Excessive Exogenous Gonadotropins and Genetic and Pregnancy Outcomes After Euploidy Embryo Transfer: A Secondary Analysis of a Randomized Clinical Trial.

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.

Mapping the 5-HTergic neural pathways in perimenopausal mice and elucidating the role of oestrogen receptors in 5-HT neurotransmission.

Perimenopausal syndrome (PMS) encompasses neuropsychiatric symptoms, such as hot flashes and depression, which are associated with alterations in the 5-HTergic neural pathway in the brain. However, the specific changes and mechanisms underlying these alterations remain unclear. In this study, ovariectomized mice were used to successfully establish a perimenopause model, and the changes in the expression of 5-HT and its receptors (5-HT1AR and 5-HT2AR) across 72 brain regions in these ovariectomized mice were assessed by immunohistochemistry. Although both 5-HT and 5-HT1AR were widely expressed throughout the brain, only a limited number of regions expressed 5-HT2AR. Notably, decreased expression of 5-HT was observed across almost all brain regions in the ovariectomy (OVX) group compared with the Sham group. Altered expression of both receptors was found within areas related to hot flashes (the preoptic area) or mood disorders (the amygdala). Additionally, reduced oestrogen receptor (ER)α/ß expression was detected in cells in the raphe nucleus (RN), an area known to regulate body temperature. Results showed that ERα/ß positively regulate the transcriptional activity of the enzymes TPH2/MAOA, which are involved in serotonin metabolism during perimenopause. This study revealed the changes in 5-HT neuropathways (5-HT, 5-HT1AR and 5-HT2AR) in perimenopausal mice, mainly in brain regions related to regulation of the body temperature, mood, sleep and memory. This study clarified that the expression of oestrogen receptor decreased in perimenopause, which regulated the transcription levels of TPH2 and MAOA, and ultimately led to the reduction of 5-HT content, providing a new target for clinical diagnosis and treatment of perimenopausal diseases.

The impact of first-trimester subchorionic hematomas on pregnancy outcomes after euploid embryo transfer: a retrospective cohort study.

BACKGROUND: The aim of the retrospective cohort study was to investigate the prognostic effect of subchorionic hematomas (SCH) in the first trimester on pregnancy outcomes after euploid embryo transfer. METHODS: We retrospectively analyzed women achieving singleton pregnancy by PGT-A or PGT-SR from January 2017 to January 2022. Patients were enrolled in the study if they had a viable intrauterine pregnancy at ultrasound between 6 0/7 and 8 0/7 weeks of gestation. Pregnancy outcomes as well as the incidence of maternal complications were compared between patients with and without SCH. Logistic regression was used for adjusting for potential confounding factors. RESULTS: A total of 1539 women were included, of which 298 with SCH and 1241 with non-SCH. The early miscarriage rate in SCH group was significantly higher than that in the non-SCH group (10.1% vs. 5.6%, adjusted odds ratio [aOR] 1.99, 95% confidence interval [CI] 1.25-3.16, P = 0.003). The live birth rate in SCH group was significantly lower than that in the non-SCH group. (85.6% vs. 91.2%, aOR 0.57, 95% CI 0.39-0.84, P = 0.005). In addition, SCH group had an increased risk of hypertensive disorder of pregnancy (HDP) (8.9% vs. 5.2%, P = 0.022), especially in hematoma with bleeding (19.3% vs. 6.0%, P = 0.002). The incidence of gestational diabetes mellitus (GDM), major congenital abnormalities rate, normal birth weight rate and low birth weight rate were similar between the two groups. CONCLUSIONS: The presence of SCH in the first trimester was associated with worse pregnancy outcomes after euploid embryo transfer, including an increased risk of early miscarriage and hypertensive disorder of pregnancy, along with a reduced live birth rate.

Preimplantation Genetic Testing for Aneuploidy Could Not Improve Cumulative Live Birth Rate Among 705 Couples with Unexplained Recurrent Implantation Failure.

