Web-based Guidance for Assisted Reproductive Technology With an Online App (myFertiCare): Quantitative Evaluation With the HOT-fit Framework.

BACKGROUND: Assisted reproductive technologies (ARTs) are considered to be physically and mentally stressful. During their treatment trajectory, couples express high information and communication needs. They appreciate using the internet to obtain fertility-related information. In a previous study, we developed myFertiCare, an eHealth tool providing personalized information and interactive functionalities for infertile couples in order to improve patient-centered care. The app has already been successful in qualitative evaluations of usability. OBJECTIVE: The aim of the current study is to quantitatively evaluate the implementation of myFertiCare by using the human, organizational, and technology-fit (HOT-fit) framework and to study the effects of using myFertiCare on couples' knowledge about infertility, their experience of the burden of infertility, and their experience of patient-centered care. With these results, implementation can be further improved, and patient-centered care can be enhanced. METHODS: A quantitative study was performed based on the HOT-fit framework using validated questionnaires focusing on the human, organizational, and technology domains. Questions were added on the effect of using myFertiCare on couples' knowledge about infertility and treatment. Questions regarding the burden of infertility, the burden of infertility treatment, and the experience of patient-centeredness were based on the main items of the validated fertility quality of life (FertiQoL) and Patient-Centredness Questionnaire-Infertility questionnaires, respectively. Also, nonusers of the app were included to explore motivations for not using the app and identify opportunities for improvement. Finally, user data were analyzed to provide insight into multiple variables concerning app use. RESULTS: In the human and technology domains, myFertiCare showed good system usability, high user satisfaction, and high information and interface quality. In the organizational domain, implementation was considered to be sufficient by both patients and staff. Use of the app increased knowledge about the treatment, improved coping with the treatment, and enhanced the experience of patient-centeredness. User data showed that women were the main app users and that use of the app gradually declined during the treatment trajectory. CONCLUSIONS: A multi-faceted online app, myFertiCare, has been successfully evaluated quantitatively for implementation by using the HOT-fit framework. Use of the app increased knowledge about the treatment, improved coping with the treatment, and enhanced the experience of patient-centeredness. App use could be improved by creating more publicity. By providing myFertiCare, professionals in fertility care are supported in guiding patients through their treatment trajectory and in delivering patient-centered care.

Exploration of fertility and early menopause related information needs and development of online information for young breast cancer survivors.

BACKGROUND: Approximately half of premenopausal women diagnosed with breast cancer desire to conceive after they finish treatment. Counseling about the risk of infertility prior to cancer treatment has been proven to improve quality of life after cancer treatment. As a result of this, guidelines focus on informing women on this topic prior to treatment. However, it is equally important to provide fertility related information after primary treatment has been completed, when the wish to conceive might become actual. Therefore, the aim of this study was to identify the fertility and early menopause related information needs of young breast cancer survivors and to design, develop and implement online information material with input of stakeholders. METHODS: A phenomenological qualitative study consisting of four phases was performed: identification of information needs through semi-structured interviews from a professional perspective (1) and a patient perspective (2). Exploration of stakeholders perspective regarding development and implementation of online information material (3) and development and implementation of the information material (4). RESULTS: Professionals indicated that there are no guidelines regarding the provision of fertility related information during cancer survivorship. Survivors reported unmet information needs. Women identified the following as most important information needs (a) fertility preservation options, (b) the risk of menopause or infertility, and (c) long term consequences of early menopause. A wide range of stakeholders involved in breast cancer care were interviewed. Based on their proposed design the information material was implemented on a nationwide website aiming at informing and supporting breast cancer patients. CONCLUSIONS: Fertility and early menopause related information needs of young breast cancer survivors and their professionals were identified. Information material has been designed, developed and nationally implemented. This way, professionals in breast cancer care are provided with an information tool that helps them meet the information needs and preferences of their patients.

The Tell me tool: The development and feasibility of a tool for person-centred infertility care.

