Birth Weight and Adult Disease

Further evidence for the role that the early life environmental influences play in establishing the risk for disease came in the early 1990s when studies conducted by Barker and colleagues in a large cohort of men and women from Hertfordshire, UK revealed strong correlations between low birth weight and a high prevalence of metabolic diseases in later life (Table 1). Although not universally accepted, numerous epidemiological studies completed throughout the world, including other parts of the UK, Europe, US, and India, have found reproducible results in extensive population and ethnic groups and various age ranges.

The Hertfordshire study was a retrospective study that collected the birth records of 15 726 men and women born in Hertfordshire between 1911 and 1930. This study was the first to demonstrate that the incidence of death from coronary heart disease was highest in adults born with a low birth weight. Barker and colleagues replicated this finding in a cohort of 1586 men born in Sheffield, UK between 1907 and 1925. The link between low birth weight and coronary heart disease in adult life again received confirmation from studies involving over 70 000 nurses from the US born between 1921 and 1945. A study in South India demonstrated that in a cohort of 517 men and women born between 1934 and 1954, the prevalence of coronary heart disease rose to 11% when the recorded birth weight was less than 2.5 kg. In those people who had a birth weight of more than 3.1 kg the prevalence of coronary heart disease was only 3%. A Swedish study of over 14 000 men and women born in Uppsala, Sweden between 1915 and 1929 was able to clearly identify that the risk of death from cardiovascular disease was associated with being small for gestational age.

In the Hertfordshire study, Hales and Barker demonstrated a strong inverse relationship between birth weight and type 2 diabetes or impaired glucose tolerance in men aged 64 years. Similar findings have been reported in populations of men and

Table 1 Adult health characteristics associated with low birth weight

• Coronary heart disease

Hypertension

• Hypertriglyceridemia

• Impaired glucose tolerance

Insulin resistance women in other parts of Europe, Australia, and the US. Further support of the association between low birth weight and the development of metabolic disease comes from studies of monozygotic twins. Two studies have demonstrated that impaired glucose tolerance and type 2 diabetes is more prevalent in the twin with the lower birth weight.

Although initial studies focused on the relationship between cardiovascular disease and type 2 diabetes subsequent studies have reported associations with other conditions. From an early age, children born with a low birth weight demonstrate reduced endothelium-dependent dilation and increased arterial stiffness. It has been observed that this endothelial dysfunction persists into adult life. The mechanisms behind the association between low birth weight and impaired vascular function remain to be elucidated. Despite this, it has been suggested that endothelial dysfunction is an early feature and precedes the metabolic disorders that develop in low-birth-weight humans.

Whilst the association between low birth weight and high predisposition to disease has been reported quite substantially, it is important to note that a U-shape relationship does occur when investigating the association between birth weight and the development of metabolic diseases. Babies born large for gestational age are also at an elevated risk of developing diseases such as coronary heart disease and type 2 diabetes.

The etiology of breast cancer has now also been linked to prenatal influences. Investigations in Sweden, Norway, and the US have provided epide-miological data indicating that high birth weight potentially increases the risk of developing breast cancer. The specific biological mechanisms underlying this association still remain unclear. However, it has been suggested that prenatal exposure to the high level of estrogen that occurs during pregnancy may play a significant role. Other maternal hormones and growth factors may also be involved. A U-shape relationship also exists when investigating prenatal influences upon the development of breast cancer. Studies have reported birth weights below 2.5 kg and above 4 kg are significant risk factors for the development of breast cancer in women.

Underlying Mechanisms The Fetal Insulin Hypothesis

Hattersley and colleagues have suggested that the relationship between birth weight and type 2

diabetes could be mediated by mutations/polymorphisms in genes that influence insulin secretion or insulin sensitivity. Insulin is an important fetal growth factor, thus any defects in its secretion or action would result in both low birth weight and increased risk of diabetes. This is supported by studies of individuals with maturity onset diabetes of the young 2. These individuals who have mutations in the glucokinase gene have a lower birth weight compared to their unaffected siblings. The fetal insulin hypothesis therefore holds true in this rare mono-genic form of diabetes.

pancreas. This has no detrimental effect if the fetus is born into conditions of poor nutrition. Hence in sub-Saharan Africa where there is chronic malnutrition, rates of diabetes are very low. Detrimental consequences of fetal programing arise when the fetus is born into conditions that differ from those experienced in utero. The imbalance between the early and adult environments may then conflict with the programing that occurred during fetal life and predispose the offspring to the subsequent development of metabolic diseases in adulthood (Figure 1).

The Thrifty Phenotype Hypothesis

An alternative hypothesis, termed the thrifty pheno-type hypothesis, was proposed by Hales and Barker in 1992. This proposal focused on the role played by the fetal environment. It suggested that the mechanistic basis underlying the observed relationship between poor fetal growth and the future development of metabolic diseases was related to fetal nutrition.

Central to the thrifty phenotype hypothesis is the suggestion that during times of nutritional deprivation, the growing fetus undergoes metabolic adaptations that are beneficial to survival postnatally in similar conditions of poor nutrition. Such adaptations include the essential preservation of brain growth at the expense of the normal development of organs such as the liver, muscle, and the

Abnormal maternal metabolic milieu

Adverse maternal nutrition

Abnormal maternal metabolic milieu

Adverse maternal nutrition

Placental insufficiency

Poor fetal growth and abnormal metabolic programing

Placental insufficiency

Poor fetal growth and abnormal metabolic programing

Similar in utero and postnatal environments

Low risk of developing metabolic diseases

Conflicting in utero and postnatal environments

High risk of developing metabolic diseases

Figure 1 The interactions between in utero insults and the subsequent development of metabolic diseases.

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