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 €32 000 or less, 2 years of EM followed by IVF was the most cost-effective, whereas above €32 000 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 €4000 to €9000. 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 €31 000 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 €20 000 or less, the policy EM-EM-IVF had the highest probability to achieve the highest net benefit. Between €20 000 and €50 000 monetary value per live birth, it was uncertain whether EM-EM-IVF was better than EM-IUIOS-IVF, with the turning point of €32 000. When we assume a monetary value per live birth over €50 000, 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.R van Eekelen, M J Eijkemans, M Mochtar, F Mol, B W Mol, H Groen, M van Wel

Does the effectiveness of IUI in couples with unexplained subfertility depend on their prognosis of natural conception? A replication of the H2Oil study

Study question Can we replicate the finding that the benefit of IUI-ovarian stimulation (IUI-OS) compared to expectant management for couples with unexplained subfertility depends on the prognosis of natural conception?Summary answer The estimated benefit of IUI-OS did not depend on the prognosis of natural conception but did depend on when treatment was started after diagnosis, with starting IUI-OS later yielding a larger absolute and relative benefit of treatment.What is known already IUI-OS is often the first-line treatment for couples with unexplained subfertility. Two randomized controlled trials (RCTs) compared IUI-OS to expectant management using different thresholds for the prognosis of natural conception as inclusion criteria and found different results. In a previous study (a Dutch national cohort), it was found that the benefit of IUI-OS compared to expectant management seemed dependent on the prognosis of natural conception, but this finding warrants replication. Study design size durationWe conducted a secondary analysis of the H2Oil study (n = 1119), a multicentre RCT that evaluated the effect of oil-based contrast versus water-based contrast during hysterosalpingography (HSG). Couples were randomized before HSG and followed up for 3-5 years. We selected couples with unexplained subfertility who received HSG and had follow-up or pregnancy data available. Follow-up was censored at the start of IVF, after the last IUI cycle or at last contact and was truncated at a maximum of 18 months after the fertility workup.Participants/materials setting methodsThe endpoint was time to conception leading to an ongoing pregnancy. We used the sequential Cox approach comparing in each month the ongoing pregnancy rates over the next 6 months of couples who started IUI-OS to couples who did not. We calculated the prognosis of natural conception for individual couples, updated this over consecutive failed cycles and evaluated whether prognosis modified the effect of starting IUI-OS. We corrected for known predictors of conception using inverse probability weighting.Main results and the role of chanceData from 975 couples were available. There were 587 couples who received at least one IUI-OS cycle within 18 months after HSG of whom 221 conceived leading to an ongoing pregnancy (rate: 0.74 per couple per year over a median follow-up for IUI of 5 months). The median period between HSG and starting IUI-OS was 4 months. Out of 388 untreated couples, 299 conceived naturally (rate: 0.56 per couple per year over a median follow-up of 4 months). After creating our mimicked trial datasets, starting IUI-OS was associated with a higher chance of ongoing pregnancy by a pooled, overall hazard ratio of 1.50 (95% CI: 1.19-1.89) compared to expectant management. We did not find strong evidence that the effect of treatment was modified by a couple's prognosis of achieving natural conception (Akaike's Information Criterion (AIC) decreased by 1 point). The effect of treatment was dependent on when couples started IUI-OS (AIC decreased by more than 2 points). The patterns of estimated absolute chances over time for couples with increasingly better prognoses were different from the previous study but the finding that starting later yields a larger benefit of treatment was similar. We found IUI-OS increased the absolute chance of pregnancy by at least 5% compared to expectant management. The absolute chance of pregnancy after IUI-OS seems less variable between couples and starting times of treatment than the absolute chance after expectant management.Limitations reasons for cautionThis is a secondary analysis, as the H2Oil trial was not designed with this research question in mind. Owing to sample size restrictions, it remained difficult to distinguish between the ranges of prognoses in which true benefit was found.Wider implications of the findingsWe replicated the finding that starting IUI-OS later after diagnosis yields a larger absolute and relative benefit of treatment. We did not replicate the dependency of the effect of IUI-OS on the prognosis of natural conception and could not identify clear thresholds for the prognosis of natural conception when IUI-OS was and/or was not effective. Because many of these couples still have good chances of natural conception at the time of diagnosis, we suggest clinicians should advise couples to delay the start of IUI-OS for several months to avoid unnecessary treatment. Study funding/competing interestsThe H2Oil study (NTR 3270) was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The follow-up study (NTR 6577) was also an investigator-initiated study with funding by Guerbet, France. The funders had no role in study design, collection, analysis and interpretation of the data. B.W.M. is supported by an Investigator grant (GNT1176437) from the Australian National Health and Medical Research Council (NHMRC). K.D. reports receiving travel and speaker fees from Guerbet. B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. V.M. reports receiving travel- and speaker fees as well as research grants from Guerbet.R. van Eekelen, K. Rosielle, N. van Welie, K. Dreyer, M. van Wely, M. van Wely ... et al