Objective: We evaluate whether next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidy (PGT-A) improves the cumulative pregnancy outcomes of patients with unexplained recurrent implantation failure (uRIF) as compared to conventional in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI). Patients and Methods: This was a retrospective cohort study (2015-2022). A total of 705 couples diagnosed with uRIF were included in the study. 229 women transferred blastocysts based on morphological grading (IVF/ICSI) and 476 couples opted for PGT-A to screen blastocysts by NGS. Women were further stratified according to age at retrieval (<38 years and ≥38 years). The primary outcome was the cumulative live-birth rate after all the embryos were transferred in a single oocyte retrieval or until achieving a live birth. Confounders were adjusted using binary logistic regression models. Results: Cumulative live-birth rate was similar between the IVF/ICSI group and the PGT-A group after stratified by age: IVF/ICSI vs PGT-A in the <38 years subgroup (49.7% vs 57.7%, adjusted OR (95% CI) = 1.25 (0.84-1.84), P = 0.270) and in the ≥38 years subgroup (14.0% vs 19.5%, adjusted OR (95% CI) = 1.09 (0.41-2.92), P = 0.866), respectively. Nonetheless, the PGT group had a lower first-time biochemical pregnancy loss rate (17.0% vs 8.7%, P = 0.034) and a higher cumulative good birth outcome rate (35.2% vs 46.4%, P = 0.014) than the IVF/ICSI group in the <38 years subgroup. Other pregnancy outcomes after the initial embryo transfer and multiple transfers following a single oocyte retrieval were all similar between groups. Conclusion: Our results showed no evidence of favorable effects of PGT-A treatment on improving the cumulative live birth rate in uRIF couples regardless of maternal age. Use of PGT-A in the <38 years uRIF patients would help to decrease the first-time biochemical pregnancy loss and increase the cumulative good birth outcome.

Fibronectin mediates activin A-promoted human trophoblast migration and acquisition of endothelial-like phenotype.

BACKGROUND: During human early placentation, a proportion of extravillous trophoblasts (EVTs) migrate to the maternal decidua, differentiating into endovascular EVTs to remodel spiral arteries and ensure the establishment of blood circulation at the maternal-fetal interface. Inadequate EVT migration and endovascular differentiation are closely associated with adverse pregnancy outcomes such as miscarriage. Activin A and fibronectin are both secretory molecules abundantly expressed at the maternal-fetal interface. Activin A has been reported to regulate EVT biological functions. However, whether fibronectin mediates activin A-promoted EVT migration and acquisition of endothelial-like phenotype as well as the underlying molecular mechanisms remain unknown. Additionally, the role of fibronectin in pregnancy establishment and maintenance warrants further investigation. METHODS: Primary and immortalized (HTR8/SVneo) human EVTs were used as in vitro study models. Cultured human first-trimester chorionic villous explants were utilized for ex vivo validation. A local fibronectin knockdown model in ICR mouse uteri, achieved by nonviral in vivo transfection with small interfering RNA (siRNA) targeting fibronectin 1 (si-Fn1), was employed to explore the roles of fibronectin in the establishment and maintenance of early pregnancy. RESULTS: Our results showed that activin A treatment significantly induced fibronectin 1 (FN1) mRNA expression and fibronectin protein production, which is essential for human trophoblast migration and endothelial-like tube formation. Both basal and activin A-upregulated fibronectin expression were abolished by the TGF-ß type I receptor inhibitor SB431542 or siRNA-mediated knockdown of activin receptor-like kinase (ALK4) or SMAD4. Moreover, activin A-increased trophoblast migration and endothelial-like tube formation were attenuated following the depletion of fibronectin. Fibronectin knockdown via intrauterine siRNA administration reduced CD31 and cytokeratin 8 (CK8) expression at the maternal-fetal interface, resulting in a decrease in the number of implantation sites and embryos. CONCLUSIONS: Our study demonstrates that activin A promotes trophoblast cell migration and acquisition of endothelial-like phenotype via ALK4-SMAD2/3-SMAD4-mediated fibronectin upregulation. Furthermore, through a local fibronectin knockdown model in mouse uteri, we found that the absence of fibronectin at the maternal-fetal interface impedes endovascular migration of trophoblasts and decidual vascularization, thereby interfering with early embryo implantation and the maintenance of pregnancy. These findings provide novel insights into placental development during early pregnancy establishment and contribute to the advancement of therapeutic approaches for managing pregnancy complications related to trophoblast dysfunction.

