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Centre for International Child Health, Institute of Child Health, University College, London, UK
3To whom correspondence should be addressed. E-mail: s.mcgregor{at}ich.ucl.ac.uk.
| ABSTRACT |
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KEY WORDS: iron deficiency children cognition behavior development
| INTRODUCTION |
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| DEMONSTRATING CAUSAL RELATIONSHIPS |
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Demonstrating significant associations between anemia and poor
development in correlational or case-control studies is helpful in
identifying at-risk populations but cannot establish
cause-and-effect relationships. They provide no information as to the
timing of any relationship and it is possible that poor development
precedes iron deficiency. In addition, there is considerable evidence
that anemia is associated with a large number of socioeconomic and
biomedical disadvantages that can themselves affect childrens
development. Some of the factors found to be associated with both
anemia and poor cognitive development are low socioeconomic status
(Owen et al. 1971
); poverty (Czajka-Narins et al. 1978
); lack of stimulation in the home (de Andraca et al. 1990
), including lack of maternal warmth; poor maternal
education (de Andraca et al. 1990
, Idjradinata and Pollitt 1993
) and intelligence quotient
(IQ)4
(Lozoff et al. 1991
); maternal depression (de Andraca et al. 1990
); more absent fathers; low birth weight
(<2.5 kg) and early weaning (Lozoff et al. 1991
);
parasitic infection (Ramdath et al. 1995
); elevated
blood lead levels; and undernutrition. It is highly unlikely that all
of these factors are controlled for in one study, and there are
probably many other confounding factors.
Longitudinal observational studies give additional useful information about the long-term prognosis of children with anemia and the types of deficits at different stages of development. However, they also cannot provide evidence of a causal relationship, but finding reasonably consistent associations between anemia and cognitionafter controlling for the most obvious confoundersis a first step toward making causal inferences.
The most accurate way of pinpointing iron deficiency as a cause of poor development is to conduct a double-blind, randomized, controlled trial and demonstrate that producing or preventing anemia changes childrens development. Obviously, one has to use animal models for producing iron deficiency, but preventive trials beginning with nonanemic children are possible to conduct. Unfortunately, preventive trials are extremely difficult and expensive to run. They need large samples to have adequate statistical power, even in populations in which the prevalence of anemia is high. The samples must be followed for some time and it is essential that they remain intact.
Randomized controlled therapeutic trials in which iron is given to anemic children can demonstrate whether a developmental deficit is remediable with iron treatment. They are equally rigorous and are easier to conduct than preventive trials because much smaller numbers are needed. Unlike preventive trials in which a substantial proportion of the placebo children are not anemic and not all treated children are expected to benefit, in therapeutic trials, it is reasonable to expect all treated children to benefit from iron. However, failure of response to treatment does not necessarily negate the presence of a causal relationship because it is possible that the developmental deficit is irremediable at least in the short term.
| MECHANISMS |
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Evidence from children of changes to the CNS is limited. However,
investigators recently studied auditory brain stem responses in
children with anemia (Roncagliolo et al. 1998
). These
responses provide a measure of the activation of the auditory pathway
from the distal part of the acoustic nerve to the lateral lemniscus,
and the central conduction time is an indicator of CNS development. The
central conduction time was found to be prolonged in 6-mo-old children
(n = 29) with anemia compared with nonanemic children
(n = 26). Furthermore, they did not improve with
correction of anemia and the difference was greater 6 and 12 mo later.
The investigators speculated that the prolonged central conduction time
was due to changes in myelination that have been reported in
iron-deficient animals (Yu et al. 1986
). Recent work
has shown that formerly anemic children also have longer latencies in
visual evoked potentials (B. Lozoff, personal communication). None of
the above studies controlled for social background and it is possible
that deprivation could affect brain development.
Another hypothesis linking anemia to poor development is functional
isolation, which was originally conceived to explain poor development
in children with protein-energy malnutrition (Levitsky and Strupp 1995
). Anemic children explore and move around their
environment less than nonanemic children, and they induce less
stimulating behavior in their caretakers. These behaviors and the
caretakers response are thought to delay the acquisition of new
skills.
There are many reports of clinical impressions of anemic children being
fearful. More systematic observations have been made comparing anemic
with nonanemic children during testing with the Bayley Scales using the
Bayley infant behavior ratings. These studies have found that anemic
children tend to be more fearful (Lozoff et al. 1982a and 1996
), withdrawn, tense, unreactive to usual stimuli
(Lozoff et al. 1982a
), more solemn, less involved
(Honig and Oski 1984
) and more unhappy (Lozoff et al. 1996
, Walter et al. 1983
).
Surprisingly, there have been few observations in nontest situations.
In a study in the United States (Johnson and McGowan 1983
), anemic children were observed in a standard situation
that included two set tasks and free play. They were not different from
nonanemic children in activity, reactivity, emotional tone, or
attention span. However the observation period was extremely short
(total of 16 min) and unlikely to provide a representative sample of
behavior. Also, the groups showed no significant difference between
their scores on the Bayley Scales, which is unusual. In another
observation study of a very short free-play session (Lozoff et al. 1986
), children stayed closer to their mothers and this
was attributed to both the mothers and childrens behavior.
