Outcomes of Three Vasovasostomy Surgical Techniques in Vasectomized Men: A Systematic Review of the Current Literature

To investigate which surgical technique, macroscopic, microscopic or robot-assisted microscopic, shows highest postoperative patency- and pregnancy rates for vasectomy reversal (VR) by vasovasostomy (VV). This study is an updated version of the systematic review and meta-analysis entitled: “Outcomes of Macrosurgical Versus Microsurgical Vasovasostomy in Vasectomized Men: a Systematic Review and Meta-analysis” published in 2021. We performed a systematic review of the English-, Dutch-, and German-language literature that described postoperative outcomes of macroscopic, microscopic, or robot-assisted microscopic VV for VR. PubMed National Library of Medicine/MEDLINE, Embase, CENTRAL, The Cochrane Library, Web of Science and Scopus were searched from inception to June 2021. Two reviewers independently examined the studies and associated data for eligibility. Primary outcomes were postoperative patency and pregnancy rates. Data on interval to reversal (≤ 7 years and > 7 years) and postoperative complications were also extracted. Forty-nine studies met the inclusion criteria. We identified 46 retrospective studies and three randomized controlled trials (RCT). A total of 10,088 procedures were included. 6822 patients remained after loss to follow-up. The mean age at reversal of vasectomy was 38.0 years, and the mean interval to reversal was 6.5 years. The pooled mean postoperative patency rate was slightly higher after robot-assisted microsurgical VV (92.7%), compared to macrosurgical (81.9%) and pure microsurgical (90.1%) VV. Postoperative pregnancy rates were 42.7%, 69.7%, and 33.3% after macroscopic, pure microscopic and robot-assisted microscopic VV, respectively. Our results showed that microsurgical and robot-assisted microsurgical VV are associated with higher postoperative patency rates compared to the macrosurgical technique. VV with microsurgical assistance showed the highest post-operative pregnancy rates. However, more research is needed due to lack of RCTs and data on robot-assisted microsurgical VV.


Introduction
Vasectomy is a widely used form of male contraception because of its effectiveness and simplicity. An estimated 40 to 60 million men worldwide have undergone vasectomy annually [1,2]. With an increase in divorce rates, early sterilizations, a renewed desire for children, and changes in personal life, there has been an increase in men seeking to restore their fertility through vasectomy reversal [3]. Approximately 3.0 to 7.4% will eventually request a vasectomy reversal to regain fertility [4]. In most of these patients, the vas deferens are reconnected by bilateral vasovasostomy (VV), which is the most cost-effective method [5]. Possible alternatives include vasoepididymostomy (VE) or advanced This article is part of the Topical Collection on Surgery assisted reproductive technologies (ARTs) such as in vitro fertilization (IVF) [6].
In 1977, Silber introduced a microsurgical approach to VV, which quickly became the gold standard for reversal of vasectomy because of its high success rates compared to conventional macroscopic techniques [7].
Currently, a new robot-assisted microsurgical technique is gaining popularity and is developing rapidly in the field of urology. This is attributed to several potential advantages of the robotic platform, such as three-dimensional magnification, increased precision, stereotactic vision, elimination of tremor, and improved ergonomics [12][13][14]. In addition, the surgeon's autonomy is significantly increased by the ability to control three instruments and a 4th arm (camera) simultaneously [12,13]. These features have contributed to the popularity of robotic surgery for complex microsurgical procedures such as VV. However, these techniques are evolving rapidly and a current overview of the postoperative outcomes of these three surgical techniques is lacking. In this updated version of our previous systematic review and metaanalysis published in 2021 the new robot-assisted microsurgical technique has been added to be critically examined in comparison with the other two conventional techniques for VV. In addition, new data has been included and presented.
The primary purpose of this review is to compare macrosurgical, microsurgical and robot-assisted microsurgical VV based on postoperative patency and postoperative pregnancy rates. Secondary outcomes of this study include the interval to reversal (≤ 7 years and > 7 years) and the presence of postoperative complications.

Search Strategy
We performed a systematic literature review of English, Dutch, and German articles on the results of macroscopic VV, microscopic VV and robot-assisted microscopic VV for vasectomy reversal. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The following databases were systematically searched from inception to June 2021: PubMed National Library of Medicine/ MEDLINE, Embase, CENTRAL, The Cochrane Library, Web of Science, and Scopus. The keywords were 'vasovasostomy', 'vasectomy reversal', 'vasal reanastomosis', 'vasal reconnection', 'microsurgery', and 'robot'. In addition, missed relevant articles were identified by a cross-referencing. This study has been registered and published by PROSPERO (No. CRD42020194356).

