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The Benefits and Risks of Iron Supplementation in Pregnancy
and Childhood
Michael K. Georgieff1, Nancy F. Krebs2, Sarah E. Cusick1
1Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota
55454, USA;
2Department of Pediatrics, University of Colorado School of Medicine, Anschutz Medical Campus,
Aurora, Colorado 80045, USA;
Abstract
Iron deficiency is the most common micronutrient deficiency in the world and disproportionately
affects pregnant women and young children. Iron deficiency has negative effects on pregnancy
outcomes in women and on immune function and neurodevelopment in children. Iron
supplementation programs have been successful in reducing this health burden. However, iron
supplementation of iron-sufficient individuals is likely not necessary and may carry health risks
for iron-sufficient and potentially some iron-deficient populations. This review considers the
physiology of iron as a nutrient and how this physiology informs decision-making about weighing
the benefits and risks of iron supplementation in iron-deficient, iron-sufficient, and iron-
overloaded pregnant women and children.
Keywords
iron; pregnancy; infancy; supplementation; neurodevelopment; malaria
IRON AS A NUTRIENT
Iron is the most abundant element, comprising 35% of the earth’s physical mass. While most
of iron’s interactions with the environment are inorganic, it nevertheless plays a critical role
in organic biological processes in virtually all living organisms. Iron accretion by cells and
its utilization in biological processes within cells are remarkably conserved across the
taxonomic hierarchy. This speaks to its fundamental importance in sustaining the metabolic
processes essential to the survival and function of living organisms.
Iron is classified as a micronutrient. A primary nutritional role of iron is to support
erythropoiesis. Iron is prioritized to red blood cells over all other organ systems, including
the brain, in the developing fetus and young child to support hemoglobin synthesis (46, 48,
georg001@umn.edu.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the
objectivity of this review.
HHS Public Access
Author manuscript
Annu Rev Nutr
. Author manuscript; available in PMC 2020 April 21.
Published in final edited form as:
Annu Rev Nutr
. 2019 August 21; 39: 121–146. doi:10.1146/annurev-nutr-082018-124213.
Author Manuscript Author Manuscript Author Manuscript Author Manuscript
104, 161). Every cell and organ system in the body requires iron for proper development and
subsequent metabolic function. Its physiologic role in iron cluster proteins and hemoproteins
is to facilitate enzymatic processes that are essential to cellular metabolic function, including
those essential for oxygen delivery and cellular adenosine triphosphate generation. While
iron-deficiency anemia is associated with clinical symptoms, tissue-level iron deficiency and
not necessarily anemia is responsible for organ dysfunction in the iron-deficient state.
Symptoms of poor organ performance are present prior to the onset of anemia and persist
after the anemia resolves following iron treatment (8).
A precise estimate of the burden of iron deficiency is difficult to obtain because of the
various definitions of iron deficiency used worldwide. Approximately 2 billion of the earth’s
7.2 billion people are anemic, with iron deficiency as the root cause in an estimated 25% to
50% (104, 134). However, the prevalence of nonanemic iron deficiency, which is associated
with neurodevelopmental consequences, is estimated to be threefold greater than the
prevalence of iron-deficiency anemia. Conservative projections indicate that between 2 and 4
billion people, or approximately one-quarter to one-half of the world’s population, may be
iron deficient (104).
Iron-deficiency effects are particularly profound on cells with the highest metabolic rates,
presumably because iron deficiency compromises mitochondrial and cellular energetics (7).
Thus, the consequences of iron deficiency are more profound during development, when the
oxygen consumption rates of cells are highest, driven by the energy demands of growth and
differentiation. On a per kilogram of weight basis, the total-body oxygen consumption of a
neonate is three to four times greater than that of an adult. Moreover, the neonatal brain
alone utilizes 60% of that oxygen consumption, compared with 20% in the adult brain (72).
Given this large iron-dependent energy demand, the prevalence of iron deficiency is greatest
in pregnant women and young children.
The main reason to maintain iron sufficiency in these vulnerable populations is to optimize
organ development and function, including immune function and brain development (30,
46). Within the brain, iron deficiency negatively affects iron-dependent myelination,
monoamine metabolism, and cellular energetics (80, 87). Early-life iron deficiency patterns
gene expression in the brain across the lifetime via histone-mediated stable epigenetic
modifications (137, 138). These findings may explain why certain neurobehavioral effects of
early-life iron deficiency appear to be permanent (80, 86). Whether early-life iron deficiency
affects the regulation of other organ systems, including the production of red blood cells,
across the life span is being investigated (51).
Like most other nutrients, iron exhibits a U-shaped risk curve (Figure 1). The risks of iron
deficiency have been well described (80). However, as a divalent metal, iron has the
potential to react in inorganic reactions that can damage organic components of the cell.
Specifically, nonprotein-bound iron (NPBI) can react with oxygen to form reactive oxygen
species, which if unquenched, can damage lipid membranes and organelles. These are not
typically thought of as consequences of nutritional iron intake, but rather as pathologic
conditions in which iron is suddenly released in large quantities from damaged or dead cells.
The exquisitely tight, coordinated regulation of iron uptake, storage, and trafficking,
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combined with the effectiveness of iron-transport proteins (e.g., transferrin) in hiding iron
within their structures, generally prevent NPBI from being present in circulation following
conventional dietary intake of iron-containing foods (44).
Nevertheless, conditions may be present in which regulation breaks down (e.g., genetic
conditions, such as hereditary hemochromatosis) or is overwhelmed by excessively rapid
iron delivery, following which NPBI is generated and is potentially able to react with
oxygen. Excessive iron delivery could occur through the lysis of red blood cells after
transfusion or as a consequence of rapid infusion of intravenous iron. Concerns have been
raised as to whether enteral iron supplementation can result in NPBI, particularly under
conditions of high oral dosages or low binding protein concentrations. The former may
occur with aggressive enteral iron supplementation. Brittenham et al. (15) recently
demonstrated that a supplemental dose of iron sulfate on an empty stomach in healthy, iron-
replete women resulted in the appearance of NPBI but not reactive oxygen species.
Premature infants, who typically have low serum protein concentrations, including low
transferrin, and immature antioxidant systems would theoretically be at increased risk for the
presence of NPBI. Yet enteral iron doses of up to 12 mg/kg body weight in preterm infants
have not been shown to generate NPBI or evidence of reactive oxygen species (14).
Beyond the possibility of generating reactive oxygen species, competition for nutritional
iron by other highly metabolic cells, such as pathogenic organisms, must be considered as a
potential risk of nutritional iron supplementation. Enteral nonheme iron absorption is tightly
regulated by hepcidin, and the absorption rate rarely exceeds 30% (44). Thus, a large portion
of enteral iron, especially in fortified foods, is unabsorbed and is potentially available as an
essential nutrient for bacteria residing in the colon. Bacteria species have variable iron
needs, and some of the most siderophilic species include
Escherichia coli
and
Salmonella
,
both potential pathogens (99). Bifidobacteria, in contrast, have low iron requirements (70).
In addition, pathogenic organisms dwelling within the body (e.g., the malaria protozoa) also
proliferate more aggressively in iron-rich environments compared with iron-poor
environments (49). Taken together, there are good theoretical reasons to propose that while
iron shows the same general U-shaped risk curve as all nutrients, the stakes are greater from
both under- and overnutrition than for most nutrients (Figure 1).
