Department of Obstetrics and Gynecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Address reprint requests to: Sangchai Preutthipan, MD, Department of Obstetrics and Gynecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama 6 Road, Phyathai, Bangkok, 10400 Thailand. E-mail: email@example.com
The authors wish to thank Professor Pratak O-Prasertsawat for his statistical help and advice.
Received March 13, 2000. Received in revised form June 5, 2000. Accepted June 29, 2000.
Objective: To investigate the effectiveness of vaginal misoprostol for cervical priming before operative hysteroscopy and to assess the cervicouterine complications related to cervical dilatation and hysteroscopic surgery in nulliparous women.
Methods: One hundred fifty-two women with definite intrauterine lesions were randomly assigned to receive either 200 μg vaginal misoprostol or placebo. Cervical response and outcome and complications of operative hysteroscopy were assessed.
Results: Thirty-five subjects were needed in each arm to detect a type I error of 0.01 with a power of 0.99. The mean cervical dilatation estimated by Hegar dilator was significantly different between the treated group (7.3 ± 0.7 mm) and the control group (3.8 ± 1.1 mm, P < .001). In the misoprostol group, 55 (75.3%) patients needed cervical dilation, compared with 75 (94.9%, P = .001) in the placebo group. The median time of cervical dilation to Hegar number 9 was significantly shorter in the treated group (40 seconds) compared with the control group (120 seconds, P < .001). The mean operative time was significantly shorter in the treated group (36.4 ± 10.9 minutes) compared with the control group (45.9 ± 14.2 minutes, P < .001). Cervical tears occurred in nine (11.4%) patients in the control group and in one (1.4%, P = .018) in the misoprostol group. Creation of a false tract was more common in the control group. Two uterine perforations occurred in the placebo group.
Conclusion: Vaginal misoprostol applied before operative hysteroscopy reduced the need for cervical dilation, facilitated hysteroscopic surgery, and minimized cervical complications.
Operative hysteroscopy is an important therapeutic procedure in patients with intrauterine abnormality. To perform hysteroscopic surgery, the cervix must be dilated to Hegar number 8–10. One of the major problems of operative hysteroscopy is the difficulty in entering the internal cervical os with the resectoscope. The common complications encountered during hysteroscopy are mainly related to the difficulty of cervical dilation. These complications include cervical tear, creation of a false track, and uterine perforation.1–3
Some surgeons attempt to avoid cervical lacerations by inserting laminaria into the cervical canal the night before surgery.4 Others use prostaglandins, including sulprostone gel5 or metenoprost potassium,6 for cervical priming before hysteroscopy.
Misoprostol is a prostaglandin E1 analogue that is widely prescribed for prevention and treatment of gastric ulcer resulting from long-term use of nonsteroidal anti-inflammatory drugs. Misoprostol is currently available in over 60 countries worldwide.7 The primary advantages of misoprostol are cost and convenience. It is very inexpensive and can be kept at room temperature. When given orally, it is absorbed rapidly by the gastrointestinal tract and undergoes deesterification to its free acid, which is responsible for its clinical activity. The peak concentration and half life of misoprostol acid, the active metabolite, are 12 and 21 minutes, respectively.8 The total systemic bioavailability of vaginally administered misoprostol was found to be three times greater than that of orally administered misoprostol,9 and might explain why vaginal misoprostol has been reported to be more effective than oral misoprostol for medical abortion.10
Currently, misoprostol is used for cervical ripening in labor induction,11 termination of pregnancy in the first trimester,12 and for treating missed abortion.13 Ngai et al14 reported that oral misoprostol was effective for preoperative cervical dilation in women who have diagnostic hysteroscopy. Recently we showed that vaginal misoprostol facilitated cervical dilation and diagnostic hysteroscopy.15
The purpose of this randomized, placebo-controlled study was to evaluate the effectiveness of vaginal misoprostol in facilitating cervical dilation in nulliparous women before operative hysteroscopy and to identify complications related to cervical dilation and operative procedures.
