Clinical Manifestations Of Preeclampsia Research Articles

NFAT5 Is Up-Regulated by Hypoxia: Possible Implications in Preeclampsia and Intrauterine Growth Restriction.

During gestation, low oxygen environment is a major determinant of early placentation process, while persistent placental hypoxia leads to pregnancy-related complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR). PE affects 5%-8% of all pregnancies worldwide and is a cause of maternal and fetal morbidity and mortality. During placental development, persistent hypoxia due to poor trophoblast invasion and reduced uteroplacental perfusion leads to maternal endothelial dysfunction and clinical manifestation of PE. Here we hypothesized that nuclear factor of activated T cells-5 (NFAT5), a well-known osmosensitive renal factor and recently characterized hypoxia-inducible protein, is also activated in vivo in placentas of PE and IUGR complications as well as in the in vitro model of trophoblast hypoxia. In JAR cells, low oxygen tension (1% O2) induced NFAT5 mRNA and increased its nuclear abundance, peaking at 16 h. This increase did not occur in parallel with the earlier HIF1A induction. Real-time PCR and Western blot analysis confirmed up-regulation of NFAT5 mRNA and NFAT5 nuclear content in human preeclamptic placentas and in rabbit placentas of an experimentally induced IUGR model, as compared with the control groups. In vitro lambda protein phosphatase (lambda PPase) treatment revealed that increased abundance of NFAT5 protein in nuclei of either JAR cells (16 h of hypoxia) or PE and IUGR placentas is at least partially due to NFAT5 phosphorylation. NFAT5 downstream targets aldose reductase (AR) and sodium-myo-inositol cotransporter (SMIT; official symbol SLC5A3) were not significantly up-regulated either in JAR cells exposed to hypoxia or in placentas of PE- and IUGR-complicated pregnancies, suggesting that hypoxia-dependent activation of NFAT5 serves as a separate function to its tonicity-dependent stimulation. In conclusion, we propose that NFAT5 may serve as a novel marker of placental hypoxia and ischemia independently of HIF1A.

CD14++ CD16+ HLA-DR+ Monocytes in Peripheral Blood are Quantitatively Correlated with the Severity of Pre-eclampsia.

We aim to investigate the proportion and absolute counts of peripheral blood monocyte subsets in women with normal pregnancy (NP) and pre-eclampsia (PE), and their correlation with the clinical manifestation and severity of PE. Peripheral blood was obtained from women with NP (n = 30), mild PE (MPE, n = 15) and severe PE (SPE, n = 30). The proportion and absolute counts of CD16(+) monocytes and the subsets including intermediate (CD14(++) CD16(+) HLA-DR(+) ) and non-classical (CD14(+) CD16(++) HLA-DR(+) ) monocytes were determined by flow cytometric analysis. Women with MPE and SPE had significantly increased absolute count of CD14(++) CD16(+) HLA-DR(+) monocyte subsets (P < 0.01 each) as compared to NP women. In addition, there were significant differences in the absolute count of CD14(++) CD16(+) HLA-DR(+) monocyte subsets between MPE and SPE groups (P < 0.05). The proportion of CD14(++) CD16(+) HLA-DR(+) monocyte subsets was significantly increased in SPE compared to MPE and NP (P < 0.01 each). The absolute count (r = 0.332, P < 0.05) and proportion (r = 0.447, P < 0.01) of CD14(++) CD16(+) HLA-DR(+) monocytes were positively correlated with the severity of PE. Multivariate logistic regression analysis further revealed that the absolute count of CD14(++) CD16(+) HLA-DR(+) monocytes was a potential marker for PE (P < 0.01). A preferential increase in peripheral blood CD14(++) CD16(+) HLA-DR(+) monocytes is quantitatively correlated with clinical manifestation of PE.

