JPT2 Affects Trophoblast Functions and Macrophage Polarization and Metabolism, and Acts as a Potential Therapeutic Target for Recurrent Spontaneous Abortion.

Recurrent spontaneous abortion (RSA) is a pregnancy-related condition with complex etiology. Trophoblast dysfunction and abnormal macrophage polarization and metabolism are associated with RSA; however, the underlying mechanisms remain unknown. Jupiter microtubule-associated homolog 2 (JPT2) is essential for calcium mobilization; however, its role in RSA remains unclear. In this study, it is found that the expression levels of JPT2, a nicotinic acid adenine dinucleotide phosphate-binding protein, are decreased in the villous tissues of patients with RSA and placental tissues of miscarried mice. Mechanistically, it is unexpectedly found that abnormal JPT2 expression regulates trophoblast function and thus involvement in RSA via c-Jun N-terminal kinase (JNK) signaling, but not via calcium mobilization. Specifically, on the one hand, JPT2 deficiency inhibits trophoblast adhesion, migration, and invasion by inhibiting the JNK/atypical chemokine receptor 3 axis. On the other hand, trophoblast JPT2 deficiency contributes to M1 macrophage polarization by promoting the accumulation of citrate and reactive oxygen species via inhibition of the JNK/interleukin-6 axis. Self-complementary adeno-associated virus 9-JPT2 treatment alleviates embryonic resorption in abortion-prone mice. In summary, this study reveals that JPT2 mediates the remodeling of the immune microenvironment at the maternal-fetal interface, suggesting its potential as a therapeutic target for RSA.

Inflammation in recurrent miscarriage - a comprehensive perspective from uterine microenvironment and immune cell imbalance to therapeutic strategies.

Recurrent miscarriage, poses a significant challenge for many couples globally, the causes of which are not fully understood. Recent studies have shown the intricate link between uterine inflammation and recurrent miscarriages. While inflammation is essential during early pregnancy stages, especially in embryo implantation, an imbalance can lead to miscarriage. Key inflammatory mediators and an imbalance in immune cells can significantly alter and contribute to recurrent miscarriages. Lifestyle factors like smoking and obesity exacerbate inflammatory responses, increasing miscarriage risks. Understanding the interaction between the uterine environment, immune cell imbalances, and recurrent miscarriages is essential for devising effective treatments. This paper presents the latest data on inflammation's role in recurrent miscarriage, emphasizing the significance of diagnosing chronic endometritis and immune imbalances, offering practical recommendations for treatment and diagnosis.

Efficacy of mesenchymal stromal cells in the treatment of unexplained recurrent spontaneous abortion in mice: An analytical and systematic review of meta-analyses.

OBJECTIVES: Unexplained recurrent spontaneous abortion (URSA) remains an intractable reproductive dilemma due to the lack of understanding of the pathogenesis. This study aimed to evaluate the preclinical evidence for the mesenchymal stromal cell (MSC) treatment for URSA. METHODS: A meticulous literature search was independently performed by two authors across the Cochrane Library, EMBASE, and PubMed databases from inception to April 9, 2023. Each study incorporated was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias tool. The amalgamated standardized mean difference (SMD) accompanied by 95% confidence interval (CI) were deduced through a fixed-effects or random-effects model analysis. RESULTS: A total of ten studies incorporating 140 mice were subjected to data analysis. The MSC treatment yielded a significant reduction in the abortion rate within the URSA model (OR = 0.23, 95%CI [0.17, 0.3], P<0.00001). Moreover, it elicited a positive modulatory impact on the expression profiles of several inflammatory cytokines in the decidual tissue of URSA murine models, inclusive of IL4 (SMD 1.63, 95% CI [0.39, 2.86], P = 0.01), IL10 (SMD 1.60, 95% CI [0.58, 2.61], P = 0.002), IFN-γ (SMD -1.66, 95%CI [-2.79, -0.52], P = 0.004), and TNF-α (SMD -1.98, 95% CI [-2.93, -1.04], P< 0.0001). Subgroup analyses underscored that the administration mode of intraperitoneal and uterine horn injections, and sources of bone MSCs and adipose-derived MSCs contributed positively to the expression of IL4, IL10, and decreased the expression of IFN-γ in decidual tissue of URSA (P<0.05). Conversely, the tail vein injections subgroup was observed with no statistical significance (P>0.05). CONCLUSIONS: The findings underscore the considerable potential of MSCs in URSA therapy. Nonetheless, the demand for enhanced transparency in research design and direct comparisons between various MSC sources and administration routes in URSA is paramount to engendering robust evidence that could pave the way for successful clinical translation.

