Predictive Biomarker For Preeclampsia Research Articles

Maternal Serum Cyclophilin A: A Predictive Biomarker of Preeclampsia in South Indian Women

Maternal Serum Cyclophilin A: A Predictive Biomarker of Preeclampsia in South Indian Women

Tissue Factor Pathway Inhibitors as Potential Targets for Understanding the Pathophysiology of Preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy that causes maternal and perinatal morbidity and mortality worldwide. Preeclampsia is associated with complex abnormalities of the coagulation and fibrinolytic system. Tissue factor (TF) is involved in the hemostatic system during pregnancy, while the Tissue Factor Pathway Inhibitor (TFPI) is a major physiological inhibitor of the TF-initiated coagulation cascade. The imbalance in hemostatic mechanisms may lead to a hypercoagulable state, but prior research has not comprehensively investigated the roles of TFPI1 and TFPI2 in preeclamptic patients. In this review, we summarize our current understanding of the biological functions of TFPI1 and TFPI2 and discuss future directions in preeclampsia research. A literature search was performed from inception to 30 June 2022 in the PubMed and Google Scholar databases. TFPI1 and TFPI2 are homologues with different protease inhibitory activities in the coagulation and fibrinolysis system. TFPI1 is an essential physiological inhibitor of the TF-initiated extrinsic pathway of coagulation. On the other hand, TFPI2 inhibits plasmin-mediated fibrinolysis and exerts antifibrinolytic activity. It also inhibits plasmin-mediated inactivation of clotting factors and maintains a hypercoagulable state. Furthermore, in contrast to TFPI1, TFPI2 suppresses trophoblast cell proliferation and invasion and promotes cell apoptosis. TFPI1 and TFPI2 may play important roles in regulating the coagulation and fibrinolytic system and trophoblast invasion to establish and maintain successful pregnancies. Concentrations of TF, TFPI1, and TFPI2 in maternal blood and placental tissue are significantly altered in preeclamptic women compared to normal pregnancies. TFPI protein family may affect both the anticoagulant (i.e., TFPI1) and antifibrinolytic/procoagulant (i.e., TFPI2) systems. TFPI1 and TFPI2 may function as new predictive biomarkers for preeclampsia and navigate precision therapy.

Urine excretion of C3dg and sC5b-9 coincide with proteinuria and development of preeclampsia in pregnant women with type-1 diabetes.

Pregnant women with type-1 diabetes have an increased risk of preeclampsia with kidney injury and cardiovascular complications. Urine excretion of plasmin and soluble membrane attack complex (sC5b-9) is elevated in severe preeclampsia. We hypothesized a coupling between these events and that active plasmin promotes intratubular complement activation and membrane deposition. Stored urine and plasma samples from pregnant women with type-1 diabetes (n = 88) collected at gestational weeks 12, 20, 28, 32, 36 and 38 were used. In the cohort, 14 women developed preeclampsia and were compared with 16 nonpreeclampsia controls. Urine C3dg and sC5b-9-associated C9 neoantigen/creatinine ratios increased and were significantly higher in women who developed preeclampsia. Plasma concentrations did not change with gestation. Urine plasmin(ogen) correlated to urine C3dg (r = 0.51, P < 0.001) and C9 neoantigen (r = 0.68, P < 0.001); urine albumin correlated to C3dg (r = 0.44, P < 0.001) and C9 (r = 0.59, P < 0.001). Membrane-associated C3dg and C9 neoantigen was detected in urinary extracellular vesicles from patients but not controls at 36 weeks. Receiver operating characteristic curves showed that C3dg and C9 neoantigen were inferior to albumin as predictive biomarkers for preeclampsia. In preeclampsia, urinary excretion of activated complement relates significantly to albuminuria and to plasmin(ogen) but not to activation in plasma. Intratubular complement activation in preeclampsia is a postfiltration event tightly related to proteinuria/plasminogenuria and a possible mechanistic link to cellular damage and kidney injury.

