Fetal malnutrition and long-term outcomes

Abstract

Epidemiological studies have shown that lower birthweight is associated with a wide range of adverse outcomes in later life, including poorer 'human capital' (shorter stature, lower cognitive performance), increased risk factors for later disease (higher blood pressure and reduced glucose tolerance, and lung, kidney and immune function), clinical disease (diabetes, coronary heart disease, chronic lung and kidney disease), and increased all-cause and cardiovascular mortality. Higher birthweight is associated with an increased risk of cancer and (if caused by gestational diabetes) obesity and diabetes. The 'developmental origins of health and disease' hypothesis proposes that fetal nutrition has permanent effects on growth, structure and metabolism ('programming'). This is supported by studies in animals showing that maternal under- and overnutrition during pregnancy can produce similar abnormalities in the adult offspring. Common chronic diseases could potentially be prevented by achieving optimal fetal nutrition, and this could have additional benefits for survival and human capital. Recent follow-up of children born after randomized nutritional interventions in pregnancy provides weak evidence of beneficial effects on growth, vascular function, lipid concentrations, glucose tolerance and insulin resistance. Animal studies indicate that epigenetic phenomena may be an important mechanism underlying programming, and that nutritional interventions may need to start preconceptionally.

Figure 1. The fetal programming hypothesis; adult chronic disease resulting from the effects of fetal under-nutrition on the development of different tissues

Fetal under-nutrition can occur because of an inadequate maternal diet, inability of the mother to mobilise and transport sufficient nutrients, or an impaired vascular and placental supply line to the fetus. It can also occur if there is high fetal demand, for example because of faster growth. Changes in fetal structure and physiology could occur because of a simple lack of the nutrients or building blocks required to construct high-quality organs and tissues, or because of adaptations to reduce nutrient demand eg by slowing fetal growth or prioritising essential organs. Endocrine systems (especially for hormones that regulate fetal growth and maturation) are re-set, and tissues are supported or sacrificed differentially. It is hypothesised that the resulting metabolic changes persist and increase the risk of developing diabetes and cardiovascular disease, especially if additional stressors are acquired in later life (such as obesity and physical inactivity).

Figure 2. Lower birthweight followed by the development of above average weight or BMI in childhood or adulthood is associated with increased insulin resistance and impaired glucose tolerance (data from 3 Indian birth cohorts)

Figure 3. Inter-generational effects of fetal nutrition on diabetes risk.

Intergenerational under-nutrition results in low birthweight, and a number of adverse later outcomes, including impaired human capital (left-hand circle). Rapid childhood or adult weight gain on a background of low birthweight is associated with an increased risk of cardio-metabolic disease (left to right arrow), and (in women) with gestational diabetes, which exposes her fetus to excess fuel mediated teratogenesis, another route to increased diabetes risk (right-hand circle).