Characteristics and functions of memory regulatory T cells in normal pregnancy cycle and pregnancy complications.

Regulatory T cells (Tregs) are activated and expanded after exposure to fetal-specific (paternal) antigens. A proportion of Tregs differentiate into memory Tregs (mTregs), exhibiting immune memory function and exerting more potent immunosuppression than naive Tregs (nTregs). However, it is unclear how mTregs are regulated during normal and pathological pregnancies (e.g., gestational diabetes mellitus (GDM) and preeclampsia (PE)). In this study, PD-1, HLA-G, and HLA-DR expressions on memory CD4+ T cells, naive CD4+ T cells, Tregs, mTregs, and nTregs in healthy non-pregnant women (n=20), healthy first (n=20), second (n=20), and third-trimester women (n=20), postpartum women (n=20), GDM (n=20), and PE patients (n=20) were analyzed. The proportion of mTregs out of Tregs was increased (P<0.05) in the first trimester compared with that in non-pregnancy and reduced in the second and third trimesters. The proportions of PD-1+ Tregs and mTregs were significantly increased during the first trimester compared to those of non-pregnancy (P<0.01), reached their maximum in the second trimester. Moreover, the proportions of HLA-G+ memory CD4+ T cells, Tregs, and mTregs were increased in the first and second trimesters (P<0.01), reached their maximum in the third trimester. GDM patients were characterized by significantly lower percentages of PD-1+ and HLA-G+ mTregs (P<0.01), while PE patients were characterized by significantly lower percentages of HLA-G+ mTregs (P<0.01), compared with the healthy third-trimester women. In general, as demonstrated by this study, mTregs increase in number and enhance maternal-fetal immunoregulation during pregnancy, and their dysfunction can result in pregnancy complications such as GMD or PE.

Memory regulatory T cells in pregnancy.

Pregnancy requires the process of maternal immune tolerance to semi-allogeneic embryos. In contrast, an overreactive maternal immune system to embryo-specific antigens is likely to result in the rejection of embryos while damaging the invading placenta, such that the likelihood of adverse pregnancy outcomes can be increased. Regulatory T cells (Tregs) are capable of suppressing excessive immune responses and regulating immune homeostasis. When stimulating Tregs, specific antigens will differentiate into memory Tregs with long-term survival and rapid and powerful immune regulatory ability. Immunomodulatory effects mediated by memory Tregs at the maternal-fetal interface take on critical significance in a successful pregnancy. The impaired function of memory Tregs shows a correlation with various pregnancy complications (e.g., preeclampsia, gestational diabetes mellitus, and recurrent pregnancy losses). However, the differentiation process and characteristics of memory Tregs, especially their role in pregnancy, remain unclear. In this study, a review is presented in terms of memory Tregs differentiation and activation, the characteristics of memory Tregs and their role in pregnancy, and the correlation between memory Tregs and pregnancy complications. Furthermore, several potential therapeutic methods are investigated to restore the function of memory Tregs in accordance with immunopathologies arising from memory Tregs abnormalities and provide novel targets for diagnosing and treating pregnancy-associated diseases.

Poor ovarian response in assisted reproductive technology cycles is associated with anti-ovarian antibody and pro-inflammatory immune responses.

