The median duration of drug exposure was 861 (range 24–1,480) minutes for the MVI 100 group, 675 (range 80–1,516) minutes for the MVI 150 group (P=.001), and 515 (range 43–1,493) minutes for the MVI 200 group (P<.001, generalized linear model). The most common reason for removal of the study drug was onset of active labor (39.4% of participants), which occurred with similar frequencies among treatment groups (Table 2). The second most common reason for removal of the MVI 150 and MVI 200 was maternal-fetal complications, which included abnormal FHR patterns and vaginal bleeding, among others (P<.001 for each dose reservoir compared with MVI 100). Study drug in situ for 24 hours was the third most common removal reason for the MVI 100 group (22.2%); this reason was significantly less frequent for the MVI 200 group (8.4%, P=.002).
Successful cervical ripening at 12 hours was not different among the groups, with 77.78%, 77.6%, and 80.15% in the MVI 100, MVI 150, and MVI 200 groups, respectively (P=.98 and .65 for MVI 150 and MVI 200 compared with MVI 100, respectively).
Participants treated with the MVI 200 entered active labor faster than those treated with the two other doses. Median time to active labor was 1,069 minutes (range 885–1,153) for the MVI 100 group compared with 775 minutes (range 724–977) for the MVI 150 (P=.16) and 701 minutes (range 550–759) for the MVI 200 (P=.01). Women treated with the MVI 200 also had the shortest median time to any delivery mode (P<.001 MVI 100 compared with MVI 200) (Table 3).
Vaginal delivery within 24 hours was achieved for 63.8%, 66.7%, and 76.0% of participants exposed to MVI 100, MVI 150, and MVI 200, respectively (P=.54 for MVI 100 compared with MVI 150, and P=.057 for MVI 100 compared with MVI 200) (Table 3 and Fig. 2). Twenty-four percent of women receiving MVI 200 failed to achieve vaginal delivery within 24 hours compared with 36.3% of those receiving MVI 100 (P=.057, relative risk [RR] 0.66, 95% confidence interval [CI] 0.42–1.04). For nulliparous women, 67.3% treated with MVI 200 had vaginal delivery within 24 hours compared with 52.4% treated with MVI 100 (P=.14). Approximately 75% (99/136) of parous individuals delivered vaginally within 24 hours. Results by parity are presented in Table 3. Median time to vaginal delivery was more than 9 hours shorter for the MVI 200 group than for the MVI 100 group (1,181 [range 1,035–1,443] minutes, P=.02). A significantly higher proportion of MVI 200 participants delivered by any mode within 24 hours (72.5%) compared with 52.14% of MVI 100 participants (P<.001); this finding was also true for MVI 200 nulliparous and parous women separately as well as for the combined group (P=.012 and P=.016, respectively, by parity).
Oxytocin augmentation was significantly reduced for those treated with MVI 200 compared with MVI 100 (48.9% compared with 70.9%, P<.001, RR 0.70, 95% CI 0.56–0.85) (Table 4) with less than half of the MVI 200 participants requiring any oxytocin compared with more than 70% of MVI 100 participants.
Fetal heart rate patterns were found to be Eunice Kennedy Shriver National Institute of Child Health and Human Development category II or III in the majority of participants (58.0% overall) (Table 4) at some stage of their labors; most were deemed unrelated to the misoprostol vaginal insert. Category II or III patterns judged related to the use of the misoprostol vaginal insert occurred in 9 of 75 (7.6%), 27 of 125 (21.6%), and 22 of 131 (16.8%) of the MVI 100, 150, and 200 participants, respectively (P=.03 for MVI 100 compared with MVI 200).
MVI 200 was associated with an increased rate of tachysystole (54/131, 41.2%) compared with MVI 100 (23/118, 19.5%) (P<.001, RR 2.11, 95% CI 1.39–3.22), and MVI 150 (32/135, 25.6%) (P=.26, RR 1.31, 95% CI 0.82–2.11; Table 4). Tachysystole occurred with the drug in situ in 17 (14.4%) and 50 (32.8%) of MVI 100 and 200 participants, respectively (P<.001). Category II or III FHR patterns were encountered after tachysystole had occurred in nine (7.6%) and 26 (19.8%) women in the MVI 100 and 200 groups, respectively (P=.006).
