Viewpoint

Neurological effects of iron supplementation in infancy:

finding the balance between health and harm in iron-replete
infants
Dominic J Hare, Bárbara Rita Cardoso, Ewa A Szymlek-Gay, Beverley-Ann Biggs

Iron mediates many biochemical processes in neural networks that proliferate during brain development. Insufficient Lancet Child Adolesc Health 2017
iron causes irreversible neurodevelopmental deficits, and most high-income countries recommend that infants older Published Online
than 4–6 months receive additional iron via food fortification or supplementation to prevent iron-deficiency anaemia. December 1, 2017
http://dx.doi.org/10.1016/
Now that the prevalence of iron-deficiency anaemia in children has decreased to less than 10% in most developed
S2352-4642(17)30159-1
countries, concerns that the recommended intakes far exceed those required to prevent iron-deficiency anaemia have
The Florey Institute of
been raised, and emerging evidence suggests that iron overexposure could be linked to adverse outcomes later in life. Neuroscience and Mental
In this Viewpoint, we discuss the importance of iron for neurodevelopment, investigate the biochemical markers Health (D J Hare PhD,
used to assess iron stores, summarise the disparity in public health policies among high-income countries, and B R Cardoso PhD) and
Department of Medicine (Royal
discuss the potential association between iron overexposure and adverse neurological outcomes later in life. We
Melbourne Hospital) at the
present a case for new studies to establish the optimal amount of iron that both prevents deficiency and reduces the Doherty Institute, The
potential risk of long-term negative health outcomes. University of Melbourne,
Parkville, Melbourne, VIC,
Introduction both, in children that are iron replete that prevents iron- Australia (D J Hare,
Prof B-A Biggs PhD); Victorian
Iron-deficiency anaemia, particularly in infancy, can have deficiency anaemia, while mitigating the risk of adverse Infectious Diseases Service,
severe negative health effects. Symptoms include fatigue, neurodevelopmental outcomes later in life. Royal Melbourne Hospital,
headache, paleness, stomatitis, restless legs syndrome, Parkville, Melbourne, VIC,
koilonychia, bowel irritation, and impaired glucose Dietary iron and brain iron concentrations Australia (B-A Biggs); and
Institute for Physical Activity
metabolism.1,2 The burden of disease is high, spanning Several processes that are unique to the brain rely on and Nutrition, School of
lost productivity to infant and maternal mortality.3 Iron is iron redox chemistry (panel 1). Iron concentrations are Exercise and Nutrition
essential for neurodevelopment,4 and policies designed compartmentalised and regulated to prevent reactions Sciences, Deakin University,
Geelong, VIC, Australia
to reduce the prevalence of iron-deficiency anaemia with byproducts of mitochondrial respiration that drive (B R Cardoso,
in children are a crowning achievement of preventive oxidative stress (figure 1). E A Szymlek-Gay PhD)
medicine. However, the effectiveness of iron supplemen­ Uptake of iron into the brain following blood–brain Correspondence to:
tation appears to be situation dependent, with little barrier maturation has been assumed to be independent Dr Dominic J Hare, The Florey
evidence of the overall benefit in low-income and middle- of dietary iron intake in adults; however, rodent studies8 Institute of Neuroscience and
Mental Health, Parkville, VIC
income countries,5 and even less in Organisation for have shown that iron concentration in the brain increases
3052, Australia
Economic Co-operation and Development (OECD) by about 30% in healthy rats from early adulthood to dominic.hare@florey.edu.au
countries.6 The WHO’s 2016 guideline for iron death, and conservative extrapolation to human beings
supplementation in infants and children7 recommends suggests that the half-life of iron in the brain is in the
supplementing infants for only three consecutive months order of decades.8 The precise age when the blood–brain
a year, and only in areas where the prevalence of anaemia
is greater than 40%. However, the evidence of benefit is
often at odds with public health guidelines on a country- Key messages
by-country basis. • Iron is essential for healthy neurodevelopment, although
Existing policies have received criticism because of overexposure could have adverse long-term health
emerging evidence of negative long-term effects of outcomes
excessive iron exposure during neurodevelopment. WHO • Supplementation or food fortification programmes have For Food Fortification
states that obtaining additional data on the safety of iron been implemented to reduce the prevalence of iron Initiative homepage see
supplementation, including effects in children who do not deficiency and iron-deficiency anaemia in infants
http://www.ffinetwork.org
have anaemia or are not iron deficient, should be a • These supplementation and food fortification policies
research priority.7 In this Viewpoint, we critically appraise vary on a country-by-country basis
the evidence surrounding iron supplementation. • Critical windows during development reflect the dynamic
Highlighting the potential negative outcomes of nature of iron that is needed in the growing brain
overexposure, we emphasise the paucity of compelling • The long-term health outcomes of supplementing
evidence supporting or refuting the need for iron children who are iron replete are unclear
supplementation programmes, necessitating the need to • We advocate for new evidence-based studies to identify
revisit public health policies with new evidence-based appropriate iron intake concentrations that prevent
studies. We propose that a potential middle ground should deficiency while reducing risk of overexposure
be pursued for iron supplementation or fortification, or

www.thelancet.com/child-adolescent Published online December 1, 2017 http://dx.doi.org/10.1016/S2352-4642(17)30159-1 1

