C.H.D. Fall

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”.

Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease.

OBJECTIVE--To examine whether birth weight, infant weight, and childhood respiratory infection are associated with adult lung function and death from chronic obstructive airways disease. DESIGN--Follow up study of men born during 1911-30 whose birth weights, weights at 1 year, and childhood illnesses were recorded at the time by health visitors. SETTING--Hertfordshire, England. SUBJECTS--5718 men born in the county during 1911-30 and a subgroup of 825 men born in the county during 1920-30 and still living there. MAIN OUTCOME MEASURES--Death from chronic obstructive airways disease, mean forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), and respiratory symptoms. RESULTS--55 men died of chronic obstructive airways disease. Death rates fell with increasing birth weight and weight at 1 year. Mean FEV1 at age 59 to 70 years, adjusted for height and age, rose by 0.06 litre (95% confidence interval 0.02 to 0.09) with each pound (450 g) increase in birth weight, independently of smoking habit and social class. Bronchitis or pneumonia in infancy was associated with a 0.17 litre (0.02 to 0.32) reduction in adult FEV1 and with an increased odds ratio of wheezing and persistent sputum production in adult life independently of birth weight, smoking habit, and social class. Whooping cough in infancy was associated with a 0.22 litre (0.02 to 0.42) reduction in adult FEV1. CONCLUSIONS--Lower birth weight was associated with worse adult lung function. Intrauterine influences which retard fetal weight gain may irrecoverably constrain the growth of the airways. Bronchitis, pneumonia, or whooping cough in infancy further reduced adult lung function. They also retarded infant weight gain. Consistent with this, death from chronic obstructive airways disease in adult life was associated with lower birth weight and weight at 1 year. Promoting lung growth in fetuses and infants and reducing the incidence of lower respiratory tract infection in infancy may reduce the incidence of chronic obstructive airways disease in the next generation.

Early growth and death from cardiovascular disease in women.

OBJECTIVE--To determine whether the link suggested between growth in utero and during infancy and death from cardiovascular disease in men is also present in women. DESIGN--Follow up study of women and men whose birth weight and weight at 1 year of age had been recorded. SETTING--Hertfordshire, England. SUBJECTS--5585 women and 10,141 men born during 1911-30. MAIN OUTCOME MEASURES--Standardised mortality ratios for cardiovascular disease. RESULTS--Among women and men death rates from cardiovascular disease fell progressively between the low and high birth weights groups (chi 2 = 4.3, p = 0.04 for women, chi 2 = 8.5, p < 0.005 for men). Cardiovascular deaths in men but not women were also strongly related to weight at 1 year, falling progressively between the low and high weight groups (chi 2 = 27.5, p < 0.0001). The highest cardiovascular death rates in women were among those with below average birth weight but above average weight at 1 year. In men the highest rates were among those with below average birth weight and below average weight at 1 year. CONCLUSION--Relations between cardiovascular disease and birth weight are similar in men and women. In men cardiovascular disease is also related to weight gain in infancy.

Initiation of hypertension in utero and its amplification throughout life.

OBJECTIVE--To determine whether the relation between high blood pressure and low birth weight is initiated in utero or during infancy, and whether it changes with age. DESIGN--A longitudinal study of children and three follow up studies of adults. SETTING--Farnborough, Preston, and Hertfordshire, England, and a national sample in Britain. SUBJECTS--1895 children aged 0-10 years, 3240 men and women aged 36 years, 459 men and women aged 46-54 years, and 1231 men and women aged 59-71 years. The birth weight of all subjects had been recorded. MAIN OUTCOME MEASURE--Systolic blood pressure. RESULTS--At all ages beyond infancy people who had lower birth weight had higher systolic blood pressure. Systolic blood pressure was not related to growth during infancy independently of birth weight. The relation between systolic pressure and birth weight became larger with increasing age so that, after current body mass was allowed for, systolic pressure at ages 64-71 years decreased by 5.2 mm Hg (95% confidence interval 1.8 to 8.6) for every kg increase in birth weight. CONCLUSIONS--Essential hypertension is initiated in fetal life. A raised blood pressure is then amplified from infancy to old age, perhaps by a positive feedback mechanism.

