Comparison of the effects of vaginal hyoscine butylbromide and misoprostol on cervical preparation for gynecological intrauterine interventions: a double-blind clinical trial

Abstract

Background

Effective cervical preparation is crucial for procedures requiring transcervical uterine access. Insufficient dilation can complicate these interventions. While chemical agents are commonly used, the optimal method remains under investigation.

Objective

This study aimed to compare the effectiveness and safety of vaginal hyoscine butylbromide vs vaginal misoprostol for cervical preparation prior to gynecological intrauterine surgery.

Methods

This double-blind, randomized controlled trial included 71 women scheduled for gynecological intrauterine interventions requiring cervical preparation. Participants were randomly assigned to receive either vaginal hyoscine butylbromide (n=36, 40 mg total dose) or vaginal misoprostol (n=35, 200 µg) 2 to 4 hours before the procedure. The primary outcome was the diameter of the first Hegar dilator that could be inserted through the internal os without resistance. Secondary outcomes included cervicovaginal-uterine complications and drug-related side effects.

Results

The mean diameter of the first dilator passed without force was (4.91±1.10) mm in the hyoscine group and (5.54±1.50) mm in the misoprostol group; this difference was not statistically significant (P=.081). Notably, the incidence of uterine pain and cramping was significantly lower in the hyoscine group (0% vs 34.3%, P<.001), representing a key clinical advantage. No significant differences were observed in other complications or side effects between the groups. No cases of uterine or cervical rupture occurred.

Conclusion

Vaginal hyoscine butylbromide demonstrated comparable cervical dilation to misoprostol but resulted in significantly less uterine pain and cramping, which constitutes a meaningful clinical advantage. The complete elimination of uterine cramping in the hyoscine group highlights its distinct benefit as a cervical priming agent. Hyoscine appears to be a safe and more comfortable option for cervical preparation in premenopausal women undergoing gynecological procedures.

AJOG Global Reports at a Glance.

Why was this study conducted?

• •To determine whether vaginal hyoscine butylbromide provides cervical preparation comparable to misoprostol while reducing drug-related discomfort before gynecological intrauterine procedures.

Key findings

• •Hyoscine and misoprostol achieved comparable cervical dilation.
• •Hyoscine resulted in significantly less uterine pain and cramping (0% vs 34.3%, P<.001), representing a notable clinical advantage.
• •No major complications occurred in either group.

What does this add to what is known?

• •Demonstrates that hyoscine is a safe, comfortable alternative to misoprostol for cervical preparation in premenopausal women.
• •Highlights the marked reduction in uterine cramps with hyoscine as a key clinical advantage over misoprostol, maintaining efficacy while substantially reducing patient discomfort—a benefit that may favor hyoscine as the preferred cervical priming agent.

Introduction

Adequate cervical dilation is essential for many gynecological procedures that require access to the uterine cavity, such as Dilation and Curettage (D&C), hysteroscopy, endometrial ablation, Intra-Uterine Device (IUD) insertion, and sonohysteroscopy.¹ Insufficient dilation can increase procedural difficulty, duration, and the risk of complications.^1,2

Cervical preparation typically involves either mechanical or chemical methods. Mechanical tools like Hegar dilators, Laminaria tents, or Foley catheters can be used,^3,4 but they carry risks such as uterine perforation, cervical tears, creating a false passage, cervical incompetence, scarring, or later narrowing (stenosis).^1,2 Chemical agents, especially Prostaglandin analogues like misoprostol (given vaginally or orally), are often preferred because they may be more effective and safer, potentially shortening surgery time and reducing anesthesia needs.4, 5, 6 However, misoprostol can cause side effects like nausea, vomiting, diarrhea, fever, and uterine cramps. Its use might also be unsuitable if an IUD is present.^4,6 Hyoscine-N-butylbromide (HBB), which works differently as an anticholinergic and antispasmodic agent to relax smooth muscle,⁷ offers another option. While used in labor and for some cervical ripening, less is known about its specific use to prepare the cervix before procedures like D&C or hysteroscopy.^3,8, 9, 10, 11

Given the potential advantages of HBB's antispasmodic properties and the known side effects of misoprostol, this double-blind, randomized clinical trial was designed to compare the efficacy and safety profile of vaginally administered hyoscine butylbromide with vaginal misoprostol for cervical preparation before gynecological intrauterine procedures.

