Are we overusing IVF?

Peer reviewedPublisher PD

Cost-effectiveness of medically assisted reproduction or expectant management for unexplained subfertility:when to start treatment?

STUDY QUESTION Over a time period of 3 years, which order of expectant management (EM), IUI with ovarian stimulation (IUI-OS) and IVF is the most cost-effective for couples with unexplained subfertility with the female age below 38 years? SUMMARY ANSWER If a live birth is considered worth Euro32 000 or less, 2 years of EM followed by IVF was the most cost-effective, whereas above Euro32 000 this was 1 year of EM, 1 year of IUI-OS and then 1 year of IVF. WHAT IS KNOWN ALREADY IUI-OS and IVF are commonly used fertility treatments for unexplained subfertility although many couples can conceive naturally, as no identifiable barrier to conception could be found by definition. Few countries have guidelines on when to proceed with medically assisted reproduction (MAR), mostly based on the expected probability of live birth after treatment, but there is a lack of evidence to support the strategies proposed by these guidelines. The increased uptake of IUI-OS and IVF over the past decades and costs related to reimbursement of these treatments are pressing concerns to health service providers. For MAR to remain affordable, sustainable and a responsible use of public funds, guidance is needed on the cost-effectiveness of treatment strategies for unexplained subfertility, including EM. STUDY DESIGN, SIZE, DURATION We developed a decision analytic Markov model that follows couples with unexplained subfertility of which the woman is under 38 years of age for a time period of 3 years from completion of the fertility workup onwards. We divided the time axis of 3 years into three separate periods, each comprising 1 year. The model was based on contemporary evidence, most notably the dynamic prediction model for natural conception, which was combined with MAR treatment effects from a network meta-analysis on randomized controlled trials. We changed the order of options for managing unexplained subfertility for the 1 year periods to yield five different treatment policies in total: IVF-EM-EM (immediate IVF), EM-IVF-EM (delayed IVF), EM-EM-IVF (postponed IVF), IUIOS-IVF-EM (immediate IUI-OS) and EM-IUIOS-IVF (delayed IUI-OS). PARTICIPANTS/MATERIALS, SETTING, METHODS The main outcomes per policy over the 3-year period were the probability of live birth, the average treatment and delivery costs, the probability of multiple pregnancy, the incremental cost-effectiveness ratio (ICER) and finally, which policy yields the highest net benefit in which costs for a policy were deducted from the health effects, i.e. live births gained. We chose the Dutch societal perspective, but the model can be easily modified for other locations or other perspectives. The probability of live birth after EM was taken from the dynamic prediction model for natural conception and updated for Years 2 and 3. The relative effects of IUI-OS and IVF in terms of odds ratios, taken from the network meta-analysis, were applied to the probability of live birth after EM. We applied standard discounting procedures for economic analyses for Years 2 and 3. The uncertainty around effectiveness, costs and other parameters was assessed by probabilistic sensitivity analysis in which we drew values from distributions and repeated this procedure 20 000 times. In addition, we changed model assumptions to assess their influence on our results. MAIN RESULTS AND THE ROLE OF CHANCE From IVF-EM-EM to EM-IUIOS-IVF, the probability of live birth varied from approximately 54-64% and the average costs from approximately Euro4000 to Euro9000. The policies IVF-EM-EM and EM-IVF-EM were dominated by EM-EM-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. The policy IUIOS-IVF-EM was dominated by EM-IUIOS-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. After removal of policies that were dominated, the ICER for EM-IUIOS-IVF was approximately Euro31 000 compared to EM-EM-IVF. The range of ICER values between the lowest 25% and highest 75% of simulation replications was broad. The net benefit curve showed that when we assume a live birth to be worth approximately Euro20 000 or less, the policy EM-EM-IVF had the highest probability to achieve the highest net benefit. Between Euro20 000 and Euro50 000 monetary value per live birth, it was uncertain whether EM-EM-IVF was better than EM-IUIOS-IVF, with the turning point of Euro32 000. When we assume a monetary value per live birth over Euro50 000, the policy with the highest probability to achieve the highest net benefit was EM-IUIOS-IVF. Results for subgroups with different baseline prognoses showed the same policies dominated and the same two policies that were the most likely to achieve the highest net benefit but at different threshold values for the assumed monetary value per live birth. LIMITATIONS, REASONS FOR CAUTION Our model focused on population level and was thus based on average costs for the average number of cycles conducted. We also based the model on a number of key assumptions. We changed model assumptions to assess the influence of these assumptions on our results. The change in relative effectiveness of IVF over time was found to be highly influential on results and their interpretation. WIDER IMPLICATIONS OF THE FINDINGS EM-EM-IVF and EM-IUIOS-IVF followed by IVF were the most cost-effective policies. The choice depends on the monetary value assigned to a live birth. The results of our study can be used in discussions between clinicians, couples and policy makers to decide on a sustainable treatment protocol based on the probability of live birth, the costs and the limitations of MAR treatment. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the ZonMw Doelmatigheidsonderzoek (80-85200-98-91072). The funder had no role in the design, conduct or reporting of this work. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research support from ObsEva, Merck and Guerbet. TRIAL REGISTRATION NUMBER N/A

