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Effect of Chronic Iron Deficiency on Neuropsychological Domains in Infants

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 Journal http://jcn.sagepub.com/
of Child Neurology

Effect of Chronic Iron Deficiency on Neuropsychological Domains in Infants

Beatriz Beltrán-Navarro, Esmeralda Matute, Edgar Vásquez-Garibay and Daniel Zarabozo
J Child Neurol published online 29 August 2011
DOI: 10.1177/0883073811416867

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Original Article
Journal of Child Neurology
000(00) 1-7
Effect of Chronic Iron Deficiency on ª The Author(s) 2011
Reprints and permission:
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Neuropsychological Domains in Infants DOI: 10.1177/0883073811416867
http://jcn.sagepub.com

Beatriz Beltrán-Navarro, MSc1, Esmeralda Matute, PhD1,

Edgar Vásquez-Garibay, PhD2, and Daniel Zarabozo, PhD1

Abstract
The aim of this study was to assess the effects of chronic iron deficiency on neuropsychological traits in infants. We established
the nutritional iron status and assessed the neuropsychological characteristics of 58 Mexican 14- to 18-month-old infants. The
Bayley Scales of Infant Development, preschool language scales and an environmental sound perception task designed expressly
for the study, were used. The infants’ mothers were asked to fill out 2 questionnaires concerning their child’s sociodemographic
background. Six different neuropsychological domains were analyzed. Results showed that the chronic iron deficiency group did
show significantly lower scores on language, environmental sound perception, and motor measures, when compared with infants
with normal nutritional iron status at 6 and 14 to 18 months. Our conclusion is that the development of language and motor skills
and environmental sound perception appeared to be sensitive to the effects of chronic iron deficiency in infants.

Keywords
iron deficiency, neuropsychological development, infants, anemia

Received June 2, 2011. Accepted for publication June 19, 2011.

Iron deficiency is the most prevalent childhood nutritional
disorder worldwide.1,2 It can be related to such factors as a diet
low in iron, impaired intestinal iron absorption, and parasitic
infections. Since iron intervenes in numerous metabolic pro-
cesses, including oxygen transportation, adenosine triphosphate
production, metabolism of neurotransmitters, DNA synthesis,
and myelin production, several health processes could be affected
in children who have a low concentration of this element. Iron
deficiency is classified in 3 stages: (1) iron depletion, a decrease
in the normal reserve that has no functional consequences; (2) iron
deficiency without anemia, biochemical changes reflected in the
normal seric ferritin reserve; and, (3) iron deficiency anemia, sub-
normal concentrations of seric ferritin and hemoglobin.
Previous findings related to the effects of iron deficiency with-
out anemia on cognitive development in infants are inconsistent.
Some studies indicate no association, but low performance
scores on the Bayley scales of infant development3; whereas oth-
ers have found lower performance among infants on the mental,4
motor,5 and behavioral6 tests included in those scales. In more
recent studies, an adverse effect of iron deficiency without anemia
on motor development has been reported more consistently, based
on observations of motor activity at home7 and using motor devel-
opment assessment tools such as the Peabody Developmental
Motor Scale, the infant neurological international battery, and
the Bayley behavioral rating scale; or through more informal
assessments of the gross motor development milestones and a
sequential/bi-manual coordination toy retrieval task.8
With respect to iron deficiency anemia, study results are
more consistent and show a broader cognitive, motor and beha-
vioral impairment in infants. However, they cannot be consid-
ered conclusive. Several studies of infants indicate that iron
deficiency anemia is associated with significantly lower perfor-
mances on the mental,3,4,9-12 motor,4,9,10,12 and behavioral
tasks3,11,12 included in the Bayley Scales of Infant Development,
the Denver Developmental Screening Test,4 in observations of
motor activity recorded in the home,7 in a motor development
assessment battery,8 and in behavioral observations measuring
the duration and frequency of free play in both the labora-
tory13,14 and at home.14 In addition, the functional isolation
hypothesis has been explored in infants with iron deficiency
anemia. This hypothesis, derived from research on general-
ized undernutrition, holds that a decrease in the activity of
malnourished infants leads them to seek less stimulation from
their physical and social environments. In response to the
1
Instituto de Neurociencias, Universidad de Guadalajara, Guadalajara, Jalisco,
Mexico
2
Instituto de Nutrición Humana, Universidad de Guadalajara, Guadalajara,
Jalisco, Mexico
Corresponding Author:
Esmeralda Matute, PhD, Universidad de Guadalajara, Instituto de Neurociencias,
Francisco de Quevedo 180, C.P. 44130, Guadalajara, Jalisco, Mexico
Email: ematute@cencar.udg.mx

