created, and groups were compared using logistic regression (for the pooled data, with site, treatment group and initial Hb or ferritin as independent variables, as well as the interaction terms described above) and 
2 tests (for the within-site analyses).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). There were also no differences in any of these characteristics among treatment groups within each site, as shown elsewhere (17
). Compliance with giving the iron or placebo drops was 92% at 4–6 mo (89% in Honduras and 95% in Sweden) and 95% at 6–9 mo (95% in Honduras and 96% in Sweden), and was lower in the group given iron from 4 to 9 mo than in the other two groups [for placebo, Fe 6–9 and Fe 4–9 the percentages were 97, 99 and 79% at 4–6 mo (P < 0.001) and 100, 97 and 89% at 6–9 mo (P = 0.001), respectively].
Table 1
shows the anthropometric status of the infants at 4, 6 and 9 mo, and Table 2
shows the growth velocity (adjusted for covariates) and morbidity outcomes during each interval. There was no effect of iron supplementation on weight gain during the intervals of 4–6, 6–9 or 4–9 mo in the pooled analyses (sites combined) or within either site (Table 2)
, nor any interaction of treatment group with site, initial Hb or initial ferritin. Length gain from 4 to 9 mo was less in the iron-supplemented groups than in the placebo group (P = 0.049 for the overall model; P = 0.03 for Placebo vs. Fe 4–9; P = 0.04 for Placebo vs. Fe 6–9), controlling for site (Sweden vs. Honduras), infant length at 4 mo, and maternal height. Although the two iron groups had somewhat greater initial length than the placebo group (in both sites, see Table 1
), the above P-values were all <0.05 with or without initial length included in the model (because the correlation between initial length and subsequent length gain from 4 to 9 mo was weakly positive; r = 0.15; P = 0.02). The interaction of treatment group with site was not significant in the pooled analyses (nor was the interaction of treatment group with initial Hb or ferritin), but the within-site data (Table 2)
revealed that the length gain deficit in the iron-supplemented groups was greater in Sweden (0.5–0.6 cm) than in Honduras (0.2–0.3 cm). Therefore, within-site ANOVA were performed. In Honduras, the main effect of treatment group on length gain was not significant during any of the intervals. In Sweden, length gain from 6 to 9 mo differed among treatment groups (P = 0.049) [lower in the Fe 4–9 group (P = 0.02) and in the Fe 6–9 group (P = 0.10) than in the placebo group]; the effect of treatment group on length gain from 4 to 9 mo was significant when the two iron groups were combined (P = 0.04; lower in the combined iron group than in the placebo group), but not when the model included three treatment categories (P = 0.10).
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). The within-site analyses in Sweden confirmed this difference at 4–9 mo, and also showed that head circumference gain from 4 to 6 mo was less in the Fe 4–9 group than in the placebo group. There was no interaction between treatment group and initial Hb or ferritin in the models for head circumference.
The interactions between treatment group and initial Hb or ferritin were also examined separately within Honduras. For weight gain, the interactions with initial Hb were not significant but there was an interaction (P = 0.03) with initial ferritin for the interval 6–9 mo [within the lower ferritin subgroup, weight gain was lower in the Fe 6–9 group (480 ± 410 g, n = 19) than in the placebo (818 ± 409 g, n = 26) or Fe 4–9 (770 ± 425 g, n = 15) groups, whereas in the higher ferritin subgroup, there were no significant differences by treatment group]. For length gain, the interaction between treatment group and initial Hb was significant at 4–6 mo (P = 0.04), although not at 6–9 or 4–9 mo. At 4–6 mo, there was a negative effect of iron supplementation on length gain among those with initial Hb 110 g/L [Mean ± SD: 3.1 ± 0.9 vs. 2.6 ± 0.7 cm in the placebo (n = 50) vs. iron supplemented group (n = 26), P = 0.01], but no effect in those with initial Hb < 110 g/L [3.2 ± 0.8 vs. 3.3 ± 0.9 in the placebo (n = 36) vs. iron-supplemented group (n = 19)]. There were no interactions with initial ferritin for length gain. For head circumference, none of the interactions with initial Hb or ferritin were significant.
