Predicting the likelihood of successful medical treatment of early pregnancy loss: development and internal validation of a clinical prediction model.

STUDY QUESTION: What are clinical predictors for successful medical treatment in case of early pregnancy loss (EPL)? SUMMARY ANSWER: Use of mifepristone, BMI, number of previous uterine aspirations and the presence of minor clinical symptoms (slight vaginal bleeding or some abdominal cramps) at treatment start are predictors for successful medical treatment in case of EPL. WHAT IS KNOWN ALREADY: Success rates of medical treatment for EPL vary strongly, between but also within different treatment regimens. Up until now, although some predictors have been identified, no clinical prediction model has been developed yet. STUDY DESIGN, SIZE, DURATION: Secondary analysis of a multicentre randomized controlled trial in 17 Dutch hospitals, executed between 28 June 2018 and 8 January 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with a non-viable pregnancy between 6 and 14 weeks of gestational age, who opted for medical treatment after a minimum of 1 week of unsuccessful expectant management. Potential predictors for successful medical treatment of EPL were chosen based on literature and expert opinions. We internally validated the prediction model using bootstrapping techniques. MAIN RESULTS AND THE ROLE OF CHANCE: 237 out of 344 women had a successful medical EPL treatment (68.9%). The model includes the following variables: use of mifepristone, BMI, number of previous uterine aspirations and the presence of minor clinical symptoms (slight vaginal bleeding or some abdominal cramps) at treatment start. The model shows a moderate capacity to discriminate between success and failure of treatment, with an AUC of 67.6% (95% CI = 64.9-70.3%). The model had a good fit comparing predicted to observed probabilities of success but might underestimate treatment success in women with a predicted probability of success of ∼70%. LIMITATIONS, REASONS FOR CAUTION: The vast majority (90.4%) of women were Caucasian, potentially leading to less optimal model performance in a non-Caucasian population. Limitations of our model are that we have not yet been able to externally validate its performance and clinical impact, and the moderate accuracy of the prediction model of 0.67. WIDER IMPLICATIONS OF THE FINDINGS: We developed a prediction model, aimed to improve and personalize counselling for medical treatment of EPL by providing a woman with her individual chance of complete evacuation. STUDY FUNDING/COMPETING INTEREST(S): The Triple M Trial, upon which this secondary analysis was performed, was funded by the Healthcare Insurers Innovation Foundation (project number 3080 B15-191). TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT03212352.

De novo mutations in children born after medical assisted reproduction.

STUDY QUESTION: Are there more de novo mutations (DNMs) present in the genomes of children born through medical assisted reproduction (MAR) compared to spontaneously conceived children? SUMMARY ANSWER: In this pilot study, no statistically significant difference was observed in the number of DNMs observed in the genomes of MAR children versus spontaneously conceived children. WHAT IS KNOWN ALREADY: DNMs are known to play a major role in sporadic disorders with reduced fitness such as severe developmental disorders, including intellectual disability and epilepsy. Advanced paternal age is known to place offspring at increased disease risk, amongst others by increasing the number of DNMs in their genome. There are very few studies reporting on the effect of MAR on the number of DNMs in the offspring, especially when male infertility is known to be affecting the potential fathers. With delayed parenthood an ongoing epidemiological trend in the 21st century, there are more children born from fathers of advanced age and more children born through MAR every day. STUDY DESIGN, SIZE, DURATION: This observational pilot study was conducted from January 2015 to March 2019 in the tertiary care centre at Radboud University Medical Center. We included a total of 53 children and their respective parents, forming 49 trios (mother, father and child) and two quartets (mother, father and two siblings). One group of children was born after spontaneous conception (n = 18); a second group of children born after IVF (n = 17) and a third group of children born after ICSI combined with testicular sperm extraction (ICSI-TESE) (n = 18). In this pilot study, we also subdivided each group by paternal age, resulting in a subgroup of children born to younger fathers (<35 years of age at conception) and older fathers (>45 years of age at conception). PARTICIPANTS/MATERIALS, SETTING, METHODS: Whole-genome sequencing (WGS) was performed on all parent-offspring trios to identify DNMs. For 34 of 53 trios/quartets, WGS was performed twice to independently detect and validate the presence of DNMs. Quality of WGS-based DNM calling was independently assessed by targeted Sanger sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: No significant differences were observed in the number of DNMs per child for the different methods of conception, independent of parental age at conception (multi-factorial ANOVA, f(2) = 0.17, P-value = 0.85). As expected, a clear paternal age effect was observed after adjusting for method of conception and maternal age at conception (multiple regression model, t = 5.636, P-value = 8.97 × 10-7), with on average 71 DNMs in the genomes of children born to young fathers (<35 years of age) and an average of 94 DNMs in the genomes of children born to older fathers (>45 years of age). LIMITATIONS, REASONS FOR CAUTION: This is a pilot study and other small-scale studies have recently reported contrasting results. Larger unbiased studies are required to confirm or falsify these results. WIDER IMPLICATIONS OF THE FINDINGS: This pilot study did not show an effect for the method of conception on the number of DNMs per genome in offspring. Given the role that DNMs play in disease risk, this negative result is good news for IVF and ICSI-TESE born children, if replicated in a larger cohort. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Netherlands Organisation for Scientific Research (918-15-667) and by an Investigator Award in Science from the Wellcome Trust (209451). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

