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Community and International Nutrition

Daily Iron Alone but Not in Combination with Multimicronutrients Increases Plasma Ferritin Concentrations in Indonesian Infants with Inflammation^1,2

Sandhya Sankaranarayanan, Juliawati Untoro^*, Juergen Erhardt, Rainer Gross^** and Francisco J. Rosales³

Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA; ^* World Bank Office, Jakarta, Indonesia; University of Hohenheim, Stuttgart, Germany; and ^** UNICEF, New York, NY

³To whom correspondence should be addressed. E-mail: fxr5{at}psu.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Iron deficiency is a public health problem in infancy. We assessed the efficacy of iron supplements in infants with inflammation on iron status and subsequent inflammation. This was a prospective, nested, case-control study of 6- to 12-mo-old infants participating in the International Research on Infant Supplementation study, Indonesia. Cases (n = 46) were selected on the basis of their inflammation status at baseline, C-reactive protein (>5 mg/L) or -1 acid glycoprotein (>1 g/L); there were 44 controls without inflammation. Infants received 10 mg/d of elemental iron alone or in combination with multimicronutrients, or placebo. Blood samples were collected at baseline and at 6 mo for determinations of plasma ferritin, zinc, copper, retinol, ß-carotene, -tocopherol, and inflammation status. Data on breast-feeding and acute respiratory infections (ARI) were collected daily. At baseline, 33% of infants had iron deficiency, and those with inflammation had lower retinol, ß-carotene, higher concentrations of copper and higher rates of ARI compared with controls. After 6 mo, compared with infants given placebo, ferritin concentration increased significantly in infants administered iron alone independently of inflammation status at baseline or at the end of the study. In those given multimicronutrients with iron, ferritin increased significantly in infants who did not have inflammation at baseline or at the end of the study compared with those given placebo. Consequently, iron alone resolved iron deficiency, whereas multimicronutrients reduced the deterioration of iron stores compared with placebo (², P < 0.05), without enhancing inflammation. Iron alone is recommended in populations in which iron deficiency is a public health problem despite the presence of inflammation in infants who are still breast-feeding.

KEY WORDS: • acute-phase proteins • breast-feeding • ferritin • copper • retinol

Iron deficiency is a major public health problem and one of the main causes of anemia in developing countries including Indonesia. Infants and young children in developing countries are particularly vulnerable to become iron deficient; the high iron requirements during their rapid phases of growth (1) cannot be met by diet alone because it is lacking in fortified foods and includes a low intake of foods from animal sources (2,3). Thus, the prevalence of iron deficiency affects a larger proportion of infants and children (30–70%) in developing countries compared with that in industrialized nations of Europe and North America (4).

Although iron supplements are advocated for infants in anemia-prevalent areas, their effects on morbidity or the effect of morbidity on the efficacy of iron supplements has not been completely elucidated. For example, some studies showed an increase in morbidity with iron supplements. In New Zealand, Barry and Reeve (5) reported serious Escherichia coli sepsis in 2% of the Polynesian infants who received 250 mg iron dextran in 5 daily doses. Earlier studies, in which parenteral iron was used, also reported acute exacerbations of preexisting and latent infections (6,7). On the other hand, Heresi et al. (8) using iron fortified powdered cow’s milk (15 mg/100 g) in infants from birth to 15 mo of age found no effect of iron on the incidence of acute respiratory infections (ARI)⁴ or diarrhea. Dijkhuizen et al. (9) supplemented Indonesian infants for 6 mo with iron (10 mg/d) and found a significant reduction in iron deficiency, but no effect on morbidity. In this same population, Wieringa et al. (10) noted that plasma ferritin increased during infection because of the acute-phase response; consequently, the prevalence of iron deficiency was underestimated and possibly the association between morbidity and iron supplements.

