Increased salt sensitivity of ambulatory blood pressure in women with a history of severe preeclampsia.

Cardiovascular diseases are the principal cause of death in women in developed countries and are importantly promoted by hypertension. The salt sensitivity of blood pressure (BP) is considered as an important cardiovascular risk factor at any BP level. Preeclampsia is a hypertensive disorder of pregnancy that arises as a risk factor for cardiovascular diseases. This study measured the salt sensitivity of BP in women with a severe preeclampsia compared with women with no pregnancy hypertensive complications. Forty premenopausal women were recruited 10 years after delivery in a case-control study. Salt sensitivity was defined as an increase of >4 mm Hg in 24-hour ambulatory BP on a high-sodium diet. The ambulatory BP response to salt was significantly increased in women with a history of preeclampsia compared with that of controls. The mean (95% confidence interval) daytime systolic/diastolic BP increased significantly from 115 (109-118)/79 (76-82) mm Hg on low-salt diet to 123 (116-130)/80 (76-84) on a high-salt diet in women with preeclampsia, but not in the control group (from 111 [104-119]/77 [72-82] to 111 [106-116]/75 [72-79], respectively, P<0.05). The sodium sensitivity index (SSI=Δmean arterial pressure/Δurinary Na excretion×1000) was 51.2 (19.1-66.2) in women with preeclampsia and 6.6 (5.8-18.1) mm Hg/mol per day in controls (P=0.015). The nocturnal dip was blunted on a high-salt diet in women with preeclampsia. Our study shows that women who have developed preeclampsia are salt sensitive before their menopause, a finding that may contribute to their increased cardiovascular risk. Women with a history of severe preeclampsia should be targeted at an early stage for preventive measures of cardiovascular diseases.

Polymorphisms in endothelial nitric oxide synthase gene in early and late severe preeclampsia

Preeclampsia (PE) is characterized by hypertension and proteinuria, occurring after the 20th week of pregnancy in women who have had no previous symptoms. The disease progresses with generalized vasoconstriction and endothelial dysfunction. Clinically, it is important to diagnose the severe form of the disease (sPE), in which blood pressure and proteinuria are much higher. Recently, the gestational age (GA) of the onset of PE has led to the classification of this disease as early (GA <34 weeks) and late (GA >= 34 weeks). Several genetic polymorphisms affecting endothelial nitric oxide synthase (eNOS) levels or function were described, including G894T (Glu298Asp), VNTR b/a (variable-number 27-bp tandem repeat) and T-786C (promoter) polymorphisms. Thus, the aim of this study was to compare the distribution of G894T, VNTR b/a and T-786C polymorphisms and their haplotypes in Brazilian early and late sPE, as well as in normotensive pregnant. A total of 201 women were evaluated, 53 with early sPE, 45 with late sPE and 103 as normotensive pregnant women. The frequency of 894T allele was higher in late sPE vs normotensive pregnant, and 894TT genotype was higher in late sPE vs early sPE and normotensive pregnant. For VNTR b/a polymorphism, higher frequencies of aa genotype and a allele were observed in early sPE vs late sPE and normotensive pregnant. Besides, the frequency of haplotype T-b-C was higher in late sPE vs early sPE and normotensive pregnant. Considering the results found for eNOS polymorphisms, it is possible to suggest that the functional alterations induced by these two polymorphisms may influence the time of severe PE onset, although both alterations are putatively associated with low NO bioavailability. However, other studies are necessary to validate these findings and clarify this issue. (C) 2014 Elsevier Inc. All rights reserved.

