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Importance: The safety of exogenous gonadotropin treatment, based on its effect on embryos and pregnancy outcomes, remains inconclusive., Objective: To evaluate the associations of different doses and durations of gonadotropins with embryonic genetic status and pregnancy outcomes after euploid embryo transfer in couples with infertility., Design, Setting, and Participants: This study was a post hoc analysis of a multicenter randomized clinical trial (RCT) conducted at 14 reproductive centers throughout China from July 2017 to June 2018 that evaluated the cumulative live birth rate with or without preimplantation genetic testing for aneuploidy (PGT-A) among couples with infertility and good prognosis. The PGT-A group from the original RCT was selected for secondary analysis. Patients were divided into 4 groups according to the total dosage of exogenous gonadotropins and treatment duration: group 1 (≤1500 IU and <10 days), group 2 (≤1500 IU and ≥10 days), group 3 (>1500 IU and <10 days), and group 4 (>1 500 IU and ≥10 days). Group 1 served as the control group. Data were analyzed from June through August 2023., Interventions: Blastocyst biopsy and PGT-A., Main Outcomes and Measures: The primary outcomes were embryonic aneuploidy, embryonic mosaicism, and cumulative live birth rates after euploid embryo transfer., Results: A total of 603 couples (mean [SD] age of prospective mothers, 29.13 [3.61] years) who underwent PGT-A were included, and 1809 embryos were screened using next-generation sequencing. The embryo mosaicism rate was significantly higher in groups 2 (44 of 339 embryos [13.0%]; adjusted odds ratio [aOR], 1.69 [95% CI, 1.09-2.64]), 3 (27 of 186 embryos [14.5%]; aOR, 1.98 [95% CI, 1.15-3.40]), and 4 (82 of 651 embryos [12.6%]; aOR, 1.60 [95% CI, 1.07-2.38]) than in group 1 (56 of 633 embryos [8.8%]). There were no associations between gonadotropin dosage or duration and the embryo aneuploidy rate. The cumulative live birth rate was significantly lower in groups 2 (83 of 113 couples [73.5%]; aOR, 0.49 [95% CI, 0.27-0.88]), 3 (42 of 62 couples [67.7%]; aOR, 0.41 [95% CI, 0.21-0.82]), and 4 (161 of 217 couples [74.2%]; aOR, 0.53 [95% CI, 0.31-0.89]) than in group 1 (180 of 211 couples [85.3%])., Conclusions and Relevance: In this study, excessive exogenous gonadotropin administration was associated with increased embryonic mosaicism and decreased cumulative live birth rate after euploid embryo transfer in couples with a good prognosis. These findings suggest that consideration should be given to minimizing exogenous gonadotropin dosage and limiting treatment duration to improve embryo outcomes and increase the live birth rate., Trial Registration: ClinicalTrials.gov Identifier: NCT03118141.

Background: During the human menstrual cycle and pregnancy, the endometrium undergoes a series of dynamic remodeling processes to adapt to physiological changes. Insufficient endometrial remodeling, characterized by inadequate endometrial proliferation, decidualization and spiral artery remodeling, is associated with infertility, endometriosis, dysfunctional uterine bleeding, and pregnancy-related complications such as preeclampsia and miscarriage. Bone morphogenetic proteins (BMPs), a subset of the transforming growth factor-β (TGF-β) superfamily, are multifunctional cytokines that regulate diverse cellular activities, such as differentiation, proliferation, apoptosis, and extracellular matrix synthesis, are now understood as integral to multiple reproductive processes in women. Investigations using human biological samples have shown that BMPs are essential for regulating human endometrial remodeling processes, including endometrial proliferation and decidualization., Objective and Rationale: This review summarizes our current knowledge on the known pathophysiological roles of BMPs and their underlying molecular mechanisms in regulating human endometrial proliferation and decidualization, with the goal of promoting the development of innovative strategies for diagnosing, treating and preventing infertility and adverse pregnancy complications associated with dysregulated human endometrial remodeling., Search Methods: A literature search for original articles published up to June 2023 was conducted in the PubMed, MEDLINE, and Google Scholar databases, identifying studies on the roles of BMPs in endometrial remodeling during the human menstrual cycle and pregnancy. Articles identified were restricted to English language full-text papers., Outcomes: BMP ligands and receptors and their transduction molecules are expressed in the endometrium and at the maternal-fetal interface. Along with emerging technologies such as tissue microarrays, 3D organoid cultures and advanced single-cell transcriptomics, and given the clinical availability of recombinant human proteins and ongoing pharmaceutical development, it is now clear that BMPs exert multiple roles in regulating human endometrial remodeling and that these biomolecules (and their receptors) can be targeted for diagnostic and therapeutic purposes. Moreover, dysregulation of these ligands, their receptors, or signaling determinants can impact endometrial remodeling, contributing to infertility or pregnancy-related complications (e.g. preeclampsia and miscarriage)., Wider Implications: Although further clinical trials are needed, recent advancements in the development of recombinant BMP ligands, synthetic BMP inhibitors, receptor antagonists, BMP ligand sequestration tools, and gene therapies have underscored the BMPs as candidate diagnostic biomarkers and positioned the BMP signaling pathway as a promising therapeutic target for addressing infertility and pregnancy complications related to dysregulated human endometrial remodeling., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