In a more extensive study, behavior observations were made in a 15-min
free-play situation and throughout developmental testing. Children
with anemia stayed closer to their caretakers, showed less pleasure,
and were more wary, hesitant and easily tired. An average of 14 spot
observations were also made during home visits, and anemic children
were more likely to be asleep, irritable, doing nothing, being carried
or in bed, and less likely to be on the patio or playing interactively
with objects. During the Bayley test session, the anemic children made
fewer attempts at test tasks, were less playful and had poorer
attention than nonanemic children (Lozoff et al. 1998
).
These types of behaviors persisted after treatment. Most interestingly,
mothers of anemic children were rated as being less affectionate, and
even the testers behaved differently with the children, giving them
fewer tasks and making fewer attempts to elicit responses.
It is of course possible that these behaviors could be due to deprived
environments. In Jamaica, similar behavior was found in undernourished
children and the behavior was changed with stimulation alone, without
changing the childrens nutritional status (Grantham-McGregor et al. 1989
).
One study linked childrens behavior during assessment on the Bayley
Scales to their test scores (Lozoff et al. 1985
). The
children with abnormal ratings were more likely to have lower Bayley
scores. The investigators hypothesized that the anemic childrens
lower scores were mediated through behavior disturbances. There are
therefore several biologically plausible ways, demonstrated in both
animal and human research, in which iron deficiency could affect child
development.
| REVIEW OF STUDIES |
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Correlational and case-control studies.
Beginning as early as 1919, many investigators found significant
concurrent associations between hemoglobin concentrations and measures
of cognitive development or school achievement (Agarwal et al. 1987
, Clarke et al. 1991
, Florencio 1988
, Grindulis et al. 1986
, Popkin and Lim-Ybanez 1982
, Waite and Neilson 1919
,
Walker et al. 1998
, Webb and Oski 1973
).
In addition, baseline differences in developmental levels, cognition or
school achievements were found between nonanemic and anemic groups in
treatment trials. For example, in trials concerning children <2 y old,
in six of seven studies with nonanemic and anemic children
(Idjradinata and Pollitt 1993
, Lozoff et al. 1982b, 1987 and 1996
, Walter et al. 1983 and 1989
), the anemic groups had significantly lower scores on the
mental development index (MDI) of the Bayley Scales. There were only
eight nonanemic children in the seventh study (Driva et al. 1985
). Four of the studies also showed differences in the
psychomotor development index (PDI) (Idjradinata and Pollitt 1993
, Lozoff et al. 1982b and 1987
,
Walter et al. 1989
). Most of these studies had some
control for social background and biomedical conditions, but few had
extensive controls for both socioeconomic and biomedical conditions.
Although most studies found associations between anemia and a
developmental outcome, a puzzling minority of the studies failed to
find significant associations (Deinard et al. 1981 and 1986
, Huda et al. 1999
, Johnson and McGowan 1983
, Moock and Leslie 1986
). Small
sample sizes may explain some failures to find associations. Also, some
of the studies did not have measures of iron status other than
hemoglobin levels and it is possible, but not very likely, that iron
deficiency was not the commonest cause of anemia.
Although correlational studies offer the opportunity to look for
possible interactions between anemia and socioeconomic or biomedical
conditions, few investigators have attempted to do so and most had
sample sizes insufficient for doing so. Many studies of
protein-energy malnutrition and low birth weight have shown that
these conditions interact with social background and other biomedical
conditions in their effect on child development
(Grantham-McGregor et al. 1998 and 1999
, Pollitt et al. 1993
). It is likely that analogous relationships exist
with anemia. For example, anemia may have different effects in
low-birth-weight infants than in normal-birth-weight infants. Most
investigators have gone to great lengths to exclude high risk infants;
thus, information on these types of questions is scarce.
Some investigators have examined the relationships between severity of
anemia and developmental decline. In one study (Lozoff et al. 1987
), a decline in concurrent motor development was found at
hemoglobin values <105 g/L, whereas a decline in mental development
appeared at values <100 g/L. In contrast, Walter and colleagues (1989)
compared the development of children with hemoglobin
concentrations <100 g/L with those with concentrations between 105 and
109 g/L and >109 g/L. The three groups were significantly different
from each other in both their motor and mental developmental indices,
which were in the same ranking order as their hemoglobin
concentrations. Therefore it appears that the level of anemia
associated with declining development varies in different populations
Longitudinal observation studies
We identified seven studies in which hemoglobin levels in early
childhood were linked to cognitive development or school achievement in
later childhood (Cantwell 1974
, de Andraca et al. 1990
, Dommergues et al. 1989
, Hurtado et al. 1999
, Lozoff et al. 1991 and 2000
,
Palti et al. 1983 and 1985
, Wasserman et al. 1992 and 1994
). The ages and size of the samples, outcome measures
and findings are given in Table 1
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Most importantly, all studies found that formerly anemic children
continued to be at a developmental disadvantage at one or more of the
follow-up assessments. All but one study (Cantwell 1974
) reported controlling for some social background
variables, gender and birth weight. Although the size and number of
differences were reduced when scores were adjusted, some tests remained
significant in all but one study. In that study (Wasserman et al. 1994
), the final examination was at 4 y, and previous
hemoglobin levels were only inconsistently related to IQ (negative at
one age and positive at another). However, early hemoglobin levels had
been related to development at 24 mo (Wasserman et al. 1992
).
Specific functions affected.
All but one study (Hurtado et al. 1999
) had a global
measure of development, either an infant developmental assessment or an
IQ test, and these were poorer in anemic children. Specific cognitive
functions were assessed in only two studies. In Costa Rica and Chile
(de Andraca et al. 1990
, Lozoff et al. 1991 and 2000
), children were given a comprehensive battery of tests at
5 y of age. In both studies, the formerly anemic children had
deficits, which were not identical, across a wide range of functions.