The effectiveness and safety of intrauterine infusion of autologous regulatory T cells (Tregs) in patients with recurrent pregnancy loss and low levels of endometrial FoxP3+ cells: A retrospective cohort study.

PROBLEM: Regulatory T cells (Tregs) are a specialized type of T cells that help maintain immune tolerance and homeostasis. The potential of Tregs cell-based therapies in treating diseases has been demonstrated in several clinical trials, which have shown promising outcomes and high safety in autoimmune diseases, transplant rejection, and graft-versus-host disease. However, their effectiveness and safety in improving endometrial receptivity and reducing pregnancy loss in human reproduction are unknown. METHOD OF STUDY: The study used a retrospective design and included patients with recurrent pregnancy loss (RPL) and lower levels of endometrial FoxP3+ Tregs. Patients in the Tregs group (n = 33) received intrauterine Tregs infusion three times during the follicular phase, while the control group (n = 28) did not receive any intrauterine infusion. RESULTS: The intrauterine infusion of autologous Tregs increased the levels of FoxP3+ Tregs and CD56+ NK cells. Patients in the Treg group had higher live birth rates and lower miscarriage rates, especially early miscarriage rates. However, the two groups had no differences in the implantation rate, clinical pregnancy rate, and percentage of preterm delivery. CONCLUSIONS: The findings suggest that intrauterine Tregs infusion may be a potential therapeutic approach for RPL. Further research in larger clinical trials is needed to confirm these findings.

Effects of NGS-based PGT-a for idiopathic recurrent pregnancy loss and implantation failure: a retrospective cohort study.

To clarify the effect of next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidy (PGT-A) combined with trophectoderm (TE) biopsy on the pregnancy outcomes of idiopathic recurrent pregnancy loss (iRPL) and idiopathic recurrent implantation failure (iRIF), we conducted a retrospective cohort study of 212 iRPL couples and 66 iRIF couples who underwent PGT-A or conventional in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. The implantation rate (IR) per transfer (64.2%), clinical pregnancy rate (CPR) per transfer (57.5%), and live birth rate (LBR) per transfer (45%) of iRPL couples of the PGT-A treatment group were significantly higher (p < 0.05) than those of the conventional IVF/ICSI group (IR per transfer,38.2%; CPR per transfer,33.3%; LBR per transfer, 28.4%), whereas the pregnancy loss rate (PLR) per transfer was similar between the two groups. These effects were also significant (p < 0.05) in iRPL couples with advanced maternal age (AMA, ≥35 years), whereas no significant differences were found in clinical outcomes between the PGT-A and conventional IVF/ICSI groups in younger iRPL couples (<35 years). The cumulative clinical outcomes of iRPL couples were comparable between the PGT-A and conventional IVF/ICSI groups. No significant differences were found in any clinical outcomes between the PGT-A and conventional IVF/ICSI groups for young or AMA couples with iRIF. In conclusion, NGS-based PGT-A involving TE biopsy may be useful for iRPL women to shorten the time to pregnancy and reduce their physical and psychological burden, especially for iRPL women with AMA; however, couples with iRIF may not benefit from PGT-A treatment. Considering the small sample size of the iRIF group, further investigations with a larger sample size are needed to verify our findings.

Uterine Natural Killer Cells: A Rising Star in Human Pregnancy Regulation.

Uterine natural killer (uNK) cells are an immune subset located in the uterus. uNK cells have distinct tissue-specific characteristics compared to their counterparts in peripheral blood and lymphoid organs. Based on their location and the pregnancy status of the host, uNK cells are classified as endometrial NK (eNK) cells or decidua NK (dNK) cells. uNK cells are important in protecting the host from pathogen invasion and contribute to a series of physiological processes that affect successful pregnancy, including uterine spiral artery remodeling, fetal development, and immunity tolerance. Abnormal alterations in uNK cell numbers and/or impaired function may cause pregnancy complications, such as recurrent miscarriage, preeclampsia, or even infertility. In this review, we introduce recent advances in human uNK cell research under normal physiological or pathological conditions, and summarize their unique influences on the process of pregnancy complications or uterine diseases. Finally, we propose the potential clinical use of uNK cells as a novel cellular immunotherapeutic approach for reproductive disorders.

