High mobility group box 1 protein (HMGB-1): a pathogenic role in preeclampsia?

We evaluated whether preeclampsia is associated with elevated circulating levels of High mobility group box 1 protein (HMGB-1), a nuclear protein with proinflammatory effects when released extracellularly. We enrolled 48 women, 32 in third trimester pregnancy (16 with, 16 without preeclampsia), and 16 healthy non pregnant. In the peripheral blood of pregnant women, HMGB-1 concentration was assessed serially, before and after delivery. With or without preeclampsia, third trimester pregnancy was associated with elevated levels of HMGB-1. This elevation is exaggerated in preeclampsia. The source of HMGB-1 observed in these conditions is likely to involve tissues other than the placenta itself.

Periphere okklusive Vaskulopathie bei einer Patientin mit kombinierter Präeklampsie und Alpha-Thalassämie minor [Peripheral occlusive retinal vasculopathy in a woman with combined preeclampsia and alpha thalassemia minor].

Normalerweise eine Störung der ersten Schwangerschaft, ist die Präeklampsie charakterisiert durch eine arterielle Hypertonie (> 140 mmHg systolisch oder > 90 mmHg diastolisch), die in der Regel nach der 20. Schwangerschaftswoche auftritt und von einer Proteinurie begleitet wird [1]. Die Präeklampsie wird als ,,schwer" bezeichnet, wenn sie mit einer wesentlichen Erhöhung des Blutdrucks (> 160 mmHg systolisch oder > 110 mmHg diastolisch), schwerer Proteinurie, Oligurie, Lungenödem, abdominalen Schmerzen, Leberfunktionsstörungen, Thrombozytopenie und visuellen oder zerebralen Symptomen einhergeht. Eine Eklampsie wiederum ist durch die Entwicklung von tonisch-klonischen Anfällen bei einer präeklamptischen Patientin charakterisiert. Bei der Alpha-Thalassämie tritt ein Defekt von 2 oder mehr der 4 Alpha-Globin-Gene auf. Von einer Alpha-Thalassämie minor spricht man, wenn 2 Alpha-Ketten-Gene deletiert sind. Sie tritt häufig bei Menschen aus Afrika, Südostasien, dem westindischen und mediterranen Raum auf. Die Alpha-Thalassämie minor verursacht eine milde bis moderate mikrozytäre Anämie. Wir berichten über eine Patientin mit peripherer okklusiver Vaskulopathie im Rahmen einer kombinierten Präeklampsie und Alpha-Thalassämie minor.

[112-POS] : Increased post-partum prevalence of hypertension and renal dysfunction after preeclampsia

OBJECTIVES: Women with a history of preeclampsia (PE) are at increased risk of long term cardiovascular and end-stage renal diseases. However, follow up of preeclamptic women is often omitted, mainly due to a weakness of knowledge of maternal caregivers and lack of comprehensive guidelines. The aim of this study was to define the prevalence of albuminuria, high blood pressure, and renal dysfunction 6 weeks after a preeclampsia. METHODS: This is a prospective case-control study comparing women presenting with preeclampsia to an unmatched control group of women with no hypertensive disorders of pregnancy. A complete medical assessment was performed at 6 weeks post-partum. Recruitment started in June 2010. RESULTS: 324 women were included in the PE group and 50 in the control one. Characteristics of both groups and results of the medical work-up at 6 weeks post-partum are presented in Table 1. Women with preeclampsia presented with a higher BMI, higher prevalence of office high blood pressure, pathological albuminuria and renal hyper-filtration than women in the control group. CONCLUSIONS: Prevalence of post-partum hypertension, and renal dysfunction is higher in women with PE than in uncomplicated pregnancies. Systematic assessment of renal risk factors 6 weeks after preeclampsia allows identification of high-risk women and early implementation of preventive and therapeutic strategies. DISCLOSURES: A. Ditisheim: None. B. Ponte: None. G. Wuerzner: None. M. Burnier: None. M. Boulvain: None. A. Pechère-Bertschi: None.

Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia.

BACKGROUND: Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. METHODS AND RESULTS: We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean+/-SD, 32.1+/-5.6 versus 25.3+/-4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3+/-1.2% versus 8.3+/-1.4%; P<0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure (r=-0.61, P<0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid-reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. CONCLUSIONS: Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.

Vascular dysfunction in offspring of preeclampsia is related to preeclampsia per se rather than genetically determined

Objectives: Epidemiological studies suggest that adverse events in utero may predispose to premature cardiovascular disease in adulthood, but the mechanisms are not known. Recently, we found that young apparently healthy offspring of mothers with preeclampsia (PE) display systemic endothelial dysfunction. This problem could be related to PE per se or to a genetic abnormality that predisposes the mother to PE and the offspring to vascular dysfunction. To distinguish between these two possibilities, we assessed vascular function in offspring of PE, their siblings who were born after a normal pregnancy, and in control subjects.Methods: We measured endothelium-dependent vasodilation (flow-mediated vasodilation, FMD), in 10 pairs of healthy normotensive siblings, one born after PE (age 15±6 y; mean±SD), the other after normal pregnancy (17±6y) and in 17 (16±7y) controls. All subjects were born at term.Results: The vascular function in siblings of PE who were born after normal pregnancy was normal and comparable to the one in controls (8.6±1.5% vs. 8.1±1.3%, P=0.32), whereas offspring of PE displayed a roughly 30% smaller FMD than the two other groups (5.9±1.6%, P<0.005 vs. both siblings and controls, Figure). The endothelial dysfunction in the offspring of PE was not related to a difference in the central arterial blood pressure or arterial oxygen saturation, because they were comparable in the 3 groups. Figure 1. FMD in the three groups.Conclusions: These findings provide the first evidence that vascular dysfunction in offspring of PE is caused by PE itself, rather than by a genetic abnormality that predisposes the mother to PE and the offspring to a vascular defect. Prevention of PE and/or its successful treatment is expected to prevent vascular dysfunction and premature cardiovascular morbidity and mortality in the offspring.

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.

High mobility group box 1 protein (HMGB1) : a pathogenic role in preeclampsia

Introduction : la Physiopathologie maternelle de la prééclampsie s'associe typiquement à un état inflammatoire systémique modéré. La protéine "high mobility group box 1" (HMGB-1) est une protéine nucléaire ubiquitaire. En cas de stress cellulaire, elle est relâchée dans le milieu extrace llua li re et peut ainsi exercer son activité pro-inflammatoire. En cas de prééclampsie, le liquide amniotique et le cytoplasme des cellules trophoblastiques contiennent des quantités anormalement élevées de HMGB-1, mais il n'est toujours pas universellement admis que ces concentrations se retrouvent dans le sang maternel. Méthodes : nous avons recruté 32 femmes au troisième trimestre de grossesse, 16 avec et 16 sans prééclampsie. Nous avons également observé 16 femmes non enceintes et en bonne santé, appariées selon l'âge avec les femmes enceintes. Nous avons mesuré la concentration sérique de HMGB-1 chez les femmes enceintes avant, puis 24-48 heures après leur accouchement, en utilisant un kit ELISA commercial. Le même dosage a été réalisé chez les femmes non enceintes, mais à une seule reprise, au moment de leur inclusion dans l'étude. Résultats : le jour de leur inclusion dans l'étude, la concentration médiane [intervalle interquartile] de HMGB-1 chez les femmes enceintes prééclamptiques était de 2.1 ng/ml [1.1 - 3.2], de 1.1 [1.0-1.2] chez les grossesses saines (p < 0.05 vs groupe prééclamptiques) et de 0.6 [0.5 - 0.8] chez les patientes non enceintes (p < 0.01 vs deux autres groupes). Pour les deux groupes de femmes enceintes, les concentrations mesurées en post-partum ne variaient pas significativement de celles mesurées avant l'accouchement. Conclusion : avec ou sans prééclampsie, le troisième triemstre de la grossesse est associé à une élévation des taux circulants de HMGB-1. Cette augmentation est exagérée en cas de prééclampsie. L'origine de ces concentrations élevées reste à déterminer, mais elle semble impliquer d'autres organes que le placenta lui-même.

