Coronary Heart Disease Influences Acting in utero and in Early Childhood

Coronary artery disease - Influences acting in utero and in early childhood.


The search for the environmental causes of ischaemic heart disease is generally guided by a ‘destructive’ model, where the causes to be identified are thought to act in adult life and accelerate destructive processes such as the formation of atheroma, rise in blood pressure, and loss of glucose tolerance. By contrast, a ‘developmental’ model for the disease focuses on causes acting on the baby and argues that in responding to undernutrition and other adverse influences, the baby ensures its continued survival and growth at the cost of premature death from ischaemic heart disease and other chronic disorders.

Low birthweight is associated with increased rates of ischaemic heart disease and the related disorders—stroke, hypertension, and type 2 diabetes. These associations, which have been extensively replicated in studies in different countries, extend across the normal range of birthweight, and depend on lower birthweights in relation to the duration of gestation rather than the effects of premature birth. They are thought to be consequences of developmental plasticity—the phenomenon by which one genotype can give rise to a range of different physiological or morphological states in response to different environmental conditions during development.

Impaired growth in infancy and rapid childhood weight gain exacerbate the effects of impaired prenatal growth. The placenta is likely to play a key role in programming the baby.

Fetal origins

Over the past 20 years epidemiological studies have shown that people who had low birthweight, or who were thin or short at birth, are at increased risk of developing ischaemic heart disease and the related disorders stroke, hypertension, and type 2 diabetes. Associations between small size at birth and later disease, first recorded in the United Kingdom, have now been extensively replicated in studies in Europe and the United States of America. The associations extend across the whole range of birthweight and depend on lower birthweights in relation to the duration of gestation rather than the effects of premature birth. They are not the result of confounding variables acting in later life, such as low socioeconomic status and smoking.

These observations gave rise to the ‘fetal origins hypothesis’, which proposes that cardiovascular disease originates through adaptations that are made by a fetus when it is undernourished. Unlike adaptations made in adult life, those made during early development tend to have permanent effects on the body’s structure and function—a phenomenon sometimes referred to as ‘programming’.

Fetal nutrition

In common with other living creatures, human beings are ‘plastic’ in their early life, and their organs and systems are shaped by their environment at that time. The development of the sweat glands provides a simple example of this. All humans have similar numbers of sweat glands at birth, but none of them function. In the first 3 years after birth a proportion of the glands become functional, depending on the temperature to which the child is exposed. The hotter the conditions, the greater the number of sweat glands that are programmed to function. After 3 years the process is complete and the number of sweat glands is fixed. Thereafter the child who has experienced hot conditions will be better equipped to adapt to similar conditions in later life, because people with more functioning sweat glands cool down faster.

This brief description encapsulates the essence of developmental plasticity: a critical period when a system is plastic and sensitive to the environment, followed by loss of plasticity and a fixed functional capacity. For most organs and systems the critical period occurs in utero. There are good reasons why it may be advantageous in evolutionary terms for the body to remain plastic during development. It enables the production of phenotypes that are better matched to their environment than would be possible if the same phenotype was produced in all environments. Developmental plasticity is formally defined as the phenomenon whereby one genotype can give rise to a range of different physiological or morphological states in response to different environmental conditions during development.

The fetus responds to undernutrition in a number of ways. It can redistribute its cardiac output to protect key organs, the brain in particular; it can alter its metabolism, e.g. by switching from glucose to amino acid oxidation; and it can change the production of, or tissue sensitivity to, hormones regulating growth, importantly insulin. Slowing of growth is adaptive because it reduces the requirement for substrate. Experiments show that even minor modifications to the diets of pregnant animals may be followed by lifelong changes in the offspring in ways that can be related to human disease, for example raised blood pressure and altered glucose–insulin metabolism.

