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.

Chronic mountain sickness (CMS) is considered to be a loss of ventilatory acclimatization to high altitude (>2500 m) resulting in marked arterial hypoxemia and polycythemia. This case-control study explores the possibility that sleep-disordered breathing (SBD) and associated oxidative stress contribute to the etiology of CMS. Nocturnal respiratory and Sa O2 patterns were measured using standard polysomnography techniques and compared between male high-altitude residents (aged 18-25) with preclinical CMS ([excessive erythrocytosis (EE)], n=20) and controls (n=19). Measures of oxidative stress and antioxidant status included isoprostanes (8-iso-PGF2 alpha ), superoxide dismutase and ascorbic acid. EE cases had a greater apnea-hypopnea index, a higher frequency of apneas (central and obstructive) and hypopneas during REM sleep, and lower nocturnal Sa O2 compared to controls. 8-iso-PGF2 alpha was greater in EE than controls, negatively associated with nocturnal Sa O2 , and positively associated with hemoglobin concentration. Mild sleep-disordered breathing and oxidative stress are evident in preclinical CMS, suggesting that the resolution of nocturnal hypoxemia or antioxidant treatment may prevent disease progression.

Objective-This prospective study was designed to determine whether variation in angiogenic (placental growth factor [PlGF]) and/or anti-angiogenic (soluble fms-like tyrosine kinase [sFlt-1]) factors contribute to the protective effect of highland ancestry (Andean) from altitude-associated reductions in fetal growth.Study design-Plasma sFlt-1 and PlGF levels, uterine artery (UA) blood flow, and fetal biometry were determined in low-altitude (400 m; Andean n = 27, European n = 28) and highaltitude (3600 m; Andean n = 51, European n = 44) residents during pregnancy (20 and 36 weeks) and 4 months postpartum.Results-High-altitude decreased sFlt-1 levels in both groups, Andeans had lower sFlt-1, comparable PlGF, lower sFlt-1/PlGF ratios, and higher UA blood flow throughout pregnancy relative to Europeans. Altitude decreased birth weight in Europeans but not Andeans. In highaltitude Europeans sFlt-1/PlGF and sFlt-1 levels were negatively associated with UA diameter and birth weight, respectively.Conclusions-Lower sFlt-1 and sFlt-1/PLGF ratio may contribute to or result from variations in maternal vascular adaptation to pregnancy between Andean and Europeans at high altitude. Subsequently, these effects could potentially influence ancestry-associated differences in birth weight.

BACKGROUND Preeclampsia (PE) is more common at high than low altitude and contributes to the altitude-related decline in birth weight. Since inflammatory markers are implicated in PE, we asked if such markers differed in PE vs. normotensive pregnant (NORM) women residing at high altitude (3600-4100 m), and were related to uterine artery blood flow (UA BF) or fetal growth. METHODS Subjects were 33 Andean pregnant residents of Bolivia, comprising six with early-onset PE (≤ 34 wk), 12 with late-onset PE (> 34 wk), and 15 gestational-age matched NORM. Maternal pro- and anti-inflammatory cytokines were measured using a multiplex bead-based assay and UA BF by Doppler ultrasound. RESULTS PE compared to NORM women had higher levels of the pro-inflammatory cytokines IL-6 and IL-8 as well as higher levels of the anti-inflammatory cytokine IL-1ra, but only IL-6 levels were higher when gestational age was controlled. Women with early- vs. late-onset PE had higher TNFα levels, and higher IL-6 was negatively correlated with birth weight in all women at ≤ 34 wk. We suggest that pro-inflammatory factors influence both the timing and severity of PE at high altitude.

