Doctoral Dissertation Improvement: Physiological Adaptation to Pregnancy at High Altitude: A Comparative Study

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The decreased weight of the atmosphere (barometric pressure) at high altitudes (2500m or 8000 ft) reduces oxygen availability. Such reduced oxygen availability or hypoxia causes babies to grow more slowly while in the womb and weigh less at birth. Because babies who are born small have an increased risk of dying during infancy as well as later in life, such effects of high altitude are generally considered maladaptive. Babies with multiple generations of high-altitude ancestry are protected relative to newcomer groups from such harmful effects, suggesting that such long-term groups are better adapted. Since pregnancy outcome influences the reproductive fitness of three individuals (mother, father and baby), pregnancy is a logical, and likely sensitive, portion of the lifecycle during which to examine selective processes. Unknown is what permits such long-term groups to be less affected than newcomers from hypoxia-associated intrauterine growth restriction (IUGR). Moreover, even though we know that genes influence fetal growth and maternal susceptibility to pregnancy complications such as preeclampsia, the particular genes involved or the physiological processes through which they exert their effects are not well understood.In this research, we hypothesize that multigenerational high-altitude residents have undergone natural selection for genetic variants that serve to enhance maternal antioxidant capacity or reduce oxidative stress. Supporting this hypothesis are previous studies showing that 1) oxidative stress contributes to impaired maternal vascular function of preeclampsia and IUGR at low altitude; 2) residence at high altitude decreases maternal uterine artery blood flow and oxygen delivery to the baby; and 3) the activity of several antioxidative enzymes is greater in populations of highland than lowland ancestry. Unknown, however, is whether increased oxidative stress during pregnancy at high altitude contributes to the higher rates of preeclampsia and IUGR observed, or whether women of highland compared with lowland ancestry are better able to defend themselves against oxidative stress by producing fewer oxidative stressors or more antioxidants. Design: We will compare physiological measures of oxidative stress, antioxidant status, and maternal vascular adaptation to pregnancy, and fetal growth across pregnancy/fetal life persons of Andean or European ancestry who live at low (300m) or high (3600m) altitude in Bolivia. Bolivia houses the largest highland population in the Western Hemisphere. This design enables the identification of temporal relationships between maternal phenotypic responses to high-altitude pregnancy and fetal growth, and will be informative of potential adaptive pathways. Broader impacts: Maternal mortality rates in Bolivia are twice that of Latin America and its infant mortality is the highest in the Western Hemisphere. Better understanding of the genetic, physiological, socioeconomic and cultural determinants of maternal/infant health will enable better-targeted interventions. Bolivian physicians and staff will help conduct of this study, providing an opportunity to develop research skills in a country where such opportunities are limited. Study outcomes will be disseminated via conference presentations, journal articles, public talks, and university curricula in anthropology, physiology and public health.