Wolf, Samuel B. DO; Sanchez-Ramos, Luis MD; Kaunitz, Andrew M. MD
Labor induction, when performed on a patient with an unfavorable cervix, is often prolonged and difficult. Failed induction requiring cesarean delivery is common in this setting. Prostaglandin preparations and intravenous oxytocin are the most frequent pharmacologic choices used today for induction.1 Misoprostol, a synthetic analogue of prostaglandin E1, has been widely studied in a variety of dosages and routes of administration as an alternative to oxytocin. Misoprostol offers the advantage of promoting both cervical ripening and myometrial contractility.2 Oxytocin, which acts purely by stimulating uterine activity, is widely accepted as safe and effective, but its success is highly dependent on the condition of the cervix at the onset of induction.
More than 100 randomized, controlled trials have shown misoprostol to be a safe and effective agent for cervical ripening and labor induction in patients with viable pregnancies.2–6 The majority of participants in these trials have received repeated doses of 25 μg to 50 μg of intravaginally administered misoprostol. Recently, several studies assessing orally administered misoprostol for cervical ripening and labor induction have been published (Kwon JS, Mackenzie VP, Davies GA. A comparison of oral and vaginal misoprostol for induction of labor at term: a randomized trial [abstract]. Am J Obstet Gynecol 1999;180:S128; Dyar TR, Greig P, Cummings R, Nichol K. The efficacy and safety of oral versus vaginal misoprostol for the induction of term labor [abstract]. Am J Obstet Gynecol 2000;182:S135).7–17 The majority of participants included in these latter studies have received 50 μg orally every 4 hours. This dose administered orally seems to be as effective as the same dose administered vaginally.
A recently published pharmacokinetic study revealed that, when compared with the oral and vaginal routes, sublingual misoprostol achieved its peak serum concentration in an interval similar to that achieved by the oral route.18 For a given misoprostol dosage and for up to 360 minutes after administration, the area under the curve of misoprostolic acid (the primary, metabolically active metabolite of misoprostol) concentration in the sublingual group was greater than the areas under the curves for orally and vaginally administered misoprostol. Absorption and bioavailability of misoprostol thus seems to be enhanced by the sublingual route.
Benefits of the sublingual route might include less frequent need for vaginal examinations, greater freedom of position in the labor bed, and ease of administration. However, before use of the sublingual route becomes accepted, the most appropriate dosage needs to be determined. In this dose-ranging study, the efficacy of sublingually administered misoprostol at dosages of 50 μg and 100 μg were compared for indicated labor induction.
MATERIALS AND METHODS
The study population was drawn from women admitted to Shands Jacksonville for medically indicated labor induction between June 12, 2002, and December 17, 2003. The study was initiated after approval by the Shands Jacksonville and University of Florida Institutional Review Board. Patients were eligible for enrollment if they presented with obstetric or medical indications for labor induction, including hypertensive disorders of pregnancy, oligohydramnios, premature rupture of membranes, fetal growth restriction, and diabetes mellitus. Additional requirements for enrollment included absence of active labor, a normal fetal heart rate (FHR) tracing, an unfavorable cervix (Bishop score < 6), no prior hysterotomy, a singleton pregnancy in the cephalic presentation, no suspicion of fetal macrosomia, adequate clinical pelvimetry, and no contraindication to vaginal delivery or the use of prostaglandins. Explanation of the study protocol along with its potential risks and benefits was performed by either residents or attending physicians in obstetrics and gynecology. Informed consent was obtained from all participating patients before initial administration of sublingual misoprostol.
By means of a computer-generated randomization table, subjects were assigned to receive repetitive doses of either 100 μg (one half of a 200-μg tablet) or 50 μg (one half of a 100-μg tablet) of sublingual misoprostol (Cytotec, G.D. Searle and Co, Skokie, IL). All tablets were prepared and bubble-packaged by the hospital pharmacy. Although the 50-μg and 100-μg tablets differed in shape, the bisected tablets between the respective groups were relatively indistinguishable. Group allocation was performed by the pharmacy, which alone was aware of which dosage participants had been allocated to. Although clinicians were aware of which treatment arm (eg, Group A or B) participants had been assigned to, they did not know the corresponding dose for either group. Sublingual misoprostol administration was scheduled to be repeated every 4 hours until adequate uterine activity was achieved (at least 3 contractions per 10 minutes). The maximal number of drug applications was 6. Continuous electronic FHR monitoring was performed in all patients. As soon as head engagement and cervical dilation permitted, amniotomy was performed. Intrauterine pressure catheters were applied when indicated to calculate Montevideo units. The labor progress was monitored with the use of the Friedman curve. Subsequent doses of misoprostol were withheld if the patient was noted to still be having at least 3 uterine contractions in any 10-minute period. After reaching the active phase of labor (regular contractions and at least 4 cm of cervical dilation), intravenous oxytocin was administered to participants with arrest or protraction disorders if reassessment indicated a normal FHR and no overt fetopelvic disproportion. 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. Epidural anesthesia or intravenous analgesia was offered to participants in both groups.
