Medicine in the marketplace: clinician and patient views on commercial influences on assisted reproductive technology.

RESEARCH QUESTION: What are the views and experiences of patient and expert stakeholders on the positive and negative impacts of commercial influences on the provision of assisted reproductive technology (ART) services, and what are their suggestions for governance reforms? DESIGN: Semi-structured interviews were conducted with 31 ART industry experts from across Australia and New Zealand and 25 patients undergoing ART from metropolitan and regional Australia, between September 2020 and September 2021. Data were analysed using thematic analysis. RESULTS: Expert and patient participants considered that commercial forces influence the provision of ART in a number of positive ways - increasing sustainability, ensuring consistency in standards and providing patients with greater choice. Participants also considered commercial forces to have a number of negative impacts, including increased costs to government and patients; the excessive use of interventions that lack sufficient evidence to be considered part of standard care; inadequately informed consent (particularly with regard to financial information); and threats to patient-provider relationships and patient-centred care. Participants varied in whether they believed that professional self-regulation is sufficient. While recognizing the benefits of commercial investment in healthcare, many considered that regulatory reforms, as well as organizational cultural initiatives, are needed as means to ensure the primacy of patient well-being. CONCLUSIONS: The views expressed in this study should be systematically and critically examined to derive insights into how best to govern ART. These insights may also inform the design and delivery of other types of healthcare that are provided in the private sector.

Risk for Congenital Anomalies in Children Conceived With Medically Assisted Fertility Treatment : A Population-Based Cohort Study.

BACKGROUND: More than 2 million children are conceived annually using assisted reproductive technologies (ARTs), with a similar number conceived using ovulation induction and intrauterine insemination (OI/IUI). Previous studies suggest that ART-conceived children are at increased risk for congenital anomalies (CAs). However, the role of underlying infertility in this risk remains unclear, and ART clinical and laboratory practices have changed drastically over time, particularly there has been an increase in intracytoplasmic sperm injection (ICSI) and cryopreservation. OBJECTIVE: To investigate the role of underlying infertility and fertility treatment on CA risks in the first 2 years of life. DESIGN: Propensity score-weighted population-based cohort study. SETTING: New South Wales, Australia. PARTICIPANTS: 851 984 infants (828 099 singletons and 23 885 plural children) delivered between 2009 and 2017. MEASUREMENTS: Adjusted risk difference (aRD) in CAs of infants conceived through fertility treatment compared with 2 naturally conceived (NC) control groups-those with and without a parental history of infertility (NC-infertile and NC-fertile). RESULTS: The overall incidence of CAs was 459 per 10 000 singleton births and 757 per 10 000 plural births. Compared with NC-fertile singleton control infants (n = 747 018), ART-conceived singleton infants (n = 31 256) had an elevated risk for major genitourinary abnormalities (aRD, 19.0 cases per 10 000 births [95% CI, 2.3 to 35.6]); the risk remained unchanged (aRD, 22 cases per 10 000 births [CI, 4.6 to 39.4]) when compared with NC-infertile singleton control infants (n = 36 251) (that is, after accounting for parental infertility), indicating that ART remained an independent risk. After accounting for parental infertility, ICSI in couples without male infertility was associated with an increased risk for major genitourinary abnormalities (aRD, 47.8 cases per 10 000 singleton births [CI, 12.6 to 83.1]). There was some suggestion of increased risk for CAs after fresh embryo transfer, although estimates were imprecise and inconsistent. There were no increased risks for CAs among OI/IUI-conceived infants (n = 13 574). LIMITATIONS: This study measured the risk for CAs only in those children who were born at or after 20 weeks' gestation. Observational study design precludes causal inference. Many estimates were imprecise. CONCLUSION: Patients should be counseled on the small increased risk for genitourinary abnormalities after ART, particularly after ICSI, which should be avoided in couples without problems of male infertility. PRIMARY FUNDING SOURCE: Australian National Health and Medical Research Council.

Serum GDF9 and BMP15 as potential markers of ovarian function in women with and without polycystic ovary syndrome.

OBJECTIVE: Growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) are critical paracrine regulators of female fertility and are predominantly expressed by oocytes. However, it is unknown if serum concentrations reflect changes in ovarian function and/or reproductive endocrine disorders. This study aimed to determine if serum GDF9/BMP15 are associated with ovarian, pituitary, oestrogenic, androgenic and metabolic characteristics and the ovarian pathologies, polycystic ovarian morphology (PCOM) and polycystic ovary syndrome (PCOS). DESIGN: Women aged 21-45 years (n = 381) were included from a cross-sectional study at the National University Hospital, Singapore. PATIENTS: Participants were volunteers and patients with possible PCOS. MEASUREMENTS: Anthropometric measurements, transvaginal ultrasound scans and serum sampling were performed and a questionnairecompleted. Serum GDF9 and BMP15 concentrations were matched with menstrual cycle length, ovarian protein and steroid hormone production, pituitary hormone production and metabolic assessments in women with PCOM or PCOS and those with neither (control). RESULTS: Serum GDF9 and BMP15 were detectable in 40% and 41% of women, respectively and were positively correlated with each other (r = 0.08, p = 0.003). GDF9, but not BMP15, was positively correlated with ovarian volume (p = 0.02) and antral follicle count (AFC) (p = 0.004), but not with anti-Müllerian hormone (p = 0.05). However, serum GDF9 and BMP15 concentrations were not significantly different between control, PCOM and PCOS women, nor associated with androgenic or metabolic PCOS features. However, the relationship between GDF9 and AFC differed between control, PCOM and PCOS women (p = 0.02). CONCLUSIONS: Serum GDF9 and BMP15 concentrations somewhat reflect ovarian but not androgenic or metabolic characteristics of PCOS, with increased GDF9 reflecting high AFC as seen in PCOM/PCOS.

