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REVIEW ARTICLE

published: 23 September 2013


HUMAN NEUROSCIENCE doi: 10.3389/fnhum.2013.00585

Perinatal iron deficiency and neurocognitive development


Emily C. Radlowski1,2 and Rodney W. Johnson1,2,3*
1
Department of Animal Sciences, University of Illinois, Urbana, IL, USA
2
Division of Nutritional Sciences, University of Illinois, Urbana, IL, USA
3
Neuroscience Program, University of Illinois, Urbana, IL, USA

Edited by: Iron deficiency is the most common form of nutrient deficiency worldwide. It is highly
Michael Smith, Northumbria prevalent due to the limited availability of high quality food in developing countries and
University, UK
poor dietary habits in industrialized countries. According to the World Health Organization,
Reviewed by:
it affects nearly 2 billion people and up to 50% of women who are pregnant. Maternal
Anett Nyaradi, The University of
Western Australia, Australia anemia during pregnancy is especially burdensome to healthy neurodevelopment in the
Leigh Riby, Northumbria University, UK fetus because iron is needed for proper neurogenesis, development, and myelination.
*Correspondence: Maternal anemia also increases the risk of low birth weight, either due to premature birth
Rodney W. Johnson, Department of or fetal growth restriction, which is associated with delayed neurocognitive development
Animal Sciences, University of Illinois,
and even psychiatric illness. As rapid neurodevelopment continues after birth infants
4 Animal Sciences Lab, 1207 W
Gregory Drive, Urbana, IL, 61801, USA that received sufficient iron in utero, but that receive a low iron diet after 6 months of
e-mail: rwjohn@illinois.edu age, also show deficits in neurocognitive development, including impairments in learning
and memory. Unfortunately, the neurocognitive complications of iron deficiency during
critical pre- and postnatal periods of brain development are difficult to remedy, persisting
into adulthood. Thus, preventing iron deficiency in the pre- and postnatal periods is
critical as is devising new means to recapture cognitive function in individuals who
experienced early iron deficiency. This review will discuss the prevalence of pre- and
postnatal iron deficiency, the mechanism, and effects of iron deficiency on brain and
cognitive development.

Keywords: nutrition, iron deficiency, cognitive development, learning, memory, hippocampus

INTRODUCTION in different cortical regions, including the prefrontal cortex in


Iron deficiency is the primary cause of anemia, which affects human infants (Sanai et al., 2011; Feliciano and Bordey, 2012).
roughly one-quarter of the worlds population (McLean et al., Total brain volume doubles the first year and reaches 8090% of
2009). As the most prevalent micronutrient deficiency in the adult volume by age two (Knickmeyer et al., 2008). This phase of
world, iron deficiency affects all age groups, with the most rapid growth represents a sensitive period, wherein environmen-
common being children between the ages of 0 and 5 years tal insults alter neurodevelopment (McEwen, 1999).
(McLean et al., 2009). It was previously thought that neonates One such insult is iron deficiency. The hippocampus, a brain
were protected from iron deficiency, in all but the most area important in learning, memory, and cognition, is highly
severe cases of maternal anemia, due to mobilization of iron susceptible to iron deficiency during the late fetal and early
stores accumulated in utero (Allen, 2000). However, it is now neonatal time period. For example, iron deficiency in the perinatal
documented that even mild iron deficiency in the mother reduces period is associated with altered expression of genes critical for
iron stores in the fetus, resulting in a neonatal iron-deficient hippocampal development and function (Carlson et al., 2007).
condition (Rao and Georgieff, 2002). Neonatal iron deficiency is Moreover, early iron deficiency causes neurocognitive dysfunction
also greater in infants born prematurely or of a diabetic mother both during deficiency and after repletion (Beard and Connor,
(Lozoff et al., 2006). As the incidence of both these conditions 2003; Jorgenson et al., 2005). Thus, preventing iron deficiency in
is increasing worldwide (Beck et al., 2010; Martin et al., 2010; the perinatal period is critical as is devising new means to recap-
Danaei et al., 2011), it is likely that iron deficiency in infants will ture cognitive function in individuals who experienced early iron
become an even greater concern in the future. deficiency. Although iron deficiency is a major concern across the
The impact of perinatal iron deficiency on human brain and lifespan, this review will focus on the prevalence of pre- and post-
cognitive development is of particular interest because the brain natal iron deficiency, perinatal iron homeostasis, and the effects
growth spurt that begins in the last one-third of pregnancy of perinatal iron deficiency on brain and cognitive development.
continues the first 2 years after birth due to dendritic growth,
synaptogenesis, and glial cell proliferation (Courchesne et al., PREVALENCE OF IRON DEFICIENCY AND IRON DEFICIENCY
2000; Gogtay et al., 2006). Neurogenesis in the hippocampal ANEMIA
dentate gyrus also persists in the neonatal period (and throughout Of all micronutrient deficiencies, iron deficiency is most prevalent
adulthood), and recent evidence indicates lingering neurogenesis worldwide. It affects all age groups and demographics; however,

