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.

Treatment with plasma exchange of a pregnant woman with anti-PP1Pk alloimmunization: A case report.

The histo-blood group antigens P, P1 and Pk are a closely related set of glycosphingolipid structures expressed by red blood cells and other tissues. None of these three characters is expressed on p cells, a null phenotype that arises in the context of homozygous mutation of the A4GALT gene. Subjects with p phenotype spontaneously develop a natural alloantibody named anti-PP1Pk, which is a mixture of IgG and IgM against P1, P and Pk. While anti-P1 is a weak cold antibody with poor clinical significance, anti-P and anti-Pk antibodies are potent haemolysins responsible for severe hemolytic transfusion reactions. The rare anti-PP1Pk alloantibodies are associated with recurrent spontaneous abortion in the first trimester of gestation. P and Pk antigens are expressed at high levels on the placenta and antibodies directed against both these structures are deleterious to placental trophoblasts. Here we describe the use of plasma exchange (PEX) in a nulliparous 39-year-old woman with anti-PP1Pk antibodies and a history of repeated spontaneous early abortions and hypofertility. The patient underwent apheresis starting from the third week throughout the pregnancy and a healthy child was delivered by cesarean section at 35 WG. The newborn required only phototherapy within a few days of life. We can state that an early treatment with the only PEX has proven to be effective and safe in the management of a fetomaternal P-incompatibility caused by a high anti-PP1Pk titer (256).

Altered profile of plasma phospholipids in woman with recurrent pregnancy loss and recurrent implantation failure treated with lipid emulsion therapy.

BACKGROUND: Recurrent Pregnancy Loss (RPL) and Recurrent Implantation Failure (RIF) are highly heterogeneous condition and many of the mechanisms involved still require elucidation. The aim was to analyze the lipidomic profile in plasma of women with RPL and RIF before and after receiving the Lipid Emulsion Therapy (LET) containing 10% fish oil (SMOFlipid® 20%). METHODS: This study included twenty-six women with RPL or RIF from immunological or inflammatory causes, with elevated natural killer cell levels and divided into a Pregnancy Loss or a Live Birth group according to the outcome. The women received intravenous LET and sample collecting was done before the first, third and fifth dose of LET in the pregnant women. Ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-QTOF MS) and multivariate statistical methods were performed to evaluate the profile of phospholipids present in the women's plasma. RESULTS: An increase of phosphatidylcholines (PC) 40:8 and 36:5 levels with predominance of n6 polyunsaturated fatty acids (PUFA) was observed in plasma lipids of the Pregnancy Loss Group compared to Live Birth Group. We also observed an increase in the relative abundance of n3 PUFA-PC species (42:10 and 36:6) and LysoPC 15:0 with the long term use of LET. CONCLUSION: The greater availability of n3 PUFA in plasma of the pregnant women stemming from LET use can be considered advantageous regarding the alteration of the phospholipid profile and its postulated anti-inflammatory and immunomodulatory role.

Meditation and mindfulness reduce perceived stress in women with recurrent pregnancy loss: a randomized controlled trial.

RESEARCH QUESTION: Can participating in a tailored 7-week meditation and mindfulness programme with additional standard supportive care versus standard supportive care only reduce perceived stress for women with recurrent pregnancy loss (RPL)? DESIGN: A two-armed randomized controlled trial (RCT) with 12-month follow-up. In total 76 patients were enrolled and randomly assigned to either standard supportive care or to a 7-week meditation and mindfulness programme led by an instructor in addition to standard supportive care. RESULTS: At intervention completion (after 7 weeks), perceived stress decreased significantly both in the intervention group (P = 0.001) and in the control group (P = 0.006). The decrease in perceived stress in the intervention group was significantly larger (P = 0.027) compared with the control group. At the 12-month follow-up perceived stress was still significantly decreased in both groups compared with baseline (P < 0.0001 in the intervention group and P = 0.002 in the control group). CONCLUSION: This first RCT of a tailored meditation and mindfulness intervention for women with RPL documents that a 7-week daily at-home meditation and mindfulness programme combined with group sessions reduced perceived stress significantly more than a standard supportive care programme. Future studies should address the most effective format and the 'dose' needed for an impact on perceived stress levels.

