Transcriptomic responses of cumulus granulosa cells to SARS-CoV-2 infection during controlled ovarian stimulation.

Cumulus granulosa cells (CGCs) play a crucial role in follicular development, but so far, no research has explored the impact of SARS-CoV-2 infection on ovarian function from the perspective of CGCs. In the present study, we compared the cycle outcomes between infected and uninfected female patients undergoing controlled ovarian stimulation, performed bulk RNA-sequencing of collected CGCs, and used bioinformatic methods to explore transcriptomic changes. The results showed that women with SARS-CoV-2 infection during stimulation had significantly lower number of oocytes retrieved and follicle-oocyte index, while subsequent fertilization and embryo development were similar. CGCs were not directly infected by SARS-CoV-2, but exhibited dramatic differences in gene expression (156 up-regulated and 65 down-regulated). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses demonstrated a high enrichment in antiviral, immune and inflammatory responses with necroptosis. In addition, the pathways related to telomere organization and double strand break repair were significantly affected by infection in gene set enrichment analysis. Further weighted gene co-expression network analysis identified a key module associated with ovarian response traits, which was mainly enriched as a decrease of leukocyte chemotaxis and migration in CGCs. For the first time, our study describes how SARS-CoV-2 infection indirectly affects CGCs at the transcriptional level, which may impair oocyte-CGC crosstalk and consequently lead to poor ovarian response during fertility treatment.

Pregnancy outcomes after frozen-thawed embryo transfer in women with COVID-19 history: A prospective cohort study.

The clinical effect of Coronavirus disease 2019 (COVID-19) on endometrial receptivity and embryo implantation remains unclear. Herein, we aim to investigate whether a COVID-19 history adversely affect female pregnancy outcomes after frozen-thawed embryo transfer (FET). This prospective cohort study enrolled 230 women who underwent FET cycles from December 2022 to April 2023 in an academic fertility center. Based on the history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection before FET, women were divided into the infected group (n = 136) and the control group (n = 94). The primary outcome was the clinical pregnancy rate per cycle. Multivariate logistic regression analysis was conducted to adjust for potential confounders, while subgroup analysis and restricted cubic splines were used to depict the effect of postinfection time interval on FET. The results showed that the clinical pregnancy rate was 59.6% in the infected group and 63.9% in the control group (p = 0.513). Similarly, the two groups were comparable in the rates of biochemical pregnancy (69.1% vs. 76.6%; p = 0.214) and embryo implantation (51.7% vs. 54.5%; p = 0.628). After adjustment, the nonsignificant association remained between prior infection and clinical pregnancy (OR = 0.78, 95% CI: 0.42-1.46). However, the odds for clinical pregnancy were significantly lower in the ≤30 days subgroup (OR = 0.15, 95% CI: 0.03-0.77), while no statistical significance was detected for 31-60 days and >60 days subgroups compared with the uninfected women. In conclusion, our findings suggested that SARS-CoV-2 infection in women had no significant effect on subsequent FET treatment overall, but pregnancy rates tended to be decreased if vitrified-thawed embryos were transferred within 30 days after infection. A 1-month postponement should be rationally recommended, while further studies with larger sample groups and longer follow-up periods are warranted for confirmation.

Association between proliferative-to-secretory endometrial compaction and pregnancy outcomes after embryo transfer: a systematic review and meta-analysis.