It is against this background that the following sections discuss the relative benefits and risks
of iron supplementation in the two populations at greatest risk for the consequences of iron
deficiency: pregnant women and young children. Consideration is given for both populations
as to how the benefit–risk balance of enteral iron supplementation is affected by iron status.
BENEFITS AND RISKS OF IRON SUPPLEMENTATION DURING
PREGNANCY
Physiologic Considerations
Pregnancy poses a large risk of negative iron balance to a woman (39). Compared with the
nonpregnant state, iron demands are greatly amplified for two reasons. First, the
fetoplacental unit requires a large amount of iron for its own growth and development during
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gestation. One gram of iron needs to be accreted by the mother during pregnancy—of which
360 mg is transferred from the mother to the fetus, particularly during the third trimester
when growth is most rapid—in order to maintain a content of 75 mg of iron per kg body
weight of the fetus (39, 169). The pregnant woman expands her own plasma and blood
volumes to maintain proper circulation and oxygen delivery to her own organs as well as to
the placenta. The blood volume expansion consumes 450 mg of the 1 g of additional iron
required during pregnancy (39). Decreasing hepcidin concentrations during pregnancy
indicate the pregnant woman’s need to absorb more iron for both her own hemoglobin
synthesis as well as for transport across the placenta to the highly metabolic and growing
fetus (5, 142). Iron deficiency is generally acknowledged as a greater risk than iron overload
during human pregnancy (39).
The goals of maintaining iron sufficiency during pregnancy are to reduce maternal
morbidity, promote fetal health, and to set up the newborn with adequate nutrient stores for
early postnatal life. Increasing evidence supports the concept that postnatal iron status at 9
months of age depends on proper fetal iron loading during pregnancy (164). The risk of
postnatal iron deficiency in infants is reduced when neonatal iron stores are normal
following gestation, delayed cord clamping is practiced, and postnatal growth rate is not
excessive (30). It is also likely that proper loading of the newborn via the maternal–fetal
route reduces the need for excessive early iron supplementation of the infant postnatally in
certain iron-sufficient populations.
Pregnancies in Iron-Deficient Populations
There is little debate that iron-deficient women have an increased risk of adverse pregnancy
outcomes, that is, those that affect the woman, her fetus, or, consequently, her offspring.
Most studies utilize hemoglobin as the biomarker for iron status because of the ubiquitous
availability of this measurement and because iron deficiency is the most common cause of
anemia in most populations. However, anemia and iron deficiency are not synonymous,
which makes interpreting the outcomes of these studies problematic. Anemia at various time
points in pregnancy is associated with an increased risk of preterm birth (18, 52, 61, 91, 107,
113, 159, 163, 165), birth weight
<
2,500 grams (56, 91, 107, 165), and low weight for
gestational age (28, 52, 61, 107, 144) (all summarized in Reference 30). In most studies,
supplementation of anemic women with iron during pregnancy reduces the rate of iron-
deficiency anemia and nonanemic iron deficiency at term, and in some studies, it reduces the
risk of adverse outcomes, suggesting that supplementation in this population is beneficial
(101, 102) (Table 1).
A minority of clinical studies that assessed outcomes as a function of iron status used iron-
specific biomarkers as opposed to or in conjunction with hemoglobin concentrations (30,
87). Iron-specific markers can be problematic for routine screening for analytic and
interpretative reasons. The limited availability of the analytic equipment needed to measure
specific iron parameters—especially serum ferritin, percent total iron-binding capacity
saturation, soluble transferrin receptor, or hepcidin—is a major hurdle, particularly in low-
resource countries. An ideal biomarker would index the risks of negative iron balance before
physiologic consequences are present (24). Serum ferritin, which typically indexes iron
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stores, could theoretically serve this purpose since there are no known consequences of low
iron stores, per se, as long as adequate iron is available to support hematopoiesis, tissue-level
iron proteins (e.g., cytochromes), and iron transport to the fetus. However, ferritin acts as an
acute-phase reactant to infection and inflammation, which undermines its effectiveness as a
screening tool (128). Nevertheless, a meta-analysis of pregnancy outcomes as a function of
iron stores demonstrated that low iron stores, particularly during the first trimester, are
associated with a greater risk of low birth weight, prematurity, and small size for dates (101,
102).
Clinical studies have also assessed maternal iron status exclusively as a function of dietary
iron intake during pregnancy (30). This approach has potential drawbacks, including the
inherent variability of dietary recall and, more importantly, the question of whether dietary
intake is tightly linked to actual iron accretion. This linkage can be tenuous because multiple
inflammatory events during pregnancy could result in relatively less absorption of dietary
iron due to activation of hepcidin by proinflammatory cytokines, including interleukin-6
(149). Furthermore, dietary iron intake gives no information about the distribution of iron
between mother and fetus. Nevertheless, a meta-analysis of studies of maternal iron intake in
iron-deficient populations shows that iron supplementation of iron-deficient populations is
beneficial (101, 102). Neurobehavioral pathologies in offspring related to low maternal iron
intake during critical periods of pregnancy include increased risks of schizophrenia (64) and
autism (115).
Overall, clinical studies support iron supplementation of pregnant women with iron
deficiency defined by any of the three biomarker approaches (i.e., hemoglobin, serum
ferritin, or dietary intake). Little discordance exists among the three biomarkers, except in
the case of active inflammatory processes. Table 1 presents the various potential
interpretations and misinterpretations of utilizing hemoglobin or ferritin as the primary
biomarker to assess iron status.
The role of inflammation in confounding iron status assessments is important. Inflammation
activates hepcidin and thereby countermands the normal increase in iron accretion mediated
by low hepcidin concentrations during pregnancy (5, 39, 142). Hepcidin increases iron in the
storage pool, as evidenced by high serum ferritin concentrations, while shortchanging iron
availability for hemoglobin synthesis by reducing intestinal iron absorption. Chronic
inflammation results in reduced total-body iron during pregnancy and less iron availability
for the fetus, yet the condition may be interpreted as iron overload or iron sufficiency if
ferritin is the only biomarker used by the clinician to assess iron status (Table 1).
Although chronic low-grade inflammation may be relatively common in austere settings (4),
the most common inflammatory condition worldwide during pregnancy is malaria.
Worldwide, approximately 35 million pregnant women are at risk of
Plasmodium falciparum
malaria each year (154). The vast majority of populations at risk for malaria live in regions
where iron deficiency is endemic. Iron supplementation in areas where both iron deficiency
and malaria are endemic must be viewed within in the context of the 2006 landmark study
on Pemba Island, Tanzania, that found that universal, daily supplementation with iron and
folic acid increased the risk of hospitalization and death in young children (111). Subsequent
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cross-sectional studies seemed to support this association in pregnant women, finding a
lower prevalence of placental malaria among women with iron-deficiency anemia (66, 118).
In vitro studies have provided apparent mechanistic support of these findings, demonstrating
that red blood cells taken from both anemic children and anemic pregnant women support a
lower rate of
Plasmodium
growth than nonanemic red blood cells. Iron supplementation
without treatment of malaria leads to increased parasite growth in red blood cells from both
children and women (22, 49).
