Study Protocol Transvaginal Natural Orifice Transluminal Endoscopic Surgery for Tubal Ectopic Pregnancy(vNOTESTEP): a Protocol for a Randomized Controlled Trial

doi:10.21203/rs.3.rs-4815445/v1

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Study protocol

Study Protocol Transvaginal Natural Orifice Transluminal Endoscopic Surgery for Tubal Ectopic Pregnancy(vNOTESTEP): a Protocol for a Randomized Controlled Trial

https://doi.org/10.21203/rs.3.rs-4815445/v1

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Background

Tubal ectopic pregnancy poses a severe threat to the life of women in early pregnancy. There is an increasing tendency to use minimally invasive laparoscopic surgery to treat tubal ectopic pregnancies. Many retrospective studies have shown that Transvaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) has a lower rate of perioperative complications, faster postoperative recovery, and better cosmetic outcomes when treating tubal ectopic pregnancy. However, the lack of unbiased, detailed perioperative and long-term postoperative data to support the feasibility and safety of vNOTES remains contentious and may impede its acceptance in gynecology.

Methods

The vNOTESTEP study is a randomized controlled trial (RCT) that will recruit about 72 gynecologic patients with indications of laparoendoscopy for treating tubal ectopic pregnancy. Patients will be randomly divided into the vNOTES or transumbilical laparoendoscopic single-site (TU-LESS) group and undergo corresponding approach. After obtaining the participants’ consent, a perioperative assessment and a 5-year postoperative follow-up with eight visits will be conducted. Data collection will be performed perioperatively and postoperatively at designated time points, e.g., 1st, 2nd, and 3rd postoperative day; 1st, 3rd, and 6th month; and 1st, 2nd, 3rd, 4th, and 5th year after the surgery. The baseline information collection will include subjects’ sociodemographics and their health- and gestation-related history obtained from the Hospital Information System and face-to-face interviews. As planned, perioperative and postoperative outcomes will be examined based on intraoperative assessment, in-patient clinical observation, and follow-up WeChat questionnaires or clinic services. Among these outcomes, long-term postoperative results, such as sexual function, pregnancy, vaginal delivery, and incisional hernia, will be the focus.

Discussion

The vNOTESTEP study aims to assess the perioperative and long-term postoperative outcomes of vNOTES in the treatment of tubal ectopic pregnancy compared to TU-LESS, using a RCT design and focusing on patients’ sexual function, pregnancy, vaginal delivery, and incisional hernia. This two-arm, prospective vNOTESTEP study, incorporating a comprehensive long-term follow-up items, has the potential to furnish substantial and robust clinical evidence for refining and establishing guidelines for gynecologic vNOTES procedures. This initiative is also expected to enhance patients' perceptions and acceptance of this innovative minimally invasive surgical approach.

Trial registration number:

ChiCTR2400082909(registered on April 10th, 2024)

Natural orifice transluminal endoscopic surgery

surgical complications

minimal invasive surgery

long-term postoperative outcomes

female sexual function index

childbirth

Ectopic pregnancy refers to the condition that an embryo implants outside the uterine cavity which occurs most commonly in the fallopian tubes.¹ It represents a critical gynecological emergency that significantly threatens the health and life of women in early pregnancy, comprising approximately 3% of all pregnancies and 10% of all maternal morbidity. The primary treatment for tubal ectopic pregnancies is surgical intervention, among which laparoscopy is now generally preferred over laparotomy in most cases and is regarded as the standard surgical method.²

Surgeons have been endeavoring to reduce unnecessary surgical invasion caused by operations for decades.^3,4 The introduction of the fiberscope by Hirschowitz in the 1960s enabled the first visualization of the endoluminal surface of the digestive tract for diagnostic purposes and then inspired the therapeutic application of such equipment.^5,6 In the 1980s, inventions and adventurous surgical attempts by pioneering surgeons, such as Kurt Semm and P. Mouret, culminated in the instrumental and technical development of the endoscopic subspecialty.^7,8 To date, the surgical industry has experienced several generations of endoscopic instruments (e.g., fiberoptic, video, and robotic endoscopes), and revolutionary innovations in minimally invasive surgeries (MIS) (e.g., multiport laparoscopic surgery, MPL; transumbilical laparoendoscopic single-site surgery, TU-LESS surgery; and natural orifice transluminal endoscopic surgery, NOTES), among which NOTES might be the most novel and controversial. ^3,4,9,10

