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Clinical Uses of Misoprostol in Obstetricsand GynaecologyDr. Suk-wai Ngai MBBS, MRCOG, MDAssociate ProfessorDepartment of Obstetrics & Gynaecology, The University of Hong Kong

IntroductionMisoprostol is a synthetic prostaglandin E1 analogueapproved by the Food and Drug Administration (FDA)for the prevention and treatment of gastroduodenal ulcers.Norman et al. first demonstrated its uterocontractiveabortifacient properties in 19911. This publicationgenerated great interest in the search for the potential usesof misoprostol in Obstetrics and Gynecology. Misoprostolhas since been proven to be an effective agent for cervicalpriming prior to surgical abortion, medical abortion,induction of labour and prevention of postpartumhaemorrhage. In contrast to other synthetic prostaglandinanalogues, it is substantially less expensive. It does notrequire refrigeration and can be administered orally,rectally, vaginally, as well as by the sublingual route. Thepurpose of this chapter is to summarise the evidences ofits efficacy in clinical use.

Cervical Priming Prior to Surgical AbortionCervical preparation is critical to the success of surgicalabortion. It reduces the need for rapid mechanicaldilatation of the cervix which carries a significant risk ofcervical laceration with immediate morbidity, and thepossibility of remote complications such as cervicalincompetence2. Misoprostol was extensively investigatedas a cervical priming agent before surgical abortion.Bulgalho et al.3 compared the use of vaginal misoprostolversus placebo in 1994. Our group subsequentlypublished a series of studies to investigate its efficacywhen used as a cervical priming agent by the oral route.We showed that when given orally 12 h prior to vacuumaspiration, 400ug misoprostol was more effective thanpl acebo 4 a nd gemepros t 5 , a nd a s ef f ect ive asmifepristone6 for cervical priming. Dose finding studieshave determined that 400 ug vaginal misoprostol, given3-4 hours prior to the procedure, is probably the optimaltreatment for achieving adequate dilation in over 95%of women prior to suction evacuation7.

First Trimester Medical AbortionMedical abortion has become an alternative method offirst trimester pregnancy termination with the availabilityof prostaglandins in the early 1970s and anti-progesterones in the 1980s. Studies on the use ofmisoprostol alone for first trimester medical abortion havelargely been unsatisfactory. Repeated doses were required

Dr. Suk-wai Ngai

and it took a few days for the effect to complete. Theoverall successful rate ranged from 40-90%8-10. The resultswere difficult to compare because different studiesadopted different dosing regimens. In most of the studies,the daily doses of misoprostol vary from 600-1000 ug 11-13.The success rate of abortion was also not uniformlydefined. In contrast, the combination regimen ofmifepristone and misoprostol gave much more promisingresults. Jain et al.14 compared women who receivedmisoprostol alone to women who had received 600 mgmifepristone and 400 ug oral misoprostol. Successfulabortion occurred in 88% with misoprostol alone and in94% with the combination regimen. A subsequentrandomised controlled trial compared misoprostol aloneto 200 mg mifepristone combined with 800 ug vaginalmisoprostol, and found a success rate for the single drugof 88%; versus 95.7% for the combination15. Misoprostolis currently the prostaglandin used most commonly incombination with mifepristone. In standard regimensapproved by national regulatory agencies, mifepristone600 mg orally is followed by approximately 48h later by400 ug oral misoprostol given in the clinic for first trimestermedical abortion.

However, mifepristone is not widely available. The useof the misoprostol-alone regimen remains attractive inmany countries. Our group performed a pilot study onthe use of sublingual misoprostol for medical abortion.We achieved 95% complete abortion rate by using 400 ugmisoprostol every 4 hours for a maximal of five doses16.Our finding suggested that large scale prospectiverandomised trials should be conducted to work out theoptimal dosing regimen.

Second Trimester Medical AbortionAbortion-related mortality and morbidity increasesignificantly as gestation increases. Induction of abortionafter 14 weeks of gestation is associated with a sharp risein the rates of complications and in the consequent medicalcosts. Such abortions constitute only 10-15% of all inducedabortions but they are responsible for two-thirds of allmajor complications and 50% of all abortion-relatedmaternal deaths17. Different management protocols arecontinuously revised, aiming to achieve improved successrates and reduced discomfort to the patients. Medicalabortion using prostaglandin analogues alone or incombination with mifepristone has been proven to beeffective for second trimester abortion and the terminationof pregnancy with intrauterine death18-22.