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Radlowski and Johnson Perinatal iron deficiency and neurocognitive development

prevalence is higher in pubescent women, pregnant women, the physiologic mechanisms responsible for iron homeostasis
infants and preschool-age children. Rates of anemia in non- resulting in offspring that are more likely to develop iron defi-
pregnant women of childbearing age reach approximately 40% ciency in the future regardless of adequate nutrition (De Pee et al.,
in developing countries and 20% in industrialized countries 2002; Georgieff et al., 2002; Emamghorashi and Heidari, 2004.
(McLean et al., 2009). The incidence of iron deficiency anemia Multiple studies have shown that iron status in infants born to
increases further during pregnancy, with rates in developing and iron deficient mothers is still abnormally low 9 months after birth
industrialized countries reaching 59% and 24%, respectively. The despite being provided adequate dietary iron (Georgieff et al.,
large increase in iron deficiency in pregnant women in developing 2002; Geltman et al., 2004).
countries may be due to poor nutrition education and lack of The timing of iron deficiency during pregnancy is critical.
iron supplements (Pasricha et al., 2013). First, there is an important need for iron early in pregnancy
Infants born full term with an appropriate weight for gestation for neural development. In a recent study in rats, four dietary-
have iron stores that are adequate for about 6 months. This is feeding regimens were used to render the developing fetuses iron
vital because the neonatal gut is developmentally immature and deficient at different stages of gestation. Maternal iron restriction
infants are unable to regulate iron absorption until 69 months beginning prior to conception and during the first one-third of
of age (Domellf et al., 2002). Furthermore, iron content of pregnancy was associated with embryonic iron deficiency, postna-
breast milk is very low (approximately 3540 g/dL). Although tal anemia, reduced iron levels in the central nervous system, and
information on iron deficiency in infants less than 1 year of age decreased neural conduction velocities in an auditory brainstem
is lacking, the Pediatric Nutrition Surveillance System (PedNSS) response test conducted at postnatal day 45 (Mihaila et al., 2011).
reported hemoglobin in a national sample of infants from families Importantly, the functional neural impairments were not induced
participating in the Special Supplemental Nutrition Program when maternal iron restriction was initiated at the beginning
for Women, Infants, and Children (i.e., Supplemental Nutrition of the last one-third of pregnancy. Its also noteworthy that in
Assistance Program (SNAP; Polhamus et al., 2004)). In 2003, this study, the mothers were not anemic; indicating poorly timed
16.2% of infants aged 611 months, and 15% of children aged 12 iron deficiency is sufficient to disrupt neural development and
17 months qualified as having iron deficiency anemia (Polhamus function. Second, as the fetal liver continues to grow, most (>
et al., 2004). In a Brazilian community, iron deficiency anemia 66%) of the infants total body iron is acquired during the third
in infants (average age 11.6 months) reached nearly 26% (Kon- trimester of pregnancy (Allen, 2000). Hence, infants born preterm
stantyner et al., 2012); and in Canada, the rate of iron deficiency and/or low birth weight have poorer iron stores and are a high risk
anemia in Cree Indian infants (average age 9 months) was nearly population for iron deficiency (Scholl, 2011).
32% (Willows et al., 2000). Sadly, in most countries including the
U.S., the occurrence of iron deficiency worsens in preschool-aged
children (CDC, 2011; see Table 1). IRON HOMEOSTASIS IN THE BRAIN OF INFANTS
After 6 months of age, the blood-brain barrier is a major control
MATERNAL IRON DEFICIENCY AND IRON DEFICIENCY ANEMIA: point for the entry of iron into the brain, although the choroid
EFFECTS ON NEONATAL IRON STATUS plexus (the vasculature responsible for producing cerebrospinal
As iron is concerned, the developing fetus was once considered fluid) is also a location of regulation for iron entry (Beard and
a perfect parasite, able to acquire sufficient iron from the Connor, 2003). The blood-brain barrier is important, as it pre-
mother even when she was iron deficient (Young et al., 2012). vents the brain from having direct access to the iron in the blood
This notion has fallen by the wayside, however, and it is now plasma, allowing for greater regulation (Piero and Connor,
clear that neonatal iron stores can be compromised when the 2000). Transferrin (Tf) receptors are present on the endothelial
mother is iron deficient or anemic. For example, under steady- cells that make up the blood-brain barrier to allow for the binding
state conditions serum ferritin concentration correlates with total and endocytosis of transferrin-bound iron into the brain (Beard,
body iron stores. New born infants from iron deficient mothers 2001). The rate of iron entry into the brain is increased during
with low serum ferritin levels also had low serum ferritin indi- iron deficiency (Taylor et al., 1991), which is due to an increased
cating there is a limited capacity for the fetus to accumulate iron amount of Tf receptors present on the cells of the blood-brain
from low maternal stores (Jaime-Perez et al., 2005). Gestational barrier (van Gelder et al., 1998), as well as a possible role for
iron deficiency also appears to have a programming effect on regulation by astrocytes (Beard and Connor, 2003).

