ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE
Effectiveness of different routes of misoprostol administration before operative hysteroscopy: a randomized, controlled trial Taejong Song, M.D.,a Mi Kyoung Kim, M.D.,b Mi-La Kim, M.D., Ph.D.,b Yong Wook Jung, M.D.,b Bo Sung Yoon, M.D.,b and Seok Ju Seong, M.D., Ph.D.b a
Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine; and b Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, South Korea
Objective: To compare the effectiveness and patient preference of different routes of misoprostol administration before operative hysteroscopy in premenopausal women. Design: Randomized, controlled trial. Setting: University hospital. Patient(s): One hundred sixty women undergoing operative hysteroscopy. Intervention(s): Patients were randomly assigned to receive 400 mg misoprostol orally (n ¼ 40), sublingually (n ¼ 40), or vaginally (n ¼ 40) before operative hysteroscopy; the control group (n ¼ 40) did not receive any cervical priming agent. Main Outcome Measure(s): Preoperative cervical width, adverse effects, and patient preference. Result(s): The mean (SD) cervical widths for the oral, sublingual, vaginal, and control groups were 7.62 1.81 mm, 7.58 1.77 mm, 7.60 2.15 mm, and 5.65 2.12 mm, respectively, which was statistically significant. Time to cervical dilatation was also significantly longer in the control group than in the other three groups. Misoprostol-related adverse effects and hysteroscopy-related complications were comparable among the four study groups. Of all 160 subjects, 132 (82%) preferred the oral route for misoprostol administration to the sublingual or vaginal routes, or had no preference. Conclusion(s): All orally, sublingually, and vaginally administrated misoprostol is equally effective in inducing proper cervical priming before operative hysteroscopy. Considering patient preference, oral administration may be the optimal route for misoprostol administration. Use your smartphone Clinical Trial Registration Number: NCT01805115. (Fertil SterilÒ 2014;-:-–-. Ó2014 by to scan this QR code American Society for Reproductive Medicine.) and connect to the Key Words: Misoprostol, hysteroscopy, cervical priming, cervical ripening Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/songt-misoprostol-routes-operative-hysteroscopy/
W
ith the advent of operative hysteroscopy, abnormalities confined to the uterine cavity, such as endometrial polyps, submucosal myomas, uterine septa, and synechia, can be treated effectively (1–3). Access to the uterine cavity requires insertion of a resectoscope through the internal cervical os, which
necessitates cervical dilatation (i.e., up to Hegar 8–10). However, almost half of the complications of hysteroscopy occur during cervical entry (3), including cervical tears, creation of a false tract, and uterine perforation. The prevalence of these complications can be reduced if the cervix is primed beforehand (4, 5). Taking into account
Received February 28, 2014; revised and accepted April 24, 2014. T.S. has nothing to disclose. M.K.K. has nothing to disclose. M.-L.K. has nothing to disclose. Y.W.J. has nothing to disclose. B.S.Y. has nothing to disclose. S.J.S. has nothing to disclose. Reprint requests: Seok Ju Seong, M.D., Ph.D., Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, 650-9 Yeoksam-1 Dong, Gangnam-gu, Seoul 135-081, South Korea (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.04.040 VOL. - NO. - / - 2014
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
that an efficient method to facilitate an easier, uncomplicated entry during the hysteroscopic procedure could substantially minimize the risk of complications, several modalities for cervical priming before hysteroscopy have been adopted (6–9). Among them, the prostaglandin analog misoprostol (Cytotec; Pfizer) is the most frequently used agent for cervical preparation before hysteroscopy and has been tested in randomized, controlled trials (2, 10). The route of administration of misoprostol for cervical dilatation can be oral, sublingual, or vaginal. However, no solid conclusions have been reached 1
ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE as to which route is most effective for cervical dilation before operative hysteroscopy. Furthermore, no study to evaluate preference for the administration route of misoprostol in patients undergoing operative hysteroscopy has been conducted to date. The objective of this study was to compare the effectiveness and preference of different routes of misoprostol administration (orally, sublingually, vaginally, or no medication) before operative hysteroscopy in premenopausal women.