Preschool skills, fine and gross motor skills, and visual-motor
integration were affected in both studies, whereas language and global
IQ were affected in the Chilean sample (de Andraca et al. 1990
) and only performance IQ in Costa Rica (Lozoff et al. 1991
). Children in Costa Rica were reassessed between ages
11 and 14 y for an even wider range of functions (Lozoff et al. 2000
). The anemic childrens performance was worse in
practically all tested functions, but they came from more deprived
environments than did the nonanemic children. After many covariates
were controlled for, the differences were reduced to writing, reading
and arithmetic; motor skills; spatial memory; and, in the older
children only, selective attention. The childrens behavior was also
assessed by teacher and parent reports. The anemic children were
reported to have higher scores in anxiety and depression, social and
attentional problems, and total problems after covariates were
controlled for. The only other study reporting behavior
(Cantwell 1974
) reported that anemic children were
inattentive and hyperactive but gave no details.
In the four studies that assessed the childrens achievement in
preschool or school subjects or placement in special classes, all found
that formerly anemic children were poorer (de Andraca et al. 1990
, Hurtado et al. 1999
, Lozoff et al. 2000
, Palti et al. 1985
). Two studies found that
anemic children had minor neurological dysfunction at 5 (de Andraca et al. 1990
) and 7 y of age (Cantwell 1974
).
Conclusions from longitudinal studies. In conclusion, longitudinal studies indicate consistently that children who were anemic in early childhood continue to have poor cognitive and motor development and school achievement into middle childhood. There is some evidence of behavior problems and minor neurological dysfunction, but evidence is not sufficient for identifying specific cognitive deficits.
The main question is whether the control for social background was adequate. Some environmental variables may not have been controlled for in the final analyses because they were not significantly related to the outcome variable. However, with small samples, this does not necessarily mean that they were not related. It remains possible that environmental variables, measured and unmeasured, could partly or completely explain these findings.
Therapeutic treatment trials
Numerous reviews concern the requirements that must be fulfilled
in a treatment trial before it is possible to make causal inferences
(Fairchild et al. 1989
); thus, we will not discuss them
in detail. Briefly, the following must be in place: the definition of
initial iron-deficiency anemia should be clear and include at least
three criteria; the samples must be large enough to provide adequate
power; there should be a randomized control group that receives a
placebo; treatment should be effective in improving the iron status;
both tester and subjects should be blinded; and the outcome measures
should have satisfactory construct validity, be sensitive to the range
of changes expected and be reliable over time and between observers. If
the data are required for determination of policy decisions, then the
measurements must have good face validity for the policy makers. It is
probably not necessary to point out to a group of fellow researchers
that it is not always possible to meet all of these criteria for
logistical and ethical reasons, but they remain the yardstick by which
to evaluate studies.
In Tables 2
and
3
we have listed all of the treatment trials with iron-deficient
children with and without anemia (children under and over age 2 y)
that we located. We have attempted to focus on the most salient points
that help determine the validity of the studies. We have identified the
sample size and ages and type of exclusions, definition of initial iron
deficiency, manner of group assignment, content and duration of
treatment, and outcome variables. We have indicated whether a
significant treatment effect was reported. Treatment effect was
restricted to cases in which the change in development of the treated
anemic or iron-deficient group was significantly different from the
change in development of the placebo anemic or iron-deficient
group. However, we have also indicated whether the placebo and treated
groups were significantly different after treatment. For studies in
which there was no randomized anemic placebo group or the analysis of
differences in score change was not reported, we have not claimed a
treatment effect. We have also noted whether a response in hemoglobin
level was reported. We have divided the children <2 y old from those
>2 y old because the findings tend to be different.
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We identified nine studies of iron treatment in anemic children
<2 y old (Aukett et al. 1986
, Driva et al. 1985
, Harahap et al. 2000
, Idjradinata and Pollitt 1993
, Lozoff et al. 1982b, 1987 and 1996
, Oski and Honig 1978
, Walter et al. 1983 and 1989
) and one study of nonanemic iron-deficient
children (Oski et al. 1983
). Two of the studies
conducted more than one trial with the same sample (Lozoff et al. 1987
, Walter et al. 1989
), making a total of
12 trials (Table 2)
.
The definition of anemia varied from hemoglobin <110 g/L in six
studies (7 trials), <105 g/L in two studies (3 trials) and <100 g/L
in two studies. It may be relevant that two of the most experienced
investigators in this area, B. Lozoff and E. Pollitt, usually used the
lower cut-off values (Idjradinata and Pollitt 1993
,
Lozoff et al. 1982b, 1987 and 1996
).
All studies except two (Aukett et al. 1986
, Driva et al. 1985
) had criteria for other measures of iron
deficiency, and all of the studies lasting longer than 2 wk provided
evidence that the treatment given was satisfactorily delivered by
demonstrating changes in hemoglobin levels.
All but one study (Aukett et al. 1986
) used the Bayley
Scales as an outcome variable, which facilitates comparison across
studies. The Bayley is a global measure of development and gives both a
PDI and MDI. Initial differences between nonanemic and anemic children
were found in the MDI in six of seven studies reporting the comparison
and in the PDI in five of the studies.
Short-term trials.
Seven early studies were short, lasting <15 d (Oski and Honig 1978
, Oski et al. 1983
, Lozoff et al. 1982b and 1987
, Walter et al. 1983 and 1989
).