Effect of disease related biases on the subjective assessment of social functioning in Alzheimer's disease and schizophrenia patients

Background: Questionnaires are the current hallmark for quantifying social functioning in human clinical research. In this study, we compared self- and proxy-rated (caregiver and researcher) assessments of social functioning in Schizophrenia (SZ) and Alzheimer's disease (AD) patients and evaluated if the discrepancy between the two assessments is mediated by disease-related factors such as symptom severity. Methods: We selected five items from the WHO Disability Assessment Schedule 2.0 (WHODAS) to assess social functioning in 53 AD and 61 SZ patients. Caregiver- and researcher-rated assessments of social functioning were used to calculate the discrepancies between self-rated and proxy-rated assessments. Furthermore, we used the number of communication events via smartphones to compare the questionnaire outcomes with an objective measure of social behaviour. Results: WHODAS results revealed that both AD (p < 0.001) and SZ (p < 0.004) patients significantly overestimate their social functioning relative to the assessment of their caregivers and/or researchers. This overestimation is mediated by the severity of cognitive impairments (MMSE; p = 0.019) in AD, and negative symptoms (PANSS; p = 0.028) in SZ. Subsequently, we showed that the proxy scores correlated more strongly with the smartphone communication events of the patient when compared to the patient-rated questionnaire scores (self; p = 0.076, caregiver; p < 0.001, researcher-rated; p = 0.046). Conclusion: Here we show that the observed overestimation of WHODAS social functioning scores in AD and SZ patients is partly driven by disease-related biases such as cognitive impairments and negative symptoms, respectively. Therefore, we postulate the development and implementation of objective measures of social functioning that may be less susceptible to such biases.The PRISM project (www.prism-project.eu) leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This publication reflects only the authors’ views neither IMI JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein. Dr. Arango has also received funding support by the Spanish Ministry of Science and Innovation. Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF Funds from the European Commission, “A way of making Europe”, CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds. Fundación Familia Alonso and Fundación Alicia Koplowit

Cumulative live birth rates in low-prognosis women

No external funds were obtained for the present study. The OPTIMIST study was funded by The Netherlands Organization for Health Research and Development (ZonMW number 171102020).Peer reviewedPublisher PD

Preoperative predictors for residual tumor after surgery in patients with ovarian carcinoma

Objectives: Suboptimal debulking (>1 cm residual tumor) results in poor survival rates for patients with an advanced stage of ovarian cancer. The purpose of this study was to develop a prediction model, based on simple preoperative parameters, for patients with an advanced stage of ovarian cancer who are at risk of suboptimal cytoreduction despite maximal surgical effort. Methods: Retrospective analysis of 187 consecutive patients with a suspected clinical diagnosis of advanced-stage ovarian cancer undergoing upfront debulking between January 1998 and December 2003. Preoperative parameters were Karnofsky performance status, ascites and serum concentrations of CA 125, hemoglobin, albumin, LDH and blood platelets. The main outcome parameter was residual tumor >1 cm. Univariate and multivariate logistic regression was employed for testing possible prediction models. A clinically applicable graphic model (nomogram) for this prediction was to be developed. Results: Serum concentrations of CA 125 and blood platelets in the group with residual tumor >1 cm were higher in comparison to the optimally cytoreduced group (p 1 cm based on serum levels of CA 125 and albumin was established. Conclusion: Postoperative residual tumor despite maximal surgical effort can be predicted by preoperative CA 125 and serum albumin levels. With a nomogram based on these two parameters, probability of postoperative residual tumor in each individual patient can be predicted. This proposed nomogram may be valuable in daily routine practice for counseling and to select treatment modality. Copyrigh

