Journal of Molecular Neuroscience

https://doi.org/10.1007/s12031-019-01276-1

Iron Deficiency, Cognitive Functions, and Neurobehavioral

Disorders in Children
Lyudmila Pivina 1,2 & Yuliya Semenova 1,2 & Monica Daniela Doşa 3 & Marzhan Dauletyarova 4 & Geir Bjørklund 5

Received: 29 November 2018 / Accepted: 7 February 2019

# Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
More than 25% of the world’s population is affected by anemia, of which more than 50% suffers from iron deficiency anemia
(IDA). Children below 7 years of age are the population group that is most vulnerable to iron deficiency. Iron is an essential
element in brain metabolism. Iron deficiency can cause changes in neurotransmitter homeostasis, decrease myelin production,
impair synaptogenesis, and decline the function of the basal ganglia. Therefore, IDA adversely affects cognitive functions and
psychomotor development. Research has shown that iron deficiency is a frequent comorbidity in attention-deficit/hyperactivity
disorder (ADHD) and autism spectrum disorder. Iron deficiency may also induce or exacerbate deficiency of other essential
nutrients, which may have a negative impact on the developing brain and other organs in infants. Many nations of the world have
programs to control IDA based on the use of iron supplementation, intake of fortified food and drinks, improved food safety, and
monitoring of dietary diversity. Based on the current recommendations of the World Health Organization on cost-effectiveness
(WHO-CHOICE), iron fortification and iron supplementation programs can be considered cost-effective or even highly cost-
effective in most countries of the world to averting cognitive impairment.

Keywords Anemia . Iron deficiency . Children . Cognitive function . Children . ADHD . Autism . Psychomotor development

Introduction
Despite global progress achieved in medicine and science de-
velopment, anemia continues to be one of the most prevalent
disorders. More than 25% of the world’s population has signs
of anemia, and more than 50% of them, in particular women
and children below 7 years of age, suffer from iron deficiency
anemia (IDA). Iron supplementation may improve mental,
psychomotor, and physical development in children, although
evidence of such effects is rather scarce (Grantham-McGregor
* Geir Bjørklund
bjorklund@conem.org
1
Semey Medical University, Semey, Kazakhstan
2
CONEM Kazakhstan Environmental Health and Safety Research
Group, Semey Medical University, Semey, Kazakhstan
3
Department of Pharmacology, Faculty of Medicine, Ovidius
University, Constanta, Romania
4
Astana Medical University, Astana, Kazakhstan
5 ered data from 23 countries for children under 7 years old and
Council for Nutritional and Environmental Medicine (CONEM),
Toften 24, 8610 Mo i Rana, Norway
and Ani 2001). For soon 20 years ago, the International
Nutritional Anemia Consultative Group (INACG) tentatively
estimated that five billion people, or as much as 80% of the
world’s population, may be iron-deficient (INACG2000).
Children under 2 years of age are particularly sensitive to iron
deficiency due to rapid growth. Kassebaum et al. (2014) pre-
sented an estimation of the varying severity of anemia for the
period from 1990 to 2010 in 187 countries in 20 age groups
using data from the Global Burden of Diseases, Injuries and
Risk Factors (GBD) 2010 study. In 2010, the world preva-
lence of anemia was 32.91% which corresponded to 68.36
million years of life affected by disability (8.8% the total num-
ber of all cases of disability). The highest prevalence rates
were found in women of all age groups living in the countries
of South Asia and sub-Saharan Africa, while in the East Asia
countries this rate tended to decrease over the study period.
IDA prevailed in the structure of anemia. Malaria, schistoso-
miasis, and chronic kidney disease were the common causes
of this pathology. The most challenging situation is observed
in the children under 5 years, where the prevalence of anemia
has increased (Kassebaum 2016). In another study that cov-
women of reproductive age, IDA was observed in 25% of the

children (95% CI: 18.0, 32.0) and in 37.0% of the women
(95% CI: 28.0, 46.0) (Petry et al. 2016). The prevalence of
IDA in Iranian children under 18 years of age was 13.9%,
including 7.9% in the males and 8.5% in the females; iron
deficiency was found in 26.9% of all children (95% CI:
19.7–34.1) (Akbari et al. 2017). The prevalence of iron defi-
ciency in India is estimated to range from 70 to 90% (Sachdev
and Gera 2013). The significant proportions of children with
iron deficiency were in the Eastern Mediterranean (46.6%),
European (44.2%), and African (40.4%) regions (Muthayya
et al. 2013).
