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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 gestational weeks 10-16 , 20 - 24 , and 30-34 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. Compared with controls ( n = 55), PE-FGR cases ( n = 24) had lower SV, higher SVR, and greater uterine artery resistance at 10-16 wk. In addition, fetuses of women with lower SV and higher SVR at 10-16 wk showed evidence of brain sparing at 30-34 wk and had lower birth weights, respectively. Although the trajectory of SV and SVR across pregnancy was similar between groups, PE-FGR cases had a comparatively blunted rise in CO from the first to the third visit. Impaired maternal central hemodynamics and increased uteroplacental resistance precede PE-FGR onset, highlighting the potential use of such measures for identifying high-risk pregnancies at high altitudes. NEW & NOTEWORTHY In this prospective study of maternal central hemodynamics at high altitude, pregnancies later affected by preeclampsia (PE) and/or fetal growth restriction (FGR) show elevated systemic and uterine vascular resistance and reduced stroke volume as early as 10-16 wk gestation. Maternal hemodynamic assessments could facilitate early detection of high-risk pregnancies, improving resource allocation and reducing adverse outcomes. We propose an integrated model linking maternal cardiovascular performance to placental insufficiency, enhancing the understanding of PE-FGR in high-altitude settings.

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. Yet, not all babies are protected and placental pathologies associated with fetal growth restriction occur in some Andean highlanders., Methods: We examined placental metabolic function in 79 Andeans (18-45 years; 39 preeclamptic and 40 normotensive) living in La Paz, Bolivia (3600-4100 m) delivered by unlabored Cesarean section. Using a selection-nominated approach, we examined links between putatively adaptive genetic variation and phenotypes related to oxygen delivery or placental metabolism., Results: Mitochondrial oxidative capacity was associated with fetal oxygen delivery in normotensive but not preeclamptic placenta and was also suppressed in term preeclamptic pregnancy. Maternal haplotypes in or within 200 kb of selection-nominated genes were associated with lower placental mitochondrial respiratory capacity ( PTPRD [protein tyrosine phosphatase receptor-δ]), lower maternal plasma erythropoietin ( CPT2 [carnitine palmitoyl transferase 2], proopiomelanocortin, and DNMT3 [DNA methyltransferase 3]), and lower VEGF (vascular endothelial growth factor) in umbilical venous plasma ( TBX5 [T-box transcription factor 5]). A fetal haplotype within 200 kb of CPT2 was associated with increased placental mitochondrial complex II capacity, placental nitrotyrosine, and GLUT4 (glucose transporter type 4) protein expression., Conclusions: Our findings reveal novel associations between putatively adaptive gene regions and phenotypes linked to oxygen delivery and placental metabolic function in highland Andeans, suggesting that such effects may be of genetic origin. Our findings also demonstrate maladaptive metabolic mechanisms in the context of preeclampsia, including dysregulation of placental oxygen consumption., Competing Interests: Disclosures None.

