Clinical Analysis of Risk Factors and Perinatal Outcomes in Recurrent Pre-Eclampsia with Severe Features.

To analyze the differences in risk factors and pregnancy outcomes between recurrent and initial pre-eclampsia(PE) with severe features. Data from recurrent (n = 128) and initial (n = 904) PE with severe features who terminated their pregnancy or gave birth at 20 weeks of gestation or later at the tertiary teaching hospital (Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital) from January 2016 to December 2022 were collected. Risk factors for recurrent PE with severe features and differences in pregnancy outcomes between the two groups were assessed using the chi-square test, student t-test, or nonparametric test. Independent risk factors for recurrent PE with severe features were further analyzed by logistic regression. (1) Logistic regression analysis identified 3 independent risk factors for recurrent PE with severe features: history of cesarean section, rural residence and chronic hypertension. In addition, assisted reproductive technology (ART) is an independent risk factor for initial PE with severe features; (2) The incidence of oligohydramnios, chorioamnionitis, preterm birth, stillbirth, fetal growth restriction (FGR) and abnormal umbilical blood flow was higher in the recurrent PE with severe features group than in the initial PE with severe features group(P < 0.05). In contrast, the incidence of premature rupture of membrane (PROM) and postpartum hemorrhage (PPH) was higher in the group of initial PE with severe features(P < 0.05); (3) In the recurrent PE with severe features group, gestational age(GA) of birth and birth weight were lower than those in the initial PE with severe features group(P < 0.05). Also, the incidence of mild asphyxia, the rate of neonatal intensive care unit (NICU) hospitalization, length of stay in NICU, and the rate of abandoning treatment in the recurrent PE with severe features group were higher than those in the initial PE with severe features group(P < 0.05). 3 independent risk factors was identified for recurrent PE with severe features: history of cesarean section, rural residence and chronic hypertension. Women with recurrent PE with severe features are more likely to have adverse perinatal outcomes than those with initial PE with severe features.

LC-MS/MS based untargeted lipidomics uncovers lipid signatures of late-onset preeclampsia.

The mechanisms underlying late-onset preeclampsia (LOPE) remain unknown. Metabolic disturbances have been implicated as a primary factor in LOPE development. Lipids have been shown to have great clinical value in recent years. This study aimed to use lipidomics to provide evidence for the etiology and potential therapeutic approaches for LOPE. Twenty patients with LOPE and 20 healthy controls were enrolled in this study. Placental lipidomic data were acquired using liquid chromatographymass spectrometry (LC-MS/MS), and the data were analyzed by weighted gene correlation network analysis (WGCNA) and statistical methods. Of 1508 identified lipids, 226 were differentially expressed between the LOPE and control groups. In the LOPE group, the abundance of most unsaturated triglycerides (TG) increased, whereas that of other lipids, including phosphatidylcholine (PC), sphingomyelin, and phosphatidylserine (PS) increased. The WGCNA implied that the correlation network module of lipids was highly related to clinical traits. Pathway analysis revealed that these dysregulated lipids are closely related to glycerophospholipid metabolism. Lipidomics may help identify the pathogenesis underlying placental dysfunction in LOPE patients and provide potential therapeutic targets in the future.

Analysis of risk factors related to extremely and very preterm birth: a retrospective study.

