D. J. P. Barker

Fetal origins of coronary heart disease

The fetal origins hypothesis states that fetal undernutrition in middle to late gestation, which leads to disproportionate fetal growth, programmes later coronary heart disease. Animal studies have shown that undernutrition before birth programmes persisting changes in a range of metabolic, physiological, and structural parameters. Studies in humans have shown that men and women whose birth weights were at the lower end of the normal range, who were thin or short at birth, or who were small in relation to placental size have increased rates of coronary heart disease. We are beginning to understand something of the mechanisms underlying these associations. The programming of blood pressure, insulin responses to glucose, cholesterol metabolism, blood coagulation, and hormonal settings are all areas of active research.

Weight in infancy and death from ischaemic heart disease.

Environmental influences that impair growth and development in early life may be risk factors for ischaemic heart disease. To test this hypothesis, 5654 men born during 1911-30 were traced. They were born in six districts of Hertfordshire, England, and their weights in infancy were recorded. 92.4% were breast fed. Men with the lowest weights at birth and at one year had the highest death rates from ischaemic heart disease. The standardised mortality ratios fell from 111 in men who weighed 18 pounds (8.2 kg) or less at one year to 42 in those who weighed 27 pounds (12.3 kg) or more. Measures that promote prenatal and postnatal growth may reduce deaths from ischaemic heart disease. Promotion of postnatal growth may be especially important in boys who weigh below 7.5 pounds (3.4 kg) at birth.

Fetal and infant growth and impaired glucose tolerance at age 64.

OBJECTIVE--To discover whether reduced fetal and infant growth is associated with non-insulin dependent diabetes and impaired glucose tolerance in adult life. DESIGN--Follow up study of men born during 1920-30 whose birth weights and weights at 1 year were known. SETTING--Hertfordshire, England. SUBJECTS--468 men born in east Hertfordshire and still living there. MAIN OUTCOME MEASURES--Fasting plasma glucose, insulin, proinsulin, and 32-33 split pro-insulin concentrations and plasma glucose and insulin concentrations 30 and 120 minutes after a 75 g glucose drink. RESULTS--93 men had impaired glucose tolerance or hitherto undiagnosed diabetes. They had had a lower mean birth weight and a lower weight at 1 year. The proportion of men with impaired glucose tolerance fell progressively from 26% (6/23) among those who had weighted 18 lb (8.16 kg) or less at 1 year to 13% (3/24) among those who had weighed 27 lb (12.25 kg) or more. Corresponding figures for diabetes were 17% (4/23) and nil (0/24). Plasma glucose concentrations at 30 and 120 minutes fell with increasing birth weight and weight at 1 year. Plasma 32-33 split proinsulin concentration fell with increasing weight at 1 year. All these trends were significant and independent of current body mass. Blood pressure was inversely related to birth weight and strongly related to plasma glucose and 32-33 split proinsulin concentrations. CONCLUSIONS--Reduced growth in early life is strongly linked with impaired glucose tolerance and non-insulin dependent diabetes. Reduced early growth is also related to a raised plasma concentration of 32-33 split proinsulin, which is interpreted as a sign of beta cell dysfunction. Reduced intrauterine growth is linked with high blood pressure, which may explain the association between hypertension and impaired glucose tolerance.

Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X) : relation to reduced fetal growth

SummaryTwo follow-up studies were carried out to determine whether lower birthweight is related to the occurrence of syndrome X — Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia. The first study included 407 men born in Hertfordshire, England between 1920 and 1930 whose weights at birth and at 1 year of age had been recorded by health visitors. The second study included 266 men and women born in Preston, UK, between 1935 and 1943 whose size at birth had been measured in detail. The prevalence of syndrome X fell progressively in both men and women, from those who had the lowest to those who had the highest birthweights. Of 64-year-old men whose birthweights were 2.95 kg (6.5 pounds) or less, 22% had syndrome X. Their risk of developing syndrome X was more than 10 times greater than that of men whose birthweights were more than 4.31 kg (9.5 pounds). The association between syndrome X and low birthweight was independent of duration of gestation and of possible confounding variables including cigarette smoking, alcohol consumption and social class currently or at birth. In addition to low birthweight, subjects with syndrome X had small head circumference and low ponderal index at birth, and low weight and below-average dental eruption at 1 year of age. It is concluded that Type 2 diabetes and hypertension have a common origin in sub-optimal development in utero, and that syndrome X should perhaps be re-named “the small-baby syndrome”.

Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease.

