SARS-CoV-2 infection in pregnant patients on TNFα inhibitor: Real-life data with a review of literature.

Tumor necrosis factor alpha (TNFα) is involved in the occurrence of negative pregnancy outcomes. The study aimed to evaluate the safety and efficacy of the immunosuppressive TNFα inhibitors (TNFαi) in the treatment of patients with a history of recurrent reproductive failure in the context of COVID-19 pandemics. We reviewed 85 patients who received TNFαi (certolizumab pegol) during Mainland China's first wave of COVID-19 pandemic, from 21st Nov 2022-11 th Jan 2023. We also collected corresponding data from 130 pregnant patients who never used TNFαi for comparison. There were no significant differences in the history of previous pregnancy loss, miscarriage, embryo implantation failure, comorbidities and doses of COVID-19 vaccination. 82.2% and 87.7% pregnant patients contracted primary COVID-19 with symptoms in TNFαi group and no-TNFαi group. Duration of symptoms was significantly longer in TNFαi group and the incidences of cough and lethargy was significantly higher in TNFαi group. Both groups reported similar severity to same-aged close contacts, similar rates of other symptoms and hospitalization. No deaths were reported. In the in vitro fertilization (IVF) subgroup, we achieved a biochemical pregnancy loss rate of 17.4%, miscarriage rate of 21.7%, ongoing pregnancy rate and live birth rate of 34.2%. COVID-19 did not influence the live birth rate. We concluded that TNFαi administration in pregnancy was not associated with increased susceptivity to and severity of COVID-19. However, TNFαi users showed more prominent symptoms and longer recovery time. The pregnancy outcomes with TNFαi in such high-risk group for pregnancy loss was satisfactory.

Three-dimensional architecture of granulosa cell derived from oocyte cumulus complex, revealed by FIB-SEM.

The oocyte cumulus complex is mainly composed of an oocyte, the perivitelline space, zona pellucida and numerous granulosa cells. The cumulus granulosa cells (cGCs) provide a particularly important microenvironment for oocyte development, regulating its growth, maturation and meiosis. In this study, we studied the internal structures and cell-to-cell connections of mouse cGCs using focused ion beam scanning electron microscopy (FIB-SEM). We reconstructed three-dimensional models to display characteristic connections between the oocyte and cGCs, and to illustrate various main organelles in cGCs together with their interaction relationship. A special form of cilium identified in granulosa cell was never reported in previous literature.

Effect of tamoxifen in patients with thin endometrium who underwent frozen-thawed embryo transfer cycles: a retrospective study.

Introduction: Thin endometrium leads to an impaired implantation rate. The aim of the study is to compare the clinical outcomes of tamoxifen (TAM) and hormone replacement therapy (HRT) used in patients with thin endometrium (<7mm) in frozen-thawed embryo transfer (FET)cycles. Methods: A total of 176 FET cycles with thin endometrium were retrospectively analyzed in our center from Jan 2020 to May 2022. According to patients' own will, 112 patients were allocated to the HRT group and 64 patients chose the TAM protocol. Clinical outcomes were compared between two groups. Result: The duration of treatment was shorter in the TAM group(12.03±2.34d) than the HRT group (16.07±2.52 d), which was statistically different (p<0.05). The endometrial thickness on the transfer day of the TAM group (7.32±1.28 mm) was significantly thicker than that of the HRT group (6.85±0.89mm, p<0.05). The clinical pregnancy rate of the TAM group (50.0%) was higher than that of the HRT group (36.6%), but there was no significant difference (p >0.05). The early miscarriage rate was significantly lower in the TAM group compared with the HRT group (5.9% Vs 26.8%, adjusted OR 0.10, p<0.05), while the live birth rate was higher in the TAM group (46.9% Vs 26.8%, adjusted OR 2.24, p<0.05) compared with the HRT group. Conclusion: For patients with thin endometrium, TAM effectively improved the endometrial thickness and increased the live birth rate. TAM can be used as an alternative protocol for patients with thin endometrium.