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Objectives Pre-eclampsia is associated with a breakdown of maternal immune tolerance, although the role of fetal immunity is unknown. Nevertheless, morphological change of the fetal thymus is observed in pre-eclampsia. The aim of this study was to investigate fetal thymus size at mid-gestation, and its relationship to pre-eclampsia. We hypothesized that the fetal thymus would be smaller in women later diagnosed with pre-eclampsia. Methods This was a prospective cohort study performed at Nepean Hospital, Australia. Pregnant women carrying a single fetus were recruited between 15/1/2011 and 15/7/2013, during their mid-gestation scan. Within an image of the right ventricular outflow tract, fetal thymus diameter was measured as its widest diameter, perpendicular to a line connecting the sternum and spine. The Nepean obstetric database was later searched to identify pre-eclampsia diagnoses. Logistic regression techniques modelled the odds of pre-eclampsia based on fetal thymus diameter, adjusted for confounding variables. Results In total, 886 pregnancies were included (pre-eclampsia = 24, control = 862). In univariate analysis, a 1 mm decrease in thymus diameter was associated with a significantly increased odds of pre-eclampsia (OR 1.41 (1.17–1.69); p = 0.0003). Multiple logistic regression, which adjusted for gestation and maternal BMI, also showed a small thymus diameter to be significantly linked to pre-eclampsia (OR 1.47 (1.22, 1.78); p Conclusions This prospective study offers high quality evidence that the fetal thymus is altered at mid-gestation, well before any clinical manifestations of pre-eclampsia. Whether this signifies a primary role for fetal immunity in disease pathogenesis is yet to be determined. Disclosures D. Eviston: None. A. Quinton: None. A. Martin: None. R. Benzie: None. M. Peek: None. R. Nanan: None.

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.

Endothelial function and uterine perfusion and subsequent pregnancies complicated by preeclampsia

Introduction: the pathophysiology of pre-eclampsia (PE) is based on a deficiency in the placenta formation process, associated to systemic maternal endothelial dysfunction. The occurrence of these phenomena before the appearance of the clinical manifestations of PE should be investigated, considering that new propaedeutic methods are available for prediction. Objective: to compare placenta formation process and endothelial function of high-risk pregnant women and correlate them with the occurrence of PE. Patients and methods: 74 pregnant women were subjected to flow mediated dilation (FMD) of the brachial artery and Doppler flux of uterine arteries to assess the endothelial function and the placenta formation process, respectively, between the 16th and 20th gestation weeks and followed until the puerperal period. Results: 15 patients had their pregnancies complicated by PE while 59 remained normotensive until the puerperium. Patients who subsequently developed PE showed, between gestation weeks 16 and 20, high scores in the pulsatility index for uterine arteries (p<0.001), but the FDM analysis presented no difference in relation to the patients who continued normotensive. Conclusion: data suggest that deficiencies in the placenta formation process chronologically precedes the clinical manifestation of PE, which does not occur with endothelial dysfunction.

The importance of “first-blood circulation stage”, a new insight into the pathogenesis of clinical manifestations of preeclampsia

The tested hypothesis points out that exposure to environmental toxic substances originating from coal or other fossil fuels burning is the most decisive for the impacts of the metabolic synergy of nitrogen oxides as oxidants that cause hemoglobin oxidation to methemoglobin, and sulphur dioxide metabolites as inhibitors of antioxidants, in the bloodstream throughout the period of pregnancy. The main difference between the present three-stage hypothesis and other hypotheses is the assertion that, in the pathogenesis of early and late complicated pregnancy, methemoglobin takes on an important role. Methemoglobin by itself and from heme, redox-active ferric iron as a product of methemoglobin catabolism, has prooxidant properties and causes important structural and functional changes in the vascular endothelium, such as growth arrest, senescence, morphological alterations and cell apoptosis. Our own prospective study of methemoglobin in pregnancy revealed a significant rise and correlation between the ground level of SO2 and the level of methemoglobin: >1.5 g/L (r = 0.72, p 2, NOx, NO, NO2 and others) and that is an early biomarker of the identification of women with a pregnancy risk, and having an significant role upon adverse effects on mother and fetus health.

