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Objective: To compare outcomes in patients with repeated implantation failure undergoing Intracytoplasmic Sperm Injection/In vitro fertilization (IVF/ICSI) plus immunosuppressants such as prednisolone, prednisone, or cyclosporine A versus the use of IVF/ICSI alone. Data source: Databases were systematically searched in PubMed, Cochrane, and Embase databases in September 2023. Study Selection: Randomized clinical trials and observational studies with the outcomes of interest were included. Data collect: We computed odds ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). Heterogeneity was assessed using I2 statistics. Data were analyzed using Review Manager 5.4.The main outcomes were live birth, miscarriage, implantation rate, clinical pregnancy, and biochemical pregnancy. Data synthesis: Seven studies with 2,829 patients were included. Immunosuppressive treatments were used in 1,312 (46.37%). Cyclosporine A improved implantation rate (OR 1.48; 95% CI 1.01-2.18) and clinical pregnancy (1.89, 95% CI 1.14-3.14). Compared to non-immunosuppressive treatment, prednisolone and prednisone did not improve live birth (OR 1.13, 95% CI 0.88-1.46) and miscarriage (OR 1.49, 95% CI 1.07-2.09). Prednisolone showed no significant effect in patients undergoing IVF/ICSI, clinical pregnancy (OR 1.34; 95% CI 0.76-2.36), or implantation rate (OR 1.36; 95% CI 0.76-2.42). Conclusion: Cyclosporine A may promote implantation and clinical pregnancy rates. However, given the limited sample size, it is important to approach these findings with caution. Our results indicate that prednisolone and prednisone do not have any beneficial effects on clinical outcomes of IVF/ICSI patients with repeated implantation failure. PROSPERO: CRD42023449655.
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Implantação do Embrião , Imunossupressores , Humanos , Feminino , Gravidez , Imunossupressores/uso terapêutico , Ciclosporina/uso terapêutico , Injeções de Esperma Intracitoplásmicas , Taxa de Gravidez , Técnicas de Reprodução Assistida , Prednisolona/uso terapêutico , Prednisolona/administração & dosagem , Prednisona/uso terapêuticoRESUMO
Perinatal exposure to a glyphosate-based herbicide (GBH) or its active ingredient, glyphosate (Gly), has been demonstrated to increase implantation failure in rats. This study investigates potential mechanisms of action, analyzing uterine preparation towards the receptive state. Pregnant Wistar rats (F0) were treated orally with GBH or Gly (3.8 and 3.9 mg Gly/kg/day, respectively) from gestational day (GD) 9 until weaning. Adult F1 females became pregnant and uterine samples were collected on GD5 (preimplantation period). Histomorphological uterine parameters were assessed. Immunohistochemistry was applied to evaluate cell proliferation and protein expression of estrogen receptors (ERα and ERß), cell cycle regulators (PTEN, cyclin G1, p27, and IGF1R-α), and the Wnt5a/ß-catenin/FOXA2/Lif pathway. Both GBH and Gly females showed increased stromal proliferation, associated with a high expression of ERs. Dysregulation of PTEN and cyclin G1 was also observed in the Gly group. Reduced gland number was observed in both groups, along with decreased expression of Wnt5a/ß-catenin/FOXA2/Lif pathway in the glandular epithelium. Overall, GBH and Gly perinatal exposure disrupted intrinsic uterine pathways involved in endometrial proliferation and glandular function, providing a plausible mechanism for glyphosate-induced implantation failure by compromising uterine receptivity. Similar effects between GBH and Gly suggest the active principle mainly drives the adverse outcomes.
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OBJECTIVE: Many pieces of literature have reported that inherited and acquired thrombophilia might be a risk factor for recurrent implantation failure (RIF), however, most studies have only focused on RIF patients and not their male partners. We studied the possible association of paternal thrombophilia with RIF risk. METHODS: Forty-two male partners aged 20-45 suffered from RIF compared with 42 males from couples with at least one successful pregnancy. All participants were investigated for thrombophilia markers. RESULTS: The prevalence of coagulation Factor V activity was significantly higher in the case group (42.9%) than in the control group (16.7%) (p=0.008) (OR=3.75; 95% CI, 1.38, 10.12). The prevalence of protein C and protein S deficiencies in RIF patients were 4.8% and 2.4%, respectively, and 0% in the controls. The prevalence of antithrombin III (ATIII) deficiency was significantly higher in the case group (19%) than in the control group (2.4%) (p=0.01). None of MTHFR C677T and MTHFR A1298C were statistically significant between the two groups. Combined thrombophilia was 45.2% in the men of the RIF group when compared with the control, 14.2% (p=0.001) (OR = 4.95; 95% CI, 1.75-13.86). CONCLUSIONS: Paternal thrombophilia may be related to recurrent implantation failure, so evaluation of this factor in RIF patients could be used to identify relevant risk groups and may help in the proper management of these cases to enhance the chance of implantation.