Inflammation and its acute-phase response are components of the innate immune system whose activity is to contain the replication of the infecting agent (11). The inflammatory response to infection is characterized by changes in acute-phase proteins (APPs) and the systemic reduction of micronutrients (12). Although previous studies used clinical evaluations to examine the hypothesis that increased infectious morbidity is associated with iron supplementation, none have used changes in APPs to assess this association. APPs provide an advantage because their concentrations in plasma change in response to infection even when there are no apparent clinical signs (i.e., subclinical response to infection); analytically, they are accurate surrogates of infections (13). In the present study, we examined whether inflammation status at baseline enhances the association between iron supplements and inflammation at the end of the study.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
This was a prospective study of 46 cases and 44 control subjects nested within the Indonesian International Research on Infant Supplementation (IRIS) study. The IRIS was a study conducted in 4 geographically distinct populations in countries such as South Africa, Peru, Vietnam, and Indonesia (14,15). In these countries, infants aged 6–12 mo who were permanent residents of the area, in which the prevalence of anemia (Hb < 110 g/L) and vitamin A deficiency (serum retinol < 0.7 µmol/L) were 30%, were selected to participate in the study. Exclusion criteria included premature birth (<37 wk of gestation), low birth weight (<2500 g), severe wasting (<3 Z-scores), hemoglobin of <80 g/L, fever (>39°C) on the day of blood sampling, or failure to obtain informed consent form. Infants were randomly allocated to 4 different groups to receive iron alone daily, iron in combination with multimicronutrients daily, placebo, or iron in combination with multimicronutrients weekly as foodlets with a piña colada taste (16). The placebo foodlet contained no micronutrients, whereas the composition of iron alone foodlet contained 10 mg of elemental iron and that of daily multimicronutrient foodlet included 1 Recommended Daily Allowance (RDA) of vitamins A, D, E, K, C, thiamin, riboflavin, B-6, B-12, niacin, folate, iron, zinc, copper, and iodine for children aged 1–2 y, except that of zinc which was equivalent of 1 RDA for 6- to 12-mo-old infants (16). Randomization was done with a computer program and was masked from the subjects’ families and the investigators by coding. Foodlets were given as chewable tablets; the final blend was made by Roche Laboratories with quality control provided by a private laboratory in Peru (Hersil S.A., Peru) (16). A trained field worker/assistant gave the foodlet directly to the infant on 6 of the days and the mother gave the foodlet on d 7. Thus, compliance was ascertained directly for 6 d and was verified for d 7 on the next day’s visit

The study was conducted in Indonesia in the district of Magelang, its 2 subdistricts of Salam and Ngluwar, in the province of Central Java (16). The guidelines of the Council of International Organizations of Medical Sciences (1990) were followed for ethical considerations. The committee of The Medical Research Ethics of the Faculty of Medicine, University of Indonesia approved the protocol of the study. Mothers were informed about the purpose of the study and written informed consent forms were obtained from them.

The cohort of infants from Indonesia was selected in part because the ongoing study was available, and because there is little information from nonmalarious populations on iron supplementation during inflammation (17). Among those enrolled in Indonesia IRIS study (n = 260), we selected infants with inflammation as cases, on the basis of having high plasma levels of C-reactive protein (CRP > 5 mg/L), or -1 acid glycoprotein (AGP > 1 g/L) at baseline (18,19) and infants without inflammation at baseline as controls. Nested case-controls were matched by allocation to supplementation strategy, daily schedule of supplements, and length of exposure to iron alone, iron in combination with multimicronutrient supplements, or placebo. These 90 infants were randomly assigned to receive iron alone, iron in combination with multimicronutrients daily, or placebo (i.e., we did not include infants receiving weekly multimicronutrients in the present analysis). Cases and controls were followed for 6 mo, and the development of subsequent inflammation was assessed in cases and controls at the end of the study.

    Assessment of ARI and breast-feeding. The incidence of ARI was determined on the basis of daily collection of reported signs and symptoms of upper respiratory tract infections. Infants were monitored through daily visits in their homes for one or more of the following clinical signs or symptoms: head cold, cough, ear infection, and sore throat. Afterward, the number of days with the above symptoms was tallied per week for each infant; the ARI incidence rate per infant with and without inflammation was calculated, and is expressed as days per 100-infant-wk (20). The total area under the curve (AUC) for ARI incidence over the 24 wk of observation was calculated by the trapezoidal rule, from which the weekly ARI incidence was determined and compared between infants with and without inflammation.

The frequency of breast-feeding was determined using a daily questionnaire, which had the following options: never breast-fed (BF), 1–3 times BF, 4–6 times BF, > 6 times BF, and stopped BF. The questionnaire was given daily throughout the study, and the data were compiled weekly. Because almost every infant breast-fed at least once a day, infants were classified into those who breast-fed <6 times/d, and those who breast-fed 6 times/d.

