Misoprostol for Prevention of Postpartum Hemorrhage: An Evidence ...

MisoprostolforPrevention of Postpartum Hemorrhage:An Evidence-based Reviewby the United States PharmacopeiaJoyce Primo Carpenter, M.D., BSc. Pharm.Medical Information SpecialistGlobal Assistance InitiativesDeveloped: 6/16/2000Revised: 6/30/2001

This publication was made possible through support provided by the U.S. Agency for InternationalDevelopment, under the terms of Cooperative Agreement number HRN-A-00-00-00017-00. The opinionsexpressed herein are those of the author(s) and do not necessarily reflect the views of the U.S. Agency forInternational Development.For more information, contact:U.S. Agency for International DevelopmentG/PHN/HN/HPSR1300 Pennsylvania Avenue, NWWashington, DC 20523-3700 USAPhone: (202)-712-4789Fax: 202-216-3702Email: aboni@usaid.govUnited States Pharmacopeia12601 Twinbrook ParkwayRockville, MD 20852 USAPhone: (301)-816-8162Fax: (301)-816-8374Email: uspdqi@usp.org

1Misoprostol for Prevention of Postpartum Hemorrhage:An Evidence-based Review by the United States PharmacopeiaBackgroundThe third stage of labor is potentially the most dangerous part for the mother, and activemanagement is necessary. The main risk is the occurrence of postpartum hemorrhage, defined asbleeding from the genital tract of 500 mL or more in the first 24 hours following delivery of thebaby. (1) The primary cause of postpartum hemorrhage is uterine atony. Postpartum hemorrhageis an important cause of maternal morbidity and mortality worldwide, accounting for at least150,000 maternal deaths every year. (2, 46, 60) The World Health Organization (WHO) estimatesthat 20 million morbidities every year result from postpartum hemorrhage. (5)Postpartum hemorrhage in developing countriesThe decreased prevalence of postpartum hemorrhage in most developed parts of the worldprobably is due to better management of the third stage of labor. (65) However, this is not true indeveloping countries where postpartum hemorrhage is estimated to be responsible for about 28%of maternal deaths. (3, 46) It is prevalent in those countries where high multiparity, prolongedlabor, fibroids, and severe anemia (probably caused by close spacing of pregnancies, poor diet, orparasitic infections) are common (4), although most cases of postpartum hemorrhage occurwithout such predisposing factors. (65) The risk of dying from postpartum hemorrhage dependson the amount and rate of blood loss and also on the health status of the mother. (46) Whenwomen already are compromised by severe anemia and intercurrent illnesses, maternal blood lossof as little as 250 mL may be fatal. (47)Active management of the third stage of laborActive management of the third stage of labor, consisting of administration of oxytocics, earlycord clamping and cutting, and delivery of placenta by controlled traction of the umbilical cordhas been shown to lower the rate of postpartum hemorrhage. (6, 7, 14) Use of prophylacticoxytocics resulted in about a 40% reduction in the risk of postpartum hemorrhage based onanalysis of nine controlled trials comparing uterotonic drugs with a placebo or no routineprophylaxis. (8) Other measures to reduce postpartum hemorrhage such as suckling and nipplestimulation in order to stimulate the release of oxytocin have been investigated. However, morestudies are warranted, as these small preliminary trials yielded variable results. (48, 63, 64)Oxytocic agentsConventional oxytocic agents used include oxytocin, the ergot alkaloids ergonovine(ergometrine) and methylergonovine (methylergometrine), syntometrine (which consists of 5 IUoxytocin [Syntocinon] + 0.5 mg ergometrine), and prostaglandins such as carboprost.Oxytocin, the ergot alkaloids, and syntometrine are equally effective in reducing the risk ofpostpartum hemorrhage when used in the active management of labor. (13, 14, 17, 50, 57)Oxytocin, which has been used routinely for many years, is considered the drug of choice forpreventing postpartum hemorrhage because it produces the fewest side effects. (6, 58) The ergotalkaloids, which have strong uterotonic properties, can be used as second-line agents. (15, 57, 58)©2001 The United States Pharmacopeial Convention, Inc. All rights reserved

2Syntometrine, which combines the rapid onset of action of oxytocin and the prolonged action ofergometrine, is an alternative. (16, 17, 50) Prostaglandins (e.g., carboprost, sulprostone) arestrong uterotonic third-line agents used in intractable postpartum hemorrhage when fundalmassage and use of other oxytocics fail. (1, 4, 58)Several drawbacks are associated with use of these oxytocics. (9, 10) Gastrointestinal side effectsmay occur. In one comparative study, oxytocin and syntometrine caused nausea and vomiting in1% of patients. (17) In another study, syntometrine was associated with vomiting in as many as12% of patients following its administration. (49) Syntometrine is contraindicated in women withhypertension in pregnancy because it can precipitate a rise in blood pressure (in 1.2 to 13% ofpatients). (9, 39, 50) Further, syntometrine has been reported to cause cardiac arrest (51) andintracerebral hemorrhage, and these may be attributed to the ergonovine (ergometrine)component. (18, 67) A recent report associated the ergot alkaloid with acute myocardialinfarction. (56) Administration of methylergonovine to 50 patients resulted in the following sideeffects: cramping (78%), headache (27%), hypertension (22%), dizziness (20%), bradycardia(10%), tachycardia (8%), and some mild gastrointestinal side effects. (52) The prostaglandins,which are expensive agents, generally do not cause hypertension. Carboprost has been reported tocause nausea, vomiting, and diarrhea in 9% of patients. It also has been associated withoccasional hypertensive episodes and bronchospasm. (19, 20, 21, 53, 55)None of these oxytocics are stable in light or in high ambient temperatures and therefore requirerefrigeration for maintenance of the “cold chain." They also should be protected from freezing.(11, 12, 54) Further, these agents require parenteral administration. (4)MisoprostolMisoprostol, a prostaglandin E 1 analog, is used orally for the prevention and treatment ofgastric/duodenal ulcer caused by the use of nonsteroidal anti-inflammatory agents (NSAIDs). Itssafety for this indication has been established over several years. (22) Oral absorption is rapid(23, 24) and its side effects are usually mild and infrequent. (25)Misoprostol has been shown to be a potent uterotonic agent selectively binding to EP 2 or EP 3prostanoid receptors. (26) Its effect on the early pregnant uterus has been shown to be rapid. (27)It has been investigated in the induction of labor (28, 29), cervical priming (30), and induction ofabortion, either alone or in combination with mifepristone. (31, 32)Misoprostol also has been investigated in the prevention of postpartum hemorrhage, using eitherthe oral or rectal route of administration, and compared with placebo or other oxytocics (seeattached evidence tables). (33, 34, 35, 36, 37, 38, 39, 40, 41, 60, 61, 62, 68, 69) Results of mostof these studies show a trend toward less postpartum hemorrhage with misoprostol, suggestingthat it might be effective for this indication without causing serious side effects. These studies,however, failed to reveal a significant statistical difference regarding blood loss. Recent studiesindicated misoprostol is comparable to standard oxytocics. (61, 68, 69) Some experts (42) arguethat failure when the rectal route was used probably was due to a pharmacokinetic problem, sincerate of absorption of misoprostol from the rectum is yet to be determined. They suggest thatfurther research on the pharmacokinetic properties and transmucosal absorption of misoprostol iswarranted. (43)Misoprostol produces less serious side effects. Gastrointestinal disturbances are infrequent.Vomiting (8%) and diarrhea (3%) have been reported in an uncontrolled study. (40) The oralroute has been associated with dose-related shivering (19 to 62%) and pyrexia (temperature >38©2001 The United States Pharmacopeial Convention, Inc. All rights reserved

3°C) (2 to 34%). (33, 34, 38, 40, 59) Some experts believe the rectal route may proveadvantageous because it could lessen the gastrointestinal side effects. With this route, misoprostolcan be administered to patients who are vomiting or unable to take oral medications, those whoare under general anesthesia, or those with heavy vaginal bleeding. (36, 37, 43)USP Expert Advisory Panel consensus and recommendationUpon review of the studies included in the attached evidence tables on misoprostol, the consensusof the U.S. Pharmacopeia Expert Advisory Panel is that prevention of postpartum hemorrhageshould be considered as an Accepted indication in the USP Drug Information (DI) monograph onmisoprostol. They recommended misoprostol as an alternative agent in reducing the incidence ofpostpartum hemorrhage, especially in situations in which oxytocin and other uterotonic drugs arenot available. The suggested single dose is 400 to 600 micrograms given either orally or rectallyimmediately following delivery of the child. (66)Implications for developing countriesIn developing countries where there is a high incidence of severe anemia during pregnancybecause of nutritional, genetic, or environmental factors, even a relatively small reduction inpostpartum blood loss could be clinically relevant. Simple route of administration and use ofstable, inexpensive drugs are needed because many deliveries take place away from hospitals ormedical facilities and are supervised only by birth attendants (who may not be qualified toadminister parenteral oxytocics) (4, 33) or most often, not supervised at all. (54) Re-use ofneedles for parenteral administration is common practice, thus posing a major risk of the spreadof blood-borne infections such as hepatitis B, hepatitis C, or human immunodeficiency virus(HIV) infection. Further, there is lack of availability of safe blood transfusion services and priorknowledge of blood pressure often is not available. (4)Misoprostol is an inexpensive drug and easily available. It is easy to use and does not requirespecial storage conditions (i.e., can be stored easily at room temperature; is thermostable and lightstable; does not require specific conditions for transfer) and has a shelf life of several years. (44,45) These advantages make it a useful drug in reducing the incidence of postpartum hemorrhagein developing countries. (65)References:1. Prendiville W, Elborn D. Care during the third stage of labor. In: Chalmers I, Enkin M, Keirse MJNC,editors. Effective care in pregnancy and childbirth, vol I. Oxford: Oxford University Press; 1989. p. 1145-69.2. Ratnam SS, Viegas OAC, Singh K. Magnitude and causes of maternal mortality as a basis for itsprevention. In: Kassel E, Awan AK, editors. Maternal and child care in developing countries. Zurich,Switzerland: Ott Publishers; 1989. p. 80-90.3. Chamberlain GVP. The clinical aspects of massive hemorrhage. In: Patel, editor. Maternal mortality.The way forward. London: RCOG; 1992. p. 54-62.4. O’Brien P, El-Refaey H. The management of the third stage of labor using misoprostol in low riskwomen. Contemp Rev Obstet Gynecol 1997; 9(1): 27-32.5. Turmen T. Safe motherhood: a global problem. In: Report from a symposium on the prevention andmanagement of anemia in pregnancy and postpartum hemorrhage. World Health Organization. Zurich,1996. p. 1-13.6. De Groot AN. Prevention of postpartum hemorrhage. Bailliere's clinical obstetrics and gynecology 1995;9(3): 619-31.©2001 The United States Pharmacopeial Convention, Inc. All rights reserved