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Trombofilia , Humanos , Masculino , Trombofilia/epidemiologia , Adulto , Estudos de Casos e Controles , Feminino , Pessoa de Meia-Idade , Implantação do Embrião , Adulto Jovem , Gravidez , Fatores de RiscoRESUMO
Abstract Objective To compare outcomes in patients with repeated implantation failure undergoing Intracytoplasmic Sperm Injection/In vitro fertilization (IVF/ICSI) plus immunosuppressants such as prednisolone, prednisone, or cyclosporine A versus the use of IVF/ICSI alone. Data source Databases were systematically searched in PubMed, Cochrane, and Embase databases in September 2023. Study Selection Randomized clinical trials and observational studies with the outcomes of interest were included. Data collect We computed odds ratios (ORs) for binary endpoints, with 95% confidence intervals (CIs). Heterogeneity was assessed using I2 statistics. Data were analyzed using Review Manager 5.4.The main outcomes were live birth, miscarriage, implantation rate, clinical pregnancy, and biochemical pregnancy. Data synthesis Seven studies with 2,829 patients were included. Immunosuppressive treatments were used in 1,312 (46.37%). Cyclosporine A improved implantation rate (OR 1.48; 95% CI 1.01-2.18) and clinical pregnancy (1.89, 95% CI 1.14-3.14). Compared to non-immunosuppressive treatment, prednisolone and prednisone did not improve live birth (OR 1.13, 95% CI 0.88-1.46) and miscarriage (OR 1.49, 95% CI 1.07-2.09). Prednisolone showed no significant effect in patients undergoing IVF/ICSI, clinical pregnancy (OR 1.34; 95% CI 0.76-2.36), or implantation rate (OR 1.36; 95% CI 0.76-2.42). Conclusion Cyclosporine A may promote implantation and clinical pregnancy rates. However, given the limited sample size, it is important to approach these findings with caution. Our results indicate that prednisolone and prednisone do not have any beneficial effects on clinical outcomes of IVF/ICSI patients with repeated implantation failure. PROSPERO CRD42023449655
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OBJECTIVE: This study aimed to investigate whether hysteroscopy plus endometrial fundal incision (EFI) with endoscopic scissors can improve reproductive outcomes in oocyte recipients who have failed in their first egg donation cycle. METHODS: This was a prospective study (2014-2022) conducted in Assisting Nature Centre Reproduction and Genetics, Thessaloniki Greece, IVF Unit. The study population consisted of oocyte recipients with implantation failure in their first embryo transfer (ET) with donor eggs. All the recipients underwent routine evaluation during their early follicular phase, 1-3 months before the start of a new cycle with donor oocytes and were eligible to undergo EFI. RESULTS: During the study period, 218 egg recipients underwent egg donation; 126 out of 218 oocyte recipients (57.8%) did not achieve a live birth at the 1st ET. 109 of them had surplus embryos cryopreserved and underwent a second ET; 50 women consented for EFI. Both groups were similar in terms of age, years of infertility, duration of estrogen replacement protocol and number of transferred blastocysts (p>0.05). In the EFI group, 60% had normal intrauterine cavity, while 40% had minor anomalies. The pregnancy test was positive in 46% (n=23/50) in the EFI group compared with 27.1% (n=16/59) in the control group (p=0.04). Moreover, live birth rates were higher in the EFI group compared to the control group (38.0% vs. 20.3%; p=0.04). CONCLUSIONS: The findings of our study indicate that in oocyte recipients after implantation failure, diagnostic hysteroscopy plus EFI prior to subsequent ETmay increase pregnancy and live birth rates.
