Journal of Nutrition OpenSOurce Diets- www.ResearchDiets.com

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wasantwisut, E.
Right arrow Articles by Russameesopaphorn, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wasantwisut, E.
Right arrow Articles by Russameesopaphorn, W.
© 2006 American Society for Nutrition J. Nutr. 136:2405-2411, September 2006

Community and International Nutrition

Iron and Zinc Supplementation Improved Iron and Zinc Status, but Not Physical Growth, of Apparently Healthy, Breast-Fed Infants in Rural Communities of Northeast Thailand1

Emorn Wasantwisut, Pattanee Winichagoon*, Chureeporn Chitchumroonchokchai, Uruwan Yamborisut, Atitada Boonpraderm, Tippawan Pongcharoen, Kitti Sranacharoenpong and Wanphen Russameesopaphorn

Institute of Nutrition, Mahidol University, Salaya, Nakhon Pathom 73170, Thailand

* To whom correspondence should be addressed. E-mail: nupwn{at}mahidol.ac.th.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Iron deficiency is prevalent in children and infants worldwide. Zinc deficiency may be prevalent, but data are lacking. Both iron and zinc deficiency negatively affect growth and psychomotor development. Combined iron and zinc supplementation might be beneficial, but the potential interactions need to be verified. In a randomized, placebo-controlled trial using 2 x 2 factorial design, 609 Thai infants aged 4–6 mo were supplemented daily with 10 mg of iron and/or 10 mg of zinc for 6 mo to investigate effects and interactions on micronutrient status and growth. Iron supplementation alone increased hemoglobin and ferritin concentrations more than iron and zinc combined. Anemia prevalence was significantly lower in infants receiving only iron than in infants receiving iron and zinc combined. Baseline iron deficiency was very low, and iron deficiency anemia was almost nil. After supplementation, prevalence of iron deficiency and iron deficiency anemia were significantly higher in infants receiving placebo and zinc than in those receiving iron or iron and zinc. Serum zinc was higher in infants receiving zinc (16.7 ± 5.2 µmol/L), iron and zinc (12.1 ± 3.8 µmol/L) or iron alone (11.5 ± 2.5 µmol/L) than in the placebo group (9.8 ± 1.9 µmol/L). Iron and zinc interacted to affect iron and zinc status, but not hemoglobin. Iron supplementation had a small but significant effect on ponderal growth, whereas zinc supplementation did not. To conclude, in Thai infants, iron supplementation improved hemoglobin, iron status, and ponderal growth, whereas zinc supplementation improved zinc status. Overall, for infants, combined iron and zinc supplementation is preferable to iron or zinc supplementation alone.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Deficiencies of 2 important trace minerals, iron and zinc, are a major public health problem in many developing countries (1). These problems exist even among populations where severe protein-energy malnutrition has been alleviated. Iron deficiency in young children can result in impaired cognitive and psychomotor development (2–4). Iron supplementation was inconsistently shown to reverse these impairments (2,4,5). Several studies indicate that zinc deficiency results in poor growth in infants (6,7) and children (8–10) and a depressed appetite (8,11). Zinc deficiency may also lead to impaired motor development in infants (12,13) and thus can interfere with cognitive performance. Furthermore, zinc is essential for the integrity of the immune system, and a deficiency can result in reduced immunocompetence and decreased resistance to infection (14–17). Zinc supplementation administered to zinc-deficient children enhances linear growth and reduces morbidity (17). Concurrent iron and zinc deficiency may be common among populations that consume small amounts of animal-source foods. However, the use of iron and zinc together as a supplement at a prophylactic dose has provoked controversy over their potential interaction and resulting adverse impact on iron or zinc status (18) and cognition (19). More data on the biological interaction between these 2 nutrients are needed before further recommendations can be made.

Plant-based complementary foods in developing countries are poor sources for bioavailable iron, zinc, and other micronutrients. Adequate nutrients from breast milk during the first 6 mo of life, complemented by high-quality complementary food during the second half of the first year, are needed for the optimal growth and development of infants (20). The untimely introduction of poor-quality complementary food can result in an inadequate uptake of iron and can deplete iron stores. In Thailand, rice gruel or chewed glutinous rice is the main portion of complementary food introduced to young infants, even before the age of 4 mo. Although the major sources of iron and zinc in rural Thailand are animal foods, these are given to infants late or are consumed by infants only occasionally in small amounts (21). Growth faltering starts at ~6 mo of age in NE Thailand (22). Furthermore, a 1995 national nutrition survey in Thailand indicated that stunting remained at 15.6% among children <5 y (23). There are no data on zinc deficiency in Thai infants, but 34% of NE Thai school-aged children are found to be marginally zinc deficient (serum zinc <9.9 µmol/L) (24). Similarly, data on iron deficiency anemia in infants are scarce, but anemia among pregnant women and school-aged children has been a public health problem (25).