MATERIALS AND METHODS Participants This study was conducted prospectively between April 2013 and February 2014 at the Department of Obstetrics and Gynecology at the CHA Gangnam Medical Center. Symptomatic patients, who were suspected as having an intrauterine pathology, such as submucosal myoma, endometrial polyp, or other endometrial pathologic findings based on the transvaginal ultrasound, were enrolled. All patients were scheduled for elective hysteroscopic surgery in the day surgery center. The institutional review board and the Korea Food Drug Administration reviewed and approved this study protocol, including the off-label use of misoprostol for cervical priming. This study was registered with ClinicalTrials.gov (identifier: NCT01805115) and was performed in accordance with the protocol. All subjects provided written, informed consent before participation. Inclusion criteria were as follows: women who were of reproductive age and were not pregnant at the time of presentation. Exclusion criteria included any evidence of a contraindication to prostaglandins (history of severe asthma, glaucoma, pre-existing severe cardiac disease, or renal failure), or allergy to prostaglandins, any sign of genital infection, presence of significant uterovaginal prolapse that could affect administration of vaginal tablets, history of cervical surgery, presence of space-occupying lesions in the endocervical canal, and treatment with a gonadotropinreleasing hormone agonist.
Study Protocol Subjects were randomly assigned to the oral, sublingual, vaginal, or control group at a 1:1:1:1 ratio using a random permuted-block algorithm via an interactive Web-based response system (www.randomization.com). Sequentially numbered, sealed, opaque envelopes were prepared by the study nurse (not directly involved in the study), and each contained a folded slip of paper with the treatment route (orally, sublingually, vaginally, or no medication) written on it. When the subjects agreed to participate in this study at the outpatient clinic, the envelopes were opened by the study nurse, and the randomization took place. All misoprostol tablets were identical. The oral, sublingual, and vaginal groups self-administered the medications 8 hours before operative hysteroscopy. In the control group, operative hysteroscopy was performed without a misoprostol administration. To prevent bias, in all cases the vagina was cleaned, and any remnant of the misoprostol tablets was removed by the resi2
dent or physician assistant in charge before the operating surgeon began the procedure. Additionally, the subjects were asked about pain, vaginal bleeding, other misoprostolassociated side effects, and the acceptability of the selfadministration of medications through a self-reported questionnaire before entrance into the operating room. The questionnaire also asked ‘‘Given an equivalent therapeutic efficacy and safety, what is your preferred administration route of misoprostol among orally, sublingually, or vaginally?’’ and was collected by independent assessors. All of the procedures were performed by one investigator (T.S.) to reduce interassessor variability. The operator performing the procedure was blinded to the group allocation. The patients were given general intravenous anesthesia (propofol/fentanyl) after the resident or physician assistant in charge prepared the patients for surgery by disinfecting the vulva and vaginal area with a 7.5% betadine solution. After performing cervical dilatation with a Hegar dilator, a rigid resectoscope with a 10-mm outer sheath diameter and a 15 forward-oblique lens (Karl Storz) were used. The uterine cavity was distended with normal saline at an insufflation pressure of 100–150 mm Hg, with careful monitoring of the fluid balance. After surgery the patients were monitored in the postanesthesia care unit for a minimum of 2 hours and returned for follow-up visits 1 and 4 weeks after surgery.
Outcome Measures The primary outcome measure was the preoperative cervical width at the time of surgery and patient preference for the administration route of misoprostol. The cervical width was assessed by performing cervical dilation, beginning with a number 10 Hegar dilator and subsequently inserting smaller Hegar dilators until the dilator could pass through the internal os without resistance. The largest one that could be passed was recorded as the initial cervical width. Secondary outcome measurements included [1] the time required for dilation up to a number 10 Hegar; [2] the subjective ease of cervical dilation recorded by a surgeon on a 5-point Likert scale (very difficult ¼ 1, difficult ¼ 2, fair ¼ 3, easy ¼ 4, and very easy ¼ 5); [3] patient acceptability of the self-administration of medications preoperatively at home on a 5-point Likert scale (very difficult ¼ 1, difficult ¼ 2, fair ¼ 3, easy ¼ 4, and very easy ¼ 5); [4] self-reported misoprostol-associated adverse effects before the procedure, such as uterine cramping, uterine bleeding, diarrhea, nausea, vomiting, or febrile sense; and [5] complications arising within 4 weeks after surgery.