STUDY QUESTION: Does the change in endometrial thickness (EMT) from the end of the follicular/estrogen phase to the day of embryo transfer (ET) determine subsequent pregnancy outcomes? SUMMARY ANSWER: Endometrial compaction from the late-proliferative to secretory phase is not associated with live birth rate (LBR) and other pregnancy outcomes. WHAT IS KNOWN ALREADY: Endometrial compaction has been suggested to be indicative of endometrial responsiveness to progesterone, and its association with ET outcome has been investigated but is controversial. STUDY DESIGN, SIZE, DURATION: A systematic review with meta-analysis was carried out. PubMed, EMBASE, and Web of Science were searched to identify relevant studies from inception to 18 November 2022. The reference lists of included studies were also manually screened for any additional publications. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohort studies comparing ET pregnancy outcomes between patients with and without endometrial compaction were included. A review of the studies for inclusion, data extraction, and quality assessment was performed by two independent reviewers. The effect size was synthesized as odds ratio (OR) with 95% CI using a random-effects model. Heterogeneity and publication bias were assessed by the I2 statistic and Egger's test, respectively. The primary outcome was LBR. Secondary outcomes included biochemical pregnancy rate (BPR), clinical pregnancy rate (CPR), miscarriage rate (MR), ongoing pregnancy rate (OPR), and ectopic pregnancy rate (EPR). MAIN RESULTS AND THE ROLE OF CHANCE: Seventeen cohort studies involving 18 973 ET cycles fulfilled the eligibility criteria. The pooled results revealed that there were no significant differences between endometrial compaction and non-compaction groups in LBR (crude OR (cOR) = 0.95, 95% CI 0.87-1.04; I2 = 0%; adjusted OR (aOR) = 1.02, 95% CI 0.87-1.19, I2 = 79%), BPR (cOR = 0.93, 95% CI 0.81-1.06; I2 = 0%; aOR = 0.88, 95% CI 0.75-1.03, I2 = 0%), CPR (cOR = 0.98, 95% CI 0.81-1.18; I2 = 70%; aOR = 0.86, 95% CI 0.72-1.02, I2 = 13%), MR (cOR = 1.09, 95% CI 0.90-1.32; I2 = 0%; aOR = 0.91, 95% CI 0.64-1.31; I2 = 0%), and EPR (cOR = 0.70, 95% CI 0.31-1.61; I2 = 61%). The OPR was marginally higher in crude analysis (cOR = 1.48, 95% CI 1.01-2.16; I2 = 81%) among women with compacted endometrium, but was not evident in adjusted results (aOR = 1.36, 95% CI 0.86-2.14; I2 = 84%). Consistently, the pooled estimate of LBR remained comparable in further subgroup and sensitivity analyses according to the degree of compaction (0%, 5%, 10%, 15%, or 20%), type of ET (fresh, frozen, or euploid only), and endometrial preparation protocol (natural or artificial). No publication bias was observed based on Egger's test. LIMITATIONS, REASONS FOR CAUTION: Although the number of included studies is sufficient, data on certain measures, such as EPR, are limited. The inherent bias and residual confounding were also inevitable owing to the observational study design. Furthermore, inconsistent definitions of pregnancy outcomes may affect the accuracy of our pooled analysis. WIDER IMPLICATIONS OF THE FINDINGS: Given the lack of prognostic value, assessing endometrial compaction or repeated EMT measurement on the day of ET may not be necessary or warranted. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Natural Science Foundation of Jiangxi Province (20224BAB216025), National Natural Science Foundation of China (82260315), and Central Funds Guiding the Local Science and Technology Development (20221ZDG020071). The authors have no conflicts of interest to declare. REGISTRATION NUMBER: CRD42022384539 (PROSPERO).

Increased levels of villus-derived exosomal miR-29a-3p in normal pregnancy than uRPL patients suppresses decidual NK cell production of interferon-γ and exerts a therapeutic effect in abortion-prone mice.

OBJECTIVE: Recurrent pregnancy loss (RPL) patients have higher absolute numbers of decidual natural killer (dNK) cells with elevated intracellular IFN-γ levels leading to a pro-inflammatory cytokine milieu, which contributes to RPL pathogenesis. The main objective of this study was twofold: first to explore the regulatory effects and mechanisms of villus-derived exosomes (vEXOs) from induced abortion patients or RPL patients at the level of intracellular IFN-γ in dNK cells; second to determine the validity of application of vEXOs in the treatment of unexplained RPL (uRPL) through in vitro experiments and mouse models. METHODS: Exosomes were isolated from villus explants by ultracentrifugation, co-cultured with dNK cells, and purified by enzymatic digestion and magnetically activated cell sorting. Flow cytometry, enzyme-linked immunosorbent assays, and RT-qPCR were used to determine IFN-γ levels. Comparative miRNA analysis of vEXOs from induced abortion (IA) and uRPL patients was used to screen potential candidates involved in dNK regulation, which was further confirmed by luciferase reporter assays. IA-vEXOs were electroporated with therapeutic miRNAs and encapsulated in a China Food and Drug Administration (CFDA)-approved hyaluronate gel (HA-Gel), which has been used as a clinical biomaterial in cell therapy for > 30 years. In vivo tracking was performed using 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyaine iodide (DiR) labelling. Tail-vein and uterine horn injections were used to evaluate therapeutic effects of the engineered exosomes in an abortion-prone mouse model (CBA/J × DBA/2 J). Placental growth was evaluated based on placental weight. IFN-γ mRNA levels in mouse placentas were measured by RT-qPCR. RESULTS: IFN-γ levels were significantly higher in dNK cells of uRPL patients than in IA patients. Both uRPL-vEXOs and IA-vEXOs could be efficiently internalized by dNK cells, whereas uRPL-vEXOs could not reduce the expression of IFN-γ by dNK cells as much as IA-vEXOs. Mechanistically, miR-29a-3p was delivered by vEXOs to inhibit IFN-γ production by binding to the 3' UTR of IFN-γ mRNA in dNK cells. For in vivo treatment, application of the HA-Gel effectively prolonged the residence time of vEXOs in the uterine cavity via sustained release. Engineered vEXOs loaded with miR-29a-3p reduced the embryo resorption rate in RPL mice with no signs of systemic toxicity. CONCLUSION: Our study provides the first evidence that villi can regulate dNK cell production of IFN-γ via exosome-mediated transfer of miR-29a-3p, which deepens our understanding of maternal-fetal immune tolerance for pregnancy maintenance. Based on this, we developed a new strategy to mix engineered vEXOs with HA-Gel, which exhibited good therapeutic effects in mice with uRPL and could be used for potential clinical applications in uRPL treatment.

