Uterine infusion strategies for infertile patients with recurrent implantation failure: a systematic review and network meta-analysis.

BACKGROUND: Intra-uterine infusion treatments were reported to be beneficial to embryo implantation and pregnancy outcomes, and considered as potential therapies for infertile patients with recurrent implantation failure (RIF). Nevertheless, their efficiencies were controversial and there lack of consensus on which intrauterine treatment is the most effective. METHODS: All prospective trials (in Chinese or English) were searched in Databases PubMed, Cochrane, Web of Science, and CNKI from July 2013 to July 2023. We included studies that investigated various uterine infusions, including chorionic gonadotropin, granulocyte colony-stimulating factor, monocytes, platelet-rich plasma, etc. during IVF treatment and reported subsequent pregnancy outcomes. RESULTS: We finally included 56 researches, including 40 randomized controlled trials, 14 non-randomized controlled trials, and 3 prospective cohort studies. This study included a total of 11 uterine perfusion methods: Placebo, Human Chorionic Gonadotropin (HCG), Granulocyte Colony-Stimulating Factor (G-CSF), platelet-rich plasma (PRP), Peripheral Blood Mononuclear Cell (PBMC), Growth hormone (GH), dexamethasone (DEX), Embryo culture supernatant (ESC), PRP combined with G-CSF (PRP + G-CSF), RPR combined with subcutaneous injection of G-CSF (RPR + G-CSFsc), G-CSF combined with subcutaneous injection of AXaIU (G-CSF + AXaIUsc). Intrauterine infusion of HCG, PBMC, G-CSF, and PRP significantly improves pregnancy outcomes in patients with repeated implantation failure compared with blank controls or placebo, and PRP improved the clinical pregnancy and live birth most. GH and ESC infusion might improve the pregnancy outcomes, but uterine infusion of DEX was shown with high miscarriage. The combination therapy did not show a significant advantage over the mono-therapy. CONCLUSIONS: Intrauterine infusion of HCG, PBMC, G-CSF, and PRP are promising strategies for improving pregnancy outcomes for infertile patients with recurrent implantation failure. Among these treatments, PRP may be the best. More researches are required to explore the effect of drug combinations and less commonly used drugs as well. TRIAL REGISTRATION: Our study was registered in PROSPERO and the ID was CRD42023467188.

Impact of haemostasis methods during ovarian cystectomy on ovarian reserve: a pairwise and network meta-analysis.

BACKGROUND: Haemostasis during ovarian cystectomy is reported to damage the ovarian reserve, but the comparative impacts of three haemostasis methods (bipolar energy, suture and haemostatic sealant) on ovarian reserve in patients with ovarian cysts are not well known. METHODS: The Cochrane Library, PubMed and Web of Science databases were searched from the date of inception of the database to June 2022 for literature exploring the impact of haemostasis methods during ovarian cystectomy on ovarian reserve. A traditional meta-analysis was performed using Review Manager software. A network meta-analysis (NMA) was performed using Stata and GemTC software. RESULTS: The direct meta-analysis comparison indicated that the mean postoperative reduction of anti-Müllerian hormone (AMH) level was significantly higher in the electrocoagulation (bipolar) group than suture and haemostatic sealant group, both in the overall group and subgroup of women with ovarian endometrioma. In NMA, the reduction of postoperative AMH levels in the electrocoagulation (bipolar) group was higher than the suture group at 6 months with a statistical significance, and at 1, 3 and 12 months without a significant difference. The difference in the postoperative decrease of AMH level did not reach statistical significance between suture and sealant, coagulation and haemostatic sealant. The comprehensive ranking results revealed that suture treatment was, with the highest probability, beneficial to the protection of the ovarian reserve. CONCLUSIONS: There was insufficient research to detect the optimal haemostasis method for ovarian reserve preservation in ovarian cystectomy. Nevertheless, haemostasis by electrocoagulation (bipolar) should be avoided when possible, and the suture might be considered as the best choice.