Materials and methods

Study design and participants

This double-blind randomized controlled trial was conducted at Amir Al-Momenin Hospital, Semnan University of Medical Sciences teaching hospital, Semnan, Iran, from 6/ 2021 to 9/2022. To determine the appropriate sample size, we used the formula shown below, based on Hadadian and Fallahian¹⁰ study, which reported mean cervical dilation of 3.55±4.76 in the hyoscine group and 3.04±2.53 in the control group.¹⁰ Using these values, the minimum required sample size was calculated to be 50 participants (25 in each group), with a statistical power of 80% and a significance level of 0.05¹⁰:

$$\mathrm{n}={\left({\mathrm{Z}}_{(1-\alpha /2)}+{\mathrm{Z}}_{(1-\beta )}\right)}^2\left({\delta }_1^2+{\delta }_2^2\right)/{\left({\mu }_1-{\mu }_2\right)}^2$$

Considering the potential sample loss, a total of 80 participants were approached for the study. Participants were premenopausal women aged 18 to 55 years old who were undergoing gynecological procedures that required cervical preparation, the most frequent being diagnostic D&C. Exclusion criteria included pregnancy, menopause, parity of greater than 3, known anatomical genital tract abnormalities, active cervicovaginal infection or lesions, significant systemic diseases (cardiac, hepatic, respiratory including asthma, seizure disorders), and known hypersensitivity to hyoscine or prostaglandins. Of the 80 initially approached participants, all met the inclusion criteria (ie, none were excluded based on the study's medical exclusion criteria). However, 9 participants declined to provide informed consent and therefore did not proceed to randomization. The remaining 71 participants who provided consent were randomized and included in the final analysis. Figure 1 illustrates the CONSORT flow diagram of the trial (Figure 1).

Figure 1.

The study selection process.

Mahshid Khakzad et al. Comparison of the effects of vaginal hyoscine butylbromide and misoprostol on cervical preparation for gynecological intrauterine interventions: a double-blind clinical trial. Am J Obstet Gynecol 2026.

Participants were randomly assigned in a 1:1 ratio to either the hyoscine or misoprostol group using block randomization. Allocation concealment was ensured using sequentially numbered, opaque, sealed envelopes prepared by an independent statistician not involved in the trial execution.¹² A pharmacist, separate from the clinical team and outcome assessment, prepared identical-looking capsules containing either powdered hyoscine butylbromide (two 20 mg tablets, total 40 mg) or misoprostol (one 200 µg tablet). Patients, the operating gynecologist performing the procedure and assessment, and the data collectors were blinded to the treatment allocation throughout the study.

Intervention

A trained nurse administered the assigned study medication vaginally into the posterior fornix 2 hours before the scheduled procedure: either 40 mg hyoscine butylbromide (intervention group) or 200 µg misoprostol (control group).

Outcomes

The primary outcome was the maximum Hegar dilator diameter (in millimeters) that could be passed through the internal cervical os immediately before the surgical procedure without obvious resistance to the blinded gynecologist. Hegar dilators are manufactured in standardized sizes with whole-millimeter increments (eg, 3 mm, 4 mm, 5 mm); accordingly, each individual patient's cervical dilation was recorded as a whole-millimeter value corresponding to the largest dilator passed without force. The decimal values reported in the results (eg, 4.91 mm, 5.54 mm) represent the arithmetic means of these whole-millimeter recordings across participants in each group. Secondary outcomes included the duration of the procedure (documented in minutes from induction to completion of anesthesia), the incidence of cervicovaginal complications (for instance, significant vaginal bleeding requiring intervention, cervical lacerations, or uterine perforation), the incidence of drug-related side effects during the first 24 hours after the procedure (such as uterine cramp, nausea, vomiting, diarrhea, bloating, belching, dry mouth, flushing, tachycardia, blurred vision, and drowsiness), and patient‐reported pain and uterine cramping, which were assessed as present or absent (yes/no) during the preprocedural observation period.

