Fetal stress and growth restriction at high altitude

In the USA and throughout the world, fetal growth restriction (FGR), defined as 10^th percentile or less of estimated fetal weight, is a complication of 7 to 10% of pregnancies. Its relation to chronic hypoxia is complex and poorly understood. Development of the normal embryo has been shown to occur in a state of relative hypoxia. Nonetheless, beyond a certain degree of physiological adjustment, hypoxia is associated with a number of factors inimical to cell growth and function. In response to prolonged or long-term hypoxemia (LTH), a number of compensatory changes transpire in many organ systems and tissues to maintain homeostasis. These result in what has been called intrauterine growth restriction, small for gestational age, and/or growth restricted fetuses/newborn infants. Because of the relatively large fraction of pregnancies that occur in women who live at high altitude, this now is recognized as a not uncommon cause of FGR. Appreciation of the physiologic responses to high altitude acclimatization is of great interest and illustrates the evolution of ideas concerning such a physiologic stress. To explore the mechanisms of high altitude LTH in producing the FGR phenotype, many studies have been performed in the fetal sheep, and in these, a host of specific responses have been recorded in essentially every tissue and organ system that have been studied. In terms of a case study for a specific tissue, cerebral arteries of the LTH fetus demonstrate a number of significant changes that may be adaptive or maladaptive in preserving cerebral blood flow and oxygenation. In various organs a multitude of other endocrinologic, metabolic, and neurobiologic changes occur, as well as fundamental changes in structure of the placenta. In concert with these high altitude, hypoxic-induced changes, fetal hemoglobin concentration and blood volume increase to maintain tissue O₂ delivery. In contrast to the sheep, the llama fetus which has been acclimatized to high elevation for many generations demonstrates marked differences in many cardiovascular variables. In response to hypoxia, these include a marked increase in systemic vascular tone, lack of augmentation of cerebral blood flow but dramatic increases in blood flow to the myocardium and adrenal glands, and many other differences in response. The results emphasize the role of high altitude hypoxemia in modulating a number of signal transduction mechanisms in the various organs and tissues to affect protein synthesis and a mosaic of responses. These specifically highlight the array of responses in the fetus and their implications for development under conditions of high altitude induced fetal growth restriction. Of critical relevance and importance the cellular and molecular changes present lifelong consequences with a panoply of diseases in adult life. Discovery of the genes that promote acclimatization and/or prevent high altitude-associated disease may have profound implications for human well-being.