Associations of urinary heavy metals with age at menarche, age at menopause, and reproductive lifespan: A cross-sectional study in U.S. women.

Female reproductive timing and lifespan, with a close relation to long-term health outcomes, have been altered in U.S. women over the past decades. However, epidemiologic evidence of the potential causes was lacking. On the basis of 1981 naturally postmenopausal women from the National Health and Nutrition Examination Survey 1999-2020, this study aimed to investigate the associations of urinary heavy metals with age at menarche, age at menopause, and reproductive lifespan. Multivariate generalized linear regression and addictive models were used for single metal exposure analysis, and weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were employed for mixed exposures. In the fully adjusted model, higher urinary antimony concentration was associated with earlier age at menarche of 0.137 years, while higher concentrations of cadmium, cesium, lead, antimony, and thallium were associated with delayed age at menopause of 0.396-0.687 years. Additionally, urinary barium, cesium, lead, antimony, and thallium levels were associated with longer reproductive lifespan ranging between 0.277 and 0.713 years. Both WQS and BKMR models showed significantly positive associations of metal mixtures with age at menopause (ß: 0.667, 95 % CI: 0.120-1.213) and reproductive lifespan (ß: 0.686, 95 % CI: 0.092-1.280), with cadmium and lead identified as principal contributors. In conclusion, heavy metal exposures were associated with reproductive timing and lifespan of U.S. women, highlighting the need for further prevention and intervention strategies.

Identification of a novel splicing variant of thyroid hormone receptor interaction protein 13 (TRIP13) in female infertility characterized by oocyte maturation arrest.

PURPOSE: As a cause of primary female infertility, oocyte maturation arrest (OMA) is characterized by failure to obtain mature oocytes due to abnormal meiosis. We aimed to identify pathogenic variants in two sisters with OMA phenotype from a non-consanguineous family. METHODS: Whole-exome sequencing and Sanger sequencing were conducted to identify and validate the disease-causing gene variant. Additionally, we performed a minigene assay, quantitative reverse transcription PCR, and Western blotting to assess the effects of the variant. RESULTS: We identified a novel homozygous splicing variant (c.1021-11T>C) in TRIP13, which followed a recessive inheritance pattern. Minigene assay showed that the variant could disrupt the integrity of TRIP13 mRNA, as evidenced by the production of an alternative transcript with intron10 intermediate retention of 79 bp. Compared to normal controls, the expression of TRIP13 mRNA and abundance of TRIP13 protein were also significantly decreased in Epstein-Barr virus-immortalized lymphoblastoid cells derived from affected individuals. CONCLUSION: Our findings confirm the contribution of genetic factors to OMA and expand the mutation spectrum of TRIP13 in female infertility.

Effect of COVID-19 vaccination on semen parameters: A systematic review and meta-analysis.

The aim of this study was to investigate the effect of coronavirus disease 2019 (COVID-19) vaccination on semen parameters through systematic review and meta-analysis. PubMed, EMBASE, Web of Science, and Cochrane Library were comprehensively searched by June 2022. Studies were considered eligible if they compared semen parameters before and after COVID-19 vaccination or between vaccinated and unvaccinated men, with no restrictions on vaccine types or doses. The effect size was calculated as mean difference (MD) with 95% confidence interval (CI) using a random-effects model. Subgroup and sensitivity analyses were conducted to assess the sources of heterogeneity measured by the I2 statistic, with publication bias evaluated by Egger's test. Twelve cohort studies involving 914 participants fulfilled the inclusion criteria. In a comparison of vaccinated versus unvaccinated group, the pooled data revealed no significant differences in semen volume (MD = 0.18 ml, 95% CI -0.02 to 0.38), sperm concentration (MD = 1.16 million/ml, 95% CI -1.34 to 3.66), total sperm motility (MD = -0.14%, 95% CI -2.84 to 2.56), progressive sperm motility (MD = -1.06%, 95% CI -2.88 to 0.77), total sperm count (MD = 5.92 million, 95% CI -10.22 to 22.05), total motile sperm count (MD = 2.18 million, 95% CI -1.28 to 5.63), total progressively motile sperm count (MD = -3.87 million, 95% CI -13.16 to 5.43), and sperm morphology (MD = 0.07%, 95% CI -0.84 to 0.97). The results also remained similar across messenger ribonucleic acid, viral-vector, and inactivated COVID-19 vaccines. Sensitivity analysis identified two individual studies that contributed to heterogeneity, while the effect size was not materially altered. No obvious publication bias was detected among included studies. Our finding suggested that COVID-19 vaccination had no detrimental impact on semen quality, which could be potentially helpful to reduce male vaccine hesitancy and increase vaccination coverage.

