Jogc-aug_07.vp

GYNAECOLOGY
GYNAECOLOGY
A Randomized Trial of Oral Misoprostol in
Premenopausal Women Before Hysteroscopy
Sarah Healey, MD, FRCSC, Blair Butler, MD, FRCSC, F. Nicholas Kum, MD, FRCSC,
James Dunne, MD, FRCSC, Donna Hutchens, RN, BN, Joan M.G. Crane, MSc, MD, FRCSC
Department of Obstetrics and Gynecology, Eastern Health, Memorial University of Newfoundland, St. John’s NL Abstract
Méthodes : Au sein d’un hôpital de soins tertiaires, les femmes
préménopausées subissant une hystéroscopie diagnostique ont Objective: To determine if the use of oral misoprostol in
été affectées, au hasard, à un groupe se voyant administrer premenopausal women undergoing diagnostic hysteroscopy 400 mg de misoprostol ou à un groupe se voyant administrer un produces a clinically important difference in pre-procedural placebo de vitamine B6 (l’administration se déroulant par voie orale, 12 heures avant l’intervention, dans chacun de ces Methods: At a tertiary care hospital, premenopausal women
groupes). Les patientes ont été stratifiées en fonction de la parité.
undergoing diagnostic hysteroscopy were randomized to receive La dilatation préintervention du col utérin constituait le critère either 400 mg of misoprostol or a vitamin B6 placebo orally 12 d’évaluation principal. Parmi les critères d’évaluation secondaires, hours before the procedure. Patients were stratified on the basis on trouvait la nécessité de dilater davantage le col utérin, le délai of parity. The primary outcome was the pre-procedural dilatation of requis pour dilater davantage le col utérin et les effets the cervix. Secondary outcomes included the need to further dilate the cervix, the time required to further dilate the cervix, and sideeffects.
Résultats : Soixante-quatre femmes (11 nullipares et 53 pares)
subissant une hystéroscopie diagnostique ont consenti à participer Results: Sixty-four women (11 nulliparous and 53 parous)
à l’étude. Trente-trois femmes se sont vu administrer du undergoing diagnostic hysteroscopy consented to participate in misoprostol et 31, un placebo. Les données démographiques de the study. Thirty-three women received misoprostol and 31 départ n’indiquaient aucune différence en matière d’âge et de received placebo. Baseline demographics showed no difference in parité entre les deux groupes. Aucune différence significative n’a age and parity between the two groups. There were no significant été constatée en matière de dilatation préintervention (5,0 mm, differences in pre-procedural dilatation (5.0 mm vs. 4.7 mm, P = par comparaison avec 4,7 mm, P = 0,52), de nécessité de dilater 0.52), need to further dilate the cervix (56.7% vs. 63.0%, P = davantage le col utérin (56,7 %, par comparaison avec 63,0 %, 0.63), and time required to further dilate the cervix (12.7 seconds P = 0,63) et de délai requis pour dilater davantage le col utérin vs. 25.7 seconds, P = 0.27). Significantly more women in the (12,7 secondes, par comparaison avec 25,7 secondes, P = 0,27).
misoprostol group experienced menstrual-like cramping (24.2% Un nombre considérablement plus élevé de femmes du groupe vs. 3.3%, P = 0.03) and vaginal spotting (21.2% vs. 3.3%, P = « Misoprostol » ont connu des crampes de type menstruel (24,2 %, par comparaison avec 3,3 %, P = 0,03) et une Conclusion: In premenopausal women, there is no improvement in
microrragie (21,2 %, par comparaison avec 3,3 %, P = 0,05).
pre-procedural cervical dilatation with administration of oralmisoprostol 12 hours before diagnostic hysteroscopy. Further Conclusion : Chez les femmes préménopausées, aucune
research is required in both nulliparous and parous amélioration de la dilatation cervicale préintervention n’est premenopausal women to determine whether oral misoprostol constatée à la suite de l’administration de misoprostol par voie improves cervical dilatation and, if so, the ideal dose, route and orale 12 heures avant la tenue de l’hystéroscopie diagnostique.
D’autres recherches s’avèrent nécessaires, tant chez les femmespréménopausées nullipares que pares, afin de déterminer si lemisoprostol administré par voie orale améliore la dilatation Résumé
cervicale et, si tel est le cas, d’en identifier la posologie idéale.
Objectif : Déterminer si l’administration de misoprostol par voie orale
aux femmes préménopausées subissant une hystéroscopie J Obstet Gynaecol Can 2007;29(8):648–652 diagnostique génère une différence importante sur le plan cliniqueen matière de dilatation cervicale préintervention.