As the first paper in this series of Views and Reviews on randomized controlled trials (RCTs), we aim to provide the basics of RCTs in infertility research. In this paper, we discuss the need and ethical considerations of large trials in infertility research and important aspects to guarantee the quality of a trial, including protocols, registrations and monitoring, issues of study design and analysis, and reporting standards. Because most of the treatment effects we would like to study represent relatively small signal-to-noise ratios, large RCTs are required to provide sufficient power to answer these questions. Trial protocols, registrations, and monitoring facilitate the transparency of conduct, analysis, and reporting of the trial. Issues of trial design and analysis, such as nonblinding and misuse of the denominators, are common in published trials in this area and could be further improved. Finally, following the current reporting standard facilitates complete and transparent reporting, critical appraisal, and interpretation., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Multiple pregnancies are one of the major safety concerns of in vitro fertilization (IVF) due to the increased risk of maternal and neonatal complications. Single embryo transfer is the most effective way to reduce the risk of multiple pregnancies. Selection of the embryo and optimization of the implantation environment are crucial to retain the success rate when the number of transferred embryos is diminished. Fresh embryo transfer with supra-physiological levels of hormones has been suggested to have an adverse effect on implantation. Elective frozen embryo transfer has been suggested to result in a higher rate of live birth than fresh embryo transfer. However, there is still a lack of evidence from randomized clinical trials comparing the efficacy and safety between frozen and fresh single blastocyst transfers., Methods/design: We are conducting a randomized controlled trial in women aged 20-35 undergoing their first cycle of IVF with or without intracytoplasmic sperm injection. After ovarian stimulation with a gonadotropin-releasing hormone antagonist protocol, women who obtain four or more embryos on day 3 of the embryo culture are randomized into two parallel groups: a single fresh blastocyst transfer group and a single frozen blastocyst transfer group (all blastocysts vitrified and a deferred frozen blastocyst transfer). The primary outcome is singleton live birth., Discussion: The results of this study will provide evidence for the efficacy and safety of the strategy of elective frozen single blastocyst transfer in women with a good prognosis., Trial Registration: Chinese Clinical Trial Registry, ChiCTR-IOR-14005405 . Registered on 30 Oct 2014.

Objective: To evaluate the influence of previous ectopic pregnancies (EP) and different EP treatment methods on in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) outcomes., Design: Retrospective cohort study., Setting: University-based reproductive medicine center., Patient(s): Women undergoing 51,268 fresh cycles of IVF-ICSI., Intervention(s): In women who had had an EP before the IVF treatment and women who were diagnosed with fallopian disease without an EP (control group), division into three treatment subgroups: subgroup 1, conservative treatment; subgroup 2, salpingostomy; and subgroup 3 salpingectomy., Main Outcome Measure(s): Estimates of IVF-ICSI outcome and ovarian function based on number of antral follicles and rates of implantation, EP, clinical pregnancy, and delivery., Result(s): For the experimental group and the control group, there were no statistically significant differences in the rates of implantation, clinical pregnancy, or delivery. However, the risk of recurrent EP was statistically significantly higher in the experimental group compared with the control group. There were no statistically significant differences in IVF-ICSI outcomes between the three treatment subgroups in terms of the basic antral follicle number or the dominant antral follicle numbers (>1.0 cm) after surgical treatment of EP., Conclusion(s): Our results suggest that women with a prior history of EP have a higher recurrence risk of EP after IVF in comparison with women with no history of EP. Previous EP has no effect on the main IVF-ICSI outcomes. For the treatment of EP, salpingostomy and salpingectomy do not statistically significantly affect ovarian function., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the effects of sperm chromatin structure abnormalities on the outcome of in vitro fertilization and embryo transfer (IVF-ET)., Methods: Sperm DNA fragmentation and chromatin packaging defects were assessed in 136 couples undergoing IVF-ET because of infertility. The relationship between sperm DNA fragmentation, chromatin packaging defects and fertilization rate and clinical pregnancy was evaluated., Results: Both sperm DNA fragmentation and chromatin packaging defect had a negative correlation with fertilization rate (r=-0.198, P<0.05, and r=-0.389, P<0.01, respectively). Both parameters were higher in couples who failed to achieve pregnancy than those who achieved clinical pregnancy (10.74% vs. 5.40%, P<0.01 and 23.58% vs. 11.83%, P<0.01, respectively)., Conclusion: Abnormality of sperm chromatin structure is one of the reasons for IVF-ET failure. Examination of sperm chromatin structure is helpful in predicting the risk of IVF-ET failure and optimizing treatment of infertility.

Objective: To clarify the relationship between oocyte maturation and mitochondria distribution and assess the effects of in vitro maturation (IVM) on the distribution of mitochondria in human oocytes., Design: Prospective randomized trial., Setting: Hospital-based IVF center., Patient(s): One hundred fifty-eight patients undergoing intracytoplasmic sperm injection (ICSI) treatment for male factors or combined with oviduct infertility and fifteen patients undergoing controlled ovarian hyperstimulation followed by coitus or IUI., Intervention(s): Of all the 284 immature oocytes, 140 were fixed directly. The others were prepared for IVM before they were fixed. All the 21 oocytes matured in vivo were fixed directly and stained for mitochondria. Both immature and mature oocytes were stained by Mito Tracker Green FM. The distribution of mitochondria was observed using a confocal laser scanning microscope., Main Outcome Measure(s): Mitochondrial distribution., Result(s): Three mitochondria distribution patterns were identified: peripheral, semiperipheral, and evenly diffused. A peripheral distribution of mitochondria was presented by 64.1% (50/78) of the germinal vesicle (GV) oocytes; 45.2% (28/62) of the meiosis I oocytes maintained the peripheral distribution; and 38.7% (24/62) presented a diffused status. After IVM, 75.5% (80/106) of the oocytes displayed an evenly diffused type of distribution. The mitochondria were more abundant in the inner cytoplasm than in the peripheral region in most of the oocytes matured in vivo., Conclusion(s): There are obvious changes in the distribution of mitochondria in human oocytes before and after maturation. Distribution of mitochondria in oocytes matured in vitro is slightly different from that of oocytes matured in vivo. The results may partially explain the reduced developmental potential of oocytes matured in vitro compared with those matured in vivo., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Current understanding holds that Klinefelter syndrome (KS) is not inherited, but arises randomly during meiosis. Whether there is any genetic basis for the origin of KS is unknown. Here, guided by our identification of some USP26 variations apparently associated with KS, we found that knockout of Usp26 in male mice resulted in the production of 41, XXY offspring. USP26 protein is localized at the XY body, and the disruption of Usp26 causes incomplete sex chromosome pairing by destabilizing TEX11. The unpaired sex chromosomes then result in XY aneuploid spermatozoa. Consistent with our mouse results, a clinical study shows that some USP26 variations increase the proportion of XY aneuploid spermatozoa in fertile men, and we identified two families with KS offspring wherein the father of the KS patient harbored a USP26-mutated haplotype, further supporting that paternal USP26 mutation can cause KS offspring production. Thus, some KS should originate from XY spermatozoa, and paternal USP26 mutations increase the risk of producing KS offspring.

