Preeclampsia: Pathogenesis, Diagnosis and Treatment

Objective: We previously provided evidence to confirm that maternal serum levels of soluble Fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and their ratio are useful tools to direct the management of preeclampsia (PE), fetal growth restriction (FGR), and PE+FGR near delivery. In this secondary analysis, we further examine the potential additive value of maternal serum Inhibin-A, which is a hormone marker of the transforming growth factor family, to the accuracy provided by maternal serum PlGF and sFlt-1. Methods: We conducted a secondary analysis where we extracted the data of a cohort of 125 pregnant women enrolled near delivery at the clinics of the University Medical Center of Ljubljana, Slovenia. The dataset included 31 cases of PE, 16 of FGR, 42 of PE+FGR, 15 preterm delivery (PTD), and 21 unaffected controls with delivery of a healthy baby at term. Cases delivered before 34 weeks’ gestation included 10 of PE, 12 of FGR, 28 of PE+FGR, and 6 of PTD. In addition to the recorded demographic characteristics and medical history and the maternal serum levels of PlGF and sFlt-1/PlGF ratio, which were previously published, we evaluated the added value of maternal serum Inhibin-A. The predictive accuracy of each biomarker, their ratios, and combinations were estimated from areas under the curve (AUC) of receiver operating characteristics (ROC) curves, Box and Whisker plots, and by multiple regression. We estimated accuracy by the continuous marker model and a cutoff model. Results: In this study, we combined Inhibin-A with PlGF or with the sFlt-1/PlGF ratio and showed a 10–20% increase in AUCs and 15–45% increase in the detection rate, at 10% false positive rate, of PE, and a lower, but significant, increase for PE+FGR and FGR in all cases but not for FGR in early cases delivered < 34 weeks. The use of a cutoff model was adequate, although a bit higher accuracy was obtained from the continuous model. The highest correlation was found for PlGF with all three complications. Conclusion: In this secondary analysis, we have found that maternal serum Inhibin-A improves the accuracy of predicting PE and PE+FGR provided by maternal serum angiogenic markers alone, bringing the results to a diagnostic level; thus, it could be considered for directing clinical management. Inhibin-A had smaller or no added value for the accuracy of predicting FGR alone, mainly of early cases delivered <34 weeks. Full article

Objective—the objective of this study was to assess the accuracy of placental growth factor (PlGF), soluble Fms-like Tyrosine Kinase 1 (sFlt-1), and endoglin (sEng) in the diagnosis of suspected preeclampsia (PE) with and without fetal growth restriction (FGR) near delivery. Methods—this is a secondary analysis of a dataset of 125 pregnant women presenting at the high risk pregnancy clinic with suspected PE, FGR or PE + FGR in the University Medical Center of Slovenia. The dataset included 31 PE cases, 16 FGR cases, 42 PE + FGR cases, 15 cases who developed with unrelated complications before 37 weeks (wks) (PTD), and 21 unaffected controls who delivered a healthy baby at term. We also analyzed a sub-group of women who delivered early (<34 wks) including 10 PE, 12 FGR, 28 PE + FGR, and six PTD. Clinical management adhered to hospital guidelines. Marker levels were extracted from the dataset and were used to develop Receiver Operating Characteristic (ROC) curves and to calculate the area under the curve (AUC), the detection rates (DRs), and the false positive rates (FPRs). Previously published marker cutoffs for yes/no admission to hospital wards were extracted from the literature. Negative and positive predictive values (NPVs and PPVs) were evaluated for their value in determining whether hospital admission was required. Non-parametric tests were applied for statistical analysis; p < 0.05 was considered significant. Results—near delivery, all the pro-and anti-angiogenic markers provided diagnostic (ROC = 1.00) accuracy for the early (<34 wks) group of FGR. Diagnostic or near diagnostic (ROC = 0.95) accuracy was achieved by all marker for early PE + FGR but lower accuracy was achieved for early PE. For all cases, all markers, especially PlGF reached diagnostic or near diagnostic accuracy for FGR and PE + FGR. At this accuracy level, they can contribute to the clinical management of FGR, and PE + FGR. All the markers were less accurate for all PE cases. The use of published cutoffs was adequate for clinical management of FGR, whether early or for all cases, using an NPV > 90%. For PE + FGR, the PPV value approached 100%, especially for early cases, and can thus be implemented in clinical management. Neither NPV nor PPV were high enough for managing all cases of PE. There was no added value in measuring the PlGF/(sFlt-1 + sEng) ratio. Conclusion—This is the first study on a Slovenian population. It shows that near-delivery angiogenic biomarkers tests may be useful for confirming the diseases in cases where there is a diagnostic doubt. However, the clinical use of the biomarkers needs to be weighed against resources available and degree of certainty of the diagnosis made with and without them for managing suspected FGR and PE + FGR requiring delivery <34 wks, where they are very accurate, and furthermore in the management of all cases of FGR and FGR+PE. The markers were less accurate for the clinical diagnosis of PE. Full article