Sono-anatomy of the middle cervical sympathetic ganglion verified with pathology.

Objectives: Cervical discomfort and other symptoms may be attributable to the middle cervical sympathetic ganglion. The aim of this study was to explore the sonographic features of this ganglion in anatomical specimens and cadavers and evaluate the feasibility of its visualization using high-resolution ultrasonography. Methods: We examined three cervical sympathetic-ganglion specimens and two fresh cadavers using high-resolution ultrasound to explore the sonographic features of this ganglion. Basic imaging characteristics examined included the shape, echo intensity, and location of the ganglion. Core-needle biopsy was performed to examine the suspected middle cervical sympathetic ganglion in the two fresh cadavers and verify the accuracy of the sonographic identification via pathological examination. Results: The middle cervical sympathetic ganglion appeared on high-resolution ultrasonography as an oval-shaped hypoechoic structure, with at least one continuous hypoechoic line connected to each ending in the anatomical specimens and fresh cadavers, and it was distinctly different from the adjacent lymph nodes. Discussion: Based on an adequate understanding of both its location and sonographic features, the direct visualization of the middle cervical sympathetic ganglion using high-resolution ultrasonography is feasible.

Endometrial BMP2 Deficiency Impairs ITGB3-Mediated Trophoblast Invasion in Women With Repeated Implantation Failure.

BACKGROUND: Repeated implantation failure (RIF) leads to a waste of high-quality embryos and remains a challenge in assisted reproductive technology. During early human placentation, the invasion of trophoblast cells into the decidua is an essential step for the establishment of maternal-fetal interactions and subsequent successful pregnancy. Bone morphogenetic protein 2 (BMP2) has been reported to regulate endometrial receptivity and promote trophoblast invasion. However, whether there is dysregulation of endometrial BMP2 expression in patients with RIF remains unknown. Additionally, the molecular mechanisms underlying the effects of BMP2 on human trophoblast invasion and early placentation remain to be further elucidated. METHODS: Midluteal phase endometrial samples were biopsied from patients with RIF and from routine control in vitro fertilization followed by quantitative polymerase chain reaction and immunoblotting analyses. Human trophoblast organoids, primary human trophoblast cells, and an immortalized trophoblast cell line (HTR8/SVneo) were used as study models. RESULTS: We found that BMP2 was aberrantly low in midluteal phase endometrial tissues from patients with RIF. Recombinant human BMP2 treatment upregulated integrin ß3 (ITGB3) in a SMAD2/3-SMAD4 signaling-dependent manner in both HTR8/SVneo cells and primary trophoblast cells. siRNA-mediated integrin ß3 downregulation reduced both basal and BMP2-upregulated trophoblast invasion and vascular mimicry in HTR8/SVneo cells. Importantly, shRNA-mediated ITGB3 knockdown significantly decreased the formation ability of human trophoblast organoids. CONCLUSION: Our results demonstrate endometrial BMP2 deficiency in patients with RIF. ITGB3 mediates both basal and BMP2-promoted human trophoblast invasion and is essential for early placentation. These findings broaden our knowledge regarding the regulation of early placentation and provide candidate diagnostic and therapeutic targets for RIF clinical management.

Effect of SARS-CoV-2 infection and vaccine on ovarian reserve: A systematic review.

OBJECTIVE: To evaluate the effect of SARS-CoV-2 infection and vaccination on ovarian reserve. METHODS: Relevant articles were identified in the EMBASE, PubMed, and Web of Science databases from January 2020 to May 2023. Available clinical indicators of ovarian reserve, such as anti-Müllerian hormone (AMH), antral follicle count (AFC), follicle-stimulating hormone (FSH), and estradiol (E2), as well as the time interval from infection or vaccination to measurements, were assessed. RESULTS: Only 2 studies provided evidence that SARS-CoV-2 infection could damage ovarian function. In a comparison of the vaccinated and unvaccinated groups, although 1 prospective cohort study observed the transient statistically significant decrease on serum AMH levels at 3 or 6 months of follow-up, serum AMH levels remained within the normal reserve range (>1.1 ng/dl) throughout the study period. CONCLUSION: Overall, whether ovarian reserve may be affected by SARS-CoV-2 infection remains controversial and further investigations are warranted to clarify this issue. Based on the current evidence, it is safe to assume that COVID-19 vaccination does not exert any adverse effect on ovarian reserve parameters such as AMH, AFC, FSH, and E2, which will provide reassurance for women attempting to fall pregnant.

