SYMPOSIUM: HAEMATOLOGY
Iron deficiency
Katrina Pettit
Jennifer Rowley
Nick Brown
Abstract
Iron deficiency remains one of the world’s greatest public health prob-
lems. Globally it is the greatest contributor to anaemia, affecting 47%
of pre-school age children and 25% of school age children worldwide,
and is a major contributor to both physical and neuro-developmental
morbidity.
Iron deficiency results from inadequate intake, excess turnover or
excessive loss. Whilst inadequate intake is the commonest cause of defi-
ciency in children in the industrialized world, impaired absorption through
malabsorption syndromes like inflammatory bowel disease and coeliac
disease should also be considered. Blood loss additionally causes iron
deficiency, the three most common causes of which are cows’ milk enter-
opathy, menstruation and hook worm infection.
Prevention of iron deficiency, though theoretically simple, is complex
at a population level. Treatment requires appropriate management of the
underlying cause as well as additional iron replacement. In the western
world, the focus has been on preventing iron deficiency through public
education and modification of iron availability in children’s diets. It is rec-
ommended that children should not receive whole cows’ milk during the
first year of life, but should instead be given breast milk or iron fortified
formula. Worldwide management strategies again focus on dietary
improvements, as well as the control of hook worm and malaria infections
to reduce levels of iron deficiency.
Keywords anaemia; cows’ milk protein enteropathy; dietary modifica-
tion; hook worm infection; iron deficiency; malabsorption; public health
Introduction
Iron deficiency manifests when there are insufficient bioavailable
stores. This can result from inadequate intake, excess turnover
or excessive loss. It is the most common nutritional disorder in
the world, affecting large numbers of children in developing
countries but is also highly prevalent in the industrialized world.
Katrina Pettit MRCPCH MBBS is a Paediatric SpR in the Paediatric
Department, Salisbury District Hospital, Saslisbury, Wiltshire, UK.
Conflict of interests: none.
Jennifer Rowley MBChB BSc(hons) is a Paediatric ST3 in the Paediatric
Department, Salisbury District Hospital, Saslisbury, Wiltshire, UK.
Conflict of interests: none.
Nick Brown MRCP(Paeds) FRCPCH MSc epidemiology DTM&H is Paediatric
consultant in the Paediatric Department, Salisbury District Hospital,
Saslisbury, Wiltshire, UK. Conflict of interests: none.
PAEDIATRICS AND CHILD HEALTH 21:8
As the onset is insidious, estimation of the exact prevalence of
iron deficiency is difficult. Anaemia is therefore often used as
a proxy. The World Health Organization (WHO) estimates that
anaemia (the main cause of which is iron deficiency) affects 47%
of pre-school age children and 25% of school age children
worldwide, with the peak prevalence between 1 and 3 years of
age. No region is immune: even in the US, 9% of 1e3 year olds
and 16% of adolescent girls are affected (see Tables 1 and 2, and
Figure 1).
Physiology
Iron is a ubiquitous cation. In addition to its role in haemoglobin,
iron is also required in cytochromes and enzyme reactions. It is
distributed both as an active metabolite and in storage pools. In
humans it is recycled extremely effectively from ageing red blood
cells (RBCs). Iron absorption is therefore the only way of phys-
iologically manipulating stores. Iron is absorbed by the small
intestine, although typically only 10% of dietary iron is taken.
For optimal nutrition a daily intake of 8e10 mg of iron is
required to cover the iron losses from cell desquamation from the
skin and intestine and to maintain growth in children. Demands
are greatest in infancy and adolescence during periods of high
growth.
The efficacy of iron absorption is dependent on its form
when consumed. It is well absorbed in the haem form (meat)
and less well in the non-heam state as this requires both
reduction to the ferrous state and release from food binders by
gastric juices. In addition, non-heam iron absorption is reduced
by other food items (e.g. vegetable fibre phytates in cereals and
pulses, calcium and tannins in tea). Vitamin C promotes
absorption.
Once absorbed iron binds to and is transported by trans-
ferrin, a protein synthesized in the liver. Transferrin synthesis
is sensitive to iron status and therefore increases in deficiency
and decreases in chronic disease. Iron is used in erythropoiesis
or stored as either ferritin or haemosiderin. Ferritin is soluble
and freely available, and is located in the liver (hepatocytes),
bone marrow, spleen (macrophages), RBCs and serum. The
circulating ferritin level parallels the size of the total body
stores (1 ng/ml ¼ 8 mg iron in storage pool). Some iron is
additionally stored as the relatively insoluble haemosiderin in
the Kupffer cells of the liver and in macrophages of the bone
marrow.
Aetiology
Dietary inadequacy and low bioavailability
Inadequate intake qualitatively or quantitatively is the com-
monest cause of deficiency in children in the industrialized
world. As iron is poorly absorbed, a typical western diet will be
barely sufficient in meeting daily requirements. Iron in breast
milk is absorbed three times more effectively than that in
formula milk and the required intake in breast fed babies is
therefore correspondingly smaller. Iron in cows’ milk has
a poorer bioavailability. A diet containing a combination of
meat, eggs, fruit and vegetables is required for sufficient iron
intake.
339 Ó 2011 Elsevier Ltd. All rights reserved.
 SYMPOSIUM: HAEMATOLOGY

