Clinical Management Of Preeclampsia Research Articles

Preeclampsia Onset, Days to Delivery, and Autism Spectrum Disorders in Offspring: Clinical Birth Cohort Study.

Maternal preeclampsia is associated with a risk of autism spectrum disorders (ASD) in offspring. However, it is unknown whether the increased ASD risk associated with preeclampsia is due to preeclampsia onset or clinical management of preeclampsia after onset, as clinical expectant management of preeclampsia allows pregnant women with this complication to remain pregnant for potentially weeks depending on the onset and severity. Identifying the risk associated with preeclampsia onset and exposure provides evidence to support the care of high-risk pregnancies and reduce adverse effects on offspring. This study aimed to fill the knowledge gap by assessing the ASD risk in children associated with the gestational age of preeclampsia onset and the number of days from preeclampsia onset to delivery. This retrospective population-based clinical cohort study included 364,588 mother-child pairs of singleton births between 2001 and 2014 in a large integrated health care system in Southern California. Maternal social demographic and pregnancy health data, as well as ASD diagnosis in children by the age of 5 years, were extracted from electronic medical records. Cox regression models were used to assess hazard ratios (HRs) of ASD risk in children associated with gestational age of the first occurrence of preeclampsia and the number of days from first occurrence to delivery. Preeclampsia occurred in 16,205 (4.4%) out of 364,588 pregnancies; among the 16,205 pregnancies, 2727 (16.8%) first occurred at <34 weeks gestation, 4466 (27.6%) first occurred between 34 and 37 weeks, and 9012 (55.6%) first occurred at ≥37 weeks. Median days from preeclampsia onset to delivery were 4 (IQR 2,16) days, 1 (IQR 1,3) day, and 1 (IQR 0,1) day for those first occurring at <34, 34-37, and ≥37 weeks, respectively. Early preeclampsia onset was associated with greater ASD risk (P=.003); HRs were 1.62 (95% CI 1.33-1.98), 1.43 (95% CI 1.20-1.69), and 1.23 (95% CI 1.08-1.41), respectively, for onset at <34, 34-37, and ≥37 weeks, relative to the unexposed group. Within the preeclampsia group, the number of days from preeclampsia onset to delivery was not associated with ASD risk in children; the HR was 0.995 (95% CI 0.986-1.004) after adjusting for gestational age of preeclampsia onset. Preeclampsia during pregnancy was associated with ASD risk in children, and the risk was greater with earlier onset. However, the number of days from first preeclampsia onset to delivery was not associated with ASD risk in children. Our study suggests that ASD risk in children associated with preeclampsia is not increased by expectant management of preeclampsia in standard clinical practice. Our results emphasize the need to identify effective approaches to preventing the onset of preeclampsia, especially during early pregnancy. Further research is needed to confirm if this finding applies across different populations and clinical settings.

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles loaded with TFCP2 activate Wnt/β-catenin signaling to alleviate preeclampsia.

Failures in invasive extravillous trophoblasts (EVTs) migration into the maternal uterus have been noticed in preeclampsia (PE). Human umbilical cord mesenchymal stem cell (hUCMSC)-derived extracellular vesicles (EVs) have been highlighted for the role as a potential therapeutic method in PE. This study intends to investigate the mechanistic basis of hUCMSCs-derived EVs loaded with bioinformatically identified TFCP2 in the activities of EVTs of PE. Primary human EVTs were exposed to hypoxic/reoxygenation (H/R) to mimic the environment encountered in PE. The in vivo PE-like phenotypes were induced in mice by reduced uterine perfusion pressure (RUPP) surgery. CCK-8, Transwell and flow cytometry assays were performed to detect proliferation, migration, invasion and apoptosis of H/R-exposed EVTs. More importantly, EVs were extracted from hUCMSCs and transduced with ectopically expressed TFCP2, followed by co-culture with EVTs. TFCP2 was found to be down-regulated in the preeclamptic placental tissues and in H/R-exposed EVTs. hUCMSCs-EVs loaded with TFCP2 activated the Wnt/β-catenin pathway, thereby promoting the proliferative, migratory, and invasive potential of EVTs. Furthermore, overexpression of TFCP2 alleviated PE-like phenotypes in mice, which was associated with activated Wnt/β-catenin pathway. From our data we conclude that hUCMSCs-EVs overexpressing TFCP2 may be instrumental for the therapeutic targeting and clinical management of PE.

