Statistical analysis
Statistical heterogeneity between the studies was evaluated with the use of the I2 statistic, as formally suggested in the Cochrane Handbook for systematic reviews (8 ). A I2 < 50% and a p value over 0.05 were considered non-significant heterogeneity. Meta-analysis was conducted with the results being either pooled percentages or standardized mean difference (SDM) of the meta-analysed outcomes during comparisons. As per the most widely accepted definitions, difference amongst the assessed parameters was evaluated as small for SMD = 0.2; medium for SMD = 0.5; and large for SMD = 0.8, with p<0.05 being considered statistically significant for all comparisons (13 ,14 ). Where possible and most relevant, forest plots were constructed to facilitate visualization of the assessed corelations, otherwise data was provided in text, tables or supplementary material. Calculations and graphs were carried out using the Stata Statistical Software: Release 14.2 by StataCorp LP.

Results

The initial pool of 955 studies, which resulted from the preliminary search of the medical databases was refined via manual screening of the title and abstract, leading to 107 reports being moved to full-text assessment. Through constant evaluation and strict application of the pre-established inclusion criteria, 53 studies were ultimately included in this review (15-67 ). This systematic process of selection is summarized on Figure 1 . Most of the eligible studies originated from the USA, the Republic of Korea and Taiwan and the vast majority were based on data collected retrospectively from institutional medical records, with only 8 studies being conducted prospectively. 25 of the studies utilized an eligible comparator; CLM, AM or both, thus were utilized in comparative analysis. Ultimately, this systematic review included data from 7109 women. This information is summarized on Table 2 .
The mean age of the included participants ranged from 34 to 48.2 and mean BMI from 20.2 to 31. The main indications for myomectomy were clinical symptoms such as feeling of pelvic mass, pelvic pain, uterine bleeding, infertility, gastrointestinal symptoms, urinary symptoms etc and a sizeable percentage of participants had a history of prior abdominal surgery and/or caesarean section (Table 3) . With regard to RALM technical characteristics, the majority of available studies used older Da Vinci Surgical System, with only 9 studies using the 4th generation Da Vinci X and Xi systems. With regard to the procedure, the basic steps were consistent amongst all studies. Most studies used a 12mm robotic port for the camera, placed either above or below the umbilicus, with at least 2 additional, most commonly 8mm robotic ports bilaterally. A few studies used a third 8mm robotic port and most researchers used an accessory 12, 10 or 5mm port as well. The mean number of robotically excised myomas per study ranged from 1.5 to 7, as did the mean myoma diameter (3-8.3 cm), the mean diameter of the largest myoma (5-11cm) and mean myoma weight (30-450 g) (Table 4) .
With regard to risk of bias, the included studies were assessed using the tools for case series, case-control and non-randomized trials, recommended by the NIH (12 ). Based on the results of this analysis, 38 (72%) of the included studies were of “Good” quality with regard to risk of bias, 8 studies (15%) were of “Fair” quality and the remaining 7 studies (13%) were of “Poor” quality with regard to risk of bias assessment.
Heterogeneity among the studies was assessed using the I2 index. Regarding the RALM and AM comparison of primary surgical outcomes, there was statistically significant heterogeneity, namely I2=81.5% (p<0.001) for the EBL comparison, I2=83.2% (p<0.001) for the MOD comparison and I2=95.3% (p<0.001) for the LOS comparison. Heterogeneity was non-significant for the complication rate comparison (I2=0%, p=0.716) and for the transfusion rate comparison (I2=0%, p=0.418). With regard to actual outcomes, RALM had significantly lower EBL compared to AM, with SMD=0.312, p=0.004 (Figure 2a) , AM was superior with regard to MOD, requiring significantly less operation time, with SMD=1.251, p<0.001 (Figure 2b) and RALM necessitated significantly less hospitalization duration than AM, with the LOS SMD=1.368, p<0.001 (Figure 2c) . RALM had a significantly lower complication rate compared to AM, being nearly 70% safer, with OR=0.669, p=0.016 (Figure 3a) , in addition to a 40% less frequent requirement of transfusion compared to AM, with a pooled OR=0.402, p<0.001 (Figure 3b) .
For the comparison of RALM to CLM, data was stratified in groups based on overall myoma weight, so as to more thoroughly elucidate any possible applications of each methodology based on myoma burden. Statistical heterogeneity was assessed for each comparison and was significant, with I2=87.6%, p<0.001 for the EBL comparison, I2=96.6%, p<0.001 for the MOD comparison and I2=72.2%, p<0.001. Heterogeneity was non-significant for the complication rate comparison (I2=0%, p=0.596), the transfusion rate comparison (I2=18.2%, p=0.266) and the conversion to laparotomy rate comparison (I2=0%, p=0.781). With regard to outcomes, there was no statistically significant difference with regard to EBL between RALM and CLM (SMD=0.079, p=0.544), however, when data was stratified according to myoma weight, RALM caused significantly less blood loss in cases with lower myoma weight (SMD=0.272, p=0.025), while CLM was superior for the rest of the myoma cases, SMD=0.49, p=0.007(Figure 4a) . Similar to the RALM-AM comparison, RALM was inferior to CLM with regard to MOD, SMD=0.97, p<0.001(Figure 4b) , while there were no statistically significant differences between the two methods with regard to LOS, SMD=0.172, p=0.094 (Figure 4c) . Complication and transfusion rates were similar in both methods, with no statistically significant differences, SMD=0.842, p=0.596 and SMD=0.984, p=0.951 respectively (Figure 5a and 5b) . Conversion to laparotomy rate also technically showed no statistically significant difference between the two methods, however the difference was only marginally non-significant, with OR=0.533 and p=0.058 (Figure 5c) .
With regard to fertility outcomes, pregnancy rates ranged from 50-80% post-operatively, with the majority originating from spontaneous conception. Studies with sufficient follow-up, at the time of publication, demonstrated a live birth rate of 25-100%. Detailed fertility and obstetric outcomes are summarized on Table 1 .

