Search

ObjectiveTo determine if preterm birth is associated with adaptation of the hypothalamic–pituitary–adrenal (HPA) axis and whether HPA axis programming relates to the degree of prematurity (defined as extremely preterm birth at DesignThis study reports findings from a prospective birth cohort. Saliva cortisol concentrations were measured prevaccination and postvaccination, and in the morning and evening, at 4 months chronological age.SettingInfants born at a single Scottish hospital.Participants45 term-born, 42 very preterm and 16 extremely preterm infants.OutcomesCortisol stress response to vaccination (postvaccination minus prevaccination cortisol concentrations), diurnal slope (log-transformed morning minus log-transformed evening cortisol values) and mean log-transformed daily cortisol.ResultsCompared with infants born at term, infants born extremely preterm had a blunted cortisol response to vaccination (5.8 nmol/L vs 13.1 nmol/L, difference in means: −7.3 nmol/L, 95% CI −14.0 to −0.6) and a flattened diurnal slope (difference in geometric means: −72.9%, 95% CI −87.1 to −42.8). In contrast, the cortisol response to vaccination (difference in means −2.7 nmol/L, 95% CI −7.4 to 2.0) and diurnal slope at 4 months (difference in geometric means: −33.6%, 95% CI −62.0 to 16.0) did not differ significantly in infants born very preterm compared with infants born at term.ConclusionsInfants born extremely preterm have blunted cortisol reactivity and a flattened diurnal slope. These patterns of HPA axis regulation are commonly seen after childhood adversity and could contribute to later metabolic and neurodevelopmental phenotypes observed in this population.

Background Although there is longstanding evidence of the short-term benefits of promoting rapid growth for young children in low-income settings, more recent studies suggest that early weight gain can also increase the risk of chronic diseases in adults. This paper attempts to separate the effects of early life weight and length/height gains on blood pressure, body mass index (BMI), sum of skin folds and subscapular/triceps skin fold ratio at 14–15 years of age. Methods The sample comprised 833 members of a prospective population-based birth cohort from Brazil. Conditional size (weight or height) analyses were used to express the difference between observed size at a given age and expected size based on a regression, including all previous measures of the same anthropometric index. A positive conditional weight or height indicates growing faster than expected given prior size. Results Conditional weights at all age ranges were positively associated with most outcomes; each z-score of conditional weight at 4 years was associated with an increase of 6.1 mm in the sum of skin folds (95% CI 4.5 to 7.6) in adolescence after adjustment for conditional length/height. Associations of the outcomes with conditional length/height were mostly negative or non-significant—each z-score was associated with a reduction of 2.4 mm (95% CI −3.8 to −1.1) in the sum of skin folds after adjustment for conditional weight. No associations were found with the skin fold ratio. Conclusion The promotion of rapid length/height gain without excessive weight gain seems to be beneficial for long-term outcomes, but this requires confirmation from other studies.

Background People who score poorly in intellectual ability tests have shorter life expectancy. A study was undertaken to determine whether this association is different in people from different socioeconomic backgrounds. Methods The mortality of 2786 men born in Helsinki, Finland during 1934–1944 who, as military conscripts, underwent a standardised intellectual ability test comprising verbal, visuospatial and arithmetic reasoning subtests was studied. Mortality data came from the Finnish Death Register. Results Comparing men in the lowest and highest test score quartiles, HRs for all-cause mortality were 1.9 (95% CI 1.4 to 2.5) for verbal reasoning, 2.2 (95% CI 1.6 to 3.0) for visuospatial reasoning and 1.9 (95% CI 1.4 to 2.5) for arithmetic reasoning, corresponding to 2.6, 3.4 and 2.6 excess years of life lost, respectively. Associations were similar for cardiovascular and non-cardiovascular mortality. Intellectual ability scores were stronger predictors in men who grew up in middle-class families. Compared with middle-class men in the highest quartile of the visuospatial reasoning score, middle-class men in the lowest quartile lost 6.5 years of life while men from families of manual workers in the highest quartile lost 2.8 years and men in the lowest quartile lost 5.6 years. Conclusions High intellectual ability in men aged 20 protects them from mortality in later life. This effect is stronger in men who grew up in middle-class families than in those who grew up in manual worker families. This finding suggests that early life conditions that are unfavourable to the development of cognitive abilities negate the life expectancy benefits of being born into a more affluent family.

