Review ArticlesIron supplementation in early childhood: health benefits and risks1–3Lora L Iannotti, James M Tielsch, Maur...
1262                                                            IANNOTTI ET ALTABLE 1Dosage schedule for iron supplementat...
TABLE 2Development and iron supplementation1Study and                           Sample size by                            ...
1264TABLE 2 (Continued)Study and                          Sample size by                                       Eligibility...
TABLE 2 (Continued)Study and                           Sample size by                                  Eligibility and exc...
1266TABLE 3Growth and iron supplementation1Study and                                               Dosage and             ...
TABLE 3 (Continued)Study and                                                 Dosage and                 Eligibility and ex...
TABLE 4Morbidity and iron supplementation1                                                                                ...
TABLE 4 (Continued)Study and                                             Dosage and                    Eligibility and exc...
1270TABLE 4 (Continued)Study and                                           Dosage and                    Eligibility and e...
Iron supplementation in early childhood: health benefits and risks
Iron supplementation in early childhood: health benefits and risks
Iron supplementation in early childhood: health benefits and risks
Iron supplementation in early childhood: health benefits and risks
Iron supplementation in early childhood: health benefits and risks
Iron supplementation in early childhood: health benefits and risks
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Iron supplementation in early childhood: health benefits and risks

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Iron supplementation in early childhood: health benefits and risks

  1. 1. Review ArticlesIron supplementation in early childhood: health benefits and risks1–3Lora L Iannotti, James M Tielsch, Maureen M Black, and Robert E BlackABSTRACT harm is done by the iron supplementation, especially in thoseThe prevalence of iron deficiency among infants and young children children who receive no benefit. Although some studies suggestliving in developing countries is high. Because of its chemical prop- risks with iron supplementation, it is important to determineerties—namely, its oxidative potential—iron functions in several whether these risks are generally supported by available evi-biological systems that are crucial to human health. Iron, which is not dence and whether they can be mitigated with altered recom- Downloaded from www.ajcn.org at GlaxoSmithKline on July 28, 2011easily eliminated from the body, can also cause harm through oxi- mendations regarding iron supplementation. The focus of thisdative stress, interference with the absorption or metabolism of other review was to examine the evidence for the health benefits andnutrients, and suppression of critical enzymatic activities. We re- risks of preventive iron supplementation in children aged 5 y inviewed 26 randomized controlled trials of preventive, oral iron sup- developing countries.plementation in young children (aged 0 –59 mo) living in developing Iron is essential for all tissues in a young child’s developingcountries to ascertain the associated health benefits and risks. The body. Iron is present in the brain from very early in life, when itoutcomes investigated were anemia, development, growth, morbid- participates in the neural myelination processes. Other roles thatity, and mortality. Initial hemoglobin concentrations and iron status would affect growth and immune function have been postulatedwere considered as effect modifiers, although few studies included (3). Iron, which is essential to both the host and invading patho-such subgroup analyses. Among iron-deficient or anemic children, gens, must be carefully regulated to promote optimal conditionshemoglobin concentrations were improved with iron supplementa- that preserve the health of young children. Furthermore, iron cantion. Reductions in cognitive and motor development deficits were interfere with the absorption of other nutrients and, in excess, canobserved in iron-deficient or anemic children, particularly with generate free radicals that impair cellular functions and suppresslonger-duration, lower-dose regimens. With iron supplementation, enzymatic activity (4, 5).weight gains were adversely affected in iron-replete children; the Iron supplementation for children 5 y old is recommendedeffects on height were inconclusive. Most studies found no effect onmorbidity, although few had sample sizes or study designs that were on the basis of anemia prevalence (Table 1). Low-birth-weightadequate for drawing conclusions. In a malaria-endemic population infants are at high risk of iron deficiency, and the current recom-of Zanzibar, significant increases in serious adverse events were asso- mendation is that they receive supplementation from 2 mociated with iron supplementation, whereas, in Nepal, no effects on through 2 y of age. Anemia prevalence, determined by hemo-mortality in young children were found. More research is needed in globin status, is used as a practical indicator because of thepopulations affected by HIV and tuberculosis. Iron supplementation in relative difficulty in