ORCID Profile
0000-0002-6892-5574
Current Organisation
University of Amsterdam
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Publisher: Oxford University Press (OUP)
Date: 09-2020
Abstract: 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? 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. 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. 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 ided 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). 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. 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. 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. 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. 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. N/A.
Publisher: Oxford University Press (OUP)
Date: 22-02-2021
Abstract: Which agent for ovarian stimulation (OS) is the most cost-effective option in terms of net benefit for couples with unexplained subfertility undergoing IUI? In settings where a live birth is valued at €3000 or less, between €3000 and €55 000 and above €55 000, clomiphene citrate (CC), Letrozole and gonadotrophins were the most cost-effective option in terms of net benefit, respectively. IUI-OS is a common first-line treatment for couples with unexplained subfertility and its increased uptake over the past decades and related personal or reimbursed costs are pressing concerns to patients and health service providers. However, there is no consensus on a protocol for conducting IUI-OS, with differences between countries, clinics and settings in the number of cycles, success rates, the agent for OS and the maximum number of dominant follicles in order to minimise the risk of a multiple pregnancy. In view of this uncertainty and the association with costs, guidance is needed on the cost-effectiveness of OS agents for IUI-OS. We developed a decision-analytic model based on a decision tree that follows couples with unexplained subfertility from the start of IUI-OS to a protocoled maximum of six cycles, assuming couples receive four cycles on average within one year. We chose the societal perspective, which coincides with other perspectives such as that from health care providers, as the treatments are identical except for the stimulation agent. We based our model on parameters from a network meta-analysis of randomised controlled trials for IUI-OS. We compared the following three agents: CC (oral medication), Letrozole (oral medication) and gonadotrophins (subcutaneous injection). The main health outcomes were cumulative live birth and multiple pregnancy. As the procedures are identical except for the agent used, we only considered direct medical costs of the agent during four cycles. The main cost-effectiveness measures were the differences in costs ided by the differences in cumulative live birth (incremental cost-effectiveness ratio, ICER) and the probability of the highest net monetary benefit in which costs for an agent were deducted from the live births gained. The live birth rate for IUI using CC was taken from trials adhering to strict cancellation criteria included in a network meta-analysis and extrapolated to four cycles. We took the relative risks for the live birth rate after Letrozole and gonadotrophins versus CC from that same network meta-analysis to estimate the remaining absolute live birth rates. The uncertainty around live birth rates, relative effectiveness and costs 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. The agent with the lowest cumulative live birth rate over 4 IUI-OS cycles conducted within one year was CC (29.4%), followed by Letrozole (32.0%) and gonadotrophins (34.5%). The average costs per four cycles were €362, €434 and €1809, respectively. The ICER of Letrozole versus CC was €2809 per additional live birth, whereas the ICER of gonadotrophins versus Letrozole was €53 831 per additional live birth. When we assume a live birth is valued at €3000 or less, CC had the highest probability of maximally 65% to achieve the highest net benefit. Between €3000 and €55 000, Letrozole had the highest probability of maximally 62% to achieve the highest net benefit. Assuming a monetary value of €55 000 or more, gonadotrophins had the highest probability of maximally 56% to achieve the highest net benefit. Our model focused on population level and was thus based on average costs for the average number of four 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 high uncertainty surrounding our results indicate that more research is necessary on the relative effectiveness of using CC, Letrozole or gonadotrophins for IUI-OS in terms of the cumulative live birth rate. We suggest that in the meantime, CC or Letrozole are the preferred choice of agent. 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. BWM 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. All other authors have no conflicts of interest to declare. N/A.
Publisher: Oxford University Press (OUP)
Date: 04-11-2022
Abstract: For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births? In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births. Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (& % in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception (& % in 12 months), the effectiveness of IUI-OS is uncertain. We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins. We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception (& % in 12 months). The primary outcome was ongoing pregnancy leading to a live birth. Non-inferiority would be shown if the lower limit of the one-sided 90% risk difference (RD) CI was less than minus 7% compared to an expected live birth rate of 30% following IUI-OS. We calculated RD, relative risks (RRs) with 90% CI and a corresponding hazard rate for live birth over time based on intention-to-treat and per-protocol (PP) analysis. Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20% 90% CI: −30% to −9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59 RD −24%, 90% CI −36% to −13%) in line with inferiority of EM. Our trial did not reach the planned s le size, therefore the results are limited by the number of participants. This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS. The trial was supported by a grant of the SEENEZ healthcare initiative. The subsidizing parties were The Dutch Organisation for Health Research and Development (ZonMW 837004023, www.zonmw.nl) and the umbrella organization of 10 health insurers in The Netherlands. E.R.G. receives personal fees from Titus Health care outside the submitted work. M.G. declares unrestricted research and educational grants from Guerbet, Merck and Ferring not related to the presented work, paid to their institution VU medical centre. A.B.H. reports receiving travel and speakers fees from Nordic Pharma and Merck and he is member of the Nordic Pharma ANGEL group and of the Safety Monitoring Board of Womed. C.B.L. reports speakers fee from Inmed and Yingming, and his department receives research grants from Ferring, Merck and Guerbet paid to VU medical centre. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck. M.v.W. received a grant from the Netherlands Organisation for Health Research and Development ZonMW (80-8520098-91072). F.M. received two grants from the Netherlands Organisation for Health Research and Development ZonMW (NTR 5599 and NTR 6590). The other authors report no competing interest. Dutch Trial register NL5455 (NTR5599) 18 December 2015 26 January 2017
Publisher: Springer Science and Business Media LLC
Date: 17-11-2021
DOI: 10.1186/S13063-021-05772-X
Abstract: Randomised controlled trials (RCTs) evaluating ectopic pregnancy have reported many different outcomes, which are themselves often defined and measured in distinct ways. This level of variation results in an inability to compare results of in idual RCTs. The development of a core outcome set to ensure outcomes important to key stakeholders are collected consistently will guide future research in ectopic pregnancy. To develop and implement a core outcome set to guide future research in ectopic pregnancy. We have established an international steering group of key stakeholders, including healthcare professionals, researchers, and in iduals with lived experience of ectopic pregnancy. We will identify potential outcomes from ectopic pregnancy from a comprehensive literature review of published randomised controlled trials. We will then utilise a modified Delphi method to prioritise outcomes. Subsequently, key stakeholders will be invited to score potential core outcomes on a nine-point Likert scale, ranging from 1 (not important) to 9 (critical). Repeated reflection and rescoring should promote whole and in idual stakeholder group convergence towards consensus ‘core’ outcomes. We will also establish standardised definitions and recommend high-quality measurements for in idual core outcomes. COMET 1492 . Registered in November 2019.
Publisher: Georg Thieme Verlag KG
Date: 2020
Abstract: Unexplained infertility is a common diagnosis among couples with infertility. Pragmatic treatment options in these couples are directed at trying to improve chances to conceive, and consequently intrauterine insemination (IUI) with ovarian stimulation and in vitro fertilization (IVF) are standard clinical practice, while expectant management remains an important alternative. While evidence on IVF or IUI with ovarian stimulation versus expectant management was inconclusive, these interventions seem more effective in couples with a poor prognosis of natural conception. Strategies such as strict cancellation criteria and single-embryo transfer aim to reduce multiple pregnancies without compromising cumulative live birth. We propose a prognosis-based approach to manage couples with unexplained infertility so as to expose less couples to unnecessary interventions and less mothers and children to the potential adverse effects of ovarian stimulation or laboratory procedures.
No related grants have been discovered for Femke Mol.