The fetal heart rate tracings of each patient were reviewed by the author (S.W.), who was unaware of dosage assignment. Frequency and duration of tachysystole, hypertonus, and hyperstimulation syndrome were assessed. Tachysystole was defined as at least 6 contractions per 10 minutes during 2 consecutive 10-minute periods. Hypertonus was defined as a single uterine contraction lasting 2 minutes or more. Hyperstimulation syndrome was defined as the presence of tachysystole or hypertonus associated with a nonreassuring FHR pattern (fetal tachycardia, late decelerations, severe variable decelerations, or loss of FHR variability). Recognized episodes of hyperstimulation were managed by stopping oxytocin infusion, maternal repositioning, oxygen administration by face mask, subcutaneous terbutaline, and, if the sublingual contents had not been absorbed, removal by mouth washing. All episodes of hyperstimulation syndrome were included in the analysis regardless of the interval from time of misoprostol administration to the occurrence of the abnormal FHR pattern.
The primary outcome measured was the interval from the start of induction to vaginal delivery. Secondary measures of efficacy were the proportion of subjects having a vaginal delivery within 12 and within 24 hours, the number of doses of misoprostol given, the proportion of subjects given oxytocin, and the proportion of failed inductions. Labor induction was considered a failure if a patient did not enter the active phase of labor within 24 hours. Other outcomes assessed included birth weight, abnormal Apgar scores (less than 7 at 5 minutes), neonatal intensive care unit (NICU) admission, presence of meconium, and umbilical arterial pH.
Statistical analyses were performed using StatView 5.1 statistical software (SAS Institute, Inc, Cary, NC). Anticipating a 60% success rate for vaginal delivery within 24 hours for those receiving the 50-μg dosage, and aiming for an 80% success rate with the 100-μg dose, it was estimated that 182 women would need to be enrolled to obtain a power of 80% and a type I error of .05, using a 2-tailed test. Because the study was a safety and efficacy trial, an intention-to-treat analysis was conducted. The means between the groups were compared using an unpaired, 2-tailed Student t test. Fisher exact test and χ2 analysis were used to compare frequency distributions. The distribution of continuous variables was tested for normality by the Kolmogorov-Smirnov test. The Mann-Whitney U test was employed to assess data that were unevenly distributed. Statistical significance in all calculations was defined as a P < .05.
A total of 4,622 patients delivered within the study period. Of the 569 eligible subjects scheduled for labor induction, 212 (37%) consented to and were enrolled in the study (Fig. 1). Nine patients were excluded after randomization secondary to development of more than 3 spontaneous contractions in a 10-minute period (n = 5) or when a Bishop score of 6 or greater was noted subsequent to initial evaluation but before the first misoprostol dose (n = 4). None of these excluded patients received misoprostol. One patient with a history of a prior low transverse cesarean gave consent, received group assignment, and given 50 μg of sublingual misoprostol. Once this protocol violation was identified, the study drug was discontinued; however, by this time the subject was in active labor. The subject subsequently delivered vaginally with no complications and was included in the data analysis.
The distributions of patient age, gestational age, gravidity, nulliparity, race, Bishop score, and cervical dilation were similar in the 2 groups (Table 1). More than 60% of subjects in each group were nulliparous and had a Bishop score less than 4, and more than 85% of subjects in both groups had cervical dilation less than 2 cm on initial examination. Preeclampsia was the most common obstetric indication for induction. The distributions of indications for labor induction were similar for the 2 groups. For study subjects, the overall cesarean rate was 24%.
