A growing body of evidence suggests that increased cardiometabolic risk originates in the womb. Over the past few years increasing attention has been paid to the effects that nourishment in utero may have on the development of the fetus as well as on later growth, structure and metabolism of tissues and body systems. This resulted in the “fetal programming” concept as a critical parameter in explaining the early origins of cardiometabolic disorders.

Fetal programming and the risk of cardiometabolic disorders 3The “fetal programming” concept

The “fetal programming” concept was initially based on a large number of birth records, which were collected from 1911 to 1948 by a visionary midwife, Ethel Margaret Burnside.1 In the early 80s, David Barker and colleagues retrieved these records in Hertfordshire and conducted follow-up measurements in 64 years old men, linking the prevalence of cardiovascular disease (CVD) and type 2 diabetes (T2D) with their birth weight.2,3 It was shown that those men with lower birth weights had the highest death rates from ischaemic heart disease2 and a higher prevalence of T2D and glucose intolerance3 than did those of a normal birth weight (figure 1).

Fgure 1. Death rates from ischaemic heart disease and prevalence of T2D and glucose intolerance in 64 years old men per birth weight2,3

Convincing evidence that fetal under-nutrition could have a long-term influence on human health has also been provided by the Dutch Famine (1944-1945) birth cohort study,4 and was further confirmed in more cohorts worldwide the following years. All these epidemiological studies concluded that poor fetal growth results in low birth weight, increasing the risk of developing diseases in adulthood, such as CVD, glucose intolerance, T2D and hypertension.5

The “Thrifty phenotype” hypothesis

In an attempt to provide a conceptual and mechanistic framework to explain these findings, the “Thrifty phenotype” hypothesis was proposed.5,6 This hypothesis suggests that a suboptimal fetal environment may lead to low birth weight but also to physiological and/or metabolic adaptations in order to ensure adequate nutrient supply to the most vital organs, such as the brain to the detriment of others, such as the pancreas. Various factors that could lead to a suboptimal fetal environment have been identified, both from human and animal studies, as summarized in recent reviews7-9 (Table 1).

Table 1. Factors related to suboptimal fetal environment [reviewed in7-9

Indicative Factors Suggested outcomes
Maternal undernutrition
  • In humans, iron deficiency or maternal anemia in early gestation has been related to low birth weight
  • In animals, calorie, protein and iron restriction models resulted in offspring with reduction in body and organ weights, as well as metabolic disorders (e.g. obesity, impaired glucose tolerance, hypertension)
Maternal hypoxia-smoking
  • Pregnancies at high altitude have been found to induce fetal hypoxia resulting in reduced birth weight
  • Offspring of smoking mothers were found to have low birth weight and increased risk of T2D later in life
Fetal supply line dysfunction
  • Placental and uterine blood flow insufficiency has been shown to lead to inadequate supply of nutrients to satisfy fetal needs for development

These suboptimal fetal conditions seem to lead not only to low birth weight, but also to various physiological and/or metabolic adaptations of the fetus, such as (figure 2):

  • reduced pancreatic beta-cell mass
  • alterations in glucose metabolic pathways in muscle, liver and adipose tissue
  • disturbances in hypothalamic- pituitary- adrenal (HPA) axis resulting in increased appetite and reduced satiety
  • reduced number of nephrons

Figure 2. A schematic representation of the Thrifty Phenotype Hypothesis, illustrating the programming effects of a suboptimal in-utero environment on early growth and subsequent development of the metabolic syndrome (adapted from Hales and Barker7)

Although these physiological and metabolic adaptations seem to be crucial for the survival of the fetus, at the same time they lead to an increased predisposition for the development of cardiometabolic disorders, such as obesity, insulin resistance and hypertension later in life. This is even more pronounced when nutrition is more abundant in postnatal environment resulting in catch-up growth and increased central adiposity.7,10


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  3. Hales CN, Barker DJ, Clark PM, et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991; 303:1019-1022
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