Objectives: To assess whether serial measurements of childhood body mass index (BMI) give clinically useful predictions of the risk of developing adult metabolic syndrome and impaired glucose tolerance or type 2 diabetes. Design/setting: Follow-up of a community-based birth cohort in Delhi, India. Participants: 1,492 men and women aged 26-32 years whose BMI was recorded 6-monthly throughout childhood. Main outcome measures: The predictive value of childhood BMI for adult metabolic syndrome (MS) defined using waist circumference, blood pressure and fasting glucose, triglyceride and HDL-cholesterol concentrations, and impaired glucose tolerance (IGT) and diabetes (DM) diagnosed by oral glucose tolerance tests. Results: Twenty-five percent of subjects had MS and 15% had IGT/DM. Both outcomes were associated with greater childhood BMI gain (MS: OR 1.63 [95% CI 1.44 to 1.85]; IGT/DM: 1.39 [1.20 to 1.60] per unit increase in within-cohort BMI SD-score between 5-14 years). Best predictions of adult disease were obtained using a combined test comprising i) any increase in BMI SD-score between 5-14 years and ii) a BMI SD-score >0 at 14 years (MS: sensitivity 45%, specificity 78%; IGT/DM: 37%, 73%). Likelihood ratios were low (MS: 1.4-2.0; IGT/DM: 1.2-1.4). A single high BMI measurement at 14 years (overweight or obese, International Obesity Task Force criteria) was highly specific but insensitive (MS: sensitivity 7%, specificity 97%; IGT/DM: 8%, 97%). Charts for plotting BMI SD-scores through childhood were produced. Conclusions: Serial measurements of childhood BMI give useful predictions of adult risk and could guide advice to children and parents on preventing later disease.

BACKGROUND: It is generally accepted that breast feeding has a beneficial effect on the health of infants and young children. Recently, a few studies have shown that the method of infant feeding is also associated with cardiovascular disease and its risk factors in adult life. AIMS: To examine the association between the method of infant feeding in the first weeks after birth and glucose tolerance, plasma lipid profile, blood pressure, and body mass in adults aged 48-53 years. METHODS: Subjects born at term between 1 November 1943 and 28 February 1947 in the Wilhelmina Gasthuis in Amsterdam around the time of a severe period of famine (late November 1944 to early May 1945). For 625 subjects, information was available about infant feeding at the time of discharge from hospital (on average 10.4 days after birth), and at least one blood sample after an overnight fast. RESULTS: Subjects who were bottle fed had a higher mean 120 minute plasma glucose concentration after a standard oral glucose tolerance test than those who were exclusively breast fed. They also had a higher plasma low density lipoprotein (LDL) cholesterol concentration, a lower high density lipoprotein (HDL) cholesterol concentration, and a higher LDL/HDL ratio. Systolic blood pressure and body mass index were not affected by the method of infant feeding. CONCLUSIONS: Exclusive breast feeding seems to have a protective effect against some risk factors for cardiovascular disease in later life

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.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.Helsinki, Finland.3641 men who were born in Helsinki University Central Hospital during 1924-33 and who went to school in Helsinki.Hazard ratios for death from coronary heart disease.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%; P0.0001) 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.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.

Objective: To determine whether restricted growth in utero is associated with an increased risk of coronary heart disease 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 Finland 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 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. Key messages Men who were thin at birth have high death rates from coronary heart disease If, in addition, their mothers were short and heavy they have evenhigher rates Women tend to be short and heavy in populations at an intermediatestage between chronic malnutrition and adequate nutrition This may explain why rates of coronary heart disease rise as nutrition improves in a population; rates then decline with continuing nutritional improvement

BACKGROUND: Follow up studies in Britain have shown that low rates of fetal growth are followed by reduced lung function in adult life, independent of smoking and social class. It is suggested that fetal adaptations to undernutrition in utero result in permanent changes in lung structure, which in turn lead to chronic airflow obstruction. India has high rates of intrauterine growth retardation, but no study has examined the association between fetal growth and adult lung function in Indian people. We have related size at birth to lung function in an urban Indian population aged 38-59 years. METHODS: Two hundred and eighty six men and women born in one hospital in Mysore City, South India, during 1934-1953 were traced by a house-to-house survey of the city. Their mean forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were measured using a turbine spirometer. These measurements were linked to their size at birth, recorded at the time. RESULTS: In both men and women mean FEV1 fell with decreasing birthweight. Adjusted for age and height, it fell by 0.09 litres with each pound (454 g) decrease in birthweight in men (95% confidence interval (CI) 0.01 to 0.16) and by 0.06 (95% CI -0.01 to 0.13) in women. Likewise, mean FVC fell by 0.11 litres (95% CI 0.02 to 0.19) with each pound decrease in birthweight in men, and by 0.08 litres (95% CI 0.002 to 0.16) in women. FEV1 and FVC were lower in men who smoked, but the associations with size at birth were independent of smoking. Small head circumference at birth was associated with a low FEV1/FVC ratio in men which may reflect restriction in airway growth in early gestation. CONCLUSION: This is further evidence that adult lung function is "programmed" in fetal life. Smoking may be particularly detrimental to the lung function of populations already disadvantaged by poor rates of fetal growth.

