Patient and professional perspectives about using in vitro fertilisation add-ons in the UK and Australia: a qualitative study.

OBJECTIVES: In vitro fertilisation (IVF) add-ons are additional procedures offered alongside an IVF cycle with the aim of improving live birth rates. They are controversial because of the paucity of evidence to support their efficacy and safety, alongside the additional financial cost they often pose to patients. Despite this, they are popular. However, there is limited qualitative research regarding their use. The aims of the VALUE Study were to understand the decision-making process surrounding using or recommending add-ons; report sources of information for add-ons; and explore concerns for safety and effectiveness when considering their use. DESIGN: 'VALUE' is a qualitative semistructured interview study using inductive thematic analysis of anonymised transcriptions. SETTING: Participants were recruited from a broad geographical spread across the UK and Australia from public and private clinical settings. PARTICIPANTS: Patients (n=25) and health professionals (embryologists (n=25) and clinicians (n=24)) were interviewed. A purposive sampling strategy was undertaken. The sampling framework included people having state-subsidised and private cycles, professionals working in public and private sectors, geographical location and professionals of all grades. RESULTS: Patients often made decisions about add-ons based on hope, minimising considerations of safety, efficacy or cost, whereas professionals sought the best outcomes for their patients and wanted to avoid them wasting their money. The driving forces behind add-on use differed: for patients, a professional opinion was the most influential reason, whereas for professionals, it was seen as patient driven. For both groups, applying the available evidence to individual circumstances was very challenging, especially in the sphere of IVF medicine, where the stakes are high. CONCLUSIONS: There is scope to build on the quality of the discourse between patients and professionals. Patients describe valuing their autonomy with add-ons, but for professionals, undertaking informed consent will be critical, no matter where they sit on the spectrum regarding add-ons. TRIAL REGISTRATION: osf.io/vnyb9.

Is our public research money well spent? Publication of research outputs from Health Research Council of New Zealand-funded studies: a cross-sectional study.

OBJECTIVE: To evaluate the reporting of results from the projects and programmes funded by the Health Research Council (HRC) New Zealand. DESIGN: A cross-sectional analysis. SETTING: Research projects and programmes funded by the HRC New Zealand from 2006 to 2014. PARTICIPANTS: Publicly available data provided by the HRC. MAIN OUTCOME MEASURES: The number and proportion with evidence of publication and dissemination of a research output from HRC grants and the time taken to disseminate the results. RESULTS: Of the 374 HRC grants from 2006 to 2014, there was no evidence of publication or reporting of any research output for 48 studies (13%). Of the 326 (87%) grants with research outputs, there was a mean dissemination time of 4.73 years (SD 2.37). The total funding provided by the HRC was NZ$471 663 336, while the 48 grants with no evidence of dissemination represented NZ$47 095 727 (10%). CONCLUSIONS: Thirteen per cent of the HRC projects and programmes from 2006 to 2014 have not contributed to the healthcare evidence as their results remain unknown.

VALUE study: a protocol for a qualitative semi-structured interview study of IVF add-ons use by patients, clinicians and embryologists in the UK and Australia.

INTRODUCTION: For couples undergoing assisted reproduction, a plethora of adjuncts are available; these are known as 'add-ons'. Most add-ons are not supported by good quality randomised trial evidence of efficacy, with some proven to be ineffective. However, estimates suggest that over 70% of fertility clinics provide at least one add-on, often at extra cost to the patient. This study has three aims. First, to undertake a survey of in vitro fertilisation (IVF) clinics in the UK to ascertain which add-ons are being offered and at what cost. Second, to undertake qualitative semi-structured interviews of patients, clinicians and embryologists, to explore their opinions and beliefs surrounding add-ons. Third, to review the interpretation of the Human Fertilisation and Embryology Authority traffic light system, to better understand the information required by IVF patients, clinicians and embryologists when making decisions about add-ons. METHODS AND ANALYSIS: All UK IVF clinics will be contacted by email and invited to complete an online survey. The survey will ask them which add-ons they offer, at what cost per cycle and how information is shared with patients. Semi-structured interviews will be conducted in the UK and Australia with three groups of participants: (i) fertility patients; (ii) clinicians and (iii) embryologists. Participants for the interviews will be recruited via social media channels, website adverts, email and snowball sampling. Up to 20 participants will be recruited for each group in each country. Following an online consent process, interviews will be conducted via video-conferencing software, transcribed verbatim and data subjected to inductive thematic analysis. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Universities of Sheffield, Bath Spa and Melbourne. Findings will be published in a peer-reviewed journal and disseminated to regulatory bodies in the UK and Australia. A lay summary of findings will be shared via Fertility Network, UK.