Early increase in circulating carbonic anhydrase IX: A potential new predictive biomarker of preeclampsia.

Preeclampsia (PE) is a severe complication of pregnancy. The identification of a reliable predictive biomarker could help in setting up a specific preventive strategy. To this aim, we studied carbonic anhydrase IX (CAIX) as a marker of hypoxia (a pathway involved in PE pathogenesis) and compared the diagnostic accuracy of CAIX to that of the validated biomarker sFlt1/PlGF ratio. Fifteen women with overt PE and 38 women at a risk of developing PE, sampled at different time intervals during gestation (a total of 82 plasma samples collected), were enrolled and underwent the CAIX measurement. CAIX levels significantly increased (p < .001) before the onset of the disease in women (25% of the total number) who later on developed PE when compared to women who did not, starting from 28th gestational week. The best CAIX cut-off of 68.268pg/mL yielded a sensitivity of 100%, a specificity of 81.82%, and an AUC value of .9221. In our pilot study, when compared to the sFlt1/PlGF ratio, CAIX performed better in predicting PE before the clinical onset. Furthermore when implemented as CAIX/PlGF ratio, showed up to be comparable in the identification of women with overt early PE. In conclusion, CAIX could represent an effective predictive biomarker of PE, and larger studies are mandatory to validate this finding.

Decorin-induced, preeclampsia-associated microRNA-512-3p restrains extravillous trophoblast functions by targeting USF2/PPP3R1 axis.

Decorin (DCN) is a leucine-rich proteoglycan produced by chorionic villus mesenchymal cells anddecidual cells during human pregnancy. Studies from our laboratory demonstrated that decidua-derived DCN restrains multiple trophoblast functions including proliferation, migration, invasion andendovascular differentiation, mediated by DCN-binding to multiple tyrosine kinase receptors; expressed by the trophoblast. Furthermore, DCN was shown to be selectively over-produced by thedecidua in preeclampsia (PE) subjects and elevated in the second trimester maternal plasma in PE, before the appearance of clinical signs, presenting as a predictive biomarker for PE. Micro (mi)RNAs are single-stranded non-coding RNAs (17–25 nucleotides) that typically downregulate target genes by repressing translation or facilitating degradation of mRNAs. The human; placenta expresses many miRNAs, some of which are exclusively expressed by the trophoblast. Many; of these miRNAs are dysregulated in PE-associated placentas and some appear in the maternal blood as PE biomarkers. However, little is known about their contribution to the pathogenesis of PE, a multi-factorial disease associated with a hypo-invasive placenta. The objective of the present study was to examine whether exposure of extravillous trophoblast (EVT) to DCN affects expression of specific miRNAs, and to test the role of these miRNAs in altering EVT functions. We identified miR-512-3p, as one of the DCN-induced miRNAs, also upregulated in PE placentas. It was shown to be elevated in ectopic DCN-over-expressing or exogenous DCN-treated first trimester human trophoblast cell line HTR-8/SVneo. Use of miRNA-mimics and inhibitors revealed that miR-512-3p compromised trophoblast migration, invasion and VEGF-dependent endovascular differentiation. Finally, Protein Phosphatase 3 Regulatory Subunit B, Alpha (PPP3R1), a known target of miR-512-3p, was paradoxically elevated in miR-512-3p-overexpressing trophoblast and PE-associated placentas. Using Enrichr, a tool that consists of both a validated user-submitted gene list and a search engine for transcription factors, we found that PPP3R1 elevation resulted from the miRNA binding to and targeting Upstream Transcription Factor 2 (USF2) which targeted PPP3R1. These findings reveal a novel aspect of pathogenesis of PE and biomarker potentials of this miRNA in PE.