There was no main effect of treatment group on the likelihood of illness symptoms during any of the age intervals (shown within each site for diarrhea and fever in Table 1
), nor any interaction of treatment group and site. However, for diarrhea, there was an interaction (P = 0.03) of treatment group with initial Hb, controlling for site (Table 3
and Fig. 1
); among infants with Hb < 110 g/L at 4 mo, diarrhea was more common in the placebo group than in those given Fe from 4 to 9 mo, but the opposite was true among those with Hb 110 g/L. In Honduras, this interaction was only marginally significant (P = 0.08), but in the same direction. In the combined sample, there was a marginally significant interaction of treatment group with initial ferritin (P = 0.07), controlling for site (Table 3)
, but the odds ratios for each of the pairwise comparisons were not significant. Diarrheal morbidity was not associated with baseline characteristics such as infant sex (P = 0.3) or initial weight or length (P > 0.6); thus, these variables were not included in the above models.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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110 g/L. With regard to morbidity, iron supplementation reduced the likelihood of diarrhea among infants with Hb < 110 g/L at 4 mo, but increased the likelihood of diarrhea among infants with Hb 110 g/L at 4 mo. There was no significant effect on other morbidity outcomes, although it should be noted that detecting effects on morbidity generally requires larger sample sizes than achieved in this study.
These findings are consistent with the results of Idjradinata et al. (6
), who showed that iron supplementation may pose risks in iron-replete children. They found that among 47 iron-sufficient Indonesian children 12–18 mo of age, weight gain (but not length gain) was significantly lower in those given iron [3 mg/(kg · d)] for 4 mo than in those given placebo. The authors reported that the growth of the iron-deficient, anemic children in the same study was improved by iron supplementation, and that of children who were iron-deficient but not anemic was unaffected. Other studies have demonstrated either a positive effect of iron treatment (supplementation or use of fortified foods) (3
–5
) or no effect (7
–9
) on the growth of young children. However, in all of these studies except that of Dijkhuizen et al. (9
), the children were past infancy (2–5 y old) or were not fully breast-fed. Aside from the Indonesian data reported by Idjradinata et al. (6
), most investigators have not differentiated between iron-replete and iron-deficient children when examining growth effects.
The mechanism(s) underlying the growth effect observed in our study is unclear. Our study was not designed to investigate such mechanisms, but we can suggest some possibilities that would require further research. Although the dose of iron given [1 mg/(kg · d), averaging 6–9 mg/d] was lower than the amount given in most other iron supplementation trials, and was less than the prophylactic dose recommended by UNICEF [12.5 mg/d; (19
)], it is possible that the infants absorbed an excessive amount of iron. We demonstrated that regulation of iron metabolism is immature before 6 mo, and that both Hb and plasma ferritin increase with iron supplementation at this age even when the initial values are well above standard cut-off points (17
). However, in Sweden, the group given iron only after 6 mo of age (Fe 6–9) also showed slower linear growth, suggesting that this phenomenon may not completely explain the results. Greater morbidity in those given iron could impair growth, but in our analyses, the morbidity variables did not account for the growth effects observed. On the other hand, given that iron supplements given to adults (e.g., during pregnancy) sometimes reportedly provoke nausea or other gastrointestinal symptoms, there may have been a subtle effect of iron supplements on infant appetite in this study. Appetite is depressed by iron deficiency (20
), but to our knowledge there is no evidence that iron supplements can lead to the same outcome. Another possibility is that iron supplements adversely affect zinc status, which is related to child growth (21
). O’Brien et al. (22
) recently demonstrated that prenatal iron supplements impair zinc absorption in pregnant Peruvian women, although Dijkhuizen et al. (9
) found no effect of iron supplements on plasma zinc among Indonesian infants. We also did not observe any differences in plasma zinc among treatment groups in our study (unpublished data), but plasma zinc may not be an adequate indicator of zinc status in infants. Last, iron is a prooxidant and thus stimulates production of free radicals, which can cause damage via oxidation of DNA bases, cross-linking of proteins, inactivation of enzymes and lipid peroxidation. Prooxidative events may affect cellular cytokine responses, which may affect expression of genes regulating growth factors and thereby reduce growth. Knutson et al. (23
) showed increased lipid peroxidation in rats supplemented with iron daily. In their study, no adverse growth effect of iron supplements was seen in the iron-replete rats, but the situation was not entirely analogous to our study because the rats were already weaned. Young infants may be more prone to such effects because of their very rapid rate of growth.
