CORONARY HEART DISEASE

In coronary heart disease the walls of the arteries supplying blood to the muscle of his heart become hardened, and the channels within them narrowed by deposits of fats. The risk of heart disease is higher in people who had low birthweight. Risk falls progressively across the range of birthweights. People who weighed 7-pound at birth are at lower risk than those who weighed 6-pounds. People who were 9-pound babies are at lower risk than those who were 8 pounds. Studies in the US, in other European countries and in India have confirmed the first observation of the link between heart disease and birthweight, which was made in the UK. It is not babies who were small because they were born prematurely who are at increased risk of later heart disease, but babies who were small because they grew slowly.

Until recently it was thought that the heart was never sacrificed during life in the womb. Like the brain it is essential for survival and is protected, though there must come a point beyond which protection is no longer possible. In the womb, as the heart pumps blood through the blood vessels in the placenta the pressures against which it has to work shape the thickness of its muscular walls and the size of its chambers for life. The mother’s nutrition shapes the placenta; and the placenta shapes the baby’s heart.

At birth the heart is almost complete; its muscle cells are mostly mature and it needs only to enlarge as the body grows. Before birth it is sensitive to the environment. If it is undernourished it can speed up its maturation, perhaps in preparation for an early birth. This, however, leaves it with a smaller number of muscle cells, a diminished reserve for repair in later life. Another response, discovered only recently, is for the heart to slow its growth. But this too limits its reserve. Many babies are born with hearts that will be vulnerable to disease in later life.

Cholesterol is important because the body uses it to build the walls that enclose its cells. Most of the cholesterol in the body is not eaten in food but is made in the liver which controls how much cholesterol there is in the blood. A tape measure placed around the stomach of a newborn baby measures the size of its liver because, until it begins to feed, its intestines are mostly empty. There are large differences in the girth of the stomachs of newborn babies. This reflects differences in overall body size, but also the extent to which babies have traded off liver growth to protect brain growth. Remarkably, the girth of the stomach of newborn babies has been found to predict their blood cholesterol levels sixty and more years later. The greater the girth, the lower the cholesterol. We have become accustomed to the idea that high blood cholesterol, and the increased risk of heart disease linked to it, is evidence of an unhealthy diet. The truth may be that it is evidence of poor liver growth in the womb. In animals it is easy to change the activities of the liver permanently by altering the mother’s diet in pregnancy. This happens because undernutrition changes the balance of the liver’s specialist cells.

HIGH BLOOD PRESSURE

The first suggestion that high blood pressure might have its origins before birth came from studies of Swedish military recruits, and from a continuing study of a group of British men and women who were all born during the same week in 1946. The pressure in a baby’s circulation is critically important to it, because its nourishment depends on its ability to maintain an adequate pressure so that its blood flows freely through the placenta. Babies with small placentas, which have narrower blood vessels, may need to have to have higher blood pressure to maintain this flow. After birth these babies, who tend to be at the lower end of the birthweight range, continue to have higher blood pressures.

Like children, babies respond variously to undernutrition, depending on its intensity, nature and at what age it occurs. Newborn babies who were thin or short, babies with small placentas or large placentas, have all been found to have high blood pressure in later life. Yet until middle age their blood pressures are only a little higher than those of other people, insufficiently raised to be a source of concern either to themselves or their doctors. It seems that even though a baby may be born with raised blood pressure it can maintain pressures within the normal range, preserve its internal constancy, the marker of good health, for many years. Eventually, as the system begins to wear out with age, this becomes impossible and blood pressure begins to rise steeply. When blood pressure rises, it damages the control systems, which include the kidney. The gentle rise in pressure that accompanies normal aging becomes a steep rise, a climbing pathway that leads to hypertension, increased risk of heart disease or stroke and the need for treatment. People who had low birthweight are twice as likely as other people to need medicine to control their blood pressures towards the end of their lives.

Within the human kidney there are at least a million functional units called nephrons, through which blood circulates so that the waste in it can be extracted. People who had lower birthweights have up to three times fewer nephrons than people who were larger at birth. The kidney does not have high priority for growth because, in the womb, the excretion of waste is carried out by the mother’s kidney. The baby’s kidney is readily traded off. If, as a result, a kidney has fewer nephrons once the baby is born each nephron will have to process more blood than it otherwise would have. This increases the wear and tear on them, and hastens the death of nephrons that occurs with normal aging. As nephrons die, blood pressure climbs, accelerating further nephron death and, it is thought, setting in motion a self-perpetuating cycle of rising blood pressure and nephron loss.

Nephrons are made during a brief period towards the end of life in the womb. If it were possible to make more nephrons after birth, kidney transplants would not be necessary. A review of the US Kidney Transplant program showed that the worst results, with failure of the transplanted kidney after only a few months, occurred when the kidney from a small person was transplanted into a large person. A large body has more blood to be cleared of waste, and the demand on each nephron is increased beyond its capacity. The nephrons die and the kidney fails. This may explain why people who had low birthweight are more likely to develop high blood pressure if they put on weight rapidly in childhood. Their nephrons die sooner and their journey to premature death is accelerated.