PS-C30-14: A CASE OF PREECLAMPSIA DIAGNOSED BY RENAL BIOPSY

Preeclampsia is a complicat ion of pregnancy. With preeclampsia, the patients show high blood pressure and high levels of proteinuria. Preeclampsia usually begins after 20 weeks of pregnancy in women whose blood pressure had previously been in the standard range. If the patients left untreated, preeclampsia can lead to serious complications for both the mother and baby. Meanwhile, focal segmental glomerulosclerosis (FSGS) is also need to be discriminated in pregnant women with massive proteinuria. A 32-year-old woman has not been recognized hypertension, and has never been pointed out any urinary abnormality in a medical checkup. Her blood pressure gradually increased at 30 weeks of gestation. At 34 weeks gestation, blood pressure was 180/108 mmHg with medication, and she was detected proteinuria. Even after delivery, massive proteinuria (13.7 mg/gCr) was detected without microscopic hematuria. Then, renal biopsy was performed for definitive diagnosis. Histological findings showed focal endotheliosis of the glomeruli and double contour in which are the typical histological findings for preeclampsia. High levels of proteinuria after delivery is important index for medical treatment. Present case was diagnosed as preeclampsia by renal biopsy resulted in keep antihypertensive treatment without any immunosuppressant. The histological implication on our clinical management of preeclampsia may be profound for understanding of strict control of blood pressure during perinatal period.

Utility of biochemical tests in prediction, diagnostics and clinical management of preeclampsia: a review.

The most widely accepted theory for the development of preeclampsia is the “two-stage theory”. An imbalance between antiangiogenic and proangiogenic factors is considered the link between the two stages. Nowadays, an increasing amount of data is available on the use of measurements of serum concentrations of these factors in the prediction, diagnosis and management of preeclampsia. The most useful, modern biochemical test that may help in making crucial clinical decisions in patients with preeclampsia is the sFlt-1/PlGF (soluble fms-like tyrosine kinase 1/placental growth factor) ratio. The aim of this review is to present the current use of different biochemical tests in the prediction, diagnosis and management of preeclampsia. Development of these diagnostic methods in recent years and a belief in their ground-breaking role in modern management of preeclampsia make this review especially important.

Intérêts potentiels des facteurs angiogéniques placentaires comme biomarqueurs dans la pré-éclampsie pour le clinicien

The role of angiogenic factors in the onset of clinical manifestations of preeclampsia was demonstrated in 2003 by the implication of sFlt-1, PlGF and VEGF, and in 2006 by the implication of soluble endoglin. Placental ischemia and inflammation observed in preeclampsia alter both the production and progression of angiogenic factors during pregnancy. During the first trimester, the combination of PlGF with clinical, biophysical and biological factors results in a better test than the conventional one. However, the clinical value of this method remains to be confirmed. During the second and third trimesters, the sFlt-1/PlGF ratio may be used, with or without pre-existing renal disease, for short-term prediction, diagnosis, and prognosis, and to evaluate the effectiveness of preeclampsia treatment. While a sFlt-1/PlGF ratio<38 and≤33, respectively, rules out the short-term onset and diagnosis of preeclampsia, a sFlt-1/PlGF ratio≥85 between 20 and 34 weeks of pregnancy and≥110 beyond 34 weeks of pregnancy confirms a diagnosis of preeclampsia. Angiogenic and non-angiogenic preeclampsia are identified by a sFlt-1PlGF≥85 and<85, respectively, with the risk of maternal and fetal complications at two weeks differing between the two. Similarly, a sFlt-1/PlGF ratio>665 and>205, respectively, is a good short-term predictor of adverse outcomes of early and late-onset preeclampsia. These values could be incorporated into future guidelines for better clinical management of preeclampsia.

