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BACKGROUND: The relationship between placental pathology and the maternal syndrome of preeclampsia is incompletely characterized. Mismatch between placental nutrient supply and fetal demands induces stress in the syncytiotrophoblast, the layer of placenta in direct contact with maternal blood. Such stress alters the content and increases the release of syncytiotrophoblast extracellular vesicles (STB-EVs) into the maternal circulation. We have previously shown 5′-tRNA fragments (5′-tRFs) constitute the majority of small RNA in STB-EVs in healthy pregnancy. 5′-tRFs are produced in response to stress. We hypothesized STB-EV 5′-tRF release might change in preeclampsia. METHODS: We perfused placentas from 8 women with early-onset preeclampsia and 6 controls, comparing small RNA expression in STB-EVs. We used membrane-affinity columns to isolate maternal plasma vesicles and investigate placental 5′-tRFs in vivo. We quantified 5′-tRFs from circulating STB-EVs using a placental alkaline phosphatase immunoassay. 5′-tRFs and scrambled RNA controls were added to monocyte, macrophage and endothelial cells in culture to investigate transcriptional responses. RESULTS: 5′-tRFs constitute the majority of small RNA in STB-EVs from both preeclampsia and normal pregnancies. More than 900 small RNA fragments are differentially expressed in preeclampsia STB-EVs. Preeclampsia-dysregulated 5′-tRFs are detectable in maternal plasma, where we identified a placentally derived load. 5′-tRF-Glu-CTC, the most abundant preeclampsia-upregulated 5′-tRF in perfusion STB-EVs, is also increased in preeclampsia STB-EVs from maternal plasma. 5′-tRF-Glu-CTC induced inflammation in macrophages but not monocytes. The conditioned media from 5′-tRF-Glu-CTC-activated macrophages reduced eNOS (endothelial NO synthase) expression in endothelial cells. CONCLUSIONS: Increased release of syncytiotrophoblast-derived vesicle-bound 5′-tRF-Glu-CTC contributes to preeclampsia pathophysiology. [ABSTRACT FROM AUTHOR]

BACKGROUND: Early delivery in preterm preeclampsia may reduce the risks for the patient, but consequences of prematurity may be substantial for the baby. This trial evaluated whether the implementation of a risk stratification model could safely reduce prematurity. METHODS: This was a stepped-wedge cluster-randomized trial in seven clusters. Patients presenting with suspected or confirmed preeclampsia between 20+0 and 36+6 gestational weeks were considered eligible. At the start of the trial, all centers were allocated in the preintervention phase, and patients enrolled in this phase were managed according to local treatment guidance. Subsequently, every 4 months, 1 randomly allocated cluster transitioned to the intervention. Patients enrolled in the intervention phase had sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio and preeclampsia integrated estimate of risk assessments performed. If sFlt-1/PlGF ≤38 and preeclampsia integrated estimate of risk <10%, patients were considered low risk and clinicians received recommendations to defer delivery. If sFlt-1/PlGF >38 and preeclampsia integrated estimate of risk ≥10%, patients were considered not low risk, and clinicians received recommendations to increase surveillance. The primary outcome was the proportion of patients with preterm preeclampsia delivered prematurely out of total deliveries. RESULTS: Between March 25, 2017 and December 24, 2019, 586 and 563 patients were analyzed in the intervention and usual care groups, respectively. The event rate was 1.09% in the intervention group, and 1.37% in the usual care group. After prespecified adjustments for variation between and within clusters over time, the adjusted risk ratio was 1.45 ([95% CI, 1.04–2.02]; P =0.029), indicating a higher risk of preterm deliveries in the intervention group. Post hoc analysis including calculation of risk differences did not show evidence of statistical differences. Abnormal sFlt-1/PlGF was associated with a higher rate of identifying preeclampsia with severe features. CONCLUSIONS: The introduction of an intervention based on biomarkers and clinical factors for risk stratification did not lead to reductions in preterm deliveries. Further training on the interpretation of disease severity in preeclampsia and the development of additional risk stratification is needed before adoption into clinical practice. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03073317. [ABSTRACT FROM AUTHOR]

