Clinical utility of sFlt-1 and PlGF in screening, prediction, diagnosis and monitoring of pre-eclampsia and fetal growth restriction.

Pre-eclampsia (PE) is characterized by placental and maternal endothelial dysfunction, and associated with fetal growth restriction (FGR), placental abruption, preterm delivery and stillbirth. The angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are altered in pregnancies complicated by placenta-related disorders. In this Review, we summarize the existing knowledge, examining the performance of maternal PlGF, sFlt-1 and the sFlt-1/PlGF ratio for screening PE, predicting development of PE in the short term, diagnosing PE, monitoring established PE and predicting other placenta-related disorders in singleton pregnancy. We also discuss the performance of PlGF and the sFlt-1/PlGF ratio for predicting PE in twin pregnancy. For first-trimester screening in singleton pregnancy, a more accurate way of identifying high-risk women than current practice is to combine maternal PlGF levels with clinical risk factors and ultrasound markers. Later in pregnancy, the sFlt-1/PlGF ratio has advantages over PlGF because it has a higher pooled sensitivity and specificity for diagnosing and monitoring PE. It has clinical value because it can rule out the development of PE in the 1-4-week period after the test. Once a diagnosis of PE is established, repeat measurement of sFlt-1 and PlGF can help monitor progression of the condition and may inform clinical decision-making regarding the optimal time for delivery. The sFlt-1/PlGF ratio is useful for predicting FGR and preterm delivery, but the association between stillbirth and the angiogenic factors is unclear. The sFlt-1/PlGF ratio can be used to predict PE in twin pregnancy, although different sFlt-1/PlGF ratio cut-offs from those for singleton pregnancy should be applied for optimal performance. In summary, PlGF, sFlt-1 and the sFlt-1/PlGF ratio are useful for screening, diagnosing, predicting and monitoring placenta-related disorders in singleton and twin pregnancy. We propose that tests for these angiogenic factors are integrated more fully into clinical practice.© 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Soluble fms-like tyrosine kinase-1 to placental growth factor ratio: ruling out pre-eclampsia for up to 4 weeks and value of retesting.

OBJECTIVES: The soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is generally elevated some time before and at the clinical onset of pre-eclampsia. The PROGNOSIS study validated a sFlt-1/PlGF ratio cut-off of ≤ 38 to rule out the onset of pre-eclampsia within 1 week of testing in women with suspected disease. The aim of this study was to assess the predictive value of the sFlt-1/PlGF ratio to rule out the onset of pre-eclampsia for up to 4 weeks, and to assess the value of repeat measurements. METHODS: This was an exploratory post-hoc analysis of data from the PROGNOSIS study performed in pregnant women aged ≥ 18 years with suspected pre-eclampsia, who were at 24 + 0 to 36 + 6 weeks' gestation at their first clinic visit. Serum samples were collected at the first visit and weekly thereafter. sFlt-1 and PlGF levels were measured using Elecsys® sFlt-1 and PlGF immunoassays. Whether the sFlt-1/PlGF ratio cut-off of ≤ 38 used to rule out the onset of pre-eclampsia within 1 week could predict the absence of pre-eclampsia 2, 3, and 4 weeks post-baseline was assessed. The value of repeat sFlt-1/PlGF testing was assessed by examining the difference in sFlt-1/PlGF ratio 2 and 3 weeks after the first measurement in women with, and those without, pre-eclampsia or adverse fetal outcome. RESULTS: On analysis of 550 women, sFlt-1/PlGF ratio ≤ 38 ruled out the onset of pre-eclampsia 2 and 3 weeks post-baseline with high negative predictive values (NPV) of 97.9% and 95.7%, respectively. The onset of pre-eclampsia within 4 weeks was ruled out with a high NPV (94.3%) and high sensitivity and specificity (66.2% and 83.1%, respectively). Compared with women who did not develop pre-eclampsia, those who developed pre-eclampsia had significantly larger median increases in sFlt-1/PlGF ratio at 2 weeks (∆, 31.22 vs 1.45; P < 0.001) and at 3 weeks (∆, 48.97 vs 2.39; P < 0.001) after their initial visit. Women who developed pre-eclampsia and/or adverse fetal outcome compared with those who did not had a significantly greater median increase in sFlt-1/PlGF ratio over the same period (∆, 21.22 vs 1.40; P < 0.001 at 2 weeks; ∆, 34.95 vs 2.30; P < 0.001 at 3 weeks). CONCLUSION: The Elecsys® immunoassay sFlt-1/PlGF ratio can help to rule out the onset of pre-eclampsia for 4 weeks in women with suspected pre-eclampsia. © 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

The influence of migration on women's satisfaction during pregnancy and birth: results of a comparative prospective study with the Migrant Friendly Maternity Care Questionnaire (MFMCQ).