Anti-ovarian antibody (AOA) could be considered an independent marker for autoimmune ovarian disease and predicting future premature ovarian failure (POF). This study aims to investigate if AOA is associated with poor ovarian response (POR) and pro-inflammatory immune responses in women undergoing assisted reproductive technology (ART) cycles. Two hundred forty-eight women undergoing ART cycles were divided into four groups based on AOA test results and the presence of POR: POR(-)/AOA(-) group (N = 148), POR(+)/AOA(-) group (N = 34), POR (-)/AOA(+) group (N = 44), POR(+)/AOA(+) group (N = 22). The POR patients have a significantly higher prevalence of AOA than non-POR patients (P < 0.05). Peripheral blood CD56 + natural killer (NK) cell level (%), NK cytotoxicity, CD19 +CD5 + B-1 cell level (%), and IFN-γ/IL-10 producing T helper (Th) 1/Th2 cell ratios were significantly higher in POR(+)/AOA(+) group than those of other groups (P < 0.001, P < 0.005, P < 0.01, P < 0.05, respectively). TNF-α/IL-10 producing Th1/Th2 cell ratio of POR(+)/AOA(+) group was significantly higher than those of POR(+)/AOA(-) and POR(-)/AOA(-) groups (P < 0.05, respectively). Homocysteine and vitamin D levels of the POR(+)/AOA(+) group were significantly lower than those of other groups (P < 0.005, respectively). Plasminogen activator inhibiter-1 (PAI-1) level of POR(+)/AOA(+) group was significantly higher than that of POR(-)/AOA(-) group (P < 0.05). In the POR(+)/AOA(+) group, the prevalence of antiphospholipid antibodies was significantly higher than that of the POR(+)/AOA(-) group (P = 0.005). Women with autoimmune POR (POR(+)/AOA(+)) have dysregulated pro-inflammatory immune responses and metabolic factors. The diagnostic and therapeutic approaches for autoimmune POR should be differentiated from those for non-autoimmune POR.

Increased serum IL-12 levels are associated with adverse IVF outcomes.

Interleukin-12 (IL-12) is involved in the occurrence and development of many diseases, such as preeclampsia, intrauterine growth restriction, preterm labor, and recurrent pregnancy losses. This study aimed to determine whether a high serum level of IL-12 was associated with adverse in vitro fertilization (IVF) outcomes. Included infertile women with high serum IL-12 levels who underwent IVF cycles and infertile controls with pure tubal etiology. The impact of serum IL-12 on baseline and clinical characteristics, immune-related indicators, IVF laboratory, and pregnancy outcomes were compared. In addition, the correlation of follicular fluid IL-12 and serum IL-12 level and the role of IL-12 in apoptosis of granulosa cells (GCs) was investigated. Women with high serum IL-12 levels had lower numbers of retrieved oocytes, embryos, perfect and available embryos, lower rates of perfect and available embryos, and blastocyst formation. Additionally, significantly higher levels of serum Th1, Th2, and Th17-related cytokines were observed in women with high serum IL-12 levels than in the controls. Meanwhile, the follicular fluid IL-12 levels were positively correlated with serum IL-12 levels, and IL-12 promoted apoptosis of GCs in vitro. We concluded that women with serum high IL-12 levels may have adverse IVF outcomes, partly by promoting apoptosis of GCs. Therefore, early screening for cytokines, especially IL-12, and appropriate consultation for couples receiving IVF-ET should be considered. In addition, specific immune and inflammatory mechanisms associated with high serum IL-12 levels should be further explored.

Peripheral blood natural killer cell cytotoxicity in recurrent miscarriage: a systematic review and meta-analysis.

Dysregulated natural killer (NK) cells have been associated with recurrent miscarriages (RM). Studies have suggested that high peripheral blood NK cell cytotoxicities (pNKCs) are associated with an increased risk of RM. The aim of this systematic review (SR) and meta-analysis (MAs) is to investigate the difference in pNKC between nonpregnant and pregnant women with RM and controls and determine whether pNKC is reduced by immunotherapy. We searched the PubMed/Medline, Embase, and Web of Science databases. The MAs were conducted to compare pNKCs between women with and without RM before and during pregnancy as well as pre- and post-immunotherapy. Risk of bias in nonrandomized studies was assessed by the Newcastle-Ottawa Scale. Statistical analysis was performed using the Review Manager software. A total of 19 studies were included in the SR and 14 studies in the MAs. The MAs revealed higher pNKCs among nonpregnant women with RM compared to controls (MD, 7.99 95 %CI 6.40-9.58; p < 0.00001). pNKCs were also higher in pregnant women with RM than in pregnant controls (MD, 8.21 95 %CI 6.08-10.34; p < 0.00001). Women with RM showed significantly decreased pNKCs after the immunotherapy compared to before (MD, -8.20 95 %CI -10.20 - -6.19; p < 0, 00001). Additionally, there is an association between high pNKCs and the risk of pregnancy loss in women with RM. However, included studies showed substantial heterogeneities regarding the inclusion criteria of patients, techniques measuring pNKC, and types of immunotherapies. More studies are needed to evaluate the clinical efficiency of pNKCs in managing RM.

