Carbone, Jeanine F. MD; Tuuli, Methodius G. MD, MPH; Fogertey, Patricia J. RN, MSN; Roehl, Kimberly A. MPH; Macones, George A. MD, MSCE
OBJECTIVE: To test the hypothesis that use of the Foley bulb plus vaginal misoprostol will result in shorter induction-to-delivery time compared with vaginal misoprostol alone.
METHODS: We randomized 123 women undergoing induction of labor with singleton pregnancies at 24 weeks of gestation or greater with an unfavorable cervix (Bishop score 6 or lower) to Foley bulb plus vaginal misoprostol (n=56) or vaginal misoprostol alone (n=61). Women with fetal malpresentation, multifetal gestation, spontaneous labor, contraindication to prostaglandins, nonreassuring fetal heart rate tracing, intrauterine growth restriction, anomalous fetus, fetal demise, or previous cesarean delivery or other significant uterine surgery were excluded. The primary outcome measure was induction-to-delivery time. Secondary outcomes were mode of delivery, tachysystole with fetal decelerations, terbutaline use, postpartum hemorrhage, chorioamnionitis, neonatal Apgar scores, and neonatal intensive care unit admission. Analysis followed the intention-to-treat principle.
RESULTS: The mean induction-to-delivery time was shorter with the combination of the Foley bulb and vaginal misoprostol when compared with vaginal misoprostol alone (15.3±6.5 compared with 18.3±8.7 hours, difference −3.1 hours, 95% confidence interval [CI] −5.9 to −0.30). The combination also resulted in shorter induction to complete cervical dilation time (13.7±5.9 compared with 17.1±8.7 hours, difference −3.5 hours, 95% CI −6.7 to −0.4). There were no differences in labor complications or adverse neonatal and maternal outcomes.
CONCLUSION: A combination of the Foley bulb and vaginal misoprostol resulted in a shorter induction-to-delivery time when compared with vaginal misoprostol alone without increasing labor complications.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01279343.
LEVEL OF EVIDENCE: I
The rate of induction of labor in the United States has more than doubled over the last 20 years. In 2009, 23.2% of all gravid women underwent induction of labor for various indications.1 The goal of induction of labor is to achieve vaginal delivery in a safe and timely manner. It is estimated that currently the rate of labor induction in the United States is even higher. There are many proposed methods for induction of labor including mechanical (supracervical Foley bulb, laminaria tents) and chemical methods (synthetic prostaglandins, oxytocin). These methods can be used alone but are most often used in combination with each other.
A number of randomized trials have compared the use of the Foley bulb, oxytocin, and misoprostol in different combinations for induction of labor and their results are contradictory with regard to induction to delivery time, successful vaginal delivery, and labor complications.2–5 Two randomized trials compared vaginal misoprostol with the Foley bulb compared with vaginal misoprostol plus the Foley bulb. Both trials found no difference in the induction-to-delivery time.6,7 Thus, although the best agent and method for induction of labor remains uncertain, it is biologically plausible that a combination of a mechanical device (Foley bulb) and chemical agent (synthetic prostaglandin) may have an additive or synergistic effect, resulting in a greater degree of cervical ripening and shorter induction-to-delivery time. The addition of a synthetic prostaglandin to the Foley bulb may also overcome the frequent observation of cervical dilation with the Foley bulb without significant effacement.
The objective of this study was to compare the efficacy of a combination of the Foley bulb and vaginal misoprostol with vaginal misoprostol alone for labor induction. We hypothesized that use of the Foley bulb plus vaginal misoprostol will result in shorter induction-to-delivery time.
MATERIALS AND METHODS
This was a randomized clinical trial comparing the efficacy of vaginal misoprostol plus a Foley bulb with vaginal misoprostol alone for induction of labor. The study was approved by the Washington University Human Research Protection Office and was registered with the clinical trials registry (ClinicalTrials.gov #NCT01279343). Women with a singleton, viable gestation (24 weeks of gestation or greater), cephalic presenting fetus, intact membranes, and an unfavorable cervix (Bishop's score 6 or less) presenting to our labor and delivery unit for labor induction from January 6, 2011, to April 30, 2012, were evaluated for participation. Women were excluded if any of the following criteria were encountered: fetal malpresentation, multifetal gestation, spontaneous labor (regular uterine contractions with cervical change), more than five uterine contractions in 10 minutes, contraindication to prostaglandins, a Category II or greater fetal heart rate tracing, fetal growth restriction (defined as estimated fetal weight less than the 10th percentile for gestational age on the Hadlock growth standard), anomalous fetus, fetal demise, or previous cesarean delivery or other uterine surgery (myomectomy, cornual wedge resection). Eligible patients were approached by a research nurse or other members of the research team for consent to participate in the study if inclusion criteria had been met.
