One of the main adverse effects of assisted reproduction

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1 GYNAECOLOGY A Comparison of the Cost-Effectiveness of In Vitro Fertilization Strategies and Stimulated Intrauterine Insemination in a Canadian Health Economic Model Taimur Bhatti, MSc, 1 Akerke Baibergenova, MD, PhD, MPH 2 1 Programs for Assessment of Technology in Health (PATH), McMaster University and St. Joseph s Hospital, Hamilton ON 2 University of Toronto, Toronto ON Abstract Background: In vitro fertilization (IVF) with single embryo transfer (SET) has been proposed as a means of reducing multiple pregnancies associated with infertility treatment. All existing cost-effectiveness studies of IVF-SET have compared it with IVF with multiple embryo transfer but not with intrauterine insemination with gonadotropin stimulation (siui). Methods: We conducted a systematic review of studies of cost-effectiveness of IVF-SET versus IVF with double embryo transfer (DET). Further, we developed a health economic model that compared three strategies: (1) IVF-SET, (2) IVF-DET, and (3) siui. The decision analysis considered three cycles for each treatment option. IVF treatment was assumed to be a combination of cycles with transfer of fresh and frozen-thawed embryos. Probabilities used to populate the model were taken from published randomized clinical trials and observational studies. Cost estimates were based on average costs of associated procedures in Canada. Results: The results of published studies on the cost-effectiveness of IVF-SET versus IVF-DET were not consistent. In our analysis, IVF-DET proved to be the most cost-effective strategy at $35 144/live birth, followed by siui at $66 960/live birth, and IVF-SET at $ /live birth. The results were insensitive both to the cost of IVF cycles and to the probability of live birth. Conclusion: This economic analysis showed that IVF-DET was the most cost-effective strategy of the options, and IVF-SET was the least cost-effective. The results in this model were insensitive to various probability inputs and to the costs associated with siui and IVF procedures. Résumé Contexte : La fécondation in vitro (FIV) s accompagnant du transfert d un seul embryon (TSE) a été proposée comme moyen de diminuer le nombre de grossesses multiples associées à la prise en charge de l infertilité. Toutes les études de rentabilité existantes portant sur la FIV-TSE l ont comparé à la FIV s accompagnant du transfert de multiples embryons, mais non à l insémination intra-utérine s accompagnant d une stimulation aux gonadotrophines (IIUs). Méthodes : Nous avons mené une analyse systématique des études de rentabilité comparant la FIV-TSE à la FIV s accompagnant du transfert de deux embryons (TDE). Qui plus est, nous avons développé un modèle d économie sanitaire comparant trois stratégies : (1) FIV-TSE, (2) FIV-TDE et (3) IIUs. L analyse décisionnelle a pris en considération trois cycles pour chacune des options de traitement. Il a été présumé que le traitement de FIV était une combinaison de cycles de transfert d embryons frais et d embryons congelés-décongelés. Les probabilités utilisées pour peupler le modèle ont été tirées d études observationnelles et d essais cliniques randomisés publiés. Les estimations des coûts ont été fondées sur les coûts moyens d interventions connexes au Canada. Résultats : Les résultats des études publiées comparant la rentabilité de la FIV-TSE à celle de la FIV-TDE n étaient pas uniformes. Dans le cadre de notre analyse, la FIV-TDE s est avérée la stratégie la plus rentable à $/naissance vivante, suivie de l IIUs à $/naissance vivante et de la FIV-TSE à $/naissance vivante. Les résultats étaient sensibles tant au coût des cycles de FIV qu à la probabilité d une naissance vivante. Conclusion : Cette analyse économique a indiqué que la FIV-TDE était l option la plus rentable et que la FIV-TSE était l option la moins rentable. Dans le cadre de ce modèle, les résultats n étaient pas sensibles à divers intrants de probabilité ni aux coûts associés aux interventions d IIUs et de FIV. J Obstet Gynaecol Can 2008;30(5): Key Words: In vitro fertilization, intrauterine insemination, multiple birth, cost-effectiveness, economic model Competing Interests: None declared. Received on March 15, 2007 Accepted on September 26, 2007 INTRODUCTION One of the main adverse effects of assisted reproduction is multifetal pregnancy, which is known to be associated with a wide range of maternal and neonatal complications. 1 3 IVF is the only infertility treatment that permits MAY JOGC MAI

