Cost-effectiveness of ovarian stimulation with gonadotrophin and clomiphene citrate in an intrauterine insemination programme for subfertile couples

Accepted Manuscript Title: Cost-effectiveness of ovarian stimulation with gonadotrophin and clomiphene citrate in an intrauterine insemination programme for subfertile couples Author: Karen Peeraer, J. Luyten, C. Tomassetti, S. Verschueren, C. Spiessens, A. Tanghe, C. Meuleman, Sophie Debrock, Eline Dancet, T.M. D'Hooghe PII: DOI: Reference:

S1472-6483(17)30678-8 https://doi.org/10.1016/j.rbmo.2017.12.007 RBMO 1866

To appear in:

Reproductive BioMedicine Online

Received date: Revised date: Accepted date:

2-5-2017 29-11-2017 8-12-2017

Please cite this article as: Karen Peeraer, J. Luyten, C. Tomassetti, S. Verschueren, C. Spiessens, A. Tanghe, C. Meuleman, Sophie Debrock, Eline Dancet, T.M. D'Hooghe, Cost-effectiveness of ovarian stimulation with gonadotrophin and clomiphene citrate in an intrauterine insemination programme for subfertile couples, Reproductive BioMedicine Online (2017), https://doi.org/10.1016/j.rbmo.2017.12.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Short title: Cost-effectiveness of gonadotrophin versus clomiphene citrate in IUI cycles

Cost-effectiveness of ovarian stimulation with gonadotrophin and clomiphene citrate in an intrauterine insemination programme for subfertile couples Karen Peeraer,a,* J Luyten,b C Tomassetti,a S Verschueren,a C Spiessens,a A Tanghec C Meuleman,a Sophie Debrock,a Eline Dancet,a TM D’Hooghea a

Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium b Leuven Institute for Healthcare Policy – LIGB, Kapucijnenvoer 35, 3000 Leuven, Belgium c hict, Ezelstraat 69, 8000 Bruges, Belgium

Comment [MD1]: Author: please check that all address are complete and correct

*Corresponding author: Karen Peeraer, Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. Tel: + 3216340819; E-mail address: [email protected]

Key message In an intrauterine insemination programme, ovarian stimulation with low-dose human gonadotrophin compared with ovarian stimulation with clomiphene citrate results in an incremental cost-effectiveness ratio of €3615 per additional clinical pregnancy achieved.

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2 Author biography Karen Peeraer graduated in 1999 as a medical doctor at KU Leuven (Belgium) and became a specialist in obstetrics and gynaecology in 2004. In 2016, she received a PhD degree in biomedical sciences. Her fields of interest are reproductive endocrinology, pre-implantation genetic diagnosis and the (cost-)effectiveness of assisted reproduction technology.

Abstract Ovarian stimulation with low-dose human menopausal gonadotrophin (HMG) is superior to clomiphene citrate in intrauterine insemination (IUI) cycles with respect to clinical pregnancy rate, but it is unclear whether HMG is also the more cost-effective option. The aim of this study was to compare the cost-effectiveness of ovarian stimulation with low-dose subcutaneously administred HMG (37.5–75 IU per day) to orally administred clomiphene citrate (50 mg/day from day 3–7) in an IUI programme for subfertile couples. A costeffectiveness analysis was conducted using the results of a randomized trial, including 620 IUI cycles. The primary outcome was the incremental cost-effectiveness ratio (ICER) of using HMG versus clomiphene citrate. Results are presented from the healthcare payer perspective. The total cost per patient associated with one IUI treatment with HMG is €764, whereas it is €558 if clomiphene citrate is used, resulting in an incremental cost of €206 for HMG per treatment. The incremental clinical pregnancy rate of using HMG instead of clomiphene citrate, however, is also 5.7 percentage points higher, resulting in an ICER of HMG versus clomiphene citrate of €3615 per additional clinical pregnancy achieved. On average, HMG was found to be more cost-effective than clomiphene citrate.

