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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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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.

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
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-
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@
is a critical stage of development. Pediatrics 2009;123:1208–1216
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright © 2009 by the

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


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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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
FIGURE 1 months of age), but it seems that older infants (9 months
The known and postulated iron-transport processes believed to be operating in the of age) are able to downregulate gut iron transport in
neonatal duodenum. The well-accepted processes are shown in the upper part of the response to iron supplements.20 The inability of young
diagram. Dietary iron is converted to Fe2⫹ by ferroxidase enzymes to enable it to be infants to regulate gut iron absorption predisposes them
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
to iron deficiency when dietary iron is low and to iron
transported iron is then converted to Fe3⫹ by hephaestin to allow it to bind to transferrin. overload when dietary iron levels are high. Conse-
The proposed, but currently unproven, transport system is shown in the lower part of the quently, it has been suggested that excessive dietary
diagram. In this process, iron bound to lactoferrin (Lf) is transported into the enterocyte intake of iron in young infants can lead to excessive iron
via the lactoferrin receptor. The question marks indicate the unproven nature of the absorption and iron-induced oxidative damage. How-
process and the lack of knowledge concerning the fate of the iron entering the entero-
cyte by this route. 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
ferrous sulfate. Thus, the major iron-transport proteins are fed breast milk.21–24 Whether iron supplementation
of relevance in the newborn are the energy-consuming in premature infants leads to iron-induced oxidative
divalent metal transporter 1 (DMT-1) and ferroportin stress may well depend on the gestational age and the
(Fig 1). clinical treatment the infant receives.25 Smaller, younger
Most dietary iron is in the Fe3⫹ form. Before absorp- infants receiving ventilation and blood transfusions are
tion, dietary Fe3⫹ must be reduced to Fe2⫹, which seems considered more likely to show evidence of iron-induced
to occur at the apical surface of the enterocytes by fer- oxidative damage than older infants.25 The postulated
roxidase enzymes such as cytochrome b.1 Once reduced protective effect of breast milk may be related to the
to the ferrous form, the Fe2⫹ is transported into the presence of lactoferrin.26 Lactoferrin is able to bind free
enterocytes by DMT-1. This carrier transports other di- iron and consequently limit the absorption of dietary
valent metal ions such as Cu2⫹ and Zn2⫹. The trans- iron and reduce the incidence of iron-induced oxidative
porter also requires protons (H⫹) to act as cotransported stress. Breastfed infants has significantly higher total
ions with the Fe2⫹.15 Consequently, the carrier is partic- antioxidant capacity and significantly lower oxidative
ularly active in the proximal duodenum, where it en- stress index.27 There is also a positive correlation be-
counters acidic chyme leaving the stomach. The iron tween a marker of oxidative stress (total peroxide) and
transported into the cell by DMT-1 then enters a pool of plasma iron levels and a negative correlation between
iron referred to as the intracellular or “labile” pool. The total antioxidant capacity and plasma iron. These find-
identity of this pool is unclear but probably involves the ings are considered to be a result of the iron-chelating
binding of iron to cellular proteins such as ferritin or property of lactoferrin in breast milk.
