Comparison of the perinatal outcomes of expected high ovarian response patients and normal ovarian response patients undergoing frozen-thawed embryo transfer in natural/small amount of HMG induced ovulation cycles.

BACKGROUND: Due to the high risk of complications in fresh transfer cycles among expected high ovarian response patients, most choose frozen-thawed embryo transfer (FET). There are currently few researches on whether the FET outcomes of expected high ovarian response patients with regular menstrual cycles are similar to those of normal ovarian response. Therefore, our objective was to explore and compare pregnancy outcomes and maternal and neonatal outcomes of natural FET cycles between patients with expected high ovarian response and normal ovarian response with regular menstrual cycles based on the antral follicle count (AFC). METHODS: This retrospective cohort study included 5082 women undergoing natural or small amount of HMG induced ovulation FET cycles at the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University from January 1, 2017, to March 31, 2021. The population was divided into expected high ovarian response group and normal ovarian response group based on the AFC, and the differences in patient characteristics, clinical outcomes and perinatal outcomes between the two groups were compared. RESULTS: Regarding clinical outcomes, compared with the normal ovarian response group, patients in the expected high ovarian response group had a higher clinical pregnancy rate (57.34% vs. 48.50%) and live birth rate (48.12% vs. 38.97%). There was no difference in the early miscarriage rate or twin pregnancy rate between the groups. Multivariate logistic regression analysis suggested that the clinical pregnancy rate (adjusted OR 1.190) and live birth rate (adjusted OR 1.171) of the expected high ovarian response group were higher than those of the normal ovarian response group. In terms of maternal and infant outcomes, the incidence of very preterm delivery in the normal ovarian response group was higher than that in the expected high ovarian response group (0.86% vs. 0.16%, adjusted OR 0.131), Other maternal and infant outcomes were not significantly different. After grouping by age (< 30 y, 30-34 y, 35-39 y), there was no difference in the incidence of very preterm delivery among the age subgroups. CONCLUSION: For patients with expected high ovarian response and regular menstrual cycles undergoing natural or small amount of HMG induced ovulation FET cycles, the clinical and perinatal outcomes are reassuring. For patients undergoing natural or small amount of HMG induced ovulation FET cycles, as age increases, perinatal care should be strengthened during pregnancy to reduce the incidence of very preterm delivery.

Corrigendum: Fetal-maternal interactions during pregnancy: a 'three-in-one' perspective.

[This corrects the article DOI: 10.3389/fimmu.2023.1198430.].

Fetal-maternal interactions during pregnancy: a 'three-in-one' perspective.

A successful human pregnancy requires the maternal immune system to recognize and tolerate the semi-allogeneic fetus, allowing for appropriate trophoblasts invasion and protecting the fetus from invading pathogens. Therefore, maternal immunity is critical for the establishment and maintenance of pregnancy, especially at the maternal-fetal interface. Anatomically, the maternal-fetal interface has both maternally- and fetally- derived cells, including fetal originated trophoblasts and maternal derived immune cells and stromal cells. Besides, a commensal microbiota in the uterus was supposed to aid the unique immunity in pregnancy. The appropriate crosstalk between fetal derived and maternal originated cells and uterine microbiota are critical for normal pregnancy. Dysfunctional maternal-fetal interactions might be associated with the development of pregnancy complications. This review elaborates the latest knowledge on the interactions between trophoblasts and decidual immune cells, highlighting their critical roles in maternal-fetal tolerance and pregnancy development. We also characterize the role of commensal bacteria in promoting pregnancy progression. Furthermore, this review may provide new thought on future basic research and the development of clinical applications for pregnancy complications.

Engineering CoP Alloy Foil to a Well-Designed Integrated Electrode Toward High-Performance Electrochemical Energy Storage.

