nutrition and cognitive development€¦ · because their brain growth spurt occurs during the...

Nutrition and cognitive development

Ruth Morley and Alan LucasMRC Childhood Nutrition Research Centre, Institute of Child Health, London, UK

In this paper we review the evidence for such early nutritional influences oncognitive Function.

Correspondence to.Dr Ruth Morley,

MRC Childhood NutritionResearch Centre,

Inttitute of Child Health,30 Gwlford Street,

London W O N 1EH, UK

There has been a long standing interest in whether undernutrition, at asensitive or critical period of brain growth or maturation could have along lasting or permanent 'programming' influence on later cognitiveperformance1. One noteworthy example of a nutritional influence oncognitive function is maternal iodine deficiency, which may result infrank cretinism or reduced cognitive function and school performance inthe offspring2. These nutritional effects, mediated here by an endocrinemechanism, are irreversible. A key question is whether other general orspecific nutritional insufficiencies can likewise influence or 'programme'cognitive function. Given the extent and range of nutritional deficienciesworldwide, this question is of great significance for mankind.

Animal studies have demonstrated that nutritional deprivation affectsmeasures of performance3, but it is difficult to extrapolate from suchmeasures in animals (largely rodents) to human cognition, though theyare of importance in establishing both the principle and mechanism ofany associations.

Causal links between early nutrition and later cognitive performancein man have been difficult to establish. Nutritional deprivation studieswould clearly be unethical, so that most investigations have been ofnutritional supplementation in populations suffering poverty andundernutrition, which may confound the relationship, making theinfluence of undernutrition itself difficult to assess. The greatest need,identified by Birch in 19684, is for randomised trials of nutritionalintervention and outcome in man. Some such studies have beenundertaken relatively recently.

As well as overall or protein-energy nutrition, there is considerableinterest in whether a deficiency of specific nutrients at a sensitive orcritical period for brain development could result in a long term orpermanent cognitive deficit. The role of dietary iron intake in latercognitive function has been extensively researched in both animals andhumans. Zinc deficiency has also received attention in this respect. Thatbreast fed infants perform better than those fed artificially, even afteradjusting 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 notablydocosahexaenoic acid (DHA, found in human milk but not inconventional formulas) are critical nutrients for neurodevelopment.

Animal studies

Two key areas that have received attention in animal experiments are theimpact of protein-energy undernutntion and iron deficiency on laterlearning and behaviour.

Protein-energy undernutntion

Does undernutntion influence later behaviour* Rodents have beenwidely used as experimental models for determining whether there is anassociation between early nutritional deprivation and performancebecause their brain growth spurt occurs during the suckling period,when nutrition can readily be modified, for example by nutritionaldeprivation of the mother or an increase in litter size. The results of thesestudies, many of which demonstrated behavioural disadvantages forunderfed pups, were open to alternative explanations3-5. Changes in littersize or maternal nutrition, plus any effect of poor nutritional status onthe pup's interest in social interactions, inevitably affected theinteraction between pup and mother, which is important for behaviour.However, when artificially reared underfed and well fed rat pups, andmother-reared underfed and well fed pups were compared, the underfedanimals performed less well on behavioural measures, whether or notthey were reared by their mother3. Interestingly the disadvantage for theunderfed rats was greater if they were artificially fed, raising thepossibility that either maternal stimulation or one or more factors infresh maternal milk partly ameliorated the effect of poor nutrition onbrain growth or development.

A review of studies comparing the performance of well nourishedversus previously undernourished rats3, showed that a disadvantage forundernourished animals was significantly more likely if the period ofundernutntion included gestation. Interestingly, the advantage was mostoften seen in male animals.

What are the underlying mechanisms of these nutritional effects* Therat brain is less mature at birth than the human brain and postnatalundernutntion in rats (at a stage of rapid brain growth comparable with

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


the third trimester of human pregnancy) has been shown to result inimpairments in a number of different aspects of brain growth andfunction6. For example, the effect of undernutrition on the developingcerebellum was shown to result in a 15% deficit in DNA (a proxy for cellnumber). Although cortical neuronal cell numbers were not reduced bymalnutrition, other cortical structures were affected. For example, glialcell numbers were significantly reduced, as was the complexity ofcortical dendritic branching and the length and width of synapticreactive zones. Evidence emerged that some of these changes werereversible and cortical glial cell number and synapse to neurone ratio canimprove with good postnatal nutrition. Other structural changes, likereduction in the number of hippocampal granule cells, have provedirreversible7, though previously malnourished and rehabilitated animalshad an increase in the number of synapses per hippocampal neurone8.These findings illustrate the difficulty of predicting the impact ofmalnutrition on cognitive function from observed neuroanatomicalchanges.

