www.thelancet.com Vol 370 August 11, 2007 511
Nutritional iron defi ciency
Michael B Zimmermann, Richard F Hurrell
Iron defi ciency is one of the leading risk factors for disability and death worldwide, aff ecting an estimated 2 billion
people. Nutritional iron defi ciency arises when physiological requirements cannot be met by iron absorption from
diet. Dietary iron bioavailability is low in populations consuming monotonous plant-based diets. The high prevalence
of iron defi ciency in the developing world has substantial health and economic costs, including poor pregnancy
outcome, impaired school performance, and decreased productivity. Recent studies have reported how the body
regulates iron absorption and metabolism in response to changing iron status by upregulation or downregulation of
key intestinal and hepatic proteins. Targeted iron supplementation, iron fortifi cation of foods, or both, can control
iron defi ciency in populations. Although technical challenges limit the amount of bioavailable iron compounds that
can be used in food fortifi cation, studies show that iron fortifi cation can be an eff ective strategy against nutritional
iron defi ciency. Specifi c laboratory measures of iron status should be used to assess the need for fortifi cation and to
monitor these interventions. Selective plant breeding and genetic engineering are promising new approaches to
improve dietary iron nutritional quality.
Estimates of occurrence of iron defi ciency in industrial-
ised countries are usually derived from nationally
representative samples with specifi c indicators of iron
status.1 By contrast, estimates from developing countries
are often based only on haemoglobin measurements
from restricted regions or target populations, and should
be interpreted with caution. Prevalence estimates of iron
defi ciency anaemia (ie, iron defi ciency and low
haemoglobin) based on haemoglobin alone are over-
estimations because they fail to account for other causes
of anaemia, such as nutritional defi ciencies (eg,
vitamin A defi ciency), infectious disorders (particularly
malaria, HIV disease, and tuberculosis), haemo-
globinopathies, and ethnic diff erences in normal
haemoglobin distributions.2,3 For example, in Côte
d’Ivoire, iron defi ciency was detected with specifi c
indicators of iron status in about 50% of anaemic women
and children.4 Even in industrialised countries,
haemoglobin alone, which is used to detect iron
defi ciency anaemia, has poor sensitivity and specifi city.5
Anaemia is regarded as a public health problem when
the frequency of low haemoglobin values is more than
5% in the population.6
WHO estimates that 39% of children younger than
5 years, 48% of children between 5 and 14 years, 42% of
all women, and 52% of pregnant women in developing
countries are anaemic,6 with half having iron defi ciency
anaemia.7 According to WHO, the frequency of iron
defi ciency in developing countries is about 2∙5 times that
of anaemia.6 Iron defi ciency is also common in women
and young children in industrialised countries. In the
UK, 21% of female teenagers between 11 and 18 years,
and 18% of women between 16 and 64 years are iron
defi cient.8 In the USA, 9–11% of non-pregnant women
aged between 16 and 49 years are iron defi cient, and
2–5% have iron defi ciency anaemia, with more than
twofold higher frequency in poorer, less educated, and
minority populations.9 In pregnant women of low-income
areas in the USA, the frequency of iron defi ciency
anaemia in the fi rst, second, and third trimesters is 2%,
8%, and 27%, respectively.9 In France, iron defi ciency and
iron defi ciency anaemia aff ect 29% and 4% of children
younger than 2 years;10 in the USA, 2% of children
between 1 and 2 years have iron defi ciency anaemia.1
Human beings are unable to excrete iron actively, so its
concentration in the body must be regulated at the site of
iron absorption in the proximal small intestine (fi gure).
Diets contain both haem and non-haem (inorganic) iron;
each form has specifi c transporters. A putative intestinal
haem iron transporter (HCP1) has been identifi ed, which
is upregulated by hypoxia and iron defi ciency, and might
also transport folate.11,12 Transport of non-haem iron from
the intestinal lumen into the enterocytes is mediated by
the divalent metal ion transporter 1 (DMT1).13 DMT1
transports only ferrous iron, but most dietary iron that
enters the duodenum is in the ferric form. Therefore,
ferric iron must be fi rst reduced to ferrous iron, possibly
by the brush border ferric reductase, duodenal
cytochrome b (DCYTB),14 or by other reducing agents,
such as ascorbic acid. Once inside the enterocyte, iron
that is not directly transferred to the circulation is stored
as ferritin and ultimately is lost when the cell is sloughed
at the villus tip. Effl ux of iron across the basolateral
membrane into the blood is mediated by the transport
protein ferroportin 1, and the iron oxidase, hephaestin.
