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 PreeclampsiaNovelty and Significance
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.
- angiogenic factors
- antiangiogenic factors
- sFlt1-PlGF ratio
Preeclampsia is a multisystem disorder in pregnancy. With an incidence of 2% to 5% of all pregnancies, it is a frequent pregnancy-related disease and a major cause of maternal and fetal morbidity and mortality.1 Preeclampsia is defined as the new-onset of hypertension (≥140/90 mm Hg on 2 separate occasions ≥4 hours apart) and proteinuria (≥300 mg/24 h).2 The simplicity of this definition contrasts with the complexity of the disease. The pathophysiology of preeclampsia is not conclusively resolved up to now. Early-onset preeclampsia, defined as the onset before 34 weeks of gestation, comprises the mal implantation of the placenta, insufficient spiral-artery remodeling, prevalently resulting in intrauterine growth restriction and an altered expression of placental proteins such as soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factors (PlGFs).3 In contrast, late-onset preeclampsia, defined as the onset after 34 weeks of gestation, is not necessarily accompanied by placental dysfunction4 but angiogenic and antiangiogenic factors are also dysregulated, though to a less dramatic extent.5
We and others have previously shown that the sFlt-1/PlGF ratio is elevated in patients with preeclampsia.6–10 The automated measurement of the sFlt-1/PlGF ratio detects early-onset preeclampsia with a sensitivity of 89% and a specificity of 97% when the single, gestation-wide cutoff of 85 is used.8 Recently, Rana et al9 have shown that in patients with signs and symptoms for the disease, an sFlt-1/PlGF ratio ≥85 predicts the occurrence of preeclampsia-related adverse maternal and fetal outcomes, irrespective of the presence of a diagnosis of preeclampsia according to the gold standard.
With accumulating evidence of the importance of the sFlt-1/PlGF ratio as a diagnostic and prognostic marker, the limitations and benefits of its clinical use have to be assessed. Up to now, only 1 cutoff (85) exists, irrespective of the gestational week tested, with limited diagnostic accuracy especially in late-onset preeclampsia. This cutoff was based on a preliminary analysis of a multicenter case–control study consisting of 71 patients with preeclampsia and a matched cohort of 280 control patients.
Here, we report the final analysis of a multicenter case–control study including a total of 1149 patients. 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. To better reflect the putatively different pathophysiology of early-onset and late-onset preeclampsia, diagnostic accuracy of 2 separate cutoffs framing an equivocal zone was determined for the early and late phase of gestation.
Singleton pregnancies were enrolled at 9 European perinatal care centers. An identical study protocol and data collection form was used at each center. The local ethics committees and institutional review boards approved the study, and all subjects gave their written informed consent before participation.
Preeclampsia was defined according to the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.11 The syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome), superimposed preeclampsia, and intrauterine growth restriction were defined as previously published.8 In this study, patients with any form of preeclampsia or HELLP were combined in the preeclampsia/HELLP group (preeclampsia/HELLP) for analysis. A pregnancy outcome was defined as normal if the mother was not diagnosed with any form of preeclampsia/HELLP and the infant was not diagnosed with intrauterine growth restriction. Investigators were blinded to sFlt-1 and PlGF levels which prevented an influence of this information on decision making and defining time point of delivery.
A total of 1149 individuals were enrolled in the study: 915 singleton pregnancies with normal pregnancy outcome and 234 singleton pregnancies with preeclampsia outcome. At least 100 preeclampsia/HELLP cases for each early and late gestational phase were determined by study protocol as target numbers for the nested case–control population. Recruitment was performed in a prospective manner until these targets were obtained with the consequence of enrolling 1149 patients.
Two subsets of this data collective were built (Figure S1 in the online-only Data Supplement). For analysis of reference ranges, maximum 1 visit from each subject per gestational age window was included in case of follow-up visits in the control group. Therefore, this subset contains 1685 control visits from 877 subjects. An additional 38 control subjects either contributed samples only before week 10 or were not normotensive and were therefore excluded from the reference range analysis. For the determination of gestational age–dependent reference values, we analyzed 7 gestational age windows: window 1: 10+0 to 14+6 weeks of gestation; window 2: 15+0 to 19+6 weeks of gestation; window 3: 20+0 to 23+6 weeks of gestation; window 4: 24+0 to 28+6 weeks of gestation; window 5: 29+0 to 33+6 weeks of gestation; window 6: 34+0 to 36+6 weeks of gestation; and window 7: 37+0 weeks of gestation to delivery. All gestational age windows comprise 5 weeks except window 3 (20–23+6 weeks of gestation) and window 6 (34+0–36+6 weeks of gestation), acknowledging clinical thresholds at 24+0 (viability), 34+0 (early/late preeclampsia), and 37+0 weeks of gestation (preterm birth).
