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. We hypothesized that, in pregnancies with normal fetal growth at high altitude, K+ channel-dependent vasodilatation of myometrial arteries is increased compared to those from healthy pregnant women at a lower altitude (∼1700 m). Using pharmacological modulation of two K+ channels, ATP-sensitive (KATP ) and large-conductance Ca2+ -activated (BKCa ) K+ channels, we assessed the vasodilatation of myometrial arteries from appropriate for gestational age (AGA) pregnancies in women living at high or low altitudes. In addition, we evaluated the localization of these channels in the myometrial arteries using immunofluorescence. Our results showed an endothelium-dependent increase in KATP -dependent vasodilatation in myometrial arteries from high versus low altitude, whereas vasodilatation induced by BKCa activation was reduced in these vessels. Additionally, KATP channel co-localization with endothelial markers was reduced in the high-altitude myometrial arteries, which suggested that the functional increase in KATP activity may be by mechanisms other than regulation of channel localization. These observations highlight an important contribution of K+ channels to the human uterine vascular adaptation to pregnancy at high altitude serving to maintain normal fetal growth under conditions of chronic hypoxia. KEY POINTS: High-altitude (>2500 m or 8200 ft) residence reduces uterine blood flow during pregnancy and fetal growth. Animal models of high altitude/chronic hypoxia suggest that these reductions are partially due to reduced vascular K+. channel responses, such as those elicited by large conductance Ca2+ -activated (BKCa ) and ATP-sensitive (KATP ) K+ channel activation. We found that women residing at high versus low altitude during pregnancy showed diminished myometrial artery vasodilatory responses to endothelium-independent BKCa channel activation but greater responses to endothelium-dependent KATP channel activation. Our observations indicate that KATP channels play an adaptive role in maintaining myometrial artery vasodilator sensitivity under chronic hypoxic conditions during pregnancy. Thus, KATP channels represent potential therapeutic targets for augmenting uteroplacental blood flow and, in turn, preserving fetal growth in cases of uteroplacental hypoperfusion.

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. 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.

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 Hemolysis, Elevated Liver enzymes, and Low Platelets (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. We also compared blood-pressure changes longitudinally during pregnancy and the frequency of HDP in 454 high (>2500 m)- vs. low (<1700 m)-altitude Colorado residents delivering in 2013 and 2014, and matched for maternal risk factors. Data were compared between altitudes using t-tests or chi-square, and by multiple or logistic regression analyses to adjust for risk factors and predict specific hypertensive or neonatal complications. RESULTS: Statewide, high-altitude residence increased the frequency of each HDP disorder separately or all combined by 33%. High-altitude women studied longitudinally also had more HDP accompanied by higher blood pressures throughout pregnancy. The frequency of low birth weight infants (<2500 g), 5-min Apgar scores <7, and NICU admissions were also greater at high than low altitudes statewide, with the latter being accounted for by the increased incidence of HDP. CONCLUSIONS: Residence at high altitude constitutes a risk factor for HDP and recommends increased clinical surveillance. The increased incidence also makes high altitude a natural laboratory for evaluating the efficacy of predictive biomarkers or new therapies for HDP.

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. METHODS: We measured gene expression and protein levels of AMPK and its upstream regulators and downstream targets in human placentas from high (>2500 m) vs. moderate (~1700 m) and low (~100 m) altitude. RESULTS: We found that phosphorylated AMPK protein levels and its downstream target TSC2 were increased in placentas from high and moderate vs. low altitude, whereas the phosphorylated form of the downstream target translation repressor protein 4E-BP1 was increased in high compared to moderate as well as low altitude placentas. Mean birth weights progressively fell with increasing altitude but no infants, by study design, were clinically growth-restricted. Gene expression analysis showed moderate increases in PRKAG2, encoding the AMPK γ2 subunit, and mechanistic target of rapamycin, MTOR, expression. DISCUSSION: These results highlight a differential regulation of placental AMPK pathway activation in women residing at low, moderate or high altitude during pregnancy, suggesting AMPK may be serving as a metabolic regulator for integrating hypoxic stimuli with placental function.