Summary: Currently, obesity has achieved epidemic levels in reproductive‐aged women with a myriad of consequences. Obesity is susceptible to several reproductive complications that eventually affect fertility rates. These complications originate from the deteriorated quality of oocytes from mothers with obesity, which increases the probability of chromosomal aneuploidy, elevated reactive oxygen species production, compromised embryonic developmental competency, and eventually reduced fertility. Maternal obesity is linked to pregnancy complications such as implantation error, abortion, miscarriage, and early pregnancy loss. This review highlights the adverse effects of maternal obesity on female fertility, with a focus on the mechanistic link between maternal obesity and oocyte quality and discusses possible measures to reduce its associated risks. [ABSTRACT FROM AUTHOR]

Objective: To identify the influence of different infertility causes and assisted reproductive technology (ART) treatment on perinatal outcomes and clarify the relationship between the maternal pathophysiological changes and artificial interventions. Methods: A total of 1,629 fertile women and 27,112 infertile women with sole infertility causes were prospectively recruited from July 2014 to December 2017, and 9,894 singletons were finally enrolled into the study. Pregnancies with more than one cause of infertility and/or multiple births were excluded. According to the causes of infertility and the exposure of ART treatment, the participants were divided into four groups, namely, fertile naturally conceived (NC) group, infertile NC group, female factor ART group, and male factor ART group. Perinatal outcomes, including gestational age of delivery (GA), birth weight (BW), preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), and large for gestational age (LGA), were compared among groups. Logistic regression was performed for the adjustment of several covariates. Result(s): The birth outcomes of the infertile NC group and fertile NC group, female factor ART group, and infertile NC group were comparable. Compared to the fertile NC group, the female factor ART group had a shorter GA (39.0 ± 1.6 vs. 39.3 ± 1.5 weeks, BW: P < 0.05). An interaction test showed that ART treatment had an interaction on the effect of female infertility on GA (P = 0.023). The female factor ART group also had a higher risk of PTB (OR 1.56, 95% CI 1.18–2.07) and LGA (OR 1.27, 95% CI 1.10–1.47) compared to the fertile NC group. The risk of PTB was increased for tubal factor ART (OR 1.49, 95% CI 1.12–2.00), ovulatory dysfunction ART (OR 1.87, 95% CI 1.29–2.72), and unexplained infertility ART (OR 1.88, 95% CI 1.11–3.17). The risk of LGA was increased for tubal factor ART (OR 1.28, 95% CI 1.11–1.48) and ovulatory dysfunction ART (OR 1.27, 95% CI 1.03–1.57). Conclusion(s): Our findings indicated that ART treatment could amplify the adverse effect of female infertility on neonates. Women with tubal factor infertility, ovulatory dysfunction, and unexplained infertility have a higher risk of PTB after ART treatment. Thus, clinicians should be vigilant in such patients and provide corresponding prevention strategies before and during pregnancy. [ABSTRACT FROM AUTHOR]

Oocyte maturation is vital to attain full competence required for fertilization and embryogenesis. NLRP14 is preferentially expressed in mammalian oocytes and early embryos. Yet, the role and molecular mechanism of NLRP14 in oocyte maturation and early embryogenesis are poorly understood, and whether NLRP14 deficiency accounts for human infertility is unknown. Here, we found that maternal loss of Nlrp14 resulted in sterility with oocyte maturation defects and early embryonic arrest (EEA). Nlrp14 ablation compromised oocyte competence due to impaired cytoplasmic and nuclear maturation. Importantly, we revealed that NLRP14 maintained cytoplasmic UHRF1 abundance by protecting it from proteasome-dependent degradation and anchoring it from nuclear translocation in the oocyte. Furthermore, we identified compound heterozygous NLRP14 variants in women affected by infertility with EEA, which interrupted the NLRP14-UHRF1 interaction and decreased UHRF1 levels. Our data demonstrate NLRP14 as a cytoplasm-specific regulator of UHRF1 during oocyte maturation, providing insights into genetic diagnosis for female infertility. [Display omitted] • NLRP14 is required for oocyte maturation and early embryonic development • Loss of Nlrp14 compromises oocyte competence by impairing nuclear and cytoplasmic maturation • NLRP14 interacts with UHRF1 to regulate its cytoplasmic abundance and localization • NLRP14 variants are identified in women affected by infertility with early embryonic arrest Zhang et al. show that NLRP14 is essential for oocyte maturation and competence required for early embryogenesis. NLRP14 maintains cytoplasmic UHRF1 abundance by protecting it from degradation and anchoring it from nuclear accumulation, and its deficiency accounts for female infertility in both mice and human. [ABSTRACT FROM AUTHOR]