Allogeneic lymphocytes immunotherapy in female infertility: Lessons learned and the road ahead.

The endometrium is an essential tissue in the normal immunologic dialogue between the mother and the conceptus, which is necessary for the proper establishment and maintenance of a successful pregnancy. It's become evident that the maternal immune system plays a key role in the normal pregnancy's initiation, maintenance, and termination. In this perspective, the immune system contributes to regulating all stages of pregnancy, thus immunological dysregulation is thought to be one of the major etiologies of implantation failures. Many researchers believe that immune therapies are useful tactics for improving the live births rate in certain situations. Lymphocyte immunotherapy (LIT) is an active form of immunotherapy that, when used on the relevant subgroups of patients, has been shown in multiple trials to dramatically enhance maternal immunological balance and pregnancy outcome. The primary goal of LIT is to regulate the immune system in order to create a favorable tolerogenic immune milieu and tolerance for embryo implantation. However, there are a plethora of influential factors influencing its therapeutic benefits that merit to be addressed. The objective of our study is to discuss the mechanisms and challenges of allogeneic LIT.

Gonadotropin-releasing hormone agonist downregulation combined with hormone replacement therapy improves the reproductive outcome in frozen-thawed embryo transfer cycles for patients of advanced reproductive age with idiopathic recurrent implantation failure.

BACKGROUND: To determine whether gonadotropin-releasing hormone (GnRH) agonist downregulation combined with hormone replacement therapy (HRT) can improve the reproductive outcomes in frozen-thawed embryo transfer cycles for older patients (aged 36-43 years) with idiopathic recurrent implantation failure (RIF). METHODS: This retrospective cohort study involved 549 older patients undergoing their third cleavage-stage embryo or blastocyst transfer over a 5-year period (January 2015-December 2020) at Northwest Women's and Children's Hospital after in vitro fertilization/intracytoplasmic sperm injection cycles. Patients with known endometriosis or adenomyosis were excluded from the study. The patients were divided into three groups according to the endometrial preparation protocol: the natural cycle (NC) group (n = 65), the HRT group (n = 194), and the GnRH agonist downregulation combined with HRT cycle (GnRH agonist-HRT) group (n = 290). The primary outcome was the live birth rate, and the secondary outcomes were the clinical pregnancy, miscarriage, and ongoing pregnancy rates. RESULTS: The live birth rate in the GnRH agonist-HRT group (36.55%) was higher than that in the HRT group (22.16%) and NC group (16.92%) (P < 0.0001). Similarly, a logistic regression model adjusting for potential confounders showed that the live birth rate was higher in the GnRH agonist-HRT group than in the HRT group (odds ratio, 0.594; 95% confidence interval, 0.381-0.926; P = 0.021) and NC group (odds ratio, 0.380; 95% confidence interval, 0.181-0.796; P = 0.010). CONCLUSIONS: The GnRH agonist-HRT protocol improves the live birth rate in frozen-thawed embryo transfer cycles for patients of advanced reproductive age with RIF. We hypothesize that the GnRH agonist-HRT protocol enhances implantation-related factors and promotes optimal endometrial receptivity, leading to an improved live birth rate. These findings are also useful for further investigating the underlying mechanism of the GnRH agonist-HRT protocol in improving the reproductive outcomes for patients of advanced reproductive age with RIF. TRIAL REGISTRATION: This research protocol was approved by the hospital institutional ethics committee (No. 2021002).

Toward more accurate prediction of future pregnancy outcome in couples with unexplained recurrent pregnancy loss: taking both partners into account.

