Placental Adaptation to Hypoxia: The Case of High-Altitude Pregnancies

Even in the highest inhabited regions of the world, well above 2500 m altitude, women become pregnant and give birth to healthy children. The underlying adaptation to hypobaric hypoxia provides interesting insights into the physio(patho)logy of the human placenta. Although increasing altitude is regularly associated with fetal growth restriction (FGR), oxygen deficiency does not appear to be a direct cause. Rather, placental oxygen consumption is reduced to maintain the oxygen supply to the fetus. This comes at the expense of placental synthesis and transport functions, resulting in inappropriate nutrient supply. The hypoxia-inducible factor (HIF-1α), which modulates the mitochondrial electron transport chain to protect placental tissue from reactive oxygen species, plays a key role here. Reduced oxygen consumption also reflects decreased placental vascularization and perfusion, which is accompanied by an increased risk of maternal pre-eclampsia at high altitude. In native highlanders, the latter seems to be attenuated, partly due to a lower release of HIF-1α. In addition, metabolic peculiarities have been described in indigenous people that enhance glucose availability and thus reduce the extent of FGR. This review attempts to revisit the (albeit incomplete) knowledge in this area to draw the clinical reader's attention to the crucial role of the placenta in defending the fetus against hypoxia.