Randomization was achieved by computer-generated random sequences. On enrollment, an opaque envelope was opened containing the participant's enrollment number and assignment to either the Foley plus vaginal misoprostol or vaginal misoprostol alone. Women in the misoprostol-only group received 25 micrograms of misoprostol per vagina every 4 hours. Once the cervix became favorable (Bishop's score greater than 6) or the patient was in active labor, misoprostol administration was discontinued. Further management of labor was at the discretion of the labor team with expectant management, amniotomy, or intravenous (IV) oxytocin per protocol. If indicated, IV oxytocin was started per standard protocol after 4 hours from the last misoprostol dose. Oxytocin was administered per standard protocol starting at 2 milliunits/min increasing by 2 milliunits every 20 minutes until regular uterine contractions occur.
Women in the combination group received vaginal misoprostol per standard protocol at 25 micrograms every 4 hours. In addition, a Foley bulb was inserted digitally or by direct visualization with the aid of a sterile speculum. The Foley was inserted through the internal cervical os, filled with 60 mL of normal saline, and then pulled snugly against the internal os. The catheter of the Foley bulb was taped to the patient's inner thigh under gentle traction. If the Foley bulb was unable to be placed, the patient was examined every 4 hours and Foley bulb placement was reattempted if Bishop's score was still 6 or less. When the Foley bulb had fallen out, further management of labor was at the discretion of the labor team and included expectant management, amniotomy, or IV oxytocin. If indicated, IV oxytocin was started per standard protocol after 4 hours from the last misoprostol dose. Oxytocin was administered per standard protocol starting at 2 milliunits/min increasing by 2 milliunits every 20 minutes until regular uterine contractions occur. Other aspects of labor management were similar for both groups, including continuous electronic fetal monitoring with either external Doppler device or fetal scalp electrode. Uterine contraction assessment was performed with either an external tocodynamometer or an internal pressure catheter. Amniotomy was performed when feasible at the discretion of the health care provider.
Participant data including demographic characteristics, medical and pregnancy history, labor course, and outcomes were collected by a dedicated research nurse. Each indication for labor induction was documented. Postdate induction was defined as a pregnancy being induced for being past the estimated date of confinement (greater than 40 weeks of gestation). After each delivery, the fetal heart rate tracing was carefully reviewed for the presence of tachysystole (greater than five uterine contractions in 10 minutes) with subsequent decelerations requiring terbutaline or cessation of oxytocin infusion.
An independent three-member data safety and monitoring board conducted one planned interim analysis after half of the patients were enrolled with induction-to-delivery time as the primary outcome of interest. None of the investigators were involved in the interim analysis. The significance level for the interim analysis was calculated using the Haybittle-Peto stopping boundaries.8
The primary outcome measure was induction-to-delivery time. Secondary outcomes were mode of delivery, tachysystole (defined as greater than five uterine contractions in 5 minutes) with fetal heart rate decelerations requiring terbutaline use, postpartum hemorrhage (defined as estimated blood loss greater than 500 mL for vaginal delivery or greater than 1,000 mL for cesarean delivery), chorioamnionitis, neonatal Apgar scores, and neonatal intensive care unit admission.
The sample size was estimated a priori based on the primary outcome. We assumed a mean induction-to-delivery time of 17.0±7.8 hours with vaginal misoprostol based on previously published data.9 We estimated that 122 women would be needed for 80% to detect a 4-hour difference in mean induction-to-delivery time between the two groups using a two-tailed t test and α of 0.05.
Analysis was based on the intent-to-treat principle; participants were analyzed in the groups to which they were randomized whether or not they received the assigned intervention. Selected baseline characteristics and outcome measures were compared using the independent t test for continuous variables and the χ2 test or Fisher’s exact test for categorical variables as appropriate. The mean induction-to-delivery times in the two groups were compared using the independent t test. Induction-to-delivery time was also analyzed using Kaplan-Meier survival analysis. Survival functions of the two groups were compared using the log-rank test. Analyses were performed using STATA 10.0. Tests with P<.05 were considered significant.
A total of 123 women were enrolled from February 2011 to April 2012 (Fig. 1). Of these, 59 women were assigned to vaginal misoprostol plus Foley bulb, whereas 64 were assigned to the vaginal misoprostol-only group. Fifty-seven of the 59 assigned to the combination group received the allocated intervention, whereas two did not. Among the 64 patients assigned to vaginal misoprostol only, 58 received the allocated intervention, whereas six did not. Three women in each group were excluded after enrollment for meeting one or more exclusion criteria: four were excluded as a result of an indication for induction being fetal growth restriction and two were excluded as a result of Category III fetal heart rate tracings on admission. This yielded 56 patients in the combination group and 61 patients in the vaginal misoprostol-alone group for analysis.
