Fetal origins of adult disease---the hypothesis revisited

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Abstract
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 signals3) 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.5–8 If these phenomena applied in humans, it would be a matter of major public health and clinical importance. #### Summary points The hypothesis that adult disease has fetal origins is plausible, but much supportive evidence is flawed by incomplete and incorrect statistical interpretation When size in early life is related to later health outcomes only after adjustment for current size, it is probably the change in size between these points (postnatal centile crossing) rather than fetal biology that is implicated Even when birth size is directly related to later outcome, some studies fail to explore whether this is partly or wholly explained by postnatal rather that prenatal factors These considerations are critical to understanding the biology and timing of “programming,” the direction of future research, and future public health interventions The 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 favoured9), and observational. Inferences from data based on observational approaches …