IVF and IUI in couples with unexplained infertility (FIIX study): study protocol of a non-inferiority randomized controlled trial.

STUDY QUESTIONS: In couples with unexplained infertility and a poor prognosis of natural conception, are four cycles of IUI with ovarian stimulation (IUI-OS) non-inferior to one completed cycle of IVF for the outcome of cumulative live birth? Are four cycles of IUI-OS associated with a lower cost per live birth compared to one completed cycle of IVF? Will four cycles of IUI-OS followed by one complete cycle of IVF result in as many live births at lower cost per live birth, than two complete cycles of IVF? Will four cycles of IUI-OS followed by two complete cycles of IVF result in more live births at lower cost per live birth, than two complete cycles of IVF alone? WHAT IS KNOWN ALREADY: IUI is widely used in the USA, the UK and Europe as a low cost, less invasive alternative to IVF for couples with unexplained infertility. Although three to six cycles of IUI were comparable to IVF in the three major studies carried out to date, gonadotrophin ovarian stimulation was used in the majority of cases, and this also resulted in a high multiple pregnancy rate in some studies. Ovarian stimulation with clomiphene citrate is known to have lower multiple pregnancy rates. STUDY DESIGN SIZE DURATION: The FIIX study is a multicentre, open label, parallel, pragmatic non-inferiority randomized controlled trial of 580 couples with unexplained infertility comparing four cycles of IUI-OS with clomiphene citrate and one completed cycle of IVF. Variable block randomization stratified by age and clinic with electronic allocation will be used. PARTICIPANTS/MATERIALS SETTING METHODS: Couples with poor prognosis for natural conception and who are eligible for publicly funded fertility treatment in six fertility clinics in New Zealand. STUDY FUNDING/COMPETING INTERESTS: Auckland Medical Research Fund (3718892/1119003), A+ Trust, Auckland District Health Board (A + 8479), Maurice and Phyllis Paykel Trust (3718514). No competing interests. TRIAL REGISTRATION NUMBER: ACTRN12619001003167. TRIAL REGISTRATION DATE: 15 July 2019. DATE OF FIRST PATIENT'S ENROLMENT: 02/08/2019.

Clinician Identification of Birth Asphyxia Using Intrapartum Cardiotocography Among Neonates With and Without Encephalopathy in New Zealand.

