Prolonged labor is a common problem, especially among nulliparous women. It can result in a negative birth experience1,2 and can be associated with fetal distress resulting in emergency cesarean delivery.3,4 Advanced maternal age, induction of labor, prelabor rupture of the membranes, early admission to the delivery unit, epidural analgesia, and high levels of maternal stress hormones during childbirth are also associated factors, although the cause in most cases is unknown.5–7
Although oxytocin augmentation of uterine contractions is widely used to treat slow labor, cervical ripening is poor. Prostaglandin agents are another choice for labor induction or augmentation as they cause cervical effacement and dilatation and stimulate myometrial contractions. Misoprostol, a synthetic prostaglandin E1 analogue, was initially used to treat peptic ulcers caused by prostaglandin synthetase inhibitors. In April 2002, the U.S. Food and Drug Administration revised the original labeling of misoprostol and approved it for use in pregnancy.8 Because misoprostol is a powerful uterotropic and uterotonic agent, it is ideal for labor augmentation.
Since the 1992 letter by Margulies et al published in The Lancet,9 and the initial American clinical report by Sanchez-Ramos et al detailing the use of misoprostol for cervical ripening and labor induction,10 there has been growing interest in this agent.11–13 Nonetheless, excessive uterine contractility resulting in fetal distress is a cause for concern.14–21 Based on misoprostol pharmacokinetics22 and clinical trial findings, including lower incidence of uterine hyperstimulation and a shorter active phase interval,23,24 titrated oral misoprostol solution for labor induction can be given with consideration for individual differences and responses to its administration. The aim of this randomized clinical trial was to compare the labor outcomes of patients treated for labor augmentation with titrated oral misoprostol solution or titrated intravenous oxytocin.
MATERIALS AND METHODS
This prospective randomized clinical trial was conducted in the Department of Obstetrics and Gynecology at the Labor and Delivery Unit of China Medical University Hospital. Patients were recruited from March 2008 to December 2009. This study was approved by the institutional review board, and written informed consent was obtained from each participant admitted to the Labor and Delivery Unit before enrollment in the study.
Inclusion criteria were pregnancy between 36 and 42 weeks of gestation, a live singleton fetus in cephalic presentation, no history of uterine surgery, spontaneous onset of active labor with regular contractions, an effaced cervix dilated between 3 cm and 9 cm, and a reassuring fetal heart rate (FHR) pattern. Exclusion criteria were nonreassuring FHR pattern, parity greater than five, any contraindication to labor or vaginal delivery or both, epidural analgesia, significant maternal cardiac, renal or hepatic disease, and hypersensitivity to misoprostol or prostaglandin analogues.
During the study period, 827 women fulfilled the inclusion criteria. On admission to the delivery unit, they were asked to participate in the study. Participation in the study was accepted by 712 women who were in active labor. Less than one third (32.4%) of these women developed inadequate uterine contractions (two or fewer contractions per 10 minutes) for at least 30-minute windows in the first stage of active labor (n=231) within 1 hours after admission. They all received cervical examinations during which the cervical scores were determined. Then they were randomized into the two study treatment groups (Fig. 1). The treatment arm allocation was determined using a computer-generated table of random numbers. The randomization assignments were placed into opaque, sealed envelopes. When inadequate uterine contractions occurred, the envelope was opened by the patient's obstetrician to determine the treatment allocation. It was not possible to blind the study participants and personnel from knowledge of which intervention a participant received because the two methods were clearly different.
In the titrated oxytocin group, we gave oxytocin via the intravenous route by pump initially set to deliver 1 milliunit/min for 20 minutes, and then increase the rate by 1 milliunit/min every 20 minutes until adequate uterine contractions were attained.