47. Prendiville WJ. The prevention of postpartum hemorrhage-optimizing routine management of the thirdstage of labor. Eur J Obstet Gynecol Reprod Biol 1996; 69: 19-24.8. Elbourne D, Prendiville W, Chalmers I. Choice of oxytocic preparation for routine use in themanagement of the third stage of labour: an overview of the evidence from controlled trials. Br J ObstetGynaecol 1988; 95(1): 17-30.9. McDonald S, Prendiville W, Blair E. Randomized controlled trial of oxytocin alone vs oxytocin andergometrine in active management of third stage of labor. Br Med J 1993; 307: 1167-71.10. Prendiville WJ, Elbourne DR, McDonald S. Active versus expectant management of the third stage oflabor. In: Neilson JP, Crowther CA, Hodnett E, et al., editors. Pregnancy and childbirth module of theCochrane database of systematic reviews. The Cochrane Collaboration: issue 1. Oxford: Update Software;1997.11. Hogerzeil HV, Walker GJA, de Goerje MJ. Stability of injectable oxytocics in tropical climates. WorldHealth Organization: Geneva, 1993.12. Hogerzeil HV, Walker GJ. Instability of methylergometrine in tropical climates: an overview. Eur JObstet Gynecol Reprod Biol 1996; 69(1): 25-9.13. Nordstrom L, Fogelstam K, Fridman G, et al. Routine oxytocin in the third stage of labor: a placebocontrolled randomized trial. Br J Obstet Gynaecol 1997; 104 (7): 781-6.14. Rogers J, Wood J, McCandlish R, et al. Active versus expectant management of third stage of labor:the Hinchingbrooke randomized trial. Lancet 1998; 351 (9104): 693-9.15. De Groot AN, van Dongen PW, Vree TB, et al. Ergot alkaloids. Current status and review of clinicalpharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology. Drugs1998; 56(4): 523-35.16. Mitchell GG, Elbourne DR. The Salford Third Stage Trial. Oxytocin plus ergometrine versus oxytocinalone in the active management of the third stage of labor. Online J Curr Trials 1993; Doc No 83.17. Yuen PM, Chan NS, Yim SF, et al. A randomized double blind comparison of syntometrine andsyntocinon in the management of the third stage of labor. Br J Obstet Gynaecol 1995; 102(5): 377-80.18. Ringrose CAD. The obstetrical use of ergot. Can Med Assoc J 1962; 87: 712-4.19. Chua S, Chew SL, Yeoh CL, et al. A randomized controlled study of prostaglandin 15-methyl F2 alphacompared with syntometrine for prophylactic use in the third stage of labor. Aust N Z J Obstet Gynaecol1995; 35(4): 413-6.20. Laajoki VI, Kivikoski AI. Sulprostone in the control of postpartum hemorrhage. Acta Chir Hung 1986;27(3): 165-8.21. Van Selm M, Kanhai HH, Keirse MJ. Preventing the recurrence of atonic postpartum hemorrhage: adouble-blind trial. Acta Obstet Gynaecol Scand 1995; 74(4): 270-4.22. Collins PW. Misoprostol: discovery, development, and clinical application. Med Res Rev 1990; 10:149-72.23. Karim A. Antiulcer prostaglandin misoprostol: single and multiple dose pharmacokinetic profile.Prostaglandins 1987; 33 (Suppl): 40-50.24. Zieman M, Fong SK, Benonitz NL, et al. Kinetics of misoprostol with oral or vaginal administration.Obstet Gynecol 1997; 90: 88-92.25. Inman WH. Report on current PEM studies: drugs for peptic ulcer or reflux. Prescription EventMonitoring News 1991; 7: 32-4.26. Senior J, Marshall K, Sangha R, et al. In vitro characterization of prostanoid receptors on humanmyometrium at term pregnancy. Br J Pharmacol 1993; 108: 501-6.27. Norman JE, Thong KJ, Baird DT. Uterine contractility and induction of abortion in early pregnancy bymisoprostol and mifepristone. Lancet 1991; 338: 1233-6.28. Fletcher H, Mitchell S, Frederick J, et al. Intravaginal misoprostol versus dinoprostone as cervicalripening and labor inducing agents. Obstet Gynecol 1994; 83: 244-7.29. Windrim R, Bennet K, Mundle W, et al. Oral administration of misoprostol for labor induction: arandomized controlled trial. Obstet Gynecol 1997; 89: 392-7.30. El-Refaey H, Calder L, Wheatley DN, et al. Cervical priming with prostaglandin E1 analogues:gemeprost and misoprostol. Lancet 1994; 343: 1207-9.31. El-Refaey H, Hinshaw K, Templeton A. The abortifacient effect of misoprostol in the second trimester.Hum Reprod 1993; 8: 1744-6.©2001 The United States Pharmacopeial Convention, Inc. All rights reserved

532. El-Refaey H, Rajasekar D, Abdalla M, et al. Induction of abortion with mifepristone (Ru 486) and oralor vaginal misoprostol. N Engl J Med 1995; 332: 983-7.33. Surbek DV, Fehr PM, Hosli I, et al. Oral misoprostol for third stage of labor: a randomized placebocontrolledtrial. Obstet Gynecol 1999; 94(2): 255-8.34. Amant F, Spitz B, Timmerman D, et al. Misoprostol compared with methylergometrine for theprevention of postpartum hemorrhage: a double-blind randomized trial. Br J Obstet Gynaecol 1999; 106:1066-70.35. Diab KM, Ramy AR, Yehia MA. The use of rectal misoprostol as active pharmacological managementof the third stage of labor. J Obstet Gynaecol Res 1999; 25(5): 327-32.36. Bamigboye AA, Hofmeyer GJ, Merrell DA. Rectal misoprostol in the prevention of postpartumhemorrhage: a placebo-controlled trial. Am J Obstet Gynecol 1998; 179: 1043-6.37. O'Brien P, El-Refaey H, Gordon AAA, et al. Rectally administered misoprostol for the treatment ofpostpartum hemorrhage unresponsive to oxytocin and ergometrine: a descriptive study. Obstet Gynecol1998; 92(2): 212-4.38. Hofmeyer GJ, Nikodem VC, De Jager M, et al. A randomized placebo controlled trial of oralmisoprostol in the third stage of labor. Br J Obstet Gynaecol 1998; 105(9): 971-5.39. Bamigboye AA, Merrell DA, Hofmeyer GJ, et al. Randomized comparison of rectal misoprostol withsyntometrine for the management of third stage of labor. Acta Obstet Gynecol Scand 1998; 77(2): 178-81.40. El-Refaey H, O'Brien P, Morafa W, et al. Use of misoprostol in the prevention of postpartumhemorrhage. Br J Obstet Gynaecol 1997; 104 (3): 336-9.41. El-Refaey H, O'Brien P, Morafa W, et al. Misoprostol for third stage of labor. Lancet 1996 [letter to theeditor]; 347: 1257.42. Ramsey PS, Ramin KD, Bradle SS. Rectal misoprostol in the prevention of postpartum hemorrhage[letter to the editor]. Am J Obstet Gynecol 1999; 6 (pt 1): 1601.43. Hofmeyer GJ, Bamigboye AA. In reply [letter to the editor]. Am J Obstet Gynecol 1999; 6 (pt 1):1601-2.44. Kararli T, Catalano T, Needham TE, et al. Mechanism of misoprostol stabilization in hydroxypropylmethylcellulose. Adv Exp Med Biol 1991; 302: 275-89.45. Gaud HT, Connors KA. Misoprostol dehydration kinetics in aqueous solution in the presence ofhydroxypropylmethylcellulose. J Pharm Sci 1992; 81: 145-8.46. Kwast BE. Postpartum hemorrhage: its contribution to maternal mortality. Midwifery 1991; 7: 64-70.47. Lawson JB. Obstetric hemorrhage. In: Lawson JB, Steward DB, editors. Obstetrics and gynecology inthe tropics. London: Edward Arnold; 1967. p. 155-9.48. Bullough CHW, Msuku RS, Karondie L. Early suckling and postpartum hemorrhage: controlled trialdeliveriesby traditional birth attendants. Lancet 1989; 522-5.49. Prendiville WL, Harding JE, Elbourne DR, et al. The Bristol third stage trial: active versusphysiological management of the third stage of labor. Br Med J 1988; 297: 1295-300.50. Khan GQ, John IS, Chan T, et al. Abu Dhabi third stage trial: oxytocin versus syntometrine in theactive management of the third stage of labor. Eur J Obstet Gynecol 1995; 58: 147-51.51. Department of Health and Social Security. Report on confidential inquiries into maternal deaths in theUnited Kingdom 1970-1972. London: HMSO; 1975.52. Forman JB, Sullivan RL. The effects of intravenous injections of ergonovine and methergine on thepostpartum patients. Am J Obstet Gynecol 1952; 63: 640-4.53. Hayashi RH, Castillo VIS, Noah ML. Management of severe postpartum hemorrhage with aprostaglandin F 2a analogue. Obstet Gynecol 1984; 63: 806-8.54. Panel reviewer #1 comment, 5/2000.55. Panel reviewer #2 comment, 5/2000.56. Yaegashi N, Miura M, Okamura K. Acute myocardial infarction associated with postpartum ergotalkaloid administration. Int J Gynecol Obstet 1999: 64(1): 67-8.57. Sorbe B. Active pharmacologic management of the third stage of labor. A comparison of oxytocin andergometrine. Obstet Gynecol 1978; 52(6): 694-7.58. Kelsey JJ, Prevost RR. Drug therapy during labor and delivery. Am J Hosp Pharm 1994; 51: 2394-402.59. Lumbiganon P, Hofmeyer J, Gulmezoglu AM, et al. Misoprostol dose-related shivering and pyrexia inthe third stage of labor. Br J Obstet Gynaecol 1999; 106: 304-8.©2001 The United States Pharmacopeial Convention, Inc. All rights reserved

