Comparison of immune-related gene signatures and immune infiltration features in early- and late-onset preeclampsia.

BACKGROUND: Preeclampsia, a severe pregnancy syndrome, is widely accepted divided into early- and late-onset preeclampsia (EOPE and LOPE) based on the onset time of preeclampsia, with distinct pathophysiological origins. However, the molecular mechanism especially immune-related mechanisms for EOPE and LOPE is currently obscure. In the present study, we focused on placental immune alterations between EOPE and LOPE and search for immune-related biomarkers that could potentially serve as potential therapeutic targets through bioinformatic analysis. METHODS: The gene expression profiling data was obtained from the Gene Expression Omnibus database. ESTIMATE algorithm and Gene Set Enrichment Analysis were employed to evaluate the immune status. The intersection of differentially expressed genes in GSE74341 series and immune-related genes set screened differentially expressed immune-related genes. Protein-protein interaction network and random forest were used to identify hub genes with a validation by a quantitative real-time PCR. Kyoto Encyclopedia of Genes and Genomes pathways, Gene Ontology and gene set variation analysis were utilized to conduct biological function and pathway enrichment analyses. Single-sample gene set enrichment analysis and CIBERSORTx tools were employed to calculate the immune cell infiltration score. Correlation analyses were evaluated by Pearson correlation analysis. Hub genes-miRNA network was performed by the NetworkAnalyst online tool. RESULTS: Immune score and stromal score were all lower in EOPE samples. The immune system-related gene set was significantly downregulated in EOPE compared to LOPE samples. Four hub differentially expressed immune-related genes (IL15, GZMB, IL1B and CXCL12) were identified based on a protein-protein interaction network and random forest. Quantitative real-time polymerase chain reaction validated the lower expression levels of four hub genes in EOPE compared to LOPE samples. Immune cell infiltration analysis found that innate and adaptive immune cells were apparent lacking in EOPE samples compared to LOPE samples. Cytokine-cytokine receptor, para-inflammation, major histocompatibility complex class I and T cell co-stimulation pathways were significantly deficient and highly correlated with hub genes. We constructed a hub genes-miRNA regulatory network, revealing the correlation between hub genes and hsa-miR-374a-5p, hsa-miR-203a-3p, hsa-miR-128-3p, hsa-miR-155-3p, hsa-miR-129-2-3p and hsa-miR-7-5p. CONCLUSIONS: The innate and adaptive immune systems were severely impaired in placentas of EOPE. Four immune-related genes (IL15, GZMB, IL1B and CXCL12) were closely correlated with immune-related pathogenesis of EOPE. The result of our study may provide a new basis for discriminating between EOPE and LOPE and acknowledging the role of the immune landscape in the eventual interference and tailored treatment of EOPE.

Lipidomic signatures in patients with early-onset and late-onset Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific clinical syndrome and can be subdivided into early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE) according to the gestational age of delivery. Patients with preeclampsia have aberrant lipid metabolism. This study aims to compare serum lipid profiles of normal pregnant women with EOPE or LOPE and screening potential biomarkers to diagnose EOPE or LOPE. METHODS: Twenty normal pregnant controls (NC), 19 EOPE, and 19 LOPE were recruited in this study. Untargeted lipidomics based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to compare their serum lipid profiles. RESULTS: The lipid metabolism profiles significantly differ among the NC, EOPE, and LOPE. Compared to the NC, there were 256 and 275 distinct lipids in the EOPE and LOPE, respectively. Furthermore, there were 42 different lipids between the LOPE and EOPE, of which eight were significantly associated with fetal birth weight and maternal urine protein. The five lipids that both differed in the EOPE and LOPE were DGTS (16:3/16:3), LPC (20:3), LPC (22:6), LPE (22:6), PC (18:5e/4:0), and a combination of them were a potential biomarker for predicting EOPE or LOPE. The receiver operating characteristic analysis revealed that the diagnostic power of the combination for distinguishing the EOPE from the NC and for distinguishing the LOPE from the NC can reach 1.000 and 0.992, respectively. The association between the lipid modules and clinical characteristics of EOPE and LOPE was investigated by the weighted gene co-expression network analysis (WGCNA). The results demonstrated that the main different metabolism pathway between the EOPE and LOPE was enriched in glycerophospholipid metabolism. CONCLUSIONS: Lipid metabolism disorders may be a potential mechanism of the pathogenesis of preeclampsia. Lipid metabolites have the potential to serve as biomarkers in patients with EOPE or LOPE. Furthermore, lipid metabolites correlate with clinical severity indicators for patients with EOPE and LOPE, including fetal birth weight and maternal urine protein levels.

