Pediatric Hfinatotog; and Otu.otogt. 21: .521-534, 2004 ^ TaylorStFrancisCopyright © Taylor X: Fninci.s Inc. TP healthsciencesISSN: 0888-0018 prim / I521-0C69 onlineDOI: 10.1080/08880010490477310

CLINICOLABORATORY FINDINGS AND TREATMENTOE IRON DEEICIENCY ANEMIA IN CHILDHOOD

John P. Panagiotou, MD D Department of Pediatric Hematology-Oncology,"Aghia Sophia" Children's Hospital, Athens, Greece

Konstantinos Douros, MD D Department of Pediatrics, "Thriassion" GeneralHospital, Athens, Greece

D One of the major cau.ses of anemia in childhood xuorldwide is iron deficiency. Its prevalence

depends mainly on age, being higher in infancy and adokscence. Its etiology vanes, but poor iron

diet is considered the commonesl causative factor. Belter ladies may be needed, like the targeted

screening of children who belong to high-risk groups, to eradicate childhood iron deficiency. The

amount of the body iron regulates its absorption from the gut through mechanisms that are still

poorly understood. Early identification of iron deficiency is essential for the prevention not only of

anemia but also the numerous and long-term consequences caused by the lack of iron. Many tests are

available for the diagno.sis of the disease. Some of them seem very promising for the early detection of

iron deficiency, but further research is needed before they become widely acceptable in clinical practice.

Treatment is based on oral iron salts, which do not have any serious side effects.

Keywords, childhood, etiology, iron-deficiency anemia, prevention, treatment

Iron is an essential nutrient well known to the ancient Greeks, and it wasrecognized as a blood component more than 200 years ago [1]. Iron defi-ciency is the single most common nutritional disorder worldwide and theleading cause of anemia during infancy and childhood [2]. Its appearancein early childhood, especially if severe and prolonged, can adversely affectbehavior and psychomotor development, side effects that may not always befully reversible even with complete correction of iron deficiency [3].

This article reviews the epidemiology, etiology, clinical manifestations,laboratory findings, diagnosis, treatment, and prevention strategies of iron-deficiency anemia during the whole childhood.

DEFINITION OE IRON DEEICIENCY ANEMIA (IDA)

Anemia is a relatively common finding and correct diagnosis can usuallybe established with relatively little discomfort for patient and little laboratorycost. Finding the cause is always important.

Received 21 October 2003; accepted 27 April 2004.Address correspondence to John P. Panagiototi, MD, Gennadioti 1, 184 52 Nikea, Athens, Greece.

E-mail: costasdouros@freemail.gr

521

522 / . P. Panagiotou and K. Douros

TABLE 1 Values for Hemoglobin, Hematocrit, Retictilocytes, and MCV DuringInfancy and Ghildhood

Gord blood2wk3 mo6 mo-6 yr7-12 yr

Hb

Mean

16.816.512.012.013.0

(g/dL)

Range

13.7-20.113.0-20.09.5-14.5

10.5-14.011.0-16.0

Ht 1

Mean

5550363738

(%)

Range

45-6542-6631-4133-4234-40

MGV

lowest

110

70-7476-80

RtG (%)

5.01.01.01.01.0

During infancy and childhood the normal ranges for hemoglobin andhematocrit levels vary significantly and for this reason diagnosis of anemiadepends on normal values for each examined age (Table 1). A characteristicexample is that of normal neonates who show an increased hemoglobin levelafter birth (15-22 g/dL), whereas, during infancy, under normal circum-stances, have hemoglobin level as low as 10 g/dL, while premature infantscan reach a nadir hemoglobin level of 7-8 g/dL in the 8th-10th postnatalweek [4]. Thereafter, the normal values gradually increase until adult valuesare reached after puberty.