2 quantification and control of the risk associated with multiple pregnancies. In IVF, this risk is defined by the number of embryos transferred in a given cycle. Advances in IVF techniques in the last decade have made it possible to transfer only a single embryo with an acceptable probability of pregnancy, a strategy known as an elective SET. This possibility has led to the promotion of IVF-SET as a solution to the problem of multiple pregnancies associated with assisted reproduction. 1 3 As a result, several European countries in which IVF treatment is subsidized by the government (Finland, Sweden, Belgium, and the Netherlands) have started promoting the policy of routine SET in IVF cycles. 1,4,5 In contrast, in North America, IVF is mainly accessible only in the private sector, without government subsidy. In the United States, the availability and extent of IVF insurance coverage varies across states. 6 In Canada, IVF treatment is partially funded in only two provinces (Ontario and Prince Edward Island), 7 and Quebec provides partial reimbursement through a tax credit. In the absence of comprehensive coverage, the majority of patients pay for an IVF procedure. Therefore, both patients and providers often prefer to transfer multiple embryos in IVF cycles in order to maximize the chance of success per cycle. Not surprisingly, the average rate of multiple pregnancies after IVF in North America is higher than that in Europe: in Europe the rate is about 24%, 8 but in Canada it is 30%, 9 and in the United States it is 34%. 10 Published economic studies have drawn inconsistent conclusions regarding the cost-effectiveness associated with IVF-SET and IVF-DET. A decision analysis by De Sutter et al. in 2002 did not demonstrate any substantial difference between IVF-SET and IVF-DET in cost per child born. 11 Two later prospective studies, 12,13 however, showed that although more IVF-SET cycles were needed to achieve birth rates similar to those achieved with IVF-DET, the avoidance of multiple pregnancies with use of IVF-SET (and the associated high costs of neonatal care) render it more cost-effective than IVF-DET. The Danish health technology assessment report was undertaken to assess the potential effect on the national health care system of DET HOM IVF NICU RCT SET siui ABBREVIATIONS double embryo transfer higher-order multiple in vitro fertilization neonatal intensive care unit randomized controlled trial single embryo transfer stimulated intrauterine insemination making IVF-SET a mandatory policy in Denmark. 14 The report demonstrated that promoting IVF-SET would lead to an increase in the number of IVF cycles and associated procedures (such as hormonal stimulation and embryo freezing and thawing), which in turn would necessitate the employment and education of additional staff. As a result, the public health system might incur an additional financial burden. 15,16 The lack of consistency in the findings of economic studies to date could be explained by differences in the types of costs considered and the perspective used (i.e., patient, care provider, payer, or other). The objective of this study was to evaluate the cost-effectiveness of IVF-SET in the Canadian context from the perspective of public payers. Unlike previous studies, this study compares the cost-effectiveness of IVF-SET not only with IVF-DET but also with intrauterine insemination with gonadotropin stimulation. The reason for inclusion of siui in our comparison is that it is the closest alternative reproductive technology to IVF and is more widely insured that IV F in Canada. METHODS A Markov decision model was developed, using TreeAge Pro 2006 software (TreeAge Software Inc., Williamstown, MA). The model considered three treatment options: (1) siui, (2) IVF-SET, and (3) IVF- DET. One of the assumptions made in the model was that all patients were women under the age of 36 years, with no previous siui or IVF treatment and a good fertility prognosis. Only short-term costs were considered (i.e., long-term costs of the complications associated with multiple births were excluded). In addition, the costs of drugs for ovarian stimulation as well as those used in conjunction with IVF treatment were included in the analysis. The total cost of drugs per cycle was