Balance de Hierro

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DOI: 10.1542/neo.12-3-e1482011;12;e148Neoreviews

Carissa Cheng and Sandra JuulIron Balance in the Neonate

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Iron Balance in the NeonateCarissa Cheng, RD,*

Sandra Juul, MD, PhD

Author Disclosure

Ms Cheng and Dr Juul

have disclosed no

financial relationships

relevant to this

article. This

commentary does not

contain a discussion

of an unapproved/investigative use of a

commercial product/

device.

AbstractIron is essential for growth and development, and deficiency during gestation and

infancy may have lifelong effects. Iron is necessary for oxygen transport, cellular

respiration, myelination, neurotransmitter production, and cell proliferation. Iron

deficiency may decrease hippocampal growth and alter oxidative metabolism, neuro-

transmitter concentrations, and fatty acid and myelination profiles throughout the

brain. Excellent articles and reviews have been published on the effect of iron on

cognitive development. This review highlights more recent findings, focusing on the

role of iron in brain development during gestation and early life, and discusses

implications for practice in the neonatal intensive care unit.

Objectives After completing this article, readers should be able to:

1. Name sites of iron absorption and regulation.

2. List the consequences of iron deficiency and excess for the neonate.

3. Choose an appropriate tool for iron assessment.

4. Discuss practical challenges to providing iron to neonates.

5. List iron intake recommendations for preterm infants.

BackgroundIron status of the neonate is a balance between iron accretion during gestation, iron

utilization and loss, and iron acquired postnatally, either through enteral or parenteral

routes (Fig. 1). Thus, maternal and fetal conditions as well as postnatal experiences affect

neonatal iron status. Iron is a transition metal that readily converts between the ferrous(2) and ferric (3) oxidation states. In biochemical systems, iron is often found in the

catalytic site of enzymes, where it facilitates redox reactions. Its redox properties provide

protein function but can also be dangerous because inappropriate oxidation may cause

cellular damage. Free iron in a biologic system can convert between oxidation states,

generating free radicals. Polyunsaturated fatty acids, which are found in cell membranes,

are especially susceptible to damage by free radicals. To protect the organism, iron is

sequestered by proteins throughout absorption, transport,

storage, and as it performs its physiologic functions. (1)

Among other functions, iron is essential for development

of the nervous system. Myelination, neurotransmission, den-

dritogenesis, and neurometabolism are dependent on iron.

(2)(3)(4) Iron deficiency during the late fetal and the early

infant periods may result in decreased cellular respiration in

the hippocampus and frontal cortex, abnormal neurotrans-

mitter concentrations, and alterations in fatty acid and my-

elination profiles. (2) Iron deficiency in infancy may have a

lasting impact on cognitive, socioemotional, and motor

functions. (4) The effects of iron deficiency on brain struc-

ture and function are interrelated; neuronal development

affects behavior that, in turn, affects brain development. (4)

*Nutritional Sciences Program, University of Washington, Seattle, WA.

Department of Pediatrics, Division of Neonatology, University of Washington, Seattle, WA.

Abbreviations

DMT1: divalent metal transporter-1

DcytB: duodenal cytochrome BEpo: erythropoietin

HCP-1: heme carrier protein 1

IRE/IRP: iron response element/iron regulatory protein

MCV: mean cell volume

sTfR: soluble transferrin receptor

TIBC: total iron binding capacity

ZnPP/H: zinc protoporphyrin-to-heme ratio

Article nutrition

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Thus, having the appropriate amount of iron is essentialbecause both deficiency and excess can be harmful.

Absorption, Transport, and Storage of Iron inInfants

AbsorptionThe uptake of iron by the enterocyte is an important

regulatory step in body iron content. Iron can be ab-

sorbed into the enterocyte as heme iron or nonheme iron

(both ferrous and ferric forms). Heme iron is soluble in

the duodenum and is absorbed as an intact metallo-

protein via heme carrier protein 1 (HCP-1) (Fig. 2A).

Ferrous iron is then released from heme via heme oxy-genase. (5) Unbound iron is absorbed into the entero-

cyte in the ferrous or ferric form. In the duodenum,

nonheme iron is converted to the ferrous (II) form by

ascorbic acid and duodenal cytochrome B (DcytB) on

the surface of the brush border (Fig. 2B). (6) Ferrous

iron then binds to divalent metal transporter-1

(DMT1) and is transferred into the enterocyte. (5) Ex-

pression of DcytB and DMT1 are regulated by the iron

content of the enterocyte (6) and transcription factors

sensitive to hypoxia and intracellular iron concentration.