However, two recent randomized placebo-controlled trials have not supported a harmful link
between healthy iron status and the risk of malaria in pregnant women. The trials
demonstrate the importance of treating the malaria first and then addressing iron status (37,
94). In the first study, 1,500 HIV-uninfected pregnant Tanzanian women with serum ferritin
concentrations
>
12 μg/L and hemoglobin concentrations
>
85 g/L were enrolled before 27
weeks’ gestation and were randomized to 60 mg of daily iron as ferrous sulfate or to placebo
(37). All women received monthly prenatal health checks that included malaria screening,
intermittent presumptive treatment for malaria, and antimalarial treatment if needed. Iron
supplementation was not associated with an increased risk of placental malaria or other
adverse events, and while iron did not increase birth weight, hemoglobin concentration and
iron status as measured by serum ferritin concentration were greater among women in the
iron-supplemented group. Although this study was conducted in an urban setting with a
relatively low risk of malaria, a subsequent study in a malaria-endemic area of rural Kenya
had similar findings (94). In that randomized placebo-controlled trial, daily supplements of
60 mg iron as ferrous fumarate given to pregnant women between the ages of 15 and 46
years, with no other inclusion criteria, did not increase the risk of maternal malaria and were
associated with greater birth weight, lower risk of premature birth, longer length of
gestation, and higher maternal and infant iron stores 1 month after birth when compared
with placebo.
After the Pemba study, all iron supplementation trials in malaria-endemic areas have
included a malaria control component for ethical reasons. These findings support the current
World Health Organization (WHO) recommendation for universal daily supplementation
with 30 to 60 mg elemental iron during pregnancy in regions where the prevalence of
anemia is 20% or higher, with a stipulation in malaria-endemic areas that supplementation
should be given in conjunction with “adequate measures to prevent, diagnose and treat
malaria” (157).
Pregnancies in Iron-Sufficient Populations
Further controversy with respect to the accurate diagnosis of iron status and subsequent iron
supplementation surrounds the routine iron supplementation of apparently iron-sufficient
(i.e., non-iron-deficient) women during pregnancy. The US Preventive Services Task Force
stated that there was insufficient evidence to advocate routine iron supplementation during
pregnancy (140). A similar statement from the European Food Safety Authority concluded
that iron supplementation during pregnancy should be reserved for those at risk for or with
documented iron deficiency (34). The controversy stems from the difficulty in demonstrating
any added benefit versus any potential risks of iron supplementation.
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The majority of this literature defines iron status by measuring maternal hemoglobin
concentration (30). However, precisely defining iron status in the context of what is termed
the physiologic anemia of pregnancy is problematic. The physiologic anemia of pregnancy
occurs because of a disproportionately greater expansion of the plasma volume (+50%) than
of the red cell mass (+25%), leading to a dilutional reduction in hemoglobin concentration
(146). Maternal hemoglobin concentrations between 95 and 110 g/dL have been associated
with the best pregnancy outcomes and, thus, would be considered normal (17). Hemoglobin
concentrations higher than this range have been associated with higher rates of
preeclampsia, prematurity, and fetal growth restriction (18, 52, 113, 116, 136, 166). A
smaller number of trials have assessed the effect of iron supplementation on women with
high hemoglobin concentrations (i.e.,
>
132 g/L) and found an increased rate of maternal
preeclampsia and fetal growth restriction (166).
A nonanemic hemoglobin concentration would typically be considered a biomarker of iron
sufficiency in nonpregnant women, whereas excessively high hemoglobin would be
consistent with total-body iron overload, given that iron is predominantly found in red cells.
Alternatively, elevated hemoglobin concentrations during pregnancy may not indicate iron
overload but instead reflect low plasma volume expansion, that is, cases in which the 2:1
ratio of plasma volume to red cell mass expansion is not achieved (146). In that
circumstance, serum ferritin may be normal or even low (Table 1). Thus, an elevated
hemoglobin concentration may be misinterpreted as iron overload. Studies that associate
high hemoglobin concentrations during pregnancy with poorer outcomes should be
interpreted cautiously as to whether the mechanistic causes of the poorer outcomes are a
fundamental gestational pathology that leads to low plasma volume expansion, true iron
overload, or both (162). The possibility that iron plays a primary role in plasma volume
dysregulation must be considered because such information would have a direct impact on
the decision to offer iron supplementation to women with normal or high hemoglobin
concentrations (162). The lack of adequate studies hinders the ability to provide guidelines
regarding universal iron supplementation in nonanemic pregnant women (146).
Future studies could avoid dividing pregnant women into the two traditional hemoglobin
categories, anemic or nonanemic, and instead consider a three-group model: anemic, normal,
and polycythemic. Data support this approach since a U-shaped risk curve of pregnancy
complications as a function of hemoglobin concentration has been described (146).
Moreover, women with normal hemoglobin concentrations may have preanemic iron
deficiency. Women with high hemoglobin concentrations may be iron-sufficient, but not iron
overloaded, if the high hemoglobin concentration is due solely to the failure of plasma
volume expansion (Table 1).
Assessing pregnancy outcomes as a function of iron-specific biomarkers could potentially
provide more direct insight than measuring hemoglobin alone. In turn, these markers could
be used to identify candidates for supplementation during pregnancy. Among these markers,
serum ferritin has been most often utilized in outcome studies. WHO recently assessed its
usefulness as a screening tool (156). Clinical interpretation of ferritin concentrations relies
on the understanding that if iron stores are replete, sufficient iron is present to support iron-
dependent cellular processes at the tissue level. Serum ferritin is an excellent specific metric
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for low-iron states because no condition other than iron deficiency results in low serum
ferritin concentrations. Interpreting high serum ferritin concentrations is more problematic
with respect to understanding serum ferritin’s relationship to tissue iron status. High ferritin
concentrations could indicate iron overload or, alternatively, a shift of iron into
reticuloendothelial cell storage as part of a response to inflammation (128). Mathematical
correction of ferritin concentrations for the degree of inflammation as indexed by an
inflammatory biomarker has been proposed, but has not been widely implemented (128).
The majority of published studies on pregnancy outcomes as a function of maternal iron
status utilized serum ferritin as the biomarker (30). They reported that higher ferritin
concentrations early in pregnancy were associated with more positive pregnancy outcomes,
whereas higher ferritin concentrations in the third trimester were associated with poorer
outcomes, including premature delivery and low birth weight (50, 73, 116, 131). Interpreting
these studies is difficult because it is unclear whether the high ferritin concentrations during
the third trimester indexed increased total-body iron or a shift of iron into the storage pool
due to inflammation. There is a great need for a sensitive and specific biomarker that indexes
tissue iron status and is not influenced by inflammation.
Assessing iron status by quantifying iron intake has yielded mixed results with respect to
pregnancy and offspring outcomes. On one hand, iron intake in non-iron-deficient mothers
early in pregnancy appears to protect against autism in the offspring (115), and iron intake
during the third trimester induces a more mature gray matter pattern on diffusion tensor
imaging in term infants (92). Conversely, iron supplementation in women with high
hemoglobin concentrations (i.e.,
>
132 g/L) during the second trimester leads to even higher
hemoglobin concentrations in the mother, but a greater risk of fetal growth restriction, most
likely due to maternal hypertension (166). Iron supplementation in pregnant women has also
been linked in observational studies to a greater risk of gestational diabetes mellitus (162).
Conclusions Regarding Iron Supplementation in Pregnant Women
Iron sufficiency during pregnancy results in better pregnancy outcomes for the mother and
the child. The benefits of iron supplementation outweigh the risks in women about to
become pregnant and in pregnant women with evidence of iron deficiency. Women living in
areas where iron deficiency is prevalent also benefit from routine iron supplementation
during pregnancy, even in malaria-endemic areas. In these areas, iron should be given along
with implementing malaria-control efforts, for example, insecticide-treated nets, and with
malaria diagnosis and treatment services readily available.