660. Cook CM, Spurrett MM, Murray, H. A randomized clinical trial comparing oral misoprostol withsynthetic oxytocin or syntometrine in the third stage of labor. Aust NZ J Obstet Gynaecol 1999; 39: 4: 414-9.61. Walley RL, Wilson JB, Crane JMG, et al. A double-blind placebo controlled randomised trial ofmisoprostol and oxytocin in the management of the third stage of labour. Br J Obstetrics Gynaecol 2000;107: 1111-5.62. Abdel-Aleem H, El-Nashar I, Abdel-Aleem A. Management of severe postpartum hemorrhage withmisoprostol. Intl J Gynecol Obstet 2001; 72: 75-6.63. Kim YM, Tejani N, Chayen B, et al. Management of the third stage of labor with nipple stimulation. JReprod Med 1986; 31(11): 1033-4.64. Irons DW, Sriskandabalan P, Bullough CH. A simple alternative to parenteral oxytocics for the thirdstage of labor. Int J Gynecol Obstet 1994; 46(1): 15-8.65. Panel reviewer #5 comment, 5/2000.66. USP Obstetrics and Gynecology Expert Advisory Panel Consensus on revision of misoprostol forprevention of postpartum hemorrhage, 6/2001.67. Johnstone M. The cardiovascular effects of oxytocic drugs. Br J Anaesth 1972; 44: 826-35.68. El-Refaey H, Nooh R, O’ Brien P, et al. The misoprostol third stage of labour study: a randomisedcontrolled comparison between orally administered misoprostol and standard management. Br J ObstetGynaecol 2000; 107: 1104-10.69. Ng PS, Chan ASM, Sin WK, et al. A multicentre randomized controlled trial of oral misoprostol andi.m. syntometrine in the management of the third stage of labour. Hum Reprod 2001; 16(1): 31-5.©2001 The United States Pharmacopeial Convention, Inc. All rights reserved

TABLE 1. Misoprostol for Prevention of Postpartum HemorrhageNote: The following is not intended to be an in-depth review of each article. Instead, it is a brief overview/review of the studies, assuming readers arealready familiar with the cited references.Evidence Ratings (ranked in descending order of strength):I Evidence from randomized, controlled trials or meta-analyses of a group of randomized, controlled trialsII Evidence from well-designed, internally controlled clinical trials without randomization, from cohort or case-controlled analytic studies, preferably from more thanone center, from multiple time series, or from dramatic results in uncontrolled experimentsIII Evidence from clinical trials with low power, preliminary reports of trials in progress, opinions of respected authorities on the basis of clinical experience,descriptive studies such as case reports or series, or reports of expert committeesAUTHOR/YEAR/REFERENCE # /SPONSOR(S)/EVIDENCE RATINGOR TYPE OF STUDYSurbek DV, Fehr PM,Hosli I, et al. Oralmisoprostol for third stageof labor; a randomizedplacebo-controlled trial.Obstet Gynecol 1999;94(2): 255-8.(A)Sponsor(s): NoneAffiliation(s) of theresearchers:Dept of OB-GYNUniversity of Basel,SwitzerlandStudy protocol approvedby: University of BaselHospital institutionalreview boardDESIGN/METHODS/GOALDesign:Randomized, double-blind, placebocontrolledtrialMethods:• Inclusion:- Women at low risk ofpostpartum hemorrhageundergoingvaginal deliveries• Exclusion:−multiple pregnancy−pre-eclampsia−history of postpartumhemorrhage or−antepartum hemorrhage−planned cesarean delivery• Assessments:−Primary end points:Postpartum blood loss ≥ 500mL, hematocrit values(prenatally, 24 and 48 hoursDOSE/DURATION OFTHERAPY/NDose/Duration:• Misoprostol 600mcg (n = 31) orplacebo (n = 34),one single doseorally, immediatelyafter cord clampingN = 65RESULTS/CONCLUSIONSResults:• Outcomes #1:−Mean (± standard error of themean) estimated blood loss (345 ±19.5 mL vs 417 ± 25.9 mL, P =0.31) and hematocrit difference (4.5± 0.9% vs 7.9 ± 1.2%, P = 0.014) inwomen who received misoprostoland placebo, respectively. The rateof postpartum hemorrhage, 7%versus 15% in misoprostol andplacebo group respectively, was notstatistically significant (P = 0.43)• Outcomes #2:−Length of 3rd stage of labor: 8 ±0.9 minutes in misoprostol groupvs 9 ± 1 minutes in the placebogroup−Need for additional oxytocics:16% in the misoprostol group vs38% in the placebo group (P = 0.47)−Side effects (nausea, vomiting,LIMITATIONSOF STUDY/STAFFCOMMENTSLimitations/Comments:• Baseline variables were similar in bothgroups• Except for the intervention, both groupswere treated similarly• Excellent follow-up; all patients wereaccounted for• Small sample• Although there was less postpartumhemorrhage observed in the misoprostolgroup than in the placebo group, thestudy failed to show a statisticallysignificant difference. There were fewerwomen in the misoprostol group whorequired additional oxytocics and thiswas nonstatistically significant• Authors acknowledged a weak point inthe study in that blood loss wasestimated and not measured and thatvisual estimates, although acceptable,have been shown to underestimateactual blood loss by 30 to 50%;objective estimate by© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 7

Evidence rating: Ipostpartum)−Secondary end points: Lengthof 3rd stage of labor, need foradditional oxytocics, sideeffects including nausea,vomiting, shivering,hypotension, and pain (usingvisual analog scale)−Other intervention:If IV oxytocin was used duringthe 2nd stage of labor, it wasstopped immediately afterdelivery. If uterine bleedingwas more than normal, and ifplacental separation did notoccur until 30 minutesafter delivery, additionaloxytocin was administeredintravenously in bolusesof 5 IU, repeated as necessary−A sample size of 60 wascalculated to detect a 20%difference in estimated bloodloss between groups with apower of 80%, at a significancelevel of 0.05−Statistic tests: Chi-square testor Fisher’s exact test andMann-Whitney test. A twotailedP < 0.05 was consideredstatistically significantdiarrhea, or hypotension) were notdifferent between the two groups.Shivering occurred in 22% ofpatients in the misoprostol group vs3% in the placebo group (P =0.023). Pain was similar between themisoprostol and placebo groups(mean 3.7 vs 3.4, respectively[P = 0.665]).−Fetal outcome was favorable inall womenConclusions:• Oral misoprostol administered inthe third stage of labor reducedpostpartum blood loss and might beeffective in reducing incidence ofpostpartum hemorrhagehemoglobin/hematocritdeterminations was done and showed asignificant difference• Another source of bias was the use ofadditional oxytocic by some women toprevent excessive bleeding• Shivering occurred in 22% of themisoprostol group which was significantGoal:• To investigate whether orallyadministered misoprostolduring 3rd stage of labor isefficient in reducingpostpartum blood lossAmant F, Spitz B,Timmerman D, et al.Design:Randomized, double-blind,Dose/Duration:• Misoprostol 600Results:• Outcome #1:Limitations/Comments:• Both groups received active© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 8

