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Objective: This study aims to investigate the Knowledge, Attitude, and Practice (KAP) pertaining to constipation during pregnancy among pregnant women in Shanghai., Methods: Demographic data and KAP scores were collected using a questionnaire. Differences across groups were analyzed using either Wilcoxon-Mann-Whitney tests or Kruskal-Wallis analysis of variance. Spearman's correlation analysis was utilized to evaluate the relationships between KAP scores. Multivariable logistic regression analyses were conducted to identify factors that influence KAP scores., Results: Encompassing 241 individuals (46.6%) aged between 30 and 34 years, with 349 participants (67.5%) being nulliparous. The median scores for knowledge (possible range: 0-26), attitude (possible range: 7-35), and practice (possible range: 14-70) were 22 (18, 24), 26 (23, 29), and 51 (46, 56), respectively. Multivariate analysis indicated that being a medical professional (OR = 2.222, p  = 0.043) and receiving education on constipation during pregnancy (OR = 0.432, p  < 0.001) were significantly associated with higher knowledge scores. Factors significantly associated with practice included being aged 30-34 years (OR = 2.745, p  < 0.001), aged 35 years and above (OR = 2.514, p  < 0.001), working in education (OR = 2.310, p  = 0.012), and not experiencing constipation before pregnancy (OR = 1.894, p  = 0.001)., Conclusion: Pregnant women demonstrated satisfactory knowledge, positive attitudes, and proactive practices concerning constipation during pregnancy. To further augment clinical practice, healthcare providers should tailor educational interventions and guidance specifically for pregnant women who are not medical professionals and those who have not received education and guidance related to constipation during pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lin, Yu, Gu, Hu and Zhu.)

Recurrent miscarriage (RM) is related to the dysfunction of extravillous trophoblast cells (EVTs), but the comprehensive mechanisms remain largely unexplored. We analyzed single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing and microarray datasets obtained from Gene Expression Omnibus (GEO) database to explore the hub genes in the mechanisms of RM. We identified 1724 differentially expressed genes (DEGs) in EVTs from the RM, and they were all expressed along the trajectory of EVTs. These DEGs were associated with hypoxia and glucose metabolism. Single-cell Regulatory Network Inference and Clustering (SCENIC) analysis revealed that E2F transcription factor (E2F) 8 (E2F8) was a key transcription factor for these DEGs. And the expression of ENO1 can be positively regulated by E2F8 via RNA sequencing analysis. Subsequently, we performed immunofluorescence assay (IF), plasmid transfection, western blotting, chromatin immunoprecipitation (ChIP), real-time quantitative polymerase chain reaction (qRT-PCR), and transwell assays for validation experiments. We found that the expression of alpha-Enolase 1 (ENO1) was lower in the placentas of RM. Importantly, E2F8 can transcriptionally regulate the expression of ENO1 to promote the invasion of trophoblast cells by inhibiting secreted frizzled-related protein 1/4 (SFRP1/4) to activate Wnt signaling pathway. Our results suggest that ENO1 can promote trophoblast invasion via an E2F8-dependent manner, highlighting a potential novel target for the physiological mechanisms of RM., (© 2024 Federation of American Societies for Experimental Biology.)

Introduction: Pre-eclampsia (PE) affects about 5% of Chinese pregnant women and is a major cause of maternal and perinatal morbidity and mortality. The first trimester screening model developed by the Fetal Medicine Foundation, which uses the Bayes theorem to combine maternal characteristics and medical history together with measurements of biomarkers, has been proven to be effective and has superior screening performance to that of the traditional risk factor-based approach for the prediction of PE. Prophylactic use of low-dose aspirin in women at risk for PE has resulted in a lower incidence of preterm-PE. However, there is no consensus on the preferred aspirin dosage for the prevention of preterm-PE. Evidence has also suggested that metformin has the potential benefit in preventing PE in pregnant women who are at high risk of the disorder., Method and Analysis: We present a protocol (V.2.0, date 17 March 2022) for the AVERT trial, which is a multicentre, double-blinded, 3-arm randomised controlled trial (RCT) that uses an effective PE screening programme to explore the optimal dosage of aspirin and the role of metformin for the prevention of PE among high-risk pregnant women in China. We intend to recruit 66 000 singleton pregnancies without treatment of low-dose aspirin and metformin at 11-13 weeks' gestation and all eligible women attending for their first trimester routine scan will be invited to undergo screening for preterm-PE by the combination of maternal factors, mean arterial pressure and placental growth factor. Women found to be at high risk of developing preterm-PE will be invited to take part in the RCT. This study will compare the incidence of preterm-PE with delivery at <37 weeks' gestation, as the primary outcome, of three different interventional groups: (1) aspirin 75 mg daily, (2) aspirin 150 mg daily and (3) aspirin 75 mg with metformin 1.5 g daily. 957 participants per treatment group are required to detect a significant difference of 59% in the reduction of the incidence of preterm-PE with 80% power and type I error of 5%. Pregnancy and neonatal outcomes will be collected and analysed., Ethics and Dissemination: Ethical approval for the study was obtained from the Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee (CREC Ref. No. 2021.406) in Hong Kong and the Ethics Committee of each participating hospital in Mainland China. The study is registered at ClinicalTrials.gov. The results of the AVERT trial will be disseminated at international academic conferences and published in high-impact factor journals., Trial Registration Number: NCT05580523., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Preeclampsia (PE) is one of the pregnancy complications, leading to major maternal and fetal morbidity and mortality; however, the underlying mechanisms of PE still remain unclear. We aimed to explore the role of apolipoprotein A1 (APOA1) in the pathophysiology of PE. The expression of APOA1 was elevated in both plasma and placental tissues, as detected by Western blotting, immunohistochemistry, and a qRT-PCR assay. Importantly, we detected the concentration of APOA1 using the ELISA assay in normal control women ( n = 30) and women with preeclampsia ( n = 29) from a prospective cohort study. The concentration of APOA1 was not significantly altered in plasma during early and mid-term gestation of the PE patients compared to the NP patients; however, it was elevated during late gestation. Additionally, the concentration of APOA1 was positively associated with systolic blood pressure during late gestation. The proliferation and invasion of trophoblast were all increased in HTR8/SVneo cells transfected with APOA1 siRNA and decreased in HTR8/SVneo cells treated with the recombinant human APOA1 protein (rhAPOA1). Additionally, we used public datasets to investigate the downstream genes of APOA1 and qRT-PCR for validation. Furthermore, we explored the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ) in APOA1 by using a luciferase assay, which showed that the APOA1 promoter was activated by PPARγ. Additionally, the inhibitory effect of rhAPOA1 on the ability of trophoblast invasion and proliferation can be rescued by the PPARγ inhibitor. Our findings suggest the crucial role of APOA1 in PE, which might provide a new strategy for the prevention and treatment of PE.

