A double-blind randomized controlled trial of vaginal misoprostol before outpatient hysteroscopy in postmenopausal women.
Daniela Angerame Yela, M.D., Ph.D, Fabiana Nakano, M.D.; Joao Paulo Leonardo Pinto, MD; Talita Aparecida Riegas Mendes, MD; Lucia Helena Costa Paiva, M.D., Ph.D.
Department of Obstetrics and Gynecology, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Financial disclosure/conflicts of interest: None declared.
Correspondence:
Daniela Angerame Yela
Departamento de Tocoginecologia. Faculdade de Ciências Médicas
Universidade Estadual de Campinas - UNICAMP
Rua Alexander Fleming, 101, Cidade Universitária
CEP 13083-881 - Campinas, SP, Brazil
Telephone/fax: +55-19-3521-9306
E-mail:
Precis: Previous use of misoprostol does not prepare the uterine cervix and fails to decrease pain during the performance of diagnostic hysteroscopy without anesthesia in postmenopausal women.
Abstract
Study Objective: To evaluate the efficacy of vaginal misoprostol for cervical ripening in postmenopausal women before diagnostic hysteroscopy without anesthesia. Design: double-blind randomized controlled clinical trial (Canadian Task Force Classification I) Setting: Women’s Integrated Healthcare Center (CAISM) of the University of Campinas (UNICAMP). Patients: One hundred and fifty-eight postmenopausal women Intervention: postmenopausal women received 200µg of misoprostol or placebo by the vaginal route before diagnostic hysteroscopy. Measurements and Main Results: The following variables were studied: age, parity, time since menopause, associated diseases, indication for the exam, duration of the procedure, frequency and severity of pain during exam, need for additional cervical dilatation, adverse effects and complications For statistical analysis, the chi-square tests of association were used. Fisher’s exact test and the Mann-Whitney tests were used for the comparison between groups, considering an alpha error lower than 5%. Women from both groups displayed similar characteristics. The duration of hysteroscopy was similar in both groups: 2.5±2.7 minutes for the misoprostol group and 2.1±1.6 minutes for the placebo group (p=0.43). Pain during grasping of the uterine cervix was rated as 3.29±3.09 for the misoprostol group and 3.52±3.06 for the placebo group. During exam, pain was categorized as 5.27±3.52 for the misoprostol group and 5.53±3.36 for the placebo group. During biopsy, pain was classified as 4.08±3.46 for the misoprostol group and 3.83±3.34 for the placebo group. In both groups there was no significant difference in pain severity (p=0.52, p= 0.69 and p= 0.68, respectively). Conclusion: Previous use of misoprostol does not prepare the uterine cervix and fails to decrease pain during the performance of diagnostic hysteroscopy without anesthesia in postmenopausal women.
Keywords: Hysteroscopy; postmenopausal women, misoprostol, cervical ripening.
Introduction
Hysteroscopy is commonly used in the diagnosis and treatment of intrauterine lesions such as polyps, myomas, uterine septae and adhesions. It is also used for the evaluation of abnormal uterine bleeding. Diagnostic hysteroscopy provides a panoramic view of the uterine cavity, in addition to permitting biopsy of the endometrium (1,2). The method can be performed without anesthesia. (3)
A limitation of the method is that pain may occur during the examination or unsuccessful hysteroscopy due to stenosis of the cervical os (internal orifice) (4)
Various alternatives were used in an attempt to address the problem, including a reduction in hysteroscope diameter and the use of local anesthesia in the uterine cervix (5,6). Cervical ripening can be achieved by mechanical (laminaria tents) and biochemical (prostaglandins) methods (7).
Misoprostol is a synthetic methyl-analogue of prostaglandin PGE1. Its major advantages are thermostability, a lower risk of adverse effects and low cost, when compared to natural prostaglandins. The main adverse effects of the drug are pelvic cramping, diarrhea, vomiting, genital bleeding and hyperthermia (8).
The majority of studies on this subject are conducted in a well-controlled manner and suggest favorable results with the previous use of misoprostol (9). However, evidence on the use of misoprostol in diagnostic hysteroscopy is still scarce. Furthermore, there are few studies involving patients who are in the postmenopausal period. Thus, the aim of this study was to evaluate the results of the use of misoprostol or placebo for postmenopausal women undergoing diagnostic hysteroscopy.