Haemostasis during ovarian cystectomy is reported to damage the ovarian reserve, but the comparative impacts of three haemostasis methods (bipolar energy, suture and haemostatic sealant) on ovarian reserve in patients with ovarian cysts are not well known. The level of AMH is the most widely used surrogate for ovarian reserve. Our research compared the impact of three haemostasis methods (electrocoagulation, suture and haemostatic sealant) on changes in the levels of anti-Müllerian hormone at 1, 3, 6 and 12 month(s) after the operation. The outcomes revealed that there was insufficient research to detect the optimal haemostasis method for ovarian preservation in ovarian cystectomy. Nevertheless, haemostasis by electrocoagulation (bipolar) should be avoided when possible, and the suture might be considered as the best choice.

Raised levels of chemerin in women with preeclampsia: A meta-analysis.

Chemerin is a multifunctional adipokine associated with systemic inflammation, angiogenesis, and oxidative stress. Emerging evidence suggests a potential link between chemerin and the pathogenesis of preeclampsia (PE). In this systematic review and meta-analysis, we aimed to evaluate the serum chemerin levels in women with PE. A systematic search was conducted across Medline, Web of Science, and Embase databases from inception until April 15, 2023, to identify studies comparing serum chemerin levels in pregnant women with and without PE. A random-effects model was employed to pool the results, accounting for heterogeneity. Thirteen datasets from 10 observational studies, encompassing 832 women with PE and 1298 healthy pregnant women, were analyzed. The pooled findings indicated a statistically significant elevation in serum chemerin levels in women with PE compared to controls (mean difference [MD] = 89.56 ng/mL, 95% confidence interval [CI] 62.14 - 116.98; P < 0.001; I2 = 87%). The subgroup analysis revealed consistent findings across studies that measured chemerin levels before or after the diagnosis of PE, studies that did or did not match the body mass index (BMI), and studies with varying quality scores (P values for subgroup differences were all > 0.05). Compared to controls, women with severe PE exhibited a significantly greater increase in serum chemerin levels than those with mild PE (P value for subgroup difference = 0.007). Additionally, meta-regression analysis results suggested that the mean BMI of the included pregnant women might positively modify the difference in circulating chemerin levels between women with and without PE (coefficient = 8.92; P = 0.045). In conclusion, this meta-analysis suggests a positive correlation between elevated serum chemerin levels and PE diagnosis in comparison to pregnant women without the condition.

Thyroid autoimmunity and future pregnancy outcome in women of recurrent pregnancy loss: a meta-analysis.

BACKGROUND: Thyroid autoimmunity (TAI) has been associated with the risk of recurrent pregnancy loss (RPL). This systematic review and meta-analysis was conducted to evaluate the influence of TAI on subsequent pregnancy outcome of women with RPL. METHODS: A systematic search of Medline, Web of Science, and Embase was conducted to identify studies evaluating the influence of TAI on subsequent risk of pregnancy loss (PL) in women with RPL. Study quality was evaluated via the Newcastle-Ottawa Scale. A random-effects model was utilized to pool the results, accounting for heterogeneity. RESULTS: Ten observational studies were included. Compared to women without thyroid autoantibodies, RPL women with TAI had a higher risk of PL in their subsequent pregnancy (risk ratio [RR]: 1.46. 95% confidence interval [CI]: 1.20 to 1.78, p < 0.001; I2 = 35%). Sensitivity analyses showed consistent results in studies with thyroid peroxidase antibody positivity (RR: 1.50, 95% CI: 1.23 to 1.82) and in studies with TAI assessed before pregnancy (RR: 1.28, 95% CI: 1.07 to 1.53). Subgroup analyses showed that the results were not significantly different in prospective and retrospective studies, in RPL defined as at least two or three PL, in euthyroid women and women with euthyroidism or subclinical hypothyroidism, in women with and without levothyroxine treatment, in studies reporting first-trimester or overall PL, and in studies with different quality scores (p for subgroup difference all > 0.05). CONCLUSIONS: In women with RPL, positive for TAI may be related to a higher risk of PL in subsequent pregnancy.

Postpartum women's views on human milk banking in a city in Southeast China: a cross-sectional survey.

