Estimating the impact of bias in causal epidemiological studies: the case of health outcomes following assisted reproduction.

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.

Differences in medically assisted reproduction use by sexual identity and partnership: a prospective cohort of cisgender women.

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.

Identification of two hidden clinical subgroups among men with idiopathic cryptozoospermia.

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.

Moonshots and last miles: what it may take to treat infertility for all.

Innovation in medically assisted reproduction (MAR) is at an all-time high, with new technologies being developed for the laboratory and around the patient experience, and deployed quickly and effectively. Nevertheless, substantial improvements in the success of infertility care seem to elude the field. This article presents the view that MAR is missing the key innovation motor of mechanistic knowledge, which historically relates to a lack of public resources of the kind afforded to other diseases. It is posited that unless and until we raise infertility at the level of an urgent unmet medical need in the eyes of government and national funding body, innovation will be limited in scope and impact, and be incremental in nature.

Medically assisted reproduction and mental health in adolescence: evidence from the UK Millennium Cohort Study.

BACKGROUND: The number and proportion of children conceived through medically assisted reproduction (MAR) is steadily increasing yet the evidence on their mental health in adolescence is inconclusive. Two main mechanisms with opposite effects can explain differences in mental health outcomes by conception mode: while more advantaged parental characteristics could positively influence it, higher parental stress could have a negative influence. METHODS: Linear and logistic estimations on a longitudinal population-based birth cohort study of 9,897 individuals to investigate whether adolescents conceived through MAR are more likely than naturally conceived (NC) children to experience mental health problems at age 17, as reported by adolescents themselves and their parents. We test whether this association is confounded and/or mediated by parental background characteristics collected when the cohort member was around 9 months old (maternal age, maternal education level, ethnicity, income quintile), family structure variables measured in adolescence (number of siblings in the household at age 15, parental household structure at age 14) or maternal distress at age 14. RESULTS: Children conceived naturally and through MAR self-reported similar mental health outcomes. The only differences between MAR and NC adolescents are in the parental reports, with parents who conceived through MAR reporting their children had 3.82 (95% CI: 1.140 to 11.54) and 2.35 (95% CI: 1.145 to 4.838) higher odds of falling within the high category of SDQ total difficulties and emotional symptoms scales, respectively. The results did not change on adjustment for mediators, such as maternal distress, number of siblings in the household and parental household structure. CONCLUSIONS: The results reveal a lack of or small differences in MAR adolescents' mental health outcomes compared to children who were conceived naturally. While the results based on the parental reports could suggest that MAR adolescents are at higher risk of suffering from mental health problems, the differences are small and not supported by adolescents' own reports. The difference between MAR and NC adolescent's parental report might reflect differences in parental concern, their relationship or closeness and can help to reconcile the mixed findings of previous studies.

Probability of second live birth after first natural and medically assisted reproduction-mediated live birth: A historical cohort study.

INTRODUCTION: Evidence on the role of medically assisted reproduction (MAR) in achieving the desired number of children is very limited. The aim of the current investigation was to assess the probability and the mode of conception of a second live birth according to the mode of conception of the first one. MATERIAL AND METHODS: This historical cohort study was based on administrative data from regional healthcare databases. Women hospitalized for childbirth in Lombardy between January 1, 2007 and December 31, 2017 were identified. The probability of a second live birth up to 2021 was estimated using the Kaplan-Meier method. We calculated this probability according to the mode of conception of the first birth, and the analysis was also performed in strata of maternal age at first birth. Cox proportional hazards models were fitted to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the association between mode of conception at first live birth and the probability of having a second live birth. Mothers were right-censored if they moved out of the region, died, or did not have a second live birth by the end of follow-up. RESULTS: We identified 431 333 women who had their first live birth after a natural conception and 16 837 who had their first live birth after MAR. The probability of having a second live birth was 58.6% and 32.1%, respectively in the two groups (HR = 0.68, 95% CI: 0.66-0.70). Considering solely women who naturally conceived their first live birth, the probability to have a second child with MAR was 1.1% and to have a second child naturally 59.3%. The corresponding values were 11.5% and 25.2% in the group of women with a first MAR-mediated live birth. CONCLUSIONS: In our cohort, one woman out of 10 having a first MAR-mediated live birth underwent MAR programs again. Considering women who had a first natural live birth, this proportion was drastically reduced. In the field of MAR, more attention should be given to the capacity of a couple to achieve the number of desired children.