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2 Journal of Child Neurology 000(00)
infants’ behavior, caregivers thus tend to offer less stimula-
tion. Over time, these altered behavior patterns can impede
the child’s normal acquisition of environmental information
and adversely affect her/his development.14
Although existing studies of the effects of chronic iron defi-
ciency on infant abilities are few, some have found significantly
lower scores on the Bayley mental3,10,12 and motor12 scales in
infants who have been affected by iron deficiency anemia for
more than 3 months. As we have seen, most of those studies used
standardized developmental tests, such as the Bayley scales, and
took global scores as the principal measure of outcomes.3,4,9-12
Few, however, have done analyses of specific items related to
language,12,15 attention,16 recognition memory,16,17 object per-
manence,17 and gross motor development.7,8,10,12,18
In this study, the effects of chronic iron deficiency on neu-
ropsychological traits were assessed in 14- to 18-month-old
infants who had been diagnosed with iron deficiency 1 year
earlier. To evaluate them, we used Aylward’s general neuro-
psychological design19 for early neuropsychological assessment.
Our hypothesis was that, even at such an early age, the effects of
chronic iron deficiency on neuropsychological development
would be detectable, but that no underperformance would be
found when infants at this age (14 to 18 months) presented iron
deficiency for the first time.
Methods
Selection and Description of Participants
Subjects were recruited from a previous study20 (n ¼ 154) conducted
at ‘‘Doctor Juan I. Menchaca’’ Civil Hospital in Guadalajara, Jalisco,
Mexico. In Monterrosa et al20 research, infants were followed from
birth to 6 months in a nutritional evaluation. We invited all parents
of Monterrosa et al20 sample that could be reached by telephone or
at home when their infants were 14 to 18 months old. A total of
74 families were contacted (48%), as the rest were no longer living
at the addresses recorded for the earlier study, but of those 74 only
58 mothers (38% of the total of Monterrosa et al20 sample) gave their
written consent for the blood venipuncture test required to determine
their infants’ current nutritional iron status (serum ferritin and hemo-
globin), and for the neuropsychological assessment. The Ethics
Committee/Institutional Review Boards of the Instituto de Neuro-
ciencias (Neuroscience Institute) at Universidad de Guadalajara
(University of Guadalajara) and the ‘‘Doctor Juan I. Menchaca’’
Civil Hospital approved the study design.
The inclusion criteria for Monterrosa et al20 study were: first or
second child, physiological gestation 37 weeks, birth weight
2500 grams, no perinatal pathology, no congenital malformations
or genetic alterations, no prenatal infections, Apgar 7 at 5 minutes,
and no chronic illness or neonatal hypoxia sequelae. Mothers’ ages
ranged from 18 to 33 years (mean, 25.5 years) and no iron deficiency,
with or without anemia, had occurred during their pregnancies. The
infants had been given a blood venipuncture test at 6 months to verify
their nutritional iron status (seric ferritin and hemoglobin concentra-
tion) but no neuropsychological assessments were conducted at that
time, nor were their developmental milestones registered. All the
infants that presented iron deficiency with or without anemia at that
time received oral iron therapy (daily doses of 15 mg/kg of ferrous
sulfate for 2 months).
The diagnostic biochemical criteria used by the previous study20
and in this study, were those proposed by the World Health Organiza-
tion2: for the normal iron nutritional status group, hemoglobin (grams
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per deciliter) 11 and seric ferritin (micrograms per liter) 12; for the
iron deficiency without anemia group, hemoglobin (grams per decili-
ter) 11 and seric ferritin (micrograms per liter) <12; and for the iron
deficiency anemia group, hemoglobin (grams per deciliter) <11 and
seric ferritin (micrograms per liter) <12. The hospital’s laboratory
determined the concentrations of serum ferritin using immunoab-
sorbent assay, while hemoglobin concentrations were measured using
an automated blood cell counter.
In this study, 58 infants aged 14 to 18 months were included.
According to their iron nutritional status, the infants were grouped as
follows: normal iron nutritional status, n ¼ 30; iron deficiency without
anemia, n ¼ 17; iron deficiency anemia, n ¼ 9; iron deficiency without
hemoglobin value n ¼ 2. No significant sociodemographic differences
were found among these groups. In all 4 groups, the majority of the
infants were boys, while the caregiver was most often the mother. Most
of the children were living with both parents; the majority of the fathers
were employees, while the mothers were homemakers. Mean parents’
age and parents’ number of years of schooling were also similar among
groups (Table 1).
To determine the effect of chronic iron deficiency (the presence of
iron deficiency on both blood tests: at ages 6 and 14–18 months) on
cognitive development, our main objective, 2 groups were subse-
quently formed on the basis of the presence or absence of chronic iron
deficiency at both ages tested: thus, group 1 included 25 infants that
presented normal iron nutritional status at 6 and 14–18 months (here-
inafter the always normal iron nutritional status group), while group 2
was made up of 6 infants that presented iron deficiency with or with-
out anemia at both 6 and 14–18 months (hereinafter the chronic
iron deficiency group). In the latter group, 1 infant presented iron
deficiency without anemia at both ages, 3 infants showed iron defi-
ciency without anemia at 6 months and iron deficiency anemia at
14–18 months, and 2 infants had iron deficiency without anemia at
6 months and presented iron deficiency but lacked the hemoglobin
value at 14–18 months old. No significant sociodemographic dif-
ferences were found between the 2 groups (Table 2). Twenty-
seven infants were not taken into account in the second analysis,
as 15 of them presented a disparity between the iron concentration
results on the 2 blood tests. Of the remaining 12 infants, 5 pre-
sented anemia without iron deficiency at 6 months, and no seric
ferritin or hemoglobin values were available for 7 of them at age
6 months.
Assessment
Each child was assessed using the following tests:
(1) The Bayley Scales of Infant Development.21 This test was used
to measure the mental and motor development and to evaluate the
behavior of the infants. Mental, motor, and behavioral standard scores
were computed.
(2) Preschool language scales22 were used to measure receptive
and expressive language ability. Three raw scores related to auditory
comprehension, expressive communication and total language were
taken into account. We used the raw scores because this test has not
been extensively used in Mexican populations so no normative data
is available for the country.
(3) An environmental sound perception task designed expressly
for this study to evaluate the infants’ ability to identify nonverbal
auditory stimuli. Ten physical toys or objects (dog, bird, telephone,
rooster, car, crying baby, rattle, keys, cat, train) and the recordings
(5 seconds each) of their respective sounds were used: dog bark-
ing, bird singing, telephone ringing, rooster crowing, car starting,
baby crying, rattle shaking, keys moving, cat meowing, and train
whistling. The 10 objects were placed together in front of the
child, who was then asked to listen to the sounds one-by-one and
point to the object that was related to it. One point was given for
each correct match, so the maximum score was 10. Before using
this task in this study, 14 sounds were pretested with a pilot group
Beltrán-Navarro et al 3

