The diagnostic value of angiogenic and antiangiogenic factors in differential diagnosis of preeclampsia.

The definition of preeclampsia is changing. However, with the addition of organ symptoms to the presence of hypertension in pregnancy instead of relying only on proteinuria, a more precise detection of women at risk of preeclampsia-associated adverse events has not been achieved. Instead, under the new definitions of the American College of Obstetricians and Gynecologists and of the International Society for the Study of Hypertension in Pregnancy, more women are classified as preeclamptic, with a tendency to milder disease. Furthermore, angiogenic and antiangiogenic factors have emerged as essential tools for predicting and diagnosing preeclampsia at high accuracies. Next to being rooted in the pathophysiology of the disease, they have been proven to be reliable tools for predicting and diagnosing the disease. In addition, 2 cutoffs have been evaluated for the clinical setting. As shown in the Prediction of Short-Term Outcome in Pregnant Women With Suspected Preeclampsia Study, at the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio cutoff of 38, a preeclampsia can be ruled out for 1 week with a negative predictive value of 99.3% (95% confidence interval, 97.9-99.9) and ruled in with a positive predictive value of 36.7% (95% confidence interval, 28.4-45.7). The diagnostic cutoff of 85 has been shown to accurately identify women with preeclampsia, with a sensitivity of up to 88% and a specificity of 99.5%. In this review, we highlight the central role of angiogenic and antiangiogenic factors in the differential diagnosis of women presenting at high risk of the disease, such as patients with chronic hypertension or chronic kidney disease. We will focus on their ability to predict preeclampsia-associated adverse fetal and maternal outcomes. This is only possible when critically reviewing the evolution of the definition of "preeclampsia." We show how changes in this definition shape our clinical picture of the condition and how angiogenic and antiangiogenic biomarkers might be included to better identify women destined to develop preeclampsia-related adverse outcomes.

Prediction of Preeclampsia-Related Adverse Outcomes With the sFlt-1 (Soluble fms-Like Tyrosine Kinase 1)/PlGF (Placental Growth Factor)-Ratio in the Clinical Routine: A Real-World Study.

This retrospective real-world study investigated the clinical use of the sFlt-1 (soluble fms-like tyrosine kinase 1)/PlGF (placental growth factor) ratio alone or in combination with other clinical tests to predict an adverse maternal (maternal death, kidney failure, hemolysis elevated liver enzymes low platelets-syndrome, pulmonary edema, disseminated intravascular coagulation, cerebral hemorrhage, or eclampsia) or fetal (delivery before 34 weeks because of preeclampsia and/or intrauterine growth restriction, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, placental abruption or intrauterine fetal death or neonatal death within 7 days post natum) pregnancy outcome in patients with signs and symptoms of preeclampsia. We evaluated the sFlt-1/PlGF-ratio cutoff values of 38 and 85 and evaluated its integration into a multimarker model. Of 1117 subjects, 322 (28.8%) developed an adverse fetal or maternal outcome. Patients with an adverse versus no adverse outcome had a median sFlt-1/PlGF-ratio of 177 (interquartile range, 54-362) versus 14 (4-64). Risk-stratification with the sFlt-1/PlGF cutoff values into high- (>85), intermediate- (38-85), and low-risk (<38) showed a significantly shorter time to delivery in high- and intermediate- versus low-risk patients (4 versus 8 versus 29 days). When integrating all available clinical information into a multimarker model, an area under the curve of 88.7% corresponding to a sensitivity, specificity, positive and negative predictive value of 80.0%, 87.3%, 75.0%, and 90.2% was reached. The sFlt-1/PlGF-ratio alone was inferior to the full model with an area under the curve of 85.7%. As expected, blood pressure and proteinuria were significantly less accurate with an area under the curve of 69.0%. Combining biomarker measurements with all available information in a multimarker modeling approach increased detection of adverse outcomes in women with suspected disease.

Angiosarcomas of Primary Gynecologic Origin - A Case Series and Review of the Literature.