Flow chart of study ...Image Tools
The two groups were comparable with regard to baseline characteristics including indications for induction of labor (Table 1). Most of the women were at term, nulliparous, and of black race. The most common indication for induction of labor was postdate induction. The median Bishop’s score was similar in the two groups (3 [range 0–6]).
Induction-to-delivery time was shorter by a mean of 3 hours among women induced with a combination of the Foley bulb plus misoprostol when compared with those induced with vaginal misoprostol alone (mean time 15.3±6.5 compared with 18.3±8.7 hours, mean difference −3.1 hours, 95% confidence interval [CI] −5.9 to −0.3). The time from induction to complete cervical dilation was also shorter in the combination group compared with the vaginal misoprostol-only group (mean time 13.7±5.9 compared with 17.1±8.7 hours, mean difference −3.5 hours, 95% CI −6.7 to −0.4). There was a higher rate of delivery within 24 hours in the combination group, but the difference was not statistically significant (49 [89.1%] compared with 46 [75.4%]), relative risk 1.18, 95% CI 1.00–1.40, P=.09). There were no differences in mode of delivery (Table 2). The Kaplan–Meier survival curve showed a more rapid decline in the Foley bulb plus misoprostol group of the proportion of patients remaining undelivered with time (log-rank P=.03) (Fig. 2).
Neonatal outcomes are shown in Table 3. There were no differences in birth weight, Apgar scores, or neonatal intensive care unit admissions. Umbilical cord gases were not significantly different in the two groups. Labor characteristics and complications are shown in Table 4. There were no differences in oxytocin augmentation or epidural anesthesia use. The combination group used fewer doses of misoprostol when compared with the vaginal misoprostol-alone group. There were no differences in the incidence of tachysystole with decelerations, use of terbutaline, or meconium passage in the two groups. The risks of chorioamnionitis, endometritis, and postpartum hemorrhage were also not significantly different in the two groups.
We found that use of a combination of the Foley bulb and vaginal misoprostol for induction of labor shortened induction-to-delivery time by an average of 3 hours compared with vaginal misoprostol alone. No differences were observed in labor complications or adverse neonatal and maternal outcomes.
One randomized trial examining a combination of the Foley bulb plus vaginal misoprostol compared with vaginal misoprostol alone for induction of labor found no differences in the total induction-to-delivery time. The study was small and appears to be underpowered.10 The authors did not report a primary outcome or a priori power calculation. Two other randomized trials using three arms compared vaginal misoprostol alone with Foley bulb alone compared with the combination of Foley bulb plus vaginal misoprostol. Whereas Kashian et al found vaginal misoprostol alone to be faster than the combination of the Foley bulb and vaginal misoprostol, Chung et al reported no difference in induction-to-delivery time between the three groups.6,7 Contrary to our study, there was a statistically significant increase in tachysystole, terbutaline use, and chorioamnionitis with misoprostol alone when compared with the combination group. The differences between our results and these studies may be attributable to differences in study populations, doses of misoprostol used, and sample sizes.
Our study was a relatively large randomized clinical trial comparing the combination of Foley bulb with vaginal misoprostol with vaginal misoprostol alone for induction of labor. The major strength is in the randomized design. Randomization was effective, resulting in comparable groups with regard to known and presumably unknown confounders. We included both nulliparous and multiparous women, making our results more generalizable.
Despite the strengths, there are limitations that should be considered when interpreting our results. The nature of the intervention did not permit blinding of health care providers. The absence of blinding may have influenced how patients were managed. Six participants were dropped because they met exclusion criteria after enrollment. This number is small and balanced in the two groups. There were six participants in the misoprostol-alone group who did not receive their allocated intervention; each received a Foley bulb in addition to misoprostol. In addition, two participants in the Foley bulb plus misoprostol group did not receive misoprostol. However, this crossover would tend to bias our results toward the null hypothesis of no difference. Although we did not find any differences in mode of delivery, neonatal complications, or labor complications, our study was only sufficiently powered to assess the primary outcome.
In conclusion, results of this randomized trial show that use of the Foley bulb combined with vaginal misoprostol results in a shorter induction-to-delivery time compared with vaginal misoprostol alone. These results suggest that the combination may be used to achieve timely and safe delivery in the presence of an unfavorable cervix. Although not directly evaluated in this study, shortening of induction time by 3 hours would be significant for patients, health care providers, and hospitals. Future studies should be of sufficient power to assess significant labor complications and adverse neonatal and maternal complications. In addition, studies comparing a combination of the Foley bulb plus misoprostol with the Foley bulb alone will be informative as to whether the combination is superior to the Foley bulb alone.
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