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.