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close this bookActivity, Energy Expenditure and Energy Requirements of Infants and Children (International Dietary Energy Consultative Group - IDECG, 1989, 412 pages)
close this folderEnergy requirements in normal infants and children
View the document(introductory text...)
View the documentAbstract
Open this folder and view contents1. Essential terminology and concepts
View the document2. Factorial approach to energy requirement
View the document3. The breast-fed baby as a model for energy requirements
View the document4. The doubly-labelled water method
View the document5. Application of the doubly-labelled water method to estimate energy requirement
Open this folder and view contents6. Validation studies employing doubly-labelled water
Open this folder and view contents7. Metabolisable energy and energy content of breast milk determined by the doubly-labelled water method
View the document8. How logical is the current approach to estimating energy requirements?
View the document9. Future directions
View the documentReferences

9. Future directions

The confusion in this field is part of a more general problem in infant nutrition research. It might be asked why, after intensive research throughout this century, there is still uncertainty over almost every aspect of nutritional practice. When such a large body of scientific data exists, and yet the answers remain in doubt, it seems reasonable to reappraise the questions. It is relevant in this context to consider the evolution of other areas of clinical investigation. Normally, research in clinical science is a three-phase process. Phase 1 documents anecdotal observation and clinical experience. Phase 2 includes broader-based epidemiological observation or detailed physiological experiment. Finally, in phase 3, outcome studies are employed to test the hypothesis that specific interventions result in desirable clinical outcome responses. Successful studies in this last category place clinical management on a secure scientific footing. To take an analogy: it would be of limited value to conduct a phase-2 study on the physiologic effects of a range of new blood pressure lowering agents if it had not been shown in a phase-3 study that it was actually worthwhile treating hypertension, in terms of improved outcome. It seems that infant nutrition in general, and indeed the field of energy requirements, has become largely stuck at phase 2 in its evolutionary progress. Investigators of energy metabolism have been preoccupied by phase-2 physiological research and have not addressed the critical, long-term phase-3 question: does it matter what energy intake we give infants and young children in terms of their performance and morbidity in later life?

Since this may seem, at first sight, a most difficult objective, some justification is needed for its pursuit. The possibility that dietary experience during early life has lasting consequences invokes the concept of 'programming', meaning here the general process whereby a stimulus (or insult), applied during a 'critical' or 'sensitive' period of development, has a long-term or permanent effect in the organism. Many examples (LUCAS, 1987) of programming, resulting either from internal triggers or external agents, have been described in animals and man.

There is increasing evidence that early diet may act as a programming agent in animals. It is not the purpose of this article to review these data, but a few examples will be given to illustrate the point.

A number of investigators have explored whether early dietary manipulation programs alter metabolism in ways that might be relevant to the development of obesity, abnormalities in lipid metabolism, and atherosclerosis. In HAHN'S (1984) studies on rats, litter size was manipulated. He examined outcome, for instance, when litter size was 14 or reduced to 4; in small litters the pups would be overfed during the short breast-feeding period. In adulthood, rats from small litters had significantly higher plasma cholesterol and insulin concentrations. Hahn also showed that weaning animals on to a high-carbohydrate diet in the neonatal period resulted in similar long-term effects on plasma cholesterol and insulin, and in addition influenced in adulthood the activities of key enzymes concerned with fatty acid and cholesterol metabolism (fatty acid synthetase and HMG-CoA reductase activities). Such biochemical changes in man could be important in relation to adult morbidity.

Rats are born immature, and it might be argued that they are not a good model for man, but long-term programming has also been demonstrated in primates. In a study by LEWIS and coworkers (1986), infant baboons were randomly assigned to one of three formulas for the first 4 months. The formulas provided low, normal and high energy intakes. After the 4-month period all the animals were fed in the same way. The excess weight gained during infancy in the animals with high intakes was soon lost. In males the loss was permanent; adult males overfed in infancy had normal adult weight. In female baboons, however, early overfeeding resulted in a dramatic rise in body weight and fat mass during adolescence and early adult life. In this instance, the effects of the initial 'programming' event were not manifested until much later in life, raising the important question as to how such a 'memory' could tee 'stored', passed through many cell generations, and then 'expressed'.

The influence of breast- versus formula-feeding on later lipid metabolism and vascular disease has also been explored in a series of studies by MOTT (1986), MOTT et al. (1989) and LEWIS et al. (1985) using the baboon model. In man, clearly it is not possible to randomly assign infants to breast- or formula-feeding; consequently, all outcome studies comparing the two are confounded by the considerable socioeconomic and educational differences between breast- and bottle-feeders. In baboons such randomisation is possible. In the studies of Lewis and Mott, these assignments were only applied during infancy (first 4 months); beyond that the animals were fed in the same way. Compared with the formula-fed group, those who were breast-fed in infancy had increased cholesterol absorption, reduced cholesterol turnover, higher plasma levels of LDL and VLDL cholesterol and, when placed on a high saturated fat (Western style) diet, they developed lower levels of potentially protective HDL cholesterol in adult life. These lipid abnormalities would be expected to result in an increased risk of atherosclerosis, and indeed the animals showed, at post mortem, a significantly greater area of atherosclerotic plaque if they had been breast-fed in infancy (LEWIS et al., 1985). By using formulas with different cholesterol content, the investigators found that cholesterol intake itself was not the factor which accounted for their findings, which remain unexplained. The significance of these data for man are unknown, and indeed it could be argued that, in humans, morbidity from vascular disease may be more related to thrombotic events than to atherosclerosis per se. Nevertheless, these findings indicate that early life may be a critical period for nutrition in primates and emphasise the importance of long-term, phase-3 studies on human nutrition.

In our own unit, we have strictly randomly assigned nearly 1000 preterm infants to the diet they received in the early weeks and we are now following them up indefinitely. The cohort is approaching 78 years. Data analysed so far, after blind evaluation at 18 months, show that the brief period of dietary manipulation after birth results in major differences between diet groups in growth and neurodevelopment (LUCAS et al., 1989a; LUCAS et al., 1989b). This study also serves to demonstrate the feasibility of long-term outcome studies in man.

There are a number of opportunities to examine formally the effects of early energy intake on later outcome in healthy babies, born at full term. Currently we are conducting a prospective randomised trial of energy intake in formula-fed babies with planned long-term follow-up. Interestingly, our unpublished pilot data indicate that energy intake at 3 months in normal-term infants is not related to skinfold thickness at that age, but significantly related to skinfold thickness at 2 years. Weaning is another time period when randomised intervention would be feasible. It would certainly be disappointing if, in another 20 years time, the same issues were being debated when, in the meantime, critical outcome data could have been collected on the effects of early energy intake on later growth, obesity, neurodevelopment and markers for vascular disease.