Background: Preeclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide. Identifying women with high risk of developing preeclampsia in early pregnancy remains challenging. Extracellular vesicles released from the placenta offer an attractive biomarker but have been elusive to quantify. Methods: Here, we tested ExoCounter, a novel device that immunophenotypes size-selected small extracellular vesicles <160 nm, for its ability to perform qualitative and quantitative placental small extracellular vesicles (psEV) analysis. To investigate disease-specific and gestational age-specific changes, we analyzed psEV counts in maternal plasma samples taken at each of the 3 trimesters from women who had (1) normal pregnancy (n=3); (2) women who developed early-onset preeclampsia (EOPE; n=3); and (3) women who developed late-onset preeclampsia (n=4) using 3 antibody pairs, CD10-placental alkaline phosphatase (PLAP), CD10-CD63, and CD63-PLAP. We further validated the findings in first-trimester serum samples among normal pregnancy (n=9), women who developed EOPE (n=7), and women who developed late-onset preeclampsia (n=8). Results: We confirmed that CD63 was the major tetraspanin molecule coexpressed with PLAP—a known placental extracellular vesicles marker on psEV. Higher psEV counts for all 3 antibody pairs were detected in the plasma of women who developed EOPE than the other 2 groups in the first trimester, which persisted through the second and third trimesters. Significantly higher CD10-PLAP (P <0.01) and CD63-PLAP (P <0.01) psEV counts were validated in the serum of the first trimester of women who developed EOPE compared with normal pregnancy. Conclusions: Application of the ExoCounter assay developed here could identify patients at risk of developing EOPE in the first trimester, thereby providing a window of opportunity for early intervention. [ABSTRACT FROM AUTHOR]

Preeclampsia is a systemic syndrome that seems to originate from the placenta and is associated with an imbalance between angiogenic factors in the maternal circulation. One of the well-studied and widely used factors is PlGF (placental growth factor), the levels of which drop in women destined to develop preeclampsia. This drop is known to precede the development of actual signs and symptoms of preeclampsia, thus proving to be a useful screening tool in predicting the disease. The literature varies widely in terms of the clinical usefulness of the test. We conducted a metaanalysis to study the predictive accuracy of PlGF in asymptomatic women. Our analysis included 40 studies with 3189 cases of preeclampsia and 89 498 controls. The overall predictive odds ratio of the test was 9 (6-13). Subgroup analysis evaluating various PlGF thresholds demonstrated that the predictive values were highest for PlGF levels between 80 and 120 pg/mL with a high predictive odds ratio of 25 (7-88), a sensitivity of 0.78 (95% CI, 0.67-0.86), a specificity of 0.88 (95% CI, 0.75-0.95), a positive likelihood ratio of 6.3 (95% CI, 2.7-14.7), and a negative likelihood ratio of 0.26 (95% CI, 0.16-0.42). Additionally, the accuracy was higher when the test was performed after 14 weeks of gestation (OR, 10 [7-15]) and for prediction of early onset preeclampsia (OR, 18 [9-37]). We conclude that PlGF is a useful screening tool to predict preeclampsia. Nonetheless, its utility should be judged with caution and randomized controlled trials are warranted to explore if its implementation improves perinatal outcomes in asymptomatic women. [ABSTRACT FROM AUTHOR]

NEP (neprilysin) is a widely expressed membrane-bound metalloprotease, which binds and cleaves a variety of peptides including vasodilators, natriuretics, and diuretics. Higher levels of NEP result in hypertension-a cardinal feature of the placental disease preeclampsia. Syncytiotrophoblast-derived extracellular vesicles (EVs), comprising microvesicles and exosomes, are released into the peripheral circulation in pregnancy and are postulated as a key mechanism coupling placental dysfunction and maternal phenotype in preeclampsia. We aimed to determine whether higher levels of active NEP are found in syncytiotrophoblast-derived EVs in preeclampsia compared with normal pregnancy. Using immunostaining and Western blotting, we first demonstrated that NEP levels are greater not only in preeclampsia placental tissue but also in syncytiotrophoblast-derived microvesicles and exosomes isolated from preeclampsia placentas ( P<0.05, n=5). We confirmed placental origin using antibody-coated magnetic beads to isolate NEP-bound vesicles, finding that they stain for placental alkaline phosphatase. NEP on syncytiotrophoblast-derived EVs is active and inhibited by thiorphan ( P<0.01, n=3; specific inhibitor). Syncytiotrophoblast-derived microvesicles, isolated from peripheral plasma, demonstrated higher NEP expression in preeclampsia using flow cytometry ( P<0.05, n=8). We isolated plasma exosomes using size-exclusion chromatography and showed greater NEP activity in preeclampsia ( P<0.05, n=8). These findings show that the placenta releases active NEP into the maternal circulation on syncytiotrophoblast-derived EVs, at significantly greater levels in preeclampsia. NEP has pathological roles in hypertension, heart failure, and amyloid deposition, all of which are features of preeclampsia. Circulating syncytiotrophoblast-derived EV-bound NEP thus may contribute to the pathogenesis of this disease. [ABSTRACT FROM AUTHOR]