The Role of Peritoneal Immunity in Peritoneal Endometriosis and Related Infertility.

Endometriosis is defined as a disorder in which the glands and stroma of the endometrium grow and shed periodically outside the uterine cavity. Highly prevalent in women of reproductive age, the most common clinical manifestations are chronic pelvic pain and infertility. The pathogenesis of endometriosis may be multifactorial, including factors of anatomy, immunity, inflammation, hormones (estrogen), oxidative stress, genetics, epigenetics, and environment. There are generally three types of endometriotic disease, namely peritoneal, ovarian, and deep infiltration. For the same patient, there may be a single or multiple types concurrently. The different manifestations of these types suggests that they each have their own etiology. Numerous studies have shown that the evasion of endometrial cells from peritoneal immune surveillance helps establish and maintain peritoneal endometriosis, but the specific mechanism is not well understood. Likewise, the molecular mechanisms of endometriosis-related infertility have not been clearly elucidated. This review attempts to identify the role of peritoneal immunity in peritoneal endometriosis and related infertility, especially in the aspects of molecular mechanisms.

Knuckle Pads Successfully Treated with 2% Crisaborole Ointment Combined with Triamcinolone Acetonide and Neomycin Plaster: A Case Report.

Knuckle pads (KPs) are benign hyperkeratotic fibrous thickening skin disorder characterized by nodules or plaques located on the extensor surface of the joints. However, there are no specific treatments for KPs so far. Here, we reported a case of KPs successfully treated with 2% crisaborole ointment combined with triamcinolone acetonide and neomycin plaster. This combined therapy might be a new therapeutic option for KPs.

METTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells.

γδ T cells make key contributions to tissue physiology and immunosurveillance through two main functionally distinct subsets, γδ T1 and γδ T17. m6A methylation plays critical roles in controlling numerous aspects of mRNA metabolism that govern mRNA turnover, gene expression, and cellular functional specialization; however, its role in γδ T cells remains less well understood. Here, we find that m6A methylation controls the functional specification of γδ T17 vs. γδ T1 cells. Mechanistically, m6A methylation prevents the formation of endogenous double-stranded RNAs and promotes the degradation of Stat1 transcripts, which converge to prevent over-activation of STAT1 signaling and ensuing inhibition of γδ T17. Deleting Mettl3, the key enzyme in the m6A methyltransferases complex, in γδ T cells reduces interleukin-17 (IL-17) production and ameliorates γδ T17-mediated psoriasis. In summary, our work shows that METTL3-mediated m6A methylation orchestrates mRNA stability and double-stranded RNA (dsRNA) contents to equilibrate γδ T1 and γδ T17 cells.

Iron overload in endometriosis peritoneal fluid induces early embryo ferroptosis mediated by HMOX1.

Endometriosis is one of the most common disorders that causes infertility in women. Iron is overloaded in endometriosis peritoneal fluid (PF), with harmful effects on early embryo development. However, the mechanism by which endometriosis peritoneal fluid affects embryonic development remains unclear. Hence, this study investigated the effect of iron overload on mouse embryos and elucidated the molecular mechanism. Iron overload in endometriosis PF disrupted blastocyst formation, decreased GPX4 expression and induced lipid peroxidation, suggesting that iron overload causes embryotoxicity and induces ferroptosis. Moreover, mitochondrial damage occurs in iron overload-treated embryos, presenting as decreased ATP levels, increased ROS levels and MMP hyperpolarization. The cytotoxicity of iron overload is attenuated by the ferroptosis inhibitor Fer-1. Furthermore, Smart-seq analysis revealed that HMOX1 is upregulated in embryo ferroptosis and that HMOX1 suppresses ferroptosis by maintaining mitochondrial function. This study provides new insight into the mechanism of endometriosis infertility and a potential target for future endometriosis infertility treatment efforts.

A review of the mechanisms of keratinocytes damage caused by Staphylococcus aureus infection in patients with atopic dermatitis.

