Recurrent implantation failure (RIF) is defined as the failure to achieve clinical pregnancy despite multiple transfers of high-quality embryos during assisted reproductive technology (ART) treatment. The definition of RIF has not been unified, with discrepancies primarily centering on maternal age, number of embryo transfers and total embryos transferred, criteria for high-quality embryo assessment, and estimation of cumulative pregnancy probability. In this article, we systematically review the evolution of RIF definitions and the impact of aneuploid embryo transfer on pregnancy outcomes; evaluate the diagnostic and therapeutic limitations of preimplantation genetic testing for aneuploidy (PGT-A) and endometrial receptivity analysis (ERA); re-examine the evidence-based rationale for screening chronic endometritis, endometrial microbiome, and immunological and thrombophilic factors; and highlight recent major advances in single-cell sequencing of the endometrium. We advocate for active investigation and management of identifiable pathological conditions that affect pregnancy outcomes, caution against “empirical multiple interventions,” and call for a return to the therapeutic principle of “first, do no harm.” It is anticipated that artificial intelligence-driven integrative multimodal modeling and real-world data registry studies will serve as breakthroughs for the diagnosis and treatment of RIF.
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To investigate the effect of membrane-spanning 4-domains subfamily member 6D (MS4A6D) gene knockout on the fertility of female mice.
On the basis of the successful construction of Ms4a6d gene knockout model mice, the homozygous Ms4a6d gene knockout (Ms4a6d-/-) mice at an age of different weeks were subjected. Mouse genotype was identified with RT-qPCR and agarose gel electrophoresis. HE staining, immunofluorescence assay and ELISA were used to detect serum level of anti-müllerian hormone (AMH), composition of macrophages and follicles at all levels in the ovaries of Ms4a6d-/- mice, respectively. The fertility changes in pregnant rate and average litter size of female Ms4a6d-/- mice were observed by fertility experiments.
Compared with the wild-type (Ms4a6d+/+) female mice at the same age, there were less macrophages in the ovarian tissues of the 2- and 4-week-old Ms4a6d-/- female mice (P < 0.01), but no significant difference was observed between the 2 types of mice at 8 weeks of age. For the adult Ms4a6d-/- female mice at an age of 8 weeks, the ovarian coefficient was obviously lower (P < 0.01), and the numbers of primordial, primary, secondary and antral follicles in the ovarian tissues was statistically lower (P < 0.05) when compared with the adult wild-type female mice at the same age. The serum AMH level was notably lower in the Ms4a6d-/- female mice of all ages than the wild-type ones at corresponding ages (P < 0.05). The average pregnancy rate was 56% and the litter size was 4.1±1.1 in adult Ms4a6d-/- female mice, which were significantly lower than those of wild-type mice of the same age (89% and 6.3±1.2).
Ms4a6d gene knockout decreases the number of macrophages in the ovarian tissues of adolescent females, interferes with the development of follicles in the ovarian tissues of adolescent females, and leads to a decrease in ovarian reserve in adult females and a decrease in fertility in adult females.
To investigate the high risk factors of endometrial polyps (EPs) in infertile patients and its impact on the pregnancy outcome after embryo transfer.
A case-control trail was conducted on the infertility patients who undergoing embryo transfer in our hospital for the first time after hysteroscopy from January 2016 to December 2022.Their clinical data were collected and retrospectively analyzed.Univariate and stepwise logistic regression analyses were used to identify the risk factors for EPs, and the impact of polyps on the pregnancy outcomes of assisted reproductive pregnancy was analyzed with propensity score matching (PSM) at a 1:2 ratio.
A total of 388 patients diagnosed with EPs and undergoing hysteroscopic endometrial polypectomy were assigned into the EPs group, and 2 163 non-polyp patients were into the non-EPs group.Univariate analysis showed statistical differences were observed in age[31(29, 34)vs 31(28, 33), P=0.002], history of pelvic inflammatory disease (42.78% vs 64.17%, P=0.000), age at menarche [14 (12, 14) vs 13(12, 14) years old, P=0.000], number of pregnancies[0(0, 1) vs 1(0, 2), P=0.000], primary infertility (60.30% vs 50.20%, P=0.000), duration of infertility [4(2.1, 6.0) vs 4 (2.0, 6.0) years, P=0.002], concomitant endometriosis (9.53% vs 6.52%, P=0.032), concomitant uterine fibroids (11.85% vs 6.93%, P=0.001), and basal estrogen level[38.12(27.00, 59.00)vs 36.00(25.00, 53.00)μg/L, P=0.016] between the 2 groups.Logistic stepwise regression analysis indicated that age (OR=1.082, 95%CI: 1.053~1.113, P<0.05), primary infertility (OR=2.951, 95%CI: 1.990~4.376, P<0.05), and elevated basal estrogen (OR=1.003, 95%CI: 1.001~1.005, P<0.05) were risk factors for EPs.The postoperative biochemical pregnancy rate (59.28% vs 52.70%), clinical pregnancy rate (53.09% vs 45.48%), and live birth rate (43.81% vs 35.82%) were significantly higher in the matched EPs group than the non-EPs group (P<0.05). No statistical difference was observed in pregnancy outcome in the patients with different polyp locations and sizes.The patients with multiple polyps had an obvious higher rate of early miscarriage than those with single polyp (17.27% vs 7.29%, P<0.05), while those with recurrent polyps also had a higher rate of early miscarriage than those with primary polyps (27.78% vs 11.23%, P<0.05).
Age, primary infertility, and elevated basal estrogen are risk factors for EPs in infertility patients, while hysteroscopic endometrial polypectomy prior to embryo transfer results in improved pregnancy outcomes in those with EPs.The location and size of endometrial polyps have weak impact on pregnancy outcomes following embryo transfer, but, the presence of multiple or recurrent polyps may elevate the risk of early miscarriage.
