A decision analysis of treatments for obstructive azoospermia

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1 Human Reproduction Vol.23, No.9 pp , 2008 Advance Access publication on June 13, 2008 doi: /humrep/den200 A decision analysis of treatments for obstructive azoospermia R. Lee 1,2, P.S. Li 1,3, M. Goldstein 1,2,3, C. Tanrikut 1,3, G. Schattman 3 and P.N. Schlegel 1,2,3,4 1 James Buchanan Brady Foundation, Department of Urology, Weill Medical College of Cornell University, 525 E. 68th St., Starr 900, New York, NY 10021, USA; 2 Population Council, Center for Biomedical Research, 1230 York Ave., New York, NY 10021, USA; 3 Cornell Institute for Reproductive Medicine, Weill Medical College of Cornell University, 525 E. 68th St., Starr 900, New York, NY 10021, USA 4 Correspondence address. pnschleg@med.cornell.edu BACKGROUND: Treatments for post-vasectomy obstructive azoospermia include vasectomy reversal, microsurgical epididymal sperm aspiration (MESA) or percutaneous testicular sperm extraction (TESE) with IVF/ICSI. We examined the cost-effectiveness of these treatments. METHODS: A decision analytic model was created to simulate treatment. Outcome probabilities were derived from peer-reviewed literature and the Society for Assisted Reproductive Technologies database. Procedural costs were derived from a sampling of high-volume IVF centers and the Medicare Resource Based Relative Value Scale. Indirect costs of complications, lost productivity and multiple gestation pregnancies were considered. Sensitivity analyses were performed. RESULTS: Vasectomy reversal was more cost-effective than either MESA or TESE under all probability conditions. In 1999, vasectomy reversal demonstrated superior costeffectiveness to TESE and MESA ($ versus $ and $48 055, respectively, equivalent to $ versus $ and $ in 2005 dollars). In 2005, vasectomy reversal ($20 903) remained the most cost-effective treatment over TESE ($54 797) and MESA ($56 861). The cost-effectiveness of all treatments improved over projections by inflation. The relative cost-effectiveness of the therapies was unchanged over time. CONCLUSIONS: Vasectomy reversal appears more cost-effective than percutaneous TESE and MESA for treatment of obstructive azoospermia when the impact of indirect costs is considered. The absolute cost-effectiveness of all therapies improved over time. These results may be tailored with institution-specific data to allow more individualized results. Keywords: infertility, male; azoospermia; decision support techniques; reproductive techniques, assisted; cost benefit analysis Introduction The advent of assisted reproduction technology (ART) has significantly expanded our ability to treat infertility. Infertility currently affects 15% of all couples, with an anticipated increase over the next 20 years (Thonneau et al., 1991; Stephen and Chandra, 1998). Approximately 50% of infertility may be attributed to male factors. Currently, vasectomy reversal, microsurgical epididymal sperm aspiration (MESA) and percutaneous testicular sperm extraction (TESE) with IVF/ ICSI constitute the available methods of treatment for couples with male factor infertility due to obstructive azoospermia. Although effective, these techniques are also costly with broad implications for public policy and the allocation of scarce healthcare resources. Few studies have systematically and rigorously examined the economic impact of male factor infertility treatments (Pavlovich and Schlegel, 1997; Schlegel, 1997; Meng et al., 2005; Hsieh et al., 2007). More specifically, none have examined how the financial impact of male factor infertility treatments has changed over time: has it improved, worsened or remained constant? How are the relevant economic costs defined, and how would they impact public health decisions regarding male infertility treatments? We sought to investigate and compare the economic impact of ART for obstructive azoospermia over time, utilizing decision analytic models combined with population-based data to examine the cost-effectiveness of ART treatment. Specifically, we calculated and examined how the cost per live delivery changed over time for vasectomy reversal versus MESA versus percutaneous TESE with IVF/ICSI for obstructive azoospermia. We calculated overall direct cost estimates as well as the impact of indirect factors, such as the cost of complications, lost productivity and multiple gestation pregnancies with IVF/ICSI. Sensitivity analyses were used to determine how results would change when both high and low range assumptions were used. Materials and Methods Definitions Male factor infertility was defined as indicated by the Society for Assisted Reproductive Technologies (SART) registry of the American # The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org 2043

