Laparoscopy in women with unexplained infertility: a cost-effectiveness analysis

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1 INFERTILITY Laparoscopy in women with unexplained infertility: a cost-effectiveness analysis Sharon E. Moayeri, M.D., M.P.H., M.S., a,b Henry C. Lee, M.D, M.S., c Ruth B. Lathi, M.D., a Lynn M. Westphal, M.D., a Amin A. Milki, M.D., a and Alan M. Garber, M.D., Ph.D. b,d a Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility; b Center for Primary Care Outcomes and Research; c Department of Pediatrics; and d Veterans Affairs Palo Alto Health Care System, Department of Medicine, Stanford University, Stanford, California Objective: To evaluate the cost effectiveness of laparoscopy for unexplained infertility. Design: We performed a cost-effectiveness analysis using a computer-generated decision analysis tree. Data used to construct the mathematical model were extracted from the literature or obtained from our practice. We compared outcomes following four treatment strategies: [1] no treatment, [2] standard infertility treatment algorithm (SITA), [3] laparoscopy with expectant management (LSC/EM), and [4] laparoscopy with infertility therapy (LSC/IT). The incremental cost-effectiveness ratio (ICER) was calculated, and one-way sensitivity analyses assessed the impact of varying base-case estimates. Setting: Academic in vitro fertilization practice. Patient(s): Computer-simulated patients assigned to one of four treatments. Intervention(s): Fertility treatment or laparoscopy. Main Outcome Measure(s): Incremental cost-effectiveness ratios. Result(s): Using base-case assumptions, LSC/EM was preferred (ICER ¼$128,400 per live-birth in U.S. dollars). Changing the following did not alter results: rates and costs of multiple gestations, penalty for high-order multiples, infertility treatment costs, and endometriosis prevalence. Outcomes were most affected by patient dropout from infertility treatments SITA was preferred when dropout was less than 9% per cycle. Less important factors included surgical costs, acceptability of twins, and the effects of untreated endometriosis on fecundity. Conclusion(s): Laparoscopy is cost effective in the initial management of young women with infertility, particularly when infertility treatment dropout rates exceed 9% per cycle. (Fertil Steril Ò 2009;92: Ó2009 by American Society for Reproductive Medicine.) Key Words: Cost effectiveness, dropout, endometriosis, in vitro fertilization, laparoscopy, unexplained infertility Approximately 10% to 15% of couples in the United States are diagnosed with infertility, an inability to conceive after 1 year of trying (1). Identifying the cause of infertility is complex and often reveals overlapping etiologies. After a standard evaluation, between 20% and 30% of couples will have no clearly identifiable cause for their infertility (2, 3). However, these estimates include couples in which the female partner may not have been thoroughly evaluated with laparoscopy for pelvic pathologies such as endometriosis. Female partners in infertile couples are eight times as likely as female partners in fertile couples to be diagnosed with endometriosis (4 6). The standard of care for identifying endometriosis includes diagnostic surgery, usually laparoscopy Received December 15, 2007; revised May 20, 2008; accepted May 21, 2008; published online August 22, S.E.M. has nothing to disclose. H.C.L. has nothing to disclose. R.B.L. has nothing to disclose. L.M.W. has nothing to disclose. A.A.M. has nothing to disclose. A.M.G. has nothing to disclose. Reprint requests: Sharon E. Moayeri, M.D., M.P.H., M.S., 2192 Martin Street, Suite 110, Irvine, CA (FAX: ; smoayeri@yahoo.com). (7, 8). Surgical correction with ablation or excision at the time of diagnostic laparoscopy is an accepted treatment (9). However, the role of laparoscopy as a standard approach to the management of infertility remains controversial for several reasons (10, 11). Although women with infertility have an increased prevalence of endometriosis (estimated at greater than 30%), it is difficult to predict which patients are likely to benefit from surgery (6, 12). Furthermore, prospective randomized studies exploring the effects of surgically corrected endometriosis on fecundity have been limited, are sometimes contradictory, and at best have demonstrated a modest effect(13 15). Modern fertility treatments, especially in vitro fertilization (IVF), result in marked improvements in fecundity; it is unclear whether these treatments are compromised by unrecognized endometriosis. Consequently, patients increasingly forego surgery, particularly if they are otherwise asymptomatic and their initial diagnostic studies (i.e., hysterosalpingogram) are normal (16, 17). Theoretically, there are potential benefits to routinely