BACKGROUND: Preterm birth is one of the main causes of perinatal morbidity and mortality and imposes a heavy burden on families and society. The aim of this study was to identify risk factors and analyze birth conditions and complications of newborns born at < 32 gestational weeks for extremely preterm (EP) and very preterm (VP) birth in the clinic to further extend the gestational period. METHODS: We performed a retrospective cohort study and collected data from 1598 pregnant women and 1660 premature newborns (excluding 229 premature babies who died due to severe illness and abandonment) admitted to the Obstetrics and Gynecology Hospital Affiliated with Nanjing Medical University in China from 2016 to 2020. We compared women's and newborns' characteristics by t-tests and Chi-square tests for continuous and categorical variables, respectively. Multivariable logistic regression was performed to estimate the effects of risk factors on EP and VP birth. RESULTS: We identified 3 independent risk factors for EP birth: cervical incompetency (P < 0.001); multiple pregnancy (P < 0.01), primipara (P < 0.001). Additionally, we identified 4 independent risk factors for VP birth: gestational diabetes mellitus (GDM) (P < 0.05), preterm premature rupture of membrane (PPROM) (P < 0.01), fetal intrauterine distress (P < 0.001), and hypertensive disorder complicating pregnancy (HDCP) (P < 0.001). In addition, pairwise comparisons revealed statistically significant differences in the incidence rates of neonatal pneumonia, bronchopulmonary dysplasia (BPD) and sepsis between the 28-28 + 6 and 29-29 + 6 weeks of gestation groups (P < 0.05). Compared with 28-28 + 6 weeks of gestation, neonatal complications were significantly more common at < 26 weeks of gestation (P < 0.05). The incidence rates of neonatal intracranial hemorrhage(NICH), patent ductus arteriosus(PDA), patent foramen ovale(PFO), pneumonia, BPD and sepsis were significantly higher in the 26-26 + 6 and 27-27 + 6 gestational weeks than in the 28-28 + 6 gestational weeks (P < 0.05). CONCLUSION: PPROM, is the most common risk factor for EP and VP birth, and cervical insufficiency, multiple pregnancy, and primipara are independent risk factors for EP birth. Therefore, during pregnancy, attention should be devoted to the risk factors for PPROM, and reproductive tract infection should be actively prevented to reduce the occurrence of PPROM. Identifying the risk factors for cervical insufficiency, actively intervening before pregnancy, and cervical cervix ligation may be considered to reduce the occurrence of EP labor. For iatrogenic preterm birth, the advantages and disadvantages should be carefully weighed, and the gestational period should be extended beyond 28 weeks to enhance the safety of the mother and child and to improve the outcomes of preterm birth.

The Association Between Hypertensive Disorders in Pregnancy and the Risk of Developing Chronic Hypertension.

Objective: This meta-analysis comprehensively evaluated the association between hypertensive disorders in pregnancy (HDP) and the risk of developing chronic hypertension and the associations between specific types of HDP, including preeclampsia (PE) and gestational hypertension (GH), and the risk of developing chronic hypertension. Design: Systematic review and meta-analysis. Data Sources: The PubMed, Embase and Cochrane Library databases were searched from inception to August 20, 2021. Methods: Depending on heterogeneity, the combined odds ratio (OR) of the 95% confidence interval (CI) was obtained with a random-effects or fixed-effects model. We used meta-regression analysis to explore the sources of heterogeneity. We analyzed the OR value after adjusting for age and BMI at recruitment, prepregnancy BMI, age at first delivery, and other factors. Additionally, we evaluated the results of the subgroup analysis by the year of publication (< 2016, ≥ 2016), study design, sample size (< 500, ≥ 500), region (North and South America, Europe, and other regions) and NOS score (< 7, ≥ 7). Results: Our systematic review and meta-analysis comprehensively explored the relationships between HDP, GH, and PE and chronic hypertension. Twenty-one articles that included 634,293 patients were included. The results of this systematic review and meta-analysis suggested that women with a history of HDP are almost 3.6 times more likely to develop chronic hypertension than those without a history of HDP, women with a history of GH are almost 6.2 times more likely to develop chronic hypertension than those without a history of GH, and women with a history of PE are almost 3.2 times more likely to develop chronic hypertension than those without a history of PE. In addition, we further calculated the probability of developing chronic hypertension among patients with HDP or PE after adjusting for age and BMI at recruitment, prepregnancy BMI, age at first delivery, and other factors. The results suggested that women with a history of HDP are almost 2.47 times more likely to develop chronic hypertension than those without a history of HDP and that women with a history of PE are almost 3.78 times more likely to develop chronic hypertension than those without a history of PE. People in Asian countries are more likely to develop chronic hypertension after HDP or PE, while American people are not at high relative risk. Conclusion: These findings suggest that HDP, GH, and PE increase the likelihood of developing chronic hypertension. After adjustment for age and BMI at recruitment, prepregnancy BMI, age at first delivery, and other factors, patients with HDP or PE were still more likely to develop chronic hypertension. HDP may be a risk factor for chronic hypertension, independent of other risk factors. GH and PE, as types of HDP, may also be risk factors for chronic hypertension. Systematic Review Registration: [www.ClinicalTrials.gov], identifier [CRD42021238599].