Fetal hemoglobin as a predictor in cases of pre-eclampsia

Background and Aim Fetal hemoglobin (Hb) has been described as a new predictive biomarker for pre-eclampsia and has also been hypothesized to be a causative factor. Interestingly, the heme scavenger and antioxidant α-microglobulin increases in parallel with fetal Hb. The aim was to measure the level of fetal Hb in the serum of pregnant women with pre-eclampsia. Patients and methods This a prospective study that was conducted on 100 pregnant women selected from the Obstetrics and Gynecology Department of Al-Hussein University Hospital. Results There was a significant increase in fetal Hb in the patient group more than the control group. The fetal Hb shows a high sensitivity, specificity, and accuracy in prediction of pre-eclampsia and eclampsia. Conclusion Fetal Hb was significantly higher in patients with eclampisa and pre-eclampsia. Moreover, it can be used as a predictive marker for both eclampisa and pre-eclampsia.

Analysis of serum placental growth factor levels in preeclamptic and normotensive pregnant women in Lagos, Nigeria: a worthwhile screening tool?

The clinical usefulness of serum placental growth factor (PlGF) as a predictive biomarker of preeclampsia is currently being examined. However, there are still conflicting results in the literature. We assessed the association between maternal low PlGF levels and the occurrence and severity of preeclampsia. This was an analytical cross-sectional study conducted among 60 women with preeclampsia, and an equal number of matched normotensive pregnant women. PlGF concentrations were analysed using the ELISA method. Bivariate and multivariate analysis was used to test for the association between low maternal PlGF levels and the occurrence of preeclampsia and its severity. Statistical significance was reported at p < .05. The study showed that having a low maternal PlGF level (Adjusted OR 14.23; 95%CI 8.06, 29.71) together with being primigravid (Adjusted OR 3.97; 95%CI 1.03, 6.18) and having an unbooked pregnancy (Adjusted OR 8.07; 95%CI 2.06, 19.40) were independently associated with preeclampsia. We established an association between low maternal PlGF levels and preeclampsia, but no similar association with severe preeclampsia. The use of PlGF as a potential predictive marker and a reliable screening tool may have a profound implication on the prevention of preeclampsia and the subsequent reduction in its associated morbidity and mortality. Impact statement What is already known on this subject? The utility of serum placental growth factor (PlGF) as a predictive biomarker of preeclampsia is currently being examined, however, there are conflicting results of its clinical usefulness in the literature. What do the results of this study add? This study that assessed the association between maternal low PlGF levels and the occurrence and severity of preeclampsia showed that having a low maternal PlGF level together with being primigravid and having an unbooked pregnancy were independently associated with the occurrence of preeclampsia. However, we were unable to establish any significant relationship between maternal PlGF and the severity of preeclampsia. What are the implications of these findings for clinical practice and/or further research? We opined that the use of PlGF as a potential predictive marker and a reliable screening tool may have a profound clinical implication on the prevention and reduction in the associated morbidity and mortality of preeclampsia. However, there is an urgent need for more robust longitudinal studies to define the regulation of placental vascular development and the clinical usefulness of maternal serum PlGF and other placental biomarkers as potential screening tools for preeclampsia among black African women.

Quantitative urine proteomics in pregnant women for the identification of predictive biomarkers for preeclampsia

BackgroundPreeclampsia (PE) is a life-threatening disease characterized by elevated blood pressure and proteinuria. Predictive biomarkers of PE are needed, especially those predicting PE in early pregnancy. The aim of this pilot study was to identify urine proteins that could be candidates for new non-invasive markers for PE.MethodsUrine samples at three time points of pregnancy (12–14, 18–20 and 26–28 weeks of gestation) were prospectively collected from high-risk women who subsequently developed PE (n = 7), high-risk women who did not develop PE (n = 6), and women without known risk factors for PE (n = 4). The samples were analyzed using mass spectrometry and we subsequently quantified 361 proteins used for further analysis. Rigorous statistical analysis with multiple methods was performed to identify biomarker candidates.ResultsOf the clinical risk factors analyzed, pre-pregnancy body mass index (BMIBP) was found to be the most important predictor of PE. We identified multiple proteins that correlated with BMIBP and could improve the prediction of PE in combination with BMIBP. Other statistical analyses identified six proteins that each could differentiate women who subsequently developed PE from those who did not at all three time points.ConclusionsWe identified multiple urine proteins that could be used to predict PE in combination with BMIBP. We also identified six proteins that are strong candidates for predicting PE already in early pregnancy.