Table 1. Sociodemographic Characteristics of Groups Aged 14 to 18 Months

NINS n¼30 ID Without Anemia n¼17 IDA n¼9 ID Without Hemoglobin Value n¼2 w2 P
Categorical variables
Gender, no. of boys 17 10 4 1 0.55 .90
Caregiver, % mother 83.33 76.47 77.77 50 1.43 .69
People living with the child, % both 80 76.47 88.88 50 1.64 .65
parents
Parents’ marital status, % 46.66 41.17 22.22 0 3.09 .37
cohabitation
Fathers’ occupation, % employee 93.33 100 88.88 100 1.82 .61
Mothers’ occupation, % homemaker 70 76.47 77.77 100 1.07 .78
Continuous variables: means, standard deviation
NINS n¼30 ID without anemia n¼17 IDA n¼9 ID without hemoglobin value n¼2 K P
Infants’ age in months 15.67 (1.26) 16.17 (1.27) 15.98 (1.81) 14.22 (0) 0.93 .62
Fathers’ age in years 26.20 (4.90) 26.35 (5.06) 26.67 (2.91) 22.50 (2.12) 0.59 .74
Mothers’ age in years 23.33 (3.49) 23.18 (3.12) 23.22 (2.90) 21 (1.41) 0.02 .98
Fathers’ schooling in years 9.20 (3.54) 9.75 (2.86) 8.56 (2.55) 7.50 (2.12) 0.97 .61
Mothers’ schooling in years 9.87 (3.24) 9.71 (3.36) 8.89 (3.25) 9 (4.24) 1.94 .37

Abbreviations: NINS, normal iron nutritional status group; ID without anemia, iron deficiency without anemia group; IDA, iron deficiency anemia group; ID with-
out hemoglobin value, iron deficiency without hemoglobin value group.

