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Benefits and Harms of Iron Supplementation in Iron Deficient and Iron
Sufficient Children
Magnus Domellöf, MD, PhD
Introduction
Iron deficiency anemia is the most common micronutrient deficiency worldwide with an
estimated 600 million affected individuals (1). Young children is a special risk group due to
rapid growth leading to high iron requirements. Iron is essential for the development of the
central nervous system and there is an established association between iron deficiency
anemia in young children and poor neurodevelopment. It is therefore important to prevent
iron deficiency in young children and iron supplements are often recommended to this risk
group. The period of highest iron requirements occurs at 6-12 months of age when dietary
requirements are estimated to be about 1 mg/kg/d (2). Even in affluent societies, this intake
is difficult to achieve without iron fortified foods or separate iron supplements.
However, in contrast to most other nutrients, excess iron cannot be excreted by the human
body and it has recently been suggested that excessive iron supplementation of infants may
have adverse effects on growth (3), risk of infections (4), and even on cognitive development
(5). Thus, recommendations regarding iron intake must not only prevent iron deficiency but
must also avoid unnecessary iron supplementation of iron sufficient infants.
Anemia
Many studies in children have shown that iron supplements as well as iron fortified foods
effectively increase the blood hemoglobin concentration (Hb) (2). Indeed, the Hb response
to iron treatment is long known as a golden standard to diagnose iron deficiency anemia (6).
Theoretically, iron supplements should increase Hb only in those children who are initially
iron deficient. It is more difficult to assess the effects of iron supplements in iron sufficient
children since almost all studies are carried out in risk groups, e.g. populations with a high
prevalence of iron deficiency. In a randomized, controlled iron supplementation trial in
Swedish and Honduran breast-fed infants, we showed that iron supplements given before 6
months of age increased Hb even in those infants who were initially iron replete and that Hb
response to iron supplementation was useful for the diagnosis of iron deficiency anemia only
after 6 months of age (7).
Brain development
Growth and development of the central nervous system is rapid during the first years of life.
Iron is critical for brain development since it is essential for myelination, monoamine
synthesis and and energy metabolism in neurons and glial cells (8). In animal models of iron
deficiency, reduced motor activity has been the most consistent observation (9). Negative
effects on cognitive and behavioural functions have also been observed in some studies of
iron deficient animals (8). In most of these animal studies, neurological function has not
been fully restored after iron repletion (9).
Several well performed case control studies in children have shown a consistent association
between iron deficiency anemia (IDA) and poor cognitive and behavioural performance even
though these observations may be confounded by other nutritional deficiencies and
socioeconomic factors (9, 10). Most clinical trials of iron supplementation in children
unfortunately have not included neurodevelopmental outcomes. A meta-analysis of 17
randomized clinical trials in children that did include cognitive outcomes, showed that iron
supplementation had a significant but modest positive effect on mental development index
of 1.5-2 points of 100 (11). This effect was more apparent for children who were initially
anemic, suggesting that iron supplements have positive cognitive effects in iron deficient
children. This meta-analysis showed no convincing evidenve for an effect of iron
supplements on neurodevelopmental outcomes in children below 2 years of age. This lack of
effect in the youngest infants may be due to irreversible effects of iron deficiency on the
developing brain or the fact that cognition and behaviour is more difficult to test in young
children. The possibility that iron deficiency leads to irreversible effects in young children is a
strong argument for prevention. There are very few trials of preventive iron
supplementation in young children in which neurodevelopmental outcomes have been
assessed. In one trial of in Indonesia, a positive effect of 10 mg iron daily given from 6-12
months of age was observed on psychomotor development index at 12 months (106 vs 103
in the placebo group) (12). This may not have been a purely preventive trial since 41% of the
infants had anemia at baseline.