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KEYWORDS: intrauterine insemination, gonadotrophin, cost-effectiveness, ICER

clomiphene

citrate,

human

menopausal

Introduction Parenthood is one of the most universally desired goals in adulthood (ESHRE Capri Workshop Group, 2013). Not all couples who desire a pregnancy, however, will achieve one spontaneously, and a proportion of couples will need medical help to resolve underlying fertility problems. The current worldwide prevalence of infertility is estimated to be 9%, and 56% of infertile couples seek infertility medical care at some point during their reproductive age (Boivin et al., 2007). Whether intrauterine insemination (IUI) is the most appropriate first-line treatment was challenged in 2013 by the UK National Institute of Health Care Excellence (NICE guidelines, 2013). Evidence; however, strongly recommends IUI as a safe first-line treatment for all subfertile couples except in the case of bilateral tubal obstruction, anovulation and severe oligozoospermia (Practice Committee ASRM, 2006 and 2012; Verhulst et al., 2006; Bensdorp et al., 2015; Tjon-Kon-Fat et al., 2015; Bahadur et al., 2016; Bahadur et al., 2017).

The risks of multiple births can be avoided by use of low-dose stimulation protocol, careful monitoring, the possibility of selective follicular aspiration before IUI, strict cancellation criteria, or both (Cohlen 2005; Cantineau et al., 2007; Ghesquiere et al., 2007; van Rumste et al., 2008; Dickey, 2009; Bahadur et al., 2017). Reproductive outcomes, i.e. clinical pregnancy or live birth rates, of IUI reported in studies and achieved by individual clinics, are among others influenced by the medication used for ovarian stimulation. Ovarian stimulation

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with low-dose gonadotrophins has been proven to be associated with better reproductive outcomes and a lower cancellation rate per started IUI cycle, compared with ovarian stimulation with clomiphene citrate (Cantineau et al., 2007; Peeraer et al., 2015). Therefore, IUI should be used in combination with low-dose gonadotrophins if patients are willing to administer subcutaneous injections and if patients or the healthcare payers reimbursing their treatment are willing to pay for the extra cost associated with gonadotrophin treatment (Peeraer et al., 2015). The control of healthcare costs is after all a priority on the political agenda of almost every western society (Tilburt et al., 2013; Tjon-Kon-Fat et al., 2015), and is considered especially relevant by those considering fertility care as elective (Haagen et al., 2013).

To our knowledge, no other studies have provided an estimate for the cost-effectiveness of ovarian stimulation with either gonadotrophins or clomiphene citrate in the context of an IUI programme for subfertile couples. Therefore, in this study, we constructed a decision-analytic model that compared cumulative costs and effects of using low-dose human menopausal gonadotrophin (HMG) (Menopur®) instead of clomiphene citrate (Clomid®) for ovarian stimulation before IUI.

Materials and methods This cost-effectiveness analysis (CEA) was carried out at the Leuven University Fertility Center, after approval on 25 November 2015 by the Institutional Review Board (ML2438 Amend-Id:0002) as an additional economic analysis of a previously published open-label randomized clinical trial (ClinicalTrials.gov NCT01569945) (Peeraer et al., 2015).

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Study population The target population of this cost-effectiveness analysis was derived from the study population of 330 women participating in a randomized trial evaluating reproductive outcome after IUI following ovarian stimulation with subcutaneously administered low-dose HMG (n = 322 cycles, 37.5–75 IU per day) or with orally administred clomiphene citrate (n = 298 cycles, 50 mg/day from day 3–7) (September 2004 to December 2011) (Peeraer et al., 2015). In brief, the study population included subfertile couples meeting the following inclusion criteria: having tried to conceive for at least 12 months without achieving a pregnancy; woman age 42 years of age or younger; at least one patent fallopian tube; and a total motile count of 5.0 million spermatozoa or more after sperm preparation.

Economic evaluation Model The time horizon of this CEA was set at one IUI cycle. A decision tree was used as shortterm outcome was being assessed: the population entering the model received ovarian stimulation treatment (either clomiphene citrate or HMG), in most cases followed by an IUI. Some patients did not receive an IUI, as cycles could be cancelled mostly as a result of insufficient ovarian response, premature LH peak or multifollicular ovarian response. Finally, patients entered the end health states of the model with or without a clinical pregnancy. As a result, the decision tree included four health states per treatment arm: ovarian stimulation and no IUI; ovarian stimulation and IUI; and clinical pregnancy and no clinical pregnancy (Figure 1).