collecting additional markers of iron defi-preventive programs may need to be targeted through identification of ciency. The consumption of iron-poor complementary dietsiron-deficient children. Am J Clin Nutr 2006;84:1261–76. (lacking iron-fortified foods or heme iron) is also used to justify supplementation in infants and preschool-aged children. Com-KEY WORDS Iron, supplementation, children, development, plementary foods, even with continued breastfeeding, must con-growth, infection tribute nearly 100% of dietary iron for young children because breast milk contains little iron (6). Other prevention and control approaches for iron deficiency—such as food fortification,INTRODUCTION 1 From the Department of International Health, Bloomberg School of Iron deficiency has been considered an important risk factor Public Health, Johns Hopkins University, Baltimore, MD (LLI, JMT, andfor ill health (1) and is estimated to affect 2 billion people world- REB), and the Department of Pediatrics, University of Maryland School ofwide (2). Concerns have been raised about the effects of iron Medicine, Baltimore, MD (MMB). 2deficiency in children on their health and development, which Supported by the Global Research Activity Cooperative Agreement be- tween USAID and the Johns Hopkins Bloomberg School of Public Health.have led to recommendations for supplementation of all children 3 Address reprint requests to RE Black, Department of Internationalof certain ages in populations with a high prevalence of anemia Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe(2). This recommendation for a preventive iron intervention will Street, Room E8527, Baltimore, MD 21205. E-mail: rblack@jhsph.edu.reach both children in need of additional iron and children with- Received March 23, 2006.out that need. This nondiscrimination may be acceptable if no Accepted for publication July 18, 2006.Am J Clin Nutr 2006;84:1261–76. Printed in USA. © 2006 American Society for Nutrition 1261
  2. 2. 1262 IANNOTTI ET ALTABLE 1Dosage schedule for iron supplementation1Age group Indications for supplementation Dosage schedule2 Duration 1 1Low-birthweight infants Universal supplementation 2 mg · kg body wt ·d From age 2 mo to 23 mo (2–23 mo old) 1 1Children 6–23 mo old Diet does not include foods fortified with 2 mg · kg body wt ·d From age 6 mo to 23 mo iron; anemia prevalence Œ40%Children 24–59 mo old Anemia prevalence Œ40% 2 mg · kg body wt 1 ·d 1 3 mo (up to 30 mg) 1 Adapted from reference 2. 2 Recommended forms for children: liquid, powder, or crushable tablet. Recommended iron compounds: ferrous fumarate; ferrous gluconate; ferroussulfate (7H2O); ferrous sulfate, anhydrous; ferrous sulfate, exsiccated (1 H2O).dietary improvements, and treatment of hookworm and other rupture (hemolytic anemia), deficient or abnormal synthesis ofhelminth infections—were not considered in this review. hemoglobin (eg, thalassemia), or destruction of bone marrow The objective of this review was to evaluate the health benefits (aplastic anemia) (7). In developing countries, the prevalence ofand risks of iron supplementation as a strategy to prevent iron anemia among preschool-aged children is 42%, and the regionsdeficiency in children 0 – 4 y old. Evidence (primarily) from most affected regions are Southeast Asia, Central and East Af-randomized placebo-controlled trials (RCTs) provided the basis rica, and the Eastern Mediterranean (8). Hemoglobin concentra- Downloaded from www.ajcn.org at GlaxoSmithKline on July 28, 2011for this assessment because these designs allow causal inference tions are most often used for anemia screening. In children 6 –59that is not possible with cross-sectional or quasi-experimental mo old, anemia is defined as hemoglobin 110 g/L or hematocritdesigns. 6.83 mmol/L or 0.33 L/L (9). We conducted a literature review in PubMed (National Li- Evidence of the effect of iron supplementation on anemiabrary of Medicine, Bethesda, MD) to identify studies meeting outcomes is widely available. Studies usually incorporate ironseveral criteria. The review was limited to RCTs published after status indicators, such as serum ferritin or transferrin saturation.1980 and targeting young children 0 –59 mo of age who were One meta-analysis of 21 data sets from iron supplementationliving in developing countries. Oral iron supplementation, as RCTs in children ranging in age from 0 to 12 y found a significantprevention and not therapy, was the intervention examined in difference in the mean change in hemoglobin concentrationscomparison with placebo and, in a few studies, in comparison between treatment and control groups of 7.8 g/L, or an effect sizewith other micronutrients. Trials of iron fortification or paren- of 1.49 (95% CI: 0.46, 2.51) (10).teral iron were excluded. In certain circumstances when data Of the studies we examined for development, growth, andwere scarce, as in the case of iron supplementation and HIV infectious disease outcomes (Tables 2, 3, and 4), 13 reportedinfection or tuberculosis, some observational studies were re- significantly increased hemoglobin concentrations and reducedviewed to suggest possible relations that should be further inves- anemia prevalence associated with iron supplementation oftigated with RCTs. young children (11–15, 19, 23, 30, 31). Eleven studies showed Twenty-six RCTs were identified for this review. If recent