The risk of perinatal and cardiometabolic complications in pregnancies conceived by medically assisted reproduction.

PURPOSE: To examine the impact of medically assisted fertility treatments on the risk of developing perinatal and cardiometabolic complications during pregnancy and in-hospital deliveries. METHODS: We conducted a retrospective cohort study using medical health records of deliveries occurring in 2016-2022 at a women's specialty hospital in a southern state of the Unites States (US). Pregnancies achieved using medically assisted reproductive (MAR) techniques were compared with unassisted pregnancies using propensity score matching (PSM), based on demographic, preexisting health, and reproductive factors. Study outcomes included cesarean delivery, gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), delivery complications, and postpartum readmission. We used Poisson regression with robust standard errors to generate risk ratios (RRs) and 95% confidence intervals (CIs) for all study outcomes. RESULTS: Among 57,354 deliveries, 586 (1.02%) pregnancies were achieved using MAR and 56,768 (98.98%) were unassisted ("non-MAR"). Compared to the non-MAR group, MAR pregnancies had significantly higher prevalence of all study outcomes, including GDM (15.9% vs. 11.2%, p < 0.001), HDP (28.2% vs. 21.1%, p < 0.001), cesarean delivery (56.1% vs. 34.6%, p < 0.001), delivery complications (10.9% vs. 6.8%, p = 0.03), and postpartum readmission (4.3% vs. 2.7%, p = 0.02). In a PSM sample of 584 MAR and 1,727 unassisted pregnancies, MAR was associated with an increased risk of cesarean delivery (RR = 1.11, 95% CI = 1.01-1.22); whereas IVF was associated with an increased risk of cesarean delivery (RR = 1.15, 95% CI = 1.03-1.28) and delivery complications (RR = 1.44, 95% CI = 1.04-2.01). CONCLUSIONS: Women who conceived with MAR were at increased risk of cesarean deliveries, and those who conceived with IVF were additionally at risk of delivery complications.

Exploring attitudes and experiences with reproductive genetic carrier screening among couples seeking medically assisted reproduction: a longitudinal survey study.

PURPOSE: This study aimed to assess the attitudes and experiences of subfertile couples applying for medically assisted reproduction (MAR) using their own gametes towards reproductive genetic carrier screening (RGCS) for monogenic conditions. METHODS: A prospective survey study was conducted where subfertile couples were recruited from the fertility centre of a university hospital in Flanders, Belgium. Participants were offered RGCS free of charge and completed self-administered questionnaires at three different time points. RESULTS: The study sample consisted of 26 couples. Most participants had no children, did not consider themselves as religious, and had some form of higher education. Overall, attitudes towards RGCS were mostly positive and the intention to participate in RGCS was high. Anxiety scores were only elevated and clinically relevant for a limited number of participants. A large proportion of participants would consider preventive reproductive options like prenatal diagnosis or in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) combined with pre-implantation genetic testing for monogenic conditions (PGT-M) in the event of an increased likelihood of conceiving a child with a hereditary condition. Participants were satisfied with their decision to undergo RGCS, and the majority would recommend RGCS to other couples. CONCLUSION: Our study findings suggest that subfertile couples applying for MAR using their own gametes find RGCS acceptable and have a positive attitude towards it. This study provides valuable insights into the perspectives of these couples, highlighting the need for appropriate counseling and timely information provision.

Associations between endometriosis and adverse pregnancy and perinatal outcomes: a population-based cohort study.

PURPOSE: To examine the association between endometriosis and adverse pregnancy and perinatal outcomes (preeclampsia, placenta previa, and preterm birth). METHODS: A population-based retrospective cohort study was conducted among 468,778 eligible women who contributed 912,747 singleton livebirths between 1980 and 2015 in Western Australia (WA). We used probabilistically linked perinatal and hospital separation data from the WA data linkage system's Midwives Notification System and Hospital Morbidity Data Collection databases. We used a doubly robust estimator by combining the inverse probability weighting with the outcome regression model to estimate adjusted risk ratios (RR) and 95% confidence intervals (CIs). RESULTS: There were 19,476 singleton livebirths among 8874 women diagnosed with endometriosis. Using a doubly robust estimator, we found pregnancies in women with endometriosis to be associated with an increased risk of preeclampsia with RR of 1.18, 95% CI 1.11-1.26, placenta previa (RR 1.59, 95% CI 1.42-1.79) and preterm birth (RR 1.45, 95% CI 1.37-1.54). The observed association persisted after stratified by the use of Medically Assisted Reproduction, with a slightly elevated risk among pregnancies conceived spontaneously. CONCLUSIONS: In this large population-based cohort, endometriosis is associated with an increased risk of preeclampsia, placenta previa, and preterm birth, independent of the use of Medically Assisted Reproduction. This may help to enhance future obstetric care among this population.

The Role of One-Carbon Metabolism and Methyl Donors in Medically Assisted Reproduction: A Narrative Review of the Literature.

One-carbon (1-C) metabolic deficiency impairs homeostasis, driving disease development, including infertility. It is of importance to summarize the current evidence regarding the clinical utility of 1-C metabolism-related biomolecules and methyl donors, namely, folate, betaine, choline, vitamin B12, homocysteine (Hcy), and zinc, as potential biomarkers, dietary supplements, and culture media supplements in the context of medically assisted reproduction (MAR). A narrative review of the literature was conducted in the PubMed/Medline database. Diet, ageing, and the endocrine milieu of individuals affect both 1-C metabolism and fertility status. In vitro fertilization (IVF) techniques, and culture conditions in particular, have a direct impact on 1-C metabolic activity in gametes and embryos. Critical analysis indicated that zinc supplementation in cryopreservation media may be a promising approach to reducing oxidative damage, while female serum homocysteine levels may be employed as a possible biomarker for predicting IVF outcomes. Nonetheless, the level of evidence is low, and future studies are needed to verify these data. One-carbon metabolism-related processes, including redox defense and epigenetic regulation, may be compromised in IVF-derived embryos. The study of 1-C metabolism may lead the way towards improving MAR efficiency and safety and ensuring the lifelong health of MAR infants.

Against age limits for men in reproductive care.

Almost all countries and fertility clinics impose age limits on women who want to become pregnant through Assisted Reproductive Technologies (ART). Age limits for aspiring fathers, however, are much less common and remain a topic of debate. This article departs from the principle of reproductive autonomy and a conditional positive right to receive ART, and asks whether there are convincing arguments to also impose age limits on aspiring fathers. After considering three consequentialist approaches to justifying age limits for aspiring fathers, we take in a concrete normative stance by concluding that those are not strong enough to justify such cut-offs. We reinforce our position by drawing a comparison between the case of a 39-year-old woman who wants to become a single mother via a sperm donor on the one hand, and on the other hand the same woman who wants to have a child with a 64-year-old man who she loves and who is willing to care for the child as long as he is able to. We conclude that, as long as appropriate precautions are taken to protect the welfare of the future child, couples who want to receive fertility treatment should never be limited on the basis of the age of the (male) partner. An absence of age limits for men would respect the reproductive autonomy of both the man and the woman.

Politics, law and a lack of sperm: single women and fertility treatment in the Swedish health system.

In 2016 Swedish law was amended to allow single women to access fertility treatment with donor sperm. In this paper, based on interviews, document analysis and autoethnographic insights, I examine the implementation of this law using human rights approaches, specifically the availability, accessibility, acceptability, and quality framework (AAAQ Framework). While the law extended the scope of reproductive rights, the health system was unprepared. Five years on, women seek care in the private sector or continue to travel abroad due in large part to waiting times which can be up to four years in some regions. The paper also provides a meeting point between anthropology and policy analysis. The law change provides a pathway for analyzing the Swedish health system and political context, particularly the relationships between the private and public sectors and between different regions, and the balance of responsibility between national and regional levels. While many of the challenges are unique to the Swedish context, they also offer lessons for countries which have or are considering expanding access to fertility treatment for single women and other patient groups, thus demonstrating the importance of ethnographic approaches in health policy analysis.

Evidence-based guideline: unexplained infertility†.

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.).

Genetics of infertility: a paradigm shift for medically assisted reproduction.

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.

The psychosocial outcomes of older parenthood in early to mid-childhood: a mini-review.

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.

Sexual growth and destiny beliefs: Longitudinal associations with dyadic coping among couples seeking medically assisted reproduction.

BACKGROUND: Medically assisted reproduction is a vulnerable time for couples' sexual health. Believing that sexual challenges can be worked through (i.e., sexual growth beliefs) or that these challenges indicate incompatibility (i.e., sexual destiny beliefs) may be related to dyadic coping-the strategies couples use to cope-with the physical and psychological stressors of medically assisted reproduction. AIM: In the current study we aimed to examine the longitudinal associations between typical (i.e., average) levels of sexual growth and destiny beliefs and positive and negative facets of dyadic coping and how greater than typical levels of these constructs predicted each other across time. METHODS: Couples (n = 219) seeking medically assisted reproduction were recruited for an online longitudinal, dyadic study. OUTCOMES: Couples completed online measures of sexual growth and destiny beliefs and positive and negative dyadic coping at baseline, 6-and 12-months. RESULTS: Random intercept cross-lagged panel models demonstrated that at the within-person level, reporting higher sexual growth beliefs at baseline, relative to their average across time points, was associated with lower negative dyadic coping at 6 months. Higher negative dyadic coping at 6 months, relative to their average, was linked to lower sexual growth beliefs at 12-months. When individuals reported higher sexual destiny beliefs at 6-months, relative to their average, they and their partners reported higher negative dyadic coping at 12 -months. At the between-person level, higher overall levels of sexual destiny beliefs were related to higher overall levels of negative dyadic coping. No associations with positive dyadic coping were identified. CLINICAL IMPLICATIONS: Couples may benefit from identifying and reducing unhelpful beliefs about sex and negative dyadic coping. STRENGTHS AND LIMITATIONS: Strengths of this study include our large, inclusive sample, engagement of community partners, and novel analytical approach to assess change over time. However, following couples in 6-month increments and not using questionnaires specific to medically assisted reproduction may have limited our ability to detect nuanced changes that couples experience during this time. CONCLUSION: Lower sexual growth and higher sexual destiny beliefs may promote couples' engagement in less adaptive coping behaviors as they seek medically assisted reproduction.

Partnership trajectories preceding medically assisted reproduction.

The number of people who undergo medically assisted reproduction (MAR) to conceive has increased considerably in recent decades. However, existing research into the demographics and the partnership histories of this growing subgroup is limited. Using unique data from Finnish population registers on nulliparous women born in Finland in 1971-77 (n = 21,129; ∼10 per cent of all women) who had undergone MAR treatment, we created longitudinal partnership histories from age 16 until first MAR treatment. We identified six typical partnership trajectories and used relative frequency sequence plots to investigate heterogeneity in partnership transitions within and between these groups. The majority of women (60.7 per cent) underwent MAR with their first partner, followed by women who underwent MAR in a second (21.5 per cent) or higher-order partnership (7.1 per cent), while 10.7 per cent underwent MAR without a partner. On average, women undergoing MAR were relatively young (with around half starting treatment before age 30) and were highly educated with high incomes.

Cryopreservation of Ovarian and Testicular Tissue and the Influence on Epigenetic Pattern.

Ovarian tissue cryopreservation (OTC) or testicular tissue cryopreservation (TTC) are effective and often the only options for fertility preservation in female or male patients due to oncological, medical, or social aspects. While TTC and resumption of spermatogenesis, either in vivo or in vitro, has still be considered an experimental approach in humans, OTC and autotransplantation has been applied increasingly to preserve fertility, with more than 200 live births worldwide. However, the cryopreservation of reproductive cells followed by the resumption of gametogenesis, either in vivo or in vitro, may interfere with sensitive and highly regulated cellular processes. In particular, the epigenetic profile, which includes not just reversible modifications of the DNA itself but also post-translational histone modifications, small non-coding RNAs, gene expression and availability, and storage of related proteins or transcripts, have to be considered in this context. Due to complex reprogramming and maintenance mechanisms of the epigenome in germ cells, growing embryos, and offspring, OTC and TTC are carried out at very critical moments early in the life cycle. Given this background, the safety of OTC and TTC, taking into account the epigenetic profile, has to be clarified. Cryopreservation of mature germ cells (including metaphase II oocytes and mature spermatozoa collected via ejaculation or more invasively after testicular biopsy) or embryos has been used successfully for many years in medically assisted reproduction (MAR). However, tissue freezing followed by in vitro or in vivo gametogenesis has become more attractive in the past, while few human studies have analysed the epigenetic effects, with most data deriving from animal studies. In this review, we highlight the potential influence of the cryopreservation of immature germ cells and subsequent in vivo or in vitro growth and differentiation on the epigenetic profile (including DNA methylation, post-translational histone modifications, and the abundance and availability of relevant transcripts and proteins) in humans and animals.

[Varicocele and male infertility]. / Varicocèle et infertilité masculine.

BACKGROUND: Varicocele is the most common correctable cause of male infertility. It was the subject of recent Association française d'urologie (AFU) Comité d'andrologie et de médecine sexuelle (CAMS) recommendations. Since then, the literature has provided additional information. This review will comprehensively reassess current indications for the treatment of varicocele, and revisit contemporary issues in the light of current advances. METHODS: Update of the literature search carried out as part of the CAMS recommendations for the period between 2020 and 2023. RESULTS: Microsurgical sub-inguinal varicocelectomy remains the surgical treatment of choice for infertile men with clinical varicocele and abnormal sperm parameters. It offers recurrence rates of less than 4%. It significantly improves both natural and in vitro fertilization live birth and pregnancy rates, as well as sperm count, total and progressive motility, morphology and DNA fragmentation rates. All in all, it modifies the MPA strategy in around one in two cases. Varicocele grade and bilaterality are predictive of improved sperm parameters and pregnancy rate. Treatment of subclinical varicocele is not recommended. Complications are rare, notably hydroceles (0.5%), unilateral testicular atrophy due to arterial damage (1/1000), hematomas, delayed healing and postoperative pain. Retrograde embolization is an alternative to surgery. CONCLUSION: Whenever possible, the urologist should present and discuss treatment options for varicocele with the MPA team and the patient, taking a personalized approach.

[The urologist's role in assisted reproductive technology (ART)]. / Place de l'urologue dans le parcours d'aide médicale à la procréation (AMP).

BACKGROUND: Following on from the Rapport vers une stratégie nationale de lutte contre l'infertilité (Report on a national strategy to combat infertility) submitted to the French Minister of Health in 2022, whose objective 13 is: to better identify and diagnose male infertility, we wanted to clarify with reproductive specialists what role the urologist should play in the management of the infertile couple. METHODS: An expert consensus was reached with the Pedagogical Committee and pilots of the Transversal Specialized Training in Reproductive Medicine and Biology - Andrology, and with the presidents, board and scientific council of the French Federation for Reproductive Study (FFER). RESULTS: In the case of infertility in a couple, the fertility of both partners should be assessed from the outset, and in the event of abnormality or failure of ART, the patient should be referred to a uro-andrologist for expert management. The uro-andrologist will set up medical or surgical treatments to improve the prognosis of the man's fertility, in conjunction with the entire ART team. It is also important for the urologist/andrologist to take charge of the man's health before conception, because of the benefits for the patient himself and for his offspring. CONCLUSION: This expert consensus has shed light on the role of the uro-andrologist in the ART pathway, on the need for training in Andrology and on the medical demography required.