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Clinical data sources All transition probabilities for the model are based on the results of the study of Peeraer et al. (2015) complemented with a post-hoc analysis carried out on the original data of the randomized trial (Peeraer et al., 2015). In this randomized cotrolled trial, the clinical pregnancy rate of IUI after ovarian stimulation with HMG was 12.4%, whereas it was 6.7% for IUI after ovarian stimulation with clomiphene citrate, representing an absolute difference of 5.7 percentage points between both treatment groups. The transition probabilities per treatment arm are presented in Figure 1. Cost data sources The resource use per health state and the unit costs used in the cost-effectiveness analysis are presented in Table 1. All costs were expressed in euro, and were adjusted to the price-level of 2015 using the consumer price index. Resource use was derived from the previous randomized controlled trial (Peeraer et al., 2015). This resource use was then multiplied with its corresponding unit cost to obtain the relevant total direct cost. For each health state we took into account the dosing of ovarian stimulation treatment (mg or IU), the dosing of Pregnyl (IU), follicular monitoring (consultations and sonography), blood tests performed during (17 beta-oestradiol, progesterone, LH, FSH) and after (HCG and progesterone) the ovarian stimulation treatment, follicular aspirations before IUI, and IUI procedures (preparation of spermatozoa, intrauterine injection of spermatozoa and consultation). The dosing (mg/IU per cycle) of the ovarian stimulation treatments included in our CEA corresponds to the average dosage used (Peeraer et al., 2015). If Pregnyl was used, a dose of 5000 IU was administered, according to the study protocol (Peeraer et al., 2015). As the main objective of this study was to compare the cost-effectiveness of HMG versus clomiphene citrate as ovarian stimulation treatment before IUI, the cost of being pregnant or giving birth

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was not considered in our base case analysis. To allow calculation of the costs per live birth for one of the additional scenarios of this CEA, we assumed that the ‘no live birth’ health state was not associated with any additional live birth related costs; for the ‘live birth’ health state we collected additional data on the follow-up of pregnancy (from 4 weeks after IUI onwards) and delivery of the pregnant patients of the randomized controlled trial being followed up in the Leuven University Hospital (Peeraer et al., 2015). Therefore, we relied on the resource volumes reported in hospital invoices retrieved from the hospital information system by the Department of Management Information and Reporting at the Leuven University Hospitals. The resource volumes of pregnancy follow-up and delivery included outpatient consultations, sonography, chorion villus sampling, amniocentesis, medical procedures, surgery, delivery and hospitalizations. Drugs taken at home (obtained outside the hospital) were not included in the costs. If the patients’ pregnancy follow-up was partially or fully in secondary care centres and no hospital bills (with cost data resources) were available, they were excluded from this additional cost-analysis per live birth. We replaced the hospital specific per day fee for hospitalization by a national mean fee corrected for pathology from the website of the Belgian federal government (https://tct.fgov.be). We did this replacement to avoid bias in cost due to the specific nature of a university hospital setting, and to make our analysis more representative for all Belgian centres. Other unit costs were derived from the official Belgian list prices (RIZIV/INAMI or BCFI) as advised by the Belgian guidelines for economic evaluations and budget impact analysis (Cleemput et al., 2012). Cost calculations from a societal perspective included productivity losses based on the human capital approach. Assumptions abou thours of work absenteeism are presented in Table 1. Unit costs for productivity loss as a result of work absenteeism were set at €35.28/h, according to the guidelines of the Belgian Healthcare Knowledge Centre (Cleemput et al., 2012).

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Analytic methods Base-case cost-effectiveness estimates

The main outcome of this economic evaluation was the incremental cost-effectiveness ratio (ICER), defined as the difference in costs between two treatments, divided by the differences in their clinical outcome:

. The base case of this CEA is conducted

from the healthcare payer perspective, capturing the direct healthcare costs of fertility treatment (ovarian stimulation and IUI) relevant to the patient and Belgian (private or public) insurance and considering them in relation to the achieved clinical pregnancy rate. Additional analyses A first additional analysis presents the societal perspective, by additionally including the indirect non-healthcare cost resulting from productivity losses by patients undergoing treatment. In a second additional analysis, the healthcare costs of pregnancy follow up and delivery are added to the healthcare cost of infertility treatment (ovarian stimuation and IUI; base-case scenario) and considered relatively to the number of live births (ICER = Δ costs/ Δ live birth).

