Impact of Varicocele Repair on Assisted Reproductive Technique Outcomes in Infertile Men: A Systematic Review and Meta-Analysis

Abstract

Purpose

In this systematic review and meta-analysis, we investigated assisted reproductive technology (ART) success in infertile men with clinical varicocele and abnormal semen parameters who underwent varicocele repair (VR) before the ART procedure as compared to those who did not.

Materials and Methods

A comprehensive search of the Scopus, PubMed, Embase, and Cochrane Library databases was conducted using a specific query string to identify studies examining the impact of VR on ART outcomes, including fertilization rate, clinical pregnancy, pregnancy loss, and live-birth rate, until October 2023. Outcomes were analyzed based on the type of ART. Studies on VR in infertile men with non-obstructive azoospermia and those who underwent ART only due to female factor infertility were excluded from the study.

Results

Out of 1,554 articles reviewed, only 9 met the inclusion criteria for the study. All the included articles were observational studies. The variability in study quality in the included literature resulted in a moderate overall risk of bias. Data analysis showed that for intrauterine insemination, there was no difference in the clinical pregnancy rate (odds ratio [OR] 1.01, 95% confidence interval [CI]: 0.42, 2.45; p=0.97). However, for intracytoplasmic sperm injection (ICSI), men with VR showed a significant improvement in fertilization rate (mean difference 10.9, 95% CI: 5.94, 15.89; p<0.01), clinical pregnancy rate (OR 1.38, 95% CI: 1.07, 1.78; p=0.01) and live-birth rate (OR 2.07, 95% CI: 1.45, 2.97; p<0.01), compared to men who did not undergo VR.

Conclusions

The findings of this systematic review and meta-analysis suggest that VR has a positive impact on pregnancy and live birth rates after ICSI. However, biases like small sample sizes and heterogeneous populations highlight the need for larger, well-designed prospective studies to validate these findings.

INTRODUCTION

Varicocele, an abnormal dilatation of the veins in the pampiniform plexus, is a major cause of infertility in men. It is observed in nearly 15% to 20% of the overall male population [1], in 25% of men exhibiting abnormal semen analysis, and in approximately 35% to 40% of men seeking help for infertility [2]. The prevalence of varicocele in men who have primary infertility is calculated to be 35% to 44%, whereas men with secondary infertility have a prevalence rate of 45% to 81% [1,3].

The specific mechanism by which varicocele may contribute to male infertility is still not completely understood. It is assumed that a single factor is not responsible for its negative impact on male fertility [4]. Several pathophysiological mechanisms may occur in varicocele-related male infertility, including increased reactive oxygen species (ROS) and sperm DNA fragmentation (SDF), scrotal hyperthermia, hypoxia, reflux of renal and adrenal metabolites, hormonal imbalances, and the formation of anti-sperm antibodies. In venous reflux cases, the scrotal temperature, which is usually 2℃ below that of the core body, increases, thereby impeding normal spermatogenesis [5].

In the management of varicocele, much evidence is available regarding the positive impact of varicocele repair (VR) on semen parameters [6,7]. Some studies have shown that VR positively affects sperm quality, pregnancy outcomes, and reproductive hormones [8,9,10,11,12]. However, determining the true benefit of VR on pregnancy and live birth rates in subfertile men remains a challenge [2,13]. Specifically, the impact of VR on pregnancy-related outcomes associated with assisted reproductive technology (ART) has been controversial, with mixed results in the literature. Studies by Esteves et al [14] and Gokce et al [15] demonstrated a positive association between VR and improved pregnancy outcomes in patients undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). However, Pasqualotto et al [13] reported that VR has no significant effect on improving pregnancy outcomes following these procedures. This disagreement highlights the complexity of the relationship between VR and fertility outcomes following ART. Given this limitation and the absence of robust data on other ART techniques, an update is necessary to provide more comprehensive evidence.

The European Association of Urology (EAU) and American Urological Association (AUA)/American Society for Reproductive Medicine (ASRM) guidelines all lack of clear-cut recommendations for clinicians concerning the efficacy of VR in infertile men undergoing ART. The lack of consensus highlights the varying opinions within the medical community [2]. The absence of clear directives leaves clinicians with a degree of uncertainty when making decisions about the appropriateness of VR in specific cases, emphasizing the need for personalized approaches in infertility management.