other iron-binding molecules. Ultimately, the iron is In addition to acting as an iron chelator in the gut,
transported across the basolateral border of the entero- lactoferrin has also been proposed as a means of trans-
cyte by the specific carrier ferroportin. Ferroportin is porting iron from the gut in neonatal mice via the lac-
essential for iron absorption and may be regulated by the toferrin receptor present on the apical border of entero-
iron-regulating peptide hepcidin. The transported Fe2⫹ cytes.28 This transport mechanism, which seems to be
is then oxidized to Fe3⫹ by the ferroxidase enzyme hep- responsive to iron needs,29 could potentially help to limit
haestin, which converts the iron to a form that can bind the influence of dietary iron deficiency during the period
to transferrin for transportation within the circulation.1 in which DMT-1 is poorly responsive to iron require-
Hephaestin is structurally and functionally similar to the ment. However, lactoferrin seems to enhance iron ab-
serum ferrireductase enzyme ceruloplasmin,16 which sorption in newborn calves only when fully saturated
also might have a role to play in gut Fe3⫹ oxidation.17 In with iron30; this would be unlikely to occur if luminal
contrast to the effects on ferroportin, hephaestin expres- iron level was low. Also, neonatal mice rendered lacto-
sion does not seem to be well regulated by iron status.16 ferrin deficient by knocking out the gene that expresses
It is generally considered that rat pups and healthy lactoferrin showed no evidence of reduced intestinal
term human infants are born with reasonable iron stores iron uptake,31 and transgenic mice overproducing lacto-

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ferrin did not increase the hemoglobin levels in their tory distress are likely to experience periods of hypoxia,
suckling neonates except at very high maternal dietary which puts the erythrocyte at risk.45 Erythrocytes are
iron intake.32 It is possible that lactoferrin acts mainly as also susceptible to oxidative damage, which could lead to
an iron chelator in neonatal gut but when fully saturated hemolytic iron loss. The membrane lipid composition of
with iron it may contribute to gut iron transport. erythrocytes renders the erythrocyte susceptible to lipid
Unlike the situation in the gut, liver DMT1 gene ex- peroxidation.45 Because premature infants have lower
pression in early infancy has been shown to increase antioxidant protection than older infants and show ev-
with iron deficiency and decrease during iron loading, idence of oxidative stress,42,43,47 the biochemical environ-
suggesting that the liver may play an important role as a ment in the blood of premature infants is not ideal for
sink or source for use in regulating iron metabolism the long-term survival of the erythrocytes of the new-
during early infancy when gut transport may be unre- born and those provided by packed cell transfusions.
sponsive.18 Such a view is supported by previous work A number of studies have investigated plasma iron
on very low birth weight premature infants, which dem- status in neonates. Buonocore et al48 showed the pres-
onstrated a significant positive relationship between the
ence of non–transferrin-bound iron (NTBI) in plasma of
volume of blood transfused, the level of iron in serum,
term and preterm infants and demonstrated a good cor-
and the concentration of iron in the liver.33 Thus, these
relation between the level of NTBI, oxidative stress, and
infants were capable of responding to iron overload by
neonatal brain damage. Later studies confirmed that
translocating iron from the circulation to the liver and
limiting the likelihood of iron-induced oxidative stress.33 oxidative damage to plasma proteins, including albumin,
was greater in those infants with the highest plasma
EXTRACELLULAR IRON TRANSPORT AND CELLULAR NTBI levels.7 Premature infants often require blood
IRON UPTAKE transfusions to deal with anemia of prematurity and
The major factors in the extracellular transport of iron replace blood lost by frequent phlebotomy. Elevated
are the iron-binding protein transferrin and the activity plasma malondialdehyde (a marker of oxidative dam-
of the ferroxidase enzyme ceruloplasmin, which con- age) has been reported in premature infants after packed
verts iron to the oxidized form (Fe3⫹) so that it can bind cell transfusions.43,47,49 Plasma NTBI was significantly in-
to transferrin. Many studies have consistently demon- creased in preterm infants after blood transfusion and
strated that the level of both proteins is low in newborns existed partly in the Fe2⫹ form, probably as a result of
and particularly so in premature infants.34–39 Further- reduced ferroxidase (ceruloplasmin) activity.50 This find-
more, the transferrin saturation level is high, indicating ing was specific for preterm infants and was not ob-
few available binding sites for any additional free iron. served in term infants after blood transfusion. In larger
Thus, premature infants have lower ferroxidase activity infants, the increased NTBI was not associated with in-
and poor iron-binding capacity. Because ceruloplasmin creased oxidative damage.51 These older infants may
does not readily cross the placenta, the low levels in have had a more developed antioxidant protection sys-
premature serum reflect the poor synthetic capacity of tem than the smaller infants.42,52
these infants.36 Because of the problems of the use of blood transfu-
In addition to the specific iron binding of transferrin, sions, it has become common practice to treat anemia of
there is evidence that albumin may also play a role as an prematurity with recombinant human erythropoietin.
