Clinical Features Of Preeclampsia Research Articles

Edaravone Confers Neuroprotective, Anti-inflammatory, and Antioxidant Effects on the Fetal Brain of a Placental-ischemia Mouse Model.

Reduced uterine perfusion pressure (RUPP) is a well-established model which mimics many clinical features of preeclampsia (PE). Edaravone is a free radical scavenger with neuroprotective, antioxidant and anti-inflammatory effects against different models of cerebral ischemia. Therefore, we aimed to elucidate the different potential mechanisms through which PE affects fetal brain development using our previously established RUPP-placental ischemia mouse model. In addition, we investigated the neuroprotective effect of edaravone against the RUPP-induced fetal brain development alterations. On gestation day (GD) 13, pregnant mice were divided into four groups; sham (SV), edaravone (SE), RUPP (RV), and RUPP+edaravone (RE). SV and SE groups underwent sham surgeries, however, RV and RE groups were subjected to RUPP surgery via bilateral uterine ligation. Edaravone (3mg/kg) was injected via tail i.v. injection from GD 14-18. The fetal brains from different groups were collected on GD 18 and subjected to further investigations. The results showed that RUPP altered the structure of fetal brain cortex, induced neurodegeneration, increased the expression of the investigated pro-inflammatory markers; TNF-α, IL-6, IL-1β, and MMP-9. RUPP resulted in microglial and astrocyte activation in the fetal brains, inaddition to upregulation of Hif-1α and iNOS. Edaravone conferred a neuroprotective effect via alleviating the inflammatory response, restoring the neuronal structure and decreasing oxidative stress in the developing fetal brain. In conclusion, RUPP-placental ischemia mouse model could be a useful tool to further understand the underlying mechanisms of PE-induced child neuronal alterations. Edaravone could be a potential adjuvant therapy during PE to protect the developing fetal brain. The current study investigated the effects of a placenta-induced ischemia mouse model using reduced uterine perfusion pressure (RUPP) surgery on the fetal brain development and the potential neuroprotective effects of the drug edaravone. The study found that the RUPP model caused neurodegeneration and a pro-inflammatory response in the developing fetal brain, as well as hypoxia and oxidative stress. However, maternal injection of edaravone showed a strong ability to protect against these detrimental effects and target multiple pathways associated with neuronal damage. The current study suggests that the RUPP model could be useful for further study of the impact of preeclampsia on fetal brain development and that edaravone may have potential as a therapy for protecting against this damage.

Distinct cytokine profiles in patients with preeclampsia

Preeclampsia (PE) is a common but serious pregnancy complication that adversely affects both maternal and fetal health. However, the mechanisms of its pathogenesis remain unclear, and effective biomarkers for early diagnosis are still lacking. In this retrospective study, comprehensive bioinformatic analysis and logistic regression analysis were used to compare profiles of 48 serum cytokines in 27 PE patients with those in 41 normotensive pregnant subjects. The results revealed that serum cytokine profiles accumulated to different levels between the two groups, which had significant correlations with the clinical features of PE. Nine cytokines with high discriminatory capacity for diagnosising PE (AUC ≥ 0.7) were selected for inclusion in a multivariate logistic regression model for PE and calculated as a probability diagnostic formula. This model constructed from the panel of nine cytokines had better diagnostic performance than any individual cytokine (AUC = 0.97, 95% CI 0.94-1.00, P < 0.0001), with a sensitivity of 96.30% and a specificity of 90.24%. The set of cytokine profiles and risk assessment model described here can serve as a basis for developing early clinical diagnostic and therapeutic strategies for PE.

