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There are conflicting narratives over what drives demand for add-ons. We undertook an online survey of IVF patients to determine whether patients perceive that use of IVF add-ons is driven by patients or practitioners. People who underwent IVF in the UK in the previous five years were recruited via social media Survey questions focussed on the roles of clinician offer and patient request, including who first suggested use of add-ons in IVF consultations, where patients first heard about them, and which information sources they trusted. From a total of 261 responses, 224 met the inclusion criteria. Overall, 67% of respondents had used one or more IVF add-ons, most commonly: time-lapse imaging (27%), EmbryoGlue (27%), and endometrial scratching (26%). Overall, 81% of the add-ons used were offered to participants by clinicians (compared to 19% requested by themselves). Half (54%) reported being offered add-ons during consultations, compared to 24% who initiated discussion about add-ons. Higher proportions of private patients reported being offered (90%), requesting (47%) and using (74%) add-ons than those with NHS funding (74%, 29%, 52%, respectively). The main limitations of this study are the small sample size, recruitment via a convenience sample, and the self-reported data capture which is subject to recall bias.

Trials evaluating the efficacy of IVF and various treatment options often focus on upstream outcome measures, improvements which may not translate into clinical outcome improvements. A cross-sectional online survey was distributed globally among IVF patients. Respondents were randomised to view one of 16 statements about a hypothetical IVF treatment option called ‘FertiSure’, stated to improve one of four upstream outcomes. Statements varied in whether they contained information stating that FertiSure was not proven to improve live-birth rates and about potential risks. Many patients inferred that improvements in upstream outcomes would result in improvements in the probability of live-birth. Nearly 80% of respondents were willing to use FertiSure. Respondents told that FertiSure was not proven to improve live-birth rates and were less willing to use FertiSure. More respondents agreed that FertiSure may pose a risk to patients when they were told this was the case. However, this did not affect their willingness to use FertiSure. Interestingly, 34% of respondents believed FertiSure would not improve the probability of live-birth but were still willing to use it. These results have implications for IVF clinic websites and information about treatment options which may not routinely contain statements about the limited evidence-base and possible risks.

The process of implantation is characterized by a complex cross-talk between the endometrium and the blastocyst, with the endometrium only being receptive to implantation during a transient window of implantation of approximately 2-3 days during the midsecretory phase. The timing of embryo transfer, including frozen embryo transfer, is therefore critical to the success of implantation. In this article, we discuss various elements that may guide the timing of frozen embryo transfer, including the role of endometrial characteristics such as thickness, days postovulation or length of progesterone administration, stage of the embryo, and the application of endometrial receptivity tests to guide personalized embryo transfer.

Background IVF add-ons are techniques, medicines or procedures used in addition to standard IVF with the aim of improving the chance of success. The United Kingdom’s IVF regulator, ( the Human Fertilisation Embryology Authority (HFEA) developed a traffic light system to categorise add-ons as either green, amber, or red, based on results of randomised controlled trials. Method Qualitative interviews were undertaken to explore understanding and views of the HFEA traffic light system among IVF clinicians, embryologists and IVF patients across Australia and the United Kingdom. Results A total of 73 interviews were conducted. Overall, participants were supportive of the intention of the traffic light system, however many limitations were raised. It was widely recognized that a simple traffic light system necessarily omits information which may be important to understanding the evidence base. In particular, the red category was used in scenarios that patients viewed as having different implications for their decision-making, including ‘no evidence’ and ‘evidence of harm’. Patients were surprised at the absence of any green add-ons and questioned the value of a traffic light system in this context. Many participants considered the website a helpful starting point, but desired more detail, including the contributing studies, results specific to patient demographics (e.g., 35 years), and inclusion of more options (e.g. acupuncture). Overall, participants believed the website to be reliable and trustworthy, particularly due to the Government affiliation, and despite some concerns regarding transparency and an overly cautious regulator. Conclusion Participants identified many limitations with the current application of the traffic light system. These could be considered in any future updates to the HFEA website and for others developing similar decision support tools.

Add-ons at the time of in vitro fertilisation (IVF) have become commonplace, despite a general lack of evidence that they are effective and safe. The 'Colorado Protocol' is a commonly used add-on consisting of aspirin, steroid and an antibiotic. Before commencing planning for a clinical trial evaluating the Colorado Protocol, researchers and funders need evidence that the Colorado Protocol is being prescribed, and to be assured that sufficient numbers of participants can be recruited for a clinical trial.To survey fertility clinicians and patients on attitudes toward use of add-ons during IVF, willingness of patients to be randomly assigned to an add-on trial treatment or placebo, and what would be the clinically meaningful outcomes, using the Colorado Protocol as a test case.Two online surveys were conducted: clinicians from fertility clinics across the United Kingdom, Australia, and New Zealand; and patients from Auckland-based clinics and NZ patient support groups.Of 58 clinicians, 44 (75%) had recommended an add-on within the preceding year. Thirty-nine (67%) clinicians were aware of the Colorado Protocol, with 17 (29%) having recommended it within the preceding year. Of the 289 patients, 80% indicated willingness to take trial medications during IVF, and 68% were willing to be randomly assigned to the placebo arm of a trial. The median perceived minimum clinically important difference in live births in both samples was 5%.A future trial of this add-on in IVF would be supported by patients in the context of the New Zealand fertility healthcare system.