In national samples of 9921 10 year olds and 3259 adults in Britain systolic blood pressure was inversely related to birth weight. The association was independent of gestational age and may therefore be attributed to reduced fetal growth. This suggests that the intrauterine environment influences blood pressure during adult life. It is further evidence that the geographical differences in average blood pressure and mortality from cardiovascular disease in Britain partly reflect past differences in the intrauterine environment. Within England and Wales 10 year olds living in areas with high cardiovascular mortality were shorter and had higher resting pulse rates than those living in other areas. Their mothers were also shorter and had higher diastolic blood pressures. This suggests that there are persisting geographical differences in the childhood environment that predispose to differences in cardiovascular mortality.

INFANT MORTALITY, CHILDHOOD NUTRITION, AND ISCHAEMIC HEART DISEASE IN ENGLAND AND WALES

Although the rise in ischaemic heart disease in England and Wales has been associated with increasing prosperity, mortality rates are highest in the least affluent areas. On division of the country into two hundred and twelve local authority areas a strong geographical relation was found between ischaemic heart disease mortality rates in 1968-78 and infant mortality in 1921-25. Of the twenty-four other common causes of death only bronchitis, stomach cancer, and rheumatic heart disease were similarly related to infant mortality. These diseases are associated with poor living conditions and mortality from them is declining. Ischaemic heart disease is strongly correlated with both neonatal and postneonatal mortality. It is suggested that poor nutrition in early life increases susceptibility to the effects of an affluent diet.

Fetal and placental size and risk of hypertension in adult life.

OBJECTIVE--To study the effect of intrauterine growth and maternal physique on blood pressure in adult life. DESIGN--A follow up study of infants born 50 years previously whose measurements at birth were recorded in detail. SETTING--Preston, Lancashire. SUBJECTS--449 Men and women born in hospital in Preston during 1935-43 and still living in Lancashire. MAIN OUTCOME MEASURES--Placental weight, birth weight, and blood pressure at age 46 to 54 years. RESULTS--In both sexes systolic and diastolic pressures were strongly related to placental weight and birth weight. Mean systolic pressure rose by 15 mm Hg as placental weight increased from less than or equal to 1 lb (0.45 kg) to greater than 1.5 lb and fell by 11 mm Hg as birth weight increased from less than or equal to 5.5 lb to greater than 7.5 lb. These relations were independent so that the highest blood pressures occurred in people who had been small babies with large placentas. Higher body mass index and alcohol consumption were also associated with higher blood pressure, but the relations of placental weight and birth weight to blood pressure and hypertension were independent of these influences. CONCLUSIONS--These findings show for the first time that the intrauterine environment has an important effect on blood pressure and hypertension in adults. The highest blood pressures occurred in men and women who had been small babies with large placentas. Such discordance between placental and fetal size may lead to circulatory adaptation in the fetus, altered arterial structure in the child, and hypertension in the adult. Prevention of hypertension may depend on improving the nutrition and health of mothers.

The Developmental Origins of Adult Disease

Low birthweight is now known to be associated with increased rates of coronary heart disease and the related disorders stroke, hypertension and non-insulin dependent diabetes. These associations have been extensively replicated in studies in different countries and are not the result of confounding variables. They extend across the normal range of birthweight and depend on lower birthweights in relation to the duration of gestation rather than the effects of premature birth. The associations are thought to be consequences of developmental plasticity, the phenomenon by which one genotype can give rise to a range of different physiological or morphological states in response to different environmental conditions during development. Recent observations have shown that impaired growth in infancy and rapid childhood weight gain exacerbate the effects of impaired prenatal growth. A new vision of optimal early human development is emerging which takes account of both short and long-term outcomes.

Catch-up growth in childhood and death from coronary heart disease: longitudinal study

Abstract Objective: To examine whether catch-up growth during childhood modifies the increased risk of death from coronary heart disease that is associated with reduced intrauterine growth. Design: Follow up study of men whose body size at birth was recorded and who had an average of 10 measurements taken of their height and weight through childhood. Setting: Helsinki, Finland. Subjects: 3641 men who were born in Helsinki University Central Hospital during 1924-33 and who went to school in Helsinki. Main outcome measures: Hazard ratios for death from coronary heart disease. Results: Death from coronary heart disease was associated with low birth weight and, more strongly, with a low ponderal index at birth. Men who died from coronary heart disease had an above average body mass index at all ages from 7 to 15 years. In a simultaneous regression the hazard ratio for death from the disease increased by 14% (95% confidence interval 8% to 19%; P<0.0001) for each unit (kg/m3) decrease in ponderal index at birth and by 22% (10% to 36%; P=0.0001) for each unit (kg/m2) increase in body mass index at 11 years of age. Body mass index in childhood was strongly related to maternal body mass index, which in turn was related to coronary heart disease. The extent of crowding in the home during childhood, although related to body mass index in childhood, was not related to later coronary heart disease. Conclusion: The highest death rates from coronary heart disease occurred in boys who were thin at birth but whose weight caught up so that they had an average or above average body mass from the age of 7 years. Death from coronary heart disease may be a consequence of poor prenatal nutrition followed by improved postnatal nutrition.

