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A dose-finding study of oral misoprostol for labor augmentation
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www. AJOG.org
A dose-finding study of oral misoprostol for labor augmentation Kathryn S. Villano, MD; Julie Y. Lo, MD; James M. Alexander, MD; Donald D. McIntire, PhD; Kenneth J. Leveno, MD OBJECTIVE: We designed a dose-finding trial of oral misoprostol ad-
ministered 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 g every 4 hours, (2) 50 g every 4 hours, (3) 100 g every 4 hours, (4) 50 g every 2 hours, and (5) 75 g every 4 hours. RESULTS: A total of 46 women were enrolled. Baseline uterine ac-
tivity approximately doubled with 4 of the regimens and tripled with
the highest dosage regimen (100 g) (P ⬍ .001). The 100-g regimen was truncated due to excessive uterine hyperstimulation (40%). CONCLUSION: An oral dose of 75 g 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.
Key words: dose-finding, labor augmentation, oral misoprostol, phase I trial
Cite this article as: Villano KS, Lo JY, Alexander JM, et al. A dose-finding study of oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011;204:560.e1-5.
S
timulation 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%.1 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.2,3 Indeed, there are several
From the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX (all authors), and Regional Obstetric Consultants, Jacksonville, FL (Dr Villano). Presented at the 73rd Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, VA, Jan. 31-Feb. 2, 2011. Received Oct. 18, 2010; revised Feb. 14, 2011; accepted Feb. 24, 2011. Reprints: Kathryn S. Villano, MD, 836 Prudential Dr., Suite 1800, Jacksonville, FL 32207. [email protected]. 0002-9378/$36.00 © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.02.064
560.e1
reports on the efficacy and safety of misoprostol–a synthetic prostaglandin E1. 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.4 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.5 We considered misoprostol to be advantageous because it permitted us to forego timeconsuming 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
American Journal of Obstetrics & Gynecology JUNE 2011
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.6 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 (ⱖ6 contractions in a 10minute period) or hypertonus (ⱖ1 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.7 As described by Piantadosi,8 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
SAAOG Papers
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TABLE 1
TABLE 2
Demographic characteristics of 46 nulliparous women enrolled in dose-ranging study of misoprostol
Oral misoprostol regimens studied
Characteristic
Women
Race/ethnicity
42 (91)
..................................................................................................
African American
No. of women
1
10
2 3
Misoprostol dose, g
Dosing interval, h
25
4
10
50
4
6
100
4
4
10
50
2
5
10
75
4
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
..................................................................................................
Hispanic
Regimen no.
1 (2)
..................................................................................................
White
2 (4.3)
Asian
1 (2)
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Villano. Oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011.
.................................................................................................. ...........................................................................................................
Maternal age, y
23.6 ⫾ 5.2
Gestational age, wk
39.9 ⫾ 0.8
........................................................................................................... ...........................................................................................................
Cervical dilation at enrollment, cm
4 (4.5)
...........................................................................................................
Birthweight, g
3459 ⫾ 402
...........................................................................................................
All data shown as n (%), mean ⫾ SD, or median (first and third quartiles). Villano. Oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011.
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.7
M ATERIALS AND M ETHODS 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 pregnancyrelated 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.9 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
ⱖ4500 g, or (9) a prior delivery of a fetus ⱖ20 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) ⱕ3 women developed uterine tachysystole (ⱖ6 contractions in a 10-minute period) or hypertonus (ⱖ1 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 ⱕ4 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 200250 MVU. Using this regimen, uterine tachysystole or hypertonus (as defined in the previous paragraph) is encountered in 31% of patients.9 Thus, the safety criteria reflect the tolerance of these side ef-
JUNE 2011 American Journal of Obstetrics & Gynecology
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SAAOG Papers
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TABLE 3
Course of labor following oral misoprostol Variable
Regimen 1, n ⴝ 10
Regimen 2, n ⴝ 10
Regimen 3, n ⴝ 6
Regimen 4, n ⴝ 10
Regimen 5, n ⴝ 10
Montevideo units
.......................................................................................................................................................................................................................................................................................................................................................................
