Iron Homeostasis in the Neonate

Keith J. Collard
Pediatrics 2009;123;1208-1216
DOI: 10.1542/peds.2008-1047

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://www.pediatrics.org/cgi/content/full/123/4/1208

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
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REVIEW ARTICLE

Iron Homeostasis in the Neonate

Keith J. Collard, BSc, MSc, PhD

Peninsula Allied Health Centre, School of Health Professions, University of Plymouth, Plymouth, United Kingdom
The author has indicated he has no financial relationships relevant to this article to disclose.

ABSTRACT
The regulation of the availability of micronutrients is particularly critical during
periods of rapid growth and differentiation such as the fetal and neonatal stages. Both
iron deficiency and excess during the early weeks of life can have severe effects on www.pediatrics.org/cgi/doi/10.1542/
peds.2008-1047
neurodevelopment that may persist into adulthood and may not be corrected by
restoration of normal iron levels. This article provides a succinct overview of our doi:10.1542/peds.2008-1047
current understanding of the extent to which newborns, particularly premature Key Words
growth and development, iron
newborns, are able (or not able) to regulate their iron status according to physiologic homeostasis, infant, newborn, premature
need. Postnatal development of factors important to iron homeostasis such as intes-
Abbreviations
tinal transport, extracellular transport, cellular uptake and storage, intracellular DMT-1— divalent metal transporter 1
regulation, and systemic control are examined. Also reviewed are how factors NTBI—non–transferrin-bound iron
peculiar to the sick and premature neonate can further adversely influence iron Accepted for publication Aug 21, 2008
homeostasis and exacerbate iron-induced oxidative stress, predispose the infant to Address correspondence to Keith J. Collard,
bacterial infections, and, thus, compromise his or her clinical situation further. The BSc, MSc, PhD, University of Plymouth, School
of Health Professions, Peninsula Allied Health
article concludes with a discussion of the areas of relative ignorance that require Centre, Derriford Road, Plymouth PL6 8BH,
urgent investigation to rectify our lack of understanding of iron homeostasis in what United Kingdom. E-mail: keith.collard@
plymouth.ac.uk.
is a critical stage of development. Pediatrics 2009;123:1208–1216
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2009 by the

I
American Academy of Pediatrics
RON PLAYS AN essential role in many important biochemical processes.1 As with all
nutrients, the requirement for iron is greater during periods of rapid growth and
differentiation such as in the late fetal and neonatal period. Consequently, poor iron homeostasis during this period
can result in disordered development.
Inadequate tissue iron levels can lead to reduced erythropoiesis and poor O2-carrying capacity. The nervous
system, which develops rapidly during the late fetal and early neonatal period, seems to be particularly susceptible
to iron deficiency and excess.2 Consequently, anemia, iron deficiency, or iron excess can all have severe effects on
neurodevelopment that, in the case of iron deficiency, may not be reversed by iron supplementation,3–5 and in the
case of iron excess, may remain into adulthood.6–8 Thus, events occurring in early life can have long-lasting effects
on neuronal function in the adult. The mechanism by which iron deficiency affects brain development is incom-
pletely understood, but it may involve general metabolic deficiencies, disordered myelination, disordered synapto-
genesis,9 and changes in specific neurotransmitter function.5 Iron excess may mediate its detrimental effects through
its ability to generate free radicals via the Fenton and Heber-Weiss reactions.9
Excessive iron will also promote bacterial colonization.10 It has also been proposed that the adverse clinical
outcome of premature infants receiving blood transfusions may be related to some extent to iron-induced oxidative
damage and/or infection.11–13
Because of the importance of iron, and the detrimental effects of iron deficiency and excess, a precise regulation
of the availability of (and redox state of) physiologically active (non–protein-bound) iron in tissues is essential to
health. There is no effective route of iron excretion that may be regulated according to physiologic need. Conse-
quently, the control of tissue iron levels involves the regulation of dietary iron transport by the intestine, transport
and storage of iron within the circulation, the uptake storage and release from such cells as macrophages and
hepatocytes, and the regulation of intracellular levels within all cells. Although dietary iron absorption regulates the
intake of iron from external sources, there is a high degree of iron conservation within the body in which a
considerable amount of the iron present in hemoglobin of senescent erythrocytes is recycled through the reticu-
loendothelial system.