Nanostructured integrated electrodes with binder-free design show great potential to solve the ever-growing problems faced by currently commercial lithium-ion batteries such as insufficient power and energy densities. However, there are still many challenging problems limiting practical application of this emerging technology, in particular complex manufacturing process, high fabrication cost, and low loading mass of active material. Different from existing fabrication strategies, here using a CoP alloy foil as a precursor  a simple neutral salt solution-mediated electrochemical dealloying method to well address the above issues is demonstrated. The resultant freestanding mesoporous np-Co(OH)x /Co2 P product possesses not only active compositions of high specific capacity and large electrode packing density (>3.0 g cm-3 ) to meet practical capacity requirements, high-conductivity and well-developed nanoporous framework to achieve simultaneously fast ion and electron transfer, but also interconnected ligaments and suitable free space to ensure strong structural stability. Its comprehensively excellent electrochemical energy storage (EES) performances in both lithium/sodium-ion batteries and lithium-ion capacitors can further illustrate the effectiveness of the integrated electrode preparation strategy, such as remarkable reversible specific capacities/capacitances, dominated pseudo-capacitive EES mechanism, and ultra-long cycling life. This study provides new insights into preparation and design of high-performance integrated electrodes for practical applications.

Optimal waiting period for frozen embryo transfer after hysteroscopic polypectomy: A propensity score matching analysis.

Objective: To evaluate the optimal waiting period for frozen-thawed embryo transfer (FET) after hysteroscopic polypectomy (HSC-P). Design: Retrospective cohort. Setting: University-affiliated hospital. Patients: All patients included in this research underwent hysteroscopy before the first FET cycle after whole embryo freezing. A total of 206 patients had undergone HSC-P, and 3681 patients without endometrial polyps were defined as the controls. Interventions: HSC-P. Main outcome measures: The HSC-P group was divided into three subgroups based on the time interval between HSC-P and the start of an FET cycle. Subgroup 1 consisted of patients who underwent FET after their next menses, subgroup 2 after two menstrual cycles, and subgroup 3 after three or more menstrual cycles. Demographics, baseline in vitro fertilization (IVF) characteristics, and pregnancy outcomes, especially perinatal outcomes after FET were compared among the groups. Results: There were 137 patients in subgroup 1, 40 in subgroup 2, and 29 in subgroup 3. There were no differences in the baseline characteristics of the three groups. IVF-related data and FET-related data, such as endometrial thickness and ET no. Of embryoes, were similar among the three subgroups. The three subgroups showed no significant differences in implantation rate, biochemical pregnancy rate, abortion rate, clinical pregnancy rate or live birth rate. Besides, There was no significant difference in perinatal outcomes including very preterm delivery, preterm delivery, low birth weight, macrosomia, small for gestational age, large for gestational age, birth weight(g), birth-height(cm)and Apgar Scores. Conclusions: Compared with FET after their next menses, FET after two or more menstrual cycles after HSC-P does not necessarily produce superior outcomes.

Comparison of Perinatal Outcomes of Letrozole-Induced Ovulation and Hormone Replacement Therapy Protocols in Patients With Abnormal Ovulation Undergoing Frozen-Thawed Embryo Transfer: A Propensity Score Matching Analysis.

Background: With the increasing use of frozen embryo transfer (FET), the best endometrial preparation protocol is continuously being discussed. The hormone replacement therapy (HRT) cycle and letrozole-induced ovulation (L-OI) cycle are available protocols for patients with abnormal ovulation. Previous comparisons of the two protocols have focused on pregnancy outcomes, with less attention to perinatal outcomes, and population heterogeneity was large; thus, convincing conclusions about which protocol is more appropriate could not be drawn. Methods: We performed a retrospective cohort study using propensity score matching (PSM) analysis for a population of patients undergoing FET cycles in the reproductive center of the Third Affiliated Hospital of Zhengzhou University from January 2016 to September 2020. The main outcome measures were clinical pregnancy rate, live birth rate, very preterm delivery (VPTD), preterm delivery (PTD), low birth weight (LBW), macrosomia, small for gestational age (SGA), large for gestational age (LGA), hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), premature rupture of membranes (PROM), placenta previa, and congenital abnormality. Results: A total of 8010 women were enrolled. Due to the large heterogeneity among the patients, we conducted 1:1 PSM, and 1461 women matched in each group. Compared with the HRT group, the L-OI group had a smaller proportion of thin endometrium (27.38% vs. 41.07%) and thicker endometrium on the day of embryo transfer (9.63 ± 1.82 vs. 8.91 ± 1.38). There were no significant differences in clinical pregnancy rate, early abortion rate or live birth rate between the groups. There was no significant difference in perinatal outcomes of singleton live birth, including VPTD, PTD, postterm delivery, LBW, macrosomia, SGA, LGA, GDM, HDP, placenta previa, and congenital malformation. Conclusion: For women with abnormal ovulation, the pregnancy and perinatal outcomes of HRT and L-OI protocols are reassuring. It seems that both protocols are safe and effective for endometrial preparation in frozen-thawed embryo transfer in the clinic.

