Indian J Pediatr (2011) 78:6572

DOI 10.1007/s12098-010-0129-7

SYMPOSIUM ON NUTRITIONAL ANEMIA - II

Iron Deficiency: Beyond Anemia

Dinesh Yadav & Jagdish Chandra

Received: 19 May 2010 / Accepted: 20 May 2010 / Published online: 3 September 2010
# Dr. K C Chaudhuri Foundation 2010

Abstract Iron deficiency is the most common nutritional

disorder affecting at least one third of worlds population.
Though anemia is common manifestation of iron deficiency, other effects of iron deficiency on various tissues,
organs and systems are usually under recognized. Impaired
brain development and cognitive, behavioural and psychomotor impairment are most worrisome manifestations of
iron deficiency. Studies have demonstrated that some of
these changes occurring during period of brain growth spurt
(<2 years age) may be irreversible. Association of iron
deficiency with febrile seizures, pica, breath holding spells,
restless leg syndrome and thrombosis is increasingly being
recognized. Impaired cell-mediated immunity and bactericidal function are generally noted in iron-deficient persons;
however, the findings are inconsistent. Despite proven
reversible functional immunological defects in vitro studies,
a clinically important relationship between states of iron
deficiency and susceptibility to infections remains controversial. Studies from malaria endemic regions have reported
increased incidence of malaria in association with iron
supplementation. These and some other aspects of iron
deficiency are reviewed in this article.

D. Yadav : J. Chandra
Department of Pediatrics, Kalawati Saran Childrens
Hospital and Lady Hardinge Medical College,
New Delhi, India
D. Yadav
e-mail: dineshmamc@gmail.com
J. Chandra (*)
Lady Hardinge Medical College,
Lecturer Flats, Flat no 5,
New Delhi 110001, India
e-mail: jchandra55@gmail.com

Keywords Iron deficiency anemia (IDA) . Cognition .

Breath holding spells (BHS) . Pica . Febrile seizure .
Thrombosis . Restless leg syndrome . Infections
Iron deficiency affects at least a third of worlds
population and second only to hunger, as a major
worldwide, nutritional problem.
-Cochrane library 2008, issue 2 [1].
This recent report from Cochrane library signifies
magnitude of iron deficiency state worldwide. Furthermore,
iron deficiency remains the most common cause of anemia.
Its prevalence depends mainly on age, being higher in
infancy and adolescence [2].
Iron deficiency anemia is a very well known concept
but what is often not appreciated is the broad canvas of
effects of iron deficiency on various tissues, organs and
systems in human beings in addition to iron deficiency
anemia (IDA) leading to concept of Iron deficiency
disease. Anemia is just one manifestation of iron
deficiency, there are other forms of mild to moderate
iron deficiency in which anemia is absent but tissue
function is impaired [3]. In iron deficiency not only tissue
delivery of oxygen is compromised but proliferation,
growth, differentiation, myelinogenesis, immune function,
energy metabolism, absorption and biotransformation are
also affected leading to abnormal growth and behaviour,
reduced cardiac performance and work efficiency, infection etc, which ultimately leads to the concept that iron
deficiency not only breaks the machine but also wrecks
the machinery [4]. This article reviews impaired brain
development, cognitive, behavioural and psychomotor
impairment, immune dysfunction and role of iron deficiency in febrile seizures, pica, breath holding spells,
restless leg syndrome and thrombosis.

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Pathogenesis
IDA is associated with increased red cell porphyrin, which
inhibits ferrochelatase enzyme, thus further inhibiting heme
synthesis. This eventually leads to decreased hemoglobin
synthesis and anemia of iron deficiency ensues. Besides
this, decreased activity of ribonucleotide reductase and
pyruvate dehydrogenase enzymes has also been demonstrated in iron deficient individuals, which explains decreased DNA synthesis and impaired cellular oxidation
respectively [5]. Perinatal iron deficiency in animal experimental models has been seen to be associated with
decreased cytochrome C activity in neonatal brain, which
is also required for cellular oxidation [6]. Iron is also
required for normal oligodendrocyte function and myelination; synthesis of neurotransmitters (Dopamine, NorEpinephrine and Epinephrine) by tryptophan hydroxylase
and tyrosine hydroxylase enzymes and for normal brain
energy metabolism.

