Nutrition and cognitive development

Ruth Morley and Alan Lucas

MRC Childhood Nutrition Research Centre, Institute of Child Health, London, UK

In this paper we review the evidence for such early nutritional influences on

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cognitive Function.

There has been a long standing interest in whether undernutrition, at a

sensitive or critical period of brain growth or maturation could have a
long lasting or permanent 'programming' influence on later cognitive
performance1. One noteworthy example of a nutritional influence on
cognitive function is maternal iodine deficiency, which may result in
frank cretinism or reduced cognitive function and school performance in
the offspring2. These nutritional effects, mediated here by an endocrine
mechanism, are irreversible. A key question is whether other general or
specific nutritional insufficiencies can likewise influence or 'programme'
cognitive function. Given the extent and range of nutritional deficiencies
worldwide, this question is of great significance for mankind.
Animal studies have demonstrated that nutritional deprivation affects
measures of performance3, but it is difficult to extrapolate from such
measures in animals (largely rodents) to human cognition, though they
are of importance in establishing both the principle and mechanism of
any associations.
Causal links between early nutrition and later cognitive performance
in man have been difficult to establish. Nutritional deprivation studies
would clearly be unethical, so that most investigations have been of
nutritional supplementation in populations suffering poverty and
undernutrition, which may confound the relationship, making the
influence of undernutrition itself difficult to assess. The greatest need,
identified by Birch in 19684, is for randomised trials of nutritional
intervention and outcome in man. Some such studies have been
undertaken relatively recently.
As well as overall or protein-energy nutrition, there is considerable
interest in whether a deficiency of specific nutrients at a sensitive or
Correspondence to.
critical period for brain development could result in a long term or
Dr Ruth Morley, permanent cognitive deficit. The role of dietary iron intake in later
MRC Childhood Nutrition cognitive function has been extensively researched in both animals and
Research Centre,
Inttitute of Child Health,
humans. Zinc deficiency has also received attention in this respect. That
30 Gwlford Street, breast fed infants perform better than those fed artificially, even after
London W O N 1EH, UK adjusting for potential confounding factors, has led to the hypothesis

Bnh»/i Medico/ BuH.tin 1997,53 (No 1).123-134 ©Th» Bntuh Counal 1997
Fetal and early childhood environment: long-term health implications

that dietary long chain polyunsaturated fatty acids, most notably

docosahexaenoic acid (DHA, found in human milk but not in
conventional formulas) are critical nutrients for neurodevelopment.

Animal studies

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Two key areas that have received attention in animal experiments are the
impact of protein-energy undernutntion and iron deficiency on later
learning and behaviour.

Protein-energy undernutntion

Does undernutntion influence later behaviour* Rodents have been

widely used as experimental models for determining whether there is an
association between early nutritional deprivation and performance
because their brain growth spurt occurs during the suckling period,
when nutrition can readily be modified, for example by nutritional
deprivation of the mother or an increase in litter size. The results of these
studies, many of which demonstrated behavioural disadvantages for
underfed pups, were open to alternative explanations3-5. Changes in litter
size or maternal nutrition, plus any effect of poor nutritional status on
the pup's interest in social interactions, inevitably affected the
interaction between pup and mother, which is important for behaviour.
However, when artificially reared underfed and well fed rat pups, and
mother-reared underfed and well fed pups were compared, the underfed
animals performed less well on behavioural measures, whether or not
they were reared by their mother3. Interestingly the disadvantage for the
underfed rats was greater if they were artificially fed, raising the
possibility that either maternal stimulation or one or more factors in
fresh maternal milk partly ameliorated the effect of poor nutrition on
brain growth or development.
A review of studies comparing the performance of well nourished
versus previously undernourished rats3, showed that a disadvantage for
undernourished animals was significantly more likely if the period of
undernutntion included gestation. Interestingly, the advantage was most
often seen in male animals.