This systematic review and meta-analysis (SRMA) aimed to investigate the impact of VR on ART success (fertilization rate, clinical pregnancy rate, and live birth rate) in infertile men with clinical varicocele. The findings of this study will help clinicians make decisions regarding the potential benefits of applying VR before ART.

MATERIALS AND METHODS

1. Search strategy

This SRMA was proposed and conducted following the Meta-Analyses and Systematic Reviews of Observational Studies (MOOSE) (Supplement Table 1) [16] and the Preferred Reporting Items for Systematic Reviews and Meta-analysis protocol (PRISMA-P) guidelines (Supplement Table 2) [17]. As previously described, a PICOS model was used for this SRMA [18]. The PICOS model of the current study is shown in Supplement Table 3.

2. Inclusion criteria

This SRMA included human randomized controlled trials (RCTs), case-control studies and cohort studies investigating ART (intrauterine insemination [IUI], IVF, and ICSI) outcomes in infertile men with clinical varicocele and abnormal semen parameters who underwent any VR procedure, including microsurgical, non-microsurgical inguinal, high retroperitoneal, laparoscopic, or embolization, before ART as compared to infertile men with clinical varicocele who proceeded directly to ART. These studies included cases where VR was applied for the first time and did not consider other types of treatments.

3. Exclusion criteria

Studies published as abstracts, conference papers, case reports, case series, reviews, or book chapters were excluded. Studies on VR in infertile men with non-obstructive azoospermia (NOA) and patients who underwent ART solely due to female factor infertility were also excluded.

4. Study outcomes

The outcomes of this SRMA included the fertilization rate (%), clinical pregnancy rate (%), pregnancy loss rate (%), and live birth rate (%).

Fertilization is the success of spermatozoa entry into a mature egg, followed by pronuclei formation. Clinical pregnancy is described as a pregnancy detected by ultrasound visualization of gestational sac(s) or clear clinical indicators of pregnancy. Pregnancy loss (per couple) refers to any pregnancy that fails to result in a live birth. Live birth (per couple) is defined as the complete expulsion or extraction of a live fetus after 22 completed weeks of gestation, which, following separation, breaths or exhibits signs of life [19].

5. Keyword string

A comprehensive search was conducted using a combination of Medical Subject Heading (MeSH) terms and free words. An initial keyword string was created on Scopus as follows: ( ( TITLE-ABS-KEY ( varicocel* AND management ) OR TITLE-ABS-KEY ( varicocel* AND embolization ) OR TITLE-ABS-KEY ( varicocel* AND embolisation ) OR TITLE-ABS-KEY ( varicocel* AND microsurg* ) OR TITLE-ABS-KEY ( varicocel* AND micro-surg* ) OR TITLE-ABS-KEY ( varicocelectom* ) OR TITLE-ABS-KEY ( varicocel* AND repair ) OR TITLE-ABS-KEY ( varicocel* AND correction ) OR TITLE-ABS-KEY ( varicocel* AND treatment ) OR TITLE-ABS-KEY ( varicocel* AND ligation ) OR TITLE-ABS-KEY ( varicocel* AND surg* ) OR TITLE-ABS-KEY ( varicocel* AND operation ) OR TITLE-ABS-KEY ( varicocel* AND radiolog* ) ) ) AND ( ( TITLE-ABS-KEY ( pregnan* ) OR TITLE-ABS-KEY ( intra-uterine AND insemination ) OR TITLE-ABS-KEY ( miscarriage* ) OR TITLE-ABS-KEY ( *birth* ) OR TITLE-ABS-KEY ( iui ) OR TITLE-ABS-KEY ( intra* AND insemination ) OR TITLE-ABS-KEY ( ivf ) OR TITLE-ABS-KEY ( in AND vitro AND fertilization ) OR TITLE-ABS-KEY ( fertilisation ) OR TITLE-ABS-KEY ( fertilization ) OR TITLE-ABS-KEY ( ICSI ) OR TITLE-ABS-KEY ( intracytopl* AND sperm AND injection ) OR TITLE-ABS-KEY ( ART ) OR TITLE-ABS-KEY ( offspring ) OR TITLE-ABS-KEY ( assisted AND reproductive AND techn* ) ) ) AND ( LIMIT-TO ( DOCTYPE , "ar" ) ). The keyword string was adapted for use in PubMed and other databases. The databases were searched for studies published until October 2023. Both English and non-English articles were included in the search.