Four of them were double-blind randomized controlled trials (DBRCT)
(Lozoff et al. 1982b and 1987
, Oski and Honig 1978
, Walter et al. 1989
) and one was a
randomized controlled trial (RCT) but without a placebo group
(Driva et al. 1985
). None of these five reported a
significant treatment benefit. Investigators in two of the studies
claimed treatment benefits. Oski and Honig (1978)
showed
that more of the treated anemic group improved 10 MDI points than did
the placebo group, but this was an exploratory post-hoc analysis.
The other study claiming benefits (Driva et al. 1985
)
showed that in the 10 d immediately after an iron injection,
children showed a significant benefit but not after that. However, the
appropriate analysis of difference between the treated and placebo
group in score changes was not reported. Further problems with this
study are that hemoglobin was the only criterion for iron deficiency
and no placebo was given.
The other two short-term trials had no randomized control groups.
Treated anemic Chilean children (Walter et al. 1983
) or
nonanemic iron-deficient children from the United States
(Oski et al. 1983
) were compared with nonanemic
iron-replete children. In Chile, the treated anemic children
improved significantly more (10 MDI points) than did the nonanemic
iron-replete children (-1 MDI point). In the American study
(Oski et al. 1983
), the nonanemic iron-deficient
groups combined gained significantly more than did the nonanemic
iron-replete and -depleted groups.
Longer-term trials.
In all, there were six studies in which anemic subjects were treated
for 26 mo (Aukett et al. 1986
, Harahap et al. 2000
, Idjradinata and Pollitt 1993
,
Lozoff et al. 1987 and 1996
, Walter et al. 1989
). Four of these trials used nonanemic iron-replete
subjects as controls (Harahap et al. 2000
, Lozoff et al. 1987 and 1998
, Walter et al. 1989
). These
studies were based on the idea that the anemic group would have an
initial deficit and should catch up with iron treatment. In three of
the studies (Lozoff et al. 1987 and 1998
, Walter et al. 1989
), the anemic group failed to show an improvement
significantly greater than the iron-replete group. However, in one
study (Lozoff et al. 1987
), the subset of children
showing complete recovery in anemia and iron status caught up to the
iron-replete group in MDI and PDI. In the fourth study
(Harahap et al. 2000
), anemic children initially had
poorer motor development and caught up with the nonanemic
children during the study.
Only two of the longer-term iron trials were DBRCT (Aukett et al. 1986
, Idjradinata and Pollitt 1993
). One
of the latter trials (Aukett et al. 1986
) failed to find
a significant treatment effect on scores of the Denver screening test;
however, the authors reported a post-hoc analysis showing that
significantly more treated anemic children gained the normal number of
items than did children in the placebo group. The other study
(Idjradinata and Pollitt 1993
) showed a large
significant treatment effect in both MDI and PDI.
Discussion.
There is no good evidence from RCT that short-term iron treatment
benefits the development of anemic young children. However the anemic
groups were very small in all five of the studies and one contained
only 12 subjects. No investigators reported the studys statistical
power to show differences, but it must have been extremely low. In the
four studies reporting the scores of placebo and iron-treated
anemic groups, the iron-treated group improved more than the
placebo group (Driva et al. 1985
, Lozoff et al. 1982b and 1987
, Oski and Honig 1978
). Thus the
hypothesis cannot be considered to have been tested rigorously.
However, it may be that it takes longer than 2 wk for the type of
skills measured by the Bayley Scales to develop. It is possible that
other behaviors such as attention and motivation could change.
The Indonesian study (Idjradinata and Pollitt 1993
) is
unique in being a DBRCT with long treatment and using the Bayley test.
It is also unique in showing a clear significant treatment effect in
both MDI and PDI. The treated children showed an extremely large
improvement in both indices. The size of the increase is surprisingly
large for a 4-mo period. However, in one other study (Oski et al. 1983
), children showed a similar increase in less time. In
the only other DBRCT with this age group (Aukett et al. 1986
), the Denver screening test was used as the outcome
measure. This test is not sensitive to small differences and was
intended to screen for children with abnormal development. Most studies
indicate that the development of anemic children is within the normal
distribution.
In four long-term trials (Harahap et al. 2000
,
Lozoff et al. 1987 and 1996
, Walter et al. 1989
), using only nonanemic iron-replete groups as
controls, the anemic group did not catch up to the nonanemic group in
three but did in one (Harahap et al. 2000
). There are at
least two reasons why it is not possible with this design to infer the
presence or absence of a causal relationship. First, most children
improve slightly with test practice and we cannot be sure that
untreated anemic and nonanemic children respond in the same way. It is
possible that anemic children have poor test behavior and do not learn
as much as the nonanemic children from the test experience and thus
improve less. In this case, improving the same amount as nonanemic
children could actually represent an iron response that would not be
detected. Another possibility is that anemic childrens fearful and
unresponsive behavior causes them to perform badly at the first test
and subsequently improve more that the nonanemic group.
When we examined the four studies with placebo anemic and nonanemic
iron-replete groups there were no consistent differences between
the groups in their changes in Bayley scores between tests. The change
in scores in nonanemic and anemic placebo groups were +6 and +2
(Lozoff et al. 1987
), +5.1 and +5.5 (Lozoff et al. 1982b
), +8.3 and +6.7 (Walter et al. 1989
),
+2.1 and +0.5 (Idjradinata and Pollitt 1993
),
respectively.