Material and Methods
A double-blind randomized clinical trial was conducted in postmenopausal women undergoing diagnostic hysteroscopy without anesthesia and with previous application of 200 µg of misoprostol or placebo. Both tablets were administered by the vaginal route for cervical ripening at the Women’s Integrated Healthcare Center (CAISM) of the University of Campinas (UNICAMP) from September 2014 to February 2016.
One hundred and fifty-eight (158) patients were included in the study, and randomly allocated into two groups (79 using 200µg of misoprostol and 79 using placebo).
Sample size was based on the prevalence of scores above five on the visual analog pain scale during the procedure, in patients receiving misoprostol and placebo, observed in previous studies of 44.6% and 66.7% (10). For calculation, an identical proportion of patients was considered in both groups (1:1), Significance level was 5% and power of the test was 80% for the chi-square test, resulting in n=158 cases, divided into two groups (n=79 in each group).
Inclusion criteria were menopausal women who had an indication for endometrial evaluation such as polyps, myomas, endometrial thickening seen during ultrasonography, or genital bleeding. All patients signed consent term in order to participate in the study. Exclusion criteria were genital infection, previous hysteroscopy, women who had never had sexual intercourse, uterine malformations, women with mental illness or women undergoing pelvic radiotherapy.
Randomization was performed with a random number computer-generated table in Evitable, part of the Epi-Info 6.04d software program. Patients were allocated to both study groups only after their consent terms were signed.
Envelopes sequentially numbered from 1-158 were prepared. Each number corresponded to a 200 µg tablet of misoprostol or placebo (drug labelled A or B), according to the random number table. The 200 µg misoprostol tablets were prepared by Pfizer, a pharmaceutical company that also manufactured placebo tablets particularly for the research, with shape, size, color and weight similar to the active drug.
The tablets were stored in paper envelopes and the contents were only known to the pharmacist responsible. After study inclusion, the numbered envelope was opened to each woman, and the main investigator inserted the tablets into the posterior vaginal cul-de-sac of these women. Women were instructed to return to the hospital within 6 hours to undergo the examination. All procedures were performed by the main investigator in a surgical setting, without anesthesia. In all hysteroscopies, a rigid hysteroscope was used, based on a 2.9-mm rod-lens system with a 30-degree forward oblique view (Karl Storz GmbH, Tuttlingen, Alemanha). The technique was applied as described by Tantini (11). In all women a speculum was used, and a Pozzi tenaculum forceps was used to grasp the uterine cervix. CO2 was the distension media and endometrial biopsy was performed with a pipelle.
The duration of the procedure was measured with a Casio chronometer (Casio, Inc., Tokyo, Japan), starting with the introduction of the hysteroscope through the external cervical os until its removal through the same route at the end of the procedure. The presence and severity of pain during cervical grasping with a Pozzi tenaculum forceps, during and after the exam was evaluated. Since pain is a subjective experience, it is naturally hard to measure. Therefore, the use of standardized instruments is important to overcome this problem, making it possible to compare different thearapeutic techniques. In this study, a visual analog scale (VAS) was used, ranging from no pain to the worse pain imaginable. The correlated numerical rating scale was printed on the back of the scale (12).
Before the procedure, the VAS was presented to study participants, explaining the aims and procedures for pain evaluation. The need for additional cervical dilatation and the presence of secondary effects, including genital bleeding, nausea, vomiting, diarrhea, and hyperthermia were recorded. Complications such as uterine perforation, false passage, lacerations of the uterine cervix and infections were evaluated.
The present study was approved by the Research Ethics Committee of this institution, under number 286144 and registered in REBEC (Registration of Brazilian clinical trials).
For statistical analysis, the chi-square tests of association were used. Fisher’s exact test and the Mann-Whitney test were used for the comparison between groups, considering an alpha level (Type I error) below 5%. For the performance of these procedures, the SAS computer program version 9.04 was used.
Results
Women from both groups diplayed similar characteristics relative to age, body mass index, time since menopause, parity, number of cesarean sections, race, religion, marital status, profession, school education and diseases associated with arterial hypertension and diabetes (Table 1).