Ferroportin 1 also mediates export of iron from other
Lancet 2007; 370: 511–20
Laboratory for Human
Nutrition, Swiss Federal
Institute of Technology, Zürich,
(M B Zimmermann MD,
R F Hurrell PhD); and Division of
Human Nutrition, Wageningen
University, The Netherlands
(M B Zimmermann)
Dr Michael B Zimmermann,
Laboratory for Human Nutrition,
Swiss Federal Institute of
Schmelzbergstrasse 7, LFV E 19,
CH-8092 Zürich, Switzerland
Search strategy and selection criteria
We searched PubMed, Current Contents Connect, and ISI Web
of Science for articles in English, French, German, and Spanish.
We searched for “iron”, “iron defi ciency”, “anaemia”, “nutrition”,
“haemoglobin”, “bioavailability”, “supplementation”,
“fortifi cation”, “plant breeding”, and “genetic engineering”. We
mainly selected publications from the past 5 years, but did not
exclude highly regarded earlier publications.
www.thelancet.com Vol 370 August 11, 2007
cells, including macrophages.15 Iron defi ciency and
hypoxia stimulate duodenal expression of DMT1, DCYTB,
and ferroportin, and thereby increase iron absorption.14,16
Hepcidin is a regulatory hormone secreted by the liver
that inhibits both the absorption and release of iron from
macrophages and other cell types.17 Hepcidin seems to
bind to ferroportin 1 at the basolateral membrane of the
enterocyte, causing its internalisation and degradation.18
The internalisation and degradation processes decrease
iron transfer into the blood, and additional iron is lost in
sloughed enterocytes. In iron defi ciency, hepcidin release
from the liver is decreased, thereby increasing iron
absorption to the maximum.19,20 In the erythroid iron
cycle, senescent red cells are broken down mainly by
macrophages in the spleen, and the extracted iron is
returned to the circulation where it binds to transferrin.
Transferrin binds to specifi c transferrin receptors (TfRs)
on erythroid precursors in the bone marrow, and the cycle
is completed when new erythrocytes enter the circulation
in the following 7–10 days. Iron defi ciency increases iron
transfer through the cycle to the maximum by stimulating
increased ferroportin expression on macrophages,21
hepatic synthesis of transferrin, and expression of TfR1 in
the bone marrow and other tissues.22
Within cells, iron status upregulates or downregulates
various proteins that are implicated in iron homoeostasis
(notably ferritins and TfR1) at the post-transcriptional
level by binding of iron regulatory proteins to specifi c
non-coding sequences in their mRNAs, known as
iron-responsive elements.23–25 Scarce data from DNA
microarrays suggest that various genes are modulated by
iron status, including those encoding retinoblastoma
(RB), p21, cyclin D3, cyclin E1, v-myc myelocytomatosis
viral oncogene homolog (MYC), cyclin-dependent kinase 2
(CDK2), cyclin A, FAS ligand (FASL), and inducible nitric
oxide synthase (iNOS); many of these genes are not
directly related to iron metabolism.26,27 Additionally,
haemochromatosis (HFE), TfR2, haemochromatosis
type 2 (HFE2), and SMAD family member 4 (SMAD4) in
hepatocytes have been identifi ed as regulators of hepcidin
expression, and thus of intestinal iron transport and
During gestation, the fetus stores about 250 mg of iron.
These stores are drawn on during breastfeeding, because
breastmilk supplies only about 0∙15 mg of absorbed iron
per day, whereas requirements for absorbed iron are
about 0∙55 mg per day.29 Low birthweight infants do not
store an adequate amount of iron during fetal life and are
at high risk of developing iron defi ciency while being
breastfed. During growth in childhood, about 0∙5 mg of
iron per day is absorbed in excess of body losses; adequate
amounts of iron during growth typically results in a
70-kg man accumulating about 4 g of body iron.30 About
2∙5 g of body iron is within haemoglobin and about 1 g is
stored as ferritin or haemosiderin, mainly in the liver.
Men absorb and excrete about 0∙8 mg of iron per day,
and women, during childbearing years, should absorb
almost twice as much (1∙4 mg per day) to cover menstrual
losses.30 The usual diet of a population strongly aff ects
iron bioavailability31 (see below); thus, recommended
intakes for iron depend on diet characteristics (table 1).
