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Iron deficiency in children (infancy through adolescence) 

Updated 2013 May 07 01:33:00 PM: BCSH guideline on laboratory diagnosis of functional iron deficiency (Br J Haematol 2013 Jun) view updateShow more updates

Related Summaries:    

Iron deficiency anemia in adults Anemia - differential diagnosis Iron preparations, oral Differentiating beta-thalassemia minor from iron deficiency anemia

General Information Description:   

iron deficiency is most common nutritional deficiency worldwide, common in children(1, 2, 5) iron deficiency anemia is low hemoglobin level due to iron deficiency(1) iron deficiency anemia is typically a hypochromic microcytic anemia

Definitions: 

iron deficiency defined by(4) o decreased serum ferritin o decreased transferrin saturation (iron/total iron-binding capacity) o increased free erythrocyte protoporphyrin (also called zinc protoporphyrin) anemia defined by age- and gender-dependent hemoglobin or hematocrit levels(4)

Organs involved:    

blood bone marrow spleen liver

Who is most affected: 

in children and adolescents(1, 2) o premature and low-birth-weight infants o infants aged 6-20 months especially with


  

o o o o o

feeding of cow's milk or unfortified formula milk as primary dietary intake milk or formula intake > 600 mL/day or > 6 breast feeds/day (can displace solid food intake) pubescent children adolescent females athletes who train strenuously overweight children children with low socioeconomic level

Incidence/Prevalence:   

iron deficiency is most common nutritional deficiency worldwide, common in children(1, 2, 5) iron deficiency is most common cause of anemia (1, 2, 5) estimated prevalence of iron deficiency in United States o

Estimated Prevalence of Iron Deficiency in National Health and Nutrition Examination Survey (NHANES): 19991988-1994 2000 Toddlers aged 1-2 years 7% 9% Children aged 3-5 years 5% 3% Children aged 6-11 years 4% 2% Males aged 12-15 years 5% 1% (aged 12-69 years) Males aged 16-69 years 2% Females aged 12-49 years 12% 11% Mexican American females and females of black 19%15%-19% race aged 12-49 years 22% Females aged 12-15 years 9% 9% Females aged 16-19 years 16% 11% References - MMWR Morb Mortal Wkly Rep 2002 Oct 11;51(40):897 , JAMA 2002 Nov 6;288(17):2114 o

7.8% iron deficiency anemia and 38% iron deficiency in rural Alaska Native children  based on study in 688 children aged 7-11 years from 10 predominantly Alaska Native villages in southwestern Alaska  Reference - Pediatrics 2006 Mar;117(3):e396 9.4% prevalence of iron deficiency anemia and 14% prevalence of iron deficiency in infants in Estonia o based on cross-sectional sample of 177 infants aged 9-12 months from 7 counties in Estonia


o Reference - Medicina (Kaunas) 2007;43(12):947 PDF World Health Organization (WHO) estimates of anemia prevalence (hemoglobin < 100 g/L) in children < 5 years old in 1993-2005 o Africa - 64.6% (95% CI 61.7%-67.5%) o Asia - 47.7% (95% CI 45.2%-50.3%) o Latin America and Caribbean - 39.5% (95% CI 36%-43%) o Oceania - 28% (95% CI 15.8%-40.2%) o Europe - 16.7% (95% CI 10.5%-23%) o North America - 3.4% (95% CI 2%-4.9%) o Reference - WHO 2008 PDF

Causes and Risk Factors Causes:   

inadequate iron intake(1, 2, 3) reduced gastrointestinal iron absorption(1, 2, 3) blood loss(1, 2, 3)

Pathogenesis: 

failure to produce hemoglobin due to lack of iron(1, 5)

Likely risk factors: 

inadequate iron intake(1) o use of cow's milk or non-iron-fortified formula in infancy (deficiency rare in breastfed infants ≤ 6 months old) o excessive milk intake (cow's milk or formula intake > 600 mL/day or > 6 breast feeds/day) at age 8 months associated with low iron intake and anemia  based on British cohort study  928 term infants had milk intake assessed at 8 months and hemoglobin and ferritin levels measured at 8 and 12 months  prevalence of anemia by World Health Organization criteria (hemoglobin < 11 g/dL)  in overall cohort - 23% at age 8 months, 18% at age 12 months  in formula-fed infants - 20% at age 8 months, 15% at age 12 months  in cow's milk-fed infants - 28% at age 8 months, 27% at age 12 months  in breastfed infants - 32% at age 8 months, 27% at age 12 months  prevalence of low ferritin levels (< 16 mcg/L)  in overall cohort - 3% at age 8 months, 4% at age 12 months


in formula-fed infants - 2% at age 8 months, 3% at age 12 months  in cow's milk-fed infants - 7% at age 8 months, 11% at age 12 months  in breastfed infants - 5% at age 8 months, 5% at age 12 months  excessive milk intake (cow's milk or formula intake > 600 mL/day or > 6 breast feeds/day) associated with decreased intake of solid food sources of iron  Reference - Arch Dis Child 2007 Oct;92(10):850 o prolonged bottle-feeding and Mexican American ethnicity associated with increased risk in young children  based on cross-sectional survey of 2,121 children aged 1-3 years from National Health and Nutrition Examination Survey III (NHANES III) from 1988-1994 in United States  prevalence of iron deficiency, defined as any 2 abnormal iron status values for age and gender (transferrin saturation, free erythrocyte protoporphyrin, serum ferritin)  6% in white children  8% in black children  17% in Mexican American children  prevalence of iron deficiency in infants bottle-fed for  ≤ 12 months 3.8%  13-23 months 11.5%  24-48 months 12.4%  Mexican ethnicity and bottle feeding > 24 months were independent risk factors  Reference - Arch Pediatr Adolesc Med 2005 Nov;159(11):1038 o daytime bottle feeding associated with increased risk in toddlers  based on observational cohort study  150 children aged 12-38 months were evaluated for iron status and daytime cup vs. bottle use for milk consumption  insufficient blood quantities for some measurements in some children  comparing bottle vs. cup  iron depletion in 37% of 78 children vs. 18% of 67 children (relative risk [RR] 1.81, 95% CI 1.09-3.01)  iron deficiency anemia in 4% of 78 children vs. 2% of 62 children (not significant)  increased risk of iron depletion with bottle-feeding correlated with increased age  adjusted RR 1.31 at 18 months (p < 0.05)  adjusted RR 2.5 at 24 months (p < 0.05)  Reference - Arch Pediatr Adolesc Med 2006 Nov;160(11):1114 (2) o vegetarian diet reduced gastrointestinal iron absorption(1) o celiac disease


o o o

surgical removal of small bowel segments gastrectomy reduced acid secretion from Helicobacter pylori infection blood loss (1) o gastrointestinal blood loss  microscopic bleeding associated with use of unmodified cow's milk  Meckel diverticulum  juvenile polyps  peptic ulcer disease  inflammatory bowel disease  hemorrhagic telangiectasia  nonsteroidal anti-inflammatory drugs (1) o renal blood loss  paroxysmal nocturnal hemoglobinuria  immunoglobulin A nephropathy (Berger syndrome) (1) o alveolar hemorrhage  pulmonary hemosiderosis  Goodpasture syndrome (1) o parasitic infections o excessive menstrual bleeding o fetomaternal or twin-to-twin transfusion overweight children more likely to have iron deficiency o based on cross-sectional survey of 9,698 children aged 2-17 years from National Health and Nutrition Examination Survey III (NHANES III) from 1988 to 1994 in United States o prevalence of iron deficiency increased as body mass index (BMI) increased  2.1% in normal weight children  5.3% in children at risk for overweight (BMI ≥ 85th to < 95th percentile for age)  5.5% in overweight children (BMI ≥ 95th percentile for age) o risk of iron deficiency increased in children at risk for overweight or overweight  odds ratio 2 for children at risk for overweight (95% CI 1.2-3.5)  odds ratio 2.3 for overweight children (95% CI 1.4-3.9) o Reference - Pediatrics 2004 Jul;114(1):104

Factors not associated with increased risk: 

exclusive breastfeeding of term infants not associated with iron deficiency or iron deficiency anemia in first 6 months of life o based on prospective cohort study o 102 exclusively breastfed term infants of anemic and non-anemic mothers were evaluated for iron status in cord blood, and at ages 14 weeks and 6 months o normal iron status in all infants throughout study o Reference - Int Breastfeed J 2008 Mar 1;3:3


Complications and Associated Conditions Complications: 

complications of iron deficiency(1) o koilonychia - thin, concave fingernail with raised ridges o stomatitis o glossitis o pica

Associated conditions:  

 

iron deficiency may be associated with lead poisoning because iron deficiency enhances lead absorption conditions that may be associated with iron deficiency(1) o abnormal psychomotor development o breath-holding spells o restless legs syndrome (RLS) o attention-deficit hyperactivity disorder (ADHD) o Tourette syndrome o stroke iron deficiency anemia may be associated with ischemic stroke in children < 3 years old o based on small case-control study o 15 children aged 12-38 months hospitalized with stroke and 143 healthy outpatient controls were evaluated o children were identified from stroke registry and were previously healthy without other known stroke risk factors o iron deficiency anemia in 8 children with strokes (53%) vs. 12 controls (9%) o Reference - Pediatrics 2007 Nov;120(5):1053 iron deficiency associated with low vitamin D levels in Asian children living in England (BMJ 1999 Jan 2;318(7175):28 ) iron deficiency anemia associated with breath-holding spells o based on prospective cohort study o 91 children aged 6-40 months with breath-holding spells were evaluated and followed for median 45 months o 63 children (69%) had iron deficiency anemia and were treated with iron 6 mg/kg/day for 3 months o complete or partial remission of breath holding in 84% of children with iron deficiency anemia treated with iron vs. 21.4% in untreated children without anemia (p < 0.02) o Reference - Arch Dis Child 1999 Sep;81(3):261 PDF iron deficiency anemia associated with recurrent acute otitis media o based on study of 680 children with frequent otitis media and 200 healthy controls o Reference - Am J Otolaryngol 2001 Nov-Dec;22(6):391


iron deficiency and iron deficiency anemia may be associated with adverse neurodevelopmental outcomes o iron deficiency associated with lower math scores in children and adolescents  based on cross-sectional survey of 5,398 children aged 6-16 years from National Health and Nutrition Examination Survey III (NHANES III) from 1988 to 1994 in United States  3% prevalence of iron deficiency, defined as any 2 abnormal iron status values for age and gender (transferrin saturation, free erythrocyte protoporphyrin, serum ferritin)  anemia detected by standard hemoglobin values  average math test score was 93.7 in children with normal iron status compared to  87.4 in iron deficiency without anemia (p < 0.05)  86.4 in iron deficiency with anemia (p < 0.05)  Reference - Pediatrics 2001 Jun;107(6):1381 o chronic iron deficiency anemia in infancy associated with poorer social emotional development at age 4 years  based on retrospective cohort study  161 children without iron deficiency anemia were assessed for social emotional development at 4 years and compared by incidence of anemia in infancy  17% had chronic iron deficiency anemia (not corrected before 24 months)  43% had corrected iron deficiency anemia (corrected before 24 months)  40% did not have anemia in infancy or 24 months  children with chronic iron deficiency anemia compared to children without anemia in infancy had  lower positive affect (p < 0.05)  lower frustration tolerance (p < 0.05)  more passive behavior (p < 0.05)  more physical self-soothing in the stranger approach and delay of gratification (p < 0.01)  children with corrected iron deficiency anemia had similar social emotional development as children without anemia in infancy  Reference - Pediatrics 2011 Apr;127(4):e927 o iron deficiency and iron deficiency anemia each associated with poorer infant social-emotional behavior  based on observational cohort study  77 African-American infants aged 9-10 months given oral iron for 3 months were assessed for anemia, iron status, and social-emotional outcomes at baseline and age 12 months  follow-up blood testing available in < 60% of children  poorer iron status significantly associated with  increased shyness, latency to engage with examiner


o

decreased positive effect, latency to move away from examiner, orientation-engagement, soothability  Reference - J Pediatr 2008 May;152(5):696 iron deficiency in infancy associated with poorer performance on visual and auditory function tests in early childhood (level 3 [lacking direct] evidence)  based on cohort study without clinical outcomes  41 Chilean children aged 4 years who were diagnosed and treated for iron deficiency anemia at age 6, 12, or 18 months and 43 controls had auditory brainstem response (ABR) and visual evoked potential (VEP) testing  iron deficiency anemia in infancy associated with longer ABR and VEP latencies at age 4 years  Reference - Pediatr Res 2003 Feb;53(2):217