In Brief: Preeclampsia (PE) is a severe complication that leads to major maternal and fetal mortality and morbidity, and one of its causes is extravillous trophoblast (EVT) dysfunction. This study revealed the role of CD74 in the invasion and proliferation of EVTs., Abstract: PE is a severe hypertensive disorder during pregnancy, and one of its causes is the dysfunction of EVTs. In this study, we analyzed single-cell RNA sequencing (scRNA-seq) data of placentas from PE patients and the sirtuin 1 (SIRT1) heterozygous knockout mouse model, which exhibited typical PE-like symptoms. We identified 134 differentially expressed genes (DEGs) with similar trends in EVTs of PE patients and in parietal trophoblast giant cells (P-TGCs) of Sirt1-/- (HO) placentas from Sirt1+/- (HE) pregnant mice. Interestingly, Kyoto Encyclopedia of Genes and Genomes analysis showed that 134 overlapping genes were related to the MAPK signaling pathway. We validated several DEGs using immunofluorescence at the protein level. Finally, we selected CD74 for further experiments, which showed a decrease in EVTs of PE patients and in P-TGCs of Sirt1-/- placentas from Sirt1+/- pregnant mice. Additionally, cell proliferation assays and transwell assays showed that the proliferation and invasion abilities were decreased in CD74 knockdown HTR8/SVneo cells using lentivirus transfection, which can be improved by adding the SIRT1 agonist SRT1720 or metformin, an agonist of the MAPK signaling pathway. Importantly, the expression of CD74 can be positively regulated by SIRT1. These data suggest that CD74 plays an important protective role in the pathogenesis of preeclampsia by regulating the MAPK signaling pathway, which can be regulated by SIRT1.

Recurrent miscarriage (RM) is a pregnancy complication associated with dysregulation of the maternal-fetal interface. We aimed to identify dysfunctional interactions between trophoblast cells and decidual immune cells in RM. We downloaded single-cell RNA sequencing (scRNA-seq) datasets (GSE214607) from the Gene Expression Omnibus (GEO) datasets for further analysis using the R software. The data comprised of paired placental and decidual tissues, including those from patients diagnosed with RM and matched healthy controls. A total of 22976 cells were identified in 11 cell types, including trophoblasts, immune cells, and other cells. We divided trophoblast cells into three types and analyzed their interactions with decidual immune cells. Additionally, we re-clustered NK&T cells and macrophages, identified differentially expressed genes (DEGs), enriched their functions, and compared the cell interactions with trophoblast cells in each cell type. Our single-cell atlas of the maternal-fetal interface revealed alterations in the cellular organization of the decidua and placenta, cell type-specific transcriptome, and cell communication between immune and non-immune cells in RM, which are critical for illuminating the pathophysiology of RM., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