INTRODUCTION: Approximately 21% of Germany's inhabitants have been born abroad or are of direct descent of immigrants. A positive birth experience has an effect on a woman's mental health and her future family planning choices. While international studies showed that immigrant women are less satisfied with their birth experience, no such study has been conducted in Germany until now. METHODS: At our center of tertiary care in Berlin, with approximately 50% immigrants among patients, pregnant women of at least 18 years of age were offered participation in this study. A modified version of the Migrant Friendly Maternity Care Questionnaire (MFMCQ) designed by Gagnon et al. in German, English, French, Spanish, Arabic and Turkish was used. We compared non-immigrant women to immigrant women and women with direct descent of immigrants. For certain analysis, the latter two groups were included together under the category "migration background". RESULTS: During the study period, 184 non-immigrant, 214 immigrant women and 62 direct descendants of immigrants were included. The most frequent countries of origin were Syria (19%), Turkey (17%), and Lebanon (9%). We found a slight difference between groups regarding age (non-immigrants: mean 33 years versus women with any migration background: mean 31) as well as parity with more non-immigrants delivering their first child. No difference in the satisfaction with care was observed between immigrant and any migration background groups (p ≥ 0.093 in the two-sided Fisher's exact test). At least 75.8% of all participating women reported complete satisfaction with care during labor, birth and after birth. Interestingly, the level of German language proficiency did not influence the immigrant patient's satisfaction with care. CONCLUSION: The study results show no difference regarding overall satisfaction with care during labor and birth despite a relevant language barrier. We are for the first time providing the MFMCQ in German and Turkish. Further future analyses on the impact of patient expectations on satisfaction with care will be conducted.

[Head and Neck Cancer in Pregnancy - Recommendations for Diagnosis and Therapy With Case Report]. / Kopf-Hals-Krebs in der Schwangerschaft ­ Empfehlungen zu Diagnostik und Therapie mit Fallbericht.

Objective: The diagnosis of cancer in pregnancy is rare, but might become more relevant even for head and neck cancer patients due to a shift of age of primipara towards the last third of reproductive years. Unsureness exists about the risk and benefit of diagnostic and therapeutic cancer modalities for the unborn and established recommendations are still missing. But, according to recent data, even multimodal therapeutic approaches (e. g. surgery, radiation, chemotherapy) seem possible in face of pregnancy and should be traded against the risk of prematurity. Material and Methods: Our findings are discussed on the basis of a case report of a pregnant woman with advanced carcinoma of the outer ear canal and therapy options are formulated. Results: Sufficient performed diagnostic modalities do not reach imperilling uterus dosages. A growing number of case reports und studies did not detect any developmental disadvantage of children of prenatal exposed mothers by radiation or chemotherapy, whereas long-term impairments of premature infants are proven. Conclusion: In cancer in pregnancy, an immediate start of well-established therapy modalities like surgery and/or cisplatin-based chemoradiation seems to be possible without unjustifiable risks for the unborn.

Maternal serum sFlt-1/PlGF ratio in twin pregnancies with and without pre-eclampsia in comparison with singleton pregnancies.

OBJECTIVE: In singleton pregnancies, soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and the sFlt-1/PlGF ratio have shown utility as a diagnostic test for pre-eclampsia (PE). The objective of this study was to characterize the maternal serum levels of sFlt-1, PlGF and sFlt-1/PlGF ratio in normal and pre-eclamptic twin pregnancies. METHODS: In a European multicenter case-control study, 49 women with a twin pregnancy were enrolled, including 31 uneventful and 18 pre-eclamptic pregnancies. sFlt-1 and PlGF were measured and receiver-operating characteristics (ROC) analysis was performed. The median sFlt-1 and PlGF serum concentrations and sFlt-1/PlGF ratio were compared with those of a singleton cohort, matched for gestational age, with PE (n = 54) and with an uncomplicated pregnancy outcome (n = 238). RESULTS: In twin pregnancies with PE, sFlt-1 levels and the sFlt-1/PlGF ratio were increased and PlGF levels were decreased as compared with those of twin gestations with an uneventful pregnancy outcome (20 011.50 ± 2330.35 pg/mL vs 4503.00 ± 2012.05 pg/mL (P ≤ 0.001), 164.22 ± 31.35 vs 13.29 ± 319.64 (P ≤ 0.001), and 138.80 ± 20.04 pg/mL vs 403.00 ± 193.10 pg/mL (P ≤ 0.001), respectively). The sFlt-1/PlGF ratio did not differ between twin pregnancies with PE and singleton pregnancies with PE. In twin pregnancies with an uneventful outcome, sFlt-1 levels and sFlt-1/PlGF ratio were increased, but no differences in PlGF concentration were found when compared with that of singleton controls. ROC analysis determined 53 as an optimal cut-off of the sFlt-1/PlGF ratio for diagnosing PE in twin gestations, yielding a sensitivity of 94.4% and a specificity of 74.2%. The cut-off values established for singleton pregnancies, of 33 and 85, led to sensitivities of 100% and 83.3%, and specificities of 67.7% and 80.6%, when used to detect PE in twin pregnancies. CONCLUSIONS: Significant differences in the serum marker levels in singleton vs twin pregnancies were detected. Reference ranges of sFlt-1, PlGF and their ratio in singleton pregnancies are therefore not transferable to twin pregnancies.