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Most of the misoprostol-only regimens used in secondtrimester abortion involved vaginal administration. In theliterature, the dosage of misoprostol used in the studiesinvolving misoprostol alone varied from 100-200 ug andthe dosing interval ranged from 3 to 12 hours23, 24-29.Misoprostol at a dose of 100-200 ug every 6-12 hours givesa lower abortion rate at 48 hours and a longer induction-to-abortion interval than gemeprost24. The induction-to-abortion interval was still long even if the dosage ofmisoprostol was increased to 400-600 ug every 12 hours25,27.A randomised study demonstrated that misoprostol 400ug given vaginally every 3 hours was probably the optimalregimen for second trimester abortion29. The completeabortion rate and induction-to-abortion interval werecompromised if the dosing interval extends to 6 hours. Thisregimen of misoprostol had been shown by a randomisedstudy to be more effective when compared with thestandard regimen of gemeprost29. Recently, sublingualadministration of misoprostol has been investigated. Onepilot study using 400 ug misoprostol every 3 hours for amaximum of five doses achieved 100 percent secondtrimester abortion rate with a median induction-to-abortioninterval of 11.6 h30. In addition, the majority of womenpreferred the oral route to the vaginal route because theformer is more convenient and offers more privacy.

Intrauterine DeathInduction of labour for intrauterine death can be difficultparticularly when the cervix is unripe. The success rates ofmisoprostol alone regimen range from 67% to 100%3,31. Mostof the published regimens have recommended the vaginalroute. More recently, mifepristone has also beensuccessfully used in this aspect. Fletcher et al. reportedsuccessful induction of labour using mifepristone 200 mg12 hourly for two days31, and subsequently a prospectivedouble blind trial confirmed that mifepristone can be usefulin the management of intrauterine death32. In the latterstudy 43 women with a silent miscarriage or stillbirthreceived mifepristone 200 mg three times a day for twodays resulting in 63% of them delivering within 72 hoursof commencing treatment compared with only 17% in theplacebo group. Wahaarachchi et al. first reported acombination of vaginal and oral route19. Women received asingle dose of 200 mg mifepristone following which a 24-48 hours interval was recommended before administrationof misoprostol. For gestations of 24-34 weeks, 200 ug ofintravaginal misoprostol was administered, followed byfour oral doses of 200 ug at three hourly intervals. Gestationsover 34 weeks were given a similar regimen but a reduceddose of 100 ug misoprostol. The average induction-to-delivery interval was 8.5 hours which was the shortestamong the previous regimen. Improved patientacceptability and reduced risk of introducing intrauterineinfection are potential advantages of oral over vaginal route.

Induction of LabourInduction of labour requires a fine balance betweeninducing effective uterine contraction and maintainingfoetal wellbeing. In this field the dosage and the frequencyof drug administration are the two main issues that haveto be examined. A variety of methods have been used for

this intervention, which include catheter balloon insertion,laminaria tent insertion, prostaglandin E2 analogs, andoxytocin infusion. Many clinical trials have demonstratedthat misoprostol is effective for induction of labour at term,including prelabour rupture of membranes. These trialscompared misoprostol with oxytocin33-35, and otherprostaglandins36-39. Systematic review and meta-analysissupported than misoprostol is more effective than placeboor other prostaglandin for labour induction40,41. It canachieve a higher rate of vaginal delivery within 24 hours, ashorter induction-to-delivery interval, and significantlylower overall caesarean section rates than pooled figuresfor the control groups. However, the efficacy between oraland vaginal routes remains controversial. Adair et. al.showed that both routes were comparable as labourinduction agents42. Others reported that the vaginal routewas able to achieve a shorter induction-to-delivery interval,lower number of doses, and lower oxytocin use43,44. Thedosing regimen of labour induction has been extensivelyinvestigated as well. The available data suggest that theoptimal dose of mosoprostol for labour induction is 25 uggiven vaginally every 4 to 6 hours. Although the 50-ug doseresults in shorter induction-to-delivery interval and a higherrate of vaginal delivery45,46, the 25-ug dose was associatedwith lower incidence of tachysystole and uterinehyperstimulation. The lower-dose regimen achieved acomparable induction-delivery interval when comparedwith the high dose regimen45-49. Doses higher than 50 ugshould not be given because it has been associated with anincreased risk of serious complications50.