Is it necessary to monitor the serum luteinizing hormone (LH) concentration on the human chorionic gonadotropin (HCG) day among young women during the follicular-phase long protocol? A retrospective cohort study.

BACKGROUND: The normal physiological function of LH requires a certain concentration range, but because of pituitary desensitization, even on the day of HCG, endogenous levels of LH are low in the follicular-phase long protocol. Therefore, our study aimed to determine whether it is necessary to monitor serum LH concentrations on the day of HCG (LHHCG) and to determine whether there is an optimal LHHCG range to achieve the desired clinical outcome. METHODS: A retrospective cohort study included 4502 cycles of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) from January 1, 2016, to June 30, 2019, in a single department. The main outcome measures included retrieved eggs, available embryos, and live birth rate. RESULTS: The LHHCG was divided into five groups: Group A (LH ≤ 0.5), Group B (0.5 IU/L < LH ≤ 1.2 IU/L), Group C (1.2 IU/L < LH ≤ 2.0 IU/L), Group D (2.0 IU/L < LH ≤ 5.0 IU/L), Group E (LH > 5 IU/L). In terms of the numbers of retrieved eggs (15.22 ± 5.66 vs. 13.54 ± 5.23 vs. 12.90 ± 5.05 vs. 12.30 ± 4.88 vs. 9.6 ± 4.09), diploid fertilized oocytes (9.85 ± 4.70 vs. 8.69 ± 4.41 vs. 8.39 ± 4.33 vs. 7.78 ± 3.96 vs. 5.92 ± 2.78), embryos (7.90 ± 4.48 vs. 6.83 ± 4.03 vs. 6.44 ± 3.88 vs. 6.22 ± 3.62 vs. 4.40 ± 2.55), and high-quality embryos (4.32 ± 3.71 vs. 3.97 ± 3.42 vs. 3.76 ± 3.19 vs. 3.71 ± 3.04 vs. 2.52 ± 2.27), an increase in the LHHCG level showed a trend of a gradual decrease. However, there was no significant difference in clinical outcomes among the groups (66.67% vs. 64.33% vs. 63.21% vs. 64.48% vs. 63.33%). By adjusting for confounding factors, with an increase in LHHCG, the number of retrieved eggs decreased (OR: -0.351 95%CI - 0.453-[- 0.249]). CONCLUSION: In the follicular-phase long protocol among young women, monitoring LHHCG is recommended in the clinical guidelines to obtain the ideal number of eggs.

The altered PD-1/PD-L1 pathway delivers the 'one-two punch' effects to promote the Treg/Th17 imbalance in pre-eclampsia.

The programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway is critical for normal pregnancy by promoting regulatory T (Treg) cell development and inhibiting the Th17 response. However, the relationship between the PD-1/PD-L1 pathway and the Treg/Th17 imbalance in pre-eclampsia (PE) is an enigma. In this study, decreased PD-1 and PD-L1 expression and a Treg/Th17 imbalance were observed at the maternal-fetal interface in PE. The regulatory effects of the PD-1/PD-L1 pathway on the Treg and Th17 cell quantities were determined in vitro by targeting T-cell proliferation, differentiation and transdifferentiation. First, decreased PD-1 expression might contribute to a higher Th17 cell frequency by promoting proliferation in PE. Second, the percentages of Treg but not Th17 cells differentiated from peripheral naive CD4+ T cells were increased by PD-L1 Fc administration. This effect was accompanied by decreased PI3K/AKT/m-TOR and increased PTEN mRNA expression and was completely reversed by PD-1 blockade. Finally, the percentage of IL-17-producing Treg cells increased and was positively associated with the Th17 cell frequency in PE. Increased RORγt and IL-17 but not Foxp3 and IL-10 mRNA expression by Treg cells was observed with PD-1 blockade. Similar findings occurred when Treg cells were exposed to IL-6/IL-23/IL-1ß and were reversed by PD-L1 Fc. Taken together, our findings indicate that the PD-1/PD-L1 pathway contributes to the Treg/Th17 imbalance via 'one-two punch' approaches: (i) promoting Th17 cell proliferation, (ii) inhibiting Treg cell differentiation and (iii) enhancing Treg cell plasticity into Th17 cells in PE. The therapeutic value of PD-L1 Fc for PE treatment will be explored in the future.

The transdifferentiation of regulatory T and Th17 cells in autoimmune/inflammatory diseases and its potential implications in pregnancy complications.

In the past decades, studies have shown that a balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells plays a major role in autoimmune/inflammatory diseases as well as pregnancy complications. Decreased number and function of Tregs, and increased number of Th17 cells which often have an opposed effect of Tregs, are associated with these conditions. Recently, the plasticity of Tregs and Th17 cells has been reported to be involved in the pathogenesis of autoimmune/inflammatory diseases. Hence, we summarize the current knowledge of Tregs and Th17 cells plasticity with an emphasis on their reciprocal transdifferentiation in autoimmune/inflammatory diseases. Moreover, the regulators of the Tregs-to-Th17 cells transdifferentiation are discussed as well. Finally, by reviewing the immuno-inflammatory status of pregnancy complications, such as preeclampsia and unexplained recurrent pregnancy losses, a possibility of Tregs-to-Th17 cells transdifferentiation as an underlying immune-pathology of these conditions is discussed.

The PD-1/PD-L1 inhibitory pathway is altered in pre-eclampsia and regulates T cell responses in pre-eclamptic rats.

The programmed cell death-1(PD-1)/PD-ligand 1 (PD-L1) pathway is critical to immune homeostasis by promoting regulatory T (Treg) development and inhibiting effector T (such as Th17) cell responses. However, the association between the PD-1/PD-L1 pathway and the Treg/Th17 imbalance has not been fully investigated in pre-eclampsia (PE). In this study, we observed an inverse correlation between the percentages of Treg and Th17 cells, and the expression of PD-1 and PD-L1 on the two subsets also changed in PE compared with normal pregnancy. We further explored their relationship in vivo using the L-NG-Nitroarginine Methyl Ester (L-NAME) induced PE-like rat models, also characterized by Treg/Th17 imbalance. Administration of PD-L1-Fc protein provides a protective effects on the pre-eclamptic models, both to the mother and the fetuses, by reversing Treg/Th17 imbalance through inhibiting PI3K/AKT/m-TOR signaling and enhancing PTEN expression. In addition, we also observed a protective effect of PD-L1-Fc on the placenta by reversing placental damages. These results suggested that altered PD-1/PD-L1 pathway contributed to Treg/Th17 imbalance in PE. Treatment with PD-L1-Fc posed protective effects on pre-eclamptic models, indicating that the use of PD-L1-Fc might be a potential therapeutic target in PE treatment.

What are the roles of macrophages and monocytes in human pregnancy?

During pregnancy, the maternal immune system is challenged by the semi-allogeneic fetus, which leads to systemic and local immunity. Systemic immunity, including enhanced innate immunity with increased activation of monocytes, is induced by various placental factors. Maternal immune adaptations are most evident at the feto-maternal interface, where macrophages are enriched and communicate with various decidual leukocytes. These cells are not only contributing to the protection of the growing fetus from microorganisms, but also aiding placental development by promoting trophoblast invasion and spiral artery remodeling, and the parturition process. Thus, monocytes and macrophages concurrently play important roles throughout the trimesters. Dysregulation of these cells may thus lead to pregnancy complications, such as pre-eclampsia and preterm labor. In this review, monocytes and macrophage subsets and their roles in normal and pathological pregnancies are reviewed.

