International consensus: ovarian tissue cryopreservation in young Turner syndrome patients: outcomes of an ethical Delphi study including 55 experts from 16 different countries.

STUDY QUESTION: What is the standpoint of an international expert panel on ovarian tissue cryopreservation (OTC) in young females with Turner syndrome (TS)? SUMMARY ANSWER: The expert panel states that OTC should be offered to young females with TS, but under strict conditions only. WHAT IS KNOWN ALREADY: OTC is already an option for preserving the fertility of young females at risk of iatrogenic primary ovarian insufficiency (POI). Offering OTC to females with a genetic cause of POI could be the next step. One of the most common genetic disorders related to POI is TS. Due to an early depletion of the ovarian reserve, most females with TS are confronted with infertility before reaching adulthood. However, before offering OTC as an experimental fertility preservation option to young females with TS, medical and ethical concerns need to be addressed. STUDY DESIGN, SIZE, DURATION: A three-round ethical Delphi study was conducted to systematically discuss whether the expected benefits exceed the expected negative consequences of OTC in young females with TS. The aim was to reach group consensus and form an international standpoint based on selected key statements. The study took place between February and December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Anonymous panel selection was based on expertise in TS, fertility preservation or medical ethics. A mixed panel of 12 gynaecologists, 13 (paediatric) endocrinologists, 10 medical ethicists and 20 patient representatives from 16 different countries gave consent to participate in this international Delphi study. In the first two rounds, experts were asked to rate and rank 38 statements regarding OTC in females with TS. Participants were offered the possibility to adjust their opinions after repetitive feedback. The selection of key statements was based on strict inclusion criteria. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 46 participants completed the first Delphi round (response rate 84%). Based on strict selection criteria, six key statements were selected, and 13 statements were discarded. The remaining 19 statements and two additional statements submitted by the expert panel were re-evaluated in the second round by 41 participants (response rate 75%). The analysis of the second survey resulted in the inclusion of two additional key statements. After the approval of these eight key statements, the majority of the expert panel (96%) believed that OTC should be offered to young females with TS, but in a safe and controlled research setting first, with proper counselling and informed consent procedures, before offering this procedure in routine care. The remaining participants (4%) did not object but did not respond despite several reminders. LIMITATIONS, REASONS FOR CAUTION: The anonymous nature of this study may have led to lack of accountability. The selection of experts was based on their willingness to participate. The fact that not all panellists took part in all rounds may have resulted in selection bias. WIDER IMPLICATIONS OF THE FINDINGS: This international standpoint is the first step in the global acceptance of OTC in females with TS. Future collaborative research with a focus on efficacy and safety and long-term follow-up is urgently needed. Furthermore, we recommend an international register for fertility preservation procedures in females with TS. STUDY FUNDING/COMPETING INTEREST(S): Unconditional funding (A16-1395) was received from Merck B.V., The Netherlands. The authors declare that they have no conflict of interest.

Professionals' barriers in female oncofertility care and strategies for improvement.

STUDY QUESTION: What are healthcare professionals' barriers and strategies for improvement in female oncofertility care? SUMMARY ANSWER: Professionals perceived barriers in knowledge, attitude and organization of oncofertility care and suggested strategies to improve oncofertility care. WHAT IS KNOWN ALREADY: The potential loss of fertility is one of the most important undesirable side effects of cancer treatment in women of reproductive age. Unfortunately, despite guideline recommendations, not all patients are informed about their fertility risks and referred for fertility preservation (FP) counselling. Insight into barriers for discussing FP and appropriate referral is necessary before improvements can be made. STUDY DESIGN, SIZE, DURATION: The aim of this was study was to identify barriers and gather improvement suggestions through semi-structured in-depth interviews conducted with 24 professionals working in oncofertility care. Subsequently, an expert panel meeting was held to reach consensus on a set of improvement strategies. PARTICIPANTS/MATERIALS, SETTING, METHODS: Oncological professionals were recruited from the three Dutch expertise hospitals for female FP and their affiliated hospitals. The expert panel consisted of six healthcare professionals, five survivors and two researchers. In the Dutch setting, financial aspects do not play a role in oncofertility care. MAIN RESULTS AND THE ROLE OF CHANCE: Barriers were identified and categorized into the patient level (e.g. focus on surviving cancer), the professional level (e.g. lack of awareness, knowledge, time, and attitude), or the organizational level (e.g. unavailable written information, disagreement on who is responsible for discussing infertility risks). The expert panel reached consensus on essential elements for a multifaceted improvement programme: development of information materials (leaflets, online decision aid), education of professionals, a role for specialized oncology nurses in informing patients and patient navigators at the fertility department to facilitate referral and counselling, medical record reminders, standard consultations with a gynaecologist and agreement on responsibility. LIMITATIONS, REASONS FOR CAUTION: Selection bias could have occurred because it is likely that only professionals with interest in oncofertility care participated. However, this would mean that the barriers were underestimated. WIDER IMPLICATIONS OF THE FINDINGS: This study forms the basis for the development of a multifaceted oncofertility programme, which is essential to increase adherence to the national clinical guideline. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Radboud university medical center. The authors have declared no competing interests. Prof. Dr Braat reports unrestricted grants from Ferring BV, Serono and Goodlife, outside the submitted work. TRIAL REGISTRATION NUMBER: N/A.

Gynaecologists' view on diagnostic delay and care performance in endometriosis in the Netherlands.

RESEARCH QUESTION: To evaluate implementation of the key recommendations of the European Society of Human Reproduction and Embryology (ESHRE) guidelines on endometriosis, and to assess factors influencing diagnostic delay of endometriosis from Dutch gynaecologists' point of view. DESIGN: Questionnaire study among gynaecologists from all hospitals in the Netherlands. The questionnaire consisted of 56 questions relating to implementation of the ESHRE guidelines, organization of endometriosis care and diagnostic delay. RESULTS: Gynaecologists from 67 out of 85 hospitals completed the questionnaire. A total of 99-100% of respondents agree with, and 91-100% adhere to, the diagnosis-related recommendations in the guidelines. Diagnostic delay is estimated at 42 months. Main factors contributing to diagnostic delay according to gynaecologists are lack of knowledge and awareness of endometriosis in both patients and medical professionals, as well as limitations in diagnostics and late referral. Suggested interventions to reduce diagnostic delay are aimed at improving knowledge and awareness in both patients and medical professionals, as well as improving collaborations between medical professionals. CONCLUSIONS: Overall familiarity with, and use of, the 2014 ESHRE guidelines among Dutch gynaecologists is high. Dutch gynaecologists agree with the recommendations relating to diagnosis and adhere to them closely. Diagnostic delay, however, is still considerable; therefore, efforts to reduce diagnostic delay of endometriosis should be aimed at improving knowledge and awareness in both patients and medical professionals, as well as improving collaboration.

