Effect of pregnancy prolongation in early-onset pre-eclampsia on postpartum maternal cardiovascular, renal and metabolic function in primiparous women: an observational study.

OBJECTIVE: To evaluate the association between deferred delivery in early-onset pre-eclampsia and offspring outcome and maternal cardiovascular, renal and metabolic function in the postpartum period. DESIGN: Observational study. SETTING: Tertiary referral hospital. POPULATION: Nulliparous women diagnosed with pre-eclampsia before 34 weeks' gestation who participated in a routine postpartum cardiovascular risk assessment programme. Women with hypertension, diabetes mellitus or renal disease prior to pregnancy were excluded. METHODS: Regression analyses were performed to assess the association between pregnancy prolongation and outcome measures. MAIN OUTCOME MEASURES: Offspring outcome and prevalence of deviant maternal cardiovascular, renal and metabolic function. RESULTS: The study population included 564 women with a median pregnancy prolongation of 10 days (interquartile range [IQR] 4-18) who were assessed at on average 8 months (IQR 6-12) postpartum. Pregnancy prolongation after diagnosis resulted in a decrease in infant mortality (adjusted odd ratio [aOR] 0.907, 95% CI 0.852-0.965 per day prolongation). This improvement in offspring outcome was associated with an elevated risk of moderately increased albuminuria (aOR 1.025, 95% CI 1.006-1.045 per day prolongation), but not with aberrant cardiac geometry, cardiac systolic or diastolic dysfunction, persistent hypertension or metabolic syndrome. CONCLUSION: Pregnancy prolongation in early-onset pre-eclampsia is associated with improved offspring outcome and survival. These effects do not appear to be deleterious to short-term maternal cardiovascular and metabolic function but are associated with a modest increase in risk of residual albuminuria. TWEETABLE ABSTRACT: Pregnancy prolongation in pre-eclampsia has only a limited effect on postpartum maternal cardiovascular function.

Diagnostic accuracy of first-trimester combined screening for early-onset and preterm pre-eclampsia at 8-10 compared with 11-13 weeks' gestation.

OBJECTIVES: To compare the ability of first-trimester combined screening for pre-eclampsia (PE) to predict early-onset and preterm PE when pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) were assessed before vs after 11 weeks' gestation. METHODS: This was a secondary analysis of a prospective cohort study of singleton pregnancies undergoing routine first-trimester screening conducted at Vall d'Hebron University Hospital, Barcelona, Spain, between October 2015 and September 2017. Demographic characteristics, obstetric history, maternal history and biophysical markers (mean uterine artery pulsatility index and mean arterial blood pressure (MAP)) were recorded at the first-trimester scan (at 11 + 0 to 13 + 6 weeks' gestation). Maternal serum concentrations of PAPP-A and PlGF were assessed from the routine first-trimester blood test (at 8 + 0 to 13 + 6 weeks). Women were classified into two groups depending on whether serum biomarkers were assessed at 8 + 0 to 10 + 6 weeks or at 11 + 0 to 13 + 6 weeks. Probability scores for early-onset and preterm PE were calculated by using two different algorithms: the multivariate Gaussian-distribution model and The Fetal Medicine Foundation (FMF) competing-risks model. Receiver-operating-characteristics (ROC) curves were produced and detection rates at fixed 5% and 10% false-positive rates were computed to compare the performance of these algorithms when PAPP-A and PlGF were assessed before vs after 11 weeks. RESULTS: Of the 2641 women included, serum biomarkers were assessed before 11 weeks in 1675 (63.4%) and at or after 11 weeks in 966 (36.6%). Of these, 90 (3.4%) women developed PE, including 11 (0.4%) cases of early-onset PE and 30 (1.1%) of preterm PE. Five (45.5%) cases of early-onset and 16 (53.3%) of preterm PE were identified in the group in which serum biomarkers were assessed at 8 + 0 to 10 + 6 weeks and six (54.5%) cases of early-onset and 14 (46.7%) of preterm PE in the group in which serum biomarkers were assessed at 11 + 0 to 13 + 6 weeks. In the prediction of early-onset and preterm PE using the Gaussian algorithm, no differences were observed between the areas under the ROC curves (AUCs) when PAPP-A and PlGF were measured before or after 11 weeks. In the prediction of early-onset and preterm PE using the FMF algorithm, no differences were observed between AUCs for any of the combinations used for risk calculation when the serum biomarkers were obtained before vs after 11 weeks, except for the combination of PAPP-A and MAP, which showed a greater AUC for the prediction of early-onset PE when PAPP-A was measured at or after 11 weeks. CONCLUSIONS: The prediction of early-onset and preterm PE is similar when serum biomarkers are measured before or after 11 weeks. This allows the use of a two-step approach for PE risk assessment that permits immediate risk calculation at the time of the first-trimester scan. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Development of a Third Trimester Contingent Prognostic Prediction Scheme for Suspected Early-Onset Pre-Eclampsia.