Anaemia prevalence and number of individuals affected in pre-school age children, pregnant women and non-pregnant
women in each WHO region
WHO region Pre-school aged children Pregnant women Non-pregnant women
(0.00e4.99 years) (no age range defined) (15.00e49.99 years)

Prevalence (%) Affected (millions) Prevalence (%) Affected (millions) Prevalence (%) Affected (millions)

Africa 67.6 (64.3e71.0) 83.5 (79.4e87.6) 57.1 (52.8e61.3) 17.2 (15.9e18.5) 47.5 (43.4e51.6) 69.9 (63.9e75.9)
Americas 29.3 (26.8e31.9) 23.1 (21.1e25.1) 24.1 (17.3e30.8) 3.9 (2.8e5.0) 17.8 (12.9e22.7) 39.0 (28.3e49.7)
South-East Asia 65.5 (61.0e70.0) 115.3 (107.3e123.2) 48.2 (43.9e52.5) 18.1 (16.4e19.7) 45.7 (41.9e49.4) 182.0 (166.9e197.1)
Europe 21.7 (15.4e28.0) 11.1 (7.9e14.4) 25.1 (18.6e31.6) 2.6 (2.0e3.3) 19.0 (14.7e23.3) 40.8 (31.5e50.1)
Eastern Mediterranean 46.7 (42.2e51.2) 0.8 (0.4e1.1) 44.2 (38.2e50.3) 7.1 (6.1e8.0) 32.4 (29.2e35.6) 39.8 (35.8e43.8)
Western Pacific 23.1 (21.9e24.4) 27.4 (25.9e28.9) 30.7 (28.8e32.7) 7.6 (7.1e8.1) 21.5 (20.8e22.2) 97.0 (94.0e100.0)
Global 47.4 (45.7e49.1) 293.1 (282.8e303.5) 41.8 (39.9e43.8) 56.4 (53.8e59.1) 30.2 (28.7e31.6) 468.4 (446.2e490.6)

Adapted from: McClean E, Egli I, Cogswell M. Worldwide prevalence of anaemia 1993e2005: WHO global database on anaemia. de Benoist B, ed. WHO publications,
2008.

Table 1

Impaired absorption Increased losses

Protein energy malnutrition will impair absorption both at the
mucosal and protein synthetic level and exacerbating the defi-
ciency that such children almost invariably have. Other causes,
though relatively rare in children, are well recognized and
include malabsorption syndromes such as coeliac disease,
inflammatory bowel disease, blind loop syndrome and gastric
surgery.
Blood loss causes iron deficiency. The three most common cau-
ses are cows’ milk enteropathy, menstruation and hook worm
infection. These will be discussed in further detail. Chronic
gastrointestinal losses in older children may also result from
inflammatory bowel disease, which may be clinically ‘silent’
until anaemia is advanced due to adaptive compensation in the
haemoglobin oxygen dissociation.

