I. Herraiz

An automated method for the determination of the sFlt-1/PIGF ratio in the assessment of preeclampsia

OBJECTIVE The angiogenic and antiangiogenic factors soluble fms-like tyrosine kinase (sFlt)-1 and placental growth factor (PIGF) have been implicated in the mechanisms of disease responsible for preeclampsia (PE). Moreover, it has been proposed that the concentrations of these markers in maternal serum/plasma may have predictive value. This study evaluates a newly developed Elecsys (Roche, Penzberg, Germany) assay for sFlt-1 and PIGF and tests the value of the sFlt-1/PIGF ratio in the assessment of PE. STUDY DESIGN This multicenter case-control study included 351 patients: 71 patients with PE and 280 gestational age-matched control subjects from 5 European study centers. A total of 595 serum samples were measured for sFlt-1 and PIGF using an automated platform. RESULTS Maternal serum concentrations of sFlt-1 and PIGF significantly separated healthy women and women with PE. The sFlt-1/PIGF ratio had an area under the receiver operating characteristic curve of 0.95. The best performance was obtained in the identification of early-onset PE (area under the receiver operating characteristic curve of 0.97). CONCLUSION Measurement of sFlt-1 and PIGF and calculation of sFlt-1/PIGF ratio can be performed quickly and in a platform available in clinical laboratories. This is a substantial step forward in bringing the determination of these analytes to clinical practice in obstetrics. We propose that sFlt-1, PIGF, and sFlt-1/PIGF ratio may be of value in the prediction of PE and in the differential diagnosis of patients with atypical presentations of PE, and perhaps in the differential diagnosis of women with chronic hypertension suspected to develop superimposed PE.

The sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders and its prognostic potential in preeclamptic patients

OBJECTIVE The soluble fms-like tyrosine kinase (sFlt-1)/placental growth factor (PlGF) ratio is a reliable tool in the assessment of preeclampsia. We tested the hypothesis that the sFlt-1/PlGF ratio is able to identify women at risk for imminent delivery. We characterized the sFlt-1/PlGF ratio in different types of hypertensive pregnancy disorders. STUDY DESIGN We investigated 388 singleton pregnancies with normal pregnancy outcome, 164 with PE, 36 with gestational hypertension, and 42 with chronic hypertension. sFlt-1 and PlGF were measured in serum samples. RESULTS Patients with preeclampsia had a significantly increased sFlt-1/PlGF ratio as compared with controls and with patients with chronic and gestational hypertension in <34 weeks and ≥34 weeks (P < .001). Time to delivery was significantly reduced in women with preeclampsia in the highest quartile of the sFlt-1/PlGF ratio (P < .001). CONCLUSION The sFlt-1/PlGF ratio allows the identification of women at risk for imminent delivery and is a reliable tool to discriminate between different types of pregnancy-related hypertensive disorders.

New Gestational Phase–Specific Cutoff Values for the Use of the Soluble fms-Like Tyrosine Kinase-1/Placental Growth Factor Ratio as a Diagnostic Test for Preeclampsia

To establish gestational phase adapted cutoffs for the use of the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio as a diagnostic tool for preeclampsia in the clinical setting, a multicenter case–control study including a total of 1149 patients was performed. We report normal values of sFlt-1, PlGF, and the sFlt-1/PlGF ratio based on the analysis of a total of 877 patients with uneventful pregnancy outcome. A total of 234 patients with preeclampsia and a matched cohort consisting of 468 patients with normal pregnancy outcome were compared, and sFlt-1 and PlGF were measured on an automated platform. Separate cutoffs for the sFlt-1/PlGF ratio were determined for the early (20+0–33+6 weeks) and the late gestational phase (34+0 weeks–delivery). For each of the 2 gestational phases, 2 independent cutoffs framing an equivocal zone were determined: the first cutoff with focus on high sensitivity, and the second focusing on high specificity. Between 20+0 and 33+6 weeks, the cutoffs at ⩽33 and ≥85 resulted in a sensitivity/specificity of 95%/94% and 88%/99.5%, respectively. An sFlt-1/PlGF ratio of ⩽33 had the lowest likelihood of a negative test (0.05; 95% confidence interval, 0.02–0.13), whereas values ≥85 had the highest likelihood of a positive test (176; 95% confidence interval, 24.88–1245). After 34+0 weeks, the cutoffs at ⩽33 and ≥110 yielded a sensitivity/specificity of 89.6%/73.1% and 58.2%/95.5%, respectively. The approach to use multiple cutoffs for the early and late gestational phase enhances the diagnostic accuracy of the sFlt-1/PlGF ratio as a diagnostic tool for preeclampsia.

Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of pre-eclampsia in singleton pregnancy: implications for clinical practice

Pre-eclampsia (PE) is a leading cause of maternal and fetal/neonatal morbidity and mortality worldwide. Clinical diagnosis and definition of PE is commonly based on the measurement of non-specific signs and symptoms, principally hypertension and proteinuria1–3. However, due to the recognition that measurement of proteinuria is prone to inaccuracies and the fact that PE complications often occur before proteinuria becomes significant, most recent guidelines also support the diagnosis of PE on the basis of hypertension and signs of maternal organ dysfunction other than proteinuria3–5. Furthermore, the clinical presentation and course of PE is variable, ranging from severe and rapidly progressing early-onset PE, necessitating preterm delivery, to late-onset PE at term. There may be associated intrauterine growth restriction (IUGR), further increasing neonatal morbidity and mortality. These features suggest that the classical standards for the diagnosis of PE are not sufficient to encompass the complexity of the syndrome. Undoubtedly, proper management of pregnant women at high risk for PE necessitates early and reliable detection and intensified monitoring, with referral to specialized perinatal care centers, to reduce substantially maternal, fetal and neonatal morbidity6,7. In the decade since Maynard et al.8 reported that excessive placental production of soluble fms-like tyrosine kinase receptor-1 (sFlt-1), an antagonist of vascular endothelial growth factor and placental growth factor (PlGF), contributes to the pathogenesis of PE, extensive research has been published demonstrating the usefulness of angiogenic markers in both diagnosis and the subsequent prediction and management of PE and placenta-related disorders. Various reports have demonstrated that disturbances in angiogenic and antiangiogenic factors are implicated in the pathogenesis of PE and have possible relevance in the diagnosis and prognosis of the disease. Increased serum levels of sFlt-1 and decreased levels of PlGF, thereby resulting in an increased sFlt-1/PlGF ratio, can be detected in the second half of pregnancy in women diagnosed to have not only PE but also IUGR or stillbirth, i.e. placenta-related disorders. These alterations are more pronounced in early-onset rather than late-onset disease and are associated with severity of the clinical disorder. Moreover, the disturbances in angiogenic factors are reported to be detectable prior to the onset of clinical symptoms (disease), thereby allowing discrimination of women with normal pregnancies from those at high risk for developing pregnancy complications, primarily PE9–30. Plasma concentrations of angiogenic/antiangiogenic factors are of prognostic value in obstetric triage: similar to the progressively worsening clinical course observed in women with early-onset PE, changes in the angiogenic profile leading to a more antiangiogenic state can be found. Current definitions of PE are poor in predicting PE-related adverse outcomes. A diagnosis of PE based on blood pressure and proteinuria has a positive predictive value of approximately 30% for predicting PE-related adverse outcomes31. Estimation of the sFlt-1/PlGF ratio allows identification of women at high risk for imminent delivery and adverse maternal and neonatal outcome23,30,32–35. Moreover, it has also been shown that the time-dependent slope of the sFlt-1/PlGF ratio between repeated measurements is predictive for pregnancy outcome and the risk of developing PE, and repeated measurements have been suggested36. However, the ‘optimal’ time interval for a follow-up test remains unclear. Finally, high values are closely related to the need to deliver immediately22,23,37. Additionally, in normal and complicated pregnancies, angiogenic factors are correlated with Doppler ultrasound parameters, mainly uterine artery (UtA) indices38–42. Combining the sFlt-1/PlGF ratio with UtA Doppler ultrasound, at the time of diagnosis of early-onset PE, has prognostic value mainly for perinatal complications, being limited for the prediction of maternal complications37,43. The additional measurement of the sFlt-1/PlGF ratio has been shown to improve the sensitivity and specificity of Doppler measurement in predicting PE44–48, supporting its implementation in screening algorithms. Whereas studies on the predictive efficacy of the sFlt-1/PlGF ratio in the first trimester have yielded contradictory results49, reports on the use of this marker as an aid in prediction from the mid trimester onwards have led to its suggested use as a screening tool, especially for identifying all women developing PE and requiring delivery within the subsequent 4 weeks50–52. This short review of the literature highlights that measurement of the sFlt-1/PlGF ratio has the potential to become an additional tool in the management of PE, particularly as automated tests that allow rapid and easy measurement of these markers are now widely available. Nevertheless, although these markers were incorporated recently into the German guidelines53, no formal recommendation regarding how to use sFlt-1, PlGF or the sFlt-1/PlGF ratio has been established in any official protocol. The purpose of this paper is to answer questions that are frequently asked around the use of the sFlt-1/PlGF ratio in the diagnosis and prediction of PE and regarding the implications for clinical practice, in particular, ‘When?’ and ‘In which women?’ should the sFlt-1/PlGF ratio be measured and, ‘What should be done with the results?’, and to provide guidance to educate physicians on the use of the sFlt-1/PlGF ratio in clinical practice. To achieve this, international experts in the use of angiogenic markers have strived to develop a consensus statement on the clinical use of the sFlt-1/PlGF ratio and the consequential management in pregnant women with suspected PE or at a high risk of developing PE.

