Why heart disease mortality is low in France. Commentary: intrauterine nutrition may be important.
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Embryonic and Fetal Development↗
Biomedical subjects
D J Barker
Publications and source records attributed to D J Barker.
The fetal origins of type 2 diabetes mellitus.
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Birth Weight↗
Catch-up growth in childhood and death from coronary heart disease: longitudinal study.
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.
Adolescent↗
The long-term outcome of retarded fetal growth.
Recent findings suggest that many human fetuses 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 and the related disorders stroke, diabetes and hypertension.
Adolescent↗
The intra-uterine origins of disturbed cholesterol homeostasis.
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Anthropometry↗
Blood pressure in adults after prenatal exposure to famine.
BACKGROUND: Many studies have shown that low birth weight is associated with high blood pressure. The composition of the diet of pregnant women has also been found to affect blood pressure in their children. We assessed the effect of prenatal exposure to the Dutch famine of 1944-1945, during which the caloric intake from protein, fat and carbohydrate was proportionally reduced, on blood pressures in adults now aged about 50 years. METHODS AND RESULTS: We measured blood pressures at home and in the clinic among people born at term in one hospital in Amsterdam, The Netherlands, between November 1 1943 and February 28 1947, for whom we had detailed birth records. Blood pressures of people exposed to famine during late (n = 120), mid-(n = 109) or early gestation (n = 68) were compared with those of people born in the year before or conceived in the year after the famine (unexposed subjects, n = 442). No effect of prenatal exposure on systolic and diastolic blood pressure was observed. The mean systolic blood pressure taken in the clinic in those exposed in late gestation, and adjusted for sex and age, was 1.3 mmHg higher than in the unexposed group (95% confidence interval -1.9 to 4.4). The mean systolic blood pressure differed by -0.6 mmHg (95% confidence interval -3.9 to 2.7) for those exposed in mid-gestation and -1.7 mmHg (95% confidence interval -5.6 to 2.2) for those exposed in early gestation. People who were small at birth had higher blood pressures. A 1 kg increase in birth weight was associated with a decrease of 2.7 mmHg (95% confidence interval 0.3 to 5.1) in systolic blood pressure. Analyses of blood pressures measured at home gave similar results. CONCLUSION: High blood pressure was not linked to prenatal exposure to a balanced reduction of macronutrients in the maternal diet. However, it was linked to reduced fetal growth. We postulate that it might be the composition rather than the quantity of a pregnant woman's diet that affects her child's blood pressure in later life.
Adult↗
Early growth and cardiovascular disease.
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Birth Weight↗
Fetal origins of cardiovascular disease.
Low birthweight, thinness and short body length at birth are now known to be associated with increased rates of cardiovascular disease and non-insulin dependent diabetes in adult life. The fetal origins hypothesis proposes that these diseases originate through adaptations which the fetus makes when it is undernourished. These adaptations may be cardiovascular, metabolic or endocrine. They permanently change the structure and function of the body. Prevention of the diseases may depend on prevention of imbalances in fetal growth or imbalances between prenatal and postnatal growth, or imbalances in nutrient supply to the fetus.
Adult↗
Glucose tolerance in adults after prenatal exposure to famine.