A final additional analysis represents a cumulative model in which women can receive up to six IUI cycles in case the previous cycles do not result in clinical pregnancy. For the cumulative model, we started from the base-case scenario. All patients with a negative outcome were assumed to start a new cycle in the same treatment arm, and the overall cancellation rate and pregnancy rate and cost per treatment cycle were assumed to remain the same during additional cycles.

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Uncertainty analysis Model robustness was tested for our main ICER (HMG versus clomiphene citrate), using one-way sensitivity analysis (OWSA) and probabilistic sensitivity analysis (PSA). The OWSA examines the effect of the change of a single model parameter on the model result. Parameters were varied from 70% to 130% of their given value, except for the parameters, which cannot exceed 100% (values expressed in %). The cost-effectiveness of IUI depends on the reproductive outcomes of individual clinics (Bahadur et al., 2016); Figure 2 devotes particular attention to the difference in pregnancy rates. The PSA value was randomly drawn from a probability distribution determined for each included parameter (Supplementary Table 1). This process was repeated 5000 times, for all variables combined, to assess the effect of the overall parameter uncertainty that is present in the model. The results of the OWSA is presented by means of a Tornado Diagram, whereas the PSA is presented by means of a cost-effectiveness acceptability curve (Figure 3). Results Base-case analysis Taking into account all costs associated with ovarian stimulation and IUI, and the probability of receiving IUI, the total cost of an average patient associated with one HMG treatment cycle was €764 and €558 respectively for clomiphene citrate. The clinical pregnancy rate per IUI cycle was 12.4% in the HMG group and 6.7% in the clomiphene citrate group. So, there was an additional cost of €206 per treatment cycle for using HMG instead of clomiphene citrate, but also a 5.7 percentage points higher incremental clinical pregnancy rate. When comparing one IUI treatment with HMG and clomiphene citrate with a ‘no treatment’ scenario with zero cost and effect, the average cost-effectiveness of clomiphene citrate was €8312 per clinical pregnancy achieved, whereas HMG would cost €6152 per clinical

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pregnancy achieved. Clomiphene citrate is less expensive per cycle, but more expensive per pregnancy achieved. When we compare HMG with clomiphene citrate, this led to an ICER of €3615 (

per additional clinical pregnancy gained. According to the results of our

randomized controlled trial (Peeraer et al., 2015), the number needed to treat (NNT), was 18 in order to obtain an extra pregnancy after HMG treatment compared with clomiphene citrate treatment, and this additional clinical pregnancy is associated with an additional cost of €3615. These results are graphically represented on the cost-effectiveness plane in Figure 4. As can be seen, clomiphene citrate is dominated by extension by HMG: a decision-maker willing to pay €558 for a clomiphene citrate treatment with a pregnancy rate of 6.7% must also be willing to pay €764 for a HMG-treatment with a pregnancy rate of 12.4% (more effective and more cost-effective). Additional analyses Higher ICER values were found from a societal perspective. As more patients received IUI in the HMG arm (95.3%) than in the clomiphene citrate arm (84.6%), more work absenteeism was generated in the HMG arm. Inclusion of this cost for productivity loss resulted in slightly higher ICERs, especially for HMG. For instance, the ICER comparing HMG with clomiphene citrate increased from €3615 to €4413. If the costs per live birth are considered instead of the costs per clinical pregnancy, the costs for an additional live birth as a result of treatment with HMG would be €10688. In this scenario, the average healthcare costs of pregnancy follow-up and delivery (€6883) were added to the healthcare cost of infertility treatment (ovarian stimulation and IUI; base-case scenario) (Table 1). To simulate clinical reality, we also present a cumulative analysis, taking into account that women can have up to six cycles of IUI treatment in case the first cycles do not result in

