Cervical priming refers to dilating or softening of the cervix by mechanical or medical means before an intervention in pregnant or nonpregnant women 1. Misoprostol is a stable synthetic prostaglandin E1 analog used for prophylaxis and treatment of peptic ulcer. It is inexpensive, can be stored at room temperature, and is available worldwide.
When used before surgical abortion, cervical priming has been shown to result in a shorter operation time, in reduced blood loss, and in easier mechanical dilatation 2,3. It may also reduce the incidence of complications during the procedure and is therefore recommended by a number of guidelines 4,5.
Cervical priming is especially useful in pain reduction and can be used either in addition to or instead of local anesthesia. It is also advantageous in procedures performed under general anesthesia as the anesthetic does not have to be as deep 6.
Various studies have shown that misoprostol also has a beneficial effect on preoperative cervical ripening in women who require hysteroscopic surgery 7,8.
Priming before hysteroscopy resulted in an increase in cervical dilatation and a lower rate of cervical laceration 9. The results in premenopausal and postmenopausal women are conflicting 10,11. In this study we aimed to assess the efficacy of vaginal misoprostol for cervical ripening in premenopausal and postmenopausal women before dilatation and curettage in gynecological procedures such as endometrial biopsy.
Materials and methods
This was a randomized controlled clinical trial conducted among 200 women undergoing dilatation and curettage for endometrial biopsy at Suez Canal University from January 2011 to January 2012. After obtaining approval from our Ethics Committee and a written informed consent from all participants, the present study was conducted as a randomized, double-blind, placebo-controlled trial. The women were divided randomly and equally into two groups. Group A (the study group) included 100 women (50 women each in the premenopausal and postmenopausal subgroups) who received two tablets of 400 µg misoprostol vaginally (mesotac; Sigma, SAE, Egypt). Group B (the control group) also comprised 100 women (50 women each in the premenopausal and postmenopausal subgroups) who received two tablets of 500 mg metronidazole as placebo. The boundaries for the trials were calculated on the basis of primary outcomes of a difference of at least 1 mm in cervical dilatation, with the assumption of a type 1 error of 0.05 and a power of 0.95, 100 women in each subgroup either pre-menopausal or postmenopausal subgroups 12.
We have included premenopausal, postmenopausal, nulliparous and parous women with apparently normal nondialated undilated cervices on clinical examination and with no previous history of cervical dystocia.
Our exclusion criteria were patients who had history of allergy or a contra indication to prostaglandins; a history of glaucoma, bronchial asthma, irritable bowel syndrome, cardiac diseases, hypertension, or renal failure; history of hormonal therapy; had cervical neoplasia, genital prolapse, or cervical incompetence; a history of any cervical surgery or manipulation; a history of cervical cerculage during a previous pregnancy; previous cauterization for cervical erosion, or surgery for uterine or cervical anomaly; had undergone a previous cervical dilatation operation with resultant apparent cervical tears or lacerations or history of hemorrhagic disorder.
Details of medical, obstetric, and gynecological history were obtained by subjecting all participants to a physical examination; data on their personal history were also obtained. The study group received two tablets of 400 µg misoprostol vaginally, whereas the control group received two tablets of 250 mg metronidazole as placebo vaginally 13. The placebo tablets were identical to misoprostol in appearance and dosing schedule. Patients and surgeons were blinded to patient allocations. Randomization was carried out using closed opaque envelopes containing a paper in which the type of intervention to be carried out was mentioned. The sealed envelopes were opened just before administering the drugs, which were inserted deep into the posterior fornix of the vagina without revealing the type of tablet to the patients. The tablets were inserted 10–12 h before dilatation and curettage.
Each group received the dose 10–12 h before the procedure. We used metronidazole tablets as placebo because it is absorbed through the vaginal epithelium, has no effect on cervical tissue or the uterine musculature, and also has no significant systemic effects 13.