Information and decision support needs: A survey of women interested in receiving planned oocyte cryopreservation information.

PURPOSE: Identifying the information and decision support needs of women interested in receiving planned oocyte cryopreservation (POC) information. METHODS: An online survey of Australian women, aged 18-45, interested in receiving POC information, proficient in English, with internet access. The survey covered POC information sources, information delivery preferences, POC and age-related infertility knowledge (study-specific scale), Decisional Conflict Scale (DCS), and time spent considering POC. Target sample size (n=120) was determined using a precision-based method. RESULTS: Of 332 participants, 249 (75%) had considered POC, whilst 83 (25%) had not. Over half (54%) had searched for POC information. Fertility clinic websites were predominately used (70%). Most (73%) believed women should receive POC information between ages 19-30 years. Preferred information providers were fertility specialists (85%) and primary care physicians (81%). Other methods rated most useful to deliver POC information were online. Mean knowledge score was 8.9/14 (SD:2.3). For participants who had considered POC, mean DCS score was 57.1/100 (SD:27.2) and 78% had high decisional conflict (score >37.5). In regression, lower DCS scores were associated with every 1-point increase in knowledge score (-2.4; 95% CI [-3.9, -0.8]), consulting an IVF specialist (-17.5; [-28.0, -7.1]), and making a POC decision (-18.4; [-27.5, -9.3]). Median time to decision was 24-months (IQR: 12.0-36.0) (n=53). CONCLUSION: Women interested in receiving POC information had knowledge gaps, and wanted to be informed about the option by age 30 years from healthcare professionals and online resources. Most women who considered using POC had high decisional conflict indicating a need for decision support.

Androgen signaling in adipose tissue, but less likely skeletal muscle, mediates development of metabolic traits in a PCOS mouse model.

Polycystic ovary syndrome (PCOS) is a common, multifactorial disorder characterized by endocrine, reproductive, and metabolic dysfunction. As the etiology of PCOS is unknown, there is no cure and symptom-oriented treatments are suboptimal. Hyperandrogenism is a key diagnostic trait, and evidence suggests that androgen receptor (AR)-mediated actions are critical to PCOS pathogenesis. However, the key AR target sites involved remain to be fully defined. Adipocyte and muscle dysfunction are proposed as important sites involved in the manifestation of PCOS traits. We investigated the role of AR signaling in white adipose tissue (WAT), brown adipose tissue (BAT), and skeletal muscle in the development of PCOS in a hyperandrogenic PCOS mouse model. As expected, dihydrotestosterone (DHT) exposure induced key reproductive and metabolic PCOS traits in wild-type (WT) females. Transplantation of AR-insensitive (AR-/-) WAT or BAT from AR knockout females (ARKO) into DHT-treated WT mice ameliorated some metabolic PCOS features, including increased body weight, adiposity, and adipocyte hypertrophy, but not reproductive PCOS traits. In contrast, DHT-treated ARKO female mice transplanted with AR-responsive (AR+/+) WAT or BAT continued to resist developing PCOS traits. DHT-treated skeletal muscle-specific AR knockout females (SkMARKO) displayed a comparable phenotype with that of DHT-treated WT females, with full development of PCOS traits. Taken together, these findings infer that both WAT and BAT, but less likely skeletal muscle, are key sites of AR-mediated actions involved in the experimental pathogenesis of metabolic PCOS traits. These data further support targeting adipocyte AR-driven pathways in future research aimed at developing novel therapeutic interventions for PCOS.NEW & NOTEWORTHY Hyperandrogenism is a key feature in the pathogenesis of polycystic ovary syndrome (PCOS); however, the tissue sites of androgen receptor (AR) signaling are unclear. In this study, AR signaling in white and brown adipose tissue, but less likely in skeletal muscle, was found to be involved in the development of metabolic PCOS traits, highlighting the importance of androgen actions in adipose tissue and obesity in the manifestation of metabolic disturbances.

Population-wide contribution of medically assisted reproductive technologies to overall births in Australia: temporal trends and parental characteristics.