NOTES is an evolving concept of performing endoscopic surgeries through natural orifices such as the mouth, esophagus, rectum, urethra, and vagina to avoid visible abdominal scars.¹¹ Its feasibility in humans was first validated by the transgastric appendicectomy performed by Rao and Reddy in 2003.¹² Subsequently, other laparoendoscopic surgeries were performed via NOTES, including cholecystectomy,¹³ gastrostomy,¹⁴ nephrectomy,¹⁵ oophorectomy,¹⁶ and ovarian cystectomy.^17,18 NOTES, as a state-of-the-art technique in the MIS subspecialty, outperformed many other approaches in reducing postoperative pain and hemorrhage, and improving cosmetic outcomes, as reported in previous publications.^19,20 However, it has been criticized for its narrow working angles and operative space, seemingly unnecessary incision of a functional natural orifice, difficulty in suturing and accessing targeted organs, and steep learning curve.²¹

The aforementioned drawbacks seen in other NOTES approaches are avoided to a remarkable extent in the NOTES conducted in a transvaginal manner, abbreviated as vNOTES. Thus, this approach is preferred by many surgeons, especially those familiar with pelvic anatomy.^22,23 Gynecologic and urologic advocates for vNOTES have reasoned that it is quite promising in actualizing the concept of MIS due to the good ductility, strong healing ability, increased operative space, easier removal of resected tissues, better safety than the digestive tract, few fornical nerves and vessels, and adjacency to the urogenital organs and peritoneal cavity of the vagina.^21,24 Since the first transvaginal endoscopic cholecystectomy was conducted by the Brazilian doctor Zorron and his colleagues,²⁵ many novel improvements of vNOTES can now be found in publications (e.g., robotically assisted vNOTES and the use of different body postures),^26–28 and almost all benign gynecologic diseases have been reportedly treated by vNOTES.^{17,19,28–30} In some cases, vNOTES was even utilized to treat early-stage gynecologic malignant tumors.³¹

However, there have been controversies or ambiguities regarding the impact of vNOTES on patients’ sexual function, pregnancy, vaginal delivery, unintended damage to adjacent organs, incisional complications, its acceptability among the public, and technical difficulties.^19,20 To evaluate the safety and effectiveness of vNOTES, the gynecologic field has conducted many clinical studies to determine its risks and advantages from multiple perspectives, although most of which were retrospective.^{19,24,32–35} Due to the short history, lack of qualified clinical evidence, and low public familiarity of vNOTES, as well as the fact that few medical institutions and surgeons can perform it, very few of these studies established a long-term follow-up cohort on vNOTES’ application in gynecology. Besides, except for the HALON study and NOTABLE studies on vNOTES or laparoscopic hysterectomy and adnexectomy proposed by Baekelandt et al.,^36–39 randomized control rials (RCT) were rarely used in the study of vNOTES; thus, bias may exist in previous publications. Therefore, more solid, convincing, higher class, and diverse clinical evidence on vNOTES are needed.