At present, programs for control of IDA envisage the use of
iron treatment on a continuous or intermittent basis, intake of
iron sprinkles or fortified food and drinks, improved food
safety, and monitoring of dietary diversity. The risk of anemia
development is strongly associated with a high prevalence of
infectious and inflammatory diseases, in particular, malaria.
Based on the concept of the World Health Organization
(WHO), careful epidemiological evaluation and control over
causative agents, design, and implementation of the most ef-
fective interventions capable of satisfying the needs of the
population alone with security measures are the milestones
for global preventive strategies targeted on anemia reduction
especially in low income countries (Pasricha et al. 2013a, b).
Many countries in the world have developed programs to
control IDA based on the use of iron supplementation, intake
of fortified food and drinks, improved food safety, and mon-
itoring of dietary diversity. The aim of this review is to clarify
the association between iron deficiency, cognitive functions,
and neurobehavioral disorders in children.
Iron Deficiency or Anemia in Children
and Impaired Psychomotor Development
Iron takes part in a diversity of metabolic processes in the cen-
tral nervous system. The role of iron in the synthesis of neural
transmitters makes it very important for brain development both
antenatally and postnatally. The hematoencephalic barrier con-
trols the iron concentration in the cerebral structures. Iron defi-
ciency may result in decreased production of myelin, impaired
synaptogenesis, and decline in the function of the basal ganglia,
which adversely affect the psychomotor development and men-
tal capacity (Dommergues et al. 1989; Vallée 2017).
Numerous studies have linked iron deficiency or anemia in
children with impaired psychomotor development. In a meta-
analysis that combined 17 studies (2416 children with febrile
convulsions and 2387 healthy children as control), a signifi-
cant association of convulsions with IDA was found (OR,
1.98; 95% CI, 1.26–3.13; p = 0.003). The study was based
on an assessment of diagnostic criteria such as serum iron,
plasma ferritin, and mean corpuscular volume (MCV). In the
study, plasma ferritin (OR, 3.78; 95% CI, 1.80–7.94;
J Mol Neurosci
p < 0.001) and MCV (OR, 2.08; 95% CI, 1.36–3.17; p =
0.001) were the most reliable indicators (Gera et al. 2009).
The Denver II Developmental Screening Test (DDST-II) is
an internationally recognized tool used to assess the psycho-
motor development in children. Pala et al. (2010) applied it to
evaluate the psychomotor development in children with iron
deficiency and IDA in comparison with healthy controls,
based on the following criteria: the test result was considered
to be a Bdelay^ if a child scored over 90th percentile, and it
was considered to be a Bcaution^ if a child scored between the
75th and 90th percentiles. Children with IDA had abnormal
test results in nearly 68% of the cases, and iron deficiency was
manifested by impaired psychomotor development in 22% of
the children. Meanwhile, 15% of healthy children with normal
hematological parameters had abnormal DDST-II results.
When anemic children were compared with non-anemic chil-
dren, the difference in the proportion of abnormal scores was
significant (p < 0.01). However, this was not true for children
with iron deficiency (p = 0.203) (Pala et al. 2010).
Long-term follow-up for the development of children pre-
sented with IDA in infancy showed that despite the treatment
provided, children had lower academic performance and de-
creased fine motor skills even 10 years’ posttreatment. Also,
declined auditory cortex-evoked responses along with heart
rate variability during the sleep-wake cycle were noted which
are considered to be associated with a decrease in myelin
synthesis due to iron deficiency (Walter 2003).
An observational study comprising 106 African American
children with identified iron deficiency helped to establish an
association between body iron status and such indicators of
psychomotor development as Peabody Developmental Motor
Scale (PDMS), the motor quality factor of the Bayley
Behavioral Rating Scale, and sequential or bimanual coordi-
nation in toy retrieval. The general linear model analysis was
carried out, which helped to identify the linear effects of iron
parameters on developmental landmarks, PDMS (as a sugges-
tive trend), the Infant Neurological International Battery
(INFANIB) standing item, overall motor quality, and toy-
retrieval task. Developmental landmarks relied on iron defi-
ciency with or without anemia as the threshold for effects,
while assessment of toy retrieval was based on INFANIB
standing item, motor quality, and presence of IDA. Children
with iron deficiency showed signs of reduced motor function
even when anemia was absent (Shafir et al. 2008). These
findings were supported by another study, which established
a reduction in mean mental developmental index (MDI), psy-
chomotor developmental index (PDI), and mean speech de-
velopment quotients in children with IDA at the time of ex-
amination or those who suffered from IDA in the past as
compared with healthy controls (Hokama et al. 2005).
