The effect of high altitude on reducing birth weight is markedly less in populations of high- (e.g., Andeans) relative to low-altitude origin (e.g., Europeans). Uterine artery (UA) blood flow is greater during pregnancy in Andeans than Europeans at high altitude; however, it is not clear whether such blood flow differences play a causal role in ancestry-associated variations in fetal growth. We tested the hypothesis that greater UA blood flow contributes to the protection of fetal growth afforded by Andean ancestry by comparing UA blood flow and fetal growth throughout pregnancy in 137 Andean or European residents of low (400 m; European n = 28, Andean n = 23) or high (3,100-4,100 m; European n = 51, Andean n = 35) altitude in Bolivia. Blood flow and fetal biometry were assessed by Doppler ultrasound, and maternal ancestry was confirmed, using a panel of 100 ancestry-informative genetic markers (AIMs). At low altitude, there were no ancestry-related differences in the pregnancy-associated rise in UA blood flow, fetal biometry, or birth weight. At high altitude, Andean infants weighed 253 g more than European infants after controlling for gestational age and other known influences. UA blood flow and O(2) delivery were twofold greater at 20 wk in Andean than European women at high altitude, and were paralleled by greater fetal size. Moreover, variation in the proportion of Indigenous American ancestry among individual women was positively associated with UA diameter, blood flow, O(2) delivery, and fetal head circumference. We concluded that greater UA blood flow protects against hypoxia-associated reductions in fetal growth, consistent with the hypothesis that genetic factors enabled Andeans to achieve a greater pregnancy-associated rise in UA blood flow and O(2) delivery than European women at high altitude.

Multigenerational (Andean) compared with shorter-term (European) high-altitude residents exhibit less hypoxia-associated reductions in birth weight. Because differences in arterial O(2) content are not responsible, we asked whether greater pregnancy-associated increases in uterine artery (UA) blood flow and O(2) delivery were involved. Serial studies were conducted in 42 Andean and 26 European residents of La Paz, Bolivia (3600 m) at weeks 20, 30, 36 of pregnancy and 4 mo postpartum using Doppler ultrasound. There were no differences postpartum but Andean vs. European women had greater UA diameter (0.65 +/- 0.01 vs. 0.56 +/- 0.01 cm), cross-sectional area (33.1 +/- 0.97 vs. 24.7 +/- 1.18 mm(2)), and blood flow at week 36 (743 +/- 87 vs. 474 +/- 36 ml/min) (all P < 0.05) and thus 1.6-fold greater uteroplacental O(2) delivery near term (126.82 +/- 18.47 vs. 80.33 +/- 8.69 ml O(2).ml blood(-1).min(-1), P < 0.05). Andeans had greater common iliac (CI) flow and lower external iliac relative to CI flow (0.52 +/- 0.11 vs. 0.95 +/- 0.14, P < 0.05) than Europeans at week 36. After adjusting for gestational age, maternal height, and parity, Andean babies weighed 209 g more than the Europeans. Greater UA cross-sectional area at week 30 related positively to birth weight in Andeans (r = +0.39) but negatively in Europeans (r = -0.37) (both P < 0.01). We concluded that a greater pregnancy-associated increase in UA diameter raised UA blood flow and uteroplacental O(2) delivery in the Andeans and contributed to their ability to maintain normal fetal growth under conditions of high-altitude hypoxia. These data implicate the involvement of genetic factors in protecting multigenerational populations from hypoxia-associated reductions in fetal growth, but future studies are required for confirmation and identification of the specific genes involved.

