NK and T Cell Subtypes in the Endometrium of Patients with Recurrent Pregnancy Loss and Recurrent Implantation Failure: Implications for Pregnancy Success.

BACKGROUND: RPL and RIF are challenges in reproductive medicine. The immune system plays a pivotal role in endometrial receptivity, successful implantation, and pregnancy complications. Immunological changes have been associated with RPL and RIF. Understanding immune dysregulation especially in NK and T cell subtypes may lead to better diagnostic concepts and treatments. From July 2019 to August 2020 patients with RPL and RIF underwent a standardized diagnostic procedure including endometrial biopsies. Immune cell analysis was performed using flow cytometry. Patients were contacted in March 2023 and interviewed concerning their pregnancy outcomes following diagnostics. RESULTS: Out of 68 patients undergoing endometrial biopsies, 49 patients were finally included. Live birth rates were high with 72% in RPL and 86% in RIF. Immune cell analysis revealed that patients with RPL had more cytotoxic CD56dimCD16high cells, while RIF patients had more CD56+ uNK cells. RPL patients with pregnancy complications showed increased NKT cell percentages. CONCLUSION: Our findings suggest specific immune changes in RPL and RIF patients, offering potential therapeutic targets. Tailored immunotherapy based on endometrial immunophenotyping might be an option, but further research is needed.

Antibiotic-free vaginal microbiota transplant with donor engraftment, dysbiosis resolution and live birth after recurrent pregnancy loss: a proof of concept case study.

Background: Vaginal dysbiosis covers imbalances in the vaginal microbiota, defined by altered composition of bacteria, viruses, and fungi and is associated with euploid pregnancy losses, premature birth, infertility, or bacterial vaginosis. A large proportion of women who have vaginal dysbiosis do not experience any symptoms. Antibiotics are the traditional treatment, recently combined with local probiotics in some cases. Vaginal Microbiota Transplantation (VMT) with eubiotic vaginal bacterial microbiota after antibiotic eradication of pathogens has successfully been performed in a case study with five patients, but no VMT has been performed without the use of antibiotics. Methods: This is a proof of concept case study. The patient was found to have vaginal dysbiosis at the RPL clinic at Copenhagen University Hospital Hvidovre, Denmark on the 23rd of June 2021. She was offered and accepted to receive experimental treatment in the form of a VMT as a compassionate use case. VMT is the transfer of cervicovaginal secretions (CVS) from a healthy donor with a Lactobacillus-dominant vaginal microbiome to a recipient with a dysbiotic vaginal microbiome. CVS is a mixture of e.g., mucus, bacteria, metabolites present in the vaginal canal. Potential donors were thoroughly screened for the absence of STIs, and the most suitable donor sample for the specific patient in this study was determined via an in vitro microbiome competition assay. Findings: A 30-year-old patient with one livebirth and a complicated pregnancy history of two stillbirths and 1 s trimester pregnancy loss in gestational weeks 27 (2019), 17 (2020) and 23 (2020) respectively with complaints of vaginal irritation and discharge that had aggravated in all her pregnancies. Her vaginal microbiome composition showed a 90% dominance of Gardnerella spp. After one VMT there was a complete shift in microbiome composition to 81.2% L. crispatus and 9% L. jensenii with a concurrent resolvement of vaginal symptoms. Single nucleotide polymorphism-analysis confirmed her microbiome to be of donor origin and it remain stable now 1.5 years after the VMT. Five months after the VMT she became pregnant and has successfully delivered a healthy baby at term. Interpretation: Here we report a successful VMT with confirmed donor strain engraftment followed by a successful pregnancy and delivery after a series of late pregnancy losses/stillbirths. Findings suggest that VMT is a potential treatment for severe vaginal dysbiosis. Further, larger studies are required. Funding: The study was partially funded (i.e., analysis costs) by Freya Biosciences Aps, Fruebjergvej, 2100 Copenhagen, Denmark.

Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry No. 015/050, May 2022).