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STUDY QUESTION: Does a personalized embryo transfer (pET) guided by tests for endometrial receptivity (TER) increase the effectiveness of ART procedures? SUMMARY ANSWER: The use of TER-guided pET is not supported by current published evidence in women without repeated implantation failure (RIF), while in women with RIF more research is needed to assess a potential benefit. WHAT IS KNOWN ALREADY: Implantation rates are still far from ideal, especially in some patients that have RIF with good-quality embryos. As a potential solution, a wide range of diverse TER use different sets of genes to identify displacements of the window of implantation to adjust the individual length of progesterone exposure in a pET. STUDY DESIGN, SIZE, DURATION: A systematic review with meta-analysis was performed. Search terms included endometrial receptivity analysis, ERA, personalized embryo transfer. CENTRAL, PubMed, Embase, reference lists, clinical trials registers, and conference proceedings (search date October 2022) were searched, with no language restrictions. PARTICIPANTS/MATERIALS, SETTING, METHODS: Randomized controlled trials (RCTs) and cohort studies comparing a pET guided by TER vs standard embryo transfer (sET) in different subgroups that undergo ART were identified. We also investigated pET in non-receptive-TER vs sET in receptive-TER, and pET in a specific population vs sET in a general population. Risk of bias (RoB) was assessed with the Cochrane tool and ROBINS-I. Only those with low/moderate RoB underwent meta-analysis. The GRADE approach was used to evaluate the certainty of evidence (CoE). MAIN RESULTS AND THE ROLE OF CHANCE: We screened 2136 studies and included 35 (85% used ERA and 15% used other TER). Two studies were RCTs comparing endometrial receptivity analysis (ERA)-guided pET vs sET in women with no history of RIF. In women without RIF, no important differences (moderate-CoE) were found in live birth rates and clinical pregnancy rates (CPR). We also performed a meta-analysis of four cohort studies that were adjusted for confounding. In agreement with the RCTs, no benefits were found in women without RIF. However, in women with RIF, low CoE suggests that pET might improve the CPR (OR 2.50, 95% CI 1.42-4.40). LIMITATIONS, REASONS FOR CAUTION: We found few studies with low RoB. Only two RCTs in women without RIF were published, and none in women with RIF. Furthermore, the heterogeneity observed in populations, interventions, co-interventions, outcomes, comparisons, and procedures limited the pooling of many of the included studies. WIDER IMPLICATIONS OF THE FINDINGS: In the population of women without RIF, in agreement with previously published reviews, pET did not prove to be more effective than sET and, therefore, it precludes the routine use of this strategy in this population until more evidence is available. However, more research is advisable in women with RIF as low-certainty evidence from observational studies adjusted for confounders suggests that the CPR might be higher with pET guided by TER in this population. Although this review presents the best available evidence, it is still insufficient to change current policies. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. There are no conflicts of interest to declare. REGISTRATION NUMBER: PROSPERO CRD42022299827.
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Implantação do Embrião , Transferência Embrionária , Gravidez , Feminino , Humanos , Taxa de Gravidez , Transferência Embrionária/métodos , Implantação do Embrião/genética , Endométrio/diagnóstico por imagem , Progesterona , Nascido Vivo/epidemiologiaRESUMO
OBJECTIVE: The embryo implantation includes a complex sequence of signaling events, comprising numerous molecular mediators, such as ovarian hormones, cytokines, adhesion molecules and, growth factors. One of the critical factors in angiogenesis is the vascular endothelial growth factor (VEGF). The VEGF plays a pivotal role in embryonic development, decidua vascularization and placental angiogenesis. Furthermore, the P53 gene and its negative regulator, murine double minute 2 (MDM2), are major players in reproductive processes. This study aimed to assess the association of polymorphisms of the VEGF and the MDM2 genes with idiopathic recurrent implantation failure. METHODS: We genotyped 60 women with previous idiopathic recurrent implantation failures and 60 fertile women as controls. Restriction Fragment Length Polymorphism (RFLP) and Sanger sequencing were used for genotyping the rs2010963 and the rs1570360 polymorphisms in VEGF; and the rs2279744 in MDM2 genes. RESULTS: Results indicated a higher frequency of the VEGF rs1570360 AA genotype and A allele in patients with a history of idiopathic implantation failure [OR=6.4 (1.22 - 33.64), p-value=0.02)]. However, the frequency of VEGF +405 G/C and MDM2 SNP309 T/G [(OR=3 (0.5 - 16) p-value=0.2, OR=1.18 (0.3 - 3.7) p-value=0.7, respectively)] genotypes were not significantly different between cases and controls. CONCLUSIONS: The VEGF polymorphism may influence embryo implantation and the VEGF rs1570360 AA genotype may predispose to the risk of recurrent implantation failure after IVF.
