There are many indications for term labor inductions, including postterm pregnancy, preeclampsia, diabetes mellitus, oligohydramnios, intrauterine fetal growth restriction, and abnormal antepartum fetal surveillance results.1 With more than 15% of all gravid women requiring aid in cervical ripening and labor induction, there is widespread interest in, and demand for, an effective and safe method of assistance. The immature cervix is the greatest barrier to labor induction. Because oxytocin only affects uterine contractions and not cervical ripening, prostaglandin agents are the first choice for labor inductions because they exert a local effect on the cervix, causing effacement and dilatation, and stimulate myometrial contraction, increasing the likelihood of success. Dinoprostone has been the agent of choice for preinduction cervical ripening for several decades and is currently one of the pharmacologic agents approved by the U.S. Food and Drug Administration for this indication. Although widely used, it has two disadvantages: It is expensive, and it requires continuous refrigeration. Thus, there is a need for less costly and less temperature-sensitive alternatives. Misoprostol, a synthetic prostaglandin E1 analogue, has been proposed as an alternative agent for preinduction cervical ripening. Misoprostol was initially used to treat peptic ulcers caused by prostaglandin synthetase inhibitors, and was approved by the U.S. Food and Drug Administration for obstetric use in April 2002.
Since the 1992 letter of Margulies et al published in the Lancet (Margulies M, Campos Perez G, Voto LS. Misoprostol to induce labor [letter]. Lancet 1992;339:64) and the initial American clinical report by Sanchez-Ramos et al2 (1993) detailing the use of misoprostol for cervical ripening and labor induction, there has been growing interest in this agent.3–5 Although the oral dosage of 100 mcg was previously advocated as a preferred dose by Wing et al,6 more recent reports by the Cochrane review,7 other review,8 and forthcoming WHO recommendation have identified 50 mcg as the highest dose that should be used. The recommended dose by vaginal route is 25 mcg every 4 hours.8 However, excessive uterine contractility resulting in fetal distress is a cause for concern.6–17 Comparing the oral and vaginal administration of misoprostol, the oral administration is easier and has greater acceptability among women. Further, absorption is more rapid and possibly more predictable, with a peak serum concentration after oral administration of 34 minutes and a half-life of 20–40 minutes. Peak serum concentration for vaginal administration is 60–80 minutes, and this level is sustained for up to 4 hours.18 Although the direct local effect of vaginal administration on cervical ripening may be advantageous,19 the shorter half-life of oral delivery may be beneficial in the event of uterine hyperstimulation.
Based on pharmacokinetics, findings with previously reported regimens, and the incidence of uterine hyperstimulation, it seems reasonable to suggest that oral misoprostol should be administered in small, frequent doses, titrated against the uterine response.20–22 The aim of this randomized clinical trial was to compare the safety and efficacy of titrated oral with vaginally administered misoprostol for labor induction.
MATERIALS AND METHODS
This randomized clinical trial was conducted in the Departments of Obstetrics and Gynecology at the Labor and Delivery Units of China Medical University Hospital and Beigang Hospital. Patients were recruited from July 2005 through March 2007. This study was approved by the Institutional Review Board, and written informed consent was obtained from each participant.
Inclusion criteria were as follows: pregnancy between 34 and 42 weeks of gestation; admitted for labor induction because of either medical, obstetric, or psychosocial indications; live singleton; Bishop score less than or equal to 6; cephalic presentation; and a reassuring fetal heart rate (FHR) pattern. Exclusion criteria were as follows: nonreassuring fetal heart rate pattern; parity more than five; any contraindication to labor and/or vaginal delivery; uterine scar; suspected placental abruption with abnormal FHR pattern; vaginal bleeding other than “bloody show”; cervical dilatation greater than or equal to 4 cm; uterine contractions greater than or equal to three in 10 minutes; significant maternal cardiac, renal, or hepatic disease; and hypersensitivity to misoprostol or prostaglandin analogues.
The treatment arm allocation was determined using a computer-generated table of random numbers. The randomization assignments were placed into opaque, sealed envelopes. All eligible women were invited to participate, and after obtaining informed written consent, the next envelope in sequence was opened by the patient’s obstetrician to determine the treatment allocation. This study was not placebo controlled, therefore women and clinicians were aware of the allocated treatment.