To understand how the developing fetus and newborn can or cannot cope with iron deficiency and excess, and
how iron dysregulation may or may not have significant short- and long-term consequences, a knowledge of the
functional development of the factors involved in iron homeostasis is required.14

INTESTINAL IRON TRANSPORT

The main food source for infants is breast milk or formula. Breast milk does not contain heme iron. Consequently,
nonheme iron that is bound to milk proteins or to other lower molecular weight substances is the main source of
dietary iron for infants. In addition, for cases in which there is a need for iron supplementation, it may be given as

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FIGURE 1
The known and postulated iron-transport processes believed to be operating in the
neonatal duodenum. The well-accepted processes are shown in the upper part of the
diagram. Dietary iron is converted to Fe2⫹ by ferroxidase enzymes to enable it to be
transported into the enterocyte by DMT-1. Within the enterocyte the iron remains within
the enterocyte (mostly bound to ferritin) or transported out by ferroportin (FPN). The
transported iron is then converted to Fe3⫹ by hephaestin to allow it to bind to transferrin.
The proposed, but currently unproven, transport system is shown in the lower part of the
diagram. In this process, iron bound to lactoferrin (Lf) is transported into the enterocyte
via the lactoferrin receptor. The question marks indicate the unproven nature of the
process and the lack of knowledge concerning the fate of the iron entering the entero-
cyte by this route.
ferrous sulfate. Thus, the major iron-transport proteins
of relevance in the newborn are the energy-consuming
divalent metal transporter 1 (DMT-1) and ferroportin
(Fig 1).
Most dietary iron is in the Fe3⫹ form. Before absorp-
tion, dietary Fe3⫹ must be reduced to Fe2⫹, which seems
to occur at the apical surface of the enterocytes by fer-
roxidase enzymes such as cytochrome b.1 Once reduced
to the ferrous form, the Fe2⫹ is transported into the
enterocytes by DMT-1. This carrier transports other di-
valent metal ions such as Cu2⫹ and Zn2⫹. The trans-
porter also requires protons (H⫹) to act as cotransported
ions with the Fe2⫹.15 Consequently, the carrier is partic-
ularly active in the proximal duodenum, where it en-
counters acidic chyme leaving the stomach. The iron
transported into the cell by DMT-1 then enters a pool of
iron referred to as the intracellular or “labile” pool. The
identity of this pool is unclear but probably involves the
binding of iron to cellular proteins such as ferritin or
other iron-binding molecules. Ultimately, the iron is
transported across the basolateral border of the entero-
cyte by the specific carrier ferroportin. Ferroportin is
essential for iron absorption and may be regulated by the
iron-regulating peptide hepcidin. The transported Fe2⫹
is then oxidized to Fe3⫹ by the ferroxidase enzyme hep-
haestin, which converts the iron to a form that can bind
to transferrin for transportation within the circulation.1
Hephaestin is structurally and functionally similar to the
serum ferrireductase enzyme ceruloplasmin,16 which
also might have a role to play in gut Fe3⫹ oxidation.17 In
contrast to the effects on ferroportin, hephaestin expres-
sion does not seem to be well regulated by iron status.16
It is generally considered that rat pups and healthy
term human infants are born with reasonable iron stores
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that may be sufficient to tide them over their early
postnatal life18,19 when the ability to regulate iron uptake
according to dietary supply may not be well developed.20
Studies in newborn rats showed that both DMT1 and
ferroportin gene expression increased in response to iron
deficiency at postnatal day 20 but not at postnatal day
10. This indicated that gut iron transport was not re-
sponsive to iron status in early infancy, but it developed
during later infancy.18 In early infancy the rat pup will be
unable to upregulate intestinal iron transport in re-
sponse to low dietary iron and may also be unable to
downregulate in response to increased iron intake. In
human infants there also seems to be little or no homeo-
static regulation of gut absorption in young infants (⬍6
months of age), but it seems that older infants (9 months
of age) are able to downregulate gut iron transport in
response to iron supplements.20 The inability of young
infants to regulate gut iron absorption predisposes them
to iron deficiency when dietary iron is low and to iron
overload when dietary iron levels are high. Conse-
quently, it has been suggested that excessive dietary
intake of iron in young infants can lead to excessive iron
