Early Human Development 66 (2002) 67 – 79

www.elsevier.com/locate/earlhumdev

Spontaneous motor activity in human infants with

iron-deficiency anemia
R.M. Angulo-Kinzler a,b,*, P. Peirano c, E. Lin a,
M. Garrido c, B. Lozoff b
a
Division of Kinesiology, Center for Human Motor Research, University of Michigan, 401 Washtenaw Avenue,
Ann Arbor, MI 48109-2214, USA
b
Center for Human Growth and Development, University of Michigan, USA
c
Laboratory of Sleep and Functional Neurobiology, Institute of Nutrition and Food Technology (INTA),
University of Chile, Chile

Received 5 August 2000; received in revised form 24 December 2000; accepted 1 February 2001

Abstract

This study compared spontaneous motor activity in 6-month-old Chilean infants with or without
iron-deficiency anemia (IDA) who were otherwise healthy. Activity was assessed in conjunction
with polysomnographic recording during an afternoon nap in 11 infants with IDA and 15 with
normal hemoglobin levels. All infants were given oral iron, and activity was reassessed at 12 and 18
months. Using actigraphs placed on the ankle, the frequency of movement units per minute was
determined for each waking/sleep state. The total amount of time infants were in an alert – active state
before and after the nap was used to calculate the proportion of movements/minute of waking. There
were no differences between anemic and nonanemic infants in total recording time, duration of sleep,
or motor activity during sleep. However, infants with IDA showed reduced motor activity during
waking at all ages. The magnitude of the differences increased at 12 and 18 months. Thus, IDA was
associated with reduced motor activity in infants even after iron treatment. It will be important to
confirm these results in a larger sample and to determine the 24-h pattern of motor activity, since
reduced motor activity may limit infants’ opportunities to explore and learn from the social and
physical environment. D 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Iron-deficiency anemia; Spontaneous motor activity; Nonanemic infants

*
Corresponding author. Division of Kinesiology, Center for Human Motor Research, University of
Michigan, 401 Washtenaw Avenue, Ann Arbor, MI 48109-2214, USA. Tel.: +1-734-647-9851; fax: +1-734-936-
1925.
E-mail address: rangulo@umich.edu (R.M. Angulo-Kinzler).

0378-3782/02/$ - see front matter D 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 7 8 - 3 7 8 2 ( 0 1 ) 0 0 2 3 8 - 9
68 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79

1. Introduction

There is ample reason to suspect that iron-deficiency might alter spontaneous motor
activity in infants. In rodents, iron-deficiency anemia (IDA) has been reported to reduce
overall activity [1] and to alter the organization of its circadian pattern, including a total
reversal [2,3]. One study that systematically varied the timing of iron-deficiency during
early development also found that iron-deficient rats moved less in a home-orienting task
[4]. In the single study of motor activity in the iron-deficient primate—a small pilot project
involving juvenile monkeys, even mild iron-deficiency anemia dramatically decreased
running and playing [5]. In the adult human, iron-deficiency anemia and, in some cases,
iron-deficiency without anemia reduce maximal physical performance, submaximal
endurance, and work productivity (see reviews [6– 10]). In school-aged children, the
few published studies of iron-deficiency and motor activity report decreased activity [11 –
13]. Thus, evidence from animal models and studies of human children and adults
indicates that iron-deficiency alters motor activity.
However, there is little information on this question in the iron-deficient human infant.
The lack of research is striking, especially since infants and toddlers are among the groups
at highest risk for iron-deficiency. Furthermore, in infancy, physical activity plays
additional important roles in learning from the environment and in cognitive development
[14]. To date, the only observations of activity in iron-deficient anemic infants are
contained in a study of play behavior and mother – infant interaction. Using crude
measures of activity (crossing gridlines in a playroom, moving beyond arm’s length from
the mother, etc.), the study’s results suggested decreased activity [15].
The purpose of the present study was to assess the levels of spontaneous motor
activity in infants with and without IDA. This pilot study was conducted in Chile and
applied advanced methods of measuring activity in a controlled but ecologically valid
situation– activity immediately before and after an afternoon nap. We hypothesized that
IDA infants would demonstrate lower levels of motor activity compared to control
infants.
Infant health is generally excellent in Chile, but iron-deficiency on a dietary basis has
been common. Previous studies show that 27 –35% of Chilean infants, including those
solely breast fed, develop iron-deficiency anemia at 9– 18 months of age, and bio-
chemical evidence of iron-deficiency is present in 43 –65% [17,18]. Routine pediatric
care and infant feeding practices in Chile during this study did not include iron
supplementation.