There are a few recent studies suggesting that excessive iron intake can have negative
effects on brain development. In a mouse model, Parkinson-like progressive midbrain
neurodegeneration was seen after a period of high dietary iron intake (13). These findings
are supported by preliminary data from a randomized, controlled trial in which healthy,
Chilean infants, with a birth weight of ≥3 kg and without IDA at 6 months of age were
randomized to receive fortified formula with a high (12 mg/L) or low (2.3 mg/L) iron content
from 6 to 12 months of age (5). Motor development, cognitive development, spatial
memory, reading and arithmetic and visual-motor integration was assessed at 10 years of
age. The high iron group had lower scores on all of these outcomes, significantly so for
spatial memory and visual-motor integration scores. Effects depended on initial iron status:
High iron formula had a more negative effect on the outcome measures in children who
were initially iron sufficient (higher Hb) while the opposite was true in infants with an initial
lower Hb. The effect size in visual-motor integration was 2 standard deviations
corresponding to a score difference of 15 points of 100. The physiological mechanisms
behind this possible negative effect of excessive iron intake on cognitive development is
unknown but iron-mediated oxidative stress has been suggested (13).
Growth
Most iron supplementation studies in children show no overall effect of iron on growth
although a few studies in iron deficient infants have shown a positive effect and some recent
studies have suggested that iron supplements given to iron sufficient children may have a
negative effect on growth (14).
In a recent meta-analysis of the effects of micronutrients on growth of children under 5
years of age, 27 randomized, controlled studies of iron supplementation were included (15).
In this meta-analysis, there was no significant overall effect of iron supplements on either
weight or length gain. There were also no significant differences when studies were
stratified by mean baseline Hb. However, without access to original data it was not possible
to investigate the possible interaction between baseline Hb (or iron status) and iron
supplements on growth at the individual level.
Four studies to date have shown a negative effect of iron supplements on the growth of
young children. In contrast to other studies, these have stratified the children based on
initial iron status. Idjradinata investigated the effect of iron (3 mg/kg daily) during 4 months
in iron sufficient 12-18-months old children in Indonesia and observed a significantly lower
weight gain in the iron group (560 vs 848 g, p=0.02) (16). The growth of the iron-deficient,
anemic children in the same study was improved by iron supplementation. In a study of
breast-fed Swedish and Honduran infants, we showed that iron supplementation (1 mg/kg
daily) from 4-9 months of age had a negative effect on length gain (3). This effect was
restricted to the more well-nourished Swedish infants and to Honduran infants with an intial
Hb of > 110 g/L. In infants with initial Hb < 110 g/L, no effect on length gain was observed.
Majumdar et al randomized 100 iron replete children (6-24 months old) to receive iron
supplements (2 mg/kg daily) or placebo while 50 iron deficient children received 6 mg/kg
daily during 4 months (17). Compared to the placebo group, iron supplementation resulted
in a significantly increased weight and length gain in iron deficient children but a significantly
decreased weight and length gain in iron sufficient children. Most recently, Lind et al
investigated the growth of iron replete Indonesian infants from an iron supplementation
trial (18). In this study, 680 infants were randomized to receive iron supplements (10 mg
daily) with or without zinc supplement from 6-12 months of age. No overall effect of iron on
growth was observed but when infants were stratified by initial iron status, a significant
negative effect of iron supplementation on weight gain was observed in those infants who
were initially iron replete (n=154). The effect was substantial with a difference of > 400 g
between iron supplemented and non supplemented iron replete infants. Iron supplemented,
iron replete infants also had significantly lower serum zinc concentrations.
The mechanism behind the possible negative effect of iron supplementation on growth in
iron sufficient young children is not known. An interaction with zinc absorption or zinc
metabolism has been suggested (see also below) since it is known that zinc deficiency has a
negative effect on growth (19). The finding of lower serum zinc concentrations in iron
supplemented iron-replete infants in the Lind study would support that hypothesis.
However, in our previous study, no difference in serum zinc was observed (3). Other possible
mechanisms include pro-oxidative effects of iron or a decreased dietary intake due to
gastrointestinal side effects of iron supplements or an increased susceptability for
gastroenteritis. In our study, iron supplements increased episodes of diarrhea in iron
sufficient infants while the opposite was observed in iron deficient infants (3).
