Implementing targeted expectant management in fertility care using prognostic modelling: a cluster randomized trial with a multifaceted strategy.

What is the effectiveness of a multifaceted implementation strategy compared to usual care on improving the adherence to guideline recommendations on expectant management for couples with unexplained infertility? The multifaceted implementation strategy did not significantly increase adherence to guideline recommendations on expectant management compared to care as usual. Intrauterine insemination (IUI) with or without ovarian hyperstimulation has no beneficial effect compared to no treatment for 6 months after the fertility work-up for couples with unexplained infertility and a good prognosis of natural conception. Therefore, various professionals and policy makers have advocated the use of prognostic profiles and expectant management in guideline recommendations. A cluster randomized controlled trial in 25 clinics in the Netherlands was conducted between March 2013 and May 2014. Clinics were randomized between the implementation strategy (intervention, n = 13) and care as usual (control, n = 12). The effect of the implementation strategy was evaluated by comparing baseline and effect measurement data. Data collection was retrospective and obtained from medical record research and a patient questionnaire. A total of 544 couples were included at baseline and 485 at the effect measurement (247 intervention group/238 control group). Guideline adherence increased from 49 to 69% (OR 2.66; 95% CI 1.45-4.89) in the intervention group, and from 49 to 61% (OR 2.03; 95% CI 1.38-3.00) in the control group. Multilevel analysis with case-mix adjustment showed that the difference of 8% was not statistically significant (OR 1.31; 95% CI 0.67-2.59). The ongoing pregnancy rate within six months after fertility work-up did not significantly differ between intervention and control group (25% versus 27%: OR 0.72; 95% CI 0.40-1.27). There is a possible selection bias, couples included in the study had a higher socio-economic status than non-responders. How this affects guideline adherence is unclear. Furthermore, when powering for this study we did not take into account the unexpected improvement of adherence in the control group. Generalization of our results to other countries with recommendations on expectant management might be questionable because barriers for expectant management can be very different in other countries. Furthermore, due to a large variation in improved adherence rate in the intervention group it will be interesting to further analyse the process of implementation in each clinic with a process evaluation on professionals and couples' exposure to and experiences with the strategy. Supported by Netherlands Organisation for Health Research and Development (ZonMW, project number 171203005). No competing interests. Dutch trial Register, www.trialregister.nl NTR3405. 19 April 2012. 10 July 2012.

Kersten FAM ，Nelen WLDM ，van den Boogaard NM ，van Rumste MM ，Koks CA ，IntHout J ，Verhoeve HR ，Pelinck MJ ，Boks DES ，Gianotten J ，Broekmans FJM ，Goddijn M ，Braat DDM ，Mol BWJ ，Hermens RPGM ，Improvement study group ... -  《-》

Tailored expectant management in couples with unexplained infertility does not influence their experiences with the quality of fertility care.