improvements in other iron status indicators: serum iron, serummeta-analyses of RCTs have been performed, results are given, ferritin, transferrin saturation, and free erythrocyte protoporphy-even though selection criteria such as the age of the children may rin (11, 13, 15, 16, 19, 20, 23, 24, 30 –32). Of the 5 studieshave differed slightly. The outcomes examined in these iron reporting no significant effect on hemoglobin concentrations insupplementation trials were grouped into the following catego- the entire sample or particular strata (11, 16, 17, 24, 32), 4 showedries: anemia and iron status, development (including cognition, improvements in iron status markers (11, 16, 24, 32). This in-motor skills, and language), growth, morbidity, and mortality. To consistent effect on hemoglobin concentrations may be indica-highlight particular findings, these outcome categories were then tive of the varied causes of anemia in these study populations.placed within the sections of the review as either benefits or risks. Sustained significant (P 0.022) improvements in hemoglobinHowever, findings were not consistent across many of these out- concentrations 7 mo after a 3-mo treatment period were found incomes, and this variability deserves careful consideration when pol- one study (21), whereas another study found that only serumicy is made for programs in countries throughout the world. ferritin concentrations remained significantly higher in the treat- ment group 6 mo after cessation of supplementation (31). He- moglobin improvements appeared to be related to baseline statusBENEFITS OF IRON SUPPLEMENTATION IN EARLY (11, 17) and to exposure to anemia risk factors in addition to ironCHILDHOOD deficiency (ie, residence in malarial endemic regions) (16, 32). Possible beneficial effects of iron supplementation in youngchildren are primarily in the realms of anemia prevention andimprovements in developmental outcomes. Development Iron supplementation has been hypothesized to have benefitsAnemia in children that prevent possible detrimental effects of iron de- Anemia may be due to iron deficiency (inadequate iron intake, ficiency during development. The pace of neurologic develop-poor iron absorption, or excess iron losses), insufficient hema- ment in young children aged 0 – 4 y is rapid, including criticaltopoiesis (eg, from vitamin B-12 deficiency), loss of blood (hem- periods of neural circuit formation and myelination occurring inorrhagic anemia), premature red blood cell plasma membrane the brain. Iron’s role in the brain is likely to be multifaceted and
  3. 3. TABLE 2Development and iron supplementation1Study and Sample size by Eligibility and exclusion Outcomelocation Age group supplement Dosage and duration criteria Baseline status measures Results nBlack et al, 6–12 mo old Total: 221 Ferrous sulfate (20 mg) Age 6 mo; not receiving Iron: 10.3 0.8 BSID II; HOME Significantly smaller decrease in Bangladesh Iron group: 49 riboflavin (1 mg) formula; MUAC 110 mm; Zinc: 10.5 1.0 scale orientation engagement (17) Zinc group: 49 Zinc acetate (20 mg) hemoglobin 90 g/L; no Iron zinc: 10.5 1.0 (exploration) scores in iron and Iron zinc group: riboflavin (1 mg) obvious neurologic disorders, Multivitamin: 10.5 0.8 iron zinc groups than in 43 Iron (20 mg) zinc physical disabilities, or Riboflavin: 10.8 1.4 placebo group (P  0.05); PDI Multivitamin (20 mg) riboflavin chronic illness scores from 6 mo to 12 mo of group: 35 (1 mg) age decreased less for iron Riboflavin group: Multivitamins (with iron zinc and multivitamins (P  45 and zinc) 0.05); hemoglobin at baseline Riboflavin and change in hemoglobin not Weekly dose associated with development 6-mo duration outcomesIdjradinata and 12–18 mo old Total: 126 IDA group: ferrous Attending clinic at Padjadjaran IDA group: hemoglobin MDI; PDI Significant changes in mean mental Pollitt, IDA group: 50 sulfate (3 mg · kg 1 · University; birth weight 105 g/L, TS 10%, development and psychomotor Indonesia Iron-deficient, d 1) or placebo Œ2500 g; singleton; no major serum ferritin 12 g/L scores of IDA infants, but not in (11) nonanemic Iron-deficient, congenital anomalies or Iron-deficient, nonanemic other groups; developmental group: 29 nonanemic group: perinatal complications; no group: hemoglobin delay reversed after 4 mo of Iron-sufficient ferrous sulfate (3 mg · jaundice treated with 120 g/L, TS 10%, treatment group: 47 kg 1 · d 1) or placebo phototherapy; no hospital serum ferritin 12 g/L 4-mo duration admission or supplementation Iron-sufficient group: with micronutrients during hemoglobin 120 g/L, the 6 mo before enrollment; TS Œ 10%, serum no clinically identified ferritin Œ12 g/L neuromotor delay; no chronic illness or folic acid deficiency; hemoglobin Œ80 g/L; no abnormal hemoglobin or thalassemia; weight, length, and head circumference within 2 SD of reference standardsLind et al, 6 mo old Total: 666 Iron (10 mg/d) Resident in Purworejo, Central Hemoglobin 114 g/L Anthropometric Iron improved BSID psychomotor Indonesia Iron group: 166 Zinc (10 mg/d) Java; singleton infants; age  (hemoglobin 110 g/L indexes; development index significantly (18) Iron zinc group: Iron (10 mg) zinc (10 6 mo observed in 41%, developmental more than did placebo; no effect 164 mg) Exclusions: metabolic or hemoglobin 110 g/L indexes on morbidity; no effect of iron Zinc group: 167 Placebo neurologic