1 Department of Obstetrics and Gynaecology, National University of Singapore, Singapore and 2 Biostatistics Consultancy Unit,National University of Singapore Medical Institute, Singapore
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Abstract |
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Key words: acetic acid/pre-abortion cervical priming/vaginal misoprostol
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Introduction |
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In all our previous studies (Fong et al., 1998; Singh et al., 1998
), the misoprostol tablets used were wetted only with water before introduction into the posterior vaginal fornix. Using 400 µg vaginal misoprostol, almost all patients (96.7%) achieved a successful cervical dilatation of
8 mm, whereas only seven (23%) of 30 women achieved this with 200 µg of misoprostol. However, at the time of vacuum aspiration it was quite common to identify particulate remnants of the tablets, albeit in varying proportions. This finding of incomplete dissolution of misoprostol tablets in the vagina has also been reported by others (Zieman et al., 1997
). Since it is desirable to achieve a constant plasma profile, it is important to develop a preparation or medium that would ensure more complete dissolution of the vaginal misoprostol tablets to achieve optimal efficacy. Misoprostol is said to liquefy better in an acidic medium [American Hospital Formulary Service (AHFS) Drug Information, 1998]. Thus, the objective of our study was to determine whether a 200 µg misoprostol tablet wetted with acetic acid before being introduced into the posterior vaginal fornix of nulliparous women is more efficacious than the same dose wetted in water in achieving a cervical dilatation of
8 mm. If proven successful, this would help to lower the optimal dose for pre-abortion cervical priming and thus perhaps further reduce the side effects associated with the current recommended 400 µg dose.
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Materials and methods |
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The study was performed in double-blind fashion and the women were randomized to the two groups by their opening one of 120 sequentially numbered, sealed envelopes, prepared using random number tables. As termination of pregnancy was performed on a day-surgery basis, the women were admitted on the morning of the procedure, having fasted overnight. The vaginal pH of each woman was measured, using a pH dipstick, and was between 3.5 and 5.0. During vaginal examination on the morning of surgery, 200 µg of misoprostol dissolved either in water or acetic acid, was placed into the posterior vaginal fornix by a doctor who ultimately did not assess treatment outcome. The pH of the acetic acid used (2.0) was clearly lower than that of the normal vagina. No premedication was given, but analgesics were available should the women experience pain. Blood pressure, pulse rate, temperature and occurrence of side effects such as abdominal pain, vaginal bleeding, nausea, vomiting, fever and diarrhoea were recorded. The severity of abdominal pain was assessed using a three-point response scale: no pain; minimal or moderate pain requiring no analgesics; and severe pain requiring analgesics. Pre-operative blood loss from the vagina was monitored using a measuring cylinder, together with the degree of soaking of the sanitary pad.
Vacuum aspiration was performed (by K.S. and Y.F.F.) under general anaesthesia (as is the general practice in Singapore) at 34 h after insertion of the misoprostol. The randomization schedule was unknown to the surgeons. The presence of products of conception at the cervical os before starting the procedure was recorded. The degree of cervical dilatation before vacuum aspiration was measured with Hegar dilators in a descending order, starting with Hegar 12. The size of the largest Hegar dilator that could be passed into the cervical os without resistance was recorded as the cervical dilatation achieved. If the cervix had dilated to at least 8 mm, no further dilatation was performed and the pregnancy was evacuated with a size 8 vacurette. Other parameters assessed during the operation included the amount of further dilatation required (if less than Hegar 8) to permit passage of the suction vacurette and intra-operative blood loss. Intra-operative blood loss was measured as the total volume of uterine aspirate after sieving away products of conception. On completion of the procedure, the uterus was curetted clean with a small sharp uterine curette. The products of conception were confirmed histologically. Following the operation, the women were kept in hospital for 34 h before being discharged; all attended for follow-up 6 weeks later when a pelvic examination was performed and their Hb level checked.
The sample size was estimated with the assumption of a type I error of 0.05, a power of 0.80 and a 25% difference in outcome, namely difference in pre-operative cervical dilatation and side effects between the two groups studied. Using an established method (Fisher and Van Belle, 1993), the sample size for each group in the study should be 51. Assuming a 10% default at follow-up, the number chosen was 60; therefore, the total sample size was 120.
Statistical analyses were performed using Student's t-test, Fisher's exact test and analysis of variance. Variables that were normally distributed are presented as mean and SEM. Differences in the age of women, gestational age, pre-operative and post-operative Hb, mean cervical dilatation and blood loss during the operation were compared using Student's t-test. In addition, odds ratios with 95% confidence interval were calculated for successful cervical dilatation, which was defined as 8 mm after cervical priming. The frequency of pre-operative side effects was compared with Fisher's (two-tailed) exact test.
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Results |
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At the follow-up visit of 6 weeks, all women in the study had resumed their menses. None had any persistent or delayed side effects, and there was no significant difference between pre-operative and post-operative Hb in either group (Table I).
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Discussion |
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On the assumption that a relationship exists between misoprostol plasma concentration and therapeutic effect, we used acetic acid to dissolve vaginally administered misoprostol, the intention being to improve its efficacy for pre-abortion cervical priming. However, our results showed no statistically significant improvement in achieving a cervical dilatation of 8 mm, or in mean baseline cervical dilatation using acetic acid. A 200 µg quantity of intravaginal misoprostol, when dissolved in water, is as effective as a 200 µg quantity when dissolved in acetic acid and used 34 h before vacuum aspiration for pre-abortion cervical priming.
Thus, the use of an acidic medium does not improve the efficacy of misoprostol at a 200 µg dose level, and 400 µg is required to achieve optimal cervical softening, as shown in our previous studies (Singh et al., 1998). However, as plasma concentrations of misoprostol were not measured, there is potential for future research in which these are measured following vaginal administration of the drug.
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Acknowledgments |
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Notes |
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References |
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Submitted on November 16, 1998; accepted on February 25, 1999.