Diagnosis Of Early-onset Preeclampsia Research Articles

Pregnancy-Specific Beta-1-Glycoprotein 1 Increases HTR-8/SVneo Cell Migration through the Orai1/Akt Signaling Pathway.

The impaired invasion ability of trophoblast cells is related to the occurrence of preeclampsia (PE). We previously found that pregnancy-specific beta-1-glycoprotein 1 (PSG1) levels were decreased in the serum of individuals with early-onset preeclampsia (EOPE). This study investigated the effect of PSG1 on Orai1-mediated store-operated calcium entry (SOCE) and the Akt signaling pathway in human trophoblast cell migration. An enzyme-linked immunosorbent assay (ELISA) was used to determine the level of PSG1 in the serum of pregnant women with EOPE. The effects of PSG1 on trophoblast proliferation and migration were examined using cell counting kit-8 (CCK8) and wound healing experiments, respectively. The expression levels of Orai1, Akt, and phosphorylated Akt (p-Akt) were determined through Western blotting. The results confirmed that the serum PSG1 levels were lower in EOPE women than in healthy pregnant women. The PSG1 treatment upregulated the protein expression of Orai1 and p-Akt. The selective inhibitor of Orai1 (MRS1845) weakened the migration-promoting effect mediated by PSG1 via suppressing the Akt signaling pathway. Our findings revealed one of the mechanisms possibly involved in EOPE pathophysiology, which was that downregulated PSG1 may reduce the Orai1/Akt signaling pathway, thereby inhibiting trophoblast migration. PSG1 may serve as a potential target for the treatment and diagnosis of EOPE.

Clinical Comparative Analysis of Early-Onset Preeclampsia Combined with HELLP Syndrome

To explore the clinical characteristics of early-onset preeclampsia (PE) combined with HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and to improve the capacity for early diagnosis and treatment. Pregnant women who received treatment at Women's Hospital, School of Medicine, Zhejiang University between March 2014 and October 2021 were retrospectively enrolled. There were two patient groups, the HELLP group consisting of 70 cases of early-onset PE combined with HELLP syndrome and the control group consisting of 140 cases of early-onset PE without HELLP syndrome. Patients in the two groups were matched by age. The general clinical data, characteristics of pathogenesis, and laboratory findings of the patients were collected and the perinatal outcomes of the two groups were compared and analyzed. 1) There was no significant difference in gravidity, pre-delivery body mass index, years from the last delivery, and family history of diabetes mellitus and hypertension between the two groups. 2) The highest systolic blood pressure, highest diastolic blood pressure during the pregnancy, and the postpartum hospital length-of-stay ( P<0.001) in the HELLP group were higher than those in the control group. The gestational age at the time of the diagnosis of PE ( P=0.001) and the gestational age at delivery ( P<0.001) in the HELLP group were significantly earlier than those in the control group. The difference between the gestational age at the time of blood pressure elevation and that at the time of delivery ( P<0.001), and the gestational age difference between the diagnosis of early-onset PE and delivery ( P=0.027) were lower than those in the control group. The incidences of eclampsia in the HELLP group, pleural effusion, and ascites were higher than those of the control group. 3) Neonates in the HELLP group had a higher probability of being admitted to NICU and developing cyanotic/pale asphyxia ( P<0.001). 4) Before the termination of pregnancy, the HELLP group had higher levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, creatinine, urea, random glucose, lactate dehydrogenase, activated partial thromboplastin time, and the last 24-hour urine protein quantification than those of the control group (all P<0.05), while the platelet (PLT) counts were significantly lower than those of the control group ( P<0.001). 5) There was a significant correlation between PLT counts in the second trimester and the onset of HELLP syndrome ( P=0.006), with the area under the ROC curve reaching 0.746 (95% CI: 0.596-0.897). In comparison with early-onset PE patients without HELLP syndrome, patients with early-onset PE combined with HELLP syndrome are diagnosed for PE at an earlier gestational age, have higher blood pressure, are more prone to serious pregnancy complications, and have longer postpartum hospital length-of-stay and worse neonatal outcomes. Close monitoring of PLT counts of early-onset PE patients in the second trimester may help predict subsequent HELLP syndrome.

Prediction of Delivery Within 7 Days After Diagnosis of Early Onset Preeclampsia Using Machine-Learning Models.