(7) Ferric iron (III) binds chelators in the small intestine

and is absorbed via a 3 integrin and mobilferrin pathway(Fig. 2C). (8) After entry into the enterocyte, ferric iron

is reduced by paraferritin and binds mobilferrin. Ferrous

iron from all three entry pathways is released into the

intracellular iron pool and used for cellular metabolism,

stored as ferritin, or transferred out of the enterocyte

(Fig. 2D). (6) Iron is released by ferroportin at the

basolateral membrane, where it is oxidized by hephaestin

and binds to transferrin for transport (Fig. 2E).

Iron release from the enterocyte into the bloodstream

is a tightly regulated process. When the body is iron-

replete, hepcidin binds ferroportin at the basolateral

surface of the enterocyte, inducing internalization and

degradation of the protein (Fig. 2F). This blocks iron

release, and iron is incorporated into ferritin in the en-

terocyte, which is lost when the cells are sloughed. Hep-

cidin expression is increased in response to iron overload

and inflammation and is reduced in response to increased

erythropoiesis, hypoxia, and iron deficiency. (5) Hep-

cidin production is also reduced during pregnancy, al-

lowing for increased maternal iron absorption. (6) In

murine models, hepcidin regulation has been demon-

strated by inflammatory cytokines, bone morphogenetic

protein signaling, and toll-like receptors. (9) A recent

study in mice has demonstrated that H-ferritin, as well as

hepcidin, is required for regulation of intestinal iron

efflux. (10)

TransportFerric iron is transported through the bloodstream

bound primarily to transferrin, a protein that has two

iron-binding sites. (1) Some iron is also found associated

with albumin or small molecules. In the bloodstream,

transferrin is typically one third saturated with iron.

Binding of free iron by proteins not only protects the

body from damage by free radicals but also sequesters

free iron from bacteria, which use host iron for reproduc-

tion. (5)

Tissue UptakeFor iron uptake in most tissues, transferrin binds to

transferrin receptors on the surface of the cell, and the

transferrin receptortransferrin complex is endocytosed.

Protons are pumped into the endosome, lowering the

pH and releasing iron from the transferrin. The free iron

is released into the cell for use, and the transferrin is

released back into the bloodstream. The number of

transferrin receptors expressed on the cell surface is reg-

ulated by intracellular iron concentrations. In a low-iron

state, expression of the transferrin receptor is increased

and expression of ferritin is reduced. Conversely, when

the intracellular iron concentration is high, expression ofthe transferrin receptor is reduced while expression of

ferritin is increased. (5)

StorageApproximately 75% of somatic iron is contained in he-

moglobin, 15% in storage sites (liver, bone marrow, and

spleen), and 10% in regulatory proteins. Iron is efficiently

recycled from senescent red blood cells. Erythrocytes are

phagocytosed by macrophages in the spleen, where they

are lysed and the protein is degraded. The released iron

can either be stored in the macrophage or sent back into

circulation bound to plasma transferrin. (5) Ferroportin

Figure 1. Iron balance in the neonate is a balance between

iron input from prenatal placental transfer; enteral and

parenteral iron intake; and transfusions and iron loss viaphlebotomy, gastrointestinal loss, and iron use for growth.

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is a transmembrane protein that transports iron from the

inside to the outside of a cell. It is found on the surface of

cells that store or transport iron, including enterocytes,

hepatocytes, and macrophages in the reticuloendothelial

system. Ferritin, a 24-subunit hollow protein sphere, is

the primary iron storage protein. Ferritin concentration

is regulated by intracellular iron content via the iron

response element/iron regulatory protein (IRE/IRP)

system. When iron content is low, the IRP binds the

IRE on ferritin mRNA and blocks translation. For release

from ferritin, iron is reduced to the ferrous form and exits

through pores in the ferritin protein. On the cell surface,

iron is reoxidized by ceruloplasmin for transport. (11)

Iron loss is not regulated by the human body and occurs

primarily by sloughing of iron-containing enterocytes or

via blood loss in menstruating females.

Special Considerations for InfantsRegulatory mechanisms present in adults may not be

fully developed in infants. In mice, ferroportin and

DMT1 are not expressed on the enterocyte surface until

late infancy, indicating that the structure for iron regula-

tion continues to develop postnatally. This is also true in

rats. Expression of DMT1 and ferroportin is not upregu-

Figure 2. Iron transport through the enterocyte. A. Heme iron is absorbed as an intact metalloprotein via heme carrier protein 1

(HCP-1). Ferrous iron is released from heme via heme oxygenase. B. Nonheme iron is converted to the ferrous form by ascorbic acidand duodenal cytochrome B (DcytB) on the surface of the brush border. Ferrous iron then binds to divalent metal transporter-1

(DMT1) and is transferred into the enterocyte. C. Ferric iron binds chelators in the small intestine and is absorbed via a 3 integrin

and mobilferrin pathway. After entry into the enterocyte, ferric iron is reduced by paraferritin and binds mobilferrin. D. Ferrous iron

from all three entry pathways is released into the intracellular iron pool and used for cellular metabolism, stored as ferritin, or

transferred out of the enterocyte. E. Iron is released by ferroportin at the basolateral membrane, where it is oxidized by hephaestinand binds to transferrin for transport. F. When the body is iron-replete, hepcidin binds ferroportin (IREG1) at the basolateral surface

of the enterocyte, inducing internalization and degradation of the protein.