Post-partum persistence of abnormal circadian pattern of blood pressure after preeclampsia [109-POS]

OBJECTIVES: Blunted nocturnal dip of blood pressure (BP) and reversed circadian rhythm have been described in preeclampsia (PE). Non-dipper status and preeclampsia are both associated with an increased risk of cardiovascular disease later in life. Complete recovery of BP in PE is reported to occur over a variable period of time. Twenty-four hours-ambulatory blood pressure measurement (ABPM) in the post-partum follow-up after a PE has not been described. The aim of this study was to assess 24h-ambulatory blood pressure pattern after a PE and to determine the prevalence of non-dipper status, nocturnal hypertension, white coat hypertension and masked hypertension. METHODS: This is an observational, prospective study on women who suffered from a preeclampsia. A 24h-ABPM was done 6 weeks post-partum at the Hypertension Unit of the University Hospitals of Geneva, concomitantly with a clinical and biological evaluation. RESULTS: Forty-five women were included in a preliminary analysis. Mean age was 33±6years, 57.3% were Caucasian, mean BMI before pregnancy was 24±5kg/m(2). Office and ambulatory BP are shown in Table 1. Prevalence of nocturnal hypertension was high and half of the women had no nocturnal dipping. The diagnosis of hypertension based on office BP was discordant with the diagnosis based on ABPM in 25% of women. CONCLUSIONS: The prevalence of increased nighttime BP and abnormal BP pattern is high at 6weeks post-partum in preeclamptic women. Early assessment of BP with ABPM after preeclampsia allows an early identification of women with persistent circadian abnormalities who might be at increased risk. It also provides a more accurate assessment than office BP. DISCLOSURES: A. Ditisheim: None. B. Ponte: None. G. Wuerzner: None. M. Burnier: None. M. Boulvain: None. A. Pechère-Bertschi: None.

Prediction of preeclampsia by means of Doppler flowmetry of uterine artery and flow-mediated dilation of brachial artery

Objective To evaluate the association of Doppler of uterine artery and flow-mediated dilation of brachial artery (FMD) in the assessment of placental perfusion and endothelial function to predict preeclampsia. Materials and Methods A total of 91 patients considered as at risk for developing preeclampsia were recruited at the prenatal unit of the authors' institution. All the patients underwent FMD and Doppler of uterine arteries between their 24th and 28th gestational weeks. Calculations of sensitivity and specificity for both isolated and associated methods were performed. Results Nineteen out of the 91 patients developed preeclampsia, while the rest remained normotensive. Doppler flowmetry of uterine arteries with presence of bilateral protodiastolic notch had sensitivity of 63.1% and specificity of 87.5% for the prediction of preeclampsia. Considering a cutoff value of 6.5%, FMD showed sensitivity of 84.2% and specificity of 73.6%. In a parallel analysis, as the two methods were associated, sensitivity was 94.2% and specificity, 64.4%. Conclusion The association of Doppler study of uterine arteries and FMD has proved to be an interesting clinical strategy for the prediction of preeclampsia, which may represent a positive impact on prenatal care of patients considered as at high-risk for developing such a condition.

Early screening for preeclampsia

Preeclampsia, which affects about 3 to 5% of pregnant women, is the most frequent medical complication in pregnancy and the most important cause of maternal and perinatal morbidity and mortality. During the past three decades, numerous clinical, biophysical, and biochemical screening tests have been proposed for the early detection of preeclampsia. Literature shows large discrepancies in the sensitivity and predictive value of several of these tests. No single screening test used for preeclampsia prediction has gained widespread acceptance into clinical practice. Instead, its value seems to be in increasing the predictive value of panels of tests, which include other clinical measurements. The aim of this review was to examine the combination of maternal risk factors, mean arterial blood pressure, and uterine artery Doppler, together with biomarkers in the preeclampsia prediction.

