Where the O2 goes to: preservation of human fetal oxygen delivery and consumption at high altitude

Abstract

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, decreased, and the fetal / 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.

Figure 1. Umbilical vein diameter, flow velocity and volumetric blood flows in low- and high-altitude fetuses of European versus Andean ancestry

A, the diameter of the umbilical vein was smaller in both ancestry groups at high altitude (*P < 0.001). The magnitude of the reduction was similar between ancestry groups (–12% in Europeans, –13% in Andean, P= 0.87). Umbilical venous diameter was smaller in women of European ancestry, regardless of altitude (†P < 0.0001). B, there were no differences in the mean flow velocity of blood travelling through the umbilical vein within each altitude. However, there was a trend towards reduced mean flow velocity at high altitude among the European women only (P= 0.06). C, altitude decreased volumetric blood flow (*P < 0.0001) to a similar degree in both ancestry groups (–32% European, –27% Andean, P= 0.61). Volumetric blood flow through the umbilical vein was lower in European than in Andean women regardless of altitude (†P < 0.0001).

Figure 3. Oxygen delivery, fetal fractional O₂ extraction and consumption

A, umbilical oxygen delivery did not differ between altitudes within each ancestry group (P= 0.77 European, P= 0.99 Andean), but was lower in European than Andean women regardless of altitude (P < 0.001). B, fetal oxygen extraction was similar at low and high altitude in Andean pregnancies (P= 0.96) and in European pregnancies (P= 0.13). However, probably because European women have lower oxygen delivery to begin with, percentage fetal O₂ extraction from the umbilical vein to the umbilical artery was greater in European than in Andean women, regardless of altitude (†P < 0.01). The range for fetal O₂ extraction was 35–93% at low altitude and 20–93% at high altitude. C, oxygen consumption per kg fetal weight was similar in all four groups.

Figure 2. Fetal blood gas relationships

A, the correlation between the umbilical venous and determined by the blood gas analyses was plotted for each of the four groups using a third order polynomial (best fit regression). The low altitude curves overlap for Europeans (□) and Andeans (○). High altitude left-shifts the / curve (P < 0.05), with Andean fetuses (•, continuous line) showing a progressively greater leftward shift with increasing when compared with the Europeans (▪, dashed–dotted line). This results in differences at which the blood is 50% saturated (indicated by the line at 50% on the y axis). The P₅₀ for is equivalent at 400 m (28.4 versus 28.5 for European (dotted line) and Andean (dashed line), respectively). In contrast the blood is half-saturated with oxygen at 25.8 mmHg at 3600 m in Europeans, and 23.4 mmHg at 3600 m in Andean, P < 0.05). The Andean fetuses at 3600 m thus maintain saturation at higher levels for a given when compared with Europeans. (400 m European y=–92.8 + 8.64x– (–0.16x²) + 0.001x³, r²= 0.94, P < 0.0001; 400 m Andean y=–16.4 + 1.09x+ 0.81x²– 0.001x³, r²= 0.97, P < 0.0001; 3600 m European y=–122.4 + 13.33x–0.32x²+ 0.003x³, r²= 0.90, P < 0.0001; 3600 m Andean y=–7.0 – 0.98x+ 0.24x²– 0.004x³, r²= 0.97, P < 0.0001.) B, the maternal curves relating to are also left-shifted at high altitude, but without any apparent difference due to ethnicity at low or high altitude. The line symbols are the same as in A. (400 m European y=–9.6 + 2.94x– 0.81x²– 0.001x³, r²= 0.97, P < 0.0001; 3600 m European y=–122.4 + 13.13x– 0.32x²+ 0.003x³, r²= 0.91, P < 0.0001; 400 m Andean y=–15.7 + 1.02x+ 0.08x²– 0.001x³, r²= 0.97, P < 0.0001; 3600 m Andean y=–1.9 – 1.59x+ 0.27x²– 0.005x³, r²= 0.98, P < 0.0001.) C shows the correlation between maternal and fetal at the two altitude combined. For any given value of maternal , the Andean fetus has a lower than the European fetus. (y= 34.1 + 0.33x, r²= 0.06, P < 0.05 European; y= 30.4 + 0.46x, r²= 0.12, P < 0.005.)