Immune checkpoint inhibitors and reproductive failures.

The human conceptus is a semi-allograft, which is antigenically foreign to the mother. Hence, the implantation process needs mechanisms to prevent allograft rejection during successful pregnancy. Immune checkpoints are a group of inhibitory pathways expressed on the surface of various immune cells in the form of ligand receptors. Immune cells possess these pathways to regulate the magnitude of immune responses and induce maternal-fetal tolerance. Briefly, 1) CTLA-4 can weaken T cell receptor (TCR) signals and inhibit T cell response; 2) The PD-1/PD-L1 pathway can reduce T cell proliferation, enhance T cell anergy and fatigue, reduce cytokine production, and increase T regulatory cell activity to complete the immunosuppression; 3) TIM3 interacts with T cells by binding Gal-9, weakening Th1 cell-mediated immunity and T cell apoptosis; 4) The LAG-3 binding to MHC II can inhibit T cell activation by interfering with the binding of CD4 to MHC II, and; 5) TIGIT can release inhibitory signals to NK and T cells through the ITIM structure of its cytoplasmic tail. Therefore, dysregulated immune checkpoints or the application of immune checkpoint inhibitors may impair human reproduction. This review intends to deliver a comprehensive overview of immune checkpoints in pregnancy, including CTLA-4, PD-1/PD-L1, TIM-3, LAG-3, TIGIT, and their inhibitors, reviewing their roles in normal and pathological human pregnancies.

Unexplained recurrent pregnancy loss: Novel causes and advanced treatment.

In this study, recent research focusing on recurrent pregnancy loss (RPL) are reviewed. Recurrent pregnancy loss is a devastating reproductive health burden that affects about 5% of couples trying to conceive globally. Currently, there are few evidence-based diagnostic and treatment strategies for RPL. More so, the number of unexplained etiology cases in patients with RPL arrives at 50%. Here, we discuss the progress in diagnosis and treatment of unexplained RPL, as well as recommended treatment strategies and controversial etiologies.

Anticardiolipin and/or anti-ß2-glycoprotein-I antibodies are associated with adverse IVF outcomes.

Objective: The purpose of the study is to evaluate the effects of anticardiolipin (aCL) and/or anti-ß2-glycoprotein-I (aß2GPI) antibodies, namely antiphospholipid antibodies (aPL), on in vitro fertilization (IVF) outcomes. Materials and methods: The study group comprised infertile women with aPL undergoing IVF-ET cycles. Controls were infertile women with tubal etiology without aPL. The impact of aPL on reproductive outcomes, such as oocyte quality, embryo quality, and implantation capacity, was compared between the study group and controls. Additionally, peripheral blood T cell subsets, such as T helper (Th)1, Th2, Th17, and T regulatory (Treg) cells and cytokines, were analyzed by the flow cytometry. Differences between the study group and controls were analyzed. Results: A total of 132 infertile women, including 44 women with aPL, and 88 controls were sequentially recruited for this study. Women with aPL had lower numbers of total and perfect/available embryos and lower rates of MII oocytes, blastocyst formation, perfect and available embryos, implantation, clinical pregnancy, and take-home baby. Additionally, imbalanced Th1/Th2 and Th17/Treg ratios, significantly higher levels of serum IL-2, TNF-α, IFN-γ, and IL-17A, and a significantly lower serum IL-4 were noticed in women with aPL compared to controls. Conclusion: Women with aPL such as aCL and/or aß2GPI antibodies were associated with adverse IVF outcomes. Early screening for aPL and appropriate consultation for couples undergoing IVF should be considered. In addition, underlying immunopathology and inflammatory immune mechanisms associated with aPL should be further explored.

