Human Reproduction, Vol. 14, No. 6, 1635-1637,
June 1999
© 1999 European Society of Human Reproduction and Embryology
Does an acidic medium enhance the efficacy of vaginal misoprostol for pre-abortion cervical priming?
1 Department of Obstetrics and Gynaecology, National University of Singapore, Singapore and 2 Biostatistics Consultancy Unit,National University of Singapore Medical Institute, Singapore
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Absorption pharmacokinetics reveal a relationship between plasma concentrations of misoprostol and its therapeutic effect. To achieve a constant plasma profile and optimal efficacy, it is important to develop a medium that ensures complete dissolution of vaginal misoprostol tablets. Vaginal misoprostol is said to liquefy better in an acidic medium; thus, the aim of this study was to determine whether a 200 µg misoprostol tablet dissolved in acetic acid would be more efficacious than 200 µg misoprostol dissolved in water for pre-abortion cervical priming. A total of 120 healthy nulliparous women requesting legal termination of pregnancy between 6–12 weeks gestation were allocated randomly to either of the study groups. Vacuum aspiration was performed 3–4 h after insertion of the misoprostol tablet. Using Hegar's dilator, the degree of cervical dilatation before operation was measured. Of 60 women, 14 (23%) achieved a cervical dilatation of
8 mm when the misoprostol dose was dissolved in acetic acid; 12 (20%) achieved a similar cervical dilatation when the dose was dissolved in water. The mean cervical dilatation for the acid and water media used was 6.3 mm and 6.2 mm respectively; these differences were not statistically significant, neither were pre-operative and intra-operative blood losses statistically different between the two groups. Twenty-four (40%) and four (7%) respectively of women in whom a water medium was used experienced vaginal bleeding and abdominal pain; 20 (33%) and 0 women respectively among those in whom an acetic acid medium was used experienced vaginal bleeding and abdominal pain. These differences in side effects were not statistically significant. Our study shows that the use of acetic acid to dissolve vaginal misoprostol does not improve the efficacy in achieving successful cervical dilatation for pre-abortion cervical priming.
Key words: acetic acid/pre-abortion cervical priming/vaginal misoprostol
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Misoprostol, a synthetic analogue of naturally occurring prostaglandin E1, has been used for several years to prevent and treat peptic ulcers, and is now being used successfully for pre-abortion cervical priming (El-Refaey et al., 1994
; Lawrie et al., 1996). This approach reduces the risks of cervical damage and uterine perforation (Schultz et al., 1983; Grimes et al., 1984) and is therefore especially recommended in nulliparous women seeking termination of first-trimester pregnancy (Royal College of Obstetricians and Gynaecologists, 1997). The optimal clinical dose of vaginal misoprostol for pre-abortion cervical priming appears to be 400 µg, administered 3–4 h before vacuum aspiration (Singh et al., 1998).
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.
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
In total, 120 nulliparous women between 6–12 weeks gestation, requesting legal termination of a first-trimester pregnancy, were recruited for the study. The gestational age was determined by reliable menstrual history and confirmed by pelvic examination or ultrasound. Their pre-operative baseline haemoglobin (Hb) was also measured, and only those women with a pre-operative Hb >10 gm/dl were recruited. Informed consent was obtained from all women.
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 3–4 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 3–4 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.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
The two treatment groups were similar in relation to maternal and gestational age (Table I
). None of the women aborted during the interval between misoprostol administration and the scheduled time of evacuation of the uterus.
|
Among the group in which the misoprostol tablet was wetted in water, 12 (20%) women achieved a cervical dilatation of
8 mm. When the misoprostol tablet was wetted with acetic acid, 14 (23%) women achieved a similar successful dilatation. The mean cervical dilatation for the water and acid media was 6.2 mm and 6.3 mm respectively (Table II). The differences in both these parameters were not statistically significant. Similarly, there was no statistically significant difference between groups in terms of pre-operative and intra-operative blood loss (Table II).
|
Twenty-four (40%) women in the group in which a water medium was used experienced vaginal bleeding, compared with 20 (33%) of those in whom acetic acid was used. Four women, all of whom received the water medium, experienced abdominal pain, but none required analgesics for pain relief. There was no statistically significant inter-group difference with regard to reports of vaginal bleeding or abdominal pain. No women in either group experienced nausea, vomiting, diarrhoea or fever.
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
).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
Misoprostol is said to liquefy better in an acidic medium (AHFS Drug Information, 1998). An on-line electronic search of medical literature revealed only one study in Turkey (Ficicioglu et al., 1996
) in which an acidic medium was used for vaginal misoprostol, a 200 µg misoprostol tablet being introduced into the posterior fornix with one tablet of gyno-flor to create an acidic medium that would enhance misoprostol absorption. After 5 h, 72.5% of women had achieved a successful cervical dilatation of 8 mm. Absorption pharmacokinetics of misoprostol (Zieman et al., 1997) revealed that, compared with oral administration, application of vaginal misoprostol resulted in peak plasma concentrations being reached more slowly, being slightly lower, and sustained for up to 4 h. Consequently the systemic bioavailability of vaginal misoprostol was 3-fold that of the orally administered drug.
