Obstetrics & Gynecology Email Alerts
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Obstetrics & Gynecology 2001;98:107-112
© 2001 by The American College of Obstetricians and Gynecologists
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Carlan, S. J.
Right arrow Articles by O’Brien, W. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Carlan, S. J.
Right arrow Articles by O’Brien, W. F.

ORIGINAL RESEARCH

Safety and Efficacy of Misoprostol Orally and Vaginally: A Randomized Trial

S. J. Carlan, MD, Sheila Bouldin, MD, RPh, Danielle Blust, MD and William F. O’Brien, MD

From the Department of Obstetrics and Gynecology, Arnold Palmer Hospital for Children and Women, Orlando, Florida; and Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida.

Address reprint requests to: S. J. Carlan, MD, Department of Obstetrics and Gynecology, Orlando Regional Healthcare System, 105 West Miller Street, Orlando, FL 32806; E-mail: scarlan{at}orhs.org


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To compare the safety and efficacy accompanying oral and vaginal misoprostol for cervical ripening.

METHODS: One thousand four women with medical or obstetric indications for labor induction and unripe cervices were randomly assigned to receive oral or vaginal misoprostol. Initial doses of 200 µg oral and 50 µg vaginal misoprostol were increased to 300 µg oral and 100 µg vaginal after two doses, to a maximum of six doses. Misoprostol was given every 6 hours in both groups. We anticipated that 11% of women treated vaginally would require intervention during the ripening process. Intervention was defined as interruption of the ripening process before labor or Bishop score of 7 or a lack of response to six misoprostol doses.

RESULTS: Five hundred three subjects were assigned to oral and 501 to vaginal administration. Oral misoprostol was associated with significantly higher frequencies of intervention (67 [13.3%] versus 42 [8.4%], P = .01), tachysystole (114 [23.6%] versus 85 [17.6%], P = .02), and hyper-stimulation (90 [18.6%] versus 66 [13.7%], P = .04). There were no significant differences in cesarean rates (147 [29.2%] versus 120 [24.0%], P = .06), mean number of misoprostol doses used (1.5 versus 1.6, P = .18), or hours from drug administration to delivery (24.5 versus 25.4, P = .77) between the oral and vaginal groups, respectively. The numbers of deliveries between the groups within 24 hours was different (271 [56%] versus 290 [60%], P = .02), oral and vaginal, respectively. No adverse neonatal outcomes were noted.

CONCLUSION: Oral misoprostol has similar efficacy as vaginal misoprostol but is associated with a higher frequency of excessive uterine contractility and intervention.

Approximately one in six pregnancies exceeding 24 weeks’ gestation in the United States ends with labor induction.1 Attempted induction despite an unripe cervix is challenging and often results in failure.2 Although many methods3,4 of preinduction cervical ripening have been proposed, prostaglandins are the current agents of choice. Misoprostol (Cytotec, G.D. Searle Co., Chicago, IL) is an inexpensive synthetic prostaglandin E1 analogue,5 which is readily absorbed and has potent uterotonic properties when administered either vaginally or orally.6,7 Vaginal misoprostol has been studied extensively and is established as an effective method of preinduction cervical ripening.8–10 Oral administration has obvious appeal but has been studied less extensively. The systemic bioavailability of orally administered misoprostol is one-third that of vaginal misoprostol,7,11 thus, higher doses are required. The reports on oral misoprostol suggest as doses are raised and dosing intervals shortened, the efficacy significantly improves. With improved efficacy, however, comes a higher chance of excessive uterine activity that may require immediate intervention to prevent fetal asphyxia.12,13 Although misoprostol has been shown to be highly effective in most studies, safety remains a major concern. The purpose of this study is to evaluate the safety and efficacy of oral misoprostol compared to vaginal administration.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study population consisted of 1004 women admitted to Arnold Palmer Hospital for medically indicated labor inductions between May 1997 and November 1999. Approval was obtained from the Orlando Regional Investigational Review Committee; candidates had a singleton live gestation, Bishop score2 under 7, estimated fetal weight under 4500 g, and gestational age exceeding 24 weeks. Exclusion criteria included vaginal bleeding, nonreassuring fetal heart rate, breech, uterine contractions at a frequency of least four in a 20-minute period, labor, or a contraindication to vaginal birth.