Nonanemic controls are helpful in assessing whether iron-deficient
anemic children catch up to nonanemic children. However, anemic
children usually come from poorer environments that should be
controlled for before catch-up is examined. Most investigators
restricted the range of social background and biomedical conditions
found in the study children, but few controlled further for
environmental factors when examining catch-up. Of the five
longer-term studies that had nonanemic groups, the treated anemic
group failed to catch up to the nonanemic group in scores on the Bayley
test in three studies (Lozoff et al. 1987 and 1996
,
Walter et al. 1989
). Anemic children in the two other
studies caught up to the nonanemic group (Harahap et al. 2000
, Idjradinata and Pollitt 1993
). It is
difficult to explain why children in two studies caught up and those in
the others did not. Duration of treatment did not explain this because
the Costa Rican study (Lozoff et al. 1996
) had the
longest treatment period. Severity of anemia did not explain this
either because two of the studies had less severe criteria for anemia
than did the Indonesian study (Idjradinata and Pollitt 1993
). Disparities in social background between the anemic and
nonanemic groups may explain some of the failure to catch up.
Outcome measures.
The Bayley test is a global measure and gives little indication as to
any specific cognitive deficit. Its predictive ability in y 1 of life
is extremely limited, but increases in y 2 (Colombo 1993
). Other measures of infant cognitive development such as
novelty preference and fixation time (Colombo 1993
,
Goswami 1998
) might be more sensitive and predictive in
y 1. However, the Bayley test was sensitive to initial differences
between anemic and nonanemic groups in nearly all studies. Furthermore,
marked changes were found with iron treatment in the Indonesian study
(Idjradinata and Pollitt 1993
) in both MDI and PDI. The
PDI of the Bayley test has also been sensitive to changes from
nutritional supplementation in studies of protein-energy
malnutrition (Husaini et al. 1991
, Joos et al. 1983
).
Summary. In general, these studies are difficult to interpret mainly because so few were RCT and the samples were often extremely small. There has been a hesitancy to use placebo groups in the field of iron deficiency on ethical grounds. This is the main reason we do not have clear answers to the important question of whether iron treatment can benefit the development of anemic children. There is no clear evidence that short-term iron treatment has such a benefit; however, the question has not been tested rigorously. Long-term treatment has clearly been shown to benefit the development of anemic children in only one relatively small study. We could find no other study that had rigorously evaluated (with an RCT) the effect with sensitive outcome measures. In several studies, but not all, anemic children have failed to catch up to nonanemic children with iron treatment. We located no study that looked at the effect of anemia in high-risk children (e.g., low birth weight)
Therapeutic treatment trials in children >2 y old
We identified 13 iron treatment trials with anemic children >2 y
of age that included iron-deficient children and one trial in
pregnant women. One reported no statistical analysis of the treatment
and will not be discussed in detail (Soemantri 1989
).
The more important details of the others are given in Table 3
.
(Bruner et al. 1996
, Deinard et al. 1986
,
Groner et al. 1986
, Lynn and Harland 1998
, Pollitt et al. 1983, 1985, 1986 and 1989
,
Seshadri and Gopaldes 1989
, Soemantri et al. 1985
, Soewondo et al. 1989
).
Comparison with nonanemic iron-replete children.
Eight studies (Deinard et al. 1986
, Pollitt et al. 1983, 1985, 1986 and 1989
, Soemantri et al. 1985
, Soemantri 1989
, Soewondo et al. 1989
) had nonanemic comparison groups and in one
(Deinard et al. 1986
), no initial difference was found
on enrollment between the groups in developmental quotient and IQ. This
study had a very wide age range (1860 mo) and scores on the Bayley
test were combined with scores on the Stanford Binet test. In the other
seven studies, the anemic children had significantly poorer cognitive
scores or school achievement than did the nonanemic iron-replete
groups in at least one test. A variety of tests have been used. In the
two studies that used a test of discrimination learning, the groups
were different (Pollitt et al. 1983 and 1986
); this test
was reported to depend largely on attention. In two of three studies
using an oddity learning test, which measures concept learning, the
groups were different (Pollitt et al. 1986
,
Soewondo et al. 1989
). IQ tests did not show differences
in three studies [the Stanford Binet test used by Pollitt et al. (1983)
and the Ravens Progressive Matrices used by
Soemantri (1989)
and Soemantri et al. (1985)
] but did in one study [the Ravens Progressive Matrices
used by Pollitt et al (1989)
]. Differences were not detected in
short-term memory in two studies (Pollitt et al. 1983 and 1986
). The Matching Familiar Figures test, which measures the
efficiency of solving a visual perceptual problem, was different in
another study (Pollitt et al. 1985
), whereas scores on
the Peabody Picture Vocabulary Test were not different in one study
(Soewondo et al. 1989
). Tests of school achievement were
given in two studies and anemic children had lower scores in both
(Pollitt et al. 1989
, Soemantri et al. 1985
).
Catch-up to nonanemic.
In the six studies showing initial differences, the anemic children in
three studies caught up to the level of nonanemic children in scores on
cognition; the anemic children in one caught up in discrimination
learning but not in oddity learning (Pollitt et al. 1986
). In contrast, children in neither of the two studies
measuring school achievement caught up (Pollitt et al. 1989
, Soemantri et al. 1985
) although they
improved on one of them (Soemantri et al. 1985
).