BackgroundEarly onset preeclampsia (eoPE) is a hypertensive disorder of pregnancy with endothelial dysfunction manifested before 34 weeks where expectant management is usually attempted. However, the timing of hospitalization, corticosteroids, and delivery remain a challenge. We aim to develop a prediction model using machine-learning tools for the need for delivery within 7 days of diagnosis (model D) and the risk of developing hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome or abruptio placentae (model HA).Materials and MethodsA retrospective cohort of singleton pregnancies with eoPE and attempted expectant management between 2014 and 2020. A Mono-objective Genetic Algorithm based on supervised classification models was implemented to develop D and HA models. Maternal basal characteristics and data gathered during eoPE diagnosis: gestational age, blood pressure, platelets, creatinine, transaminases, angiogenesis biomarkers (soluble fms-like tyrosine kinase-1, placental growth factor), and ultrasound data were pooled for analysis. The most relevant variables were selected by bio-inspired algorithms. We developed basal models that solely included demographic characteristics of the patient (D1, HA1), and advanced models adding information available at diagnosis of eoPE (D2, HA2).ResultsWe evaluated 215 eoPE cases and 47.9% required delivery within 7 days. The median time-to-delivery was 8 days. Basal models were better predicted by K-nearest-neighbor in D1, which had a diagnostic precision of 0.68 ± 0.09, with 63.6% sensitivity (Sn), 71.4% specificity (Sp), 70% positive predictive value (PPV), and 65.2% negative predictive value (NPV) using 13 variables and HA1 of 0.77 ± 0.09, 60.4% Sn, 80% Sp, 50% PPV, and 87.9% NPV. Models at diagnosis were better developed by support vector machine (SVM) using 18 variables, where D2’s precision improved to 0.79 ± 0.05 with 77.3% Sn, 80.1% Sp, 81.5% PPV, and 76.2% NPV, and HA2 had a precision of 0.79 ± 0.08 with 66.7% Sn, 82.8% Sp, 51.6% PPV, and 90.3% NPV.ConclusionAt the time of diagnosis of eoPE, SVM with evolutionary feature selection process provides good predictive information of the need for delivery within 7 days and development of HELLP/abruptio placentae, using maternal characteristics and markers that can be obtained routinely. This information could be of value when assessing hospitalization and timing of antenatal corticosteroid administration.

Longitudinal changes in angiogenesis biomarkers within 72h of diagnosis and time-to-delivery in early-onset preeclampsia.

To evaluate the association between the increment of the sFlt-1/PlGF ratio within the first 72h after the diagnosis of early-onset preeclampsia (PE) and the time-to-delivery. Secondarily we aimed to test its predictive value for maternal adverse outcomes. Retrospective cohort study of 155 women with early-onset PE and measurement of sFlt-1/PlGF at diagnosis and delivery from which the expected distributions of the daily increment (Δ) of sFlt-1/PlGF ratio, sFlt-1 and PlGF were obtained. Of them, in 110 a short-term evaluation at 72+/-24h was available and Δ72h were calculated and compared to the expected distributions. The high-risk groups were those with Δ72h sFlt-1/PlGF and Δ72h sFlt-1>3rd expected quartile or Δ72h PlGF<1st expected quartile. The low-risk groups were those with Δ72h≤0 for sFlt-1/PlGF and sFlt-1 or Δ72h PlGF≥0. The rest were considered intermediate risk. Time-to-delivery and maternal adverse outcomes were compared between the three groups. Δ72h sFlt-1/PlGF and sFlt-1>3rd quartile had a significant reduction of time-to-delivery when compared to increments<3rd quartile or≤0 (5 vs 11 vs 14days, p<0.01) and (6 vs 8 vs 15days, p<0.01), respectively. Both were limited for the prediction of maternal adverse outcomes. Δ72h PlGF showed no significant relation with time-to-deliver but all abruptio placentae had PlGF<70pg/mL at diagnosis. High Δ72h sFlt-1/PlGF and sFlt-1 are associated to a shorter time-to-delivery while low PlGF at diagnosis is associated to abruptio placentae.

