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Background: Practice variation in recurrent pregnancy loss (RPL) care is common. International guidelines vary in their recommendations for the management of RPL couples, which could lead to an increase of cross border reproductive care. Currently, the Dutch RPL guideline is being adapted from the European Society for Human Reproduction and Embryology (ESHRE) guideline. We aim to identify discrepancies between RPL guidelines and RPL practice. These discrepancies could be considered in the development of a new guideline and implementation strategies to promote adherence to new recommendations., Methods: A nationwide survey on the management of RPL patients was conducted across all 107 hospital-based obstetrics and gynaecology practices in the Netherlands. The survey was sent via the Dutch Society for Obstetricians and Gynaecologists to all affiliated clinicians. The questionnaire consisted of 36 questions divided in four sections: clinician's demographics, RPL definition, investigations and therapy. The data were compared to the recommendations given by the Dutch national guideline and the most recent guideline of the ESHRE., Results: All hospital-based practices (100%; n = 107) filled in the online questionnaire. The majority of respondents defined RPL similarly, as two or more pregnancy losses (87.4%), not obligatory consecutive (93.1%). More than half of respondents routinely perform thrombophilia screening ( 58%), although not advised by the ESHRE, while thyroid function (57%), thyroid auto-immunity (27%) and β2-glycoprotein antibodies (42%) in the context of antiphospholipid syndrome (APS) are recommended but investigated less often. Regarding parental karyotyping, 20% of respondents stated they always perform parental karyotyping, without prior risk assessment. because of RPL. Treatment for hereditary thrombophilia was frequently (43.8% (n = 137)) prescribed although not recommended. And finally, a considerable part (12-16%) of respondents prescribe medication in case of unexplained RPL., Conclusion: While many clinicians perform investigations recommended by the ESHRE, there is a considerable variation of RPL practice in the Netherlands. We identified discrepancies between RPL guidelines and RPL practice, providing possibilities to focus on multifaceted implementation strategies, such as educational intervention, local consensus processes and auditing and feedback. This will improve the quality of care provided to RPL patients and may diminish the necessity felt by patients to turn to multiple opinions or cross border reproductive care., (© 2023. The Author(s).)