disorders; and ferritin  12 g/L (BSID); alone on growth, but iron zinc Placebo group: 169 6-mo duration handicaps affecting in 8%) morbidity significantly improved knee-heel development, feeding, or Weight-for-age z score length compared with placebo; activity; severe or protracted 0.42; height-for-age z no confounding or interaction illness: hemoglobin  90 g/L score 0.57; weight- found according to initial iron for-height z score status 0.02Lozoff et al, 12–23 mo old Total: 86 Oral iron (3 mg/kg twice Resident of periurban area Anemic group: hemo- Bayley MDI; No significant differences in mental BENEFITS AND RISKS OF CHILDHOOD IRON SUPPLEMENTATION Costa Rica IDA iron- a day) Desamparados; birth weight globin 94 6 g/L; free Bayley PDI or motor test scores; mental test (15) supplemented 6-mo duration 2500 g; singleton birth; free erythrocyte scores in both IDA and group: 32 of acute or chronic medical protoporphyrin 335.3 nonanemic groups declined over Nonanemic iron- conditions 173.6 g/dL; packed 6 mo, with significantly lower supplemented IDA group: hemoglobin 100 RBC ferritin 4.4 4.7 scores in the IDA group at study group: 27 g/L plus 2 of 3 iron measures g/L; TS 8.4 2.6% entry and 3 mo Nonanemic group: indicating deficiency: serum Nonanemic group: IDA group: hemoglobin increased 27 ferritin 12 mg/L, hemoglobin 132 5 by 34 g/L at 3 mo and 35 g/L at 6 erythrocyte protoporphyrin g/L; free erythrocyte mo; anemia corrected for all by 6 Œ100 mg/dL, or transferrin protoporphyrin 59.6 mo saturation 10% 24.1 g/dL; packed Nonanemic iron-supplemented Nonanemic group: hemoglobin RBC ferritin 13.0 group: iron status improved 125 g/L 17.1 g/L; TS 16.8 1.9% 1263 (Continued) Downloaded from www.ajcn.org at GlaxoSmithKline on July 28, 2011
  4. 4. 1264TABLE 2 (Continued)Study and Sample size by Eligibility and exclusion Outcomelocation Age group supplement Dosage and duration criteria Baseline status measures ResultsLozoff et al, 6–24 mo Total: 64 Ferrous ascorbate (5 mg · Residents of Guatemala City; Anemic group: hemoglobin Bayley MDI; Deficits at baseline in psychomotor Guatemala Iron group: 31 kg 1 · d 1) or placebo hemoglobin 105 or Œ120 95 9 g/L; serum iron Bayley PDI development and mental (12) Placebo group: 33 1-wk duration g/L; no birth complications, 34.5 9.3 g/dL; TS development indexes were not acute or chronic illness, 7.9 3.1%; serum reversed in 6–8 d of treatment neonatal distress, congenital ferritin 4.0 5.0 g/ L; anomalies, developmental free erythrocyte retardation, generalized protoporphyrin 166.6 malnutrition, or iron therapy 100.1 g/dL packed during the previous mo; RBCs mature infants Nonanemic group: hemoglobin 126 5 g/L; serum iron 60.7 22.3 g/dL; TS 16.9 6.4%; serum ferritin 14.4 19.3 g/L; free erythrocyte protoporphyrin 67.9 28.5 g/dL packed RBCsSoewondo et al, 5 y Total: 127 Iron (50 mg/d) or placebo Female head of household IDA group: hemoglobin Discrimination IDA associated with visual attention Indonesia Iron group: 51 2-mo duration works as tea picker; husband Œ110 g/L plus 2 of the learning; and concept acquisition, (13) Placebo group: 76 present in household; one following: ferritin 12 three oddity corrected by iron treatment preschool-age child present; g/L, TS 16%, free learning No effect in iron-replete children family lives on a farm erythrocyte tasks; PPVT protoporphyrin Œ1.77 mmol/L RBCs Iron-depleted group: hemoglobin 110 g/L plus 2 of the following: ferritin 12 g/L, TS IANNOTTI ET AL 16%, free erythrocyte protoporphyrin Œ1.77 mmol/L RBCs Iron-replete group: hemoglobin 110 g/L plus 2 of the following: ferritin 12 g/L, TS 16%, free erythrocyte protoporphyrin 1.77 mmol/L RBCsStoltzfus et al, 6–59 mo old Total: 614 Ferrous sulfate (10 mg/d) Resident of Kengeja village on 97% were anemic Language; Language development improved Zanzibar (16) Households stratified Mebandazole (500 mg) Pemba; age eligibility for (hemoglobin  110 g/ motor score 0.8 points (range: 0.2–1.4) on by age strata and 12-mo duration language development scale L); 18% were severely 20-point scale randomly assigned was 12–48 mo and that for anemic (hemoglobin Motor development improved in to receive iron or motor development scale was 70 g/L) children with hemoglobin 90 placebo; children 12–36 mo g/L then stratified by Interaction with baseline iron allocation and hemoglobin (P 0.015) randomly assigned to receive mebendazole Iron group: 307 Placebo group: 307 Mebandazole group: 306 Placebo group: 308 (Continued) Downloaded from www.ajcn.org at GlaxoSmithKline on July 28, 2011
  5. 5. TABLE 2 (Continued)Study and Sample size by Eligibility and exclusion Outcomelocation Age group supplement Dosage and duration criteria Baseline status measures ResultsWalter et al, 12 mo old Total: 196 Iron (45 mg/d) Residents of well-defined Anemic group: hemoglobin Bayley MDI; No treatment effect was observed Chile (14) Iron group: 102 10-d duration geographical area 100 9 g/L; MCV 62 Bayley PDI for mental and psychomotor Placebo group: 94 5 gL; iron and iron- development after 10 d or 3 mo binding capacity 6.8 No differences by baseline status 2.9%; serum ferritin 5.4 After 3 mo of iron treatment, g/L; free erythrocyte anemia was corrected protoporphyrin 195 103.1 g/dL packed RBCs Non-anemic iron-deficient group: hemoglobin 121 7 g/L; MCV 70 4 gL; iron and iron- binding capacity 12.2 0.7%; serum ferritin 11.9 g/L; free erythrocyte protoporphyrin 108 33 g/dL packed RBCs Control group: hemoglobin 127 8 g/L; MCV 76 3 gL; iron and iron- binding capacity 16.7 6.3%; serum ferritin 19.8 g/L; free erythrocyte protoporphyrin 78 13 g/dL packed RBCs 1 MUAC, midupper arm circumference; BSID, Bayley Scales of Infant Development; HOME, Home Observation Measurement of Environment; PDI, Psychomotor Development Index; IDA, iron-deficiencyanemia; MDI, Bayley Mental Development Index; TS, transferrin saturation; RBC, red blood cell; PPVT, Peabody Picture Vocabulary Test; MCV, mean corpuscular volume. BENEFITS AND RISKS OF CHILDHOOD IRON SUPPLEMENTATION 1265 Downloaded from www.ajcn.org at GlaxoSmithKline on July 28, 2011