Polymorphism in the lymphotoxin-alpha gene, position +252 (rs909253), is not associated with preeclampsia development in Brazilian women

PURPOSE: To investigate the frequencies of polymorphic allele and genotypes for the LT-α gene, position +252 (rs909253), in Brazilian women with preeclampsia.METHODS: This is a case-control study, in which 30 women with preeclampsia, classified according to the criteria of the National High Blood Pressure Education Program, and 115 women in the control group, with at least two healthy pregnancies, were selected. Peripheral blood was collected, and DNA was extracted, followed by genotyping, using specific primers and restriction analysis. The genotypes obtained were AA, AG and GG. Statistical analysis was performed using the χ2association test. The Hardy-Weinberg Equilibrium was tested using the Haploview Program.RESULTS: The results showed no association between genotypes and preeclampsia development (χ2=2.0; p=0.4). When the AG and GG genotypes were grouped according to allele G presence or absence (genotype AA), the data showed that the presence of allele G was not significantly different between cases (women with preeclampsia) and controls (χ2=0.0; p=1.0). The LT-α gene polymorphism, position +252 (rs909253), seems not to be an important candidate for the development of preeclampsia. Other inflammatory genes should be researched, and studies involving gene-environment interactions should be performed, in order to reach a better understanding of the etiology of the preeclampsia.

Calciuria and preeclampsia

Urinary calcium excretion has been reported to be diminished in preeclampsia. The objective of the present study was to determine urinary calcium excretion in pregnant patients with chronic arterial hypertension (CAH) and preeclampsia (PE), and in normotensive patients (N). Forty-four pregnant patients (gestional age, 20-42 weeks; 18 CAH, 17 PE, 9 N) were evaluated for calciuria, proteinuria, plasma uric acid and blood pressure. Patients with PE (82 ± 15.1 mg/24 h) showed significantly lower calciuria (P<0.05) than the group with CAH (147 ± 24.9 mg/24 h) and the N group (317 ± 86.0 mg/24 h) (P<0.05, Student t-test). Plasma uric acid was significantly higher in the PE group (6.1 ± 0.38 mg/dl) than the CAH group (5.0 ± 0.33 mg/dl; P<0.05), which also presented higher proteinuria levels, although the difference was not statistically significant. Diastolic and systolic blood pressure did not differ between the PE (164 ± 105 mmHg) and CAH (164 ± 107 mmHg) groups. Calciuria was significantly lower in the group with preeclampsia than in the group with chronic arterial hypertension. We conclude that calciuria can be a further factor for identifying preeclampsia

Preeclampsia: from epidemiological observations to molecular mechanisms

Preeclampsia is the main cause of maternal mortality and is associated with a five-fold increase in perinatal mortality in developing countries. In spite of this, the etiology of preeclampsia is unknown. The present article analyzes the contradictory results of the use of calcium supplementation in the prevention of preeclampsia, and tries to give an explanation of these results. The proposal of an integrative model to explain the clinical manifestations of preeclampsia is discussed. In this proposal we suggest that preeclampsia is caused by nutritional, environmental and genetic factors that lead to the creation of an imbalance between the free radicals nitric oxide, superoxide and peroxynitrate in the vascular endothelium. The adequate interpretation of this model would allow us to understand that the best way of preventing preeclampsia is the establishment of an adequate prenatal control system involving adequate antioxidant vitamin and mineral supplementation, adequate diagnosis and early treatment of asymptomatic urinary and vaginal infections. The role of infection in the genesis of preeclampsia needs to be studied in depth because it may involve a fundamental change in the prevention and treatment of preeclampsia.

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.