Induction of labour with previous uterine scar is alwayschallenged. No matter what method is used, there arehigher risks of uterine rupture than those without a scar.The first randomised controlled trial of 25 ug vaginalmisoprostol for induction of labour in women with oneprior caesarean section was terminated after two womenin the misoprostol group had disruption of their uterinescar. No further prospective trials in this area has beenpublished. Plaut et al. reported a 5.5% rate of scar ruptureassociated with the use of misoprostol compared with0.2% in patients attempting vaginal birth after caesareansection with no stimulation in a retrospective study51. Withthe rising caesarean section rate, there will be an increasingnumber of women undergoing termination of pregnancyor labour induction with a previous uterine scar. Currentevidence would suggest that they are at an increased riskof scar rupture. Women should be appropriatelycounselled about the risks and consequences.

Prevention for Postpartum HaemorrhagePostpartum haemorrhage (PPH) continues to be a leadingcause of maternal morbidity and mortality worldwide.Uterotonic agents administered during the third stage oflabour have been shown to reduce the incidence of PPHby 40%52,53. Misoprsotol administered by oral, vaginal andrectal routes had been investigated. The World HealthOrganization (WHO) conducted the largest scale studyinvolving nine countries with altogether 20,000 womenwere recruited54. This trial was to compare the use of oralmisoprostol (600 ug) to 10 IU of oxytocin. The sample sizewas of adequate power to measure two outcomes: blood

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loss of 1000 ml or more and the use of additional uterotonicagents. Unfortunately, the trial had several problems: 1.it was unclear whether the women received intravenousor intramuscular oxytocin; 2. there was an unexplainedstatistical heterogenicity between the individual centresfor the primary outcome of measured blood loss. Thefinding of this large trial is often quoted as a 1% differencebetween oral misoprostol and oxytocin. The WHO trial,however proved the safety of misoprostol administeredorally at doses up to 600 ug. The alternative administeredroute including vaginal and rectal route has beeninvestigated. The pilot study by O'Brien et al reported thatmisoprostol 1000 ug given rectally is an effectiveintervention in women with PPH who are unresponsiveto standard uterotonic agents55. Subsequent observationsstudies and a recent randomised study support the use ofrectal misoprostol (800 ug) in the treatment of PPH56,57.

Side Effects and ComplicationsMinor side effects including nausea, vomiting, anddiarrhoea, are character is tics of prostaglandinadministration and are due to prostaglandin’s stimulatoryeffect on the gastrointestinal tract. Serious complicationsincluding uterine rupture, major haemorrhage andcervical tear are rare48, 57-58. Cases of uterine rupture werereported to occur with both misoprostol and gemeprost,with our without priming by mifepristone59-61. Risk factorsof uterine rupture include previous caesarean section,grand multipara, advance gestation, prolongedprostaglandin therapy and use of oxytocin in addition toprostaglandins. Cardiovascular complications areuncommon. Long term complications associated withmedical abortion in the second trimester using misoprostolwith or without mifepristone are rarely reported.

ConclusionsMisoprostol is an important medication for Obstetrics andGynaecology practice. It is effective for medical abortionin combination with mifepristone. There is solid evidencesupporting the use of misoprostol for cervical ripeningprior to first trimester suction evacuation. It is also aneffective labour inducing agent. It was proven to be safewhen used in third stage to prevent postpartumhaemorrhage. However, the use in women with previousscar should be cautious.

References1. Normal FE, Thong KF, Baird DT. Uterine contractility an induction of abortion

in early pregnancy by misoprostol and mifepristone. Lancet 1991;338:1233-1236.2. Grimes DA, Schulz KF, Cates WJ. Prevention of uterine perforation during

curettage abortion. JAMA 1984;25:2108-2111.3. Bugalho A, Bique C, Almeida L, et al. Application of vaginal misoprostol before

cervical dilatation to facilitate first trimester pregnancy interruption. ObstetGynecol 1994;83:729-731.

