Severe Form Of Preeclampsia Research Articles

Vascular Endothelial Growth Factor Ligands and Receptors That Regulate Human Cytotrophoblast Survival Are Dysregulated in Severe Preeclampsia and Hemolysis, Elevated Liver Enzymes, and Low Platelets Syndrome

Human placental development combines elements of tumorigenesis and vasculogenesis. The organ's specialized epithelial cells, termed cytotrophoblasts, invade the uterus where they reside in the interstitial compartment. They also line uterine arteries and veins. During invasion, ectodermally derived cytotrophoblasts undergo pseudovasculogenesis, switching their adhesion molecule repertoire to mimic that of vascular cells. Failures in this transformation accompany the pregnancy complication preeclampsia. Here, we used a combination of in situ and in vitro analyses to characterize the cell's expression of vascular endothelial growth factor (VEGF) family ligands and receptors, key regulators of conventional vasculogenesis and angiogenesis. Cytotrophoblast differentiation and invasion during the first and second trimesters of pregnancy were associated with down-regulation of VEGF receptor (VEGFR)-2. Invasive cytotrophoblasts in early gestation expressed VEGF-A, VEGF-C, placental growth factor (PlGF), VEGFR-1, and VEGFR-3 and, at term, VEGF-A, PlGF, and VEGFR-1. In vitro the cells incorporated VEGF-A into the surrounding extracellular matrix; PlGF was secreted. We also found that cytotrophoblasts responded to the VEGF ligands they produced. Blocking ligand binding significantly decreased their expression of integrin alpha1, an adhesion molecule highly expressed by endovascular cytotrophoblasts, and increased apoptosis. In severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome, immunolocalization on tissue sections showed that cytotrophoblast VEGF-A and VEGFR-1 staining decreased; staining for PlGF was unaffected. Cytotrophoblast secretion of the soluble form of VEGFR-1 in vitro also increased. Together, the results of this study showed that VEGF family members regulate cytotrophoblast survival and that expression of a subset of family members is dysregulated in severe forms of preeclampsia.

Second-trimester uterine artery Doppler screening in unselected populations: a review

Objective: Doppler ultrasound provides a non-invasive method for the study of the uteroplacental circulation. In normal pregnancy, impedance to flow in the uterine arteries decreases with gestation,which may be the consequence of trophoblastic invasion of the spiral arteries and their conversion into low-resistance vessels. Pre-eclampsia and fetal growth restriction are associated with failure oftrophoblastic invasion of spiral arteries, and Doppler studies, in these conditions, have shown that impedance to flow in the uterine arteries is increased. A series of screening studies involving assessmentof impedance to flow in the uterine arteries have examined the potential value of Doppler in identifying pregnancies at risk of the complications of impaired placentation. This review examines the findingsof Doppler studies in unselected populations.Methods: Searches of a computerized medical database were performed to identify relevant studies. Only those studies that provided sufficient datato allow calculation of the performance of the test were included in the analysis. Likelihood ratios were calculated for each study and are reported for pre-eclampsia, fetal growth restriction and perinataldeath as well as for more severe forms of pre-eclampsia and fetal growth restriction.Results: The literature search identified 19 relevant studies, four of which were excluded from the furtheranalysis. The main characteristics and results of the 15 remaining studies provided discrepant results, which may be the consequence of differences in Doppler technique for sampling, the definition of abnormalflow velocity waveform, differences in the populations examined, the gestational age at which women were studied and different criteria for the diagnosis of pre-eclampsia and fetal growth restriction. Nevertheless,the studies provided evidence that increased impedance to flow in the uterine arteries is associated with increased risk for subsequent development of pre-eclampsia, fetal growth restriction and perinataldeath. In addition, women with normal impedance to flow in the uterine arteries constituted a group that have a low risk of developing obstetric complications related to uteroplacental insufficiency.Conclusions:The review suggests that increased impedance to flow in the uterine arteries in pregnancies attending for routine antenatal care identifies about 40% of those who subsequently develop pre-eclampsia andabout 20% of those who develop fetal growth restriction. Following a positive test, the likelihood of these complications is increased by about 6 and 3.5 times, respectively.

