Abstract

Background

Varicoceles are associated with male subfertility; however, the mechanisms by which varicoceles affect fertility have yet to be satisfactorily explained. Several treatment options exist, including surgical or radiological treatment, however the safest and most efficient treatment remains unclear. 

Objectives

To evaluate the effectiveness and safety of surgical and radiological treatment of varicoceles on live birth rate, adverse events, pregnancy rate, varicocele recurrence, and quality of life amongst couples where the adult male has a varicocele, and the female partner of childbearing age has no fertility problems.

Search methods

We searched the following databases on 4 April 2020: the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. We also searched the trial registries and reference lists of articles.

Selection criteria

We included randomised controlled trials (RCTs) if they were relevant to the clinical question posed and compared different forms of surgical ligation, different forms of radiological treatments, surgical treatment compared to radiological treatment, or one of these aforementioned treatment forms compared to non‐surgical methods, delayed treatment, or no treatment. We extracted data if the studies reported on live birth, adverse events, pregnancy, varicocele recurrence, and quality of life.

Data collection and analysis

Screening of abstracts and full‐text publications, alongside data extraction and 'Risk of bias' assessment, were done dually using the Covidence software. When we had sufficient data, we calculated random‐effects (Mantel‐Haenszel) meta‐analyses; otherwise, we reported results narratively. We used the I² statistic to analyse statistical heterogeneity. We planned to use funnel plots to assess publication bias in meta‐analyses with at least 10 included studies. We dually rated the risk of bias of studies using the Cochrane 'Risk of bias' tool, and the certainty of evidence for each outcome using the GRADE approach.

Main results

We identified 1897 citations after de‐duplicating the search results. We excluded 1773 during title and abstract screening. From the 113 new full texts assessed in addition to the 10 studies (11 references) included in the previous version of this review, we included 38 new studies, resulting in a total of 48 studies (59 references) in the review providing data for 5384 participants. Two studies (three references) are ongoing studies and two studies are awaiting classification.

Treatment versus non‐surgical, non‐radiological, delayed, or no treatment

Two studies comparing surgical or radiological treatment versus no treatment reported on live birth with differing directions of effect. As a result, we are uncertain whether surgical or radiological treatment improves live birth rates when compared to no treatment (risk ratio (RR) 2.27, 95% confidence interval (CI) 0.19 to 26.93; 2 RCTs, N = 204; I² = 74%, very low‐certainty evidence). Treatment may improve pregnancy rates compared to delayed or no treatment (RR 1.55, 95% CI 1.06 to 2.26; 13 RCTs, N = 1193; I² = 65%, low‐certainty evidence). This suggests that couples with no or delayed treatment have a 21% chance of pregnancy, whilst the pregnancy rate after surgical or radiological treatment is between 22% and 48%. We identified no evidence on adverse events, varicocele recurrence, or quality of life for this comparison.

Surgical versus radiological treatment

We are uncertain about the effect of surgical versus radiological treatment on live birth and on the following adverse events: hydrocele formation, pain, epididymitis, haematoma, and suture granuloma. We are uncertain about the effect of surgical versus radiological treatment on pregnancy rate (RR 1.13, 95% CI 0.75 to 1.70; 5 RCTs, N = 456, low‐certainty evidence) and varicocele recurrence (RR 1.31, 95% CI 0.82 to 2.08; 3 RCTs, N = 380, low‐certainty evidence). We identified no evidence on quality of life for this comparison.

Surgery versus other surgical treatment

We identified 19 studies comparing microscopic subinguinal surgical treatment to any other surgical treatment. Microscopic subinguinal surgical treatment probably improves pregnancy rates slightly compared to other surgical treatments (RR 1.18, 95% CI 1.02 to 1.36; 12 RCTs, N = 1473, moderate‐certainty evidence). This suggests that couples with microscopic subinguinal surgical treatment have a 10% to 14% chance of pregnancy after treatment, whilst the pregnancy rate in couples after other surgical treatments is 10%. This procedure also probably reduces the risk of varicocele recurrence (RR 0.48, 95% CI 0.29, 0.79; 14 RCTs, N = 1565, moderate‐certainty evidence). This suggests that 0.4% to 1.1% of men undergoing microscopic subinguinal surgical treatment experience recurrent varicocele, whilst 1.4% of men undergoing other surgical treatments do. Results for the following adverse events were inconclusive: hydrocele formation, haematoma, abdominal distension, testicular atrophy, wound infection, scrotal pain, and oedema. We identified no evidence on live birth or quality of life for this comparison.