Baseline
98 (⫾35)
106 (⫾106)
103 (⫾47)
124 (⫾52)
110 (⫾42)
Maximum achieved
212 (⫾68)
227 (⫾44)
299 (⫾99)
206 ( ⫾68)
211 ( ⫾66)
No. of women ⬎200
6 (60)
6 (60)
5 (83)
7 (70)
6 (60)
Time from first dose to delivery, h
9.3 (⫾5)
6.2 (⫾2.5)
4.7 (⫾2)
8 (⫾4.7)
7.4 (⫾3.6)
Oxytocin required
3 (30)
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
1 (10)
0
5 (50)
2 (20)
................................................................................................................................................................................................................................................................................................................................................................................
All data shown as mean (⫾SD) or n (%). There were no significant differences between regimens. Baseline refers to 30 min before misoprostol was given. Villano. Oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011.
fects 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.9 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-g 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 g, which was the oral dosage we previously found effective for labor induction.5 That is, regimen 1 consisted of a 25-g dose, regimen 2 a 50-g dose, and regimen 3 a 100-g dose. If at any time uterine hyperstimulation or an abnormal fe560.e3
tal 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 ⱖ38.0°C. A total of 5 dosage regimens were ultimately studied. This extended the initially planned 3 cohorts where the miso-
prostol dosage escalated from 25 g to 50 g to 100 g every 4 hours (regimens 1, 2, and 3, respectively). Regimens 4 and 5 were studied because the 100-g dose produced unacceptable hyperstimulation and we sought to evaluate intermediate regimens by changing the dosage or interval. Regimen 4 utilized 50 g 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.6 Regimen 5 evaluated 75 g given every 4 hours, an intermediate dose between the 50-g dose (regimen 2) and the 100-g dose (regimen 3). Study medication was prepared by the Parkland Hospital Investigational Drug Service. Generic misoprostol 100-g tablets were halved and quartered using a special pill-cutting device and only intact segments were used. This was an open-
TABLE 4
Selected outcomes of oral misoprostol for labor augmentation Outcome
Regimen 1, Regimen 2, Regimen 3, Regimen 4, Regimen 5, n ⴝ 10 n ⴝ 10 nⴝ6 n ⴝ 10 n ⴝ 10
Uterine hyperstimulation 2 (20)
3 (30)
4 (66)
0
3 (30)
Chorioamnionitis
3 (30)
1 (17)
5 (50)
2 (20)
..............................................................................................................................................................................................................................................
6 (60)
..............................................................................................................................................................................................................................................
Cesarean indication
.....................................................................................................................................................................................................................................
Dystocia
2 (20)
0
0
2 (20)
3 (30)
Nonreassuring FHR
0
0
1 (17)
0
1 (10)
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
All data shown n (%). There were no significant differences between regimens. FHR, fetal heart rate. Villano. Oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011.
American Journal of Obstetrics & Gynecology JUNE 2011
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FIGURE
Uterine response to oral misoprostol regimen in Montevideo units (MVU)
Villano. Oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011.
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 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.
R ESULTS In all, 94 women were offered enrollment in this study. A total of 46 women
accepted, and their demographic characteristics are shown in Table 1. These women were consecutively enrolled into 1 of the 5 regimens (Table 2). Regimen 3, the 100-g dose, produced hyperstimulation in 4 of the first 6 women enrolled, exceeding the desired limit. Therefore, enrollment in this regimen was stopped in accordance with the a priori safety criteria. The course of labor before and after the various misoprostol regimens is shown in Table 3. Each misoprostol regimen significantly increased uterine activity quantified using MVU. Indeed, uterine activity approximately doubled with each of 4 of the regimens and tripled with the highest dosage regimen, ie, the 100-g dose (P ⬍ .001). The number of women ultimately achieving 200 MVU was similar among the 5 regimens and varied between 60-83% (P ⫽ .87). The elapsed time from the first dose of misoprostol to delivery appeared to follow a dose-response relationship with the longest time interval for the lowest misoprostol dose (25 g) and the shortest interval with the highest dose (100 g) (P ⫽ .24). Overall, 11 (24%) women re-