Purpose The aim of this guideline is to standardize the diagnosis and therapy of recurrent miscarriage (RM) using evidence from the recent literature. This is done by using consistent definitions, objective evaluations and standardized treatment protocols. Methods When this guideline was compiled, special consideration was given to previous recommendations in prior versions of this guideline and the recommendations of the European Society of Human Reproduction and Embryology, the Royal College of Obstetricians and Gynecologists, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine, and a detailed individual search of the literature about the different topics was carried out. Recommendations Recommendations about the diagnostic and therapeutic procedures offered to couples with RM were developed based on the international literature. Special attention was paid to known risk factors such as chromosomal, anatomical, endocrinological, physiological coagulation, psychological, infectious and immune disorders. Recommendations were also developed for those cases where investigations are unable to find any abnormality (idiopathic RM).

Biopsy-free profiling of the uterine immune system in patients with recurrent pregnancy loss and unexplained infertility.

RESEARCH QUESTION: What are the differences in menstrual blood lymphocytes between controls, patients with recurrent pregnancy loss (RPL) and patients with unexplained infertility (uINF)? DESIGN: Prospective study including 46 healthy controls, 28 RPL and 11 uINF patients. A feasibility study compared lymphocyte compositions of endometrial biopsies and menstrual blood collected during the first 48 h of menstruation in seven controls. In all patients, peripheral and menstrual blood from the first and subsequent 24 h were analysed separately by flow cytometry, focusing on the main lymphocyte populations and natural killer (NK) cell subsets. RESULTS: The first 24 h of menstrual blood resembles the uterine immune milieu as tested by endometrial biopsy. RPL patients showed significantly higher menstrual blood CD56+ NK cell numbers than controls (mean ± SD: 31.13 ± 7.52% versus 36.73 ± 5.4%, P = 0.002). Menstrual blood CD56dimCD16bright NK cells within the CD56+ NK cell population were decreased in RPL (16.34 ± 14.65%, P = 0.011) and uINF (15.7 ± 5.91%, P = 0.02) patients versus control (20.42 ± 11.53%). uINF patients had the lowest menstrual blood CD3+ T cell counts (38.81 ± 5.04%, control versus uINF: P = 0.01) and cytotoxicity receptors NKp46 and NKG2D on CD56brightCD16dim cells were higher in uINF (68.12 ± 11.84%, P = 0.006; 45.99 ± 13.83%, P = 0.01, respectively) and RPL (NKp46: 66.21 ± 15.36%, P = 0.009) patients versus controls. RPL and uINF patients had higher peripheral CD56+ NK cell counts versus controls (11.42 ± 4.05%, P = 0.021; 12.86 ± 4.29%, P = 0.009 versus 8.4 ± 3.5%). CONCLUSIONS: Compared with controls, RPL and uINF patients had a different menstrual blood-NK-subtype profile, indicating an altered cytotoxicity. In future studies, this non-invasive analysis might enable identification and monitoring of patients receiving immunomodulatory medications.

Successful isolation of viable stem cells from cryopreserved microfragmented human adipose tissue from patients with knee osteoarthritis - a comparative study of isolation by tissue explant culture and enzymatic digestion.

PURPOSE: To investigate if viable stem cells could be isolated and expanded from cryopreserved microfragmented adipose tissue (AT) harvested from patients with knee osteoarthritis. METHODS: Microfragmented abdominal AT from knee osteoarthritis patients was cryopreserved at -80 °C in cryoprotectant-medium. The samples were thawed for stem cell isolation by tissue explant culture (TEC) and enzymatic digestion (ED), respectively. Viability, population doublings, and doubling time were assessed by trypan blue staining and flow cytometry. Cell type and senescence-associated ß-galactosidase activity were analyzed by flow cytometry. Osteogenic and adipogenic differentiation was assessed quantitatively by Alizarin-Red-S and Oil-Red-O staining, respectively. RESULTS: Microfragmented AT from 7 patients was cryopreserved for a period of 46-150 days (mean (SD) 115.9 days (44.3 days)). Viable stem cells were successfully recovered and expanded from all patients using both isolation methods with no significant difference in viable population doublings or doubling time from passage 1 to 3 (p > 0.05). Low levels of senescence-associated ß-galactosidase activity was detected for both methods with no significant difference between TEC and ED (p = 0.17). Stemness was verified by stem cell surface markers and osteogenic and adipogenic differentiation performance. Adventitial stem cells (CD31-CD34+CD45-CD90+CD146-), pericytes (CD31-CD34-CD45-CD90+CD146+), transitional pericytes (CD31-CD34+CD45-CD90+CD146+), and CD271+ stem cells (CD31-CD45-CD90+CD271+) were identified using both methods. More pericytes were present when using TEC (25% (24%)) compared to ED (3% (2%)) at passage 4 (p = 0.04). CONCLUSIONS: Viable stem cells can be isolated and expanded from cryopreserved microfragmented AT using both TEC and ED. TEC provides more clinically relevant pericytes than ED.