    Anthropometric measurements. Weight and length of infants were measured on a monthly basis. Weights of the infants were recorded nearest 0.1 kg while the children were minimally clothed using electronic weighing scale (SECA). The length of the infants was measured and recorded to the nearest 0.1 cm with the children lying down using the WHO recommended length board for infants (Ahrtag). Length-for-age (LAZ) and weight-for-length (WLZ) Z-scores were calculated according to the National Center for Health Statistics with the software ANTHRO [software version 1.01; Centers for Disease Control and Prevention (CDC), Atlanta, and WHO, Geneva].

    Blood collection. Blood samples were obtained from a vein at the beginning and end of the study in heparinized tubes, and blood samples were immediately placed in a cooled Styrofoam box (4–8°C) and centrifuged within 6 h at 5000 x g for 5 min to obtain plasma. Plasma samples were stored at –70°C and sent to Germany (Micronutrient Laboratory, The Institute of Biological Chemistry and Nutrition, University of Hohenheim) for determination of micronutrient concentrations. Lyophilized aliquots were later sent to The Pennsylvania State University, where they were reconstituted with sterile water for analysis of immunological variables, acute-phase proteins.

    Biochemical analysis. Plasma retinol, ß-carotene, and vitamin E were analyzed according to the method previously described by Erhardt et al. (21). The plasma proteins were denatured by mixing 30 µL of plasma with 150 µL of extraction solvent (ethanol:n-butanol, 1:1, v/v containing 5 mg/L BHT and 4 µmol/L of Tocol as an internal standard). After this mixture was centrifuged for 5 min at 12,000 x g, 30 µL of the supernatant was analyzed using reverse-phase HPLC. Plasma ferritin was measured by standard sandwich ELISA procedure, using antibodies supplied by DAKO as previously reported (16). Iron deficiency was defined on the basis of the general recommendation of a ferritin cutoff value of <12 µg/L (4). Plasma zinc and copper concentrations were measured by flame atomic absorption spectrophotometry using a Perkin-Elmer 1100 as described earlier (16). Hypozincemia was defined as a plasma zinc concentration < 10.7 µmol/L (22).

    Determination of inflammation status. Plasma CRP and AGP were selected as biomarkers of acute-phase response because they differ from each other in onset and half-life during inflammation (18,19). CRP was measured by a standard sandwich ELISA procedure with antibodies from Dako (16). A cutoff value of 5 mg/L was used to identify those with inflammation as suggested for assays with a low limit of detection (18). AGP was measured by radial immunodiffusion using a modification of Mancini’s method (23) as previously described (12). Antiserum and calibrators were from Dako.

    Statistical analysis. Data were analyzed using SPSS version 11.5 software. Exploratory analyses were conducted to determine possible relationships among the variables; the Kolmogorov Smirnov test was done to assess the normality of the main outcomes. Levene statistics were used to determine the homogeneity of their variances, and the spread vs. level with the Levene test was used to determine the power transformation for achieving equal variances (24). Nonnormally distributed variables such as ferritin and ß-carotene were transformed using the log₁₀ function. To assess differences in plasma micronutrient concentrations at baseline among the different groups (i.e., supplementation strategy and inflammation status), a 2-factor ANOVA was used with fixed effects for inflammation status and allocation into supplementation strategy and Tukey’s correction for multiple comparisons. For categorical variables, the ² test was used. A categorical variable (SupInfa) was created to recap the allocation of infants to the different groups on the bases of supplementation strategy and inflammation status at baseline.

To assess the effect of supplementation strategy, i.e., SupInfa, inflammation status at the end of the study, and their possible interaction, a 2-factor analysis of covariance (ANCOVA) with fixed effects for SupInfa and inflammation at the end of the study was utilized. The covariate was micronutrient concentration at baseline. If the interaction between SupInfa and inflammation at the end of the study was not significant by the 2-factor ANCOVA, the estimated marginal means were used to compare groups by each level of each of the main factors with least significant difference (LSD) adjustment for multiple comparisons.

To assess the effect of supplementation strategy on iron deficiency or on inflammation status, the 2-sample test for binomial proportions for matched-pair data (McNemar’s test) was used (24). In a 2 x 2 table in which columns indicated micronutrient or inflammation status at the end of the supplementation trial, and rows indicated micronutrient or inflammation status at baseline, discordant pairs representing improvement in micronutrient status or no inflammation were compared to discordant pairs representing deterioration in micronutrients or inflammation by supplementation strategy. To assess the effect of supplementation strategy on the incidence of ARI while controlling for inflammation status, a categorical variable was created to summarize the inflammation status of infants at baseline and at the end of the study, and a two-way ANOVA was used to assess the main effects and interaction of supplementation strategy and the categorical variable. Significance was determined at P 0.05, and the values are given as mean ± SD, unless otherwise indicated.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Biomarker evidence indicative of inflammation at baseline was present in 46 infants. The demographic characteristics of these infants at baseline did not differ by inflammation status (Table 1), except for age, i.e., infants with inflammation were 1 mo older than infants without inflammation. In infants with inflammation, the plasma concentrations of CRP and AGP were significantly higher than in controls.

