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

Comparing the cumulative live birth rate of cleavage-stage versus blastocyst-stage embryo transfers between IVF cycles:a study protocol for a multicentre randomised controlled superiority trial (the ToF trial)

Introduction In vitro fertilisation (IVF) has evolved as an intervention of choice to help couples with infertility to conceive. In the last decade, a strategy change in the day of embryo transfer has been developed. Many IVF centres choose nowadays to transfer at later stages of embryo development, for example, transferring embryos at blastocyst stage instead of cleavage stage. However, it still is not known which embryo transfer policy in IVF is more efficient in terms of cumulative live birth rate (cLBR), following a fresh and the subsequent frozen-thawed transfers after one oocyte retrieval. Furthermore, studies reporting on obstetric and neonatal outcomes from both transfer policies are limited. Methods and analysis We have set up a multicentre randomised superiority trial in the Netherlands, named the Three or Fivetrial. We plan to include 1200 women with an indication for IVF with at least four embryos available on day 2 after the oocyte retrieval. Women are randomly allocated to either (1) control group: embryo transfer on day 3 and cryopreservation of supernumerary good-quality embryos on day 3 or 4, or (2) intervention group: embryo transfer on day 5 and cryopreservation of supernumerary good-quality embryos on day 5 or 6. The primary outcome is the cLBR per oocyte retrieval. Secondary outcomes include LBR following fresh transfer, multiple pregnancy rate and time until pregnancy leading a live birth. We will also assess the obstetric and neonatal outcomes, costs and patients' treatment burden. Ethics and dissemination The study protocol has been approved by the Central Committee on Research involving Human Subjects in the Netherlands in June 2018 (CCMO NL 64060.000.18). The results of this trial will be submitted for publication in international peer-reviewed and in open access journals. Trial registration number Netherlands Trial Register (NL 6857)

A de novo paradigm for male infertility

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p -value = 1.00 × 10 −5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p -value = 5.01 × 10 −4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p -value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility. Germline de novo mutations can impact individual fitness, but their role in human male infertility is understudied. Trio-based exome sequencing identifies many new candidate genes affecting male fertility, including an essential regulator of male germ cell pre-mRNA splicing

Reply to the Letters from Murray et al. and Vianna-Morgante and Costa

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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

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

BackgroundAssisted 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. ObjectiveThe 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. MethodsA 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. ResultsIn 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. ConclusionsA 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

Overbehandeling bij onverklaarde subfertiliteit

OBJECTIVE: To assess adherence to expectant management of 6-12 months in couples with unexplained subfertility, as recommended by the Dutch Networkguideline Subfertility. DESIGN: A retrospective cohort study in 25 clinics. METHOD: Couples were eligible to participate if they were diagnosed with unexplained subfertility and had a good prognosis of natural conception within one year (>30%), for these couples the network guideline recommends an expectant management. Outcomes measures are overtreatment, i.e. couples that started treatment within six months, and three quality indicators: 1) prognosis not calculated, 2) no correct expectant management advised, 3) starting treatment too soon despite a correct advise. Data collection was obtained from medical records. Multilevel regression analyses were performed to investigate associations of overtreatment with patient and clinic characteristics. RESULTS: We included 544 couples. Overtreatment occurred in 36% (N=198). In 34% (N=186) of all couples no prognosis was calculated (1), and in 42% (N=230) of all couples expectant management was not advised correctly (2). When a correct expectant management of six to twelve months was advised, 16% (N=51) started treatment too soon anyway. Overtreatment occurred more frequently in childless couples, a higher female age, and a longer duration of infertility. CONCLUSION: Our findings show that developing and publishing guideline recommendations on expectant management is not enough and that overtreatment still occurs frequently. To improve future care the next step is to evaluate a tailored implementation strategy to improve adherence to the recommendations on expectant management by the Dutch Networkguideline Subfertility

Imprinting Effect in Premature Ovarian Failure Confined to Paternally Inherited Fragile X Premutations

Fragile X premutations are considered to be a risk factor for premature ovarian failure (POF), which is usually defined as menopause at age <40 years. Since premutations may be inherited from either the mother or the father, we evaluated the influence of the inheritance pattern on the duration of reproductive life in female carriers. The occurrence of POF and age at menopause in women with a paternally inherited fragile X premutation (PIP) were compared to those in women with a maternally inherited fragile X premutation (MIP). We identified 148 women in whom the parental origin of the premutation could be determined. In 109 of these women we were able to establish whether POF had occurred: 82 women had a PIP, and 27 had a MIP. Twenty-three of the women (28%) with a PIP had POF, versus only 1 (3.7%) with a MIP (two -tailed Fisher’s exact test; P=.007). Kaplan-Meier analysis of all 148 premutations showed that the age at menopause was significantly lower in the women with a PIP than in the woman with a MIP (Breslow test in Kaplan-Meier analysis; P=.003). Our data strongly suggest that, when POF occurs in fragile X premutation carriers, a considerable proportion of the premutations are inherited paternally (parent-of-origin effect). We hypothesize that this may be owing to a paternal genomic imprinting effect