The dysregulation of skin microflora in patients with atopic dermatitis (AD) has become a research hotspot in recent years. Metagenomic studies have shown that microbial diversity is decreased, whereas the Staphylococcus aureus infection is increased in AD. Keratinocytes are the primary barrier against the invasion of external pathogenic microorganisms. Staphylococcus aureus infection can abnormally activate innate and adaptive immune responses in keratinocytes, resulting in a vicious cycle between Staphylococcus aureus infection and AD. This article reviews the mechanisms of inflammatory damage of keratinocytes induced by Staphylococcus aureus infection in patients with AD, providing a theoretical basis for the study of new targeted drugs. This review also suggests for the management of Staphylococcus aureus infection in patients with AD.

Iron overload compromises preimplantation mouse embryo development.

We and others have previously shown that abnormal pelvic environment plays an important role in the unexplained infertility of endometriosis. However, whether iron overload caused by ectopic periodic bleeding found in patients with endometriosis participates in endometriosis-associated reproductive failure is unknown. This study aimed to investigate effects of iron at level relevant to pelvic iron overload on the development of preimplantation mouse embryo. Two-cell embryos were collected, and cultured to blastocysts in G1/G2 medium supplemented with iron alone or in combination with iron chelator. The development rates, ATP level, mitochondrial membrane potential (MMP), reactive oxygen species level (ROS), and apoptotic and ferroptotic indices were compared between control and iron treatments across each specific developmental stage. Prolonged exposure to iron remarkably impaired early embryo development in vitro by hampering blastocyst formation (P < 0.001), which could be partly restored by iron chelator (P < 0.001). The arrest of embryo development was linked with iron-initiated mitochondrial dysfunction with reduction of ATP generation and MMP (P < 0.05 and P < 0.001, respectively). Impaired mitochondria altered ROS accumulation post-iron exposure at morula stage and blastocyst stage (P < 0.05). Moreover, Iron-exposed blastocyst stage embryos showed higher apoptotic and ferroptotic rates (P < 0.001 and P < 0.05, respectively). Our results highlight that pathologically relevant level of iron compromises preimplantation mouse embryo development by disrupting mitochondrial function and triggering both apoptosis and ferroptosis, which implicates that excess iron found in peritoneal fluid of women with endometriosis likely participates in endometriosis-associated reproductive failure.

Perinatal outcomes in dichorionic diamniotic twins with multifetal pregnancy reduction versus expectant management: A systematic review and meta-analysis.

BACKGROUND: Published findings on perinatal outcomes of multifetal pregnancy reduction (MPR) of dichorionic diamniotic (DCDA) twin pregnancy to singleton are controversial. We performed a meta-analysis to appraise the effects of MPR of DCDA twin pregnancy versus expectant management on perinatal outcomes. METHODS: Four electronic databases were searched from their inception to June 15, 2019, to identify publications that appraised MPR before 15 weeks of gestation. Studies reporting perinatal outcomes of both MPR of DCDA twin pregnancy to singleton and expectant management were considered. The relative risks (RRs) and mean differences with 95% confidence intervals (CIs) were pooled using a random-effects model. RESULTS: Six studies involving 7398 participants showed that MPR of DCDA twin pregnancy to singleton was associated with a lower risk of preterm birth (5 studies with 7297 participants; RR: 0.30, 95% CI: 0.22-0.40; P < .001) and higher birth weight (4 studies with 5763 participants; mean differences: 548.10 g, 95% CI: 424.04-672.15; P < .001) than expectant management; there was no difference in the occurrence of miscarriages (5 studies with 7355 participants; RR: 1.57, 95% CI: 0.90-2.75; P = .11). Sensitivity analysis showed that all the results were stable and reliable, with the omission of 2 studies with serious risk of bias. CONCLUSION: Compared to expectant management, MPR of DCDA twin pregnancy to singleton prevents preterm birth and low birth weight, without increasing the risk of miscarriages. Regarding perinatal morbidity related to preterm birth, MPR can be reserved as a remediation measure to improve the perinatal outcomes of DCDA twin pregnancies.