Applying a simplified economic evaluation approach to evaluate infertility treatments in clinical practice

Peer reviewe

Dynamic nitrogen deposition thresholds during forest stand development in a Douglas fir forest analysed with two nitrogen models SMART2 and MERLIN

In contrast to the classical critical load (CL) concept, based on long-term steady-state conditions, a dynamic deposition threshold (DDT) is introduced. This DDT takes into account all relevant dynamic aspects of vegetation development/forest growth, mineralisation, immobilisation and denitrification, depending on the successional stage of the forest. DDT values for nitrogen were determined for a Douglas fir rotation by two process-based nitrogen models SMART2 and MERLIN using three different criteria for critical nitrogen leaching. During most of the rotation time, the predicted DDT values were higher than the corresponding traditional CL. SMART2 and MERLIN predicted a maximum DDT of 4.9 and 4.6 kmol N per ha per year (69 and 64 kg N per ha per year, respectively), when accepting a critical N leaching level of 1.73 kmol N per ha per year related to impacts on ground water quality. This is due mainly to relatively high tree uptake during the first 50 years of a forest rotation, compared to a long-term estim

Limited effect of patient and disease characteristics on compliance with hospital antimicrobial guidelines

Objective: Physicians frequently deviate from guidelines that promote prudent use of antimicrobials. We explored to what extent patient and disease characteristics were associated with compliance with guideline recommendations for three common infections. Methods: In a 1-year prospective observational study, 1,125 antimicrobial prescriptions were analysed for compliance with university hospital guidelines. Results: Compliance varied significantly between and within the groups of infections studied. Compliance was much higher for lower respiratory tract infections (LRTIs; 79%) than for sepsis (53%) and urinary tract infections (UTIs; 40%). Only predisposing illnesses and active malignancies were associated with more compliant prescribing, whereas alcohol/ intravenous drug abuse and serum creatinine levels > 130 mu mol/l were associated with less compliant prescribing. Availability of culture results had no impact on compliance with guidelines for sepsis but was associated with more compliance in UTIs and less in LRTIs. Narrowing initial broad-spectrum antimicrobial therapy to cultured pathogens was seldom practised. Most noncompliant prescribing concerned a too broad spectrum of activity when compared with guideline-recommended therapy. Conclusion: Patient characteristics had only a limited impact on compliant prescribing for a variety of reasons. Physicians seemed to practise defensive prescribing behaviour, favouring treatment success in current patients over loss of effectiveness due to resistance in future patients

Comparison of model concepts for nutrient availability and soil acidity in terrestrial ecosystems