Misoprostol comparedwith methylergometrinefor the prevention ofpostpartum hemorrhage:a double-blindrandomized trial. Br JObstet Gynecol 1999;106: 1066-70.(B)Sponsor(s): NoneAffiliation(s) of theresearchers:Dept of OB-GYNUniversity HospitalLeuven, BelgiumStudy protocol approvedby: Local ethicscommitteeEvidence rating: Icontrolled trialMethods:• Inclusion:−Women who anticipatedvaginal delivery• Exclusion:−cesarean section−hypertensive disorders−gestational age < 32 weeks−intrauterine death−uterine malformations−allergy to prostaglandins oralkaloids−inflammatory bowel disease−obliterative vascular and−coronary disease−sepsis• Assessment:−Primary end points:Rate of postpartumhemorrhage, need fortherapeutic oxytocic drugs,side effects−Other end points:Length of 3 rd stage of labor,need for manual removal ofplacenta, need for bloodtransfusion (hemoglobin andhematocrit levels weremeasured on admission and onthe 3 rd day postpartum;temperature and BP valueswere recorded)−A sample size of 60 womenin each group was required toobtain a power of 90%; asample size of 100 was chosenin order to be well above thislimit−Statistic tests: Two-sample tmcg (n = 100) orplacebo, orally;andmethylergometrine 200 mcg (n =100) or placebo,injectedintravenously,after deliveryN = 213 enrolled, minus13 who wereexcluded because acesarean section wasperformed afterrandomization (n =3), or becauseno pre-partum (n =3) or postpartum (n= 7, short hospitalstay) blood samplewas taken, resultingin 200 whocompleted the study−Estimated blood loss (>500mL): 4.3% in themethylergometrine groupvs 8.3% in the misoprostol group(P = 0.57); 1% in the misoprostolgroup hadblood loss > 1000 mL and none inthe methylergometrine group−Need for additional oxytocics:12.8% in the misoprostol group vs4.4% in the methylergometrinegroup (P = 0.065)−Side effects: Shivering occurredin the misoprostol group (42%)more than in themethylergometrine group (8.5%)(P = 0.0001), which wasstatistically significant. There wasno difference between bothgroups in the occurrence of otherside effects such as nausea,vomiting, diarrhea, hot flush,headache, or vertigo• Other outcomes:−Need for manual removal ofplacenta was similar in bothgroups (3% in themethylergometrine group vs 4%in the misoprostol group [P = 1,Fisher exact test])−1 woman in each group needed ablood transfusion−The median length of labor wassimilar for both groups (P = 0.88).−Temperature, one hour afterdelivery: A significant rise intemperature (≥ 38 °C) occurred in34% in the misoprostol group and3% in the methylergometrinegroup (P = 0.0001). A rise intemperature (≥ 39 °C) occurredmanagement of the third stage equally• Demographic characteristics and laborvariables were similar• The misoprostol group had increasedneed for therapeutic oxytocics comparedwith the methylergometrine group,although this was not statisticallysignificant• Less blood loss occurred in themethylergometrine group than in themisoprostol group, although this was notstatistically significant• Incomplete data in some cases as in therecording of side effects and need foradditional oxytocics• The authors stated that the oralabsorption of misoprostol delayed theeffects on hemorrhage during the firsthour after delivery, requiring moreoxytocics for those patients, whereasparenteral injection ofmethylergometrine was effectiveimmediately. The authors suggested useof combined prophylaxis consisting of aparenteral uterotonic such asmethylergometrine to prevent uterinebleeding immediately after delivery andoral misoprostol to reduce blood loss inthe hours following delivery• Blood loss was visually estimated(subjective); hemoglobin/hematocritdeterminations were done (objective)• Significant side effects observed in themisoprostol group were shivering andpyrexia© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 9

test, chi-square test, andWilcoxon rank sum testGoal:• To compare the efficacy andside effects of misoprostol inthe prevention of postpartumhemorrhage with those ofmethylergometrineonly in the misoprostol group(8%)−No difference in systolic anddiastolic blood pressure or inhemoglobin and hematocrit valuesConclusions:• This study suggests that althoughprotection from postpartumhemorrhage using parenteralmethylergometrine and oralmisoprostol is nearly equal,misoprostol is associated withmore side effectsDiab KM , Ramy AR,Yehia MA. The use ofrectal misoprostol asactive pharmacologicalmanagement of the thirdstage of labor. J ObstetGynaecol Res 1999;25(5): 327-32.(C)Sponsor(s): NoneAffiliation(s) of theresearchers:Dept of OB-GYNAin Shams UniversityCairo, EgyptEvidence rating: IIDesign:Comparative studyMethods:• Inclusion:−Women at low risk forvaginal delivery• Exclusion:−grandmultiparity (parity ≥5)−under anticoagulant therapy−placenta previa−antepartum hemorrhage−polyhydramnios−intrauterine fetal death−previous postpartumhemorrhage−uterine scar−prolonged (≥ 24 hours) orrapid (≤ 2 hours)−under epidural anesthesia−contraindications such ashypertension or cardiacdiseases• Assessments:Dose and duration:• Misoprostol 200mcg (n = 25) or400 mcg (n = 45)rectally, oroxytocin 5 Unitsplus ergometrine0.2 mg IM (n =70)N =140Results:• Outcomes:Estimated blood loss: mean − 234 ±11 in misoprostol group vs 273 ± 12in the oxytocin/ergometrine group;need for additional oxytocics: 4 inmisoprostol group vs 15 inoxytocin/ergometrine group; sideeffects: nausea, vomiting, anddiarrhea occurred in 8 patients in themisoprostol group and none in theother group; shivering occurred in 5patients in the misoprostol group andnone in the other group; postpartumsystolic hypertension: less in themisoprostol group (112 ± 1.4 in themisoprostol group vs 122 ± 1.6 inthe oxytocin/ergometrine group);postpartum diastolic hypertension:less in the misoprostol group (73 ±1.1 in the misoprostol group vs 78 ±1.8 in the oxytocin/ergometrinegroup); duration of the 3rd stage wassimilar in both groups (mean: 2.97 ±0.14 in the misoprostol group vs 3.1± 0.13 in the oxytocin/ergometrineLimitations/Comments:• No mention of randomized concealedallocation• Both groups received similar activemanagement of the 3rd stage• Nonblind• Baseline characteristics were similar inboth groups• All patients were accounted for• Blood loss visually estimated(subjective); hemoglobin/hematocritdeterminations were done (objective)• There was less blood loss (significant atP = < 0.01) and need for additionaloxytocics in the misoprostol group thanin the oxytocin/ergometrine group• Mild gastrointestinal side effectsoccurred more in the misoprostol group.However, hypertension occurred morein the oxytocin/ergometrine group© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 10

−End points:Duration of 3rd stage oflabor (prolonged if ≥ 30min), amount of blood loss(≥ 500 mL), need foradditional therapeuticoxytocics, perineal trauma(episiotomy/tear), sideeffects such as nausea,vomiting, shivering,hypertension (systolic BP ≥150 mm Hg, or diastolic BP≥ 100 mm Hg), neonataloutcome; pre- andpostpartum hemoglobin andhematocrit determinations−After delivery of the fetus,any oxytocin infusion usedfor laboraugmentation was stoppedand plain 5% glucose wasadministered. In the event ofexcessive bleeding,additional therapeuticuterotonic agents wereadministered consisting of0.2 mg ergometrine IM plus30 Units oxytocin by IVinfusionin 500 mL glucose 5%.−Statistic tests: Student's ttest, Fisher’s exact testgroup); none needed manualremoval of placenta, none neededblood transfusion; postpartumhemoglobin and hematocrit levelswere significantly decreased in theoxytocin/ergometrine groupConclusions:• Rectal misoprostol may be usedsafely as an active pharmacologicalmanagement in the 3rd stage oflabor. Further studies are needed toexplore the exact dose to be usedrectallyGoal:• To determine the safety andefficacy of administration ofmisoprostol rectally,compared to combinedintramuscular administrationof oxytocin and ergometrineas uterotonic agents in the© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 11

active management of the 3rdstage of laborBamigboye AA,HofmeyerGJ, Merrell DA. Rectalmisoprostol in theprevention of postpartumhemorrhage: a placebocontrolledtrial. Am JObstet Gynecol, 1998;179: 1043-6(D)Sponsor(s): NoneAffiliation(s) of theresearchers:Dept of OB-GYNCoronation HospitalNatalspruit HospitalUniversity ofWitwatersrandJohannesburg, SouthAfricaStudy protocol approvedby: Committee forResearch on HumanSubjects of the Universityof WitwatersrandEvidence rating: IDesign:Randomized, placebo-controlledstudyMethods:• Inclusion:−Pregnant women at low riskin labor• Assessment:−Primary end points:Excessive bleeding/blood lossmeasured, need for additionaloxytocic agents, need foroxytocin infusion−Secondary end points:Spontaneous delivery ofplacenta, duration of3rd stage of labor, side effects,especially shivering−Other intervention: IMadministration of 1 ampulsyntometrine (ergometrine0.5 mg/oxytocin 5 IU) forsigns of excessive blood lossand if bleeding persisted,infusion of oxytocin 20 Unitsin 1 L lactated Ringer'ssolution−Sample size of 550 wascalculated to give an 80%chance of detecting areduction in blood loss >1000mL from 12.5 to 5%,determined from datafrom 2 previous randomizedtrials showing estimatedpostpartum hemorrhageof 13.5% w/ physiologicDose/Duration:• Misoprostol,rectal, 400 mcg (n= 271), or placebo(n = 275) within 1minute afternormal vaginaldelivery andclamping of thecordN = 550 enrolled minus 4(records untraced)= 546 analyzedResults:• Outcomes #1:−Blood loss of ≥1000 mL in4.8% in the misoprostol groupand in 7% in the placebo group(RR 0.69 [95% CI, 0.35−1.37])(P = 0.37); additional oxytocicagent needed by 3.3% inmisoprostol group and 4.7% inthe placebo group (RR 0.70[95% CI, 0.31−1.62]) (P = 0.54);oxytocin infusion required by1.8 and 4.4%, respectively (RR0.42 [95% CI, 0.15−1.18]) (P =0.15)• Outcomes #2:−The mean duration of the thirdstage of labor was 6.6 minutes inthe misoprostol group and 6.4minutes in the placebo group−Vomiting reported in 1 womanin each group−Shivering reported in 1 womanin the misoprostol group and 4womenin the placebo group (7.1%)Conclusions:• Postpartum use of 400 mcg ofrectal misoprostol was welltolerated and associated w/ anonsignificant trend toward lesspostpartum hemorrhage. Lowside effect profile whencompared to oral route ofadministration. Potential benefitof misoprostol may be greater inan environment in whichLimitations/Comments:• Double-blinding was not achieved dueto inability to obtain identical-lookingplacebo tablets from manufacturer• Potential to demonstrate a difference inthe rate of excessive blood loss betweenthe misoprostol & placebo groups waslimited by the need to administeroxytocic agents as soon as blood lossappeared excessive• Incidence of postpartum hemorrhage inthe control group (7%) was lower thanthat on which the power calculationswere based (12.5%)• No mention of exclusion criteria• Baseline variables were similar for bothgroups• Except for the intervention, both groupswere treated in the same manner• Clinical estimate of blood loss wasdone with detailed description of howblood loss was collected and measured(e.g., pan collection and blood-soiledlinen, etc. weighed); nohemoglobin/hematocritdeterminations were done• Good follow-up• Although there was less postpartumhemorrhage observed in themisoprostol group than in the placebogroup, the study failed to reveal asignificant statistical differenceregarding blood loss between the twogroups. (Power analysis was done at thestart of the trial.) Also, there was lessneed for further oxytocics postpartumin the misoprostol group than inplacebo group, but the difference was© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 12