Levels of dimethylarginines and cytokines in mild and severe preeclampsia

The objectives were 1. to evaluate if the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine was altered in mild and severe forms of preeclampsia, and 2. to assess the relationship between dimethylarginines and the cytokine response in preeclampsia. Asymmetric and symmetric dimethylarginine were measured with high performance liquid chromatography in women with mild (n=13) and severe (n=32) preeclampsia and in normotensive pregnant controls (n=20). Interleukin-4, -6, -8, -10 and tumor necrosis factor-alpha were analyzed by immunoassays in women with mild (n=8) and severe (n=17) preeclampsia and in normotensive pregnant controls (n=14). The Mann Whitney U-test and Spearman Rank test were used for statistical analysis. The plasma levels of dimethylarginine were increased in preeclamptic subjects. The elevation of symmetric dimethylarginine was more pronounced than that of asymmetric dimethylarginine. The control levels of interleukin-6, -8 and -10 were significantly higher at term than at gestational week 32-36. Interleukin-6 and -8 were significantly elevated in subjects with severe, but not mild, preeclampsia, whereas TNF-alpha and IL-10 were not significantly altered. Symmetric dimethylarginine levels correlated significantly with arterial blood pressure and serum levels of creatinine and uric acid. Dimethylarginine levels in plasma were, however, not related to the cytokine response. Plasma concentrations of both asymmetric and symmetric dimethylarginine were significantly elevated both in mild and severe preeclampsia. Symmetric, but not asymmetric, dimethylarginine correlated to the severity of the condition. Plasma levels of interleukin-6 and -8 were also elevated in severe preeclampsia but no direct correlations were found between these cytokines and dimethylarginines.

HELLP syndrome and factor V Leiden

The association of thrombophilia and obstetrical complications is documented and well consistent with the hypothesis of an insufficient placental perfusion due to fibrin deposition as a major underlying pathophysiological mechanism. Factor V Leiden is one of the most frequent thrombophilic mutations. A high prevalence of this mutation has recently been reported in a group of 21 German women with haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. In this respect, we studied the prevalence of factor V Leiden in 18 women who were consecutively diagnosed at our Department of Obstetrics and Gynaecology as having HELLP syndrome, between 1995 and 1999. Women were tested either at the time of diagnosis or months or years after delivery for coagulation parameters, protein C (PC), protein S (PS), antithrombin III, lupus-like anticoagulant, anticardiolipin antibodies (ACA), activated protein C (APC) resistance and detection of the G1691A mutation (factor V Leiden). In all women, the parameters studied were normal and in none of the investigated cases was the G1691A mutation found. HELLP being a severe form of preeclampsia, we think that the reported association between factor V Leiden and HELLP may reflect the well-known association with preeclampsia.

Association of HELLP syndrome with autoimmune antibodies and glucose intolerance.

HELLP syndrome is a severe form of preeclampsia, characterized by hemolysis (H), elevated liver enzymes (EL), and low platelets (LP), whose pathogenesis is unclear. Autoimmunity is thought to play an important role. After the observation of development of type 1 diabetes in a patient with HELLP syndrome, we assumed a possible disease association based on autoimmune reactions. We examined 70 women with HELLP syndrome for the presence of autoimmune markers and glucose intolerance. Free thyroxine, triiodothyronine, thyroid-stimulating hormone, anti-thyroglobulin antibodies, thyroperoxidase antibodies, thyrotropin receptor antibodies, antinuclear antibodies (ANAs) and anti-DNA, islet cell antibodies, GADA, an oral glucose tolerance test, and HbA1c were determined postpartum. Patients with positive autoimmune markers or glucose intolerance were prospectively followed and repeated testing was performed. There were 60 women with a normal course of pregnancy matched for age, BMI, and number of pregnancies, which served as a control group. From the HELLP patients, 22 (31%) compared with only 6 (10%) control subjects had autoimmune antibodies (P < 0.01). There were 16 HELLP patients (23%) who exhibited only 1 kind of autoantibody (5 ANA, 9 thyroid antibodies, and 2 GADA), whereas in 6 HELLP patients (8.5%) 2 different antibodies were found. In all but 4 patients of the study group, these antibodies disappeared during 3 +/- 1.5 years of follow-up. Glucose intolerance was detected in 22 (31%) of the HELLP patients, 17 of them had impaired glucose tolerance (IGT), and 5 had diabetes, whereas only 4 subjects (6.5%) with IGT at postpartum were found in the control group (P < 0.01). During the follow-up, 2 HELLP patients were still diabetic and another 2 HELLP patients (1 GADA positive) had IGT versus 1 control subject. Our data give evidence that HELLP syndrome is associated with various autoimmune antibodies and glucose intolerance. Because glucose intolerance and/or autoimmune markers persisted during long-term follow-up in 6 patients with HELLP syndrome versus 1 in the control group, it may become advisable to reexamine patients with HELLP syndrome for detection of diabetes and autoimmune disorders.