Figure 4. Correlations among fetal variables

A, the mean flow velocity of the blood travelling through the umbilical vein is inversely related to the diameter of the vein velocity (r²= 0.45, P < 0.0001 all subjects). (400 m Europeans (dotted line) y= 18.6 – 9.69x, r²= 0.26, P < 0.0005; 3600 m Europeans (dashed–dotted line) y= 18.4 – 12.91x, r²= 0.30, P < 0.0005; 400 m Andean (dashed line) y= 18.41 – 9.58x, r²= 0.28, P < 0.0002; 3600 m Andean (continuous line) y= 18.26 – 10.96x, r²= 0.22, P < 0.005.) The slope of the relationship is similar between altitudes (centre inset left, P= 0.40) and did not differ between ancestry groups (P= 0.56). B, fetal fractional O₂ extraction is increased when umbilical venous O₂ delivery is reduced (r²= 0.35, P < 0.0001, all subjects). Fetuses receiving less O₂ through the umbilical vein increase their umbilical venous to arterial oxygen extraction. (400 m Europeans (dotted line) y= 83.3–0.62x, r²= 0.21, P < 0.005; 3600 m Europeans (dashed–dotted line) y= 93.22 – 0.84x, r²= 0.33, P < 0.005; 400 m Andean (dashed line) y= 78.31 – 0.50x, r²= 0.20, P < 0.01; 3600 m Andean (continuous line) y= 80.0 – 0.62x, r²= 0.28, P < 0.0005). The slope of the relationship is similar between altitudes (centre inset right, P= 0.81) and did not differ between ancestry groups (P= 0.61).

Figure 5. Fetal adaptive range. Geometric and line symbols are the same as in prior figures

A, fetal oxygen consumption per kg fetal weight increases as oxygen delivery is increased (r²= 0.50, P < 0.0001, all subjects). Fetuses receiving more O₂ through the umbilical vein have greater O₂ consumption relative to their weight (400 m Europeans y= 6.3 + 0.41x, r²= 0.491, P < 0.0001; 3600 m Europeans y= 6.1 + 0.46x, r²= 0.45, P < 0.0001; 400 m Andean y= 6.2 + 0.42x, r²= 0.56, P < 0.0001; 3600 m Andean y= 7.9 + 0.33x, r²= 0.35, P < 0.0001.) The slope of the relationship is similar between altitudes (centre inset left, P= 0.59) and did not differ between ancestry groups (P= 0.50). B, fetal oxygen extraction is correlated with umbilical arterial , such that those fetuses with the greatest O₂ extraction have the lowest arterial (r²= 0.64, P < 0.0001 all subjects). (400 m Europeans y= 34.6 – 0.29x, r²= 0.71, P < 0.0001; 3600 m Europeans y= 42.3 – 0.38x, r²= 0.69, P < 0.0001; 400 m Andean y= 29.6 + 0.20x, r²= 0.31, P < 0.0005; 3600 m Andean y= 32.0 – 0.26x, r²= 0.75, P < 0.0001.) The slope of the relationship is virtually identical between altitudes (centre inset right, P= 0.98), and did not differ between ancestry groups (P= 0.26).

Figure 6. Blood flow, oxygen delivery and birth weight

Geometric and line symbols are the same as in prior figures. A, across the entire sample, variation in blood flow through the umbilical vein (the total fetal nutrient supply) accounted for 17% of the variation in birth weight (P < 0.0001), but did not attain significance within each of the 4 groups (400 m Europeans y= 3049 + 1.15x, r²= 0.06, P= 0.11; 3600 m Europeans y= 2624 + 1.68x, r²= 0.09, P= 0.08; 400 m Andean y= 3443 + 0.221x, r²= 0.00, P= 0.64; 3600 m Andean y= 2867 + 1.65x r²= 0.08, P= 0.08). However when considered by altitude alone, birth weight is more closely correlated with blood flow at high altitude (inset left, 3600 m y= 3576 + 2.32x, r²= 0.16, P < 0.001; 400 m y= 3201 + 0.78x, r²= 0.04, P= 0.05), while the slopes between ancestry groups did not differ (P= 0.11). Nonetheless, for any given level of blood flow the European babies weigh ∼230 g less than Andean infants at high altitude. B, across the entire sample, variation in umbilical oxygen delivery accounted for 12% of the variation in birth weight (P < 0.0001) but this is due largely to the high altitude subjects (inset, right). Among all high altitude subjects 17% of the variation in birth weight was accounted for by oxygen delivery (y= 2724 + 13.72x, r²= 0.17, P < 0.001), while at low altitude only 3% of the variation was explained by oxygen delivery (y= 3271 + 6.17x, P= 0.12). The slopes did not differ between ancestry groups (0.56). The data again indicate that for any given oxygen delivery, the European neonate at high altitude is smaller.