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STUDY QUESTION What are the current national medically assisted reproduction (MAR) data collection systems across EU Member States, and how can these countries contribute to a unique, cycle-by-cycle registry for the European Monitoring of Medically Assisted Reproduction (EuMAR) project? SUMMARY ANSWER The study identified significant variation in MAR data collection practices across Member States, with differences in data types, collection methods, and reporting requirements; the EuMAR project emerges as an opportunity to enhance data standardization and improve MAR data collection in the EU. WHAT IS KNOWN ALREADY There is a need for new approaches in MAR data collection that include long-term and cross border follow-up. The EuMAR project intends to establish a unified, cycle-by-cycle registry of data on MAR treatments in EU countries, from which accurate cumulative outcomes can be calculated. STUDY DESIGN, SIZE, DURATION This cross-sectional study involved a survey and interviews with stakeholders from 26 EU Member States conducted in 2023 over a period of seven months. PARTICIPANTS/MATERIALS, SETTING, METHODS Representatives from national competent authorities and professional associations involved in MAR data collection in EU countries were invited to complete the survey and interviewed to assess current data flows, information requirements, and their interest in the EuMAR project. MAIN RESULTS AND THE ROLE OF CHANCE Half of the participating countries reported having a national MAR registry with cycle-by-cycle data (n = 13), while 31% reported having a national registry with aggregated data (n = 8) and 19% reported having no national registry (n = 5). Of the countries with a national cycle-by-cycle registry, eight countries collect identifiable data, five countries collect pseudonymized data, and one country collects fully anonymized data. Informed consent is required in 10 countries. The main advantages that participants expected from a European registry like EuMAR were the possibility of obtaining national statistics in the absence of a national registry and improving the calculation of cumulative outcomes. LIMITATIONS, REASONS FOR CAUTION The results of the study are based on self-reported data, which may be subject to bias, however, the validity of the collected information was verified with different means, including follow-up calls for clarifications and sharing final transcript reports. The feasibility of the proposed data flow models will be tested in a pilot study. WIDER IMPLICATIONS OF THE FINDINGS Despite the heterogeneity of data collection practices across EU countries, the results show that stakeholders have high expectations of the benefits that the EuMAR registry can bring, namely the improvement of data consistency, cross-border comparability, and cumulative live birth rates, leading to better information for patients, health care providers and policy makers. STUDY FUNDING/COMPETING INTEREST(S) The EuMAR project was co-founded by ESHRE and the European Commission (101079865—EuMAR–EU4H-2021-PJ2). No competing interests were declared. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does medically assisted reproduction (MAR) use among cisgender women differ among those with same-sex partners or lesbian/bisexual identities compared to peers with different-sex partners or heterosexual identities? SUMMARY ANSWER Women with same-sex partners or lesbian/bisexual identities are more likely to utilize any MAR but are no more likely to use ART (i.e. IVF, reciprocal IVF, embryo transfer, unspecified ART, ICSI, and gamete or zygote intrafallopian transfer) compared to non-ART MAR (i.e. IUI, ovulation induction, and intravaginal or intracervical insemination) than their different-sex partnered and completely heterosexual peers. WHAT IS KNOWN ALREADY Sexual minority women (SMW) form families in myriad ways, including through fostering, adoption, genetic, and/or biological routes. Emerging evidence suggests this population increasingly wants to form genetic and/or biological families, yet little is known about their family formation processes and conception needs. STUDY DESIGN, SIZE, DURATION The Growing Up Today Study is a US-based prospective cohort (n = 27 805). Participants were 9–17 years of age at enrollment (1996 and 2004). Biennial follow-up is ongoing, with data collected through 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS Cisgender women who met the following criteria were included in this sample: endorsed ever being pregnant; attempted a pregnancy in 2019 or 2021; and endorsed either a male- or female-sex partner OR responded to questions regarding their sexual identity during their conception window. The main outcome was any MAR use including ART (i.e. procedures involving micromanipulation of gametes) and non-ART MAR (i.e. nonmanipulation of gametes). Secondary outcomes included specific MAR procedures, time to conception, and trends across time. We assessed differences in any MAR use using weighted modified Poisson generalized estimating equations. MAIN RESULTS AND THE ROLE OF CHANCE Among 3519 participants, there were 6935 pregnancies/pregnancy attempts and 19.4% involved MAR. A total of 47 pregnancies or pregnancy attempts were among the same-sex partnered participants, while 91 were among bisexual participants and 37 among lesbian participants. Participants with same-sex, compared to different-sex partners were almost five times as likely to use MAR (risk ratio [95% CI]: 4.78 [4.06, 5.61]). Compared to completely heterosexual participants, there was greater MAR use among lesbian (4.00 [3.10, 5.16]) and bisexual (2.22 [1.60, 3.07]) participants compared to no MAR use; mostly heterosexual participants were also more likely to use ART (1.42 [1.11, 1.82]) compared to non-ART MAR. Among first pregnancies conceived using MAR, conception pathways differed by partnership and sexual identity groups; differences were largest for IUI, intravaginal insemination, and timed intercourse with ovulation induction. From 2002 to 2021, MAR use increased proportionally to total pregnancies/pregnancy attempts; ART use was increasingly common in later years among same-sex partnered and lesbian participants. LIMITATIONS, REASONS FOR CAUTION Our results are limited by the small number of SMW, the homogenous sample of mostly White, educated participants, the potential misclassification of MAR use when creating conception pathways unique to SMW, and the questionnaire's skip logic, which excluded certain participants from receiving MAR questions. WIDER IMPLICATIONS OF THE FINDINGS Previous studies on SMW family formation have primarily focused on clinical outcomes from ART procedures and perinatal outcomes by conception method, and have been almost exclusively limited to European, clinical samples that relied on partnership data only. Despite the small sample of SMW within a nonrepresentative study, this is the first study to our knowledge to use a nonclinical sample of cisgender women from across the USA to elucidate family formation pathways by partnership as well as sexual identity, including pathways that may be unique to SMW. This was made possible by our innovative approach to MAR categorization within a large, prospective dataset that collected detailed sexual orientation data. Specifically, lesbian, bisexual, and same-sex partnered participants used both ART and non-ART MAR at similar frequencies compared to heterosexual and different-sex partnered participants. This may signal differential access to conception pathways owing to structural barriers, emerging conception trends as family formation among SMW has increased, and a need for conception support beyond specialized providers and fertility clinics. STUDY FUNDING/COMPETING INTEREST(S) The research reported in this publication was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health (NIH), under award number R01MD015256. Additionally, KRSS is supported by NCI grant T32CA009001, AKH by the NCI T32CA057711, PC by the NHLBI T32HL098048, BM by the Stanford Maternal Child Health Research Institute Clinical Trainee Support Grant and the Diversity Fellowship from the American Society for Reproductive Medicine Research Institute, BGE by NICHD R01HD091405, and SM by the Thomas O. Pyle Fellowship through the Harvard Pilgrim Health Care Foundation and Harvard University, NHLBI T32HL098048, NIMH R01MH112384, and the William T. Grant Foundation grant number 187958. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The first author recently had a leadership role in the not-for-profit program, The Lesbian Health Fund, a research fund focused on improving the health and wellbeing of LGBTQ+ women and girls. The fund did not have any role in this study and the author's relationship with the fund did not bias the findings of this manuscript. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Researchers interested in causal questions must deal with two sources of error: random error (random deviation from the true mean value of a distribution), and bias (systematic deviance from the true mean value due to extraneous factors). For some causal questions, randomization is not feasible, and observational studies are necessary. Bias poses a substantial threat to the validity of observational research and can have important consequences for health policy developed from the findings. The current piece describes bias and its sources, outlines proposed methods to estimate its impacts in an observational study, and demonstrates how these methods may be used to inform debate on the causal relationship between medically assisted reproduction (MAR) and health outcomes, using cancer as an example. In doing so, we aim to enlighten researchers who work with observational data, especially regarding the health effects of MAR and infertility, on the pitfalls of bias, and how to address them. We hope that, in combination with the provided example, we can convince readers that estimating the impact of bias in causal epidemiologic research is not only important but necessary to inform the development of robust health policy and clinical practice recommendations. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Are there subgroups among patients with cryptozoospermia pointing to distinct etiologies? SUMMARY ANSWER We reveal two distinct subgroups of cryptozoospermic (Crypto) patients based on testicular tissue composition, testicular volume, and FSH levels. WHAT IS KNOWN ALREADY Cryptozoospermic patients present with a sperm concentration below 0.1 million/ml. While the etiology of the severely impaired spermatogenesis remains largely unknown, alterations of the spermatogonial compartment have been reported including a reduction of the reserve stem cells in these patients. STUDY DESIGN, SIZE, DURATION To assess whether there are distinct subgroups among cryptozoospermic patients, we applied the statistical method of cluster analysis. For this, we retrospectively selected 132 cryptozoospermic patients from a clinical database who underwent a testicular biopsy in the frame of fertility treatment at a university hospital. As controls (Control), we selected 160 patients with obstructive azoospermia and full spermatogenesis. All 292 patients underwent routine evaluation for endocrine, semen, and histological parameters (i.e. the percentage of tubules with elongated spermatids). Moreover, outcome of medically assisted reproduction (MAR) was assessed for cryptozoospermic (n = 73) and Control patients (n = 87), respectively. For in-depth immunohistochemical and histomorphometrical analyses, representative tissue samples from cryptozoospermic (n = 27) and Control patients (n = 12) were selected based on cluster analysis results and histological parameters. PARTICIPANTS/MATERIALS, SETTING, METHODS This study included two parts: firstly using clinical parameters of the entire cohort of 292 patients, we performed principal component analysis (PCA) followed by hierarchical clustering on principal components (i.e. considering hormonal values, ejaculate parameters, and histological information). Secondly, for histological analyses seminiferous tubules were categorized according to the most advanced germ cell type present in sections stained with Periodic acid Schif. On the selected cohort of 39 patients (12 Control, 27 cryptozoospermic), we performed immunohistochemistry for spermatogonial markers melanoma-associated antigen 4 (MAGEA4) and piwi like RNA-mediated gene silencing 4 (PIWIL4) followed by quantitative analyses. Moreover, the morphologically defined Adark spermatogonia, which are considered to be the reserve stem cells, were quantified. MAIN RESULTS AND THE ROLE OF CHANCE The PCA and hierarchical clustering revealed three different clusters, one of them containing all Control samples. The main factors driving the sorting of patients to the clusters were the percentage of tubules with elongated spermatids (Cluster 1, all Control patients and two cryptozoospermic patients), the percentage of tubules with spermatocytes (Cluster 2, cryptozoospermic patients), and tubules showing a Sertoli cells only phenotype (Cluster 3, cryptozoospermic patients). Importantly, the percentage of tubules containing elongated spermatids was comparable between Clusters 2 and 3. Additional differences were higher FSH levels (P  < 0.001) and lower testicular volumes (P  < 0.001) in Cluster 3 compared to Cluster 2. In the spermatogonial compartment of both cryptozoospermic Clusters, we found lower numbers of MAGEA4+ and Adark spermatogonia but higher proportions of PIWIL4+ spermatogonia, which were significantly correlated with a lower percentage of tubules containing elongated spermatids. In line with this common alteration, the outcome of MAR was comparable between Controls as well as both cryptozoospermic Clusters. LIMITATIONS, REASONS FOR CAUTION While we have uncovered the existence of subgroups within the cohort of cryptozoospermic patients, comprehensive genetic analyses remain to be performed to unravel potentially distinct etiologies. WIDER IMPLICATIONS OF THE FINDINGS The novel insight that cryptozoospermic patients can be divided into two subgroups will facilitate the strategic search for underlying genetic etiologies. Moreover, the shared alterations of the spermatogonial stem cell compartment between the two cryptozoospermic subgroups could represent a general response mechanism to the reduced output of sperm, which may be associated with a progressive phenotype. This study therefore offers novel approaches towards the understanding of the etiology underlying the reduced sperm formation in cryptozoospermic patients. STUDY FUNDING/COMPETING INTEREST(S) German research foundation CRU 326 (grants to: SDP, NN). Moreover, we thank the Faculty of Medicine of the University of Münster for the financial support of Lena Charlotte Schülke through the MedK-program. We acknowledge support from the Open Access Publication Fund of the University of Münster. The authors have no potential conflicts of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

The field of reproductive genetics has undergone significant advancements with the completion of the Human Genome Project and the development of high-throughput sequencing techniques. This has led to the identification of numerous genes involved in both male and female infertility, revolutionizing the diagnosis and management of infertility patients. Genetic investigations, including karyotyping, specific genetic tests, and high-throughput sequencing, have become essential in determining the genetic causes of infertility. Moreover, the integration of genetics into reproductive medicine has expanded the scope of care to include not only affected individuals or couples but also their family members. Genetic consultations and counselling play a crucial role in identifying potentially affected relatives and offering tailored therapy and the possibility of fertility preservation. Despite the current limited therapeutic options, an increasing understanding of genotype–phenotype correlations in infertility genes holds promise for improved treatment outcomes. The availability of genetic diagnostic tools has reduced the number of idiopathic infertility cases by providing accurate aetiological diagnoses. The transition from research to clinical practice in reproductive genetics requires the establishment of genetic consultations and data warehousing systems to provide up-to-date information on gene–disease relationships. Overall, the integration of genetics into reproductive medicine has brought about a paradigm shift, emphasizing the familial dimension of infertility and offering new possibilities for personalized care and family planning. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the recommended management for couples presenting with unexplained infertility (UI), based on the best available evidence in the literature? SUMMARY ANSWER The evidence-based guideline on UI makes 52 recommendations on the definition, diagnosis, and treatment of UI. WHAT IS KNOWN ALREADY UI is diagnosed in the absence of any abnormalities of the female and male reproductive systems after 'standard' investigations. However, a consensual standardization of the diagnostic work-up is still lacking. The management of UI is traditionally empirical. The efficacy, safety, costs, and risks of treatment options have not been subjected to robust evaluation. STUDY DESIGN, SIZE, DURATION The guideline was developed according to the structured methodology for ESHRE guidelines. Following formulation of key questions by a group of experts, literature searches, and assessments were undertaken. Papers written in English and published up to 24 October 2022 were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the available evidence, recommendations were formulated and discussed until consensus was reached within the guideline development group (GDG). Following stakeholder review of an initial draft, the final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE This guideline aims to help clinicians provide