Hypertensive disorders in pregnancy

Hypertension in pregnancy is defined by a systolic blood pressure > or = 140 mm Hg and a diastolic blood pressure of > or = 90 mm Hg or by a rise in blood pressure of systolic > or = 30 mm Hg and diastolic > or = 15 mm Hg. High blood pressures are found in 5-10% of all pregnancies. The outcome of pregnancy is influenced by the fact whether there occurs a proteinuria in addition to hypertension. While the prognosis of an isolated hypotension is good, the combination of hypertension and proteinuria leading to preeclampsia is the primary cause of maternal death in many countries and is responsible for 20-25% of perinatal mortality. A simple classification divides between chronic hypertension, preeclampsia, preeclampsia superimposed on chronic hypertension and transient hypertension. With chronic hypertension pregnancy outcome is determined by a preexisting nephropathy and the occurrence of a superimposed preeclampsia. Preeclampsia and superimposed preeclampsia are pregnancy induced multiorganic diseases, endangering both the mother and the fetus. Transient hypertension is a benign pathology, which occurs toward the end of pregnancy usually on the basis of a latent essential hypertension, which is laid open through pregnancy. While a severe chronic hypertension in pregnancy must be treated to prevent a hypertensive maternal encephalopathy, a less severe chronic hypertension should not be treated as the risk of a superimposed preeclampsia and the maternal and fetal outcome cannot be influenced by antihypertensive therapy. The incidence of preeclampsia is 3-5% in nulliparae and 0.5% in multiparae. Preeclampsia is a severe and dangerous pathology with an unknown etiology. Pregnancy termination is the only causal therapy. At present it is still recommended to terminate a severe preeclampsia after stabilizing the mother, irrespective of gestational age. In less severe preeclampsia occurring before 32 weeks of gestation, termination of pregnancy can be postponed under intensive monitoring and a prophylaxis with magnesium sulfate in order to accelerate the fetal lung maturation with glucocorticoids. A conservative management in the case of a HELLP-syndrome (Haemolyis, Elevated Liver enzymes, Low Platelets), which is a very severe form of preeclampsia, is not recommended because it hasn't been validated in prospective controlled studies. The most dangerous complication of preeclampsia is eclampsia, which is defined by general tonic-clonic convulsions before or after birth. The most effective prophylaxis of eclamptic attacks is the intravenous therapy with magnesium sulfate. A primary prohylaxis for preeclampsia doesn't exist. Treatment with low-dose aspirin in high-risk patients, i.e. after a severe preeclampsia, in cases of chronic hypertension, in cases of nephropathy and in cases with antiphospholipid-syndrome++ can be recommended. The prophylactic use of low-dose heparin, which has lead to a significant decreased incidence of preeclampsia in retrospective analysis, is now the object of a randomized, controlled trial in our hospital. All women who suffered from a preeclampsia should have a check-up after 3-6 months. Preexisting pathologies are found in up to 40% of patients, mostly in multiparae, i.e. chronic hypertension, nephropathy, endocrine pathologies, anomalies of blood coagulation and antiphospolipid-syndrome.

Is proteinuric pre-eclampsia a different disease in primigravida and multigravida?

