Risk Factors for Postpartum Hemorrhage in Severe Pre-Eclampsia: A Retrospective Single-Centre Study of 1953 Cases.

BACKGROUND Severe pre-eclampsia (sPE) and postpartum hemorrhage (PPH) in pregnancy have serious impact on maternal and fetal health and life. Co-occurrence of sPE and PPH often leads to poor pregnancy outcomes. We explored risk factors associated with PPH in women with sPE. MATERIAL AND METHODS This retrospective study included 1953 women with sPE who delivered at the Women's Hospital of Nanjing Medical University between April 2015 and April 2023. Risk factors for developing PPH in sPE were analyzed, and subgroups were analyzed by delivery mode (cesarean and vaginal). RESULTS A total of 197 women with PPH and 1756 women without PPH were included. Binary logistic regression results showed twin pregnancy (P<0.001), placenta accreta spectrum disorders (P=0.045), and placenta previa (P<0.001) were independent risk factors for PPH in women with sPE. Subgroup analysis showed risk factors for PPH in cesarean delivery group were the same as in the total population, but vaginal delivery did not reduce risk of PPH. Spinal anesthesia reduced risk of PPH relative to general anesthesia (P=0.034). Vaginal delivery group had no independent risk factors for PPH; however, magnesium sulfate (P=0.041) reduced PPH incidence. CONCLUSIONS Women with twin pregnancy, placenta accreta spectrum disorders, placenta previa, and assisted reproduction with sPE should be alerted to the risk of PPH, and spinal anesthesia should be preferred in cesarean delivery. Magnesium sulfate should be used aggressively in women with sPE; however, the relationship between magnesium sulfate and PPH risk needs further investigation.

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.

Aspirin for the prevention of preeclampsia: A systematic review and meta-analysis of randomized controlled studies.

Background: The results of randomized controlled studies on aspirin for the prevention of preeclampsia (PE) are conflicting, and some of the related meta-analyses also have limitations or flaws. Data sources: A search was conducted on PubMed, Embase, and Cochrane Central Register of Controlled Trials databases, with no time or language restrictions. Study eligibility criteria: Randomized controlled studies comparing aspirin for the prevention of PE were conducted. Methods: Systematic reviews were performed according to the Cochrane Manual guidelines. A fixed-effects model or a random-effects model was chosen to calculate pooled relative risks with 95% confidence intervals based on the heterogeneity of the included studies. The study aimed to investigate the effect of aspirin on the development of PE in high-risk and general populations of women. Publication bias was assessed by funnel plots. All included studies were assessed for bias by the Cochrane Manual of Bias Assessment. Subgroup analyses were conducted on the aspirin dose, time of initial aspirin intervention, and the region in which the research was conducted, to explore the effective dose of aspirin and time of initial aspirin intervention and to try to find sources of heterogeneity and publication bias. Results: A total of 39 articles were included, including 29 studies involving pregnant women at high risk for PE (20,133 patients) and 10 studies involving a general population of pregnant women (18,911 patients). Aspirin reduced the incidence of PE by 28% (RR 0.72, 95% CI 0.62-0.83) in women at high risk for PE. Aspirin reduced the incidence of PE by 30% in the general population (RR 0.70, 95% CI 0.52-0.95), but sensitivity analyses found that aspirin in the general population was not robust. A subgroup analysis showed that an aspirin dose of 75 mg/day (RR 0.50, 95% CI 0.32-0.78) had a better protective effect than other doses. Starting aspirin at 12-16 weeks (RR 0.62, 95% CI 0.53-0.74) of gestation or 17-28 weeks (RR 0.62, 95% CI 0.44-0.89) reduced the incidence of PE by 38% in women at high risk for PE, but the results were more reliable for use at 12-16 weeks. Heterogeneity and publication bias of the included studies may be mainly due to the studies completed in Asia. Conclusion: Aspirin is recommended to be started at 12-16 weeks of pregnancy in women at high risk for PE. The optimal dose of aspirin to use is 75 mg/d. Systematic review registration: [www.ClinicalTrials.gov], identifier [CRD42022319984].

Dissecting the Roles of Lipids in Preeclampsia.

Preeclampsia is a multisystem pregnancy disorder that is characterized by different degrees of placental malperfusion, with release of antiangiogenic factors into the circulation, leading to maternal vascular endothelial injury and high blood pressure. As a major cause of maternal and perinatal mortality and morbidity worldwide, once preeclampsia has been diagnosed, there are no curative treatments except for delivery. Lipids serve as ubiquitous and multifunctional metabolites that are integral and essential to many diverse functions on both a cellular and organismal level. Lipid metabolic abnormalities have emerged as potential risk factors for the development and progression of preeclampsia. This review comprehensively examines decades of discovery to illuminate the roles of lipids and dysregulation in the levels of various lipid classes in preeclampsia. In addition, the roles of lipids are summarized to further understand the pathogenic mechanisms of preeclampsia. Overall, the review highlights the promising potential of pathophysiology and lipid-targeting therapeutic strategies in preeclampsia.