BACKGROUND: Donor human milk is the best alternative for preterm infants when their mother's own milk is insufficient or unavailable. The development of human milk banks in China started late, and in most of these banks, the amount of donor human milk is insufficient for clinical demand. Moreover, many mothers are reluctant to use donor human milk due to safety concerns. It is important to understand the potential supply and demand of donor human milk before establishing a new human milk bank. This study aimed to understand women's acceptance of human milk banking in Wenzhou, southeastern China. METHODS: A cross-sectional study was conducted in three community health centers in Wenzhou, southeast China, in December 2020. Data were collected from 305 postpartum women selected through convenience sampling. Sociodemographic, perinatal and breastfeeding characteristics, awareness and knowledge of human milk banking and willingness to donate human milk, and to accept donor human milk were assessed. Multivariable logistic regression analysis was used to explore independent predictors of willingness to donate human milk and to accept donor human milk. RESULTS: Only 17% (52/305) of our participants had heard of human milk banking prior to this survey. The prevalence of willingness to donate human milk and use donor human milk in our study was 73.4% (224/305) and 44.6% (136/305), respectively. Employment (adjusted odds ratio [AOR] 2.30; 95% confidence interval [CI] 1.17, 4.50) and human milk banking knowledge (AOR 1.23; 95% CI 1.12, 1.35) were independent predictors of willingness to donate human milk. Monthly household income in the previous year (AOR 2.18; 95% CI 1.17, 4.06), awareness of human milk banking (AOR 2.41; 95% CI 1.24, 4.67) and knowledge of human milk banking (AOR 1.22; 95% CI 1.11, 1.35) were significantly associated with willingness to accept donor human milk. CONCLUSIONS: In our study, awareness of human milk banks among women in the first year postpartum was low. More mothers were willing to donate human milk than to use donor human milk to feed their children. In our study, knowledge of human milk banking was a predictor of both willingness to donate human milk and willingness to use donor human milk. Programs with detailed information on human milk banking are needed to help mothers improve their knowledge and increase acceptance of human milk banking.

Chemerin promotes the pathogenesis of preeclampsia by activating CMKLR1/p-Akt/CEBPɑ axis and inducing M1 macrophage polarization.

A higher ratio of M1/M2 macrophages and an elevated chemerin level are both related to increased risk of preeclampsia. However, the crosstalk between these two events and their collective contribution to preeclampsia are not well understood. In this study, we assessed the impacts of chemerin chemokine-like receptor 1 (CMKLR1)/p-Akt/CEBPα axis in regulating macrophage polarization and mediating the pathogenic effects of chemerin on preeclampsia. We showed that chemerin, in a dose- and time-dependent manner, stimulated M1 macrophage polarization, inhibited macrophage-induced trophoblast invasion and migration, and suppressed macrophage-mediated angiogenesis. All these chemerin-induced phenotypes are essentially mediated by sequentially CMKLR1, Akt activation, and CEBPα. Mechanistically, CEBPα acted as a transcriptional activator for both IRF8 and chemerin. In vivo, chemerin aggravated preeclampsia, while α-NETA, an inhibitor for CMKLR1, significantly suppressed M1 macrophage polarization and alleviated preeclampsia. In summary, chemerin, by activating CMKLR1/Akt/CEBPα axis, forms a positive feedback loop, promotes M1 macrophage polarization, suppresses trophoblast migration/invasion and angiogenesis, and contributes to preeclampsia. Therefore, targeting chemerin signaling may benefit the prevention and/or treatment of preeclampsia.

HOXA9-induced chemerin signals through CMKLR1/AMPK/TXNIP/NLRP3 pathway to induce pyroptosis of trophoblasts and aggravate preeclampsia.