Iron deficiency represents a total-body iron deficit, resulting from im-balance between iron requirements and iron supply. This deficit initiallyis compensated by the mobilization of iron stores, which are representedby ferritin levels. Three successive stages of iron deficiency may be distin-guished [4—6]. Initially, storage iron deficiency is recognized by a decreasedserum ferritin (SF) concentration without any biochemical evidence of irondeficiency. Later on, iron deficiency results in low serum ferritin (below12 Mg/L) and iron concentration, progressive rise in the concentration ofserum-transferring receptor (TfR), increase in free erythrocyte protopor-phyrin (FEP), and low serum transferrin saturation. During this period,erythropoiesis becomes affected, although hemoglobin levels remain withinnormal limits. Finally, anemia occurs when the supply of iron to the bonemarrow is sufficiently impaired presenting with a decrease in Hb concentra-tion below of the 5th percentile of the reference range for age and sex. Atthe same time, there is a decrease in the synthesis of iron metalloenzymes,which are vital components of many metabolic pathways.

EPIDEMIOLOGY OE IDA AND IRON METABOLISM

The prevalence of IDA varies widely depending on a variety of factors,such as the age, ethnic composition, socioeconomic status, dietary habits,and the criteria used to establish the diagnosis [5]. In general, IDA is mostcommon among children aged 6 months to 3 years, its prevalence dropsamong school-age children, but increases again during adolescence [7].

Iron-Deficiency Anemia in Childhood 523

Normal-term infants are born with sufficient iron stores, having approx-imately 75 mg of elemental iron per kilogram of body weight [8], Total-body iron changes vary little for the first 4 months of life so there are noincreased requirements during this period. In addition, the reduction of Hblevels from 18 g/dL at birtb to 14 g/dL during the first 2 weeks of life re-leases iron, which is stored and gradually reused. Good absorption of humanmilk and the increased use of iron-fortified formula, especially in developedcountries, fulfill the iron requirements in these ages, resulting in reductionof cases with IDA during the first 4 months [9, 10], However, infants whocontinue to receive only breast milk after the first 6 months of life are at in-creased risk. Also at risk are infants who, despite current policy, switch froman infant formula to whole cow's milk before the age of 1 year [11], Be-tween 4 and 12 months total-body iron increases by about 130 mg and anexternal source of iron is necessary. If this is not met, iron deficiency andsubsequently IDA develop after the age of 1 year [12],

The highest prevalence of IDA occurs in toddlers and adolescents be-cause the increment in hemoglobin iron per unit of body weight is greatestat these ages [7, 12], The prevalence drops among school-age children butincreases again during adolescence [5], Factors that are implicated in this in-crease are mainly the dietary characteristics of adolescents. Many girls try tocontrol their weight and inadvertently limit iron intake, while many adoles-cents pass through a temporary period of vegetarianism because of concernswith animal welfare. Moreover, athletic performance may lead to blood lossfrom the gut and urinary tract, so athletic girls who have passed menarcbeand are trying to slim may be at particular risk of iron deficiency [13],

IRON METABOLISM

Tbe human body contains about 3-4 g of iron [14], Iron is absorbedmainly in tbe duodenum and upper jejunum, is transported in blood bytransferrin, and it is found either biologically active (70-90%) or stored(10-30%), Tbe former is found mainly incorporated in hemoglobin, andthe latter in the reticuloendothelial cells (bone marrow, liver, spleen) as fer-ritin, a labile and readily accessible source of iron, or in an insoluble formas bemosiderin [15],

The amount of iron absorption increases when iron deficiency exists,while when stores are high, much of the iron absorbed by the mucosal cellsis returned into the intestinal lumen by desquamation [16], Although theentire process of the regulation of iron absorption is still poorly under-stood, three ways are being considered [17], Tbe first is by dietary iron.Following an oral iron load, the absorption rate diminishes even if thereis a systemic iron deficiency. It is believed that the intracellular accumula-tion of iron decreases further absorption. The second way depends on the

524 /. P. Panagiotou and K. Douros

total-body iron stores and is termed the stores regulator. It works with a mech-anism still unknown and is capable of increasing iron absorption by only 2-3times. It has been postulated that the saturation of circulating transferrinaffects the iron "set point" of developing duodenal enterocytes. The thirdway is the erylhropoielic regulator. Through this mechanism the iron absorp-tion can be increased greatly in cases of ineffective erythropoiesis, even incases where an iron overload exists, Tbalassemia, sideroblastic anemia, andother congenital disorders of red cell maturation are some examples. It isworth mentioning that such an increase in iron absorption does not happenin cases of anemias that are characterized by peripberal destruction, sucb assickle cell and autoimmune hemolytic anemias. The mediator of this proce-dure remains unknown.

