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...

Evolutionary trade-offs required for bipedalism and brain expansion influence the pregnancy rise in uterine artery (UtA) blood flow and, in turn, reproductive success. We consider the importance of UtA blood flow by reviewing its determinants and presenting data from 191 normotensive (normal, n ¼ 125) or hypertensive ( preeclampsia (PE) or gestational hypertension (GH), n ¼ 29) Andean residents of very high (4100-4300 m) or low altitude (400 m, n ¼ 37). Prior studies show that UtA blood flow is reduced in pregnancies with intrauterine growth restriction (IUGR) but whether the IUGR is due to resultant fetal hypoxia is unclear. We found higher UtA blood flow and Doppler indices of fetal hypoxia in normotensive women at high versus low altitude but similar fetal growth. UtA blood flow was markedly lower in early-onset PE versus normal high-altitude women, and their fetuses more hypoxic as indicated by lower fetal heart rate, Doppler indices and greater IUGR. We concluded that, despite greater fetal hypoxia, fetal growth was well defended by higher UtA blood flows in normal Andeans at high altitude but when compounded by lower UtA blood flow in early-onset PE, exaggerated fetal hypoxia caused the fetus to respond by decreasing cardiac output and redistributing blood flow to help maintain brain development at the expense of growth elsewhere. We speculate that UtA blood flow is not only an important supply line but also a trigger for stimulating the metabolic and other processes regulating feto-placental metabolism and growth. Studies using the natural laboratory of high altitude are valuable for identifying the physiological and genetic mechanisms involved in human reproductive success.

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The reduction in infant birth weight and increased frequency of preeclampsia (PE) in high-altitude residents have been attributed to greater placental hypoxia, smaller uterine artery (UA) diameter, and lower UA blood flow (Q(UA)). This cross-sectional case-control study determined UA, common iliac (CI), and external iliac (EI) arterial blood flow in Andeans residing at 3,600-4,100 m, who were either nonpregnant (NP, n = 23), or experiencing normotensive pregnancies (NORM; n = 155), preeclampsia (PE, n = 20), or gestational hypertension (GH, n = 12). Pregnancy enlarged UA diameter to ~0.62 cm in all groups, but indices of end-arteriolar vascular resistance were higher in PE or GH than in NORM. Q(UA) was lower in early-onset (≤34 wk) PE or GH than in NORM, but was normal in late-onset (>34 wk) illness. Left Q(UA) was consistently greater than right in NORM, but the pattern reversed in PE. Although Q(CI) and Q(EI) were higher in PE and GH than NORM, the fraction of Q(CI) distributed to the UA was reduced 2- to 3-fold. Women with early-onset PE delivered preterm, and 43% had stillborn small for gestational age (SGA) babies. Those with GH and late-onset PE delivered at term but had higher frequencies of SGA babies (GH=50%, PE=46% vs. NORM=15%, both P < 0.01). Birth weight was strongly associated with reduced Q(UA) (R(2) = 0.80, P < 0.01), as were disease severity and adverse fetal outcomes. We concluded that high end-arteriolar resistance, not smaller UA diameter, limited Q(UA) and restricted fetal growth in PE and GH. These are, to our knowledge, the first quantitative measurements of Q(UA) and pelvic blood flow in early- vs. late-onset PE in high-altitude residents.

Schizencephaly is an unusual condition of obscure etiology. Most theories of pathogenesis postulate an in utero insult leading to maldevelopment rather than destruction of brain. The cause has most often been described as vascular or idiopathic dysgenesis. The authors report a case in which two in utero ultrasound (US) examinations performed at 31 and 36 menstrual weeks demonstrated progressive deterioration of the relatively narrow, symmetrical clefts connecting the lateral ventricles with the subarachnoid space into broad defects that corresponded to the entire distribution of the middle cerebral arteries. The findings in this case document progressive destruction of brain tissue in utero and are consistent with a vascular cause rather than a failure of formation of portions of the cerebral mantle.

Routine obstetric ultrasound (US) examinations in a 33-year-old woman revealed a normal fetal gallbladder at 24 menstrual weeks but multiple structures in the gallbladder with findings typical of gallstones at 37 menstrual weeks. No other abnormalities were present. Three days after a term delivery, an abdominal US examination again demonstrated multiple gallstones. When the infant was 6 weeks old, a follow-up abdominal US study showed no evidence of gallstones. This case, as well as one previously reported, demonstrates that findings typical of gallstones may be seen in the fetus, and that these structures may spontaneously resolve.

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The hypoxia of residence at high compared to moderate altitude lowered birth weight but did not significantly alter MUA or mid-thigh fetal subcutaneous tissue mass or Doppler indices of vascular function.