A survey conducted in South Africa on children below
6 months of age investigated the association between the prev-
alence of anemia, growth retardation, and psychomotor
J Mol Neurosci
development. The prevalence of anemia and growth retarda-
tion composed 36.4% and 28.5%, respectively, while multiple
regression analysis established associations between birth
weight and combined psychomotor scores (β = − 3.427 (−
4.603, 1.891), p < 0.001) (Rothman et al. 2018). Those chil-
dren who had lower hemoglobin level than 10.5 g/dL and had
anemia in more than 3 months also had significantly lower
motor scores than the healthy controls (p < 0.05). Also, these
children experienced reduced language capabilities and de-
creased body balance-coordination skills as compared to con-
trols. If iron deficiency progressed to established anemia, the
negative effects lasted for not less than 3 months, even when
iron treatment was provided (Walter et al. 1989).
The findings of a systematic review with meta-analysis
suggest that short-term iron treatment within 5–11 days pro-
vided to children with IDA below 3 years of age fails to dem-
onstrate conclusive evidence of positive effects in relation to
psychomotor development (Logan et al. 2001). Nevertheless,
the findings of other studies prove that in case of timely and
adequate anemia management, the difference in psychomotor
development is diminished, which justifies the necessity of
early investigation and appropriate treatment enabling social
and intellectual maturation of children (Matiashvili et al.
2012). In a study by Soewondo (1995), it was noted that
developmental delay completely disappeared after 4 months
of treatment with iron supplementation (Soewondo 1995).
Moreover, the prevention of psychomotor retardation in chil-
dren has to be started at the time of pregnancy and be based on
the mother ’s iron status, nutrition, and bad habits
(Chmielewska et al. 2015; Iglesias et al. 2018).
Iron Deficiency and Cognitive Functions
in Children
Some observational studies suggest an association between
anemia and impaired cognitive functions such as
concentration, intellectual status, memory, and learning
skills. A study by Hurtado et al. (1999) showed that children
younger than 10 years who at an early age had IDA had
increased risk of moderate mental retardation. This relation-
ship did not depend on birth weight, socioeconomic status,
age, and education of the mother, gender, or nationality
(Hurtado et al. 1999). Children of primary school age, who
had IDA in infancy with hemoglobin levels below 100 g/L,
scored lower on tests for intellectual development rates
(Lozoff et al. 1991). These results indicate how important it
is to monitor anemia in infancy (Lozoff et al. 1991).
Improved cognitive development due to long-term prophy-
lactic oral administration of low-dose iron proves a relation-
ship between iron deficiency and child development
(Grantham-McGregor and Fernald 1997; Buys et al. 2005;
Iannotti et al. 2006). A systematic review including 14
randomized controlled trials conducted on children over
6 years of age, adolescents, and women, showed that iron
supplementation improves attention and concentration regard-
less of the initial iron level (SMD 0.59, 95% CI 0.29; 0.90).
Although in anemic children a 2.5 point (95% CI 1.24; 3.76)
increase in intelligence quotient (IQ) was observed, this was
not true for non-anemic individuals as well as for effects of
iron intake on memory, psychomotor, or learning skills
(Falkingham et al. 2010).
The effects of iron deficiency on schooling were over the
past decades of years extensively discussed in the internation-
al literature, and most of the studies come from developing
countries. In a randomized controlled trial, Soemantri et al.
(1985) investigated the effect of iron supplementation on ed-
ucational achievement and concentration in Indonesian prima-
ry school children. Independently of their hematological pa-
rameters, those children who received iron supplementation
had significantly higher scores than children who received
placebo in terms of school achievements and concentration
tests (Soemantri et al. 1985). Baumgartner et al. (2012)
assessed cognitive functions in 6–11-year-old children who
received iron and omega-3 fatty acid supplementation alone
and in combination. A group of children with IDA who re-
ceived iron supplementation had increased number of words
recalled, improved long-term memory, and retrieval as com-
pared with non-anemic iron-deficient children (Baumgartner
et al. 2012). A study by Low et al. (2013) showed that daily
iron intake in children aged 5–12 years improved global cog-
nitive assessment (SMD 0.50, CI 95% 0.11; 0.90, p = 0.01),
IQ for children with anemia (SMD 4.55, 95% CI 0.16; 8.94,
p = 0.04), and the level of concentration and attention. Iron
supplementation also improved age-adjusted height and
weight in children with anemia. Dietary iron intake reduced
the risk to develop anemia by 50% and the risk of iron defi-
ciency by 79%. Data about the safeness of iron supplementa-
tion was limited (Low et al. 2013).
