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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Florida Health Science Center, Jacksonville, Florida.
Address reprint requests to: Luis Sanchez-Ramos, MD, University of Florida Health Science Center, Department of Obstetrics and Gynecology, 653-1 West 8th Street, Jacksonville, FL 32209; E-mail: luis.sanchez{at}jax.ufl.edu.
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ABSTRACT |
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METHODS: A total of 177 women who presented with an indication for cervical ripening and labor induction were randomly assigned to one of two treatment groups: 1) intravaginal misoprostol in dry tablet form, or 2) intravaginal misoprostol moistened with 1 mL of 3% acetic acid solution. The primary outcome assessed was the interval from start of induction to vaginal delivery. To detect at least a 3.5-hour difference in the primary outcome with 80% power, 87 subjects were required in each group.
RESULTS: Among 162 patients evaluated, 80 were allocated to the misoprostol dry group and 82 to the misoprostol moistened group. No significant difference was noted for the mean ± standard deviation interval to vaginal delivery: 1130 ± 636 minutes for the group who received dry tablets and 1004 ± 636 minutes for those who received moistened misoprostol tablets (P = .25). Additionally, no statistically significant differences were noted between the groups with respect to need for oxytocin, proportion of patients delivered after a single dose, intrapartum complications (including tachysystole and uterine hyperstimulation), mode of delivery, or perinatal outcomes.
CONCLUSION: Tablet moistening with 3% acetic acid solution does not seem to improve the efficacy of intravaginally administered misoprostol for labor induction.
Misoprostol has become one of the most important medications for labor induction in the United States and other parts of the world.1 In 1993, we first reported our experience with intravaginal misoprostol for induction of labor with a viable fetus.2 Since that report, a large number of randomized controlled trials in nearly 6200 women and three meta-analyses have confirmed misoprostol’s safety and efficacy for labor induction.3–5 However, misoprostol’s optimal dose and route of administration remain uncertain.
Although the intravaginal administration of misoprostol tablets at doses of 25 µg and 50 µg have been the dosage forms most commonly used, the reported efficacy with this regimen has varied substantially. A recent meta-analysis showed that the mean interval to vaginal delivery among participants in the reviewed trials ranged from 6.9 to 23.2 hours for patients receiving misoprostol.4
Absorption of vaginally administered misoprostol tablets may vary according to the medium in which it is placed. At the time of repeat dosing, it is quite common to identify variably sized particulate remnants of the tablets.6 Others have also reported this finding of incomplete dissolution of misoprostol tablets in the vagina. A preparation with predictable dissolution characteristics might facilitate development of safer and more effective dosing protocols for vaginal administration of misoprostol in labor induction patients.
Although no pharmacokinetic studies directly address the impact of moistening misoprostol tablets with regard to its absorption, indirect evidence suggests that moistened tablets may enter the circulation more rapidly.7–9 Misoprostol tablets are known to liquefy better in an acidic medium.10 However, a recent study in which misoprostol tablets were moistened with acetic acid did not improve the efficacy in achieving successful cervical dilatation.11
The objective of this randomized controlled trial was to determine whether a 50-µg misoprostol tablet moistened with acetic acid and subsequently introduced into the posterior vaginal fornix is more efficacious than the same dose in dry tablet form.
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MATERIALS AND METHODS |
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Patients were eligible for enrollment if they presented with obstetric or medical indications for labor induction. Additional requirements for enrollment included: absence of active labor or abnormal fetal heart rate (FHR) tracing, unscarred uterus, singleton pregnancy with cephalic presentation, and no contraindications to vaginal delivery. Either a resident or attending physician in obstetrics and gynecology who explained the study protocol along with potential risks and benefits obtained informed consent at presentation for labor induction.