BACKGROUND: An important-and often missing-element of person-centred care is the inclusion of individual patients' values and preferences. This is challenging but especially important for high-burden fertility treatments. We describe the development of a clinical tool that aims to facilitate the delivery of person-centred fertility care by giving insight into the patients' values and preferences. METHODS: We developed the Tell me tool following the three principles of user-centred design: (1) early and continual focus on users; (2) iterative design; (3) measurement of user behaviour. Accordingly, our methods consisted of three phases: (1) conducting semi-structured interviews with 18 couples undergoing fertility treatment, followed by a consensus meeting with relevant stakeholders; (2) performing seven iterative improvement rounds; (3) testing the feasibility of the tool in 10 couples. RESULTS: The Tell me tool consists of a ranking assignment of 13 themes and two open-ended questions. These themes relate to the couples' wellbeing and experience of the treatment, such as mental health and shared decision making. The open-ended questions ask them to write down what matters most to them. The field test showed variation between the individual patients' answers. The tool proved to highlight what is important to the individual patient and gives insight into patients' personal contexts. CONCLUSIONS: We developed a tool that gives insight into the values and preferences of the individual patient. The tool seems feasible for facilitating person-centred fertility care. PATIENT OR PUBLIC CONTRIBUTION: The tool was developed with a user-centred design that strongly involved patients.

Web-Based Guidance Through Assisted Reproductive Technology (myFertiCare): Patient-Centered App Development and Qualitative Evaluation.

BACKGROUND: Providing patient-centered fertility care is known to improve quality of life and can reduce anxiety and depression. In a previous study, we established the need for a web-based app providing personalized information and interactive functionalities among couples undergoing intracytoplasmic sperm injection with surgically retrieved sperm. OBJECTIVE: This study aimed to design, develop, and qualitatively evaluate a multifaceted web-based app for infertile couples undergoing intracytoplasmic sperm injection with surgically retrieved sperm during their treatment trajectory. METHODS: The web-based app was developed in three phases: (1) we established a patient-centered functional design, (2) developed the app in collaboration with medical and technical professionals, and (3) qualitatively evaluated the app among couples using a think-aloud method. RESULTS: The basis of the app is the couple's visualized treatment trajectory. The app provides personalized and interactive functionalities; for example, customized information and communication options. During qualitative evaluation, myFertiCare was highly appreciated and received a median score of 8 out of 10. The main improvements made upon conclusion of the think-aloud sessions were related to faster login and easier app navigation. CONCLUSIONS: A patient-centered web-based app aimed at guiding couples through their fertility treatment course was systematically designed, developed, and positively evaluated by patients and medical and technical professionals.

Key recommendations for high-quality female oncofertility care based on international clinical practice guidelines.

RESEARCH QUESTION: Which guideline-based key recommendations can be selected for high-quality female oncofertility care? DESIGN: The Delphi method was used to select a set of key recommendations for female oncofertility care. First, recommendations from (inter)national clinical practice guidelines were selected in four domains: risk communication, referral, counselling and decision-making. Thereafter, they were scored, per domain, on their importance for high-quality oncofertility care by a multidisciplinary, oncofertility expert panel, consisting of patients, referrers and counsellors, in two Delphi rounds. Finally, the selected key recommendations were presented for approval in a third round. Differences in perspectives between subgroups of the expert panel were analysed. RESULTS: A panel of 86 experts was asked to select key recommendations for high-quality oncofertility care. Eleven key recommendations were selected. Key recommendations in the domains risk communication and referral focused on information provision and offering referral to a reproductive specialist to female cancer patients. With the counselling domain, key recommendations focused on all aspects of counselling, including different methods, safety, pros and cons. In the decision-making domain, key recommendations focused on shared decision-making and supporting the decision with written information. The final set of key recommendations was approved by 91% of the experts. Differences in perspectives were found between subgroups. Patients found recommendations on decision-making and information provision more important. CONCLUSION: A set of 11 key recommendations for high-quality female oncofertility care was selected by a multidisciplinary expert panel. The involvement of the perspectives of patients, referrers and counsellors led to this valid, acceptable and credible set of key recommendations.

Barriers and facilitators to the timely diagnosis of endometriosis in primary care in the Netherlands.