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 werenot, and the extent of recovery after re-feeding varied between tasks. Forexample, in one study there was no effect of undernutrition on positiondiscrimination, a reversible effect on brightness discrimination but apermanent impairment of pattern discrimination.

Several studies demonstrated that stimulation (like stroking rat pups)during or soon after the period of undernutntion ameliorated laterbehavioural deficits, giving rise to the hypothesis that early under-nutrition resulted in a long-lasting impairment in exploratory or leaningbehaviour, which can be ameliorated by stimulation.

Whether such changes in brain structure or function, or in behaviourcan be extrapolated to the human and whether they would cause longterm cognitive impairment are open to debate.

Iron deficiency

Iron is an essential part of a number of haem-containing mitochondrialenzymes, like flavoproteins. It is also important as a co-factor forenzymes involved in the metabolism of catecholamines, includingdopamine, 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


concentration despite subsequent iron sufficiency, though at later agesthe deficits were reversible with iron supplementation9. Rats with thepermanent deficits performed significantly less well than controls inmaze learning tasks.

Whether there is a similar critical period when iron deficiencypermanently affects the human brain is explored in this article.

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 undernutritionor those whose growth was stunted (low weight for height) perform lesswell than adequately nourished and normally grown children10-11. Inmany, though not all, studies, poor nutritional status has been associatedwith lower cognitive or attainment scores. However, retrospectivestudies of subjects who were malnourished versus well nourished inchildhood are generally too confounded to yield interpretable data, smceundernourished children came largely from poor and undernourishedpopulations, with higher childhood morbidity and parents who were lessable to care for and stimulate their children. Attempts have been made tomatch controls for social background, with similar findings.

In Guatemala a large study was conducted in four villages, withsimilar populations and lifestyle. In two a high energy, high proteindrink was supplied and in the others a low calorie one; both wereavailable ad libitum to pregnant women and children up to the age of 7years. Beneficial effects of supplementation with the high energy, highprotein drink were seen at the end of the intervention period and inmeasures of school achievement in adolescence12>13.

Sibling controls have also been used. In about half of these studies theindex undernourished children performed less well than the controlsiblings, though the siblings will probably have been exposed to somedegree of undernutrition11.

Breast milk: Children who were breast fed have often been shown toperform better in terms of tests of development or cognition, verbalability or school performance14"18. Results have been similar in bothchildren born at term and preterm. However, there are two majorsources of confounding.

126 British MmdicalRullmtm 1997,53 (No 1)


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

2. Mothers who choose to breast feed are different from mothers whochoose not to. In studies conducted on subjects born in the last fewdecades, the findings are confounded by the fact that breast fedchildren come from a higher socio-economic group than those fedformula. Thus any differences may reflect higher parental educationallevel, better nutrition and housing, a more stimulating environment,better access to pre-school education or a more positive attitude toeducation.

Many studies have adjusted for a range of potentially confoundingfactors and in most cases the advantage for breast fed children hasremained. There is a need, however, to devise studies which avoidconfounding. In two parallel trials of neonatal nutrition in children bornpreterm (described in detail below, Fig. 1), we found that even afteradjusting for confounding factors there was a developmental advantagein both Bayley Mental Development Index at 18 months post term19andin IQ at 7.5-8 years18 for those children whose mothers had chosen toprovide their own breast milk. In this study the mothers expressed theirbreast milk and it was fed to the infant via a nasogastric tube. When weconsidered only those infants whose mothers did not go on to breastfeed, the advantage was unchanged, demonstrating that the observeddevelopmental advantage for preterm children receiving breast milk isindependent of any closeness or intimacy associated with breast feedingitself.

Two studies were conducted on subjects born at a time whenartificially fed children came from the most socio-economicallyadvantaged stratum of society. Hoeffer studied children born in the USbetween 1915-1921 and showed that breast fed children performedbetter than those who were artificially fed, though children who wereexclusively 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 somecases after being randomised to receive iron supplementation) have beenshown to have lower developmental scores than those with haemoglobinlevels in the accepted normal range11-23-24. Infants who were studied byLozoff 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 beenanaemic, regardless of treatment group and despite similar mean currenthaemoglobin values in the two groups. These results were confounded

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


STUDY 1 , comparing banked donor milk with pretarm formula

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

No

IRandomlte to

Banked donor milk vs Preterm formulaas sole diets

n=159

Yes

IRandomise to

Banked donor milk vs Preterm formulaas supplements to mother's milk

n-343

STUDY 2, comparing term with preterm formula

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

Fig. 1 Study design.

baby

1No

IRandomise to

Term formula vs Preterm formulaas sole diets

n=160

IYes

IRandomise to

Term formula vs Preterm formulaas supplements to mother's milk

n=264

by socio-economic differences between previously anaemic and non-anaemic children but, even after adjustment for these, the anaemic groupperformed less well. Whether this was because important confoundingfactors were unidentified or inadequately measured is debated. However,these data raise the possibility that iron deficiency anaemia in infancydoes 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 highrisk families or children suffering mild to moderate undernutrition orstunted growth (low height for age).