The lack of a positive effect of iron supplementation on growth among the Honduran infants with low initial Hb is noteworthy given the uncertainty about whether iron deficiency affects growth (3
–5
,7
9
). In the Honduran population, growth faltering among breast-fed infants does not become obvious until after 9 mo (when comparing average rates of growth with those of breast-fed infants in affluent populations) (24
). The current study ended at 9 mo, before the most vulnerable period, and thus may have been unable to detect a positive growth effect. Alternative explanations are that the iron deficiency observed was not severe enough to affect growth, or that other constraints on growth, such as zinc status, morbidity or prenatal "programming" of postnatal growth, may have limited the ability of these infants to accelerate growth in response to iron.
The effect of iron treatment on morbidity has long been controversial. It is clear that iron deficiency can impair immune function, but it has been more difficult to demonstrate that this leads to a greater incidence of infection (16
). At the other end of the spectrum, iron excess may also contribute to a greater risk of infection if the pathogens have access to more free iron (i.e., more than can be bound by iron-binding proteins) for their own growth and reproduction. Oppenheimer (16
) suggested that growth of organisms that spend part of their life cycle intracellularly, such as plasmodia, mycobacteria and invasive salmonellae, is more likely to be enhanced by iron treatment. It is also possible that high iron intake affects cytokine production and peroxidative stress locally in the intestinal mucosa, thereby affecting immune function and diarrheal disease. In rats, iron supplementation increased mucosal ferritin level and peroxidative stress in the intestine (25
). Iron-binding proteins such as transferrin and lactoferrin have been shown to inhibit bacterial growth by making iron unavailable to the pathogen. Lactoferrin is a major protein in human milk and is thought to be one of the factors contributing to lower rates of infection in breast-fed infants. If lactoferrin is saturated with iron, however, this protective effect is reduced (26
). For this reason, it is possible that excess iron increases risk of infection among breast-fed infants, whereas there may be no effect of excess iron among formula-fed infants because lactoferrin is not present in the formulas.
The morbidity results of iron treatment trials in young children have been mixed. Some of the older studies showed a reduction in certain types of infections (e.g., respiratory infections) with iron treatment in disadvantaged populations (16
), whereas more recent studies have generally shown no effect (12
–14
) or an increased risk of diarrhea (10
). Infants may be more vulnerable than older children to the potentially deleterious effects of iron on gastrointestinal infections. Mitra et al. (11
) evaluated the effect of iron supplements (15 mg/d for 15 mo) in 349 Bangladeshi children, 2–48 mo of age. There were no significant effects of iron on morbidity in the group as a whole, but in those <12 mo of age, the incidence of dysentery was increased by 49%. By contrast, infants may be less vulnerable to the potentially deleterious effects of iron on malaria. In children and adults, therapeutic doses of iron may increase the risk of clinical malaria (16
), but no such effect was observed in young infants (15
).
Our morbidity data should be interpreted with caution, given the relatively small sample sizes and the somewhat inconsistent findings depending on whether initial Hb or ferritin was used when examining the interactions between iron supplementation and initial iron status. Moreover, the Hb cut-off value used, <110 g/L, may not adequately reflect "low" iron status because data presented elsewhere indicate that this cut-off value is too high (27
). It should also be noted that Hb may be influenced by nonnutritional factors as well as nutrient deficiencies other than iron, although we found no evidence of the latter in a subsample of 24 blood samples from the Honduran cohort in this study or in our other studies in this population (unpublished data). The cut-off value used here for "low" ferritin at 4 mo (<50 µg/L) is much higher than the typical cut-off value (<12 µg/L); thus, this categorization of initial iron status is also open to criticism. Despite these limitations, the morbidity data indicate that initial hematological status should be considered when analyzing the results of iron intervention trials. Iron supplementation may reduce the risk of diarrhea among infants with "low hemoglobin" (30% of our subjects had Hb < 110 g/L), but increase it among infants with "normal" hemoglobin (70% of our subjects had Hb 110 g/L). In most other studies, the data were not analyzed separately for subgroups categorized by Hb level or iron status, or the sample was confined to those with low iron status. This may explain the mixed findings of previous studies.
