A Randomized Clinical Trial Comparing the Effect of Rectal Misoprostol with Intramyometrial Vasopressin on Blood Loss during Laparoscopic Myomectomy.

Uterine fibroids (leiomyomas) are among the most common benign tumors affecting women of reproductive age, often leading to symptoms such as menorrhagia, pelvic pain, and infertility.[ 1 ] Laparoscopic myomectomy has emerged as a preferred minimally invasive surgical approach for the removal of fibroids, offering advantages such as reduced postoperative pain, shorter hospital stays, and faster recovery. However, one of the major intraoperative challenges during laparoscopic myomectomy is excessive blood loss, which can obscure the surgical field, prolong operative time, increase the risk of transfusion, and potentially compromise patient outcomes.[ 2 ] Various pharmacological agents have been employed to reduce intraoperative bleeding. According to Cochrane Database of Systematic Reviews done by Kongnyuy and Wiysonge in 2014, where they reviewed 18 studies with a total of 1250 women who had myomectomy for uterine fibroids. All studies compared an intervention to reduce bleeding during myomectomy with either a placebo or no such treatment. It was found that vaginal insertion of misoprostol and infiltration of vasopressin into the uterine muscle are effective in reducing bleeding during myomectomy.[ 3 ] Vasopressin stimulates uterine muscle contractions by acting through myometrial V1a receptors, which exist in the myometrium of both pregnant and non-pregnant uterus.[ 4 ] The use of Vasopressin was first reported by Dillon in 1962 for open myomectomy.[ 5 ] Several studies have demonstrated that vasopressin significantly reduces intraoperative blood loss during myomectomy.[ 6 ] However, concerns regarding systemic side effects such as bradycardia, hypertension, and myocardial ischemia limit its universal application.[ 7 ] Misoprostol, a prostaglandin E1 analogue with uterotonic properties, has also been studied in different routes of administration, including rectal, for its ability to reduce uterine bleeding. Randomized trials have shown that rectal misoprostol significantly decreases intraoperative bleeding during myomectomy and hemorrhage.[ 8 ] Misoprostol has many advantages, which include lower cost, thermal and light stability, shelf-life of long years, easy to use, and few self-limiting side effects (abdominal pain, nausea and vomiting, chills, fever, headache, and vertigo) at the dose of 400 µg.[ 9 ] There are very few studies comparing these two agents in a prospective trial.[ 10 ] Although vasopressin’s efficacy in minimizing intraoperative blood loss during myomectomy is well established, its use may be limited by potential cardiovascular side effects and the need for precise intraoperative administration. A direct comparison between these two agents is therefore justified to evaluate whether misoprostol, with its ease of administration and favorable safety profile, can achieve hemostatic outcomes comparable to vasopressin. Such an assessment is particularly relevant in resource-limited settings or in patients where vasopressin use is contraindicated. So, this study aims to compare the efficacy of rectal misoprostol combined with intramyometrial normal saline versus intramyometrial vasopressin in reducing blood loss during laparoscopic myomectomy.