Table 2. Sociodemographic Characteristics of Groups at 6 and 14 to wing. Each child’s mother was present in the room throughout the
18 Months Old evaluation process. It is important to note that this was a blind study,
so the psychologist in charge of assessing the infants had no knowl-
Always NINS Chronic ID edge of their iron nutritional status. The assessment sessions lasted
n¼25 n¼6 w2 P 2 hours. Finally, the blood venipuncture process was carried out by
a trained pediatric nurse on the same day as the neuropsychological
Categorical variables assessment, but in a different room. The psychologist was not present.
Gender, no. of boys 13 2 0.67 .65
Caregiver, % mother 88 66.66 1.62 .20
People living with the 84 66.66 0.93 .33
child, % both parents
Statistics
Parents’ marital status, 48 16.66 1.95 .16 All data were analyzed using the Statistical Package for the Social
% cohabitation Sciences (SPSS) for Windows, release 11.5.0.23 Standard scores
Fathers’ occupation, 92 100 0.51 .47 for the Bayley Scales of Infant Development and raw scores for
% employee the preschool language scale were obtained. Later, the raw scores
Mothers’ occupation, 76 83.33 0.14 .70 from the tasks included in the tests were converted into percen-
% homemaker tages and arranged in 6 neuropsychological domains: environmen-
Continuous variables: means, standard deviation tal sound perception, receptive language, expressive language, fine
Always Chronic ID U P motor abilities, gross motor abilities, and executive function
NINS n¼25 n¼6 (namely, A-not-B, problem solving, and tool use) following the
Infants’ age in months 15.65 (1.27) 15 (1.37) 44.50 .12 general neuropsychological design proposed by Aylward19 for
Fathers’ age in years 26.20 (5.24) 23.50 (2.34) 54.50 .30 early neuropsychological assessment. Cronbach a analysis was
Mothers’ age in years 23.20 (3.48) 22.67 (4.32) 60 .44 then applied and found internal consistency reliability among the
Fathers’ schooling in years 8.64 (2.81) 8.83 (1.94) 74 .95 items in each 1 of the 6 neuropsychological domains, as follows: envi-
Mothers’ schooling in 9.52 (2.97) 10 (4.42) 72 .87 ronmental sound perception, a (0.6727); receptive language,
years a (0.7809); expressive language, a (0.7650); fine motor abilities,
a (0.5541); gross motor abilities, a (0.7579); and executive function,
Abbreviations: Always NINS, always normal iron nutritional status group; a (0.6320).
Chronic ID, chronic iron deficiency group. Two analyses were carried out, the first included n ¼ 56 infants
divided into 3 groups: (1) normal iron nutritional status, n ¼ 30; (2)
iron deficiency without anemia, n ¼ 17; and, (3) iron deficiency ane-
mia, n ¼ 9. In the second analysis (n ¼ 31), 2 groups were compared:
group 1 was the always normal iron nutritional status, n ¼ 25; and
of 26 infants (10 girls, 16 boys) aged 14 to 22 months (mean, 16 group 2 was the chronic iron deficiency, n ¼ 6.
months), used to assess the adequacy of this task for this age The categorical variables were analyzed using chi square, while the
range. A mean of 5 (standard deviation 2.36) correct answers was continuous variables were examined with the Mann Whitney-U test
obtained. Ten of the 14 sounds were chosen, as the other 4 proved for the 2 groups, and the Kruskal-Wallis test for the 3 groups. The
difficult to identify at this age. level of significance was set at P  .05.
Evaluations of the infants and interviews with their mothers were Because we had only 2 small groups for the second analysis, we
all conducted by the first author in a spacious, well-lit room, free of used not only statistical significance to evaluate the results, but also
distractions, in ‘‘Doctor Juan I. Menchaca’’ Civil Hospital’s nutrition strengthen the statistical analysis by applying the effect size of

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4 Journal of Child Neurology 000(00)

Table 3. Assessment Scores, Means, and Standard Deviationa

NINS n¼30 ID Without Anemia n¼17 IDA n¼9 K P

Bayley Scales of Infant Development: standard scores
Mental 96.60 (9.94) 94.29 (12.98) 94.44 (19.09) 0.44 .79
Motor 111.67 (10.20) 110 (9.40) 107.89 (10.38) 0.82 .66
Behavioral 55.63 (26.52) 55.76 (26.97) 47.89 (42.56) 0.20 .90
Preschool language scale: raw scores
Auditory comprehension 22.30 (1.74) 22.35 (1.27) 22.33 (0.86) 1.23 .53
Expressive communication 22.53 (2.81) 22.41 (3.39) 21.67 (3.24) 0.70 .70
Total language 44.83 (3.83) 44.76 (3.88) 44 (3.74) 0.54 .76
Neuropsychological domains: raw scores converted to % of correct answers
Environmental sound perception 44.67 (24.17) 39.41 (19.51) 23.33 (18.02) 5.34 .06
Receptive language 60.58 (17.75) 56.39 (17.15) 56.85 (13.15) 1.53 .46
Fine motor abilities 54.17 (13.39) 52.94 (11.46) 50 (7.07) 1.34 .50
Gross motor abilities 65.34 (15.82) 65.22 (8.67) 61.11 (18.95) 0.63 .72
Expressive language 47.50 (18.32) 45 (19.28) 39.44 (19.43) 1.41 .49
Executive function 80 (22.28) 69.41 (33.25) 66.66 (31.62) 1.70 .42

Abbreviations: NINS, normal iron nutritional status group; ID without anemia, iron deficiency without anemia group; IDA, iron deficiency anemia group.
a
Standard deviations are presented within parentheses.