Typically, there is little additional benefit to supplementing a nutrient that is already replete
in an individual. This approach may also apply to iron supplementation of iron-sufficient or
iron-overloaded pregnant women, for whom little additional benefit would be expected and
potential risks exist. However, the inability to reliably distinguish total-body iron status from
three iron-replete states of hemoglobin in nonanemic women—nonanemic iron deficiency,
optimal iron status, and iron overload—presents a major problem in terms of benefit–risk
analysis since the effects of iron supplementation on these three states likely differ. A more
complete assessment of iron status, made by measuring both hemoglobin and ferritin
concentrations simultaneously, would resolve certain, but not all, ambiguities. The addition
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of hepcidin concentration to the arma-mentarium of iron screening tools would greatly
enhance the clarification of who would benefit from enteral iron supplementation. Because
hepcidin is upregulated by high iron status and by inflammation, elevated concentrations in
iron-sufficient, iron-overloaded, and inflamed individuals would reduce or abolish
absorption. In those cases, enteral iron supplementation would be pointless (i.e.,
nonabsorbed) or risky (i.e., nonabsorbed plus adversely altering the microbiome).
Conversely, low hepcidin concentrations would indicate individuals for whom the benefits of
iron supplementation would likely outweigh risks.
BENEFITS AND RISKS OF IRON SUPPLEMENTATION IN EARLY
CHILDHOOD
Physiologic Considerations
Early childhood, especially the first 3 years, is a period of rapid growth and development for
all organ systems, particularly the brain. Newborns have higher hemoglobin concentrations
(79) and iron stores, as reflected in their serum ferritin concentrations (121), than older
infants. Both decline with age (54, 167), and the iron that is liberated is utilized for
expansion of the red cell mass that occurs with the physical growth of the infant and for
biochemical reactions to catalyze tissue development and function.
Evidence from humans (47, 103), monkeys (106), sheep (161), rats, and mice (150)
demonstrates that the brain’s iron status is compromised before the iron status of the red
cells. This prioritization explains why anemia is the end-stage of iron deficiency and why
monitoring hemoglobin concentration is a poor (and late) measure of iron status in children.
Studies in humans (83, 86) and preclinical models (41, 114, 139) demonstrate that brain iron
deficiency early in life confers a risk for poorer brain function in adulthood. The clinical
consequences of early-life iron deficiency include poorer school achievement, lower job
potential, and increased risks of psychopathology (86). Recent preclinical studies suggest
that the failure of brain systems to be properly constructed during this critical period (41) is
responsible for behavioral abnormalities in adulthood (67, 138).
The brain systems that are rapidly developing prior to birth and during the first year after
birth include the monoaminergic neurotransmitter systems (9, 160) and the hippocampus
(41), and the process of myelination (25). Early-life iron deficiency results in abnormal
neuronal structure (16, 41) and function (105), metabolism (106), gene expression (138), and
neurotransmitter concentrations (139) in adulthood. The areas of the brain that have been
identified as affected in preclinical models are concordant with the abnormal behaviors
documented in humans (80, 87), indicating a high biological plausibility for the long-lasting
effects of early-life iron deficiency on the human brain (87).
Whereas brain and behavior are major outcome variables in many studies of childhood iron
deficiency, it is clear that the function of other systems, especially innate immunity, also
depends on iron sufficiency (30). Thus, preventing iron deficiency is important because of its
long-term cost to society, and it is a far better strategy than treating iron-deficiency anemia
once it is present.
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The appropriate-for-gestational-age term neonate who received the benefits of delayed cord
clamping has enough iron in red cells and storage pools to sustain tissue iron sufficiency for
at least 4 months and, perhaps, for as long as 6 months, even on a diet with as low an iron
content as human breast milk (30, 77). This sustainability assumes that the infant’s postnatal
growth rate (and hence expansion of the red cell volume) is appropriate as defined by
WHO’s growth curves; rapid infant weight gain is associated with earlier depletion of infant
stores.
The exceptions to this trifecta of term infants with normal iron stores, delayed cord
clamping, and reasonable postnatal growth velocity are common, not just in low-resource
countries but also in high-resource ones. Reduced fetal iron accretion can occur as a function
of maternal iron deficiency, defined as a hemoglobin concentration of
<
85 mg/L or a serum
ferritin concentration of
<
13 μg/L (119), or both. Other gestational conditions that reduce
neonatal supply include premature delivery and fetal growth restriction due to maternal
hypertension (19). The former complicates
>
10% of pregnancies and is important because
the majority of fetal iron is accreted during the last trimester (169). The earlier the preterm
delivery, the greater the risk for subsequent iron deficiency (32). The postnatal iron
requirements of the preterm infant are two- to threefold greater than those of the term infant
(32). Approximately 50% of newborns with fetal growth restriction have ferritin
concentrations below the fifth percentile, indicative of compromised iron stores at birth and
greater risk for postnatal iron deficiency at an earlier age (19). Worldwide, the most common
cause of fetal growth restriction is maternal undernutrition (which includes iron deficiency),
whereas in the United States it is maternal hypertension, including preeclampsia. Maternal
smoking during pregnancy and pregestational or gestational diabetes mellitus are significant
risk factors for low fetal iron status (121, 129). These two common gestational conditions
complicate
>
10% of pregnancies.
Given how common these potential risks to fetal and neonatal iron status are, measuring iron
status at birth would be useful to provide information about which babies are already iron
deficient at birth or at an increased risk for earlier postnatal iron deficiency. The current
American Academy of Pediatrics (AAP) policy of screening for iron deficiency via
assessment of hemoglobin concentration at 1 year of age may be ineffective because it fails
to consider that all other organ systems are affected prior to the onset of anemia (6). A
biomarker that indexes the risk to organ systems other than the erythron is urgently needed
to inform decisions about iron supplementation (46), particularly because nonanemic iron
deficiency is threefold more common than iron-deficiency anemia and is also associated
with altered neurobehavioral development (83). Recent changes by WHO to utilize serum
ferritin as opposed to or in addition to hemoglobin and by the AAP to add reticulocyte
hemoglobin content are steps in the right direction. However, all of the commonly used iron-
specific biomarkers (e.g., serum ferritin, soluble transferrin receptor, percentage total iron-
binding capacity saturation) are influenced by inflammation. Unlike the case in adults (44),
the regulation of hepcidin in very young infants is not well understood or described.
The following sections review the benefits and risks of iron supplementation in populations
with or at high risk for iron deficiency and those that are iron sufficient or at low risk for iron
deficiency. As with the literature on iron supplementation during pregnancy, the lack of
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adequate biomarkers of iron status and bioindicators of the physiologic consequences of
alterations in iron status causes significant problems for reaching universal conclusions
regarding supplementation in young infants (87).
Iron-Deficient Populations of Children
Iron-deficient pediatric populations are found predominantly, but not exclusively, in low-
resource settings. Rates upward of 80% have been reported in certain low-resource settings,
while Europe reports rates ranging from 4% to 50% in 6- to 36-month-olds, with a greater
predominance in Eastern Europe compared with Western Europe (141). The current rate of
iron deficiency in 1-to 2-year-olds in the United States is 13.5% (55). The benefits and risks
of iron supplementation in iron-deficient populations can be thought of as striking a balance
between the individual and societal downsides of iron deficiency as it relates to lost
intellectual potential and poorer immune capacity versus any potential risks of infection
posed to individuals by iron supplementation.