This study aimed to identify if the clinical features of proteinuric pre-eclampsia or the biochemical markers of endothelial dysfunction associated with this syndrome are altered according to parity in a direction that would suggest a different pathophysiology. Groups of 27 primigravid and 35 multigravid women with pre-eclampsia (defined as blood pressure &gt; 140/90 mmHg and 2+ proteinuria) were studied ante-partum, and at 6 weeks and 6 months post-partum. Clinical markers of severity of pre-eclampsia, including blood pressure, markers of renal, hepatic and coagulatory function, and biochemical markers of endothelial dysfunction were measured. Fetal outcome was assessed by birthweight and birthweight percentile. Ante-partum systolic blood pressure was 10 mmHg higher in the primigravida, and this difference was independent of age and anti-hypertensive medication. Analysis of systolic blood pressure before and after delivery showed the primigravid women to have elevated systolic blood pressure over the whole time period (P&lt; 0.01). The primigravid women had more severe hepatic dysfunction, with elevated aspartate aminotransferase levels, but plasma creatinine, proteinuria, platelet counts and haematocrit were similar, indicating that renal and coagulatory function and plasma volume were affected to the same extent in the two groups and were independent of parity. Birthweight was similar in the two groups, and the percentage of infants weighing less than the 10th centile for gestation was also similar. Biochemical markers of endothelial dysfunction, assessed by measuring the urinary prostacyclin metabolite 2,3-dinor-6-oxo-prostaglandin F1α and plasma endothelin 1, did not differ according to parity. There were no differences in a number of other biochemical markers of pre-eclampsia, including plasma albumin, uric acid, triacylglycerol, and total, low-density lipoprotein and high-density lipoprotein cholesterol. Basophil, monocyte and lymphocyte counts were elevated before delivery in primigravid women with pre-eclampsia. The differences in lymphocyte counts persisted post-partum. Further studies are required to clarify the role, if any, of monocytes, basophils and lymphocytes in the pathophysiology of pre-eclampsia. In conclusion, the elevated systolic blood pressure and raised aspartate aminotransferase levels observed in primigravida suggest a more severe form of pre-eclampsia. The lack of differences in birthweight and other biochemical and endothelial markers of severity of pre-eclampsia do not suggest a different pathophysiology; however, the persistently higher white cell counts in the primigravid pre-eclamptics are of interest, and might reflect differences in immune responses in the two groups. We suggest that studies of the pathophysiology of pre-eclampsia should include multigravida, as long as there is adequate post-partum follow-up to exclude underlying disease.

Is proteinuric pre-eclampsia a different disease in primigravida and multigravida?

This study aimed to identify if the clinical features of proteinuric pre-eclampsia or the biochemical markers of endothelial dysfunction associated with this syndrome are altered according to parity in a direction that would suggest a different pathophysiology. Groups of 27 primigravid and 35 multigravid women with pre-eclampsia (defined as blood pressure >140/90 mmHg and 2+ proteinuria) were studied ante-partum, and at 6 weeks and 6 months post-partum. Clinical markers of severity of pre-eclampsia, including blood pressure, markers of renal, hepatic and coagulatory function, and biochemical markers of endothelial dysfunction were measured. Fetal outcome was assessed by birthweight and birthweight percentile. Ante-partum systolic blood pressure was 10 mmHg higher in the primigravida, and this difference was independent of age and anti-hypertensive medication. Analysis of systolic blood pressure before and after delivery showed the primigravid women to have elevated systolic blood pressure over the whole time period (P<0.01). The primigravid women had more severe hepatic dysfunction, with elevated aspartate aminotransferase levels, but plasma creatinine, proteinuria, platelet counts and haematocrit were similar, indicating that renal and coagulatory function and plasma volume were affected to the same extent in the two groups and were independent of parity. Birthweight was similar in the two groups, and the percentage of infants weighing less than the 10th centile for gestation was also similar. Biochemical markers of endothelial dysfunction, assessed by measuring the urinary prostacyclin metabolite 2, 3-dinor-6-oxo-prostaglandin F(1alpha) and plasma endothelin 1, did not differ according to parity. There were no differences in a number of other biochemical markers of pre-eclampsia, including plasma albumin, uric acid, triacylglycerol, and total, low-density lipoprotein and high-density lipoprotein cholesterol. Basophil, monocyte and lymphocyte counts were elevated before delivery in primigravid women with pre-eclampsia. The differences in lymphocyte counts persisted post-partum. Further studies are required to clarify the role, if any, of monocytes, basophils and lymphocytes in the pathophysiology of pre-eclampsia. In conclusion, the elevated systolic blood pressure and raised aspartate aminotransferase levels observed in primigravida suggest a more severe form of pre-eclampsia. The lack of differences in birthweight and other biochemical and endothelial markers of severity of pre-eclampsia do not suggest a different pathophysiology; however, the persistently higher white cell counts in the primigravid pre-eclamptics are of interest, and might reflect differences in immune responses in the two groups. We suggest that studies of the pathophysiology of pre-eclampsia should include multigravida, as long as there is adequate post-partum follow-up to exclude underlying disease.