Excessive Lipid Peroxidation in Uterine Epithelium Causes Implantation Failure and Pregnancy Loss.

The uterine epithelium undergoes a dramatic spatiotemporal transformation to enter a receptive state, involving a complex interaction between ovarian hormones and signals from stromal and epithelial cells. Redox homeostasis is critical for cellular physiological steady state; emerging evidence reveals that excessive lipid peroxides derail redox homeostasis, causing various diseases. However, the role of redox homeostasis in early pregnancy remains largely unknown. It is found that uterine deletion of Glutathione peroxidase 4 (GPX4), a key factor in repairing oxidative damage to lipids, confers defective implantation, leading to infertility. To further pinpoint Gpx4's role in different cell types, uterine epithelial-specific Gpx4 is deleted by a lactotransferrin (Ltf)-Cre driver; the resultant females are infertile, suggesting increased lipid peroxidation levels in uterine epithelium compromises receptivity and implantation. Lipid peroxidation inhibitor administration failed to rescue implantation due to carbonylation of major receptive-related proteins underlying high lipid reactive oxygen species. Intriguingly, superimposition of Acyl-CoA synthetase long-chain family member 4 (ACSL4), an enzyme that promotes biosynthesis of phospholipid hydroperoxides, along with uterine epithelial GPX4 deletion, preserves reproductive capacity. This study reveals the pernicious impact of unbalanced redox signaling on embryo implantation and suggests the obliteration of lipid peroxides as a possible therapeutic approach to prevent implantation defects.

Identification of cryptic balanced translocations in couples with unexplained recurrent pregnancy loss based upon embryonic PGT-A results.

PURPOSE: The goal of this study is to determine whether any balanced translocation (BT) had been missed by previous karyotyping in patients with unexplained recurrent pregnancy loss (uRPL). METHODS: This case series included 48 uRPL-affected couples with normal karyotypes. The embryos from these couples have all undergone preimplantation testing for aneuploidies (PGT-A). Based on the PGT-A's results, 48 couples could be categorized into two groups: 17 couples whose multiple embryos were detected with similar structural variations (SVs, segmental/complete) and 31 couples without such findings but who did not develop any euploid embryo despite at least three high-quality blastocysts being tested. The peripheral blood sample of each partner was then collected for mate-pair sequencing (MPseq) to determine whether any of them were BT carriers. RESULTS: MPseq analyses identified 13 BTs in the 17 couples whose multiple embryos had similar SVs detected (13/17, 76.47%) and three BTs in the 31 couples without euploid embryo obtained (3/31, 9.7%). Among the 16 MPseq-identified BTs, six were missed due to the limited resolution of G-banding karyotyping analysis, and the rest were mostly owing to the similar banding patterns and/or comparable sizes shared by the two segments exchanged. CONCLUSION: A normal karyotype does not eliminate the possibility of carrying BT for couples with uRPL. The use of PGT-A allows us to perceive the "carrier couples" missed by karyotyping analysis, providing an increased risk of finding cryptic BTs if similar SVs are always detected on two chromosomes among multiple embryos. Nonetheless, certain carriers with translocated segments of sub-resolution may still go unnoticed.

Does reciprocal translocation affect the meiotic segregation products of non-translocation chromosomes?

