Fetal Origins Of Adult Disease

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Until recently it was generally considered that the chronic non-communicable diseases of adulthood, heart disease, hypertension, diabetes and cancer, were caused by a genetic predisposition acting with lifestyle factors such as smoking, diet and activity. Over the last decade it has become clear that other factors may play a substantial role, and in particular programming of the metabolic capacity during early life may be especially important. The first evidence for this proposition came form a series of epidemiological studies carried out by Barker and his colleagues which suggested that growth during early life potentially represents a major risk factor for the later development of ischaemic heart diseases4;13 The proposition is that early nutritional exposure programmes future metabolic competence and behaviour by imprinting a change upon genomic expression. The first evidence came from ecological studies which showed that geographical differences in death from ischaemic heart disease in England and Wales were related to differences in infant mortality 70 years ago14, suggesting that growth and development in the perinatal period may be related to an important risk factor for heart disease. In retrospective cohort studies ofmen and women born in Hertfordshire between 191 1-1930 and Sheffield between 1907 and 1924, it was shown that those with the lowest weight at birth and 1 year had the highest death rates for heart disease, and thus for example in Hertfordshire men the standard mortality rate was 11 1 for those less than 18 lbs at 1 year compared with 42 in those weighing over 27 lbs atone year15-16 Early growth relates directly to current clinical evidence of coronary vascular disease17, and also to risk factors (such as hypertension, diabetes or obesty)4;13 and intermediary markers (such as blood lipids and clotting factors), for ischaemic heart disease18-20. The general nature ofthese observations has been replicated in many studies throughout the world, and the weight of evidence is such that it can be stated with reasonable confidence that the pace and pattern of early growth represents a major risk factor for the development ofdisease during later life. However, this statement it too bald for the more fundamental implication carried by the relationships which have been characterised. Thus although disease or death has been used as a sharp end point to characterise the clinical importance of the relationships, the metabolic basis for the pathological changes is evident from much earlier in life. Thus for example, in studies carried out in children in England, India, Jamaica and elsewhere, the metabolic differences which underlies the risk of disease are already evident, from as early as 3 or 4 years of age21 Thus programmed metabolic changes contribute to the determination of the capacity for metabolic function during the entire life of an individual. The metabolic function of an adult, represents the cumulative experience oftheir environmental exposure throughout their entire life experience. At each age the memory of past metabolic experience contributes to determining current metabolic behaviour, to a greater or lesser degree, although the greatest impact appears to be related to experience during pre-natal life or in infancy.

One of the more important features of the observations made by Barker's group, which are often ignored, or misinterpreted, is that the changes described operate in a graded fashion, across the range of birth weights, which in the past have been considered to be normal. There has been the tendency to interpret the observations as being a feature ofbabies of lower birth weight, which has very easily been translated to a feature ofbabies of low birth weight, that is obviously pathological limitations in growth and development. The implication that the changes are graded across the normal range ofbirth weight, rather than a pathological feature which is expressed below some critical cut-offpoint has major implication which are often not appreciated, in terms ofthe basis ofthe changes and the implications which they carry for health during pregnancy and later in life for the offspring.

Despite the obvious dependence of fetal growth on the delivery of nutrients from the mother, it has been difficult to demonstrate simple relationships between maternal diet, energy or nutrient consumption, during pregnancy and the growth of the fetus. Although it has been possible to show relations between size at birth and the maternal intake of macronutrients, and selected micronutrients, the relative contribution to the variability in birth weight appears modest, explaining ofthe order of3 to 5% of the variability in birth weight22-24. This is similar to the 5 to 7% of variation in birth weight explained by smoking22. When characterising the nutritional status of an individual, the dietary intake is only one part, and body composition and the functional ability or the metabolic state of adaptation also have to be taken into consideration25. Thus, relative to the explanatory power of dietary consumption, maternal fat mass during pregnancy showed a much stronger relationship with the blood pressure of the child at 11 years of age26. When measures of maternal metabolic function are used to assess the competence of the mother for carrying a pregnancy, the relationship with growth are much more evident. For example, the visceral mass of the mother shows a close relationship with the amount ofprotein which she synthesises on a daily basis, and this in turn is related to the growth of the fetus27. Thus, at least 20% of the variability in length of the newborn could be attributed to variations in maternal protein synthesis, a very strong explanatory variable. The importance ofmaternal body composition as a measure of her metabolic competence is further emphasised by findings of inter-generational relationships28. From studies carried out in Finland. Heart disease was most common in men who were born light, especially in those who were thin at birth. The risk was even greater in men who had mothers who were short, especially if the mothers were short and fat. The authors suggest that in societies, or individuals, in transition from poorer to improved social circumstance women move from being short and thin to being short and fat, before they become taller. They suggest that in this way the diseases of affluence mark the demographic transition, a biological marker of inter-generational competence and availability of food29

In all the epidemiological studies, there tends to be a loss in the associations between birth size and measures ofmetabolic competence until after 2-3 years of age, and again around adolescence until its completion. Both these time periods represent the transition between the different phases of growth: infant to child and child to adolescence. This raises the question of the need for an established drive to growth, or growth trajectory for exposing the relationships in population studies. It raises the possibility that during childhood a growth hormone drive is required to expose the potential limitation in the underlying metabolic capacity for specific functions, and it is for this reason that height itselfis a good proxy for metabolic capacity.

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