Table 1 | Prevalence of iron deficiency anemia around the world.

Iron deficiency anemia Iron deficiency

Industrialized countries Pregnant women 24% Iron deficiency is not commonly tested for
Infant (012 months) 16.2% and rates around the world are unknown at
Children (15 years) 25% this time, but estimated to be much higher
Developing countries Pregnant women 59% than for iron deficiency anemia
Infant (012 months) 40%
Children (15 years) 67%

McLean et al. (2009), Polhamus et al. (2004), Chaparro (2008).

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Radlowski and Johnson Perinatal iron deficiency and neurocognitive development

In the newborn infant, the story is a bit different. At birth, the during this period, lower I.Q. and achievement test scores have
blood-brain barrier is incompletely developed: it prevents iron still been found after treatment (Lozoff, 1989).
transport proteins from diffusing into the brain but it lacks the Many studies have investigated the impact of neonatal iron
ability to transfer iron from the blood into the brain parenchyma status at various times during this critical period and the effects
(Collard, 2009). Studies done in rat pups showed that iron reg- that decreased iron levels have on cognition. In Papua New
ulatory proteins, which are involved with the regulation of Tf Guinea, infants who were given an iron dextran shot at 2 months
receptor, were not readily expressed until post-natal day 15, when of age had longer attention spans at 1 year of age when compared
peak myelination occurs in the rat (Siddappa et al., 2002). It is to control (Heywood et al., 1989). A study done in Costa Rica
not known for human infants when the blood-brain barrier fully found that infants who had lower iron levels scored lower in the
matures, but it has been estimated to occur by 6 months of age Bayley Scales of Infant Development tests in both cognitive and
(Rice and Barone, 2000). During prenatal development iron accu- motor skill tests (Lozoff, 1989). In Guatemala, researchers found
mulates in the brain so levels are highest immediately after birth that an intramuscular injection of iron dextran improved Bayley
(Siddappa et al., 2003). Due to poor bioavailability and low levels Scales of Infant Development test scores in babies 624 months
of iron in human breast milk, infant brain iron concentration old after just one week, while oral supplementation did not show
decreases the first 6 months after birth, until the gastrointestinal an effect within the week studied (Lozoff et al., 1982). In Chile,
tract and blood-brain barrier mature and are able to absorb infants 3 months of age, were given either iron fortified formula or
dietary iron and regulate its entry into the brain, respectively. This control diet for 12 months (Walter et al., 1983). At the conclusion
coincides with the onset of myelination and an increase in trans- of the diet intervention, Bayley Scales of Infant Development were
ferring mRNA levels in brain (Connor et al., 1987; Connor and administered. After the initial test, all infants received a trial of
Menzies, 1996; Roncagliolo et al., 1998). Since oligodendrocytes orally administered ferrous sulfate daily and then retested within
synthesize Tf, the brain is the only organ in which Tf mRNA 15 days (Walter et al., 1983). A similar relationship between low
increases post-natally (Bloch et al., 1985). The developmental iron levels and lower Bayley Scales of Infant Development scores
timeline for mechanisms responsible for iron homeostasis under- was found (Walter et al., 1983). Studies in Indonesia found that 8
score the importance of maternal iron status during pregnancy. weeks of oral supplementation of iron in anemic preschool aged
Once iron penetrates the blood-brain barrier, much less is children reduced deficits in visual attention and concept acquisi-