174. Evaluation of sFlt-1/PlGF ratio for improving clinical management of pre-eclampsia: Experience in a tertiary hospital

Introduction Management of pregnant women with gestational hypertension (GH) varies according to the severity of the disease. An imbalance of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), is involved in pre-eclampsia (PE) pathogenesis. An elevated ratio(>110) is highly predictive of PE, whereas the diagnosis of PE can be ruled out within one week for low ratio( Objective The main objective of this study was to assess whether the cutoff value in late pregnancy (>34 weeks) help to management the preeclampsia. Methods We performed an observational study to evaluate serum sFlt-1/PlGF ratio (Roche Diagnostics Cobas e411 system) for differential diagnosis and the severity of disease from 2018 February to April (three months). Thirty-seven women with singleton pregnancies diagnosis withsuspected preeclampsia were enrolled. Serum sFlt-1 and PlGF were measured when they admitted (>34 weeks). The sFlt-1, PlGF, and the maternal clinical data were obtained. Results Among the 37 patients included, 25 had a sFlt-1/PlGF ratio lower than 38; only one diagnosis with PE leading to a negative predictive value of 96%. Two patients diagnosed with clinical PE as the ratio higher than 110. For the rest 10 patients had a sFlt-1/PlGF ratio between 38 and 110, four of them diagnosis with clinical PE. There were five patients with thrombocytopenia, the sFlt-1/PlGF ratio were all lower than 38 and rule out for HELLP. All patients were delivered without adverse maternal and neonatal outcomes. Discussion The serum sFlt-1/PlGF ratio showed highly value of differential diagnosis for ruling out PE. In our data, four of ten patients had a sFlt-1/PlGF ratio between 38 and 110 diagnosed with clinical PE, the cutoff value may be considering more clinical experience. Using these biomarkers in routine management of PE may improve clinical management of suspect patients. It need more clinical experience in future.

The Use of Soluble FMS-like Tyrosine Kinase 1/Placental Growth Factor Ratio in the Clinical Management of Pre-eclampsia.

Hypertensive disorders of pregnancy in particular the category preeclampsia (PE), remains a major cause of both maternal and fetal morbidity and mortality. Angiogenic growth factors (PlGF and VEGF) and their tyrosine kinase receptors -1 and 2 (Flt-1 and KDR) are involved in both fetal and placental development. Inadequate placentation and the consequent release of antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) is thus instrumental in the etiology of this disease. sFlt-1 binds to both angiogenic growth factors and neutralizes their effect thereby creating an angiogenic imbalance. This imbalance is frequently reported in women diagnosed with preeclampsia occurring before the clinical manifestation of the disease. The recent prognostic value of the sFlt-1/PlGF ratio has received considerable attention as a risk indicator of preeclampsia development. The aim of this review is to highlight the current advances in the diagnostic utility of the sFlt-1/PlGF ratio with regards to preeclampsia development.

P 22 Analytical evaluation of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) on Brahms Kryptor automated immunoassay for the diagnosis of preeclampsia