Statistical analysis

Data were analyzed using SPSS software, version 24 (IBM Corp., Armonk, NY, USA). Continuous variables were compared using the independent samples Student’s t-test (for normally distributed data) or the Mann-Whitney U test (for non-normally distributed data). Normality was assessed using the Shapiro-Wilk test. Categorical variables were compared using the chi-square test or Fisher’s exact test, as appropriate based on expected cell counts. A 2-sided P-value less than .05 was considered statistically significant. Results are presented as mean ± standard deviation (SD) for normally distributed continuous data, median (interquartile range) for skewed data, and frequency (percentage) for categorical data.

Ethical considerations

The Ethics Committee of Semnan University of Medical Sciences approved the study protocol (Approval Code: IR.SEMUMS.REC.1399.324, 28/02/2021). The trial was registered with the Iranian Registry of Clinical Trials (IRCT registration number: IRCT20151228025732N68, 25/05/2021). All participants gave written informed consent before joining the study.

Results

A total of 71 women were randomized and completed the study: 36 in the hyoscine group and 35 in the misoprostol group. The baseline demographic and clinical characteristics, including age distribution, parity, and previous mode of delivery, were comparable between the 2 groups (P>.05 for all comparisons) (Table 1).

Table 1.

Baseline demographic and clinical characteristics of participants

Characteristic	Group	N	Percent (%)	P-valuea
Age Group (yrs)				.713
<30	Hyoscine	4	11.1
	Misoprostol	5	14.3
30–39	Hyoscine	15	41.7
	Misoprostol	18	51.4
40–49	Hyoscine	15	41.7
	Misoprostol	10	28.6
≥50	Hyoscine	2	5.6
	Misoprostol	2	5.7
Parity				.714
1	Hyoscine	7	19.4
	Misoprostol	10	28.6
2	Hyoscine	27	75.0
	Misoprostol	19	54.3
3	Hyoscine	2	5.6
	Misoprostol	6	17.1
Mode of delivery				.199
Vaginal	Hyoscine	28	77.8
	Misoprostol	25	71.4
Cesarean	Hyoscine	8	22.2
	Misoprostol	10	28.6

^aP-values calculated using Chi-square test or Fisher's exact test as appropriate.

Mahshid Khakzad et al. Comparison of the effects of vaginal hyoscine butylbromide and misoprostol on cervical preparation for gynecological intrauterine interventions: a double-blind clinical trial. Am J Obstet Gynecol 2026.

The primary outcome, the mean diameter of the first Hegar dilator passed without force, was (4.91±1.10) mm (median 5 mm) in the hyoscine group and (5.54±1.50) mm (median 6 mm) in the misoprostol group. This difference did not reach statistical significance (P=.081).

No serious intraoperative complications, such as uterine perforation or cervical laceration, occurred in either group. The rates of clinician-observed vaginal bleeding during the procedure were low and similar in both groups (11.1% in hyoscine vs 11.4% in misoprostol, P=.564) (Table 2).

Table 2.

Cervicovaginal-uterine complications

Complication	Status	Group	N	Percent (%)	P-valuea
Pain (reported)	Yes	Hyoscine	0	0.0	<.001
		Misoprostol	18	51.4
	No	Hyoscine	36	100.0
		Misoprostol	17	48.6
Vaginal bleeding	Yes	Hyoscine	4	11.1	.564b
		Misoprostol	4	11.4
	No	Hyoscine	32	88.9
		Misoprostol	31	88.6
Uterine rupture	Yes	Hyoscine	0	0.0	>.99b
		Misoprostol	0	0.0
	No	Hyoscine	36	100.0
		Misoprostol	35	100.0
Cervical laceration	Yes	Hyoscine	0	0.0	>.99b
		Misoprostol	0	0.0
	No	Hyoscine	36	100.0
		Misoprostol	35	100.0

^aP-values calculated using Chi-square test unless otherwise specified.

^bFisher's exact test.

Note: "Pain (Reported)" reflects drug-related cramping pain assessed prior to the procedure.

Mahshid Khakzad et al. Comparison of the effects of vaginal hyoscine butylbromide and misoprostol on cervical preparation for gynecological intrauterine interventions: a double-blind clinical trial. Am J Obstet Gynecol 2026.

