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Department of Pediatrics, School of Medicine, Program of International Nutrition, University of California, Davis, CA 95616
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONProtein-energy malnutrition and...PEM and the critical...Beneficial effects of...Gaps in knowledgeAreas that require further...Iron deficiency anemia in...Support from neurobiological...SUMMARYREFERENCES |
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KEY WORDS: • protein-energy malnutrition • iron • anemia • cognition • development.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONProtein-energy malnutrition and...PEM and the critical...Beneficial effects of...Gaps in knowledgeAreas that require further...Iron deficiency anemia in...Support from neurobiological...SUMMARYREFERENCES |
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Several researchers have attempted to determine whether the effects of PEM on child development are long lasting and permanent, particularly as they relate to cognition. A large body of data has been accumulated in an attempt to resolve this issue, using animal models and longitudinal studies of children. Conclusive answers are not yet available, but we are more knowledgable than we were two to three decades ago.
As investigators of iron deficiency anemia, we are now asking the same question. Is the cognitive delay incurred by iron deficiency anemia in infants irreversible? With new concepts of developmental psychobiology in mind and data from PEM research, I would like to address in this paper the putative permanent effects of early iron deficiency anemia on later developmental outcomes.
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Protein-energy malnutrition and development |
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TOPABSTRACTINTRODUCTIONProtein-energy malnutrition and...PEM and the critical...Beneficial effects of...Gaps in knowledgeAreas that require further...Iron deficiency anemia in...Support from neurobiological...SUMMARYREFERENCES |
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One distinct characteristic of the research on PEM and child
development is the selective focus on learning and intelligence.
Clinical and field studies used primarily mental development scales for
infants and toddlers, and IQ tests or cognitive tasks for older
children. Some studies that followed subjects up to the school years
measured variables related to school readiness and performance
(Chavez et al. 1995
, Pollitt et al. 1993
). Researchers in the field today regret the adoption of
such a restricted view because the oversight has been costly. Cognition
maintains close functional ties with emotional regulation, motor
development and motor activity; it is now recognized that these domains
are the centerpieces of the psychobiology of human development
(Thelen and Smith 1998
) and that together they
contribute to shape the course of child development (Gottlieb et al. 1998
).
PEM and animal models.
Historically, work in animals on the functional consequences of energy
and protein deprivation has moved in two directions. One approach has
moved toward an understanding of the developmental changes in the
anatomy and biochemistry of the brain in experimental animals
(Dobbing J. 1990
, Winick and Noble 1966
) The other approach has moved toward describing the
compromise of behavioral competence (Barnes et al. 1970
,
Cowley and Griesel 1963
, Platt and Stewart 1968
, Zimmermann 1969
). This research on animal
behavior goes far beyond learning. As early as the 1960s, researchers
documented the long-lasting effects of malnutrition on alterations
in eating behavior, increased emotionality and anxiety, increased
reactivity to unfamiliar environment and disturbed social behavior
(Levitsky and Strupp 1995
).
The following section discusses the vulnerability of the human organism during the early stages of development and the validity of the critical period hypothesis for child development.
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PEM and the critical period hypothesis |
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TOPABSTRACTINTRODUCTIONProtein-energy malnutrition and...PEM and the critical...Beneficial effects of...Gaps in knowledgeAreas that require further...Iron deficiency anemia in...Support from neurobiological...SUMMARYREFERENCES |
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,
Levistsky and Strupp 1995
). These observations gave
credibility to the hypothesis that a nutritional insult during
suckling, which is a critical period of cerebral growth, has permanent
functional effects. However, only part of this premise has been
validated. Researchers who initially documented the effects on rodent
cerebral growth did not allow enough time for catch-up growth to
occur. After a period of malnutrition, cortical cell division lasts
longer than that of controls. Although there is the opportunity for
recovery, there is also evidence of permanent cortical injury.
Limitations in the density and arborizations of dendrites and width of
the cortical cells have been established. Neurotransmitter systems are
also altered permanently. For example, the number of norepinephrine
receptors is reduced compared with controls (Levitsky and Strupp 1995
). The external validity of observations in laboratory animals and their generalizability to the mental development of undernourished children were not obvious. It has taken >20 y to accumulate evidence from longitudinal studies of undernourished children to address some aspects of this issue. No definitive answers are yet warranted, but the available data show that improvements in the quality and quantity of the diet and in the satisfaction of basic needs prevent or remediate at least in part the early effects of malnutrition.