We conclude that a cautious approach is warranted with regard to routine iron supplementation during infancy. Among infants with low Hb, iron supplementation is unlikely to pose significant risks and has been shown to reduce the risk of anemia (17
). However, universal daily iron supplementation of breast-fed infants may present risks for those with normal Hb, who may be a large proportion of the population, even in low income countries. Although targeting is costly and sometimes impractical, it may be a safer option in such situations. Alternatively, less frequent administration of iron supplements (e.g., weekly) may reduce the likelihood of potentially adverse effects (28
,29
). Sungthong et al. (29
) recently reported that height gain of children 6–13 y of age in Thailand was significantly lower in those given iron supplements daily for 16 wk than in those given them weekly, with height gain in the placebo group intermediate. No such difference was found in a similar study of school children in Indonesia (30
), but that study included only anemic children, whereas the Thailand study included both anemic and nonanemic children. Weekly vs. daily iron supplementation has not yet been evaluated in infants. Another option is to use an alternative mode of administering iron to infants, such as iron fortification of complementary foods. This strategy may be less likely than ingestion of iron supplements to affect growth (31
), but is suitable only after 6 mo of age when introduction of complementary foods is recommended. Further research is required to identify the safest and most effective way to ensure adequate iron status during infancy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: Fe 4–9, group receiving iron supplement from 4 to 9 mo of age; Fe 6–9, group receiving placebo from 4 to 6 mo and iron from 6 to 9 mo; Hb, hemoglobin; Placebo, group receiving placebo from 4 to 9 mo.
Manuscript received 11 February 2002. Initial review completed 26 March 2002. Revision accepted 16 August 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Institute of Medicine (1993) Iron Deficiency Anemia: Recommended Guidelines for the Prevention, Detection and Management Among U.S. Children and Women of Childbearing Age 1993 National Academy Press Washington, DC. .
2. Danish National Board of Health and Welfare (Sundhetsstyrelsen) (1998) [Recommendations for Infant Nutrition] 1998 Copenhagen Denmark. .
3. Aukett, M. A., Parks, Y. A., Scott, P. H. & Wharton, B. A. (1986) Treatment with iron increases weight gain and psychomotor development. Arch. Dis. Child. 61:849-857.[Abstract]
4. Bhatia, D. & Seshadri, S. (1993) Growth performance in anemia and following iron supplementation. Indian Pediatr 30:195-200.[Medline]
5. 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.
6. Idjradinata, P., Watkins, W. & Pollitt, E. (1994) Adverse effect of iron supplementation on weight gain of iron-replete young children. Lancet 343:1252-1254.[Medline]
7. Rahman, M. M., Akramussaman, 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.
8. Morley, R., Abbott, R., Fairweather-Tait, S., MacFadyen, U., Stephenson, T. & Lucas, A. (1999) Iron fortified follow on formula from 9 to 18 months improves iron status but not development or growth: a randomised trial. Arch. Dis. Child. 81:247-252.
9. Dijkhuizen, M. A., Wieringa, F. T., West, C. E., Martuti, S. & Muhilal, (2001) Effects of iron and zinc supplementation in Indonesian infants on micronutrient status and growth. J. Nutr. 131:2860-2865.
10. Brunser, O., Espinoza, J., Araya, M., Pacheco, I. & Cruchet, S. (1993) Chronic iron intake and diarrhoeal disease in infants. A field study in a less-developed country. Eur. J. Clin. Nutr. 47:317-326.[Medline]
11. Mitra, A. K., Akramussaman, S. M., Fuchs, G. J., Rahman, M. M. & Mahalanabis, D. (1997) Long-term oral supplementation with iron is not harmful for young children in a poor community of Bangladesh. J. Nutr. 127:1451-1455.
12. Heresi, G., Pizarro, F., Olivares, M., Cayazzo, M., Hertrampf, E., Walter, T., Murphy, J. R. & Stekel, A. (1995) Effect of supplementation with an iron-fortified milk on incidence of diarrhea and respiratory infection in urban-resident infants. Scand. J. Infect. Dis. 27:385-389.[Medline]
13. Berger, J., Dyck, J. L., Galan, P., Aplogan, A., Schneider, D., Traissac, P. & Hercberg, S. (2000) Effect of daily iron supplementation on iron status, cell-mediated immunity, and incidence of infections in 6–36 month old Togolese children. Eur. J. Clin. Nutr. 54:29-35.[Medline]
14. Javaid, N., Haschke, F., Pietschnig, B., Schuster, E., Huemer, C., Shebaz, A., Ganesh, P., Steffan, I., Hurrel, R. & Secretin, M. C. (1991) Interactions between infections, malnutrition and iron nutritional status in Pakistani infants. Acta. Paediatr. Scand. 374:141-150.