Molecular mechanisms in IL-1β-mediated decorin production by decidual cells.

Decorin, a small leucine-rich proteoglycan produced by decidual cells restrains trophoblast differentiation, migration and invasiveness of extra-villous trophoblast cells. Decidual overproduction of decorin is associated with preeclampsia, and elevated decorin levels in maternal plasma are a predictive biomarker of preeclampsia. Furthermore, decorin plays an autocrine role in maturation of human endometrial stromal cells into decidual cells. Thus, a balanced decorin production by the decidua is critical for healthy pregnancy. However, the molecular mechanisms regulating decorin production by the decidua are unclear. Interleukin-1 beta is an inflammation-associated multi-functional cytokine, and is reported to induce decidualization in primates. Hence, the present study was designed: (i) to test if exogenous Interleukin-1 beta stimulated decorin production by human endometrial stromal cells; and if so, (ii) to identify the cellular source of Interleukin-1 beta in first trimester decidual tissue; (iii) to identify the downstream molecular partners in Interleukin-1 beta mediated decorin production by human endometrial stromal cells. Results revealed that (i) amongst multiple pro-inflammatory cytokines tested, Interleukin-1 beta alone stimulated decorin production by these cells; (ii) both macrophages and decidual cells in first trimester decidua produced Interleukin-1 beta; (iii) Interleukin-1 beta mediated decorin production was dependent on Interleukin-1 receptor activation, followed by activation and nuclear translocation of nuclear factor kappa B and its binding to the decorin promoter. These results reveal that Interleukin-1 beta plays a novel role in inducing decorin production by human endometrial stromal cells by activating nuclear factor kappa B.

Decorin production by the human decidua: role in decidual cell maturation.

Decidualization involves the proliferation and differentiation of fibroblast-like endometrial stromal cells into epithelioid-shaped and secretory 'decidual' cells in response to steroid hormones. Human decidual cells produce insulin-like growth factor-binding protein-1 and prolactin (PRL), two well-recognized markers of decidual cell maturation and a proteoglycan decorin (DCN). We reported that DCN restrains the human trophoblast renewal, migration, invasion and endovascular differentiation needed for uterine arterial remodeling during normal pregnancy. DCN overproduction by the decidua is associated with a hypo-invasive placenta and a serious pregnancy disorder, pre-eclampsia (PE). Furthermore, elevated maternal plasma DCN levels during the second trimester is a predictive biomarker of PE. While these paracrine roles of decidua-derived DCN on trophoblast physiology and pathology have been well-defined, it remains unknown whether DCN plays any autocrine role in decidual cell development. The objectives of this study were to examine: the kinetics of DCN production during decidualization of human endometrial stromal cells; gestational age-related changes in DCN production by the first trimester decidua; and a possible autocrine role of DCN on decidual cell maturation. We found that DCN production is enhanced during decidualization of both primary and immortalized human endometrial stromal cells in vitro and during early gestation in decidual samples tested ex vivo, and that it is important for endometrial stromal cell maturation into a decidual phenotype. Decorin-depleted human endometrial stromal cells exposed to decidualizing stimuli failed to mature fully, as evidenced by fibroblastoid morphology, reduced insulin-like growth factor-binding protein-1 and PRL expression, and reduction in cellular ploidy. We identified heart and neural crest derivatives-expressed protein 2, and progesterone receptor as potential downstream mediators of DCN effects.

Maternal serum trimethylamine-N-oxide is significantly increased in cases with established preeclampsia.