The main outcome measures were assessment of baseline cervical width and the number of women who required further cervical dilatation. The secondary measures were duration of the procedure, complications, and associated side effects such as nausea, vomiting, diarrhea, uterine cramping, or vaginal bleeding. The primary outcome measure was determined by introducing the largest sized Hegar’s dilator that could be inserted without resistance at the beginning of the surgical procedure. Further dilatation was carried out in case of inefficient cervical dilatation. The time required to dilate the cervix up to 8 mm was assessed. The resistance of the internal cervical os observed by the investigator was classified as ‘easy’, ‘usual’ or ‘difficult or failed’, and blood loss during insertion was classified as scarce, usual, or abundant. In addition, on the basis of the ease or difficulty of dilation in each woman, the investigators were asked to judge whether the patients had been pretreated with misoprostol. The difficulty of the procedure was also noted from the patient’s point of view. The general experience of the procedure was reported by the patient as very satisfied, satisfied or neutral, or unsatisfied.
Microsoft Excel 2003 (Microsoft Corporation, New York, USA) and SPSS (SPSS Inc., Chicago, Illinois, USA) version 15 for Microsoft Windows were used to analyze data. Data were statistically described in terms of mean, SD, frequencies (the number of cases), and percentages. For quantitative variables the Student t-test and analysis of variance were used to test the significance of differences, and for categorical data the χ 2-test was performed. A P-value less than 0.05 was considered statistically significant.
The women in the study and control groups (premenopausal and postmenopausal) were matched with respect to their characteristics, including age, BMI, parity, number of miscarriages, and number of previous cesarean sections (Table 1).
There was no statistically significant difference between the placebo and misoprostol groups in either premenopausal or postmenopausal women with respect to indications for dilatation and curettage. The most common indications in postmenopausal women were bleeding and abnormal endometrial thickness as determined by ultrasound (Table 2).
Premenopausal and postmenopausal women who received misoprostol had higher baseline cervical dilatation compared with women in the placebo group (P=0.001). Premenopausal women had higher cervical dilatation than did postmenopausal women when both received misoprostol (P=0.001). Further, cervical dilatation was required more in women of the placebo group, with a statistically significant difference between the premenopausal and postmenopausal groups. Misoprostol helped to reduce the time taken for dilatation, with a statistically significant difference between premenopausal and postmenopausal women; however, the time taken was much shorter in premenopausal women. Blood loss and degree of resistance were less evident with the use of misoprostol among premenopausal and postmenopausal women, without a statistically significant difference. The rate of failure and amount of inadequate tissue were very low among premenopausal and postmenopausal women in the placebo and misoprostol groups. Women receiving misoprostol had higher acceptability for the procedure compared with women in the placebo group, without a statistically significant difference (Table 3).
The most commonly reported side effects of misoprostol were mild vaginal bleeding (20% of both premenopausal and postmenopausal women) and mild abdominal cramps (10% of postmenopausal and 12% of premenopausal women). No statistically significant difference was reported between premenopausal and postmenopausal women using misoprostol with regard to the incidence of preoperative side effects and complications. Reported complications included cervical injury, uterine perforation, and false passage, with incidence ranging from 2 to 8% (Table 4).
Patient satisfaction with the treatment method was significantly higher in the misoprostol group than in the placebo group among both premenopausal and postmenopausal women (Table 5).
Dilation and curettage is frequently performed for different gynecological problems either for diagnostic or for therapeutic purposes. Cervical dilatation is the most unpleasant part during these procedures. Cervical priming before operative procedures facilitates the operation and reduces the risk of complications of mechanical dilation such as cervical laceration, creation of a false passage, and uterine perforation. Agents commonly used for this purpose include laminaria tents and various prostaglandin preparations 14.