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.

Fertility navigators in female oncofertility care in an academic medical center: a qualitative evaluation.

PURPOSE: To explore patients' and professionals' experiences with fertility navigators in female oncofertility care. METHODS: Semi-structured in-depth interviews were conducted with nine female cancer patients and six healthcare professionals to explore their experiences. They were recruited from an academic medical center (referral clinic for female fertility preservation care). Data were analyzed using the concepts of grounded theory. RESULTS: Patients were satisfied about the supportive role of the fertility navigator in their fertility preservation process: fertility navigators added value as they became "familiar faces" and provided information, emotional support, personal care, and served as patients' primary contact person. The fertility navigators had a pleasant collaboration with professionals and supported professionals by taking over tasks. To improve the role of fertility navigators, it was suggested that they should always be present in fertility preservation counseling, and attention should be paid to their availability to improve continuity of care. CONCLUSION: Fertility navigators provide personal care, improve satisfaction in patients in their oncofertility process, and support professionals. The overview of issues that need to be addressed when assigning fertility navigators in female oncofertility care combined with the improvement suggestions could be used by other centers when considering implementing fertility navigators.

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.

To Freeze or Not to Freeze? An Update on Fertility Preservation In Females with Turner Syndrome.

Introduction Infertility is a major concern for females with Turner syndrome (TS), regardless of their age. While fertility preservation is now routinely offered to girls and young women with cancer, there are currently no recommendations on fertility preservation in girls and young women with TS who generally face an even higher risk for infertility. Despite the lack of international guidelines, preservation procedures have been performed experimentally in females with TS. Methods A systematic literature search based on the PRISMA-P methodology for systematic reviews was performed in order to collect all published data on fertility preservation options in females with TS between January 1980 and April 2018. A total number of 67 records were included in this review. The records were screened for information regarding cryopreservation of mature oocytes and ovarian tissue in females with TS. Two ongoing trials on fertility preservation in young females with TS were also included. Results Cryopreservation of oocytes or ovarian tissue has been performed experimentally in >150 girls and adolescents with TS over the last 16 years. The efficacy of fertility preservation options in females with TS is still unknown due to the lack of follow-up data. Conclusion The efficacy of fertility preservation procedures in females with TS is still unknown. Future studies with focus on efficacy, safety and long-term follow-up are desperately needed.

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.

Klinefelter syndrome and fertility-Impact of X-chromosomal inheritance on spermatogenesis.

