Background and Rationale Hysterectomy remains one of the most frequently performed gynecological surgical procedures worldwide. Over the past three decades, advancements in surgical techniques have led to a rise in minimally invasive methods, including vaginal hysterectomy (VH), laparoscopic hysterectomy (LH), robot-assisted laparoscopic hysterectomy (RH), and the more recent vaginal natural orifice transluminal endoscopic surgery (vNOTES). These minimally invasive approaches are favored as they have demonstrated a reduction in surgical morbidity compared to traditional abdominal hysterectomy. While VH is generally considered the most minimally invasive, offering advantages such as fewer complications, shorter surgical times, and faster postoperative recovery, its global incidence has been decreasing in favor of laparoscopic techniques.
vNOTES represents a cutting-edge development in gynecological surgery, ingeniously combining the benefits of a conventional vaginal approach with advanced endoscopic visualization through a transvaginal GelPort. This innovative technique aims to provide a scarless abdominal outcome while maintaining a comprehensive endoscopic view of the surgical field. Earlier, smaller-scale studies have hinted at the promising advantages of vNOTES. For instance, the single-center HALON trial, a 1:1 RCT involving 70 participants, suggested that vNOTES was not inferior to conventional laparoscopy for successful benign hysterectomy, correlating with more same-day discharges, reduced surgical time, less postoperative pain, and fewer complications. A subsequent systematic review and meta-analysis published in 2020, which incorporated the HALON trial and five observational studies, further supported these findings. It reported that vNOTES, when compared to total laparoscopic hysterectomy (TLH), was associated with significantly shorter operation times (a mean difference of 16.73 minutes), reduced length of hospital stay (a mean difference of 0.58 days), and less estimated blood loss (a mean difference of 98.87 mL). Crucially, this review found no significant differences in intraoperative or postoperative complications, readmission rates, 24-hour postoperative pain scores, or hemoglobin drop on day 1 postoperatively.
Despite these encouraging preliminary results, a significant limitation of previous research, including the HALON trial, has been the restricted generalizability of their findings due to small sample sizes and their single-center nature. Furthermore, a notable criticism of the HALON trial was its omission of a direct comparison between vNOTES and conventional VH. The VaNoLaH trial protocol directly addresses these gaps, emphasizing the urgent need for larger, multi-center, pragmatic RCTs to provide robust, generalizable evidence.
Study Design and Methodology The VaNoLaH trial is designed as a multicenter, non-blinded, pragmatic RCT. Its primary objective is to evaluate hysterectomy for benign disease across different surgical approaches, aiming to recruit 1000 women aged 18-75 years. To achieve a comprehensive comparison while maintaining ethical considerations, the trial is structured into two identical substudies (Group A and Group B):
- Group A (VH vs. vNOTES): If the surgeon determines that a conventional VH is both safe and technically feasible, eligible patients will be randomized to either VH or vNOTES hysterectomy.
- Group B (LH vs. vNOTES): If a conventional VH is not considered safe or feasible by the surgeon, patients will be randomized to either LH or vNOTES hysterectomy.
This innovative two-step randomization strategy is deliberately implemented to prevent ethical dilemmas that could arise from randomizing patients to a VH when the surgeon perceives it as technically challenging (e.g., due to large uterine size), which might otherwise lead to increased complications. For instance, larger uteri are more likely to be channeled into the LH group, where 50% will then be randomized to vNOTES. Patients are excluded if their hysterectomy is for Stage II+ prolapse (as part of a prolapse repair), endometriosis, or if they have clinically relevant comorbidities requiring extended inpatient postoperative care, a history of rectal surgery, suspected rectovaginal endometriosis or malignancy, suspected obliterated pouch of Douglas (due to severe pelvic inflammatory disease or other causes), active lower genital tract infection, or pregnancy.
Randomization will be performed using permuted blocks via REDCap software and will be stratified based on key patient characteristics: uterus size (longitudinal length over or under 15 cm), history of previous cesarean section (yes/no), and body mass index (BMI over or under 35). The surgeons performing the procedures will not be blinded to the allocated technique. A critical aspect of the trial is the requirement that all participating surgeons are beyond their learning curves for all three surgical techniques (VH, LH, and vNOTES). Specifically, they must have a minimum of three years of experience as independent vaginal and laparoscopic surgeons and have performed at least 50 vNOTES cases. Surgeries will commence before 12:00 to facilitate assessment of same-day discharge. Patient recruitment began in 2024 and is expected to conclude in 2026, with participation from 10 to 20 centers across multiple countries.
Outcomes Measured The primary outcome of the VaNoLaH trial is the proportion of women who are discharged from the hospital within 12 hours after surgery. This is contingent on the patient’s preference, adherence to local hospital discharge criteria, and the absence of complications.
Secondary outcomes will encompass a comprehensive range of clinical and patient-reported measures, including:
- Total duration of hospitalization.
- Rates of conversion to an alternative surgical approach.
- The total duration of the surgical procedure.
- The incidence of intraoperative complications, such as visceral injuries (e.g., to the bladder, ureter, bowel, or vessels).
- The incidence and severity (classified according to the Clavien-Dindo system) of postoperative complications occurring within the first six weeks following surgery.
- Rates of readmission requiring hospitalization for any adverse event causally related to the gynecological intervention within six weeks post-surgery.
- Patient-reported outcome measures, specifically focusing on sexual function, which will be assessed using the validated Short Female Sexual Function Index questionnaire sent to patients via email three months postoperatively.
Statistical Analysis and Generalizability Statistical analysis for the primary and binary secondary outcomes will employ a two-sided Cochran-Mantel-Haenszel test, stratified by uterus size, prior cesarean section, and BMI. A 5% significance level will be adopted. Continuous secondary outcomes will be analyzed using analysis of variance. The analysis will primarily follow an “intention-to-treat” principle, with “per protocol” and sensitivity analyses also performed to ensure robustness. No interim analyses are planned for this multicenter pragmatic trial.
Strengths and Limitations The study’s strengths lie in its pragmatic, non-blinded, multicenter RCT design, which is expected to yield generalizable results reflective of real-life clinical settings. By integrating multiple centers and countries, the trial accounts for variations in local practices and healthcare systems, enhancing the applicability of its findings. Furthermore, the study rigorously adheres to the IDEAL framework for surgical innovation, positioning it as a Stage 3 (Assessment) trial aimed at validating promising earlier results in a larger, diverse context. This structured evaluation is vital for the evidence-based introduction of new surgical procedures.
However, the protocol also acknowledges certain limitations: a cost-effectiveness analysis will not be performed due to the inherent differences in healthcare systems across participating countries. Additionally, the study will not include a robotic arm comparison, primarily due to the limited number of surgeons proficient in all four minimally invasive hysterectomy techniques. A potential source of bias is recognized in the experience levels of participating surgeons, as many may have more extensive experience with VH or LH compared to the relatively newer vNOTES, which could subtly favor the outcomes of the more established techniques.
Ethics and Dissemination The VaNoLaH trial protocol has received ethical approval from the main center, Imelda Hospital in Belgium, and from the ethical boards in other participating countries such as Sweden, Croatia, Switzerland, and Israel. All procedures involving human participants are conducted in accordance with the 1963 Helsinki Declaration. The trial is registered under the number NCT05971875, and its results will be submitted for publication in peer-reviewed international journals.
In conclusion, the VaNoLaH trial represents a crucial, meticulously designed multi-center RCT poised to provide high-quality, generalizable evidence on the comparative advantages of vNOTES hysterectomy against conventional vaginal and laparoscopic approaches for benign gynecological conditions, with a particular focus on patient recovery and sexual quality of life.