Noninvasive Prenatal Diagnosis of Hypohidrotic Ectodermal Dysplasia by Tooth Germ Sonography.

PURPOSE: Hypohidrotic ectodermal dysplasia, a potentially life-threatening heritable disorder, may be recognized already in utero by characteristic features such as oligodontia and mandibular hypoplasia. As therapeutic options and prognosis depend on the time point of diagnosis, early recognition was attempted during routine prenatal ultrasound examinations. SUBJECTS AND METHODS: Fetuses of nine pregnant women (one triplet and eight singleton pregnancies) with family histories of hypohidrotic ectodermal dysplasia were investigated by sonography between the 20th and 24th week of gestation. RESULTS: In 4 male and 2 female fetuses reduced amounts of tooth germs were detected, whereas 5 fetal subjects showed the normal amount. Three-dimensional ultrasound evaluation revealed mandibular hypoplasia in 5 of the 6 fetuses with oligodontia. Molecular genetic analysis and/or clinical findings after birth confirmed the prenatal sonographic diagnosis in each subject. CONCLUSION: In subjects with a family history of hypohidrotic ectodermal dysplasia, the diagnosis of this rare condition can be established noninvasively by sonography in the second trimester of pregnancy. Early recognition of the disorder may help to prevent dangerous hyperthermic episodes in infancy and may allow timely therapeutic interventions.

[Predictive value of the sFlt1/PlGF ratio for the diagnosis of preeclampsia in high-risk patients]. / Wertigkeit des sFlt1/PlGF-Quotienten als Prädiktionsparameter bei Schwangeren mit erhöhtem Präeklampsierisiko.

BACKGROUND: A dysbalance of proangiogenic [placental growth factor (PlGF)] and antiangiogenic [soluble fms-like tyrosine kinase 1 (sFlt-1)] proteins is known to cause the symptoms of preeclampsia (PE), HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) or intrauterine growth restriction (IUGR). An increased sFlt-1/PlGF ratio ≥85 is considered a reliable diagnostic marker. Altered sFlt1 and PlGF concentrations can be detected several weeks prior to the onset of clinical symptoms. In this study we analysed the role of the sFlt1/PlGF ratio as a predictive marker for preeclampsia in a high-risk patient group. PATIENTS AND MATERIALS: We prospectively included 68 singleton pregnancies with at least one risk factor for PE, HELLP syndrome or IUGR. During the study the patients were divided into one group with symptoms (patient group) and one group without symptoms (control group) for the above-mentioned diseases. The sFlt1/PlGF ratios were measured on admission and during the course of pregnancy. RESULTS: During pregnancy 41% of patients developed PE, HELLP syndrome or IUGR. An increase of the absolute value of the sFlt1/PlGF ratio ≥85 was only observed in the patient group and was found to be a predictive factor for PE, HELLP syndrome or IUGR at 25+0 to 31+0 weeks of gestation (p=0.005) and after 35+0 weeks of gestation (p=0.044). Alterations of the sFlt1/PlGF ratio were observed in all patients but were higher in the patient group from 7-10 weeks prior to delivery and with the highest peak 0-2 weeks prior to delivery. Compared to the control group (mean±SD 66.9±134) absolute values of sFlt1/PlGF ratio were significantly (p=0.021) increased 0-2 weeks prior to delivery in the patient group (mean±SD 393.3±147.4). An increase of the sFlt1/PlGF ratio ≥85 0-2 weeks before delivery has shown to be predictive for one of the mentioned diseases (p=0.025). CONCLUSIONS: In high-risk patients the sFlt1/PlGF ratio can be used for an individual risk assessment with regard to PE, HELLP syndrome or IUGR. Serial measurements permit a risk-adapted prenatal care of these patients.