This study aimed to identify the expression profile of mRNAs and analyze the associated pathways in hypoxia-induced trophoblast cells to understand the effect of hypoxia on the pathophysiology of preeclampsia (PE). We downloaded two gene expression datasets (GSE47187 and GSE60432) from the Gene Expression Omnibus (GEO) datasets to identify altered transcriptomes. GEO2R, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) networks were used to reveal the functional roles and regulatory networks of the differentially expressed genes (DEGs). In total, 224 DEGs (91 upregulated and 133 downregulated) were identified, and the "HIF-1 signaling pathway" was activated in placentas from patients with PE. We validated the expression levels of five proteins in the plasma of NP and PE patients during early or late pregnancy using western blotting. In primary trophoblast cells cultured under hypoxic conditions, 754 DEGs were identified, including 362 upregulated and 392 downregulated genes. These DEGs were associated with the "HIF-1signaling pathway," "response to hypoxia," and several glucose metabolism pathways. In addition, a PPI network was constructed, and an important module, including 18 hub genes, was identified. Finally, we validated 18 hub genes using qRT-PCR. Furthermore, we performed microarray profiling of hypoxia-treated HTR8/SVneo cells (immortalized human first-trimester extravillous trophoblast cells) to validate the DEGs and pathways identified in hypoxia-induced primary trophoblast cells. Our results stress the differential expression profiles of mRNAs in hypoxia-induced trophoblast cells, which provide potential pathophysiological mechanisms for preeclampsia., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Preeclampsia (PE) is a common pregnancy complication, and placental hypoxia is one of its causes. We aimed to identify the transcriptional profile and construct a long non-coding RNAs (lncRNA)-centered competing endogenous RNAs (ceRNA) network in hypoxia-induced HTR8/SVneo cells. We used datasets from the GEO database to identify important pathways in PE. We performed microarray profiling and functional analysis to identify differentially expressed long non-coding RNAs (lncRNAs), differentially expressed profiles of microRNA (miRNAs), and differentially expressed profiles of messenger RNA (mRNAs) in hypoxia-induced HTR8/SVneo cells. The candidates were validated using quantitative reverse transcription polymerase chain reaction. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses were performed to understand the functional significance of differentially expressed genes. Finally, we constructed an lncRNA-centered ceRNA network. Several hub genes were validated both in placentas from PE and normal pregnancy, and in hypoxia-induced HTR8/SVneo cells. The hypoxic response pathway was involved in the pathophysiology of PE. Subsequently, we identified 536 differentially expressed profiles of lncRNAs (183 upregulated and 353 downregulated), 46 differentially expressed profiles of miRNAs (35 upregulated and 11 downregulated), and 2782 differentially expressed profiles of mRNAs (DEmRNAs) (1031 upregulated and 1751 downregulated) in hypoxia-induced HTR8/SVneo cells. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed potential pathways affected by these genes, such as angiogenesis, the HIF-1 signaling pathway, and the PI3K-Akt signaling pathway. The ceRNA network comprised 35 lncRNAs, 11 miRNAs, 27 mRNAs, and 2 hub lncRNAs, which might play a vital role in placental functions and PE. Our results revealed the transcriptome profile and constructed an lncRNA-centered ceRNA network in hypoxia-induced HTR8/SVneo cells, thereby providing potential therapeutic targets for PE., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Pre-eclampsia is a severe pregnant complication, mainly characterized by insufficient trophoblast invasion, impaired uterine spiral artery remodeling, placental hypoxia and ischemia, and endothelial dysfunction. However, the potential mechanisms of pre-eclampsia remain unclear. SIRT1 is a NAD+-dependent deacetylase, involving in multiple biological processes, including energy metabolism, oxidative stress, inflammatory response, and cellular autophagy. Several studies showed that SIRT1 might play a vital role in the pathogenesis of pre-eclampsia. In this review, we aim to integrate the latest research on SIRT1 and pre-eclampsia to explore the comprehensive mechanisms of SIRT1 in pre-eclampsia. More specifically, SIRT1 might affect placental development and trophoblast invasion through autophagy and senescence in pre-eclampsia, and SIRT1 protects vascular endothelial cells from oxidative stress, inflammatory response, autophagy, and senescence. Furthermore, SIRT1 deficiency mice showed typical pre-eclampsia-like performances, which can be reversed via direct SIRT1 supplement or SIRT1 agonist treatment. Additionally, resveratrol, a SIRT1 agonist, attenuates vascular endothelial injury and placental dysfunction, and exerts protective effect on decreasing blood pressure. In this review, we provide new insights into the development of pre-eclampsia, which can establish a theoretical basis for prevention and treatment for pre-eclampsia. Besides, we also propose questions that still need to be further addressed in order to elucidate the comprehensive molecular mechanisms of pre-eclampsia in the future., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

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.

Objective: To improve perinatal management for hypertensive disorders in pregnancy (HDP) using checklists., Methods: A pre-post evaluation of the implementation of checklists was performed. The checklist for HDP was adapted for the local context through expert consultations and had been used within peripartum since September 2017. Data of 763 women with singleton pregnancies diagnosed with HDP were collected between April 2016 and March 2019 at the Obstetrics & Gynecology Hospital of Fudan University. The monitoring and control groups consisted of 394 and 369 cases, respectively. Analysis was carried out by intention-to-treat with respect to maternal and fetal complications and delivery outcomes., Results: After the implementation of the checklists, patients had a significant reduction in anti-hypertensive treatment both orally (P = 0.028) and intravenously (P = 0.003), and increased utilization rate of MgSO 4 management (P < 0.001). Gestation was prolonged in the expectant treatment (P = 0.012) and the rate of elective and intrapartum cesarean delivery decreased (P < 0.001 and P = 0.001, respectively). The neonates of these patients had a low rate of admission to the neonatal intensive care unit (P < 0.001)., Conclusion: National clinical guidelines complied critically after the implementation of the checklists. These checklists could be used for improving the quality of the clinical strategy and treatment, which benefitted perinatal management., (© 2021 International Federation of Gynecology and Obstetrics.)