Do couples who were eligible for tailored expectant management (TEM) and did not start treatment within 6 months after the fertility work-up, have different experiences with the quality of care than couples that were also eligible for TEM but started treatment right after the fertility work-up? Tailored expectant management of at least 6 months in couples with unexplained infertility is not associated with the experiences with quality of care or trust in their physician. In couples with unexplained infertility and a good prognosis of natural conception within 1 year, expectant management for 6-12 months does not compromise ongoing birth rates and is equally as effective as starting medically assisted reproduction immediately. Therefore, TEM is recommended by various international clinical guidelines. Implementation of TEM is still not optimal because of existing barriers on both patient and professional level. An important barrier is the hesitance of professionals to counsel their patients for TEM because they fear that patients will be dissatisfied with care. However, if and how adherence to TEM actually affects the couples' experience with care is unknown. Experiences with the quality care can be measured by evaluating the patient-centredness of care and the patients' trust in their physician. This is a retrospective cross-sectional study. A survey with written questionnaires was performed among all couples who participated in the retrospective audit of guideline adherence on TEM in 25 Dutch clinics. Couples were eligible to participate if they were diagnosed with unexplained infertility and had a good prognosis (>30%) of natural conception within 1 year based on the Hunault prediction model. We used patient's questionnaires to collect data on the couples' experience with the quality of care and possible confounders for their experiences other than having undergone TEM or not. Multilevel regression analyses were performed to investigate case-mix adjusted association of TEM with the patient-centredness of care (PCQ-Infertility) and the patients' trust in their physician (Wake Forest Trust Scale). Couples who adhered to TEM experienced the quality of care on the same level as couples who were exposed to early treatment, i.e. started fertility treatment within 6 months after fertility work-up. There were no associations between adherence to TEM and the patient-centredness of care or the patients' trust in their physician. Because this study is retrospective, recall bias might occur. Furthermore, we were unable to measure the difference in experience with care over time. Therefore, our results have to be interpreted carefully. Prospective research on couples undergoing TEM have to be performed to provide more detailed insight in the patients' experiences with the decision making process and subsequently the expectant period. Tackling the barriers surrounding TEM, i.e. better counselling and more patient information material, could further improve patient experiences with the quality of care for couples who are advised TEM. Supported by Netherlands Organisation for Health Research and Development (ZonMW). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none. www.trialregister.nl NTR3405.

Kersten FA ，Hermens RP ，Braat DD ，Tepe E ，Sluijmer A ，Kuchenbecker WK ，Van den Boogaard N ，Mol BW ，Goddijn M ，Nelen WL ，Improvement study Group ... -  《-》

Overtreatment in couples with unexplained infertility.

What is the percentage of overtreatment, i.e. fertility treatment started too early, in couples with unexplained infertility who were eligible for tailored expectant management? Overtreatment occurred in 36% of couples with unexplained infertility who were eligible for an expectant management of at least 6 months. Prognostic models in reproductive medicine can help to identify infertile couples that would benefit from fertility treatment. In couples with unexplained infertility with a good chance of natural conception within 1 year, based on the Hunault prediction model, an expectant management of 6-12 months, as recommended in international fertility guidelines, prevents unnecessary treatment. A retrospective cohort study in 25 participating clinics, with follow-up of all couples who were seen for infertility in 2011-2012. In all, 9818 couples were seen for infertility in the participating clinics. Couples were eligible to participate if they were diagnosed with unexplained infertility and had a good prognosis of natural conception (>30%) within 1 year based on the Hunault prediction model. Data to assess overtreatment were collected from medical records. Multilevel regression analyses were performed to investigate associations of overtreatment with patient and clinic characteristics. Five hundred and forty-four couples eligible for expectant management were included in this study. Among these, overtreatment, i.e. starting medically assisted reproduction within 6 months, occurred in 36%. The underlying quality indicators showed that in 34% no prognosis was calculated and that in 42% expectant management was not recommended. Finally, 16% of the couples for whom a correct recommendation of expectant management for at least 6 months was made, started treatment within 6 months anyway. Overtreatment was associated with childlessness, higher female age and a longer duration of infertility. No associations between overtreatment and clinic characteristics were found. The response rate was low compared with other fertility studies. Evaluation of possible selection bias showed that responders had a higher socio-economic status than non-responders. Our findings show that developing and publishing guideline recommendations on tailored expectant management (TEM) is not enough and that overtreatment still occurs frequently. Future research should focus on tailored efforts to implement guideline recommendations on TEM. Supported by Netherlands Organisation for Health Research and Development (ZonMW). ZonMW had no role in designing the study, data collection, analysis and interpretation of data or writing of the report. Competing interests: none. www.trialregister.nl NTR3405.

Kersten FA ，Hermens RP ，Braat DD ，Hoek A ，Mol BW ，Goddijn M ，Nelen WL ，Improvement Study Group ... -  《-》

Expectant management versus IUI in unexplained subfertility and a poor pregnancy prognosis (EXIUI study): a randomized controlled trial.

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 (>30% 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 (<30% 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 (<30% 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 sample 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.