With the use of testicular sperm extraction (TESE), spermatozoa can be retrieved in about 30%-50% of men with Klinefelter syndrome (KS). The reason for the absence or presence of spermatozoa in half of the men with KS remains unknown. Therefore, the search for an objective marker for a positive prediction in finding spermatozoa is of significant clinical value to avoid unnecessary testicular biopsies in males with (mostly) low testicular volume and impaired testosterone. The objective of this study was to determine whether paternal or maternal inheritance of the additional X-chromosome can predict the absence or presence of spermatogenesis in men with KS. Men with KS who have had a testicular biopsy for diagnostic fertility workup TESE were eligible for inclusion. Buccal swabs from nine KS patients and parents (trios) were taken to compare X-chromosomal inheritance to determine the parental origin of both X-chromosomes in the males with KS. Spermatozoa were found in TESE biopsies 8 of 35 (23%) patients after performing a unilateral or bilateral TESE. Different levels of spermatogenesis (from the only presence of spermatogonia, up to maturation arrest or hypospermatogenesis) appeared to be present in 19 of 35 (54%) men, meaning that the presence of spermatogenesis not always yields mature spermatozoa. From the nine KS-trios that were genetically analysed for X-chromosomal inheritance origin, no evidence of a correlation between the maternal or paternal origin of the additional X-chromosome and the presence of spermatogenesis was found. In conclusion, the maternal or paternal origin of the additional X-chromosome in men with KS does not predict the presence or absence of spermatogenesis.

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.

Cost-effectiveness of 'immediate IVF' versus 'delayed IVF': a prospective study.

STUDY QUESTION: How does the cost-effectiveness (CE) of immediate IVF compared with postponing IVF for 1 year, depend on prognostic characteristics of the couple? SUMMARY ANSWER: The CE ratio, i.e. the incremental costs of immediate versus delayed IVF per extra live birth, is the highest (range of €15 000 to >€60 000) for couples with unexplained infertility and for them depends strongly on female age and the duration of infertility, whilst being lowest for endometriosis (range 8000-23 000) and, for such patients, only slightly dependent on female age and duration of infertility. WHAT IS KNOWN ALREADY: A few countries have guidelines for indications of IVF, using the diagnostic category, female age and duration of infertility. The CE of these guidelines is unknown and the evidence base exists only for bilateral tubal occlusion, not for the other diagnostic categories. STUDY DESIGN, SIZE, DURATION: A modelling approach was applied, based on the literature and data from a prospective cohort study among couples eligible for IVF or ICSI treatment, registered in a national waiting list in The Netherlands between January 2002 and December 2003. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 5962 couples was included. Chances of natural ongoing pregnancy were estimated from the waiting list observations and chances of ongoing pregnancy after IVF from follow-up data of couples with primary infertility that began treatment. Prognostic characteristics considered were female age, duration of infertility and diagnostic category. Costs of IVF were assessed from a societal perspective and determined on a representative sample of patients. A cost-effectiveness comparison was made between two scenarios: (I) wait one more year and then undergo IVF for 1 year and (II) immediate IVF during 1 year, and try to conceive naturally in the following year. Comparisons were made for strata determined by the prognostic factors. The final outcome was a live birth. MAIN RESULTS AND THE ROLE OF CHANCE: The gain in live birth rate of the immediate IVF scenario versus postponed IVF increased with female age, and was independent from diagnostic category or duration of infertility. By contrast, the corresponding increase in costs primarily depended on diagnostic category and duration of infertility. The lowest CE ratio was just below €10 000 per live birth for endometriosis from age 34 onwards at 1 year duration. The highest CE ratio reached €56 000 per live birth for unexplained infertility at age 30 and 3 years duration, dropping to values below € 30 000 per live birth from age 32 onwards. It reached values below €20 000 per live birth with 3 years duration at age 34 and older. The CE ratio was in between for the three other diagnostic categories (i.e. Male infertility, Hormonal and Immunological/Cervical). LIMITATIONS, REASONS FOR CAUTION: We applied estimates of chances with IVF, excluding frozen embryos, for which we had no data. Therefore, we do not know the effect of frozen embryo transfers on the CE. WIDER IMPLICATIONS OF THE FINDINGS: The duration of infertility at which IVF becomes cost-effective depends, firstly, on the level of society's willingness to pay for one extra live birth, and secondly, given a certain level of willingness to pay, on the woman's age and the diagnostic category. In current guidelines, the chances of a natural conception should always be taken into account before deciding whether to start IVF treatment and at which time. STUDY FUNDING/COMPETING INTEREST(S): Supported by Netherlands Organisation for Health Research and Development (ZonMW, grant 945-12-013). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none.