Iron and Brain

Behavioral and cognitive dysfunctions are most worrisome
manifestations of iron deficiency. Recent research has
revealed that anemia is a late manifestation of iron
deficiency, brain iron deficiency occurs even with normal
levels of hemoglobin, as iron is prioritized to red blood
cells over all other organs including brain [6]. The
biological basis of the behavioural and cognitive developmental delays observed in iron-deficient infants is not
completely understood but possibilities include: a) abnormalities in neurotransmitter metabolism b) decreased
myelin formation, and c) alterations in brain energy
metabolism [5].
Brain growth spurt takes place in last trimester of fetal
life and continues during first two years of childhood.
Animal studies have revealed that brain iron content is
maximum at birth, decreases during early infancy and
again increases with weaning. Brain iron has heterogenous distribution in brain with basal ganglia, substantia
nigra and deep cerebellar nuclei being richer in iron
content [5]. Iron deficiency during this period of growth
spurt has been shown to be associated with irreversible
cognitive and developmental delay. Besides this, developing human hippocampus, an area involved in memory
processing, is much more vulnerable to perinatal iron
deficiency [6].
Evoked potential studies have been undertaken to
look for adverse effects of iron deficiency on neural
tissues. These studies have advantage of avoiding
potential inherent confounding factors including anemia
and low socioeconomic status. Many of these studies

Indian J Pediatr (2011) 78:6572

have reported longer latencies on brainstem auditary

evoked potential and visually evoked potentials in
formerly iron deficient children, suggestive of hypomyelination in these children. One of the studies suggested
gradual catching up of conduction velocity in IDA
children, though it still remained slower in children with
early age of onset of iron deficiency, suggestive of
longer lasting effects of iron deficiency anemia in this
age group [710].
There are clinical studies in literature to assess effect of iron
on cognition, including observational, interventional and
preventive trials in various age groups. These studies have
been divided in 2 age groups (<2 years and >2 years), as
outcome of iron therapy has been found to be different in both
groups.

IDA and Infants <2 Years Age

In infants, adverse effects of iron deficiency on behaviour are of special concern because the later part of the
brain growth spurt coincides with the period in which
iron deficiency anemia is most prevalent (624 months
of age). Observational studies have suggested that iron
deficient children have lower IQ scores, decreased
attentiveness and lower scores on tests of academic
performance compared with non-anemic controls. However, a cause and effect relationship could not be
established because of associated multiple confounding
factors in most of the studies including low socioeconomic status, poverty, lack of stimulation at home, poor
parental education, maternal depression, low birth
weight, faulty feeding, malnutrition, parasitic infestations
and elevated lead levels. Among initial intervention
trials, Oski and Honig studied 24 infants aged 9 to
26 months with iron deficiency anemia. Mental and
motor scales were administered before and 1 week after
parenteral iron therapy to experiment group. They
demonstrated significant increase in mental and physical
developmental scores in experimental group and concluded that iron therapy was associated with quantifiable
improvement in tests of behavioural and developmental
performance within 1 week [11].
Later, Lozoff et al studied effects of short term oral
iron therapy on developmental deficits in iron deficient
infants 6 to 24 months of age. Bayley scale of infant
development was administered before and after 1 week
of oral iron treatment. The mean pre-treatment mental
developmental index of anemic group was significantly
lower than nonanemic infants. However, contrary to the
findings of Oski and Honig, they did not observe
significant increase in mental developmental index after
1 week of oral iron therapy. They postulated possible