We implemented a community-based, randomized controlled trial that provided 6 mo of supplementation to 4 to 6-mo–old infants in rural NE Thailand. The daily supplementation of iron and/or zinc among these rural Thai infants was conducted to test the hypothesis that supplementation of iron or zinc alone, or iron and zinc combined, can improve iron and zinc status and growth of infants 4–6 mo of age compared with infants receiving a placebo. The interactions between iron and zinc on iron and zinc status indicators were also examined. This article reports the efficacy of these supplements on biochemical and anthropometric outcomes.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
Study site and study design

The study sites were 3 rural districts of Khon-Kaen Province, located ~450 km northeast of Bangkok. These districts are similar to other rural northeast districts, based on socio-demographic profiles for population, village, and household size. A total of 106 villages were included in the study. Most of the inhabitants were engaged in subsistence agriculture. The study was a randomized 2 x 2 factorial, double-blind, placebo-controlled trial, with infants receiving iron-only, zinc-only, iron plus zinc supplements, or a placebo. A sample size of 130 infants/group was calculated to detect a difference in length-for-age (LAZ)2 of 0.15 (with a SD of 0.9) with 95% CI and power of 0.90 among the groups, or to detect a difference in LAZ of 0.11 when using factorial analysis. Allowing for a dropout of 15%, a sample size of 150/group was included. The study was approved by the Human Ethics Committee of Mahidol University.

Subject recruitment and randomization to treatment

Lists of infants aged <6 mo were obtained from the local health personnel and village health volunteers. When eligible infants reached the age of 4–6 mo, a verbal informed consent was obtained from the mothers or caretakers. The same information about the project was explained a second time and the verbal informed consent verified. Eligibility criteria were that infants were predominantly breast fed and free from apparent congenital abnormalities and that their parents agreed to participate in the study. Infants having hemoglobin (Hb) <80 g/L, chronic illnesses, or who were bottle fed were excluded. A total of 675 infants (339 boys and 336 girls) aged 4–6 mo were enrolled in the study. Infants were stratified by age and sex and then random numbers were used to assign individual infants to supplemental groups. The randomization was done by a statistician who was not involved in the study.

The supplements and monitoring of compliance

Supplements were made by PT Kenrose as a syrup and supplied by UNICEF of Indonesia. The bottles of syrup were coded at the production site. The code allocation was kept at UNICEF, Jakarta, until the end of data analysis. The syrup contained either 5 g/L (89.5 mmol/L) iron (as ferrous sulfate), 5 g/L (76.5 mmol/L) zinc (as zinc sulfate), or both iron and zinc in the same concentrations. The 4 types of supplements were indistinguishable in appearance, color, taste, or odor. All supplements contained vitamin C (15 g/L). Vitamin A drops at a dose of 1500 µg retinol equivalent (RE) were given to each subject at the beginning of the study. Each mother was provided with 2 bottles of syrup and a calendar to record each time she administered the syrup. Mothers were carefully instructed, in the presence of village health volunteers from respective communities, to administer the supplement using an oral medication syringe (2 mL/dose, equivalent to 10 mg of iron or zinc/d). Supplements were given between meals to avoid interference from the absorption of food. The supplement was given daily for a duration of 6 mo. The village health volunteers were trained and visited each family 2–3 times/wk to identify problems associated with the ingestion of the supplement, to encourage mothers to administer the supplements, and to keep a record of infants' illness (symptoms). Every week, 4 field workers were assigned to visit each village to check on each mother and to assist village health volunteers in monitoring the compliance and morbidity data. Supplement compliance was recorded by mothers or village health volunteers onto a monthly calendar provided with each supplement bottle. These records were reviewed weekly by field workers. At the monthly field visit, the research team measured the leftover syrup collected by the village health volunteers and dispensed new bottles to be distributed to the mothers.

Data collection

    Socio-demographics, health, feeding practices, and morbidity status. A culturally appropriate questionnaire, which included socio-economic status, household income, maternal age, weight, height, and medicinal supplements that mothers gave to their infants during the month prior to the intervention, was completed by the mothers at enrollment. Once each month, the research data collection team visited the field area. Data on the infant's health and feeding practices (breast-feeding frequency and intake of complementary food) were also collected. During the monthly field visit, morbidity records from the village health volunteers were verified with the mother by one of the investigators. When applicable, morbidity was also verified with the health card at the health centers or district hospital.

    Anthropometry. Anthropometric measurements were performed on each infant using standard procedures (26). The child's body weight (wearing light clothing) was measured to the nearest 5 g using a portable beam balance (Detecto Infant Scale). Recumbent length was measured to the nearest 0.1 cm using a length of wooden board with a sliding foot piece. Anthropometry was assessed every 2 mo by 2 field researchers who were standardized periodically during the data collection. The coefficient of reliability, based on technical error of measurement (27), was 0.98. Two readings were taken at each measurement. For all infants, LAZ, weight-for-age Z-scores (WAZ), and weight-for-length Z-scores (WLZ) were calculated (EpiInfo 6.02) and based on the National Center for Health Statistics of 1977 (28). Birth weight data were retrieved from the baby's health card. Most of the births in the study area occurred at the district hospital where birth weight was measured at the time of birth and recorded on the baby's health card. Gestational age was estimated by recalling the last menstrual period and the completed weeks of gestation were recorded. Once a woman was suspected of being pregnant by the village health volunteers, she was invited to meet with the research team at monthly field visits to obtain the earliest possible recall of the last menstrual period.