Nutritional iron defi ciency arises when physiological
requirements cannot be met by iron absorption from
diet. Dietary iron bioavailability is low in populations
consuming monotonous plant-based diets with little
meat.32 In meat, 30–70% of iron is haem iron, of
which 15–35% is absorbed.33 However, in plant-based
diets in developing countries most dietary iron is
non-haem iron, and its absorption is often less
than 10%.32,33 The absorption of non-haem iron is
increased by meat and ascorbic acid, but inhibited by
phytates, polyphenols, and calcium.33 Because iron is
present in many foods, and its intake is directly related to
energy intake,30 the risk of defi ciency is highest when
iron requirements are greater than energy needs. This
Blood Gut lumen
Figure: Regulation of intestinal iron uptake
Haem iron is taken up by the haem iron transporter (HCP), undergoes endocytosis, and Fe²⁺ (ferrous iron) is
liberated within the endosome or lysosome. Non-haem iron includes Fe²⁺ and Fe³⁺ (ferric iron) salts. Fe³⁺ is reduced
to Fe²⁺ by ascorbic acid in the lumen or by membrane ferrireductases that include duodenal cytochrome B (DCYTB).
At the apical membrane, the acid microclimate provides an H⁺ electrochemical gradient that drives Fe²⁺ transport
into the enterocyte via the divalent metal-ion transporter (DMT1). At the basolateral membrane, iron transport to
transferrin in the circulation is mediated by ferroportin 1, in association with hephaestin. Hepcidin, produced by the
liver, binds to ferroportin 1, causing its internalisation and degradation and decreasing iron transfer into the blood.
Numbers are mg per day. Recommended daily intake for iron depends on the bioavailability of the diet: diet rich in
vitamin C and animal protein=15%; diet rich in cereals, low in animal protein, but rich in vitamin C=10%; diet poor in
vitamin C and animal protein=5%.31
Table 1: Selected recommended daily intakes for iron,31 by estimated dietary iron bioavailability
www.thelancet.com Vol 370 August 11, 2007 513
situation happens in infants and young children,
adolescents, and in menstruating and pregnant women.
During infancy, rapid growth exhausts iron stores
accumulated during gestation and often results in
defi ciency, if iron-fortifi ed formula or weaning foods are
not supplied. Excessive early consumption of cows’ milk
can also contribute to early-childhood iron defi ciency.34 In
a study of infants aged 6 months, frequency of iron
defi ciency anaemia was lowest in infants fed iron-fortifi ed
formula (about 1%) but occurred in 15% of breastfed
infants, and 20% of infants fed cows’ milk or non-fortifi ed
formula.35 In the USA, the introduction of iron-fortifi ed
weaning foods in the 1970s was associated with a
reduction in the frequency of iron defi ciency anaemia in
infants and preschool children.36 In many developing
countries, plant-based weaning foods are rarely fortifi ed
with iron, and the frequency of anaemia exceeds 50% in
children younger than 4 years.6 In schoolage children,
iron status typically improves as growth slows and diets
become more varied.
The frequency of iron defi ciency begins to rise again,
mainly in female individuals, during adolescence, when
menstrual iron losses are superimposed with needs for
rapid growth. Because a 1 mL loss of blood translates into
a 0∙5 mg loss of iron, heavy menstrual blood loss (>80 mL
per month in about 10% of women) sharply increases the
risk for iron defi ciency.37 Other risk factors for iron
defi ciency in young women are high parity, use of an
intrauterine device, and vegetarian diets.38 During
pregnancy, iron requirements increase three-fold because
of expansion of maternal red-cell mass and growth of the
fetal–placental unit.36 The net iron requirement during
pregnancy is about 1 g (equal to that contained in about
4 units of blood), most of which is needed in the last
2 trimesters.39 During lactation, because only about
0∙25 mg of iron per day is excreted into breastmilk and
most women are amenorrhoeic, iron requirement is
low—only half of that of non-pregnant, non-lactating
Increased blood loss from gastrointestinal parasites
aggravates dietary defi ciencies in many developing
countries. Infections with Trichuris trichiura (whipworm)
and Necator americanus (hookworm) cause intestinal
blood loss and are important causes of iron defi ciency
anaemia.40–43 Revised estimates indicate that hookworms
affl ict more than 700 million people in tropical and
subtropical regions.44 In endemic areas, hookworm
infection is estimated to account for 35% of iron
defi ciency anaemia and 73% of its severe form,45 and
deworming decreases the occurrence of anaemia.44,46,47 In
a trial in Nepal, women who were given albendazole in
the second trimester of pregnancy had a lower rate of
severe anaemia during the third trimester, gave birth to
infants of greater weight, and mortality of infants at
6 months decreased.48 Iron defi ciency anaemia can also
be caused by impaired iron absorption. Gastric acid is