HELLP Syndrome a Severe Form of Preeclampsia: a Comparative Study of Clinical and Laboratorial Parameters

The objective of this study was to compare clinical, laboratorial, maternal and perinatal results between HELLP Syndrome and severe Preeclampsia. An observational study comparing women with HELLP Syndrome (n=71) to women with severe preeclampsia (n=253) was done. The authors analyzed the early course of the pathologies and the outcomes in both groups. HELLP syndrome occurred in 28% of all the cases and was more frequent at gestational age before 32 weeks (n=39 – 55%) than severe preeclampsia (n=108 - 42%), with more newborns weighting less than 1500g (27 – 38.6% vs 65 – 25.6%; p=0.036). Thrombocytopenia below 100 000/μL (aOR, 2.14; 95% CI, 1.49 – 3.06) and LDH>1 000 UI/L (aOR: 5.17; 95% CI 2.19 – 12.16) were risk factors for HELLP. Maternal morbidity (eclampsia, abruptio placentae, and acute renal failure) was similar in both cohorts; eight stillbirths (6 in severe preeclampsia and 2 in HELLP Syndrome) occurred. There were no maternal deaths. In conclusion, in this study the authors confirmed that HELLP Syndrome is a severe form of preeclampsia with an earlier presentation in pregnancy, worst laboratorial findings and more prematurity rates.

CHANGES IN FETAL AND MATERNAL DOPPLER PARAMETERS OBSERVED DURING ACUTE SEVERE HYPERTENSION TREATMENT WITH HYDRALAZINE OR LABETALOL: A RANDOMIZED CONTROLLED TRIAL

We evaluated 16 pregnant women with gestational age between 20 and 32 weeks in acute severe hypertension which were randomly allocated to receive either hydralazine or labetalol. Blood pressure and Doppler ultrasound parameters from maternal uterine and fetal middle cerebral and umbilical arteries were assessed during acute severe hypertension and after treatment. A significant reduction in systolic and diastolic blood pressure was observed in both groups. A significant change in Doppler parameters was observed only in pregnant women who received hydralazine: an increase in uterine arteries resistance index. We concluded that both drugs were highly effective in reducing blood pressure in these women. Despite the observed increase in resistance index of uterine arteries associated with hydralazine, the use of hydralazine and labetalol were not related to any significant changes in fetal Doppler, which is reassuring about the safety of these drugs when treating acute severe hypertension in pregnancy. (E-mail: wpmartins@gmail.com) (C) 2011 World Federation for Ultrasound in Medicine & Biology.

Markers of insulin resistance and sedentary lifestyle are predictors of preeclampsia in women with adverse obstetric results

Some thrombophilias and severe preeclampsia may increase the risk for preterm deliveries and fetal death due to placental insufficiency. Our objective was to evaluate clinical and laboratory data as predictors of preeclampsia in a population of mothers with 3rd trimester fetal losses or preterm deliveries. In a longitudinal retrospective study, 54 consecutive women (age range: 16 to 39 years) with normotensive pregnancies were compared to 79 consecutive women with preeclampsia (age range: 16 to 43 years). Weight accrual rate (WAR) was arbitrarily defined as weight gain from age 18 years to the beginning of pregnancy divided by elapsed years. Independent predictors of preeclampsia were past history of oligomenorrhea, WAR >0.8 kg/years, pre-pregnancy or 1st trimester triglyceridemia >150 mg/dL, and elevated acanthosis nigricans in the neck. In a multivariate logistic regression model, two or more predictors conferred an odds ratio of 15 (95%CI [5.9-37]; P < 0.001) to develop preeclampsia (85% specificity, 73% sensitivity, c-statistic of 81 ± 4%; P < 0.0001). Clinical markers related to insulin resistance and sedentary lifestyles are strong independent predictors of preeclampsia in mothers with 3rd trimester fetal losses or preterm deliveries due to placental insufficiency. Women at risk for preeclampsia in this particular population might benefit from measures focused on overcoming insulin resistance.