performing laparoscopy in infertile women. First, it is possible /09/$36.00 Fertility and Sterility â Vol. 92, No. 2, August doi: /j.fertnstert Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 to avoid fertility treatments and their direct as well as indirect financial and social costs such as multiple gestation pregnancy (10, 18). Second, intraoperative findings can guide postsurgical management, circumventing treatments that are of low benefit and costly (19). Third, surgically correcting endometriosis may enhance response to fertility treatments or mitigate the effects of comorbidities such as pelvic pain (20). The complexity of deciding if and when laparoscopy should be performed to diagnose and treat endometriosis among infertile women is highlighted by an opinion from the Practice Committee of the American Society of Reproductive Medicine: the treatment of endometriosis. raises a number of complex clinical questions that do not have simple answers. There are few infertility problems requiring greater clinical acumen. (6). The committee suggests, Laparoscopy should be seriously considered before applying aggressive empirical treatments involving significant cost and/or potential risks (21). The objective of our study was to determine whether laparoscopy is a cost-effective alternative to a standard infertility treatment algorithm (SITA), as previously described by Karande et al. (22), for the initial management of unexplained infertility. In addition, we will also characterize the factors that influence the cost-effectiveness of laparoscopy. MATERIALS AND METHODS We performed a cost-effectiveness analysis using a computerized decision analysis tree (TreeAge Pro Suite 2006; TreeAge Software, Inc., Williamstown, MA) with a Markov process to approximate cycle specific outcomes based on estimated probabilities and costs. The outcome was defined as the cost per live birth, ideally a singleton. Using a simulated cohort of 1000 women with unexplained infertility, the treatment costs and health effects of four strategies were calculated over a 1-year period. Because our time frame was brief, discounting was not applied (23 25). Our analysis took a societal perspective whereby we incorporated the costs for managing various pregnancy outcomes (i.e., singleton versus multiple gestation). Estimates used to build the model and establish the typical, or base case, scenario were abstracted from the medical literature or approximated from the data of the Stanford Reproductive Endocrinology and Infertility Clinic. Only direct medical costs were included. We used one-way sensitivity analyses to evaluate the impact of changing key assumptions used in the base case. Specifically, we inserted a range of reasonable estimates for many of the model variables to evaluate which variables had the greatest influence on our conclusion. We will be outlining the details on the sensitivity analyses. Institutional review board approval for exempt protocol status was obtained through the Research Compliance Office at Stanford University. Details of Computer Simulation Model Patient characteristics We assumed that patients were normally ovulating women of less than 37 years of age with no identifiable cause of infertility who had completed an evaluation that included a hormone assessment, semen analysis, and hysterosalpingogram. Treatment strategies Figure 1 represents a simplified overview of the model. There are four treatment strategies. Estimates for the base case and ranges used for sensitivity analyses are summarized in Table 1 and were derived mostly from randomized clinical trials and/or meta-analyses, as referenced. All four treatment groups had the same proportion of mild (stages I/II) endometriosis (48%, range: 25% to 75%), severe (stages III/IV) endometriosis (15%, range: 5% to 25%), or no endometriosis (37%, range: 0 to 70%) (4, 13, 26, 27). Strategy 1 represents a no-intervention group. We included this group for two reasons. First, there is a reasonable background rate of spontaneous pregnancy in this population of young women with unexplained infertility of 1-year duration (28). Second, patient dropout from treatment is high, particularly among young women who may delay treatment if the cause for their infertility is unidentified. The second strategy, SITA, is a typical clinical algorithm for managing young infertile women (2, 22). Patients initiated treatment with a cycle of clomiphene citrate and intrauterine insemination (CC-IUI), completing up to three cycles until a pregnancy was achieved. Those who did not conceive after three cycles underwent increasingly aggressive treatments: three cycles of gonadotropins with IUI (GT-IUI) and, ultimately, four cycles of IVF. In the third and fourth strategies, diagnostic laparoscopy with ablation of endometriosis, when