  6. 6. 1266TABLE 3Growth and iron supplementation1Study and Dosage and Eligibility and exclusion Baseline Outcomelocation Age group Sample size duration criteria status measures Results nAngeles et al, 2–5 y old Total: 76 Ferrous sulfate (30 mg/d) WAZ between 2 and 3 Iron group: hemoglobin Weight, height, dietary Increases in height and HAZ in Indonesia Iron: 39 2-mo duration SDs 102 9 g/L intake, hemoglobin, treatment group were larger (19) Placebo: 37 Hemoglobin Œ 80 to 110 Placebo group: hemoglobin serum ferritin; fever than those in control group (P g/L 103 8 g/L (temperature Œ 37°C);  0.01); hemoglobin, serum Ferritin 120 g/L WAZ 2.53 diarrhea (Œ4 watery ferritin, and MCV improved HAZ 2.33 stools/d); RTI significantly WHZ 1.48 Frequency of fever, respiratory infections, and diarrhea was significantly less in treatment group Study was adjusted for food intake effect on growth; decreased morbidity in supplementation group is suggested to have mediated the growth increaseDewey et al, 4–9 mo old Total: 131 Ferrous sulfate (1 mg · Gestational age 37 wk; Hemoglobin 90 g/L Blood samples at 4, 6, and Reduced gains in length in Sweden and kg 1 · d 1) from 4 to birth weight Œ2500 g; no 9 mo (hemoglobin, children 4–6 mo old and Honduras 6 mo of age chronic illness; maternal ferritin, erythrocyte hemoglobin 110 g/L in iron (26) Placebo from 4 to 6 mo age 16 y; infant zinc protoporphyrin, groupDomellof et al, of age and then ferrous exclusively breastfed at 4 MCV, plasma Weight gain lower in the infants Sweden and sulfate (1 mg · kg 1 · mo (received 90 mL transferrin receptor); receiving iron for 6–9 mo than Honduras d 1) from 7 to 9 mo of infant formula/d since C-reactive protein; birth in those receiving placebo (23) age birth); mother intended to weight; weight, length, within lower ferritin subgroup Placebo from 4 to 9 mo continue breastfeeding and head circumference No significant effect on morbidity, of age until infant age 9 mo by month; nutrient intake but diarrhea was less common in complementary foods; at 4 mo in infants in both morbidity by maternal Honduras and Sweden who had IANNOTTI ET AL records on calendar baseline hemoglobin 110 g/L; (stool frequency, infants with hemoglobin 110 consistency, cough, g/L at baseline had more fever, nasal congestion diarrhea or discharge, diarrhea, From age 4 to 6 mo, hemoglobin vomiting, or skin rash); and ferritin improved; from age morbidity by 6 to 9 mo, iron status indicators pediatrician diagnosis improved but not hemoglobin; IDA was significantly reduced at 9 moDijkhuizen et 4 mo old Total: 478 Iron (10 mg/d) Age; resident of any of 6 Hemoglobin and plasma — No effect on growth; hemoglobin al, Iron (10 mg/d) zinc adjacent villages in West ferritin not reported at and plasma ferritin Indonesia (10 mg/d) Java; exclusion based on baseline concentrations significantly (20) 6-mo duration chronic or severe illness, Iron-supplemented group higher in iron-treated group severe clinical baseline status: malnutrition, or congenital WAZ 0.06 anomalies HAZ 0.89 WHZ 0.77Dossa et al, 3–5 y old Total: 140 Iron (60 mg/d) Age 3–5 y; resident of semi- Hemoglobin 10.1 g/L; 76% Anthropometric measures; No effect on growth in study Benin (21) Iron (60 mg/d) rural area of southern were anemic hemoglobin; eggs/g groups or stratified groups by albendazole Benin; exclusion: no acute (hemoglobin 110 g/L) feces nutritional and hemoglobin 3-mo duration disease WAZ 1.59 status HAZ 2.03 WHZ 0.53 (Continued) Downloaded from www.ajcn.org at GlaxoSmithKline on July 28, 2011
  7. 7. TABLE 3 (Continued)Study and Dosage and Eligibility and exclusion Baseline Outcomelocation Age group Sample size duration criteria status measures ResultsIdjradinata et 12–18 mo Total: 47 Ferrous sulfate (3 mg · Birth weight Œ2500 g; singleton Iron-replete (hemoglobin Weight, length, and arm Reduced rate of weight gain in al, old kg 1 · d 1) pregnancy; no major congenital Œ 120 g/L; TS Œ10%; circumference iron group (x SE: 0.106 Indonesia 4-mo duration anomalies or perinatal serum ferritin Œ12 g/ (bi-weekly); morbidity 0.011 versus 0.070 0.011 (27) complications; no jaundice L) (pediatrician kg/2 wk, P 0.02) treated with phototherapy; no diagnosis); illness No significant differences in hospital admission or incidence length and arm circumference supplementation with (gastrointestinal, upper No significant difference in micronutrients during the 6 mo or lower respiratory respiratory or gastrointestinal before enrollment; no chronic tract infection) for 2 wk infections illness or folic acid deficiency; (Other confounding factors not hemoglobin Œ80 g/L; no signs corrected for) of abnormal hemoglobin or thalassemia; weight, length, and