Oral misoprostol, low dose vaginal misoprostol, and vaginal dinoprostone for labor induction: Randomized controlled trial

Autoři: David C. Young aff001;  Tina Delaney aff001;  B. Anthony Armson aff001;  Cora Fanning aff001
Působiště autorů: Department of Obstetrics & Gynaecology, Dalhousie University, Halifax, Nova Scotia, Canada aff001;  Department of Obstetrics & Gynaecology, IWK Health Centre, Halifax, Nova Scotia, Canada aff002;  Department of Obstetrics & Gynaecology, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada aff003
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0227245



To compare effectiveness and safety of oral misoprostol (50 μg every four hours as needed), low dose vaginal misoprostol (25 to 50 μg every six hours as needed), and our established dinoprostone vaginal gel (one to two mg every six hours as needed) induction.

Materials and methods

Consenting women with a live term single cephalic fetus for indicated labor induction were randomized (3N = 511). Prior uterine surgery or non-reassuring fetal surveillance were exclusions. Concealed computer generated randomization was stratified and blocked. Newborns were assessed by a team unaware of group assignment. The primary outcome was time from induction at randomization to vaginal birth for initial parametric analysis. Sample size was based on mean difference of 240 minutes with α2 = 0.05 and power 95%. Non-parametric analysis was also pre-specified ranking cesareans as longest vaginal births.


Enrollment was from April 1999 to December 2000. Demographics were similar across groups. Analysis was by intent to treat, with no loss to follow up. Mean time (±SD) to vaginal birth was 1356 (±1033) minutes for oral misoprostol, 1530 (±3249) minutes for vaginal misoprostol, and 1208 (±613) minutes for vaginal dinoprostone (P = 0.46, ANOVA). Median times to vaginal birth were 1571, 1339, and 1451 minutes respectively (P = 0.46, Kruskal-Wallis). Vaginal births occurred within 24 hours in 44.9, 53.5 and 47.7% respectively (P = 0.27, χ2). There were no significant differences in Kaplan Meier survival analyses, cesareans, adverse effects, or maternal satisfaction. The newborn who met birth asphyxia criteria received vaginal misoprostol, as did. all three other newborns with cord artery pH<7.0 (P = 0.04, Fisher Exact).


There was no significant difference in effectiveness of the three groups. Profound newborn acidemia, though infrequent, occurred only with low dose vaginal misoprostol.

Klíčová slova:

Birth – Hypertensive disorders in pregnancy – Labor and delivery – Neonates – Oral administration – Oxytocin – Randomized controlled trials – Parametric analysis


1. ACOG Practice Bulletin No. 107. American College of Obstetricians and Gynecologists. Induction of labor. Obstet Gynecol 2009;114:386–97. doi: 10.1097/AOG.0b013e3181b48ef5 19623003

2. Society of Obstetricians and Gynaecologists of Canada. SOGC Clinical Practice Guideline No 296. Induction of Labour, 2013. J Obstet Gynaecol Can 2013;35:840–57. doi: 10.1016/S1701-2163(15)30842-2 24099451

3. Alfirevic Z, Keeney E, Dowswell T, Welton NJ, Dias S, Jones LV, et al. Labour induction with prostaglandins: a systematic review and network meta-analysis. BMJ 2015;350:h217. doi: 10.1136/bmj.h217 25656228

4. Grobman WA, Rice MM, Reddy UM, Tita AT, Silver RM, Mallett G et al. Labour induction versus expectant management in low-risk nulliparous women. N Engl J Med 2018;379:513–23. doi: 10.1056/NEJMoa1800566 30089070

5. Kelly A, Malik S, Smith L, Kavanagh J, Thomas J. Vaginal prostaglandin (PGE2 and PGF2α) for induction of labour at term. Cochrane Database Syst Rev 2009;4:CD003101. http://dx.doi.org/10.1002/14651858,cd003101.pub2

6. Boulvain M, Kelly A, Irion O. Intracervical prostaglandins for induction of labour. Cochrane Database Syst Rev 2008;1:CD006971. http://dx.doi.org/10.1002/14651858.cd006971

7. Rayburn WF, Wapner RJ, Barss VA, Spitzberg E, Molina RD, Mandsager N, et al. An intravaginal controlled-release prostaglandin E2 pessary for cervical ripening and initiation of labor at term. Obstet Gynecol 1992;79:374–9. doi: 10.1097/00006250-199203000-00009 1738517

8. French L. Oral prostaglandin E2 for induction of labour. Cochrane Database of Systemic Reviews: John Wiley & Sons, Ltd; 2001.