Endometrial scratching is a common IVF add-on. In 2015, a survey in Australia, New Zealand and the United Kingdom (UK) reported that 83% of fertility specialists recommended endometrial scratching for IVF. Several large trials have since been published reporting no clear evidence for improved live birth rates following endometrial scratching before IVF. An online survey was undertaken to ascertain the current practices and views across Australia, New Zealand, and the UK. A total of 121 eligible responses were received between October and December 2020 (fertility specialists (n = 61), embryologists (n = 26) and fertility nurses (n = 24)). Among fertility specialists, 34% currently offer endometrial scratching, mostly in the case of recurrent implantation failure. Most respondents were neutral or did not believe endometrial scratching improved pregnancy and live birth rates (>90%), except for in women with recurrent implantation failure (29% believed it can increase pregnancy and live birth rates in this group). More than half of respondents viewed reducing psychological distress as a benefit of endometrial scratching (55%). Among fertility specialists not offering endometrial scratching, 51% previously offered it but no longer do. The decline in use over the last five years likely reflects a response to recent evidence reporting no benefit from the procedure.

Objective To examine the disposition outcomes and disposition intentions of elective egg freezers (EEFs) toward their surplus frozen oocytes and the psychosocial determinants underlying these. Design A systematic review and meta-analysis. Setting Not applicable. Patient(s) Actual EEFs (women with oocytes in storage), potential EEFs (women investigating elective oocyte cryopreservation or about to freeze their oocytes), and women of reproductive age (women in the community aged ≥18 years). Intervention(s) A systematic review was undertaken and electronically searched MEDLINE, Embase, and PsycINFO on the Ovid platform for conference abstracts and peer-reviewed articles, published in English after January 1, 2010. A search strategy combined synonyms for oocyte, cryopreservation, donation, disposition, elective, and attitude. Eligible studies assessed disposition outcomes (how an oocyte was disposed of) and disposition intentions (how women intend to dispose of an oocyte) and/or the psychosocial determinants underlying disposition outcomes and intentions. The Joanna Briggs Institute Prevalence Tool was used to assess the risk of bias. A meta-analysis using random effects was applied to pool proportions of women with similar disposition intentions toward their oocytes. Main Outcome Measure(s) Disposition outcomes and intentions toward surplus frozen oocytes: donate to research; donate to others; discard; unsure. Psychosocial determinants (beliefs, attitudes, barriers, and facilitators) of disposition outcomes and intentions. Result(s) A total of 3,560 records were identified, of which 22 (17 studies) met the inclusion criteria (8 studies from Europe, 7 from North America, and 2 from Asia). No studies reported on past oocyte disposition outcomes. Seventeen studies reported on the future disposition intentions of 5,446 women. Only 2 of the 17 studies reported on the psychosocial determinants of oocyte disposition intentions. There was substantial heterogeneity in the pooled results, which was likely a result of the significant variation in methodology. Actual EEFs were included in eight studies (n = 873), of whom 53% (95% confidence interval [CI], 44–63; I2, 87%) would donate surplus oocytes to research, 31% (95% CI, 23–40; I2, 72%) were unsure, 26% (95% CI, 17–38; I2, 92%) would donate to others, and 12% (95% CI, 6–21; I2, 88%) would discard their eggs. Psychosocial determinants: One study reported that 50% of these women were aware of friends and/or family having difficulty conceiving, which may have contributed to their willingness to donate to others. Potential EEFs were included in 4 studies (n = 645), of whom 38% (95% CI, 28–50; I2, 84%) would donate to research, 32% (95% CI, 17–51; I2, 91%) would donate to others, 29% (95% CI, 17–44; I2, 89%) would discard, and 7% (95% CI, 1–27; I2, 77%) were unsure. Psychosocial determinants: No studies. Women of reproductive age were included in 5 studies (n = 3,933), of whom 59% (95% CI, 48–70; I2, 97%) would donate to research and 46% (95% CI, 35–57; I2, 98%) would donate to others. “Unsure” and “discard” were not provided as response options. Psychosocial determinants: One study reported that the facilitators for donation to others included a family member or friend in need, to help others create a family, financial gain, to further science, and control or input over the selection of recipients. Barriers for donation included fear of having a biological child they do not know or who is raised by someone they know. Conclusion(s) No studies reported on the disposition outcomes of past EEFs. Disposition intentions varied across the three groups; however, “donating to research” was the most common disposition preference. Notably, the second disposition preference for one-third of actual EEFs was “unsure” and for one-third of potential EEFs was “donate to others.” There were limited studies for actual and potential EEFs, and only two studies that explored the psychosocial determinants of oocyte disposition intentions. Additionally, these data suggest that disposition decisions change as women progress on their egg freezing journey, highlighting the importance of ongoing contact with the fertility team as intentions may change over time. More research is needed to understand the psychosocial determinants of oocyte disposition decisions so fertility clinics can provide EEFs with the support and information they need to make informed decisions about their stored eggs and reduce the level of uncertainty reported among EEFs and the potential risk of psychological distress and regret. Clinical Trial Registration Number PROSPERO 2020: CRD42020202733

Background In vitro fertilisation (IVF) 'add-ons' are extra (non-essential) procedures, techniques or medicines, which usually claim to increase the chance of a successful IVF outcome. Use of IVF add-ons is believed to be widespread in many settings; however, information about add-on availability in Australasia is lacking. Aims To understand which add-ons are advertised on Australasian IVF clinic websites, and what is the evidence for their benefit. Materials and methods A systematic assessment of website content was undertaken between December 2019-April 2020, capturing IVF add-ons advertised, including costs, claims of benefit, statements of risk or limitations, and evidence of effectiveness for improving live birth and pregnancy. A literature review assessed the strength and quality of evidence for each add-on. Results Of the 40 included IVF clinics websites, 31 (78%) listed one or more IVF add-ons. A total of 21 different add-ons or add-on groups were identified, the most common being preimplantation genetic testing for aneuploidies (offered by 63% of clinics), time-lapse systems (33%) and assisted hatching (28%). In most cases (77%), descriptions of the IVF add-ons were accompanied by claims of benefit. Most claims (90%) were not quantified and very few referenced scientific publications to support the claims (9.8%). None of the add-ons were supported by high-quality evidence of benefit for pregnancy or live birth rates. The cost of IVF add-ons varied from $0 to $3700 (AUD/NZD). Conclusions There is widespread advertising of add-ons on IVF clinic websites, which report benefits for add-ons that are not supported by high-quality evidence.

