Fetal growth, high altitude, and evolutionary adaptation: a new perspective.

Residence at high altitude is consistently associated with low birthweight among placental mammals. This reduction in birthweight influences long-term health trajectories for both the offspring and mother. However, the physiological processes that contribute to fetal growth restriction at altitude are still poorly understood, and thus our ability to safely intervene remains limited. One approach to identify the factors that mitigate altitude-dependent fetal growth restriction is to study populations that are protected from fetal growth restriction through evolutionary adaptations (e.g., high altitude-adapted populations). Here, we examine human gestational physiology at high altitude from a novel evolutionary perspective that focuses on patterns of physiological plasticity, allowing us to identify 1) the contribution of specific physiological systems to fetal growth restriction and 2) the mechanisms that confer protection in highland-adapted populations. Using this perspective, our review highlights two general findings: first, that the beneficial value of plasticity in maternal physiology is often dependent on factors more proximate to the fetus; and second, that our ability to understand the contributions of these proximate factors is currently limited by thin data from altitude-adapted populations. Expanding the comparative scope of studies on gestational physiology at high altitude and integrating studies of both maternal and fetal physiology are needed to clarify the mechanisms by which physiological responses to altitude contribute to fetal growth outcomes. The relevance of these questions to clinical, agricultural, and basic research combined with the breadth of the unknown highlight gestational physiology at high altitude as an exciting niche for continued work.