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].

Conservative management versus cesarean hysterectomy in patients with placenta increta or percreta.

OBJECTIVE: To compare conservative management and cesarean hysterectomy in patients with placenta increta or percreta. MATERIALS AND METHODS: In this multicenter retrospective study, we recorded data on 2219 patients with placenta increta or percreta from 20 tertiary care centers in China from 1 January 2011 to 31 December 2015. Propensity score analysis was used to control for baseline characteristics. We divided patients into conservative management (C) and hysterectomy (H) groups. The primary outcome was operative/postoperative maternal morbidity; secondary outcomes were maternal-neonatal outcomes. RESULTS: In total, 17.9% (398/2219) of patients had placenta increta and percreta; 82.1% (1821/2219) of the patients were in group C. After propensity score matching, 140 pairs of patients from the two groups underwent one-to-one matching. Group C showed less average blood loss within 24 h of surgery (1518 ± 1275 vs. 4309 ± 2550 ml in group H, p<.001). There were more patients with blood loss >1000 ml in group H than in group C (93.6% [131/140] vs. 61.4% [86/140], p<.001). More patients received blood transfusions in group H than in group C (p=.014). There was no significant difference between the groups in terms of bladder injury, postoperative anemia, fever, and disseminated intravascular coagulation. Neonatal outcomes in the two groups were similar. CONCLUSION: Either conservative management or hysterectomy should be considered after thorough evaluation and detailed discussion of risks and benefits. A balance between bleeding control and fertility can be achieved.

A randomized controlled trial of low-dose aspirin for the prevention of preeclampsia in women at high risk in China.

BACKGROUND: Low-dose aspirin has been the most widely studied preventive drug for preeclampsia. However, guidelines differ considerably from country to country regarding the prophylactic use of aspirin for preeclampsia. There is limited evidence from large trials to determine the effect of 100 mg of aspirin for preeclampsia screening in women with high-risk pregnancies, based on maternal risk factors, and to guide the use of low-dose aspirin in preeclampsia prevention in China. OBJECTIVE: The Low-Dose Aspirin in the Prevention of Preeclampsia in China study was designed to evaluate the effect of 100 mg of aspirin in preventing preeclampsia among high-risk pregnant women screened with maternal risk factors in China, where preeclampsia is highly prevalent, and the status of low-dose aspirin supply is commonly suboptimal. STUDY DESIGN: We conducted a multicenter randomized controlled trial at 13 tertiary hospitals from 11 provinces in China between 2016 and 2019. We assumed that the relative reduction in the incidence of preeclampsia was at least 20%, from 20% in the control group to 16% in the aspirin group. Therefore, the targeted recruitment number was 1000 participants. Women were randomly assigned to the aspirin or control group in a 1:1 allocation ratio. Statistical analyses were performed according to an intention-to-treat basis. The primary outcome was the incidence of preeclampsia, diagnosed along with a systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg after 20 weeks of gestation, with a previously normal blood pressure (systolic blood pressure of <140 mm Hg and diastolic blood pressure of <90 mm Hg), and complicated by proteinuria. The secondary outcomes included maternal and neonatal outcomes. Logistic regression analysis was used to determine the significance of difference of preeclampsia incidence between the groups for both the primary and secondary outcomes. Interaction analysis was also performed. RESULTS: A total of 1000 eligible women were recruited between December 2016 and March 2019, of which the final 898 patients were analyzed (464 participants in the aspirin group, 434 participants in the control group) on an intention-to-treat basis. No significant difference was found in preeclampsia incidence between the aspirin group (16.8% [78/464]) and the control group (17.1% [74/434]; relative risk, 0.986; 95% confidence interval, 0.738-1.317; P=.924). Likewise, adverse maternal and neonatal outcomes did not differ significantly between the 2 groups. Meanwhile, the incidence of postpartum hemorrhage between the 2 groups was similar (6.5% [30/464] in the aspirin group and 5.3% [23/434] in the control group; relative risk, 1.220; 95% confidence interval, 0.720-2.066; P=.459). We did not find any significant differences in preeclampsia incidence between the 2 groups in the subgroup analysis of the different risk factors. CONCLUSION: A dosage of 100 mg of aspirin per day, initiated from 12 to 20 gestational weeks until 34 weeks of gestation, did not reduce the incidence of preeclampsia in pregnant women with high-risk factors in China.