Cervical ripening was performed in the antepartum unit adjacent to the labor suite, and continuous fetal heart rate and uterine activity were monitored in all patients. Bishop scores were assigned by admitting physicians. Sonography was performed to document fetal presentation, weight, and amniotic fluid volume. Episodes of excessive uterine activity were managed with a standard combination of maneuvers including change in maternal position, oxygen administration, and terbutaline 250 µg given subcutaneously. Persistent abnormal fetal heart rate patterns resulted in intervention by removing the patient from the study and transferring her to the labor suite. An urgent cesarean delivery was defined as a cesarean performed during the ripening process for abnormal fetal heart rate that did not respond to standard maneuvers.

Intervention was defined as interruption of the ripening process for any reason before either labor or a Bishop score of 7, or a lack of response to six misoprostol doses. Success was defined as either onset of labor or a postcervical ripening Bishop score of at least 7 with no intervention within six misoprostol doses. Active labor was defined as regular uterine contractions every 2–3 minutes with cervical change. Abnormal fetal heart rate patterns were defined as the presence of either fetal tachycardia, bradycardia, late decelerations, or a moderate to severe deceleration of fetal heart rate.11 Physician preference to intervene was defined as patient removal from the study based solely on the attending physician’s decision. Twenty-minute tachysystole was defined as at least six contractions in 10 minutes for two consecutive 10-minute periods,8 and hypersystole as a single contraction with a duration of at least 2 minutes.14 Hyperstimulation was defined as either tachysystole or hypersystole associated with an abnormal fetal heart rate pattern. Intrapartum fetal heart rate patterns were classified according to Kubli et al.15

Computer randomization was performed, and a series of consecutively numbered opaque envelopes was generated in blocks of 50 with equal numbers of oral and vaginal assignments. As each subject gave consent for the study, the next envelope was opened. The medication regimens could be re-administered every 6 hours for a total of six doses. In the oral group, after the first two doses of 200 µg, the dose was increased to 300 µg for the duration of the study (up to a total of 1600 µg). In the vaginal group, after the first two doses of 50 µg, the dose was increased to 100 µg for the duration of the study (up to a total of 500 µg). The 200-µg oral dose was given as a single tablet with water.

Subsequent 300-µg doses were given as a single 200-µg and a single 100-µg pill together. A small snack was given before each oral dose. A standard method of preparation and insertion of vaginal misoprostol was used.10 In women who had not entered labor, the entire procedure (without ultrasound) was repeated. The subjects received misoprostol serially until the Bishop score was at least 7, labor occurred, intervention was required, or a total of 1600 µg in the oral group and 500 µg in the vaginal group was used, at which point the study was considered complete. Those patients still in the study after six doses were deemed failures and managed at the discretion of the attending obstetrician. Induction and augmentation of labor with oxytocin were performed according to ACOG guidelines.16

All randomized subjects were included in the statistical analysis. The primary outcome measure was the incidence of intervention. Secondary outcome measures included rates of tachysystole and hyperstimulation. The entry and outcome data were analyzed using SPSS-PC+ (Statistical Package for the Social Sciences, Chicago, IL) programs by {chi}2 and t test for unequal variances when appropriate. Analysis was performed on an intention-to-treat basis except where indicated. The Mann-Whitney U test was used for nonparametric assessment of two independent samples. We estimated that at least 483 subjects would be required in each group to have an 80% power to detect a 50% increase in intervention from 11% in the vaginal group10 to 17.5% in the oral group assuming alpha = .05.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
One thousand four patients were enrolled, 503 in the oral and 501 in the vaginal group (Figure 1Go). Thirty-seven patients did not receive their assigned medication with the most common reason being onset of labor between randomization and application of medication. The oral and vaginal misoprostol groups were comparable in all measured demographic and obstetric variables (Table 1Go). The reasons for ripening and induction were similar between the groups (Table 2Go). Sixty-seven (13.3%) and 42 (8.4%) women in the oral and vaginal groups, respectively, had intervention before labor or Bishop score of 7 (P = .01, {chi}2). There was significantly more intervention in the oral group for abnormal fetal heart rate patterns (Table 3Go).



