Disclaimers W HAT IS THE MOST EFFICIENT METHOD OF • Principal Investigator for Cytokine Pharmasciences, developer of the LABOR INDUCTION ? misoprostol vaginal insert (MVI) Deborah A. Wing, M.D., M.B.A. • Consultant for Ferring Pharmaceuticals Professor, Department of Obstetrics-Gynecology • Off-label use of misoprostol will be University of California, Irvine Antepartum and Intrapartum Management discussed Conference • Author, UpToDate University of California, San Francisco June 12, 2016 Objectives Labor induction in the United States • To discuss various pharmacologic Natality Statistics: 2014 and mechanical methods of labor induction and the evidence-base for • 3.99 million live births their use • 23.2% require induction of labor • To evaluate if an optimal • Doubled since 1990 method for labor induction exists Martin JA et al. Natl Vital Stat Rep . 2016;64(1):1-63. National Center for Health Statistics. www.cdc.gov/nchs/fastats/births.htm.
Role of Cervix in Risk of Cervical Assessment Modified Bishop Score Cesarean Following Induction at Term in Nulliparae 0 1 2 3 Factors (N=7282) Estimated RR (95% CI) Length (cm) 3 2 1 0 Spontaneous labor Referent (*Effacement) 0-30% 40-50% 60-70% >80% with Bishop score ≥ 5 Dilatation <1 1-2 3-4 >4 Bishop score <5 1.76 (1.48-2.09) (cm) Station -3 -2 -1 0 Induction 1.77 (1.46-2.11) Consistency Firm Moderate Soft Induction and 3.00 (2.38-3.73) Location Posterior Mid Anterior Bishop score <5 Bishop EH. Obstet Gynecol 1964: 24:266 Johnson DA et al. Am J Obstet Gynecol . 2003;188(6):1565-1569. Cochrane Systematic Review: Mechanical methods for induction of labor Methods of cervical ripening Issue 2, 2012. Art. No.: CD001233 Pharmaceutical Mechanical • 71 studies, n=9722 Estrogens Membrane Sweeping • Comparison with no treatment: Relaxin Amniotomy – Women who did not achieve vaginal delivery Oxytocin Hygroscopic dilators within 24 hr (RR 0.90; 95% CI 0.64 to 1.26). Prostaglandin E1 Foley balloon – Risk of cesarean was similar between groups (6 catheters studies; 416 women, RR 1.00; 95% CI 0.76 to Prostaglandin E2 1.30). Nitric oxide donors – There were no cases of severe neonatal and maternal morbidity.
Cochrane Systematic Review: Cochrane Systematic Review: Mechanical methods for induction of labor Mechanical methods for induction of labor Issue 2, 2012. Art. No.: CD001233 Issue 2, 2012. Art. No.: CD001233 • Comparison with intracervical PGE2 (14 • Comparison with vaginal PGE2 (17 studies;1784 women), no significant difference in studies; 1894 woman): women not achieving vaginal delivery within 24 hrs – Women who did not achieve vaginal • Reduced the risk of hyperstimulation with FHR delivery within 24 hrs was not significantly changes when compared with vaginal prostaglandins: different (3 studies; 586 women RR 1.72; vaginal PGE2 (8 studies; 1203 women, RR 0.16; 95% CI 0.06 to 0.39) and misoprostol (3% versus 95% CI 0.90 to 3.27) 9%) (9 studies; 1615 women, RR – No increase in cesareans (RR 1.19, 95% 0.37; CI 0.62-2.29). 95% CI 0.25 to 0.54). Cochrane Systematic Review: Cochrane Systematic Review: Mechanical methods for induction of labor Mechanical methods for induction of labor Issue 2, 2012. Art. No.: CD001233 CONCLUSIONS • Risk of cesarean between • Comparison with oxytocin, reduced risk of cesarean (5 studies; 398 women, RR 0.62; 95% mechanical methods and CI 0.42 to 0.90). prostaglandins was comparable. • Likelihood of vaginal delivery within 24 hr was not • Frequency of undelivered within 24 reported. • Hyperstimulation with FHR changes was hrs similar although slightly higher reported in one study (200 participants), and did rate in multiparas. not differ. • No reported cases of severe maternal or • Lesser hyperstimulation. neonatal morbidity.