Pre-eclampsia is a severe hypertensive disorder of pregnancy (HDP), mainly characterized by new-onset hypertension with proteinuria after 20-week gestation. Sirtuin1 (SIRT1), a class III histone deacetylase, is associated with the regulation of various pathophysiological processes, including inflammation, immune response, metabolism, and autophagy. However, the effect of SIRT1 in the pathogenesis of pre-eclampsia remains to be elucidated. In this study, we found that the expression of SIRT1 was relatively lower in the placentas and serum samples of pre-eclampsia patients. Typical pre-eclampsia-like symptoms, such as hypertension, proteinuria, fetal growth restriction, kidney injury, and a narrow placental labyrinth layer, were observed in SIRT1 knockdown (SIRT1 +/- ) mice. Of note, these performances could be improved after the intraperitoneal injection of SIRT1 agonist SRT2104. More importantly, we found that the efficacy of progesterone on attenuating symptoms of PE was profoundly better than that of metformin in SIRT1 +/- mice. In addition, our results suggested that progesterone can promote the invasion and inhibit the apoptosis of trophoblasts. These data suggest that SIRT1 plays an important role in pre-eclampsia and that progesterone alleviates pre-eclampsia-like symptoms mediated by SIRT1 deficiency.

Preeclampsia is a severe complication of pregnancy characterised by variable degrees of placental malperfusion. A growing body of evidence indicates that soluble endoglin and soluble fms-like tyrosine kinase-1 (sFlt-1) play important pathophysiological roles in preeclampsia, causing endothelial dysfunction, hypertension, and multiorgan injury. A drug that is safe in pregnancy and inhibits placental sFlt-1 and soluble endoglin secretion would be an attractive treatment strategy for preeclampsia. Procyanidin B2, a bioactive food compound, has been reported to exert multiple beneficial functions. Placental explant cultures in vitro are useful for studying tissue functions including release of secretory components, pharmacology, toxicology, and disease processes. The reduced uterine perfusion pressure (RUPP) rat model has been widely used as a model of preeclampsia. We aimed to investigate the effect of procyanidin B2 on preeclampsia via using placental explant cultures and RUPP rat model. In this study, we demonstrated that procyanidin B2 reduced soluble endoglin and sFlt-1 secretion from human umbilical vein endothelial cells (HUVECs), primary trophoblasts, and placental explants from preeclamptic pregnancies. Moreover, procyanidin B2 alleviated endothelial dysfunction and impaired angiogenesis induced by sFlt-1, including increasing the migration, invasion and angiogenesis of endothelial cells and decreasing the expression of vascular cell adhesion molecule-1 (VCAM-1) and leukocyte adhesion on HUVECs. In addition, procyanidin B2 promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation and induced peroxisome proliferator-activated receptor γ (PPARγ) expression in primary placental tissues and endothelial cells. Importantly, Nrf2 specifically binds to the PPARγ promoter region (-1227/-1217) and enhances its transcriptional activity. Procyanidin B2 inhibits sFlt-1 secretion via the Nrf2/PPARγ axis. In the RUPP rat model of preeclampsia, procyanidin B2 attenuated RUPP-induced maternal angiogenic imbalance, hypertension and improved placental and foetal weight. Taken together, our results demonstrate that procyanidin B2 inhibits sFlt-1 secretion and ameliorates endothelial dysfunction and impaired angiogenesis via the Nrf2/PPARγ axis in preeclampsia. Procyanidin B2 may be a novel therapeutic agent for treatment of preeclampsia., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aim: Whether the use of dinoprostone pessary increased the vaginal delivery rate of labor induction in Chinese nulliparous women with term premature rupture of membranes (PROM) and unfavorable cervices?, Methods: PROM women at term with singleton pregnancies and Bishop scores ≤4 who needed labor induction were enrolled in this retrospective study. They received either the dinoprostone pessary followed by oxytocin infusion if necessary (n = 102, PGE2 group) or oxytocin infusion alone (n = 103, oxytocin group)., Results: Compared with oxytocin infusion alone, vaginal delivery within 12 h and total vaginal delivery were higher in the PGE2 group (28.4% vs 7.8%, p = 0.0001; 79.4% vs 62.1%, p = 0.009, respectively). There were no statistical differences between the two groups in terms of maternal and neonatal outcomes, such as postpartum hemorrhage, endometritis, third- and fourth-degree vaginal lacerations and neonatal weight, 1- and 5-min Apgar score ≤7, neonatal jaundice, and neonatal unit admission (p > 0.05). However, there was a higher rate of uterine hyperstimulation in the PGE2 group (20.6% vs 3.9%, p < 0.0001). The effective rate of cervical ripening increased in the PGE2 group at 8 and 12 h of labor induction (p < 0.001)., Conclusions: Despite higher rates of uterine hyperstimulation, the use of dinoprostone was associated with higher rates of vaginal deliveries in Chinese nulliparous women with term PROM and Bishop scores ≤4, compared with use of oxytocin only., (© 2021 Japan Society of Obstetrics and Gynecology.)