absorption and iron-induced oxidative damage. How-
ever, a number of studies have failed to show any evi-
dence of increased oxidative stress in very low birth
weight infants (⬍32 weeks’ gestation) who are given
significant oral iron supplementation, particularly if they
are fed breast milk.21–24 Whether iron supplementation
in premature infants leads to iron-induced oxidative
stress may well depend on the gestational age and the
clinical treatment the infant receives.25 Smaller, younger
infants receiving ventilation and blood transfusions are
considered more likely to show evidence of iron-induced
oxidative damage than older infants.25 The postulated
protective effect of breast milk may be related to the
presence of lactoferrin.26 Lactoferrin is able to bind free
iron and consequently limit the absorption of dietary
iron and reduce the incidence of iron-induced oxidative
stress. Breastfed infants has significantly higher total
antioxidant capacity and significantly lower oxidative
stress index.27 There is also a positive correlation be-
tween a marker of oxidative stress (total peroxide) and
plasma iron levels and a negative correlation between
total antioxidant capacity and plasma iron. These find-
ings are considered to be a result of the iron-chelating
property of lactoferrin in breast milk.
In addition to acting as an iron chelator in the gut,
lactoferrin has also been proposed as a means of trans-
porting iron from the gut in neonatal mice via the lac-
toferrin receptor present on the apical border of entero-
cytes.28 This transport mechanism, which seems to be
responsive to iron needs,29 could potentially help to limit
the influence of dietary iron deficiency during the period
in which DMT-1 is poorly responsive to iron require-
ment. However, lactoferrin seems to enhance iron ab-
sorption in newborn calves only when fully saturated
with iron30; this would be unlikely to occur if luminal
iron level was low. Also, neonatal mice rendered lacto-
ferrin deficient by knocking out the gene that expresses
lactoferrin showed no evidence of reduced intestinal
iron uptake,31 and transgenic mice overproducing lacto-
PEDIATRICS Volume 123, Number 4, April 2009 1209
ferrin did not increase the hemoglobin levels in their
suckling neonates except at very high maternal dietary
iron intake.32 It is possible that lactoferrin acts mainly as
an iron chelator in neonatal gut but when fully saturated
with iron it may contribute to gut iron transport.
Unlike the situation in the gut, liver DMT1 gene ex-
pression in early infancy has been shown to increase
with iron deficiency and decrease during iron loading,
suggesting that the liver may play an important role as a
sink or source for use in regulating iron metabolism
during early infancy when gut transport may be unre-
sponsive.18 Such a view is supported by previous work
on very low birth weight premature infants, which dem-
onstrated a significant positive relationship between the
volume of blood transfused, the level of iron in serum,
and the concentration of iron in the liver.33 Thus, these
infants were capable of responding to iron overload by
translocating iron from the circulation to the liver and
limiting the likelihood of iron-induced oxidative stress.33
EXTRACELLULAR IRON TRANSPORT AND CELLULAR
IRON UPTAKE
The major factors in the extracellular transport of iron
are the iron-binding protein transferrin and the activity
of the ferroxidase enzyme ceruloplasmin, which con-
verts iron to the oxidized form (Fe3⫹) so that it can bind
to transferrin. Many studies have consistently demon-
strated that the level of both proteins is low in newborns
and particularly so in premature infants.34–39 Further-
more, the transferrin saturation level is high, indicating
few available binding sites for any additional free iron.
Thus, premature infants have lower ferroxidase activity
and poor iron-binding capacity. Because ceruloplasmin
does not readily cross the placenta, the low levels in
premature serum reflect the poor synthetic capacity of
these infants.36
In addition to the specific iron binding of transferrin,
there is evidence that albumin may also play a role as an
antioxidant by binding free iron and limiting its ability to
generate free radicals.40 Albumin is particularly adept at
binding Fe2⫹, the potentially damaging form of iron.
Furthermore, the ability of albumin to bind iron seems
to be particularly important in newborns as a defense
against iron-induced oxidative damage.41 A number of
studies have reported significantly lower serum albumin
levels in premature infants compared with term in-
fants.36 Not only is plasma albumin level low in prema-
ture infants, but it is also susceptible to oxidative dam-
age,7 which would further limit its ability to bind iron.