2. Methods

2.1. Subjects

The activity study was conducted in Chile between 1991 and 1996 in conjunction with
the neurophysiological components of a larger study [16] on the behavioral and neuro-
maturational effects of iron-deficiency anemia in infancy. Infant activity could be
measured in only a subset of the infants, as funding limitations precluded activity
 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79 69

monitoring in all babies. Nonetheless, studying spontaneous motor activity with more
advanced techniques promised to provide new information about the effects of iron-
deficiency in human infants.
Potential study participants were identified during regular pediatric visits at community
clinics of the national health system in four contiguous working-class communities on the
southeastern outskirts of Santiago, Chile. At the 4-month clinic visit, infants were
evaluated to make sure that those considered for study participation were healthy, using
the following entrance criteria: birth weight
3.0 kg, singleton birth, no major congenital
anomalies, no major birth or neonatal complications, no emergency Caesarian section, no
jaundice requiring phototherapy, no hospitalization for other than an uncomplicated
problem, no chronic illness, no iron therapy, and no evidence on pediatric physical
examination of failure to thrive, specific nutrient deficiency, or other condition that could
interfere with development. Exclusion criteria were specific to successful completion of
the study: residence outside the identified neighborhoods; lack of a stable, literate
caregiver who was available to accompany the infant for project appointments; another
infant less than 12 months of age in the household; infant in day care [19].
Between 5 and 6 months, a finger-stick hemoglobin determination was performed
(HemoCue1, Leo Diagnostics, Helsingborg, Sweden [20]). For infants with a HemoCue
value < 103 g/l [10.3 g/dl], a venipuncture blood specimen was promptly obtained for
determination of iron status. The following measures were performed by the hematology
laboratory at Institute of Nutrition and Food Technology (INTA) University of Chile,
which is the reference laboratory for all of Chile and for other parts of South America:
hemoglobin, hematocrit, mean cell volume (MCV) (using Coulter Model ZBI, Hialeah,
FL) [21]; serum ferritin [22]; and erythrocyte protoporphyrin (EP) (Hematofluorometer,
Helena Laboratories, Beaumont, TX) [23]. Anemia at 6 months was defined as a venous
hemoglobin  100 g/l (10.0 g/dl) [24]. The level for the screening HemoCue value was
chosen to be somewhat higher to increase the chances that all infants with venous Hb
levels of 100 g/l (10.0 g/dl) or lower would be identified. Iron-deficiency was defined as
two or more iron measures in the deficient range (MCV < 70 fl [25], EP > 1.77 mmol/l
(100 mg/dl) red blood cells [26], serum ferritin < 12 mg/l [26]) and/or increase in
hemoglobin
10 g/l (1.0 g/dl) after 6 months of iron therapy [25]. These cut-offs for
anemia and iron measures were based on the consensus of the hematologists of the
project (T. Walter) and its External Advisory Committee (P. Dallman, F. Viteri, and R.
Yip), using normative data establishing levels approximately 2 SD from the mean for 5-
to 6-month-olds. For each iron-deficient –anemic infant, an infant with a normal Hemo-
Cue value was randomly selected to receive a venipuncture. Those who were clearly
nonanemic (Hb
115 g/l (11.5 g/dl)), regardless of iron status, constituted the compar-
ison group.
All infants in the study were treated orally for 1 year with 15 mg/day of elemental iron
as ferrous sulfate (Fer-in-Sol1). This dose was intended to be therapeutic for anemic
infants and prophylactic for nonanemic infants during the period between 6 and 12 months
and prophylactic for all infants thereafter. Adherence was monitored during weekly home
visits and monthly pediatric clinic visits. A venipuncture was repeated at 12 months to
determine response to therapy, using hemoglobin level and iron status measures. A finger-
stick hemoglobin level was obtained at 18 months to monitor maintenance of response.
70 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79

Project personnel and parents understood that all infants would receive oral iron, but
neither parents nor project personnel were informed of a child’s hematologic status until
study completion. All aspects of the study were explained to parents of qualifying infants,
and signed informed consent was obtained. The research protocol was approved by the
Institutional Review Boards of the University of Michigan Medical Center, Ann Arbor, of
INTA, University of Chile, Santiago, and of the Office of Protection from Research Risks,
NIH.
This report compares motor activity patterns in 11 infants who had iron-deficiency
anemia at 6 months with 15 infants who had normal hemoglobin levels. These were well-
nourished babies, whose growth was at the US 50 – 75th percentile, on average, both at
birth and upon entry into the study at 6 months. Their overall development was com-
parable to that of US infants.