Additional factors that influence tbe absorption rate are the compositionof the diet and the efficacy and integrity of the mucosa of the upper smallbowel [18], Tbere are two kinds of iron in the diet with respect to the mech-anism of absorption, heme and nonheme, utilizing two different receptorson the mucosal cells, Heme iron, found in meat, poultry, and fish, consti-tutes about 5-10% of the daily iron intake in most industrialized countries,and is highly bioavailable, being 2-3 times more absorbable than nonhemeiron. Its absorption is less influenced by body iron stores, and the only di-etary factor that negatively acts on the absorption procedure is calcium [19,20], Within the mucosal cells, an enzyme splits heme, releasing iron into thecirculation.

The main sources of nonbeme iron are plant-based foods, eggs, and iron-fortified foods, primarily in the form of ferric complexes [21], In the processof digestion, the iron is reduced from tbe ferric to the ferrous form, which ismore readily absorbed. Its absorption is enhanced by ascorbic acid and hy-drochloric acid, and inhibited by phytates (in bran), polyphenols (in certainvegetables and legumes), tannins (in tea), calcium, and pbosphate (in highconcentration in unmodified cow's milk) [16, 22],

After having been absorbed by the enterocytes, the iron must cross theserosal membrane to enter the circulation. Studies in animals have shownthat a protein similar to ceruloplasmin is probably responsible for this trans-port [14, 23], Once iron has traversed the serosal membrane it is bound totransferrin, wbicb is its main vebicle in tbe serum and extracellular fluid.The transferrin-iron complex beads for the marrow and liver through thecirculation, Transferrin's high affinity for iron protects the body from freeiron, but has the drawback of competing witb iron cbelators. This is the rea-son why the development of efficient and easy to use chelators is a difficulttask.

The transferrin-iron complexes attach to transferrin receptors, whichare found on every nucleated cell's surface. Liver, placenta, and develop-ing red cells are equipped with large numbers of sucb receptors. After tbe

Iron-Deficiency Anemia in Chitdhood 525

new complexes of transferrin-iron-transrerrin receptor have been formedon cell surface, tbey are internalized into endosomes, Tbese endosomes un-dergo acidification, and when the pH is <6 transferrin both loses its iron andbecomes more tightly bound to transferrin receptor. Finally, the transferrin'smolecules return to the circulation, whereas iron exits the endosome and ei-ther incorporates into enzymes or is stored in the ferritin molecules [24],

Ferritin is the major device cells use to store iron. It consists of 24 similarsubunits, which form a kind of cage. Up to 4500 iron molecules can congre-gate in the cavity of this cage [25], The regulation of iron mobilization fromferritin still remains obscure, altbough a lot of research has been focusedon tbis matter recently [26], Opening tbe ferritin pore for iron release bymutation of conversed amino acids at interhelix and loop sites [27],

About 80% of tbe circulating iron, through a similar pathway, is utilizedby the developing red cells for the hemoglobin formation [17], Tbe circu-lating red cells at tbe end of their life span either are lysed, releasing theirhemoglobin in tbe plasma, or are taken up by macropbages in tbe spleen,liver, and bone marrow, Hemopexin and haptoglobin are the plasma pro-teins responsible for binding free heme and hemoglobin, respectively. Thecomplexes that are formed are finally taken up by hepatocytes through en-docytosis [17], As for the red cells that were removed by macrophages, theyundergo intracellular processing. The procedure ends with the release ofiron in the circulation and its conveyance to the liver with transferring [24],

ETIOLOGY

Though various factors may cause IDA, nutritional factors are the mostfrequent causes in infancy and childhood (Table 2), Rapid growth duringthe first 2 years of life and again during adolescence under conditions ofeither decreased or deficient iron uptake may result in IDA, More vulnerableare preterm infants and twins, baving botb lower iron stores at birth and amore rapid growth. Their blood volume expansion may be so rapid that theiriron stores may be depleted by 2-3 months of age. Proportional growth spurtoccurs during adolescence and increased iron requirements are needed tomaintain positive balance [5], Especially for adolescent girls, there is moreneed for iron because of menstrual blood loss, which is about 40 mL (20 mgiron) per period [28],