What are the underlying mechanisms of these nutritional effects* The

rat brain is less mature at birth than the human brain and postnatal
undernutntion in rats (at a stage of rapid brain growth comparable with

124 Bnfii/i Medical Bullatm 1997,53 (No 1)

 Nutrition and cognitive development

the third trimester of human pregnancy) has been shown to result in

impairments in a number of different aspects of brain growth and
function6. For example, the effect of undernutrition on the developing
cerebellum was shown to result in a 15% deficit in DNA (a proxy for cell
number). Although cortical neuronal cell numbers were not reduced by
malnutrition, other cortical structures were affected. For example, glial
cell numbers were significantly reduced, as was the complexity of

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cortical dendritic branching and the length and width of synaptic
reactive zones. Evidence emerged that some of these changes were
reversible and cortical glial cell number and synapse to neurone ratio can
improve with good postnatal nutrition. Other structural changes, like
reduction in the number of hippocampal granule cells, have proved
irreversible7, though previously malnourished and rehabilitated animals
had an increase in the number of synapses per hippocampal neurone8.
These findings illustrate the difficulty of predicting the impact of
malnutrition on cognitive function from observed neuroanatomical
changes.
Early malnutrition also produces long term alterations in neurotrans-
mitter metabolism, one being down-regulation of (3-adrenergic receptors,
with possible effects on ability to respond to stressful situations.
Some areas of behaviour in rats were affected whereas others were
not, and the extent of recovery after re-feeding varied between tasks. For
example, in one study there was no effect of undernutrition on position
discrimination, a reversible effect on brightness discrimination but a
permanent impairment of pattern discrimination.
Several studies demonstrated that stimulation (like stroking rat pups)
during or soon after the period of undernutntion ameliorated later
behavioural deficits, giving rise to the hypothesis that early under-
nutrition resulted in a long-lasting impairment in exploratory or leaning
behaviour, which can be ameliorated by stimulation.
Whether such changes in brain structure or function, or in behaviour
can be extrapolated to the human and whether they would cause long
term cognitive impairment are open to debate.

Iron deficiency

Iron is an essential part of a number of haem-containing mitochondrial

enzymes, like flavoproteins. It is also important as a co-factor for
enzymes involved in the metabolism of catecholamines, including
dopamine, the major neurotransmitter in the extra-pyramidal system.
Studies in the rat have shown that early iron deprivation (at 10 days)
led to a permanent reduction in brain iron and dopamine D2 receptor site

Bntish Mtd>cal Bulletin 1997;33 (No 1) 125

Fetal and early childhood environment: long-term health implications

concentration despite subsequent iron sufficiency, though at later ages

the deficits were reversible with iron supplementation9. Rats with the
permanent deficits performed significantly less well than controls in
maze learning tasks.
Whether there is a similar critical period when iron deficiency
permanently affects the human brain is explored in this article.

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Studies of nutrition and neurodevelopment in humans
Evidence from epidemiological studies

Protein-energy undernutrition: Numerous observational studies ex-

plore whether children with severe or mild to moderate undernutrition
or those whose growth was stunted (low weight for height) perform less
well than adequately nourished and normally grown children10-11. In
many, though not all, studies, poor nutritional status has been associated
with lower cognitive or attainment scores. However, retrospective
studies of subjects who were malnourished versus well nourished in
childhood are generally too confounded to yield interpretable data, smce
undernourished children came largely from poor and undernourished
populations, with higher childhood morbidity and parents who were less
able to care for and stimulate their children. Attempts have been made to
match controls for social background, with similar findings.
In Guatemala a large study was conducted in four villages, with
similar populations and lifestyle. In two a high energy, high protein
drink was supplied and in the others a low calorie one; both were
available ad libitum to pregnant women and children up to the age of 7
years. Beneficial effects of supplementation with the high energy, high
protein drink were seen at the end of the intervention period and in
measures of school achievement in adolescence12>13.
Sibling controls have also been used. In about half of these studies the
index undernourished children performed less well than the control
siblings, though the siblings will probably have been exposed to some
degree of undernutrition11.

Breast milk: Children who were breast fed have often been shown to
perform better in terms of tests of development or cognition, verbal
ability or school performance14"18. Results have been similar in both
children born at term and preterm. However, there are two major
sources of confounding.

126 British MmdicalRullmtm 1997,53 (No 1)

 Nutrition and cognitive development

1. The intimacy of breast feeding may be important for infant

development.
2. Mothers who choose to breast feed are different from mothers who
choose not to. In studies conducted on subjects born in the last few
decades, the findings are confounded by the fact that breast fed
children come from a higher socio-economic group than those fed
formula. Thus any differences may reflect higher parental educational

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level, better nutrition and housing, a more stimulating environment,
better access to pre-school education or a more positive attitude to
education.