the best care for couples with UI. As UI is a diagnosis of exclusion, the guideline outlined the basic diagnostic procedures that couples should/could undergo during an infertility work-up, and explored the need for additional tests. The first-line treatment for couples with UI was deemed to be IUI in combination with ovarian stimulation. The place of additional and alternative options for treatment of UI was also evaluated. The GDG made 52 recommendations on diagnosis and treatment for couples with UI. The GDG formulated 40 evidence-based recommendations—of which 29 were formulated as strong recommendations and 11 as weak—10 good practice points and two research only recommendations. Of the evidence-based recommendations, none were supported by high-quality evidence, one by moderate-quality evidence, nine by low-quality evidence, and 31 by very low-quality evidence. To support future research in UI, a list of research recommendations was provided. LIMITATIONS, REASONS FOR CAUTION Most additional diagnostic tests and interventions in couples with UI have not been subjected to robust evaluation. For a large proportion of these tests and treatments, evidence was very limited and of very low quality. More evidence is required, and the results of future studies may result in the current recommendations being revised. WIDER IMPLICATIONS OF THE FINDINGS The guideline provides clinicians with clear advice on best practice in the care of couples with UI, based on the best evidence currently available. In addition, a list of research recommendations is provided to stimulate further studies in the field. The full guideline and a patient leaflet are available in www.eshre.eu/guideline/UI. STUDY FUNDING/COMPETING INTEREST(S) The guideline was developed by ESHRE, who funded the guideline meetings, literature searches, and dissemination of the guideline in collaboration with the Monash University led Australian NHMRC Centre of Research Excellence in Women's Health in Reproductive Life (CREWHIRL). The guideline group members did not receive any financial incentives; all work was provided voluntarily. D.R. reports honoraria from IBSA and Novo Nordisk. B.A. reports speakers' fees from Merck, Gedeon Richter, Organon and Intas Pharma; is part of the advisory board for Organon Turkey and president of the Turkish Society of Reproductive Medicine. S.B. reports speakers' fees from Merck, Organon, Ferring, the Ostetric and Gynaecological Society of Singapore and the Taiwanese Society for Reproductive Medicine; editor and contributing author, Reproductive Medicine for the MRCOG, Cambridge University Press; is part of the METAFOR and CAPE trials data monitoring committee. E.B. reports research grants from Roche diagnostics, Gedeon Richter and IBSA; speaker's fees from Merck, Ferring, MSD, Roche Diagnostics, Gedeon Richter, IBSA; E.B. is also a part of an Advisory Board of Ferring Pharmaceuticals, MSD, Roche Diagnostics, IBSA, Merck, Abbott and Gedeon Richter. M.M. reports consulting fees from Mojo Fertility Ltd. R.J.N. reports research grant from Australian National Health and Medical Research Council (NHMRC); consulting fees from Flinders Fertility Adelaide, VinMec Hospital Hanoi Vietnam; speaker's fees from Merck Australia, Cadilla Pharma India, Ferring Australia; chair clinical advisory committee Westmead Fertility and research institute MyDuc Hospital Vietnam. T.P. is a part of the Research Council of Finland and reports research grants from Roche Diagnostics, Novo Nordics and Sigrid Juselius foundation; consulting fees from Roche Diagnostics and organon; speaker's fees from Gedeon Richter, Roche, Exeltis, Organon, Ferring and Korento patient organization; is a part of NFOG, AE-PCOS society and several Finnish associations. S.S.R. reports research grants from Roche Diagnostics, Organon, Theramex; consulting fees from Ferring Pharmaceuticals, MSD and Organon; speaker's fees from Ferring Pharmaceuticals, MSD/Organon, Besins, Theramex, Gedeon Richter; travel support from Gedeon Richter; S.S.R. is part of the Data Safety Monitoring Board of TTRANSPORT and deputy of the ESHRE Special Interest Group on Safety and Quality in ART; stock or stock options from IVI Lisboa, Clínica de Reprodução assistida Lda; equipment/medical writing/gifts from Roche Diagnostics and Ferring Pharmaceuticals. S.K.S. reports speakers' fees from Merck, Ferring, MSD, Pharmasure. HRV reports consulting and travel fees from Ferring Pharmaceuticals. The other authors have nothing to disclose. DISCLAIMER This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.) [ABSTRACT FROM AUTHOR]

Recent decades have seen a global trend towards delaying parenthood, referred to as the 'postponement transition'. Whilst there is plentiful research regarding obstetric and paediatric outcomes related to delayed parenthood, relatively little is known about the psychosocial outcomes associated with advanced parental age during early and middle childhood. This mini-review examines the current literature regarding the psychosocial functioning of families headed by older parents. First, we give an overview of the literature that examines the psychological wellbeing of older first-time parents. We then review the literature regarding the quality of the parent–child relationship in older parent families. Finally, we discuss the psychosocial adjustment and cognitive development of children of older parents. We conclude with suggestions for future research avenues. [ABSTRACT FROM AUTHOR]

Study questionDoes parental fertility, measured by time to pregnancy (TTP), or use of medically assisted reproduction (MAR) affect pubertal development in the offspring?Summary answerNeither TTP nor type of MAR treatment had clinically relevant implications for mean age at achieving individual pubertal milestones or overall timing of puberty in boys and girls.What is known alreadyParental TTP and MAR have been associated with impaired semen quality in adult sons. Timing of puberty reflects earlier signals of reproductive health, but it remains unclear whether parental fertility or MAR affects pubertal development, especially in the growing generation of children conceived by IVF or ICSI.Study design, size, durationIn this study, 15 819 children born by mothers in the Danish National Birth Cohort from 2000 to 2003 participated in a nationwide puberty cohort (participation rate = 70%). Parental TTP and use of MAR were reported by mothers in early pregnancy and children's pubertal development data was self-recorded in web-based questionnaires from 11 years of age and 6 monthly throughout puberty (2012-2018).Participants/materials, setting, methodsPubertal development in children (of planned pregnancies, n = 13 285) born by untreated subfecund (TTP: 6-12 months) (n =2038), untreated severely subfeund (TTP: >12 months) (n = 1242), treated subfecund (n = 230) and treated severely subfecund (n = 1234) parents were compared to children born to more fertile parents (TTP: ≤5 months). We estimated mean monthly differences in mean age at achieving individual pubertal milestones (i.e. age at menarche, voice break, first ejaculation and Tanner stages 2, 3, 4 and 5 for breast or genital development and pubic hair growth) and a combined indicator of timing of puberty. Further, we compared mean age at achieving the individual pubertal milestones in children born by use of IVF or ICSI (n = 480) with children born by controlled ovarian stimulation or ovulation induction with or without intrauterine insemination (n = 902).Main results and the role of chanceWe found tendencies towards slightly later mean age at male pubertal timing and slightly earlier mean age at female pubertal timing among children born by untreated subfecund, treated subfecund, untreated severely subfecund and treated severely subfecund parents. There were no specific patterns with increasing TTP, use of MAR nor type of MAR treatment, and the magnitude of the mean differences for individual milestones and overall timing of puberty were small, i.e. 0.9 months (95% CI: -1.0; 2.8) for first ejaculation and -0.5 months (95% CI: -2.0; 1.0) months for age at menarche in boys and girls, respectively, born by treated severely subfecund parents when compared with children born by more fertile parents.Limitations, reasons for cautionNon-differential misclassification of the self-reported information on parental TTP and pubertal development in the offspring may serve as an alternative explanation of the findings, possibly biasing the estimates towards the null. The information on pubertal development was collected from around 11 years of age and onwards.Wider implications of the findingsThis study adds to the growing body of literature suggesting only limited harmful effects of parental subfecundity and MAR on offspring's long-term growth and development.Study funding/competing interest(s)This work was supported by the Danish Council for Independent Research [DFF 4183-00152]; and the Faculty of Health at Aarhus University. The authors have no financial relationships or competing interests to disclose.