BACKGROUND: Endometriosis is an invalidating gynaecological condition in women of reproductive age, and a frequent cause of infertility. Unfortunately, the condition is characterized by a long interval between onset of symptoms and diagnosis. GPs in the Netherlands are educated to provide basic gynaecological care and serve as gatekeepers for specialist medical care. Therefore, it is of great importance that they recognize signs and symptoms possibly caused by endometriosis to initiate adequate actions. OBJECTIVE: The main objective of this study was to identify barriers and facilitators to the timely diagnosis of endometriosis from the GPs' perspective. METHODS: Semi-structured focus group discussions with GPs were organized throughout the Netherlands. The participants were encouraged to brainstorm about their perspective on daily practice regarding endometriosis and suggestions for interventions to enable early diagnosis and treatment. Analysis was based on grounded theory methodology. RESULTS: Forty-three GPs participated in six focus groups. Analysis of the transcripts revealed relevant determinants of practice in four main themes: professionals' experience and competence, patient characteristics, guideline factors and professional collaboration. A lack of knowledge and awareness appeared to result in a low priority for establishing the diagnosis of endometriosis, especially in young women. Infertility, patient engagement and a recent serious case or training facilitated referral. CONCLUSION: Several factors in daily primary health care contribute to the diagnostic delay in endometriosis. Future interventions to reduce this delay may be aimed at increasing awareness by means of education, incorporating the subject into national clinical guidelines and improvements in interdisciplinary collaboration.

Enhancing the safety of ovarian cortex autotransplantation: cancer cells are purged completely from human ovarian tissue fragments by pharmacological inhibition of YAP/TAZ oncoproteins.

STUDY QUESTION: Is it possible to eliminate metastasized cancer cells from ovarian cortex fragments prior to autotransplantation without compromising the ovarian tissue or follicles? SUMMARY ANSWER: Ex vivo pharmacological inhibition of YAP/TAZ by Verteporfin enabled us to efficiently eradicate experimentally induced small tumours, derived from leukaemia and rhabdomyosarcoma, from human ovarian tissue fragments. WHAT IS KNOWN ALREADY: Autotransplantation of ovarian tissue fragments that contain metastasized tumour cells may reintroduce the malignancy to the recipient. In order to enhance safety for the patient there is a strong need for protocols that effectively purges the ovarian tissue from malignant cells ex vivo prior to transplantation, without compromising ovarian tissue integrity. STUDY DESIGN, SIZE, DURATION: Tumour foci were experimentally induced in human ovarian cortex tissue fragments derived from at least three patients by micro-injection of cancer cell lines. Next, the tissue fragments were cultured to allow formation of metastasis-like structures followed by a 24 h ex vivo treatment with the YAP/TAZ inhibitor Verteporfin to eradicate the cancer cells. A control treatment was included in all experiments. The purged ovarian cortex fragments were cultured for an additional 6 days to allow any possibly surviving cancer cells to establish new metastatic foci. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human ovarian tissue was obtained after female-to-male sex reassignment surgery. Human rhabdomyosarcoma, leukeamia, breast cancer and Ewing's sarcoma cell lines were utilized for the induction of tumour foci. Tumour specific (immuno)histochemistry and RT-PCR were used for the detection of residual cancer cells after ex vivo treatment. Ovarian tissue and follicle integrity after exposure to Verteporfin was evaluated by histology, a follicular viability assay and a glucose uptake assay. MAIN RESULTS AND THE ROLE OF CHANCE: Metastasized rhabdomyosarcoma and leukaemia cells could be effectively purged from ovarian cortex tissue by a 24 h ex vivo treatment with Verteporfin, while breast cancer and Ewing's sarcoma did not respond to this treatment. Ovarian tissue integrity was not affected by purging, as no statistically significant difference (P > 0.05) was observed in the percentage of morphologically normal follicles, percentage of follicles with apoptotic cells, follicular viability or glucose uptake between the control treated ovarian cortex and Verteporfin treated ovarian cortex. LIMITATIONS, REASONS FOR CAUTION: Our tumour model is based on growth of human cancer cell lines. It is unclear whether these cells reflect the behaviour of malignant cells that have metastasized to the ovary during natural disease progression. Furthermore, the functionality of the ovarian tissue after ex vivo treatment requires further investigation in vivo. WIDER IMPLICATIONS OF THE FINDINGS: The results indicate that ex-vivo tumour cell purging of human ovarian cortex fragments intended for fertility preservation purposes is feasible by short-term pharmacological treatment. Effective purging of the ovarian cortex tissue enhances safety of ovarian cortex autotransplantation for the patient. This increases the likelihood that this form of fertility restoration may become an option for patients with malignancies for which ovarian cortex transplantation is currently considered unsafe. STUDY FUNDING/COMPETING INTEREST(S): Unconditional funding was received from Merck B.V. The Netherlands (Number 2016-FERT-1) and the foundation 'Radboud Oncologie Fonds' (Number KUN 00007682). The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: NA.