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. Here we hypothesized that AMPK-dependent vasodilation was increased in MAs from high versus low-altitude (<1,700 m) Colorado women with appropriate for gestational age (AGA) pregnancies and reduced in IUGR pregnancies regardless of altitude. Vasoreactivity studies showed that, in AGA pregnancies, MAs from high-altitude women were more sensitive to vasodilation by activation of AMPK with A769662 due chiefly to increased endothelial nitric oxide production, whereas MA responses to AMPK activation in the low-altitude women were endothelium independent. MAs from IUGR compared with AGA pregnancies had blunted vasodilator responses to acetylcholine at high altitude. We concluded that 1) blunted vasodilator responses in IUGR pregnancies confirm the importance of MA vasodilation for normal fetal growth and 2) the increased sensitivity to AMPK activation in AGA pregnancies at high altitude suggests that AMPK activation helped maintain MA vasodilation and fetal growth. These results highlight a novel mechanism for vasodilation of MAs under conditions of chronic hypoxia and suggest that AMPK activation could provide a therapy for increasing uteroplacental blood flow and improving fetal growth in IUGR pregnancies.NEW & NOTEWORTHY Intrauterine growth restriction (IUGR) impairs infant well- being and increases susceptibility to later-in-life diseases for mother and child. Our study reveals a novel role for AMPK in vasodilating the myometrial artery (MA) from women residing at high altitude (>2,500 m) with appropriate for gestational age pregnancies but not in IUGR pregnancies at any altitude.

High Altitude Reduces NO-Dependent Myometrial Artery Vasodilator Response During Pregnancy.

The chronic hypoxia of high-altitude (HA) residence reduces uterine artery blood flow during pregnancy, likely contributing to an increased frequency of preeclampsia and intrauterine growth restriction. We hypothesized that this lesser pregnancy blood flow rise was due, in part, to reduced vasodilation of myometrial arteries (MAs). Here, we assessed MA vasoreactivity in healthy residents of high (2902±39 m) or low altitude (LA; 1669±10 m). MA contractile responses to potassium chloride, phenylephrine, or the thromboxane A2 agonist U46619 did not differ between LA and HA women. Acetylcholine vasodilated phenylephrine or U466119 preconstricted MAs at LA, yet had no effect on HA MAs. In contrast, another vasodilator, bradykinin, relaxed MAs from both altitudes similarly. At LA, the NO synthase inhibitor L-NG-nitroarginine methyl ester decreased both acetylcholine and bradykinin vasodilation by 56% and 33%, respectively. L-NG-nitroarginine methyl ester plus the COX (cyclooxygenase) inhibitor indomethacin had similar effects on acetylcholine and bradykinin vasodilation (68% and 42% reduction, respectively) as did removing the endothelium (78% and 50% decrease, respectively), suggesting a predominantly NO-dependent vasodilation at LA. However, at HA, L-NG-nitroarginine methyl ester did not change bradykinin vasodilation, whereas indomethacin or endothelium removal decreased it by 28% and 72%, respectively, indicating impaired NO signaling at HA. Suggesting that the impairment was downstream of eNOS (endothelial NO synthase), HA attenuated the vasodilation elicited by the NO donor sodium nitroprusside. We concluded that reduced NO-dependent MA vasodilation likely contributes to diminished uteroplacental perfusion in HA pregnancies.

Gestational Diabetes Prevalence at Moderate and High Altitude.