Development of a quality of life questionnaire for transgender individuals during hormone therapy (iTransQol).

PURPOSE: Quality of life (QoL) is a complex term, including mental, physical and social health, and everyone's individual environment. While transgender individuals still often report lower QoL than other individuals, they can benefit substantially from gender affirming therapy. The aim of this study was to develop a questionnaire to determine QoL in transgender individuals during gender affirming hormone therapy (GAHT). METHODS: A multi-step questionnaire development process was performed. In phase 1, a list of key issues was established by reviewing relevant literature. In phase 2, n = 38 transgender individuals as well as n = 6 practitioners evaluated the questionnaire (iTransQoL) in terms of relevance, meaning, comprehensibility and redundancy. Psychometric testing of the questionnaire was performed in phase 3 with n = 40 transgender individuals. The external validity of the iTransQoL was tested by comparison with three validated health questionnaires. RESULTS: The exploratory factor analysis indicated an underlying four-factor solution. Psychometric testing showed acceptable to good overall reliability (α = 0.73-0.83) for the total score and the four subscales as well as good validity indices. Based on the results, a final version of the iTransQoL was established. CONCLUSION: The iTransQoL is a reliable and valid tool to evaluate QoL of transgender individuals during GAHT.

Partners matter: The psychosocial well-being of couples when dealing with endometriosis.

BACKGROUND: Endometriosis is often associated with severe dysmenorrhea, pelvic pain and dyspareunia and has a high impact on daily life as well as sexuality. Quality of partnership positively influences the course of various diseases and ability to cope with emotional and physical distress. However, studies focusing on the male partners of endometriosis patients are rare, and even less is known about the reciprocal relationship in these couples. Therefore, this study aims to explore the interrelations in couples with endometriosis in matters of psychological distress, sexual and partnership satisfaction and social support. METHODS: The cross-sectional study was conducted in two university-affiliated fertility centres in Germany and Austria with n = 104 female/male couples affected by endometriosis. Participants completed a questionnaire regarding endometriosis, partnership, sexuality, stress, anxiety, depression and social support. Both women and men were asked about the impact of women's endometriosis-related pain (IEP) on their everyday life (e.g. leisure time). Data were analysed using the Actor-Partner-Interdependence Model. RESULTS: Significant partner effects were evident: High depression, anxiety and stress scores in women were associated with a higher IEP in men (all p ≤ 0.01), reciprocally high stress and depression scores in men were correlated with a higher IEP in women (all p ≤ 0.05). Less sexual satisfaction in women was associated with a higher IEP in men (p = 0.040). There was a significant reciprocal association between the perceived lack of understanding from the social environment and a higher IEP, for both women (p = 0.022) and men (p = 0.027). CONCLUSIONS: The male partner should be taken into account when counselling or treating women with endometriosis. Our study shows a high interdependence and reciprocal influence from both partners-positively and negatively-concerning psychological distress and sexual satisfaction. Furthermore, there ought to be more awareness for the psychosocial impact of endometriosis, especially in regard to social support and understanding. Talking about and improving sexual satisfaction as well as enhancing stress reducing techniques may hold great benefits for dealing with endometriosis. Registration number The study is registered with the German Clinical Trials Register (DRKS), number DRKS00014362.