management of the 3rd stagecompared w/ 4.1% w/ activemanagement−Statistic tests: Fisher’s exacttest, Mann-Whitney testoxytocic agents are not availablenonsignificant• Side effects observed were mildGoal:• To investigate the use of rectalmisoprostol compared withplacebo in preventingpostpartum hemorrhageO'Brien P, El-Refaey H,Gordon AAA, et al.Rectally administeredmisoprostol for thetreatment of postpartumhemorrhage unresponsiveto oxytocin andergometrine: a descriptivestudy. Obstet Gynecol1998; 92(2): 212-4.(E)Sponsor(s): NoneAffiliation(s) of theresearchers:Dept of OB-GYNUniversity CollegeHospitalLondon, UKEvidence rating: IIIDesign:Descriptive studyMethods:• Inclusion:−Women with postpartumhemorrhage unresponsive tooxytocin & ergometrine (n =10) or when ergometrine wascontraindicated, oxytocinalone (n = 4)• Assessment:−Blood loss−Labor complications−Other intervention: OxytocinIV infusion (40 Units in 500mL normal saline over 15minutes and bolus (10 to 20Units), ergometrine (0.5 to 1mg IM or IV), or carboprostGoal:• To investigate whetherrectally administeredmisoprostol is an effectivetreatment for postpartumhemorrhage unresponsive toconventional first-linemanagementDose/Duration:• Misoprostol 1000mcg (five tablets)rectally, whileawaitingcarboprost. Ifcarboprost wasready foradministrationbeforemisoprostol, thewoman wasexcluded from thestudy andcarboprost wasadministeredaccording tohospital policyN = 14Results:• Blood loss:−Hemorrhage was controlled inall 14 women & sustaineduterine contraction was producedw/in 3 minutes followingadministration of misoprostol.No woman required any furtheruterotonic treatment−Median estimated blood losswas 1000 mL; 9 women (64%)had blood loss of 1000 mL ormore; 11 women (79%) requireda blood transfusion, with 2patients requiring overnight stayin intensive care unit. All 14women made full recovery−Some of the complications thatdeveloped were preeclampsiaand DICConclusions:• Rectally administeredmisoprostol is an effectivetreatment for postpartumhemorrhage unresponsive tooxytocin & ergometrine & maybe an alternative to parenteralprostaglandins. The authorsLimitations/Comments:• Authors stated that the possibility cannotbe ruled out that these women respondedto the previously administered oxytocics orto the combined effects of the oxytocicsand misoprostol, rather than to themisoprostol alone. However, they addedthat IV oxytocics have a rapid onset ofaction and that an appropriate therapeuticinterval had passed; any effect onhemorrhage may have occurred by thetime misoprostol was administered• Small sample• Uncontrolled study and, therefore, wouldbe difficult to conclude that the resolutionof postpartum bleeding was due tomisoprostol. The observed effect could bedue to the previously administeredoxytocics or a combination of these drugswith misoprostol• Ten of the 14 women included in the studywere high risk as evidenced by thecomplications reported (preeclampsia,DIC, breech, etc.); almost all requiredblood transfusion• No mention of side effects. Use of a higherdose (1000 mcg) did not result in shivering© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 13

suggested that absorption ofmisoprostol is mucousmembranedependent & rectalabsorption might be just aseffective as vaginal or oralabsorption• Rectal administration appears tobe ideal, given that women undergeneral anesthesia cannot begiven oral medication & thatvaginal administration isunlikely to be effective in thepresence of heavy vaginalbleeding• Misoprostol is inexpensive &stable & has considerablepotential to reduce maternalmortality in developing countries.Authors suggested the need forfurther investigation, both fordeveloped and developingcountriesHofmeyr GJ, NikodemVC, De Jager M, et al. Arandomized placebocontrolledtrial of oralmisoprostol in the thirdstage of labor. Br J ObstetGynaecol 1998; 105(9):971-5.(F)Sponsor(s): South AfricanMedical Research CouncilAffiliation(s) of theresearchers:Dept of OB-GYNCoronation HospitalUniversity ofDesign:Randomized, double-blind, placebocontrolledtrialMethods:• Inclusion:−Low-risk women expectedto deliver vaginally• Exclusion:−women in labor withoxytocin infusion inprogress at the time ofdelivery−hypertension−diabetes−previous cesarean section• Assessment:−Primary end points:Dose/Duration:• Misoprostol 400mcg (n = 250),orally, or placebo(n = 250), afterdeliveryN=500Results:• Outcomes #1:−Blood loss of > 1000 mL: 6%in the misoprostol group vs.9.2% in the placebo group (RR0.65 [95% CI, 0.35−1.22]) (P =0.18)−Need for additional oxytocics:8.4% in the misoprostol group vs13% in the placebo group (RR0.64 [95% CI, 0.38−1.07]) (P =0.08); oxytocin infusion wasrequired by 2.8% in themisoprostol group and 8.4% inthe placebo group (RR 0.33 [CI0.14−0.77]) (P = 0.006) w/c isstatistically significant• Outcomes #2:Limitations/Comments:• Authors stated that the actual differencebetween the two groups may have beenlimited by the policy of earlyconventional oxytocic management themoment bleeding appeared to be morethan usual• Double-blinding was achieved in spiteof the use of unidentical-lookingplacebo tablets• Baseline variables were similar for bothgroups• Clinical estimate of blood loss withwell-described method of how bloodloss was collected and measured (e.g.,pan collection and blood-soiled linen,etc. weighed); hemoglobin/hematocritdeterminations were not done© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 14

WitwatersrandJohannesburg, SouthAfricaEvidence rating: IMeasured blood loss ≥1000mL and need forconventional oxytocics−Secondary end points:Duration of 3rd stage,manual removal ofplacenta, blood transfusion,side effects−Cointervention:Conventional oxytocics(Syntometrine [1 ampul] IMor oxytocin [10 IU] or forsevere bleeding, an IVinfusion of oxytocin [20 IUin 100 mL saline]) were notgiven routinely unlessnecessary−A sample size of 496 wascalculated to detect areduction in the incidenceof measured blood loss of ≥1000 mL from 12.5 to 5%with 80% power at the 5%level of certainty−Statistic tests: Chi-squaretest or Fisher’s exact testGoal:• To compare the effectivenessof misoprostol, 400 mcg,administered orally, withplacebo in the routinemanagement of the 3rd stageof labor−Side effects results werestatistically significant,occurring in 22% in themisoprostol group and 10% inthe placebo group (RR 2.08[95% CI 1.35−3.20]) (P = 0.001)with shivering more common inmisoprostol group (19%) vsplacebo group (5.2%) (RR 3.69[95% CI 2.05−6.64]) (P= 800 mL (not apredefined end point in thisstudy but was used to comparewith the results from a recentSwedish trial using this as endpoint): 11.2% for misoprostoland 17.2% for placebo (RR 0.65[95% CI 0.42−1.01] (P = 0.055)Conclusions:• Misoprostol shows promise as amethod of reducing the risk ofpostpartum hemorrhage.Shivering is a common sideeffect. Further research todetermine misoprostol's efficacywith certainty is needed• Except for the intervention, both groupswere treated in the same manner• Complete follow-up• Although there was less postpartumhemorrhage observed in themisoprostol group than in the placebogroup, the study failed to reveal asignificant statistical differenceregarding blood loss between the twogroups. (Power analysis was done atthe start of the trial.) The misoprostolgroup had less need for furtheroxytocics postpartum, but thedifference was nonsignificant• Mild side effects; shiveringsignificantly occurred in themisoprostol groupBamigboye AA, MerrellDA, Hofmeyer GJ, et al.Randomized comparisonof rectal misoprostol withsyntometrine for theDesign:Randomized, comparative studyMethods:• Inclusion:Dose/Duration:• Misoprostol (n =250) 400 mcgrectally, orsyntometrine (n =Results:• Outcomes:−Blood loss > 500 mL: 0.9% inthe misoprostol group vs 0.4% inthe syntometrine group (RRLimitations/Comments:• Recording of trial data was incompletein several cases• Bias may have been introduced thatprobably favored the syntometrine© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 15

management of the thirdstage of labor. Acta ObstetGynecol Scand 1998;77(2): 178-81.(G)Sponsor(s): South AfricanMedical Research CouncilAffiliation(s) of theresearchers:Dept of OB-GYNNatalspruit HospitalCoronation HospitalUniversity ofWitwatersrandJohannesburg, SouthAfricaEvidence rating: I−Low risk women in labor• Hypertension(contraindication) detectedafter enrollment excludedsome women fromsyntometrine group• Assessments:−End points: Estimatedblood loss, blood pressure,hemoglobin level, durationof 3rd stage of labor−Statistic tests: Chi squaretest or Fisher’s exact test,Mann-Whitney testGoal:• To compare the effectivenessof rectal misoprostol (400mcg) with syntometrine (1ampul) in the management ofthe 3rd stage of laborN = 491241) 1 ampul IM,after delivery2.02% [ 95% CI 0.18−22] P =0.6)−BP systolic > 140 mm Hg: 15%in the misoprostol group vs 19%in the syntometrine group (RR0.79% [ 95% CI 0.53-1.2] P =0.3)−BP diastolic > 90 mm Hg: 4.6%in the misoprostol group vs 13%in the syntometrine group (RR0.37% [ 95% CI 0.19−0.72] P =0.004)−Hemoglobin