Increased demand
Children have an increased demand for iron at times of rapid
growth during their first year of life. Sufficient iron stores are
usually acquired as a foetus to support growth up to the age of 6
months. Infants born prematurely may not have fully established
these stores and will have additional iron requirements. From 6
months of age, iron in milk alone is insufficient to support this
continued rapid growth. Additional dietary iron is required to
prevent deficiency. Iron requirements are again increased during
the rapid growth phase of adolescence.
Cows’ milk enteropathy: it is well established that infants fed
on cows’ milk or cows’ milk based formula can develop
a subclinical or overt colitis. This occult blood loss has
a marked impact on the iron stores of younger babies. From the
age of 6 months onwards studies have shown a gradual
decrease in the amount of occult blood present, until the effect
is largely gone at a year. For this reason it is recommended
children should not be fed whole cows’ milk until after 1 year.
The only acceptable alternatives are iron fortified formula or
breast milk.

Menstruation: menstruation in adolescent girls has been shown

to decrease the iron stores. This is problematic in a population
with a tendency to have a low iron diet, although a good dietary
Haemoglobin thresholds used to define anaemia iron intake will preclude the adverse effects of this.
Age or gender group Haemoglobin
threshold (g/L) Hook worm infection: hook worm is caused by Ancylostoma
duodenale or Necator americanus and affects an estimated one
Children (0.50e4.99 years) 110 billion people worldwide. Eggs passed in the stool hatch into
Children (5.00e11.99 years) 115 larvae which can survive for 3 weeks until they penetrate human
Children (12.00e14.99 years) 120 skin when people walk barefoot on infested soil. The larvae
Non-pregnant women (>15.00 years) 120 reach the lungs via blood vessels, penetrate into pulmonary
Pregnant women 110 alveoli, ascend the bronchial tree to the epiglottis, and are
Men (>15.00 years) 130 swallowed. The larvae develop into adults in the small bowel
where they attach to the wall and feed on the hosts’ blood. Adult
Adapted from: McClean E, Egli I, Cogswell M. Worldwide prevalence of
anaemia 1993e2005: WHO global database on anaemia. de Benoist B, ed.
worms may live for around 2 years. This chronic blood loss
WHO publications, 2008. causes iron deficiency.
The prevalence of hook worm infection increases with age
Table 2 reaching a plateau in late adolescence. A study of children in

