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

Balanced ternary addition using a gated silicon nanowire

We demonstrate the proof of principle for a ternary adder using silicon metal-on-insulator single electron transistors (SET). Gate dependent rectifying behavior of a single electron transistor results in a robust three-valued output as a function of the potential of the SET island. Mapping logical, ternary inputs to the three gates controlling the potential of the SET island allows us to perform complex, inherently ternary operations, on a single transistor

Cost-effectiveness of ovarian stimulation agents for IUI in couples with unexplained subfertility

Acknowledgements The authors wish to thank M.P. Diamond, R.S. Legro, K. Peeraer, M. Erdem, T. Dankert, and R. Ecochard, on behalf of the IUI IPDMA collaboration, for providing data from their RCTs for the IPDMA of which the results are used in a sensitivity analysis. Funding This work was supported by ZonMw Doelmatigheidsonderzoek, grant 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).Peer reviewedPublisher PD

International student mobility and labour market outcomes: an investigation of the role of level of study, type of mobility, and international prestige hierarchies

Over the last decades, there has been increasing interest in the topic of international student mobility (ISM). However, there is surprisingly little analysis of the ways in which different characteristics and types of short-term ISM or the importance of host education systems and labour markets may affect early career outcomes of formerly mobile graduates. Therefore, in this study we explore, first, the relationship between participation in ISM at the Bachelor and Master level and graduates’ wages and the duration of education-to-work transitions. Second, we investigate variations in ISM’s labour market outcomes according to the type of mobility: study, internships, or combinations of both. Third, we examine the relationship between labour market outcomes of formerly mobile students and the country of destination’s position in higher education international prestige hierarchies and labour market competitiveness. We use the Dutch National Alumni Survey 2015, a representative survey of higher education graduates in the Netherlands, conducted 1.5 years after graduation. Before controlling for selection into ISM, the results suggest the existence of labour market returns to ISM and that the heterogeneity of ISM experiences matters, as labour market outcomes vary according to the level of study, the type of mobility and the positioning of the country of destination in international prestige hierarchies. However, after controlling for selection into ISM through propensity score matching, the differences in early career outcomes between formerly mobile and non-mobile graduates disappear, suggesting that they cannot be causally attributed to their ISM-experience. We explain these results with reference to the characteristics of the Dutch education system and labour market, where restricted possibilities for upward vertical mobility limit returns to ISM in the local labour market

Human keratinocyte sensitivity towards inflammatory cytokines varies with culture time

Proliferating keratinocyte cultures have been reported to synthesize higher concentrations of prostaglandin (PG) E than confluent ones. As interleukin-1 (IL-1) stimulates keratinocyte PGE synthesis we investigated whether the degree of confluency of the keratinocyte culture modified the response of the cells to IL-1. It was found that IL-1α (100 U/ml) stimulated PGE2 synthesis by proliferating (7 days in culture) but not differentiating (14 days in culture) keratinocytes. Similar effects were observed using tumour necrosis factor-α. Both arachidonic acid (AA) and the calcium ionophore A23187 stimulated PGE2 synthesis by 7 and 14 day cultures although the increase was greatest when 7 day cultures were used. Our data indicate that there is a specific down-regulation of the mechanism(s) by which some inflammatory cytokines stimulate keratinocyte eicosanoid synthesis as cultured keratinocytes begin to differentiate

Toric intraocular lenses for correction of astigmatism in keratoconus and after corneal surgery

Purpose: To describe the results of cataract extraction with toric intraocular lens (IOL) implantation in patients with preexisting astigmatism from three corneal conditions (keratoconus, postkeratoplasty, and postpterygium surgery). Methods: Cataract patients with topographically stable, fairly regular (although sometimes very high) corneal astigmatism underwent phacoemulsification with implantation of a toric IOL (Zeiss AT TORBI 709, Alcon Acrysof IQ toric SN6AT, AMO Tecnis ZCT). Postoperative astigmatism and refractive outcomes, as well as visual acuities, vector reduction, and complications were recorded for all eyes. Results: This study evaluated 17 eyes of 16 patients with a mean age of 60 years at the time of surgery. Mean follow-up in this study was 12 months. The corrected distance Snellen visual acuity (with spectacles or contact lenses) 12 months postoperatively was 20/32 or better in 82% of eyes. The mean corneal astigmatism was 6.7 diopters (D) preoperatively, and 1.5 D of refractive cylinder at 1-year follow-up. No vision-compromising intra- or postoperative complications occurred and decentration or off-axis alignment of toric IOLs were not observed. Conclusion: Phacoemulsification with toric IOL implantation was a safe and effective procedure in the three mentioned corneal conditions. Patient selection, counseling, and IOL placement with optimal astigmatism correction are crucial

Review of the safety, efficacy, costs and patient acceptability of recombinant follicle-stimulating hormone for injection in assisting ovulation induction in infertile women

Anovulation is a common cause of female subfertility. Treatment of anovulation is aimed at induction of ovulation. In women with clomiphene-citrate resistant WHO group II anovulation, one of the treatment options is ovulation induction with exogenous follicle-stimulating hormone (FSH or follitropin). FSH is derived from urine or is produced as recombinant FSH. Two forms of recombinant FSH are available – follitropin alpha and follitropin beta. To evaluate the efficacy, safety, costs and acceptability of recombinant FSH, we performed a review to compare recombinant FSH with urinary-derived FSH products. Follitropin alpha, beta and urinary FSH products appeared to be equally effective in terms of pregnancy rates. Patient safety was also found to be comparable, as the incidence of side effects including multiple pregnancies was similar for all FSH products. In practice follitropin alpha and beta may be more convenient to use due to the ease of self-administration, but they are also more expensive than the urinary products.Marleen Nahuis, Fulco van der Veen, Jur Oosterhuis, Ben Willem Mol, Peter Hompes, Madelon van Wel