Blood collection

A blood sample was taken from a subset of infants (whose mothers agreed to blood collection) at baseline and the end of the 6-mo supplementation period. Nonfasting blood samples were taken at 800 and 1400 h. Three mL of blood was obtained from the antecubital vein, using regular syringes. Random samples of syringes from each batch were tested for contamination by iron and zinc and were found to be uncontaminated. All glassware, plasticware, and microcontainer tubes were acid-washed. One mL of blood was put in a tube containing the anticoagulant, EDTA, and 2 mL were allowed to clot and then were centrifuged for serum.

Blood samples were stored in a cool box immediately after the blood was taken. Separation of serum was done at the hospital laboratory and completed by 1500 of each field visit day. Samples were frozen at –20°C prior to analyses for zinc and ferritin. Hemoglobin was determined by the cyanmethemoglobin method (29), and serum ferritin by enzyme-linked immunoassay (30,31), using the ES-33 system (Boehringer Mannheim). Serum zinc was measured by graphite furnace atomic absorption spectrophotometry (WL 213.9, current 15 mA and slit high 0.7) (32). For both ferritin and zinc, the initial and final samples were analyzed in the same batch. Certified reference materials were used for Hb, serum ferritin, and zinc. CBC-8 hematology controls (from R&D Systems) were used for quality control of Hb, and had the following values (means ± SD): low, 61 ± 3; normal, 134 ± 4; and high, 178 ± 5 g/L. The mean (SD, %CV) for ferritin references were as follows: low, 12.8 (1.11, 3.1%); normal, 90.2 (5.5, 4.0%); and high, 550 (25.0, 5.2%) µg/L. For serum zinc (using the Bovine Serum Reference Material 1598, National Institute of Standards and Technology) the means ± SD value was 13.6 ± 0.9 µmol/L vs. a pooled serum mean (SD, %CV) of 13.6 µmol/L (0.1, 0.89%).

Because there was no consensus on the cutoff for defining anemia, iron deficiency, and iron deficiency anemia for young infants, the following were used: whereas WHO recommended Hb <110 g/L to define anemia in children <5 (33), Domellöf et al. (34) proposed age-specific Hb cutoffs for defining anemia with <105 g/L for 4- to 6-mo–old infants and <100 g/L for 9-mo–old infants. However, there were no data for 10- to 12-mo olds. In the present study, infants were measured at 4–6 mo at baseline, and at 10–12 mo at the end point. Thus, anemia was defined as Hb either below the age-specific cutoffs from Domellöf et al., Hb <105 g/L at 4–6 mo of age and Hb <100 g/L at 10–12 mo, or at the WHO recommended cutoff of <110 g/L for infants. In addition, the age-specific cutoffs for ferritin were also proposed (<20 µg/L for 4 mo, <9 µg/L for 6 mo, and <5 µg/L for 9 mo). However, only a few infants at these ages in the present study had ferritin <12 µg/L. Therefore, 2 cutoffs were used for defining iron deficiency (ID), namely, ferritin <12 or <20 µg/L. For iron deficiency anemia (IDA), the 2 cutoff systems for Hb and ferritin, <12 or <20 µg/L, were used. For serum zinc, the cutoff of <9.9 µmol/L and <10.7 µmol/L for the fasting and nonfasting states were used, respectively (35).

Statistical analysis

Data were checked for normality, using the Kolmogorov-Smirnov test of normality. Because of skewed data on serum concentrations of ferritin and zinc, these data were transformed to natural logarithms. Differences among groups were analyzed with ANOVA for continuous variables and the chi-square test for prevalence. Where there was a significant effect, multiple comparisons were performed using the Bonferroni post-hoc test. The estimated-effect sizes were analyzed using the postintervention values as the dependent variable in an ANCOVA model, in which the baseline values were included as a covariate. Gender and/or birth weight were included in the model as potential confounders. Similar analysis procedures were performed for both biochemical and anthropometric parameters. Main effects were considered significant at P < 0.05, and interactions were considered significant at P < 0.1. Differences were considered significant at P < 0.05. SPSS, version 11.5, was used for all statistical analysis.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Trial profile. In total, 609 infants completed the study and were included in the analysis. There were 9, 13, 24, and 19 infants from the placebo, iron, zinc, and iron plus zinc groups, respectively, who did not complete the study (Fig. 1). Reasons for dropout during the study included health problems (n = 2), moving (n = 49), and side effects attributed to the supplements (severe diarrhea, n = 3). Infants whose mothers introduced bottle feeding during the study (n = 4) and those not cooperative (n = 5) were excluded from the analysis. Infants not completing the study did not differ from those who completed the study in any of the characteristics at baseline. Infants who had biochemical data did not differ from those without these data in their sex, age, and anthropometric measurements, both at study entry or exit. The median compliance was >90% [median (range) of 96 (57–100), 96 (70–100), 95 (70–100), and 95 (71–100) for placebo, iron, zinc, and iron plus zinc groups, respectively]. More than 95% of infants received >80% of intended doses of each of the supplements. Supplement compliance among the groups did not differ.