LncRNA KCNQ1OT1 attenuates myocardial injury induced by hip fracture via regulating of miR-224-3p/GATA4 axis.

OBJECTIVE: This article aims to discuss the role of l KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) in myocardial injury caused by a hip fracture and further investigate its potential molecular mechanisms. METHODS: X-Ray and H&E staining are used to observe hip fracture and pathological changes of myocardial tissue. ELISA and kits are used to detect inflammatory cytokines, lactate dehydrogenase (LDH), and creatine kinase (CK) in serum. The proliferation and apoptosis of H9c2 are determined by CCK-8 and flow cytometry. RT-qPCR and Western blot are applied to quantitatively assess the expression of related genes. Bioinformatics analysis is performed to search the downstream target of KCNQ1OT1 and miR-224-3p. Furthermore, the interaction is verified by a luciferase reporter assay. RESULTS: A hip fracture model was successfully established. The high expression of inflammatory cytokines and cardiac injury markers indicated that hip fracture successfully induced myocardial injury. In TNF-ɑ treated cardiomyocyte model, high expression of KCNQ1OT1 promoted H9c2 cell proliferation and inhibited apoptosis. Furthermore, in the myocardial injury model rats induced by hip fracture, a high expression of KCNQ1OT1 reduced pathological damage in the myocardial tissue. Further research illustrated that miR-224-3p was the direct target of KCNQ1OT1, and GATA4 was the direct target of miR-224-3p. Importantly, functional research findings indicated that KCNQ1OT1 regulated myocardial injury caused by hip fracture via targeting the miR-224-3p/GATA4 axis. CONCLUSION: Our study demonstrates that the KCNQ1OT1 suppresses myocardial injury via mediating miR-224-3p/GATA4, which provides a latent target for myocardial injury treatment.

The COL-4A1 polypeptide destroy endothelial cells through the TGF-ß/PI3K/AKT pathway.

Preeclampsia (PE) is commonly considered as a placental disorder in pregnancy. Until now, the etiology and pathological mechanism of PE have remained ambiguous. Although PE can lead to a variety of maternal and infant complications, there are still no effective treatments. This study aimed to explore the correlation between the novel polypeptide COL-4A1 and PE, and to identify the underlying mechanism by which this polypeptide may function and to explore new therapeutic targets for PE. A rat model of PE was established and used to verify the function of the polypeptide COL-4A1 in vivo. Additionally, human umbilical vascular endothelial cells (HUVECs) were cultured with or without COL-4A1 and TNF-α (20 ng/ml). Cell Counting Kit-8 (CCK-8), wound-healing, Transwell and tube formation assays were used to evaluate cell proliferation, migration and angiopoiesis. RNA sequencing and mass spectrometry were conducted to explore the underlying downstream mechanism of COL-4A1. In vivo, COL-4A1 increased blood pressure and elevated the risk of fetal growth restriction (FGR) which was induced by lipopolysaccharide (LPS) in the rat model. In vitro, COL-4A1 significantly inhibited the proliferation and migration of HUVECs. After culture with COL-4A1, compared to control group the adhesive ability and level of reactive oxygen species (ROS) were enhanced and tube formation ability was decreased. Furthermore, Western blotting (WB) and pull-down assays were conducted to explore the underlying mechanism by which COL-4A1 functions, and the TGF-ß/PI3K/AKT pathway was identified as the potential pathway involved in its effects. In summary, these results revealed that the polypeptide COL-4A1 caused PE-like symptoms in cells and a rat model. Through the TGF-ß/PI3K/AKT pathway, COL-4A1 interferes with the pathogenesis of PE. Thus COL-4A1 is expected to become a potential target of PE, providing a basis for exploring the treatment of PE.