To compare the levels of trimethylamine-N-oxide (TMAO) in sera of normal and preeclamptic pregnancies and to explore whether serum TMAO level was associated with the severity of preeclampsia. Eighty-six pregnant women in the third trimester were enrolled in this case control study. Levels of TMAO were quantified by a novel liquid chromatography/tandem mass spectrometry-based method in fasting serum samples from 43 preeclamptic women and 43 normotensive controls. Clinical characteristics, serum biomarkers of inflammation (IL-1β) and biomarkers of endothelial dysfunction (sVCAM-1, sFlt-1) were assessed. TMAO levels were significantly higher in women with preeclampsia than those with normal pregnancy. The serum levels of TMAO were positively correlated with systolic blood pressure (r = 0.602, P < 0.001), urinary protein levels (r = 0.557, P < 0.001) and the serum levels of IL-1β (r = 0.633, P < 0.001), sVCAM-1 (r = 0.719, P < 0.001) as well as sFlt-1 (r = 0.763, P < 0.001) in patients with PE. Elevated TMAO levels are associated with higher risk of preeclampsia and correlate with increased systemic inflammation and endothelial dysfunction. Further validation of these findings with more robust multicenter prospective and longitudinal characterization of maternal serum TMAO in pregnancy may be carried out in subsequent investigations to determine its suitability as a predictive biomarker for preeclampsia.

Association between serum CA125 levels in preeclampsia and its severity among women in Lagos, South-West Nigeria

ABSTRACTBackground: Preeclampsia is a syndrome of unknown etiology characterized by hypertension, proteinuria, and/or organ dysfunction. CA125 is an antigenic determinant recognized by the murine monoclonal antibody OC125 quantified by radioimmunoassay. Its role in obstetrics is yet to be fully understood as most clinical trials advocating its uses are widely experimental in nature and unacknowledged. Aim: This study was done to assess the relationship between serum concentration of CA125 in normal pregnancies and those complicated with preeclampsia. Methods: A case–control study involving 70 women diagnosed with preeclampsia and 70 healthy controls matched for age, parity, and gestational age at enrollment. Venous samples were collected from each participant after informed consent was obtained. The preeclampsia group was further subdivided into mild and severe preeclampsia and all participants were followed up till delivery with records of delivery, maternal, and neonatal outcomes obtained thereafter. Serum CA125 levels were determined by standard enzyme-linked immunosorbent assay (ELISA) method. Hypothesis testing was done using chi-square test for categorical variables, and the independent-samples t-test and ANOVA for numerical variables. All significances were reported at P < 0.05. Results: The mean serum level of CA125 in women with preeclampsia was significantly greater than those with normal pregnancy (54.17 IU/mL vs. 12.49 IU/mL, P < 0.05). CA125 level also correlated positively with systolic blood pressure (r = 0.406, P < 0.05), diastolic blood pressure (r = 0.433, P < 0.05), serum uric acid levels (r = 0.407, P = 0.001), platelet levels (r = 0.341, P = 0.001), and urinary protein levels (r = 0.325, P = 0.002). The CA125 levels between the three categories of participants in the study were: normotensive control (12.49 ± 6.62 mIU/L), mild preeclampsia (29.43 ± 3.7 mIU/L), and severe preeclampsia (64.25 ± 9.21 mIU/L), respectively (P = 0.023). Conclusion: We can infer from this study that increased maternal serum CA 125 levels are associated with the preeclampsia and its severity. However, further validation of these findings with more robust multicenter prospective and longitudinal characterization of maternal serum CA125 profiles in pregnancy should be carried out in subsequent investigations to determine its suitability as a predictive biomarker for preeclampsia in women of African descent.

Are Placental Cell-Derived Exosomes a Predictive Biomarker of Preeclampsia?