History and Physical History: Chief concern (CC):  

may be asymptomatic symptoms usually only occur with severe iron deficiency anemia, such as (1) o pallor o sleepiness o anorexia o tachycardia o stomatitis o dysphagia

History of present illness (HPI): 

possible history of(1) o pica (eating non-nutritional items such as soil, chalk, foam for > 1 month)  case report of pica for fresh, whole tomatoes can be found in N Engl J Med 1999 Jul 1;341(1):60  review of pica can be found in J Am Board Fam Pract 2000 SepOct;13(5):353, commentary can be found in J Am Board Fam Pract 2001 Jan-Feb;14(1):80 o breath-holding spells o attention-deficit hyperactivity disorder o Tourette syndrome o restless legs syndrome o stroke beeturia (pink or red urine after ingestion of beets; attributed to increased iron absorption) reported in 10%-14% of general population vs. 66%-80% of patients with untreated iron deficiency anemia (Lancet 1999 Sep 18;354(9183):1032)


Past medical history (PMH): 

ask about menstrual history (interval, duration, flow)

Social history (SH): 

ask about diet

Physical: General physical:  

abnormal findings usually found only with severe anemia (1) general findings may include(1) o failure to thrive  may occur with chronic deficiency  may be due to underlying cause of anemia such as malabsorption, malnutrition, or parasitic infestation o abnormal psychomotor development

Skin: 

pallor may predict anemia in children, but not sufficiently accurate to replace laboratory testing (level 2 [mid-level] evidence) o based on systematic review of studies limited by statistical heterogeneity o systematic review of 11 studies in children aged 0-18 years evaluating accuracy of conjunctival, palmar, or nail bed pallor in predicting anemia using hemoglobin as reference standard o all studies were performed in developing countries (8 in Africa, 1 in Pakistan, 1 in Bangladesh, 1 in Brazil) o most studies were in children < 5 years old o studies used hemoglobin thresholds of 11 g/dL (110 g/L), 8 g/dL (80 g/L), 7 g/dL (70 g/L), and/or 5 g/dL (50 g/L) o sensitivities varied from 29.2% to 80.9% with different hemoglobin thresholds For Hemoglobin < 11 g/dL (110 g/L):

Sensitivity Specificity Positive likelihood ratio Negative likelihood ratio

Nail Bed Palmar Pallor (n = Conjunctival Pallor (n = 3,885) Pallor (n = 3,195) 2,534) 39.2% 43.6% 29.2% 86.7% 81.4% 88.5% 3

2.3

2.7

0.7

0.7

0.8


For Hemoglobin < 11 g/dL (110 g/L): Nail Bed Palmar Pallor (n = Conjunctival Pallor (n = 3,885) Pallor (n = 3,195) 2,534) Post-test probability of anemia at 8% 21% 19% 17% prevalence Post-test probability of anemia at 50% 75% 73% 70% prevalence Post-test probability of anemia at 80% 92% 92% 90% prevalence * Differences between types of pallor no longer present when outliers excluded. For Hemoglobin < 5 g/dL (50 g/L): Palmar Conjunctival Nail Bed Pallor (n = Pallor (n = Pallor (n = 10,623) 12,780) 12,649) Sensitivity 56.6% 47.6% 61.1% Specificity 87.9% 88.1% 87.7% Positive likelihood 7.7 8.4 7.9 ratio Negative likelihood 0.5 0.6 0.4 ratio o o

rates of false positives and false negatives too high for clinical diagnosis Reference - BMC Pediatr 2005 Dec 8;5:46

HEENT:  

stomatitis or glossitis(1) conjunctival pallor (BMC Pediatr 2005 Dec 8;5:46)

Cardiac:  

tachycardia(1) Grade I-II/VI heart murmur(1)

Abdomen: 

splenomegaly(1)

Extremities:


 

koilonychia (spooning of the nails)(1) palmar or nail bed pallor (BMC Pediatr 2005 Dec 8;5:46)

Diagnosis Making the diagnosis: 

 

iron deficiency diagnosed by 2 of o decreased serum ferritin o decreased transferrin saturation (iron/total iron-binding capacity) o increased free erythrocyte or zinc protoporphyrin levels o Reference - MMWR Morb Mortal Wkly Rep 2002 Oct 11;51(40):897 iron deficiency anemia diagnosed when iron deficiency is accompanied by anemia (low hemoglobin level) anemia defined by hemoglobin levels according to the Centers for Disease Control and World Health Organization(2) o infants aged 0.5-4.9 years < 11 g/dL (110 g/L) o children aged 5-11.9 years < 11.5 g/dL (115 g/L) o menstruating women < 12 g/dL (120 g/L) o pregnant women < 11 g/dL (110 g/L) o men < 13 g/dL (130 g/L) bone marrow biopsy demonstrating lack of iron is definitive for iron deficiency (but response to trial of iron usually sufficient to confirm diagnosis)(2)

Rule out: 

  

other causes of hypochromic microcytic anemia (1, 2) o thalassemia minor  beta-thalassemia minor or alpha-thalassemia trait  see also Differentiating beta-thalassemia minor from iron deficiency anemia o lead poisoning o anemia of chronic disease sideroblastic anemia - presence of almost complete transferrin saturation can differentiate from iron deficiency anemia(2) celiac disease(1) see also Anemia - differential diagnosis

Testing overview:  

 

serum ferritin alone is test of choice for iron deficiency(1) complete blood count (CBC)(1) o hemoglobin/hematocrit (Hb/Hct) o red cell indices (important to classify as hypochromic, microcytic anemia; otherwise consider additional cause of anemia) reticulocyte count(1) peripheral smear review(1)


iron studies(1) o iron (Fe) o total iron-binding capacity (TIBC) o transferrin receptor assay - soluble transferrin receptor (sTfR)

Blood tests: 

findings in iron deficiency anemia(1, 2, 5) o decreased  red blood cells (RBC)  mean corpuscular volume (MCV)  mean corpuscular hemoglobin concentration (MCHC)  reticulocyte count  iron (Fe)  ferritin  transferrin saturation o increased  total iron-binding capacity (TIBC)  free erythrocyte protoporphyrin (FEP) or zinc protoporphyrin (ZnPP)  platelets  soluble transferrin receptor comparison of complete blood count findings in pre-anemic and anemic phases(1) o latent phase (low iron and iron-binding capacity, reduced erythropoiesis, no anemia)  red blood cells microcytic and hypochromic  decreased mean corpuscular volume and mean hemoglobin content (MCH)  increased red blood cell distribution width (RDW) o frank anemia  decreased hematocrit and hemoglobin (< 11 g/dL [110 g/L])  white blood cells usually normal  thrombocytosis common  blood smear shows  microcytosis  hypochromia  anisocytosis  poikilocytosis  elliptocytes and cigar-shaped red cells in severe anemia  with coexisting folate deficiency  MCV may be normal  macrocytes and microcytic cells present o anemia may be poorly predictive of iron deficiency in toddlers  based on National Health and Nutrition Examination Survey (NHANES) 1988-1994  toddlers aged 12-35 months had iron deficiency prevalence 6%-18%  anemia as screening tool for iron deficiency showed  30% sensitivity


 29% positive predictive value Reference - Pediatrics 2005 Feb;115(2):315, commentary can be found in J Fam Pract 2005 Jun;54(6):496, Am Fam Physician 2005 Nov 1;72(9):1842, or in Pediatrics 2005 Nov;116(5):1258 normal laboratory values by age and gender (5) o normal hemoglobin and hematocrit levels 

Normal Hemoglobin and Hematocrit Levels by Age: Age Hemoglobin Hematocrit 1-3 days 18.5 g/dL (185 g/L) 56% 2 weeks 16.6 g/dL (166 g/L) 53% 1 month 13.9 g/dL (139 g/L) 44% 2 months 11.2 g/dL (112 g/L) 35% 6 months 12.6 g/dL (126 g/L) Not specified 6 months to 2 years 12 g/dL (120 g/L) 36% 2-6 years 12.5 g/dL (125 g/L) 37% 6-12 years 13.5 g/dL (135 g/L) 40% 12-18 years (males) 14.5 g/dL (145 g/L) 43% 12-18 years (females) 14 g/dL (140 g/L) 41%

o

o

 may be transiently lower with infection normal serum ferritin levels(1)  newborn – 6-400 ng/mL (13.5-898.8 pmol/L)  age 1-6 months – 6-410 ng/mL (13.5-921.2 pmol/L)  age 7 months to 5 years – 6-80 ng/mL (13.5-179.8 pmol/L)  age 6-10 years – 10-55 ng/mL (22.5-123.6 pmol/L)  age 10-19 years – 23-70 ng/mL (51.7-157.3 pmol/L)  ferritin is single best measure of body iron stores in children  may be increased with concomitant  infection  inflammation  chronic disorders  hepatic disorders  malignancy  elevated C-reactive protein and alpha(1)-acid glycoprotein both associated with elevated serum ferritin levels  based on calculations from data in 32 studies with 8,796 apparently healthy subjects evaluating the influence of the inflammatory markers C-reactive protein and alpha(1)-acid glycoprotein on serum ferritin levels  Reference - Am J Clin Nutr 2010 Sep;92(3):546 transferrin saturation(1)  age 1-5 years – 7%-44%


age 6-9 years – 17%-42% age 10-14 years – 11%-36% (1) o zinc protoporphyrin (free erythrocyte protoporphyrin) levels  substitution of zinc for iron during chelation with protoporphyrin during heme biosynthesis when insufficient iron available  levels increase with iron depletion  level affected by inflammation and chronic disease, but not by acute infection  normal values vary  whole blood erythrocyte protoporphyrin level ≥ 35 mcg/dL considered high (Am Fam Physician 2002 Oct 1;66(7):1217 )  normal values for zinc protoporphyrin levels may be affected by ethnic differences (level 2 [mid-level] evidence)  based on diagnostic cohort study with same reference standard not applied to all subjects  2,814 children aged 5-15 years from Cote d'Ivoire and Morocco were evaluated for iron deficiency  hemoglobin level used to define anemia in Cote d'Ivoire was 10 g/L (1 g/dL) lower than level used in Morocco  diagnostic cutoffs for zinc protoporphyrin levels in detecting iron deficiency and iron deficiency anemia were higher in Ivorian than Moroccan children  Reference - Am J Clin Nutr 2005 Mar;81(3):615 (1) o soluble transferrin receptor levels (in mg/L)  age 6-24 months – 1.37-2.85  age 2-6 years – 1.05-3.05  age 7-12 years – 1.16-2.72  age 13-17 years – 0.97-2.6  based on increase in transferrin receptor presentation by erythroblasts in iron deficiency transferrin receptor assay o may distinguish iron deficiency anemia from anemia of chronic disease o number of transferrin receptors increased in iron deficiency anemia and normal in anemia of chronic disease o serum transferrin receptor assay by enzyme-linked immunosorbent assay (ELISA) testing seems as reliable as bone marrow aspiration o Reference - BMJ 1999 Apr 10;318(7189):991 differentiating beta-thalassemia minor from iron deficiency anemia o simple blood tests may not adequately differentiate iron deficiency anemia and beta-thalassemia minor in the setting of microcytic anemia o several formulas or indices have been developed to attempt to help clinicians distinguish between these 2 conditions o findings strongly suggestive of beta-thalassemia minor include (level 2 [mid-level] evidence)  


o

o

o

England and Fraser index {MCV - RBC - (5 × Hb) - k} with value < 0  see DynaMed calculator for England Fraser Index for Differentiating Beta-thalassemia Trait from Iron-deficiency  Sirdah formula {MCV - RBC - 3 x Hb} with value < 27 findings suggestive of beta-thalassemia minor include (level 2 [mid-level] evidence) 2  Green and King index {(MCV × RDW)/(Hb × 100)} with value < 65 (or cutoff dependent on cell counting instrument used)  see DynaMed calculator for Green King Index for Differentiating Beta-thalassemia Trait from Iron-deficiency findings suggestive of iron deficiency anemia include (level 2 [mid-level] evidence)  Ricerca index {RDW/RBC} with value > 4.4 see Differentiating beta-thalassemia minor from iron deficiency anemia for details