 Viewpoint
Panel 1: Biochemical function and trafficking of iron in the brain
• Iron is a cofactor in the enzymes that synthesise the neurotransmitters serotonin,
γ-aminobutyric-acid (GABA), dopamine, and associated catecholamines
• Oligodendrocytes are enriched with iron and are responsible for the biosynthesis of
myelin sheaths
• Distribution of iron is compartmentalised, with higher concentrations within grey
matter—specifically within the basal ganglia and midbrain
• Primary transport of iron across the blood–brain barrier is via transcytosis of the
transferrin–transferrin receptor-1 complex from the luminal side of brain capillary
endothelial cells and released into the CNS by divalent metal transporter-1
• Astrocytes and other support cells secrete apotransferrin and small ligands that, in
turn, distribute iron to areas in need, including to neurons via endocytosis of the same
transferrin receptor complex
• The concentration of iron in the brain that accumulates during normal ageing is
different depending on the anatomical region of the brain
• A likely route of iron export from the brain is via cerebrospinal fluid in the
subarachnoid space and eventual return to the bloodstream
See Online for appendix barrier is fully formed is a matter of some debate: studies
in human beings are scarce, and although the barrier is
impermeable to macromolecules at birth, tight junctions
continue to develop for an unknown period during
infancy, enabling diffusion of small molecules into the
CNS.9
Critical windows for iron and neurodevelopment
In exposure biology, critical windows are periods when
factors such as nutritional deficiency, environmental
exposure, and gut microbiota can influence
neurodevelopment. For iron at least three such windows
exist, these include: the preconception and in-utero
period, when the fetus is dependent on maternal iron
supplies that seed and support neurodevelopment; the
first 6 months of life, when iron is recycled from excess
haemoglobin and is essential for myelin synthesis;
and the following 6–24 months, when iron-dependent
neurotransmitter pathways are established (figure 2). An
infant’s brain at birth is approximately a third the volume
of an adult brain, and it increases by 64% over the first
3 months,13 and by age 10 years the total iron content of
the brain increases from 10 to 50% of an adult brain’s
iron content.14
Although we focus on dietary supplementation during
the window of 6–24 months, the importance of the
preceding periods should not be viewed in isolation.
Maternal factors including iron deficiency, diabetes,
smoking, intrauterine growth restriction, multiple
gestations, and fetal haemorrhage can negatively affect an
infant’s iron stores at birth.15 Maternal iron and folic acid
supplementation reduces mortality and improves infant
iron status; although, excessive iron intake is also linked
to gestational diabetes.16 Prenatal iron and folic acid
improves neurological function in late childhood
(7–9 years) in countries where iron-deficiency anaemia is
endemic.17 However, maternal iron deficiency or iron-
2 www.thelancet.com/child-adolescent Published online December 1, 2017 http://dx.doi.org/10.1016/S2352-4642(17)30159-1
deficiency anaemia does not appear to be associated with
impaired cognitive or motor function in offspring at
12 months.18 Evidence supporting the benefits of maternal
iron supplementation during pregnancy is hetero­
geneous19 and larger randomised controlled trials are
needed.
The in-utero environment is anoxic, and an infant is
born with excess haemoglobin (about 170 g/L) that
provides sufficient iron for the first 4–6 months of life.
Intake of iron from breastmilk (containing <1 mg/L) is
generally thought to be adequate during this time;
although, an apparent absence of iron export from
mammalian secretory cells has given cause for some to
claim that human breastmilk contains no iron of
nutritional value, and dietary supplementation should be
considered.20 On the basis of heterogeneous results
from randomised controlled trials, opinions among
specialists are conflicting as to whether the neuro­
developmental benefits of supplemental iron are
measurable (appendix pp 2–4). For instance, a randomised
controlled trial in China21 comparing maternal and
neonatal iron supplementation found that gross motor-
function indices improved with treatment after birth,
regardless of intake during pregnancy, whereas a
prospective longitudinal study in Spain22 found that
psychomotor development was more advanced in low-
iron breastfed 6-month-old infants than in mixed-fed
children who had a higher dietary iron intake. To date, the
best evidence regarding long-term neuro­developmental
outcomes in iron-replete infants recommends delayed
cord clamping (≥180 sec) to maximise iron transfer,
although the benefits are not apparent until the child is
aged 4 years.23
The evidence that the behavioural effects of iron
deficiency or iron-deficiency anaemia during infancy are
permanent is conflicting. Biochemical studies have
focused on rodents, and although these provide useful
information on neurochemical development, many
assumptions are extrapolated to human beings.24 A
Cochrane review25 acknowledged that the deleterious
effects of iron-deficiency anaemia on the brain are
probably irreversible, and yet evidence of the short-term
benefits of iron therapy is absent and the long-term
effects remain unknown. Longitudinal cohort studies26–28
have identified associations between iron deficiency and
iron-deficiency anaemia and neurological development,
although with multiple confounders. For example, iron
deficiency and iron-deficiency anaemia in infancy were
associated with risk-taking behaviour into adolescence
and poor emotional processing in childhood (attributed
to stunted development of neurotransmitter pathways)
in a prospective cohort of Chilean children aged 10 and
14 years, controlling for socioeconomic status, home
environment, and family stability.26 However, other
confounding effects cannot be discounted—eg, chronic
inflammation and assessment. Supplementing children
who have iron deficiency or iron-deficiency anaemia
 Viewpoint

Duodenum Circulation CNS

Lactotransferrin
from breastmilk Blood–brain barrier

Hepcidin

Iron

Transferrin

Iron-fortified formula
Neurons

Astrocytes
Haem

N N

HO O

Ferritin
Enterocytes

Figure 1: Schematic of dietary iron intake and transit to the CNS

Iron is absorbed in the duodenum from either naturally occurring or fortified products. Once exiting enterocytes, iron is loaded onto transferrin, which distributes
iron around the body. At the blood–brain barrier, iron is imported via transferrin receptor-mediated endocytosis and released into the CNS, reloaded onto transferrin,
and delivered to the various brain regions.

during the 6–24-month period had improved social–
emotional and behavioural outcomes, but not global
developmental scores.27 The lead investigator of the
Chilean study described the benefits on motor and
cognitive functions as “subtle”,28 and that improved
nutrition in a contemporary Chilean (or other iron-
replete) setting could give different results.28 A 2013
systematic review and meta-analysis29 of daily iron
supplementation in children aged 4–23 months found
that although intervention prevented iron-deficiency
anaemia, it increased adverse effects (vomiting, fever)
and showed no evidence of improved neurodevelopment.29
Iron deficiency versus iron-deficiency anaemia
The clinical distinction between iron deficiency and iron-
deficiency anaemia is of great importance with respect to
clinical management. Bermejo and García-López define
iron deficiency as “the decrease of the total content of
iron in the body” and iron-deficiency anaemia as
“when [iron deficiency] is sufficiently severe to reduce