There is little disagreement that most term neonates are born with iron stores adequate to last
them for up to 6 months, but that after that time, a source of dietary iron is required to
prevent iron deficiency and anemia (30, 170). Thus, the question of whether to provide iron
supplementation at some point during the first few months of life at a dose that supports
optimal growth and development is not in debate. By 6 months of age, all infants who were
born iron sufficient need a dietary source of iron because fetal stores will have been
exhausted and human breast milk does not contain adequate iron to support the
erythropoietic and tissue-driven iron needs of the infant.
Multiple common gestational conditions place the newborn at risk for lower than normal
iron stores. These conditions (e.g., fetal growth restriction, severe maternal iron-deficiency
anemia) are more common in low-resource countries and set up the newborn for an earlier
onset of postnatal iron deficiency. Exacerbating postnatal factors include rapid postnatal
growth rate, earlier introduction of complementary foods with poor iron content and/or
bioavailability, and frequent illnesses, including infections that limit food intake and activate
hepcidin-driven reductions in iron absorption (23, 170).
Iron supplementation is beneficial if the goal is to alleviate anemia. Clinical studies, both
observational and randomized controlled trials (RCTs), demonstrate that iron and
multimicronutrient supplementation are effective in improving iron status and reducing the
rate of iron-deficiency anemia in iron-deficient populations of infants, whether the
supplementation is through the iron-fortification of formula or milk, or administration of
medicinal iron (108, 112, 125, 145, 152, 168, 170). Hematologic recovery from iron-
deficiency anemia through iron supplementation occurs at all ages, whereas neurobehavioral
recovery is not always complete (86, 87). There is minimal literature on the recovery of
immune health following iron supplementation in iron-deficient populations.
The literature is robust with respect to the effect of iron status on neurodevelopment. Iron
deficiency is associated with neurobehavioral abnormalities while the infant is deficient (3,
83, 109, 110, 120). Some abnormalities continue long after treatment of iron deficiency with
iron supplements (80, 86). A series of reports in the
Lancet
and by the BOND (Biomarkers
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of Nutrition for Development) iron work group identified 20 studies that showed poorer
functioning in multiple neurodevelopmental domains in iron-deficient children or children
with iron-deficiency anemia (87, 147, 148). Findings of particular concern include lower
general mental functioning (1, 57, 62, 81, 85, 151), poorer motor performance (1, 62, 85),
and a general loss of capacity relative to an iron-sufficient population across childhood (80).
Whether iron supplementation as a preventative or a treatment strategy is effective against
these neurobehavioral deficits in populations at risk for iron deficiency depends on the age
range of the children, the timing of the intervention, the baseline rate and the degree of iron
deficiency in the population, and the selection of appropriately sensitive and specific
neurodevelopmental outcome indicators. Interpreting the specific role of iron is made more
complicated when iron is provided as part of a generalized nutritional plan (e.g., fortified
formula or milk) or as a multimicronutrient supplement.
Overall, iron supplementation in populations at increased risk for iron-deficiency anemia
improves motor outcomes (12, 74, 84, 127), neurocognitive and language outcomes (84,
127), and social development (12, 74, 84). The effects can be long-lasting. Infants with
hemoglobin concentrations
<
105 g/L who were randomized to iron-supplemented infant
formula (12.7 mg/L) at 6 months of age had better 10-year outcomes than those randomized
to a low-iron formula (2.3 mg/L) (84). A greater impact on neurodevelopment has been
found with earlier supplementation, including starting during the fetal period via maternal
supplementation (20, 21, 26, 93). Later supplementation (e.g., after 1 year of age) was not
beneficial from a neurodevelopmental stand-point, suggesting that the critical period for
providing supplementation to ensure iron sufficiency to protect neurodevelopment is earlier
in life and includes the late fetal period (20, 21, 26, 93).
Iron status can be defined using various biomarkers. These include assessing anemia (with
supporting evidence that the anemia is due to iron deficiency), iron-specific markers, and
iron intake. The bulk of the literature has focused on preventing, detecting, and treating iron-
deficiency anemia. However, nonanemic iron deficiency, as indexed by altered iron-specific
markers, is associated with worse neurobehavioral function, including poorer motor function
(83), social function (83), speed of processing (3), and recognition memory (45, 120). A
recent RCT of mainly nonanemic iron-deficient 9- to 24-month-old infants with 6 mg
iron/kg body weight demonstrated recovery of serum ferritin concentrations, although
neurodevelopmental outcomes were not measured (133). Specific cutoffs for serum ferritin
concentration to detect neurodevelopmental deficits are present for neonates (3, 45, 120) but
not for other ages.
Studies of populations with increased early-life iron requirements—for example, those born
following gestational conditions that resulted in inadequate fetal iron loading, such as
maternal hypertension or premature delivery—indicate a positive role for iron
supplementation in preserving neurobehavioral development. Breastfed Swedish infants with
birth weights between 2,000 and 2,500 g as a result of either late preterm birth or
intrauterine growth restriction were randomized to iron supplementation of 0, 1, or 2 mg/kg
body weight (11). The group randomized to no supplementation had a higher rate of iron
deficiency and iron-deficiency anemia in the first year of life and an increased rate of mild
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neurodevelopmental abnormalities at 8 years of age compared with the group that received
either of the two supplemental doses (10, 11). Preterm infants who received iron
supplementation earlier in their neonatal course have higher mental processing composite
scores at 5 years of age (40, 124).
Given the beneficial effects of supplementing iron-deficient infants, consideration must still
be given as to whether there are any contraindications to iron supplementation in this
population. In 1998, in response to the mounting evidence of the potentially permanent
neurobehavioral consequences of iron deficiency in young children, WHO issued a
recommendation for daily, universal iron supplementation of all children aged 6 to 59
months living in areas where the prevalence of anemia was 40% or greater (126). The Pemba
trial (described in the section Pregnancies in Iron-Deficient Populations) first tested this
recommendation, enrolling
>
30,000 children between the ages of 4 and 48 months and
randomizing them to daily supplementation with 12.5 mg iron and folic acid with or without
zinc or to placebo (111).
The iron-containing arms of the Pemba trial were halted by the study’s data and safety
monitoring board after only 18 months because of a 12% increased risk of serious adverse
events (i.e., hospitalizations and deaths) among children who received iron compared with
those who did not. A concurrent study of identical design and equivalent size conducted by
the same researchers in Nepal (135), where there is no malaria, found no harmful effect of
iron supplementation, leaving researchers to conclude that iron supplementation in malaria-
endemic areas may be risky.
A Pemba substudy assessed roughly 3,000 children who had better access to health care and
also measurements of hemoglobin and zinc protoporphyrin (ZPP) and found that the harmful
effect of iron appeared to be confined only to those children who were iron replete (ZPP
<
80 μmol/mol heme) (111). In contrast, iron-deficient children (ZPP ≥ 80 μmol/mol heme)
benefited from iron, experiencing significantly fewer serious adverse events compared with
iron-deficient children who received placebo. The resulting recommendation from WHO
was to halt universal supplementation in malaria-endemic areas and to screen for iron
deficiency before giving the supplement (158). However, this screen-and-treat approach
failed to gain momentum in the field because of the expense of screening in the low-resource
settings where malaria is endemic and the impossibility of conventional interpretation of
iron biomarkers in areas where infection and resulting inflammation are commonplace.