syntometrine not included)El-Refaey H, O'Brien P,Morafa W, et al. Use ofmisoprostol in theprevention of postpartumhemorrhage. Br J ObstetGynaecol 1997; 104(3):336-9.(H)Sponsor(s): NoneAffiliation(s) of theresearchers:Dept of OB-GYNUniversity CollegeHospitalLondon, UKEvidence rating: IIIDesign:Prospective, observational studyMethods:• Inclusion:−Women undergoingvaginal delivery• Exclusion:−placenta previa−multiple pregnancy−intrauterine death−gestational age < 32 weeks−history of postpartumhemorrhage−in the 6th pregnancy ormore−cesarean section−pre-eclampsiaAssessments:−Primary end point:Postpartum blood loss ≥500 mL−Secondary end points:Severe postpartum bloodloss (> 1000 mL),secondary postpartumhemorrhage, need for bloodtransfusion, and need forfurther oxytocics−Other end points: Lengthof 3rd stage, rate of manualremoval of placenta, needfor subsequent evacuationof the uterus, hemoglobinconcentration and packedcell volume, side effectssuch as vomiting, diarrhea,shivering, and hypertension(defined as a diastolic BPDose/Duration:• Misoprostol 600mcg, orally,immediatelyafter deliveryN = 237Results:• Outcome #1:−Blood loss ≥ 500 mL occurredin 6% of patients• Outcome #2:−None had blood loss ≥ 1000 mL−No secondary postpartumhemorrhage was reported−1% required blood transfusion−5% needed further oxytocicdrug• Outcome #3:−Median length of 3rd stage oflabor was 5 minutes−2% required manual removal ofplacenta−None required surgicalevacuation of uterus−2% had postpartum hemoglobin< 9 grams/dL−Side effects: vomiting (8%),diarrhea (3%), shivering (62%)−No differences found insystolic/diastolic BP pre- andpostpartum−Temperature significantlyincreased by 0.5 ºC (P = 0.001)Conclusions:• Misoprostol may be effective inthe prevention of postpartumhemorrhage & has few sideeffects• The rate of postpartumhemorrhage with misoprostol(6%), need for furthertherapeutic oxytocics (5%), andthe length of the 3rd stage arelower than those reported whenLimitations/Comments• Uncontrolled study and therefore, wouldbe difficult to conclude that theresolution of postpartum hemorrhagewas due to misoprostol• Shivering as a side effect occurred in62% of patients© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 17

≥100 mm Hg or a systolicBP ≥150 mm Hg)−Cointervention:Syntometrine IM whennecessary−Statistical tests: paired ttest, chi-square testGoal:• To investigate the use of oralprostaglandin E 1 analog,misoprostol, in the preventionof postpartum hemorrhage;ascertain the rate of postpartumhemorrhage3rd stage is managedphysiologically. Results are alsocomparable with those ofsyntometrine. (Reviews ofprophylactic administration ofoxytocics in the 3rd stage oflabor showed a decrease in therate of postpartum hemorrhagefrom 18% to 5%; the need fortherapeutic oxytocics is reducedfrom 30% to 6%; and the lengthof the 3rd stage reduced from 15minutes to 5 minutes.)• A double-blind randomized trialof oral misoprostol & IMsyntometrine is requiredEl-Refaey H, O'Brien P,Morafa W, et al.Misoprostol for the thirdstage of labor. Lancet1996 [letter]; 347(9010):1257.(I)Affiliation(s) of theresearchers:Dept of OB-GYNUniversity CollegeHospitalLondon, UKEvidence rating: IIIDesign:ObservationalMethods:• Inclusion:−Women in labor with meanage of 27.7 years• Assessment:−Primary end point: Incidenceof postpartum hemorrhage(estimated blood loss of 500mL or more)−Other end points such as sideeffects (vomiting, diarrhea,shivering, hypertension)−Cointervention:Syntometrine, if there wasclinical indicationGoal:To investigate whether activemanagement of the 3rd stageof labor can be carried outDose & Duration:• Misoprostol 600mcg (three tablets)orally immediatelyafter delivery andclamping andcutting of the cordN = 100Results:• Outcome #1:−An estimated blood loss of 500mL occurred in 3 patients−Blood loss of > 500 mL occurredin 3 patients−No patient had blood loss of 1000mL or more−Median blood loss for the studypopulation was 200 mL• Other outcomes:−Mild gastrointestinal side effectswere infrequent with loose stoolsreported by 3 patients; shiveringoccurred in 68 patients, and a meanreduction of 1 mm Hg in systolicand 1.2 mm Hg in diastolic BP wasobserved w/c were statisticallynonsignificant−Manual removal of the placentawas required by 2 patients−Blood transfusion was required byLimitations/Comments:• This brief report (preliminary observation)is a letter to the editor and does not includedescription of detailed methodology.Although this study showed lesspostpartum blood loss, reliability of data isin question because of incomplete nature ofevidence• Shivering was noted in 68 patients© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 18

safely with misoprostol1 patient w/ broad ligamenthematoma that was managedconservatively−Syntometrine was used in 6patients−Mean duration of labor was 5minutesConclusions:• Misoprostol can be used in themanagement of the third stage oflabor. The frequency of postpartumhemorrhage (6%), need for furthertherapeutic oxytocics (6%), and thelength of the 3rd stage of labor(median 5 minutes) in this studyare considerably lower than thosereported when the 3rd stage ismanaged physiologically andsimilar to results with the use ofsyntometrineWalley RL, Wilson JB,Crane JMG, et al. Adouble-blind placebocontrolled randomisedtrial of misoprostol andoxytocin in themanagement of the thirdstage of labour. Br JObstet Gynaecol 2000;107: 1111-5.(J)Sponsors: MaterCare Intl,Canadian IntlDevelopment AgencyAffiliation(s) of theresearchers:Design:Randomized, double-blind, placebocontrolledtrialMethods:• Inclusion:-Women in labor• Exclusion:-grand multiparity (> gravida5)-multiple gestation-gestation < 32 weeks-gestational hypertension withthe HEELP (hemolysis,elevated liver enzymes, lowplatelets) syndrome-hydramnios, previous PPH-cesarean delivery-coagulation abnormalitiesDose/Duration:With delivery of anteriorshoulder• Misoprostol 400mcg in powderedform (in 50 mL ofwater) orally and 1mL normal saline(placebo) IM (n =203)• Powdered lactoseplacebo (in 50 mLof water) and 1 mLoxytocin 10 IU IM(n = 198)N = 401 women enrolled,of whom 392 hadpre- and post-Results:• Primary outcome:-No significant difference betweenthe 2 groups in drop in hemoglobinconcentrations (from a mean 11.1[SD 1.3] to 10.5 [1.3] in themisoprostol group and 10.9 [1.2] to10.4 [1.3] in the oxytocin group,RR (95% CI) was 1.5% [−1.0 to4.0%], P = 0.25). Other measuresof postpartum hemoglobinconcentrations were not differentbetween the 2 groups• Secondary outcomes includeestimated blood loss, length of the3 rd stage, and use of additionaloxytocics were similar between thegroups• Shivering occurred more frequentlyLimitations/Comments:• Demographic variables were similar inboth groups• Outstanding follow-up• Equal treatment for both groups with theexception of the intervention; activemanagement of 3 rd stage with controlledcord traction until delivery of placenta withIV oxytocin when necessary for blood loss> 1000 mL• Authors stated the following reasons whythey chose change in hemoglobinconcentration as primary outcome: First,the incidence of PPH is such that a verylarge study would be required to evaluate asignificant change in PPH as the primaryoutcome and such a study would need to bemulticentered and may require undue timeto completion; second, excessive blood© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 19

Dept of OB-GYN andNursing MemorialUniversity ofNewfoundland, Canada;University Dept of OB-GYN University of GhanaMedical School, Accra,GhanaStudy protocol approvedby: Human InvestigationCommittee of the Facultyof Medicine, MemorialUniversity ofNewfoundland and KorleBu Teaching HospitalEvidence rating: I-precipitous labor (< 3 hours)-chorioamnionitis-oxytocin induction oraugmentation of labor-known hypersensitivity toprostaglandins-hemoglobin concentration of< 8 grams/dL• Assessments:-Primary end point: A drop inhemoglobin concentration. Achart review of 50 womenfound a standard deviation inthe drop of hemoglobinconcentration of 0.3 grams/dL.A difference of drop >0.1grams/dL between themisoprostol and oxytocin groupwas considered clinicallyimportant. Hemoglobindetermination was done preandpost-delivery (12 hours [±4 hours])-Secondary end points:Estimated blood loss, length ofthe 3 rd stage, use of additionaloxytocics, side effectsincluding nausea, vomiting,diarrhea, shivering, andelevated temperature (within 1hour of delivery)-Other intervention: IVoxytocin as standard hospitalmanagement when estimatedblood loss was > 1000 mL-Sample size was calculatedusing a two tailed α = 0.05 andβ = 0.10, finding 191 womenrequired per groupStatistic tests used: Parametricand nonparametric in analyzingdelivery hemoglobinresults (200 in themisoprostol groupand 192 in theoxytocin group)in women who receivedmisoprostol and this wasstatistically significant (22.2% inthe misoprostol group vs 5.7% inthe oxytocin group, RR 4.73 [95%CI 2.31−9.68], P = < 0.0001);temperature ≥ 37.5 °C was presentin the misoprostol group but wasnot statistically significant (7.4%vs 3.3% in the misoprostol andoxytocin groups, respectively, RR2.35 [95% CI 0.84−6.58], P = 0.11)• There were no differences betweenthe 2 groups with regard to otherside effects such asnausea,vomiting, and diarrheaConclusion :• Oral misoprostol appears to be aseffective as intramuscular oxytocinin minimizing blood loss in lowriskwomen in the 3 rd stage oflabor; it has great potential for usein the 3 rd stage of labor indeveloping countriesloss may be difficult to define clinically,especially if it is based on subjectiveobservations; blood loss based on clinicalassessment often is underestimated.Hemoglobin or hematocrit determination ismore objective measure. Authorsrecognized that the objective laboratorymeasurement is serving only as proxy forthe clinical outcome of excessive bloodloss• Mild side effects; there was a trend towardelevated temperature postpartum in themisoprostol group but this was notstatistically significant; shivering probablywas related to a prostaglandin E 1 effect oncentral thermoregulatory centers© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 20

