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.

Baseline population data and participant disposition

Recruitment began in December 1999. 841 men (419 allocated to the fascial interposition group and 422 to the non-fascial interposition group) were enrolled and had vasectomies before recruitment was halted in May 2001; they constituted the treated population. 826 men returned for at least one semen analysis; they constituted the primary analysis population (Figure 2). The baseline data (Table 1) included all participants who returned for at least one semen analysis. The final follow-up visits were completed in June 2002. Unless specified, the efficacy results presented below are from the primary analysis population, and the safety results are from the treated population. 15 men did not return for any semen analyses and were excluded from the primary analysis population. 24 men were lost to follow up before reaching success, being declared a failure, or completing 34 weeks of follow-up (Figure 2).

Time to success based on semen analyses

For the primary analysis population, the survival curves for time to azoospermia and time to severe oligozoospermia showed highly significant differences between the two groups, in favor of fascial interposition (Figure 3). The HRs were 1.35 for azoospermia and 1.32 for severe oligozoospermia (P < 0.0001 for both outcomes).

When time to severe oligozoospermia was examined by age group, men younger than 35 years were significantly more likely to reach oligozoospermia than men of the same age in the non-fascial interposition group (Table 2). HRs were 1.7 (P = 0.0003) for men younger than 30 years and 1.3 (P = 0.03) for men 30 to 34 years old. Men 35 years and older still benefited from fascial interposition, but differences in time to oligozoospermia between the fascial interposition and non-fascial interposition groups were not statistically significant (HR, 1.17 and P = 0.15 for men 35 to 39 years old; HR, 1.21 and P = 0.11 for men at least 40 years old).

In summary, the advantage of fascial interposition was more consistent across age groups when based on time to oligozoospermia than when based on time to azoospermia.

With respect to median time to success, men reached severe oligozoospermia six to eight weeks before they reached azoospermia. Among men in the fascial interposition group, the median times to success were four weeks using the oligozoospermia endpoint and 10 weeks using the azoospermia endpoint. Among men in the non-fascial interposition group, the median times to success were six and 14 weeks, respectively.

Failures based on semen analyses

Pregnancies and later follow up

Four pregnancies were reported during the study period (two in each group). Semen analyses performed close to the dates of conception showed that the semen of all four men contained motile sperm. The estimated time between vasectomy and the date of conception ranged from 41 to 91 days. Based on subsequent semen analyses, one case in each group was a success and one a failure. Three of the four pregnancies occurred at one center.

Among the 77 men with vasectomy failures, 36 (46.8%) accepted an offer of extended follow up (12 from the fascial interposition group and 24 from the non-fascial interposition group). 10 (27.8%) of these 36 men eventually became azoospermic or severely oligospermic (three of 12 in the fascial interposition group and seven of 24 in the non-fascial interposition group), generally between 22 and 42 weeks postvasectomy. At the 52-week visit, persistent sperm were found in 24 men who had been classified as vasectomy successes or indeterminate. 17 of the 24 had sperm concentrations of less than 100,000 sperm/mL. Of the 7 who had higher concentrations, two had been classified as successes (likely with subsequent late recanalization): one had concentrations of 100,000 sperm/mL and the other 400,000 sperm/mL. The remaining five had been classified as indeterminate and had concentrations ranging from 125,000 to 27 million sperm/mL. Six of the seven were in the non-fascial interposition group.

We collected supplementary follow-up data from 46 (59.8%) of the 77 men who had vasectomy failures. 29 of these men had undergone repeat vasectomies; 15 men had not had a repeat vasectomy at last contact; and the wives of two men had undergone postpartum tubal ligations.

Surgical procedures

Surgery took approximately two to three minutes longer when it included fascial interposition than when it did not. Mean surgical times were 14.3 minutes for the fascial interposition group versus 11.7 minutes for the non-fascial interposition group (P < 0.0001). The median surgical times were 12 minutes for the fascial interposition group versus 10 minutes for the non-fascial interposition group. The range of operating times was 5–60 minutes versus 4–75 minutes, respectively. Only three sites had cases with operating times longer than 30 minutes. At one of those sites, teaching activities contributed to the longer operating times.

The fascial interposition technique posed some difficulty for surgeons in 58 (13.8%) of 419 cases. However, surgeons in only nine (2.1%) of the 419 cases were unable to perform the fascial interposition procedure on one or both vas. Surgical difficulties with other aspects of the vasectomy procedure were not affected by the use of fascial interposition (data not shown).

Safety results

As indicated by reported analgesic use, postsurgical pain was mild, brief, and virtually identical in both groups. Among 820 men with data on postsurgical pain, 528 (64.4%) reported taking no analgesics. 231 (28.2%) reported analgesic use for one to three days, 47 (5.7%) for up to one week, and 14 (1.7%) for more than a week.

In the early follow-up period, within six weeks of surgery, 74 (17.7%) of the 419 men in the fascial interposition group versus 62 (14.7%) of the 422 men in the non-fascial interposition group reported one or more related adverse events. Although slightly more adverse events occurred in the fascial interposition group, the difference was not significant (P = 0.23).

The two diagnoses responsible for the slight difference in adverse events between the fascial interposition and the non-fascial interposition groups were sperm granuloma in 41 (9.8%) versus 29 (6.9%) of the cases and epididymitis or orchitis in 12 (2.9%) versus six (1.4%) of the cases, respectively. Three of the eight centers accounted for virtually all of the reports of sperm granuloma. Common events that occurred in equal numbers between groups were scrotal pain or swelling in 22 cases (2.6%) and hematomas in 12 (1.4%). The hematomas were small (2 cm or less in diameter), and none required drainage. Infections occurred in four (0.48%) of the cases (two in each group).

675 (89%) of 757 men classified as vasectomy successes or indeterminate attended the 12-month follow-up visit. At that visit, we asked the men if they had had any scrotal pain within the past three months. 652 (97%) reported no pain. In the fascial interposition group, nine (2.6%) of 346 reported pain (seven mild and two moderate); in the non-fascial interposition group, 14 (4.3%) of 326 (11 mild and three moderate). No men reported severe pain.

Three serious adverse events were considered related to the vasectomy. One man in each treatment group was hospitalized for epididymo-orchitis (one with onset one day and one with onset two months postvasectomy); and a man in the fascial interposition group was hospitalized with a painful granuloma of the spermatic cord eight months postvasectomy. Two of the three men were hospitalized for only one night. Two other men were hospitalized for events involving the genitourinary system: elective hernia surgeries one month and one year postvasectomy. These events were considered unrelated to vasectomy.