BACKGROUND: Reduced growth in utero is associated with type 2 (non-insulin-dependent) diabetes and impaired glucose tolerance in adult life. There is no direct evidence in human beings that maternal nutrition during gestation affects insulin-glucose metabolism. We investigated glucose tolerance in people born around the time of famine in the Netherlands during 1944-45. METHODS: We included 702 people born between Nov 1, 1943, and Feb 28, 1947, in Amsterdam, for whom we had detailed prenatal and birth records. We compared glucose and insulin responses to a standard oral glucose load in participants exposed to famine at any stage during gestation (exposed participants) with those who were born in the year before or conceived in the year after the famine (non-exposed participants). FINDINGS: Glucose concentrations were increased 2 h after a standard glucose load among exposed participants (p = 0.006), and were highest in men and women exposed during mid and late gestation. Mean 2 h glucose concentration among non-exposed participants was 5.8 mmol/L; concentrations were 0.5 mmol/L (95% CI 0.1-0.9) higher among participants exposed during late gestation, 0.4 mmol/L (0-0.8) higher among those exposed during mid gestation, and 0.1 mmol/L (-0.4 to 0.6) among those exposed during early gestation. Participants born as thin babies to mothers with low bodyweights had the highest concentrations and concentrations were especially high among people exposed to famine who became obese as adults. Prenatal exposure to famine was related to increased fasting proinsulin (p = 0.05) and 2 h insulin concentrations (p = 0.04), which suggests an association with insulin resistance. INTERPRETATION: Prenatal exposure to famine, especially during late gestation, is linked to decreased glucose tolerance in adults. Poor nutrition in utero may lead to permanent changes in insulin-glucose metabolism, even if the effect on fetal growth is small. This effect of famine on glucose tolerance is especially important in people who become obese.
Birth Weight↗
Size at birth, maternal weight, and type 2 diabetes in South India.
Recent research in Europe and the USA has shown that adults who had a low birthweight or who were thin at birth with a low ponderal index (birthweight/length3) tend to be insulin resistant and have an increased risk of developing Type 2 diabetes mellitus. Low birthweight and Type 2 diabetes are common in India. We have studied glucose and insulin metabolism in 506 men and women (aged 39-60 years) born in a hospital in Mysore, South India, which kept detailed obstetric records from 1934. The prevalence of Type 2 diabetes was 15%. In contrast to Western populations, higher rates were found in men and women who were short at birth (p = 0.07) and had a high ponderal index (p = 0.05). Their mothers tended to be heavier than average during pregnancy (p = 0.004). Higher ponderal index at birth was also associated with a lower 30 minute insulin increment (p = 0.009), a marker of reduced beta cell function. We speculate that the rise in Type 2 diabetes in Indian urban populations may have been triggered by mild obesity in mothers, leading to glucose intolerance during pregnancy, macrosomic changes in the fetus, and insulin deficiency in adult life.
Adult↗
Fetal growth and hyperinsulinaemia in adult life.
To explore the relation between reduced fetal growth and impaired glucose tolerance in adult life, an oral glucose tolerance test (75 g glucose) was carried out on 218 men and women, now aged around 50 years, who had been measured in detail at birth. Measurements of plasma concentrations of glucose and insulin were made at 0, 30, and 120 min. Fasting plasma concentrations of proinsulin and 32-33 split proinsulin were also measured. People in the highest category of birthweight tended to have the lowest plasma concentrations of insulin as adults at both 0 and 120 min, though both these relations were weak. Plasma insulin concentrations in adult life were more strongly related to abdominal circumference at birth than to birthweight. After adjusting for sex and body mass index, mean insulin concentrations at 0 min fell from 50 pmol l-1 to 46 pmol l-1 (p = 0.04) and at 120 min from 235 pmol l-1 to 144 pmol l-1 (p = 0.003) between people whose abdominal circumference at birth had been less than 11.5 in and those who abdominal circumference had been greater than 13 in. Plasma glucose concentrations at 120 min also fell with increasing abdominal circumference at birth. Because abdominal circumference at birth is an indicator of the growth of the liver in fetal life, one interpretation of these findings is that the sensitivity of the liver to insulin is permanently reduced if the intrauterine development of this organ is impaired.
Adult↗
Weight gain in pregnancy, triceps skinfold thickness, and blood pressure in offspring.