4. Ngai SW, Tang OS, Lao T, Ho PC. Ma HK. Oral misoprostol versus placebo forcervical dilatation before vacuum aspiration in first trimester pregnancy. HumanReproduction 1995;10:1220-1222.

5. Ngai SW, Au Yeung KC, Lao , Ho PC. Oral misoprostol versus vaginal gemeprostfor cervical dilatation prior to vacuum aspiration in women in sixth to twelfthweek of gestation. Contraception 1995;51:347-50.

6. Ngai SW, Au Yeung KC, Lao T, Ho PC. Oral misoprostol versus mifepristone forcervical dilation before vacuum aspiration in first trimester nulliparous pregnancy:a double blind prospective randomised study. Br J Obstet Gynaecol;103:1120-23.

7. MacIsaac L, Grossman D, Bailistreri E, Darney P. A randomised controlled trialof laminaria, oral misoprostol, and vaginal misoprostol before abortion. ObstetGynecol 1999;93:766-70.

8. Creinin MD & Vittinghoff E. Methotrexate and misoprostol vs misoprostol alonefor early abortion. A randomised controlled trial. Journal of American MedicalAssociation 1994;272:1190-1195.

9. Bugalho A, Faundes A, Jamisse L et . Evaluation of the effectiveness of vaginalmisoprostol to induce first trimester abortion. Contraception 1996;53:244-246.

10. Koopersmith TB & Mishell Fr. Dr. The use of misoprostol for termination of earlypregnancy. Contraception 1996;53:238-242.

11. Carbonell JL, Varela L, Velazco A, et al. The use of misoprostol for termination ofearly pregnancy. Contraception 1997;55:165-168.

12. Carbonell JL, Varela L, Velazco A, et al. Vaginal misoprostol 600 ug for earlyabortion. Eur J Contracept Reprod Health Care 2000;5:46-41.

13. Carbonell JL, Rodriguezz J, Aragon S, et al. Vaginal misoprostol 100 microg forearly abortion. Contraception 2001;63:131-136.

14. Jain JK, Dutton C, Harwood B et al. A prospective randomised, double-blinded,placebo-controlled trial comparing mifepristone and vaginal misoprostol tovaginal misoprostol alone for elective termination of early pregnancy. HumanReproduction 2002;17:1477-1482.

15. Tang OS, Ho PC. Pilot study on the use of sublingual misoprostol for medicalabortion. Contraception 2001;64:315-317.

16. Tietze C. Second trimester abortion: a global view. In Berger GS, Brenner WE &Keith LG (eds) Second trimester abortion. Boston: John Wright, 1981;pp:1-11.

17. Chittacharoen A, Herabutya Y, Punyavachira P. A randomised trial of oral andvaginal misoprotol to manage delivery in cases of foetal death. Obstet Gynecol2003;10:70-3.

18. Wagaarachchi PT, Ashok PW, Narvekar NN, Smith NC, Templeton A. Medicalmanagement of late intrauterine death using a combination of mifepristone andmisoprostol. BJOG 2002;109:443-7.

19. Ashok PW, Templeton A. Nonsurgical mid-trimester termination of pregnancy:a review of 500 consecutive cases. BJOG 1999;106:706-10.

20. Wong KS, Ngai SW, Yeo EL, Tang LC, Ho PC. A comparison of two regimens ofintravaginal misoprostol for termination of second trimester pregnancy: arandomised comparative trial. Human Reprod 2000;15:709-12.

21. Bugalho A, Bique C, Machungo F, Faaundes A. Induction of labour with intravaginalmisoprostol in intrauterine death. Am J Obstet Gynecol 1994;171:538-41.

22. Wong KS, Ngai CSW, Wong AYK, Tang LCH & Ho PC. Vaginal misoprostolcompared with vaginal gemeprost in termination of second trimester pregnancy.Contraception 1998; 58:207-10.

23. Nuutila M, Toivonen J, Ylikorkala O & Halmesmaki E. A comparison betweentwo doses of intravaginal misoprostol and gemeprost for induction of second-trimester abortion. Obstetrics & Gynecology 1997; 90:896-900.

