Maternal oxygen delivery is not related to altitude- and ancestry-associated differences in human fetal growth

Abstract

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 polymorphism. 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), approximately 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.

Figure 1. Diameters and mean blood flow velocities from the left and the right arteries

A, external iliac artery diameter was similar at low and high altitude and between European and Andean ancestry groups. B, external iliac artery mean flow velocity was increased at high altitude (P < 0.05) in both ancestry groups, but did not differ between the ancestry groups. C, uterine artery diameter was smaller in women of European ancestry, regardless of altitude (†P < 0.0001). Altitude reduced uterine artery diameter in both ancestry groups to a similar degree (*P < 0.05, −7% Andean and −11% in Europeans, P= 0.58). D, there were no differences in the mean flow velocity of blood travelling through the uterine arteries within each altitude. However, mean flow velocity was reduced at high altitude (P < 0.01). The reduction was similar in European (−10%) versus Andean women (−16%, P= 0.24).

Figure 2. Bilateral arterial blood flows (left and right summed for each individual), and the estimated lower body blood flow (sums of both uterine and both external iliac arteries)

A, bilateral external iliac blood flow did not differ between altitudes or ancestry groups. B, bilateral uterine artery blood flow (the sum of the left and right artery within each individual) was lower in European than Andean women, regardless of ancestry (†P < 0.005). Bilateral uterine artery blood flow was reduced at high relative to low altitude (P < 0.0001) and the magnitude of the decrease was similar in European (−27%) versus Andean (26%) women (P= 0.94). C, total lower body blood flow (the sum of both uterine arteries and both external iliac arteries within each individual) was lower in European than Andean women (*P < 0.01). Total lower body blood flow was decreased at high relative to low altitude (P < 0.001). The decrease was similar in European (−14%) and Andean women (−20%, P= 0.45).

Figure 3. Total uterine arterial oxygen delivery

A, there was no difference in total (bilateral) uterine arterial oxygen delivery between ancestry groups within each altitude. Uterine arterial oxygen delivery was decreased at high altitude (*P < 0.01). The magnitude of decrease was similar in both ancestry groups (−16% European, −11% Andean, P= 0.75). B, when normalized for birth weight (ml kg⁻¹ min⁻¹), total oxygen delivery (sum of the left and right uterine arteries for each pregnancy) was the same in all four groups.

Figure 4. Percentage of European admixture present in Andean women in relation to birth weight at low (A) and high altitude (B)

The percentage of European admixture present in Andean women was negatively related to birth weight at both low (A) and high altitude (B). A, y= 3698 − 9.7x, r²= 0.14, P < 0.05; B, y= 3544 − 14.4x, r²= 0.19, P < 0.01.

Figure 5. Individual women's bilateral uterine arterial oxygen delivery in relation to the weight of their newborns

This scatter plot of all the individual women's bilateral uterine arterial oxygen delivery in relation to the weight of their newborns shows birth weight can vary by as much as 1500 g (dashed lines) for any given level of oxygen delivery. While the relationship between birth weight and oxygen delivery is significant when all the data are considered, interindividual variation in oxygen delivery explains only 4% of the variation in birth weight (y= 2.12x+ 3120, P < 0.01, r²= 0.04). This very modest correlation is entirely accounted for by the European migrants to high altitude (see Table 3).

Figure 6. Bilateral uterine blood flow and oxygen delivery in relation to birth weight for each of the four altitude and ancestry groups

A, the regression lines for bilateral uterine blood flow in relation to birth weight for each of the four altitude and ancestry groups. The slopes represent the regression of all data points for each group. Each line is anchored at the beginning and end of the range of data represented on the x axis, in order to show the extensive overlap of the values between the 4 groups. Altitude reduces birth weight for any given value of blood flow, with the impact markedly more pronounced in the European than Andean women. Andean women at both 400 m and 3600 m show greater fetal growth for any given level of blood flow relative to the European women at the same altitude. B, the same relationship but using oxygen delivery as the independent variable.