[Prevention of preterm birth by Shirodkar cerclage--clinical results of a retrospective analysis]. / Klinische Ergebnisse der Cerclage nach Shirodkar bezüglich der Prävention der Frühgeburtlichkeit--eine retrospektive Analyse.

In spite of the continuous progress in prenatal care, 1 out of 10 babies is born too early--tendency rising worldwide. As a consequence of the heterogeneous aetiology of preterm birth, there is still no single and efficient interventional therapy. Cerclage is one option for pregnancies with cervical insufficiency, whereas the clinical benefit is discussed controversially. We analyzed in a retrospective study with 120 patients the effect of a cerclage intervention regarding pregnancy prolongation. Patients with cervical incompetence and Shirodkar cerclage were compared to those undergoing conservative treatment. As expected, gestational age at delivery was significantly lower after emergency cerclage (31 weeks) compared to prophylactic (36 weeks) and therapeutic cerclage (35 weeks). Prolongation differs significantly between the prophylactic (18 weeks), therapeutic (14 weeks) and emergency cerclage (10 weeks) groups. Conservative management achieved 8 weeks prolongation. Of note, particularly emergency cerclage in cases with advanced cervical incompetence resulted in a substantially higher pregnancy prolongation (10 weeks) compared to no intervention (one week). The efficiency of cerclage operations has to be assessed in a differentiated manner based on the clinical situation and indication. The clinical benefit depends strongly on proper patient selection.

Serum levels of the adipokine zinc-α2-glycoprotein are increased in preeclampsia.

BACKGROUND: Preeclampsia (PE) is associated with facets of the metabolic syndrome and an increased future metabolic and cardiovascular risk for mother and newborn. Recently, zinc-α2-glycoprotein (ZAG) has been proposed as a new adipokine involved in the pathogenesis of obesity. AIM: In the current study, we investigated ZAG serum levels in PE patients as compared to healthy gestational age-matched controls. SUBJECTS AND METHODS: We quantified serum concentrations of ZAG in patients with PE (no.=37) as compared to healthy gestational age-matched controls (no.=37) by enzyme-linked immunosorbent assay. Furthermore, association of this adipokine with renal function, glucose and lipid metabolism, as well as inflammation was studied. RESULTS: Median serum ZAG levels were 1.4-fold higher in PE patients (58.8 mg/l) as compared to controls (41.9 mg/l) (p<0.01). Furthermore, circulating ZAG was positively correlated to systolic and diastolic blood pressure, creatinine, triglycerides, and leptin in univariate analyses. In multiple regression analysis, creatinine remained independently associated with ZAG. CONCLUSIONS: We demonstrate that maternal ZAG serum concentrations are significantly increased in PE. Furthermore, renal function is an independent predictor of circulating ZAG.

Optimization of monosaccharide determination using anthranilic acid and 1-phenyl-3-methyl-5-pyrazolone for gastropod analysis.

The protein-linked glycomes and, thereby, the range of individual monosaccharides of invertebrates differ from those of mammals due to a number of special modifications; therefore, it is necessary to adapt methods for monosaccharide analysis in order to cover these. We optimized the labeling procedure for anthranilic acid (AA) and 1-phenyl-3-methyl-5-pyrazolone (PMP) and the subsequent separation of the labeled monosaccharides on high-performance liquid chromatography (HPLC), with the result that we were able to identify 26 different monosaccharides. The detection limit for anthranilic acid derivatives obtained was 65 fmol, and a reliable quantification of samples was possible up to 200 nmol under the tested conditions. PMP derivatives showed a significantly higher detection limit but allow quantification of larger sample amounts. Applying these methods on snails, their impressive set of monosaccharide constituents, including methylated sugars, was shown.

Serum levels of the adipokine lipocalin-2 are increased in preeclampsia.

BACKGROUND: Preeclampsia (PE) is a serious complication in pregnancy which increases the future risk for vascular and metabolic disease in both mother and newborn. Recently, lipocalin-2 has been introduced as a novel adipokine which contributes to obesity, insulin resistance, and vascular disease. AIM: In the current study, we investigated lipocalin-2 serum levels in PE patients as compared to healthy gestational age-matched controls. SUBJECTS AND METHODS: Lipocalin-2 serum concentrations were quantified by enzyme-linked immunosorbent assay in control (no.=22) and PE (no.=22) patients. Furthermore, lipocalin-2 levels were correlated to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. RESULTS: Median maternal lipocalin-2 concentrations were significantly increased in PE (121.3 µg/l) as compared to control subjects (99.8 µg/l) (p<0.05). Furthermore, circulating lipocalin 2 correlated positively with diastolic blood pressure, creatinine, and C reactive protein. In multivariate analyses, creatinine and C reactive protein remained independently associated with lipocalin-2 levels. CONCLUSIONS: We demonstrate that maternal lipocalin-2 concentrations are significantly increased in PE. Furthermore, markers of renal function and inflammation independently predict circulating lipocalin-2.