Techniques used for IUI: is it time for a change?

STUDY QUESTION: Are the guidelines for the technical aspects of IUI (WHO, 2010) still in accordance with the current literature? SUMMARY ANSWER: In general, the laboratory guidelines of the World Health Organization (WHO) are a suitable protocol, although the evidence is not always conclusive and some changes are advisable. WHAT IS KNOWN ALREADY: Lack of standardization of the technical procedures required for IUI might result in inter-laboratory variation in pregnancy rates. Most centers still use their own materials and methods even though some guidelines are available. STUDY DESIGN, SIZE, DURATION: A structural review focusing on the association between pregnancy rates and the procedures of semen collection (e.g. ejaculatory abstinence, collection place), semen processing (e.g. preparation method, temperature during centrifugation/storage), insemination (e.g. timing of IUI, bed rest after IUI) and the equipment used. PARTICIPANTS/MATERIALS, SETTING, METHODS: A literature search was performed in Medline and the Cochrane library. When no adequate studies of the impact of a parameter on pregnancy results were found, its association with sperm parameters was reviewed. MAIN RESULTS AND THE ROLE OF CHANCE: For most variables, the literature review revealed a low level of evidence, a limited number of studies and/or an inadequate outcome measure. Moreover, the comparison of procedures (i.e. semen preparation technique, time interval between semen, collection, processing and IUI) revealed no consensus about their results. It was not possible to develop an evidence-based, optimal IUI treatment protocol. LIMITATIONS, REASONS FOR CAUTION: The included studies exhibited a lack of standardization in inclusion criteria and methods used. WIDER IMPLICATIONS OF THE FINDINGS: This review emphasizes the need for more knowledge about and standardization of assisted reproduction technologies. Our literature search indicates that some of the recommendations in the laboratory guidelines could be adapted to improve standardization, comfort, quality control and to cut costs. STUDY FUNDING/COMPETING INTEREST(S): The Dutch Foundation for Quality Assessment in Medical Laboratories (SKML), Nijmegen, The Netherlands. S.K. and W.N. have no conflicts of interest to disclose. C.B. and A.W. are members of the board of the SKML. With a grant from SKML, L.L. was paid for her time to perform the research and write the publication. D.B. received grants from Merck Serono, Ferring and MSD, outside the submitted work. REGISTRATION NUMBER: N/A.

General practitioners' adherence to work-up and referral recommendations in fertility care.

STUDY QUESTION: What is the current guideline adherence by general practitioners (GPs) for work-up and subsequent referral from primary to secondary care for patients suffering from infertility? SUMMARY ANSWER: Guideline adherence by GPs concerning infertility was 9.2% in couples referred. WHAT IS KNOWN ALREADY: Adherence to recommendations can decrease unnecessary referral, diagnostics and treatments, and consequently result in lower expenditures. Moreover, patients can be saved from unnecessary hospital visits, emotional burden and out of pocket costs. STUDY DESIGN, SIZE, AND DURATION: A retrospective cohort study among 306 patients referred for basic fertility work-up between January 2011 and June 2013 from primary care to a secondary care teaching hospital or a tertiary hospital with IVF facilities. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Couples were eligible to participate when there was no previous referral for fertility problems and the duration of the child wish was <2 years. Data to assess guideline adherence were collected from the referral letter and the medical records. A patient questionnaire was used to determine patients' general and fertility-related characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: The GP performed a Chlamydia Antibody Titre (CAT) testing and semen analysis as recommended in 15.9% and 42.2% of the referred patients, respectively. According to the guideline, 39% of the couples were under referred (i.e. not immediately referred as recommended), 8.8% were unnecessarily referred and the CAT and semen analysis were unnecessarily repeated in secondary care in 80.0% and 57.1% of cases, respectively. LIMITATIONS REASONS FOR CAUTION: We could not include non-referred patients with expectant management in primary care, an unknown number of whom became pregnant in this period. This may have resulted in an underestimation of primary care performance. WIDER IMPLICATIONS OF THE FINDINGS: Our findings show that guideline adherence concerning work-up and subsequent referral for fertility problems is low. The influence of patient demands for referral remains largely unknown. Barriers and facilitators for guideline adherence should be determined to develop interventions to improve guideline adherence in the areas of work-up and referral for fertility care and to diminish duplicate tests in secondary care. STUDY FUNDING/COMPETING INTEREST(S): Funded by CZ, a Dutch healthcare insurer (grant number AFVV 11-232). CZ had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: None. TRIAL REGISTRATION NUMBER: Not applicable.

Implementing targeted expectant management in fertility care using prognostic modelling: a cluster randomized trial with a multifaceted strategy.

STUDY QUESTION: What is the effectiveness of a multifaceted implementation strategy compared to usual care on improving the adherence to guideline recommendations on expectant management for couples with unexplained infertility? SUMMARY ANSWER: The multifaceted implementation strategy did not significantly increase adherence to guideline recommendations on expectant management compared to care as usual. WHAT IS KNOWN ALREADY: Intrauterine insemination (IUI) with or without ovarian hyperstimulation has no beneficial effect compared to no treatment for 6 months after the fertility work-up for couples with unexplained infertility and a good prognosis of natural conception. Therefore, various professionals and policy makers have advocated the use of prognostic profiles and expectant management in guideline recommendations. STUDY DESIGN, SIZE, DURATION: A cluster randomized controlled trial in 25 clinics in the Netherlands was conducted between March 2013 and May 2014. Clinics were randomized between the implementation strategy (intervention, n = 13) and care as usual (control, n = 12). The effect of the implementation strategy was evaluated by comparing baseline and effect measurement data. Data collection was retrospective and obtained from medical record research and a patient questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 544 couples were included at baseline and 485 at the effect measurement (247 intervention group/238 control group). MAIN RESULTS AND THE ROLE OF CHANCE: Guideline adherence increased from 49 to 69% (OR 2.66; 95% CI 1.45-4.89) in the intervention group, and from 49 to 61% (OR 2.03; 95% CI 1.38-3.00) in the control group. Multilevel analysis with case-mix adjustment showed that the difference of 8% was not statistically significant (OR 1.31; 95% CI 0.67-2.59). The ongoing pregnancy rate within six months after fertility work-up did not significantly differ between intervention and control group (25% versus 27%: OR 0.72; 95% CI 0.40-1.27). LIMITATIONS REASONS FOR CAUTION: There is a possible selection bias, couples included in the study had a higher socio-economic status than non-responders. How this affects guideline adherence is unclear. Furthermore, when powering for this study we did not take into account the unexpected improvement of adherence in the control group. WIDER IMPLICATIONS OF THE FINDINGS: Generalization of our results to other countries with recommendations on expectant management might be questionable because barriers for expectant management can be very different in other countries. Furthermore, due to a large variation in improved adherence rate in the intervention group it will be interesting to further analyse the process of implementation in each clinic with a process evaluation on professionals and couples' exposure to and experiences with the strategy. STUDY FUNDING/COMPETING INTEREST(S): Supported by Netherlands Organisation for Health Research and Development (ZonMW, project number 171203005). No competing interests. TRIAL REGISTRATION NUMBER: Dutch trial Register, www.trialregister.nl NTR3405. TRIAL REGISTRATION DATE: 19 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: 10 July 2012.