BACKGROUND: Up-regulated chemerin correlates with the risk and the severity of preeclampsia. In this study, we examined impacts and underlying mechanisms by which chemerin regulates pyroptosis and trophoblast inflammation. METHODS: An in vivo preeclampsia model was established in rats and trophoblasts challenged with hypoxia/reoxygenation (H/R) with or without exogenous chemerin were used as the in vitro model. Expressions of homeobox A9 (HOXA9), chemerin, chemerin receptor (the chemokine-like receptor 1 (CMKLR1)), activated AMP-activated protein kinase (AMPK), thioredoxin-interacting protein (TXNIP), and markers related to NOD-like receptor pyrin-containing receptor 3 (NLRP3) inflammasome were examined by Western blot, and in response to AMPK inhibitor, targeting CMKLR1 or HOXA9. Cell viability and death were examined by CCK-8 and Hoechst staining, respectively. Productions of IL-1ß and IL-18 in serum or culture medium were measured by ELISA. Transcriptional regulation of HOXA9 on chemerin was examined by combining expressional analysis, chromatin immunoprecipitation, and luciferase reporter assays. RESULTS: Up-regulations of HOXA9, chemerin, CMKLR1, TXNIP, and NLRP3 inflammasome were observed in both in vivo and in vitro models of preeclampsia, which were associated with increased death of trophoblasts and productions of IL-1ß and IL-18. CMKLR1 and activated-AMPK essentially mediated chemerin effects in trophoblasts. HOXA9 directly activated the transcription of chemerin. CONCLUSIONS: HOXA9 directly activates the transcription of chemerin, which, by activating the AMPK/TXNIP/NLRP3 inflammasome, promotes pyroptosis and inflammation of trophoblasts, and contributes to preeclampsia. Therefore, targeting chemerin signaling may benefit the prevention and/or treatment of preeclampsia.

Gonadotropin versus Follicle-Stimulating Hormone for Ovarian Response in Patients Undergoing in vitro Fertilization: A Retrospective Cohort Comparison.

BACKGROUND: Poor ovarian responders generally refer to patients who respond poorly to ovarian stimulation for assisted reproductive techniques (ART) such as in-vitro fertilization (IVF) and hence experience low live birth rate. Various controlled ovarian stimulation (COS) protocols have been developed during the past 3 decades for IVF/ICSI to improve oocyte quality and ultimately live birth rate, to increase ovarian response in POR patients, and to reduce the risk of ovarian hyperstimulation syndrome. Both highly puri?ed human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) have been widely used for COS during IVF/ICSI. Their in?uence on treatment outcome in women undergoing IVF/ICSI hasbeen actively debated. OBJECTIVES: To compare highly purified human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. METHODS: This retrospective cohort study included 60 patients with poor ovarian response (30 received hp-hMG and 30 received rFSH) undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. Pregnancy-related outcomes, ovarian response, oocyte, and embryo parameters were compared between the 2 groups. Additionally, serum insulin-like growth factor-1 and insulin-like growth factor binding protein-1 levels on the day of oocyte retrieval were compared between the 2 groups. RESULTS: The 2 treatments resulted in comparable numbers of oocytes retrieved and embryos, comparable oocyte retrieval rate, mature oocyte rate, and fertilization rate, and also comparable clinical pregnancy rates, implantation rates, and miscarriage rate. However, hp-hMG led to statistically insignificant higher viable embryo rate (54.0% vs 44.8%; P = 0.174) and live birth rate per pregnancy (16.7% vs 10%) versus rFSH. Finally, statistically significantly higher serum insulin-like growth factor-1 level (178.53 [13.70] ng/mL vs 164.93 [12.17] ng/mL; P = 0.01) and statistically insignificantly lower serum insulin-like growth factor binding protein-1 level (19.53 [3.56] ng/mL vs the lower insulin-like growth factor binding protein-1 level SD is (2.76 [20.83] ng/mL; P > 0.05) on the day of oocyte retrieval were associated with hp-hMG versus rFSH. CONCLUSIONS: hp-HMG and rFSH did not lead to significantly different treatment outcomes in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol, although significantly higher serum insulin-like growth factor-1 level and insignificantly lower serum insulin-like growth factor binding protein-1 level on the day of oocyte retrieval associated with hp-HMG might suggest a beneficial endocrine environment. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

AP2γ mediated downregulation of lncRNA LINC00511 as a ceRNA suppresses trophoblast invasion by regulating miR-29b-3p/Cyr61 axis.