INTRODUCTION: Short-term prediction of pre-eclampsia (PE) using soluble FMS-like tyrosine kinase-1 (sFlt-1)/ placental growth factor (PlGF) ratio has high false-positive rate. Therefore, we developed a prognostic prediction tool that predicts early-onset PE leading to delivery within 1 week on pregnancies with an sFlt-1/PlGF ratio above 38 and compared it with an analogous model based on sFlt-1/PlGF ratio and with the 655 sFlt-1/PlGF ratio cutoff. METHODS: Cohort study of 363 singleton pregnancies with clinical suspicion of PE before 34 weeks of gestation, allowing repeated assessments (522). 213 samples with an sFlt-1/PlGF ratio above 38 were assessed to construct and identify the best-fit linear mixed model. N-terminal pro-B-type natriuretic peptide (NT-proBNP), sFlt-1 MoM, PlGF MoM, and sFlt-1/PlGF ratio combined with gestational age (GA) were assessed. RESULTS: None of the pregnancies with an sFlt-1/PlGF ratio of 38 or below developed early-onset PE (309 samples from 240 pregnancies). Conversely, 47 women of 213 assessments (22.1%) with an sFlt-1/PlGF ratio above 38 developed the assessed outcome. The selected model included sFlt-1 MoM, NT-proBNP, and GA. Differences in area under the curve were observed between the selected model and the GA + sFlt-1/PlGF model (p = 0.04). At an sFlt-1/PlGF ratio cutoff of 655, detection rate was 31.9% (15/47), while the selected model detection was 55.3% (26/47) (p = 0.008). DISCUSSION: Considering repeated assessments, the sFlt-1/PlGF ratio of 38 or below adequately ruled out early-onset PE, leading to delivery within 1 week. However, when sFlt-1/PlGF ratio is above 38, the prediction tool derived from linear mixed model based on GA, NT-proBNP, and sFlt-1 MoM, provided a better prognosis prediction than the sFlt-1/PlGF ratio.

Down-regulated FOXA1 in early-onset pre-eclampsia induces apoptosis, and inhibits migration and invasion of trophoblast cells.

BACKGROUND: Pre-eclampsia (PE) is a major cause of maternal and neonatal mortality and morbidity. Abnormal invasion of trophoblast cells is a major pathogenesis observed in PE. In the present study, we aimed to explore the association between forkhead box A1 (FOXA1) and early-onset pre-eclampsia (EOPE) and to determine the effects of FOXA1 on trophoblast cell apoptosis, migration and invasion. METHODS: Clinical data and placentas of patients with EOPE and normal pregnant women were collected in the First Affiliated Hospital of Hainan Medical College. The protein expression levels of FOXA1 in the clinical samples were evaluated by western blotting and immunohistochemistry. The effects of FOXA1 knockdown on HTR-8/SVneo cell apoptosis, migration and invasion were evaluated by flow cytometry, wound healing and transwell invasion assays, respectively. RESULTS: The western blot and immunohistochemical analysis showed that FOXA1 protein expression in placenta of EOPE group was significantly lower than that of normal group. The expression of FOXA1 in the placentas of EOPE and normal pregnant women was negatively correlated with systolic pressure and diastolic pressure. The expression of FOXA1 in EOPE and normal pregnant women was positively correlated with gestation weeks at delivery and neonatal birthweight. In vitro functional studies showed that silencing FOXA1 increased apoptosis, and inhibited the migration and invasion of HTR-8/SVneo cells. CONCLUSIONS: Down-regulation of FOXA1 in the placentas may indicate poor prognosis of EOPE. Silencing of FOXA1 induced apoptosis in trophoblast cells, and impaired the migratory and invasive capacity of trophoblast cells. FOXA1 may represent a potential therapeutic target for EOPE.

Comparison of the transcriptional profile in the decidua of early-onset and late-onset pre-eclampsia.