Regarding drug-related side effects, a marked difference was observed in the incidence of uterine cramping, representing a key finding of this trial. No patients (0/36, 0%) in the hyoscine group reported cramping, compared to 12 patients (12/35, 34.3%) in the misoprostol group (P<.001). Similarly, the general reporting of "Pain" (reflecting cramping/procedural discomfort related to drug effect) was absent in the hyoscine group vs present in 51.4% of the misoprostol group (P<.001) (Table 2). Other side effects, such as nausea (0% vs 5.7%) and diarrhea (0% vs 11.4%), were infrequent and occurred only in the misoprostol group, with differences not reaching statistical significance (P=.239 and P=.054 respectively). No instances of bloating or belching were reported in either group (Table 3).

Table 3.

Drug-related side effects

Side Effect	Status	Group	N	Percent (%)	P-valuea
Uterine cramps	Yes	Hyoscine	0	0.0	<.001b
		Misoprostol	12	34.3
	No	Hyoscine	36	100.0
		Misoprostol	23	65.7
Nausea	Yes	Hyoscine	0	0.0	.239b
		Misoprostol	2	5.7
	No	Hyoscine	36	100.0
		Misoprostol	33	94.3
Diarrhea	Yes	Hyoscine	0	0.0	.054b
		Misoprostol	4	11.4
	No	Hyoscine	36	100.0
		Misoprostol	31	88.6
Bloating	Yes	Hyoscine	0	0.0	>.99b
		Misoprostol	0	0.0
	No	Hyoscine	36	100.0
		Misoprostol	35	100.0
Belching	Yes	Hyoscine	0	0.0	>.99b
		Misoprostol	0	0.0
	No	Hyoscine	36	100.0
		Misoprostol	35	100.0

^aP-values calculated using Chi-square test unless otherwise specified.

^bFisher's exact test.

Mahshid Khakzad et al. Comparison of the effects of vaginal hyoscine butylbromide and misoprostol on cervical preparation for gynecological intrauterine interventions: a double-blind clinical trial. Am J Obstet Gynecol 2026.

Discussion

This double-blind, randomized controlled trial demonstrated that vaginal hyoscine butylbromide achieved a degree of cervical dilation comparable to vaginal misoprostol when used for preparation before gynecological intrauterine procedures in premenopausal women. While the mean initial dilation was slightly greater with misoprostol, the difference was not statistically significant (P=.081). Of particular clinical relevance, hyoscine was associated with significantly less uterine pain and cramping compared to misoprostol (0% vs 34.3%, P<.001). This substantial reduction in uterine cramps represents a distinct advantage of hyoscine, as cramping is one of the most common sources of patient discomfort during cervical preparation. Both treatments exhibited a favorable safety profile, with no serious adverse events recorded.

Our findings regarding the efficacy of hyoscine for cervical ripening are generally consistent with previous reports, including those by Hadadianpour and colleagues, which also suggested hyoscine's utility, particularly in premenopausal women undergoing intrauterine procedures.^6,10,13 However, direct comparisons between studies are challenging due to variations in methodology, including drug dosage, timing of administration, definition of successful dilation, patient populations (eg, inclusion of postmenopausal women), and the specific procedures performed. The mean dilation achieved in both groups (approximately 5–5.5 mm) is generally considered clinically adequate for inserting instruments required for D&C or hysteroscopy. The slight, nonsignificant trend towards greater dilation with misoprostol may be less clinically relevant when weighed against the side effect profile.

A key finding of our study is the significantly lower incidence of uterine cramping and associated pain in the hyoscine group, which warrants particular emphasis. None of the patients receiving hyoscine reported cramping, whereas over a third of those receiving misoprostol did (0% vs 34.3%, P<.001). This aligns with hyoscine's established antispasmodic properties resulting from its anticholinergic action on smooth muscle.⁷ This finding is also consistent with studies showing hyoscine can reduce the need for opioid analgesia during labor.¹⁴ While 1 study investigating the addition of hyoscine to misoprostol for medical abortion did not find a significant difference in pain scores,⁷ the different clinical context (abortion induction vs preprocedural ripening) and the combined drug use may account for this discrepancy. The marked reduction in uterine cramps and associated pain observed in our study represents a significant clinical advantage for patient comfort during cervical preparation, and this benefit should be considered alongside the comparable dilation efficacy when choosing a cervical priming agent.