Our institute has been striving for a better surgical performance of and the clinical studies on gynecologic vNOTES for years.^26,32,35 Accordingly, with 500–600 vNOTES and 1000–2000 TU-LESS cases performed annually, we have gained extensive experience in these surgeries and trained approximately 20 laparoscopic specialists in our gynecology department. Our previous retrospective studies have found that vNOTES has a low incidence of perioperative complications during surgery when treating adnexal diseases such as ovarian cysts and tubal pregnancy, but the conversion rates of vNOTES is slightly higher than that of TU-LESS.^40,41 Considering that TU-LESS has been accepted as a feasible and safe MIS procedure in treating multiple gynecologic diseases and has many similarities and controversies with vNOTES,^18,35,42,43 we designed this vNOTESTEP study to evaluate the merits and demerits of vNOTES in treating tubal ectopic pregnancy in comparison with TU-LESS, improve vNOTES’ preoperative patient selection, and provide solid evidence for formulating its clinical guidebook. Through this study, we hope to apply the RCT design and to evaluate the perioperative outcomes of both approaches. We will also conduct a long-term and detailed follow-up plan to reveal the impact of vNOTES on female sexual function, pregnancy, vaginal delivery, and incisional hernia (IH).

Study design

The vNOTESTEP is a double blind RCT on patients with tubal ectopic pregnancy (vNOTES or TU-LESS). It aims to evaluate the perioperative and the long-term postoperative outcomes, especially the impact on patients’ sexual function, pregnancy, and vaginal delivery, of vNOTES compared with the TU-LESS approach. It was designed and will be conducted in CWCCH from 2024 to 2030 (2 years for recruitment and 3–5 years for follow-up). CWCCH is a university teaching hospital and a regional training center for vNOTES with nearly 20 gynecologic endoscopic specialists who are proficient in performing both approaches (they collectively have experience conducting 500–600 vNOTES cases and 1000–2000 TU-LESS cases over the past 3 years). The hospital provides annual training courses for gynecologists and has already trained more than 70 qualified graduates. Randomization and grouping will be performed for each indication by the cohort manager (CM) after the stratification in a computer-generated manner. Subsequently, identifiable patient information will be removed to safeguard privacy. The data sheet containing patients' recruitment numbers and baseline information will be concealed. Outcome assessors (OA) will be blinded to this information. Surgeons will receive only essential patient details pertinent to conducting vNOTES or TU-LESS surgery. The patient allocation and treatment assignment will remain undisclosed. Two OAs will follow-up perioperative and long-term postoperative outcomes. OA1 will evaluate incisional wounds and document any associated complications, with long-term follow-up regarding the incisional wounds also conducted by OA1. To maintain blinding, both umbilical and vaginal surgical sites, regardless of incision, will be dressed similarly during postoperative hospitalization. OA2 will be responsible for assessing non-incisional wound-related perioperative and long-term postoperative outcomes. In the scenario of severe incisional complications, blinding will be ended, and appropriate treatment will be administered. Information exchange concerning the study among CM, OA, and cohort coordinators (CC) will be restricted until the study's completion.

Study population

Sample size calculation

The methodology for calculating the sample size in this research is based on the NOTABLE cohort study.³⁹ To ensure the statistical power is sufficient to rule out any significant clinical inferiority of vNOTES compared to laparoscopy, we referenced our previous studies which show a conversion rate for vNOTES procedures treating tubal ectopic pregnancies between 1.83% and 3.07%, leading us to estimate a surgical success rate of around 95%.^41,44 A one-sided non-inferiority test for the primary outcome was employed in the sample size calculation. Due to its enhanced cosmetic outcomes, vNOTES is anticipated to be more favored by patients.⁴⁵ We postulate that vNOTES would be preferred even if its success rate in removing ectopic gestational sacs is 15% potentially lower than that of TU-LESS, which leaves inevitable scars. Non-inferiority will be confirmed if the 15% margin is above the upper limit of the 95% confidence interval for the difference in success rates between the two methods. To ensure 85% power for demonstrating non-inferiority with an assumed 95% success rate in both groups, 54 cases in total are necessary. We raised the target sample size to allow for a 20% dropout rate. Considering an anticipated 20% loss to follow-up, we opted to enroll 72 participants in the vNOTESTEP study, split evenly with 36 participants per group.