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 Viewpoint
Anoxic Oxygen replete
Rapid fetal Neonatal Brain volume expansion
haemoglobin haemoglobin Proliferation of neurotransmitters
synthesis recycling
Blood–brain barrier tight
Iron concentration
junction closure
Exclusive
breastfeeding Formula or mixed feeding and complementary foods
2nd 3rd Birth 6 12
Trimesters Age (months)
Iron supplementation and iron-rich diet
Iron supplementation and restricted diet
Figure 2: Trajectory of infant iron concentrations and critical windows of neurodevelopment
Full-term and exclusively breastfed infants with healthy mothers should have similar iron concentrations that
diverge when iron rich (formula or complementary solid foods, or both; blue line) or poor (red line) diets are
introduced. Illustrative trajectories of iron intake are based on data from Atkins and colleagues,10 Baker and
colleagues,11 Domellöf and colleagues,4 and Ramakrishnan and Yip.12
erythropoiesis”.30 Iron deficiency affects approximately
2 billion people worldwide,31 with iron-deficiency
anaemia being the most common cause of anaemia.3
Iron-deficiency anaemia is a global health concern, and
policies of iron supplementation or food fortification, or
both, have reduced global prevalence of iron-deficiency
anaemia in children younger than 5 years, with WHO
data estimating a decrease from 47% in 1995 to 43% in
2011; although, the prevalence was only 11% in high-
income countries in 2011.32
The prevalence of iron deficiency is approximately
double that of iron-deficiency anaemia,33 and iron
deficiency can be considered as prodromal to iron-
deficiency anaemia, in that iron stores in the body are
depleted in the absence of clinical symptoms. Whether
iron deficiency is pathological is still under contention,
since most studies in human beings have examined
neurodevelopmental deficits only in individuals with iron-
deficiency anaemia, and are often of poor quality. One
example of a study in which iron deficiency and iron-
deficiency anaemia were poorly defined was published in
1983,34 wherein investigators used a single intramuscular
injection of iron to assess behavioural outcomes in infants
who were stratified as “iron sufficient”, “iron depleted”, or
“iron deficient”.34 By modern guidelines, all groups in this
study would be defined as non-anaemic (haemoglobin
levels >110 g/L). Clinical classification was made according
to serum ferritin and erythrocyte porphyrin concentrations.
Only infants considered as “iron deficient” (ferritin
<12 µg/L; erythrocyte porphyrin >300 µg/L) showed
improvements in the Bayley Mental Development Index,
with “iron depleted” infants (using the same parameters,
with erythrocyte porphyrin concentrations <300 µg/L)
showing no difference after intervention. In a later
discussion,35 the same authors used the terms iron
deficiency and iron-deficiency anaemia interchangeably.
4 www.thelancet.com/child-adolescent Published online December 1, 2017 http://dx.doi.org/10.1016/S2352-4642(17)30159-1
More studies on the neurodevelopmental effects of iron
deficiency, as opposed to focusing only on iron-deficiency
anaemia, are necessary to better inform public health
policies. The scarcity of well conducted studies that
categorically show iron deficiency causes adverse
neurodevelopmental outcomes poses the question of
whether iron deficiency requires clinical intervention. If
markers of iron deficiency remain stable and an infant
shows no evidence of adverse health effects, iron
supplementation might be unnecessary, and could even
lead to long-term negative health outcomes.
A clinical diagnosis of iron deficiency and iron-
24 deficiency anaemia is established by measuring iron-
associated proteins in the blood. The latest guidelines
from the American Academy of Pediatrics (AAP)
Committee on Nutrition11 established a panel of
diagnostic biomarkers (panel 2). However, aside from the
generally accepted cutoff for iron-deficiency anaemia in
infants of less than 110 g/L of haemoglobin in the blood,
contention regarding the precise analytical values for
other biomarkers exists as a result of a degree of
disconnection between clinicians and biochemists
concerning their specific function in maintaining iron
homoeostasis.
Treating iron deficiency and iron-deficiency
anaemia in infants
For iron deficiency and iron-deficiency anaemia, iron
supplementation and fortification of food products
remains a primary point-of-care strategy for addressing
these conditions in areas of high prevalence—ie, in many
low-income and middle-income countries.3
However, in many high-income countries, fortification
of infant formula has been commonplace for decades.
The Australian Institute for Health and Welfare reports
that 96% of infants in Australia are initially breastfed, but
only 39% are exclusively breastfed for longer than
4 months, and 15% for more than 6 months.43 A large
cohort study10 in Australia showed that formula accounts
for 44% of dietary iron intake at age 9 months.
Guidelines for fortification of infant formula varies
between countries. Recommendations published in 2010
from the AAP Committee on Nutrition to prevent iron
deficiency and iron-deficiency anaemia in children aged
0–3 years are shown in panel 3.11 These recommendations
incited debate among prominent members of the infant
nutrition community. Hernell and Lönnerdal44 criticised
the study by Friel and colleagues45 that formed the
groundwork for these recommendations, stating that
their double-masked randomised controlled trial
assessing iron supplementation in healthy breastfed
infants was underpowered, and that Friel and colleagues
themselves stated in their report that “A larger study
[ focusing] on the long-term developmental outcomes is
needed before recommendations can be considered
regarding the whole population of breast-fed infants.”45
Hernell and Lönnerdal stated that fortification of infant