2 Lee et al. Society for Reproductive Medicine: specifically, the male partner in a couple who has been attempting conception for more than 12 months must have demonstrated abnormal sperm concentration or motility (fewer than 20 million sperm/cc or,40% motility) (The Male Infertility Best Practice Policy Committee of the American Urological Association and the Practice Committee of the American Society for Reproductive Medicine, 2006). Delivery after IVF was defined as the birth of at least one live baby after a minimum of 28 weeks of gestation as a result of a cycle of IVF. Deliveries were distinguished from births to avoid the potential confusion of counting multiple births separately. Multiple births per IVF cycle however were considered in the analysis. Cost per cycle Direct costs It was assumed that each man would require basic evaluation for male infertility, including a comprehensive office consultation, FSH and testosterone blood tests, two semen analyses and a follow-up visit to review findings. Similarly, each woman would require basic evaluation for female infertility, including a comprehensive office consultation, hormonal evaluation, serial ultrasounds and pregnancy tests and multiple follow-up visits. IVF procedural costs were obtained by querying the five highest volume IVF facilities in the USA as determined by the 2005 SART database: Boston IVF, Boston, MA; Shady Grove Fertility Reproductive Science Center, Rockville, MD; Reproductive Medicine Associates of New Jersey, Morristown, NJ; Huntington Reproductive Center, Pasadena, CA and Weill Medical College of Cornell University Center for Reproductive Medicine and Infertility, New York, NY (Centers for Disease Control and Prevention, 2005). Procedural costs encompassing professional, facility and anesthesia components for vasectomy reversal, MESA and TESE were derived by analysis of national pricing trends as defined by published sources, including the Medicare Resource Based Relative Value Scale (RBRVS), which functions as a standard for other fee schedules in the USA (Centers for Disease Control and Prevention, 2005; Wasserman, 1999, 2005). In addition, male procedural costs were also queried for sensitivity analysis at high-volume andrology centers, including Baylor College of Medicine, Houston, TX; Cleveland Clinic, Cleveland, OH; University of California at San Francisco, San Francisco, CA; University of Illinois at Chicago, Chicago, IL and Weill Medical College of Cornell University Center for Male Reproductive Medicine and Microsurgery, New York, NY. All cases of MESA and TESE were assumed to require IVF. Costs were assumed to be equal to charges in order to best evaluate overall impact to society (Table I). Indirect costs Lost productivity due to recovery from male-related intervention, as well as due to IVF-related obstetric complications, was accounted for using a 2005 median income rate of $ per year for women and $ per year for men as calculated by the US Census Bureau; corresponding wages for 1999 were $ and $ (US Census Bureau, 2005). Adjustment for inflation for all cost figures was based on medical care-specific consumer price index (CPI) data over the relevant time periods as calculated by the US Department of Labor (US Department of Labor, 2006). Maternal risks from IVF include ovarian hyperstimulation syndrome, pelvic hemorrhage, infection, stroke, myocardial infarction and possibly ovarian cancer (Schenker, 1993). Schenker and Ezra (1994) estimated that maternal complications occur in 3 6% of all ART cases. Major maternal complications occur in % of cases (Edwards et al., 1989). We therefore estimated the rate of 2044 Table I. Probability and costing parameters used for decision modeling. Probabilities Probability of successful sperm retrieval Percutaneous TESE in