AIM: To compare early-onset pre-eclampsia (EOPE) and late-onset pre-eclampsia (LOPE) and provide insight into the pathophysiology of pre-eclampsia (PE). METHODS: Our recent work compared the transcriptomics in decidua of EOPE, LOPE and normal pregnancies (NP). RESULTS: We found there are a significant number of genes uniquely expressed in the decidua of EOPE and LOPE comparing with NP. Moreover, EOPE and LOPE have their distinct profiles. Unique EOPE-associated genes were mainly involved in apoptosis related pathways such as 'apoptosis' and 'Ras signaling pathway'. PIK3CB and BCL-2 are the core regulatory genes in EOPE decidua, their abnormal expression caused decidual abnormal apoptosis which is relevant to the pathogenesis of EOPE. Whereas, LOPE is a more complicated entity which has more special LOPE-associated genes involved in decidua differentiation, especially in 'gap junction pathway', 'vascular smooth muscle contraction' and 'long-term depression'. PIK3CB, FLT1, CBLC and ITGA7 are the core regulatory genes differentially expressed in EOPE decidua comparing with LOPE. CONCLUSION: In brief, the different decidual transcriptomics of EOPE and LOPE may correlate with their different etiology. These findings highlight the complex pathophysiology of PE and provide potential targets for a new treatment strategy in patients with PE.

The long noncoding RNA uc.294 is upregulated in early-onset pre-eclampsia and inhibits proliferation, invasion of trophoblast cells (HTR-8/SVneo).

Recently, a large number of long noncoding RNAs (lncRNAs) have been reported in human diseases that are evolutionarily conserved and are likely to play a role in many biological events including pre-eclampsia. In our previous research, we selected thousands of lncRNAs for their relationship with early-onset pre-eclampsia. Among these lncRNAs, a lncRNA named uc.294 attracted our attention, was once reported to specifically be expressed at a high level in the early-onset of pre-eclampsia. This study aims to investigate the function of uc.294 in early-onset pre-eclampsia and the possible mechanism. The uc.294 expression level in early-onset pre-eclampsia or in normal placenta tissues was evaluated by quantitative real-time polymerase chain reaction. To detect the proliferation, invasion, and apoptosis capacity of the trophoblast cells, we performed the Cell Counting Kit-8 assay, transwell assay, and flow cytometry, respectively. Here we report, for the first time, that uc.294 inhibits proliferation, invasion, and promotes apoptosis of trophoblast cells HTR-8/SVneo by working in key aspects of biological behaviors. However, how uc.294 acts to regulate gene functions in early-onset pre-eclampsia needs further exploration.

Cost-effectiveness of first-trimester screening with early preventative use of aspirin in women at high risk of early-onset pre-eclampsia.

OBJECTIVE: Pre-eclampsia (PE) remains a leading cause of maternal and fetal morbidity and mortality. A first-trimester screening algorithm predicting the risk of early-onset PE has been developed and validated. Early prediction coupled with initiation of aspirin at 11-13 weeks in women identified as high risk is effective at reducing the prevalence of early-onset PE. The aim of this study was to evaluate the cost-effectiveness of this first-trimester screening program coupled with early use of low-dose aspirin in women at high risk of developing early-onset PE, in comparison to current practice in Canada. METHODS: A decision analysis was performed based on a theoretical population of 387 516 live births in Canada in 1 year. The clinical and financial impact of early preventative screening using the Fetal Medicine Foundation algorithm for prediction of early-onset PE coupled with early (< 16 weeks) use of low-dose aspirin in those at high risk was simulated and compared with current practice using decision-tree analysis. The probabilities at each decision point and associated costs of utilized resources were calculated based on published literature and public databases. RESULTS: Of the theoretical 387 516 births per year, the estimated prevalence of early PE based on first-trimester screening and aspirin use was 705 vs 1801 cases based on the current practice. This was associated with an estimated total cost of C$9.52 million with the first-trimester screening program compared with C$23.91 million with current practice for the diagnosis and management of women with early-onset PE. This equals an annual cost saving to the Canadian healthcare system of approximately C$14.39 million. CONCLUSIONS: The implementation of a first-trimester screening program for PE and early intervention with aspirin in women identified as high risk for early PE has the potential to prevent a significant number of early-onset PE cases with a substantial associated cost saving to the healthcare system in Canada. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Maternal left ventricular hypertrophy and diastolic dysfunction and brain natriuretic peptide concentration in early- and late-onset pre-eclampsia.