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clinical pregnancy. In this cumulative model, after six cycles, we estimated that 34% of the patients in the clomiphene citrate arm and 55% of patients in the HMG arm would reach clinical pregnancy. The costs accumulated over these six cycles is €2834 and €3377 in the clomiphene citrate and HMG arm, respectively. This results in a cumulative ICER of HMG versus clomiphene citrate of €2612 per clinical pregnancy achieved (Table 2). Sensitivity analysis As explained in our methods section, the robustness of the ICER of our main analysis comparing HMG with clomiphene citrate from a healthcare payer perspective, was tested with an OWSA and PSA (Figure 3). The results of the OWSA shows that the model was most sensitive to the parameter ‘clinical pregnancy rate per cycle after IUI’ in both treatment groups. When this clinical pregnancy rate was varied between 70% and 130% of its default value, the ICER varied between €10.403 and €2.187 for variations in the clinical pregnancy rate in the HMG treatment arm and between €2.744 and €5.294 for variations in the clinical pregnancy rate in the clomiphene citrate treatment arm. In Figure 2, a range of differences in pregnancy rate per cycle of HMG versus clomiphene citrate (from 1 to 15 percentage points) the resulting incremental cost per pregnancy achieved. Subsequently, the model was most sensitive to the drug cost of HMG, the proportion of patients in the clomiphene citrate treatment arm that received both ovarian stimulation and IUI and the dosing (IU) of HMG in the ovarian stimulation and IUI group. When varying the default values of these parameters between 70% and 130%, the ICER varied between (€2796–€4433), (€4541–€2929), (€2833– €4397), respectively. The PSA, represented in the cost-effectiveness acceptability curve in Figure 3B shows that for a willingness to pay of about €4000 per clinical pregnancy achieved, our model estimates that about 50% of the estimated ICERs would fall below that threshold. At €10 000, about 90% of the ICERs would be deemed cost-effective.

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Discussion To our knowledge, no previous study has compared the cost-effectiveness of ovarian stimulation with low-dose HMG with ovarian stimulation with clomiphene citrate in an IUI programme for subfertile couples. Our results indicate that, although HMG-treatment is more expensive per cycle than clomiphene citrate treatment, it offers better value-for-money as it is less costly per clinical pregnancy achieved. These results are of particular relevance for Belgium and all countries in which clomiphene citrate is considered the first choice for ovarian stimulation before IUI. In Belgium, the use of gonadotrophins for ovarian stimulation with or without IUI has been regulated by law in 2006 and again in 2008 (Belgisch Staatsblad, 2006; Belgisch Staatsblad, 2008). Before this law came into force, ovarian stimulation before IUI could be carried out with either clomiphene citrate or gonadotrophins. According to this new legislation, only clomiphene citrate can be used as a first-line treatment for ovarian stimulation before IUI, and gonadotrophins can only be reimbursed in selected cases. This legislation, based on considerations of cost, is not in line with results from observational and randomized studies suggesting that IUI after ovarian stimulation with gonadotrophins results in higher pregnancy rates than IUI after ovarian stimulation with clomiphene citrate (Karlstrom et al., 1993; Balasch et al., 1994; Kamel et al., 1995; Karande et al., 1995; Manganiello et al., 1997; Hannoun et al., 1998; Mattoras et al., 2002; Cantineau et al., 2007; Berker et al., 2011; Peeraer et al., 2015).

Our finding that the costs of ovarian stimulation with low-dose HMG combined with IUI are more expensive then those of ovarian stimulation with clomiphene citrate is in line with the