Placenta is endocrine organ that regulate biological function of several maternal tissues and fetal organs by specific mechanisms of cell-to-cell cooperation, which is realized via exosomes’ secretion. Exosomes delivery some molecules, i.e., active proteins, pro-coagulants, growth factors, lipids, enzymes, micro-RNAs to target cells and induce autocrine / paracrine effects on vasculature and trophoblast. Interestingly, circulating number of exosomes derived from placenta cells in healthy pregnancies increases in 50-100 fold times to healthy volunteers and they may be detected in several biological fluids across all gestation age starting with 6 weeks of gestation. Moreover, pregnancies at risk of preeclampsia exhibit extremely increased levels of total exosomes and placental cell-derived-exosomes in blood when compared with woman at risk free of preeclampsia. Taking into consideration this fact, measure of circulating number of placental cell-derived-exosomes could be an individual probe for personification of a risk of life-threatening event across pregnancy. The short communication is depicted the role of placental cell-derived-exosomes as biomarker of preeclampsia in asymptomatic pregnancies.

Nested case-control study reveals increased levels of urinary proteins from human kidney toxicity panels in women predicted to develop preeclampsia.

The aim of this study was to evaluate the usefulness of urine concentrations of 12 proteins as a risk parameter for developing preeclampsia (PE). A nested case-control study was designed to determine protein concentrations in urine from women predicted to develop PE (WPD-PE) and normotensive pregnancies (controls). Protein profiles were determined at 12, 16 and 20 gestational weeks (GW) using the Bio-Plex Pro human kidney toxicity Panel 1 and Panel 2 (Bio-Rad). Receiver operating characteristic (ROC) curve analyses were performed. Correlations between proteins and clinical parameters at the time of PE diagnosis were also assessed. Significant differences were observed in urine cystatin C (Cys C) levels at 16 and 20GW and clusterin at 20GW between WPD-PE and controls (P<0.05). ROC analysis revealed that Cys C at 16GW had the highest area under the ROC curve (0.758). At 16GW, patients with urine Cys C levels above 73.7ng/mL had eightfold increased odds for developing PE (odds ratio 7.92; 95% CI 1.3-47.5; P=0.027). A positive correlation was found between urinary Cys C (at 16 and 20GW) and leukocyte counts, total proteins, aspartate aminotransferase, alanine aminotransferase, bilirubin and lactate dehydrogenase at the time of PE diagnosis (P value<0.05). Urinary Cys C and clusterin showed predictive value for PE development in our cohort. Further studies are needed to validate their use as predictive biomarkers for PE and/or their participation in PE pathogenesis.

Fetal hemoglobin, α1-microglobulin and hemopexin are potential predictive first trimester biomarkers for preeclampsia.

Overproduction of cell-free fetal hemoglobin (HbF) in the preeclamptic placenta has been recently implicated as a new etiological factor of preeclampsia. In this study, maternal serum levels of HbF and the endogenous hemoglobin/heme scavenging systems were evaluated as predictive biomarkers for preeclampsia in combination with uterine artery Doppler ultrasound. Case-control study including 433 women in early pregnancy (mean 13.7weeks of gestation) of which 86 subsequently developed preeclampsia. The serum concentrations of HbF, total cell-free hemoglobin, hemopexin, haptoglobin and α1-microglobulin were measured in maternal serum. All patients were examined with uterine artery Doppler ultrasound. Logistic regression models were developed, which included the biomarkers, ultrasound indices, and maternal risk factors. There were significantly higher serum concentrations of HbF and α1-microglobulin and significantly lower serum concentrations of hemopexin in patients who later developed preeclampsia. The uterine artery Doppler ultrasound results showed significantly higher pulsatility index values in the preeclampsia group. The optimal prediction model was obtained by combining HbF, α1-microglobulin and hemopexin in combination with the maternal characteristics parity, diabetes and pre-pregnancy hypertension. The optimal sensitivity for all preeclampsia was 60% at 95% specificity. Overproduction of placentally derived HbF and depletion of hemoglobin/heme scavenging mechanisms are involved in the pathogenesis of preeclampsia. The combination of HbF and α1-microglobulin and/or hemopexin may serve as a prediction model for preeclampsia in combination with maternal risk factors and/or uterine artery Doppler ultrasound.

