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The Role of Laparoscopic Surgery in the Treatment of Advanced Uterine Prolapse: A Systematic Review of the Literature

The aim of this review is to investigate and compare all laparoscopic techniques that can be used in the surgical repair of advanced uterine prolapse. A systematic search of the PubMed, Scopus, Cochrane CENTRAL, and Clinicaltrials.gov databases was performed for articles published up to December 2020, reporting data on the treatment of severe uterine prolapse using laparoscopic procedures. Only studies in the English language, with a patient sample of ≥20 and a follow-up time of ≥12 months were included. The final synthesis of this review consisted of six studies. The main laparoscopic procedures reported were vaginally assisted laparoscopic sacrocolpopexy, vaginally assisted laparoscopic uterine sacropexy, laparoscopic sacrocolpopexy with laparoscopic supracervical hysterectomy, laparoscopic inguinal ligament suspension with uterine preservation, and laparoscopic uterosacral ligament suspension combined with trachelectomy. All procedures involved mesh placement, except for laparoscopic uterosacral ligament suspension. All procedures reported anatomical cure rates > 90%. Vaginally assisted laparoscopic sacrocolpopexy had the largest amount of intraoperative blood loss whilst vaginally assisted laparoscopic uterine sacropexy was associated with bladder injuries intraoperatively. All vaginally assisted procedures reported cases of mesh extrusion postoperatively. Laparoscopic inguinal ligament suspension was the operation with the longest mean operative and hospitalization time. Conversions were not reported. The present study shows that minimally invasive surgery can be used efficiently as an alternative to open surgery in the treatment of severe uterine prolapse.

The objective of this review is to investigate the laparoscopic techniques used in the surgical repair of advanced uterine prolapse, to compare them regarding their outcomes, and to discuss their indications in the treatment of severe POP based on the most recent data in the literature.

Materials and methods
The present study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [20].

Eligibility criteria
All English-language studies, enrolling ≥ 20 patients, with follow-up ≥ 12 months and reporting on the treatment of advanced uterine prolapse (stage ≥ III by the POP-Q system) with laparoscopic techniques were included in this review. Randomized controlled trials, clinical trials, cohort studies, and case series were also included in this review while editorials, letters to the editor, case reports, reviews, and meta-analyses were excluded.

Screening process
The titles and abstracts of the articles that resulted from the literature search were screened to determine which studies were relevant to our object. Once the duplicates were recognized and removed, all relevant articles were then retrieved in full text and reviewed by two separate authors for inclusion or exclusion in accordance with our eligibility criteria. The reference lists of the articles that were retrieved in full text and included in this review were additionally searched for relevant articles in the field that may have been missed by the digital search, and any eligible articles identified in this way were also included in this review. Any discrepancies on selection were resolved by the consensus of all authors.

Data extraction
Our extracted data included patient demographics such as age, body mass index (BMI), parity, menopausal status, and surgical history, as well as POP characteristics (type, stage, and associated symptoms). Moreover, operation parameters, including the type of operation, operative time, estimated blood loss, intra/postoperative complications, and conversions, were also assessed. Hospital stay and concurrent procedures were additionally appraised. Finally, we evaluated the treatment outcome of each surgical operation by assessing four different parameters: i. Anatomical cure rate, ii. Presence of recurrent prolapse after surgery, iii. Patient satisfaction, iv. Post-operative symptoms/findings.

Results
The database search using the aforementioned combination of keywords identified 349 records from PubMed (n = 269), Scopus (n = 63), Cochrane Library (n = 17), and ClinicalTrials.gov (n = 0). After the removal of the duplicates, the remaining 181 records were screened for eligibility based on the title and the abstract of the article. This searching strategy resulted in 34 English-language articles that were retrieved in full text. Subsequently, those articles were reviewed by two different authors for inclusion or exclusion according to our predetermined eligibility criteria. After the exclusion of 28 articles that involved hysterectomized women, patients with POP stage <ΙΙΙ, follow-up time<12 months, or patient sample size<20, six eligible articles emerged from this process and were included in our review. Figure 1 summarizes our data search strategy.

Quality Assessment
The quality of the included RCTs was evaluated using the modified Jadad score [21]. The quality of the nonrandomized studies was assessed according to Methodological Items for Non-Randomized Studies (MINORS) [22]. Two authors independently performed the procedure. The Jadad scale for the included RCT scored 5 (max 5) and the MINORS scale provided a mean score of 12.7 for the four included non-comparative studies (range 12-14, max16) and a score of 22 for the included comparative study (max 24).

