An overview of evidence for a causal relation between iron deficiency
during development and deficits in cognitive or behavioral function1–3
Joyce C McCann and Bruce N Ames
This review, intended for a broad scientific readership, summarizes
iron deficiency with (ID?A) or without (ID-A) anemia during de-
velopment and deficits in subsequent cognitive or behavioral per-
formance. An overview of expert opinion and major evidence in
humans and animals is provided. Cognitive and behavioral effects
observed in humans with ID-A and in animals with ID?A are pro-
vided in tables. The degree to which 5 conditions of causality are
satisfied and whether deleterious effects of ID-A might be expected
to occur are discussed. On the basis of the existing literature, our
of causality (association, plausible biological mechanisms, dose re-
sponse, ability to manipulate the effect, and specificity of cause and
effect) are partially satisfied in humans, animals, or both, a causal
connection has not been clearly established. In animals, deficits in
motor activity are consistently associated with severe ID?A, but
have not been clearly shown. Resistance to iron treatment was ob-
served in most trials of children ?2 y of age with ID?A, but not in
older children. Similar observations were made in rodents when
age and in adolescents with ID-A, evidence suggests cognitive or
ies conducted in either humans or animals prevents a thorough
Am J Clin Nutr 2007;85:931–45.
havior, learning, memory, gestation, pregnancy, brain, neurology,
infants, childhood, rodent studies
Iron, anemia, iron deficiency, cognition, be-
A large body of research suggests that an inadequate dietary
supply of any of a number of essential micronutrients can ad-
versely affect brain function (1–6). Some studies also suggest
cognitive function (7, 8). The brain is at its most vulnerable
ter of fetal life and the first 2 y of childhood—a period of rapid
brain growth termed the “brain growth spurt” (9). This review is
part of a series intended to provide critical summaries of the
available experimental evidence pertinent to whether causal
linkages exist between individual micronutrient deficiencies
during this critical period and subsequent brain function. We
recently reviewed evidence of a causal relation between cogni-
tive dysfunction and n?3 fatty acid deficiency (5) or choline
availability (6) during development.
optimal brain function would have major public health implica-
tions. Large segments of the world (including the United States)
population, particularly the poor, are known to be undernour-
ished in a number of micronutrients (10–12). A major effort to
poor, will be well justified. One of us has discussed such an
approach as a relatively inexpensive and efficacious adjunct to
current public health programs (13, 14).
Dietary iron deficiency sufficient to cause anemia (ID?A) is
widespread in underdeveloped countries (15, 16). Even in coun-
is below the Estimated Average Requirement (EAR) for ?16%
Examination Survey (NHANES) of 1999–2000 reported that,
among all age groups examined, the estimated prevalence of
ID?A was greatest in adolescent girls (9–16%) and in young
Worldwide, the economic effect of ID?A has been estimated to
be in the billions of dollars (22).
are other causes of iron deficiency in children. Infants subjected
to conditions of pregnancy resulting in intrauterine growth re-
striction (IUGR), infants who are small-for-gestational age
(SGA), infants of diabetic mothers (IDMs), or infants born of
preeclamptic mothers can also be iron deficient (23–27). The
or behavioral deficits in such children; several reviews and ex-
amples are cited (28–34). Other factors associated with iron
Research Institute, Oakland, CA.
2Supported by the Bruce and Giovanna Ames Foundation (JCM), a grant
from the National Center on Minority Health and Health Disparities (P60-
and Alternative Medicine (K05 AT001323-01) (BNA).
3Reprints not available. Address reprint requests to JC McCann or BN
Ames, Children’s Hospital Oakland Research Institute, 5700 Martin Luther
King Jr Way, Oakland, CA 94609. E-mail: email@example.com,
Received May 15, 2006.
Accepted for publication October 10, 2006.
Am J Clin Nutr 2007;85:931–45. Printed in USA. © 2007 American Society for Nutrition
by guest on May 14, 2011
deficiency in infants are early umbilical cord clamping, prema-
turity, and fetal blood loss (35).