known about how it is distributed to different brain regions. Most tion compared to children who were not given supplementation
likely Tf (secreted by the choroid plexus, which is another point (Soewondo et al., 1989). Also in Indonesia, when 1218 month
of regulation) is the primary method for the distribution of iron old infants that were diagnosed with iron deficiency anemia
in the brain (Beard, 2001); however, it is also possible for iron to were given an oral iron intervention, Bayley Scales of Infant
be transported by binding to ferritin (Piero and Connor, 2000). Development scores significantly improved compared to those
The iron can then be taken up by cells in various brain regions given a placebo, even after only 4 months of supplementation
that express receptors for Tf and/or ferritin, with the expression (Idjradinata and Pollitt, 1993). Nine and twelve month old infants
of these receptors as the mechanism of regulation (Beard and were tested for their ability to discriminate a highly familiar
Connor, 2003). This leads to an uneven distribution of iron stimulus, their mothers face, from a strangers face using an elec-
between the various brain regions, which changes throughout troencephalogram (Burden et al., 2007). At 9 months infants that
the lifetime (Beard, 2001). In general, the globus pallidus, red were iron sufficient showed greater attentional response to the
nucleus, substantia nigra, and caudate putamen have higher iron mothers face and greater updating of memory to the strangers
concentrations throughout life, and the brain tends to accumulate face, while iron deficient infants did not show this response until
iron with age (Piero and Connor, 2000). 12 months of age, suggesting a delay in cognitive development
(Burden et al., 2007). It has also been demonstrated that infants
NEUROCOGNITIVE DEFICITS RESULTING FROM PERINATAL IRON with low serum ferritin concentrations have abnormal auditory
DEFICIENCY recognition memory (Siddappa et al., 2004). The infants in this
One of the first studies to look at the effect of iron deficiency on study did not discriminate a familiar stimulus (mothers voice)
cognition in humans used the Bayley Scales of Infant Develop- from a novel stimulus (strangers voice) with the same vehemence
ment, which assess motor, language, and cognitive development as an iron sufficient infant (Siddappa et al., 2004). These findings
in infants and toddlers, and compared 926 month old infants suggest abnormalities in structures that mediate recognition and
who were given iron supplements to those given a placebo. Each memory function, including the hippocampus (Georgieff, 2008).
group was tested and then re-tested within 8 days of the initial Being iron deficient at birth seems to cause long term deficits as
exam. The results showed an improved scores within the Mental well. Five year old children, who were born either iron deficient,
Development Index for the iron supplemented group (Oski and scored lower on tests of language ability, fine-motor skills, and
Honig, 1978), which resulted in a surge of interest in this topic tractability, when compared to children who were iron sufficient
(Yehuda et al., 2010). Many different studies have looked at iron at birth (Tamura et al., 2002). In Israel, it was found that children
deficiency during various times of development; however, the who were born premature and had low ferritin levels at birth
most sensitive period (and the period that can cause the most performed significantly worse on tests involving spatial cognition
irreversible damage) is the neonatal period, which is between 0 and processing of auditory signals when tested at 9 to 10 years of
and 24 months of age (Pollitt, 1993). Although supplementation age, even though their hemoglobin levels had returned to normal
with iron has been shown to correct some of the cognitive deficits (Armony-Sivan et al., 2004; Yehuda and Yehuda, 2006). Another