24. Perry KG, Rinehart BK, Terrrone DA et al. Second trimester uterine evacuation: acomparison of intra-amniotic (15S)-15-methyl-prostaglanidn F2 and intravaginalmisoprostol American Journal of Obstetrics and Gynaecology 1999;181:1057-1072.

25. Jain JK, Kuo J & Mishell R. A comparison of two dosing regimens of intravaginalmisoprostol for second-trimester pregnancy termination. Obstetrics & Gynecology1999;93:571-5.

26. Wong KS, Ngai CSW, Yeo ELK, Tang LCH & Ho PC. A comparison of tworegimens of intravaginal misoprostol for termination of second trimesterpregnancy: a randomised comparative trial. Human Reproduction 2000;15:709-12.

27. Herabutya Y & O-Prasertsawat. Second trimester abortion using intravaginalmisoprostol. International Journal of Gynecology & Obstetrics 1998;60:161-5.

28. Ho PC, Ngai SW, Liu KL, Wong GCY, Lee SWH. Vaginal misoprostol comparedwith oral misoprostol in termination of second-trimester pregnancy. Obstetrics &Gynecology 1997;90:735-8.

29. Tang OS & Ho PC. Pilot study on the use of sublingual misoprostol for medicalabortion. Contraception 2001;64:315-317.

30. Fletcher HM, Wharf G, Simeon D et al. Induction of labour with intravaginalmisoprostol versus dinoprostone in intrauterine death: a retrospective study.Journal of Obstetrics an Gynecology 1996;16:155-158.

31. Cabrol D, D Yuoire MD, Mermet E et al. Induction of labour with mifepristoneafter intrauterine death. Lancet 1985;ii:10-19.

32. Kramer RL, Gilson GF, Morrison DS, Martin D, Gonzales JL, Qualls CR. Arandomised trial of misoprostol and oxytocin for induction of labour: Safety andefficacy. Obstet Gynecol 1997;89:387-391.

33. Sanchez-Ramos L, Chen AH, Kaunitz AM, gaudier FL, Delke I. Labour inductionwith intravaginal misoprostol in term premature rupture of membranes: Arandomised study. Obstet Gynecol 1997;89:909-912.

34. Wing DA, Paul RH. Induction of labour with misoprostol for premature ruptureof membranes beyond thirty-six weeks’ gestation. Am J Obstet Gynecol 1998;179:94-99.

35. Wing DA, Jones MM, Rahall A, Goodwin TM, Paul RH. A comparison ofmisoprostol and prostaglandin E2 el for preinduction cervical priming and labourinduction. Am J Obstet Gynecol 1995;172:1804-1810.

36. Varaklis K, Gumina R, Stubblefield PG. Randomsied controlled trial of vaginalmisoprostol and intracervical prostaglandin E2 gel for induction of labour atterm. Obstet Gynecol 1995;86:541-544.

37. Buser D, Mora G, Arias F. An randomised comparison between misoprostol anddinoprostone for cervical ripening and labour induction in patients withunfavorable cervices. Obstet Gynecol 1997;89:981-585.

38. Surbek DV, Boesigner H, Hoesli I, Pavic N, Holzreve W. A double-blindcomparison of the safety and efficacy of intravaginal misoprostol andprostaglandin E2 to induce labour. Am J Obstet Gynecol 1997;177:1018-1023.

39. Hofmeyr GJ. Vaginal misoprostol for cervical ripening and labour induction inlate pregnancy (Cochrane review). In:The CochraneLibrary, Issue 4, Oxford:Update Software; 1999.

40. Sanchez-Ramos L, Kaunitz AM, Wears RL, et al. Misoprostol for cervical ripeningand labour induction: a meta-analysis. Obstet Gynecol 1997;89:633-642.

41. Adair D, Weeks JW, Barrilleauz S, et al. Oral or vaginal misoprostol administrationfor induction of labour: a randomised, double-blind trial. Obstet Gynecol 1998;92:8:810-813.

42. Toppozada MK, Anwar MY, Hassan HA, et al. Oral or vaginal misoprostol forinduction of labour. Int J Gynecol Obstet 1997;56:135-139.