Many studies have adjusted for a range of potentially confounding

factors and in most cases the advantage for breast fed children has
remained. There is a need, however, to devise studies which avoid
confounding. In two parallel trials of neonatal nutrition in children born
preterm (described in detail below, Fig. 1), we found that even after
adjusting for confounding factors there was a developmental advantage
in both Bayley Mental Development Index at 18 months post term19and
in IQ at 7.5-8 years18 for those children whose mothers had chosen to
provide their own breast milk. In this study the mothers expressed their
breast milk and it was fed to the infant via a nasogastric tube. When we
considered only those infants whose mothers did not go on to breast
feed, the advantage was unchanged, demonstrating that the observed
developmental advantage for preterm children receiving breast milk is
independent of any closeness or intimacy associated with breast feeding
itself.
Two studies were conducted on subjects born at a time when
artificially fed children came from the most socio-economically
advantaged stratum of society. Hoeffer studied children born in the US
between 1915-1921 and showed that breast fed children performed
better than those who were artificially fed, though children who were
exclusively breast fed beyond 9 months did less well20. A study of elderly
subjects born in the UK in the 1930s showed that despite lower socio-
economic status those who were breast fed had higher unadjusted IQ2*21.

Iron deficiency: Children who have iron deficiency anaemia (in some
cases after being randomised to receive iron supplementation) have been
shown to have lower developmental scores than those with haemoglobin
levels in the accepted normal range11-23-24. Infants who were studied by
Lozoff et al in Costa Rica were followed up at the age of 5 years23.
Children who had been anaemic in infancy (haemoglobin <10 g/100 ml)
had lower developmental scores at age 5 than those who had not been
anaemic, regardless of treatment group and despite similar mean current
haemoglobin values in the two groups. These results were confounded

Bnhj/iAUdico/Bu//«tm 1997,53 {No. 1) 127

Fetal and early childhood environment: long-term health implications

STUDY 1 , comparing banked donor milk with pretarm formula

Mother was asked whether she wished to provide her own expressed breast milk for her
baby

No Yes

I
Randomlte to
I
Randomise to

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Banked donor milk vs Preterm formula Banked donor milk vs Preterm formula
as sole diets as supplements to mother's milk
n=159 n-343

STUDY 2, comparing term with preterm formula

Mother was asked whether she wished to provide her own expressed breast mHk for her
baby

1
No
I
Yes

I I
Randomise to
Randomise to
Term formula vs Preterm formula Term formula vs Preterm formula
as sole diets as supplements to mother's milk
Fig. 1 Study design. n=160 n=264

by socio-economic differences between previously anaemic and non-

anaemic children but, even after adjustment for these, the anaemic group
performed less well. Whether this was because important confounding
factors were unidentified or inadequately measured is debated. However,
these data raise the possibility that iron deficiency anaemia in infancy
does have a longer term negative influence on cognition.

Evidence from randomised trials

Protein-energy undernutrition: Randomised trials of nutritional inter-

ventions have been undertaken largely in developing countries in high
risk families or children suffering mild to moderate undernutrition or
stunted growth (low height for age).
In a study in Taiwan nutrient supplementation was given to high risk
mothers during pregnancy and lactation without giving supplements to
their offspring25. Mothers («=255) were randomly allocated a nutrient
supplemented or placebo drink. Children of supplemented mothers had
a small but significant advantage in motor development at 8 months, but

128 Bnt/s/i MidKal BulUtm 1997£3 (No 1)

 Nutrition and cognitive development

mental scores were unaffected and there were no IQ differences at 5

years of age.
In Bogota, Colombia, 433 nutritionally at risk pregnant women were
randomly allocated to 6 groups. They or their children (or both) received
supplementation during different periods up to 3 years. In two groups
the offspring also received stimulation. The intervention period lasted
until children reached 3 years. At the age of about 7 years nutrient

