Outcomes of Macrosurgical Versus Microsurgical Vasovasostomy in Vasectomized Men: a Systematic Review and Meta-analysis

In order to restore fertility by vasectomy reversal, vasovasostomy (VV) is one of the most chosen options. During this procedure, the vas deferens is anastomosed either by a macro- or microscopical technique. Up to date, it is unknown which of these techniques shows best overall post-procedure patency and pregnancy rates. The purpose of this systematic review and meta-analysis is to reach a consensus on which technique is best for vasovasostomy and thereby better counsel patients and practitioners. A systematic review and meta-analysis on macroscopic and microscopic VV for vasectomy reversal was performed. PubMed, The Cochrane Library, Embase, and Web of Science were systematically searched from inception until 2019. Studies and associated data were evaluated by two reviewers. Primary, data on post-operative patency and pregnancy rates, interval to reversal, and post-operative complications were extracted. Proportions (95% CI) and heterogeneity scores (I2) were calculated, using a random effects model. A total of 8305 patients were included by 25 studies. Descriptive analysis showed higher post-operative patency (80.5% vs 91.4%) and pregnancy rates (47.7% vs 73.3%) after microscopic vasovasostomy. Meta-analysis produced post-operative patency proportions of 0.80 (95% CI, 0.76–0.84) and 0.88 (95% CI, 0.83–0.92) after macro- and microscopic VV respectively. Proportions of post-operative pregnancy were 0.43 (95% CI, 0.35–0.50) after macroscopic VV and 0.47 (95% CI, 0.31–0.62) after microsurgical VV. Microscopic VV is associated with higher post-operative patency and pregnancy rates compared to macroscopic vasovasostomy. However, further research is needed because of shortage in high methodological quality and variety.


Introduction
Vasectomy is a safe and effective form of contraception, and it is estimated that millions of men undergo vasectomy worldwide [1]. In the USA alone, 527,476 vasectomies were performed in 2015 [2]. During this procedure, the vas deferens is surgically interrupted on both sides with the aim of resulting in permanent infertility. Of all vasectomized men, 3.0-7.4% request vasectomy reversal because they regret their decision [3][4][5]. This mainly concerns patients who are sterilized at a young age, couples with a renewed desire for children, and patients with changes in their personal life. The options for va sal rec ons truc tion i nclu de vas ova sos t omy or vasoepididymostomy.
In most patients who desire vasectomy reversal, a vasovasostomy is conducted to reconnect the vas deferens [6]. Within this procedure, a distinction is made between macroscopic and microscopic surgical techniques. The macroscopic method is performed with the naked eye or assisted by a loupe and uses stents or full-thickness sutures. Advantages of this technique are the reduced costs, decreased operative time, and reduced demand for certain operative skills [7]. The microscopic technique is conducted with the support of strong magnification (16× to 25×) and uses full-thickness or double-layered sutures [8]. By using these types of magnification, the ends of the vas deferens may be better positioned, which could result in a more accurate alignment of both ends and reduce the chance of postoperative sperm leakage and its associated consequences [8].
Until the mid-1970s, only one method was available: the macroscopic technique, which was the gold standard for vasovasostomy. At that time, the first microsurgical approached vasovasostomy was introduced by Silber (1977), and a new, more precise technique emerged [9][10][11]. In the past decade, the use of an operation microscope for vasovasostomy has gained popularity, and most expert surgeons use this microsurgical approach. However, some surgeons claim that careful use of macroscopic surgery with reliable materials and experience of the surgeon still results in high postprocedure outcomes.
In recent decades, several studies examining one or both methods have been published. However, an up-to-date review comparing the outcomes for both techniques is missing. Therefore, a review of the currently available data is performed. This study aims to review the literature to obtain a clear picture of the different surgical techniques used for vasovasostomies and to assess which method, macroscopic or microscopic, shows best overall postprocedure outcomes, such as patency and pregnancy rates.

Literature Search
A systematic literature review was performed pertaining to the outcomes of macroscopic vasovasostomy, microscopic vasovasostomy, or both surgical techniques for vasectomy reversal. This systematic review was executed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. The systematic search was performed in PubMed National Library of Medicine, The Cochrane Library, Embase, and Web of Science from inception up to October 2019. The following terms, including synonyms and closely related words, were used: 'vasovasostomy', 'microsurgery', and 'vasectomy reversal'. The full literature search can be found in the Supplementary Information. In addition, a cross-reference search was performed to identify missed relevant articles.

Inclusion and Exclusion Criteria
Comparative studies between macrosurgical and microsurgical vasovasostomy for vasectomy reversal were considered eligible for inclusion if they reported relevant outcomes such as pregnancy rate, patency rate, postoperative complications, and/or length of interval. All patients had to be first time reversals. Studies on macroscopic or microscopic vasovasostomy alone were also included. The articles were preferably written in English or Dutch. Studies on vasoepididymostomy and robotic vasectomy reversal were excluded. Animal studies, systematic reviews, case report studies, case series, foreign language articles, and articles lacking an abstract were also excluded, as well as studies of patients who underwent vasovasostomy for any reasons other than vasectomy reversal and studies that did not mention any relevant outcomes.