Background: Seminal plasma contains signaling molecules capable of modulating the maternal immune environment to support implantation and pregnancy. Prior studies indicated that seminal plasma induces changes in gene transcription of maternal immune cells. Reduced immune suppressive capacity may lead to pregnancy loss. The aim of this study was to investigate the immunomodulating effects of seminal plasma on T cells and monocytes in the context of recurrent pregnancy loss (RPL)., Methods: Female T cells and monocytes were incubated with seminal plasma of 20 males in unexplained RPL couples (RPL males) and of 11 males whose partners had ongoing pregnancies (control males). The effect of seminal plasma on messenger RNA (mRNA) expression of immune cells was measured. Levels of mRNA expression were related to key signaling molecules present in the seminal plasma. Agglomerative hierarchical cluster analysis was performed on seminal plasma expression profiles and on mRNA expression profiles., Results: Expression of CD25 and anti-inflammatory IL-10 by female T cells was significantly lower after stimulation with seminal plasma of RPL males compared to control males. Female monocytes treated with seminal plasma of RPL males showed an immune activation signature of relatively elevated HLA-DR expression. Expression of these T cell and monocyte components was particularly correlated with the amounts of TGF-β and VEGF in the seminal plasma., Conclusion: Our findings indicate that seminal plasma has immunomodulating properties on female immune cells compatible with the induction of a more regulatory phenotype, which may be impaired in cases of unexplained RPL., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Study Question: What is the predictive performance of a currently recommended prediction model in an external Dutch cohort of couples with unexplained recurrent pregnancy loss (RPL)?, Summary Answer: The model shows poor predictive performance on a new population; it overestimates, predicts too extremely and has a poor discriminative ability., What Is Known Already: In 50-75% of couples with RPL, no risk factor or cause can be determined and RPL remains unexplained. Clinical management in RPL is primarily focused on providing supportive care, in which counselling on prognosis is a main pillar. A frequently used prediction model for unexplained RPL, developed by Brigham et al. in 1999, estimates the chance of a successful pregnancy based on number of previous pregnancy losses and maternal age. This prediction model has never been externally validated., Study Design, Size, Duration: This retrospective cohort study consisted of 739 couples with unexplained RPL who visited the RPL clinic of the Leiden University Medical Centre between 2004 and 2019., Participants/materials, Setting, Methods: Unexplained RPL was defined as the loss of two or more pregnancies before 24 weeks, without the presence of an identifiable cause for the pregnancy losses, according to the ESHRE guideline. Obstetrical history and maternal age were noted at intake at the RPL clinic. The outcome of the first pregnancy after intake was documented. The performance of Brigham's model was evaluated through calibration and discrimination, in which the predicted pregnancy rates were compared to the observed pregnancy rates., Main Results and the Role of Chance: The cohort included 739 women with a mean age of 33.1 years (±4.7 years) and with a median of three pregnancy losses at intake (range 2-10). The mean predicted pregnancy success rate was 9.8 percentage points higher in the Brigham model than the observed pregnancy success rate in the dataset (73.9% vs 64.0% (95% CI for the 9.8% difference 6.3-13.3%)). Calibration showed overestimation of the model and too extreme predictions, with a negative calibration intercept of -0.46 (95% CI -0.62 to -0.31) and a calibration slope of 0.42 (95% CI 0.11-0.73). The discriminative ability of the model was very low with a concordance statistic of 0.55 (95% CI 0.51-0.59). Recalibration of the Brigham model hardly improved the c-statistic (0.57; 95% CI 0.53-0.62)., Limitations, Reasons for Caution: This is a retrospective study in which only the first pregnancy after intake was registered. There was no time frame as inclusion criterium, which is of importance in the counselling of couples with unexplained RPL. Only cases with a known pregnancy outcome were included., Wider Implications of the Findings: This is the first study externally validating the Brigham prognostic model that estimates the chance of a successful pregnancy in couples with unexplained RPL. The results show that the frequently used model overestimates the chances of a successful pregnancy, that predictions are too extreme on both the high and low ends and that they are not much more discriminative than random luck. There is a need for revising the prediction model to estimate the chance of a successful pregnancy in couples with unexplained RPL more accurately., Study Funding/competing Interest(s): No external funding was used and no competing interests were declared., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: International guidelines recommend to offer supportive care during a next pregnancy to couples affected by recurrent pregnancy loss (RPL). In previous research, several options for supportive care have been identified and women's preferences have been quantified. Although it is known that RPL impacts the mental health of both partners, male preferences for supportive care have hardly been explored., Methods: A cross-sectional study was conducted in couples who visited a specialized RPL clinic in the Netherlands between November 2018 and December 2019. Both members of the couples received a questionnaire that quantified their preferences for supportive care in a next pregnancy and they were asked to complete this independently from each other. Preferences for each supportive care option were analysed on a group level (by gender) and on a couple level, by comparing preferences of both partners., Results: Ninety-two questionnaires (completed by 46 couples) were analysed. The overall need for supportive care indicated on a scale from 1 to 10 was 6.8 for men and 7.9 for women (P = 0.002). Both genders preferred to regularly see the same doctor with knowledge of their obstetric history, to make a plan for the first trimester and to have frequent ultrasound examinations. A lower proportion of men preferred a doctor that shows understanding (80% of men vs. 100% of women, P = 0.004) and a doctor that informs on wellbeing (72% vs. 100%, P = ≤0.000). Fewer men preferred support from friends (48% vs. 74%, P = 0.017). Thirty-seven percent of men requested more involvement of the male partner at the outpatient clinic, compared to 70% of women (P = 0.007). In 28% of couples, partners had opposing preferences regarding peer support., Conclusions: While both women and men affected by RPL are in need of supportive care, their preferences may differ. Current supportive care services may not entirely address the needs of men. Health care professionals should focus on both partners and development of novel supportive care programs with specific attention for men should be considered., (© 2021. The Author(s).)

Background: Seminal plasma contains a wide range of cytokines, chemokines and growth factors. Part of these signalling molecules assist in inducing a state of active maternal immune tolerance towards the fetus. Disbalances in seminal plasma content may contribute to pregnancy loss. This study investigated cytokine expression profiles in seminal plasma of male partners of couples with unexplained recurrent pregnancy loss (RPL) and the association with clinical and lifestyle characteristics, including smoking, alcohol consumption and body mass index (BMI)., Methods: In the seminal plasma of 52 men who visited a specialised RPL clinic the levels of 25 pre-selected cytokines, chemokines and growth factors were measured by Bio-Plex assay or ELISA. Two-way hierarchical cluster analysis was performed. Identified patient clusters were compared on clinical and lifestyle characteristics., Results: Two distinct cytokine expression profiles in the seminal plasma were revealed by cluster analysis. Patient cluster I showed relatively higher levels of pro-inflammatory cytokines, including IL-1α, IL-1β, IL-6, IL-8, IL-12, IL-18 and TNF-α, compared to Patient cluster II. Men belonging to Patient cluster I were significantly older and had significantly more lifestyle risk factors compared to men in Patient cluster II., Conclusion: Cluster analysis suggested the existence of a less favourable pro-inflammatory cytokine expression profile, being present in part of men affected by RPL and associated with advanced male age and lifestyle risk factors. These findings may serve as a starting point for further research into underlying mechanisms and ultimately lead to novel diagnostic and therapeutic approaches for couples with RPL., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

This commentary reflects on the effectiveness of progesterone in early pregnancy complications. Several studies have investigated the role of progesterone in women with bleeding in early pregnancy and in women with recurrent miscarriages. These publications suggests that first trimester use of progesterone is not effective to prevent miscarriages when there is blood loss in the first trimester, and that it is also not effective to prevent new miscarriages in women with recurrent miscarriages in their history. However, subgroup analysis tells us it might be effective to prevent new miscarriages in women with blood loss in the first trimester and three earlier miscarriages. Expert groups in the Netherlands are currently considering recommendations on the prescription of progesterone for women with early pregnancy complications.