Study sites and participants
The study was conducted at eight outpatient clinics in urban locations in Brazil, El Salvador, Mexico (two clinics), Nepal, Panama, Sri Lanka, and the USA, and was conducted in compliance with the Helsinki Declaration. Family Health International's (FHI's) institutional review board (IRB) approved the study on August 28, 1998, and it was also approved by individual IRBs at five of the eight sites. Because the remaining three sites did not have their own IRBs, FHI's IRB acted as their primary IRB. All participants gave written informed consent.
Men who requested a vasectomy at the study clinics were screened for eligibility and invited to join the study if they met all requirements. To be eligible for the study, men had to (a) satisfy the local clinic's criteria for vasectomy and (b) be willing to provide a prevasectomy semen sample and additional semen samples per the planned follow-up schedule. Men were compensated for the time and inconvenience of returning for frequent semen analyses. The compensation amounts were determined separately for each site. Exclusion criteria included (a) a history of previous vasectomy or other genital surgery; (b) clinical evidence of an acute illness including sexually transmitted infections; (c) history of a bleeding disorder; and (d) a large varicocele or other scrotal mass.
Participants were randomized to the fascial interposition or non-fascial interposition group. We used a block randomization method with randomly permuted block sizes of four, eight, and 12 participants. For allocation concealment, FHI provided the randomization assignments to the investigators in sequentially numbered, opaque sealed envelopes that were opened just prior to the vasectomy procedure. The surgeons knew the technique being used, but the laboratory staff who were conducting the semen analyses were not aware of the group assignments.
Vasectomy techniques
Prior to the study, the researchers – all experienced vasectomy surgeons – attended an investigators meeting where the vasectomy techniques were standardized with the help of two experienced vasectomy trainers. All surgeons used the no-scalpel approach to the vas [19]. The vas was then occluded using two silk sutures, and an approximately 1-cm segment of vas between the ligatures was excised. For the fascial interposition technique, a suture was used to contain the testicular end of the vas inside the fascial sheath; the prostatic end remained outside (Figure 1).
The investigators completed questionnaires immediately following each procedure, noting any difficulty experienced with parts of the vasectomy procedure (e.g. isolating the vas, using the fascial interposition technique). At two-week follow-up visits and at any unscheduled visits during the first six weeks, the investigators examined each patient and completed a questionnaire noting findings such as sperm granulomas, hematomas, epididymitis, or wound infection. The diagnosis of sperm granuloma was based on the clinical finding of swelling at the vasectomy site. It was not based on histology. We defined wound infection as a clinical sign of infection (i.e. local inflammation) for which a clinician had prescribed antibiotics.
Semen analysis
We performed standardized semen analyses two weeks postvasectomy and then every four weeks through 34 weeks, or until success or failure. For men without earlier vasectomy failure (i.e. those classified as vasectomy success or indeterminate), we performed semen analysis again at 52 weeks.
Laboratory methods were based on procedures recommended by the World Health Organization [20]. Briefly, participants were asked to produce a semen sample in a private room at the clinic. Semen was examined within one hour of collection. An aliquot was examined by phase-contrast microscopy at high power magnification (400×) to estimate sperm concentration. Based on the estimated concentration, dilutions were prepared to assess exact sperm concentration and motility. The concentration and motility of each sample were determined using a Neubauer hemocytometer. Samples with very low sperm numbers (<5 sperm per high power field) on the initial exam were centrifuged for 15 minutes at 600 g and then assessed for sperm concentration and motility as described above. Each laboratory conducted periodic quality-control tests.
Study outcomes
The primary study outcome for vasectomy success was time to azoospermia, defined as two consecutive azoospermic specimens taken at least two weeks apart. Two other study outcomes were (1) time to azoospermia or to severe oligozoospermia in two consecutive specimens taken at least two weeks apart, and (2) vasectomy failure based on the results of semen analysis. We defined severe oligozoospermia as 1 to <100,000 sperm/mL.
