Induction of labor can be a time- and personnel-consuming process, taxing resources in a labor and delivery unit. Cervical ripening before induction with prostaglandin agents has been demonstrated to decrease induction time and need for oxytocin.1,2 Administration of long-acting or serial dose prostaglandin must be performed in the inpatient setting due to the increased risk of uterine hyperstimulation and need for repeated dosing, possibly negating some of the benefits of reduced oxytocin use achieved by cervical ripening. The optimal ripening protocol, which is effective at reducing the time for administration of oxytocin but can be administered in an outpatient setting, is not known.
Prior studies have demonstrated the low risk of uterine hyperstimulation after a single dose of intracervical dinoprostone gel and serial low dose misoprostol (25 μg).3,4 Serial doses of misoprostol have been administered in the outpatient setting with no adverse effects noted.5,6 No trial has examined the efficacy of a single dose of misoprostol followed by induction with oxytocin.
Our hypothesis was that a single dose of misoprostol before oxytocin induction would decrease oxytocin use during induction. The aim of this study was to compare the effect of misoprostol or dinoprostone gel administered in an outpatient setting on the cumulative dose and time of oxytocin administration during induction of labor.
PATIENTS AND METHODS
The study protocol was approved by the institutional IRB at the University of Vermont and conducted between November 1999 and December 2001. All eligible patients presenting for cervical ripening were allowed participation. A total of 133 patients received cervical ripening during the study period, 84 of whom chose to participate. Inclusion criteria were an established obstetric provider with whom emergency contact and care was available; Bishop score 6 or less, singleton, intact membranes, cephalic presentation, reactive nonstress test before drug administration. Exclusion criteria included Bishop score more than 6, contractions more than 3 per 10 minutes before drug administration, any contraindication to induction of labor, any uterine scar, or ruptured membranes. All patients had received ongoing prenatal care by an established obstetric provider (or provider group). Patients were randomly assigned after the nonstress test. Sequential opaque envelopes denoted the group assignment, which was assigned in the envelope by a random numbers table.
The primary outcome variable was cumulative oxytocin dose and duration and oxytocin dose intensity (dose divided by duration). Secondary outcomes were onset of labor (including spontaneous rupture of membranes) during ripening, failed or serial induction, and short-term neonatal outcome (Apgar score, neonatal intensive care unit admission). Every chart was reviewed for determination of oxytocin use, onset of labor, and complications during ripening or induction. The nursing labor flow sheet, which documents all medications, contraction pattern, and fetal heart rate assessment in 15-minute intervals, was used to determine oxytocin use, contraction pattern, and medical interventions during labor. The amount of oxytocin used was counted as the cumulative dose and duration of oxytocin infusion as documented in the nursing notes. Tachysystole was defined as at least 6 contractions in 10 minutes for 2 consecutive 10-minute segments. Uterine hyperstimulation was defined as tachysystole associated with nonreassuring fetal heart rate monitoring. Labor was defined as regular, painful uterine contractions with cervical change or spontaneous rupture of membranes. Serial induction was defined as events in which the oxytocin infusion was halted due to absence of painful regular contractions with cervical change or spontaneous rupture of membranes after at least 8 hours, with restarting of oxytocin after a period of at least 8 hours. Failed induction occurred when painful, regular contractions with cervical change were not achieved and the patient was delivered by cesarean with failed induction as the sole indication. Time from admission to delivery was the time from admission for labor or induction until delivery. If the patient received ripening medication but was unable to be discharged, the entire time from admission for ripening to delivery was counted.