antioxidant by binding free iron and limiting its ability to For erythropoietin to work effectively, supplementary
generate free radicals.40 Albumin is particularly adept at iron is usually required, given either in milk or intrave-
binding Fe2⫹, the potentially damaging form of iron. nously. One study reported a transient increase in
Furthermore, the ability of albumin to bind iron seems plasma malondialdehyde after intravenous iron,53 but
to be particularly important in newborns as a defense most studies have failed to show any increase in oxida-
against iron-induced oxidative damage.41 A number of
tive stress after dietary iron supplementation.23,54 This
studies have reported significantly lower serum albumin
has been interpreted as being a result of the substantial
levels in premature infants compared with term in-
increase in iron utilization during treatment with eryth-
fants.36 Not only is plasma albumin level low in prema-
ropoietin, which would reduce the amount of free iron
ture infants, but it is also susceptible to oxidative dam-
age,7 which would further limit its ability to bind iron. available to generate free radicals.
Oxidative stress is commonly seen in premature in- The iron status of neonates may also be influenced by
fants42,43 and has been considered as a major contributing the timing of the clamping of the umbilical cord at birth.
factor in the development of complications of prematu- Delayed clamping of the umbilical cord allows extra
rity such as chronic lung disease42–44 and retinopathy of transfer of fetal blood from the placenta to the infant.
prematurity.11 This may result in 20% to 60% more erythrocytes in the
Another source of plasma iron is that released from infant. There is evidence that this procedure may pre-
hemolyzed erythrocytes. Neonatal erythrocytes are vent the subsequent development of anemia and limit
more likely to release free iron than those of adults,45 the need for packed cell transfusions with the potential
and fetal hemoglobin is more prone to release iron than problems that this may cause (see above). Consequently,
adult hemoglobin.46 Furthermore, neonatal erythrocytes delayed clamping of the cord is now recommended as a
exposed to hypoxia release more iron than those in a simple procedure to enhance the iron status of new-
normoxic environment. Premature infants with respira- borns.55–57

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BRAIN IRON TRANSPORT AND HOMEOSTASIS tion related to the brain areas deficient in myelination.69
The development of the rat brain and human brain have Moreover, iron supplementation subsequent to the de-
a number of similarities in that both involve consider- velopment of hypomyelination is unable to correct the
able postnatal development,58 which makes the rat brain motor and cognitive defects caused by the initial iron
a useful model. At birth in both species the blood-brain deficiency. Specific deficits occur in the striatal dopa-
barrier is incomplete59 and lacks the ability to regulate mine system, indicating poor development of the basal
the transfer of material from the blood to the interstitial ganglia system, which is important for the initiation and
fluid of the brain. The point at which the blood-brain control of movement,5 and in the developing hippocam-
barrier matures is not fully established, but it probably pus and cortex, which are important for memory and
occurs within 7 to 10 days of birth in the rat and may cognitive functions.64 Perinatal iron deficiency in rat
take up to 6 months in the human.59 Thus, the ability to pups disrupts dendritic growth in the hippocampus,70
regulate brain iron availability according to need may which would have adverse effects on synaptogenesis.
not be well developed in early life,60,61 and infant rats and Studies on rats have shown that iron deficiency also
humans may be susceptible to the effects of iron defi- predisposes the developing brain to injury mediated by
ciency and excess in the early neonatal period. Further- even mild hypoxia-ischemia.71
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
Very little is known about the development of the intra-
to oxidative stress42,43 would be most vulnerable.