Inclusion and Exclusion Criteria
Studies that reported surgical and patient outcomes of macroscopic, microscopic, and robot-assisted microscopic VV for vasectomy reversal were eligible for inclusion. Comparative studies were also included. All procedures had to be a first reversal. Non-English, non-Dutch and non-German articles were excluded, as were systematic reviews, case report studies, case series, animal studies, and articles without an abstract. Studies on vasoepididymostomy or patients who underwent VV for a reason other than vasectomy reversal were also excluded. Figure 1 shows a flow chart of study selection, inclusions, and exclusions.

Data Collection
Two reviewers (M. D. and Y. B.) independently performed the literature search and data extraction. First, title and abstract were screened. Then the full text of potentially relevant articles was obtained and screened by the same reviewers. Any disagreements between the two reviewers were resolved through discussion. Once the inclusion criteria were met, relevant study parameters for this systematic review were extracted from each article using standardized forms and tables. These included study characteristics, patient demographics, method of VV, postoperative patency and pregnancy rates, interval to reversal, postoperative complications, and definitions of patency and pregnancy. The primary outcomes were postoperative patency and pregnancy rates. The secondary outcomes were the interval to reversal (≤ 7 years and > 7 years) and the presence of postoperative complications. In this review, patency is defined as the presence of any, motile, sperm cells in postoperative semen samples. Pregnancy is defined as successful natural conception, regardless of the course and outcome of the pregnancy.

Analysis
All data were subdivided by method of VV: macrosurgical, microsurgical and robot-assisted microsurgical. Loupe or non-magnified vasovasostomies were defined as macrosurgical. For microsurgical vasovasostomies, a surgical microscope (× 2.3-25) was used. When robotic support was added (Da Vinci robotic platform), it was classified as robot-assisted microsurgical VV. For descriptive analysis, averages of overall postoperative patency and pregnancy rates, subdivided according to surgical technique, were calculated by combining data of each included study. To provide comprehensive overviews, these averages were pooled from both retrospective studies and RCTs.

Overview of Included Studies
A total of 49 studies met the inclusion criteria (Fig. 1). The year of publication ranged from 1980 to 2020. Forty-six publications (94%) were retrospective studies and represented level IIb evidence according to the Oxford Centre for Evidence-Based Medicine ( Table 1). The remaining three articles were Randomized Controlled Trials (RCT) (6%) and represented level Ib evidence. Most studies were conducted in the USA (n = 17), followed by the United Kingdom (n = 6) and South Korea (n = 6). A total of 10,088 procedures were included. After loss to follow-up, 6822 procedures remained (Table 1). Sample sizes ranged from 7 to 4010 patients. Overall, 1754 procedures were macrosurgical, 4930 microsurgical and 191 robot-assisted microsurgical. The mean patient age was 38.0 years (range 30.0-46.0), and the mean interval to reversal was 6.5 years (range 4.2-11.1) ( Table 2).

Robot-Assisted Microscopic
Two (6%) studies discussed postoperative pregnancy rates and robot-assisted microsurgical VV for vasectomy reversal. The mean postoperative pregnancy rate after this type of VV was 33.3% (11/33). Overall, pregnancy rates ranged from 7.7 to 50.0% [14,50]. Santomauro et al. investigated the possible influence of the length of interval to reversal ≤ 7 years on the probability of becoming pregnant [14]. Of all 13 procedures included in this study, 1 (7.7%) pregnancy was reported. On the other hand, none of the studies assessed the consequence of the obstruction interval > 7 years on postoperative pregnancy rates. Four studies did not provide clear information on pregnancy rates or mean interval to reversal (Table 2) [12,50,56,57].