Patient Demographics, POP Characteristics, and Preoperative Symptoms
Patient demographics are presented in detail in Table 2. All studies included in this review involved patients with uterovaginal prolapse stage ≥ III by the POP-Q system with or without concurrent cystocele/rectocele. Voiding symptoms and urgency were reported as preoperative symptoms in one study in our review [18]. Additionally, two studies involved a total of 42 patients (11.7%) with concomitant urinary stress incontinence (USI) preoperatively [18][19], and one study reported eight patients (2.2%) with urge incontinence (UI) prior to surgery [18]. In four studies, data regarding preoperative symptoms were not available [17,[23][24][25]. Table 3 lists POP characteristics and patient preoperative symptoms.

Previous Pelvic/Abdominal Operations
Two studies in our review involved patients that had undergone pelvic/abdominal operations in the past [18,23]. More specifically, in the Morciano et al. RCT, 18/84 (21.4%) patients had been subjected to a cesarian section in the past, whilst 11/84 (13.1%) patients reported a history of other previous abdominal procedures [23]. Additionally, in the Fayyad et al. study, 6/70 (8.6%) patients had a previous operation for anterior vaginal wall repair [18]. Three studies reported no previous pelvic or abdominal operations [17,19,25], and in one study, data regarding the patient's surgical history were not available [24]. Previous pelvic/abdominal operations are shown in Table 4.

Operation-Related Data
The mean operative time varied depending on the procedure within a range of 51-164 min. More specifically, combined trachelectomy with LULS had the shortest mean duration, which was 51.0 ± 8.4 min [24], whilst uterine LILS with mesh was the procedure with the longest mean operative time, estimated at 163.8 ± 41.3 min [25]. Furthermore, trachelectomy with LULS was the operation with the least intraoperative bleeding (32.0 ± 17.5 ml) [24]. On the contrary, vaginally assisted laparoscopic sacrocolpopexy had the largest amount of intraoperative blood loss (310 ml) [17].
None of the studies included in this review reported conversions to open surgery. Hospitalization time varied within a range of 36 hours-five days and was associated with the type of procedure. Patients that underwent VALUES with mesh reported the shortest hospitalization time (36 hours) [18], whilst patients that were subjected to uterine LILS with mesh required the longest hospital stay (five days) [25]. Table 5 summarizes all the operative data from the included studies.

Complications
In our review, we separated surgical-related complications into two main categories: intraoperative complications and postoperative complications.
Neither of the included studies reported mesh erosion postoperatively. On the contrary, mesh exposure was reported in two studies [18][19]. More specifically, Fayyad et al. [18] reported one case of post-menopausal bleeding combined with mesh exposure after VALUES, whilst Athanasiou et al. reported two cases of mesh extrusion after VALS [19]. Based on the aforementioned studies, the mesh exposure rates after VALUES and VALS in our review were estimated at 1.4% and 2.1%, respectively.
Postoperative fever was reported in Morciano et al. RCT [23] after LSH plus LSC in 3/84 (3.6%) patients, whilst pelvic hematoma occurred in 2/70 (2.8%) patients in Fayyad et al. study [18] after VALUES. Finally, in the Athanasiou et al. study [17], one patient (3.7%) complained about the presence of a prolene suture visible at the vaginal vault two months after VALS, which was ultimately removed under local anesthesia. All intraand postoperative complications for each study can be found in detail in Table 5.

Concurrent Procedures
Three studies reported hysterectomy (total or subtotal) as one of the main concomitant procedures [17,19,23]. Morciano et al. [23] performed laparoscopic supracervical hysterectomy in all their patients prior to LSC, whilst in both Athanasiou et al. studies [17,19] all patients underwent vaginal hysterectomy during the first step of the VALS operation. Unilateral/bilateral salpingo-oophorectomy was also performed when indicated during hysterectomy, with laparoscopy being the preferred approach for the procedure [17,19].
Concurrent pelvic floor repair operations were also reported in our review. More specifically, in three different studies [17][18]24], a total of 74 patients (21.2%) underwent anterior colporrhaphy for concomitant cystocele, whilst three studies reported a total of 74 rectocele cases (21.2%) that were subjected to a concomitant posterior colporrhaphy/perineorrhaphy for their treatment [17,19,24]. Moreover, four studies involved a total of 51 patients (14.6%) that underwent a sling placement procedure for USI symptoms [17][18][19]24]. Finally, other concomitant operations reported were intrauterine devices removal, ovarian cyst resection, and diagnostic curettage [24]. Table 6 summarizes all concurrent procedures for each study.