2.2. Procedures

Assessments in the sleep laboratory were scheduled for the time when each infant was
usually fed just before an afternoon nap, based on parental report of the infant’s daily
routine. A familiar caregiver, generally the mother, remained with the infant throughout
the session. Infants were connected to monitoring equipment and then encouraged to
become comfortable in the laboratory during a midday meal. After feeding their infants,
caregivers settled the babies for a nap following their usual home routine. Recording
started at this point. All infants in this study fell asleep and woke up spontaneously. When
the caregiver determined that the infant was fully awake and ready to leave, the session
ended after at least 15 min of wakefulness.
Motor activity was measured by actigraphs (Ambulatory Monitoring). The actigraph is
a computerized activity monitor with a piezoelectric sensor sensitive to accelerations
above 0.01 g per rad/sec and an internal memory. The actigraph counted each detected
acceleration, digitizing and storing in memory the total number of accelerations –
decelerations (movement units) per 2-sec interval. Actigraphs were placed on the infants’
right ankles with a Velcro band. The weight and dimensions of this device are minimal
(56.7 gm, 4.45  3.3  0.97 cm) and do not interfere with infant actions. Concurrently, the
following activities were collected simultaneously throughout the session by means of a
polysomnograph (TECA 1A97): EEG, EOG, EMG, motor activity, ECG, airflow,
respiratory efforts, oximetry and temperature.
Assessments were performed before iron therapy (when infants were 6 months old and
newly identified as IDA or control) and after oral iron, at 12 and 18 months. A limited
number of actigraphs meant that all infants could not receive activity assessments at every
age point. Which infants received activity monitoring was solely determined by the
availability of activity devices. Not all actigraphic recordings were technically adequate,
and not all children came for the three assessments. Satisfactory recordings were available
for nine anemic and seven controls infants at 6 months, four anemic and 11 control
infants at 12 months, and six anemic and 11 control infants at 18 months. As only three
babies had good quality activity recordings at all three ages, the analyses reported here are
cross-sectional. There were no differences between children who did or did not have
activity data, or who did or did not complete the year in the study with respect to such
 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79 71

factors as gender, birth weight, growth, motor and mental test scores, and family
background.

2.3. Data reduction

The actigraph data were downloaded using a special interface unit (Ambulatory
Monitoring, AMI, USA) to a PC computer. All researchers involved in data collection
and processing remained blind to the infants’ condition. For each infant, the level of motor
activity was evaluated by the frequency of movement units produced during the pre-nap,
nap, and post-nap periods. The filter of the actigraph was set to a level of 18 to be com-
patible with Sadeh et al.’s [27,28] automatic algorithm that classifies waking, quiet sleep
and active sleep on a minute-by-minute basis. The sleep laboratory’s experienced personnel
also classified sleep states and waking periods visually according to the temporal con-
cordance of EEG, EOG and EMG criteria [29]. The comparison of the two methods yielded
an average minute-by-minute agreement of 84.3% for waking, quiet sleep, and active sleep
states. Due to the greater precision of expert visual coding, we based state classification
(wakefulness, active sleep, quiet sleep and indeterminate sleep) on these data [29].
A customized program calculated the total number of movement units produced per
minute for each state. We then calculated the total amount of time that each infant was in
an alert – active state before and after the nap. These calculations were used to compute the
proportion of movements per minute pre- and post-nap for each infant. Because infants
spent different lengths of time in the laboratory and were awake for different periods of
time, we normalized the activity data (movement units per minute) by the ratio of these
two time variables.

2.4. Statistical analysis

An initial step of statistical analysis was to determine whether motor activity was correlated
with family or child characteristics, including mental and motor development test scores.
Analysis of variance and the Student’s t-test were used to determine differences
between infants who had iron-deficiency anemia at 6 months and the nonanemic control
group. Two-tailed tests of significance were used, with an alpha level of 0.05.

3. Results

There were no differences between anemic and nonanemic groups in characteristics

related to gender, birth weight, growth at 6 months, breast feeding, mental or motor
development test scores (see Table 1).
Pearson correlations were computed to determine whether motor activity was correlated
with child or family characteristics. Even with a relatively liberal level of statistical
significance ( p < 0.10), there was only one significant correlation (between the primary
caregiver’s level of education and motor activity at 18 months, r = 0.54). The correlations
between motor activity and mental and motor development test scores were not statisti-
cally significant.
72 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79

