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

Abstract

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 IUGR or preeclampsia at low altitude. The high-altitude vessels are also more sensitive to the vasodilatory actions of adenosine monophosphate 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.

Time Domains of Hypoxia Responses and -Omics Insights

“…One such strategy has focused on determinants of birth weight since a) birth weight is the most important determinant of neonatal or infant mortality, b) mortality risk during pregnancy and through the first year of life is greater than at any other time prior to the end of the reproductive period (i.e., the period during which natural selection is acting), and c) the profound effect of high altitude to reduce birth weight ( Jensen and Moore, 1997 ). Tibetan and Andean ancestry confer protection against hypoxia-associated reductions in birth weight compared to newcomer groups residing at the same altitude, reviewed in Moore (2021) . In Andeans, this effect appears to stem, in part, from greater uteroplacental blood flow and O 2 delivery during pregnancy at high altitude in women of Andean versus European ancestry ( Julian et al, 2009 ).…”

High Altitude Pregnancies and Vascular Dysfunction: Observations From Latin American Studies

“…In fact, at altitudes higher than 2,500 m above sea level, most mammals (including humans) undergo decreased O 2 saturation and hypoxemia (Moore, 2001 ; Herrera et al, 2015 ). This chronic hypoxemia during pregnancy drives several maternal, placental, fetal, and postnatal consequences that affect oncoming health (Yzydorczyk et al, 2017 ; Ducsay et al, 2018 ; Moore, 2021 ).…”

Genomic Diversity Profiling and Breed-Specific Evolutionary Signatures of Selection in Arunachali Yak

“…Most of these adaptations are genetically fixed in highlanders, thus conferring them protection against adverse climatic conditions [ 9 ]. Genomic studies have shown that the most common genes responsible for adaptation in highlander species include those involved in hypoxia-inducible factor (HIF) pathway like EPAS1 , EGLN1 , EGLN2 , VEGF , EPO , NOS and EDN [ 10 , 11 ]. Further, different populations of the same species may possess varying adaptations in their genomes in response to difference in altitude and vegetation [ 12 , 13 ].…”