formula with 12 mg/L of iron is unnecessarily high, and
questioned the interpretation of bio­markers used by the
investigators. Furthermore, Furman commented that
calls to supplement exclusively breastfed infants were
“premature”,46 and raised concerns regarding the
supplementation of iron to infants who are iron replete,
noting that information on negative health outcomes was
available, and advocated for delayed cord clamping to be
added to the AAP recommendations. The AAP’s own
independent Section on Breastfeeding published in 201047
noted that they were consulted by Baker, Greer, and the
Committee on Nutrition before publication of the 2011
guidelines,11 but the AAP failed to report that the Section
on Breastfeeding was in disagreement with the overall
conclusions of the issued recommendation, and had
published their own alternative guidelines in 2009.48 The
Section on Breastfeeding also echoed concerns regarding
oversupplementation and risks of long-term negative
health outcomes.
In response to these comments, Baker and Greer
defended the use of Friel and colleagues’ results to set
guidelines and cited that the paucity of studies assessing
long-term outcomes did not outweigh benefits: “[i]ron
deficiency occurs long before there is overt an[a]emia and
may have long-lasting consequences. Because of the very
low iron content of human milk, exclusively breastfed
infants are at risk of iron deficiency. Supplementing
breastfed infants would protect them; why put these
infants at any risk when no appreciable harm of iron
supplementation has been convincingly demonstrated?”49
Since the AAP’s guidelines were first released, a
randomised controlled trial of iron supplementation
(1 mg/kg per day as an additive to breastmilk or formula)
including an iron-replete patient group focusing on
psychomotor and mental development outcomes has
commenced (NCT02242188), and the Benefits and Risks
of Iron interventionS in Children (BRISC) trial in
Bangladesh (ACTRN12617000660381) has been registered.
Hernell and Lönnerdal’s reply44 to the AAP cited studies
from Europe, where recommendations on iron
supplementation are more conservative. The position of
the European Society for Paediatric Gastroenterology,
Hepatology and Nutrition (ESPGHAN; panel 4)4 includes
comprehensive definitions of iron deficiency and iron-
deficiency anaemia. Notably, when ESPGHAN formed
an international advisory group and released their global
standard for infant formula composition, one member
withdrew support for the proposed range of iron
fortification levels (0·3–1·3 mg per 100 kcal for cow milk
formula; 0·45–2·0 mg per 100 kcal for soy) on the basis
of them being too low per the standards of their national
advisory body. A subsequent Mead Johnson Pediatric
Nutrition Institute Iron Expert Panel meeting in
November, 2014, reported that “panel members were in
agreement that the current levels of iron fortification of
infant formulas in the US are not optimal and do not
reflect current evidence for iron requirements in this age
www.thelancet.com/child-adolescent Published online December 1, 2017 http://dx.doi.org/10.1016/S2352-4642(17)30159-1
Viewpoint
Panel 2: The American Academy of Pediatrics Committee on Nutrition’s
recommended diagnostic biomarkers for iron deficiency and iron-deficiency
anaemia11
Haemoglobin
• Most commonly used clinical biomarker of iron deficiency and iron-deficiency anaemia
• Diagnosis of iron-deficiency anaemia is defined as haemoglobin <110 g/L at age
6 months to 5 years, <115 g/L at age 6–11 years, and <120 g/L for adults and children
older than 11 years
• Haemoglobin status has low specificity and sensitivity36
• US National Health and Nutrition Examination Survey III data showed that
haemoglobin was associated with unacceptable levels of false positives and negatives
in diagnosing iron deficiency and iron-deficiency anaemia in children37
• Reticulocyte (immature erythrocytes) haemoglobin content indicates iron status
within a 1–2-day period
Transferrin
• An 80 kDa glycoprotein with two iron binding sites
• Iron is loaded onto transferrin by two ferroxidase proteins: ceruloplasmin (circulation)
and hephaestin (within intestinal enterocytes)
• Largest contributor to circulating iron concentrations after haemoglobin
• Transferrinsat is the percentage of transferrin binding sites occupied
• Acute-phase inflammatory response can cause false-positive iron deficiency or
iron-deficiency anaemia diagnoses
• Clinical assays of transferrinsat are imprecise and have poor sensitivity to small
changes38
Transferrin receptor-1
• A regulator of evolutionarily conserved iron uptake and transport mechanisms;
transcription and expression dictated by cellular iron concentrations
• Serum transferrin receptor-1 combined with other markers improves the diagnostic
accuracy of iron deficiency and iron-deficiency anaemia, and can distinguish between
iron-deficiency anaemia and non-iron-deficiency aneamia39
Serum ferritin
• High-capacity storage protein capable of binding up to 4500 iron atoms
• Not synthesised in serum, rarely saturated, and iron load across multiple human
individuals is very variable40
• No clinically approved assays for ferritin saturation exist, and serum ferritin
concentration is typically used as a proxy for iron concentration
• Contribution to circulating iron is small compared with haemoglobin or transferrin
(approximately 5% of transferrin iron)
• A major inflammatory response protein and should be assessed in concert with other
inflammatory markers
Hepcidin
• Proposed master regulator of iron homoeostasis
• Synthesised by the liver (and to a lesser extent in the brain) to inhibit cellular iron
export41
• Strong antimicrobial properties and acute-phase inflammatory response factor
• Accurate analytical assays for clinical translation still require validation42
group”.51 Although the panel’s recommendations still
advocated fortification of infant formulas, they suggested
concentrations be more in line with the ESPHGAN
guidelines, and reflected the changing attitudes with
respect to iron exposure during critical windows of
neurodevelopment.
5
 Viewpoint
Panel 3: Summary of the American Academy of Pediatrics Committee on Nutrition
recommendations for iron intake in children and infants11