9. Garris RE, Kirkwood CF. Misoprostol: A prostaglandin E1 analogue. Clin Pharm 1989;8:627–44. 2507215

10. Sanchez-Ramos L, Kaunitz AM, Del Valle GO, Delke I, Schroeder PA, Briones DK. Labor induction with the prostaglandin E1 methyl analogue misoprostol versus oxytocin: A randomized trial. Obstet Gynecol 1993;81:332–6. 8437780

11. Fletcher HM, Mitchell S, Simeon D, Frederick J, Brown D. Intravaginal misoprostol as a cervical ripening agent. Br J Obstet Gynaecol 1993;100:641–4. doi: 10.1111/j.1471-0528.1993.tb14230.x 8369246

12. Wing DA, Jones MM, Rahall A, Goodwin TM, Paul RH. A comparison of misoprostol and prostaglandin E2 gel for preinduction cervical ripening and labor induction. Am J Obstet Gynecol 1995;172:1804–10. doi: 10.1016/0002-9378(95)91415-3 7778636

13. Mundle WR, Young DC. Vaginal misoprostol for induction of labour: A randomized controlled trial. Obstet Gynaecol 1996;88:521–5.

14. WHO recommendations for induction of labour. Geneva: World Health Organisation; 2011. ISBN 9789241501156/en. www.who.int/reproductivehealth/publications/maternal_health

15. Windrim R, Bennett K, Mundle W, Young DC. Oral administration of misoprostol for labour induction: a randomized controlled trial. Obstet Gynaecol 1997;89:392–7.

16. Bennett KA, Butt K, Crane JMG, Hutchens D, Young DC. A masked randomized comparison of oral and vaginal administration of misoprostol for labor induction. Obstet Gynecol 1998;92:481–6. doi: 10.1016/s0029-7844(98)00226-9 9764615

17. Alfirevic Z, Aflaifel N, Weeks A. Oral misoprostol for induction of labour. The Cochrane database of systematic reviews. 2014;(6):Cd001338. doi: 10.1002/14651858.CD001338.pub3 CD001338.pub3 24924489

18. Muzonzini G, Hofmeyr GJ. Buccal or sublingual misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev 2004;4:CD004221. http://dx.doi.org/10.0002/14651858.cd004221.pub2

19. Hofmeyr GJ, Gulmezoglu AM, Pileggi C. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev 2010;10:CD000941. http://dx.doi.org/10.1002/14651858.cd000941.pub2

20. Jozwiak M, Bloemenkamp KW, Kelly AJ, Mol BW, Irion O, Boulvain M. Mechanical methods for induction of labour. Cochrane Database Syst Rev 2012;3:CD001233. http://dx.doi.org/10.1002/14651858.cd001233.pub2

21. Jozwiak M, Oude Rengerink K, Benthem M, van Beek E, Dijksterhuis MGK, de Graaf IM, et al. Foley catheter versus vaginal prostaglandin E2 gel for induction of labour at term (PROBAAT trial): an open-label, randomized controlled trial. Lancet 2011;378:2095–103. doi: 10.1016/S0140-6736(11)61484-0 22030144

22. Ten Eikelder MLG, Oude Rengerink K, Jozwiak M, de Leeuw JW, de Graaf IM, van Pampus MG, et al. Induction of labour at term with oral misoprostol versus Foley catheter (PROBAAT-II): a multicenter randomized controlled non-inferiority trial. Lancet 2016;387:1619–28. doi: 10.1016/S0140-6736(16)00084-2 26850983

23. Alfirevic Z, Keeney E, Dowswell T, Welton NJ, Medley N, Dias S, et al. Methods to induce labour: a systematic review, network meta-analysis and cost-effectiveness analysis. BJOG 2016;123:1462–70. doi: 10.1111/1471-0528.13981 27001034

24. Alfirevic Z, Keeney E, Dowswell T, Welton NJ, Medley N, Dias S, et al. Which method is best for the induction of labour? A systematic review, network meta-analysis and cost-effectiveness analysis. Health Technol Assess 2016;20(65). doi: 10.3310/hta20650 27587290

25. Weeks AD, Navaratnam K, Alfirevic Z. Simplifying oral misoprostol protocols for the induction of labour. BJOG 2017;124,1642–5. doi: 10.1111/1471-0528.14657 28342186

26. Thornton J. Feedback 2014;2:326–7 in Alfirevic Z, Aflaifel N, Weeks A. Oral misoprostol for induction of labour. Cochrane Database Syst Rev 2014;6:CD001338.

27. Meinert CL. Sample Size, Number of Treatment Groups. In: Clinical Trials–Design, Conduct, and Analysis. Oxford University Press, 1986, pg.74.