6. Data collection and management

1) Identification and screening for eligibility

Initial manual screening of the retrieved abstracts was conducted in duplicate. The eligibility of the identified abstracts was considered based on this study’s inclusion and exclusion criteria and following the PICOS model (Supplement Table 3). The full texts of potentially eligible articles were downloaded and screened for eligibility before data extraction and quality assessment. After selecting eligible studies, an additional search was performed to identify narrative and systematic reviews on the topic. A manual search of papers quoted in these reviews was done to determine whether any paper needed to be added to our database.

2) Data extraction

Data were extracted from eligible studies for which the full text was available. The extracted information included general study characteristics (first author’s name, year of publication, study design, sample size in the experimental and control groups), and clinical characteristics of participants in the experimental and control groups including male age, female partner age, female gynecological examination (normal/abnormal), duration of infertility, laterality and grade of varicocele, testis size, and type of ART. Additionally, the type of VR and the time lapse between VR and ART were recorded in the experimental group. The data on the ART outcomes included the fertilization rate (%), clinical pregnancy rate (%), pregnancy loss rate (%), and live birth rate (%).

3) Accuracy of data collection

Screening for eligibility and data extraction were performed in duplicate, and the data were cross matched in each subgroup. Disagreements were resolved through further discussion and consensus. The data extraction sheet was verified by carefully reviewing the original articles.

4) Quality assessment

The quality of the studies included in this SRMA was assessed by the Cambridge Quality Checklists (CQC) [20]. The quality assessment was done in duplicate, and each subgroup was cross matched. The CQC ranges from the lowest score of 2 to a maximum score of 15. The CQC does not establish a clear threshold to distinguish between high and low-quality research. However, elevated CQC scores indicate more robust inferences.

5) Statistical analysis

The in-between-study heterogeneity was evaluated using the I² statistic and the Cochrane Q test [21], and an I² value of >50% indicating the presence of inbetween-studies heterogeneity [22]. Random and fixed effect models were used for high and low heterogeneity, respectively. The restricted maximum-likelihood estimator [23,24,25] was used to calculate the in-between study variance (tau²), and the inverse variance method was used to pool the effect size. Publication bias was assessed using a funnel plot. Sensitivity analysis was done by excluding one study at a time (leave-one-out method) and observing the changes in the pooled effect size. A study is sensitive when it significantly changes the pooled effect size when removed. The statistical analysis was performed using the R programming language R version 4.1.2 (https://www.r-project.org/), and a p-value <0.05 indicated a statistically significant difference between groups.

The limited data availability of specific parameters such as laterality and grade of varicocele, VR method, and the duration from VR to ART rendered it unfeasible to conduct subgroup analysis within the scope of this study.

RESULTS

The extensive search of medical databases resulted in 1,554 records. After removing 611 duplicates, 943 items were assessed for eligibility.

In the abstract eligibility screening phase, 171 publications were identified as review articles, book chapters, case reports, or editorials and were therefore excluded. An additional 711 records were excluded based on their titles or abstracts. The full text of 7 non-English articles underwent thorough examination and analysis by 2 of the Global Andrology Forum members [26,27,28] to ensure a thorough analysis of the articles. In the eligibility phase, 36 papers were excluded based on the full-text review. Out of the initial set, nine articles [13,14,15,29,30,31,32,33,34] met our inclusion criteria. The PRISMA-P flowchart is illustrated in (Fig. 1). A detailed list of excluded studies and the reason for exclusion is provided in Supplement Table 4.

Fig. 1. The flowchart of the study according to PRISMA-P guidelines (Shamseer et al, 2015) [20]. ART: assisted reproductive technology.

1. Characteristics of the included studies

The data on the first author, year of publication, study design, type of VR, number of cases, number of controls, type of ART procedure, time from VR to the ART procedure, and the evaluated outcome for each study are detailed in Table 1.