BACKGROUND: High-altitude (HA) pregnancies have been associated with decreased glucose levels and increased insulin sensitivity versus sea level. Our objective was to determine if the prevalence of gestational diabetes mellitus (GDM) and the impact of demographic characteristics on GDM diagnosis differed at moderate altitude (MA) versus HA. METHODS: Using a retrospective cohort design, we compared women living at HA (>8250 ft) and MA (4000-7000 ft) during pregnancy. Exclusion criteria were as follows: multiple gestation, preexisting diabetes, unavailable GDM results, or relocation from a different altitude during pregnancy. GDM diagnosis was determined using Carpenter and Coustan criteria. Data were compared by t-test (continuous variables) or chi-squared tests (categorical variables). Univariate, multivariate, and stepwise regression models were used to assess the impact of various factors on GDM prevalence. RESULTS: There was no difference in GDM prevalence between altitudes in these populations; the relationship between altitude and GDM was nonsignificant in all regression analyses. At MA, maternal age, Hispanic ethnicity, body mass index (BMI), and gestational age (GA) at testing increased GDM incidence in univariate analyses. At HA, maternal age, Hispanic ethnicity, and multiparity increased GDM incidence in univariate analyses. CONCLUSION: While GDM prevalence did not differ between MA and HA, the impact of maternal demographic characteristics on GDM risk varied by altitude group. Higher BMI and greater GA at testing increased the incidence of GDM at MA, but not at HA. Multiparity had an effect at HA, but not MA. These differences may represent subtle differences in glucose metabolism at HA.

Gottesfeld-Hohler Memorial Foundation Zika Virus Think Tank Summary.

At a think tank bringing together experts on fetal neuroimaging, obstetric infectious diseases, and public health, we discussed trends in all of these areas for Zika virus. There is a wide variety of imaging findings in affected fetuses, influenced by timing of infection and probably host factors. The resources for diagnosis and interventions also vary by location with the hardest hit areas often having the fewest resources. We identified potential areas for both research and clinical collaboration as the Zika virus epidemic continues to evolve.

Comparison of congenital pulmonary airway malformation volume ratios calculated by ultrasound and magnetic resonance imaging.

OBJECTIVE: To compare congenital pulmonary airway malformation (CPAM) volume to head circumference ratios (CVRs) determined by different imaging modalities and calculation techniques. METHODS: Fetal thoracic lesion images by ultrasound (US) and magnetic resonance imaging (MRI) were retrospectively reviewed and the CVRs were calculated. The CVR(US) was determined by the standard method. The CVR(MRI) was calculated from T2-weighted sequences (HASTE/SSH-TSE) in two ways, dimensional measurements analogous to US technique (MRI-D) and by using a MRI-software calculated volume (MRI-V). CVR values between methods were compared using Wilcoxon matched-pairs signed-rank testing, Bland-Altman analyses, and Spearman correlations. RESULTS: Appropriate images were available to compare CVR(US) to CVR(MRI-D) for 20 patients and CVR(US) to CVR(MRI-V) for 18 patients. There were no significant differences in CVR values between modalities. By Bland-Altman analyses, the CVR measurements were largely within the limits of agreement: 18 of 20 for CVR(MRI-D) and 17 of 18 for CVR(MRI-V), with a slight bias towards larger measurements by MRI. CONCLUSIONS: Though values varied between modalities for individual patients, there was no systematic difference in CVRs determined by US or MRI. Fetal prognostic category for CPAMs did not change based on MRI in any patient in this series.

Preeclampsia in high risk women is characterized by risk group-specific abnormalities in serum biomarkers.

OBJECTIVE: To determine if early pregnancy serum biomarkers in high-risk women who develop preeclampsia vary according to risk factor. STUDY DESIGN: We performed a secondary analysis of the Maternal-Fetal Medicine Units Network randomized controlled trial of low-dose aspirin for the prevention of preeclampsia in high-risk women. Serum biomarker levels at enrollment (before initiation of aspirin or placebo) were compared between women who did and did not develop preeclampsia, both for the group as a whole and within each of 4 high-risk groups (insulin-dependent diabetes, hypertension, multiple gestation, and previous preeclampsia) using a regression model adjusting for gestational age at collection and prepregnancy body mass index. RESULTS: 1258 women were included (233 with insulin-dependent diabetes, 387 with chronic hypertension, 315 with a multiple gestation, 323 with previous preeclampsia). Multiple early pregnancy serum biomarkers differed between women who did and did not develop preeclampsia. Each high-risk group had a unique and largely nonoverlapping pattern of biomarker abnormality. Differences between those who did and did not develop preeclampsia were noted in vascular cell adhesion molecule in the diabetes group; human chorionic gonadotropin, soluble tumor necrosis factor receptor-2, tumor necrosis factor-alpha, selectin and angiogenin in the chronic hypertension group; interleukin-6, placental growth factor, soluble fms-like tyrosine kinase plus endoglin to placental growth factor ratio in the multiple gestation group; and angiogenin in the previous preeclampsia group. CONCLUSION: Patterns of serum biomarkers vary by high-risk group. These data support the hypothesis that multiple pathogenic pathways lead to the disease recognized clinically as preeclampsia.