Hypertensive disorder in pregnancy is a disease that occurs during pregnancy. We aimed to analyze the morbidity and maternal and infant outcomes with respect to the hypertensive disorder in pregnancy in China in 2018. Clinical data of 38 590 cases from 161 hospitals were retrospectively collected. The differences in morbidity and maternal and infant mortality among the major regions and provinces were compared. The overall national average morbidity was 4.74%, and the ratios of gestational hypertension, preeclampsia, eclampsia, chronic hypertension, and chronic hypertension with superimposed preeclampsia were 29.17%, 55.02%, 0.66%, 6.53%, and 8.62%, respectively. The overall maternal mortality was 0.61/100 000, and the case fatality was 0.13%. Morbidity associated with hypertensive disorder in pregnancy was 7.74% in North China, 6.62% in Northwest China, 6.40% in Central China, 5.83% in Northeast China, 4.28% in East China, 3.85% in South China, and 2.88% in Southwest China. The morbidity in each province was 1.62-11.28%. The overall perinatal mortality was 3.59% (81.09% for stillbirths; 18.91% for neonatal deaths). Perinatal mortality decreased with increasing gestational weeks from 24 to 37 + 6 weeks. Perinatal mortality for delivery at 32 weeks of gestation in all regions of the country was <10%. Morbidity varied across regions in China, with the lowest in Southwest and the highest in North China. The low maternal mortality is related to the large-scale development of standardized maternal health care in China. For severe hypertensive disorder patients, gestation should be prolonged to 32 weeks as often as possible for better neonatal survival rates., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Trial of labor after a previous cesarean delivery (TOLAC) has reduced the rate of cesarean sections (CS). Nevertheless, the widespread use of TOLAC has been limited by an increase in adverse outcomes, the most serious one being the risk of symptomatic uterine rupture, which is possibly associated with oxytocin. In this meta-analysis, we explored the risk association between oxytocin use and uterine rupture in TOLAC., Methods: Multiple electronic databases (PubMed, Embase, Web of Science, and Google Scholar) were searched for cross-sectional studies reporting on TOLAC, oxytocin and uterine rupture, which were published between January 1986 and October 2019. The bias-corrected Hedge's g was calculated as the effect size using the random-effects model. A two-sample Z test was used to compare the differences in synthetic rates between groups. The Newcastle-Ottawa Scale (NOS) was used to evaluate the risk of bias. Quality of the evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) certainty ratings system., Results: A total of 14 studies, which included 48,457 women who underwent TOLAC, met the inclusion criteria. The pooled rate of vaginal birth after a cesarean section (VBAC) and the rate of uterine rupture in spontaneous labor were 74.3 and 0.7%, respectively. In addition, the pooled rate of VBAC and the rate of uterine rupture in the induction labor group was 60.7 and 2.2%, respectively. The women who had spontaneous labor had a significantly higher rate of VBAC (p = 0.001) and a lower rate of uterine rupture (p = 0.0003) compared to induced labor. The pooled rates of uterine rupture in women using oxytocin and women not using oxytocin in TOLAC were 1.4% and 0.5%, respectively, and the difference was significant (p = 0.0002). Also, the synthetic rate of uterine rupture in oxytocin augmentation among women with spontaneous labor and women who had a successful induction of labor were 1.7% and 2.2%, respectively, without significant difference (p = 0.443)., Conclusions: Women with induced labor had a higher risk of uterine rupture compared to women with spontaneous labor following TOLAC. Oxytocin use may increase this risk, which could be influenced by the process of induction or individual cervix condition. Consequently, simplified and standardized intrapartum management, precise protocol, and cautious monitoring of oxytocin use in TOLAC are necessary.

Introduction: Circular RNAs (circRNAs) are non-coding RNAs that are implicated in preeclampsia (PE) pathogenesis; however, their expression and functions in PE remain unclear. In this study, we aimed to investigate the expression of circRNAs in PE and construct a competing endogenous RNA (ceRNA) network, and analyze the associated pathways in PE pathogenesis., Methods: We performed circRNA sequencing to identify the differential expression profile of circRNAs in PE as compared to normal pregnancy. The circRNA candidates were validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Subsequently, we used datasets from the GEO database to generate the interaction network between circRNAs, microRNAs (miRNAs), and mRNAs. GO and KEGG enrichment analyses were performed to understand the functional significance of the differentially expressed circRNAs in PE., Results: We identified 361 differentially expressed circRNAs (252 upregulated and 109 downregulated) in preeclamptic placentas. Within the selected 31 circRNAs, 6 of them were verified by qRT-PCR. GO and KEGG analyses revealed the potential pathways affected by these circRNAs, e.g., T cell receptor signaling and MAP kinase pathways. A total of 134 miRNAs and 199 mRNAs were revealed to be differentially expressed in PE by analyzing datasets from the GEO database. The circRNA-miRNA-mRNA network comprised 206 circRNAs, 50 miRNAs, and 38 mRNAs. KEGG analysis of the 38 mRNAs included pathways involved in AMPK and PI3K-Akt signaling., Discussion: Our results reported the differential expression profile of circRNAs and the circRNA-miRNA-mRNA network in PE, which provides potential therapeutic targets for this disease., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: The objective of this study is to identify the maternal and neonatal outcomes in women with placenta increta or placenta percreta in China., Materials and Methods: We retrospectively analyzed 2219 cases from 20 tertiary care centers in China between January 2011 and December 2015. All cases were diagnosed of placenta increta or placenta percreta, based on either intraoperative findings or histopathological findings., Results: The incidence of placenta increta and placenta percreta progressively increased from 0.18% in 2011 to 0.78% in 2015. Compared with the placenta increta, placenta percreta was strongly related to serious adverse outcomes: postpartum hemorrhage (65.9% versus 38.6%, p = .003), blood transfusion (86.2% versus 46.5%, p < .001), hysterectomy (43.3% versus 11.2%, p < .001), preterm birth (65.7% versus 49.9%, p < .001), and the need for neonatal intensive care unit (NICU) admission (54.5% versus 36.7%, p < .001)., Conclusion: The incidence of placenta increta and placenta percreta is likely to increase in China. The depth of placenta implantation is associated with the severity of outcomes. Placenta percreta tends to have worse maternal and neonatal outcomes.