This retrospective cohort study aimed to assess the effect of chromosomal reciprocal translocation on meiotic segregation products of non-translocation chromosomes. A total of 744 reciprocal translocation carriers and 875 non-carriers were included in this study. A total of 6,832 blastocysts were biopsied and tested by next-generation sequencing. Blastocysts from the carrier group were classified into five subgroups according to the theoretical segregation pattern of quadrivalent structure. For carrier patients, normal meiotic segregation products of the non-translocation chromosome were classified after excluding the segregation modes of the quadrivalent structure. The proportion of normal non-translocation chromosome meiotic segregation products was similar between the carrier and noncarrier groups (p = 0.69). The generalized Estimation Equation revealed that there was no correlation between reciprocal translocation and meiotic segregation products of non-translocation chromosomes. Moreover, subgroup analyses showed that the segregation modes of quadrivalent structure (p = 0.00) and carrier's gender (p = 0.00) may affect the meiotic segregation products of non-translocation chromosomes. In conclusion, reciprocal translocation does not directly reduce the proportion of normal segregation products of non-translocation chromosomes. The difference among subgroups of different quadrivalent segregation patterns implied that interchromosomal effect may exist but the high incidence of chromosomal abnormalities for reciprocal translocation carriers should not be attributed to interchromosomal effect.

OGM and WES identifies translocation breakpoints in PKD1 gene in an polycystic kidney patient and healthy baby delivered using PGT.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common autosomal dominant genetic diseases. Whole exome sequencing (WES) is a routine tool for diagnostic confirmation of genetic diseases, and it is usually performed to confirm the clinical diagnosis in ADPKD. Reciprocal translocation is the most common chromosomal structural abnormalities and most of its carriers have normal phenotypes until they are encountered infertility problems in adulthood. However, for the polycystic kidney disease caused by abnormal chromosome structure, WES is difficult to achieve the purpose of gene diagnosis. METHODS: ADPKD-related genes were detected by WES; Chromosomal karyotyping and Optical Genome Mapping (OGM) were used to detect structural variant; The genomic break-point locations and the abnormal splicing were detected by reverse transcription-PCR and Sanger sequencing; The karyomapping gene chip and Next-Generation Sequencing (NGS) were performed to screen aneuploidy and to distinguish the non-carrier embryos from the carrier embryos. RESULTS: No pathogenic variant was found after the first round of WES analysis. Karyotyping data showed 46, XX, t (16; 17) (p13.3; q21.3). With the help of OGM, the translocation breakpoint on chromosome 16 was located within the PKD1 gene. With re-analysis of WES raw data, the breakpoint of translocation was verified to be located at the c.10618 + 3 of PKD1 gene. Based on this molecular diagnosis, a non-carrier embryo was selected out from three blastocysts. With preimplantation genetic testing (PGT) after in vitro fertilization (IVF), it was then transferred into uterus. With confirmation by prenatal and postnatal testing, the pedigree delivered a healthy baby. CONCLUSION: We identified a case of ADPKD caused by balanced translocation and assisted the patient to have a healthy child. When the phenotype was closely related with a monogenic disease and the WES analysis was negative, chromosomal structural analysis would be recommended for further genetic diagnosis. Based on the precision diagnosis, preventing the recurrence of hereditary diseases in offspring would be reachable.

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

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

Pregnancy and neonatal outcomes in infertile patients with positive tuberculin skin test results.

RESEARCH QUESTION: 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? DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.

Transient receptor potential M2 channel in the hypothalamic preoptic area and its impact on thermoregulation during menopause.