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.

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.

Prediction model for live birth in ICSI using testicular extracted sperm.

STUDY QUESTION: Which parameters have a predictive value for live birth in couples undergoing ICSI after successful testicular sperm extraction (TESE-ICSI)? SUMMARY ANSWER: Female age, a first or subsequent started TESE-ICSI cycle, male LH, male testosterone, motility of the spermatozoa during the ICSI procedure and the initial male diagnosis before performing TESE were identified as relevant and independent parameters for live birth after TESE-ICSI. WHAT IS KNOWN ALREADY: In reproductive medicine prediction models are used frequently to predict treatment success, but no prediction model currently exists for live birth after TESE-ICSI. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study between 2007 and 2015 in two academic hospitals including 1559 TESE-ICSI cycles. The prediction model was developed using data from one centre and validation was performed with data from the second centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included couples undergoing ICSI treatment with surgically retrieved sperm from the testis for the first time. In the development set we included 526 couples undergoing 1006 TESE-ICSI cycles. In the validation set we included 289 couples undergoing 553 TESE-ICSI cycles. Multivariable logistic regression models were constructed in a stepwise fashion (P < 0.2 for entry). The external validation was based on discrimination and calibration. MAIN RESULTS AND THE ROLE OF CHANCE: We included 224 couples (22.3%) with a live birth in the development set. The occurrence of a live birth was associated with lower female age, first TESE-ICSI cycle, lower male LH, higher male testosterone, the use of motile spermatozoa for ICSI and having obstructive azoospermia as an initial suspected diagnosis. The area under the receiver operating characteristic (ROC) curve was 0.62. From validation data, the model had moderate discriminative capacity (c-statistic 0.67, 95% confidence interval: 0.62-0.72) but calibrated well, with a range from 0.06 to 0.56 in calculated probabilities. LIMITATIONS, REASONS FOR CAUTION: We had a lack of data about the motility of spermatozoa during TESE, therefore, we used motility of the spermatozoa used for ICSI after freeze-thawing, information which is only available during treatment. We had to exclude data on paternal BMI in the model because too many missing values in the validation data hindered testing. We did not include a histologic diagnosis, which would have made our data set less heterogeneous and, finally, our model may not be applicable in centres which have a different policy for the indication for performing sperm extraction. The prognostic value of the model is limited because of a low 'area under the curve'. WIDER IMPLICATIONS OF THE FINDINGS: This model enables the differentiation between couples with a low or high chance to reach a live birth using TESE-ICSI. As such it can aid in the counselling of patients and in clinical decision-making. STUDY FUNDING/COMPETING INTERESTS: This study was partly supported by an unconditional grant from Merck Serono (to D.D.M.B. and K.F.) and by the Department of Obstetrics and Gynaecology of Radboud University Medical Center, Nijmegen, The Netherlands, the Department of Obstetrics and Gynaecology, Jeroen Bosch Hospital, Den Bosch, The Netherlands, and the Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands. Merck Serono had no influence in concept, design, nor elaboration of this study. TRIAL REGISTRATION NUMBER: Not applicable.

Prediction model for obtaining spermatozoa with testicular sperm extraction in men with non-obstructive azoospermia.