Biopsy and pathology: 

bone marrow aspirate stained for iron is gold standard for iron deficiency in adult, but not useful in infants and small children because iron not stored as marrow hemosiderin(1)

Treatment Treatment overview: 

iron supplementation o oral iron supplementation usually first-line therapy  dosing - elemental iron 3-6 mg/kg/day in 3 divided doses for about 4 months  forms of oral iron include ferrous sulfate, ferrous fumarate, and ferrous gluconate  single-daily dosing and 3 times daily dosing appear to have similar efficacy for improving hemoglobin and ferritin levels in children with anemia (level 3 [lacking direct] evidence)  gastrointestinal (GI) side effects include  constipation - treat with laxatives, stool softeners, and adequate fluid intake  nausea and vomiting  diarrhea  dark-colored stools  abdominal distress  iron (III)-hydroxide polymaltose complex associated with fewer GI symptoms and well-absorbed o parenteral iron supplementation  indications


    

o

diet o o o

Diet:

gastrointestinal disease interfering with absorption or intake noncompliance with oral therapy intolerance to oral iron refractory bleeding due to chronic disease hemoglobin < 6 g/dL (60 g/L) with signs of poor perfusion in patient unable to be transfused (for example, refusal due to religious objections)  avoid intramuscular dosing if possible due to risk of local sarcomas, sterile abscesses, and skin discoloration  iron dextran (DexFerrum, INFeD) - 50 mg elemental iron per mL  give test dose prior to all therapeutic doses, dosing based on weight  risk of anaphylactic shock  sodium ferric gluconate (Ferrlecit) - 12.5 mg elemental iron per mL  used for patients on hemodialysis  1.5 mg/kg (up to 125 mg/dose) at or during hemodialysis for 8 sequential dialysis sessions  decreased risk of anaphylaxis compared to iron dextran  ferric carboxymaltose (Ferinject) approved in United Kingdom and 17 other European countries  possible adverse events include arthralgia, myalgia, fever, anaphylactic shock efficacy of iron supplementation  for children < 2-3 years old with iron deficiency anemia, effect of iron treatment on cognitive or psychomotor development is uncertain  for children > 2 years old with anemia, iron treatment may improve cognitive testing outcomes but not school achievement (level 2 [midlevel] evidence)  iron supplementation in children with iron deficiency but without anemia (level 2 [mid-level] evidence)  may improve symptoms of attention deficit hyperactivity disorder (ADHD)  may improve cognitive function in adolescent girls  iron supplementation (but not Helicobacter pylori eradication) improves anemia and iron deficiency in children with iron deficiency and Helicobacter pylori infection (level 3 [lacking direct] evidence)

increase dietary intake of iron-rich foods (such as red meat, poultry, fish) decrease intake of food products that decrease iron absorption vitamin C generally recommended to improve absorption (grade C recommendation [lacking direct evidence]) but evidence in children limited and inconsistent follow-up to evaluate response to treatment o hemoglobin level should increase by about 1 g/dL (10 g/L) every 2-3 weeks o ferritin level may take up to 4 months to return to normal


iron-rich foods include(3) o heme iron sources (highly bioavailable with limited influence from other dietary factors)  red meat  poultry  fish o non-heme iron sources (bioavailability strongly influenced by other dietary factors)  iron-fortified breads and cereals (iron content varies from 4.5-18 mg/serving)  lentils, beans  dark green vegetables (for example, spinach)  raisins, apricots, prunes factors associated with decreased iron absorption(2, 3) o vegetarian diet o calcium inhibits both heme and non-heme iron through variety of mechanisms o medications that increase gastric pH (for example, antacids, proton pump inhibitors, H2 blockers) o phytate-containing foods (for example, legumes, whole grains) o soybean protein has inhibitory effect independent of phytate mechanism o tannic acid from  tea  coffee  red wine vitamin C (ascorbic acid) (3) o vitamin C reported to improve absorption of non-heme iron o vitamin C generally recommended to improve absorption (grade C recommendation [lacking direct evidence]) but evidence in children limited and inconsistent  higher ascorbic acid content of orange juice not associated with increased iron absorption compared to apple juice when taken with identical meals (level 3 [lacking direct] evidence)  based on small randomized crossover trial without clinical outcomes  21 healthy children aged 3-6 years were randomized to orange vs. apple juices containing isotope-labelled ferrous sulfate with identical meals on one day and the alternate juice on the next day  comparing orange juice vs. apple juice  mean ascorbic acid intake 35.9 mg vs. 4.5 mg (p < 0.001)  median iron absorption was 7.78% vs. 7.17% (not significant)  Reference - Arch Pediatr Adolesc Med 2003 Dec;157(12):1232 , commentary can be found in Am Fam Physician 2004 Sep 1;70(5):948


iron absorption greater when supplement given to toddlers with juice rather than milk (level 3 [lacking direct] evidence)  based on small cohort study without clinical outcomes  10 infants aged 12-15 months were given 5 mg of stable isotope-labelled iron and 16 mg of ascorbic acid with cow's milk followed 2 hours later by 5 mg of differently labelled iron and 8 mg of ascorbic acid with apple juice (containing 42 mg of ascorbic acid)  mean iron absorption 13.7% with juice vs. 5.7% with cow's milk (p < 0.001)  Reference - Pediatr Res 1996 Jan;39(1):171

Medications: Oral iron supplementation: 

oral iron supplementation usually first-line therapy(1, 2, 3) o see Iron Preparations, Oral for prescribing information o general considerations  elemental iron is amount of iron in supplement available for absorption  absorption  absorbed in duodenum, absorption enhanced by gastric acidity  absorption best if given on empty stomach but may cause gastrointestinal (GI) discomfort  discomfort decreased with full stomach but absorption reduced  meat proteins and vitamin C increase non-heme iron absorption  avoid foods high in tannates, phytates, or medications that increase gastric pH decrease absorption if possible  time-release capsules not recommended o dosing - elemental iron 3-6 mg/kg/day in 3 divided doses for about 4 months o forms of oral iron include ferrous sulfate, ferrous fumarate, and ferrous gluconate  ferrous salts  ferrous fumarate (elemental iron 330 mg/g)  available in 100 mg (33 mg iron) chewable tablets as Feostat  ferrous sulfate (elemental iron 200 mg/g) Ferrous Sulfate Oral Solution: Dose Range (for 3-6 Formulation Dose Strength mg/kg/day) Fer-Gen-Sol 125 mg (25 mg 0.2-0.4 mL/kg 3 times


Ferrous Sulfate Oral Solution: Dose Range (for 3-6 Formulation Dose Strength mg/kg/day) Drops iron) per 5 mL daily 220 mg (44 mg 0.114-0.227 mL/kg 3 Elixir iron) per 5 mL times daily 300 mg (60 mg 0.083-0.167 mL/kg 3 Solution iron) per 5 mL times daily   

ferrous gluconate (elemental iron 120 mg/g) see Iron Preparations, Oral for details ferrous sulfate, gluconate, and fumarate have similar efficacy and tolerability for equal doses of elemental iron (Prescriber's Letter 2008 Aug;15(8):47)  iron (III)-hydroxide polymaltose complex associated with fewer GI symptoms and well absorbed  liquid iron preparations may be alternative in patients who have poor iron absorption because of poor dissolution of coating o GI side effects include  constipation – treat with laxatives, stool softeners, and adequate fluid intake  nausea and vomiting  diarrhea  dark-colored stools  abdominal distress recommended treatment for iron deficiency in young children (infants and toddlers) (grade C recommendation [lacking direct evidence]) o based on expert opinion o oral ferrous sulfate (3 mg/kg/day of elemental iron) o increase in hemoglobin > 1 g/dL after 4 weeks suggests diagnosis of iron deficiency o continue supplementation for 2 months after correction of anemia o recheck hemoglobin at end of treatment and 6 months later o Reference - J Fam Pract 2006 Jul;55(7):629 single-daily dosing and 3 times daily dosing appear to have similar efficacy for improving hemoglobin and ferritin levels in children with anemia (level 3 [lacking direct] evidence) o based on randomized trial without clinical outcomes o 557 children aged 6-24 months with hemoglobin 70-99 g/L (7-9.9 g/dL) were randomized to ferrous sulfate drops (40 mg elemental iron) once daily vs. 3 times daily for same total dose for 2 months o hemoglobin > 10 g/dL (100 g/L) achieved in 61% with once daily vs. 56% with 3 times daily dosing (not significant) o ferritin levels increased in both groups o no differences in adverse effects


o

Reference - Pediatrics 2001 Sep;108(3):613 , commentary can be found in J Fam Pract 2002 Jan;51(1):82 FDA ordered seizure of Tri-Med Laboratories ferrous sulfate drops for infants due to being unapproved and adulterated (FDA Press Release 2010 Oct 27)

Parenteral iron supplementation: 

 

indications(1, 2) o gastrointestinal disease interfering with absorption or intake o noncompliance with oral therapy o intolerance to oral iron o refractory bleeding due to chronic disease o hemoglobin (Hb) < 6 g/dL (60 g/L) with signs of poor perfusion in patient unable to be transfused (for example, refusal due to religious objections) avoid intramuscular dosing if possible due to risk of local sarcomas, sterile abscesses, and skin discoloration(1) formulations o iron dextran (DexFerrum, INFeD) - 50 mg elemental iron per mL  give test dose prior to all therapeutic doses  FDA notified healthcare providers of reports of anaphylactic-type reactions following parenteral administration of iron dextran injection (FDA MedWatch 2009 Oct 16)  dose by weight 

Weight-Based Dosing: Weight Formula 5-15 kg (11-33 [0.0442 × weight in kg × (12 g/dL - Hb)] + lbs) (0.26 × weight in kg) ≥ 15 kg (33 [0.0442 × weight in kg × (14.8 g/dL - Hb)] + lbs) (0.26 × weight in kg) Maximum Dose by Weight: Weight Maximum Dose < 5 kg (11 lbs) 25 mg of iron (0.5 mL) 5-9 kg (11-21 50 mg of iron (1 mL) lbs) ≥ 10 kg (22 lbs) 100 mg of iron (2 mL) 

o

low-molecular-weight iron dextran reported to have lower rate of anaphylaxis than high-molecular-weight iron dextran when IV iron is used (level 3 [lacking direct] evidence) (letter in N Engl J Med 2007 Jul 5;357(1):93)  see Iron Dextran for details sodium ferric gluconate (Ferrlecit) - 12.5 mg elemental iron per mL


indicated for hemodialysis patients with iron deficiency anemia on epoetin therapy  safety and efficacy not established in children < 6 years old  1.5 mg/kg (up to 125 mg/dose) at or during hemodialysis for 8 sequential dialysis sessions (2)  test dose not required (2)  decreased risk of anaphylaxis compared to iron dextran  see Sodium Ferric Gluconate for details o iron sucrose (Venofer) - 20 mg elemental iron per mL  indicated for use in dialysis patients receiving erythropoietin, and non-dialysis-depended chronic kidney disease (regardless of erythropoietin use), who have iron deficiency anemia  safety and efficacy not established in children < 18 years old  see Iron Sucrose for details o ferric carboxymaltose (Ferinject) approved in United Kingdom and 17 other European countries adverse events(1, 2) o arthralgia o myalgia o headache o fever o anaphylactic shock