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lated in iron-deficient rat pups by 10 days of age but

increases by 20 days. In humans, a randomized, con-

trolled trial found that at 6 months of age, iron absorp-

tion was not different between iron-sufficient and

-deficient infants, but at 9 months of age, unsupple-

mented infants increased iron absorption. (12) This sug-

gests that before 6 months of age, infants are unable to

modulate iron absorption in response to iron status.

Consequences of Iron Deficiency and ExcessEffects of Maternal and Perinatal IronDeficiency: Cell Culture and Animal Models

Approximately 80% of iron transfer to the fetus occurs

during the third trimester of pregnancy. In rats, when

maternal iron stores are inadequate, expression of pla-cental transferrin receptor and IRE-regulated DMT1

increase to augment iron transfer to the fetus. An in vitro

model of placental iron deficiency shows similar results,

with increased iron transfer from the apical to basolateral

side of BeWo cells, a commercially available human pla-

cental cell line. (13) These mechanisms may mitigate the

fetal effects of maternal iron deficiency, but severe ma-

ternal iron deficiency may affect fetal neurodevelopment

irreversibly.

Structural changes in iron-deficient rodents include

reduced myelin content, (14) shortened hippocampal

dendritic arbors, (15) and reduction of proteins neces-sary for myelin compaction. (16) The degree of neuronal

myelination of rat pups from mothers fed iron-deficient

and iron-supplemented diets during pregnancy and lac-

tation were compared. The iron-deficient rat pups had

reduced brain and spinal cord myelination compared

with iron-replete pups. (14) Similar results have been

shown in iron-deficient mice. (16) Maternal iron defi-

ciency is associated with reduced brain iron concentra-

tions, altered dopamine metabolism, and changes in

myelin fatty acid composition. (17) Decreased neuronal

metabolic activity has also been observed in iron-

deficient rats. Cytochrome c oxidase activity is reducedin the hippocampus, dentate gyrus, piriform cortex, me-

dial dorsal thalamic nucleus, and the cingulate cortex of

iron-deficient rats, indicating that areas of the brain

involved in memory processing are selectively affected by

iron deficiency. (18) Iron-deficient rats also have reduced

oligodendrocyte metabolic activity, as measured by ac-

tivity of 2,3-cyclic nucleotide 3-phosphohydrolase,

lower concentrations of myelin basic protein, alterations

in fatty acid composition of hindbrain phospholipids,

and reduced cytochrome oxidase activity compared with

iron-sufficient rats. Iron deficiency during gestation and

early postnatal life both show these results. (19)

Behavioral changes also occur. These include poorer

learning capacity (20) and spatial navigation (21) and

increased hesitancy (21) and anxiety. (22) These changes

may be irreversible because reversal of iron deficiency

after weaning did not improve deficits in sensorimotor

function, increased hesitancy to explore, and spatial

learning. (21)

Effects of Maternal Iron Deficiency:Human Data

The consequences of iron deficiency on the human fetus

are less well characterized because ethically sound, ran-

domized, controlled trials in this population are difficult

to design. However, some information on the effects of

iron deficiency can be gleaned from developing countrieswhere iron deficiency during pregnancy is common.

Evidence is also available from the literature on iron

supplementation during pregnancy.

Because the placenta adapts to increased iron transfer

to the fetus in the presence of maternal iron deficiency,

the fetus is relatively protected until severe maternal

deficiency develops. At birth, most studies have shown

minimal differences in iron status (cord blood hemoglo-

bin, serum iron, serum ferritin, and total iron-binding

capacity [TIBC]) between iron-supplemented and non-

supplemented mothers, although serum ferritin tends to

be higher in infants born to nonanemic mothers. (23)Follow-up evaluation suggests that maternal iron supple-

mentation may protect the infant from developing iron

deficiency anemia. Infants born with low ferritin stores

tend to continue to have lower iron stores than age- and

weight-matched controls at 9 to 12 months of age. (24)

Neonatal and Infant Iron DeficiencyIron deficiency in infancy appears to affect socioemo-

tional, cognitive, and motor function negatively. Iron-

deficient infants are less engaged with their environment

and are more shy, hesitant, solemn, and difficult to

soothe. (25) They demonstrate slower auditory neuraltransmission speed, (26) poorer recognition memory,

