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A <strong>double</strong>-<strong>blind</strong> <strong>randomized</strong> <strong>controlled</strong> <strong>trial</strong> <strong>of</strong> <strong>vaginal</strong><br />

<strong>misoprostol</strong> <strong>for</strong> cervical priming be<strong>for</strong>e outpatient<br />

hysteroscopy<br />

Akmal El-Mazny, M.D., F.I.C.S., and Nermeen Abou-Salem, M.D.<br />

Department <strong>of</strong> Obstetrics and Gynecology, Faculty <strong>of</strong> Medicine, Cairo University, Cairo, Egypt<br />

Objective: To evaluate the efficacy and safety <strong>of</strong> <strong>vaginal</strong> <strong>misoprostol</strong> <strong>for</strong> cervical priming be<strong>for</strong>e diagnostic outpatient<br />

hysteroscopy (OH) without anesthesia.<br />

Design: Double-<strong>blind</strong> <strong>randomized</strong> <strong>controlled</strong> <strong>trial</strong>.<br />

Setting: University teaching hospital.<br />

Patient(s): One hundred fifty patients requiring diagnostic OH <strong>for</strong> investigation <strong>of</strong> infertility or abnormal uterine<br />

bleeding in the reproductive age.<br />

Intervention(s): Patients were randomly allocated into two equal groups (n ¼ 75). In group I, 200 mg <strong>misoprostol</strong><br />

was inserted into the posterior <strong>vaginal</strong> <strong>for</strong>nix 3 hours be<strong>for</strong>e OH; in group II (control), <strong>vaginal</strong> examination was<br />

per<strong>for</strong>med without <strong>misoprostol</strong> administration. A rigid 30 4-mm hysteroscope was used in the vaginoscopic<br />

technique.<br />

Main Outcome Measure(s): Ease <strong>of</strong> cervical entry (Likert scale), procedural time, patient acceptability (Likert<br />

scale), and pain scoring (visual analog scale).<br />

Result(s): Vaginal <strong>misoprostol</strong> significantly facilitated the procedure; cervical entry was easier, procedural time<br />

was shorter, patient acceptability was higher, and pain scoring was lower in group I compared with group II.<br />

Side effects <strong>of</strong> <strong>misoprostol</strong> were infrequent, minor, and transient. No complications were reported.<br />

Conclusion(s): The regimen <strong>of</strong> 200 mg <strong>vaginal</strong> <strong>misoprostol</strong> administered 3 hours be<strong>for</strong>e diagnostic OH is a simple,<br />

effective, and safe method <strong>of</strong> cervical priming to facilitate the procedure without anesthesia. (Fertil SterilÒ 2011;96:<br />

962–5. Ó2011 by American Society <strong>for</strong> Reproductive Medicine.)<br />

Key Words: Misoprostol, cervical priming, outpatient hysteroscopy<br />

Hysteroscopy is considered the ‘‘gold standard’’ <strong>for</strong> diagnosing intrauterine<br />

pathology (1). With the invention <strong>of</strong> the miniature hysteroscope,<br />

it is possible to per<strong>for</strong>m hysteroscopy in an <strong>of</strong>fice<br />

setting (outpatient hysteroscopy [OH]) without anesthesia <strong>for</strong> diagnostic<br />

indications and certain operative procedures (2). However,<br />

the experience <strong>of</strong> pain related to the procedure can be a major limitation<br />

<strong>for</strong> OH as a standard <strong>of</strong> care (3). This is <strong>of</strong>ten caused by the<br />

diameter <strong>of</strong> the hysteroscope and/or cervical resistance (4).<br />

Several alternatives have been proposed to per<strong>for</strong>m the procedure<br />

with an acceptable patient compliance. Local anesthetic reduces the<br />

pain experienced by women during OH. This occurs with paracervical<br />

and intracervical injections <strong>of</strong> anesthetic but not with transcervical<br />

and topical application; paracervical injection seems to be the<br />

most effective method <strong>of</strong> administering local anesthetic <strong>for</strong> the procedure<br />

(5). Nevertheless, the injection <strong>of</strong> paracervical anesthetic<br />

may cause pain and bleeding (6).<br />

Cervical priming refers to dilating or s<strong>of</strong>tening <strong>of</strong> the cervix by<br />

mechanical (e.g., laminaria) or medical (e.g., prostaglandins) means<br />

be<strong>for</strong>e an intervention in pregnant (cervical ripening) or nonpregnant<br />

women (7). Misoprostol is a synthetic analogue <strong>of</strong> prostaglandin<br />