Fetal and infant origins of adult disease

AbstractBackground. Many human fetuses and infants have to adapt to a limited supply of nutrients, and in doing so they permanently change their physiology and metabolism. These programmed changes may be the origins of a number of diseases in later life, including coronary heart disease, stroke, diabetes and hypertension. Coronary heart disease. We have become accustomed to the idea that coronary heart disease, the commonest cause of death in the Western world, may result from the “unhealthy” lifestyle that is associated with increasing affluence. The influences of this “unhealthy” lifestyle (e. g. obesity, cigarette smoking, dietary fat, stress), however, go only a small way towards explaining why increasing affluence in the Third world is so regularly followed by epidemics of the disease, or why in the Western world these epidemics have risen steeply to become the commonest cause of death but thereafter have declined. Neither do they explain why the highest rates of coronary heart disease in Western countries occur among the poor? Fetal origins. Answers to these questions may come from an understanding of how the structure of the heart and processes such as blood pressure regulation and the way the body handles sugar and fat are established in the womb. The “fetal origins” hypothesis states that coronary heart disease and the disorders related to it – hypertension, adult-onset diabetes and stroke – originate through adaptations that the fetus makes when it is under-nourished. Unlike adaptations made in adult life those made during early development tend to have permanent effects on the bodys structure and function – a phenomenon sometimes referred to as programming. They allow the fetus to survive and continue to grow but at the price of a shortened life.ZusammenfassungHintergrund. Viele Säuglinge und Kinder müssen sich an ein limitiertes Nahrungsangebot anpassen, wobei sie ständig ihre Physiologie und ihren Stoffwechsel verändern. Diese programmierten Änderungen sind möglicherweise der Grund von verschiedenen Erkrankungen des Erwachsenenalters wie koronarer Herzkrankheit, Schlaganfall, Diabetes Typ II und Bluthochdruck. Koronare Herzkrankheit. Allgemein wird angenommen, dass koronare Herzkrankheit, die häufigste Todesursache in der westlichen Welt, eine Folge des “ungesunden” Lebensstils ist, der mit steigendem Wohlstand einhergeht. Die Einflüsse dieses Lebensstils (z. B. Adipositas, Zigarettenrauchen, diätetische Fettaufnahme, Stress) erklären jedoch kaum, warum steigender Wohlstand in der Dritten Welt regelmäßig von Epidemien der koronaren Herzerkrankung gefolgt ist oder warum die Häufigkeit dieser Erkrankung in der westlichen Welt zunächst steil anstieg, bis sie zur häufigsten Todesursache geworden war, nun aber abfällt. Sie erklären auch nicht, warum die höchsten Raten der koronaren Herzkrankheit in der westlichen Welt bei der sozial schwachen Bevölkerung gefunden werden. Ursprünge im fetalen Alter. Antworten auf diese Fragen geben uns möglicherweise Erkenntnisse darüber, wie die Struktur des Herzens und Prozesse wie die Blutdruckregulation und die Verwertung von Zucker und Fett im Körper bereits im Mutterleib festgelegt werden. Die Hypothese des “fetalen Ursprungs” geht davon aus, dass koronare Herzkrankheit und die mit ihr verbundenen Funktionsstörungen – Bluthochdruck, Diabetes Typ II und Schlaganfall – aus Anpassungsvorgängen des Fetus an Unterernährung resultieren. Im Gegensatz zu Anpassungsvorgängen im Erwachsenenalter haben Anpassungsvorgänge der frühen Entwicklung eher permanente Effekte auf die Struktur und Funktion des Körpers, ein Phänomen, das manchmal mit Programmierung umschrieben wird. Diese Anpassungsvorgänge erlauben es dem Fetus, zu überleben und weiter zu wachsen, allerdings um den Preis eines verkürzten Lebens.