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Radlowski and Johnson Perinatal iron deficiency and neurocognitive development

study showed similar results in that Costa Rican teens that were ence memory, suggesting the hippocampus is highly vulnerable to
severely iron deficient during infancy, despite resolution of ane- iron deficiency in the pre-natal period (Ranade et al., 2013). How-
mia while an infant, showed deficits when given neurocognitive ever, the fact that performance of the post-natal iron deficient
tests (Trail Making test, Intra-Extra-dimensional Shift, Stockings group was intermediate to the other iron deficient groups and
of Cambridge, Spatial Working Memory, Rapid Visual Informa- control confirms that the window of vulnerability to iron defi-
tion Processing, Pattern Recognition Memory, and Spatial Recog- ciency for the hippocampus does not close immediately at birth.
nition Memory) at the age of 19 years old, when compared to Iron deficiency decreases brain iron concentration, which leads
teens that were iron sufficient during infancy (Lukowski et al., to numerous behavioral symptoms, such as irritability, apathy,
2010). reduced ability to concentrate, and other cognitive deficits (Piero
Of course, studies in animals have greatly advanced the knowl- and Connor, 2000) (Table 2). Other important behavioral prob-
edge of iron deficiency and its effects on cognitive performance. lems have been reported in association with iron deficiency as
The fact that the avoidance response is affected by iron deficiency well. For example, children with Attention Deficit Hyperactivity
was one of the first cognitive aspects studied in rodents. Rats Disorder (ADHD) were found to have lower levels of serum
placed on an iron deficient diet at an early age showed deficits ferritin, an indication of reduced iron storage (Konofal et al.,
in both passive avoidance, where the rat had to inhibit its activity 2004). Iron-deficient animals develop ADHD-like behavior that
(i.e., not leave a platform and enter a chamber) in order to avoid has been linked to the dopaminergic system (Lahat et al., 2011).
shock, and active avoidance (i.e., where rats had to move into Deficits in motor development are also a symptom of iron defi-
another chamber of the testing area in order to avoid shock) ciency in the neonate. In addition to cognitive development, the
(Weinberg et al., 1979, 1981). Fear conditioning (as measured by Bayley Scales of Infant Development also assesses fine and gross
heart rate deceleration in a cage where the rat had been shocked motor skills. Numerous studies (Lozoff et al., 1982; Walter et al.,
previously, as well as exposure to a tone that was played during 1983; Lozoff, 1989; Idjradinata and Pollitt, 1993) indicate iron
the shock in a novel cage) was also impaired in iron deficient rats deficiency is associated with poorer scores in the motor function
(McEchron et al., 2005). assessment within of the Bayley Scales of Infant Development.
Iron deficient diets also resulted in cognitive deficits in the Further, anemic infants had low Mental and Psychomotor Devel-
Morris Water Maze, a hippocampal-dependent task which opment Index scores, even after 3 months of iron therapy. The
requires the rat to develop a spatial map of the area surrounding anemic infants also showed deficits in language capability and
the pool in order to reach a hidden platform (Yehuda and coordination (Walter et al., 1989). In rodents, iron deficiency is
Youdim, 1989). Similar deficits were observed in a water Y-maze associated with delayed development of surface righting, bar hold,
(where the rat had two choices and a dry platform was placed at forelimb placing, and negative geotaxis (Beard et al., 2006).
the end of the arm of the correct choice as a reward), including
increased incorrect arm entries and a longer time to reach the IRON UTILIZATION WITHIN THE BRAIN
platform (Yehuda et al., 1986), both of which indicate cognitive So what are some potential mechanisms underlying iron
deficits. A recent study with piglets also demonstrated the effects deficiency-related deficits in cognition? Iron is important
of early-life iron deficiency on hippocampal-dependent learning for erythropoiesis, formation of hemoglobin and myoglobin,
(Rytych et al., 2012). Neonatal piglets placed on liquid diets of gene transcription, cellular enzyme reactions, and important
varying iron content (adequate, mildly deficient, and a severely oxidation-reduction actions (Lieu et al., 2001). All of these, of
deficient) 2 days after birth underwent repeated cognitive testing course, are important for proper brain function, so it is not
beginning about 2-weeks later using a T-maze task to measure surprising that iron deficiency results in behavioral disorders
spatial learning and memory. Severely iron deficient piglets were and deficits in learning and memory (Rao and Georgieff, 2007).
not able to successfully learn the task, while mildly deficient In humans, the hippocampus matures most rapidly over a
piglets took longer to learn compared to controls. In addition short period of time: from late gestation to 23 years of age.
to poor performance, both sets of iron deficient piglets had less During this period, there is an increase in iron uptake and
iron present in the hippocampus compared to controls (Rytych utilization as well as neurogenesis, dendrite growth, myelination,
et al., 2012). These rodent and piglet studies confirmed that the synaptogenesis, and neurotransmitter synthesis (Fretham et al.,
magnitude of the cognitive effects observed correlated with the 2011). Hippocampal-dependent memory appears and matures
duration and severity of the iron deficiency. between 318 months of age (Nelson, 1995). Because infants are
The timing of iron deficiency during the perinatal period can unable to fully regulate iron transport across the blood-brain
also affect learning and memory. A pre-natal, post-natal, and barrier the first 6 months after birth, it is paramount that infants
pre+post-natal iron deficiency paradigm was used with mice pups have adequate iron stores at birth.
to examine the effects of iron deficiency on learning and memory Although hippocampal neurogenesis continues into
(Ranade et al., 2013). Mice pups that were pre-natal iron deficient adulthood, it occurs at a much greater rate prenatally and
or pre+ post-natal iron deficient performed poorly in a radial in the early postnatal period (Figure 1). The newborn neurons
arm maze task; performance was better for pups in the post-natal integrate into the developing neural circuitry and are thought
deficient group, although their performance did not match that to be important for learning and memory. Thus, in critical
of pups provided adequate iron in both the pre- and postnatal developmental periods environmental insults that inhibit
periods. Even when pre-natal iron deficient pups became iron suf- neurogenesis or alter neuron maturation will likely affect present
ficient after birth, they still exhibited a poor ability to utilize refer- and future behavior. Iron deficiency has been shown to inhibit

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Radlowski and Johnson

Table 2 | Neurobehavioral consequences of iron deficiency.