OBJECTIVE: To determine whether women who are poorly nourished in early pregnancy, as determined by triceps skinfold thickness, or who have poor pregnancy weight gain have offspring with higher blood pressure (BP). METHODS: We evaluated 296 11-year-old children born to women who had taken part in a study of nutrition in pregnancy. Women had been weighed at 18 and 28 weeks' gestation and had had their triceps skinfold thickness measured at 18 weeks. In our follow-up study, their children were weighed and had their BP recorded. Blood pressure was adjusted for weight, gender, ethnic group, cuff size, and time of measurement. RESULTS: The children's mean (standard deviation [SD]) systolic BP was 106 (12) mmHg and their mean (SD) diastolic BP was 62 (7) mmHg. Maternal triceps skinfold thickness at 18 weeks' gestation and maternal pregnancy weight gain between 18 and 28 weeks' gestation were weakly inversely related to the children's BP. However, among women with triceps skinfold thickness at 18 weeks below the group median (15 mm), reduced pregnancy weight gain was associated with significantly higher BP in the offspring; systolic pressure increased by 11.3 mmHg (95% confidence interval [CI] 2.2, 20.4) and diastolic pressure by 10.1 mmHg (95% CI 3.2, 17.1) for each kilogram-per-week decrease in pregnancy weight gain. CONCLUSION: In women who were poorly nourished in early pregnancy, reduced pregnancy weight gain was associated with higher BP in the 11-year-old offspring. We suggest that fetal adaptations to poor maternal nutrition lead to elevated BP in childhood but adequate maternal weight gain during pregnancy may protect against this.
Adaptation, Physiological↗
Does raised intraocular pressure begin in utero?
AIM: To determine whether fetal and infant growth, as assessed by weight at birth and weight at 1 year, are related to intraocular pressure. METHODS: 717 men and women born in Hertfordshire between 1920 and 1930, for whom records of birth weight and weight at 1 year were available, were examined. Visual fields were assessed using the Takagi central 25 degrees 75 point static threshold screening program. Tonometry was performed using the Perkin's tonometer. The disc was assessed by direct ophthalmoscopy through dilated pupils. RESULTS: A significant inverse relation was found between systolic blood pressure and birth weight. However, no association was found between birth weight or weight at 1 year and intraocular pressure, cup/disc ratio, or visual field defects. CONCLUSIONS: There was no evidence to support fetal or infant growth as being important factors for the subsequent development of raised intraocular pressure.
Aged↗
Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome?
Recent studies have shown that reduced fetal growth is associated with the development of the insulin resistance syndrome in adult life. The mechanisms are not known. However increased activity of the hypothalamic-pituitary-adrenal axis (HPAA) may underlie this association; the axis is known to be reset by fetal growth retardation in animals, and there is evidence in humans of an association between raised HPAA activity and the insulin resistance syndrome. We have, therefore, examined the relations among size at birth, plasma cortisol concentrations, and components of the insulin resistance syndrome in a sample of healthy men. We measured 0900 h fasting plasma cortisol and corticosteroid-binding globulin levels in 370 men who were born in Hertfordshire, UK, between 1920-1930 and whose birth weights were recorded. Fasting plasma cortisol concentrations varied from 112-702 nmol/L and were related to systolic blood pressure (P = 0.02), fasting and 2-h plasma glucose concentrations after an oral glucose tolerance test (P = 0.0002 and P = 0.04), plasma triglyceride levels (P = 0.009), and insulin resistance (P = 0.006). Plasma cortisol concentrations fell progressively (P = 0.007) from 408 nmol/L in men whose birth weights were 5.5 lb (2.50 kg) or less to 309 nmol/L among those who weighed 9.5 lb (4.31 kg) or more at birth, a trend independent of age and body mass index. These findings suggest that plasma concentrations of cortisol within the normal range could have an important effect on blood pressure and glucose tolerance. Moreover, this study provides the first evidence that intrauterine programming of the HPAA may be a mechanism underlying the association between low birth weight and the insulin resistance syndrome in adult life.
Aged↗
In utero programming of chronic disease.
1. Many human fetuses have to adapt to a limited supply of nutrients. In doing so they permanently change their structure and metabolism. 2. These 'programmed' changes may be the origins of a number of diseases in later life, including coronary heart disease and the related disorders stroke, diabetes and hypertension. 3. This review examines the evidence linking these diseases to fetal undernutrition and provides an overview of previous studies in this area.