A total of 70 women were enrolled in the study with equal distribution between the group [ Figure 1 : CONSORT diagram]. Final analysis was performed for 64 women due to missing data of 6 (4 in Group I and 2 in Group II). The baseline clinical characteristics between the groups were similar except for the location of the myoma; posterior location was more common in Group I (17/31, 54.8%) and fundal in Group II (12/33, 36.3%) [ Table 1 ]. Rest parameters importantly, number of myoma, FIGO type, and size of myoma were comparable between the groups. Consort diagram of included patients Baseline clinicodemographic characteristics of the included patients FIGO: Federation of gynecology and obstetrics, BMI: Body mass index, AUB: Abnormal uterine bleeding, CPP: Chronic pelvic pain Table 2 demonstrates the intraoperative and postoperative characteristic of the patients. Blood loss was significantly higher in Group I (misoprostol) compared to Group II (vasopressin) (320.9 ± 131.9 vs. 246 ± 119.3, P value 0.02). Consistent with this finding, the drop in hemoglobin was higher in Group I compared to Group II (mean difference −2.38 ± 1 vs. −1.5 ± 1.2, P = 0.02). Operative time (minutes) was also longer in Group I (median, 95%CI: 120 (90–158.2) vs. 96 (90–135.89), P = 0.49), although the difference did not reach statistical significance. None of the patient required conversion to laparotomy in Group I; however, one patient required this in Group II. Of note, none of the patient in both the groups required hysterectomy. 4 (12.9%) patients in Group I and 1 (3%) in Group II required blood transfusion. Intraoperative MAP (mmHg) was higher in Group II than Group I (110 ± 13.3 vs. 101 ± 13.7, P = 0.02) after 30 min of vasopressin injection. Heart rate did not differ significantly among the groups. 9.6% of patients in Group I developed hypercapnia compared to 6% from Group II ( P = 0.14). There was no difference in postoperative complications between the groups. Two (6.4%) patients in Group I and 3 (9%) in Group II developed fever within 48 h of surgery. Perioperative characteristics of the included patients *30 min after vasopressin injection/normal saline injection, # 1 h after surgery, a Student Independent t -test, b Mann–Whitney test, c Paired sample t -test. Hb: Hemoglobin, MAP: Mean arterial pressure, CI: Confidence interval, SD: Standard deviation As the primary outcome of the study was blood loss, an ANCOVA was conducted to evaluate the effect of group on intraoperative blood loss (ml), controlling for fibroid diameter, FIGO type, fibroid location, and the number of fibroids. The assumption of homogeneity of error variances was met, as indicated by Levene’s test, F (1, 62) =0.0002, P = .989. After controlling for covariates, misoprostol-vasopressin, fibroid diameter, and number of fibroids were significant predictor of blood loss. The rest of the parameters, such as FIGO type, location, previous surgery, and presence of endometriosis, did not affect the primary outcome [ Table 3 ]. Figure 2 shows the estimated marginal mean of intraoperative blood loss between the groups after controlling for covariates. Mean difference of intraoperative blood loss between the group Analysis of covariance for intra-operative blood loss Levene’s test: P =0.989 (equal variance), Normality: P =0.449. Model R 2 Adjusted=0.045, Adjusted R 2 =0.397

Vasopressin appears to be more effective than misoprostol in reducing intraoperative blood loss during myomectomy, with a similar safety profile. Given its efficacy and manageable side effects, vasopressin should be considered a preferred pharmacologic adjunct in surgical planning for myomectomy, particularly in cases anticipated to involve high blood loss. Future larger-scale, RCTs are warranted to confirm these findings. Sangam Jha: Conceptualization, clinical work, writing and reviewing the manuscript; Vikas Chandra Jha: data analysis and reviewing manuscript; Sharda Jha: Data collection and analysis. All authors have read and agreed to the final version of the manuscript. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. There are no conflicts of interest.

This prospective study compared the intraoperative and postoperative outcomes of misoprostol and vasopressin use in women undergoing myomectomy, with intraoperative blood loss as the primary outcome. Our findings demonstrated a statistically significant reduction in blood loss in the vasopressin group compared to the misoprostol group (320.9 ± 131.9 vs. 246 ± 119.3, P value 0.02). In addition, the drop in hemoglobin was significantly less in the vasopressin group, reinforcing the superior hemostatic efficacy of vasopressin. Although operative time was longer in the misoprostol group, this difference did not reach statistical significance. Our findings are consistent with previous studies that have reported the higher efficacy of vasopressin in reducing blood loss compared to placebo during myomectomy[ 11 12 13 14 15 16 17 ] or tourniquet applied at the uterine isthmus.[ 18 ] Vasopressin can be injected either in the perivascular area of the uterine artery or subcapsular area of myoma.[ 12 19 ] When injected into the myometrium near myoma, it causes intense local vasoconstriction of arterioles and capillaries, thus providing a relatively bloodless surgical field which allows the surgeon to identify tissue planes more clearly and perform the enucleation more quickly.