Spearman r2 (squared r), a standardized, objective measure of
the magnitude of an observed effect.
Results
In the first analysis, no differences among groups were found
(Table 3).
The second analysis compared the scores obtained by the
always normal iron nutritional status group (n ¼ 25) with those
of the chronic iron deficiency group (n ¼ 6). This comparison
showed that the latter had achieved significantly lower scores
on the Bayley motor scale, in expressive communication, and
on the total language subscale of the preschool language scale.
Later analysis of the neuropsychological domains showed that
the chronic iron deficiency group had lower scores than the
always normal iron nutritional status group on environmental
sound perception, receptive language, gross motor abilities and
expressive language. To reinforce the statistical analysis,
Spearman r2 (r squared) was applied to measure the effect size
of chronic iron deficiency. This measure showed an effect of
medium size, per Cohen,24 for environmental sound perception
and expressive language; an effect larger than small size, also
per Cohen,24 was evident in the scores for receptive language
and gross motor abilities (Table 4). It is worthwhile to note the
importance of our findings of the effect size, since the analysis
was conducted with such a small sample.
Discussion
The main aim of this study was to ascertain if an early chronic iron
deficiency effect on cognitive, motor, and behavioral develop-
ment is observable when infants are 14 to 18 months old.
The first analysis was conducted to determine whether iron
deficiency presented for the first time at 14 to 18 months of age
affects neuropsychological development, but the comparison of
3 groups of infants (normal iron nutritional status, iron
deficiency without anemia, and iron deficiency anemia)
showed no differences among them.
Previous studies of infants have reported negative effects of
iron deficiency anemia on scores attained on the Bayley mental
scale,3,4,9,10-12,15 the Denver Developmental Screening Test,4 and
the Bayley motor scale.4,9,10,12 Moreover, those studies have
observed certain behavioral peculiarities that led to the infants
studied being characterized as fearful,3 insecure,3,14 unhappy,14
cautious,3,11 less active, indecisive, less participatory, irritable,
less attentive,12,14,25 with tendencies to isolation,14,25 and difficult
to calm once angry or upset (eg, after crying).25
In contrast, findings for iron deficiency without anemia
groups have been inconclusive, neither entirely consistent nor
coincident. On the 1 hand, Lozoff et al3 found that iron defi-
ciency without anemia is not associated with low scores on
developmental tests, nor with behavioral alterations, and that
only the iron deficiency anemia condition affects cognitive,
motor and behavioral development in infants. Similarly, Dei-
nard et al6 reported no differences between infants with moder-
ate and severe iron deficiency without anemia compared with a
normal iron nutritional status group, though variations in their
behavioral characteristics were seen. Finally, Oski et al26 iden-
tified only a trend toward lower scores on the Bayley mental
scale in the iron deficiency without anemia group.
Contrary to those results, Akman et al4 and Baptista-
González et al5 found that iron deficiency without anemia does
indeed affect cognitive development, and that its effect is
already evident during infancy. Moreover, this latter work5
pointed out that the degree of cognitive impairment increases
with the severity of the iron deficiency condition.
The fact that we found no differences among groups can be
related to the similarity of the sociodemographic context and
perinatal background of the 3 groups included in our study (see
Methods, and Table 1).
Indeed, several of the studies that found an effect of iron defi-
ciency anemia on cognitive, motor, or behavioral development

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Beltrán-Navarro et al 5

Table 4. Assessment Scores, Means, and Standard Deviationa

Always NINS n¼25 Chronic ID n¼6 U P Spearman r2

Bayley Scales of Infant Development: standard scores
Mental 97.04 (8.96) 94.67 (17.09) 68.00 .72 0.004
Motor 112.72 (10.58) 102.50 (7.06) 32.00 .03* 0.155
Behavioral 56.40 (27.37) 33.67 (32.51) 44.50 .12 0.077
Preschool language scale: raw scores
Auditory comprehension 22.32 (1.65) 22 (0.89) 53.00 .25 0.044
Expressive communication 22.92 (2.73) 19.83 (1.47) 22.00 .007* 0.239
Total language 45.24 (3.81) 41.83 (1.47) 38.00 .01* 0.187
Neuropsychological domains: raw scores converted to % of correct answers
Environmental sound perception 44.40 (24.84) 10 (15.49) 18.00 .004* 0.300
Receptive language 60.93 (17.71) 47.05 (8.31) 33.00 .03* 0.150
Fine motor abilities 55.40 (13.06) 45 (7.07) 39.50 .07 0.107
Gross motor abilities 65.91 (16.16) 48.88 (19.06) 36.00 .04* 0.140
Expressive language 49.80 (17.99) 29.16 (7.35) 19.50 .005* 0.300
Executive function 78.40 (23.03) 63.33 (34.44) 57.00 .34 0.030