present, was initiated at the outset of treatment. Because the diagnosis of endometriosis was made at laparoscopy only strategies 3 and 4 led to different interventions after surgery. These two strategies evaluate which is the optimum approach after the diagnosis and surgical treatment of endometriosis: proceeding immediately to fertility treatment versus awaiting spontaneous pregnancy. Specifically, in strategy 3, laparoscopy with expectant management (LSC/EM), we examined the effect of surgically correcting endometriosis without the added benefit of infertility treatments. All women underwent diagnostic/therapeutic laparoscopy followed by expectant management for those with endometriosis versus SITA for those with no endometriosis. Surgically treated patients were managed expectantly because this is a common approach that assumes a major cause of infertility, namely endometriosis, has been corrected (6, 13). In contrast, in the fourth strategy we explored the potential value of laparoscopy for providing intraoperative information that tailors specific fertility treatments after surgery. Patients diagnosed with severe endometriosis were triaged 472 Moayeri et al. Cost effectiveness of laparoscopy for infertility Vol. 92, No. 2, August 2009

3 FIGURE 1 Decision tree model (simplified). to immediate IVF and completed up to four cycles. Patients diagnosed and treated for stage I/II endometriosis preceded to the SITA algorithm in the immediate postoperative menstrual cycle. This option not only took into account the potential of bypassing treatments likely to be of low value, but it also addressed the possible synergistic effect of laparoscopy on enhancing response to fertility treatments in women who have undergone surgical correction of their endometriosis (20). Patients without endometriosis (i.e., truly unexplained infertility) entered the SITA protocol postoperatively because the cause of their infertility is unknown and infertility treatment may improve their chances for conception compared with expectant management alone. Markov states The outcome of each treatment arm was derived from a Markov model (labeled with a circled M in Fig. 1). Movement between states depended on treatment path probabilities. The probability of live birth and treatment costs were cumulative and cycle specific, estimated by a simulation using five health states and 10 stages. All patients began the Markov process in the infertile state (beginning health state), moving to continued infertility (transition state), pregnancy (transition state), live birth (absorbing state), or dropout (absorbing state), as predicted by stage-specific probabilities. Patients received a maximum of 10 months of treatment, concluding with the achievement of an ongoing pregnancy. Patients who failed to conceive or those who miscarried reentered the model through the pathway from which they were last treated. Treatments are completed within a 1-year time frame. Each stage reflected a 1-month increment during which a patient could undergo a cycle of therapy as determined by the decision tree. Cycle-specific outcomes were based on average fecundity rates for each type of infertility treatment (i.e., CC-IUI, GT-IUI, IVF) and were assumed to be the same within each type of therapy (i.e., all three CC-IUI cycles have the same probability of pregnancy). Success rates were adjusted to reflect the strategic path entered by the patient, including whether endometriosis is present, its severity, and whether it is surgically treated. For patients with unexplained infertility we assumed the following baseline live-birth rates, which were estimated from the literature: 3% for no treatment, 7% for CC-IUI, 15% for GT-IUI, and 36% for IVF (see Table 1) (29 34). Unfortunately, the literature has been unclear regarding the degree to which surgical correction of endometriosis before fertility treatment improves fecundity, particularly for cases of moderate or severe endometriosis (35 37). Studies have suggested that after surgical correction of minimal to mild endometriosis the pregnancy rate with fertility treatment improves and is comparable to the rate observed in women treated for unexplained infertility (13, 29, 30, 32). For the purposes of our model, we assumed that surgical correction of endometriosis of any stage is beneficial, but to address the uncertainty in our estimate we used a wide range of values in our sensitivity analyses (see Table 1). Consequently, in the cohort with endometriosis who did not undergo surgical correction of their disease, we assumed Fertility and Sterility â 473