Clinical effects of iron treatment for anemia: 

in infants < 2 years old with iron deficiency anemia, effect of iron treatment on cognitive development is uncertain o based on review of studies with mechanism of study selection not stated o review of 9 studies of iron treatment in children < 2 years old with anemia and 1 study of non-anemic children with iron deficiency o treatments included oral (medication and/or fortified formula or milk) and intramuscular iron therapy o definition of anemia varied between studies o iron therapy associated with significant improvement on Bayley scales compared to placebo in subgroup of 50 infants aged 12-18 months with iron deficiency anemia in 1 trial o no other studies showed benefit o Reference - J Nutr 2001 Feb;131(2S-2):649S in children < 3 years old with iron deficiency anemia, effect of iron treatment on psychomotor development is uncertain o based on Cochrane review o systematic review of 5 randomized trials evaluating effects of iron therapy (oral or intramuscular) on psychomotor development in 180 children < 3 years old with iron deficiency anemia o no significant differences in psychomotor development measures at 5-11 days in pooled analysis of 4 trials


o

nonsignificant trend toward benefit in psychomotor development after > 30 days in analysis of 2 trials with 160 children o Reference - systematic review last updated 2001 Feb 26 (Cochrane Library 2001 Issue 2:CD001444) for children > 2 years old with anemia, iron treatment may improve cognitive testing outcomes but not school achievement (level 2 [mid-level] evidence) o based on review of studies with mechanism of study selection not stated o review of 9 randomized trials of iron treatment in children > 2 years old o improvement in cognitive outcomes shown clearly in 4 trials, considered likely in 3 trials and not shown in 2 trials o Reference - J Nutr 2001 Feb;131(2S-2):649S iron supplementation may improve nonverbal learning in children aged 6-11 years with iron deficiency anemia (level 2 [mid-level] evidence) o based on randomized trial with inadequate description of handling missing data o 321 children aged 6-11 years with iron deficiency were randomized to 4 groups and followed for 8.5 months  iron sulfate 50 mg orally daily for 4 days/week  DHA 420 mg/EPA 80 mg fatty acids in 2 capsules daily for 4 days/week  iron plus DHA/EPA  placebo o 90% completed cognitive testing but 99.3% included in analyses (inadequate description of imputation of missing data) o no significant difference in nonverbal or verbal learning scores overall o in subgroup of 66 children with anemia, iron supplementation associated with  improvement in nonverbal learning score  trend toward improvement in verbal learning score (p = 0.07) o Reference - Am J Clin Nutr 2012 Dec;96(6):1327 no randomized trials identified to evaluate iron supplementation in HIVinfected children ≤ 12 years old  o o

based on Cochrane review Reference - Cochrane Database Syst Rev 2009 Jan 21;(1):CD006736

Helicobacter pylori infection:  

see also Helicobacter pylori infection iron supplementation (but not H. pylori eradication) improves anemia and iron deficiency in children with iron deficiency and H. pylori infection (level 3 [lacking direct] evidence) o based on randomized trial without clinical outcomes


o

o

200 Bangladeshi children aged 2-5 years with iron deficiency or iron deficiency anemia and H. pylori infection (by positive urea breath test) were randomized to 1 of 4 groups  2-week anti-H. pylori therapy (amoxicillin, clarithromycin, and omeprazole) plus 90-day oral ferrous sulfate therapy  2-week anti-H. pylori therapy alone  90-day oral ferrous sulfate alone  placebo iron supplementation associated with improved iron deficiency anemia, iron deficiency, and anemia compared to H. pylori therapy alone and placebo (p < 0.0001) Rates of Treatment Failure: Anti-H. Pylori Iron Anti-H. Pylori Placebo Therapy plus Iron Alone Therapy Alone For iron deficiency anemia For iron deficiency For anemia

o

11%

0%

33%

45%

19%

7%

65%

78%

34%

27%

65%

78%

Reference - Gastroenterology 2008 Nov;135(5):1534 H. pylori eradication does not appear to improve iron deficiency or mild anemia in children (level 2 [mid-level] evidence) o based on randomized trial without blinding o 219 children aged 7-11 years in rural Alaska with iron deficiency and H. pylori infection were randomized (by household) to open-label H. pylori eradication therapy vs. no eradication therapy (control)  iron deficiency defined as serum ferritin < 10 mcg/L (22.5 pmol/L)  H. pylori infection determined by 13-C urea breath test  H. pylori eradication therapy given for 2 weeks, repeated at 2 months if persistent H. pylori infection  all children given iron supplementation for 6 weeks o comparing H. pylori eradication therapy vs. no eradication therapy  iron deficiency in 32% vs. 39% at 2 months (not significant)  iron deficiency in 65% vs. 72% at 14 months (not significant)  anemia (Hb < 11.5 mg/dL [115 g/L]) in 22% vs. 14% at 14 months (not significant) o Reference - J Infect Dis 2006 Feb 15;193(4):537, commentary can be found in J Infect Dis 2006 Sep 1;194(5):714 o comparing H. pylori eradication therapy vs. no eradication therapy at 40month follow-up in 80.4% of children  iron deficiency in 52% vs. 58% (adjusted relative risk 0.92, not significant)


 

o

o

anemia in 12% vs. 21% (adjusted relative risk 0.54, not significant) iron deficiency anemia in 5% vs. 19% (adjusted relative risk 0.25, p < 0.05) children with vs. without H. pylori infection at 40 months had no difference in prevalence reduction of  iron deficiency  anemia  iron deficiency anemia Reference - J Infect Dis 2009 Mar 1;199(5):652

Iron deficiency without anemia: 

iron supplementation may improve symptoms of attention deficit hyperactivity disorder (ADHD) in children with low iron stores (level 2 [mid-level] evidence) o based on small randomized trial o 23 non-anemic children aged 5-8 years with ADHD and serum ferritin level < 30 ng/mL (67.4 pmol/L) were randomized to ferrous sulfate 80 mg/day orally vs. placebo for 12 weeks o 1 child discontinued due to constipation, 1 child lost to follow-up o iron supplementation associated with  Clinical Global Impression Severity much or very much improved (p < 0.01)  decrease in ADHD rating scale total score (p < 0.008)  trend toward improvement on Conners' Parent (p = 0.055) and Teacher (p = 0.076) Rating Scales o Reference - Pediatr Neurol 2008 Jan;38(1):20, commentary can be found in Pediatr Neurol 2008 Jul;39(1):73 iron supplementation may improve cognitive function in non-anemic adolescent girls with iron deficiency (level 2 [mid-level] evidence) o based on randomized trial without intention-to-treat analysis o 81 high school girls with iron deficiency (ferritin < 12 ng/mL [27 pmol/L]) but no anemia were randomized to ferrous sulfate 650 mg vs. placebo orally twice daily for 8 weeks o treated girls performed better than controls on verbal learning and memory test o no significant differences in several other cognitive tests o Reference - Lancet 1996 Oct 12;348(9033):992, editorial can be found in Lancet 1996 Oct 12;348(9033):973

Other management: 

child development support program for children with iron deficiency anemia may improve social-emotional responsiveness (level 2 [mid-level] evidence) o based on randomized trial with allocation concealment not stated o 277 children aged 6 or 12 months from Chile were randomized to intervention visits (weekly visits with program to support child


o o o

o

development) vs. surveillance only visits (weekly visit to record data) for 12 months 157 children had iron deficiency anemia at time of enrollment and 130 children were clearly not anemic infants with iron deficiency anemia had significantly lower ratings in positive social-emotional responsiveness at baseline social-emotional responsiveness score changes  were similar between the children in the intervention group with and without iron deficiency and the surveillance only group that were not anemic  were significantly lower in children with iron deficiency anemia who had surveillance only compared to all 3 other groups Reference - Pediatrics 2010 Oct;126(4):e884

Follow-up: 

evaluation of response to treatment (1) o reticulocytosis expected in 48-72 hours (2) o hemoglobin level 1 g/dL (10 g/L) increase should occur every 2-3 weeks (2) o ferritin level may take up to 4 months to return to normal for oral iron therapy check hemoglobin level after 1-month trial(2) o if response is adequate (1-2 g/dL [10-20 g/L] increase in hemoglobin level)  continue iron therapy  recheck hemoglobin level in 2-3 months o if response is inadequate consider  malabsorption  ongoing blood loss  unknown lesion  noncompliance  consider parenteral iron therapy if inadequate response to oral treatment

Prognosis  

resolution expected with appropriate treatment iron deficiency in infancy associated with lower cognitive scores in young adulthood, especially among poorer children (level 2 [mid-level] evidence) o based on prospective cohort study with high loss to follow-up o 185 healthy infants enrolled at age 12-23 months in urban community in Costa Rica were evaluated at ages 5, 11-14, 15-17, and 19 years o follow-up evaluations completed in 65% at age 19 years o for children in middle socioeconomic strata  iron deficiency associated with 8-9 point lower cognitive scores consistently over time  comparing children with vs. without iron deficiency  mean cognitive scores 101.2 vs. 109.3 in infancy  mean cognitive scores 98.2 vs. 107.6 at age 19 years


o

o o

for children in lower socioeconomic strata  iron deficiency associated with 10 point lower cognitive score in infancy (93.1 vs. 102.8)  decline faster in children with iron deficiency and reached 25 points at age 19 years (70.4 vs. 95.3) Reference - Arch Pediatr Adolesc Med 2006 Nov;160(11):1108 earlier analysis of same study showed cognitive and behavioral deficits > 10 years after treatment in 166 children from original cohort (Pediatrics 2000 Apr;105(4):E51 )

iron deficiency anemia associated with poorer object permanence and shortterm memory in infants o based on cohort study of 28 infants (aged 9 months) with iron deficiency anemia compared to 49 healthy infants o cognitive testing completed at 9 months and 12 months o poor socioemotional scores in infants with anemia associated with decreased cognitive scores o Reference - Pediatrics 2010 Aug;126(2):e427

Prevention and Screening Prevention: American Academy of Pediatrics clinical report: 

American Academy of Pediatrics (AAP) recommendations for diagnosis and prevention of iron deficiency and iron deficiency anemia in infants and children (03 years) o for term infants  if breastfed (exclusive or partial) - iron 1 mg/kg/day liquid oral supplement beginning at 4 months and continued until complementary iron-containing foods are started  if formula-fed  iron needs usually met with standard infant formula (iron content 10-12 mg/L) and iron-containing foods starting after 4-6 months  whole milk not recommended before age 12 months  at age 6-12 months - iron liquid oral supplement if iron needs (11 mg/day) not met by diet o for preterm infants  all should receive ≥ 2 mg/kg/day until age 12 months  if breastfed - iron 2 mg/kg/day supplement beginning at 1 month until using iron-fortified formula or eating iron-containing food  exception - no supplementation for infants with iron load from packed red blood cells via several transfusions


o

o

o

o o

for children aged 1-3 years - iron supplement if iron needs (7 mg/day) not met by food rich in iron and vitamin C (liquid supplement if aged 12-36 months or chewable multivitamin if ≥ 3 years old) universal anemia screening at 12 months recommended  determine hemoglobin levels  assess risk factors including  low socioeconomic status (especially Mexican American descent)  history of prematurity or low birth weight  exposure to lead  breastfeeding exclusively beyond 4 months without iron supplement or weaning to whole milk or inadequate iron rich foods  feeding problems  poor growth  inadequate nutrition  additional screening at ages 1-3 years if at risk, including inadequate dietary iron intake if hemoglobin < 11 mg/dL at 12 months  evaluate for iron deficiency anemia  additional testing may include  serum ferritin  serum C-reactive protein level  reticulocyte hemoglobin concentration  if mild anemia (hemoglobin 10-11 mg/dL) - an alternative approach is empiric iron supplementation and diagnosis of iron deficiency anemia if hemoglobin level increases by > 1 mg/dL after 1 month  if anemia or iron deficiency confirmed, closely monitor and document adequate treatment AAP supports development of transferrin receptor 1 assay standards for use in infants and children Reference - AAP Clinical Report on diagnosis and prevention of iron deficiency and iron deficiency anemia in infants and young children (0-3 years of age) (Pediatrics 2010 Nov;126(5):1040 PDF or at National Guideline Clearinghouse 2011 Jun 13:25643)