Materials and Methods
This study was approved by the Departmental Ethics Committees. On the basis of our previous study, the mean difference in cervical width between the misoprostol and the placebo groups was 1.6 mm, and the variance was also 1.6 mm. These numbers were used for calculation of the sample size. Thirty-five subjects were needed in each arm to detect a type I error of 0.01 with a power of 0.99.15
From October 1998 through December 1999, 174 women who had completed a routine investigation for infertility were recruited at Ramathibodi Hospital. These women were suspected of having intrauterine abnormalities by hysterosalpingography, ultrasonography, or hydrohysterography that required further confirmation of the diagnosis and treatment by hysteroscopy. Patients with intrauterine pathology were treated with operative hysteroscopy after the diagnostic procedure. Patients with early pregnancy, genital tract infection, and normal hysteroscopic findings were excluded. The study was carried out in a double-masked manner on an outpatient basis. After informed consent was obtained, randomization was done using a random number to assign patients to receive either 200 μg of misoprostol or an identical appearing placebo (a lactose filler) that was placed in the posterior vaginal fornix 9–10 hours before operative hysteroscopy. With the women in lithotomy position, a number-1 Hegar dilator was inserted through the internal os, followed by successively larger Hegar dilators, until resistance was met. The cervical width, assessed by the size of Hegar dilator, was then noted. For diagnostic purposes, if the endocervical canal was tight, the cervix was dilated to Hegar number 6. The time taken to this stage was noted. After the completion of the diagnostic procedure, women with intrauterine pathology proceeded to operative hysteroscopy. For the operative procedures, if the endocervical canal was judged tight, the cervix was dilated to Hegar number 9, and the time taken was again noted. The time taken to complete the operative procedures was also noted.
Hysteroscopy was performed mostly in the proliferative phase of the menstrual cycle under general anesthesia using propofol as a total intravenous anesthesia. Diagnostic hysteroscopy was done with a standard rigid hysteroscope with a 5.5-mm diagnostic sheath (Karl Storz, GmbH, Tuttlingen, Germany). Operative procedures were done using either a 7-mm operative sheath or a resectoscope with an outer sheath 9 mm in diameter (Karl Storz). The technique of operative hysteroscopy has been described previously.16 Operative hysteroscopies were performed by the same operator (SP) during this period. Concurrent laparoscopy was done only if uterine perforation or anomalies were suspected.
Outcomes assessed include cervical width before hysteroscopy, number and percentage of patients who required cervical dilatation, combined time of cervical dilatation up to Hegar number 6 and 7–9 before inserting the operative instrument, duration of the operative hysteroscopy, cervicouterine complications related to cervical dilatation and hysteroscopic surgery, and associated adverse effects.
The data was analyzed using the unpaired t test or Mann-Whitney U test, χ2 and Fisher exact test where appropriate, with P < .05 considered statistically significant.
Twenty-two patients were excluded. Three were in early pregnancy, two had genital tract infections, and 17 had normal hysteroscopic findings. Among the remaining nulliparous 152 patients recruited, 73 were allocated to misoprostol and 79 to placebo. Most of them had primary infertility. The two treatment groups were similar with respect to type of operative hysteroscopy (Table 1) and age, body weight, and number of patients with previous cervical dilatation (Table 2). The outcomes of vaginal misoprostol, placebo, and the complications of both groups are shown in Table 2. The mean cervical widths for the misoprostol and placebo groups were 7.3 ± 0.7 and 3.8 ± 1.1 mm, respectively (P < .001). In the misoprostol group, 55 (75.3%) patients required cervical dilation before operative hysteroscopy compared with 75 (94.9%) patients in the placebo group (P = .001). The median times needed to dilate the cervix up to Hegar number 9 for the misoprostol and the placebo groups were 40 and 120 seconds, respectively (P < .001). The mean times for operative hysteroscopy for the misoprostol and the placebo groups were 36.4 ± 10.9 and 45.9 ± 14.2 minutes, respectively (P < .001). The adverse effects noted in the misoprostol group were mild lower abdominal pain in 26 (35.6%, P < .001), slight vaginal bleeding in 14 (19.2%, P = .002), nausea in five (6.9%, P = .105), watery diarrhea in three (4.1%, P = .108), and feeling an increase in body temperature in seven (9.6%, P = .088) patients. In the placebo group, the same adverse effects were found in five (6.3%), two (2.5%), one (1.3%), none (0%), and two (2.5%) patients, respectively. Cervical tears were detected in nine patients (11.4%, P = .018) in the placebo group. Seven of nine cervical tears in the control group required cervical suture. In the misoprostol group, cervical tear occurred in only one patient (1.4%) and did not require suturing. Creation of a false track during cervical dilation occurred in five patients (6.3%, P = .212) in the placebo group compared with one patient (1.4%) in the misoprostol group. There were two uterine perforations (2.5%, P = .497) in the placebo group. One occurred during cervical dilation and the other occurred during hysteroscopic resection of a submucous myoma. Three patients in the misoprostol group and two patients in the placebo group were admitted for overnight observation for postoperative bleeding after hysteroscopic resection of a large submucous myoma. The rest were discharged a few hours after surgery.