Indian J Pediatr (2011) 78:6572

irreversibility of cognitive impairment in iron deficient

infants [12]. Same authors further studied effect of oral
and parenteral (intramuscular) iron therapy in double blind
randomized controlled trial in Costa Ricccan infants aged
1223 months, with various degree of iron deficiency.
Lower mental and motor scores were observed in iron
deficient infants. Though, there was no improvement in
scores after 1 week of therapy, lower mental and motor
scores improved after 3 months of iron therapy with
improvement in anemia and iron deficiency state. However, significantly lower mental and motor scores persisted
among majority of the initially anemic infants who had
more severe or chronic iron deficiency state compared to
non-anemic children, despite correction of anemia. These
infants were found to have evidence of iron deficiency
despite iron therapy (in recommended doses) for 3 months
[13]. Further, extension of iron therapy for 6 months was
also associated with persistent lower mental scores despite
good hematological response and correction of iron
deficiency state in 2 studies [14, 15].
Lozoff et al followed same cohort of Costa Riccan
infants after 5 years and 10 years to look for long term
behavioural and developmental outcome of iron deficiency
anemia. They observed that children who had severe and/or
chronic iron deficiency in infancy scored lower on
measures of mental and motor functioning. After control
for background factors, differences remained statistically
significant in arithmetic achievement and written expression, motor functioning and some specific cognitive
processes. A large number of the formerly iron-deficient
children had repeated a grade and/or were referred for
special services or tutoring. Their parents and teachers rated
their behaviour as more problematic to several areas,
agreeing in increased concerns about anxiety/depression,
social problems, and attention problems [16, 17]. Similar
long term follow up study by Palti et al in Israeli children
observed lower developmental and IQ scores at 4 years of
age in children, who were treated for iron deficiency in
infancy [18].
Thus, these studies indicate that iron deficiency anemia
in infancy, perhaps of particular severity and chronicity, has
irreversible cognitive impairment. This hypothesis was
further supported by series of studies in rats, in which a
brief period of induced iron deficiency anemia in young rat
produced a deficit in brain iron and behavioural effects that
persisted into later life despite correction of associated
anemia [1921]. These studies also indicated irreversible
changes in dopamine biology associated with neonatal iron
deficiency, despite replenishment of iron status [22, 23].
A recent review by Mc-Gregor et al, suggested that
children who were anemic in early childhood (<24 months)
continue to have poor cognitive and motor development and
school achievement into middle childhood despite correction

67

of anemia. However, available studies were difficult to

interpret because only few were RCT and the samples were
often extremely small. There had been a hesitancy to use
placebo groups in the field of iron deficiency on ethical
grounds. In several studies, but not all, anemic children have
failed to catch up to nonanemic children with iron treatment
[24]. Meta analysis of available studies suggests that poorer
test performance in children <2 years of age is more resistant
to improvement with iron supplementation [25, 26].

IDA in Children >2 Years Age

Observational studies in children over 2 years have reported
poorer cognition and school achievement in iron deficient
children [24]. Adolescent girls are particularly susceptible to
iron deficiency because of poor dietary intake along with
increased iron requirement related to rapid growth and
menstrual blood loss and are at greater risk of cognitive
impairment.
In therapeutic trials, few randomized controlled trials are
available, as withholding iron to iron deficient children was
considered unethical. Hence, most of the studies have no
controls. Pollitt et al studied children with iron deficiency
anemia with mean age of 9.5 years. Oral ferrous sulphate
50 mg daily was given in this randomized controlled trial.
They observed significant improvement in mental scores in
iron treated anemic children compared to placebo treated
anemic children. Further efficiency scores of iron treated
anemic children became similar to that of non-anaemic
children [27].
Similar results were reproduced by Seshadri et al in
school age iron deficient children. Significant improvement
in test scores for attention, discrimination, memory,
perception and visual-motor coordination were observed
in iron treated group compared to placebo treated group in
later two studies by above authors [28].
In an another recent study, Halterman et al studied effect
of iron supplementation in iron deficient adolescents. They
identified children with iron deficiency with or without
anemia and observed lower standardized math scores
among iron deficient school children and adolescents,
including those with iron deficiency without anemia [29].
Bruner et al also conducted therapeutic trial in iron
deficient non-anemic adolescent girls and demonstrated
significant improvement in tests of verbal learning and
memory along with hematological improvement in iron
treated group [30].
Meta-analysis of such studies by Sachdev et al also
concluded that significant improvement was evident in iron
deficient children >7 years of age with iron therapy [25].
Hence, contrary to young infants, iron therapy is
beneficial in older children and associated with significant

68

improvement in cognitive scores, which are evident even in

non-anemic iron deficient children.