When considering both vaginal and abdominal delivery, the interval from induction to delivery was significantly shorter in the 100-μg group. The time to delivery remained significantly shorter in the 100-μg group even when vaginal deliveries were analyzed independently. Furthermore, the number of women delivering vaginally in less than 12 and less than 24 hours was significantly higher in the 100-μg group. Additionally, the time to complete cervical dilation, need for oxytocin augmentation, and number of failed inductions was lower in the 100-μg group (Table 2). Among patients who received oxytocin augmentation, subjects assigned to the 100-μg group required a lower total dose of the drug and a shorter duration of administration, both differences statistically significant. The total number of misoprostol doses administered and the number of subjects delivering after a single dose were not significantly different between the 2 groups. Oxytocin was initiated in patients having cervical dilation less than 3 cm significantly more often in the 50-μg group. Differences between the groups with respect to maximum and mean rate of oxytocin administration were not significant (Table 3).
The incidence of tachysystole was more than twice as high in the 100-μg group. However, no significant difference in the incidence of hyperstimulation syndrome or administration of terbutaline was noted between the 2 treatment groups (Table 4). A higher incidence of tetanic contractions (hypertonus without fetal heart rate abnormalities) was noted in the 50-μg group. Misoprostol was discontinued more frequently in the 50-μg group, most often due to a physician management decision to start oxytocin. Finally, there were no statistically significant differences seen for maternal complications, incidence of abnormal FHR, mode of delivery, birth weight, or perinatal outcomes (Tables 2, 4, and 5).
There were 11 cases of hyperstimulation syndrome in the 100-μg group and 8 cases in the 50-μg group. Fourteen of these cases occurred within 6 hours of misoprostol administration; of these, 9 occurred within the first hour. Of the 5 participants who developed hyperstimulation more than 6 hours after misoprostol administration, 4 were preterm and all were receiving oxytocin augmentation in the active phase of labor at the time of the adverse event.
Six of the 19 cases of hyperstimulation syndrome involved subjects with pregnancies less than 37 weeks gestation (3 in each treatment group). Four participants in this subset were participants who had hyperstimulation syndrome more than 6 hours after misoprostol administration. Two of these preterm infants, (both in the 50-μg group) were admitted to the NICU. The first, induced for maternal chronic hypertension with superimposed preeclampsia, was born at 33–34 weeks gestation with a birth weight of 1,561 g, and admitted for neonatal respiratory distress syndrome. The other infant, also born at 33–34 weeks gestation with a birth weight of 1,239 grams induced for intrauterine growth restriction, was admitted due to respiratory acidosis (cord pH 7.11). Induction indications for the other 4 participants with preterm gestations were preeclampsia (n = 2), and nonreassuring fetal testing (n = 2).
Most of the studies assessing the effectiveness of sublingual misoprostol have involved use of this prostaglandin as an abortifacient. Tang and colleagues18 performed a pharmacokinetic study that clearly showed higher peak plasma concentrations of sublingually administered misoprostol when compared with the same dosage administered orally, vaginally, or vaginally with water. They later performed a pilot study followed by a prospective randomized trial that compared equal dosages of 600 μg administered vaginally and sublingually in the management of missed abortion and found no statistically significant pharmacokinetic differences between the routes. Ease of administration was noted to be higher in the sublingual group.19,20 In a study design similar to ours, Shetty and colleagues16 found that significantly more women delivered within 24 hours when 50 μg of misoprostol was administered sublingually as opposed to orally. They followed this with a randomized study that showed no significant difference in efficacy between a 50-μg sublingual dosage and a 100-μg oral dosage.17 This trial compares these 2 dosages administered by the sublingual route and demonstrates a substantially greater efficacy with the higher dose.
In this study, misoprostol was discontinued almost twice as frequently in the 50-μg group. Many of these study drug discontinuations occurred when contractions were too frequent to administer another misoprostol dose in patients with no significant change in cervical dilation and were usually due to physician impatience. In many of these instances, a Foley catheter was placed into the cervix with traction applied and oxytocin initiated. A subanalysis was performed on the data removing all participants in whom misoprostol discontinuation due to “physician choice” occurred, which did not affect the statistical significance of the primary or secondary outcome variables.
Overall, rates of hyperstimulation syndrome were higher (9%) in this study than in other clinical trials of sublingual misoprostol for labor induction.16,17 In Shetty's study comparing sublingual (n = 42) with oral (n = 35) administration of 50 μg misoprostol, only 1 case of hyperstimulation syndrome was observed; this was in the sublingual group. In Shetty's second trial, which compared 50 μg of sublingual with 100 μg of oral misoprostol (n = 250), the incidence of hyperstimulation syndrome was 1.6% in each group. Variable definitions as well as diverse approaches to labor management might account for these substantial differences in reported rates of hyperstimulation syndrome. In our study, 5 of the 19 episodes of hyperstimulation syndrome occurred 6 hours or more after administration of the last dose of misoprostol. In contrast, the timing of the occurrence of hyperstimulation syndrome with respect to misoprostol administration was not reported by Shetty. Furthermore, neither of Shetty's trials enrolled subjects less than 37 weeks of gestation. Six of the 19 cases of hyperstimulation syndrome in this study occurred in participants less than 37 weeks of gestation.