The characteristics of antigenic specificity of memory regulatory t cells in women with unexplained recurrent pregnancy loss.

Regulatory T cells (Tregs) proliferate after encountering the fetal antigen, which plays an important role in maintaining maternal-fetal tolerance. Activated Tregs increase number and function after antigen encounter and develop memory. Upon subsequent antigen exposure, Treg cells re-expand more rapidly. However, the characteristics of memory regulatory T cells (mTregs) during normal pregnancy and unexplained recurrent pregnancy loss (URPL) have not been elucidated well. In this study, we analyzed the proportion of Tregs and mTregs in the peripheral blood and their surface expression of PD-1, CCR6, and HLA-G in normal non-pregnant (n = 20) and pregnant (n = 20) women, and non-pregnant (n = 20) and pregnant URPL (n = 20) women. We found that the proportions of mTregs in lymphocytes, CD3+ T cells, CD4+ T cells, and Tregs were lower in pregnant URPL patients than in normal pregnant women. The proportions of CD4+CD45RO+ Th cells in lymphocytes, CD3+ T, and CD4+ T cells in the pregnant URPL group were the highest among the four groups (P < 0.05). There were no significant differences among the other three groups (P > 0.05). The proportions of CD4+/CCR6+/mTregs, CD4+/PD-1+/mTregs, CD4+/HLA-G+/mTregs were significantly lower in the non-pregnant normal group and non-pregnant URPL group than in normal pregnant group and pregnant URPL group (P < 0.05, respectively). The proportions of CD4+/CCR6+ mTregs, CD4+/PD-1+/mTregs, CD4+/HLA-G+/mTregs were lower in pregnant URPL group than in normal pregnant group (P < 0.05, respectively). These findings indicate that fetal antigen-specific mTregs play an important role in pregnancy maintenance, and the dysregulation of mTreg may contribute to URPL.

Evaluation of NKp46 expression and cytokine production of decidual NK cells in women with recurrent pregnancy loss.

Purpose: NKp46, a receptor on NK cells, is involved in cytotoxicity and cytokine production. The authors aimed to evaluate the effect of NKp46 on decidual NK (dNK) cells during pregnancy and whether it can be a marker for immunological abnormalities in women with recurrent pregnancy loss (RPL). Methods: Flow-cytometric analysis was made to assess NKp46 expression and intracellular cytokine production of dNK cells. The proportion of NKp46+ dNK cells was analyzed among RPL patients who aborted karyotypically normal pregnancies and those who either aborted karyotypically abnormal pregnancies or without genetic studies, and controls who were going through the induced abortion. Results: The %NKp46+ and %NKp46bright dNK cells were significantly lower in the RPL women who aborted karyotypically normal pregnancies than in the control group. The %NKp46bright dNK cells were significantly correlated with the NK1/NK2 ratio of dNK cells. The %NKp46+ dNK cell cutoff for RPL with immunological abnormalities was determined by the ROC curve analysis. In women with the low %NKp46+ dNK, NK1/NK2 ratios were significantly higher than those with the high. Conclusion: RPL patients with an immunological abnormality have decreased NKp46 expression and NK1 shift in dNK cells. NKp46 expression could be a marker for RPL of immunological abnormalities.

The Dietary Inflammatory Index as a predictor of pregnancy outcomes: Systematic review and meta-analysis.

Unhealthy diets have been linked to low-grade chronic inflammation, a condition known to play a role in the pathophysiology of non-communicable diseases as well as pregnancy complications. The Dietary Inflammatory Index (DII) is a tool for evaluating the inflammatory potential of various diets. The goal of this systematic review and meta-analysis is to assess the current state of evidence on the use of DII as a predictor of pregnancy outcomes in pregnant women. This study was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PROSPERO, number CRD42021288966). DII was evaluated as a predictor of obstetric complications in observational studies. The search was conducted in PubMed/Medline, Embase, and Web of Science. Data from eligible studies were extracted independently by two reviewers. The Newcastle-Ottawa Scale was used to assess the methodological quality of the studies. A total of eight studies were eligible for the review. In a meta-analysis of continuous and categorical variables, DII was a predictor of any obstetric complications [mean difference: 0.39, 95 %CI 0.02-0.75, (p = 0.04); and odds ratio: 1.24, 95 %CI 1.11-1.40, (p = 0.0002)]. High DII was associated with pregnancy complications, particularly preeclampsia/hypertensive disorder of pregnancy and preterm birth. The DII is a tool that can assist in the food and therapeutic planning of pregnant women with obstetric risks. Well-designed clinical trials are necessary, especially studies that focus on recurrent pregnancy losses and implantation failures.