Teenage girls at the beginning of menstruations frequently
develop IDA. Based on the fact that this period often corre-
sponds with intensive schooling, girls’ academic performance
may be jeopardized. The effects of iron treatment on memory
and attention of non-anemic adolescent girls with iron defi-
ciency were evaluated in a double-blind, placebo-controlled
clinical trial conducted by Bruner et al. (1996). Post-
intervention measurements of verbal learning and memory
showed that girls who received iron supplementation per-
formed significantly better (p < 0.02) on the tests than girls
in the placebo group (Bruner et al. 1996). The study that
was carried out could complement these findings by Nelson
(1996), who suggested that the learning ability of British ad-
olescent girls may be affected by iron deficiency (Nelson
1996). Both researchers advocated for the use of iron supple-
mentation in this subgroup of school-age children.

A systematic review of randomized clinical trials on the
efficacy of oral administration of iron or iron-rich milk and
cereals in children younger than 27 months showed a moder-
ate increase in mental development using the Bayley mental
and psychomotor development indices (SMD 0.95 (95% CI -
0.56 to 2.46, p = 0.22; p = 0.016 for heterogeneity). For IQ
scores in the children older than 8 years, SMD was 0.41
(p < 0.001). There was not found a positive influence on mo-
tor development score (SMD 0.09, 95% CI −0.08; 0.26, p =
0.28) (Sachdev et al. 2005).
There are till now inaccuracies in the assessment of the
safety of iron supplementation programs (Schümann et al.
2007). A study by Pasricha et al. (2013a, b) showed a de-
creased risk of anemia and iron deficiency in children aged
4 months to 2 years who received iron supplements. However,
iron supplementation did not give a significant difference in
the mental or psychomotor development or the children’s
height and weight gain, but it was associated with high risk
of vomiting (risk ratio 1.38, 95% CI 1.10; 1.73) and fever
(1.16, CI 1.02; 1.31). Further large randomized controlled
trials with long-term follow-up are needed (Pasricha et al.
2013a, b).
Iron and Neurobehavioral Disorders
Iron deficiency affects not only memory, attention, cognitive,
and motor abilities but also emotional and psychological be-
havior. The mechanisms are linked to long-term changes in
the metabolism of dopamine, GABA, hippocampal function
and structure, and myelinization (Georgieff 2011; Kim and
Wessling-Resnick 2014). Attention-deficit/hyperactivity dis-
order (ADHD) and autism spectrum disorder (ASD) are two
of the most common neurobehavioral disorders in children.
As reported below, recent studies have investigated the rela-
tionship between these disorders and iron deficiency.
Iron Deficiency and Attention-Deficit/Hyperactivity
Disorder
The results of the studies about the association between iron
deficiency and ADHD are inconsistent and contradictory
(Doom et al. 2015). One of the studies demonstrated that
ADHD is accompanied by a decrease in serum ferritin levels
(SMD = − 0.40, 95% CI − 0.66; − 0.14), although a correla-
tion between iron levels and ADHD has not been established
(SMD = − 0.026, 95% CI − 0.29; − 0.24) (Wang et al. 2017).
These results were supported by data from another study con-
ducted on children with ADHD. A significant association has
been found between the severity of symptoms and serum fer-
ritin levels, as well as low levels of thalamic iron. Children
with sleep disorders have a higher risk to develop iron defi-
ciency. At the same time, anemia reduces the effectiveness of
J Mol Neurosci
treatment with psychotropic drugs. These data indicate the
need for screening of children with ADHD to detect iron de-
ficiency (Cortese et al. 2012a, b).
A meta-analysis that combined 17 trials that investigated
the associations between ADHD and iron status/iron deficien-
cy demonstrated that the levels of ferritin and peripheral serum
ferritin were substantially lower in children with ADHD (chil-
dren with ADHD = 1560, control group = 4691, p = 0.013).
