Maternal hypercholesterolemia would increase the incidence of embryo aneuploidy in couples with recurrent implantation failure.

BACKGROUND: The association of dyslipidemia with embryo development and pregnancy outcomes is largely unknown, especially in unexplained recurrent implantation failure (uRIF) patients. Here, this study aimed to explore the impact of abnormal blood lipid levels on embryo genetic status and pregnancy outcomes after preimplantation genetic testing for aneuploidy (PGT-A) from a clinical perspective. METHODS: This study retrospectively analyzed 502 patients diagnosed as uRIF. They were divided into four groups according to the levels of cholesterol and triglyceride: nonhyperlipidemia group (NonH group), simple hypercholesterolemia group (SHC group), simple hypertriglyceridemia group (SHC group) and mixed hyperlipidemia group (MixH group). At the same time, patients were divided into non-low HDL-C group and low HDL-C group according to their HDL-C level. The outcomes of embryos genetic testing and pregnancy outcomes after PGT-A was analyzed between groups. Binary logistic regression and/or generalized estimating equation (GEE) model were conducted to investigate the association of different types of dyslipidemia with embryonic aneuploidy rate and cumulative live-birth rate. RESULTS: 474 women who met the inclusion criteria were divided into four groups: NonH group (N = 349), SHC group (N = 55), SHT group (N = 52) and MixH group (N = 18). Compared with the NonH group, SHC group had a significantly increased rate of embryo aneuploidy [48.3% vs. 36.7%, P = 0.006; adjusted OR (95% confidence interval) = 1.52(1.04-2.22), P = 0.029], as well as a reduced number of good-quality embryos on day 5 or 6 [3.00 ± 2.29 vs. 3.74 ± 2.77, P = 0.033]. The SHC group showed a tendency of a lower cumulative live birth rate (47.0% vs. 40.0%), a lower incidence of good birth outcome (37.2% vs. 34.5%) and a higher risk of clinical pregnancy loss (11.1% vs. 17.9%), but did not reach statistical significance (P > 0.05). The incidences of obstetric or neonatal complications and other adverse events were similar in the four groups. Whether patients have low HDL-C did not differ in pregnancy outcomes. CONCLUSIONS: We found that uRIF women with hypercholesterolemia had an increased proportion of aneuploid embryos and a reduced proportion of high-quality embryos, while different types of hyperlipidemia had no correlation with cumulative live birth rate as well as pregnancy and neonatal outcomes.

Study on Correlation between Peripheral Blood Lymphocyte Subsets and Un-explained Repeated Implantation Failure / 实用妇产科杂志

Objective:To analyze the correlation between peripheral blood lymphocyte subsets and unex-plained repeated implantation failure(URIF),and to investigate its predictive value for the diagnosis of URIF.Methods:A total of 156 patients with URIF who underwent treatment in the Department of Reproductive Medi-cine,The Second Affiliated Hospital of Kunming Medical University from October 1,2019 to December 1,2021 was selected as the URIF group.Meanwhile,age-matched 41 women with a history of healthy delivery in the past one year were selected as the control group.The percentages of peripheral blood lymphocyte subsets in the two groups were measured by flow cytometry,and the results were statistically analyzed.Receiver operating charac-teristic(ROC)curve was used to evaluate the predictive effect of lymphocyte subsets on URIF.Results:Com-pared with the control group,the percentage of CD3 + CD4 +[(34.03±7.26)%vs.(36.79±6.35)%,P = 0.017]、CD3 +HLA-DR +[(2.60±2.28)%vs.(3.60±2.39)%,P =0.017]、CD3 + CD16 + CD56 +[(1.24±1.04)%vs.(2.62±2.57)%,P<0.000]and CD4 +/CD8 +(1.37±0.48 vs.1.57±0.51,P =0.023)were sig-nificantly increased in URIF group,and were related to the increase of previous failure times to a certain extent.ROC analysis showed that CD3 + CD4 +>35.35%(AUC 0.624),CD3 + HLA-DR +>2.35%(AUC 0.669),CD3 +CD16 +CD56 +>1.86%(AUC 0.660)and CD4 +/CD8 +>1.26(AUC 0.628)could be used as an inde-pendent predictor for the diagnosis of URIF.Among the pair-wise combined indexes,CD3 + HLA-DR + combined with CD3 + CD16 + CD56 + had the highest prediction accuracy(AUC 0.739,Sensitivity 73.3%,Specificity 68.3%).The combination of the four indicators had the highest accuracy(AUC0.767,Sensitivity 68.6%,Specifici-ty 73.2%).Conclusions:There is immune dysfunction in patients with URIF,and the imbalance of peripheral blood lymphocyte subsets may be an important factor leading to embryo implantation failure.CD3 +CD4 +、CD4 +/CD8 +、CD3 +HLA-DR +and CD3 +CD16 +CD56 +could be used as independent indicators for the diagnosis of abnormal peripheral blood lymphocyte subsets in patients with URIF.The combination of them improves the accuracy of prediction,and it has a positive reference significance for dynamic monitoring and early intervention of URIF pa-tients in the process of assisted reproduction technology.

Improved pregnancy outcomes of cyclosporine A on patients with unexplained repeated implantation failure in IVF/ICSI cycles: A retrospective cohort study.