Poor iron diet is a major etiologic factor to the development of IDA,Both breast and cow's milk bave low levels of iron, containing less than 0,3-1 mg/L, The iron content of human is highest in early transitional milk(0,97 mg/L) [29] but decreases steadily during lactation, reaching a levelof approximately 0,3 mg/L by tbe age of 5 months [30], It is important tostress the high bioavailability of breast milk, possibly because of tbe lower cal-cium content and the presence of lactoferrin [22], Nevertheless, prolonged

526 / P. Panagiotou and K. Douros

TABLE 2 Causes of Iron-Deficiency Anemia in Children

Increased physiologic demandsRapid growth

Blood loss (hemorrhage)MenstrualCastrointestinalPulmonaryPerinatalUrinary

Inadequate iron intakeProlonged exclusive breast feedingDecreased availability and/or bioavailability of dietary iron

MalabsorptionExtended gastrointestinal surgeryTropical and nontropical sprue

Defective plasma iron transportCongenital atransferrinemiaDefective transferrins

breast-feeding without iron supplementation may lead to IDA in 30% ofthese infants at 12 months of age [31].

Malabsorption of iron is an uncommon cause of IDA in children. Ex-tended gastrointestinal surgery or nosologic syndromes such as tropical andnontropical sprue may result in impaired iron absorption and IDA [32].Blood loss is another important factor, with miscellaneous etiology, whichmay cause iron deficiency and subsequently IDA. In infants and older chil-dren the commonest causes of chronic IDA from occult bleeding are lesionsof the gastrointestinal tract (e.g., peptic ulcer and Meckel's diverticulum),consumption of whole cow's milk in infants younger than 12 months, pul-monary hemosiderosis, and hookworm infestation [5, 12].

Very rarely, IDA may result from congenital atransferrinemia or defec-tive transferrins. Congenital atransferrinemia is inherited as an autosomalrecessive disorder in which absorbed iron is either free or loosely boundto plasma proteins other than transferrin. Moreover, the uptake of iron bynormoblasts is insufficient and much of the iron is taken by the liver [4].Defective transferrin molecules is an extremely rare condition that disruptsthe delivery of iron to the bone marrow with resultant IDA [4].

CLINICAL AND LABORATORY FINDINGS

Symptoms and signs of IDA vary with the severity of the deficiency andare often nonspecific. Mild IDA is usually asymptomatic. In infants with moresevere IDA pallor, irritability, fatigue, and delayed motor development arecommon, while in the case of feeding with unfortified cow's milk they maybe fat and flabby with poor muscle tone. In older children pallor is the

Iron-Deficiency Anemia in Childhood 527

most frequent presenting feature and is accompanied by weakness, dizziness,easy fatigability, irritability, and anorexia, while a history of pica is common.In severe IDA, diaphoresis, dyspnea, tachycardia, soft ejection systolic flowmurmurs, and cardiomegaly may occur [33]. IDA may also produce generalclinical manifestations that do not have any association with iron deficiency,such as headache, paresthesia, angular stomatitis, and gastric atrophy. Also,blue sclerae might be an extra sign due to impairment of collagen synthe-sis with resulting thinning of the sclerae [34]. Very rare complications of se-vere pediatric IDA are Plummer-Vinson syndrome (postcricoid eosophagealweb, glossitis, dysphagia), atrophy of skin, and koilonychias [8, 35].

A matter of great interest is the proven associations of numerous con-ditions with IDA, especially during the first 2 years of life. First, numerousstudies have shown the existing association of delayed psychomotor develop-ment with IDA due to either low brain iron and reduced neurotransmitterlevel or systemic effects of hypoxia [36]. One recent study showed that ado-lescents who were iron deficient as infants had diminished performance ona number of tests of cognition, attention, and motor function, comparedwith those who had not been iron deficient as infants [37]. Second, chronicsevere iron deficiency is often associated with reduced growth rate, espe-cially among preschool children, and several studies have shown that ironsupplementation improves physical growth [38]. Third, geophagia or com-pulsive eating of dirt (pica) is more common in iron-deficient children [39],and considerable evidence suggests that iron deficiency is usually the causeand pica the consequence [40]. It is notable that iron therapy is followedby an abrupt loss of pica. Fourth, iron deficiency is known to adversely af-fect immune functions by causing decreased myeloperoxidase activity, re-duced bactericidal capacity, a quantitative decrease in the number of circu-lating T cells, impaired mitogenic response, and poor natural killer activity[30].