Study Question: Is the chance of childbirth, and risk of infertility, pregnancy loss and need for assisted reproduction different for women with asthma compared to women without asthma?Summary Answer: Women with asthma had comparable chances of giving birth compared to the reference population, however, their risk of both infertility and pregnancy loss, as well their need for medically assisted reproduction, was higher.What Is Known Already: Reproductive dysfunction has been reported among women with asthma, including longer time to pregnancy, increased risk of pregnancy loss and a higher need of medically assisted reproduction, but their risk of clinical infertility is unknown.Study Design, Size, Duration: This longitudinal register-based cohort study included all women with a healthcare visit for delivery, infertility, pregnancy loss or induced abortion in the southernmost county in Sweden, over the last 20 years.Participants/materials, Setting, Methods: Using the Skåne Healthcare Register, we identified all women aged 15-45 between 1998 and 2019, who received a diagnosis of asthma before their first reproductive outcome (n = 6445). Chance of childbirth and risk of infertility, pregnancy loss and assisted reproduction were compared to a healthcare seeking population of women without any asthma (n = 200 248), using modified Poisson regressions.Main Results and the Role Of Chance: The chance of childbirth was not different between women with asthma versus those without, adjusted risk ratio (aRR) = 1.02, 95% CI: 1.01-1.03. The risk of seeking care for infertility was increased, aRR = 1.29, 95% CI: 1.21-1.39, and women with asthma more often needed assisted reproduction aRR = 1.34 95% CI: 1.18-1.52. The risk of suffering a pregnancy loss was higher, aRR = 1.21, 95% CI: 1.15-1.28, and induced abortions were more common, aRR = 1.15, 95% CI: 1.11-1.20, among women with asthma.Limitations, Reasons For Caution: The study was an observational study based on healthcare visits and lacked detailed anthropometric data, thus residual confounding cannot be excluded. Only women with a healthcare visit for a reproductive outcome were included, which cannot be translated into pregnancy intention. A misclassification, presumed to be non-differential, may arise from an incorrect or missing diagnosis of asthma or female infertility, biasing the results towards the null.Wider Implications Of the Findings: This study points towards reproductive dysfunction associated with asthma, specifically in regards to the ability to maintain a pregnancy and the risk of needing medically assisted reproduction following clinical infertility, but reassuringly the chance of subsequently giving birth was not lower for these women.Study Funding/competing Interest(s): This article is part of the ReproUnion collaborative study, co-financed by EU Interreg ÖKS, Capital Region of Denmark, Region Skåne and Ferring Pharmaceuticals. The authors have no competing interests to disclose.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Is female infertility among women seeking medically assisted reproduction (MAR) associated with prevalent as well as incident multiple sclerosis (MS)?Summary Answer: Women with a record of female infertility did not have an increased risk of developing MS compared with apparent fertile women; however, the prevalence of MS was slightly higher among women undergoing MAR compared with women who had a child without MAR, but this was not related to origin of infertility (i.e. male versus female factor infertility).What Is Known Already: Women with MS have fewer children compared with women without MS. Persons with MS more often have other coexisting autoimmune disorders including hypothyroidism compared with the general population. Thyroid dysfunction is associated with ovarian cause of infertility, miscarriage and ovarian failure. Conversely, women with endometriosis, that is highly associated with infertility, also more often have other coexisting autoimmune diseases including MS and hypothyroidism compared with the general population. However, whether the low fertility rate among women with MS is due to a genetically predisposition to other autoimmune and endocrine disorders that leads to reduced fertility, or an active choice of the woman, disease-related pathology or treatment-specific effect on endocrine and/or ovarian function, is not completely understood.Study Design, Size, Duration: A register-based cohort study of a total of 310 357 women from 1996 to 2018. A cross-sectional design was used for analysing prevalence of MS, whereas a cohort design with up to 24 years of follow-up was used for analysing incidence of MS.Participants/materials, Setting, Methods: Three cohorts were included in the study (i) 55 404 women with a female infertility diagnosis registered in the Danish IVF register; (ii) 25 096 women with only male factor infertility recorded in the IVF register and thus no female infertility diagnosis and (iii) 229 857 age- and calendar-matched women with a record of first child birth in the Danish Medical Birth Register (DMBR) and no record ever in the IVF register. The prevalence and incidence of MS in the female infertility cohort were compared with the two control cohorts of apparent fertile women using log-binomial regression and Cox proportional hazard regression, respectively.Main Results and the Role Of Chance: The crude prevalence of having MS per 1000 persons was 3.2 for women who had undergone MAR treatment regardless of origin of infertility (i.e. male versus female factor infertility) and 2.3 for fertile DMBR controls. The age, calendar and educational level adjusted prevalence ratio of having a diagnosis of MS at the first MAR treatment was 1.27 (95% CI 1.07-1.52) for infertile women compared with fertile DMBR controls, and 1.00 (95% CI 0.77-1.31) for comparison to women with a male partner with infertility who had also undergone MAR treatment. We found no association between incident MS and female infertility compared with either of the control groups of fertile women.Limitations, Reason For Caution: The cohort of infertile women is highly selected on the basis of their choice of having fertility treatment and thus does not include women with unestablished infertility or women who, for some reason, have chosen not to have MAR treatment. Additionally, due to the nature of the observational study design, we cannot exclude the possibility of unmeasured and/or residual confounding.Wider Implications Of the Findings: Our results suggest that women with MS may undergo MAR treatment more often than women without MS due to more awareness about the possibility of MAR treatments, sexual dysfunction related to MS disease, but also need for timing of the pregnancy to avoid an unnecessary long time period without disease modifying therapy-especially of high efficacy-and hence a wish to conceive quickly. These findings are important for clinicians dealing with women with MS of childbearing age.Study Funding/competing Interest(s): The authors received no financial support for the study. T.I.K. has served on a scientific advisory board for Novartis and has received support for congress participation from Biogen. M.M. has served on scientific advisory boards for Biogen, Sanofi, Roche, Novartis, Merck, Abbvie and Alexion. She has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi and Genzyme and has received research support and support for congress participation from Biogen, Genzyme, Roche, Merck and Novartis. The remaining authors declare no conflict of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Is there a difference in the breast cancer risk among women who underwent ART treatments compared to those who underwent medically assisted reproduction (MAR) infertility treatments or women of reproductive age in the general population?Summary Answer: The risk of breast cancer among women treated by ART was similar to the risk among women treated by MAR and women who did not undergo fertility treatments.What Is Known Already: Studies investigating breast cancer risk in women who have undergone fertility treatments have provided conflicting results.Study Design, Size, Duration: A retrospective, population-based cohort study included women who underwent ART or MAR treatments and women who did not undergo fertility treatments from 1994 to 2019.Participants/materials, Setting, Methods: Women who underwent ART were matched one to one with women who underwent MAR treatments and one to one with woman from the general population of reproductive age, by year of birth and year of first delivery or nulliparity status. MAR women were also matched to ART women by treatment initiation calendar year. All included women were members of Maccabi Healthcare Services. Data regarding demographics, fertility treatments, BRCA mutation and possible confounders were obtained from the computerized database of electronic health records. The incidence of breast cancer after fertility treatments was compared to the matched controls.Main Results and the Role Of Chance: Of 8 25 721 women of reproductive age, 32 366 women who underwent ART were matched with patients treated by MAR (n = 32 366) and 32 366 women of reproductive age. A total of 984 women (1.0%) were diagnosed with breast cancer (mean follow-up period, 9.1 ± 6.3 years; interquartile range [IQR], 3.8-13.7 years). The incidence rates of breast cancer per 10 000 person-years were 11.9 (95% CI, 10.7-13.3), 10.7 (95% CI, 9.6-11.9) and 10.7 (95% CI, 9.6-12.0) in the ART group, MAR group and general population, respectively. The crude risk for breast cancer was similar in the ART group compared with the general population (hazard ratio (HR) = 1.10, 95% CI, 0.94-1.28) and in the ART group compared with the MAR group (HR = 1.00, 95% CI, 0.86-1.16). Further adjustment for age, BMI, smoking, socioeconomic status and parity did not substantially impact the hazard rates for breast cancer (ART vs general population: HR = 1.10, 95% CI, 0.94-1.28; ART vs MAR: HR = 0.99, 95% CI, 0.85-1.16). Among women diagnosed with breast cancer, the prevalence of BRCA1/2 mutations and tumour staging did not differ between the ART, MAR and general population groups. Among women who underwent ART, no correlation was found between breast cancer and the number of ART cycles or the use of recombinant medications or urine-derived medications.Limitations, Reasons For Caution: The mean age of women at the end of follow-up was only 42 years thus the study was not powered to detect potential differences in the risk of postmenopausal breast cancer. In addition, we did not sub-classify the exposed patients by the reason for infertility.Wider Implications Of the Findings: Breast cancer incidence following ART was comparable to that in the general population or following MAR. Women undergoing fertility treatments and their clinicians may be reassured about the safety of assisted reproduction technologies in terms of premenopausal breast cancer risk.Study Funding/competing Interest(s): No specific funding was used and there are no competing interests.