Figure 1
View larger version (17K):
[in this window]
[in a new window]
  		Figure 1  Trial profile.

 
    Background characteristics. The majority of the mothers had a primary education, and 20–27% had a secondary education. Their incomes were derived from both agricultural and nonagricultural activities. Maternal age, height, parity, education, and income did not differ among the groups. Baseline characteristics did not differ among the 4 groups (Table 1). The mean age of infants at baseline was 4.5 mo. The incidence of low birth weight and preterm delivery (gestational age <37 wk) was 9 and 11%, respectively. The prevalence of low birth weight or preterm delivery did not differ among groups. Overall, the study infants were apparently healthy with only 3% stunted (LAZ <–2, NCHS) and none were underweight. The LAZ of infants in the zinc group tended to be worse than other groups (P = 0.055).


View this table:
[in this window]
[in a new window]
  		TABLE 1 Baseline characteristics of infants who completed the study1

 
    Biochemical indicators. The mean concentrations of hemoglobin and zinc, and the median concentration of ferritin in serum, did not differ among the groups at baseline (Table 2). After 6 mo of supplementation, infants receiving iron supplements (iron and iron plus zinc groups) had significantly higher hemoglobin concentrations than those receiving a placebo or zinc (Table 2). Infants not receiving iron had a decrease in hemoglobin concentrations of 11.0 g/L between baseline and 6 mo (P < 0.001). The declines in hemoglobin concentrations in the placebo and zinc groups might have been due to the lack of supplemental iron. The overall effect of iron supplementation on end point hemoglobin concentrations was an increase of 10.8 (95% CI: 8.0, 13.6) g/L, whereas the effect of zinc supplementation with or without iron was a decrease in hemoglobin concentrations by 3.4 g/L (95% CI: –6.3, 0.6). The interaction between the 2 nutrients on hemoglobin concentrations was not significant.


View this table:
[in this window]
[in a new window]
  		TABLE 2 Biochemical indicators of infants at baseline and after 6-mo supplementation with iron, zinc, or both

 
Baseline ferritin concentrations did not differ among the groups (P = 0.201) but, after 6-mo of supplementation, the 2 groups receiving iron supplementation (iron or iron plus zinc) had significantly higher ferritin concentrations than those receiving only zinc or placebo (P < 0.001). There also was an interaction between iron and zinc supplementation (P = 0.044). With iron supplementation, ferritin concentration increased by 31.8 µg/L (95% CI: 27.1, 36.6), but a decrease of 8.5 µg/L (95% CI: 0.10, 0.14) occurred with zinc supplementation.

Similarly, serum zinc concentrations (P < 0.001) differed among groups at the end of the study. Infants receiving zinc had the highest serum zinc concentration (P < 0.001), but the zinc concentrations of the 2 groups that received iron did not differ, and both were higher than that of the placebo group. The interaction between iron and zinc supplementation on serum zinc concentration was significant (P < 0.001). The overall effect of iron supplementation on end point serum zinc concentrations was a decrease of 0.8 µmol/L, compared with an increase of 3.0 µmol/L from zinc supplementation (P < 0.001).

    Prevalence of anemia, ID, IDA, and zinc deficiency. At baseline, the overall prevalence of anemia was 18% using the age-specific cutoff of Hb <105 g/L and 28.8% using the WHO cutoff of Hb <110 g/L; groups did not differ for either cutoff (P > 0.1) (Table 3). Reduced anemia prevalence was greater in infants receiving only iron than in infants receiving iron and zinc but, in both groups, the reduction was more than the placebo group (P < 0.05). Infants receiving only zinc had a greater prevalence of anemia than the placebo group when both cutoffs, 105/100 g/L and 110 g/L, were used.