Improved detection of CFTR variants by targeted next-generation sequencing in male infertility: a case series.

RESEARCH QUESTION: Congenital bilateral absence of vas deferens (CBAVD) is characterized by 'obstructive azoospermia' in male patients with primary infertility. In the routine clinical workup of infertile men, patients with an absence of vas deferens are screened for CFTR variants. However, current genetic testing panels do not cover all variants, missing some CBAVD cases. Here, CFTR testing was explored by targeted next-generation sequencing (NGS) to improve variant detection. DESIGN: Five individuals with heterozygous pathogenic CFTR variants were identified using targeted NGS in a cohort of 1112 idiopathic infertile men with azoospermia or severe oligozoospermia. Pre-screening exclusion criteria were CBAVD by clinical examination with positive CFTR sequence analysis as part of routine fertility workup. RESULTS: Cases 1, 2 and 3 presented with CBAVD after which CFTR screening by mutation panel analysis was negative. Case 4 presented with congenital unilateral absence of vas deferens, after which CFTR panel analysis identified a heterozygous p.(Phe508del) variant. Case 5 presented with a palpable vas deferens so CFTR panel analysis was not offered. In all five men, targeted NGS revealed additional pathogenic variants: p.(Arg117Cys) and p.(Arg1158*) (case 1); p.(Asp110His) and p.(Ser945Leu) (case 2); p.(Arg248Thr) and p.(Phe508Cys) (case 3); p.(Gly463Ser) (case 4); p.(Phe508del) (case 4 and 5); and p.(Arg117His) (case 5). CONCLUSIONS: Targeted NGS led to the detection of five infertile men with CFTR variants who would otherwise have remained undiagnosed after routine genetic screening during the fertility workup for azoospermia or severe oligozoospermia. Given the wide availability of affordable targeted NGS, the data suggest that full gene analysis, and not mutation panels, should be considered to screen CFTR in azoospermic men.

Assessment of reflectance confocal microscopy for non-invasive selection of optimal ovarian cortex fragments for autotransplantation.

RESEARCH QUESTION: Can reflectance confocal microscopy (RCM) be used to determine follicle density in human ovarian cortex fragments that are intended for fertility restoration? DESIGN: RCM was used on living cortex tissue fragments derived from five bovine ovaries and 13 human ovaries. All tissue fragments were cryopreserved and thawed before RCM analysis. Follicle numbers and distribution were determined by RCM and histology. Before and after RCM, general tissue viability and follicle integrity were assessed by a glucose uptake assay and neutral red staining, respectively. RESULTS: RCM can detect all stages of follicle development in living ovarian tissue to a maximum depth of 250 µm. In bovine tissue, all follicles were located within this 0-250 µm range. In human ovarian tissue, follicles were also present below the 250 µm RCM threshold, implying that only a percentage of the total number of follicles could be detected with RCM. The percentage of follicles detected by RCM appeared to be age dependent. The RCM procedure did not affect the glucose uptake by the tissue, whereas neutral red staining indicated a high level of follicle survival. CONCLUSION: In this proof of concept study, we have shown that RCM is a promising technique to determine the density of follicles ex vivo in living human ovarian cortex fragments, apparently without compromising the vitality of the tissue. Safety studies and further optimization of the RCM technique with a focus on increasing the penetration depth are required before clinical use of RCM.

The impact of menstrual symptoms on everyday life: a survey among 42,879 women.