The role of immunologic tests for subfertility in the clinical environment.

Unexplained subfertility and implantation failures not only are emotionally and physically distressing but also become a significant obstacle to reproductive-age couples who wish to build their family. Often, the currently recommended evaluation for these couples is significantly limited, and many of causes remain unexplained. To obtain an accurate diagnosis and treatment, proper evidence-based laboratory evaluation should be performed. Immune tests for women with subfertility and implantation failures are essential to recognize the immune etiology and appropriate therapeutic strategies. This review focuses on currently used immune tests for subfertile women.

Cutting edge: the regulatory mechanisms of macrophage polarization and function during pregnancy.

Macrophages are highly diverse cells and represent the major antigen-presenting cell at the maternal-fetal interface. Except for protecting the embryo with half of the paternal antigens from attack by the maternal immune system, decidua macrophages also have a critical role in implantation, trophoblast invasion, spiral artery remodeling, angiogenesis, and pathogen clearance. The classically activated (M1) and alternatively activated (M2) macrophages are the simplified classifications of macrophages, often applied to differentiate decidual macrophages. Particular phenotypes and functions of macrophages corresponding to each phase of the menstrual cycle and pregnancy are critical for establishing and maintaining pregnancy. Aberrant dynamics of decidual macrophages are associated with multiple pregnancy complications, such as recurrent pregnancy loss, preeclampsia, and preterm birth. Although various factors are related to decidual macrophage polarization, including cytokines, growth factors, hormones, and transcription factors, the potential regulatory mechanisms underlying decidual macrophage polarization are still unclear. Therefore, a thorough understanding of macrophage function and regulatory mechanism during pregnancy is critical to clarify the pathogenesis of pregnancy complications. In this review, we first describe an overview of the origin, phenotype, and function of macrophages in the uterus. Secondly, we propose emerging concepts explaining how macrophage polarization and functions are regulated, including immunometabolism, epigenetics, immune checkpoint, and microorganisms. Finally, we review the potential relationship among these novel factors in regulating the function of the immune system.

Dynamic changes in regulatory T cells during normal pregnancy, recurrent pregnancy loss, and gestational diabetes.

Regulatory T cells (Tregs) are critical to regulating maternal T-cell activation against trophoblast; however, the characteristics of maternal Tregs during pregnancy have not been elucidated well. In this study, we analyzed the proportion of CD4+ and CD8+ Tregs in the peripheral blood and their surface expression of PD-1, GITR, HLA-G, and CTLA-4 in normal pregnant women during the first (n = 28), second (n = 43), and the third trimester (n = 33), non-pregnant women (n = 57), pregnant women with a history of recurrent pregnancy loss (RPL) during the first trimester (n = 21), and pregnant women with gestational diabetes mellitus (GDM) during the second (n = 17) and third trimester (n = 28). The proportions of CD4+ and CD8+ Tregs were higher in normal pregnant women than that of non-pregnant women (P < 0.01 respectively). The proportion of CD4+ Tregs was peaked during the second trimester and then decreased. Contrarily, the proportion of CD8+ Tregs was increased throughout gestation and peaked during the third trimester. Proportions of CD4+/PD-1+ Tregs, CD4+/GITR+ Tregs, CD8+/PD-1+ Tregs, and CD8+/CTLA-4+ Tregs peak during the third trimester of normal pregnancy. Pregnant women with RPL and GDM had lower proportions of CD4+ Tregs (P < 0.05 and P < 0.01 respectively) and higher proportions of CD8+ Tregs (P < 0.01 and P < 0.01 respectively) than those of normal pregnancies.Together, our findings indicate that CD4+ and CD8+ Tregs play different roles in pregnancy maintenance, and the dysregulation may contribute to obstetrical complications.