View this table:
[in this window]
[in a new window]
  		TABLE 3 Prevalence of anemia, ID, IDA, and zinc deficiency in infants at baseline and after 6-mo supplementation with iron, zinc, or both12

 
Despite the high prevalence of anemia in most groups, at baseline, very few infants had ID and IDA when ferritin <12 µg/L was used; but the prevalence became more substantial when a higher cutoff for ferritin (<20 µg/L) was used. Using age-specific cutoffs for Hb, there was no IDA (Hb <105 + ferritin <12 µg/L) in all groups at baseline. However, at postintervention, the prevalence of IDA (Hb <100 + ferritin <12 µg/L) increased in the placebo group and was especially increased in the group with zinc only. Using a higher ferritin cutoff with age-specific Hb cutoffs, IDA at baseline was corrected in the iron and the iron plus zinc groups. On the contrary, the prevalence of IDA increased markedly in the other 2 (no iron) groups, especially among infants receiving only zinc (15.4 and 27.6%, respectively). Overall, the prevalence of ID and IDA decreased among infants receiving iron alone or iron combined with zinc more than among infants in the placebo or zinc group. Similar patterns in the prevalence of IDA from baseline among groups were observed using the WHO cutoff for Hb (>110 g/L for infants of all ages).

The reduction in the prevalence of low serum zinc concentrations was substantial and clearest in the infants supplemented with zinc only (<2% had low serum zinc based on both cutoffs). A decrease in prevalence of low serum zinc also occurred in infants receiving iron only, defined either as <10.7 or <9.9 µmol/L, whereas the prevalence in the iron plus zinc group was almost the same as in the iron group. The prevalence of low serum zinc was higher in the placebo group at the end of supplementation than in all other groups, regardless of the cutoffs used.

    Growth. Infants gained 1.59 ± 0.49 kg and increased 8.5 ± 1.4 cm in length. Supplementation did not affect the linear growth of infants; neither LAZ nor length differed among the groups at the end of supplementation. Even when only infants with LAZ below –1.5 at recruitment (n = 67) were considered, there were no significant effects of supplementation.

When data were analyzed by ANCOVA, controlled for gender and birth weight, iron supplementation significantly improved ponderal growth, with an estimated effect size of 80 g over the 6-mo supplementation period (P = 0.034). Similarly, the WLZ were improved by iron supplementation (P = 0.003). Zinc supplementation did not improve any growth indicators. Zinc and iron tended to interact to affect the LAZ (P = 0.103) but not the other anthropometric indicators (Table 4).


View this table:
[in this window]
[in a new window]
  		TABLE 4 Growth of the infants after 6-mo supplementation with iron, zinc, or both1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
Despite global concerns about micronutrient deficiencies and their health and functional consequences among young children, data in Thailand are scarce due to limitations in blood examination. Iron deficiency anemia is known to be prevalent in developing countries, but data on zinc deficiency in young children are limited. To our knowledge, this study is the first to show that zinc deficiency is a problem among infants. Using a conservative cutoff of 9.9 µmol/L (35), more than half of the infants in the placebo group were zinc deficient.

ID and IDA were surprisingly low, given the high prevalence of anemia (Hb <110 g/L at >20%). In this region, hemoglobinopathies, especially heterozygous E, were reported to be as high as 35–40% among pregnant women and school-aged children (36,37). This could partially explain our finding. Serum ferritin concentrations did not differ among normal Hb-type children or among those with heterozygotes E (HbAE) but were significantly higher among children with homozygotes E (37). Because the predominant form of abnormal Hb in this region is HbAE (~85–90%), the relatively high ferritin found among infants in this study should not be attributed to this condition. In addition, according to the illness-symptoms records kept by mothers and village health volunteers on their compliance calendar, infant morbidity was low. The use of a more definitive indicator to rule out or confirm inflammation, such as C-reactive protein, would provide a clearer explanation of the situation. The low morbidity and the reasonably good hygienic condition of the community, however, suggested that infection might not be a problem. Finally, vitamin A is known to be a significant determinant of Hb, especially among school-aged children in NE Thailand (37). Although Vitamin A supplementation was given at baseline, the dose might not have been adequate to maintain serum retinol level during the entire 6-mo period of this study. Hence, vitamin A deficiency could underlie the anemia observed in infants at the end point of supplementation.

Regardless of the ferritin cutoffs (12 or 20 µg/L) used, an improvement in the prevalence of ID and IDA after iron supplementation was clearly observed, compared with the placebo group, which suggests the benefit of iron supplementation in reducing anemia in late infancy. Infants receiving the placebo or zinc had a decrease in hemoglobin concentrations of >10g/L over the 6-mo supplementation period, whereas infants receiving iron alone or iron combined with zinc had no decrease, or only a small decrease, in hemoglobin concentrations. Hemoglobin concentrations substantially change during infancy, and the current cutoffs for anemia have been recently questioned (34). The prevalence of anemia remains high without iron supplementation. The present study shows, however, that infants can sustain hemoglobin concentrations when they are provided with sufficient iron. Moreover, the marked decline in ferritin and zinc concentrations in the placebo group between recruitment and end of the study clearly shows that iron or zinc status can be compromised in infants who do not receive iron or zinc during the second half of infancy.