Complicaciones de la preeclampsia severa y su relación con variables demográficas y obstétricas

Introducción: La preeclampsia severa es una de las principales patologías que afectan a las mujeres embarazadas, sus complicaciones tienen un alto impacto en la salud del binomio madre-hijo. Materiales y métodos: Se realizo una serie de casos, durante un periodo de 1 año se revisaron las historias clínicas de las pacientes que ingresaron a la unidad de cuidado intensivo obstétrico de la Clínica Orquídeas, con diagnóstico de preeclampsia severa. Se describieron los datos demográficos y las complicaciones. Se realizó análisis univariado con las variables de interés y se calcularon diferencias significativas por medio del test exacto de Fisher. Resultados: Se registraron 196 pacientes con preeclampsia severa en el periodo de estudio. Las complicaciones mas frecuentes fueron síndrome HELLP (30,6%), insuficiencia renal aguda (16,3%) y edema pulmonar (10,2%); el ingreso de las pacientes con preeclampsia severa a la UCIO en embarazo aumenta el riesgo de sufrir complicaciones. El síndrome de HELLP se presento con mayor frecuencia en pacientes que realizaron 6 o mas controles prenatales (p=0.066). Discusión: Los resultados evidencian una prevalencia de preeclampsia severa mayor que la observada por otros autores, probablemente por ser una UCI exclusivamente obstétrica. Las complicaciones mas frecuentes son concordantes con otros estudios publicados. El mayor riesgo de complicaciones asociadas en pacientes que ingresan embarazadas a la UCIO podría estar en relación a la severidad de la patología. Se requieren estudios analíticos para establecer asociaciones entre cada una de las complicaciones y sus factores condicionantes.

Desenlaces maternos y fetales en el manejo expectante de la preeclampsia lejos del término

Introducción La preeclampsia hace parte del espectro de los trastornos hipertensivos asociados al embarazo y es causa de alta morbimortalidad materna. La edad gestacional ha sido relacionada con la presentación más severa de esta cuando ocurren lejanas al término. Hoy en día existe la posibilidad de proporcionar manejo expectante en estos casos en unidades de cuidado obstétrico especializadas, con el fin de disminuir el riesgo de morbimortalidad asociada a la prematurez extrema. Metodología Se realizó un estudio de corte transversal que incluyó pacientes con preeclampsia lejos del término entre las 24 y 34 semanas que recibieron manejo expectante entre 2009 y 2012 en la Unidad de Cuidado Intensivo Obstétrico de la Clínica Colsubsidio Orquídeas. Resultados Se incluyeron 121 pacientes con preeclampsia lejos del término, quienes recibieron manejo expectante. La edad promedio fue 29.8, el promedio de días de manejo expectante fue 4 días, con una mediana de tres días. La edad gestacional de ingreso fue 30 1/7 semanas y la edad promedio de terminación 30 5/7 semanas. El 88.4% recibieron esquema de maduración completo. El 81.6% presentaron preeclampsia severa. El desenlace materno más frecuente fue Síndrome Hellp (37%) y el desenlace fetal fue restricción de crecimiento intrauterino (29%). Discusión Se debe considerar el manejo expectante en toda paciente con preeclampsia previa a la semana 34 para manejo antenatal con corticoesteroides, el cual demostró ser un factor protector para muerte perinatal temprana. No se encontraron diferencias significativas entre la aparición de complicaciones y la cantidad de días de manejo expectante.

Antioxidant therapy to prevent preeclampsia - A Randomized controlled trial

OBJECTIVE: To study whether antioxidant supplementation will reduce the incidence of preeclampsia among patients at increased risk.METHODS: A randomized, placebo-controlled, double-blind clinical trial was conducted at four Brazilian sites. Women between 12 0/7 weeks and 19 6/7 weeks of gestation and diagnosed to have chronic hypertension or a prior history of preeclampsia were randomly assigned to daily treatment with both vitamin C (1,000 mg) and vitamin E (400 International Units) or placebo. Analyses were adjusted for clinical site and risk group (prior preeclampsia, chronic hypertension, or both). A sample size of 734 would provide 80% power to detect a 40% reduction in the risk of preeclampsia, assuming a placebo group rate of 21% and alpha=.05. The a level for the final analysis, adjusted for interim looks, was 0.0458.RESULTS: Outcome data for 707 of 739 randomly assigned patients revealed no significant reduction in the rate of preeclampsia (study drug, 13.8% [49 of 355] compared with placebo, 15.6% [55 of 352], adjusted risk ratio 0.87 [95.42% confidence interval 0.61-1.25]). There were no differences in mean gestational age at delivery or rates of perinatal mortality, abruptio placentae, pre-term delivery, and small for gestational age or low birth weight infants. Among patients without chronic hypertension, there was a slightly higher rate of severe preeclampsia in the study group (study drug, 6.5% [11 of 170] compared with placebo, 2.4% [4 of 168], exact P=.11, odds ratio 2.78, 95% confidence interval 0.79-12.62).CONCLUSION: This trial failed to demonstrate a benefit of antioxidant supplementation in reducing the rate of preeclampsia among'patients with chronic hypertension and/or prior preeclampsia.