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: What is the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on the outcome of a pregnancy after medically assisted reproduction (MAR)?Summary Answer: Our results suggest that MAR pregnancies are not differentially affected by SARS-CoV-2 infection compared to spontaneous pregnancies.What Is Known Already: Information on the effects of coronavirus disease 2019 (COVID-19) on pregnancy after MAR is scarce when women get infected during MAR or early pregnancy, even though such information is vital for informing women seeking pregnancy.Study Design, Size, Duration: Data from SARS-CoV-2 affected MAR pregnancies were collected between May 2020 and June 2021 through a voluntary data collection, organised by the European Society of Human Reproduction and Embryology (ESHRE).Participants/materials, Setting, Methods: All ESHRE members were invited to participate to an online data collection for SARS-CoV-2-infected MAR pregnancies.Main Results and the Role Of Chance: The dataset includes 80 cases from 32 countries, including 67 live births, 10 miscarriages, 2 stillbirths and 1 maternal death. An additional 25pregnancies were ongoing at the time of writing.Limitations, Reasons For Caution: An international data registry based on voluntary contribution can be subject to selective reporting with possible risks of over- or under-estimation.Wider Implications Of the Findings: The current data can be used to guide clinical decisions in the care of women pregnant after MAR, in the context of the COVID-19 pandemic.Study Funding/competing Interest(s): The authors acknowledge the support of ESHRE for the data registry and meetings. J.S.T. reports grants or contracts from Sigrid Juselius Foundation, EU and Helsinki University Hospital Funds, outside the scope of the current work. The other authors declare that they have no conflict of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Is cord blood DNA methylation associated with having been conceived by medically assisted reproduction?Summary Answer: This study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation.What Is Known Already: Medically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes.Study Design, Size, Duration: We investigated the association of DNA methylation and medically assisted reproduction using a case-control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort).Participants/materials, Settings, Methods: We assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls).Main Results and the Role Of Chance: The ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling.Limitations, Reasons For Cautions: While insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction.Wider Implications Of the Findings: Newborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health.Study Funding/competing Interests(s): This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union's Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700.D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Which agent for ovarian stimulation (OS) is the most cost-effective option in terms of net benefit for couples with unexplained subfertility undergoing IUI?Summary Answer: In settings where a live birth is valued at €3000 or less, between €3000 and €55 000 and above €55 000, clomiphene citrate (CC), Letrozole and gonadotrophins were the most cost-effective option in terms of net benefit, respectively.What Is Known Already: IUI-OS is a common first-line treatment for couples with unexplained subfertility and its increased uptake over the past decades and related personal or reimbursed costs are pressing concerns to patients and health service providers. However, there is no consensus on a protocol for conducting IUI-OS, with differences between countries, clinics and settings in the number of cycles, success rates, the agent for OS and the maximum number of dominant follicles in order to minimise the risk of a multiple pregnancy. In view of this uncertainty and the association with costs, guidance is needed on the cost-effectiveness of OS agents for IUI-OS.Study Design, Size, Duration: We developed a decision-analytic model based on a decision tree that follows couples with unexplained subfertility from the start of IUI-OS to a protocoled maximum of six cycles, assuming couples receive four cycles on average within one year. We chose the societal perspective, which coincides with other perspectives such as that from health care providers, as the treatments are identical except for the stimulation agent. We based our model on parameters from a network meta-analysis of randomised controlled trials for IUI-OS. We compared the following three agents: CC (oral medication), Letrozole (oral medication) and gonadotrophins (subcutaneous injection).Participants/materials, Setting, Methods: The main health outcomes were cumulative live birth and multiple pregnancy. As the procedures are identical except for the agent used, we only considered direct medical costs of the agent during four cycles. The main cost-effectiveness measures were the differences in costs divided by the differences in cumulative live birth (incremental cost-effectiveness ratio, ICER) and the probability of the highest net monetary benefit in which costs for an agent were deducted from the live births gained. The live birth rate for IUI using CC was taken from trials adhering to strict cancellation criteria included in a network meta-analysis and extrapolated to four cycles. We took the relative risks for the live birth rate after Letrozole and gonadotrophins versus CC from that same network meta-analysis to estimate the remaining absolute live birth rates. The uncertainty around live birth rates, relative effectiveness and costs was assessed by probabilistic sensitivity analysis in which we drew values from distributions and repeated this procedure 20 000 times. In addition, we changed model assumptions to assess their influence on our results.Main Results and the Role Of Chance: The agent with the lowest cumulative live birth rate over 4 IUI-OS cycles conducted within one year was CC (29.4%), followed by Letrozole (32.0%) and gonadotrophins (34.5%). The average costs per four cycles were €362, €434 and €1809, respectively. The ICER of Letrozole versus CC was €2809 per additional live birth, whereas the ICER of gonadotrophins versus Letrozole was €53 831 per additional live birth. When we assume a live birth is valued at €3000 or less, CC had the highest probability of maximally 65% to achieve the highest net benefit. Between €3000 and €55 000, Letrozole had the highest probability of maximally 62% to achieve the highest net benefit. Assuming a monetary value of €55 000 or more, gonadotrophins had the highest probability of maximally 56% to achieve the highest net benefit.Limitations, Reasons For Caution: Our model focused on population level and was thus based on average costs for the average number of four cycles conducted. We also based the model on a number of key assumptions. We changed model assumptions to assess the influence of these assumptions on our results.Wider Implications Of the Findings: The high uncertainty surrounding our results indicate that more research is necessary on the relative effectiveness of using CC, Letrozole or gonadotrophins for IUI-OS in terms of the cumulative live birth rate. We suggest that in the meantime, CC or Letrozole are the preferred choice of agent.Study Funding/competing Interest(s): This work was supported by ZonMw Doelmatigheidsonderzoek, grant 80-85200-98-91072. The funder had no role in the design, conduct or reporting of this work. BWM is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research support from ObsEva, Merck and Guerbet. All other authors have no conflicts of interest to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Is the microRNA (miRNA) expression pattern of cumulus oophorus cells (COCs) in women undergoing medically assisted reproduction (MAR) procedures differentially modulated according to patient age and gonadotropin treatment strategy?Summary Answer: Maternal age is an independent factor impacting miRNA expression in COCs while gonadotropin treatment may affect follicular miRNA expression and IVF efficacy.What Is Known Already: Epigenetic mechanisms in female infertility are complex and poorly studied. DNA methylation, histone modifications, miRNAs and nucleosome positioning influence cellular machinery through positive and negative feedback mechanisms either alone or interactively. miRNAs are important regulators during oogenesis, spermatogenesis and early embryogenesis, and are reported to play a role in regulating crosstalk between the oocyte and COCs. Although miRNome analysis has been performed in female human reproductive tissues (endometrium, myometrium, cervix and ovaries), epigenetic modifications in women with infertility have not been explored in detail. In addition, the impact of gonadotropin treatments during MAR on miRNA expression in COCs has not been fully investigated.Study Design, Size, Duration: This study was carried out in 53 COC samples obtained from mature metaphase II (MII) oocytes in 53 women undergoing MAR treatment. A total of 38 samples for assay development were pooled by maternal age and gonadotropin treatment into four predetermined subgroups: ≥36 years and recombinant human FSH (r-hFSH), n = 10; ≥36 years and r-hFSH+ recombinant human-luteinizing hormone (r-hLH), n = 10; ≤35 years and r-hFSH, n = 9; ≤35 years and r-hFSH+r-hLH, n = 9. miRNome profiles were determined and compared between subgroups. Expression of defined miRNAs was validated in the remaining fifteen samples, representative of each subgroup, by quantitative polymerase chain reaction (PCR).Participants/materials, Setting, Methods: COCs were processed for miRNA-enriched total RNA extraction and pooled in homogeneous subgroups to obtain a sufficient