Multiple birth rates after fertility treatment are still high in many countries. Multiple births are associated with increased rates of preterm birth and low birth weight babies, in turn increasing the risk of severe morbidity for the children. The multiple birth rates vary in different countries between 2% and 3% and up to 30% in some settings. Elective single-embryo transfer, particularly in combination with frozen-embryo transfer and milder stimulation in ovulation induction/intrauterine insemination, to avoid multifollicular development is an effective strategy to decrease the multiple birth rates while still achieving acceptable live-birth rates. Although this procedure is used successfully in many countries, it ought to be implemented broadly to improve the health of the children. One at a time should be the normal routine.

Objective Menopause is the natural cessation of menstruation and may be accompanied by troublesome symptoms including hot flushes and night sweats (vasomotor symptoms) and genitourinary symptoms. Randomized trials evaluating the safety and effectiveness of interventions for these symptoms have reported a wide range of outcomes and used inconsistent measures. This variation precludes comparing and combining data from different trials. To overcome this limitation, we will develop a Core Outcome Set for Menopausal Symptoms. Methods We will systematically review the literature to identify the outcomes reported in the interventional trials for vasomotor and genitourinary symptoms. This list will be entered into a two-round modified Delphi survey to be completed by clinicians, researchers, and consumers (women who have experienced menopause). Participants will score outcomes on a nine-point scale from "not important" to "critically important." Representatives from each stakeholder group will then meet to discuss the results and finalize the Core Outcome Set. Ethics approval was not required as this was considered service evaluation and development. The study is registered with the Core Outcome Measures in Effectiveness Trials Initiative (http://www.comet-initiative.org/studies/details/917). Results An agreed upon set of minimum outcomes and outcome measures will facilitate combining and comparing findings from future trials of treatments for menopausal symptoms. Conclusions This Core Outcome Set will better enable women and clinicians to select effective treatments, improve the quality of trial reporting, reduce research wastage, and improve care for women with troublesome menopausal symptoms. VIDEO SUMMARY:: http://links.lww.com/MENO/A633.

Background Clinical trials generally each collect their own data despite routinely collected health data (RCHD) increasing in quality and breadth. Our aim is to quantify UK-based randomised controlled trials (RCTs) accessing RCHD for participant data, characterise how these data are used and thereby recommend how more trials could use RCHD. Methods We conducted a systematic review of RCTs accessing RCHD from at least one registry in the UK between 2013 and 2018 for the purposes of informing or supplementing participant data. A list of all registries holding RCHD in the UK was compiled. In cases where registries published release registers, these were searched for RCTs accessing RCHD. Where no release register was available, registries were contacted to request a list of RCTs. For each identified RCT, information was collected from all publicly available sources (release registers, websites, protocol etc.). The search and data extraction were undertaken between January and May 2019. Results We identified 160 RCTs accessing RCHD between 2013 and 2018 from a total of 22 registries; this corresponds to only a very small proportion of all UK RCTs (about 3%). RCTs accessing RCHD were generally large (median sample size 1590), commonly evaluating treatments for cancer or cardiovascular disease. Most of the included RCTs accessed RCHD from NHS Digital (68%), and the most frequently accessed datasets were mortality (76%) and hospital visits (55%). RCHD was used to inform the primary trial (82%) and long-term follow-up (57%). There was substantial variation in how RCTs used RCHD to inform participant outcome measures. A limitation was the lack of information and transparency from registries and RCTs with respect to which datasets have been accessed and for what purposes. Conclusions In the last five years, only a small minority of UK-based RCTs have accessed RCHD to inform participant data. We ask for improved accessibility, confirmed data quality and joined-up thinking between the registries and the regulatory authorities. Trial registration PROSPERO CRD42019123088.

Contains fulltext : 283099.pdf (Publisher’s version ) (Open Access) BACKGROUND: Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg. METHODS: ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing ≥14 kg and

Contains fulltext : 282959.pdf (Publisher’s version ) (Open Access) BACKGROUND: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. METHODS: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to