Oxidative stress is commonly seen in premature in-
fants42,43 and has been considered as a major contributing
factor in the development of complications of prematu-
rity such as chronic lung disease42–44 and retinopathy of
prematurity.11
Another source of plasma iron is that released from
hemolyzed erythrocytes. Neonatal erythrocytes are
more likely to release free iron than those of adults,45
and fetal hemoglobin is more prone to release iron than
adult hemoglobin.46 Furthermore, neonatal erythrocytes
exposed to hypoxia release more iron than those in a
normoxic environment. Premature infants with respira-
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tory distress are likely to experience periods of hypoxia,
which puts the erythrocyte at risk.45 Erythrocytes are
also susceptible to oxidative damage, which could lead to
hemolytic iron loss. The membrane lipid composition of
erythrocytes renders the erythrocyte susceptible to lipid
peroxidation.45 Because premature infants have lower
antioxidant protection than older infants and show ev-
idence of oxidative stress,42,43,47 the biochemical environ-
ment in the blood of premature infants is not ideal for
the long-term survival of the erythrocytes of the new-
born and those provided by packed cell transfusions.
A number of studies have investigated plasma iron
status in neonates. Buonocore et al48 showed the pres-
ence of non–transferrin-bound iron (NTBI) in plasma of
term and preterm infants and demonstrated a good cor-
relation between the level of NTBI, oxidative stress, and
neonatal brain damage. Later studies confirmed that
oxidative damage to plasma proteins, including albumin,
was greater in those infants with the highest plasma
NTBI levels.7 Premature infants often require blood
transfusions to deal with anemia of prematurity and
replace blood lost by frequent phlebotomy. Elevated
plasma malondialdehyde (a marker of oxidative dam-
age) has been reported in premature infants after packed
cell transfusions.43,47,49 Plasma NTBI was significantly in-
creased in preterm infants after blood transfusion and
existed partly in the Fe2⫹ form, probably as a result of
reduced ferroxidase (ceruloplasmin) activity.50 This find-
ing was specific for preterm infants and was not ob-
served in term infants after blood transfusion. In larger
infants, the increased NTBI was not associated with in-
creased oxidative damage.51 These older infants may
have had a more developed antioxidant protection sys-
tem than the smaller infants.42,52
Because of the problems of the use of blood transfu-
sions, it has become common practice to treat anemia of
prematurity with recombinant human erythropoietin.
For erythropoietin to work effectively, supplementary
iron is usually required, given either in milk or intrave-
nously. One study reported a transient increase in
plasma malondialdehyde after intravenous iron,53 but
most studies have failed to show any increase in oxida-
tive stress after dietary iron supplementation.23,54 This
has been interpreted as being a result of the substantial
increase in iron utilization during treatment with eryth-
ropoietin, which would reduce the amount of free iron
available to generate free radicals.
The iron status of neonates may also be influenced by
the timing of the clamping of the umbilical cord at birth.
Delayed clamping of the umbilical cord allows extra
transfer of fetal blood from the placenta to the infant.
This may result in 20% to 60% more erythrocytes in the
infant. There is evidence that this procedure may pre-
vent the subsequent development of anemia and limit
the need for packed cell transfusions with the potential
problems that this may cause (see above). Consequently,
delayed clamping of the cord is now recommended as a
simple procedure to enhance the iron status of new-
borns.55–57
BRAIN IRON TRANSPORT AND HOMEOSTASIS
The development of the rat brain and human brain have
a number of similarities in that both involve consider-
able postnatal development,58 which makes the rat brain
a useful model. At birth in both species the blood-brain
barrier is incomplete59 and lacks the ability to regulate
the transfer of material from the blood to the interstitial
fluid of the brain. The point at which the blood-brain
barrier matures is not fully established, but it probably
occurs within 7 to 10 days of birth in the rat and may
take up to 6 months in the human.59 Thus, the ability to
regulate brain iron availability according to need may
not be well developed in early life,60,61 and infant rats and
humans may be susceptible to the effects of iron defi-
ciency and excess in the early neonatal period. Further-
more, oxidative stress may also damage the blood-brain
barrier.62 Thus, the premature infant with an incomplete
blood-brain barrier and the possibility of being subjected
to oxidative stress42,43 would be most vulnerable.