Catching up in school achievement would presumably take a long time
because not only do children have to function well but they also need
the opportunity to learn missed material. This may not occur in schools
without facilities to give children personal attention.
Study design.
Three early studies (Deinard et al. 1986
, Pollitt et al. 1983 and 1986
) had only nonanemic children as controls
and suffer from the problems discussed previously; we will therefore
not discuss these three further. One study had controls matched for
age, gender and IQ but the method of assignment is not clear
(Lynn and Harland 1998
). Nine of the remaining studies
were randomized controlled trials. One did not give a placebo
(Seshadri and Gopaldes 1989
, study 1), but the others
were all double blind. Several had sample sizes of <30 in each
treatment group (Table 3)
but four had reasonably adequate or good
numbers (Bruner et al. 1996
, Pollitt et al. 1989
, Seshadri and Gopaldes 1989
, study 4;
Soemantri et al. 1985
). The study conducted by
Lynn and Harland (1998)
had large groups but most
children were not anemic.
School achievement.
Two studies had robust designs and adequate sample sizes and examined
school achievement, which has obvious policy implications. In
Indonesia, anemic children showed a clear improvement with treatment
(Soemantri et al. 1985
), but it is puzzling that neither
the placebo anemic group nor the two nonanemic groups made any
improvement in 3 mo of schooling. This lack of progress suggests that
the school was not teaching effectively; if this was the case, it may
be that the treated anemic childrens ability to take tests in general
improved rather than they had learned more. This would impute such
factors as attention and motivation. An alternative explanation is that
the test was insensitive over a certain level, causing a ceiling
effect. In the other study (Pollitt et al. 1989
),
children in Thailand showed no improvement with treatment. The
criterion for anemia in that study was high, hemoglobin <120 g/L, and
the placebo group actually improved by 14 g/L, probably secondary to
the deworming. It is possible that the placebo group responding to
improved iron status may have threatened the integrity of the trial. In
contrast, in the Indonesian study, the criterion for anemia was lower
(<110 g/L) and the placebo groups hemoglobin levels declined by 17
g/L during the study. A further consideration is that the children were
tested in groups in the Thailand study, which is unlikely to be as
accurate as individual testing; it is not clear how testing was
conducted in the Indonesian study.
Cognition.
In another Indonesian study with only 24 treated anemic children
(Soewondo et al. 1989
), no effect was found on
vocabulary scores (Peabody Picture Vocabulary Test), and many children
were on the floor of the discrimination learning test, making its
validity doubtful. In the oddity test, after initial test scores were
controlled for, there was no significant difference between the
iron-treated and placebo anemic groups, but an interaction occurred
between treatment and group in two of four tasks. The treated anemic
group improved more than the treated nonanemic group, indicating some
catch-up. Only limited details were available from an Egyptian
study (Pollitt et al. 1985
). The Matching Familiar
Figures test was used; the efficiency of the treated anemic children
improved significantly, and they were significantly better than the
placebo group at post-test. Group differences in change of scores
were not reported. There were four studies from India (Seshadri and Gopaldes 1989
) and in each the children were randomly
assigned to treatment or control, regardless of hemoglobin level. The
first study had no placebo; in the second study the children were given
folic acid as well as iron, which may have had an independent benefit.
However, the iron-treated group was significantly better than the
control group at the end in the second study. In the third study, the
treated group improved significantly in most of the cognitive tests,
whereas the placebo group did not. At the end, the treated groups had
higher scores than the nontreated groups. In the fourth study,
iron-treated anemic children improved more than the
placebo-treated anemic children in two of four tasks. There was a
suggestion of a treatment effect in all four studies, but none reported
the significance level of differences in change of scores by the
randomized groups. Only the fourth study reported difference between
the groups in change of scores, but they restricted the analysis to
anemic children only, thus breaking the paired randomized design. It is
probable that there was a treatment effect in the third and fourth
studies.
In an English study (Lynn and Harland 1998
), there was
no overall treatment effect. When the children were divided into
subgroups by iron status, the subgroup with low iron status (ferritin
<12 µg/L) showed a significant treatment effect on a test
of visual reasoning. However, the findings were inconsistent and the
group with moderate iron status showed no benefit from treatment,
whereas the group with high iron status showed significant benefits.
Also, ascorbic acid was given in the iron treatment and may have had an
independent effect.
In a trial with pregnant women, the treatment group improved significantly more than the placebo group in a test of short-term memory (digit span) and a test of attention (Consonant Trigrams). There was however, a large loss (n = 10) from the control group, leaving only 9 children.
The final study was with nonanemic iron-deficient older girls
(Bruner et al. 1996
). It was a well-conducted trial
except that they did not have three measures of iron deficiency.
Several cognitive functions were assessed, including auditory divided
attention, speed of coding, visual search and attention, and verbal
learning. There was no treatment effect on the first three tests. The
learning test comprised three parts, and a significant effect was found
in free call but not in delayed recall or recognition. Three other
randomized trials included nonanemic iron-deficient or
iron-depleted children in this age range (Pollitt et al. 1985 and 1989
, Soewondo et al. 1989
). They all
failed to find any treatment effect, but the samples were smaller.
Summary. As with the younger children, anemic children usually had poorer cognition and school achievement than nonanemic children. They tended to catch up with repeated testing and treatment in cognition but not in school achievement.