Post-hoc evaluation of peripheral blood natural killer cell cytotoxicity in predicting the risk of recurrent pregnancy losses and repeated implantation failures.

Peripheral blood NK cytotoxicity assay (NKC) is one of the commonly utilized diagnostic tools for recurrent pregnancy losses (RPL) and repeated implantation failures (RIF). In this retrospective cohort study, we aimed to assess the cutoff values of NKC for RPL and RIF. A total of 883 women were included in this study; 24 nonpregnant fertile women, 604 nonpregnant women with three or more RPL, 163 nonpregnant women with two or more of RIF, 48 normal pregnant women, and 44 pregnant women with a history of RPL. Peripheral blood NKC assay was performed by flow cytometry. The differences between groups were analyzed using Student's t-test, a logistic regression analysis, and the area under the receiver operating characteristic curve analysis. Both nonpregnant fertile and normal pregnant women had significantly lower NKC at an effector to target cell ratio (E:T) of 50:1 (13.5 ± 1.1% and 12.9 ± 1.0%, respectively) when compared to women with RPL and RIF, and pregnant women with a history of RPL (23.6 ± 0.3%, 23.9 ± 0.5%, and 23.7 ± 1.0%, P < 0.0001 respectively). In addition, the area under the receiver operating characteristics curve for RPL and RIF using pre-conception NKC was 0.863 (P < 0.0001) and 0.879 (P < 0.0001), respectively, and for RPL using post-conception NKC was 0.736 (P = 0.001). These findings suggest that NKC significantly distinguishes nonpregnant women with RPL and RIF from fertile controls and pregnant RPLwomen from normal pregnant controls.

The Update Immune-Regulatory Role of Pro- and Anti-Inflammatory Cytokines in Recurrent Pregnancy Losses.

Recurrent pregnancy losses (RPL) is a common reproductive disorder with various underlying etiologies. In recent years, rapid progress has been made in exploring the immunological mechanisms for RPL. A propensity toward Th2 over Th1 and regulatory T (Treg) over Th17 immune responses may be advantageous for reproductive success. In women with RPL and animals prone to abortion, an inordinate expression of cytokines associated with implantation and early embryo development is present in the endometrium or decidua secreted from immune and non-immune cells. Hence, an adverse cytokine milieu at the maternal-fetal interface assaults immunological tolerance, leading to fetal rejection. Similar to T cells, NK cells can be categorized based on the characteristics of cytokines they secrete. Decidual NK (dNK) cells of RPL patients exhibited an increased NK1/NK2 ratio (IFN-γ/IL-4 producing NK cell ratios), leading to pro-inflammatory cytokine milieu and increased NK cell cytotoxicity. Genetic polymorphism may be the underlying etiologies for Th1 and Th17 propensity since it alters cytokine production. In addition, various hormones participate in cytokine regulations, including progesterone and estrogen, controlling cytokine balance in favor of the Th2 type. Consequently, the intricate regulation of cytokines and hormones may prevent the RPL of immune etiologies. Local or systemic administration of cytokines or their antagonists might help maintain adequate cytokine milieu, favoring Th2 over Th1 response or Treg over Th17 immune response in women with RPL. Herein, we provided an updated comprehensive review regarding the immune-regulatory role of pro- and anti-inflammatory cytokines in RPL. Understanding the roles of cytokines involved in RPL might significantly advance the early diagnosis, monitoring, and treatment of RPL.

Changes in the T-helper 1 and 2 cell populations during pregnancy in tacrolimus-treated women with repeated implantation failure and recurrent pregnancy loss.