quired oxytocin with no appreciable differences between the regimens (P ⫽ .14). Of the 11 women who required oxytocin, the mean birthweight was not significantly different (3575 g vs 3423 g, P ⫽ .28). As shown in Table 4, the rate of uterine hyperstimulation appeared to follow a dose and dosing interval relationship (P ⫽ .06) with the exception of regimen 4 where the women received 50 g every 2 hours and none experienced hyperstimulation. This seeming advantage was offset, however, by the highest rate of oxytocin requirement. Cesarean delivery and its indications were not related to the misoprostol regimen used (P ⫽ .29) and corresponded to the rates expected for nulliparous women delivered at our hospital. The incidence of chorioamnionitis tended to parallel the labor times as well as need for oxytocin. The Figure depicts the change in uterine activity displayed in MVU over time for each of the regimens studied. Regimens 1, 2, 4, and 5 (the regimens involving 25- to 75-g doses) all depict similar changes–all of them essentially doubled the baseline uterine activity. Regimen 3, the 100-g dose regimen, tripled the baseline uterine activity. When these changes are examined utilizing a repeated measures random effects model wherein a linear trend is assumed for the data, a significant difference is seen between regimens (P ⫽ .021). This difference is driven by the effect of the 100-g dose regimen. Excluding the 100-g regimen from the analysis removes the statistical significance. Infant outcomes, both at birth and during the neonatal periods, were evaluated. It was found that 45 of the 46 infants had completely unremarkable courses to include Apgar scores of 9 at 5 minutes and no significant acidemia in umbilical artery blood. One infant delivered by cesarean section for dystocia had Apgar scores of 3 at 1 minute and 7 at 5 minutes. This infant was hypotensive at birth and required intubation. Fetal-maternal hemorrhage was diagnosed and the infant did well following transfusion. The mother had received two 25-g doses of misoprostol 4 hours apart and reached a
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560.e4
SAAOG Papers maximum of 250 MVU. There was no uterine hyperstimulation in this case.
C OMMENT The purpose of this study was to gain experience on the safety of various dosage regimens when misoprostol is used for augmentation of labor. Although we have considerable experience with this agent for labor induction, we were concerned that the effects of misoprostol might be substantially different in women with preexisting uterine activity–albeit insufficient for progress of labor. Ideally, a regimen of oral misoprostol used for labor augmentation should be comparable to oxytocin, both in efficacy and sideeffect profile, namely hyperstimulation risk. A dose-finding study by virtue of the small sample size must be subjectively interpreted. This caveat aside, we interpret our findings to be that there is a doseresponse relationship between misoprostol and normal uterine contractions, as well as uterine hyperstimulation. Doses as low as 25 g do have an effect in stimulating labor, albeit with a potentially longer time to delivery and a higher rate of chorioamnionitis. We were unable to discern appreciable differences in other outcomes such as need for oxytocin stimulation (a surrogate for misoprostol failure), route of delivery, and the indication for cesarean delivery. Similarly, none of the regimens could be directly linked to compromised infant outcomes. Putting all of this together, we conclude that an oral 75-g dose of misoprostol given at a 4-hour interval for a maximum of 2 doses was the maximum tolerated regimen. We searched PubMed for publications on the use of misoprostol for labor augmentation and found no reports. Search
560.e5
www.AJOG.org terms included: “misoprostol,” “augmentation,” “active labor,” “arrest of dilation,” “prolonged labor,” and “protracted labor.” However, in one report on misoprostol induction, Hofmeyr and colleagues10 noted that they used an oral misoprostol solution for labor augmentation in women who had been induced with misoprostol, but who had failed to progress in labor. They used 5- to 20-g doses administered hourly in 58 women and found this regimen to be well tolerated. However, this part of the augmentation process was not evaluated separately from the initial induction phase. These investigators speculated that higher misoprostol doses would be required. The only other information we could find on the use of misoprostol for augmentation was in the clinical trials registry of the National Institutes of Health. This was a study currently in progress at the China Medical University Hospital in Taiwan whereby oral misoprostol is being compared to oxytocin infusion.11 This phase I trial demonstrates the feasibility of using oral misoprostol for labor augmentation. Ideally, the dose selected should provide the most efficacy within acceptable toxicity parameters. In this case, efficacy may be defined as cervical change or adequate MVU if cervical change does not take place, and ultimately vaginal delivery. Toxicity should include uterine hyperstimulation and/or fetal compromise. This study establishes the maximum tolerated dose as 75 g. Further randomized trials will be required to determine the efficacy and further delineate the risks of this regimen. We recently registered our own, now in progress, randomized trial using the 75-g misoprostol regimen described in this report. The results of this randomized trial, and hopefully other trials of