BACKGROUND: Menstrual symptoms such as dysmenorrhea, heavy menstrual bleeding, and perimenstrual mood disorders are known to be widespread among the general population. From studies in patients with endometriosis and premenstrual disorder, it has been shown that these symptoms can have a large impact on women's quality of life and account for substantial health care use. Furthermore, it is estimated that many women initially do not consult a doctor while facing menstrual symptoms. Consequently, the impact of menstrual symptoms on daily activities in the general population is unknown. OBJECTIVE: To obtain a nationwide overview of menstrual symptoms and their impact on everyday activities. STUDY DESIGN: Nationwide, cross-sectional, internet-based survey among 42,879 women aged 15-45 years, conducted from July to October 2017. OUTCOME MEASURES: presence of menstrual symptoms, pain or intensity score, impact on daily activities. RESULTS: Dysmenorrhea was the most common symptom, with a prevalence of 85%, followed by psychological complaints (77%), and tiredness (71%). During their menstrual period, 38% of all women reported not to be able to perform all their regular daily activities. From the women that had to skip tasks because of their symptoms, only 48.6% told their family that menstrual symptoms were the reason for the transfer of tasks. CONCLUSION: Menstrual symptoms are widespread among the general population. One in 3 women quit daily activities owing to menstrual symptoms. Half of all women did not mention menstrual complaints being the reason for transferring tasks in a family setting. These results must be interpreted with caution owing to the potential for selection bias. However, considering the impact of menstrual symptoms on daily activities in a large group of women, it is time to open the societal dialogue and improve education for both patients and doctors.

Iatrogenic and non-iatrogenic causes of female fertility loss that may indicate fertility preservation.

Due to advances in fertility preservation options and improvements in life expectancy, there is growing need for fertility preservation counseling for women at risk for premature ovarian insufficiency. The aim of this review is to provide an overview of various causes of female fertility loss and to raise awareness for counseling women about their options for fertility preservation. Furthermore, for counseling of women not only at the time of gonadotoxic treatment but also post-treatment and also of women with other benign causes of increased risk for impaired fertility or premature ovarian insufficiency.

Clinical practice guidelines for fertility preservation in young women undergoing gonadotoxic treatment: an overview and critical appraisal of methodological quality and content.

RESEARCH QUESTION: What is the methodological quality and content of internationally available clinical practice guidelines (CPGs) on fertility preservation (FP) care in adult women? DESIGN: Internationally available CPGs on FP care in adult women were identified after conducting an extensive literature search and consulting (inter)national key experts. The methodological quality of the CPGs was appraised by an (inter)national panel of experts using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. The content of the best CPGs, scoring ≥60% for the domain 'Rigour of development' of the AGREE II instrument, was extracted and categorized according to their topic. RESULTS: Thirty of the 1808 documents found were included. After consulting (inter)national key experts, 30 CPGs were included, six of which scored ≥60% for their 'Rigour of development'. The number of FP-related topics discussed by these six CPGs ranged from 4 to 12. The number of recommendations provided by the CPGs on these topics varied. The number of topics to which ≥5 recommendations were dedicated ranged from 0 to 4 between CPGs. CONCLUSION: CPGs on the subject of FP care are available, but there is room for improvement in quality and content. Although written for use in daily practice, the CPGs can also be used to develop quality indicators to monitor the quality of current FP care or to evaluate future improvement initiatives.

Complete protection against cryodamage of cryopreserved whole bovine and human ovaries using DMSO as a cryoprotectant.

PURPOSE: This study aims to determine the optimal cryopreservation protocol for whole ovaries intended for preservation of fertility in women. METHODS: We investigated the optimal cryopreservation procedure for whole ovaries in a bovine model. The following parameters were investigated to determine their effect on ovarian tissue viability: type of cryoprotectant, administration route of the cryoprotectant (perfusion and/or submersion), and the maximum tolerable interval between death of the animal and start of the cryopreservation process. The resulting optimal cryopreservation procedure for bovine ovaries was subsequently tested on human ovaries. In vitro glucose uptake, histology, and immunohistochemistry were used to assess the integrity of the ovarian tissue. RESULTS: Starting the cryopreservation procedure (including perfusion with and submersion in DMSO) within 10-15 min after death of the animal proved critical, resulting in a 90-100% protection level against cryodamage. When cryopreserving human ovaries using the same protocol, over 95% protection against cryodamage was observed on all tissue levels. In addition, no apparent morphological damage to either the follicles or the vascular endothelium was observed. CONCLUSION: Our findings suggest that using the optimized protocol presented in this paper allows good cryopreservation of whole human ovaries and represents an important step in considering whole ovary autotransplantation for clinically applied fertility preservation.