STUDY QUESTION: In a country with supportive funding for medically assisted reproduction (MAR) technologies, what is the proportion of MAR births over-time? SUMMARY ANSWER: In 2017, 6.7% of births were conceived by MAR (4.8% ART and 1.9% ovulation induction (OI)/IUI) with a 55% increase in ART births and a stable contribution from OI/IUI births over the past decade. WHAT IS KNOWN ALREADY: There is considerable global variation in utilization rates of ART despite a similar infertility prevalence worldwide. While the overall contribution of ART to national births is known in many countries because of ART registries, very little is known about the contribution of OI/IUI treatment or the socio-demographic characteristics of the parents. Australia provides supportive public funding for all forms of MAR with no restrictions based on male or female age, and thus provides a unique setting to investigate the contribution of MAR to national births as well as the socio-demographic characteristics of parents across the different types of MAR births. STUDY DESIGN, SIZE, DURATION: This is a novel population-based birth cohort study of 898 084 births using linked ART registry data and administrative data including birth registrations, medical services, pharmaceuticals, hospital admissions and deaths. Birth (a live or still birth of at least one baby of ≥400 g birthweight or ≥20 weeks' gestation) was the unit of analysis in this study. Multiple births were considered as one birth in our analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included a total of 898 084 births (606 488 mothers) in New South Wales and the Australian Capital Territory, Australia 2009-2017. We calculated the prevalence of all categories of MAR-conceived births over the study period. Generalized estimating equations were used to examine the association between parental characteristics (parent's age, parity, socio-economic status, maternal country of birth, remoteness of mother's dwelling, pre-existing medical conditions, smoking, etc.) and ART and OI/IUI births relative to naturally conceived births. MAIN RESULTS AND THE ROLE OF CHANCE: The proportion of MAR births increased from 5.1% of all births in 2009 to 6.7% in 2017, representing a 30% increase over the decade. The proportion of OI/IUI births remained stable at around 2% of all births, representing 32% of all MAR births. Over the study period, ART births conceived by frozen embryo-transfer increased nearly 3-fold. OI/IUI births conceived using clomiphene citrate decreased by 39%, while OI/IUI births conceived using letrozole increased 56-fold. Overall, there was a 55% increase over the study period in the number of ART-conceived births, rising to 56% of births to mothers aged 40 years and older. In 2017, almost one in six births (17.6%) to mothers aged 40 years and over were conceived using ART treatment. Conversely, the proportion of OI/IUI births was similar across different mother's age groups and remained stable over the study period. ART children, but not OI/IUI children, were more likely to have parents who were socio-economically advantaged compared to naturally conceived children. For example, compared to naturally conceived births, ART births were 16% less likely to be born to mothers who live in the disadvantaged neighbourhoods after accounting for other covariates (adjusted relative risk (aRR): 0.84 [95% CI: 0.81-0.88]). ART- or OI/IUI-conceived children were 25% less likely to be born to immigrant mothers than births after natural conception (aRR: 0.75 [0.74-0.77]). LIMITATIONS, REASONS FOR CAUTION: The social inequalities that we observed between the parents of children born using ART and naturally conceived children may not directly reflect disparities in accessing fertility care for individuals seeking treatment. WIDER IMPLICATIONS OF THE FINDINGS: With the ubiquitous decline in fertility rates around the world and the increasing trend to delay childbearing, this population-based study enhances our understanding of the contribution of different types of MARs to population profiles among births in high-income countries. The parental socio-demographic characteristics of MAR-conceived children differ significantly from naturally conceived children and this highlights the importance of accounting for such differences in studies investigating the health and development of MAR-conceived children. STUDY FUNDING/COMPETING INTEREST(S): This study was funded through Australian National Health and Medical Research Council (NHMRC) grant: APP1127437. G.M.C. is an employee of The University of New South Wales (UNSW) and Director of the National Perinatal Epidemiology and Statistics Unit (NPESU), UNSW. The NPESU manages the Australian and New Zealand Assisted Reproduction Database with funding support from the Fertility Society of Australia and New Zealand. C.V. is an employee of The University of New South Wales (UNSW), Director of Clinical Research of IVFAustralia, Member of the Board of the Fertility Society of Australia and New Zealand, and Member of Research Committee of School of Women's and Children's Health, UNSW. C.V. reports grants from Australian National Health and Medical Research Council (NHMRC), and Merck KGaA. C.V. reports consulting fees, and payment or honoraria for lectures, presentations, speakers, bureaus, manuscript, writing or educational events or attending meeting or travel from Merck, Merck Sparpe & Dohme, Ferring, Gedon-Richter and Besins outside this submitted work. C.V. reported stock or stock options from Virtus Health Limited outside this submitted work. R.J.N. is an employee of The University of Adelaide, and Chair DSMC for natural therapies trial of The University of Hong Kong. R.J.N. reports grants from NHMRC. R.J.N. reports lecture fees and support for attending or travelling for lecture from Merck Serono which is outside this submitted work. L.R.J. is an employee of The UNSW and Foundation Director of the Centre for Big Data Research in Health at UNSW Sydney. L.R.J. reports grants from NHMRC. The other co-authors have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Patient burden and healthcare resource utilization of regimens for ovarian stimulation.

RESEARCH QUESTION: Do women receiving corifollitropin alfa with a gonadotrophin-releasing hormone (GnRH) antagonist experience less emotional and/or physical exhaustion than women receiving standard of care gonadotrophin with daily administration of GnRH agonist or antagonist? DESIGN: The CoRifollitropin EvAluation in PracTicE (CREATE) study was a prospective observational study of fertility clinics in 17 countries in Europe and the Asia-Pacific region. Women undergoing IVF were categorized by treatment. Group A received single-dose corifollitropin alfa plus a GnRH antagonist; group B received usual care daily gonadotrophin regimens with a GnRH agonist or antagonist; and group B1i received daily GnRH agonist injections. For the primary analysis, two items from the Controlled Ovarian Stimulation Impact questionnaire were used to assess the level of emotional and physical exhaustion associated with ovarian stimulation. Secondary end-points included the impact of ovarian stimulation-related healthcare resource use. RESULTS: No statistical difference was found between the percentage of participants reporting emotional exhaustion in group A (11.6%) and B (13.1%) or the percentage reporting being 'often' or 'always' physically exhausted. More participants in group B1i (16.4%) reported being emotionally exhausted 'often' or 'always' during ovarian stimulation compared with group A (11.6%; P = 0.026). Patient questionnaire scores for psychological impact were higher in group A compared with group B, indicating less negative impact (72.7 versus 70.9; P = 0.004). Group A had fewer clinic visits, physician consultations, nurse contacts and transvaginal ultrasound scans (all P < 0.001) than group B1. CONCLUSIONS: Treatment with corifollitropin alfa resulted in similar or numerically small differences in psychological impact and lower clinic service use compared with daily gonadotrophin regimens.