needed to maintain ferric iron forms in solution, and
achlorhydria might be a substantial cause of iron
defi ciency, mainly in elderly people, in whom atrophic
gastritis is common.49 Other common causes of lowered
iron absorption and iron defi ciency are mucosal atrophy
in coeliac disease50,51 and, possibly, Helicobacter pylori
infection,52 although a study of iron absorption showed
no eff ect of H pylori.53
Adverse eff ects
The high frequency of iron defi ciency anaemia in the
developing world has substantial health and economic
costs. In an analysis of ten developing countries, the
median value of physical productivity losses per year due
to iron defi ciency was about US$0∙32 per head, or
0∙57% of the gross domestic product.54 In the WHO
African subregion, it is estimated that if iron fortifi cation
reached 50% of the population, it would avert
570 000 disability adjusted life years (DALYs) every year.55
During the fi rst two trimesters of pregnancy, iron
defi ciency anaemia increases the risk for preterm labour,
low birthweight, infant mortality, and predicts iron
defi ciency in infants after 4 months of age.56,57 Estimates
are that anaemia accounts for 3∙7% and 12∙8% of maternal
deaths during pregnancy and childbirth in Africa and
Asia, respectively.58 Data for the adverse eff ects of iron
defi ciency on cognitive and motor development in children
are equivocal because environmental factors limit their
interpretation.59–61 Several studies reported adverse eff ects
of iron defi ciency anaemia on infant development that
might be only partly reversible.59,60 Other studies suggest
that no convincing evidence exists that iron defi ciency
anaemia aff ects mental or motor development in children
younger than 2 years, but that iron defi ciency adversely
aff ects cognition in school
school-children have decreased motor activity, social
inattention, and decreased school performance.60 Whether
adverse eff ects of iron defi ciency on neuromotor devel-
opment are due to anaemia or absence of iron in the
developing brain is unclear.62 Iron defi ciency anaemia
increases susceptibility to infections, mainly of the upper
respiratory tract, which happen more often and have a
longer duration in anaemic than in healthy children.63 A
recent study showed no positive eff ect of iron supple-
mentation on physical growth during childhood.64 The
response to iodine prophylaxis is reduced in goitrous
children with defi ciencies of both iodine and iron,65,66
probably because of impairment of the haem-dependent
enzyme, thyroid peroxidase.67 Iron supplementation can
increase low serum retinol concentrations in iron-defi cient
children.68,69 Iron defi ciency might increase the risk for
chronic lead poisoning in children exposed to
environmental lead.70 In adults, physical activity is
reduced,71 and manual labourers in developing countries
are more productive if they are given iron and treated for
hookworm and other infections.72 Iron defi ciency, even in
the absence of anaemia, might cause fatigue and reduce
www.thelancet.com Vol 370 August 11, 2007
Table 2 shows useful indicators for diagnosis of iron
defi ciency anaemia in population studies. The major
diagnostic challenge is to diff erentiate between iron
defi ciency anaemia in otherwise healthy individuals and
anaemia of chronic disease. Infl ammatory disorders
increase circulating hepcidin concentrations,90 and
hepcidin blocks iron release from enterocytes and the
reticuloendothelial system,17 resulting in iron-defi cient
erythropoiesis. If chronic, infl ammation can produce
anaemia of chronic disease. The distinction between
anaemia of chronic disease and iron defi ciency anaemia
is diffi cult because increased
concentration in anaemia does not exclude iron
defi ciency anaemia in the presence of infl ammation. A
widely used marker of infl ammation is the C-reactive
protein (CRP), but the extent of increase of CRP
concentration that invalidates the use of serum ferritin
to diagnose iron defi ciency is unclear; CRP values higher
than 10–30 mg/L have been used. Moreover, during the
acute-phase response, the increase of CRP concentration
is typically of shorter duration than the increase of
serum ferritin. Alternative markers such as α1-acid
glycoprotein (AGP) might be useful because AGP tends
to increase later during infection than CRP, and remains
high for several weeks.90 A distinct advantage of the
soluble transferrin receptor (sTfR) is that it might
diff erentiate iron defi ciency anaemia from anaemia of
chronic disease.79,91 Thus, in surveys in developing
countries with a high frequency of infection, in addition
to serum ferritin and haemoglobin measurements,80
laboratory assessment should include sTfR, zinc
protoporphyrin (ZPP), and CRP, AGP, or both,4 although
the sensitivity and specifi city of sTFR and ZPP are low
in these settings.78 In an anaemic individual with high
CRP, AGP, or both, high sTfR and ZPP concentrations
are likely to mean concurrent iron defi ciency, despite
high serum ferritin.