Discussion

In this systematic review, we examined the application of RALM, one of the newest minimally invasive available techniques for the treatment of uterine fibroids and compared it to the other two established methodologies, namely AM and CLM. All available studies with data on RALM was collected and the information extracted on tables. RALM was compared to AM favourably in almost all aspects apart from operation duration. Operation duration was also more favourable in CLM than RALM, with the rest of the assessed outcomes not being significantly different between the two methods. The exceptions to that were EBL for lesser myoma burden patients, which was significantly more favourable in RALM and conversion to AM rate, which only marginally lacked statistical significance.
The findings of the present systematic review are indicative of the wider trend of minimally invasive surgery expansion and proliferation in more and more fields of Gynaecologic Surgery. Our findings with regard to AM and RALM comparison are in complete agreement with Wang et al (68 ), who conducted a similar meta-analysis in 2018. However, there are differences when the comparison of RALM and CLM is concerned. In their analysis, as was the case in ours as well, Wang et al showed that there were no statistically significant differences in transfusion rates or LOS between RALM and CLM (68 ). Additionally, they showed that there was a statistically significant difference in conversion to laparotomy rate (68 ) between the two methods. In our analysis, while conversion rate difference was non-significant, this was only by a very small margin, thus findings on conversion rate are in actuality quite similar. Wang et al also showed statistically significant differences in complication rates, although when complications were analyzed in subgroups, the differences were non-significant, similar to our general observations with regard to complications. Another difference between the two analyses was with regard to EBL, as Wang et al. showed there was a statistically significant difference between RALM and CLM, regardless of other conditions. This held true in our analysis only for lower overall myoma burden patients, with the overall differences not being statistically significant. Finally, with regard to operative time, Wang et al. showed that there were no statistically significant differences, while in our analysis CLM was significantly faster. However, regarding this particular comparison, in the meta-analysis by Wang et al, the difference was only marginally statistically significant (68 ).
These differences between the two studies may be attributed to differences in baseline characteristics of the patients, as in multiple studies the two groups had statistically significant difference with regard to myoma number, size, weight etc. Additionally, since the more modern studies also included patients operated on using the latest Da Vinci surgical system platforms, the observed discrepancies may be attributed to inexperience of the surgeon or the ancillary staff for these first reported cases. Furthermore, in both analyses, there was statistically significant heterogeneity amongst the included primary comparisons, thus the results of the meta-analysis might be affected in both cases.
With regard to the findings of the present study, the apparent disadvantage of RALM versus CLM, namely the unfavourable comparison to the other two methods with regard to operation duration, while indeed constituting a notable drawback, may be acceptable if patient risk of morbidity and mortality is significantly reduced in return. Additionally, based on the data collected during the present study, RALM operation duration is following a downward trend already (Figure 6) , and is likely to continue to do so in the future given the continuous growth of robotic technology (69 ) and improvement of training standards. When the inevitable comparison to CLM is made, RALM proved to be superior with regard to EBL in patients with smaller overall myoma weights. These cases usually include patients with smaller myomas, a situation where the absolute control and precision that the robotic surgical system offers is best utilized, minimizing injuries and thus resulting in reduced blood loss. Additionally, the fact that RALM offered up to 50% reduced risk of conversion to laparotomy, a complication associated with further, severe complications and an overall more adverse outcome (70 ); reinforces the safety and risk minimization aspect emphasized by robotic technology.
Robotic surgery has been a rapidly developing field in recent years, particularly as far as Gynaecological Surgery is concerned. The robotic equipment was designed to surpass the limitation of conventional laparoscopy, providing superior, three-dimensional visualization of the surgical site, increased magnification of areas of interest, enhanced dexterity via highly articulating surgical instruments and absent tremor (71 ,72 ). Additionally, the ergonomic working configuration of the console ensures reduced strain, be it physical or mental, to the surgeon, with significant improvement to surgery ergonomics (73 ,74 ), a vital feature especially for high-volume surgeons and/or multi-hour procedures. Given the prevalence of uterine fibroids and the effect that they may have on quality of life and fertility, a safe, effective, reliable and ergonomic approach such as RALM is a necessary and beneficial addition to the modern Gynaecologic Surgeon’s arsenal (75 ).
Research on the applicability of robotic systems in Gynaecologic Surgery, and in fibroid management in particular, is still lacking. Future research projects should aim to design a randomized trial for RALM and CLM comparison, as such a study has not been conducted yet and would provide valuable insight. Additionally, further specialized applications and indications for robotic surgery should be sought, as such data may be utilized in updating management algorithms and promote robotic surgery to patients who truly stand to gain the most from this advanced method.
The present study does come with certain limitations, which should be acknowledged. Firstly, there was statistically significant heterogeneity in the pooled available data, which may have introduced bias, affecting the results of the analysis. Additionally, there were not enough studies utilizing the latest advances in robotic technology, i.e. 4th generation Da Vinci surgical systems, which may be more representative of the capabilities of modern systems, since robotics is such a rapidly evolving field. Finally, not enough primary data was available to further stratify patients and thus to test the performance of the three therapeutic approaches in more specific cases.

Conclusion

RALM is a safe and effective therapeutic option for uterine fibroids, which is superior to AM in almost every regard and offers significant risk reduction and safety over CLM. Robotic technology, as well as surgical skill is likely to further improve in the future, thus enhancing the benefits already offered by this technology. Further primary research should focus on establishing patient subgroups which would most benefit from this advanced methodology.
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