The Impact and Management of Iron

Deficiency Anemia in Young Children

Ponpon Idjradinata
Department of Child Health School of
Medicine Universitas Padjadjaran

1
 Stage of iron deficiency
Stage 1 (Depletion) Stage 2 (Decreased Stage 3 (Decreased Hgb
transport) production)

Diminishing iron These iron stores are Overt anemia– the iron
stores – insufficient depleted further and begin supply is insufficient to
iron supply to impair Hgb synthesis maintain normal levels of
Hgb
Low serum ferritin
(< 10 ng/ml)
Low transferrin
saturation (< 10 %)

• High EP (≥ 35 mcg/dl of
whole blood)
• High RDW
Cut-off values for infants • Low MCV (< 70 µm3 [70 fL]
• Low Hgb (< 11 g/dL [110
g/L]

Dallman PR. West J Med 1981; 134:498 2

 •Indonesia (SKRT 2001) :
Developing countries: Anemia1 <5 years 48.1%; <1 year 55%)

< 5 years : 39%

5 – 14 years : 48%
50 % having IDA2
All women : 42%
Pregnant women : 52%

Iron deficiency: 2.5 times that of anemia1

Industrialized countries: IDA
1-2 years : 2% (USA)3
< 2 years : 4% (France, 29% ID)4
Non-pregnant women : 2-5%(USA, 9-11% ID)5
Female 11-18 years : (UK, 21% ID)6

1. WHO/UNICEF/UNU. Geneva: World Health Organization; 2001.

2. DeMaeyer E, Adiels-Tegman M. World Health Statistics Quarterly 1985; 38: 303–16.
3. CDC. MMWR Morb Mortal Wkly Rep 2002; 51: 897–99.
4. Hercberg S, Preziosi P, Galan P. Public Health Nutr 2001; 4: 537–45.
5. Scholl TO. Am J Clin Nutr 2005; 81: 1218S–22S.
3
6. Heath AL, Fairweather-Tait SJ. Best Pract Res Clin Haematol 2002; 15: 225–41.
 HCP: haem iron
Haem
transporterivalent Hephaestin Transferrin
iron

Dietary iron HCP Hepcidin

Ferroportin1

Non haem iron

Fe3+

Ascorbic acid
DCYTB
DCYTB:
duodenal DMT1 Ferritin
cytochrome b Fe2+

DMT1: divalent
metal ion
transporter 1
Duodenal enterocyte

Gut lumen Blood

Zimmermann MB, Hurrell RF. Lancet 2007; 370:511-20 4

 Physiology1,2
Normal Infants
During These stores are drawn
250 mg on during breastfeeding
gestation:

Breastmilk
0.15 mg
supplies:
per day
LBW infants do not store an
adequate amount of iron during
0.55 mg fetal life !!
Requirements:
per day

1. Fomon SJ. In Mosby-Year Book, 1993: p239–59.

2. Institute of Medicine. In National Academy Press, 2001: 290–393.
5
 CAUTION

Estimated daily iron requirements (mg/ day)

Urine, sweat, Growth Total
feces
Children (average) 0.5 0.6 1.1
• rapid growth1
• excessive early consumption of cow’s milk2

This group is more likely to develop iron deficiency. Therefore this group is particularly
likely to develop iron deficiency if there is additional iron loss or prolonged reduced
intake.

Increased blood loss

Infections with Trichuris trichiura3, Necator americanus4

•Hookworms afflict more than 700 million people in tropical and
subtropical regions5
• In endemic areas, hookworm infection 35-73% IDA6
1. Institute of Medicine. In National Academy Press, 2001: 290–393.
2. Moy RJ. Clin Lab Haematol 2006; 28: 291–98.
3. Cooper ES, Bundy DAP. Ballieres Clin Trop Med Commun Dis 1987; 3: 629–43.
4. WHO 1996. WHO/CTD/SIP/ 96.1. Geneva: WHO.
5. Bungiro R, Cappello M. Curr Opin Infect Dis 2004; 17: 421–26. 6
6. Stoltzfus RJ, Chwaya HM, Tielsch J, et al. Am J Clin Nutr 1997; 65: 153–59.
Benefits

Iron supplementation in young children

• realms of anemia prevention

• improvements in developmental
outcomes

7
 Development
 Iron – neurologic development
• neural circuit formation & myelination

• oligodendrocytes – proper myelination of the neurons used in sensory

systems (visual, auditory) and learning and interacting behaviors1
• dopaminergic neurotransmitter system related to behavior
development (eg, inhibition, affect, attention processing, and
extraneous motor developments)2
• cofactor for enzymes that synthesize neurotransmitter (tryptophan
hydroxylase [serotonin] and tyrosine hydroxylase [norepinephrine,
dopamine])2
• lead and other neurotoxic metals – to be absorbed during ID3

