Lower uterine artery blood flow and higher endothelin relative to nitric oxide metabolite levels are associated with reductions in birth weight at high altitude

Abstract

Moore LG. Lower uterine artery blood flow and higher endothelin relative to nitric oxide metabolite levels are associated with reductions in birth weight at high altitude. Am J Physiol Regul Integr Comp Physiol 295: R906 -R915, 2008. First published June 25, 2008 doi:10.1152/ajpregu.00164.2008.-Reduced uteroplacental blood flow is hypothesized to play a key role in altitude-associated fetal growth restriction. It is unknown whether reduced blood flow is a cause or consequence of reduced fetal size. We asked whether determinants of uteroplacental blood flow were altered prior to reduced fetal growth and whether vasoactive and/or angiogenic factors were involved. Women residing at low (LA; 1600 m, n ϭ 18) or high altitude (HA; 3100 m, n ϭ 25) were studied during pregnancy (20, 30, and 36 wk) and 4 mo postpartum (PP) using Doppler ultrasound. In each study, endothelin (ET-1), nitric oxide metabolites (NO x), soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PlGF) levels were quantified. At HA, birth weights were lower (P Ͻ 0.01) and small-for-gestational age was more common (P Ͻ 0.05) compared with LA. HA was associated with lower uterine artery (UA) diameter (P Ͻ 0.01) and blood flow (P Ͻ 0.05). Altitude did not affect ET-1, sFlt-1 or PlGF; however, ET-1/NO x was greater and NOx lower during pregnancy and PP at HA vs. LA. ET-1/NO x was negatively associated with birth weight (20 wk, P Ͻ 0.01; 36 wk, P ϭ 0.05) at LA and HA combined. At HA, UA blood flow (30 wk) was positively associated with birth weight ( †). UA blood flow and ET-1/NO x levels accounted for 45% (20 wk) and 32% (30 wk) of birth weight variation at LA and HA combined, primarily attributed to effects at HA. We concluded that elevated ET-1/NO x and altered determinants of uteroplacental blood flow occur prior to altitude-associated reductions in fetal growth, and therefore, they are likely a cause rather than a consequence of smaller fetal size. fetal growth restriction; hypoxia; small-for-gestational age; uteroplacental oxygen delivery; pregnancy SMALL-FOR-GESTATIONAL AGE (SGA) is a common complication of pregnancy that raises the risk of morbidity and mortality during the perinatal period, as well as in later life (2, 11). Among the many determinants of SGA is the chronic hypoxia of residence at high altitude (Ն2,500 m; 8,200 ft). Birth weight declines progressively, and potently, with increasing altitude such that infants born to women permanently residing at elevations Ն2,500 m are at a greater risk of low birth weight than infants born at lower altitudes (13-15, 34). Altitudinal differences in gestational age, socioeconomic status, parity, maternal height, or the frequency of hypertensive complications do not explain the degree to which birth weight decreases with altitude, indicating that it is likely chronic hypoxia per se that is decreasing fetal growth (12,13,15). Despite the pervasive effect of high altitude on birth weight, the mechanisms by which hypoxia acts to reduce fetal growth are not well understood.A considera...

Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates

“…Hospital-based studies have documented that the risk of adverse perinatal outcomes is increased with extreme maternal Hcts (Moore et al, 2001a;Gonzales et al, 2009) (Fig.4). During pregnancy at high altitude, elevated Hct and the associated increase in blood viscosity contribute to an increased risk of stillbirth, preterm birth, and reduced birth weight, all of which appear to stem from a reduced uterine artery blood flow and, consequently, a reduced rate of O 2 delivery to the uteroplacental circulation (Moore et al, 1982;Moore et al, 2001a;Moore et al, 2001b;Zamudio et al, 1995;Wilson et al, 2007;Julian et al, 2008;Julian et al, 2009b). For this reason, acclimatized lowlanders at high altitude generally experience especially high rates of adverse pregnancy outcomes.…”

The effect of high altitude on endothelial and vascular dysfunction markers in preeclamptic patients

“…Xiao et al suggested that high altitude hypoxia altered uterine vessels myogenic activity via enhanced oxidative stress (34). Residence at high altitude per se was reported to induce significant elevation of several vasoconstriction relative to vasodilatation mediators (3,18). This effect is apparently more pronounced during pregnancy, with greater levels of certain vasoconstrictor, inhibition of other vasodilator mediators, compared with low-altitude pregnancy.…”

Effects of altitude changes on Doppler flow parameters for uterine, umbilical, and mid-cerebral arteries in term pregnancy: A pilot study

“…They found a lowered birth weight at a high altitude than at a moderate altitude, but they reported no significant differences in the Doppler indices of the umbilical and mid-cerebral arteries. Julian et al (13) found no differences at any time in the umbilical or mid-cerebral arteries Doppler flow parameters at low altitude than high altitude. Indeed, the fetus of pregnant sheep acclimatized to long-term hypoxia had similar increases in the cerebral blood flow and cerebral tissue oxygenation to the fetus at a low altitude (26).…”

“…Kumtepe et al (8) demonstrated a greater incidence of eclampsia among women living at high altitudes (>1500 m). There are studies in the literature comparing the effect of altitude on maternal and fetal Doppler flow parameters; however, these studies have conflicting results (9)(10)(11)(12)(13)(14)(15). For instance, Galan et al (14) reported no uteroplacental or fetal vascular Doppler velocimetry differences between moderate highlanders and lowlanders, whereas Krampl et al (11) reported a lower impedance of uterine artery blood flow in women living at a high altitude than at the sea level.…”