(27) and slower motor function. The severity of iron

deficiency affects the degree of socioemotional behav-

ioral differences. Socioemotional behavior was assessed

among 77 infants ages 9 to 10 months who received

iron supplementation for 3 months. Linear effects of iron

status were found for shyness, orientation-engagement,

soothability, positive affect, and latency to engagement

with examiner. (25)

Iron deficiency in infancy has been associated with

long-termnegativeoutcomes.Theseincludealteredsleep-

wake cycles at preschool age, (28) reduced learning

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capacity and positive task orientation in elementary-age

children, (29) behavioral problems in adolescence, (30)

and deficits in executive function and recognition mem-

ory in young adulthood. (31)

The effect of iron supplementation was evaluated in a

blinded study of 77 term breastfed infants randomized to

either 7.5 mg/day of elemental iron or placebo from 1 to

6 months of age. Iron supplementation resulted in sig-

nificantly higher visual acuity and psychomotor develop-

ment index at 13 months of age, suggesting there may be

some benefit to supplementation in breastfed infants.

(32) It has been questioned whether iron supplementa-

tion in breastfed infants might increase the risk of infec-

tion. A systematic review in 2002 found no evidence of

increased infection in children receiving iron supplemen-tation, although the risk of diarrhea was increased. Thir-

teen of the 28 studies in this review were conducted in

infants, and a variety of iron supplementation methods,

including parenteral iron, enteral iron, or iron-fortified

formula, were included. (33) The American Academy of

Pediatrics recommends that exclusively breastfed infants

receive 1 mg/kg per day of iron at 4 months of age. (34)

Iron Deficiency in Preterm InfantsPreterm infants are at increased risk for long-term con-

sequences of iron deficiency because they are born before

the bulk of placental iron transfer. The human braintriples in weight as it develops between 24 and 44 weeks

postconception. Areas of significant development in-

clude the visual and auditory cortexes, capability for

receptive language and executive function, and the neu-

ronal basis for learning. Because neuronal development

requires iron, these processes are vulnerable to iron defi-

ciency in the preterm infant. (2)

Tsunenobu and associates (35) examined the correla-

tion between umbilical cord ferritin values and perfor-

mance on mental and psychomotor tests at 5 years of age.

Children whose serum ferritin concentrations were in the

lowest quartile at birth performed the worst. In thesample, 13% of the children (n278) were born preterm

and 22% were small for gestational age. The percentage

of low birthweight was highest in the lowest quartile of

serum ferritin values. This study highlights the possibility

that inadequate iron accretion during gestation may have

long-term developmental effects.

Steinmacher and colleagues (36) evaluated the neu-

rodevelopment of a cohort of 5-year-old children who

weighed less than 1,301 g at birth and had been random-

ized to early (as soon as enteral feedings reached

100 mL/kg per day) or late (61 days of age) iron

supplementation. The follow-up study showed a trend

toward better neurodevelopmental outcome in the chil-

dren who received early iron supplementation, but it was

underpowered.

Consequences of Iron Excess: Neonates andInfants

Like iron deficiency, iron excess can have adverse effects.

Iron is a pro-oxidant and may damage lipids, polysaccha-

rides, DNA, and proteins through free radical formation.

(1) Iron is more likely to cause peroxidation of poly-

unsaturated fatty acids when adequate antioxidants, es-

pecially vitamin E, are not available. (37) Because of

these effects, concern has been raised that providing

routine iron supplementation to iron-sufficient infants

might negatively affect long-term development, al-though this was not borne out in a study supplementing

iron-sufficient infants age 6 to 18 months who were

followed until 10 years of age. (38)

Consequences of Iron Excess: Preterm InfantsProviding excess iron might be particularly harmful to

preterm infants, who are at increased risk for oxidative

injury for several reasons, including immature antioxi-

dant defense systems. (39) Neonates tend to have low

TIBC; high saturation of circulating transferrin; and low

concentrations of ceruloplasmin, unbound transferrin,

and albumin, all of which bind free iron. (40) Althoughno direct link has been shown between iron excess and

disease in preterm infants, concerns have been raised

about the potential for iron to cause increased oxidative

stress, which may contribute to complications of pre-

maturity such as retinopathy of prematurity (41) or

bronchopulmonary dysplasia. (42) Short-term studies

indicate that iron does not induce oxidative stress, as

measured by isoprostanes and antioxidant status, when

provided to stable, growing low-birthweight infants at

doses ranging from 2 to 12 mg/kg per day or at a

twice-daily dose of 9 mg per day. (43)(44)