Statistical Analysis The sample size was calculated on the basis of a previous study, in which the cervical widths, after 400 mg oral misoprostol or placebo, were 8.2 2.3 mm and 7.5 2.2 mm, respectively (11). We assumed that equivalence was of clinical significance if the difference in the initial cervical width was .999 >.999 >.999 < .001
1 (2.5)
0
1 (2.5)
1 (2.5)
>.999
Note: Data are expressed as mean SD, median (range), or number (percentage) if appropriate. a For calculation of the mean, categories were assigned the following values: 1 ¼ very difficult, 2 ¼ difficult, 3 ¼ fair, 4 ¼ easy, 5 ¼ very easy. Higher mean indicates an easier cervical dilatation or better acceptability. b These include cervical tears, creation of a false tract, and uterine perforation. Song. Misoprostol in operative hysteroscopy. Fertil Steril 2014.
4
VOL. - NO. - / - 2014
Fertility and Sterility®
FIGURE 2
Patient preference for the administration routes of misoprostol. Song. Misoprostol in operative hysteroscopy. Fertil Steril 2014.
agent before hysteroscopy. This finding is consistent with a recent meta-analysis (2) that analyzed 21 randomized, controlled trials involving 1,786 subjects and evaluated the effects of misoprostol before hysteroscopy for cervical dilatation. The mean cervical width before hysteroscopy was significantly wider in premenopausal women treated with misoprostol compared with placebo (mean difference [95% confidence interval (CI)]: 2.47 mm [1.81–3.13 mm]). Furthermore, cervical laceration was significantly lower in subjects treated with misoprostol than in subjects treated with placebo (relative risk [95% CI]: 0.22 [0.09–0.54]). These authors concluded that misoprostol before hysteroscopy facilitates an easier and uncomplicated procedure in premenopausal women. In our study most subjects (82%) preferred the oral route for misoprostol administration before hysteroscopy. Because this study was the first to evaluate patient preference for the route of administration before hysteroscopy, there was no reference in the literature for a direct comparison. However, our results are in line with those of Saxena et al. (12), who reported patient preference for misoprostol administration for cervical priming before suction evacuation in first-trimester abortions, in which 98% of patients stated that they prefer the oral route over the sublingual route if the option were available. Therefore, we believe that oral misoprostol administration before operative hysteroscopy is the preferred route of administration. The frequencies and types of adverse effects were similar among the three misoprostol groups, consistent with findings from previous studies (13, 14). However, the frequency of adverse effects was lower than in previous studies. This discrepancy might be due to a relatively short time between medication and hysteroscopy, because the symptoms related to adverse effects could be masked during surgery under general anesthesia and after the procedure. Furthermore, similar to previous studies, there was no delay in the planned procedure based on misoprostol use, and all VOL. - NO. - / - 2014
adverse effects were tolerable without the need for additional treatment. Although the difference did not did not reach statistical significance (P¼ .052), the rates of adverse effects in the three misoprostol groups were higher than that in the control group (22.5%–25.0% vs. 5.0%). This result is in line with a recent meta-analysis that analyzed seven randomized, controlled trials involving 568 subjects and evaluated the use of misoprostol in operative hysteroscopy (10). Compared with the placebo group, there was an increase in side effects (cramps, vaginal bleeding, nausea, and diarrhea) in the misoprostol group (relative risk [95% CI]: 4.28 [1.43–12.85]). The researchers concluded that current evidence does not support the routine use of preoperative misoprostol in operative hysteroscopy (10). Our study had several limitations. First, the measurement of cervical width was not objective. It has been suggested that the forced applied during cervical dilation can be measured by a tensinometer to overcome this drawback (15). However, measurements by a Hegar dilator have been acceptable and used in many previous studies (2, 6, 9–14). Second, the control group was not given a ‘‘placebo’’ intervention, which might have led to a reduction of adverse effects related to misoprostol medication. Meanwhile, the strength of this study is that a single surgeon performed all surgical procedures, including cervical dilation and hysteroscopy, thus excluding interassessor variability. In conclusion, we found that cervical widths and adverse effects were comparable, regardless of the route of misoprostol administration. Considering patient preference and acceptability, we recommend the oral administration of misoprostol before hysteroscopy. Additional randomized, controlled trials are required to confirm or reject the results of this study.
REFERENCES 1.
2.
3.
4. 5. 6.
7.
8.