Exploring the Importance of Differential Expression of Autophagy Markers in Term Placentas from Late-Onset Preeclamptic Pregnancies.

Preeclampsia (PE) is a serious hypertensive disorder affecting 4-5% of pregnancies globally, leading to maternal and perinatal morbidity and mortality and reducing life expectancy in surviving women post-gestation. Late-onset PE (LO-PE) is a clinical type of PE diagnosed after 34 weeks of gestation, being less severe than the early-onset PE (EO-PE) variant, although both entities have a notable impact on the placenta. Despite the fact that most studies have focused on EO-PE, LO-PE does not deserve less attention since its prevalence is much higher and little is known about the role of the placenta in this pathology. Via RT-qPCR and immunohistochemistry methods, we measured the gene and protein expressions of several macroautophagy markers in the chorionic villi of placentas from women who underwent LO-PE (n = 68) and compared them to normal pregnancies (n = 43). We observed a markedly distinct expression pattern, noticing a significant drop in NUP62 expression and a considerable rise in the gene and protein expressions of ULK1, ATG9A, LC3, ATG5, STX-17, and LAMP-1 in the placentas of women with LO-PE. A major induction of autophagic processes was found in the placental tissue of patients with LO-PE. Abnormal signaling expression of these molecular patterns in this condition aids in the understanding of the complexity of pathophysiology and proposes biomarkers for the clinical management of these patients.

Combined maternal risk factors and the Quadruple test to predict late-onset preeclampsia in pregnant Thai women.

BACKGROUND: This study aimed to evaluate the predictive power of a model combining maternal risk factors and the Quadruple screen test for late-onset preeclampsia (PE). METHODS: All pregnant women that received the Quadruple test for Down syndrome at 15+ 0-20+ 6 weeks' gestation were recruited. Maternal serum α-fetoprotein, ß-human chorionic gonadotropin, unconjugated estriol, and inhibin A were measured as multiples of the median. A logistic regression model was used to identify predictors associated with late-onset PE with severe features. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to assess the model's predictive ability. RESULTS: Fifty-five of the 2,000 pregnant women had PE, and 31 of 55 women had late-onset PE. Multivariate analysis identified maternal age ≥ 35 years, inhibin A, history of previous PE, history of infertile, cardiac disease, chronic hypertension, and thyroid disease as significant risk factors. The area under the curve of the receiver operating characteristic curve was 0.78. The likelihood ratio to predict late-onset PE was 49.4 (total score > 60). CONCLUSIONS: Our model combining serum inhibin A with maternal risk factors was useful in predicting late-onset PE. Close monitoring of these patients is recommended.

First trimester serum apolipoproteins in the prediction of late-onset preeclampsia.