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supplemented children performed better in Reading Readiness tests26-27.
There have been a number of intervention studies in children, though
many were small. In Jamaica28, 129 stunted children aged 9-24 months
were randomly allocated to four groups; non-intervened, nutrient
supplemented, supplemented and stimulated, or stimulated alone. After
a two year intervention both supplemented and stimulated children had
significantly higher Griffiths mental development scores than the control
group. Children who were both supplemented and stimulated had the
highest scores.
In a homogeneous population living on tea plantations in West Java,
day-care centres were randomly designated nutrient supplement provid-
ing centres or control centres, for 6-20 month old infants. The
nutritional intervention lasted 90 days, after which supplemented
children had significantly higher Bayley motor scale scores29.
Longer term post-intervention data are not available from these
studies.
In 1982 we started a nutritional intervention study in low birthweight
children, a group who are at high risk of poor early nutrition and failure
to thrive and are at a stage of rapid brain growth and maturation. Milks
routinely fed to them at that time differed substantially in nutrient
content, ranging from donor breast milk (from unrelated breast feeding
mothers in the community) to a standard term or nutrient enriched
preterm formula designed to meet the special nutrient needs of babies
born preterm, a time of rapid growth. It was both a practical and
ethically undertaken randomised trial; the results were needed for
informed management decisions. Furthermore, there were large differ-
ences in nutrient content between the allocated milks, so we could
investigate, in a randomised prospective intervention trial, whether early
nutrition influences later cognitive status. Altogether 926 infants, born
weighing under 1850 g in 5 centres in the UK in 1982-1984 were
randomly allocated their early enteral diet. The randomisation was as
shown in Figure 1. Study 1 compared banked donor milk with the
preterm formula fed either as sole diets or as a supplement to the
mother's expressed breast milk, if she could not provide enough milk to
meet her infant's needs. Study 2 compared a standard term formula with
the preterm formula, again as sole diets or as a supplement to mother's
milk. The sole diet and supplement groups were separately randomised

British Medical Bulletin 1997^3 (No 1) 129

Fetal and early childhood environment: long-term health implications

and data could, therefore, be analysed separately for these groups, or

combined.
The assigned diets were fed, on average, for only the first 4 weeks of
life. After this period children were fed as their parents chose. Surviving
children were assessed at 18 months post term using the mental and
motor scales of the Bayley scales of infant development30.
Study 2, the comparison between term and preterm formula, was

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completed first. In the group fed the milks as their sole diet, the PDI
advantage for those fed preterm formula was 14.7 points. The effect of
diet on development was greatest in children born small for gestation age
and in males, in both of these subgroups there were significant
advantages in both the Bayley Mental Development Index (MDI) and
PDI, with significant interactions between diet and both size for
gestation and sex.
Enteral intake in these preterm infants was variable, with some
/ children needing prolonged intravenous feeding. When only those
children who had received the assigned milk for at least 2 weeks were
included in analyses, there were significant and larger developmental
advantages in both MDI and PDI for those fed preterm rather than term
formula. In children fed the allocated milk as their sole diet for at least 2
weeks the advantages were 9 points (P<0.05) and 15 points (F<0.01),
respectively.
Preliminary (unpublished) data suggest that the effect of diet on
performance, especially in verbal IQ and in male children, is persisting to
7.5-8 years, when cognitive function is highly predictive of that in
adulthood.

Breast milk: In study 1 (see Fig. 1), a unique group of children were
randomly allocated human breast milk. The milk was fed by nasogastric
tube to infants whose mothers had chosen not to provide their own
breast milk. The two major potential areas of confounding were avoided
in this study because all the mothers had chosen not to provide breast
milk, avoiding social and demographic confounding and since the
infants were fed by nasogastric tube the human milk fed group were not
exposed to the influence of intimacy with the mother during breast
feeding. In a comparison of infants fed donor milk with those fed
standard term formula (from two parallel trials and all with mothers
who had chosen not to provide breast milk), the human milk group had
significantly higher PDI31. Furthermore, despite substantial nutrient
differences between the banked donor milk and preterm formula, there
was no advantage for the preterm formula fed group. These findings
contrast sharply with those from study 2 (preterm versus preterm
formula comparison) and lend weight to the hypothesis that human milk
does contains a factor or factors which promote neurodevelopment and

130 Bnhih Medical BvlUhn 1997,33 (No 1)

 Nutrition and cognitive development

ameliorate the adverse effects of poor nutrition. Candidate factors

include the range of biologically active peptides in milk32, (including
nerve growth factor and insulin-like growth factors). The extent to
which these reach target tissues in the infant and whether they are
important for brain development is not understood.
Human milk also contains a range of long chain polyunsaturated fatty
acids (LCPUFAs), notably docosahexaenoic acid (DHA, 22:6a>3),

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whereas conventional formulas contain a negligible amount33. The brain
and retina are rich in DHA34 and there is considerable interest in
whether the DHA available to the infant from human milk might be the
explanation, at least in part, for the developmental advantage generally
associated with breast feeding. A number of studies have been
undertaken to investigate whether DHA supplementation of formula
milk promotes development in term or preterm infants.