Indian J Pediatr (2011) 78:6572

which might explain various forms of pica. Besides this, a

central mechanism due to deficiency of iron requiring
enzymes in central nervous system has also been postulated
[37].

Preventive Trials
Preventive trials aim to determine whether the development
of iron deficiency anemia and developmental deficits can
be prevented in hematologically normal children if they are
supplemented with iron. Two recent trials reported beneficial effects of iron therapy in infancy. In first trial, Friel et al
studied a group of breastfed children supplemented with
iron or placebo from ages 1 to 6 month. At 1218 month of
age, higher visual acuity scores and improved performance
on the Bayley Psychomotor Development Index (but not on
the Mental Development Index) were observed [31]. In
second much larger trial by Lozoff et al, children were
examined at 1 year of age after 6 month of iron
supplementation. They observed differences in specific
behavioural and developmental outcomes but not on global
test scores. Infants who did not receive supplemental iron
processed information slower and were less likely to show
positive affect, interact socially, or check their caregivers
reactions. They crawled somewhat later and were more
likely to be tremulous [32].
Both above trials suggested developmental and behavioural benefits from iron supplementation in healthy full
term infants; however, larger field trials are required before
its incorporation in national health policies.

IDA and Pica

Pica is defined as compulsive ingestion of non-food
substances. Various forms of pica have been described in
association with iron deficiency anemia including geophagia (eating clay or dirt), pagophagia (ice), amylophagia
(starch) and ryzophagia (raw rice). Its association with iron
deficiency is widely recognized. Earlier it was believed that
pica causes iron deficiency anemia. However, Coltman and
Carlander proved it wrong and demonstrated that ice and
starch do not displace iron-containing food in the diet, nor
do they interfere with iron absorption [33, 34].
Reynolds et al studied patients with pica in 1968 and
demonstrated disappearance of symptoms of pagophagia
with correction of iron deficiency anemia [35]. Similarly,
other workers have also reported resolution of pagophagia
with iron supplementation, even before correction of
anemia [36, 37]. These studies suggest that pica is a
reversible manifestation of iron deficiency state.
Exact pathophysiology of pica in association with iron
deficiency state is unknown but decreased activity of
cytochrome oxidase in buccal mucosa have been reported,

IDA and Breath Holding Spells

Breath-holding spells (BHS) occur to some degree in up to
27% of healthy children [38]. DiMario noted that the term
is a misnomer that implies a voluntary action resulting in a
prolonged inspiration, whereas in actuality the spells are
involuntary, reflexive, and occur during expiration [39].
The presence of an underlying dysfunctional autonomic
nervous system in children with BHS has been proposed by
some workers [39, 40], whereas others have reported their
association with iron deficiency anemia. Holowach et al
demonstrated that children with severe BHS had significantly lower haemoglobin values than children in a control
group. They speculated that children with anemia have
decreased cerebral oxygen tension at baseline making these
children more susceptible to the chain of events leading to
loss of consciousness during BHS [41]. Bhatia et al also
observed that children with BHS had significantly lower
haemoglobin and serum iron values, a lower percentage of
transferrin saturation, and higher TIBC than those of
controls [42]. Several other workers have studied the role
of iron in resolution of BHS and reported significant benefit
from iron treatment [4345].
The exact role of iron in BHS is not known. However,
abnormalities in catecholamine metabolism and various
neurotransmitters may explain association of BHS with iron
deficiency anemia. The correction of spells with iron therapy
may be related to the functional restoration of these neurotransmitters [45]. Besides this, Mocan et al have hypothesised that the clinical and haematological picture of BHS
may be related to the interactions of cerebral erythropoietin,
nitric oxide and interleukin1. They postulated that increased
brain erythropoietin production has a protective effect during
BHS, but if this does not compensate for the severity of
anoxic spells, then seizures may develop [46].

