1 Service de Gynécologie-Obstétrique, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris (AP-HP), 157 rue de la Porte-de-Trivaux, 92141 Clamart cedex and 2 Service de Biostatistique et Informatique Médicale, Hôpital Saint-Louis, 1, Avenue Claude Vellefaux, 75475 Paris cedex 10, France
3 To whom correspondence should be addressed. e-mail: herve.fernandez{at}abc.ap-hop-paris.fr
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Abstract |
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Key words: cervical ripening/misoprostol/operative hysteroscopy/pre-menopausal women/vaginal route
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Introduction |
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Misoprostol, a synthetic prostaglandin E1 analogue widely prescribed for prevention and treatment of gastric ulcers, has been shown to have cervical ripening effects in both pregnant and non-pregnant patients when administered either orally or vaginally (Ngai et al., 1997; Preutthipan et al., 2000
). The systemic bioavailability of misoprostol is three times greater when it is administered vaginally than orally (Zieman et al., 1997
) and suggests that vaginal administration could be dosed at longer intervals than oral. The purpose of this randomized, placebo-controlled study was to evaluate the effectiveness of vaginal misoprostol in facilitating cervical dilatation in non-menopausal women before operative hysteroscopy and to identify the best dose.
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Materials and methods |
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Surgeons and operating theatre nurses who removed the tablets which were not totally disintegrated after 4 h were blinded to patient allocation. The study was approved by the institutional review board before it began. The study was set in one centre.
Patients who were considered medically fit were scheduled for operative hysteroscopy under general anaesthesia with a 10 mm hysteroscope during the follicular phase of their cycles.
The primary outcome measure in this study was cervical width, which was assessed by the subjective force required to enter the cervical os without resistance with successive Hegar dilators from 38 mm. Surgery was performed by two investigators (Drs Fernandez or Chauveaud-Lambling) to reduce individual variability. Secondary outcome measurements included the subjective ease of cervical dilatation, the time required for dilatation up to Hegar 10, pre-operative pain, and the adverse effects and complications of the procedure (cervical injuries, uterine perforation, false track, bleeding). Pain tolerance evaluated by a visual analogue scale (VAS) and side-effects were noted by the surgical nurses before the procedure.
The exclusion criteria were: contraindication to prostaglandins (asthma, glaucoma, hypertension), history of cervical surgery or of cervical incompetence, and treatment with GnRH agonists.
Sample size was calculated with a test that had an of 0.01 and a
of 0.20. The study had the power to detect a 50% difference between the treatment and control groups, as shown by Preutthipan et al. (1999
).
Statistical analysis
Results are presented as the mean ± SD (range) for quantitative variables and frequency (percentage) for qualitative variables. Analysis of the trial was performed according to the intention-to-treat principle and the patients number was calculated to find a difference in the efficacy of the treatment. Groups were compared at inclusion with the KruskalWallis test. For the principal and secondary endpoints, each treatment group was compared with the placebo group. Experimental groups that differed significantly from the placebo group were also compared with one another. Wilcoxon rank sum tests were used for the quantitative variables, since the distribution of the variables was obviously not Gaussian. Fishers exact tests were used for qualitative variables.
To take multiple testing into account in the assessment of the subjective outcome criteria, the significance level was set at 0.01. For the other global group comparisons, the significance level was P < 0.05.
All analyses were performed with S-Plus 2000 software (MathSoft Inc., USA).
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Results |
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All inclusion and exclusion criteria in the study were met. Nonetheless one patient had to withdraw from the study because she was found during surgery to be pregnant. The data for this patient were included in the analysis, in compliance with the principle of intention-to-treat analysis. Similarly, one patient received a different treatment than that to which she was randomly allocated. Indeed, she received placebo tablets instead of 800 µg of misoprostol. So, the analysis considered her to be in the group to which she was allocated, that is, group 1 (Table I).
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Discussion |
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To limit the bias due to dilatation, we excluded menopausal women and the women treated with GnRH agonists and we always operated during the follicular phase. Cooper et al. (1996) showed that the lack of estrogen induced by agonists may explain the inefficacy of misoprostol.
The route of administration and the delay separating misoprostol administration from the surgery were justified by the study on misoprostol absorption kinetics (Zieman et al., 1997). The comparative analysis of the serum levels of the principal metabolite of misoprostol revealed that bioavailability was best following vaginal administration (Tmax = 80 ± 27 min), followed by a plateau phase lasting several hours. Moreover, since all our patients underwent outpatient surgery, this facilitated the organization of the study and seemed to ensure that we were in compliance with prescriptions and could monitor possible side-effects during hospitalization.
The lack of efficacy of misoprostol, at three successive doses, may therefore be related to the time period separating its administration (vaginal or oral) from the surgery. Indeed, in our series the tablets were never disintegrated totally at the time of surgery. Thomas et al. (2002) and Preutthipan et al. (1999
) reported in larger series that administration respectively of 400 µg oral misoprostol 12 or 24 h before surgery or 200 µg vaginal misoprostol 910 h before surgery demonstrated an increased ease of cervical dilatation, but at the price of mild side-effects such as diarrhoea, cramps and vaginal bleeding, which were reported in an average of 25% of cases.
Nonetheless, no placebo-controlled trials so far have shown a significant diminution in the rate of severe complications such as cervical laceration or perforation. Does the surgeons subjective assessment that dilatation is facilitated, when combined with a side-effect rate of 25%, justify the prescription of misoprostol before operative hysteroscopy? We must answer that no benefit was demonstrated when misoprostol is given 4 h before the intervention, since our study confirmed the inefficacy of this protocol. Twelve hours earlier, that is, at home, the night before the procedure, without the ability to treat the side-effects, the answer could be positive, but the risk:benefit ratio needs more thorough assessment. The sublingual administration of 100 µg of misoprostol 12 h before surgery is not efficacious (Bisharah et al., 2003), even though Tang et al. (2002
) found a peak of high concentration after sublingual administration.
In conclusion, administration of misoprostol up to 800 µg 4 h before operative hysteroscopy showed no evidence of promoting cervical dilatation. Other studies assessing the efficacy and optimizing the dose of misoprostol are necessary to learn whether there is any real effect of this product on the cervix or only the surgeons subjective assessment.
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Acknowledgements |
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References |
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Submitted on February 4, 2004; accepted on April 14, 2004.
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