Hum. Reprod. Advance Access originally published online on April 3, 2006
Human Reproduction 2006 21(8):2167-2170; doi:10.1093/humrep/del098
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Misoprostol for cervical ripening in non-pregnant women: a randomized double-blind controlled trial of oral versus vaginal regimens
Department of Obstetrics and Gynecology, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand. E-mail: chchaina{at}yahoo.com
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Abstract |
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BACKGROUND: The objective was to compare the efficacy of oral versus vaginal misoprostol for cervical ripening in non-pregnant women. METHODS: Sixty non-pregnant women scheduled for diagnostic hysteroscopy were randomized by computerized randomization schedule to 400 µg of misoprostol orally (n = 30) or 200 µg vaginally (n = 30) administered 12 h prior to surgery. The diameter of the cervical canal measured with a Hegar dilator, adverse events and any complications were recorded and compared between the two groups. RESULTS: The mean pre- and post-medication cervical canal diameter and cervical diameter difference were 2.00 ± 1.93 versus 2.37 ± 1.83 mm (P = 0.453), 5.10 ± 1.75 versus 5.60 ± 1.69 mm (P = 0.265) and 3.10 ± 1.79 versus 3.23 ± 1.74 mm (P = 0.771) in the oral and vaginal group, respectively. Seven patients in the oral group and one patient in the vaginal group experienced diarrhoea within 24 h of administration of the misoprostol. CONCLUSION: Oral misoprostol 400 µg had similar efficacy in cervical ripening to 200 µg of vaginal misoprostol.
Key words: cervical ripening/hysteroscopy/misoprostol/oral/vaginal
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Introduction |
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Hysteroscopy is an important procedure used for the diagnosis and treatment of a variety of gynaecological problems. Many patients require cervical dilatation prior to hysteroscopy. A cervical tear, a false tract, bleeding or a uterine perforation have all been reported to occur during the dilatation procedure. Because of these complications, medical means of softening or dilating the cervix, known as ripening, has become an integral part of the pre-operative care.
Misoprostol, a synthetic prostaglandin E1 analogue, has been demonstrated to have cervical ripening effects in both pregnant and non-pregnant patients (Ngai et al., 1995
, 1997). Misoprostol can be administered either orally or vaginally (Ngai et al., 1997; Preutthipan and Herabutya, 1999, 2000; Thomas et al., 2002). Oral misoprostol 400 µg administered 12 h (Ngai et al., 1997) or misoprostol 200 µg applied vaginally 9–10 h (Preutthipan and Herabutya, 1999, 2000) before hysteroscopy has been reported to be effective for pre-operative cervical dilatation. The pharmacokinetic profile of misoprostol indicates a lower Cmax after vaginal administration, compared to oral, but a longer duration of blood levels. These data are interpreted as indicating a better effect on cervical ripening because of the sustained blood levels (Zieman et al., 1997). However, women in Southeast Asia appear to prefer oral over vaginal therapy.
The present study was designed to compare oral versus vaginal misoprostol on cervical dilatation when administered 12 h prior to scheduled diagnostic hysteroscopy.
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Materials and methods |
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The study was performed at Songklanagarind Hospital, Prince of Songkla University, Thailand. The study was approved by the Ethics Committee of the Faculty of Medicine. Informed consent was obtained from each woman prior to the procedure. Every patient who was a candidate for hysteroscopy was invited to participate. We acquired and analysed data on 60 premenopausal women who agreed to participate in the study. We did not determine the number of women to whom the protocol was offered and who declined to participate. Sixty patients suspected of having intrauterine pathology were enrolled in the study from January 2004 to February 2005. The inclusion criteria were women who were not allergic to prostaglandins, were not pregnant and who had no contraindication to hysteroscopy. Exclusion criteria were a history of inflammatory bowel disease, allergy to prostaglandins, signs of infection of the vagina or cervix, cardiovascular disease and a history of treatment with a GnRH agonist. Each woman was scheduled for diagnostic hysteroscopy. We used a 4 mm hysteroscope with a 5.5 mm outer sheath (Karl Stroz, Germany) during this study.
The study was a prospective randomized double-blind, double-dummy, clinical trial with patients allocated to either oral or vaginal misoprostol by a computerized randomization schedule. The medical school pharmacy produced placebo tablets that had external characteristics (same size and colour) identical to misoprostol (Cytotec 200 µg, Pharmacia Limited, Morpeth, UK). Each patient was prescribed two tablets orally and one tablet vaginally the night before the operation. The patients allocated to the oral group were administered misoprostol 400 µg orally and one placebo tablet vaginally. Patients allocated to the vaginal group were administered two placebo tablets orally and misoprostol 200 µg vaginally.
Each participant underwent a vaginal speculum examination, and the cervical diameter was measured with a Hegar dilator in the outpatient clinic without any anaesthesia prior to the administration of misoprostol. The diameter of the cervical canal was assessed by placing increasing sized Hegar dilators with minimal pressure through the cervical canal to a distance of 3 cm. The largest Hegar dilator that could be easily inserted into the cervical canal was considered to be the cervical diameter. The cervical diameter was re-evaluated immediately prior to beginning the hysteroscopy in the operating theatre (12 h after administration of misoprostol) using the same technique but under general anaesthesia. At the time of surgery, if the cervical canal was too small or too tight precluding passing the hysteroscope, then further dilatation was performed to a Hegar number 6.
