Vasovasostomy

The first-line method for surgical reconstruction of obstructive azoospermia secondary to vasectomy consists of vasovasostomy, in which the obstructed length of vas deferens is excised and the cut ends are reanastomosed . Microsurgical reconstruction seems to be superior to macrosurgical reconstruction and currently represents the standard of care. Variations of the microsurgical technique exist, including multilayer vasovasostomy versus a modified single-layer adaptation.

Vasoepididymostomy

Some patients with obstructive azoospermia require a vasoepididymostomy instead of a vasovasostomy if their epididymis is found to be obstructed. Vasoepididymostomy consists of anastomosing a patent epididymal tubule directly to the vas deferens, thus bypassing any obstruction in the epididymis distal to the tubule. Multiple techniques have been described, although three variations are currently used: direct end-to-end, direct end-to-side, and end-to-side intussusception . Epididymal obstruction and the need for vasoepididymostomy seem to be related to the duration of deferential obstruction . Fuchs and Burt , for example, reported that 62% of patients who had undergone vasectomy at least 15 years before reversal required vasoepididymostomy. Significantly lower patency and pregnancy rates have been reported after vasoepididymostomy compared with vasovasosotomy .

Microsurgical epididymal sperm aspiration

Microsurgical epididymal sperm aspiration (MESA) was introduced in the 1980s by Temple-Smith and colleagues and Silber and colleagues originally to enable sperm retrieval in the setting of congenital bilateral absence of the vas deferens. It consists of microsurgically exposing the epididymis, incising the epididymal tunic, and then aspirating sperm-filled epididymal fluid. MESA enables the collection of large quantities of motile sperm for cryopreservation.

Percutaneous epididymal sperm aspiration

Percutaneous epididymal sperm aspiration (PESA) was introduced in 1994 by Craft and Shrivastav as a simpler, less invasive alternative to MESA for patients with obstructive azoospermia who were unable to undergo or who decided against surgical reconstruction. A needle is introduced through the skin into the epididymis and is then aspirated. Three pregnancies (43%) were obtained in seven couples, and one set of twins was delivered in the original description . Criticisms of this technique include frequently unreliable sperm retrieval . Our data analysis focuses on the more reliable microsurgical approach.

Some surgeons prefer MESA or PESA as the source of sperm in obstructive azoospermia, because epididymal sperm tend to be more mature and are obtainable in higher, bankable numbers relative to that obtained from the testis . In 1998, Sheynkin and colleagues , compared percutaneous and microsurgical sperm retrieval in men with obstructive azoospermia. Nine men underwent simultaneous MESA, testicular fine needle aspiration, and PercBiopsy. As expected, the mean number of sperm retrieved via MESA (15 × 10 ⁶ ) was higher than that retrieved percutaneously (testicular fine needle aspiration = 0.014 × 10 ⁶ and PercBiopsy = 0.116 × 10 ⁶ ). Overall, testicular sperm aspiration pregnancy rates have been reported to be as high as 31%, with a calculated live delivery rate of 27% if one assumes a miscarriage rate of 11.6% rate after ICSI . Similarly, PESA pregnancy rates have been reported to be as high as 43%, with a calculated live delivery rate of 38% if one makes a similar assumption regarding ICSI miscarriage rate .

Open testis biopsy

The original description of sperm retrieval for assisted reproduction by open testicular biopsy was proposed by Silber and colleagues in 1995. Multiple pieces of testicular tissue from the same incision are taken for use in IVF/ICSI.

Microsurgical testicular sperm extraction

Microsurgical testicular sperm extraction (TESE), as described by Schlegel and colleagues in 1999, uses the operating microscope to identify larger caliber, sperm-containing seminiferous tubules. Microsurgical TESE is traditionally used in the setting of nonobstructive azoospermia and offers the advantages of less bleeding and greater sperm extraction per gram of testicular tissue extracted. It plays little role in the setting of obstructive azoospermia.

Percutaneous testicular sperm extraction

Like PESA, percutaneous TESE offers a less costly and invasive alternative to its microsurgical counterpart. A needle is introduced percutaneously into the testis and is then aspirated; the tissue obtained is then processed for use in IVF. Percutaneous TESE also represents a less invasive choice compared with open testis biopsy, although less tissue is generally obtained with the percutaneous technique. Belker and colleagues described a 100% sperm retrieval rate when used in obstructed patients. Fine-needle mapping as described by Turek and colleagues is designed for use in nonobstructive azoospermia and plays little role in this particular analysis.