A promising novel biomarker for early-onset preeclampsia: soluble trigger receptor expressed on myeloid cells-1 (sTREM-1)

Background We aimed to explore TREM-1 activation in pregnant women who has preeclampsia through the measurement of its soluble form sTREM. Methods A prospective cohort study was conducted. Participants were recruited from antenatal clinic between 1 May 2019 and 31 August 2019, and they all provided written informed consent for participation. Women between 18 and 42 years of age who were diagnosed with early or late-onset preeclampsia (LOP) were offered participation if they did not have any known systemic disease (chronic hypertension, diabetes, hypothyroidism, chronic renal-liver diseases, etc.); autoimmune disorders; multiple pregnancies; presence of fetal structural and chromosomal anomalies; placenta previa; cholestasis of pregnancy; preterm delivery; evidence of chronic and active infection. The primary outcome of the study was to assess any difference between groups in terms of the diagnostic value of sTREM level. Results A total of 80 patients were enrolled; proven early-onset preeclampsia (EOP) (n = 20), LOP (n = 30), and control (n = 30) groups. There was no significant difference among the groups in terms of age and BMI. Mean gestational age at diagnosis of EOP; 30 ± 1.9 and LOP; 34.7 ± 1.9 weeks gestation. The mean sTREM level was 160.130 ± 1.65 pg/ml in the EOP group, 119.337 ± 2.04 pg/ml in LOP group, and 87.764 ± 1.69 pg/ml in the control group. According to subgroup analysis, sTREM levels were significantly higher in EOP group than control group. Conclusions sTREM might be a promising biomarker for early detection of EOP. However, future studies are necessary to confirm this hypothesis.

Identification of Key Genes and Long Noncoding RNA-Associated Competing Endogenous RNA (ceRNA) Networks in Early-Onset Preeclampsia.

Background Preeclampsia (PE) is a pregnancy-specific hypertension syndrome and is one of the leading causes of maternal and perinatal morbidity and mortality. Long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in many diseases, including preeclampsia. The present study is aimed at identifying the key genes and lncRNA-associated competing endogenous RNA (ceRNA) networks in early-onset preeclampsia (EOPE). Methods We investigated expression profiles of differentially expressed lncRNAs (DElncRNAs) and genes (DEGs) in placental tissues of EOPE and healthy controls with Human LncRNA Array v4. The potential functions of DEGs and DElncRNAs were predicted using the clusterProfiler package. The lncRNA-mRNA coexpression network was constructed via Pearson's correlation coefficient. The protein-protein interaction (PPI) network of DEGs was constructed, and the hub genes were obtained using the STRING database and Cytoscape. The ceRNA networks were constructed based on miRWalk and LncBase v2. qRT-PCR was performed to confirm the expression of lncRNA MIR193BHG, PROX1-AS1, and GATA3-AS1. ROC curves were performed to assess the clinical value of lncRNA MIR193BHG, PROX1-AS1, and GATA3-AS1 in the diagnosis of EOPE. Results We found 6 hub genes (SPP1, CCR2, KIT, ENG, ACKR1, and FLT1) altered in placental tissues of EOPE and constructed a ceRNA network, including 21 lncRNAs, 3 mRNAs, and 69 miRNAs. The expression of lncRNA MIR193BHG and GATA3-AS1 were elevated and showed good clinical values for diagnosing EOPE. Conclusion This study provides novel insights into the lncRNA-related ceRNA network in EOPE and identified two lncRNAs as potential prognostic biomarkers in EOPE.

Relationship between antithrombin activity and interval fromdiagnosis to delivery among pregnant women with early-onset pre-eclampsia.

To determine the cutoff of antithrombin activity for predicting the interval from diagnosis of early-onset pre-eclampsia to delivery. At Hokkaido University Hospital, Japan, data were retrospectively assessed on antithrombin activity measured at both diagnosis of pre-eclampsia and delivery among women with singleton pregnancy and pre-eclampsia (defined by combined gestational hypertension and proteinuria) between 2009 and 2017. The timing of delivery was determined by maternal and fetal well-being. Among 2904 singleton deliveries, antithrombin activity was measured for 94 (3.2%) women diagnosed with pre-eclampsia. The median (range) interval was significantly longer for 38 (40%) women with early-onset than for 56 (60%) women with late-onset pre-eclampsia (6.5 [0-27] vs 1 [0-29] days, respectively; P<0.001). In the early-onset group, median antithrombin activity at diagnosis was significantly lower for 19 women with an interval of less than 7days (72% [60%-92%]) than for 19 women with a longer interval (≥7days) (84% [59%-110%]; P=0.012). Antithrombin activity of 78% at diagnosis of early-onset pre-eclampsia was optimal for predicting a delivery interval of less than 7days. A cutoff of 78% antithrombin activity at diagnosis of early-onset pre-eclampsia might be used as a predictor of delivery within 7days.