Diagnostic and predictive biomarkers for pre-eclampsia in patients with established hypertension and chronic kidney disease

Women with chronic kidney disease (CKD) and chronic hypertension (CHT) frequently develop superimposed pre-eclampsia, but distinction from pre-existing disease is challenging. Plasma placental growth factor (PlGF), B-type natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL), and serum relaxin concentrations were quantified in a longitudinal prospective cohort of 121 women with CKD: 44 with chronic hypertension, and 79 healthy controls. Biomarker concentrations were compared with 32 women with pre-eclampsia without pre-existing disease. Test performance was evaluated for diagnosis of superimposed pre-eclampsia requiring delivery within 14days of sampling. PlGF was evaluated as a promising marker in a validation cohort of women with suspected pre-eclampsia (29 with CKD; 94 with chronic hypertension; 29 with superimposed pre-eclampsia requiring delivery within 14 days) and compared with women without pre-existing disease (290 with no pre-eclampsia and 176 with pre-eclampsia requiring delivery within 14 days). From 20and up to 42 weeks of gestation, lower maternal PlGFconcentrations had high diagnostic accuracy for superimposed pre-eclampsia requiring delivery within 14days (receiver operator characteristic 0.85) and confirmed in the validation cohort. The other plasma and serum biomarkers were not discriminatory. Thus, plasma PlGF concentrations could potentially help guide clinical decision making regarding admission and delivery for superimposed pre-eclampsia.

Ischemia-Modified Albumin (IMA): A Novel Marker for Preeclampsia Independent of Uterine Artery Notching Identified by Doppler Ultrasound

Objective: To determine the predictive value of second trimester serum ischemia-modified albumin (IMA) levels for preeclampsia (PE), small for gestational age (SGA) and gestational diabetes mellitus (GDM). Methods: The study was conducted at a tertiary care hospital between May and August 2014. Healthy pregnant women (n = 88) who were screened for fetal anomalies with ultrasound at 20–24 weeks of gestation were included in the study. Doppler measurements of the bilateral uterine arteries were performed in all the patients. Serum samples were obtained for an IMA assay. The maternal serum IMA levels were compared in pregnant women who had normal and abnormal uterine artery Doppler findings, including notching, and also in pregnant women who subsequently developed PE, SGA, and GDM during the follow-up period. Results: Uterine artery notching was not significantly predictive for PE, GDM or SGA (p > 0.05). There was no significant difference between notching of the uterine arteries and serum IMA levels (p > 0.05). Eight pregnant women (9.1%) subsequently developed PE. Serum IMA levels were significantly elevated in patients with PE compared with patients who did not subsequently develop PE (p = 0.002). However, serum IMA levels were not significantly different in patients who subsequently developed SGA and GDM compared with women who did not (p > 0.05). There was no correlation between serum IMA levels and maternal characteristics and laboratory findings. Conclusion: Maternal serum IMA levels at 20–24 weeks’ gestation might be a predictive biomarker for PE, independent of notching of the uterine arteries, maternal characteristics and laboratory findings.

The predictive value of the first-trimester maternal serum chemerin level for pre-eclampsia