In a study in Taiwan nutrient supplementation was given to high riskmothers during pregnancy and lactation without giving supplements totheir offspring25. Mothers («=255) were randomly allocated a nutrientsupplemented or placebo drink. Children of supplemented mothers hada small but significant advantage in motor development at 8 months, but

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


mental scores were unaffected and there were no IQ differences at 5years of age.

In Bogota, Colombia, 433 nutritionally at risk pregnant women wererandomly allocated to 6 groups. They or their children (or both) receivedsupplementation during different periods up to 3 years. In two groupsthe offspring also received stimulation. The intervention period lasteduntil children reached 3 years. At the age of about 7 years nutrientsupplemented children performed better in Reading Readiness tests26-27.

There have been a number of intervention studies in children, thoughmany were small. In Jamaica28, 129 stunted children aged 9-24 monthswere randomly allocated to four groups; non-intervened, nutrientsupplemented, supplemented and stimulated, or stimulated alone. Aftera two year intervention both supplemented and stimulated children hadsignificantly higher Griffiths mental development scores than the controlgroup. Children who were both supplemented and stimulated had thehighest 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. Thenutritional intervention lasted 90 days, after which supplementedchildren had significantly higher Bayley motor scale scores29.

Longer term post-intervention data are not available from thesestudies.

In 1982 we started a nutritional intervention study in low birthweightchildren, a group who are at high risk of poor early nutrition and failureto thrive and are at a stage of rapid brain growth and maturation. Milksroutinely fed to them at that time differed substantially in nutrientcontent, ranging from donor breast milk (from unrelated breast feedingmothers in the community) to a standard term or nutrient enrichedpreterm formula designed to meet the special nutrient needs of babiesborn preterm, a time of rapid growth. It was both a practical andethically undertaken randomised trial; the results were needed forinformed management decisions. Furthermore, there were large differ-ences in nutrient content between the allocated milks, so we couldinvestigate, in a randomised prospective intervention trial, whether earlynutrition influences later cognitive status. Altogether 926 infants, bornweighing under 1850 g in 5 centres in the UK in 1982-1984 wererandomly allocated their early enteral diet. The randomisation was asshown in Figure 1. Study 1 compared banked donor milk with thepreterm formula fed either as sole diets or as a supplement to themother's expressed breast milk, if she could not provide enough milk tomeet her infant's needs. Study 2 compared a standard term formula withthe preterm formula, again as sole diets or as a supplement to mother'smilk. The sole diet and supplement groups were separately randomised

British Medical Bulletin 1997^3 (No 1) 129


and data could, therefore, be analysed separately for these groups, orcombined.

The assigned diets were fed, on average, for only the first 4 weeks oflife. After this period children were fed as their parents chose. Survivingchildren were assessed at 18 months post term using the mental andmotor scales of the Bayley scales of infant development30.

Study 2, the comparison between term and preterm formula, wascompleted first. In the group fed the milks as their sole diet, the PDIadvantage for those fed preterm formula was 14.7 points. The effect ofdiet on development was greatest in children born small for gestation ageand in males, in both of these subgroups there were significantadvantages in both the Bayley Mental Development Index (MDI) andPDI, with significant interactions between diet and both size forgestation 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 wereincluded in analyses, there were significant and larger developmentaladvantages in both MDI and PDI for those fed preterm rather than termformula. In children fed the allocated milk as their sole diet for at least 2weeks the advantages were 9 points (P<0.05) and 15 points (F<0.01),respectively.

Preliminary (unpublished) data suggest that the effect of diet onperformance, especially in verbal IQ and in male children, is persisting to7.5-8 years, when cognitive function is highly predictive of that inadulthood.