American Journal of Obstetrics & Gynecology JUNE 2011
misoprostol for labor augmentation, must be evaluated critically prior to consideration of this drug for labor augmentation outside of research protocols. f REFERENCES 1. Martin JA, Menacker F. Expanded health data from the new birth certificate, 2004. Natl Vital Stat Rep 2007;55:1-22. 2. American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 10: induction of labor. Washington, DC: ACOG; 1999. 3. American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 49: dystocia and augmentation of labor. Washington, DC: ACOG; 2003. 4. Alfirevic Z, Weeks A. Oral misoprostol for induction of labor. Cochrane Database Syst Rev 2006;2:CD001338. 5. Lo JY, Alexander JA, McIntire DD, Leveno KJ. Ruptured membranes at term: a randomized, double-blind trial of oral misoprostol for labor induction. Obstet Gynecol 2003;101: 685-9. 6. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects. Int J Gynaecol Obstet 2007;99:S160-7. 7. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research. US Food and Drug Administration: Center for Drug Evaluation and Research Handbook. Revised March 16, 1998. Available at: http://www.fda.gov/cder/handbook/ Phase1.htm. Accessed May 1, 2009. 8. Piantadosi S. Clinical trials: a methodologic perspective, 2nd ed. New York, NY: Wiley-Interscience; 2005. 9. Satin AJ, Leveno KJ, Sheman ML, McIntire D. High-dose oxytocin: 20- versus 40-minute dosage interval. Obstet Gynecol 1994;83: 234-8. 10. Hofmeyr GJ, Alfirevic Z, Matonhodze B, Brocklehurst P, Campbell E, Nikodem VC. Titrated oral misoprostol solution for induction of labor: a multi-center, randomized trial. BJOG 2001;108:952-9. 11. Cheng S. Efficacy and safety study of titrated oral misoprostol solution for labor augmentation. Available at: http://clinicaltrials.gov/ ct2/show/NCT00695331. Accessed May 1, 2009.
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A dose-finding study of oral misoprostol for labor augmentation Kathryn S. Villano, MD; Julie Y. Lo, MD; James M. Alexander, MD; Donald D. McIntire, PhD; Kenneth J. Leveno, MD OBJECTIVE: We designed a dose-finding trial of oral misoprostol ad-
ministered 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 g every 4 hours, (2) 50 g every 4 hours, (3) 100 g every 4 hours, (4) 50 g every 2 hours, and (5) 75 g every 4 hours. RESULTS: A total of 46 women were enrolled. Baseline uterine ac-
tivity approximately doubled with 4 of the regimens and tripled with
the highest dosage regimen (100 g) (P ⬍ .001). The 100-g regimen was truncated due to excessive uterine hyperstimulation (40%). CONCLUSION: An oral dose of 75 g 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.
Key words: dose-finding, labor augmentation, oral misoprostol, phase I trial
Cite this article as: Villano KS, Lo JY, Alexander JM, et al. A dose-finding study of oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011;204:560.e1-5.
S
timulation 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%.1 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.2,3 Indeed, there are several
From the Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX (all authors), and Regional Obstetric Consultants, Jacksonville, FL (Dr Villano). Presented at the 73rd Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Hot Springs, VA, Jan. 31-Feb. 2, 2011. Received Oct. 18, 2010; revised Feb. 14, 2011; accepted Feb. 24, 2011. Reprints: Kathryn S. Villano, MD, 836 Prudential Dr., Suite 1800, Jacksonville, FL 32207. [email protected]. 0002-9378/$36.00 © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.02.064
560.e1
reports on the efficacy and safety of misoprostol–a synthetic prostaglandin E1. 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.4 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.5 We considered misoprostol to be advantageous because it permitted us to forego timeconsuming 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
American Journal of Obstetrics & Gynecology JUNE 2011
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.6 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 (ⱖ6 contractions in a 10minute period) or hypertonus (ⱖ1 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.7 As described by Piantadosi,8 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
SAAOG Papers
www.AJOG.org
TABLE 1
TABLE 2
Demographic characteristics of 46 nulliparous women enrolled in dose-ranging study of misoprostol
Oral misoprostol regimens studied
Characteristic
Women
Race/ethnicity
42 (91)
..................................................................................................