Misoprostol is manufactured as an oral tablet and is water-soluble. The uterine activity produced by an oral solution is faster and stronger than that of an oral tablet, or when given by the rectal or vaginal route.23 One tablet of misoprostol is 200 mcg. In this study, a tablet was divided into one-eighth or dissolved in 200 mL tap water in a medicine bottle by the on-duty nurse, depending on the route of administration.24 The misoprostol solution was used completely within 24 hours after preparation or discarded. Women assigned to the vaginal misoprostol group received 25 mcg every 4 hours until attaining a more favorable cervix (Bishop score greater than or equal to 7) or adequate uterine activity (greater than or equal to three contractions in 10 minutes) or entering active labor. If needed, oxytocin was initiated 4 hours after the last misoprostol dose. Women assigned to the titrated oral route were induced with a basal unit of 20 mL misoprostol solution (1 mcg/mL) prepared as described above. The 1-hour interval between oral administrations was determined based on the mathematical model of the time to peak serum concentration and half-life of oral misoprostol after absorption, which virtually maintains a steady serum level of misoprostol acid without large fluctuations and increases by one and one third the peak serum concentration of 20 mcg absorptive misoprostol every four hours.22 The administration procedure followed these guidelines:
1. Initial administration of 20 mcg per hour was undertaken until adequate uterine contractions were achieved. If contractions did not occur after four of the above doses, the dosage was increased to 40 mcg and repeated every hour until uterine contractions were achieved, with a maximum of four more doses. If response still remained poor after eight hours, the dosage was increased to 60 mcg per hour until adequate contractions occurred. The instructions for nothing by mouth were not prohibited during the latent phase of the course of labor.
2. Once uterine activity was deemed adequate, no further misoprostol was given.
3. If contractions subsequently became inadequate, hourly doses of misoprostol solution were started at 10 mcg and could be increased to 20 mcg and perhaps 40 mcg based on uterine responsiveness. This process was repeated until adequate uterine contractions occurred.
The procedural guidelines common to the administration of misoprostol by the vaginal route or the titrated oral route were as follows:
1. Fetal heart rate and uterine activity were continuously monitored throughout labor induction.
2. Induction failure was defined as not entering into the active phase after 36 hours of misoprostol treatment with a maximal cumulative dosage of 1,600 mcg.
3. Intravenous magnesium sulfate (4 g during 30 minutes) could be given at physician discretion if uterine hyperstimulation occurred.
4. If rupture of membranes had not occurred despite a Bishop’s score of 9 or above, artificial rupture of the membrane could be performed at physician discretion.
5. Supplemental oxytocin could be used at physician discretion when uterine contractions were inadequate when entering into the active phase because of poor response to misoprostol.
6. Cesarean delivery was offered to all patients after induction failure or a prolonged active phase.
Adequate uterine contractions in this study were defined as occurring every 2–3 minutes and lasting 60–90 seconds, with an intrauterine pressure 50–60 mm Hg. Tachysystole was defined as the presence of at least six contractions in 10 minutes over 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. Fetal heart rate changes considered to be nonreassuring were late deceleration, severe variable deceleration, prolonged deceleration, tachycardia, or reduced FHR variability requiring intervention either by tocolytics or delivery.
The primary measures used to evaluate efficacy were the interval from the first misoprostol dose to vaginal delivery and the percentage of women who delivered infants vaginally within 12 hours and 24 hours of induction. The primary measures used to evaluate safety were incidence of tachysystole, hypertonus, uterine hyperstimulation, and nonreassuring FHR. The secondary measures used to evaluate efficacy or safety included total dosage of misoprostol, rate of women given oxytocin, cesarean delivery and induction failure, neonatal outcomes including lower Apgar score (less than 7 at 5 minutes), and admittance to the neonatal unit. The occurrence of treatment adverse effects and characteristics of patients including age, body height, body weight, parity, gestational age at induction, indication for induction, and cervical score before the start of induction were also recorded.