Uterine microbiota plasticity during the menstrual cycle: Differences between healthy controls and patients with recurrent miscarriage or implantation failure.

In contrast to the former notion of a sterile womb, sequencing techniques have proven a bacterial colonization of the uterus. However, timing of microbiota analysis regarding possible intra-cycle variations as well as specific alterations in patients with recurrent miscarriage (RM) or recurrent implantation failure (RIF) remain unknown. In total, n = 20 RM-, n = 20 RIF-patients and n = 10 healthy controls were included in this prospective study. In every subject, uterine flushing was performed during follicular, ovulatory and luteal phase. Bacterial DNA was isolated and 16S amplicon sequencing analysis of the V3-V4 region was carried out. Diversity measures were compared between samples from the disease groups and the control group separately for each timepoint of the menstrual cycle and over time. In the control group a significant decrease of species richness and evenness was shown around ovulation which remained at this lower level during the luteal phase (Shannon index), indicating a more uniform distribution of microbiota (p < 0.05). This loss of diversity during the menstrual cycle was not apparent in RIF and RM patients. A higher similarity was seen in taxonomic distribution between RM and RIF patients compared to the control group. Longitudinal dynamics included increases in Firmicutes (controls and RM only) and a concomitant loss of Proteobacteria in controls that was not present in RIF and RM. We demonstrate longitudinal intra-cycle-dependent changes in the endometrial microbiota of healthy controls. An increased diversity in both patient groups could be the cause or consequence of a micro-environment that is more prone to pregnancy failures.

Sexual function in male cancer survivors is not correlated to sperm quality.

PURPOSE: Both infertility and erectile dysfunction (ED) are known long-term consequences of cancer treatment in young male cancer survivors. In the present study, we aimed to assess whether sperm quality and sexual function in male cancer survivors are associated. METHODS: In this prospective study, n = 244 patients male cancer survivors who underwent sperm analysis and cryopreservation between 2008 and 2018 prior to the initiation of gonadotoxic treatment were invited. In total n = 50 had a follow-up sperm analysis and completed two questionnaires, the Aging Males' Symptom Scale (AMS) and the International Index of Erectile Function (IIEF-EF). Differences between the individual parameters were analyzed using the Wilcoxon or Mann Whitney test. RESULTS: Azoospermia was present in n = 16/50 (32.0%) patients at time of follow-up. ED occurred in n = 9/43 (20.9%) patients and was observed more frequently in patients with oligo- or azoospermia than in those with normospermia, even though this association was not statistically significant. Sperm parameters (total sperm count, sperm concentration, progressive motility) did not differ between time of cryopreservation and time of follow-up. Mean total, somatic, psychological, and sexual AMS score was 23.6, 9.9, 6.6, and 6.8, respectively. Mean total IIEF-EF score was 27.3, indicating mainly mild ED. CONCLUSIONS: More than one-third of cancer patients suffered from azoospermia, and ED was primarily present in this subgroup. We recommend implementing the screening of sexual dysfunction in the annual sperm testing that should be offered to all men after gonadotoxic treatment. Our study highlights the importance of counseling young cancer patients on both aspects-future infertility and sexual function-prior to treatment and at follow-up visits.

Recurrent Spontaneous Miscarriage: a Comparison of International Guidelines.

While roughly 30% of all women experience a spontaneous miscarriage in their lifetime, the incidence of recurrent (habitual) spontaneous miscarriage is 1 - 3% depending on the employed definition. The established risk factors include endocrine, anatomical, infection-related, genetic, haemostasis-related and immunological factors. Diagnosis is made more difficult by the sometimes diverging recommendations of the respective international specialist societies. The present study is therefore intended to provide a comparison of existing international guidelines and recommendations. The guidelines of the ESHRE, ASRM, the DGGG/OEGGG/SGGG and the recommendations of the RCOG were analysed. It was shown that investigation is indicated after 2 clinical pregnancies and the diagnosis should be made using a standardised timetable that includes the most frequent causes of spontaneous miscarriage. The guidelines concur that anatomical malformations, antiphospholipid syndrome and thyroid dysfunction should be excluded. Moreover, the guidelines recommend carrying out pre-conception chromosomal analysis of both partners (or of the aborted material). Other risk factors have not been included in the recommendations by all specialist societies, on the one hand because of a lack of diagnostic criteria (luteal phase insufficiency) and on the other hand because of the different age of the guidelines (chronic endometritis). In addition, various economic and consensus aspects in producing the guidelines influence the individual recommendations. An understanding of the underlying decision-making process should lead in practice to the best individual diagnosis and resulting treatment being offered to each couple.