The association between chronic liver diseases and preeclampsia

BackgroundPreeclampsia is a multisystem disorder characterized by an abnormal vascular response to placentation associated with increased systemic vascular resistance. As liver involvement is one of the main clinical features of preeclampsia, we sought to determine if there is an association between chronic liver diseases and preeclampsia.MethodsA retrospective matched case–control analysis was conducted in a tertiary medical center. Three hundred eleven (311) pregnant women with preexisting chronic liver disease (study group), including viral and autoimmune hepatitis, non-alcoholic fatty liver, Wilson disease, and cirrhosis, were match for age, parity, and number of fetuses to 933 healthy pregnant women (control group). The primary outcome measure was the incidence of preeclampsia in each group. Secondary outcome measures were obstetrical and neonatal complications. Confounders found to be significant on univariate analysis were evaluated using logistic regression models, and odds ratios (OR) and confidence intervals (CI) were calculated.ResultsPreeclampsia was diagnosed in 28 women (9.0%) in the study group and 33 women (3.54%) in the control group (p < 0.001).On multivariate analysis adjusted for maternal age, parity, previous preeclampsia, chronic hypertension, gestational diabetes mellitus, pregestational diabetes mellitus, antiphospholipid syndrome, and mode of conception, chronic liver disease was found to be an independent risk factor for preeclampsia (aOR 2.631, 95% CI 1.518–4.561). Although there was no difference in the gestational week at delivery between the groups (38.6 ± 2.13 vs. 38.8 ± 2.17 for study and control group, respectively, p = 0.410), the study group had a lower mean neonatal birthweight (3088 ± 551 vs. 3182 ± 566 g, p = 0.011). There were no between-group differences in the other parameters evaluated.ConclusionIn our study, preexisting chronic liver disease was associated with a 2.6-fold increased risk of preeclampsia.

THE IMPORTANCE OF B2 CELLS IN THE HYPERTENSION AND PATHOPHYSIOLOGY OF PLACENTAL ISCHEMIA DURING PREGNANCY

Objective: Preeclampsia (PE), is characterized by placental ischemia, inflammation, hypertension and IUGR. Antibodies activating the angiotensin II type I receptor (AT1-AA) activate cytolytic Natural Killer cells (NK) and cause clinical features of PE. The Reduced uterine perfusion pressure (RUPP) pregnant rat model of PE has elevated AT1-AA, NK cells and blood pressure. B cell depletion or AT1-AA epitope binding protein (‘n7AAc’) improved hypertension and AT1-AA activity and NK cells in RUPP rats. One unanswered question is the importance of B2 cells vs B1 cells in the production of the AT1-AA and thus the pathology of PE. Design and method: To test this hypothesis, splenic B Cells and B2 cells were isolated from RUPP rats on Gestation Day (GD) 19 and transferred into NP rats on GD12. Blood pressure (MAP) and cNKs were measured by flow cytometry on GD19. To test the role of AT1-AA in the hypertension, ‘n7AAc’ was administered to a group of recipient rats on GD14. Results: MAP increased in NP+RUPP B cells to 117 ± 1 mmHg, n = 10, and to 111 mmHg ± 3, n = 8, in NP+RUPP B2 cells, compared to NP rats, n = 10 (p &lt; 0.001). ‘n7AAc’ attenuated hypertension in response to total RUPP B cells (99 mmHg ± 6, n = 5)(p &lt; 0.01) and in response to RUPP B2 s (100 mmHg ± 5, p = 0.08). Circulating and placental cNKs were elevated with total RUPP B cells and RUPP B2 cells compared to NP. Circulating cNKs were elevated in NP+RUPPBcells (6 ± 2.5, n = 5)(p &lt; 0.01) and in NP+RUPP B2 cells (8 ± 3.33, n = 4)(p &lt; 0.01) compared to NP (0.67 ± 0.33, n = 10). Placental cNKs were elevated in NP+RUPPBcells (2.32 ± 0.73, n = 6)(p &lt; 0.01) and in NP+RUPP B2 cells (1.33 ± 0.24, n = 3)(p &lt; 0.01) compared to NP (0.2250 ± 0.133, n = 10). Conclusions: We conclude that RUPP total B Cells and RUPP B2 cells cause hypertension and NK cell activation via secretion of the AT1-AA during pregnancy. However, our studies do not rule out the importance of B1 cells in hypertension and AT1-AA production during PE or RUPP. Future studies from our laboratory will further examine B1 cells in the pathology of PE.

Associations between pre-pregnancy body mass index and occurrence and clinical features of preeclampsia