IDA and Febrile Seizure

Febrile seizures are the most common type of seizures,
occurring in 25% of all children [47]. Kebrinsky et al
studied the role of iron in febrile seizures and they reported
significantly increased incidence of iron deficiency in nonseizure group compared to seizure group. They postulated
that iron deficiency may raise the seizure threshold and
protect against the development of febrile seizures [48].
However, most of the subsequent studies have reported low

Indian J Pediatr (2011) 78:6572

iron status as a possible risk factor for first febrile seizure.

Pisacane et al first reported increased occurrence of febrile
sizure in iron deficient children <2 years of age [49].
Similarly, Daoud et al and Rehman et al also reported
significantly lower plasma ferritin levels in children with
febrile seizure compared to controls [50, 51]. They
postulated that low plasma ferritin levels may lower the
seizure threshold, as iron is important for the function of
various enzymes and neurotransmitters in central nervous
system [50].
Exact etiology of febrile seizures is not clear, however,
iron dependent metabolism of several neurotransmitters,
enzyme activity and cerebral erythropoietin has been
postulated as causative factor for seizures. No therapeutic
trial has been reported to look for beneficial effects of iron
therapy in febrile seizure patients.

69

bocytosis in children with iron deficiency anemia [61]. In

addition to the increased thrombotic risk associated with
high platelet count, other possible mechanisms suggested
is decrease in antioxidant defence in iron deficiency
anemia leading to increased oxidant stress, which in turn
may result in a tendency toward platelet aggregation [62].
Reduced deformability and increased viscosity of microcytic red blood cells in iron deficiency may be contributory by affecting blood flow patterns within the vessels
[55]. Furthermore, anemic hypoxia secondary to iron
deficiency could precipitate situations of increased metabolic stress (i.e., infections) particularly in vulnerable
areas of the brain supplied by end arteries, such as the
basal ganglia, thalamus, and hypothalamus resulting in
stroke [63].

IDA and Restless Leg Syndrome (RLS)

IDA and Thrombosis
Over the last few years association of iron deficiency and
thrombotic complications is being increasingly recognized.
Nagai et al reported a case of severe iron deficiency with
marked thrombocytosis (platelet count 1,020109/l) that
was complicated by central retinal vein occlusion [52].
Kinoshita et al described two cases of cerebral venous sinus
thrombosis associated with iron deficiency and normal
platelet count [53]. Similarly, Benedict et al reported three
cases of cerebral sinovenous thrombosis in association with
iron deficiency anemia [54]. Other workers have also
described cases of stroke or sinovenous thrombosis with
IDA [5557].
Maguire et al recently reviewed association between iron
deficiency anemia and stroke in young children. They
observed that IDA accounted for more than half of stroke
cases in children without any other known underlying
prothrombotic state, suggesting that iron deficiency anemia
is significant risk factor for stroke. They further observed
that previously healthy children who develop venoocclusive stroke were 10 times more likely to have IDA
than healthy children who do not develop stroke. They
reported that sino-venous thrombosis was more closely
associated with IDA than arterial ischemic stroke [58]. A
recent study on etiological profile of pediatric stroke in
Indian children reported higher occurrence (66.5%) of IDA
in stroke with undetermined etiology [59].
This increased incidence of thrombotic complications
in IDA has been linked to various factors. Increased level
of erythropoietin in IDA has been incriminated to have a
possible role in stimulating megakaryopoiesis, resulting in
thrombocytosis [60]. Recently, Bilic and Bilic have
reported that the amino acid sequence homology of
thrombopoietin and erythropoietin may explain the throm-

Restless leg syndrome is characterized by repeated aphasic

involuntary muscle contractions. It is mostly reported in
adult patients and largely under reported from pediatric
population. Although most of the cases with RLS are
idiopathic or hereditary; decreased brain iron content and
metabolism can also lead to RLS. Iron deficiency states
may precipitate RLS in as much as 2530% of people. MRI
studies have demonstrated decreased iron content in
substantia nigra and red nucleus.
Earley et al studied 16 patients of idiopathic RLS and
8 controls. They observed that patients with RLS had lower
CSF ferritin and higher CSF transferrin levels than controls.
Serum ferritin and transferrin levels were similar in both
groups and symptoms resolved with iron therapy [64].
Intravenous therapy was found to be more effective
compared to oral therapy in some of the studies [64, 65].
However, it is associated with significantly increased
adverse events. Although most RLS patients with low
serum ferritin values are treated with oral iron therapy, no
major trials on oral iron therapy are available in RLS [66].