Background Preeclampsia is one of the leading hypertensive disorders in pregnant women worldwide and is characterized by maternal vascular dysfunction. Current diagnosis of preeclampsia in the U.S. is based on non-specific tests such as new onset of hypertension and proteinuria after 20 weeks of gestation. More recently, two emerging biomarkers anti-angiogenic factor soluble fms-like tyrosine kinase 1 (sFlt-1) and pro-angiogenic factor placental growth factor (PlGF), have been demonstrated to be involved in the pathophysiology of preeclampsia. Studies have shown that the usefulness of sFlt-1/PlGF ratio in confirming or ruling out suspected preeclampsia cases. Thus, wider availability of the automated measurement of sFlt-1 and PlGF has the potential of improving the clinical management of preeclampsia. Methods This study examined K2-EDTA plasma samples from 50 patients on Brahms Kryptor, an automated immunoassay platform. QC materials were used to access intra- and inter-precision of the assay. Lower limit of quantitation and interference studies were determined using pooled patient plasma. Results The sFlt-1 and PlGF assays demonstrated an analytical measuring range of 90–69,000 pg/mL and 11–7000 pg/mL, respectively (r2 > 0.99). Lower limit of quantitation (20% CV) was interpolated to be 35 pg/mL for sFlt-1 and 10 pg/mL for PlGF. Total precision for both assay displayed CVs of y = 0.9939x-37.15 with an overall bias of 90.35 for sFlt-1; and y = 0.8936x + 2.562, with an overall bias of −39.644 for PlGF. The larger differences in overall bias based on individual tests however was greatly improved when a ratio of sFlt-1/PlGF is taken into account for method comparison, yielding an equation of y = 1.05x + 0.02, with an overall bias of 0.84. Conclusion The pre-eclamptic biomarkers, sFlt-1 and PlGF assayed on the Brahms Kryptor platform, demonstrate good analytical performance and are acceptable for clinical studies defining the role of these biomarkers for preeclampsia.

112 Massive proteinuria in superimposed preeclampsia significantly increased the maternal organ involvements

Introduction It is recently recognized that the amount of proteinuria is not mainly contributed to the prognosis of preeclampsia or superimposed preeclampsia [1]. Thus the severity of proteinuria tends to be unimportant and unreliable criteria for the management of preeclamptic disease. On the other hand, it is reported that preeclampsia with greater proteinuria was easy to lead the complication of the adverse maternal outcomes [2]. We now studied how the amount of proteinuria is correlated to the maternal complications especially in superimposed preeclampsia. Methods The retrospective observational study according to the standard clinical management of preeclampsia was performed in 56 pregnant cases of superimposed preeclampsia. All cases were hospitalized for the management of preeclamptic conditions and should terminate the pregnancy in the state of uncontrollable severe high blood pressure, massive proteinuria (over 10 g/day), the complications of the maternal organ involvements such as HELLP syndrome or fetal jeopardy conditions. The urinary protein was evaluated by the daily urinary collection, or spot urine/creatinine ratio. Univariate and multivariate logistic regression analysis were conducted how the obstetric features such as the severity of blood pressure, proteinuria, or the onset of disease could correlate to these organ involvements. Statistical analysis was performed using with SPSS v21. Result 25 (43.9%) cases complicated with any maternal organ involvements were observed in 59 cases. The involvements of HELLP syndrome, thrombocytopenia, or elevated liver enzymes (HELLP related disorders) were observed in 19 cases (33.3%), and those of maternal CNS disorders such as eclampsia was 2 cases (3.5%). Proteinuria over 3 g/day were correlated to any of maternal organ involvements (adjusted Odds ratio 2.86, 95%CI 0.63–13.02, p = 0.18), and more the onset of diastolic high BP under 28 weeks gestation correlated significantly (aOR 4.57, 95%CI 0.86–24.22, p = 0.07) . No relations between the maternal organ involvements and high blood pressure in superimposed preeclampsia. HELLP related disorders tended more correlation to high proteinuria of 3–8 g/day (aOR 4.30 95%CI 0.93–19.80, p = 0.06), 8–12 g/day (aOR 3.74, 95%CI 0.63–22.32, p = 0.15), and showed significantly high correlation to proteinuria over 12 g/day (aOR 12.678, 95%CI 1.53–105.2, p = 0.02). Conclusion 59 cases of superimposed preeclampsia showed high rate of any of the maternal organ involvements in this observational study. These involvements were correlated to the early onset of hypertension under 28 weeks, and had more correlation to high amount of proteinuria than severe hypertension. Furthermore massive proteinuria over 12 g/day had significantly correlated to HELLP related disorders. Additionally not massive but large amount of proteinuria, that is under12 g/day did not show linear increase in complicating the maternal involvements. We then concluded the necessity of measuring the amount of proteinuria in the management of superimposed preeclampsia, and the massive proteinuria over 12 g/day might have the risk of complicating with the maternal organ involvements especially HELLP syndrome or its correlating disorders.