Objective: To investigate the associations between pre-pregnancy body mass index (BMI) and occurrence and clinical features in pregnant women complicated by preeclampsia (PE). Methods: We recruited 42 427 pregnant women who were diagnosed with intrauterine pregnancy at Shenzhen Maternity and Child Healthcare Hospital from July 2017 to December 2019, with a gestational age of 6~8+6 weeks, excluding those with basic diseases and incomplete medical records. Among them, 659 were diagnosed with PE. According to the pre-pregnancy BMI, the pregnant women were divided into underweight group (42 cases), normal body weight group (422 cases), overweight group (138 cases) and obesity group (57 cases). Maternal outcomes (the occurrence of preeclampsia, cesarean delivery rate) and neonatal outcomes (birth weight, Apgar score and neonatal ICU admission) were recorded. The maternal outcomes, gestational age of delivery, delivery mode, newborn birth weight, Apgar score and admission to neonatal ICU were compared among the pregnant women in each group. Logistic regression model was established to analyze the influence of different pre-pregnancy BMI on the occurrence and clinical features of PE. Results: The incidence of PE was 1.55% (659/42 427), and the incidence of PE was 0.61% (42/6 941), 1.44% (422/29 297), 2.62% (138/5 273) and 6.22% (57/916) in the underweight group, the normal weight group, the overweight group and the obesity group, respectively. After adjustment for age, parity, educational level, history of preeclampsia, and in vitro fertilization and embryo transfer (IVF-ET), compared with normal group, the adjusted OR for developing early-onset PE were 0.57 (95%CI: 0.29-1.02) for underweight, 1.03 (95%CI: 0.65-1.56) for overweight and 2.15 (95%CI: 1.03-4.02) for obesity groups. The OR for developing late-onset PE were 0.50 (95%CI: 0.33-0.72) for underweight, 1.57 (95%CI: 1.23-1.99) for overweight and 4.25 (95%CI: 3.00-5.91) for obesity group. The OR for PE without severe features were 0.54 (95%CI: 0.30-0.89), 1.40 (95%CI: 0.97-1.99) and 5.11 (95%CI: 3.22-7.84) for underweight, overweight and obesity groups, respectively. The OR for severe PE were 0.51 (95%CI: 0.33-0.75), 1.42 (95%CI: 1.10-1.83) and 2.97 (95%CI: 1.95-4.38) for underweight, overweight and obesity groups, respectively. The median neonate birth weight in women with PE were 2 420 g (1 602-2 845 g), 2 435 g (1 692-3 030 g), 2 540 g (1 922-3 132 g), and 2 950 g (2 050-3 360 g) for underweight, normal, overweight and obesity groups, respectively. The neonatal birth weight in obesity group was heavier than that in normal group (P<0.05). The incidence rates of large for gestational age (LGA) in PE women were 0 (0/42), 3.3% (14/422), 7.3% (10/138) and 17.5% (10/57) for underweight, normal, overweight and obesity groups, respectively. The incidence rate of LGA in obesity group was higher than that in normal group (P<0.05). Conclusions: Pre-pregnancy obesity is an independent risk factor for PE. Obesity related PE is more likely associated with late-onset PE and LGA. It is recommended to control weight before pregnancy, limit weight gain during pregnancy and control blood pressure to reduce the incidence of PE and ensure the safety of mother and child.

Mild thrombocytopenia indicating maternal organ damage in pre\u2010eclampsia: a cross\u2010sectional study

BackgroundCurrently, there is a disagreement between guidelines regarding platelet count cut-off values as a sign of maternal organ damage in pre-eclampsia; the American College of Obstetricians and Gynecologists guidelines state a cut-off value of < 100 × 109/L; however, the International Society for the Study of Hypertension in Pregnancy guidelines specify a cut-off of < 150 × 109/L. We evaluated the effect of mild thrombocytopenia: platelet count < 150 × 109/L and ≥ 100 × 109/L on clinical features of pre-eclampsia to examine whether mild thrombocytopenia reflects maternal organ damage in pre-eclampsia.MethodsA total of 264 women were enrolled in this study. Participants were divided into three groups based on platelet count levels at delivery: normal, ≥ 150 × 109/L; mild thrombocytopenia, < 150 × 109/L and ≥ 100 × 109/L; and severe thrombocytopenia, < 100 × 109/L. Risk of severe hypertension, utero-placental dysfunction, maternal organ damage, preterm delivery, and neonatal intensive care unit admission were analyzed based on platelet count levels. Estimated relative risk was calculated with a Poisson regression analysis with a robust error.ResultsPlatelet counts indicated normal levels in 189 patients, mild thrombocytopenia in 51 patients, and severe thrombocytopenia in 24 patients. The estimated relative risks of severe thrombocytopenia were 4.46 [95 % confidence interval, 2.59–7.68] for maternal organ damage except for thrombocytopenia, 1.61 [1.06–2.45] for preterm delivery < 34 gestational weeks, and 1.35 [1.06–1.73] for neonatal intensive care unit admission. On the other hand, the estimated relative risks of mild thrombocytopenia were 0.97 [0.41–2.26] for maternal organ damage except for thrombocytopenia, 0.91 [0.62–1.35] for preterm delivery < 34 gestational weeks, and 0.97 [0.76–1.24] for neonatal intensive care unit admission.ConclusionsMild thrombocytopenia was not associated with severe features of pre-eclampsia and would not be suitable as a sign of maternal organ damage.

