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.

Fetal growth is reduced at high altitude, but the decrease is less among long-resident populations. We hypothesized that greater maternal uteroplacental O 2 delivery would explain increased fetal growth in Andean natives versus European migrants to high altitude. O 2 delivery was measured with ultrasound, Doppler and haematological techniques. Participants (n = 180) were pregnant women of self-professed European or Andean ancestry living at 3600 m or 400 m in Bolivia. Ancestry was quantified using ancestry-informative single nucleotide polymorphims. The altitude-associated decrement in birth weight was 418 g in European versus 236 g in Andean women (P < 0.005). Altitude was associated with decreased uterine artery diameter, volumetric blood flow and O 2 delivery regardless of ancestry. But the hypothesis was rejected as O 2 delivery was similar between ancestry groups at their respective altitudes of residence. Instead, Andean neonates were larger and heavier per unit of O 2 delivery, regardless of altitude (P < 0.001). European admixture among Andeans was negatively correlated with birth weight at both altitudes (P < 0.01), but admixture was not related to any of the O 2 transport variables. Genetically mediated differences in maternal O 2 delivery are thus unlikely to explain the Andean advantage in fetal growth. Of the other independent variables, only placental weight and gestational age explained significant variation in birth weight. Thus greater placental efficiency in O 2 and nutrient transport, and/or greater fetal efficiency in substrate utilization may contribute to ancestry-and altitude-related differences in fetal growth. Uterine artery O 2 delivery in these pregnancies was 99 ± 3 ml min −1 , ∼5-fold greater than near-term fetal O 2 consumption. Deficits in maternal O 2 transport in third trimester normal pregnancy are unlikely to be causally associated with variation in fetal growth.

Fetal growth is decreased at high altitude (> 2700 m). We hypothesized that variation in fetal O 2 delivery might account for both the altitude effect and the relative preservation of fetal growth in multigenerational natives to high altitude. Participants were 168 women of European or Andean ancestry living at 3600 m or 400 m. Ancestry was genetically confirmed. Umbilical vein blood flow was measured using ultrasound and Doppler. Cord blood samples permitted calculation of fetal O 2 delivery and consumption. Andean fetuses had greater blood flow and oxygen delivery than Europeans and weighed more at birth, regardless of altitude (+208 g, P < 0.0001). Fetal blood flow was decreased at 3600 m (P < 0.0001); the decrement was similar in both ancestry groups. Altitude-associated decrease in birth weight was greater in Europeans (−417 g) than Andeans (−228 g, P < 0.005). Birth weight at 3600 m was > 200 g lower for Europeans at any given level of blood flow or O 2 delivery. Fetal haemoglobin concentration was increased, P CO 2 decreased, and the fetal P O 2 /S O 2 curve was left-shifted at 3600 m. Fetuses receiving less O 2 extracted more (r 2 = 0.35, P < 0.0001). These adaptations resulted in similar fetal O 2 delivery and consumption across all four groups. Increased umbilical venous O 2 delivery correlated with increased fetal O 2 consumption per kg weight (r 2 = 0.50, P < 0.0001). Blood flow (r 2 = 0.16, P < 0.001) and O 2 delivery (r 2 = 0.17, P < 0.001) correlated with birth weight at 3600 m, but not at 400 m (r 2 = 0.04, and 0.03, respectively). We concluded that the most pronounced difference at high altitude is reduced fetal blood flow, but fetal haematological adaptation and fetal capacity to increase O 2 extraction indicates that deficit in fetal oxygen delivery is unlikely to be causally associated with the altitude-and ancestry-related differences in fetal growth.

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.