Purpose: Chromosomal polymorphisms are associated with infertility, but their effects on assisted reproductive outcomes are still quite conflicting, especially after IVF treatment. This study evaluated the role of chromosomal polymorphisms of different genders in IVF pregnancy outcomes. Methods: Four hundred and twenty-five infertile couples undergoing IVF treatment were divided into three groups: 214 couples with normal chromosomes (group A, control group), 86 couples with female polymorphisms (group B), and 125 couples with male polymorphisms (group C). The pregnancy outcomes after the first and cumulative transfer cycles were analyzed, and the main outcome measures were live birth rate (LBR) after the first transfer cycle and cumulative LBR after a complete IVF cycle. Results: Comparison of pregnancy outcomes after the first transfer cycle within group A, group B, and group C demonstrated a similar LBR as well as other rates of implantation, clinical pregnancy, early miscarriage, and ongoing pregnancy ( P > 0.05). However, the analysis of cumulative pregnancy outcomes indicated that compared with group A, group C had a significantly lower LBR per cycle (80.4 vs 68.00%), for a rate ratio of 1.182 (95% CI 1.030 to 1.356, P = 0.01) and a significantly higher cumulative early miscarriage rate (EMR) among clinical pregnancies (7.2 vs 14.7%), for a rate ratio of 0.489 (95% CI 0.248 to 0.963, P = 0.035). Conclusion: Couples with chromosomal polymorphisms in only male partners have poor pregnancy outcomes after IVF treatment manifesting as high cumulative EMR and low LBR after a complete cycle. [ABSTRACT FROM AUTHOR]

Background: Multiple pregnancies are one of the major safety concerns of in vitro fertilization (IVF) due to the increased risk of maternal and neonatal complications. Single embryo transfer is the most effective way to reduce the risk of multiple pregnancies. Selection of the embryo and optimization of the implantation environment are crucial to retain the success rate when the number of transferred embryos is diminished. Fresh embryo transfer with supra-physiological levels of hormones has been suggested to have an adverse effect on implantation. Elective frozen embryo transfer has been suggested to result in a higher rate of live birth than fresh embryo transfer. However, there is still a lack of evidence from randomized clinical trials comparing the efficacy and safety between frozen and fresh single blastocyst transfers.Methods/design: We are conducting a randomized controlled trial in women aged 20-35 undergoing their first cycle of IVF with or without intracytoplasmic sperm injection. After ovarian stimulation with a gonadotropin-releasing hormone antagonist protocol, women who obtain four or more embryos on day 3 of the embryo culture are randomized into two parallel groups: a single fresh blastocyst transfer group and a single frozen blastocyst transfer group (all blastocysts vitrified and a deferred frozen blastocyst transfer). The primary outcome is singleton live birth.Discussion: The results of this study will provide evidence for the efficacy and safety of the strategy of elective frozen single blastocyst transfer in women with a good prognosis.Trial Registration: Chinese Clinical Trial Registry, ChiCTR-IOR-14005405 . Registered on 30 Oct 2014. [ABSTRACT FROM AUTHOR]

Objective: To explore the potential damaging effect of chronic pelvic inflammation on ovarian reserve. Design: Case-control study. Patients: A total of 122 women with bilateral tubal occlusion, diagnosed by hysterosalipingography (HSG) and 217 women with normal fallopians were recruited. Measurements: Serum anti-Mullerian hormone (AMH), basic follicle-stimulating hormone (FSH), luteining hormone (LH), estradiol (E2), and testosterone (T) were measured; and antral follicle counts (AFCs) were recorded. Results: Significantly lower level of AMH was observed in women with bilateral tubal occlusion compared to control group [2.62 (2.95) ng/ml vs. 3.37 (3.11) ng/ml, P = 0.03], and the difference remained after adjustment of BMI (Padjust = 0.04). However, no statistical difference was found in the levels of FSH [7.00 (2.16) IU/L vs. 6.74 (2.30) IU/L], LH [4.18 (1.52) IU/L vs. 4.63 (2.52) IU/L], E2 [35.95 (20.40) pg/ml vs. 34.90 (17.85) pg/ml], T [25.07±11.46 ng/dl vs. 24.84±12.75 ng/dl], and AFC [6.00 (4.00) vs. 7.00 (4.00)] between two groups (p>0.05). Conclusions: Women with bilateral tubal occlusion showed decreased AMH level, suggesting that chronic pelvic inflammation may diminish ovarian reserve. More caution should be paid when evaluating the detriment of PID on female fertility. [ABSTRACT FROM AUTHOR]

Background: In premature ovarian failure (POF), cessation of menstruation occurs before the expected age of menopause. Approximately 1% of women are affected. FMR1 premutation was reported to be responsible for up to 3.3%–6.7% of sporadic POF and 13% of familial cases in Caucasians, while the data was absent in Chinese population. Therefore, the impact of FMR1 CGG repeat on ovarian reserve is needed to be investigated in large Chinese cohort. Methods: The number of FMR1 CGG repeat was determined in 379 Han Chinese women with well-defined 46, XX non-syndromic sporadic POF and 402 controls. The age of menopause onset in respect to CGG repeats was further analyzed. Results: The frequency of FMR1 premutation in Han Chinese POF was only 0.5% (2/379), although it was higher than that in matched controls (0%, 0/402), it was much lower than that reported in Caucasian with POF (3.3%–6.7%). The prevalence of intermediate FMR1 (41–54) was not increased significantly in sporadic POF than that in controls (2.9% vs. 1.7%, P = 0.343). However, POF patients more often carried a single additional CGG repeat in a single allele than did fertile women (allele-1: 29.7 vs. 28.8, P<0.001; allele-2: 32.6 vs. 31.5, P<0.001). POF patients with both alleles of CGG repeats outside (below or above) the normal range (26–34) showed an earlier age of cessation of menses than those with two alleles within normal range (hom-high/high vs. norm: 20.4±4.8 vs. 24.7±6.4, p<0.01; hom-low/high vs. norm: 18.7±1.7 vs. 24.7±6.4, p<0.01). Conclusions: FMR1 premutation seems to be an uncommon explanation for POF in Han Chinese. However, having both alleles with CGG repeats outside the normal range might still adversely affect ovarian aging. [ABSTRACT FROM AUTHOR]