amount and quality of starting material to perform the analysis. Each pooled sample underwent miRNA profiling using PCR assay system to examine expression of 752 human miRNAs without pre-amplification. Data were analyzed using the delta-delta Ct method for relative quantitation and prediction of target genes (with at least four algorithms predicting the same miRNA-gene interaction pair (HIT)>4). The miRSystem database provided functional annotation enrichment (raw P-value <0.05) of co-expressed miRNAs.Main Results and the Role Of Chance: We found distinctive miRNA expression profiles in each subgroup correlating with age and MAR stimulation. In addition, a number of selective and co-expressed miRNAs were revealed by comparative analysis. A cluster of 37 miRNAs were commonly but differentially expressed in all four pools. Significant differences were observed in expression regulation of 37 miRNAs between age groups (≤35 or ≥36) in women receiving r-hFSH+r-hLH compared to those receiving r-hFSH alone. Higher concentrations and increased numbers of miRNAs were recorded in younger than in older patients, regardless of treatment. Functional and expression studies performed to retrieve common miRNome profiles revealed an enrichment of biological functions in oocyte growth and maturation, embryo development, steroidogenesis, ovarian hyperstimulation, apoptosis and cell survival, glucagon and lipid metabolism, and cell trafficking. The highest scored pathways of target genes of the 37 common miRNAs were associated with mitogen-activated protein kinase (MAPK) signaling pathways, G alpha signaling, transcription regulation, tight junctions, RNA polymerase I and III, and mitochondrial transcription. We identified a potential age- and MAR stimulation-dependent signature in the miRNA landscape of COCs.Limitations, Reasons For Caution: We cannot rule out the possibility that other unknown individual genetic or clinical factors may have interfered with the reported results. Since miRNA profiling was conducted with a predefined array of target probes, other miRNA molecules, potentially modulated by age and hormonal stimulation, may have been missed in this study.Wider Implications Of the Findings: miRNA expression in COCs is modulated by gonadotropin treatment and correlates strongly with age. A better understanding of the expression patterns and functions of miRNAs may lead to the development of novel therapeutics to treat ovarian dysfunction and improve fertility in older women.Study Funding/competing Interest: This study was funded by Merck KGaA, Darmstadt, Germany. All authors declared no competing interest, except SL and TD who are fully employed by Merck KGaA.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Do the parent-child relationships of adolescents born after medically assisted reproduction (MAR) using the parents' own gametes differ from those of adolescents born after natural conception (NC)?Summary Answer: MAR and NC families have similar parent-child relationships in terms of closeness and conflict frequency, except that MAR mothers report being closer to their children than NC mothers.What Is Known Already: Prior work on parent-child relationships during childhood has reported mixed findings. While some studies have documented no differences between MAR and NC families, others have shown that MAR families have greater levels of warmth and positive feelings than NC families. Evidence on parent-child relationships during the adolescent period is generally positive but is limited because of the small number of existing studies and the reliance on small samples.Study Design, Size, Duration: This work is based on the UK Millennium Cohort Study, whose study members were born in 2000-2002. The analyses focused on Sweep 6 which was collected when cohort members were around 14 years old. We also relied on variables collected in Sweep 1, when cohort members were aged around 9 months, to account for characteristics that could confound or mediate the relationship between MAR and our outcomes. The attrition rate between Sweeps 1 and 6 was 36.7%.Participants/materials, Setting, Methods: The final sample consisted of 10 233 cohort members, 320 of whom were conceived with the help of MAR (3.1%). A total of six dependent variables were used to measure, when the cohort members were around 14 years old, levels of parent-child closeness and conflict, reported separately by the mother, the father and the cohort member. Linear models were used to analyse the association between parent-child relationships before and after adjustment for socio-demographic characteristics and mental health.Main Results and the Role Of Chance: Sweep 6 achieved a response rate of 76.3% of the eligible sample. The results show that, on average, MAR and NC families had similar parent-child relationships in terms of closeness and conflict frequency. The only difference was that MAR mothers reported being closer to their children than NC mothers both before (β = 0.149, P < 0.05) and after (β = 0.102, P < 0.1) adjustment for family socio-demographic characteristics and mental health.Limitations, Reasons For Caution: The outcome variables are self-reported by each of the respondents and could be subject to social desirability bias. Second, some parents may have not reported they conceived through donor insemination, which could result in the analytical sample including a small subset of children who were not genetically related to their parents. Third, the data did not include information about whether the children were aware of their conception mode, since the Millennium Cohort Study did not collect information on MAR disclosure. Moreover, they did not allow us to study other aspects of parent-child relationships. Finally, as we observed parent-child relationships at only one moment in time; we were unable to test whether they changed over time.Wider Implications Of the Findings: The results suggest that the difficulties and the stress parents underwent to conceive through MAR did not translate into more difficult parent-child relationships during adolescence. Given the increasing number of children conceived via MAR, the finding that MAR and NC families had similar parent-child relationships in terms of closeness and conflict frequency is reassuring.Study Funding/competing Interest(s): This work was supported by European Research Council agreement n. 803959 (MARTE to A.G.). The authors declare no competing interests.Trial Registration Number: n/a. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic created a significant impact on medically assisted reproduction (MAR) services. ESHRE decided to mobilize resources in order to collect, analyse, monitor, prepare and disseminate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) knowledge specifically related to ART and early pregnancy. This article presents the impact of the SARS-CoV-2 pandemic focusing on reproductive healthcare. It details the rationale behind the guidance prepared to support MAR services in organizing and managing the re-start of treatments or in case of any future wave of COVID-19 disease. The guidance includes information on patient selection and informed consent, staff and patient triage and testing, adaptation of ART services, treatment planning and code of conduct. The initiatives detailed in this article are not necessarily COVID-specific and such action plans could be applied effectively to manage similar emergency situations in different areas of medicine, in the future. [ABSTRACT FROM AUTHOR]

Time taken to achieve a live birth is an important consideration that is central to managing patient expectations during infertility treatment. However, time-related endpoints are not reported as standard in the majority of fertility-related clinical studies and there is no internationally recognized consensus definition for such endpoints. There is, therefore, a need for meaningful discussions around the selection of appropriate time-related treatment outcome measures for studies evaluating fertility treatments that will be relevant to diverse stakeholders (e.g. patients, healthcare professionals, clinical scientists, authorities and industry). Here, we provide a proposal for the evaluation of time-related outcome measures in fertility-related clinical studies, alongside associated definitions. [ABSTRACT FROM AUTHOR]

Study Question: Does the risk of low birth weight and premature birth increase with age among mothers who conceive through medically assisted reproduction (MAR)?Summary Answer: Among MAR mothers, the risk of poorer birth outcomes does not increase with maternal age at birth except at very advanced maternal ages (40+).What Is Known Already: The use of MAR treatments has been increasing over the last few decades and is especially diffused among women who conceive at older ages. Although advanced maternal age is a well-known risk factor for adverse birth outcomes in natural pregnancies, only a few studies have directly analysed the maternal age gradient in birth outcomes for MAR mothers.Study Design, Size, Duration: The base dataset was a 20% random sample of households with at least one child aged 0-14 at the end of 2000, drawn from the Finnish population register and other administrative registers. This study included children who were born in 1995-2000, because the information on whether a child was conceived through MAR or naturally was available only from 1995 onwards.Participants/materials, Setting, Methods: The outcome measures were whether the child had low birth weight (LBW, <2500 g at birth) and whether the child was delivered preterm (<37 weeks of gestation). Conceptions through MAR were identified by examining data on purchases of prescription medication from the National Prescription Register. Linear probability models were used to analyse and compare the maternal age gradients in birth outcomes of mothers who conceived through MAR or naturally before and after adjustment for maternal characteristics (i.e. whether the mother suffered from acute/chronic conditions before the pregnancy, household income and whether the mother smoked during pregnancy).Main Results and the Role Of Chance: A total of 56 026 children, 2624 of whom were conceived through MAR treatments, were included in the study. Among the mothers who used MAR to conceive, maternal age was not associated with an increased risk of LBW (the overall prevalence was 12.6%) at ages 25-39. For example, compared to the risk of LBW at ages 30-34, the