POCT Detection of Urinary Misfolded Proteins Provides Sensitive and Specific Diagnosis of Preeclampsia

Background: Aggregates of misfolded proteins, which previously were shown to be related to preeclampsia, may be used as diagnostic marker by testing patients' urine. We developed an easy-to-perform POCT (point of care test) method for detecting urinary misfolded proteins we termed Protein Test, and validated its diagnostic utility in a large clinically relevant cohort. Methods: 1,539 women hospitalized at Shengjing Hospital were eligible for the study. Urine samples were tested by Misfolded Protein Test. Consistency analysis were conducted using The American College of Obstetricians and Gynecologists (ACOG, 2013) guidelines as golden standard. Findings: Participants were randomized into training (773) and validation set (766). According to the criterion that identified in the training set, our POCT test was demonstrated in validation set having sensitivity 86.11%, specificity 96.52%, positive predictive value (PPV) 88.57%, and negative predictive value (NPV) 95.69% for diagnosis of early onset preeclampsia, and corresponding value of 75.76%, 96.89%, 69.44%, and 97.22% for all preeclampsia. In addition, patients with preeclampsia history, in-vitro fertilization (IVF), or multifetal pregnancy were demonstrated more susceptible to preeclampsia (all P values below 0.001). Primary hypertension or nephrosis (P < 0.001) were also risk factors to preeclampsia. Interpretation: Our simple and non-invasive Misfolded Protein Test for detecting misfolded proteins is highly sensitive and specific for diagnosis of preeclampsia, especially for early-onset preeclampsia. Furthermore, we confirmed in a large non-selective in-patient population that factors including preeclampsia history, abortion history, IVF, multifetal pregnancy, primary hypertension or nephrosis are each independently significant risk factors of preeclampsia. Clinical Trial Number: registered at chictr.org, number ChiCTR1800017692. Funding Statement: The authors state: study received no external funding. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This research was approved by Medical Ethics Committee of Shengjing Hospital. Written informed consent was waived due to the usage of remaining samples of Urine Routine test.

New biomarkers in diagnosis of early onset preeclampsia and imminent delivery prognosis

Several studies have revealed a high soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio in preeclamptic women. However, its role in patients with suspected preeclampsia (PE) at triage in the emergency department remains an issue and a controversial unique cutpoint of 85 has been proposed regardless of gestational age. A new cutpoint for sFlt-1/PlGF ratio was investigated to rule out PE at obstetric triage, and to assess its prognostic value for risk of imminent delivery. Blood samples from 257 pregnant women with suspected PE were obtained at obstetric triage admission. Serum PlGF and sFlt-1 were measured by an electrochemoluminiscence immunoassay (ECLIA) on the immunoanalyzer Cobas e601 (Roche Diagnostics) and the corresponding ratio was calculated. Final outcomes (mainly development of PE) were reviewed and time between clinical presentation and delivery was calculated. The best ratio cutpoint to diagnose PE changed according to gestational age: 23 (92.0% sensitivity, 81.1% specificity) and 45 (83.7% sensitivity, 72.6% specificity) for women <34 and ≥ 34 weeks' gestation, respectively. Furthermore, sFlt-1/PlGF ratio inversely correlated with time elapsed between clinical presentation and delivery, and a cutpoint of 178 could predict complications such as imminent delivery or fetal/neonatal death with a sensitivity of 70.6% and a specificity of 97.8%. The new cut-off values for the sFlt-1/PlGF ratio adjusted by the gestational age at clinical presentation can be used to rule out PE at obstetric triage and to predict imminent delivery with better accuracy than the cutpoint currently accepted.

Measurement of sST2 is comparable to PlGF in the diagnosis of early-onset pre-eclampsia

A diagnostic test to confirm pre-eclampsia would be beneficial for the clinical management of the syndrome. The Triage PlGF test is able to confirm pre-eclampsia with high accuracy, with the greatest efficacy at <35weeks gestation. We recently found that the anti-inflammatory protein sST2 is elevated in the plasma of pre-eclamptic women compared to normal controls. Here sST2 and PlGF are compared in early-onset and late-onset pre-eclamptic women. sST2 was found to be an equally good diagnostic tool for early-onset (sST2 AUC 0.944 versus PlGF AUC 0.995; not significant) but not late-onset disease.

O9. Evaluating fetal cord blood lipids and oxidized LDL status in intrauterine growth restriction and preeclampsia

quartile range, and Receiver Operator Characteristic (ROC) curves. Results: Median PlGF concentrations in cases and controls were [Triage; 12 (IQR 12–15) v 256 (IQR 130–781) pg/ml, and Delfia; 38 (IQR 28–43) v 236 (IQR 161–419) pg/ml], respectively. The area under the ROC curve (AUC) for the diagnosis of early onset preeclampsia was 1.0 (95% CI, 1.0–1.0) for Triage and 0.97 (95% CI, 0.94–1.0) for Delfia. Conclusions: The Triage PlGF assay achieves greater separation of cases from controls. Further studies are needed to understand whether differences in analytical specificity (PlGF isoforms or complexed vs non-complexed PlGF) explain the lower levels of PlGF in preeclampsia for the Triage immunoassay.

