Background and Aims: The association of dyslipidemia with reproductive outcomes is largely unknown, especially in recurrent implantation failure (RIF) patients. This study aimed to explore the impact ...of abnormal blood lipid levels on embryo genetic status and pregnancy outcomes in unexplained RIF (uRIF) patients after preimplantation genetic testing for aneuploidy (PGT-A). Method: In this retrospective study, they were divided into 4 groups according to the levels of cholesterol and triglyceride: non-hyperlipidemia group (NonH group), simple hypercholesterolemia group (SHC group), simple hypertriglyceridemia group (SHC group) and mixed hyperlipidemia group (MixH group). Additionally, patients were divided into 2 groups according to their HDL-C level. Embryos’ genetic status and pregnancy outcomes after transfer of euploid embryos were analyzed. Binary logistic regression and/or generalized estimating equation model were conducted to investigate the association of different types of dyslipidemia with aneuploid embryo rate and cumulative live-birth rate. Results: A total of 474 women 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 aneuploid embryo rate 48.3% vs. 36.7%, P=0.006; adjusted OR (95% CI) = 1.52(1.04-2.22), as well as a reduced number of good-quality blastocysts 3.00±2.29 vs. 3.74±2.77, P=0.033. The SHC group showed a lower cumulative live-birth rate (47.0% vs. 40.0%), 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. The incidences of obstetric or neonatal complications and other adverse events were similar in the four groups. Conclusion: We found that uRIF women with hypercholesterolemia had an increased proportion of aneuploid embryos and a reduced number of high-quality embryos, while different types of hyperlipidemias had no correlation with cumulative live birth rate as well as pregnancy and neonatal outcomes.
The aim of the retrospective cohort study was to investigate the prognostic effect of subchorionic hematomas (SCH) in the first trimester on pregnancy outcomes after euploid embryo transfer.
We ...retrospectively analyzed women achieving singleton pregnancy by PGT-A or PGT-SR from January 2017 to January 2022. Patients were enrolled in the study if they had a viable intrauterine pregnancy at ultrasound between 6 0/7 and 8 0/7 weeks of gestation. Pregnancy outcomes as well as the incidence of maternal complications were compared between patients with and without SCH. Logistic regression was used for adjusting for potential confounding factors.
A total of 1539 women were included, of which 298 with SCH and 1241 with non-SCH. The early miscarriage rate in SCH group was significantly higher than that in the non-SCH group (10.1% vs. 5.6%, adjusted odds ratio aOR 1.99, 95% confidence interval CI 1.25-3.16, P = 0.003). The live birth rate in SCH group was significantly lower than that in the non-SCH group. (85.6% vs. 91.2%, aOR 0.57, 95% CI 0.39-0.84, P = 0.005). In addition, SCH group had an increased risk of hypertensive disorder of pregnancy (HDP) (8.9% vs. 5.2%, P = 0.022), especially in hematoma with bleeding (19.3% vs. 6.0%, P = 0.002). The incidence of gestational diabetes mellitus (GDM), major congenital abnormalities rate, normal birth weight rate and low birth weight rate were similar between the two groups.
The presence of SCH in the first trimester was associated with worse pregnancy outcomes after euploid embryo transfer, including an increased risk of early miscarriage and hypertensive disorder of pregnancy, along with a reduced live birth rate.
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 + or - 2.29 vs. 3.74 + or - 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. Keywords: Blood lipid, Unexplained repeated implantation failure (uRIF), Preimplantation genetic testing for aneuploidy (PGT-a), Aneuploid rate, Cumulative live birth, Pregnancy outcomes
Background and Aims: Maternal age has been reported to impact on embryo genetic status. However, current data on the association between maternal age and early embryo development are limited and ...inconclusive, especially among good-prognosis women. This study aims to determine the association between female age and embryonic aneuploidy based on next generation sequencing (NGS), as well as morphological score among women aged 20-37 years with a good prognosis. Method: This is a secondary analysis of a multi-center, randomized controlled trial conducted from July 2017 through June 2018, which investigated the efficacy of preimplantation genetic testing for aneuploidy (PGT-A) in good-prognosis infertile population. The women with PGT-A treatment were divided into three groups (20-24 yrs, 25-30 yrs, 31-37 yrs) according to maternal age. The diversity of embryo testing results based on NGS and morphological score were compared between three groups. Results: A total of 1809 embryos were analyzed in this study. The rates of embryonic overall aneuploidy (14.5%) and monosomy (3.0%) among females in the 25-30 age group were lower than those (aneuploidy 21.3%, monosomy 6.9%) in the 31-37 age group (adjusted P= 0.009, 0.004, respectively). However, the rates of embryonic aneuploidy (18.9%) and monosomy (3.9%) of females in the 20-24 age group did not differ from other two age groups. Although there was no significant difference in subsegmental aneuploidy rate among the three groups (P=0.215), the variation trend with age was consistent with that of embryonic aneuploidy. There was no significant difference in embryo morphological scores between the three groups. Conclusion: For young infertile women with a good prognosis, embryonic aneuploidy and monosomy are more likely to occur in advanced age more than 30 years. And embryonic development scores do not change significantly with increasing age.