Wessel JA ，Mochtar MH ，Besselink DE ，Betjes H ，de Bruin JP ，Cantineau AEP ，Groenewoud ER ，Hooker AB ，Lambalk CB ，Kwee J ，Kaaijk EM ，Louwé LA ，Maas JWM ，Mol BWJ ，van Rumste MME ，Traas MAF ，Goddijn M ，van Wely M ，Mol F ... -  《-》

Is IVF-served two different ways-more cost-effective than IUI with controlled ovarian hyperstimulation?

What is the cost-effectiveness of in vitro fertilization (IVF) with conventional ovarian stimulation, single embryo transfer (SET) and subsequent cryocycles or IVF in a modified natural cycle (MNC) compared with intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH) as a first-line treatment in couples with unexplained subfertility and an unfavourable prognosis on natural conception?. Both IVF strategies are significantly more expensive when compared with IUI-COH, without being significantly more effective. In the comparison between IVF-MNC and IUI-COH, the latter is the dominant strategy. Whether IVF-SET is cost-effective depends on society's willingness to pay for an additional healthy child. IUI-COH and IVF, either after conventional ovarian stimulation or in a MNC, are used as first-line treatments for couples with unexplained or mild male subfertility. As IUI-COH is less invasive, this treatment is usually offered before proceeding to IVF. Yet, as conventional IVF with SET may lead to higher pregnancy rates in fewer cycles for a lower multiple pregnancy rate, some have argued to start with IVF instead of IUI-COH. In addition, IVF in the MNC is considered to be a more patient friendly and less costly form of IVF. We performed a cost-effectiveness analysis alongside a randomized noninferiority trial. Between January 2009 and February 2012, 602 couples with unexplained infertility and a poor prognosis on natural conception were allocated to three cycles of IVF-SET including frozen embryo transfers, six cycles of IVF-MNC or six cycles of IUI-COH. These couples were followed until 12 months after randomization. We collected data on resource use related to treatment, medication and pregnancy from the case report forms. We calculated unit costs from various sources. For each of the three strategies, we calculated the mean costs and effectiveness. Incremental cost-effectiveness ratios (ICER) were calculated for IVF-SET compared with IUI-COH and for IVF-MNC compared with IUI-COH. Nonparametric bootstrap resampling was used to investigate the effect of uncertainty in our estimates. There were 104 healthy children (52%) born in the IVF-SET group, 83 (43%) the IVF-MNC group and 97 (47%) in the IUI-COH group. The mean costs per couple were €7187 for IVF-SET, €8206 for IVF-MNC and €5070 for IUI-COH. Compared with IUI-COH, the costs for IVF-SET and IVF-MNC were significantly higher (mean differences €2117; 95% CI: €1544-€2657 and €3136, 95% CI: €2519-€3754, respectively).The ICER for IVF-SET compared with IUI-COH was €43 375 for the birth of an additional healthy child. In the comparison of IVF-MNC to IUI-COH, the latter was the dominant strategy, i.e. more effective at lower costs. We only report on direct health care costs. The present analysis is limited to 12 months. Since we found no evidence in support of offering IVF as a first-line strategy in couples with unexplained and mild subfertility, IUI-COH should remain the treatment of first choice. The study was supported by a grant from ZonMw, the Netherlands Organization for Health Research and Development, (120620027) and a grant from Zorgverzekeraars Nederland, the Netherlands' association of health care insurers (09-003). Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939.

Tjon-Kon-Fat RI ，Bensdorp AJ ，Bossuyt PM ，Koks C ，Oosterhuis GJ ，Hoek A ，Hompes P ，Broekmans FJ ，Verhoeve HR ，de Bruin JP ，van Golde R ，Repping S ，Cohlen BJ ，Lambers MD ，van Bommel PF ，Slappendel E ，Perquin D ，Smeenk J ，Pelinck MJ ，Gianotten J ，Hoozemans DA ，Maas JW ，Groen H ，Eijkemans MJ ，van der Veen F ，Mol BW ，van Wely M ... -  《-》