Angiogenic factors as diagnostic tests for preeclampsia: a performance comparison between two commercial immunoassays

Placental growth factor and soluble Fms-like tyrosine kinase-1 may be potential diagnostic markers of preeclampsia. We compared performances of 2 immunoassays, the Triage placental growth factor assay and the Elecsys soluble Fms-like tyrosine kinase-1/placental growth factor ratio in diagnosing preeclampsia. A single site, case-control study of 44 patients with preeclampsia and 84 matched normal pregnant controls. Samples were collected at the time of diagnosis. Assays were performed according to product inserts. Both assays had optimal performance in diagnosing early-onset preeclampsia with area under the receiver operating characteristic curves of 0.99 (Triage: 100% sensitivity, 96% specificity; Elecsys: 64% sensitivity, 100% specificity for early-onset preeclampsia). Reassignment of the Elecsys cutoff for a positive test based on receiver operating characteristic curves increased sensitivity to 92%. Using product insert cutoffs, Triage appears to have greater sensitivity at only a small reduction in specificity compared with Elecsys in the diagnosis of early-onset preeclampsia. A different cutoff may improve Elecsys sensitivity.

T13.5 Placental growth factor as a diagnostic for early onset pre-eclampsia and normotensive intrauterine growth restriction of placental origin

T13.6 – Table 2. Comparison table Normal Chronic hypertension Superimposed hypertension Pre-eclampsia Gestational hypertension Normal – P = 0.377 P = 0.031 P< 0.0001 P = 0.002 Chronic hypertension P = 0.377 – P = 0.107 P = 0.003 P = 0.021 Superimposed hypertension P = 0.031 P = 0.107 – P = 0.218 P = 0.673 Pre-eclampsia P< 0.0001 P = 0.003 P = 0.218 – P = 0.201 Gestational hypertension P = 0.002 P = 0.021 P = 0.673 P = 0.201 – sensitivity and specificity increased to 100% and 92%, respectively. Combined, a positive PlGF test was able to diagnosis early onset pre-eclampsia or nIUGR with 94% sensitivity and 93% specificity. Conclusion: This evidence suggests that PlGF can be used to confirm diagnosis of early onset pre-eclampsia and identify nIUGR of placental origin from mimics. Funding: Biosite, CIHR, MSFHR, CFRI T13.6 Urinary placental growth factor differentiates the hypertensive disorders of pregnancy Neil Campbell1, Robert Ogle1, Annemarie Hennessy2, Charlene Thornton1. 1Royal Prince Alfred Hospital, Sydney, Australia; 2University of Western Sydney and Heart Research Institute, Australia Objective: The objective of this study is to establish whether urinary placental growth factor (uPlGF) is capable of discriminating between the different types of hypertensive disease in pregnancy in the third trimester. Design: This is a prospective descriptive case control study. Setting: Royal Prince Alfred Hospital, Urban tertiary referral hospital in Sydney, Australia. The Canterbury Hospital, district general hospital, Sydney, Australia Patients: Women in the third trimester of pregnancy who were currently inpatients on the antenatal ward or patients attending the antenatal outpatients department. Interventions: Patients in the third trimester of pregnancy were selected from the above settings, reviewed for eligibility and demographic data extracted. Patients were then asked to provide a urine specimen some of which was analysed for protein and creatinine and the rest stored and then later analysed for urine PlGF level. These levels after correction for creatinine concentration were then used in the final analysis. Measurements & main results: We have identified 36 women in the hypertensive group (preeclampsia (n=15), Gestational hypertension (n=13), Chronic hypertension (n=8), Preeclampsia superimposed on chronic hypertension (n=5)) and 47 women in the normal control group. There is a statistically significant difference in PlGF levels between the preeclamptic group and the normotensive controls (P<0.0001) and also between the gestational hypertensive group and the normotensive group (P=0.002) Distributions of the preeclamptic group and gestational hypertensive group taken as a whole when compared to the chronic hypertensive group and preeclampsia superimposed on chronic hypertension group also taken as a whole showed a significant difference as well (P=0.007). Table 1. Group characteristics