Late-onset preeclampsia occurring after 34 weeks of gestation is the most common form of preeclampsia, but little is known about either etiology or prevention. Current detection methods for preeclampsia in early pregnancy have not shown promising results in detecting late-onset preeclampsia. The aim of this study was to assess whether apolipoproteins in combination with maternal medical history and biophysical factors can be used as an early detection method for late-onset preeclampsia. This nested case-cohort study was based at Odense University Hospital, Denmark. Women attending their first trimester scan were invited to participate if they understood Danish or English, were above the age of 18, and had singleton pregnancies. Blood pressure, maternal medical history, uterine artery pulsatility indices, and blood samples were collected at inclusion. Outcome data were collected from participants' medical files postpartum, and cases were selected when preeclampsia diagnostics were present. Serum samples were analyzed by targeted mass spectrometry using a biomarker panel consisting of 12 apolipoproteins. Logistic regression analyses were performed and finally receiver operating curves were completed. The cohort consisted of 27 cases and 194 normotensive controls, randomized from 340 eligible participants. Significant differences were found between the two groups' baseline characteristics but none of the apolipoproteins showed significant difference (p < 0.05). The ROC-curve combining maternal characteristics, mean arterial pressure and two apolipoproteins showed the best sensitivity of 55.5% at a 10% false-positive rate and an area under the curve of 0.873. In conclusion, apolipoproteins did not improve the detection of late-onset preeclampsia in a combined screening model.

Immunohistochemical Expression of Placental Vitamin D Receptors in Pregnancies Complicated by Early and Late-Onset Preeclampsia.

The aim of our study was to determine whether the immunohistochemical expression of placental vitamin D receptors is altered in pregnancies complicated by preeclampsia. Vitamin D receptor expression was immunohistochemically analysed in the placentas of three groups: a control group, and early- and late-onset preeclampsia groups. Total immunohistochemical intensity staining of placentas showed that the control group had a median vitamin D receptor (VDR) expression significantly higher than the placentas of mothers with early- and late-onset preeclampsia. There was no difference among the three groups in a semiquantitative analysis of VDR staining of the stroma only. Vitamin D receptors showed lower median expression in preeclampsia-affected pregnancies, especially early-onset preeclampsia. Therefore, Vitamin D receptor expression may be an important marker for normal placentation and preeclampsia onset.

Comparison of the Soluble fms-Like Tyrosine Kinase 1/Placental Growth Factor Ratio Alone versus a Multi-Marker Regression Model for the Prediction of Preeclampsia-Related Adverse Outcomes after 34 Weeks of Gestation.

INTRODUCTION: The objective of this retrospective study was to compare the predictive performance of the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio alone or in a multi-marker regression model for preeclampsia-related maternal and/or fetal adverse outcomes in women >34 weeks of gestation. METHODS: We analyzed the data collected from 655 women with suspected preeclampsia. Adverse outcomes were predicted by multivariable and univariable logistic regression models. The outcome of patients was evaluated within 14 days after presentation with signs and symptoms of preeclampsia or diagnosed preeclampsia. RESULTS: The full model integrating available, standard clinical information and the sFlt-1/PlGF ratio had the best predictive performance for adverse outcomes with an AUC of 72.6%, which corresponds to a sensitivity of 73.3% and specificity of 66.0%. The positive predictive value of the full model was 51.4%, and the negative predictive value was 83.5%. 24.5% of patients, who did not experience adverse outcomes but were classified as high risk by sFlt-1/PlGF ratio (≥38), were correctly classified by the regression model. The sFlt-1/PlGF ratio alone had a significantly lower AUC of 65.6%. CONCLUSIONS: Integrating angiogenic biomarkers in a regression model improved the prediction of preeclampsia-related adverse outcomes in women at risk after 34 weeks of gestation.

Hemodynamic pathways of gestational hypertension and preeclampsia.