Introduction: Adverse pregnancy outcomes are related to two opposite maternal factors, youth and aging. However, the change in trend of specific outcomes with childbearing age is unknown. The aim of this study was to investigate the changing trend of various maternal and neonatal outcomes with maternal age from 17 to 44 years., Material and Methods: Data were extracted from the medical records from 2011-2012 of 39 public hospitals of 14 cities in China. The eligibility criteria were primiparity and singleton birth. Join point regression analysis was used to estimate the percent change per year of age (PCA) to explore the trends of adverse pregnancy outcomes with regard to maternal age and to identify the join point of maternal age when the trend was changed., Results: A total of 89 171 women were eligible for analysis. There were four categories of trend styles. Continuously increasing trends were linear for placenta previa (PCA, 0.1%), placenta implantation (PCA, 0.09%) and postpartum hemorrhage (PCA, 0.22%), and nonlinear for gestational diabetes mellitus with one join point of 23 years (PCA, 0.17% and 0.71%) and cesarean section with four join points of 25, 28, 31 and 36 years (PCA, 1.39%, 0.34%, 1.51%, 3.49% and 0.94%). Continuously decreasing trends were linear for intrahepatic cholestasis (PCA, -0.02%) and nonlinear for anemia with one join point of 28 years (PCA, -0.49% and -0.04%). The bidirective trends were downward to upward for preterm birth (PCA, -2.93%, -0.36% and 0.38%), hypertension in pregnancy (PCA, -0.09%, 0.47%), low birthweight (PCA 0.51% and 0.38%), low 1-minute Apgar score (PCA, -0.28% and 0.07%), low 5-minute Apgar score at (PCA, -0.10% and 0.06%) and neonatal intensive care unit admission (PCA, -1.92%, -0.07% and 0.12%) with a nadir age of 28 years. The bidirective trend was upward to downward for macrosomia (PCA, 0.39% and -0.11%), with a peak age of 30 years., Conclusions: The changes in the trend of specific outcomes were different with maternal age, which means that youth, aging or both could affect the outcomes., (© 2019 Nordic Federation of Societies of Obstetrics and Gynecology.)

Preterm labour is a common pregnancy complication contributing to major maternal and fetal morbidity and mortality. We have found microRNA (miR)-212-3p, a potential infection-associated molecule, was significantly over-expressed during human preterm labour. However, the mechanism remains unknown. In this study, we have adopted a lipopolysaccharide (LPS)-induced Institute of Cancer Research murine preterm model to examine the role of miR-212-3p in the infection-induced preterm labour. Myometrial miR-212-3p expression was increased by nearly 4-fold in the term labour group (P = 0.10) and 12-fold (P = 0.03) in the LPS-induced preterm labour group compared with the non-labour group. In vitro cellular experiments confirmed that a series of pro-inflammatory cytokines, including interleukin (IL)1B (P = 0.02) and IL-6 (P = 0.01), rather than LPS (P = 0.08) itself could significantly upregulate miR-212-3p expression in human myometrial smooth muscle cells. Methyl-CpG-binding protein 2 (MeCP2), as a target gene of miR-212-3p confirmed by our dual luciferase assay, influenced myocyte contractility and connexin 43 expression which is an important contraction-associated protein. Therefore, we conclude that miR-212-3p may be involved in infection-induced preterm labour through MeCP2 and it is a promoting molecule and novel target for the diagnosis and treatment of preterm labour in the future., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The exact mechanism of preeclampsia (PE) remains unclear, accumulating researches have indicated multiple epigenetic factors relate to PE and histone methylation plays a crucial role in modifying the gene expression. So we aimed to confirm that abnormal expression of histone demethylase JHDM1D contributes to PE and lower expression of HLA-G in PE. We tested the expression of JHDM1D, H3K9me2, and H3K27me2 in the placentas of PE and normal control (NC)women who had a healthy pregnancy with Immunohistochemistry and we found that JHDM1D, H3K9me2, and H3K27me2 were all mainly expressed in the nuclei of the extra-villous trophoblasts (EVTs). JHDM1D was lower expressed in PE than in NC placentas, corresponding with the mRNA level and protein level with qTR-PCR and western blot, while H3K9me2 and H3K27me2 were higher expressed in PE. We further investigated the biological functions of JHDM1D in HTR-8/SVneo cells. We found that siJHDM1D inhibited cell growth after 24 h of the transfection and reduced the invasion, while increasing the apoptosis of HTR-8/SVneo. We then constructed the siJHDM1D stable cell line and confirmed with CHIP-qPCR that siJHDM1D inhibited the expression of HLA-G through increased the enrichment of H3K9me2 and H3K27me2 in the JHDM1D bounding region of HLA-G. Taken together, our study confirms that decreased expression of JHDM1D is associated with PE through down-regulating HLA-G and casts new light to the diagnosis and therapy of PE.