Furthermore, although zinc supplementation was efficient in improving zinc status, the addition of iron substantially reduced this effect. On the contrary in our study, we found a beneficial effect of iron supplementation on zinc status, with serum zinc concentrations significantly higher in the infants receiving iron than infants receiving a placebo. Conflicting findings on the beneficial effect of iron supplementation on zinc status have been reported (38,39). These opposite findings may be related to the extent of the deficiency. Similar findings were reported where the level of deficiency was nearly the same as in the present study (38) but not where the deficiency was more severe (39). Both of these studies had the same study protocol. The underlying mechanisms by which iron supplementation might improve zinc status are unclear, however.

When zinc was given in combination with iron, hemoglobin concentrations were lower than when only iron was supplemented. The effect of iron supplementation in improving ferritin was also reduced when zinc was given in combination with iron, which is consistent with findings reported earlier from Indonesia (38,39) that suggest zinc supplementation might interfere with the transport of iron into the intestinal cells. However, Kordas and Stoltzfus (40) examined studies using Caco-2 cells and concluded that zinc does not depend on intestinal divalent metal transporter, and hence does not compete with iron through this mechanism.

The finding that infants receiving iron had higher serum ferritin than those receiving placebo suggests the need for additional iron from iron-rich sources during the second half of infancy. The substantial increase in the prevalence of anemia and iron deficiency anemia in the infants receiving only zinc, compared with the placebo group, is a concern. This was also consistent with a study conducted in Indonesia by Dijkhuizen et al. (38). From a public health point of view, this means that providing zinc without iron might cause a significant increase in iron deficiency with possible detrimental effects on psychomotor development. The apparent strong negative effect of zinc on hemoglobin concentrations has not been reported in children of another age range. Two studies in Indonesian infants also demonstrated an increase in the prevalence of iron deficiency anemia in infants receiving only zinc compared with iron-supplemented infants. In contrast, zinc supplementation in older Mexican children did not result in an increase in the prevalence of iron deficiency (41).

Despite the low serum zinc concentrations observed in this study, no association of zinc deficiency and stunting was found (data not shown), and zinc supplementation did not improve linear or ponderal growth. The beneficial effect of iron on ponderal growth shows that, although only 6% of the infants in the placebo group had iron deficiency anemia according to standard cutoffs, iron was beneficial for these infants.

It is important to note that other micronutrients and possibly macronutrient deficiencies may exist (38). Although the infants appeared to have adequate growth at baseline (i.e., ≤4–6 mo of age), the rapid decline of anthropometric status at the end point is a concern. Whereas the prevalence of stunting increased from 3 to 11%, the prevalence of WAZ below –2 was as high as 20% compared with only 0.2% at baseline. The lowest prevalence of stunting and underweight was observed in the iron group at the end of the intervention period (9 vs. 11–12% for LAZ and 15.7 vs. 18–23% for WAZ in other groups) (data not shown). This pattern clearly indicates that supplementation with only 2 micronutrients (as used in this study) does not prevent a faltering in growth. This was also noted in another recent study (42).

In conclusion, anemia and iron and zinc deficiencies are a problem among apparently healthy infants in NE Thailand. Without iron and/or zinc supplementation, anemia, iron, and zinc deficiency can be aggravated, as found in the placebo group. Consequently, such deficits may affect crucial developmental functions. The low prevalence of ID and IDA warrants additional study to identify causes of anemia among young infants. The roles of hemoglobinopathy and possible confounding effects of mild infection need to be verified before a definitive conclusion can be made for a situation in which mild infection and concurrent marginal micronutrient deficiencies may exist, such as in the present study population. In this study, iron supplementation increased ferritin, reduced iron deficiency, iron deficiency anemia, and overall anemia, improved serum zinc, and benefited ponderal growth, whereas zinc supplementation improved zinc status. Despite the interaction between iron and zinc, overall, the benefit from providing both micronutrients may outweigh the risk of functional consequences associated with these deficiencies.


   ACKNOWLEDGMENTS
 
We thank Dr. Frank Wieringa and Dr. Marjoleine Dijkhuizen for advice on statistical analysis and structure of the article.


   FOOTNOTES
 
1 Supported by UNICEF and the Thrasher Research Fund. Back

2 Abbreviations used: WAZ, weight-for-age Z-score; LAZ, length-for-age Z-score; WLZ, weight-for-length Z-score; Hb, hemoglobin, ID, iron deficiency; IDA, iron deficiency anemia; RE, retinol equivalent. Back

Manuscript received 23 December 2005. Initial review completed 7 February 2006. Revision accepted 1 June 2006.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

1. Tomkins A. Malnutrition, morbidity and mortality in children and their mothers. Proc Nutr Soc. 2000;59:135–46.[Medline]

2. Oski FA, Honig AS, Helu B, Howanitz P. Effect of iron therapy on behavior performance in nonanemic, iron- deficient infants. Pediatrics. 1983;71:877–80.[Abstract/Free Full Text]

3. Walter T, De Andraca I, Chadud P, Perales CG. Iron deficiency anemia: adverse effects on infant psychomotor development. Pediatrics. 1989;84:7–17.[Abstract/Free Full Text]