head circumference 2 SDs of reference standardsLind et al, 6-mo old Total: 666 Iron (10 mg/d) Resident in Purworejo, Central Hemoglobin 114 g/L Anthropometric indexes; No effect of iron alone on growth Indonesia Iron group: 166 Zinc (10 mg/d) Java; singleton infants  6 mo (hemoglobin 110 g/L developmental indexes but iron zinc significantly (18) Iron zinc Iron (10 mg) zinc (10 old; exclusions: metabolic or observed in 41%; (BSID); morbidity improved knee-heel length as group: 164 mg) neurologic disorders; handicaps hemoglobin 110 and compared with placebo; iron Zinc group: 167 6-mo duration affecting development, feeding, ferritin 12 g/L significantly improved BSID Placebo group: or activity; severe or protracted observed in 8%) psychomotor development 169 illness; hemoglobin 90 g/L WAZ 0.42 index as compared with HAZ 0.57 placebo; no effect on morbidity WHZ 0.02Majumdar et 6–24 mo Total: 150 Iron-replete group: iron Birth weight Œ2500 g; singleton Hemoglobin 139 g/L Anthropometric indexes In iron-deficient children, al, India old Iron-replete (2 mg · kg 1 · d 1) pregnancy; weight, length, and Iron-replete group: (weight, length, head significantly greater mean (25) group: Iron-deficient group: iron head circumference within 2 hemoglobin Œ110 g/L, circumference) monthly weight gain (P  Iron: 50 (6 mg · kg 1 · d 1) SDs of NCHS reference; diet of serum ferritin Œ12 g/ 0.001) and linear growth (P  Placebo: 50 4-mo duration adequate protein, calories, and L, TS Œ 10% 0.001) Iron-deficient micronutrients; exclusions: Iron-deficient group: In iron-replete children, group: 50 major congenital anomaly or hemoglobin 50–110 g/L, significantly less weight gain prenatal complications, serum ferritin 12 g/ (P  0.001) and linear growth hospital admission or iron L, TS 10% (P  0.001) supplementation during the months before enrollment, chronic illness, anemia beyond iron deficiency, or recent blood transfusionPalupi et al, 2–5 y old Total: 194 Ferrous sulfate (15 Registered at village health center Hemoglobin 113 g/L Worm infestation (as No effect on changes in height or Indonesia Iron: 96 mg/wk) WAZ 1.84 indicated by stool weight (SD was large for (22) Placebo: 98 2-mo duration HAZ 1.92 microscopy) increase in hemoglobin WHZ 0.85 concentration in both iron and placebo groups; no hookworm prevalence and no additional effect of anthelminth treatment)Rahman et al, 0.5–6 y old Total: 317 Ferrous gluconate (15 Resident in poor periurban WAZ 2.4 No differences in weight or height Bangladesh mg/d) vitamins A, community of Dhaka; HAZ 2.3 increments between BENEFITS AND RISKS OF CHILDHOOD IRON SUPPLEMENTATION (28) D, and C exclusions: congenital WHZ 1.3 intervention and control groups 1-y duration abnormality, metabolic disorder, No hemoglobin reported No differences when stratified by or any clinical sign of anemia age or nutritional categoriesRosado et al, 1.5–3 y old Total: 219 Ferrous sulfate (20 mg/d) Resident in 1 of 5 rural Hemoglobin 108 g/L RTI (runny nose, common No effect on growth velocity or Mexico (24) Iron: 109 Ferrous sulfate zinc communities WAZ 1.6 cold, sore throat, body composition Placebo: 110 methionine HAZ 1.6 cough); diarrhea Zinc and zinc iron significantly 12-mo duration WHZ 0.7 (maternal reporting); decreased diarrhea (P  0.01) Serum ferritin group: fever (maternal and disease episodes (P  Placebo: 20.1 44.6 reporting) 0.03) Iron: 21.2 38.1 (No effect with iron alone) Zinc: 18.9 15.8 Zinc iron: 14.7 15.6 1 WAZ, weight-for-age z score; HAZ, height-for-age z score; MCV, mean corpuscular volume; WHZ, weight-for-height z score; RTI, respiratory tract infection; IDA, iron deficiency anemia; TS, transferrin 1267saturation; BSID, Bayley Scales of Infant Development; NCHS, National Center for Health Statistics. Downloaded from www.ajcn.org at GlaxoSmithKline on July 28, 2011
  8. 8. TABLE 4Morbidity and iron supplementation1 1268Study and Dosage and Eligibility and exclusion Outcomelocation Age group Sample size duration criteria Baseline status measures Results nAngeles et al, 2–5 y old Total: 76 Ferrous sulfate (30 WAZ between 2 and 3 SD Iron group: hemoglobin 102 Weight, height, dietary intake; Frequency of fever, respiratory Indonesia (19) Iron: 39 mg/d) Hemoglobin Œ80 to 110 g/L 9 g/L hemoglobin; serum ferritin; fever infections, and diarrhea significantly Placebo: 37 2-mo duration Ferritin  120 g/L Placebo group: hemoglobin 103 (temperature Œ 37°C); diarrhea less in treatment group 8 g/L (Œ4 watery stools/d); respiratory Increases in height and HAZ in WAZ 2.53 tract infection treatment group were larger than in HAZ 2.33 control group (P  0.01) WHZ 1.48 Hemoglobin, serum ferritin, and MCV significantly improved (Study adjusted for effect of food intake on growth; study suggested that the lower morbidity in the supplementation group mediated a growth increase)Berger et al, 6–36 mo Total: 197 Iron betainate (2–3 mg Resident in selected village; aged 6–36 Iron group: hemoglobin 98.9 Upper RTI; lower RTI; malaria: No effect on incidence of infections or Togo (31) old Iron: 100 · kg 1 · d 1) mo; hemoglobin 80 g/L 11.6 g/L, TS 18.3 10.1%, parasite density measured smear; malaria Placebo: 97 3-mo duration serum ferritin 109.2 110.6 diarrhea; cutaneous infecti on; After adjustment for baseline status, 9-mo follow-up g/L, free erythrocyte fever; worms hemoglobin TS, and ferritin at 3 mo protoporphyrin 105 63 