Six months after daily supplementation with iron alone, iron in combination with multimicronutrients, or placebo, the plasma concentrations of micronutrients differed among the groups (Table 3). Infants receiving iron alone had significantly higher plasma ferritin concentrations than infants receiving placebo after controlling for ferritin concentrations at baseline. The ANCOVA indicated that ferritin concentrations increased in infants receiving iron alone independently of inflammation status at baseline (i.e., no differences among the groups receiving iron alone), or at the end of the study (interaction term, P > 0.5). However, inflammation at the end of the study resulted in higher ferritin concentrations in infants receiving placebo, iron alone or with multimicronutrients compared with those without inflammation (i.e., differences between marginal means, P < 0.01). Inflammation increased plasma ferritin by 1.5 µg/L (i.e., contrast between inflammation vs. no inflammation, P < 0.01). In infants receiving iron with multimicronutrient supplements, ferritin concentrations were significantly higher in those who did not have inflammation at baseline or at the end of the study compared with those receiving placebo (Table 3). Plasma retinol concentrations were not affected by supplementation strategy (ANCOVA, P = 0.84), but were reduced by inflammation at the end of the study (ANCOVA, P = 0.01). Inflammation at the end of the study reduced plasma retinol by 0.12 µmol/L (i.e., contrast between inflammation vs. no inflammation, P = 0.01). Plasma concentrations of ß-carotene and -tocopherol were not affected by supplementation strategy or inflammation at the end of the study after adjusting for baseline concentrations. Plasma zinc concentrations were affected by inflammation at the end of the study; the ANCOVA indicated that inflammation reduced zinc concentrations by 0.82 µmol/L (i.e., contrast between inflammation vs. no inflammation, P = 0.02). Although iron in combination with multimicronutrient supplementation had a positive effect on zinc concentrations compared with iron alone, it was not significant (i.e., contrasting multimicronutrients vs. iron alone, P = 0.06). Plasma concentrations of copper increased by 4.7 µmol/L with inflammation (ANCOVA, P < 0.001).

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

In the present study, a change in inflammation status was the main morbidity outcome measured in relation to the effect of iron supplements. The inflammatory response experienced by these infants at baseline was significantly associated with a reduction in plasma retinol of 34% (Table 2) (i.e., relative difference in plasma retinol between those with and without inflammation). Recently, Thurnham et al. (30) showed that mild or first-stage subclinical inflammation is associated with a reduction in plasma or serum retinol of 16–18%; however, as disease progresses, acute inflammation is associated with a reduction in retinol concentrations of 25–32%. The kinds of infections usually associated with this type of inflammatory response causing a reduction in retinol are malaria, ARI, or diarrheal diseases (31). Thus, the inflammatory response of infants in the present study was equal in magnitude to that associated with acute or chronic infections. Indeed, the inflammatory response of these infants was significantly associated with ARI. The AUC was 50% higher in infants with inflammation compared with that in infants without inflammation. Although signs and symptoms of diarrheal disease were collected in the present study, the incidence of diarrhea (i.e., number of days with liquid stools per week) was very low in this population, and the rates of diarrhea did not differ between the groups (data not shown). Thus, the results from the present analysis and their inference pertain primarily to ARI.

The population from which this subsample of infants was drawn had been identified as having probable need of micronutrient intervention as part of IRIS study protocol (IRIS I). In Purworejo, Indonesia, the prevalence of iron deficiency in 6-mo-old infants was reported at 15%, and only 5% of infants were stunted (29). Similarly, in rural areas of West Java, 20% of young infants (median age 6.6 mo) were iron deficient, 17% were hypozincemic, and only 7% were stunted, whereas none was wasted (9). In the present study, more infants were iron deficient (37%), hypozincemic (51.2%), stunted (9.1%), and wasted (6.8%). However, these infants were older at enrollment, median age 9.7 mo (quartiles, 7.9–10.6 mo), compared with those in previous studies. These results suggest that older infants in Indonesia have poorer nutritional status than younger infants. Because we did not collect information on the adequacy of dietary intakes, it is not possible to ascertain a cause of their undernutrition. Nonetheless, these results emphasize the need for complementary feeding along with single- or multi-micronutrient supplements for older infants.