Multispectral autofluorescence characteristics of reproductive aging in old and young mouse oocytes.

Increasing age has a major detrimental impact on female fertility, which, with an ageing population, has major sociological implications. This impact is primarily mediated through deteriorating quality of the oocyte. Deteriorating oocyte quality with biological age is the greatest rate-limiting factor to female fertility. Here we have used label-free, non-invasive multi-spectral imaging to identify unique autofluorescence profiles of oocytes from young and aged animals. Discriminant analysis demonstrated that young oocytes have a distinct autofluorescent profile which accurately distinguishes them from aged oocytes. We recently showed that treatment with the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) restored oocyte quality and fertility in aged animals, and when our analysis was applied to oocytes from aged animals treated with NMN, 85% of these oocytes were classified as having the autofluorescent signature of young animals. Spectral unmixing using the Robust Dependent Component Analysis (RoDECA) algorithm demonstrated that NMN treatment altered the metabolic profile of oocytes, increasing free NAD(P)H, protein bound NAD(P)H, redox ratio and the ratio of bound to free NAD(P)H. The frequency of oocytes with simultaneously high NAD(P)H and flavin content was also significantly increased in mice treated with NMN. Young and Aged + NMN oocytes had a smoother spectral distribution, with the distribution of NAD(P)H in young oocytes specifically differing from that of aged oocytes. Identifying the multispectral profile of oocyte autofluorescence during aging could have utility as a non-invasive and sensitive measure of oocyte quality.

Four-dimensional ultrasound biometry following botulinum toxin type A injection to the pelvic floor.

AIMS: The objective of this study was to provide follow-up data on four-dimensional ultrasound (4DUS) morphometry for women having botulinum toxin type A (BoNT-A) treatment of pelvic floor tension myalgia (PFTM). MATERIALS AND METHODS: A prospective cohort study was performed from October 2013 to June 2018, recruiting women scheduled for BoNT-A injection in the pelvic floor musculature. Translabial 4DUS, vaginal pressure assessment by manometry and pain visual analog scales (VAS) were performed on all women before injection and again at 4, 12, and 26 weeks. The BoNT-A injection was performed under 4DUS guidance. RESULTS: Twenty-nine women had 44 injections over the course of the study. Although improvements were seen in VAS scores for dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia, there were no significant differences in ultrasound biometry at either rest, Valsalva, or on contraction when comparing postinjection measurements at 4, 12, and 26 weeks with pre-injection baseline. Similarly, vaginal pressure readings at rest demonstrated a significant improvement throughout the 4, 12, and 26 week follow-up, with a reduction in maximal contraction at 4 and 12 but not 26 weeks. CONCLUSIONS: This study demonstrates that 4DUS biometry of the pelvic floor does not correlate with clinical pain and vaginal pressure outcomes for BoNT-A injection in the context of PFTM.

A prospective, single-centre, single-arm, open label study of the long term use of a gonadotropin releasing hormone agonist (Triptorelin SR, 11.25 mg) in combination with Tibolone add-back therapy in the management of chronic cyclical pelvic pain.

BACKGROUND: Chronic cyclic pelvic pain (CCPP) affects women's quality of life and pituitary downregulation is often used for symptomatic relief. However, prolonged suppression of ovarian function is associated with menopausal side effects and can lead to osteoporosis. Currently, the use of gonadotropin releasing hormone agonists (GnRHa) for treatment of CCPP is usually restricted to 6-9 months, limiting their efficacy. There is limited information regarding safety and efficacy with longer-term use. The aim of this study is to examine the safety and efficacy of long-term (24 months) pituitary down-regulation with the GnRHa (Triptorelin SR) with add-back therapy (ABT) using Tibolone for symptom relief in women with CCPP. METHODS: A single-arm, prospective clinical trial at a Tertiary University Teaching Hospital of 27 patients receiving Triptorelin SR (11.25 mg) and Tibolone (2.5 mg). Outcomes measures were the safety of treatment assessed by clinical examination, haematological markers, liver and renal function tests and bone mineral density (BMD) at 12, 18 and 24 months as well as at 6 months post-treatment. Pain and health-related quality of life (HR-QoL) assessed using the endometriosis health profile (EHP-30) and chronic pain grade (CPG) questionnaires. RESULTS: There was no evidence for any significant harmful effects on any of the measured haematological, renal or liver function tests. Although results regarding the effect on BMD are not conclusive there is an increased risk of development of osteopaenia after 12 months of treatment. Pain and HRQoL assessments showed significant improvement during medication, but with deterioration after treatment cessation. CONCLUSION: Long- term Triptorelin plus Tibolone add-back therapy in women suffering from CCPP does not appear to be associated with significant serious adverse events apart from the possibility of deterioration in the BMD that needs to be monitored. This mode of therapy appears to be effective in pain relief and in improving quality of life over a 24-month period. TRIAL REGISTRATION: Clinical trials database NCT00735852.

Projecting future utilization of medically assisted fertility treatments.