Therapeutic role of granulocyte colony-stimulating factor (G-CSF) for infertile women under in vitro fertilization and embryo transfer (IVF-ET) treatment: a meta-analysis.

OBJECTIVE: The aim of this meta-analysis is to explore the beneficial role of granulocyte colony-stimulating factor (G-CSF) on infertile women under artificial reproduction technology treatment. METHOD: Medline, Embase and ISI Web of Science databases were searched to identify relevant randomized control trials. Studies before July, 2017 were included for primary screening. Meta-analysis of the total and subgroup patients was conducted, and relative risks (RRs) and their 95% confidence intervals (95% CI) were calculated by a fixed-effect model if no heterogeneity (evaluated as I2 statistic) existed. Otherwise, a random-effects model was adopted. Subgroup analysis was performed by administrating route or clinical indication. Egger test and influence analysis were conducted to evaluate the publication bias and study power, respectively. RESULTS: The final selection enrolled 10 RCTs, involving 1016 IVF-ET cycles (521 distributed to the G-CSF group and 495 to the control). Compared with control group, G-CSF administration could significantly improve clinical pregnancy rate (CPR, RR 1.89, 95% CI 1.53-2.33), while it had no beneficial effect on embryo implantation rate (IR, RR 1.84, 95% CI 0.84-4.03). The subgroup analysis by administration route showed that both uterine infusion and subcutaneous injection can produce a substantial increase in CPR, with the pooled RRs (95% CI) 1.46 (1.04-2.05) and 2.23 (1.68-2.95), respectively. Nevertheless, most of included RCTs dealt with the RIF subjects, and the pooled analysis of this data showed a higher PR and IR in G-CSF group as compared to that in the control, with the RRs (95% CI) 2.07 (1.64-2.61) and 1.52 (1.08-2.14), respectively. Egger regression test did not demonstrate any significance for the publication bias. CONCLUSION: G-CSF administration has a beneficial role on the clinical outcome after embryo transfer by both routes of local infusion and systematic administration, especially for the cases with RIF. Further RCTs are needed to investigate the role of G-CSF in thin endometrium patients.

Establishment of mouse endometrial injury model by curettage or coagulation / 浙江大学学报·医学版

To establish mouse endometrial injury model by curettage or coagulation.Female ICR mice were randomly allocated into 2 groups: in curettage group, a blunt 20G needle was inserted in one uterine horn with 0.05 megapascals negative pressure; in coagulation group, one uterine horn was coagulated using a monopolar electric needle with 0.5 watts power. In both groups the contra-lateral uterine horn was used as control. The morphological changes and thickness of endometrium were evaluated 1 week after operation. The endometrial samples were taken on d4 of pregnancy, and the expressions of endometrial receptivity-related cytokines were examined. The number of implanted embryos on each side of uterus was calculated on d10 of pregnancy.There was no difference in operation time between 2 groups. In both groups, the endometrial glands and stroma were significantly reduced, and the endometrial thickness was also significantly decreased on injury side compared to contra-lateral horn. However, local injury was more severe in coagulation group, uterine obliteration and hydrops were developed in 2 mice of coagulation group, and none in curettage group. The expressions of leukemia inhibitory factor (LIF) and oncostatin M (OSM) were significantly reduced on injured side in both groups compared to opposite side; however, the expression of LIF and OSM in curettage group was higher than that in coagulation group. The numbers of implanted embryos were decreased in both groups on injured side compared to opposite side, and fetal death was only observed in coagulation group.Both curettage and coagulation can make injury on mouse endometrium, impair endometrial receptivity and reduce fertility. Curettage can cause moderate injury, and coagulation may lead to more severe injury.

A comparison of intrauterine balloon, intrauterine contraceptive device and hyaluronic acid gel in the prevention of adhesion reformation following hysteroscopic surgery for Asherman syndrome: a cohort study.