4 TABLE 1 Base-case assumptions and ranges used for sensitivity analysis. Base case Range Source Probability assumptions [%] [%] Endometriosis prevalence Stages I/II (4, 13, 26, 27) Stages III/IV (4, 13, 26, 27) Per cycle pregnancy rate No treatment 3 (29) Clomiphene citrate IUI 7 (30, 33, 68) Gonadotropins IUI 15 (32, 68) In vitro fertilization 36 (34) Miscarriage rate 20 (41) Per cycle dropout rate (44, 45) Endometriosis-related reduction in fecundity Stages I/II (13) Stages III/IV (38 40) Multiple gestation rate No treatment Singleton 98.6 (43) Twins 1.3 (43) High-order multiples 0.01 (43) SITA Singleton 75 (22, 42) Twins 20 (22, 42) High-order multiples 5 (22, 42) In vitro fertilization Singleton 65 (34) Twins 31 (34) High-order multiples 4 (34) Utility of birth outcome [Weight] [Weight] Singleton 1 (50) Twin (50) High-order multiples (50) No birth 0 (50) Cost assumptions [$US] [$US] Singleton birth 14, ,000 (47) a Twin birth 56,400 30,000 80,000 (47) a High-order multiple birth 163,200 75, ,000 (47) a Laparoscopy 10, ,000 ST-REI Clomiphene citrate IUI ST-REI Gonadotropins IUI ST-REI In vitro fertilization 11, ,200 ST-REI Abbreviations: IUI, intrauterine insemination; SITA, standard infertility treatment algorithm; ST-REI, Stanford Center for Reproductive Endocrinology and Infertility. a Adjusted using U.S consumer price index (46). that fecundity was lower compared with women without endometriosis: a 40% reduction (range: 0 to 60%) for those with untreated mild endometriosis (13), and a 55% reduction (range: 25% to 75%) for those with untreated severe disease (38 40), and the rate of spontaneous abortion was estimated at 20% per pregnancy (41). The expected rate of multiple gestation pregnancy for each treatment strategy was abstracted from the literature and is summarized in Table 1 (22, 34, 42, 43). Our model considered various treatment protocols pursued for 12 months. Although the duration of infertility may affect 474 Moayeri et al. Cost effectiveness of laparoscopy for infertility Vol. 92, No. 2, August 2009

5 fecundability, we assumed that fecundity is constant throughout this short time period. Thus, our model assumed that women who conceive near the end of the study period are as likely to succeed as women who became pregnant earlier in the year. Finally, patients undergoing infertility treatments demonstrate a high rate of dropout for emotional, financial, and psychological reasons. In the base-case model, 10% of women drop out per treatment cycle (range: 5% to 15%) (44, 45). Costs Treatment costs were extrapolated from the literature or estimated from our institutional data. All monetary units were converted into the equivalent of 2006 U.S. dollars using the Consumer Price Index (46). Because nationally representative data are unavailable, the costs of laparoscopy and infertility treatments were derived from our institution. Using reimbursement data from accounts received at our facility during the prior billing period, we estimated the average cost of laparoscopy to be $10,000 (minimum of $4,000 to maximum of $27,000). This estimate included costs related to surgeon, anesthesiologist, medications, facility fees, laboratory, pathology, and complications. Overall, 95% of cases cost between $5000 and $15,000. Given the wide variability for the cost of laparoscopy, estimates were varied from $5000 to $20,000 in sensitivity analyses (see Table 1). For estimating infertility treatment cycle costs, we calculated the bundled charges based on typical services, procedures, and medications used for each treatment protocol (i.e., CC-IUI, GT-IUI, or IVF). This charge was adjusted by determining the portion of patients with insurance coverage and reimbursement rates within our practice. Specifically, nearly 45% of our patients had infertility treatment insurance coverage, and average reimbursements (including patient copayments) were approximately 60% of billed charges. The estimated per cycle cost for CC-IUI, GT-IUI, and IVF was: $800, $3,200, and $11,000, respectively. Because infertility costs can vary appreciably, these estimates were adjusted by 20% in sensitivity analyses. Calculation results are summarized in Table 1. Costs related to treatment outcomes were available and derived from the literature. Costs associated with birth were adjusted for the multiplicity of the pregnancy. Our estimates incorporated hospital charges from antepartum services, delivery, and neonatal care up to hospital discharge of both mother and child. In a previous study, singletons had costs of $9845, twins $37,947, and high-order multiples $109,765 (47). We updated this estimate using the consumer pricing index and we varied it in the sensitivity analyses as outlined in Table 1 (46). Outcomes The cumulative rates for live birth, dropout, and continued infertility were determined for each strategy, as was the estimated cost and health effect. Using these values, we computed the incremental cost-effectiveness ratio (ICER). The ICER is calculated by dividing the difference in costs between two strategies