Risks associated with repeated blood transfusionshave primarily been studied in patients who have thalas-

semia major. Treatment for this autosomal recessive dis-

order includes frequent transfusion, which is associated

with increased accumulation of hepatic iron, cardiac

complications, increased incidence and severity of infec-

tions, altered immune function, and endocrinopathies

(eg, diabetes, hypothyroidism). (39) These term infants

differ from preterm infants requiring multiple transfu-

sions because the requirement for transfusions in preterm

infants is largely due to phlebotomy losses. (45) The risk

or benefit of restrictive versus liberal transfusion guide-

lines is still not known. (46)(47) An increased risk of

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apnea and severe brain hemorrhage or periventricular

leukomalacia was reported in one single-center trial, (47)

but this risk was not corroborated in a larger multicenter,

randomized, controlled trial. (46) The long-term neuro-

development measured 18 to 21 months after transfu-

sion with restrictive or liberal guidelines showed no

difference. (48)

Assessment of Iron StatusAssessing Iron Status in Adults

Traditional measures of iron status include hematocrit

and hemoglobin, red cell indices, serum ferritin, serum

iron, and TIBC. Each test identifies iron availability at a

different point in iron metabolism. The clinicians choice

of test(s) for iron status is driven by the question beingasked, coexisting factors that may affect the laboratory

test, and the sensitivity and specificity of the test.

Hemoglobin and hematocrit are the least sensitive

measures of iron deficiency. (49) Iron deficiency anemia

is microcytic and hypochromic. Low mean cell volume

(MCV) is consistent with iron deficiency but may also

reflect dysfunction of hemoglobin synthesis. (50) Serum

ferritin reflects iron stores. Low serum ferritin is specific

for iron deficiency. (51) However, ferritin is an acute-

phase protein and may increase during infection, mask-

ing low stores. Serum iron concentration identifies ad-

vanced iron deficiency but has low sensitivity. It isaffected by iron intake and time of day, (49) is elevated in

erythropoietic dysfunction, and decreased during infec-

tion or inflammation. (50) The TIBC primarily reflects

the amount of available unbound transferrin and is ele-

vated in iron deficiency. Historically, TIBC was standard

for measuring iron status, but it has been largely replaced

by serum ferritin. Synthesis of the soluble transferrin

receptor (sTfR) is increased when intracellular iron is

insufficient. Increased sTfR is observed in iron deficiency

or when erythropoiesis elevates cellular iron needs. This test

is specific for iron deficiency in patients who are suspected

to have nutritional iron deficiency or anemia of chronicdisease, but it is affected by hematologic disorders. (49)

Assessing Iron Status in InfantsThe tests used to assess iron status are affected by hema-

tologic changes after birth. Thus, standard reference

ranges must be interpreted with caution when evaluating

the iron status of preterm and even term infants in the

first 6 months after birth. In a group of term 9- to

12-month-old infants who had iron deficiency defined by

sTfR greater than 2.45 mg/L, the sensitivity of hemo-

globin (67%) was lower than that of serum ferritin (83%)

and MCV (86%), while the specificity of hemoglobin was

higher than the other tests. This indicates that serum

ferritin and MCV may be better screening tests for iron

deficiency than hemoglobin assessment. (52)

Serum ferritin may be affected by length of gestation,

sex, maternal iron status, maternal-fetal nutrient exchange,

(51) hypoxemia, reduced placental perfusion in utero, (53)

and inflammation. (49) The effect of inflammation is espe-

cially important in preterm infants, who have reduced iron

stores and are at increased risk for infection.

sTfR exhibits developmental changes in the first 2

postnatal years, but sTfR and the ratio of sTfR to serum

ferritin may be better markers than ferritin alone for

detection of iron deficiency. (54)

Hemoglobin concentrations change during gestation

and the first few postnatal months. Hemoglobin risesfrom 11 to 12 g/dL (110 to 120 g/L) at 22 to 24 weeks

to 13 to 14 g/dL (130 to 140 g/L) at term. As eryth-

ropoiesis slows after birth (due to reduced erythropoietin

[Epo] production in response to increased oxygenation),

the hemoglobin concentration drops, then rises again by

6 months as erythropoiesis increases again. The drop in

hemoglobin concentration after birth is greater in pre-

term than term infants. By 4 to 8 weeks after birth, the

average hemoglobin concentration of a preterm infant

(1,500 g birthweight) is 8 g/dL (80 g/L).

Difficulties in Assessing Infant Iron Status andAnemia of Prematurity

The gestational-appropriate development and hemato-

poietic changes that take place after birth include

changes in hemoglobin concentration and red cell size.

Iatrogenic changes also occur in preterm infants.

The anemia of prematurity is a hypoproliferative, nor-

mochromic, normocytic anemia characterized by re-

duced production of Epo. (55) The decrease in Epo

production is caused by the transition from a hypoxic

intrauterine environment to the relatively hyperoxic

extrauterine environment. In addition, fetal Epo is pro-

duced by the liver, which is relatively insensitive tohypoxia, whereas by term gestation, Epo is primarily

produced by the kidney, which is more responsive to

hypoxia. Additional contributors to anemia in the pre-

term infant include phlebotomy losses, the shortened red

blood cell life span, iron deficiency, and inflammation.