obstructive 100% 100% azoospermia Probability of patency after vasectomy 81% 81% reversal Probability of successful delivery After vasectomy reversal 42% 42% After IVF for obstructive 44% 44% azoospermia Probability of seeking 2nd treatment 50% 50% Probability of multiple gestation pregnancy after IVF Singleton 72.0% 70.4% Twin 25.9% 23.7% Triplet 2.1% 5.8% Procedural costs Male evaluation $ 606 $ 786 Microsurgical vasectomy reversal $2916 $3478 Resource Based Relative Value Scale (RBRVS) Microsurgical vasectomy reversal $ N/A (selected centers) Microsurgical epididymal sperm $1439 $1704 aspiration (MESA) (RBRVS) MESA (selected centers) $7398 N/A Percutaneous TESE (RBRVS) $ 577 $ IVF/ICSI cycle $ $ 9765 Standard deviation IVF/ICSI costs $3725 $2908 Indirect costs (probability adjusted) Lost productivity After vasectomy reversal $ 497 $ 438 After TESE $ 497 $ 438 After MESA $ 497 $ 438 After IVF/ICSI $1389 $1175 Complications After vasectomy reversal $ 38 $ 38 After TESE $ 77 $ 76 After MESA $ 77 $ 76 After IVF/ICSI $ 253 $ 196 Multiple gestation After spontaneous pregnancy $ $ Singleton $ $ Twin $1524 $1182 Triplet After IVF/ICSI $ $ Singleton $ $9819 Twin $ $ Triplet $4193 $9079 Spontaneous twin rate 2.2% 2.2% All costs are probability adjusted and include relevant anesthesia and ambulatory surgery fees for surgical procedures. major maternal complications to be 0.2%, those of minor complications to be 5%. The costs of maternal complications were determined from the peer-reviewed literature (Neumann et al., 1994). Complications from male intervention include bleeding, infection, testicular atrophy and risks associated with anesthesia; these were estimated to occur at a rate of 0.3 2% based on estimates from the peerreviewed literature (Schlegel, 1997; Pavlovich and Schlegel, 1997; Holman et al., 2000; Goldstein, 2002). Cost of treatment was therefore based on a complication rate of 1% with the cost of scrotal exploration and hydrocelectomy/hematoma evacuation for MESA or TESE, in addition to 7 days of lost work (Pavlovich and Schlegel, 1997). Multiple gestation pregnancies constitute an important aspect of IVF-related outcomes. Multiple gestation pregnancies are associated with higher rates of neonatal complications and longer intensive care unit stays compared with singleton infants (Neumann et al.,

3 Optimal treatments for obstructive azoospermia 1994). The costs of multiple gestation pregnancies were determined from the peer-reviewed literature (Callahan et al., 1994; Neumann et al., 1994) (Table I). Pregnancy rates Population-based data were gathered for the years 2005 and 1999, the former representing the latest year for which complete data were readily available and the latter the earliest year for which robust SART data existed for TESE. Pregnancy rates for vasectomy reversal and MESA were derived as volume-weighted averages from the peer-reviewed literature (Tables I and II). Specifically, the peer-reviewed literature was queried for articles pertaining to microsurgical vasectomy reversal and MESA by conducting a Medline search utilizing the terms vasectomy reversal, vasovasostomy, vasoepididymostomy, sperm retrieval, sperm aspiration and MESA. All relevant studies were identified, and only articles presenting original primary data sufficient to calculate patency, when relevant, and live delivery rates were included for analysis. No material changes were observed between 2005 and Pregnancy and delivery rates for TESE with IVF/ ICSI were queried from the SART database for the corresponding years (Table I). The percentage of singleton, twin and higher-order multiple-gestation pregnancies conceived as a result of assisted reproduction in the relevant years for those with male factor infertility undergoing TESE with IVF/ICSI was determined by the SART database. On the basis of previously published data for spontaneous abortion rates after ICSI, adjustments of 11.6% spontaneous abortion rates were applied to IVF clinical pregnancy rates when only the latter were available to approximate delivery rates (Spandorfer et al., 2004). Table II. Patency and delivery rates after vasectomy reversal and MESA from the peer-reviewed literature. Vasectomy reversal studies Patency rate Live delivery rate Belker et al. (1991) 1231/1469 (84%) 664/1469 (45%) Boorjian