estimated to range from $500 to $1500 for siui and from $2500 to $4500 for IVF. These cost estimates were obtained from expert consultations and from the websites of infertility clinics (the Appendix shows a list of these websites with estimated cost of drugs for siui and IVF patients). We used the mid-point of these ranges for our base case analysis, while the extremes were employed during sensitivity analyses. The perspective of the public payer was employed in this study. The decision nodes for intrauterine insemination are illustrated in Figure 1 and those of IVF-SET and IVF-DET are illustrated in Figure 2. Base Case Model For the base case model, IVF treatment was assumed to be a combination of fresh and cryopreserved embryo transfers with a maximum of three treatment cycles. The probabilities of pregnancy and live births used as inputs into the model for cryopreserved cycles were lower than those used 412 MAY JOGC MAI 2008

3 A Comparison of the Cost-Effectiveness of In Vitro Fertilization Strategies and Stimulated Intrauterine Insemination Figure 1. Decision Node Representing siui for fresh cycles. However, for the IUI procedure the transition probabilities remained the same throughout all three cycles. The base case probabilities (with associated ranges) employed by the decision model for each treatment option both for cycles associated with fresh and cryopreserved embryos are shown in Table 1. Base case costs (with associated ranges) that were used in the decision model are shown in Table 2. The measure of effectiveness was the number of live births, and the cost-effectiveness was estimated as cost per live birth. Stimulated IUI In the case of siui, the model was constructed with the understanding that a small proportion of women do not continue on to undergo a cycle of siui. This may occur for various reasons, such as unexpected spontaneous pregnancy, temporary disagreement between partners, or simply a change of mind. Of these patients, a small proportion will drop out of treatment entirely, while the remaining women subsequently re-attempt a cycle of siui. Of those who proceed, some are successful in achieving pregnancy, and others are not. Of those who are not successful, a small proportion will drop out, and the remainder will recycle for another attempt. Of those women who do become pregnant, a proportion will experience a miscarriage. This experience causes a small proportion to drop out while others continue to undergo another cycle of siui. The probability of success in achieving pregnancy, as well as a successful delivery after pregnancy, is the same regardless of the stage of treatment. A successful pregnancy results in a single or multiple birth. Each of these can be either a vaginal delivery or a Caesarean section. A small proportion of each type of delivery leads to infants being admitted for observation in the NICU. This was factored into the model. In Vitro Fertilization (IVF-SET and IVF-DET) The situation for both IVF-SET and IVF-DET is similar to siui with a few exceptions. First, the initial treatment cycle of IVF is performed using fresh embryos, while the subsequent treatment cycles are performed using cryopreserved embryos. Therefore, the probability of both a successful pregnancy and a successful birth depends on the cycle of IVF a patient is in. Second, the scenario for delivery of MAY JOGC MAI

4 Figure 2. Decision Node Representing IVF-SET and IVF-DET* *Decision node layout for IVF-DET is identical to IVF-SET. The associated probabilities are variable. IVF-SET and IVF-DET depends on whether or not an embryo can be cryopreserved. According to expert opinion, in approximately 25% of IVF treatment cycles it is not possible to cryopreserve any embryos for subsequent use (Robert Casper, personal communication). Therefore, in approximately 75% of either IVF-SET or IVF-DET cases, we assumed that a female was able to undergo a maximum of three cycles of IVF. Realistically, in the remaining 25% of cases, we assumed that 50% of females were able to undergo a maximum of two treatment cycles, and 50% were able to undergo only a maximum of one cycle of IVF. Third, in virtually all cases, a successful delivery results in either a singleton or twin birth. Therefore, the probability of a higher order multiple birth is assumed to be zero. In addition, the probability of a twin birth further drops to zero after the first cycle in the case of IVF-SET. In