Chemerin is a novel adipokine linked to inflammation. The cross-sectional studies have reported that maternal chemerin serum concentrations are significantly increased in pre-eclampsia. However, limited data are available regarding the cause-effect relationship between chemerin and pre-eclampsia. The aim of this prospective observational study was to evaluate predictive significance of the first-trimester maternal serum chemerin levels for pre-eclampsia and to further confirm the hypothesis that chemerin is an important causative factor in the pathogenesis of pre-eclampsia. 518 pregnancy women were recruited. The first-trimester maternal serum chemerin levels were determined using enzyme-linked immunosorbent assay. The first-trimester maternal serum chemerin levels were statistically significantly elevated in women with pre-eclampsia compared with those without pre-eclampsia and in severe pre-eclampsia women compared with mild pre-eclampsia women. Serum chemerin levels remained positively associated with plasma C-reactive protein levels using a linear regression model. A logistic-regression analysis demonstrated that body mass index and serum chemerin levels appeared to be the independent predictors of pre-eclampsia. A receiver–operating characteristic curve analysis identified that serum chemerin levels predicted pre-eclampsia with high predictive value. The predictive value of the chemerin concentrations was similar to that of body mass index. Chemerin improved the predictive value of body mass index statistically significantly. Thus, our results suggest that high serum chemerin levels are associated with inflammation and pre-eclampsia independently, as well as chemerin may play a role as predictive biomarker for pre-eclampsia and be an important causative factor in the pathogenesis of pre-eclampsia.

Vasopressin in preeclampsia: a novel very early human pregnancy biomarker and clinically relevant mouse model.

Preeclampsia, a cardiovascular disorder of late pregnancy, is characterized as a low-renin hypertensive state relative to normotensive pregnancy. Because other nonpregnant low-renin hypertensive disorders often exhibit and are occasionally dependent on elevated arginine vasopressin (AVP) secretion, we hypothesized a possible use for plasma AVP measurements in the prediction of preeclampsia. Copeptin is an inert prosegment of AVP that is secreted in a 1:1 molar ratio and exhibits a substantially longer biological half-life compared with AVP, rendering it a clinically useful biomarker of AVP secretion. Copeptin was measured throughout pregnancy in maternal plasma from preeclamptic and control women. Maternal plasma copeptin was significantly higher throughout preeclamptic pregnancies versus control pregnancies. While controlling for clinically significant confounders (age, body mass index, chronic essential hypertension, twin gestation, diabetes mellitus, and history of preeclampsia) using multivariate regression, the association of higher copeptin concentration and the development of preeclampsia remained significant. Receiver operating characteristic analyses reveal that as early as the sixth week of gestation, elevated maternal plasma copeptin concentration is a highly significant predictor of preeclampsia throughout pregnancy. Finally, chronic infusion of AVP during pregnancy (24 ng per hour) is sufficient to phenocopy preeclampsia in C57BL/6J mice, causing pregnancy-specific hypertension, renal glomerular endotheliosis, proteinuria, and intrauterine growth restriction. These data implicate AVP release as a novel predictive biomarker for preeclampsia very early in pregnancy, identify chronic AVP infusion as a novel and clinically relevant model of preeclampsia in mice, and are consistent with a potential causative role for AVP in preeclampsia in humans.

Maternal and fetal factors and placentation: implications for pre-eclampsia.

The etiology of preeclampsia is still mysterious and a source of a variety of hypotheses. Accordingly, there is a number of theories present today describing different pathways how this disorder may develop. The most cited hypothesis on the etiology of preeclampsia is based on an inadequate remodeling of uterine spiral arteries in the placental bed due to superficial trophoblast invasion followed by placental hypoxia. Since maternal blood into the placenta is only established after week 12 of gestation, an effect of a failure in arterial remodeling can only affect the placenta starting with the second trimester of pregnancy. Recent studies on early predictive biomarkers for preeclampsia (such as PP13, fetal hemoglobin and PIGF) have indicated that there are changes of the villous trophoblast already weeks before the onset of maternal blood flow into the placenta, i.e. during mid first trimester. Moreover, a number of studies has shown that in cases with impaired trophoblast invasion resulting in inadequate remodeling of uterine spiral arteries placental hypoxia does not occur. In all these studies where mostly indirect assessments of placental oxygen have been performed, a higher oxygen partial pressure within the placenta has been measured. This is in clear contrast to the old hypothesis where placental hypoxia is essential for the etiology of preeclampsia. New biomarkers from the maternal and/or fetal compartment for the early prediction of preeclampsia may help in identifying the real etiology of preeclampsia. We need to use this momentum to decipher the real causes of this syndrome.