This study estimates the future utilization of medically assisted fertility treatments in Australia, focusing on assisted reproductive technologies (ARTs), intrauterine insemination (IUI), and ovulation induction. A multistate cohort component population projection model is used to determine future fertility rates from 2016 to 2026 by age and education level. These are combined with information on recent trends in use and success rates to indirectly estimate future age-specific probabilities of fertility treatment utilization. The number of ART cycles is expected to increase by 61 per cent between 2016 and 2026 if treatment success rates remain at 2015 levels, or by 34 per cent if recent improvements in ART success rates continue. The model also predicts that numbers of IUI cycles and ovulation induction cycles will decrease by 17 and 3 per cent, respectively. This research confirms the importance of including both technological improvements and socio-demographic changes when predicting future fertility treatment utilization.

The Development of an International Oncofertility Competency Framework: A Model to Increase Oncofertility Implementation.

BACKGROUND: Despite international evidence about fertility preservation (FP), several barriers still prevent the implementation of equitable FP practice. Currently, oncofertility competencies do not exist. The aim of this study was to develop an oncofertility competency framework that defines the key components of oncofertility care, develops a model for prioritizing service development, and defines the roles that health care professionals (HCPs) play. MATERIALS AND METHOD: A quantitative modified Delphi methodology was used to conduct two rounds of an electronic survey, querying and synthesizing opinions about statements regarding oncofertility care with HCPs and patient and family advocacy groups (PFAs) from 16 countries (12 high and 4 middle income). Statements included the roles of HCPs and priorities for service development care across ten domains (communication, oncofertility decision aids, age-appropriate care, referral pathways, documentation, oncofertility training, reproductive survivorship care and fertility-related psychosocial support, supportive care, and ethical frameworks) that represent 33 different elements of care. RESULTS: The first questionnaire was completed by 457 participants (332 HCPs and 125 PFAs). One hundred and thirty-eight participants completed the second questionnaire (122 HCPs and 16 PFAs). Consensus was agreed on 108 oncofertility competencies and the roles HCPs should play in oncofertility care. A three-tier service development model is proposed, with gradual implementation of different components of care. A total of 92.8% of the 108 agreed competencies also had agreement between high and middle income participants. CONCLUSION: FP guidelines establish best practice but do not consider the skills and requirements to implement these guidelines. The competency framework gives HCPs and services a structure for the training of HCPs and implementation of care, as well as defining a model for prioritizing oncofertility service development. IMPLICATIONS FOR PRACTICE: Despite international evidence about fertility preservation (FP), several barriers still prevent the implementation of equitable FP practice. The competency framework gives 108 competencies that will allow health care professionals (HCPs) and services a structure for the development of oncofertility care, as well as define the role HCPs play to provide care and support. The framework also proposes a three-tier oncofertility service development model which prioritizes the development of components of oncofertility care into essential, enhanced, and expert services, giving clear recommendations for service development. The competency framework will enhance the implementation of FP guidelines, improving the equitable access to medical and psychological oncofertility care.

Infertility management in women and men attending primary care-patient characteristics, management actions and referrals.

STUDY QUESTION: How did general practitioners (GPs) (family physicians) manage infertility in females and males in primary care between 2000 and 2016? SUMMARY ANSWER: The number of GP infertility consultations for females increased 1.6 folds during the study period, with 42.9% of consultations resulting in a referral to a fertility clinic or specialist, compared to a 3-fold increase in the number of consultations for men, with 21.5% of consultations resulting in a referral. WHAT IS KNOWN ALREADY: Infertility affects one in six couples and is expected to increase with the trend to later childbearing and reports of declining sperm counts. Despite GPs often being the first contact for infertile people, very limited information is available on the management of infertility in primary care. STUDY DESIGN, SIZE, DURATION: Data from the Bettering the Evaluation and Care of Health programme were used, which is a national study of Australian primary care (general practice) clinical activity based on 1000 ever-changing, randomly selected GPs involved in 100 000 GP-patient consultations per year between 2000 and 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Females and males aged 18-49 years attending GPs for the management of infertility were included in the study. Details recorded by GPs included patient characteristics, problems managed and management actions (including counselling/education, imaging, pathology, medications and referrals to specialists and fertility clinics). Analyses included trends in the rates of infertility consultations by sex of patient, descriptive and univariate analyses of patient characteristics and management actions and multivariate logistic regression to determine which patient and GP characteristics were independently associated with increased rates of infertility management and referrals. MAIN RESULTS AND THE ROLE OF CHANCE: The rate of infertility consultations per capita increased 1.6 folds for women (17.7-28.3 per 1000 women aged 18-49 years) and 3 folds for men over the time period (3.4-10.2 per 1000 men aged 18-49 years). Referral to a fertility clinic or relevant specialist occurred in 42.9% of female infertility consultations and 21.5% of male infertility consultations. After controlling for age and other patient characteristics, being aged in their 30s, not having income assistance, attending primary care in later years of the study and coming from a non-English-speaking background, were associated with an increased likelihood of infertility being managed in primary care. In female patients, holding a Commonwealth concession card (indicating low income), living in a remote area and having a female GP all indicated a lower adjusted odds of referral to a fertility clinic or specialist. LIMITATIONS, REASONS FOR CAUTION: Data are lacking for the period of infertility and infertility diagnosis, which would provide a more complete picture of the epidemiology of treatment-seeking behaviour for infertility. Australia's universal insurance scheme provides residents with access to a GP, and therefore these findings may not be generalizable to other settings. WIDER IMPLICATIONS OF THE FINDINGS: This study informs public policy on how infertility is managed in primary care in different patient groups. Whether the management actions taken and rates of secondary referral to a fertility clinic or specialist are appropriate warrants further investigation. The development of clinical practice guidelines for the management of infertility would provide a standardized approach to advice, investigations, treatment and referral pathways in primary care. STUDY FUNDING/COMPETING INTEREST(S): This paper is part of a study being funded by an Australian National Health and Medical Research Council project grant APP1104543. G.C. reports that she is an employee of The University of New South Wales (UNSW) and Director of the National Perinatal Epidemiology and Statistics Unit (NPESU), UNSW. The NPESU manages the Australian and New Zealand Assisted Reproductive Technology Database on behalf of the Fertility Society of Australia. W.L. reports being a part-time paid employee and minor shareholder of Virtus Health, a fertility company. R.N. reports being a small unitholder in a fertility company, receiving grants for research from Merck and Ferring and speaker travel grants from Merck. TRIAL REGISTRATION NUMBER: NA.