INTRODUCTION
Key Words: Hysteroscopy, misoprostol, cervical dilatation, cervical
As minimally invasive procedures become the standard surgical approach and as minimizing operating time becomes critical, the ability to perform procedures underlocal anaesthesia carries an advantage. Before making hysteroscopy under local anaesthesia the standard of care in our centre, we sought to identify techniques to improve patient acceptance and to simplify the procedure.
l AUGUST JOGC AOÛT 2007
A Randomized Trial of Oral Misoprostol in Premenopausal Women Before Hysteroscopy Misoprostol, a prostaglandin E1 analogue used for treat- The primary outcome was the pre-procedural measured ment of gastric ulcers induced by nonsteroidal anti inflam- dilatation of the cervix. The need to further dilate the cervix, matory drugs, has been shown to be effective in priming the the time required to further dilate the cervix, and side cervix for induction of labour and before curettage for sur- effects including nausea, vomiting, diarrhea, abdominal gical abortion.1–6 However, reports of its effectiveness in cramping, vaginal bleeding/spotting, and headache were hysteroscopy related to cervical dilatation have describedconflicting results.2,7–16 A systematic review by our group To help ensure compliance, patients were contacted by tele- concluded that misoprostol appears to be promising as a phone on the night before surgery to remind them to take cervical ripening agent prior to hysteroscopy, but further the medication. All but one woman took the assigned medi- research is needed to identify the ideal dose, route, and cation. On arrival at the day surgery unit, the women were asked to complete a questionnaire regarding any side effects The purpose of this double-blind randomized controlled experienced. They were also asked if they would take the trial was to determine if oral misoprostol would improve medication if they required hysteroscopy again.
pre-procedural cervical dilatation in premenopausal womenand avoid the need to dilate the cervix before a diagnostic The patients were taken to the operating room and under- went general anaesthesia using a standard protocol. Theywere placed in lithotomy position and prepared and draped MATERIAL AND METHODS
in the standard surgical fashion. A weighted speculum was This study was performed between January 2001 and Janu- placed into the vagina to allow visualization of the cervix.
ary 2003 in the Department of Obstetrics and Gynecology, We then attempted to insert Hegar dilators into the cervical Health Sciences Centre, Eastern Health, Memorial Univer- canal, beginning with the largest (#9) and continuing with sity of Newfoundland, St. John’s, Newfoundland, a tertiary progressively smaller dilators until the dilator passed easily, care centre. The study was approved by the Human Investi- in order to determine the pre-procedural diameter. If the gation Committee of Memorial University and the Ethics diameter of the cervical canal measured less than the diame- Board of the hospital. Patients were recruited from gynae- ter of the diagnostic hysteroscope (6 mm), the time required cology clinics by their attending physicians, and written to dilate the cervix was recorded in seconds. The remaining procedure was completed according to standard protocolfor hysteroscopy.
Subjects eligible for the study were healthy premenopausalwomen, 19 years and over, who were scheduled for diag- The required sample size was calculated based on the mean nostic hysteroscopy. The exclusion criteria were known pre-procedural dilatation. A standard deviation of 1.3 mm hypersensitivity or allergy to prostaglandins, seizure was used from previous research,2 and the clinically impor- disorder, or liver disease with abnormal liver function tests.
tant difference of 1 mm was chosen on the basis of inter- Consenting women were randomized using a computer- views with gynaecologists. A difference of 1 mm was felt to generated list of random numbers to receive either 400 mg be clinically important as it may mean the difference of misoprostol or 50 mg vitamin B6 (used as placebo) orally between requiring and not requiring additional cervical dila- 12 hours prior to the procedure. The oral route was chosen tation. As any additional dilatation can be associated with as it would be easy and convenient for women to potential complications, even a 1 mm difference was there- self-administer. The hospital pharmacy dispensed the medi- fore felt to be clinically significant. The number of women cation according to the random assignment. The women required to demonstrate this difference, with a power of and health care providers were blinded to the treatment 80% and a significance level of 5%, was 28 per group, or 56 allocation. Women were stratified based on parity; a parous woman was defined as a woman who had had a deliveryafter 20 weeks’ gestation.
The data were analyzed on the basis of intent to treat, usingSPSS Shapiro-Wilks test was used to determine normality of thedata. Continuous data were analyzed with the Student t test.
ABBREVIATIONS
The Fisher exact test and chi-squared test were used to ana-lyze proportions. Significance was set at P < 0.05. The CONSORT criteria for randomized clinical trials was AUGUST JOGC AOÛT 2007 l
GYNAECOLOGY
Figure. Flow diagram of study enrolment
Table 1. Demographics and cervical dilatation
Time required to further dilate cervix (seconds) *Mean and student t test; †n (%) and chi-square test.
cervical laceration or uterine perforation were reported.