4. Lozoff B, Brittenham G, Wolf AW, McClish DK, Kuhnert PM, Jimenez E, Jimenez R, Mora LA, Gomez I, Krauskoph D. Iron deficiency anemia and iron therapy effects on infant developmental test performance. Pediatrics. 1987;79:981–95.[Abstract/Free Full Text]

5. Idjradinata P, Pollitt E. Reversal of developmental delays in iron deficient anemic infants treated with iron. Lancet. 1993;341:1–4.[Medline]

6. Walravens PA, Hambidge KM. Growth of infants fed a zinc supplemented formula. Am J Clin Nutr. 1976;29:1114–21.[Abstract/Free Full Text]

7. Schlesinger L, Arevalo M, Arredondo S, Diaz M, Lonnerdal B, Stekel A. Effect of a zinc-fortified formula on immunocompetence and growth of malnourished infants. Am J Clin Nutr. 1992;56:491–8.[Abstract/Free Full Text]

8. Chen XC, Yin TA, He JS, Ma QY, Han ZM, Li LX. Low levels of zinc in hair and blood, pica, anorexia and poor growth in Chinese preschool children. Am J Clin Nutr. 1985;42:694–700.[Abstract/Free Full Text]

9. Gibson RS, Smit Vanderkooy PD, MacDonald AC, Goldman A, Ryan BA, Berry M. A growth limiting, mild zinc deficiency syndrome in some southern Ontario boys with low height percentiles. Am J Clin Nutr. 1989;49:1266–73.[Abstract/Free Full Text]

10. Brown KH, Peerson JM, Rivera J, Allen LH. Effect of supplemental zinc on the growth and serum zinc concentrations of prepubertal children: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2002;75:1062–71.[Abstract/Free Full Text]

11. Umeta M, West CE, Haider J, Deurenberg P. Hautvast, JGAJ. Zinc supplementation and stunted infants in Ethiopia,: a randomized controlled trial. Lancet. 2000;355:2021–6.[Medline]

12. Bentley ME, Caulfield LE, Ram M, Santizo MC, Hurtado E, Rivera JA, Ruel MT, Brown KH. Zinc supplementation affects the activity patterns of rural Guatemalan infants. J Nutr. 1997;127:1333–8.[Abstract/Free Full Text]

13. Sazawal S, Bentley M, Black RE, Dhingra P, George S, Bhan MK. Effect of zinc supplementation on observed activity in low socioeconomic Indian preschool children. Pediatrics. 1996;98:1132–7.[Abstract/Free Full Text]

14. Black RE. Therapeutic and preventive effects of zinc on serious childhood infectious diseases in developing countries. Am J Clin Nutr. 1998;68:476s–9s.[Medline]

15. Bhutta ZA, Bird SM, Black RE, Brown KH, Meeks Gardner J, Hidayat A, Khatun F, Martorell R, Ninh NX, et al. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. Am J Clin Nutr. 2000;72:1516–22.[Abstract/Free Full Text]

16. Walker CF, Black RE. Zinc and the risk for infectious disease. Annu Rev Nutr. 2004;24:255–75.[Medline]

17. Roy SK, Tomkins AM, Haider R, Behren RH, Akramuzzaman SM, Mahalanabis D, Fuchs GJ. Impact of zinc supplementation on subsequent growth and morbidity in Bangladeshi children with acute diarrhoea. Eur J Clin Nutr. 1999;53:529–34.[Medline]

18. Walker CF, Kordas K, Stoltzfus RJ, Black RE. Interactive effects of iron and zinc on biochemical and functional outcomes in supplementation trials. Am J Clin Nutr. 2005;82:5–12.[Abstract/Free Full Text]

19. Black MM, Baqui AH, Zaman K, Persson AK, Arifeen SE, Le K, Mc Nary SW, Parveen M, Hamadani JA, Black RE. Iron and zinc supplementation promote motor development and exploratory behavior among Bangladeshi infants. Am J Clin Nutr. 2004;80:903–10.[Abstract/Free Full Text]

20. Dewey KG, Brown KH. Update on technical issues concerning complementary feeding of young children in developing countries and implications for intervention programs. Food Nutr Bull. 2003;24:5–28.[Medline]

21. Tontisirin K, Winichagoon P, Chavasit V, Yamborisut U. Supplementary feeding. In: Winichagoon et al., editors. Integrating food and nutrition into development. Thailand's experiences and future visions. Mahidol University, Thailand: Institute of Nutriton; 1992. p. 133–45.