The development of the blood-brain barrier and the
ability to regulate iron availability seem to coincide with
the iron needs of the developing brain. Thus, brain iron
levels, the activity of the transport proteins, and the
proteins that regulate their expression are relatively low
at postnatal days 0 to 5 in the rat and peak at around
postnatal days 15 to 16 when there is considerable my-
elination, neuronal growth, and metabolic activity.60,61
Within the brain there are regional variations in iron
transport and availability during development, which
probably reflect the differences in the point at which,
and the rate at which, different brain regions develop
and mature.59–61,63 Thus, the brain of the developing rat
seems to adapt to iron deficiency and repletion by reg-
ulating iron availability on a regional basis61 according to
need.60 These changes do not necessarily fully compen-
sate for the lack of iron availability, and functional de-
fects in particular brain regions may not be corrected
despite correcting the iron levels by iron supplementa-
tion.64 Whether iron supplementation is able to correct
for iron deficiency may depend upon the point at which
iron supplementation occurs relative to the develop-
mental stage of the brain region at the point of supple-
mentation. Studies in rat pups born to iron-deficient
dams showed that repletion of iron commencing at post-
natal day 4 (ie, before the peak iron demand) was able to
correct the effect of iron deficiency on both iron levels
and monoamine function in various brain regions.65
However, using a similar experimental paradigm, reple-
tion of iron around postnatal day 21 (ie, beyond the
peak in iron demand) was unable to completely correct
for the deficits in monoamine function despite correcting
iron levels. 64,66 Although very little has been done on
human infants, early enteral iron supplementation in
premature infants has also shown some beneficial effect
on cognitive and psychomotor function.67
There is a significant accumulation of iron by oligo-
dendrocytes at the onset of myelination68 and a reduc-
tion in the degree of oligodendrocyte maturation and
myelin formation in iron-deficient rat pups.69 There is a
clear correlation between lack of myelination in specific
brain areas and deficiencies in motor and cognitive func-
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tion related to the brain areas deficient in myelination.69
Moreover, iron supplementation subsequent to the de-
velopment of hypomyelination is unable to correct the
motor and cognitive defects caused by the initial iron
deficiency. Specific deficits occur in the striatal dopa-
mine system, indicating poor development of the basal
ganglia system, which is important for the initiation and
control of movement,5 and in the developing hippocam-
pus and cortex, which are important for memory and
cognitive functions.64 Perinatal iron deficiency in rat
pups disrupts dendritic growth in the hippocampus,70
which would have adverse effects on synaptogenesis.
Studies on rats have shown that iron deficiency also
predisposes the developing brain to injury mediated by
even mild hypoxia-ischemia.71
CELLULAR IRON METABOLISM
Very little is known about the development of the intra-
cellular iron-regulating mechanisms. What little is
known concerns brain tissue. There are regional varia-
tions in the developmental expression of the iron-regu-
latory proteins IRP1 and IRP2, the transporter DMT-1,
and the transferrin receptor in the neonatal rat brain.60,61
This is believed to reflect the relative importance of
specific brain regions at particular points in their devel-
opment but at the same time make other regions more
susceptible to the consequences of iron deficiency and
excess.61
SYSTEMIC REGULATION
For adequate iron homeostasis, a precise communication
is needed between the level of iron in the extracellular
phase, cells that consume iron such as erythrocyte pre-
cursors, and cells that store iron or absorb it from the
diet. It was shown recently that this communication
seems to be mediated by the antimicrobial peptide hep-
cidin, which is predominantly synthesized within and
released from hepatocytes.72,73 Hepcidin operates as a
negative feedback regulator of iron homeostasis. It binds
to ferroportin on enterocytes, macrophages, and the pla-
centa. Binding of hepcidin induces internalization and
degradation of ferroportin, which limits the entry of iron
into the extracellular fluid. Conversely, decreased hep-
cidin expression leads to enhanced activity of ferroportin
and increased iron absorption by the enterocyte and
increased release from macrophages, which leads to el-
evated extracellular iron availability.