Preeclampsia and diuresis criteria: our experience at the University of Iowa Hospitals and Clinics

Preeclampsia is a multisystem disorder that complicates approximately 5-8% of pregnancies. It is known that the clinical manifestations of preeclampsia are a result of widespread vasoconstriction. It is therefore thought that the onset of diuresis may signal a reversal of this vasoconstriction, and thus resolution of the disease. This retrospective cohort study was conducted at the University of Iowa Hospitals and Clinics (UIHC) to validate our diuresis criteria and determine if there was a trend for diuresis that was dependent on the type of preeclampsia. This study suggests that the diuresis curves for those women with mild preeclampsia and severe preeclampsia do not vary significantly after the first 5 hours We were able to separate the women with severe preeclampsia into two groups, one of which would have met our diuresis criteria prior to 24 hours and the other of which would not have met diuresis criteria at 24 hours post-delivery.

Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease.

Preeclampsia is a clinical syndrome defined as the new onset of hypertension and proteinuria during the second half of pregnancy.1 It afflicts 3% to 5% of pregnancies and is a leading cause of maternal mortality, especially in developing countries.2,3 Because the only known remedy is delivery of the placenta, in developed countries preeclampsia is an important cause of premature delivery, usually medically indicated for the benefit of the mother. This results in infant morbidity and substantial healthcare expenditure.4 Despite the considerable morbidity and mortality, the cause of preeclampsia has remained enigmatic. Both hypertension and proteinuria implicate the endothelium as the target of the disease. The hypertension of preeclampsia is characterized by peripheral vasoconstriction and decreased arterial compliance.5,6 The proteinuria of preeclampsia is associated with a pathognomonic renal lesion known as glomerular endotheliosis, in which the endothelial cells of the glomerulus swell and endothelial fenestrations are lost.7,8 Podocyturia has been recently associated with preeclampsia during clinical disease9; however, whether this is the cause or effect of proteinuria is unknown. The glomerular filtration rate is decreased compared with normotensive pregnant women; in rare cases, acute renal failure may develop. Preeclampsia is a systemic vascular disorder that may also affect the liver and the brain in the mothers. When the liver is involved, women may present with abdominal pain, nausea, vomiting, and elevated liver enzymes. Pathological examination of the liver reveals periportal and sinusoidal fibrin deposition and, in more extreme cases, hemorrhage and necrosis.10 The severe preeclampsia variant HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurs in ≈20% of women with severe preeclampsia,11 and is named not only for the liver involvement, but also for the disorder of the coagulation system that develops.12 Approximately 20% of …

Preeclampsia: Effect on the Fetus and Newborn

Preeclampsia (PE) is the most common medical complication in pregnancy and a major cause of maternal and fetal morbidity and mortality. This disease is a great challenge for obstetricians because there are no effective interventions to treat or prevent it, and antenatal care involves a difficult balance between the risks for women to continue pregnancy and the risks for the baby’s early birth. Fetal complications in PE are directly related to gestational age and the severity of maternal disease and include increased rates of preterm delivery, intrauterine growth restriction, placental abruption, and perinatal death. The major complications for the newborn are related to prematurity, although the data on the morbidity and outcome for preterm infants of women who have PE are conflicting, and few studies address this issue. The pathogenesis of PE involves abnormal placentation associated with immune and vascular events that result in endothelial dysfunction and clinical manifestations of PE. This disease has been associated with imbalance in angiogenic factors and oxidative stress. Nevertheless, only a limited number of studies have been carried out on fetuses and newborns that suggest that infants born from women who have PE are exposed to increased oxidative stress. Because oxidative stress and free radicals may play roles in several neonatal diseases, a direct effect of maternal disease on neonatal outcome is expected, and further research on such neonates, in the short- and long-term, is urgently needed.

Pré-eclâmpsia: estresse oxidativo, inflamação e disfunção endotelial

Preeclampsia is a systemic syndrome characterized by inflammatory and antiangiogenic states. The pathogenesis of preeclampsia involves deficient trophoblast invasion that is responsible for altered uterine blood flow and placental oxidative stress. The damaged placenta produces higher concentrations of sFlt-1, a soluble receptor for VEGF and PlGF that is released in the maternal circulation and is involved in endothelial dysfunction. Actually, all processes involved in inflammation, endothelial dysfunction and oxidative stress are strongly correlated and act in a synergistic way. Recent data have shown that an increase in serum concentrations of sFlt-1 initiates 5 to 6 weeks before the clinical manifestations of preeclampsia and these alterations correlate with a decrease in serum concentrations of PlGF. Therefore, both sFlt-1 and PlGF have been suggested to be useful for an early-diagnosis of preeclampsia. The knowledge about the role of antiangiogenic factors in the pathogenesis of preeclampsia has raised the possibility of a therapy involving these factors.In this article we revisited the pathogenesis of preeclampsia addressing its antiangiogenic and inflammatory states.In conclusion, we correlated these alterations with the higher risk for cardiovascular diseases presented by these women in future life.