the data on an intent-to-treatbasis; primary outcomemeasure was assessed byStudent’s t test and significantat P < 0.05; secondaryoutcomes was at P < 0.01 toaccount for multiple testing(Bonferroni correction)Goal:• To compare in a blindedfashion the effectiveness ofmisoprostol 400 mcgadministered orally withoxytocin 19 IU administeredintramuscularly, routinely inthe 3 rd stage of labor tominimize blood lossAbdel-Aleem H, El-Nashar I, Abdel-Aleem A.Management of severepostpartum hemorrhagewith misoprostol. Intl JGynecol Obstet 2001; 72:75-6.(K)Sponsor(s): NoneAffiliation(s) of theresearchers: Dept of OB-GYN, Assiut University,EgyptStudy protocol approvedby: Ethical committee ofDept of OB-GYN, AssiutUniversityEvidence rating: IIIDesign:Descriptive prospective studyMethods:• Inclusion:Women with severe postpartumhemorrhage not responding tooxytocin, methylergometrine,and enzaprost (a prostaglandinF 2α ); mean age was 28.2 years,mean parity was 3.8; fourteenhad hospital delivery, 4 hadcommunity delivery of whom 2had acute inversion of theuterus in addition to atonicpostpartum hemorrhage;thirteen delivered vaginally, 5by CS; 12 showed risk factorsfor postpartum hemorrhage• Assessment:-Outcome: Cessation ofbleedingDose/Duration:• Misoprostol 1000mcg rectally forcontinuous bleedinggiven a few minutesafter otheruterotonics wereadministered (n=14); 600 mcg (n =4)N = 18Results:• 16 patients (88.2%) respondedpromptly to misoprostol; bleedingstopped within 30 seconds to 3minutes (mean = 1.4 minutes)• 2 patients failed to respond and weresubjected to subtotal hysterectomyConclusion:• Rectal misoprostol is an effectiveline of treatment in cases of atonicpostpartum hemorrhage refractory toother uterotonic drugs, particularlywhere other prostaglandins are notavailable or affordableLimitations/Comments• Authors stated that on the basis of their data,it is difficult to exclude with certainty thepossibility that cessation of bleeding wasdue to the previously administered oxytocicor to the combination of oxytocic andmisoprostol, rather than to misoprostol alone• Authors agreed with other investigators’opinions (Ramsey et al.) on the importanceof characterizing the absorption andpharmacokinetics of transrectal misoprostoland the need for a properly designedrandomized trial• Small sample• Uncontrolled study and therefore, would bedifficult to conclude that the resolution ofpostpartum bleeding was due to misoprostol© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 21

-Other interventions:• Oxytocin IV (bolus 10 to20 IU and infusion 20 IUin 500 mL saline) andmethylergometrine up to0.4 mg IV as first aidmeasures in all patients• enzaprost was used incases unresponsive to theprevious uterotonics on sixpatients; however,enzaprost was notavailable for the rest of thepatients• Surgery (ligation of theuterine and/or internaliliac arteries orhysterectomy) as a lastresort for cases notresponding to rectalmisoprostol-All patients were managedaccording to hospital protocolwhich included resuscitation ofthe patient, exclusion oftraumatic bleeding, andmassage of the uterus/bimanualcompressionGoal:• To explore the use of rectalmisoprostol in the treatment ofsevere cases of atonicpostpartum hemorrhage notresponding to oxytocin andmethergineEl-Refaey H, Nooh R,O’Brien P, et al. TheDesign:Randomized, controlled, open trialDose/Duration:• Misoprostol 500Results:• Primary end point:Limitations/Comments:• Baseline characteristics were similar in both© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 22

misoprostol third stage oflabour study: arandomised controlledcomparison betweenorally administeredmisoprostol and standardmanagement. Br J ObstetGynaecol 2000; 107:1104-10.(L)Sponsor(s): NoneAffiliation(s) of theresearchers:Dept of OB-GYN,University CollegeHospital, London Schoolof Hygiene and TropicalMedicine, London, UKStudy protocol approvedby: Local research ethicscommitteeEvidence rating: IMethods:• Inclusion:-vaginal delivery• Exclusion:-cesarean section-history of severe asthma(requiring hospital admissionand steroids)-water birth• Assessments:-Primary end point:Postpartum blood loss (PPHdefined as estimated blood loss≥ 500 mL, and severe PPH asestimated blood loss > 1000 mL-Secondary end points:Incidence and severity of sideeffects (nausea, vomiting,abdominal pain, diarrhea, hotflushes, headache, tiredness,dizziness, shivering)-Other end points were:Need for blood transfusion, useof other oxytocic drugs, lengthof the 3 rd stage of labor, manualremoval of the placenta,hemoglobin concentration andhematocrit pre- and postdelivery, management of theumbilical cord, blood pressure,temperature, vomiting,analgesia for ‘after pains’-This study was based on asample size of 1000 womenallowing investigators to detecta difference in the incidence ofPPH (from 5 to 10%) with apower of 80% at a two-sidedsignificance level of 5%-Statistic tests used : chi-squaremcg orallyimmediately afterbirth of the babyand clamping anddivision of theumbilical cord (n =501)• Other oxytocics(either syntometrineIM, except inwomen withpregnancy-inducedhypertension orwith cardiac diseasewho were givensyntocinon 10 UnitsIM instead, orergometrine 500 mgIM for women athigh risk of atonicPPH) given after thedelivery of theanterior shoulder (n= 499)N = 1000Incidence of PPH was 12% in themisoprostol group, compared with11% with other oxytocicsIncidence of severe PPH (blood loss> 1000 mL) was 2% in both groups• Secondary end points:Nausea, headache, dizziness, andtiredness were reported more oftenin the other oxytocics group; therewere no differences in the incidenceof vomiting, abdominal pain,diarrhea, and hot flushes; shiveringoccurred more often in themisoprostol group (72%) vs otheroxytocics group (37%)• Other end points:-Manual removal of the placenta,need for blood transfusion, andlength of the 3 rd stage of labor weresimilar in both groups-Need for further oxytocics wasslightly higher in the misoprostolgroup (14 vs 10%) but this was notstatistically significant (P = 0.08)-Hemoglobin and hematocrit levelsand blood pressure were similar inboth groups-Increase in temperature wassignificantly greater in themisoprostol group (mean 0.59 vs0.25; P < 0.001)-Management of the umbilical cordand need for analgesia for ‘afterpains’ were similar in both groupsConclusion:• Oral misoprostol for the preventiongroups• Authors acknowledged the trial was notlarge enough to establish equivalencebetween misoprostol and standard oxytocicsin the prevention of PPH. They estimatedthat the incidence of PPH would be 5% withstandard oxytocics and that an increase to6% with misoprostol would beunacceptable. This would require more than16,000 participants in a randomized trial (α= 0.05; 1-β= 0.80). The incidence of severePPH (which may be life-threatening) withstandard oxytocics in this trial was 2% andauthors considered an increase in theincidence to 2.5% as unacceptable (α =0.05; 1-β= 0.80). Authors claimed this trialwas large enough to exclude doubling of allPPH and a tripling of severe PPH withmisoprostol. A larger trial or the results ofsmaller trials combined is required toestablish equivalence of misoprostol withstandard oxytocics• Good follow-up• Blood loss was estimated subjectively bythe midwife although objectivedeterminations (hemoglobin andhematocrit) were also done and values weresimilar in both groups• Nonblind, which might have influenced themidwives in their ascertainment of PPH, assuggested by the high rate of PPH in womenreceiving standard oxytocics (11%), which ismore than double the rate used to estimatenumber of women required for the trial• Response bias. There were morequestionnaires on side effects returned bywomen who received misoprostol; authorsargue it is unlikely that this bias couldaccount for the sizeable differences in theincidence of some of the side effects, such asheadache and shivering© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 23

