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Background/aims To evaluate the cost-effectiveness of non-invasive monitoring tests to detect the onset of neovascular age-related macular degeneration (nAMD) in the unaffected second eye of patients receiving treatment for unilateral nAMD in a UK National Health Service (NHS) hospital outpatient setting. Methods A patient-level state transition model was constructed to simulate the onset, detection, and treatment of nAMD in the second eye. Five index tests were compared: self-reported change in visual function, Amsler test, clinic measured change in visual acuity from baseline, fundus assessment by clinical examination or colour photography, and spectral domain optical coherence tomography (SD-OCT). Diagnosis of nAMD was confirmed by fundus fluorescein angiography (FFA) before prompt initiation of antivascular endothelial growth factor treatment. Quality-adjusted life-years (QALYs) and costs of health and social care were modelled over a 25-year time horizon. Results SD-OCT generated more QALYs (SD-OCT, 5.830; fundus assessment, 5.787; Amsler grid, 5.736, patient's subjective assessment, 5.630; and visual acuity, 5.600) and lower health and social care costs (SD-OCT, £19 406; fundus assessment, £19 649; Amsler grid, £19 751; patient's subjective assessment, £20 198 and visual acuity, £20 444) per patient compared with other individual monitoring tests. Probabilistic sensitivity analysis indicated a high probability (97%-99%) of SD-OCT being the preferred test across a range of cost-effectiveness thresholds (£13 000-£30 000) applied in the UK NHS. Conclusions Early treatment of the second eye following FFA confirmation of SD-OCT positive findings is expected to maintain better visual acuity and health-related quality of life and may reduce costs of health and social care over the lifetime of patients. [ABSTRACT FROM AUTHOR]

Study Question: What are couples' preferences for fresh embryo transfer versus freezing of all embryos followed by frozen embryo transfer and the associated clinical outcomes that may differentiate them?Summary Answer: Couples' preferences are driven by anticipated chances of live birth, miscarriage, neonatal complications, and costs but not by the differences in the treatment process (including delay of embryo transfer linked to frozen embryo transfer and risk of ovarian hyperstimulation syndrome (OHSS) associated with fresh embryo transfer).What Is Known Already: A policy of freezing all embryos followed by transfer of frozen embryos results in livebirth rates which are similar to or higher than those following the transfer of fresh embryos while reducing the risk of OHSS and small for gestational age babies: it can, however, increase the risk of pre-eclampsia and large for gestational age offspring. Hence, the controversy continues over whether to do fresh embryo transfer or freeze all embryos followed by frozen embryo transfer.Study Design, Size, Duration: We used a discrete choice experiment (DCE) technique to survey infertile couples between August 2018 and January 2019.Participants/materials, Setting, Methods: We asked IVF naïve couples attending a tertiary referral centre to independently complete a questionnaire with nine hypothetical choice tasks between fresh and frozen embryo transfer. The alternatives varied across the choice occurrences on several attributes including efficacy (live birth rate), safety (miscarriage rate, neonatal complication rate), and cost of treatment. We assumed that a freeze-all strategy prolonged treatment but reduced the risk of OHSS. An error components mixed logit model was used to estimate the relative value (utility) that couples placed on the alternative treatment approaches and the attributes used to describe them. Willingness to pay and marginal rates of substitution between the non-cost attributes were calculated. A total of 360 individual questionnaires were given to 180 couples who fulfilled the inclusion criteria, of which 212 were completed and returned Our study population included 3 same sex couples (2 females and 1 male) and 101 heterosexual couples. Four questionnaires were filled by one partner only. The response rate was 58.8%.Main Results and the Role Of Chance: Couples preferred both fresh and frozen embryo transfer (odds ratio 27.93 and 28.06, respectively) compared with no IVF treatment, with no strong preference for fresh over frozen. Couples strongly preferred any IVF technique that offered an increase in live birth rates by 5% (P = 0.006) and 15% (P < 0.0001), reduced miscarriage by 18% (P < 0.0001) and diminished neonatal complications by 10% (P < 0.0001). Respondents were willing to pay an additional £2451 (95% CI 604 - 4299) and £761 (95% CI 5056-9265) for a 5 and 15% increase in the chance of live birth, respectively, regardless of whether this involved fresh or frozen embryos. They required compensation of £5230 (95% CI 3320 - 7141) and £13 245 (95% CI 10 110-16 380) to accept a 10 and 25% increase in the risk of neonatal complications, respectively (P < 0.001). Results indicated that couples would be willing to accept a 1.26% (95% CI 1.001 - 1.706) reduction in the live birth rate for a 1% reduction in the risk of neonatal complications per live birth. Older couples appeared to place less emphasis on the risk of neonatal complications than younger couples.Limitations, Reasons For Caution: DCEs can elicit intentions which may not reflect actual behaviour. The external validity of this study is limited by the fact that it was conducted in a single centre with generous public funding for IVF. We cannot rule out the potential for selection or responder bias.Wider Implications Of the Findings: If a strategy of freeze all was to be implemented it would appear to be acceptable to patients, if either success rates can be improved or neonatal complications reduced. Live birth rates, neonatal complication rates, miscarriage rates, and cost are more likely to drive their preferences than a slight delay in the treatment process. The results of this study have important implications for future economic evaluations of IVF, as they suggest that the appropriate balance needs to be struck between success and safety. A holistic approach incorporating patient preferences for expected clinical outcomes and risks should be taken into consideration for individualized care.Study Funding/competing Interest(s): No external funding was sought for this study. A.M. is the chief investigator of the randomized controlled trial 'Freeze all'. S.B. is an Editor in Chief of Human Reproduction Open. The other co-authors have no conflicts of interest to declare. Graham Scotland reports non-financial support from Merck KGaA, Darmstadt, Germany, outside the submitted work.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Introduction: Several diagnostic tests are often adopted into diagnostic pathways for specific indications without strong evidence to support their use. In this context, real-world prospective cohort studies in combination with decision modelling can generate evidence to support decision-making. The Early Detection of neovascular Age-Related Macular Degeneration (EDNA) study was a prospective cohort designed to assess the diagnostic accuracy and cost-effectiveness of several diagnostic monitoring tests used in routine practice for the detection of neovascular age-related macular degeneration (nAMD) in the second eye of patients being treated for unilateral disease. Methods: Five-hundred and fifty-two participants with newly diagnosed unilateral nAMD were monitored for up to 3 years in 24 UK eye clinics. The diagnostic monitoring performance of five index tests was compared: self-reported change in visual function, Amsler test, clinic measured change in visual acuity, fundus assessment by clinical examination or colour photography, and spectral-domain optical coherence tomography (SD-OCT). The reference standard was fundus fluorescein angiography (FFA). A patient-level state transition model was used to simulate the onset of nAMD in the second eye, and assess the impact of different tests on the timing of detection and treatment, and associated costs and quality adjusted life years (QALYs) over a 25-year time-horizon. Results: One hundred and forty-five (26.3%) patients developed active nAMD in the study eye, of whom 120 had an FFA at detection. SD-OCT had the highest sensitivity (91.7 percent (95% CI: 85.2-95.6) and provided high specificity (87.8% (95% CI: 83.8-90.9)). It generated more QALYs and lower health and personal social care costs compared to all other monitoring tests. The combination of SD-OCT with fundus-examination provided a marginal increase in sensitivity over OCT alone, but the associated incremental cost-effectiveness ratios was >GBP 100,000 per QALY. Conclusions: The efficiency of diagnostic pathways for nAMD may be improved by using SD-OCT alone to monitor the second eye of people being treated for unilateral disease. Prospective cohort studies embedded into routine practice offer value for informing decisions surrounding the use of technologies already in routine use. [ABSTRACT FROM AUTHOR]

Economic evaluations of the value-for-money of Medically Assisted Reproduction (MAR) interventions are increasingly important due to growing pressure on healthcare budgets. Although such evaluations are commonplace in the published literature, the number/methodological complexity of different evaluations available, and the challenges specific to MAR interventions, can complicate the interpretation of such analyses for fertility treatments. This article aims to serve as an educational resource and provide context on the design/interpretation of economic analyses for MAR interventions. Several areas are relevant for first-line providers and decision makers: scope of analysis, comparator used, perspective/time horizon considered, outcomes used to measure success, and how results from cost-effectiveness studies can be summarised and used in clinical practice. We aim to help clinicians better understand the strengths/weaknesses of economic analyses, to enable the best use of the evidence in practice, so resources available for MAR interventions can provide maximum value to patients and society., Competing Interests: Declaration of competing interest The authors in this manuscript were qualified according to ICMJE criteria and has received no fees for their authorship. ML and TDH are employees of Merck Healthcare KGaA, Darmstadt, Germany. Outside of the submitted manuscript, MPC has received honoraria for a lecture from Merck KGaA, Darmstadt, Germany; AR has received, individually or as part of his institution, grants, honoraria or consultation fees from Merck Healthcare, Darmstadt, Germany, Ferring and MSD. The remaining authors report no disclosures., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Freezing all embryos, followed by thawing and transferring them into the uterine cavity at a later stage (freeze-all), instead of fresh-embryo transfer may lead to improved pregnancy rates and fewer complications during in vitro fertilisation and pregnancies resulting from it., Objective: We aimed to evaluate if a policy of freeze-all results in a higher healthy baby rate than the current policy of transferring fresh embryos., Design: This was a pragmatic, multicentre, two-arm, parallel-group, non-blinded, randomised controlled trial., Setting: Eighteen in vitro fertilisation clinics across the UK participated from February 2016 to April 2019., Participants: Couples undergoing their first, second or third cycle of in vitro fertilisation treatment in which the female partner was aged < 42 years., Interventions: If at least three good-quality embryos were present on day 3 of embryo development, couples were randomly allocated to either freeze-all (intervention) or fresh-embryo transfer (control)., Outcomes: The primary outcome was a healthy baby, defined as a live, singleton baby born at term, with an appropriate weight for their gestation. Secondary outcomes included ovarian hyperstimulation, live birth and clinical pregnancy rates, complications of pregnancy and childbirth, health economic outcome, and State-Trait Anxiety Inventory scores., Results: A total of 1578 couples were consented and 619 couples were randomised. Most non-randomisations were because of the non-availability of at least three good-quality embryos ( n  = 476). Of the couples randomised, 117 (19%) did not adhere to the allocated intervention. The rate of non-adherence was higher in the freeze-all arm, with the leading reason being patient choice. The intention-to-treat analysis showed a healthy baby rate of 20.3% in the freeze-all arm and 24.4% in the fresh-embryo transfer arm (risk ratio 0.84, 95% confidence interval 0.62 to 1.15). Similar results were obtained using complier-average causal effect analysis (risk ratio 0.77, 95% confidence interval 0.44 to 1.10), per-protocol analysis (risk ratio 0.87, 95% confidence interval 0.59 to 1.26) and as-treated analysis (risk ratio 0.91, 95% confidence interval 0.64 to 1.29). The risk of ovarian hyperstimulation was 3.6% in the freeze-all arm and 8.1% in the fresh-embryo transfer arm (risk ratio 0.44, 99% confidence interval 0.15 to 1.30). There were no statistically significant differences between the freeze-all and the fresh-embryo transfer arms in the live birth rates (28.3% vs. 34.3%; risk ratio 0.83, 99% confidence interval 0.65 to 1.06) and clinical pregnancy rates (33.9% vs. 40.1%; risk ratio 0.85, 99% confidence interval 0.65 to 1.11). There was no statistically significant difference in anxiety scores for male participants (mean difference 0.1, 99% confidence interval -2.4 to 2.6) and female participants (mean difference 0.0, 99% confidence interval -2.2 to 2.2) between the arms. The economic analysis showed that freeze-all had a low probability of being cost-effective in terms of the incremental cost per healthy baby and incremental cost per live birth., Limitations: We were unable to reach the original planned sample size of 1086 and the rate of non-adherence to the allocated intervention was much higher than expected., Conclusion: When efficacy, safety and costs are considered, freeze-all is not better than fresh-embryo transfer., Trial Registration: This trial is registered as ISRCTN61225414., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 25. See the NIHR Journals Library website for further project information.

Study Question: Does a policy of elective freezing of embryos, followed by frozen embryo transfer result in a higher healthy baby rate, after first embryo transfer, when compared with the current policy of transferring fresh embryos?, Summary Answer: This study, although limited by sample size, provides no evidence to support the adoption of a routine policy of elective freeze in preference to fresh embryo transfer in order to improve IVF effectiveness in obtaining a healthy baby., What Is Known Already: The policy of freezing all embryos followed by frozen embryo transfer is associated with a higher live birth rate for high responders but a similar/lower live birth after first embryo transfer and cumulative live birth rate for normal responders. Frozen embryo transfer is associated with a lower risk of ovarian hyperstimulation syndrome (OHSS), preterm delivery and low birthweight babies but a higher risk of large babies and pre-eclampsia. There is also uncertainty about long-term outcomes, hence shifting to a policy of elective freezing for all remains controversial given the delay in treatment and extra costs involved in freezing all embryos., Study Design, Size, Duration: A pragmatic two-arm parallel randomized controlled trial (E-Freeze) was conducted across 18 clinics in the UK from 2016 to 2019. A total of 619 couples were randomized (309 to elective freeze/310 to fresh). The primary outcome was a healthy baby after first embryo transfer (term, singleton live birth with appropriate weight for gestation); secondary outcomes included OHSS, live birth, clinical pregnancy, pregnancy complications and cost-effectiveness., Participants/materials, Setting, Methods: Couples undergoing their first, second or third cycle of IVF/ICSI treatment, with at least three good quality embryos on Day 3 where the female partner was ≥18 and <42 years of age were eligible. Those using donor gametes, undergoing preimplantation genetic testing or planning to freeze all their embryos were excluded. IVF/ICSI treatment was carried out according to local protocols. Women were followed up for pregnancy outcome after first embryo transfer following randomization., Main Results and the Role of Chance: Of the 619 couples randomized, 307 and 309 couples in the elective freeze and fresh transfer arms, respectively, were included in the primary analysis. There was no evidence of a statistically significant difference in outcomes in the elective freeze group compared to the fresh embryo transfer group: healthy baby rate {20.3% (62/307) versus 24.4% (75/309); risk ratio (RR), 95% CI: 0.84, 0.62 to 1.15}; OHSS (3.6% versus 8.1%; RR, 99% CI: 0.44, 0.15 to 1.30); live birth rate (28.3% versus 34.3%; RR, 99% CI 0.83, 0.65 to 1.06); and miscarriage (14.3% versus 12.9%; RR, 99% CI: 1.09, 0.72 to 1.66). Adherence to allocation was poor in the elective freeze group. The elective freeze approach was more costly and was unlikely to be cost-effective in a UK National Health Service context., Limitations, Reasons for Caution: We have only reported on first embryo transfer after randomization; data on the cumulative live birth rate requires further follow-up. Planned target sample size was not obtained and the non-adherence to allocation rate was high among couples in the elective freeze arm owing to patient preference for fresh embryo transfer, but an analysis which took non-adherence into account showed similar results., Wider Implications of the Findings: Results from the E-Freeze trial do not lend support to the policy of electively freezing all for everyone, taking both efficacy, safety and costs considerations into account. This method should only be adopted if there is a definite clinical indication., Study Funding/competing Interest(s): NIHR Health Technology Assessment programme (13/115/82). This research was funded by the National Institute for Health Research (NIHR) (NIHR unique award identifier) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. J.L.B., C.C., E.J., P.H., J.J.K., L.L. and G.S. report receipt of funding from NIHR, during the conduct of the study. J.L.B., E.J., P.H., K.S. and L.L. report receipt of funding from NIHR, during the conduct of the study and outside the submitted work. A.M. reports grants from NIHR personal fees from Merck Serono, personal fees for lectures from Merck Serono, Ferring and Cooks outside the submitted work; travel/meeting support from Ferring and Pharmasure and participation in a Ferring advisory board. S.B. reports receipt of royalties and licenses from Cambridge University Press, a board membership role for NHS Grampian and other financial or non-financial interests related to his roles as Editor-in-Chief of Human Reproduction Open and Editor and Contributing Author of Reproductive Medicine for the MRCOG, Cambridge University Press. D.B. reports grants from NIHR, during the conduct of the study; grants from European Commission, grants from Diabetes UK, grants from NIHR, grants from ESHRE, grants from MRC, outside the submitted work. Y.C. reports speaker fees from Merck Serono, and advisory board role for Merck Serono and shares in Complete Fertility. P.H. reports membership of the HTA Commissioning Committee. E.J. reports membership of the NHS England and NIHR Partnership Programme, membership of five Data Monitoring Committees (Chair of two), membership of six Trial Steering Committees (Chair of four), membership of the Northern Ireland Clinical Trials Unit Advisory Group and Chair of the board of Oxford Brain Health Clinical Trials Unit. R.M. reports consulting fees from Gedeon Richter, honorarium from Merck, support fees for attendance at educational events and conferences for Merck, Ferring, Bessins and Gedeon Richter, payments for participation on a Merck Safety or Advisory Board, Chair of the British Fertility Society and payments for an advisory role to the Human Fertilisation and Embryology Authority. G.S. reports travel and accommodation fees for attendance at a health economic advisory board from Merck KGaA, Darmstadt, Germany. N.R.-F. reports shares in Nurture Fertility. Other authors' competing interests: none declared., Trial Registration Number: ISRCTN: 61225414., Trial Registration Date: 29 December 2015., Date of First Patient’s Enrolment: 16 February 2016., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To evaluate the diagnostic accuracy of routinely used tests of visual function and retinal morphology compared with fundus fluorescein angiography (FFA) to detect onset of active macular neovascularization in unaffected fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD)., Design: Prospective diagnostic accuracy cohort study conducted in 24 eye clinics in the United Kingdom over 3 years., Participants: Older adults (>50 years) with recently diagnosed unilateral nAMD with a fellow (study) eye free of nAMD., Methods: Self-reported vision, Amsler, clinic-measured visual acuity (VA), fundus assessment, and spectral domain OCT. The reference standard is FFA., Main Outcome Measures: Sensitivity and specificity of the 5 index tests., Results: Of 552 participants monitored for up to 3 years, 145 (26.3%) developed active nAMD in the study eye, of whom 120 had an FFA at detection and constituted the primary analysis cohort. Index test positives at nAMD detection in those confirmed by FFA were self-reported vision much worse (5), distortion on Amsler (33), 10-letter decrease in acuity from baseline (36), fundus examination (64), and OCT (110). Percentage index test sensitivities were: self-reported vision 4.2 (95% confidence interval [CI], 1.6-9.8); Amsler 33.7 (95% CI, 25.1-43.5); VA 30.0 (95% CI, 22.5-38.7); fundus examination 53.8 (95% CI, 44.8-62.5); and OCT 91.7 (95% CI, 85.2-95.6). All 5 index test specificities were high at 97.0 (95% CI, 94.6-98.5), 81.4 (95% CI, 76.4-85.5), 66.3 (95% CI, 61.0-71.1), 97.6 (95% CI, 95.3-98.9), and 87.8 (95% CI, 83.8-90.9), respectively. The combination of OCT with one other index test that was a secondary outcome measure increased sensitivity marginally and decreased specificity for all combinations except fundus examination., Conclusions: Tests of self-reported change in vision, unmasking of new distortion, measurements of acuity, and fundus checks to diagnose active nAMD performed poorly in contrast to OCT. Our findings support a change to guidelines in clinical practice to monitor for onset of nAMD., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)