et al. (2004) 196/213 (92%) 168/213 (79%) Chan and Goldstein (2004) 22/27 (82%) 22/27 (82%) Deck and Berger (2000) NA/29 (NA) NA/29 (NA) Fuchs and Burt (2002) 147/173 (85%) 66/173 (38%) Heidenreich et al. (2000) 120/156 (77%) 81/156 (52%) Kolettis et al. (2002) 57/74 (77%) 26/74 (35%) Kolettis et al. (2003a) 37/46 (81%) 15/46 (33%) Kolettis and Thomas (1997) 49/58 (85%) 21/58 (36%) Kolettis et al. (2003b) 30/32 (93%) 18/32 (56%) Matthews et al. (1995) 164/200 (82%) 65/200 (32%) Nalesnik and Sabanegh (2003) 44/73 (60%) 21/73 (28%) Schlegel and Goldstein (1993) 77/110 (70%) 43/110 (39%) Silber (1989) NA/190 (NA) 81/190 (42%) Thomas (1987) 172/228 (75%) 59/228 (26%) Total 2346/2888 (81%) 1348/3078 (44%) MESA Studies Patency rate Live delivery rate Anger et al. (2004) NA 21/30 (70%) Devroey et al. (1995) NA 3/7 (40%) Heidenreich et al. (2000) NA 19/69 (28%) Janzen et al. (2000) NA 82/141 (58%) Oates et al. (1996) NA 8/31 (26%) Schlegel et al. (1995) NA 13/27 (48%) Schroeder-Printzen et al. (2000) NA 35/93 (38%) Sharma et al. (1997) NA 64/131 (49%) Shibahara et al. (1999) NA 5/18 (30%) Silber et al. (1994) NA 20/48 (42%) Tournaye et al. (1994) NA 3/14 (21%) Tournaye et al. (1999) NA 48/176 (27%) Zenke et al. (2004) NA 4/10 (44%) Total NA 372/843 (44%) Decision modeling Algorithms were created to model treatment decisions and their outcomes for obstructive azoospermia (Fig. 1). Vasectomy reversal was modeled and compared against both MESA and percutaneous TESE. In the decision model, the cost per live delivery represented the endpoint for comparing the outcomes of the branches. This cost was calculated using the cumulative costs of each outcome in the specific branch, divided by the number of live deliveries achieved in that branch. Assumptions made include: (i) pregnancy rates remain stable even over subsequent treatments and (ii) the fraction of couples pursuing subsequent treatment after failure of primary therapy remained constant at 50% in each decision arm. Decision models were evaluated using Data v10 software (Treeage Software Inc., MA, USA). The cost per live delivery was calculated for all male factor infertility patients in 2005 and compared with that of The most cost-effective treatment and year was that which demonstrated a lower cost per live delivery on an inflation-adjusted basis. Sensitivity analyses were carried out to evaluate model robustness and detect threshold conditions. Results The baseline decision analysis favored vasectomy reversal over both percutaneous TESE and MESA, at a cost of $ versus $ and $ in 1999, equivalent to $ versus $ and $ in 2005 dollars (Fig. 2). In 2005, vasectomy reversal ($20 903) remained the most cost-effective treatment over percutaneous TESE ($54 797) and MESA ($56 861). The absolute cost-effectiveness of vasectomy reversal improved 17%, TESE 7% and MESA 8% over projections by inflation, mainly due to improvements in IVF delivery and complication rates. Table III demonstrates the calculated cost per pregnancy for vasectomy reversal, MESA and percutaneous TESE when varying the patency rate after vasectomy reversal between 50% and 100% and the rate of successful delivery after IVF/ ICSI between 20% and 100%. Sensitivity analysis reveals that vasectomy reversal is superior to the other two treatments under all tested conditions, i.e. a threshold condition was not identified. Figure 1: Decision analytic model for pregnancy after obstructive azoospermia secondary to vasectomy. Initial choice of therapy is between vasectomy reversal, MESA or TESE. 2045

4 Lee et al. Figure 2: Baseline cost-effectiveness analysis with cost projections as determined by medical care-specific consumer price index deflator. In recognition that male procedural costs may vary significantly from RBRVS values, an additional sensitivity analysis was undertaken to evaluate the model with fiscal year 2005 cost parameters from five high-volume andrology centers. With a mean MESA cost of $7398 and a mean vasectomy reversal cost of $13 630, the cost-effectiveness of vasectomy reversal in 2005 deteriorated to $ versus TESE ($54 797) and MESA ($65 443) (Table IV). The rank order of relative cost-effectiveness between the three therapies, however, did not change. To account for the possibility that couples presenting for infertility treatment may