Effects of fetal and postnatal growth on adult diseases

Ischaemic heart disease

An important clue suggesting that ischaemic heart disease originates during fetal development came from studies of death rates among babies in the United Kingdom during the early 1900s. The usual certified cause of death in newborn babies at that time was low birthweight. Death rates in the newborn differed considerably between one part of the country and another, being highest in the northern industrial towns and the poorer rural areas in the north and west. This geographical pattern in death rates was shown to closely resemble today’s large variations in death rates from ischaemic heart disease, variations that form one aspect of the continuing inequalities in health in the United Kingdom. This led to the hypothesis that low rates of growth before birth are linked to the development of ischaemic heart disease in adult life.

The subsequent studies that confirmed this association were based on the simple strategy of examining men and women in middle and late life whose body size at birth was recorded. In the first study of this kind 16 000 men and women born in Hertfordshire (southern England) during 1911 to 1930 were traced from birth. Death rates from ischaemic heart disease fell twofold between those at the lower and upper ends of the birthweight distribution. Later studies showed that it was people who were small at birth because they failed to grow, rather than because they were born early, who were at increased risk of the disease. There is a graded nature of the association between birthweight and ischaemic heart disease which implies that normal variations in the food supply from normal healthy mothers to their babies have profound long-term effects.

The association between low birthweight and ischaemic heart disease has since been confirmed in studies in Finland, Sweden, the United Kingdom, and the United States of America. Among 80 000 women in the American Nurses Study there was a twofold fall in the relative risk of nonfatal ischaemic heart disease across the range of birthweight. An association between low birthweight and prevalent ischaemic heart disease has also been shown in a small study in South India.


The pattern of body proportions at birth which predicts stroke is different to that which predicts ischaemic heart disease. Studies in Sheffield (northern England) and Helsinki (Finland) found increased rates among people who had a low ratio of birthweight to head circumference. One interpretation of this is that normal head growth was sustained at the cost of interrupted growth of the body in late gestation. ‘Brain-sparing’ patterns of growth can result from diversion of cardiac output to the brain at the expense of the abdominal viscera, importantly the liver. Preliminary evidence suggests that this has lasting effects on liver function, including altered regulation of low density lipoprotein (LDL) cholesterol.

Type 2 diabetes

Studies of the mechanisms linking low birthweight with cardiovascular disease have shown that the progressive fall in disease rates across the range of birthweight is paralleled by progressive falls in type 2 diabetes, a major risk factor for the disease. The original observation made among men in Hertfordshire (Table 1) has now been extensively replicated in men and women. Both insulin resistance and deficiency in insulin production are thought to be important in the pathogenesis of type 2 diabetes, and there is evidence that both may originate during fetal life. There is now a substantial literature showing that low birthweight is associated with insulin resistance. Men and women who had low birthweight also have a high prevalence of the ‘metabolic syndrome’ in which impaired glucose tolerance, hypertension, and raised serum triglyceride concentrations occur in the same patient: they are insulin resistant and hyperinsulinaemic.

Table 1 Percentage of men in Hertfordshire with type 2 diabetes or impaired glucose tolerance (2-h plasma glucose concentration 7.8 mmol/litre or more) according to birthweight
Weight (pounds) % of men Odds ratio (95% CI)a
≤5.5 40 6.6 (1.5–28)
–6.5 34 4.8 (1.3–17)
–7.5 31 4.6 (1.4–16)
–8.5 22 2.6 (0.8–8.9)
–9.5 13 1.4 (0.3–5.6)
>9.5 14 1.0
p for trend <0.001  

a Adjusted for current BMI.

A number of studies have shown that people who had low birthweight are already insulin resistant in childhood. A study of men and women who were in utero during the wartime famine in the Netherlands provides direct evidence that maternal undernutrition can programme insulin resistance and type 2 diabetes in the offspring. The ‘Dutch famine’ began abruptly in November 1944 and ended with the liberation of the Netherlands in 1945. The official rations varied between 400 and 800 calories per day. Men and women exposed to the famine in utero had higher 2-h plasma glucose concentrations after a standard oral glucose challenge than those born before or conceived after it. They also had higher fasting plasma proinsulin and 2-h plasma insulin concentrations, indicating insulin resistance.