Tacrolimus has received considerable attention as a treatment approach for infertility associated with maternal-foetal immune abnormalities, such as repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). This study examined the changes in T-helper (Th) 1 and 2 cell populations during pregnancy in peripheral blood of tacrolimus-treated RIF patients who delivered a liveborn infant from August 2012 to February 2020 at the National Centre for Child Health and Development. A total of 58 eligible study subjects were divided into two groups according to the presence of a history of RPL: (i) RIF-alone group (n = 31); and (ii) RIF-plus-RPL group (n = 27). In a flow cytometric analysis, the Th1/Th2 cell ratios were significantly higher before pregnancy than after pregnancy, and during the first trimester than the second trimester in the RIF-alone group (p = 0.0071 and p = 0.0087, respectively). However, no significant differences were present in the RIF-plus-RPL group. Although the Th1 immunity was suppressed under tacrolimus treatment in both groups, a delayed reduction in the Th1 cell percentage after initiation of treatment was observed in the RIF-plus-RPL group. In conclusion, the cellular immune alterations in tacrolimus-treated patients with RIF were different depending on the presence or absence of a history of RPL.

Anti-Ro/SSA and/or anti-La/SSB antibodies are associated with adverse IVF and pregnancy outcomes.

Anti-Ro/SSA and/or anti-La/SSB antibodies (anti-SSA/SSB) were reported to increase the risk of recurrent pregnancy loss. However, the effects of anti-SSA/SSB antibodies on in-vitro fertilization (IVF) and pregnancy outcomes were still unclear. The purpose of the study was to determine whether anti-SSA/SSB antibodies were detrimental to IVF and pregnancy outcomes. This study included 55 anti-SSA/SSB antibodies-positive women and 61 anti-SSA/SSB antibodies-negative control women receiving gonadotropin-releasing hormone (GnRH) agonist long protocol (n = 30 and 39, respectively) or GnRH antagonist protocol (n = 25 and 22, respectively) for in-vitro fertilization and embryo transfer (IVF-ET). The impact of anti-SSA/SSB antibodies on immune-related indicators, fertilization, embryo development and pregnancy outcomes were analyzed. With either GnRH agonist or antagonist protocol, women with anti-SSA/SSB had higher levels of peripheral blood cytokines, including TNF-α and IL-17A, lower levels of peripheral blood Th and NK cells, and poor IVF outcomes, including lower number of retrieved oocytes and embryos, lower M II oocytes rate, blastocyst formation rate, and perfect and available embryo rates. Moreover, clinical pregnancy rate, implantation rate, take-home baby rate, and birth weight were significantly lower in the study group as compared with those of the control group. In conclusion, women with anti-SSA/SSB are associated with adverse IVF and pregnancy outcomes. Screening for these antibodies and proper counselling of couples undergoing IVF-ET should be considered. Underlying immunopathology associated with SSA/SSB antibodies and reproduction should be explored further.

COVID-19 and miscarriage: From immunopathological mechanisms to actual clinical evidence.

The association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the first half of pregnancy and pregnancy loss is still unknown. Infections by other coronaviruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV), appear to increase the risk of miscarriage. The purpose of this study is to assess whether SARS-CoV-2 infection increases the risk of miscarriage. Firstly, a narrative review of the literature on animal and human studies was performed to analyze the immunopathological mechanisms of SARS-CoV-2 infection during preconception and early pregnancy, by which it may increase the risk of miscarriage. Secondly, a systematic review/meta-analysis of studies was conducted to assess the prevalence of miscarriage in COVID-19 patients diagnosed during pregnancy. Meta-analysis of proportions was used to combine data, and pooled proportions were reported. Seventeen case series and observational studies and 10 prevalence meta-analyses were selected for the review. The estimate of the overall miscarriage rate in pregnant women with COVID-19 was 15.3 % (95 % CI 10.94-20.59) and 23.1 (95 % CI 13.17-34.95) using fixed and random effect models, respectively. Based on the data in the current literature, the miscarriage rate (<22 weeks gestation) in women with SARS-CoV-2 infection is in the range of normal population. Well-designed studies are urgently needed to determine whether SARS-CoV-2 infection increases the risk of miscarriage during periconception and early pregnancy.