Abbreviations: Always NINS, always normal iron nutritional status group; Chronic ID, chronic iron deficiency group.
a
Standard deviations are presented within parentheses.
*P < .05.

have also identified an association between iron deficiency ane-
mia and certain demographic differences,10 including family
composition,3,10 the intellectual and educational characteristics
of mothers (lower intelligence quotient,10 fewer years of school-
ing3,12), and some personality traits of the infants themselves
(eg, higher timidity).17
It is important to mention that the World Health Organiza-
tion2 reported a disparity in the prevalence of iron deficiency
without anemia/iron deficiency anemia in preschool children
between developed (10%–20%) and developing countries
(30%–80%). The differences in the prevalence of iron defi-
ciency without anemia/iron deficiency anemia between these
types of countries could be related to variations in the socio-
economic and cultural background that characterized each one.
Thus, the association between iron deficiency (with or with-
out anemia) and socioeconomic indicators of poverty can
represent confounding variables for interpreting the effect of
iron deficiency (with or without anemia) on psychomotor devel-
opment, because when family and biological variables are con-
trolled for, the effect of iron deficiency (with or without anemia)
decreases, as in our study. It is important to consider that risk
factors do not normally occur in isolation and that a combination
of a larger number of such factors increases the probability
that infants will achieve lower scores in cognitive, motor,
or behavioral development.
The second analysis was conducted to explore our main
objective; that is, to determine whether early chronic iron defi-
ciency affects cognitive, motor, and behavioral development.
One unpredicted finding was that at 6 months of age, 7 infants
presented iron deficiency and at 14 to 18 months, 6 of those chil-
dren still had that deficiency, despite having received oral iron
therapy (daily doses of 15 mg/kg of ferrous sulfate for 2 months).
The literature contains reports that between 36%10 and
57.89%12 of infants with moderate iron deficiency anemia fully
corrected their iron and hemoglobin values after receiving
3 months of iron supplementation. Treatment failure found in this
study can be related to the discontinuation or irregular administra-
tion of treatment, as Mexico has a high incidence of interruptions
of therapeutic treatments for various diseases (55.5%–60%),
especially chronic ones, complex treatments, treatments of more
than 7 days’ duration, and in pediatric patients.27
Concerning the comparison of the task scores between the
2 groups, infants with chronic iron deficiency underperformed
the always normal iron nutritional status group on 4 of the
6 neuropsychological domains that were assessed: environ-
mental sound perception, gross motor, receptive language, and
expressive language. It is noteworthy that the scores achieved
on the scales used to evaluate these 2 groups all fell within the
normal range, a pattern that has been observed in other stud-
ies.4,10,12 According to the World Health Organization,2 infants
that presented iron deficiency will have a delay in their psycho-
motor development, and when they reach school age they will
show impaired performance in tests related to language, motor
skills, and coordination, equivalent to a 5- to 10-point deficit in
intelligence quotient. However, to our knowledge, mental defi-
ciency in those children has never been reported.
Lozoff et al3,10 and Walter et al12 already reported a negative
effect of chronic iron deficiency (3 months) on cogni-
tive,3,10,12 motor12 and language12 development in infants. Upon
doing follow-up on their samples, they found that this effect was
still observable in school performance during childhood and
even adolescence.28-32
In infancy, language and motor skills undergo rapid deve-
lopment, while in this same period we also see advances in
other cognitive domains; for example, executive functions.
While our study found no differences in the tasks related to exec-
utive functions (A-not-B, problem solving, tool use), Carter
et al17 reported lower scores on the object permanence task,
though not on the A-not-B test, in infants from 9 to 10 months
with iron deficiency anemia. In general, greater variability in