Effectiveness of empathic caring on stress and depression for women with recurrent miscarriage: A randomized controlled trial.

AIM: The purpose of this study was to investigate the effectiveness of empathic caring on sleep quality, depression, stress, and social support in women with recurrent miscarriage. MATERIALS AND METHODS: Sixty-two eligible women were randomly assigned to either the experimental group (n = 31), which received three face-to-face nursing counseling sessions, or the control group (n = 31). Outcome measures included the Pittsburgh Sleep Quality Index, Edinburgh Prenatal Depression Scale, Perceived Stress Scale, and Interpersonal Support Evaluation List. RESULTS: Paired-sample t-tests revealed that, after receiving nursing counseling, the participants in the experimental group showed significant decreases in stress and depression. However, no significant mean differences were found in the control group between the pretest and the 12-week posttest for any of the four outcome measures. CONCLUSION: Clinical healthcare professionals may incorporate empathic caring into health-promotion protocols to assist women with recurrent miscarriage to improve their psychosocial health.

Effect of Japanese herbal Kampo medicines on live birth rate in women with recurrent pregnancy loss.

OBJECTIVE: To determine the effectiveness of Japanese Kampo medicines on the overall live birth rate among patients with recurrent pregnancy loss (RPL) in a real-world setting. METHODS: In the current retrospective cohort study, we used the JMDC Claims Database to extract information on women diagnosed with RPL between January 1, 2005 and August 31, 2018. Eligible women were divided into two groups according to Kampo medicines administered as treatments for RPL. The primary outcome was the live birth rate during the study period. Propensity score matching, Kaplan-Meier cumulative incidence plots, log-rank test, and Cox proportional-hazards regression model were used to compare the primary outcome between patients with and without Japanese herbal Kampo medicines. RESULTS: Among 5517 eligible patients, 1652 used Kampo medicines and 3865 did not. After propensity score matching, the live birth rate at 2.0 years was 15.7% in the Kampo group and 11.2% in the non-Kampo group. At 4.0 years, the difference between the two groups had slightly increased. The overall live birth rate differed significantly between the two groups (hazard ratio 1.32, 95% confidence interval 1.13-1.53; P < 0.001). CONCLUSION: Japanese herbal Kampo medicines may improve the live birth rate in patients with RPL.

Intralipid therapy for unexplained recurrent miscarriage and implantation failure: Case-series and literature review.

INTRODUCTION: In retrospective cohort study of women with unexplained recurrent implantation failure (RIF) and miscarriage (RM), we analyzed the efficacy and safety of intralipid therapy to obtain a live birth. PATIENTS AND METHODS: Women with unexplained RM and/or RIF were included from 2015 to 2018 from three French university hospitals. RESULTS: Among 187 women treated for unexplained recurrent miscarriages and implantation failures, 26 women with median age of 36 years (29-43) received intralipid therapy. Among these 26 women, 10 women with a median age of 33 years (31-40) had a history of spontaneous recurrent miscarriages, with a median of 5 (4-8) previous miscarriages. Live births occurred in 7 (70 %) pregnancies under intralipids and were significantly more frequent than in women with recurrent miscarriages who did not receive intralipid therapy (n = 20, p = 0.02). Age, number of previous miscarriages, and additional therapies did not significantly differ between the two groups. Among the 26 included women, 16 had a history of recurrent implantation failures, with median age of 37 years (29-43) and median 9.5 (3-19) embryo transfers. Clinical pregnancy occurred in 9 (56 %) women receiving intralipids after embryo transfers under intralipids among which 5 (55 %) resulted in a live birth. Comparing successful pregnancies under intralipids with those with fetal loss, no significant differences have been noted. CONCLUSION: Intralipids could be an effective and safe therapy in women with unexplained recurrent miscarriages and infertility.

Efficacy of intrauterine administration of autologous peripheral blood mononuclear cells on the pregnancy outcomes in patients with recurrent implantation failure: A systematic review and meta-analysis.