Decidual vasculopathy at late gestation was shown to be associated with spiral artery remodeling at implantation. Dramatic decidual vascular transformation from early to late stage pregnancy suggests a dynamic spatiotemporal relationship between the various vascular components in spiral artery remodeling and decidual vasculopathy. The central and peripheral portions of 105 placentas with decidual vasculopathy at term were examined with or without preeclampsia to see if temporal vascular regeneration was present. Central and peripheral vasculopathy and central and peripheral regeneration were compared. The peripheral portion showed more decidual vasculopathy (88 of total 105, 83.8%) than central portion (72 of total 105, 68.6%, p < 0.0001). However, central portion showed more vascular regeneration (51 of total 105, 48.6%) than the peripheral portion (23 of total 105, 21.9%, p < 0.0001). There was no difference in vasculopathy or regeneration with or without preeclampsia. Spiral artery remodeling is non-synchronous during placental growth and vascular regeneration. This spatiotemporal sequence may help interpretation of morphologic changes of decidual vasculopathy. Full article

Purpose: To determine whether high-dose intravenous vitamin C reduces oxidative stress in patients with severe preeclampsia in the first days postpartum. Methods: Biomarkers of oxidative stress were assessed as secondary outcomes of a single-center, randomized, placebo-controlled trial. Thirty-four patients with singleton pregnancies complicated by severe features of preeclampsia were randomized into two groups: intravenous vitamin C (1.5 g/6 h) (n = 17) or placebo (n = 17). Urinary concentrations of dityrosine, 8-hydroxy-2-deoxyguanosine (8-OHdg), 8-isoprostane, and N epsilon-(hexanoyl) lysine (HEL) were measured at days one and three after delivery and normalized for urinary creatinine in 22 of patients included (12 in vitamin C and 10 in placebo group). The Mann–Whitney U-test was used to compare values of oxidative stress biomarkers at days one and three after delivery in vitamin C vs. placebo groups (p ≤ 0.05 significant). Results: Dityrosine and 8-OHdg values did not differ significantly between the two study groups at day one after delivery (p = 0.23 and p = 0.77, respectively), but were significantly lower in the vitamin C group compared to the placebo group at day three after delivery (p = 0.04 and p = 0.03, respectively). Values of 8-isoprostane and HEL did not differ significantly between the two study groups at day one (p = 0.41 and p = 0.42, respectively), as well as at day three, after delivery (p = 0.25 and p = 0.24, respectively). Conclusion: High-dose intravenous vitamin C treatments in patients with severe preeclampsia reduced urinary levels of dityrosine and 8-OHdg (markers of protein and DNA oxidative damage, respectively) on day three after delivery. Vitamin C treatment had no significant effect on lipid peroxidation biomarkers, i.e., 8-isoprostane and HEL. Full article

Aim: Spiral artery remodeling at early pregnancy is characterized by two distinct mechanisms with two morphologic features, namely, trophoblastic-dependent vascular invasion with “plugging”, and trophoblastic-independent mural muscular hypertrophy/hyperplasia, both of which lead to the blocking or narrowing of the arterial lumen with the consequence of reduced maternal blood flow to the developing embryo. Methods: Review of historic literature in light of the new discovery of CD56 (NCAM) expression on endovascular trophoblasts at late gestation, in relation to placental lateral growth with vascular regeneration. Results: Reduced maternal blood flow to the embryo results in a hypoxic condition critical for trophectoderm differentiation and proliferation. Hypoxia is also important for the development of hemangioblasts of vasculogenesis, and hematopoiesis of the placental villi. Up to 13 weeks, both uteroplacental and fetoplacental circulations are established and hypoxic condition relieved for normal fetal/placenta development by ultrasonography. The persistence of trophoblastic plugging and/or mural muscular hypertrophy/hyperplasia leads to persistent reduced maternal blood flow to the placenta, resulting in persistent hypoxia and increased angiogenesis, with a constellation of pathologic features of maternal vascular malperfusion atlate gestation. Wilm’s tumor gene (WT1) expression appears to be central to steroid and peptide hormonal actions in early pregnancy, and vascular regeneration/restoration after pregnancy. Conclusions: Spiral artery remodeling at early pregnancy leads to hypoxia with vascular transformation, and the establishment of uteroplacental circulation results in relief of hypoxia. The hypoxia–re-oxygenation sequence may provide insights into the mechanism of normal fetal/placental development and associated pregnancy complications, such as preeclampsia. Full article