Table 1. Main characteristics of the included studies.

Author	Year	Study design	Patient (n)	Control (n)	Patient age (y)	Controls’ age (y)	Type of ART	Type of VR	Mean time from VR to ART procedure (mo)	Outcome
Al-Mohammady et al [29]	2019	Case-control study	50	50	NA	NA	ICSI	Non-microsurgical sub-inguinal open surgery	12	Fertilization rate, clinical pregnancy rate
Gokce et al [15]	2013	Case-control study	168	138	34.8±4.3	34.4±4.1	ICSI	Microsurgical	7.2	Clinical pregnancy rate, miscarriage rate, and live birth rate
Pasqualotto et al [13]	2012	Case-control study	169	79	36.1±0.5	37.8±0.4	ICSI	Microsurgical	NA	Fertilization rate, implantation rate, clinical pregnancy rate, miscarriage rate
Esteves et al [14]	2010	Case-control study	80	162	35.8±5.4	35.4±6.3	ICSI	Microsurgical	6.2	Fertilization rate, clinical pregnancy rate, miscarriage rate, live birth rate
Baazeem et al [30]	2009	Case-control study	38	27	34.9±5.5	36.2±5.5	IUI	Microsurgical	NA	Clinical pregnancy rate
			34	27			ICSI
Zini et al [31]	2008	Case-control study	70	48	35.6±5.6	35.9±5.3	IUI	Microsurgical	NA	Clinical pregnancy rate
			55	49			ICSI
Boman et al [32]	2008	Retrospective cohort	12	10	35.9±4.5	38.3±5.8	IUI	Microsurgical	NA	Clinical pregnancy rate
			6	9			ICSI
Daitch et al [33]	2001	Case-control study	34	24	NA	NA	IUI	Non-microsurgical, microsurgical	NA	Clinical pregnancy rate, miscarriage rate, live birth rate
Marmar et al [34]	1992	Non-randomized trial	16	7	32.4±4.3	34.6±4.1	IUI	NA	NA	Clinical pregnancy rate

ART: assisted reproductive technique, VR: varicocele repair, IUI: intrauterine insemination, ICSI: intracytoplasmic sperm injection, NA: not available.

2. Results of the quality assessment

The results of the quality assessment of the included studies using the CQC are shown in Table 2. Of the 9 studies included in this meta-analysis, 6 had a total CQC score between 8 and 10 [13,14,15,29,32,33], and the remaining 3 had a total score of 5 [30,31,34].

Table 2. Results of the quality of evidence assessment.

Author	Year	Cambridge quality checklist
		Checklist for correlates (0–5)	Checklist for risk factors (1–3)	Checklist for causal risk factor (1–7)	Total score (2–15)
Al-Mohammady et al [29]	2019	2	3	5	10
Gokce et al [15]	2013	2	2	5	9
Pasqualotto et al [13]	2012	2	2	5	9
Esteves et al [14]	2010	2	2	6	10
Baazeem et al [30]	2009	1	2	2	5
Zini et al [31]	2008	1	2	2	5
Boman et al [32]	2008	1	2	5	8
Daitch et al [33]	2001	2	2	5	9
Marmar et al [34]	1992	1	2	2	5

3. Impact of VR on IUI outcomes

1) Clinical pregnancy following the IUI cycles

The random effect model was used due to interstudy heterogeneity (I²=50%, Q p-value 0.09). Five studies were included [30,31,32,33,34]. The meta-analyses included 170 and 116 men in the VR and untreated varicocele groups. The pooled estimate was not significantly different between the compared groups (OR 1.01, 95% CI: 0.42, 2.45; p=0.97) (Fig. 2A). Sensitivity analysis revealed that no studies influenced the pooled estimate when these studies were removed (Fig. 2B). Publication bias is demonstrated in the funnel plot (Fig. 2C).

Fig. 2. Forest plot (A) and sensitivity analysis (B) of positive clinical pregnancy following intrauterine insemination (IUI) in infertile couples in whom the male partner underwent varicocele repair (VR) compared to those without VR (untreated varicocele). Results are expressed as odds ratio (OR) and 95% confidence interval (CI). (C) Funnel plot showing publication bias of studies reporting clinical pregnancy outcome following IUI in infertile couples in whom the husband underwent VR compared to those without VR (untreated varicocele).