Misoprostol is manufactured as a water-soluble oral tablet. One 200-microgram tablet of misoprostol was completely dissolved in 200 mL of tap water with stirring bar in a medicine bottle by the duty nurse. The misoprostol solution was stored in this medicine bottle at the nurses' station and used completely within 24 hours after preparation or discarded. Women were given one basal unit of 20 mL of misoprostol solution (1 microgram/mL, 20 micrograms total) prepared as described above. The 1-hour interval between oral misoprostol administrations was determined based on a mathematical model of the time to peak serum concentration (Tmax, 34 minutes) and half-life (T1/2, 20–40 minutes) of oral misoprostol after absorption, which virtually maintains a steady serum level of misoprostol acid without large fluctuations and can increase by 1.33 times the peak serum concentration (Cmax) of 20 micrograms of absorptive misoprostol after 4 hours.24 It can be expected that the pharmacokinetics of misoprostol may not change when it is given after onset of spontaneous labor. However, the total dosage can be smaller than that of induction. The administration procedure in the titrated oral misoprostol group adhered to these guidelines:
1. Misoprostol was initially administered at a dose of 20 micrograms/h until adequate uterine contractions were achieved. If contractions did not occur after 4 hours (four doses), the dosage was increased to 40 micrograms and repeated every hour until uterine contractions occurred. Nothing by mouth, except medication, was allowed during the active phase of labor.
2. Adequate uterine contractions were defined as three or more in 10 minutes over 30-minute windows. Once uterine activity was adequate over 1 hour, no further misoprostol was given.
3. If contractions subsequently became inadequate, hourly doses of misoprostol solution were started at 10 micrograms/h and could be increased to 20 micrograms/h and to as much as 40 micrograms/h based on uterine responsiveness. This process was repeated until adequate uterine contractions occurred.
The procedural guidelines common to the administration of intravenous oxytocin or oral misoprostol solution were as follows:
1. Both fetal heart rate and uterine activity with only external technique were continuously monitored throughout labor augmentation.
2. The maximum dosing rate of oxytocin was 20 milliunits/min and the maximum cumulative dosage of misoprostol was 1,600 micrograms.
3. Intravenous magnesium sulfate (4 g over 30 minutes) could be given at the discretion of the physician if uterine hyperstimulation occurred.
4. The active phase was defined as achieving adequate uterine contractions with cervical dilatation greater than 3 cm.
5. Failure to progress was defined as the cervical dilation or fetal descent without any progress for 3 hours after entering the active labor phase as augmented by the agent.
6. Cesarean delivery was offered to all patients after failure of labor to progress or when nonreassuring FHR occurred.
Adequate uterine contractions were defined as occurring every 2–3 minutes and lasting 60–90 seconds with an intrauterine pressure more than 50 mm Hg. Tachysystole was defined as the presence of at least six contractions in 10 minutes for at least two 10-minute windows. Hypertonus was defined as a single contraction lasting more than 2 minutes. Hyperstimulation was defined as tachysystole or hypertonus with nonreassuring FHR changes. FHR changes considered to be nonreassuring were late deceleration, severe variable deceleration, prolonged deceleration, tachycardia, or reduced FHR variability requiring intervention with either tocolytics or delivery.25
The primary parameters used to evaluate efficacy were the interval from the start of augmentation to vaginal delivery and the percentage of women who delivered their newborns vaginally within 12 or 24 hours of this interval. The primary parameters used to evaluate adverse events were incidence of tachysystole, hypertonus, uterine hyperstimulation, and nonreassuring FHR. The secondary parameters used to evaluate efficacy or adverse events included total dosage of oxytocin or misoprostol, rates of cesarean births and failure to progress, and neonatal outcomes, including lower Apgar score (less than 7 at 5 minutes after birth) and admittance to the neonatal intensive care unit (NICU). The occurrence of treatment side effects and characteristics of patients, including age, body height, body weight, parity, gestational age at labor, and cervical score before the start of augmentation, were also recorded.
We determined that 108 women in each group were required to provide a power of 80% and 5% of two-sided type 1 error to detect a 10% difference in the cumulative distribution function between null hypothesis and alternative hypothesis for a median augmentation–to–vaginal delivery interval of 5.20 hours. This was calculated with the null hypothesis that the cumulative probability of the augmentation–to–vaginal delivery interval of 5.20 hours was 0.5 (that is, the null hypothesis assumed that the median was 5.20 hours for both groups) and the alternative hypothesis assumed that this number was the value for the cumulative probability of 0.4 for the intervention group. This information came from our pilot study. The sample size was adjusted to allow for an estimated protocol violation rate of 10% in each study group. The χ2 test and Fisher exact test were performed to compare categorical variables, and the Wilcoxon rank sum test was performed to compare continuous variables between the titrated oral misoprostol and intravenous oxytocin groups. Fisher exact test was used when the assumptions of the χ2 test were violated. The data were analyzed by intention to treat. Relative risks (RRs) and their 95% confidence intervals (CIs) were used to estimate the strength of association between two groups (titrated oral misoprostol compared with titrated intravenous oxytocin). All reported P values are those of two-sided tests; statistical significance was set at P<.05. All analyses were performed using SAS 9.1.