Selection of key recommendations for the management of women with endometriosis by an international panel of patients and professionals.

STUDY QUESTION: Can the differences in patients' and professionals' perspective regarding essential endometriosis care be accommodated in one set of key recommendations? SUMMARY ANSWER: Consensus between patients and professions on a key set of recommendations for essential endometriosis care was achieved. WHAT IS KNOWN ALREADY: Guideline development alone will not lead to healthcare improvement. Quality indicators are needed to monitor actual care and guideline adherence. These can help with better implementation of the ESHRE guidelines in European hospitals and thereby improve the quality of endometriosis care. The first step in the development of quality indicators is to select a compact set of key recommendations. STUDY DESIGN, SIZE AND DURATION: Using a RAND modified Delphi method, this study reports the systematic selection of key recommendations based on the ESHRE guideline 'Management of Women with Endometriosis' by an international expert panel of both patients and professionals during the study period of September 2015 and December 2015. PARTICIPANTS, SETTING, METHODS: An international panel of patients (n = 10) and medical professionals (n = 11) rated and prioritized the 83 recommendations extracted from the ESHRE guideline for relevance in three rounds. A strict consensus methodology was used to select key recommendations. The main outcome measure was one set of key recommendations for endometriosis care. MAIN RESULTS AND THE ROLE OF CHANCE: A representative set of 17 key recommendations was selected from the preliminary set of 83 recommendations. This selection covers all dimensions of endometriosis care, including diagnosis, treatment of endometriosis-associated pain, treatment of endometriosis-associated infertility and miscellaneous topics such as prevention, menopause and relationship with cancer. Of the 21 experts, 17 participated in at least one round while 16 (76.2%) participated in all 3 rounds. LIMITATIONS, REASONS FOR CAUTION: The feasibility of the selected key recommendations was not assessed in this study. As not all panel members took part in all three rounds, some response bias may have occurred. WIDER IMPLICATIONS OF THE FINDINGS: This set of key recommendations is the first step in the development of quality indicators for monitoring and improving endometriosis care. The set is generic and can be used in hospitals internationally. A practice test should be conducted to assess the feasibility of our key recommendations in clinical practice. STUDY FUNDING/COMPETING INTERESTS: No funding was received for the conduct of this study. Members of the EndoKey study group did not receive payment. The authors and members of the EndoKey study group have no conflict of interest.

Klinefelter syndrome and fertility: sperm preservation should not be offered to children with Klinefelter syndrome.

STUDY QUESTION: Should fertility preservation be offered to children with Klinefelter syndrome (KS)? SUMMARY ANSWER: Current evidence shows that fertility preservation should not be offered to adolescents with KS younger than 16 years because of lower retrieval rates for germ cells by testicular sperm extraction (TESE) compared with retrieval rates for adolescents and adults between 16 and 30 years. WHAT IS KNOWN ALREADY: KS, the most common chromosomal disorder in men leading to non-obstructive azoospermia, is caused by the presence of at least one additional X chromosome. The onset of puberty in adolescents with KS leads to progressive degeneration of the testicular environment. The impact of the subsequent tissue degeneration on fertility potential of patients with KS is unknown, but in previous literature it has been suggested that fertility preservation should be started in adolescents as early as possible. However spermatozoa can be found by TESE in about 50% of adults with KS despite severe testicular degeneration. This review discusses the current evidence for fertility preservation in children and adolescents and possible prognostic markers for fertility treatment in KS. STUDY DESIGN, SIZE, DURATION: An extensive literature search was conducted, searching Pubmed, Embase, Cinahl and Web of Science from origin until April 2016 for 'Klinefelter syndrome' and 'fertility' and various synonyms. Titles and abstracts have been scanned manually by the authors for eligibility. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total 76 studies were found to be eligible for inclusion in this review. Information from the papers was extracted separately by two authors. MAIN RESULTS AND THE ROLE OF CHANCE: Various studies have shown that pre-pubertal children with KS already have a reduced number of germ cells despite a normal hormonal profile during childhood. The presence of spermatozoa in the ejaculate of adolescents with KS is extremely rare. Using TESE, the retrieval rates of spermatozoa for adolescents younger than 16 years old are much lower (0-20%) compared with those for adolescents and young adults between 16 and 30 years old (40-70%). Although spermatogonia can be found by TESE in about half of the peri-pubertal adolescents, there are currently no clinically functional techniques for their future use. Children and adolescents need to be informed that early fertility preservation before the age of 16 cannot guarantee fertility later in life and may even reduce the chances for offspring by removing functional immature germ cells which may possibly develop into spermatozoa after puberty. Furthermore, except for the age of patients with KS, there are no identified factors that can reliably be used as a predictive marker for fertility preservation. LIMITATIONS, REASONS FOR CAUTION: Most of the evidence presented in this review is based on studies including a small number of adolescents with KS. Therefore, the studies may have been underpowered to detect clinically significant differences for their various outcomes, especially for potential predictive factors for fertility preservation, such as hormone levels. Furthermore, the population of patients with KS diagnosed during childhood might be different from the adult population with KS where the diagnosis is based on infertility. Results based on comparisons between the two groups must be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: Despite the limitations, this review summarizes the current evidence for managing fertility preservation in patients with KS to provide optimal health care. STUDY FUNDING/COMPETING INTERESTS: There was no funding for this study. S.F., Y.H., K.D., W.L.M.N., D.S., H.L.C.-v.d.G. and L.R. declare to have no conflicts of interests. D.D.M.B. reports grants from Merck Serono, grants from Ferring and grants from MSD, outside the submitted work. K.F. reports personal fees from MSD (commercial sponsor), personal fees from Ferring (commercial sponsor), grants from Merck-Serono (commercial sponsor), grants from Ferring (commercial sponsor) and grants from MSD (commercial sponsor), outside the submitted work.

Tailored expectant management in couples with unexplained infertility does not influence their experiences with the quality of fertility care.