OBJECTIVE: Pre-eclampsia (PE) is associated with maternal cardiac remodeling and diastolic dysfunction. The aim of this study was to assess and compare maternal left ventricular structure and diastolic function and levels of brain natriuretic peptide (BNP) in women with early-onset (< 34 weeks' gestation) vs those with late-onset (≥ 34 weeks' gestation) PE. METHODS: This was a prospective, cross-sectional, observational study of 30 women with early-onset PE, 32 with late-onset PE and 23 normotensive controls. Maternal cardiac structure and diastolic function were assessed by echocardiography and plasma levels of BNP were measured by enzyme immunoassay. RESULTS: Early- and late-onset PE were associated with increased left ventricular mass index and relative wall thickness compared with normotensive controls. In women with early-onset PE, the prevalence of concentric hypertrophy (40%) and diastolic dysfunction (23%) was also significantly higher (both P < 0.05) compared with women with late-onset PE (16% for both). Maternal serum BNP levels were significantly higher (P < 0.05) in women with early-onset PE and correlated with relative wall thickness and left ventricular mass index. CONCLUSIONS: Early-onset PE is associated with more severe cardiac impairment than is late-onset PE, as evidenced by an increased prevalence of concentric hypertrophy, diastolic dysfunction and higher levels of BNP. These findings suggest that early-onset PE causes greater myocardial damage, increasing the risk of both peripartum and postpartum cardiovascular morbidity. Although these cardiovascular effects are easily identified by echocardiographic parameters and measuring BNP, further studies are needed to assess their clinical utility. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Prediction of pre-eclampsia and its subtypes in high-risk cohort: hyperglycosylated human chorionic gonadotropin in multivariate models.

BACKGROUND: The proportion of hyperglycosylated human chorionic gonadotropin (hCG-h) to total human chorionic gonadotropin (%hCG-h) during the first trimester is a promising biomarker for prediction of early-onset pre-eclampsia. We wanted to evaluate the performance of clinical risk factors, mean arterial pressure (MAP), %hCG-h, hCGß, pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF) and mean pulsatility index of the uterine artery (Uta-PI) in the first trimester in predicting pre-eclampsia (PE) and its subtypes early-onset, late-onset, severe and non-severe PE in a high-risk cohort. METHODS: We studied a subcohort of 257 high-risk women in the prospectively collected Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) cohort. Multivariate logistic regression was used to construct the prediction models. The first model included background variables and MAP. Additionally, biomarkers were included in the second model and mean Uta-PI was included in the third model. All variables that improved the model fit were included at each step. The area under the curve (AUC) was determined for all models. RESULTS: We found that lower levels of serum PlGF concentration were associated with early-onset PE, whereas lower %hCG-h was associated with the late-onset PE. Serum PlGF was lower and hCGß higher in severe PE, while %hCG-h and serum PAPP-A were lower in non-severe PE. By using multivariate regression analyses the best prediction for all PE was achieved with the third model: AUC was 0.66, and sensitivity 36% at 90% specificity. Third model also gave the highest prediction accuracy for late-onset, severe and non-severe PE: AUC 0.66 with 32% sensitivity, AUC 0.65, 24% sensitivity and AUC 0.60, 22% sensitivity at 90% specificity, respectively. The best prediction for early-onset PE was achieved using the second model: AUC 0.68 and 20% sensitivity at 90% specificity. CONCLUSIONS: Although the multivariate models did not meet the requirements to be clinically useful screening tools, our results indicate that the biomarker profile in women with risk factors for PE is different according to the subtype of PE. The heterogeneous nature of PE results in difficulty to find new, clinically useful biomarkers for prediction of PE in early pregnancy in high-risk cohorts. TRIAL REGISTRATION: International Standard Randomised Controlled Trial number ISRCTN14030412 , Date of registration 6/09/2007, retrospectively registered.

Maternal serum irisin levels in early and late-onset pre-eclamptic and healthy pregnancies.

The aim of the study was to investigate whether plasma irisin concentrations differ between uncomplicated, early-onset and late-onset pre-eclamptic pregnancies. This cross-sectional study was conducted on 27 women with early-onset, 27 women with late-onset pre-eclampsia (PE) and 26 healthy pregnant women. Maternal levels of serum irisin were measured with the use of an enzyme-linked immunosorbent assay kit. The mean maternal serum irisin level of early-onset PE was significantly lower than late-onset PE (1.14 ± 0.56 vs. 1.46 ± 0.59, p < .05) and control subjects (1.14 ± 0.56 vs. 3.14 ± 0.81, p < 0.001). The mean maternal serum irisin level of late-onset PE was significantly lower than the control group (1.46 ± 0.59 vs. 3.14 ± 0.81, p < 0.001). Maternal serum irisin levels are decreased in pre-eclamptic pregnancies. Low levels of irisin may be the result or the cause of pathologic changes in PE. Impact statement What is already known on this subject? There are only two studies in the literature evaluating maternal serum irisin levels in pre-eclamptic pregnancies. One study demonstrated decreased maternal serum irisin levels in pre-eclamptic patients and the other found no significant difference between pre-eclamptic and control pregnancies. What do the results of this study add? The present study demonstrates that serum irisin levels were significantly lower in pre-eclampsia than normotensive pregnancies. Furthermore, we have also demonstrated for the first time that women with EO-PE had significantly lower levels of serum irsin than women with LO-PE. What are the implications of these findings for clinical practice and/or further research? Low levels of irisin may be the result or the cause of pathologic changes in pre-eclampsia. More studies are needed to evaluate the relationship between irisin and pre-eclampsia.