Gestational hypertension and preeclampsia are the 2 main types of hypertensive disorders in pregnancy. Noninvasive maternal cardiovascular function assessment, which helps obtain information from all the components of circulation, has shown that venous hemodynamic dysfunction is a feature of preeclampsia but not of gestational hypertension. Venous congestion is a known cause of organ dysfunction, but its potential role in the pathophysiology of preeclampsia is currently poorly investigated. Body water volume expansion occurs in both gestational hypertension and preeclampsia, and this is associated with the common feature of new-onset hypertension after 20 weeks of gestation. Blood pressure, by definition, is the product of intravascular volume load and vascular resistance (Ohm's law). Fundamentally, hypertension may present as a spectrum of cardiovascular states varying between 2 extremes: one with a predominance of raised cardiac output and the other with a predominance of increased total peripheral resistance. In clinical practice, however, this bipolar nature of hypertension is rarely considered, despite the important implications for screening, prevention, management, and monitoring of disease. This review summarizes the evidence of type-specific hemodynamic profiles in the latent and clinical stages of hypertensive disorders in pregnancy. Gestational volume expansion superimposed on an early gestational closed circulatory circuit in a pressure- or volume-overloaded condition predisposes a patient to the gradual deterioration of overall circulatory function, finally presenting as gestational hypertension or preeclampsia-the latter when venous dysfunction is involved. The eventual phenotype of hypertensive disorder is already predictable from early gestation onward, on the condition of including information from all the major components of circulation into the maternal cardiovascular assessment: the heart, central and peripheral arteries, conductive and capacitance veins, and body water content. The relevance of this approach, outlined in this review, openly invites for more in-depth research into the fundamental hemodynamics of gestational hypertensive disorders, not only from the perspective of the physiologist or the scientist, but also in assistance of clinicians toward understanding and managing effectively these severe complications of pregnancy.

Comparison of clinical features and pregnancy outcomes in early- and late-onset preeclampsia with HELLP syndrome: a 10-year retrospective study from a tertiary hospital and referral center in China.

BACKGROUND: Early-onset preeclampsia (EO-PE) and late-onset preeclampsia (LO-PE) are different subtypes of preeclampsia. We conducted this study to analyze the similarities and differences in the clinical features and pregnancy outcomes in EO- and LO-PE with HELLP syndrome. METHODS: This was a retrospective study in a tertiary hospital. Eighty-three parturients with HELLP syndrome were allocated into two groups based on the timing of preeclampsia onset: EO-PE with HELLP (n = 47) and LO-PE with HELLP (n = 36). RESULTS: In total, 31.9% and 63.9% of women in the EO-PE with HELLP and LO-PE with HELLP groups, respectively, were asymptomatic at diagnosis (P = 0.004, OR = 0.265 (0.106-0.662)). Headache or visual symptoms were more frequent in the EO-PE group than in the LO-PE group (48.9% vs. 25%, P = 0.026, OR = 0.348 (0.135-0.896)). Women in the EO-PE with HELLP group had higher SBP and DBP than those in the LO-PE with HELLP group. Laboratory tests, including platelets, liver function, and hemolysis, which are the main indicators for the diagnosis of HELLP syndrome, showed almost no significant differences between the two groups, with kidney function being the only difference observed. Women in the EO-PE with HELLP group had higher Scr than those in the LO-PE with HELLP group. The degree of proteinuria was higher in the EO-PE group than in the LO-PE with HELLP group. The incidence of severe maternal complications was significantly higher in the EO-PE group than in the LO-PE with HELLP group (25.5% vs. 5.6%, P = 0.016, OR = 0.172 (0.036-0.824)). In total, 57.4% and 8.3% of neonates in the EO-PE and LO-PE with HELLP groups were admitted to the NICU, and the difference was statistically significant, even after adjustment for the delivery week (P = 0.009, OR = 0.830 (0.729-0.944)). Postpartum HELLP syndrome was more common in the LO-PE group than in the EO-PE group (30.6% vs. 4.3%, P = 0.001, OR = 9.9 (2.031-48.256)). CONCLUSIONS: Compared with LO-PE with HELLP patients, EO-PE with HELLP patients have more obvious kidney damage, higher blood pressure and a higher risk of adverse maternal and neonatal outcomes. Patients with LO-PE need to be alerted to the occurrence of HELLP syndrome after delivery.

Evaluating the predictive value of fetal Doppler indices and neonatal outcome in late-onset preeclampsia with severe features: a cross-sectional study in a resource-limited setting.