Increasing evidence has revealed a close relationship between non-coding RNAs and recurrent implantation failure (RIF). However, the role of circular RNAs (circRNAs) in RIF pathogenesis remains ...largely unknown. Microarray analyses were used to identify the differentially expressed circRNA-circSTK40. Functional experiments, including decidualization induction and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, were performed to determine the effects of circSTK40 on human endometrial stromal cells (ESCs). The interactions between circSTK40 and proteins were investigated by RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation (coIP) assays. We observed that circSTK40 expression was upregulated in the RIF midluteal-phase endometrial samples. circSTK40 overexpression in ESCs inhibited the decidualization process but concurrently enhanced cell survival during stress. Mechanistically, circSTK40 directly bound to HSP90 and CLU, thus functioning as a scaffold to block their interactions and hinder the proteasomal degradation of HSP90. The resulting high levels of HSP90 led to the activation of the AKT pathway and downregulation of FOXO1 expression. Inhibitors of AKT (MK-2206) and HSP90 (17AAG) both abolished the effects of circSTK40 overexpression in ESCs and increased the decidualization levels in a dose-dependent manner. Our findings indicate a novel epigenetic mechanism for RIF pathogenesis involving circSTK40 activity and provide a foundation for targeted treatments in patients with low endometrial receptivity.
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We identified a novel upregulated circRNA (circSTK40) in midluteal-phase endometrium from recurrent implantation failure (RIF) patients, which impaired endometrial receptivity in RIF via modulating the HSP90/AKT/FOXO1 axis. Our findings indicate a novel epigenetic mechanism for RIF pathogenesis and provide a foundation for targeted treatments in patients with low endometrial receptivity.
Purpose
To investigate the associations of previous pregnancy failures, including implantation failures (IFs), biochemical pregnancy losses (BPLs), and early (EMs) and late miscarriages (LMs), with ...blastocyst aneuploidy and pregnancy outcomes after PGT-A.
Methods
This study included 792 couples who underwent PGT-A after multiple pregnancy failures. Subgroup analyses were used to compare the blastocyst aneuploidy rate (BAR), implantation rate (IR), early miscarriage rate (EMR), and live birth rate (LBR). Multiple linear and logistic regression models were used to evaluate the associations. The control group comprised couples with ≤ 2 IFs, ≤ 1 BPL, ≤ 1 EM, and no LM.
Results
Notably, a history of ≥ 4 IFs was significantly associated with an increase in aneuploid blastocysts (42.86% vs. 33.05%,
P
= 0.044, B = 10.23 for 4 IFs; 48.80% vs. 33.05%,
P
= 0.002, B = 14.43 for ≥ 5 IFs). Women with ≥ 4 prior EMs also harbored more aneuploid blastocysts (41.00% vs. 33.05%,
P
= 0.048; B = 9.23). Compared with the control group, women with ≥ 4 prior EMs had a significantly higher EMR (6.58% vs. 31.11%,
P
< 0.001, OR = 6.49) and a lower LBR (53.49% vs. 34.18%,
P
= 0.007, OR = 0.56) after euploid transfer. Moreover, a history of LM(s) was associated with adverse pregnancy outcomes after PGT-A (OR for EM = 3.16; OR for live birth = 0.48). However, previous BPLs and 2 EMs were not associated significantly with blastocyst aneuploidy and pregnancy outcomes after PGT-A.