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study by Haagen et al., (2013) comparing the cost-effectiveness of optimal guideline adherence in IUI care with suboptimal guideline adherence. The total medical cost for stimulated IUI cycle using gonadotrophins was €1052 (our study: €764) and €572 using clomiphene citrate (our study: €558). We hypothesize that the lower cost in the gonadotrophin-stimulated IUI group in our study, when compared with the Haagen study, can be explained by a lower starting dose of gonadotrophin in our study (37–75 IU). Although the mean dose or starting dose of gonadotrophin was not mentioned in the study by Haagen et al., 2013), we know that the starting dose of gonadotrophins for ovarian stimulation before IUI was higher in most studies comparing clomiphene citrate and gonadotrophins for ovarian stimulation before IUI (Peeraer et al., 2015). The cost-effectiveness between IUI with clomiphene citrate or HMG was not analysed in the study by Haagen et al. (2013), as this was not the objective of their study. The fact that we added a model to calculate the ICER based on expecting couples to take part in multiple IUI cycles besides the ICER based on couples taking part in one cycle only, is in line with ‘real world practice’ where clinics and health insurance companies offering packages of IUI treatment during multiple cycles rather than IUI treatment during one cycle only (Dutch Society of Obstetrics and Gynaecology (NVOG) guideline, 2000; Dickey et al., 2002; Custers et al., 2008; ESHRE Capri Workshop Group, 2009; Haagen et al., 2010; 2013; Merviel et al., 2010). Our cumulative costeffectiveness analysis shows that the more cycles patients have, the lower the ICER or costs per additional pregnancy achieved with HMG rather than clomiphene citrate. This can be explained by the lower number of patients having to start new cycles in the case of HMG compared with clomiphene citrate as they will be more likely to be pregnant. This cumulative cost-effectiveness analysis also demonstrated that it will take twice as many cycles of IUI to reach a cumulative pregnancy rate of 33% in the clomiphene citrate group compared with the HMG group (Table 2). Finally, like another cost-effectiveness analysis (Tjon-Kon-Fat et al.,

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2016), our study confirms the relevance of IUI as first-line treatment based on its costeffectiveness. We do, however, encourage clinics to use HMG rather than clomiphene citrate to optimize their IUI clinical pregnancy rate, if in line with the treatment preference of their patients (Dancet et al., 2014). We advise this to all clinics, irrespective of their IUI-pregnancy rates, as demonstrated in Figure 2 of our results. Our study is marked by some limitations. First, as unit costs were estimated using Belgium reference prices, and cost calculations were based on the practice in Belgium, countryspecific prices and assumptions need to be considered before generalizing these results to other countries. Second, when compared with no treatment, the additional cost required to achieve an additional clinical pregnancy after ovarian stimulation with IUI was €8313 when clomiphene citrate was used for ovarian stimulation, and €6.153 when HMG was used for ovarian stimulation. Nevertheless, no treatment will result in zero cost but might still result in a spontaneous pregnancy. Unfortunately, it was not possible to assess the effectiveness of one cycle ‘no treatment’, as the prediction of the spontaneous pregnancy rate in a subfertile population is highly variable, depends on many female and male factors, and is mostly expressed over a time period of 1 year and not cycle based (Hunault et al., 2004). Third, the effect on the cost-effectiveness when comparing more cycles was reported by an additional cumulative analysis. A limitation for this additional cumulative analysis is that reproductive outcome after IUI for both treatment groups was known for one cycle, and not cumulatively for a number of cycles. Therefore, we had to make a simulation taking into account the success rates per cycle. Fourth, the costs of multiples could not be included in our additional cost-effectiveness analysis focusing on costs per live birth, as the only four twins of our randomized controlled trial sample were born in another hospital for which we have no cost data. Our randomized controlled trialdid not, however, indicate that the type of ovarian stimulation defines the likeliness of multiple birth (Peeraer et al., 2015).

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In conclusion, our study showed that, in an IUI programme, ovarian stimulation with lowdose HMG is more expensive per cycle, but more cost-effective per achieved clinical pregnancy than ovarian stimulation with clomiphene citrate. The results should be useful for clinical decision-making between patients and professionals, and can be helpful for policymakers to better understand and control healthcare costs related to fertility treatment.

References

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National Institute for Health and Clinical Excellence (NICE) guidelines.