View larger version (22K):
[in this window]
[in a new window]
  		Figure 1. Flow of patients through the protocol.

Carlan. Oral Misoprostol. Obstet Gynecol 2001.

 

View this table:
[in this window]
[in a new window]
  		Table 1. Demographics and Obstetric Variables
 

View this table:
[in this window]
[in a new window]
  		Table 2. Indication for Delivery
 

View this table:
[in this window]
[in a new window]
  		Table 3. Reasons for Intervention
 
Twenty-seven of the patients (14 oral [2.8%] and 13 vaginal [2.6%]) required urgent cesarean deliveries during the ripening process for abnormal fetal heart rate with and without documented excessive uterine contractility (P = .85, {chi}2). All but three of these women had received only a single dose of misoprostol at the time of their abnormal fetal heart rate tracing. The mean (± standard deviation) number of misoprostol doses was 1.5 ± 1 versus 1.6 ± 1 in the oral and vaginal groups, respectively ([-.04, .21], P = .18, Student t test). Two hundred seventy-one (56%) and 290 (60%) of the oral and vaginal groups, respectively, delivered within 24 hours of first dose (P = .20, {chi}2). Outcomes during ripening were different between the groups (Table 4Go). In patients who received medication, the labor chronology was not different between the groups (Table 5Go).


View this table:
[in this window]
[in a new window]
  		Table 4. Outcomes During Ripening*
 

View this table:
[in this window]
[in a new window]
  		Table 5. Labor Chronology
 
Labor and delivery variables are shown in Table 6Go. The indications for cesarean delivery were similar between the groups, the most frequent indication being fetal distress in 70 (14%) and 58 (12%) oral versus vaginal, respectively (P = .27, {chi}2). There was one failed ripening in each group. Table 7Go compares the complications that occurred during labor and neonatal outcomes. There were no uterine ruptures.


View this table:
[in this window]
[in a new window]
  		Table 6. Labor and Delivery Variables
 

View this table:
[in this window]
[in a new window]
  		Table 7. Intrapartum Complications and Neonatal Outcome
 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Previous randomized studies investigating oral misoprostol for cervical ripening have evaluated different doses, dosing intervals, and controls. The maximum single dose studied has been 50 µg,11,17–19 100 µg,20–22 and 200 µg.23–26 The maximum total dose and dosing intervals varied widely. All had as the primary outcome variable a measure of efficacy and each concluded that oral misoprostol was effective. All investigations mentioned safety and complications but, with isolated exceptions,23 there was little information regarding intervention during the ripening process.

The two studies with the highest reported tachysystole rates used sequential oral misoprostol in starting doses of 100 µg21 and 200 µg25 and recorded rates of 33% and 38.7% of tachysystole, respectively, in the oral group. Our lower rate of 23.6% may reflect our study design requiring that patients eat before taking the pill.27 To further evaluate excessive uterine contractility, we collected the number of patients who had six or more contractions in a 10-minute window,17 and found another 66 (13.6%) and 64 (13.3%) of the oral and vaginal groups, respectively, who met this criteria (P = .86, {chi}2).

Our hyperstimulation rate for both oral and vaginal administration was 18.6% and 13.7%, respectively, which was also lower than Adair et al’s.25 They recorded a hyperstimulation rate for oral administration of 44% and a vaginal rate of 18%, but their definition included patients who received terbutaline. Ngai et al21 had 0% hyperstimulation using 100 µg orally, and Bartha et al26 reported a hyperstimulation rate of 6% after a single 200-µg dose orally. When we investigated abnormal fetal heart rate tracings in our patients that were not associated with documented excessive uterine activity, we found another 17 (3.4%) and 23 (4.6%) of oral and vaginal patients, respectively, who developed nonreassuring tracings sometime during the ripening period (P = .33, {chi}2). This finding may simply reflect difficulty in sustaining tocodynamometry in some patients but, considering the known rapid and predictable increase in uterine tone,6 this finding is not surprising. Why there should be such a wide variation in reported tachysystole and hyperstimulation may also be a reflection of study design, patient population, or even the fact that classification of excessive uterine contractions and abnormal fetal heart rate during ripening is highly subjective.17

