Plasma concentrations of soluble endoglin versus standard evaluation in patients with suspected preeclampsia

Abstract

Background: The purpose of this study was to compare plasma soluble endoglin (sEng) levels with standard clinical evaluation or plasma levels of other angiogenic proteins [soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF)] in predicting short-term adverse maternal and perinatal outcomes in women with suspected preeclampsia presenting prior to 34 weeks.

Methods and findings: Data from all women presenting at <34 weeks for evaluation of preeclampsia with singleton pregnancies (July 2009-October 2010) were included in this analysis and sEng levels were measured at presentation. Data was analyzed for 170 triage encounters and presented as median {25-75(th) centile}. Thirty-three percent of patients (56 of 170) experienced an adverse outcome. sEng levels (ng/ml) were significantly elevated in patients who subsequently experienced adverse outcomes compared to those who did not (32.3 {18.1, 55.8} vs 4.8 {3.2, 8.6}, p<0.0001). At a 10% false positive rate, sEng had higher detection rates of adverse outcomes than the combination of highest systolic blood pressure, proteinuria and abnormal laboratory tests (80.4 {70.0, 90.8} vs 63.8 {51.4, 76.2}, respectively). Subjects in the highest quartile of sEng were more likely to deliver early compared to those in the lowest quartile (HR: 14.96 95% CI: 8.73-25.62, p<0.0001). Natural log transformed sEng correlated positively with log sFlt1 levels (r = 0.87) and inversely with log PlGF levels (r = -0.79) (p<0.0001 for both). Plasma sEng had comparable area under the curve for prediction of adverse outcomes as measurement of sFlt1/PlGF ratio (0.88 {0.81, 0.95} for sEng versus 0.89 {0.83, 0.95} for sFlt1/PlGF ratio, p = 0.74).

Conclusions: In women with suspected preeclampsia presenting prior to 34 weeks of gestation, sEng performs better than standard clinical evaluation in detecting adverse maternal and fetal outcomes occurring within two weeks of presentation. Soluble endoglin was strongly correlated with sFlt1 and PlGF levels, suggesting common pathogenic pathways leading to preeclampsia.

Figure 1. sEng levels among women with suspected preeclampsia. A: Distribution of sEng levels at initial presentation according to diagnosis ascertained at 2 weeks.

Median and 25^th−75^th percentile for sEng levels at presentation stratified by diagnosis. All diagnoses were ascertained 2weeks after presentation. All p values presented on the figure are compared to those without a diagnosis at 2weeks (“normal”, reference). The median (25th, 75^th percentile) of sEng (ng/ml) for each group are as follows: Normal = 4.8 (3.5, 7.1), PE = 30.2 (12.7, 55.7), gestational HTN = 6.2 (4.5, 14.0), chronic HTN = 4.6 (3.0, 9.4). B: Distribution of sEng levels at initial presentation according to adverse outcomes ascertained at 2 weeks. Median and 25^th−75^th percentile for sEng levels at presentation stratified by adverse outcomes. All outcomes were ascertained 2weeks after presentation. All p values presented on the figure are compared to those without an adverse outcome at 2weeks (“normal”, reference). The median (25th, 75^th percentile) of sEng (ng/ml) for each group are as follows: No adverse outcome = 4.8 (3.2, 8.6), adverse outcome = 32.3 (18.1, 55.8), elevated liver function tests/low platelets = 32.9 (21.8, 40.0), small for gestational age (SGA) = 69.9 (32.8, 99.0), abruption = 22.2 (21.8, 38.2).

Figure 2. sEng levels and predictive risk of adverse outcome.

The cumulative predicted risk of adverse outcomes at different levels of sEng. The sample sizes shown below the figure represent the number of patients at risk for each 20ng/ml increment of sEng.

Figure 3. Kaplan-Meier estimates of time to delivery according to sEng quartiles.

Kaplan-Meier survival function for time to delivery in all participants by quartile of sEng is depicted. Subjects remained in the analysis until delivery. Univariate Cox Proportional Hazard Models showed quartiles 3 and 4 of sEng had a significantly higher risk of early delivery (HR: 3.14, 95% CI: 1.99−4.98 and HR: 14.96, 95% CI: 8.73−25.62; both p<0.0001) compared to the lowest quartile. The second quartile showed no significant differences in time to delivery compared to quartile 1 (p = 0.07).

Figure 4. Correlation between sFlt1 and sEng (panel A) and between PlGF and sEng (Panel B).

Variables were natural log transformed and p-values were derived from Pearson correlation coefficients.