Impaired maternal central hemodynamics precede the onset of vascular disorders of pregnancy at high altitude.

Hypertensive disorders of pregnancy represent an escalating global health concern with increasing incidence in low- to middle-income countries and high-income countries alike. The current lack of methods to detect the subclinical stages of preeclampsia (PE) and fetal growth restriction (FGR), two common vascular disorders of pregnancy, limits treatment options to minimize acute- and long-term adverse outcomes for both mother and child. To determine whether impaired maternal cardiovascular or uteroplacental vascular function precedes the onset of PE and/or FGR (PE-FGR), we used noninvasive techniques to obtain serial measurements of maternal cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR), and uterine and fetal arterial resistance at , -, and for 79 maternal-infant pairs in La Paz-El Alto, Bolivia (3,850 m), where the chronic hypoxia of high altitude increases the incidence of PE and FGR.

Maternal adiponectin restores cholinergic vasodilation in resistance vessels from adult offspring exposed to maternal obesity .

Maternal obesity increases the risk of cardiovascular and metabolic disease in the offspring both during childhood and adult life. Pregnant women and mice with obesity have lower circulating levels of adiponectin (ADN) compared to lean controls. ADN is an adipokine involved in regulating energy metabolism, vascular function, and placental function.

Genomic Selection Signals in Andean Highlanders Reveal Adaptive Placental Metabolic Phenotypes That Are Disrupted in Preeclampsia.

Background: The chronic hypoxia of high-altitude residence poses challenges for tissue oxygen supply and metabolism. Exposure to high altitude during pregnancy increases the incidence of hypertensive disorders of pregnancy and fetal growth restriction and alters placental metabolism. High-altitude ancestry protects against altitude-associated fetal growth restriction, indicating hypoxia tolerance that is genetic in nature.

Increased adherence to ACOG diagnostic guidelines for HDP following a workshop in Bolivia, a LMIC.

Objectives: Hypertensive disorders of pregnancy (HDP) exert a heavy mortality burden in low- to middle-income countries (LMIC). ACOG revised HDP diagnostic guidelines to improve identifying pregnancies at greatest risk but whether they are used in LMIC is unknown.

Study Design: We held a workshop to review ACOG guidelines in La Paz, Bolivia (BO) and then reviewed prenatal, labor and delivery records for all HDP diagnoses and twice as many controls at its three largest delivery sites during the year before and the nine months after a workshop (n = 1376 cases, 2851 controls during the two periods).

Altered placental ion channel gene expression in preeclamptic high-altitude pregnancies.

High-altitude (>2,500 m) residence increases the risk of pregnancy vascular disorders such as fetal growth restriction and preeclampsia, each characterized by impaired placental function. Genetic attributes of highland ancestry confer relative protection against vascular disorders of pregnancy at high altitudes. Although ion channels have been implicated in placental function regulation, neither their expression in high-altitude placentas nor their relationship to high-altitude preeclampsia has been determined.

Adaptive responses in uteroplacental metabolism and fetoplacental nutrient shuttling and sensing during placental insufficiency.

Glucose, lactate, and amino acids are major fetal nutrients. During placental insufficiency-induced intrauterine growth restriction (PI-IUGR), uteroplacental weight-specific oxygen consumption rates are maintained, yet fetal glucose and amino acid supply is decreased and fetal lactate concentrations are increased. We hypothesized that uteroplacental metabolism adapts to PI-IUGR by altering nutrient allocation to maintain oxidative metabolism.

High altitude differentially modulates potassium channel-evoked vasodilatation in pregnant human myometrial arteries.

High-altitude (>2500 m or 8200 ft) residence reduces uterine artery blood flow during pregnancy, contributing to an increased incidence of preeclampsia and intrauterine growth restriction. However, not all pregnancies are affected by the chronic hypoxic conditions of high-altitude residence. K channels play important roles in the uterine vascular adaptation to pregnancy, promoting a reduction in myogenic tone and an increase in blood flow.

Why is human uterine artery blood flow during pregnancy so high?

In healthy near-term women, blood flow to the uteroplacental circulation is estimated as 841 mL/min, which is greater than in other mammalian species. We argue that as uterine venous Po sets the upper limit for O diffusion to the fetus, high uterine artery blood flow serves to narrow the maternal arterial-to-uterine venous Po gradient and thereby raise uterine vein Po. In support, we show that the reported levels for uterine artery blood flow agree with what is required to maintain normal fetal growth.

ACOG and local diagnostic criteria for hypertensive disorders of pregnancy (HDP) in La Paz-El Alto, Bolivia: A retrospective case-control study.

Background: Hypertensive disorders of pregnancy (HDP) are a leading cause of maternal death in low- to middle-income countries (LMIC). The American College of Obstetricians and Gynecologists (ACOG) updated diagnostic guidelines to align signs and symptoms with those associated with maternal death. We performed an observational study to ask whether ACOG guidelines were employed and associated with adverse outcomes in La Paz-El Alto, Bolivia, an LMIC.

Vascular Disorders of Pregnancy Increase Susceptibility to Neonatal Pulmonary Hypertension in High-Altitude Populations.

Background: Preeclampsia and fetal growth restriction increase cardiopulmonary disease risk for affected offspring and occur more frequently at high-altitude (≥2500 m). Retrospective studies indicate that birth to a preeclampsia woman at high altitude increases the risk of pulmonary hypertension (PH) in later life. This prospective study asked whether preeclampsia with or without fetal growth restriction exaggerated fetal hypoxia and impaired angiogenesis in the fetal lung, leading to neonatal cardiopulmonary circulation abnormalities and neonatal or infantile PH.

How hypoxia slows fetal growth: insights from high altitude.