The regulation of hepcidin expression is currently
unclear, but a number of genes have been suggested to
be involved,74 and it has been suggested that factors that
are known to influence hepcidin expression such as
inflammatory cytokines, plasma iron levels, anemia, and
hypoxia may mediate their effects by regulating the
expression of these genes.75 However, the exact relation-
ship between these factors, the genes, and hepcidin ex-
pression is currently unclear.1 The work reviewed above
was conducted mainly on animal models and adult hu-
mans. There is currently very little known of the regu-
lation of hepcidin production in the neonate.
The precursor protein prohepcidin was detected in
PEDIATRICS Volume 123, Number 4, April 2009 1211
cord blood of healthy term infants, and the levels tended
to increase postnatally.76 There was no clear relationship
between the level of prohepcidin and iron homeostasis,
which is in agreement with studies on adults77 and in-
fants.78 Hepcidin expression in the premature neonate
may be influenced by a number of confusing signals.
Inadequate delivery of O2 to tissues, which would occur
in anemia, would be expected to result in a homeostatic
decrease in hepcidin synthesis.79 However, because
erythropoiesis is the major regulator of hepcidin produc-
tion,80 the poor erythropoietic activity, which is a major
contributor to anemia of prematurity, would be ex-
pected to blunt the erythropoiesis-induced reduction of
hepcidin secretion. Precisely where the hepcidin level
balances out in this situation is unknown. The anemia of
prematurity might be expected to inhibit hepcidin ex-
pression. This would permit all available iron to be ab-
sorbed from the gut or released from store to facilitate
erythropoiesis, which is the process with the greatest
need for available iron in the premature infant.81 Ane-
mia of prematurity is complicated by the relatively small
circulating volume, loss of blood by repeated phlebot-
omy, and hemorrhagic conditions of prematurity.35 As
noted previously, red blood cell survival is also low.81 In
premature infants, the major source of erythropoietin is
the liver not kidney, the liver production of erythropoi-
etin in response to hypoxia is more sluggish than kidney,
and the hormone is also cleared more rapidly in prema-
ture infants. In addition, iron stores build up in propor-
tion to gestational age, so premature infants are likely to
have limited iron stores. This may be further compli-
cated by maternal and placental health during preg-
nancy, which will influence transfer of iron from mother
to fetus.82
Treatment of anemia of prematurity is mainly by
administration of erythropoietin with accompanying
iron supplementation and/or blood transfusions. Both
these procedures may influence hepcidin production in
a complex way. Erythropoietin administration would be
expected to stimulate erythropoiesis, cause an inhibition
of hepcidin expression,83 and lead to an enhancement of
iron availability from gut and internal storage. In adult
rats, injection of recombinant human erythropoietin led
to a redistribution of iron to meet the needs of erythro-
poiesis.84 This included the release of iron from the liver,
a reduction in serum iron, and an increase in duodenal
iron uptake mediated by an increase in DMT-1 expres-
sion and the expression of the ferroxidase enzyme that
converts iron to the ferrous form. This may have been
mediated by reduced hepcidin secretion, which would
enable enhanced duodenal iron uptake to meet the de-
mands of erythropoiesis.84 In support of these findings,
suppression of erythropoiesis led to enhanced hepcidin
expression,83 and anemia caused by phlebotomy caused
a dramatic decrease in hepcidin messenger RNA levels,
but only if erythropoiesis was ongoing as a response to
the anemia.85 Packed cell transfusions would be ex-
pected to enhance erythrocyte numbers and enhance
plasma iron levels. Both would be expected to enhance
hepcidin expression. Thus, getting the balance right in
terms of ensuring iron availability, adequate erythropoi-
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esis, and maximizing O2-carrying capacity seems prob-
lematic.
One study found that hepcidin administration to
iron-deficient mice led to a rapid and dose-dependent
reduction in blood iron levels.86 The tissue distribution of
radiolabeled hepcidin showed greatest levels in the
spleen, duodenum, and, to a lesser extent, liver. These
tissues are well endowed with ferroportin, a major target
of hepcidin. The results suggest that exogenous hepcidin
can reduce the ferroportin-mediated export of iron from
enterocytes, macrophages, and, to a lesser extent, liver.