Uteroplacental acute atherosis (AA) is a pregnancy-specific arterial lesion resembling early stages of atherosclerosis. AA is frequent in preeclamptic pregnancies, which associate with increased long-term maternal risk of atherosclerotic cardiovascular disease. We hypothesized that AA in pregnant women associates with classical risk factors for cardiovascular disease, including hypertension, hyperlipidemia, glucose intolerance, elevated C-reactive protein, age, and body mass index. We included 237 women delivered by cesarean section (healthy pregnancies, n=94; preeclampsia, n=87; pregestational and gestational diabetes mellitus, n=39; diabetes mellitus with preeclampsia, n=17). They provided blood before delivery for biomarker analyses. AA was diagnosed by immunohistochemistry in uteroplacental (decidual) tissue collected after placental removal. Statistical analyses were performed with Mann-Whitney test. Levels of traditional cardiovascular markers were not associated with decidual AA within the groups of women with normotensive pregnancies, preeclampsia, diabetes mellitus, or diabetes mellitus superimposed with preeclampsia. However, the oldest patient age quartile (36-43 years old) with AA had significantly higher levels of LDL (low-density lipoprotein) and apolipoprotein B (both P<0.01) than women of the same age without AA. AA was associated with elevated median prepregnancy/early pregnancy systolic blood pressure ( P=0.01) in the total cohort, but as preeclampsia was strongly associated with this finding ( P<0.01), this was likely caused by a large proportion of preeclamptic pregnancies in the AA group (62.7%). Our findings demonstrate that dyslipidemia associated with cardiovascular risk is a feature of uteroplacental AA in older women, not of AA in pregnancy in general. [ABSTRACT FROM AUTHOR]

Preeclampsia is a major cause of morbidity and mortality worldwide. Numerous candidate biomarkers have been proposed for diagnosis and prediction of preeclampsia. Measurement of maternal circulating angiogenesis biomarker as the ratio of sFlt-1 (soluble FMS-like tyrosine kinase-1; an antiangiogenic factor)/PlGF (placental growth factor; an angiogenic factor) reflects the antiangiogenic balance that characterizes incipient or overt preeclampsia. The ratio increases before the onset of the disease and thus may help in predicting preeclampsia. We conducted a meta-analysis to explore the predictive accuracy of sFlt-1/PlGF ratio in preeclampsia. We included 15 studies with 534 cases with preeclampsia and 19 587 controls. The ratio has a pooled sensitivity of 80% (95% confidence interval, 0.68-0.88), specificity of 92% (95% confidence interval, 0.87-0.96), positive likelihood ratio of 10.5 (95% confidence interval, 6.2-18.0), and a negative likelihood ratio of 0.22 (95% confidence interval, 0.13-0.35) in predicting preeclampsia in both high- and low-risk patients. Most of the studies have not made a distinction between early- and late-onset disease, and therefore, the analysis for it could not be done. It can prove to be a valuable screening tool for preeclampsia and may also help in decision-making, treatment stratification, and better resource allocation. [ABSTRACT FROM AUTHOR]

Preeclampsia, a multisystem hypertensive disorder of pregnancy, is associated with increased systemic vascular resistance. Placentae from patients with preeclampsia have reduced levels of endothelial nitric oxide synthase (eNOS) and, thus, less nitric oxide (NO). Syncytiotrophoblast extracellular vesicles (STBEV), comprising microvesicles (STBMV) and exosomes, carry signals from the syncytiotrophoblast to the mother. We hypothesized that STBEV-bound eNOS (STBEV-eNOS), capable of producing NO, are released into the maternal circulation. Dual-lobe ex vivo placental perfusion and differential centrifugation was used to isolate STBEV from preeclampsia (n=8) and normal pregnancies (NP; n=11). Plasma samples of gestational age-matched preeclampsia and NP (n=6) were used to isolate circulating STBMV. STBEV expressed placental alkaline phosphatase, confirming placental origin. STBEV coexpressed eNOS, but not inducible nitric oxide synthase, confirmed using Western blot, flow cytometry, and immunodepletion. STBEV-eNOS produced NO, which was significantly inhibited by N  G-nitro-l-arginine methyl ester (eNOS inhibitor; P<0.05) but not by N-(3-(aminomethyl) bezyl) acetamidine) (inducible nitric oxide synthase inhibitor). STBEV-eNOS catalytic activity was confirmed by visualizing eNOS dimerization. STBEV-eNOS was more abundant in uterine vein compared with peripheral blood, indicating placental origin. STBEV isolated from preeclampsia-perfused placentae had lower levels of STBEV-eNOS (STBMV; P<0.05) and overall lower NO activity (STBMV, not significant; syncytiotrophoblast extracellular exosomes, P<0.05) compared with those from NP. Circulating plasma STBMV from preeclampsia women had lower STBEV-eNOS expression compared with that from NP women (P<0.01). This is the first observation of functional eNOS expressed on STBEV from NP and preeclampsia placentae, as well as in plasma. The lower STBEV-eNOS NO production seen in preeclampsia may contribute to the decreased NO bioavailability in this disease. [ABSTRACT FROM AUTHOR]

The article discusses the associations between pregnancy and long-term maternal cardiovascular health. Topics covered include the association of preeclampsia and fetal growth restriction and future cardiovascular disease (CVD) risk, the role of pregnancy-induced hypertension or preeclampsia on prematurity, miscarriage, and future CVD risk, and the higher risk for CVD in women who develop gestational diabetes mellitus (GDM).