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Placenta , Fator A de Crescimento do Endotélio Vascular , Animais , Feminino , Humanos , Camundongos , Gravidez , Estudos de Casos e Controles , Irã (Geográfico) , Polimorfismo Genético , Proteínas Proto-Oncogênicas c-mdm2/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
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.
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Aborto Habitual , Ácidos Graxos Ômega-3 , Humanos , Feminino , Gravidez , Fosfolipídeos , Aborto Habitual/terapia , Aborto Habitual/etiologia , Ácidos Graxos Ômega-3/uso terapêutico , Emulsões Gordurosas Intravenosas , Cromatografia LíquidaRESUMO
Recurrent implantation failure (RIF) has been used to describe embryos' failure to implant following IVF, arising concerns about the importance of its treatment. Growth hormone (GH) has been studied as one of the possible co-interventions. Our updated review evaluated GH intervention vs. no intervention from randomized controlled trials (RCTs) in RIF patients. Electronic searches on The Menstrual Disorders and Subfertility Group (MDSG), The Cochrane Central Register for Clinical Trials, PubMed MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, and Google Scholar up to August 2021 identified 2 RCTs and compiled with the above inclusion criteria. The risk of bias (ROB) and the quality of evidence were assessed according to the Cochrane Collaboration tool and GRADE group guidelines. Meta-analysis found higher rates of clinical pregnancy (OR: 4.97 CI 95% 2.05 to 12.05), live birth (OR: 5.13 CI 95% 2.03 to 12.91), and implantation (OR: 3.88 CI 95% 1.91 to 7.88) when compared GH to no intervention; as well as an increased endometrial thickness (mean difference: 1.14 CI 95% -0.0 to 2.28). However, this review cannot provide a strong recommendation due to the quality of evidence rated as "very low quality of evidence" in all the outcomes for reasons such as methodology issues, heterogeneity, intervention regimen, and limited sample sizes with large confidence intervals and a low number of events. We emphasize the importance of upcoming high-quality research and the need for consensus concepts in RIF patients, which may be a minority; it is still one of the highest impacts on life quality.
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Implantação do Embrião , Gravidez Múltipla , Gravidez , Feminino , Humanos , Nascido Vivo , Hormônio do Crescimento , Taxa de GravidezRESUMO
OBJECTIVE: Repeated implantation failure (RIF) is a major challenge in reproductive medicine. On the other hand, there has not yet been established a confirmed outcome regarding the usage of platelet-rich plasma (PRP) in women undergoing intracytoplasmic injection (ICSI) or in-vitro fertilization (IVF); hence, the objective of this study was to evaluate the effect of the intrauterine infusion of PRP on pregnancy outcomes in women undergoing ICSI. METHODS: In this prospective double-blind clinical trial, 100 women with at least two previous unexplained RIF, who were candidates for frozen-thawed embryo transfer, were allocated into two groups. One subgroup of patients was treated by intrauterine infusion of PRP (0.5CC, contained platelet 4-5 times more than a peripheral blood sample, which was performed 48 hours before blastocyst transfer) and the other subgroup was treated by intrauterine catheterization only. We compared the implantation rates between the two groups. RESULTS: The pregnancy rate was 20% in the intervention subgroup, while in the control subgroup it was 13.33%; therefore, there was a significant statistical difference between the two groups. CONCLUSIONS: According to this paper, PRP could be successful in improving the pregnancy outcome in RIF patients, and we highly recommend other studies with larger samples to confirm the PRP therapy efficacy in RIF patients.