the case of IVF-DET, while this does not necessarily drop to zero in subsequent cycles, it is still lower than that of the first cycle. Sensitivity Analyses Appropriate scenario analyses were performed using high and low values of both probabilities and costs to model the base case, best case, and worst case situations. To model the situation as closely as possible on clinical practice, further sensitivity analysis was performed to account for those women who are unable to cryopreserve embryos and therefore are forced to abandon treatment before having completed three cycles. Since expert opinion suggested that cryopreservation was not possible in approximately 25% of situations, we used a 75% 25% split in our base case model for women who were able versus those who were not able to cryopreserve their embryos for all three cycles. We altered this to a 50% 50% split in our sensitivity analysis to observe any differences in results with a conservative assumption that approximately 50% of females were unable to cryopreserve embryos for cycles subsequent to the first. In addition, we conducted extensive one-way and two-way sensitivity analyses on costs. 414 MAY JOGC MAI 2008

5 A Comparison of the Cost-Effectiveness of In Vitro Fertilization Strategies and Stimulated Intrauterine Insemination Table 1. Decision Analysis Transition Probabilities IUI IVF-SET IVF-DET Attributes Fresh cycle probability (range) Fresh cycle probability (range) Cryopreserved cycle probability (range) Fresh cycle probability (range) Cryopreserved cycle probability (range) Cycle being cancelled before treatment Dropping out after cycle is 0.01* cancelled Pregnancy 0.15 ( ) 27,30, ( ) ( ) ( ) ( ) 4,34 Dropping out if achieving pregnancy is unsuccessful Delivery 0.11 ( ) 26,30, ( ) ( ) ( ) ( ) 4,34 Dropping out after loss of successful pregnancy 0.01* Singleton Birth ,27, ,34 Caesarean section after singleton birth Infant kept in NICU after singleton birth Twin Birth ,34 Caesarean section after twin birth Infant kept in NICU after twin birth , , , , ,40 Higher-order multiple birth ,37,41 Caesarean section after 1 higher-order multiple birth Infant kept in NICU after higher-order multiple birth 1 *Expert opinion. According to the literature, 42% (21) after 6 cycles (~7% per cycle); since it is lower in the first three cycles we assumed a value of 5%. The rates of CS and NICU admissions were assumed to be 100% in the case of higher-order multiple births. RESULTS The base case analysis demonstrated that IVF-DET was the most cost-effective strategy at $14 409/live birth, followed by siui at $66 960/live birth and IVF-SET at $ /live birth. Sensitivity Analyses In order to check for the robustness of our model, we conducted a scenario analysis and estimated cost-effectiveness for the best and worst case scenarios by varying the probabilities of pregnancy and delivery for each of the three interventions considered. The ranges of probabilities were estimated from the literature and are listed in Table 1. As shown in Table 3, IVF-DET remained the most cost- effective strategy (ranging from $26 429/live birth to $81 032/live birth) in each of the three scenarios created, followed by siui (ranging from $43 660/live birth to $90 260/live birth). IVF-SET remained the least cost-effective strategy in each of the three scenarios created, ranging from $50 330/live birth to $ /live birth. It was important to factor into the model that it might not always be possible to select quality embryos for cryopreservation after the first ovarian stimulation in all three cycles of IVF. For this reason, we conducted an additional analysis in which we assumed that in IVF-SET and IVF-DET only 50% of women who began IVF treatment were able to use cryopreserved embryos after the first cycle and complete a maximum of three cycles. This is in comparison with the base case, in which 75% of women were assumed to be able to cryopreserve embryos for use in subsequent cycles up to MAY JOGC MAI