BACKGROUND This retrospective cohort study was to determine the frequency and types of chromosomal abnormalities in Han Chinese women with well-documented premature ovarian failure (POF). METHODS Karyotype analysis and correlation to phenotypes were performed on 531 Chinese patients with proven POF (FSH > 40 mIU/ml) attending four reproductive centers in China. G-banded metaphase chromosomes were prepared and analyzed, with mosaicism excluded by counting up to 100 cells from lymphocytes. RESULTS Chromosomal abnormalities were present in 64 of 531 (12.1%) POF cases, of which 32 were X-structural aberrations (7 mosaic): 15 del(Xq), 2 del(Xp), 11 isochromosomes [6 i(Xp); 5 i(Xq)], 1 ring chromosome (mosaic), 1 inversion (mosaic), 1 isodicentric chromosome and 1 complex arrangement. Nine non-mosaic X-autosome translocations were detected, all but 1 involving Xq. Aneuploidy without a structurally abnormal X was found in 19 cases: 7 non-mosaic 45,X, 9 45,X mosaicisms and 3 47,XXX (1 mosaic with 46,XX line). Karyotypic abnormalities were more frequent in patients with primary amenorrhea (15/70, 21.4%) than those with secondary amenorrhea (49/461, 10.6%; P = 0.01). 45,X and 45,X/46,XX mosaicism were the complements most frequently associated with primary amenorrhea (46.7%). Two of the three cases with 46,XY or 45,X/46,XY karyotype presented with ‘secondary amenorrhea’. One balanced autosomal Robertsonian translocation was also detected. CONCLUSIONS The overall prevalence of chromosomal abnormalities was 12.1% in this first large scale report of chromosomal aberrations in Chinese women with POF. In one of the largest samples of women with POF reported from any population, the prevalence of X-structural abnormalities, X-autosome translocations and X aneuploidy confirms the essential role X chromosomal abnormalities play in POF. [ABSTRACT FROM AUTHOR]

The purpose of this study was to explore the effects of cumulus cells on vitreous cryopreservation of human mature oocytes and clinical pregnancy outcomes. The study was divided into group A (cumulus cells were removed from the oocytes before freezing) containing 24 participants and 193 oocytes and group B (cumulus cells were retained with the oocytes before freezing) containing 26 participants and 240 oocytes. Based on no significant differences in age, duration of infertility, infertile causes, and number of retrieved oocytes between both groups when oocytes were retrieved from infertile women, we found that the survival rate of post thaw oocytes (88% vs 58%), cleavage rate (80% vs 56%), and high-quality embryo rate (75% vs 59%) were significantly higher in group B than in group A. Under the conditions that there were no significant differences between the 2 groups in the general status of the participants undergoing embryo transfer, the embryo implantation rate (37% vs 15%) and the clinical pregnancy rate (50% vs 17%) were significantly higher in group B than in group A, all with Ps < .05. We conclude that the retention of cumulus cells can improve the developmental competence of vitrified–thawed human mature oocytes and clinical pregnancy outcomes. [ABSTRACT FROM PUBLISHER]

Aim: To investigate whether early apoptotic changes in spermatozoa can be significant markers for sperm quality. Methods: Two early apoptotic changes in the semen of 56 men were assessed using Annexin V (AN)/propidium iodide (PI) staining for phosphatidylserine externalization and JC-1 staining for mitochondrial membrane potential (MMP). The results were compared with conventional semen parameters and DNA fragmentation identified using the TUNEL assay. Results: The different labeling patterns in the bivariate Annexin V/PI analysis identified four distinctive spermatozoa populations. The percentage of AN-/PI- spermatozoa positively correlated with conventional semen parameters and MMP, but negatively correlated with TUNEL (+) spermatozoa. As for the AN-/PI+ fraction, we found an opposite result in comparison to AN-/PI- spermatozoa. The level of early apoptotic AN+/PI- spermatozoa negatively correlated with MMP and sperm motility. The level of late apoptotic AN+/PI+ spermatozoa negatively correlated with conventional semen parameters and MMP, and positively correlated with TUNEL (+) spermatozoa. MMP positively correlated with conventional semen parameters, but negatively correlated with TUNEL (+) spermatozoa. Conclusion: Although early apoptotic AN+/PI- spermatozoa only negatively correlates with sperm motility, the differences in proportion of each subpopulation of spermatozoa (especially, the percentage of AN-/PI- spermatozoa), and decreased MMP might be significant markers for diagnosing male infertility. They possibly bring additional information to predict the outcome of in vitro fertilization. [ABSTRACT FROM AUTHOR]

A number of genes involved in zygotic genome activation (ZGA) have been identified, but the RNA‐binding maternal factors that are directly related to ZGA in mice remain unclear. The present study shows that maternal deletion of Igf  2bp2 (also commonly known as Imp2) in mouse embryos causes early embryonic developmental arrest in vitro at the 2‐cell‐stage. Transcriptomics and proteomics analyses of 2‐cell‐stage embryos in mice reveal that deletion of IMP2 downregulates the expression of Ccar1 and Rps14, both of which are required for early embryonic developmental competence. IGF2, a target of IMP2, when added in culture media, increases the proportion of wild‐type embryos that develop successfully to the blastocyst stage: from 29% in untreated controls to 65% (50 × 10−9m IGF2). Furthermore, in an experiment related to embryo transfer, foster mothers receiving IGF2‐treated embryos deliver more pups per female than females who receive untreated control embryos. In clinically derived human oocytes, the addition of IGF2 to the culture media significantly enhances the proportion of embryos that develop successfully. Collectively, the findings demonstrate that IMP2 is essential for the regulation and activation of genes known to be involved in ZGA and reveal the potential embryonic development‐related utility of IGF2 for animal biotechnology and for assisted reproduction in humans. [ABSTRACT FROM AUTHOR]