We currently do not know how well the hepcidin system
is developed in neonates. When we are clearer about the
development and function of hepcidin in neonates, it
may be worth considering the use of hepcidin treatment
in iron-overload conditions, particularly after erythro-
cyte transfusion.
Premature infants with respiratory stress will suffer
periods of hypoxia. Hypoxia independently suppresses
hepcidin expression.87 Furthermore, it is believed that it
is the hypoxia resulting from the anemia that is the
signal causing suppression of hepcidin expression rather
than the iron deficiency of the anemia (which also
would tend to suppress hepcidin secretion).88 Brief peri-
ods of hypoxia, or periods of ischemia and reperfusion,
will also generate free radicals.89 Choi et al90 presented
evidence to suggest that reactive oxygen species gener-
ated during hypoxia suppress hepcidin expression by
impairing the binding of transcription factors to the pro-
moter region of the hepcidin gene.
Inflammation is a major factor in the development of
some complications of prematurity, such as chronic lung
disease.91 If hepcidin expression is weak in premature
infants, they would be unable to adequately upregulate
hepcidin release in response to inflammatory cytokines.
As a result, the plasma free iron levels would remain at
an abnormally high level. This would exacerbate oxida-
tive stress and promote infection, factors that contribute
to chronic lung disease of prematurity.13 Consequently, a
vicious cycle could be generated and maintained.
However, we currently we know little about the de-
velopment and function of hepcidin in neonates, and
until we fill this gap in our knowledge, many of the
questions posed above will remain unresolved.
CONCLUSIONS
The current status of our understanding of iron ho-
meostasis in the neonate, and particularly the premature
neonate, is summarized in Table 1.
The inability to regulate iron absorption by the gut
according to physiologic need may render the neonate
susceptible to iron deficiency or excess, both of which
can have adverse effects on neuronal development. In
addition, this could interfere with other processes such
as erythropoiesis and cause generalized oxidative dam-
age. The exact cause of the inability to regulate gut iron
availability is currently unclear. It may be related to a
poorly developed hepcidin system, poorly developed
iron transporters, or both.
Similarly, the inability to regulate iron availability in
the brain in the early neonatal period, when the blood-
 TABLE 1 Summary of the Major Characteristics of the Neonate That Affect Iron Homeostasis and the Potential Pathophysiological
Consequences of These Characteristics
Factor
Intestinal transport
Inability to regulate iron absorption from the gut
Inability to upregulate in response to low dietary intake
Inability to downregulate in response to high dietary intake
Liver iron transport
DMT1 gene expression in liver increases in iron deficiency and decreases
during iron loading
Extracellular iron transport and storage
Transferrin levels low and highly saturated
Ceruloplasmin levels low
Low plasma albumin level; albumin damaged by free radicals
Plasma iron
Increase in plasma non–protein-bound iron due to the above
Brain iron transport and availability
Reduced ability to regulate iron entry into the brain before maturation of the
blood-brain barrier
Erythrocytes
Increased hemolysis caused by low survival time of neonatal erythrocytes,
hemolysis of stored/transfused erythrocytes, or free radical–mediated
damage to erythrocyte membrane
Systemic regulation: hepcidin
Expression may be low, particularly in infants born before term and in term
infants in the first weeks of life
Expression may be suppressed by anemia of prematurity (may be related to
the hypoxia of the condition 关see below兴)
Expression may be low in hypoxia
Inflammatory cytokines unable to upregulate hepcidin
Expression may be inhibited by reactive oxygen species
brain barrier is not fully mature, would render the de-
veloping brain susceptible to the consequences of iron
deficiency and, to a lesser extent, iron excess.
The binding of iron to specific and nonspecific iron-
binding proteins in plasma may be compromised and
predispose to elevated free non–protein-bound iron,
which may lead to iron-induced oxidative stress and
predispose the infant to bacterial infection. Hemolysis of
neonatal and transfused erythrocytes would exacerbate
the situation further.