E1 which can be given orally, <strong>vaginal</strong>ly, sublingually, buccally,<br />

or rectally (8). There is evidence supporting the use <strong>of</strong> <strong>misoprostol</strong><br />

Received February 15, 2011; revised March 28, 2011; accepted April 8,<br />

2011.<br />

A.E-M. has nothing to disclose. N.A-S. has nothing to disclose.<br />

Reprint requests: Akmal El-Mazny, M.D., F.I.C.S., Department <strong>of</strong> Obstetrics<br />

and Gynecology, Faculty <strong>of</strong> Medicine, Cairo University, Cairo, Egypt<br />

(E-mail: dr_akmalelmazny@yahoo.com).<br />

962<br />

as a cervical priming agent be<strong>for</strong>e some gynecologic procedures,<br />

such as intrauterine device insertion (9) and hysteroscopy (10).<br />

The objective <strong>of</strong> the present study was to evaluate the efficacy and<br />

safety <strong>of</strong> <strong>vaginal</strong> <strong>misoprostol</strong> <strong>for</strong> cervical priming to facilitate the<br />

procedure <strong>of</strong> diagnostic OH without the use <strong>of</strong> anesthesia, in patients<br />

with infertility or abnormal uterine bleeding (AUB).<br />

MATERIALS AND METHODS<br />

This <strong>double</strong>-<strong>blind</strong> <strong>randomized</strong> <strong>controlled</strong> <strong>trial</strong> was conducted at the<br />

OH Clinic <strong>of</strong> the Department <strong>of</strong> Obstetrics and Gynecology, Faculty<br />

<strong>of</strong> Medicine, Cairo University, from August 2009 to January 2011.<br />

The study population consisted <strong>of</strong> 150 patients requiring a diagnostic<br />

OH <strong>for</strong> investigation <strong>of</strong> infertility or AUB in the reproductive age.<br />

The study protocol was approved by the Scientific Research Committee<br />

<strong>of</strong> the department, and in<strong>for</strong>med consent was obtained<br />

from each <strong>of</strong> the patients.<br />

The exclusion criteria included: 1) contraindications to OH—<br />

marked cervical stenosis, recent or current pelvic inflammatory<br />

disease, known cervical malignancy, pregnancy, pr<strong>of</strong>use uterine<br />

bleeding, or recent uterine per<strong>for</strong>ation; 2) contraindications to prostaglandins—known<br />

sensitivity to prostaglandins, cardiovascular<br />

disease, hypertension, severe bronchial asthma, renal failure, or<br />

glaucoma; 3) previous cesarean delivery; 4) previous cervical surgery;<br />

and 5) neurologic disorders affecting the evaluation <strong>of</strong> pain.<br />

The patients were allocated into two groups with a ratio <strong>of</strong> 1:1 by<br />

using computer-generated random numbers: group I (<strong>misoprostol</strong><br />

group) and group II (control group). The patients were <strong>blind</strong>ed to<br />

group allocation. All patients underwent <strong>vaginal</strong> examination 3<br />

Fertility and Sterility â Vol. 96, No. 4, October 2011 0015-0282/$36.00<br />

Copyright ª2011 American Society <strong>for</strong> Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2011.04.049


hours be<strong>for</strong>e OH. In group I, 200 mg <strong>misoprostol</strong> (Misotac; Sigma<br />

Pharm) moistened with saline solution was inserted into the posterior<br />

<strong>for</strong>nix during the examination; in group II, the <strong>vaginal</strong> examination<br />

was per<strong>for</strong>med without <strong>misoprostol</strong> administration (no placebo<br />

was needed).<br />

All patients underwent postmenstrual OH between days 7 and 11<br />

<strong>of</strong> the cycle (except in patients with irregular bleeding). The operator<br />

per<strong>for</strong>ming the procedure was <strong>blind</strong>ed to group allocation. A<br />

rigid 30 4-mm hysteroscope (Karl Storz Endoscopy) was used<br />

without anesthesia or analgesia. The uterine cavity was distended<br />

with normal saline solution at a pressure <strong>of</strong> 100–120 mm Hg. The<br />

vaginoscopic ‘‘no touch’’ technique was followed; no speculum or<br />

tenaculum was used.<br />

The main outcome measures included: 1) ease <strong>of</strong> entry <strong>of</strong> the<br />