Breast milk: In study 1 (see Fig. 1), a unique group of children wererandomly allocated human breast milk. The milk was fed by nasogastrictube to infants whose mothers had chosen not to provide their ownbreast milk. The two major potential areas of confounding were avoidedin this study because all the mothers had chosen not to provide breastmilk, avoiding social and demographic confounding and since theinfants were fed by nasogastric tube the human milk fed group were notexposed to the influence of intimacy with the mother during breastfeeding. In a comparison of infants fed donor milk with those fedstandard term formula (from two parallel trials and all with motherswho had chosen not to provide breast milk), the human milk group hadsignificantly higher PDI31. Furthermore, despite substantial nutrientdifferences between the banked donor milk and preterm formula, therewas no advantage for the preterm formula fed group. These findingscontrast sharply with those from study 2 (preterm versus pretermformula comparison) and lend weight to the hypothesis that human milkdoes contains a factor or factors which promote neurodevelopment and

130 Bnhih Medical BvlUhn 1997,33 (No 1)


ameliorate the adverse effects of poor nutrition. Candidate factorsinclude the range of biologically active peptides in milk32, (includingnerve growth factor and insulin-like growth factors). The extent towhich these reach target tissues in the infant and whether they areimportant for brain development is not understood.

Human milk also contains a range of long chain polyunsaturated fattyacids (LCPUFAs), notably docosahexaenoic acid (DHA, 22:6a>3),whereas conventional formulas contain a negligible amount33. The brainand retina are rich in DHA34 and there is considerable interest inwhether the DHA available to the infant from human milk might be theexplanation, at least in part, for the developmental advantage generallyassociated with breast feeding. A number of studies have beenundertaken to investigate whether DHA supplementation of formulamilk 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 lasttrimester of pregnancy and for several months after birth35. There isgood evidence that the DHA content of the infant's diet is reflected in thecomposition of the infant's tissues36'37.

To date there are few published data on the influence of LCPUFAsupplementation on developmental status and most studies have beentoo small to provide convincing evidence38. The issue of whether dietarylong chain polyunsaturated fatty acids in infancy confer a cognitiveadvantage and are at least part of the explanation for the generally foundadvantage for breast fed subjects is as yet unresolved. The results ofcurrent large randomised trials of dietary LCPUFA are awaited withinterest.

Dietary iron

Iron deficiency anaemia is considered the most common nutritionaldeficiency disease in infants and children in the West, with around 10%of children affected, and its prevalence has been estimated at around50% 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 reducethe incidence of iron deficiency anaemia in the West. Evidence fromobservational studies suggests that children with iron deficiency anaemiasuffer a developmental disadvantage, so supplementation is most likely

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Fetal and early childhood environment' long-term health implications

to be beneficial in this group. However, there are ethical difficulties inrandomising anaemic children to iron supplementation or placebo.

In most of the intervention trials (mainly conducted in less developedcountries) there was no evidence of developmental benefit from ironsupplementation11, though the interventions were generally very short.In a study of healthy formula fed infants from very low income familiesin the West (a high risk group for iron deficiency anaemia) thoserandomly assigned iron fortified rather than standard formula hadsignificantly higher Bayley motor scale scores than the controls at 9 and12 months41. The effect did not persist to 18 months, but 46% ofsubjects had dropped out of the study, raising the possibility of selectionbias. Positive evidence for the importance of iron in development comesfrom a randomised trial conducted by Idjradinata et al42. Children aged12-18 months with iron deficiency anaemia were randomly allocated aplacebo or ferrous sulphate. The children given 3 mg/kg of ferroussulphate per day showed marked improvements in both Bayley MDI andPDI after 4 months of treatment, whereas there was no significantchange in the scores of the placebo group. Although the number ofsubjects was small, great care was taken to investigate the possibility ofconfounding, which in any case could be expected to have a lesspowerful influence on change in scores. Longer term follow up data arerequired 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 developmentcontinues to be debated. Previous studies of malnourished babies indeveloping countries may sometimes have been motivated by politicalneeds to stimulate aid programmes, though it should be unnecessary toprove that malnutrition damages a baby's brain in order to provide astimulus to reduce poverty and hunger.

However, despite many studies that have related early undernutritionto later cognitive deficits, extensive reviews43"45 of this body of workhave suggested that most studies were too confounded by flaws in designto provide compelling evidence. More recently, however, tightlydesigned nutritional intervention studies have provided new and moreconvincing evidence that the brain may be vulnerable to suboptimalnutrition in early life. For instance, the new randomised trials of earlynutrition in preterm babies suggest that nutrition prior to full term mayhave 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)


make children brighter? Should long chain lipids be added to infantformulas? Is iron deficiency, so prevalent worldwide, really a significanthazard for cognitive development? The intense focus on these issues andthe new understanding of the importance of conducting studies withstrict experimental design is likely to provide much better answers thanwe have had so far.

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nutrition and cognitive development€¦ · because their brain growth spurt occurs during the...

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