STUDY QUESTION: Do couples who were eligible for tailored expectant management (TEM) and did not start treatment within 6 months after the fertility work-up, have different experiences with the quality of care than couples that were also eligible for TEM but started treatment right after the fertility work-up? SUMMARY ANSWER: Tailored expectant management of at least 6 months in couples with unexplained infertility is not associated with the experiences with quality of care or trust in their physician. WHAT IS KNOWN ALREADY: In couples with unexplained infertility and a good prognosis of natural conception within 1 year, expectant management for 6-12 months does not compromise ongoing birth rates and is equally as effective as starting medically assisted reproduction immediately. Therefore, TEM is recommended by various international clinical guidelines. Implementation of TEM is still not optimal because of existing barriers on both patient and professional level. An important barrier is the hesitance of professionals to counsel their patients for TEM because they fear that patients will be dissatisfied with care. However, if and how adherence to TEM actually affects the couples' experience with care is unknown. Experiences with the quality care can be measured by evaluating the patient-centredness of care and the patients' trust in their physician. STUDY DESIGN, SIZE, DURATION: This is a retrospective cross-sectional study. A survey with written questionnaires was performed among all couples who participated in the retrospective audit of guideline adherence on TEM in 25 Dutch clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples were eligible to participate if they were diagnosed with unexplained infertility and had a good prognosis (>30%) of natural conception within 1 year based on the Hunault prediction model. We used patient's questionnaires to collect data on the couples' experience with the quality of care and possible confounders for their experiences other than having undergone TEM or not. Multilevel regression analyses were performed to investigate case-mix adjusted association of TEM with the patient-centredness of care (PCQ-Infertility) and the patients' trust in their physician (Wake Forest Trust Scale). MAIN RESULTS AND THE ROLE OF CHANCE: Couples who adhered to TEM experienced the quality of care on the same level as couples who were exposed to early treatment, i.e. started fertility treatment within 6 months after fertility work-up. There were no associations between adherence to TEM and the patient-centredness of care or the patients' trust in their physician. LIMITATIONS, REASONS FOR CAUTION: Because this study is retrospective, recall bias might occur. Furthermore, we were unable to measure the difference in experience with care over time. Therefore, our results have to be interpreted carefully. WIDER IMPLICATIONS OF THE FINDINGS: Prospective research on couples undergoing TEM have to be performed to provide more detailed insight in the patients' experiences with the decision making process and subsequently the expectant period. Tackling the barriers surrounding TEM, i.e. better counselling and more patient information material, could further improve patient experiences with the quality of care for couples who are advised TEM. STUDY FUNDING/COMPETING INTERESTS: Supported by Netherlands Organisation for Health Research and Development (ZonMW). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none. TRIAL REGISTRATION NUMBER: www.trialregister.nl NTR3405.

Cost-effectiveness of embryo transfer strategies: a decision analytic model using long-term costs and consequences of singletons and multiples born as a consequence of IVF.

STUDY QUESTION: What is the cost-effectiveness of elective single embryo transfer (eSET) versus double embryo transfer (DET) strategies from a societal perspective, when applying a time horizon of 1, 5 and 18 years? SUMMARY ANSWER: From a short-term perspective (1 year) it is cost-effective to replace DET with single embryo transfer; however when intermediate- (5 years) and long-term (18 years) costs and consequences are incorporated, DET becomes the most cost-effective strategy, given a ceiling ratio of €20 000 per quality-adjusted life years (QALY) gained. WHAT IS ALREADY KNOWN: According to previous cost-effectiveness research into embryo transfer strategies, DET is considered cost-effective if society is willing to pay around €20 000 for an extra live birth. However, interpretation of those studies is complicated, as those studies fail to incorporate long-term costs and outcomes and used live birth as a measure of effectiveness instead of QALYs. With this outcome, both multiple and singletons were valued as one live birth, whereas costs of all children of a multiple were incorporated. STUDY DESIGN, SIZE, DURATION: A Markov model (cycle length: 1 year; time horizon: 1, 5 and 18 years) was developed comparing a maximum of: (i) three cycles of eSET in all patients; (ii) four cycles of eSET in all patients; (iii) five cycles of eSET in all patients; (iv) three cycles of standard treatment policy (STP), i.e. eSET in women <38 years with a good quality embryo, and DET in all other women; and (v) three cycles of DET in all patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Expected life years (LYs), child QALYs and costs were estimated for all comparators. Input parameters were derived from a retrospective cohort study, in which hospital resource data were collected (n=580) and a parental questionnaire was sent out (431 respondents). Probabilistic sensitivity analysis (5000 iterations) was performed. MAIN RESULTS AND THE ROLE OF CHANCE: With a time horizon of 18 years, DETx3 is most effective (0.54 live births, 10.2 LYs and 9.8 QALYs) and expensive (€37 871) per couple starting IVF. Three cycles of eSET are least effective (0.43 live births, 7.1 LYs and 6.8 QALYs) and expensive (€25 563). We assumed that society is willing to pay €20 000 per QALY gained. With a time horizon of 1 year, eSETx3 was the most cost-effective embryo transfer strategy with a probability of being cost-effective of 99.9%. With a time horizon of 5 or 18 years, DETx3 was most cost-effective, with probabilities of being cost-effective of 77.3 and 93.2%, respectively. LIMITATIONS, REASONS FOR CAUTION: This is the first study to use QALYs generated by the children in the economic evaluation of embryo transfer strategies. There remains some disagreement on whether QALYs generated by new life should be used in economic evaluations of fertility treatment. A further limitation is that treatment ends when it results in live birth and that only child QALYs were considered as measure of effectiveness. The results for the time horizon of 18 years might be less solid, as the data beyond the age of 8 years are based on extrapolation. WIDER IMPLICATIONS OF THE FINDINGS: The current Markov model indicates that when child QALYs are used as measure of outcome it is not cost-effective on the long term to replace DET with single embryo transfer strategies. However, for a balanced approach, a family-planning perspective would be preferable, including additional treatment cycles for couples who wish to have another child. Furthermore, the analysis should be extended to include QALYs of family members. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant (grant number 80-82310-98-09094) from the Netherlands Organization for Health Research and Development (ZonMw). There are no conflicts of interest in connection with this article. TRIAL REGISTRATION NUMBER: Not applicable.

Overtreatment in couples with unexplained infertility.