(45) At what point this anemia becomes pathologic and

the appropriate clinical response to such a development

is an area of ongoing research. Approximately 85% of

extremely low-birthweight infants are transfused with

adult red blood cells, further complicating the ability to

assess iron status because circulating blood reflects both

the babys and the transfused adult cells.

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New Possibilities for Assessment of Iron Statusof Infants

One candidate test for detection of iron-deficient eryth-

ropoiesis is the zinc protoporphyrin-to-heme ratio

(ZnPP/H). ZnPP/H measures the amount of zinc rel-

ative to iron incorporated into the protoporphyrin ring

during heme synthesis. Figure 3 depicts the balance

between the ZnPP molecule and heme. Because the

body prioritizes iron for hematopoiesis, ZnPP/H is a

sensitive indicator of iron deficiency. The only known

cause of increased formation of zinc protoporphyrin is

increased iron-deficient erythropoiesis. As a result, this

test is specific for iron-deficient erythropoiesis (not nec-

essarily iron deficiency) of any cause. (49) A density

gradient can be used to separate denser, mature erythro-cytes from their lighter, immature counterparts. Measur-

ing the ZnPP/H on this top fraction may further in-

crease the sensitivity of this test to identify conditions

associated with impaired erythrocyte iron delivery. (56)

The sensitivity and specificity of ZnPP/H in preterm and

term infants, especially in special conditions such as nu-

tritional inadequacy or zinc deficiency, have not been

clearly determined. A normal range for ZnPP/H of

preterm infants has been proposed, (57) but the sample

size was small.

Prevention and Treatment of Iron Deficiencyin the Preterm InfantPreterm birth increases the risk for iron deficiency. Cel-

lular immaturities and reduced iron delivery may nega-

tively affect the iron status of the preterm infant. Type of

feeding (formula, human milk, soy-based formula, or use

of fortifier) also affects iron delivery.

The intestinal epithelium develops rapidly after birth,

stimulated by growth factors in amniotic fluid, co-

lostrum, and human milk. (58) Similarly, other tissues in

the preterm infant are not fully developed. Although

these do not have direct influence on iron absorption,

they may affect iron utilization in the preterm infant.

Iron Supplementation: EnteralThe optimal timing and dosage of iron supplementa-

tion for the preterm infant has been extensively studied.

The American Academy of Pediatrics recently issued

new iron recommendations, indicating that breastfed,iron-sufficient term infants typically have iron stores at

birth that last until 4 months of age, when either iron-

containing complementary foods or an iron supplement

should be introduced. (34) Preterm infants are born with

less total iron stores and have significant iatrogenic blood

loss, necessitating earlier supplementation.

Low-birthweight infants who begin iron supplemen-

tation (2 mg/kg per day) at 2 weeks of age have better

iron status at 3 to 6 months of age than infants who only

receive iron before 6 months if they develop iron defi-

ciency. (59) Two studies (60)(61) have tested whether

early iron supplementation in very low-birthweight in-fants (early iron started at 14 days of age or when the

infant was tolerating 100 mL/kg per day enteral feed-

ings; late iron started at 61 days of age) improved serum

ferritin at 2 months. Neither study showed a difference in

serum ferritin at 2 months of age, but blood transfusions

and iron deficiency were reduced in one study. (60) The

second study (61) was underpowered. (62) Arnon and

associates (37) reported improved iron status of preterm

infants at 4 and 8 weeks when iron supplementation

began at 2 weeks rather than 4 weeks of age. No negative

effects of early supplementation were reported. These

studies indicate that early supplementation may be neu-tral at worst and helpful at best.

Human milk is the best choice for term infants, but

human milk alone does not provide adequate nutrients

for the growing preterm infant. Iron absorption is af-

fected by protein composition. Iron absorption from

human milk, whey- or casein-based cow milk formulas,

and soy formulas has been compared. Iron is best ab-

sorbed from human milk and is more readily available

from whey-based than casein-based formula. (63)(64)

Estimated availability of iron from soy-based formulas

varies. The whey-to-casein ratio, (64) type of iron com-

pound, (65) and amounts of ascorbic acid and phytates

Figure 3. Zinc replaces iron in the center of protoporphyrin IX

when iron is in low supply.

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(66) all affect availability. Although iron may be less

readily available from soy-based formulas, it is similar to

cow milk formulas in preventing iron deficiency in in-

fancy. However, soy-based infant formulas are not rec-

ommended for use in preterm infants (unless other for-

mulas are contraindicated).

