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DOI: 10.1542/neo.12-3-e1482011;12;e148Neoreviews
Carissa Cheng and Sandra JuulIron Balance in the Neonate
http://neoreviews.aappublications.org/content/12/3/e148located on the World Wide Web at:
The online version of this article, along with updated information and services, is
.ISSN:60007. Copyright 2011 by the American Academy of Pediatrics. All rights reserved. Print
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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.
nutrition iron
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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.
nutrition iron
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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
nutrition iron
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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.
nutrition iron
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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.
nutrition iron
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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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Medicine Content Specifications
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Recognize the causes of iron deficiency
anemia and various prevention measures.
Recognize the clinical and diagnostic features, laboratory
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nutrition iron
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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.
nutrition iron
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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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