Increased vasopressin secretion during preeclampsia despite normal plasma osmolality

Preeclampsia (PE) is a cardiovascular disorder that affects 4–7% of pregnancies and typically involves new onset hypertension, proteinuria, and edema. Diagnosis of the disorder is formally performed in the second half of gestation based upon clinical signs, but we and others have discovered that maternal plasma levels of copeptin (CPP, the stable C‐terminal fragment of arginine vasopressin, AVP) are elevated already in the first trimester and are highly predictive of the development of PE. Further, chronic low‐dose AVP infusion is sufficient to model almost all the clinical features of PE in pregnant mice. Our objective is therefore to understand the cause of elevated AVP secretion in human PE. Previous studies indicate that blood volume is reduced during PE, but no change in osmolality has been noted. We therefore hypothesized (i) that plasma AVP levels are elevated in early gestation of pregnancies that later develop PE, and (ii) that elevated AVP and CPP secretion during PE is secondary to altered volume regulation. Blood samples (1st and 2nd trimester) from women who later developed PE or represent clinically‐matched case controls were obtained from the Maternal Fetal Tissue Bank (IRB#200910784) at the University of Iowa. Consistent with our first hypothesis, plasma levels of AVP, assessed by ELISA after Sep‐Pak C18 reversed solid phase extraction, were increased in 1st and 2nd trimester from women who later developed PE (25.5±3.6, n=63 vs 52.1±22.2, n=5 pg/mL, mean±SEM, p=0.01) despite no change in osmolality (279.6±0.7, n=46 vs 277.5±1.2, n=4 mOsm/kg H2O). Plasma sodium was increased in 1st and 2nd trimesters before the onset of PE (133.9±0.6, n=91 vs 138.5±0.6, n=6 mmol/L, p&lt;0.05), but potassium was unchanged (4.13±0.05 vs 4.38±0.14 mmol/L). These findings support the conclusions that (i) AVP levels are indeed increased in early pregnancy before the onset of clinical symptoms of PE, as was suspected based upon previous studies of CPP; that (ii) the defended osmolality set‐point is similar between control and PE pregnancies, and therefore chronically elevated osmolality is unlikely to be the major cause of elevated AVP secretion during PE, and that (iii) offsetting changes in concentrations of individual osmolytes may be present during PE.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cumulative dose of bevacizumab associates with albuminuria rather than podocyturia in cancer patients

Angiogenesis inhibition with bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGF-A), is an anticancer treatment associated with hypertension and renal glomerular toxicity referred to as a preeclampsia-like syndrome. In preeclampsia, podocyturia predates proteinuria and clinical features of preeclampsia, and is regarded as a biomarker of ongoing glomerular injury. Using a quantitative polymerase chain reaction of the podocyte-specific molecules nephrin, podocin, and VEGF-A in the urine, we examined whether podocyturia is present in bevacizumab-treated cancer patients, and whether it relates to proteinuria and the cumulative dose of bevacizumab. Urine samples were cross-sectionally collected from 43 bevacizumab-treated patients, 21 chemotherapy-treated patients, and 7 healthy controls. Urinary protein-to-creatinine ratio (mean and range) was 32.0 mg/mmol (5.2–284.4) in the bevacizumab group, compared with 11.4 mg/mmol (1.1–21.0) in the chemotherapy group and 7.4 mg/mmol (3.9–16.5) (P < .05) in healthy controls, whereas urinary albumin-to-creatinine ratio values in the three groups were, respectively, 18.9 mg/mmol (0.1–227.7), 1.5 mg/mmol (0.2–3.5), and 0.2 mg/mmol (0.1–0.4) (P < .05). The cumulative dose of bevacizumab ranged from 550 to 93,628 mg. Urinary podocin mRNA expression was undetectable in 59% of participants, urinary nephrin mRNA expression per mmol creatinine ranged from 0.0 to 5.3 and urinary VEGF-A mRNA expression from 0.0 to 2.7. Urinary nephrin mRNA expression did not correlate to the albumin-to-creatinine ratio or the cumulative dose of bevacizumab, whereas the latter correlated with the albumin-to-creatinine ratio (r = 0.77; P < .001). Our results demonstrate that the cumulative dose of bevacizumab is closely correlated with albuminuria but not with podocyturia as measured with the quantitative polymerase chain reaction technique, challenging the feasibility of this measurement to monitor ongoing glomerular injury in patients chronically treated with bevacizumab.