When subgroup analysis was performed for parous and Sixty-four premenopausal women were enrolled and under- nulliparous women, there were no significant differences went diagnostic hysteroscopy, 33 women receiving between the groups in these outcomes (Table 2). From the misoprostol and 31 receiving placebo. Fifty-three women questionnaire, more patients in the misoprostol group were parous and 11 were nulliparous (Figure). Data were experienced menstrual-like cramping and vaginal spotting missing on pre-procedural dilatation for three women in the (Table 3). Despite the higher rates of these side effects, only misoprostol group and three women in the placebo group; one woman in the misoprostol group indicated she would on post-procedural dilatation for three women in the not take the medication again for this procedure.
misoprostol group and two women in the placebo group;on time required to further dilate the cervix for three DISCUSSION
women in the misoprostol group and two women in theplacebo group; and on side effects for one woman in the The utility of diagnostic hysteroscopy could be improved by facilitating its use in an office setting. One limiting factor is There were no differences between the misoprostol and cervical dilatation. If misoprostol could decrease or elimi- placebo groups in the need for further cervical dilatation nate the need for the cervical dilatation, hysteroscopy could (relative risk 0.88; 95% CI 0.54–1.45), pre-procedural dila- be accomplished more easily. We undertook this study to tation (mean difference 0.32, 95% CI 0.66–1.30), or time determine if the use of misoprostol would improve baseline required to further dilate the cervix (mean difference 13 sec- cervical dilatation before diagnostic hysteroscopy and obvi- onds, 95% CI 36.5–10.5) (Table 1). No complications of l AUGUST JOGC AOÛT 2007
A Randomized Trial of Oral Misoprostol in Premenopausal Women Before Hysteroscopy Table 2. Subgroup analysis of parous versus nulliparous women
Time required to further dilate the cervix (seconds) *chi-square test (%);†Fisher exact test; ‡Student t test Table 3. Side effects and satisfaction survey results
The research to date using misoprostol clearly demonstrates its placebo group; again most patients were nulliparous.8 The effectiveness in cervical ripening on a well-estrogenized cervix proportion of parous patients in our study was much higher in pregnant women, both early and late in pregnancy.1–6 As we (82.8%) and may account for the difference in our findings.
Other studies not finding a benefit with use of misoprostol misoprostol, it appears that it may not be as effective in before hysteroscopy involve hypoestrogenic women.10–14 hypoestrogenic women; studies have shown no effect on Unlike previous studies, our study failed to show a benefit pre-procedural dilatation of the cervix in women who were from use of oral misoprostol before hysteroscopy in postmenopausal or taking GnRH agonists.10–14,16 premenopausal women. The timing of administration of A clinically significant outcome in this context is to elimi- misoprostol (12 hours prior to hysteroscopy) is similar to nate the need for cervical dilatation. In a study by other studies.2, 7,8,10 However, some of the previous studies Preutthipan et al., only 6.5% women in the vaginal used misoprostol administered vaginally,7,9 whereas we misoprostol group needed pre-procedural dilatation com- used oral administration. Studies of the pharmacokinetics pared with 31% in the placebo group, but all patients in this of misoprostol show vaginal administration is associated study were nulliparous.7 This result was echoed in a second with a longer time to peak serum misoprostol levels than study on operative hysteroscopy by the same group in 2000, oral administration, but with longer bioavailability.18,19 showing 75% of women in the misoprostol group required Because the single dose of misoprostol was given 12 hours cervical dilatation compared with 95% of women in the before the procedure, this may explain the difference AUGUST JOGC AOÛT 2007 l
GYNAECOLOGY
between our findings and others. Perhaps a better effect on REFERENCES
cervical ripening may be seen if the hysteroscopy is per- 1. Ngai SW, Tang OS, Lao T, Ho PC, Ma HK. Oral misoprostol versus formed sooner after the oral dose of misoprostol.
placebo for cervical dilatation before vacuum aspiration in first trimesterpregnancy. Hum Reprod 1995;10:1220–2.
On review of the side effects and reported satisfaction, all 2. Ngai SW, Chan YM, Liu KL, Ho PC. Oral misoprostol for cervical priming but one woman reported they would take the drug again.
in non-pregnant women. Hum Reprod 1997;12:2373–5.
This appeared to indicate that despite a significant increase 3. Goldberg AB, Carusi DA, Meckstroth KR. Misoprostol in gynecology. Curr in the rates of spotting and cramping, these side effects were not bothersome enough to prohibit its use.