HELLP SYNDROME: An Anesthesiologist's Perspective

Classic preeclampsia or pregnancy-induced hypertension (PIH), a hypertensive disorder peculiar to pregnancy, has diverse and widespread pathophysiology and has long been known to be associated with intravascular hemolysis, coagulopathies, and elevated serum transaminases. 13,25,42,50 Weinstein, 73 in 1982, used the acronym to describe the syndrome of hemolytic anemia, liver dysfunction, and thrombocytopenia, which develops as an atypical, complicated form of severe preeclampsia—eclampsia. HELLP syndrome is also associated with multisystem failure due to widespread circulatory dysfunction. This article presents an overview of the pathophysiology and clinical manifestations of HELLP syndrome and presents guidelines for anesthetic management. H emolysis, e levated l iver enzymes, and l ow p latelet count (HELLP) syndrome is a disease of preeclamptic women. 72 It is part of a continuum of a disease that includes severe preeclampsia 34 and postpartum eclampsia. 67 This uncommon form of preeclampsia may initially have a misleading, benign clinical appearance wherein patients first present with minimal changes in platelet count, liver function tests, blood pressure, and little or no renal dysfunction. Such patients may progress rapidly to a fully developed HELLP syndrome characterized by hemolysis and marked signs of liver and coagulation abnormalities. Together, these symptoms are life threatening.

Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome: a review of diagnosis and management

Hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome is a form of severe preeclampsia that threatens the gravida and her fetus. In this report, the diagnostic criteria and maternal and fetal risks of HELLP are defined. Prompt recognition and treatment in tertiary centers is emphasized, because the prognosis can be adversely affected by delayed or less than optimal diagnosis and treatment. Management guidelines are offered for treating this disorder. The potential roles of corticosteroids, plasmapheresis, and expectant management are critically evaluated. Subsequent pregnancy outcome, contraception, and preventative strategies are considered.

Increased release of tumor necrosis factor-alpha and interleukin-6 in women with the syndrome of hemolysis, elevated liver enzymes, and low platelet count.

Complement is activated in preeclampsia and complement products are known to activate macrophages. The aim of this study was to determine whether the macrophage derived cytokines, interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha, are released in patients with a form of severe preeclampsia characterized by the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome). Complement activation and plasma levels of cytokines were studied in 11 women with HELLP syndrome and in 11 controls with uncomplicated pregnancies. To further evaluate the connection between complement activation and cytokine release an in vitro study on heparinized whole blood incubated with recombinant C5a was performed. In the HELLP group, complement anaphylatoxin C5a was increased in plasma at delivery (p < 0.01) and one day after delivery (p < 0.05), terminal C5b-9 complement complex was elevated in plasma at delivery (p < 0.001) and one day after (p < 0.01), plasma levels of interleukin-6 were increased one day after delivery (p < 0.01), and plasma concentrations of tumor necrosis factor-alpha were elevated at delivery (p < 0.01), compared with corresponding levels in controls. All parameters normalized within one week. Interleukin-I beta did not differ between the groups. In vitro, recombinant C5a incubated in whole blood gave a dose-dependent release of interleukin-6. No increased release of interleukin-1 or tumor necrosis factor-alpha was seen after incubation. Since cytokine release occurs in severe preeclampsia, inflammatory mechanisms may participate in the pathophysiology of severe preeclampsia.