Although three Cochrane Reviews of iron supplementation in children in malaria-endemic
areas conducted after the Pemba study found no harmful effects provided that malaria
control and treatment resources were in place (95–97), iron supplementation programs in
these areas where the public health need is potentially the greatest were drastically cut back
or eliminated altogether.
Red blood cells from anemic children in malaria-endemic areas are more resistant to
invasion by the malaria parasite, and this resistance is reversed with iron supplementation
(22). Because the malaria parasite preferentially invades reticulocytes, the transient
reticulocytosis that follows iron supplementation could explain the increased frequency of
clinical malaria that occurs with the provision of supplemental iron (49). This mechanism
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would not explain the increased frequency of nonmalarial infections, including diarrhea and
respiratory infections, reported in children who received supplemental iron, either in the
form of a supplement or micronutrient powder, in areas where malaria or other infections are
endemic (65, 123, 143). The explanation may reside in the gut bacterial microbiome. In two
separate studies of African infants, the regular consumption of iron-fortified biscuits and
iron-fortified food powders shifted the profile of the gut microbiota from one in which more
beneficial bifidobacteria barrier strains presided to one where pathogenic enterobacteria
strains prevailed (132). Recent preclinical models also suggest that pathogenic shifts in the
gut microbiome are associated not only with diarrheal illness but also with an increased risk
of a range of respiratory viruses, including respiratory syncytial virus and pneumococcal
pneumonia (117). Recent work suggests that these effects of iron on the microbiome and the
resulting morbidity may be mitigated by lowering the dose of iron to approximately 5 mg
and giving it in conjunction with a prebiotic, such as galacto-oligosaccharide (98). This
combination reduced anemia in Kenyan children with the same efficacy as a 12.5 mg dose of
iron and was also associated with a significantly lower frequency of respiratory infections
(99).
The absorbability of iron and the corollary question about the amount of residual iron
delivered to the gut microbiotic community is particularly pertinent for children living in
low-resource malaria-endemic areas, as these children typically have a higher baseline level
of inflammation due to poor sanitation, unclean water, and crowded living conditions. The
resultant inflammation and accompanying high hepcidin concentration likely limit the
absorbability of supplemental iron, leaving more iron in the gut lumen to the potential
benefit of pathogenic bacteria.
Delaying the provision of iron until the resolution of inflammation and the nadir of hepcidin
is a key element of a successful and safe pediatric iron program in areas endemic for malaria
and other infections. This concept has recently been demonstrated in a series of studies
examining the timing of iron therapy relative to antimalarial treatment in Ugandan children
with iron deficiency and malaria (26, 27, 65). The standard of care for co-occurring iron
deficiency and malaria is to treat both simultaneously, a practice supported by three
Cochrane Reviews and WHO guidelines (153). Recent research shows that staging the
interventions, by treating children with either severe or uncomplicated malaria first and
delaying the start of iron until 28 days after the onset of antimalarial treatment, leads to a
greater reduction in hepcidin, greater incorporation of iron into red blood cells, and fewer
infectious illnesses compared with children started on iron concurrently with antimalarial
treatment. Whether the initial better incorporation of iron with delayed provision results in
better long-term iron status and neurodevelopment is currently being tested (26, 27, 65).
In the absence of the eradication of malaria, the optimal method for safe maintenance of
healthy iron status in children living in these areas remains unclear. However, providing
smaller amounts of iron at times when hepcidin is lowest appears to be part of an effective
solution. These components are reflected in WHO’s current recommendations, which again
stipulate delivering universal iron supplementation to children between the ages of 6 and 59
months in regions where the prevalence of anemia is 40% or greater, but delivering it
intermittently (i.e., once, twice, or three times per week) where anemia prevalence is 20% to
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40% (155). In areas of where malaria is endemic, this supplementation should be given
concomitantly with efforts to control, diagnose, and treat malaria (155).
In addition to any potential risk of iron supplementation on infection rates and microbiome
alterations, investigators have been concerned about iron’s ability to induce reactive oxygen
species. This reaction occurs in the setting of NPBI, which would be most likely to occur in
settings of large iron doses in patients with low iron-binding protein concentrations. The
generation of reactive oxygen species, as indexed by biomarkers of the process, has failed to
be found in multiple studies of iron supplementation in premature infants (121). Premature
infants receiving doses as high as 18 mg of iron/day fail to show evidence of such a response
(14). Nevertheless, it remains prudent to assess this risk as a safety measure in future trials
because high-dose iron will be required to support the erythropoietic benefits of recombinant
erythropoietin therapy in preterm infants (121).
Iron-Sufficient Populations of Children
Although iron deficiency is the most common nutrient deficiency worldwide, the reality is
that the majority of newborn infants are likely to be iron sufficient, with normal iron storage
pools. In this context, a policy of universal dietary iron supplementation of all newborn
infants, both those who are iron sufficient and those at risk for iron deficiency, is
questionable unless there are absolutely no risks to iron supplementation, an assumption that
is not supported by the discussion in the preceding sections.
Any potential negative effects of iron supplementation should be understood within the
context of the iron status of the infant. It is worth considering a distinction between the
labels iron replete and iron overload as they relate to biomarkers of iron status in infants.
True iron overload is rare in neonates and infants. The genetic syndromes responsible for
neonatal iron overload are often fatal. Infants with neonatal polycythemia (e.g., infants of
diabetic mothers), who appear to be iron overloaded, as defined by an elevated hemoglobin
concentration, actually have lower storage and tissue iron contents (47, 103). This
combination of high hemoglobin and low serum ferritin concentrations indicates a shift of
iron—that is, iron has been prioritized for erythropoiesis through chronic fetal hypoxemia—
rather than iron overload. Multiple red cell transfusions could cause iron overload, but
infants who receive such therapy are relatively rare and would not drive universal policies.
Nevertheless, two interesting studies that demonstrate the potential neurodevelopmental risk
of iron overload illustrate the need for better differentiation between iron-replete and iron-
overload states (82, 130).
Tamura et al. (130) demonstrated that the school-age outcomes of newborns who were
divided into quartiles of cord blood serum ferritin concentrations were poorer for the
children in the lowest (i.e., iron-deficient children) and highest quartiles. While the former
finding is not surprising and is consistent with other neurodevelopmental studies of
newborns with low ferritin concentrations (3, 45, 120), the latter finding was unexpected.
The etiology of the high ferritin concentrations in the upper-quartile newborns is not known
and may represent inflammation (with its own risks to neurodevelopment), iron overload (by
unknown mechanisms), or both. Postnatal iron intake was not assessed in this cohort and
thus not factored into the assessment of the school-age outcomes.