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43. Nopdonrattakoon L,. A comparison between intravaginal and oral misoprostol forlabour induction: a randomised controlled trial. J Obstet Gynecol Res 2003;29:87-91.

44. Farah LA, Sanchez-Ramos L, Rosa C, et al. Randomised trial of two doses of theprostaglandin E1 analog misoprostol for labour induction. Am J Obstet Gynecol1997;177:364-369.

45. Srisomboon J, Tongsong T, Tosiri V. Preinduction cervical ripening withintravaginal prostaglandin E1 methyl analogue misoprostol: a randomisedcontrolled trail. J Obstet Gynaecol Res 1996;22f:119-124.

46. Wing DA, Paul RH. A comparison of differing dosing regimens of vaginallyadministered misoprostol for preinduction cervical ripening and labour induction.Am J Obstet Gynecol 1996;175:158-164.

47. Diro M, Adra A, Gilles JM, et al. A double-blind randomised trial of two doseregimens of misoprostol for cervical ripening and labour induction. J Matern FoetalMed 1999;8:114-118.

48. Meydanli MM, Caliskan E, Furak F, et al. Labour induction post-term with 25micrograms vs 50 micrograms of intravaginal misoprostol. Into J Gynoecia Obstetric2003;81:249-255.

49. Majuro F, Nostrum L, Landmark G. No benefit, but increased harm from highdose (100ug) misoprostol for induction of labour: a randomised trial of high vslow (50ug) dose misoprostol. J Obstet Gynaecol 2002;22:61614-61617.

50. Plaut MM, Schwartz ML, Lubarsky SL. Uterine rupture associated with the useof misprostol in the gravid patient with a previous caesarean section. Am J ObstetGynecol 1999;180:1535-1542.

51. Bugalho A, Daniel A, Faundes A, Cunha M. Misoprostol for prevention ofpostpartum haemorrhage. Int J Gynecol Obstet 2001;73:1-6.

52. Prendivi lle W, Elbourne D, Chalmers I. The effects of routine oxytocinadministration in the management of the third stage of labour: and overview ofthe evidence form controlled trials. Br J Obstet Gynaecol 1988;95:3-16.

53. Gulmezoglu AM, Villar J, Ngoc NT, et al. WHO multicentre randomised trial ofmisoprostrol in the management of third stage of labour. Lancet 2001;358:689-695.

54. O’Brien P, El Refaey H, Gordon A et al. Rectally administered misoprostol for thetreatment of postpartum haemorrhage unresponsive to oxytocin and ergometrine:a descriptive study. Obstetrics and Gynaecology 1998;92:212-214.

55. Abdel-Aleem H, El Nasdhar I & Abdel-Aleem A. Management of severepostpartum haemorrhage with misoprostol. Inter J Gyn & Obstet 2001;72:75-76.

56. Lokugamage AU, Sullivan KR, Biculescu I et al. A randomised study comparingrectally administered misoprostol versus Syntometrine combined with anoxytocin infusion for the cessation of primary postpartum haemorrhage. ActaObs Gyn Scan 2001;80:835-839.

57. UK Multicenter Study Group, Oral mifepristone 600 mg and vaginal gemeprostfor mid-trimester induction of abortion. Contraception 1997;56:361-366.

58. Gemzell-Danielsson K & Oslund E. Termination of second trimester pregnancywith mifepristone and gemeprost. The clinical experience of 197 conseccutivecases. Acta Obstetrica et Gynaecologica Scandinavica 2000;709:702-706.

59. Chen M, Shih JC, Chiu WT & Hsieh FJ. Separation of caesarean scar during second-trimester intravaginal misoprostol abortion. Obstetrics and Gynecology 1999;94:840

60. Norman JE. Uterine rupture during therapeutic abortion in the second trimesterusing mifepristone and prostaglandin. Bristish Journal of Obstetrics and Gynaecology1995;102:332-3.

61. Wiener JJ & Evans AS. Uterine rupture in midtrimester abortion. A complicationof gemeprost vaginal pessaries and oxytocin, Case report. British Journal ofObstetrics and Gynaecology 1990;97:1061-2.

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