Flash pulmonary edema during cesarean section in a woman with preeclampsia.

BACKGROUND: Pulmonary edema may complicate preeclampsia. We report intraoperative flash pulmonary edema in a preeclamptic woman with Rendu-Osler-Weber syndrome. CASE: The patient was admitted at 33(+6) weeks gestation with preeclampsia. After rapid sequence induction and endotracheal intubation for cesarean section, flash pulmonary edema developed without evidence of cardiac dysfunction. She was mechanically ventilated and treated with furosemide. Following brisk diuresis she was extubated the next day and discharged on postoperative day 9 in good clinical condition. CONCLUSION: Endotracheal intubation for general anesthesia can cause acutely increased blood pressure, which, with concomitant low oncotic pressure, we believe contributed to intraoperative flash pulmonary edema. We present this case to raise awareness of this complication when general anesthesia is used for cesarean section in preeclampsia.

Magnesium sulfate for the treatment of eclampsia: a brief review.

BACKGROUND AND PURPOSE: Magnesium sulfate is used extensively for prevention of eclamptic seizures. Empirical and clinical evidence supports the effectiveness of magnesium sulfate; however, questions remain as to its safety and mechanism. This review summarizes current evidence supporting the possible mechanisms of action and several controversies for magnesium sulfate treatment. SUMMARY OF REVIEW: Several mechanisms are presented, including the effects of magnesium sulfate on peripheral and cerebral vasodilation, blood-brain barrier protection, and as an anticonvulsant. CONCLUSIONS: Though the specific mechanisms of action remain unclear, the effect of magnesium sulfate in the prevention of eclampsia is likely multi-factorial. Magnesium sulfate may act as a vasodilator, with actions in the peripheral vasculature or the cerebrovasculature, to decrease peripheral vascular resistance or relieve vasoconstriction. Additionally, magnesium sulfate may also protect the blood-brain barrier and limit cerebral edema formation, or it may act through a central anticonvulsant action.

Magnesium sulphate treatment decreases blood-brain barrier permeability during acute hypertension in pregnant rats.

Eclampsia is associated with increased blood-brain barrier (BBB) permeability and formation of cerebral oedema. Magnesium sulphate is used to treat eclampsia despite an unclear mechanism of action. This study was to determine the effect of magnesium sulphate on in vivo BBB permeability and formation of cerebral oedema during acute hypertension and on brain aquaporin-4 (AQP4) protein expression. An in vivo model of hypertensive encephalopathy was used in late-pregnant (LP) rats following magnesium sulphate treatment, 270 mg kg(-1) i.p. injection every 4 h for 24 h. Permeability of the BBB was determined by in situ brain perfusion of Evan's Blue (EB) and sodium fluorescein (NaFl), and dye clearance determined by fluorescence spectrophotometry. Cerebral oedema was determined following acute hypertension by measuring brain water content. The effect of magnesium treatment on AQP4 expression was determined by Western blot analysis. Acute hypertension with autoregulatory breakthrough increased BBB permeability to EB in both brain regions studied (P < 0.05). Magnesium attenuated BBB permeability to EB during acute hypertension by 41% in the posterior cerebrum (P < 0.05) but had no effect in the anterior cerebrum (P > 0.05). Treatment with magnesium did not change NaFl permeability, cerebral oedema formation or AQP4 expression. In summary, BBB permeability to Evan's Blue was increased by acute hypertension in LP rats, and this was attenuated by treatment with magnesium sulphate. The greatest effect on BBB permeability to EB was in the posterior cerebrum, an area particularly susceptible to oedema formation during eclampsia.