risk was 0.22 percentage points lower (95% CI: -3.2, 2.8) at ages 25-29 and was 1.34 percentage points lower (95% CI: -4.5, 1.0) at ages 35-39. The risk of LBW was increased only at maternal ages ≥40 (six percentage points, 95% CI: 0.2, 12). Adjustment for maternal characteristics only marginally attenuated these associations. In contrast, among the mothers who conceived naturally, the results showed a clear age gradient. For example, compared to the risk of LBW (the overall prevalence was 3.3%) at maternal ages 30-34, the risk was 1.1 percentage points higher (95% CI: 0.6, 1.6) at ages 35-39 and was 1.5 percentage points higher (95% CI: 0.5, 2.6) at ages ≥40. The results were similar for preterm births.Limitations, Reason For Caution: A limited number of confounders were included in the study because of the administrative nature of the data used. Our ability to reliably distinguish mothers based on MAR treatment type was also limited.Wider Implications Of the Findings: This is the first study to analyse the maternal age gradient in the risk of adverse birth outcomes among children conceived through MAR using data from a nationally representative sample and controlling for important maternal health and socio-economic characteristics. This topic is of considerable importance in light of the widespread and increasing use of MAR treatments.Study Funding/competing Interest(s): Funding for this project was provided by the European Research Council (grant no. 803959 MARTE to Alice Goisis and grant no. 336475 COSTPOST to Mikko Myrskylä). E.S. reports personal fees from Theramex, personal fees from Merck Serono, personal fees from Health Reimbursement Arrangement, non-financial support from Merck Serono and grants from Ferring, grants from Theramex, outside the submitted work. The remaining authors have no competing interests.Trial Registrtion Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: What is the risk of death among men with oligospermia, unspecified male factor and azoospermia in the years following fertility treatment?Summary Answer: No significantly elevated risk was observed among men with oligospermia and unspecified male factor, while an increased risk was found among men with azoospermia.What Is Known Already: Previous studies have shown associations between male factor infertility and risk of death, but these studies have relied on internal reference groups and the risk of death according to type of male infertility is not well characterized.Study Design, Size, Duration: In this prospective record-linkage cohort study, we identified men who had undergone medically assisted reproduction (MAR) between 1994 and 2015. Data was linked to the Danish causes of death register and sociodemographic registers through personal identification numbers assigned to all Danish citizens at birth.Participants/materials, Setting, Methods: Men that had undergone MAR in Denmark (MAR Cohort; n = 64 563) were identified from the Danish IVF register, which includes data on whether infertility was due to male factor. For each man in the MAR cohort, five age-matched men who became fathers without fertility treatment were selected from the general population (non-MAR fathers; n = 322 108). Men that could not adequately be tracked in the Danish CPR register (n = 1259) and those that were censored prior to study entry (n = 993) were excluded, leaving a final population of 384 419 men. Risk of death was calculated by Cox regression analysis with age as an underlying timeline and adjustments for educational attainment, civil status and year of study entry. The risk of death was compared among men with and without male factor infertility identified from the IVF register (internal comparisons) as well as to the non-MAR fathers (external comparison).Main Results and the Role Of Chance: The risk of death between the MAR cohort (all men, regardless of infertility) and the non-MAR fathers was comparable [hazard ratio (HR), 1.07; 95% CI, 0.98-1.15]. When the MAR cohort was limited to infertile men, these men were at increased risk of death [HR, 1.27; 95% CI, 1.12-1.44]. However, when stratified by type of male factor infertility, men with azoospermia had the highest risk of death, which persisted when in both the internal [HR, 2.30; 95% CI, 1.54-3.41] and external comparison [HR, 3.32; 95% CI, 2.02-5.40]. No significantly elevated risk of death was observed among men with oligospermia [HR, 1.14; 95% CI, 0.87-1.50] and unspecified male factor [HR, 1.10; 95% CI, 0.75-1.61] compared with the non-MAR fathers. The same trends were observed for the internal comparison.Limitations, Reasons For Caution: Duration of the follow-up was limited and there is limited generalizability to infertile men who do not seek fertility treatment.Wider Implications Of the Findings: Using national health registers, we found an increased risk of death among azoospermic men while no increased risk was found among men with other types of infertility. For the azoospermic men, further insight into causal pathways is needed to identify options for monitoring and prevention.Study Funding/competing Interest(s): This study is part of the ReproUnion collaborative study, co-financed by the European Union, Interreg V ÖKS. C.G.'s research stay at Stanford was funded by grants from the University of Copenhagen, Kong Christian den Tiendes Fond, Torben og Alice Frimodt Fond and Julie Von Müllen Fond. M.E. is an advisor for Sandstone and Dadi. All other authors declare no conflict of interests.Trial Registration Number: Not relevant. [ABSTRACT FROM AUTHOR]

Study Question: Are urinary phthalate metabolites associated with reduced antral follicle growth among women in an infertility setting?Summary Answer: Higher urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites were associated with significant decreases in antral follicle count (AFC) among women seeking infertility care.What Is Known Already: Experimental animal studies show that DEHP accelerates primordial follicle recruitment and inhibits antral follicle growth. Whether phthalates also reduce the growing antral follicle pool in humans remains unknown.Study Design, Size, Duration: We examined the association between urinary phthalate metabolites and AFC using prospective data from 215 females recruited between 2004 and 2012 in the Environment and Reproductive Health (EARTH) study.Participants/materials, Setting, Methods: We quantified the urinary concentrations of 11 phthalate metabolites. We estimated the geometric mean for all urine samples provided prior to unstimulated day 3 AFC assessment for each woman. We evaluated the association of AFC with ∑DEHP (molar sum of four DEHP metabolites) and individual phthalate metabolites using Poisson regression, adjusting for age, BMI and smoking.Main Results and the Role Of Chance: We observed significant decreases in mean AFC for all higher quartiles of ∑DEHP as compared with the lowest quartile. Compared with women in the first quartile of ∑DEHP, women in the second, third and fourth quartiles had a -24% (95% confidence interval (CI): -32%, -16%), -19% (95% CI: -27%, -9%), and -14% (95% CI: -23%, -5%) decrease in mean AFC. The absolute mean AFC in the first quartile was 14.2 follicles (95% CI: 13.2, 15.2) compared with 10.7 follicles (95% CI: 9.9, 11.6) in the second quartile. We observed similar trends among the four individual DEHP metabolites. There was no consistent change in AFC among the remaining phthalate metabolite concentrations evaluated.Limitations, Reasons For Caution: We demonstrated a negative association between DEHP and a well-established marker of ovarian reserve among a subfertile population. However these findings may not be generalizable to women without fertility concerns, and we cannot rule out co-exposure to other chemicals.Wider Implications Of the Findings: Environmental chemicals that inhibit the size of the growing antral follicle pool can impair fertility and reduce fecundity. This study suggests evidence in need of further investigation on the impact of phthalates on the human oocyte and follicular development.Study Funding/competing Interests: Work supported by grants ES009718, ES022955, ES000002, and T32ES007069 from the National Institute of Environmental Health Sciences (NIEHS) and grant T32 DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). C.M. was supported by a post-doctoral training award from the Canadian Institutes of Health Research. There are no competing interests to declare. [ABSTRACT FROM AUTHOR]

This Task Force document discusses ethical issues arising with requests for medically assisted reproduction from people in what may be called ‘non-standard’ situations and relationships. The document stresses that categorically denying access to any of these groups cannot be reconciled with a human rights perspective. If there are concerns about the implications of assisted reproduction on the wellbeing of any of the persons involved, including the future child, a surrogate mother or the applicants themselves, these concerns have to be considered in the light of the available scientific evidence. When doing so it is important to avoid the use of double standards. More research is needed into the psychosocial implications of raising children in non-standard situations, especially with regard to single women, male homosexual couples and transsexual people. [ABSTRACT FROM PUBLISHER]