Objective: With a high incidence of insulin resistance, central obesity and dyslipidemia, women with polycystic ovary syndrome are susceptible to metabolic syndrome (MetS). Our objective was to explore whether metabolic syndrome had an effect on overall female fertility and in vitro fertilization outcomes in infertile women with polycystic ovary syndrome.Study Design: This was a secondary analysis of a multicenter randomized trial in 1508 women with polycystic ovary syndrome, which was originally designed to compare the live birth rate after fresh-embryo transfer vs frozen embryo transfer (Frefro-PCOS). At baseline, metabolic parameters, including body mass index, waist and hip circumference, blood pressure, lipid profile, fasting, and 2 hour glucose and insulin levels after a 75 g oral glucose tolerance test were measured. All subjects were divided into a metabolic syndrome group (metabolic syndrome) and absence of metabolic syndrome group (nonmetabolic syndrome) according to diagnostic criteria. Descriptive statistics and logistic regression models tested the association between metabolic syndrome and overall fertility and in vitro fertilization cycle stimulation characteristics and clinical outcomes.Results: Metabolic syndrome was identified in 410 of 1508 infertile women with polycystic ovary syndrome (27.2%). Patients with metabolic syndrome had longer infertility duration (4.0 ± 2.2 vs 3.7 ± 2.2, P = .004) compared with those without metabolic syndrome. During ovarian stimulation, those with metabolic syndrome required significantly higher and longer doses of gonadotropin and had lower peak estradiol level, fewer retrieved oocytes, available embryos, a lower oocyte utilization rate, and ovarian hyperstimulation syndrome than those with nonmetabolic syndrome. The cumulative live birth rate did not show a significant between-group difference (57.8% vs 62.2%, P = .119). Multivariate logistic regression analysis adjusted for age, duration of infertility, body mass index, thyroid-stimulating hormone, metabolic syndrome group, homeostatic model assessment of insulin resistance, metformin utilization, number of available embryos, and embryos transferred showed that the number of embryos transferred and the number of available embryos were positively but metabolic syndrome negatively associated with the cumulative live birth rate (odds ratio, 2.18, 1.10, and 0.70, respectively, P < .05).Conclusion: Women with polycystic ovary syndrome with metabolic syndrome have a negative impact from female fecundity, and this suggests an adverse effect on in vitro fertilization cycle stimulation characteristics and clinical outcomes. [ABSTRACT FROM AUTHOR]

This study aimed to examine the relationship between the anxiety and depressive trajectory of women conceived through assisted reproductive technology (ART) and their children's emotional and behavioral problems. This prospective cohort study including 18,711 women, was conducted between July 2014 and December 2017. Self-rating scales for anxiety and depression were used before treatment, during the first trimester, and two to three years postpartum. A latent class growth analysis identified their maternal anxiety and depressive symptom trajectories. Multiple comparison and linear regression models were performed to assess the relationships between maternal trajectories and their offspring's emotional and behavioral problems. Three longitudinal heterogeneous trajectories of maternal anxiety and depressive symptoms were identified: resilient, recurrent, and emergent. After adjusting for covariates, children with mothers in the recurrent and emergent trajectory groups had higher Child Behavior Checklist/2–3 scores. Additionally, the participants with a recurrent trajectory had lower education and employment levels and younger maternal age at delivery. They also had a history of ovarian surgery, primipara, secondary infertility, polycystic ovary syndrome, and more embryo transferred cycles, including intracytoplasmic sperm injections. Those with resilient trajectories had higher antral follicle counts and GnRH antagonist protocol. Finally, the participants with emergent trajectories had a lower monthly income, primipara, ectopic pregnancy, and fresh embryo transfers. Infertile women's psychological stress was not alleviated by the ART—sociodemographic, infertility-related and treatment-related characteristics determined three mental health trajectories. Children with mothers in recurrent and emergent trajectories showed higher odds of experiencing emotional and behavioral problems. • Three maternal mental trajectories were identified in women who conceived through ART. • Sociodemographic, infertility-related, and treatment-related risk characteristics determined three mental trajectories. • The intergenerational influences of the three maternal mental trajectories on the emotional and behavioral problems in their children were also verified. [ABSTRACT FROM AUTHOR]

Objective: To examine different expression profiles of plasma exosomal microRNA (miRNA) in polycystic ovary syndrome (PCOS) patients and controls, and their potential roles in PCOS pathogenesis.Design: Experimental study.Setting: Center for reproductive medicine.Patient(s): Seventy-five PCOS patients and 75 age-matched controls.Intervention(s): Plasma exosomes miRNAs sequenced from 15 PCOS patients and 15 controls.Main Outcome Measure(s): Plasma exosomal miRNA expression and the correlation between PCOS phenotypes and miRNA expression.Result(s): The sequenced plasma exosomes miRNAs were further determined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in a larger cohort, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Correlation analysis and receiver operating characteristic (ROC) curve analysis were used to determine the association between PCOS phenotypes and miRNA expression. The miRNA sequencing revealed 34 exosomal miRNAs were differentially expressed between PCOS patients and controls. Via qRT-PCR, five differentially expressed miRNAs (miR-126-3p, miR-146a-5p, miR-20b-5p, miR-106a-5p, and miR-18a-3p) were identified. The GO and KEGG analyses predicted their target functions included axon guidance, mitogen-activated protein kinase (MAPK) signaling, endocytosis, circadian rhythms, and cancer pathways. The expression of these miRNAs correlated with menstrual cycle, antral follicle count, hormone level, and combined yielded a ROC curve area of 0.781 in discriminating PCOS patients from the controls.Conclusion(s): Differential expression of plasma exosomal miRNAs may confer a risk of PCOS and may be helpful in distinguishing PCOS patients from controls. Certain miRNA expression may associated to the disease progression, which could help in an epigenetic understanding of the pathophysiology of PCOS. [ABSTRACT FROM AUTHOR]