One item that has not been systematically reported before but may be an effective marker of safety is intervention required during the ripening process. We found a high incidence of intervention in both oral and vaginal groups. Nonreasurring fetal heart rate patterns was the most common reason for intervention, and in both groups the median number of misoprostol that had been used at the time of intervention was 1 (P = .70, Mann-Whitney U). The median hours to develop the abnormal fetal heart rate tracing that led to removing the patient from the study, however, was surprisingly long (9.5 versus 8.5) in the oral and vaginal, respectively (P = .87, Mann-Whitney U). This illustrates the potent and persistent effects misoprostol has on myometrial activity at these doses.

Ngai et al23 noted one of his patients underwent an emergency cesarean delivery for late decelerations after 15 minutes from taking an oral 200-µg dose. Windrim et al20 and Wing et al22 noted specifically none of their patients required cesarean for abnormal fetal heart rate tracing in the ripening period. We noted a total of 27 (2.8%) of patients who received misoprostol underwent an urgent cesarean delivery during the ripening procedure. Each patient underwent the established standard maneuvers to relieve the abnormal fetal heart rate tracing before proceeding to the cesarean. The primary indication for cesarean in all of these cases was an abnormal fetal heart rate pattern, and all except three had the cesarean after the first misoprostol administration.

Our data agree with other publications suggesting that oral misoprostol is effective for cervical ripening, and neonatal outcomes do not differ11,17–22,25,26 between oral misoprostol and control groups.

At the doses used in this protocol, the incidence of intervention, abnormal contraction patterns, and urgent cesarean is high. We conclude that the doses suggested by Wing et al22 (100 µg orally and 25 µg vaginally) appear to offer the best in both efficacy and safety. We also acknowledge the potential for bias because our study design did not require blinding of the investigator. However, the use of strict study and labor and delivery protocols should have reduced any bias to a minimum.


   Footnotes
 
PII S0029-7844(01)01369-2

Received November 1, 2000. Received in revised form January 3, 2001. Accepted February 8, 2001.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Ventura SJ, Martin JA, Curtin SC, Mathews TJ. Births: Final data for 1997. National Center for Health Statistics. National Vital Statistics Reports, 1999;47:1–96.

2. Bishop EH. Pelvic scoring for elective induction of labor. Obstet Gynecol 1964;24:266–8.[Free Full Text]

3. Sanchez-Ramos L, Kaldnitz AM, Conner P. Hydroscopic cervical dilatation of the cervix. A comparison with PGE2 gel. J Reprod Med 1992;37:355–9.[Medline]

4. Xenakis EM-J, Piper JM, Conway DL, Langer O. Induction of labor in the nineties: Conquering the unfavorable cervix. Obstet Gynecol 1997;90:235–9.[Abstract]

5. Garris RE, Kirkwood CF. Misoprostol: A prostaglandin E1 analogue. Clin Pharm 1989;8:627–44.[Medline]

6. Danielsson KG, Marions L, Rodriguez A, Spur BW, Wong PYK, Bygdeman M. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol 1999;93:275–80.[Abstract/Free Full Text]

7. Zieman M, Fong SK, Benowitz NL, Bankster D, Darney PD. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90:88–92.[Abstract]

8. Sanchez-Ramos L, Kaunitz AM, Del Valle GO, Delke I, Schroeder PA, Brones DK. Labor induction with a prostaglandin E1 methyl analogue misoprostol versus oxytocin: A randomized trial. Obstet Gynecol 1993;81:332–6.[Abstract/Free Full Text]

9. 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]

10. Carlan SJ, Bouldin S, O’Brien WF. Extemporaneous preparation of misoprostol gel for cervical ripening: A randomized trial. Obstet Gynecol 1997;90:911–5.[Abstract]

11. Wing DA, Hamm D, Paul RH. A comparison of orally administered misoprostol with vaginally administered misoprostol for cervical ripening and labor induction. Obstet Gynecol 1999;180:1155–60.

