Hypoxia, fetal growth and early origins of disease: the Andean curse on the Conquistadors

The genetic potential for fetal growth is influenced by the available nutrient and oxygen supply to the unborn child. However, the contribution of each of these components, and in particular of fetal oxygenation, to the control of prenatal growth has been difficult to isolate. This is partly because all conditions associated with fetal hypoxia, either in health or disease, are also affected by reductions in fetal nutrition. For instance, maternal chronic experimental hypoxia in rats slows fetal growth but it also reduces maternal food intake (De Grauw et al. 1986). In humans, birth weight is reduced with increasing altitude (Moore et al. 2004) and in sea level pregnancies with placental insufficiency (Barker, 1998). Because most high altitude populations are impoverished, and placental insufficiency decreases nutrient and oxygen transfer to the baby, the extent to which the reduction in fetal growth under these conditions is governed by fetal under-nutrition or under-oxygenation, again, remains uncertain. A study by Zamudio et al. (2007) in this issue of The Journal of Physiology is an attempt to determine in humans the relative importance of genetic, developmental and environmental causes for high altitude-associated intrauterine growth restriction in a country uniquely placed to address the question.

Bolivia lies in the heart of South America and is conveniently split by the Andean Cordillera into two halves, residing at extremely different altitudes. La Paz is to the West of the country standing at approximately 4000 m above sea level. In marked contrast, as the country spans into the Amazon to the East, there are several sea level regions including Santa Cruz, the second largest Bolivian city. Bolivia is also made up of striking economically divergent populations with varied ethnicity. A large component of the inhabitants are of Andean origin with a high percentage of poverty. Inhabitants of European ancestry maintain a standard of living similar to that in affluent populations in the UK (Mapa de pobreza, 1995).

Previous studies have shown that pregnancy at high altitude restricts fetal growth but, rather counter-intuitively, babies born from low-income families in La Paz are born heavier than babies born from high-income highland families (Giussani et al. 2001). This is because low-income families in La Paz are mostly Aymara Indians, and prolonged high altitude residence ancestry develops a protection against the effects on fetal growth of prenatal hypoxia, the longest resident population experiencing the least decline, while the shortest historical residents, the greatest decline (Julian et al. 2007). Importantly, the level of protection is so strong that it overpowers the effect of possible undernutrition on fetal growth, even in highly impoverished Andean mothers. Since its introduction, the physiology underlying this Andean curse on the Conquistadors has gathered increasing attention.

The study of Zamudio et al. (2007) is an exceptional contribution to this knowledge, as it brings together teams of scientific and clinical experts to assess oxygen delivery at extreme altitude in La Paz and at sea level in Santa Cruz, in European and Andean pregnancies, with historical residence quantified using single nucleotide polymorphisms. The study tested the hypothesis that greater maternal uteroplacental oxygen delivery would explain increased fetal growth at altitude in Andeans versus Europeans. They conclude that genetically mediated differences in maternal oxygen delivery do not explain the Andean advantage. Rather, the mechanism underlying this protection is likely to reside within the feto-placental unit, perhaps due to differences in fetal substrate utilization.

Embedded in the wealth of data is another important point. Since slow fetal growth is associated with an increased risk of heart diseases in later life (Barker, 1998), it is of interest whether the prevalence of cardiovascular disease is increased at high altitude relative to sea level, and whether developmental hypoxia alone, independent of the maternal nutritional status, can programme an early origin of disease. However, the negligible number of studies in which basal arterial blood pressure was measured in adult residents rather than climbers at high altitude report conflicting data, inconsistencies that may be related to the altitude residence ancestry of the individuals under study (Giussani, 2006). Zamudio et al. (2007) show that systolic blood pressure is markedly elevated in term pregnant women at high altitude relative to sea level, however, the increment is greatly diminished in Andean women (Fig. 1). These results, albeit in pregnancy, not only support the concept that developmental hypoxia may trigger an increased susceptibility to hypertension in adulthood, but they highlight that the Andean curse on the Conquistadors spans from the physiology of the unborn child to disease in later life.

Figure 1. Arterial blood pressure in sea level and high altitude pregnancy.

Systolic blood pressure (mean +s.e.m.) in pregnant women at term of European ancestry at sea level (open columns, n= 44) or high altitude (filled columns, n= 37) and in pregnant women at term of Andean ancestry at sea level (n= 46) or high altitude (n= 33). *P < 0.05, sea level versus altitude.