Patient selection

Inclusion criteria

Patients with tubal ectopic pregnancy;

Sign the informed consent form

Aged above 18 years old;

Indications for laparoscopy;

Exclusion criteria

Patients who are not yet sexually active;

Suspected pelvic inflammation;

Stenosis of vagina;

Vaginitis

Severe pelvic adhesion;

History of herniation;

History of rectal surgery

Study interventions

The vNOTES and TU-LESS procedures performed and the equipment applied in the present study will be similar to those described in previous publications.^41,44 Both surgical approaches will be performed by the same group of experienced gynecologic endoscopic professionals to minimize performance bias. Approximately, 10 members have more than 20 years of gynecological work experience and perform more than 100 TU-LESS and 50 vNOTES each year. The other 10 group members have more than 10 years of work experience and perform 50–100 TU-LESS and approximately 25 vNOTES cases annually. All surgeons have completed the learning curve stage.

Recruitment procedures and follow-up plan

Recruitment: The enrolment flowchart and follow-up plan for the vNOTESTEP study are shown in Fig. 1. Three nurses who received standardized training will be designated as CCs to inform patients of the study details, especially the necessity and potential inconvenience of participating in several follow-up visits and completing multiple questionnaires. Patients will be included in the cohort after they have signed consent forms. Then, the CCs will collect their baseline information through the Hospital Information System (HIS).

Perioperative management: Subsequently, preoperative assessment will be performed to determine a suitable surgical approach. Intraoperative and short-term postoperative assessments and data collection will be conducted using the HIS. Participants’ preoperative Female Sexual Function Index (FSFI) and postoperative Visual Analog Scale (VAS) will also be collected during this period. Several WeChat chatting groups will be established beforehand for the management, education, and follow-up of recruited patients who will be invited to join prior to their discharge from the hospital.

Postoperative follow-up: During the 4-year postoperative period, eight follow-up visits will be carried out at the following time points: during the 1st, 3rd, and 6th month and 1st, 2nd, 3rd, and 4th year. During these visits, calibrated scales and questionnaires will be applied, as listed in Table 1 and described in later subsections. Questionnaires will be returned and uploaded to the server automatically upon completion. During follow-up, ultrasound monitoring and gynecologic physical investigations will also be performed when necessary.

Table 1

A list of items applied in the follow-up visits of the CLOCKBEGIN study
Items	Brief description	Time points
Body image questionnaire (BIQ)	1) Consists of eight items assessing recipients’ postoperative body image and cosmetic perception. 2) Items 1–5 survey on recipients’ perception of, satisfaction with, and attitudes toward their bodily appearance. 3) Items 6–8 evaluate patients’ satisfaction with the physical appearance of their surgical scars.	1st month
Visual Analog Scale (VAS)	1) This scale consists of a 10 cm-long line with two ends representing extremes of pain intensity, such as no pain or extreme pain. 2) Patients rate the intensity of their pain by placing a mark on the line. The VAS will be scored by the length from the “no pain” end of the scale to the mark they make. 3) Categorization of VAS scores: less than 1, painless; 1–3, mild; 4–6, moderate; 7–10, severe pain.	1st, 2nd, and 3rd days
The Female Sexual Function Index (FSFI)	1) The maximum obtainable score is 95. 2) A score lower than 26.5 implicates impaired sexual function. 3) Consists of 19 questions involving six different aspects regarding females’ sexual experience: libido, arousal, lubrication, orgasm, satisfaction, and pain. 4) Recipients of hysterectomy are exempted.	3rd and 6th months
Pregnancy and Delivery Questionnaire (PDQ)	1) A self-designed questionnaire of recipients’ postoperative gestational history. 2) Consists of seven questions, including whether the patient got pregnant or not after the surgery, the method of conception and delivery, parity of the pregnancy, and if vaginal laceration or IH occurred. 3) Recruited patients will be suggested to receive pregnancy check-ups and delivery at CWCCH. 4) Recipients of hysterectomy are exempted.	6th month; 1st, 2nd, 3rd, 4th, and 5th years
Incisional hernia (IH)	1) Gynecologic physical examinations and image investigations like ultrasonic monitoring, CT, or MRI will be performed to diagnose IH. 2) If confirmed, patients will receive a repair surgery with mesh. 3) Content, type, and concomitant symptoms of herniation will be recorded.	1st and 3rd months; 1st, 2nd, 3rd, 4th, and 5th years

Quality control and cohort maintenance

Quality assessment of the returned questionnaires will be conducted by the CCs. Once a low-quality questionnaire is identified, the recipient will be politely asked to re-complete it. Special incentives are provided for the enrolled patients to avoid a loss to follow-up, including free follow-up clinic services, partial reimbursement of examination fees, and a “green channel” for them to abolish waiting time. Moreover, the CCs will also post helpful healthcare tips, medical education articles or videos, and important notices for patients in the follow-up WeChat group. The cohort manager (CM) will also be available in the WeChat group to provide direct online medical counseling for participants in need. For patients lost to follow-up, the CCs will try to contact and ask them for cooperation through phone calls or WeChat messages.

Items of follow-up visits

Items of follow-up visits of the vNOTESTEP study include scales, questionnaires, and clinical investigations. We will apply well-established and qualified scales or questionnaires to evaluate the postoperative outcomes of the vNOTES and TU-LESS procedures. The Chinese version (Mandarin if conducted verbally) of the questionnaires used in this study were all produced by professional translators and validated by independent back translation from Chinese to English. Outcomes such as Body Image Questionnaire (BIQ), VAS, Female Sexual Function Index (FSFI), and Pregnancy and Delivery Questionnaire (PDQ) will be used to examined patient-reported outcome measures (PROMs) for the consideration of patient-centeredness. For convenience and privacy concerns, these questionnaire surveys will be conducted anonymously using the WeChat questionnaire mini program. Face-to-face interviews or phone calls will be performed by the CM when necessary. Clinical investigations will be conducted during follow-up visits to examine the incidence of IH for each participant. Information will be collected and uploaded into our self-established database by the CCs. The details of each item are described below:

Body Image Questionnaire (BIQ)

The BIQ comprises eight items assessing recipients’ postoperative body image and cosmetic perception. Items 1–5 survey recipients’ perception of, satisfaction with, and attitudes toward their bodily appearance, and items 6–8 evaluate patients’ satisfaction with the physical appearance of their surgical scar. ^46,47 The BIQ survey will be conducted for all participants during the 1st month follow-up visit.

Visual Analog Scale (VAS)

The VAS is one of the most commonly used scales for evaluating postoperative pain. It comprises a 10 cm-long line with two ends representing extremes of pain intensity (painless and extremely painful, respectively). Patients in the vNOTESTEP study will be asked to rate the intensity of their pain by marking their rating on the line on the 1st, 2nd, and 3rd postoperative days. The VAS will be scored by the length from the end of the line meaning “no pain” to the mark they make. Subsequently, their VAS scores will be graded as follows: less than 1 cm, painless; 1–3 cm, mild; 4–6 cm, moderate; 7–10 cm, extremely painful. The CCs will record patients’ VAS scores in a timely manner and upload these data into our database.

Female Sexual Function Index (FSFI)

The FSFI is a validated and widely applied scale with a maximum obtainable score of 95. It comprises 19 questions involving six different aspects regarding women’s sexual experience: libido, arousal, lubrication, orgasm, satisfaction, and pain.⁴⁸ A score lower than 26.5 implicates impaired sexual function.⁴⁹ The CLOCKBEGIN study applies its validated Chinese version. The FSFI survey will be conducted both preoperatively and postoperatively. Since patients who received vNOTES surgery are not allowed to have sexual intercourse for 1 month after the surgery to allow the vaginal incision to heal, the FSFI survey will be conducted during the 3rd and 6th month’s follow-up visits. Considering that many other factors will impact the results of FSFI for a long postoperative period, the FSFI questionnaires will not be used in later follow-up visits.⁵⁰

Pregnancy and Delivery Questionnaire (PDQ)

The PDQ is a self-designed questionnaire on recipients’ postoperative gestational history (see Appendix 1). It comprises seven questions about the presence of pregnancy after the surgery, conception and delivery, mono- or multiparity, and vaginal laceration or incision hernia (IH). PDQ will be conducted for every participant (except those who have undergone hysterectomy) at every follow-up visit (except the 1st month). In addition, recruited patients will be advised to undergo pregnancy check-ups and delivery at CWCCH; thus, more pregnancy- and delivery-related information could be directly obtained from the HIS.

Clinical investigation

At every postoperative follow-up visit, every subject will undergo gynecologic physical investigations to check the incidence of herniation. Patients with suspected IH (those complaining about incisional pain or bulge) will be advised to undergo proper abdominal imaging investigations, such as ultrasonic monitoring, computer tomography (CT), or magnetic resonance imaging (MRI), to check for evidence of port IH. Experienced gynecologists will provide medical advice based on the findings of these investigations. If diagnosed with IH, the patient will be treated appropriately. The CCs will record the content, type, and concomitant symptoms of herniation and upload them to our database.

Data collection and management

Gynecologists from in-patient and outpatient departments will complete the first recording of preoperative and surgical assessment of participants into the HIS and perform face-to-face interviews or phone calls with recruited surgery recipients. A gynecologic laparoendoscopic specialist will work as the CM and be delegated to manage the cohort and CCs. The CCs will be designated to obtain consent, perform and assist with patient follow-up visits, and complete the data collection. Blinding measures will also be taken to minimize the risk of bias. The surgical approaches of participants will be hidden by the CM before CCs collect perioperative outcomes and follow-up data. Moreover, randomization will be conducted in the work assignments of CCs by the CM. A self-built database was established to store the information collected by the CCs.

Baseline information

The baseline information of the study participants will be recorded in the HIS by gynecologists at the outpatient department. After obtaining patient consent, the CCs will collect and upload the following information to our cohort database: age, education, occupation, family income, lifestyle (current or previous cigarette and alcohol consumption), comorbidities, history of drug use, gestation and surgery, height, weight, and body mass index (BMI).

Perioperative assessment and short-term postoperative outcomes

The primary short-term outcome is completion of surgery using allocated techniques. The secondary short-term outcomes include the intraoperative complications such as unintended impairment of adjacent organs, volume of blood loss, causes and types of surgical conversion, and vNOTES and TU-LESS operation duration will be roundly collected. Participants’ short-term postoperative outcomes, such as hospital stay, exhaust time, and short-term postoperative complications, such as bleeding, wound infection, pain, postoperative urinary retention, and febrile morbidity, will be recorded in detail by the OAs. All the patients’ perioperative complications will be carefully collected through the HIS and classified according to the Clavien–Dindo classification, which is a widely accepted ranking system to classify surgical complications.⁵¹

Long-term postoperative outcomes

The long-term postoperative outcomes of vNOTES are of great significance for guideline formulation but remain lacking. Therefore, in the vNOTESTEP study, we plan to carry out a detailed long-term follow-up plan to collect evidence regarding such outcomes. The primary long-term outcomes are completion of vaginal delivery and occurrence of concurrent wound complications. The remaining items will be listed as secondary long-term outcomes, including cosmetic satisfaction, impact on patients’ sexual functions, pregnancy, and IH. The plan is presented in detail in Fig. 1 and Table 1.

Economic evaluation

An economic evaluation, the Cost-effectiveness analysis model, will be carried out to compare the costs of vNOTES versus TU-LESS. Such an evaluation only includes the perioperative period, given that little postoperative cost is involved in both approaches. It consists of the costs of hospitalization, surgery, and medical consumables. The results will be provided for guideline formulation and clinical consultation with patients intending to undergo vNOTES or TU-LESS.

Statistical analysis

Statistical Package for the Social Sciences (Version 25.0, IBM, Armonk, New York, the United States), and R language will be applied for the statistical analysis of the CLOCKBEGIN study. The t-test and Mann–Whitney test will be used to analyze continuous variables. Normally distributed data will be presented as means ± standard deviations, and non-normally distributed data as medians and interquartile ranges. Categorical variables will be represented by numbers and percentages and examined using the chi-square or Fisher’s exact test. In addition, to reduce or analyze bias, propensity score matching (PSM), stratification, multivariate analysis, Cox regression, or generalized estimating equations (GEE) will be applied when appropriate. Statistical significance will be set at p < 0.05.

Tubal ectopic pregnancy presents a significant threat to the life and well-being of women during early pregnancy. Presently, there is a growing preference for using minimally invasive laparoscopic procedures to manage tubal ectopic pregnancies.^2,52

Due to vNOTES’ multiple advantages in treating benign gynecologic conditions, as described in the previous section, it is preferentially applied by many gynecologic endoscopic specialists.²² Correspondingly, many efforts have been made to prove the safety, feasibility, and effectiveness of vNOTES’ application in gynecology.^34,53 Currently, there are several retrospective studies on vNOTES for tubal pregnancy, indicating that it has a lower incidence of perioperative adverse outcomes compared to other laparoscopic techniques, better cosmetic results, and faster postoperative recovery.^41,44 Nevertheless, the absence of an unbiased design, qualified and long-term postoperative results, as well as the relatively higher financial cost of the vNOTES approach may dampen its reliability and preferability when recommending this approach to patients.^19,20,33

Many previous surveys on women’s perception of and attitude toward vNOTES indicated that, because of the inevitable culdotomy performed during vNOTES, their major concerns centered on its potential impact on incisional complications, sexual function, pregnancy, and vaginal delivery.^54–56 A retrospective observational study of 76 patients with a median follow-up of 77 postoperative months indicated that their hybrid-NOTES approach had no significant impact on recipients’ pregnancy, gestational weeks at delivery, or vaginal delivery,⁵⁷ but they only included transvaginal removal of resected specimens rather than vNOTES surgery in treating gynecologic disease. In addition, a recent publication showed that the majority of women who underwent gynecologic vNOTES surgery could undergo normal pregnancy and vaginal delivery; however, as the sample size was small (9 cases), this might have yielded quite limited statistical significance and bias.³² Although a few attempts at using RCT to investigate the merits and demerits of vNOTES versus TU-LESS were already proposed and even carried out, their follow-up period and items were relatively limited.^37–39 Moreover, many reports indicated that vNOTES has little negative influence on patients’ sexual function; however, they merely focused on its non-gynecologic application among non-Chinese populations and little of them applied the double blind RCT design.^58–60

Another focus of the CLOCSTEP study is the incidence of postoperative IH. To date, studies reporting this issue are extremely scarce. Although many studies have shed light on the incidence rate of IH in TU-LESS and indicated that its overall incidence rate is about 5–7% and 1–30% in obese patients,^61,62 these results have only limited value for vNOTES guideline formulation as the two surgical approaches are too anatomically different. Theoretically, vNOTES might outperform TU-LESS in avoiding IH in cases of obesity, but clinical evidence is needed to verify this hypothesis.

The steep learning curve of vNOTES has also caused misgivings among professionals and challenged gynecologists in the early stages of learning vNOTES⁹. However, after several years of technique learning and clinical practice, it is easy to establish the operative platform in vNOTES (within 10 minutes in most cases). It is noticeably easier than TU-LESS when treating obese patients; this is supported by a case report of vNOTES’ application in cholecystectomy for a morbidly overweight patient.⁶³

The technical and instrumental innovations of vNOTES have improved the feasibility and efficiency of such approaches. We recently reported our innovative application of the prone position of vNOTES in myomectomy of the posterior uterine wall.²⁶ The technical similarity between vNOTES and TU-LESS has highlighted certain instrumental compatibility between these two approaches. As a result, the jaw-droppingly fast advancement of the equipment and techniques used in TU-LESS concomitantly propels the development of vNOTES, which means that many current technical bottlenecks of vNOTES may be circumvented in the future.

In summary, in the present protocol, we introduced our conceptions of the vNOTESTEP prospective cohort study, hoping to reveal the qualified perioperative and postoperative outcomes of vNOTES in treating ectopic pregnancy. A limitation of the present study is the lack of multicentric cooperation and sole focus on the regional Chinese population. This two-arm, prospective vNOTESTEP study with a long-term and detailed follow-up plan and a double blinded RCT design can provide valuable and solid clinical evidence for the refinement and guideline formulation of vNOTES in treating tubal ectopic pregnancy. This project would also improve patients’ perceptions and acceptability of this novel MIS approach.

vNOTES

Transvaginal Natural Orifice Transluminal Endoscopic Surgery

MIS

Minimally Invasive Surgery

TU-LESS

Transumbilical Laparoscopic Single Site Surgery

MPL

Multiport Laparoscopic Surgery

vNOTESTEP

Transvaginal Natural Orifice Transluminal Endoscopic Surgery in Treating Ectopic Pregnancy cohort study

NOTABLE

Transvaginal natural orifice transluminal endoscopic surgery (vNOTES) adnexectomy for benign pathology compared with laparoscopic excision

HALON

Hysterectomy by transabdominal laparoscopy or natural orifice transluminal endoscopic surgery

CWCCH

Chengdu Women’s and Children’s Central Hospital

RCT

Randomized Control Rial

BMI

body mass index

Cohort Coordinator

Cohort Manager

Outcome Assessors

HIS

Hospital Information System

BIQ

Body Image Questionnaire

FSFI

Female Sexual Function Index

PROMs

Patient Reported Outcome Measures

VAS

Visual Analog Scale

PDQ

Pregnancy and Delivery Questionnaire

Incisional Hernia

Computer Tomography

MRI

Magnetic Resonance Imaging

GEE

generalized estimating equations

Ethics approval and consent to participate

This study was approved by the ethics committee of Chengdu Women's and Children's Central Hospital [No.WCCH-B2024(14)]. Before commencement, this protocol was also officially registered on the Chinese Clinical Trial Registry website (http://www.chictr.org.cn) with register number (ChiCTR2400082909) on April 10^th, 2024. During the preoperative consultation, patients were well-informed of the potential risks and advantages of vNOTES and TU-LESS approaches. Written informed consent was obtained from all the participants during the preoperative consultation. All identifiable private information were deleted or not transcribed while extracting the patients’ pathological and clinical characteristics from the Hospital Information System to protect patients’ privacy.

Consent for publication

Not applicable.

Availability of data and materials

No additional data available.

Competing interests

The authors declare no conflict of interest.

Funding

The financial support of this work is provided by Chengdu High-level Key Clinical Specialty Construction Project, Fifth Round of Chengdu Municipal Science and Technology Research Program (Grant number:2021-YF05-00627-SN), Chengdu Municipal Medical Research Project in 2023 (Grant number:2023352), Japan China Sasakawa Medical Fellowship Program (Grant number:4408), and Tianfu Jincheng Laboratory Foundation (TFJC2023010001).

Author contribution

Xinyu Xiao, Tianjiao Liu, and Dan Feng conceptualized the study and drafted the manuscript. Xin Li designed the standard operating procedures and tested their utility and feasibility before patient recruitment. Tianjiao Liu and Xin Li contributed to the design of statistical analyses. Dan Feng, Li He and Yonghong Lin critically reviewed the manuscript and provided professional suggestions. All authors participated in revising and approving the final manuscript for submission.

Acknowledgements

None

Competing interests

None declared.

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Study Protocol Transvaginal Natural Orifice Transluminal Endoscopic Surgery for Tubal Ectopic Pregnancy(vNOTESTEP): a Protocol for a Randomized Controlled Trial

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Background

Methods

Study design

Study population

Sample size calculation

Patient selection

Study interventions

Recruitment procedures and follow-up plan

Quality control and cohort maintenance

Items of follow-up visits

Data collection and management

Baseline information

Perioperative assessment and short-term postoperative outcomes

Long-term postoperative outcomes

Economic evaluation

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