Dietary issues:  

minimum iron requirement is ≥ 10 mg/day(1) infant formulas should be iron-fortified o based on American Academy of Pediatrics (AAP) statement o Reference - Pediatrics 1999 Jul;104(1):119 , commentary can be found in Pediatrics 2000 Nov;106(5):1166 o commentary recommending iron-fortified vitamin preparations to replace recommendation for anemia screening at age 1-2 years can be found in Pediatrics 2000 Jun;105(6):1370 (Pediatric Notes 2000 Jul 6;24(27):105)


o

changing to iron supplemented formula milk from unmodified cow's milk may prevent iron deficiency anemia and reduce decline in psychomotor development in inner city infants (level 2 [mid-level] evidence)  based on randomized trial without blinding  100 infants aged 5.7-8.6 months whose mothers had already elected to use unmodified cow's milk as infant's milk source were randomized to change to iron supplemented formula milk vs. continue with unmodified cow's milk until age 18 months  85 infants completed trial  comparing formula vs. cow's milk  anemia (defined as hemoglobin < 11 mg/dL [110 g/L]) at age 18 months in 2% vs. 33% (p < 0.001, NNT 4)  mean decrease in psychomotor development scores from enrollment to age 24 months was 9.3 points vs. 14.7 points (p < 0.02)  Reference - BMJ 1999 Mar 13;318(7185):693 , correction can be found in BMJ 2000 Jul 1;321(7252):23  editorial suggests that results are inconclusive (BMJ 1999 Mar 13;318(7185):697 in J Watch 1999 May 1;19(9):73) o iron-fortified infant formula may be associated with poorer developmental outcomes at 10 years in infants with high hemoglobin levels (level 2 [mid-level] evidence)  based on long-term follow-up of randomized trial  835 healthy full-term infants randomized to iron-fortified infant formula (mean iron 12.7 mg/L) vs. low-iron infant formula (mean iron 2.3 mg/L) from 6-12 months  473 (57%) assessed at 10 years  iron-fortified infant formula associated with worse developmental outcomes at 10 years in terms of spatial memory and visual-motor integration, IQ, arithmetic achievement, visual perception, and motor coordination  iron-fortified infant formula (compared to low-iron infant formula) associated with  worse outcomes in infants with high hemoglobin levels (> 12.8 g/dL) at 6 months  better outcomes in infants with low hemoglobin levels (< 10.5 g/dL) at 6 months  Reference - Arch Pediatr Adolesc Med 2012 Mar;166(3):208 introduce complementary foods at age 6 months(1, 3) o meat better source of iron than unfortified plant foods o iron-rich foods include  meat (heme iron)  iron-fortified breads and cereals (non-heme iron)  kidney, lima, navy, black, and pinto beans (non-heme iron)  dark green vegetables such as spinach (non-heme iron)  raisins, apricots, prunes


micronutrient-fortified milk and cereal food associated with increased hemoglobin levels and reduced anemia in children up to age 3 years in developing countries (level 3 [lacking direct] evidence) o based on systematic review without clinical outcomes o systematic review of 18 randomized trials evaluating micronutrient-fortified milk or cereal food compared to nonfortified food in 5,468 children aged 6 months to 5 years o most trials had poor reporting of randomization methods, unclear allocation concealment, and/or selective reporting o iron plus multimicronutrient fortification of milk or cereal associated with  reduced risk of anemia by 57% in analysis of 6 trials  risk ratio 0.5 (95% CI 0.33-0.75)  NNT 5-12 with 34% response rate in control group  increased hemoglobin levels (weighted mean difference 0.87 g/dL, 95% CI 0.57-1.16) in analysis of 13 trials, results limited by heterogeneity  increased retinol levels (weighted mean difference 3.7 mcg/dL, 95% CI 1.3-6.1) in analysis of 4 trials  no significant differences in zinc serum levels in 5 trials  conflicting evidence on growth, functional measures, and morbidity in analysis of all 18 trials o Reference - BMC Public Health 2012 Jul 6;12:506

home fortification of foods with multiple micronutrient powders reduces incidence of anemia and iron deficiency in children aged 2-24 months in low income countries (level 3 [lacking direct] evidence) o based on Cochrane review without clinical outcomes o systematic review of 8 randomized trials evaluating multiple micronutrient powders consumed with food at home by children aged 6-23 months o all trials performed in low income countries in Asia, Africa, and Caribbean o trials lasted 2-12 months o trials included children aged 6-36 months, analyses used data only for children < 24 months old when possible o micronutrient powders contained 5-15 nutrients (all included at least iron, zinc, and vitamin A) o comparing micronutrient powders to placebo or no intervention, micronutrient powders associated with  lower incidence of anemia in analysis of 6 trials with 1,447 children  risk ratio (RR) 0.69 (95% CI 0.6-0.78)  NNT 5-8 with 60% anemia in placebo or no intervention group  lower incidence of iron deficiency in analysis of 4 trials with 586 children  RR 0.49 (95% CI 0.35-0.67)  NNT 4-7 with 48% iron deficiency in placebo or no intervention group


o

o o 

comparing micronutrient powders to iron supplementation, no significant difference in  incidence of anemia in 1 trial with 145 children  hemoglobin levels in analysis of 2 trials with 278 children, analysis limited by significant heterogeneity too few reports of side effects and morbidity (including malaria) to draw conclusions Reference - Cochrane Database Syst Rev 2011 Sep 7;(9):CD008959

fortified flour with sodium iron edetic acid (NaFeEDTA) iron may reduce prevalence of iron deficiency anemia in children in Kenya (level 2 [mid-level] evidence) o based on randomized trial with allocation concealment not stated o 516 children aged 3-8 years in Kenya were randomized to porridge 5 times weekly for 5 months made with whole maize flour served in 1 of 4 ways  unfortified  fortified with high-dose NaFeEDTA (56 mg/kg)  fortified with low-dose NaFeEDTA (28 mg/kg)  fortified with electrolytic iron (56 mg/kg) o anemia defined as hemoglobin  < 11 g/dL (110 g/L) in children < 5 years old  < 11.5 g/dL (115 g/L) in children > 5 years old o iron deficiency defined as plasma ferritin  < 12 mcg/L (27 pmol/L) in children < 5 years old  < 15 mcg/L (33.7 pmol/L) in children > 5 years old o prevalence of iron deficiency anemia by group  10.2% with unfortified flour  1.7% with fortified high-dose NaFeEDTA flour (NNT 12)  8.6% with fortified low-dose NaFeEDTA flour (not significant)  21.3% with fortified electrolytic iron flour (NNH 9) o fortified flour was supplemented with nutritional mix containing vitamin A, thiamine, riboflavin, and niacin o Reference - Lancet 2007 May 26;369(9575):1799, editorial can be found in Lancet 2007 May 26;369(9575):1766 fortified rice may reduce iron deficiency in school children in India (level 2 [mid-level] evidence) o based on randomized trial with allocation concealment not stated o 184 children aged 6-13 years were randomized to rice-based lunch fortified with 20 mg Fe as micronized ground ferric pyrophosphate vs. unfortified control meal for 7 months o all children had deworming at baseline and 3.5 months o comparing fortified rice vs. control  iron deficiency in  78% vs. 79% at baseline  25% vs. 49% at 7 months (NNT 4)  iron deficiency anemia in  30% vs. 28% at baseline


o 

 15% vs. 27% at 7 months (NNT 9) Reference - Am J Clin Nutr 2006 Oct;84(4):822

office-based intervention may not decrease iron depletion but may decrease bottle use among infants (level 3 [lacking direct] evidence) o based on randomized trial without clinical outcomes o 251 healthy infants aged 9 months randomized to parental intervention (counseling at 9- and 15-month visits on risk of continued bottle-feeding) vs. control (standard care) o comparing intervention vs. control at 2 years  iron depletion in 12% vs. 17% (not significant)  bottle use during day in 15% vs. 40% (p = 0.0004)  bottle use at night in 3% vs. 10% (p = 0.05)  age when cup use started 9.4 months vs. 11 months (p = 0.001) o Reference - Pediatrics 2010 Aug;126(2):e343

Iron supplementation: Infants: 

United States Preventive Services Task Force (USPSTF) 2006 recommendations for iron supplementation in children(4) o routine iron supplementation recommended for asymptomatic infants aged 6-12 months who are at increased risk for iron deficiency anemia (USPSTF Grade B recommendation) which includes those who are  recent immigrants  preterm infants  low-birth-weight infants  among female adolescents - fad dieters, obese adolescents o insufficient evidence to recommend for or against routine iron supplementation for asymptomatic children aged 6-12 months who are at average risk for iron deficiency anemia (USPSTF Grade I recommendation) iron supplementation dosing for infants at high-risk of developing iron deficiency(1) o preterm - 2 mg/kg/day beginning at age 2 months; consider additional 1 mg/kg/day for infants on preterm formula o very low birth weight - 4 mg/kg/day beginning at age 2 months iron supplementation associated with reduced risk of iron deficiency anemia in low-birth-weight or premature infants (level 2 [mid-level] evidence) o based on systematic review of trials without blinding o systematic review of 15 studies (10 randomized trials) evaluating iron supplementation or iron-fortified formula in infants < 2,500 g at birth or < 35 weeks gestational age o iron supplementation started 2 weeks to 3 months after birth and continued for 1 week to 18 months o no meta-analysis performed due to heterogeneity of dosing and treatment duration across studies


o

o

o o

oral iron supplementation associated with significant reduction in risk of iron deficiency anemia or iron deficiency compared to control (placebo or no intervention) in 4 trials with 434 infants no significant difference in growth parameters (length, height, weight, and head circumference) comparing iron supplementation to placebo in 5 trials with 476 infants insufficient evidence to assess effects of iron supplementation on neurologic development Reference - BMC Pediatr 2012 Jul 16;12(1):99 PDF

early iron supplementation in extremely low-birth-weight infants may reduce blood transfusions after day 14 (level 2 [mid-level] evidence) o based on randomized trial with high loss to follow-up and without intentionto-treat analysis o 204 infants with birth weight < 1,301 g were stratified by need for transfusion within first 7 days of life and randomized to early vs. late enteral iron supplementation of milk feeds  early iron supplementation  ferrous sulfate 2 mg/kg/day as soon as 100 mL/kg/day of enteral feedings tolerated  dose increased to 4 mg/kg/day for hematocrit < 0.3  late iron supplementation  ferrous sulfate 2 mg/kg/day started at 61 days of life  ferrous sulfate 4 mg/kg/day started at any time during study for diagnosis of iron deficiency, defined as any of  ferritin < 12 mcg/L (27 pmol/L)  transferrin saturation < 17%  relative increase in absolute reticulocyte count by 50% 1 week after onset of iron supplementation o no erythropoietin given o 133 infants (65%) completed study and were analyzed o comparing early vs. late iron  iron deficiency in 14.7% vs. 24.6% based on ferritin or transferrin saturation levels (not significant)  transfusion after day 14 in 43% vs. 68% (p = 0.0052, NNT 4) o Reference - Pediatrics 2000 Oct;106(4):700

daily iron supplementation may decrease risk of iron deficiency anemia in marginally low-birth-weight infants (level 2 [mid-level] evidence) o based on randomized trial with low adherence o 285 marginally low-birth-weight infants (2,000-2,500 g) randomized to iron supplement 2 mg/kg vs. 1 mg/kg vs. placebo daily between ages 6 weeks and 6 months o 22% had poor compliance o iron supplementation associated with lower incidence of iron deficiency (p < 0.001) and iron deficiency anemia (p = 0.004)