Economic evaluation of Community Level Interventions for Pre-eclampsia (CLIP) in South Asian and African countries: a study protocol.

BackgroundGlobally, hypertensive disorders of pregnancy, particularly pre-eclampsia and eclampsia, are the leading cause of maternal and neonatal mortality, and impose substantial burdens on the families of pregnant women, their communities, and healthcare systems. The Community Level Interventions for Pre-eclampsia (CLIP) Trial evaluates a package of care applied at both community and primary health centres to reduce maternal and perinatal disabilities and deaths resulting from the failure to identify and manage pre-eclampsia at the community level. Economic evaluation of health interventions can play a pivotal role in priority setting and inform policy decisions for scale-up. At present, there is a paucity of published literature on the methodology of economic evaluation of large, multi-country, community-based interventions in the area of maternal and perinatal health. This study protocol describes the application of methodology for economic evaluation of the CLIP in South Asia and Africa.MethodsA mixed-design approach i.e. cost-effectiveness analysis (CEA) and qualitative thematic analysis will be used alongside the trial to prospectively evaluate the economic impact of CLIP from a societal perspective. Data on health resource utilization, costs, and pregnancy outcomes will be collected through structured questionnaires embedded into the pregnancy surveillance, cross-sectional survey and budgetary reviews. Qualitative data will be collected through focus groups (FGs) with pregnant women, household male-decision makers, care providers, and district level health decision makers. The incremental cost-effectiveness ratio will be calculated for healthcare system and societal perspectives, taking into account the country-specific model inputs (costs and outcome) from the CLIP Trial. Emerging themes from FGs will inform the design of the model, and help to interpret findings of the CEA.DiscussionThe World Health Organization (WHO) strongly recommends cost-effective interventions as a key aspect of achieving Millennium Development Goal (MDG)-5 (i.e. 75 % reduction in maternal mortality from 1990 levels by 2015). To date, most cost-effectiveness studies in this field have focused specifically on the diagnostic and clinical management of pre-eclampsia, yet rarely on community-based interventions in low-and-middle-income countries (LMICs). This study protocol will be of interest to public health scientists and health economists undertaking community-based trials in the area of maternal and perinatal health, particularly in LMICs.Trial registrationClinicalTrials.gov: NCT01911494

Activin and NADPH-oxidase in preeclampsia: insights from in vitro and murine studies

Clinical management of preeclampsia has remained unchanged for almost 5 decades. We now understand that maternal endothelial dysfunction likely arises because of placenta-derived vasoactive factors. Activin A is one such antiangiogenic factor that is released by the placenta and that is elevated in maternal serum in women with preeclampsia. Whether activin has a role in the pathogenesis of preeclampsia is not known. To assess the effects of activin on endothelial cell function, we cultured human umbilical vein endothelial cells in the presence of activin or serum from normal pregnant women or pregnant women with preeclampsia, with or without follistatin, a functional activin antagonist or apocynin, a NADPH oxidase (Nox2) inhibitor. We also administered activin to pregnant C57Bl6 mice, with or without apocynin, and studied maternal and fetal outcomes. Last, we assessed endothelial cell Nox2 and nitric oxide synthase expression in normal pregnant women and pregnant women with preeclampsia. Activin and preeclamptic serum induced endothelial cell oxidative stress by Nox2 up-regulation and endothelial cell dysfunction, which are effects that are mitigated by either follistatin or apocynin. The administration of activin to pregnant mice induced endothelial oxidative stress, hypertension, proteinuria, fetal growth restriction, and preterm littering. Apocynin prevented all of these effects. Compared with normal pregnant women, women with preeclampsia had increased endothelial Nox2 expression. An activin-Nox2 pathway is a likely link between an injured placenta, endothelial dysfunction, and preeclampsia. This offers opportunities that are not novel therapeutic approaches to preeclampsia.