We present an overview of evidence relevant to establishing
whether a causal link exists between dietary iron deficiency
during development and subsequent cognitive or behavioral
function. The degree to which this evidence satisfies 5 causal
criteria, slightly modified from the original formulation (36), is
examined: 1) a consistent association, 2) a dose-response rela-
effect, and 5) a plausible biological rationale. To address these
evidence and other information that is difficult or impossible to
cannot be done in humans, such as mechanistic studies that cor-
relate changes in biochemical indicators of brain function to
greater flexibility of design is possible in animal experiments,
this review addresses an issue of importance to pediatrics by
taking into account the full array of relevant scientific evidence
from both human and animal systems.
An in-depth methodologic review of this large body of evi-
dence is beyond the scope of this review; systematic critical
reviews were relied on to the extent possible. There are several
iron-deficient animals has not been conducted. We searched the
and author searches, using the National Library of Medicine’s
PUBMED and Science Citation Index Cited References data-
review articles. Abstracts were not included.
oxygen transport, ATP production, DNA synthesis, mitochon-
drial function, and protection of cells from oxidative damage, as
discussed in many reviews (41–44). The average concentration
of iron in the brain is far higher than that of all other metals,
by enzymes involved in specific brain functions, including my-
elination (50–52) and synthesis of the neurotransmitters seroto-
nin (tryptophan hydroxylase) (53) and dopamine (tyrosine hy-
droxylase), a precursor to epinephrine and norepinephrine (54).
Accretion of iron by the brain
and continues after birth up to 30–50 y of age (58, 59). Unless
maternal iron deficiency is severe, term infants are generally
considered to be protected from ID?A through the first few
months of life (60–62), but as iron stores are used up, a sharp
decline occurs in serum ferritin (63, 64) and the infant becomes
deficiency (65, 66). Studies in rats indicate a similar pattern of
with the rapid turnover of iron in plasma (70, 71).
functions, particularly the Bayley Scales of Infant Development
(72), have been most commonly used in children ?2 y of age,
although some tests that target cognitive function more specifi-
been used. In older children, a broader range of tests have been
used, including the Stanford-Binet Intelligence Scale (74), the
Wechsler Intelligence Scale for Children (WISC) (75), several
attentional tests (eg, 76), and school achievement tests. A few
human experiments also used electrophysiologic measures (77–
and Ani (38).
In the 2 nonhuman primate studies identified, a wide range of
ilar to human tests, such as an adaptation (80) of the Fagan Test
of Infant Intelligence (73). In rodents, motor or exploratory ac-
hole board, or home orientation and open-field tests. However,
some methods that target cognitive functions, such as learning
and memory, more directly, such as the Morris water maze (81)
and passive or active avoidance tests (82), were also used. For
the article by Metz et al (83).
Definition of iron deficiency with and without anemia
ity of dietary restriction but also on the stage of development
during which iron deficiency occurs and the duration of dietary
restriction (84–87). Dietary iron deficiency results in biochem-
ical changes in the blood and reduced concentrations of iron in
dietary iron deficiency sufficient to deplete ferritin stores and to
reduce serum hemoglobin to the point of anemia. Individuals
with depleted iron stores and serum hemoglobin concentrations
generally considered to be iron deficient anemic (ID?A) (15,
44). Hemoglobin cutoff values varied somewhat among human
studies, as noted by reviewers (38).
Many studies in humans have examined possible linkages
between iron deficiency (primarily ID?A) and concurrent or
concurrent effects may reflect neurochemical changes resulting
from iron deficiency at the time of testing, demonstration that a
permanent developmental change has occurred requires evi-
dence of effects in formerly iron-deficient children (40).
Reviewers emphasize the importance of making causal infer-
ences only from studies with designs that minimize potential
confounding (1, 38–40, 84, 99). For example, the anemia that ac-
companies ID?A can be a potentially serious confounder in case-
relations between cognitive or behavioral outcomes and socioeco-
MCCANN AND AMES
by guest on May 14, 2011
least potentially confounded study designs, double-blind placebo-
als are the most informative from a causal perspective; see several
reviews for discussion (38, 40, 99). Unless otherwise noted, repre-
sentative studies cited below had a DBRCT design; the reader is
referred to reviews cited for additional references.