2013

(www.nice.org.uk) Peeraer, K., Debrock, S., De Loecker, P., Tomassetti, C., Laenen, A., Welkenhuysen, M., Meeuwis, L., Pelckmans, S., Mol, B.W., Spiessens, C., De Neubourg, D., D'Hooghe, T.M., 2015. Low-dose human menopausal gonadotrophin versus clomiphene citrate in subfertile couples treated with intrauterine insemination: a randomized controlled trial. Hum. Reprod. 30, 1079-1088. Practice Committee of the American Society for Reproductive Medicine, 2006. Effectiveness and treatment for unexplained infertility. Fertil. Steril. 86, S111-S114. Practice Committee of the American Society for Reproductive Medicine, 2012. Endometriosis and infertility: a committee opinion. Fertil. Steril. 98, 591-598. Tilburt, J.C., Wynia, M.K., Sheeler, R.D., Thorsteinsdottir, B., James, K.M., Egginton, J.S., Liebow, M., Hurst, S., Danis, M., Goold, S.D., 2013. Views of US physicians about controlling health care costs. JAMA 310, 380-388. Tjon-Kon-Fat, R.I., Bensdorp, A.J., Bossuyt, P.M., Koks, C., Oosterhuis, G.J., Hoek, A., Hompes, P., Broekmans, F.J., Verhoeve, H.R., de Bruin, J.P., van Golde, R., Repping, S., Cohlen, B.J., Lambers, M.D., van Bommel, P.F., Slappendel, E., Perquin, D., Smeenk, J., Pelinck, M.J., Gianotten, J., Hoozemans, D.A., Maas, J.W., Groen, H., Eijkemans, M.J., van der Veen, F., Mol, B.W., van Wely, M., 2015. Is IVF-served two different ways-more costeffective than IUI with controlled ovarian hyperstimulation? Hum. Reprod. 30, 2331-2339. van Rumste MM, Custers IM, van der Veen F, van Wely M, Evers JL, Mol BW. The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: a meta-analysis. Hum Reprod Update 2008;14:563-570.

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20

Verhulst, S.M., Cohlen, B.J., Hughes, E., Te Velde, E., Heineman, M.J., 2006 & 2012. Intrauterine insemination for unexplained subfertility. Cochrane Database Syst. Rev. 18, CD001838. Review. Update in: Cochrane Database Syst. Rev. 9, CD001838. https://tct.fgov.be: 28/11/2017 http://www.bcfi.be: 28/11/2017 http://www.riziv.fgov.be: 28/11/2017 Declaration T D’Hooghe and K Peeraer were supported by the Clinical Research Foundation of UZ Leuven, Belgium. The study medication was provided by the Ferring company (Copenhagen, Denmark). The Ferring company was not involved in the study design, data analysis, writing and submission of the paper. Thomas D’Hooghe was involved in patient recruitment and data analysis before he became Vice-President, Global Medical Affairs Fertility at Merck (October 2015). The other authors have no conflict of interest to declare.

Figure legends Figure 1: Decision tree analytic model and transition probabilities (base-case scenario). HMG, human menopausal gonadotrophin; IUI, intrauterine insemination. Figure 2: Incremental cost per clinical pregnancy achieved of human menopausal gonadotrophin (HMG) versus clomiphene citrate per percentage point difference in clinical pregnancy rate per cycle of HMG versus clomiphene citrate. ICER, incremental costeffectiveness ratio.

Figure 3: Sensitivity analysis. The results of the one-way sensitivity analysis (OWSA) is presented by means of a (A) Tornado Diagram, whereas the probabilistic sensitivity analysis (PSA) is presented by means of a (B) cost-effectiveness acceptability curve. HMG, human menopausal gonadotrophin; ICER, incremental cost-effectiveness ratio; IUI, intrauterine insemination; WTP, willingness-to-pay. Figure 4: Cost-effectiveness plane of IUI treatment with clomiphene citrate (orange spot) and HMG (green spot) versus no treatment (blue spot). HMG, human menopausal gonadotrophin; IUI, intrauterine insemination.

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21 Table 1. Resource use and unit costs. Health state

No IUI

Resource type

Resource usage (number of units)

Cost per unit

Source

Clomiphene citrate

HMG

Clomiphen e citrate

HM G

Ovarian stimulation (Clomid®/Menopur 75®)