A total of 231 consenting women were randomized into the two study groups; 118 (51.1%) to titrated oral misoprostol solution, and 113 (48.9%) to titrated intravenous oxytocin (Fig. 1). In the titrated oral misoprostol group, one woman asked for epidural analgesia and another woman underwent an emergency cesarean delivery because of nonreassuring FHR. In the titrated intravenous oxytocin group, one woman had a nonreassuring FHR pattern. These three women did not receive their assigned treatment; however, they were included in the analysis as it was by intention to treat. The incidence of these cases in the two groups was less than the upper limit of 10% of the estimated sample size when the sample size was initially calculated. Therefore, it was not considered likely to have affected the results.
The characteristics of the women are shown in Table 1. The two groups were similar with respect to maternal age, gestational age, maternal body height and weight, maternal parity, Bishop score, and rupture of membranes at start of augmentation.
Table 2 shows the labor outcomes. The median interval from the start of augmentation to vaginal delivery was 5.22 hours (3.77–8.58 hours, 25th–75th percentile) in the titrated oral misoprostol group, and 5.20 hours (3.23–6.50 hours, 25th–75th percentile) in the titrated intravenous oxytocin group (P=.019). The active phase intervals did not differ between the two treatment groups (P=.146). Of the women who completed vaginal delivery within 12 hours, 92 (78.0%) were in the titrated oral misoprostol group and 97 (85.8%) were in the titrated intravenous oxytocin (P=.121; RR 0.91, 95% CI 0.80–1.03). There were also no significant differences between two groups who delivered vaginally within 24 hours (P=.744).
Although the occurrence of tachysystole differed significantly (P=.023) between the two groups, the occurrence of hypertonus, hyperstimulation, and use of tocolysis for hyperstimulation did not differ between the groups. Tachysystole developed in 7 women (5.9%) in the titrated oral misoprostol group and in 17 women (15.0%) in the titrated intravenous oxytocin group (RR 0.39, 95% CI 0.17–0.91). When tachysystole occurred, the misoprostol or oxytocin was halted, and oxygen and hydration with lactated ringer's solution were given immediately in both groups. Of these 24 women, uterine hyperstimulation occurred in one woman (0.8%) in the titrated oral misoprostol group and in two women (1.8%) in the titrated intravenous oxytocin group. The fetal heart beat pattern returned to normal within 5 minutes in these women, so they were not given magnesium sulfate for tocolysis. All 24 women had vaginal deliveries. There was another case of uterine hyperstimulation in a woman in the titrated oral misoprostol group and she underwent emergency cesarean delivery for nonreassuring FHR.
The median total dosage was 60.0 micrograms (40.0–80.0 micrograms) in the titrated oral misoprostol group, and 1,225.0 milliunits (697.5–1,892.5 milliunits) in the titrated intravenous oxytocin group. All were within safe limits of dosage. The modes of vaginal and cesarean deliveries did not differ significantly between the two groups. Twelve patients (10.2%) in the titrated oral misoprostol group underwent cesarean births compared with 13 patients (11.5%) in the titrated intravenous oxytocin group (P=.744; RR 0.88, 95% CI 0.42–1.85). The indications for cesarean delivery were due to failure of labor to progress and nonreassuring FHR.
The common side effects of misoprostol included nausea, vomiting, diarrhea, pyrexia, and shivering. Nausea, vomiting, shivering, and pyrexia occurred in four women in the titrated oral misoprostol group; none of these side effects occurred among the women in the titrated intravenous oxytocin group.