cellular iron-regulating mechanisms. What little is
The development of the blood-brain barrier and the
known concerns brain tissue. There are regional varia-
ability to regulate iron availability seem to coincide with
tions in the developmental expression of the iron-regu-
the iron needs of the developing brain. Thus, brain iron
latory proteins IRP1 and IRP2, the transporter DMT-1,
levels, the activity of the transport proteins, and the
and the transferrin receptor in the neonatal rat brain.60,61
proteins that regulate their expression are relatively low
This is believed to reflect the relative importance of
at postnatal days 0 to 5 in the rat and peak at around
specific brain regions at particular points in their devel-
postnatal days 15 to 16 when there is considerable my-
opment but at the same time make other regions more
elination, neuronal growth, and metabolic activity.60,61
susceptible to the consequences of iron deficiency and
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 SYSTEMIC REGULATION
and mature.59–61,63 Thus, the brain of the developing rat For adequate iron homeostasis, a precise communication
seems to adapt to iron deficiency and repletion by reg- is needed between the level of iron in the extracellular
ulating iron availability on a regional basis61 according to phase, cells that consume iron such as erythrocyte pre-
need.60 These changes do not necessarily fully compen- cursors, and cells that store iron or absorb it from the
sate for the lack of iron availability, and functional de- diet. It was shown recently that this communication
fects in particular brain regions may not be corrected seems to be mediated by the antimicrobial peptide hep-
despite correcting the iron levels by iron supplementa- cidin, which is predominantly synthesized within and
tion.64 Whether iron supplementation is able to correct released from hepatocytes.72,73 Hepcidin operates as a
for iron deficiency may depend upon the point at which negative feedback regulator of iron homeostasis. It binds
iron supplementation occurs relative to the develop- to ferroportin on enterocytes, macrophages, and the pla-
mental stage of the brain region at the point of supple- centa. Binding of hepcidin induces internalization and
mentation. Studies in rat pups born to iron-deficient degradation of ferroportin, which limits the entry of iron
dams showed that repletion of iron commencing at post- into the extracellular fluid. Conversely, decreased hep-
natal day 4 (ie, before the peak iron demand) was able to cidin expression leads to enhanced activity of ferroportin
correct the effect of iron deficiency on both iron levels and increased iron absorption by the enterocyte and
and monoamine function in various brain regions.65 increased release from macrophages, which leads to el-
However, using a similar experimental paradigm, reple- evated extracellular iron availability.
tion of iron around postnatal day 21 (ie, beyond the The regulation of hepcidin expression is currently
peak in iron demand) was unable to completely correct unclear, but a number of genes have been suggested to
for the deficits in monoamine function despite correcting be involved,74 and it has been suggested that factors that
iron levels. 64,66 Although very little has been done on are known to influence hepcidin expression such as
human infants, early enteral iron supplementation in inflammatory cytokines, plasma iron levels, anemia, and
premature infants has also shown some beneficial effect hypoxia may mediate their effects by regulating the
on cognitive and psychomotor function.67 expression of these genes.75 However, the exact relation-
There is a significant accumulation of iron by oligo- ship between these factors, the genes, and hepcidin ex-
dendrocytes at the onset of myelination68 and a reduc- pression is currently unclear.1 The work reviewed above
tion in the degree of oligodendrocyte maturation and was conducted mainly on animal models and adult hu-
myelin formation in iron-deficient rat pups.69 There is a mans. There is currently very little known of the regu-
clear correlation between lack of myelination in specific lation of hepcidin production in the neonate.
brain areas and deficiencies in motor and cognitive func- The precursor protein prohepcidin was detected in

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cord blood of healthy term infants, and the levels tended esis, and maximizing O2-carrying capacity seems prob-
to increase postnatally.76 There was no clear relationship lematic.
between the level of prohepcidin and iron homeostasis, One study found that hepcidin administration to
which is in agreement with studies on adults77 and in- iron-deficient mice led to a rapid and dose-dependent
fants.78 Hepcidin expression in the premature neonate reduction in blood iron levels.86 The tissue distribution of
may be influenced by a number of confusing signals. radiolabeled hepcidin showed greatest levels in the
Inadequate delivery of O2 to tissues, which would occur spleen, duodenum, and, to a lesser extent, liver. These
in anemia, would be expected to result in a homeostatic tissues are well endowed with ferroportin, a major target
decrease in hepcidin synthesis.79 However, because of hepcidin. The results suggest that exogenous hepcidin
erythropoiesis is the major regulator of hepcidin produc- can reduce the ferroportin-mediated export of iron from
tion,80 the poor erythropoietic activity, which is a major enterocytes, macrophages, and, to a lesser extent, liver.