Treatment Outcomes
The treatment outcomes of each surgical operation were evaluated by assessing four different parameters: i. Anatomical cure rate, ii. Presence of recurrent prolapse after surgery, iii. Patient satisfaction, iv. Postoperative symptoms/findings. Table 7 lists, in detail, the aforementioned parameters for each study.  Anatomical cure rate: The anatomical cure rates between the different surgical approaches regarding the treatment of severe uterovaginal prolapse were similar in our review, with no significant differences being reported. All procedures resulted in an anatomical cure rate of >90%, within a range of 91.4-100%.
More specifically, in the Morciano et al. RCT [23], LSH plus LSC with mesh resulted in an anatomical cure rate of 97.6% in each treatment group, whereas in the Athanasiou et al. prospective studies, the VALS anatomical cure rate was estimated at 100% [17] and 95.7% [19], respectively, differences that can be attributed to the longest follow-up and largest sample size of the second study.
In terms of uterine preservation, LILS of the uterus showed an anatomical cure rate of 94.3% in the Li et al. study [25], whereas the VALUES procedure resulted in a 91.4% success rate in the Fayyad et al. study [18]. Finally, Sun et al. [24] reported a 100% anatomical cure rate for combined LULS with trachelectomy in the treatment of advanced uterovaginal prolapse.
Based on the aforementioned studies, the anatomical cure rate for each procedure was 97.6% for LSC plus LSH, 95.7-100% for VALS, 94.3 for LILS of the uterus, 100% for combined LULS with trachelectomy, and 91.4% for VALUES.
Recurrent prolapse: Four out of the six included studies in our review reported postoperative recurrences [18][19]23,25] More specifically, one study reported recurrences after LSC plus LSH [23], one study after VALS [19], one study after VALUES [18], and one study after LILS with uterine preservation [25]. Two studies reported no recurrences during the follow-up period [17,24].
As far as the LSC plus LSH procedure is concerned, in the Morciano et al. RCT where anatomic failure was defined as prolapse stage ≥ II in any site, the recurrence rate was estimated at 2.4% in each LSC treatment group [23]. Furthermore, in the Athanasiou et al. study (2018), failures after VALS (4.3%) included one case of anatomical recurrence (1.1%), one woman reporting vaginal bulge symptoms postoperatively (1.1%), and two cases of reoperation (2.1%) [19]. Additionally, Fayyad et al. reported as recurrences after VALUES three cases of anterior vaginal wall prolapse stage ≥II (4.3%) and three cases of uterine prolapse stage IV (4.3%) [18]. Finally, in the Li et al. study, two cases of prolapse stage ≥III (5.7%) were reported as recurrences after LILS with uterine preservation [25]. Based on the included studies of this review, recurrence rates for LSC plus LSH, VALS, VALUES, LILS of the uterus, and LULS with trachelectomy were 2.4%, 0-4.3%, 8.6%, 5.7%, and 0%, respectively.
Patient satisfaction: Patient satisfaction was reported in four out of the six included studies [17][18][19]24]. In three of them, it was evaluated by using the Patient Global Impression of Improvement (PGI-I) scale [17][18][19], whereas in one study, the question: "How satisfied are you with the results of your surgery?" was used to determine patient satisfaction after surgery [24].
More specifically, in the Athanasiou et al. study in 2012 [17], 92.5% of patients reported being ''very much better'' or ''much better'' after the VALS operation, with the same percentage giving the same answers in the study that followed in 2018 [19]. Moreover, in the Fayyad et al. study [18], 85.7% of the patients reported being ''very much better'' or ''much better'' after VALUES for advanced uterine prolapse, whereas, in the Sun et al. study [24], combined LULS and trachelectomy achieved a 100% satisfaction rate in treating severe uterine prolapse. Finally, data on patient satisfaction were not available in the Morciano et al. and Li et al. studies [23,25]. Based on the aforementioned studies, patient satisfaction for each operation was estimated at 92.5% for VALS, 90.5% for LILS of the uterus, 100% for combined LULS with trachelectomy, and 85.7% for VALUES.
Postoperative symptoms/findings: Postoperative patient symptoms were reported in three out of the six included studies [17][18][19]; in the other three studies, data regarding patient symptoms after surgery were not available [23][24][25].