Identification of potential crucial genes associated with early-onset pre-eclampsia via a microarray analysis.

AIM: This study aimed to identify potential key genes related to early-onset pre-eclampsia (EOPET), and to obtain a better understanding of the molecular mechanisms of this disease. METHODS: The microarray dataset GSE44711 was obtained from the Gene Expression Omnibus, including eight chorionic villi samples from EOPET placentas and eight normal controls. The differentially expressed genes (DEG) were identified using the LIMMA package, and their potential functions were predicted by Gene Ontology (GO) enrichment analysis. Furthermore, protein-protein interactions (PPI) were obtained from the STRING database, and the PPI network was visualized by Cytoscape software. Then, significant modules were screened out from the PPI network, and GO enrichment analysis for DEG in modules was performed. Also, the potential transcription factors (TF) regulating DEG in modules were predicted, and TF-DEG network was visualized by Cytoscape. RESULTS: A total of 270 upregulated and 200 downregulated DEG were identified. A set of DEG was related to functions such as female pregnancy and hormone metabolic process (e.g. NGF). In PPI network modules, some DEG (e.g. SERPINE1 and FN1) were significantly associated with anatomical structure morphogenesis, and some other DEG (e.g. GZMA) were relevant to the immune system process. Furthermore, SERPINE1, NGF, and FN1 interacted with each other and were regulated by RELA. CONCLUSION: The DEG related to hormone metabolic process (e.g. NGF), anatomical structure morphogenesis (e.g. SERPINE1 and FN1), and immune system process (e.g. GZMA) are predicted to play significant roles in the progress of EOPET, which will be confirmed by experiments in future.

Uterine artery Doppler and sFlt-1/PlGF ratio: prognostic value in early-onset pre-eclampsia.

OBJECTIVE: To evaluate the performance of the mean uterine artery pulsatility index (UtA-PI) and the automated measurement of the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio for the prognostic assessment of both maternal and perinatal outcomes, and the time-to-delivery interval in early-onset (≤ 34 + 0 weeks) pre-eclampsia (PE) cases with attempted expectant management. METHODS: Fifty-one singleton pregnancies with early-onset PE were enrolled in the study. Mean UtA-PI and sFlt/PlGF ratio were measured at diagnosis. The association of each marker and their combinations with adverse maternal and perinatal outcomes was assessed by univariable comparisons and multivariable logistic regression analysis and time-to-delivery interval by survival analysis. RESULTS: Twenty-six (51%) had adverse maternal outcome and 14 (27%) had adverse perinatal outcome. At the time of onset of PE, only gestational age was significantly related to maternal complications. Gestational age at onset, mean UtA-PI and sFlt-1/PlGF ratio were significantly associated with perinatal complications, their combination reaching a sensitivity of 64% with 95% specificity, and an area under the receiver-operating characteristics curve of 0.89 (95% CI, 0.79-0.99). Regarding the time until delivery, 92% (12/13) of cases with sFlt-1/PlGF ratio > 655 and 39% (15/38) of cases with a ratio ≤ 655 delivered within the first 48 h, 8% (1/13) and 19% (7/38), respectively, delivered between 48 h and 7 days and 0% (0/13) and 42% (16/38), respectively, delivered after 7 days. CONCLUSION: Mean UtA-PI and sFlt-1/PlGF ratio in combination with gestational age are useful for the prognostic assessment of perinatal complications at the time of diagnosis of early-onset PE, but this combination has limited value for the prediction of maternal complications. Moreover, sFlt-1/PlGF ratio > 655 is closely related to the need to deliver within 48 h. [[ArtCopyrightmsg]].

Evaluating mean platelet volume and platelet distribution width as predictors of early-onset pre-eclampsia: a prospective cohort study.