• Full-term infants who are exclusively breastfed beyond age 4 months are at risk of
iron deficiency, and should receive oral iron at a dose of 1 mg/kg until complementary
foods are introduced, including iron-fortified cereals
• Infants aged 0–12 months receive an adequate iron supply from a commercial
formula, which contains 10–12 mg/L in the USA; from 4–6 months complementary
foods, including iron-fortified cereals, should be introduced
• Iron intake between ages 6 and 12 months should be 11 mg/day, sourced from both
fortified and naturally iron-rich foods.
• Infants aged 1–3 years should receive 7 mg/day of iron, primarily through iron-rich
foods, including red meat, vegetables, and fruits that are rich in vitamin C, which
promotes iron absorption in the gut; if this diet cannot be provided, oral supplements
can be given up to age 3 years, and chewable vitamin preparations should be added
beyond this age
• Preterm infants require additional iron (2 mg/kg per day) up to age 12 months and
weaning to iron-fortified infant formula is recommended
• Assessment for iron deficiency and iron-deficiency anaemia should be done at age
12 months, primarily assessed by measuring haemoglobin concentrations and, if risk
of iron deficiency or iron-deficiency anaemia is indicated, other biomarkers listed in
panel 2 should be measured
Panel 4: Summary of ESPGHAN statements and recommendations on iron intake in
children and infants4
• Iron absorption in infants is generally low, but endogenous response mechanisms
might increase intake when dietary iron concentrations are low
• Iron-deficiency anaemia causes long-lasting neurodevelopmental deficits, but iron
overexposure is also associated with stunted growth, increased infection risk, and
potential neurodevelopmental deficits; evidence of neurodevelopmental benefits of
supplementation is conflicting
• ESPGHAN recommendations are more moderate than those of the AAP’s Committee
on Nutrition; they state that no convincing evidence is available to support
supplementation in full-term breastfed infants up to age 6 months
• In European pregnant women, iron supplementation does not seem to have had an
effect on neonatal iron status
• Delayed cord clamping improves iron status in neonates
• Formula-fed infants who are aged 0–6 months should receive 2·0–8·5 mg/L of iron,
and little evidence supports setting an optimal concentration range for follow-on
(>6 months) formulas
• Iron supplementation does not reduce the proportion of infants with iron-deficiency
anaemia in populations with low (<5–10%) prevalence at age 6 months, although
neurodevelopment might be improved in formula-fed infants under 6 months;
however, this supplementation strategy does prevent iron-deficiency anaemia in
infants who are aged 6–12 months
• Introduction of naturally iron-rich complementary foods at age 4–12 months prevents
iron-deficiency anaemia, and treatment with supplements from age 4–12 months are
only effective in populations with high (>10%) prevalence of iron-deficiency anaemia
• The European Union has a non-binding directive with a suggested range for iron of
3·6–14·0 mg/L50
AAP=American Academy of Pediatrics. ESPGHAN=European Society for Paediatric Gastroenterology,
Hepatology and Nutrition.
6 www.thelancet.com/child-adolescent Published online December 1, 2017 http://dx.doi.org/10.1016/S2352-4642(17)30159-1
Iron intake concentrations in other high-income
countries that have specific policies in place tend to
fall somewhere between the AAP and ESPHGAN
recommendations, or have no set guidelines (appendix
p 5). In the UK, infant formulas average at 6 mg/L of
iron and follow-on formulas at 10 mg/L of iron.52
Australia does not specify a value for all formulas (Food
Standards Australia and New Zealand advise
5·5–13·6 mg/L for follow-on formulas, which is under
review), but states that, at around 6 months, “[t]o prevent
iron deficiency, iron-containing nutritious foods are
recommended to be included in the first foods.”53 This
statement is important, since increasing iron intake
from complementary foods is often not accounted for
when guidelines for iron supplementation are set
(figure 2). Japan has no policy on the iron fortification of
formula54 and has substantially higher rates of long-term
breastfeeding than other high-income countries.55
Does the chemical state of iron matter?
The iron in human breastmilk is primarily bound to
lactotransferrin, with a smaller contribution from ferritin
and α-lactalbumin. Relative to protein-bound iron,
breastmilk contains very little inorganic iron.
Lactotransferrin has a normal concentration range of
2–3 g/L in human breastmilk and reaches 7 g/L in
colostrum, equating to around 0·35 mg/L of iron. Infant
formulas are typically fortified with inorganic iron at
higher concentrations. We did an extensive review56 of
the reported iron concentrations in breastmilk and
fortified formulas, and showed that iron-fortified milk
substitutes contained, on average, around 20 times more
iron than normal breastmilk.
The difference in chemical state is one of the primary
justifications given by the AAP in their 2010 recom­
mendations,11 citing a Committee on Nutrition report57
that claimed that more than 50% of the iron in breastmilk
is absorbed in the infant gut, whereas less than 12% of
inorganic iron added to bovine-derived formulas is
absorbed. These figures are not referenced, and the
source of this information in the committee report is
unknown. More comprehensive studies58,59 have assessed
differential uptake of inorganic iron versus protein-
bound iron from breastmilk, although the expense of
small-scale trials using isotope tracing has resulted in
considerable disparity in reported uptakes. In one
study,58 investigators used an isotopic tracer in both
normal unfortified breastmilk and breastmilk fortified
with iron, and found that the uptake of iron in infants at
age 6 months was the same (at approximately 16%) for
both milks, with absorption from unfortified breastmilk
only increasing to around 30% at age 9 months. A
similar study59 with formula fortified with α-lactalbumin
and casein-glycomacropeptide to promote iron
absorption, showed no significant difference in iron
uptake between formula preparations and breastmilk. A
study60 in which investigators used an iron isotope tracer