Infections
In addition to the immune response, host organisms can combat pathogens by depleting
them of essential nutrients. Iron has a pivotal role in the defence agains infections since it is
essential for the growth of virtually all pathogens – bacteria, protozoa and viruses. As a part
of the acute phase response in humans, free iron is depleted from the systemic circulation
down to 10-24 mmol/L (20). The mechanism is believed to involve the induction of hepcidin
production in the liver, leading to a down-regulation of intestinal iron absorption and
sequestration of iron in reticulo-endothelial macrophages (21). Ferritin – an iron
sequestering protein – is also increased as a part of the acute phase response, further
contributing to the reduction of iron available for pathogens. Conversely, microorganisms –
especially bacteria – have evolved elaborate methods for iron retreival to be able to cause
invasive infections in humans (22).
This delicate balance between host and pathogen may be disturbed by iron supplementation
and it has indeed been suggested already in the 1800s that iron supplements could increase
the risk of infection. Two meta-analyses on the subject in 2001-2002 came to conflicting
conclusions: Gera and Sachdev found no overall increase in infections except for an
increased risk of diarrhea (23). Oppenheimer, however, found that iron supplementation
was associated with an increased risk for clinical attacks of malaria and other infections in
malarious regions (24). The increased risk for infections was particularly observed in trials in
which parenteral or high dose oral supplementation (> 2 mg/kg/d) was used.
Interestingly, the malaria parasite is unable to utilize heme iron even though it grows in red
blood cells, surrounded by an abundance of hemoglobin (25). Instead, plasmodia are
dependent on the very small pool of free iron in the cytoplasm, making them susceptible to
changes in iron concentrations caused by nutritional factors.
In 2003, a large RCT of iron supplementation in Pemba, Zanzibar had to be terminated due
to serious adverse effects (4). In this trial, 24076 children aged 1-35 mo were randomized to
daily oral supplementation with iron (12.5 mg) and folic acid (with or without zinc) or
placebo. The dose of iron was halved in infants < 12 mo. In the groups receiving iron and
folic acid, there was a 15% increased risk of death and an 11% increased risk of hospital
admission. A substudy suggested that the risk for serious adverse events was higher in
infants who were initially iron replete, i.e. those with higher Hb and lower zinc
protoporphyrin (ZPP). These results were later supported by a RCT in Peruvian children (0.5-
15 y), showing that iron supplementation (15 mg daily) resulted in an increased morbidity
due to Plasmodium vivax malaria (26).
Using the same study design as the Zanzibar trial, another large RCT was performed in a
region with a low prevalence of malaria (southern Nepal) (27). In this trial, iron
supplementation resulted in a significant reduction in anemia but no increased risk for
death, diarrhea, dysentery or respiratory infections.
Taken together, these studies suggest that iron supplementation of children is safe with
regard to infections in non-malarious regions. In malarious regions, iron deficient children
are likely to benefit from iron supplementation while there is an increased risk for severe
malaria infections in those who are iron sufficient.
Interactions with other minerals
Since thers is no mechanism for iron excretion in humans, regulation of iron absorption is
critical. The molecular mechanisms for iron absorption in the intestine have recently been
characherized and the main iron transporter is believed to be divalent metal transporter 1
(DMT1) at the apical membrane and ferroportin 1 at the basolateral membrane of the
enterocyte (2). There are possible metabolic interactions between iron and several other
minerals.
Lead
Lead exposure in children may lead to poor cognitive performance, especially in children
with blood lead concentrations > 10 µg/dL but also at lower levels. Iron deficiency in children
is a risk factor for lead poisoning and it has been suggested that this is caused by an up-
regulation of DMT1 in a state of iron deficiency, leading to an increased intestinal absorption
of lead. Thus, iron supplementation of iron deficient, lead exposed children, may reduce the
adverse effects of lead exposure. Some studies indeed indicate that iron supplements given
to iron deficient, lead exposed school children, reduce blood lead concentrations but there is
yet no evidence that this results in improved cognitive performance (2).
Zinc
Zinc deficiency often coexists with iron deficiency in young children in developing countries,
and combined iron and zinc supplementation is therefore often recommended. However, a
competitive inhibition of iron on zinc absorption has been suggested, possibly resulting in a
negative effect of iron supplementation on zinc status.