in addition possess higher incomes than the national median, an additional sensitivity analysis was undertaken to evaluate the model utilizing the top quintile household income as reported for 2005 by the US Census Bureau (US Census Bureau, 2005). With a top quintile income of $ , a mean MESA cost of $7398 and a mean vasectomy reversal cost of $13 630, the costeffectiveness of vasectomy reversal further deteriorated to $ versus TESE ($64 477) and MESA ($77 378) (Table IV). Again, the rank order of relative cost-effectiveness between the three therapies did not change. All analyses take into account both the direct costs associated with the procedure in addition to specific indirect costs, including the cost of multiple-gestation pregnancies and delivery, and the cost of complications associated with ART. Discussion ART has clearly expanded our ability to effectively treat male factor infertility. However, it represents a costly technology with health implications to the individual and public policy implications to society, especially in the setting of an anticipated rise in the number of infertile couples. It is surprising then that few studies have systematically examined the economic impact of ART for male factor infertility (Pavlovich and Schlegel, 1997; Schlegel, 1997; Meng et al., 2005; Hsieh et al., 2007). In this study, we attempt to structure and elucidate the relevant cost-effectiveness elements for the treatment of obstructive azoospermia. Our decision analysis suggests that vasectomy reversal is more cost-effective than either MESA or TESE for the treatment of obstructive azoospermia, consistent with the results of prior studies (Pavlovich and Schlegel, 1997; Schlegel, 1997; Meng et al., 2005). Like Pavlovich and Schlegel (1997), we found the cost-effectiveness of MESA and TESE with IVF/ICSI to be similar and significantly worse than vasectomy reversal. Unlike previous studies, such as by Meng et al. (2005), however, we found no evidence of a threshold effect with reversal. Our sensitivity analysis showed that the cost-effectiveness of vasectomy reversal was superior to MESA and TESE under all conditions. This has several implications. For example, even if surgical reconstruction required uni- or bilateral vasoepididymostomy, a situation 2046

5 Optimal treatments for obstructive azoospermia Table III. Two-way sensitivity analysis: cost per live delivery for vasectomy reversal, MESA and percutaneous TESE over a range of vasectomy reversal patency rates and IVF live delivery rates Probability patent reconstruction MESA Probability of 1 $ $ $ $ $ Vasectomy reversal successful $ $ $ $ $ TESE pregnancy from $ $ $ $ $ MESA first IVF cycle 0.8 $ $ $ $ $ Vasectomy reversal $ $ $ $ $ TESE $ $ $ $ $ MESA 0.6 $ $ $ $ $ Vasectomy reversal $ $ $ $ $ TESE $ $ $ $ $ MESA 0.4 $ $ $ $ $ Vasectomy reversal $ $ $ $ $ TESE $ $ $ $ $ MESA 0.2 $ $ $ $ $ Vasectomy reversal $ $ $ $ $ TESE $ $ $ $ $ Probability patent reconstruction MESA Probability of 1 $ $ $ $ $ Vasectomy reversal successful $ $ $ $ $ TESE pregnancy from $ $ $ $ $ MESA 1st IVF cycle 0.8 $ $ $ $ $ Vasectomy reversal $ $ $ $ $ TESE $ $ $ $ $ MESA 0.6 $ $ $ $ $ Vasectomy reversal $ $ $ $ $ TESE $ $ $ $ $ MESA 0.4 $ $ $ $ $ Vasectomy reversal $ $ $ $ $ TESE $ $ $ $ $ MESA 0.2 $ $ $ $ $ Vasectomy reversal $ $ $ $ $ TESE $ $ $ $ $ Table IV. One-way sensitivity analysis: cost per live delivery for vasectomy reversal, MESA and percutaneous TESE using (i) male procedural costs from selected high-volume andrology centers and (ii) male procedural costs from selected high-volume andrology centers in addition to 2005 top quintile household income. Cost-effectiveness (cost per live delivery) 2005 base 2005 with selected high-volume andrology center costs Vasectomy reversal $ $ $ Percutaneous TESE $ $ $ MESA $ $ $ with selected high-volume andrology center costs and top quintile household income more likely in patients with a longer duration of obstruction, e.g. the additional cost per pregnancy generated by the lower patency rates is still outweighed by the cost of IVF in MESA and TESE, i.e. the duration of obstruction becomes an insignificant factor in deciding which therapy to recommend. Conversely, the improved cost-effectiveness from an enhanced ability to achieve successful delivery with IVF is still