However, there was no significant difference in serum iron
and transferrin levels between the two groups. Also, children
with iron deficiency had significantly more severe symptoms
of ADHD as compared to healthy controls (OR = 1.636, p =
0.031). Further longitudinal studies are needed to confirm
these associations and to elucidate the potential mechanisms
(Tseng et al. 2018).
Iron Deficiency and Autism Spectrum Disorder
Iron deficiency is a frequent comorbidity in ASD due to food
selectivity provoked by stereotyped behavior—one of the dis-
order’s hallmarks (Herguner et al. 2012). On the other hand,
children with IDA tend to come from a less privileged socio-
economic background, which might deteriorate their ability to
seek healthcare services. Taking into account that iron is es-
sential for normal cognitive functioning, its deficiency may
prevent children from obtaining new skills and abilities and
make the manifestation of ASD even more severe (Schopler
et al. 1980). In other words, the interrelation between iron
deficiency and ASD appears to be bidirectional.
Several studies attempted to describe the parameters of iron
deficiency, i.e., hemoglobin concentration, ferritin, and
hematocrit, in children with ASD in comparison with
healthy controls. Bener et al. (2017) established that ASD
children had significantly lower (p = 0.003) mean serum iron
level as compared with healthy controls (74.13 ± 21.61 μg/dL
and 87.59 ± 23.36 μg/dL, respectively), as well as mean he-
moglobin concentration (12.03 ± 2.13 g/dL versus 12.86 ±
2.02 g/dL, p < 0.001), ferritin level (36.57 ± 5.12 ng/mL ver-
sus 38.49 ± 5.73 ng/mL, p < 0.001), and hematocrit level
(36.32 ± 2.81 versus 39.07 ± 2.66, p < 0.001) (Bener et al.
2017). Gunes et al. (2017) shared similar findings: all param-
eters, like hemoglobin concentration, hematocrit level, and
mean serum iron level were significantly (p < 0.05) lower in
the children with ASD than in neurotypical controls.
Moreover, the parameters of iron deficiency correlated with
autism severity. Children with intellectual disability had sig-
nificantly lower levels (p < 0.05) of hemoglobin and hemato-
crit, while children with severe autism had significantly lower
hemoglobin concentration (Gunes et al. 2017). Although re-
cent meta-analysis failed to confirm a significant difference in
serum ferritin level between ASD and neurotypical children
(k = 4, Hedges g = 0.016, 95% CI − 0.482; 0.515, p = 0.949),
the prevalence of coexisting ASD and ID was significantly
J Mol Neurosci
higher than in neurotypical controls (Tseng et al. 2018). There
is a need to monitor the iron deficiency parameters in all chil-
dren with ASD as a part of their routine examination.
Sidrak et al. (2014) reported on the prevalence of iron de-
ficiency in children with global developmental delay (GDD)
and/or ASD and established that children with GDD without
ASD had lower rates of iron depletion (1.8%) and iron defi-
ciency without anemia (5.5%) as compared with ASD chil-
dren with or without GDD, for whom the same parameters
comprised 3.0% and 7.5%, respectively. However, children
with GDD but no ASD had higher rates of IDA (5.5%) as
compared to ASD children with or without GDD (3.0%) al-
though this finding was not statistically significant (p = 0.211)
(Sidrak et al. 2014).
Low iron intake during pregnancy and the period of
breastfeeding has a negative impact on the risk of ASD devel-
opment. Mothers who gave birth to a child with ASD were
less prone to take iron-fortified foods or supplements during
the specified period (OR = 0.63, 95% CI 0.44; 0.91) and gen-
erally had significantly lower daily iron intake (51.7 mg/day,
SD 34.0) than mothers who gave birth to a child with no ASD
(57.1 mg/day, SD 36.6). As a further matter, the lowest quin-
tile of iron intake during pregnancy and breastfeeding was
associated with an increased risk of ASD development in
comparison with the highest quintile. Maternal iron supple-
mentation may be used as a part of the preventive strategies
for ASD (Schmidt et al. 2014).
Iron supplementation in children with ASD may have a
beneficial effect on sleep quality. The results of an 8-week
clinical trial with an intake of oral iron supplement in a dose
of 6 mg/kg/day showed that the occurrence of restless sleep
improved significantly (p = 0.04) in 29% of children with
ASD. Nonetheless, the delayed sleep onset improved insignif-
icantly (35% of children as compared with 44% at baseline).