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)., Main Outcome Measures: HDP diagnoses, maternal, and infant characteristics., Results: Bolivian and ACOG criteria identified similar frequencies of gestational hypertension (GH) or eclampsia, but preeclampsia with severe features (sPE) was under- and preeclampsia without severe features (PE) over-reported during both periods. Increases occurred after the workshop in testing for proteinuria and the detection of abnormal laboratory values and severe hypertension in HDP women. Any adverse maternal outcome occurred more frequently after the workshop in women with BO PE or sPE diagnoses who met ACOG sPE criteria., Conclusions: Utilization of ACOG guidelines increased following the workshop and improved identification of PE or sPE pregnancies with adverse maternal outcomes. Continued use of a CLAP perinatal form recognizing HELLP as the only kind of sPE resulted in under-reporting of sPE., Funding: NIH TW010797, HD088590, HL138181., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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. Here, we measured the expression of 26 ion-channel genes in placentas from preeclampsia cases and normotensive controls in La Paz, Bolivia (3,850 m). In addition, we correlated gene transcription to maternal and infant ancestry proportions. Gene expression was assessed by PCR, genetic ancestry evaluated by ADMIXTURE , and ion channel proteins localized by immunofluorescence. In preeclamptic placentas, 11 genes were downregulated ( ABCC9 , ATP2A2 , CACNA1C , KCNE1 , KCNJ8 , KCNK3 , KCNMA1 , KCNQ1 , KCNQ4 , PKD2 , and TRPV6 ) and two were upregulated ( KCNQ3 and SCNN1G ). KCNE1 expression was positively correlated with high-altitude Amerindian ancestry and negatively correlated with non-high altitude. SCNN1G was negatively correlated with African ancestry, despite minimal African admixture. Most ion channels were localized in syncytiotrophoblasts (Cav1.2, TRPP2, TRPV6, and Kv7.1), whereas expression of Kv7.4 was primarily in microvillous membranes, Kir6.1 in chorionic plate and fetal vessels, and MinK in stromal cells. Our findings suggest a role for differential placental ion channel expression in the development of preeclampsia. Functional studies are needed to determine processes affected by these ion channels in the placenta and whether therapies directed at modulating their activity could influence the onset or severity of preeclampsia.

Mundo, William, Lilian Toledo-Jaldin, Alexandrea Heath-Freudenthal, Jaime Huayacho, Litzi Lazo-Vega, Alison Larrea-Alvarado, Valquiria Miranda-Garrido, Rodrigo Mizutani, Lorna G. Moore, Any Moreno-Aramayo, Richard Gomez, Patricio Gutierrez, and Colleen G. Julian. Is maternal cardiovascular performance impaired in altitude-associated fetal growth restriction? High Alt Med Biol . 23:352-360, 2022. Introduction: The incidence of fetal growth restriction (FGR) is elevated in high-altitude resident populations. This study aims to determine whether maternal central hemodynamics during the last trimester of pregnancy are altered in high-altitude FGR. Methods: In this cross-sectional study of maternal-infant pairs (FGR, n  = 27; controls, n  = 26) residing in La Paz, Bolivia, maternal heart rate, cardiac output (CO), stroke volume, and systemic vascular resistance (SVR) were assessed using continuous-wave Doppler ultrasound. Transabdominal Doppler ultrasound was used for uterine artery (UtA) resistance indices and fetal measures. Maternal venous soluble fms-like tyrosine kinase-1 (sFlt1) levels were measured. Results: FGR pregnancies had reduced CO, elevated SVR and UtA resistance, fetal brain sparing, and increased maternal sFlt1 versus controls. Maternal SVR was positively associated with UtA resistance and inversely associated with middle cerebral artery resistance and birth weight. Maternal sFlt1 was greater in FGR than controls and positively associated with UtA pulsatility index. Women with elevated sFlt1 levels also tended to have lower CO and higher SVR. Conclusion: Noninvasive assessment of maternal cardiovascular function may be an additional method for detecting high-risk pregnancies at high altitudes, thereby informing the need for increased surveillance and appropriate allocation of resources to minimize adverse outcomes.

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., Methods and Results: We studied 79 maternal-infant pairs (39 preeclampsia, 40 controls) in Bolivia (3600-4100 m). Cord blood erythropoietin, hemoglobin, and umbilical artery and venous blood gases were measured as indices of fetal hypoxia. Maternal and cord plasma levels of angiogenic (VEGF [vascular endothelial growth factor]) and antiangiogenic (sFlt1 [soluble fms-like tyrosine kinase]) factors were determined. Postnatal echocardiography (1 week and 6-9 months) assessed pulmonary hemodynamics and PH. Preeclampsia augmented fetal hypoxia and increased the risk of PH in the neonate but not later in infancy. Pulmonary abnormalities were confined to preeclampsia cases with fetal growth restriction. Maternal and fetal plasma sFlt1 levels were higher in preeclampsia than controls and positively associated with PH., Conclusions: The effect of preeclampsia with fetal growth restriction to increase fetal hypoxia and sFlt1 levels may impede normal development of the pulmonary circulation at high altitude, leading to adverse neonatal pulmonary vascular outcomes. Our observations highlight important temporal windows for the prevention of pulmonary vascular disease among babies born to highland residents or those with exaggerated hypoxia in utero or newborn life.

