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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)- vs. low (

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

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.

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 (2,500 m) with appropriate for gestational age pregnancies but not in IUGR pregnancies at any 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.

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.

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-N G -nitroarginine methyl ester decreased both acetylcholine and bradykinin vasodilation by 56% and 33%, respectively. L-N G -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-N G -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.

Background In prenatal diagnosis, a thickened nuchal translucency (NT) is one of the most sensitive and specific markers for several defects but it may also be found in 5% of healthy fetuses. The pathophysiological causes that lead to an increase in NT are not yet fully understood. Metabolomics represents a new promising approach, useful for studying different metabolites in biological organisms in response to environmental stressors. The aim of our study was to investigate the metabolomic profile of the amniotic fluid samples (AFS) of euploid fetuses with enlarged nuchal translucency (ENT) compared to a control group (C group). Methods This study was carried out on a group of women who underwent second-trimester amniocentesis for advanced maternal age (C group) or for NT ≥95th percentile (ENT group) found during first-trimester aneuploidy screening. AFS were analyzed with proton nuclear magnetic resonance (1H-NMR) and high-performance liquid chromatography (HPLC), and subsequent multivariate and univariate statistical analyses were conducted, followed by pathway analysis. Results In total, 67 AFS from the C group and 23 from the ENT group were analyzed. Partial least square discriminate analysis was carried out (R2X=0.784, R2Y=0.658, Q2=0.622, P Conclusion Metabolomic studies enable the identification of metabolic alterations occurring in fetuses with ENT. These findings may provide a new basis for better understanding the pathophysiological mechanisms in this prenatal phenomenon.

The objective of the study is to evaluate low-dose aspirin (LDA) for pre-eclampsia prevention in twin gestations with elevated maternal serum human chorionic gonadotropin (hCG).Secondary analysis of the Maternal-Fetal Medicine Units High-Risk Aspirin trial for pre-eclampsia prevention. A threshold hCG level for predicting pre-eclampsia was identified in placebo-randomized patients. Pre-eclampsia incidence and time of onset were compared between treatment groups, overall and by hCG threshold category.Pre-eclampsia incidence was lower with LDA than with placebo (6% vs 16%, OR 0.32, 95% CI 0.12 to 0.82). An hCG threshold of 29.96 IU ml(-1) best predicted pre-eclampsia. In patients with hCG29.96 IU ml(-1), the differences in pre-eclampsia incidence or time of onset were not significant. In patients with hCG29.96 IU ml(-1), LDA was associated with lower pre-eclampsia incidence than placebo (6% vs 23%, OR 0.21, 95% CI 0.06 to 0.79) and delayed onset.Twin gestations with elevated hCG levels may benefit from LDA for pre-eclampsia prevention.

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.

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). 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.

To compare congenital pulmonary airway malformation (CPAM) volume to head circumference ratios (CVRs) determined by different imaging modalities and calculation techniques.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.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.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.

This study compared the vasodilatory responses to magnesium sulfate (MgSO4) of cerebral and mesenteric resistance arteries and determined whether the responses varied between different gestational groups. Third-order branches (4 (1.2 mM) HEPES buffer solution with increasing concentrations of MgSO4 (4, 6, 8, 16, and 32 mM) and measuring lumen diameter at each concentration. All groups exhibited concentration-dependent dilation to MgSO4, decreasing the amount of tone in the vessels. However, MA were significantly more sensitive to MgSO4 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 MgSO4. The percent dilation at 32 mM MgSO4 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 MgSO4 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 MgSO4-induced vasodilation suggests that the prophylactic effect of MgSO4 on eclamptic seizures may be more closely related to the lowering of systemic blood pressure than to an effect on cerebral blood flow.

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder. Ultrasound (US) findings can include enlarged echogenic kidneys in utero and cysts in multiple organs in adults. Though a highly penetrant disease, due to varied clinical expression and the typical late onset of symptoms, reproductive-aged women may not know their carrier status. We present two cases in which fetal US findings suggested ADPKD and additional evaluation identified likely maternal ADPKD as well.

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.

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 (P0.05). Magnesium attenuated BBB permeability to EB during acute hypertension by 41% in the posterior cerebrum (P0.05) but had no effect in the anterior cerebrum (P0.05). 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.

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 P