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Beneficial effects of nutritional interventions and environmental changes |
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TOPABSTRACTINTRODUCTIONProtein-energy malnutrition and...PEM and the critical...Beneficial effects of...Gaps in knowledgeAreas that require further...Iron deficiency anemia in...Support from neurobiological...SUMMARYREFERENCES |
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A study in Guatemala showed that adolescents who had received a
supplement of 11.5 g of protein and 682 kJ pre- and postnatally
during the first 24 mo of life scored significantly higher on
tests of knowledge, numeracy, reading and vocabulary than subjects who
had received a 246-kJ supplement during the same period (Pollitt et al. 1993
). The subjects enrolled in the study after the
first 24 mo of life also benefited from the high protein and energy
supplement but to a lesser degree than those enrolled at an earlier
age. Social and economic variables appear to moderate the effects
because the beneficial effect was restricted to children at the lowest
level of the socioeconomic scale.
Another study in Colombia (Pollitt and Perez-Escamilla,
unpublished) showed that a comprehensive experimental intervention that
included health care, supplementary feeding and educational
opportunities, beginning at 42 mo of life, also benefited cognition.
During the intervention period, beneficial cognitive effects were
observed, but they faded away after the intervention ended. A third
study demonstrated that a 90-d high energy supplement during infancy
had long-lasting effects on cognition (Pollitt et al. 1997
). Children (n = 334) aged 6–60 mo
living on rural tea plantations in West Java participated in a 3-mo
randomized trial to test the effects of a dietary supplement providing
~ 1672 kJ energy/d with about the same nutrient density as local
foods. Two thirds of the original sample were enrolled in a
follow-up study 8 y after the experiment. Several measures of
intelligence and information processing were used to evaluate the study
groups. The supplemented group showed no differences from those in the
control group. However, when the analysis was limited to subjects who
had received the supplement before the age of 18 mo, the supplemented
children performed better than control children on a test of a very
specific cognitive domain, working memory.
Grantham-McGregor and Buchanan (1982)
published a case
report study in Jamaica of an 8-mo-old severely malnourished child who
was hospitalized. After rehabilitation, the child’s IQ was ~70 and
he went back to the same environment that contributed to his original
malnutrition. Two years later, the child was adopted by a school
teacher. By age 5, the child’s IQ was higher than the average IQ of
children of lower socioeconomic status in Jamaica.
Similar information exists for adopted girls from an orphanage in Korea
(Winick et al. 1975
). All of the children were taken to
the adoption agency when they were <2 y old; they were adopted by
American families when they were <3 y old. At the time of adoption,
they were classified into groups indicating whether they were
malnourished, moderately well nourished or healthy. When the children
were in elementary school, the mean IQ of these three groups was 102,
106 and 112, respectively. The only significant difference was between
the malnourished and the healthy group (P < 0.001). Although the IQ of the malnourished group was lower, it should
be noted that it was within the normal range of the standardized U.S.
population.
Tentative conclusions.
In communities in which malnutrition is endemic, supplementary feeding that meets nutritional requirements of children during the first 18–24 mo of life may help to prevent part of the cognitive delays caused by extreme poverty and malnutrition. At times, these effects will be restricted to fairly specific cognitive processes. Once past the 18- to 24-mo period, the developmental benefits of the supplement will vary as a function of the breadth (e.g., nutrition, health, education) and duration of the intervention, i.e., the broader and the longer the duration of the intervention, the higher the probabilities of recovery. In addition, moderating factors can either maintain such beneficial effects or modify them by either decreasing or increasing the severity of the functional insult.