Preeclampsia is a leading cause of perinatal maternal-foetal mortality and morbidity. The aim of this study is to identify the key microRNAs and genes in preeclampsia and uncover their potential functions. We downloaded the miRNA expression profile of GSE84260 and the gene expression profile of GSE73374 from the Gene Expression Omnibus database. Differentially expressed miRNAs and genes were identified and compared to miRNA-target information from MiRWalk 2.0, and a total of 65 differentially expressed miRNAs (DEMIs), including 32 up-regulated miRNAs and 33 down-regulated miRNAs, and 91 differentially expressed genes (DEGs), including 83 up-regulated genes and 8 down-regulated genes, were identified. The pathway enrichment analyses of the DEMIs showed that the up-regulated DEMIs were enriched in the Hippo signalling pathway and MAPK signalling pathway, and the down-regulated DEMIs were enriched in HTLV-I infection and miRNAs in cancers. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses of the DEGs were performed using Multifaceted Analysis Tool for Human Transcriptome. The up-regulated DEGs were enriched in biological processes (BPs), including the response to cAMP, response to hydrogen peroxide and cell-cell adhesion mediated by integrin; no enrichment of down-regulated DEGs was identified. KEGG analysis showed that the up-regulated DEGs were enriched in the Hippo signalling pathway and pathways in cancer. A PPI network of the DEGs was constructed by using Cytoscape software, and FOS, STAT1, MMP14, ITGB1, VCAN, DUSP1, LDHA, MCL1, MET, and ZFP36 were identified as the hub genes. The current study illustrates a characteristic microRNA profile and gene profile in preeclampsia, which may contribute to the interpretation of the progression of preeclampsia and provide novel biomarkers and therapeutic targets for preeclampsia.

Preeclampsia is associated with developmental delay in infants and with an increased risk of various diseases in adulthood, including hypertension and epilepsy. It has been reported that several organs show developmental retardation and functional deficiency in offspring of preeclamptic rats. However, the developmental and functional changes in brains of the offspring of preeclamptic rats remain unknown. Here, we established a preeclampsia-like rat model induced using Nω-nitro-L-arginine methyl ester (L-NAME) to analyze the developmental and functional changes in brains of the offspring. Body and brain weights were decreased in the L-NAME group at postnatal day 0 (P0). However, there were no significant differences between the L-NAME and control groups in brain and body weights at P56. Upon further analysis, we detected a deficiency in neurogenesis, but not in apoptosis, which contributed to the smaller brains of the offspring in the L-NAME group at P0. Additionally, we observed an increase in gliogenesis to compensate for the brain weights of the offspring at P56. Although the weight and laminar structure of the brains were essentially normal at P56, spatial learning and memory were severely impaired. We also found that adult hippocampal neurogenesis was disrupted in the offspring from preeclampsia-like rats, which may explain the cognitive deficiency. Moreover, qRT-PCR revealed a reduced expression of neurogenesis-related genes in the offspring. Overall, we have described the deleterious effects of preeclampsia on the brains of offspring, providing clues to the cellular and molecular mechanisms involved in this pathogenesis, which may aid in the development of therapeutic approaches.

Spontaneous preterm labor is an important complication in perinatology characterized by early onset myometrium contractions leading to labor at preterm. However, the exact mechanism that maintain uterine quiescence and promote increased uterine contractility during labor were incompletely defined. MicroRNAs is a class of short non-coding RNAs that regulate gene expression at the post-transcriptional level by binding the 3' untranslated region of target mRNAs and play an important role in biological process and cellular functions. We hypothesized we could find differentially expressed microRNAs in the myometrium of women in spontaneous preterm labor. Thus, a microarray analysis of miRNAs of preterm myometrium was performed. 18 out of the 2006 detected microRNAs were found to be significantly dysregulated in myometrium in labor verse not in labor at preterm. Biological validation by quantitative real-time polymerase chain reaction confirms us a consistence rate of 83.3% (5 out of 6) with microarray analysis. The target genes for validated microRNAs were predicted by three algorithms (PicTar, TargetScan, and miRanda). Most of the potential targets of the miRNAs were relevant to positive regulation of cardiac muscle hypertrophy, reduction of cytosolic calcium ion concentration and relaxation of cardiac muscle as well as prostate cancer, adherents junction, regulation of actin cytoskeleton and regulation and other factor-regulated calcium reabsorption. Our result illustrates a characteristic microRNA profile in myometrium tissues and provides a new understanding of the process involved in spontaneous preterm labor.