Kidney failure is commoner in South Carolina than in any other state in the US. It is usually preceded by high blood pressure or diabetes, but there are other causes. More men than women are affected, and people as young as 20 get it. To have kidney failure at so young an age is almost unheard off in many states. Many patients are poor, and the main burden falls on African-Americans in whom it is five times more common than it is among whites. We know all this because the costs of treatment, whether renal dialysis or kidney transplantation, are born by the Federal Government who keep accounts of what they spend and where they spend it. South Carolina is part of the so-called ‘Stroke Belt’, the cluster of states in the Deep South with high rates of stroke. Every baby born in the state since 1950 had its birthweight recorded on its birth certificate. It has therefore been relatively simple to show that people with kidney failure tend to have had lower birthweight. The high rates of kidney failure in the state may be the result of an unusually large number of people being born with below average numbers of nephrons. If their kidneys are damaged by diabetes or other disorders they fail rapidly.

STROKE

The word ‘stroke’ is used to describe damage to the brain resulting from lack of blood when arteries burst or become blocked. Like heart disease it is a result of hardening of the arteries and high blood pressure. For more than half a century strokes have been more common in the southeast of the USA than anywhere else in the country. The so-called ‘stroke belt’ comprises a contiguous cluster of states in the southeast, with South Carolina as the focus. High death rates from stroke affect men and women, blacks and whites, with especially high rates in young blacks. High blood pressure is also more common in the ‘stroke belt’. Despite intensive investigations over many years there is no agreed explanation for the existence of the belt. There seems to be no common lifestyle differences that would explain it, and neither do differences in medical care offer an explanation.

There are, however, two clues. The first comes from South Carolina which for decades has had the highest death rates from stroke in the United States, with rates 50% to 60% above the national average. Within the state stroke is most common among people who were born there; it is less common among those born elsewhere in the southeast; and least common in those born outside the southeast. To be part of the stroke belt you have to be born there. This conclusion is supported by findings among black people in New York. As a group they have high death rates from stroke, but these high rates are confined to people who were born in the southern states.

The second clue to the stroke belt is that within the belt the highest death rates are in people with poor education, low incomes and unskilled occupations. Among affluent people there is no excess of stroke mortality in the southeast, no stroke belt. The two clues suggest that stroke originates before birth, and is therefore linked to mothers, and specifically to mothers from poor backgrounds. There is important new evidence on this. Studies in Helsinki, Finland, show that the mothers of men and women who had high blood pressure and suffered a stroke had small pelvic bones. These are known to be a persisting consequence of undernutrition during infancy, in particular lack of Vitamin D. To understand the US stroke belt we may therefore need to go back to the childhoods of the mothers of people now getting strokes. This is a one century backwards leap to a time when malnutrition was widespread among people living in the stroke belt. The social disruption which began in the Civil War and continued until the depression brought with it food shortages and vitamin deficiencies. The babies of mothers born at this time may have been vulnerable to stroke because the blood vessels in their brains were poorly developed, and weakened with advancing age, bursting or becoming blocked.

TYPE 2 DIABETES & OBESITY

Before birth insulin commands the baby’s growth. It ensures that the speed of growth matches the availability of food. People develop the common form of diabetes, which begins in adulthood, for two reasons: either their bodies do not make enough insulin, or their tissues do not respond to it. Insulin is made by the pancreas in cells called beta cells. These beta cells develop before birth. In animals whose mothers were under-nourished the beta cells do not function properly. They are less able to make insulin and meet the challenges of managing the body’s sugar. One of these challenges is obesity, which makes the body less responsive to insulin, so that more of it is required. A reduced ability to make insulin, combined with an excess requirement for it, makes it impossible to maintain the amount of sugar in the blood at normal levels. The levels rise; diabetes develops.

Obesity is not the only cause of loss of responsiveness, so-called “resistance”, to insulin. Sensitivity to insulin is established in the womb. At any body weight people who were small at birth are more resistant than those who were large. It seems to be the thin, low birthweight baby that is most prone to becoming insulin resistant later. Like thin children, thin babies lack muscle though they may also lack fat. If you run your fingers down the thigh of a thin newborn baby you will readily feel the bone because the muscle is sparse. Muscle seems to have a low priority in the womb, and its growth is readily sacrificed if a baby is undernourished.

In the short-term resistance to insulin could be beneficial. If the muscles of an undernourished baby become resistant to insulin, more sugar will remain in the blood. This sugar will be available to the brain whose growth is thereby protected. Insulin resistance could be part of a system that enables the baby to be thrifty in its use of sugar. Priority is given to maintaining sufficient sugar in the blood rather than storing it in the muscles. Thrifty handling of sugar becomes ‘hard-wired’ and persists through life. It becomes a liability when food becomes more freely available after birth. The blood becomes flooded with sugar, and obesity makes the body still more resistant to insulin. Diabetes develops.