For receiver operating characteristics (ROC) curves and analysis of the cutoff, a total of 234 subjects with a preeclampsia/HELLP outcome were matched to 468 subjects with uneventful pregnancy outcomes. Only visits from subjects with a gestational age of ≥20+0 weeks were included. In patients with preeclampsia/HELLP, only the first visit after confirmation of the diagnosis was included in the analysis. A preeclampsia pregnancy was defined as early onset if preeclampsia was diagnosed at a visit before week 34 (≤33+6 weeks of gestation). In case preeclampsia was diagnosed at >34+0 weeks of gestation, the patient was assigned to the late-onset preeclampsia group. Patients of the preeclampsia/HELLP group were matched pairwise by gestational week to a healthy control in a 1:2 manner, resulting in a double sample size of the control group. A control patient only donated samples either to the early- or the late-onset preeclampsia group, and no repeated samples were used in the case–control cohort.
In a separate descriptive subgroup analysis, patients with superimposed preeclampsia (n=14), isolated HELLP (n=15), preeclampsia not being severe or complicated by HELLP syndrome (n=99), and patients with severe preeclampsia (n=106) were analyzed.
Samples and Immunoassays
Serum samples were collected according to a common standard operating procedure at each center. Single measurements were performed for sFlt-1 and PlGF on the fully automated Roche Elecsys system (Elecsys PlGF, human PlGF, and Elecsys sFlt-1, sFlt-1) as described previously, and the sFlt-1/PlGF ratio was calculated for each sample.12,13 Only serum samples were analyzed in this study, results in plasma samples may differ.
Basic statistics (mean, median, SD, quartiles, and range) were performed for sFlt-1, PlGF, and the sFlt-1/PlGF ratio. To compare clinical subgroups, descriptive statistics (median±interquartil ranges) were generated. Gestational age–dependent reference values were determined per time window as quantiles. For the statistical comparison of marker levels in the respective clinical groups, data were transformed as appropriate and either parametric (ANOVA, t test) or nonparametric (Wilcoxon/Kruskal–Wallis) tests were applied. All P values are 2-tailed. Statistical significance was assigned when a P value was <0.05. All statistical analyses were performed using SAS. ROC analysis was used for the evaluation of the area under curve and the sensitivity and specificity as a function of cutoff for markers sFlt-1, PlGF, and sFlt-1/PlGF ratio. Positive and negative likelihood ratios (LR+/LR−) were calculated. Gerhard plots were generated to find optimized cutoff values for the single markers and the ratio. A generalized linear regression model with a γ-distributed response regarding the positively skewed, continuous distribution was applied to test for confounding effects of body mass index and maternal age.
Demographic and Clinical Baseline Characteristics
No significant differences were found in age, height, and weight between patients with early- or late-onset preeclampsia and their gestational age–matched controls. As expected, patients with preeclampsia had a significantly earlier date of delivery, higher systolic and diastolic blood pressure, higher body mass index, and lower neonatal birth weight (P<0.05 or P<0.001 where appropriate, Table S1).
Gestational Age–Dependent Normal Values
Normal values for the sFlt-1/PlGF ratio as well as the single markers were generated in 7 gestational age windows from women with uneventful pregnancy outcome (Table 1). As ex pected, the sFlt-1/PlGF ratio showed an U-shaped curve with median sFlt-1 concentrations rising and PlGF values exhibiting a bell-shaped curve in the course of pregnancy (Figure S2a–S2c).
sFlt-1 and PlGF Values in Different Clinical Subsets of preeclampsia
In patients with preeclampsia/HELLP, circulating serum concentrations of sFlt-1 were elevated, PlGF levels were decreased, and the sFlt-1/PlGF ratio was increased when compared to patients with uneventful pregnancy outcome. The median sFlt-1/PlGF ratio in all patients with preeclampsia/HELLP was 185 (n=234; 25th–75th centile, 92.5–427) versus 7.78 (n=468; 25th–75th centile, 3.29–23.9; P<0.001) in women with uneventful pregnancy outcome (Figure 1A, left). In patients with superimposed preeclampsia, the median sFlt-1/PlGF ratio was 75.4 (n=14; 25th–75th centile, 18.0–141); in patients with isolated HELLP, 420 (n=15; 25th–75th centile, 192–814); in patients with preeclampsia not being severe or complicated by HELLP syndrome, 116 (n=99; 25th–75th centile, 51.7–202); and in patients with severe preeclampsia, 350 (n=106; 25th–75th centile, 170–574; P<0.001 Kruskal–Wallis for subgroup comparison; Figure 1A, right).