STUDY QUESTION: Can an externally validated model, based on biological variables, be developed to predict successful sperm retrieval with testicular sperm extraction (TESE) in men with non-obstructive azoospermia (NOA) using a large nationwide cohort? SUMMARY ANSWER: Our prediction model including six variables was able to make a good distinction between men with a good chance and men with a poor chance of obtaining spermatozoa with TESE. WHAT IS KNOWN ALREADY: Using ICSI in combination with TESE even men suffering from NOA are able to father their own biological child. Only in approximately half of the patients with NOA can testicular sperm be retrieved successfully. The few models that have been developed to predict the chance of obtaining spermatozoa with TESE were based on small datasets and none of them have been validated externally. STUDY DESIGN, SIZE, DURATION: We performed a retrospective nationwide cohort study. Data from 1371 TESE procedures were collected between June 2007 and June 2015 in the two fertility centres. PARTICIPANTS/MATERIALS, SETTING, METHODS: All men with NOA undergoing their first TESE procedure as part of a fertility treatment were included. The primary end-point was the presence of one or more spermatozoa (regardless of their motility) in the testicular biopsies.We constructed a model for the prediction of successful sperm retrieval, using univariable and multivariable binary logistic regression analysis and the dataset from one centre. This model was then validated using the dataset from the other centre. The area under the receiver-operating characteristic curve (AUC) was calculated and model calibration was assessed. MAIN RESULTS AND THE ROLE OF CHANCE: There were 599 (43.7%) successful sperm retrievals after a first TESE procedure. The prediction model, built after multivariable logistic regression analysis, demonstrated that higher male age, higher levels of serum testosterone and lower levels of FSH and LH were predictive for successful sperm retrieval. Diagnosis of idiopathic NOA and the presence of an azoospermia factor c gene deletion were predictive for unsuccessful sperm retrieval. The AUC was 0.69 (95% confidence interval (CI): 0.66-0.72). The difference between the mean observed chance and the mean predicted chance was <2.0% in all groups, indicating good calibration. In validation, the model had moderate discriminative capacity (AUC 0.65, 95% CI: 0.62-0.72) and moderate calibration: the predicted probability never differed by more than 9.2% of the mean observed probability. LIMITATIONS, REASONS FOR CAUTION: The percentage of men with Klinefelter syndrome among men diagnosed with NOA is expected to be higher than in our study population, which is a potential selection bias. The ability of the sperm retrieved to fertilize an oocyte and produce a live birth was not tested. WIDER IMPLICATIONS OF THE FINDINGS: This model can help in clinical decision-making in men with NOA by reliably predicting the chance of obtaining spermatozoa with TESE. STUDY FUNDING/COMPETING INTEREST: This study was partly supported by an unconditional grant from Merck Serono (to D.D.M.B. and K.F.) and by the Department of Obstetrics and Gynaecology of Radboud University Medical Center, Nijmegen, The Netherlands, the Department of Obstetrics and Gynaecology, Jeroen Bosch Hospital, Den Bosch, The Netherlands, and the Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands. Merck Serono had no influence in concept, design nor elaboration of this study. TRIAL REGISTRATION NUMBER: Not applicable.

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.

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.

A preliminary study on a new model system to evaluate tumour-detection and tumour-purging protocols in ovarian cortex tissue intended for fertility preservation.