High circulating levels of cholesterol, particularly low density lipoprotein (LDL) cholesterol and the clotting factors fibrinogen and factor VII, are associated with increased risk of myocardial infarction. Variations in the plasma levels of these factors are determined in part by polymorphisms in the genes concerned and also by weight at 1 year (infant weight). We have looked at the possibility of interactions between these genetic factors and infant weight in a sample of 290 men and 192 women from Hertfordshire using the beta-fibrinogen G/A-455, factor VII R353Q, and ApoE polymorphisms. The rare allele frequencies of the three polymorphisms were 0.19 for beta-fibrinogen, 0.10 for factor VII, and 0.07 and 0.13 for the 2 and 4 alleles of ApoE, and these frequencies were not different in subjects of different infant weight. In this sample, the polymorphisms showed the expected effects on plasma levels of fibrinogen, factor VII, and LDL cholesterol. The A-455 allele was associated with higher fibrinogen levels but the effect was only statistically significant in women (p = 0.003). The R353 allele was associated with higher factor VII activity in both men and women (p < 0.0001 for both). The ApoE2 allele was associated with lower levels of LDL cholesterol (p = 0.03 in men, p = 0.006 in women), while the ApoE4 allele was associated with higher levels (p < 0.001 in men, not significant in women). In this sample of men and women the effect of low infant weight was only associated with significant effects on fibrinogen and LDL cholesterol in the group of men (p = 0.005 and p = 0.008 respectively). Compared with the E3E3 subjects, the LDL lowering effect of the E2 allele and the raising effect of the E4 allele was greater in those with low infant weight compared with those with high infant weight (low v high infant weight for E2: 12.7% v 9.4%; for E4 12.7% v 8.5%). Although in this sample the interactive effect did not reach statistical significance, the additive effect of ApoE genotype and low infant weight on determining plasma LDL cholesterol levels, if confirmed, may be of relevance in determining a person's future risk of atherosclerosis.

OBJECTIVE--To test the hypothesis that reduced fetal growth leads to altered plasma insulin-like growth factor-1 (IGF-1) concentrations in childhood. DESIGN--A follow up study of 4 year old children whose birth weights were recorded, and of 7 year old children whose weight, length, head circumference, and placental weight were measured at birth. SETTING--Pune, India, and Salisbury, England. SUBJECTS--200 children born during October 1987 to April 1989 in the King Edward Memorial Hospital, Pune, weighing over 2.0 kg at birth and not requiring special care, and 244 children born during July 1984 to February 1985 in the Salisbury Health District and still living there. MAIN OUTCOME MEASURE--Plasma IGF-1 concentrations. RESULTS--In both groups of children, and consistent with findings in other studies, plasma IGF-1 concentrations were higher in taller and heavier children, and higher in girls than boys. Allowing for sex and current size, concentrations were inversely related to birth weight (Pune p = 0.002; Salisbury p = 0.003). Thus at any level of weight or height, children of lower birth weight had higher IGF-1 concentrations. The highest concentrations were in children who were below average birth weight and above average weight or height when studied. Systolic blood pressures were higher in children with higher IGF-1 concentrations (Pune p = 0.01; Salisbury p = 0.04). CONCLUSIONS--Children of lower birth weight develop higher circulating concentrations of IGF-1 than expected for their height and weight. This is consistent with the hypothesis that under-nutrition in utero leads to reprogramming of the IGF-1 axis. The increase of plasma IGF-1 concentrations in low birthweight children may also be linked to postnatal catch-up growth. High IGF-1 concentrations may be one of the mechanisms linking reduced fetal growth and high blood pressure in later life.

OBJECTIVE--To examine how fetal and infant growth are related to left ventricular mass in adult life. DESIGN--A follow up study of men born during 1920-30 whose birth weights and weights at 1 year were recorded. SETTING--Hertfordshire, England. SUBJECTS--290 men born and still living in East Hertfordshire, England. MAIN OUTCOME MEASURE--Left ventricular mass calculated from measurements of interventricular septal thickness and left ventricular posterior wall thickness and left ventricular internal diameter at end diastole measured by M mode echocardiography. RESULTS--Left ventricular mass was highest in men with the lowest weight at 1 year and fell with increasing weight at 1 year (r = 0.18, P = 0.01). Left ventricular mass was not related to birth weight. The relation with weight at 1 year was independent of factors in adult life known to influence left ventricular mass, including body size, systolic blood pressure, and age. The enlarged left ventricular mass associated with reduced growth in infancy was concentric, affecting both the interventricular septum and the left ventricular posterior wall. Concentric left ventricular hypertrophy is known to be associated with increased death rates from coronary artery disease. CONCLUSION--Low weight at 1 year is associated with concentric enlargement of the left ventricle in adult life. This is consistent with a previous finding of higher mortality from cardiovascular disease in men of low weight at 1 year, and provides further evidence that cardiovascular disease may be partly programmed in early life. The left ventricular enlargement may be a long term result of haemodynamic changes in utero or of persisting changes in growth factor concentrations.