Plasma levels of TAM receptors and ligands in severe preeclampsia.

Preeclampsia (PE) is a multifactorial dysfunction characterized by hypertension with characteristics of systematic endothelial activation. It is widely accepted that vascular disorder and deficient trophoblast invasion are involved in PE. Tyro3/Axl/MerTK (TAM) family receptors are tyrosine-kinase receptors and may exert a diverse range of functions such as cell proliferation, migration, and vascular angiogenesis. The role of TAM signaling in severe PE patients remains unclear. Therefore, the aim of this study was to investigate involvement of the TAM axis in the pathogenesis of PE. A total of 36 severe PE patients and 40 age- and gender-matched healthy pregnant women (controls) were enrolled in this study. Plasma levels of soluble TAM receptors (Tyro3, Axl, MerTK) and ligands (Gas6 and ProS) were then measured using an enzyme-linked immunosorbent assay (ELISA). We evaluated the association between the expression of these proteins and the clinical features of PE. Plasma levels of sMerTK and sAxl were significantly higher in severe PE patients than in control women during pregnancy. The plasma concentrations of sMerTK and sAxl in severe PE patients correlated positively with systolic and diastolic blood pressure, and plasma sAxl levels demonstrated a significant correlation to proteinuria. In contrast, reduced levels of Gas6 were inversely associated with urine protein in PE patients. Elevated expression of the plasma levels of sMerTK and sAxl, as well as the reduction of Gas6 were observed in severe PE patients. Furthermore, these changes were correlated with disease activity. TAM signaling might play a role in the pathogenesis of PE.

Helicobacter pylori infection contributes to placental impairment in preeclampsia: basic and clinical evidences.

Preeclampsia (PE) is a major cause of maternal and neonatal morbidity and mortality. Epidemiological association between Helicobacter pylori (Hp) infection and PE onset has been widely shown. The aim of this study was to analyze a possible correlation between Hp infection and the severity of clinical presentation of PE and to identify an immunologic mechanism triggered by Hp infection potentially contributing to the pathogenesis of PE. Sera from 93 preeclamptic women and 87 healthy pregnant women were tested for Hp infection by immunoassay and for anti-CagA antibodies by Western blot assay. The serologic results were correlated with the clinical features of PE. The functional effect of serum IgG fractions, positive or negative for Hp, from preeclamptic women or controls were tested on trophoblast and endothelial cell cultures and in a murine model of angiogenesis. Preeclamptic women showed higher seroprevalence of Hp infection (57.0%) compared to controls (33.3%) (P<.001). The seropositivity for CagA-positive strains of Hp was 45.2% in preeclamptic women vs 13.7% in controls (P<.001). In PE women, Hp infection was associated with abnormality of uterine arteries Doppler (P<.001). Hp+ IgG fractions from preeclamptic women bound to trophoblast and endometrial endothelial cell cultures, reducing in vitro invasiveness and angiogenesis, respectively, and inhibited angiogenesis in mice. Our data show, for the first time, an association between Hp infection and PE with abnormal uterine arteries Doppler velocimetry, suggesting a role for Hp infection in impairing placental development and increasing the risk to develop PE. This study opens the new perspective of a potential screening and treatment for Hp infection in pregnancy.

Number of decidual natural killer cells & macrophages in pre-eclampsia.