by the difference in health outcomes between two strategies; the comparisons are made relative to the next best strategy, not to a single comparator strategy. The main outcome is cost per live birth. Our model assigned a different value per birth for singletons and for multiple births. Multiple gestation pregnancies, which are more common with infertility treatments, are associated with significant medical and social costs (48, 49). Consequently, we assumed that multiple gestation births resulted in lower benefits than a singleton birth, which we considered as the ideal outcome (50). Using a preference weight ( utility ), we adjusted the effectiveness of treatment by the multiplicity of the pregnancy. The best outcome, a singleton pregnancy, was valued at one. The worst outcome, no pregnancy, was valued at zero. Preference weights were 0.8 (range: ) for twin pregnancies and 0.6 (range: ) for high-order multiple gestations. Because there are no established utilities for these outcomes, we varied the utility values in sensitivity analyses (50). RESULTS Base Case Table 2 summarizes the number of patients within each Markov health state at the end of the study period. Compared with the no-treatment baseline, strategy 3 (LSC/EM, laparoscopy followed by expectant management in patients with surgically corrected endometriosis, and SITA in patients with truly unexplained infertility) had the lowest incremental cost-effectiveness ratio (ICER) at $128,399 per live birth (Table 3, Fig. 2). Strategy 2, SITA, had intermediate costs ($27,000) and effectiveness (0.416), but produced the highest ICER ($145,742) compared with LSC/EM. The fourth strategy, laparoscopy followed by tailored infertility treatment (LSC/IT), was the most effective (0.494) and costly ($38,000), resulting in a lower ICER than SITA ($141,512 per live birth compared with LSC/EM). Accordingly, SITA was eliminated through extended dominance because a more expensive intervention had a lower cost-effectiveness ratio (LSC/IT) than the lower cost option (SITA) (24). Note that the cumulative effect may not reflect the number of live births because not all pregnancies were treated equally. Specifically, as described previously, multiple gestation pregnancies were considered a suboptimal outcome and were valued lower than singleton pregnancies. Sensitivity Analyses Sensitivity analyses revealed that patient dropout from infertility treatments had the greatest impact on the outcome. Changes in the following variables also altered the outcome, but to a lesser extent: cost of laparoscopy, preference weight ( utility ) for twins, and effects of endometriosis on fecundity (Table 4). The LSC/EM strategy was eliminated by Fertility and Sterility â 475

6 TABLE 2 Base-case outcomes. No endometriosis Stages I/II endometriosis Stages III/IV Endometriosis Strategy 1, No treatment Live births (N) Singleton (N) Twins (N) HOM (N) Infertile (N) Strategy 2, SITA Live births (N) Singleton (N) Twins (N) HOM (N) Infertile (N) Dropout (N) Strategy 3, LSC/EM [SITA] [EM] [EM] Live births (N) Singleton (N) Twins (N) HOM (N) Infertile (N) Dropout (N) 447 N/A N/A Strategy 4, LSC/IT [SITA] [SITA] [IVF] Live births (N) Singleton (N) Twins (N) HOM (N) Infertile (N) Dropout (N) Abbreviations: EM, expectant management; IT, infertility treatment; LB, live birth; LSC, laparoscopy; SITA, standard infertility treatment algorithm. either strict or extended dominance (24). (Strict dominance means that a more costly strategy is less effective. Extended dominance means that a more expensive intervention has a lower cost-effectiveness ratio than a lower cost option.) The preferred strategy became SITA when the dropout rate per fertility treatment cycle was less than 9% (ICER ¼ $123,980 per live birth); twins were valued nearly equal to a singleton pregnancy (ICER ¼ $125,000 per live birth); laparoscopy costs exceeded $10,700 (ICER ¼ $131,300 per live birth); or endometriosis reduced fecundity by less than 35% ($128,200 per live birth). In no case was the fourth strategy (LSC/IT), which included laparoscopy followed by tailored infertility treatment, selected. The following factors had a relatively small impact on the model: risk of multiple gestation pregnancies, preference for high-order multiples, cost of multiple gestation births, cost of infertility treatments, and prevalence of endometriosis. DISCUSSION Using base-case estimates, we demonstrated that laparoscopy followed by expectant management after surgical correction of endometriosis (LSC/EM, strategy 3) was cost effective. For our base case, we assumed that fertility treatments resulted in dropout rates of at least 10% per cycle, laparoscopy cost $10,000, a twin birth was less favorable than a singleton, and endometriosis reduced fecundity by more than 40%. Using sensitivity analyses, we found that dropout rate from fertility treatments had the largest impact on the ICER; therefore, it was the most important factor for determining when laparoscopy was the optimum choice specifically, when dropout from fertility treatments exceeded 9%. Other factors that mattered to a lesser extent included the cost of laparoscopy, acceptability of twins, and the estimated reduction in fecundity from untreated endometriosis. Our conclusions were insensitive to variations in the risk of multiple gestation 476 Moayeri et al. Cost effectiveness of laparoscopy for infertility Vol. 92, No. 2, August 2009