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The RCT of iron supplementation of infant formula performed in Chile that demonstrated a
benefit of iron-fortified infant formula (12.7 mg/L) on hematologic and neurodevelopmental
outcomes (84) also demonstrated that infants with excessively high hemoglobin
concentrations (i.e.,
>
125 g/L) who were randomized to iron-fortified formula at 6 months
had poorer neurodevelopment at 10 years of age (82). The number of infants in this group
was small (
n
= 26), the etiology of their relative polycythemia/iron overload at 6 months was
unclear, and no mechanistic studies were performed because the finding was a secondary
analysis of neurodevelopmental data collected 10 years later. The negative effect of higher
levels of iron fortification in infant formula on neurodevelopment was not seen in children
with normal hemoglobin concentrations (i.e., between 105 and 125 g/L), and the same
degree of fortification improved neurodevelopment in children with hemoglobin
concentrations of
<
105 g/L (82, 84). These two studies raise the possibility that some infants
who would normally have been assigned to an iron-replete or iron-sufficient category by
ferritin (130) or hemoglobin (82) concentration may instead have had underlying
abnormalities that led to an iron-overload state and that neurologic morbidities that may be
associated with an iron-overload state may be further exacerbated by high-iron diets.
The risks and benefits of dietary iron delivery in presumably iron-sufficient, but not iron-
overloaded, infants and young children have been the focus of recent reviews and were a
major influence on the decision by the US National Institute of Health’s Office of Dietary
Supplements to convene a workshop that took place in 2017 (134) as well as the work of an
expert panel that occurred in 2015 (68).
The iron status of infants as a function of iron in the diet has been extensively studied.
Human breast milk contains approximately 0.5 mg/L of iron. Irrespective of whether this
iron is more absorbable or not, this amount is not sufficient to supply the iron needs of the
growing infant without concomitant mobilization of stored iron (30, 70). Ferritin
concentrations decrease during the first 6 postnatal months in breastfed infants (167).
Breastfed infants not supplemented with iron or iron-containing foods will typically exhaust
iron stores by 6 months of age, and, thus, the rate of iron deficiency in exclusively breastfed
infants at 7 months of age is greater than 30% (71). Iron supplementation slows this decline
(167). Thus, the issue is not whether breastfed infants need iron supplementation, but when
to introduce a source of iron. To answer this question, consideration should be given to
factors that affect the benefit–risk balance. The benefits of maintaining iron sufficiency—
whether through endogenous stores accrued prenatally or through postnatal supplementation
—have been discussed.
The iron content of the most highly fortified formulas is as high as 12–14 mg/L, thus far
exceeding the amount in human breast milk. The fortification of infant formula at 12 mg/L
began more than 50 years ago when the prevalence of iron deficiency in infants in the United
States approached 40% and was a major public health risk. Fortification at this level was
successful in reducing the prevalence of iron deficiency to much lower levels (55). Studies
assessed whether there were increased rates of diarrheal illness, gastrointestinal distress, or
changes to stool bacterial content. Although the stool of infants receiving highly fortified
formula had a greater content of siderophilic bacteria that are potential pathogens (e.g.,
E.
coli
), no increases in diarrheal illness or gastrointestinal symptoms have been found (70,
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122). Interestingly, the intake of medicinal iron results in a different microbiome profile than
intake of highly fortified formula (122). It should be noted that this recent study was
performed in Sweden, where a lower infection burden and low rate of infant mortality from
infectious diseases are present (122).
The original assumptions behind delivering fortification at such a high level from birth were
likely misguided because of the lack of knowledge of the regulation of iron absorption by
hepcidin. At that time, breastfeeding rates in the United States were at their lowest point.
Formulas contained only the amount of iron inherent to breast milk (i.e., approximately 1.15
mg/L), and infants were often switched to cow’s milk, another low-iron beverage, at 6
months of age. It was thought that intensely fortified infant formula delivered from birth
would result in infants storing additional iron beyond their immediate needs in order to have
a reserve for what was inevitably a negative iron balance state in the second 6 months of the
first year.
The discovery of hepcidin as a master regulator of gut absorption provided evidence that the
goal of storing extra iron was not likely to be achieved. Intestinal iron absorption ranges
from 4% to 40% based on hepcidin activity (44). Hepcidin is secreted by the liver in
response to sensors of iron status (44). As a negative regulator of intestinal absorption,
hepcidin levels are high when the individual is iron sufficient, thereby limiting iron
absorption, and low when an individual is iron deficient, thereby promoting absorption (44).
It is likely that young infants receiving formula fortified to 12 mg/L were iron replete with
high hepcidin levels, effectively reducing iron absorption to a low percentage and preventing
the intended storage of excess iron. The developmental ontogeny of effective hepcidin
regulation has not yet been completely defined, although evidence suggests that it is intact
by 6 weeks post-term gestational age (38). Hepcidin has been detected in preterm infants,
but the fact that isotope studies of iron absorption in preterm infants consistently
demonstrate an absorption rate of 35% to 40% (35, 53, 89) in spite of a wide range of iron
statuses, (79, 121) suggests that it may not be functional in that population.
A study in Sweden, a country with a low prevalence of iron deficiency, compared providing
formula fortified with 4 mg/L versus 7 mg/L starting at birth and revealed no difference in
hemoglobin concentrations (78). Infants fed the 4 mg/L formula had higher soluble
transferrin receptor than those fed the 7 mg/L formula, indicating a more iron-deficient state.
While there is no physiologic consequence of these changes, it does suggest that 4 mg/L
places the infant in a slightly negative iron balance. This evidence of negative iron balance
provided the rationale for the AAP’s statement advocating for at least 4.5 mg/L of iron in
formula (2).
The timing of iron exposure in iron-sufficient populations is key. The RCT in a high-risk
Chilean population began the iron intervention at 6 months of age and showed that 2.4 mg/L
was not sufficient to support iron status, albeit one could argue that many of the infants were
already total-body iron compromised at the time of randomization (84). In contrast, the
Swedish study began delivering iron-supplemented formula at birth in a population with a
very high likelihood of iron sufficiency at birth (78).
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Dose consistency is also an important factor. The United States utilizes a one-size-fits-all-
ages approach, with infant formulas designed to be utilized from day 1 to 12 months of age
(59). Europe utilizes formulas that gradually step up the iron concentration as babies age.
This approach makes sense since there appears to be little physiologic rationale to
supplement iron starting at birth in iron-sufficient populations with adequate neonatal
hemoglobin and ferritin concentrations (31, 59).
If there were no risks to iron supplementation, management would be relatively
straightforward, and universal supplementation, medicinally or through the diet, would be
acceptable. However, the potential risks of infant iron supplementation have been identified
(59, 70, 77) and include (
a
) compromise of the status of other divalent metals, especially
zinc; (
b
) an altered gut microbiome, with a potentially increased infection risk; and (
c
)
growth restriction. These risks, especially the effects on the microbiome, have not been
defined by rigorous trials (70).
Iron in doses typically prescribed to nonanemic healthy infants does not appear to have an
adverse effect on either copper or zinc absorption, but it does affect plasma and serum zinc
concentrations (33, 36, 58, 70, 75). This range of iron delivery is well beyond typical iron
supplementation or fortification regimens. Thus, negative effects on other divalent metals are
avoidable with low or moderate iron doses (70).
The intestinal intraluminal iron environment influences the microbiome, which is highly
mutable and is establishing itself in the first months after birth. A low intraluminal iron
concentration favors the growth of the preferred
Lactobacillus
organisms, while high iron
fosters a shift in the microbiome toward potentially pathogenic
Bacteroides
and
E. coli
as
early as 1 week of postnatal age (69, 90, 99). High intraluminal iron most likely occurs in
the setting of high dietary iron intake or inflammation. Both are high hepcidin states in
which iron absorption is low and unabsorbed iron is more likely to be retained
intraluminally. Whether the shift in microbiome character increases the incidence of clinical
infectious diseases or alters the developing innate immune system in iron-sufficient
populations remains an area of intense study, the results of which will likely inform policy in
the future.