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

Prenatal diagnosis of right aortic arch: associated findings, pregnancy outcome, and clinical significance of vascular rings

To analyze the characteristics and clinical implications of right aortic arch (RAA) detected in fetal life.

Application of a first‐trimester prediction model for pre‐eclampsia based on uterine arteries and maternal history in high‐risk pregnancies

To assess the value of a prediction model for pre‐eclampsia (PE) in the first trimester (Ultrasound Obstet Gynecol 2007;30:742–794) for the prediction of late (>34 weeks) and early (≤34 weeks) PE in a high‐risk population.

Prenatal Detection of Congenital Heart Defects: A Survey on Clinical Practice in Spain

Introduction: Second-trimester fetal screening for congenital heart defects (CHD) included in routine obstetric care provides relevant information for decision making. The aim of this study was to describe the clinical practice of prenatal detection of CHD in terms of the process and results. Methods: The characteristics and results of ultrasound screening for major CHD were documented using data provided by hospitals for a national survey in Spain over the period of 2004–2006. Sixty-seven percent of eligible centers (56/83), covering 36% of total births nationwide, responded to the survey; 33 of these returned complete data regarding the screening results. Results: The number of major CHD occurring in the centers which provided data with results of screening was 1,060. The overall prenatal detection rate of major CHD was 65.7% (95% CI 57.8–74.7), but the detection rate in the routine second-trimester scan was 52.6% (95% CI 45.6–60.8). In 61% of these cases the parents chose to terminate the pregnancy. Two independent predictors of increased detection by center were identified: first, the uniformity and systematic character of the examination of the heart showing at least the 4-chamber view and outflow tracts (prevalence ratio 1.3, 95% CI 1.0–1.8) and second, the local availability of specialists in fetal echocardiography (prevalence ratio 1.4, 95% CI 1.1–1.9). Conclusions: The detection of major CHD in the first half of pregnancy has an important impact on parental decision making. The prenatal screening program for CHD should be globally strengthened in terms of qualifications and methodological approaches. To improve its performance locally, close collaboration with fetal heart specialists should be promoted.

Hypoplastic left heart syndrome diagnosed in fetal life: associated findings, pregnancy outcome and results of palliative surgery.

To analyze the main prenatal characteristics of hypoplastic left heart syndrome (HLHS), its association with extracardiac anomalies including increased nuchal translucency (NT) and the outcome of affected patients.

Uterine artery Doppler and sFlt‐1/PlGF ratio: usefulness in diagnosis of pre‐eclampsia

To evaluate the usefulness of the mean pulsatility index of the uterine arteries (mPI‐UtA) and automated measurement of the soluble fms‐like tyrosine kinase 1 (sFlt‐1)/placental growth factor (PlGF) ratio on suspicion or at diagnosis of pre‐eclampsia (PE).