This thesis has shed light on RPL practice and the management of RPL couples in need of counselling towards future pregnancies. Both clinical practice research and prediction research indicate that... Show moreThis thesis has shed light on RPL practice and the management of RPL couples in need of counselling towards future pregnancies. Both clinical practice research and prediction research indicate that there is room for improvements in RPL practice and RPL counselling. We studied quality of care by diving into clinical practice variation and quality of counselling by diving into prediction research.In the absence of effective treatment options that increase live birth rates in RPL couples, counselling towards future pregnancies plays a key role and enables couples to make an informed decision regarding further pregnancy attempts. This will still be present when future treatment options are investigated or discovered, as these models could then evaluate the effects of these treatments on performance of the model. It is therefore of utmost importance that prediction models are well developed and validated for use in clinical practice.In an era of technological advancement bringing societies, researchers and clinicians from all over the world more closely together, it is time to step up and work together, to unify RPL care and to create collaborations that hugely impact RPL research which can lead to high impact publications that can unravel the mysteries of RPL. Show less
Recurrent pregnancy loss (RPL) is a poorly understood condition that comes with many uncertainties, both for affected couples and healthcare providers. Important goals are to provide answers to... Show moreRecurrent pregnancy loss (RPL) is a poorly understood condition that comes with many uncertainties, both for affected couples and healthcare providers. Important goals are to provide answers to these couples and to improve their pregnancy outcomes. To achieve this, we need a better understanding of contributing and predictive factors. Until now, the male role in RPL has been underexposed. In this thesis, we aimed to expand our knowledge regarding the ‘forgotten father’ in RPL. We have found strong clues that in RPL, male contribution really matters.The main conclusions are that advanced paternal age and paternal smoking are associated with an increased risk of pregnancy loss, that inclusion of paternal factors into a prediction model improves the accuracy of predicting ongoing pregnancy after RPL, and that impaired immunomodulatory effects of seminal plasma may play a role in RPL. At the same time, our studies have led to new questions and uncovered new challenges, which are excellent opportunities for further research. Show less
Fosse, N.A. du; Lashley, E.E.L.O.; Anholts, J.D.H.; Beelen, E. van; Cessie, S. le; Lith, J.M.M. van; ... ; Hoorn, M.L.P. van der 2022
Background: Seminal plasma contains signaling molecules capable of modulating the maternal immune environment to support implantation and pregnancy. Prior studies indicated that seminal plasma... Show moreBackground: 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-beta 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. Show less
This special issue of Reproductive Sciences is focusing on ethnic health disparity and its impact on (fe)male reproduction. Indeed, studies regarding underlying mechanisms, interventions and... Show moreThis special issue of Reproductive Sciences is focusing on ethnic health disparity and its impact on (fe)male reproduction. Indeed, studies regarding underlying mechanisms, interventions and prognosis in reproduction are underexposed for the non-White male and female. Here, we call for documentation of race and ethnicity in the analysis and management of couples with recurrent pregnancy loss. Show less
Fosse, N.A. du; Hoorn, M.L.P. van der; Koning, R. de; Mulders, A.G.M.G.J.; Lith, J.M.M. van; Cessie, S. le; Lashley, E.E.L.O. 2022
Objective: To identify, besides maternal age and the number of previous pregnancy losses, additional characteristics of couples with unexplained recurrent pregnancy loss (RPL) that improve the... Show moreObjective: To identify, besides maternal age and the number of previous pregnancy losses, additional characteristics of couples with unexplained recurrent pregnancy loss (RPL) that improve the prediction of an ongoing pregnancy.Design: Hospital-based cohort study in couples who visited specialized RPL units of two academic centers between 2012 and 2020.Setting: Two academic centers in the Netherlands.Patients: Clinical data from 526 couples with unexplained RPL were used in this study.Intervention(s): None.Main Outcome Measures: The final model to estimate the chance of a subsequent ongoing pregnancy was determined using a backward selection process and internally validated using bootstrapping. Model performance was assessed in terms of calibration and discrimination (area under the receiver operating characteristic curve).Results: Subsequent ongoing pregnancy was achieved in 345 of 526 couples (66%). The number of previous pregnancy losses, maternal age, paternal age, maternal body mass index, paternal body mass index, maternal smoking status, and previous in vitro fertilization/intracytoplasmic sperm injection treatment were predictive of the outcome. The optimism-corrected area under the receiver operating characteristic curve was 0.63 compared with 0.57 when using only the number of previous pregnancy losses and maternal age.Conclusions: The identification of additional predictors of a subsequent ongoing pregnancy after RPL, including male characteristics, is significant for both clinicians and couples with RPL. At the same time, we showed that the predictive ability of the current model is still limited and more research is warranted to develop a model that can be used in clinical practice. (C) 2021 by American Society for Reproductive Medicine. Show less