Discussion
3.0% to 7.4% of all vasectomized men will eventually request a vasectomy reversal to regain fertility [4]. In most cases, this is achieved by bilateral VV, which is the most cost-effective method [5]. The microsurgical approached vasovasostomy became the golden standard since its introduction in the 1970s [7]. However, the conventional macrosurgical technique is still widely used. Our previous systematic review and meta-analysis showed superiority of the microsurgical conducted VV over the macrosurgical conducted VV based on postoperative patency (0.88 vs 0.80) and pregnancy proportions (0.47 vs 0.43) [11].
Currently, a new robot-assisted microsurgical technique is gaining popularity and developing rapidly in the field of urology [12][13][14]. To date, it is still not clear which technique is superior and achieves the highest rates of postoperative patency and pregnancy. Therefore, the purpose of our review is to compare macrosurgical-, microsurgical-, and robotassisted microsurgical VV for surgical and patient outcomes.
Forty-nine studies with a total of 10.088 procedures were included in this review, of which 6822 remained after loss to follow-up. Most of these publications were retrospective (N = 46), three were RCTs ( Table 1).
Analysis of the literature showed a mean postoperative patency of 81.9% and 90.1% after macrosurgical and microsurgical VV, respectively, while 92.7% of patients showed patency after robot-assisted microsurgical vasovasostomy. The mean postoperative pregnancy rate was 42.7% after macrosurgical VV and 69.7% after microsurgical VV as 33.3% managed to conceive after robot-assisted micro surgical VV. These findings were supported by all comparative studies [8,9,12,18,21,24,27,50], except for Safarinejad et al. [17]. After including a mean interval to reversal ≤ 7 years, postoperative patency rates remained in favor of microsurgical (87.8%) and robot-assisted microsurgical VV (89.1%) compared to macrosurgical VV (80.5%). Patency rates after a mean interval to reversal > 7 years were highest after robot-assisted microsurgical VV (100%) compared to microsurgical (85.2%) and macrosurgical VV (81.7%). When including the interval to reversal highest pregnancy rates were found after microsurgical VV, 57.3% and 40.0% after ≤ 7 years and > 7 years, respectively (Table 2). Clarification of surgery-related complications was not possible due to minimal reported information.
In general, the use of the microscope and robot in vasovasostomy seems to be in advantage. Previous literature has suggested that with the microsurgical and robot-assisted microsurgical technique, a more precise mucosa-to-mucosa anastomosis between the smaller lumen of the distal vas and the dilated lumen of the proximal vas can be achieved. This precise and watertight anastomosis prevents leakage of semen and therefore the formation of sperm granuloma and strictures [18,41,48,53,58]. Furthermore, the addition of a robotic platform provides even greater precision compared to microscopic use alone. This has been attributed to several potential advantages such as three-dimensional magnification, stereotactic vision, elimination of tremor, improved ergonomics, and the ability to operate three instruments and a 4th arm (camera) simultaneously [12,13]. However, these latter suggestions are not reflected in the overall pregnancy rate after robot-assisted microsurgical VV. Higher postoperative pregnancy rates should be expected given all the potential benefits of robot-assisted microsurgical VV.
Strengths of this study include the clear and comprehensive overview of most recent and relevant data on different surgical techniques for VV and thus the critical assessment of the introduction of robot-assisted microsurgery in this field of urology. Moreover, this systematic review is the first to evaluate and compare conventional macro-and microsurgery with robot-assisted microsurgery used in VV. Other strengths of this study include the narrow focus of the research question, the extensive search for evidence, and the criterion-based selection of relevant data.
There are several limitations to this study. First, there is considerable heterogeneity among the studies regarding the definitions of postoperative patency and pregnancy (Table 3). Most studies defined patency as the presence of any, motile, sperm cells in the ejaculate at follow-up semen analyses while the vast majority defined pregnancy as any successful postoperative conception, regardless of the outcome. Second, the surgical method used varied from study to study and was primarily based on preference of the surgeon responsible. For example, the sutures used for anastomosis varied from 6-0 to 10-0 nylon, and in some cases Prolene stents were used to facilitate  patency. Third, most included studies were of retrospective nature and therefore did not support the highest level of evidence. Fourth, assessment of one of our secondary outcomes, postoperative complication rate, was not possible due to the lack of data. Other limitations include the lack of RCTs, comparable studies, data on robot-assisted microsurgical VV, and data on surgeon experience. These inconsistencies make it difficult to compare all included studies, and findings should be interpreted with caution.

Conclusion
Based on the best available evidence, we observed higher patency rates after microsurgical and robot-assisted microsurgical VV compared to the macrosurgical technique. VV with microsurgical assistance showed the highest post-operative pregnancy rates. Inclusion of the interval to reversal did not change these insights. However, no definitive conclusions and recommendations can be drawn from these data because of the considerable interstudy heterogeneity due to differences in the definitions of endpoints used and variation in surgical methods. In addition, there is a lack of data on robotassisted microsurgical VV and RCTs. Given these findings, consensus on definitions of post-operative endpoints is important and more RCTs comparing all three techniques are needed.
Authors' Contributions MD: conceptualization/conceived and designed research, methodology, data inclusion, data analyzing, writing-original draft preparation, resource, has read and approved the manuscript. YB: methodology, data inclusion, data analyzing, writing-review and editing, has read and approved the manuscript. JZ: writing-review and editing, validation of study concept and data, supervision, has read and approved the manuscript. All authors read and approved the final manuscript.

Funding Not applicable
Data Availability All data and material will be available.

Ethics Approval Not applicable
Consent to Participate Not applicable Consent for Publication As corresponding author, I confirm that the manuscript has been read and approved for publication by all the named authors. Consent for publication of an external partner is not applicable.

Conflicts of Interest
The authors declare that they have no conflicts of interest.

Code Availability Not applicable
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