High altitude decreases birth weight, but this effect is diminished in long vs. short-resident, high-altitude populations. We asked whether women from long vs. short-resident, high-altitude populations had higher arterial oxygenation levels by comparing 42 Andean and 26 European residents of La Paz, Bolivia (3,600 m), serially during pregnancy (weeks 20, 30, and 36) and again 4 mo postpartum. Pregnancy raised hypoxic ventilatory sensitivity threefold, resting ventilation (V E), and arterial O2 saturation (SaO 2 ) in both groups. Ancestry, as identified using 81 genetic markers, correlated with respiratory pattern, such that greater Andean ancestry was associated with higher respiratory frequency and lower tidal volume. Pregnancy increased total blood and plasma volume ϳ40% in both groups without changing red blood cell mass relative to body weight; hence, hemoglobin fell. The hemoglobin decline was compensated for by the rise in V E and SaO 2 with the result that arterial O2 content (Ca O 2 ) was maintained near nonpregnant levels in both groups. Birth weights were similar for all Andean and European babies, but after adjusting for variation in gestational age, maternal height and parity, Andeans weighed 209 g more than Europeans. Babies with heavier birth weights and greater ponderal indices were born to Andean women with higher V E during pregnancy. We concluded that while maternal V E and arterial oxygenation were important, some factor other than higher Ca O 2 was responsible for protecting Andeans from altitude-associated reductions in fetal growth.hypoxia; ventilation; ventilatory control; infant birth weight; fetal growth; genetics of birth weight; human adaptation; respiratory pattern RESIDENCE AT HIGH ALTITUDE (Ͼ8,000 ft, 2,500 m) exerts among the most powerful effects on birth weight with values falling, on average, 121 g per 1,000 m in Colorado high-altitude (Ͼ2,500 m, 8,000 ft) residents (15). This effect is due primarily to a slowing of fetal growth, not shortened gestation, and is greater than the effects of parity, the number of prenatal visits, or moderate maternal smoking on birth weight. Existing data indicate that the birth weight fall is not due to socioeconomic or other known risk factors (6, 15), but rather to the effects of hypoxia itself.Some 140 million persons live at high altitude, making them the largest single group at risk of low birth weight (16). While birth weight declines in all populations studied to date, the magnitude of fall varies, being least in long-and greatest in short-resident groups. For example, across a 2,700 -4,700 m (8,900 -15,500 ft) altitude range, birth weight decreases three times as much in Han ("Chinese") compared with Tibetans (24). In La Paz, Bolivia, at 3,600 m (11,880 ft), women of indigenous (Aymára or Quechua) ancestry give birth to heavier weight infants than European women, regardless of whether the data are adjusted for differences in maternal body size, nutrition, or the mother's own altitude of birth and development (9).On the basis of our previo...

Mechanisms underlying sex-related differences in adaptation to high altitude were investigated by assessing the turnover of dopamine and noradrenaline in structures of the chemoafferent pathway, i.e. carotid body and brainstem noradrenergic cell groups (A1, A5, A6, A2 to which chemosensory fibres project). The influence of gender was assessed in male and female rats reared at an altitude of 3600 m, whereas the influence of endogenous sex hormones was evaluated by castration. Haematocrit, red blood cell count and plasma erythropoietin levels were lower in females than in males (-5%, -15%, -53%, respectively). Dopamine and noradrenaline turnover were higher in female structures (carotid body: +51%; A2: +140%; A1: +54%; A5: +27%). Dopamine and noradrenaline turnover in carotid body and brainstem cell groups were differently affected by castration, i. e. enhanced by orchidectomy (carotid body: +134%; A2: +120%; A1: +69%; A5: +67%) but inhibited by ovariectomy (carotid body: -33%; A2: -92%). Orchidectomy elicited a reduction in haematocrit (-10%), haemoglobin concentration (-8%) and red blood cell count (-24%), whereas haematological status remained unaltered after ovariectomy. Therefore, both gender and endogenous sex steroids may control catecholamine activity differently in structures involved in the chemoafferent pathway, thus providing a neurochemical basis for sex-related differences in adaptation to hypoxia.

Perinatal exposures exert a profound influence on physiological function, including developmental processes vital for efficient pulmonary gas transfer throughout the lifespan. We extend the concept of developmental programming to chronic mountain sickness (CMS), a debilitating syndrome marked by polycythemia, ventilatory impairment, and pulmonary hypertension that affects ∼10% of male high-altitude residents. We hypothesized that adverse perinatal oxygenation caused abnormalities of ventilatory and/or pulmonary vascular function that increased susceptibility to CMS in adulthood. Subjects were 67 male high-altitude (3,600-4,100 m) residents aged 18-25 yr with excessive erythrocytosis (EE, Hb concentration ≥18.3 g/dl), a preclinical form of CMS, and 66 controls identified from a community-based survey (n = 981). EE subjects not only had higher Hb concentrations and erythrocyte counts, but also lower alveolar ventilation, impaired pulmonary diffusion capacity, higher systolic pulmonary artery pressure, lower pulmonary artery acceleration time, and more frequent right ventricular hypertrophy, than controls. Compared with controls, EE subjects were more often born to mothers experiencing hypertensive complications of pregnancy and hypoxia during the perinatal period, with each increasing the risk of developing EE (odds ratio = 5.25, P = 0.05 and odds ratio = 6.44, P = 0.04, respectively) after other factors known to influence EE status were taken into account. Adverse perinatal oxygenation is associated with increased susceptibility to EE accompanied by modest abnormalities of the pulmonary circulation that are independent of increased blood viscosity. The association between perinatal hypoxia and EE may be due to disrupted alveolarization and microvascular development, leading to impaired gas exchange and/or pulmonary hypertension.