BACKGROUND: Preeclampsia constitutes a major health problem with substantial maternal and perinatal morbidity and mortality. The aim of this study was to detect the diagnostic efficacy of fetal Doppler in predicting adverse outcomes in severe late onset preeclampsia (LOP). METHODS: A prospective study was conducted among childbearing women who presented with severe LOP and matched controls. Umbilical artery (UA) and middle cerebral artery (MCA) Doppler indices including pulsatility index (PI), resistance index (RI), systolic/diastolic ratio (S/D) and cerebroplacental ratio (CPR) were measured. RESULTS: All UA indices were significantly higher in the case group compared to the controls (p < 0.001). UA PI and RI were significantly correlated with all neonatal adverse outcomes except cord pH status (p < 0.05). Abnormal CPR was the most sensitive index that positively correlated with intrauterine growth retardation (IUGR), low 5- minute Apgar score and neonatal intensive care unit admission (79, 72.8 and 73.3%, respectively). In the same context, Abnormal UA PI and RI represented the most specific tool for predicting IUGR, low 1- and 5- minutes Apgar score with positive predictive values were 52, 87 and 57%, respectively. CONCLUSION: In severe LOP, UA Doppler remains the preferential indicator for adverse birth outcomes with CPR is the best index that could be solely used for predicting such outcome.

Maternal Adverse Outcomes in Hypertensive Disorders of Pregnancy and Their Association with Serum Adiponectin and Redox Markers.

Background: Premature termination of pregnancy because of unmanageable maternal complications in hypertensive disorders of pregnancy (HDP) results in adverse neonatal outcome. Identification of biochemical derangements associated with maternal complications may help in the better medical management of the mother resulting in better neonatal outcomes. Method: Healthy pregnant women (C); pregnant women with gestational hypertension (GH), and preeclampsia (late [LP] and early [EP] onset) were studied. Maternal serum redox markers and adipokines were evaluated for their association with maternal complications. Results: Adiponectin levels were significantly raised in preeclampsia groups when compared with control and GH groups. Univariate and multivariate analysis confirmed that malondialdehyde (MDA) and total antioxidant status (TAS) were associated with eclampsia; adiponectin and TAS with HELLP syndrome; adiponectin, MDA and TAS with severe preeclampsia; and adiponectin with impaired renal function. Conclusion: We identified that increased serum adiponectin, MDA, and TAS were associated with adverse maternal outcomes.

[Glucose Metabolism-Derived Nicotinamide Adenine Dinucleotide Phosphate in Late-Onset Preeclampsia Placenta Tissue and Its Correlation with Oxidative Stress].

Objective: To study the changes in the expression of nicotinamide adenine dinucleotide phosphate (NADPH), a glucose metabolism-derived antioxidant, in late-onset preeclampsia (LOPE) placenta tissue and the correlation with oxidative stress. Methods: A total of 13 normal pregnant women and 13 pregnant women with LOPE who were hospitalized in the Obstetrics Department, the First Affiliated Hospital of Chongqing Medical University and who underwent elective cesarean section between November 2020 and October 2021 were included in the study. Placenta tissues were collected from the subjects. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) assay was done to determine the ROS levels in the placenta tissues of the LOPE group and the normal control group. Spectrophotometric analysis was conducted to determine the levels of NADPH, glutathione (GSH), and glucose, and the expressions and activities of glucose-6-phosphate dehydrogenase (G6PD) and phospho-gluconate dehydrogenase (PGD), key rate-limiting enzymes of the pentose phosphate pathway (PPP), in the placenta tissues of the LOPE group and the normal control group. Western blot was done to determine changes in the protein expressions of phosphofructokinase 1 (PFK1), a key rate-limiting enzyme of the glycolytic pathway, G6PD, and PGD in the placenta tissues from the two groups. Results: ROS levels in the placenta tissue of the LOPE group were significantly higher than those of the control group ( P<0.05). The levels of NADPH and GSH, two antioxidants, and glucose in the LOPE placenta were significantly higher than those of the control group ( P<0.05). The expression of PFK1 was significantly elevated in the LOPE group ( P<0.05). However, there were no significant differences in the activities and protein expression of G6PD and PGD between the two groups. Conclusion: Glucose metabolism reprogramming takes place in LOPE placenta tissue, which may be one of the causes of the abnormal elevation of NADPH and GSH.