The cervical diameter was evaluated by one physician, the Principal Investigator (PI, the author C.C.), who was blinded to the route of medication. The vagina of each patient was cleansed by the on-duty physician to remove any remaining fragments of the vaginal placebo, or misoprostol tablets prior to the PI assessing the cervical change to maintain blindness.
The cervical diameter after misoprostol was the primary outcome of the study. The secondary outcome was any treatment-emergent adverse effect(s). Other data analysed included the number and percentage of patients requiring cervical dilatation, the duration of the hysteroscopy procedure (from the time the hysteroscope was first inserted until the completion of the hysteroscopic examination) and any complications related to the procedure. These results were compared between each group.
A sample size calculation was computed by using a two-tailed test with an 
level of 0.05 and a 95% power. The mean cervical diameter following oral and vaginal misoprostol of 400 and 200 µg has been reported to be 6 (Ngai et al., 1997) and 7.3 mm (Preutthipan and Herabutya, 2000), respectively. To detect a difference of this magnitude required at least 54 patients (27 patients per group). The actual sample size was 30 participants per group to allow for the possibility of greater variability in cervical diameter than that reported in previous studies. Data are presented as the mean ± SD or the number of cases. The cervical diameter and operative time were compared by the Student’s t-test. Adverse effects and associated complications were evaluated by the Chi-squared test. The Fisher’s exact test was used instead of the Chi-squared test when any of the cells in a cross-tabulation contained fewer than five subjects. A P-value <0.05 was considered to indicate statistical significance.
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Results |
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Random allocation was confirmed by the similarities in the demographics of the women in each group (Table I). The mean age of the women in the oral and vaginal misoprostol groups was 38.13 ± 6.17 and 37.8 ± 6.52 years, and the mean parity was 0.77 ± 1.04 and 0.8 ± 1.03 (range 0–3) respectively. The clinical diagnosis in each group of participants is presented in Table I.
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There was no significant difference in mean pre-medication cervical diameter (2.00 ± 1.93 versus 2.37 ± 1.83 mm, P = 0.453) between the women randomized to either the oral or the vaginal misoprostol (Table II). The mean post-medication or pre-operative cervical diameter (evaluated 12 h after misoprostol administration) was 5.10 ± 1.75 versus 5.60 ± 1.69 mm (P = 0.265) in the oral and vaginal groups respectively (Table II). The mean cervical diameter difference (3.10 ± 1.79 versus 3.23 ± 1.74 mm, P = 0.771) was not significantly different between groups.
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The operating time for diagnostic hysteroscopy was 4.53 ± 2.21 and 4.53 ± 1.59 min in the oral and vaginal groups, respectively. One patient in each group required further cervical dilatation prior to the diagnostic hysteroscopy. The time required for cervical dilatation in these two patients was 2 min for the one patient in the oral group and 12 min for the one patient in the vaginal group.
A cervical tear occurred during the operative procedure in one and two patients in the oral and vaginal groups, respectively. The cervical tear required suturing to control bleeding in one patient in each group. One other patient in the vaginal group needed only pressure on the cervix to control bleeding.
Seven patients (23.3%) in the oral misoprostol group and 13 patients (43.3%) in the vaginal misoprostol group had remnants of the vaginal tablet visible at the time of hysteroscopy ascertained by the on-duty physician. This finding was not significantly different between the two groups (P = 0.100) (Table II).
The incidence of treatment-emergent adverse effects was not statistically significant between the treatment groups. (Table III).
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Discussion |
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Our study compared the change in cervical diameter before and after medication. The change in cervical diameter after misoprostol was the same in both groups, approximately 3.0 mm (range 0–6 mm). This finding supports our conclusion that there is no difference in the degree of cervical ripening between the oral and vaginal routes of administration. The change in the cervical diameter is crucial in assessing the real efficacy of misoprostol. Our data are the first to compare directly oral versus vaginal misoprostol for cervical priming before hysteroscopy. We have found that the cervical diameter after administration of misoprostol is approximately 3 mm when compared to baseline. This information is important to the physician in determining whether misoprostol should be used prior to a procedure requiring cervical dilatation.