OBJECTIVE: To compare the efficacy of intrauterine balloon, intrauterine contraceptive device and hyaluronic acid gel in the prevention of the adhesion reformation after hysteroscopic adhesiolysis for Asherman's syndrome. STUDY DESIGN: Retrospective cohort study of 107 women with Asherman's syndrome who were treated with hysteroscopic division of intrauterine adhesions. After hysteroscopic adhesiolysis, 20 patients had intrauterine balloon inserted, 28 patients had intrauterine contraceptive device (IUD) fitted, 18 patients had hyaluronic acid gel instilled into the uterine cavity, and 41 control subjects did not have any of the three additional treatment measures. A second-look hysteroscopy was performed in all cases, and the effect of hysteroscopic adhesiolysis was scored by the American Fertility Society classification system. RESULTS: Both the intrauterine balloon group and the IUD group achieved significantly (P<0.001) greater reduction in the adhesion score than that of the hyaluronic acid gel group and control group. The efficacy of the balloon was greater than that of the IUD (P<0.001). There was no significant difference in results between the hyaluronic acid gel group and the control groups. CONCLUSION: The insertion of an intrauterine balloon or intrauterine device is more effective than the use of hyaluronic acid gel in the prevention of intra-uterine adhesion reformation.

[Effects of early intervention of second-look office hysteroscopy in the prevention of adhesion reformation for moderate-severe Asherman's syndrome].

OBJECTIVE: To compare the efficacy of different time interval in the prevention of adhesion reformation after hysteroscopic adhesiolysis for moderate-severe Asherman's syndrome. METHODS: A total of 125 women with moderate-severe Asherman's syndrome undergoing hysteroscopic division of intrauterine adhesion were enrolled into this retrospective cohort study. All patients underwent second-look hysteroscopy after a certain period of the first hysteroscopic adhesiolysis, and the operation would be performed again if any adhesion existed. According to the different time interval of hysteroscopy examination, they were divided into 3 groups: A: < 1 month (n = 50), B:1-2 months (n = 39), C >2 months (n = 36). The effect of hysteroscopic adhesiolysis was evaluated by American Fertility Society (AFS) score. RESULTS: The AFS score decreased significantly after hysteroscopic adhesiolysis in each group and the normal uterine rate was up to 64.8%. The median of decreased AFS score and normal uterine rate were as follows:group A:7 point and 78%, group B:7 point and 66.7%, group C:5 point and 44.4%. And groups A and B achieved significantly (P < 0.01) greater reductions in the adhesion score than that of group C. The median time of recovery to normal uterine cavity were 1.64, 2.75 and 5.26 months in each group and great differences existed among them (P < 0.01). CONCLUSION: The time interval of second-look hysteroscopy less than 1 month offers a better prognosis in the prevention of adhesion reformation for moderate-severe Asherman's syndrome.

Outcome of in vitro fertilization in endometriosis-associated infertility: a 5-year database cohort study.

BACKGROUND: Endometriosis affects natural fertility through various approaches, and in vitro fertilization (IVF) is a good treatment. But the IVF result of endometriosis patients is still under debate. We investigated the effect of endometriosis on IVF by analyzing the data from a single reproductive center. METHODS: A retrospective, database-searched cohort study was performed. Relevant information was collected from the electronic records of women who underwent IVF/intracytoplasmic sperm injection between January 2006 and December 2010 in the Assisted Reproductive Unit of Sir Run Run Shaw Hospital. Patients with endometriosis were enrolled the study group. The rest of the women formed the control group. The main outcome was the clinical pregnancy rate. Secondary outcomes were oocytes retrieved number, fertilization rate, high-quality embryo rate, number of high-quality embryo for embryo transplantation, and implantation embryo/high-quality embryo ratio (IE/HQE ratio). Comparisons were performed by the c(2)-test and independent t-test. RESULTS: The endometriosis group (n = 177) had a markedly lower oocytes retrieved number, fertilization rate, implantation rate, and clinical pregnancy rate (7.6 ± 5.1, 63.6%, 27.7%, and 45.2%, respectively) compared with the non-endometriosis group (n = 4267; 11.8 ± 7.3, 68.4%, 36.2%, and 55.2%, respectively). Stratified analysis showed that this difference was found in the subgroup younger than 35-years old, while only fertilization rate and implantation rate were different in the elder subgroup. The ratio of high-quality embryos transferred is lower in endometriosis group (53.7% vs. 71.8%, P < 0.05), but there is no difference in IE/HQE ratio between two groups. There is no significant difference in fertilization rate, implantation rate, and clinical pregnancy rate between mild and severe endometriosis patients. CONCLUSIONS: Endometriosis patients suffer a decreasing IVF pregnancy rates mainly caused by reducing oocytes number and fertilization rate, regardless of the severity of the disease. Appropriate intracytoplasmic sperm injection manipulation might improve the outcomes of IVF.

