Preeclampsia Risk Evaluation for 2nd and 3rd Trimester

The B·R·A·H·M·S™ PlGF plus KRYPTOR is to be used in conjunction with the B·R·A·H·M·S™ sFlt-1 KRYPTOR along with other laboratory tests and clinical assessments to aid in the risk assessment of pregnant women (singleton pregnancies between gestational age 23+0 to 34+6/7 weeks) hospitalized for hypertensive disorders of pregnancy (preeclampsia, chronic hypertension with or without superimposed preeclampsia, or gestational hypertension) for progression to preeclampsia with severe features (as defined by American College of Obstetricians (ACOG) guidelines) within two weeks of presentation.¹

Although the cause of preeclampsia remains unclear, the syndrome may be initiated by an imbalance of placental factors that induce endothelial dysfunction. The antiangiogenic factor sFlt-1 (soluble fms-like tyrosine kinase) acts as potent antagonist of proangiogenic factors, such as Placental Growth Factor (PlGF), by adhering to the receptor-binding domains, preventing the interaction with endothelial receptors and thereby inducing endothelial dysfunction.² During pregnancy, PlGF levels increase progressively in first and second trimester and decrease towards term. In women with clinical preeclampsia, sFlt-1 levels are significantly increased while concentrations of circulating free PlGF are B·R·A·H·M·S™ GmbH B·R·A·H·M·S™ sFlt-1/PlGF plus significantly decreased. Significantly reduced levels of free PlGF have been shown in pregnant women who subsequently develop preeclampsia.^3,4 Measurement of sFlt-1 levels together with PlGF levels in maternal serum starting in mid-pregnancy can improve the current assessment of patients with suspected preeclampsia, which includes clinical symptoms, proteinuria and uterine artery Doppler velocimetry.

The tests B·R·A·H·M·S™ sFlt-1 KRYPTOR and B·R·A·H·M·S™ PlGF plus KRYPTOR help to inform clinicians which patient would be at higher risk for developing the ACOG classification of PE with severe features. Therefore, women whose test was positive (i.e. high risk) would receive stepped-up care. The elevation in the sFlt-1/PlGF ratio antedates ACOG defined thresholds for delivery (e.g., LFT elevations, thrombocytopenia abnormal umbilical Doppler), and therefore is useful to step-up appropriate care and intensify surveillance before severe features develop.

Interpretation of results: B·R·A·H·M·S™ PlGF plus KRYPTOR and B·R·A·H·M·S™ and the sFlt-1 KRYPTOR assays measure two different biomarkers associated with preeclampsia. sFlt-1 (soluble fms-like tyrosine kinase 1) and PIGF (placental growth factor) are both associated with placental dysfunction during pregnancy These are each measured, then a ratio of the two biomarkers is calculated. The ratio is the sFlt-1 concentration divided by the PlGF concentration (both expressed in the same units pg/mL). The ratio is a unitless whole number. This calculation can be performed on the B-R-A-H-M-S™ KRYPTOR analyzer.

The current standard of care is currently defined by the ACOG standard and does not include the usage of a medical devices or IVD.

The intended use of the device (B·R·A·H·M·S™ sFlt-1 KRYPTOR and B·R·A·H·M·S™ PlGF plus KRYPTOR that are used to derive a ratio of sFlt-1/PlGF) is to be used as an aid in risk assessment of patients with clinical signs and symptoms consistent with development of preeclampsia with severe features (as defined by ACOG guidelines). The test is indicated for use in pregnant women, with singleton pregnancies (gestational age 23+0 to 34+6/7 weeks) hospitalized for hypertensive disorders of pregnancy (preeclampsia, chronic hypertension with or without superimposed preeclampsia or gestational hypertension), within two weeks of presentation.

For the sFlt-1/PlGF ratio, the clinical cut-off was established in the PRAECISp clinical study (NCT03815110). The cut-off of 40 was derived in a derivation cohort of 220 patients. This cut-off was then validated in a validation cohort of 520 patients.⁵

If the result of the ratio is higher or equal to 40, the pregnant woman would be at high risk for progression to preeclampsia with severe features within two weeks.

If the result of the ratio is lower than 40, the pregnant woman would be at low risk for progression to preeclampsia with severe features within two weeks.

B·R·A·H·M·S™ PlGF plus KRYPTOR and B·R·A·H·M·S™ sFlt-1 KRYPTOR are indicatated to be used as an aid in the management of the patient and are prognostic assays intended to stratify hospitalized patients in two risk groups (low risk and high risk of progression to pre-eclampsia with severe features within two weeks from presentation). The assay results should only be used in conjunction with information available from clinical evaluations and other standard of care procedures. The test result is not to be used to replace clinical judgement.

B·R·A·H·M·S™ PlGF plus KRYPTOR must be run in conjunction with B·R·A·H·M·S™ sFlt-1 KRYPTOR and the same patient sample must be used to run both assays. B·R·A·H·M·S™ sFlt-1 KRYPTOR and B·R·A·H·M·S™ PIGF plus KRYPTOR are not intended to be used individually. Use of another manufacturer's assays may result in significantly different results.

B·R·A·H·M·S™ PlGF plus KRYPTOR and B·R·A·H·M·S™ sFlt-1 KRYPTOR should not be used for 1) a woman with a woman with a multiple pregnancy because the safety and effectiveness of the device has not been established in pregnant women with a multiple pregnancy (i.e. pregnancy with more than one fetus); 2) a woman receiving intravenous heparin within 24 hours of testing because the safety and effectiveness of the device has not been established in pregnant women who received intravenous heparin within 24 hours of testing the device; or 3) a woman receiving exogenous PlGF-2 or PlGF-3 for therapeutic use at concentration higher than 100 pg/mL because the safety and effectiveness of the device has not been established in pregnant women who received exogenous PlGF-2 or PlGF-3 for therapeutic use at concentration higher than 100 pg/mL. The B·R·A·H·M·S™ PlGF plus KRYPTOR assay was found in bench studies to be impacted by PlGF-2. With samples at equal levels of PlGF (i.e. PlGF-1) and PlGF-2, the reported concentration is within 1% compared to samples without PlGF-2. The normal endogenous level of PlGF-2 in samples collected from pregnant women has not been established.

The clinical management of each patient should be dependent on the patient's health care provider's recommendations as inferred from their clinical status. Therefore, the test results should not be used as a deciding factor to change management plans, and especially not for decisions of pregnancy delivery or for patient discharge from hospital.

The results of the test are not intended for making a diagnosis of preeclampsia or preeclampsia with severe features.

The results of the test are not a stand-alone test for monitoring of hypertensive disorders of pregnancy. The results of the test are not intended to inform the healthcare provider whether or not to change treatment, including medication or hospitalization.

Homogenous immunoassay

Low risk for progression to preeclampsia with severe features within two weeks: The woman at low risk for progression to preeclampsia with severe features within 2 weeks would receive standard care including expectant management according to the ACOG guidelines. A woman with "false negative" result would continue to receive existing standard of care including monitoring of future signs of preeclampsia with severe features.

High risk for progression to preeclampsia with severe features within two weeks: The woman at high risk for progression to preeclampsia with severe features within two weeks would receive stepped up care according to the ACOG guidelines. The elevation in the sFlt- 1/PlGF ratio antedates ACOG defined criteria for delivery (e.g., LFT elevations, thrombocytopenia abnormal umbilical Doppler), and therefore is useful to step-up appropriate care and intensify surveillance before severe features develop. A woman with "false positive" result would receive stepped up care and would not be harmed by additional monitoring.