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6 Journal of Child Neurology 000(00)
the expression of cognitive development is characteristic of
younger age groups when a cognitive domain is just beginning
to develop; thus, our results suggest that at the ages we studied,
it is too early to perceive the effects of chronic iron deficiency on
functions that attain higher levels of development later in life,
such as executive functions. Hence, we would expect that the
effects of chronic iron deficiency on those functions would
appear at more advanced ages, so longitudinal studies covering
a wider age range are needed to assess the effect of infantile
chronic iron deficiency on executive functions.
During the last trimester of pregnancy and the first 2 years of
postnatal life, rapid brain growth occurs. This is called a
‘‘growth spurt,’’ a period in which the central nervous system
is extremely vulnerable to nutritional deficiencies. Although
there is a greater chance of recovery in early stages of develop-
ment, it is probable that in these stages chronic iron deficiency
does affect brain plasticity significantly and its effects would
appear primarily in a lag in language and motor development.
At older ages, the effects of iron deficiency might be mani-
fested in other, more complex, and sophisticated cognitive
functions.
In conclusion, our study has produced 4 main findings. First,
we found that almost all the infants that presented iron defi-
ciency at 6 months still had it at 14 to 18 months. Second,
chronic iron deficiency has an effect on cognitive and motor
development that is evident during infancy and expressed in
poor performance on tasks related to language, motor abilities
and environmental sound perception. Third, no effect of
nonchronic iron deficiency was evident, suggesting that when
iron deficiency is nonchronic it has adverse effects on a child’s
neuropsychological development only when combined with
certain environmental and biological variables. This could
explain the fact that, in some studies, nonchronic iron defi-
ciency is related to low scores. Finally, the observable effect
of the actual scores achieved were all within the broad range
of normal; from a neurodevelopmental perspective none would
be considered significantly delayed or justify a developmental
diagnosis at this moment of development. However, evaluating
other aspects that can be examined at older ages, such as
mathematics skills, reading, memory, attention, and executive
functions could reflect a greater impact on cognition. Thus, the
results for the age group studied in this research cannot be
generalized to other cohorts, due to the absence of cognitive
functions that only become evident later in life. Longitudinal
studies over a wider age range can provide information on
changes in the manifestations of the effects of chronic iron defi-
ciency on neuropsychological development in relation to the
age of children.
Acknowledgments
The authors gratefully acknowledge Jissela Alfaro from the Instituto
de Nutrición Humana (Human Nutrition Institute) of Universidad de
Guadalajara (University of Guadalajara), in Guadalajara, Jalisco,
Mexico, for her assistance in recruiting the participants. We thank the
nurses and laboratory assistants at the ‘‘Doctor Juan I. Menchaca’’ Civil
Hospital in Guadalajara, Jalisco, Mexico, for performing the
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venipuncture blood process and determining the infants’ iron nutri-
tional status. We are very grateful to the infants and their parents for
their voluntary participation in the study. Research was carried out at
the Instituto de Neurociencias (Neuroscience Institute) of Universidad
de Guadalajara (University of Guadalajara), the Instituto de Nutrición
Humana (Human Nutrition Institute) of Universidad de Guadalajara
(University of Guadalajara) and the ‘‘Doctor Juan I. Menchaca’’ Civil
Hospital, in Guadalajara, Jalisco, México. Some sections of this article
were presented at the International Neuropsychological Society’s Mid-
year Meeting in 2008.
Author Contributions
The details of each author’s contribution to the study are as follows:
BB-N: This research was for her MSc thesis. She contacted partici-
pants’ mothers, evaluated the subjects, built the databases, did the sta-
tistical analysis and literature search, and prepared the first draft and
amendments to the text. EV-G: A pediatrician with a PhD in nutrition,
he served as the nutritional expert. He was the coordinator of the Mon-
terrosa et al20 study, and provided information from that work, as well
as space in the ‘‘Doctor Juan I. Menchaca’’ Civil Hospital’s nutrition
wing. Finally, he made arrangements with the hospital’s laboratory for
the analyses of the infants’ iron nutritional status. DZ was the statisti-
cal analysis expert for the study. He provided advice and reviewed the
Methodology and Statistical Analysis sections of the study. EM was
the Project Director, participated actively in all aspects of the work,
and contributed directly to the article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
Ethical Approval
Participants’ mothers gave their written consent for both the blood
venipuncture test required to determine their infants’ current nutri-