Individualized versus standard FSH dosing in women starting IVF/ICSI:An RCT. Part 2: The predicted hyper responder

STUDY QUESTION: Does a reduced FSH dose in women with a predicted hyper response, apparent from a high antral follicle count (AFC), who are scheduled for IVF/ICSI lead to a different outcome with respect to cumulative live birth rate and safety? SUMMARY ANSWER: Although in women with a predicted hyper response (AFC > 15) undergoing IVF/ICSI a reduced FSH dose (100 IU per day) results in similar cumulative live birth rates and a lower occurrence of any grade of ovarian hyperstimulation syndrome (OHSS) as compared to a standard dose (150 IU/day), a higher first cycle cancellation rate and similar severe OHSS rate were observed. WHAT IS KNOWN ALREADY: Excessive ovarian response to controlled ovarian stimulation (COS) for IVF/ICSI may result in increased rates of cycle cancellation, the occurrence of OHSS and suboptimal live birth rates. In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can be used to predict response to COS. No consensus has been reached on whether ORT-based FSH dosing improves effectiveness and safety in women with a predicted hyper response. STUDY DESIGN SIZE, DURATION: Between May 2011 and May 2014, we performed an open-label, multicentre RCT in women with regular menstrual cycles and an AFC > 15. Women with polycystic ovary syndrome (Rotterdam criteria) were excluded. The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. Secondary outcomes included the occurrence of OHSS and cost-effectiveness. Since this RCT was embedded in a cohort study assessing over 1500 women, we expected to randomize 300 predicted hyper responders. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with an AFC > 15 were randomized to an FSH dose of 100 IU or 150 IU/day. In both groups, dose adjustment was allowed in subsequent cycles (maximum 25 IU in the reduced and 50 IU in the standard group) based on pre-specified criteria. Both effectiveness and cost-effectiveness were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: We randomized 255 women to a daily FSH dose of 100 IU and 266 women to a daily FSH dose of 150 IU. The cumulative live birth rate was 66.3% (169/255) in the reduced versus 69.5% (185/266) in the standard group (relative risk (RR) 0.95 [95%CI, 0.85-1.07], P = 0.423). The occurrence of any grade of OHSS was lower after a lower FSH dose (5.2% versus 11.8%, RR 0.44 [95%CI, 0.28-0.71], P = 0.001), but the occurrence of severe OHSS did not differ (1.3% versus 1.1%, RR 1.25 [95%CI, 0.38-4.07], P = 0.728). As dose reduction was not less expensive (€4.622 versus €4.714, delta costs/woman €92 [95%CI, -479-325]), there was no dominant strategy in the economic analysis. LIMITATIONS, REASONS FOR CAUTION: Despite our training programme, the AFC might have suffered from inter-observer variation. Although strict cancellation criteria were provided, selective cancelling in the reduced dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as first cycle live birth rates did not differ from the cumulative results, the open design probably did not mask a potential benefit for the reduced dosing group. As this RCT was embedded in a larger cohort study, the power in this study was unavoidably lower than it should be. Participants had a relatively low BMI from an international perspective, which may limit generalization of the findings. WIDER IMPLICATIONS OF THE FINDINGS: In women with a predicted hyper response scheduled for IVF/ICSI, a reduced FSH dose does not affect live birth rates. A lower FSH dose did reduce the incidence of mild and moderate OHSS, but had no impact on severe OHSS. Future research into ORT-based dosing in women with a predicted hyper response should compare various safety management strategies and should be powered on a clinically relevant safety outcome while assessing non-inferiority towards live birth rates. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by The Netherlands Organization for Health Research and Development (ZonMW, Project Number 171102020). SCO, TCvT and HLT received an unrestricted research grant from Merck Serono (the Netherlands). CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV and Merck Serono for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657. TRIAL REGISTRATION DATE: 20 December 2010. DATE OF FIRST PATIENT’S ENROLMENT: 12 May 2011