PAEDIATRICS AND CHILD HEALTH 21:8 340 Ó 2011 Elsevier Ltd. All rights reserved.
 SYMPOSIUM: HAEMATOLOGY
Category of public health significance (anaemia prevalence)
Normal (<5.0%)
Mild (5.0–19.9%)
Figure 1 Adapted from: McClean E, Egli I, Cogswell M. Worldwide prevalence of anaemia 1993e2005: WHO global database on anaemia. de Benoist B, ed.
WHO publications, 2008.
Zanzibar showed that 62% were anaemic, with 82% of this being
attributable to iron deficiency, of which the strongest predictor
was hook worm infection. Another study of an Australian
aboriginal community showed hook worm infection was
endemic, being present in 93% of children. The hook worm
infection was significantly associated with iron deficiency and
anaemia in people over 14 years.
Manifestations
Anaemia
The most common manifestation of iron deficiency is anaemia.
Anaemia occurs when iron stores have been exhausted and
there is insufficient iron for the synthesis of haemoglobin. A
haemoglobin level of 110 g/litre is the cut off below which
anaemia is said to be present (see Table 2). As this progresses
microcytosis and then hypochromia develop and the reticulo-
cyte count falls. The anaemia then causes symptoms of fatigue,
loss of stamina, shortness of breath, weakness, dizziness, loss of
appetite and pallor. If severe and untreated cardiac failure can
ensue.
Pregnancy and birth weight
Pregnant women are particularly vulnerable to iron deficiency
and iron deficiency anaemia. The WHO estimates that the prev-
alence of anaemia in pregnant women is 41.8% worldwide. The
increased incidence of iron deficiency and anaemia in women
pre-pregnancy is a major contributing factor. However, even
women who enter pregnancy with good iron stores are at risk of
iron deficiency due to the extra demands of supporting a growing
foetus. Evidence shows that anaemia in pregnancy is a risk factor
for preterm delivery and subsequent low birth weight, and iron
PAEDIATRICS AND CHILD HEALTH 21:8
Moderate (20.0–29.9%) No data
Severe (≥40.0%)
deficiency is also associated with low birth weight and poor
obstetric outcome.
Development
Iron deficiency anaemia in early life is related to altered
behavioural and neural development. Iron is essential for the
proper neurogenesis and differentiation of certain brain cells.
Studies show that iron deficient pregnant mothers who
remain so in the early weeks of breast feeding are more likely
to have babies who display long-term developmental prob-
lems as this time period is critical for the baby’s developing
brain.
Further studies have shown that iron deficiency in infancy
(up to 2 years of age) is related to poorer cognitive, motor and
socio-emotional function, as well as persisting neurophysio-
logic differences from pre-school children right up to adoles-
cents. In older pre-school children, development is also
affected by iron deficiency, causing poorer motor, cognitive
and language development as well as a poorer learning
performance and behaviour. Severe iron deficiency has addi-
tionally been associated with thrombotic stroke in this age
group.
Immunological
The role of iron in immune function is controversial. There
may be subtle measurable humoural immune differences in
iron deficient children relative to their iron replete counter-
parts, the clinical significance appears minimal. It is likely that
at least part of the explanation lies in the fact that many
infective organisms (including the plasmodia causing malaria)
require iron as a metabolic co-factor and that deficiency
protects the host. This could certainly explain the consistent
341 Ó 2011 Elsevier Ltd. All rights reserved.
 SYMPOSIUM: HAEMATOLOGY
observation that malnourished children have a lower inci-
dence of complicated malaria than their well nourished
counterparts.
Treatment
Underlying cause
The treatment of iron deficiency includes appropriate
management of the underlying cause and additional iron
replacement. Iron supplements are taken orally and continued
for 6 months after the haemoglobin has normalized (if this
was also reduced) to allow the iron stores to be replenished.
The different ferrous salts are very similar in terms of efficacy
of absorption of iron (those available include fumarate,
gluconate and sulphate). Therefore choice of preparation is
decided by palatability, incidence of side effects and cost. The
oral dose of elemental iron is 3e6 mg/kg (maximum 200 mg)
in two to three divided doses. The haemoglobin concentration
should rise by 1e2 g/litre per day or 20 g/litre over 3e4
weeks. Poor compliance is the commonest reason for lack of
response. Once replenished, iron supplements should be
stopped to prevent the toxicity that occurs with chronic over-
load including pancreatic, pituitary, hepatic and cardiac depo-
sition. Blood transfusions in children are only required if the
child is compromised and/or at risk of high output cardiac
failure.
Public health
In order to tackle the problem globally the WHO has made
specific recommendations including:
 Reducing poverty
 Improving access to diversified diets
 Improve health services and sanitation
 Promote better care and feeding practices
These recommendations are in keeping with the Millennium
Development Goals (MDGs) 1e4.
UK: in the UK, as in much of the western world, the focus has
been on preventing iron deficiency through public education and
measures to increase iron availability in children’s diets. In
pregnancy women are screened for iron deficiency anaemia and
treated if necessary. However, iron is not given routinely to
prevent deficiency during pregnancy.
In the first year of life it is recommended that children should
not receive whole cows’ milk but should instead be given breast
milk or iron fortified formula. In addition many cereals for
infants and the rest of the population are fortified with iron.
Current recommendations for weaning babies advise introducing
a varied and iron rich diet from 6 months of age, from which the
iron sources should be available in both haem (meat) and non-
haem forms. When cows’ milk is introduced it should not be in
excess. For older children and teenagers the recommendations
are still largely around having a varied diet, and additionally
state that tea should not be drunk at mealtimes, but orange juice
can be.
Worldwide: around the world the cause of iron deficiency is
much more likely to be secondary to malnutrition and chronic
infection. However, it remains the case that improvement in diet
PAEDIATRICS AND CHILD HEALTH 21:8
is the best long-term solution to both prevent and treat this
deficiency. The WHO recommends that each region is assessed
according to its’ needs and that a practical approach is taken to
assess groups most at risk. They suggest reviewing eating
patterns, the content and bioavailability of iron and absorption
inhibitors and enhancers, to determine where practical imple-
mentations can be made. The iron status before and after
changes are implemented should be assessed. In addition
worldwide food fortification is recommended but this should be
individualized to the region, to allow maximal benefit to the
population being served.
Infection control: in large parts of the world helminth infec-
tion is an important cause of iron deficiency. Treatment is with
anti helminth medications such as mebendazole, usually for 3
days. However re-infection is a real problem as a previous
infection does not incur immunity. Effective prevention is by
not walking barefoot and through the sanitary disposal of
faeces.
Scenarios
Scenario 1
Jessica is the 14-month-old baby of a young first time single
mother, who lives with her maternal grandparents. She is
referred for assessment by her Health Visitor who has noticed
a striking pallor when seen for her MMR vaccination. She is
markedly anaemic but otherwise well. There is no hep-
atosplenomegaly or lymphadenopathy. Her Hb is 3 and MCV 56.
On questioning about her diet, the mother informs you she was
instructed by her own mother that babies should be fed only
cows’ milk from the age of 1 month until they are walking. As
she is well she is treated with dietary advice and iron supple-
mentation and 3 months later her Hb is normal.
Comment: This is a common misconception in older genera-
tions. Cows’ milk is unsuitable for babies until a year of age as
the iron is poorly bioavailable. It can cause gastrointestinal blood
loss through a mild colitis and fills babies’ stomachs so they have
no appetite for solids.
Scenario 2
Ed, a 15-year-old boy, is referred for delayed puberty. He feels
constantly tired and has intermittent abdominal pain both put
down to exam stress. Other than mild pallor and scattered oral
ulceration examination is normal. His Hb is 67 g/litre, MCV 70
and CRP 78 mg/dl. The clinical impression of Crohn’s is
confirmed by upper GI endoscopy and biopsy, and he responds
well to induction with elemental diet.
Comment: The older the child, the more likely the pathology
is non-dietary.
Scenario 3
Ellie, a 12-year-old girl, is referred for assessment of her chronic
fatigue. Examination is unremarkable but her Hb is 7 and MCV
67. On closer questioning she reveals that, like her mother, her
periods started at the age of 11 and have always been very heavy.
She responds well to iron replacement and the oral contraceptive
pill.
Comment: Easily missed at this age but easily treated. A
342 Ó 2011 Elsevier Ltd. All rights reserved.
 SYMPOSIUM: HAEMATOLOGY