A continuous oxygen supply is vital for fueling fetal growth, yet we know surprisingly little as to the precise mechanisms by which hypoxia reduces fetal growth. Animal models, while important, are limited by the enormous variability in mammalian physiologic responses to pregnancy. One of the earliest models for understanding hypoxia-induced reductions in fetal growth came from studies at high altitude that showed high altitude to have one of the strongest depressant effects on fetal growth.

Uteroplacental nutrient flux and evidence for metabolic reprogramming during sustained hypoxemia.

Gestational hypoxemia is often associated with reduced birth weight, yet how hypoxemia controls uteroplacental nutrient metabolism and supply to the fetus is unclear. This study tested the effects of maternal hypoxemia (HOX) between 0.8 and 0.

High altitude regulates the expression of AMPK pathways in human placenta.

Introduction: High-altitude (>2500 m) residence augments the risk of intrauterine growth restriction (IUGR) and preeclampsia likely due, in part, to uteroplacental hypoperfusion. Previous genomic and transcriptomic studies in humans and functional studies in mice and humans suggest a role for AMP-activated protein kinase (AMPK) pathway in protecting against hypoxia-associated IUGR. AMPK is a metabolic sensor activated by hypoxia that is ubiquitously expressed in vascular beds and placenta.

Hypoxia-induced inhibition of mTORC1 activity in the developing lung: a possible mechanism for the developmental programming of pulmonary hypertension.

Perinatal hypoxia induces permanent structural and functional changes in the lung and its pulmonary circulation that are associated with the development of pulmonary hypertension (PH) in later life. The mechanistic target of the rapamycin (mTOR) pathway is vital for fetal lung development and is implicated in hypoxia-associated PH, yet its involvement in the developmental programming of PH remains unclear. Pregnant C57/BL6 dams were placed in hyperbaric (760 mmHg) or hypobaric chambers during gestation (505 mmHg, through ) or from weaning through adulthood (420 mmHg, through 8 wk).

HYPOXIA AND REPRODUCTIVE HEALTH: Reproductive challenges at high altitude: fertility, pregnancy and neonatal well-being.

High altitude offers a natural laboratory for studying the effects of chronic hypoxia on reproductive health. Counter to early accounts, fertility (the number of livebirths) appears little affected although stillbirths are more common. Birth weights are lower due to fetal growth restriction, not shortened gestation.

AMP-activated protein kinase activator AICAR attenuates hypoxia-induced murine fetal growth restriction in part by improving uterine artery blood flow.

Key Points: Pregnancy at high altitude is associated with a greater incidence of fetal growth restriction due, in part, to lesser uterine artery blood flow. AMP-activated protein kinase (AMPK) activation vasodilates arteries and may increase uterine artery blood flow. In this study, pharmacological activation of AMPK by the drug AICAR improved fetal growth and elevated uterine artery blood flow.

AMPK activation in pregnant human myometrial arteries from high-altitude and intrauterine growth-restricted pregnancies.

High-altitude (>2,500 m) residence increases the incidence of intrauterine growth restriction (IUGR) due, in part, to reduced uterine artery blood flow and impaired myometrial artery (MA) vasodilator response. A role for the AMP-activated protein kinase (AMPK) pathway in protecting against hypoxia-associated IUGR is suggested by genomic and transcriptomic studies in humans and functional studies in mice. AMPK is a hypoxia-sensitive metabolic sensor with vasodilatory properties.

High-altitude residence alters blood-pressure course and increases hypertensive disorders of pregnancy.

Objectives: To determine whether the full spectrum of hypertensive disorders of pregnancy (HDP) - comprising gestational hypertension; preeclampsia with or without severe features; eclampsia; and emolysis, levated iver enzymes, and ow latelets (HELLP) Syndrome - is increased at high (≥2500 m, 8250 ft) compared with lower altitudes in Colorado independent of maternal background characteristics, and if so their relationship to neonatal well-being.

Methods: A retrospective cohort study was conducted using statewide birth-certificate data to compare the frequency of gestational hypertension, preeclampsia (with or without severe features), eclampsia, HELLP Syndrome, or all HDP combined in 617,958 Colorado women who lived at high vs. low altitude (<2500 m) and delivered during the 10-year period, 2007-2016.

Author Correction: Hypoxia causes reductions in birth weight by altering maternal glucose and lipid metabolism.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Uteroplacental Ischemia Is Associated with Increased PAPP-A2.

Residence at high altitude (> 2500 m) has been associated with an increased frequency of preeclampsia. Pappalysin-2 (PAPP-A2) is an insulin-like growth factor binding protein-5 (IGFBP-5) protease that is elevated in preeclampsia, and up-regulated by hypoxia in placental explants. The relationships between PAPP-A2, altitude, and indices of uteroplacental ischemia are unknown.

Peroxisome proliferator-activated receptor gamma blunts endothelin-1-mediated contraction of the uterine artery in a murine model of high-altitude pregnancy.

The environmental hypoxia of high altitude (HA) increases the incidence of intrauterine growth restriction (IUGR) approximately threefold. The peroxisome proliferator-activated receptor γ (PPAR-γ), a ligand-activated nuclear receptor that promotes vasorelaxation by increasing nitric oxide and downregulating endothelin-1 (ET-1) production, has been implicated in IUGR. Based on our prior work indicating that pharmacologic activation of the PPARγ pathway protects against hypoxia-associated IUGR, we used an experimental murine model to determine whether such effects may be attributed to vasodilatory effects in the uteroplacental circulation.

Effect of high altitude on human placental amino acid transport.

Women residing at high altitudes deliver infants of lower birth weight than at sea level. Birth weight correlates with placental system A-mediated amino acid transport capacity, and severe environmental hypoxia reduces system A activity in isolated trophoblast and the mouse placenta. However, the effect of high altitude on human placental amino acid transport remains unknown.