to measure iron uptake in human adult erythrocytes
from natural and simulated breastmilk, as well as
formulas, showed 15% of the iron from natural human
breastmilk was found in red blood cells, compared with
less than 10% of iron from simulated breastmilk and
less than 5% of iron from infant formulas. The authors
noted that erythrocyte uptake represented 80% of the
absorbed iron in the participants, with the fate of the
remaining 20% unknown. Higher concentrations of
iron in formula results in a greater net uptake than from
human breastmilk, even though iron in breastmilk is
more bioavailable than that in infant formula. The
addition of lactotransferrin into infant formulas could
better reflect the chemical form of iron in breastmilk,
and rodent studies have shown that fortification with
apo-lactotransferrin and inorganic iron increases total
absorption.61 Similar effects, including responses from
iron-store biomarkers, were observed in exclusively
breastfed infants supplemented with milk that contained
lactotransferrin.62 A compensatory effect is apparent on
iron uptake when lactotransferrin is added to formulas,
as was found by Hernell and Lönnerdal,63 with the
addition of bovine lactotransferrin to infant formula
containing 2–4 mg/L of inorganic iron showing no effect
on circulating iron concentrations. This trial did make
other important observations, including that 20 (34%) of
59 participants (who were aged <6 months) had
haemoglobin concentrations below 110 g/L at the end of
the study, and yet showed no symptoms of iron-
deficiency anaemia, leading the authors to suggest that
the haemoglobin cutoff for iron-deficiency anaemia was
too high. Additionally, formula containing 1·6 mg/L of
iron was sufficient to meet the health needs of a
6-month-old infant, a concentration that is less than 10%
of the AAP recommendation. A larger-scale trial by the
same researchers comparing low-iron infant formula
(ie, lactotransferrin sourced) with high (inorganic) iron
formula is underway (NCT02103205).
Interactions between iron and other minerals
Few high-quality studies have been done on the effects
of iron supplementation on infants when taken
as a multivitamin or mineral preparation,64 with
most randomised controlled trials focused on the
administration of micronutrient mixtures to pregnant
women. Compounds such as phytates and oxalates form
stable complexes with iron in the gastrointestinal tract
and prevent the uptake of non-haem iron, whereas
calcium appears to inhibit the release of iron from
enterocytes into the circulatory system.65 Experimental
assessment of how multiple nutrients at a range of doses
effect not only health outcomes but also iron uptake is a
challenging task and is likely to be pieced together from
individual studies and settings. For instance, data are
conflicting as to whether coadministration of zinc and
iron results in the competitive uptake of the two divalent
metals, and the effects appear to be dose dependent.66 The
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Viewpoint
most comprehensive systematic review67 to date reported
that treating zinc deficiency with supplementation does
not affect iron status, whereas randomised controlled
trials of cosupplementation were mostly observational
(eg, increasing zinc dose was not associated with iron
deficiency) and could not resolve discordance in the
literature regarding potential adverse effects on clinical
outcomes related to iron deficiency and iron-deficiency
anaemia.
Iron fortification and natural sources
One of the most common so-called first foods, along with
fruits and vegetables, is infant cereals, which are
routinely fortified with inorganic iron. If a formula-fed
infant continues on a mixed diet that includes a
component of infant formula, this additional source
could further add to the bioavailable iron consumed. In
an Australian study, 9-month-old infants received 28% of
their dietary iron intake from specific infant and toddler
food products excluding formula,10 many of which are
fortified with iron. Australia does not mandate iron
fortification of cereals, although voluntary addition is
commonplace in foods marketed for infants. In toddlers
(older than 20 months) their primary iron source shifts
to cereal products (eg, flour, grains) that are consumed by
the general population, which accounted for 43% of their
total iron intake.10 This transition to foods that are not
infant specific substantially changes the amount of
dietary iron to which a growing child is exposed.
Accurately assessing the total dietary iron intake of a
toddler is clearly a challenging task.
Fortification of infant formulas has successfully
reduced the prevalence of iron deficiency and iron-
deficiency anaemia in infants and children in high-
income countries, although this policy was preceded by
the fortification of wheat, maize, and rice with iron
to address iron-deficiency anaemia in the general
population. The American Medical Association adopted
a policy of iron fortification in 1936.68 Both the USA and
the UK have a compulsory iron fortification of flour,
Australia maintains a voluntary programme of
fortification, and countries including Norway, Denmark,
and Sweden prohibited iron fortification in the mid-to-
late 20th century. Denmark and Sweden cited the
absence of evidence that fortification with iron reduced
total prevalence of iron-deficiency anaemia, and that
potential adverse health effects dictated their directive.
Before this prohibition, Sweden had the highest flour
fortification levels (65 mg/kg) of any country.69
Longitudinal studies following the prohibition of iron
fortification have shown that the prevalence of iron-
deficiency anaemia is steady, whereas disease
progression of hereditary haemochromatosis, which
has a significantly higher frequency in Scandinavian
populations, has slowed.69,70
The AAP’s guidelines list recommended foods for
boosting iron concentrations,11 with estimated elemental
7
 Viewpoint
iron content per serving. Excluding fortified products,
haem-containing foods are the richest source of iron.
Introduction of haem-rich meat undoubtedly has a
substantial effect on iron stores, since absorption of
haem is more efficient than inorganic iron. Haem is
transported across the duodenum via an independent
transporter.71 Although haem-containing foods are
consumed in smaller amounts, the iron is two to three
times more bioavailable than inorganic iron and
absorption is not affected by other chemicals.72
Risks and negative health outcomes in
iron-supplemented infants and children
Short-term adverse health effects
Iron supplementation can cause adverse health events,
even in populations that are clinically anaemic. In her
overview of clinical, pathological, and therapeutic aspects
of iron-deficiency anaemia, Camaschella33 identified
nausea, vomiting, constipation, and dysgeusia as the
most common acute side-effects of iron supplementation.
Intravenous iron therapy has a similar side-effect profile,
in addition to pruritus, myalgia, and other localised
sources of pain.73 A systematic review and meta-analysis29
on infants aged 4–23 months receiving direct supple­
mentation reported increased risk ratios for vomiting
and fever (which could be antecedent to infection),
regardless of whether the recipients had anaemia or were
iron replete; although, the authors noted that higher-
powered studies are needed to confirm the adverse effect
profiles.
The chemical state of the iron supplement does
appear to influence its side-effect profile. A systematic
review74 of adverse events in 111 trials of supplementation
with various preparations of iron found that extended-
release ferrous sulfate with mucoproteose was best
tolerated, whereas ferrous fumarate was associated with
the highest proportion of reported adverse events.
Although hetero­ geneity in the data precluded meta-
analysis, the large sample size (n >10 000) allowed the
authors to state the limitations of the trials that were
studied while still reporting their findings with a high
degree of confidence.
Iron supplementation and infection
Consideration should also be given to the adverse effects
of iron intervention studies, particularly considering that
iron depletion can protect against microbial pathogens.75
A particularly interesting perspective was described by
Quinn,76 who hypothesised that the depletion of iron
stores in an infant at age 6 months could in fact be a
conserved evolutionary mechanism to restrict the access
of pathogenic microbiota to iron. Quinn posited that
introduction of iron-fortified formulas after the age of
6 months could undermine this adaptive mechanism
that has been in place long before both the agricultural
revolution and introduction of fortification programmes,
and could result in an increased risk of gastrointestinal
8 www.thelancet.com/child-adolescent Published online December 1, 2017 http://dx.doi.org/10.1016/S2352-4642(17)30159-1
disease in areas with poor hygiene and sanitation. Jaeggi
and colleagues77 supported this concept in a randomised
controlled trial of iron-fortified porridge that they fed to
Kenyan infants with iron-deficiency anaemia for
4 months. They found that children that were fed both
the low (2·5 mg iron per day, as a ferric sodium ethylene
diaminetetraacetate [NaFeEDTA] micronutrient powder)
and high iron (12·5 mg per day, as a ferrous fumarate
micronutrient powder) showed a significant increase in
pathological bacteria in the gastrointestinal tract. A
subsequent randomised controlled trial78 in the same
setting found that the delivery of iron as an equimolar
mixture of NaFeEDTA and ferrous fumarate micro­
nutrient powder totalling 5 mg per day, with the inactive
maltodextrin component of the preparation replaced
with probiotic galacto-oligosaccharides, decreased iron-
deficiency anaemia by 50% without adversely affecting
the gut microbiome when compared with children who
were receiving the equivalent 5 mg of iron alone.
A long-standing concern regarding iron supple­
mentation has been the potential risk in areas where
malaria is endemic. The WHO’s guidelines for daily iron
supplementation7 state that strong, high-quality evidence
exists to support iron supplementation only in
conjunction with measures to prevent, diagnose, and
treat malaria.7 If in place, surveillance and treatment
services should ensure the risk of infection is not
increased in children who are supplemented with iron.29
Delaying the administration of supplemental iron to
children with malaria who had anaemia until 28 days
after the administration of antimalarial therapies did not
affect their overall response in a randomised controlled
trial in Uganda,79 since at 56 days after treatment their
replenishment of iron stores was not substantially
different to those who started antimalarial drugs and
supplemental iron treatment concurrently.79
Pasricha and colleagues29 did not identify an association
between iron supplementation and respiratory tract
infections. Other factors could contribute to reduced
infection risk—eg, combined administration of iron with
long-chain polyunsaturated fatty acids has inherent anti-
inflammatory properties80 and lactotransferrin is
antimicrobial.81 A large randomised controlled trial
in Pakistan82 found a strong association between iron
supplementation of infants who were aged 6–18 months
and incidence of diarrhoea, as well as some respiratory
difficulties.
Effects on growth
The AAP and ESPGHAN both acknowledge that
iron stores are adequate during the first 4–6 months
of life of a full-term infant, and thus
iron supplementation is unnecessary. The AAP also
acknowledges that iron overload can occur as a result of
excessive intake, although it did not discuss the
potential adverse effects when issuing their guidelines
for infants and children.11 Conversely, the recommen­