There is a Strong Association between Early Preeclampsia and Congenital Heart Defects: A Large Population-Based, Retrospective Study.

OBJECTIVE: The aim of this study was to determine the prevalence of congenital heart defects and examine their association with preeclampsia (PE). METHODS: A clinical-based, retrospective study was conducted in Shenzhen between 2004 and 2017. Data were collected from Shenzhen Maternal and Child Health Hospital Medical Record Database. This study included all infants who were born at the hospital with or without heart defects and their mothers (N = 177,434 newborns). Data processing and analysis were performed by SPSS23.0 (Chicago, IL, USA). RESULTS: 6,852 women (3.9%) were diagnosed as PE and 1,289 newborns (7.30 per 1,000) have congenital heart disease (CHD). Prevalence of CHD in newborns of women with PE is 15.8 per 1,000 significantly higher than the overall prevalence (7.30 per 1,000). CHD in newborns has strong association with PE, especially early-onset PE (adjusted OR 3.29 and 95% CI 2.15-5.03) and severe PE (adjusted OR 2.75 and 95% CI 2.13-3.56). Among those with CHD, infants of preeclamptic women had higher prevalence of tetralogy of Fallot (43.78 vs. 28.14 per 100,000), atrial septal defect (335.67 vs. 53.93 per 100,000), ventricular dysplasia (102.16 vs. 89.69 per 100,000), and ventricular septal defect (525.39 vs. 212.22 per 100,000) than pregnant women with non-PE. CONCLUSION: PE, especially early-onset PE and severe PE, is strongly associated with offspring CHD. Our results help advance the current understanding of the association between PE and offspring CHD. So preventing PE and reducing PE may have a beneficial effect on the offspring CHD.

Plasma Endocan Levels in Early and Late-Onset Preeclampsia.

BACKGROUND: Preeclampsia (PE) may represent an inflammatory process. Endocan (ESM-1) is a marker of endothelial inflammation. We compared plasma endocan levels between PE and control groups and between early and late-onset PE. Study design: Maternal plasma endocan levels were measured in 41 preeclampsia (PE) pregnancies - 25 early-onset (<34 weeks); 16 late-onset (≥34 weeks), and 37 non-complicated pregnancies (22 matched with early-onset PE, 15 with late onset). Results: There was no significant differences between plasma endocan levels of patients with PE and control group (468.8(IQR: 169.7)ng/L vs 462.4(IQR: 321.1)ng/L, p > 0.05), between early and late-onset PE (458.8(221.8)ng/L vs 469.8(122.6)ng/L, p > 0.05), between early-onset PE and corresponding control group (458.8(221.8)ng/L vs 506.2(1481.9)ng/L, p > 0.05), or late-onset PE and corresponding control group (469.8(122.6)ng/L vs 451.0(85.1)ng/L, p > 0.05). Conclusion: There was no significant difference between endocan levels of early or late-onset PE compared with their corresponding control groups, nor between early and late-onset preeclampsia groups.

Validation of the 34-week gestation as definition of late onset preeclampsia: Testing different cutoffs from 30 to 37 weeks on a population-based cohort of 1700 preeclamptics.