Background Optimising maternal nutrition is important for improving child health in both the short and longer term. Micronutrient deficiency is common in women in low- and middle-income countries (LMICs). Multiple micronutrient supplementation in pregnant women reduces the proportion of babies born with low birth weight and has recently been recommended to improve child survival, growth and health. We reviewed the evidence that multiple micronutrient supplementation influences mortality and health outcomes in childhood. Method We searched systematically for follow-up reports from all trials in a 2012 Cochrane review of multiple micronutrient supplementation in pregnancy. The intervention group included three or more micronutrients. The control group received iron and folic acid. Median time of onset varied from 9 to 23 weeks. Primary outcomes were offspring mortality, height and weight expressed as z scores, and head circumference, presented as unadjusted differences in means or proportions (intervention minus control). Secondary outcomes included other anthropometry, body composition, blood pressure, cognitive outcomes and lung function. Results Nineteen follow-up reports were found from nine trials. Six of the trials used the UNIMMAP supplement containing 15 micronutrients in their recommended daily allowances. The other three trials had similar constituents and doses. Data for mortality estimates were available from all trials. Meta-analysis (n = 9) showed no difference in mortality (risk difference −0.05 per 1000 livebirths; 95% CI –5.25, 5.15). Six trials investigated anthropometry and found no difference at follow-up in weight-for-age z score (0.02; 95% CI −0.03, 0.07), height-for-age z score (0.01; 95% CI −0.04, 0.06), or head circumference (0.11 cm; 95% CI −0.03, 0.26). No differences were seen in cognitive function (with the exception of motor ability in one study), body composition, blood pressure, or respiratory outcomes. The trials were generally of high quality and differential loss to follow-up and publication bias did not appear important. Conclusions Despite current recommendations for multiple micronutrient supplementation to replace iron and folic acid in pregnancy, the current evidence from long-term follow-up studies does not show improvements in child survival or growth.

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

Objective: To determine whether low birth weight and low weight at 1 year are followed by an increased prevalence of coronary heart disease in adult life. Design: A follow up study of men born during 1920–30 whose birth weights and weights at 1 year were recorded. Setting: Hertfordshire, England. Subjects: 290 men born and still living in East Hertfordshire. Main outcome measure: The prevalence of coronary heart disease, defined by the Rose/WHO chest pain questionnaire, standard electrocardiographic criteria, or history of coronary artery angioplasty or graft surgery. Results: 42 (14%) men had coronary heart disease. Their mean birth weight, 7.9 lb (3600 g), was the same as that of the other men. Their mean weight at 1 year, 21.8 lb (9.9 kg), was 1 lb (454 g) lower (95% confidence interval 0.1 to 1.8, P=0.02). Percentages of men with coronary heart disease fell from 27% in those who weighed 18 lb (8.2 kg) or less at 1 year to 9% in those who weighed more than 26 lb (11.8 kg) (P value for trend=0.03). This trend occurred in both smokers and non-smokers and within each social class. Conclusion: These findings add to the evidence that coronary heart disease is “programmed” during early growth. Key messages Key messages This is consistent with the association between low weight at 1 year and increased death rates from coronary heart disease The association between low weight at 1 year and coronary heart disease occurs in smokers and non-smokers and in each social class This adds to evidence that influences acting before 1 year of age have an important effect on the risk of developing coronary heart disease

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.

OBJECTIVE--To determine how fetal growth is related to death from cardiovascular disease in adult life. DESIGN--A follow up study of men born during 1907-24 whose birth weights, head circumferences, and other body measurements were recorded at birth. SETTING--Sheffield, England. SUBJECTS--1586 Men born in the Jessop Hospital. MAIN OUTCOME MEASURE--Death from cardiovascular disease. RESULTS--Standardised mortality ratios for cardiovascular disease fell from 119 in men who weighed 5.5 pounds (2495 g) or less at birth to 74 in men who weighed more than 8.5 pounds (3856 g). The fall was significant for premature cardiovascular deaths up to 65 years of age (chi 2 = 5.0, p = 0.02). Standardised mortality ratios also fell with increasing head circumference (chi 2 = 4.6, p = 0.03) and increasing ponderal index (weight/length3) (chi 2 = 3.8, p = 0.05; for premature deaths chi 2 = 6.0, p = 0.01). They were not related to the duration of gestation. Among men for whom the ratio of placental weight to birth weight was in the highest fifths the standardised mortality ratio was 137. CONCLUSION--These findings show that reduced fetal growth is followed by increased mortality from cardiovascular disease. They suggest that reduction in growth begins early in gestation. They are further evidence that cardiovascular disease originates through programming of the body's structure, physiology, and metabolism by the environment during fetal life. Maternal nutrition may have an important influence on programming.