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Implantação do Embrião , Plasma Rico em Plaquetas , Transferência Embrionária , Feminino , Fertilização in vitro , Humanos , Gravidez , Taxa de Gravidez , Estudos ProspectivosRESUMO
Proper communication between natural killer cells and the human leukocyte antigens of the embryonic trophoblast at the maternal-fetal interface during pregnancy is essential for successful reproduction. However, specific combinations of embryonic human leukocyte antigen-C with killer immunoglobulin-like receptors on decidual natural killer cells (the immunological code of pregnancy) can be associated with obstetric morbidity and pregnancy loss. This article presents an updated review of the mechanisms underlying the interaction between embryonic human leukocyte antigen-C and maternal killer immunoglobulin-like receptors and their relevance to the physiology and pathophysiology of human reproduction.
Una adecuada comunicación entre las células asesinas naturales en la interfase materno-fetal con las moléculas de los antígenos de histocompatibilidad del trofoblasto embrionario es clave en el éxito de la reproducción. Sin embargo, combinaciones de determinados antígenos leucocitarios humanos tipo C embrionarios con los receptores tipo inmunoglobulina presentes en las células asesinas naturales deciduales (el código inmunológico del embarazo), pueden asociarse con morbilidad obstétrica y pérdidas gestacionales. En este artículo se presenta una revisión actualizada de los mecanismos subyacentes a la interacción entre el antígeno de histocompatibilidad tipo C embrionario y los receptores tipo inmunoglobulina maternos, y su relevancia tanto en la fisiología como en la fisiopatología de la reproducción humana.
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Aborto Habitual/imunologia , Antígenos HLA-C/imunologia , Células Matadoras Naturais/imunologia , Placentação/fisiologia , Receptores KIR/imunologia , Medicina Reprodutiva , Útero/imunologia , Aborto Espontâneo/imunologia , Implantação do Embrião/imunologia , Feminino , Antígenos HLA , Antígenos HLA-C/fisiologia , Humanos , Células Matadoras Naturais/fisiologia , Gravidez , Receptores KIR/fisiologiaRESUMO
STUDY QUESTION: Does hysteroscopic endometrial peeling improve reproductive outcomes in women with implantation failure? DESIGN: In this case series, 66 women underwent an hysteroscopic endometrial peeling and subsequently, a single frozen embryo transfer. RESULTS: After the exclusion of patients with intraoperative incidental findings, pregnancy was achieved in 63% (42/66) of the women who underwent hysteroscopic endometrial peeling and subsequently a single frozen embryo transfer, clinical pregnancy rate was observed in 57% (38/66) of the patients and, clinical pregnancy loss occurred in 10% (4/38). CONCLUSION: this novel surgical technique seems to increase implantation as well as clinical pregnancy rates in women with repeated implantation failure. We can hypothesize that the controlled and subtle degree of endometrial injury generated by the peeling generates an inflammatory cascade that enhances implantation.
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Histeroscopia/normas , Doenças Uterinas/cirurgia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Histeroscopia/métodos , Histeroscopia/estatística & dados numéricos , México , Resultado do Tratamento , Doenças Uterinas/epidemiologiaRESUMO
OBJECTIVE: The recent improvement in sequential media has refocused its attention on the role of human blastocysts in ART, not only because of its advantages but also because of the possible cancellation of embryo transfer when relying on blastocyst transfer only. Hence, the idea of sequential transfer on day 3 and day 5 was proposed. Objective: To compare the pregnancy outcomes of sequential embryo transfer on day 3 and day 5, versus cleavage transfer on day 3 and blastocyst transfer on day 5 in cases of recurrent implantation failure. METHODS: This was a prospective and randomized trial, in which 210 qualified patients with recurrent implantation failures undergoing IVF/ICSI were randomized into three groups, each group included 70 patients. Embryo transfer was performed in day 3 in the first group, day 5 (blastocyst transfer) in the second group and sequential embryo transfer in days 3 and 5 in the third group. We assessed pregnancy outcomes from all the three groups. Results: Clinical pregnancy and live birth rates were significantly higher in the sequential group than either group day-3 or day-5 of embryo transfer in cases with recurrent implantation failures. CONCLUSIONS: Sequential embryo transfer in cases with recurrent implantation failures and adequate number of retrieved oocytes is associated with higher implantation and clinical pregnancy rates, and it is advocated for patients having an adequate number of good quality embryos.