Selected cutoff values to defi ne iron
Haemoglobin (g/L)6 months–5 years <110
6 years–11 years <115
Non-pregnant women <120
Pregnant women <110
Children older than 11 years and
When used alone, it has low specifi city and sensitivity
A reliable, but late indicator of iron defi ciency
Low values can also be due to thalassaemia
In infants and young children <27·5
In adults ≤28·0
A sensitive indicator that falls within days of onset of iron-defi cient erythropoiesis75,76
False normal values can occur when MCV is increased and in thalassaemia76
Wider use is limited because it can only be measured on a few models of analyser
It can be measured directly on a drop of blood with a portable haematofl uorometer77
A useful screening test in fi eld surveys, particularly in children,78 in whom uncomplicated iron
defi ciency is the primary cause of anaemia
Red cells should be washed before measurement78 because circulating factors, including
serum bilirubin, can spuriously increase values
Lead poisoning can increase values, particularly in urban and industrial settings70
It is inexpensive, but its use is limited by diurnal variation in serum iron and by many clinical
disorders that aff ect transferrin concentrations27,79
It is probably the most useful laboratory measure of iron status;80 a low value of SF is
diagnostic of iron defi ciency anaemia in a patient with anaemia
In healthy individuals, SF is directly proportional to iron stores: 1 μg/L SF corresponds to
8–10 mg body iron or 120 μg storage iron per kg bodyweight81
As an acute-phase protein, SF increases independent of iron status by acute or chronic
infl ammation; it is also unreliable in patients with malignancy, hyperthyroidism, liver
disease, or heavy alcohol intake27
Main determinants are the erythroid mass in the bone marrow and iron status; thus, sTfR is
increased by enhanced erythropoiesis and iron defi ciency79,82
sTfR is not substantially aff ected by the acute-phase response,79 but it might be aff ected by
malaria,83,84 age, and ethnicity78
Its application limited by high cost of commercial assays and lack of an international
This ratio is a quantitative estimate of total body iron; the logarithm of this ratio is directly
proportional to the amount of stored iron in iron-replete patients and the tissue iron defi cit
in iron defi ciency85
In elderly people, this ratio might be more sensitive than other laboratory tests for iron
This ratio cannot be used in individuals with infl ammation because SF might be high
independent of iron stores
This ratio is assay specifi c85
Although it is only validated for adults,85 this ratio has been used in children4,32,87,88
5 years or younger >70
Children older than 5 years >80
Children older than 5 years on washed
red cells >40
Transferrin saturation <16%
Serum ferritin (SF)
5 years or younger <12
Children older than 5 years <15
In all age groups in the presence of
Cutoff varies with assay, and with
patient age and ethnic origin
Table 2: Indicators of iron defi ciency anaemia
www.thelancet.com Vol 370 August 11, 2007 515
Three main strategies for correcting iron defi ciency in
populations exist, alone or in combination: education
combined with dietary modifi cation or diversifi cation, or
both, to improve iron intake and bioavailability; iron
supplementation (provision of iron, usually in higher
doses, without food); and iron fortifi cation of foods. A
new approach is biofortifi cation via plant breeding or
genetic engineering. Although dietary modifi cation and
diversifi cation is the most sustainable approach, change
of dietary practices and preferences is diffi cult, and foods
that provide highly bioavailable iron (such as meat) are
Iron supplementation can be targeted to high-risk groups
(eg, pregnant women), and can be cost eff ective,55 but the
logistics of distribution and absence of compliance are
major limitations. For oral supplementation, ferrous iron
salts (ferrous sulphate and ferrous gluconate) are
preferred because of their low cost and high bioavailability.