BACKGROUND/AIM: Angiosarcoma of primary gynecologic origin is an extremely rare and highly malignant tumor of endothelial origin with a 5-year survival rate of less than 35%. To date, only 61 cases have been described in the literature. The aim of this study was to present more cases and discuss potential therapy options. CASE REPORT: The following case series presents three cases of gynecologic angiosarcomas that were under therapy at the Charité - University medicine of Berlin from June 2014 to February 2018. RESULTS: Two of the cases deal with primary angiosarcomas of the uterus whereas the third case was diagnosed after the suspicion of a recurrence of a poorly differentiated squamous cell carcinoma of the cervix uteri. In case one a 75-year old patient with initial postmenopausal bleeding and a tumor mass of the uterus is described. After surgery a hemangiosarcoma of the uterus was confirmed. After two months the patient presented with a presacral peritoneal sarcomatosis. Chemotherapy of weekly paclitaxel was administered. Case two deals with a patient presenting with abdominal pain. A uterine sarcoma with infiltration of the parametry and angiosarcomatosis peritonei was diagnosed during an emergency laparotomy because of spontaneous peritoneal bleeding. Moreover, osseous metastasis was found. The patient underwent weekly paclitaxel. Due to tumor progression, chemotherapy was changed to doxorubicin and olaratumab and radiotherapy was induced. The patient died 33 months after initial diagnosis. Case three describes a 34-year old patient with suspected local recurrence of cervical cancer with infiltration of the bladder. During TURB an angiosarcoma was found. Following laparoscopy revealed peritoneal metastasis. The patient underwent weekly paclitaxel followed by a paclitaxel and pazopanib maintainance therapy which showed a regression. Due to progression afterwards, chemotherapy was changed to gemcitabine and docetaxel and gemcitabine monotherapy. The patient died 33 months after initial diagnosis. CONCLUSION: Even though there is no evidence on standard treatment of this extremely rare and aggressive tumor entity of the female genital tract the patients showed the longest stability of disease during chemotherapy with weekly paclitaxel.

Diagnosis of preeclampsia and fetal growth restriction with the sFlt-1/PlGF ratio: Diagnostic accuracy of the automated immunoassay Kryptor®.

OBJECTIVE: We aimed to characterize the diagnostic accuracy of the Kryptor® assay for sFlt-1 and PlGF in maternal serum samples of uneventful singleton pregnancies and subjects with preeclampsia (PE) and PE-related outcomes such as fetal growth restriction (FGR). Longitudinal reference ranges of the sFlt-1 and PlGF level in the course of normal pregnancies were generated. METHODS: A cohort of subjects with PE and PE-related outcomes including FGR in the third trimester was compared to a cohort of women with uneventful outcome. Serum levels of sFlt-1, PlGF level as well as the sFlt-1/PlGF ratio was analysed with the Kryptor® assay and compared between the case- and control groups. Cut-off values were generated and diagnostic accuracy examined. RESULTS: Longitudinal reference ranges of the sFlt-1 and PlGF level in healthy pregnancies were in line with those levels measured with other immunoassays. Comparison of the sFlt-1/PlGF ratio between PE-related outcomes including FGR or PE and healthy controls showed a high diagnostic accuracy with an area under the curve (AUC) of 0.917 for PE-related outcomes and 0.919 for PE.

Angiogenic Markers and Cardiovascular Indices in the Prediction of Hypertensive Disorders of Pregnancy.