Data Extraction
The literature search was performed by two reviewers (M. D and Y. B). Any discrepancies between these two authors were resolved by discussion until consensus was reached. First, the title and abstract of the eligible articles were screened. Subsequently, the full text of the selected articles was screened. When the inclusion criteria were met, data extraction was performed using standardized tables. Patient characteristics, type of intervention, postoperative patency and pregnancy rates, mean interval to reversal, the presence of postoperative complications, and time to follow-up were extracted from the included articles. The primary outcomes of interest were postoperative patency and pregnancy rates. Patency is defined as the presence of any motile sperm at postoperative semen analysis without using specific cutoff values. Additionally, pregnancy is defined as a successful natural conception after vasal surgery, regardless of the number, course, and outcome of this pregnancy. Secondary outcomes included postoperative complications (minor or severe), mean interval to reversal (divided into two groups: ≤ 7 years and > 7 years), and time to follow-up.

Analysis
For descriptive analysis, data were subdivided based on the strength of magnification and defined as either macrosurgical or microsurgical. All vasovasostomies that were performed with the use of loupe magnification (×2.5-4) or without magnification at all were defined as macrosurgical. In microscopic vasovasostomies, an operating microscope, with strengths ranging from ×10 to ×16-25 and without robotic support, was used. Averages of primary outcomes were calculated to make more reliable and all-encompassing statements when comparing these techniques. These averages were pooled from both retrospective studies and RCTs combined and not only within a certain quality range because heterogeneity scores (I 2 ) and results hardly changed when differences in study design were taken into account.
If eligible, studies were included in the meta-analysis. A pooled proportion and the corresponding 95% confidence intervals were calculated to obtain an overall estimated effect size for the association between macro-and microsurgery and postoperative patency and pregnancy. Meta-analysis was performed using a random effects model, and heterogeneity was assessed by the I 2 statistic. Statistical significance was defined as a 2-sided P value < 0.05. All analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria).

Article Demographics and Patient Characteristics
In total, 1501 articles were collected through the initial literature search. After removal of duplicates, 839 studies remained. From these articles, 802 were excluded after screening titles and abstracts because of irrelevant subject matter. Of the 37 publications that were eligible for full text screening, twelve were excluded because the relevant outcome parameters were unclear, or they did not mention any of these parameters at all. The remaining 25 studies met the criteria for study inclusion (Fig. 1). These studies were published over an interval of 39 years (1980-2019). The vast majority (22 publications, 88%) were performed retrospectively and represented level IIb evidence. The remaining three articles were RCTs (12%) and represented level Ib evidence according to the Oxford Centre for Evidence-Based Medicine. In the included studies, a total of 8305 patients were included, with an average of 332 per study (range: 12-4010). After loss to follow-up, 5184 patients remained ( Table 1). The average age was 38.1 years, and the mean interval to reversal was 7.1 years. A total of 1195 patients underwent macrosurgical vasovasostomy, while the remaining 3989 patients underwent microsurgical vasovasostomy ( Table 2). The average year of publication for both modalities was 1999.  [7,12,14,17,18,27,[32][33][34][35]. Overall, patency ranged from 73.0 to 96.3% [17,35]. Moreover, of 246 men with a mean interval to reversal ≤ 7 years, 189 (76.8%) had patency [17,27,34,35]. In 260 patients who reported a mean interval to reversal > 7 years, 209 (80.4%) had patency [7,12,18]. Three studies did not report any mean interval to reversal (Table 2) [14,32,33].
A total of fourteen studies on the relationship between postoperative pregnancy rates and macroscopic vasovasostomy were included in the meta-analysis. The random effects model presented a pregnancy proportion of 0.43 (95% CI, 0.35-0.50), with a statistical heterogeneity of I 2 =81% (T 2 =0.0138, p < 0.01), which was considerable (Fig.  3). Fifteen studies reported postoperative pregnancy rates according to microscopic vasovasostomy. The corresponding pregnancy proportion was 0.47 (95% CI, 0.31-0.62), and the heterogeneity in this model was considered very high, with I 2 =99% (T 2 =0.0917, p < 0.01) (Fig. 3).
Furthermore, two studies reported the incidence of postoperative complications after microscopic vasovasostomies [15,24]. Complications occurred in 28 patients (17.3%) and consisted mainly of haematomas, wound infections, and orchitis. Exact numbers were not given. However, none of these complications was specifically related to the microsurgical technique used [15,24]. Of the remaining four studies that mentioned complications as an outcome, only one reported a postoperative complication [19,26,29,30]. This complication was not operation related and not further specified or related to an operation technique.