The present study used a randomized double-blind protocol to compare the effectiveness of vaginal misoprostol with that of the placebo for cervical priming before dilatation and curettage in premenopausal and postmenopausal women. We found that vaginal misoprostol was more effective than the placebo for cervical dilatation; there was a significant difference between the study and control groups in both premenopausal and postmenopausal women with respect to cervical dilatation, as determined by the increased basal cervical width in the misoprostol group.
Ngai et al. 15 had reported that oral misoprostol was effective for preoperative cervical dilatation in nonpregnant women. Following this study, many reports supported this beneficial effect of misoprostol, used either vaginally or orally 16–18.
The present study was in accordance with the studies by Thomas et al. 11, Kant et al. 18, Oppegaard et al. 19, and Gkrozou et al. 20, who showed that vaginal misoprostol has a significant effect on cervical dilatation in the total population of premenopausal and postmenopausal women to a statistically significant extent. However, Gkrozou et al. 20 concluded that there is insufficient evidence to recommend the routine use of misoprostol before every hysteroscopy.
Our findings were inconsistent with the results reported by Perrone et al. 21. They found no evidence of an effect on cervical resistance, on the success rate of obtaining a biopsy, and on the ease of performing a biopsy. This may be because of the shorter interval between administration of misoprostol and analysis of results in their study (3 vs. 12 h in the present study). Other studies also reported that preoperative use of vaginal misoprostol did not reduce the cervical resistance, particularly in postmenopausal women 10,22,23. This might be because of the hypoestrogenic state in postmenopausal women. Bisharah et al. 23 had reported that misoprostol did not produce a cervical priming effect when used in women in the hypoestrogenic state induced by leuprolide acetate injection 23.
In premenopausal women, studies have found 200, 400, or 1000 µg of vaginal misoprostol or 400 µg of oral misoprostol administered at least 9–12 h preoperatively to be superior to placebo 15,23–25. Other studies showed that vaginal misoprostol administered for shorter intervals (4–6 h preoperatively) had no effect 4,26. Therefore, the time to adequate cervical ripening may be different for pregnant and nonpregnant women and for premenopausal and postmenopausal women. In the present study, misoprostol was administered at a dose of 400 μg 10–12 h before the procedure.
Batukan et al. 27 compared vaginal versus oral misoprostol and showed that vaginal administration of misoprostol is more effective than the oral route for preoperative cervical ripening in premenopausal women. Inconsistent with these findings, Lee et al. 28 found no favorable effect of vaginal misoprostol over sublingual or oral misoprostol.
A review of seven randomized controlled trials reported that current evidence does not support the routine use of preoperative misoprostol in operative hysteroscopy 29.
In the present study, the most common side effects observed in the misoprostol group were mild vaginal bleeding (20% of both premenopausal and postmenopausal women) and mild abdominal cramps (10% of postmenopausal and 12% of premenopausal women). Inconsistent with our findings, Thomas et al. 11 reported a significant difference in the incidence of side effects between the misoprostol-administered groups and the control group.
No statistically significant difference was reported between premenopausal and postmenopausal women using misoprostol with regard to the incidence of complications. The reported complications included cervical injury, uterine perforation, and false passage, with incidence ranging from 2 to 8%. Unlike our findings, uterine perforation was reported in two patients of the vaginally administered misoprostol group in the study by Bunnasathiansri et al. 30, whereas no uterine perforation was reported in the placebo group. In the study by Thomas et al. 11, four cases of cervical lacerations and two cases of uterine perforation were reported in the orally administered misoprostol group and the placebo group, respectively. In the study by Bisharah et al. 23, one patient with cervical injury was reported in the misoprostol group, whereas no complications were reported in the placebo group.
We have found that vaginal misoprostol has a promising significant benefit when used for cervical priming in premenopausal and postmenopausal women with tolerable minor side effects.
Evidence from a large, controlled, double-blind study is needed to recommend the routine use of misoprostol before every gynecological surgery in nonpregnant women.
Conflicts of interest
There are no conflicts of interest.
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