dations of ESPGHAN state: “Because high iron intakes
may have adverse effects in iron-replete infants, it is
important to identify iron requirements in young
children and to identify risk groups that benefit from
higher iron intakes.”4
One of the most studied outcomes of supplementation
during infancy is the effect on growth. A review83 of
26 randomised controlled trials involving children aged
0–59 months identified a negative effect on weight when
children who were iron replete were supplemented, and
inconclusive evidence that iron supplementation affected
height. A systematic review and meta-analysis84 of
21 randomised controlled trials in infants, children,
and adolescents, and seven in pregnant women, showed
no measurable benefit of iron intervention on a range
of infant growth markers. A subsequent randomised
controlled trial85 done in marginally low-birthweight
infants who were supplemented with iron from
0–6 months did not find any measurable effects
on anthropometric measures; whereas, a randomised
controlled trial86 that focused primarily on children who
were iron replete indicated that excess iron intake retarded
growth. Although somewhat paradoxical, considering the
importance of iron for growth and development, evidence
suggests that iron supplementation has little effect (on
growth) regardless of whether an infant is iron deficient or
replete, and could in fact be detrimental when in excess.4 In
particular, more attention should be paid to both beneficial
and adverse health effects of supplementation to infants
who have sufficient iron stores.6
Effects on neurodevelopment
In contrast to the understanding of iron deficiency and
iron-deficiency anaemia and neurodevelopment,87
relatively little is known about the acute health effects of
iron overload on the developing brain. In 2005, Georgieff
and Innis wrote: “No study has convincingly
demonstrated that nutritional iron overload contributes
to adverse neurodevelopment in preterm infants”88—a
comment that could be extended to full-term infants.
However, a study by Buonocore and colleagues89 of
infants who had birth asphyxia showed that the non-
transferrin-bound iron content of blood was an extremely
effective marker for neurodevelopmental outcomes, with
high concen­trations (>849 µg/L) related to neurodisability,
measured by in-vivo imaging of ischaemic damage and
the Bayley Scales of Infant Development. The authors
speculated that, in addition to being a suitable predictive
marker for poor neuro­developmental outcomes, the high
concen­trations of non-transferrin-bound iron were also
contributing to CNS injury by enhancing oxidative stress
and damage to lipid membranes.
The potential for iron-mediated brain injury begins in
utero. The placenta ensures the fetus has adequate access
to iron even when maternal iron deficiency is present,
although little is known about how the placenta responds
to maternal iron overload. Tamura and colleagues90
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Viewpoint
reported an association between fetal iron status and
mental and psychomotor development at age 5 years,
with both low and high iron status correlating with poor
full-scale intelligence quotient testing.
Infants who have severe anaemia and receive iron
supplementation still show signs of poor developmental
and behavioural outcomes 10 years after intervention.91
Follow-up studies such as these are the most powerful
tool for assessing the possible neurological effects of iron
supplementation, although tracing cohorts over an
extended period of time can be a costly and lengthy
exercise. Lozoff and colleagues28 revisited a randomised
controlled trial of iron supplementation of Chilean
infants without anaemia who were given high
(12·7 mg/L) or low (2·3 mg/L) iron-fortified formula. Of
the original population, 473 (57%) of 835 Chilean infants
were assessed at 10 years. In every measured category of
neuro­ development, the high-iron formula group
performed more poorly than the low-iron group,
although not in global development scores.27 Clearly the
loss of over 40% of the study population to follow-up
restricts the conclusions that can be drawn from this
study, and the authors acknowledged that high variance
in haemoglobin concentrations restricted analytical
power in each comparison group and warned against
making changes in practice on the basis of these results
alone.
An increased rate of iron accumulation in the brain
beyond that of normal ageing has been linked to the
development of some neurodegenerative diseases.56
Localised iron-induced oxidative stress can result in
chronic and irreversible neuron death.92 We have
hypothesised that early-life dietary iron overexposure
could be a risk factor for such neurodegenerative
diseases,56 and that the excessive fortification of foods to
which infants are exposed creates an unnecessary risk of
developing diseases with few treatment options. The
long-standing association between brain iron
accumulation and Parkinson’s disease has resulted in
more attention being paid to potential sources that
increase iron in the brains of individuals with this
condition. The primary concern is that, in the infant gut
and brain, adequate feedback mechanisms that limit
excessive iron uptake might not be properly developed.
In a reply to the recommendations set by the AAP,
Furman46 cited the trial by Domellöf and colleagues93 that
showed iron absorption did not influence haemoglobin
concentrations, stating that “it seems that 4- to
6-month-olds will absorb the additional iron they receive
regardless of whether they need it”.
Is iron supplementation during infancy a risk factor for
neurodegeneration?
We previously56,94 proposed that overexposure of infants
to iron during the 6–24 month critical window of
iron-dependent neurodevelopment gives a so-called head
start to natural iron accumulation, which could become
9
 Viewpoint
Panel 5: Lessons from genetic disorders that feature iron overload
• Patients with heterozygous hereditary haemochromatosis (caused by the mutated
HFE gene) do not typically show evidence of iron overload, but do absorb more iron in
the gut than usual; homozygotes manifest symptoms of iron overload; diagnosis of
hereditary haemochromatosis in infants and children is rare, since iron deposition that
is substantial enough to cause pathology can take many years; symptoms include
growth retardation, lactic acidosis, aminoaciduria, and hypotransferrinaemia and the
associated effects on erythropoiesis, although effects on the immature brain are
unclear
• Juvenile haemochromatosis is a pathologically distinct condition resulting from
mutations to either the HFE2 gene encoding haemojuvelin or the HAMP gene
encoding hepcidin
• Neonatal haemochromatosis is phenotypically similar to juvenile haemochromatosis;
however, iron deposition occurs at a faster rate, resulting in rapid liver failure,
stillbirth, death during the immediate postnatal period, or the urgent need for a liver
transplant; it is not associated with an HFE mutation, and the direct cause is unknown;
liver failure typically precedes neurological symptoms
• Early-onset, rapidly progressing neurodegeneration with brain iron accumulation that
occurs in childhood causes parkinsonism and associated movement disorders
• Transfusion-dependent thalassaemias, particularly in mothers and pregnant women,
require careful management to prevent the potential negative effects of iron overload in
the fetus and neonate; the different thalassaemias have similar symptomatic profiles, in
addition to an increased risk of diabetes, splenomegaly, cardiomyopathy,
hyperthyroidism, and pulmonary hypertension; thalassaemias are often misdiagnosed as
iron-deficiency anaemia, and thus the risks of iron supplementation can be substantial
• Most association studies between genetic disorders of iron overload and
neurodegeneration have focused only on the frequency of mutations; studies are
needed that directly assess iron status, concentrations of iron in the brain, and the
prevalence of neurodegeneration in populations with inherited disorders, particularly
in whom iron overload is well managed
pathological when the individual is 60 years or older,
substantially increasing the risk of Parkinson’s disease.
Iron turnover in the brain is slow and concentrations
increase with age.56 Much can be learned about iron
overload and the effects exerted on the brain from genetic
disorders (panel 5), and although these disorders are an
acute response to iron overload, they provide important
For WHO Nutrition homepage clues to what deleterious effects iron overload can have,
see http://www.who.int/
particularly during ageing.
nutrition/en
Animal studies have provided important insight into
For WHO Anaemia Health Topic
page see http://www.who.int/
the biochemical mechanisms of iron storage and
topics/anaemia/en/ dyshomoeostasis in neurodegenerative disorders,
particularly Parkinson’s disease, as well as potential
therapies to reduce brain iron concentrations (panel 6).
The pilot trial by Devos and colleagues97 showed that
the strong chelator deferiprone reduced the
concentration of iron in the brains of a neurotoxin
mouse-model of parkinsonism and human beings with
early-stage Parkinson’s disease, with the human group
also showing marked improvement in the Unified
Parkinson’s Disease Rating Scale. This work preceded
the commencement of the FAIRPARK II phase 2 trial
of deferiprone (NCT02728843). If FAIRPARK II proves
to be successful, deferiprone could potentially be given
10 www.thelancet.com/child-adolescent Published online December 1, 2017 http://dx.doi.org/10.1016/S2352-4642(17)30159-1
Panel 6: Insights into the role of iron from animal studies
• Mice orally supplmented with 40 times the typical iron
concentrations of mouse milk during 10–17 days
postpartum (equivalent to the first 12 months in human
neonates)—reflecting the proportional difference
between human breastmilk and the AAP’s
recommendations—showed increased concentrations of
iron in the substantia nigra pars compacta (the primary
site of neurodegeneration in Parkinson’s disease) from
2 months, oxidative stress at 12 months, and
dopamine-specific cell loss from 16 months95
• Evidence suggests a synergistic relationship between iron
concentration in the brain and the Parkinson’s
disease-associated protein α-synuclien;96 iron
supplementation to both wild-type mice and mice
expressing the Ala53Thr mutation of α-synuclien with
impaired dopamine metabolism was sufficient to cause
increased concentrations of iron in the brain and nigral
cell loss at age 8–12 months
• Chronic treatment of mice with the iron chelator
clioquinol at age 5 months was unable to arrest extensive
age-related neurodegeneration, even though clioquinol
returned the concentration of iron in the brain to
baseline, indicating that α-synuclien and iron exert
neurotoxic effects before therapeutic intervention
AAP=American Academy of Pediatrics
as a preventive treatment, and at-risk patients with
high brain iron concentrations resulting from high
dietary iron exposure could benefit from short courses
of treatment with the chelator to reduce iron
accumulation to the baseline concentrations of normal
ageing.94
Conclusion
As the collective understanding of iron biochemistry
grew throughout the 20th century, the importance of
maintaning an iron-replete biological system became
apparent, with awareness of the role of nutrition and
signs and symptoms of anaemia increasing worldwide.
Accordingly, ensuring that a population has sufficient
access to dietary iron is an ongoing public health
endeavour. However, unlike other essential
micronutrients that have well described toxic effects
when in excess, such as manganese and selenium, the
potential toxicity of dietary iron overload is not often
considered. Furthermore, following the commentary of
experts in the field about the AAP Committee on
Nutrition’s most recent recommendations for preventing
iron deficiency and iron-deficiency anaemia, signs are
encouraging that the guidelines will be revisited and that
new and thorough clinical trials in infants who are iron
replete will take place in line with the recommendations
of WHO.7