Cochrane Systematic Review: Cochrane Systematic Review: Vaginal prostaglandins for cervical ripening Vaginal prostaglandins for cervical ripening and induction of labor and induction of labor (Issue 3, 2014, Art. No.: CD003101) (Issue 3, 2014, Art. No.: CD003101) � 70 trials, involving 11,487 women • PGE2 tablets, gels and pessaries appear to be as effective as each other, any � PGE2 probably increase successful vaginal delivery rates in 24 hours and increase uterine differences between formulations are hyperstimulation with FHR change rates, but marginal but may be important. do not effect or reduce cesarean rates. • Cost considerations should be made. � PGE2 increases cervical favorability but do not increase operative delivery rates. Cochrane Systematic Review: Cochrane Systematic Review: Vaginal misoprostol for cervical ripening and Vaginal misoprostol for cervical ripening and induction of labor : CONCLUSIONS induction of labor (Issue 10., 2010. No.: CD000941 ) • Vaginal misoprostol in doses above 25 � 121 trials mcg four-hourly was more effective than � Primary comparisons: conventional methods of labor induction, � Placebo/no treatment but with more uterine hyperstimulation. � Oxytocin • Lower doses were similar to conventional � Vaginal prostaglandins methods in effectiveness and risks. � Cervical prostaglandins � Low dosage versus higher dosage
Cochrane Systematic Review: Misoprostol Vaginal Insert Vaginal misoprostol for cervical ripening and induction of labor : CONCLUSIONS •Hydrogel polymer base measuring • Vaginal route should not be researched approximately 30 x further as another Cochrane review has 10 x 0.8 mm shown that the oral route of administration is •Absorbable preferable to the vaginal route. reservoir dose of • Professional and governmental bodies should misoprostol (the agree guidelines for use of misoprostol, MVI); the MVI is not based on best available evidence and local biodegradable circumstances. •Retrieval system Primary Efficacy MISO-OBS-303: PHASE III MVI Median Time to Vaginal Delivery � Multi-center trial, n=1300 � Comparison of MVI 200 mcg versus dinoprostone vaginal insert � Efficacy ◦ Time to vaginal delivery � Safety markers: Cesarean rates, uterine contractile abnormalities, nneonatal outcomes ◦ Clinical Trials: NCT01127581 Kaplan-Meier estimates of time to vaginal delivery. P < .001 (2-sided log-rank test). Wing DA. Obstet Gynecol. 2013 122:201-9 Women with cesarean deliveries were censored using a time of 109.1 hours Women who did not deliver during the first hospitalization were censored using a time of 76.2 hours. MVI = misoprostol vaginal insert; DVI = dinoprostone vaginal insert. 2 0
Primary Safety Secondary Efficacy Cesarean Rates MVI 200 DVI Outcome (n = 678) (n = 680) P value a Median time to any 18.3 27.3 < .001 delivery, hr (95% CI) (17.2 — 19.5) (26.2 — 28.9) Median time to active 12.1 18.6 < .001 labor, hr (95% CI) (12.0 — 12.9) (18.1 — 22.5) Predelivery oxytocin 324/674 497/671 < .001 b administration, n (%) (48.1) (74.1) b P values obtained from a Fisher ’ ’ s exact test for women who delivered during the first hospitalization. ’ ’ a P values from 2-sided log-rank tests. MVI = misoprostol vaginal insert; DVI = dinoprostone vaginal insert; CI = confidence interval. Relative risk = 0.96 [95% CI: 0.80 – 1.15]; P = .65 based on 2-sided χ 2 test. Analysis based on the ITT population: MVI 200, n = 678; DVI, n = 680. MVI = misoprostol vaginal insert; DVI = dinoprostone vaginal insert. 2 2 1 2 Summary of Safety Safety Drug-Related Adverse Events • Tachysystole: 13.1% v. 4.3%, p=0.001 Subject/Neonate, n (%) b MVI 200 DVI Incidence of Related AEs a (n = 678) (n = 680) Intrapartum 89 (13.1) 29 (4.3) Fetal heart rate disorder 34 (5.0) 9 (1.3) Abnormal labor affecting fetus 41 (6.0) 8 (1.2) Abnormal uterine contractions 13 (1.9) 4 (0.6) Meconium in amniotic fluid 8 (1.2) 4 (0.6) Vulvovaginal burning sensation 0 2 (0.3) Premature separation of placenta 2 (0.3) 0 Postpartum c 1 (0.3) 1 (0.3) Neonatal c 5 (0.7) 1 (0.1) a As determined by the Investigator. b A subject who reported 2 or more adverse events with different preferred terms in the same system organ class was counted only once for that term using the incident with the strongest relationship to the study treatment. c There were no related individual AEs experienced by ≥ 2 subjects/neonates during the postpartum or neonatal periods. 2 3
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