The increased cervical diameter found in this study 5.10 ± 1.75 versus 5.60 ± 1.69 mm after oral or vaginal misoprostol was similar, but not identical to the increase in cervical diameter after use of either oral (400 µg) or vaginal (200 µg) misoprostol reported in previous studies. Misoprostol 400 µg administered orally 12 h before the procedure resulted in a mean cervical diameter of 6.0 ± 1.3 mm in the misoprostol group compared to 3.2 ± 1.3 mm in the placebo group (P < 0.001) in premenopausal women undergoing hysteroscopy for infertility (Ngai et al., 1997). Preutthipan and Herabutya (1999) investigated 91 infertility patients scheduled for hysteroscopy. The subjects were randomized to vaginal misoprostol 200 µg or placebo, and Hegar dilators were used to estimate the cervical diameter. The mean cervical diameter was significantly different between the misoprostol group (7.0 ± 1.0 mm) compared to the placebo group (3.8 ± 1.2 mm). Preutthipan and Herabutya (2000) randomly assigned 152 premenopausal patients to receive either a vaginal placebo or misoprostol 200 µg 9–10 h before operative hysteroscopy. The mean Hegar dilator size in the treated group was 7.3 ± 0.7 mm versus 3.8 ± 1.1 mm in the placebo (P < 0.001).
We assessed cervical force in this study based on the ease of passage of the Hegar dilator. We did not measure quantitatively the force required to dilate the cervix in this study, but the clinical assessment was that there was no difference between the two treatment arms. A cervical tonometer was used to measure the peak force required to enter the internal cervical os with successive dilator from 3 to 9 mm by El-Rafaey et al. (1994) and Ngai et al. (1997). Baseline dilatation was the first dilator to produce a peak force above 5N. The cumulative forces needed for cervical dilatation were lower in the misoprostol group compared to placebo. All physicians use their clinical judgment to determine when cervical dilatation should be discontinued by evaluating both the force and the condition of the cervix. Our study is most applicable to the real clinical situation, since only one physician evaluated the pressure needed to dilate the cervical canal.
The time interval between administration of misoprostol and cervical dilatation is important. Our study found that an interval of 10–12 h after misoprostol administration results in increased cervical dilatation and ease of further cervical dilatation if required. This is in agreement with other investigators (Ngai et al., 1997; Preutthipan and Herabutya, 1999, 2000). Fernandez et al. (2004) randomly assigned four groups of 12 premenopausal women to receive either placebo or vaginal misoprostol in doses of 200, 400 or 800 µg 4 h before operative hysteroscopy. Vaginal misoprostol did not change or alter the requirement for cervical dilatation with this time interval. There was no evidence that the hysteroscopic surgery was facilitated, and there was increased pre-operative pain in this study.
Vaginal misoprostol for medical abortion or prior to vacuum aspiration has an additional benefit that of increasing uterine contractility (Danielsson et al., 1999). This misoprostol effect on uterine contractility is not needed in non-pregnant women undergoing diagnostic hysteroscopy where cervical priming is the main objective.
The incidence of treatment-emergent adverse events was not significantly different between the two groups. The symptoms that occurred were felt to be associated with misoprostol, but none of the women required additional medication to treat any symptom. These findings underscore the mild and transient nature of these side effects.
There was more diarrhoea in the oral group compared to the vaginal group (seven patients versus one patient or 23.3 versus 3.3%, P = 0.052). Although these data are interesting, they are of borderline statistical significance. Our study had only 30 participants in each arm and was not powered to detect a difference in side effects. The increased occurrence of diarrhoea may have been the result of the higher dose of oral misoprostol. Because diarrhoea is a known side effect of misoprostol, some authors have advocated the vaginal route over the oral in order to reduce its occurrence.
The vaginal route of administration of medication is not acceptable to all women. The majority of women, especially in Asian countries, prefer oral medication. Unless a clear benefit to the patient for vaginal misoprostol can be identified, we feel that the oral route should be used preferentially since we found comparable changes in cervical dilatation.
Fragments of the vaginal tablets used for first-trimester termination of pregnancy have been found in the vagina. This finding is thought to be due to the incomplete dissolution of the misoprostol tablets (Zieman et al., 1997; Fong et al., 1998; Singh et al., 1998, 1999; Danielsson et al., 1999). We observed remnants of the vaginal tablets in seven patients (23.3%) and 13 patients (43.3%) (P = 0.100) in the oral and vaginal groups, respectively. The incidence of vaginal fragments was not statistically different between the two groups. The finding of fragments in both groups reduced any potential bias in the cervical diameter measurement, which may have resulted if the fragments had been found exclusively in the vaginal misoprostol group.
In summary, this study is the first to compare cervical diameter changes between oral and vaginal misoprostol administration. Our results show a significant increase in cervical diameter after administration of misoprostol but no significant difference between either route of administration. The adverse effects possibly related to misoprostol were similar in both groups. Therefore, patients who feel uncomfortable with the use of vaginal misoprostol can be counselled that the oral route is equally efficacious.
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Acknowledgements |
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The authors are grateful to David F. Archer, MD, Professor of Obstetrics and Gynecology, Director of CONRAD, Clinical Research Center at Jones Institute for Reproductive Medicine, Eastern Virginia Medical School for his valuable comments and editing and Alan Geater, PhD of the Epidemiology Unit, Prince of Songkla University, for his suggestion about statistical analysis. This study was funded by The Faculty of Medicine, Prince of Songkla University.
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References |
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Submitted on December 7, 2005; resubmitted on January 23, 2006; resubmitted on February 21, 2006; accepted on March 9, 2006.
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