One in every nine couples suffers from implantation defects and pregnancy failures. In spite of many contributions that ART has given to infertility treatment, there are many reports of the failure of ART. Therefore, scientists suggested many complementary therapies for use besides ART to improve the quality of infertility treatments. Intrauterine PBMC-therapy is one of these complementary therapies that were used before IVF. Studies that examined PBMC treatment in women with at least three IVF/ET failure were included in this review. These studies involved RCT and quasi-experimental (non-randomized experimental) studies. A three-step search strategy was used for published and unpublished clinical trials written in English and Persian. No time limitation was set for studies. Study selection according to the inclusion criteria and methodological quality assessment and data extraction were done by two independent reviewers, which result in five studies being included (two RCTs and three quasi-experimental studies). Finally, all of these article extracted data were pooled in a statistical meta-analysis. Findings demonstrated that implantation, pregnancy and live birth rate were statistically increased and the miscarriage rate was significantly decreased in the PBMC-treated group than that non-treated group. In conclusion, based on the evidence, PBMCs can be an effective therapeutic approach in women with at least three IVF/ET failure and lacking initial inflammation that is essential for implantation.

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.

Using autologous intrauterine platelet-rich plasma to improve the reproductive outcomes of women with recurrent implantation failure.

OBJECTIVE: Reproductive clinics are often faced with cases of repeated implantation failure (RIF). This study evaluated whether platelet-rich plasma (PRP) might improve the implantation outcomes of patients suffering from RIF. METHODS: Thirty women with RIF submitted to frozen-thawed embryo transfers were included in the study. Intrauterine infusions of autologous purified platelet preparations were administered 48 hours prior to embryo transfer. Differences in implantation, clinical pregnancy, and miscarriage rates of cycles with and without PRP infusions were analyzed. RESULTS: The implantation rate seen in the PRP group was 6.7%. No significant difference was found the between the implantation, clinical pregnancy, ongoing pregnancy, and miscarriage rates of frozen-thawed embryo transfers with and without PRP infusion. However, the effect size of PRP infusion (Cohen's d=0.39) on implantation rates revealed a relationship in medium strength. CONCLUSION: Platelet-rich plasma might potentially yield beneficial effects as a safe therapeutic option offered alongside other treatments designed to improve the reproductive outcomes of women with repeated implantation failure.

Intrauterine administration of hCG-activated autologous human peripheral blood mononuclear cells (PBMC) promotes live birth rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure.

Recurrent implantation failure refers to unsuccessful implantation after repeated transfers of morphologically good quality embryos into a normal uterus. Recently, accumulating evidence has suggested that local immune cells at the implantation site have actively contributed to embryo implantation. Our aim was to study the effects of intrauterine administration of hCG-activated autologous human PBMC on clinical pregnancy, implantation rates and live birth rate of patients who received frozen/thawed embryo transfer. We observed patients with one to three failed transplantations cannot benefit from the administration, but the rate of clinical pregnancy (39.58% vs. 14.29%), live birth (33.33% vs. 9.58%) and implantation (22.00% vs. 4.88%) were significantly increased in patients with four or more failures, respectively. For patients with endometrial thickness more than 7mm and less than 8mm on day of embryo transfer, the implantation rate (22.69% vs. 14.21%) and the live birth rate significantly higher in the PBMC-treated group; For patients who had RIF and received frozen/thawed early cleavage stage embryo transfer, the live birth delivery rate (29.63% vs. 13.33%) significant higher in PBMC-treated group. These findings indicate that intrauterine administration of hCG-activated autologous PBMC effectively improves the IVF outcomes for RIF patients, especially for the RIF patients with cleavage stage embryo transfer, patients with thin endometrial thickness also benefit from this approach.

[Male factors and countermeasures for recurrent spontaneous abortion].

Recurrent spontaneous abortion (RSA) has a very complicated pathogenesis and male factors for this condition should not to be ignored, which are mainly related to genetics, immunology, infection, sperm quality, and others. In case of RSA, an etiological screening ought to be performed for the husband, which involves general, genetic and immunological examinations and infection detection. According to specific etiological factors, such measures as genetic consultation, immunotherapy, and traditional Chinese medication can be taken, which may contribute to the outcome of pregnancy.

Intralipid supplementation in women with recurrent spontaneous abortion and elevated levels of natural killer cells.