PROBLEM: Repeated implantation failure (RIF) is a daunting obstacle restricting the further improvement of embryo implantation rate (IR) and live birth rate (LBR). The beneficial effect of cyclosporine A (CsA) on reproductive outcomes of unexplained RIF(URIF) was explored after de novo embryo transfer (ET). METHOD OF STUDY: A retrospective cohort study was conducted, comparing pregnancy outcomes of 146 cycles (CsA group, n = 62; control group, n = 84) at the IVF center of Suzhou Municipal Hospital from April 2016 to March 2020. RESULTS: Baseline and transfer cycle characteristics of participants were comparable between groups. Overall, CsA exerted obvious improvement on IR (51.16% vs 31.97%, P = .006), clinical pregnancy rate (CPR) (58.06% vs 38.10%, P = .017), and LBR (48.39% vs 32.14%, P = .047). Especially, CsA showed remarkably enhancement on IR (41.38% vs 14.63%, P = .012), CPR (47.62% vs 17.24%, P = .021) of non-high quality embryos. No difference in obstetric and pediatric complications was observed, and no birth defects were reported under CsA application. CsA was found to be a predictor of clinical pregnancy [fine adjusted OR 2.360, 95 % CI 1.165-4.781; P = .017] and live birth [fine adjusted OR 2.339, 95% CI 1.124-4.867; P = .023] for multivariate logistic regression. Not surprisingly, the number of high quality embryos should also be considered as an independent predictor for clinical pregnancy [fine adjusted OR 1.637,95%CI 1.027-2.609; P = .038] and live birth [fine adjusted OR 1.890, 95% CI 1.165-3.068; P = .010]. CONCLUSION: CsA application in patients with URIF promotes the pregnancy outcomes and does not increase the risk of obstetric and pediatric complications.

Differential expression of innate/adaptive immunity genes induced by endometrial scratching as a hopeful approach for implantation boosting in unexplained, repeated implantation failure: An RCT.

BACKGROUND: Endometrial scratching (ES) has been proposed as a potential treatment for implantation improvement in unexplained repeated implantation failure (uRIF) patients, however, little is known about its exact molecular mechanisms. OBJECTIVE: This randomized controlled trial (RCT) was conducted on twenty uRIF patients to investigate the expression of innate and adaptive immune signaling genes after ES. METHODS: Ten uRIF patients in the intervention (twice endometrial sampling in follicular and luteal phases) and 10 uRIF patients in the control group (only luteal phase sampling) were randomly enrolled. Gene expression analysis with innate and adaptive immune response PCR-array kit between intervention and control groups were performed. RESULTS: Among innate immune-associated genes, a significant decrease was observed in the expression of APCS, CPR, CCL2, NLRP3, HLA-A, TLR3 and TLR4 in the intervention group. In adaptive immune-related genes, the expression level of CD80, CD86, CXCR3, IFNγ, IFNα1, IFNß, MBL2, CCR6, CCR8 and IL17A were decreased and CSF2, GATA3, and IL4 increased significantly in the intervention group (P < 0.05). Of 14 uRIF patients, five live birth (35.71 %) was achieved. CONCLUSION: ES in uRIF patients may exert positive effects on the endometrial preparation which increases its receptivity for embryo implantation by modulating the expression of an array of immune signaling pathway genes.

NKG2D as a Cell Surface Marker on γδ-T Cells for Predicting Pregnancy Outcomes in Patients With Unexplained Repeated Implantation Failure.

Maternal immune tolerance to semi-allogeneic fetus is essential for a successful implantation and pregnancy. Growing evidence indicated that low cytotoxic activity of γδ-T cells, which is mediated by activation and inhibitory receptors, is important for establishment of maternal immune tolerant microenvironment. However, the correlation between receptors on peripheral blood γδ-T cells, such as NKG2D, CD158a, and CD158b, and pregnancy outcome in patients with unexplained repeated implantation failure (uRIF) remains unclear. In this study, the association between the expression level of these receptors and pregnancy outcome in patients with uRIF was investigated. Thirty-eight women with uRIF were enrolled and divided into two groups: successful group and failed group, according to the pregnancy outcome on different gestational periods. The percentage of NKG2D+ γδ-T cells in lymphocytes was significantly higher in uRIF patients who had failed clinical pregnancy in subsequent cycle, compared with those who had successful clinical pregnancy. However, there were no differences about the frequencies of CD158a+ and CD158b+ γδ-T cells between the successful and failed groups. The receiver operating characteristic curve exhibited that the optimal cut-off value of NKG2D+ γδ-T cells was 3.24%, with 92.3% sensitivity and 66.7% specificity in predicting clinical pregnancy failure in uRIF patients. The patients with uRIF were further divided into two groups, group 1 (NKG2D+ γδ-T cells <3.24%) and group 2 (NKG2D+ γδ-T cells ≥3.24%), based on the cut-off value. The live birth rate of patients in the group 1 and group 2 were 61.5 and 28.0%, respectively. Kaplan-Meier survival curve further suggested that the frequency of NKG2D+ γδ-T cells in lymphocytes negatively correlated with live birth rate in patients with uRIF. In conclusion, our study demonstrated that the frequency of peripheral blood NKG2D+ γδ-T cells among lymphocytes is a potential predictor for pregnancy outcome in uRIF patients.