contributor to anemia of prematurity, would be ex- We currently do not know how well the hepcidin system
pected to blunt the erythropoiesis-induced reduction of is developed in neonates. When we are clearer about the
hepcidin secretion. Precisely where the hepcidin level development and function of hepcidin in neonates, it
balances out in this situation is unknown. The anemia of may be worth considering the use of hepcidin treatment
prematurity might be expected to inhibit hepcidin ex- in iron-overload conditions, particularly after erythro-
pression. This would permit all available iron to be ab- cyte transfusion.
sorbed from the gut or released from store to facilitate Premature infants with respiratory stress will suffer
erythropoiesis, which is the process with the greatest periods of hypoxia. Hypoxia independently suppresses
need for available iron in the premature infant.81 Ane- hepcidin expression.87 Furthermore, it is believed that it
mia of prematurity is complicated by the relatively small is the hypoxia resulting from the anemia that is the
circulating volume, loss of blood by repeated phlebot- signal causing suppression of hepcidin expression rather
omy, and hemorrhagic conditions of prematurity.35 As than the iron deficiency of the anemia (which also
noted previously, red blood cell survival is also low.81 In would tend to suppress hepcidin secretion).88 Brief peri-
premature infants, the major source of erythropoietin is ods of hypoxia, or periods of ischemia and reperfusion,
the liver not kidney, the liver production of erythropoi- will also generate free radicals.89 Choi et al90 presented
etin in response to hypoxia is more sluggish than kidney, evidence to suggest that reactive oxygen species gener-
and the hormone is also cleared more rapidly in prema- ated during hypoxia suppress hepcidin expression by
ture infants. In addition, iron stores build up in propor- impairing the binding of transcription factors to the pro-
tion to gestational age, so premature infants are likely to moter region of the hepcidin gene.
have limited iron stores. This may be further compli- Inflammation is a major factor in the development of
cated by maternal and placental health during preg- some complications of prematurity, such as chronic lung
nancy, which will influence transfer of iron from mother disease.91 If hepcidin expression is weak in premature
to fetus.82 infants, they would be unable to adequately upregulate
Treatment of anemia of prematurity is mainly by hepcidin release in response to inflammatory cytokines.
administration of erythropoietin with accompanying As a result, the plasma free iron levels would remain at
iron supplementation and/or blood transfusions. Both an abnormally high level. This would exacerbate oxida-
these procedures may influence hepcidin production in tive stress and promote infection, factors that contribute
a complex way. Erythropoietin administration would be to chronic lung disease of prematurity.13 Consequently, a
expected to stimulate erythropoiesis, cause an inhibition vicious cycle could be generated and maintained.
of hepcidin expression,83 and lead to an enhancement of However, we currently we know little about the de-
iron availability from gut and internal storage. In adult velopment and function of hepcidin in neonates, and
rats, injection of recombinant human erythropoietin led until we fill this gap in our knowledge, many of the
to a redistribution of iron to meet the needs of erythro- questions posed above will remain unresolved.
poiesis.84 This included the release of iron from the liver,
a reduction in serum iron, and an increase in duodenal CONCLUSIONS
iron uptake mediated by an increase in DMT-1 expres- The current status of our understanding of iron ho-
sion and the expression of the ferroxidase enzyme that meostasis in the neonate, and particularly the premature
converts iron to the ferrous form. This may have been neonate, is summarized in Table 1.