Although iron is best absorbed from human milk,

because the iron content of human milk is low, the total

amount of iron an infant absorbs may be higher from

formulas. The ideal amount of iron to provide in iron-

fortified formulas is still an area of investigation; most

preterm formulas in the United States contain 1.8 mg/

100 kcal. The estimated oral iron requirement for pre-

term infants is 2 to 4 mg/kg per day, which may be lessin an infantreceiving redblood cell transfusions. TheAmer-

ican Academy of Pediatrics recommends that infants not

receiving human milk receive an iron-fortified formula and

that preterm infants receive at least 2 mg/kg per day of

elemental iron from 1 to 12 months of age. (34)

Iron Supplementation: ParenteralParenteral iron has been considered as an option for

patients who are unable to absorb adequate iron enter-

ally. It has been used effectively to improve iron status

and promote erythropoiesis in preterm infants. However,parenteral iron is not as safe as enteral iron. Risks include

neonatal sepsis, (67) iron overload, (68) and anaphylaxis.

(69) Consensus on the best iron solution, dosage, and

route of administration has not been reached. Dosage,

timing, route of administration, and use with Epo has

varied in studies of preterm infants. (70)(71) In utero

iron accretion is estimated at 1.6 to 2.0 mg/kg per day

during the third trimester. (72) It has been suggested

that a parenteral iron dose of 1 mg/kg per day may meet

iron needs; (71) this dose has been successfully used in

preterm infants also receiving recombinant Epo.

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American Board of Pediatrics Neonatal-Perinatal

Medicine Content Specifications

Understand the mechanism and gestational

timing of placental transfer of iron to the

fetus and its effect on iron stores in

newborn infants.

Recognize the causes of iron deficiency

anemia and various prevention measures.

Recognize the clinical and diagnostic features, laboratory

findings, management, and long-term consequences of iron

deficiency anemia.

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Longitudinal evaluation of externalizing and internalizing behaviorproblems following iron deficiency in infancy. J Pediatr Psychol.2010;35:29630531. Lukowski AF, Koss M, Burden MJ, et al. Iron deficiency ininfancy and neurocognitive functioning at 19 years: evidence oflong-term deficits in executive function and recognition memory.Nutr Neurosci. 2010;13:547032. Friel JK, Aziz K, Andrews WL, Harding SV, Courage ML,Adams RJ. A double-masked, randomized control trial of ironsupplementation in early infancy in healthy term breast-fed infants.

J Pediatr. 2003;143:58258633. Gera T, Sachdev HP. Effect of iron supplementation on in-cidence of infectious illness in children: systematic review. BMJ.2002;325:114234. Baker RD, Greer FR. Clinical reportdiagnosis and preventionof iron deficiency and iron-deficiency anemia in infants and youngchildren (03 years of age). Pediatrics. 2010;126:1040105035. Tsunenobu T, Goldenberg RL, Hou J, et al. Cord serumferritin concentrations and mental and psychomotor developmentof children at five years of age. J Pediatr. 2002;140:16517036. Steinmacher J, Pohlandt F, Bode H, Sander S, Kron M, FranzAR. Randomized trial of early versus late enteral iron supplementa-tion in infants with a birth weight of less than 1301 grams: neuro-cognitive development at 5.3 years corrected age. Pediatrics. 2007;

120:53854637. Arnon S, Regev RH, Bauer S, et al. Vitamin E levels duringearly iron supplementation in preterm infants. Am J Perinatol.

2009;26:38739238. Gahagan S, Yu S, Kaciroti N, Castillo M, Lozoff B. Linear and

ponderal growth trajectories in well-nourished, iron-sufficient in-

fants are unimpaired by iron supplementation. J Nutr. 2009;139:

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39. Ozment CP, Turi JL. Iron overload following red blood celltransfusion and its impact on disease severity. Biochim Biophys Acta.

2009;1790:694701

40. Collard K. Iron homeostasis in the neonate. Pediatrics. 2009;123:12081216

41. Inder TE, Clemett RS, Austin NC, Graham P, Darlow BA.High iron status in very low birth weight infants is associated with

an increased risk of retinopathy of prematurity. J Pediatr. 1997;

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42. Silvers KM, Gibson AT, Russell JM, Powers HJ. Antioxidantactivity, packed cell transfusions, and outcome in premature infants.