Discussion
A majority of patients who request vasectomy reversal will eventually undergo vasovasostomy. Since the introduction of the microsurgical technique in 1977 by Silber, different methods for vasovasostomy, macroscopic and microscopic, have been used [9]. To date, it is still not clear which technique is superior and achieves the highest postoperative patency and pregnancy rates. The aim of this review was therefore to systemically review the literature on macroscopic and microscopic vasovasostomy techniques to better counsel patients and practitioners.
We included a total of 8316 patients, of which 5184 remained after loss to follow-up in 25 studies. Most of these publications were retrospective (n=22) [7, 9, 12, 14-24, 27-29, 31-35], and three were RCTs (Table 1) [13,26,30]. Reviewing the literature showed a mean postoperative Fig. 1 Flow chart of study selection and inclusion patency of 80.5% and 91.4% after macroscopic and microscopic vasovasostomy, respectively. The mean incidence of postoperative pregnancy was 47.7% after macroscopic surgery and 73.3% after microsurgery. All comparative studies [13,19,26,28,29], except for Safarinejad et al. [30], supported these higher postprocedure outcomes in favour of the microsurgical technique, without taking into account statistical significance ( Table 2). In fact, these results were less consistent when including the interval to reversal. The group of patients with a mean interval to reversal > 7 years showed higher patency rates after macroscopic vasovasostomy. Additionally, a higher incidence of postoperative pregnancies after macrosurgical reconstruction of the vas deferens in the population of men with a mean obstruction interval ≤ 7 years was found. Clarification of surgery-related complications in general was not possible due to minimal reported information.
Our meta-analysis of all twenty-two retrospective studies and three RCTs presented similar results as the initial pooled analysis, with statistical evidence in favour of microsurgical vasovasostomy. In both patency (0.80 vs 0.88) and pregnancy (0.43 vs 0.47), the random effects model demonstrated a higher proportion after microsurgical vasal reconstruction. However, these outcomes are weakened by the high heterogeneity across studies, which in particular affected the analysis by the random effects models of the microscopic technique, with I 2 values of 93% and 99%. This variation is mainly caused by differences in population size and surgical methods and to a lesser extent by different follow-up times. Furthermore, bias as a result of the inclusion of the RCTs is unlikely, as the total number of patients per analysis and overall heterogeneity (I 2 ) did not change dramatically. Because of these unchanged heterogeneous populations, diagnostic accuracy may not have been affected.
Overall, there seems to be a slight advantage to use of the microscope in vasovasostomy. Previous literature has suggested that with the microsurgical technique, a more accurate 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 sperm leakage and thereby the formation of sperm granuloma and strictures [16,28,29,[36][37][38]. Patency of sperm is hereby retained. Approximation of the mucosal edges without microscopic magnification often results in a disparity between both ends due to small anatomical dimensions [29]. Anastomosis is thereby less precise, which in turn affects postoperative patency and pregnancy.
Our findings must be interpreted with caution because of heterogeneity in definitions of postoperative patency and pregnancy. For patency, most studies focused on the presence of any motile sperm cells in the ejaculate at follow-up, while others used minimum sperm counts of 5, 10 or 20 million/ml. The same applies for pregnancy: the vast majority reported successful, natural, and postoperative conceptions, while some studies reviewed full-term pregnancies or the first postoperative pregnancies only. Because of these inconsistencies, it is difficult to compare all studies.
Another important limitation is that the surgical methods used differed across studies in more than just the strength of magnification. Depending on the surgeon responsible, onelayer sutures, modified one-layer sutures (full thickness), two-layer sutures, or Prolene stents were used for anastomosis. Suture material varied between 6.0, 8.0, 9.0, and 10.0 nylon, and the number of sutures used during vasovasostomy was even less consistent. This makes it hard to determine if the differences in postoperative patency and pregnancy rates were due to the strength of magnification or to the suture techniques and materials used. Furthermore, although scientific research has shown a decrease in female fertility with ageing [39] and physiological variations in sperm density and semen quality among men [40], most studies have not corrected for the age of female partners and the differences in sperm density and semen quality between men. Other limitations of this study were the lack of data on surgeon experience, the retrospective nature of most included studies, different follow-up times, and the lack of comparable studies.
One of the strengths of this study is the clear and reproducible methodology used for performing the systematic review and meta-analysis. Furthermore, this systematic review with meta-analysis, executed according to the PRISMA guidelines, is the first to critically examine the introduction of microsurgery for vasovasostomy in comparison with conventional macrosurgery. The ability to pool and analyse different randomized controlled trials and retrospective studies provides an important overview of data and allows statements to be made about the current state of affairs in this area of urological surgery. Urologists, practitioners, and healthcare institutions may now substantiate their preferences and decisions about vasal reconstruction surgery methods based on scientific research.

Conclusions
Based on a meta-analysis of the best available literature, microsurgically conducted vasovasostomy demonstrated higher postoperative patency and pregnancy rates than macrosurgical techniques. Solely after inclusion of the interval to reversal, some groups seemed to benefit more from macroscopic vasal surgery.
However, definitive conclusions cannot be drawn because of high interstudy heterogeneity owing to discrepancies in surgical methods to anastomose, differences in population sizes, and significant variation in definitions of used endpoints. In view of these data, further research is needed to create the possibility to perform a larger, uniform metaanalysis with a more statistically reliable random effects model.

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Declarations
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.

Conflict of Interest The authors declare no competing interests.
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