OBJECTIVE--To examine whether method of infant feeding is associated with adult serum lipid concentrations and mortality from ischaemic heart disease. DESIGN--Follow up study of men born during 1911-30. SETTING--Hertfordshire, England. SUBJECTS--5718 men, for 5471 of whom information on infant feeding had been recorded by health visitors and 1314 of whom had died. 485 of the men born during 1920-30 and still living in Hertfordshire who had blood lipid measurements. MAIN OUTCOME MEASURES--Death from ischaemic heart disease; serum cholesterol and apolipoprotein concentrations. RESULTS--474 men had died from ischaemic heart disease. Standardised mortality ratios were 97 (95% confidence interval 81 to 115) in men who had been breast fed and had not been weaned at 1 year, 79 (69 to 90) in breast fed men who had been weaned at 1 year, and 73 (59 to 89) in men who had been breast and bottle fed. Compared with men weaned before one year men not weaned had higher mean serum concentrations of total cholesterol (6.9 (not weaned) v 6.6 (weaned) mmol/l), low density lipoprotein cholesterol (5.0 v 4.6 mmol/l) and apolipoprotein B (1.14 v 1.08 g/l). Men who had been bottle fed also had a high standardised mortality ratio for ischaemic heart disease (95; 68 to 130) and high mean serum concentrations of total cholesterol (7.0 mmol/l), low density lipoprotein cholesterol (5.1 mmol/l), and apolipoprotein B (1.14 g/l). In all feeding groups serum apolipoprotein B concentrations were lower in men with higher birth weight and weight at 1 year. CONCLUSIONS--Age of weaning and method of infant feeding may influence adult serum low density lipoprotein cholesterol concentrations and mortality from ischaemic heart disease. Adult serum apolipoprotein B concentrations are related to growth in fetal life and infancy.

To study maternal and fetal influences on blood pressure in childhood 405 children aged 4 years who were born and still resident in the Salisbury health district were visited at home for blood pressure and growth measurements. Information on the pregnancy, delivery, and baby was abstracted from the routine obstetric notes. Similar to recent findings in adults, the child's systolic pressure was inversely related to birth weight and positively related to placental weight. Systolic pressure at 4 years increased by 1.2 mm Hg for every SD decrease in the ratio of head circumference to length at birth, and by 1.1 mm Hg for every SD decrease in ponderal index at birth. Mothers whose haemoglobin concentrations fell below 100g/l during pregnancy had children whose systolic pressures were on average 2.9 mm Hg higher than the children of mothers with higher haemoglobin concentrations. Patterns of placental weight, birth weight, head circumference, and length that are associated with high blood pressure in adults are also associated with higher blood pressure in 4 year old children. Identification of the intrauterine influences that lead to these patterns of fetal growth could lead to the primary prevention of hypertension.

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.

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.

Background and Aims In a prospective pregnancy cohort study, we investigated the association of early growth with blood pressure at 5–6 years of age. Methods Our study was based on 2,338 children who were born healthy at ≥ 37 completed weeks gestation with on average 7 measures of growth (weight and length) from birth to age 12 months. We used conditional weight, a residual of current weight regressed on prior weights, to represent deviations from expected weight gain from 0 to 1, 1 to 3, 3 to 6, and 6 to 12 months. The same method was applied for conditional length and body mass index. Associations of these measures with systolic and diastolic blood pressure at the age of 5–6 years were modeled before and after adjustment for current body mass index and height. Results Higher weight-, length-, and bmi conditionals (expressing faster growth) were associated with higher blood pressure, with the exception of conditional growth between birth and 1 month. Adjusted for current height and body mass index, almost none of the conditionals were associated with blood pressure. However, lower birth weight and lower weight and height conditionals 0 to 1 month were associated with higher systolic blood pressure at age 5–6 years. Conclusions We infer that the inverse association between prenatal and first month growth with childhood blood pressure may reflect a programming effect, while the positive association between infant growth after 1 month with childhood blood pressure probably reflects an effect of the tracking of body size.

STUDY OBJECTIVE--The aim was to provide benchmarks by which to judge the success of behaviour change and the cervical cancer screening programme in England and Wales in reducing mortality from this disease over the next decade. DESIGN--Log-linear models and cervical cancer mortality data by age and marital status from 1959-88 were used to predict future mortality in England and Wales. MEASUREMENTS AND MAIN RESULTS--Recombining "predicted" deaths in marital status groups for 1984-88 gave a closer agreement to total mortality observed in those years than predictions based on past trends from 1959-83 among women of all statuses combined. Mortality for 1989-2003 was then predicted, using the data for 1959-1988. CONCLUSIONS--The reaggregated marital status forecasts of mortality provide an upper boundary which future observed mortality should not cross if primary and secondary prevention measures are working effectively. The method allows swift comparison of observation with expectation and therefore the rapid evaluation of the overall performance of preventive strategies.