Affected process Population Measure Iron Supplement Result Possible cause Source
supplement? administration
and timing

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Behavior Costa Rican Observation in clinic Yes Behavior Marked differences in Inhibited Lozoff et al., 1998
infants 1223 and at home using assessed before behavior were found between neurotransmitter
months, IDA (n = bayley scales of and after 3 the IDA and IS group despite function,
52), IS (n = 139) infant development. months of iron resolution of anemia from hypomyelination, and
Spatial relations, therapy iron therapy. IDA infants delayed
affective state, remained close to caregivers neuromaturation from
behavior in relation at all times, and showed ID may lead to
to toys and in increased fearfulness, behavioral differences
relation to caregiver wariness, hesitance, when compared to IS
unhappiness, and tension infants
Behavior-ADHD French children, Conners Parent No NA Serum ferritin was Low ferritin may be Konofal et al.,
age 415 years Rating Scale (CPRS). significantly lower in children responsible for altered 2004
old, ADHD (n = Serum ferritin, with ADHD compared to dopaminergic
45), control (n = hemoglobin, control, while other blood neurotransmission
27) hematocrit, and iron measure were the same. which can affect brain
levels in blood were Serum ferritin levels inversely dopaminergic activity in

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measured correlated with CPRS scores children and contribute
to ADHD
Motor Inner city infants, Peabody No NA Poorer motor function found Impaired myelination in Shafir et al., 2008
development 910 months, ID Developmental in IDA and ID infants, the corticospinal tract
(n = 28), IDA (n = Motor Scales, Infant compared to IS. 34% of IS may delay/alter normal
28), IS (n = 21) Neurological infants were standing alone, if development and
International Battery not walking (19%) by 9 refinement of motor
(IFANIB), toy retrieval months age, while only 19% skills. ID induced
task of ID and IDA infants could changes to dopamine
stand alone. ID infants function within the
showed deficits in toy basal ganglia may
retrieval task as well explain poor
performance in toy
retrieval task
(Continued)
Perinatal iron deficiency and neurocognitive development

September 2013 | Volume 7 | Article 585 | 5


Table 2 | Continued.

Affected process Population Measure Iron Supplement Result Possible cause Source
supplement? administration
and timing
Radlowski and Johnson

Sensory systems Chilean children, Auditory Brainstem Yes Children were Formerly IDA children had ID effects pathway Algarn et al.,
4 years old, IDA Response (ABR), supplemented for significantly longer latencies transmission in both 2003
(n = 41), IS (n = and Visual Evoked 6 months to a for all ABR and VEP waves visual and auditory
43) Potentials (VEP) year when 6 compared to IS children. systems. May be due

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month18 Amplitudes were not different to hypomyelination.
months old. between groups Differences in latency,
These are but not amplitude,
formerly deficient support this hypothesis.
children Latency changes relate
to increases in
conduction velocity
during axonal
myelination
IQ Egyptian children, Weschler No NA The mean IQ of the IDA group Iron deficiency can Mubarak et al.,
age 612, IDA (n intelligence scale. was significantly lower than cause changes to 2010
= 22), and IS (n = Revised behavior the IS group. IDA children hemoglobin
16) problem checklist: showed significant concentrations, and
conduct disorder, differences in motor control mean corpuscular
socialized compared to the two other volume. In this study,
aggression, attention groups, and attention both measures were
problem-immaturity, problems were higher in both predictive of attention

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anxiety-withdrawal, anemic groups compared to deficit or motor excess
psychotic behavior, IS, but highest in IDA
motor excess
Memory Chilean children, Recognition memory Yes Children were Although accuracy within the Iron deficiency during Congdon et al.,
10 years old, task using supplemented for task was the same for both formative years may 2012.
Formerly Iron Electrophysiological 6 months to a groups, FID children took have long lasting effects
Deficient (FID; n Recording and year when 6 significantly longer to and cause deficiencies
= 19) and control Processing (ERP) month18 complete the task compared in neural circuitry and
(n = 23) months old. to controls. The FID group hypomyelination. The
These are also had longer latency in the differences seen in the
formerly deficient FN400 and P300 components FID group in the FN400
children of ERP testing, suggesting a component measure
delay in crucial memory may also be due to
searching processes and difficulty accessing
neural circuitry, respectively semantic memory to
complete the task at
the same level as the
controls

Abbreviations: ID = Iron Deficiency, IDA = Iron Deficiency Anemia, IS = Iron Sufficient


Perinatal iron deficiency and neurocognitive development

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Radlowski and Johnson Perinatal iron deficiency and neurocognitive development

FIGURE 1 | Time course of different processes in brain development involved in learning and memory over the first year of life, highlighting periods
of vulnerability to iron deficiency. Color intensity corresponds with the start, as well as peaks within each process.