Angiogenic and antiangiogenic factors have proven to be an accurate predictive means of preeclampsia. Echocardiographic studies have shown that women with preeclampsia exhibit significant cardiovascular strain, especially early-onset preeclampsia. The aim of this study is to determine preeclampsia risk with soluble fms-like tyrosin kinase 1/placental growth factor ratio, serum NT-proBNP (N-terminal pro B-type natriuretic peptide), and biophysical markers of cardiovascular function in a prospective case-control study. We examined a cohort of 110 pregnant women with uneventful pregnancy outcome (controls) and 129 with hypertensive pregnancy disorders, including 77 with preeclampsia and 52 with pregnancy-induced hypertension. Cardiac indices were obtained with a USCOM-1A monitor, and soluble fms-like tyrosin kinase 1, placental growth factor, and NT-proBNP were measured in serum samples on automated platforms. Logistic regression, as well as Cox proportional hazard analysis, was performed. There were significant contributions from all variables tested, except for heart rate, stroke volume index, and cardiac index to the prediction model. When testing accuracy of respective markers in combination (full model) versus individual markers (soluble fms-like tyrosin kinase 1/placental growth factor ratio and total peripheral resistance) was compared. The soluble fms-like tyrosin kinase 1/placental growth factor ratio and total peripheral resistance performed as good as the full model, except for hypertensive pregnancy disorders and pregnancy-induced hypertension, where the full model performed better. The additional assessment of biophysical and biochemical markers of cardiovascular strain in pregnancy increases the detection of the composite group of hypertensive pregnancy disorders, while not significantly improving detection of preeclampsia alone. This offers a more precise insight into the pathogenesis of the disease, as well as offering a window for intervention, possibly decreasing cardiovascular mortality in these women.

Pregnancies in Women Aged 45 Years and Older - a 10-Year Retrospective Analysis in Berlin.

Introduction Improved fertility treatment options and a change in the socio-cultural concept of family planning, especially in industrialized regions, has led to an increasing number of births by women of advanced maternal age, which is associated with a higher rate of complications. The aim of this study was to analyze pregnancy outcomes in women aged ≥ 45 years in an inner-city German hospital and to compare these results to those of a younger cohort. Materials and Methods Over a 10-year period from January 2004 to May 2015, the pregnancy outcomes of all 186 women aged ≥ 45 years who delivered in our hospital were compared in a 1 : 1 ratio to those of a cohort of 29-year old women. Results The rates of assisted reproduction (34 vs. 3 %), multiple pregnancies (16 vs. 5 %) and cesarean section (59 vs. 29 %) were significantly increased in the study group. There was an increased risk of preterm delivery (28 vs. 11 %), preeclampsia, gestational diabetes and premature rupture of membranes in the advanced maternal age group. Conclusion Advanced maternal age leads to higher rates of fetal and maternal complications. These findings should be taken into account when planning assisted reproduction and obstetrical care in women with advanced maternal age.

Characterization of the soluble fms-like tyrosine kinase-1 to placental growth factor ratio in pregnancies complicated by fetal growth restriction.

OBJECTIVE: To characterize the values of the soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio in pregnancies with fetal growth restriction with or without concurrent preeclampsia or hemolysis, elevated liver enzymes and low platelets syndrome (HELLP) and in pregnancies with normally grown fetuses with or without concurrent preeclampsia or HELLP. METHODS: This is a case-control study performed in two centers (Berlin and Madrid) consisting of 171 singleton pregnancies complicated by fetal growth restriction (n=27), preeclampsia or HELLP (n=105) or preeclampsia or HELLP and fetal growth restriction (n=39) pairwise matched by gestational age with 171 healthy control pregnancies. Automated measurement of sFlt-1 and PlGF in maternal serum samples was performed after diagnosis (cases) and in gestational-age matched healthy control samples. Samples were analyzed for two timeframes: before and at or after 34 weeks of gestation. RESULTS: Pregnancies with fetal growth restriction, preeclampsia or HELLP, and preeclampsia or HELLP and fetal growth restriction showed higher median values of sFlt-1/PlGF ratio than control pregnancies both before 34 weeks of gestation (90, 231, 514, and 3, respectively, P<.001) and at or after 34 weeks of gestation (117, 66, 165, and 11, respectively, P<.001). The differences among the case subgroups were not statistically different. CONCLUSION: Fetal growth restriction is characterized by elevated maternal sFlt-1/PlGF ratio, reaching values as high as those observed in preeclampsia or HELLP. LEVEL OF EVIDENCE: II.