Placental biomarkers can help the clinical management of pre-eclampsia

A recent symposium held in June 2011, ‘Placental Biomarkers and the Clinical Management of Pre-Eclampsia’ reviewed the current incidence, challenges and outcomes associated with pre-eclampsia. Attracting over 250 delegates from all sectors of the perinatal professions, the sessions also looked at the potential role of new placental biomarkers to definitively ‘rule in’ and ‘rule out’ placental dysfunction in pregnant women with suspected pre-eclampsia before 35 weeks of pregnancy, particularly with reference to their impact on improved management of patients, outcomes, resources and costs.

Potential Roles of Angiotensin Receptor-Activating Autoantibody in the Pathophysiology of Preeclampsia

Preeclampsia affects ≈7% of first pregnancies and is one of the leading causes of maternal and neonatal mortality and morbidity in the United States and the world.1–3 The clinical hallmarks of the disorder include hypertension, proteinuria, hypercoagulability, edema, and placental abnormalities. In advanced stages, clinical symptoms include cerebral edema, renal failure, and the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. The clinical management of preeclampsia is hampered by the lack of reliable diagnostic tests and effective therapy for the disorder. In some cases, termination of pregnancy is the only available option to prevent further deterioration of the fetus and mother. Fifteen percent of all preterm births are indicated early deliveries for preeclampsia.3 The resulting preterm births and the associated increased infant morbidity and mortality are especially disheartening consequences of preeclampsia. Despite being one of the leading causes of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Roberts and colleagues4,5 were among the first to propose that alterations in endothelial cell function by activating agents produced by the placenta initiate the clinical syndromes of preeclampsia. Circulating factors, such as inflammatory cytokines, endothelin, and soluble vascular endothelial growth factor receptor termed soluble fms-like tyrosine kinase-1 (sFlt-1), are elevated in preeclamptic women and are proposed to be important links between placental ischemia and endothelial dysfunction.5–9 In particular, recent studies have shown that preeclampsia is associated with the presence of maternal autoantibodies capable of binding to and activating the angiotensin (Ang) receptor type-1 (AT1).10–15 AT1 receptor agonistic antibodies, herein termed AT1-AA, are rarely seen in normotensive pregnant women.10,11 Since the initial discovery of these autoantibodies, considerable evidence supporting a pathophysiological role of AT1-AA in preeclampsia has …

Inflammation and pre-eclampsia

Pre-eclampsia is a common and potentially dangerous disorder of human pregnancy. The maternal syndrome of hypertension, proteinuria and oedema is part of a severe systemic inflammatory response that includes leukocyte and endothelial cell activation. Although the origins of pre-eclampsia remain unclear, a major cause is the failure to develop an adequate blood supply to the placenta, leading to placental oxidative stress. This results in the excess release of placental factors, such as syncytiotrophoblast debris or soluble fms-like tyrosine kinase-1 (sFlt-1), the soluble receptor for vascular endothelial growth factor (VEGF), into the maternal circulation, where they trigger an inflammatory response and endothelial dysfunction. Alternatively, pre-eclampsia can develop in the presence of a normal placenta in women that are susceptible to systemic inflammation, such as with chronic cardiovascular disease or diabetes. While clinical management of pre-eclampsia does not currently include anti-inflammatory agents, current research is focusing on ways to reduce inflammation and oxidative stress.