Pro- versus anti-inflammatory cytokine balance is important for successful pregnancy. Chronic hypoxia alters cytokine levels and increases the frequency of fetal growth restriction (FGR). Multigenerational Andean (AND) versus shorter duration European (EUR) high-altitude (HA) residents are protected from altitude-associated FGR. To address whether ancestry group differences in cytokine levels were involved, we conducted serial studies in 56 low-altitude ([LA]; 400 m; n = 29 AND and n = 27 EUR) and 42 HA residents (3600-4100 m; n = 19 ANDs and n = 23 EURs). Pregnancy raised pro- (interleukin 1β [IL-1β]) and anti- (IL-10) inflammatory cytokines and HA lowered IL-6 and tumor necrosis factor-α (TNF-α) near term. There were no ancestry group differences in cytokine levels at any time, but HA reduced IL-1β in ANDs only near term. Higher IL-1β levels correlated with uterine artery (UA) blood flow at 20 weeks in ANDs at HA, suggesting that IL-1β may play a role in AND protection from altitude-associated reductions in fetal growth.

Objective: To determine the role of antioxidant & oxidative status in the protection of uterine artery blood flow (UAVF) & fetal growth at high altitude in Andean populations. Methods: Erythrocyte catalase (CAT) & superoxide dismutase (SOD), plasma isoprostanes (8‐ISO‐PGF‐2α) & UA VF were measured at 20 & 36w of pregnancy & and in the non‐pregnant state in Andean (AND) & European (EUR) women at low (LA, 416m) or high (HA, 3600m) altitude. CAT, SOD & 8‐iso‐PGF‐2α were assessed by spectrometry, UA VF by Doppler ultrasound & birth weight (BW) by medical records review. Data was analyzed by t‐tests, 1‐ & 2‐way ANOVA. Results: At LA, ancestry had no effect on CAT or SOD. AND had higher CAT (20 & 36w p<0.05) & SOD activity (36w p<0.05) than EUR at HA. At HA, UA diameter and UA VF were greater in AND than EUR. Altitude decreased BW in AND (p<0.05) and EUR (p<0.01), and at HA EUR ancestry reduced BW (β= − 0.238 p<0.05). Small‐for‐gestational age (SGA) infants occurred 2‐times more frequently at HA than LA in EUR. SOD was lower at 20w in SGA at both altitues, or HA alone (all p<0.05). In EUR, CAT tended to be lower at 20w in SGA. 8‐ISO‐PGF2α reduced UA diam (p<0.05) & UA VF (p<0.01) in all women. Conclusion: Elevated endogenous antioxidant activity may contribute to the protection against altitude‐associated reductions in UA blood flow & fetal growth afforded by Andean ancestry. NIH HL079647,AHA 0610129Z & NSF BCS‐064719.

INTRODUCTION. An imbalance between angiogenic and anti‐angiogenic factors likely plays an etiological role in fetal growth restriction. Since multigenerational high‐altitude (HA) Andean (AND) vs. shorter‐term, European (EUR) ancestry protects against fetal growth restriction at HA, we hypothesized that the angiogenic factor PlGF was elevated and the anti‐angiogenic factor sFlt‐1 reduced. MATERIALS AND METHODS. Pregnant women residing at low (400 m; AND n=36, EUR n=39) or high (3600m; AND n=46, EUR n=33) altitude in Bolivia were studied at 20 and 36 wk of pregnancy and 4 mo postpartum. Plasma sFlt1 and PlGF levels were determined by ELISA and data analyzed by ANOVA. RESULTS. Pregnancy increased PlGF and sFlt‐1 in EUR and AND women (p<0.001). PlGF increased in AND women at HA in early pregnancy and declined at 36 wk compared EUR values (interaction between pregnancy, altitude and ancestry, p<0.05). At HA, sFlt‐1 was greater in EUR than AND women at 20 and 36 wk (p<0.001). The sFlt‐1/PlGF ratio rose from 20 wk to 36 wk in EUR women at both altitudes and in HA AND women but not in the LA AND, and tended to be lower in AND vs. EUR women near term (p<0.10). CONCLUSIONS. Lower sFLT‐1 and higher PlGF levels may help protect multigenerational AND compared with shorter‐term EUR HA‐residents from fetal growth restriction. (NIH HL079647 and HL 14985)