The fetal origins hypothesis—10 years on

Events before birth remain important, but we need to consider later modifiers too

Epidemiological studies have largely contributed to our understanding of the natural history of coronary heart disease. Although clinical manifestations of the disease usually become evident in adult life, early signs are recognisable in childhood. The discovery that individuals who develop coronary heart disease grow differently during early life has led to the recognition of new developmental models for the disease. In 1995 David Barker wrote: “The fetal origins hypothesis states that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease.”1 Now, 10 years later, the importance of events before birth for lifetime health has been confirmed in many populations.2^–4 In humans, birth size serves as a marker of the intrauterine environment. Considering that birth size is just one snapshot of the trajectory of fetal growth it is fascinating that long term health outcomes are predicted by the body size of the newborn.

The association between birth size and cardiovascular morbidity is largely modified by growth later in life. The highest risk of coronary heart disease is seen among individuals who were born small and became heavier during childhood.4^–6 Most previous studies have been done in males but in this issue we have a paper based on findings from the nurses' health study following up over 66 000 female nurses.7 This study confirms the inverse associations between birth weight and risk of cardiovascular disease in women. Risk of coronary heart disease was highest among women who were smaller at birth and who grew up to be heavier adults. The risk of coronary heart disease was not elevated among women with lower birth weight who remained relatively lean in adult life. Obviously the consequences of becoming heavier in childhood and adulthood are conditioned and modified by growth in the womb and do not depend solely on the absolute level of body weight attained. After an intrauterine lesion, regulatory mechanisms may maintain homoeostasis for years until further damage because of obesity or other influences initiates a self perpetuating cycle of progressive functional loss leading to disease. Therefore we need to recognise the importance of modifiers working later in life.

Not only fetal growth but also growth during early childhood is a major player in the game of long term health outcomes.8 9 The most unfavourable growth pattern seems to be thinness at birth and during early childhood followed by a rapid increase in body weight. These observations are globally of extreme importance since malnutrition in early life is a widespread health problem. The impact of the problem is easy to understand knowing that approximately a third of the world's children suffer from protein energy malnutrition. Stunted children are at high risk of becoming overweight. The public health implication of this is naturally to prevent excess childhood and adult weight gain, with the intervention especially targeted at those born small.

Although the evidence for an association between impaired fetal growth and increased risk of coronary heart disease is compelling, it is premature to make policy recommendations in order to increase birth weight. Interventions to increase birth weight could even be harmful. Many of the current findings have emerged from historical cohorts. Future studies should be long term prospective studies collecting biological samples to increase our understanding of the underlying processes. In the future, individual tailoring of lifestyle and pharmaceutical interventions according to early growth patterns and genetic setting may maximise benefits in the prevention of cardiovascular disease and other non-communicable diseases.

We are beginning to see that adult degenerative diseases are associated with different patterns of growth—the same disease may even originate through more than one pathway.10 Unfortunately what optimal growth is and how this can be achieved is not clear. Obviously this is also related to the measured outcome. The development of most non-communicable diseases entails several interactions, including genetic ones.11 From a public health point of view we need to keep in mind that adult diseases are not programmed as such but the tendency towards a disease is programmed. The early risk factors are to a large extent modified by a huge range of factors working during the whole life course and lifestyle matters from the cradle to the grave.12 Adult diseases can therefore best be focused on from a life cycle perspective. The promise of the fetal origins paradigm is that attending to the health of women of reproductive age will have profound impact on the wellbeing of their offspring. The importance of this issue closely parallels WHO's World Health Report 2005— “Make every mother and child count.”

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