A Novel Peptide Ameliorates TNFα- and LPS-Induced Endothelia Dysfunction in Preeclampsia.

BACKGROUND: To investigate the protective effects of the novel peptide antiendothelial dysfunction peptide in preeclampsia (AEDPPE) on tumor necrosis factor α (TNFα)- and lipopolysaccharide (LPS)-induced injury in the vascular endothelium in preeclampsia. METHODS: The effects of AEDPPE on TNFα-induced vascular endothelial injury were assessed by enzyme-linked immunosorbent assay, quantitative real-time PCR, mitochondrial membrane potential assay, Cell Counting Kit-8 assay, THP-1 monocyte-human umbilical vein endothelial cell (HUVEC) adhesion assay, endothelial tube-forming assay, transcriptomic analysis, preeclamptic symptom analysis, and histological analysis in preeclampsia-like rat models induced by LPS. RESULTS: AEDPPE alleviated the upregulation of antiangiogenic factors including soluble fms-like tyrosine kinase-1, endothelin-1, and tissue plasminogen activator and attenuated the reduction in mitochondrial potential induced by TNFα in HUVECs. In addition, AEDPPE treatment counteracted the decrease in tube formation and decreased the numbers of THP-1 monocytes attached to HUVECs caused by TNFα. Mechanistically, cytokine-cytokine receptor interactions enriched many genes and the TNF signaling pathway may be involved in this phenomenon. Moreover, cotreatment with LPS and AEDPPE significantly reversed the preeclampsia-like phenotype including hypertension and proteinuria and improved the functions of the kidney and placenta. CONCLUSIONS: AEDPPE effectively ameliorated the vascular endothelial injury induced by TNFα and LPS in preeclampsia. We suggest that AEDPPE may be a novel therapeutic candidate for preeclampsia treatment. These findings demonstrate that AEDPPE may play an effective role in ameliorating vascular endothelial dysfunction and be a potential therapeutic agent for preeclampsia.

Integrated microarray analysis of key genes and a miRNA­mRNA regulatory network of early­onset preeclampsia.

Early­onset preeclampsia (EOPE) is a serious threat to maternal and foetal health. The present study aimed to identify potential biomarkers and targets for the treatment of EOPE. Expression profiles of placenta from patients with EOPE and healthy controls (GSE103542, GSE74341 and GSE44711) were downloaded from the Gene Expression Omnibus database. Integrated analysis revealed 246 genes and 28 microRNAs (miRNAs) that were differentially expressed between patients with EOPE and healthy controls. Differentially expressed genes (DEGs) were primarily enriched in 'biological processes', such as 'cell adhesion', 'female pregnancy', 'extracellular matrix organization' and 'response to hypoxia'. Significant pathways associated with DEGs primarily included 'focal adhesion', 'ECM­receptor interaction', 'PI3K­Akt signaling' and 'ovarian steroidogenesis'. A Protein­Protein Interaction network of DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins online database, and epidermal growth factor receptor, collagen α­1(I) chain, secreted phosphoprotein 1, leptin (LEP), collagen α­2(I) chain (COL1A2), plasminogen activator inhibitor 1 (SERPINE1), Thy­1 membrane glycoprotein, bone morphogenetic protein 4, vascular cell adhesion protein 1 and matrix metallopeptidase 1 were identified as hub genes. The alterations of hsa­miR­937, hsa­miR­148b*, hsa­miR­3907, hsa­miR­367*, COL1A2, LEP and SERPINE1 in placenta were validated using our local samples. Our research showed that the expression of hsa­miR­937, hsa­miR­1486*, hsa­miR­3907, hsa­miR­367* and hub genes in the placenta were closely associated with the pathophysiology of EOPE. hsa­miR­937, hsa­miR­1486*, hsa­miR­3907, hsa­miR­367* and hub genes could serve as biomarkers for diagnosis and as potential targets for the treatment of EOPE.