PP080. First trimester umbilical artery end-diastolic flow and pulsatility index: Comparison between preeclampsia and control.

INTRODUCTION The appearance of end-diastolic flow velocities (EDF) in the umbilical artery (UA), usually between 10 and 14 weeks of gestation, has been associated with the opening of the spiral arteries and consequently of the intervillous space. OBJECTIVES The aim of our study was to compare first trimester UA pulsatility index (PI) and EDF between women who developed preeclampsia (cases) and controls. METHODS Our database was searched for cases who had UA Doppler between 10-14 weeks. UA PI and EDF were compared between cases and two gestational age (GA) matched controls. RESULTS 15 cases with severe preeclampsia (PE) were matched to 30 controls. GA with negative EDF was lower than with positive EDF (12.1±0.79 vs. 12.8±0.34; p=0.001). UA PI in cases was higher than in controls, although not significant (cases: 2.18±0.6 vs. CONTROLS 1.92±0.48; p=0.12). However, comparing groups with negative EDF, the difference became significant (PI cases: 2.45±0.57 vs. PI controls: 1.94±0.56; p=0.038), while no difference was found comparing groups with positive EDF. CONCLUSION First trimester UA PI is significantly higher in women which will develop PE than in controls. Interestingly, the timing of screening for PE by UA Doppler seems to play an important issue.

The elevation in circulating anti-angiogenic factors is independent of markers of neutrophil activation in preeclampsia

Background - Severe preeclampsia is associated with increased neutrophil activation and elevated serum soluble endoglin (sEng) and soluble Flt-1 (sFlt-1) in the maternal circulation. To dissect the contribution of systemic inflammation and anti-angiogenic factors in preeclampsia, we investigated the relationships between the circulating markers of neutrophil activation and anti-angiogenic factors in severe preeclampsia or systemic inflammatory state during pregnancy. Methods and results - Serum sEng, sFlt-1, placenta growth factor, interleukin-6 (IL-6), calprotectin, and plasma a-defensins concentrations were measured by ELISA in 88 women of similar gestational age stratified as: severe preeclampsia (sPE, n = 45), maternal systemic inflammatory response (SIR, n = 16) secondary to chorioamnionitis, pyelonephritis or appendicitis; and normotensive controls (CRL, n = 27). Neutrophil activation occurred in sPE and SIR, as a-defensins and calprotectin concentrations were two-fold higher in both groups compared to CRL (P < 0.05 for each). IL-6 concentrations were highest in SIR (P < 0.001), but were higher in sPE than in CRL (P < 0.01). sFlt-1 (P < 0.001) and sEng (P < 0.001) were ˜20-fold higher in sPE compared to CRL, but were not elevated in SIR. In women with sPE, anti-angiogenic factors were not correlated with markers of neutrophil activation (a-defensins, calprotectin) or inflammation (IL-6). Conclusions - Increased systemic inflammation in sPE and SIR does not correlate with increased anti-angiogenic factors, which were specifically elevated in sPE indicating that excessive systemic inflammation is unlikely to be the main contributor to severe preeclampsia.

