By Ahizechukwu C. Eke, MD, PhD, MPH
Assistant Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: In this randomized, noninferiority, clinical trial of pregnant women who underwent induction of labor with misoprostol compared to dinoprostone, the rate of vaginal delivery within 24 hours was higher in the misoprostol group. Maternal satisfaction, assessed by a visual analog scale, also was higher. Although the noninferiority of dinoprostone to misoprostol could not be demonstrated, the clinical risk-to-benefit ratio justifies the use of both drugs.
SOURCE: Gaudineau A, Senat MV, Ehlinger V, et al. Induction of labor at term with vaginal misoprostol or a prostaglandin E2 pessary: A non-inferiority randomized controlled trial. Am J Obstet Gynecol 2021; Apr 19. doi: 10.1016/j.ajog.2021.04.226. [Online ahead of print].
Induction of labor is a common practice in the United States.1,2 Between 2012 and 2017, the rate of induction more than doubled from a rate of approximately 9% to a rate of 23% of all deliveries in the United States.1 The rate of labor induction likely will continue to increase, especially after the findings of the ARRIVE randomized clinical trial, which demonstrated that elective induction of labor in nulliparous women with low-risk pregnancies at 39 weeks may reduce the need for cesarean deliveries when compared to expectant management.2 Therefore, understanding the safety, efficacy, and adverse effect profiles of medications used for labor induction is important.
Labor induction can be accomplished by mechanical (e.g., Foley bulb) and non-mechanical (e.g., pharmacological methods) methods, for which misoprostol (a prostaglandin E1 analogue) and dinoprostone (a prostaglandin E2 analogue) have been used off-label for decades.3
Although a number of randomized clinical trials have evaluated vaginal misoprostol vs. dinoprostone, their safety profiles have not been evaluated comprehensively and satisfactorily in a prospective manner using large sample sizes.4 Therefore, Gaudineau and colleagues designed this study — the CYTOPRO (CYTOtec vs. PROpess) trial — to test the hypothesis that a 25-mcg dose of vaginal misoprostol administered every four hours would be noninferior to a 10-mg dose of dinoprostone pessary.4
The CYTOPRO trial was a randomized, noninferiority, controlled trial conducted at four hospitals in France that participate in the Groupe de Recherche en Obstétrique et Gynécologie.4 Inclusion criteria were pregnant women ≥ 18 years of age with a viable singleton gestation in cephalic presentation undergoing induction of labor at a gestational age of ≥ 36 weeks, with an unfavorable cervix (Bishop score of ≤ 5) and three or fewer uterine contractions in 10 minutes, as recorded by a 30-minute electronic fetal monitoring (EFM) at the time of admission.4 Women were excluded if they had a previous cesarean delivery, any known allergy or intolerance to prostaglandin agents, and any contraindications to vaginal delivery.4
Using computer randomization, the investigators randomized participants to either the misoprostol group or the dinoprostone group. Participants received either a 25-mcg dose of vaginal misoprostol or a 10-mg slow-release dinoprostone pessary. The primary outcome was the cesarean delivery rate following induction of labor with misoprostol or dinoprostone.4 Secondary outcomes included fever ≥ 38.5°C during labor, use of episiotomy, third- and fourth-degree perineal lacerations, postpartum hemorrhage, uterine tachysystole, uterine rupture, vaginal delivery within 24 hours, rate of pitocin use, satisfaction with labor process, neonatal seizure, admission to the neonatal intensive care unit, arterial umbilical cord pH of < 7.05, five-minute Apgar score of < 7, meconium-stained amniotic fluid, meconium aspiration, and neonatal death.4 A sample size of 790 women per group was sufficient to demonstrate statistically significant differences between the misoprostol and dinoprostone arms based on a baseline cesarean delivery rate of 20% in the dinoprostone group, assuming 80% power, type 1 error rate of 0.025% (one-sided test), and a noninferiority margin of ≥ 5% in absolute difference in cesarean delivery rates when induction of labor is performed with misoprostol vs. dinoprostone (if misoprostol truly is not inferior).