Background & objectives:The process of human placentation is complex and still not well understood. This study was aimed to examine the relationship between clinical features of pre-eclampsia and degree of trophoblastic invasion after its immunohistochemical visualization in the context of possible alterations in the number of natural killer (NK) cells and macrophages in the decidua.Methods:This prospective study included a study group comprising 30 pregnant women with pre-eclampsia delivered by caesarean section and a control group comprising 20 healthy pregnant women also delivered by caesarean section. Samples of placental bed obtained during caesarean section were analyzed after immunohistochemical labelling CD56+ NK cells, CD68+ macrophages and cytokeratin 7 trophoblastic cells.Results:In pre-eclampsia, there was a significantly lower number of CD56+ NK cells in the decidua (P<0.001) and a higher number of CD68+ macrophages (P<0.001) compared to control group. In the subgroup of pre-eclampsia with intrauterine growth retardation (IUGR), a significantly greater number of NK cells (P<0.05) was recorded, as well as an increased number of macrophages, but not significantly compared to pre-eclampsia without IUGR. There was no significant difference in the distribution of these cells in the decidua in relation to the severity of pre-eclampsia. CD56+ NK cells were significantly less (P<0.05) and macrophages were more (P<0.05) in the group with poor trophoblastic invasion.Interpretation & conclusions:Alterations in the number of immune cells in relation to the degree of trophoblastic invasion indicated their role in aetiopathogenesis of pre-eclampsia, while the direct association between their number and severity of pre-eclampsia was not confirmed.

The changes of LCHAD in preeclampsia with different clinical features and the correlation with NADPH P47-phox, p38MAPK-α, COX-2 and serum FFA and TG

Objective To investigate the changes of fatty acid oxidase in the placenta of preeclampsia cases with different clinical features, and the relationship with oxidative stress and inflammatory response. To study the correlation of serum free fatty acid (FFA) and triglycerides (TG) level in early second trimester with the molecular changes of the long-chain fatty acid oxidase in the third trimester. Methods This was prospective cohort study, in which cases with singleton pregnancies who archived in Haidian Maternal and Children's Hospital, Beijing, from January 1st 2012 to May 31st, with regular prenatal care were included. Doppler ultrasound was used for screening for the presence of early diastolic notch of uterine artery at 22-24 weeks of gestation. All the 101 cases with the early diastolic notch of uterine artery were included as the notch group, and 377 cases without the early diastolic notch of uterine artery were included as the non-notch group. The perinatal outcomes and the incidence of hypertensive disorders in pregnancy of the two groups were observed. The serum level of FFA and TG was tested, and the mRNA and protein expression of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), P47-phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, p38 mitogen-activated protein kinase α(p38MAPK-α) and cyclooxygenase-2 (COX-2) were detected using real-time quantitative PCR and western blot. The relationship between serum level of FFA and TG and the mRNA and protein expression of LCHAD, NADPH P47-phox,p38MAPK-α and COX-2 of the placental tissue specimens were analyzed. Results (1) In the notch group, there were 9 cases of early-onset preeclampsia, 15 cases of late-onset preeclampsia and 10 cases of gestational hypertension; and there were 8 cases of late-onset preeclampsia and 18 cases of gestational hypertension in the non-notch group. 15 cases with normal blood pressure in each group were randomly selected as the control group.(2)The serum level of TG of cases of early-onset preeclampsia, late-onset preeclampsia and gestational hypertension in the notch group were(2.0 ± 0.8),(1.8 ± 0.6) and(1.9±0.7)mmol/L, and that of FFA were(0.68±0.26), (0.52±0.10) and (0.52±0.17) mmol/L, respectively. The serum level of TG of cases of late-onset preeclampsia and gestational hypertension in the non-notch group were(1.6±0.6) and (1.4±0.4) mmol/L, and that of FFA were (0.49±0.11) and (0.48±0.05) mmol/L, respectively. The serum level of TG and FFA in the control group were (1.4±0.5) and (0.52±0.06) mmol/L, respectively. The TG level of the notch group was higher than that of the control group, and the difference was statistically significant (P 0.05) . (6) The mRNA expression of placental LCHAD in the early-onset preeclampsia in the notch group was significantly negatively correlated with the mRNA expression of placental NADPH P47-phox and COX-2 (r=- 0.877,-0.762,P<0.05). The mRNA expression of placental LCHAD in the control group was significantly negatively correlated with the mRNA expression of placental COX-2 (r=-0.565,P<0.01). The protein expression of placental LCHAD in the early-onset preeclampsia in the notch group was significantly negatively correlated with the protein expression of NADPH P47-phox (r=-0.818,P<0.01). The protein expression of placental LCHAD in the control group was significantly negatively correlated with the protein expression of COX-2 (r=-0.502,P<0.01). Conclusions The placental mRNA and protein expression of long-chain fatty acid oxidation enzymes were different in different clinical features of preeclampsia, which were reduced more obviously in the early-onset preeclampsia in the notch group than that of the late-onset preeclampsia in the notch group, and were negatively correlated with the elevated serum FFA level, significantly enhanced oxidative stress and inflammatory response, but with no correlation with serum TG level. Key words: Pre-eclampsia; 3-Hydroxyacyl CoA dehydrogenases; NADPH oxidase; Fatty acids, nonesterified; Triglycerides; Oxidative stress