Standard therapy for iron defi ciency anaemia in adults is
a 300-mg tablet of ferrous sulphate (60 mg of iron) three
or four times per day. Although absorption is enhanced
when given on an empty stomach, nausea and epigastric
pain might develop. If these side-eff ects arise, lower
doses between meals should be attempted, or iron should
be provided with meals, although food reduces absorption
of medicinal iron by about two-thirds.79 Alternatively, oral
iron supplements can be supplied every few days; this
regimen might increase fractional iron absorption.92 In
studies supported by WHO in southeast Asia, iron and
folic acid supplementation every week to women of
childbearing age improved iron nutrition and reduced
iron defi ciency anaemia.92 In industrialised countries,
universal iron supplementation of pregnant women is
widely advocated even though so far little evidence exists
that it improves maternal or fetal outcomes. However, in
two controlled trials of prenatal iron supplementation in
iron-replete, non-anaemic low-income pregnant women
in the USA, iron supplementation increased birthweight,
reduced incidence of preterm delivery, or both, but did
not aff ect prevalence of anaemia during the third
trimester.93,94 Iron supplementation during pregnancy is
advisable in developing countries, where women often
enter pregnancy with low iron stores.1
Untargeted iron supplementation in children in tropi-
cal countries, mainly in areas of high transmission
of malaria, is associated with increased risk of
serious infections.95,96 In a region of endemic malaria in
east Africa, untargeted supplementation with iron
(12∙5 mg per day) and folic acid in preschool children
increased risk of severe illness and death.97 Although iron
supplements were thought to be the cause, provision of
folic acid might have reduced the eff ectiveness of
anti-folate antimalarial drugs,98 and thereby contributed
to morbidity.99 A similar study in Nepal, which is a
non-malarial area, showed no eff ects of iron and folic acid
on infection-related morbidity.100 A recent WHO report
stated that iron and folic acid supplementation should be
targeted to children who are anaemic and at risk of iron
defi ciency, and concurrent protection from malaria and
other infectious diseases should be provided.101
Iron fortifi cation is probably the most practical,
sustainable, and cost-eff ective long-term solution to
control iron defi ciency at the national level.55,102,103 Overall
cost-eff ectiveness for iron fortifi cation is estimated to be
$66–70 per DALY averted.103 Fortifi cation of foods with
iron is more diffi cult than it is with other nutrients, such
as iodine in salt and vitamin A in cooking oil. The most
bioavailable iron compounds are soluble in water or
diluted acid, but often react with other food components
to cause off -fl avours, and colour changes, fat oxidation, or
both.33 Thus, less soluble forms of iron, although less well
absorbed, are often chosen for fortifi cation to avoid
unwanted sensory changes. Fortifi cation with low iron
doses is more similar to the physiological environment
than is supplementation and might be the safest
intervention.101,102 Iron fortifi cation of milk or cereals does
not increase infection-related morbidity in children
younger than 18 months.95 In an analysis of four studies
of infants receiving iron-fortifi ed foods, the regimen did
not cause visible adverse eff ects and signifi cantly protected
against the development of respiratory tract infections
(incidence rate ratio 0∙92, 95% CI 0∙86–0∙98; p=0∙02).96
Although little direct evidence exists, the reduction in
occurrence of iron defi ciency in young children in
industrialised countries has been attributed to iron
fortifi cation of infant formulas and weaning foods.
Iron-fortifi ed foods distributed through the Special
Supplemental Nutrition Program for Women, Infants,
and Children (WIC) have probably contributed to the fall
of iron defi ciency in underprivileged preschool children
in the USA.104 At present, the low frequency of iron
defi ciency anaemia in adolescent and young women in
the USA might be at least partly due to consumption of
iron-fortifi ed wheat fl our, although other factors,
including open-market fortifi cation of food products, and
use of vitamin and mineral supplements, have also had a
role. More-specifi c evidence is provided by retrospective
studies from Sweden that reported decrease of iron
intake105 and increase of iron defi ciency in young women106
since iron fortifi cation of wheat fl our was discontinued
in 1994. By contrast, fi ndings from Denmark, where iron
fortifi cation of wheat fl our was discontinued in 1987,
suggest no change in the frequency of iron defi ciency in
adults older than 40 years,107,108 but the data might have
been confounded by the eff ects of increasing bodyweight,
alcohol consumption, or both, contributing to increased
values or serum ferritin.
www.thelancet.com Vol 370 August 11, 2007
Universal iron fortifi cation is generally recommended
for countries where the risk of developing iron defi ciency
is high for all groups other than adult men and
postmenopausal women.102 Up to now, no clear indication
of effi cacy of iron fortifi cation in developing countries
existed, because of several factors (panel 1). However,
recent studies have shown convincingly that iron
fortifi cation can be eff ective.66,88,109–112 The iron compound
and type of fortifi cation should be chosen on the basis of
the fortifi cation vehicle, iron requirements of the target
population, and iron bioavailability of the local diet
(panel 2). Effi cacy should be monitored with measure-
ments of serum ferritin and, when possible, serum
transferrin receptor, in addition to haemo globin.66,80,88,109–113
Iron fortifi cation eff orts have been accelerated by the
Global Alliance for Improved Nutrition (GAIN), an
alliance of United Nation agencies, national govern-
ments, development agencies, and the private sector,
funded mainly by the Bill & Melinda Gates Foundation.