Effect of endometrial thickness on obstetric and neonatal outcomes in assisted reproduction: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to explore the relationship of endometrial thickness (EMT) with obstetric and neonatal outcomes in assisted reproductive cycles. METHODS: PubMed, EMBASE, Cochrane Library and Web of Science were searched for eligible studies through April 2023. Obstetric outcomes include placenta previa, placental abruption, hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM) and cesarean section (CS). Neonatal outcomes include birthweight, low birth weight (LBW), gestational age (GA), preterm birth (PTB), small for gestational age (SGA) and large for gestational age (LGA). The effect size was estimated as odds ratio (OR) or mean difference (MD) with 95% confidence interval (CI) using a random-effects model. Inter-study heterogeneity was assessed by the chi-square homogeneity test. One-study removal method was used to determine the sensitivity of the meta-analysis. RESULTS: Nineteen studies involving 76,404 cycles were included. The pooled results revealed significant differences between the thin endometrium group and the normal group in placental abruption (OR = 2.45, 95% CI: 1.11-5.38, P = 0.03; I2 = 0%), HDP (OR = 1.72, 95% CI: 1.44-2.05, P < 0.0001; I2 = 0%), CS (OR = 1.33, 95% CI: 1.06-1.67, P = 0.01; I2 = 77%), GA (MD = -1.27 day, 95% CI: -2.41- -1.02, P = 0.03; I2 = 73%), PTB (OR = 1.56, 95% CI: 1.34-1.81, P < 0.0001; I2 = 33%), birthweight (MD = -78.88 g, 95% CI: -115.79- -41.98, P < 0.0001; I2 = 48%), LBW (OR = 1.84, 95% CI: 1.52-2.22, P < 0.00001; I2 = 3%) and SGA (OR = 1.41, 95% CI: 1.17-1.70, P = 0.0003; I2 = 15%). No statistical differences were found in placenta previa, GDM, and LGA. CONCLUSION: Thin endometrium was associated with lower birthweight or GA and higher risks of placental abruption, HDP, CS, PTB, LBW and SGA. Therefore, these pregnancies need special attention and close follow-up by obstetricians. Due to the limited number of included studies, further studies are needed to confirm the results.

Association between serum progesterone levels on the day of frozen-thawed embryo transfer and pregnancy outcomes after artificial endometrial preparation.

BACKGROUND: Previous studies have examined that a range of optimal serum P level during the implantation period was associated with optimal live birth rates. However, those results obtained with vaginal or intramuscular route of progesterone administration for luteal phase support (LPS) alone. Is there a relationship between the serum progesterone (P) on the day of frozen-thawed embryo transfer (FET) with the likelihood of a live birth (LB) in artificial cycles (AC) when using a combination of oral dydrogesterone and vaginal progesterone for LPS? METHODS: This was a retrospective study of 3659 FET cycles with artificial endometrial preparation in a Chinese tertiary-care academic medical centre from January 2015 to February 2017. Endometrial preparation was performed using estradiol (E2) valerate (Fematon-red tablets) 8 mg/d beginning on day 3 of the cycle, followed by administration of P both orally (8 mg/d Fematon-yellow tablets) and vaginally (400 mg/d; Utrogestan). The primary endpoint was live birth rate (LBR). The association between the serum P level on the embryo transfer day and pregnancy outcomes was evaluated by univariable and multivariable logistic regression analysis. RESULTS: The LBRs according to the serum P quartiles were as follows: Q1: 35.7%; Q2: 37.4%; Q3: 39.1% and Q4: 38.9%. Logistic regression analysis showed that the odds of a LB were not significantly different between the low (P < 7.9 ng/mL) and high (P ≥ 7.9 ng/mL) progesterone groups before or after adjustment (crude OR = 0.89, 95% CI: 0.76-1.04; adjusted OR = 0.89, 95% CI: 0.75-1.04). CONCLUSION: The present study suggests that the serum P levels on the day of embryo transfer (ET) do not correlate with the likelihood of a LB in artificial cycles when using a combination of oral dydrogesterone and vaginal progesterone for luteal phase support.

Dietary regulation of intestinal stem cells in health and disease.