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Podocyturia Predates Proteinuria and Clinical Features of Preeclampsia

Podocyturia, the shedding of live podocytes, is present at delivery in women with preeclampsia. The aim of this study was to test whether podocyturia is present earlier in pregnancy and predicts for preeclampsia. We also aimed to compare test characteristics of podocyturia with those of angiogenic factors previously implicated in the pathogenesis of this disorder. We prospectively enrolled 315 women who provided blood and urine samples at the end of the second trimesters of their pregnancies (median, 27 gestational weeks) and within 24 hours of their deliveries (median, 39.5 gestational weeks). Blood samples were analyzed for angiogenic markers, including placental growth factor, the soluble receptor fms-like tyrosine kinase receptor-1 for vascular endothelial growth factor, and endoglin. The urine sediments were analyzed for podocytes, identified by staining for podocin after culturing the urinary sediments for 24 hours. This analysis included all women who developed preeclampsia (n=15), gestational hypertension (n=15), and a subsample of women who remained normotensive throughout pregnancy (n=44), matched for maternal age and number of previous pregnancies to those who developed preeclampsia. At the second trimester collection, all women who developed preeclampsia had podocyturia, compared with none of those who remained normotensive or were diagnosed with gestational hypertension. Podocyturia in the second trimester had a significantly greater sensitivity and specificity for the subsequent diagnosis of preeclampsia than any single angiogenic marker or a combination thereof. Screening for podocyturia at the end of the second trimester may allow for accurate identification of pregnant women at risk for preeclampsia.

PM.18 Maternal Resting Peripheral Blood Flow and Tissue Oxygenation in Pregnancies Complicated with Pre-Eclampsia and IUGR

BackgroundPre-eclampsia is characterised by hypertension and proteinuria and associated with systemic hypoperfusion of multiple maternal organs. Intrauterine growth restriction (IUGR) is a recognised complication of pre-eclampsia and the two conditions...

Angiotensin Receptor Agonistic Autoantibody Is Highly Prevalent in Preeclampsia

Preeclampsia (PE), a syndrome affecting 5% of pregnancies, characterized by hypertension and proteinuria, is a leading cause of maternal and fetal morbidity and mortality. The condition is often accompanied by the presence of a circulating maternal autoantibody, the angiotensin II type I receptor agonistic autoantibody (AT 1 -AA). However, the prevalence of AT 1 -AA in PE remains unknown, and the correlation of AT 1 -AA titers with the severity of the disease remains undetermined. We used a sensitive and high-throughput luciferase bioassay to detect AT 1 -AA levels in the serum of 30 normal, 37 preeclamptic (10 mild and 27 severe), and 23 gestational hypertensive individuals. Here we report that AT 1 -AA is highly prevalent in PE (≈95%). Next, by comparing the levels of AT 1 -AA among women with mild and severe PE, we found that the titer of AT 1 -AA is proportional to the severity of the disease. Intriguingly, among severe preeclamptic patients, we discovered that the titer of AT 1 -AA is significantly correlated with the clinical features of PE: systolic blood pressure ( r =0.56), proteinuria ( r =0.70), and soluble fms-like tyrosine kinase-1 level ( r =0.71), respectively. Notably, only AT 1 -AA, and not soluble fms-like tyrosine kinase-1, levels are elevated in gestational hypertensive patients. These data serve as compelling clinical evidence that AT 1 -AA is highly prevalent in PE, and its titer is strongly correlated to the severity of the disease.

Differential effects of sera from normotensive and hypertensive pregnant women on Ca(2+) metabolism in normal vasular smooth muscle cells.