1. Lozoff B, Black MM. In: Pettifor JM, Zlotkin S, eds. Basel, Switzerland: Nestec Ltd, 2004:119 –35.
2. Beard J. J Nutr 2003;133:1468S–72S.
3. Kwong WT, Friello P, Semba RD. Sci Total Environ 2004;330:21–37. 8
 Iron deficiency consequences
 The association between IDA and diminished mental,
motor, and behavioral functioning is well establish

• reversal of the anemia did not improve standardized scores1,2

• these effects appear to be long-lasting despite correction of the
ID3,4

1. Walter T, DeAndraca I, Chadud P, Perales CG. Pediatrics. 1989;84:7-17.

2. Lozoff B, Brittenham GM, Wolf AW, McClish DK, Kuhnert PM, Jimenez E, et al. Pediatrics. 1987;79(6):981-
95[Published erratum appears in Pediatrics 1988;81:683]
3. Lozoff B, Jimenez E, Wolf AW. N Engl J Med. 1991;325:687-94.
4. Lozoff B, Jimenez E, Hagen J, Mollen E, Wolf AW. Pediatrics 2000;105:E51.
9
 Iron deficiency consequences (cont.)

• studies in rat models demonstrated that iron deficiency anemia

in early life causes a deficiency in dopamine receptors that could
not be corrected by reversing the anemia1,2
• the behavior and affect of children whose anemia was corrected
before the age of 24 months were comparable to those children
who were non-anemic throughout infancy3

to prevent iron deficiency in children before

the second year of life

1. Ben-Shachar D, Ashkenazi R, Youdim MB. Int J Dev Neurosci. 1986;4:81-8.

2. Yehuda S, Youdim ME, Mostofsky DI. Pharmacol Biochem Behav. 1986;25(1):141-4
3. Chang S, Wang L, Wang Y, Brouwer ID, Kok FJ, Lozoff B, Chen C. Pediatrics published online Mar 21,
2011;127(4):e927-e33.
10
 Strategies for the prevention of ID:

• education combined with dietary modification or diversification,

or both, to improve iron intake and bioavailability

• iron supplementation (provision of iron, usually in higher doses,

without food)

• iron fortification of foods

• biofortification via plant breeding or genetic engineering

• Although dietary modification and diversification is the most sustainable approach,

change dietary practices and preferences is difficult, and foods that provide highly
bioavailable iron (such as meat) are expensive.

11
 American Academy of Pediatrics Committee on Nutrition
Recommendation for the Prevention of Iron Deficiency*

1. Breastfeed for first six to 12 months of age

2. If using formula, use only iron-fortified infant formula
3. No whole cow’s milk during the first year of life due to increase
occult gastrointestinal bleeding
4. When solid foods are introduced at four to six months of age, it
should be with iron-rich cereals.

*American Academy of Pediatrics Committee on Nutrition. Pediatrics 1992;89:1105-9.

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 Supplementation
 Targeted to high-risk groups1 (e.g., infants, young
children)
• ferrous iron salts (ferrous sulphate and ferrous
gluconate) : low cost and high bioavailability
• dose : 3 to 6 mg/kg/day
• major limitations : logistic of distribution and absence of
compliance
• nausea and epigastric pain
• lower doses between meals2
• provided with meals : reduces absorption

 Untargeted: in areas of high transmission of

malaria5 : increased risk of serious infections4,5
1. Baltussen R, Knai C, Sharan M. J Nutr 2004; 134: 2678–84.
2. Cook JD. Best Pract Res Clin Haematol 2005; 18: 319–32.
3. Oppenheimer SJ. J Nutr 2001; 131: 616S–33S.
4. Gera T, Sachdev HP. BMJ 2002; 325: 1142.
13
5. Sazawal S, Black RE, Ramsan M, et al. Lancet 2006; 367: 133–43.
 Supplementation (cont.)

Iron Polymaltose Complex (IPC)

• IPC is a novel iron preparation : non-ionic ferric iron and polymaltose
• Iron absorption from IPC is physiologically controlled and it is by an active
process – apotransferrin1
• iron absorption from IPC will be rapid in anemic condition and absorption
will slow down or halt when the iron store reaches the optimum level
• no overloading of iron1

• it does not produce free radicals

• in avoiding the gastro-intestinal irritation
• do not stain the teeth
• high elemental content of iron facilitates once a day dosing.