As for the improvement of baseline irritability following treat-
ment, only a trend toward positive change was observed
(Dosman et al. 2007).
The Effects of Iron Deficiency on Brain Biochemistry
and Neurobehavioral Development
Iron is essential for the early development of the brain and is
needed for the proper behavioral organization (Kim and
Wessling-Resnick 2014). Decreased level of iron impacts neu-
rotransmitter homeostasis, and the conduction of impulses in
cortical fibers. Iron deficiency also reduces the metabolism of
monoamine and brain myelination (Beard 2003; Beard and
Connor 2003; Kim and Wessling-Resnick 2014).
Iron is a cofactor of the enzyme tyrosine hydroxylase,
which reduces the rate of dopamine synthesis (Sachdev
1993). A decrease in dopamine transfer accompanies iron de-
ficiency through frontal-striatal circuits and the mesocortical
pathway (Erikson et al. 2000; Beard et al. 2002; Lukowski
et al. 2010; Lozoff 2011). In iron-deficient children, disorders
of dopamine metabolism in the mesolimbic area may lead to
alteration of behavioral, social, and emotional impairments
(Lozoff 2011). In children with ASD, dopamine has been
considered a predictive biomarker (Hassan et al. 2018).
Changes in the concentration of iron in the brain have ef-
fects on the homeostasis of γ-aminobutyric acid (GABA) and
glutamate. These changes not only cause deficits in motor
skills and learning/memory capacity but also lead to psycho-
logical and emotional problems (Kim and Wessling-Resnick
2014). An imbalance between the inhibitory neurotransmitter
GABA and excitatory neurotransmitters leads to symptoms of
ADHD (Edden et al. 2012; Gallo and Posner 2016). Research
has shown that persons with ADHD have decreased levels of
GABA in the central nervous system and decreased iron levels
in the basal ganglia (Hill 1985; Youdim et al. 1989). In the
thalamus of children with ADHD, the iron levels are signifi-
cantly reduced (Cortese et al. 2012a, b). Recent research
shows that raised plasma concentration of GABA can be used
as a predictor of ASD development (Al-Otaish et al. 2018).
Cost-Effectiveness of Iron Supplementation and Iron
Fortification Programs
To adequately treat iron deficiency, a proper diagnosis has to
be made, and the underlying causes need to be eliminated.
Iron deficiency is primarily treated through nutritional im-
provement. Various food products are rich in iron, and the
absorption of iron is highest from meat and meat products.
However, since this category of products cannot constitute
the entire diet, other food products rich in iron also need to
be considered. Such products include shellfish, legumes, eggs,
dry fruits, and some vegetables, especially spinach. Beside
this, it is important to consider the factor of iron absorption
that might be affected by environmental factors, as well as
other food products and the pH level in the duodenum
(Özdemir 2015).
The abundance of evidence exists relating to the dose and
the period the iron replacement therapy is administrated. Quite
often inappropriately, low iron doses are prescribed since high
doses of iron are associated with side effects which may lead
to interruption of the therapy. Whenever it is possible, oral
iron preparations should be preferred because they are the
cheapest and the oral route of administration is less invasive
and has fewer side effects than the parenteral route. Oral iron
treatment also is more economical than parenteral treatment.
The most commonly used dosage for oral iron supplementa-
tion is 3–6 mg/kg/day, which is recommended divided into
one or two doses between meals. The goal is to obtain a rise
in the hemoglobin level by 1 g iron/day within 4 weeks
(Kleinman and Greer 2011).
As iron deficiency has a profound effect on cognitive
health and psychomotor development of affected children,

which may last till later life, it remains an important public
health problem in many developing countries as well as a
barrier to the income growth of the poor. Since children from
lower socio-economic classes are vulnerable to the irrevers-
ible effects of iron deficiency on cognitive functions and psy-
chomotor development, the cost-effectiveness of iron supple-
mentation to tackle this problem has to be scrutinized
(Hurtado et al. 1999). Since each 1.0 g/dL decrease in hemo-
globin concentration results in long-lasting loss of intelligence
quotient equal to 1.73 points (Stoltzfus et al. 2004), many
countries introduced iron supplementation and iron fortifica-
tion at a national level. Both clinical and economic impacts of
these programs require careful consideration (Gould 2017).