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 3–4 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.
|
Acknowledgments |
|---|
We would like to thank the staff of the Fertility Control Clinic, National University Hospital for recruiting and motivating the patients, and Triffany for the excellent secretarial assistance.
|
Notes |
|---|
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, National University Hospital,Lower Kent Ridge Road, Singapore 119074
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
|---|
American Hospital Formulary Service Drug Information (1998) Gastrointestinal drugs. American Society of Health System Pharmacists Publication, 56, 2445–2450.
El-Refaey, H., Calder, I., Wheatley, D.N. and Templeton, A. (1994) Cervical priming with prostaglandin E1 analogues, misoprostol and gemeprost. Lancet, 343, 1207–1209.[Web of Science][Medline]
Ficicioglu, C., Tasdemir, M. and Tasdemir, S. (1996) Effect of vaginal misoprostol application for cervical softening in pregnancy interruption before ten weeks of gestation. Acta Obstet. Gynecol. Scand., 75, 54–56.[Medline]
Fisher and Van Belle (1993) Biostatistics: A Methodology for the Health Service. Chichester Wiley Interscience Publications, pp. 155–159.
Fong, Y.F., Singh, K. and Prasad, R.N.V. (1998) A comparative study using two dose regimens (200 µg or 400 µg) of vaginal misoprostol for pre-operative cervical dilatation in first trimester nulliparae. Br. J. Obstet. Gynaecol., 105, 413–417.[Web of Science][Medline]
Grimes, D.A., Schultz, K.F. and Cates, W.J. (1984) Prevention of uterine perforation during curettage abortion. JAMA, 251, 2108–2111.
Lawrie, A., Penney, G. and Templeton, A. (1996) A randomized comparison of oral and vaginal misoprostol for cervical priming before suction termination of pregnancy. Br. J. Obstet. Gynaecol., 103, 1117–1119.[Web of Science][Medline]
Royal College of Obstetricians and Gynaecologists (1997) Guidelines on Induced Abortion. vol. 11, pp. 1–10.
Schultz, K.F., Grimes, D.A. and Cates, W.J. (1983) Measures to prevent cervical injury during suction curettage abortion. Lancet, i, 1182–1184.
Singh, K., Fong, Y.F., Prasad, R.N.V. and Dong, F. (1998) A randomised trial to determine the optimal dosage of vaginal misoprostol for pre-abortion cervical priming. Obstet. Gynecol., 92, 795–798.[Web of Science][Medline]
Zieman, M., Fong, S.K., Benowitz, N.L. et al. (1997) Absorption kinetics of misoprostol with oral or vaginal administration. Obstet. Gynecol., 90, 88–92.[Web of Science][Medline]
Submitted on November 16, 1998; accepted on February 25, 1999.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Choksuchat, S. Cheewadhanaraks, C. Getpook, V. Wootipoom, and K. Dhanavoravibul Misoprostol for cervical ripening in non-pregnant women: a randomized double-blind controlled trial of oral versus vaginal regimens Hum. Reprod., August 1, 2006; 21(8): 2167 - 2170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Yilmaz, S. Kelekci, I. E. Ertas, S. Kahyaoglu, M. Ozel, N. Sut, and N. Danisman Misoprostol moistened with acetic acid or saline for second trimester pregnancy termination: a randomized prospective double-blind trial Hum. Reprod., November 1, 2005; 20(11): 3067 - 3071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. S. Tang, C. C.W. Chan, E. H.Y. Ng, S. W.H. Lee, and P. C. Ho A prospective, randomized, placebo-controlled trial on the use of mifepristone with sublingual or vaginal misoprostol for medical abortions of less than 9 weeks gestation Hum. Reprod., November 1, 2003; 18(11): 2315 - 2318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. S. Tang, J. Xu, L. Cheng, S. W.H. Lee, and P. C. Ho Pilot study on the use of sublingual misoprostol with mifepristone in termination of first trimester pregnancy up to 9 weeks gestation Hum. Reprod., July 1, 2002; 17(7): 1738 - 1740. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. S. Tang, B.Y. Miao, S. W.H. Lee, and P. C. Ho Pilot study on the use of repeated doses of sublingual misoprostol in termination of pregnancy up to 12 weeks gestation: efficacy and acceptability Hum. Reprod., March 1, 2002; 17(3): 654 - 658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. S. Tang, H. Schweer, H.W. Seyberth, S. W.H. Lee, and P. C. Ho Pharmacokinetics of different routes of administration of misoprostol Hum. Reprod., February 1, 2002; 17(2): 332 - 336. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||