Iron and Infections

Iron is required for normal immune function, cell
differentiation and growth. Iron is also required for
peroxide generating mechanisms, cytokine production
and myeloperoxidase function in neutrophils. Impaired
cell-mediated immunity and bactericidal function are
generally noted in iron-deficient persons; however, the
findings are inconsistent.
In vitro studies have reported deleterious effects of iron
deficiency on cellular defences that are reversible with iron
therapy. These include: a) reduced neutrophil function with

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decreased myeloperoxidase activity and nitro blue toluene

reduction reversed by iron administration. Intracellular
bactericidal activity has been reported as impaired, but not
all studies give consistent results, b) depression of Tlymphocyte numbers with thymic atrophy reported in most
but not all studies, c) defective T lymphocyte-induced
proliferative response, d) impaired natural killer cell
activity, e) impaired interleukin-2 production by lymphocytes, f) reduced production of macrophage migration
inhibition factor, and g) reversible impairment of delayed
cutaneous hypersensitivity, including tuberculin reactivity
[67].
Certain invasive pathogens have their own powerful
siderophores and iron supplementation may be deleterious
in association with these infections [68]. Because of the
above conflicting reports, in vivo studies in iron deficient
animals and humans have been done. Animal studies
revealed that effects of iron therapy are microorganism
specific and that iron deficiency may be protective against
intracellular pathogens. Observational studies in iron
deficient humans have also revealed increased incidence
of bacterial infections [69]. On the contrary, decreased
malaria infection is reported in iron deficient human
beings compared to controls [70, 71]. A recent review of
iron intervention trials in non-malarious regions has
concluded that that parenteral iron administration at birth
is associated with significant risk of severe sepsis and
meningitis [67]. Oral iron supplementation and food
fortification was associated with significantly lower risk
of respiratory infections and slight lower risk of diarrheal
disease in two large studies conducted in early part of last
century [72, 73]. However, four iron fortification studies
conducted in late 90s failed to show any benefit or harm
from iron therapy [7477]. Contrary to this, review of iron
intervention trials in malaria endemic areas has revealed
that there was a significant increase in clinical malaria
attack rates in 5 of 9 studies and no rate reductions; a
significant increase in clinical pneumonia rates in 2 of 5
studies with no rate reductions and a significant increase
in other nonmalarial infectious disease in 4 of 8 studies
with no rate reduction [67].
To summarize, despite proven reversible functional
immunological defects in vitro studies, a clinically important relationship between states of iron deficiency and
susceptibility to infections remains controversial, difficult
to prove and may depend on other immune factors in the
community. Experimental and in vitro animal studies
suggest that intracellular organisms, such as plasmodia,
mycobacteria and invasive salmonellae may be enhanced
by iron therapy. Besides this, no significant beneficial effect
of iron supplementation has been demonstrated on immunity and infection reduction in both non-malarious and
malaria endemic regions.

Indian J Pediatr (2011) 78:6572

Conclusions
Being most common nutritional disorder, it is imperative to
recognize effects and long term consequences of iron
deficiency. Though anemia is common, iron deficiency
state without anemia is largely under-recognized. Studies
have reported lower cognitive scores even in children with
iron deficiency without anemia. Irreversible cognitive
impairment has been reported in children who experienced
iron deficiency during period of critical brain growth
(<2 years of age). Iron deficiency anemia is highly
prevalent in India (reported 55.7% to 85.1% in different
states in NFHS-3) [78] and much larger population having
iron deficiency without anemia; hence, it is critical to
recognize the cognitive impairment and treat early.

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