KRYPTOR-automated angiogenic factor assays and risk of preeclampsia-related adverse outcomes

ABSTRACT

Objective: To evaluate KRYPTOR assays for circulating soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) in risk assessment of adverse outcomes in women with suspected preeclampsia. Methods: We studied 412 women carrying a singleton pregnancy from a previous study cohort who were evaluated for suspected preeclampsia. Another 434 nonpreeclamptic patients with plasma samples drawn throughout pregnancy were used to derive normative data. Plasma sFlt1 and PlGF levels were measured on the automated KRYPTOR platform and evaluated for prediction of adverse maternal and perinatal outcomes within 2 weeks. Normative values were used to create a ratio of markers and these values were reported as multiples of median (MoM) for women with and without adverse outcomes. The KRYPTOR assay results were also compared with previously reported measurements obtained using the automated Elecsys platform. Results: Among participants presenting at <34 weeks (N = 110), patients with subsequent adverse outcome had higher sFlt1, lower PlGF, and higher sFlt1/PlGF ratio compared with women without adverse outcomes: the median (25th, 75th centile) sFlt1 (pg/ml), 9030 (3197, 12,140) versus 1976 (1248, 2937); PlGF (pg/ml), 36 (16, 111) versus 318 (108, 629); and ratio, 285.6 (32.2, 758.5) versus 6.1 (2.3, 20.3) (all p < 0.0001). Higher sFlt1/PlGF ratio correlated negatively with timing of delivery (r = −0.60, p < 0.001) and the risk of adverse outcomes was markedly elevated among women in highest tertile compared with lower tertile (odds ratio, 14.77; 95% confidence interval (CI), 4.28–51.00). The addition of sFlt1/PlGF ratio (≥85) to hypertension and proteinuria significantly improved the prediction for subsequent adverse outcomes (AUC 0.89 (95% CI): 0.82, 0.95) for hypertension, proteinuria, and sFlt1/PlGF (AUC = 0.75 (0.65, 0.85)) for hypertension alone (p = 0.002). Compared with normative controls, women who were evaluated for preeclampsia without adverse outcomes had higher MoM for sFlt1/PlGF ratio; these values were further elevated in women with adverse outcomes. sFlt1/PlGF ratios measured on the KRYPTOR platform were highly correlated with measurements obtained using Elecys platform (r = 0.97, p < 0.001). Conclusions: In women with suspected preeclampsia presenting prior to 34 weeks of gestation, KRYPTOR assays for circulating sFlt1 and PlGF when used in conjunction with standard clinical evaluation performs well in the prediction of adverse maternal and perinatal outcomes occurring within 2 weeks of presentation.

KEYWORDS:

• Adverse maternal and perinatal outcomes
• angiogenic factors
• hypertension
• KRYPTOR assay
• proteinuria
• suspected preeclampsia
• triage

Acknowledgment

KRYPTOR assays used in the research for angiogenic factors were kindly provided by ThermoFisher Scientific.

Declaration of interest

Ravi Thadhani and S. Ananth Karumanchi are co-inventors on patents related to preeclampsia biomarkers that are held at Massachusetts General Hospital and Beth Israel Deaconess Medical Center. Ravi Thadhani and S. Ananth Karumanchi have financial interest in Aggamin LLC. Ravi Thadhani and Sarosh Rana report serving as consultant to Roche Diagnostics. S. Ananth Karumanchi reports serving as a consultant to Siemens Diagnostics and Roche Diagnostics. All other authors report no conflict of interest.

Funding

Ravi Thadhani received funding from K24 award from NIH and S. Ananth Karumanchi was supported by Howard Hughes Medical Institute and has received grant support from ThermoFisher Scientific.

Additional information

Funding

Ravi Thadhani received funding from K24 award from NIH and S. Ananth Karumanchi was supported by Howard Hughes Medical Institute and has received grant support from ThermoFisher Scientific.