Erythrocyte Glutathione Peroxidase Activity in Hypertensive Complications of Pregnancy

Thirty-nine patients with hypertensive complications of pregnancy were analyzed in the third trimester with respect to erythrocyte glutathione peroxidase (GSHPx) activity. Patients with severe or superimposed preeclampsia had significantly higher activities of GSHPx than those with mild preeclampsia. We suggest that a high level of GSHPx in the severe forms of preeclampsia reflects the greatly increased peroxide load generated in this disease and is of compensatory nature, responding to the disturbed peroxide and prostaglandin metabolism.

Syndrome of Hemolysis, Elevated Liver Enzymes, and Low Platelet Count (The HELLP Syndrome): A Case Report

Syndrome of Hemolysis, Elevated Liver Enzymes, and Low Platelet Count (The HELLP Syndrome): A Case Report

Clinical aspects of antenatal glucocorticoid treatment for prevention of neonatal respiratory distress syndrome.

Main indications for antenatal administration glucocorticoid to pregnant women are premature contractions, hemorrhage during pregnancy, conditions of fetal distress and maternal diseases. There are some absolute or relative contraindications as well: severe forms of preeclampsia, diabetes mellitus, premature rupture of membranes, maternal and/intrauterine infections. In a retrospective evaluation of the data obtained at our institution of 637 nonrandomized cases from the years 1980-1985, we could demonstrate the dependence of the therapeutic results on the sex of the newborn. The RDS incidence is significantly different after betamethasone prophylaxis. It was 1/25 (4%) in girls compared to 13/31 (42%) in boys. A marked reduction of the RDS incidence is only detectable after betamethasone therapy from the 32nd to the 34th week of gestation. Thus we recommend RDS prophylaxis for all patients with premature contraction, mainly between the 32nd and 34th week of pregnancy. In addition, it should be given in cases of confirmed lung immaturity. Special restrictions are necessary in cases of preeclampsia, eclampsia, diabetes and confirmed maternal infections. In the group of diabetes or preeclampsia patients an RDS prophylaxis should only be given, if at all, when it can be performed under intensive care conditions.

The Incidence of Severe Pre-eclampsia amongst Mothers and Mothers-in-Law of Pre-eclamptics and Controls

In order to distinguish between a maternal, fetal or maternal and fetal genetic predisposition towards severe pre-eclampsia, the first pregnancies of 158 mothers and 160 mothers-in-law of pre-eclamptic women and of matched controls were analysed. Fourteen per cent of mothers of pre-eclamptics were found to have had severe pre-eclampsia, confirming previous suggestions that the condition runs in families', in contrast to only a 3% incidence amongst mothers of controls. The incidence in mothers-in-law of both pre-eclamptics and controls was 4%, in full agreement with a maternal genotype hypothesis and suggesting that the fetal genotype plays, at most, only a minor role in the aetiology of severe pre-eclampsia. The data are in agreement with the hypothesis that a single recessive gene acting in the mother could be responsible for severe pre-eclampsia, but multifactorial inheritance is not ruled out. Mild pre-eclampsia showed no such familial tendency, indicating that the mild and severe forms of pre-eclampsia may represent separate pathological entities.

The indicence of severe pre-eclampsia amongst mothers and mothers-in-law of pre-eclamptics and controls.

In order to distinguish between a maternal, fetal or maternal and fetal genetic predisposition towards severe pre-eclampsia, the first pregnancies of 158 mothers and 160 mothers-in-law of pre-eclamptic women and of matched controls were analysed. Fourteen per cent of mothers of pre-eclamptics were found to have had severe pre-eclampsia, confirming previous suggestions that the condition "runs in families', in contrast to only a 3% incidence amongst mothers of controls. The incidence in mothers-in-law of both pre-eclamptics and controls was 4%, in full agreement with a maternal genotype hypothesis and suggesting that the fetal genotype plays, at most, only a minor role in the aetiology of severe pre-eclampsia. The data are in agreement with the hypothesis that a single recessive gene acting in the mother could be responsible for severe pre-eclampsia, but multifactorial inheritance is not ruled out. Mild pre-eclampsia showed no such familial tendency, indicating that the mild and severe forms of pre-eclampsia may represent separate pathological entities.