Search strategy and selection criteria
We identified references for this Viewpoint through searches
of PubMed and Google Scholar with the search terms “iron
supplementation”, “iron fortification”, “iron deficiency an[a]
emia”, “brain iron”, and related terms from Jan 1, 1900, to
June 30, 2017. Articles were also identified through searches
of the authors’ own collections. Only papers published in
English were reviewed. The final reference list was generated
on the basis of originality and relevance to the broad scope of
this Viewpoint.
The evidence we have presented in this Viewpoint
gives added justification for re-examining public health
approaches to treating iron deficiency and iron-deficiency
anaemia (if indeed iron deficiency needs intervention).
Fortification is certainly more economically viable, but
with it comes the added risk of negative health outcomes
in children who are iron replete. Supplementation on a
case-by-case basis, using a comprehensive panel of
biomarkers of iron-deficiency anaemia, would probably
be a more effective means for disease mitigation without
the added risk, although the economic implications
would need to be considered. Whether the withdrawal of
food-fortification programmes can offset the cost of
clinical screening in infants and children suspected of
being iron deficient is yet to be fully assessed. What is
clear from the evidence presented here is that little
consensus exists on what the precise benefits and
potential harms of iron supplementation are; numerous
studies have identified a benefit in settings where iron-
deficiency anaemia is endemic, in terms of restoring
haematological markers to those considered acceptable
(panel 2), although the effects on neurodevelopment are
not as obvious. Iron is crucial for neurodevelopment,
although direct intervention has become somewhat
controversial, and will remain so until further large-scale
longitudinal trials are able to categorically confirm or
refute long-term benefits.
Contributors
DJH conceived and drafted the manuscript. BRC, EAS-G and B-AB
contributed to, edited, and approved the final version of the manuscript.
Declaration of interests
DJH reports grants from the Australian National Health and Medical
Research Council during the conduct of this study; and grants and
materials support from Agilent Technologies and the Australian
Research Council outside the submitted work. All other authors declare
no competing interests.
Acknowledgments
The Florey Institute acknowledges the Victorian Government’s
Operational Infrastructure Support Program.
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