were significantly improved; at 9 mo, g/dL packed RBCs only ferritin remained significantly Placebo group: hemoglobin higher in treatment group 100.4 10.6 g/L, TS 17.0 (Treatment and placebo groups were 7.78%, serum ferritin 109.7 also given malaria prophylaxis and 138.6 g/L, free deworming) erythrocyte protoporphyrin 101 62 g/dL packed RBCsChippaux et al, 6–36 mo Total: 190 Iron betainate (2.5 mg Hemoglobin 80 g/L NA Malaria (smear positive); antibody No effect on infant susceptibility to Togo (33) old Iron: 95 · kg 1 · d 1) titers malaria or immune response Placebo: 95 3-mo duration High parasitanemia frequency in all 9-mo follow-up groups during rainy season IANNOTTI ET AL No variation in antibody tiersDewey et al, 4–9 mo old Total: 131 Ferrous sulfate (1 mg · Gestational age 37 wk; birth weight Hemoglobin Œ90 g/L Blood samples at 4, 6, and 9 mo No significant effect on morbidity in the Honduras and kg 1 · d 1) Œ2500 g; no chronic illness; (hemoglobin, ferritin, erythrocyte data from Honduras but in the Seweden (26) Iron (4–9 mo) maternal age 16 y; infant zinc protoporphyrin, mean combined data from Honduras andDomellof Placebo (4–6 mo) exclusively breastfed at 4 mo corpuscular volume, plasma Sweden, diarrhea was less common et al, iron (6–9 mo) (received 90 mL infant formula/d transferrin receptor); C-reactive at 4 mo in supplemented infants with Honduras and Placebo (4–9 mo) since birth); mother intended to protein; birth weight; weight, baseline hemoglobin 110 g/L; Sweden (23) continue breastfeeding until 9 mo of length, and head circumference by infants with hemoglobin 110 g/L at age month; nutrient intake in baseline had more diarrhea complementary foods; morbidity Reduced gains in length in children 4–6 by maternal record on a calendar mo old and with hemoglobin 110 (stool frequency; stool g/L in the iron group consistency; cough, fever, nasal Weight gain lower in the group congestion or discharge; diarrhea, receiving iron for 6–9 mo than in the vomiting, or skin rash) placebo group within the lower Morbidity by pediatrician diagnosis ferritin subgroupIdjradinata et al, 12–18 mo Total: 47 Ferrous sulfate (3 mg · Birth weight Œ2500 g; singleton Iron-replete hemoglobin group: Weight, length and arm No significant difference in respiratory Indonesia (27) old Iron: 24 kg 1 · d 1) pregnancy; no major congenital Œ120 g/L; TS Œ10%; serum circumference (biweekly); or gastrointestinal infections Placebo: 23 4-mo duration anomalies or perinatal ferritin Œ12 g/L morbidity (pediatrician diagnosis); Reduced rate of weight gain in iron complications; no jaundice treated illness incidence (gastrointestinal group (x SE: 0.106 0.010 versus with phototherapy; no hospital or upper or lower respiratory tract 0.070 0.011; kg/2 wk, P 0.02) admission or supplementation with infection for 2 wk No significant differences in length and micronutrients during the 6 mo arm circumference before enrollment; no chronic illness (Other confounding factors were not or folic acid deficiency; hemoglobin corrected for) Œ80 g/L; no signs of abnormal hemoglobin or thalassemia; weight, length, and head circumference 2 SDs of reference standards (Continued) Downloaded from www.ajcn.org at GlaxoSmithKline on July 28, 2011
  9. 9. TABLE 4 (Continued)Study and Dosage and Eligibility and exclusion Outcomelocation Age group Sample size duration criteria Baseline status measures ResultsLind et al, 6 mo old Total: 666 Iron (10 mg/d) Resident in Purworejo, Central Java; Hemoglobin 114 g/L Anthropometric indexes; No effect on morbidity Indonesia (18) Iron: 166 Zinc (10 mg/d) singleton infants;  6 mo old; (hemoglobin  110 g/L development indexes (BSID); No effect of iron alone on growth but Iron zinc: Iron (10 mg) zinc exclusions: metabolic or neurologic observed in 41%; hemoglobin morbidity iron zinc significantly improved 164 (10 mg) disorders; handicaps affecting  110 and ferritin  12 g/L knee-heel length as compared with Zinc: 167 6-mo duration development, feeding, observed in 8%) placebo Placebo: 169 or activity; severe or protracted WAZ 0.42 Iron significantly improved BSID illness; hemoglobin  90 g/L HAZ 0.57 psychomotor development index WHZ 0.02 compared with placeboMebrahtu et al, 6–59 mo Total: 614 Ferrous sulfate (10 Resident of Kengeja village on Pemba 94.4% were anemic Blood films were assessed monthly No significant effects on malariometric Tanzania (32) old Households mg/d) (hemoglobin 110 g/L) for prevalence and density of measures or after adjustment for age stratified Mebandazole (500 17% were severely anemic infection and season by age and mg) (hemoglobin 70 g/L) randomly 12-mo duration 80% were infected with assigned to Plasmamodium falciparum receive 48.1% had HAZ  2 iron or placebo, and then children stratified by iron allocation and randomly assigned to mebendazole Iron: 307 Placebo: 307 Mebandazole: 306 Placebo: 308Menendez et al, 2 mo old Total: 832 Ferrous glycine sulfate Birth weight Œ1500 g; PCV Œ 25% at P P group: PCV 33.3 5.6 Malaria (axillary temperature No effect on frequency of malaria; Tanzania (27) (2 mg · kg 1 · d 1) 8 wk; exclusions: congenital I P group: PCV 33.4 5.0 Œ35.5°C with asexual P. 12.8% protective efficac y ( 12.8– Deltaprim malaria malformation, congenital or neonatal D P group: PCV 33.4 6.4 falciparum parasitemia of any 32.5%) prophylaxis infection P I group: PCV 33.0 5.3 density) 4-mo duration 