To investigate the value and safety of microdissection testicular sperm extraction(MD-TESE)for patients with non-obstructive azoospermia(NOA).
A retrospective analysis study of 176 NOA patients diagnosed in our center from July 1, 2017 to March 15, 2022. According to sperm retrieval methods, they were divided into MD-TESE group and testicular sperm aspiration(TESA)group. The time of procedure, intra-operative bleeding, surgical complications(such as hematoma), sperm retrieval rate(SRR)and clinical outcome of in vitro fertilization were compared between the 2 groups.
There were no significant differences between the 2 groups in age, body mass index(BMI), testicular volume, and levels of testosterone(T), luteinizing hormone(LH), anti-Müllerian hormone(AMH)and follicle-stimulating hormone(FSH)(P>0.05). The MD-TESE group had obviously longer operation time(P<0.001)and lower incidence of testicular hematoma rate[2.4%(1/42)vs 7.5%(10/134)] than the TESA group. No infections were observed in either group. SRR was significantly higher in MD-TESE group than the TESA group[38.1%(16/42)vs 9.0%(12/134), P<0.001]. When the obtained sperms were used in intracytoplasmic sperm injection(ICSI), no obvious differences were seen in the fertilization rate, cleavage rate, and clinical pregnancy rate between the MD-TESE group and TESA group(65.1% vs 58.3%, 93.9% vs 71.4%, 50.0% vs 50.0%).
MD-TESE is a safe and effective method for sperm retrieval in NOA patients, especially in those with cryptorchidism, viral orchitis and Y-chromosome AZFc microdeletions.
To investigate the impact of chronic endometritis (CE) on pregnancy outcome in patients with assisted reproduction and to evaluate the clinical significance of normative therapy.
A retrospective analysis was performed on infertile patients with chronic endometritis who received assisted reproductive technology during January 2019 to January 2021 in our center. According to the number of CD138-positive cells in endometrial tissues, they were divided into severe group (>10/HPF) and mild group (≤10/HPF). Then according to whether CE was clearly cured after standard treatment with antibiotics, they were divided into cured group and treated group. The differences of biochemical pregnancy rate, clinical pregnancy rate, early abortion rate, embryo implantation rate and live birth rate were compared among different groups of patients.
A total of 155 patients were enrolled, including 56 patients in the cured group and 99 patients in the treated group. And there were 91 patients with mild CE and 64 with severe CE. The number of CD138-positive cells in the cured group was significantly higher than that in the treated group (19.32±13.72 vs 11.52±10.32, P<0.05). There were no significant differences in embryo implantation rate (34.95% vs 27.42%, P=0.219) and early abortion rate (13.33% vs 25.00%, P=0.235) between the 2 groups. The biochemical pregnancy rate (64.29% vs 43.43%, P=0.013), clinical pregnancy rate (53.57% vs 36.36%, P=0.037) and live birth rate (46.43% vs 27.27%, P=0.016) were obviously higher in the cured group than the treated group. In mild CE, there were no statistical differences in biochemical pregnancy rate, clinical pregnancy rate, early abortion rate, live birth rate and embryo implantation rate the clinical outcomes between the cured group and the treated group. In severe CE, the cured group had obviously higher biochemical pregnancy rate (76.47% vs 43.33%, P=0.007), clinical pregnancy rate (64.71% vs 33.33%, P=0.012) and live birth rate (58.82% vs 20.00%, P=0.002) than the treated group.
CE has a negative impact on assisted reproductive outcomes, and standard antibiotic treatment can improve the pregnancy outcomes in the patients.
To analyze and compare the clinical features and outcomes of in vitro fertilization-embryo transfer (IVF-ET) cycles in normal responders using gonadotrophin (Gn) releasing hormone (GnRH) antagonist or GnRH agonist long protocol.
The clinical data of patients who received IVF treatment and had normal ovarian response to GnRH antagonist or GnRH agonist long protocol in our reproductive center from January 2017 to March 2019 were collected. According to the treatment protocol and the fresh embryo transplanted or not, these patients were divided into Group A (receiving GnRH antagonist, but no fresh embryo transplanted, n=128), Group B (GnRH antagonist, with fresh embryo transplanted, n=138), and Group C (GnRH agonist long protocol, with fresh embryo transplanted, n=720). Besides, the frozen embryo transfer (FET) cycles of Group A were analyzed, and served as Group D. The thickness of endometrium on luteal conversion day and outcome of Group D were compared with those of Group B and Group C.
①The duration and dosage of Gn were shorter and less in Group A and B than Group C, and statistical difference was seen in Gn duration (P<0.05), and in Gn dosage only between Group A and C (P<0.05). ②On HCG day, the serum estradiol (E2) level were lower in Group A and B than Group C (P<0.05), the endometrium of Group C was the thickest, and the thickness of endometrium on luteal conversion day of Group D was lower than that on the HCG day of Group A, B and C, where the differences between Group A and B, and Group C and D were statistically significant (P<0.05). ③ The number of oocytes obtained in Group A and B were less than that in Group C (P<0.05), but there were no statistical difference in metaphase Ⅱ (MⅡ) oocyte rate, normal fertilization rate and high-quality embryo rate among Group A, B and C. ④ Biochemical pregnancy rate and clinical pregnancy rate had no statistical differences among Group B, C, and D (P<0.05). Group B had the lowest implantation rate but the highest miscarriage rate, and had obvious differences with Group C (P<0.05).
GnRH antagonist protocol can obtain similar oocytes and embryos as the GnRH-a long protocol in normal response population. However, the antagonist may exert negative impact on endometrial receptivity and result in low pregnancy rate and high abortion rate.
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