OBJECTIVE: To investigate the efficacy of intralipid supplementation in women with recurrent spontaneous abortion (RSA) and elevated natural killer cell activity undergoing in vitro fertilization/intracytoplasmic sperm injection. METHODS: Between February 10, 2013, and April 30, 2015, a double-blind randomized controlled study was conducted at a center in Egypt. Women with unexplained secondary infertility, RSA, and elevated levels of natural killer cells (>12%) were enrolled and randomly assigned to receive intralipid (2mL diluted at 20% in 250mL saline) or saline (250mL) infusion on the day of oocyte retrieval using random numbers and sealed envelopes. Patients and attending physicians were masked to group assignment. The infusions were repeated within 1week of a positive pregnancy test and then every 2weeks until the end of the first trimester. The primary outcome was chemical pregnancy 14days after embryo transfer. Analyses were by intention-to-treat. RESULTS: Overall, 296 women were enrolled. Chemical pregnancy was recorded for 84 (58.3%) of 144 women in the intralipid group and 76 (50.0%) of 152 in the control group (P=0.129). CONCLUSION: Intralipid supplementation did not increase frequency of chemical pregnancy. However, findings related to ongoing pregnancy and live birth should be investigated further. ClinicalTrials.gov:NCT01788540.

Effectiveness and potential mechanisms of intralipid in treating unexplained recurrent spontaneous abortion.

AIM: Abnormal natural killer (NK) cell activity has been suggested to be a high-risk factor associated with unexplained recurrent spontaneous abortion (URSA). Intralipid, like immunoglobulin, is able to lower the activity of NK cells, which has been reported to be useful for improving URSA outcomes in pregnancy. This study aimed to determine whether intralipid could be used as an alternative treatment to intravenous immunoglobulin (IVIG) which is expensive and has many side-effects. METHODS: A prospective, randomized clinical trial was conducted from December 2010 to December 2012. Eligible participants were matched and sorted randomly into the intralipid and the IVIG group. The primary outcome was the rate of successful pregnancy. In addition, comparisons of peripheral NK cell activities were accessed by flow cytometry. Moreover, the effects of intralipid on trophoblasts were investigated using a Matrigel assay with the JEG-3 cell line. RESULTS: Seventy-six patients in the intralipid group and 78 in the IVIG group completed the trial. There were no statistically significant differences in successful pregnancy rates between the two groups (92.1 vs 88.2 %, P = 0.415). The reduced NK cell concentrations revealed the cytotoxic effects of the treatments in both groups. The invasive ability of JEG-3 cells was inhibited during co-culture with patient PBMCs. However, the inhibitory effect could be alleviated if the patient PBMCs were stimulated with intralipid. CONCLUSIONS: Intralipid can be used as an alternative treatment to IVIG for URSA, and its potential mechanism of action may occur by regulating NK cell function and promoting trophoblast invasion.

Clinical observations of sequential therapy with Chinese medicine and hysteroscopic mechanical stimulation of the endometrium in infertile patients with repeated implantation failure undergoing frozen-thawed embryo transfer.

OBJECTIVES: To investigate the clinical effect of sequential therapeutic intervention Yupei Qisun [compensating for weakness by invigorating Kidney (Shen) and Spleen (Pi) in advance] in Chinese medicine (CM) and hysteroscopic endometrial mechanical stimulation on the treatment of infertile patients with repeated implantation failure (RIF); and to study the differences in patients' endometrial thickness and type on the day of embryo transfer, serum hormone levels on embryo transfer day and clinical pregnancy outcomes. METHODS: In the clinical study, 168 frozen-thawed embryo transfer (FET) cycles for couples with RIF conforming to the research protocol were randomly divided into three groups: a CM group with 56 cycles (CM combined with FET), a hysteroscopy group with 55 cycles (hysteroscopic endometrial mechanical stimulation), and a control group with 57 cycles (conventional FET). Differences in endometrial thickness on the embryo transfer day, levels of serum estradiol (E2) and progesterone (P) on the embryo transfer day, the E2/P ratio on the embryo transfer day, biochemical and clinical pregnancy rates, implantation rate, abnormal pregnancy rate and other indices were compared among the three groups. RESULTS: Endometrial thickness, E2 and P levels, and the E2/P ratio on embryo transfer day and other factors had no significant differences among groups. The biochemical pregnancy, clinical pregnancy, and implantation rates of the CM and hysteroscopy groups were significantly higher than the control group (P<0.05), and there were no significant differences between these two groups. The abnormal pregnancy rate had no significant difference among the three groups. CONCLUSIONS: Sequential therapy of Yupei Qisun could significantly improve the clinical outcomes of rif-fet cycles, being equivalent to hysteroscopic endometrial mechanical stimulation, and provided a reliable method to treat such infertile couples.