The sample size calculation was based on 25% of the incidence of the primary outcome, vaginal delivery within 12 hours, as previously reported in pilot study of labor induction with titrated oral misoprostol.22 Detection of an increase to 50% with 95% certainty and 90% power with an additional 20% sample size for potential loss of control group subjects during the labor course was estimated to require 110 women in each group. The data were analyzed by intention-to-treat and statistical analysis was performed using χ2 test, Fisher exact test, Student t test, and Wilcoxon rank sum test where appropriate. We used SPSS 12.0 for Windows (SPSS Corporation, Chicago, IL) statistical software for all computations.
A total of 220 women were enrolled in the study. The trial profile is shown in Figure 1. Thirteen women were excluded because they requested and underwent cesarean deliveries without medical indications or had epidural analgesia during the course of labor. The incidences of missing data points were 8.2% in the titrated oral and 3.6% in the vaginal group. These percentages were less than the upper limit of 20% estimated to lead to lost control when the sample size was calculated initially. Therefore, these exclusions were not considered likely to have affected the results. Of the 207 women included, 101 (48.8%) received titrated oral misoprostol, and 106 (51.2%) received vaginal misoprostol.
The demographic characteristics and indications for induction are shown in Table 1. The two groups were similar with respect to body weight and Bishop score less than or equal to 3 at entry. Because the maternal age, gestational age, and body height were not considered factors that were likely to affect labor course, the small differences in these factors between the two groups could be neglected. However, because there were more nulliparous women in the vaginal group, a stratified analysis needed to be performed when the primary measures of efficacy were evaluated. Most of the indications for induction were similar between the two groups except that there were more women with premature rupture of membrane (PROM) in the titrated oral group. Artificial rupture of membranes was performed when the Bishop score was greater than or equal to 9, and this procedure could have decreased the bias from the unbalanced number of cases with PROM.
The median interval from the first dose of misoprostol to vaginal delivery was 8.2 hours in the titrated oral group and 17.6 hours in the vaginal group (P<.01). There were significantly more women who delivered vaginally within 12 hours or 24 hours in the titrated oral group than in the vaginal group (74.3% compared with 25.5%, relative risk [RR] 8.44, 95% confidence interval [CI] 4.52–15.76 or 94.1% compared with 53.8%, RR 13.61, 95% CI 5.49–33.78) (Table 2). Analysis stratified by parity status was used to control for the parity-confounding effect in the comparison of the incidence of vaginal delivery within 12 hours or 24 hours between the two groups. The initial results, however, also held in this analysis.
There were no significant differences in the occurrence of tachysystole, hypertonus, and nonreassuring FHR between the two groups. Tachysystole developed in 7 (6.9%) women in the titrated oral group and 16 (15.1%) women in the vaginal group (RR 0.42, 95% CI 0.16–1.07). When tachysystole occurred, the misoprostol was halted immediately in the titrated oral group. This explains why no case of uterine hyperstimulation occurred in the titrated oral group. By contrast, uterine hyperstimulation occurred in 12 (11.3%) women in the vaginal group. Ten of these women received tocolysis and four of them underwent urgent delivery by cesarean method. Nonreassuring FHR patterns that necessitated urgent delivery were noted in two (2.0%) women in the titrated oral group and 10 (9.4%) women in the vaginal group (RR 0.19, 95% CI 0.04–0.91). Of these, 1 of 2 and 6 of 10 underwent cesarean delivery, respectively. Induction failure did not occur in any patient in the titrated oral group but occurred in 11 (10.4%) women in the vaginal group (RR 0.04, 95% CI 0.00–0.70).
The median total dosage was 180 mcg in the titrated oral group and 50 mcg in the vaginal group (P<.01). Although the total dosage of titrated oral misoprostol ranged from 40 mcg to 1,120 mcg, only 10.9% (11 of 101) of patients in the titrated oral misoprostol group needed oxytocin augmentation, which was a far lower percentage than the 53.8% (57 of 106) in the vaginal misoprostol group (RR 0.11, 95% CI 0.05–0.22). The mode of delivery differed significantly between the two groups. Eighteen (17.0%) patients in the vaginal group underwent cesarean delivery compared with only four (4.0%) patients in the titrated oral group (RR 0.20, 95% CI 0.07–0.62). The indications for cesarean delivery included failure to progress, nonreassuring FHR, or others. Twenty of the 22 cesarean deliveries were in nullipara, and two of them were in multipara. There was also no significant difference in parity between women who underwent cesarean delivery in the two groups.