Sperm banking before gonadotoxic treatment: is it worth the effort?

We aimed to compare the sperm quality in different cancer types and benign diseases before gonadotoxic treatment, and assess the usage rate of cryopreserved sperm for assisted reproductive treatment (ART). This retrospective study was conducted at two university clinics between January 2008 and July 2018. A total of 545 patients suffering from cancer or benign diseases were included in the study. The pretreatment sperm analyses were based on the World Health Organization (WHO) guidelines. Patients with testicular malignancy (TM) showed a significantly lower sperm count (median [interquartile range]: 18.7 × 106 [5.3 × 106-43.0 × 106] ml-1; P = 0.03) as well as total sperm count (42.4 × 106 [13.3 × 106-108.5 × 106] per ejaculate; P = 0.007) compared to other malignant and benign diseases. In addition, patients with nonseminomatous TM showed the lowest sperm count (14.3 × 106 [6.0 × 106-29.9 × 106] ml-1, vs seminomas: 16.5 × 106 [4.6 × 106-20.3 × 106] ml-1; P = 0.001). With reference to the WHO 2010 guidelines, approximately 48.0% of the patients with TM and 23.0% with hematological malignancies (HM) had oligozoospermia. During the observation period, only 29 patients (5.3%) used their frozen sperms for 48 ART cycles, resulting in 15 clinical pregnancies and 10 live births. The sperm quality varies with the type of underlying disease, with TM and HM patients showing the lowest sperm counts. Due to the observed low usage rate of cryopreserved sperm, further patient interviews and sperm analyses should be included in the routine oncologic protocols to avoid unnecessary storage expenses. However, sperm banking is worth the effort as it provides hope for men who cannot reproduce naturally after gonadotoxic treatment.

Immunological Risk Factors in Recurrent Pregnancy Loss: Guidelines Versus Current State of the Art.

Around 1-5% of all couples experience recurrent pregnancy loss (RPL). Established risk factors include anatomical, genetic, endocrine, and hemostatic alterations. With around 50% of idiopathic cases, immunological risk factors are getting into the scientific focus, however international guidelines hardly take them into account. Within this review, the current state of immunological risk factors in RPL in international guidelines of the European Society of Reproduction and Embryology (ESHRE), American Society of Reproductive Medicine (ASRM), German/Austrian/Swiss Society of Obstetrics and Gynecology (DGGG/OEGGG/SGGG) and the Royal College of Obstetricians and Gynecologists (RCOG) are evaluated. Special attention was drawn to recommendations in the guidelines regarding diagnostic factors such as autoantibodies, natural killer cells, regulatory T cells, dendritic cells, plasma cells, and human leukocyte antigen system (HLA)-sharing as well as treatment options such as corticosteroids, intralipids, intravenous immunoglobulins, aspirin and heparin in RPL. Finally, the current state of the art focusing on both diagnostic and therapeutic options was summarized.

Different Background: Natural Killer Cell Profiles in Secondary versus Primary Recurrent Pregnancy Loss.