The effects of timing on the cost-effectiveness of interventions for workers on sick leave due to low back pain

Objective To examine the effects of different timing of structured interventions for workers on sick leave due to low back pain on return to work (RTW), and the consequences for costs and benefits. Methods Literature reviews were conducted to identify RTW curves and to estimate treatment effects, costs and benefits of structured interventions among workers on sick leave due to low back pain. RTW curves were mathematically described by Weibull functions and intervention effects, expressed by hazard ratios, were used to adjust these Weibull functions. Subsequently, these functions were used to evaluate the theoretical effects of interventions on reduction in number of days on sick leave and on the benefit-cost ratio. Results The cost-benefits of a RTW intervention among workers on sick leave due to low back pain were determined by the estimated effectiveness of the intervention, the costs of the intervention, the natural course of RTW in the target population, the timing of the enrolment of subjects into the intervention, and the duration of the intervention. Conclusion With a good RTW in the first weeks, the only early interventions likely to be cost-beneficial are inexpensive work-focused enhancements to early routine care, such as accommodating workplaces. Structured interventions are unlikely to have an additional impact on the already good prognosis when offered before the optimal time window at approximately 8 to 12 weeks. The generalisibility of the effectiveness of a RTW intervention depends on the comparability of baseline characteristics and RTW curves in target and source populations

FSH response-dose can be predicted in ovulation induction for normogonadotropic anovulatory infertility

The patient group with the best step-down profile for ovulation induction exhibited the closest match between the clinically applied and calculated starting dose of gonadotropins. Therefore, this study provides support for the concept that the individual effective FSH starting dose for gonadotropin induction of ovulation in anovulatory infertile patients can be predicted on the basis of initial screening characteristics, such as body mass index, clomiphene resistance or failure, free IGF-I and FSH. This may result in more effective patient treatment protocols, reduced complication rates and health-economic benefits

Recurrent pre-clinical pregnancy loss is unlikely to be a "cause" of unexplained infertility

BACKGROUND A proportion of women with ‘unexplained’ infertility may present with subfertility because their pregnancies fail before they are clinically recognized. In order to test whether pre-clinical early pregnancy losses (EPL) occur more frequently in women with unexplained infertility, serial urinary hCG concentrations were measured to compare EPL per cycle rates following spontaneous conception in patients with unexplained infertility versus healthy volunteers.METHODS Sixty patients under 39 years of age with unexplained infertility and 60 healthy controls, who were trying to conceive spontaneously, participated in this study. All participants were asked to collect daily urine samples from cycle day 14 until menstruation for three consecutive cycles or until a positive pregnancy test was obtained.Urinary hCG and creatinine levels were measured by immunoassay. Implantation was detected when urinary hCG levels rose above reference levels constructed from samples obtained from 12 women not attempting to conceive. EPL rates were determined by a linear mixed model using logarithmically transformed hCG/creatinine data.RESULTS In the 133 cycles of 60 women with unexplained infertility, just one implantation was detected, which became an ongoing pregnancy. In contrast, in 103 such cycles in 46 control patients, 30 implantations were detected (24 clinical pregnancies, 6 cases of EPL). The odds ratio for EPL/cycle in the unexplained versus control group was 0 (95% confidence interval: 0–0.795, P= 0.026).CONCLUSIONS Our data do not support the hypothesis that recurrent EPL may present as unexplained infertility. Post-implantation failure is therefore unlikely to contribute significantly to the presentation of subfertility.<br/