The prediction of early preeclampsia: Results from a longitudinal proteomics study

Abstract

Objectives To identify maternal plasma protein markers for early preeclampsia (delivery <34 weeks of gestation) and to determine whether the prediction performance is affected by disease severity and presence of placental lesions consistent with maternal vascular malperfusion (MVM) among cases. Study design This longitudinal case-control study included 90 patients with a normal pregnancy and 33 patients with early preeclampsia. Two to six maternal plasma samples were collected throughout gestation from each woman. The abundance of 1,125 proteins was measured using high-affinity aptamer-based proteomic assays, and data were modeled using linear mixed-effects models. After data transformation into multiples of the mean values for gestational age, parsimonious linear discriminant analysis risk models were fit for each gestational-age interval (8–16, 16.1–22, 22.1–28, 28.1–32 weeks). Proteomic profiles of early preeclampsia cases were also compared to those of a combined set of controls and late preeclampsia cases (n = 76) reported previously. Prediction performance was estimated via bootstrap. Results We found that 1) multi-protein models at 16.1–22 weeks of gestation predicted early preeclampsia with a sensitivity of 71% at a false-positive rate (FPR) of 10%. High abundance of matrix metalloproteinase-7 and glycoprotein IIbIIIa complex were the most reliable predictors at this gestational age; 2) at 22.1–28 weeks of gestation, lower abundance of placental growth factor (PlGF) and vascular endothelial growth factor A, isoform 121 (VEGF-121), as well as elevated sialic acid binding immunoglobulin-like lectin 6 (siglec-6) and activin-A, were the best predictors of the subsequent development of early preeclampsia (81% sensitivity, FPR = 10%); 3) at 28.1–32 weeks of gestation, the sensitivity of multi-protein models was 85% (FPR = 10%) with the best predictors being activated leukocyte cell adhesion molecule, siglec-6, and VEGF-121; 4) the increase in siglec-6, activin-A, and VEGF-121 at 22.1–28 weeks of gestation differentiated women who subsequently developed early preeclampsia from those who had a normal pregnancy or developed late preeclampsia (sensitivity 77%, FPR = 10%); 5) the sensitivity of risk models was higher for early preeclampsia with placental MVM lesions than for the entire early preeclampsia group (90% versus 71% at 16.1–22 weeks; 87% versus 81% at 22.1–28 weeks; and 90% versus 85% at 28.1–32 weeks, all FPR = 10%); and 6) the sensitivity of prediction models was higher for severe early preeclampsia than for the entire early preeclampsia group (84% versus 71% at 16.1–22 weeks). Conclusion We have presented herein a catalogue of proteome changes in maternal plasma proteome that precede the diagnosis of preeclampsia and can distinguish among early and late phenotypes. The sensitivity of maternal plasma protein models for early preeclampsia is higher in women with underlying vascular placental disease an...

Changes in pregnancy-related serum biomarkers early in gestation are associated with later development of preeclampsia

“…The diagnostic performance of the panel was similar among the different types of PE (earlyonset vs. late-onset, mild vs. severe). Compared to a recent proteomics study where different models were predictive at different GA windows [64], our model with 6 proteins works across 5-30 wks of GA, which is more useful when exact gestational age is unknown. Therefore, this model may offer a new investigational approach towards the understanding of placental biology during pregnancy as well as guiding innovative methods for PE diagnosis.…”

Uterine Artery Doppler Ultrasonography for First Trimester Prediction of Preeclampsia in Individuals at Risk from Low-Resource Settings

“…Recent years have seen important progress in understanding the pathogenesis of this disorder, as well as its prevention [2]. Additionally, a wide range of potential biomarkers for prediction of preeclampsia have been studied: maternal characteristics (African-American ethnicity, body mass index, pregestational diabetes mellitus, systolic blood pressure, educational level), pregnancy-associated plasma protein A (PAPP-A), A Disintegrin and Metalloprotease 12 (ADAM-12), placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), placental protein 13 (PP13), proteomics studies, Doppler ultrasonography, and many others [3][4][5][6][7][8].…”

Pre-Pregnancy Obesity vs. Other Risk Factors in Probability Models of Preeclampsia and Gestational Hypertension

“…Early PE (onset <34th week) is characterized by a more severe course, more frequent complications in the mother, and complications in the fetus (intrauterine growth restriction (IUGR), as well as fetal hypoxia or death of the fetus), which may suggest a significant contribution of placental circulation pathology. In late PE, the placenta is often normal; therefore, this form of the disease may be characterized by a lower frequency of fetal complications [13,16,[27][28][29]. It was also found that PE manifesting mainly maternal symptoms may display risk factors similar to those of GH (obesity, insulin-resistance, hyperlipidemia, and chronic hypertension), which may suggest the presence of disorders in the mother's blood vessels before pregnancy [13].…”