4. Meckstroth KR, Darney PD. Prostaglandins for first-trimester termination.
Best Pract Res Clin Obstet Gynaecol 2003;17:745–63.
It is important that the limitations of the study be 5. Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening addressed. Several different surgeons performed the and induction of labour. Cochrane Database of Systematic Reviews 2003, hysteroscopies, but over 80% of the procedures were per- formed by a single surgeon. We did not attempt to measure 6. Alfirevic Z, Weeks A. Oral Misoprostol for induction of labour. Cochrane Database of Systematic Reviews 2006, Issue 2.Art. No.:CD001338.
the force required to dilate the cervix, as has been done by 7. Preutthipan S. Herabutya Y. A randomized controlled trial of vaginal some investigators10,12; however, we feel that the actual cer- misoprostol for cervical priming before hysteroscopy. Obstet Gynecol vical dilatation and the need to dilate the cervix further are more important clinical outcomes. Unfortunately, we do 8. Preutthipan S, Herabutya Y. Vaginal misoprostol for cervical priming not have information on women who were eligible for the before operative hysteroscopy: A randomized controlled trial. ObstetGynecol 2000;96:890–4.
study but were not approached or declined to participate.
9. Atay V, Duru NK, Pabuccu R, Ergun A, Tokac G, Aydin BA. Vaginal Nevertheless, the age and parity of the women in the study misoprostol for cervical dilatation before operative office hysteroscopy.
are reflective of the population of premenopausal women 10. Ngai SW, Chan YM, Ho PC. The use of misoprostol prior to hysteroscopy Although we performed secondary analyses based on par- in postmenopausal women. Hum Reprod 2001;16:1486–8.
ity, we did not have adequate statistical power to evaluate 11. Fung TM, Lam MH, Wong SF, Ho LC. A randomized placebo-controlled the primary outcome in these subgroups, particularly in the trial of vaginal misoprostol for cervical priming before hysteroscopy inpostmenopausal women. BJOG 2002;109:561–5.
nulliparous group. Perhaps it is in this group that 12. Cooper KG, Pinion SB, Bhattacharya S, Parkin DE. The effects of the misoprostol has the most beneficial effect. We recognize gonadotrophin releasing hormone analogue (goserilin) and prostaglandin E1 that the diameter of the hysteroscope used in our centre (misoprostol) on cervical resistance prior to transcervical resection of the during the study (6 mm) is larger than that of currently avail- endometrium. Br J Obstet Gynaecol 1996:103:375–8.
able office hysteroscopes (1–5 mm). Use of smaller hystero- 13. Thomas JA, Leyland N, Durand N, Windrim RC. The use of oral scopes is less likely to require additional dilatation, and this misoprostol as a cervical ripening agent in operative hysteroscopy: adouble-blind, placebo controlled trial. Am J Obstet Gynecol may explain the number of women requiring additional cer- vical dilatation in our study (59.6%). Finally, women in the 14. Bisharah M, Al-Fozan H, Tulandi T. A randomized trial of sublingual study had diagnostic hysteroscopy performed in the operat- misoprostol for cervical priming before hysteroscopy. J Am Assoc Gynecol ing room under general anaesthetic because there was no space available at that time in our outpatient clinics. We 15. Fernandez H, Alby JD, Tournoux C, Chauveaud-Lambling A, deTayrac R, acknowledge that in many centres, hysteroscopy is per- Frydman R, et al. Vaginal misoprostol for cervical ripening before operative formed in an office setting, but this was not the standard hysteroscopy in pre-menopausal women: A double-blind placebo-controlledtrial with three dose regimens. Hum Reprod 2004;19:1618–21.
practice at the time of the study. We wanted to determine ifmisoprostol would help facilitate the procedure before 16. Crane JMG, Healey S. Use of misoprostol before hysteroscopy: a systematic review. J Obstet Gynaecol Can 2006;28:373–9.
beginning to do the procedure in an office setting.
17. Moher D, Schulz KF, Altman D. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group CONCLUSION
randomized trials. CONSORT group (Consolidated Standards of Reporting In contrast to previous reports, we did not find that oral misoprostol given 12 hours prior to hysteroscopy improved 18. Zieman M, Fong SK, Benowitz NL, Banskter D, Darney PD. Absorption kinetics of misoprostol with oral and or vaginal administration. Obstet cervical dilatation. Further research is required, in both nulliparous and parous premenopausal women, to deter- 19. Daneilsson KG, Marions L, Rodriguez A, Spur BW, Wong PYK, Bygdeman mine if there is indeed a beneficial effect and, if so, the ideal M. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol 1999;93:275–80.
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Source: http://jogc.org/abstracts/full/200708_Gynaecology_1.pdf