Cardiovascular disease and postnatal growth

Postnatal growth modifies the increased risk of ischaemic heart disease associated with small body size at birth. One important source of information on this is the Helsinki birth cohort comprising 13 000 people born in Helsinki during 1934–44. The height and weight of each infant was measured on an average of eight occasions between birth and 2 years of age, and on a further eight occasions between 2 and 11 years. This made it possible to examine, for the first time, the paths of childhood growth that precede the development of cardiovascular disease and type 2 diabetes in adult life. The mean body size of the boys and girls who later had ischaemic heart disease, stroke, or type 2 diabetes was below the average at birth. Between birth and 2 years of age their body size fell further in relation to that of other children, so that at 2 years they were thin or short. After that age those who developed ischaemic heart disease or type 2 diabetes put on weight rapidly, reaching the average weight and body mass index before 10 years of age. Those who developed type 2 diabetes gained weight most rapidly. Tables 2 and 3 show the combined effects of low birthweight, low body mass index (BMI) at 2 years, and high BMI at 11 years on the later risk of ischaemic heart disease in men and women.

Table 2 Hazard ratios (95% confidence intervals) for ischaemic heart disease according to birthweight and BMI at 2 years of age: boys and girls combined
Birthweight (kg) BMI at age 2 (kg/m2)
<16 16–17 >17
<3.0 1.9 (1.3–2.8) 1.9 (1.2–3.0) 1.3 (0.7–2.2)
3.0–3.5 1.5 (1.0–2.1) 1.6 (1.1–2.2) 1.2 (0.8–1.8)
>3.5 1.7 (1.2–2.5) 1.5 (1.1–2.2) 1.0


Table 3 Hazard ratios (95% confidence intervals) for ischaemic heart disease according to children’s BMI at 2 and 11 years of age.
BMI at age 2 (kg/m2) BMI at age 11 (kg/m2)
<16 16–17.5 >17.5
<16 1.6 (0.8–3.3) 2.4 (1.2–4.9) 3.0 (1.4–6.3)
16–17 1.4 (0.7–3.1) 1.6 (0.8–3.3) 1.9 (0.9–3.9)
>17 1.0 1.3 (0.6–2.7) 1.1 (0.5–2.3)

In contrast to the findings for ischaemic heart disease, children who later developed stroke grew slowly in height after 2 years and remained short and thin. This observation may be relevant to the wider ecology of cardiovascular disease. Ischaemic heart disease is a disorder of Westernization, one feature of which is improved childhood nutrition and more rapid gain in body mass index. Stroke is common in the developing countries and among poorer communities in the Western world, where failure to thrive before and after birth may not be followed by compensatory weight gain in later childhood.


A clinical study of people aged 60 years in the Helsinki birth cohort showed that two different paths of growth preceded the development of two different groups of patient with hypertension. One group was obese and insulin resistant, two features of the metabolic syndrome, and were already being treated for hypertension. They had small body size at birth and low weight gain from birth to 2 years, but grew rapidly after that. Table 4 shows the combined effects of birthweight and current adult weight on the prevalence of hypertension in this group. The prevalence ranges from 4% among people with birthweight above 4 kg but current weights in the lowest fifth, to 63% among those with birthweight of 3 kg or less but current weights in the highest fifth. A second group of patients had atherogenic lipid profiles and had not been previously diagnosed as having hypertension, but their blood pressures were classified as hypertensive under current definitions. They were short at birth, had low weight gain from birth to 2 years, and remained small after 2 years of age. The first of these two different paths of growth is the one associated with ischaemic heart disease, whilst the second is the one associated with stroke. They may lead to hypertension and cardiovascular disease through different biological mechanisms, and may therefore respond differently to medication.

Table 4 Percentage prevalence of hypertension according to birthweight and current weight among men and women in Helsinki
Birthweight (kg) Fifths of current weight (kg) All
Men –74.8 –81.5 –88.0 –96.5 >96.5  
Women –62.6 –68.7 –75.2 –83.9 >83.9  
–3.0 28 36 33 50 63 40(396)
–3.5 18 22 25 40 56 32(792)
–4.0 19 25 18 34 52 30(612)
>4.0 4 19 22 21 35 24(202)
All 20(401) 26(400) 24(401) 38(400) 52(400) 32(2002)

Figures in parentheses are numbers of subjects.