[Early recurrent miscarriage: Evaluation and management]. / Fausses couches précoces « à répétition ¼ : bilan et prise en charge.

OBJECTIVE: To establish recommendations for early recurrent miscarriages (≥3 miscarriages before 14weeks of amenorrhea). MATERIALS AND METHODS: Literature review, establishing levels of evidence and recommendations for grades of clinical practice. RESULTS: Women evaluation includes the search for a diabetes (grade A), an antiphospholipid syndrome (APS) (grade A), a thyroid dysfunction (grade A), a hyperprolactinemia (grade B), a vitamin deficiency and a hyperhomocysteinemia (grade C), a uterine abnormality (grade C), an altered ovarian reserve (grade C), and a couple chromosome analysis (grade A). For unexplained early recurrent miscarriages, treatment includes folic acid and progesterone supplementation, and a reinsurance policy in the first quarter (grade C). It is recommended to prescribe the combination of aspirin and low-molecular-weight heparin when APS (grade A), glycemic control in diabetes (grade A), L-Thyroxine in case of hypothyroidism (grade A) or the presence of thyroid antibodies (grade B), bromocriptine if hyperprolactinemia (grade B), a substitution for vitamin deficiency or hyperhomocysteinemia (grade C), sectionning a uterine septum (grade C) and treating an uterine acquired abnormality (grade C). CONCLUSION: These recommendations should improve the management of couples faced with early recurrent miscarriages.

Intralipid therapy for recurrent implantation failure: new hope or false dawn?

Recurrent embryo implantation failure (RIF) is a disorder with potentially devastating physiological and psychological manifestations for those affected. Although its prevalence is not uncommon, many of the mechanisms involved still require elucidation. Both organ-specific and systemic autoimmunity are associated with an increased prevalence of recurrent miscarriage and reproductive failure, rendering the role of the maternal immunological system in fertility a key concept. It is believed by some that central to this theme is the maternal cytokine profile, with particularly T-helper (Th) cells. Immune modulating therapies have therefore been mooted as potential therapeutic strategies. Recent reports of high pregnancy rates achievable in women with RIF have added fuel to the debate regarding the effectiveness of intralipid in modulating the immune system. We would like to assess if there is sufficient current evidence of acceptable quality to permit an assumption that intralipid therapy is an effective treatment for women undergoing repeated assisted reproduction cycles. We have concluded that appropriately controlled, large-scale, confirmatory studies are necessary to prove the efficacy of intralipid before it can be recommended for routine use.

Supportive care for women with unexplained recurrent miscarriage: patients' perspectives.

BACKGROUND Supportive care is currently the only 'therapy' that can be offered to women with unexplained recurrent miscarriage (RM). What these women themselves prefer as supportive care in their next pregnancy has never been substantiated. Therefore the aim of this study was to explore what women with unexplained RM prefer as supportive care during their next pregnancy. METHODS We performed explorative, semi-structured, in-depth interviews. The interviews were performed with 15 women with unexplained RM who were actively seeking conception. All interviews were conducted by telephone. The interviews were fully transcribed and two researchers independently identified text segments from the transcribed interviews and categorized them in the appropriate domain. RESULTS Women identified 20 different supportive care options; 16 of these options were preferred for their next pregnancy. Examples of the preferred supportive care were early and frequently repeated ultrasounds, ßHCG monitoring, practical advice concerning life style and diet, emotional support in the form of counselling, a clear policy for the upcoming 12 weeks and medication. The four supportive care options that were not preferred by the women were admittance to a hospital ward at the same gestational age as previous miscarriages, Complementary Alternative Medicine, ultrasound every other day and receiving supportive care from their general practitioner. CONCLUSIONS Our study identified several relevant preferences for supportive care in women with unexplained RM. Many of these can be offered by the gynaecologist and will help in guaranteeing high-quality patient-centred care.