Humans at high altitude: Hypoxia and fetal growth

Abstract

High-altitude studies offer insight into the evolutionary processes and physiological mechanisms affecting the early phases of the human lifespan. Chronic hypoxia slows fetal growth and reduces the pregnancy-associated rise in uterine artery (UA) blood flow. Multigenerational vs. shorter-term high-altitude residents are protected from the altitude-associated reductions in UA flow and fetal growth. Presently unknown is whether this fetal-growth protection is due to the greater delivery or metabolism of oxygen, glucose or other substrates or to other considerations such as mechanical factors protecting fragile fetal villi, the creation of a reserve protecting against ischemia/reperfusion injury, or improved placental O2 transfer as the result of narrowing the A-V O2 difference and raising uterine PvO2. Placental growth and development appear to be normal or modified at high altitude in ways likely to benefit diffusion. Much remains to be learned concerning the effects of chronic hypoxia on embryonic development. Further research is required for identifying the fetoplacental and maternal mechanisms responsible for transforming the maternal vasculature and regulating UA blood flow and fetal growth. Genomic as well as epigenetic studies are opening new avenues of investigation that can yield insights into the basic pathways and evolutionary processes involved.

Metabolic basis to Sherpa altitude adaptation

“…Hence selection might occur if the disadvantageous variant is associated with poorer survival to reproductive age and beyond, including greater fetal/neonatal mortality. Evidence supports precisely such effects, with fetal growth at altitude being poorer in Lowlander populations than in many native highlanders (47), including Tibetans (48) and Sherpas (49). Likewise, gene variants may affect survival through childhood or fecundity/fertility in the hypoxic environment.…”

Graduated effects of high-altitude hypoxia and highland ancestry on birth size

“…Multiple independent groups have also shown that (31). It is also known that high altitude impairs the pregnancy-associated increase in uterine blood flow, but this defect is significantly diminished in highland native pregnancies (18). Another interesting possibility is one of placental reprogramming, raised by Zamudio and Illsley, which supports the preferential anaerobic consumption of glucose by the placenta for protecting fetal oxygen delivery at altitude (32).…”

“…Populations established at high altitude are therefore unique, permitting the investigation of adaptive biological traits during pregnancy and early development to the common, selective pressure of exaggerated fetal hypoxia. Accordingly, many seminal studies have reported that pregnancy at high altitude not only leads to low birth weight (23)(24)(25)(26)(27), but that this effect is reduced in populations with a prolonged high-altitude native ancestry, as in Andeans and Tibetans (14)(15)(16)(17)(18). The selected advantageous traits of highaltitude native ancestry that reduce fetal growth restriction are so powerful that they overwhelm any additional detrimental effects of maternal malnutrition on fetal growth.…”

“…More than 140 million people live at altitudes >2,500 m where lowered oxygen availability has been shown to reduce fetal growth and birth weight, thus comprising the largest single human group at risk for fetal growth restriction. Of note, multigenerational highaltitude populations demonstrate protection against the effects of high-altitude hypoxia on fetal growth (14)(15)(16)(17)(18). Experimental studies in animal models support the likelihood that prenatal hypoxia can program cardiac, vascular, and metabolic dysfunction in the adult offspring (19)(20)(21), and that high-altitude ancestry protects against the effect of chronic hypoxic development on fetal growth (22).…”

Cardiovascular Adaptation to High-Altitude Hypoxia

“…The conventional definition of high-altitude hypoxia (HAH) is that arterial blood O 2 saturation (SaO 2 ) in body measurably begins to fall at altitudes >2500 m [1]. It is one of the hypoxemic types, which is due to a decrease in the amount of breathable oxygen caused by the low atmospheric pressure of high altitudes, and in turn low maximal oxygen uptake (VO 2 max), and the arterial partial pressure of O 2 (PaO 2 ) in the body [2].…”