Nine studies compared open inguinal surgical treatment to retroperitoneal surgical treatment. Due to small sample sizes and methodological limitations, we identified neither treatment type as superior or inferior to the other regarding adverse events, pregnancy rates, or varicocele recurrence. We identified no evidence on live birth or quality of life for this comparison.

Radiological versus other radiological treatment

One study compared two types of radiological treatment (sclerotherapy versus embolisation) and reported 13% varicocele recurrence in both groups. Due to the broad confidence interval, no valid conclusion could be drawn (RR 1.00, 95% CI 0.16 to 6.20; 1 RCT, N = 30, very low‐certainty evidence). We identified no evidence on live birth, adverse events, pregnancy, or quality of life for this comparison.

Authors' conclusions

Based on the limited evidence, it remains uncertain whether any treatment (surgical or radiological) compared to no treatment in subfertile men may be of benefit on live birth rates; however, treatment may improve the chances for pregnancy. The evidence was also insufficient to determine whether surgical treatment was superior to radiological treatment. However, microscopic subinguinal surgical treatment probably improves pregnancy rates and reduces the risk of varicocele recurrence compared to other surgical treatments. High‐quality, head‐to‐head comparative RCTs focusing on live birth rate and also assessing adverse events and quality of life are warranted. 

Author(s)

Emma Persad, Clare AA O'Loughlin, Simi Kaur, Gernot Wagner, Nina Matyas, Melanie Rosalia Hassler-Di Fratta, Barbara Nussbaumer-Streit

Abstract

Plain language summary

Surgery or radiological treatment for varicoceles in subfertile men

Background

A varicocele is a dilatation (enlargement) of the veins along the spermatic cord (the cord suspending the testis) in the scrotum. Dilatation occurs when valves within the veins along the spermatic cord fail and allow retrograde blood flow, causing a backup of blood. Surgical treatment involves the closing off of the vessels, typically with sutures or clips. Radiological treatment involves both embolisation, in which the vessel is blocked with small particles, or sclerotherapy, where an agent is administered that damages the vessels, causing them to shrink. The mechanisms by which varicoceles might affect fertility, or the mechanisms by which surgical or radiological treatment of varicoceles might restore fertility, have not yet been explained.

Review question

We reviewed the evidence for the effect of varicocele treatment on live birth, adverse events, pregnancy rate, varicocele recurrence, and quality of life in subfertile couples where the male has a varicocele, and the female partner of childbearing age has no fertility problems.

Study characteristics

We found 48 randomised controlled trials (a type of study in which people are assigned to one of two or more treatment groups using a random method) comparing treatment versus no treatment or versus a different treatment method in a total of 5384 men. The evidence is current to April 2020.

Key results

We are uncertain whether surgical or radiological treatment improves live birth rates when compared to no treatment. Treatment may improve pregnancy rates compared to delayed or no treatment. The evidence suggests that couples with no or delayed treatment have a 21% chance of pregnancy, whilst the pregnancy rate after surgical or radiological treatment is between 22% and 48%. Data were lacking on adverse events, varicocele recurrence, and quality of life.

We are uncertain about the effect of surgical versus radiological treatment on live birth, pregnancy rate, varicocele recurrence, and the adverse event hydrocele formation. Data were lacking on quality of life for this comparison.

Microscopic subinguinal surgical treatment probably improves pregnancy rates slightly compared to other surgical treatments. This suggests that couples with microscopic subinguinal surgical treatment have a 10% to 14% chance of pregnancy after treatment, whilst the pregnancy rate in couples after other surgical treatments is 10%. This procedure also probably reduces the risk of varicocele recurrence. This suggests that 0.4% to 1.1% of men undergoing microscopic subinguinal surgical treatment experience recurrent varicocele, whilst 1.4% of men undergoing other surgical treatments do. Results on adverse events were inconclusive. Data were lacking on live birth and quality of life.