STUDY QUESTION: What is the percentage of overtreatment, i.e. fertility treatment started too early, in couples with unexplained infertility who were eligible for tailored expectant management? SUMMARY ANSWER: Overtreatment occurred in 36% of couples with unexplained infertility who were eligible for an expectant management of at least 6 months. WHAT IS KNOWN ALREADY: Prognostic models in reproductive medicine can help to identify infertile couples that would benefit from fertility treatment. In couples with unexplained infertility with a good chance of natural conception within 1 year, based on the Hunault prediction model, an expectant management of 6-12 months, as recommended in international fertility guidelines, prevents unnecessary treatment. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study in 25 participating clinics, with follow-up of all couples who were seen for infertility in 2011-2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: In all, 9818 couples were seen for infertility in the participating clinics. Couples were eligible to participate if they were diagnosed with unexplained infertility and had a good prognosis of natural conception (>30%) within 1 year based on the Hunault prediction model. Data to assess overtreatment were collected from medical records. Multilevel regression analyses were performed to investigate associations of overtreatment with patient and clinic characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Five hundred and forty-four couples eligible for expectant management were included in this study. Among these, overtreatment, i.e. starting medically assisted reproduction within 6 months, occurred in 36%. The underlying quality indicators showed that in 34% no prognosis was calculated and that in 42% expectant management was not recommended. Finally, 16% of the couples for whom a correct recommendation of expectant management for at least 6 months was made, started treatment within 6 months anyway. Overtreatment was associated with childlessness, higher female age and a longer duration of infertility. No associations between overtreatment and clinic characteristics were found. LIMITATIONS, REASONS FOR CAUTION: The response rate was low compared with other fertility studies. Evaluation of possible selection bias showed that responders had a higher socio-economic status than non-responders. WIDER IMPLICATIONS OF THE FINDINGS: Our findings show that developing and publishing guideline recommendations on tailored expectant management (TEM) is not enough and that overtreatment still occurs frequently. Future research should focus on tailored efforts to implement guideline recommendations on TEM. STUDY FUNDING/COMPETING INTERESTS: Supported by Netherlands Organisation for Health Research and Development (ZonMW). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none. TRIAL REGISTRATION NUMBER: www.trialregister.nl NTR3405.

Decision-making in female fertility preservation is balancing the expected burden of fertility preservation treatment and the wish to conceive.

STUDY QUESTION: What are the decisive factors in fertility preservation (FP) decision-making in young women scheduled for gonadotoxic therapy? SUMMARY ANSWER: FP decision-making in young women scheduled for gonadotoxic therapy is mainly based on weighing two issues: the intensity of the wish to conceive a child in the future and the expected burden of undergoing FP treatment. WHAT IS KNOWN ALREADY: Future fertility is of importance for young cancer patients whose reproductive function is being threatened by oncological therapy. To prevent or reduce severe psychological effects of infertility as well as feelings of regret about their FP decision after cancer treatment, the quality of fertility preservation counselling (FPC) should be improved. To improve care, those issues forming a decisive factor in FP decision-making for patients should be clarified, as these issues deserve extensive discussion during FPC. Until now, decisive factors have not been isolated from the complex interplay of all aspects of FP that women contemplate during FP decision-making. STUDY DESIGN, SIZE, DURATION: By using a mixed methods methodology, a questionnaire developed after qualitative research involving a selected group of five women who previously received FPC was retrospectively sent to eligible patients (n = 143) who had received FPC (1999 - July 2013) and to whom at least one FP option was offered. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients had received FPC at a university hospital in the Netherlands, in a setting where financial factors do not play a role in FP. They were aged ≥16 years and were scheduled for gonadotoxic treatment. The relationship between patients' baseline characteristics, their attributed importance to 28 relevant importance items and their FP choices was investigated. MAIN RESULTS AND THE ROLE OF CHANCE: After five interviews, 28 importance items for FP decision-making were identified and included in our questionnaire. Of these 28 importance items, 24 items could be clustered into seven importance themes. A total of 87 patients (61%) responded to our questionnaire. After performing a multivariable logistic regression analysis, proceeding with FP was related to higher attributed importance during FP decision-making to the theme 'Wish to conceive (in the future)' (odds ratio (OR) 10.8, 95% confidence interval (CI) 3.5-34.4) and the item 'Having a stable partner relationship' (OR 2.0, 95% CI 1.0-4.1), while higher attributed importance to the theme 'Expected burden of FP' during FP decision-making (OR 0.08, 95% CI 0.02-0.3) more often resulted in refraining from treatment. LIMITATIONS, REASONS FOR CAUTION: Besides possible recall and selection bias, the fact that this study was performed in Dutch patients aged ≥16 years counselled in a single centre, where finance was not an additional consideration, possibly limits the generalizability of our results to a broader European population of cancer patients. Furthermore, we are not able to draw conclusions about the causality of the associations observed in our study. WIDER IMPLICATIONS OF THE FINDINGS: The wish to conceive and the expected burden of FP treatment should be discussed carefully with patients during FP decision-making, either by the referring healthcare provider or by reproductive medicine specialist. Prospective research is needed to explore the causality of the associations found in this study. Furthermore, in order to deliver high quality patient-centred care, the development of tools to explore patients' wish to conceive (for example in different age categories) and tools to provide clear information about the burden of FP treatments (using the preferred information channels suggested by patients) is needed. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Radboud Institute for Health Sciences (research school affiliated to the Radboud university medical center). The authors have declared no conflicts of interest with respect to this work.

Total motile sperm count: a better indicator for the severity of male factor infertility than the WHO sperm classification system.