The safety profile observed in our study was excellent for both agents. Serious complications like uterine perforation or cervical laceration did not occur. Other side effects commonly associated with misoprostol, such as nausea and diarrhea, were infrequent and not significantly different between groups, although they only occurred in the misoprostol arm. The overall low incidence of side effects (apart from cramping with misoprostol) is consistent with previous literature on both drugs used for gynecological indications.^6,7,13,14

The mechanism by which hyoscine facilitates cervical preparation likely involves relaxation of cervical smooth muscle via its anticholinergic effects, contributing to softening and dilation. Its pronounced effect on reducing uterine cramping further underscores its value as an antispasmodic. This dual action—promoting dilation while minimizing associated discomfort—positions hyoscine as an attractive alternative to prostaglandins. The complete absence of uterine cramping in the hyoscine group (0%) compared to a substantial incidence in the misoprostol group (34.3%) is arguably the most clinically significant finding of this trial. Cramping during cervical preparation is a major contributor to patient anxiety and discomfort, and eliminating this side effect may improve patient acceptance of and compliance with preprocedural cervical priming. Clinically, our results suggest that hyoscine could be offered as the preferred cervical priming agent, particularly for patients concerned about potential pain or cramping, without significantly compromising the adequacy of cervical preparation for common intrauterine procedures.

Strengths of this study include its randomized, double-blind design, which minimizes bias. However, certain limitations should be acknowledged. Pain and uterine cramping were assessed only as present or absent (yes/no), and a continuous pain scoring tool such as the Visual Analog Scale (VAS) was not used; consequently, mean pain intensity scores could not be compared between groups, which limits the ability to quantify the degree of pain reduction with hyoscine. Future studies should incorporate validated continuous pain assessment instruments (eg, VAS) to enable more nuanced comparison of analgesic outcomes. The study population consisted solely of premenopausal women; therefore, the findings may not be generalizable to postmenopausal women, in whom cervical dilation can often be more challenging. The study was conducted at a single center, which might limit external validity. Although the sample size was based on power calculations, it might still have been insufficient to detect potentially clinically relevant differences in dilation between the groups.

Future research should include larger, multicenter randomized trials to confirm these findings with greater statistical power. Investigating the efficacy and safety of hyoscine in postmenopausal women is particularly warranted. Further studies could also explore optimal dosing regimens, timing of administration, and alternative routes (eg, comparing intracervical to vaginal) for hyoscine in this context.

Conclusion

In this study of premenopausal women undergoing gynecological intrauterine procedures, vaginal hyoscine butylbromide resulted in cervical dilation comparable to that achieved with vaginal misoprostol. Importantly, hyoscine use was associated with significantly less uterine pain and cramping—with no patients in the hyoscine group experiencing cramps compared to over a third in the misoprostol group—and demonstrated a favorable safety profile. These findings suggest that vaginal hyoscine butylbromide is a viable and more comfortable alternative for cervical preparation in this patient population, with the significant reduction of uterine cramps representing a notable clinical benefit.

Ethics approval

Research reported in this publication was approved by the ethics committee of Semnan University of Medical Sciences, Semnan, Iran (IR.SEMUMS.REC.1399.324, 28/02/2021). The trial was registered with the Iranian Registry of Clinical Trials (IRCT registration number: IRCT20151228025732N68, 25/05/2021).

Consent for publication

We confirm that all methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all subjects.

Funding

No funding was received for this study.

Data availability statements

The data that support the findings of this study are available from the corresponding author upon reasonable request.

CRediT authorship contribution statement

Mahshid Khakzad: Validation, Project administration, Methodology, Data curation, Conceptualization. Safa Mousavi: Writing – review & editing, Writing – original draft, Visualization, Formal analysis. Sadra Sarandili: Writing – review & editing, Writing – original draft, Formal analysis. Majid Mirmohammadkhani: Writing – review & editing, Supervision, Formal analysis. Shahrzad Aghaamoo: Writing – review & editing, Supervision, Methodology, Conceptualization.

Declaration of competing interest

The authors declare that they have no competing interests.