The median sFlt-1/PlGF ratio in patients with early-onset preeclampsia was 424 (n=100; 25th–75th centile, 186–717) versus 129 (n=134; 25th–75th centile, 59–207; P<0.001) in late-onset cases. Patients with uncomplicated pregnancies ≤33+6 weeks of gestation (n=200) had a median sFlt-1/PlGF ratio of 3.68 (25th–75th centile, 2.03–7.50) versus 16.2 (25th–75th centile, 6.50–37.0; P<0.001) in control patients ≥34+0 weeks of gestation (n=268; Figure 1B).
Diagnostic Accuracy of sFlt-1, PlGF, and the sFlt-1/PlGF Ratio in Early- and Late-Onset preeclampsia
In the ROC analysis, sFlt-1/PlGF ratio exhibited a superior performance to the single parameters in diagnosing preeclampsia (Figure 2). For all patients with preeclampsia/HELLP, the ROC area under curve was 0.94 (95% confidence interval [CI], 0.92–0.96). For sFlt-1 ROC analysis showed a diagnostic accuracy of 0.92 (95% CI, 0.89–0.94), whereas PlGF yielded an area under curve of only 0.91 (95% CI, 0.88–0.93) (Figure 2).
An optimized cutoff was evaluated based on the ROC analysis. For the whole gestational phase, the optimized cutoff was found to be 34.1, resulting in a sensitivity of 91% and a specificity of 83.6%. When analyzing the preeclampsia/HELLP group divided by early- and late-onset preeclampsia, for early-onset preeclampsia an optimized cutoff of 38.5 resulted in a sensitivity of 93% and a specificity of 97%. For late-onset preeclampsia, a cutoff of 34.6 resulted in a sensitivity of 88.8% and a specificity of 74.6% (Tables 2 and 3).
Definition of Gestational Phase–Specific Cutoff Values
Separate cutoffs were determined for the early gestational phase (20+0–33+6 weeks of gestation) and for the late gestational phase (34+0 weeks of gestation–delivery). Moreover, to enhance the diagnostic accuracy of the sFlt-1/PlGF ratio, for each of the gestational phases, an equivocal zone between 2 cutoff values was established. For the early gestational phase, the rationale for choosing the cutoffs was to reach a ≥95% sensitivity (at the low cutoff) and ≥95% specificity (at the high cutoff; Figure 3). In this group, a cutoff of 33 resulted in a sensitivity of 95% and a specificity of 94%, corresponding to an LR− of 0.05 (95% CI, 0.02–0.13) and an LR+ of 15.8 (95% CI, 9.13–27.5). In total numbers, 95 of 100 patients were correctly classified as having preeclampsia, whereas 188 of 200 were correctly diagnosed as not having preeclampsia. However, in the same early phase, a cutoff of 85 resulted in a sensitivity of 88% and a specificity of 99.5% and yielded an LR+ of 176 (95% CI, 24.9–1245) and an LR− of 0.12 (95% CI, 0.07–0.21). All 200 patients bar one were correctly classified as healthy, using the cutoff of 85. In combining the cutoffs ≤33/≥85, 95 of 100 preeclamptic patients were correctly classified and only 5 were incorrectly diagnosed as not being preeclamptic, whereas only 1 in 100 healthy pregnancies was incorrectly classified as having preeclampsia (Tables 2 and 3).
For the late gestational phase, the cutoffs were chosen to reach a minimum of 95% specificity for the early cases of late-onset preeclampsia/HELLP (≥34–< 37 weeks of gestation). Here, a cutoff of 33 resulted in a sensitivity of 89.6%, a specificity of 73.1%, an LR− of 0.14 (95% CI, 0.09–0.24), and an LR+ 3.33 (95% CI, 2.71–4.10). However, a cutoff of 110 resulted in a sensitivity of 58.2% and a specificity of 95.5%, corresponding to an LR+ of 13 (95% CI, 7.34–23.0) and an LR− of 0.44 (95% CI, 0.36–0.54). Therefore, when combining the cutoffs of ≤33/≥110, a sensitivity of 89.6% and a specificity of 95.5% were reached (Tables 2 and 3).