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Gaps in knowledge |
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TOPABSTRACTINTRODUCTIONProtein-energy malnutrition and...PEM and the critical...Beneficial effects of...Gaps in knowledgeAreas that require further...Iron deficiency anemia in...Support from neurobiological...SUMMARYREFERENCES |
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Areas that require further investigation |
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TOPABSTRACTINTRODUCTIONProtein-energy malnutrition and...PEM and the critical...Beneficial effects of...Gaps in knowledgeAreas that require further...Iron deficiency anemia in...Support from neurobiological...SUMMARYREFERENCES |
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Undernourished infants and toddlers are often irritable, clingy, fussy,
easily frustrated and fearful of novel stimuli compared with
better-nourished children (Graves 1976
). Reports of
these characteristics have a long history in the clinical descriptions
of malnourished children. Similarly, as noted, alterations in emotion
and motivation were among the first distinctive behaviors described in
laboratory animals in experimental studies of malnutrition and
behavior. Compared with controls, rodents with a history of
undernutrition show erratic motivation, increased emotionality, greater
anxiety and poor adaptation to distressing environmental stimuli
(Levitsky and Strupp 1995
).
Motor development and activity.
Although large amounts of data exist on the effects of PEM on physical
growth and there is documentation that PEM also limits motor
development, there has been little work done on the functional
relationships among growth, motor development and motor activity
(Meeks-Gardner and Grantham-McGregor 1998
). Body
size, body proportions and body mass along with muscle and bone
strength also affect the onset of locomotion (Thelen and Smith 1998
). The physics and engineering of the
biological-mechanical system play key roles in motor actions. In
humans, for example, the infant’s balance and extensor muscle strength
must reach critical values to enable the infant to support its weight
in a stable manner on one leg, while it lifts the other to take a step
(Thelen and Smith 1998
).
Comments.
Studies of PEM and child development have been compartmentalized in
that only specific aspects have been assessed, without consideration of
the different variables that also affect development. The developmental
interrelationship of these variables has been ignored, yet early in
life, physical growth, motor development, motor activity and emotional
regulation are not independent of each other (Pollitt in press
). For instance, self-initiated locomotion (e.g.,
crawling, walking) represents motor changes that are critical for the
development of visual perception, spatial orientation and emotional
regulation (Adolph 1997
). Further, as noted, the
variability among children to deal with their social and physical
environment does not depend on differences in cognition alone. Personal
style such as the capacity to inhibit inappropriate behaviors and to
cope effectively with internal and external stimuli will influence a
child’s behavioral-emotional adjustment and the ability to
function in different contexts.
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Iron deficiency anemia in children |
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TOPABSTRACTINTRODUCTIONProtein-energy malnutrition and...PEM and the critical...Beneficial effects of...Gaps in knowledgeAreas that require further...Iron deficiency anemia in...Support from neurobiological...SUMMARYREFERENCES |
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, Seshadri et al. 1982
, Watkins and Pollitt 1998
).
However, there are noteworthy exceptions. Lozoff and her collaborators
documented changes in the regulation of emotions among
iron-deficient anemic infants through several publications
(Lozoff and Brittenham 1986
, Lozoff et al. 1986
). Such infants present wariness, hesitancy, tiredness,
inattentiveness and general lack of involvement with testing stimuli
(Lozoff et al. 1998
). Furthermore, as in the case of
PEM, several studies have shown that iron-deficient anemic children
demonstrate delayed motor skills as documented by comparatively poor
scores in the Bayley Scales of Motor Development. There is also
evidence that iron deficiency in laboratory animals imposes limitations
in physical activity levels (Hunt et al. 1994
).
About 25 y ago, Cantwell (1974)
first reported that
iron deficiency anemia could produce long-lasting neuropsychologic
effects. Thereafter, several studies have shown an association between
iron deficiency and poor performance later in life (Palti et al. 1983
). A recent epidemiologic study conducted in Florida
addressed the relationship of early nutrition and mental function later
in life (Hurtado et al. 1999
); that study offers
suggestive evidence of this association. The study linked the health
records of 5411 children, 1–5 y old, who had been enrolled in the
Special Supplemental Program for Women, Infants, and Children (WIC)
with mental function assessed from school records. Researchers
attempted to determine the association between anemia [hemoglobin (Hb)
<2 SD of the median reference standard] and
mental retardation. Mild-to-moderate mental retardation (i.e., educable
mentally handicapped or trainable mentally handicapped) was evaluated
according to the criteria used by the Florida Department of Education.