Associations between low birthweight and raised systolic and diastolic pressure in childhood and adult life have been extensively documented around the world, but the associations tend to be small. A 1 kg difference in birthweight is associated with around 3 mmHg difference in systolic pressure. The contrast between this small effect and the large effect on hypertension (Table 4 suggests that lesions that accompany poor fetal growth and tend to elevate blood pressure have a small influence on blood pressure within the normal range because counter-regulatory mechanisms can maintain normal blood pressure levels for many years.

Studies in humans and animals show that slow fetal growth is accompanied by a reduced number of nephrons at birth, which is a lifelong allocation as there is little capacity to develop new nephrons after birth. One hypothesis seeks to link this to the subsequent development of hypertension by arguing that a reduced nephron number results in hyperfiltration of each nephron. Hyperfiltration leads to glomerular hypertension and sclerosis and—ultimately—to nephron death, when counter-regulatory mechanisms are no longer able to maintain homeostasis and there begins a cycle of rising blood pressure, resulting in further nephron death, leading to a further rise in blood pressure. Rapid increase in body size after birth may exacerbate glomerular injury because greater body size leads to increased excretory loads and enhanced glomerular hyperfiltration. Indirect evidence in support of this has come from a study of the kidneys of people killed in road accidents: those being treated for hypertension had fewer, but larger, glomeruli.

The processes that link slow growth during infancy with later hypertension and stroke are not known. One possibility is that it is accompanied by impaired development of the cerebral vasculature at a critical period of early postnatal life. There is also evidence that it is accompanied by impaired development of the liver and altered set points for the regulation of cholesterol.

Other considerations

Role of the placenta

The placental weight of a baby at birth is associated with its risk of developing hypertension and ischaemic heart disease in later life. Associations with low placental weight have been found in some studies, while associations with high placental weight have been found in others. These two different associations may reflect different placental responses to undernutrition. Observations in animals show that in response to undernutrition in pregnancy the placenta may reduce its growth or, if the mother was well nourished at the time of conception, the placenta may enlarge. There is preliminary evidence of a similar phenomenon in humans. Placental enlargement may be an adaptive response to undernutrition that allows the fetus to extract more nutrients from the mother. It has costs, however, as the fetus has to share its nutrients with an enlarged placenta. These costs may include ischaemic heart disease and hypertension. The placenta is highly responsive to nutrition, oxygen, and its hormonal environment, its biology suggesting that it must play a central role in the genesis of cardiovascular disease, though one about which remarkably little is known.

Recent studies have explored the relation between the size and shape of the placental surface at birth, markers of its function, and chronic disease in later life. The surface is oval, with its length and breadth routinely recorded in some hospitals in the past. Growth of the placental surface seems to be polarized, with growth along the length being aligned with the rostro-caudal growth of the fetus, while growth along the breadth is more nutritionally sensitive. It is the size of the breadth that predicts later cardiovascular disease. The predictions are conditioned by the mother’s nutritional state, and differ in men and women. Boys invest less in placental growth than girls do.

Maternal nutrition

The nutrition of the fetus depends on the nutrition of the mother. In recent years ‘maternal nutrition’ has been equated with the diets of pregnant women. This is too limited a definition. The availability of nutrients to the fetus is influenced by the mother’s nutrient stores and metabolism, as well as by her diet during pregnancy. In developing countries many babies are undernourished because their mothers are chronically malnourished. Despite current levels of nutrition in Western countries, the nutrition of many fetuses and infants remains suboptimal because the nutrients available are unbalanced or because their delivery is constrained by maternal metabolism. Mellanby wrote in 1933 that “it is certain that the significance of correct nutrition in child-bearing does not begin in pregnancy itself or even in the adult female before pregnancy. It looms large as soon as a female child is born and indeed in its intrauterine life”. Maternal nutrition defined in this way encompasses the nutritional experience of the mother through fetal life and childhood, and into adolescence and adult life. The mother’s early nutritional experience establishes her metabolism and hormonal profile, and during pregnancy these shape the baby’s development. The ecology of cardiovascular disease—stroke in particular—may depend more on the mother’s early nutritional experience than on events during pregnancy.