o

o o 

2 mg/kg supplement associated with significantly higher blood concentrations of hemoglobin and ferritin than placebo and 1 mg/kg supplementation no significant differences in growth rates Reference - Pediatrics 2010 Oct;126(4):e874

iron supplementation from age 4-6 months may reduce incidence of iron deficiency anemia at age 9 months in breastfed infants in at-risk population (level 2 [mid-level] evidence) o based on randomized trial with allocation concealment not stated o 101 Swedish and 131 Honduran term infants aged 4 months who were breastfed exclusively to age 6 months and partially to age 9 months were randomized to 1 of 3 treatment groups  iron supplementation 1 mg/kg/day from age 4-9 months  placebo from 4-6 months followed by iron supplementation from age 6-9 months  placebo from age 4-9 months o iron deficiency anemia in 9% of supplemented vs. 29% of controls (NNT 5) in Honduras o no significant differences in Swedish children where prevalence of iron deficiency anemia was < 3% o Reference - J Pediatr 2001 May;138(5):679 o in this trial, iron reduced diarrhea in infants with initial hemoglobin < 11 g/dL (110 g/L) but increased diarrhea in infants with initial hemoglobin > 11 g/dL (110 g/L), possible negative effect on short-term growth during study, but no long-term follow-up done (J Nutr 2002 Nov;132(11):3249 PDF) addition of iron to multivitamins at age 6 months may not prevent anemia or iron deficiency at age 9-12 months (level 2 [mid-level] evidence) o based on randomized trial with high loss to follow-up o 376 infants aged 5-7 months presenting for 6-month well-child visit were randomized to multivitamin drops with vs. without elemental iron 10 mg as 1 mL orally daily for 3 months o 284 infants (75%) had lab tests at age 9-12 months o comparing multivitamin drops with vs. without elemental iron, no significant differences in  anemia (defined as hemoglobin < 11 g/dL [110 g/L]) in 22% vs. 19%  mean hemoglobin 11.7 g/dL (117 g/L) vs. 11.7 g/dL (117 g/L)  other hematologic indices  iron status measures o Reference - Pediatrics 2004 Jul;114(1):86 , commentary can be found in Am Fam Physician 2004 Nov 1;70(9):1762 iron supplementation from age 1-6 months may improve visual acuity and psychomotor development at age 12-18 months (level 2 [mid-level] evidence) o based on randomized trial with high dropout rate o 77 term, exclusively breastfed infants randomized to ferrous sulfate supplementation (elemental iron 7.5 mg/day) vs. placebo from age 1-6


o o

o  

months and were followed to age 12 months for blood and developmental testing follow-up for blood testing in 57% at age 12 months and developmental assessment in 60% at age 12-18 months (mean age 13 months) iron supplementation associated with  nonsignificant trend toward improved visual acuity (p = 0.07)  improved visual acuity in subgroup analysis excluding noncompliers (p < 0.05)  higher Bayley psychomotor developmental index scores (100 vs. 93, p < 0.05)  higher mean hemoglobin level and mean corpuscular volume (p < 0.05)  no significant differences in mental developmental index Reference - J Pediatr 2003 Nov;143(5):582, editorial can be found in J Pediatr 2003 Nov;143(5):554

iron supplementation not associated with significant differences in growth or hematologic outcomes in exclusively breastfed infants (level 2 [mid-level] evidence) o based on small randomized trial o 79 exclusively breastfed healthy infants aged 4 months were randomized to oral iron supplementation 1 mg/kg/day vs. 7 mg/kg weekly vs. no supplementation for 3 months o no significant differences in iron deficiency, iron deficiency anemia, weight, height, or head circumference o Reference - J Pediatr Hematol Oncol 2004 May;26(5):284 in J Fam Pract 2005 Dec;54(12):1089 o DynaMed commentary -- study tended toward benefit with iron 1 mg/kg daily or iron 7 mg/kg weekly and sample size too small to exclude benefits addition of Sprinkles micronutrient powder to caregiver education may decrease anemia and iron deficiency in infants in Cambodia (level 2 [mid-level] evidence) o based on cluster-randomized trial without placebo control or intention-totreat analysis o 20 healthcare center areas with 1,071 infants aged 6-7 months randomized to micronutrient Sprinkles daily vs. no Sprinkles for 6 months and followed up to 18 months o caregivers of all infants received education emphasizing increased consumption of animal-source foods o at baseline 84% had anemia (hemoglobin < 11 g/dL) and 11% had iron deficiency (ferritin < 12 ng/mL) o 5% were lost to follow-up at 6 months (6% at 18 months) and were excluded from analyses o comparing Sprinkles vs. no Sprinkles  anemia at 6 months in 66.7% vs. 84.7% (p = 0.001, NNT 6)  anemia at 18 months in 49.4% vs. 56.7% (p = 0.08)


o o o

o

moderate anemia (hemoglobin < 10 g/dL) at 6 months in 21.5% vs. 47.3% (p < 0.001, NNT 4)  iron deficiency at 6 months in 19% vs. 42.9% (p < 0.001, NNT 5) no significant differences at 18 months in moderate anemia or iron deficiency no significant differences at 6 or 18 months in zinc deficiency or vitamin A deficiency increase in iron deficiency from baseline to 6 months in both groups attributed to increase in iron requirements in growing infants with inadequate nonmilk iron nutrition sources Reference - Arch Pediatr Adolesc Med 2012 Sep 1;166(9):842

Children and adolescents: 

iron supplementation may be associated with slightly improved language development in preschool children (level 2 [mid-level] evidence) o based on randomized trial with high loss to follow-up o 684 children aged 6-59 months in Zanzibar randomized by household to iron vs. placebo and randomized by child to antihelminthic treatment with mebendazole were assessed for development of language and motor skills o 359 children (52%) eligible for language assessment at 12 months o iron therapy associated with improvement of questionable clinical significance in  language development  motor development in children with severe anemia only o no significant improvement in language or motor development associated with mebendazole o Reference - BMJ 2001 Dec 15;323(7326):1389 , editorial can be found in BMJ 2001 Dec 15;323(7326):1377 iron supplementation does not appear to increase incidence of infectious illnesses in children (level 2 [mid-level] evidence) o based on systematic review of randomized trials with heterogeneity o systematic review of 28 randomized placebo-controlled trials evaluating effect of iron supplementation on incidence of infectious illnesses in 7,892 children o age ranges for specific trials included infants, aged 8-12 years, and many groups in between o trials had clinical, methodologic, and statistical heterogeneity, including lack of consistent definitions for individual clinical morbidities o no significant differences in incidence of infection or adverse events, except possible increase in diarrhea (equivalent to 1 additional diarrheal episode every 2 child-years) o Reference - BMJ 2002 Nov 16;325(7373):1142 , commentary can be found in BMJ 2002 Nov 16;325(7373):1125 , J Pediatr 2003 May;142(5):588 intermittent iron supplementation may decrease risk of anemia and iron deficiency in infants and children, but may be less effective than daily iron


supplementation (level 3 [lacking direct] evidence); very limited evidence suggests no differences in cognitive or growth outcomes (level 2 [mid-level] evidence) o based on Cochrane review of trials with limited evidence for clinical outcomes o systematic review of 33 randomized or quasi-randomized trials evaluating intermittent iron supplementation in 13,114 infants and children from 20 countries in Latin America, Africa, and Asia o 7 trials only assessed patients with anemia, 3 trials excluded patients with anemia, and other 23 trials anemia prevalence 15%-90% at baseline o 19 trials compared intermittent iron supplementation to no supplementation or placebo  intermittent iron supplementation associated with decreased risk of anemia in analysis of 10 trials with 1,824 patients  risk ratio (RR) 0.51 (95% CI 0.37-0.72)  NNT 4-7 with 51% risk of anemia in no intervention or placebo group  analysis limited by significant heterogeneity  intermittent iron supplementation associated with decreased risk of iron deficiency in analysis of 3 trials with 431 patients  RR 0.24 (95% CI 0.06-0.91)  NNT 2-19 with 60% risk of iron deficiency in no supplementation or placebo group  analysis for magnitude of effect limited by heterogeneity, but all 3 trials suggested similar direction of effect  no significant differences in  cognitive development (1 trial)  intelligence quotient, language development, and mathematics performance (1 trial)  height and weight outcomes (3 trials) o 21 trials compared intermittent to daily iron supplementation  intermittent iron supplementation associated with increased risk of anemia in analysis of 6 trials with 980 patients  RR 1.23 (95% CI 1.04-1.47)  NNH 8-96 with 26% risk of anemia in daily iron supplementation group  intermittent iron supplementation associated with increased risk of iron deficiency in 1 trial with 76 patients (32% vs. 8%, p = 0.022, NNH 4)  no significant differences in  intelligence quotient, language development, and mathematics performance (1 trial)  height and weight outcomes (3 trials) o Reference - Cochrane Database Syst Rev 2011 Dec 7;(12):CD009085 

iron supplementation in malaria-endemic areas


o

o

oral iron supplementation does not appear to increase risk of clinical malaria or death in areas with regular malaria surveillance and treatment (level 2 [mid-level] evidence)  based on Cochrane review with wide confidence intervals  systematic review of 71 individually- and cluster-randomized trials comparing oral iron supplementation (with or without folic acid) vs. placebo or no treatment in 45,353 children < 18 years old living in malaria-endemic areas  iron fortification was excluded  co-administration of antimalarials and/or antiparasitics was permitted  clinical malaria defined as fever (usually > 37.5 degrees C [99.5 degrees F]) and parasitemia  severe malaria defined as clinical malaria with high grade parasitemia or requiring hospital admission  wide confidence intervals for most outcomes cannot exclude clinically relevant benefit or harm of iron  comparing iron to placebo or no treatment, no significant differences in  clinical malaria in analysis of 13 trials with 5,351 children  severe malaria in analysis of 4 trials  mortality in analysis of 13 trials with 3,798 children in hyperor holo-endemic settings (risk difference +2.42 deaths per 1,000 children, 95% CI -6.47 to + 11.34 deaths per 1,000 children)  mortality in analysis of 9 trials with 4,846 children in hypoor meso-endemic settings (risk difference -1.24 deaths per 1,000 children, 95% CI -4.37 to + 1.88 deaths per 1,000 children)  comparing iron plus antimalarial to placebo in analysis of 3 trials with 728 patients  iron plus antimalarial associated with lower incidence of clinical malaria  risk ratio 0.54 (95% CI 0.43-0.67)  NNT 5-8 with 41% clinical malaria in placebo group  results limited by significant heterogeneity  no significant difference in mortality  iron plus folic acid supplementation associated with increased risk of clinical malaria in analysis of 6 trials conducted in areas without access to malaria prevention and treatment services (largest trial described below)  Reference - Cochrane Database Syst Rev 2011 Oct 5;(10):CD006589 routine iron and folic acid supplementation in preschool children with high rates of malaria may increase mortality (level 2 [mid-level] evidence)  based on subgroup analysis of randomized trial


    

22,959 households with 32,155 children aged 1-35 months in Pemba, Zanzibar (a small island in Tanzania, East Africa with 405 malariainfective bites per person per year) were randomized to 1 of 4 groups taking 1 tablet daily (half tablet if < 1 year old) of  iron 12.5 mg, folic acid 50 mcg, and zinc 10 mg  zinc 10 mg  iron 12.5 mg and folic acid 50 mcg  placebo all children given vitamin A 200,000 units (100,000 units if < 1 year old) every 6 months trial stopped early in groups taking iron and folic acid (with or without zinc) due to increased adverse events in interim analysis maximum duration of follow-up 18 months, mean follow-up 383 days zinc trial ongoing and not included in analysis analysis presented for 24,076 children in iron and folic acid groups and in placebo group (percent using child-years of follow-up as denominator)  4,393 children (18%) withdrew or moved out of area 

Outcomes: Iron/Folic Acid/Zinc 1.87% (p = 0.21, 1.8% (p = 0.35, NNH 400 but not NNH 555 but not significant) significant) 11.1% (p = 0.02, 10.6% (p = 0.16) NNH 71)