Indications for the performance of hysteroscopy were also similar in both groups. Approximately 50% of the indications were due to postmenopausal bleeding and the other half was due to endometrial thickening. The endometrial lining found on ultrasound measured an average of 10mm for the group using misoprostol and 9 mm for the group using placebo (p=0.65) (Table 2).
Of the 79 randomized women undergoing hysteroscopy and using misoprostol, the exam could not be performed in 12 women due to severe stenosis associated with pain. Of the 79 randomized women undergoing hysteroscopy and using placebo, the exam failed to be performed in 14 women due to the same reason. Regarding pain in both groups, the majority of women experienced pain during grasping of the uterine cervix, during the exam and during biopsy. There was no need for cervical dilatation in the majority of women from both groups. The group of women using misoprostol had significantly more side effects (25.3%) than the group using placebo (2.5%). (Table 3). The adverse effects reported were vaginal bleeding, pelvic cramping and diarrhea. There were no complications with the use of placebo. In the misoprostol group, there were 2 patients with lacerations and 2 with the creation of false passages (p=0.12).
The duration of hysteroscopy was similar in both groups: 2.5±2.7 minutes for the misoprostol group and 2.1±1.6 minutes for the placebo group (p=0.43). Pain on grasping of the uterine cervix was rated as 3.29±3.09 for the misoprostol group and 3.52±3.06 for the placebo group. During the exam, pain severity was classified as 5.27±3.52 for the misoprostol group and 5.53±3.36 for the placebo group and during biopsy. Pain was rated as 4.08±3.46 for the misoprostol group and 3.83±3.34 for the placebo group. In both groups, there was no significant difference in pain severity (p=0.52, p= 0.69 and p= 0.68, respectively). (Table 4)
Discussion
Misoprostol is a medication that has been used in non-pregnant women for cervical ripening prior to IUD insertion, endometrial biopsy, artificial intrauterine insemination procedure and hysteroscopy (13)
Various studies show that misoprostol facilitates the performance of hysteroscopy in women in the menacme by decreasing pain during the procedure (14, 15,16 )
There are few studies regarding this issue in menopausal women. In our study, we found that no benefits arose from using misoprostol before diagnostic hysteroscopy performed without anesthesia.
An Indian study with 50 postmenopausal women suggested that 200 mg of misoprostol given by the vaginal route 12 hours before hysteroscopy, could be an effective medication for the preparation of the uterine cervix (17). In a similar manner, a Brazilian study with 120 women also suggested that 200mg of misoprostol administered by the vaginal route could reduce pain severity during hysteroscopy in postmenopausal women (10). Larger doses of misoprostol (1000mg) associated with estrogen therapy are also thought to have an effect on cervical preparation (18).
A systematic review evaluating 17 randomized studies concluded that there was very little evidence to recommend the routine use of misoprostol before hysteroscopy. (2). In contrast, another review study indicated that the use of misoprostol was advantageous in postmenopausal women before the performance of hysteroscopy only if the procedure was performed with a 5-mm hysteroscope (6).
More recently, review sudies suggest that misoprostol should be used for uterine cervical preparation only in women experiencing menacme, since the drug has no effect on cervical preparation of postmenopausal women (1, 9). When used by another route, misoprostol also seems to have no significant effect on cervical preparation. A study with the use of 200mg of sublingual misoprostol showed that the drug does not have a significant action on uterine cervical preparation in menopausal women(19). However, another study using sublingual misoprostol showed its effect on the uterine cervix of postmenopausal women during surgical hysteroscopy, i.e. misoprostol facilitated dilatation of the uterine cervix (20).
In our study, women using misoprostol displayed significantly more adverse effects (genital bleeding, cramping pain and diarrhea) than the placebo group. These results are similar to those found in the literature. A review with 32 studies showed that misoprostol has more effects than placebo (risk difference 0.07, 95% CI 0.01-0.12) (9). However, some studies show that there is no difference between the adverse effects reported with the use of misoprostol and placebo (p = 0.62, p=0.70) (10).
Conclusion
It may be concluded that misoprostol has no effect on cervical preparation in postmenopausal women and thus its use is not recommended before diagnostic hysteroscopy in this particular group of women.
References
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