The mother’s body composition before and during pregnancy is an important influence in programming the fetus. The children of overweight mothers are at increased risk of ischaemic heart disease and type 2 diabetes. The raised plasma glucose concentrations in overweight women, which necessarily lead to higher glucose intakes by the fetus, may be one adverse influence. There is now a strong body of evidence suggesting that mothers who are thin also afford an unfavourable environment to their fetuses, leading to insulin resistance and raised blood pressure in the offspring. In the Dutch famine, for example, it was people born to mothers with the lowest weights in pregnancy who had the highest 2-h plasma glucose concentrations. Maternal thinness may have different consequences for the fetus depending on whether it reflects low body muscularity, low body fat, or low weight gain in pregnancy. Mothers’ diet in pregnancy has been directly related to cardiovascular risk factors in the offspring during adult life in studies in Scotland. The blood pressures of men and women were related to the balance of animal protein and carbohydrate in their mothers’ diets in late pregnancy, while high intakes of fat and protein were associated with insulin deficiency. In fetal programming boys seem to be more responsive to their mothers’ current diets, while girls respond more to their mothers’ lifetime nutrition and metabolism.


We are beginning to understand the biological processes that may underlie these mechanisms. Changes occur at different levels and include allocation of stem cells and alteration of gene expression in the embryo; changes in heart, renal and liver growth; and alteration in metabolic and hormonal setpoints. These changes can make systems more vulnerable to disruptive influences in postnatal life, which include rapid weight gain, oxidative stresses (including smoking), environmental stress, and an inappropriate diet.

Studies of programming in fetal life and infancy are now established in the agenda for medical research. They have refocused attention on maternal nutrition and fetal growth. The search for the environmental causes of ischaemic heart disease has hitherto been guided by a ‘destructive’ model, where causes to be identified act in adult life and accelerate destructive processes: the formation of atheroma, rise in blood pressure, and loss of glucose tolerance. There is now a ‘developmental’ model for the disease, where the causes to be identified act on the baby, in responding to which the baby ensures its continued survival and growth at the expense of premature death from ischaemic heart disease.

The effects of low birthweight on later disease have been shown to be conditioned by the presence of genetic polymorphisms. Interactions between the effects of genes and nutrition during development would be expected as a manifestation of phenotypic plasticity. The effects of birthweight on later disease are also modified by the postnatal environment, by living conditions during childhood, by adult lifestyles and by the path of postnatal growth. It seems that the pathogenesis of cardiovascular disease and type 2 diabetes cannot be understood within a model in which risks associated with adverse influences at different stages of life add to each other. Rather, disease is the product of branching paths of development, with the environment triggering the branching. The path of development that follows each branch determines the individual’s vulnerability to the next adverse influence that lies ahead.

Further reading

Barker DJP (1998). Mothers, babies and health in later life, 2nd edition. Churchill Livingstone, Edinburgh.
Barker DJP (ed.) (2000). Fetal origins of cardiovascular and lung diseases. NIH Monograph Series, Marcel Decker, New York.
Barker DJP et al. (2009). Growth and chronic disease: findings in the Helsinki Birth Cohort. Ann Hum Biol, 36, 445–58.
Burton GJ, Barker DJP, Moffett A, Thornburg K (eds) (2011). The placenta and human developmental programming. Cambridge University Press, Cambridge.
Gluckman P, Hanson M (eds) (2006). Developmental origins of health and disease. Cambridge University Press, Cambridge.
Harding JE (2001). The nutritional basis of the fetal origins of adult disease. Int J Epidemiol, 30, 15–23.
McCance RA. (1962). Food, growth and time. Lancet, ii, 621–6.
Mellanby E. (1933). Nutrition and child-bearing. Lancet, ii, 1131–7.
Phillips DIW (1996). Insulin resistance as a programmed response to fetal undernutrition. Diabetologia, 39, 1119–22.
Stearns S (ed.) (1998). Evolution in health and disease. Oxford University Press, Oxford