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.

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sTWEAK concentrations are lower in patients with GDM compared with healthy pregnant women, and low concentrations of sTWEAK are associated with insulin resistance. These findings suggest that insulin resistance during pregnancy is closely linked to inflammatory imbalance and sTWEAK may represent a new candidate associated with GDM.