Clark TJ, Voit D, Gupta JK, Hyde C, Song F, Khan KS. Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia: a systematic quantitative review. JAMA 2002;288:1610–21. Polyzos NP, Zavos A, Valachis A, Dragamestianos C, Blockeel C, Stoop D, et al. Misoprostol prior to hysteroscopy in premenopausal and postmenopausal women. A systematic review and meta-analysis. Hum Reprod Update 2012;18:393–404. Jansen FW, Vredevoogd CB, van Ulzen K, Hermans J, Trimbos JB, TrimbosKemper TC. Complications of hysteroscopy: a prospective, multicenter study. Obstet Gynecol 2000;96:266–70. Grimes DA, Schulz KF, Cates WJ Jr. Prevention of uterine perforation during curettage abortion. JAMA 1984;251:2108–11. Schulz KF, Grimes DA, Cates W Jr. Measures to prevent cervical injury during suction curettage abortion. Lancet 1983;1:1182–5. Darwish AM, Ahmad AM, Mohammad AM. Cervical priming prior to operative hysteroscopy: a randomized comparison of laminaria versus misoprostol. Hum Reprod 2004;19:2391–4. Gupta N, Gupta B, Dadhwal V, Mittal S. Efficacy of intrauterine lignocaine plus vaginal misoprostol for pain relief in premenopausal women undergoing endometrial aspiration and ambulatory hysteroscopy. Acta Obstet Gynecol Scand 2010;89:1066–70. Lin YH, Hwang JL, Seow KM, Huang LW, Chen HJ, Hsieh BC. Laminaria tent vs misoprostol for cervical priming before hysteroscopy: randomized study. J Minim Invasive Gynecol 2009;16:708–12.
5
ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE 9.
10. 11.
12.
6
Preutthipan S, Herabutya Y. A randomized comparison of vaginal misoprostol and dinoprostone for cervical priming in nulliparous women before operative hysteroscopy. Fertil Steril 2006;86:990–4. Selk A, Kroft J. Misoprostol in operative hysteroscopy: a systematic review and meta-analysis. Obstet Gynecol 2011;118:941–9. Thomas JA, Leyland N, Durand N, Windrim RC. The use of oral misoprostol as a cervical ripening agent in operative hysteroscopy: a double-blind, placebo-controlled trial. Am J Obstet Gynecol 2002;186:876–9. Saxena P. Comparison between the sublingual and oral route of misoprostol for preabortion cervical priming in first trimester abortions. Hum Reprod 2004;19:77–80.
13.
14.
15.
Choksuchat C, Cheewadhanaraks S, Getpook C, Wootipoom V, Dhanavoravibul K. Misoprostol for cervical ripening in non-pregnant women: a randomized double-blind controlled trial of oral versus vaginal regimens. Hum Reprod 2006;21:2167–70. Batukan C, Ozgun MT, Ozcelik B, Aygen E, Sahin Y, Turkyilmaz C. Cervical ripening before operative hysteroscopy in premenopausal women: a randomized, double-blind, placebo-controlled comparison of vaginal and oral misoprostol. Fertil Steril 2008;89:966–73. Ngai SW, Chan YM, Liu KL, Ho PC. Oral misoprostol for cervical priming in non-pregnant women. Hum Reprod 1997;12:2373–5.
VOL. - NO. - / - 2014
Effectiveness of different routes of misoprostol administration before operative hysteroscopy: a randomized, controlled trial Taejong Song, M.D.,a Mi Kyoung Kim, M.D.,b Mi-La Kim, M.D., Ph.D.,b Yong Wook Jung, M.D.,b Bo Sung Yoon, M.D.,b and Seok Ju Seong, M.D., Ph.D.b a
Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine; and b Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, South Korea
Objective: To compare the effectiveness and patient preference of different routes of misoprostol administration before operative hysteroscopy in premenopausal women. Design: Randomized, controlled trial. Setting: University hospital. Patient(s): One hundred sixty women undergoing operative hysteroscopy. Intervention(s): Patients were randomly assigned to receive 400 mg misoprostol orally (n ¼ 40), sublingually (n ¼ 40), or vaginally (n ¼ 40) before operative hysteroscopy; the control group (n ¼ 40) did not receive any cervical priming agent. Main Outcome Measure(s): Preoperative cervical width, adverse effects, and patient preference. Result(s): The mean (SD) cervical widths for the oral, sublingual, vaginal, and control groups were 7.62 1.81 mm, 7.58 1.77 mm, 7.60 2.15 mm, and 5.65 2.12 mm, respectively, which was statistically significant. Time to cervical dilatation was also significantly longer in the control group than in the other three groups. Misoprostol-related adverse effects and hysteroscopy-related complications were comparable among the four study groups. Of all 160 subjects, 132 (82%) preferred the oral route for misoprostol administration to the sublingual or vaginal routes, or had no preference. Conclusion(s): All orally, sublingually, and vaginally administrated misoprostol is equally effective in inducing proper cervical priming before operative hysteroscopy. Considering patient preference, oral administration may be the optimal route for misoprostol administration. Use your smartphone Clinical Trial Registration Number: NCT01805115. (Fertil SterilÒ 2014;-:-–-. Ó2014 by to scan this QR code American Society for Reproductive Medicine.) and connect to the Key Words: Misoprostol, hysteroscopy, cervical priming, cervical ripening Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/songt-misoprostol-routes-operative-hysteroscopy/