OBJECTIVE: To identify, besides maternal age and the number of previous pregnancy losses, additional characteristics of couples with unexplained recurrent pregnancy loss (RPL) that improve the prediction of an ongoing pregnancy. DESIGN: Hospital-based cohort study in couples who visited specialized RPL units of two academic centers between 2012 and 2020. SETTING: Two academic centers in the Netherlands. PATIENTS: Clinical data from 526 couples with unexplained RPL were used in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURES: The final model to estimate the chance of a subsequent ongoing pregnancy was determined using a backward selection process and internally validated using bootstrapping. Model performance was assessed in terms of calibration and discrimination (area under the receiver operating characteristic curve). RESULTS: Subsequent ongoing pregnancy was achieved in 345 of 526 couples (66%). The number of previous pregnancy losses, maternal age, paternal age, maternal body mass index, paternal body mass index, maternal smoking status, and previous in vitro fertilization/intracytoplasmic sperm injection treatment were predictive of the outcome. The optimism-corrected area under the receiver operating characteristic curve was 0.63 compared with 0.57 when using only the number of previous pregnancy losses and maternal age. CONCLUSIONS: The identification of additional predictors of a subsequent ongoing pregnancy after RPL, including male characteristics, is significant for both clinicians and couples with RPL. At the same time, we showed that the predictive ability of the current model is still limited and more research is warranted to develop a model that can be used in clinical practice.

Effect of Prepregnancy Lymphocyte Active Immunotherapy on Unexplained Recurrent Miscarriage, Pregnancy Success Rate, and Maternal-Infant Outcome.

OBJECTIVE: To evaluate the effect of prepregnancy lymphocyte active immunotherapy on unexplained recurrent miscarriage, pregnancy success rate, and maternal-infant outcome. METHODS: A total of 124 patients with recurrent miscarriage admitted to our hospital from January 2018 to December 2020 were selected as the research objects and divided into the experimental group and the control group according to the random number table method, with 62 patients in each group. The experimental group was treated with lymphocyte active immunotherapy, and the control group was given conventional treatment. The pregnancy success rate, estrogen indexes, hemorheology indexes, and psychological state of the two groups were compared. RESULTS: The experimental group garnered a notably higher pregnancy success rate and a prominently lower miscarriage rate than the control group (P < 0.05). Better results of self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were observed in the experimental group, as compared to the control group (P < 0.05). The experimental group yielded more desirable results in terms of treatment satisfaction, estrogen indexes, and hemorheology indexes in comparison with the control group (P < 0.05). CONCLUSION: The use of lymphocyte active immunotherapy for patients with unexplained recurrent miscarriage can significantly increase the pregnancy success rate, optimize the maternal-infant outcome, drive down the miscarriage rate, and ameliorate the patient's estrogen levels and hemorheology indicators, which is worthy of promotion and application in clinical practice.

The Impact of New Immunological Therapeutic Strategies on Recurrent Miscarriage and Recurrent Implantation Failure.

Maternal-fetal immune dysregulation is one of the risk factors that increases the probability of embryo rejection and reproductive failure. The stimulation of immunological tolerance and suppression of immunological rejection are prerequisites for protecting embryos and preventing immunological attacks. Hence, it appears that immunomodulatory and immunosuppressive therapies can manage reproductive failures by controlling immune cells. The current medical literature has shown that immunotherapy approaches and cell therapy have promising results in improving pregnancy outcomes and live birth rates. These outcomes are obtained by regulating maternal immune responses, and exerting positive effects on human reproductive processes.

Crosstalk Between Trophoblasts and Decidual Immune Cells: The Cornerstone of Maternal-Fetal Immunotolerance.

The success of pregnancy relies on the fine adjustment of the maternal immune system to tolerate the allogeneic fetus. Trophoblasts carrying paternal antigens are the only fetal-derived cells that come into direct contact with the maternal immune cells at the maternal-fetal interface. The crosstalk between trophoblasts and decidual immune cells (DICs) via cell-cell direct interaction and soluble factors such as chemokines and cytokines is a core event contributing to the unique immunotolerant microenvironment. Abnormal trophoblasts-DICs crosstalk can lead to dysregulated immune situations, which is well known to be a potential cause of a series of pregnancy complications including recurrent spontaneous abortion (RSA), which is the most common one. Immunotherapy has been applied to RSA. However, its development has been far less rapid or mature than that of cancer immunotherapy. Elucidating the mechanism of maternal-fetal immune tolerance, the theoretical basis for RSA immunotherapy, not only helps to understand the establishment and maintenance of normal pregnancy but also provides new therapeutic strategies and promotes the progress of immunotherapy against pregnancy-related diseases caused by disrupted immunotolerance. In this review, we focus on recent progress in the maternal-fetal immune tolerance mediated by trophoblasts-DICs crosstalk and clinical application of immunotherapy in RSA. Advancement in this area will further accelerate the basic research and clinical transformation of reproductive immunity and tumor immunity.

