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Laparoscopic vs transvaginal cuff closure after total laparoscopic hysterectomy: a randomized trial by the Italian Society of Gynecologic Endoscopy

Published:February 03, 2018DOI:https://doi.org/10.1016/j.ajog.2018.01.029

      Background

      Vaginal cuff dehiscence following hysterectomy is considered an infrequent but potentially devastating complication. Different possible techniques for cuff closure have been proposed to reduce this threatening adverse event.

      Objective

      The aim of the present randomized study was to compare laparoscopic and transvaginal suture of the vaginal vault at the end of a total laparoscopic hysterectomy, in terms of incidence of vaginal dehiscence and vaginal cuff complications. Factors associated with vaginal dehiscence were also analyzed. This article presents the results of the interim analysis of the trial.

      Study Design

      Patients undergoing total laparoscopic hysterectomy for benign indications were randomized at the time of colpotomy to receive vaginal closure through transvaginal vs laparoscopic approach using a 1:1 ratio. Allocation concealment was obtained using a password-protected randomization database. Monopolar energy for colpotomy was set at 60W. Vaginal closure was performed with a single-layer running braided and coated 0-polyglactin suture. In all cases an attempt was performed to include the posterior peritoneum in the suture. Laparoscopic knots were tied intracorporeally. All patients were scheduled for a postoperative follow-up visit 3 months after surgery, to detect possible vaginal cuff complications. Univariate and multivariable analyses were performed to identify independent predictors of vaginal cuff dehiscence after total laparoscopic hysterectomy.

      Results

      After enrollment of 1408 patients, a prespecified interim analysis was conducted. Thirteen (0.9%) women did not undergo the postoperative assessment and were excluded. Baseline characteristics of the 1395 patients included (695 in the transvaginal group and 700 in the laparoscopic group) were similar between groups. Patients in the transvaginal group had a significantly higher incidence of vaginal dehiscence (2.7% vs 1%; odds ratio, 2.78; 95% confidence interval, 1.16–6.63; P = .01) and of any cuff complication (9.8% vs 4.7%; odds ratio, 2.19; 95% confidence interval, 1.43–3.37; P = .0003). Based on these findings, the data monitoring committee recommended that the trial be terminated early. After multivariable analysis, transvaginal closure of the vault was independently associated with a higher incidence of vaginal dehiscence and any vaginal complication; premenopausal status and smoking habit were independently associated with a higher risk of dehiscence.

      Conclusion

      Laparoscopic closure of the vaginal cuff at the end of total laparoscopic hysterectomy is associated with a significant reduction of vaginal dehiscence, any cuff complication, vaginal bleeding, vaginal cuff hematoma, postoperative infection, need for vaginal resuture, and reintervention.

      Key words

      Why was this study conducted?

      • The best approach to close the vaginal cuff at the end of laparoscopic hysterectomy has been the subject of heated debate.

      Key findings

      • Compared to transvaginal closure with suture of the vaginal cuff at the end of a total laparoscopic hysterectomy, laparoscopic closure with suture is associated with a lower rate of vaginal dehiscence, vaginal bleeding, cuff hematoma, postoperative infection, need for vaginal resuture, reintervention, and any vaginal complication.

      What does this add to what is known?

      • Contrary to the available evidence (coming from retrospective studies), this randomized trial demonstrates that laparoscopic suture with intracorporeal knots should be considered as the preferred approach for vaginal cuff closure at the end of a total laparoscopic hysterectomy.

