Fetal origins of adult disease---the hypothesis revisited

The idea that stimuli or insults during critical or sensitive periods in early life can have lifetime consequences is well established in developmental biology and has been termed "programming." 1 The first evidence for programming, obtained over 100 years ago, confirmed the critical period for imprinting in birds. 2 Programming stimuli may be generated endogenously (for instance, internal hormonal signals 3 ) or they may be environmental.One important type of environmental programming is that induced by early nutrition.Since McCance's studies in the 1960s on the long term effects of early nutrition in rats, 4 numerous animal studies have shown that nutrition in infancy or fetal life can induce lifetime effects on metabolism, growth, and neurodevelopment and on major disease processes such as hypertension, diabetes, atherosclerosis, and obesity. 5-8If these phenomena applied in humans, it would be a matter of major public health and clinical importance. Fetal origins hypothesisThe considerable research focused on early programming of adult outcomes in humans has taken two approaches: experimental, using early randomised nutritional interventions with prospective follow up (an approach that we have favoured 9 ), and observational.Inferences from data based on observational approaches require more careful interpretation.Some of the most thought provoking observational studies are those of Barker et al. 10 They have shown that small size at birth or in infancy is associated with an increased propensity to adverse health outcomes in adulthood-including abnormal blood lipid values, diabetes, hypertension, and death from ischaemic heart disease.These important primary observations have led to the fetal origins hypothesis. 10Small body size or body shape at birth (or subsequently) has been seen as a marker of poor fetal nutrition, which, it is suggested, results in fetal adaptations that programme future propensity to adult disease. Adjusting for subsequent sizeSome observational studies show a direct association between small size in early life (for example, low birth weight) and current, adult health outcomes. 11-1518192021 Adjusting for current size has been justified on the grounds that birth weight or size is positively related to later size, and also that current weight or fatness is positively related to the outcome variable of interest (for example, blood pressure), and if not adjusted for could obscure a negative relation between birth weight and the outcome variable. 22However, other reasons have been advanced, some of which are hard to understand.In one study of birth weight and later blood pressure in children, adjustment for current weight was said to be "justified . . .because while childhood body size seems to confound the association, in adulthood this confounding is less apparent." 16Other authors fail to justify; they simply state that the results were adjusted for adult body mass index. 17The statistical implications of adjusting for birth size or size in infancy concurrently with some later measure of size do not seem to have been fully understood, or at least communicated.Yet appropriate statistical interpretation is vital for the biological understanding of nutritional programming, as is shown below.