Maternal Adaptation to High-altitude Pregnancy: An Experiment of Nature—A Review
Introduction
Hypoxia is a frequent complication of prenatal life. When prolonged, it is associated with intrauterine growth restriction (IUGR) (Table 1) and increased perinatal mortality and morbidity. Whereas persons are subject to chronic hypoxia in utero at all elevations, the largest single group of persons at risk is the 140 million worldwide residents of high altitude(>2500 m or 8000 ft) [1]. There has been a long and productive history of studies of pregnancy, fetal and neonatal life at high altitude. The initial observations on a population level that fetal growth restriction and preterm delivery were separable causes of low birth weight were made there nearly 50 years ago ([2]reviewed in [3]). Not only was this crucial in terms of our current understanding of the causes of low birth weight but was followed by continued investigations demonstrating the utility of charting newborn birth weight in relation to gestational age as a predictor of infant mortality [4]. This system continues to be used worldwide; its introduction constitutes one of the truly great public health advances of our time. The first recognition that chronic hypoxia was part of the aetiology of pre-eclampsia was also made at high altitude [5]. Continuing investigations by several investigative groups [6], [7], [8], [9]are rapidly expanding our knowledge of the cellular and molecular mechanisms by which hypoxia influences the maternal, placental and fetal responses required to successfully produce the next generation.
Here we begin with a brief review of the magnitude and cause of the altitude-associated increase in IUGR. Because studies have been conducted at a range of elevations on three continents (North America, South America, Asia), we ask whether the decline in infant birth weight varies among populations and if so, what mechanisms are likely involved. We then move to a consideration of the physiological factors controlling uteroplacental blood flow since altered uteroplacental blood flow is a core predictor of pregnancy abnormalities [10]. After reviewing recent research addressing the effects of chronic hypoxia on uteroplacental blood flow, we ask whether these effects vary among populations or species in relation to the altitude-associated increase in IUGR. Finally, we consider the role that genetic factors may play in the population and species differences observed in altitude-associated IUGR, hypothesizing that variation in hypoxia-sensitive genes might be involved. We review the role played by the hypoxia-inducible factor (HIF) pathway since it is responsible for regulating most of the oxygen-sensitive genes. After surveying the HIF-regulated and regulatory genes differentially affected by pregnancy and chronic hypoxia, we consider the possibility that such genes may have been acted upon by natural selection in populations long resident at high altitude. We conclude with some future directions for research aimed at advancing our understanding of the genetic mechanisms regulating maternal physiological responses to human pregnancy.
Section snippets
Magnitude and cause of the birth weight decline
In Colorado and elsewhere, infant birth weight declines with increasing altitude, averaging a 100 g fall per 1000 m altitude gain (nearly a quarter of a pound per 3000 ft) [11], [12]. While convenient to express in this fashion, the decline in birth weight is actually curvilinear with the ‘breakpoint’ occurring about 2000 m or 6600 ft [13], consistent with the shape of the haemoglobin-oxygen dissociation curve. The entire distribution of birth weights is shifted to lower values, rather than
Normoxic pregnancy
Pregnancy affects all the determinants of O2delivery to the uteroplacental circulation. Ventilation rises, although this does not normally change arterial O2saturation since values are already nearly maximal. Haemoglobin declines due to greater plasma than red cell mass expansion and reduces arterial O2content. Thus a rise in blood flow is entirely responsible for increasing O2delivery to the uteroplacental circulation.
The rise in uteroplacental blood flow is due, in turn, to higher cardiac
Do genetic factors influence maternal vascular adaptation to pregnancy?
Population and species differences in the magnitude of hypoxia-associated IUGR suggest the involvement of genetic factors. Such genetic involvement is consistent with other studies suggesting associations between specific genetic variants and pre-eclampsia or IUGR [80], [81], [82], [83], [84], [85]. In evaluating the kinds of genetic factors that might be involved, we (and others) have been struck by the observation that many of the candidate genes thus far identified are part of the HIF
Genomic approaches for identifying candidate genes
Genomic approaches have been infrequently applied to pregnancy complications but offer considerable power for determining interindividual variation in risk factors for complex diseases [91], [92]. Such approaches include ones which take advantage of the possibility that natural selection has acted to differentiate one population, in this case Andeans, from other groups with shorter duration of high-altitude exposure with respect to genes influencing uteroplacental blood flow and fetal growth.
Directions for future study
Thus, the available data suggest that UA blood flow is lower during pregnancy at high altitude in settings where IUGR is most pronounced. Further the variation in hypoxia-associated IUGR that is evident both within as well as between species suggests important avenues for future studies designed to address the contribution of genetic factors to maternal vascular adaptation to pregnancy. Future studies are required for assaying additional SNPs near the candidate, HIF-targeted genes to verify the
Acknowledgments
Our appreciation is extended to the many subjects who have participated in our studies of pregnancy at high altitudes in Colorado, Peru, Tibet and Bolivia and to the technical staff at the Women's Health and Colorado High-Altitude Research Centers, the Bolivian High-Altitude Biology Institute, the Pennsylvania Department of Anthropology and the other sites which have cooperated with us in the past. We especially thank Ms Wendy MacCannell for her help with the preparation of this article and
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