      Introduction

      Hysterectomy is the most common surgical intervention on the female genital tract following cesarean delivery.
      • Clarke-Pearson D.L.
      • Geller E.J.
      Complications of hysterectomy.
      As a consequence of the frequency with which this surgery is needed, even uncommon complications can affect large numbers of patients, and if not managed appropriately may represent a significant health care burden. The first total laparoscopic (LPS) hysterectomy (TLH) was performed in 1989 by Harry Reich
      • Reich H.
      Laparoscopic hysterectomy.
      and, since then, the advent of minimally invasive techniques has allowed a substantial decrease in the rate of open abdominal hysterectomies, with significant benefits in terms of shorter postoperative hospital stay, faster return to daily activities, and reduced overall costs.
      • Warren L.
      • Ladapo J.A.
      • Borah B.J.
      • Gunnarsson C.L.
      Open abdominal versus laparoscopic and vaginal hysterectomy: analysis of a large United States payer measuring quality and cost of care.
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      • Kovanda C.
      • Cammarano C.
      Comparison of laparoscopic-assisted vaginal hysterectomy with traditional hysterectomy for cost-effectiveness to employers.
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      • Bochner A.
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      • Uccella S.
      • Cromi A.
      • Bogani G.
      • Casarin J.
      • Formenti G.
      • Ghezzi F.
      Systematic implementation of laparoscopic hysterectomy independent of uterus size: clinical effect.
      At the same time, however, these improvements were paralleled by a concerning increase in the rate of vaginal cuff dehiscence.
      • Hur H.C.
      • Donnellan N.
      • Mansuria S.
      • Barber R.E.
      • Guido R.
      • Lee T.
      Vaginal cuff dehiscence after different modes of hysterectomy.
      • Ceccaroni M.
      • Berretta R.
      • Malzoni M.
      • et al.
      Vaginal cuff dehiscence after hysterectomy: a multicenter retrospective study.
      • Uccella S.
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      • Cromi A.
      • et al.
      Vaginal cuff dehiscence in a series of 12,398 hysterectomies: effect of different types of colpotomy and vaginal closure.
      The breakdown of the vaginal vault is a potentially life-threating complication, since evisceration can lead to serious sequelae including sepsis and bowel perforation. It has been estimated that the risk of vaginal cuff dehiscence following open or vaginal hysterectomy is between 0.1–0.2%, whereas it has been reported to be 5–10 times higher in minimally invasive procedures.
      • Uccella S.
      • Ceccaroni M.
      • Cromi A.
      • et al.
      Vaginal cuff dehiscence in a series of 12,398 hysterectomies: effect of different types of colpotomy and vaginal closure.
      Putative risk factors for vaginal dehiscence traditionally include precocious resumption of coital activity after surgery, vaginal atrophy, and conditions associated with poor wound healing (eg, diabetes, corticosteroid therapy). However, the understanding of the etiology is far from complete and preventive measures are mainly based on opinions and tradition. Although several investigators have recently focused on this issue, the small sample size, limitations inherent to retrospectively designed studies, and methodological flaws severely undermine the reliability of these studies.
      • Iaco P.D.
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      • Alboni C.
      • et al.
      Transvaginal evisceration after hysterectomy: is vaginal cuff closure associated with a reduced risk?.
      • Zapardiel I.
      • Zanagnolo V.
      • Peiretti M.
      • Maggioni A.
      • Bocciolone L.
      Avoiding vaginal cuff dehiscence after robotic oncological surgery.
      • Jeung I.C.
      • Baek J.M.
      • Park E.K.
      • et al.
      A prospective comparison of vaginal stump suturing techniques during total laparoscopic hysterectomy.
      • Siedhoff M.T.
      • Yunker A.C.
      • Steege J.F.
      Decreased incidence of vaginal cuff dehiscence after laparoscopic closure with bidirectional barbed suture.
      • Blikkendaal M.D.
      • Twijnstra A.R.H.
      • Pacquee S.C.L.
      • et al.
      Vaginal cuff dehiscence in laparoscopic hysterectomy: influence of various suturing methods of the vaginal vault.
      • Nawfal A.K.
      • Eisenstein D.
      • Theoharis E.
      • Dahlman M.
      • Wegienka G.
      Vaginal cuff closure during robotic-assisted total laparoscopic hysterectomy: comparing Vicryl to barbed sutures.
      • Einarsson J.I.
      • Cohen S.L.
      • Gobern J.M.
      • et al.
      Barbed versus standard suture: a randomized trial for laparoscopic vaginal cuff closure.
      • Neubauer N.L.
      • Schink P.J.
      • Pant A.
      • Singh D.
      • Lurain J.R.
      • Schink J.C.
      A comparison of 2 methods of vaginal cuff closure during robotic hysterectomy.
      • Ardovino M.
      • Castaldi M.A.
      • Fraternali F.
      • et al.
      Bidirectional barbed suture in total laparoscopic hysterectomy and lymph node dissection for endometrial cancer: technical evaluation and 1-year follow-up of 61 patients.
      • Bogliolo S.
      • Nadalini C.
      • Iacobone A.D.
      • Musacchi V.
      • Carus A.P.
      Vaginal cuff closure with absorbable bidirectional barbed suture during total laparoscopic hysterectomy.
      • Fanning J.
      • Kesterson J.
      • Davies M.
      • et al.
      Effects of electrosurgery and vaginal closure technique on postoperative vaginal cuff dehiscence.
      • Morgan-Ortiz F.
      • Contreras-Soto J.O.
      • Soto-Pineda J.M.
      • Zepeda M.A.
      • Peraza-Garay F.J.
      Comparison between unidirectional barbed and polyglactin 910 suture in vaginal cuff closure in patients undergoing total laparoscopic hysterectomy.
      • Medina B.C.
      • Giraldo C.H.
      • Riaño G.
      • Hoyos L.R.
      • Otalora C.
      Barbed suture for vaginal cuff closure in laparoscopic hysterectomy.
      • Kim M.J.
      • Kim S.
      • Bae H.S.
      • Lee J.K.
      • Lee N.W.
      • Song J.Y.
      Evaluation of risk factors of vaginal cuff dehiscence after hysterectomy.
      • Drudi L.
      • Press J.Z.
      • Lau S.
      • et al.
      Vaginal vault dehiscence after robotic hysterectomy for gynecologic cancers: search for risk factors and literature review.
      A recent meta-analysis (mainly of case series and case-control studies) has suggested that a transvaginal (TV) approach to vaginal cuff closure at the end of a totally endoscopic hysterectomy significantly reduces the risk of postoperative vaginal breakdown.
      • Uccella S.
      • Ghezzi F.
      • Mariani A.
      • et al.
      Vaginal cuff closure after minimally invasive hysterectomy: our experience and systematic review of the literature.
      This finding has been supported by a subsequent retrospective study from Italian high-volume centers, showing that a TV approach to vault closure is associated with a 4-fold reduction in the risk of cuff dehiscence compared to LPS suturing.
      • Uccella S.
      • Ceccaroni M.
      • Cromi A.
      • et al.
      Vaginal cuff dehiscence in a series of 12,398 hysterectomies: effect of different types of colpotomy and vaginal closure.
      Other smaller studies have provided similar results.
      • Iaco P.D.
      • Ceccaroni M.
      • Alboni C.
      • et al.
      Transvaginal evisceration after hysterectomy: is vaginal cuff closure associated with a reduced risk?.
      • Blikkendaal M.D.
      • Twijnstra A.R.H.
      • Pacquee S.C.L.
      • et al.
      Vaginal cuff dehiscence in laparoscopic hysterectomy: influence of various suturing methods of the vaginal vault.
      Since TLH has been defined by some authors as a procedure entirely performed by LPS, “including cuff closure,”
      • Aarts J.W.
      • Nieboer T.E.
      • Johnson N.
      • et al.
      Surgical approach to hysterectomy for benign gynecological disease.
      the above findings (if confirmed) may have a practice-changing impact, to minimize the morbidity associated with TLH. However, these studies have been largely criticized for the lack of prospective data collection and of a standardized postoperative assessment,
      • Uccella S.
      • Cromi A.
      • Bogani G.
      • Casarin J.
      • Formenti G.
      • Ghezzi F.
      Systematic implementation of laparoscopic hysterectomy independent of uterus size: clinical effect.
      • Uccella S.
      • Ghezzi F.
      • Mariani A.
      • et al.
      Vaginal cuff closure after minimally invasive hysterectomy: our experience and systematic review of the literature.
      thus precluding the possibility to systematically capture this rare complication that almost invariably occurs several days/weeks after discharge.
      Our aim was therefore to conduct a randomized study to compare LPS and TV closure of the vaginal vault at TLH, in terms of the risk of dehiscence (primary outcome) and other vaginal cuff complications (secondary outcomes). Concurrently, we investigated possible factors independently associated with the risk of developing vaginal cuff complications.