Epidemiologist who created a new area of research into the developmental origins of health and disease

Background and Aims In a prospective cohort study (the ABCD study), we investigated the association of early growth with (precursors of) childhood obesity. Methods Our study was based on 2,338 term born children with on average 7 measures of growth (weight and length) from birth to age 12 months. We used conditional weight, a residual of current weight regressed on prior weights, to represent deviations from expected weight gain from 0 to 1, 1 to 3, 3 to 6, and 6 to 12 months. The same method was applied for conditional length and body mass index. Relations of these measures with height, body mass index, fat mass (adjusted for height and fat free mass) and waist-to-height ratio (WHtR) at age 5–6 were explored using linear regression analysis. Results Higher birth weight, weigh conditionals and bmi conditionals for all periods in infancy (expressing faster growth) were associated with increased height, body mass index, fat mass and WHtR. Furthermore, although higher length conditionals after 3 months were associated with higher childhood bmi, no association was found with fat mass. Higher length conditionals were associated with lower WHtR. Conclusions Faster prenatal growth and subsequent faster infant weight- and bmi gain were associated with greater childhood body size, more fat tissue mass and more central adipose distribution. Conversely, although rapid length gain after 3 months was associated with greater childhood body size, this was not accompanied by more fat tissue mass, yet with less central adipose distribution.

Objectives The authors aimed to establish gestation specific reference intervals for Doppler indices of fetal cardiac function from 12 to 40 weeks of pregnancy. Methods In a cross-sectional observational study of singleton pregnancies, examinations were performed in 221 women evenly distributed across each week of pregnancy from 12 to 40 weeks. Each mother was scanned once. For the mitral valve, the velocity and duration of the early (E) and atrial (A) waves and interval (a) between E/A complexes was recorded. For the aortic valve, the duration (b), peak and average flow velocity in systole was measured. For each the authors averaged values from three consecutive complexes. Myocardial performance index (MPI) was calculated as (a–b)/b. The aortic valve diameter was measured and the left heart cardiac output was calculated. Results The authors estimated the mean of a fetal measurement using a cubic polynomial in gestational age. The authors then modelled the absolute residual as a linear function of gestational age to estimate the SD. The authors combined these estimates to generate centile graphs for the outlet peak systolic velocity, time averaged velocity and the aortic valve diameter, mitral E/A ratio, left heart cardiac output and MPI. Conclusion Fetal cardiac physiology can be studied and Doppler indices reliably measured as early as the late first trimester of pregnancy. Study of development of fetal cardiac function and may eventually provide better understanding of changes which may predispose to adult cardiac disease.

Evidence is growing that the metabolic abnormalities which lead to coronary heart disease are programmed by undernutrition in utero. Undernutrition of the fetus leads to small size and disproportionate body form at birth, which are now known to be linked to metabolic abnormalities in later life.1 Abdominal circumference may be measured routinely at birth and indicates liver growth in utero as well as the fatness of the abdominal wall. A recent study showed that men who had a small abdominal circumference at birth had raised serum concentrations of total and low density lipoprotein cholesterol.2 They also had raised plasma concentrations of fibrinogen, another major risk factor for coronary heart disease that is regulated by the liver.3 These associations were independent of social class, current body weight, cigarette smoking, and alcohol consumption. They suggest that impaired …

Objective: To determine whether men who grew slowly in utero or during infancy are more vulnerable to the later effects of poor living conditions on coronary heart disease. Design: Follow up study of men for whom there were data on body size at birth and growth and social class during childhood, educational level, and social class and income in adult life. Setting: Helsinki, Finland. Participants: 3676 men who were born during 1934-44, attended child welfare clinics in Helsinki, were still resident in Finland in 1971, and for whom data from the 1980 census were available. Main outcome measures: Hospital admission for or death from coronary heart disease. Results: Men who had low social class or low household income in adult life had increased rates of coronary heart disease. The hazard ratio among men with the lowest annual income ( Conclusion: Men who grow slowly in utero remain biologically different to other men. They are more vulnerable to the effects of low socioeconomic status and low income on coronary heart disease.