Table 1
Characteristics of infants at 6 months of age
(n) Infants with iron-deficiency Nonanemic
anemia (11) controls (15)
Gender (male) 73% 60%
Birth weight (kg) 3.39 ± 0.11 3.59 ± 0.10
Gestational age (weeks) 38.7 ± 0.39 39.5 ± 0.34
Growth at 6 months
Weight (kg) 8.52 ± 0.26 8.03 ± 0.22
Length (cm) 66.8 ± 0.87 66.2 ± 0.59
Head circumference (cm) 44.0 ± 0.36 43.8 ± 0.26
Bayley Scale of Infant Development
Mental developmental index 97.5 ± 6.06 103.8 ± 3.69
Psychomotor developmental index 91.5 ± 4.61 97.8 ± 3.15
Duration of breastfeeding (months) 9.7 ± 2.35 9.7 ± 1.88
Values of continuous variables are means ± SE. There were no statistically significant differences comparing
infants with iron-deficiency anemia at 6 months and nonanemic controls, using analysis of variance for
continuous variables and the Fisher exact test for categorical variables.

3.1. Hematologic status

Data on the infants’ initial hematologic status and the change after oral iron are
provided in Table 2. Infants who had iron-deficiency anemia at 6 months showed an
excellent response to iron therapy. All responded to iron with an increase in hemoglobin of
10 g/l (1.0 g/dl) or more, confirming that each one had been iron-deficient and had been
able to absorb and utilize medicinal iron. At 12 months, the average hemoglobin level in
the anemic group increased approximately 24 g/l (2.4 g/dl), compared to 3 g/l (0.3 g/dl) in
the nonanemic group. At 18 months, there were no differences between the formerly
anemic and nonanemic infants in finger-stick hemoglobin levels. In addition, there were
marked improvements in MCV, EP, and ferritin at 12 months among infants who were
anemic at 6 months and modest changes in the nonanemic group. Only one infant still had
iron-deficiency anemia at 12 months, and this child had shown a good increase in
hemoglobin (23 g/l (2.3 g/dl)). A single nonanemic infant met criteria for iron-deficiency
on study entry. This infant and three others in the nonanemic group showed an increase in
hemoglobin of 10 g/l (1.0 g/dl) or more. The uniformity of response to iron in the anemic
group and general absence of iron-deficiency in the nonanemic group made it impossible
to examine activity differences among iron-deficient nonanemic infants or anemic infants
who failed to respond to iron therapy. Thus, our study cannot address questions about the
motor activity effects of iron-deficiency without anemia.

3.2. Duration of waking and sleeping

The average total observation times for the anemic group were 125, 132, and 164 min
at 6, 12, and 18 months, respectively. The observation times for the control group were
similar (146, 134, and 150 min at 6, 12, and 18 months, respectively). The variability in
standard deviation was homogeneous for both groups (range 23 –64).
 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79 73

Table 2
Initial iron status and hematologic change after 6 months of oral iron therapy
(n) Infants with iron-deficiency anemia at 6 months (11) Nonanemic controls (15)
Finger-stick hemoglobin (g/l) [g/dl]
6 months 92.0 ± 3.27 [9.2 ± 0.33] 118.0 ± 2.09 [11.8 ± 0.21] ***
Venous hemoglobin (g/l) [g/dl]
6 months 93.0 ± 2.65 [9.3 ± 0.26] 122.6 ± 1.14 [12.3 ± 0.11] ***
12 months 116.9 ± 1.96 [11.7 ± 0.20] 126.0 ± 2.04 [12.6 ± 0.20] **
Finger-stick hemoglobin (g/l) [g/dl]
18 months 129.0 ± 3.74 [12.9 ± 0.37] 129.1 ± 2.76 [12.9 ± 0.28]
Erythrocyte protoporphyrin (mmol/l) [mg/dl red blood cells]
6 months 3.62 ± 0.48 [204.3 ± 27.2] 1.57 ± 0.09 [89.0 ± 5.27] **
12 months 1.69 ± 0.12 [95.5 ± 6.72] 1.35 ± 0.04 [76.5 ± 2.50] *
Mean cell volume (fl)
6 months 64.2 ± 1.51 73.5 ± 0.59 ***
12 months 71.4 ± 1.45 77.5 ± 0.72 **
Ferritin (mg/l)
6 months 5.0 ± 1.30 17.6 ± 2.63 ***
12 months 15.5 ± 3.23 21.4 ± 3.95
Unless otherwise specified, values are means ± SE based on venous blood specimens. Levels of significance
compare infants who had iron-deficiency anemia at 6 months with nonanemic controls, using analysis of variance.
* p < 0.05.
** p < 0.01.
*** p < 0.001.