Erythrocyte Markers of Oxidative Stress in Higher Age-Group Preeclamptic and Normal Pregnant Mothers

Preeclampsia can have significant impact on health of both mother and fetus. It had been proposed that maternal endothelial cell dysfunction is the key event resulting in the diverse clinical manifestations of preeclampsia and evidence has since accumulated. Research in recent times is indicative of the role of oxidative stress in the endothelial cell dysfunction. Preeclampsia is more common in first pregnancy and studies have further shown an increase in risk of preeclampsia with maternal age. The aim of this study was to explore the status of oxidative stress in higher age-group preeclamptic and normal pregnant mother. The study included 20 normal pregnant women and 60 preeclamptic women. They were allocated into 4 subgroups between ages 20–25, 26–30, 31–35, and 36–40. Erythrocytes were analyzed for the following antioxidant enzymes, i.e., glutathione peroxidase, superoxide dismutase and catalase.Lipid peroxidation product, malondialdehyde, was analyzed to determine oxidative stress. The results showed an increase in oxidative stress, and high magnitude suppression/decrease in antioxidant enzymes activities in erythrocytes with increase in age groups in both preeclamptic and normal pregnant women. This indicates that an increase in the risk of preeclampsia with maternal age could be due to an increase in oxidative stress with age. This further attests to the role of oxidative stress in preeclampsia.

Low catechol-O-methyltransferase and 2-methoxyestradiol in preeclampsia: more than a unifying hypothesis

Preeclampsia is a systemic disorder of pregnancy characterized by widespread maternal endothelial dysfunction. Clinical manifestations of preeclampsia include placental hypoxia, hypertension, proteinuria and fluid retention. The condition is common and affects over 5% of all pregnancies, thus remaining a leading cause of maternal and fetal morbidity and mortality worldwide [1]. Pregnancies complicated by preeclampsia are associated with greater risk and earlier onset of cardiovascular disease in both mother and infant [2,3]. Preeclampsia originates in the placenta, as it may occur only in the presence of placenta or a hydatiform mole and resolves dramatically postpartum after the delivery of the placenta. Generalized endothelial dysfunction resulting in vasoconstriction and end-organ ischaemia is attributed in all of the clinical aspects of the maternal syndrome in preeclampsia. Search for a unique circulating factor [4] resulted in an identification of multiple factors of endothelial dysfunction, activation and oxidative stress. A major breakthrough was achieved during the past five years by a series of experimental and clinical studies from Karumanchi and associates implicating that changes in circulating angiogenic factors play a decisive role in the pathogenesis of preeclampsia (reviewed in [5]). Increased expression of soluble fms-like tyrosine kinase 1 (sFlt1), a variantofthemembrane-boundvascularendothelialgrowth factor (VEGF)-receptor 1 that consists of the extracellular ligand-binding domain, was associated with decreased placental growth factor (PIGF) and VEGF signalling and consecutive defective angiogenesis [6]. Soluble Flt1 acts as a natural antagonist of the circulating VEGF and increases from mid-gestation onwards, to reach the peak 5–8 weeks before the onset of the maternal syndrome [7]. Soluble

449: Human telomerase reverse transcriptase (hTERT) mRNA expression in hypertensive disorders of pregnancy