Evaluation of paternal lymphocyte immunotherapy and potential biomarker mixed lymphocyte reaction-blocking factor in an Argentinian cohort of women with unexplained recurrent spontaneous abortion and unexplained infertility.

PROBLEM: Analyze the effect of paternal immunotherapy treatment (PIT) in primary and secondary unexplained recurrent spontaneous abortion (URSA) and unexplained infertility (UI). METHODS OF STUDY: A retrospective study analyzed a two-year follow-up between the generation of MLR-Bfs after PIT treatment (or controls first consultation) and a live birth. Recruited patients included primary URSA with two or more miscarriages at <12 weeks gestation, secondary URSA with previous live birth before two or more miscarriages, and UI with inability to conceive after 2 years of regular unprotected intercourse or in vitro fertilizations (IVF). PIT treated were compared with untreated controls. RESULTS: Primary URSA: live birth was 241/416 (58%) versus 64/282 (23%) controls (p < .0001). Up to age 35, success was 158/217 (73%) and 37/144 (26%) controls (p < .0001). With 3 or more previous URSA, success was 90/135 (67%) versus 17/79 (22%) controls (p < .0001). Between ages 36 and 40, success was 69/147(47%) versus 22/98 (22%) controls (p < .0003), with 3 or more previous URSA live birth was 45/95 (47%) versus 6/46 (13%) controls (p < .0001). In UI, live birth was 99/298 (33%) versus 54/263 (21%) in controls (p < .0009) that increased under age 35 to 53/116 (46%) in treated versus 26/101 (26%) controls (p < .0056). In PIT treated, IVF success required a median of 1 (1.37 ± 0.67) versus a median of 3 IVF procedures (2.75 ± 0.84) in controls. CONCLUSION: PIT is a successful treatment for primary and secondary URSA, and UI. PIT reduced the number of IVF required for achieving pregnancy.

Perda gestacional de repetição: aspectos psíquicos e terapias comportamentais / Recurrent pregnancy loss: psychic aspects and behavioral therapies

A perda gestacional de repetição (PGR) é definida classicamente como três perdas consecutivas antes de 20 semanas de gestação. Ela afeta aproximadamente 3% dos casais que tentam conceber, quando se consideram pelo menos duas perdas, e cerca de 1%, quando acima de três perdas. A PGR está associada a diferentes fatores causais. Algumas mulheres não terão nenhuma anormalidade identificável nos protocolos investigativos atuais. O aborto pode causar doenças mentais, tais como depressão e ansiedade, e ser responsável por sentimentos como medo, raiva e culpa. Embora existam intervenções já estabelecidas para pacientes com perda gestacional com fator causal determinado, não existe nenhum tratamento comprovadamente efetivo em mulheres com perda gestacional inexplicada. O oferecimento do chamado Tender Loving Care pode levar a melhores resultados gestacionais nessas pacientes. Este artigo irá fazer uma revisão sobre os aspectos psíquicos em PGR e o cuidado suportivo que poderá ser realizado nessas pacientes.(AU)

Recurrent pregnancy loss (RPL) is classically defined as three consecutive losses before 20 weeks of gestation. It affects approximately 3% of couples who try to conceive, when considering at least two losses, and about 1%, when considering three or more. RPL is associated with different causal factors. Some women will have no identificable abnormalities in current investigative protocols. Abortion can cause mental illness, such as depression and anxiety, and be responsible for feelings like fear, anger and guilt. Although there are interventions already established for patients with pregnancy loss with a determined causal factor, there is no proven effective treatment for women with unexplained pregnancy loss. The offer of the so-called Tender Loving Care can lead to better pregnancy results in these patients. This article will review the psychic aspects of recurrent pregnancy losses and the supportive care that can be performed in these patients.(AU)

Thin endometrium problem in IVF programs.

METHODS: Observational, comparative, prospective, multicenter study (n = 425). Group 1 (n = 228) received estradiol hemihydrate (Divigel, Orion Corporation, Finland), group 2 (n = 197) received oral estradiol valerate (Proginova, Delpharm Lille, France). RESULTS: An increase in endometrial thickness was comparable (10.1 (2.0) mm versus 10.0 (2.3) mm; p = .571). There was significantly shorter mean duration of estrogen therapy (13.9 (3.9) days versus 14.7 (4.7) days; p = .038) and lower total dose in group 1 (43.6 (27.3) mg versus (71.9 (37.2) mg; p = .0001). Pregnancy rates were comparable (143/228 (62.7%) versus 105/197 (53.3%); p = .077) so as "take home baby" rates (80/228 (35.1%) versus 68/197 (34.5%); p = .077). CONCLUSION: Estrogens improve the state of the endometrium and increase pregnancy rates in cases of thin endometrium in in vitro fertilization programs. The use of transdermal estrogens (Divigel, Orion Corporation, Finland) ensures an adequate increase in endometrial thickness and significantly lower estrogen doses.