[Use of angiogenic factors (sFlt-1/PlGF ratio) to confirm the diagnosis of preeclampsia in clinical routine: first experience]. / Angiogene Faktoren zur Diagnosesicherung bei Präeklampsie in der klinischen Routine: erste Erfahrungen.

INTRODUCTION: In the clinical routine, the diagnosis of preeclampsia is often challenging. Not all pregnant women with signs and symptoms of preeclampsia develop the disease. Recently, the assessment of the sFlt-1/PlGF ratio in the serum of pregnant women has been proposed as an aid in the diagnosis of preeclampsia. PATIENTS AND METHODS: In a retrospective, monocentric case-control study, we reviewed 30 cases of patients who presented with the clinical symptoms of hypertensive disorders of pregnancy in the delivery ward. Next to the standard diagnostic algorithm for preeclampsia, the sFlt-1/PlGF ratio was determined using the automated Elecsys® platform. RESULTS: In 12/30 cases (40%), the diagnosis of a hypertensive pregnancy disorder was confirmed with an sFlt1/PlGF ratio of >85. In 18/30 (60%) cases, a ratio <85 excluded the diagnosis of preeclampsia at the time of presentation and allowed an adaptation of the patient's surveillance programme. CONCLUSION: In the clinical setting of "suspected preeclampsia", determination of the sFlt-1/PlGF ratio can serve as an aid in the diagnosis of hypertensive disorders in pregnancy. The reliable exclusion of the diagnosis "preeclampsia" can help in an appropriate and cost-effective management of patients with signs and symptoms of the disease.

[Angiogenic factors and their role in pathogenesis and prediction of preeclampsia]. / Angiogene Faktoren und ihre Rolle in der Entstehung und Vorhersage der Präeklampsie.

Angiogenic factors like placental growth factor (PlGF) and its anti-angiogenic antagonists soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) are closely related to the pathogenesis of preeclampsia and intrauterine growth restriction (IUGR). The discovery and investigation of these angiogenic factors could characterize important pathogenetic mediators of preeclampsia or even the cause for placental dysfunctions. These anti-angiogenic proteins are dramatically elevated in maternal circulation weeks prior to the onset of the syndrome preeclampsia. Since it is known that altered maternal sFlt1, sEng and PlGF levels are detectable weeks prior to the onset of these pregnancy complications, it was the aim of the study to investigate the predictive value of these markers in high-risk second trimester pregnancies characterized by abnormal uterine perfusion. Using both factors, sFlt1 and PlGF, early-onset preeclampsia can be predicted with 83% sensitivity and 95% specificity. Combined analysis of sEng and sFlt1 is able to predict early-onset PE even with a sensitivity of 100% and a specificity of 93.3%. This shows, that the concurrent measurement of uterine perfusion and angiogenic factors allows an efficient prediction of early-onset pregnancy complications, particularly preeclampsia. The next step will be the development of therapeutic tools that have positive impact on the clinical symptoms via the inhibition of sFlt1 and or sEng.

Angiotensin II type 1 receptor has impact on murine placentation.

Impaired placentation is a key step in the pathogenesis of important pregnancy disorders such as preeclampsia and fetal growth restriction. A role of angiotensin II in placental development can be assumed from the expression of angiotensin receptors on trophoblast from the earliest stages of pregnancy. To understand the role of angiotensin II type 1 (AT1) receptors in placental development, we investigated placentae of AT1a-deficient mice early in pregnancy (day 13 postconception). The number of alive newborns was significantly reduced in AT1a-deficient mice caused by placental malformations in 30% of all utero-placental units. Importantly, no embryonic structure was observable within the uterine segments harboring the malformed placentae. Immunohistochemistry with an antibody against murine betahCG-equivalent stained homogeneously in almost all cells in the altered placentae indicating still an endocrine-active trophoblast. However, the typical structure of the murine wild-type placenta in spongiotrophoblast, giant cells, and labyrinth was abolished in malformed placental tissue deficient in the AT1a receptor. Recent epidemiological studies revealed the detrimental effect of an AT1 blockade for fetal outcome due to renal malformations and a reduced birth weight. For the latter, our findings provide an early mechanistic explanation. The lack in AT1 stimulation causes an impaired trophoblast maturation leading to impaired placental function.