From September 2012 to June 2015, 790 pregnant women received misoprostol and 790 women received dinoprostone. A total of 945 women (59.8%) were nulliparous and 635 women (40.2%) were parous. The baseline characteristics were similar in both groups.4 However, the cesarean delivery rate was 22.2% (175/790) in the misoprostol group and 19.9% (157/790) in the dinoprostone group, a difference of 2.3%, with a 95% upper-bound confidence interval (CI) limit of 5.6%, which exceeded the limit for noninferiority (P = 0.092). The cesarean delivery rate for non-reassuring fetal heart tones was slightly higher in the misoprostol group (risk difference [RD], 2.2; 95% CI, -0.3 to 4.6), but similar cesarean delivery rates were demonstrated for arrest of labor between the two groups (RD, -0.8; 95% CI, -0.3 to 1.6).4 Meconium aspiration occurred in 1.0% of neonates in the misoprostol group compared with 0.3% in the dinoprostone group. Vaginal delivery within 24 hours after commencement of induction of labor was higher in the misoprostol arm compared to the dinoprostone arm (59.3% vs. 45.7%, P < 0.001). Conversely, labor augmentation with oxytocin was lower in the misoprostol arm when compared to the dinoprostone arm (58.7% vs. 67.2%, P < 0.001). Women randomized to the misoprostol arm reported a significantly higher level of maternal satisfaction (78% of women, mean visual analog scale score, 7.1 ± 2.4) compared to those in the dinoprostone arm (63% of women, mean visual analog scale score, 5.8 ± 3.1; P < 0.001).4
COMMENTARY
Although misoprostol and dinoprostone both are prostaglandins, they have different pharmacokinetic profiles. Following insertion into the posterior vaginal fornix, vaginal misoprostol plasma concentrations gradually increase, reaching a maximum concentration after 70 to 80 minutes, before slowly being eliminated, with plasma levels still detectable six hours after administration.5,6 In contrast, vaginal dinoprostone pessary undergoes slower absorption (absorbed at a rate of 0.3 mg per hour over 12 hours) and elimination.5 The slower rate of absorption and time to reach maximum concentration for dinoprostone after vaginal administration may account for its longer duration of action and decreased clearance from the plasma. These differences in misoprostol and dinoprostone pharmacokinetics partly account for their differences in safety, efficacy, and adverse effect profiles.
The authors used a noninferiority, randomized trial design to study the association between misoprostol and dinoprostone and the risk of cesarean delivery.4 They noted the difference in the absolute rate of cesarean deliveries between the two groups was 2.3%, with a 95% upper-bound CI limit of 5.6%, which was greater than the noninferiority boundary of 5% used in the study. The primary objective of noninferiority trials is to show that a new treatment is no worse (noninferior) when compared to the standard-of-care treatment, usually within a pre-specified noninferior margin with reference to a primary outcome.7 Noninferiority randomized clinical trials of pharmacologic agents used for labor induction are critically important in obstetrics in demonstrating decreased adverse effects of using different pharmacologic doses or agents relative to an existing standard, especially because induction of labor is a common practice in the United States. Using noninferiority trials, current pharmacologic therapies used for labor induction can be compared in head-to-head randomized trials to determine if these therapies are noninferior. Although Gaudineau et al could not demonstrate noninferiority of a 25-mcg dose of vaginal misoprostol every four hours when compared to the dinoprostone pessary for cesarean delivery rates following induction of labor, the confidence limit of the difference was sufficiently close to that of misoprostol.
In conclusion, since this is a noninferiority trial, a reasonable conclusion for clinicians in practice would be that dinoprostone pessary is noninferior to misoprostol when used for induction of labor. As such, interpreting this study as “misoprostol is as ‘effective’ as dinoprostone” would be incorrect, since the primary aim of noninferiority trials is to evaluate that a new therapy is “no worse” than standard therapy. Currently, the American College of Obstetricians and Gynecologists recommends low-dose (25 mcg) vaginal misoprostol as the first-line pharmacologic agent for labor induction.8
REFERENCES
- Handal-Orefice RC, Friedman AM, Chouinard SM, et al. Oral or vaginal misoprostol for labor induction and cesarean delivery risk. Obstet Gynecol 2019;134:10-16.
- Grobman WA, Rice MM, Reddy UM, et al. Labor induction versus expectant management in low-risk nulliparous women. N Engl J Med 2018;379:513-523.
- Levine LD, Downes KL, Elovitz MA, et al. Mechanical and pharmacologic methods of labor induction: A randomized controlled trial. Obstet Gynecol 2016;128:1357-1364.
- Gaudineau A, Senat MV, Ehlinger V, et al. Induction of labor at term with vaginal misoprostol or a prostaglandin E2 pessary: A noninferiority randomized controlled trial. Am J Obstet Gynecol 2021; Apr 19. doi: 10.1016/j.ajog.2021.04.226. [Online ahead of print].
- Bygdeman M. Pharmacokinetics of prostaglandins. Best Pract Res Clin Obstet Gynecol 2003;17:707-716.
- Tang OS, Schweer H, Seyberth HW, et al. Pharmacokinetics of different routes of administration of misoprostol. Hum Reprod 2002;17:332-336.
- Mulla SM, Scott IA, Jackevicius CA, et al. How to use a noninferiority trial: Users’ guides to the medical literature. JAMA 2012;308:2605-2611.
- [No authors listed]. ACOG Practice Bulletin No. 107: Induction of labor. Obstet Gynecol 2009;114:386-397.
In this randomized, noninferiority, clinical trial of pregnant women who underwent induction of labor with misoprostol compared to dinoprostone, the rate of vaginal delivery within 24 hours was higher in the misoprostol group. Maternal satisfaction, assessed by a visual analog scale, also was higher. Although the noninferiority of dinoprostone to misoprostol could not be demonstrated, the clinical risk-to-benefit ratio justifies the use of both drugs.
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