African American
No. of women
1
10
2 3
Misoprostol dose, g
Dosing interval, h
25
4
10
50
4
6
100
4
4
10
50
2
5
10
75
4
.............................................................................................................................................................................................................................................. .............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
..................................................................................................
Hispanic
Regimen no.
1 (2)
..................................................................................................
White
2 (4.3)
Asian
1 (2)
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Villano. Oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011.
.................................................................................................. ...........................................................................................................
Maternal age, y
23.6 ⫾ 5.2
Gestational age, wk
39.9 ⫾ 0.8
........................................................................................................... ...........................................................................................................
Cervical dilation at enrollment, cm
4 (4.5)
...........................................................................................................
Birthweight, g
3459 ⫾ 402
...........................................................................................................
All data shown as n (%), mean ⫾ SD, or median (first and third quartiles). Villano. Oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011.
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.7
M ATERIALS AND M ETHODS 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 pregnancyrelated 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.9 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
ⱖ4500 g, or (9) a prior delivery of a fetus ⱖ20 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) ⱕ3 women developed uterine tachysystole (ⱖ6 contractions in a 10-minute period) or hypertonus (ⱖ1 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 ⱕ4 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 200250 MVU. Using this regimen, uterine tachysystole or hypertonus (as defined in the previous paragraph) is encountered in 31% of patients.9 Thus, the safety criteria reflect the tolerance of these side ef-
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TABLE 3
Course of labor following oral misoprostol Variable
Regimen 1, n ⴝ 10
Regimen 2, n ⴝ 10
Regimen 3, n ⴝ 6
Regimen 4, n ⴝ 10
Regimen 5, n ⴝ 10
Montevideo units
.......................................................................................................................................................................................................................................................................................................................................................................
Baseline
98 (⫾35)
106 (⫾106)
103 (⫾47)
124 (⫾52)
110 (⫾42)
Maximum achieved
212 (⫾68)
227 (⫾44)
299 (⫾99)
206 ( ⫾68)
211 ( ⫾66)
No. of women ⬎200
6 (60)
6 (60)
5 (83)
7 (70)
6 (60)
Time from first dose to delivery, h
9.3 (⫾5)
6.2 (⫾2.5)
4.7 (⫾2)
8 (⫾4.7)
7.4 (⫾3.6)
Oxytocin required
3 (30)
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
1 (10)
0
5 (50)
2 (20)
................................................................................................................................................................................................................................................................................................................................................................................
All data shown as mean (⫾SD) or n (%). There were no significant differences between regimens. Baseline refers to 30 min before misoprostol was given. Villano. Oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011.
fects 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.9 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-g 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 g, which was the oral dosage we previously found effective for labor induction.5 That is, regimen 1 consisted of a 25-g dose, regimen 2 a 50-g dose, and regimen 3 a 100-g dose. If at any time uterine hyperstimulation or an abnormal fe560.e3
tal 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 ⱖ38.0°C. A total of 5 dosage regimens were ultimately studied. This extended the initially planned 3 cohorts where the miso-
prostol dosage escalated from 25 g to 50 g to 100 g every 4 hours (regimens 1, 2, and 3, respectively). Regimens 4 and 5 were studied because the 100-g dose produced unacceptable hyperstimulation and we sought to evaluate intermediate regimens by changing the dosage or interval. Regimen 4 utilized 50 g 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.6 Regimen 5 evaluated 75 g given every 4 hours, an intermediate dose between the 50-g dose (regimen 2) and the 100-g dose (regimen 3). Study medication was prepared by the Parkland Hospital Investigational Drug Service. Generic misoprostol 100-g tablets were halved and quartered using a special pill-cutting device and only intact segments were used. This was an open-
TABLE 4
Selected outcomes of oral misoprostol for labor augmentation Outcome
Regimen 1, Regimen 2, Regimen 3, Regimen 4, Regimen 5, n ⴝ 10 n ⴝ 10 nⴝ6 n ⴝ 10 n ⴝ 10
Uterine hyperstimulation 2 (20)
3 (30)
4 (66)
0
3 (30)
Chorioamnionitis
3 (30)
1 (17)
5 (50)
2 (20)
..............................................................................................................................................................................................................................................