6 Table 2. Costs associated with giving birth, infertility treatment procedures and infertility drugs Physician Costs* Type of birth Total cost ($) Vaginal delivery 396 Caesarean section 704 Multiple birth (each additional birth) 145 Hospital Costs 42 Vaginal delivery Type of birth Normal Birth Baby admitted to NICU Singleton Double Triplet Caesarean section Type of birth Normal birth Baby admitted to NICU Singleton Double Triplet Infertility Treatment Costs 42 Type of procedure Total Cost per cycle ($) IUI 1282 IVF 5000 IVF cycle (cryopreserved embryo) 1000 Annual storage fee (cryopreserved embryo) Infertility Drug Costs Type of procedure Total Cost per cycle ($) 225 IUI IVF IVF cycle (cryopreserved embryo) *These physician costs do not include the cost of antennal visits. Source: Ontario Physician Schedule of Benefits, Expert opinion a maximum of three cycles. In the sensitivity analysis, the model assumed that the remaining 50% had limited ability to employ cryopreserved embryos and were able to complete only one or two cycles of IVF. The results are shown in Table 3. The sensitivity analysis indicated that IVF-DET was the most cost-effective strategy in all three scenarios, despite conservative estimates of the proportion of women who were able to complete a maximum of three cycles of IVF-SET or IVF-DET (base case, best case, and worst case). Sensitivity analyses were also conducted with respect to costs. First, an analysis was conducted to determine the optimal average cost for three cycles of IVF (shown in Figure 3a). The analysis indicated that below a cost of $ per cycle (for each of the three cycles) IVF-DET remained the most cost-effective strategy. However, above the threshold of $ per cycle of IVF, siui dominated as the most cost-effective strategy. An analysis was then conducted on the cost of a fresh cycle of IVF, assuming that costs of any subsequent cryopreserved cycles remained constant at $4500 (the average cost of an IVF cycle, including drugs, using cryopreserved embryos). As illustrated in Figure 3b, IVF-DET remained the most cost-effective strategy when the cost of a fresh cycle of IVF was varied from $3000 to $ Similarly, the cost of the fresh cycle 416 MAY JOGC MAI 2008

7 A Comparison of the Cost-Effectiveness of In Vitro Fertilization Strategies and Stimulated Intrauterine Insemination Table 3. Results: Cost-effectiveness scenario analysis Base case ($/live birth) Best case ($/live birth) Worst case ($/live birth) IUI IVF-SET (assuming 75% 25% split between those who are able versus those who are not able to cryopreserve embryos for a maximum of 3 cycles of treatment) IVF-SET (assuming 50% 50% split between those who are able versus those who are not able to cryopreserve embryos for a maximum of 3 cycles of treatment) IVF-DET (assuming 75% 25% split between those who are able versus those who are not able to cryopreserve embryos for a maximum of 3 cycles of treatment) IVF-DET (assuming 50% 50% split between those who are able versus those who are not able to cryopreserve embryos for a maximum of 3 cycles of treatment) was then assumed to be constant at $8725 (cost of IVF cycle, including drugs, using fresh embryos) while a sensitivity analysis was conducted on the cost of subsequent cryopreserved cycles of IVF. As illustrated in Figure 3c, this analysis revealed that IVF-DET remained the most cost-effective strategy across a varying range of costs from $3000 to $8000. DISCUSSION This health economic model demonstrated that IVF with double embryo transfer is the most cost-effective strategy for assisted reproduction and that IVF with single embryo transfer is the least cost-effective strategy. These findings are similar to those reported by a recently published Danish health technology assessment report. 14 The most apparent explanation for IVF-DET being a more cost-effective strategy than IVF-SET appears to be the higher pregnancy rate and live birth rate associated with IVF-DET, because procedure costs are similar. The costs of long-term complications associated with multiple births were not included in the analysis. The inclusion of long-term costs has the potential to affect the results because IVF-DET is associated with a higher rate of twin deliveries than IVF-SET. However, because of the unavailability of such long-term data at the time of analysis, this will have to be a consideration for future research. On the other hand, despite siui having relatively low costs compared to IVF-DET, it was not as cost-effective because of the significantly lower chances of both pregnancy and live birth than IVF-DET. However, when compared with IVF-SET, siui appeared to be more cost-effective because of the higher costs associated with IVF-SET. The main advantage of an IVF-SET procedure is the avoidance of multiple pregnancies, which often occur as a result of siui procedures. This advantage is not easily captured because of the lack of long-term data to quantify these benefits. On the national level, the significance of a SET-mediated reduction in post-ivf multiple births is determined by the proportion of SETs carried out in all IVF cycles. It has been shown that this proportion is influenced by IVF funding policies. 