tional iron status (seric ferritin and hemoglobin), and the neuropsycho-
logical assessment. The Ethics Committee/Institutional Review
Boards of both the Instituto de Neurociencias (Neuroscience Institute)
at the Universidad de Guadalajara (University of Guadalajara) and the
‘‘Doctor Juan I. Menchaca’’ Civil Hospital approved the study design.
References
1. UNICEF, WHO. Prevention and Control of Iron Deficiency Anemia
in Women and Children. Geneva, Switzerland: UNICEF/WHO;
1999.
2. WHO. Iron Deficiency Anaemia: Assessment, Prevention, and Con-
trol a Guide for Programme Managers. Geneva, Switzerland:
WHO; 2001.
3. Lozoff B, Wolf AW, Jimenez E. Iron-deficiency anemia and infant
development: effects of extended oral iron therapy. J Pediatr.
1996;129:382-389.
4. Akman M, Cebeci D, Okur V, et al. The effects of iron deficiency
on infants’ developmental test performance. Acta Paediatr. 2004;
93:1391-1396.
Beltrán-Navarro et al
5. Baptista-González HA, Rosenfeld F, Ramı́rez A, et al. Diferencias
en el crecimiento y neurodesarrollo en el lactante menor deficiente
de hierro no anémico. Bol Med Hosp Infant Mex. 2004;61:9-18.
6. Deinard A, Gilbert A, Dodds M, Egeland B. Iron deficiency and
behavioral deficits. Pediatrics. 1981;68:828-833.
7. Olney D, Pollitt E, Kariger P, et al. Young Zanzibari children with
iron deficiency, iron deficiency anemia, stunting, or malaria have
lower motor activity scores and spend less time in locomotion.
J Nutr. 2007;137:2756-2762.
8. Shafir T, Angulo R, Jing J, et al. Iron deficiency and human motor
development. Early Hum Dev. 2008;84:479-485.
9. Idjradinata P, Pollitt E. Reversal of developmental delays in iron
deficient anemic infants treated with iron. Lancet. 1993;341:1-4.
10. Lozoff B, Brittenham GM, Wolf AW. Iron deficiency anemia and
iron therapy: effects on infant developmental test performance.
Pediatrics. 1987;79:981-995.
11. Walter T, Kovalskys J, Stekel A. Effect of mild iron deficiency on
infant mental development scores. J Pediatr. 1983;102:519-522.
12. Walter T, de Andraca I, Chadud P, Perales CG. Iron deficiency
anemia: adverse effects on infant psychomotor development.
Pediatrics. 1989;84:7-17.
13. Lozoff B, Klein N, Prabucki KM. Iron-deficient anemic infants at
play. J Dev Behav Pediatr. 1986;7:152-158.
14. Lozoff B, Klein N, Nelson E, et al. Behavior of infants with iron
deficiency anemia. Child Dev. 1998;69:24-36.
15. Lozoff B, Brittenham GM, Viteri E, et al. Developmental deficits
in iron-deficient infants: effects of age and severity of iron lack.
J Pediatr. 1982;101:948-952.
16. Burden M, Westerlund A, Armony-Sivan N, et al. An event related-
potential study of attention and recognition memory in infants with
iron deficiency anemia. Pediatrics. 2007;120:336-345.
17. Carter RC, Jacobson JL, Burden M, et al. Iron deficiency anemia
and cognitive function in infancy. Pediatrics. 2010;126:427-434.
18. Kariger P, Stoltzfus R, Olney D, et al. Iron deficiency and phys-
ical growth predict attainment of walking but not crawling in
poorly nourished Zanzibari infants. J Nutr. 2005;135:814-819.
19. Aylward GP. Infant and Early Childhood Neuropsychology. New
York, NY: Plenum Press; 1997.
Downloaded from jcn.sagepub.com at SAGE Publications on September 7, 2011
View publication stats
7
20. Monterrosa E, Frongillo E, Vásquez-Garibay E, et al. Predomi-
nant breast-feeding from birth to six months is associated with
fewer gastrointestinal infections and increased risk for iron defi-
ciency among infants. J Nutr. 2008;138:1499-1504.
21. Bayley N. In: Bayley Scales of Infant Development. 2nd ed. San
Antonio, TX: The Psychological Corporation; 1993.
22. Zimmerman IL, Steiner VG, Pond RE. In: Preschool Language
Scale. 4th ed. Spanish. San Antonio, TX: The Psychological
Corporation; 2002.
23. Statistical Package for the Social Sciences (SPSS) for Windows.
Rel. 11.5.0. Chicago, IL: SPSS Inc.; 2002.
24. Field A. Discovering statistics using SPSS. London, England:
Sage; 2009.
25. Lozoff B, De Andraca I, Castillo M, et al. Behavioral and devel-
opmental effects of preventing iron-deficiency anemia in healthy
full-term infants. Pediatrics. 2003;112:846-854.
26. Oski FA, Honig AS, Helu B, Howanitz P. Effect of iron therapy
on behavior performance in non-anaemic iron-deficient infants.
Pediatrics. 1983;71:877-880.
27. Reyes H, Guiscafré H, Muñoz O, et al. Factores asociados a
incumplimiento terapéutico y costo del desperdicio de antimicro-
bianos en infección respiratoria alta y diarrea aguda. Fármacos.
1998;1:10-13.
28. Lozoff B, Jimenez E, Hagen J, et al. Poorer behavioral and devel-
opmental outcome more than 10 years after treatment for iron
deficiency in infancy. Pediatrics. 2000;105:1-11.
29. Lozoff B, Jimenez E, Smith JB. Double burden of iron deficiency
in infancy and low socioeconomic status: a longitudinal analysis
of cognitive test scores to age 19 years. Arch Pediatr Adolesc
Med. 2006;160:1108-1113.
30. Lozoff B, Jimenez E, Wolf AW. Long-term developmental out-
come of infants with iron deficiency. N Engl J Med. 1991;325:
687-694.
31. Rivera F, Walter T. Efecto de la anemia ferropriva en el lactante
sobre el desarrollo psicológico del escolar. Rev Chil Pediatr.
1996;67:141-147.
32. Walter T. Impact of iron deficiency on cognition in infancy and
childhood. Eur J Clin Nutr. 1993;47:307-316.