(1) Background: Prior studies suggested a significant impact of previous live births on peripheral natural killer cells (pNK) in patients with recurrent pregnancy loss (RPL). Patients with primary RPL (pRPL, no live birth) showed higher numbers of pNK than secondary RPL patients (sRPL, ≥ 1 live birth). (2) Methods: To further determine immunological differences between RPL patients and controls, we analysed pNK subpopulations and activation markers in pRPL (n = 47), sRPL (n = 24) and controls with previous live birth (sCtrl, n = 25) and nullipara (pCtrl, n = 60) within a prospective study. Percentages and numbers of CD56dimCD16bright cells, subpopulations and activation markers (CD57+, CD62L+, NKG2D+, NKp46+) were measured in non-pregnant RPL patients and n = 85 controls (n = 60 pCtrl, n = 25 sCtrl) in the mid-luteal phase by flow cytometry. (3) Results: Compared to sRPL patients, sCtrls showed higher CD56+ and CD56dimCD16bright numbers. Further, sRPL patients showed lower numbers of CD56dimCD16brightNKG2D+ and CD56dimCD16brightNKp46+ than sCtrls. (4) Conclusion: We suggest a chronic immune stimulation leading to a lower NK-cell count in sRPL patients with a lower NK cytotoxicity. This underlines the necessity to investigate pNK subpopulations as well as pRPL and sRPL separately to delineate the immune alterations in RPL.

Recurrent miscarriage is not associated with a higher prevalence of inherited and acquired thrombophilia.

PROBLEM: Although not being recommended in guidelines, many physicians perform routine screening for thrombophilia in RM patients suspecting a higher prevalence in these patients. The aim of this study was to analyze the prevalence of inherited and acquired thrombophilia in a large cohort of RM patients. METHOD OF STUDY: Within a multicenter case-control study, n = 820 RM patients and n = 141 controls were included. The prevalence of inherited and acquired thrombophilia including deficiency of protein C/S and antithrombin, elevation of factor VIII activity, APC resistance including mutation in the factor V Leiden gene, mutation in the prothrombin gene and antiphospholipid antibodies were assessed. Further, we performed a meta-analysis of the prevalence of thrombophilia in RM patients including studies between 01/2000 and 01/2020. RESULTS: An antiphospholipid syndrome (APLS) was only present in RM patients. Increased factor VIII concentration was significantly more prevalent in controls (RM vs controls: 5.8% vs 11.0%). None of the other thrombophilia did differ significantly between RM patients and controls. The meta-analysis revealed no significant difference in the occurrence of these thrombophilia between RM patients and controls. CONCLUSION: The prevalence of inherited thrombophilia does not differ between RM patients and controls. When analyzing rare events like thrombophilia, a high number of patients are needed to obtain reliable results, which might explain contradictory findings in previous studies analyzing small cohorts of RM patients. Despite being less prevalent than previously described, we still recommend screening for APLS as it is associated with severe pregnancy complications.

Two of a kind? Immunological and clinical risk factors differ between recurrent implantation failure and recurrent miscarriage.

Recurrent miscarriage (RM) and recurrent implantation failure (RIF) are unsolved challenges in reproductive medicine. Whether RIF patients share the same risk factors as RM patients is a matter of debate. Besides clinical factors, immune alterations are discussed in both conditions. The scope of this study was to compare the prevalence of clinical and immunological risk factors in a large cohort of RM and RIF patients. Between 11/2011 and 02/2019, 613 RM and 185 RIF patients were included. A screening for anatomical malformations, endocrine, autoimmune, prothrombotic and parental chromosomal disorders was performed. The immune status was assessed using flow cytometry analysis of peripheral lymphocyte subpopulations and uterine natural killer cells (uNK cells) using immunohistochemistry. RM patients showed a higher rate of intrauterine adhesions and elevated antinuclear antibodies ≥ 1:160 (p < 0.05). A higher prevalence of submucous fibroids and increased factor VIII levels were observed in RIF patients (p < 0.05). The prevalence of an antiphospholipid syndrome (APLS) was low and did not differ between the two groups. RIF patients had higher numbers of peripheral regulatory T-cells (p < 0.05). Significant more RIF patients were diagnosed with elevated uNK cells (p < 0.05). Differences in clinical and immunological risk factors of RM and RIF patients reflect different entities. Lower Tregs in RM and higher uNK cells in RIF patients might be related to the previous exposure of the immune system to fetal cells. The low prevalence of an APLS indicates a potential overestimation of this factor in the pathophysiology of RM and RIF.

Diagnosis and Therapy Before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015-085, February 2019) - Part 1, Basic Assessment of the Woman.

