Dying prematurely from a chronic disease could well be the pay-off for successfully adapting to ensure your survival in the womb.
The search for the causes of chronic disease has up until now been guided by a "destructive" model. The causes to be identified act in adult life and accelerate destructive processes, such as raised blood pressure and hardening of the arteries. But what is emerging is a new "developmental" model. The causes to be identified act on the baby. In adapting to them, the baby ensures its continued survival and growth at the expense of its longevity. Premature disability and death from chronic disease may be the price of successful adaptations that ensure survival in utero .
Over the past ten years, epidemiological studies have shown that people who had low birth weight or who were thin or short at birth are at increased risk of developing coronary heart disease and related disorders: stroke, hypertension and non-insulin-dependent diabetes. These observations have given rise to the "foetal origins hypothesis", which proposes that cardiovascular disease originates through adaptations made by a foetus when it is undernourished.
These adaptations can be metabolic, hormonal or the redistribution of cardiac output to protect key organs and, importantly, the brain. They may be associated with slowing of growth, which is also adaptive because it reduces the foetus's requirement for nutrients.
Unlike adaptations made in adult life, those made during early development tend to have permanent effects on the body's structure and function - a phenomenon sometimes referred to as programming. At least some of these effects, raised blood pressure, for example, are harmful in the long term and lead to disease.
The development of the sweat glands provides a useful example of programming, albeit in this instance it occurs after birth. All humans have similar numbers of sweat glands at birth, but none functions.
In the first three years after birth, a proportion of the glands become functional, depending on the temperature to which the child is exposed. The hotter the conditions, the greater the number of sweat glands that are programmed to function. After three years, the programming is complete and the number of sweat glands is fixed. Thereafter, the child who has experienced hot conditions will be better equipped to adapt to similar conditions in later life, because people with more functioning sweat glands cool down faster.
This encapsulates the essence of programming: a critical period when a system is plastic and sensitive to the environment, followed by loss of plasticity and a fixed functional capacity. There are good reasons why it may be advantageous, in evolutionary terms, for the body to remain plastic during development. Plasticity enables the foetus to receive a "weather forecast" from its mother that prepares it for the type of world in which it will have to live.
If the mother is poorly nourished, she signals to her unborn baby that the environment it is about to enter is likely to be harsh. The baby responds to these signals by adaptations, such as reduced body size and altered metabolism, which help it to survive a shortage of food after birth. In this way, programming gives a species the ability to make short-term adaptations within one generation, in addition to the long-term genetic adaptations that come from natural selection.
Why should foetal adaptations to undernutrition or other adverse influences lead to disease in later life? One possibility is that disease is a consequence of an erroneous weather forecast. If a foetus that has adapted to poor nutrition experiences good nutrition after birth, it may be disadvantaged. A "thrifty phenotype" may be metabolically less able to withstand excess. Ideas about postnatal disadaptions, contained in the "thrifty phenotype hypothesis", are useful in attempting to explain why western diseases, such as non-insulin-dependent diabetes and coronary heart disease, increase so steeply when chronically malnourished communities become better nourished.
A remarkable set of birth and child growth records in Helsinki is giving insights into pathways of prenatal and postnatal growth that lead to chronic disease. Thinness at birth, shown by a low ponderal index, is associated with an increased risk of coronary heart disease, irrespective of childhood body mass (a measure of fatness). But the risk is greatest in men who were thin at birth but reached an above-average body mass in childhood.
One possible interpretation of this is that it is a thrifty phenotype effect, a poorly nourished foetus being disadapted by good nutrition in postnatal life. Alternatively, it could be that uneven or imbalanced rates of growth, with slow growth in utero followed by accelerated or "catch-up" growth after birth, is intrinsically damaging. Slow growth in utero leads to reduced numbers of cells in organs such as the kidney and these may be unable to meet the metabolic demands of large body size after birth.
In India and other areas of the developing world, there are steeply rising epidemics of coronary heart disease, which will soon become the most common cause of death in the world. Prevention of these epidemics may depend more on protecting the nutrition of girls and young women, and hence promoting growth in the womb, than on the avoidance of nutrition excess in middle life.
David Barker is director, MRC Environmental Epidemiology Unit, University of Southampton.