BACKGROUND: Long noncoding RNA LINC00511 has been identified to be aberrant expression and may as a tumor oncogene in various carcinomas. However, the potential role of LINC00511 in the onset of Preeclampsia (PE) pathogenesis remains unexplored. METHODS: Placental tissues from patients with PE were collected to detect expression levels of LINC00511 by qRT-PCR. Human HTR-8/SVneo trophoblast cell line was cultured, CCK-8 assay, wound healing assay and transwell assay were performed to determine the regulation of trophoblast biological function by LINC00511. Bioinformatics analysis, chromatin immunoprecipitation (ChIP), luciferases reporter assay were performed to verify the regulatory mechanism of LINC00511. RESULTS: LINC00511 was aberrantly down-regulated in placental tissues of PE patients. Overexpression of LINC00511 promoted trophoblast cell proliferation, migration and invasion. The transcription factor AP2γ directly binds to the promoter region of LINC00511 to activate transcription. In addition, LINC00511 was enriched in cytoplasm and functioned as a molecular spong for miR-29b-3p, antagonizing its ability to repress Cyr61 protein translation. CONCLUSION: This study demonstrated that AP2γ mediated downregulation of LINC00511 suppresses trophoblast invasion by regulating miR-29b-3p/ Cyr61 axis.

Serum chemerin level in women with PCOS and its relation with the risk of spontaneous abortion.

BACKGROUND AND AIM: Insulin resistance (IR) was recognized as a risk factor for the occurrence of abortion in patients with polycystic ovary syndrome (PCOS). Chemerin was an adipokine which could induce IR and associated with reproductive process closely. However, few studies have inquired the relativity between chemerin and the occurrence of abortion in patients with PCOS. The aim of this study was to evaluate the relationship between serum chemerin and the occurrence of abortion in women with PCOS. METHODS: We recruited 198 women with PCOS to participate in our study. On the third day of menstrual cycle or a random day in women with amenorrhea, we obtained their venous blood and measured the fasting insulin, fasting plasma glucose, total cholesterol, high density lipoprotein cholesterol, triglyceride, chemerin, and hormones including FSH, E2, P, PRL, LH, and T. Additionally, BMI, HOMA-IR and LH/FSH of each subject were calculated. Finally, 58 of them were included in the study, in which 30 of them had normal pregnancy and the other 28 had an early miscarriage. We compared the biochemical characteristics between the normal pregnancy group and abortion group by independent-samples t test. RESULTS: In our study, those with a normal pregnancy had a lower level of BMI, FINs, HOMA-IR, and chemerin compared to abortion patients (p < .05). After adjusted for BMI, only chemerin was associated with the occurrence of abortion in PCOS patients (p < .05). CONCLUSIONS: Serum chemerin level is associated with the occurrence of abortion in patients with PCOS. Thus, serum chemerin may serve as a biomarker to identify pregnant women with PCOS who are at particular risk for later abortion, and who may benefit from prevention strategies.

Role of chemerin/CMKLR1 in the maintenance of early pregnancy.

Chemerin is a cytokine that attracts much attention in the reproductive process. This study aimed to explore the effects of chemerin and its receptor chemokine-like receptor 1 (CMKLR1) on the maintenance of early pregnancy. The expression levels of chemerin and CMKLR1 in the decidua tissues of 20 early normal pregnant women and 20 early spontaneous abortion women were examined by Western blot and real-time polymerase chain reaction analyses. CMKLR1 receptor antagonist (α-NETA) was then intrauterinely injected into normal pregnant mice model to assess its effect on the outcome of pregnancy and the phosphorylation rate of ERK1/2 in decidua tissues.We found that the expression level of chemerin in women who had experienced early spontaneous abortion was lower than in those who had experienced normal early pregnancy (P < 0.01); conversely, CMKLR1 expression was higher in the former than in the latter (P < 0.01). In a pregnant-mouse model, the embryo resorption rate of α-NETA group was higher than that in the negative control group (61.5% vs. 10.8%) (P < 0.001). Compared with the control group, ERK1/2 phosphorylation in decidua tissues decreased in the α-NETA-treated group (P < 0.01). These results suggested that the inhibition of the chemerin/CMKLR1 signaling pathway can lead to the abortion of mouse embryos, and that chemerin/CMKLR1 may play an important role in the maintenance of early pregnancy possibly by regulating ERK1/2 phosphorylation.

Correlation between unexplained recurrent spontaneous abortion with CD4+CD25+ regulatory T-cell and killer cell immunoglobulin-like receptor levels.