outweighed by the indirect costs of the therapy. The consideration of indirect costs represents the major difference in our analysis, compared with other systematic studies of male infertility. Indirect costs have traditionally been difficult to measure and have thus been excluded from many cost-effectiveness analyses regarding ART (Gold et al., 1996; Deck and Berger, 2000; Meng et al., 2005; Hsieh et al., 2007). We believe, however, that in a study designed to truly measure total economic impact to society of treatment for male infertility, the importance of capturing not only direct costs but also any accompanying effects on loss of life, livelihood or health that may occur as the result of disease or medical care is paramount. Indeed, the magnitude of these indirect costs appears to significantly alter the outcome of our decision model compared with prior studies. For instance, by our calculations, the probability- and inflation-adjusted cost of multiple gestation pregnancies alone outweighs the procedural cost of an IVF cycle in both the base and latter years of the study. The decision models provide a structured analysis of relevant factors in assisted reproduction. Part of the strength in the study is driven by the use of empirical data as taken from the peer-reviewed literature and high-volume IVF centers; we 2047

6 Lee et al. have sought to create a model as broadly generalizable as possible. Additionally, the use of sensitivity analysis allows for tailoring and adjustment to individual practitioner success rates, in terms of patency and live delivery after IVF. Additionally, geographic or institution-specific costing data may be substituted to customize calculations for a particular ART center. It is important to note that several factors were not considered in the analysis. First, costs were assumed to be equal to charges in order to best evaluate the overall impact of ART on society. However, the impact to individual patients and therefore individual patient willingness to undergo ART will vary depending on the extent of specific health insurance coverage. The decision models also did not consider downstream costs of raising children conceived by ART; higher rates of chromosomal anomalies, prematurity and low birthweight are found in ART children (Hansen et al., 2002; Olson et al., 2005). The costs of such problems were not addressed in this analysis. Our model also did not examine the complex issue of maternal age impact on fecundity. For example, vasectomy reversal is a suboptimal therapy when maternal age is greater; couples would be more likely to choose MESA or TESE in the interests of expediting the time to pregnancy and delivery, yet our analysis does not account for such situations. In addition, IVF itself is also suboptimal in the setting of advanced maternal age; determining whether vasectomy reversal or an IVF-based therapy would have superior outcome in this situation is extremely difficult, although studies such as that by Hsieh et al. (2007) have begun to systematically examine this issue. Finally, some of the broader effects of ART were also not considered. The economic impact of multiple births, for instance, on downstream social welfare and public health programs may become significant in the future. As a cost-effectiveness analysis, the broader question of who should be allowed to have access to ART remains largely unaddressed. Should the ability to pay determine access? What proportion of public resources should optimally be used to help pay for ART versus other potentially life-saving or extending technologies? What is the most efficient allocation of these resources, and how does one determine who should be the recipients? Further refinements to future studies should therefore include consideration of these unanswered questions and issues. Author s Role All authors have (i) made substantial contributions to conception and design, or acquisition of data or analysis and interpretation of data; (ii) drafted the article or revised it critically for important intellectual content and (iii) given final approval for this version to be published. Acknowledgements We wish to acknowledge the generous contribution of data by Drs Larry Lipshultz and Craig Niederberger for this study. 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