Preeclampsia (PE) is a severe pregnancy-induced disorder characterized by hypertension and proteinuria and a leading cause of perinatal maternal-fetal mortality and morbidity in developing countries. Dysregulated human leukocyte antigen (HLA)-G was found in placentas as well as in maternal sera from PE patients; however, the reason for this difference is unknown. As accumulating evidence has confirmed that DNA methylation is an important mechanism for regulating gene expression, we sought to test the hypothesis that alteration in the DNA methylation of the HLA-G promoter region is responsible for decreased expression of HLA-G in PE. Bisulfite pyrosequencing showed that a series of CpG sites in the HLA-G promoter region were significantly more highly methylated in PE than in normal pregnancy (NP). Interestingly, the hypermethylated CpG sites were mostly reported to be binding sites of active transcription factors. To further investigate the regulation of HLA-G methylation, we also defined the expression patterns of DNA methyltransferases (DNMTs) in placental tissue using immunohistochemistry and quantitative polymerase chain reaction analyses. Here, we demonstrate that DNMT-1 is overexpressed and HLA-G expression is reduced in PE women when compared with NP. Furthermore, both treatment with the DNMT inhibitor 5-aza-2'-deoxycytidine and specific knockdown of DNMT-1 using siRNAs can significantly increase the expression level of HLA-G in a trophoblastic cell line, indicating the potential mechanism of DNMT-1-mediated DNA methylation in HLA-G regulation. Taken together, our research confirms that DNMT-1-mediated promoter hypermethylation of HLA-G is associated with PE. These findings provide new insights into the diagnosis and treatment of PE., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: To evaluate the natural history and outcome of pregnancies in patients with placental chorioangioma., Methods: A total of 16 placentas with a histologic diagnosis of chorioangioma were identified, and the natural history and outcome of pregnancy were evaluated. This study was approved by the Institutional Ethics Committees of our unit, and written informed consent was obtained from all study participants., Results: Thirteen of the 16 cases were associated with a wide variety of fetal complications. Two-thirds of the cases developed complications that either required elective delivery because of fetal distress (n = 4), fetal heart failure (n = 1), oligohydramnion (n = 1), and premature labor of dichorionic twins (n = 1) or resulted in intrauterine fetal death and termination of pregnancy (n = 2)., Conclusions: Placental chorioangioma was associated with the development of polyhydramnios, fetal growth restriction, and fetal distress in a significant number of cases. The size, vascularity, and location of the chorioangioma may be three independent factors of maternal and fetal complications. Any of these three factors can influence the outcome of pregnancy. Close antenatal examination should be routinely practiced to allow the timely diagnosis of early fetal heart failure., (Copyright © 2013 Wiley Periodicals, Inc.)

Transformation of the spiral arteries including the displacement of vascular endothelial cells by extravillous trophoblasts is an essential prerequisite to normal placentation. However, the activated endothelial cells resist the invasion of trophoblasts, which contributes to the pathologies of some pregnant disorders. Our previous studies have demonstrated that Cyclosporin A (CsA) promotes the migration and invasion of human first-trimester trophoblasts. In the present study, we further investigated whether CsA could promote the ability of trophoblasts to displace the activated human umbilical vein endothelial cell (HUVEC) monolayers and the possible molecular mechanisms. Human choriocarcinoma Jar cells were used as a model of invasive trophoblasts. CsA pretreated JAR cells (red) were added to HUVEC monolayers (green) activated with either necrotic JAR cells or tumor necrosis factor alpha (TNFα). The ability of JAR cells to displace HUVECs from the monolayers was examined by confocal microscopy. The effects of CsA on Titin and E-cadherin expression, matrix metalloproteinases (MMPs) activity and CXCL12 secretion of JAR cells were evaluated by western blot, gelatin zymography and enzyme-linked immunosorbent assay (ELISA), respectively. We found that CsA pretreatment increased the ability of JAR cells to displace activated HUVECs from the monolayers. However, the displacement was reduced by untreated JAR cells. Moreover, CsA pretreatment up-regulated Titin expression, down-regulated E-cadherin expression, improved MMP2 and MMP9 activity, and increased the CXCL12 secretion in JAR cells. These results indicate that CsA may improve the trophoblast invasion to activated HUVEC monolayers through different downstream targets, and ultimately, improve the transformation and remodeling of spiral arteries.

Previous studies showed that aberrant HLA-G expression in trophoblast cells plays important roles in trophoblast invasion; however, the mechanisms remain to be explored. In this study, we found that suppressed HLA-G expression could dramatically decrease the mRNA and protein expression levels of matrix metalloproteinase 2 and matrix metalloproteinase 9, and in the proteome assay, there were 3 identified proteins namely, prefoldin 1, eukaryotic translation elongation factor 2 and malate dehydrogenase 2, which were verified by Western blot and known to be associated with invasion, cell cycle and cell metabolism, respectively. Collectively, our study indicated a potential involvement of HLA-G in autocrine networks that may regulate prefoldin, MMPs and trophoblast invasion at the maternal-fetal interface in human pregnancy.