      Materials and Methods

      Recruitment in to the study was initiated in February 2015 and involved 8 Italian institutions (Varese, Policlinico Gemelli-Rome, Avellino, Bologna, Brescia, Chieti, Acquaviva, Parma), under the endorsement of the Italian Society of Gynecologic Endoscopy. Authorization by the institutional review board and by the ethical committee at the promoting center (University of Insubria) was obtained in December 2014. Local institutional review boards and ethical committees approved the protocol at each participating institution. The trial was registered on clinicaltrials.gov with protocol number NCT02453165 and adhered to the CONSORT statement.
      • Schulz K.F.
      • Altman D.G.
      • Moher D.
      for the CONSORT Group
      CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials.
      This article presents the results of the interim analysis of the trial, which was planned when the first half of the sample size was completed. Recruitment was ceased in May 2017.

      Patients

      All women who were scheduled for elective TLH were considered eligible. Inclusion criteria were: (1) age ≥18 years; (2) completion of the entire procedure by LPS approach up to colpotomy; (3) benign condition as indication to hysterectomy. Exclusion criteria were: (1) invasive malignant uteroovarian disease diagnosed before surgery or at frozen section; (2) previous radiation therapy; (3) known allergy to suturing materials used in the study; (4) inability to express adequate informed consent to participate in the study. The presence of unexpected malignancy at final histology was not considered as an exclusion criterion.

      Allocation concealment, randomization, and blinding

      Allocation concealment was ensured by the creation of a password-protected randomization database. Block randomization was used, generated by computer with randomization blocks of 20. Randomization was performed at the time of the completion of hysterectomy and immediately before initiating cuff closure. Patients signed the informed consent at the time of hospital admission or during the preadmission evaluation and they were randomized using a 1:1 ratio to receive either TV (experimental arm) or LPS closure (comparator arm), and they were blinded to the allocation arm, up to the completion of the study. While blinding of surgeons to the allocation arm was not possible, the investigators performing postoperative follow-up were blinded.

      Interventions

      All the institutions involved represent high-volume referral centers with >500 gynecologic interventions per year. At each center, surgeons perform both advanced LPS procedures and vaginal surgery.
      Colpotomy at the vaginal fornices was performed in all cases with a monopolar hook/spatula set at 60W using a pure cutting waveform. In both arms the vaginal cuff suture was performed with a single-layer technique, placing an angular stitch tied at 1 angle of the vaginal apex and then performing a running suture starting from the contralateral angle. A braided and coated 0-polyglactin suture on a half-circle HR26 needle was used. Intracorporeal knot-tying technique was used in the LPS arm.
      In all cases an attempt was performed to include the peritoneum of the posterior-inner aspect of the vaginal cuff in the suture. LPS control of hemostasis was performed in all cases at the end of vaginal cuff closure using bipolar forceps.

      Postoperative recommendations and follow-up

      At the time of discharge all patients were recommended to avoid vaginal intercourse for at least 2 months and they were followed up 3 months postoperatively. The physicians performing the follow-up visits were not involved in the surgical procedures and they were blinded to the type of vaginal cuff closure performed during the intervention. The 3-month follow-up period was chosen because it has been shown that almost all vaginal cuff dehiscences after TLH occur within 2 months after surgery.
      • Fitch K.
      • Huh W.
      • Bochner A.
      Open vs minimally invasive hysterectomy: commercially insured costs and readmissions.
      Additionally, at 3 months, reabsorption of the suture material has occurred, so that it is virtually impossible (even for expert investigators) to elicit the type of cuff closure that took place (whether LPS or vaginal).
      Vaginal dehiscence was defined as any separation at the level of the vaginal vault. Vaginal bleeding was defined as any bleeding, either objectively assessed or subjectively reported. Complete dehiscence was defined as complete cuff separation with concomitant evidence of protrusion of bowel or any abdominal organ through the breakdown, whereas partial dehiscence was considered as any separation with no clear protrusion of abdominal content. Vaginal cuff hematoma was considered as any blood collection at the level of the vaginal vault, detected at TV ultrasound, while vaginal cuff infection was defined as any postoperative infection with signs and symptoms of vaginal cuff involvement. According to Rosenthal et al,
      • Rosenthal R.
      • Hoffmann H.
      • Clavien P.A.
      • Bucher H.C.
      • Dell-Kuster S.
      Definition and classification of intraoperative complications (CLASSIC): Delphi study and pilot evaluation.
      intraoperative complications were defined as any deviation from the ideal intraoperative course occurring between skin incision and skin closure, while we considered postoperative complications in accordance with the Clavien-Dindo classification.
      • Dindo D.
      • Demartines N.
      • Clavien P.A.
      Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey.
      Ascertainment of vaginal complications was performed on the basis of: (1) objective evaluation at the time of the follow-up visit; and/or (2) reports of hospital admission, visits to the emergency department, or physicians’ evaluation during the 3-month follow-up period at the time of obtaining a recent medical history.

      Sample size calculation and interim analysis

      The sample size calculation was performed using software G* Power, Version 3.115 (Franz Faul, Universitat Kiel, Kiel, Germany). The largest series in the available literature up to 2014 reported that the incidence of vaginal cuff dehiscence following TLH is approximately 1% after LPS closure and about 0.2% in case of TV closure.
      • Hur H.C.
      • Donnellan N.
      • Mansuria S.
      • Barber R.E.
      • Guido R.
      • Lee T.
      Vaginal cuff dehiscence after different modes of hysterectomy.
      • Uccella S.
      • Ceccaroni M.
      • Cromi A.
      • et al.
      Vaginal cuff dehiscence in a series of 12,398 hysterectomies: effect of different types of colpotomy and vaginal closure.
      With alpha = 0.05 and beta = 0.80, we calculated that 1258 patients in each arm was necessary to demonstrate an 80% reduction in the rate of dehiscence when TV rather than LPS closure was used. Considering an anticipated drop-out rate of 10%, we planned to enroll a total of 2768 patients.
      According to the Pocock rule, and following the SPIRIT guidelines, an interim analysis was planned when 50% of the patients enrolled had completed the 3-months postoperative observation period.
      • Chan A.-W.
      • Tetzlaff J.M.
      • Gøtzsche P.C.
      • et al.
      SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials.
      The interim analysis was performed by the study data monitoring committee, an independent organization composed of 2 physicians and expert biostatisticians, not involved in the recruitment, treatment, or follow-up of patients. Blinding of these investigators was maintained. The reason for early termination of the study for efficacy reasons was because of the clear superiority of one approach over the other. This was defined as the presence in 1 of the 2 groups of the following prespecified outcomes: (1) alpha ≤0.01 with power ≥0.85 for the primary endpoint (vaginal dehiscence); (2) alpha ≤0.01 and power ≥0.85 for the secondary endpoint (any cuff complication); (3) at least 4 secondary endpoints all significantly less common in 1 of the 2 groups. Delayed observations were included in this analysis, according to Choi and Lee.
      • Choi S.C.
      • Lee Y.J.
      Interim analyses with delayed observations in clinical trials.

      Statistical analysis

      Statistical analysis was performed using GraphPad Prism 5.0 for Windows (GraphPad Software, San Diego, CA) and SPSS, Version 21.0 for Windows (IBM Corp, Armonk, NY). Variables with normal distribution were expressed as mean ± SD, whereas non-Gaussian variables were expressed as median (range). The Student t and Mann-Whitney U tests were used to compare continuous variables in case of Gaussian and non-Gaussian distribution, respectively. Comparisons of proportions was performed with the χ2 test. Type I (alpha) error was set at 0.05. Statistical significance was defined when P < .05 (2-tailed).
      The primary outcome of this study was the rate of vaginal cuff dehiscence. Secondary outcomes were vaginal bleeding, vaginal cuff hematoma, postoperative infection, vaginal resuturing, any reoperation, and a combined outcome defined as “any cuff complication,” including any patient with at least 1 vaginal dehiscence, vaginal hematoma, vaginal bleeding, postoperative infection, or vaginal resuturing.
      Possible factors associated with the risk of vaginal cuff dehiscence and any cuff complication were also analyzed to provide additional insight. Factors potentially associated with the occurrence of these complications were analyzed by univariate analysis. The variables with at least a borderline association (P ≤ .10) were then included in a multiple logistic regression model to verify which is independently associated with the outcome of interest. For continuous variables entered in the multivariable analysis, receiver operating characteristic curves were constructed to identify threshold values with the best sensitivity and specificity for the prediction of the outcome of interest.
      Data were analyzed according to the intention-to-treat principle. As a sensitivity analysis, a per-protocol comparison was also accomplished, including only patients in whom no protocol violation occurred.

      Results

      Interim analysis and early termination of the trial

      After enrollment of 1408 patients who met the inclusion and exclusion criteria, an interim analysis was conducted. Observed differences exceeded the prespecified boundaries and the data monitoring committee suggested early termination of the trial.

      Findings

      Of the 1408 patients enrolled, 13 (0.9%) did not perform the postoperative assessment and were excluded from the analysis. Therefore, the intention-to-treat analysis included a total of 1395 women, 695 in the TV group and 700 in the LPS group. A total of 45 protocol violations were observed: 7 in the TV and 38 in the LPS group. The per-protocol analysis was then performed on 1350 subjects: 688 and 662 in the TV and LPS groups, respectively (Figure 1). Six patients had a diagnosis of unexpected malignancy at definitive histology (4 had nonmyoinvasive endometrial cancer and 2 had IA1 cervical cancer without lymphovascular space invasion).
      Figure thumbnail gr1
      Figure 1Study flowchart
      Algorithm of study protocol.
      F-U, follow-up; LPS: laparoscopic.
      Uccella et al. Vaginal cuff closure in laparoscopic hysterectomy. Am J Obstet Gynecol 2018.
      Table 1 shows the demographic characteristics of patients in the 2 groups (intention-to-treat analysis). Perioperative characteristics of the 2 groups are provided in Table 2. Patients in the TV group had a significantly higher incidence of vaginal dehiscence (the primary outcome of the study: 2.7% vs 1% in the TV vs LPS groups, respectively, for a relative risk reduction of 63% in the LPS group compared with the TV group), overall postoperative complications, any cuff complication, and all the types of complications involving cuff closure. The incidence of postoperative adverse events excluding cuff complications as well as the rate of vaginal eviscerations were similar between groups. Figure 2 provides details of the comparison between the 2 groups in terms of all types of vaginal complications; data regarding partial dehiscence (as opposed to complete dehiscence) are also provided.
      Table 1Demographic characteristics of laparoscopic and transvaginal groups of vaginal cuff closure
      CharacteristicTV group

      N = 695
      LPS group

      N = 700
      P value
      Age, y49.5 ± 7.550.1 ± 8.1.11
      BMI, kg/m225 ± 5.325.4 ± 5.2.14
      Obesity102 (14.7%)109 (15.6%).71
      Parous378 (54.4%)376 (53.7%).80
      Indication
       - Fibroids440 (63.3%)434 (62%).62
       - Endometrial hyperplasia74 (10.7%)81 (11.6%).65
       - CIN29 (4.2%)27 (3.9%).76
       - Endometriosis66 (9.5%)66 (9.4%).97
       - Abnormal uterine bleeding28 (4%)26 (3.7%).76
       - Others58 (8.3%)66 (9.4%).48
      Previous LPS93 (13.4%)81 (11.6%).14
      Previous open surgery262 (37.7%)267 (38.1%).86
      Diabetes23 (3.3%)31 (4.4%).28
      Smoking habit115 (16.5%)115 (16.4%).95
      Corticosteroid therapy20 (2.9%)18 (2.6%).73
      Postmenopausal status179 (25.8%)209 (29.8%).12
      Sexually active576 (82.9%)561 (80.1%).46
      BMI, body mass index; CIN, cervical intraepithelial neoplasia; LPS, laparoscopic; TV, transvaginal.
      Uccella et al. Vaginal cuff closure in laparoscopic hysterectomy. Am J Obstet Gynecol 2018.
      Table 2Perioperative characteristics of laparoscopic and transvaginal groups of vaginal cuff closure
      CharacteristicTV group

      N = 695
      LPS group

      N = 700
      P value
      Operative time, min90.6 ± 44.792.6 ± 43.7.30
      Estimated blood loss, mL50 (0–1000)70 (0–1100).14
      Uterine weight, g339.8 ± 307.2323.5 ± 310.1.32
      Intraoperative complications26 (3.7%)15 (2.1%).08
      Postoperative complications83 (11.9%)51 (7.3%).003
      Any cuff complication68 (9.8%)33 (4.7%).0003
      Postoperative complications, no cuff complications15 (2.2%)18 (2.6%).62
      Vaginal dehiscence19 (2.7%)7 (1%).01
      Vaginal evisceration2 (0.3%)3 (0.4%).66
      Vaginal cuff hematoma20 (2.9%)7 (1%).01
      Postoperative vaginal bleeding34 (4.9%)19 (2.7%).03
      Postoperative infection30 (4.3%)6 (0.9%)<.0001
      Reintervention27 (3.9%)11 (1.6%).008
      Vaginal cuff resuturing16 (2.3%)6 (0.9%).03
      LPS, laparoscopic; TV, transvaginal.
      Uccella et al. Vaginal cuff closure in laparoscopic hysterectomy. Am J Obstet Gynecol 2018.
      Figure thumbnail gr2
      Figure 2Vaginal cuff complications stratified by surgical approach
      Vaginal complications stratified according to study group and type of complication. ∗ P<.05.
      Uccella et al. Vaginal cuff closure in laparoscopic hysterectomy. Am J Obstet Gynecol 2018.
      Table 3 shows the univariate and multivariable analysis of factors associated with vaginal dehiscence after TLH. Smoking habit was independently associated with a higher risk of dehiscence, whereas postmenopausal status and LPS closure were identified as independent protective factors.
      Table 3Univariate and multivariable analysis of factors associated with vaginal cuff dehiscence
      CharacteristicUnivariate analysisMultivariable analysis
      Dehiscence

      N = 26
      No dehiscence

      N = 1369
      P valueOR (95% CI)P value
      Age, y48.3 ± 5.849.8 ± 7.9.33
      BMI24.4 ± 4.125.4 ± 5.3.37
      Obesity4 (15.4%)207 (15.2%)1.00
      Center of enrollment
       - A6 (23.1%)419 (30.6%)0.54 (0.17–1.72).30
       - B6 (23.1%)141 (10.3%)1.33 (0.41–4.34).63
       - C3 (16.5%)48 (3.5%)2.66 (0.63–11.26).18
       - D1 (3.8%)73 (5.3%)0.51 (0.06–4.39).54
       - E0118 (8.6%)0.22 (0.02–3.56).29
       - F2 (7.7%)120 (8.8%)0.60 (0.12–3.04).53
       - G2 (7.7%)206 (15%)0.47 (0.09–2.40).36
       - H6 (23.1%)244 (17.8%).101.37 (0.56–3.39).49
      Indication
       - Fibroids15 (57.7%)859 (62.7%)
       - Endometrial Hyperplasia2 (7.7%)153 (11.2%)
       - CIN1 (3.8%)55 (4%)
       - Endometriosis3 (11.5%)129 (9.4%)
       - Abnormal uterine bleeding3 (11.5%)51 (3.7%)
       - Others2 (7.7%)122 (8.9%).47
      Parity13 (50%)741 (54.1%).69
      Diabetes054 (3.9%).62
      Smoking habit9 (34.6%)221 (16.1%).03
      Statistically significant.
      2.65 (1.09–6.34)
      Statistically significant.
      .026
      Statistically significant.
      Corticosteroid therapy1 (3.8%)37 (2.7%).72
      Postmenopausal status3 (11.5%)405 (29.6%).04
      Statistically significant.
      0.21 (0.06–0.87)
      Statistically significant.
      .03
      Statistically significant.
      Sexually active24 (92.3%)1111 (81%).76
      Uterus weight, g345 ± 309331 ± 234.82
      Operative time, min83 ± 35.591.8 ± 44.4.32
      Estimated blood loss, mL92.3 ± 12099.8 ± 83.75
      Transvaginal closure19 (73.1%)676 (49.4%).01
      Statistically significant.
      2.58 (1.08–6.22)
      Statistically significant.
      .036
      Statistically significant.
      Values are reported as mean (SD) or as median (range).
      BMI, body mass index; CI, confidence interval; CIN, cervical intraepithelial neoplasia; OR, odds ratio.
      Uccella et al. Vaginal cuff closure in laparoscopic hysterectomy. Am J Obstet Gynecol 2018.
      a Statistically significant.
      Table 4 shows the univariate and multivariable analysis of factors associated with the occurrence of any cuff complication. There was a tendency toward a significant association between smoking habit and any cuff complication; increasing age was associated with a lower risk of any cuff complication, whereas TV closure remained an independent predictor of postoperative adverse events at the level of the vaginal vault.
      Table 4Univariate and multivariable analysis of factors associated with any cuff complication
      CharacteristicUnivariate analysisMultivariable analysis
      Cuff complication

      N = 101
      No cuff complication

      N = 1294
      P valueOR (95% CI)P value
      Age, y48.5 ± 7.650.1 ± 7.9.060.63 (0.40–1.00).05
      BMI, kg/m224.5 ± 4.425.4 ± 5.3.11
      Overweight36 (35.6%)559 (43.2%).14
      Indication
       - Fibroids60 (59.4%)814 (62.9%)1.16 (0.57–2.36).68
       - Endometrial Hyperplasia5 (5%)150 (11.6%)0.40 (0.12–1.37).15
       - CIN7 (6.9%)49 (3.8%)1.57 (0.53–4.65).42
       - Endometriosis10 (9.9%)122 (9.4%)1.47 (0.57–3.80).42
       - Abnormal uterine bleeding7 (6.9%)47 (3.6%)1.99 (0.67–5.89).21
       - Others12 (11.9%)112 (8.7%).081.42 (0.76–2.68).27
      Parity61 (60.4%)693 (53.6%).25
      Diabetes6 (5.9%)48 (3.7%).29
      Smoking habit27 (26.7%)203 (15.4%).009
      Statistically significant.
      1.60 (0.97–2.64).07
      Corticosteroid therapy2 (2%)36 (2.8%)1.00
      Postmenopausal status22 (21.8%)348 (26.9%).25
      Sexually active93 (92.1%)1140 (88.1%).82
      Uterus weight, g307 ± 263334 ± 312.40
      Operative time, min87.9 ± 44.291.9 ± 44.2.38
      Estimated blood loss, mL95.5 ± 116100 ± 120.72
      Transvaginal closure68 (67.4%)627 (48.5%)<.001
      Statistically significant.
      2.15 (1.38–3.35)
      Statistically significant.
      .001
      Statistically significant.
      Age >45 y has been considered as cut-off value for multivariable analysis, after calculation of receiver operating characteristic curves.
      BMI, body mass index; CI, confidence interval; CIN, cervical intraepithelial neoplasia; OR, odds ratio.
      Uccella et al. Vaginal cuff closure in laparoscopic hysterectomy. Am J Obstet Gynecol 2018.
      a Statistically significant.
      Although randomization was not stratified by site of enrollment, we did not find any interinstitutional imbalance in terms of allocation between the 2 groups (Supplementary Table 1). Supplementary Table 2, Supplementary Table 3 provide the details of the per-protocol analysis. TV closure was associated with a higher risk of vaginal dehiscence and any cuff complication when analysis was restricted only to those patients who completed the treatment originally allocated.
      Details regarding the coexistence of vaginal dehiscence, vaginal hematoma, and postoperative infections are provided in Figure 3, Figure 4. Ten patients had both vaginal dehiscence and concomitant infection or hematoma (Figure 3); when stratifying on the type of approach to cuff closure, 8 patients in the TV vs 2 in the LPS group had concomitance of dehiscence and hematoma (Figure 4). No patient in the LPS had coexistence of dehiscence and infection.
      Figure thumbnail gr3
      Figure 3Coexistence of vaginal dehiscence, cuff hematoma, and infection
      Figure thumbnail gr4
      Figure 4Coexistence of vaginal dehiscence, cuff hematoma, and infection by type of surgical approach

      Comment

      Contrary to the initial study hypothesis, we found that TV closure at the end of a TLH is associated with a significantly higher incidence of both vaginal dehiscence and any vaginal cuff complication. The results of the present trial appear surprising in light of the previous literature suggesting a lower risk of dehiscence when TV cuff closure is adopted.
      • Uccella S.
      • Ceccaroni M.
      • Cromi A.
      • et al.
      Vaginal cuff dehiscence in a series of 12,398 hysterectomies: effect of different types of colpotomy and vaginal closure.
      • Iaco P.D.
      • Ceccaroni M.
      • Alboni C.
      • et al.
      Transvaginal evisceration after hysterectomy: is vaginal cuff closure associated with a reduced risk?.
      • Uccella S.
      • Ghezzi F.
      • Mariani A.
      • et al.
      Vaginal cuff closure after minimally invasive hysterectomy: our experience and systematic review of the literature.
      Only 1 small study by Kim et al
      • Kim M.J.
      • Kim S.
      • Bae H.S.
      • Lee J.K.
      • Lee N.W.
      • Song J.Y.
      Evaluation of risk factors of vaginal cuff dehiscence after hysterectomy.
      on 274 patients showed a superiority of LPS closure compared to the vaginal approach. Possible reasons for the unexpected results include control of selection bias by random allocation to treatment arms, implementation of a standardized technique for performing colpotomy and cuff closure, and an adequate and specific follow-up evaluation to detect complications. Indeed, previous studies suffered from inherent limitations of a retrospective design, and this may have led to misleading conclusions.
      A further key point is that surgical outcomes are inevitably and directly dependent on a surgeon’s ability and working conditions. Refinements in technology and techniques over time may have played a role in improving the laparoscopists’ ability to perform intracorporeal closure of the vagina. Indeed, most previous series date back to the 1990s, when 3-dimensional and/or high-definition/ultra-high-definition optical cameras were not yet available and there was still lower familiarity with LPS suturing techniques.
      Several hypotheses could be proposed to explain the superiority of LPS closure. First, performing the suture intraabdominally allows the surgeon to incorporate the peritoneum in the suture more easily than TV, at least posteriorly. Closing the possible gap between the vaginal mucosa and the pouch of Douglas may decrease postoperative oozing at this level, thus reducing the likelihood of vaginal cuff hematomas, bleeding, and infections, which may be possible background for loss of tensile strength of the suture and finally vault separation. Second, the magnification of the LPS view, despite possibly leading the surgeon to incorporate a smaller amount of tissue in the suture,
      • Uccella S.
      • Ceccaroni M.
      • Cromi A.
      • et al.
      Vaginal cuff dehiscence in a series of 12,398 hysterectomies: effect of different types of colpotomy and vaginal closure.
      may allow a better visualization of the vaginal supportive structures and a better reapproximation of wound margins, particularly in cases of poor vaginal access (eg, narrow or atrophic vagina, obese patients). Although in several minimally invasive gynecological surgical centers, LPS has partly replaced vaginal surgery, the expertise of the surgeons at the participating centers makes it highly unlikely that they performed poor techniques, when the vaginal cuff was closed TV.
      Another finding of this study is that, besides the approach to vaginal cuff closure, postmenopausal status as well as smoking habit play a role in the occurrence of vaginal cuff complications. It is noteworthy that postmenopausal status seems to be a protective factor against vaginal dehiscence. Since coitus is a well-recognized trigger for vaginal breakdown,
      • Ceccaroni M.
      • Berretta R.
      • Malzoni M.
      • et al.
      Vaginal cuff dehiscence after hysterectomy: a multicenter retrospective study.
      we can speculate that women after menopause had a lower risk of vaginal cuff dehiscence due to decline in sexual frequency associated with aging.
      • Karraker A.
      • Delamater J.
      • Schwartz C.R.
      Sexual frequency decline from midlife to later life.
      Of note, in a retrospective study on 31 patients with vaginal dehiscence following hysterectomy, older age and obesity were associated with a lower incidence of cuff breakdown.
      • Donnellan N.M.
      • Mansuria S.
      • Aguwa N.
      • Lum D.
      • Meyn L.
      • Lee T.
      Obesity and older age as protective factors for vaginal cuff dehiscence following total hysterectomy.
      Our results do not confirm the protective role of body mass index (BMI), however, we emphasize that our population had a generally low incidence of obesity (approximately 15%), likely due to the fact that the prevalence of BMI >30 is rather low in Italy. Therefore, our findings should be applied with caution to populations with a higher mean BMI.
      We recognize that our study has some possible limitations: to avoid the potential confounding effect of various surgical techniques or materials (eg, use of different sutures, interrupted stitches, double-layer closure) we standardized the procedure to include a single-layer running unlocked suture with a braided and coated polyglactin material. As a consequence, our results may be applicable only to this suturing protocol. Some surgeons close the vagina with interrupted figure-of-eight stitches. However, the largest studies on this issue have described the same running technique that we utilized in the present trial
      • Uccella S.
      • Ceccaroni M.
      • Cromi A.
      • et al.
      Vaginal cuff dehiscence in a series of 12,398 hysterectomies: effect of different types of colpotomy and vaginal closure.
      • Uccella S.
      • Ghezzi F.
      • Mariani A.
      • et al.
      Vaginal cuff closure after minimally invasive hysterectomy: our experience and systematic review of the literature.
      and this type of closure technique is likely to be the most commonly used; hence this increases the generalizability of our results. Secondly, we were not able to investigate the role of barbed sutures, a recent alternative to traditional materials. Although more expensive and associated with the possible risk of postoperative bowel adhesions,
      • Köhler G.
      • Mayer F.
      • Lechner M.
      • Bittner R.
      Small bowel obstruction after TAPP repair caused by a self-anchoring barbed suture device for peritoneal closure: case report and review of the literature.
      preliminary studies have demonstrated very promising results of self-anchoring materials in terms of reduction of vaginal cuff dehiscence.
      • Nawfal A.K.
      • Eisenstein D.
      • Theoharis E.
      • Dahlman M.
      • Wegienka G.
      Vaginal cuff closure during robotic-assisted total laparoscopic hysterectomy: comparing Vicryl to barbed sutures.
      • Einarsson J.I.
      • Cohen S.L.
      • Gobern J.M.
      • et al.
      Barbed versus standard suture: a randomized trial for laparoscopic vaginal cuff closure.
      • Neubauer N.L.
      • Schink P.J.
      • Pant A.
      • Singh D.
      • Lurain J.R.
      • Schink J.C.
      A comparison of 2 methods of vaginal cuff closure during robotic hysterectomy.
      • Ardovino M.
      • Castaldi M.A.
      • Fraternali F.
      • et al.
      Bidirectional barbed suture in total laparoscopic hysterectomy and lymph node dissection for endometrial cancer: technical evaluation and 1-year follow-up of 61 patients.
      However, further evidence is required before drawing a definitive conclusion on barbed sutures. Finally, we should again underline that this trial (as all the studies on surgical technique) is strongly affected by an unavoidable human component: in fact, suturing and tying of surgical knots introduces the potential of human error and interoperator variability. Intuitively, different surgeons and different centers may obtain different results in knot tying and suturing (both from a TV and a LPS approach), depending on attitudes, dexterity, training, experience, and context. Of interest, our data show no significant impact of the participating center on the risk of cuff dehiscence.
      Our study also has several strengths that we would like to emphasize. The randomized design, the standardization of the procedure, the dedicated follow-up program, and the sample size all confer reliability and robustness for our results. The consistency of the data across primary and secondary outcomes reinforces our results, while the involvement of high-volume centers under the endorsement of the Italian Society of Gynecologic Endoscopy ensures that surgical procedures were adequately and efficiently performed. The present study is also of value for providing new insight in the possible risk factors for vaginal dehiscence and vaginal cuff complications, since, up to now, etiological hypotheses were based mainly on a priori position rather than on solid evidence.
      In conclusion, LPS closure of the vaginal cuff at the end of TLH has been proven to be associated with less vaginal dehiscence, vaginal cuff hematomas, vaginal bleeding, vaginal resuture, and postoperative infections, compared to the TV suturing route. This study may change practice due to its impact and represents an important step toward an evidence-based approach to TLH, and more so in general, toward a standardization of gynecological surgical procedures.

      Acknowledgment

      We thank the Italian Society of Gynecologic Endoscopy for the endorsement of this work.

      Appendix

      Supplementary Table 1Patients randomized to transvaginal or laparoscopic arm, according to center of enrollment
      CharacteristicTV group

      N = 695
      LPS group

      N = 700
      P value
      Center of enrollment.79
       - A206219
       - B7374
       - C3021
       - D3737
       - E5365
       - F6260
       - G103105
       - H131119
      LPS, laparoscopic; TV, transvaginal.
      Uccella et al. Vaginal cuff closure in laparoscopic hysterectomy. Am J Obstet Gynecol 2018.
      Supplementary Table 2Demographic characteristics of per protocol population: comparison between laparoscopic and transvaginal groups of vaginal cuff closure
      CharacteristicTV group

      N = 688
      LPS group

      N = 662
      P value
      Age, y49.5 ± 7. 450 ± 8.2.22
      BMI, kg/m225 ± 5.325.3 ± 5.1.61
      Obesity101 (14.7%)102 (15.4%).71
      Parous372 (54.1%)355 (53.7%).87
      Indication
       - Fibroids438 (63.7%)413 (62.4%)
       - Endometrial hyperplasia72 (10.5%)71 (10.7%)
       - CIN28 (4.1%)25 (3.8%)
       - Endometriosis65 (9.4%)63 (9.5%)
       - Abnormal uterine bleeding28 (4.1%)24 (3.6%)
       - Others58 (8.4%)65 (9.8%).96
      Previous LPS93 (13.5%)77 (11.6%).30
      Previous open surgery261 (37.9%)255 (38.5%).82
      Diabetes23 (3.3%)31 (4.7%).44
      Smoking habit114 (16.6%)112 (16.9%).89
      Corticosteroid therapy20 (2.9%)17 (2.6%).92
      Postmenopausal status175 (25.4%)190 (28.7%).32
      Sexually active574 (83.4%)542 (81.9%).45
      BMI, body mass index; CIN, cervical intraepithelial neoplasia; LPS, laparoscopic; TV, transvaginal.
      Uccella et al. Vaginal cuff closure in laparoscopic hysterectomy. Am J Obstet Gynecol 2018.
      Supplementary Table 3Perioperative characteristics of laparoscopic and transvaginal groups of vaginal cuff closure (per protocol analysis)
      CharacteristicTV group

      N = 688
      LPS group

      N = 662
      P value
      Operative time, min90.5 ± 44.893.7 ± 43.6.18
      Estimated blood loss, mL50 (0–1000)70 (0–1100).19
      Uterine weight, g342.3 ± 308.2328.3 ± 315.1.32
      Intraoperative complications25 (3.7%)13 (2.1%).07
      Postoperative complications83 (12.1%)47 (7.1%).008
      Any cuff complication68 (9.9%)33 (5%).003
      Postoperative complications, no cuff complications15 (2.2%)14 (2.1%).93
      Vaginal dehiscence19 (2.8%)7 (1.1%).01
      Vaginal evisceration2 (0.3%)3 (0.5%).62
      Vaginal cuff hematoma20 (2.9%)7 (1.1%).01
      Postoperative vaginal bleeding34 (4.9%)19 (2.9%).05
      Postoperative infection30 (4.4%)6 (0.9%)<.0001
      Reintervention27 (4.1%)11 (1.7%).01
      Vaginal cuff resuturing16 (2.3%)6 (0.9%).04
      LPS, laparoscopic; TV, transvaginal.
      Uccella et al. Vaginal cuff closure in laparoscopic hysterectomy. Am J Obstet Gynecol 2018.

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