HYPERTENSIVE DISORDERS OF PREGNANCY YALI XIONG, DAN LIEBERMANN, ELI J HOLTZMAN, BARBARA HOFFMAN, STACEY JERONIS, SARMINA HASSAN, ENRIQUE HERNANDEZ, OSSIE GEIFMAN-HOLTZMAN, Temple University School of Medicine, Temple University, Obstetrics & Gynecology, Philadelphia, Pennsylvania, Temple University School of Medicine, Temple University, Department of Biochemistry, Fels Institute, Philadelphia, Pennsylvania, Sheba Medical Center, Tel-Aviv University, Israel, Nephrology and Hypertension Unit, Ramat-Gan, Israel OBJECTIVE: To assess hTERT mRNA levels and telomerase activity in different categories of hypertensive disease in pregnancy. STUDY DESIGN: Fresh placental biopsies were collected from 60 patients: the preeclampsia study group, 32 pregnant patients (8 term (T) and 24 preterm (PT) gestation) and non-preeclampsia, control group, 29 pregnant patients (16 T and 13 PT). Total RNA was isolated from placenta tissue and reversely transcribed to c-DNA. The hTERT mRNA relative expression level was detected with a probespecific real-time quantitative PCR assay using -actin as the reference gene. Statistical analysis was performed using the student t test. Parallel experiments to detect the telomerase activity were also employed with the TRAPeze gel-based telomerase detection assay: telomerase from each placental sample was isolated and applied to add telomeric repeats (GGTTAG) onto the 3= end of a substrate oligonucleotide. The extended products were amplified by PCR and the telomerase activity was determined by the size of the extended product with PAGE gel electrophoresis. RESULTS: The ratio of average hTERT mRNA levels in the study group were higher than those in the control group in both preterm (1.71 versus 0.88, p 0.05) and term placentas (1.66 versus 1.15, p 0.05). In the study group, the HELLP cases and the severe preeclampsia cases had the highest average ratios of hTERT mRNA levels: 1.81, 1.80 respectively. The average ratios of eclamptic and preeclamptic mRNA levels were 1.76 and 1.65. In both the preeclamptic (ratio: 1.78 versus 1.54, p 0.05) and control groups (ratio: 1.13 versus 0.93, p 0.05), hTERT mRNA levels were higher in the placentas obtained from patients with Body-mass index (BMI) above 30 compared with patients with lower BMI. The telomerase activity differences were not detected using TRAPeze gel-based telomerase detection assay. CONCLUSION: This work provides novel data on telomerase biology which correlates the elevated hTERT mRNA expression with the progressive clinical manifestations of preeclampsia

Emerging Roles of Antiangiogenic and Angiogenic Proteins in Pathogenesis and Prediction of Preeclampsia

Hypertensive disorders are a major cause of maternal and fetal death, especially in developing nations, with the pregnancy-specific disease preeclampsia-eclampsia responsible for most of this mortality. Preeclampsia, recognized by ancient Greeks, was only sporadically investigated until late last century, current literature still labeling this disorder a “disease of theories.” Thus, not surprisingly, we have started the new millennium unable to predict or prevent preeclampsia, and management strategies remain but supportive, with pregnancy termination still the only definitive “therapy.” This may be about to change, as focused research, mainly in the past decade, has resulted in dramatic progress regarding pathogenesis of disease manifestations and risk assessment, while investigators have begun designing and testing definitive therapy.1 There are still a myriad of uncertainties and unanswered questions to address, but here we summarize the extent of 1 new and exciting chapter in preeclampsia research: the roles of angiogenic and antiangiogenic factors, to which an article in this issue by Rana and colleagues,2 contributes. A landmark report published in 2003 set the stage for all that followed.3 Dr Karumanchi’s laboratory, previously involved in renal cancer research, changed its focus to the kidney in preeclampsia. Using microarray chip technology, they probed gene expression profiles in placentas of women with preeclampsia and those with uncomplicated pregnancies. Of course many differences were noted, but one that caught the investigators’ attention was upregulation of the mRNA for the antiangiogenic protein soluble fms-like tyrosine kinase 1 (abbreviated as sFlt-1 or sVEGFR-1) in placentas from women with preeclampsia. Aware that de novo hypertension and proteinuria were 2 disturbing side effects of certain antiangiogenic compounds tested in cancer patients, these …

Analysis of cardiovascular oscillations: A new approach to the early prediction of pre-eclampsia