Arch Dis Child Fetal Neonatal Ed. 1998;78:F214F219

43. Braekke K, Bechensteen AG, Halvorsen BL, Blomhoff R,Haaland K, Staff AC. Oxidative stress markers and antioxidant

status after oral iron supplementation to very low birth weightinfants. J Pediatr. 2007;151:2328

44. Miller SM, McPherson RJ, Juul SE. Iron sulfate supplementa-tion decreases zinc protoporphyrin to heme ratio in premature

infants. J Pediatr. 2006;148:4448

45. Widness JA. Pathophysiology of anemia during the neonatalperiod, including anemia of prematurity. NeoReviews. 2008;9:e520

46. Kirpalani H, Whyte RK, Andersen C, et al. The PrematureInfants in Need of Transfusion (PINT) study: a randomized, con-

trolled trial of a restrictive (low) versus liberal (high) transfusion

threshold for extremely low birth weight infants. J Pediatr. 2006;

149:301307

47. Bell EF, Strauss RG, Widness JA, et al. Randomized trial ofliberal versus restrictive guidelines for red blood cell transfusion in

preterm infants. Pediatrics. 2005;115:1685169148. WhyteRK, Kirpalani H, Asztalos EV,et al. Neurodevelopmen-tal outcome of extremely low birth weight infants randomly as-

signed to restrictive or liberal hemoglobin thresholds for blood

transfusion. Pediatrics. 2009;123:207213

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50. Worwood M. The laboratory assessment of iron statusanupdate. Clin Chim Acta Int J Clin Chem. 1997;259:323

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52. Vendt N, Talvik T, Kool P, et al. Reference and cut-off valuesfor serum ferritin, mean cell volume, and hemoglobin to diagnoseiron deficiency in infants aged 9 to 12 months. Medicina (Kaunas).2007;43:69870253. Chockalingam UM, Murphy E, Ophoven JC, Weisdorf SA,Georgieff MK. Cord transferrin and ferritin values in newborninfants at risk for prenatal uteroplacental insufficiency and chronichypoxia. J Pediatr. 1987;111:28328654. Olivares M, Walter T, Cook JD, Hertrampf E, Pizarro F.Usefulness of serum transferrin receptor and serum ferritin indiagnosis of iron deficiency in infancy. Am J Clin Nutr. 2000;72:1191119555. Bishara N, Ohls RK. Current controversies in the managementof the anemia of prematurity. Semin Perinatol. 2009;33:293456. Blohowiak SE, Chen ME, Repyak KS, et al. Reticulocyteenrichment of zinc protoporphyrin/heme discriminates impaired

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patients. J Pediatr. 2003;142:27327858. Buccigrossi V, De Marco G, Bruzzese E, et al. Lactoferrininduces concentration-dependent functional modulation of intesti-

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59. Lundstrom U, Siimes MA, Dallman PR. At what age does ironsupplementation become necessary in low-birth-weight infants?

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60. Franz AR, Mihatsch WA, Sander S, Kron M, Pohlandt F.Prospective randomized trial of early versus late enteral iron supple-

mentation in infants with a birth weight of less than 1301 grams.

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NeoReviews Quiz

11. The uptake of iron by the enterocyte is an important regulatory step in body iron homeostasis. Of thefollowing, the absorption of heme iron in the enterocyte is primarily regulated by:

A. Beta-3 integrin.B. Divalent metal transporter-1.C. Duodenal cytochrome B.D. Heme carrier protein 1.E. Paraferritin.

12. The release of iron from the enterocyte into the bloodstream is a tightly regulated process, influenced bythe iron status of the body. Of the following, the release of iron from the enterocyte into the bloodstreamis primarily regulated by:

A. Ferroportin.B. Hephaestin.C. Mobilferrin.D. Paraferritin.E. Transferrin.

13. Preterm infants are at increased risk for long-term neurodevelopmental consequences of iron deficiencybecause they are deprived of placental iron transfer from shortened gestation. Conversely, preterm infantsare also at increased risk for potential oxidative complications of iron excess from repeated bloodtransfusions. Assessment of iron status, therefore, is important in the nutritional management of preterminfants. Of the following, the most specific blood test of iron status in preterm infants is themeasurement of:

A. Erythropoietin.

B. Ferritin.C. Hemoglobin.D. Soluble transferrin receptor.E. Total iron-binding capacity.

14. In iron deficiency, another trace element is incorporated into the protoporphyrin ring of the hememolecule. This observation has led to the development of a new test that can be used as a sensitivemarker of iron-deficient erythropoiesis. Of the following, the candidate trace element used as a measureof iron-deficient erythropoiesis is:

A. Chromium.B. Copper.C. Manganese.D. Selenium.E. Zinc.

15. The optimal timing and dosage of iron supplementation for preterm infants has been studied extensively.Of the following, the best suggested postnatal age for starting iron supplementation (2.0 mg/kg per day)in preterm infants is at:

A. Birth.B. 2 weeks.C. 4 weeks.D. 2 months.E. 4 months.

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DOI: 10.1542/neo.12-3-e1482011;12;e148Neoreviews

Carissa Cheng and Sandra JuulIron Balance in the Neonate

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