INTRODUCTION: Early onset preeclampsia (EOP) and late onset preeclampsia (LOP) have been differentiated with a cut-point of ≤34 weeks. This classical definition has never been examined with respect to maternal characteristics by different gestational age cut-points. We examined maternal characteristics in a population-based cohort of 1736 preeclamptic deliveries at different gestational age cut-points from 30 to 37 weeks (CO30 to CO37). MATERIAL AND METHODS: Eighteen-year observational population-based historical cohort study (2001-2018). All consecutive births delivered at the Centre Hospitalier Universitaire Hospitalier Sud Reunion's maternity. Standardized epidemiological perinatal database. RESULTS: The incidence of EOP was lower in adolescents (1.8% vs 3.5%, odds ratio [OR] 0.50, P = .17). Conversely, the odds of LOP was increased for women over 35, beginning at C030 (OR 1.13, P = .02) and this effect (OR = 1.2) was still detectable at C037 (P = .06). Among primigravid women, the incidence of EOP was lower than LOP (OR ranging from 0.71 to 0.82 for different CO). Conversely, the incidence of LOP was higher (adjusted OR about 2.7 [CO30-CO34] with a rise to 3.3 at CO37 (P < .001). Women with EOP had a lower body mass index (BMI) as compared with LOP at CO34 and CO37. The adjusted OR (per 5 kg/m2 increment) declined from 1.06 to 1.03 from CO30 to C037 in EOP women. Conversely, for LOP, the adjusted odds ratio (aOR) increased from 1.04 to 1.06 from CO30 to CO37 (P < .001). Gestational diabetes mellitus was not associated with LOP at any cut-off (aOR 1.07, NS) but was protective against EOP from CO30 to CO34 (aOR 0.42, 0.61 and 0.73, respectively, P < .001). This protective effect disappeared at CO37. Chronic hypertension and history of preeclampsia were both EOP and LOP risks but with a much stronger effect for EOP (chronic hypertension: aOR 6.0-6.5, history of preeclampsia: aOR 12-17). CONCLUSIONS: The 34th week of gestation appears to provide a reasonable cut-point to differentiate between EOP and LOP. Additional research is needed to better describe the possible differences in the pathophysiology of these different phenotypes.

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.

Preeclampsia: a gestational cardiorenal syndrome.

It is generally accepted today that there are two different types of preeclampsia: an early-onset or placental type and a late-onset or maternal type. In the latent phase, the first one presents with a low output/high resistance circulation eventually leading in the late second or early third trimester to an intense and acutely aggravating systemic disorder with an important impact on maternal and neonatal mortality and morbidity; the other type presents initially as a high volume/low resistance circulation, gradually evolving to a state of circulatory decompensation usually in the later stages of pregnancy, with a less severe impact on maternal and neonatal outcome. For both processes, numerous dysfunctions of the heart, kidneys, arteries, veins and interconnecting systems are reported, most of them presenting earlier and more severely in early- than in late-onset preeclampsia; however, some very specific dysfunctions exist for either type. Experimental, clinical and epidemiological observations before, during and after pregnancy are consistent with gestation-induced worsening of subclinical pre-existing chronic cardiovascular dysfunction in early-onset preeclampsia, and thus sharing the pathophysiology of cardiorenal syndrome type II, and with acute volume overload decompensation of the maternal circulation in late-onset preeclampsia, thus sharing the pathophysiology of cardiorenal syndrome type 1. Cardiorenal syndrome type V is consistent with the process of preeclampsia superimposed upon clinical cardiovascular and/or renal disease, alone or as part of a systemic disorder. This review focuses on the specific differences in haemodynamic dysfunctions between the two types of preeclampsia, with special emphasis on the interorgan interactions between heart and kidneys, introducing the theoretical concept that the pathophysiological processes of preeclampsia can be regarded as the gestational manifestations of cardiorenal syndromes.

Histological Features of Shallow Placental Implantation Unify Early-Onset and Late-Onset Preeclampsia.

Preeclampsia is distinguishable from other hypertensive conditions of pregnancy by its high rates of decidual arteriopathy, the uterine type of chronic hypoxic placental injury, the occurrence of villous infarctions, and clusters of multinucleate trophoblasts in the maternal floor. To retrospectively study the clinical and placental phenotypes of 230 women with early-onset preeclampsia, 261 women with late-onset preeclampsia, and 5059 women without hypertension in pregnancy (comparative group), 24 clinical and 46 placental phenotypes were statistically compared (analysis of variance, χ2 with Bonferroni correction). The frequency of decidual arteriopathy (both hypertrophic and atherosis), patterns of chronic hypoxic placental injury, villous infarction, membrane laminar necrosis, membrane microscopic chorionic pseudocysts, clusters of maternal floor multinucleated trophoblasts, excessive number of extravillous trophoblasts, and intervillous thrombi was strikingly higher in both late-onset preeclampsia and early-onset preeclampsia than in the comparative group without hypertension in pregnancy. All 3 patterns of chronic hypoxic placental injury were 2- to 3-fold more common in preeclampsia. Although the preuterine pattern was as common in early-onset preeclampsia as it was in late-onset preeclampsia, the postuterine pattern was 2-fold more common in early-onset preeclampsia, and chronic villitis of unknown etiology was more common in late-onset preeclampsia than in the other 2 groups. Features of shallow placental implantation occurred at the same frequency in early-onset preeclampsia as in late-onset preeclampsia, which reflects an underlying common pathological mechanism in both subgroups of preeclampsia, while hypoxic lesions and patterns of placental injury were more common in early-onset preeclampsia than in late-onset preeclampsia, which correlates with more severe clinical outcomes of the former.