Growth in utero and serum cholesterol concentrations in adult life.

OBJECTIVE--To see whether reduced rates of fetal growth are related to raised serum cholesterol concentrations in adult life. DESIGN--Follow up study of men and women whose size at birth had been recorded. SETTING--Jessop and Northern General Hospitals, Sheffield. SUBJECTS--219 men and women born in the Jessop Hospital during 1939-40. MAIN OUTCOME MEASURES--Serum concentrations of total cholesterol, low density lipoprotein cholesterol, and apolipoprotein B. RESULTS--Men and women who had had a small abdominal circumference at birth had raised serum concentrations of total and low density lipoprotein cholesterol and apolipoprotein B. This was independent of the duration of gestation. Serum concentrations of total cholesterol fell by 0.25 mmol/l (95% confidence interval 0.09 to 0.42) with each 1 in (2.54 cm) increase in abdominal circumference. The corresponding figure for serum low density lipoprotein cholesterol was 0.26 mmol/l (0.11 to 0.42) and for serum apolipoprotein B 0.04 g/l (0.02 to 0.07). Small head and chest circumferences at birth and short length were each associated with raised serum low density lipoprotein cholesterol concentrations but the trends disappeared in a simultaneous regression with abdominal circumference at birth. The association between abdominal circumference at birth and low density lipoprotein cholesterol concentration was independent of social class, current body weight, cigarette smoking, and alcohol consumption. CONCLUSION--Raised serum cholesterol concentrations in adult life are associated with impaired growth during late gestation, when fetal undernutrition has a disproportionate effect on liver growth. Impaired liver growth may permanently alter low density lipoprotein cholesterol metabolism.

Fetal growth and coronary heart disease in South India

BACKGROUND Coronary heart disease is predicted to become the commonest cause of death in india within 15 years People from India living overseas already have high rates of the disease that are not explained by known coronary risk factors. Small size at birth is a newly described risk factor for coronary heart disease, but associations between size at birth and the disease have not been examined in India. METHODS We studied 517 men and women who were born between 1934 and 1954 in a mission hospital in Mysore, South India, and who still lived near to the hospital. We related the prevalence of coronary heart disease, defined by standard criteria, to their birth size. FINDINGS 25 (9%) men and 27 (11%) women had coronary heart disease. Low birthweight, short birth length, and small head circumference at birth were associated with a raised prevalence of the disease. Prevalence fell from 11% in people whose birthweights were 5.5 lb (2.5 kg) or less to 3% in those whose birthweights were more than 7 lb (3.1 kg), p for trend = 0.09. The trends were stronger and statistically significant among people aged 45 years and over (p = 0.03 for birthweight, 0.04 for length, and 0.02 for head circumference). High rates of disease were also found in those whose mothers had a low body weight during pregnancy. The highest prevalence of the disease (20%) was in people who weighted 5.5 lb (2.5 kg) or less at birth and whose mothers weighted less than 100 lb (45 kg) in pregnancy. These associations were largely independent of known coronary risk factors. INTERPRETATION In India, as in the UK, coronary heart disease is associated with small size at birth, suggesting that its pathogenesis is influenced by events in utero. The association with low maternal bodyweight is further evidence that the disease originates through fetal undernutrition. Prevention of the rising epidemic of the disease in India may require improvements in the nutrition and health of young women.