neurogenesis in the developing hippocampus. Young rats whose dendritic arbor structure, a spines morphology can impact its
mothers were fed an iron-deficient diet and who were born with function (Spruston, 2008). At post-natal day 15, CA1 pyramidal
iron deficiency, showed decreased brain-derived neurotrophic neurons in rats that underwent a period of iron deficiency in
factor (BDNF) levels, down-regulation of BDNF target genes, utero showed reduced dendritic branching and smaller spine
and altered neuronal differentiation (Tran et al., 2008). Another head diameters (Brunette et al., 2010). Smaller spine heads could
study was carried out to investigate the effects of perinatal iron reduce conduction velocity resulting in less coordinated input to
deficiency on hippocampal development in mice (Ranade et al., the soma as well as represent smaller post-synaptic density which
2013). Iron deficiency in the pre- or postnatal period reduced could also affect signal transmission (Hodgkin, 1954).
BDNF and neurogenesis in the hippocampal dentate gyrus of Consistent with the structural changes noted above, iron defi-
pups. The impact of iron deficiency persisted, as the numbers ciency also impacts synaptic plasticity in the developing hip-
of hippocampal pyramidal and granule cells were reduced in pocampus of rats (Jorgenson et al., 2005). For example, prena-
adults. Moreover, the structural and molecular defects in the pups tal iron deficiency disrupted synaptic plasticity in the develop-
were correlated with performance in hippocampal-dependent ing CA1 region of the hippocampus, but these differences were
behavioral tasks, with pups from dams that were iron deficient also apparent in adulthood, after iron repletion. When iron was
throughout pregnancy and lactation displaying a broad array replete, rat pups demonstrated no developmental increase in
of defects, while pups from dams that were iron deficient only synaptic strength, as seen in control animals. It is hypothesized
during pregnancy or during lactation displaying subsets of that major developmental events related to proper dendrite out-
defects. These findings suggest that iron homeostasis is critical growth and synaptogenesis were thwarted due to the unavailabil-
for the expression of neurotrophic factors that support brain ity of adequate iron (Jorgenson et al., 2005). This certainly may
development and provide a molecular basis for behavioral deficits contribute to the lasting effects of iron deficiency on hippocam-
related to perinatal iron deficiency (Lozoff et al., 2006). pal structure and function.
Iron deficiency can cause changes to neuronal morphology. In addition to marked changes in dendrite out growth and
Neuronal shape is directly related to the computations performed synaptogenesis, hypomyelination occurs when iron availability is
by the cell and is crucial to information processing. Two key limited. Proper myelination is important for rapid impulse trans-
morphological features of neurons are dendritic arbor structure mission along axons. Myelination begins in the third trimester of
and spine density and geometry (Spruston, 2008). The developing the fetal period and progresses rapidly through infancy (Figure 1;
arbor requires external inputs to stimulate and support branching Nakagawa et al., 1998). In the central nervous system, oligoden-
morphogenesis. The arbor relies on external cues BDNF that drocytes are responsible for myelination of axons. As mentioned
signal via their respective transmembrane proteins. These in turn before, oligodendrocytes synthesize Tf to mobilize needed iron,
modulate factors that facilitate elongation and branching by pro- assuming it is readily available. Studies in humans and rats have
moting or reducing actin polymerization (Ackermann and Matus, demonstrated that iron deficiency can severely affect myelination.
2003; Sekino et al., 2007). This process is not restricted to early Increased latency of auditory brain stem potentials and visual
developmental periods because it is also necessary for reshaping evoked potentials (indirect markers of myelination) has been
neural circuitry during experience-dependent learning through- reported in iron deficient children (Roncagliolo et al., 1998;
out life (i.e., synaptic plasticity; Figure 1; Bagot et al., 2009). Like Algarn et al., 2003). Oligodendrocytes synthesize fatty acids and

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Radlowski and Johnson Perinatal iron deficiency and neurocognitive development