Unmarried men have higher rates of cardiovascular disease and a shorter lifespan than married men.1 The hypotheses that have been proposed to explain this are either that healthier men tend to marry or that the social support offered by marriage is protective. It is also possible that factors leading people to remain unmarried are linked with the susceptibility to cardiovascular disease. As small size at birth is associated with an increased risk of cardiovascular disease,2 we hypothesised that restriction of prenatal growth might be associated with marital status. We tested this in two long term prospective birth cohorts of men who belonged to generations in which marriage was a social norm. We studied 3577 men born at the Helsinki University Central Hospital, Finland, during 1924-33.3 We linked the birth data for …

EDITOR,—In their study of men in Uppsala, David A Leon and colleagues found that the highest blood pressures were in men who had been small babies but grew to be tall adults.1 They argue that these babies failed to achieve their growth potential in utero. We replicated their analysis in three studies of men born in England (in Hertfordshire (in 1920-30, n = 841), Preston (1935-43, n = 239), and Sheffield (1939-41, …

OBJECTIVE--To determine relation between schoolchildren's blood pressure, glycated haemoglobin level, and cholesterol concentration and their anthropometry, socioeconomic status, and birth measurements. DESIGN--Retrospective cohort study. SETTING--27 schools closest to University Hospital of the West Indies, Kingston, Jamaica. SUBJECTS--2337 children aged 6-16 years who were born at university hospital were recruited, and their birth records were recovered: 1610 had suitable records, 659 had records including birth length, and 610 of these were prepubertal. MAIN OUTCOME MEASURES--Blood pressure, glycated haemoglobin level, serum cholesterol concentration, anthropometry at birth, current anthropometry, and socioeconomic status. RESULTS--Multiple regression analysis showed that children's systolic blood pressure was inversely related to their birth weight (P < 0.0001) and directly related to their current weight. Glycated haemoglobin level was higher in children with thicker triceps skinfolds (P < 0.001) and who had been shorter at birth (P = 0.003). Serum cholesterol concentration was inversely related to current height (P = 0.001) and to length at birth (P = 0.09) and was directly related to triceps skinfold thickness and higher socioeconomic status (P < 0.001). CONCLUSIONS--Blood pressure in childhood was inversely related to birth weight and directly to current weight. Glycaemic control and serum cholesterol were related to short length at birth, height deficit in childhood, and childhood obesity.

One theory suggests that depression in adult life originates through parental indifference, abuse, and other adverse influences in childhood. The possible contribution of development in infancy has received little attention.1 We therefore examined the association between infant growth and later suicide in 15500 men and women. Depression underlies 70% of deaths by suicide.2 As previously described, all births in Hertfordshire from 1911 onwards were notified by the attending midwife.3 Health visitors saw the babies periodically throughout infancy, recorded the method of feeding, and wrote general comments on the baby's development and well being. At 1 year the babies were weighed. We traced 10141 (79%) of the boys born during 1911-30 and 5585 (60%) of the girls born during 1923-30. The average birthweight and weight at 1 year of those who were traced were the same as those of the babies who were not traced. We compared the numbers of deaths from suicide at ages 20-74 …

Analysis of routinely published abortion and fertility data for England and Wales between 1968 and 1980 shows that the age-specific abortion rates increased from 1968 until about 1973 when the rates peaked for all ages; rates then declined until 1977 but have subsequently returned to higher levels. Two factors are implicated: (1) the recent changes are related to parallel changes in the fertility rate; but (2) there is also a tendency for recent cohorts of women to resort to abortion more readily. These relationships are derived from analyses of fertility rates and abortion ratios, the proportion of conceptions that result in abortions. The results are discussed in terms of attitudes and practices related to birth control.

Analysis of trends in mortality from respiratory cancer among women shows that, contrary to previous interpretation, there is no suggestion of any increase over time which might be due to recent increases in exposures to carcinogens. Although there are upward trends in the number of deaths, the crude death rate, and the age standardised rate, these are shown to be related to the aging of earlier cohorts of women who have experienced high mortality rates. More recent cohorts, born since the middle 1920s, show a decline. A simple technique to identify trends in different cohorts is described, and it is shown to be linked to the age-period-cohort modelling approach to investigating time trends. Dangers inherent in ignoring either period or cohort effects when describing one of these factors are discussed.

During the second world war there were large changes in consumption of fats, fibre, and sugar in Britain. These changes matched recent recommendations made by the Committee on Medical Aspects of Food Policy (COMA) with the object of reducing the incidence of coronary heart disease (CHD). It is widely believed that CHD mortality fell during the war. This paper re-examines CHD mortality among middle-aged people in England and Wales from 1931 to 1967. After allowance for changes in the rules for coding cause of death, and for the sharp increase in all-causes mortality in 1940, there is little to suggest that time trends in CHD were much influenced by the war. Because of confounding variables, this does not argue against the COMA report. However, it gives no support to the view that compliance with the recommendations on fat, fibre, and sugar will lead, by itself, to an appreciable fall in CHD mortality in middle-aged people.