The study design is summarized in Figure 1. Patients were admitted to the Labor and Delivery unit the late afternoon or evening before induction as outpatients and placed on continuous fetal monitoring. After a reactive nonstress test, informed consent was obtained, and the patient was randomly assigned to misoprostol or prostaglandin gel. Patients in the misoprostol group received 25 μg (one quarter of a 100-μg tablet) per vagina; those in the prostaglandin gel group (dinoprostone) received 0.5 mg of dinoprostone gel (Prepidil, Pharmacia & Upjohn, Inc, Kalamazoo, MI) intracervically in an unblinded fashion. Misoprostol tablets were cut on the Labor and Delivery unit using a pill cutter obtained by the pharmacy for the first two thirds of the study; for the last one third of the study, pills were cut in the pharmacy (because of a hospital policy change; a similar pill cutter was used), and one quarter of a tablet was sent to the Labor and Delivery unit. All patients underwent continuous fetal monitoring for 3 hours after drug application. The attending physician made the decision regarding discharge after the monitoring period based upon the clinical status of the patient. All patients were scheduled to return to labor and delivery within 18 hours after drug administration for oxytocin induction. If Labor and Delivery was too busy to proceed with oxytocin, the patient had a cervical examination to assess the posttreatment Bishop score and a nonstress test. Patients were called to return when a bed was available. All patients were admitted in labor or for oxytocin induction within 24 hours of ripening. Patients who went into labor (including those with spontaneous rupture of membranes even without regular uterine contractions) were admitted at presentation. Patients in labor or with spontaneous rupture of membranes before initiation of oxytocin were not included in the posttreatment Bishop score analysis.
Oxytocin administration was at the discretion of the attending physician, starting between 0.5–2 mU/min and increased by 1–2 mU/min every 15–30 minutes. All obstetric management, including amniotomy, was at the discretion of the attending provider.
A study group of 30 patients per arm would be required to observe a decrease in oxytocin use by 35%, assuming a decrease from 90% of patients requiring oxytocin for the initiation of labor to 60% with 80% power (α = 0.05).7 The dose of oxytocin was calculated as the cumulative dose until delivery of the infant. The duration of oxytocin infusion was calculated as the cumulative time an oxytocin infusion was running until delivery. The dose intensity of oxytocin in milliunits per minute was calculated as the cumulative dose divided by the time. Rates and proportions were compared using χ2 or Fisher exact test; nonnormal data (admission to delivery time, pretreatment Bishop score) were compared using the Mann-Whitney rank sum test (unpaired) or Wilcoxon signed rank test (paired, pretreatment compared with posttreatment Bishop score); normal data (oxytocin use) were compared using the Student t test. P < .05 was considered significant.
All outcomes were calculated as intent to treat. Two patients in the misoprostol group were excluded from the oxytocin data. One patient was excluded from the spontaneous labor and oxytocin data because she received an incorrect dose of misoprostol (a full 100-μg tablet). She was included in the data regarding complications of misoprostol (hyperstimulation or tachysystole), mode of delivery, and neonatal outcome data. She underwent an uneventful labor and spontaneous vaginal delivery, requiring no oxytocin, with no neonatal adverse outcome. A second patient was excluded from the oxytocin data, serial induction, delivery less than 24 or 48 hours, failed induction data, and time intervals involving delivery because her fetus was found to be presenting as a breech on admission for oxytocin. She underwent cesarean delivery without induction or complication. This patient was included in other outcome data, including the time from administration of ripening agent to admission, mode of delivery, and neonatal outcome data.
Patient demographics and the indication for induction are summarized in Table 1. Forty-two patients were randomly assigned to receive misoprostol and 42 patients to receive dinoprostone gel. There were no differences between groups regarding parity, indication for induction, or pretreatment Bishop score. Pregnancies of 41 weeks of gestation or more and postterm (≥ 42 weeks of gestation) pregnancies accounted for the single most common indication for induction. Other indications included elective (3 patients in each group), macrosomia, intrauterine growth restriction (< 10% by ultrasound), oligohydramnios, history of fetal demise, fetal isolated limb defect, unstable lie, and maternal medical indications (cholestasis, pruritus of pregnancy, thrombophilia, cystic fibrosis, and renal disease).