Polyunsaturated fatty acids

The brain and retina are rich in both DHA and arachidonic acid (AA)
and uptake by these tissues increases substantially during the last
trimester of pregnancy and for several months after birth35. There is
good evidence that the DHA content of the infant's diet is reflected in the
composition of the infant's tissues36'37.
To date there are few published data on the influence of LCPUFA
supplementation on developmental status and most studies have been
too small to provide convincing evidence38. The issue of whether dietary
long chain polyunsaturated fatty acids in infancy confer a cognitive
advantage and are at least part of the explanation for the generally found
advantage for breast fed subjects is as yet unresolved. The results of
current large randomised trials of dietary LCPUFA are awaited with
interest.

Dietary iron

Iron deficiency anaemia is considered the most common nutritional

deficiency disease in infants and children in the West, with around 10%
of children affected, and its prevalence has been estimated at around
50% in less developed countries40, where it is associated with poverty,
malnutrition and disease, especially parasitic infections. Iron supple-
mentation of milk formulas or weaning foods has been shown to reduce
the incidence of iron deficiency anaemia in the West. Evidence from
observational studies suggests that children with iron deficiency anaemia
suffer a developmental disadvantage, so supplementation is most likely

BnhshMtdicalBviUhn 1997^3 {No. 1) 131

Fetal and early childhood environment' long-term health implications

to be beneficial in this group. However, there are ethical difficulties in

randomising anaemic children to iron supplementation or placebo.
In most of the intervention trials (mainly conducted in less developed
countries) there was no evidence of developmental benefit from iron
supplementation11, though the interventions were generally very short.
In a study of healthy formula fed infants from very low income families
in the West (a high risk group for iron deficiency anaemia) those

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randomly assigned iron fortified rather than standard formula had
significantly higher Bayley motor scale scores than the controls at 9 and
12 months41. The effect did not persist to 18 months, but 46% of
subjects had dropped out of the study, raising the possibility of selection
bias. Positive evidence for the importance of iron in development comes
from a randomised trial conducted by Idjradinata et al42. Children aged
12-18 months with iron deficiency anaemia were randomly allocated a
placebo or ferrous sulphate. The children given 3 mg/kg of ferrous
sulphate per day showed marked improvements in both Bayley MDI and
PDI after 4 months of treatment, whereas there was no significant
change in the scores of the placebo group. Although the number of
subjects was small, great care was taken to investigate the possibility of
confounding, which in any case could be expected to have a less
powerful influence on change in scores. Longer term follow up data are
required to determine whether any benefits from early iron supplemen-
tation persist beyond the intervention period in infancy.

Overview
The importance of early nutrition for later cognitive development
continues to be debated. Previous studies of malnourished babies in
developing countries may sometimes have been motivated by political
needs to stimulate aid programmes, though it should be unnecessary to
prove that malnutrition damages a baby's brain in order to provide a
stimulus to reduce poverty and hunger.
However, despite many studies that have related early undernutrition
to later cognitive deficits, extensive reviews43"45 of this body of work
have suggested that most studies were too confounded by flaws in design
to provide compelling evidence. More recently, however, tightly
designed nutritional intervention studies have provided new and more
convincing evidence that the brain may be vulnerable to suboptimal
nutrition in early life. For instance, the new randomised trials of early
nutrition in preterm babies suggest that nutrition prior to full term may
have profound later effects, with major implications for clinical practice.
But there is still much that remains unresolved: does breast feeding really

132 Bntii/i MedicalBulUhn 1997,53 (No. 1)

 Nutrition and cognitive development

make children brighter? Should long chain lipids be added to infant

formulas? Is iron deficiency, so prevalent worldwide, really a significant
hazard for cognitive development? The intense focus on these issues and
the new understanding of the importance of conducting studies with
strict experimental design is likely to provide much better answers than
we have had so far.

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