Therapeutic potential of statins and the induction of heme oxygenase-1 in preeclampsia

Heme oxygenase (Hmox) is an endogenous system that offers protection against placental cytotoxic damage associated with preeclampsia. The Hmox1/carbon monoxide (CO) pathway inhibits soluble Flt-1 (sFlt-1) and soluble Endoglin (sEng). More importantly, statins induce Hmox1 and suppress the release of sFlt-1 and sEng; thus, statins and Hmox1 activators are potential novel therapeutic agents for treating preeclampsia. The contribution of the Hmox system to the pathogenesis of preeclampsia has been further indicated by the incidence of preeclampsia being reduced by a third in smokers, who had reduced levels of circulating sFlt-1. Interestingly, preeclamptic women exhale less CO compared with women with healthy pregnancies. Hmox1 is reduced prior to the increase in sFlt-1 as Hmox1 mRNA expression in the trophoblast is decreased in the first trimester in women who go on to develop preeclampsia. Induction of Hmox1 or exposure to CO or bilirubin has been shown to inhibit the release of sFlt-1 and sEng in animal models of preeclampsia. The functional benefit of statins and Hmox1 induction in women with preeclampsia is valid not only because they inhibit sFlt-1 release, but also because statins and Hmox1 are associated with anti-apoptotic, anti-inflammatory, and anti-oxidant properties. The StAmP trial is the first randomized control trial (RCT) evaluating the use of pravastatin to ameliorate severe preeclampsia. This proof-of-concept study will pave the way for future global RCT, the success of which will greatly contribute to achieving the United Nations Millennium Development Goals (MDG4 and MDG5) and offering an affordable and easily accessible therapy for preeclampsia. © 2014 The Authors.

Antenatal corticosteroids impact the inflammatory rather than the antiangiogenic profile of women with preeclampsia

Circulating antiangiogenic factors and proinflammatory cytokines are implicated in the pathogenesis of preeclampsia. This study was performed to test the hypothesis that steroids modify the balance of inflammatory and proangiogenic and antiangiogenic factors that potentially contribute to the patient’s evolving clinical state. Seventy singleton women, admitted for antenatal corticosteroid treatment, were enrolled prospectively. The study group consisted of 45 hypertensive women: chronic hypertension (n=6), severe preeclampsia (n=32), and superimposed preeclampsia (n=7). Normotensive women with shortened cervix (<2.5 cm) served as controls (n=25). Maternal blood samples of preeclampsia cases were obtained before steroids and then serially up until delivery. A clinical severity score was designed to clinically monitor disease progression. Serum levels of angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF], soluble endoglin [sEng]), endothelin-1 (ET-1), and proinflammatory markers (IL-6, C-reactive protein [CRP]) were assessed before and after steroids. Soluble IL-2 receptor (sIL-2R) and total immunoglobulins (IgG) were measured as markers of T- and B-cell activation, respectively. Steroid treatment coincided with a transient improvement in clinical manifestations of preeclampsia. A significant decrease in IL-6 and CRP was observed although levels of sIL-2R and IgG remained unchanged. Antenatal corticosteroids did not influence the levels of angiogenic factors but ET-1 levels registered a short-lived increase poststeroids. Although a reduction in specific inflammatory mediators in response to antenatal steroids may account for the transient improvement in clinical signs of preeclampsia, inflammation is unlikely to be the major contributor to severe preeclampsia or useful for therapeutic targeting.

Antenatal corticosteroids impact the inflammatory rather than the antiangiogenic profile of women with preeclampsia

Circulating antiangiogenic factors and proinflammatory cytokines are implicated in the pathogenesis of preeclampsia. This study was performed to test the hypothesis that steroids modify the balance of inflammatory and proangiogenic and antiangiogenic factors that potentially contribute to the patient's evolving clinical state. Seventy singleton women, admitted for antenatal corticosteroid treatment, were enrolled prospectively. The study group consisted of 45 hypertensive women: chronic hypertension (n=6), severe preeclampsia (n=32), and superimposed preeclampsia (n=7). Normotensive women with shortened cervix (<2.5 cm) served as controls (n=25). Maternal blood samples of preeclampsia cases were obtained before steroids and then serially up until delivery. A clinical severity score was designed to clinically monitor disease progression. Serum levels of angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF], soluble endoglin [sEng]), endothelin-1 (ET-1), and proinflammatory markers (IL-6, C-reactive protein [CRP]) were assessed before and after steroids. Soluble IL-2 receptor (sIL-2R) and total immunoglobulins (IgG) were measured as markers of T- and B-cell activation, respectively. Steroid treatment coincided with a transient improvement in clinical manifestations of preeclampsia. A significant decrease in IL-6 and CRP was observed although levels of sIL-2R and IgG remained unchanged. Antenatal corticosteroids did not influence the levels of angiogenic factors but ET-1 levels registered a short-lived increase poststeroids. Although a reduction in specific inflammatory mediators in response to antenatal steroids may account for the transient improvement in clinical signs of preeclampsia, inflammation is unlikely to be the major contributor to severe preeclampsia or useful for therapeutic targeting. © 2014 American Heart Association, Inc.