Interaction effects between iron and zinc in clinical supplementation trials have been
reviewed in 2005 (28). In 9 of 10 reviewed trials of iron-only supplementation given to
children, there was no effect of iron supplementation on serum zinc. In all 4 reviewed trials
of combined iron and zinc supplementation, the addition of iron to zinc supplements had no
adverse effect on serum zinc. However, it is important to realize that, even though there is
no better biomarker, serum zinc is not a sensitive marker of zinc status, especially not in mild
and moderate zinc deficiency.
Regarding functional outcomes, a few trials have suggested a negative effect of the addition
of iron to zinc supplements. Berger showed in 2006 that the addition of iron reduced the
positive effect of zinc on serum zinc and weight gain (29). Similarly, Lind showed that
combined supplementation had less positive effect on growth than zinc supplementation
alone and that iron supplementation of iron-replete infants resulted in poorer weight gain
and lower serum zinc concentrations (18).
Even though iron and zinc are chemically similar, they do not seem to share the same
absorptive pathway in the intestine since zinc is mainly shuttled across the enterocyte by
specialized zinc tranporters (Zip-4 and ZnT-1) (30). We have recently shown in a stable
isotope study that iron supplements do not reduce intestinal zinc absorption in healthy,
breast-fed infants (31). This does however not exclude other mechanisms for interaction.
Copper
There are several known interactions between iron and copper metabolism and these two
minerals have a common apical enterocyte transporter (DMT1) (2). We have shown that
iron supplementation of infants reduced copper/zinc-dependent superoxide dismutase
activity, suggesting a negative effect on copper status (32). However, this effect may be due
to interactions beyond the absorption step, since we and others have shown that iron
supplements do not reduce copper absorption in infants (31, 33).
Mode of administration
In almost all studies that have demonstrated adverse effects of iron in iron-replete children,
medicinal iron supplements (iron drops) has been used rather than iron fortified foods. This
prompted us to investigate the possibility that medicinal iron supplements have different
physiological effects than iron fortified foods. In a secondary analysis of two clinical trials, we
compared infants who had received the same dose of iron from medicinal iron drops and
from iron fortified foods. Interestingly, iron given as medicinal iron drops increased serum
ferritin, suggesting that it was primarily deposited into iron stores, while iron given as iron
fortified foods increased Hb, suggesting that it was primarily used for Hb synthesis. We
speculate that a dose of iron given once daily gives a higher peak of serum iron, inducing
hepcidin which diverts iron to storage. It is possible that such peaks of serum iron, possibly
leading to higher concentrations of free iron, would increase the risk for adverse effects,
especially in iron replete infants.
Conclusions
In conclusion, there are now several studies suggesting that even though iron supplements
given to iron deficient children may reduce anemia, improve cognitive outcome and even
improve growth and reduce the risk of infections, iron supplements given to iron replete
children may instead have adverse effects on infections (malaria), growth and possibly even
cognitive development. With one exception, these adverse effects were only observed in
infants receiving medicinal iron supplements.
The most severe adverse effect is the increased malaria-related mortality. The implication in
malarious regions is that general iron supplementation of children should be avoided. In
those regions, a cautious supplementation approach needs to be adopted, based either on
screening or combining iron supplements with infection control measures.
The implication with regard to growth is more complicated. Since the growth inhibition is
not likely to be permanent and since iron supplements has important positive effects in iron
deficient children, general iron supplementation should not be discouraged in areas with a
high prevalence of iron deficiency. However, in populations with a low prevalence of iron
deficiency, general supplementation should be avoided.
The most difficult problem is how to assess the risk for poor cognitive development in young
children receiving high dose iron fortified foods. This concern is based on a single study in
humans and needs to be verified. Nevertheless, manufacturers of iron fortified foods for
infants and young children should probably avoid very high doses of iron fortification.
More studies are urgently needed to better determine the risks and benefits of iron
supplementation and iron fortified foods given to iron deficient and iron sufficient children.
It is important that all clinical trials of iron supplements and iron fortified foods in children
include functional outcomes and long term follow-up.
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Iron defici
ency
Iron excess
Anemia
Poor
neurodevelopment
Infections (malaria)
Poor growth
Poor neurodevelopment?