6 (60)
..............................................................................................................................................................................................................................................
Cesarean indication
.....................................................................................................................................................................................................................................
Dystocia
2 (20)
0
0
2 (20)
3 (30)
Nonreassuring FHR
0
0
1 (17)
0
1 (10)
..................................................................................................................................................................................................................................... ..............................................................................................................................................................................................................................................
All data shown n (%). There were no significant differences between regimens. FHR, fetal heart rate. Villano. Oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011.
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FIGURE
Uterine response to oral misoprostol regimen in Montevideo units (MVU)
Villano. Oral misoprostol for labor augmentation. Am J Obstet Gynecol 2011.
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 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.
R ESULTS In all, 94 women were offered enrollment in this study. A total of 46 women
accepted, and their demographic characteristics are shown in Table 1. These women were consecutively enrolled into 1 of the 5 regimens (Table 2). Regimen 3, the 100-g dose, produced hyperstimulation in 4 of the first 6 women enrolled, exceeding the desired limit. Therefore, enrollment in this regimen was stopped in accordance with the a priori safety criteria. The course of labor before and after the various misoprostol regimens is shown in Table 3. Each misoprostol regimen significantly increased uterine activity quantified using MVU. Indeed, uterine activity approximately doubled with each of 4 of the regimens and tripled with the highest dosage regimen, ie, the 100-g dose (P ⬍ .001). The number of women ultimately achieving 200 MVU was similar among the 5 regimens and varied between 60-83% (P ⫽ .87). The elapsed time from the first dose of misoprostol to delivery appeared to follow a dose-response relationship with the longest time interval for the lowest misoprostol dose (25 g) and the shortest interval with the highest dose (100 g) (P ⫽ .24). Overall, 11 (24%) women re-
quired oxytocin with no appreciable differences between the regimens (P ⫽ .14). Of the 11 women who required oxytocin, the mean birthweight was not significantly different (3575 g vs 3423 g, P ⫽ .28). As shown in Table 4, the rate of uterine hyperstimulation appeared to follow a dose and dosing interval relationship (P ⫽ .06) with the exception of regimen 4 where the women received 50 g every 2 hours and none experienced hyperstimulation. This seeming advantage was offset, however, by the highest rate of oxytocin requirement. Cesarean delivery and its indications were not related to the misoprostol regimen used (P ⫽ .29) and corresponded to the rates expected for nulliparous women delivered at our hospital. The incidence of chorioamnionitis tended to parallel the labor times as well as need for oxytocin. The Figure depicts the change in uterine activity displayed in MVU over time for each of the regimens studied. Regimens 1, 2, 4, and 5 (the regimens involving 25- to 75-g doses) all depict similar changes–all of them essentially doubled the baseline uterine activity. Regimen 3, the 100-g dose regimen, tripled the baseline uterine activity. When these changes are examined utilizing a repeated measures random effects model wherein a linear trend is assumed for the data, a significant difference is seen between regimens (P ⫽ .021). This difference is driven by the effect of the 100-g dose regimen. Excluding the 100-g regimen from the analysis removes the statistical significance. Infant outcomes, both at birth and during the neonatal periods, were evaluated. It was found that 45 of the 46 infants had completely unremarkable courses to include Apgar scores of 9 at 5 minutes and no significant acidemia in umbilical artery blood. One infant delivered by cesarean section for dystocia had Apgar scores of 3 at 1 minute and 7 at 5 minutes. This infant was hypotensive at birth and required intubation. Fetal-maternal hemorrhage was diagnosed and the infant did well following transfusion. The mother had received two 25-g doses of misoprostol 4 hours apart and reached a