Pre-eclampsia (PE) is a serious disorder with high morbidity and mortality occurring during pregnancy; 3%-5% of all pregnant women are affected. Early prediction is still insufficient in clinical practice. Although most pre-eclamptic patients show pathological uterine perfusion in the second trimester, this parameter has a positive predictive accuracy of only 30%, which makes it unsuitable for early, reliable prediction. The study is based on the hypothesis that alterations in cardiovascular regulatory behavior can be used to predict PE. Ninety-six pregnant women in whom Doppler investigation detected perfusion disorders of the uterine arteries were included in the study. Twenty-four of these pregnant women developed PE after the 30th week of gestation. During pregnancy, additional several noninvasive continuous blood pressure recordings were made over 30 min under resting conditions by means of a finger cuff. The time series extracted of systolic as well as diastolic beat-to-beat pressures and the heart rate were studied by variability and coupling analysis to find predictive factors preceding genesis of the disease. In the period between the 18th and 26th weeks of pregnancy, three special variability and baroreflex parameters were able to predict PE several weeks before clinical manifestation. Discriminant function analysis of these parameters was able to predict PE with a sensitivity and specificity of 87.5% and a positive predictive value of 70%. The combined clinical assessment of uterine perfusion and cardiovascular variability demonstrates the best current prediction several weeks before clinical manifestation of PE.

Amniotomy in labor

pregnancies. TBARS levels reflect oxidative stress and seem to increase in certain complications of pregnancy [3]. In this study, TBARS levels increased both in maternal and umbilical cord plasma of preeclamptic patients while levels in placenta did not change. Increased TBARS levels reflect lipid peroxidation in cells and may suggest decreased enzymatic free radical scavenging capacity in preeclamptic patients. These findings are consistent with previous studies that search factors involved in the pathogenesis of preeclampsia [4]. Multiple factors result in endothelial cell dysfunction and contribute to the clinical manifestations of preeclampsia [4]. References

Hepatocyte growth factor as a second trimester marker for preeclampsia

PREECLAMPSIA CHRISTOPHER ROBINSON, DONNA JOHNSON, Medical University of South Carolina, Obstetrics and Gynecology, Charleston, South Carolina OBJECTIVE: Hepatocyte growth factor (HGF), a hormone produced by placental trophoblasts, is recognized as an important cytokine involved in placental development. HGF knockout animal models display a phenotype of placental insufficiency. HGF has been shown to be reduced in human serum at the onset of clinical preeclampsia. This study was undertaken to determine if serum HGF levels are altered in the second trimester prior to the onset of clinical preeclampsia. STUDY DESIGN: Following IRB approval, serum drawn from 15-20 weeks gestation was obtained from 70 C storage for healthy controls and patients who developed severe preeclampsia as defined by ACOG criteria. Patients were matched for age and gestational age at blood draw. HGF concentration was quantitated by ELISA and reported as mean G standard deviation in pg/mL. Statistical analysis was performed with independent sample T test, chi square, and Fisher’s exact test where appropriate. RESULTS: 44 controls and 37 patients with severe preeclampsia were enrolled. Age (p=0.48) and gestational age at blood draw (p=0.27) were both similar between groups. However, HGF was not different in second trimester serum in patients who later developed severe preeclampsia compared to healthy normotensive patients (1330 G 690 vs. 1130 G 580, p=0.27). CONCLUSION: Although HGF has been reported to be altered in serum of patients who have clinical manifestations of preeclampsia, it does not appear to be altered earlier as measured in the second trimester. HGF alone is not a candidate marker for early detection of preeclampsia as measured in the second trimester.