IDA infants generally spent less time in an alert – active state. The average grand total
duration of waking, combining pre- and post-nap periods in all ages, was 102.1 min
(SD = 17.0) for the IDA group, compared to 144.7 min (SD = 14.3) for the nonanemic
group. A two-way ANOVA (group x age) showed in a significant group main effect
( F(1,42) = 8.46, p < 0.01). Post hoc comparisons to determine when differences in waking
duration occurred indicated a suggestive trend at 6 months ( F(1,14) = 3.62, p < 0.08) and a
significant difference at 18 months ( F(1,15) = 4.61, p < 0.05), Fig. 1. Thus, differences
remained even after 1 year of iron therapy.
We also observed a tendency (although the differences were not significant) for longer
nap duration and more sleep state transitions in IDA infants at each age. Corresponding to
the relative decrease in the alert –active state within observations generally comparable in
time, the difference in nap duration between anemic and nonanemic groups increased with
age (8.6, 16.4, and 31.1 min at 6, 12, and 18 months, respectively). All analyses of motor
activity therefore controlled for differences in the duration of different states and the
proportion of observation time in each state.

3.3. Time to fall sleep

Infants with IDA fell sleep faster, on average, than non-IDA infants. At 6, 12 and 18
months of age, infants with IDA fell asleep in a mean of 19.7 (SD = 20.9), 11.7 (SD = 14.9)
and 16.5 (SD = 13.6) min, respectively, after starting to be settled for their nap. In contrast,
it took an average of 32.0 (SD = 6.2), 23.6 (SD = 18.0), and 25.4 (SD = 10.2) min for
74 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79

Fig. 1. Total waking duration (means ± SE) during a spontaneous afternoon nap for infants with IDA and controls
at 6 (C = 7, IDA = 9), 12 (C = 11, IDA = 4), and 18 (C = 11, IDA = 6) months of age. All infants received oral iron
drops beginning at 6 months of age. * p < 0.05, yp < 0.10.

nonanemic infants to fall asleep at 6, 12 and 18 months, respectively. A two-way ANOVA

(group and age) yielded a significant group difference ( F(1,42) = 6.05, p < 0.05). There
were no significant group differences at any age in the amount of waking time prior to
arrival to the laboratory.

3.4. Total motor activity before and after the nap period

IDA infants demonstrated less spontaneous motor activity around the nap session,
expressed as the proportion of movement units/minute of waking time (Fig. 2). In a two-
way ANOVA (group x age), group was the only significant effect ( F(1,42) = 8.0, p < 0.01).
Further analysis at the individual age points showed statistically significant group differ-
ences at 12 and 18 months (t = 8.43, p < 0.05, and t = 10.02, p < 0.01, respectively).

Fig. 2. Total motor activity (means ± SE) during waking around an afternoon nap in infants with IDA and controls
at 6 (C = 7, IDA = 9), 12 (C = 11, IDA = 4), and 18 (C = 11, IDA = 6) months of age. * p < 0.05, * * p < 0.01.
 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79 75

In these analyses, we controlled for differences between infants in time to fall asleep
and/or readiness to leave the laboratory upon waking by normalizing the mean move-
ments/minute for the proportion of each infant’s total observation that was spent in the
alert –active state.

4. Discussion

Using sophisticated quantitative techniques, this study points to a reduction in

spontaneous motor activity during wakefulness around an afternoon nap in young infants
who had iron-deficiency anemia. With the exception of Edgerton et al.’s [8] small study of
16 plantation workers in Sri Lanka, we have been unable to identify other studies that
apply such advanced methodology to the question of the effects of iron-deficiency anemia
on human motor activity. We therefore present our results despite the limitations of small
sample size and incomplete longitudinal data, emphasizing that the findings are best used
to generate hypotheses for systematic study in future investigations. With these precau-
tions in mind, our results suggest that infants who were anemic at 6 months showed
reduced motor activity during waking with lower frequency of spontaneous movements at
12 and 18 months. These differences were observed after iron treatment and ultimate
correction of anemia by 18 months. In fact, the differences between the control group and
the IDA infants became larger with age.
IDA infants also fell asleep faster than controls and spent less time in an alert – active
state. These observations suggest that the differences between IDA and control infants are
not only in motor domain. Changes in motor activity in young infants may result from
disruption of the daily routine, fatigue, motivation or novelty of the environment.
Therefore, our results may indirectly indicate that infant with IDA, even after treatment,
are more disrupted and fatigued by an afternoon trip to the laboratory and the novelty of
the environment. This hypothesis could be systematically tested in human infants by
comparing naptime behavior in familiar and unfamiliar settings.
The capacity to perform sufficient and varied motor actions depends on many factors.
We previously proposed a conceptual model of the factors that contribute to the poorer
development of infants with IDA [15]. In that model, both organismic and environmental
factors were included. Applying the same concepts to the present study, the possibility that
the observed differences in motor activity also relate to environmental factors should be
considered. If IDA infants responded to the novel setting of the neurophysiology
laboratory with more behavioral inhibition then control infants, or if control infants
responded with more engagement or excitement, differences in motor activity could result.
Such possibilities should be considered in future studies.
From a neurophysiological perspective, iron is involved in many processes that could
help account for the study’s findings. During the period of iron-deficiency, effects on
muscle function, oxygen transport, neurotransmitter function and myelination seem
particularly relevant to motor activity. It is well known that iron may affect the aerobic
capacity of an individual, as iron is an essential part of the hemoglobin molecules that
transport oxygen throughout the body and in muscle enzyme activity. In other studies,
infants with iron-deficiency anemia have been rated as more easily fatigued during a 30- to
76 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79