The aim of the study was to provide reference ranges and cutoffs for the clinical use of the sFlt-1/PlGF ratio as an aid in diagnosis of preeclampsia. Previous work from our group as well as from others has consistently shown that the automated measurement of sFlt-1, PlGF and the calculation of the sFlt-1/PlGF ratio is a reliable tool for the diagnosis of preeclampsia.8,10,13–15
We reported earlier a cutoff of 85 for the sFlt-1/PlGF ratio as an aid in diagnosis of preeclampsia regardless of the gestational week tested. This preliminary cutoff was based on a case–control cohort of 71 patients with preeclampsia and 280 control patients.8 In the preliminary analysis, a cutoff of 85 resulted in a sensitivity of 82% and a specificity of 95% for diagnosing preeclampsia. For the subgroup early-onset preeclampsia, the same cutoff value (85) for the sFlt-1/PlGF ratio resulted in a sensitivity of 89% and a specificity of 97%. The cutoff was selected to generate a high specificity in a trade-off with sensitivity of the test.
After concluding the multicenter case–control study, we were now able to look at a total of 234 patients with preeclampsia and 915 control subjects. In-depth analysis of the whole study cohort revealed a different performance of the sFlt-1/PlGF ratio. Now, the single cutoff of 85 resulted in a sensitivity of 75.6% and a specificity of 95.5%. For the subgroup of early-onset preeclampsia, the single cutoff of 85 resulted in a sensitivity of 88% and a specificity of 99.5%.
We calculated optimized cutoffs based on the ROC analysis. For the whole gestational phase, a single, optimized cutoff of 34.1 resulted in a sensitivity of 91% and a specificity of 83.6%. Preeclampsia is a heterogeneous disease with marked differences in presentation and outcome especially between early-onset (≤33+6 weeks of gestation) and late-onset disease (≥34+0 weeks of gestation). The putatively different underlying pathophysiological mechanisms of the early- and late-onset preeclampsia are reflected by a different performance of sFlt-1, PlGF, and the sFlt-1/PlGF ratio. We therefore aimed to adequately reflect the putative 2 diseases of preeclampsia in defining different cutoffs for the early- and late-onset disease. Introducing 2 cutoffs for the different disease entities resulted in a higher accuracy in identifying the disease.
Gestational Phase–Dependent Cutoffs Framing an Equivocal Zone Enhance Diagnostic Accuracy
To accurately classify a patient with early-onset preeclampsia, it is necessary to have a high sensitivity. The number of false-negative test results has to be low in order not to miss a diseased patient. When applying the cutoff of 33 with a sensitivity of 95%, we would have correctly classified 95 of 100 patients in our cohort. The associated LR− is 0.05. On the contrary, the demand to accurately rule out the disease in patients with unspecific symptoms requires a high specificity. When applying the upper cutoff of 85, the specificity of 99.5 would correctly classify 199 of 200 patients as healthy. The corresponding LR+ is 176. Therefore, the use of the 2 cutoffs in our setting would result in a correct diagnosis of all bar 1 as not having preeclampsia and in an incorrect diagnosis of only 5 of 100 as falsely not having the disease. The equivocal zone contains 7% of the patients with preeclampsia/HELLP and 5.5% of the controls in the early gestational phase. However, the equivocal zone for late-onset preeclampsia contains 31.3% of the preeclampsia/HELLP and 22.4% of the control patients in the late gestational phase. The establishment of the equivocal zone allows for the identification of patients at intermediate risk. A precise diagnosis at the outer borders, combined with a necessity of timely retesting in patients inside the equivocal zone, allows for maximum diagnostic safety.
Our study has limitations. We have performed a case–control study with a 2:1 matching in the ROC group. Because of the design, with a constructed incidence of preeclampsia of 33.3%, we were not able to calculate positive or negative predictive values. Individual cutoffs could be established only for 2 gestational phases. The data set is too small to establish cutoffs for shorter time intervals, which resulted in a sudden change of cutoffs at 34+0 weeks of gestation. For the late gestational age group, there is a significant proportion of patients inside the equivocal zone. Almost 30% of the patients with preeclampsia/HELLP and almost 25% of the controls need to be retested. For these patients, data are lacking on when and how often they have to be retested. We evaluated singleton pregnancies in this study, therefore our results only apply to this group of patients. It is known, however, that multifetal gestations exhibit different patterns of angiogenic factor serum levels with healthy twin pregnancies exhibiting a 3-fold increase in the sFlt-1/PlGF ratio as compared with singleton pregnancies.16 Therefore, caution must be taken when applying the reference ranges and cutoffs found in this study to multifetal gestations. Furthermore, it is noteworthy that only a small proportion of patients in this European study are of other than white origin. Therefore, results may vary in populations with a different racial background and thus different disease prevalence. Further studies are needed to clarify these points.