• Thus IPC may have a potential role in longer term supplementation programme2
(5 drops of IPC (12.5 mg/ml) as preventive dose and 10 drops as therapeutic dose in
6-24 mo old children).3
1. Geisser P. Properties and pharmacokinetics of iron salts and iron complexes. Research Department.
Hausamann Laboratories. INC, Switzerland
2. Jacobs P, Wood L, Bird AR. Better tolerance pf iron polymaltose complex compared with ferrous sulphate in the
treatment of anemia. Haematology 2000; 5: 77-83
3. Stoltzfus R, Dreyfuss M. Guidelines for the use of iron supplements to prevent and treat iron deficiency
14
anemia. INACG/WHO/UNICEF Report, 1998
 Fortification

• probably the most practical, sustainable, and cost-effective

long term solution to control ID at the national level1
• bioavailable iron off-flavors, color changes, fat oxidation2
• not cause visible adverse effects & protected against the
development of respiratory tract infections3,4
• Industrialized countries : infant formulas and weaning foods5

1. Baltussen R, Knai C, Sharan M. J Nutr 2004; 134: 2678–84.

2. Hurrell RF. Nutr Rev 2002; 60: S7–15.
3. WHO and FAO. Eds. Allen L, de Benoist B, Dary O, Hurrell R. Geneva, WHO, 2006.
4. Gera T, Sachdev HP. BMJ 2002; 325: 1142.
5. Owen AL, Owen GM. J Am Diet Assoc 1997;97: 777–82. 15
 Ferrazone® ferric sodium EDTA (ethylenediaminetetraacetate trihydrate)

• does not adversely affect the absorption of other nutrients, including zinc,
copper, calcium, magnesium, and manganese
• highly bioavailable, despite the presence of inhibitors of iron absorption in
foods, particularly in subjects with low iron status
• administration of ferric sodium EDTA in the diet would not result in a greater
uptake of iron once nutritional requirements for iron are met; no evidence of iron
overload
• no adverse effects were reported in humans subjected to longterm ferric
sodium EDTA fortification trials
• 0.2 mg iron/kg body weight/day (approximately 12.0 mg iron/person/day) from
fortified foods
•WHO, FAO, E.U.

Overall, the results of toxicological and clinical studies of ferric sodium EDTA and
other sources of iron and EDTA support the safe intake of Ferrazone® ferric
sodium EDTA by humans

Source: Therapeutic of Ferrazone, Dr. Carel Wreesmann, Akzo Nobel

16
 Biofortification
 Some studies suggest that iron content can be
increased in staple foods by plant breeding, genetic
engineering, or both
• iron content in rice can be increased two-to-three fold
by introduction of ferritin gene from soy bean1
• to lower the phytic acid content of rice by introduction
a phytase from Aspergillus fumigatus2
• iron uptake from soils might be increased by
introduction of a ferric reductase gene into plant roof
systems3

1.

1.2.Goto F, Yoshihara T, Shigemoto N, Toki S, Takaiwa F. Nature Biotech 1999; 17: 282–86.
2. Lucca P, Hurrell R, Potrykus I. Theor Appl Genet 2001; 102: 392–97.
3. Samuelsen AI, Martin RC, Mok DW, Mok MC. J Plant Physiol 1998; 118:51–58.
3.
17
 Primary Prevention
• hinges on healthy feeding practices
 breastfeeding
• breast milk is low in iron content, about 50% of iron is
absorbed1
• dietary iron supplement : Iron-fortified cereal3 / oral iron
supplement, using ferrous sulfate drops
 for term infants starting 42 - 61 months of age, 1 mg
elemental iron/kg/day
 preterm and low birth weight infants starting 2-44 weeks
of age, 2 mg elemental iron/kg/day
 Iron-fortified formula

1. Oski FA. N Engl J Med 1993;329:190-3.

2. Booth IW, Aukett MA. Arch Dis Child 1997: 76:549-54.
3. U.S. Preventive Service Task Force. Guide to clinical preventive services. 2d ed. Baltimore: Williams &
Wilkins, 1996;231-46.
4. Earl RO, Woteki CE. Washington DC: National Academy Press, 1993.
18
Primary Prevention (cont.)
• hinges on healthy feeding practices
 the strict avoidance of cow’s milk in the first 12 months of
life
• cow’s milk

• low in iron and its iron is poorly absorbed1

• decreases the absorption of iron from other
dietary sources1
• gastrointestinal blood loss2
 in the second year of life, cow’s milk consumption should be
limited to less than 24 oz per day3

1. Dallman PR, Siimes MA, Stekel A. Am J Clin Nutr 1980; 33:86-118.

2. Ziegler EE, Fomon SJ, Nelson SE et al. J Pediatr 1990; 116:11-8
3. Centers for Disease Control and Prevention. Morb Mortal Wkly Rev MMWR 1998; 47(RR-3):1-
29.
19
 Secondary Prevention
 Screening1,2
• Risk Factors for Iron Deficiency in the First Year of Life
• Diet
o Cow’s milk ingestion
o Low-iron formula
o Breastfeeding without iron supplementation