Neonatal Adverse Outcomes of Induction and Expectant Management in Fetal Growth Restriction: A Systematic Review and Meta-Analysis.

Background and Objective: Fetal growth restriction (FGR) is a pathological condition in which the fetus cannot reach its expected growth potential. When it is diagnosed as a suspected FGR, it remains an unsolved problem whether to direct induction or continue expectant management. To effectively reduce the incidence of neonatal adverse outcomes, we aimed to evaluate whether either method was associated with a lower incidence of neonatal adverse outcomes. Methods: We searched the relevant literature through the PubMed, Web of Science, and Cochrane Library from inception to January 10, 2020. We defined induction as the experimental group and expectant management as the control group. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects models owing to heterogeneity. Furthermore, we conducted a sensitivity analysis to explore the robustness of the included literature. We used the Newcastle-Ottawa scale (NOS) to evaluate the quality of the available studies. We applied the funnel plot to describe the publication bias. Additionally, subgroup analysis based on the study method, sample size, area, NOS score, Apgar score <7 at 5 min, definition of suspected FGR, severity, and neonatal adverse outcomes were performed to further evaluate the differences between the induction and expectant management. Results: Our study included a total of eight articles with 6,706 patients, which consisted of four randomized controlled trials (RCTs), three retrospective cohort studies, and one prospective cohort study. The total pooled OR and 95% CI between the induction group and the expected management group was 1.38 (95% CI, 0.84-2.28) in the random model. The heterogeneity was I 2 = 84%, P < 0.01. The sensitivity analysis showed that the neonatal adverse outcomes of induction vs. expectant management still presented similar outcomes after omitting of any one of these studies. The funnel plot and linear regression equation showed that there was no publication bias in our study (P = 0.75). Subgroup analysis showed that induction increased the neonatal adverse outcome risks of hypoglycemia and respiratory insufficiency (ORneonatal hypoglycaemia = 8.76, 95% CI: 2.57-29.90; ORrespiratory insufficiency = 1.74, 95% CI: 1.35-2.24, respectively). However, no significant differences were observed based on the other subgroups (all P > 0.05). Conclusion: Regardless of induction or expectant management of a suspected FGR, the neonatal adverse outcomes showed no obvious differences. More studies should be conducted and confounding factors should be taken into consideration to elucidate the differential outcomes of the two approaches for suspected FGR.

Roles of microRNAs in preeclampsia.

Preeclampsia (PE) is a complex disorder that is characterized by hypertension and proteinuria after the 20th week of pregnancy, and it causes most neonatal morbidity and perinatal mortality. Most studies suggest that placental dysfunction is the main cause of PE. However, genetic factors, immune factors, and systemic inflammation are also related to the pathophysiology of this syndrome. Thus far, the exact pathogenesis of PE is not yet fully understood, and intense research efforts are focused on PE to elucidate the pathophysiological mechanisms. MicroRNAs (miRNAs) refer to small single-stranded and noncoding molecules that can negatively regulate gene expression, and miRNA regulatory networks play an important role in diverse pathological processes. Many studies have confirmed deregulated miRNA in pregnant patients with PE, and the function and mechanism of these differentially expressed miRNA are gradually being revealed. In this review, we summarize the current research about miRNA involved in PE, including placenta-specific miRNA, their predictive value, and their function in the development of PE. This review will provide fundamental evidence of miRNA in PE, and further studies are necessary to explore the roles of miRNA in the early diagnosis and treatment of PE.

Down-regulated expressed protein HMGB3 inhibits proliferation and migration, promotes apoptosis in the placentas of fetal growth restriction.