There were eight DBRCT with anemic subjects or a mixture of anemic and
nonanemic subjects and another in which the method of assignment is not
given and ascorbic acid was given with the treatment (Lynn and Harland 1998
). In two trials (Groner et al. 1986
, Soemantri et al. 1985
), significant
treatment effects were reported by randomized group. In another two,
significant treatment effects were found in the subgroups of anemic or
most iron-deficient children (Lynn and Harland 1998
,
Seshadri and Gopaldes 1989
, study 4). Data suggestive of
treatment benefits was reported from three other studies
(Pollitt et al. 1985
, Seshadri and Gopaldes 1989
, studies 2 and 3). All three reported significant
differences at the end but did not analyze differences in change in
scores. These studies were reported as conference proceedings or a
letter, and details were not available. In two studies, no significant
treatment effect was reported (Pollitt et al. 1989
,
Soewondo 1995
).
Some of the studies were small and must have had limited power to show differences. None reported long-term follow-up of children to determine whether benefits arose later or whether benefits were sustained.
Nonanemic iron-deficient or depleted children.
We identified three randomized trials with nonanemic iron-deficient
children >2 y old. Although one trial found a treatment effect in one
of several tests (Bruner et al. 1996
), three other
studies with smaller samples did not (Pollitt et al. 1985 and 1989
, Soewondo et al. 1989
). In addition, one
study in the <2 y age range included iron-deficient children and
found no benefit from treatment (Idjradinata and Pollitt 1993
). Therefore the evidence for an effect of treatment is
weak.
Preventive treatment trials
We identified six preventive trials (Heywood et al. 1989
, Lozoff 1997
, Moffatt et al. 1994
, Morley et al. 1999
, Walter et al. 1989
, Williams et al. 1999
) (Table 4
). Two trials are difficult to interpret. A large number of the children
became infected with malaria and this confused the results in one study
(Heywood et al. 1989
). In the second study
(Walter et al. 1989
), the analysis was not reported for
the original randomized groups; instead the groups were pooled and all
anemic children were found to have significantly lower scores than the
nonanemic groups in MDI and PDI. These two studies will not be
discussed further.
|
In three of the studies, some beneficial response to iron treatment was
found. In Canada (Moffatt et al. 1994
), children were
supplemented from 2 mo of age and were tested at 6, 9, 12 and 15 mo.
The iron-fortified group had significantly higher PDI scores than
did the placebo group at 9 mo (4 points) and 12 mo (6.3 points), but
the benefit was only 2.9 PDI points at 15 mo and no longer significant.
There was no significant effect on MDI. The difference between the
groups in percentage anemic was greatest at 6 mo (19.9%) and had
become small by 15 mo (8%). The loss from the study was approximately
one third but the investigators controlled for any difference between
lost and tested children. The findings suggest that the effect of iron
deficiency is transient.
In England (Williams et al. 1999
), children were
supplemented from 7 to 18 mo of age and benefits were not found until
24 mo. The global developmental quotient fell 5.4 points more in the
nonfortified group than in the fortified group (P < 0.05). The scores of all subscales fell less in the iron-fortified
than nonfortified group but the personal social subscale was the only
one to show a significant treatment effect. This was the only study to
follow children for as long as 17 mo, including 6 mo after the
cessation of treatment; thus, it is conceivable that other studies may
have had undetected benefits. The main problem with the study is that
fortified formula was given to one group and money to buy cows milk
to the other group. It is possible that other constituents in the
formula were responsible for the benefits or that cows milk reduced
the absorption of other nutrients. Also, the study was not double
blind. The loss was not large (15%), but unfortunately this included
two children excluded from the nonfortified group because of anemia and
two from the fortified group excluded because of failed protocol. Some
children were already anemic on enrollment at 7 mo (fortified 13%,
nonfortified 16%). The difference in hemoglobin levels between the
groups was considerable at 12 mo (31%) and at 18 mo was 24%.
A Chilean study (Lozoff 1997
) probably had the greatest
statistical power. The children showed no benefit on the Bayley test,
but at 12 mo the fortified group had shorter fixation times on the
Fagan test (Lozoff, personal communication), which is thought to
indicate better attention and ability to encode stimuli. However,
within the groups, the anemic children did not have longer fixation
times than nonanemic children. This study was the shortest and,
furthermore, all anemic children were excluded at enrollment;
therefore, any case of anemia would have been of short duration and not
have been present for at least the first 6 mo of life. Both of these
factors may have played a role in the lack of effect on the Bayley test
scores. The Fagan test predicts later mental development and is
probably more sensitive to small cognitive differences. However, the
lack of consistency within the groups in the relation between fixation
times and anemia makes the finding difficult to interpret. Details of
the study are not yet fully reported; thus, in-depth evaluation is
not possible.
In contrast to the above, another English study (Morley et al. 1999
) found no benefit from 9 mo of iron treatment begun at age
9 mo. Fewer than one third of the children had hemoglobin levels
available at the beginning and end and these were considered not valid
because of technical problems (Lucas, personal communication). The
other measures of iron status indicate very little iron deficiency;
thus, the study would have had limited power to show benefits from
treatment. The results are therefore not possible to evaluate except
that there was no apparent harmful effect of giving iron to nonanemic
children.
Conclusions.