BACKGROUND: Decreased estrogen levels can cause abnormal thermosensitivity of the preoptic area (POA) in the hypothalamus during menopause, which may cause hot flashes. Thermosensitive transient receptors (ThermoTRPs) affect the thermosensitivity of neurons. It is worth exploring whether ThermoTRPs change under low estrogen state and participate in the abnormal thermoregulation of POA. METHODS: Adult female Sprague-Dawley rats were randomly divided into sham operation (SHAM), ovariectomy (OVX) and estrogen treatment after ovariectomy (OVX+E) groups. Under 10 â„ƒ, 18 â„ƒ, 25 â„ƒ, 37 â„ƒ and 45 â„ƒ incubations, their skin temperature was monitored and the expression of TRPA1, TRPM8, TRPM2, and TRPV1 in POA were investigated. RESULTS: The skin temperature of ovariectomized rats changed faster and more dramatically under different incubation temperatures. The results at mRNA level show that only the expression of TRPM2 decreased in POA of OVX group compared with the other two groups at 25 â„ƒ, TRPA1 expression in POA of the three groups increased at 10 â„ƒ, TRPM8 increased at 10 â„ƒ and 18 â„ƒ, TRPV1 increased at 10 â„ƒ and 45 â„ƒ, while the expression of TRPM2 decreased at 10 â„ƒ and 18 â„ƒ and increased at 37 â„ƒ and 45 â„ƒ. In all these cases, the magnitudes of the changes were less in the OVX group relative to the other two groups. The further immunohistochemical and Western blot results of TRPM2 and the activated TRPM2 positive cells labeled by c-Fos were consistent with the results of mRNA level. CONCLUSIONS: The expression and thermosensitivity of TRPM2 in POA changed greatly under different incubation temperatures, but the changes in ovariectomized rats were less. This may be the key factor triggering thermoregulation dysfunction under low estrogen and may cause hot flashes.

Impact of thyroid autoimmunity on pregnancy outcomes in euthyroid patients with recurrent implantation failure.

RESEARCH QUESTION: Does thyroid autoimmunity (TAI) adversely affect pregnancy outcomes after IVF/intracytoplasmic sperm injection (ICSI) in euthyroid patients with recurrent implantation failure (RIF)? DESIGN: This retrospective cohort study was conducted at the Reproductive Hospital Affiliated with Shandong University from November 2016 to September 2021. A total of 1031 euthyroid patients diagnosed with RIF were enrolled. Based on serum thyroid autoantibody concentrations, the participants were divided into two groups: the TAI-positive group (219 women with RIF) and the TAI-negative group (812 women with RIF). The parameters were compared between the two groups. Additionally, logistic regression was used to adjust related confounders for primary outcomes, and subgroup and stratified analyses were performed according to different thyroid autoantibody types and TSH concentrations. RESULTS: There was no significant difference in ovarian reserve, ovarian response, embryo quality, pregnancy outcome or neonatal outcome between the two groups (P > 0.05). After adjustments for age, body mass index, thyroid-stimulating hormone and free thyroxine, the biochemical pregnancy rate in the TAI-positive group was significantly lower than that in the TAI-negative group (odds ratio 1.394, 95% CI 1.023-1.901, adjusted P = 0.036). Regarding the implantation rate, clinical pregnancy rate, pregnancy loss rate, stillbirth rate and live birth rate, no significant differences were observed even with subgroup and stratified analyses (P > 0.05). CONCLUSIONS: TAI had no impact on pregnancy outcomes in euthyroid RIF patients who underwent IVF/ICSI. In clinical practice, interventions targeting thyroid autoantibodies in these patients should be implemented with caution and additional evidence is needed.

Insufficient GDF15 expression predisposes women to unexplained recurrent pregnancy loss by impairing extravillous trophoblast invasion.

Insufficient extravillous trophoblast (EVT) invasion during early placentation has been shown to contribute to recurrent pregnancy loss (RPL). However, the regulatory factors involved and their involvement in RPL pathogenesis remain unknown. Here, we found aberrantly decreased growth differentiation factor 15 (GDF15) levels in both first-trimester villous and serum samples of unexplained recurrent pregnancy loss (URPL) patients as compared with normal pregnancies. Moreover, GDF15 knockdown significantly reduced the invasiveness of both HTR-8/SVneo cells and primary human EVT cells and suppressed the Jagged-1 (JAG1)/NOTCH3/HES1 pathway activity, and JAG1 overexpression rescued the invasion phenotype of the GDF15 knockdown cells. Induction of a lipopolysaccharide-induced abortion model in mice resulted in significantly reduced GDF15 level in the placenta and serum, as well as increased rates of embryonic resorption, and these effects were reversed by administration of recombinant GDF15. Our study thus demonstrates that insufficient GDF15 level at the first-trimester maternal-foetal interface contribute to the pathogenesis of URPL by impairing EVT invasion and suppressing JAG1/NOTCH3/HES1 pathway activity, and suggests that supplementation with GDF15 could benefit early pregnancy maintenance and reduce the risk of early pregnancy.