W
ith the advent of operative hysteroscopy, abnormalities confined to the uterine cavity, such as endometrial polyps, submucosal myomas, uterine septa, and synechia, can be treated effectively (1–3). Access to the uterine cavity requires insertion of a resectoscope through the internal cervical os, which
necessitates cervical dilatation (i.e., up to Hegar 8–10). However, almost half of the complications of hysteroscopy occur during cervical entry (3), including cervical tears, creation of a false tract, and uterine perforation. The prevalence of these complications can be reduced if the cervix is primed beforehand (4, 5). Taking into account
Received February 28, 2014; revised and accepted April 24, 2014. T.S. has nothing to disclose. M.K.K. has nothing to disclose. M.-L.K. has nothing to disclose. Y.W.J. has nothing to disclose. B.S.Y. has nothing to disclose. S.J.S. has nothing to disclose. Reprint requests: Seok Ju Seong, M.D., Ph.D., Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, 650-9 Yeoksam-1 Dong, Gangnam-gu, Seoul 135-081, South Korea (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2014 0015-0282/$36.00 Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.04.040 VOL. - NO. - / - 2014
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
that an efficient method to facilitate an easier, uncomplicated entry during the hysteroscopic procedure could substantially minimize the risk of complications, several modalities for cervical priming before hysteroscopy have been adopted (6–9). Among them, the prostaglandin analog misoprostol (Cytotec; Pfizer) is the most frequently used agent for cervical preparation before hysteroscopy and has been tested in randomized, controlled trials (2, 10). The route of administration of misoprostol for cervical dilatation can be oral, sublingual, or vaginal. However, no solid conclusions have been reached 1
ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE as to which route is most effective for cervical dilation before operative hysteroscopy. Furthermore, no study to evaluate preference for the administration route of misoprostol in patients undergoing operative hysteroscopy has been conducted to date. The objective of this study was to compare the effectiveness and preference of different routes of misoprostol administration (orally, sublingually, vaginally, or no medication) before operative hysteroscopy in premenopausal women.
MATERIALS AND METHODS Participants This study was conducted prospectively between April 2013 and February 2014 at the Department of Obstetrics and Gynecology at the CHA Gangnam Medical Center. Symptomatic patients, who were suspected as having an intrauterine pathology, such as submucosal myoma, endometrial polyp, or other endometrial pathologic findings based on the transvaginal ultrasound, were enrolled. All patients were scheduled for elective hysteroscopic surgery in the day surgery center. The institutional review board and the Korea Food Drug Administration reviewed and approved this study protocol, including the off-label use of misoprostol for cervical priming. This study was registered with ClinicalTrials.gov (identifier: NCT01805115) and was performed in accordance with the protocol. All subjects provided written, informed consent before participation. Inclusion criteria were as follows: women who were of reproductive age and were not pregnant at the time of presentation. Exclusion criteria included any evidence of a contraindication to prostaglandins (history of severe asthma, glaucoma, pre-existing severe cardiac disease, or renal failure), or allergy to prostaglandins, any sign of genital infection, presence of significant uterovaginal prolapse that could affect administration of vaginal tablets, history of cervical surgery, presence of space-occupying lesions in the endocervical canal, and treatment with a gonadotropinreleasing hormone agonist.