[ 11 ] In the present study too operative time (uterine incision to closure of the myometrial defect) was shorter in the vasopressin group, although the difference could not reach statistical significance (96 min vs. 120 min, P value 0.49). We used a diluted dose of vasopressin (20U in 200 ml) in our study, although comparisons between the dilute and concentrated vasopressin doses revealed no statistically significant differences in surgical blood loss or the need for blood transfusion ( P > 0.05), the diluted dose remained effective and safe.[ 20 ] In contrast, the hemostatic effect of misoprostol, a synthetic prostaglandin E1 analog, appears to be less predictable. While some studies have reported modest benefits of preoperative vaginal misoprostol in reducing blood loss,[ 21 22 ] few have reported no significant difference in blood loss between women who received and did not receive misoprostol before myomectomy.[ 23 ] In the present study, the blood transfusion rate was higher in the misoprostol group compared to the vasopressin group (12.9% vs. 3%). The decision to transfuse blood was based on the presence of any of the three factors: an intraoperative estimated blood loss exceeding 500 mL, a postoperative day-1 hemoglobin level below 8 g/dL, and/or the presence of significant anemia-related signs and symptoms such as pallor, lightheadedness, or dizziness during mobilization. Our results suggest that misoprostol alone may not be sufficient as a hemostatic adjunct compared to vasopressin. The higher blood transfusion requirement in the misoprostol group further underscores this point. Protopapas et al . in a retrospective study had reported that misoprostol was largely comparable to vasopressin in terms of estimated blood loss across most subgroups, with even superior performance in patients with ≥4 fibroids or tumors ≥7 cm;[ 24 ] however, our present study demonstrated a significantly higher intraoperative blood loss in the misoprostol group compared to the vasopressin group. This discrepancy could be attributed to several factors, like differences in study design (retrospective vs. RCT), dosing protocols (vaginal vs rectal), and timing of drug administration. Second, the vasoconstrictive potency of vasopressin likely provides a more immediate and consistent reduction in blood flow during enucleation, particularly in highly vascular myomas, compared to the indirect uterotonic effect of misoprostol, which may be slower and more variable in onset. Overall, while misoprostol remains a valuable alternative, especially where vasopressin is contraindicated, our results suggest that vasopressin may offer more consistent and superior control of intraoperative bleeding in myomectomy, regardless of fibroid number or size. Although a few studies have suggested an additive effect of misoprostol when used in combination with vasopressin compared to vasopressin alone on reducing estimated blood loss in laparoscopic myomectomy, direct comparisons between misoprostol and vasopressin as standalone hemostatic agents in laparoscopic myomectomy remain limited.[ 10 ] This underscores a significant gap in the existing literature regarding the identification of hemostatic agents that are both universally applicable and easy to administer in minimally invasive surgical settings. Interestingly, although vasopressin use was associated with higher MAP (101 ± 13.7 vs. 110 ± 13.3 at P < 0.02, 30 min postadministration), no serious cardiovascular complications were reported in either group. This is reassuring and aligns with previous findings that, although vasopressin can cause transient cardiovascular effects, it remains generally safe when used in appropriate doses and under close monitoring.[ 14 24 ] There was no significant difference in heart rate or postoperative complications between the groups. Although the rate of hypercapnia was higher in the misoprostol group (9.6% vs. 6%), the difference did not reach the statistical significance, which is in alignment of previous study.[ 24 ] The more commonly reported side effects of a 400 μg dose of misoprostol include abdominal pain (79.6%), chills (17.3%), nausea and vomiting (10.2%), headache and vertigo (7.1%), and diarrhea (4.1%).[ 9 ] However, in the present study, only fever was observed in 2 out of 31 patients in the misoprostol group, suggesting a fewer and lower incidence of systemic side effects in our cohort. A notable strength of our study is the ANCOVA performed to evaluate predictors of blood loss. After controlling for covariates, the number and size of myomas were significantly associated with increased intraoperative blood loss, corroborating findings from previous literature.[ 24 25 ] Other factors such as FIGO type, location, or history of prior surgery did not significantly impact the primary outcome in our cohort. This study has a few limitations. First, all surgeries were performed by a single surgeon, which may limit the generalizability of the findings. Second, although multiple baseline variables were accounted for, the possibility of unmeasured confounding factors cannot be entirely excluded. Third, using a per-protocol analysis may introduce bias, particularly if missing data are not missing at random. This potential limitation should be considered when interpreting the study results.