Subjects were assigned to receive moistened or dry misoprostol tablets by means of a computer-generated randomization table. Group allocation was predetermined, and the information was maintained in the research section of the hospital pharmacy. Once a subject was enrolled in the study, the pharmacy forwarded the proper dose of the study drug to the labor and delivery suite. Cervical ripeness (Bishop score) and cervical dilatation were assessed before administration of the study drugs. Each patient received 1/2 of a 100-µg (50-µg) tablet of misoprostol (Cytotec, Pharmacia & Upjohn, Peapack, NJ) inserted digitally into the posterior vaginal fornix. Women randomized to the moistened misoprostol group underwent tablet moistening with 1 mL of nonbuffered 3% acetic acid solution (pH 2.5) before intravaginal insertion. Labor induction was performed on an inpatient basis with continuous electronic fetal monitoring and tocodynamometry. Patients without evidence of regular uterine activity (less than three contractions in 10 minutes) received repeated doses of either moistened or dry misoprostol tablets (50 µg) every 4 hours up to a maximum of six doses (300 µg). Resident physicians under close faculty supervision made decisions regarding amniotomy, analgesia, epidural anesthesia, and oxytocin augmentation. As soon as cervical dilatation permitted, artificial rupture of membranes was performed, and an intrauterine pressure catheter and a scalp electrode were applied. The same intrapartum management guidelines were followed in each group. Repeated doses of misoprostol were not administered during the latent phase of labor if the patient was noted to have at least three uterine contractions in any 10-minute period or at any time during the active phase. Patients in the active phase of labor with arrest of dilatation (no change in cervical dilatation for 2 or more hours at a dilatation of at least 5 cm) received oxytocin augmentation. Oxytocin was started at 1–2 mU/min and was gradually increased in dose increments of 1–2 mU/min at 30-minute intervals as needed. A continuous electronic infusion pump controlled the oxytocin infusion rate.
The FHR and uterine contractility patterns were reviewed by one of the authors (CD) who was unaware of group assignment. Tachysystole was defined as at least six contractions for two consecutive 10-minute periods. Hyperstimulation syndrome was defined as the presence of tachysystole associated with nonreassuring FHR patterns (fetal tachycardia, late decelerations, severe variable decelerations, and/or loss of variability). Recognized episodes of hyperstimulation were managed with maternal repositioning, oxygen administration, subcutaneous terbutaline, and occasionally digital removal of the intravaginal tablet. When feasible, fetal scalp pH sampling was performed in patients with persistent nonreassuring FHR patterns. Physicians managing labor were not blinded to study group allocation.
The primary outcome for this study was the interval from start of induction to vaginal delivery. Secondary outcomes included the proportion of patients who delivered after a single dose, incidence of tachysystole and hyperstimulation, need for oxytocin, vaginal delivery within 24 hours, and mode of delivery. Other outcomes assessed included birth weight, abnormal Apgar scores (less than 7 at 5 minutes), and neonatal intensive care unit admissions.
For the primary outcome, time to vaginal delivery, sample size was estimated using a two-tailed test of significance with 
of 0.05 and ß of 0.20. From our published meta-analysis, the mean start-to-vaginal delivery interval with misoprostol was approximately 15 ± 8.2 hours.3 Eighty-seven patients in each group provided a power of 0.80 to at least detect a 3.5-hour difference between study groups. Statistical analyses were performed with Statview 4.5 statistical software (SAS Institute, Inc., Cary, NC). An unpaired two-tailed Student t test was used to compare continuous data. The Mann-Whitney U test was employed to assess nonparametric data. 
2 analysis or Fisher exact test was used to compare frequency distributions. The senior author (LSR), who performed the statistical analyses, was unaware of group assignment. Throughout all analyses, P < .05 was considered statistically significant.
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RESULTS |
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). The exclusion of ten randomized participants because of favorable cervical examination was in error. None of these subjects received the study drugs. Likewise, the initial inclusion of five women with malpresentation, fetal demise, or previous cesarean represents instances of protocol violations.
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). Likewise, indications for labor induction were similar in both study groups. Pregnancy-induced hypertension and oligohydramnios were the most common obstetric indications for labor induction (Table 2).
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). Likewise, no significant differences were noted for the incidence of tachysystole and hyperstimulation. The mode of delivery pattern was nearly identical in both groups (Table 4). No significant differences were noted for birth weights, abnormal Apgar scores, or the proportion of neonates admitted to the neonatal intensive care unit (Table 5). None of the patients allocated to receive moistened misoprostol tablets reported any adverse side effects.
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DISCUSSION |
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Although the impact of moistening of misoprostol tablets administered intravaginally had not been previously assessed in patients with term intrauterine pregnancies, several trials reported their experience in patients undergoing abortions. Carbonell et al reported an overall success rate of 94% for patients undergoing an abortion at 70 days’ gestation or less.7 In that study, patients received 800 µg of misoprostol vaginally, repeated 48 hours later if needed. The women douched with sterile water the night before misoprostol administration, and the tablets were moistened with water before being inserted vaginally. Creinin et al12 performed a randomized multicenter trial to evaluate if moistened misoprostol tablets resulted in a more rapid abortion and a higher rate of complete abortion compared with dry misoprostol tablets when administered intravaginally for medical abortion after methotrexate. The authors concluded that tablet moistening before vaginal administration did not statistically improve efficacy. Similarly, Jain et al13 noted that the abortion rate with intravaginally administered moistened misoprostol tablets was similar to that with the combination of mifepristone and oral misoprostol. Wiebe9 found that moistened misoprostol tablets at doses of 600 µg and 800 µg appeared more effective for medical termination of early pregnancy than dry tablets. However, in both studies, side effects were more frequent in the group of women receiving moistened tablets.