The clinical features of preeclampsia have been traditionally ascribed to a generalized vascular endothelial cell dysfunction. The present study investigates the effect of sera from preeclamptic women and normal pregnancy on the metabolism of intracellular Ca(2+) concentration ([Ca(2+)](i)) in normal cultured vascular smooth muscle cells (VSMC). Sera were obtained from normotensive pregnant women (NTP) (n = 17), preeclamptic women (PE) (n = 15), pregnant women with chronic (essential) hypertension (pregnant EHT) (n = 8), non-pregnant women with essential hypertension (non-pregnant EHT) (n = 12), and age-matched non-pregnant normotensive women (NNP) (n = 18). Serum (10%) was applied to both primary cultures of rat aortic smooth muscle cells and to the A-10 vascular muscle cell line. Levels of [Ca(2+)](i) were determined fluorometrically. After a 4-h incubation with serum, basal [Ca(2+)](i) was not significantly altered. However, compared with normal pregnant sera, PE sera markedly reduced hormonally induced Ca(2+) transients. Thus, following acute stimulation of rat VSMC (primary cultures) with 10(-8)M angiotensin II, peak [Ca(2+)](i) responses (% increment over baseline) were 443 +/- 22, 184 +/- 18, 259 +/- 12, 274 +/- 23, and 255 +/- 15% in NTP, PE, pregnant EHT, non-pregnant EHT, and NNP, respectively (P <0.01 PE versus NTP, P <0.05 PE versus NNP and pregnant and non-pregnant EHT). These effects of sera on [Ca(2+)](i) were qualitatively reproduced in platelets obtained from healthy volunteers. Also, depolarization-activated Ca(2+) influx in VSMC was affected by the different sera groups in a manner similar to that seen with hormonally induced [Ca(2+)](i) responses. The altered [Ca(2+)](i) changes by PE sera disappeared 5 wk after delivery. The effect of the different sera groups on hormonally triggered Ca(2+) transients in normal VSMC, as well as the normalization of [Ca(2+)](i) responses after delivery, suggest the presence of a circulating serum factor in PE. Inasmuch as [Ca(2+)](i) is the major determinant of VSMC tone, it is possible that consequent to the attenuation of [Ca(2+)](i) responses, this putative circulating factor counterbalances the intense vasoconstriction in PE.

High plasma cellular fibronectin levels correlate with biochemical and clinical features of preeclampsia but cannot be attributed to hypertension alone

Current concepts of the pathogenesis of preeclampsia involve the generalized dysfunction of maternal vascular endothelial cells. We measured the endothelial isoform of fibronectin as a marker of endothelial cell injury throughout pregnancy in a prospective, case-control study. Nineteen women met strict criteria for the diagnosis of preeclampsia. Nineteen normal pregnant women, and 19 women with gestational hypertension but without other stigmata of preeclampsia (transient hypertension) were selected from the same cohort and matched according to race, age, nulliparity, and gestational age at delivery. Plasma levels of cellular fibronectin were significantly elevated in women meeting strict clinical and biochemical criteria for preeclampsia but not in women with normal pregnancies or transient hypertension. Moderate but significant elevations in mean levels were found in the second trimester in women destined to have preeclampsia, as compared with matched normal and transient hypertension groups (p \\lt 0.05). The results indicate that elevated plasma levels of cellular fibronectin are not simply the result of increased blood pressure but reflect a maternal insult specific to the syndrome of preeclampsia. Elevation of the mean concentration during the midtrimester is consistent with the hypothesis that endothelial cell injury is a specific lesion that occurs early in the course of preeclampsia, before clinical signs and symptoms.

Control of Vascular Reactivity in Pregnancy Induced Hypertension

To evaluate the possibility that vascular reactivity in umbilical artery is different in normal and pre-eclamptic condition, we assessed an “in vitro study” on strips of umbilical arteries removed at the end of normal and pre-eclamptic pregnancy. We studied the reactivity of those arteries to prostaglandin A1 and prostaglandin F2α-The dose-response analysis to prostaglandins on normal umbilical arteries were between 10−7 and 10−4; in contrast, the results obtained on arteries removed at the end of pre-eclamptic pregnancies were not consistent. In this group a tendency to two different distributions seemed to occur and was related to different clinical features of pre-eclampsia, namely the early and the late onset of the disease. Our results suggest that the various clinical pictures of pre-eclampsia correlate with different conditions of vascular reactivity.

Circulating immune complexes in pre-eclampsia.

Sixteen patients with severe pre-eclampsia had more IgG-containing and C1q-binding circulating soluble immune complexes than did 16 matched women with normal pregnancies. The clinical features of preeclampsia may be explained by damage due to such complexes, although raised complex levels were also present in a few women with normal pregnancies. As immune complexes are so heterogenous in terms of the type of antigen, class and subclass of immunoglobulin, size, and complement-binding capacity, further investigations are needed to determine their role in normal and pre-eclamptic pregnancies.