It was a randomized, double-blind, controlled trial conducted in the department of obstetrics and gynecology, All India Institute of Medical Sciences, Patna, from July 2023 to August 2024. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Ethics Committee of All India Institute of Medical Sciences, Patna (Approval No. AIIMS/Pat/IEC/2022/1037; approval date: March 31, 2023). Written informed consent was obtained from all patients in the study. This randomized controlled trial (RCT) was registered prospectively under Clinical Trials Registry–India (CTRI/2023/05/053204). Women with symptomatic myomas planned for laparoscopic myomectomy were screened for the study. Inclusion criteria were: age 20–40 years, not responding to medical management, with 5 or less symptomatic fibroids. Patients who had completed family and desires hysterectomy, those with medical conditions that could worse with abdominal distention and Trendelenburg position, diffuse leiomyomata, pregnancy, h/o adverse reaction to vasopressin or misoprostol, bleeding and coagulation disorder, history of previous laparotomy, and severe anemia were excluded from the study. The sample size was calculated with reference to the intraoperative blood loss as the primary outcome measure. To ensure the study had at least 80% power with a two-sided significance level of 0.05, a retrospective chart review of patients undergoing laparoscopic myomectomy with dilute vasopressin was performed. In a pilot sample of 50 patients, the mean intraoperative blood loss was 225.2 mL (standard deviation [SD] 57.0 mL). Considering a 20% reduction in blood loss to be clinically significant, the required sample size was calculated to be 32 patients per group. Allowing for a 10% dropout rate, the final target enrollment was set at 35 patients per group. Preoperative evaluation was performed for each patient. Clinicodemographic details such as age, BMI, parity, chief complaints, any associated comorbid status, number, size, and location of myoma, international federation of gynecology and obstetrics (FIGO) type were recorded. Laboratory parameters such as hemoglobin, hematocrit, white blood cell count, and platelet count were also recorded. Participants were randomly assigned into two groups using a computer-generated randomization table with 1:1 group allocation. Group I (Misoprostol Group) received 400 µg of rectal misoprostol 60 min before surgery and 100 ml of 0.9% normal saline intramyometrial during surgery before putting the uterine incision. Group II (Vasopressin Group) received intramyometrial injection of 20 units of vasopressin diluted in 200 ml of 0.9% normal saline just before uterine incision. All the included patients had rectal examination before surgery, and only Group I received misoprostol. The drug was inserted by residents who were not involved in surgery. Vasopressin solution or normal saline was prepared by a circulatory nurse, loaded in syringe, and kept on the OT trolley according to the generated random number, and at the time of analysis, the code was broken to see which patient had received which assigned treatment. The operating surgeon was blinded to the assigned treatment. All surgeries were performed by the same surgeon to avoid any bias related to surgical technique and complications, using a standardized four-port laparoscopic technique under general anesthesia. After inspecting the pelvis and mapping the myoma, the assigned intervention was administered before enucleation. Myomectomy started with an incision over the myoma bulge with the Harmonic Ace ultrasonic system, and a myoma screw was used for countertraction. Myomectomy was performed using blunt and sharp dissection. Myometrial defect was approximated using 1-0 V-LOC sutures, a delayed absorbable barbed suture. Blood loss was estimated by measuring the volume collected in a suction jar. Operative time (uterine incision to closure of the defect), any intraoperative complications, intraoperative heart rate, blood pressure, electrocardiogram readings were recorded. Mean arterial pressure (MAP) was calculated using the formula MAP = DP + 1/3 (SP–DP). The need of blood transfusion was decided by anesthetist if the amount of blood loss was >1L, or there was hemodynamic instability even with a lesser amount of blood loss. All patients received preoperative and postoperative antibiotic as per institute protocol. In postoperative period, the weight of the myoma and the number of myoma were assessed. Any postoperative complications, duration of hospital stay were recorded. Complete blood count was sent on the next day of operation. Fever was defined as core body temperature >38°C within 48 h of surgery. We performed perprotocol analysis. Data were presented as number and percentage, mean with SD for parametric data, and median with 95% confidence interval (CI) for nonparametric data. Chi-square was used to compare categorical data between the groups. Independent sample t -test (parametric data) or Mann–Whitney (nonparametric data) was used to compare continuous data between the groups, and paired sample t -test was used to comparing continuous data before and after the procedure. To study the impact of group difference on the primary outcome (blood loss), we performed an analysis of covariance (ANCOVA). P < 0.05 was considered statistically significant. Analysis was performed using MedCalc® version 23.2.1 (MedCalc Software Ltd, Ostend, West Flanders, Belgium).