Microsurgical epididymal sperm aspiration

Microsurgical epididymal sperm aspiration (MESA) was introduced in the 1980s by Temple-Smith and colleagues and Silber and colleagues originally to enable sperm retrieval in the setting of congenital bilateral absence of the vas deferens. It consists of microsurgically exposing the epididymis, incising the epididymal tunic, and then aspirating sperm-filled epididymal fluid. MESA enables the collection of large quantities of motile sperm for cryopreservation.

Percutaneous epididymal sperm aspiration

Percutaneous epididymal sperm aspiration (PESA) was introduced in 1994 by Craft and Shrivastav as a simpler, less invasive alternative to MESA for patients with obstructive azoospermia who were unable to undergo or who decided against surgical reconstruction. A needle is introduced through the skin into the epididymis and is then aspirated. Three pregnancies (43%) were obtained in seven couples, and one set of twins was delivered in the original description . Criticisms of this technique include frequently unreliable sperm retrieval . Our data analysis focuses on the more reliable microsurgical approach.

Some surgeons prefer MESA or PESA as the source of sperm in obstructive azoospermia, because epididymal sperm tend to be more mature and are obtainable in higher, bankable numbers relative to that obtained from the testis . In 1998, Sheynkin and colleagues , compared percutaneous and microsurgical sperm retrieval in men with obstructive azoospermia. Nine men underwent simultaneous MESA, testicular fine needle aspiration, and PercBiopsy. As expected, the mean number of sperm retrieved via MESA (15 × 10 ⁶ ) was higher than that retrieved percutaneously (testicular fine needle aspiration = 0.014 × 10 ⁶ and PercBiopsy = 0.116 × 10 ⁶ ). Overall, testicular sperm aspiration pregnancy rates have been reported to be as high as 31%, with a calculated live delivery rate of 27% if one assumes a miscarriage rate of 11.6% rate after ICSI . Similarly, PESA pregnancy rates have been reported to be as high as 43%, with a calculated live delivery rate of 38% if one makes a similar assumption regarding ICSI miscarriage rate .

Open testis biopsy

The original description of sperm retrieval for assisted reproduction by open testicular biopsy was proposed by Silber and colleagues in 1995. Multiple pieces of testicular tissue from the same incision are taken for use in IVF/ICSI.

Microsurgical testicular sperm extraction

Microsurgical testicular sperm extraction (TESE), as described by Schlegel and colleagues in 1999, uses the operating microscope to identify larger caliber, sperm-containing seminiferous tubules. Microsurgical TESE is traditionally used in the setting of nonobstructive azoospermia and offers the advantages of less bleeding and greater sperm extraction per gram of testicular tissue extracted. It plays little role in the setting of obstructive azoospermia.

Percutaneous testicular sperm extraction

Like PESA, percutaneous TESE offers a less costly and invasive alternative to its microsurgical counterpart. A needle is introduced percutaneously into the testis and is then aspirated; the tissue obtained is then processed for use in IVF. Percutaneous TESE also represents a less invasive choice compared with open testis biopsy, although less tissue is generally obtained with the percutaneous technique. Belker and colleagues described a 100% sperm retrieval rate when used in obstructed patients. Fine-needle mapping as described by Turek and colleagues is designed for use in nonobstructive azoospermia and plays little role in this particular analysis.

Costs

Costs may be broken down into two main components: direct and indirect . Direct costs encompass expenditures for medical products or services, including office examination fees, surgeon fees for microsurgical reconstruction or sperm retrieval, associated anesthesia and operating room or facility fees, recovery room fees, the cost of diagnostic imaging tests, the cost of blood tests, the cost of gonadotropins if IVF/ICSI is used, and finally the cost of the IVF cycle, including all technical and professional fees if sperm retrieval is chosen. Indirect costs represent the economic impact that occurs from morbidity, mortality, or loss of livelihood secondary to a procedure. In this analysis, indirect costs would represent the economic impact of procedure-associated complications, lost productivity because of time away from work, and the impact from multiple gestation pregnancies that may ensue.

This analysis uses complication and multiple gestation rate data that have appeared in the peer-reviewed literature. Male infertility procedure-related complications include bleeding, infection, and testicular atrophy and occur at a rate of 0.3% to 2% . Maternal complications caused by IVF are estimated to occur in 3% to 6% of all cases and include ovarian hyperstimulation syndrome, pelvic hemorrhage, infection, stroke, myocardial infarction, and possibly ovarian cancer . The impact of multiple gestation pregnancies has been well studied. Such pregnancies are associated with higher rates of neonatal complications and longer intensive care unit stays compared with singleton infants . Much of the increase in costs associated with higher order gestations can be traced to greater neonatal lengths of stay in addition to greater direct use of medical resources.