One of the major problems of hysteroscopy, especially operative hysteroscopy, is the difficulty in entering the internal cervical os with the outer sheath of the hysteroscope, because of the discrepancy of the diameter between the os and the outer sheath. Methods of cervical priming and dilation before hysteroscopy should decrease complications associated with difficult cervical dilation when using the operative hysteroscope or resectoscope.
Reported in a randomized study of the safety and efficacy of laminaria for cervical softening and dilating the cervix before resectoscopy, Ostrzenski4 found that the average time to reach adequate preresectoscopic dilatation was 38 seconds compared with 11 minutes and 25 seconds (P < .05) in those without laminaria. In the treated group, adequate dilatation was obtained in all 30 patients compared with 25 (83.3%) in the control group (P < .05).
Rath et al5 reported that cervical priming with intracervical sulprostone gel before diagnostic hysteroscopy led to a significant reduction in the force required to dilate the cervix. Hald et al6 reported that vaginal use of metenoprost potassium before outpatient hysteroscopy in infertile patients provided sufficient dilatation of the cervical canal to permit the insertion of a hysteroscope without additional mechanical dilation. Ngai et al14 compared oral misoprostol with placebo for cervical priming in nonpregnant women before diagnostic hysteroscopy. They found significant reduction in the amount of force required to dilate the cervix to 8 mm (40.1 compared with 103.7 newtons P < .001). The mean baseline cervical dilatation was significantly greater in the misoprostol group (6.0 compared with 3.3 mm, P < .001). The mean duration of the operation was similar between groups.
More recently we reported that vaginal misoprostol decreased the cervical resistance in nulliparous women who had diagnostic hysteroscopy and facilitated the procedure.15 The present study used a randomized double-masked protocol to compare the effectiveness of vaginal misoprostol with placebo for cervical priming before operative hysteroscopy. We found that vaginal misoprostol was more effective than placebo for cervical dilatation. The baseline cervical dilatation was significantly greater after treatment. Vaginal misoprostol significantly reduced the need for and length of time for cervical dilation to Hegar number 9, as well as the length of time for hysteroscopic surgery. The perceived force required to dilate the cervix was less after treatment with misoprostol, but this force was not measured objectively. Four patients in the placebo group did not need cervical dilation preoperatively; all had previous cervical dilation. This study shows the advantages of using 200 μg of vaginal misoprostol preoperatively in nonpregnant patients who have operative hysteroscopy when 9 mm cervical dilatation is necessary.
Itzkowic and Beale1 reported three cases of uterine perforation associated with endometrial ablation. The predisposing factors in two cases were previous caesarean delivery and difficulty in cervical dilation. Vilos et al3 reported their experience with 800 hysteroscopic endometrial ablations in which the overall complication rate was 3.9%. Cervical trauma and uterine perforation were the most common complications, and included creating a false passage during cervical dilatation in six patients, uterine perforation from dilator in four patients, resectoscope in two patients, and laminaria in one patient.
Misoprostol use led to greater baseline cervical dilatation and reduction in mechanical dilation of the cervix. A wide cervical dilatation needed to accommodate operative hysteroscopic instruments can be approached more easily and safely than a stiff and narrow cervical canal. As shown in this study, there was a significant difference in cervical injury during cervical dilatation. Only one (1.4%) cervical tear occurred in the treated group compared with nine patients (11.4%, P = .018) in the control group, seven of whom required suturing. In fact, the cervical tear in the treated group occurred in a patient who had severe intrauterine adhesion with cervical stenosis.
In the study by Rath et al,5 ten patients with primary infertility received intracervical application of sulprostone gel for cervical priming before hysteroscopy. Only one patient complained of slight lower abdominal pain. Hald et al6 reported that the major adverse effects in 15 patients who had vaginal meteneprost potassium for cervical priming before hysteroscopy were mostly gastrointestinal symptoms. The significant adverse effects of vaginal misoprostol administration found in this study were similar to those we reported previously,15 including mild lower abdominal pain (35.6%, P < .001) and slight vaginal bleeding (19.2%, P = .002). All nine patients who perceived increased body temperature had no measurable fever.
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