Hepcidin expression and release in early life is cur-
rently poorly understood in human infants, but studies
on animals suggest that it may not be able to respond to
signals such as hypoxia, iron levels, and inflammatory
cytokines to regulate iron levels according to need. If
hepcidin expression is well regulated in the neonatal
period, it nevertheless may be suppressed by hypoxia
and reactive oxygen species generated by hyperoxia and
other factors discussed above. However, at present, it is
unclear to what extent hepcidin expression and regula-
tion is operating in the neonate, particularly the prema-
Downloaded from www.pediatrics.org. Provided by Indiana Univ - ACQ Dept on June 15, 2010
Consequence
Possible iron deficiency in infants with poor dietary intake
Possible iron overload in infants fed formula containing supplementary iron
Liver may regulate iron availability when gut transport is compromised
Poor transport capacity; possible increase in plasma NTBI levels
Reduced ability to oxidize Fe2⫹ to Fe3⫹ to enable binding to transferrin;
poor binding to transferrin; possible increases in free iron (particularly
Fe2⫹)
Reduction in plasma iron-binding capacity; increase in free non–protein-
bound iron levels
Increased production of free radicals (Fenton and Heber-Weiss reactions);
predisposes the infant to infections such as pulmonary infections in
ventilated infants
Unable to upregulate transport to provide sufficient iron in iron-deficient
infants in the early neonatal period; possible susceptibility to brain iron
overload in iron excess in early neonatal period
Increased plasma iron levels (with the above consequences)
Unable to respond to the presence of iron by increasing hepcidin synthesis
and release; poor regulation of body iron levels (eg, unable to regulate
gut absorption 关see ⬙Intestinal transport⬙ above兴); may lead to enhanced
gut iron absorption and enhanced release from macrophages; may
contribute to raised plasma iron levels
As listed above, but may be beneficial in allowing as much iron as possible
for erythropoiesis
As listed above in infants with respiratory distress or anemia
Unable to mediate anemia of inflammation
As listed above
ture neonate. Because of the pivotal role of hepcidin in
regulating iron homeostasis, detailed investigations into
hepcidin regulation and function in the neonatal period
are urgently required.
ACKNOWLEDGMENTS
Studies conducted in our laboratory that are referenced in
this article were funded by the National Health Service
Executive South and West Research and Development
Directorate.
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AT MIT, LARGE LECTURES ARE GOING THE WAY OF THE BLACKBOARD

“For as long as anyone can remember, introductory physics at the Massachu-

setts Institute of Technology was taught in a vast windowless amphitheater
known by its number, 26 –100. Squeezed into the rows of hard, folding
wooden seats, as many as 300 freshmen anxiously took notes while the
professor covered multiple blackboards with mathematical formulas and
explained the principles of Newtonian mechanics and electromagnetism. But
now, with physicists across the country pushing for universities to do a better
job of teaching science, MIT has made a striking change. The physics depart-
ment has replaced the traditional large introductory lecture with smaller
classes that emphasize hands-on, interactive, collaborative learning. Last fall,
after years of experimentation and debate and resistance from students, who
initially petitioned against it, the department made the change permanent.
Already, attendance is up and the failure rate has dropped by more than 50%.
MIT is not alone. Other universities are changing their ways, among them
Rensselaer Polytechnic Institute, North Carolina State University, the Uni-
versity of Maryland, the University of Colorado at Boulder and Harvard. In
these institutions, physicists have been pioneering teaching methods drawn
from research showing that most students learn fundamental concepts more
successfully, and are better able to apply them, through interactive, collabo-
rative, student-centered learning. The traditional 50-minute lecture was
geared more toward physics majors, said Eric Mazur, a physicist at Harvard
who is a pioneer of the new approach, and whose work has influenced the
change at MIT ’The people who wanted to understand,’ Professor Mazur said,
‘had the discipline, the urge to sit down afterward and say, “Let me figure this
out.”’ But for the majority, he said, a different approach is needed. ’Just as
you can’t become a marathon runner by watching marathons on TV,’ Pro-
fessor Mazur said, ‘likewise for science, you have to go through the thought
processes of doing science and not just watch your instructor do it.’”
Rimer S. New York Times. January 13, 2009
Noted by JFL, MD

1216 COLLARD
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 Iron Homeostasis in the Neonate
Keith J. Collard
Pediatrics 2009;123;1208-1216
DOI: 10.1542/peds.2008-1047
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