It is important to note that the true cost of care is best represented by the amount resources consumed in providing that care. Because the true economic burden of providing services is usually difficult to measure, charges are instead used as a proxy . Charges are set by the marketplace and may not accurately reflect the true burden of providing care, although they do represent the best available metric for cost-effectiveness evaluations.

Effectiveness

Multiple definitions of success are possible when treating obstructive azoospermia. Patency, as signified by the return of sperm to the ejaculate, may be used as one measure of success with surgical reconstruction. Successful fertilization and pregnancy after reconstruction or sperm retrieval may constitute a separate metric. Finally, delivery of at least one or more live children after either treatment may represent yet another measure of success. It is the opinion of the authors that live delivery represents the most relevant and appropriate metric to consider: the outcome of most value to couples is the delivery of at least one live child. All other markers of success are of secondary value.

Analysis and evaluation methods

Economic analyses weave the dual components of cost and effectiveness into a rational framework for decision making. Because choices must be made between alternative uses of scarce or limited health care resources, economic analyses are able to consider cost and outcome to arrive at an optimal allocation decision . Different types of economic analyses include cost-identification analysis, cost-effectiveness analysis, and cost-benefit analysis .

Cost-identification analysis consists of ascertaining the economic resources involved in providing a product or service or that involved in disease burden. Cost-identification studies do not consider the benefits derived from the expenditure of economic resources. In contrast, cost-effectiveness analysis considers the cost of providing a service in addition to the benefit or outcome that arises from that service; the metric given in this type of analysis usually refers to cost per unit of outcome. This evaluation allows a comparison of the relative value of different treatment approaches. Cost-benefit analyses attempt to determine if a given outcome is worth its requisite cost to an individual. Clinical outcomes are translated into monetary terms via willingness-to-pay approaches and the outcomes compared with the benefits on a direct monetary basis.

Like most infertility-related peer-reviewed literature, this article focuses primarily on cost-effectiveness analysis as a method of identifying optimal treatment for obstructive azoospermia. First, the effectiveness and then more importantly the cost effectiveness of IVF treatments in general are examined because they constitute a major component of treatment by sperm retrieval. The analysis then focuses on examining male factor infertility treatments for obstructive azoospermia in similar fashion.

Effectiveness of in vitro fertilization for male factor infertility

The most complete set of data regarding the effectiveness of IVF for male factor infertility is found within the Society of Assisted Reproductive Technology (SART) database, published by the Centers for Disease Control and Prevention under the 1992 Fertility Clinic Success Rate and Certification Act . A summary of SART data from 1995, the first available year, to 2004, the latest available year, is shown in Table 1 . Although the number of total IVF cycles has risen from approximately 46,000 to 89,500 cycles over the intervening years, the percentage of cycles undertaken for male factor infertility alone has declined from a peak of 32% to the current level of 17%. Similarly, the percentage of total ICSI cases used for male infertility cases has declined from 57.8% in 2001 to 51.4% in 2004. The live delivery rate for male factor infertility IVF cases in contrast has improved from 21% to 33% over the same time period.

One should note that although the SART summary data offer an impression of the effectiveness of IVF-driven treatments for male factor infertility, they do not offer fine enough resolution to distinguish IVF treatments undertaken for obstructive versus nonobstructive azoospermia cases. SART data reflect a mixture of the two. Theoretically, however, IVF treatments undertaken solely for obstructive azoospermia should be even more effective than the outcomes reported by SART, as the nonobstructive azoospermia cases reported by SART would be expected to generally yield lower live delivery rates compared with their obstructive counterparts.

Cost effectiveness

Neumann and colleagues were the first to study the cost of a successful live delivery with an IVF pregnancy. Direct and indirect costs were considered in this analysis. The cost per live delivery ranged from $66,667 in 1992 dollars with one cycle of IVF to $114,286 by the sixth cycle in the study. A subgroup analysis that examined couples with advanced maternal age (ie, > 40 years) and male-factor subfertility (ie, sperm concentration < 20 million/mL or motility < 40%) was conducted. The cost per live delivery increased to $160,000 for the first cycle to $800,000 by the sixth cycle.