In the present study, oral iron supplements alone or with multimicronutrients did not affect the inflammatory response to ARI. The association between inflammation and ARI incidence was proportional and significant, and although oral iron supplements significantly increased ferritin concentrations from baseline to the end of the study, iron alone did not increase the inflammatory response associated with ARI at the end of the study (Table 4). Dewey et al. (28) showed a mild interaction between initial high ferritin concentrations (i.e., cutoff value of 50 µg/L) and oral iron supplements on diarrheal morbidity. In the present study, <18% of infants at baseline had ferritin values 50 µg/L, whereas 75% of infants in Dewey’s study had ferritin concentration 50 µg/L. These results suggest that the relative severity of iron deficiency may determine whether oral iron supplements may enhance morbidity or its inflammatory response.

Alternatively, other explanations for a lack of effect of iron on morbidity might include an inflammatory response that lessened as the study ended, or the possibility that the sample size did not provide enough statistical power to reject the null hypothesis when it was false. By the end of the study, the proportion of children with inflammation did not differ from baseline by treatment group (Table 4), and the concentration of AGP (1009.0 ± 290.0 mg/L) at the end of the study did not differ from baseline concentrations (Table 1) in those with inflammation (paired t test, P > 0.05). In addition, the AUC for ARI incidence in infants with inflammation remained higher throughout the study period compared with that in infants without inflammation. These findings suggest that the inflammatory response to ARI did not change throughout the study. In this regard, it is important to note that this was a community-based study; thus, the rate of ARI reflected mainly upper respiratory tract infections and the type of inflammation associated with it. In the BOSTID community-based studies of children < 5 y old from Kenya, Nigeria, Papua New Guinea, the Philippines, Thailand, Colombia, Uruguay, and Guatemala, the rate of ARI ranged from 12.7 to 16.8 episodes/100 children-wk, whereas lower respiratory tract infection (pneumonia) ranged from 0.2 to 3.4 new episodes/100 children-wk (32). Children in these communities spent from 21.7 to 40.1% of the observed time with upper respiratory tract infections (32). In the present study, children with inflammation had respiratory symptoms 27% (4511/16,800 d/100-infants) of the observed period. Thus, the ARI that these children experienced was within the limits of ARI observed in other community-based studies. Moreover, a sample size of 15/group provided >90% statistical power in assessing an increase in AGP from a mean of 796.7 mg/L (i.e., baseline concentration among those without inflammation) to 1000.0 mg/L (i.e., cutoff value indicating inflammation) with a one-tail of 0.05. Thus, there was sufficient statistical power to prevent a type II error. Finally, the dose of iron provided to these infants was 10 mg/d, which is lower than the current RDA of 11 mg/d recommended by the Institute of Medicine for infants 7–12 mo old and young children. This dose, however, was not associated with increasing morbidity or mortality in the United States or in other studies conducted in Indonesia (9,29)

In summary, the present study showed that in a population in which iron deficiency is a public health problem, supplementation with oral iron is necessary irrespective of the presence of inflammation. Moreover, this study showed that although multimicronutrient supplements with iron did not completely resolve iron deficiency compared with iron alone, multimicronutrient supplements prevented the worsening of iron status compared with infants receiving placebo. Although infants receiving multimicronutrients had higher mean concentrations of retinol and zinc than infants receiving placebo, these changes were not significant after controlling for inflammation.

	FOOTNOTES

 
¹ Presented in part at Experimental Biology 02, April 2002, New Orleans, LA [Sankaranarayanan, S., Untoro, J., Rosales, F. J., Erhardt, J. & Gross, R. (2002) Iron supplementation improves iron status despite inflammation. FASEB J. 16: 710.7 (abs.)].

² Funded by UNICEF, New York, NY.

⁴ Abbreviations used: AGP, -1 acid glycoprotein; APPs, acute phase proteins; ARI, acute respiratory infection; AUC, area under the curve; BF, breast-feeding; CRP, C-reactive protein; IRIS, International Research on Infant Supplementation; LAZ, length-for-age Z-score; WLZ, weight-for-length Z-score.

Manuscript received 12 January 2004. Initial review completed 11 February 2004. Revision accepted 12 May 2004.

	LITERATURE CITED

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

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