Abnormal liver growth in utero and death from coronary heart diseaseBMJ 1995; 310 doi: https://doi.org/10.1136/bmj.310.6981.703 (Published 18 March 1995) Cite this as: BMJ 1995;310:703
- D J P Barker, directora,
- C N Martyn, clinical scientista,
- C Osmond, statisticiana,
- G A Wield, systems analysta
- a MRC Environmental Epidemiology Unit (University of Southampton), Southampton General Hospital, Southampton SO16 6YD
- Correspondence to: Professor Barker.
- Accepted 21 February 1995
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 liver growth in utero may be an early stage in the pathogenesis of coronary heart disease.
Methods and results
A standardised record form was kept for each woman admitted to the Jessop Maternity Hospital in Sheffield. From 1922 onwards, abdominal circum-ference was included among the measurements made on the baby at birth. We have traced 1973 (79%) of 2513 singleton boys born alive during 1922-30. The method of follow up has been described.2 3 The abdominal circumference of 1819 of the 1973 boys had been recorded. A total of 174 of them had died from coronary heart disease (International Classification of Diseases (9th revision) codes 4100-4149).
The men's mean birth weight was 7.5 pounds (3400 g) and their mean abdominal circumference was 12.3 inches (31.2 cm). The table shows their death rates from coronary heart disease, expressed as standardised mortality ratios with the average for England and Wales as 100. Men with below average birth weight had higher death rates, as would be expected from previous findings.1 Mortality ratios showed a U shaped relation with abdominal circumference. Further examination showed that this was the result of opposing trends at birth weights below and above the average. Below the mean birth weight standardised mortality ratios fell with increasing abdominal circumference whereas above it they rose. The difference in these two trends was significant (x2=8.2, P=0.004 interaction term in log-linear model). P values for the individual trends were 0.11 and 0.02, respectively. The trends with chest circumference were similar, but weaker (x2 for difference=3.3, P=0.07). There were no significant trends with head circumference or crown-heel length. Opposing trends in mortality from all causes with abdominal circumference corresponded to those in coronary heart disease mortality but were not significant.
Gestation period was known in 1278 (70%) of the men, estimated from the mother's last menstrual period. We examined coronary heart disease death rates in the 1183 who were born at term. The opposing trends in standardised mortality ratios with abdominal circumference were similar to those of all men (table).
We have found that among men whose birth weights were below average those who had a small abdominal circumference at birth had raised death rates from coronary heart disease. This is consistent with the association between small abdominal circumference at birth and raised serum cholesterol and plasma fibrinogen concentrations, found in a separate sample of men.2 3 In late gestation the fetus responds to undernutrition by sustaining growth of the brain at the expense of growth of the trunk.4 This adaptation compromises the liver and seems permanently to alter low density lipoprotein cholesterol and fibrinogen metabolism.
Among men with above average birth weight those who had a large abdominal circumference at birth had raised death rates from coronary heart disease. The babies of women who develop impaired glucose tolerance in pregnancy become macrosomic. During their accelerated growth in late gestation the fetus's abdomen enlarges rapidly.5 The processes underlying this are not known, though deposition of glycogen in the liver has been suggested.
Our findings suggest that both reduced and accelerated liver growth in late gestation are early determinants of coronary heart disease.