Events within the ripening period are summarized in Table 2. The proportion of patients unable to be discharged after drug administration was similar. Of the 5 patients unable to be discharged after receiving misoprostol, 4 were having regular uncomfortable contractions consistent with early labor; 1 patient had tachysystole without fetal heart rate changes after receiving an incorrect dose of misoprostol but required no further treatment. Of the 4 patients unable to be discharged after receiving dinoprostone gel, 2 had nonreassuring fetal heart rate changes that were not associated with clinically apparent contractions and resolved spontaneously, 1 had uterine tachysystole without fetal heart rate changes and required no treatment, and 1 had hypertension. No patient required cesarean delivery or experienced uterine hyperstimulation syndrome during the ripening period. In nonlaboring patients, the Bishop score increased after treatment in both groups. There was no between-group difference in either the change of Bishop score or the Bishop score measured posttreatment.
The interval from the administration of ripening agent to admission was shorter for patients who received misoprostol (excluding patients who were not discharged as noted in Table 2). Data are presented as mean ± standard error of the mean (SEM) and (range). For dinoprostone (n = 38): 15.1 ± 0.5 (10–22) hours. For misoprostol (n = 37): 12.6 ± 0.7 (5–24) hours; P = .003. The subset of patients returning for oxytocin induction without labor had a similar outpatient latency. For dinoprostone (n = 33): 15.1 ± 0.5 hours. For misoprostol (n = 22): 14.3 ± 0.8 hours; P = .33. In the subset of patients who returned in labor, those that received misoprostol returned for admission more quickly. For dinoprostone (n = 5): 14.9 ± 0.8. For misoprostol (n = 15): 11.8 ± 0.9; P = .02. Thus, the shortened interval from drug administration to admission is a reflection of the return of laboring patients after receiving misoprostol.
Labor characteristics are presented in Table 3. The incidence of labor before oxytocin induction was significantly greater in women receiving misoprostol compared with dinoprostone (odds ratio [OR] 5.2, 95% confidence interval [CI] 1.7–13.6, P = .002, number needed to treat = 3.1). This observation remained significant when analysis was restricted to nulliparous patients (OR 4.8, 95% CI 1.4–14.1, P = .01, number needed to treat = 2.9). Patients receiving misoprostol were less likely to require serial induction (OR 0.11, 95% CI 0.03–0.93, P = .03, number needed to treat = 6.1), although there was no difference in the percentage of women delivered within 24 or 48 hours or the rate of failed induction.
Oxytocin use was significantly decreased in those women receiving misoprostol, with a 44% reduction in cumulative dose of oxytocin, a 33% decrease in cumulative duration of oxytocin, and 35% reduction in the dose intensity of oxytocin (Fig. 2). These findings persisted when only the data from nulliparous patients were analyzed. Data are presented as mean ± SEM. Dose (in milliunits) for dinoprostone (n = 29) was 11,981 ± 1,891 and for misoprostol (n = 27) was 6,848 ± 1,474 (P = .04). Time (in minutes) for dinoprostone was 855 ± 90 and for misoprostol was 587 ± 98 (P = .05). The dose intensity (in milliunits per minute) for dinoprostone was 11.6 ± 1.2 and for misoprostol was 7.3 ± 1.2 (P = .02). In the women who required oxytocin for the initiation of labor (misoprostol n = 21; dinoprostone n = 35), those receiving misoprostol required less oxytocin per unit time (milliunits per minute) (dinoprostone 12.9 ± 0.8, misoprostol 10.3 ± 1.0, P = .05) but similar overall dose (milliunits) (dinoprostone 12,848 ± 8,900, misoprostol 8,725 ± 6,686, P = .07) and time (minutes) (dinoprostone 908 ± 68, misoprostol 755 ± 87, P = .17).
Misoprostol reduced the time from admission to delivery by 22%. The median time for women who received dinoprostone was 15.4 hours (25% 11.8 hours, 75% 20.8 hours) compared with 11.9 hours (25% 7.6 hours, 75% 20.0 hours, P = .05) for women who received misoprostol. When data were analyzed by labor status, those patients in labor within the ripening period spent 28% less time in labor and delivery than those who did not enter labor. Combining those in labor after dinoprostone or misprostol (n = 25), the median time in labor and delivery was 10.9 hours (25% 5.5 hours, 75% 16.5 hours) compared with the combined set of patients with no labor after either drug (n = 57), for whom the median was 15.3 hours (25% 11.5 hours, 75% 21.0 hours, P = .004). Together, these findings suggest that the decrease in admission to delivery time was a reflection of the increased rate of labor associated with misoprostol.