Introduction Supporting and counselling couples with fertility issues prior to starting ART is a multidisciplinary diagnostic and therapeutic challenge. The first German/Austrian/Swiss interdisciplinary S2k guideline on "Diagnosis and Therapy Before Assisted Reproductive Treatments (ART)" was published in February 2019. This guideline was developed in the context of the guidelines program of the German Society of Gynecology and Obstetrics (DGGG) in cooperation with the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). Aims One third of the causes of involuntary childlessness are still unclear, even if the woman or man have numerous possible risk factors. Because the topic is still very much taboo, couples may be socially isolated and often only present quite late to a fertility center. At present, there is no standard treatment concept, as currently no standard multidisciplinary procedures exist for the diagnostic workup and treatment of infertility. The aim of this guideline is to provide physicians with evidence-based recommendations for counselling, diagnostic workup and treatment. Methods This S2k guideline was developed on behalf of the Guidelines Commission of the DGGG by representative members from different professional medical organizations and societies using a structured consensus process. Recommendations The first part of this guideline focuses on the basic assessment of affected women, including standard anatomical and endocrinological diagnostic procedures and examinations into any potential infections. Other areas addressed in this guideline are the immunological workup with an evaluation of the patient's vaccination status, an evaluation of psychological factors, and the collection of data relating to other relevant factors affecting infertility. The second part will focus on explanations of diagnostic procedures compiled in collaboration with specialists from other medical specialties such as andrologists, human geneticists and oncologists.

Diagnosis and Treatment Before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015-085, February 2019) - Part 2, Hemostaseology, Andrology, Genetics and History of Malignant Disease.

Introduction Supporting and counselling couples with fertility issues prior to starting ART is a multidisciplinary diagnostic and therapeutic challenge. The first German-language interdisciplinary S2k guideline on "Diagnosis and Therapy Before Assisted Reproductive Treatments (ART)" was published in February 2019. The guideline was developed in the context of the guidelines program of the German Society of Gynecology and Obstetrics (DGGG) in cooperation with the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). Aim In one third of cases, the cause of involuntary childlessness remains unclear, even if the woman or man have numerous possible risk factors. Because the topic is still very much taboo, couples may be socially isolated and often only present quite late to a fertility center. There is no standard treatment concept for these patients at present, as there are currently no standard multidisciplinary procedures for the diagnostic workup and treatment of infertility. The aim of this guideline is to provide physicians with evidence-based recommendations for counselling, diagnosis and treatment. Methods This S2k guideline was developed on behalf of the Guidelines Commission of the DGGG by representative members from different professional medical organizations and societies using a structured consensus process. Recommendations This second part of the guideline describes the hematological workup for women as well as additional diagnostic procedures which can be used to investigate couples and which are carried out in cooperation with physicians working in other medical fields such as andrologists, geneticists and oncologists.

Uterine natural killer cells in patients with idiopathic recurrent miscarriage.

PROBLEM: Uterine natural killer (uNK) cells are major players during implantation and early pregnancy. The aim of our study was to analyze uNK cell concentration in the endometrium of idiopathic recurrent miscarriage (iRM) patients and fertile controls. METHOD OF STUDY: Out of n=130 couples with ≥3 consecutive, clinical RM screened according to a standardized diagnostic protocol, n=58 patients with iRM were identified. Endometrial biopsies were investigated in patients and n=17 fertile women (controls) via immunohistochemistry. RESULTS: Compared to controls, the concentration of uNK cells was significantly higher in iRM patients (257±212 vs. 148±73 uNK cells/mm², P=.04). IRM patients showed a higher prevalence of >300 uNK cells/mm² than controls (34.5% vs. 5.9%, P=.02). In 88% of controls and 62% of iRM patients, uNK cells were detected within the range of 40-300/mm². CONCLUSION: Idiopathic recurrent miscarriage patients showed higher uNK cell levels than controls supporting the possible impact of uNK cells in the pathophysiology of miscarriage. Our cutoff levels might help to select RM patients which may benefit from immunomodulatory treatment.