Results indicated that after controlling for birth weight, maternal
education, sex, race-ethnicity, age of mother and age of child, a
decrement of one unit in Hb was associated with an increased risk of
1.28 (odds ratio) of mild-to-moderate mental retardation.
Lozoff et al. (in press) recently reported on the mental and motor
function of 12-y-old subjects who had been treated for iron deficiency
anemia in infancy. Biochemical tests had been used to establish the
iron status of the children when they were infants, ~12–23 mo old.
All of the 191 iron-deficient anemic infants had been placed on a
successful iron therapy program for 3 mo. Those infants classified as
moderately anemic obtained lower mental and motor scores before and
after treatment than those classified as normal. The mildly anemic
subjects were also at a disadvantage in motor, but not in mental
development. Ten years later, 87% of the original sample were enrolled
in the follow-up study and were classified into one of four groups:
1) moderate iron deficiency anemia; 2)
iron deficiency before and after treatment (children with higher Hb
levels who still had biochemical evidence of iron deficiency after 3 mo
of therapy); 3) iron deficiency fully corrected; and
4) good iron status before and after treatment. For
statistical purposes, the first two groups were combined (i.e.,
iron-deficient group) and compared with the last-mentioned
group. After adjustment for covariates, the iron-deficient anemic
group had poorer scores than the comparison group in the arithmetic and
reading component of the wide-range achievement test. These
findings are consistent with the 5-y follow-up data (Lozoff et al. 1991
).
The results of the Lozoff studies are noteworthy but there are concerns regarding study design. Even though the investigators controlled carefully for some of the potential confounders, the quasi-experimental design did not allow them to ensure the control of other confounders of perhaps greater importance. In particular, there was no way to determine whether the internal family environment and caretaking processes among the severely anemic children were different from those of the well-nourished children.
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Support from neurobiological data |
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TOPABSTRACTINTRODUCTIONProtein-energy malnutrition and...PEM and the critical...Beneficial effects of...Gaps in knowledgeAreas that require further...Iron deficiency anemia in...Support from neurobiological...SUMMARYREFERENCES |
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, Dallman and Spirito 1977
). For example, Dallman et al. (1975)
showed
substantive reduction of cerebral iron after the full repletion of body
iron in rats that became iron deficient for short periods at the time
of weaning [see also Felt and Lozoff (1996)
]. In
normal rats during this period, brain iron is accumulating at its
highest pace (Beard et al. 1993
). The depletion of iron
in the brain (Erikson et al. 1997
) affects neuronal
processes and neurotransmitter metabolic changes critically involved in
the development of particular behavioral domains. For example, it is
plausible that either delays in the timing of myelination
(Connor and Menzies 1996
) or changes in D2 dopamine
receptors (Ashkenazi et al. 1982
), or both, may explain
the delays in motor development that have been reported in
iron-deficient anemic infants and children. Comments.
Data from animal models provide some support for the claims that early iron deficiency anemia is a cause of impaired cognitive function in later life. Changes in D2 receptors, delays in the formation of the myelin sheath or alterations in neural networks would be the intervening variable between deficiency and function. Despite this evidence, I would still advocate caution and scientific objectivity based on the following arguments.
1) Studies of PEM show that environmental factors can moderate the relationship between early nutritional insult and later developmental disadvantage.
2) Profound salutary developmental changes can occur after the age of fastest brain growth when the environment changes and the child’s basic needs are met without interruption.
3) There are no data that show that the observed delays of cognition reported for children in middle or late childhood, who were iron deficient as infants, were not a result of intrafamily process variables. Control of potential confounders in studies is usually restricted to structural variables rather than to variables depicting caretaking and interactive processes within the family.
4) There is no documentation that shows that the cerebral alterations produced by experimentally induced iron deficiency anemia in rodents are the underpinning for cognitive delays of children.
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SUMMARY |
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TOPABSTRACTINTRODUCTIONProtein-energy malnutrition and...PEM and the critical...Beneficial effects of...Gaps in knowledgeAreas that require further...Iron deficiency anemia in...Support from neurobiological...SUMMARYREFERENCES |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONProtein-energy malnutrition and...PEM and the critical...Beneficial effects of...Gaps in knowledgeAreas that require further...Iron deficiency anemia in...Support from neurobiological...SUMMARYREFERENCES |
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