Fetal growth restriction (FGR) is one of the major complications of pregnancy, which can lead to serious short-term and long-term diseases. High-mobility group box 3 (HMGB3) has been found to contribute to the development of many cancers. However, the role of HMGB3 in the pathogenesis of FGR is blank. Here, we measured the expression level of HMGB3 in the placenta tissues of six normal pregnancies and five FGR patients by western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). CCK8 assay, transwell assay and flow cytometry were used to detect the functional effects of overexpression and silencing of HMGB3 on the HTR8/SVneo trophoblast cell line. The results showed that the protein levels of HMGB3 were significantly decreased in FGR placentas compared to normal controls, while mRNA levels of HMGB3 were not significantly altered. Furthermore, when overexpressed of protein HMGB3 of the trophoblast cells, the proliferation and migration abilities were significantly promoted, and the apoptosis abilities of these cells were statistically inhibited. Cell functional experiments showed the opposite results when the expression of HMGB3 was silent. And the expression of cell function-related genes PCNA, Ki67, Tp53, Bax, MMP-2 and E-cadherin was observed to show corresponding changes by qRT-PCR. The results of mass spectrometry showed that HMGB3 may directly or indirectly interact with 71 proteins. In summary, our results indicated that HMGB3 might be of very great significance to the pathogenesis of FGR and might play the role by leading the dysfunction of placental villous trophoblast cells and through the interaction with some other proteins.

Comparative proteomics of umbilical vein blood plasma from normal and gestational diabetes mellitus patients reveals differentially expressed proteins associated with childhood obesity.

PURPOSE: Offspring obesity is one of long-term complications of gestational diabetes mellitus (GDM). The aim of this study is to identify proteins differentially expressed in the umbilical vein blood plasma, which could become markers for early diagnosis of childhood obesity. EXPERIMENTAL DESIGN: Umbilical vein plasma samples were collected from 30 control and 30 GDM patients in 2007-2008 whose offspring were suffering from obesity at 6-7 years old. Multiplexed isobaric tandem mass tag labeling combined with LC-MS/MS was used to identify differentially expressed proteins. Ingenuity pathway analysis was performed to identify canonical pathways, biological functions, and networks of interacting proteins. Western blotting was used to verify the expression of three selected proteins. RESULTS: A total of 318 proteins were identified, of which 12 proteins were upregulated in GDM group while 24 downregulated. Lipid metabolism was the top category identified by ingenuity pathway analysis. Three randomly chosen proteins were validated by Western blotting, which were consistent with LC-MS. CONCLUSION: There are significant differences of protein profile in the umbilical vein blood plasma between normal and GDM patients with obese offspring. The results indicate that a variety of proteins and biological mechanisms may contribute to childhood obesity.

Comparative proteomic profile of the human placenta in normal and fetal growth restriction subjects.

BACKGROUND: Fetal growth restriction (FGR) is the main cause of intrauterine fetal death and the second leading cause of death in the neonatal period. A large body of evidence suggests that FGR may be associated with the placenta, although its etiology and pathogenesis remain to be fully elucidated. METHODS AND RESULTS: To better understand the molecular mechanisms underlying the pathological development of the placenta in FGR, we used tandem mass tags (TMTs) to construct a large-scale comparative proteomic profile of human placentas from normal and FGR pregnancies. A total of 1,198 kinds of proteins were identified in the control and FGR placentas, of which 95 were differentially expressed between two groups. Ingenuity Pathway Analysis (IPA) was used to organize these differentially expressed proteins into networks of interacting proteins and to identify the modules of functionally related proteins. Western blotting was used to verify the expression patterns of several randomly selected proteins. CONCLUSION: The placentas of women with FGR displayed significant proteome differences compared with normal pregnancy. The results indicate that a variety of mechanisms and proteins may contribute to the development of FGR. Further studies and validations are required to elucidate the exact roles of these proteins in FGR pathogenesis.