In a cost–benefit analysis that included 5000 simulated
Pakistani infants at 6–12 months, Sharieff et al. (2008)
projected the effect of home fortification with iron sprinkles
on IQ scores and lifetime earnings. The study also estimated
the effect of zinc fortification on morbidity and mortality due
to diarrhea. After random assignment to treatment and placebo
groups for 4 months, all individuals were followed for 55 years
in a Markov process of time cycles, which allowed establish-
ing that decreased rate of diarrhea and increased hemoglobin
concentrations were associated with reduced child mortality
related to diarrheal illnesses, higher IQ scores, and generally
higher earnings. These findings enabled the conclusion that in
a setting of the developing countries, home fortification with
sprinkles can be considered a cost-effective strategy with
long-lasting benefits far outweighing its costs (Sharieff et al.
2008).
Baltussen et al. (2004) estimated the cost-effectiveness
of iron supplementation and iron fortification programs in
four subregions of the world (African, South American,
European, and Southeast Asian) using the population
model designed to estimate the lifelong impact of these
programs on individuals benefiting from them. Annually,
iron supplementation would avert 12,482 disability-
adjusted life years (DALYs) in the European subregion,
247,383 DALYs in South American subregion, and al-
most 2.5 million DALYs in the African and Southeast
Asian subregions, while iron fortification would avert
8849 DALYs in the European subregion, 138,461
DALYs in South American subregion, and more than
1.0 million DALYs in the African and Southeast Asian
subregions (Baltussen et al. 2004).
In ten developing countries, the production losses due to
iron deficiency in terms of decreased physical productivity
were estimated to be 0.57% of the gross domestic product
(GDP) (around USD 2.32 per capita), while the combined
median physical and cognitive losses resulted in 4.05% of
the GDP (or USD 16.78 per capita). The median benefit–
cost ratio value for long-lasting iron fortification programs
was assumed to be 6:1 for a cost of USD 1.33 per case of
anemia prevented, and it raised to 36:1 when the model
J Mol Neurosci
included cognitive improvements as potential future benefits
(Horton and Ross 2003).
Research has shown that the effectiveness of iron prepara-
tions increases due to synergistic interactions with other
micronutrients and vitamins (Bjørklund et al. 2017). For pre-
vention and treatment of childhood anemia at a population
level in India, the policy thrust can only be done according
to a program of iron implementation, where only 3.8–4.7% of
the preschoolers receive iron-folate supplements
(Swaminathan et al. 2013). There is an urgent need for effec-
tive governance and implementation of iron supplementation.
A cluster-randomized controlled trial was conducted in China
to evaluate the effects of a nutritional powder, containing iron
and other micronutrients, in the prevention/treatment of ane-
mia and developmental delay in rural children aged 6–
11 months. Six months after the MMP administration, the
hemoglobin concentrations of the children had increased
(marginal effect 1.77 g/L, 95% CI 0.017–3.520, p value =
0.048) and improved cognitive development was observed
(marginal effect 2.23 points, 95% CI 0.061–4.399, p value =
0.044). However, there was not found a significantly im-
proved motor development, and 48% (721) of the children
remained cognitively delayed at the end line (Luo et al.
2017). In children under 3 years of age with established
IDA, a systematic review by Wang et al. (2013) showed that
iron given in combination with vitamin C for 30 days did not
significantly improve the psychomotor development or the
cognitive functions of the children. Only one of these studies
proved moderate evidence for cognitive improvements after
4 months with intervention (the Bayley Mental Development
Index was 18.80, 95% CI 10.17; 27.43, p < 0.0001) (Wang
et al. 2013). The use of multi-nutrient food supplements con-
taining iron or folic acid together with iron demonstrated
changes in intellectual development according to the
Wechsler Intelligence Scale for Children-Fourth Edition
(WISC-IV) (Li et al. 2015). The prophylactic administration
of folic acid to pregnant women or provision of micronutrient
supplements within the entire period of the pregnancy resulted
in 1.13 times (95% CI, 0.15–2.10) increase in the IQ scores of
their children (mean age 11.7 years). The offspring of women
who received both iron and folic acid supplementation had
2.03 times (95% CI, 0.61–3.45) higher scores on the verbal
comprehension index compared to the children of the untreat-
ed women. Also, the children of mothers who took supple-
ments with micronutrients during the pregnancy had a 2.6-fold
excess in their IQ scores (95% CI, 0.98–3.94) compared to
children of mothers who only received supplements contain-
ing folic acid and iron (Zhu et al. 2018).