[Analysis of risk factors for triplet pregnancy after a simultaneous transfer of triplicate embryos].

OBJECTIVE: To analyze the risk factors for triplet pregnancy after a simultaneous transfer of triplicate embryos. METHODS: The investigators carried out a retrospective analysis of 769 cycles in which three embryos were transferred in one treatment cycle, including 298 fresh embryo transfer (ET) cycles and 471 frozen-thawed ET (FET) cycles. The impact of patient age and the number of good embryos transferred on the rates of clinical pregnancy and triplet pregnancy was studied according to different cycle types. RESULTS: (1) The rates of clinical and triplet pregnancy were significantly higher in the FET group (P < 0.05) than those in the fresh ET group; (2) all patients with a triplet pregnancy in the fresh ET group (n = 6) were younger than 35 years old (P < 0.01). There was no significant difference between the subgroups in the FET cycle according to patient age (P > 0.05); (3) when none, 1, 2 or 3 good embryos were transferred in the fresh ET cycle, the clinical pregnancy rates were 28.3%, 46.7%, 50.6% and 58.7% and the triplet pregnancy rates 0, 2.3%, 4.7% and 6.8% respectively. A similar clinical pregnancy rate (P > 0.05) and a significantly lower triplet pregnancy rate (P < 0.05) were observed when 1 good embryo was transferred versus 2 good embryos (P < 0.05). When 0, 1, 2 or 3 good embryos were transferred in the FET cycle, the clinical pregnancy rates were 38.9%, 54.8%, 59.7%, 63.9% and the triplet pregnancy rates 0, 5.0%, 13.8%, 15.8% respectively. A similar clinical pregnancy rate (P > 0.05) and a significantly lower triplet pregnancy rate (P < 0.05) were observed when 1 good embryo was transferred versus two good embryos (P < 0.05). All triplet pregnancies occurred in cycles in which more than 1 good embryo was transferred (P < 0.05). CONCLUSION: The patients have more triplet pregnancies in the FET cycle than in the fresh ET cycle. In the FET cycle, the patient age is irrelevant. It is recommended that no more than 2 embryos should be transferred. Selective single blastocyst embryo transfer is preferable if there are more than 2 good embryos available for transfer. No more than 2 embryos should be transferred in the fresh ET cycle if good embryos are available and a patient is under 35 years old.

Maintenance of early pregnancy without early hormone support after frozen-thawed embryo transfer in hormone replacement treatment cycles.

OBJECTIVE: To report two successful pregnancies after frozen-thawed ET in discontinued hormone replacement treatment cycles. DESIGN: Case report. SETTING: University hospital. PATIENT(S): Two infertile patients. INTERVENTION(S): Hormone replacement treatment for endometrial preparation and frozen-thawed ET. MAIN OUTCOME MEASURE(S): Ovarian ultrasonography, serial hormone measurements of serum E2 and P, successful pregnancy, and follow-up visit. RESULT(S): One patient discontinued both E2 and P support 2 weeks after ET. The other discontinued estrogen support on the day preceding ET. No spontaneous follicle development was observed by ultrasonography, and no increase in serum P concentration was observed. Both patients became pregnant and achieved deliveries. CONCLUSION(S): These two cases show that maintenance of pregnancy is possible without early hormone support in hormone replacement treatment cycles.