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Fase de Clivagem do Zigoto , Transferência Embrionária , Blastocisto , Feminino , Fertilização in vitro , Humanos , Gravidez , Taxa de Gravidez , Estudos ProspectivosRESUMO
PROBLEM: Lymphocyte immunotherapy (LIT) emerged in the early 1980s as a new therapeutic proposal for couples with a history of recurrent miscarriages (RM). However, in the early 2000s, the effectiveness of LIT was questioned. Recently, meta-analyses have observed the effectiveness and safety of LIT in treating couples with RM. Some studies evaluated the use of LIT in recurrent implantation failure (RIF) in in vitro fertilization cycles. METHODS: This systematic and narrative review evaluated the data available in the literature regarding the efficacy and safety of the use of LIT. Searches in PubMed/Medline, Embase, and Cochrane Library databases were conducted, using the following keywords: "recurrent miscarriage," "lymphocyte immunotherapy," and "recurrent implantation failure". RESULTS: This review describes the historical aspects of LIT and discusses its protocols, mechanisms of action, side effects, complications, and current evidence of the effectiveness in cases of reproductive failure. It also discusses the use of LIT during the COVID-19 pandemic and new immunological therapies. CONCLUSION: In the vast majority of studies, the use of LIT for RM couples has shown an improvement in pregnancy outcomes. The most of the current studies that support the evidence are quasi-experimental, with few randomized, double-blind studies (Level of evidence III). However, the current evidence are not convincing for the use of LIT in RIF patients.
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Aborto Habitual/terapia , COVID-19 , Imunoterapia , Transfusão de Linfócitos , Linfócitos , Pandemias , SARS-CoV-2 , Feminino , Humanos , GravidezRESUMO
Altered immune and/or inflammatory response plays an important role in cases of recurrent pregnancy loss (RPL) and repeated implantation failure (RIF). Exacerbation of the maternal immune response through increased NK cell activity and inflammatory cytokines can cause embryo rejection leading to abortion or embryo implantation failure. Immunosuppressors or immunomodulators can help or prevent this condition. Currently, lipid emulsion therapy (LET) has emerged as a treatment for RPL and RIF in women with abnormal NK cell activity, by decreasing the exacerbated immune response of the maternal uterus and providing a more receptive environment for the embryo. However, the mechanisms by which the intralipid acts to reduce NK cell activity are still unclear. In this review, we focus on the studies that conducted LET to treat patients with RPL and RIF with abnormal NK cell activity. We find that although some authors recommend LET as an effective intervention, more studies are necessary to confirm its effectiveness in restoring NK cell activity to normal levels and to comprehend the underlying mechanisms of the lipids action in ameliorating the maternal environment and improving the pregnancy rate.
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Aborto Habitual/terapia , Lipídeos/uso terapêutico , Aborto Habitual/diagnóstico , Aborto Habitual/etiologia , Citocinas , Gerenciamento Clínico , Suscetibilidade a Doenças , Implantação do Embrião , Emulsões , Feminino , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Lipídeos/administração & dosagem , Ativação Linfocitária/genética , Gravidez , Resultado do TratamentoRESUMO
Introduction. Implantation failure appears to be a significant factor in Assisted reproductive technique (ART) procedures. Even a mature endometrium may be non-receptive, preventing implantation or rejection of implanted embryo in early months of pregnancy, resulting in miscarriage or unexplained infertility with or without other associated factors. Objective. To investigate causes of failed implantation inspite of uneventful Grade I embryo transfer in ART procedure Material and Method. 90 women aged range between 25-40 yr old who visited Department of Reproductive Medicine at Calcutta Fertility Mission, over a period of 24 months(January 2017 to December 2019) , satisfying the inclusion criteria, were enrolled in this observational study. Endometrial aspirate histopathology was done along with ∞5ß3 integrin expression. They were treated with natural micronized progesterone (NMP) or oral dydrogesterone and results of endometrial changes were statistically analyzed. Results. 28.89% and 31.11% of women were seen to have mid-secretory changes of the endometrium after being treated with NMP and dydrogesterone respectively. Integrins were expressed in only 59.26% of women with mid-secretory endometrium and 5.41% of early secretory endometrium, which was statistically significant (p value <0.001). Conclusion. About 70% patients even after treatment with estrogen and progestin did not have adequate response in endometrial maturation. Not all patients with mid-secretory endometrium had integrin positive, when tested. NMP and oral Dydrogesterone have similar effect in endometrial maturation as well as in yielding successful pregnancy in some patients with previously failed In-vitro fertilization embryo transfer (IVF-ET).