GAIN has awarded $38 million in grants to food
fortifi cation programmes in 14 countries, including iron
fortifi cation of soy sauce in China, fi sh sauce in Vietnam,
and wheat and maize fl our in South Africa.
The foods most often used for mass fortifi cation are the
staple cereal fl ours. Iron is only poorly absorbed from
high-extraction fl ours because of the presence of phytate
and other inhibitory factors.114,115 Dried ferrous sulphate
can be used in wheat fl our that is consumed shortly after
it is milled, but in most developing countries fl our is
stored for longer periods. Thus, elemental iron powders,
which are less reactive, are widely used, despite their lower
bioavailability.109,115,116 Findings from an effi cacy trial in
Thailand suggest that two forms of elemental iron,
electrolytic iron and hydrogen-reduced iron, might be
useful for fortifi cation, but their bioavailability is
only 50–79% that of ferrous sulphate.109 Two other forms
of reduced iron, carbon-monoxide-reduced and atomised
iron, are poorly absorbed and unlikely to be useful for food
fortifi cation. A trial in Sri Lanka failed to show a reduction
in anaemia occurrence after 2 years of fortifi cation of
low-extraction wheat fl our with either electrolytic or
reduced iron, but fortifi cation was probably too low.117
Wheat fl our fortifi cation with ferrous sulphate in Chile at
30 mg/kg has probably contributed to a strong decrease in
iron defi ciency.118 Fortifi cation of maize fl our in South
Africa with ferrous fumarate has shown eff ectiveness in
lowering anaemia, and improving iron status and motor
develop ment of infants in poor settings.119 Clear guide -
lines on wheat fl our fortifi cation have recently been
Sodium iron ethylenediaminetetraacetic
(NaFeEDTA) has shown eff ectiveness as a fortifi cant in
sugar in Guatemala,121 curry powder in South Africa,122
soy sauce in China,123 fi sh sauce in Vietnam,110 and maize
fl our in Kenya.124 NaFeEDTA is absorbed 2–3 times more
than ferrous sulphate from diets high in phytic acid,125
but is approved as a food additive only at 0∙2 mg iron a
day as NaFeEDTA per kg bodyweight, which limits its
usefulness as a fortifi cant for infants and children.126
NaFeEDTA does not promote fat oxidation in stored
cereals and is the only soluble iron compound that does
not precipitate peptides in fi sh and soy sauces. Use of
micronised ground ferric pyrophosphate, a white-coloured
iron compound with good bioavailability, has allowed
successful fortifi cation of colour-sensitive food vehicles,
such as low-grade salt in Africa66,113 and rice in India.88 A
micronised, dispersible ferric pyrophosphate127 and
ferrous bisglycinate, an aminoacid chelate,111 are iron
fortifi cants particularly useful for liquid products.
Infants and young children in developing countries are
at high risk of iron defi ciency and might not be reached by
universal fortifi cation programmes. Chile has shown
convincing evidence of the benefi t of targeted fortifi cation
Panel 1: Failure to determine the eff ectiveness of iron
fortifi cation programmes in developing countries3,33
Failure of eff ectiveness
• Use of iron compounds with low bioavailability or failure
to enhance absorption from inhibitory diets
• Inadequate iron fortifi cation
• Consumption of fortifi ed food too low to deliver
• High frequency of parasitic infections that cause blood
loss (eg, hookworm)
• High frequency of infection, infl ammation, or both, that
impairs iron metabolism and erythropoiesis (eg, malaria)
Failure to detect eff ectiveness
• Failure to defi ne iron status with specifi c indicators clearly
• Failure to recognise other causes of anaemia
• Poor programme control and enforcement
Panel 2: Iron compound that can be used for iron
fortifi cation of food in order of preference102
Most foods (eg, cereal fl ours)
• Ferrous sulphate
• Ferrous fumarate
• Encapsulated ferrous sulphate or fumarate
• Electrolytic iron (at twice the amount vs ferrous sulphate)
• Ferric pyrophosphate (at twice the amount vs
For high phytate cereal fl ours and high peptide sauces
(eg, fi sh and soy sauce)
For liquid milk products
• Ferrous biglycinate
• Micronised dispersible ferric pyrophosphate
• Ferric ammonium citrate
www.thelancet.com Vol 370 August 11, 2007 517
of powdered milk with ferrous sulphate and ascorbic acid,
with frequency of anaemia decreasing from 27% to 9%.128
By contrast, distribution of a milk-based iron-fortifi ed
weaning food in Mexico for 1 year did not improve iron
status, possibly because of the poor bioavailability of the
reduced iron used as a fortifi cant.129 Complementary food
supplements that are added to the infant’s food immediately
before consumption have been developed. Three types of
supplements have been tested: powders (sprinkles),
crushable tablets, and fat-based spreads.130–132 Iron status
was improved in Ghanaian infants with home fortifi cation
with powder containing encapsulated ferrous fumarate.132
The variation in the iron content of cultivars of wheat,
bean, cassava, maize, rice, and yam133–137 suggests that
selective breeding might increase iron content of staple
foods. However, although diff erences in iron content
exist in wheat (25–56 mg/kg) and rice (7–23 mg/kg),
most of the iron is removed during the milling process.