FURTHER READING
American Academy of Pediatrics Committee on Nutrition. The use of whole
cows’ milk in infancy e committee on nutriton. Pediatrics 1992; 89:
1105e9.
Booth IW, Aukett MA. Iron deficiency anaemia in infancy and early
childhood. Arch Dis Child 1997; 76: 549e53.
Huang SC, Yang YJ, Cheng CN, et al. The etiology and treatment outcome
of iron deficiency and iron deficiency anemia in children. J Pediatr
Hematol Oncol 2010; 32: 282e5.
McClean E, Egli I, Cogswell M. In: de Benoist B, ed. Worldwide prevalence
of anaemia 1993e2005: WHO global database on anaemia. WHO
Publications, 2008.
Stoltzfus RJ, Dreyfuss ML, Chwaya H, Albonico M. Hookworm control
as a strategy to prevent iron deficiency. Nutr Rev 1997; 55:
223e32.
United Nations millennium development goals, www.un.org/
millenniumgoals; 2000.
WHO, UNICEF, UNU. Iron deficiency anaemia: assessment, prevention, and
control. WHO/NHD/01.3. Geneva, Switzerland: World Health Organi-
zation, 2001.
Practice points
C Untreated iron deficiency in young children can cause neuro-
developmental delay which may be irreversible.
C Iron deficiency can occur independently of iron deficiency anaemia
and any child with chronic ill health should be investigated for it.
C The commonest cause of iron deficiency is diet related.
C In older children with iron deficiency blood loss should be
considered.
C In global terms hook worm eradication and malaria control
would reduce levels of iron deficiency greatly.
Acknowledgement
Thanks to Rebecca Moon for her helpful comments.

PAEDIATRICS AND CHILD HEALTH 21:8 343 Ó 2011 Elsevier Ltd. All rights reserved.