10-mo follow-upMitra et al, 2–48 mo Total: 349 Ferrous gluconate (15 Exclusions: critically ill, congenital Diarrhea ( 3 liquid stools/d and No effect on number of episodes, mean Bangladesh old Iron: 172 mg/d) malformations, metabolic disorders maternal report for breastfed duration of each episode, total days (34) Placebo: 177 Vitamins infants): dysentery (blood, mucus, of illness due to diarrhea, dysentery, 3-mo duration or both in stools) and acute respiratory infection Acute respiratory infection Œ50 49% of children 12 mo old had an breaths/min in child 1 y old, increase in the number of episodes of 40 breaths/min in child 1–5 y old dysentery in supplementation groupPalupi et al, 2–5 y old Total: 194 Ferrous sulfate (15 Registered at village health center 10 g/L Worm infestation (as indicated by No effect on hookworm prevalence BENEFITS AND RISKS OF CHILDHOOD IRON SUPPLEMENTATION Hemoglobin 112 Indonesia Iron: 96 mg/wk) stool microscopy) (122) Placebo: 98 2-mo durationRosado et al, 1.5–3 y old Total: 219 Ferrous sulfate (20 Resident in 1 of 5 rural communities; Hemoglobin 108 g/L RTI (runny nose, common cold, sore No effect on morbidity with iron Mexico (24) Iron: 109 mg/d) age as stated WAZ 1.6 throat, cough); diarrhea (maternal treatment alone Placebo: 110 Ferrous sulfate zinc HAZ 1.6 reporting); fever (maternal No effect on growth velocity or body methionine WHZ 0.7 reporting) composition 12-mo duration and Serum ferritin group: follow-up Placebo: 20.1 44.6 Iron: 21.2 38.1 Zinc: 18.9 15.8 Zinc iron: 14.7 15.6 (Continued) 1269 Downloaded from www.ajcn.org at GlaxoSmithKline on July 28, 2011
  10. 10. 1270TABLE 4 (Continued)Study and Dosage and Eligibility and exclusion Outcomelocation Age group Sample size duration criteria Baseline status measures ResultsSazawal et al, 1–35 mo Total: 24 076 Ferrous sulfate (12.5 Age; resident on island of Pemba; no Serious adverse events; all-cause 12% greater risk of mortality or severe Tanzania (36) old Iron folic mg) severe malnutrition; substudy mortality; cause-specific mortality; illness leading to hospitalization with acid: 7950 Folic acid (50 g) exclusion: hemoglobin 70 g/L hospitalizations; malaria (parasite iron and folic acid (2–23%; P Iron folic Zinc (10 mg) count and fever), meningitis, 0.02) acid Tablet daily for diarrhea, dysentery, pneumonia 16% greater risk of adverse events due zinc: 8120 children Œ 12 mo to malaria (2–32%; P 0.03) Placebo: old; half-tablet for No effect with cumulative dose 8006 children 12 mo Substudy findings: in iron-deficient Substudy: old anemic children, iron and folic acid 2413 12-mo duration treatment significantly reduced the risk of adverse events (RR: 0.51; 95% CI: 0.31, 0.83; P 0.006) In iron-replete children, the trend was toward greater risk of adverse events: with anemia (RR: 2.00; 95% CI: 0.46, 8.75; P 0.36); without anemia (RR: 1.51; 95% CI: 0.54, 3.98; P 0.41) [Children with malaria (parasite count Œ5000 and axillary temperature Œ37.5 °C) were given a dose of sufadoxine/pyrimethamine]Smith et al, 6 mo–5 y Total: 213 Ferrous sulfate in Hemoglobin and MCV 3% of Hemoglobin and MCV 3rd Malaria (axillary temperature Significantly increased fever-associated Gambia (37) old Iron: 106 orange juice reference population percentile of reference Œ37.5°C with P. falciparum severe malaria in iron-treated group Placebo: 107 (3–6 mg · kg 1 · Exclusion: infants with hemoglobin population positivity) than in placebo group d 1) 50 g/L 3-mo duration IANNOTTI ET ALTielsch et al, 1–35 mo Total: 25 490 Placebo, iron and folic 1–35 mo living in study area All cause mortality; secondary: No effect on mortality: iron and folic Nepal (30) old acid, zinc, iron and cause-specific mortality; incidence acid (HR 1.03, 95% CI: 0.78, 1.37) folic acid zinc: or severity of diarrhea; dysentery; or iron and folic acid zinc (HR Ferrous sulfate ARI, clinic utilization 1.00, 95% CI: 0.74, 1.34) (12.5 mg) No significant differences in attack rates Folic acid (50 g) for diarrhea, dysentery, or respiratory Zinc (10 mg) infections Tablet daily for children Greater risk of “other infections” and aged 12 mo; deaths in iron and folic acid group half-tablet for children aged 12 mo 12-mo durationvan den  30 mo Total: 100 Ferrous sulfate Hemoglobin 50 g/L; positive smear Hemoglobin 41 8 g/L Malaria (smear positive); pneumonia; No effect on rate of parasitemia or Hombergh et old Iron: 50 (200 mg/d) for malaria parasites; exclusions: other infections parasite density al, Tanzania Placebo: 50 Folic acid cerebral malaria, nonfalciparum Increase in morbidity from other causes (35) 3-mo duration and malaria, sickle cell anemia, other in iron group (P 0.004) follow-up significant illness Significant difference in pneumonia incidence; higher in iron group (P 0.004) 1 WAZ, weight-for age z score; HAZ, height-for-age z score; WHZ, weight-for-height z score; MCV, mean corpuscular volume; TS, transferrin saturation; RTI, respiratory tract infection; RBC, red blood cell;NA, not applicable; BSID, Bayley Scales of Infant Development; P P, placebo placebo; I P, iron placebo; D P, Deltaprim malaria syrup placebo; D I, Deltaprim malaria syrup iron; PCV, packedcell volume; ARI, acute respiratory infection: bpm, beats/min; RR, risk ratio; HR, hazard ratio. Downloaded from www.ajcn.org at GlaxoSmithKline on July 28, 2011

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