Fosse, N.A. du; Lashley, E.E.L.O.; Treurniet, T.T.; Lith, J.M.M. van; Cessie, S. le; Boosman, H.; Hoorn, M.L.P. van der 2021
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... Show moreBackground 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. Show less
Fosse, N.A. du; Lashley, E.E.L.O.; Beelen, E. van; Meuleman, T.; Cessie, S. le; Lith, J.M.M. van; ... ; Hoorn, M.L.P. van der 2021
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... Show moreBackground: 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-1 alpha, IL-1 beta, IL-6, IL-8, IL-12, IL-18 and TNF-alpha, 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. Show less
Youssef, A.; Lashley, L.; Dieben, S.; Verburg, H.; Hoorn, M.L. van der 2020
Research question: The definition of recurrent pregnancy loss (RPL) differs internationally. The European Society of Human Reproduction and Embryology (ESHRE) defines RPL as two or more pregnancy... Show moreResearch question: The definition of recurrent pregnancy loss (RPL) differs internationally. The European Society of Human Reproduction and Embryology (ESHRE) defines RPL as two or more pregnancy losses. Different definitions lead, however, to different approaches to care for couples with RPL. This study aimed to determine whether the distribution of RPL-associated factors was different in couples with two versus three or more pregnancy losses. If a similar distribution were found, couples with two pregnancy losses should be eligible for the same care pathway as couples with three pregnancy losses.Design: This single-centre, retrospective cohort study investigated 383 couples included from 2012 to 2016 at the Leiden University Medical Center RPL clinic. Details on age, body mass index, smoking status, number of pregnancy losses, mean time to pregnancy loss and performed investigations were collected. The prevalence of uterine anomalies, antiphospholipid syndrome, hereditary thrombophilia, hyperhomocysteinaemia, chromosomal abnormalities and positive thyroid peroxidase antibodies were compared in couples with two versus three or more pregnancy losses.Results: No associated factor was found in 71.5% of couples with RPL. This did not differ statistically between couples with two versus three or more pregnancy losses (73.6% versus 70.6%; P = 0.569). The distribution of investigated causes did not differ between the two groups.Conclusions: As the distribution of associated factors in couples with two versus three or more pregnancy losses is equal, couples with two pregnancy losses should be eligible for the same care pathway as couples with three. This study supports ESH RE's suggestion of including two pregnancy losses in the definition of RPL. Show less
Youssef, A.; Vermeulen, N.; Lashley, E.E.L.O.; Goddijn, M.; Hoorn, M.L.P. van der 2019
Investigations and treatment options of recurrent pregnancy loss (RPL) differ internationally. This manuscript reviews the similarities and differences between international guidelines. The... Show moreInvestigations and treatment options of recurrent pregnancy loss (RPL) differ internationally. This manuscript reviews the similarities and differences between international guidelines. The European Society of Human Reproduction and Embryology (ESHRE) guideline (2017), the American Society for Reproductive Medicine (ASRM) Committee Opinion (2013) and the Royal College of Obstetricians and Gynaecologists (RCOG) guideline (2011) were appraised using the AGREE II criteria. The guidelines were checked for definitions, risk factors, investigations and therapeutic options. The guidelines agreed on acquired thrombophilia analysis. All guidelines agreed on a regimen for the treatment of antiphospholipid antibody syndrome consisting of aspirin and heparin, but only the ESHRE guideline specified the order of starting these medications. Treatment of thrombophilia and uterine anomalies was advised against; all guidelines recommended supportive care for unexplained RPL. The guidelines did not agree on the definition of RPL and differed in investigations regarding lifestyle, karyotype analysis of parents and/or pregnancy tissue, and the diagnostic tool for uterine anomalies. All three guidelines indicate an association between lifestyle and RPL; the ESHRE recommends health behaviour changes. Couples suffering from RPL should be informed about possible investigations and treatment options, and whether those are evidence-based. It is important for clinicians to realize that the guidelines differ internationally. Show less