Wnt signaling pathway in early- and late-onset preeclampsia: evaluation with Dickkopf-1 and R-Spondin-3 glycoproteins.

OBJECTIVE: Wnt signaling has been identified as an essential pathway that can direct cell proliferation, migration, and tissue homeostasis. This study aimed to evaluate the role of Wnt signaling pathway in early-onset and late-onset preeclampsia (PE) using serum Dickkopf-1 and R-Spondin-3 glycoproteins. STUDY DESIGN: A total of 80 pregnant women were included in this study. The patients were divided into three groups: (1) control (2) early-onset PE, and (3) late-onset PE. The serum levels of Dickkopf-1 and R-Spondin-3 were measured using an enzyme-linked immunosorbent assay. RESULTS: Of the 80 pregnant women enrolled in the study, 27 were control, 27 had early-onset PE, and 26 had late-onset PE. No differences were found in the maternal age, gravida, parity, and body mass index among the groups (P = 0.536, 0.230, 0.202, and 0.642, respectively). The serum level of Dickkopf-1 was significantly higher in the early-onset PE group compared with the control group (P = 0.006). The serum level of Dickkopf-1 was statistically similar in control group compared to late-onset PE group (P = 0.064). However, no significant difference was found in the serum levels of Dickkopf-1 and R-Spondin-3 between the early- and late-onset PE groups (P > 0.05). Additionally, the Spearman's correlation analysis revealed a significant negative correlation between maternal serum level of Dickkopf-1 and maternal age (r = - 0.522, P = 0.005). CONCLUSION: The increased serum level of Dickkopf-1 might be associated with the process of pathogenesis of early-onset PE. Further studies would elucidate their exact roles in the pathogenesis of PE.

Low Serum Levels of HtrA3 at 15 Weeks of Gestation Are Associated with Late-Onset Preeclampsia Development and Small for Gestational Age Birth.

OBJECTIVE: The aim of this study was to investigate the potential utility of serum HtrA1 and HtrA3, serine proteases that are highly expressed in the developing placenta, at 15 and 20 weeks of gestation for predicting later development of adverse pregnancy outcomes of preeclampsia (PE), gestational hypertension (GHT), preterm birth (PTB), and small for gestational age (SGA) birth. METHODS: This is a nested case control study of 665 samples (330 controls, 335 cases) from the Adelaide SCOPE cohort. The cases included were 92 PE, 71 GHT, 56 PTB, and 116 SGA. Samples were assessed by ELISA and data adjusted for maternal age, BMI, socioeconomic index, hCG, and smoking status. Multivariate logistic regression was performed with other biochemical and biophysical parameters available for these samples. RESULTS: HtrA1 did not differ between the controls and cases. In contrast, HtrA3 was significantly lower at 15 weeks in pregnancies that later developed late-onset PE (LPE) or resulted in SGA birth, with an area under the ROC curve (AUC) of 0.716 and 0.790, respectively. The combination of HtrA3 with PAPP-A, uterine, and umbilical Doppler improved the AUC to 0.755 for LPE and 0.844 for SGA. CONCLUSION: HtrA3 at 15 weeks is associated with, and may be useful for, the early detection of LPE development and SGA birth.