Between birth and one year babies get fatter and their body mass indices, weight/height², rise sharply. After that age, as the child grows taller, but does not continue to require large fat stores, the body mass index falls. At around six years of age the body mass index begins to rise again, the so called 'adiposity rebound'. The timing of this rebound is critically important to the later development of obesity and diabetes. Adiposity rebound at an early age is a strong predictor of both disorders in adult life. For reasons that we do not understand low weight gain during infancy, leading to thinness at two years, triggers an early adiposity rebound. The thin two year old is therefore at the greatest risk of diabetes in later life.

OSTEOPOROSIS

The strength of a bone depends on its size and the density of the calcium salts within it. This ‘bone mass’ reaches a peak in early adult life and thereafter gradually declines. The risk of osteoporotic fractures, that occur in the hip, spine or forearm, therefore depends on the peak bone mass attained and the subsequent rate of loss. Low birth weight babies have a lower bone mass which persists throughout their lives. People who were small at birth or who did not thrive during infancy also have life-long alterations in two hormones, growth hormone and cortisol, which influence bone mass. These alterations lead both to lower peak bone mass and to more rapid loss of bone mass with age.

The risk of an osteoporotic fracture is higher in older people who are frail. Slow growth in the womb and during the first few months after birth is accompanied by a reduction in the amount of muscle that is laid down. This is a lifelong problem because little new muscle is made after that age, and therefore people who had low birthweight tend to have low muscle mass through their lives. In old age their weakness can be measured by the reduced strength of their hand grip; and by their being readily fatigued by simple repetitive movements. They are less fit, a term which includes the body’s strength, flexibility and endurance. Within a group of people, the least fit have at least twice the death rates at each age compared to the most fit.

AGING

The western lifestyle has brought heart disease, diabetes and obesity but it has also brought a remarkable increase in the number of years we live. In the past hundred years, the average lifespan in the US has increased from forty-nine to seventy-six years. We do not know why. Simple explanations like better food, better hygiene, better medical care, leave unexplained why people in Japan live longer than people in the US, or why, within the US, there is such a wide variation in lifespan.

Early pointers to the importance of the first few years of life in determining lifespan were calculations showing that, within western countries, each generation has lower death rates than the previous one at every age from birth to old age. It is as though from its earliest beginnings the vitality of each succeeding generation is enhanced beyond that of the generation that precedes it. Not only do a greater proportion of people attain eighty, ninety, even a hundred years of age but they reach these ages in better health: they are fitter and more mentally active than ever before. At any given age they are biologically younger than previous generations. 75 years of age today is biologically the same as 65 years in the past. Within western countries, the places where people have the longest life expectancy are the places where people are not only healthier but are biologically younger. In Scotland old people in Edinburgh, the wealthy capital city, are four years biologically younger than people of the same age in nearby Glasgow, a historically poor city of slums and shipyards.

Aging is inevitable, but the rate at which we age is determined by the conditions of our lives. The realisation that different paths of early growth and development make people more or less vulnerable to aging processes is new; and at this time we only see the picture in outline. It is clear, however, that low birthweight in a baby born at term is a simple and available marker of a path of development that is sub-optimal and makes a person vulnerable to the stresses of later life. There are two different challenges in middle and old age. One is to slow the rate of biological aging: the other is to prevent age-related diseases, importantly heart disease, diabetes and osteoporosis. The two challenges are linked but the second is not an inevitable consequence of the first.

People differ in their inner environments, in the settings within their bodies by which they maintain an internal constancy. Some people need more sleep than others. Some people react more calmly to the ups and downs of life than others. These internal ‘homeostatic’ settings are established through our experiences as a baby and young child. Once established, internal constancy has to be maintained in the face of assaults from the outside world, and failure to maintain constancy leads to disease – high blood pressure, high blood sugar, thin bones. People who had low birthweight have more fragile ‘homeostatic’ settings that are more readily perturbed by the outside world. Older people who weighed 5, 6 or 7 pounds at birth may need protection from harmful influences that are of lesser or even no consequence to people who weighed 8, 9 or 10 pounds.

BREAST & OVARY CANCER

Because women who develop breast cancer tend to have begun their menstrual periods at an earlier age than the average it has long been suspected that the disease originates in childhood. Studies have shown that, as a group, women who have breast cancer had above average birthweight, suggesting that the disease begins in the womb. In Finland researchers examined the size and shape of the pelvic bones in mothers whose daughters developed breast or ovarian cancer. In the past the pelvic bones were routinely measured in antenatal clinics because a small or deformed pelvis, the result of rickets in childhood, caused problems during childbirth. The width of the pelvic bones is established at puberty, when girl’s hips become broader. This reshaping of the hips depends on adequate nutrition, and on the hormone estrogen, which begins to circulate in the girls blood at that time. Broad hips in a woman may be a sign of high levels of estrogen in the blood which continue through reproductive life.

The Finnish studies showed that the daughters of women with broad hips are at increased risk of cancers of the breast and ovary. One explanation of this is that, in the weeks after conception, an embryo is in direct contact with the mother’s body fluids, including the estrogen circulating in her blood. The stem cells for the breast and ovary are laid down at that time. If a mother has high levels of estrogen this could make the stem cells genetically unstable and prone to cancer in later life. Studies of life in the womb are now yielding new clues to the causes of a number of cancers.