New insights into the etiology of preeclampsia:identification of key elusive factors for the vascular complications

The incidence of preeclampsia is reduced by a third in smokers, but not in snuff users. Soluble Flt-1 (sFlt-1) and soluble endoglin (sEng) are increased prior to the clinical onset of preeclampsia. Animals exposed to high circulating levels of sFlt-1 and sEng elicit severe preeclampsia-like symptoms. Smokers have reduced circulating sFlt-1 and cigarette smoke extract decreases sFlt-1 release from placental villous explants. An anti-inflammatory enzyme, heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO), inhibit sFlt-1 and sEng release. Women with preeclampsia exhale less CO than women with normal pregnancies and HO expression decreases as the severity of preeclampsia increases. In contrast, sFlt-1 levels increase with increasing severity. More importantly, chorionic villous sampling from women at eleven weeks gestation shows that HO-1 mRNA expression is decreased in women who go on to develop preeclampsia. Collectively, these facts provide compelling evidence to support the proposition that the pathogenesis of preeclampsia is largely due to loss of HO activity. This results in an increase in inflammation and excessive elevation of the two key anti-angiogenic factors responsible for the clinical signs of preeclampsia. These findings provide strong evidence for a protective role of HO-1 in pregnancy and identify HO as a target for the treatment of preeclampsia. The cardiovascular drugs, statins, stimulate HO-1 expression and inhibit sFlt-1 release in vivo and in vitro, thus, they have the potential to ameliorate early onset preeclampsia. The StAmP trial is underway to address this and if positive, its outcome will lead to the very first therapeutic intervention to prolong affected pregnancies.

Use of a Minimally Invasive Uncalibrated Cardiac Output Monitor in Patients Undergoing Cesarean Section under Spinal Anesthesia: Report of Four Cases

Bliacheriene F, Carmona MJC, Barretti CFM, Haddad CMF, Mouchalwat ES, Bortlotto MRFL, Francisco RPV, Zugaib M - Use of a Minimally Invasive Uncalibrated Cardiac Output Monitor in Patients Undergoing Cesarean Section under Spinal Anesthesia: Report of Four Cases. Background and Objectives: Hemodynamic changes are observed during cesarean section under spinal anesthesia. Non-invasive blood pressure (BP) and heart rate (HR) measurements are performed to diagnose these changes, but they are delayed and inaccurate. Other monitors such as filling pressure and cardiac output (CO) catheters with external calibration are very invasive or inaccurate. The objective of the present study was to report the cardiac output measurements obtained with a minimally invasive uncalibrated monitor (LiDCO rapid) in patients undergoing cesarean section under spinal anesthesia. Case report: After approval by the Ethics Commission, four patients agreed to participate in this study. They underwent cesarean section under spinal anesthesia while at the same time being connected to the LiDCO rapid by a radial artery line. Cardiac output, HR, and BP were recorded at baseline, after spinal anesthesia, after fetal and placental extraction, and after the infusion of oxytocin and metaraminol. We observed a fall in BP with an increase of HR and CO after spinal anesthesia and oxytocin infusion; and an increase in BP with a fall in HR and CO after bolus of the vasopressor. Conclusions: Although this monitor had not been calibrated, it showed a tendency for consistent hemodynamic data in obstetric patients and it may be used as a therapeutic guide or experimental tool.