There were no differences in neonatal outcomes (Table 3), except for two newborns with an Apgar scores less than 7 at 1 minute after birth in the titrated oral misoprostol group. Five newborns (4.2%) were admitted to the NICU in the titrated oral misoprostol group, and two (1.8%) were admitted to the NICU in the titrated intravenous oxytocin group (P=.447; RR 2.39, 95% CI 0.47–12.09). All five of the newborns admitted to the NICU in the titrated oral misoprostol group underwent long intervals of augmentation of more than 8 hours or labor failed to progress. One of two newborns in the titrated intravenous oxytocin group underwent a long interval of augmentation of more than 8 hours.
This study compared the efficacy of titrated oral misoprostol solution with intravenous oxytocin infusion for labor augmentation when inadequate uterine contractions occurred. There were no significant differences between the two groups that delivered vaginally within 12 or 24 hours. Side effects and neonatal outcomes also did not differ between the two groups.
Cesarean birth rates are greater than 20% in many developed countries.26 The main diagnosis contributing to the high rate in nulliparous women is dystocia or prolonged labor. A policy of early amniotomy with oxytocin administration for the prevention of delay in labor progress is associated with a modest reduction in the rate of cesarean births.27 There is no significant difference in cesarean delivery rate, neonatal outcome, and maternal outcome between the low and high doses of oxytocin on labor augmentation except for labor augmentation interval.28 However, oxytocin administration through the intravenous route needs to be under the control of an intravenous pump machine and may be inconvenient in certain settings. Multiple trials have shown that misoprostol is an effective agent for cervical ripening and labor induction. The study of orally administered misoprostol compared with titrated intravenous oxytocin for labor induction in women with favorable cervical condition (Bishop score of 6 or more) showed no benefit and higher likelihood of uterine hyperstimulation.29 Therefore, the regular orally administered misoprostol of fixed dosage without individualization is not an ideal choice. The concept that titrated oral misoprostol administration is associated with lower incidences of uterine hyperstimulation and cesarean deliveries than vaginal misoprostol for labor induction in patients with unfavorable cervical status is well established.24 Because titrated oral misoprostol solution is easier to administer than titrated intravenous oxytocin, we found it worth conducting this randomized controlled trial to examine the optimal treatment regimen for labor augmentation.
Parameters used to assess efficacy included the interval from the start of augmentation to vaginal delivery, the percentage of women who delivered their newborns vaginally within 12 and 24 hours of augmentation, and rate of failure to progress. According to the pharmacokinetics, the onset time and administration route of oxytocin is better than that of misoprostol. In this study, it was expected that the titrated intravenous oxytocin would be more effective than titrated oral misoprostol in terms of the interval of augmentation to vaginal delivery. However, the difference of these intervals is not significant in actual clinical practice. Vaginal delivery within 12 or 24 hours is the more important clinical factor. We found that there were no significant differences between the groups in the percentages of women who delivered their newborns vaginally within 12 or 24 hours of augmentation and in the rate of failure to progress. Therefore, labor augmentation with titrated oral misoprostol solution is an effective alternative method.
The parameters used to assess adverse outcomes in this study were incidence of tachysystole, hypertonus, uterine hyperstimulation, neonatal outcomes with low Apgar score, and NICU admission. Tachysystole occurred in both groups, and administration of these agents was halted immediately until uterine contractions became inadequate and tocolysis with magnesium sulfate was unnecessary. This suggests that administering misoprostol in small, frequent doses with continuous adjustment according to response is also a better way to avoid uterine hyperstimulation and is analogous to the conventional titrated use of oxytocin.
The maximal cumulative dosage of 320.0 micrograms for the titrated oral misoprostol group and the maximal dosing rate of 10 milliunits/min for the titrated intravenous oxytocin group were all within the safe limits for administration. Therefore, occurrences of common side effects and poor neonatal outcomes were rare in the two groups. Most importantly, the rates of cesarean delivery and failure of labor to progress were low in the two groups. This suggests that repeated small oral doses of misoprostol have uterotonic effects similar to those of oxytocin.
In conclusion, titrated oral misoprostol solution was observed to be similar to intravenous oxytocin infusion in labor augmentation and may be an alternative to the traditional oxytocin. In addition, misoprostol offers several advantages over oxytocin such as longer shelf life, stability at room temperature, and easy administration.
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