Study Protocol Subjects were randomly assigned to the oral, sublingual, vaginal, or control group at a 1:1:1:1 ratio using a random permuted-block algorithm via an interactive Web-based response system (www.randomization.com). Sequentially numbered, sealed, opaque envelopes were prepared by the study nurse (not directly involved in the study), and each contained a folded slip of paper with the treatment route (orally, sublingually, vaginally, or no medication) written on it. When the subjects agreed to participate in this study at the outpatient clinic, the envelopes were opened by the study nurse, and the randomization took place. All misoprostol tablets were identical. The oral, sublingual, and vaginal groups self-administered the medications 8 hours before operative hysteroscopy. In the control group, operative hysteroscopy was performed without a misoprostol administration. To prevent bias, in all cases the vagina was cleaned, and any remnant of the misoprostol tablets was removed by the resi2
dent or physician assistant in charge before the operating surgeon began the procedure. Additionally, the subjects were asked about pain, vaginal bleeding, other misoprostolassociated side effects, and the acceptability of the selfadministration of medications through a self-reported questionnaire before entrance into the operating room. The questionnaire also asked ‘‘Given an equivalent therapeutic efficacy and safety, what is your preferred administration route of misoprostol among orally, sublingually, or vaginally?’’ and was collected by independent assessors. All of the procedures were performed by one investigator (T.S.) to reduce interassessor variability. The operator performing the procedure was blinded to the group allocation. The patients were given general intravenous anesthesia (propofol/fentanyl) after the resident or physician assistant in charge prepared the patients for surgery by disinfecting the vulva and vaginal area with a 7.5% betadine solution. After performing cervical dilatation with a Hegar dilator, a rigid resectoscope with a 10-mm outer sheath diameter and a 15 forward-oblique lens (Karl Storz) were used. The uterine cavity was distended with normal saline at an insufflation pressure of 100–150 mm Hg, with careful monitoring of the fluid balance. After surgery the patients were monitored in the postanesthesia care unit for a minimum of 2 hours and returned for follow-up visits 1 and 4 weeks after surgery.
Outcome Measures The primary outcome measure was the preoperative cervical width at the time of surgery and patient preference for the administration route of misoprostol. The cervical width was assessed by performing cervical dilation, beginning with a number 10 Hegar dilator and subsequently inserting smaller Hegar dilators until the dilator could pass through the internal os without resistance. The largest one that could be passed was recorded as the initial cervical width. Secondary outcome measurements included [1] the time required for dilation up to a number 10 Hegar; [2] the subjective ease of cervical dilation recorded by a surgeon on a 5-point Likert scale (very difficult ¼ 1, difficult ¼ 2, fair ¼ 3, easy ¼ 4, and very easy ¼ 5); [3] patient acceptability of the self-administration of medications preoperatively at home on a 5-point Likert scale (very difficult ¼ 1, difficult ¼ 2, fair ¼ 3, easy ¼ 4, and very easy ¼ 5); [4] self-reported misoprostol-associated adverse effects before the procedure, such as uterine cramping, uterine bleeding, diarrhea, nausea, vomiting, or febrile sense; and [5] complications arising within 4 weeks after surgery.
Statistical Analysis The sample size was calculated on the basis of a previous study, in which the cervical widths, after 400 mg oral misoprostol or placebo, were 8.2 2.3 mm and 7.5 2.2 mm, respectively (11). We assumed that equivalence was of clinical significance if the difference in the initial cervical width was .999 >.999 >.999 < .001
1 (2.5)
0
1 (2.5)
1 (2.5)
>.999
Note: Data are expressed as mean SD, median (range), or number (percentage) if appropriate. a For calculation of the mean, categories were assigned the following values: 1 ¼ very difficult, 2 ¼ difficult, 3 ¼ fair, 4 ¼ easy, 5 ¼ very easy. Higher mean indicates an easier cervical dilatation or better acceptability. b These include cervical tears, creation of a false tract, and uterine perforation. Song. Misoprostol in operative hysteroscopy. Fertil Steril 2014.
4
VOL. - NO. - / - 2014
Fertility and Sterility®
FIGURE 2
Patient preference for the administration routes of misoprostol. Song. Misoprostol in operative hysteroscopy. Fertil Steril 2014.