Since the study conducted by Neumann and colleagues, various other groups have examined the costs of IVF. Chambers and colleagues performed a population-based costing study of resources consumed during ART in Australia using a decision analytic model that drew upon data from the Australian and New Zealand Assisted Reproduction Database. Direct costs were queried from various fertility centers and rebates through the Medicare or Pharmaceutical Benefit Scheme. The cost per live delivery was calculated to be $32,903 in 2005 Australian dollars, although this cost increased to $182,794 for women older than 42 years. The most complete survey of IVF costs was perhaps undertaken in a review by Collins in 2002. The use of IVF was studied in 48 countries, where direct and some indirect costs were considered. The mean cost per live delivery in the United States was estimated to be $58,394 in 2002 dollars per live birth, compared with $22,048 in non-US countries. As in previous studies, multiple gestation pregnancies were shown to pose a significant economic burden, costing 36% more than regular IVF singleton pregnancies. Price elasticity estimates indicate that a 10% decrease in IVF/ICSI costs would result in a 30% increase in overall ART use. Of note, the study emphasized that most IVF-related economic studies in the peer-reviewed literature possessed no outcomes assessment or comparison with alternative policies.

The costs of multiple gestation pregnancies have been well studied. The landmark study by Callahan and colleagues demonstrated that predicted charges for an IVF singleton pregnancy were $9845 in 1991 dollars, compared with $37,947 for twins and $107,965 for triplets. Low birthweight and gestational age were found to represent the major contributors to the increased use of health care resources with IVF-related multiple gestation pregnancies . Subsequent studies have confirmed the major contribution of multiple gestation pregnancies toward overall IVF cost. Lukassen and colleagues retrospectively compared the relative cost of twin versus singleton IVF pregnancies in a single institutional study in the Netherlands from 1995 to 2001. They calculated the cost of twin pregnancies to be €13,469 in 2002 euros, more than five times higher than the €2,550 of a singleton pregnancy, because of longer maternal and neonatal admissions. Ledger and colleagues modeled the cost impact to the British National Health System of IVF-related multiple births and concluded that multiple gestation pregnancies represented 56% of the cost of all IVF pregnancies, although they represented less than one third of the total number of maternities in the United Kingdom. Singletons cost £3313 in £ year 2002 sterling, whereas twins cost £9122, and triplets cost £32,354. Wølner-Hanssen and Rydhstroem modeled the use of single-embryo transfer, compared with actual standard two-embryo transfer protocols, and concluded that although more cycles would be needed to achieve a single live delivery with single-embryo transfer, the strategy would still be more cost efficient than the standard two-embryo transfer protocol because of the lower rate of twin pregnancies.

The highest quality studies to examine the cost effectiveness of IVF consist of three randomized controlled trials ( Table 2 ). As the earliest, the Ontario trial compared one stimulated treatment cycle without embryo freezing versus a 6-month period of untreated observation or elective conventional therapy, including ovulation induction and intrauterine insemination (IUI), in the 1980s . The live delivery rate was 10% in the former group versus 6% in the latter. The marginal cost of live delivery was calculated as $89,427 in 1992 Canadian dollars. A major weakness of the trials was that it occurred in the 1980s; ostensibly, the effectiveness of ART treatments has since improved considerably. A second trial in Illinois compared 46 couples undergoing IVF to 50 couples randomized to 6 months of standard therapy that consisted of three clomiphene cycles and three gonadotropin cycles followed by four IVF cycles . The former group achieved a 35% pregnancy rate, whereas the latter group achieved a 56% pregnancy rate. As with the Ontario trial, only direct costs were considered. The marginal cost of an additional live delivery was calculated to be −$21,627 in 1999 dollars (ie, IVF was deemed to be not only more expensive but also to offer less benefit). The final trial occurred in the Netherlands . Eighty-six couples with idiopathic subfertility or male subfertility were assigned to six cycles of IUI alone, 85 to six cycles of IUI with ovarian hyperstimulation, and 87 to six cycles of IVF. After 3.5 years, the live birth rates were 7.4%, 8.7%, and 12.2%, respectively. Couples in the IVF arm were more likely to discontinue treatment before the maximum of six attempts. IUI (10,406 NLG per live delivery for male subfertility in 1995 NLG) and IUI with ovarian hyperstimulation (15,448 NLG per live delivery) were found to be more cost effective than IVF (37,185 NLG per live delivery), even at higher maternal ages, when the effectiveness of IUI declines. Questions regarding the generalizability of the Netherlands trial arise because few couples undergo more than three IVF cycles, whereas the trial tested up to six cycles. Overall, these three trials differed in terms of patient population, treatments offered, and country-specific health economic systems, thus potentially accounting for the differences in results seen. It was unclear whether these studies included patients with obstructive azoospermia undergoing sperm acquisition and IVF.

Table 2

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