Objective
We designed a dose-finding trial of oral misoprostol administered for labor augmentation.
Study Design
Healthy, nulliparous women in active labor and diagnosed with arrest of dilation were enrolled in cohorts of 10 at a time. Five regimens were studied: (1) 25 μg every 4 hours, (2) 50 μg every 4 hours, (3) 100 μg every 4 hours, (4) 50 μg every 2 hours, and (5) 75 μg every 4 hours.
Results
A total of 46 women were enrolled. Baseline uterine activity approximately doubled with 4 of the regimens and tripled with the highest dosage regimen (100 μg) ( P < .001). The 100-μg regimen was truncated due to excessive uterine hyperstimulation (40%).
Conclusion
An oral dose of 75 μg of misoprostol given at a 4-hour interval for a maximum of 2 doses is the highest tolerated dose. Randomized, controlled trials will be required before a regimen is employed routinely.
Stimulation of labor has become one of the most commonly used obstetric procedures in the United States. For example, the first data from the 2003 revision of the US Standard Certificate of Live Birth show that induction of labor was used in 26% of live births and augmentation of preexisting labor in another 24%. Put another way, it is estimated that 50% of women undergo stimulation of labor in the United States. Stimulation of labor typically employs oxytocin, although a variety of prostaglandin preparations have been used for either cervical ripening or actual labor stimulation. Indeed, there are several reports on the efficacy and safety of misoprostol–a synthetic prostaglandin E 1 . In a recent Cochrane systematic review (2006) 41 trials involving 8606 women were found in which misoprostol was studied. It was concluded that oral misoprostol was an effective agent for stimulation of labor. However, there remained questions about its safety because of a relatively high rate of uterine hyperstimulation and the lack of appropriate dose-finding studies. Importantly, there were no trials of misoprostol used for augmentation–only for induction.
We surmised that there has been reluctance to use misoprostol with its high rate of uterine hyperstimulation in women experiencing ineffective labor for fear that an already contracting uterus might be more likely to develop hyperstimulation. We had previously studied misoprostol for labor induction and found this agent to be both effective and safe when compared to placebo. We considered misoprostol to be advantageous because it permitted us to forego time-consuming oxytocin infusion in approximately 60% of women undergoing labor induction at our hospital. This prompted us to consider the use of misoprostol in women receiving labor stimulation for ineffective progress of spontaneous labor, ie, augmentation.
Administering misoprostol orally rather than vaginally was chosen for this purpose. As women undergoing augmentation of labor generally have ruptured membranes and are of advanced dilation, we were concerned that the absorption via the vaginal route may be unpredictable. There is vast experience in the pharmacokinetics of oral administration of misoprostol, and the laboring state was not expected to change the absorption and peak serum levels appreciably.
This report describes a dose-finding study done in preparation for a follow-on randomized trial of misoprostol in women requiring augmentation. Our hypothesis was that a dose-response relationship exists between the dose and timing interval of oral misoprostol and resulting uterine hyperstimulation. For the purposes of this study, the term “uterine hyperstimulation” included: uterine tachysystole (≥6 contractions in a 10-minute period) or hypertonus (≥1 contractions lasting >120 seconds) with or without associated abnormal fetal heart rate patterns. In other words, a woman need only have excessive uterine activity to be placed in the category of hyperstimulation, without having evidence of fetal compromise. We patterned this study after a Food and Drug Administration phase I clinical trial.
As described by Piantadosi, the purpose of a phase I clinical trial is to “establish a safe dose and schedule of administration” of a new drug, or in this case, a drug used for a new purpose. Phase I trials designs are described as “adaptive,” which means that the decision to proceed to the next higher dose is dependent on the effects observed at the current dose. Typically, the initial dose chosen is small, and the dose is doubled until adverse effects of the drug exceed prespecified parameters. It is not uncommon for intermediate regimens to be evaluated after the “toxic dose” is identified. Generally, only 20-80 patients are enrolled in phase I trials. Therefore, phase I trials can only provide limited evidence regarding effectiveness of the drug due to the small numbers of patients enrolled.
Materials and Methods
The study protocol was developed by investigators in the department of obstetrics and gynecology and approved by the institutional review board (IRB) of the University of Texas Southwestern Medical Center at Dallas. A stipulation of the IRB approval of this study required submission of outcome data after completion of each dose regimen for IRB review and approval prior to enrollment of any women in subsequent regimens. Therefore, an extended amount of time was required to complete this study. From July 1, 2007, through September 16, 2008, healthy, nulliparous women diagnosed with arrest of dilation were evaluated for participation in this study at Parkland Hospital, Dallas, TX. In order to be considered for enrollment, women had to be healthy (no medical or pregnancy-related illnesses), between 36-42 weeks’ gestation, with a cephalic singleton pregnancy in spontaneous active labor.
Active labor was diagnosed when cervical dilation had reached 4 cm. If such a woman had achieved at least 4 cm cervical dilation and subsequently did not further dilate over 2-4 hours, an amniotomy was performed to augment her labor if her membranes were not already ruptured. At the same time an intrauterine pressure catheter was placed to determine if her contractions were adequate. A woman with no further change in dilation 2-4 hours after amniotomy with <200 Montevideo units (MVU) of uterine activity was diagnosed to have arrest of dilation due to inadequate uterine contractions. Our standard of care in such women was stimulation of labor with intravenous oxytocin according to a dosage schedule previously reported. It was at this point that we offered participation in this study in lieu of oxytocin infusion.