Despite the higher incidence of uterine hyperstimulation in our study, the incidence of adverse perinatal and maternal outcomes was similar to rates observed in both studies by Shetty. Specifically, no infants born to subjects allocated to the 100-μg misoprostol group had low Apgar scores at 5 minutes or were admitted to the NICU. Almost one half of the cases of hyperstimulation occurred in the first hour after drug administration (n = 9). Therefore, increased surveillance might be warranted due to the need for added nursing intervention during this time period.
This trial adds to the substantial literature confirming that misoprostol is a highly effective pharmacologic agent for labor induction. This trial's findings indicate that the higher (100-μg) dose is more effective. Patterns of practice should not be implemented on the basis of 1 randomized trial; however, future studies of the sublingual route of administration of misoprostol for labor induction should include a 100-μg arm.
1. American College of Obstetricians and Gynecologists. Induction and augmentation of labor. ACOG Technical Bulletin No. 217. Washington, DC: ACOG; 1995.
2. 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.
3. Li XM, Wan J, Xu CF, Zhang Y, Fang L, Shi ZJ, Li K. Misoprostol in labour induction of term pregnancy: a meta-analysis. Chin Med J (Engl) 2004;117:449–52.
4. Hofmeyr GJ, Gulmezoglu AM. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Reviews 2, 2004;CD00075320.
5. Hofmeyr GJ, Gulmezoglu Am, Alfirevic Z. Misoprostol for induction of labor: a systematic review. Br J Obstet Gynaecol 1999;106:798–803.
6. Sanchez-Ramos L, Kaunitz AM, Delke I. Labor induction of 25 microg versus 50 microg intravaginal misoprostol: a systematic review. Obstet Gynecol 2002;99:145–51.
7. Fisher SA, Mackenzie VP, Davies GAL. Oral versus vaginal misoprostol for induction of labor: a double-blind randomized controlled trial. Am J Obstet Gynecol 2001;185:906–10.
8. Shetty A, Danielian P, Templeton A. A comparison of oral and vaginal misoprostol tablets in induction of labour at term. BJOG 2001;108:238–43.
9. Wing DA, Park MR, Paul RH. A randomized comparison of oral and intravaginal misoprostol for labor induction. Obstet Gynecol 2000;95:905–8.
10. Windrim R, Bennett K, Mundle W, Young DC. Oral administration of misoprostol for labor induction: a randomized controlled trial. Obstet Gynecol 1997;89:392–7.
11. 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.
12. Butt KD, Bennett KA, Crane JM, Hutchen D, Young DC. Randomized comparison of oral misoprostol and oxytocin for labor induction in term prelabor membrane rupture. Obstet Gynecol 1999;94:994–9.
13. Bennett KA, Butt K, Crane JM, Hutchens D, Young DC. A masked randomized comparison of oral and vaginal administration of misoprostol for labor induction. Obstet Gynecol 1998;92:481–6.
14. Adair CD, 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.
15. Danielsson KG, Marions L, Rodriguez A, Spur BW, Wong PY, Bydgeman M. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol 1999;93:275–80.
16. Shetty A, Danielian P, Templeton A. Sublingual misoprostol for the induction of labor at term. Am J Obstet Gynecol 2002;186:72–6.
17. Shetty A, Mackie L, Danielian P, Rice P, Templeton A. Sublingual compared with oral misoprostol in term labour induction: a randomised controlled trial. BJOG 2002;109:645–50.
18. Tang OS, Ho PC. Pharmacokinetics of different routes of administration of misoprostol. Hum Reprod 2002;17:332–6.
19. Tang OS, Ho PC. Pilot study on the use of sublingual misoprostol for medical abortion. Contraception 2001;64:315–7.
20. Tang OS, Lau WN, Ng EH, Lee SW, Ho PC. A prospective randomized study to compare the use of repeated doses of vaginal with sublingual misoprostol in the management of first trimester silent miscarriages. Hum Reprod 2003;18:176–81.
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