The severity of anemia depends on the degree of iron deficiency, andthe Hb level may be as low as 3-4 g/dL. Typically in IDA, Hb and MCV arereduced, red cell distribution width (RDW) is increased (i.e., microcytosisand anisocytosis), and the shape of the cell cytogram scatter is moved downand to the left with a large proportion of cells in the hypochromic micro-cytic zone [12]. The relative number of reticulocytes is usually normal orslightly elevated, but the absolute reticulocyte count is often low, indicatingan insufficient response to anemia [41]. The white blood cell count is usu-ally normal, while platelet count varies from thrombocytopenia to thrombo-cytosis. In general, thrombocytosis is associated with blood losses, whereasthrombocytopenia often is associated with more severe anemia [5].

Regarding the iron status in IDA, low serum iron, elevated total iron-binding capacity (TIBC), and decreased transferrin saturation are found.TIBC reflects the total amount of transferrin available in the blood, and

528 J. P. Panagiotou and K. Douros

levels greater than 400 /xg/dL suggest iron deficiency, whereas values lessthan 200 /ig/dL characterize inflammatory diseases [5]. The role of thesetests in the diagnosis of IDA should be reevaluated because of their unpre-dictable variability and relative insensitivity [42-44].

Ferritin and serum-transferrin receptor (sTfR) are more sensitive indi-cators of early iron deficiency. Both undergo a gradual change as iron storesdecrease from normal levels to those found in IDA. The continuous processof iron depletion passes through 3 stages. The first stage, where a progressivedecrease in serum ferritin takes place, represents the depletion of storageiron compartments. The sTfR, which reflects the functional iron compart-ments (i.e., hemoglobin, myoglobin, cytochromes, etc.), remains stable. Thesecond stage is characterized by the depletion of functional iron compoundsand the beginning of iron-deficient erythropoiesis (IDE). The indicator ofthis phase is the elevated concentration of sTfR. Finally, the third stage be-gins with the fall of Hb below the lower normal limits due to the continuingIDE, and, as a consequence, IDA ensues.

Ferritin measurements have been used to distinguish normality fromIDA, so the reference limits have been designed for this purpose. Disagree-ment still remains on the value of ferritin that indicates clinically relevantstorage iron depletion. This is chiefly attributed to the large physiologicvariability occurring between individual patients [46, 47]. Another confus-ing factor is that ferritin is a well-known acute phase reactant that rises ininflammatory diseases [46, 48]. In any case, levels ranging between 10 and20 fA-g/h are considered indicative of depletion of iron stores, while levelsless than 10 fJ.g/h are diagnostic of iron deficiency. In reverse, levels greaterthan 50 Mg/L argue against the diagnosis of iron deficiency, even in thepresence of other conditions that may cause an elevation of the ferritin level[5].

The functional iron status can be estimated better with the measure-ment of sTfR instead of ferritin. Apart from that, sTfR is not an acute phasereactant, so its concentrations remain unchanged in inflammatory diseases[45, 49]. Its day-to-day fluctuation is limited, so it is much more acceptablethan other conventionally used indices, as, for example, transferrin satura-tion [50]. sTfR concentrations exceeding 2.75 mg/L, but not 3.6 mg/L,are deemed to define those having depletion of the functional iron com-partment leading to IDE, whereas sTfR levels above 3.6 mg/L indicate IDA[45,49].

As mentioned above, serum ferritin reflects the storage iron compart-ment, whereas sTfR reflects the functional iron compartment. These twoindices can be combined in the sTfR/log ferritin ratio (TfR-E index), whichis very useful for the estimation of the entire range of body iron stores[51]. A ratio of 1.8 or greater indicates storage iron depletion, whereas 2.2or greater indicates IDE. Some evidence suggests that this index might be

Iron-Deficiency Anemia in Childhood 529

sensitive enough for the detection of iron-deficient states in cases where fer-ritin and sTfR are borderline [45].

A hematologic index currently in use for the assessment of functionaliron status is the measurement of hypochromic red cells (HYPO). Sinceerythrocytes have a relatively long life span of about 120 days, the HYPOindex provides information over a several-month period, so it is a late indi-cator of iron-restricted erythropoiesis [52]. Another noteworthy index is thereticulocyte Hb content (CHr), which can be used as an early marker of func-tional iron deficiency (ID), since reticulocytes circulate in the bloodstreamfor only 1-2 days [53, 54]. Unfortunately, the aforementioned hematologicindices have two major drawbacks. First, they are available only on analyzersfrom a single manufacturer and, second, various cutoff values for functionalID have been reported in literature, ranging from 2 to 10% for HYPO and23 ng to 29 ng for CHr [52, 53, 55, 56].

Another investigation, as diagnostic or screening method, is the level offree erythrocyte (EPP) or zinc (ZPP) protoporphyrin. EPP reflects the ad-equacy of iron delivery to the erythroid precursors in the bone marrow. Itslevel is increased in IDA, and values greater than 3 A'-g/g of Hb are consid-ered abnormal [57].

DIFFERENTIAL DIAGNOSIS

Although no single test can reliably document iron-deficiency, in manycases, low values of Hb-MCV-MCH and high values of RDW-EPP providestrong supportive findings. So the differential diagnosis includes otherhematologic diseases that are characterized by hypochromia and microcy-tosis (Table 3).

Thalassemic syndromes, which belong in hypochromic microcytic ane-mias, should be considered in infants, especially in endemic regions.Infants with thalassemia have an elevated number of erythrocytes, normalor increased levels of serum iron and ferritin, while TIBC is normal. TheRDW is usually lower in terms of IDA levels, and using cytometry plots,the proportion (%) of hypochromic cells is lower than the proportion ofmicrocytic cells. On electrophoretic studies the HbA2 level is elevated in

TABLE 3 DiiTerendal Diagnosis of Iron-Deficiency Anemia from OtherHypochromic-Microcytic Anemia

Thalassemic syndromes Lead poisoningChronic disease Vitamin Bg responsive

Infection Copper deficiencyCancer Sideroblastic anemia (some)InflammationRenal disease

530 / . P. Panagiotou and K. Douros

j8-thalassemia minor, but the value is falsely low if iron deficiency coexists.Therefore, in cases of clinical suspicion repeated testing is necessary afteriron-replacement therapy [5, 12, 58].

The anemia of chronic inflammation or infection is classically nor-mochromic and normocytic, but in about 20-30% of infected children maybe bypochromic. It is the result of a decreased red blood cell survival, dimin-ished reutilization of iron, impaired iron mobilization from macrophages bytransferrin, and decreased intestinal absorption of iron. Characteristic lab-oratory findings of this disorder should be considered a decreased TIBC, anormal RDW, an increased serum ferritin level, and a normal serum trans-ferrin receptor level [5, 12, 59]. An elevated serum transferrin receptor levelis characteristic of iron deficiency irrespective of whether the patient has co-existing anemia of chronic disease [60].

SCREENING AND PREVENTION

Strategies for prevention can be achieved by screening tests, avoidanceof blood loss, and by giving supplementary iron or fortification of foods. Thebest way to prevent iron deficiency is by dietary interventions. Promotion of adiet containing more bioavailable iron like red meat, poultry, and fish wouldbe very efficient for infants and children above 6 months of age. However,more promising seems to be the fortification of foods with iron. These can beeither staple foods like flour or more specific foods, such as infant formula,infant cereals, and breakfast cereals. The former would probably help moreadults and adolescents, but the latter would be a continous source of ironfor tbose who are most in need, namely infants and small children [11, 61].

The proper age for screening tests is not apparent and depends onwhether children belong to high-risk groups for IDA. Prematurity, low birthweight, early consumption of cow's milk, fast growth rate, low-iron diet, andlimited access to food are considered the major risk factors [20]. All thesechildren must be screened between the ages of 9 and 12 months, and laterbetween the ages of 1 and 5 years [12]. On the other hand, in populationsnot at high risk, only those children with known risk factors need to bescreened [20].

Supplementation is generally not favored for prevention because a toxicmedicine is put into the household and compliance is poor [12]. Addition-ally, there are a few publications describing slower growth in iron-repleteinfants receiving liquid iron supplementation. However, no such adverse ef-fect has been described for iron-fortified foods [62-64]. But there are condi-tions in which iron administration is necessary and if not given then IDA willoccur. Eull-term or preterm infants who are exclusively breast-fed must startiron supplementation at 4-6 and 2 months of age, respectively. The dosageof iron for full-term infants should be 1 mg/kg per day, while for preterm

Iron-Deficiency Anemia in Childhood 531

infants the dosage depends on birth weight and varies between 2 and 4mg/kg per day. Infants who are not breast-fed should receive iron-fortifiedformula up to 12 months of age [57].

Proportional situations may be found among adolescents in whom irondeficiency is the most common cause of anemia. Surveys reflect an iron-deficiency prevalence up to 24% and overt anemia in 10% of high schoolstudents [65]. Also, IDA is a common disorder in the athletes, especiallyin girls [66]. Because females, besides having lower Hb levels, tend to havehigher iron losses and, as a consequence, higher prevalence of IDA [67].

TREATMENT PLAN

The goals of treatment of iron deficiency should be twofold: replenish-ment of body iron stores and correction of underlying diseases. Treatmentis based on oral administration of one of the ferrous salts, among which fer-rous sulfate is preferred because of high bioavailability and low cost. It mustbe pointed out that ferrous sulfate is 20% elemental iron by weight, and thatoptimal response is achieved with a dosage of elemental iron of 6 mg/kgper day in 2 or 3 divided doses. The medicine must be given between mealsand not with milk. Side effects are uncommon and dose related. The mostfrequent are transient staining of teeth, nausea, constipation, diarrhea, andabdominal pain [67, 68]. Reducing the dosage of the medication or givingit with food minimizes these side effects.

Apart from oral administration there are parenteral iron preparationsthat are alternative solutions in cases of patients noncompliant with oraltherapy or genuine intolerance of oral iron, and in malabsorption situationscompromising gastrointestinal iron absorption. The dosage of iron (mg)may be calculated by using the following formula: deficient Hb (g/dL) xbody weight (kg) x 0.22. The most severe side effect is anaphylaxis and atolerance test must be performed. Other side effects of parenteral admin-istration are nausea, vomiting, abdominal pain, flushing, fever, headache,malaise, shivering, myalgia, arthralgia, urticaria, lymphadenopathy, pleuraleffusion, hypotension, and shock [68]. Intramuscular injection of iron ispainful and may be associated with permanent staining of the skin, mus-cle necrosis, and sterile abscesses [68]. Iron dextran preparations for intra-muscular or intravenous administration have been in use for many years.Recently, however, there has been concern about their safety since theyhave been assosiated with life-threatening reactions [69]. Two new nondex-tran preparations for intravenous administration are now being tested: ironsucrose and sodium ferric gluconate complex. Both seem to be associatedwith a markedly lower incidence of life-threatening anaphylactoid reactions.Nonanaphylactoid reactions also seem to be extremely uncommon [70, 71].

532 J. P. Panagiotou and K. Douros

The regular response of IDA is an important diagnostic and therapeu-tic feature. Within 72-96 h after administration of iron peripheral reticulo-cytosis is noted, which is followed by an increase of Hb levels as much as0.5 g/dL/day [41]. Failure to respond to iron therapy may be caused bypoor compliance, an inadequate iron dose, an ineffective iron preparation,ongoing blood loss, coexistent disease resulting in nonabsorption or nonu-tilization of iron, or a misdiagnosis [41]. Iron replacement should continuefor 3 months more after the Hb level is within the normal range for age andgender [72].

In conclusion, IDA is the most common anemia in infancy and child-hood, which must be differentiated from other microcytic anemias. Strate-gies for prevention are screening, health education, fiscal measures, foodfortification, and supplementation. Iron fortification of formulas and cerealsis the most effective method of prevention and has reduced the prevalenceof this disease. However, pediatricians should be cognizant of its presence,especially in high-risk children (preterm infants, children of immigrants orminorities, etc.).

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