15. Menendez, C., Kahigwa, E., Hirt, R., Vounatsou, P., Aponte, J. J., Font, F., Acosta, C. J., Schellenberg, D. M., Galindo, C. M., Kimario, J., Urassa, H., Brabin, B., Smith, T. A., Kitua, A. Y., Tanner, M. & Alonso, P. L. (1997) Randomised placebo-controlled trial of iron supplementation and malaria chemoprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants. Lancet 350:844-850.[Medline]
16. Oppenheimer, S. J. (2001) Iron and its relation to immunity and infectious disease. J. Nutr. 131:616S-635S.
17. Domellöf, M., Cohen, R. J., Dewey, K. G., Hernell, O., Landa Rivera, L. & Lönnerdal, B. (2001) Iron supplementation of breast-fed Honduran and Swedish infants from 4 to 9 months of age. J. Pediatr. 138:679-687.[Medline]
18. SAS Institute Inc. (1987) SAS-PC Software, version 6.03 1987 SAS Institute Cary, NC. .
19. UNICEF/UNU/WHO/MI Technical Workshop (1998) Preventing Iron Deficiency in Women and Children 1998 UNICEF New York, NY. .
20. Topaloglu, A. K., Hallioglu, O., Canim, A., Duzovali, O. & Yilgor, E. (2001) Lack of association between plasma leptin levels and appetite in children with iron deficiency. Nutrition 17:657-659.[Medline]
21. Brown, K. H., Peerson, J. M. & Allen, L. H. (1998) Effect of zinc supplementation on children’s growth: a meta-analysis of intervention trials. Sandstrom, B. Walter, P. eds. Trace Elements, Growth and Development: Role of Trace Elements for Health Promotion and Disease Prevention Bibl. Nutr. Dieta 54:76-83 .
22. O’Brien, K. O., Zavaleta, N., Caulfield, L. E., Wen, J. & Abrams, S. A. (2000) Prenatal iron supplements impair zinc absorption in pregnant Peruvian women. J. Nutr. 130:2251-2255.
23. Knutson, M. D., Walter, P. B., Ames, B. N. & Viteri, F. E. (2000) Both iron deficiency and daily iron supplements increase lipid peroxidation in rats. J. Nutr. 130:621-628.
24. Dewey, K. G. (1997) Cross-cultural patterns of growth and nutritional status of breastfed infants. Am. J. Clin. Nutr. 67:10-17.[Abstract]
25. Srigiridhar, K. & Nair, K. M. (1998) Iron-deficient intestine is more susceptible to peroxidative damage during iron supplementation in rats. Free Radic. Biol. Med. 25:660-665.[Medline]
26. Andersson, Y., Lindquist, S., Lagerqvist, C. & Hernell, O. (2000) Lactoferrin is responsible for the fungistatic effect of human milk. Early Hum. Dev. 59:95-105.[Medline]
27. Domellöf, M., Dewey, K. G., Lönnerdal, B., Cohen, R. J. & Hernell, O. () Diagnostic criteria for iron deficiency in infants: time for a re-evaluation. J. Nutr. in press..
28. Viteri, F. E. (1996) Weekly compared with daily iron supplementation. Am. J. Clin. Nutr. 63:610-612.
29. Once weekly is superior to daily iron supplementation on height gain, but not on hematological improvement among schoolchildren in Thailand. J. Nutr. 132:418-422.
30. 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 12:69-74.
31. Walter, T., Dallman, P. R., Pizarro, F., Velozo, L., Pena, G., Bartholmey, S. J., Hertrampf, E., Olivares, M., Letelier, A. & Arredondo, M. T. (1993) Effectiveness of iron-fortified infant cereal in prevention of iron deficiency anemia. Pediatrics 91:976-982.
32. Hamill, P.V.V., Drizd, T. A., Johnson, C. L., Reed, R. B. & Roche, A. F. (1976) NCHS Growth Charts, 1976. Vital and Health Statistics, Series II 1976 Health Resources Administration, DHEW Rockville, MD. .
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