Date Published: June 4, 2019
Publisher: Public Library of Science
Author(s): Adi L. Tarca, Roberto Romero, Neta Benshalom-Tirosh, Nandor Gabor Than, Dereje W. Gudicha, Bogdan Done, Percy Pacora, Tinnakorn Chaiworapongsa, Bogdan Panaitescu, Dan Tirosh, Nardhy Gomez-Lopez, Sorin Draghici, Sonia S. Hassan, Offer Erez, Fatima Crispi.
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. 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. 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). 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 and in those with a severe phenotype.
Preeclampsia is a major obstetrical syndrome [1–3], classified according to the time of its clinical manifestation as “early preeclampsia” if it occurs prior to 34 weeks of gestation and, otherwise, as “late preeclampsia” [4–10]. The 34-week cut-off is most commonly used [9,11,12] given the substantial decline in maternal [6,13–17] and neonatal [8,13,18–24] morbidity compared to later gestational ages.
In the early preeclampsia group, 33% (11/33) of the women delivered a small-for-gestational-age neonate, 73% (24/33) had placental lesions consistent with MVM and 70% (23/33) were severe cases. Cases were diagnosed from 24.6 to 33.4 weeks of gestation. Other characteristics of the study population classified by outcome and presence of placental MVM lesions are shown in Table 1.
Aptamer-based proteomic profiling of maternal plasma identified novel as well as previously known markers for early preeclampsia. At 16.1–22 weeks of gestation, more than two-thirds of patients who subsequently develop early preeclampsia can be identified by an elevated MMP-7 and gpIIbIIIa in maternal plasma (10% FPR). High abundance of siglec-6, VEGF121, and activin-A observed in the maternal circulation at 22.1–28 weeks of gestation was more specific to early rather than late preeclampsia. Proteomic markers were more sensitive for early preeclampsia cases with placental lesions consistent with MVM as well as those with a severe phenotype.