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.

The Association Between ABO Blood Group and Preeclampsia: A Systematic Review and Meta-Analysis.

Objective: This meta-analysis comprehensively evaluated the association between ABO blood group and the risk of preeclampsia (PE). Design: Systematic review and meta-analysis. Data sources: PubMed, Web of Science, and ScienceDirect databases from their inception to September 23, 2020. Methods: Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were obtained through random-effects and fixed-effects models according to heterogeneity. Meta-regression analysis was applied to explore the source of heterogeneity. We conducted a subgroup analysis by the publication year, study design, state, and Newcastle-Ottawa Scale (NOS) score. In addition, we calculated the rate of each ABO blood group in PE by total pooled effects. Results: A total of 12 articles with 714,153 patients were included in our analysis. Compared with people without PE (control group), the O blood group presented a lower risk of PE (OR 0.95, 95% CI 0.93-0.97). The AB (OR 1.46, 95% CI 1.12-1.91) blood group presented a higher risk. However, the total pooled OR and 95% CI for the A (OR 1.02, 95% CI 0.90-1.16) and B (OR 1.02, 95% CI 0.98-1.05) blood groups were not significant. The funnel plot and linear regression equation showed that there was no publication bias for the O, A, or B blood groups (all P > 0.05). However, the funnel plot and linear regression equation for the AB blood group were obviously asymmetric (P < 0.05), and the publication bias persisted even after the trim-and-fill method was applied (P < 0.05). Multivariable meta-regression analysis did not find a specific source of heterogeneity. The A blood group showed an association with early-onset PE (OR 0.53, 95% CI 0.33-0.83), and the other blood groups showed no significant differences. In PE, the rates of the O, A, B, and AB blood groups decreased gradually (0.39, 0.33, 0.19, 0.07). Conclusion: These findings suggest that pregnant women with AB blood group are more likely to develop PE, and more attention should be paid to AB blood group whose blood pressure is high but not sufficient to diagnose PE. Systematic Review Registration: Prospero CRD42021227930.

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.

High expression of an unknown long noncoding RNA RP11-290L1.3 from GDM macrosomia and its effect on preadipocyte differentiation.

AIMS: Gestational diabetes mellitus (GDM)-induced macrosomia is predominantly characterized by fat accumulation, which is closely related to adipocyte differentiation. An unknown long noncoding RNA RP11-290L1.3, referred to as RP11, was identified to be dramatically upregulated in the umbilical cord blood of women with GDM-induced macrosomia in our previous study. We conducted this study to identify the function of RP11 in GDM-induced macrosomia. METHODS: The effects of RP11 gain- and loss-of-function on HPA-v (human preadipocytes-visceral) adipogenesis were determined with lentivirus mediated cell transduction. The mRNA and protein expression levels of adipogenesis makers were evaluated by qPCR/Western blot. Then, we performed the microarray and pathway analysis to explore the possible mechanisms by which RP11 regulates adipogenesis. RESULTS: Overexpression of RP11 significantly enhanced adipocyte differentiation and increased the mRNA and protein expression levels of adipogenesis makers, such as PPARγ, SREBP1c, and FASN by qPCR/Western blot. Knockdown of RP11 showed opposite effects. Microarray and pathway analysis showed, after RP11 knockdown, 1612 genes were upregulated, and 583 genes were down-regulated which were found to be mainly involved in metabolic pathways, insulin signaling pathway and MAPK signaling pathway. CONCLUSION: In conclusion, the unknown lncRNA RP11 serves as a positive factor on preadipocyte differentiation which could shed light on fetal fat accumulation in GDM.

The Novel Peptide AEDPPE Alleviates Trophoblast Cell Dysfunction Associated With Preeclampsia by Regulating the NF-κB Signaling Pathway.

