Table 1

Early fetal origin hypotheses developing studies

Author and title of study	Year of publication	Study population	Main observations and interpretations
Forsdahl. Are poor living conditions in childhood and adolescence an important risk factor for arteriosclerotic heart disease? ²	1977	20 northern counties in Norway; men and women aged 40–69 who lived their infancy, childhood and youth in 1896 to 1925.	In the counties where infant mortality (INFmo) was high, the same generation had both a high total mortality and ischaemic heart disease (IHD) mortality in middle age. Variations in IHD mortality rate between counties is linked to variations in poverty in childhood and adolescence because INFmo is a reliable index of standard of living. Forsdahl suggested that poverty followed by prosperity is a risk factor for IHD.
Barker et al. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales.³	1986	England and Wales; county boroughs (CBs, larger towns), London boroughs (LBs), urban areas (metropolitan boroughs and urban districts), rural areas within counties. IHD rates in 1968-78 (35–74 years); INFmo in 1921-25.	On division of the country into 212 local authority areas a strong geographical relation was found between IHD mortality rates at ages 35–74 years and INFmo in 1921-25. IHD mortality rates are highest in the least affluent areas. It was suggested that poor nutrition in early life increases susceptibility to the effects of an affluent diet in later life, and that predisposition to IHD is related to nutrition during prenatal period and early childhood.
Barker et al. Weight in infancy and death from ischaemic heart disease.⁴	1989	Six districts of Hertfordshire, England; 5654 men born in 1911-30.	One of the first articles about hypothesis of an effect of early life factors on IHD. Men with the lowest weights at birth and at 1 year had the highest death rates from IHD. The standardised mortality ratio (SMR) fell from 104 in men whose birth weight was 2.5 kg or less to 62 in those who weighed between 4.0–4.3 kg, but rose slightly in the highest birth weight category. The paper showed the relation for the first time. Though inaccuracies, eg, in birth weight measurements, exist this gives evidence of the importance of fetal life on subsequent diseases. The interpretation was that greater early growth will reduce deaths from IHD. Later in 1990s it was shown that those who where thin at birth but caught up during infancy were particularly prone to IHD risk.
Barker et al. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease.13	1989	England, Wales, and Scotland. (1) In 1970 one week sample, n=9921 in the analyses. (2) In 1946 one week stratified sample (MRC national survey), n=3259.	In children at 10 years and adults at 36 years systolic blood pressure was inversely related to birth weight (independent of gestational age). Within England and Wales 10 year olds living in areas with high cardiovascular disease (CVD) mortality were shorter and had higher resting pulse rates than those living in other areas. Their mothers were also shorter with higher diastolic blood pressure. This suggested there are persisting geographical differences in the childhood environment that predispose to differences in CVD mortality.
Barkeret al. Fetal and placental size and risk of hypertension in adult life.12	1990	Preston, Lancashire, UK n(men and women)=449	In both sexes systolic and diastolic blood pressure were strongly related to placental weight and birth weight. The highest blood pressures occurred in the people who had been small babies with large placentas. Discordance between placental and fetal size may lead to circulatory adaptation in the fetus, altered arterial structure in the child, and hypertension in the adult. It was discussed that women's nutrition in childhood may be linked to blood pressure in the next generation.
Hales et al. Fetal and infant growth and impaired glucose tolerance at age 64.14	1991	468 men born in 1920-30, (in Hertfordshire, England) aged 64 had a standard 75 g oral glucose tolerance test.	Men who were found to have impaired glucose tolerance or diabetes had had a lower mean birth weight and a lower weight at 1 year. Reduced early growth was also related to a raised plasma concentration of 32-33 split proinsulin. These trends were independent of current body mass. The results may be a consequence of fetal undernutrition and programming of the endocrine pancreas. The researchers favoured environmental explanation for their findings instead of genetic determination, on the one hand because disturbance of insulin production was manifested by growth failure in early life long before the onset of adult glucose intolerance, and on the other hand because maternal nutrition was thought to have a strong influence on fetal and infant growth.
Barkeret al. The relation of small head circumference and thinness at birth to death for cardiovascular disease in adult life.⁸	1993	Sheffield, England n(men)= 1586	SMR 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. SMR also fell with increasing head circumference and increasing ponderal index. They were not related to the duration of gestation. The findings showed that reduced fetal growth is followed by increased mortality from CVD. Based on this further evidence for the first time it was proposed that CVD originates through programming of the body's structure by the environment during fetal life.