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Humanos , Feminino , Adulto , Implantação do Embrião , Progesterona/administração & dosagem , Integrinas , Técnicas de Reprodução Assistida , Didrogesterona/administração & dosagem , Eficácia de Contraceptivos , Infertilidade Feminina/terapiaRESUMO
Studies have investigated the gestational outcomes of new immunological therapies in the treatment of patients with recurrent implantation failure (RIF) in assisted reproductive technology (ART). The objective of this article is to assess the current state of evidence available in the literature on intrauterine perfusion immunotherapies in women undergoing ART treatments. By considering the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), the authors performed systematic review by searching the databases of PubMed/MEDLINE and Scopus using the following key words: "recurrent implantation failure," "intrauterine infusion," "Platelet-Rich Plasma (PRP)," "Peripheral Blood Mononuclear Cells (PBMC)," "Granulocyte Colony-Stimulating Factor (G-CSF)," and "Human Chorionic Gonadotropin (hCG)." The authors analyzed the indications and the impact of new immunological therapies with intrauterine infusions on the pregnancy outcomes of patients undergoing ART. PRP, PBMC, G-CSF, and hCG were the four most used immunological therapies with intrauterine infusion. These new therapies appear to improve the results of ART treatments in cases of RIF. However, the small number of studies does not allow definitive conclusions about the effectiveness of these therapies.
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Transfusão de Sangue Intrauterina/métodos , Imunoterapia/métodos , Leucócitos Mononucleares/imunologia , Complicações na Gravidez/terapia , Gravidez , Gonadotropina Coriônica/metabolismo , Implantação do Embrião , Feminino , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Leucócitos Mononucleares/transplante , Plasma Rico em Plaquetas , Complicações na Gravidez/imunologia , Resultado da GravidezRESUMO
OBJECTIVE: Our primary objective was to evaluate the endometrial changes before and after the transfer of endometrial mesenchymal stem cells (enMSCs) in a population of thinned endometrium women, with absence or hypo-responsiveness to estrogen and repeated implantation failure (RIF). The secondary objective was to evaluate the clinical outcomes of the intervention in terms of clinical pregnancy (CP), early abortions, ongoing pregnancy and live birth delivery rate (LBDR) per in vitro fertilization (IVF) cycle. METHODS: A longitudinal and experimental study. The intervention was defined as "subendometrial inoculation of enMSCs," and the post-intervention changes were evaluated by the following variables: endometrial thickness (Eth), endometrial flow cytometry (enFC), endometrial histopathology (enHP) and endometrial immunohistochemistry (enIHQ). The variables were analyzed after the intervention (Post-treatment) regarding previous values (Pretreatment). RESULTS: Eth values before and after treatment with enMSCs were 5.24±1.24 mm vs. 9.93±0.77 (p=0.000), respectively. Endometrial Flow Cytometry showed significant differences in favor of Normalized variables in the post-treatment assessment, associated with the pretreatment, LT/Li, LB/Li, NK/Li, CD8/CD3+ and CD4/CD8 (p≤0.015), respectively. Only two variables Li/PC and CD4/CD3 had NS (p=0.167 and 0.118). A similar analysis was performed on enHP with an HP increase post-treatment (p=0.007). The CP rate was 79.31% (23/29), a live birth delivery rate per embryo transfer was 45.45% (10/22) and ongoing pregnancy 7/29 (24.14%). CONCLUSION: Subendometrial enMSCs inoculation produces a significant increase in endometrial thickness; normalize the enHP, enIHQ and enFC. As a result, IVF after treatment with enMSCs yields a higher rate of CP and LBDR.
Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Endométrio , Infertilidade/terapia , Células-Tronco Mesenquimais/citologia , Doenças Uterinas/terapia , Adulto , Implantação do Embrião/fisiologia , Endométrio/citologia , Endométrio/patologia , Feminino , Citometria de Fluxo , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Gravidez , Medicina RegenerativaRESUMO
OBJECTIVE: To evaluate whether or not one should use a new Protocol for Endometrial Receptivity Improvement (PRIMER) based on platelet-rich plasma (PRP) and granulocyte colony-stimulation factor (G-CSF) to enhance ongoing pregnancy rates in patients with recurrent implantation failure (RIF). METHODS: Women undergoing IVF/ICSI were prospectively divided into two groups: - PRIMER/RIF group (n:33): patients with RIF (defined as ≥2embryo transfers (ETs) and at least 5 morphologically good embryos transferred) in which intrauterine PRP injection and subcutaneous G-CSF-injection were performed. - Control group (n:33): patients in their first IVF/ICSI attempt/cycle (without PRP or G-CSF injection). The PRP was prepared using autologous fresh-whole blood processed to increase platelet-concentration in 2 to 4 fold. All patients undergoing the PRP-treatment received 0.7ml of it through intrauterine-injection 48 hours before the ET. G-CSF (300mg/0.5ml) started simultaneously to PRP and was administered subcutaneously every week. RESULTS: Regarding implantation, clinical pregnancy and miscarriage rates, we found no statistically significant difference (18.2% versus 17.6%, p=0.90; 36.4% versus 30.3%, p=0.61 and 25.0% versus 9.0%, p=0.43, respectively). The use of PRIMER enabled RIF patients (previous ET µ: 4.0±1.5) to reach similar ongoing pregnancy and live birth rates like those patients who had their first IVF/ICSI cycle attempt (27.3% versus 27.3%, p=0.99). CONCLUSIONS: Our results showed, for the first time, evidence that this therapeutic protocol (PRIMER) could be used as a feasible treatment based on biological rationale for patients with RIF, considering its promising outcomes, it is a simple procedure and not associated with patient complications.
Assuntos
Aborto Habitual/terapia , Transfusão de Componentes Sanguíneos/métodos , Implantação do Embrião , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Plasma Rico em Plaquetas/fisiologia , Terapias em Estudo/métodos , Aborto Habitual/patologia , Adulto , Implantação do Embrião/efeitos dos fármacos , Implantação do Embrião/fisiologia , Transferência Embrionária/métodos , Endométrio/efeitos dos fármacos , Endométrio/patologia , Feminino , Fertilização in vitro/métodos , Humanos , Recém-Nascido , Nascido Vivo , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Gravidez , Taxa de Gravidez , Falha de TratamentoRESUMO
Abstract Sirtuin 1 has an important role in cellular processes, including apoptosis and cellular stress. The purpose of this study was to assess serum sirtuin 1 levels in women with recurrent implantation failure (RIF). In this cross-sectional study, we included 28 women with RIF, 29 healthy women who had conceived by in vitro fertilization (IVF), and 30 women with a 1-cycle failure of IVF as controls. Human serum nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin-1 (SIRT1/SIRT2L1) levels were detected using a commercial colorimetric kit. Recurrent implantation failure patients have higher sirtuin 1 levels than non-pregnant women and healthy pregnant women, but this difference did not reach statistical significance due to the low number of patients in our study. These higher sirtuin 1 levels may result from the inflammation imbalance of RIF patients. The only statistically significant correlation found was between age and sirtuin (r = 0.277, p = 0.009).
Resumo A sirtuína 1 tem importante função nos processos celulares, incluindo a apoptose e o estresse celular. O objetivo deste estudo é o de avaliar níveis de sirtuína 1 em mulheres com falhas recorrentes de implantação (FRI). Neste estudo cruzado, incluímos 28 mulheres com FRI, 29 mulheres saudáveis que deram à luz por fertilização in vitro (FIV) bem-sucedida, e 30 mulheres com 1 ciclo de FIV malsucedido como controle. Os níveis de sirtuína 1 em soro humano de desacetilase dependente de dinucleotídeo de nicotinamida adenina (DNA) (SIRT1/SIRT2L1) foram detectados usando um kit colorimétrico comercial. Pacientes com FRI tiveram níveis de sirtuína 1 superiores às pacientes grávidas e aos controles, mas esta diferença não atingiu significância estatística devido ao baixo número de pacientes envolvidos. Estes níveis mais altos de sirtuína 1 podem ser resultado da inflamação desigual em pacientes com FRI. A única correlação estatisticamente significante encontrada foi entre idade e sirtuína (r = 0,277, p = 0,009).