mediated by reduced hepcidin secretion, which would The inability to regulate iron absorption by the gut
enable enhanced duodenal iron uptake to meet the de- according to physiologic need may render the neonate
mands of erythropoiesis.84 In support of these findings, susceptible to iron deficiency or excess, both of which
suppression of erythropoiesis led to enhanced hepcidin can have adverse effects on neuronal development. In
expression,83 and anemia caused by phlebotomy caused addition, this could interfere with other processes such
a dramatic decrease in hepcidin messenger RNA levels, as erythropoiesis and cause generalized oxidative dam-
but only if erythropoiesis was ongoing as a response to age. The exact cause of the inability to regulate gut iron
the anemia.85 Packed cell transfusions would be ex- availability is currently unclear. It may be related to a
pected to enhance erythrocyte numbers and enhance poorly developed hepcidin system, poorly developed
plasma iron levels. Both would be expected to enhance iron transporters, or both.
hepcidin expression. Thus, getting the balance right in Similarly, the inability to regulate iron availability in
terms of ensuring iron availability, adequate erythropoi- the brain in the early neonatal period, when the blood-

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TABLE 1 Summary of the Major Characteristics of the Neonate That Affect Iron Homeostasis and the Potential Pathophysiological
Consequences of These Characteristics
Factor Consequence
Intestinal transport
Inability to regulate iron absorption from the gut
Inability to upregulate in response to low dietary intake Possible iron deficiency in infants with poor dietary intake
Inability to downregulate in response to high dietary intake Possible iron overload in infants fed formula containing supplementary iron
Liver iron transport
DMT1 gene expression in liver increases in iron deficiency and decreases Liver may regulate iron availability when gut transport is compromised
during iron loading
Extracellular iron transport and storage
Transferrin levels low and highly saturated Poor transport capacity; possible increase in plasma NTBI levels
Ceruloplasmin levels low Reduced ability to oxidize Fe2⫹ to Fe3⫹ to enable binding to transferrin;
poor binding to transferrin; possible increases in free iron (particularly
Low plasma albumin level; albumin damaged by free radicals Reduction in plasma iron-binding capacity; increase in free non–protein-
bound iron levels
Plasma iron
Increase in plasma non–protein-bound iron due to the above Increased production of free radicals (Fenton and Heber-Weiss reactions);
predisposes the infant to infections such as pulmonary infections in
ventilated infants
Brain iron transport and availability
Reduced ability to regulate iron entry into the brain before maturation of the Unable to upregulate transport to provide sufficient iron in iron-deficient
blood-brain barrier infants in the early neonatal period; possible susceptibility to brain iron
overload in iron excess in early neonatal period
Increased hemolysis caused by low survival time of neonatal erythrocytes, Increased plasma iron levels (with the above consequences)
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 Unable to respond to the presence of iron by increasing hepcidin synthesis
infants in the first weeks of life 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
Expression may be suppressed by anemia of prematurity (may be related to As listed above, but may be beneficial in allowing as much iron as possible
the hypoxia of the condition 关see below兴) for erythropoiesis
Expression may be low in hypoxia As listed above in infants with respiratory distress or anemia
Inflammatory cytokines unable to upregulate hepcidin Unable to mediate anemia of inflammation
Expression may be inhibited by reactive oxygen species As listed above

brain barrier is not fully mature, would render the de- ture neonate. Because of the pivotal role of hepcidin in
veloping brain susceptible to the consequences of iron regulating iron homeostasis, detailed investigations into
deficiency and, to a lesser extent, iron excess. hepcidin regulation and function in the neonatal period
The binding of iron to specific and nonspecific iron- are urgently required.
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 ACKNOWLEDGMENTS
predispose the infant to bacterial infection. Hemolysis of Studies conducted in our laboratory that are referenced in
neonatal and transfused erythrocytes would exacerbate this article were funded by the National Health Service
the situation further. Executive South and West Research and Development
Hepcidin expression and release in early life is cur- Directorate.
rently poorly understood in human infants, but studies
on animals suggest that it may not be able to respond to
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783–788 min Neonatol. 2003;8(1):29 –38


“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

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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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