The Prediction of Gestational Hypertension, Preeclampsia and Fetal Growth Restriction via the First Trimester Screening of Plasma Exosomal C19MC microRNAs

Abstract

The aim of the study was to verify if quantification of placental specific C19MC microRNAs in plasma exosomes would be able to differentiate during the early stages of gestation between patients subsequently developing pregnancy-related complications and women with the normal course of gestation and if this differentiation would lead to the improvement of the diagnostical potential. The retrospective study on singleton Caucasian pregnancies was performed within 6/2011-2/2019. The case control study, nested in a cohort, involved women that later developed GH (n = 57), PE (n = 43), FGR (n = 63), and 102 controls. Maternal plasma exosome profiling was performed with the selection of C19MC microRNAs with diagnostical potential only (miR-516b-5p, miR-517-5p, miR-518b, miR-520a-5p, miR-520h, and miR-525-5p) using real-time RT-PCR. The down-regulation of miR-517-5p, miR-520a-5p, and miR-525-5p was observed in patients with later occurrence of GH and PE. Maternal plasma exosomal profiling of selected C19MC microRNAs also revealed a novel down-regulated biomarker during the first trimester of gestation (miR-520a-5p) for women destinated to develop FGR. First trimester circulating plasma exosomes possess the identical C19MC microRNA expression profile as placental tissues derived from patients with GH, PE and FGR after labor. The predictive accuracy of first trimester C19MC microRNA screening (miR-517-5p, miR-520a-5p, and miR-525-5p) for the diagnosis of GH and PE was significantly higher in the case of expression profiling of maternal plasma exosomes compared to expression profiling of the whole maternal plasma samples.

Keywords: C19MC microRNA; exosomes; expression; fetal growth restriction; gestational hypertension; plasma; prediction; preeclampsia; pregnancy-related complications; screening.

Figure 1

Down-regulation of miR-517-5p, miR-520a-5p, and miR-525-5p in plasma exosomes during the first trimester of gestation in women with later onset of GH or PE.(a–c) Decreased levels of miR-517-5p, miR-520a-5p, and miR-525-5p were observed in circulating plasma exosomes within 10 to 13 weeks of gestation in women affected with GH or PE when the comparison to the controls was performed using non-parametric statistical test (the Kruskal-Wallis test). GH: gestational hypertension; PE: preeclampsia. Outliers are marked by circles (⸰), and extremes by asterisks (*).

Figure 1

Down-regulation of miR-517-5p, miR-520a-5p, and miR-525-5p in plasma exosomes during the first trimester of gestation in women with later onset of GH or PE.(a–c) Decreased levels of miR-517-5p, miR-520a-5p, and miR-525-5p were observed in circulating plasma exosomes within 10 to 13 weeks of gestation in women affected with GH or PE when the comparison to the controls was performed using non-parametric statistical test (the Kruskal-Wallis test). GH: gestational hypertension; PE: preeclampsia. Outliers are marked by circles (⸰), and extremes by asterisks (*).

Figure 2

ROC curves—individual C19MC microRNA biomarkers—evaluation of the potential of the first trimester C19MC microRNA screening in plasma exosomes to predict later onset of GH. Decreased levels of miR-517-5p, miR-520a-5p, and miR-525-5p were detected in women destinated to develop GH when the comparison to the controls was performed both (a–c). GH: gestational hypertension.

Figure 3

ROC curves—the best combination of C19MC microRNA biomarkers—evaluation of the potential of the first trimester C19MC microRNA screening in plasma exosomes to predict later onset of GH. The combination of miR-520a-5p and miR-525-5p showed the best predictive performance for the prediction of the later occurrence of GH (66.07% sensitivity at 10.0% FPR). GH: gestational hypertension.

Figure 4

ROC curves—individual C19MC microRNA biomarkers—evaluation of the potential of the first trimester C19MC microRNA screening in plasma exosomes to predict subsequent onset of PE. Decreased levels of miR-517-5p, miR-520a-5p, and miR-525-5p were detected in women destinated to develop PE when the comparison to the controls was performed (a–c). PE: preeclampsia.

Figure 4

ROC curves—individual C19MC microRNA biomarkers—evaluation of the potential of the first trimester C19MC microRNA screening in plasma exosomes to predict subsequent onset of PE. Decreased levels of miR-517-5p, miR-520a-5p, and miR-525-5p were detected in women destinated to develop PE when the comparison to the controls was performed (a–c). PE: preeclampsia.

Figure 5

ROC curves—the best combination of C19MC microRNA biomarkers—evaluation of the potential of the first trimester C19MC microRNA screening in plasma exosomes to predict subsequent onset of PE. The combination of miR-517-5p, miR-520a-5p, and miR-525-5p showed the best predictive performance for the prediction of the later occurrence of PE (44.19% sensitivity at 10.0% FPR). PE: preeclampsia.

Figure 6

Down-regulation of miR-520a-5p in plasma exosomes during the first trimester of gestation in women with subsequent onset of FGR. Decreased levels of miR-520a-5p were observed in circulating plasma exosomes within 10 to 13 weeks of gestation in women affected with FGR when the comparison to the controls was performed using the Kruskal-Wallis test. FGR: fetal growth restriction. Outliers are marked by circles (⸰), and extremes by asterisks (*)

Figure 7

ROC curves—evaluation of the potential of the first trimester miR-520a-5p biomarker screening in plasma exosomes to predict subsequent onset of FGR. Decreased levels of miR-520a-5p were detected in women destinated to develop FGR when the comparison to the controls was performed. FGR: fetal growth restriction.