Discussion
The present study indicates that laparoscopic surgery, although more technically demanding and timeconsuming, is associated with less intraoperative bleeding [23][24][25], shorter hospitalization time [18], and similar anatomical outcomes compared to open surgery regarding the treatment of advanced apical prolapse, which is in accordance with current literature [26][27]. However, surgeons should be aware that adequate surgical skills and a good learning curve of the operation that they perform is needed in order to ensure a satisfactory anatomic result and safety for their patients [28].
Age, BMI, menopausal status, and parity should be taken into consideration before proceeding in the surgical treatment of severe POP. In advanced-age, obese, postmenopausal women with severe uterine prolapse, removal of the uterus is preferred to hysteropexy due to the fact that these women are at increased risk of endometrial cancer development if the uterus remains [29]. However, hysterectomy alone is not an adequate treatment and an apical suspension procedure should be performed at the same time in order to reduce the risk of recurrent POP [10,30].
VALS can be effectively performed in those women in order to correct not only their severe uterovaginal prolapse but also the concurrent multicompartmental prolapse that these women may have, resulting in anatomical cure rates of 95.7-100% in our review [17,19]. Although this technique resulted in the highest mesh extrusion rate in our review (2.1%), this rate is considered to be generally low, taking into account that the reported incidence of the mesh-related complications, including mesh extrusion, in patients undergoing LSC with the use of polypropylene mesh, is up to 3.4%, and that this rate is significantly increased in cases of vaginal insertion of the mesh [31][32].
Alternatively, laparoscopic hysterectomy combined with LSC can be performed for POP repair in this patient group with similar anatomic outcomes (97.6%) but longer operative times that can be attributed to the laparoscopic route of hysterectomy during this procedure. As far as operative time is concerned, the Morciano et al. study showed that a single running locked suture is preferred to multiple interrupted stitches during mesh fixation, as it can significantly reduce the mesh fixation time (24 vs. 39 min; p < 0.01) and total operative time (121 vs. 138 min; p < 0.05) of the aforementioned procedure [23].
On the other hand, in young nulliparous women with uterine prolapse, preservation of the uterus is equally important to anatomical success [33][34]. Moreover, hysterectomy is usually associated with vaginal shortening, which may result in sexual dysfunction [35]. Therefore, uterine preserving techniques, such as VALUES, LILS of the uterus, and trachelectomy with LULS, constitute good options for young, sexually active women who desire future childbearing [18,[24][25].
More specifically, the VALUES procedure resulted in a 91.4% success rate in treating severe uterovaginal prolapse in the Fayyad et al. prospective study. The main advantage of VALUES included the extraperitoneal attachment of the mesh to the cervix, which provided efficient support to the lower part of the cervix in cases of cervical elongation and allows easy cutting of the tail of the mesh from the sacrum should hysterectomy be required in the future. In terms of complications, VALUES was the only operation in our review with intraoperative complications, reporting two inadvertent bladder injuries during the procedure (2.9%), which were repaired successfully at the time of surgery. Postoperatively, the low incidence of mesh complications (1.4%) was explained by the rich blood supply to the vaginal part of the cervix where the mesh was attached and the use of light-weight type 1 polypropylene mesh, which reduces mesh complications [18].
Furthermore, LILS of the uterus can be effectively performed in women with severe prolapse that desires uterine preservation with anatomical cure rates estimated at 94.3% based on the data of our review. In the Li et al. study, no intraoperative complications were reported during LILS and none of the patients developed mesh-related complications postoperatively. The authors claimed that the absence of mesh complications postoperatively is a result of a technique of complete mesh peritonization that reduces the risk of mesh erosion into the rectum or ureter. However, LILS was associated with the longest hospitalization time in our review (5 days), a factor that should be taken into consideration when evaluating the surgical technique in terms of hospital cost [25].
Moreover, trachelectomy with LULS was the operation with the shortest mean surgical time in our review (51.0 ± 8.4 min), which additionally reported the least intraoperative bleeding (32.0 ± 17.5 ml) [24]. Although this uterine-sparing operation resulted in a 100% anatomical cure rate and reported no intra/postoperative complications, it is probably is not the best choice for women who desire childbirth due to the fact that trachelectomy is associated with preterm premature rupture of the membranes and preterm birth [36][37].
Women who present with severe uterovaginal prolapse are more likely to have defects that involve various levels of pelvic support [12]. Therefore, concomitant surgery should be performed during the primary procedure in order to address concurrent pelvic floor defects [13]. In the included studies of this review, the operation of choice for the treatment of concurrent cystocele was anterior colporrhaphy (21.2%) [17][18]24], whilst when a rectocele was present, it was treated with posterior colporrhaphy/perineorrhaphy (21.2%) [17,19,24]. Additionally, the presence of USI and other urinary symptoms was an indication for antiincontinence surgery, which included sling placements procedures (14.6%) [17][18][19]24].

Strengths and limitations
The strength of our study emerges from the meticulous analysis of all the parameters of the included studies and from the fact that all studies that were included in this review reported strictly on the treatment of uterine prolapse stage ≥III, without involving patients with lesser stages of POP that could alter the results of our study. Moreover, all included studies had a follow-up of at least 12 months and a population sample of > 20 patients. The limitations of our study are the small number of the included RCTs (1) and the fact that some data under examination are not available in some of the included studies. Finally, due to the restricted amount of existing evidence and the heterogeneous data of the included studies, no further statistical analysis was possible.

Conclusions
It seems that the balance is in favor of laparoscopic surgery in terms of intraoperative blood loss and admission time, with similar anatomical outcomes compared to open surgery, as far as the treatment of severe uterine prolapse is concerned. However, more well-designed cohort studies are required in order to verify the results of this review and provide pelvic surgeons with more evidence for the management of this surgically demanding health problem.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.