A long-standing concern has been whether early-life iron supplementation reduces growth
velocity (77). Studies have had equivocal results from which it is difficult to draw firm
conclusions. A meta-analysis of 35 studies of iron supplementation in children from a wide
age range and in whom initial iron status was usually not known showed an overall effect of
linear growth suppression (100), but results of individual studies vary widely. The lack of
consistent findings may reflect which infants were supplemented (iron-deficient versus iron-
sufficient), their diets (human breast milk versus infant formula), the amount of iron
provided, and the method of supplementation (medicinal iron versus fortified formula).
Medicinal iron supplementation dosed at 1 mg/kg body weight daily in 4- to 6-month-old
term breastfed infants in Sweden and in Honduras yielded different results. The Honduran
infants, who were likely at high risk for negative iron balance or frank iron deficiency,
improved their iron status and did not have growth suppression (29). In contrast, the iron-
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sufficient Swedish infants did not increase their iron status, as would have been expected,
but did show linear growth suppression. The Honduran infants showed growth suppression
only if they had hemoglobin concentrations
>
110 g/L, likely indicating an iron-replete state.
Several other studies of iron supplementation starting in late infancy and ranging up to 2
years of age showed negative effects on growth if the infants were iron sufficient (63, 76, 88)
but beneficial effects on iron and hematologic statuses without growth restriction if the
infants were iron deficient at the start of treatment. Interestingly, other studies, including the
RCT from Chile that identified a neurodevelopmental risk with iron supplementation of 6-
month-olds who had high hemoglobin concentrations (82), did not show an adverse effect of
iron on growth (42, 43).
As noted, the studies that demonstrated growth-suppression effects were conducted in older
infants. No growth differences were seen in 1- to 6-month-old infants receiving formula
containing 4 versus 2 mg/L of iron (60). Infants randomized to iron-fortified formula
containing either 7.4 or 12.7 mg/L also showed no difference in growth and no evidence of
growth suppression (13). These sets of studies suggest that older age and a medicinal versus
an infant formula–based iron source may be important factors to consider in iron
supplementation of already iron-sufficient infants.
CONCLUSIONS
In the clearly iron-sufficient newborn, there is little if any benefit to beginning iron
supplementation at birth. However, allowing iron stores to decrease to levels that threaten
availability for developing tissues (without a source of dietary iron) is also potentially risky,
particularly as the infant approaches and exceeds 6 months of age. A gradual introduction of
iron into the diet between months 3 and 5 appears to maximize the benefit–risk ratio, as the
risk of infection declines after 3 months of age as immune competence builds.
Close monitoring of iron status and iron homeostasis is key. Management of all populations
would be easier if total-body iron status were estimated at birth via hemoglobin and ferritin
concentrations (47) and at mid-year, depending on the risk factors for poor iron status.
Waiting until 12 months and measuring only the hemoglobin concentration is simply not
defensible policy with what is now known about risks to iron status and the negative effects
of preanemic iron deficiency on the brain (83). In the future, the measurement of hepcidin
will likely be used to guide iron therapy. Infants with low hepcidin levels likely require iron,
while those with high levels are not likely to benefit from iron supplementation and may
well be at risk for adverse effects.
ACKNOWLEDGMENTS
This work was supported by grants from the National Institutes of Health to M.K.G. (R01-HD089989,
HD29421-20, R01-NS099178, R01-HD094809), N.F.K. (2UG1HD076474-06), and S.E.C. (R01 HD092391-01,
R03 HD074262) and from the Bill & Melinda Gates Foundation (OPP1055867).
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NPBI: nonprotein-bound iron
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WHO: World Health Organization
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AAP: American Academy of Pediatrics
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RCT: randomized controlled trial
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Figure 1.
The U-shaped risk curve exhibited by most nutrients. Iron has a narrower adequacy range
(
red dashed lines
), and risks from deficiency or overload states are greater compared with
those from most other nutrients.
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Georgieff et al. Page 34
Table 1
Interpretation and risk–benefit analysis of maternal iron supplementation during pregnancy based on whether
hemoglobin or ferritin was used as the primary biomarker to assess iron status and the information added by a
second biomarker
Primarymarker Literatureinterpretation
Biochemical
interpretation with
second biomarker
Agreement
between
literature and
biochemical
finding?
Low hepcidin
(likely response
to therapy)
Estimate of risk-
benefit of routine
supplementationa
Hemoglobin
Low Iron-deficiency anemia Low ferritin: iron-
deficiency anemia Low ferritin: yes Low ferritin: yes B ≫ R
Normal ferritin:
anemia of
inflammation
Normal ferritin:
unknown because
total-body iron is
unmeasurable
Normal ferritin:
no Unknown, but R > B
because iron will not be
absorbed in high
hepcidin state
High ferritin: anemia
of inflammation High ferritin:
unknown because
total-body iron is
unmeasurable
High ferritin: no
Normal Iron sufficient Low ferritin: low-iron
state Low ferritin: no Low ferritin: yes B > R
Normal ferritin: iron
sufficient Normal ferritin:
yes Normal ferritin:
no Unknown
High ferritin: iron
overload High ferritin: no High ferritin: no R > B
High Iron sufficient Low ferritin:
polycythemia by
volume contraction or
other non-iron-related
condition
Low ferritin:
nonanemia iron
deficiency
Low ferritin: yes R > B
Normal ferritin:
polycythemia by
volume contraction or
other non-iron-related
condition
Normal ferritin:
iron overload Normal ferritin:
no R > B
High ferritin: iron
overload High ferritin: iron
overload High ferritin: no R > B
Ferritin
Low Low-iron state Low hemoglobin:
iron-deficiency
anemia
Low hemoglobin:
partly Low
hemoglobin: yes B ≫ R
Normal hemoglobin:
nonanemia iron
deficiency
Normal
hemoglobin: yes Normal
hemoglobin: yes B > R
High hemoglobin:
polycythemia by
volume contraction or
other non-iron-related
condition
High hemoglobin:
no High
hemoglobin: no R > B
Normal Iron sufficient Low hemoglobin:
anemia of
inflammation
Low hemoglobin:
no Low
hemoglobin: no R > B
Normal hemoglobin:
iron sufficient Normal
hemoglobin: yes Normal
hemoglobin: no Unknown
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Georgieff et al. Page 35
Primarymarker Literatureinterpretation
Biochemical
interpretation with
second biomarker
Agreement
between
literature and
biochemical
finding?
Low hepcidin
(likely response
to therapy)
Estimate of risk-
benefit of routine
supplementationa
High hemoglobin:
polycythemia by
volume contraction or
other non-iron-related
condition
High hemoglobin:
no High
hemoglobin: no R > B
High Iron sufficient Low hemoglobin:
anemia of
inflammation
Low hemoglobin:
no Low
hemoglobin: no R > B
Normal hemoglobin:
iron overload Normal
hemoglobin: no Normal
hemoglobin: no R > B
High hemoglobin:
iron overload High hemoglobin:
no High
hemoglobin: no R > B
Abbreviations: B, benefit; R, risk.
a
Estimate of whether the risk (R) of adverse outcomes or the benefit (B) associated with iron supplementation is greater, given each combination of
iron markers.
Annu Rev Nutr
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