agent before hysteroscopy. This finding is consistent with a recent meta-analysis (2) that analyzed 21 randomized, controlled trials involving 1,786 subjects and evaluated the effects of misoprostol before hysteroscopy for cervical dilatation. The mean cervical width before hysteroscopy was significantly wider in premenopausal women treated with misoprostol compared with placebo (mean difference [95% confidence interval (CI)]: 2.47 mm [1.81–3.13 mm]). Furthermore, cervical laceration was significantly lower in subjects treated with misoprostol than in subjects treated with placebo (relative risk [95% CI]: 0.22 [0.09–0.54]). These authors concluded that misoprostol before hysteroscopy facilitates an easier and uncomplicated procedure in premenopausal women. In our study most subjects (82%) preferred the oral route for misoprostol administration before hysteroscopy. Because this study was the first to evaluate patient preference for the route of administration before hysteroscopy, there was no reference in the literature for a direct comparison. However, our results are in line with those of Saxena et al. (12), who reported patient preference for misoprostol administration for cervical priming before suction evacuation in first-trimester abortions, in which 98% of patients stated that they prefer the oral route over the sublingual route if the option were available. Therefore, we believe that oral misoprostol administration before operative hysteroscopy is the preferred route of administration. The frequencies and types of adverse effects were similar among the three misoprostol groups, consistent with findings from previous studies (13, 14). However, the frequency of adverse effects was lower than in previous studies. This discrepancy might be due to a relatively short time between medication and hysteroscopy, because the symptoms related to adverse effects could be masked during surgery under general anesthesia and after the procedure. Furthermore, similar to previous studies, there was no delay in the planned procedure based on misoprostol use, and all VOL. - NO. - / - 2014
adverse effects were tolerable without the need for additional treatment. Although the difference did not did not reach statistical significance (P¼ .052), the rates of adverse effects in the three misoprostol groups were higher than that in the control group (22.5%–25.0% vs. 5.0%). This result is in line with a recent meta-analysis that analyzed seven randomized, controlled trials involving 568 subjects and evaluated the use of misoprostol in operative hysteroscopy (10). Compared with the placebo group, there was an increase in side effects (cramps, vaginal bleeding, nausea, and diarrhea) in the misoprostol group (relative risk [95% CI]: 4.28 [1.43–12.85]). The researchers concluded that current evidence does not support the routine use of preoperative misoprostol in operative hysteroscopy (10). Our study had several limitations. First, the measurement of cervical width was not objective. It has been suggested that the forced applied during cervical dilation can be measured by a tensinometer to overcome this drawback (15). However, measurements by a Hegar dilator have been acceptable and used in many previous studies (2, 6, 9–14). Second, the control group was not given a ‘‘placebo’’ intervention, which might have led to a reduction of adverse effects related to misoprostol medication. Meanwhile, the strength of this study is that a single surgeon performed all surgical procedures, including cervical dilation and hysteroscopy, thus excluding interassessor variability. In conclusion, we found that cervical widths and adverse effects were comparable, regardless of the route of misoprostol administration. Considering patient preference and acceptability, we recommend the oral administration of misoprostol before hysteroscopy. Additional randomized, controlled trials are required to confirm or reject the results of this study.
REFERENCES 1.
2.
3.
4. 5. 6.
7.
8.
Clark TJ, Voit D, Gupta JK, Hyde C, Song F, Khan KS. Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia: a systematic quantitative review. JAMA 2002;288:1610–21. Polyzos NP, Zavos A, Valachis A, Dragamestianos C, Blockeel C, Stoop D, et al. Misoprostol prior to hysteroscopy in premenopausal and postmenopausal women. A systematic review and meta-analysis. Hum Reprod Update 2012;18:393–404. Jansen FW, Vredevoogd CB, van Ulzen K, Hermans J, Trimbos JB, TrimbosKemper TC. Complications of hysteroscopy: a prospective, multicenter study. Obstet Gynecol 2000;96:266–70. Grimes DA, Schulz KF, Cates WJ Jr. Prevention of uterine perforation during curettage abortion. JAMA 1984;251:2108–11. Schulz KF, Grimes DA, Cates W Jr. Measures to prevent cervical injury during suction curettage abortion. Lancet 1983;1:1182–5. Darwish AM, Ahmad AM, Mohammad AM. Cervical priming prior to operative hysteroscopy: a randomized comparison of laminaria versus misoprostol. Hum Reprod 2004;19:2391–4. Gupta N, Gupta B, Dadhwal V, Mittal S. Efficacy of intrauterine lignocaine plus vaginal misoprostol for pain relief in premenopausal women undergoing endometrial aspiration and ambulatory hysteroscopy. Acta Obstet Gynecol Scand 2010;89:1066–70. Lin YH, Hwang JL, Seow KM, Huang LW, Chen HJ, Hsieh BC. Laminaria tent vs misoprostol for cervical priming before hysteroscopy: randomized study. J Minim Invasive Gynecol 2009;16:708–12.
5
ORIGINAL ARTICLE: GYNECOLOGY AND MENOPAUSE 9.
10. 11.
12.
6
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