28. ACOG Committee Opinion. Fetal distress and birth asphyxia. 137 April 1994. The American college of Obstetricians and Gynecologists, Washington, DC.

29. Curtis P, Evans S, Resnick J. Uterine hyperstimulation: The need for standard terminology. J Reprod Med 1987;32:91–5. 3560084

30. Hofmeyr GJ, Alfirevic Z, Kelly AJ, Kavanagh J, Thomas J, Neilson JP, et al. Methods for cervical ripening and labour induction in late pregnancy; generic protocol. Cochrane Database of Systematic Review 2009, Issue 3. Art. No.: CD002074. doi: 10.1002/14651858.CD002074.pub2

31. Hodnett ED, Simmons-Tropea DA. The labor agentry scale; psychometric properties of an instrument measuring control during childbirth. Res Nurs Health 1987;10:301–10. doi: 10.1002/nur.4770100503 3671777

32. Norman GR, Streiner DL. Biostatistics: the bare essentials. Fourth edition. Shelton CT; People’s Medical Publishing House. 2014.

33. Tukey J. Comparing individual means in analysis of variance. Biometrics 1949;5(2):99–114. 18151955

34. Dunn OJ. Multiple comparisons using rank sums. Technometrics 1964; 5:241–252.

35. Lauzon L, Fahey J, Ezurike H. Temporal trends in maternal characteristics in Nova Scotia. Abstract # P-OBS-RN-119. J Obstet Gynaecol Can 2019;41:723

36. Nova Scotia Atlee perinatal database report of indicators 2005–14 available at http://rcp.nshealth.ca

37. Nova Scotia Atlee perinatal database report of indicators 2000–09 available at http://rcp.nshealth.ca

38. Schoen C, Navathe R. Failed induction of labor. Semin Perinatol 2015;39:483–7. http://dx.doi.org/10.1053/j.semperi.2015.07.013. O146-0005/©Elsevier Inc. 26341068

39. Lehmann EL. Parametric versus nonparametrics: two alternative methodologies. J Nonpara Stat 2009;21:397–405 doi: 10.1080/10485250902842727

40. Zieman M, Fong SK, Benowitz NL, Banskter D, Darney PD. Absorption kinetics of misoprostol with oral or vaginal administration. Obstet Gynecol 1997;90:88–92. doi: 10.1016/S0029-7844(97)00111-7 9207820

41. Tang OS, Schweer H, Seyberth HW, Lee SWH, HO PC. Pharmacokinetics of different routes of administration of misoprostol. Human Reproduction 2002;17:332–6. doi: 10.1093/humrep/17.2.332 11821273

42. Cicinelli E, De Ziegler D, Bulletti C, Matteo MG, Schonauer LM, Galantino P. Direct transport of progesterone from vagina to uterus. Obstet Gynecol 2000;95:403–6. doi: 10.1016/s0029-7844(99)00542-6 10711552

43. Gemzell-Danielsson KG, Marions L, Rodriguez A, Spur BW, Wong PYK, Bygdeman M. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet Gynecol 1999;93:275–80. doi: 10.1016/s0029-7844(98)00436-0 9932569

44. Mundle S, Bracken H, Khedikar V, Mulik J, Faragher B, Easterling T, et al. Foley catheterisation versus oral misoprostol for induction of labour in hypertensive women in India (INFORM): a multicenter, open-label, randomized controlled trial. Lancet 2017;390:669–80. doi: 10.1016/S0140-6736(17)31367-3 28668289

45. Stephenson ML, Wing DA. A novel misoprostol delivery system for induction of labor: clinical utility and patient considerations. Drug Des Devel Ther 2015; 9: 2321–27. doi: 10.2147/DDDT.S64227 25960635

46. Wing DA, Brown R, Plante LA, Miller H. Rugarn O, Powers BL. Misoprostol vaginal insert and time to vaginal delivery: a randomized controlled trial. Obstet Gynecol 2013;122:201–9. doi: 10.1097/AOG.0b013e31829a2dd6 23857539

47. Rugarn O, Tipping D, Powers B, Wing DA. Induction of labour with retrievable prostaglandin vaginal inserts: outcomes following retrieval due to an intrapartum adverse event. BJOG 2017;124:796–803. doi: 10.1111/1471-0528.14147 27307397

48. Rouse DJ. The misoprostol vaginal insert: Déjà vu all over again. Obstet Gynecol 2013;122:193–4 doi: 10.1097/AOG.0b013e31829c5abd 23969783

49. Robinson JN. Induction of labour: many choices, but still in search of the perfect protocol. BJOG 2017;124:803. doi: 10.1111/1471-0528.14186 27347665

Článek vyšel v časopise


2020 Číslo 1
Nejčtenější tento týden