We are uncertain about the effects of open inguinal surgical treatment versus retroperitoneal surgical treatment on adverse events, pregnancy rates, or varicocele recurrence. Data were lacking on live birth and quality of life.

We are uncertain about the effects of radiological treatment (sclerotherapy versus embolisation) on varicocele recurrence. Data were lacking on live birth, adverse events, pregnancy, and quality of life.

Certainty of the evidence

Our findings were inconclusive, as the certainty of the available evidence ranged from moderate to very low depending on outcome. More research is needed with live birth or pregnancy rate as the primary outcome.

Author(s)

Emma Persad, Clare AA O'Loughlin, Simi Kaur, Gernot Wagner, Nina Matyas, Melanie Rosalia Hassler-Di Fratta, Barbara Nussbaumer-Streit

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Varicocele treatment, when compared to non‐surgical, non‐radiological, delayed, or no treatment, showed a beneficial effect on pregnancy rate amongst 1193 men with mixed semen analysis. Nine men would need to be treated for one to benefit.

Microscopic subinguinal surgical treatment, when compared to other surgical treatment, showed a beneficial effect on pregnancy rate amongst 1473 men. Ten men would need to be treated for one to benefit. The same comparison showed a beneficial effect on varicocele recurrence rate amongst 1565 men. Fifteen men would need to be treated for one to benefit.

The direct comparison of other treatment methods did not permit us to draw any valid conclusions about the superiority or inferiority of one intervention over another on pregnancy, varicocele recurrence, or adverse events. How any of these interventions impact quality of life is unclear, as this outcome was not measured in any study.

Implications for research 

The ideal trial design for the 'treatment versus non‐surgical, delayed, or no treatment' comparison would be to compare a group of men undergoing the treatment procedure with the other group obtaining a sham surgical procedure. Any other design is potentially biased by the placebo effect of having had the operation performed. However, such a trial design would be difficult to obtain ethical committee approval, as it would put the control group at risk of surgical and anaesthetic complications without any possibility of benefit (Hargreave 1997). As all studies included in the current review mostly considered invasive treatment, blinding of the investigator, participant, or assessor to the procedure performed was rarely performed. However, the outcome measures of this review, live birth and pregnancy rate, were unambiguous. As a result, apart from the placebo effect, no other negative factors of the lack of blinding were presumed to have affected the conclusions drawn.

Although a trial is the most optimal design to assess the efficacy of the 'treatment versus treatment' comparison, potential bias cannot be ruled out, particularly as the the studies were not blinded. However, as blinding was difficult due to the nature of the invasive treatments performed and as lack of blinding was unlikely to influence the outcomes assessed, all studies were graded at a low risk of bias for blinding. Nevertheless, studies that could implement blinding and mitigate potential bias would be ideal.

The studies included in the current review of varicocele treatment were heterogeneous. This indicates the need for a large, properly conducted randomised controlled trial of varicocele treatment in men with varicocele and sperm defects, from couples with otherwise unexplained subfertility. However, we realise that it will become increasingly difficult to conduct such a study, as the introduction of in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) in the fertility clinic will make many men reluctant to take the risk of being allocated to the no‐treatment arm of such a study, whilst a robust treatment of proven effectiveness is readily available in the form of IVF/ICSI. The issue will be further compounded by the fact that as many couples today tend to delay their first pregnancy, they are likely to feel pressed for time to conceive once they have decided in their mid‐ to late‐thirties to seek professional help for their fertility issues. Nevertheless, in countries or couples where IVF/ICSI is not a feasible option, varicocele treatment will continue to be performed and contribute to clinical knowledge and research.

In the future, authors should strive to report adverse events alongside outcomes, as this was poorly done in the studies assessed and has large implications on the overall success and practicality of the treatment of varicoceles.

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