Conclusion
A history of high-order IFs or EMs and existence of LM(s) were significantly associated with blastocyst aneuploidy and adverse pregnancy outcomes after PGT-A, whereas no such associations were observed with BPLs or 2 EMs.
Background and Aims: The safety of exogenous gonadotropins regarding its impact on embryos as well as pregnancy outcomes is still inconclusive. This study aimed to evaluate the effects of different ...doses and duration of gonadotropins on embryonic genetic status, pregnancy outcomes in infertile women with a good prognosis. Method: This is a secondary analysis of a multi-center, randomized controlled trial conducted from July 2017 through June 2018, which investigated the efficacy of preimplantation genetic testing for aneuploidy (PGT-A) in good-prognosis infertile population. Couples with PGT-A treatment were included in this study, and were divided into four groups according to the total dosage of exogenous gonadotropins and the duration of stimulation: Group1,2,3,4 with gonadotropins doses and stimulation duration Formula: see text1500 IU, <10 days; Formula: see text1500 IU, Formula: see text10 days; >1500 IU, <10 days; >1500 IU, Formula: see text10 days, respectively. Group 1 served as the control group. The main outcome measures were the rates of embryonic aneuploidy, mosaicism and cumulative live birth after transfers of euploid embryos. Results: A total of 579 couples were included, with 1737 embryos being genetically screened using NGS. After adjusting for confounding factors, embryo mosaicism rate was significantly increased in Group 2, 3, 4 in comparison with Group 1 (Group 2,3,4: 13.4%, 14.8%, 12.4%, respectively, vs. Group1: 8.9%; adjusted OR 95% CI: 1.651.07, 2.54, Formula: see text=0.024; 1.761.02, 3.30, Formula: see text=0.041; 1.501.01, 2.22, Formula: see text=0.043; respectively). There was no association between gonadotropins dose or duration and embryo aneuploidy rate. The cumulative live-birth rate was significantly lower in Group 2, 3 and 4 than that in Group 1 (Group 2,3,4: 73.2%, 64.8%, 75.2%, respectively, vs. Group 1: 85.0%; adjusted OR 95% CI: 0.50 0.28, 0.89, Formula: see text=0.019; 0.340.17, 0.68, Formula: see text=0.002; 0.590.35, 0.98, Formula: see text=0.043; respectively). Conclusions: High dose, prolonged ovarian stimulation may increase mosaic embryo rate and decrease cumulative live-birth rate after transfers of euploid embryos.in infertile women with a good prognosis.
Recurrent implantation failure (RIF) is a disease associated with endometrial receptivity dysfunction. Retinoic acid receptor alpha (RARα) is an important protein in many biological processes, such ...as differentiation and development. However, the exact underlying mechanism whereby RARα affects RIF remains unknown. This study investigated RARα expression and its contribution in the mid-luteal phase endometria of patients with RIF.
The expression levels of RARα and CCAAT/enhancer-binding protein (C/EBP) β in the endometria of the RIF and normal group were investigated using western blotting and immunohistochemistry. In
experiments, immortal telomerase-transformed human endometrial stromal cells (T-HESCs) were incubated with medroxyprogesterone-17-acetate (MPA) and cyclic adenosine monophosphate (cAMP) for 4 days to induce decidualization. The expression levels of the decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein-1 (IGFBP-1) were determined using quantitative polymerase chain reaction. RARα was knocked down using a small interfering RNA, and C/EBPβ was overexpressed from an adenoviral vector. The transcriptional regulation of
by RARα was determined by chromatin immunoprecipitation (ChIP) assay and luciferase assays.
We found that the expression levels of RARα decreased in the mid-luteal endometria of RIF patients. After 4 days of decidualization induction
, RARα knockdown impaired the decidualization of T-HESCs and downregulated the expression of C/EBPβ. The restoration of C/EBPβ expression rescued the RARα knockdown-induced suppression of T-HESC decidualization. In ChIP analysis of lysates from decidualized T-HESCs, the
promoter region was enriched in chromatin fragments pulled down using an anti-RARα antibody. However, the relationship between
transcription and RARα expression levels was only observed when the decidualization of T-HESCs was induced by the addition of cAMP and MPA. To identify the binding site of RARα/retinoid X receptor α, we performed luciferase assays. Mutation of the predicted binding site in
(-2,009/-1,781) decreased the transcriptional activity of the reporter. To confirm this mechanism, the expression levels of C/EBPβ in the mid-luteal endometria of RIF patients were determined and found to decrease with decreased RARα expression levels.