OH into the cervix recorded on a 5-point Likert scale (11): very<br />

difficult ¼ 1, difficult ¼ 2, fair ¼ 3, easy ¼ 4, and very easy ¼ 5;<br />

2) procedural time from introduction <strong>of</strong> the OH through the external<br />

cervical os and the visualization <strong>of</strong> the uterine cavity; 3) patient acceptability<br />

recorded by the patient on a 5-point Likert scale; 4) pain<br />

scoring recorded by the patient on a 10-point visual analog scale<br />

(VAS) (12); 5) side effects <strong>of</strong> <strong>misoprostol</strong>; and 6) complications<br />

<strong>of</strong> OH.<br />

Statistical Analysis<br />

Continuous data were expressed as mean SD and compared by using<br />

the Student t test. Categorical data were expressed as n (%) and<br />

compared by using the chi-square test or Fisher exact test as appropriate.<br />

All reported P values are two tailed, and the level <strong>of</strong> statistical<br />

significance was .05. Data analysis was per<strong>for</strong>med by using the Statistical<br />

Package <strong>for</strong> the Social Sciences, v16.0 (SPSS).<br />

RESULTS<br />

The study population consisted <strong>of</strong> 150 patients allocated into two<br />

groups: group I (<strong>misoprostol</strong> group; 75 patients) and group II (control<br />

group; 75 patients). There was no statistically significant difference<br />

in the clinical characteristics (age, gravidity, parity, and<br />

nulliparous rate) between the two groups. The indications <strong>of</strong> hysteroscopy<br />

(primary infertility, secondary infertility, and AUB)<br />

were also not significantly different (Table 1).<br />

The use <strong>of</strong> <strong>vaginal</strong> <strong>misoprostol</strong> significantly facilitated the<br />

procedure <strong>of</strong> OH. Cervical entry (Likert scale) was easier in group<br />

I (3.47 1.05) than in group II (2.93 1.02): P¼.002. Procedural<br />

time (minutes) from introduction <strong>of</strong> the OH through the external cervical<br />

os and the visualization <strong>of</strong> the uterine cavity was shorter in<br />

group I (1.95 0.47) than in group II (2.48 0.56): P


TABLE 2<br />

Main outcome measures.<br />

Variable Group I: <strong>misoprostol</strong> (n [ 75) Group II: control (n [ 75) P value<br />

Ease <strong>of</strong> cervical entry a<br />

3.47 1.05 2.93 1.02 .002<br />

Procedural time (min) 1.95 0.47 2.48 0.56 < .001<br />

Patient acceptability a<br />

2.87 0.96 2.51 0.89 .019<br />

Pain scoring b<br />

3.26 1.56 4.87 1.79 < .001<br />

Note: Values presented as mean SD.<br />

a<br />

According to 5-point Likert scale.<br />

b<br />

According to 10-point visual analog scale.<br />

El-Mazny. Misoprostol be<strong>for</strong>e <strong>of</strong>fice hysteroscopy. Fertil Steril 2011.<br />

dilatation, but it has increased side effects, mainly diarrhea and shivering<br />

(16).<br />

In agreement with our results, Sordia-Hernandez et al. (17) reported<br />

that <strong>vaginal</strong> <strong>misoprostol</strong> at a dose <strong>of</strong> 200 mg inserted 12 hours<br />

apart, starting 24 hours be<strong>for</strong>e OH without anesthesia <strong>for</strong> investigation<br />

<strong>of</strong> infertility, considerably reduces pain and the time needed <strong>for</strong><br />

hysteroscopy compared with oral <strong>misoprostol</strong> administration and<br />

placebo. They reported only one patient with nausea and two patients<br />

with referred abdominal pain in the <strong>vaginal</strong> <strong>misoprostol</strong> group<br />

(n ¼ 20). Choksuchat et al. (18) also found that 200 mg <strong>vaginal</strong> <strong>misoprostol</strong><br />