Diet is a critical regulator for physiological metabolism and tissue homeostasis, with a close relation to health and disease. As an important organ for digestion and absorption, the intestine comes into direct contact with many dietary components. The rapid renewal of its mucosal epithelium depends on the continuous proliferation and differentiation of intestinal stem cells (ISCs). The function and metabolism of ISCs can be controlled by a variety of dietary patterns including calorie restriction, fasting, high-fat, ketogenic, and high-sugar diets, as well as different nutrients including vitamins, amino acids, dietary fibre, and probiotics. Therefore, dietary interventions targeting ISCs may make it possible to prevent and treat intestinal disorders such as colon cancer, inflammatory bowel disease, and radiation enteritis. This review summarised recent research on the role and mechanism of diet in regulating ISCs, and discussed the potential of dietary modulation for intestinal diseases.

Effect of previous wedge resection for interstitial pregnancy on pregnancy and neonatal outcomes following frozen-thawed embryo transfer (FET) cycles of IVF/ICSI: a retrospective study.

OBJECTIVE: The present study aimed to evaluate pregnancy and neonatal outcomes in women, with a previous history of wedge resection for interstitial pregnancy, in frozen-thawed embryo transfer (FET) cycles of IVF/ICSI. METHODS: The present study involved a retrospective case-control assessment of 75 cases and 375 control subjects over 6 years in a single center. To compare pregnancy and neonatal outcomes between cases, treated using wedge resection, and controls without any previous history of ectopic pregnancy, propensity score matching (1:5) was utilized. The study also compared subgroups in the case group. RESULTS: Women with previous wedge resection exhibited higher rates of ectopic pregnancy and uterine rupture rate as compared to control subjects (9.1% vs 1.3%, P = 0.025 and 4.5% vs 0%, P = 0.035, respectively). No statistically significant differences were recorded between the two cohorts with regard to clinical pregnancy rate, live birth rate, and neonatal outcomes. For pregnancy type subgroup analysis, Z-score and rates of large for gestational age were recorded to be significantly lower in twin pregnancy subgroup when compared with singleton pregnancy subgroup (0.10 (- 0.59, 0.25) vs 0.50 (- 0.97, 1.39), P = 0.005; 4.5% vs 26.1%, P = 0.047, respectively). CONCLUSION: The results of the present study indicated that previous wedge resection correlated to a higher risk of ectopic pregnancy and uterine rupture. However, it might not be related to an increased risk of adverse neonatal outcomes. The study recommended cesarean section in these patients. Further studies are required to verify the validity of current recommendations.

Increased blastomere number is associated with higher live birth rate in day 3 embryo transfer.

PURPOSE: To study the relationship between blastomere number and pregnancy outcomes of day 3 embryo transfers. METHODS: This retrospective cohort study included 2237 fresh single day 3 embryo transfer cycles from October 2013 to November 2020. Patients were divided into six groups according to the blastomere number on day 3: ≤ 6-cell (n = 100), 7-cell (n = 207), 8-cell (n = 1522), 9-cell (n = 187), 10-cell (n = 91) and ≥ 11-cell (n = 130). Generalized estimating equation analysis based on multivariate logistic regression model was performed to adjust for potential confounders. RESULTS: The live birth rate (LBR) was 19.0%, 27.1%, 38.9%, 32.1%, 44.0% and 53.8% for the ≤ 6-cell, 7-cell, 8-cell, 9-cell, 10-cell and ≥ 11-cell groups, respectively (P < 0.001). Specifically, the ≤ 6-cell group was associated with reduced LBR compared with the 8-cell group (aOR 0.50, 95% CI 0.29-0.86; P = 0.013). Conversely, the odds of live birth were significantly increased in patients transferred with 10-cell embryos (aOR 1.62, 95% CI 1.03-2.53; P = 0.035) and ≥ 11-cell embryos (aOR 2.14, 95% CI 1.47-3.11; P < 0.001) when using the 8-cell embryo group as reference. Similar trends were also observed in the rates of positive hCG test and clinical pregnancy, while no significant differences were detected in miscarriage risk. CONCLUSION: Increased blastomere number was associated with higher LBR in fresh single day 3 embryo transfer cycles. This finding questions the consensus on the reduced developmental potential of fast-cleaving embryos. Further large prospective studies are warranted for confirmation.

Impact of inactivated SARS-CoV-2 vaccination on embryo ploidy: a retrospective cohort study of 133 PGT-A cycles in China.