The high mortality from chronic bronchitis in England and Wales and the excess of urban over rural mortality are unexplained. On dividing England and Wales into 212 local authority areas a strong geographical relation was found between death rates from chronic bronchitis and emphysema in 1959-78 and infant mortality from bronchitis and pneumonia during 1921-5. It was concluded that this relation provided strong evidence of a direct casual link between acute lower respiratory infection in early childhood and chronic bronchitis in adult life. Regression analysis suggested that infection in early childhood had a greater influence than cigarette smoking in determining the geographical distribution of chronic bronchitis. National time trends reflected the influence of both factors. Chronic air pollution in adult life may be less important a cause of chronic bronchitis than previously supposed.

Geographical differences in maternal mortality in England and Wales during 1911-4 correlate closely with death rates from stroke in the generation born around that time. The geographical distribution of stroke is more closely related to past maternal mortality than to any leading cause of death, past or present, except ischaemic heart disease, for which correlation coefficients with stroke are similar. This relation is new evidence that poor health and physique of mothers are important determinants of the risk of stroke among their offspring.

In a search for clues to previously industrial carcinogens the occupational and smoking histories of young and middle aged men with different types of cancer were compared. The study population comprised men aged 18-54 and resident in the counties of Cleveland, Humberside, and Cheshire (including the Wirral). From hospital and cancer registration records 2942 members of the study population in whom cancers were diagnosed during the period 1975-80 were identified retrospectively. The occupational and smoking histories of these patients were sought by a postal questionnaire addressed either to the patients themselves or, if they had died, to their next of kin. The overall response rate to the questionnaire was 52.1%. Additionally, limited occupational information was obtained for 89% of cases from their hospital notes. Analysis of these data suggests that no serious bias arose as a consequence of the incomplete response to the questionnaire. This paper concentrates on the results for cancers of the respiratory tract and mesothelioma. Mesothelioma was found to cluster in laggers, electricians, and shipyard workers, and nasal carcinoma in woodworkers. Carcinomas of the larynx and of the bronchus were examined by formal statistical techniques, each being compared with a control group made up of all other cancers combined. Several interesting occupational and industrial associations were shown, in particular, an excess of bronchial carcinoma in the leather industry (RR = 2.6, CI 1.2-6.0), in building labourers (RR = 1.7, CI 1.0-2.9) and other construction workers (RR = 1.8, CI 1.0-3.0), in bakers and pastry cooks (RR = 3.6, CI 1.3-10.4). and in cooks (RR = 2.5, CI 1.2-5.1). In addition, a small cluster of lung tumours was observed in men who had worked as dental mechanics.

Cancer mortality rates in England and Wales were analysed so to describe simultaneously changes affecting successive generations--that is, associated with period of birth--as well as changes associated with the period of which the deaths took place. When mortality from all cancers was considered the analysis implied that, contrary to a widely held view, the rate of death from cancer had been declining in each sex in successive generations. For men the decline had occurred in generations born since 1900, whereas for women the peak came in the 1925 birth group. On the other hand, there had been little decline in the rates associated with period of death. Five examples of cancers of specific organs for which the trends contrasted are shown.

In a search for clues to previously unrecognised industrial carcinogens the occupational and smoking histories of young and middle aged men with different types of cancer have been compared. The study population comprised men aged 18-54 and resident in the counties of Cleveland, Humberside, and Cheshire (including the Wirral). Within this population 2942 patients in whom cancers were first diagnosed during the period 1975-80 were identified retrospectively from hospital and cancer registration records. Lifetime occupational and smoking histories were then sought from these subjects (or if they had died by proxy from their next of kin), using a postal questionnaire. The overall response rate was 52.1%. Analysis of limited occupational data obtained from the hospital notes of 89% of the patients suggests that no serious bias arose from the incomplete response to the questionnaire. The present paper describes the findings for non-respiratory cancers. Some tumours did not occur with sufficient frequency to warrant formal statistical analysis. Nevertheless, examination of the histories of patients with these cancers showed several interesting occupational clusters. In particular, five out of 29 patients with acute myeloid leukaemia had worked in electrical trades. The more common cancers were studied by statistical techniques. A large number of possible occupational associations were examined, and some will probably have achieved conventional levels of statistical significance by chance. The results should therefore be interpreted with caution, taking into account evidence from other studies and the biological plausibility of suggested hazards. Among the more interesting findings were an excess of bladder cancer in lorry drivers (RR=1.6, CI 1.0-2.4) and in men employed in the manufacture of vegetable and animal oils and fats (RR = 4.8, CI 1.8-12.9).

Etude de 188 malades atteints de lithiase urinaire certaine et autant de temoins normaux appropries. Dans 2/3 des cas les malades presentent une activite fibrinolytique urinaire inferieure a la normale