BACKGROUND: Platelets are pivotal players in the pathophysiology of pre-eclampsia, with observed lower counts in affected individuals compared to normotensive counterparts. Despite advancements, the elusive cause of pre-eclampsia persists, motivating intense global efforts to identify reliable predictors. The currently recommended predictors of pre-eclampsia are not readily available in many resource-limited regions like Nigeria. This cohort study explores the potential of mean platelet volume (MPV) and platelet distribution width (PDW) as predictive markers of early-onset pre-eclampsia. Both platelet indices are components of the full blood count, a widely available routine test in pregnancy. METHODS: In this prospective cohort study, 648 healthy pregnant women attending antenatal care at Lagos State University Teaching Hospital and General Hospital Ifako-Ijaiye, Lagos, were recruited between 14-18weeks gestational age. Platelet count (PC), MPV and PDW were measured from their venous blood at recruitment. Participants were monitored until 34weeks of gestation, focusing on the occurrence of early-onset preeclampsia as the outcome of interest. Individuals with chronic medical conditions were excluded from the study. Data analysis involved t-test, Chi-Square and Mann-Whitney U tests, with statistical significance set at a confidence level of 95% and p < 0.05. Sensitivity, specificity, and predictive values were determined using receiver operating characteristics (ROC) curves. RESULTS: The incidence of early-onset pre-eclampsia in the study was 5.9%. Women who later developed pre-eclampsia had higher median MPV and PDW at 14-18weeks (10.8 fl. and 24.8 fl.) compared to normotensive women (8.1 fl. and 13.3 fl.)(p < 0.001). The median PC was lower in pre-eclamptics (190 × 103/µl) compared to normotensives(264 × 103/µl)(p < 0.001). Using Youden's test, cut-off values identified: PC < 211.5 × 103/µl, MPV > 9.4 fl., and PDW > 21.3 fl., predicted early-onset pre-eclampsia with 96.6% sensitivity and 65.6% specificity for PC; 79.3% sensitivity and 97.7% specificity for PDW; and 82.8% sensitivity and 96.1% specificity for MPV. Cut-offs of PC < 185 × 103/µl, MPV > 10.7 fl., and PDW > 28.3 fl., predicted severe early-onset pre-eclampsia with 100.0% sensitivity and 90.9% specificity for PC, 100.0% sensitivity and 99.4% specificity for MPV, and 100.0% sensitivity and 99.8% specificity for PDW, with corresponding area under the ROC curves of 0.983, 0.996, and 0.998, respectively. CONCLUSION: The evaluation of MPV and PDW between 14 and 18 weeks of gestation appears to be a reliable predictor of severe early-onset pre-eclampsia.

Subphenotypes of severe early-onset pre-eclampsia at hospital admission. A Latin American single-center exploratory latent class analysis.

OBJECTIVES: To identify distinct subphenotypes of severe early-onset pre-eclampsia in Latin America and analyze biomarker and hemodynamic trends between subphenotypes after hospital admission. METHODS: A single-center prospective cohort study was conducted in Colombia. The latent class analysis identified subphenotypes using clinical variables, biomarkers, laboratory tests, and maternal hemodynamics. Class-defining variables were restricted to measurements at and 24 h after admission. Primary and secondary outcomes were severe maternal and perinatal complications. RESULTS: Among 49 patients, two subphenotypes were identified: Subphenotype 1 (34.7%) had a higher likelihood of an sFlt-1/PlGF ratio ≤ 38, maternal age > 35, and low probability of TPR > 1400, CO <8, and IUGR; Subphenotype 2 (65.3%) had a low likelihood of an sFlt-1/PlGF ratio < 38, maternal age > 35, and high probability of TPR > 1400, CO <8, and IUGR. At 24 h postadmission, 64.7% of subphenotype 1 patients changed to subphenotype 2, while 25% of subphenotype 2 patients were reclassified as subphenotype 1. Subphenotype 1 displayed significant changes in CO and TPR, while subphenotype 2 did not. Maternal complications were more prevalent in subphenotype 2, with an odds ratio of 5.3 (95% CI: 1.3-22.0; P = 0.02), but no significant differences in severe neonatal complications were observed. CONCLUSIONS: We identified two distinct subphenotypes in a Latin American cohort of patients with severe early-onset pre-eclampsia. Subphenotype 2, characterized by higher TPR, sFlt-1, and serum creatinine and lower CO and PlGF at admission, was associated with worse maternal outcomes and appeared less modifiable after in-hospital treatment.

Materno-fetal outcome with PlGF above or below cutoff during second half of pregnancy in high-risk women.