BACKGROUND: Unsubstantiated concerns have been raised on the potential correlation between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and infertility, leading to vaccine hesitancy in reproductive-aged population. Herein, we aim to evaluate the impact of inactivated SARS-CoV-2 vaccination on embryo ploidy, which is a critical indicator for embryo quality and pregnancy chance. METHODS: This was a retrospective cohort study of 133 patients who underwent preimplantation genetic testing for aneuploidy (PGT-A) cycles with next-generation sequencing technology from June 1st 2021 to March 17th 2022 at a tertiary-care medical center in China. Women fully vaccinated with two doses of Sinopharm or Sinovac inactivated vaccines (n = 66) were compared with unvaccinated women (n = 67). The primary outcome was the euploidy rate per cycle. Multivariate linear and logistic regression analyses were performed to adjust for potential confounders. RESULTS: The euploidy rate was similar between vaccinated and unvaccinated groups (23.2 ± 24.6% vs. 22.6 ± 25.9%, P = 0.768), with an adjusted ß of 0.01 (95% confidence interval [CI]: -0.08-0.10). After frozen-thawed single euploid blastocyst transfer, the two groups were also comparable in clinical pregnancy rate (75.0% vs. 60.0%, P = 0.289), with an adjusted odds ratio of 6.21 (95% CI: 0.76-50.88). No significant associations were observed between vaccination and cycle characteristics or other laboratory and pregnancy outcomes. CONCLUSIONS: Inactivated SARS-CoV-2 vaccination had no detrimental impact on embryo ploidy during in vitro fertilization treatment. Our finding provides further reassurance for vaccinated women who are planning to conceive. Future prospective cohort studies with larger datasets and longer follow-up are needed to confirm the conclusion.

Microenvironment-Protected Exosome-Hydrogel for Facilitating Endometrial Regeneration, Fertility Restoration, and Live Birth of Offspring.

Thin endometrium is a primary cause of failed embryo transfer, resulting in long-term infertility and negative family outcomes. While hormonal treatments have greatly improved fertility results for some women, these responses remain unsatisfactory due to damage and infection of the complex endometrial microenvironment. In this study, a multifunctional microenvironment-protected exosome-hydrogel is designed for facilitating endometrial regeneration and fertility restoration via in situ microinjection and endometrial regeneration. This exosome hydrogel is formulated via Ag+ -S dynamic coordination and fusion with adipose stem cell-derived exosomes (ADSC-exo), yielding an injectable preparation that is sufficient to mitigate infection risk while also possessing the antigenic contents and paracrine signaling activity of the ADSC source cells, enabling regeneration of the endometrial microenvironment. In vitro, this exosome-hydrogel exerts an outstanding neovascularization-promoting effect, increased human umbilical vein endothelial cell proliferation and tube formation for 1.87 and 2.2 folds. In vivo, microenvironment-protected exosome-hydrogel also reveals to promote neovascularization and tissue regeneration while suppressing local tissue fibrosis. Importantly, regenerated endometrial tissue is more receptive to give embryos and birth to a healthy newborn. This microenvironment-protected exosome-hydrogel system offers a convenient, safe, and noninvasive approach for repairing thin endometrium and fertility restoration.

Construction of lncRNA-related competing endogenous RNA network and identification of hub genes in recurrent implantation failure.

BACKGROUND: The mechanism of recurrent implantation failure (RIF) is unclear at present and poor endometrial receptivity may be one of the leading reasons. This study aims to construct a competing endogenous RNA (ceRNA) network and identify potential hub genes underlying the development of RIF. METHODS: Weighted gene co-expression network analysis was performed based on differentially expressed mRNAs (DEMs) and lncRNAs (DELs) from the GSE111974 dataset. Functional enrichment analyses of gene modules were conducted using Gene Ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway. A lncRNA-miRNA-mRNA ceRNA regulatory network was constructed according to predictive interaction derived from the LncRNADisease, miRTarBase, miRDB and TargetScan databases. Topological analysis determined the key genes with the highest centroid and their expressions were further verified using public datasets and quantitative real-time polymerase chain reaction. RESULTS: A total of 1500 DEMs and 3 DELs were significantly up-regulated, whereas 1022 DEMs and 4 DELs were significantly down-regulated in the RIF group compared with the control group. Six functional co-expression modules were enriched in various biological processes, such as cell adhesion, regulation of cell motility and cellular response to vascular endothelial growth factor stimulus. Five hub genes were identified in the ceRNA network, of which GJA1 was down-regulated whereas TET2, MAP2K6, LRRC1 and TRPM6 were up-regulated in RIF endometrium. CONCLUSIONS: We constructed a lncRNA-associated ceRNA network and identified five novel hub genes in RIF. This finding could be helpful to understand the molecular mechanism for RIF pathogenesis, and may provide novel insights for its early diagnosis and treatment.

Adverse effects of pre-pregnancy maternal underweight on pregnancy and perinatal outcomes in a freeze-all policy.