6,22,23 However, as demonstrated by the European experience, although public funding of IVF noticeably reduces post-ivf multiple pregnancies, it does not solve the problem completely. Interestingly, according to the European registry of assisted reproduction, the average rate of multiple pregnancies after IVF is still higher than that after siui at 24% and 12%, respectively. 8 This is largely due to the fact that even when IVF is paid for, SET is not a suitable option for all infertile couples. For example, in Finland, the country with the longest experience with IVF-SET and the lowest rate of IVF-associated multiple pregnancies (15.4%), SET was performed only in 38.7% of all IVF cycles in By comparison, in Canada the proportion of SET performed for all IVF cycles in 2003 was 10%. 17 In practice, some limiting factors often associated with IVF-SET procedures might be responsible for their limited uptake in certain countries. The two major factors are advancing female age and a previous history of infertility treatment. Most of the RCTs designed to estimate the cost-effectiveness of IVF-SET were conducted among women under 36 years of age. 24 Only two recent studies showed promising results in using IVF-SET in older women. 25,26 Although one of these studies suggested that embryo morphology rather than the woman s age determines the chance of pregnancy, 26 it is generally accepted that embryo quality is strongly related to a woman s age. 27 Although IVF-DET is associated with higher rates of twin births than IVF-SET despite costs that are similar, it is MAY JOGC MAI

8 Figure 3a. Cost-effectiveness versus per cycle cost of IVF (same for each cycle) $300,000 Average Cost-Effectiveness ($/live birth) $250,000 $200,000 $150,000 $100,000 $50,000 $- $3,000 $4,000 $5,000 $6,000 $7,000 $8,000 $9,000 $10,000 $11,000 $12,000 $13,000 $14,000 $15,000 siui IVF-SET IVF-DET Average cost of a cycle of IVF ($ CND) Figure 3b. Cost-effectiveness versus cost of first cycle of IVF $140,000 Average Cost-Effectiveness ($/live birth) $120,000 $100,000 $80,000 $60,000 $40,000 $20,000 $- $3,000 $3,750 $4,500 $5,250 $6,000 $6,750 $7,500 $8,250 $9,000 $9,750 $10,500 $11,250 $12,000 siui IVF-SET IVF-DET Cost of a fresh cycle of IVF ($ CND) important to have this as a comparator because of patient preferences. A significant proportion of infertile couples do not object to the possibility of having a multiple birth despite the associated risks 26 ; in fact, they consider twins as being an ideal outcome of infertility treatment. 28 A recent Canadian study, based on a survey of 801 female and male infertility patients attending a tertiary level fertility clinic in Montreal showed that 41% of patients desired a multiple (twin) birth. 29 The desire for multiple births is positively associated with certain patient characteristics such as older age of the female partner, 30 longer duration of infertility, 29,30 nulliparity, 28 and a history of infertility treatment. 29 An interesting finding in the present study was that siui, in terms of cost-effectiveness, has an intermediate position between IVF-DET and IVF-SET. In spite of having lower success rates, siui still remains the first line of treatment for infertility in many countries (excluding cases of bilateral tubal obstruction and severe male infertility). 18,19 The major advantages of siui over IVF are its relative simplicity, lower invasiveness, and lower costs. On the other hand, the chief disadvantage of siui is its inability to control for the risk of multiple pregnancies. In reality, however, the relative contribution of siui to the number of multiple births resulting from infertility treatment might be lower than that of IVF, 418 MAY JOGC MAI 2008