Preeclampsia remains a major problem worldwide for mothers and babies. Despite intensive study, we have not been able to improve the management or early recognition of preeclampsia. At least part of this is because of failure to standardize the approach to studying this complex syndrome. It is possible that within the syndrome there may be different phenotypes with pathogenic pathways that differ between the subtypes. The capacity to recognize and to exploit different subtypes is of obvious importance for prediction, prevention, and treatment. We present a strategy for research to study preeclampsia, which will allow discrimination of such possible subtypes and also allow comparison and perhaps combinations of findings in different studies by standardized data and biosample collection. To make studies relevant to current clinical practice, the definition of preeclampsia can be that currently used and accepted. However, more importantly, sufficient data should be collected to allow other diagnostic criteria to be used and applied retrospectively. To that end, we present what we consider to be the minimum requirements for a data set in a study of preeclampsia that will facilitate comparisons. We also present a comprehensive or optimal data set for in-depth investigation of pathophysiology. As we approach the definition of phenotypes of preeclampsia by clinical and biochemical criteria, adherence to standardized protocols will hasten our understanding of the causes of preeclampsia and development of targeted treatment strategies. [ABSTRACT FROM AUTHOR]

The article discusses the redefinition of preeclampsia using the placental biomarker placenta growth factor (P1GF). Preeclampsia has been subcategorized by clinical severity determined by maternal and fetal factors. The use of P1GF is expected to enhance the reliability and reproducibility of outcome evaluation in the research of prediction, diagnosis, or prevention. This will pave the way for an improvement in diagnostic clarity, risk stratification, and care allocation.

The article investigates whether those who develop early onset disease have unique adverse blood pressure characteristics. 140 women were studied 6-13 years either after pregnancy complicated by preeclampsia or after a normotensive pregnancy. Mothers who developed early onset preeclampsia and the offspring of that pregnancy display specific adverse blood pressure characteristics later in life.

This article presents information from a case-control study of 30 gestational age-matched women with preeclampsia to determine if the activation of autoantibodies against the angiotensin II type 1 receptor circulate in such women and are involved in the pathogenesis of preeclampsia. It was determined that such angiotensin receptors are common in patients with preeclampsia and that although tyrosine kinase is a superior biomarker, the angiotensin receptor is a better biomarker in late cases.

A state of insulin resistance has been demonstrated in active preeclampsia, and women with clinical evidence of insulin resistance are at higher risk to develop this syndrome during pregnancy. Recently, inositol phosphoglycan P-type, a putative second messenger of insulin action, has been implicated in the pathophysiology of preeclampsia and is increased in the placenta, amniotic fluid, and maternal urine of preeclamptic women compared with normal pregnant women. We report here a case-control study to assess the potential of urinary levels of inositol phosphoglycan P-type as a screening test for preeclampsia. Twenty-seven preeclamptic women and 47 healthy pregnant women were recruited. A polyclonal antibody-based ELISA was developed to detect levels of inositol phosphoglycan P-type in urine. Its content in urinary specimens was found to be 30-fold higher in preeclamptic subjects than control subjects (329.1+/-21.8 versus 9.2+/-1.5; P<0.001), with a higher level in all of the preeclamptic cases. For 6 women who developed preeclampsia, >1 gestational date sample of urine was available, and retrospective analysis showed a significant time-related increase of the urinary level of inositol phosphoglycan P-type

Genu valgum is a risk factor for patellar instability. The study purpose was to report on preliminary results of medial patellofemoral ligament (MPFL) reconstruction and simultaneous growth modulation, in patients with patellar instability and genu valgum. A total of seven patients (eight knees) with MPFL reconstruction and medial transphyseal screw insertion for genu valgum correction were assessed using full-length radiographs. Genu valgum corrected from 13.1° to 3.7° at mean 11.7 months, without compromising patellar stability. One patient each had 6° overcorrection and 5° rebound valgus. Guided growth using transphyseal screw during MPFL reconstruction could achieve deformity correction without interference with MPFL graft placement.