Women's adjustment trajectories during IVF and impact on mental health 11-17 years later.

STUDY QUESTION: Do patients present different adjustment trajectories during and after IVF treatment? SUMMARY ANSWER: Most women show resilient trajectories during and after IVF treatment but 37% show temporary or chronic maladjustment during IVF and 10% are maladjusted 11-17 years after treatment. WHAT IS KNOWN ALREADY: Research on patient psychosocial adjustment during treatment has contributed to identifying the most distressful stages of IVF treatment and profiling patients at risk for emotional maladjustment at these specific stages. This knowledge is currently driving the deliverance of psychosocial care at fertility clinics by tailoring it to patients' risk profiles and specific treatment stages. However, current care does not take into consideration how individuals adjust across the entire treatment pathway. This can be assessed by profiling individual adjustment trajectories. STUDY DESIGN, SIZE, DURATION: A longitudinal cohort study with five assessment moments that combines data from two different studies, the STRESSIVF and OMEGA projects. Participants enrolled in the STRESSIVF study (started IVF in 1998-2000) were assessed before and after the first IVF treatment cycle and 6 months and 2.5 years after the last IVF cycle. A subset participated in the OMEGA project (started IVF in 1995-2000) and reported on their mental health 11-17 years after treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Three hundred and forty-eight women participated in the STRESSIVF project and 108 of these in the OMEGA. Anxiety was measured with the State and Trait Anxiety Inventory, depression with the Beck Depression Inventory and mental health with the Mental Health Inventory. Latent class growth mixed modelling was carried out to identify distinct anxiety and depression trajectories over the four STRESSIVF study assessment moments. Multinominal logistic regressions were conducted to investigate predictors of trajectory membership, and stepwise linear regressions were performed to investigate if adjustment trajectories predicted mental health 11-17 years after IVF treatment. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 67 and 86% of women showed normal levels of anxiety and depression, respectively, throughout treatment (resilient trajectories), 24 and 33% experienced anxiety and depression only during treatment (recovery trajectories), 4.6 and 4.9% experienced anxiety and depression only after treatment (delayed trajectories), and 4.3% showed chronic anxiety (chronic trajectory, not identified for depression). Non-resilient trajectories were associated with unsuccessful treatment, marital dissatisfaction, lack of social support and negative infertility cognitions. One in 10 women had a delayed or chronic trajectory and these trajectories predicted serious mental health impairment 11-17 years after treatment. LIMITATIONS, REASONS FOR CAUTION: The study only focuses on women. In the OMEGA project adjustment was assessed using a mental health measure. Although we could investigate how trajectories predicted mental health, it would have been preferable to map anxiety and depression trajectories up to 11-17 years after treatment. Missing analysis showed selective dropout from the study but this was accounted for by using mixed models and imputation procedures. Finally, data on other life stressors were not collected; therefore any contribution from these events cannot be assessed. WIDER IMPLICATIONS OF THE FINDINGS: Fertility health-care providers have been called upon considering their responsibility in supporting patients in the aftermath of treatment. Results show it is possible to profile different groups of at-risk women at the start of the treatment and tailor psychosocial support to risk profile to promote health adjustment during treatment and thereafter. STUDY FUNDING/COMPETING INTERESTS: This study was supported by a grant from the Dutch Cancer Society (2006-3631) and the Praeventiefonds (28-3012). No competing interests exist.

Clinically applied procedures for human ovarian tissue cryopreservation result in different levels of efficacy and efficiency.

PURPOSE: Different protocols are being used worldwide for the cryopreservation of human ovarian tissue for fertility preservation purposes. The efficiency and efficacy of the majority of these protocols has not been extensively evaluated, possibly resulting in sub-optimally cryopreserved ovarian tissue. To address the impact of this issue, we assessed the effects of two clinically successful human ovarian tissue slow-freezing cryopreservation procedures on the quality of the cryopreserved tissue. METHODS: To differentiate between cryopreservation (C) versus thawing (T) related effects, four combinations of these two (A and B) very different cryopreservation/thawing protocols (ACAT, ACBT, BCAT, BCBT) were studied. Before and after cryopreservation and thawing, the percentage of living and morphologically normal follicles, as well as the overall tissue viability, was assessed. RESULTS: Our experiments revealed that the choice of the cryopreservation protocol noticeably affected the overall tissue viability and percentage of living follicles, with a higher viability after protocol BC when compared to AC. No statistically significant differences in tissue viability were observed between the two thawing protocols, but thawing protocol BT required considerably more human effort and materials than thawing protocol AT. Tissue morphology was best retained using the BCAT combination. CONCLUSION: Our results indicate that extensive and systematical evaluation of clinically used protocols is warranted.