9 A Comparison of the Cost-Effectiveness of In Vitro Fertilization Strategies and Stimulated Intrauterine Insemination Figure 3c: Cost-effectiveness versus cost of second and third cycles of IVF $160,000 Average Cost-Effectiveness ($/live birth) $140,000 $120,000 $100,000 $80,000 $60,000 $40,000 $20,000 $- $3,000 $4,000 $5,000 $6,000 $7,000 $8,000 Cost of a cryopreserved cycle of IVF ($ CND) siui IVF-SET IVF-DET because of the higher success rates of IVF. 3 According to some North American data, even after limiting comparison only to successful cycles, the rate of multiple births after siui ranges from 21% 20 to 29% 21 and is approximately 30% to 34% after IVF. 9,10 Although the majority of multiple births after siui are twins, the chief concern associated with siui is the higher rate of high order multiple births (i.e., those resulting in delivery of more than twins) than that associated with IVF. 8 The economic model presented in this analysis has some limitations. First, only short-term costs of multiple pregnancies were considered. The analysis did not include the costs of miscarriages, maternal morbidity, or costs associated with complications such as cerebral palsy and other developmental complications in the newborn. These costs were not included because they are difficult to define and quantify without making numerous assumptions. Second, societal costs such as loss of productivity, absence from work, and reduced quality of life for the mother were not considered. Third, the probabilities used in our model were largely derived from European RCTs, which might show higher success rates of IVF-SET arising from the longer experience with SET in Europe. However, lower success rates of IVF-SET would have further decreased the cost-effectiveness of SET, confirming that IVF-SET was indeed the least cost-effective strategy for assisted reproduction for the patient population considered in this analysis. CONCLUSION Within the limitations of this model, the results of this study show that IVF-DET is the most cost-effective strategy for assisted reproduction and that IVF-SET is the least cost-effective. The results were insensitive to the success rates. The sensitivity analyses indicated that IVF-DET remained the most-cost effective strategy despite varying the probabilities associated with successful pregnancies and deliveries. In addition, the cost-effectiveness of IVF-DET was also insensitive to the costs of IVF involving transfer of fresh and cryopreserved embryos. The main limitation of the model was the inability to include the long-term costs associated with children born as a result of a multiple pregnancy. REFERENCES 1. Ombelet W, De Sutter P, Van der EJ, Martens G. Multiple gestation and infertility treatment: registration, reflection and reaction the Belgian project. Hum Reprod Update 2005;11: Fauser BC, Devroey P, Macklon NS. Multiple birth resulting from ovarian stimulation for subfertility treatment. Lancet 2005;365(9473): Multiple gestation pregnancy. The ESHRE Capri Workshop Group. Hum Reprod 2000;15: Hyden-Granskog C, Tiitinen A. Single embryo transfer in clinical practice. Hum Fertil (Camb) 2004;7: Bergh C. Single embryo transfer: a mini-review. Hum Reprod 2005;20: Jain T, Harlow BL, Hornstein MD. Insurance coverage and outcomes of in vitro fertilization. N Engl J Med 2002;347: Corabian P. In vitro fertilization and embryo transfer as a treatment for infertility Technology Assessment Report. Alberta Heritage Foundation for Medical Research Andersen AN, Gianaroli L, Felberbaum R, de Mouzon J, Nygren KG. Assisted reproductive technology in Europe, Results generated from European registers by ESHRE. Hum Reprod 2006;21: Canadian Fertility and Andrology Society. Human assisted reproduction live birth rates for Canada. CFAS press release [web page]. November 17, [cited August 11, 2006]. Available at: news/nov asp. Accessed March 10, Centers for Disease Control and Prevention. Assisted reproductive technology [web page] [cited October 6, 2006]. Available at: Accessed March 10, MAY JOGC MAI

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The costs [cited November 14, 2006]. Available at: H E.pdf. Accessed March 10, APPENDIX Clinic websites with estimates of drug prices for siui and IVF patients IVF Victoria Fertility Centre. Victoria BC. Fee schedule on website: Genesis Fertility Centre. Vancouver BC. Fee schedule on website: fees/ index.htm. London Health Sciences Centre Reproductive Endocrinology and Infertility Program. London ON. Fee schedule on website: costmed.asp Ottawa Fertility Centre. Ottawa ON. Fee schedule on website: patientcentre_ fees.htm. siui London Health Sciences Centre Reproductive Endocrinology and Infertility Program. London ON. Fee schedule on website: fertility.ca/ costmed.asp 420 MAY JOGC MAI 2008