Cognitive or behavioral performance of children with
iron deficiency sufficient to cause anemia
Collectively, expert reviewers discussed ?40 studies of var-
ious experimental designs that examined the performance of
children or adolescents with ID?A in cognitive or behavioral
tests (1, 37–40, 88–97); ?60% of the tests were conducted in
ioral tests administered at the beginning of iron-treatment trials
(100–103). For such children, reviewers agreed that there was a
consistent association between ID?A and poor performance
relative to control subjects (1, 37–40, 90–97). Two comprehen-
sive critical reviews of studies involving children identified as
ID?A at ages ?2 y (38, 89) also concluded that, in most cases,
performance was poorer, at least on some tests (104–106).
deficiency per se to poor test performance. Interpretation is lim-
ited, not only by potential confounding due to unaccounted so-
cioeconomic factors, but by the potential confounding factor of
anemia that accompanies the iron deficiency of ID?A. In rats,
anemia per se does not result in biochemical brain effects asso-
behavioral tests is confounded by generalized effects of anemia
on physical energy levels (49, 112–116) as opposed to specific
effects of iron deficiency in the brain.
Cognitive or behavioral outcomes in formerly anemic
Effect of iron treatment on cognition or behavior in children
A critical question motivating a great deal of research in the
field is whether and how long the effects of ID?A on cognitive
or behavioral function persist after children are no longer iron
38) critically assessed ?20 iron-treatment trials involving chil-
dren with ID?A, most of which had a DBRCT design.
These and other reviewers (1, 37, 38, 117) concluded that, in
general, poorer test performance of children with ID?A tended
119) but was more resistant to improvement in children ?2 y of
age (101–103). As investigators discussed, this observation is
compatible with damage from iron deficiency during brain de-
tainties associated with this conclusion, such as the limited sta-
tistical power of studies that did not observe a treatment effect
trials. Only 2 longer-term (2–4 mo) trials reviewed were
DBRCTs (120, 121), and 1 of these (120) observed that perfor-
mance deficits improved with treatment.
The finding that the cognitive performance of children with
ID?A at an early age is resistant to improvement with iron
treatment is supported by several long-term follow-up studies
(38). We point particularly to the widely cited longitudinal ob-
servational study of Lozoff et al (40, 122, 123), who followed a
group of Costa Rican children for ?10 y. In this study, children
who formerly had ID?A (initially treated for 3 mo with iron)
11–14 y of age. Extensive test batteries included measures of
intelligence quotient, verbal and quantitative learning, memory,
and other reviewers (37, 38, 99), although this study provides
was not a DBRCT and did not have a placebo control group.
Auditory evoked potentials
An outcome measure that avoids the potentially confounding
factors of anemia and socioeconomic conditions uses auditory
evoked potentials, which are noninvasive electrophysiologic
measures of how long it takes the acoustic nerve to transmit
sound from the ear to the brain. This time is inversely related to
the degree of myelination; the technique is commonly used to
detect hypomyelination associated with various diseases (77).
rate of myelination in control children and children with ID?A
(125–130). The results are briefly summarized below.
The most commonly cited of these studies is that of Lozoff et
al (125, 126). In this experiment, conduction times were mea-
sured over a 4-y period in Chilean children with ID?A and
control subjects. Children were identified as having ID?A or as
control subjects at 5–6 mo of age, and all children received iron
supplements for 1.5 y. Although results at later time points sug-
gested that the formerly ID?A group was gradually catching up
points examined. Shankar et al (129) observed a significant cor-
group of children with ID?A ranging in age from 3 to 11 y.
Several other reports that measured auditory evoked potentials
a wide range (7–24 mo) (127).
ID?A and developmental deficits can be prevented in hemato-
difficulty in obtaining sufficient power in such trials to detect
concluded that the few trials conducted provided only limited
evidence of benefit.
Two recent trials are noted (131, 132). Friel et al (132) con-
on the Bayley Psychomotor Development Index (but not on the
Mental Development Index) were observed (132), which led
investigators to conclude that supplementation might have ben-
iron supplementation, did not observe an effect on Psychomotor
IRON AND COGNITION
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