Comparison of activin A and cell-free fetal DNA levels in maternal plasma from patients at high risk for preeclampsia

We examined the concentration of activin A in a prospective manner before the clinical manifestation of preeclampsia and compared the data with those of cell-free fetal DNA in the maternal plasma. The levels of activin A were analysed by enzyme-linked immunosorbent assay (ELISA) for pregnant women: (1) with preeclampsia (n = 34) in the third-trimester and normal controls (n = 44); and (2) at-risk of preeclampsia in the second-trimester (n = 15) as indicated by uterine artery Doppler and normal controls (n = 68). Correlation between activin A level and cell-free fetal DNA level was examined using the Spearman rank test. The level of plasma activin A was significantly higher in the preeclamptic samples (12.056 vs 7.068 ng/mL, p = 0.000). The increase in the activin A concentration was observed prior to the onset of preeclampsia (3.483 vs 1.324 ng/mL, p = 0.000). This increase in activin A correlated significantly with the increased level of cell-free fetal DNA, in the maternal circulation prior to the onset of preeclampsia (r = 0.977, p = 0.000). Our data suggest that circulatory activin A could be an independent biomarker for the early identification and monitoring of preeclampsia.

Angiotensin II Type 1 Receptor Agonistic Antibodies Reflect Fundamental Alterations in the Uteroplacental Vasculature

Abnormal uterine perfusion detected by Doppler sonography reflects impaired trophoblast invasion, a factor involved in the pathogenesis of pregnancy complications such as preeclampsia or intrauterine growth retardation. Recent studies have demonstrated an autoantibody against the angiotensin type 1 (AT1) receptor in pregnant women with preeclampsia. Our aim was to determine whether the AT1 autoantibody precedes the clinical symptoms and is thus predictive of preeclampsia. We therefore detected this antibody in serum from second trimester pregnancies with abnormal uterine perfusion because these women show an indirect sign of inadequate trophoblast invasion. Then the AT1 autoantibody distribution/concentration was compared with that of women at term with or without pregnancy pathology. The AT1 autoantibody was already detectable in second trimester pregnant women with abnormal uterine perfusion before the clinical manifestation of preeclampsia (80%). However, it was also found in second trimester pregnant women with abnormal uterine perfusion who later developed intrauterine growth retardation (60%) or even had a normal course of pregnancy (62%). In the third trimester, the AT1 autoantibody was demonstrated in 89% of patients with manifest preeclampsia, 86% of those with manifest intrauterine growth retardation, and even in healthy pregnant women at term with a history of abnormal uterine perfusion in the second trimester. We conclude that the AT1 autoantibody is an early but nonspecific marker for preeclampsia. The generation of this antibody seems to be associated with distinct types of pregnancy disorders resulting from impaired placental development. The AT1 autoantibody may thus be causative for pathological uteroplacental perfusion.

Circulating levels of the antiangiogenic marker sFLT-1 are increased in first versus second pregnancies

Preeclampsia is far more common in women's first pregnancy but the mechanism of this association is unknown. Altered angiogenesis, marked by increased levels of circulating soluble fms-like tyrosine kinase (sFlt-1), an inhibitor of placental growth factor (PlGF) and vascular endothelial growth factor, has been implicated in the pathogenesis of preeclampsia. We tested the hypothesis that nulliparous women demonstrate increased sFlt-1 levels compared with multiparous women, suggesting an overall increase in relative antiangiogenesis during first pregnancies. We measured sFlt-1 and PlGF levels in early pregnancy serum samples from the first 2 completed pregnancies of 97 women who participated in the MOMS cohort study. Repeated measures analyses demonstrated that sFlt-1 levels were significantly increased in first compared with second pregnancies (877+/-598 pg/mL vs 728+/-399 pg/mL; P=.01) but there was no significant difference in PlGF levels (45.3+/-40.7 pg/mL vs 40.1+/-31.9 pg/mL; P=.14). After adjusting for age, gestational age, blood pressure, body mass index, smoking, and the interpregnancy time interval, the residual decrease in sFlt-1 levels from the first to the second pregnancy remained significant at 107 pg/mL (P=.04). Significant interaction between ethnicity and pregnancy order on sFlt-1 levels was observed such that Hispanic women demonstrated greater sFlt-1 levels than white women during their first pregnancy but lower levels in their second pregnancies. Increased sFlt-1 secretion in first versus second pregnancies may account in part for the increased risk of preeclampsia among nulliparous women. Additional studies are needed to verify these findings and to further examine ethnic differences in angiogenesis factors and their potential impact on the incidence of preeclampsia.