To estimate the lifetime health and cost consequences of
IDA, Wieser et al. (2017) developed the health economic
simulation model in 6- to 59-month-old Pakistani children
based on the data obtained from the 2012–2013 Pakistan
Demographic and Health Survey, which included a
J Mol Neurosci
representative sample of 14,000 households. The societal
costs of impaired cognitive development caused by IDA
amounted to 2148 million USD in future production losses
(after the age of 5) and to 1392 million DALYs. The costs
were lower in wealthier households due to the lower preva-
lence and severity of iron deficiency and the lower number of
children (Wieser et al. 2017).
Based on the current WHO recommendations on cost-
effectiveness (WHO-CHOICE), an intervention is regarded
as highly cost-effective if the cost per DALY is less than one
GDP per capita and it is viewed as cost-effective if the cost per
DALY is around one to three GDP per capita (WHO 2016),
both iron fortification and iron supplementation programs
could be considered as cost-effective or even highly cost-
effective in most countries of the world in terms of averting
cognitive impairment.
Figure 1 presents a schematic view of how iron deficiency
might affect lifetime earnings and the rationale to implement
iron fortification and iron supplementation programs. In pop-
ulations with iron-deficient children, public health interven-
tions can improve work productivity in adulthood through the
iron-related neurocognitive effects. This judgment is support-
ed by the following considerations: (i) each 10-g/L increment
in hemoglobin concentration results in a rise of IQ equal to
1.73 points (Stoltzfus et al. 2004), (ii) this increment of IQ
scores has a long-lasting effect (Campbell et al. 2001), and (iii)
each one-point increase in IQ scores leads to a 1.1% wages
growth in adult life (Alderman et al. 1996).
Improper
cognitive
development
Impaired
psychomotor
development
Growth
retardation
Neuro-
behavioral
dysfunction
Anemia or Cognitive and
iron neurobehavioral
deficiency disorders
Fig. 1 How iron deficiency anemia in childhood may lead to loss of earnings in adult life
Concluding Remarks
The carried-out analysis of published papers bears witness to
high global prevalence of anemia and iron deficiency among
women of reproductive age, children, and infants, especially
in low-income countries. Screening for anemia has to be ini-
tiated in 1-year-old children following the recommendations
of the American Academy of Pediatrics and the WHO (Wang
2016). There are numerous evidences that IDA is associated
with cognitive impairment, psychomotor disorders, and be-
havioral problems in children of different age. Disorders of
attention, emotion, intelligence, and sensory perception are
the most common cognitive functions impaired by iron defi-
ciency. These effects that can last a long period can have a
negative impact on learning capability and acquisition of pro-
fessional skills (Radlowski and Johnson 2013; Jáuregui-
Lobera 2014). The importance of iron deficiency and IDA
raises multiple discussions and determines the need for clini-
cal and economic studies devoted to treatment and prevention
with iron supplementation or increased intake of dietary iron
in pregnant women and children of early age (Larson et al.
2017). Deficiency of other trace elements, like zinc, selenium,
and copper, as well as folic acid and vitamins A and C in
addition to iron deficiency, plays a role in the development
of cognitive impairment and psychomotor disorders. It is cru-
cial to consider the fact that iron deficiency will lead to en-
hancing or suppressing absorption of other essential trace el-
ements. Therefore, the management of iron deficiency among
Reduced IQ
Decreased
fine motor
skills
GDD and/or
ASD
Poor
concentration
Reduced
school
achievements
Low wages
GDP losses
DALY losses

high-risk populations such as pregnant mothers and young
children should be considered carefully to prevent any subse-
quent adverse effects on health. Even though many studies
included in this review have a methodological difference,
the evidence exists that micronutrient supplementation (in-
cluding iron) improves cognitive functions in children.
There is a need to carry out more high-quality prospective
placebo-controlled trials to develop and successfully imple-
ment effective intervention programs to combat nutritional
and micronutrient deficiencies, as well as to address the prob-
lems faced by the children with deficiencies of iron and trace
elements.
Author Contributions All authors confirmed they have contributed to the
intellectual content of this paper and have met the following three require-
ments: (a) significant contributions to the conception and design, acqui-
sition of data, or analysis and interpretation of data; (b) drafting or revis-
ing the article for intellectual content; and (c) final approval of the pub-
lished article.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Publisher’s Note Springer Nature remains neutral with regard to juris-
dictional claims in published maps and institutional affiliations.
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