2) Live-birth rate following the IUI procedure

Since the number of studies was <2, this outcome could not be meta-analyzed. The only study analyzing this outcome demonstrated higher live birth rates per cycle in patients who underwent VR than in those without varicocele treatment (11.8% vs. 2.1%, p=0.007) [33].

4. Impact of VR on ICSI outcomes

1) Fertilization rates following the ICSI procedure

A fixed effect model was used (I²=0, Q p-value 0.38). Two studies were included [14,29]. The meta-analysis included 130 and 212 men in the VR and untreated groups. The pooled estimate was significantly higher in the VR group (mean difference 10.9, 95% CI: 5.94, 15.89; p<0.01) (Fig. 3A). Publication bias is demonstrated in the funnel plot (Fig. 3B).

Fig. 3. (A) Forest plot showing the meta-analysis of fertilization rates following intracytoplasmic sperm injection (ICSI) in infertile men with varicocele repair (VR) compared to no VR (untreated varicocele). (B) Funnel plot showing publication bias of studies reporting fertilization outcome following ICSI in infertile men with VR compared to no VR (untreated varicocele). SD: standard deviation, 95% CI: 95% confidence interval.

2) Clinical pregnancy following the ICSI procedure

A fixed effect model was used (I²=38%, Q p-value 0.1). Seven studies were included [13,14,15,29,30,31,32]. The meta-analysis included 562 and 514 men in the VR and untreated varicocele groups, respectively. The pooled estimate was significantly greater in the VR group (OR 1.38, 95% CI: 1.07, 1.78; p=0.01) (Fig. 4A). The sensitivity analysis revealed two studies that changed the pooled estimate when removed (Fig. 4B) [14,15]. Publication bias is demonstrated in the funnel plot (Fig. 4C).

Fig. 4. Forest plot (A) and sensitivity analysis (B) of clinical pregnancy outcome following intracytoplasmic sperm injection (ICSI) in infertile men with varicocele repair (VR) compared to no VR (untreated varicocele). (C) Funnel plot showing publication bias of studies reporting clinical pregnancy outcome following ICSI in infertile men with VR compared to no VR (untreated varicocele). OR: odds ratio, 95% CI: 95% confidence interval.

3) Live birth rate following the ICSI procedure

A fixed effect model was used (I²=0%, Q p-value 0.6). Two studies were included [14,15]. The meta-analysis included 248 and 300 men in the VR and untreated varicocele groups, respectively. The pooled estimate was significantly greater in the VR group (OR 2.07, 95% CI: 1.45, 2.97; p<0.01) (Fig. 5A). The small number of studies and participants may limit the generalizability of the findings and can lead to inaccurate interpretation of the publication bias demonstrated in the funnel plot (Fig. 5B).

Fig. 5. Forest plot of live birth outcome following intracytoplasmic sperm injection (ICSI) in infertile men with varicocele repair (VR) compared to no VR (untreated varicocele). (B) Funnel plot showing the publication bias of studies reporting live birth outcome following ICSI in infertile men with VR compared to no VR (untreated varicocele). OR: odds ratio, 95% CI: 95% confidence interval.

There were no adequate data on pregnancy loss outcomes either in IUI or ICSI procedures. Additionally, due to the limited number of included studies, data on subgroup parameters such as female age, female examination, classification of varicocele, grade of varicocele, method of VR, and the duration between treatment and ART were scarce, and we were unable to conduct subgroup statistical analysis.

DISCUSSION

The significance of VR before ART in infertile men with clinical varicocele has been a matter of debate, and its application in clinical practice remains limited. This study explored the effectiveness of VR in enhancing the outcomes of ART. In the IUI group, the results indicated that VR did not improve clinical pregnancy rates. However, significant enhancements in both clinical pregnancy rates and live births were observed in the ICSI group among patients who underwent VR compared to those who did not. No publication bias was detected for the tested parameters. For the clinical pregnancy rate following the IUI and ICSI procedures and the live birth rate following the ICSI procedure, no study was sensitive enough to change the conclusions of our findings.