7 TABLE 3 Summary of base-case scenario: base-case cost, effectiveness, and incremental cost-effectiveness ratio. Strategy Cost ($US) Effect (LB) ICER ($/LB) No treatment Baseline LSC/EM 23, ,399 a SITA 27, Eliminated b LSC/IT 38, ,512 c Note: See Figure 2 for graph. Estimates adjusted for prevalence of endometriosis and multiple gestations. Abbreviations: EM, expectant management; ICER, incremental cost-effectiveness ratio; IT, infertility treatment; LB, live birth; LSC, laparoscopy; SITA, standard infertility treatment algorithm. a LSC/EM ICER calculated relative to no treatment baseline. b Eliminated by extended dominance. c Compared with LSC/EM after eliminating SITA. pregnancies, cost of fertility treatments, cost of multiple gestation births, prevalence of endometriosis, and the preference weight for triplets. A European study similarly found that surgery was cost effective compared with IVF for patients with early stage endometriosis, but that IVF was preferred in cases of severe disease (51). However, this study had two important differences from ours. First, the study used costs derived from the United Kingdom, which has a national health-care system and thus limits U.S. comparisons. Second, for women with mild endometriosis, laparoscopy was the surgical intervention, but for severe endometriosis patients received laparotomy, which is more costly than laparoscopy. Fertility services are elective, and insurance coverage varies. Therefore, non-medical factors such as treatment costs, physician specialization, and financial incentives are likely to guide treatment decisions, but these are difficult to characterize in an analytical framework (25, 52 54). Patient preference for treatments and alternatives (i.e., spontaneous versus assisted conception, adoption, and child-free living) and time-to-conceive, which were left out of the model, may influence treatment decisions and outcomes because longer durations of infertility may alter quality of life and family-size goals. For example, endometriosis frequently recurs, and there is some clinical evidence to support proceeding immediately to infertility treatment after surgery (55). According to our model, this type of strategy (LSC/IT) leads to a higher ICER ($141,500 per live birth), but it is an appropriate choice if the patient is willing to pay at least this amount for a successful pregnancy. FIGURE 2 Base-case scenario: Summary Base-case scenario: base-case cost, effectiveness, and incremental cost-effectiveness ratio. See Table 3. (EM, expectant management; ICER, incremental cost-effectiveness ratio; IT, infertility treatment; LB, live birth; LSC, laparoscopy; SITA, standard infertility treatment algorithm.) 0.50 LSC/IT 0.45 ICER= $139,900/LB SITA Effectiveness, LB ICER = $128,400/LB ICER= $145,700/LB LSC/EM ICER = $141,500/LB* *SITA eliminated because LSC/IT had a lower costeffectiveness ratio than SITA No Treatment ,000 10,000 15,000 20,000 25,000 30,000 35,000 40,000 Cost, $ Fertility and Sterility â 477

8 TABLE 4 Sensitivity analyses: summary of variables whereby changes in base case estimates led to SITA as the preferred treatment strategy. Variable Base-case values Critical point in base-case assumptions where SITA dominates LSC/EM ICER where SITA becomes the preferred strategy ($/LB) Infertility dropout per cycle 10% <9% 123,980 Cost of laparoscopy $10,000 >$10, ,293 Preference weight, twins 0.8 > ,006 Reduced fecundity from endometriosis 40% 55% <35% 128,242 Abbreviations: HOM, high-order multiple gestation; ICER, incremental cost effectiveness ratio; LB, live birth; LSC/EM, laparoscopy/expectant management; SITA, standard infertility treatment algorithm. A limitation of many cost analyses that examine infertility treatments is the use of an arbitrary outcome measure (i.e., cost per live birth) (49). There is no appropriate, consistently used measure, such as quality adjusted life years (QALY), for valuing and comparing infertility treatments. Furthermore, many studies that use cost per live birth report the average cost-effectiveness ratio rather than the incremental costeffectiveness ratio (3). This is misleading when comparing multiple alternatives (23). Some investigators have examined a