STUDY QUESTION: Is it possible to create a model system that mimics ovarian metastatic disease in order to devise new strategies to detect cancer cells and prevent cancer cell transmission via ovarian tissue autotransplantation in cancer survivors? SUMMARY ANSWER: Injection of bovine or human ovarian cortex fragments with cells from different cancer types led to the formation of proliferating tumour masses and newly formed small metastatic lesions. WHAT IS KNOWN ALREADY: Autotransplantation of ovarian tissue comes with the major concern of cancer cells possibly being present in the tissue. A model system to develop strategies aimed at enhancing the safety of ovarian tissue autotransplantation is currently lacking. STUDY DESIGN, SIZE, DURATION: The ability of injected human leukaemia, lymphoma, Ewing's sarcoma or breast cancer cells to proliferate and form tumour-like structures in bovine and human ovarian cortex tissue in vitro was assessed. The injected cells were from human cancer cell lines. After 4 days of culture, some tissue fragments were harvested for standard histological staining and immunohistochemical staining of tumour cell specific antigens and the Ki67 proliferation marker, while the remaining fragments were incubated for an additional 6 days (bovine tissue) or 3 days (human tissue) before analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Experiments were performed with ovarian tissue from women after prophylactic salpingo-oophorectomy. Bovine ovarian tissue was obtained at an abattoir. Glucose uptake during in vitro culture was monitored to quantify the viability of tissue. Tumour formation was assessed at Day 4 and Day 10 in bovine ovarian tissue and at Day 4 and Day 7 in human ovarian tissue, using histology and immunohistochemistry. MAIN RESULTS AND THE ROLE OF CHANCE: We found that bovine and human ovarian cortex tissue could be cultured for up to 10 and 7 days, respectively, without any loss of viability. Our preliminary results show that all cell lines tested were capable of forming proliferating tumours in ovarian cortex tissue in vitro. Lymphoma and breast cancer cells produced small metastases near the original lesions. LIMITATIONS, REASONS FOR CAUTION: The tumour model presented was based on the growth of human cancer cell lines in ovarian cortex tissue. It is unknown whether these cells behave differently from malignant cells derived from primary tumours. In addition, the human ovarian tissue was derived from women over 39 years of age, which is obviously considerably older than patients opting for ovarian tissue cryopreservation. WIDER IMPLICATIONS OF THE FINDINGS: Our model system will facilitate the development of procedures to detect cancer cells in, or purge cancer cells from, human ovarian tissue. STUDY FUNDING/COMPETING INTERESTS: Unconditional funding was received from the Radboud Institute for Health Sciences, KiKa Foundation and Merck Serono. There are no conflicts of interest to declare.

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.

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.

Comparison of two models predicting IVF success; the effect of time trends on model performance.

STUDY QUESTION: How well does the recently developed UK model predicting the success rate of IVF treatment (the 2011 Nelson model) perform in comparison with a UK model developed in the early 1990s (the Templeton model)? SUMMARY ANSWER: Both models showed similar performance, after correction for the increasing success rate over time of IVF. WHAT IS KNOWN ALREADY: For counselling couples undergoing IVF treatment it is of paramount importance to be able to predict success. Several prediction models for the chance of success after IVF treatment have been developed. So far, the Templeton model has been recommended as the best approach after having been validated in several independent patient data sets. The Nelson model, developed in 2011 and characterized by the largest development sample containing the most recently treated couples, may well perform better. STUDY DESIGN, SIZE, DURATION: We tested both models in couples that were included in a national cohort study carried out in the Netherlands between the beginning of January 2002 and the end of December 2004. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analysed the IVF cycles of Dutch couples with primary infertility (n = 5176). The chance of success was calculated using the two UK models that had been developed using the information collected in the Human Fertilisation and Embryology Authority database. Women were treated in 1991-1994 (Templeton) or 2003-2007 (Nelson). The outcome of success for both UK models is the occurrence of a live birth after IVF but the outcome in the Dutch data is an ongoing pregnancy. In order to make the outcomes compatible, we used a factor to convert the chance of live birth to ongoing pregnancy and use the overall terms 'success or no success after IVF'. The discriminative ability and the calibration of both models were assessed, the latter before and after adjustment for time trends in IVF success rates. MAIN RESULTS AND THE ROLE OF CHANCE: The two models showed a similarly limited degree of discriminative ability on the tested data (area under the receiver operating characteristic curve 0.597 for the Templeton model and 0.590 for the Nelson model). The Templeton model underestimated the success rate (observed 21% versus predicted 14%); the Nelson model overestimated the success rate (observed 21% versus predicted 29%). When the models were adjusted for the changing success rates over time, the calibration of both models considerably improved (Templeton observed 21% versus predicted 20%; Nelson observed 21% versus predicted 24%). LIMITATIONS, REASONS FOR CAUTION: We could only test the models in couples with primary infertility because detailed information on secondary infertile couples was lacking in the Dutch data. This shortcoming may have negatively influenced the performance of the Nelson model. WIDER IMPLICATIONS OF THE FINDINGS: The changes in success rates over time should be taken into account when assessing prediction models for estimating the success rate of IVF treatment. In patients with primary infertility, the choice to use the Templeton or Nelson model is arbitrary.