OBJECTIVE: To evaluate the materno-fetal outcome of high-risk women using placental growth factor (PlGF). METHODS: This prospective cohort study was performed at a tertiary care hospital from September 2019 to April 2022. Women having clinically major or minor high risk factors of pre-eclampsia were included after consent. The placental growth factor (PlGF) was evaluated among high-risk women at 20-22, 28-30, and 34-36 weeks of gestation. They were followed throughout pregnancy until delivery. Materno-fetal outcome was evaluated based on PlGF levels at three different time points. The gestational age specific cutoff was derived. Those with levels below cutoff were taken as cases and those with values above cutoff were considered as controls. The odds of having complications if the PlGF was below cutoff were determined. RESULTS: Out of 287 high-risk women, 46 (16%) had pre-eclampsia (PE). The derived cutoff of PlGF was 224, 211, and 176 pg/mL at 20-22, 28-30, and 34-36 weeks, respectively. With PlGF below the cutoff at 20-22 weeks the odds of having HELLP syndrome was 15.8, with low PlGF at 28-30 weeks the odds for developing early onset PE was 11.3. Low PlGF was also significantly associated with preterm delivery (P < 0.001) and early onset FGR (P < 0.001). The sensitivity (91.7%) and specificity (78.5%) of PlGF for PE prediction was highest at 28-30 weeks. CONCLUSION: Low PlGF at 28-30 weeks was associated with high likelihood of developing early onset PE, and the PlGF cutoff should be gestational age specific.

First-trimester screening for pre-eclampsia and small for gestational age: A comparison of the gaussian and Fetal Medicine Foundation algorithms.

OBJECTIVE: Pre-eclampsia (PE) and small for gestational age (SGA) can be predicted from the first trimester. The most widely used algorithm worldwide is the Fetal Medicine Foundation (FMF) algorithm. The recently described Gaussian algorithm has reported excellent results although it is unlikely to be externally validated. Therefore, as an alternative approach, we compared the predictive accuracy for PE and SGA of the Gaussian and FMF algorithms. METHODS: Secondary analysis of a prospective cohort study was conducted at Vall d'Hebron University Hospital (Barcelona) with 2641 singleton pregnancies. The areas under the curve for the predictive performance for early-onset and preterm PE and early-onset and preterm SGA were calculated with the Gaussian and FMF algorithms and subsequently compared. RESULTS: The FMF and Gaussian algorithms showed a similar predictive performance for most outcomes and marker combinations. Nevertheless, significant differences for early-onset PE prediction favored the Gaussian algorithm in the following combinations: mean arterial blood pressure (MAP) with pregnancy-associated plasma protein A, MAP with placental growth factor, and MAP alone. CONCLUSIONS: The first-trimester Gaussian and FMF algorithms have similar performances for PE and SGA prediction when applied with all markers within a routine care setting in a Spanish population, adding evidence to the external validity of the FMF algorithm.

Comprehensive analyses of DNA methylation of the TIMP3 promoter in placentas from early-onset and late-onset preeclampsia.

Preeclampsia (PE) is classified into late-onset (LOPE) or early-onset (EOPE) according to gestational age of onset (≥34 or <34 weeks, respectively), and into preterm and term (delivery at <37 or ≥37 weeks, respectively). An imbalanced expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) impairs proper placentation in PE, and DNA methylation (DNAm) may affect their expression. We performed comprehensive analyses of DNAm and TIMP3 expression in placentas from PE reclassified into EOPE, LOPE, and term PE. We identified significant differentially methylated probes at the TIMP3 promoter in PE (28), EOPE (38), LOPE (20), and term PE (4) compared to controls, and in EOPE vs. LOPE (8). Moreover, we found a hypomethylation >70% in all groups (except EOPE vs. LOPE) and an increased TIMP3 expression in corresponding placental samples from PE, EOPE and LOPE compared to controls (p<0.05). Our findings highlight the role of DNAm of the TIMP3 promoter region regarding an epigenetic mechanism in PE.

The evaluation of some serum immunochemical markers in early onset pre-eclamptic women from Algeria.

PROBLEM: Progress in understanding the underlying mechanism responsible for the syndrome pre-eclampsia should reconfigure antenatal clinical care and minimize human and financial costs, yet at present there is no accurate theory that permits development of reliable predictive tests and prophylactic intervention to mitigate disease. To contribute to this ongoing effort, we aimed to assess various circulating markers pertaining to different theories. METHOD OF STUDY: Serum samples from thirty-four women with established early onset preeclampsia (ePE) were assessed in terms of oxidative stress (malondialdehyde- MDA), angiogenic status (PlGF & sFLT-1), complement system (The alternative pathway- AP50 and complement factor H- CFH) and circulating inflammatory markers (Interleukin 6- IL-6 & Procalcitonin- PCT). Control groups of gestational age matched patients included 20 gestational hypertensive (GH) and six normotensive pregnant women (NPW). RESULTS: Our work shows that PlGF is the only serum marker who does exhibit a continued decrease from NPW to GH to ePE (rpearson = -.428, p = .002). The ePE group had a profound impairment in circulating PlGF (66.93 ± 20.62 pg/ml) compared to GH (142.67 ± 39.79 pg/ml; p = .069) and NPW (636.83 ± 392.66 pg/ml; p = .002). Then, PlGF >71.29 pg/ml pg/ml is the cut-off that has the highest negative predictive value enabling exclusion of ePE (Sp 78%, Se 70%, p = .000). No such interesting results could be obtained with the other markers. CONCLUSION: Our data confirm that the angiogenic factor PlGF may be highly relevant in biological mechanisms underlying the development of ePE.