A deficiency of RARα expression in the mid-luteal endometrium inhibits decidualization due to the downregulation of
transcription. This is a potential mechanism contributing to RIF.
Background and Aims: Cesarean delivery (CD) rates continue to rise worldwide. Prior studies have indicated that CD is associated with not only various gynaecological symptoms and obstetric ...complications but also lower probability of subsequent fertility. However, the recognition about impact of CD on clinical outcomes in subsequent IVF/ICSI-FET is very limited. The purpose was to investigate the effects of previous CD on pregnancy and neonatal outcomes in single frozen-thawed embryo transfer (FET) cycles so that women with a previous cesarean delivery can be given detailed fertility counseling during the ART process. Methods: This is a large retrospective cohort study including a total of 5,750 patients who desired to transfer single vitrified-thawed blastocyst from the same oocyte retrieval cycle as their last live birth between January 2011 and January 2021 in a center for reproductive medicine in Shandong, China, comprising FET cycles of 3,853 previous single CD and 1,897 previous single vaginal delivery (VD). Results: Women with a previous CD had significantly lower rates of biochemical pregnancy (64.52% vs. 71.48% before propensity score matching (PSM), P<0.001; and 65.58% vs. 71.49% after PSM, P<0.001), clinical pregnancy (58.16% vs. 65.79% before PSM, P<0.001; and 59.22% vs. 66.17% after PSM, P<0.001) and live birth (48.17% vs. 55.82% before PSM, P<0.001; and 49.29% vs. 56.10% after PSM, P<0.001) than those with a previous VD. Meanwhile, the CD rate was significantly higher in the CD group (97.85% vs. 18.53% before PSM, P<0.001; and 98.02% vs. 20.51% after PSM, P<0.001). The rates of multiple pregnancy, miscarriage, ectopic pregnancy, multiple live birth, labor complications and preterm and neonatal outcomes were comparable between the two groups. Conclusion: Compared to VD, a previous CD is associated with a significant reduction in the rates of biochemical pregnancy, clinical pregnancy and live birth in patients undergoing subsequent single frozen-thawed blastocyst transfer.
Background and Aims: Hereditary nephropathy, including monogenic nephropathy, is an important cause of renal insufficiency and end-stage renal disease. Therefore, genetic blockade is necessary for ...couples with monogenic nephropathy. Following routine application of prenatal diagnosis, preimplantation genetic testing for monogenic disorders (PGT-M) has been applied to the genetic blockade of monogenic disease patients. The purpose of this study is to retrospectively analyze genetic counseling process for patients with nephropathy-related disease and provide clinical overviews of patients with monogenic nephropathy who underwent PGT-M. Method: A single-center retrospective cohort study was conducted at Center for Reproductive Medicine, Shandong University from January 2014 to December 2022. 352 couples with nephropathy-related disease were included in the cohort totally. Statistical analysis was performed using Statistical Package for Social Science software 26.0. Results: Of the 352 couples with nephropathy-related disease, 291 underwent genetic counseling, followed by 180 accepting genetic screening. 104 couples with monogenic nephropathy indications proceeded with PGT-M, including 91 of autosomal dominant inheritance, 9 of autosomal recessive inheritance, 3 of X-linked dominant inheritance, and one of X-linked recessive inheritance. 498 blastocysts were tested by PGT-M combined with preimplantation genetic testing for aneuploidy (PGT-A), making 72 transferable embryos, 249 non-transferable embryos, 72 genetic counseling embryos and 7 amplification failedembryos. Finally, 80 vitrified-thawed single blastocyst transfer cycles were performed. Live births occurred in 38 women, of which 37 transferred embryos with non-pathogenic genotypes. The results of prenatal diagnosis of all newborns were consistent with the testing results for embryos transferred. The cumulative live birth, biochemical pregnancy, clinical pregnancy, ongoing pregnancy and pregnancy loss rates were 36.54%, 56.73%, 49.04%, 7.69%, and 22.03% respectively. Conclusion: PGT-M is an effective means of genetic blockade for couples with monogenic nephropathy. The absence of genetic abnormalities detected by prenatal diagnosis in healthy newborns without monogenic nephropathy also underscore its validity.
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