Midpregnancy prediction of pre-eclampsia using serum biomarkers sFlt-1 and PlGF

Highlights

• Midpregnancy PlGF was significantly lower in women who developed early-onset or preterm PE.

• Midpregnancy sFlt-1 levels did not predict the later development of PE.

• For midpregnancy prediction of preterm PE, PlGF MoM and sFlt-1/PlGF MoM performed similarly.

• sFlt1/PlGF ratio using raw data values performed best for prediction of early-onset pre-eclampsia.

• Predictive performance for PlGF and sFlt-1 testing was similar among the three immunoassay platforms.

Abstract

Objectives

Pre-eclampsia remains a significant cause of morbidity and mortality. Placental biomarkers soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) have been investigated previously for their ability to predict pre-eclampsia. We compared the performance of these biomarkers for midpregnancy pre-eclampsia prediction using three different immunoassay platforms.

Study design

Prospective study including singleton pregnancies 19–22 weeks’ gestation. Maternal bloods were collected at recruitment. Screening performances using receiver operating characteristic (ROC) curves for PlGF and sFlt-1/PlGF ratio raw data and MoM values in isolation were evaluated for three immunoassay platforms using selected cut-off values.

Main outcome measures

Pre-eclampsia was defined as early-onset (<34 weeks’ at delivery) and preterm (<37 weeks’ at delivery).

Results

For prediction of preterm pre-eclampsia, PlGF MoM and sFlt-1/PlGF ratio MoM performed similarly, with areas under the curve (AUC), detection rates (DR) and false positive rates (FPR) for PlGF MoM and sFlt-1/PlGF ratio MoM being 0.77–0.79 and 0.71–0.74, 62.5% for both and 9.7–14.9 and 10.7–17.7, respectively. For the prediction of early-onset pre-eclampsia, sFlt-1/PlGF ratio raw data and MoM values performed similarly, with AUC, DR and FPR being 0.92–0.97 and 0.93–0.96, 100% for both, and 4.13–16.9 and 9.4–12.2, respectively.

Conclusions

For midpregnancy prediction of preterm pre-eclampsia, PlGF MoM for all three platforms and sFlt-1/PlGF ratio MoM for the two platforms that tested sFlt-1 performed similarly. For midpregnancy prediction of early-onset pre-eclampsia at midpregnancy, sFlt-1/PlGF ratio raw data and MoM values using the early-onset cut-off for the two platforms that tested sFlt-1 gave similar performance from a clinical perspective.

Introduction

Pre-eclampsia is a multisystem disorder which affects 3% of pregnancies in Australia [1] and is responsible for a substantial degree of maternal and perinatal morbidity and mortality [2]. Although a complete understanding of the pathophysiological basis for this condition remains elusive, dysregulation of circulating angiogenic biomarkers arising from deficient placentation [3] is thought to play a central role. In 2004, it was demonstrated that increased levels of angiogenic biomarkers soluble fms-like tyrosine kinase 1 (sFlt-1) and decreased levels of placental growth factor (PlGF) can predict the subsequent onset of pre-eclampsia [4].

As a result of increased sFlt-1 levels, reduced PlGF and vascular endothelial growth factor (VEGF) levels may halt placental vascular growth much earlier in pregnancies affected by pre-eclampsia than in normal pregnancy. This proposed mechanism for the development of pre-eclampsia has been supported by previous research [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. PlGF concentrations have been demonstrated to be decreased in women with pre-eclampsia as early as 13 weeks’ gestation, with significantly decreased levels of PlGF and increased levels of sFlt-1 recorded from 9 to 11 weeks before the onset of symptoms, with deviations in biomarker values becoming more pronounced 5 weeks prior to symptom onset [4].

Current evidence indicates that screening for pre-eclampsia during the second trimester may be less useful than screening during the first trimester, as the window of opportunity for women considered high risk for pre-eclampsia to benefit from aspirin administration will have diminished [17], [18]. However, given that around one-third of Australian women do not begin their antenatal care until after 14 weeks’ gestation [19], screening beyond this gestation would prove useful, to avoid unnecessary interventions in low risk women and ensure that those at high risk are triaged to appropriate models of care.

PlGF has been clinically validated in the PELICAN study [20] to confirm the diagnosis of pre-eclampsia in symptomatic patients and to stratify their risk of requiring delivery within a fortnight. The PROGNOSIS study [21] successfully derived and validated an sFlt-1/PlGF ratio cut-off to predict the presence or absence of pre-eclampsia in the short term in women with features of pre-eclampsia, concluding that an sFlt-1/PlGF ratio of 38 or lower can be used to reliably exclude pre-eclampsia within the next 7 days in women in whom the syndrome is clinically suspected. The COMPARE study [22], published in 2018, compared the performance of three PlGF-based kits (DELFIA Xpress PlGF 1-2-3™ test, Triage PlGF test and Elecsys immunoassay sFlt-1/PlGF ratio) in prediction of delivery within a fortnight of testing in symptomatic patients prior to 35 weeks’ gestation. The study demonstrated similar test results between platforms and established PlGF < 150 pg/mL as a cut-off to rule out suspected pre-eclampsia for the DELFIA Xpress PlGF 1-2-3™ test.

Despite these compelling findings, it has taken a long time for PlGF and sFlt-1/PlGF ratio testing to be implemented into clinical practice [23], [24], [25]. The aim of this study was to determine how well serum PlGF and/or the sFlt-1/PlGF ratio, or both, when tested at midpregnancy using three different immunoassay platforms, perform for the prediction of subsequent pre-eclampsia.