12. Curtis P, Evans S, Resnick J. Uterine hyperstimulation: The need for standard terminology. J Reprod Med 1987; 32:91–5.[Medline]

13. Wing DA, Paul RH. A comparison of different dosing regimens of vaginally administered misoprostol for preinduction cervical ripening and labor induction. Am J Obstet Gynecol 1996;175:158–64.[Medline]

14. Weingold AB, DeJesus TPS, O’Keiffe J. Oxytocin challenge test. Am J Obstet Gynecol 1975;123:460–72.

15. Kubli FW, Hon EH, Khazin AF, Takemura H. Observations on heart rate on pH in human fetus during labor. Am J Obstet Gynecol 1969;104:1190–206.[Medline]

16. American College of Obstetricians and Gynecologists. Induction of labor. ACOG technical bulletin no. 217. Washington DC: American College of Obstetricians and Gynecologists, 1995.

17. Bennett KA, Butt K, Crane JMG, Hutchens D, Young DC. A masked randomized comparison of oral and vaginal administration of misoprostol for labor induction. Obstet Gynecol 1998;92:481–6.[Abstract]

18. Abramovici D, Goldwasser S, Mabie BC, Mercer BM, Goldwasser R, Sibai BM. A randomized comparison of oral misoprostol versus Foley catheter and oxytocin for induction of labor at term. Am J Obstet Gynecol 1999;181: 1108–12.[Medline]

19. Butt KD, Bennett KA, Crane JMG, Hutchens D, Young DC. Randomized comparison of oral misoprostol and oxytocin for labor induction in term prelabor membrane rupture. Obstet Gynecol 1999;94:994–9.[Abstract/Free Full Text]

20. Windrim R, Bennett K, Mundle W, Young D. Oral administration of misoprostol for labor induction: A randomized control trial. Obstet Gynecol 1997;89:392–7.[Abstract]

21. Ngai SW, Chan YM, Lam SW, Lao TT. Labor characteristics and uterine activity: Misoprostol compared with oxytocin in women at term with prelabor rupture of the membranes. Br J Obstet Gynecol 2000;107:222–7.

22. Wing DA, Park MR, Paul RH. A randomized comparison of oral and intravaginal misoprostol for labor induction. Obstet Gynecol 2000;95:905–8.[Abstract/Free Full Text]

23. Ngai SW, To WK, Lao T, Ho PC. Cervical priming with oral misoprostol in prelabor rupture of membranes at term. Obstet Gynecol 1996;87:923–6.[Abstract]

24. Toppozada MK, Anwar MY, Hassan HA, el-Gazaerly WS. Oral or vaginal misoprostol for induction of labor. Int J Gynecol Obstet 1997;56:135–9.[Medline]

25. Adair DC, Weeks JW, Barrilleaux S, Edwards M, Burlison K, Lewis DF. Oral or vaginal misoprostol administration for induction of labor: A randomized, double-blind trial. Obstet Gynecol 1998;92:810–3.[Abstract]

26. Bartha JL, Comino-Delgado R, Garcia-Benasach F, Martinez-Del-Fresno P, Moreno-Corral LJ. Oral misoprostol and intracervical dinoprostone for cervical ripening and labor induction: A randomized comparison. Obstet Gynecol 2000;96:465–9.[Abstract/Free Full Text]

27. Benet LZ, Kroetz DL, Sheiner LB. Pharmacokinetics: The dynamics of drug absorption, distribution, and elimination. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, eds. Goodman and Gilman’s the pharmacologic basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996:3–29.




This article has been cited by other articles:


Home page
 Obstet GynecolHome page
R. Hall, M. Duarte-Gardea, and F. Harlass
Oral Versus Vaginal Misoprostol for Labor Induction
Obstet. Gynecol., June 1, 2002; 99(6): 1044 - 1048.
[Abstract] [Full Text] [PDF]

Home page
 Obstet GynecolHome page
J. M. Crane, D. Young, K. Butt, M. Delaney, D. Hutchens, and S. J. Carlan
Safety and Efficacy of Misoprostol Orally and Vaginally: A Randomized Trial
Obstet. Gynecol., November 1, 2001; 98(5): 875 - 876.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Carlan, S. J.
Right arrow Articles by O’Brien, W. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Carlan, S. J.
Right arrow Articles by O’Brien, W. F.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS