Imaging-guided shortened interpregnancy interval following myomectomy in China: protocol for a multicentre prospective randomised controlled trial

Uterine fibroids are the most common benign tumours in women of reproductive age, with an estimated prevalence of 30%–40%. 1 2 Based on their anatomical location, the Federation of Gynecology and Obstetrics (FIGO) classification system categorises uterine fibroids into nine subtypes ( figure 1 ). The extent of damage to the myometrium and endometrium during myomectomy varies according to the FIGO type. Fibroids can impair female fertility by causing infertility, miscarriage and pregnancy complications through mechanisms such as distorting the uterine cavity, obstructing tubal ostia and inducing abnormal expression of molecular factors like endometrial Vascular Endothelial Growth Factor (VEGF). 3 4 Approximately 30% of infertile patients require myomectomy to improve fertility. Although pregnancy rates increase significantly after surgery, the associated risk of pregnancy complications cannot be overlooked. 5 Among these, uterine rupture or dehiscence is the most severe complication, predominantly occurring in patients after surgery for intramural fibroids (FIGO types I–VI). 6 The reported incidence of uterine rupture after myomectomy is approximately 0.5%, which is comparable to the risk during trial of labour after caesarean (TOLAC) (0.7%–1.1%). 7 8 For intramural fibroids, surgery often requires deep myometrial incision and multilayer suturing, which may increase the likelihood of suboptimal scar healing. However, current evidence primarily derives from retrospective case series, and approximately 15%–30% of cases are excluded from analysis because of missing data. Consequently, prior studies have not demonstrated a statistically significant association between the anatomical characteristics of intramural fibroids and uterine rupture risk. 6 9 10 There is an urgent need for high-quality prospective studies for further validation. Currently, no consensus guideline defines the optimal interpregnancy interval (IPI) following myomectomy. Existing evidence, primarily based on clinical experience, commonly recommends waiting 1–2 years postoperatively before attempting conception to reduce the risk of complications such as uterine rupture. However, this recommendation lacks specific evidence-based support for myomectomy. A review analysing the pregnancy intervals of 3852 patients after myomectomy reported that the actual time to conception averaged 17.6 months, with a median of 13.3 months. Notably, physician recommendations for postoperative IPI were highly inconsistent: 33.9% of experts recommended 6–12 months, 28.7% advised 12–18 months, 23.4% suggested 3–6 months, 11.5% recommended more than 18 months and the remaining very few experts recommended 0–3 months. 11 – 13 Imaging studies indicate that collagen fibres realign in organised patterns at the uterine incision site by 12 weeks postmyomectomy, suggesting myometrial scar healing and functional recovery. 14 Additionally, ultrasound demonstrates a 50%–70% reduction in uterine scar volume and restoration of haemodynamic parameters to baseline levels within 3–6 months postoperatively, signifying stabilisation of uterine function. 15 Furthermore, our preliminary study, using our hospital-based perinatal big data platform, established a data linkage for approximately 1000 patients from myomectomy to perinatal outcomes. Consistent with the literature, 12 16 – 18 we found that few studies report a significant association between the postoperative IPI and uterine rupture. Although many clinicians consider a history of myomectomy an absolute contraindication for TOLAC due to a perceived increased risk of uterine rupture compared to the general population, sufficient evidence supporting this view is still lacking. 19 To date, few studies have directly investigated the association between shortening the postoperative IPI and pregnancy outcomes, and conclusions on this issue remain controversial. 12 18 20 However, an inappropriate postoperative IPI may exacerbate fertility pressure in women of advanced maternal age, potentially leading to irreversible ovarian function decline due to ineffective waiting. 21 The risk of developing uterine fibroids increases with age, 22 and the recurrence risk after surgery is estimated to exceed 50% within 5 years. 23 24 Therefore, high-quality clinical evidence-based research is needed to provide individualised recommendations on appropriate IPI for patients following myomectomy. Following imaging confirmation of satisfactory scar healing at 6 months postoperatively, this trial aims to evaluate the safety and cumulative live birth rate (CLBR) of a shortened IPI guidance protocol of 6 months following myomectomy, compared with the conventional 12-month IPI guidance protocol. We hypothesise that the 6-month IPI guidance protocol is non-inferior to the 12-month IPI protocol regarding the incidence of myomectomy-related adverse pregnancy outcomes.

This study is a prospective, multicentre, non-inferiority randomised controlled trial (RCT) that will be conducted at the International Peace Maternity and Child Health Hospital, Shanghai, China, the Obstetrics and Gynecology Hospital of Fudan University and the Shanghai First Maternity and Infant Hospital. The study will be conducted from 24 November 2025 to 31 August 2028, with the recruitment period running concurrently. Aged 20–45 years. 6–8 weeks postmyomectomy (laparoscopic, abdominal or hysteroscopic) with confirmed absence of complications (eg, infection, haemorrhage). FIGO type I–VI uterine fibroids, with no full-thickness uterine wall penetration during myomectomy. Clear desire to conceive within 2 years postoperatively. Confirmed normal uterine cavity morphology postoperatively. Provision of written informed consent. FIGO type 0 or VII uterine fibroids, or diffuse uterine leiomyomatosis. Uncorrected intrauterine adhesions, stage III–IV endometriosis (American Society for Reproductive Medicine staging), tubal obstruction or diminished ovarian reserve (diagnosis based on the 2022 Chinese Expert Consensus). 25 Serious systemic comorbidities, active autoimmune disorders or a history of malignancy. History of thromboembolic disease, hormone-dependent tumours, uncontrolled hepatic dysfunction or documented contraindications to surgery. Confirmed ongoing pregnancy. Planned participation in other reproductive intervention trials, or use of long-acting hormonal agents within 3 months. Inability to comply with follow-up protocols or refusal to use the designated contraceptive regimen. Women of reproductive age who attend outpatient clinic review at 6–8 weeks after myomectomy and have a recent fertility plan will be evaluated for trial enrolment. After providing written informed consent (see online supplemental material ), all participants will undergo baseline assessments including questionnaires, clinical data collection, and routine examinations to determine eligibility. Screening documentation will be completed for all candidates to minimise selection bias. All enrolled participants will undergo a standardised 6-month contraceptive protocol postoperatively. At the 6-month timepoint, standardised ultrasound and pelvic MRI will be performed. Uterine incision healing will be independently assessed by two radiologists blinded to clinical information, and they will be blinded to the specific group assignments of the subjects as well. Subjects exhibiting imaging features suggestive of deficient healing, including disruption of myometrial continuity, myometrial thinning at the scar site, abnormal echogenicity or uterine contour deformities will be excluded from randomisation and continue contraception under extended monitoring. Eligible participants will then be randomised 1:1 using a computer-generated block randomisation sequence (block size=4), with no stratification factors. Allocation will be implemented according to the system-generated sequence and managed by an independent contract research organisation. The intervention group may commence pregnancy attempts immediately after randomisation (total postoperative contraception: 6 months), while the control group continues contraception for an additional 6 months after randomisation (total postoperative contraception: 12 months). Because the intervention involves different contraception durations and requires ongoing follow-up, participant and clinician blinding is not feasible; therefore, the trial will be open-label. To reduce bias, outcome assessors, imaging evaluators and data analysts will remain blinded to group assignment. To minimise the risk of bias, the study will introduce the following methodological controls: (1) allocation concealment will be achieved through a central randomisation system; (2) the primary endpoint and key safety events will be adjudicated by an independent blinded endpoint adjudication committee based on standardised definitions; (3) subjective indicators such as patients’ fertility anxiety will be collected using the hospital’s electronic patient-reported outcome system to reduce interference from investigator assessment. MRI (T2-weighted sequences, dynamic contrast-enhanced) and ultrasound (grayscale imaging, Doppler flow, elasticity imaging) data will be acquired. Key anatomical and functional regions will be annotated by one senior radiologist and one senior sonographer, respectively. Assessments will be performed at 1, 3, 6 and 12 months postoperatively and will include: (1) myometrial thickness at the scar site (measured at the thinnest portion), (2) fibrotic volume within the scar region, (3) myometrial continuity, (4) overall uterine morphology and (5) the status of adjacent pelvic organs. If the imaging evaluation at 6 months postoperatively demonstrates satisfactory scar healing, the participants will then omit the 12-month postoperative examination. Postoperative contraception will be recommended for 6 months after myomectomy. Acceptable contraceptive methods include condoms or oral contraceptives, initiated after the first postoperative menses. Participants will be permitted to attempt conception immediately after randomisation. Postoperative contraception will be recommended for 12 months after myomectomy. Acceptable contraceptive methods include condoms or oral contraceptives. Participants will continue contraception for an additional 6 months after randomisation. Standardised preconception guidance will be provided, including basal body temperature charting, ovulation predictor kit utilisation and recommendations on intercourse frequency. Patients and the public were not involved in the design, recruitment or conduct of this study. The results will be disseminated to participants through open-access publications and our local trial teams. The incidence of obstetric complications following myomectomy Adverse pregnancy outcomes associated with surgical approach, fibroid characteristics and postoperative uterine healing status, including: Preterm birth (PTB): delivery at ≥28 weeks and <37 completed weeks of gestation; early PTB: 28–<34 weeks; late PTB: 34–<37 weeks. Both spontaneous and iatrogenic PTB will be captured. Postpartum haemorrhage (PPH): blood loss ≥500 mL following vaginal delivery or ≥1000 mL after caesarean delivery within 24 hours, or any blood loss accompanied by signs or symptoms of hypovolaemia. Uterine rupture refers to a breach in the uterine wall (either the corpus or lower uterine segment) occurring during pregnancy or labour. A complete uterine rupture involves full-thickness disruption of the myometrium, including the serosal layer, resulting in communication between the uterine cavity and the abdominal cavity, with or without extrusion of the fetus or placenta into the abdomen; this is confirmed by imaging (ultrasound/MRI) showing complete myometrial discontinuity or by direct intraoperative visualisation of fetal or placental tissues in the abdominal cavity. Incomplete rupture denotes myometrial disruption with preserved serosal integrity, maintaining separation of uterine and peritoneal cavities while retaining fetal and placental contents within the uterus, radiographically characterised by focal myometrial defects with intact serosa or contour bulging. Diagnosis primarily relies on the classic clinical triad comprising sudden onset of severe abdominal pain with cessation of uterine contractions, fetal distress (manifested predominantly by abnormal fetal heart rate patterns) and maternal signs of hypovolemic shock. CLBR: proportion of randomised participants achieving at least one live birth (delivery ≥28 weeks with neonatal survival ≥24 hours) among all randomised subjects completing at least one follow-up after contraception cessation. Pregnancy outcome measures: natural conception rate, miscarriage rate, caesarean section rate, clinical pregnancy rate. Multimodal imaging scar score: a comprehensive score of scar healing generated by a deep learning model based on ultrasound and MRI parameters. In this study, an adverse event (AE) refers to any unfavourable medical occurrence during the study period, from randomisation until the end of pregnancy or the follow-up endpoint, regardless of whether it is causally related to the study intervention (pregnancy interval). A serious adverse event (SAE) is defined as any event that results in death, is life-threatening, requires hospitalisation or prolongs existing hospitalisation, results in persistent or significant disability or necessitates important medical intervention to prevent one of these outcomes. AE will be tabulated using a subject-based approach. For each AE category, each participant will contribute at most one occurrence in the primary AE summaries, even if multiple episodes of the same AE occur during follow-up. Transfusion of packed red blood cells due to uterine rupture or PPH will be classified as an SAE. Uterine rupture will be treated as the principal SAE and an AE of special interest. All AEs will be actively solicited and documented by the study physicians during follow-up visits, and verified against medical records. Suspected SAEs will undergo independent assessment by the research team to determine severity. AE reporting is not influenced by group assignment information. Our preliminary findings, derived from a retrospective cohort study using our hospital’s perinatal big-data platform and supported by relevant published literature, 12 indicated that the incidence of at least one of the prespecified adverse pregnancy outcomes—uterine rupture, PPH or PTB—was approximately 17%, which refers to this participant-level composite outcome and was not obtained by adding the incidences of the three individual components. The non-inferiority margin was prespecified as an absolute difference of 10% for the composite primary outcome. Thus, assuming a 17% event rate in the control group, an event rate of up to 27% in the intervention group would meet the statistical criterion for non-inferiority. This margin was defined for the composite outcome and was not intended to imply that a 10% increase in the incidence of uterine rupture alone would be clinically acceptable. The rationale for the margin considered the potential benefits of a shorter postoperative IPI, including reducing the risk of age-related decline in ovarian function and fibroid recurrence in women of advanced maternal age. The three components of the composite outcome will nevertheless be reported and analysed separately, with uterine rupture prespecified as a key safety outcome. Using a randomisation allocation ratio of 1:1, a one-sided α level of 0.05, and a statistical power of 80% (β=0.20), sample size estimation was performed using PASS 15 software (V.15.0.5). This calculation indicated that 175 participants per group (350 total) were required. Accounting for a 10% rate of loss to follow-up or dropout, the sample size was further increased to a total of 384 participants (192 per group). Primary inferences will be based on the intention-to-treat analysis set. All randomised participants will be analysed according to their assigned groups, irrespective of their actual contraceptive duration, early or delayed conception attempts, contraceptive method changes or other protocol deviations. Given the non-inferiority design of this trial, a per-protocol (PP) analysis will additionally be performed as a supportive analysis. The PP set comprises participants who adhered to the protocol after randomisation and have complete, evaluable primary outcome data. Participants with major protocol deviations will be excluded from PP analysis (eg, pregnancy attempts/conception during the mandated contraception window in the control group, or unjustified prolonged contraception beyond the permitted window in the intervention group). Continuous variables, if normally distributed, will be presented as mean±SD, compared between groups using the independent samples t-test; non-normally distributed continuous variables will be presented as median with IQR, analysed using the non-parametric Mann-Whitney U test. Categorical variables will be expressed as percentages and compared using the χ 2 test or Fisher’s exact test. Subgroup analyses will be performed based on FIGO classification, surgical approach, mode of delivery and other relevant factors. Cox proportional hazards models will be constructed to calculate HRs between the intervention and control groups within strata. The primary composite endpoint will be analysed using the Win Ratio method. Comparisons between the intervention and control groups will follow a hierarchical rule: first, the incidence of uterine rupture; if no difference, then PPH and finally, PTB. The Win Ratio and its CI will be used to comprehensively assess the overall impact of different IPIs on pregnancy outcomes. Each component of the composite primary outcome will also be analysed separately as secondary outcomes. Non-inferiority testing for the primary endpoint will employ a one-sided significance level of α=0.05; all other statistical tests will use a two-sided α=0.05. All statistical analyses will be performed using R software (V.3.5.1; R Foundation for Statistical Computing, Vienna, Austria). Candidate screening will be conducted 6 weeks postoperatively, with collection of data on fibroid type and location, surgical approach and indications, postoperative uterine healing status by imaging and relevant laboratory tests. Subsequent quarterly follow-up assessments during the contraceptive phase will include: verification of contraceptive adherence, documentation of AEs, imaging surveillance and psychological status evaluation. At the 6-month postoperative outpatient visit, eligibility will be confirmed via ultrasonography to exclude poor uterine healing prior to randomisation. At contraception cessation (6 months postoperatively for intervention group, 12 months for control group), the following will be documented: myometrial healing grade assessed by ultrasound or MRI and fertility status. Preconception follow-up will continue quarterly until a positive pregnancy test is obtained. During late pregnancy, monthly follow-up will include ultrasound measurement of scar thickness, placental location, placenta accreta risk assessment and screening for uterine rupture warning signs. Delivery records will include mode of delivery and intraoperative blood loss; suspected uterine rupture will require intraoperative confirmation and pathological validation. Postpartum evaluation at 42 days will include ultrasound assessment of uterine involution, scar healing and maternal-neonatal outcomes. The postrandomisation follow-up period will extend to 24 months. Follow-up duration will be determined by clinical status: for delivery outcomes, the actual delivery date will define the valid endpoint. Follow-up will conclude after collecting key outcomes at the 42-day postpartum visit. For pregnancy loss (spontaneous abortion, missed abortion, termination), pregnancy outcome date will serve as the endpoint, after which safety follow-up will continue until completing 24 months postrandomisation. Participants who neither conceive within 24 months nor reach a pregnancy outcome will have their follow-up endpoint at 24 months postrandomisation. For early discontinuation, last valid assessment date will be the endpoint ( figure 2 ). An interim analysis will be conducted when approximately 50% of participants have reached a pregnancy outcome. A prespecified use of the O’Brien-Fleming alpha spending function will be used, with a corresponding two-sided boundary value of Z≈3.0 (p≈0.0015). The interim analysis will evaluate the safety of the shortened IPI guidance strategy and assess trial futility. A Data and Safety Monitoring Board (DSMB) will be established to conduct real-time risk assessment, which will initiate an emergency evaluation and recommend trial termination if the uterine rupture rate or pregnancy complication rate in the intervention group proves significantly higher than that in the control group. The final analysis will use the remaining alpha, and the overall Type I error rate will be controlled at a two-sided level of 0.05.

This prospective, multicentre RCT aims to provide high-quality evidence to guide individualised contraceptive timing after myomectomy. By incorporating standardised imaging assessment of uterine scar healing before allowing pregnancy attempts, the study aims to support more individualised decision-making and to address current evidence gaps in fertility management following myomectomy. Given the inherent differences between individualised contraceptive timing guidance and standardised waiting periods, coupled with the need for postoperative follow-up, blinding of surgeons and participants is not feasible. Therefore, our trial adopts an open-label design. However, to minimise the risk of bias, outcome assessment, imaging evaluation and data analysis will be performed using blinding methods. The primary composite endpoint will be assessed using the Win Ratio method, with component outcomes prioritised according to their clinical significance. However, it must be noted that while the trial is powered for this composite measure, it is not individually powered to detect statistically significant differences in rare events such as uterine rupture. The expected low incidence of rupture means the study can only provide meaningful insights into the composite outcome rather than the specific risk of rupture, which still warrants further studies with larger sample sizes. Shortening IPI in the intervention group can potentially increase the risk of complications such as uterine rupture during pregnancy. To reduce this risk, patients will undergo postoperative screening via ultrasound and MRI before randomisation. Those with poorly healed uterine scars will have their contraceptive period extended. This non-inferiority trial aims to demonstrate that the shortened IPI after myomectomy is not inferior to the conventional one in terms of adverse pregnancy outcomes, thereby ensuring safety assurance. The study protocol has been approved by the Institutional Review Boards of the Obstetrics and Gynecology Hospital of Fudan University, the Shanghai First Maternity and Infant Hospital and the China Welfare Institute International Peace Maternity and Child Health Hospital (approval number: GKLW-A-2025-108-01). Any protocol amendments (including revisions to the informed consent form or study documents) will require prior ethics approval. Written informed consent will be obtained from all participants. The results of this study will provide evidence for the optimal IPI after myomectomy and the primary results will be submitted for publication in a peer-reviewed scientific journal. Following the publication, a lay summary of the main findings will be prepared and disseminated to all participants who request it. Authors contributions HX is the principal investigator, who designed the study and contributed to the investigation. YH and CZ drafted the manuscript and conducted the investigation. JZ, WL and DY contributed to the study design and assisted with the investigation. HX and FS critically revised the manuscript. All authors read and approved the final version of the manuscript. Guarantor: Hong Xu takes full responsibility for the integrity of the work. Funding This study was supported by the Shanghai Municipal Science and Technology Commission Medical Innovation Research Special Project (202540073). The funder provided financial support only. However, they will not be directly involved in data management, statistical analyses, or monitoring. Competing interests None declared. Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting, dissemination of this research. Patient consent for publication Not applicable. Ethics approval The research protocol was approved by the Ethics Committee of the International Peace Maternity and Child Health Hospital (GKLW-A-2025-108-01). Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available from the corresponding author upon reasonable request. Supplemental material The informed consent form used in this study is provided as Supplemental Material. This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.