Previous studies have demonstrated that VR improves fertilization outcomes in patients undergoing ART. However, the available evidence remains inconclusive [14,35]. The low quality of the studies evidence may be attributed to the study design, as almost all the studies were retrospective, and there was a lack of randomized clinical trials. In addition, previous SRMAs on the topic included a limited number of studies from those screened, underscoring the scarcity of evidence analyzing ART outcomes in patients undergoing VR (Table 3).

Table 3. Evidence derived from previous meta-analyses comparing ART outcomes between treated and untested varicocele patients indicates a positive impact of surgical intervention.

Study	Studies included	No. of cases	IUI outcome	IVF outcome	ICSI outcome	Results
Esteves et al [35] (2016)	4	870	-	-	Pregnancy outcome and live birth rate	VR improved the clinical pregnancy rate (OR=1.59) and live birth rate (OR=2.17) compared to untreated varicocele
Kirby et al [36] (2016)	7	1,241	-	Live birth rate	Pregnancy outcome and live birth rate	VR increased live birth rates for oligospermic individuals (OR=1.699) and those in the combined oligospermic/azoospermic groups (OR=1.761). Pregnancy rates were elevated in the azoospermic group (OR=2.336) and the combined oligospermic/azoospermic groups (OR=1.760). Additionally, patients undergoing IUI after VR experienced higher live birth rates (OR=8.360) compared to untreated varicocele
Kohn et al [37] (2017)	8	885	Pregnancy outcome	Pregnancy outcome	Live-birth rate	VR improved pregnancy outcomes in patients undergoing ICSI compared to untreated varicocele

ART: assisted reproductive technique, VR: varicocele repair, IUI: intrauterine insemination, IVF: in vitro fertilization, ICSI: intracytoplasmic sperm injection, OR: odds ratio.

The current meta-analysis includes a larger number of studies on this topic (9 studies), and the fertilization rate was analyzed for the first time. Some included studies received relatively high-quality assessment scores (8 to 10), suggesting a lower risk of bias; others received lower scores (total score of 5), indicating a higher risk of bias. Hence, the overall risk of bias in the meta-analysis could be considered moderate, reflecting the variability in study quality among the included literature. However, an inherent publication bias may exist with studies reporting successful ART outcomes and not reporting failures of ART.

Few studies in the literature with similar outcomes agree with our results. A meta-analysis by Kirby et al [36], which included seven studies and 1,241 patients, concluded that in males with NOA or severe oligospermia and varicocele, VR results in increased sperm retrieval rates for NOA patients undergoing testicular sperm extraction and in increased pregnancy outcomes and live-birth rates in infertile couples undergoing ART. Another meta-analysis by Esteves et al [35] showed improved pregnancy outcomes and live birth rates after performing VR before ICSI. Additionally, a study by Kohn et al [37] revealed that VR improved pregnancy outcomes in patients undergoing ICSI.

The AUA/ASRM guidelines recommend that VR should be considered for men with palpable varicocele(s), infertility, and abnormal semen parameters, except for azoospermic men (Moderate Recommendation; Evidence Level: Grade B) [36], with strong advise against surgery for men with non-palpable varicocele(s) (Strong Recommendation; Evidence Level: Grade C) [38]. At the same time, the EAU guidelines provide strong recommendations for VR in infertile men with clinical varicocele, abnormal semen parameters, and unexplained infertility in a couple where the female has good ovarian reserve [7]. EAU also recommends VR in males exhibiting elevated SDF levels and experiencing unexplained infertility or suffering from unsuccessful ART, including recurrent miscarriage, failure of embryogenesis and implantation (weak recommendation) [36].

The findings of our meta-analysis endorse VR before conducting ICSI as a potentially effective treatment strategy for infertile men with clinical varicocele. This approach leads to higher fertilization and live birth rates compared to performing ICSI without VR. However, for the IUI procedure, no definitive conclusions can be drawn about the effectiveness of VR on IUI success. The existing studies examining the impact of VR on IUI outcomes are retrospective and involve relatively small patient numbers. There is a lack of randomized trials and an absence of data on time to pregnancy, treatment duration, and the need for repeated treatments. Future large-scale studies are needed to determine if VR affects IUI outcomes [39].