Pregnancy following diagnosis of premature ovarian insufficiency: a systematic review.

The aim of this review is to report the occurrence of pregnancies in women with premature ovarian insufficiency (POI), naturally or with different treatments (hormonal replacement therapy, IVF, in-vitro maturation and stem cell therapy). This study involved an exhaustive search of the electronic databases MEDLINE, PubMed and Embase covering the period January 2000 to January 2018. A combination of Medical Subject Heading and text words was used to generate a subset of citations, including studies involving POI ('premature menopause' or 'premature ovarian failure' or 'POI' or 'hypergonadotrophic amenorrhoea'). This subset of citations was then combined with 'AND' to the Medical Subject Heading term 'pregnancy'. Fifteen studies were included in this review. Two randomized controlled trials, two observational studies, and 11 interventional studies reporting cases of pregnancy in women with POI were included. This review reports pregnancy rates across studies ranging from 2.2% to 14.2%. Mean age in patients who achieved a pregnancy was 30 years, highlighting that oocyte quality in these patients is likely unaffected. No treatment has thus far shown its superiority in improving fertility in women with POI. Recent advances in options such as in-vitro maturation and stem-cell therapy, however, are likely to be the future of treatment and may generate new hope for these patients.

Live birth rate and obstetric complications following the hysteroscopic management of intrauterine adhesions including Asherman syndrome.

STUDY QUESTION: What are the live birth rate and risks of obstetric complications following the surgical management of intrauterine adhesions (IUA) such as Asherman syndrome (AS)? SUMMARY ANSWER: The live birth rate is 63.7%, and obstetric complications including placentation issues, prematurity and postpartum hysterectomy require that pregnancies in women after treatment for IUA should be considered moderate to high risk. WHAT IS KNOWN ALREADY: Studies reviewing short-term surgical, menstrual and fertility outcomes following hysteroscopic management are reassuring, with success correlated to the severity of IUA. There are limited data reporting live birth, neonatal and maternal complications. STUDY DESIGN, SIZE, DURATION: This retrospective study included all women treated for IUA by hysteroscopic synechiolysis under fluoroscopic guidance in two tertiary University-affiliated hospitals. All women reported at least one pre-treatment symptom including menstrual dysfunction, subfertility or pelvic pain and intended to become pregnant post-treatment. Survival curve analysis was performed for time to pregnancy, and obstetric data were collated from a National Obstetric Database for delivery and neonatal outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 154 women were included in the study. Surgical intervention involved hysteroscopic synechiolysis under fluoroscopic guidance until cavity restoration was confirmed. Questionnaires regarding fertility and its outcomes were sent to all women undergoing surgery, with analysis of menstrual, fertility rates and outcomes of those pregnancies including risks and complications to the woman and the offspring. MAIN RESULTS AND THE ROLE OF CHANCE: Women were followed up for a minimum of 1 year (range: 1-14 years) from index surgery. The chance of pregnancy was 98/124 (79.0% CI: 63.6, 83.1%) in women wishing to conceive and the chance of a live birth was 79/124 (63.7% CI: 51.3, 70.7%). The chance of a miscarriage was 29/124 (23.4% CI: 18.8, 37.1%). There were 93 live births in 79 women following surgery, with detailed obstetric data available for 85 of these births. They were complicated by abnormal placentation in 15/85 (17.6% CI: 13.0, 30.2%), postpartum hysterectomy in 4/85 (4.7% CI: -0.4, 7.0%), and prematurity in 25/85 (29.4% CI: 17.0, 35.3%) women. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study and extended follow-up time may cause selection and recall bias, however, pregnancy and its outcomes-particularly in women with problems of subfertility-are frequently key milestones, with birthdates readily recalled. Menstrual outcomes are more likely to be subject to recall bias. WIDER IMPLICATIONS OF THE FINDINGS: Our surgical data are similar to the published literature with reassuring short-term outcomes for menstruation and cavity reconstruction following surgery for IUA. Long-term outcomes including pregnancy rates were higher than published data, however, the obstetric and neonatal complication rates were increased, indicating a continuation of risk beyond infertility and into pregnancy. An altered biochemical or vascular environment is a possible explanation for impaired implantation resulting in poorer reproductive obstetric and neonatal outcomes. The relative rarity of IUA-particularly severe disease-makes prospective data collection difficult. Our data suggest that women with IUA should be treated as moderate-high risk obstetric patients in subsequent pregnancy and counselled appropriately. STUDY FUNDING/COMPETING INTEREST(S): No funding and no competing interests.