Throughout the text and tables, the second outcome (time to azoospermia or to severe oligozoospermia) is referred to as severe oligozoospermia.
We defined the date of vasectomy success as the date of the first of two azoospermic or severely oligospermic semen samples. Because older men take longer to reach azoospermia, we analyzed the data by age group in addition to examining overall effects. In the analyses of time to success, once a man met the definition of a vasectomy failure, he was classified as such and was considered as remaining a failure through 34 weeks, whether or not he continued clinical follow-up visits.
To define vasectomy failure, we used a criterion for early failure based on a report by Alderman [21]: the presence of more than 5 million motile sperm/mL at week 14 or later. We initially defined late failure as any motile sperm at 26 weeks or later. After the study began, we amended this because of the concern that motility could be difficult to evaluate in semen samples with very low sperm concentrations. The amended criterion specified the presence of more than 100,000 sperm/mL with any sperm motility. If a participant's semen analyses did not meet the primary criterion for success (azoospermia) or the criterion for failure, his outcome was indeterminate.
Partway through the study, the protocol was amended to gather extended follow-up data (up to 52 weeks) on men who were classified as vasectomy failures. This amendment facilitated clinicians' follow-up of men classified as early failures, to determine whether they would become azoospermic with longer follow-up. For men who became clinical successes with longer follow-up, their statuses were not changed for the life-table analyses of time to success.
Sample size estimation
We chose a study size of 1200 men, with 150 to be enrolled at each of the eight sites. We based this sample size on data showing that the cumulative chance of success through 22 weeks is about 82% for vas occlusion without fascial interposition, when success is defined as two consecutive azoospermic samples at least two weeks apart [7]. Assuming that the cumulative chance of success through 34 weeks of follow-up is 85% when fascial interposition is not used, and 90% when fascial interposition is used, enrolling at least 1156 participants would assure 90% power to detect a difference between the groups, with a one-sided test and an alpha of 0.05.
Statistical analysis methods
Cox proportional hazards regression was used to estimate anticipated improvement in the hazard ratio [HR] for successful vasectomy for the fascial interposition group versus the non-fascial interposition group, controlling for age and for surgeon experience (three surgeon groups based on prior experience with fascial interposition). A one-sided test with an alpha of 0.05 was used. We chose to use a one-sided test because of expert opinion that fascial interposition might improve vasectomy effectiveness and was very unlikely to have a negative effect. An age-by-treatment interaction was found in this primary comparison, so both overall and age-specific HRs were determined to more adequately explain the impact of fascial interposition on time to vasectomy success.
Kaplan-Meier product limit estimates, with 95% confidence intervals [CIs], of the probabilities of success at each scheduled week of follow-up through week 34 were determined overall, by treatment group and, because of the age-by-treatment interaction, by treatment group and age group. Peto's standard error [22] was used to compute the 95% CIs.
The proportions of vasectomy failures in the treatment groups were estimated and compared using logistic regression, controlling for age and surgeon experience.
A two-way analysis of variance that controlled for surgeon experience and participant age was used to compare duration of surgical procedure. Incidence of any surgical difficulty and of adverse events related to vasectomy were compared using a Mantel-Haenszel test, stratified by surgeon experience. The treatment-by-surgeon experience interactions for these comparisons were tested using the Breslow-Day test.
Interim analysis
We conducted a single planned interim analysis after the first 400 participants had completed 10 weeks of follow up. The results were reviewed by a data safety monitoring board (DSMB) composed of three independent and experienced researchers: a urologist, a statistician, and a clinical epidemiologist. The DSMB reviewed only the primary study outcome (i.e. time to azoospermia). Though a difference by age group complicated the DSMB's review of the results [18], the interim analysis showed a significant overall effect in favor of fascial interposition at the predefined significance level (P < 0.01). As a result, we halted recruitment in May 2001, but follow up continued for all enrolled participants.