260.3 3

mg

573. 2

IU

€0.02

€ 0.26

Pregnyl 5000 IU

0

Syringe

0

Syringe

€6.94

1.33

Consultation s

€24.48

a

Peeraer et al. (2015) + BCFI a

Peeraer et al. (2015) + BCFI

Follicular monitoring, n

IUI

a

Consultation

2.74

Sonography

2.74

Tests

1.33

Tests

€26.42

Peeraer et al. (2015) + RIZIV

Blood tests during cycle, n

2.74

Tests

1.53

Tests

€45.52 per test

Peeraer et al. (2015) + RIZIV

Blood tests post cycle, n

0.13

Tests

0

Tests

€39.80 per test

Peeraer et al. (2015) + RIZIV

Follicular aspirations, n

0

Procedures

0

Procedures

Peeraer et al. (2015)

a

IUI, n

0

Procedures

0

Procedures

Peeraer et al. (2015)

a

Ovarian stimulation (Clomid ®/Menopur 75®)

249.8 5

mg

601. 6

IU

Pregnyl 5000 IU

1

Syringe

1

Syringe

2.07

Consultations 2.58

Consultations

€0.02

Peeraer et al. (2015) + RIZIV a

€ 0.26

a

a

a

Peeraer et al. (2015) + BCFI a

€6.94

Peeraer et al. (2015) + BCFI

€24.48

Peeraer et al. (2015) + RIZIV

Follicular monitoring, n Consultation

Consultation

a

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22 s Sonography

a

2.07

Tests

2.58

Tests

€26.42

Peeraer et al. (2015) + RIZIV

Blood tests during cycle, n

2.09

Tests

2.5

Tests

€45.52 per test

Peeraer et al. (2015) + RIZIV

Blood tests post cycle, n

1.13

Tests

1.5

Tests

€39.80 per test

Peeraer et al. (2015) + RIZIV

Follicular aspirations, n

0.12

Procedures

0.03

Procedures

€230.43 per procedure

Peeraer et al. (2015) + RIZIV

Preparation of spermatozoa

1

Procedures

1

Procedures

€137.24 per procedure

Peeraer et al. (2015) + RIZIV

intrauterine injection of spermatozoa

1

Procedures

1

Procedures

€164.9 per procedure

Peeraer et al. (2015) + RIZIV

Consultation

1

1

Consultation s

a

a

a

IUI, n

Consultations

€24.48

a

a

a

Peeraer et al. (2015) + RIZIV

No clinical pregnancy

No cost

0

Units

0

Units

Model decision

Clinical pregnancy

No cost

0

Units

0

Units

Model decision

No live birth

No cost

0

Units

0

Units

Model decision

Live birth

Average cost per pregnancy follow up and for delivery

1

Units

1

Units

Productivity loss

Hours of work absenteeism

€6882.72 per live birth

€35.28/h

Model decision + Peeraer et al. (2015)

a

b

KCE report 183C (2012) + indexation c 2016

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23 Follicular monitoring (woman)

2 h/monitoring

Assumption

Blood tests post cycle (woman)

2 h/test

Assumption

IUI (woman + man)

4 h/IUI

Assumption

a

Peeraer et al. (2015) plus additional analysis conducted on original data. Cleemput et al. (2012). c http://statbel.fgov.be/en/statistics/figures/economy/consumer_price_index/health_index/ BCFI, Belgian Center for Pharmacotherapeutic Information; HMG, human menopausal gonadotrophin; IUI, intrauterine insemination; KCE, Belgian Health Care Knowledge Centre; RIZIV, National Institute for Healthcare and indemnity Insurance. b

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24 Table 2. Results: cumulative analysis. Cycle 1 Total cost of clomiphene citrate arm, € Clinical pregnancy clomiphene citrate arm, % Going to next clomiphene citrate cycle, % Total cost of HMG arm, € Clinical pregnancy HMG arm, % Going to next HMG cycle, % Cumulative ICER, €

Cycle 2

Cycle 3

Cycle 4

Cycle 5

Cycle 6

557.91

1078.37

1563.90

2016.85

2439.39

2833.58

7

13

19

24

29

34

93 764.33

87 1433.71

81 2019.94

76 2533.35

71 2982.98

66 3376.75

12

23

33

41

48

55

88

77

67

59

52

45

3614.55 3440.21 3253.70 3054.15 2840.63 HMG, human menopausal gonadotrophin; ICER, incremental cost-effectiveness ratio.

2612.16

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25 Figure 1.

Figure 2.

Page 25 of 28

26 Figure 3A.

Page 26 of 28

27 Figure 3B.

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28

PeeraerKarenFOTO.jpg

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