The mode of delivery, cesarean delivery for failed inductions, and indications for cesarean delivery were similar between the groups (Table 4). The duration of oxytocin infusion before requiring cesarean delivery was similar between the groups. The mean ± SEM for the dinoprostone group (n = 8) was 13.4 ± 3.7 hours, and for the misoprostol group (n = 8) was 13.7 ± 2.7 hours, P = .95. The only patient who underwent a cesarean delivery without oxytocin use was found to have a breech presentation before induction. Both patients who required cesarean delivery for failed induction received more than 24 hours of oxytocin with inability to perform amniotomy.
There were no differences in birthweight or short-term neonatal outcomes of birthweight (mean ± SEM in grams for dinoprostone was 3,532 ± 74, and for misoprostol was 3,698 ± 75, P = .12), Apgar score less than 7 at 5 minutes (Apgar score less than 7 for dinoprostone was 0/42, and for misoprostol was 1/42, P = 1.00), or admission to the neonatal intensive care unit (NICU) (admissions for dinoprostone were 5/42, and for misoprostol were 4/42, P = 1.00). The one neonate with Apgar score less than 7 after maternal misoprostol administration also received oxytocin and required an operative vaginal delivery for nonreassuring fetal assessment. The indications for NICU admission after misoprostol were nonreassuring fetal assessment (n = 2), maternal magnesium use for preeclampsia (n = 1), and micrognathia (n = 1). The indications for NICU admission after dinoprostone were tight nuchal cord and operative vaginal delivery (n = 1), thick meconium (n = 2), congential absence of a limb (n = 1), and not noted (n = 1).
There was no difference in the frequency of adverse events between the groups. One patient had a medication dosage error, receiving a full tablet of misoprostol (100 μg). She proceeded into labor, did not receive oxytocin, and had an uneventful vaginal delivery. No uterine hyperstimulation occurred before oxytocin. Oxytocin infusion was complicated by uterine hyperstimulation in 2 patients who received misoprostol and 1 patient who received dinoprostone; the latter required a single dose of terbutaline for treatment. No patient required a cesarean delivery for uterine hyperstimulation.
The major finding in this study is that a single dose of misoprostol administered as an outpatient before oxytocin induction, when compared with dinoprostone gel, reduces the cumulative dose and duration of oxytocin needed for induction of labor. These data suggest that a single dose of misoprostol is more effective than a single dose of prostaglandin gel for preparation of labor induction.
Our findings are largely explained by the increased frequency of labor within the preinduction ripening period and the reduced dose intensity in those women that required oxytocin for initiation of labor. One of the most surprising aspects of this study was the high frequency of labor after a single dose of misoprostol. In a review comparing 25 μg and 50 μg of misoprostol for labor induction, Sanchez-Ramos3 reported an overall labor rate ranging between 2- 26% after a single dose of misoprostol. In each of these protocols, repeated dosing every 3–6 hours occurred in the absence of regular contractions was used if labor was not achieved after a single dose. Our observation of a labor rate nearly twice that expected after a single dose may be related to the time allowed to progress into labor before repeat dosing. Wing8 found that most women required serial doses of misoprostol for approximately 8 hours (2.6 doses with every 3 hour dosing) for initiation of labor. Our findings of return in labor within 12 hours of a single dose suggest that it may be the time from the initial dose of misoprostol, rather than the number of doses per se, that is most important in achieving labor. The requirement for a period of latency before the onset of labor is biologically plausible, because this time may be necessary for the formation of gap junctions and regulation of prostaglandin-induced myometrial or cervical changes.9 The clinical benefit of a single misoprostol dose followed by longer latency is not only the ease of administration and induction but also the potential to decrease tachysystole, a limitation of serial dose regimens, without sacrificing efficacy.