Ovarian Stimulation for In Vitro Fertilization and Long-term Risk of Breast Cancer.

IMPORTANCE: Previous studies of breast cancer risk after in vitro fertilization (IVF) treatment were inconclusive due to limited follow-up. OBJECTIVE: To assess long-term risk of breast cancer after ovarian stimulation for IVF. DESIGN, SETTING, AND PARTICIPANTS: Historical cohort (OMEGA study) with complete follow-up through December 2013 for 96% of the cohort. The cohort included 19,158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5950 women starting other fertility treatments between 1980 and 1995 (non-IVF group) from all 12 IVF clinics in the Netherlands. The median age at end of follow-up was 53.8 years for the IVF group and 55.3 years for the non-IVF group. EXPOSURES: Information on ovarian stimulation for IVF, other fertility treatments, and potential confounders was collected from medical records and through mailed questionnaires. MAIN OUTCOMES AND MEASURES: Incidence of invasive and in situ breast cancers in women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013). Breast cancer risk in the IVF group was compared with risks in the general population (standardized incidence ratios [SIRs]) and the non-IVF group (hazard ratios [HRs]). RESULTS: Among 25,108 women (mean age at baseline, 32.8 years; mean number of IVF cycles, 3.6), 839 cases of invasive breast cancer and 109 cases of in situ breast cancer occurred after a median follow-up of 21.1 years. Breast cancer risk in IVF-treated women was not significantly different from that in the general population (SIR, 1.01 [95% CI, 0.93-1.09]) and from the risk in the non-IVF group (HR, 1.01 [95% CI, 0.86-1.19]). The cumulative incidences of breast cancer at age 55 were 3.0% for the IVF group and 2.9% for the non-IVF group (P = .85). The SIR did not increase with longer time since treatment (≥20 years) in the IVF group (0.92 [95% CI, 0.73-1.15]) or in the non-IVF group (1.03 [95% CI, 0.82-1.29]). Risk was significantly lower for those who underwent 7 or more IVF cycles (HR, 0.55 [95% CI, 0.39-0.77]) vs 1 to 2 IVF cycles and after poor response to the first IVF cycle (HR, 0.77 [95% CI, 0.61-0.96] for <4 vs ≥4 collected oocytes). CONCLUSIONS AND RELEVANCE: Among women undergoing fertility treatment in the Netherlands between 1980 and 1995, IVF treatment compared with non-IVF treatment was not associated with increased risk of breast cancer after a median follow-up of 21 years. Breast cancer risk among IVF-treated women was also not significantly different from that in the general population. These findings are consistent with absence of a significant increase in long-term risk of breast cancer among IVF-treated women.

Effect of maternal and treatment-related factors on the prevalence of birth defects after PESA-ICSI and TESE-ICSI: a retrospective cohort study.

INTRODUCTION: We performed a retrospective cohort study with the aim to evaluate the effect of maternal and treatment-related factors on the prevalence of birth defects after intracytoplasmic sperm injection (ICSI) using percutaneous epididymal sperm aspiration (PESA) and testicular sperm extraction (TESE). MATERIAL AND METHODS: 643 newborns born after PESA-ICSI (n = 406) and TESE-ICSI (n = 237) in Radboud University Medical Center, after a gestational age of 12 weeks, 1 January 2002-1 January 2011 and 1 March-1 November 2014, respectively, were included in this study. Three sources of data were used for analysis: questionnaires, national obstetrics registration forms, and a lab-database of all ICSI treatments. Data were analyzed using generalized estimating equations and logistic regression analysis. RESULTS: The prevalence of major birth defects in newborns born after PESA-ICSI was 6.9% and after TESE-ICSI was 5.9% (odds ratio 0.89, 95% confidence interval 0.46-1.75). No significant association was found between maternal or treatment-related factors and the prevalence of birth defects. CONCLUSIONS: We found a similar overall prevalence of birth defects in newborns born after PESA-ICSI and TESE-ICSI. The maternal and treatment-related factors investigated did not show a significantly increased cumulative risk of birth defects.