45-min developmental test [15]. However, we observed differences only after iron
treatment when all anemic infants showed an increase in hemoglobin of at least 10 g/l
(1.0 g/dl) and no infant had a hemoglobin level lower than 116 g/l (11.6 g/dl) at 18 months
of age.
The explanation for differences in activity after (but not during) the period of IDA is not
obvious. However, disruptions in neurotransmitter function and myelination are possibil-
ities. There is considerable evidence that iron-deficiency alters dopaminergic functioning
in different areas of the brain, among which are the basal ganglia. The role of the basal
ganglia and dopaminergic function in motor movement is well-established, and earlier
studies ascribed reduced motor activity in iron-deficient animals to a dopamine-mediated
process [3,30], but the dopaminergic system has a variety of roles, including motor and
motivational functions. For instance, dopamine has the general function of facilitating
neural processes subserving goal-directed behavior (motor activity being one of them)
[31]. Dopamine also appears to exert a modulatory influence on the salience of incentive
and reward, thus affecting motivational aspects of behavior. Further, dopamine facilitates
the coupling between motivation and action, and facilitates sensory-motor coherence via
the thalamus and back to the cortex [31,32]. Thus, reduced dopaminergic function could
result in reduced activity through several mechanisms. Finally, since dopamine appears to
be the latest monoaminergic neurotransmitter system to attain adult levels in the brain (at
least in rat and mouse models [33]), it is conceivable that the effect of postnatal IDA would
be most evident in this system.
Our finding of increasing differences in motor activity between anemic and nonanemic
groups over a year during which iron status responded to therapy contrasts with the only
other study to monitor activity mechanically in humans. In that study, there was an 80%
daily activity increase among anemic women who received iron supplement for a month,
compared to little or no change in those receiving placebo [34]. One possible explanation
for the lack of correction in physical activity in our study is that iron-deficiency and iron
treatment have different effects depending on developmental period. The importance of
timing is suggested by a recent study of early iron overload, which showed that the motor
activity deficits in adult rodents depended on the specific postnatal time at which iron
overload occurred [35]. Although this proposition needs further testing, the pattern of
increasing differences despite a year of iron therapy remarkably parallels that reported for
auditory brainstem responses (ABRs) [16]. Like motor activity, differences in nerve
conduction velocity between anemic and nonanemic groups became more pronounced at
12 and 18 months. Roncagliolo et al. [16] argued that impaired myelination was a
plausible explanation for the ABR findings.
The similarity in the activity and ABR results makes it tempting to suggest a shared
underlying mechanism. There is little question that iron is required for normal myelination
[34,36,37]. Thus, brain regions and functional systems which are rapidly myelinating in
early infancy might be especially affected by iron-deficiency. It is therefore reasonable to
postulate that iron-deficiency might decrease the efficiency of neural signaling in a variety
of systems, some of which might influence motor activity. For instance, slower nerve
conduction in the auditory and/or visual pathways reducing the availability or timeliness of
sensory feedback might reduce spontaneous motor activity. The above argument, while
indicating ways that differences in ABRs and motor activity might both be explained by
 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79 77

impaired myelination, is highly speculative. More research in animal models will be

crucial in elucidating the underlying mechanism(s) for altered motor activity in IDA.
Sustained decreases in motor activity for whatever reason may have negative con-
sequences for the human infant. Motor activity is an important means by which infants
explore their world and develop cognitive and social competence as well as improved
motor functioning. Spending less time in an alert –active state, especially if over the whole
day, could result in decreased opportunities to interact with the physical and social
environment. A reduction in overall motor activity and engagement could produce
changes in some experience-expectant developmental processes (re-routing development),
which in turn could affect the experiential processes of development [38]. If the early
insult of IDA limits the ways in which infants seek, receive, and/or are rewarded by
interactions with the physical and social environment, there could clearly be cascading
effects on behavior and development. Over time, these limitations could contribute to the
poorer cognitive, motor, and social – emotional functioning reported in school-aged
children and young adolescents who had iron-deficiency in infancy [15,39,40].