12 hours be<strong>for</strong>e conventional diagnostic hysteroscopy had<br />

efficacy similar to 400 mg oral <strong>misoprostol</strong> <strong>for</strong> cervical ripening,<br />

with less side effects.<br />

Darwish et al. (19) reported that 200 mg intra<strong>vaginal</strong> <strong>misoprostol</strong><br />

and endocervical laminaria were equally effective in inducing<br />

proper cervical priming be<strong>for</strong>e operative hysteroscopy in patients<br />

with diagnosed intrauterine lesions. Nevertheless, they observed<br />

that <strong>misoprostol</strong> may be superior, owing to easy application, reduced<br />

cost, and patient convenience and acceptability. Preutthipan et al.<br />

FIGURE 1<br />

Main outcome measures.<br />

10<br />

9<br />

8<br />

7<br />

6<br />

5<br />

4<br />

3<br />

2<br />

1<br />

0<br />

3.47<br />

2.93<br />

Ease <strong>of</strong> cervical entry<br />

(Likert scale)<br />

El-Mazny. Misoprostol be<strong>for</strong>e <strong>of</strong>fice hysteroscopy. Fertil Steril 2011.<br />

1.95<br />

Group I: <strong>misoprostol</strong><br />

Group II: control<br />

2.48<br />

(20) also found that <strong>vaginal</strong> <strong>misoprostol</strong> is more effective than dinoprostone<br />

<strong>for</strong> cervical priming in nulliparous women be<strong>for</strong>e hysteroscopic<br />

surgery. Although more side effects were observed in the<br />

<strong>misoprostol</strong>-treated patients, they were mild.<br />

Batukan et al. (21) reported that 400 mg <strong>vaginal</strong> <strong>misoprostol</strong> 10–<br />

12 hours be<strong>for</strong>e operative hysteroscopy is more effective than the<br />

oral route <strong>for</strong> preoperative cervical ripening in premenopausal<br />

women. Da Costa et al. (22) also found that 200 mg <strong>of</strong> <strong>vaginal</strong> <strong>misoprostol</strong><br />

reduced pain severity during diagnostic hysteroscopy in<br />

postmenopausal women. However, Oppegaard et al. (23) concluded<br />

that 1,000 mg <strong>vaginal</strong> <strong>misoprostol</strong> 12 hours be<strong>for</strong>e operative hysteroscopy<br />

has a significant cervical ripening effect compared with placebo<br />

in premenopausal but not postmenopausal women.<br />

In contrast to our results, Fernandez et al. (24) found that <strong>vaginal</strong><br />

<strong>misoprostol</strong> applied 4 hours be<strong>for</strong>e operative hysteroscopy<br />

in premenopausal women, at three different doses (200, 400, or<br />

800 mg), did not reduce the need <strong>for</strong> cervical dilatation, did not<br />

facilitate hysteroscopic surgery, and increased preoperative pain.<br />

Valente et al. (25) also observed that with the dose used in their<br />

2.87<br />

2.51<br />

Procedural time (min) Patient acceptability<br />

(Likert scale)<br />

3.26<br />

4.87<br />

Pain scoring (visual<br />

analogue scale)<br />

964 El-Mazny and Abou-Salem Misoprostol be<strong>for</strong>e <strong>of</strong>fice hysteroscopy Vol. 96, No. 4, October 2011


TABLE 3<br />

Side effects.<br />

Variable Group I: <strong>misoprostol</strong> (n [ 75) Group II: control (n [ 75) P value<br />

Nausea 7 (9.3) 2 (2.7) .166<br />

Vomiting 2 (2.7) 0 (0.0) .497<br />

Abdominal pain 6 (8.0) 4 (5.3) .745<br />

Diarrhea 4 (5.3) 1 (1.3) .367<br />

Fever 3 (4.0) 0 (0.0) .245<br />

Shivering 3 (4.0) 1 (1.3) .620<br />

Note: Values presented n (%).<br />

El-Mazny. Misoprostol be<strong>for</strong>e <strong>of</strong>fice hysteroscopy. Fertil Steril 2011.<br />

study (400 mg); <strong>vaginal</strong> <strong>misoprostol</strong> induced <strong>vaginal</strong> bleeding and<br />

precluded diagnostic anesthesia-free hysteroscopy in patients <strong>of</strong> reproductive<br />

age. Singh et al. (26) found that 400 mg <strong>vaginal</strong> <strong>misoprostol</strong><br />

4–6 hours be<strong>for</strong>e diagnostic hysteroscopy did not facilitate<br />

cervical dilation. Although it did effect a reduction in pain scores,<br />

there was no difference in patient satisfaction, need <strong>for</strong> analgesia,<br />

or sedation.<br />

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as a cervical priming agent is a simple method to facilitate<br />

the procedure <strong>of</strong> diagnostic OH without anesthesia in patients<br />

with infertility or AUB. Reduction <strong>of</strong> <strong>misoprostol</strong> dosage (200 mg)<br />

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965

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