Fetal growth and impaired glucose tolerance in men and women

SummaryA follow-up study was carried out to determine whether reduced fetal growth is associated with the development of impaired glucose tolerance in men and women aged 50 years. Standard oral glucose tolerance tests were carried out on 140 men and 126 women born in Preston (Lancashire, UK) between 1935 and 1943, whose size at birth had been measured in detail. Those subjects found to have impaired glucose tolerance or non-insulin-dependent diabetes mellitus had lower birthweight, a smaller head circumference and were thinner at birth. They also had a higher ratio of placental weight to birthweight. The prevalence of impaired glucose tolerance or diabetes fell from 27% in subjects who weighed 2.50 kg (5.5 pounds) or less at birth to 6% in those who weighed more than 3.41 kg (7.5 pounds) (p < 0.002 after adjusting for body mass index). Plasma glucose concentrations taken at 2-h in the glucose tolerance test fell progressively as birthweight increased (p < 0.004), as did 2-h plasma insulin concentrations (p < 0.001). The trends with birthweight were independent of duration of gestation and must therefore be related to reduced rates of fetal growth. These findings confirm the association between impaired glucose tolerance in adult life and low birthweight previously reported in Hertfordshire (UK), and demonstrate it in women as well as men. It is suggested that the association reflects the long-term effects of reduced growth of the endocrine pancreas and other tissues in utero. This may be a consequence of maternal undernutrition.

Fetal and infant growth and cardiovascular risk factors in women.

Abstract Objective: To examine whether cardiovascular risk factors in women are related to fetal and infant growth. Design: Follow up study of women born 1923-30 whose birth weights and weights at one year were recorded. Setting: Hertfordshire. Subjects: 297 women born and still living in East Hertfordshire. Main outcome measures: Plasma glucose and insulin concentrations during a standard oral glucose tolerance test; fasting plasma proinsulin and 32-33 split proinsulin concentrations; blood pressure; fasting serum total, low density lipoprotein and high density lipoprotein cholesterol, triglyceride, and apolipoprotein A I and B concentrations; and plasma fibrinogen and factor VII concentrations. Results: Fasting plasma concentrations of glucose, insulin, and 32-33 split proinsulin fell with increasing birth weight (P=0.04, P=0.002, and P=0.0002 respectively, when current body mass index was allowed for). Glucose and insulin concentrations 120 minutes after an oral glucose load showed similar trends (P=0.03 and P=0.02). Systolic blood pressure, waist:hip ratio, and serum triglyceride concentrations also fell with increasing birth weight (P=0.08, P=0.07, and P=0.07 respectively), while serum high density lipoprotein cholesterol concentrations rose (P=0.04). At each birth weight women who currently had a higher body mass index had higher levels of risk factors. Conclusion: In women, as in men, reduced fetal growth leads to insulin resistance and the associated disorders: raised blood pressure and high serum triglyceride and low serum high density lipoprotein cholesterol concentrations. The highest values of these coronary risk factors occur in people who were small at birth and become obese. In contrast with men, low rates of infant growth did not predict levels of risk factors in women. Key messages Key messages They have increased levels of cardiovascular risk factors associated with insulin resistance The highest levels of these risk factors are in people who were small at birth and obese as adults Unlike in men, low rates of growth in infancy are not linked to coronary heart disease in women

Early growth and abdominal fatness in adult life.

STUDY OBJECTIVE--The aim was to determine whether abdominal fatness in adult men is associated with retarded growth in fetal life and infancy. DESIGN--This was a follow up study of (1) men born during 1920-30 whose birthweights and weights at one year were recorded at the time by health visitors; and (2) men born during 1935-43 whose size at birth was measured in detail. The main outcome measure was the ratio of waist circumference to hip girth. SETTING--Hertfordshire and Preston, England. SUBJECTS--Subjects were 845 men born in east Hertfordshire who still live there; and 239 men born in Preston who still live in or close to the city. MAIN RESULTS--After allowing for body mass index, mean waist to hip ratio fell with increasing birthweight and rose as the ratio of placental weight to birthweight increased. These trends were independent of duration of gestation and therefore reflected retarded fetal growth. Waist to hip ratio also fell with increasing weight at one year. All these trends were independent of adult height, alcohol consumption, smoking, social class, and age. CONCLUSIONS--The tendency to store fat abdominally, which is known to increase the risk of cardiovascular disease and diabetes independently of obesity, may be a persisting response to adverse conditions and growth failure in fetal life and infancy.