22. Chusilp K, Somnasang P, Kridpon W, Wongkham S, Sribonlue P, Mahaverawat U, Yongvanit P, Sawakontha S, Waterlow J. Observation on the development of stunting in children of the Khon Kaen region of Thailand. Eur J Clin Nutr. 1992;46:475–87.[Medline]

23. Division of Nutrition, Department of Health, Ministry of Public Health. The 4th National Nutrition Survey. 1995.

24. Udomkesmalee E, Dhanamitta S, Yhoung-aree J, Rojroongwasinkul N, Smith JC. Biochemical evidence suggestive of suboptimal zinc and vitamin A status in school children in Northeast Thailand. Am J Clin Nutr. 1990;52:564–7.[Abstract/Free Full Text]

25. Winichagoon P. Prevention and control of anemia: Thailand experiences. J Nutr. 2002;132:862s–6s.[Medline]

26. Gibson RS. Principles of nutritional assessment. New York: Oxford University Press. 1990. p.163–86.

27. Ulijaszek SJ, Kerr DA. Anthropometric measurement error and the assessment of nutritional status. Br J Nutr. 1999;82:165–77.[Medline]

28. Hamill PV, Drizd TA, Johnson CL, Reed RB, Roche AF, Moore WM. Physical growth: national center for health statistics percentiles. Am J Clin Nutr. 1979;32:607–29.[Abstract/Free Full Text]

29. Cortius HCM, Roth M. Clinical biochemistry principle and methods. New York: Walter de Gruyter Berlin.1974. p.1306–12.

30. Alfrey CP. Serum ferritin assay. CRC Crit Rev Lab Sci. 1978;9:179–203.

31. Jacobs A, Miller F, Worwood M, Beamish MR, Wardrop CA. Ferritin in the serum of normal subjects and patients with iron deficiency and iron overload. BMJ. 1972;4:206–8.[Medline]

32. D'Haese PC, Lamberts LV, Vanheule AO, De Broe ME. Direct determination of zinc in serum by Zeeman atomic absorption spectrometry with a graphite furnace. Clin Chem. 1992;38:2439–43.[Abstract/Free Full Text]

33. World Health Organization (WHO). Iron deficiency anaemia assessment, prevention, and control. A guide for programme managers. Geneva: World Health Organization; 2001.

34. Domellöf M, Dewey KG, Lönnerdal B, Cohen RJ, Hernell O. The diagnostic criteria for iron deficiency in infants should be reevaluated. J Nutr. 2002;132:3680–6.[Abstract/Free Full Text]

35. International Zinc Nutrition Consultative Group (IZiNCG). Technical document #1. Assessment of the risk of zinc deficiency in populations and options for its control. Food Nutr Bull. 2004;25:S130–62.

36. Charoenlarp P, Dhanamitta S, Keawvichit R, Silprasert A, Suwanaradd C, Na-Nakorn S, Prawatmuang P, Vatanavicharn S, Nutcharas U, Pootrakul PA. WHO collaborative study on iron supplementation in Burma and in Thailand. Am J Clin Nutr. 1988;47:280–97.[Abstract/Free Full Text]

37. Thurlow RA, Winichagoon P, Green T, Wasantwisut E, Pongcharoen T, Baily KB, Gibson RS. Only a small proportion of anemia in northeast Thai schoolchildren is associated with iron deficiency. Am J Clin Nutr. 2005;82:380–7.[Abstract/Free Full Text]

38. Dijkhuizen MA, Wieringa FT, West CE, Martuti S, Muhilal. Effects of iron and zinc supplementation in Indonesian infants on micronutrient status and growth. J Nutr. 2001;131:2860–5.[Abstract/Free Full Text]

39. Lind T, Lönnerdal B, Stenlund H, Ismail D, Seswandhana R, Ekström EC, Persson LÅ. A community-based randomized controlled trial of iron and zinc supplementation in Indonesian infants: interactions between iron and zinc. Am J Clin Nutr. 2003;77:883–90.[Abstract/Free Full Text]

40. Kordas K, Stoltzfus RJ. New evidence of iron and zinc interplay at the enterocyte and neural tissues. J Nutr. 2004;134:1295–8.[Abstract/Free Full Text]

41. Rosado JL, Lopez P, Munoz E, Martinez H, Allen LH. Zinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers. Am J Clin Nutr. 1997;65:13–9.[Abstract/Free Full Text]

42. Ramakrishnan U, Aburto N, McCabe G, Martorell R. Multimicronutrient interventions but not vitamin A or iron interventions alone improve child growth: results of 3 meta-analyses. J Nutr. 2004;134:2592–602.[Abstract/Free Full Text]




This article has been cited by other articles:


Home page
 J. Nutr.Home page
F. T. Wieringa, J. Berger, M. A. Dijkhuizen, A. Hidayat, N. X. Ninh, B. Utomo, E. Wasantwisut, P. Winichagoon, and for the SEAMTIZI (South-East Asia Multi-country Tr
Combined Iron and Zinc Supplementation in Infants Improved Iron and Zinc Status, but Interactions Reduced Efficacy in a Multicountry Trial in Southeast Asia
J. Nutr., February 1, 2007; 137(2): 466 - 471.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wasantwisut, E.
Right arrow Articles by Russameesopaphorn, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wasantwisut, E.
Right arrow Articles by Russameesopaphorn, W.

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]