Thus, to increase iron concentration in milled wheat up
to 40 mg/kg, which is the fortifi cation level commonly
used in wheat fl our, might be diffi cult.120 This problem
was evident when the eff ectiveness of a rice cultivar high
in iron was tested in a feeding trial in Filipino women
consuming either the high-iron rice (3∙21 mg/kg) or a
local variety (0∙57 mg/kg) for 9 months.135 Possibly
because the high-iron rice added only an extra 1∙5 mg of
iron a day to the diet, no clear benefi t of iron status was
seen. Iron absorption from other cereals and legumes
(many of which have high native iron content) is low
because of their high contents of phytate and
polyphenols.138 Donangelo and colleagues139 compared
iron bioavailability from two varieties of red beans: an
iron-rich genotype (containing 65% extra iron) and a
low-density genotype. Only a small amount of iron was
absorbed from both cultivars, probably because of their
high phytate and polyphenol content. Decrease of the
content of these inhibitors in high-iron cultivars might
be needed to have a positive eff ect on human nutrition.
Genotypes of maize, barley, and rice have been identifi ed
that are low-phytic-acid mutants, with phytic acid
phosphorus content decreased by up to two-thirds
compared with wild type.140 Although such reductions
might improve iron absorption from diets containing
small amounts of meat and ascorbic acid,141 phytic acid
content might be needed to be lowered by more than
90% to increase iron absorption from the monotonous
cereal-based diets seen in many developing countries.142
Because of these limitations, genetic engineering
might prove to be the most eff ective way to have a useful
amount of absorbable iron in plant foods.143,144 Iron
content in rice can be increased two-to-three fold by
introduction of the ferritin gene from soy bean145 or
phaseolus vulgaris.146 Iron uptake from soils might be
increased by introduction of a ferric reductase gene into
plant root systems.147 To lower the phytic acid content of
rice, Lucca and colleagues146 introduced a phytase from
Aspergillus fumigatus that was developed to withstand
food processing. Although phytase activity increased
seven-fold, it proved to be unstable and was destroyed
when rice was cooked. Overall, these studies suggest that
iron content can be increased in staple foods by plant
breeding, genetic engineering, or both.
Nutritional iron defi ciency is still common in young
women and children in developing countries where
monotonous, plant-based diets provide low amounts of
bioavailable iron. The high prevalence of iron defi ciency
in the developing world has substantial health and
economic costs. However, more data are needed on the
functional consequences of iron defi ciency; for example,
the eff ect of iron status on immune function and
cognition in infants and children needs to be clarifi ed.
Continuing rapid ad vances in understanding the
molecular mechanisms of iron absorption and
metabolism might enable development of new strategies
to combat iron defi ciency. Although technical challenges
limit the amount of bioavailable iron that can be added
to many foods, evidence from controlled trials has
shown that iron fortifi cation can eff ectively control iron
defi ciency. Whether iron fortifi cation can be successful
in tropical areas without concurrent control of malaria
and hookworm infections remains to be seen. Specifi c
laboratory measures of iron status—eg, serum ferritin,
sTfR, and zinc protoporphyrin—should be used to
assess the need for fortifi cation and for monitoring.
Because of fi ndings showing the risks of untargeted
iron supplementation in young children, development
of new strategies are urgently needed to provide
additional dietary iron to susceptible infants and young
children in developing countries who might not be
reached by universal fortifi cation programmes. New
methods to enhance native iron content of plant-based
staple foods are also needed. Selective plant breeding
and genetic engineering are promising new approaches
to improve dietary iron bioavailability; however, a major
challenge is to show that they can increase iron content
to nutritionally useful levels and that the additional iron
Confl ict of interest statement
We declare that we have no confl ict of interest.
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