Acknowledgements

Funded by the U.S. National Institutes of Health (R01 HD33487 and T37 TW00035)
and the Chilean Agency for Funding in Science and Technology (FONDECYT,
#1000657) grants.

References

[1] Hunt JR, Zito CA, Erjavec J, Johson LK. Severe or marginal iron deficiency affects spontaneous physical
activity in rats. Am J Clin Nutr 1994;59:413 – 8.
[2] Glover J, Jacobs A. Activity pattern of iron-deficient rats. BMJ 1972;2:627 – 8.
[3] Youdim MBH, Yehuda S, Ben-Uriah Y. Iron deficiency-induced circadian rhythm reversal of dopaminergic-
mediated behaviours and thermoregulation in rats. Eur J Pharmacol 1981;74:295 – 301.
[4] Felt BT, Lozoff B. Brain iron and behavior of rats are not normalized by treatment of iron deficiency anemia
during early development. J Nutr 1996;126:693 – 701.
[5] Munro N. A three year study of iron deficiency and behavior in rhesus monkeys. Int J Biosocial Res
1987;9:35 – 62.
[6] Lozoff B, Brittenham GM. Behavioral aspects of iron deficiency. Prog Hematol 1986;14:23 – 53.
[7] Dallman PR. Iron deficiency: distinguishing the effects of anemia from muscle iron deficiency on work
performance. In: Saltman P, Hegenauer J, editors. The Biochemistry and Physiology of Iron. Amsterdam:
Elsevier; 1982. p. 509 – 23.
[8] Edgerton VR, Gardner GW, Ohira Y, Gunawardena KA, Senewiratne B. Iron deficiency anemia and its
effect on worker productivity and activity patterns. BMJ 1979;2:1546 – 9.
[9] Zhu YI, Haas JD. Altered metabolic response of iron-depleted nonanemic women during a 15-km time trial.
J Appl Psychol 1998;256:E401 – 5.
[10] Haas JD, Brownlie T, Zhu YI. Belmont conference: critical review of evidence that iron deficiency anemia
causes reduced work capacity. Iron-Deficiency Anemia: Reexamining the Nature and Magnitude of the
Public Health Problem. Geneva: WHO; 2000, in press.
[11] Bhatia D, Seshadri S. Anemia, undernutrition and physical work capacity of young boys. Indian Pediatr.
1987;24:133 – 9.
[12] Harahap H, Jahari AB, Husaini M, Saco-Pollitt C, Pollitt E. Effects of an energy and micronutrient supple-
78 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79