Cesareans were performed in 28.1% of participants overall, with 31.4%, 30.4%, and 22.9% of individuals undergoing cesarean delivery in the MVI 100, 150, and 200 groups, respectively (P=.15, RR 0.73, 95% CI 0.48–1.10 for MVI 100 compared with MVI 200). Nonreassuring FHR was the most common reason for cesarean delivery (11.0% of participants overall) with arrested dilatation as the second most common reason (10.2%) (Table 5). Cesarean deliveries performed for nonreassuring FHR related to the study drug occurred in 2.7% of participants (1.7%, 2.4%, and 3.8% for the MVI 100,150, and 200, respectively). Uterine contractile events resulted in a cesarean delivery in one participants; this was an MVI 100 individual (0.8%) and was attributed to hyperstimulation syndrome. Seventeen participants who had the study drug removed after achieving onset of active labor ultimately went on to have a cesarean delivery (4.6%); these were distributed equally among the groups (6.0%, 3.2%, and 4.6% for MVI 100, 150, and 200, respectively). In contrast, having the inserts in situ for more than 24 hours led to cesarean delivery in a disproportionate percentage of cases, with cesarean deliveries in 13 (11.1%) and eight (6.4%) participants exposed to MVI 100 and MVI 150, respectively, compared with three (2.3%) of the individuals treated with the MVI 200.
No maternal or neonatal deaths occurred during the study and no adverse events led to premature withdrawal of any participants. Systemic adverse events such as nausea, vomiting, and diarrhea in mother or neonate occurred with less than 1% incidence in any treatment group (data not shown). The mean birth weights and Apgar scores were similar among the groups. There were no differences in other neonatal outcomes between groups (Table 6).
With induction of labor becoming increasingly more common, it is important to identify an agent that can safely and effectively ripen cervices and induce labor. Ideally, a cervical ripening and labor-inducing agent would mimic the natural cascade of events of human parturition and reduce overall time to delivery without increasing the likelihood of cesarean. However, induction of labor has been associated with increased rates of cesarean deliveries by some,9 although the increase is not universally observed.10 It is important that any induction method demonstrate no increase in this important safety parameter.
We demonstrated that the MVI 200 significantly reduced time to any delivery mode compared with the MVI 100. The MVI 200 also significantly reduced the time to vaginal delivery. Use of the MVI 200 resulted in significantly more vaginal deliveries within 12 hours (P=.02) compared with the MVI 100 dose reservoir. A total of 76.0% of MVI 200–treated women delivered vaginally by 24 hours compared with 63.8% of MVI 100–treated women (P=.057). Use of the MVI 200 also reduced the necessity for oxytocin augmentation of labor. These results were associated with a nonsignificant reduced RR of cesarean delivery for women treated with MVI 200 compared with MVI 100 patients.
Removal of the study drug insert owing to adverse event was more frequent for the MVI 200 and MVI 150 groups compared with the MVI 100 group. Invariably, we found these adverse events leading to removal were almost always associated with retrospectively diagnosed tachysystole. We found that this method often led to observations that were discrepant from the bedside assessment, and resulted in tabulation of adverse events that were often well tolerated and did not result in discontinuation of the study drug. However, cesarean deliveries attributable to nonreassuring FHR occurred at a higher rate with MVI 200 than with MVI 100 (Table 5).
We acknowledge the limitations of this randomized controlled trial, which include a potential lack of generalizability due to restrictions imposed by our inclusion criteria, and a limited sample size by which to be able to detect rare events in laboring mothers or neonates.
All three dose reservoirs tested in this study were well tolerated. There was a dose-dependent increase in the number of participants with treatment-related adverse events with the most reported in the MVI 200 treatment group. These were mostly uterine contractile abnormalities that were retrospectively identified. Although no assessment was made of contraction duration, intensity, or quality,8 these findings provide reassurance that the misoprostol vaginal insert did not appear to potentiate the effects of oxytocin, in contrast to use of some other labor induction agents.11–13
The results of this phase II investigation are comparable with results of Miso-Obs-004, a phase III investigation5 insofar as the 118 women treated with the MVI 100 in the phase II investigation had similar efficacy outcomes to the 428 MVI 100–treated women and the 436 Cervidil–treated women in the phase III study.
In summary, there was a dose response in favor of the efficacy of the MVI 200 among the three treatment arms. Mothers treated with MVI 200 went into labor sooner and delivered more rapidly, all with less use of oxytocin. However, this was accompanied by a substantively higher rate of uterine tachysystole and more cesarean deliveries for nonreassuring FHR patterns than the MVI 100, although the overall rate of cesarean delivery was lowest for women exposed to the MVI 200. The safety of MVI 200 is of critical importance, and the balance between safety and efficacy can be determined only with additional large-scale investigations in various clinical settings. Further development is planned.
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