A recent comparison of inpatient serial dose misoprostol compared with dinoprostone gel or pessary demonstrated a decrease in oxytocin use and labor and delivery cost with inpatient administration of serial dose misoprostol.10 Using this outpatient protocol, we observed a similar decrease in oxytocin use as well as a 22% decrease in admission to delivery time. These data suggest that a single dose of misoprostol, administered during a short hospital stay, has the potential to decrease use of labor and delivery resources for labor induction.
There is debate in the literature regarding the safety of discharge from the hospital (and continuous monitoring) within a few hours of misoprostol administration because of the possibility for uterine hypertonus, abnormalities of the fetal heart rate, and poor fetal outcome. We found no difference in the incidence of these events within 3 hours of monitoring. Uterine hyperstimulation occurred only after the use of oxytocin. Misoprostol has been administered in an outpatient setting in two similar studies with reassuring findings. Stitely6 examined daily dosing of misoprostol compared with placebo and found misoprostol to be more effective at initiating labor, with a 44% incidence of labor after one dose of misoprostol, similar to our observations. In his report, all reports of fetal heart rate abnormalities were within the first hour of dosing. Incerpi et al5 administered a single dose of misoprostol to patients with diabetes, with follow-up in 3–4 days if labor had not occurred. He did not observe any abnormality of uterine contraction or fetal heart rate during the outpatient period. In the current study, no cesarean delivery was performed during the ripening period.
This study was not sufficiently powered to address the safety of outpatient administration due to the low incidence of poor fetal outcome. There was a single dosing error, in which a patient received the full 100-μg tablet of misoprostol. Pill cutting in the pharmacy, with the correct dose sent to the labor and delivery suite, can reduce this type of medication error.
Of interest was the finding that uterine hyperstimulation or cesarean delivery for any indication occurred only after the initiation of oxytocin. Patients received oxytocin for an average of 13 hours before requiring cesarean delivery, supporting the safety of a single dose of misoprostol for preoxytocin induction cervical ripening. Ten percent of the patients receiving misoprostol underwent cesarean delivery for nonreassuring fetal heart rate monitoring, consistent with prior studies.8 This observation emphasizes the importance of careful management of oxytocin after misoprostol, rather than a risk associated with a single dose of misoprostol alone.
The criteria to participate in this trial created a highly selective population. The most important of these was that all patients in this study had an identifiable attending physician whom they contacted directly with any questions or problems and were able to return to the hospital immediately. All patients had admission paperwork completed at the time of preinduction ripening and were known to both the nursing and resident staff on labor and delivery. This close follow-up may have contributed to the safety observed in this study and would limit the use of this protocol to such a tightly controlled system. We cannot exclude the possibility of enrollment bias at the level of the attending physician, with enrollment of only those patients perceived to be at lowest risk. However, of all patients receiving cervical ripening over the study period, 63% volunteered to participate. This high level of enrollment likely reflects the mostly low-risk nature of our patient population, which has few patients presenting at term requiring induction without meeting the eligibility criteria.
The treatment group was not blinded. It is unlikely that the difference in the onset of labor within the ripening period could be influenced by bias, because all patients had progressive cervical dilation or objective evidence of spontaneous rupture of membranes. If lower doses of oxytocin were used because of the knowledge of misoprostol administration, but without biologic effect, we would expect increased duration of oxytocin use and increased failed inductions associated with misoprostol, the opposite of our observations. Thus, bias due to lack of blinding is an unlikely explanation of our results.
In summary, a single dose of misoprostol is more effective than dinoprostone at preinduction preparation for induction, with labor onset during ripening contributing to decreased oxytocin use and admission to delivery time. Our findings suggest that latency of approximately 15 hours after a single low dose of misoprostol can provide induction benefit and may minimize the problem of uterine tachysystole/ hyperstimulation associated with repeated dosing. Outpatient administration may be considered in a select patient population.