STOWA heeft het initiatief genomen om samen met een aantal partijen een klimaatrobuuste Waterwijzer Natuur (WWN) te ontwikkelen. Een instrument dat de effecten van klimaatverandering en het waterbeheer op de terrestrische vegetatie van natuurgebieden dient te kunnen berekenen. Klimaatverandering zal vooral gevolgen voor natuurlijke vegetaties hebben via veranderingen in de waterbalans. Die veranderingen werken namelijk door op de bodemtemperatuur en de hoeveelheid vocht, zuurstof en nutriënten die voor de planten in het wortelmilieu beschikbaar zijn. Klimaatverandering noopt dan ook tot het stellen van enkele essentiële vragen, zoals: Welke maatregelen zijn er nodig om natuurdoelen in de toekomst zeker te stellen? Welke alternatieve doelen kunnen we overwegen als in het verleden vastgestelde natuurdoelen niet meer haalbaar blijken te zijn onder een veranderend klimaat? Waar liggen straks, in het klimaat van de toekomst, de beste kansen voor het creëren van hotspots van biodiversiteit? Dit rapport geeft een overzicht van de overeenkomsten en verschillen van de wijze waarop PROBE (KWR) en VSD+ (WEnR) de nutriëntenbeschikbaarheid en zuurgraad in (half)natuurlijke terrestrische ecosystemen voorspellen in afhankelijkheid van milieu, (vnl. atmosferische depositie), klimaat (vnl. temperatuur en neerslag) en waterbeheerscenario’s

The benefits and harms of receiving a polycystic ovary syndrome diagnosis: a qualitative study of women's experiences

Study Question: What are the benefits and harms of receiving a polycystic ovary syndrome (PCOS) diagnosis in a community sample of women, including impact on psychosocial wellbeing, lifestyle choices and behaviour? Summary Answer: Although some women benefit considerably from the diagnosis, such as through increased awareness and reassurance, women with minimal symptoms may experience more harm than benefit, including long-lasting anxiety and altered life plans. What Is Known Already: Disease labels can validate symptoms and play a vital role in understanding and coping with illness; however, they can also cause harm by evoking illness schemas about severity and permanence. Regarding PCOS, the diagnostic criteria have expanded over time to include women with milder phenotypes (such as those without signs of androgen excess). This has occurred despite limited investigation of the benefits and harms of the diagnosis and has increased the number of women diagnosed. Study Design, Size, Duration: Semi-structured interviews were conducted face-to-face or by telephone with 26 participants from April-July 2018 to explore women's experiences with the diagnosis, including the benefits and harms of receiving the diagnosis and the impact on their life. Participants/Materials, Setting, Methods: In total, 26 women in the community self-reporting a diagnosis of PCOS (reporting mild to severe symptoms) made by a medical doctor, aged 18-45 years and living in Australia were recruited through social media. Data were analysed thematically using Framework analysis. Main Results and the Role of Chance: The study identified a range of both positive and negative effects of a PCOS diagnosis in the immediate, short and long-term, which were influenced by symptom severity, expectations and experience. For women with previously unexplained and bothersome symptoms, it was a relief to receive a diagnosis, and this resulted in an increased understanding about the importance of a healthy lifestyle. By contrast, women with milder symptoms often reported feeling shocked and overwhelmed by the diagnosis, consequently experiencing anxiety about the associated long-term risks. The majority of women, regardless of symptom severity, experienced prolonged worry and anxiety about infertility, resulting for some in risk taking with contraception, unintended pregnancies, pressure to conceive early or altered life plans. With time, many women developed positive coping strategies and perceived the diagnosis to be valuable, including those who felt they had experienced minimal benefit or even harm. Limitations, Reasons for Caution: PCOS diagnosis was self-reported and the sample was highly educated. Wider Implications of the Findings: Fear of infertility was salient for many women, underscoring the need for accurate information, counselling and reassurance of fertility potential. Given the risk of significant consequences, health professionals should use a tailored approach to PCOS diagnosis to increase the benefits of appropriate and timely diagnosis for women affected by significant symptoms, while reducing the harms of unnecessarily labelling healthy women for whom the benefits of a diagnosis are small.T. Copp, J. Hersch, D.M. Muscat, K.J. McCaffery, J. Doust, A. Dokras, B.W. Mol, and J. Janse

Clinicians' perspectives on diagnosing polycystic ovary syndrome in Australia: a qualitative study

STUDY QUESTION: What are clinicians' views about the diagnosis of polycystic ovary syndrome (PCOS), and how do they handle any complexities and uncertainties in practice?SUMMARY ANSWER: Clinicians have to navigate many areas of complexity and uncertainty regarding the diagnosis of PCOS, related to the diagnostic criteria, limitations in current evidence and misconceptions surrounding diagnosis, and expressed concern about the risk and consequences of both under- and overdiagnosis.WHAT IS KNOWN ALREADY: PCOS is a complex, heterogeneous condition with many areas of uncertainty, raising concerns about both underdiagnosis and overdiagnosis. Quantitative studies with clinicians have found considerable variation in diagnostic criteria used and care provided, as well as a lack of awareness around the breadth of PCOS features and poor uptake of recommended screening for metabolic complications. Clinicians' views about the uncertainties and complexities of diagnosing PCOS have not been explored.STUDY DESIGN, SIZE, DURATION: Semi-structured telephone interviews were conducted with clinicians from September 2017 to July 2018 to explore their perceptions about the diagnosis of PCOS, including how they handle any complexities and uncertainties in practice.PARTICIPANTS/MATERIALS, SETTING, METHODS: A group of 36 clinicians (15 general practitioners, 10 gynaecologists and 11 endocrinologists) currently practicing in Australia, were recruited through advertising via professional organisations, contacting a random sample of endocrine and gynaecology teams across Australia and snowballing. Transcribed audio-recordings were analysed thematically using Framework analysis.MAIN RESULTS AND THE ROLE OF CHANCE: Clinicians expressed a range of uncertainties and complexities regarding the diagnosis of PCOS, which were organised into three areas: (i) establishing diagnosis (e.g. lack of standardisation regarding diagnostic cut-offs, risk of misdiagnosis), (ii) factors influencing the diagnostic process (e.g. awareness of limitations in evidence and consideration of the benefits and harms) and (iii) strategies for handling challenges and uncertainties (e.g. using caution and communication of uncertainties). Clinicians also varied in their concerns regarding under- and overdiagnosis. Overall, most felt the diagnosis was beneficial for women provided that it was the correct diagnosis and time was taken to assess patient expectations and dispel misconceptions, particularly concerning fertility.LIMITATIONS, REASONS FOR CAUTION: There is possible selection bias, as clinicians who are more knowledgeable about PCOS may have been more likely to participate. Clinicians' views may also differ in other countries.WIDER IMPLICATIONS OF THE FINDINGS: These findings underscore the vital need to first consider PCOS a diagnosis of exclusion and use caution before giving a diagnosis in order to reduce misdiagnosis, as suggested by clinicians in our study. Until there is greater standardisation of diagnostic criteria, more transparent conversations with women may help them understand the uncertainties surrounding the criteria and limitations in the evidence. Additionally, clinicians emphasised the importance of education and reassurance to minimise the potential harmful impact of the diagnosis and improve patient-centred outcomes

Prediction of Mortality in Very Premature Infants: A Systematic Review of Prediction Models

CONTEXT Being born very preterm is associated with elevated risk for neonatal mortality. The aim of this review is to give an overview of prediction models for mortality in very premature infants, assess their quality, identify important predictor variables, and provide recommendations for development of future models. METHODS Studies were included which reported the predictive performance of a model for mortality in a very preterm or very low birth weight population, and classified as development, validation, or impact studies. For each development study, we recorded the population, variables, aim, predictive performance of the model, and the number of times each model had been validated. Reporting quality criteria and minimum methodological criteria were established and assessed for development studies. RESULTS We identified 41 development studies and 18 validation studies. In addition to gestational age and birth weight, eight variables frequently predicted survival: being of average size for gestational age, female gender, non-white ethnicity, absence of serious congenital malformations, use of antenatal steroids, higher 5-minute Apgar score, normal temperature on admission, and better respiratory status. Twelve studies met our methodological criteria, three of which have been externally validated. Low reporting scores were seen in reporting of performance measures, internal and external validation, and handling of missing data. CONCLUSIONS Multivariate models can predict mortality better than birth weight or gestational age alone in very preterm infants. There are validated prediction models for classification and case-mix adjustment. Additional research is needed in validation and impact studies of existing models, and in prediction of mortality in the clinically important subgroup of infants where age and weight alone give only an equivocal prognosis.Stephanie Medlock, Anita C. J. Ravelli, Pieter Tamminga, Ben W. M. Mol, Ameen Abu-Hann