Child↗
Fetal growth, length of gestation, and polycystic ovaries in adult life.
BACKGROUND: Polycystic ovaries are a common disorder associated with menstrual irregularities, subfertility, hirsutism, acne, and a range of endocrine abnormalities, including high concentrations of plasma luteinising hormone (LH) and excessive androgen production. The pathophysiology is not understood. We investigated whether the disorder originates during intrauterine life. METHODS: We examined 235 women aged 40-42 years who were born in Sheffield, UK. We related the prevalence of polycystic ovaries and the plasma concentrations of gonadotropin hormones and androgens to the women's body size at birth, and the length of gestation. FINDINGS: 49 (21%) of the women had polycystic ovaries. We defined two groups of women with the disorder, which correspond to the two groups that commonly present clinically. The first group comprised obese women who were androgenised, with higher than normal concentrations of plasma LH and testosterone. These women had above-average birthweight and were born to overweight mothers. The second group comprised women of normal weight who had high plasma LH, but normal testosterone concentrations. These women were born after term (40 weeks' gestation). INTERPRETATION: The two common forms of polycystic ovary syndrome have different origins in intrauterine life. Obese, hirsute women with polycystic ovaries have higher than normal ovarian secretion of androgens that are associated with high birthweight and maternal obesity. Thin women with polycystic ovaries have altered hypothalamic control of LH release resulting from prolonged gestation.
Adult↗
Mother's weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study.
OBJECTIVE: To determine whether restricted growth in utero is associated with an increased risk of coronary heart disease are among men in Finland, where rates of the disease are among the highest in the world. DESIGN: Follow up study. SETTING: Helsinki, Finland. SUBJECTS: 3302 men born in Helsinki University Central Hospital during 1924-33 who went to school in the city of Helsinki and were resident in Finalnd in 1971. MAIN OUTCOME MEASURES: Standardised mortality ratios for coronary heart disease. RESULTS: Men who were thin at birth, with low placental weight, had high death rates from coronary heart disease. Men whose mothers had a high body mass index in pregnancy also had high death rates. In a multivariate analysis the hazard ratio for coronary heart disease was 1.37 (95% confidence interval 1.20 to 1.57) (P < 0.0001) for every standard deviation decrease in ponderal index at birth and 1.24 (1.10 to 1.39) (P = 0.0004) for every standard deviation increase in mother's body mass index. The effect of mother's body mass index was restricted to mothers of below average stature. CONCLUSION: These findings suggest a new explanation for the epidemics of coronary heart disease that accompany Westernisation. Chronically malnourished women are short and light and their babies tend to be thin. The immediate effect of improved nutrition is that women become fat, which seems to increase the risk of coronary heart disease in the next generation. With continued improvements in nutrition, women become taller and heavier; their babies are adequately nourished; and maternal fatness no longer increases the risk of coronary heart disease, which therefore declines.
Aged↗
Is the age of menopause determined in-utero?
OBJECTIVE: To determine whether age at menopause is related to size at birth. DESIGN: A follow-up study of two groups of women whose size at birth was recorded. SETTING: Hertfordshire and Sheffield, England. POPULATION: 755 women aged 60-71 years born in Hertfordshire; 235 women aged 40-42 years born in the Jessop Hospital, Sheffield. MAIN OUTCOME MEASURES: Age at natural menopause or serum follicle stimulating hormone concentration greater than 25 IU/ml. RESULTS: Age at menopause was unrelated to birth weight. However, it occurred at a younger age in women who had low weight at 1 year. This was independent of their body weight and smoking habits. In the population of younger women those who had had an early menopause tended to have been short at birth, with a high ponderal index (birth weight/length3). CONCLUSION: Growth retardation in late gestation, leading to shortness at birth and low weight gain in infancy, may be associated with a reduced number of primordial follicles in the ovary leading in turn to an earlier menopause.
Adult↗