• Prenatal/perinatal
o Anemia during pregnancy
o Poorly controlled diabetes
o Low birth weight
o Prematurity
o Multiple gestation
• Low Socioeconomic background
• Rate of weight gain greater than average
1. Pizarro F, Yip R, Dallman PR, Olivares M, Her-trampf E, Walter T. J Pediatr. 1991;118:687–92.
2. U.S. Preventive Services Task Force. Guide to clinical preventive services. 2d ed. Baltimore: Williams &
Wilkins, 1996;231–46. 20
 Secondary Prevention (cont.)
 Screening
• First year of life & toddler
• Term infant : 92 – 121 months of age
• Preterm and low-birth-weight2 : 3 – 6
months of age
• Toddler3 : toddlers at risk : 15 and 18 months
and 24 months
o past history of IDA
o cow’s milk consumption > 24 oz per day
o diet low in iron and vitamin C
o recent immigration from a developing country

1. U.S. Preventive Services Task Force. Guide to clinical preventive services. 2d ed. Baltimore: Williams &
Wilkins, 1996;231–46.
2. Earl RO, Woteki CE, Washington, D.C.: National Academy Press, 1993.
3. Centers for Disease Control and Prevention. Morb Mortal Wkly Rev MMWR. 1998;47(RR-3):1–29.
21
 Secondary Prevention (cont.)1,2
• The ideal screening test would be capable of identifying
iron deficiency in the absence of anemia
• the treatment of iron deficiency in the pre-anemic stage,
preventing iron deficiency anemia and its associated mental,
motor, and behavior effects
• no such test is widely used at this time
• The standard test : Hb or Ht
• Serum ferritin, transferrin saturation, and erythrocyte
protophorphyrin
• Erythrocyte protophorphyrin + Hb
• Red-cell distribution width (RDW) + Hb

1. Dallman PR. West J Med. 1981;134:496–505.

2. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL. JAMA. 1997;277:973–6.

22
 Therapeutic Trial of Iron1

Baseline Hgb •once daily before

breakfast
• vitamin C (orange
Iron for one month (3 mg juice)
• length of treatment:
elemental iron/kg/day 3 months
• elemental iron 3
mg/kg, orally (ferrous
Repeat Hgb sulfate-20% elemental
iron)

1 g/dl (10 g/L) or greater Complete a course of

increase in Hgb iron therapy2,3

A therapeutic trial of oral iron remains the gold standard for establishing a
diagnosis of iron deficiency
1. Dallman PR. West J Med 1981; 134:498
2. Dallman PR, Siimes MA, Stekel A. Am J Clin Nutr. 1980;33:86–118. 23
3. Earl RO, Woteki CE, Washington, D.C.: National Academy Press, 1993.
 Risks on Iron Supplementation
• Iron is not easily eliminated from the body
Excess of iron

the generation of Interference The growth The

hydroxyl radicals/free with absorption and suppression
radicals of other proliferation of enzyme
essential of invading activity in
nutrients pathogens host defense
Oxydative damage to
DNA, proteins, and
lipids • not found •Hypoferremia; iron inhibits the
significant expression of inducible nitric
growth effects acid synthase (iNOS) – down
Detrimental to • an adverse regulates the formation of nitric
cognitive, motor, and effect in iron- oxide in macrophages
behavioral replete
development ? children Malaria, HIV,
Tuberculosis !? 24
Risks on Iron Supplementation
 Iron is not easily eliminated from the body
Excess of iron : this detrimental effect is likely limited to case
of genetically susceptible children

• mutations in the gene encoding pantothenat kinase 2 (PANK 2) : neuronal

brain accumulation (dystonia, dysarthria, rigidity, and early death)
• animal models shown potential neurologic dysfunctions

• defense systems in the body protect against free radical damage :

 lactoferrin from breast milk may be used for iron chelation
 antioxidants (selenium or glutathione) protect against free radical

malnourished children may

be deficient in antioxidants
25
Conclusion
• Nutritional iron deficiency is still common among young children
in developing countries where monotonous, plant based diets
provide low amounts of bioavailable iron

• Treatment with iron among iron deficiency anemic young children

can reverse anemia and restore iron sufficiency, yet the poorer
developmental functioning appear to persist

• Intervention should focus on the primary prevention of iron

deficiency

• Education combined with dietary modification or diversification

or both
•Fortification
• Supplementation
• Selective plant breeding and genetic engineering
• All infants and toddlers who did not receive primary prevention
should be screened for iron deficiency. A positive screening test is
an indication for a therapeutic trial of iron 26
 Thank you
and
have a nice
day