Predicting first-trimester outcome of embryos with cardiac activity in women with recurrent spontaneous abortion.

OBJECTIVE: This study was performed to evaluate the capability of routine clinical indicators to predict the early outcome of embryos with cardiac activity in women with recurrent spontaneous abortion (RSA). METHODS: A retrospective cohort study of pregnant women with a history of RSA in a Chinese tertiary hospital was performed using unadjusted and multivariable logistic regression. RESULTS: Of 789 pregnant women with RSA, 625 (79.21%) had ongoing pregnancy, whereas 164 (20.79%) developed abortion before 20 full weeks of gestational age even after embryonic heart motion was detected. The final model had an area under the curve of 0.81 (95% confidence interval, 0.78-0.84) with a sensitivity of 74.39%, a specificity of 76.00%, and a false-positive rate of 52.32% at a fixed detection rate of 90%. CONCLUSIONS: The combination of multiple routine clinical indicators was valuable in predicting the early outcome of embryos with cardiac activity in viable pregnancies with RSA. However, this model might result in a high false-positive rate with a fixed detection rate of 90%; other markers must be investigated to identify first-trimester RSA once positive embryonic heart motion is established.

Endometrial Immune Profiling: A Method to Design Personalized Care in Assisted Reproductive Medicine.

Objective: To assess the efficiency of the endometrial immune profiling as a method to design personalized care to enhance the pregnancy rate in a large heterogeneous infertile population. We hypothesized that some reproductive failures could be induced by a uterine immune dysregulation which could be identified and corrected with a targeted plan. Design: Prospective cohort study. Setting: Multicentric study. Intervention(s) and Main outcome measure(s): One thousand and seven hundred thirty-eight infertile patients had an immune profiling on a timed endometrial biopsy between 2012 and 2018. This test documented the absence or the presence of an endometrial immune dysregulation and identified its type. In case of dysregulation, a targeted personalized plan was suggested to the treating clinician aiming to supply the anomaly. One year after the test, the clinician was contacted to provide the outcome of the subsequent embryo transfer with the applied suggested plan. Result(s): After testing, 16.5% of the patients showed no endometrial immune dysregulation, 28% had a local immune under-activation, 45% had a local immune over-activation, and 10.5% had a mixed endometrial immune profile. In patients with a history of repeated implantation failures (RIF) or recurrent miscarriages (RM), the pregnancy rate was significantly higher if an endometrial dysregulation was found and the personalized plan applied, compared to the patients with an apparent balanced immune profile (respectively 37.7 and 56% vs. 26.9 and 24%, p < 0.001). In contrast, in good prognosis IVF (in vitro fertilization) subgroup and patients using donor eggs, this difference was not significant between dysregulated and balanced subgroups, but higher pregnancy rates were observed in absence of dysregulation. For patients with immune over-activation, pregnancy rates were significantly higher for patients who had a test of sensitivity, regarding the type of immunotherapy introduced, when compared to the ones who did not (51 vs. 39.9%, p = 0.012). Conclusion(s): Local endometrial immunity appears to be a new and important parameter able to influence the prognosis of pregnancy. Targeted medical care in case of local immune dysregulation resulted in significantly higher pregnancy rates in RIF and RM patients.

Laparoscopic Cervical Encerclage in Pregnancy in 6 Steps.

