High-altitude hypoxia and preeclampsia

Abstract

The influence of hypoxia (lowered arterial blood and/or tissue PO2) on fetoplacental development and the role of hypoxia in preeclampsia are major research foci in perinatal biology. While animal and cell models are of utility, we do not know whether artificial hypoxic stimuli mimic the pathological conditions attributed to hypoxic stress in vivo; we cannot distinguish the effects of hypoxia from under- or overlying pathologies. High altitude (>2700 m) is the natural experiment we can use to distinguish pathology from adaptation in human pregnancy. The two best known impacts of high altitude on pregnancy outcome are reduced fetal growth and an increased incidence preeclampsia. This review focuses on the mechanisms by which altitude increases maternal risk for the development of preeclampsia. The review first considers the evidence that placental hypoxia is causally involved in the development of preeclampsia. It then focuses on how data from studies of pregnant women at high altitude support (or do not support) etiological models of preeclampsia. Considered are the theories that reduced uteroplacental blood flow, circulating factors of placental origin, placental oxidative stress and increased maternal vascular reactivity are etiological in preeclampsia. The data suggest that oxidative stress and endothelial dysfunction have pathophysiological origins that are independent of placental hypoxia. We conclude that altitude shifts the individual risk for the development of preeclampsia because of impacts on multiple physiological systems, no one of which can be specifically pointed to as causal.

Figure 1.

Individual susceptibility is a prominent contributor to the development of preeclampsia; obesity, variation in thresholds for inflammatory response, vascular sensitivity, insulin sensitivity or other characteristics can contribute to increased susceptibility. At the top of the model we show that impaired trophoblast invasion is a common feature of the disease, and while as yet the cause of impaired invasion is unknown there is good evidence to support disrupted oxygen sensing and immunological interactions as playing a role (these issues are reviewed elsewhere in this volume). At high altitude trophoblast invasion is impaired and uterine blood flow is reduced. This review considers how these two observations may translate into specific features of preeclampsia, such as placental oxidative stress, altered production of growth factors and increased vascular responsiveness

Figure 2.

Shown here are the results of microarray analysis of pooled placental samples from term explants cultured under 3% oxygen, preeclamptics, high altitude, age-matched controls for the preeclamptic patients and low altitude controls for the high altitude patients. This analysis is based on self-organizing maps. Of the 1700 genes represented on the microarray plate, areas of increased gene expression are shown in red and areas of decreased gene expression are shown in blue. The methodological details of the analysis, the results from a targeted analysis of the maximally different areas of these microarrays, the list of individual gene differences and the validation of differences in selected individual genes between altitude, explants, preeclampsia and controls are in reference . This figure is reprinted here to highlight the broad similarity in the pattern of gene expression between the in vitro and in vivo models of placental hypoxia (3% O₂, preeclampsia and high altitude) and their divergence from the controls (AMC at sea level and low altitude). Reprinted by permission from 31.

Figure 3.

Model for how chronic mild hypoxemia due to high-altitude residence, operating on multiple maternal physiological characteristics, may right-shift the population-wide risk of preeclampsia.