The prediction of late-onset preeclampsia: Results from a longitudinal proteomics study

Abstract

BackgroundLate-onset preeclampsia is the most prevalent phenotype of this syndrome; nevertheless, only a few biomarkers for its early diagnosis have been reported. We sought to correct this deficiency using a high through-put proteomic platform.MethodsA case-control longitudinal study was conducted, including 90 patients with normal pregnancies and 76 patients with late-onset preeclampsia (diagnosed at ≥34 weeks of gestation). Maternal plasma samples were collected throughout gestation (normal pregnancy: 2–6 samples per patient, median of 2; late-onset preeclampsia: 2–6, median of 5). The abundance of 1,125 proteins was measured using an aptamers-based proteomics technique. Protein abundance in normal pregnancies was modeled using linear mixed-effects models to estimate mean abundance as a function of gestational age. Data was then expressed as multiples of-the-mean (MoM) values in normal pregnancies. Multi-marker prediction models were built using data from one of five gestational age intervals (8–16, 16.1–22, 22.1–28, 28.1–32, 32.1–36 weeks of gestation). The predictive performance of the best combination of proteins was compared to placental growth factor (PIGF) using bootstrap.Results1) At 8–16 weeks of gestation, the best prediction model included only one protein, matrix metalloproteinase 7 (MMP-7), that had a sensitivity of 69% at a false positive rate (FPR) of 20% (AUC = 0.76); 2) at 16.1–22 weeks of gestation, MMP-7 was the single best predictor of late-onset preeclampsia with a sensitivity of 70% at a FPR of 20% (AUC = 0.82); 3) after 22 weeks of gestation, PlGF was the best predictor of late-onset preeclampsia, identifying 1/3 to 1/2 of the patients destined to develop this syndrome (FPR = 20%); 4) 36 proteins were associated with late-onset preeclampsia in at least one interval of gestation (after adjustment for covariates); 5) several biological processes, such as positive regulation of vascular endothelial growth factor receptor signaling pathway, were perturbed; and 6) from 22.1 weeks of gestation onward, the set of proteins most predictive of severe preeclampsia was different from the set most predictive of the mild form of this syndrome.ConclusionsElevated MMP-7 early in gestation (8–22 weeks) and low PlGF later in gestation (after 22 weeks) are the strongest predictors for the subsequent development of late-onset preeclampsia, suggesting that the optimal identification of patients at risk may involve a two-step diagnostic process.

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

“…We hypothesized that similar temporal placenta-related protein expression patterns 224 should be conserved in mouse pregnancies, therefore, we explored our EN- PE is based on the presence of maternal hypertension and proteinuria [38]. Previous 252 transcriptomic [39][40][41][42][43][44][45] and proteomic [2,[46][47][48][49][50] Our findings of serum protein levels during a normal pregnancy are consistent with those 261 from previous studies. They are in line with the ranges reported in healthy pregnancies and have 262 similar patterns during the pregnancy as previous results [51][52][53][54][55][56][57][58][59].…”

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

“…The ratio of sFlt-1 and PlGF has been shown to effectively differentiate PE from normal term pregnancies, but only after 25 weeks of gestation [27]. Previous transcriptomic [52][53][54][55][56][57][58] and proteomic [2,[59][60][61][62][63] profiling of normal and complicated pregnancies have identified disease-specific expression patterns and signaling networks, which suggest candidate biomarkers for possible early clinical diagnoses and for offering new biological insights. Our findings suggest that a composite placental-related protein panel from serial blood collection (for MSE calculations) may provide a diagnostic test to assess PE earlier (~10 weeks of gestation) than previously suggested by sFlt-1 and PlGF (after 25 weeks of gestation as observed in this study).…”

Doppler ultrasound and photoplethysmographic assessment for identifying pregnancy‑induced hypertension

“…The equation for PPG RI was expressed as PPG RI=systolic peak amplitude/diastolic peak amplitude x100 ( Fig. 1A), or in the absence of a diastolic peak, PPG RI=systolic peak amplitude/inflection point amplitude x100 (18)(19)(20) (Fig. 1B).…”