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., Methods: Medical records for all HDP discharge diagnoses ( n = 734) and twice as many controls ( n = 1647) were reviewed for one year at the three largest delivery sites. For the 690 cases and 1548 controls meeting inclusion criteria (singleton, 18-45 maternal age, local residence), health history, blood pressures, symptoms, lab tests, HDP diagnoses (i.e., gestational hypertension [GH]; preeclampsia [PE]; haemolysis, low platelets, high liver enzymes [HELLP] syndrome, eclampsia), and adverse outcomes were recorded. Bolivian diagnoses were compared to ACOG guidelines using accuracy analysis and associated with adverse outcomes by logistic regression., Findings: Both systems agreed with respect to eclampsia, but only 27% of all Bolivian HDP diagnoses met ACOG criteria. HDP increased adverse maternal- or perinatal-outcome risks for both systems, but ACOG guidelines enabled more pre-delivery diagnoses, graded maternal-risk assessment, and targeting of HDP terminating in maternal death., Interpretation: Bolivia diagnoses agreed with ACOG guidelines concerning end-stage disease (eclampsia) but not the other HDP due mainly to ACOG's recognition of a broader range of severe features. ACOG guidelines can aid in identifying pregnancies at greatest risk in LMICs, where most maternal and perinatal deaths occur., Funding: NIH TW010797, HD088590, HL138181, UL1 TR002535., Competing Interests: Declaration of interests The corresponding and all other authors of this manuscript declare no conflicts of interest.

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. We aimed to evaluate the association of altitude, preeclampsia, and uterine artery flow or vascular resistance with PAPP-A2 levels. PAPP-A2, uterine artery diameter, volumetric blood flow, and pulsatility indices were measured longitudinally in normotensive Andean women residing at low or high altitudes in Bolivia and in a separate Andean high-altitude cohort with or without preeclampsia. PAPP-A2 levels increased with advancing gestation, with the rise tending to be greater at high compared to low altitude, and higher in early-onset preeclamptic compared to normotensive women at high altitude. Uterine artery blood flow was markedly lower and pulsatility index higher in early-onset preeclamptic normotensive women compared to normotensive women. PAPP-A2 was unrelated to uterine artery pulsatility index in normotensive women but positively correlated in the early-onset preeclampsia cases. We concluded that PAPP-A2 is elevated at high altitude and especially in cases of early-onset preeclampsia with Doppler indices of uteroplacental ischemia.

The goals of the United Nation's Millennium Summit for reducing maternal mortality have proven difficult to achieve. In Bolivia, where maternal mortality is twice the South American average, improving the diagnosis, treatment and ultimately prevention of preeclampsia is key for achieving targeted reductions. We held a workshop in La Paz, Bolivia to review recent revisions in the diagnosis and treatment of preeclampsia, barriers for their implementation, and means for overcoming them. While physicians are generally aware of current recommendations, substantial barriers exist for their implementation due to geographic factors increasing disease prevalence and limiting health-care access, cultural and economic factors affecting the care provided, and infrastructure deficits impeding diagnosis and treatment. Means for overcoming such barriers include changes in the culture of health care, use of standardized diagnostic protocols, the adoption of low-cost technologies for improving the diagnosis and referral of preeclamptic cases to specialized treatment centers, training programs to foster multidisciplinary team approaches, and efforts to enhance local research capacity. While challenging, the synergistic nature of current barriers for preeclampsia diagnosis and treatment also affords opportunities for making far-reaching improvements in maternal, infant and lifelong health., (Copyright © 2019 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

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 = 125) or hypertensive (preeclampsia (PE) or gestational hypertension (GH), n = 29) Andean residents of very high (4100-4300 m) or low altitude (400 m, n = 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., (© 2015 The Author(s) Published by the Royal Society. All rights reserved.)

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.

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.