STUDY OBJECTIVE: Cervical insufficiency occurs in 0.1% to 1 % of all pregnancies and is associated with a high risk of second-trimester abortion and/or preterm delivery [1]. Laparoscopic encerclage is highly recommended for a previous failed vaginal encerclage and is superior to the laparotomy approach in terms of low morbidity and faster recovery [2]. Laparoscopic encerclage in pregnancy is more challenging than that in the nonpregnant state. This is because of the enlarged uterine size, engorged uterine vessels, and infeasibility of using a uterine manipulator. The standardization and description of the technique are the main objectives of this video (Video 1). We have described the surgery in 6 steps that could make this procedure easier and safer. DESIGN: A step-by-step video demonstration of the technique. SETTING: Paul's Hospital, Centre for Advanced Endoscopy & Infertility Treatment, Kochi, India. A 29-year-old pregnant woman, gravida 3 abortions 2, at 13 weeks period of gestation, with a history of 2 second-trimester abortions owing to cervical insufficiency. The patient had a failed vaginal cervical encerclage at 18 weeks in the second pregnancy. INTERVENTIONS: This is a step-wise laparoscopic approach for successful cervical encerclage in pregnancy. In this video, we demonstrate our technique for laparoscopic cervical encerclage in a pregnant woman's uterus in 6 steps using a Mersilene tape (Ethicon US, LLC, Somerville, NJ) as follows: (1) Opening the uterovesical fold and dissecting the bladder, (2) opening the left broad ligament and creating a window, (3) opening the right broad ligament and creating a window, (4) placing the Mersilene tape on the left side medial to the uterine vessels at the cervicoisthmic junction, (5) placing the Mersilene tape on the right side medial to the uterine vessels at the cervicoisthmic junction, (6) tying the Mersilene tape anteriorly. CONCLUSION: The standardization of laparoscopic cervical encerclage in pregnancy using the above 6 steps could make this procedure easier and safer to perform. Moreover, the standardization of the surgical technique could shorten the learning curve.

Mesenchymal stem cells alter the frequency and cytokine profile of natural killer cells in abortion-prone mice.

Natural killer cells, which play a pivotal role in the establishment and maintenance of normal pregnancy, are the most abundant leukocytes at the fetomaternal interface that their subsets frequencies and cytokine profile are influential factors in the preservation of the decidual tolerogenic microenvironment. Any imbalance in NK cells' frequency and functions could be associated with pregnancy failure. Mesenchymal stem cells (MSCs) are shown to have immunomodulatory effects on NK cells and their cytokine profile. The purpose of this study is to evaluate the impact of MSCs therapy on the cytokine profiles and subpopulations of NK cells in a murine model of recurrent pregnancy loss. Adipose-derived MSCs were injected intraperitoneally to the abortion-prone mice on Day 4.5 of gestation. The abortion rate was determined after MSCs administration and the frequency and cytokine profiles of the different subsets of NK cells were determined using the flow cytometry. Our results showed that, in abortion-prone mice, the frequency of CD49b+ NK cells was significantly higher than normal pregnant mice that decreased after therapy. We also demonstrated that MSCs downregulated the production of IFN-γ and upregulated IL-4 and IL-10 production by uNK cells. These findings indicate that MSCs can decrease the infiltration of CD49b+ NK cells to the fetomaternal interface and modulate the cytokine profile of NK cells from inflammatory to tolerogenic profile and thereby improve the tolerogenic microenvironment at the fetomaternal interface in benefit of pregnancy maintenance.

Laser irradiation pretreatment improves endometrial preparation of frozen-thawed embryo transfer in recurrent implantation failure patients.

Recurrent implantation failure (RIF) remains a clinical dilemma. Helium-Neon (He-Ne) laser irradiation has recently become more popular under certain clinical conditions. Given the unique therapeutic effects, we were interested in determining whether pretreatment with He-Ne laser irradiation prior to frozen-thawed embryo transfer (FET) would improve the microcirculation and cause the release of growth factors and cytokines, thus improving endometrial receptivity and the clinical pregnancy rates. Patients chose for themselves whether to proceed with (n = 29) or without (n = 31) pretreatment with He-Ne laser irradiation prior to FET. The clinical pregnancy rate (37.9%) and implantation rate (20.3%) were higher in the laser-treatment group than in the control group (35.5% and 15.9%, respectively, p = .844 and .518, respectively). The live birth rate was higher in the laser-treatment group (27.6% vs. 25.8%, respectively, p = .876) and the miscarriage rate was lower in the laser-treatment group (18.2% and 27.3%, respectively, p = .611). No side effects or complications from laser irradiation were encountered in patients who received the laser treatment. We concluded that pretreatment with He-Ne laser prior to FET may be an alternative choice for RIF-affected women; however, additional well-designed prospective studies are necessary to determine the precise clinical value of this treatment.