In cases of infertility associated with advanced maternal age, there is a lack of data regarding the potential beneficial effect of VR on pregnancy outcomes prior to ART, leading to challenges in guidance and management [40,41]. Although current evidence suggests that correcting a clinical varicocele can enhance pregnancy outcomes in couples intending to pursue IVF or ICSI [42], there remains a scarcity of supportive data regarding the efficacy of VR in cases of advanced maternal age and potential ART [43].

Given that the average time from VR to conception typically exceeds 6 to 12 months, current clinical protocols for treating females over the age of 35 years with a partner who has a varicocele include the immediate implementation of ART in conjunction with VR [44]. Additionally, the initiation of ICSI procedures is recommended when the female partner is older than 37 years [45].

Some existing studies have shown that increased SDF and seminal oxidative stress increase pregnancy loss in ART and negatively affect embryo development [46,47]. However, VR has been shown to ameliorate oxidative stress and reduce sperm DNA damage [48,49]. Hence, VR can notably aid in the recovery of male fertility in cases where an individual is dealing with varicocele and has severely deteriorated semen parameters. This procedure may lead to the use of less invasive treatments or enhance ART outcomes, with improving general pregnancy and live birth rate [50].

In a clinical context, these results can guide clinicians to make more informed decisions and provide optimal treatment strategies for infertile men with clinical varicocele, ultimately improving their chances of achieving successful outcomes in assisted reproduction.

1. SWOT analysis

Utilizing the strengths, weaknesses, opportunities, and threats (SWOT) analysis, we summarize the strengths, weaknesses, opportunities, and threats of our meta-analysis on ART outcomes after VR (Fig. 6).

Fig. 6. The strengths, weaknesses, opportunities, and threats (SWOT) analysis of the study of assisted reproductive technology (ART) outcomes after varicocele repair. VR: varicocele repair, RCTs: randomized controlled trials.

2. Limitations of the study

While the current study substantiates the benefits of VR in enhancing ART outcomes, we acknowledge several limitations. After screening numerous studies, only nine met the inclusion criteria primarily due to poor study design and incomplete or inadequate reporting of ART outcomes, highlighting a need for more robust research. Furthermore, only two of these nine studies had a sample size exceeding 100 subjects, indicating that the majority had small sample sizes. Critical was that most studies did not have a randomization design, and no RCTs were included. Notable heterogeneity was observed among the included studies. Additionally, all other studies were dated except one published post-2015 that addressed ART-related outcomes.

The quality of evidence provided by our meta-analysis could not be more robust due to several compromising factors. We found a notable publication bias, with studies preferentially reporting successful ART outcomes and omitting failures. This bias could only be rigorously rectified through future studies of randomized and prospective designs. Crucial baseline characteristics of the infertile males, such as testicular size and hormonal levels, were omitted from our analysis. Similarly, baseline semen parameters were not incorporated, and the presence of studies with lower baseline parameters might indicate an inherently poorer prognosis for VR, introducing further bias. Therefore, conducting subset analyses could be beneficial in delineating more precise outcomes.

3. Recommendations for future studies

Well-designed studies, specifically RCTs, are necessary to provide robust clinical evidence on the optimal application of VR for men with varicocele-associated infertility. However, they can be challenging to conduct. Future studies are warranted to investigate the effects of various parameters, such as patient age, grade of varicocele, and duration post-VR, on the success of ART procedures. Conducting subgroup analyses based on relevant variables will allow us to determine potential sources of heterogeneity and provide more reliable results.

CONCLUSIONS

The findings of our SRMA support a positive effect of VR before ICSI on pregnancy and live birth rates. Well-designed RCTs are needed to validate these results and further elucidate the impact of VR on ART outcomes across different patient populations.

Supplementary Materials

Supplementary materials can be found via https://doi.org/10.5534/wjmh.240132.

Supplement Table 1

MOOSE Guidelines of Reporting Checklist for Authors, Editors, and Reviewers of Meta-analyses of Observational Studies

Supplement Table 2

PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) checklist

Supplement Table 3

Participants, interventions, comparators, and outcomes (PICO)

Supplement Table 4

Studies excluded from this systematic review and meta-analysis