Background: Preeclampsia (PE) is a serious risk to the health of pregnant women and fetuses during pregnancy, and there is no effective treatment for this condition. Although many reports have confirmed the therapeutic effects of peptides in diseases, the role of peptides in PE remains poorly understood. Methods: A differentially expressed peptide in PE (AEDPPE) is derived from heat-shock protein beta-1 (HSPB1), amino acids 100 to 109 (DVNHFAPDEL), which we identified in a previous study. We synthesized AEDPPE and investigated its effect on HTR-8/SVneo cell function using a Cell Counting Kit-8, flow cytometric assay, and Transwell and wound-healing assays. Quantitative reverse transcription-PCR and ELISA were used to determine cytokine expression. Pull-down assay, mass spectrometry, Western blot analysis, and immunofluorescence were used to explore the potential targets and signaling pathways regulated by AEDPPE. Finally, we assessed the effect of AEDPPE in the lipopolysaccharide (LPS)-induced PE-like rat model. Results: AEDPPE significantly promoted the migration and invasion of HTR-8/SVneo cells, and it decreased the expression of interleukins 1 beta (IL-1ß), interleukin 6 (IL-6), and interleukin 8 (IL-8). These functions performed by AEDPPE remained evident after injury to HTR-8/SVneo cells with tumor necrosis factor-alpha (TNF-α), and AEDPPE reversed the elevated sFlt-1/PlGF ratio induced by TNF-α. AEDPPE may exert these biological effects by binding to heat-shock protein 90ß (HSP 90ß) and, thus, affect the NF-κB signaling pathway. In an LPS-induced PE-like rat model, AEDPPE significantly improved PE symptoms and fetal rat outcomes. Conclusion: Our study showed that AEDPPE enhanced trophoblast migration and invasion and reduced inflammatory cytokine expression, and we hypothesized that these actions involved the NF-κB signaling pathway. The use of AEDPPE may thus develop into a novel modality in the treatment of PE.

A novel peptide relieves endothelial cell dysfunction in preeclampsia by regulating the PI3K/mTOR/HIF1α pathway.

Preeclampsia (PE) is a pregnancy­specific complication characterized by hypertension and proteinuria, and it is one of the primary global causes of maternal and perinatal mortality. Poor remodeling of placental arteries and endothelial dysfunction serve important roles in the pathogenesis of PE. Peptide derived from complement C4 A chain (PDCC4) was identified in our previous peptidome analysis of serum from patients with PE. The present study aimed to investigate the effect of PDCC4 on endothelial dysfunction in PE. TNF­α stimulated HUVECs were employed to mimic endothelial dysfunction in PE, and Cell Counting Kit 8 assay, wound healing assay, tube formation assay, RNA­sequencing (seq) and western blot analysis were performed using HUVECs. Moreover, an in vivo model of PE was established using pregnant rats treated with lipopolysaccharide (LPS), and blood pressure monitoring, histopathological examination, ELISA and immunohistochemistry were performed on rats. It was found that TNF­α impaired proliferation, migration and tube formation of HUVECs, but pretreatment with PDCC4 moderated these effects. RNA­seq and western blotting demonstrated that the PI3K/mTOR/HIF1α signaling pathway was activated by PDCC4, and a selective PI3K inhibitor reversed the protective function of PDCC4 on TNF­α stimulated HUVECs. Additionally, PDCC4 alleviated hypertension, histopathological changes of placenta and kidney and the expression levels of endothelial injury markers and inflammatory cytokines induced by LPS in rats. These results suggested that PDCC4 relieved endothelial dysfunction in PE via PI3K/mTOR/HIF1α signaling pathway and may be a potential therapy for PE.

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.

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.

Distinct expression profiles of peptides in placentae from preeclampsia and normal pregnancies.

This study sought to identify potential bioactive peptides from the placenta that are involved in preeclampsia (PE) to obtain information about the prediction, diagnosis and treatment of PE. The liquid chromatography/mass spectrometry was used to perform a comparative analysis of placental peptides in normal and PE pregnancies. Gene ontology (GO), pathway analysis and ingenuity pathway analysis (IPA) were used to evaluate the underlying biological function of the differential peptides based on their protein precursors. Transwell assays and qPCR were used to study the effect of the identified bioactive peptides on the function of HTR-8/SVneo cells. A total of 392 upregulated peptides and 420 downregulated peptides were identified (absolute fold change ≥ 2 and adjusted P value < 0.05). The GO analysis, pathway analysis, and IPA revealed that these differentially expressed peptides play a role in PE. In addition, the up-regulated peptide "DQSATALHFLGRVANPLSTA" derived from Angiotensinogen exhibited effect on the invasiveness of HTR-8/SVneo cells. The current preliminary research not only provides a new research direction for studying the pathogenesis of PE, but also brings new insights for the prediction, diagnosis and treatment of PE.

Analysis of factors related to preterm birth: a retrospective study at Nanjing Maternity and Child Health Care Hospital in China.