In-vitro regulation of primordial follicle activation: challenges for fertility preservation strategies.

Ovarian tissue is increasingly being collected from cancer patients and cryopreserved for fertility preservation. While the only available option to restore fertility is autologous transplantation, this treatment is not appropriate for all patients due to the risk of reintroducing cancer cells and causing disease recurrence. Harnessing the full reproductive potential of this tissue to restore fertility requires the development of culture systems that support oocyte development from the primordial follicle stage. While this has been achieved in the mouse, the goal of obtaining oocytes of sufficient quality to support embryo development has not been reached in higher mammals despite decades of effort. In vivo, primordial follicles gradually exit the resting pool, whereas when primordial follicles are placed into culture, global activation of these follicles occurs. Therefore, the addition of a factor(s) that can regulate primordial follicle activation in vitro may be beneficial to the development of culture systems for ovarian tissue from cancer patients. Several factors have been observed to inhibit follicle activation, including anti-Müllerian hormone, stromal-derived factor 1 and members of the c-Jun-N-terminal kinase pathway. This review summarizes the findings from studies of these factors and discusses their potential integration into ovarian tissue culture strategies for fertility preservation.

Preserving fertility in women with cancer (PreFer): Decision-making and patient-reported outcomes in women offered egg and embryo freezing prior to cancer treatment.

OBJECTIVE: Women of childbearing age with new cancer diagnoses have to make rapid decisions about fertility preservation (FP) before starting cancer treatment (CT). The aim of the PreFer study was to explore this FP decision-making process and its impact on patient-reported outcomes (PROMs) and health-related quality of life (HRQoL). METHODS: A prospective, mixed-methods design was used (questionnaires, in-depth interviews). Interviews were analysed using thematic analysis. Fifty-eight women with new cancer diagnoses were recruited. Comparisons were made between women who declined FP referral in oncology (Group1) and women who chose referral (Group2). Group 2 was further split into those who had some FP (2A) and those who did not (2B). Questionnaires and PROMs were administered prior to and after the fertility consultation, before the start of CT and 3 months post CT. Interviews were conducted with one participant from Group 2. RESULTS: HRQoL was negatively affected, particularly depression. Women's lack of understanding about the relationship between CT and fertility were evident. Five themes emerged from the interviews as barriers and facilitators to the FP decision-making process. CONCLUSION: The results indicate that better information and support resources aimed at women to support their decision making are needed, such as patient decision-aids. Women from Group 1 were found to suffer significantly worse depression compared with the general UK population, highlighting the need for psychological support in the FP care-pathway and for research exploring the contributions of depression and hopelessness to the decision-making process.

Inter-observer and intra-observer agreement between embryologists during selection of a single Day 5 embryo for transfer: a multicenter study.

STUDY QUESTION: What is the inter-observer and intra-observer agreement between embryologists when selecting a single Day 5 embryo for transfer? SUMMARY ANSWER: The inter-observer and intra-observer agreement between embryologists when selecting a single Day 5 embryo for transfer was generally good, although not optimal, even among experienced embryologists. WHAT IS KNOWN ALREADY: Previous research on the morphological assessment of early stage (two pronuclei to Day 3) embryos has shown varying levels of inter-observer and intra-observer agreement. However, single blastocyst transfer is now becoming increasingly popular and there are no published data that assess inter-observer and intra-observer agreement when selecting a single embryo for Day 5 transfer. STUDY DESIGN, SIZE, DURATION: This was a prospective study involving 10 embryologists working at five different IVF clinics within a single organization between July 2013 and November 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: The top 10 embryologists were selected based on their yearly Quality Assurance Program scores for blastocyst grading and were asked to morphologically grade all Day 5 embryos and choose a single embryo for transfer in a survey of 100 cases using 2D images. A total of 1000 decisions were therefore assessed. For each case, Day 5 images were shown, followed by a Day 3 and Day 5 image of the same embryo. Subgroup analyses were also performed based on the following characteristics of embryologists: the level of clinical embryology experience in the laboratory; amount of research experience; number of days per week spent grading embryos. The agreement between these embryologists and the one that scored the embryos on the actual day of transfer was also evaluated. Inter-observer and intra-observer variability was assessed using the kappa coefficient to evaluate the extent of agreement. MAIN RESULTS AND THE ROLE OF CHANCE: This study showed that all 10 embryologists agreed on the embryo chosen for transfer in 50 out of 100 cases. In 93 out of 100 cases, at least 6 out of the 10 embryologists agreed. The inter-observer and intra-observer agreement among embryologists when selecting a single Day 5 embryo for transfer was generally good as assessed by the kappa scores (kappa = 0.734, 95% CI: 0.665-0.791 and 0.759, 95% CI: 0.622-0.833, respectively). The subgroup analyses did not substantially alter the inter-observer and intra-observer agreement among embryologists. The agreement when Day 3 images were included alongside Day 5 images of the same embryos resulted in a change of mind at least three times by each embryologist (on average for <10% of cases) and resulted in a small decrease in inter-observer and intra-observer agreement between embryologists (kappa = 0.676, 95% CI: 0.617-0.724 and 0.752, 95% CI: 0.656-808, respectively).The assessment of the inter-observer agreement with regard to morphological grading of Day 5 embryos showed only a fair-to-moderate agreement, which was observed across all subgroup analyses. The highest overall kappa coefficient was seen for the grading of the developmental stage of an embryo (0.513; 95% CI: 0.492-0.538). The findings were similar when the individual embryologists were compared with the embryologist who made the morphological assessments of the available embryos on the actual day of transfer. LIMITATIONS, REASONS FOR CAUTION: All embryologists had already completed their training and were working under one organization with similar policies between the five clinics. Therefore, the inter-observer agreement might not be as high between embryologists working in clinics with different policies or with different levels of training. WIDER IMPLICATIONS OF THE FINDINGS: The generally good, although not optimal uniformity between participating embryologists when selecting a Day 5 embryo for transfer, as well as, the surprisingly low agreement when morphologically grading Day 5 embryos could be improved, potentially resulting in increased pregnancy rates. Future studies need to be directed toward technologies that can help achieve this. STUDY FUNDING/COMPETING INTERESTS: None declared. TRIAL REGISTRATION NUMBER: Not applicable.