H3K27me3-modulated Hofbauer cell BMP2 signalling enhancement compensates for shallow trophoblast invasion in preeclampsia.

BACKGROUND: Preeclampsia (PE) is a common hypertensive pregnancy disorder associated with shallow trophoblast invasion. Although bone morphogenetic protein 2 (BMP2) has been shown to promote trophoblast invasion in vitro, its cellular origin and molecular regulation in placenta, as well as its potential role in PE, has yet to be established. Additionally, whether BMP2 and/or its downstream molecules could serve as potential diagnostic or therapeutic targets for PE has not been explored. METHODS: Placentas and sera from PE and healthy pregnant women were subjected to multi-omics analyses, immunoblots, qPCR, and ELISA assays. Immortalized trophoblast cells, primary cultures of human trophoblasts, and first-trimester villous explants were used for in vitro experiments. Adenovirus expressing sFlt-1 (Ad Flt1)-induced PE rat model was used for in vivo studies. FINDINGS: We find globally decreased H3K27me3 modifications and increased BMP2 signalling in preeclamptic placentas, which is negatively correlated with clinical manifestations. BMP2 is derived from Hofbauer cells and epigenetically regulated by H3K27me3 modification. BMP2 promotes trophoblast invasion and vascular mimicry by upregulating BMP6 via BMPR1A-SMAD2/3-SMAD4 signalling. BMP2 supplementation alleviates high blood pressure and fetal growth restriction phenotypes in Ad Flt1-induced rat PE model. INTERPRETATION: Our findings demonstrate that epigenetically regulated Hofbauer cell-derived BMP2 signalling enhancement in late gestation could serve as a compensatory response for shallow trophoblast invasion in PE, suggesting opportunities for diagnostic marker and therapeutic target applications in PE clinical management. FUNDING: National Key Research and Development Program of China (2022YFC2702400), National Natural Science Foundation of China (82101784, 82171648, 31988101), and Natural Science Foundation of Shandong Province (ZR2020QH051, ZR2020MH039).

The effect of parental carrier of de novo mutated vs. inherited balanced reciprocal translocation on the chance of euploid embryos.

OBJECTIVE: To evaluate whether the effect of de novo mutated balanced reciprocal translocation on the rate of euploid embryos varied from inherited balanced reciprocal translocation. DESIGN: A retrospective cohort study compared the percentage of euploid embryo and proportion of patients with at least 1 euploid embryo between de novo mutated balanced reciprocal translocation (i.e., the group of de novo mutated carriers) and inherited balanced reciprocal translocation (i.e., the group of inherited carriers). SETTING: An academic fertility center. PATIENT(S): A total of 413 couples with balanced reciprocal translocation (219 female carriers and 194 male carriers) who underwent their first cycle of preimplantation genetic testing for structural rearrangements were included. INTERVENTION(S): Carriers of balanced reciprocal translocation either de novo mutated or inherited. MAIN OUTCOME MEASURE(S): The percentage of euploid embryo and proportion of patients with at least 1 euploid embryo. RESULT(S): The carriers of the de novo mutated balanced reciprocal translocation had a lower percentage of euploid embryos (19.5% vs. 25.5%), and were less likely to have at least 1 euploid embryo (47.1% vs. 60.1%) compared with the carriers of the inherited balanced reciprocal translocation. In the male-carrier subgroup, the percentage of euploid embryos (16.7% vs. 26.7%) and proportion of patients with at least 1 euploid embryo (41.9% vs. 67.5%) were lower among the de novo mutated carriers than those among the inherited carriers. However, in the female-carrier subgroup, there was no statistically significant difference in the percentage of euploid embryos (22.4% vs. 24.4%) or the proportion of patients with at least 1 euploid embryo (52.3% vs. 53.7%) between the de novo mutated carriers and inherited carriers. CONCLUSION(S): The de novo mutated balanced reciprocal translocation was associated with a lower percentage of euploid embryos and lower chance of obtaining at least 1 euploid embryo than the inherited balanced reciprocal translocation.