STUDY QUESTION Do patients at risk for psychological maladjustment during fertility treatment present lower intentions to comply with recommended treatment than patients not at risk? SUMMARY ANSWER Patients at risk of psychological maladjustment present similar high intentions to comply with recommended fertility treatment to those not at risk but their intentions are conditioned by the degree of control they perceive over their fertility and its treatment and their capacity to accept a future without biological children. WHAT IS KNOWN ALREADY Infertile couples refer to the psychological burden of treatment as one of the most important reasons for withdrawal from recommended treatment. The SCREENIVF can be used before treatment to screen patients at risk for psychological maladjustment by assessing five risk factors: anxiety, depression, helplessness and lack of acceptance cognitions and social support. STUDY DESIGN, SIZE, DURATION Cross-sectional study. First, we investigated the psychometric properties of the Portuguese version of the SCREENIVF. Secondly, we investigated associations between risk for psychological maladjustment and intentions to comply with treatment. PARTICIPANTS/ MATERIALS, SETTING, METHODS Two hundred and ninety-one women and 92 men undergoing any stage of fertility treatment at Portuguese infertility clinics were recruited online or in the clinical setting (55% response rate). Participants completed questionnaires that assessed their emotional adjustment, quality of life and compliance intentions. MAIN RESULTS AND ROLE OF CHANCE The confirmatory factor analysis for the SCREENIVF indicated good fit [χ2 = 188.50, P < 0.001; comparative fit index = 0.97; root-mean-square error of approximation = 0.06 (90% CI 0.05–0.07)] and all dimensions were reliable (α ≥ 0.70, except depression for men: α = 0.66). Fifty-two percent of women and 30% of men were at risk for maladjustment. Women and men at risk and not at risk for maladjustment reported similar intentions to comply with treatment (P > 0.05). Cognitive risk factors moderated negative associations found between distress and compliance intentions. Higher anxiety was associated with lower compliance intentions for patients with lower helplessness cognitions (β = −0.45, P = 0.01) and men with higher acceptance cognitions (β = −0.60; P = 0.03), but not for patients with higher helplessness cognitions (β = 0.25, P = 0.13) and men with lower acceptance cognitions (β = 0.38; P = 0.21). Higher depression was associated with lower compliance intentions for patients with higher helplessness cognitions (β = −0.33, P = 0.02), but not for patients with lower helplessness cognitions (β = 0.19, P = 0.30). LIMITATIONS, REASONS FOR CAUTION Few men participated and thus only medium-to-large effect sizes could be detected for them. Forty-eight percent of participants were recruited online and this could have resulted in higher rates of patients at risk. WIDER IMPLICATIONS OF THE FINDINGS The SCREENIVF is not useful to identify patients at risk for non-compliance. However, the clinic staff should be aware that patients who score high on helplessness cognitions and low on acceptance may need additional decisional aid to make autonomous and satisfying decisions about uptake of treatment. The Portuguese version of the SCREENIVF is valid and reliable and can be used with women undergoing any type of fertility treatment. STUDY FUNDING/ COMPETING INTEREST(S) S.G. received a postdoctoral fellowship from the Portuguese Foundation for Science and Technology (FCT-SFRH/BPD/63063/2009). There are no conflicts of interest to declare. [ABSTRACT FROM AUTHOR]

BACKGROUND This study evaluated couples' perceptions of preparatory psychosocial counselling prior to participation in medically assisted reproduction (MAR). METHODS Eighty-three couples about to undergo IUI treatment were asked about their expectations regarding a subsequent single psychosocial counselling session and assessed in terms of their levels of infertility-specific stress, anxiety and depressive symptoms. Afterwards, participants rated their satisfaction with different elements of the session. RESULTS Almost two-thirds of women and one-half of men expected counselling to be important, and the majority anticipated that the session would be helpful and informative. Views of preparatory counselling were significantly more positive afterwards, indicating that a focused session addressing issues of treatment concerns, goal setting and managing infertility stress was more beneficial than anticipated. Those experiencing higher levels of infertility-specific stress expected the counselling session to be more important, and elevated stress and greater utilization of social support were predictive of post-counselling satisfaction. CONCLUSIONS Preparatory psychosocial counselling provided with a specific and practical focus appears to be a potentially important and helpful service prior to MAR. Clinics should not assume that patients can accurately judge the benefits of counselling before actually engaging in the session. Identifying patients most likely to benefit and providing a clear rationale may further increase receptivity to this proactive counselling service. While patients characterize this intervention as beneficial, it is not yet known if these benefits translate into improved management of treatment procedures. [ABSTRACT FROM AUTHOR]

BACKGROUND: Most studies on disclosure of mode of conception after fertility treatment have focused on donor insemination. We present a large, longitudinal cohort study of fertility patients who conceived through a variety of fertility treatments, including both non-donor and donor techniques. [ABSTRACT FROM PUBLISHER]

Study Question: Over a time period of 3 years, which order of expectant management (EM), IUI with ovarian stimulation (IUI-OS) and IVF is the most cost-effective for couples with unexplained subfertility with the female age below 38 years?Summary Answer: If a live birth is considered worth €32 000 or less, 2 years of EM followed by IVF was the most cost-effective, whereas above €32 000 this was 1 year of EM, 1 year of IUI-OS and then 1 year of IVF.What Is Known Already: IUI-OS and IVF are commonly used fertility treatments for unexplained subfertility although many couples can conceive naturally, as no identifiable barrier to conception could be found by definition. Few countries have guidelines on when to proceed with medically assisted reproduction (MAR), mostly based on the expected probability of live birth after treatment, but there is a lack of evidence to support the strategies proposed by these guidelines. The increased uptake of IUI-OS and IVF over the past decades and costs related to reimbursement of these treatments are pressing concerns to health service providers. For MAR to remain affordable, sustainable and a responsible use of public funds, guidance is needed on the cost-effectiveness of treatment strategies for unexplained subfertility, including EM.Study Design, Size, Duration: We developed a decision analytic Markov model that follows couples with unexplained subfertility of which the woman is under 38 years of age for a time period of 3 years from completion of the fertility workup onwards. We divided the time axis of 3 years into three separate periods, each comprising 1 year. The model was based on contemporary evidence, most notably the dynamic prediction model for natural conception, which was combined with MAR treatment effects from a network meta-analysis on randomized controlled trials. We changed the order of options for managing unexplained subfertility for the 1 year periods to yield five different treatment policies in total: IVF-EM-EM (immediate IVF), EM-IVF-EM (delayed IVF), EM-EM-IVF (postponed IVF), IUIOS-IVF-EM (immediate IUI-OS) and EM-IUIOS-IVF (delayed IUI-OS).Participants/materials, Setting, Methods: The main outcomes per policy over the 3-year period were the probability of live birth, the average treatment and delivery costs, the probability of multiple pregnancy, the incremental cost-effectiveness ratio (ICER) and finally, which policy yields the highest net benefit in which costs for a policy were deducted from the health effects, i.e. live births gained. We chose the Dutch societal perspective, but the model can be easily modified for other locations or other perspectives. The probability of live birth after EM was taken from the dynamic prediction model for natural conception and updated for Years 2 and 3. The relative effects of IUI-OS and IVF in terms of odds ratios, taken from the network meta-analysis, were applied to the probability of live birth after EM. We applied standard discounting procedures for economic analyses for Years 2 and 3. The uncertainty around effectiveness, costs and other parameters was assessed by probabilistic sensitivity analysis in which we drew values from distributions and repeated this procedure 20 000 times. In addition, we changed model assumptions to assess their influence on our results.Main Results and the Role Of Chance: From IVF-EM-EM to EM-IUIOS-IVF, the probability of live birth varied from approximately 54-64% and the average costs from approximately €4000 to €9000. The policies IVF-EM-EM and EM-IVF-EM were dominated by EM-EM-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. The policy IUIOS-IVF-EM was dominated by EM-IUIOS-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. After removal of policies that were dominated, the ICER for EM-IUIOS-IVF was approximately €31 000 compared to EM-EM-IVF. The range of ICER values between the lowest 25% and highest 75% of simulation replications was broad. The net benefit curve showed that when we assume a live birth to be worth approximately €20 000 or less, the policy EM-EM-IVF had the highest probability to achieve the highest net benefit. Between €20 000 and €50 000 monetary value per live birth, it was uncertain whether EM-EM-IVF was better than EM-IUIOS-IVF, with the turning point of €32 000. When we assume a monetary value per live birth over €50 000, the policy with the highest probability to achieve the highest net benefit was EM-IUIOS-IVF. Results for subgroups with different baseline prognoses showed the same policies dominated and the same two policies that were the most likely to achieve the highest net benefit but at different threshold values for the assumed monetary value per live birth.Limitations, Reasons For Caution: Our model focused on population level and was thus based on average costs for the average number of cycles conducted. We also based the model on a number of key assumptions. We changed model assumptions to assess the influence of these assumptions on our results. The change in relative effectiveness of IVF over time was found to be highly influential on results and their interpretation.Wider Implications Of the Findings: EM-EM-IVF and EM-IUIOS-IVF followed by IVF were the most cost-effective policies. The choice depends on the monetary value assigned to a live birth. The results of our study can be used in discussions between clinicians, couples and policy makers to decide on a sustainable treatment protocol based on the probability of live birth, the costs and the limitations of MAR treatment.Study Funding/competing Interest(s): This work was supported by the ZonMw Doelmatigheidsonderzoek (80-85200-98-91072). The funder had no role in the design, conduct or reporting of this work. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research support from ObsEva, Merck and Guerbet.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]