Studies around the world have shown that people who had low birthweight have increased risk of coronary heart disease, stroke, type 2 diabetes, hypertension and osteoporosis. These associations are the result of slow growth in utero rather than premature birth. Slow fetal growth is primarily determined by poor nutrient delivery to the fetus from the mother, although there are other influences such as hypoxia and stress. The associations between birthweight and chronic disease extend across the normal range of birthweight. A person who weighed 3.0 kilogram is at lower risk than a person who weighed 2.5 kg. A person who weighed 4.0 kg is at lower risk than a person who weighed 3.5 kg. This implies that normal variations in the delivery of nutrients to the babies of normal healthy mothers have profound long-term effects.

Associations between birthweight and chronic disease are thought to reflect developmental plasticity. All living things are plastic while they develop. A single genotype can give rise to a range of different structures and functions in response to environmental conditions during development.

People differ from one another not only through the genes they acquire at conception but through alterations in gene expression induced by nutrition and other influences during development. A genetic polymorphism may have different effects in people who had different birthweights. The effects of the pro12pro polymorphism of the PPAR-Y gene on insulin resistance provides an example of this.

Small babies are biologically different to large babies throughout their lives. The differences include (1) a reduced functional capacity in key organs, for example fewer nephrons in the kidney, (2) altered structure, for example in the heart and its vasculature, (3) altered metabolic settings, including resistance to insulin. In addition alterations in gene expression during development can change an individual’s responses to the environment in adult life. People who were small at birth are more vulnerable to the adverse effects of obesity, a poor diet and psycho-social stress in later life.

Studies of a cohort of 8,600 people in Finland have shown that children who later develop coronary heart disease grow differently to other children before and after birth. They grow slowly in utero, and put on weight slowly in the first two years after birth. At two years of age they are thin. Thereafter they put on weight rapidly. At school age they are not the most overweight children but they are the children putting on weight most rapidly. When, after a period of undernutrition, normal nutrition is restored many animals have a period of rapid weight gain and growth. This "compensatory" growth necessarily has costs. In humans the costs of rapid compensatory weight gain after being thin at 2 years may include the development of a high fat mass in relation to muscle mass and associated insulin resistance.

Children who later develop type 2 diabetes also grow slowly in utero and put on weight slowly in the first two years after birth. Thereafter they have rapid ‘compensatory’ weight gain so that their body mass index (weight/height2) rises progressively above the average. After the age of 2 years the body mass index of all children falls until around 6 years of age before increasing again – the so-called adiposity rebound. The age of adiposity rebound ranges from around 3 to 8 years or more. Children who are thin at around 2 years of age tend to have an early adiposity rebound. This leads to a high body mass index in childhood and an increased risk of type 2 diabetes in adult life.

Babies born during the war-time famine in Holland had birthweights around 200 g below the average. Today, sixty years later, they are insulin resistant and at increased risk of type 2 diabetes. During gestation a baby’s nutrition does not depend on what the mother eats each day. That would be too dangerous a strategy. It also lives off stored nutrients and the turnover of protein and fat in the mother’s tissues. Mothers’ lean and fat mass have long-term effects on their offspring which include their sensitivity to insulin. One process through which mothers’ diets and body composition influence the baby’s development is through alteration in regional blood flow, which has selective effects on the growth of particular organs. Findings with new assisted reproduction techniques in humans, and experiments in animals, suggest that the trajectory of fetal growth through gestation is established in response to the mother’s nutritional state around the time of conception.

If each person in the Finnish cohort had been in the highest third of birthweight (above 8 pounds, 3.6 kg) and had lowered their standard deviation score for body mass index between ages 3 and 11 years the incidence of type 2 diabetes would have been reduced by 57%. Similarly there would have been large reductions in coronary heart disease and stroke. Prevention of coronary heart disease and type 2 diabetes may depend on (1) mothers having a varied and balanced diet, begun before conception, (2) protection of infant growth, (3) prevention of rapid weight gain in young children.