Placebo Iron/Folic Acid Deaths

1.62%

Hospital 9.7% admissions Hospital admission or 11.3% death Malariarelated 4.79% mortality 

12.3% (p = 0.09, NNH 100

12.9% (p = 0.01, NNH 62)

5.56% (p = 0.05, NNH 129)

5.57% (p = 0.04, NNH 129)

Reference - Lancet 2006 Jan 14;367(9505):133, correction can be found in Lancet 2006 Jan 28;367(9507):302, editorial can be found in Lancet 2006 Jan 14;367(9505):90, commentary can be found in Lancet 2006 Mar 11;367(9513):816 in similar trial in Nepal (low risk of malaria), supplements not associated with increased mortality (level 2 [mid-level] evidence)  based on randomized trial stopped early without preestablished stopping rule


25,940 children aged 1-36 months were randomized to 1 tab (1/2 tab if < 1 year old) of 1 of 4 daily oral supplements  iron 12.5 mg and folic acid 50 g  zinc 10 mg  iron 12.5 mg, folic acid 50 g, and zinc 10 mg  placebo  trial stopped early for iron and folic acid due to no findings of beneficial effect and no difference in mortality rate compared to placebo  zinc alone vs. placebo portion of trial in progress  no significant differences in mortality comparing iron/folic acid vs. iron/folic acid/zinc vs. placebo groups  no significant differences in rates of diarrhea, dysentery, or respiratory infections but data consistent with modest protective effects  Reference - Lancet 2006 Jan 14;367(9505):144 , editorial can be found in Lancet 2006 Jan 14;367(9505):90, commentary can be found in Lancet 2006 Mar 11;367(9513):816 o supervised weekly iron and folic acid supplementation may prevent anemia in healthy adolescent girls in Nepal and may be effective alternative to daily dosing (level 2 [mid-level] evidence)  based on randomized trial with allocation concealment not stated  209 healthy adolescent girls (median age 15 years) in Nepal were randomized to ferrous sulfate 350 mg and folic acid 1.5 mg once daily for 90-100 days vs. same drugs under supervision once weekly for 14 weeks vs. no drugs  prevalence of anemia (defined as hematocrit < 36%) at end of study  20% with daily supplementation (compared to 68.6% at baseline)  13.4% with supervised weekly supplementation (compared to 70.1% at baseline)  65.3% with no supplementation (compared to 68.1% at baseline)  Reference - Arch Pediatr Adolesc Med 2002 Feb;156(2):131 , editorial can be found in Arch Pediatr Adolesc Med 2002 Feb;156(2):128 powdered micronutrient formulation (Sprinkles) o powdered formulation (Sprinkles) may be an alternative iron formulation (ferrous fumarate) for prevention of childhood iron deficiency (PLoS Med 2005 Jan;2(1):e1 ), commentary can be found in PLoS Med 2005 Jul;2(7):e188 sale of Sprinkles micronutrient powder through community vendors may reduce anemia and iron deficiency in young children in resource-poor settings (level 2 [mid-level] evidence) o based on cluster-randomized trial without intention-to-treat analysis


o o o o

60 villages in Western Kenya randomized to sale of Sprinkles sachets by community vendors for children aged 6-35 months vs. no intervention 862 of 1,063 children had 12-month follow-up sale of Sprinkles through vendors associated with significant improvement in hemoglobin concentrations, iron deficiency, and vitamin A deficiency Reference - Am J Clin Nutr 2012 May;95(5):1223

Other prevention strategies: 

iron cooking pots for households in less-developed countries may be beneficial (level 2 [mid-level] evidence) o based on randomized trial without allocation concealment o 407 Ethiopian children aged 2-5 years were randomized by household to receive an iron vs. aluminum cooking pot and were assessed for growth and hemoglobin levels o after 1 year of being fed food cooked in pot, iron pot associated with  mean 1.3 g/dL (13 g/L) greater increase in hemoglobin concentration (p < 0.05)  mean 0.6 cm greater gain in length after adjustment for baseline length (p < 0.05)  mean 0.1 kg greater gain in weight after adjustment for baseline weight (not significant) o Reference - Lancet 1999 Feb 27;353(9154):712, editorial can be found in Lancet 1999 Feb 27;353(9154):690, commentary can be found in BMJ 1999 Nov 27;319(7222):1432 delayed umbilical cord clamping and umbilical cord milking o delayed umbilical clamping (2 minutes) can increase neonatal iron stores by about 33% (75 mg)(1) o in term infants  delayed cord clamping in term infants may increase infant ferritin and hemoglobin levels (level 3 [lacking direct] evidence) but with increased risk of jaundice requiring phototherapy (level 2 [mid-level] evidence)  based on Cochrane review without adequate statistical power to rule out clinically important difference for some outcomes  systematic review of 11 randomized trials comparing early vs. late cord clamping in 2,989 women and their term infants  comparing early cord clamping (within 60 seconds) vs. late cord clamping (≥ 1 minute after birth)  postpartum hemorrhage (≥ 500 mL) in 13.2% vs. 11.6% in analysis of 4 trials with 1,878 women (not significant)  severe postpartum hemorrhage (≥ 1,000 mL) in 2.5% vs. 3.1% in analysis of 4 trials with 1,684 women (not significant)


jaundice requiring phototherapy in 3.3% vs. 5.5% in analysis of 5 trials with 1,762 infants (p = 0.02, NNT 46 favoring early clamping)  late cord clamping associated with increased newborn hemoglobin levels (weighted mean difference 2.17 g/dL [21.7 g/L]) in analysis of 3 trials with 671 infants (p = 0.025), results limited by heterogeneity (p < 0.00001) and effect did not persist after 6 months  infant ferritin levels remained higher in late clamping group at 6 months in 1 trial with 315 infants (p = 0.0028)  Reference - Cochrane Database Syst Rev 2008 Apr 16;(2):CD004074 delaying cord clamping by 2 minutes following birth improves surrogate outcomes (anemia) in term infants (level 3 [lacking direct] evidence)  based on systematic review reporting surrogate outcomes  systematic review including 8 randomized trials and 7 nonrandomized trials with 1,912 infants born after at least 37 weeks gestation  comparing early cord clamping vs. late (delayed at least 2 minutes) cord clamping  87% vs. 47% anemia at age 2-3 months (p < 0.001, NNT 3) based on 2 trials with 119 infants  delayed cord clamping increased mean hematocrit at 6 hours, 24-48 hours and 5 days  no significant difference in mean hematocrit at 2-3 months in meta-analysis of 3 trials, but individual trials had inconsistent results  delayed cord clamping increased mean blood viscosity at 2-4 hours and 5 days  3.4% vs. 12.7% polycythemia at 7 hours (p = 0.02, NNH 10) based on 2 trials with 236 infants  1% vs. 5.7% polycythemia at 24-48 hours (p = 0.03, NNH 21) based on 7 trials with 403 infants  11.7% vs. 16.6% clinical jaundice at 24-48 hours (p = 0.05, NNH 20) based on 8 trials with 1,009 infants  1.9% vs. 3.4% phototherapy for jaundice (not significant) based on 3 trials with 699 infants  Reference - JAMA 2007 Mar 21;297(11):1241, editorial can be found in JAMA 2007 Mar 21;297(11):1257, commentary can be found in BMJ 2007 Aug 18;335(7615):312, Am Fam Physician 2008 Jan 15;77(2):231 delayed cord clamping by 3 minutes may reduce risk of iron deficiency at 4 months in term infants (level 3 [lacking direct] evidence)  based on randomized trial without clinical outcomes


o

400 term infants randomized to delayed umbilical cord clamping (≥ 3 minutes after delivery) vs. early umbilical cord clamping (≤ 10 seconds after delivery)  comparing delayed vs. early umbilical cord clamping at 4 months  iron deficiency in 0.6% vs. 5.7% (p = 0.01, NNT 20)  mean ferritin concentration 117 mcg/L vs. 81 mcg/L (p < 0.001)  mean hemoglobin concentration 113 g/L vs. 113 g/L (not significant)  anemia (defined as hemoglobin concentration < 105 g/L) in 1.25% vs. 1.2% (not significant)  anemia at 2 days in 1.2% for delayed groups vs. 6.3% for early group (p = 0.02, NNT 20)  no significant differences in postnatal respiratory symptoms, polycythemia, or hyperbilirubinemia requiring phototherapy  Reference - BMJ 2011 Nov 15;343:d7157 , editorial can be found in BMJ 2011 Nov 15;343:d7127  delaying cord clamping for 3 minutes recommended in resource poor settings (grade C recommendation [lacking direct evidence])  based on extrapolation from 4 randomized trials in industrialized settings  Reference - BMJ 2006 Nov 4;333(7575):954, commentary can be found in BMJ 2006 Nov 18;333(7577):1073 in preterm infants  delaying umbilical cord clamping by 30-180 seconds in preterm infants may decrease intraventricular hemorrhage, necrotizing enterocolitis, and rate of transfusion for anemia (level 2 [midlevel] evidence)  based on Cochrane review of trials with methodologic limitations  systematic review of 15 randomized trials comparing delayed vs. early umbilical cord clamping in 738 infants aged < 37 weeks gestation at birth  all trials had ≥ 1 of these limitations  inadequate or unclear allocation concealment  lack of or unclear blinding  range for delay in cord clamping was 30-180 seconds  delayed umbilical cord clamping associated with decreased  rate of transfusion for anemia in analysis of 7 trials with 392 infants  risk ratio (RR) 0.61 (95% CI 0.46-0.81)  NNT 6-15 with transfusion for anemia in 36% of early umbilical cord clamping group  intraventricular hemorrhage (all grades) in analysis of 10 trials with 539 infants


 

RR 0.59 (95% CI 0.41-0.85) NNT 9-34 with intraventricular hemorrhage in 20% of early umbilical cord clamping group  necrotizing enterocolitis in analysis of 5 trials with 241 infants  RR 0.62 (95% CI 0.43-0.9)  NNT 6-33 with necrotizing enterocolitis in 31% of early umbilical cord clamping group  no significant differences in  infant death (RR 0.63, 95% CI 0.31-1.28) in analysis of 13 trials with 668 infants  respiratory distress syndrome (RR 1.16, 95% CI 0.891.50) in analysis of 3 trials with 105 infants  grade 3 or 4 intraventricular hemorrhage (RR 0.68, 95% CI 0.23-1.96) in analysis of 6 trials with 305 infants  periventricular leukomalacia (RR 1.02, 95% CI 0.195.56) in analysis of 2 trials with 71 infants  Reference - Cochrane Database Syst Rev 2012 Aug 15;(8):CD003248 delayed cord clamping by 3 minutes associated with higher hemoglobin levels in preterm infants (level 3 [lacking direct] evidence)  based on randomized trial in 37 premature infants with gestational age 34 weeks to 36 weeks, 6 days and without clinical outcomes  Reference - Arch Dis Child Fetal Neonatal Ed 2008 Jan;93(1):F20 delayed cord clamping by 30 seconds may increase hematocrit at 4 hours in premature infants (level 3 [lacking direct] evidence)  based on randomized trial without clinical outcomes  33 premature infants born at gestational age 22-28 weeks randomized to delayed cord clamping at 30-45 seconds vs. early cord clamping at < 10 seconds  mean hematocrit at 4 hours 45% with delayed cord clamping vs. 40% with early cord clamping (p < 0.05)  no significant differences in hourly mean arterial blood pressure during first 12 hours; hematocrit at 2, 4 and 6 weeks; or transfusions  Reference - J Perinatol 2011 Apr;31 Suppl 1:S68

prenatal supplementation with iron or iron plus folic acid may not improve clinical outcomes (level 2 [mid-level] evidence) but may prevent anemia and iron deficiency at term (level 3 [lacking direct] evidence) o based on Cochrane review limited by heterogeneity


o

o o o

o o o

systematic review of 49 randomized or quasi-randomized trials comparing iron supplementation (with or without folic acid) vs. placebo or no treatment in 23,200 pregnant women most results limited by significant heterogeneity (p < 0.1) antenatal iron supplementation increased hemoglobin levels in maternal blood both antenatally and postnatally daily antenatal iron supplementation  associated with lower maternal risk of iron deficiency and irondeficiency anemia at term  greater risk of side effects and hemoconcentration (hemoglobin > 13 g/dL [130 g/L]) no evidence of differences between daily and weekly supplementation for outcome of gestational anemia no significant differences between groups for any clinical outcomes, but limited data reported Reference - Cochrane Database Syst Rev 2009 Oct 7;(4):CD004736