couple s willingnessto-pay (WTP) for a live birth (56, 57). These studies found that infertile couples WTP for treatment typically exceeds the treatment s costs. One U.S. study found that couples would pay $20,000 (converted to 2006 dollars) for a 10% chance of having a baby, which the investigators extrapolated to a WTP of $200,000 for a 100% chance of a successful pregnancy (46, 56). Cost-benefit analyses that use WTP for pregnancy in this way are uncommon; most studies report average cost per live birth or an equivalent (25, 58, 59). This permits comparison of infertility treatments that result in pregnancy, but it does not allow comparison of medical interventions in different clinical situations. Several factors are worth considering when interpreting the findings of our study. First, the impact of endometriosis on fecundity and the effect of fertility treatments on women with endometriosis (surgically treated or not) are not completely understood. Although it is generally accepted that endometriosis impairs fertility, the role of laparoscopy in the routine management of couples with unexplained infertility remains controversial. One of two randomized studies (criticized for being statistically underpowered) failed to find a statistically significant improvement in fecundity after surgically treating endometriosis (14). Alternatively, a larger randomized trial and a subsequent meta-analysis found a statistically significant improvement in fecundity (approximately 1.6 times) after surgical correction of early stage endometriosis compared with no treatment (12, 13). There are no comparable randomized trials for patients with stage III/IV endometriosis. Several reports with conflicting results have attempted to address the beneficial role of surgery to treat severe endometriosis before IVF (35 37). A meta-analysis suggested that advanced endometriosis is likely to impair fecundity even in patients who use advanced reproductive technologies, but the role of surgery was not specifically addressed (39). Recognizing that limited data are available to sufficiently answer this question, we used sensitivity analyses to vary widely the assumed effects of advanced endometriosis on fecundity. We concluded that LSC/ EM is cost effective if untreated endometriosis reduces fecundity by at least 35%, which is less than the estimated effects reported in the literature for either early or late stage endometriosis. Second, only medical costs were included. Indirect costs (such as lost time from work) may be sizable in absolute terms, but a prior study concluded that such costs were negligible in the context of high direct costs of fertility treatments (60). Third, our study accounted for expenditures up to and including the neonatal period. It did not take into account the costs of handicaps due to preterm deliveries that are more common after multiple birth pregnancies. These expenses result in several-fold increased costs (61, 62). However, our conclusion remained unchanged even when we assumed that high-order multiple gestation pregnancies cost up to $300,000, which is consistent with other estimates (18, 63). Moreover, because we limited analysis to the neonatal period, the potential benefits to parent and society from each healthy child that is born the most common outcome was not explicitly modeled. The reduction in value that we assigned to pregnancies resulting in either a twin or high-order multiple is not as severe as some investigators suggest it should be (50, 64). Medically, a singleton pregnancy is ideal, but studies indicate that many couples place an equal or even higher value on a twin pregnancy (65, 66). Additionally, most twin births 478 Moayeri et al. Cost effectiveness of laparoscopy for infertility Vol. 92, No. 2, August 2009

9 result in healthy babies, thereby potentially improving the cost effectiveness of each infertility cycle in which a pregnancy occurs (63, 67). Laparoscopy followed by expectant management is cost effective in the management of young couples with otherwise unexplained infertility, particularly when dropout from fertility treatments is likely to exceed 9% per cycle consistent with rates reported in the literature (44). However,aswehavediscussed, proceeding with a standard infertility treatment algorithm is justified under certain clinical circumstances. The following factors do not statistically significantly affect the cost effectiveness of laparoscopy: cost of fertility treatments, risks and costs of multiple gestation pregnancies, prevalence of endometriosis, and preference weight for high-order multiples. Laparoscopy is a cost-effective component of infertility management in appropriate situations, particularly when patients are likely to discontinue fertility treatments. 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