The present study investigated the correlation between unexplained recurrent spontaneous abortion (URSA) with CD4+CD25+ regulatory T-cell (Treg) and killer cell immunoglobulin-like receptor (KIR)-2DL1 levels. A total of 76 URSA patients were enrolled (35 without pregnancy, Group A, and 41 with early abortion, Group B). Additionally, 30 patients who received a regular abortion as planned (Group C) and 30 healthy volunteers (Group D) were selected. Peripheral venous blood and fresh decidual tissue samples were obtained from all the patients, and flow cytometry was performed to detect CD4+CD25+Treg and Foxp3 transcription factor levels. mRNA and protein KIR-2DL1 expression levels were assayed using quantitative PCR and western blot analysis, respectively. No statistically significant differences in peripheral venous blood CD4+CD25+Treg/CD4+ and Foxp3+/CD4+CD25+Treg cell proportions were found among the groups (P>0.05). However, the decidual tissues of Group C presented significantly higher levels of both cell types versus other groups (P<0.05). No statistically significant differences were found in comparisons among Groups A, B, and D (P>0.05). In peripheral venous blood, mRNA and protein KIR-2DL1 expression levels in Group C were significantly higher than those in the other three groups (P<0.05), but again, there were no statistically significant differences among Groups A, B, and D (P>0.05). In decidual tissues, KIR-2DL1 levels were significantly higher in Group C relative to Groups A, B, and D (P<0.05). Decreased CD4+CD25+Treg counts and KIR-2DL1 expression levels were closely associated with the onset of URSA. CD4+CD25+Tregs mainly exert their effects on decidual tissues, while KIR-2DL1 can act on peripheral venous blood and decidual tissues. These may present new targets for early intervention in URSA.

Serum chemerin level during the first trimester of pregnancy and the risk of gestational diabetes mellitus.

OBJECTIVE: To investigate the association between chemerin level in the first trimester of pregnancy and the risk of gestational diabetes mellitus. METHODS: The blood samples of 212 women at 8-12 weeks of gestation were collected. After screening for gestational diabetes mellitus (GDM), 19 women with GDM and 20 women randomly selected from 144 women with normal glucose tolerance (NGT) were included in the study. Blood samples were collected from these women. Triglycerides, glucose, total cholesterol, and HDL cholesterol, LDL cholesterol, insulin and chemerin were measured. Gestational weight gain and body mass index was assessed. RESULTS: Serum levels of chemerin were significantly elevated during late gestation, and the risk of GDM was positively associated with maternal serum chemerin in the first trimester. CONCLUSION: Serum chemerin level during the first trimester of pregnancy has the potential to predict risk of GDM.

Netrin-1 attenuates cardiac ischemia reperfusion injury and generates alternatively activated macrophages.

Ischemia reperfusion (IR) injury is a major issue in cardiac transplantation and inflammatory processes play a major role in myocardial IR injury. Netrin-1 is a laminin-related protein identified as a neuronal guidance cue and netrin-1 expressed outside the nervous system inhibits migration of leukocytes in vitro and in vivo and attenuates inflammation-mediated tissue injury. In our study, hearts of C57BL/6 mice were flushed and stored in cold Bretschneider solution for 8 h and then transplanted into syngeneic recipient. We found that netrin-1 decreased cardiomyocyte apoptosis and recruitment of neutrophils and macrophages. Troponin T (TnT) production on 24 h after myocardial IR injury was reduced by netrin-1 administration. Cardiac output at 60 mmHg of afterload pressure was significantly increased in hearts with netrin-1 administration (IR + Netrin-1: 59.9 ± 5.78 ml/min; IR: 26.2 ± 4.3 ml/min; P < 0.05). Netrin-1 treatment increased expression of the alternatively activated macrophage (AAM) markers arginase-1 (Arg-1) and mannose receptor (MR) and promoted proliferator-activated receptor γ (PPARγ) expression in cardiac allograft. Furthermore, decreased TnT expression and reduced allograft infiltration of neutrophils and monocytes/macrophages by netrin-1 was abolished with addition of PPARγ antagonist. In conclusion, netrin-1 attenuates cardiac IR injury and generates AAM which contributes to the protective effect of netrin-1.