HYPOXIA AND REPRODUCTIVE HEALTH: Reproductive challenges at high altitude: fertility, pregnancy and neonatal well-being.

High altitude offers a natural laboratory for studying the effects of chronic hypoxia on reproductive health. Counter to early accounts, fertility (the number of livebirths) appears little affected although stillbirths are more common. Birth weights are lower due to fetal growth restriction, not shortened gestation. Multigenerational (Andean or Tibetan) compared with newcomer residents appear relatively protected from pregnancy loss as well as altitude-associated fetal growth restriction, perhaps due in part to preservation of the normal rise in uterine artery blood flow. Myometrial artery vasodilator response, a key determinant of uterine blood flow, is blunted in healthy Colorado high-altitude residents, similar to what occurs in intrauterine growth restriction or preeclampsia at low altitude. The high-altitude vessels are also more sensitive to the vasodilatory actions of AMP kinase (AMPK) activation. The gene region containing PRKAA1 (coding for AMPK's alpha-1 catalytic subunit) has been acted upon by natural selection in Andeans and is related to preservation of normal blood flow and fetal growth at high altitude, suggesting one mechanism by which high-altitude adaptation may have been achieved. Preeclampsia is more common at high altitudes but unknown is whether multigenerational residents are protected relative to newcomers. Postnatal loss is diminished in Tibetans vs Han with equal access to health care, perhaps due in part to better maintained arterial O2 saturation during infancy. Finally, pregnancy and intrauterine development not only affect immediate survival but also susceptibility to the later-in-life cardiovascular disease, chronic mountain sickness.