Women were excluded from participation if they had any of the following: (1) >200 MVU when measured using an intrauterine pressure catheter, (2) a nonreassuring fetal heart rate tracing, (3) meconium-stained amnionic fluid, (4) previous uterine incision, (5) maternal fever or other evidence of clinical chorioamnionitis, (6) pregnancy-induced hypertension or any other pregnancy-related complications, (7) known fetal anomalies, (8) estimated fetal weight of ≥4500 g, or (9) a prior delivery of a fetus ≥20 weeks’ gestation.
A standard dose-finding design for phase I trials was utilized wherein the dose was doubled until excessive side effects were encountered. Women were enrolled in cohorts of 10 at a time, starting from a lower dose and proceeding to higher dosing regimens until hyperstimulation occurred. It was decided a priori that a dosage regimen would be deemed safe if 3 conditions were met: (1) ≤3 women developed uterine tachysystole (≥6 contractions in a 10-minute period) or hypertonus (≥1 contractions lasting >120 seconds) with or without associated abnormal fetal heart rate patterns, (2) no woman developed uterine tachysystole or hypertonus requiring an emergent cesarean delivery, and (3) no women delivered a baby with poor neonatal outcome measures (defined as a 5-minute Apgar score of ≤4 or an umbilical artery pH of <7.0). On the other hand, if at least 9 of 10 women at a given dosage level achieved adequate uterine activity defined as >200 MVU, the drug was deemed effective for labor augmentation at that dose. In that case, there would be no need to escalate the dosing and the study would be completed.
These safety and efficacy criteria were developed utilizing the known side-effect profile and efficacy of the oxytocin regimen employed in our institution. Specifically, oxytocin is administered starting at a low dose and increasing the dose every 40 minutes with a goal of 200-250 MVU. Using this regimen, uterine tachysystole or hypertonus (as defined in the previous paragraph) is encountered in 31% of patients. Thus, the safety criteria reflect the tolerance of these side effects in up to 3 of the 10 women enrolled in a given regimen cohort, as long as maternal and fetal well-being is not impacted. This oxytocin regimen produces at least 200 MVU in 90% of patients. Therefore, optimal efficacy was defined as 9 of the 10 women in a cohort achieving adequate MVU.
Written informed consent was obtained in the woman’s primary language. Specifically, women were counseled regarding the risks of failure of the medication to augment labor, prolonged labor, infection during labor, excessive uterine contractions, and fetal distress potentially leading to cesarean delivery and/or poor neonatal outcome, as well as nausea, vomiting, and diarrhea as side effects of the medication. After enrollment, baseline fetal heart rate and maternal contraction patterns were recorded for 30 minutes prior to administration of the study drug. Fetal heart rate and maternal contractions were then recorded continuously for the remainder of the woman’s labor and delivery course, and stored in a computer database for analysis.
A total of 3 successive cohorts of 10 women each were planned, beginning with a 25-μg misoprostol dose given orally at a 4-hour interval up to a maximum of 2 doses. We used the standard dose-finding design wherein the dose was doubled until reaching 100 μg, which was the oral dosage we previously found effective for labor induction. That is, regimen 1 consisted of a 25-μg dose, regimen 2 a 50-μg dose, and regimen 3 a 100-μg dose. If at any time uterine hyperstimulation or an abnormal fetal heart rate tracing was encountered, no further doses of misoprostol were administered. If the second dose of misoprostol was held due to hyperstimulation, the women were eligible to be given oxytocin. Hyperstimulation was treated by placing the woman in a lateral position and oxygen (10 L/min) was given by face mask. Terbutaline or other tocolytic agents were not administered. If misoprostol was found to be ineffective, ie, MVU were <200 and there was lack of normal progress of labor, oxytocin infusion was initiated as soon as 1 hour following the second dose of misoprostol. Cervical examinations were performed as deemed necessary by the attending clinicians. Labor epidural analgesia was offered and provided upon request. The diagnosis of chorioamnionitis was made in women who developed a fever of ≥38.0°C.
A total of 5 dosage regimens were ultimately studied. This extended the initially planned 3 cohorts where the misoprostol dosage escalated from 25 μg to 50 μg to 100 μg every 4 hours (regimens 1, 2, and 3, respectively). Regimens 4 and 5 were studied because the 100-μg dose produced unacceptable hyperstimulation and we sought to evaluate intermediate regimens by changing the dosage or interval. Regimen 4 utilized 50 μg given every 2 hours rather than every 4 hours. The shorter dosage interval was evaluated in light of the known pharmacokinetics of orally administered misoprostol, ie, the plasma concentration at 2 hours is nearly undetectable, and is identical to the plasma concentration at 4 hours. Regimen 5 evaluated 75 μg given every 4 hours, an intermediate dose between the 50-μg dose (regimen 2) and the 100-μg dose (regimen 3).
Study medication was prepared by the Parkland Hospital Investigational Drug Service. Generic misoprostol 100-μg tablets were halved and quartered using a special pill-cutting device and only intact segments were used. This was an open-label study. After consultation with the Food and Drug Administration, it was determined that an Investigational New Drug designation was not required for this trial, as the use of misoprostol for labor stimulation has been extensively studied in other settings.
Due to the small numbers in each cohort, statistically significant differences were expected to be difficult to determine in this phase I trial. Nonetheless, labor outcomes of each regimen were compared using analysis of variance. Uterine activity measured in MVU at baseline and peak following administration of misoprostol was compared using Student t test. Analysis of frequency data was accomplished using the Pearson χ 2 . When comparing the effect of each regimen over time, a linear effect of the dose upon uterine activity was assumed. Regimens were compared using a random effects model for repeated measures. For all analyses a P value of < .05 was considered significant.
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