The safety and efficacy of controlled ovarian hyperstimulation for fertility preservation in women with early breast cancer: a systematic review.

STUDY QUESTION: Can controlled ovarian hyperstimulation (COH) for fertility preservation be effectively conducted in women with breast cancer without worsening their prognosis? SUMMARY ANSWER: COH with co-administration of letrozole suppresses oestradiol levels without significantly impacting oocyte yield or decreasing disease-free survival rates. WHAT IS KNOWN ALREADY: Oestradiol has the capacity to stimulate the proliferation of breast cancer cells. COH can cause oestradiol levels to rise by an order of magnitude above physiological levels. Concern exists regarding the effect of supra-physiological oestradiol levels in women with a recent diagnosis of breast cancer. STUDY DESIGN, SIZE, DURATION: A systematic review of the literature was performed using MEDLINE (PubMed database), EMBASE and the Cochrane Library. The search was restricted to articles written in English. No restrictions regarding the date of publication were applied. Safety was assessed in terms of relapse rates and cancer-related mortality rates. Peak oestradiol concentrations were recorded for different stimulation protocols. Efficacy was measured in terms of the total number of oocytes collected and proportion of mature oocytes. The primary outcome was mortality/recurrence in premenopausal women with Stage I-IIIB breast cancer who underwent COH in the immediate post-operative period, prior to chemotherapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: This is a systematic review of randomized control trials (RCTs), case control and cohort studies reporting on the primary outcome of mortality/recurrence after COH in women with early breast cancer, or secondary outcomes of oocyte yield and peak oestrogen concentration. Owing to the small number of RCTs available, other study types were included. The last electronic search was run in April 2016. Two prospective non-randomized studies reported relapse and breast cancer-related mortality rates in 397 women with breast cancer, of whom 149 underwent COH. Twelve studies reported the peak oestradiol concentrations of 882 women undergoing COH with letrozole co-administration. Four studies compared the oocyte yield of 248 women who underwent COH plus letrozole with 254 women who underwent standard COH. Two studies compared peak oestradiol concentrations and oocyte yield in 61 women who underwent COH with tamoxifen co-administration and 49 women who underwent COH without tamoxifen. One study compared letrozole and tamoxifen co-administration, and another study compared the co-administration of letrozole and anastrozole. MAIN RESULTS AND THE ROLE OF CHANCE: The search identified 1002 records of which 15 were included in the final analysis. There was no evidence of a decline in relapse-free survival rates in the two studies of women with breast cancer who received COH with letrozole co-administration compared with women who did not undergo fertility preservation procedures. The largest of these studies reported recurrences in 6/120 (5.0%) women who received COH plus letrozole compared with 12/217 (5.5%) women who did not undergo COH (mean follow-up 5.0 versus 6.9 years; hazard ratio for recurrence 0.77, 95%CI 0.28-2.13). Conclusions regarding women with breast cancer who received tamoxifen during COH could not be made due to insufficient data. Peak oestradiol concentrations (338-829 pg/ml) were suppressed by letrozole when commenced on Days 2-3, with no decrease in oocyte yield. Tamoxifen does not suppress oestradiol concentrations, but may convey protection via its inhibitory action on the oestrogen receptor. LIMITATIONS, REASONS FOR CAUTION: Any statements regarding the safety of COH in women with breast cancer are based on a limited number of observational studies. High quality evidence is unlikely to become available for ethical and practical reasons. Whilst available data do not indicate a decline in disease-free survival, a small effect cannot be excluded. Breast cancers are heterogeneous in their genetic profile and receptor status, making the results of studies difficult to generalize to individual cases. The implication of alterations in other hormone levels such as androgens, progestins or vascular endothelial growth factor secondary to COH in women with breast cancer has not been quantified. WIDER IMPLICATIONS OF THE FINDINGS: The co-administration of 5 mg of letrozole daily commencing on Day 2 and continuing throughout COH is recommended as it reduces peak oestradiol concentrations without significantly decreasing oocyte yield. The use of a GnRH agonist trigger is beneficial as oestradiol concentrations rapidly decrease post-administration and rates of ovarian hyperstimulation are lower than with an hCG trigger, without a corresponding reduction in clinical pregnancy or live birth rates in cryopreservation cycles. The protective effect of tamoxifen has not been evaluated although theoretically may be of benefit due to its action on the oestrogen receptor. STUDY FUNDING/COMPETING INTEREST(S): None. REGISTRATION NUMBER: None.