ment on iron deficiency anemia, physical activity, and motor and mental development in undernourished
children in Indonesia. Eur J Clin Nutr 2000;54:S114 – 9.
[13] Jahari AB, Saco-Pollitt C, Husaini M, Pollitt E. Effects of energy and micronutrient supplementation on
motor development and motor activity in undernourished children in Indonesia. Eur J Clin Nutr 2000;54:
S60 – 8.
[14] Bertenthal BI, Campos JJ. A systems approach to the organizing effects of self-produced locomotion during
infancy. In: Rovee-Collier C, Lipsitt L, editors. Advances in infancy research. Norwood, N.J.: Ablex;
1990. p. 1 – 60.
[15] Lozoff B, Klein NK, Nelson EC, McClish DK, Manuel M, Chacon ME. Behavior of infants with iron
deficiency anemia. Child Dev 1998;69:24 – 36.
[16] Roncagliolo M, Garrido M, Walter T, Peirano P, Lozoff B. Evidence of altered central nervous system
development in infants with iron deficiency anemia at 6 mo: delayed maturation of auditory brain stem
responses. Am J Clin Nutr 1998;68:683 – 90.
[17] Walter T, Olivares M, Hertrampf E. Field trials of food fortification with iron: the experience in Chile. In:
Lonnerdal B, editor. Iron Metabolism in Infants. Boca Raton, FL: CRC Press; 1990. p. 127 – 155.
[18] Olivares M, Walter T, Hertrampf E, Pizarro F, Sketel A. Prevention of iron deficiency by milk fortification:
the Chilean experience. Acta Paediatr Scand, Suppl 1989;316:109 – 13.
[19] Walter T, Pino P, Pizarro F, Lozoff B. Prevention of iron-deficiency anemia: comparison of high- and low-
iron formula in full-term healthy infants. J Pediatr 1998;132:635 – 40.
[20] Cohen AR, Seidl-Friedman J. HemoCue system for hemoglobin measurement. Am J Clin Pathol 1988;90:
302 – 5.
[21] Dacie JV, Lewis SM. Practical Haematology. Edinburgh: Churchill Livingstone; 1975.
[22] Ram G, Duplock L, Powell L, Hallyday J. Sensitive and rapid colorimetric immunoassay of ferritin in
biological samples. Clin Chem 1990;36:837 – 49.
[23] Chisolm J, Brown DH. Microscale protofluorometric determination of ‘‘free erythrocyte protoporphyrin’’
(Protophorphyrin IX). Clin Chem 1975;21:1669 – 82.
[24] Nathan DG, Orkin SH. Hematology of Infancy and Childhood. Philadelphia: Saunders; 1998.
[25] Dallman PR, Reeves JD, Driggers DA, Lo EYT. Diagnosis of iron deficiency: the limitations of laboratory
tests in predicting response to iron treatment in 1-year-old infants. J Pediatr 1981;98:376 – 81.
[26] Deinard AS, Schwartz S, Yip R. Developmental changes in serum ferritin and erythrocyte protoporphyrin in
normal (nonanemic) children. Am J Clin Nutr 1983;38:71 – 5.
[27] Sadeh A, Lavie P, Scher A, Tirosh E, Epstein R. Actigraphic home-monitoring sleep-disturbed and control
infants and young children: a new method for pediatric assessment of sleep – wake patterns. Pediatr 1991;87:
494 – 9.
[28] Sadeh A, Acebo C, Seifer R, Aytur S, Carskadon MA. Activity based assessment of sleep – wake patterns
during 1st year of life. Infant Behav Dev 1995;18:329 – 37.
[29] Peirano P, Fagioli I, Singh BB, Salzarulo P. Effect of early human malnutrition on waking and sleep
organization. Early Hum Dev 1989;20:67 – 76.
[30] Youdim MBH, Yehuda S, Ben-Uriah Y. Brain iron: a lesson from animal models. Am J Clin Nutr 1989;50:
618 – 29.
[31] Depue RA, Collins PF. Neurobiology of the structure of personality: dopamine, facilitation of incentive
motivation, and extraversion. Behav Brain Sci 1999;22:491 – 569.
[32] Carlsson A. Speculations on the control of mental and motor functions by dopamine modulated cortico-
striato-thalamo-cortical feedback loops. Mt Sinai J Med 1988;55:6 – 10.
[33] Agrawal HD, Glisson SN, Himwich WA. Changes in monoamines of rat brain during postnatal ontogeny.
Biochim Biophys 1966;130:511 – 3.
[34] Larkin EC, Rao GA. Importance of fetal and neonatal iron: adequacy for normal development of central
nervous system. In: Dobbing J, editor. Brain, Behaviour, and Iron in the Infant Diet. London: Springer-
Verlag; 1990. p. 43 – 62.
[35] Fredriksson A, Schroder N, Eriksson P, Izquierdo I, Archer T. Maze learning and motor activity in adult
mice induced by iron exposure during a critical postnatal period. Dev Brain Res 2000;119:65 – 74.
[36] Connor JR, Menzies SL. Relationship of iron to oligodendrocytes and myelination. GLIA 1996;17:83 –
93.
 R.M. Angulo-Kinzler et al. / Early Human Development 66 (2002) 67–79 79

[37] Yu GS, Steinkirchner TM, Rao GA, Larkin EC. Effect of prenatal iron deficiency on myelination in rat pups.
Am J Pathol 1986;125:620 – 4.
[38] Black JE, Jones TA, Nelson CA, Greenough WT. Neural plasticity and developing brain. In: Alessi NE,
Coyle JT, Harrison SI, Eth S, editors. The Handbook of Child and Adolescent Psychiatry. New York: Wiley;
1998. p. 31 – 53.
[39] Hurtado EK, Claussen AH, Scott KG. Early childhood anemia and mild/moderate mental retardation. Am J
Clin Nutr 1999;69:115 – 9.
[40] Ryan AS. Iron-deficiency anemia in infant development: implications for growth, cognitive development,
resistance to infection, and iron supplementation. Yearb Phys Anthropol 1997;40:25 – 62.