Fetal growth and congenital heart disease at high altitude.

High-altitude pregnancy lowers birth weight, and highland ancestry protects against this. Mechanisms mediating both effects are of interest, and alterations in uterine blood flow and placental metabolism have been implicated. However, this review highlights studies combining the chicken embryo model with high-altitude incubation, which reveal direct depressive effects of altitude on fetal growth and direct protective effects of highland ancestry, despite the absence of a mammalian uterine artery or placenta. Since low birth weight has been linked with high cardiovascular risk in offspring, there is also interest in the mechanisms underlying this relationship. Further work in the chicken embryo has shown that hypoxic incubation triggers congenital heart disease and programmes cardiovascular disease in the adult bird, and that highland ancestry confers protection against these effects. Therefore, these studies in the chicken embryo are important because they unveil that altitude and highland ancestry must affect prenatal growth and developmental origins of heart disease by mechanisms acting on the fetus, in addition to maternal or placental effects. The nature of these direct effects is likely epigenetic; however, they remain little studied and unidentified. Such research is paramount as it has the potential to lead to discoveries of novel fundamental biological pathways with therapeutic application of human relevance.This article is part of the discussion meeting issue 'Pregnancy at high altitude: the challenge of hypoxia'.