Screening: 

insufficient evidence to recommend for or against routine screening for iron deficiency anemia in asymptomatic children aged 6-12 months (USPSTF Grade I recommendation)(4) blood testing o hematocrit may not be an adequate screening test to detect iron deficiency in infants (level 2 [mid-level] evidence)  based on cohort study with possible selection bias  321 infants aged 9-18 months from low-income families had hematocrit and serum ferritin testing  selection and recruitment process unclear  infants with previously diagnosed iron deficiency anemia, acute illness, or on iron supplementation were excluded  anemia defined as hematocrit ≤ 33%  iron deficiency defined as ferritin < 10 mcg/L (22.5 pmol/L)  iron deficiency without anemia in 15.9%  iron deficiency anemia in 0%  non-iron deficiency anemia in 1.9%  Reference - J Fam Pract 1996 Mar;42(3):237, commentary can be found in J Fam Pract 1996 Sep;43(3):223 o anemia may be poorly predictive of iron deficiency  based on National Health and Nutrition Examination Survey (NHANES) 1988-1994  1,289 children aged 12-35 months were assessed for hemoglobin levels and iron status  anemia (defined as hemoglobin < 11 g/dL [110 g/L]) as predictor of iron deficiency had  30% sensitivity  29% positive predictive value


o

o

o

o

Reference - Pediatrics 2005 Feb;115(2):315, commentary can be found in J Fam Pract 2005 Jun;54(6):496, Am Fam Physician 2005 Nov 1;72(9):1842, or in Pediatrics 2005 Nov;116(5):1258 discussion recommending postponing hematocrit screening for iron deficiency anemia until second year of life can be found in Pediatrics 2001 Sep;108(3):e56 for positive anemia screen (by hemoglobin or hematocrit levels) in 1-yearold, cause is most likely iron deficiency; empiric iron therapy (3-6 mg elemental iron/kg/day) recommended (grade B recommendation [inconsistent or limited evidence]) and response confirms diagnosis (J Fam Pract 2005 Mar;54(3):272), correction can be found in J Fam Pract 2005 Dec;54(12):1095 reticulocyte hemoglobin content may be more sensitive but less specific than hemoglobin in screening for iron deficiency in healthy infants (level 2 [mid-level] evidence)  based on prospective cohort study with high loss to follow-up  202 healthy infants aged 9-12 months had blood testing for iron deficiency and anemia at baseline and after ≥ 3 months (but before second birthday)  follow-up completed in 73%  transferrin saturation < 10% used as reference standard for iron deficiency  iron deficiency detected in 11.4%  comparing reticulocyte hemoglobin content < 27.5 pg vs. hemoglobin < 11 g/dL (110 g/L) as screening tools  sensitivity 83% vs. 26%  specificity 72% vs. 95%  positive predictive value 27.5% vs. 40%  negative predictive value 97% vs. 91%  Reference - JAMA 2005 Aug 24-31;294(8):924 , commentary can be found in Am Fam Physician 2006 Jan 15;73(2):312 zinc protoporphyrin may be more sensitive but less specific than hemoglobin for detecting iron deficiency (level 2 [mid-level] evidence)  based on cross-sectional study with unreliable reference standard  180 children aged 1.5-5 years from low-income households in United States were screened for iron deficiency by zinc protoporphyrin and hemoglobin levels  reference standard was serum ferritin level but reliability strongly affected by recent illness  iron deficiency (defined as serum ferritin ≤ 15 mcg/L [33.7 pmol/L]) detected in 34.6%  comparing hemoglobin < 11.1 g/dL (111 g/L) (or < 11 g/dL [110 g/L] if < 2 years old) vs. zinc protoporphyrin > 69 mcmol/mol heme as screening tools  sensitivity 11% vs. 28%  specificity 94% vs. 72%  positive predictive value 50% vs. 34%


 Reference - Pediatrics 2006 Jul;118(1):224 dietary questions for screening young children have inconsistent results o dietary questions may be useful as screening tool for identifying children at low-risk for iron deficiency anemia (level 3 [lacking direct] evidence)  based on retrospective record review  305 African-American children aged 15-60 months on federal assistance were evaluated for dietary history and microcytic anemia as proxy for iron deficiency anemia  dietary deficiency defined as ≥ 1 of  < 5 servings each of meat, grains, vegetables, and fruit per week  > 16 ounces of milk/day  daily intake of fatty snacks, sweets, or > 16 ounces of soft drink  8% prevalence of microcytic anemia (hemoglobin < 11 g/dL [110 g/L], mean corpuscular volume < 73 femtoliters [fL])  12% prevalence of low hemoglobin (< 11 g/dL [110 g/L]) with or without microcytosis  dietary deficiency had 71% sensitivity, 79% specificity, and 97% negative predictive value for microcytic anemia  Reference - Pediatrics 1996 Dec;98(6 Pt 1):1138, commentary can be found in Pediatrics 2001 Sep;108(3):823 o dietary and health questions as a first-stage screening test were neither sensitive nor specific enough to predict iron deficiency anemia, anemia, or iron deficiency in inner-city children at high-risk for iron deficiency (level 2 [mid-level] evidence)  based on cross-sectional study with inadequate power  282 children aged 9-30 months had complete blood count and serum ferritin level and were assessed for dietary and health history by parental questionnaire  35% prevalence of anemia, defined as hemoglobin < 11 g/dL (110 g/L)  8% prevalence of iron deficiency, defined as ferritin < 10 mcg/L (22.5 pmol/L) or mean corpuscular volume < 70 fL  parental dietary and health questions not sufficiently sensitive nor specific to predict iron deficiency anemia or iron deficiency  Reference - Pediatrics 2000 Jun;105(6):1254, commentary can be found in Pediatrics 2001 Sep;108(3):823

urinary hepcidin level might detect iron deficiency in children before anemia (level 3 [lacking direct] evidence) o based on case-control study without validation o Reference - Ital J Pediatr 2011 Aug 11;37:37


case presentation of screening for iron deficiency anemia (including iron supplementation for children and pregnant women) can be found in Am Fam Physician 2009 May 15;79(10):897

Guidelines and Resources Guidelines: International guidelines: 

World Health Organization (WHO) position statement on weekly iron-folic acid supplementation (WIFS) in women of reproductive age for promoting optimal maternal and child health can be found at WHO 2009 English PDF Arabic PDF Chinese PDF French PDF Russian PDF Spanish PDF

WHO statement on iron supplementation of young children in regions where malaria transmission is intense and infectious disease highly prevalent can be found at WHO 2006 PDF

United States guidelines: 

Centers for Disease Control and Prevention (CDC) recommendation on prevention and control of iron deficiency can be found in MMWR Recomm Rep 1998 Apr 3;47(RR-3):1

United States Preventive Services Task Force (USPSTF) recommendation on screening for iron deficiency anemia (including iron supplementation for children and pregnant women) can be found at USPSTF 2006 May USPSTF 2006 PDF or at National Guideline Clearinghouse 2006 May 22:9274, supporting systematic review can be found at USPSTF Evidence Synthesis 2006 Apr 21 American Academy of Pediatrics (AAP) o recommendation on anemia screening (as part of periodicity schedule for preventive pediatric health care) can be found at AAP 2008 o clinical report on diagnosis and prevention of iron deficiency and iron deficiency anemia in infants and young children (0-3 years of age) can be found in Pediatrics 2010 Nov;126(5):1040 National Institutes of Health (NIH) dietary supplement fact sheet on iron can be found at NIH 2007 Aug 24

Institute of Medicine (IOM) dietary reference on intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc can be found in National Academies Press; 2001: 290

National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) clinical practice recommendations o on anemia in chronic kidney disease can be found in Am J Kidney Dis 2006 May;47(5 Suppl 3):S11 or at NKF KDOQI 2006 PDF, correction can be


o o o

found in Am J Kidney Dis 2006 Sep;48(3):518, summary can be found in Am J Health Syst Pharm 2007 Jul 1;64(13 Suppl 8):S8 on anemia in chronic kidney disease in transplant recipients can be found in Am J Kidney Dis 2006 May;47(5 Suppl 3):S109 on anemia in chronic kidney disease in children can be found in Am J Kidney Dis 2006 May;47(5 Suppl 3):S86 2007 update of hemoglobin target can be found at NKF KDOQI

United Kingdom guidelines: 

British Committee for Standards in Haematology (BCSH) guideline on laboratory diagnosis of functional iron deficiency can be found in Br J Haematol 2013 Jun;161(5):639

European guidelines: 

National Committee of Hematology (Comité Nacional de Hematología) guideline on diagnosis and treatment of iron deficiency anemia can be found in Arch Argent Pediatr 2009 Aug;107(4):353 [Spanish]

Australian and New Zealand guidelines: 

Royal Australasian College of Physicians (RACP) policy statement on iron deficiency in pre-school children can be found in J Paediatr Child Health 2007 JulAug;43(7-8):513

Review articles:      

review of nutritional iron deficiency can be found in Lancet 2007 Aug 11;370(9586):511, commentary can be found in Lancet 2007 Dec 8;370(9603):1906 review of testing iron status in microcytic anemia can be found in BMJ 2006 Oct 14;333(7572):791, commentary can be found in BMJ 2006 Nov 4;333(7575):972 review of IV iron in anemia can be found in Lancet 2007 May 5;369(9572):1502, commentary can be found in Lancet 2007 Aug 11;370(9586):481 review of management of common forms of anemia can be found in Am Fam Physician 1999 Mar 15;59(6):1598 review of evaluation of anemia in children can be found in Am Fam Physician 2010 Jun 15;81(12):1462 reviews on prevention of iron deficiency anemia o review of prevention of iron deficiency in infants and toddlers can be found in Am Fam Physician 2002 Oct 1;66(7):1217 o review of role of nutrition in infants and children in prevention of iron deficiency anemia can be found in CMAJ 2003 Jan 7;168(1):59 , commentary can be found in CMAJ 2003 Apr 29;168(9):1109 o editorial on neonatal prevention of iron deficiency can be found in BMJ 1996 Jan 20;312(7024):136 PDF


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review of iron homeostasis in the neonate can be found in Pediatrics 2009 Apr;123(4):1208 review of disorders of iron metabolism can be found in N Engl J Med 1999 Dec 23;341(26):1986, correction can be found in N Engl J Med 2000 Feb 3;342(5):364, commentary can be found in N Engl J Med 2000 Apr 27;342(17):1293 review of anemia in low-income and middle-income countries can be found in Lancet 2011 Dec 17;378(9809):2123 case presentation of child with rickets, iron deficiency anemia, and severe proteincalorie malnutrition can be found in N Engl J Med 2009 Jan 22;360(4):398, commentary can be found in N Engl J Med 2009 Apr 9;360(15):1572

MEDLINE search: 

to search MEDLINE for (Iron deficiency anemia children) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis

Patient Information   

handout on iron deficiency anemia from Patient UK handout on iron deficiency anemia from American Academy of Family Physicians or in Spanish handouts from National Anemia Action Council (NAAC) o handout on iron deficiency anemia in infants from NAAC o handout on iron deficiency anemia in school-aged children from NAAC o patient information on iron deficiency anemia in adolescents from NAAC handout on prevention of iron deficiency in infants and toddlers can be found in Am Fam Physician 2002 Oct 1;66(7):1227

Iron deficiency in children  
Iron deficiency in children  
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