In a study similar to ours, Singh et al11 performed a randomized double-blind trial to compare the efficacy of tablet moistening in two groups of women undergoing an abortion between 6–12 weeks’ gestation. Women in each group received 200 µg of intravaginally administered misoprostol; tablet moistening with acetic acid in one group was compared with moistening with water in the other group. The authors concluded that the use of acetic acid did not improve the efficacy in achieving successful cervical dilatation for preabortion cervical ripening.
The volume of the moistening agent was similar to that selected by an earlier investigator.13 We used 3% acetic acid as the moistening and acidifying agent because of its acidic pH (2.5), nontoxic properties and availability.
The final number of participants fell slightly below the size estimated in power analysis. However, the obtained sample size afforded 78% power to detect a difference as low as 3.5 hours for the primary outcome (time to vaginal delivery).
Physicians responsible for intrapartum management were not blinded formally to study group allocation. Therefore, differential intrapartum management, including decisions regarding timing of amniotomy, or use of oxytocin augmentation, could have biased our results. Although some physicians making intrapartum management decisions may have been aware of the patient’s study group, few such physicians had direct involvement in the study. Therefore, substantial bias introduced by differential intrapartum management seems unlikely.
Unfortunately, we did not assess vaginal pH or the presence of bacterial vaginosis. Vaginal pH might be an important factor when evaluating the absorption kinetics of intravaginal misoprostol.14 Perhaps use of a larger amount of an acidifying agent may be advantageous in those with an abnormally high preinduction vaginal pH. Further studies investigating the pharmacodynamics and pharmacokinetics of vaginally administered misoprostol are needed.
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Footnotes |
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Received October 22, 2001. Received in revised form February 5, 2002. Accepted February 21, 2002.
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REFERENCES |
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2. Sanchez-Ramos L, Kaunitz AM, Del Valle GO, Delke I, Schroeder PA, Briones DK. Labor induction with the prostaglandin E1 methyl analogue misoprostol versus oxytocin: A randomized trial. Obstet Gynecol 1993;81: 332–6.
3. Sanchez-Ramos L, Kaunitz AM, Wears RL, Delke I, Gaudier FL. Misoprostol for cervical ripening and labor induction: A meta-analysis. Obstet Gynecol 1997;89: 633–42.[Abstract]
4. Sanchez-Ramos L, Kaunitz AM. Misoprostol for cervical ripening and labor induction: A systematic review of the literature. Clin Obstet Gynecol 2000;43:475–88.[Medline]
5. Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev 2001;(2)CD000941.
6. Zieman M, Fong SK, Benowitz NL, Brankster D, Darney PD. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90:88–92.[Abstract]
7. Carbonell JL, Varela L, Velazco A, Fernandez C. The use of misoprostol for termination of early pregnancy. Contraception 1997;55:165–8.[Medline]
8. Carbonell JL, Varela L, Velazco A, Cabezas E, Tanda R, Sanchez C. Vaginal misoprostol for late first trimester abortion. Contraception 1998;57:329–33.[Medline]
9. Wiebe ER. Misoprostol administration in medical abortion: A comparison of three regimens. J Reprod Med 2001;46:125–9.[Medline]
10. Karim A, Rozek LF, Smith ME, Kowalski KG. Effects of food and antacid on oral absorption of misoprostol, a synthetic prostaglandin E1 analog. J Clin Pharmacol 1989; 29:439–43.[Abstract]
11. Singh K, Fong YF, Prasad RNV, Dong F. Does an acidic medium enhance the efficacy of vaginal misoprostol for pre-abortion cervical priming? Hum Reprod 1999;14: 1635–7.
12. Creinin MD, Carbonell JL, Schwartz JL, Varela L, Tanda R. A randomized trial of the effect of moistening misoprostol before vaginal administration when used with methotrexate for abortion. Contraception 1999;59:11–6.[Medline]
13. Jain JK, Meckstroth KR, Mishell DR. Early pregnancy termination with intravaginally administered sodium chloride solution-moistened misoprostol tablets: Historical comparison with mifepristone and oral misoprostol. Am J Obstet Gynecol 1999;181:1386–91.[Medline]
14. Gunalp S, Bildirici I. The effect of vaginal pH on the efficacy of vaginal misoprostol for induction of labor. Acta Obstet Gynecol Scand 2000;79:283–5.[Medline]
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  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]
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