BACKGROUND: Underweight and overweight may affect reproduction and interfere with treatment of infertility. In the present retrospective analysis, we sought to evaluate the effect of low body mass index (BMI) on pregnancy and perinatal outcomes in frozen-thawed embryo transfer (FET) cycles. METHODS: This study involved 8755 FET cycles in a single IVF center during the period from January 2009 to December 2018. Both pregnancy and perinatal outcomes were assessed in women who were underweight, normal weight, and overweight as defined based on a respective BMI < 18.5 kg/m2, ≥ 18.5 BMI < 24.9 kg/m2, and BMI ≥ 25 kg/m2. RESULTS: Being underweight was linked to reduced implantation rates as compared to a normal weight (33.56% vs. 37.26%). Similarly, when comparing outcomes in underweight women to those in normal weight women, rates of clinical pregnancy (48.14% vs. 53.85%) and ongoing pregnancy (43.04% vs. 50.47%) were reduced. Rates of miscarriage were markedly reduced in the normal weight group relative to the overweight group (10.73% vs. 13.37%). Perinatal outcomes were largely comparable for all groups, with the exception of very low birth weight rates (normal weight:0.58% vs. overweight: 2.03%), very small for gestational age rates (normal weight:1.31% vs. overweight:3.55%) and very preterm delivery rates (normal weight:0.82% vs. overweight: 2.03%), which were significantly elevated for overweight mothers. CONCLUSIONS: These results indicate that being underweight is linked to negative pregnancy outcomes when undergoing FET-based IVF.

Value of endometrial thickness change after human chorionic gonadotrophin administration in predicting pregnancy outcome following fresh transfer in vitro fertilization cycles.

PURPOSE: To study whether the change of endometrial thickness (EMT) between the day of human chorionic gonadotrophin (hCG) administration and the day of embryo transfer has any impact on pregnancy outcome in fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. METHODS: This single-center retrospective cohort study included 2620 patients undergoing their first consecutive autologous IVF/ICSI cycles from January 2003 to December 2012. Patients were categorized into three groups based on the percentage change of post-hCG EMT: > 10% decrease, ± 10% plateau and > 10% increase. The primary outcome was live birth rate. RESULTS: Live birth rates were similar in the EMT decrease, plateau and increase groups (27.4% [174/635], 29.7% [300/1010] and 27.6% [269/975]; P = 0.649). Compared with the plateau group, both EMT decrease (crude odds ratio [cOR] 0.89, 95% confidence interval [CI] 0.72-1.11) and increase (cOR 0.90, 95% CI 0.74-1.10) on the day of transfer did not affect the likelihood of live birth. The non-significant association was maintained after controlling for major confounding factors, with the adjusted OR being 0.92 (95% CI 0.73-1.16) and 0.92 (95% CI 0.75-1.13) for the decrease and increase groups, respectively. CONCLUSION: EMT change after hCG administration did not provide significant prognostic information for pregnancy outcome in fresh IVF/ICSI cycles. This finding should offer reassuring information for patients with decreased EMT on the day of embryo transfer while questioning the necessity of EMT re-measurement prior to transfer as a routine practice.

Adherence to healthy dietary patterns and outcomes of assisted reproduction: a systematic review and meta-analysis.

This systematic review and meta-analysis aimed to evaluate the association between adherence to a healthy dietary pattern and outcomes of assisted reproductive techniques (ARTs). PubMed, Embase and Web of Science were searched for eligible studies through December 2019 according to the population, intervention, comparison, outcome and study design (PICOS) criteria. Eight prospective cohort studies (S) reporting pregnancy outcomes (O) of higher vs lower adherence to a healthy dietary pattern (I/C) in women undergoing ART treatment (P) were included, involving a total of 2229 women with 2067 embryo transfer cycles. The pooled odds ratio (OR) for positive pregnancy test, clinical pregnancy and ongoing pregnancy/live birth was 0.82 (95% confidence interval [CI] 0.65-1.03), 0.99 (95% CI 0.68-1.44) and 1.30 (95% CI 0.81-2.09), respectively. In conclusion, greater adherence to a healthy dietary pattern rich in vegetables, fruits, whole grains, legumes and fish, may not be significantly related to ART success.

Association between peak serum estradiol level during controlled ovarian stimulation and neonatal birthweight in freeze-all cycles: a retrospective study of 8501 singleton live births.