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C OMMENT The purpose of this study was to gain experience on the safety of various dosage regimens when misoprostol is used for augmentation of labor. Although we have considerable experience with this agent for labor induction, we were concerned that the effects of misoprostol might be substantially different in women with preexisting uterine activity–albeit insufficient for progress of labor. Ideally, a regimen of oral misoprostol used for labor augmentation should be comparable to oxytocin, both in efficacy and sideeffect profile, namely hyperstimulation risk. A dose-finding study by virtue of the small sample size must be subjectively interpreted. This caveat aside, we interpret our findings to be that there is a doseresponse relationship between misoprostol and normal uterine contractions, as well as uterine hyperstimulation. Doses as low as 25 g do have an effect in stimulating labor, albeit with a potentially longer time to delivery and a higher rate of chorioamnionitis. We were unable to discern appreciable differences in other outcomes such as need for oxytocin stimulation (a surrogate for misoprostol failure), route of delivery, and the indication for cesarean delivery. Similarly, none of the regimens could be directly linked to compromised infant outcomes. Putting all of this together, we conclude that an oral 75-g dose of misoprostol given at a 4-hour interval for a maximum of 2 doses was the maximum tolerated regimen. We searched PubMed for publications on the use of misoprostol for labor augmentation and found no reports. Search
560.e5
www.AJOG.org terms included: “misoprostol,” “augmentation,” “active labor,” “arrest of dilation,” “prolonged labor,” and “protracted labor.” However, in one report on misoprostol induction, Hofmeyr and colleagues10 noted that they used an oral misoprostol solution for labor augmentation in women who had been induced with misoprostol, but who had failed to progress in labor. They used 5- to 20-g doses administered hourly in 58 women and found this regimen to be well tolerated. However, this part of the augmentation process was not evaluated separately from the initial induction phase. These investigators speculated that higher misoprostol doses would be required. The only other information we could find on the use of misoprostol for augmentation was in the clinical trials registry of the National Institutes of Health. This was a study currently in progress at the China Medical University Hospital in Taiwan whereby oral misoprostol is being compared to oxytocin infusion.11 This phase I trial demonstrates the feasibility of using oral misoprostol for labor augmentation. Ideally, the dose selected should provide the most efficacy within acceptable toxicity parameters. In this case, efficacy may be defined as cervical change or adequate MVU if cervical change does not take place, and ultimately vaginal delivery. Toxicity should include uterine hyperstimulation and/or fetal compromise. This study establishes the maximum tolerated dose as 75 g. Further randomized trials will be required to determine the efficacy and further delineate the risks of this regimen. We recently registered our own, now in progress, randomized trial using the 75-g misoprostol regimen described in this report. The results of this randomized trial, and hopefully other trials of
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misoprostol for labor augmentation, must be evaluated critically prior to consideration of this drug for labor augmentation outside of research protocols. f REFERENCES 1. Martin JA, Menacker F. Expanded health data from the new birth certificate, 2004. Natl Vital Stat Rep 2007;55:1-22. 2. American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 10: induction of labor. Washington, DC: ACOG; 1999. 3. American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 49: dystocia and augmentation of labor. Washington, DC: ACOG; 2003. 4. Alfirevic Z, Weeks A. Oral misoprostol for induction of labor. Cochrane Database Syst Rev 2006;2:CD001338. 5. Lo JY, Alexander JA, McIntire DD, Leveno KJ. Ruptured membranes at term: a randomized, double-blind trial of oral misoprostol for labor induction. Obstet Gynecol 2003;101: 685-9. 6. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects. Int J Gynaecol Obstet 2007;99:S160-7. 7. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research. US Food and Drug Administration: Center for Drug Evaluation and Research Handbook. Revised March 16, 1998. Available at: http://www.fda.gov/cder/handbook/ Phase1.htm. Accessed May 1, 2009. 8. Piantadosi S. Clinical trials: a methodologic perspective, 2nd ed. New York, NY: Wiley-Interscience; 2005. 9. Satin AJ, Leveno KJ, Sheman ML, McIntire D. High-dose oxytocin: 20- versus 40-minute dosage interval. Obstet Gynecol 1994;83: 234-8. 10. Hofmeyr GJ, Alfirevic Z, Matonhodze B, Brocklehurst P, Campbell E, Nikodem VC. Titrated oral misoprostol solution for induction of labor: a multi-center, randomized trial. BJOG 2001;108:952-9. 11. Cheng S. Efficacy and safety study of titrated oral misoprostol solution for labor augmentation. Available at: http://clinicaltrials.gov/ ct2/show/NCT00695331. Accessed May 1, 2009.