STUDY QUESTION: Does the prewash total motile sperm count (TMSC) have a better predictive value for spontaneous ongoing pregnancy (SOP) than the World Health Organization (WHO) classification system? SUMMARY ANSWER: The prewash TMSC shows a better correlation with the spontaneous ongoing pregnancy rate (SOPR) than the WHO 2010 classification system. WHAT IS KNOWN ALREADY: According to the WHO classification system, an abnormal semen analysis can be diagnosed as oligozoospermia, astenozoospermia, teratozoospermia or combinations of these and azoospermia. This classification is based on the fifth percentile cut-off values of a cohort of 1953 men with proven fertility. Although this classification suggests accuracy, the relevance for the prognosis of an infertile couple and the choice of treatment is questionable. The TMSC is obtained by multiplying the sample volume by the density and the percentage of A and B motility spermatozoa. STUDY DESIGN, SIZE, DURATION: We analyzed data from a longitudinal cohort study among unselected infertile couples who were referred to three Dutch hospitals between January 2002 and December 2006. Of the total cohort of 2476 infertile couples, only the couples with either male infertility as a single diagnosis or unexplained infertility were included (n = 1177) with a follow-up period of 3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: In all couples a semen analysis was performed. Based on the best semen analysis if more tests were performed, couples were grouped according to the WHO classification system and the TMSC range, as described in the Dutch national guidelines for male infertility. The primary outcome measure was the SOPR, which occurred before, during or after treatments, including expectant management, intrauterine insemination, in vitro fertilization or intracytoplasmic sperm injection. After adjustment for the confounding factors (female and male age, duration and type of infertility and result of the postcoital test) the odd ratios (ORs) for risk of SOP for each WHO and TMSC group were calculated. The couples with unexplained infertility were used as reference. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 514 couples did and 663 couples did not achieve a SOP. All WHO groups have a lower SOPR compared with the unexplained group (ORs varying from 0.136 to 0.397). Comparing the couples within the abnormal WHO groups, there are no significant differences in SOPR, except when oligoasthenoteratozoospermia is compared with asthenozoospermia [OR 0.501 (95% CI 0.311-0.809)] and teratozoospermia [OR 0.499 (95% CI: 0.252-0.988)], and oligoasthenozoospermia is compared with asthenozoospermia [OR 0.572 (95% CI: 0.373-0.877)]. All TMSC groups have a significantly lower SOPR compared with the unexplained group (ORs varying from 0.171 to 0.461). Couples with a TMSC of <1 × 10(6) and 1-5 × 10(6) have significantly lower SOPR compared with couples with a TMSC of 5-10 × 10(6) [respectively, OR 0.371 (95% CI: 0.215-0.64) and OR 0.505 (95% CI: 0.307-0.832)]. LIMITATIONS, REASON FOR CAUTION: To include all SOPs during the follow-up period of 3 years, couples were not censured at the start of treatment. WIDER IMPLICATIONS OF THE FINDINGS: Roughly, three prognostic groups can be discerned: couples with a TMSC <5, couples with a TMSC between 5 and 20 and couples with a TMSC of more than 20 × 10(6) spermatozoa. We suggest using TMSC as the method of choice to express severity of male infertility. STUDY FUNDING/COMPETING INTERESTS: None.

Hospital costs during the first 5 years of life for multiples compared with singletons born after IVF or ICSI.

STUDY QUESTION: Do in vitro fertilization (IVF) multiples generate higher hospital costs than IVF singletons, from birth up to age 5? SUMMARY ANSWER: Hospital costs from birth up to age 5 were significantly higher among IVF/ICSI multiple children compared with IVF/ICSI singletons; however, when excluding the costs incurred during the birth admission period, hospital costs of multiples and singletons were comparable. WHAT IS KNOWN ALREADY: Concern has risen over the long-term outcome of children born after IVF. The increased incidence of multiple births in IVF as a result of double-embryo transfer predisposes children to a poorer neonatal outcome such as preterm birth and low birthweight. As a consequence, IVF multiples require more medical care. Costs and consequences of poorer neonatal outcomes in multiples may also exist later in life. STUDY DESIGN, SIZE, DURATION: All 5497 children born from IVF in 2003-2005, whose parents received IVF or ICSI treatment in one of five participating Dutch IVF centers, served as a basis for a retrospective cohort study. Based on gestational age, birthweight, Apgar and congenital malformation, children were assigned to one of three risk strata (low-, moderate- or high-risk). PARTICIPANTS/MATERIALS, SETTING, METHODS: To enhance the efficiency of the data collection, 816 multiples and 584 singletons were selected for 5-year follow-up based on stratified (risk) sampling. Parental informed consent was received of 322 multiples and 293 singletons. Individual-level hospital resource use data (hospitalization, outpatient visits and medical procedures) were retrieved from hospital information systems and patient charts for 302 multiples and 278 singletons. MAIN RESULTS AND THE ROLE OF CHANCE: The risk of hospitalization (OR 4.9, 95% CI 3.3-7.0), outpatient visits (OR 2.6, 95% CI 1.8-3.6) and medical procedures (OR 1.7, 95% CI 1.2-2.2) was higher for multiples compared with singletons. The average hospital costs amounted to €10 018 and €2093 during the birth admission period (P < 0.001), €1131 and €696 after the birth admission period to the first birthday (not significant (n.s.)) and €1084 and €938 from the second to the fifth life year (n.s.) for multiples and singletons, respectively. Hospital costs from birth up to age 5 were 3.3-fold higher for multiples compared with singletons (P < 0.001). Among multiples and singletons, respectively, 90.8 and 76.2% of the total hospital costs were caused by hospital admission days and 8.9 and 25.2% of the total hospital costs during the first 5 years of life occurred after the first year of life. LIMITATIONS, REASONS FOR CAUTION: Resource use and costs outside the hospital were not included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the increased use of healthcare resources by IVF/ICSI multiples compared with IVF/ICSI singletons. Single-embryo transfer may result in substantial savings, particularly in the birth admission period. These savings need to be compared with the extra costs of additional embryo transfers needed to achieve a successful pregnancy. Besides costs, health outcomes of children born after single-embryo transfer should be compared with those born after double-embryo transfer. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a research grant (grant number 80-82310-98-09094) from the Netherlands Organization for Health Research and Development (ZonMw). There are no conflicts of interest in connection with this article. TRIAL REGISTRATION NUMBER: Not applicable.

Referral for fertility preservation counselling in female cancer patients.

STUDY QUESTION: What changes can be detected in fertility preservation (FP) counselling (FPC) over time and what are the determinants associated with the referral of newly diagnosed female cancer patients, aged 0-39 years, to a specialist in reproductive medicine for FPC? SUMMARY ANSWER: Although the absolute number of patients receiving FPC increased over time, only 9.8% of all potential patients (aged 0-39 years) were referred in 2011 and referral disparities were found with respect to patients' age, cancer diagnosis and healthcare provider-related factors. WHAT IS KNOWN ALREADY: Referral rates for FPC prior to the start of gonadotoxic cancer treatment are low. Determinants associated with low referral and referral disparities have been identified in previous studies, although there are only scarce data on referral practices and determinants for FPC referral in settings with reimbursement of FP(C). STUDY DESIGN, SIZE, DURATION: We conducted a retrospective observational and questionnaire study in a Dutch university hospital. Data on all female cancer patients counselled for FP in this centre (2001-2013), as well as all newly diagnosed female cancer patients aged 0-39 years in the region (2009-2011) were collected. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were retrieved from medical records (FPC patients), cancer incidences reported by the Dutch Cancer Registry (to calculate referral percentages) and referring professionals (to identify reasons for the current referral behaviour). MAIN RESULTS AND THE ROLE OF CHANCE: In 2011, a total of 9.8% of the patients were referred for FPC. Patients aged 20-29 years or diagnosed with breast cancer or lymphoma were referred more frequently compared with patients under the age of 20 years or patients diagnosed with other malignancies. The absolute numbers of patients receiving FPC increased over time. Healthcare provider-related determinants for low referral were not starting a discussion about fertility-related issues, not knowing where to refer a patient for FPC and not collaborating with patients' associations. LIMITATIONS, REASONS FOR CAUTION: Actual referral rates may slightly differ from our estimation as there may have been patients who did not wish to receive FPC. Sporadically, patients might have been directly referred to other regions or may have received ovarian transposition without FPC. By excluding skin cancer patients, we will have underestimated the group of women who are eligible for FPC as this group also includes melanoma patients who might have received gonadotoxic therapy. WIDER IMPLICATIONS OF THE FINDINGS: The low referral rates and referral disparities reported in the current study indicate that there are opportunities to improve referral practices. Future research should focus on the implementation and evaluation of interventions to improve referral practices, such as information materials for patients at oncology departments, discussion prompts or methods to increase the awareness of physicians and patients of FP techniques and guidelines. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Radboud university medical center and the Radboud Institute for Health Sciences. The authors have declared no conflicts of interest with respect to this work. TRIAL REGISTRATION NUMBER: Not applicable.