Predictive Value of Second-Trimester Maternal Lipid Profiling in Early-Onset Pre-eclampsia: A Prospective Cohort Study and Nomogram.

Purpose: Maternal lipid profile in second trimester has rarely been investigated in the risk assessment for pre-eclampsia (PE). Since early-onset PE often companied by much worse clinical outcomes, thus, we aimed to evaluate the predictive value of second-trimester maternal lipid profiling for early-onset PE. Methods: A prospective cohort study was conducted to measure the second-trimester maternal lipid profile of pregnant women from January to December 2019. The pairwise association between maternal lipid profile and PE onset or pregnancy termination time was quantified. Multiple logistic regression was preformed to define risk factors for early-onset PE, and a nomogram for early-onset PE was developed. The net benefit of our model was evaluated by calibration curve and decision curve analyses. Results: We enrolled 5,908 pregnant women and they were divided into healthy (n = 5,789), late-onset PE (n = 64), and early-onset PE (n = 55) groups. Total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c) were elevated in patients with PE, while high-density lipoprotein cholesterol (HDL-c) was decreased in patients with PE. TC, TG, and LDL-c were negatively correlated with PE onset time or gestational week at delivery. Receiver operating characteristic curves (ROC) defined the cutoff values of TG and HDL-c, and the final regression model included five statistically significant risk predictors for early-onset PE (maternal age of ≥35 years, multipara, pre-pregnancy body mass index (BMI) ≥25 kg/m2, second trimester TG ≥ 2.59 mmol/L and second trimester HDL-c ≤ 2.03 mmol/L. The nomogram had an excellent diagnostic performance (area under the curve = 0.912, sensitivity = 92.7%, and specificity = 76%) and was further validated with good calibration and positive net benefits in a decision curve analysis. Conclusions: An abnormally increased TG concentration and a decreased HDL-c concentration might serve as predictors of early-onset PE. Whether blood lipid-lowering measures can improve severe PE prognosis require further clarification.

Urinary Congophilia Confirmed With the CapCord Test Is Associated With Pregnancy Outcomes in Women With Early-Onset Pre-eclampsia.

Background: The association between misfolded proteins presented in the urine of pregnant women and pregnancy outcomes associated with early-onset pre-eclampsia (PE) remains unclear. This study aimed to investigate this association to examine the predictive value of urinary congophilia in the prognostication of pregnancy outcomes in this patient group in the Chinese population. Materials and Methods: This study included 1,397 patients, of which 46, 147, and 8 patients had gestational hypertension, PE, and chronic hypertension, respectively, and 1,196 were healthy controls undergoing the CapCord test for urinary congophilia. Patients with PE were divided into early- and late-onset groups. Patients with early-onset PE were further divided into iatrogenic prematurity and full-term delivery groups, the rates of urinary congophilia were compared between the groups; additionally, this patient group was divided into positive and negative urinary congophilia groups, clinical characteristics and pregnancy outcomes were compared between the groups. Univariate and multivariate logistic regression analyses were performed. Results: A total of 113 (76.9%) of 147 patients in the PE group had urinary congophilia; this rate was higher than that observed in the other three groups (χ2 = 780.892, p < 0.001). Gestational age in the early-onset PE group at both onset and delivery was lower than that in the late-onset PE group (p < 0.001). The rates of iatrogenic prematurity and hemolysis, elevated liver enzymes, and low platelet count syndrome were both higher in the early-onset PE group than in the late-onset PE group (p < 0.001, p < 0.05). In addition, the rate of urinary congophilia in the early-onset PE group was higher than that in the late-onset PE group (χ2 = 13.297, p < 0.001). Urinary congophilia was an independent risk factor for iatrogenic prematurity among patients with early-onset PE in both univariate [odds ratio (OR) 17.143, 95% confidence interval (CI): 4.719-62.271; p < 0.001] and multivariate (OR 18.174; 95% CI: 4.460-74.063; p < 0.001) analyses. Patients with early-onset PE and urinary congophilia were more likely than their counterparts without urinary congophilia to deliver at a lower gestational age, present with iatrogenic prematurity, and have a shorter latency period between onset and delivery. Conclusion: Urinary congophilia confirmed with the CapCord test may help predict pregnancy outcomes in patients with early-onset PE.