The influence of sperm motility and cryopreservation on the treatment outcome after intracytoplasmic sperm injection following testicular sperm extraction.

INTRODUCTION: It is already known that embryo quality is a major contributing factor to the outcome of assisted reproduction techniques. This study focuses on treatment variables that might be of importance to the outcome of intracytoplasmic sperm injection following testicular sperm extraction (TESE-ICSI) in non-obstructive azoospermia. MATERIAL AND METHODS: A retrospective cohort study was conducted at a Dutch tertiary care academic training hospital between July 2009 and December 2013. With logistic regression analysis we explored the influence of treatment variables, including testicular sperm parameters - (i) motile or tail touch spermatozoa, and (ii) use of fresh or frozen testicular semen-samples - on biochemical and ongoing pregnancy rates after single (n = 393) and double embryo transfer (n = 352). RESULTS: Multivariate logistic regression analysis identified the rank of the TESE-ICSI attempt [odds ratio (OR) 0.8, 95% confidence interval (95% CI) 0.70-0.93], the number of embryos available for transfer (OR 1.1, 95% CI 1.06-1.19) and quality of the embryo(s) transferred (OR 12.8, 95% CI 5.00-32.67) as possible predictors of biochemical pregnancy, whereas only embryo quality (OR 16.9, 95% CI 5.23-54.87) was independently associated with ongoing pregnancy. CONCLUSIONS: The use of cryopreserved testicular sperm does not negatively influence the ongoing pregnancy and live birth rate after TESE-ICSI. However, sperm motility seems to increase the pregnancy rate through its influence on embryo quality. Therefore, fresh TESE has no added value when there is still cryopreserved testicular sperm available. Motile sperm is preferred for injection, but the use of tail touch sperm results in an acceptable treatment outcome.

A qualitative study on trainees' and supervisors' perceptions of assessment for learning in postgraduate medical education.

INTRODUCTION: Recent changes in postgraduate medical training curricula usually encompass a shift towards more formative assessment, or assessment for learning. However, though theoretically well suited to postgraduate training, evidence is emerging that engaging in formative assessment in daily clinical practice is complex. AIM: We aimed to explore trainees' and supervisors' perceptions of what factors determine active engagement in formative assessment. METHODS: Focus group study with postgraduate trainees and supervisors in obstetrics and gynaecology. RESULTS: Three higher order themes emerged: individual perspectives on feedback, supportiveness of the learning environment and the credibility of feedback and/or feedback giver. CONCLUSION: Engaging in formative assessment with a genuine impact on learning is complex and quite a challenge to both trainees and supervisors. Individual perspectives on feedback, a supportive learning environment and credibility of feedback are all important in this process. Every one of these should be taken into account when the utility of formative assessment in postgraduate medical training is evaluated.

An exploratory study into the effect of time-restricted internet access on face-validity, construct validity and reliability of postgraduate knowledge progress testing.

BACKGROUND: Yearly formative knowledge testing (also known as progress testing) was shown to have a limited construct-validity and reliability in postgraduate medical education. One way to improve construct-validity and reliability is to improve the authenticity of a test. As easily accessible internet has become inseparably linked to daily clinical practice, we hypothesized that allowing internet access for a limited amount of time during the progress test would improve the perception of authenticity (face-validity) of the test, which would in turn improve the construct-validity and reliability of postgraduate progress testing. METHODS: Postgraduate trainees taking the yearly knowledge progress test were asked to participate in a study where they could access the internet for 30 minutes at the end of a traditional pen and paper test. Before and after the test they were asked to complete a short questionnaire regarding the face-validity of the test. RESULTS: Mean test scores increased significantly for all training years. Trainees indicated that the face-validity of the test improved with internet access and that they would like to continue to have internet access during future testing. Internet access did not improve the construct-validity or reliability of the test. CONCLUSION: Improving the face-validity of postgraduate progress testing, by adding the possibility to search the internet for a limited amount of time, positively influences test performance and face-validity. However, it did not change the reliability or the construct-validity of the test.