Do infertile women with positive tuberculin skin test (TST) results have a higher risk of adverse pregnancy outcomes after IVF or intracytoplasmic sperm injection and embryo transfer (ICSI–ET) and does preventive anti-tuberculosis treatment applied to infertile women with positive TST results before IVF/ICSI–ET affect pregnancy and neonatal outcomes? This was a retrospective cohort analysis of 6283 infertile women who underwent IVF/ICSI–ET treatment for the first time at the Reproductive Hospital affiliated to Shandong University from November 2016 to September 2022. None of the participants had prior tuberculosis or active tuberculosis. According to their TST results, 5947 patients who had never received preventive anti-tuberculosis treatment were divided into a TST-positive group (1704 cases) and a TST-negative group (4243 cases). A total of 504 patients with TST (+++) results (using the 20 mm sclerosis threshold) were divided into a treated TST (+++) group (336 cases) and an untreated TST (+++) group (168 cases) according to whether they received preventive anti-tuberculosis treatment before IVF/ICSI–ET. The outcome measures were pregnancy outcomes and neonatal outcomes. There were no significant differences in pregnancy or neonatal outcomes between the TST-positive group and the TST-negative group (P > 0.05). In the TST (+++) group, there were no significant differences in pregnancy or neonatal outcomes between the treated TST (+++) group and the untreated TST (+++) group (P > 0.05). For infertile women undergoing IVF/ICSI–ET without prior tuberculosis or active tuberculosis, positive TST results and preventive anti-tuberculosis treatments prior to IVF/ICSI–ET do not affect pregnancy or neonatal outcomes. [ABSTRACT FROM AUTHOR]

The prevalence of infertility in couples actively trying to conceive is 25%. What is the consultation-seeking behaviour, diagnosis and related treatment in infertile couples across China? Large cross-sectional population-based study in 2010–2011, in which 25,270 couples from eight provinces/municipalities in China were approached by a multistage stratified cluster sampling strategy. Among the 2680 couples reporting infertility, 1246 infertile couples consulted a fertility doctor. Age of the couple, man's body mass index and women's educational level were found to be associated with consultation behaviour. After the fertility work-up, diagnoses were tubal infertility (n = 353, 28.3%), unexplained infertility (n = 311, 25.0%), male infertility (n = 234, 18.8%), ovulatory disorder (n = 194, 15.6%) and endometriosis (n = 34, 2.7%), while 8.6% (n = 107) were not classified. Most couples received non-assisted reproductive technology (ART) fertility treatment (n = 906, 89.3%), with a proportion using traditional Chinese medicine (TCM) (n = 298, 29.4%). Intrauterine insemination (n = 62, 6.1%) and IVF/intracytoplasmic sperm injection (n = 57, 5.6%) were less frequent. Medical treatment and outcomes among five subtypes of infertility were also reported: about 30% of couples with unexplained infertility (n = 94, 30.3%) or male infertility (n = 67, 29.0%) used TCM to treat infertility. Apart from patients with endometriosis, of whom 20.6% (n = 7) received ART, patients with other infertility subtypes rarely received ART. For subsequent fertility outcome, 94% of them did not achieve a pregnancy. The prevalence of infertility in China is high, but the uptake of treatment is relatively low. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of frozen embryo transfer on maternal and neonatal complications of singleton and twin pregnancies compared with fresh embryo transfer in women with polycystic ovary syndrome (PCOS).Design: A secondary analysis of a multicenter, randomized, controlled trial comparing live birth after frozen vs. fresh embryo transfer (FreFro-PCOS).Setting: Reproductive medicine centers.Patient(s): A total of 1,508 patients with a diagnosis of PCOS who were undergoing IVF were enrolled.Intervention(s): On day of oocyte retrieval, eligible patients were randomized to the fresh or frozen embryo transfer groups. Up to two embryos were transferred in both groups. All pregnancies were followed up until delivery.Main Outcome Measure(s): Gestational diabetes mellitus, pre-eclampsia, preterm birth, small for gestational age, and large for gestational age.Result(s): The risks of gestational diabetes mellitus, preterm birth, and small for gestational age were comparable between the frozen and fresh embryo transfer groups in both singleton and twin births. However, singleton infants born after frozen embryo transfer were more likely to be large for gestational age (25.2% vs. 17.5%; relative risk 1.44, 95% confidence interval 1.01-2.07, P=.044) than those born after fresh embryo transfer. Twin pregnancy after frozen embryo transfer had a higher risk of pre-eclampsia (12.0% vs. 2.8%; relative risk 4.31, 95% confidence interval 1.27-14.58, P=.009) than those after fresh embryo transfer.Conclusion(s): In women with PCOS, frozen embryo transfer resulted in an increased risk of large for gestational age in singleton pregnancy and a higher risk of pre-eclampsia in twin pregnancy.Clinical Trial Registration Number: NCT01841528. [ABSTRACT FROM AUTHOR]