STUDY QUESTION: Is there an association between peak serum estradiol (E2) level during controlled ovarian stimulation (COS) and neonatal birthweight in freeze-all cycles? SUMMARY ANSWER: Peak serum E2 level during ovarian stimulation is not associated with neonatal birthweight in freeze-all cycles. WHAT IS KNOWN ALREADY: Supraphysiologic E2 levels during COS have been demonstrated to generate a suboptimal peri-implantation endometrial environment and thus lead to adverse neonatal outcomes in fresh embryo transfer cycles. Previous experimental studies also suggested a potential influence of superovulation on oocyte epigenetic programming, but whether it translates into altered phenotypes of fetal growth and development remains unclear in clinical practice. By segmenting the process of COS and embryo transfer, the freeze-all policy provides a novel model to investigate the sole impact of ovarian stimulation on oocytes after ruling out the effects of hyperestrogenic milieu on endometrium in fresh cycles. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of 8501 patients who underwent their first COS cycles with a freeze-all strategy and delivered live-born singletons in subsequent frozen-thawed embryo transfer cycles from January 2007 to December 2016 at a tertiary-care academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were categorized into six groups according to E2 level on trigger day in regular increments of 1000 pg/mL: <1000, 1000-1999, 2000-2999, 3000-3999, 4000-4999 and ≥5000 pg/mL. Univariable and multivariable linear regression and logistic regression analysis were performed to assess the independent association between peak E2 level and measures of neonatal birthweight including absolute birthweight, Z-score, low birthweight (LBW) and small-for-gestational age (SGA). MAIN RESULTS AND THE ROLE OF CHANCE: The six groups did not differ significantly in birthweight, Z-score or the incidence of LBW and SGA. Compared with the E2 <1000 pg/mL group, the adjusted mean difference (95% confidence interval [CI]) of stratified higher E2 groups was 17.2 (-31.0-65.5), 12.3 (-35.9-60.5), -4.1 (-51.9-43.7), -0.6 (-48.9-47.8) and -3.6 (-50.0-42.8) g for birthweight, and 0 (-0.11-0.10), 0.02 (-0.08-0.12), 0.04 (-0.06-0.14), -0.01 (-0.11-0.10) and -0.04 (-0.14-0.06) for Z-score, respectively. Regarding the outcomes of LBW and SGA, no increased risks were observed in each E2 category, with the adjusted odds ratio (95% CI) being 1.21 (0.68-2.16), 1.0 (0.58-1.90), 0.90 (0.50-1.63), 0.93 (0.51-1.69) and 1.08 (0.61-1.90) for LBW, and 0.97 (0.58-1.64), 1.06 (0.63-1.77), 0.77 (0.46-1.31), 0.71 (0.41-1.22) and 1.00 (0.60-1.65) for SGA, respectively. LIMITATIONS, REASONS FOR CAUTION: The study was retrospective in design, and other unknown confounding factors may not be included for adjustment. Furthermore, the generalization of the study finding could be limited to some extent by the majority of double cleavage-stage embryo transfer and difference in birthweight reference percentiles between Chinese and other populations. WIDER IMPLICATIONS OF THE FINDINGS: Our observations suggest that the hyperestrogenic milieu during COS does not seem to pose adverse effects on neonatal birthweight after frozen-thawed embryo transfer, which provides reassuring information for high ovarian responders in freeze-all cycles concerning their offspring's health. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Key Research and Development Program of China (SQ2018YFC100163) and National Natural Science Foundation of China (81571397, 81771533). The authors declare no conflict of interest.

Association between endometrial thickness and neonatal outcomes in intrauterine insemination cycles: a retrospective analysis of 1,016 live-born singletons.

BACKGROUND: Decreased endometrial thickness (EMT) has been suggested to be associated with reduced birthweight of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) newborns. Considering the differences in ovarian stimulation degree and laboratory procedures between IVF/ICSI and IUI treatment, we aim to investigate whether EMT has any influence on IUI infant outcomes as well. METHODS: This was a retrospective cohort study of 1016 patients who had singleton livebirths after IUI treatment cycles from January 2008 to December 2018 at a tertiary-care academic medical center in China. Patients were categorized into three groups by the 10th and 90th percentile of peak EMT: ≤7.6, 7.7-13.0 and ≥ 13.1 mm. The primary outcomes of the study were preterm birth (PTB), low birthweight (LBW) and small-for-gestational age (SGA). Multiple regression analyses were performed after controlling for a variety of potential confounders. RESULTS: No significant differences were found among the three groups in gestational age, birthweight and birthweight Z-score. Compared with the EMT 7.7-13.0 mm group, the incidences of PTB, LBW and SGA were 5.5% (adjusted odds ratio [aOR] 0.81, 95% confidence interval [CI] 0.33-2.01), 6.4% (aOR 1.44, 95% CI 0.58-3.58) and 7.3% (aOR 1.21, 95% CI 0.53-2.76) in the EMT ≤7.6 mm group, respectively. Similarly, EMT ≥13.1 mm was not significantly associated with risks of PTB (aOR 0.63, 95% CI 0.24-1.65), LBW (aOR 0.57, 95% CI 0.17-1.95) and SGA (aOR 0.73, 95% CI 0.28-1.92). The odds of other adverse neonatal outcomes, including macrosomia, large-for-gestational age and major congenital malformations, did not show significant differences before and after adjustment in both EMT ≤7.6 and ≥ 13.1 mm groups. CONCLUSIONS: EMT is not independently associated with adverse perinatal outcomes in IUI cycles. This novel finding would provide reassuring information for IUI patients with thin endometrial linings regarding their neonatal health. However, further prospective cohort studies with larger datasets are needed to confirm the conclusion.