Only three of the prophylactic studies can be assessed. All found at
least a hint of some improvements, albeit in one study, treatment was
confounded by formula (Williams et al. 1999
). The other
two studies were double-blind control trials. In the Canadian study
(Moffatt et al. 1994
), the benefits were small,
transient and limited to motor development. In the other study
(Lozoff 1997
), benefits were not found on the Bayley
test and inconsistent benefits were found on the Fagan test. These
findings provide extremely limited evidence that preventing
iron-deficiency anemia produces benefits to development. When
benefits were found, they were transient or small. Longer-term
follow-up may help to interpret the Chilean data.
| OVERALL COMMENTS |
|---|
|
|
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Another problem is that many studies suffered from lack of statistical power; future studies not only should be randomized trials but also should have adequate sample sizes. A further problem is that when studies use a battery of tests and analyze several different scores from each test, there is a danger of spurious significant effects.
Last, there is an extreme lack of data on high risk children. In countries with large populations of high risk children, such as children with low birth weight, this may be important.
| OVERALL CONCLUSION |
|---|
|
|
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Anemic children <2 y old
There is no good evidence from RCT that short-term iron treatment benefits the development of anemic young children, but this has not been examined with rigor. The evidence of benefits from long-term trials is insufficient for drawing conclusions or extrapolating to other populations. There are insufficient RCT on the topic and larger studies are required in which both short- and long-term effects are assessed.
In several but not all studies, anemic children have failed to catch up
to nonanemic children with iron treatment. This indicates that either
their poor development is not caused by anemia or that the effect is
irremediable by iron treatment alone, at least in the short term. This
is surprising, considering the plasticity of child development;
however, a vulnerable period exists for iodine deficiency and there is
limited evidence that the first 2 y of life may be critical for
protein-energy malnutrition (Grantham-McGregor and Ani 2001
). It
may be that improvements in the environment may be necessary for anemic
children to catch up.
Anemic children >2 y old
Anemic older children also usually had poorer cognition and school achievement than did nonanemic children. They usually catch up in cognition with repeated testing and treatment but not in school achievement.
There are more RCT with this age group, and it was clearly shown that children benefited from iron treatment in four studies and a treatment benefit was highly likely in three others. However, two studies showed no effect. At present, the evidence for a beneficial effect of iron treatment on cognition in anemic older children is reasonably convincing, but it would be helpful to run one or two more rigorous RCT with detailed reporting of the results.
Preventive trials
Only limited data from preventive studies support a causal relationship. Preventing iron deficiency anemia can produce benefits to development but they are small and may be transient. The Chilean study should be followed up for longer to determine the implications of the benefits on the Fagan test.
It is difficult to come to unequivocal overall conclusions concerning the effects of iron deficiency in the first 2 y. There is some evidence of a causal relationship but this tends to be inconsistent. There are too few randomized trials of adequate size and appropriate analyses to make firm conclusions. More large randomized trials with anemic children are required before we can inform policy with confidence.
However, considering the stronger evidence of a causal relationship in school children it would be surprising if younger children were not also affected.
DISCUSSION
Participants: Lozoff, Pollitt, Grantham-McGregor, Beard, Haas, Habicht, Schultink, Sazawal, Allen, Lynch.
Dr. Lozoff: First, it is very sobering. I have been working on iron deficiency for 25 years now, and really trying to do good studies. After all this effort, we still cannot give definite answers.
Second, I was pleased to see that we did not buy in totally to the reasoning that if we could show that we could correct it, that would be the proof that iron was the cause. There was a period in the literature where, if you did not show that you corrected it with the iron treatment, people would conclude iron deficiency could not be the cause, because you correct the anemia, you correct the development. I was trying to think of an analogy for this. Take tuberculosis. A child comes into the hospital with tuberculosis meningitis. You give antituberculosis drugs. The child still has neurological sequelae. Well, the child might have had a neglectful or a misguided family, but the child nonetheless had tuberculosis meningitis. Tuberculosis has been cleared from the body. There was unequivocally a treatment response, but you still have a long-lasting effect. So, it is just fallacious thinking to hold as the only criterion that you reverse it with iron treatment and I was pleased that Dr. McGregor made that so clear. It would be great if we could do it, because that would settle the whole thing, but the reverse does not hold true.
Third, I want to highlight the unresolved issues as I see them. We have not really been looking at specific central nervous system functions. As we do that, we are going to have to revisit this iron deficiency without anemia. We have got to revisit these more sensitive measures. Similarly, we have got to revisit everything about what treatment affects or does not affect as you get more measures that make sense in terms of what iron is doing.
Finally, one comment about the magnitude of effect. The Bayley for infants and toddlers has been the only measure that we really have had. So, it has been used not just in iron deficiency but in a whole host of early biological risks. The magnitude of the differences that we have observed between anemic and nonanemic kids on the Bayley is of the same order of magnitude that is widely accepted as being clinically relevant and important, whether it is low birth weight or cocaine or alcohol or any of those things. I shared Dr. Pollitts concern about the Bayley Scales, but I wanted to be sure that we at least gave that information to everybody.
Dr. Pollitt: The data have shown differences in the Bayley Scales that were based on children who were 18 mo or older. They probably do have significant value. I am arguing that it is at the younger ages that the data are not good. Second, we also have to understand that a 35 point difference in the Bayley Mental Development Index may actually represent only about 12 wk of difference in development. In other words, a 3 or 5 point difference, as has been reported, does not correspond to a difference of 3 mo of development. It is equivalent to 15 d.
Dr. Lozoff: Six to 19 points difference in your study?
Dr. Pollitt: Nineteen points actually represents about a month and a half.
Dr. Grantham-McGregor: That is quite a lot in a young infants life. It is not like a month and a half in my life.
Dr. Beard: I would like all three of the pr