Treatment adverse effects were similar in the two groups except that no patient in the vaginal group experienced nausea, vomiting, and diarrhea, whereas in the titrated oral group nausea occurred in 11 (10.9%) women, vomiting in nine (8.9%), and diarrhea in five (5.0%). There were no differences in neonatal outcomes (Table 3) except for fewer patients with Apgar scores less than 7 at 1 minute in the titrated oral group (RR 0.10, 95% CI 0.01–0.76). However, it was noted that the labor course of induction was more than 24 hours in five of six newborns with Apgar scores less than 7 at 5 minutes in the vaginal group.
Multiple trials have shown that misoprostol is an effective agent for cervical ripening and labor induction. Vaginal as well as oral misoprostol administration has been used, with 25 mcg every 4 hours widely accepted as the most effective regimen with the least number of complications. The optimal dose of oral misoprostol has not been established.
The purpose of this study was to compare the efficacy and safety of a novel dosing regimen of titrated oral misoprostol with the standard regiment of vaginal misoprostol every 4 hours. The rationale for this study stems from the proven efficacy and pharmacokinetics of oral misoprostol, and the extreme interindividual and intraindividual variation in terms of uterine sensitivity. Uterine hyperstimulation is always a concern in either regular or stepwise administration of oral misoprostol every 4 hours.25 To avoid uterine hyperstimulation and shorten the interval from induction to vaginal delivery, we adopted the principle that misoprostol should be administered orally in small, frequent doses (one dose per hour generally), titrated against uterine response and analogous to the conventional titrated use of oxytocin. This method is easier to administer than vaginal suppositories and is less expensive than intravenous oxytocin administered by an infusion pump.
There were more nulliparous women in the titrated oral group because this study did not use a double placebo. The women and clinicians were aware of the allocated treatment and our unit has had a large amount of previous experience with titrated oral misoprostol. We considered the possible implications that patients and staff might prefer a titrated oral misoprostol and might “dislike” the vaginal approach simply due to its comparative inconvenience. These were the unavoidable sources of potential bias in this study.
Measures used to assess efficacy were the interval from the first misoprostol dose to vaginal delivery, the percentage of women who delivered infants vaginally within 12 and 24 hours of induction, and the induction failure rate. Although there were more women with PROM in the titrated oral group, artificial rupture of the membrane was performed when the Bishop’s score was greater than or equal to 9, which may have decreased related bias. Therefore, our results still support the finding that the outcomes of the titrated oral misoprostol group were superior to the vaginal misoprostol group.
The measures used to assess safety in this study were incidence of tachysystole, hypertonus, uterine hyperstimulation, neonatal outcomes with low Apgar scores, and neonatal unit admission. Although tachysystole occurred in seven (6.9%) patients of titrated oral misoprostol group, the oral intake of misoprostol solution was halted immediately in these patients until uterine contractions became inadequate. Then, a small dosage of misoprostol was added to augment uterine contractions. None of the patients in the titrated oral misoprostol group had developed uterine hyperstimulation. These results suggest that small dosage increments, with continuous adjustment according to response, is a better way to decrease the incidence of uterine hyperstimulation.
The median total dosage was 180 mcg in the titrated oral group, which was 3.6 times that of vaginal group. Because the misoprostol has both uterotropic and uterotonic effects, the need of oxytocin augmentation was less in the titrated oral group. Although the common maternal adverse effects of nausea, vomiting, and diarrhea were significantly more frequent in the titrated oral misoprostol group, these incidences were not greater than those reported in a previous study that used high oral doses.17 In addition, these common adverse effects could easily be decreased by using antiemetics or antidiarrheals.
The most important finding of this study was the significantly lower cesarean delivery rate in the women who received the titrated oral misoprostol regimen. This finding suggests that repeated small oral doses of misoprostol ripened the cervix and overcame the cervical barrier, resulting in a high rate of vaginal delivery. In conclusion, we have shown that titrated oral misoprostol is associated with a lower incidence of uterine hyperstimulation and a lower cesarean delivery rate than vaginal misoprostol for labor induction in patients with unfavorable cervix.
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