Importance: Despite improvements in antenatal care and increasing cesarean delivery rates, birth asphyxia leading to neonatal encephalopathy (NE) continues to contribute to neonatal death and long-term neurodevelopmental disability. Cardiotocography (CTG) has been used in labor for several decades to detect a stressed fetus so that delivery can be expedited and NE avoided. Objective: To investigate whether experienced clinicians can detect and respond to abnormal readings from CTGs during the penultimate hour before birth in infants with moderate to severe NE but no acute peripartum event. Design, Setting, and Participants: This case-control study included 10 practicing obstetricians and midwives at maternity hospitals in New Zealand. Participants, who were masked to the perinatal outcome, were asked to assess CTG tracings from 35 neonates with NE and evidence of birth hypoxia (ie, cases) and 105 neonates without NE or birth hypoxia (ie, controls), all of whom were born in 2010 to 2011. Data analysis was conducted from May to December 2017. Exposures: Brief clinical details and 1 hour of CTG tracings from the penultimate hour before birth were provided for each baby. Clinicians assessed the CTG tracings and recommended a plan. Main Outcomes and Measures: Intra-assessor and interassessor agreement on CTG findings and action plans as well as sensitivity (ie, detection of NE) and specificity (ie, ruling out those without NE) for the assessment of abnormal CTG readings leading to immediate action (ie, fetal blood sample or immediate delivery) were reported. Results: A total of 35 infants (mean [SD] gestational age, 40 [1.4] weeks; 16 [45.7%] cesarean deliveries) were designated cases, and 105 infants (mean [SD] gestational age, 39.4 [1.2] weeks; 22 [21.0%] cesarean deliveries) were designated controls. No infants had congenital anomalies. The mean (range) sensitivity for detection of abnormal CTG results and for recommending immediate action for all assessors was 75% (63%-91%) and 41% (23%-57%), respectively, with a mean (range) specificity of 67% (53%-77%) and 87% (65%-99%), respectively. A sensitivity analysis including only assessors with 80% or more interassessor agreement only differed from the main analysis by 6% or less (mean [range] sensitivity for detection, 76% [63%-91%]; sensitivity for action plan, 36% [25%-49%]; specificity for detection, 71% [53%-77%]; and specificity for action plan, 93% [88%-99%]). Conclusions and Relevance: Experienced clinicians detected 3 of 4 infants who were subsequently diagnosed with NE. Action to expedite delivery was recommended for more than 40% of infants with NE. These results indicate that CTG does not identify all infants at risk of NE, and that there is a need for further investment in new approaches to fetal surveillance in labor.

Effectiveness of social egg freezing: protocol for systematic review and meta-analyses.

INTRODUCTION: Social egg freezing is storing egg for the purpose of preserving fertility and delayed childbearing. Currently, little is known about the utilisation and effectiveness of this approach. This review aims to determine (1) the proportion of women who used their stored eggs, and (2) the egg survival rate through vitrification, and the clinical pregnancy rate and live birth rate per 100 women partaking in the procedure, and among women who stored their eggs for medical reasons. METHODS AND ANALYSES: This systematic review will be done according to the items listed in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Embase, Scopus, The Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the Cochrane Library and Health Technology Assessment databases will be searched to identify eligible studies published since 2012. Two reviewers will independently appraise the eligibility and quality of the studies based on preset checklists and extract the data using a data extraction template. Outcomes of interest are proportion of women who used their stored eggs, egg survival rate, pregnancy rate and live birth rates. We will determine the presence heterogeneity among studies using the Cochrane's Q test. The percentage of total variation across studies, which is due to statistical heterogeneity, will be calculated using the I2 statistics. Outcomes of interest will be pooled together using metaprop programme STATA V.14. ETHICS AND DISSEMINATION: For this review, ethical committee approval is not required. We will use publically available data from previously published studies. The final report of the review will be disseminated through publication on national or international journal, and it will be presented on different scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42018114254.

Female subfertility.

Subfertility is common and affects one in six couples, half of whom lack an explanation for their delay in conceiving. Developments in the diagnosis and treatment of subfertility over the past 50 years have been truly remarkable. Indeed, current generations of couples with subfertility are more fortunate than previous generations, as they have many more opportunities to become parents. The timely access to effective treatment for subfertility is important as many couples have a narrow window of opportunity before the age-related effects of subfertility limit the likelihood of success. Assisted reproduction can overcome the barriers to fertility caused by tubal disease and low sperm count, but little progress has been made in reducing the effect of increasing age on ovarian function. The next 5-10 years will likely see further increases in birth rates in women with subfertility, a greater awareness of lifestyle factors and a possible refinement of current assisted reproduction techniques and the development of new ones. Such progress will bring challenging questions regarding the potential benefits and harms of treatments involving germ cell manipulation, artificial gametes, genetic screening of embryos and gene editing of embryos. We hope to see a major increase in fertility awareness, access to safe and cost-effective fertility care in low-income countries and a reduction in the current disparity of access to fertility care.

Intrauterine insemination with ovarian stimulation versus expectant management for unexplained infertility (TUI): a pragmatic, open-label, randomised, controlled, two-centre trial.

BACKGROUND: Women with unexplained infertility are often offered intrauterine insemination (IUI) with ovarian stimulation as an alternative to in-vitro fertilisation (IVF). However, little evidence exists that IUI is an effective treatment. In 2013, the UK National Institute for Health and Care Excellence recommended that IUI should not be routinely offered for couples with unexplained infertility. METHODS: For this pragmatic, open-label, randomised, controlled, two-centre study, we enrolled women attending two fertility clinics in New Zealand with unexplained infertility and an unfavourable prognosis of natural conception. Participants were randomly assigned (1:1) using a computer-generated randomisation sequence, prepared by an independent statistician, to either three cycles of IUI with ovarian stimulation (with either oral clomifene citrate [50-150 mg, days 2-6] or oral letrozole [2·5-7·5 mg, days 2-6], with choice of ovarian stimulation made by the clinic) or three cycles of expectant management (couples advised to be sexually active around the likely time of ovulation and provided with a diary to record the first day of each menstrual cycle and dates of sexual activity) in blocks of four, six, and ten, without stratification. The participating couple and the clinicians were informed of treatment allocation. The primary outcome was cumulative livebirth rate in the intention-to-treat population. The safety analyses were done in the intention-to-treat population. This study was prospectively registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612001025820. FINDINGS: Between March 12, 2013, and May 12, 2016, we randomly assigned 101 women to IUI with ovarian stimulation and 100 to expectant management, all of whom were included in the primary efficacy analysis and safety analyses. Women assigned to IUI had a higher cumulative livebirth rate than women assigned to expectant management (31 [31%] livebirths among 101 women vs nine [9%] livebirths among 100 women; risk ratio [RR] 3·41, 95% CI 1·71-6·79; p=0·0003). Of 31 livebirths in the IUI group, 23 resulted from IUI cycles and eight were conceived without assistance before or between IUI cycles. Of nine livebirths in the expectant management group, one patient was pregnant from IUI with ovarian stimulation at study entry and one had received off-protocol treatment (IVF). Two sets of twins were born, both in the IUI group (one from a cancelled cycle for over-response). INTERPRETATION: IUI with ovarian stimulation is a safe and effective treatment for women with unexplained infertility and an unfavourable prognosis for natural conception. FUNDING: Auckland Medical Research Foundation, Evelyn Bond Fund of Auckland District Health Board, Mercia Barnes Trust of Royal Australian and New Zealand College of Obstetricians and Gynaecologists, Maurice and Phyllis Paykel Trust, and The Nurture Foundation for Reproductive Research.

Incidence, risk factors and perinatal outcomes for placenta accreta in Australia and New Zealand: a case-control study.

OBJECTIVE: Estimate the incidence of placenta accreta and describe risk factors, clinical practice and perinatal outcomes. DESIGN: Case-control study. SETTING: Sites in Australia and New Zealand with at least 50 births per year. PARTICIPANTS: Cases were women giving birth (≥20 weeks or fetus ≥400 g) who were diagnosed with placenta accreta by antenatal imaging, at operation or by pathology specimens between 2010 and 2012. Controls were two births immediately prior to a case. A total of 295 cases were included and 570 controls. METHODS: Data were collected using the Australasian Maternity Outcomes Surveillance System. PRIMARY AND SECONDARY OUTCOME MEASURES: Incidence, risk factors (eg, prior caesarean section (CS), maternal age) and clinical outcomes of placenta accreta (eg CS, hysterectomy and death). RESULTS: The incidence of placenta accreta was 44.2/100 000 women giving birth (95% CI 39.4 to 49.5); however, this may overestimated due to the case definition used. In primiparous women, an increased odds of placenta accreta was observed in older women (adjusted OR (AOR) women≥40 vs <30: 19.1, 95% CI 4.6 to 80.3) and current multiple birth (AOR: 6.1, 95% CI 1.1 to 34.1). In multiparous women, independent risk factors were prior CS (AOR ≥2 prior sections vs 0: 13.8, 95% CI 7.4 to 26.1) and current placenta praevia (AOR: 36.3, 95% CI 14.0 to 93.7). There were two maternal deaths (case fatality rate 0.7%).Women with placenta accreta were more likely to have a caesarean section (AOR: 4.6, 95% CI 2.7 to 7.6) to be admitted to the intensive care unit (ICU)/high dependency unit (AOR: 46.1, 95% CI 22.3 to 95.4) and to have a hysterectomy (AOR: 209.0, 95% CI 19.9 to 875.0). Babies born to women with placenta accreta were more likely to be preterm, be admitted to neonatal ICU and require resuscitation.

Gynaecologists and industry: ain't no sunshine.

The field of reproductive medicine is known for its innovations, and where there is innovation there is marketing and engagement with the doctors who are potential prescribers and users of those innovations. Financial connections between drug and device manufacturers with doctors have been extensively debated over the past decade. On one hand, relationships between doctors and industry could be considered synergistic by allowing the development of improved treatments. On the other hand, payment (and other benefits) from industry to doctors may subtly shift the main objective of the collaboration from patients' health to mutual benefits for both doctors and industry. Fertility patients can be considered 'vulnerable' as they face the multiple challenges of seeking to be parents, understanding complex and expensive fertility treatments that are by no means universally successful, and at the same time are under pressure because of their ever-increasing age. They are entitled to receive the most cost-effective treatments. We suggest that specialists in the field of reproductive medicine should be transparent about the receipt of financial benefits, including funding from industry, as it may be influencing both research outcomes and treatments that patients are offered. We also recommend that payments arising from industry-sponsored research should be centralized in institutional funds and not paid directly to researchers. And there should be transparency about the source and the purpose of the payment. Industry sponsorship of medical societies and their educational events should be kept to a minimum and declared quantitatively in societies' websites and scientific programme brochures. Industry sponsorship of scientific meetings should not include the right to host educational symposia or speakers within the programme. All speakers should declare their conflicts of interest (COIs) at their meetings. Guideline groups should require all members to declare their financial COIs before meeting and exclude or limit those members with COI. Governmental authorities should not allow continuing medical education credits to those educational events not complying with the above policies. The crucial role of medical journals as 'gatekeepers' for identifying 'science' must be reaffirmed.

Clinical trial registration in fertility trials - a case for improvement?

STUDY QUESTION: What is the prevalence and source of prospectively and retrospectively registered and unregistered trials in fertility treatments? SUMMARY ANSWER: Trial registration is low and does not appear to be changing over the 5 years studied. WHAT IS KNOWN ALREADY: Trial registration is associated with lower risk of bias than in unregistered trials. STUDY DESIGN, SIZE, DURATION: The Cochrane Gynaecology and Fertility Group's specialised register was searched on 5 November 2015 for randomised controlled trials (RCTs) published from January 2010 to December 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible trials included randomised women or men for fertility treatments, were published in full text, and written in English. Two reviewers independently assessed trial registration status for each trial, by searching the publication, trial registries, and by contacting the original authors. MAIN RESULTS AND ROLE OF CHANCE: Of 693 eligible RCTS, only 44% were registered trials. Of 309 registered trials, 21.7% were prospectively registered, 15.8% were registered within 6 months of first patient enrolment and 62.5% were retrospectively registered trials. Prospective trial registration by country varied from 0% to 100%. The highest frequency of prospective trial registration amongst the top 10 publishing countries was 31% in the Netherlands. LIMITATIONS, REASONS FOR CAUTION: Only English language trials were included in this review. WIDER IMPLICATIONS OF THE FINDINGS: Prospective trial registration is still low. Journals, funders and ethics committees could have a greater role to increase trial registration. STUDY FUNDING/COMPETING INTERESTS: University of Auckland. No competing interests.

Baseline anatomical assessment of the uterus and ovaries in infertile women: a systematic review of the evidence on which assessment methods are the safest and most effective in terms of improving fertility outcomes.

BACKGROUND: This review focuses on the initial presentation of women who suspect that they are infertile, and how best to assess the anatomy of their uterus and ovaries in order to investigate the cause of their infertility, and potentially improve desired fertility outcomes. This review was undertaken as part of a World Health Organization initiative to assess the evidence available to address guidance for the diagnosis and treatment of infertility within a global context. Providing access to care for infertile women will help to ease the psycho-social burdens, such as ostracization, intimate partner violence and other negative consequences of being involuntarily childless or unable to become pregnant despite desiring a biological child or children. OBJECTIVE AND RATIONALE: The aim of this paper was to present an evidence base for the diagnostic and prognostic value of various investigations used for detecting uterine and/or ovarian pathology in women presenting at fertility clinics for their initial assessment. SEARCH METHODS: We performed a comprehensive search of relevant studies on 28 August and 10 September 2014. A further search was performed on 6 June 2016 to ensure all possible studies were captured. These strategies were not limited by date or language. The search returned 3968 publications in total; 63 full text articles were retrieved and 10 additional studies were found through hand-searching. After excluding 54, a total of 19 studies were analysed. We extracted and tabulated data on the characteristics, quality and results of each eligible study and combined the findings in a narrative synthesis. Risk of bias was assessed according to article type using tools such as assessment of the methodological quality of systematic reviews, Newcastle Ottawa Scale, Cochrane risk of bias tool, quality assessment tool for diagnostic accuracy studies and quality in prognostic studies. Nineteen studies were selected as being the best evidence available. A narrative synthesis of the data was undertaken. Discussion of the data, and resultant consensus for best practice were accomplished in a consensus expert consultation in Geneva, October 2015. An independent expert review process concerning this work and outcomes was conducted during 2016. OUTCOMES: The draft recommendations presented here apply to infertile women whether or not they are undergoing fertility treatment. Transvaginal ultrasound (TVUS) should be offered to all infertile women with symptoms or signs of anatomic pelvic pathology. TVUS should not be offered routinely to women without symptoms of pelvic pathology. Hysteroscopy should be offered if intrauterine pathology is suspected by TVUS. Hysteroscopy should not be routinely offered to infertile women who have normal TVUS findings. In women who have normal TVUS findings and are undergoing IVF, hysteroscopy does not improve the outcome. Good practice points recommend that providers of fertility care should confirm that all infertile women have a recent pelvic examination, recent cervical screening and well-woman screening in line with local guidelines. Additionally, hystero-contrast salpingography in infertile women does not improve clinical pregnancy rates with expectant management in heterosexual couples and should not be offered as a therapeutic procedure. Most of the findings of this review on diagnosis are based on a low, or very low, quality of evidence, according to GRADE Working Group (grading of recommendations, assessment, development and evaluation) criteria. A low quality grading indicates that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate, while a very low grade indicates that any estimate of effect is very uncertain. WIDER IMPLICATIONS: This review provides the most reliable evidence available to guide clinicians worldwide in the initial, evidence-based investigation of women with fertility problems in order to undertake the most useful investigation and avoid the burden of unnecessary tests.

Clinical trial registration was not an indicator for low risk of bias.

OBJECTIVES: To determine the prevalence of registered trials and to evaluate the risk of bias between registered and unregistered clinical trials. STUDY DESIGN AND SETTING: The Cochrane Gynecology and Fertility Group's specialized register was searched on November 5, 2015, for randomized controlled trials published from 2010 to 2014. Studies were selected if they had randomized women or men for fertility treatments, were published in full text and written in English. Two reviewers then independently assessed trial registration status for each trial, by searching the publication, trial registries, and by contacting the original authors. RESULTS: Of 693 eligible randomized controlled trials, only 44% were found to be registered. Unregistered clinical trials had smaller sample sizes than registered trials (P < 0.001). A random subsample of 125 registered and 125 unregistered trials was assessed for risk of bias using five of the Cochrane Risk of Bias "domains." Registered and unregistered trials differed in their risk of bias for random sequence generation (P = 0.001), allocation concealment (P = 0.003), and selective reporting (P < 0.001) but not blinding or incomplete outcome data (P > 0.05) domains. Only 54 (43.2%) of the 125 registered trials were registered prospectively. This study has the following limitations. Only English language trials were included in this review. We were unable to obtain protocols for the unregistered trials and therefore were unable to assess the risk of bias in the selective reporting domain. CONCLUSIONS: All available trials should be included in systematic reviews and assessed for risk of bias as there are both registered trials with high risk of bias and unregistered trials with low risk of bias and by excluding unregistered trials more than half of the available evidence will be lost.

There were large discrepancies in risk of bias tool judgments when a randomized controlled trial appeared in more than one systematic review.

OBJECTIVES: To assess the consistency in risk of bias (RoB) judgments across Cochrane reviews for studies appearing in more than one Cochrane review in the field of subfertility. STUDY DESIGN AND SETTING: We retrieved any study that had been used more than once in systematic reviews present on the Cochrane Database of Systematic Reviews in the area of subfertility. We then retrieved the recorded RoB assessments for these studies and looked at the consistency of judgments made between different authoring teams on the same trials. RESULTS: From the 156 bias judgments that were completed by at least two separate groups of authors, 45% of these judgments differed. For the domains of random sequence generation and incomplete outcome data, there was reasonably high level of agreement (71% and 79%, respectively). However, for the domain of blinding, agreement was reached in only 35% of cases. CONCLUSION: This assessment of how consistently the RoB is being applied in Cochrane reviews has shown that, especially in some domains, there are large discrepancies in how RoB is being evaluated. Further work needs to be undertaken to improve the application of this tool.

Population trends and live birth rates associated with common ART treatment strategies.

STUDY QUESTION: Have ART live birth rates improved in Australia over the last 12 years? SUMMARY ANSWER: There were striking improvements in per-cycle live birth rates observed for frozen/thaw embryo transfers, blastocyst transfer and single embryo transfer (SET), while live birth rates following ICSI were lower than IVF for non-male factor infertility in most years. WHAT IS ALREADY KNOWN: ART and associated techniques have become the predominant treatment of infertility over the past 30 years in most developed countries. However, there are differences in ART laboratory and clinical practices, and success rates worldwide. Australia has one of the highest ART utilization rates and lowest multiple birth rates in the world, thus providing a unique setting to investigate the contribution of common ART strategies in an unrestricted population of patients to ART success rates. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of 585 065 ART treatment cycles performed in Australia between 2002 and 2013 using the Australian and New Zealand Assisted Reproduction Database (ANZARD). PARTICIPANTS MATERIALS, SETTING, METHOD: An unrestricted population of all women who underwent autologous ART treatment between 2002 and 2013. Visual descriptive analysis was used to assess the trends in ART procedures by the calendar years. Adjusted odds ratios (aORs) of a live birth for four common ART techniques were calculated after controlling for important confounders including female age, infertility diagnosis, stage of the embryo (blastocyst versus cleavage stage), type of embryo (fresh versus thawed), fertilization method (IVF versus ICSI) and number of embryos transferred (SET versus multiple embryos). MAIN RESULTS AND THE ROLE OF CHANCE: The overall live birth rate per embryo transfer increased from 19.2% in 2002 to 23.3% in 2013 (21.9-24.3% for fresh embryo transfers and 14.6-23.3% for frozen/thaw embryo transfers). This occurred concurrently with an increase in SET from 29.7% to 78.9%, and an increase in the average age of women undergoing treatment from 35.0 to 35.9 years. Individuals who had a frozen/thaw embryo transfer cycle in 2002 had 43% (aOR: 0.57, 95% CI: 0.53-0.61) reduced odds of a live birth compared with a fresh embryo transfer cycle. This contrasted with 16% (aOR: 0.84, 95% CI: 0.80-0.98) reduced odds of a live birth from frozen/thaw embryo transfer cycles in 2013. In 2013, the odds of blastocyst transfer resulting in a live birth were more than twice as great as for cleavage stage transfer (aOR 2.01, 95% CI: 1.92-2.11). The adjusted odds of live birth per SET compared with multiple embryo transfer increased significantly over the last 12 years, from a 38% reduced odds of a live birth follow SET in 2002 (aOR: 062, 95% CI: 0.57-0.67) compared to an 8% reduced odds in 2013 (aOR: 0.92, 95% CI: 0.87-0.98). The aOR of a live birth using ICSI compared to IVF in non-male factor patients was lower in most years bringing into question its widespread use. LIMITATION, REASONS FOR CAUTION: This is a retrospective cohort analysis and cannot confirm causality. High-level evidence on the effectiveness of particular ART techniques, particularly ICSI and blastocyst culture, requires prospective randomized controlled trials or detailed statistical analysis using large-scale data that counts for fertilization failure, embryo loss, prognostic factors and cycle characteristics. WIDER IMPLICATION OF THE FINDINGS: The most striking improvements in ART success rates in Australia have been observed for frozen/thaw embryo transfers, blastocyst transfer and SET. Further studies of the role of ICSI in non-male factor infertility and blastocyst transfer success rates that take into account embryo loss are needed. STUDY FUNDING/COMPETING INTERESTS: No funding was received to undertake this study. The authors declare that they do not have competing interests with this study. TRIAL REGISTRATION NUMBER: NA.

Body mass index trumps age in decision for endometrial biopsy: cohort study of symptomatic premenopausal women.

BACKGROUND: Clinical guidelines recommend that women with abnormal uterine bleeding with risk factors have an endometrial biopsy to exclude hyperplasia or cancer. Given the majority of endometrial cancer occurs in postmenopausal women, it has not been widely recognized that obesity is a significant risk factor for endometrial hyperplasia and cancer in young, symptomatic, premenopausal women. OBJECTIVE: We sought to evaluate the effect of body mass index on risk of endometrial hyperplasia or cancer in premenopausal women with abnormal uterine bleeding. STUDY DESIGN: This was a retrospective cohort study in a single large urban secondary women's health service. Participants were 916 premenopausal women referred for abnormal uterine bleeding of any cause and had an endometrial biopsy from 2008 through 2014. The primary outcome was complex endometrial hyperplasia (with or without atypia) or endometrial cancer. RESULTS: Almost 5% of participants had complex endometrial hyperplasia or cancer. After adjusting for clinical and demographic factors, women with a measured body mass index ≥30 kg/m2 were 4 times more likely to develop complex hyperplasia or cancer (95% confidence interval, 1.36-11.74). Other risk factors were nulliparity (adjusted odds ratio, 3.08; 95% confidence interval, 1.43-6.64) and anemia (adjusted odds ratio, 2.23; 95% confidence interval, 1.14-4.35). Age, diabetes, and menstrual history were not significant. CONCLUSION: Obesity is an important risk factor for complex endometrial hyperplasia or cancer in premenopausal women with abnormal uterine bleeding who had an endometrial biopsy in a secondary gynecology service. As over half of women with the outcome in this study were age <45 years, deciding to biopsy primarily based on age, as currently recommended in national guidelines, potentially misses many cases or delays diagnosis. Body mass index should be the first stratification in the decision to perform endometrial biopsy and/or to refer secondary gynecology services.

Validation of local review for the identification of contributory factors and potentially avoidable perinatal deaths.

BACKGROUND: Reporting on perinatal mortality commenced 2006 in New Zealand through the Perinatal and Maternal Mortality Review Committee (PMMRC). Following review of international models, a process was developed for use in local review to identify contributory factors and potentially avoidable perinatal deaths. Local review of 720 perinatal deaths in 2009 found contributory factors in 24% of deaths and 14% to be potentially avoidable. AIMS: To validate the process of local review for identification of contributory factors and potentially avoidable perinatal deaths. MATERIAL AND METHODS: Records of 48 perinatal deaths were reviewed by an independent multidisciplinary panel using the same methodology as local review to determine agreement between local and independent review for identification of contributory factors and potentially avoidable perinatal death. RESULTS: Independent review found contributory factors in 54% of deaths compared to 40% by local review. Independent review identified eight deaths and local review identified one death with contributory factors not identified by the other review. Kappa statistic for agreement for identifying contributory factors was substantial [0.63 (0.42, 0.84)]. Independent review found 42% of deaths potentially avoidable compared to 23% by local review. Independent review identified 10 deaths and local review identified one death not identified by the other review. Kappa statistic for agreement for identifying potentially avoidable deaths was moderate [0.50 (0.26, 0.73)]. CONCLUSIONS: This study provides validation of local review for identification of contributory factors in perinatal death. The higher proportion of potentially avoidable perinatal deaths identified by independent review compared to local review requires further exploration.