cholesterol for myelin (Mackler et al., 1979; McKay et al., 1983). autism, anxiety, or depression (Calabrese et al., 2013). The SERT,
In a rat model, restriction of dietary iron during gestation and which is responsible for re-uptake of serotonin within the brain,
the early post-natal period resulted in significantly less myelin is the predominant mechanism controlling strength and duration
proteins, lipids, and cholesterol in the spinal cord, brain stem, of serotonergic neurotransmission (Gaspar et al., 2003). SERT is
and cerebellar white matter (Yu et al., 1986; Ortiz et al., 2004). expressed more during development than in adulthood (Daws
Additionally, rats that were iron deficient in the perinatal period and Gould, 2011). Iron deficiency leads to decreased expression
displayed deficits in myelinogenesis at adulthood, even though of SERT which in turn exacerbates the decreased expression of
iron stores were replete (Ortiz et al., 2004). Finally, placing rats on BDNF. As previously noted, a reduction in BDNF can have serious
an iron-deficient diet post-weaning lead to a significant decrease consequences for hippocampal structure and function leading to
in myelination indices in the hindbrain and cerebrum (Beard and deficits in learning and memory.
Connor, 2003). This suggests that the need and usage of iron by
oligodendrocytes does not end during the perinatal period and CONCLUSION
that the adult brain still requires adequate iron. Iron deficiency is the leading micronutrient deficiency in the
Iron is also essential for a number of enzymes involved in neu- world. It affects people of all ages, but is most detrimental to
rotransmitter synthesis, including tryptophan hydroxylase used infants and children. In developing countries, approximately 12%
to produce serotonin, and tyrosine hydroxylase used to synthe- of children under 5 will die from a micronutrient deficiency
size norepinephrine and dopamine. Neurotransmitter synthesis (Ahmed et al., 2012). Children who survive will likely be iron
begins during embryogenesis (Figure 1; Herlenius and Lager- deficient, if not anemic. In industrialized countries like the United
crantz, 2001). Dopamine is important for regulating cognition States, the incidence of iron deficiency is increasing, probably
and emotion, reward and pleasure, movement, and hormone due in part to the increase in the number of children and adults
release (Dunnett et al., 2005). Striatal networks, with dopamine who are overweight or obese (inflammation disrupts iron home-
as the major neurotransmitter, relate to higher order cognitive ostasis) (Del Giudice et al., 2009). As iron deficiency inhibits
and emotional processes, motivated behavior, positive affect, and learning as well as motor and emotional development, individ-
reward-related processing, as well as motor function (Dunnett uals exposed to perinatal iron deficiency are at high risk for
et al., 2005). Studies in humans have shown that young adults, failing to reach educational milestones later in life. Moreover,
who were iron deficient while an infant, tended to perform more as adults they are more likely to bear children who also expe-
poorly on tasks that involved inhibitory control, set-shifting, and rience iron deficiency. Hence, iron deficiency in one generation
planning, all of which are classified as executive functions that can beget iron deficiency in the next generation, and so on.
utilize striatal networks that rely on dopamine (Lukowski et al., Given the consequences of developmental delays in neurocog-
2010). Studies in rodents have determined that dopaminergic nitive function, such as decreased motor development, lower
neurons co-localize with iron throughout the brain, that extra- IQ, difficulties with learning and memory (refer to Table 2 for
cellular dopamine and norepinephrine are elevated in brains of more evidence), strategies to prevent perinatal iron deficiencies
iron-deficient rats, and that the density of dopamine receptors and to promote neural plasticity in individuals exposed to poor
are altered in iron deficiency. These alterations are tightly con- iron status during key developmental periods, warrants more
nected to the extent of iron loss in each brain region (Beard attention.
and Connor, 2003). Other studies demonstrate that serotonin
transporter (SERT) and norepinephrine transporter densities are ACKNOWLEDGMENTS
also altered by iron deficiency (Burhans et al., 2005). Serotonin Supported in part by HD069899 and AG16710. The authors
is particularly important for proper wiring of neural circuits and would also like to thank Jennifer Rytych for her input and help
is highly implicated in neurodevelopmental disorders, such as with the content of this article.

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Radlowski and Johnson Perinatal iron deficiency and neurocognitive development

models. Am. J. Clin. Nutr. 50, heme and nonheme sources. J. Nutr. strued as a potential conflict of Copyright 2013 Radlowski and John-
618629. 142, 3339. doi: 10.3945/jn.111. interest. son. This is an open-access article dis-
Yehuda, S., Youdim, M. E., and 145961 tributed under the terms of the Creative
Mostofsky, D. I. (1986). Brain Yu, G., Steinkirchner, T., Rao, G. A., and Received: 15 May 2013; accepted: 30 Commons Attribution License (CC BY).
iron-deficiency causes reduced Larkin, E. (1986). Effect of prenatal August 2013; published online: 23 The use, distribution or reproduction
learning capacity in rats. Pharma- iron deficiency on myelination in rat September 2013. in other forums is permitted, provided
col. Biochem. Behav. 25, 141144. pups. Am. J. Pathol. 125, 620624. Citation: Radlowski EC and Johnson the original author(s) or licensor are
doi: 10.1016/0091-3057(86)90244-3 RW (2013) Perinatal iron deficiency credited and that the original publication
Young, M. F., Griffin, I., Pressman, Conflict of Interest Statement: The and neurocognitive development. Front. in this journal is cited, in accordance
E., Mcintyre, A. W., Cooper, E., authors declare that the research Hum. Neurosci. 7:585. doi: 10.3389/ with accepted academic practice. No use,
Mcnanley, T., et al. (2012). Maternal was conducted in the absence fnhum.2013.00585 distribution or reproduction is permit-
hepcidin is associated with placental of any commercial or financial This article was submitted to the journal ted which does not comply with these
transfer of iron derived from dietary relationships that could be con- Frontiers in Human Neuroscience. terms.

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