The clinical presentation of preeclampsia is diverse, and the diagnosis of atypical cases of preeclampsia is a daily challenge to the practicing obstetrician.17 Current definitions and guidelines rely solely on the measurement of blood pressure and proteinuria to diagnose the disease.2,18 However, the measurement of blood pressure and proteinuria has low predictive accuracy of adverse maternal and fetal outcomes. Recently, Rana et al9 have shown that in women with suspected preeclampsia, the sFlt-1/PlGF ratio helps to identify those who will develop a preeclampsia-related pregnancy complication. In addition to the gold standard of preeclampsia diagnostics, the measurement of blood pressure and proteinuria, the sFlt-1/PlGF ratio is able to improve prediction of adverse preeclampsia-related outcomes.9
Various groups have shown that 1 single cutoff at 85 is not optimal for diagnosing preeclampsia or other hypertensive pregnancy disorders in all clinical settings.14,19,20 The new gestational phase–specific 2 cutoffs allow maximized accuracy of diagnosis. A more precise diagnosis and gestational phase–dependent analysis might have future therapeutic consequences. Recently, a pilot study has shown a possible therapy for women with early-onset preeclampsia. Preeclamptic women who underwent sFlt-1 apheresis had longer remaining pregnancy duration.21 Removal of sFlt-1 resulted in amelioration of kidney function and prolongation of pregnancy. Therefore, the sFlt-1/PlGF ratio might have importance as a parameter to monitor disease severity and hence therapeutic progress.
The use of an equivocal zone and focus on the outer borders of this zone to rule in or rule out patients with preeclampsia enhances the diagnostic accuracy of the sFlt-1/PlGF ratio with the potential to reduce maternal and fetal morbidity and mortality. Below 34 weeks of gestation, an sFlt-1/PlGF ratio of ≤33 is associated with an LR− of 0.05, whereas values ≥85 have a likelihood of a positive test of 176. For late-onset preeclampsia, the LR− at the cutoff ≤33 is 0.14, the LR+ at ≥110 is 13. Looking at the clinical feasibility, a simple diagnostic algorithm is desirable for the user. However, the establishment of differential cutoffs for different gestational phases instead of using 1 single cutoff value better reflects the pathophysiology of the disease. In our opinion, this approach of gestational phase–specific cutoff values provides a reasonable balance/compromise between both needs.
Sources of Funding
P. Calda has received funding by grant RVO-VFN64165/2012. The study was supported by Roche Diagnostics, Germany.
B. Denk is employed by Roche Diagnostics, Penzberg, Germany. H. Stepan has received consultancy payments from Roche regarding advice on clinical trial design. S. Verlohren has received consultancy payments from Roche regarding advice on data analysis and publication. S. Verlohren and H. Stepan received lecture fees from Roche. The other authors report no conflicts.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.113.01787/-/DC1.
- Received June 15, 2013.
- Revision received July 7, 2013.
- Accepted October 1, 2013.
- © 2013 American Heart Association, Inc.
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Novelty and Significance
What Is New?
An imbalance of angiogenic and antiangiogenic factors is involved in the pathophysiology of preeclampsia.
Automated measurement of antiangiogenic soluble fms-like tyrosine kinase-1 and angiogenic placental growth factor (PlGF) and the calculation of the soluble fms-like tyrosine kinase-1/placental growth factor ratio allows for detection of the hypertensive pregnancy disorder.
What Is Relevant?
Up to now only 1 cutoff for the clinical use of the soluble fms-like tyrosine kinase-1/placental growth factor ratio as an aid in diagnosis has been evaluated.
In the final evaluation of a multicenter study, we show here that the use of 2 gestational phase–specific cutoffs framing an equivocal zone improved the diagnostic accuracy of the test.
The use of multiple cutoffs better reflects the pathophysiological and clinical difference of early and late preeclampsia and might thus improve clinical diagnostics and management.