Empty follicle syndrome (EFS) is defined as the failure to aspirate oocytes from mature ovarian follicles during in vitro fertilization. Except for some cases caused by pharmacological or iatrogenic problems, the etiology of EFS remains enigmatic. In the present study, we describe a large family with a dominant inheritance pattern of female infertility characterized by recurrent EFS. Genome-wide linkage analyses and whole-exome sequencing revealed a paternally transmitted heterozygous missense mutation of c.400 G>A (p.Ala134Thr) in zona pellucida glycoprotein 3 ( ZP3 ). The same mutation was identified in an unrelated EFS pedigree. Haplotype analysis revealed that the disease allele of these two families came from different origins. Furthermore, in a cohort of 21 cases of EFS, two were also found to have the ZP3 c.400 G>A mutation. Immunofluorescence and histological analysis indicated that the oocytes of the EFS female had degenerated and lacked the zona pellucida (ZP). ZP3 is a major component of the ZP filament. When mutant ZP3 was co-expressed with wild-type ZP3, the interaction between wild-type ZP3 and ZP2 was markedly decreased as a result of the binding of wild-type ZP3 and mutant ZP3, via dominant negative inhibition. As a result, the assembly of ZP was impeded and the communication between cumulus cells and the oocyte was prevented, resulting in oocyte degeneration. These results identified a genetic basis for EFS and oocyte degeneration and, moreover, might pave the way for genetic diagnosis of infertile females with this phenotype. [ABSTRACT FROM AUTHOR]

Objective: To detect ZP (zona pellucida) gene (ZP1-ZP4) mutations in patients with oocyte anomalies.Design: Case-control genetic study.Setting: University-based reproductive medicine center.Patient(s): A total of 92 infertile patients with repeated cycles of oocyte maturation arrest (group I, n = 49) or oocyte morphologic defect (group II, n = 43) as well as 373 healthy controls.Intervention(s): Genomic DNA extracted from peripheral blood and coding regions of ZP genes amplified by polymerase chain reaction and sequenced by a DNA analyzer.Main Outcome Measure(s): Variant prediction of ZP genes with software.Result(s): In group I with oocyte maturation arrest, no novel variants were found. In group II with oocyte morphologic defects, four novel variants, two in the ZP1 gene [c.247T>C (p.W83R) and c.1413G>A (p.W471X)] and two in the ZP2 gene [c.1599G>T (p.R533S) and c.1696T>C (p.C566R)] were detected in 4 of 43 patients (approximately 9%) but were absent from the controls. Protein alignments showed that the four variants were highly conserved among different species, and all four variants were predicted to be deleterious by gene software predictions.Conclusion(s): ZP gene variants may account for patients with oocyte morphologic abnormalities but not for those with oocyte maturation arrest. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether the common variant rs2305957 spanning PLK4 (Polo-like kinase 4) confers risk to embryo development in Northern Chinese Han (CHN) women.Design: Genetic association study.Setting: University hospital.Patient(s): A total of 2,015 infertile women who underwent in vitro fertilization (IVF), 530 women with early recurrent miscarriage (ERM), and 600 fertile control women in the CHN population.Intervention(s): Genotyping of rs2305957 was performed by means of high-resolution melting analysis.Main Outcome Measure(s): Blastocyst formation, implantation, early miscarriage, and live birth rates in infertile women; genotype distribution at rs2305957 in ERM case and control subjects.Result(s): In the first cohort of this study, infertile women with AA genotype had a lower blastocyst formation rate than those with AG or GG genotype. No significant differences were observed in implantation rate, early miscarriage rate, or live birth rate among AA, AG, and GG subgroups. In the second cohort, common variant rs2305957 was related to ERM. Genotype frequency differences were also significant in both additive model and dominant model.Conclusion(s): Common variant rs2305957 is associated with blastocyst formation and ERM in CHN women. Further investigations of PLK4 gene during embryo development could be worthwhile. [ABSTRACT FROM AUTHOR]

• Each increase of 10 μg/m3 in PM 2.5 was associated with decreased fecundity by 11%. • It was also associated with an 20% increased likelihood of infertility. • The association might explain the increased infertility rates in polluted areas. Whether exposure to airborne particulate matter less than 2.5 μm (PM 2.5) could impact human fecundity is unclear. We aimed to evaluate the potential impact of PM 2.5 exposure on time to pregnancy (TTP) and the prevalence of infertility in the general Chinese population. We collected reproductive information, sociodemographic characteristics, and lifestyle data of 10,211 couples at risk of pregnancy from a large-scale community-based fertility survey in China. Then, we estimated each participant's 1-year, 3-year, and 5-year average PM 2.5 exposure levels based on remote sensing information. After adjusting for demographic, lifestyle, and environmental co-variables, discrete-time Cox regression models were used to estimate the fecundability odds ratio (FOR) per 10 μg/m3 change of PM 2.5. We also estimated the odds ratio (OR) of infertility per 10 μg/m3 change of PM 2.5 , using logistic regression models. Among the 10,211 couples, 6,875 (67%) had conceived spontaneously, with a median TTP of 5 months (interquartile range: 2–10 months). The median PM 2.5 exposure was 56.8 μg/m3, with a wide range of 9.2–93.5 μg/m3. In Cox regression models, each increase of 10 μg/m3 in the 1-year average PM 2.5 exposure was associated with a significant decrease in fecundity by 11% (FOR: 0.89; 95% confidence interval [CI]: 0.86–0.92). In logistic regression models, it was also associated with an 20% increased likelihood of infertility (OR: 1.20; 95% CI: 1.13–1.27). PM 2.5 exposure was associated with reduced human fecundity, presented by a longer TTP and higher odds of infertility, which might explain the increased infertility rates in areas with heavy PM 2.5 pollution. [ABSTRACT FROM AUTHOR]