Cerebral blood flow autoregulation and edema formation during pregnancy in anesthetized rats.

Eclampsia is considered a form of hypertensive encephalopathy in which an acute elevation in blood pressure causes autoregulatory breakthrough, blood-brain barrier disruption, and edema formation. We hypothesized that pregnancy predisposes the brain to eclampsia by lowering the pressure of autoregulatory breakthrough and enhancing cerebral edema formation. Because NO production is increased in pregnancy, we also investigated the role of NO in modulating autoregulation. Cerebral blood flow autoregulation was determined by phenylephrine infusion and laser Doppler flowmetry. Four groups were studied: untreated nonpregnant (n=7) and late-pregnant (days 19 to 21; n=8) Sprague-Dawley rats and nonpregnant (n=8) and late-pregnant (n=8) animals treated with an NO synthase inhibitor (N(G)-nitro-l-arginine methyl ester; 0.5 to 0.7 g/L). Brain water content and blood-brain barrier permeability to sodium fluorescein were determined after breakthrough. Pregnancy caused no change in autoregulation or the pressure of breakthrough. However, treatment with the NO synthase inhibitor significantly increased the pressure of autoregulatory breakthrough (nonpregnant: 183.6+/-3.0 mm Hg versus 212.0+/-2.8 mm Hg, P<0.05; late-pregnant: 180.8+/-3.2 mm Hg versus 209.3+/-4.7 mm Hg, P<0.05). After autoregulatory breakthrough, only late-pregnant animals showed a significant increase in cerebral edema formation, which was attenuated by NO synthase inhibition. There was no difference in blood-brain barrier permeability between nonpregnant and late-pregnant animals in response to acute hypertension, suggesting that pregnancy may predispose the brain to eclampsia by increasing cerebral edema through increased hydraulic conductivity.

Resistance artery vasodilation to magnesium sulfate during pregnancy and the postpartum state.

This study compared the vasodilatory responses to magnesium sulfate (MgSO(4)) of cerebral and mesenteric resistance arteries and determined whether the responses varied between different gestational groups. Third-order branches (<200 microm) of the posterior cerebral (PCA) and mesenteric arteries (MA) were dissected from nonpregnant (NP; n = 6), late pregnant (LP; day 19, n = 6), and postpartum (PP; day 3, n = 6) Sprague-Dawley rats. A concentration-response curve was performed by replacing the low-MgSO(4) (1.2 mM) HEPES buffer solution with increasing concentrations of MgSO(4) (4, 6, 8, 16, and 32 mM) and measuring lumen diameter at each concentration. All groups exhibited concentration-dependent dilation to MgSO(4), decreasing the amount of tone in the vessels. However, MA were significantly more sensitive to MgSO(4) than PCA. Whereas there was no difference in the response between different gestational groups in MA, the PCA from the LP and PP groups showed a significantly diminished response to MgSO(4). The percent dilation at 32 mM MgSO(4) for PCA versus MA in NP, LP, and PP animals was 36 +/- 2 vs. 51 +/- 7% (P < 0.05), 19 +/- 9 vs. 54 +/- 6% (P < 0.01 vs. PCA and NP), and 12 +/- 5 vs. 52 +/- 11% (P < 0.01 vs. PCA and NP). These results demonstrate that MgSO(4) is a vasodilator of small resistance arteries in the cerebral and mesenteric vascular beds. The refractory responses of the PCA in LP and PP groups demonstrate changes in the cerebrovascular vasodilatory mechanisms with gestation. The greater sensitivity of the MA to MgSO(4)-induced vasodilation suggests that the prophylactic effect of MgSO(4) on eclamptic seizures may be more closely related to the lowering of systemic blood pressure than to an effect on cerebral blood flow.