Preterm birth is the most important cause of neonatal mortality and morbidity worldwide. The aim of this study was to identify factors associated with preterm birth and examine the heterogeneity and interactions between these factors.We collected data from 1607 pregnant women treated at Nanjing Maternity and Child Health Care Hospital in China. The women included in the study were divided into the full-term group and the preterm-birth group. We used t-tests to compare the characteristics of age and body mass index, Chi-square tests for the other variables, and we used the Wald test to calculate the interaction between factors that may affect preterm birth. The heterogeneity test was used to study the relationship between subgroups. Multivariable logistic regression analysis was used to explore the associations between risk factors and preterm birth, which included all risk factors. All tests were 2-tailed, P < 0.05 was considered significant, and 95% confidence intervals were estimated for percentages.There was no statistical difference in basic characteristics such as age between the full-term and preterm groups. We found 6 independent risk factors that were associated with preterm birth (P < .05): preeclampsia (PE), intrahepatic cholestasis, premature rupture of the membranes (PROM), placenta previa, chorioamnionitis, and scarred uterus. Five combinations of these factors were statistically significant (P < .05) in terms of heterogeneity: PE and PROM; placenta previa and polyhydramnios; chorioamnionitis and PE; PROM and maternal body mass index; and PROM and gestational diabetes mellitus. Ultimately, the 2 subgroups that showed interactions were PE and PROM and chorioamnionitis and PE.The interaction between different factors over the course of preterm birth cannot be ignored. When independent risk factors are combined with other diseases, such as PE combined with PROM or chorioamnionitis in this study, it may more likely result in preterm birth. Thus, this situation deserves particular clinical attention.

Cys-peptide mediates the protective role in preeclampsia-like rat and cell models.

OBJECTIVE: The present study was designed to investigate whether the novel peptide cysteine-based peptide (Cys-peptide) had protective effects on preeclamptic animal and cell models. METHODS: We investigated effects of Cys-peptide on (1) preeclamptic symptoms (e.g. hypertension, proteinuria, fetal growth restriction (FGR)) in preeclampia-like rat models induced by lipopolysaccharides (LPS), (2) TNFα-induced cytotoxicity of human umbilical vascular endothelial cells (HUVECs) and HTR-8 cells (an immortalised human trophoblast cell line), (3) endothelial dysfunction and injured angiogenesis, (4) migration and invasion of trophoblast cells induced by TNFα. RESULTS: Cys-peptide ameliorated LPS-induced hypertension, proteinuria and FGR and other PE symptoms in preeclampia-like rat models. In addition, Cys-peptide attenuated TNFα-induced cytotoxicity by decreasing soluble fms-like tyrosine kinase-1 (sFlt-1), endothelin-1 (ET-1) and tissue plasminogen activator (tPA) mRNA expression in both cells. Furthermore, Cys-peptide restored endothelial dysfunction and rescued angiogenesis caused by TNFα in vitro. Importantly, Cys-peptide could reverse insufficient ability to invade and migrate of trophoblast cells. CONCLUSIONS: These results suggest Cys-peptide can play beneficial roles in preeclampsia-like rat and cell models. Therefore, we propose that Cys-peptide is probably a novel therapeutic candidate for PE.

Overexpression of Long Noncoding RNA Uc.187 Induces Preeclampsia-Like Symptoms in Pregnancy Rats.

BACKGROUND: As a serious pregnancy-specific condition, preeclampsia (PE) is a serious pregnancy-specific condition characterized by insufficient trophoblastic invasion and shallow placental implantation. Long noncoding RNA uc.187, which is transcribed from an ultra-conserved region is highly expressed in the placental tissue of patients with PE, is associated with abnormal trophoblast invasion. Therefore, we aimed to further characterize the relationship between uc.187 and PE through in vitro experimental studies to find new targets to treat PE. METHODS: In this study, we constructed PE rat models induced by lipopolysaccharide, experimented with overexpressing uc.187 and performed experiments using HTR-8/SVneo cells. RESULTS: We found uc.187 was elevated in the placenta of PE rats. By injecting pregnant rats with a lentivirus containing the lncRNA uc.187, we successfully triggered maternal hypertension along with a series of symptoms similar to PE in humans. In vitro experiments demonstrated that high levels of uc.187 lead to decreased trophoblast invasion. In addition, our results revealed that uc.187 had high expression in PE and fetal growth restricted cells, but low expression in placental site trophoblastic tumors compared with the control groups. Results of western blot and cell immunofluorescence indicated that the aberrant biological behavior of HTR-8/SVneo cells were related to the distribution of ß-catenin in the cytoplasm and nucleus. CONCLUSIONS: Taken together, our study revealed that uc.187 was negatively correlated to trophoblastic cell invasion, and overexpression of uc.187 could induce PE-like symptoms in a pregnant rat model by affecting the distribution of ß-catenin in the cytoplasm and nucleus.