STUDY QUESTIONDo randomised controlled trials (RCTs) evaluating endometrial scratching suffer from methodological issues including insufficient trial registration, statistical errors or irreproducibility, randomisation errors or miscellaneous issues?SUMMARY ANSWERThe majority of RCTs investigating endometrial scratching have methodological issues.WHAT IS KNOWN ALREADYA large number of small RCTs investigating the effectiveness of endometrial scratching prior to in vitro fertilisation (IVF) and intrauterine insemination (IUI)/intercourse have reported favourable findings. Subsequently, systematic reviews incorporating these RCTs yielded meta-analyses in favour of endometrial scratching. Endometrial scratching has been widely adopted by infertility specialists around the world. Recently, an international RCT including 1364 women reported no benefit from endometrial scratching before IVF.STUDY DESIGN, SIZE, DURATIONWe evaluated several methodological issues of RCTs investigating the effectiveness of endometrial scratching prior to IVF and IUI/intercourse. We identified 25 RCTs for IVF and 12 RCTs for IUI/intercourse with full-text publication.PARTICIPANTS/MATERIALS, SETTING, METHODSWe assessed the RCTs on the following criteria: adequacy of trial registration, statistical issues (description of statistical methods and reproducibility of univariable statistical analysis), excessive similarity or difference in baseline characteristics that is not compatible with chance (Monte Carlo simulations and Kolmogorov–Smirnov test) and miscellaneous methodological issues.MAIN RESULTS AND THE ROLE OF CHANCEOf 25 RCTs evaluating endometrial scratching prior to IVF, only eight (32%) had adequate trial registration. In total, 10 (40%) RCTs had issues regarding statistical methods. Nine (69%, 13 applicable) RCTs had at least one inconsistency between reported and reproduced univariable statistical analysis for categorical baseline/intermediate characteristics. Statistical results of at least one outcome were not reproducible in 14 (74%, 19 applicable) RCTs. Only two (8%) RCTs had none of the above issues. Suggested by the simulations, these RCTs did not significantly violate the null hypothesis that the baseline characteristics were the results of a properly conducted randomisation process (P = 0.4395).Of 12 IUI/intercourse RCTs, only 2 (17%) had adequate trial registration. In total, five (42%) studies had issues of statistical methods. Inconsistency between reported and reproduced univariable analysis for baseline/intermediate categorical variable(s) was found in four (57%, 7 applicable) RCTs. Statistical analysis was not reproducible for at least one outcome in eight (80%, 10 applicable) studies. All RCTs had at least one of the above issues. These RCTs were inconsistent with the null hypothesis that their baseline characteristics were the results of proper randomised allocation (P = 1.659*10−7).LIMITATIONS, REASONS FOR CAUTIONWe were unable to assess RCTs which were not published as full-text papers. We could not analyse individual participant data to investigate possible reasons for statistical inconsistencies. The method to infer the likelihood of proper random sampling rests on assumptions including independent baseline characteristics, simple randomisation and no publication bias.WIDER IMPLICATIONS OF THE FINDINGSThe methodological issues common to RCTs evaluating endometrial scratching may have biased the results of the trials. Further development and validation of these novel methods may be helpful for the critical appraisal of RCTs.STUDY FUNDING/COMPETING INTEREST(S)No external funding was sought to support this work. B.W.M. is supported by a National Health Medical Research Council (NHMRC) Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck and Guerbet. D.W. is supported by a grant from the Paracelsus Medical University Salzburg, Austria (PMU Research Fund—PMU FFF Number: L-18/02/006-WET) and by Drs Haackert Foundation, Germany. S.L. is an author of a trial included in this study, an author of an included systematic review and a Cochrane editor. All other authors have no conflicts of interest.TRIAL REGISTRATION NUMBERN/A

The probability of live birth from an in vitro fertilization (IVF) cycle is modest. Many additional treatments (add-ons) are available which promise to improve the success of IVF. This review summarizes the current evidence for common IVF add-ons which are suggested to improve endometrial receptivity. Systematic reviews of randomized controlled trials and individual trials were included. Five add-ons were included: immune therapies, endometrial scratching, endometrial receptivity array, uterine artery vasodilation, and human chorionic gonadotropin instillation. The results suggest there is no robust evidence that these add-ons are effective or safe. Many IVF add-ons are costly, consuming precious resources which may be better spent on evidence-based treatments or further IVF. Large randomized controlled trials and appropriate safety assessment should be mandatory before the introduction of IVF add-ons into routine practice.

The conclusion of the Human Fertilisation and Embryology Authority that ‘add-on’ therapies in IVF are not supported by high-quality evidence has prompted new questions regarding the role of the randomized controlled trial (RCT) in evaluating infertility treatments. Critics argue that trials are cumbersome tools that provide irrelevant answers. Instead, they argue that greater emphasis should be placed on large observational databases, which can be analysed using powerful algorithms to determine which treatments work and for whom. Although the validity of these arguments rests upon the sciences of statistics and epidemiology, the discussion to date has largely been conducted without reference to these fields. We aim to remedy this omission, by evaluating the arguments against RCTs in IVF from a primarily methodological perspective. We suggest that, while criticism of the status quo is warranted, a retreat from RCTs is more likely to make things worse for patients and clinicians.

OBJECTIVE: To investigate whether endometrial scratching increases the chance of live birth in women with unexplained infertility attempting to conceive without assisted reproductive technology.DESIGN: Randomized, placebo-controlled, participant-blind, multicenter international trial.SETTING: Fertility clinics.PATIENT(S): Women with a diagnosis of unexplained infertility trying to conceive without assistance.INTERVENTION(S): Participants were randomly assigned to receive an endometrial biopsy or a placebo procedure (placement of a biopsy catheter in the posterior fornix, without inserting it into the external cervical os). Both groups performed regular unprotected intercourse with the intention of conceiving over three consecutive study cycles.MAIN OUTCOME MEASURE(S): The primary outcome was live birth.RESULT(S): A total of 220 women underwent randomization. The live birth rate was 9% (10 of 113 women) in the endometrial-scratch group and 7% (7 of 107 women) in the control group (adjusted OR, 1.39; 95% CI, 0.50-4.03). There were no differences between the groups in the secondary outcomes of clinical pregnancy, viable pregnancy, ongoing pregnancy, and miscarriage. Endometrial scratching was associated with a higher pain score on a 10-point scale (adjusted mean difference, 3.07; 95% CI, 2.53-3.60).CONCLUSION(S): This trial did not find evidence that endometrial scratching improves the live birth rate in women with unexplained infertility trying to conceive without assistance.CLINICAL TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ACTRN12614000656639.

Objective Genitourinary symptoms, such as vaginal dryness and pain with sex, are commonly experienced by postmenopausal women. Comparing treatments for these genitourinary symptoms are restricted by the use of different outcome measures in clinical trials and the omission of outcomes, which may be relevant to women. The aim of this project was to develop a Core Outcome Set (COS) to be reported in clinical trials of treatments for genitourinary symptoms associated with menopause. Methods We performed a systematic review of randomized controlled trials of treatments for genitourinary symptoms associated with menopause and extracted their outcomes. This list was refined and entered into a two-round modified Delphi survey, which was open to clinicians, researchers, and postmenopausal women from November 2019 to March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." The final COS was determined following two international consensus meetings. Results A total of 26 unique outcomes were included in the Delphi process, which was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to the Delphi scores to categorize outcomes by importance, which informed the e consensus meetings, attended by 43 participants from 21 countries. The final COS includes eight outcomes: (1) pain with sex, (2) vulvovaginal dryness, (3) vulvovaginal discomfort or irritation, (4) discomfort or pain when urinating, (5) change in most bothersome symptom, (6) distress, bother or interference of genitourinary symptoms, (7) satisfaction with treatment, (8) side effects of treatment. Conclusion These eight core outcomes reflect the joint priorities of postmenopausal women, clinicians, and researchers internationally. Standardized collection and reporting of these outcomes in clinical trials will facilitate the comparison of different treatments for genitourinary symptoms, advance clinical practice, and ultimately improve outcomes for symptomatic women.

ObjectivesThe anti-Mullerian hormone (AMH) test has been promoted as a way to inform women about their future fertility. However, data consistently show the test is a poor predictor of natural fertility potential for an individual woman. As fertility centre websites are often a primary source of information for reproductive information, it is essential the information provided is accurate and reflects the available evidence. We aimed to systematically record and categorise information about the AMH test found on Australian and New Zealand fertility clinic websites.DesignContent analysis of online written information about the AMH test on fertility clinic websites.SettingAccredited Australian and New Zealand fertility clinic websites.MethodsData were extracted between April and June 2020. Any webpage that mentioned the AMH test, including blogs specifically about the AMH test posted since 2015, was analysed and the content categorised.ResultsOf the 39 active accredited fertility clinics’ websites, 25 included information about the AMH test. The amount of information varied widely, and embodied four overarching categories; (1) the utility of the AMH test, (2) who the test is suitable for, (3) possible actions in response to the test and (4) caveats and limitations of the test. Eight specific statements about the utility of the test were identified, many of which are not evidence-based. While some websites were transparent regarding the test’s limitations, others mentioned no caveats or included persuasive statements actively promoting the test as empowering for a range of women in different circumstances.ConclusionsSeveral websites had statements about the utility of the AMH test that are not supported by the evidence. This highlights the need for higher standards for information provided on fertility clinic websites to prevent women being misled to believe the test can reliably predict their fertility.

BACKGROUND: Implantation of an embryo within the endometrial cavity is a critical step in the process of in vitro fertilisation (IVF). Previous research has suggested that endometrial injury (also known as endometrial scratching), defined as intentional damage to the endometrium, can increase the chance of pregnancy in women undergoing IVF. OBJECTIVES: To assess the effectiveness and safety of endometrial injury performed before embryo transfer in women undergoing in vitro fertilisation (IVF) including intracytoplasmic sperm injection (ICSI) and frozen embryo transfer. SEARCH METHODS: In June 2020 we searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, LILACS, DARE and two trial registries. We also checked the reference sections of relevant studies and contacted experts in the field for any additional trials. SELECTION CRITERIA: Randomised controlled trials comparing intentional endometrial injury before embryo transfer in women undergoing IVF, versus no intervention or a sham procedure. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Two independent review authors screened studies, evaluated risk of bias and assessed the certainty of the evidence by using GRADE (Grading of Recommendation, Assessment, Development and Evaluation) criteria. We contacted and corresponded with study investigators as required. Due to the high risk of bias associated with many of the studies, the primary analyses of all review outcomes were restricted to studies at a low risk of bias for selection bias and other bias. Sensitivity analysis was then performed including all studies. The primary review outcomes were live birth and miscarriage. MAIN RESULTS: Endometrial injury versus control (no procedure or a sham procedure) A total of 37 studies (8786 women) were included in this comparison. Most studies performed endometrial injury by pipelle biopsy in the luteal phase of the cycle before the IVF cycle. The primary analysis was restricted to studies at low risk of bias, and included eight studies. The effect of endometrial injury on live birth is unclear as the result is consistent with no effect, or a small reduction, or an improvement (odds ratio (OR) 1.12, 95% confidence interval (CI) 0.98 to 1.28; participants = 4402; studies = 8; I(2) = 15%, moderate‐certainty evidence). This suggests that if the chance of live birth with IVF is usually 27%, then the chance when using endometrial injury would be somewhere between < 27% and 32%. Similarly, the effect of endometrial injury on clinical pregnancy is unclear (OR 1.08, 95% CI 0.95 to 1.23; participants = 4402; studies = 8; I(2) = 0%, moderate‐certainty evidence). This suggests that if the chance of clinical pregnancy from IVF is normally 32%, then the chance when using endometrial injury before IVF is between 31% and 37%. When all studies were included in the sensitivity analysis, we were unable to conduct meta‐analysis for the outcomes of live birth and clinical pregnancy due to high risk of bias and statistical heterogeneity. Endometrial injury probably results in little to no difference in chance of miscarriage (OR 0.88, 95% CI 0.68 to 1.13; participants = 4402; studies = 8; I(2) = 0%, moderate‐certainty evidence), and this result was similar in the sensitivity analysis that included all studies. The result suggests that if the chance of miscarriage with IVF is usually 6.0%, then when using endometrial injury it would be somewhere between 4.2% and 6.8%. Endometrial injury was associated with mild to moderate pain (approximately 4 out of 10), and was generally associated with some minimal bleeding. The evidence was downgraded for imprecision due to wide confidence intervals and therefore all primary analyses were graded as moderate certainty. Higher versus lower degree of injury Only one small study was included in this comparison (participants = 129), which compared endometrial injury using two different instruments in the cycle prior to the IVF cycle: a pipelle catheter and a Shepard catheter. This trial was excluded from the primary analysis due to risk of bias. In the sensitivity analysis, all outcomes reported for this study were graded as very‐low certainty due to risk of bias, and as such we were not able to interpret the study results. AUTHORS' CONCLUSIONS: The effect of endometrial injury on live birth and clinical pregnancy among women undergoing IVF is unclear. The results of the meta‐analyses are consistent with an increased chance, no effect and a small reduction in these outcomes. We are therefore uncertain whether endometrial injury improves the chance of live birth or clinical pregnancy in women undergoing IVF. Endometrial injury does not appear to affect the chance of miscarriage. It is a somewhat painful procedure associated with a small amount of bleeding. In conclusion, current evidence does not support the routine use of endometrial injury for women undergoing IVF.

OBJECTIVE Genitourinary symptoms, such as vaginal dryness and pain with sex, are commonly experienced by postmenopausal women. Comparing treatments for these genitourinary symptoms are restricted by the use of different outcome measures in clinical trials and the omission of outcomes, which may be relevant to women. The aim of this project was to develop a Core Outcome Set (COS) to be reported in clinical trials of treatments for genitourinary symptoms associated with menopause. METHODS We performed a systematic review of randomized controlled trials of treatments for genitourinary symptoms associated with menopause and extracted their outcomes. This list was refined and entered into a two-round modified Delphi survey, which was open to clinicians, researchers, and postmenopausal women from November 2019 to March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." The final COS was determined following two international consensus meetings. RESULTS A total of 26 unique outcomes were included in the Delphi process, which was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to the Delphi scores to categorize outcomes by importance, which informed the e consensus meetings, attended by 43 participants from 21 countries. The final COS includes eight outcomes: (1) pain with sex, (2) vulvovaginal dryness, (3) vulvovaginal discomfort or irritation, (4) discomfort or pain when urinating, (5) change in most bothersome symptom, (6) distress, bother or interference of genitourinary symptoms, (7) satisfaction with treatment, (8) side effects of treatment. CONCLUSION These eight core outcomes reflect the joint priorities of postmenopausal women, clinicians, and researchers internationally. Standardized collection and reporting of these outcomes in clinical trials will facilitate the comparison of different treatments for genitourinary symptoms, advance clinical practice, and ultimately improve outcomes for symptomatic women.

Background Despite the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) encouraging the use of risk-based monitoring for trials in 2013, there remains a lack of evidence-based guidelines on how to monitor. We surveyed the academic United Kingdom Clinical Research Collaboration (UKCRC) registered clinical trials units (CTUs) to find out their policy on monitoring of phase III randomised clinical trials of an investigational medicinal product (CTIMPs). Methods An online survey of monitoring policy with sections on the CTU, central monitoring and on-site monitoring was sent to all 50 UKCRC registered CTUs in November 2018. Descriptive data analysis and tabulations are reported using the total number answering each question. Results A total of 43/50 (86%) of CTUs responded with 38 conducting phase III randomised CTIMP trials. Of these 38 CTUs, 34 finished the survey. Most CTUs (36/37, 97%) use a central monitoring process to guide, target or supplement site visits. More than half (19/36, 53%) of CTUs do not use an automated monitoring report when centrally monitoring trials and all units use trial team knowledge to make a final decision on whether an on-site visit is required. A total of 31/34 (91%) CTUs used triggers to decide whether or not to conduct an on-site monitoring visit. On-site, a mixture of source data verification and checking of processes was carried out. The CTUs overwhelmingly (27/34, 79%) selected optimising central monitoring as their most pressing concern. Conclusion The survey showed a wide variation in phase III randomised CTIMP trial monitoring practices by academic clinical trials units within a single research-active country. We urgently need to develop evidence-based regulator-agreed guidance for CTUs on best practice for both central and on-site monitoring and to develop tools for all CTUs to use.

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 INTEREST(S) 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

Summary 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.

Add-on treatments are the new black. They are provided (most frequently, sold) to patients undergoing in vitro fertilization on the premise that they will improve the chances of having a baby. However, the regulation of add-ons is consistently minimal, meaning that they are introduced into routine practice before they have been shown to improve the live birth rate. Debate on the adequacy of this light-touch approach rages. Defenders argue that demands for a rigorous approval process are paternalistic, as this would delay access to promising treatments. Critics respond that promising treatments may turn out to have adverse effects on patients and their offspring, contradicting the clinician’s responsibility to do no harm. Some add-ons, including earlier versions of preimplantation genetic testing for aneuploidy, might even reduce the live birth rate, raising the prospect of desperate patients paying more to worsen their chances. Informed consent represents a solution in principle, but in practice there is a clear tension between impartial information and direct-to-consumer advertising. Because the effects of a treatment cannot be known until it has been robustly evaluated, we argue that strong evidence should be required before add-ons are introduced to the clinic. In the meantime, there is an imperative to identify methods for communicating the associated risks and uncertainties of add-ons to prospective patients.

BACKGROUND: Endometrial scratching (with the use of a pipelle biopsy) is a technique proposed to facilitate embryo implantation and increase the probability of pregnancy in women undergoing in vitro fertilization (IVF). METHODS: We conducted a pragmatic, multicenter, open-label, randomized, controlled trial. Eligible women were undergoing IVF (fresh-embryo or frozen-embryo transfer), with no recent exposure to disruptive intrauterine instrumentation (e.g., hysteroscopy). Participants were randomly assigned in a 1:1 ratio to either endometrial scratching (by pipelle biopsy between day 3 of the cycle preceding the embryo-transfer cycle and day 3 of the embryo-transfer cycle) or no intervention. The primary outcome was live birth. RESULTS: A total of 1364 women underwent randomization. The frequency of live birth was 180 of 690 women (26.1%) in the endometrial-scratch group and 176 of 674 women (26.1%) in the control group (adjusted odds ratio, 1.00; 95% confidence interval, 0.78 to 1.27). There were no significant between-group differences in the rates of ongoing pregnancy, clinical pregnancy, multiple pregnancy, ectopic pregnancy, or miscarriage. The median score for pain from endometrial scratching (on a scale of 0 to 10, with higher scores indicating worse pain) was 3.5 (interquartile range, 1.9 to 6.0). CONCLUSIONS: Endometrial scratching did not result in a higher rate of live birth than no intervention among women undergoing IVF. (Funded by the University of Auckland and others; PIP Australian New Zealand Clinical Trials Registry number, ACTRN12614000626662 .). ispartof: The New England journal of medicine vol:380 issue:4 pages:325-334 ispartof: location:United States status: published

This is a protocol for a Cochrane Review (Overview). The objectives are as follows:. To identify, systematically assess and summarise all evidence from Cochrane Reviews on treatment for heavy menstrual bleeding (HMB), through a network meta-analysis. To compare the efficacy, satisfaction and safety of different treatments available for HMB (that have been assessed in Cochrane Reviews), performing direct and indirect comparisons through a network meta-analysis.

Study question What proportion of clinicians across Australia, New Zealand and the UK are currently offering or recommending endometrial scratching for subfertility? Summary answer Eighty-three percent of clinicians responding to this survey are recommending endometrial scratching to women undergoing IVF. What is known already Endometrial scratching is currently being proposed as a technique to increase the probability of implantation in women undergoing IVF. While trial results provide evidence in favour of this procedure, there remains some uncertainty about both the extent of any beneficial effect and the subgroups of women most likely to benefit. Study design, size, duration Cross-sectional survey with responses from a total of 143 public and private fertility care providers surveyed between August and October 2015. Participants/materials, setting, methods An online survey was distributed to all 189 fertility clinics across Australia, New Zealand and the UK. All clinicians, nurses and embryologists were eligible to take part. One hundred and forty-three of the 152 responses received were eligible for inclusion, with multiple responses per clinic in 33 cases. At least one response was received from 68 clinics (36% response rate per clinic). Main results and the role of chance This survey found that 83% of clinicians commend endometrial scratching prior to IVF. Of these, 92% recommend endometrial scratching to women with recurrent implantation failure (RIF) and 6% recommend it to all women having IVF. Most respondents (73%) agreed that the procedure is beneficial in women with RIF undergoing IVF and disagreed (53%) that the procedure is beneficial for women undergoing their first IVF cycle. The most common timeframe for performing endometrial scratching is the luteal phase of the cycle prior to the IVF cycle. Additionally, only 4% of clinicians recommend endometrial scratching to women undergoing intrauterine insemination or trying to conceive naturally. Limitations, reasons for caution Fertility care providers who recommend endometrial scratching may be more likely to respond to the survey and this could exaggerate the use of the procedure reported here. Wider implications of the findings This study was conducted across three countries and may be generalizable to similar settings. While this procedure already appears to be offered by the majority of respondents, the results of further studies in this area may further refine or expand the context in which this procedure is beneficial. Study funding/competing interests No funding or competing interests. Trial registration number N/A.

BackgroundDuring a cycle of in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI), women receive daily doses of gonadotropin follicle‐stimulating hormone (FSH) to induce multifollicular development in the ovaries. Generally, the dose of FSH is associated with the number of eggs retrieved. A normal response to stimulation is often considered desirable, for example the retrieval of 5 to 15 oocytes. Both poor and hyper‐response are associated with increased chance of cycle cancellation. Hyper‐response is also associated with increased risk of ovarian hyperstimulation syndrome (OHSS). Clinicians often individualise the FSH dose using patient characteristics predictive of ovarian response such as age. More recently, clinicians have begun using ovarian reserve tests (ORTs) to predict ovarian response based on the measurement of various biomarkers, including basal FSH (bFSH), antral follicle count (AFC), and anti‐Müllerian hormone (AMH). It is unclear whether individualising FSH dose based on these markers improves clinical outcomes.ObjectivesTo assess the effects of individualised gonadotropin dose selection using markers of ovarian reserve in women undergoing IVF/ICSI.Search methodsWe searched the Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Studies Online, MEDLINE, Embase, CINAHL, LILACS, DARE, ISI Web of Knowledge, ClinicalTrials.gov, and the World Health Organisation International Trials Registry Platform search portal from inception to 27th July 2017. We checked the reference lists of relevant reviews and included studies.Selection criteriaWe included trials that compared different doses of FSH in women with a defined ORT profile (i.e. predicted low, normal or high responders based on AMH, AFC, and/or bFSH) and trials that compared an individualised dosing strategy (based on at least one ORT measure) versus uniform dosing or a different individualised dosing algorithm.Data collection and analysisWe used standard methodological procedures recommended by Cochrane. Primary outcomes were live birth/ongoing pregnancy and severe OHSS. Secondary outcomes included clinical pregnancy, moderate or severe OHSS, multiple pregnancy, oocyte yield, cycle cancellations, and total dose and duration of FSH administration.Main resultsWe included 20 trials (N = 6088); however, we treated those trials with multiple comparisons as separate trials for the purpose of this review. Meta‐analysis was limited due to clinical heterogeneity. Evidence quality ranged from very low to moderate. The main limitations were imprecision and risk of bias associated with lack of blinding.Direct dose comparisons in women according to predicted responseAll evidence was low or very low quality.Due to differences in dose comparisons, caution is warranted in interpreting the findings of five small trials assessing predicted low responders. The effect estimates were very imprecise, and increased FSH dosing may or may not have an impact on rates of live birth/ongoing pregnancy, OHSS, and clinical pregnancy.Similarly, in predicted normal responders (nine studies, three comparisons), higher doses may or may not impact the probability of live birth/ongoing pregnancy (e.g. 200 versus 100 international units: OR 0.88, 95% CI 0.57 to 1.36; N = 522; 2 studies; I2 = 0%) or clinical pregnancy. Results were imprecise, and a small benefit or harm remains possible. There were too few events for the outcome of OHSS to enable any inferences.In predicted high responders, lower doses may or may not have an impact on rates of live birth/ongoing pregnancy (OR 0.98, 95% CI 0.66 to 1.46; N = 521; 1 study), OHSS, and clinical pregnancy. However, lower doses probably reduce the likelihood of moderate or severe OHSS (Peto OR 2.31, 95% CI 0.80 to 6.67; N = 521; 1 study).ORT‐algorithm studiesFour trials compared an ORT‐based algorithm to a non‐ORT control group. Rates of live birth/ongoing pregnancy and clinical pregnancy did not appear to differ by more than a few percentage points (respectively: OR 1.04, 95% CI 0.88 to 1.23; N = 2823, 4 studies; I2 = 34%; OR 0.96, 95% CI 0.82 to 1.13, 4 studies, I2=0%, moderate‐quality evidence). However, ORT algorithms probably reduce the likelihood of moderate or severe OHSS (Peto OR 0.58, 95% CI 0.34 to 1.00; N = 2823; 4 studies; I2 = 0%, low quality evidence). There was insufficient evidence to determine whether the groups differed in rates of severe OHSS (Peto OR 0.54, 95% CI 0.14 to 1.99; N = 1494; 3 studies; I2 = 0%, low quality evidence). Our findings suggest that if the chance of live birth with a standard dose is 26%, the chance with ORT‐based dosing would be between 24% and 30%. If the chance of moderate or severe OHSS with a standard dose is 2.5%, the chance with ORT‐based dosing would be between 0.8% and 2.5%. These results should be treated cautiously due to heterogeneity in the study designs.Authors' conclusionsWe did not find that tailoring the FSH dose in any particular ORT population (low, normal, high ORT), influenced rates of live birth/ongoing pregnancy but we could not rule out differences, due to sample size limitations. In predicted high responders, lower doses of FSH seemed to reduce the overall incidence of moderate and severe OHSS. Moderate‐quality evidence suggests that ORT‐based individualisation produces similar live birth/ongoing pregnancy rates to a policy of giving all women 150 IU. However, in all cases the confidence intervals are consistent with an increase or decrease in the rate of around five percentage points with ORT‐based dosing (e.g. from 25% to 20% or 30%). Although small, a difference of this magnitude could be important to many women. Further, ORT algorithms reduced the incidence of OHSS compared to standard dosing of 150 IU, probably by facilitating dose reductions in women with a predicted high response. However, the size of the effect is unclear. The included studies were heterogeneous in design, which limited the interpretation of pooled estimates, and many of the included studies had a serious risk of bias.Current evidence does not provide a clear justification for adjusting the standard dose of 150 IU in the case of poor or normal responders, especially as increased dose is generally associated with greater total FSH dose and therefore greater cost. However, a decreased dose in predicted high responders may reduce OHSS.

STUDY QUESTIONS We aim to produce, disseminate and implement a core outcome set for future infertility research. WHAT IS KNOWN ALREADY Randomized controlled trials (RCTs) evaluating infertility treatments have reported many different outcomes, which are often defined and measured in different ways. Such variation contributes to an inability to compare, contrast and combine results of individual RCTs. The development of a core outcome set will ensure outcomes important to key stakeholders are consistently collected and reported across future infertility research. STUDY DESIGN, SIZE, DURATION This is a consensus study using the modified Delphi method. All stakeholders, including healthcare professionals, allied healthcare professionals, researchers and people with lived experience of infertility will be invited to participate. PARTICIPANTS/MATERIALS, SETTING, METHODS An international steering group, including people with lived experience of infertility, healthcare professionals, allied healthcare professionals and researchers, has been formed to guide the development of this core outcome set. Potential core outcomes have been identified through a comprehensive literature review of RCTs evaluating treatments for infertility and will be entered into a modified Delphi method. Participants will be asked to score potential core outcomes on a nine-point Likert scale anchored between one (not important) and nine (critical). Repeated reflection and rescoring should promote convergence towards consensus ‘core’ outcomes. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes. STUDY FUNDING/COMPETING INTEREST(S) This project is funded by the Royal Society of New Zealand Catalyst Fund (3712235). BWM reports consultancy fees from Guerbet, Merck, and ObsEva. R.S.L. reports consultancy fees from Abbvie, Bayer, Fractyl and Ogeda and research sponsorship from Ferring. S.B. is the Editor-in-Chief of Human Reproduction Open. The remaining authors declare no competing interests.