Deciding about fertility preservation after specialist counselling.

STUDY QUESTION: How do female patients experience fertility preservation (FP) consultation (FPC) with a specialist in reproductive medicine and subsequent decision-making on FP? SUMMARY ANSWER: Most patients had positive experiences with FPC, but negative experiences were found to be associated with decisional conflict and decision regret. WHAT IS KNOWN ALREADY: When confronted with a need for gonadotoxic treatment, girls and young women will have to make an irreversible decision with regard to FP. Patients may experience decisional conflict and develop regret about their decision during follow-up. Patients' opportunities to ask questions during FPC and their knowledge about FP have been inversely related to decisional conflict. STUDY DESIGN, SIZE, DURATION: A questionnaire on experiences with FPC, designed after qualitative research, was retrospectively distributed to 108 patients to whom FP was offered after FPC between July 2008 and July 2013. Aiming to minimize recall bias, we defined a subgroup of patients counselled since 2011 who had not yet tried to conceive after FPC. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were aged ≥16 years and had either cancer or a benign disease that required gonadotoxic therapy. They received FPC in a single university hospital in the Netherlands. Apart from patients' experiences, patients' characteristics, decisional conflict and decision regret were assessed. MAIN RESULTS AND ROLE OF CHANCE: A total of 64 patients (59.3%) responded to the questionnaire. Patients generally had positive experiences with FPC, but indicated room for improvement. Negative experiences were associated with decisional conflict regarding the FP decision (not enough time for counselling: P < 0.0001; not having the opportunity to ask all questions during FPC: P < 0.0001; not feeling supported by the counsellor during decision-making: P = 0.0003; not all applicable options were discussed: P = 0.0001; benefits and disadvantages of FP options were not clearly explained: P = 0.0005). Decisional conflict was correlated to decision regret (P < 0.0001). In the subgroup of patients counselled after 2011 who had not tried to conceive (n = 33), similar results as for the total study population were found for the association of patient experiences with decisional conflict. LIMITATIONS, REASONS FOR CAUTION: Given our retrospective design, we were not informed about the causality of the associations observed. We studied Dutch patients who were counselled in a single centre and were at least 16 years old when filling in the questionnaire. This may limit the generalizability of our data to other settings and populations. WIDER IMPLICATIONS OF THE FINDINGS: More attention should be paid to improving FPC care. Interventions aiming at improving patients' comprehension of the topic of FP and their feelings of being supported in decision-making are advisable. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Radboud Institute for Health and an unconditional grant from Merck Serono. The authors have declared no conflicts of interest with respect to this work.

ESHRE guideline: management of women with endometriosis.

STUDY QUESTION: What is the optimal management of women with endometriosis based on the best available evidence in the literature? SUMMARY ANSWER: Using the structured methodology of the Manual for ESHRE Guideline Development, 83 recommendations were formulated that answered the 22 key questions on optimal management of women with endometriosis. WHAT IS KNOWN ALREADY: The European Society of Human Reproduction and Embryology (ESHRE) guideline for the diagnosis and treatment of endometriosis (2005) has been a reference point for best clinical care in endometriosis for years, but this guideline was in need of updating. STUDY DESIGN, SIZE, DURATION: This guideline was produced by a group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to January 2012 and consensus within the guideline group on all recommendations. To ensure input from women with endometriosis, a patient representative was part of the guideline development group. In addition, patient and additional clinical input was collected during the scoping and review phase of the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: NA. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 83 recommendations on diagnosis of endometriosis and on the treatment of endometriosis-associated pain and infertility, on the management of women in whom the disease is found incidentally (without pain or infertility), on prevention of recurrence of disease and/or painful symptoms, on treatment of menopausal symptoms in patients with a history of endometriosis and on the possible association of endometriosis and malignancy. LIMITATIONS, REASONS FOR CAUTION: We identified several areas in care of women with endometriosis for which robust evidence is lacking. These areas were addressed by formulating good practice points (GPP), based on the expert opinion of the guideline group members. WIDER IMPLICATIONS OF THE FINDINGS: Since 32 out of the 83 recommendations for the management of women with endometriosis could not be based on high level evidence and therefore were GPP, the guideline group formulated research recommendations to guide future research with the aim of increasing the body of evidence. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. All guideline group members disclosed any relevant conflicts of interest (see Conflicts of interest). TRIAL REGISTRATION NUMBER: NA.

Development of guideline-based indicators for patient-centredness in fertility care: what patients add.

STUDY QUESTION: What value can patients add to the development of guideline-based quality indicators for patient-centredness in fertility care? SUMMARY ANSWER: Infertile patients mainly select different indicators and value different dimensions of patient-centredness (e.g. information and communication and access to care) than professionals (e.g. coordination and integration of care) during an indicator development process. WHAT IS KNOWN ALREADY: Patient-centredness is an important dimension for the quality of fertility care. However, this dimension is not adequately evaluated by professionals, due to a lack of quality indicators. Furthermore, it is suggested that patients select different indicators for patient-centredness than professionals, although exact differences are unknown. STUDY DESIGN, SIZE AND DURATION: The RAND-modified Delphi method (a two-step systematic consensus method) was used to develop two sets of quality indicators for patient-centredness. Similarities and differences in the indicators as well as in aspects of patient-centredness between patients' and professionals' sets of indicators were analysed descriptively. PARTICIPANTS, SETTING, METHODS: The development of quality indicators for patient-centredness was based on the national multidisciplinary Network Guideline on infertility. Two panels participated: one patients' panel (n = 19) and one multidisciplinary professionals' panel (n = 15). MAIN RESULTS AND THE ROLE OF CHANCE: From 119 formulated potential indicators of patient-centredness, the patients' panel selected a representative set of 16, while the professionals' panel selected 18. Five indicators were included in both sets. These regarded the need to perform IUI at least 6 days a week; report on treatment outcomes and complications; report on results of semen analyses in a standardized way; counsel infertile couples about the positive effects on their chance of pregnancy of the elimination of a harmful lifestyle and provide information on the negative consequences for achieving a pregnancy in case of a high BMI. Both patients and professionals put highest value on potential indicators of information and communication in fertility care. Patients also emphasized accessibility of care, whereas professionals emphasized coordination and integration as important quality measures for patient-centredness in fertility care. LIMITATIONS, REASONS FOR CAUTION: First, the total number of developed indicators in the final set is relatively large (n = 29), which could be a first potential limitation in its use for accreditation and quality monitoring. Secondly, although panel members were asked to take reliability into account during the selection procedure, the indicators still need an evaluation of the measurability and the intra- and inter-observer reliability. WIDER IMPLICATIONS OF THE FINDINGS: The final guideline-based indicator set consisting of 29 indicators represents a balanced set that is based on the expertise of all stakeholders, including patients. A next step should be the application of this set in a future practice test to assess the feasibility in daily practice. In our opinion, most quality indicators for patient-centredness could be used for monitoring and improving the quality of fertility care internationally, occasionally by a more broad interpretation (e.g. by replacing the general practitioners with other healthcare professionals engaged in the care process). STUDY FUNDING/COMPETING INTEREST(S): This study was supported by a research grant (number 150020015) from the Dutch Organisation for Health Research and Development (ZonMw) in a research programme on broadening and acceleration in multidisciplinary guideline development. The authors have no conflicts of interest to declare.