Morphological Changes and Expression of Cytokine After Local Endometrial Injury in a Mouse Model.

OBJECTIVE: To establish a mouse model for endometrial injury and determine the underlying mechanism regarding its favorable effect on embryo implantation. STUDY DESIGN: Female Kunming mice were randomly allocated into 4 groups: group I, normal control; group II, injury procedure control; and group III and group IV, the mice being scratched with a blunt syringe on the right uterine horn or both, respectively. All the mice were mated with the males during the next estrus phase. The number of implanted embryos on each side of uterus was calculated on day 8 of pregnancy. The endometrial samples were taken on day 4 of pregnancy, and the local morphological changes and cytokine expressions were examined. RESULTS: Compared to group II, our results showed that in group IV (1) there were significantly higher numbers of implanted embryos, (2) the endometrial glands and vasculatures in stroma were obviously increased and the pinopodes were abundant and well developed, and (3) the local levels of cytokines leukemia inhibitory factor (LIF) and oncostatin M (OSM) messenger RNA and protein expression were significantly increased. CONCLUSIONS: Local mechanical injury on mouse uteri enhanced endometrial receptivity and improved embryo implantation, which were correlated with the characteristic changes in endometrial morphology and the upregulation of LIF and OSM gene and protein expression.

Recent Insight into the Role of the PD-1/PD-L1 Pathway in Feto-Maternal Tolerance and Pregnancy.

Pregnancy presents a great challenge to the maternal immune system. Given that maternal alloreactive lymphocytes are not depleted during pregnancy, local and/or systemic mechanisms have to serve a central function in altering the maternal immune responses. Regulatory T cells (Tregs) and the PD-1/PD-L1 pathway are both critical in controlling the immune responses. Recent studies have proved the critical function of the PD-1/PD-L1 pathway in regulating the T-cell homeostasis and the peripheral tolerance through promoting the development and function of Tregs, and inhibiting the activation of effector T cells. The function of the PD-1/PD-L1 pathway in feto-maternal interface and pregnancy has been investigated in human and animal models of pregnancy. In this review, we provide recent insight into the role of the PD-1/PD-L1 pathway in regulating T-cell homeostasis, maternal tolerance, and pregnancy-related complications as well as its possible applicability in clinical immunotherapy.

A novel single-chain-Fv antibody against connective tissue growth factor attenuates bleomycin-induced pulmonary fibrosis in mice.

BACKGROUND AND OBJECTIVE: Connective tissue growth factor (CTGF) has been identified as playing critical roles in fibrosis and is a promising therapeutic target. In a previous study, we used a phage display library to develop a humanized single-chain variable fragment antibody (scFv) against CTGF. In the present study, the protective effect of anti-CTGF scFv against bleomycin (BL)-induced pulmonary fibrosis was investigated in mice. METHODS: The expression of α-smooth muscle actin in human embryonic lung fibroblast (HELF) cells was analysed by western blotting. A mouse model of pulmonary fibrosis was established by tracheal injection of BL (5 mg/kg). Mice received anti-CTGF scFv (4 mg/kg, three times a week) by i.v. injection. The effects of anti-CTGF scFv were evaluated by leukocyte counts in BAL fluid, hydroxyproline measurements in lung tissue and pathological examination. RESULTS: α-Smooth muscle actin expression was decreased in HELF cells treated with anti-CTGF scFv. Anti-CTGF scFv significantly reduced the numbers of inflammatory leukocytes (total and differential count) in BAL fluid, as well as the hydroxyproline content of lung tissue. The severity of alveolitis and fibrosis in the mouse model was markedly attenuated by treatment with anti-CTGF scFv. CONCLUSIONS: Anti-CTGF scFv may potentially be developed as a useful inhibitor of pulmonary fibrosis.