Quality indicators for all dimensions of infertility care quality: consensus between professionals and patients.

STUDY QUESTION: What is the relative importance of the six dimensions of quality of care according to different stakeholders and can a quality indicator set address all six quality dimensions and incorporate the views from professionals working in different disciplines and from patients? SUMMARY ANSWER: Safety, effectiveness and patient centeredness were the most important quality dimensions. All six quality dimensions can be assessed with a set of 24 quality indicators, which is face valid and acceptable according to both professionals from different disciplines and patients. WHAT IS KNOWN ALREADY: To our knowledge, no study has weighted the relative importance of all quality dimensions to infertility care. Additionally, there are very few infertility care-specific quality indicators and no quality indicator set covers all six quality dimensions and incorporated the views of professionals and patients. STUDY DESIGN, SIZE AND DURATION: A three-round iterative Delphi survey including patients and professionals from four different fields, conducted in two European countries over the course of 2011 and 2012. PARTICIPANTS/MATERIALS, SETTINGS AND METHODS: Dutch and Belgian gynaecologists, embryologists, counsellors, nurses/midwifes and patients took part (n = 43 in round 1 and finally 30 in round 3). Respondents ranked the six quality dimensions twice for importance and their agreement was evaluated. Furthermore, in round 1, respondents gave suggestions, which were subsequently uniformly formulated as quality indicators. In rounds 2 and 3, respondents rated the quality indicators for preparedness to measure and for importance (relation to quality and prioritization for benchmarking). Providing feedback allowed selecting indicators based on consensus between stakeholder groups. Measurable indicators, important to all stakeholder groups, were selected for each quality dimension. MAIN RESULTS: All stakeholder groups and most individuals agreed that safety, effectiveness and patient centeredness were the most important quality dimensions. A total of 498 suggestions led to the development of 298 indicators. Professionals were sufficiently prepared to measure 204 of these indicators. Based on importance, 52 (7-15 per dimension; round 2) and finally 24 (4 per dimension; round 3) quality indicators were selected. LIMITATIONS, REASONS FOR CAUTION: The final quality indicator set does not cover the entire care process, but rather takes a 'sample' of each quality dimension. Although the quality indicators are face valid and acceptable, their psychometric characteristics need to be tested by further research. WIDER IMPLICATIONS OF THE FINDINGS: Quality management should focus on safety, effectiveness and patient centeredness of care. Clinics can use the quality indicator set to assess all quality dimensions of their care.

Guideline adherence is worth the effort: a cost-effectiveness analysis in intrauterine insemination care.

STUDY QUESTION: Is optimal adherence to guideline recommendations in intrauterine insemination (IUI) care cost-effective from a societal perspective when compared with suboptimal adherence to guideline recommendations? SUMMARY ANSWER: Optimal guideline adherence in IUI care has substantial economic benefits when compared with suboptimal guideline adherence. WHAT IS KNOWN ALREADY: Fertility guidelines are tools to help health-care professionals, and patients make better decisions about clinically effective, safe and cost-effective care. Up to now, there has been limited published evidence about the association between guideline adherence and cost-effectiveness in fertility care. STUDY DESIGN, SIZE, DURATION: In a retrospective cohort study involving medical record analysis and a patient survey (n = 415), interviews with staff members (n = 13) and a review of hospitals' financial department reports and literature, data were obtained about patient characteristics, process aspects and clinical outcomes of IUI care and resources consumed. In the cost-effectiveness analyses, restricted to four relevant guideline recommendations, the ongoing pregnancy rate per couple (effectiveness), the average medical and non-medical costs of IUI care, possible additional IVF treatment, pregnancy, delivery and period from birth up to 6 weeks after birth for both mother and offspring per couple (costs) and the incremental net monetary benefits were calculated to investigate if optimal guideline adherence is cost-effective from a societal perspective when compared with suboptimal guideline adherence. PARTICIPANTS/MATERIALS, SETTING, METHODS: Seven hundred and sixty five of 1100 randomly selected infertile couples from the databases of the fertility laboratories of 10 Dutch hospitals, including 1 large university hospital providing tertiary care and 9 public hospitals providing secondary care, were willing to participate, but 350 couples were excluded because of ovulatory disorders or the use of donated spermatozoa (n = 184), still ongoing IUI treatment (n = 143) or no access to their medical records (n = 23). As a result, 415 infertile couples who started a total of 1803 IUI cycles were eligible for the cost-effectiveness analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Optimal adherence to the guideline recommendations about sperm quality, the total number of IUI cycles and dose of human chorionic gonadotrophin was cost-effective with an incremental net monetary benefit between € 645 and over € 7500 per couple, depending on the recommendation and assuming a willingness to pay € 20 000 for an ongoing pregnancy. LIMITATIONS, REASONS FOR CAUTION: Because not all recommendations applied to all 415 included couples, smaller groups were left for some of the cost-effectiveness analyses, and one integrated analysis with all recommendations within one model was impossible. WIDER IMPLICATIONS OF THE FINDINGS: Optimal guideline adherence in IUI care has substantial economic benefits when compared with suboptimal guideline adherence. For Europe, where over 144,000 IUI cycles are initiated each year to treat ≈ 32 000 infertile couples, this could mean a possible cost saving of at least 20 million euro yearly. Therefore, it is valuable to make an effort to improve guideline development and implementation.