test, Student’s t test, Mann-Whitney U testGoals:• To ascertain whether 500 mcgof oral misoprostol couldreplace the standard oxytocicdrugs without an increase in theincidence of postpartumhemorrhage• To assess the incidence andseverity of the side effects ofboth drug regimensof postpartum hemorrhage wascomparable to standard oxytocics.Many side effects were lesscommon with misoprostol butshivering and pyrexia were morecommon• Shivering and an increase in temperatureoccurred more in the misoprostol group andthere was a clear association between theseside effectsCook CM, Spurrett B,Murray H. A randomizedclinical trial comparingoral misoprostol withsynthetic oxytocin orsyntometrine in the thirdstage of labour. Aust NZ JObstet Gynaecol 1999; 39:4: 414-19.(M)Sponsor(s): NoneAffiliation(s) of theresearchers:Dept of OB-GYN,University of Sydney atNepean Hospital Penrith,New South WalesStudy protocol approvedby: Hospital’s EthicsCommittee (Nepean)Evidence rating: IDesign:Multicenter, blocked, randomized,controlled, open trialMethods:• Inclusion:-vaginal delivery, with orwithout the need for episiotomy• Exclusion:-cesarean section-history of severe asthma-known blood coagulationdisorders-heart disease-severe renal disease-epilepsy-hypertension significantenough to contraindicate theuse of ergometrine• Assessments:-Primary end points:Postpartum blood loss, need foruterine massage, need foradditional oxytocics (infusionof synthetic oxytocin or IM orIV ergometrine/oxytocin) in theDose/Duration:• Misoprostol 400mcg (2 tablets)orally immediatelyafter delivery of thefetal anteriorshoulder (n = 455)• Other oxytocics,either 1 ampul ofsyntometrine (0.5mg ergometrine + 5Units of oxytocin)or syntheticoxytocin (10 Units)IM after delivery ofthe anterior fetalshoulder (n = 475)N = 1024 recruited, ofwhom 94 wereexcluded prior torandomization, 930randomized, 65excluded afterrandomization andprior to treatmentResults:• Primary outcomes:-Postpartum blood loss:significantly greater overall in themisoprostol group than in thestandard oxytocic group (mean ± SDis 279 ± 14.6 in the misoprostolgroup vs 209 ± 9.0; P = < 0.001)-Need for uterine massage wasgreater in the misoprostol group(37% in the misoprostol group vs17%; RR 2.18 [95% CI 1.71−2.78])-Need for additional oxytocics wasgreater in the misoprostol group(22% in the misoprostol group vs8%; RR 2.89 [ 95% CI 2.00−4.18])-Need for blood transfusion wassimilar in both groups• Secondary outcomes:-Temperature was increased in themisoprostol group (15% in themisoprostol group vs 10%)-There was no difference in bloodpressure between the 2 groups-Hemoglobin level was lower in themisoprostol group (mean ± SD isLimitations/Comments:• Baseline variables were similar in bothgroups• Method to determine blood loss was welldescribed; blood loss was determined bothsubjectively and objectively• Good follow-up• One center had women with highantepartum levels of anemia and womenwith hemoglobin of < 90 grams per literwere routinely treated with iron up to andincluding during labor; this potentially hadan impact on the postpartum hemoglobin inthis center; however, authors stated that itseffect on outcome in the study wasminimized through the block randomization• Authors chose not to blind the study becausethe use of placebo treatment would haveincreased the cost of the trial and alsobecause recruitment would have been moredifficult as women would have had toreceive 2 modalities of treatment (IMinjection and oral tablets); also there was anethical concern regarding the use of a drugin a research context that had not beeninvestigated properly for a condition with a© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 24

3 rd stage of labor, need forblood transfusion-Secondary end points:Temperature, blood pressure,hemoglobin pre/post delivery,side effects such as vomiting,diarrhea, and shivering-Blood loss was determined bycombining the ‘estimated’ and‘measured’ amounts followingthe standard clinical practice ateach center (use of calibratedmeasuring jug, weighing ofblood-stained undersheets andpads and subtracting their dryweight)-Power calculations based on aPPH rate (≥ 500 mL) of 8% inthe current treatment rangingup to 12% with the testtreatment indicated 1862women were required for apower of 80% with aconfidence level of 95%-Statistic tests used : chi-squaretest, Student’s t testdue to need forcesarean section anddevelopment ofhypertension, 865received treatmentof whom 2 wereexcluded in theanalysis as no recordwas made of theprimary outcome ofblood loss, resultingin 863 whocompleted the study108 ± 16 in the misoprostol group vs111 ± 17; P = < 0.01) and thechange from pre- to post-deliverywas also greater in the misoprostolgroup (mean ± SD is −69 ± 17.5 inthe misoprostol group vs –4.0 ±16.7; P = < 0.015)-There was no difference in sideeffects such as vomiting anddiarrhea; however, shiveringoccurred more in the misoprostolgroup (19 vs 7%)Conclusion:• Misoprostol was not as effective asthe conventional treatments and itsoral use for PPH could not berecommended in doses of 400 mcgadministered orally after delivery ofthe fetuspotential for life-threatening blood loss; theneed for an earlier interim analysis indicatedby concerns of an apparently higher PPHrate in the misoprostol group vindicated thisdecision• Conclusion was drawn by the authors basedon the fact that the PPH rate in womenreceiving misoprostol was 15%, which ismore than double the 6% rate for womenreceiving standard injectable oxytocics; the6% rate was lower than the 8% in theirpower calculations, which did not take intoaccount the low PPH in one center• All cases of shivering were reported to bemild to moderate and required minimaltreatment• Study was immediately stopped followingthe adverse findings of the interim analysisGoals:• To compare efficacy of oralmisoprostol with traditionaluterotonic agents usedprophylactically in the 3 rd stageof laborNg PS, Chan ASM, SinWK, et al. A multicenterrandomized controlledtrial of oral misoprostoland i.m. syntometrine inthe management of thethird stage of labor. HumReprod 2001; 16(1): 31-5.Design:Prospective, multicenter,randomized, controlled, singleblindtrialMethods:• Inclusion:Dose/Duration:• Misoprostol 600mcg (three 200 mcgtablets) orallyimmediately afterdelivery of the baby(n = 1026)Results:• Primary outcome:-Amount of blood loss duringdelivery and occurrence of PPH: nosignificant difference ( ≥ 500 mL is5.8% in misoprostol group and 4.3%in syntometrine group, RR 1.37Limitations/Comments:• Baseline variables were similar in bothgroups• Excellent follow-up• Not double-blind and therefore potentialbias in assessment of blood loss and the useof additional oxytocics could not be© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 25

(N)Sponsor(s): NoneAffiliation(s) of theresearchers:Dept of OB-GYN, TheChinese University ofHong Kong Prince ofWales Hospital, Shatin,New Territories, HongKongStudy protocol approvedby: Clinical ResearchEthics Committee of theFaculty of Medicine of theChinese University ofHong KongEvidence rating: I-singleton pregnancy-vaginal delivery• Exclusion:-pre-eclampsia-cardiac disease-asthma-presence of conditionsrequiring prophylactic oxytocininfusion after delivery such asgrand multiparity (parity ≥ 4)or presence of uterine fibroids;however, those who hadoxytocin infusion during thefirst stage were included-presence of any othercontraindications for the use ofmisoprostol or syntometrine• Assessments:-Primary end point:Amount of blood loss duringdelivery and occurrence ofPPH, defined as blood loss of500 mL or more-Secondary end points:Blood pressure, pulse,temperature, duration of 3 rdstage, incidence of prolonged3 rd stage (longer than 30minutes), need for manualremoval of the placenta, use ofadditional IM syntometrine,side effects including nausea,vomiting, headache, chest pain,fever, shivering-Blood loss was assessed byclinical estimation andhemoglobin determination preandpost-delivery-3 rd stage was managed byawaiting signs of placentalseparation and placenta• Syntometrine (0.5mg ergometrine + 5Units of oxytocin) 1mL IM at deliveryof anterior shoulderof the baby (n =1032)N = 2058 recruited andrandomized[95% CI 0.94 − 2.00]; ≥ 1000 mL is0.5% in misoprostol group and 0.4%in syntometrine group, RR 1.26[95% CI 0.34 – 4.67])-There was no difference in themean fall in hemoglobinconcentration after delivery(decreased by 10 to 20% in bothgroups)• Secondary outcomes:-Blood pressure: Significantly lowerin the misoprostol group than insyntometrine group 30 min and 60min post delivery (29.2% in themisoprostol group vs 47.5%, RR0.62 [ 95% CI 0.39 – 0.96] P < 0.05and 2.1% in the misoprostol groupvs 3.9%, RR 0.55 [95%CI 0.33 –0.92] P < 0.05)-Temperature ( ≥ 38 °C):Significantly higher in themisoprostol group than insyntometrine group (8.5% in themisoprostol group vs 1.3%, RR 6.73[95% CI 3.78 – 11.98] P < 0.05)-There was no significant differencein the incidence of delayedhemorrhage within the first 24hours. Incidence of prolonged 3 rdstage (longer than 30 minutes) andincidence of blood transfusion weresimilar-Need for manual removal of theplacenta was significantly lower inthe misoprostol group (0.4% in themisoprostol group vs 1.4%, RR 0.29[95% CI 0.09 – 0.87] P < 0.05)-Need for additional oxytocic wassignificantly higher in themisoprostol group (22.6% in themisoprostol group vs 14%, RR 1.62eliminated; however, this was minimized inall cases by having the randomization,preparation, and administration of themedication carried out by independentnursing staff not involved in themanagement of the patient except for thedrug administration; authors stated that theconsistent results among the 3 participatinghospitals and a similar overall resultcompared with that reported in the literaturesuggested that the results were unlikely tobe due to bias• Amount of blood loss was assessedsubjectively (clinical estimate) andobjectively (hemoglobin concentration).Authors stated that clinical estimation ofblood loss has been shown to underestimatethe true blood loss. They acknowledged thatthis is how PPH is diagnosed and managedin actual day-to-day clinical practice.Clinical estimation is also one of the mainmethods used in some of the largerandomized controlled trials regardingmanagement of the 3 rd stage of labor. Use ofother clinical parameters such as BP andpulse pressure is not reliable. Hemoglobindetermination pre- and post delivery is amore objective method and also clinicallyimportant and relevant in that it helps in thedecision for the need for blood transfusionor iron supplementation. (It has already beensuggested that PPH be defined as aperipartum fall in hematocrit of at least 10%or hemorrhage requiring blood transfusion[ACOG 1989].) In this study, mean bloodloss for both groups was only 250 to 300mL and the incidence of PPH was low, yet15% of patients still had a 10 to 20% drop inhemoglobin concentration and 18% droppedby > 20% in both groups. Authors suggestfuture studies on the efficacy of oxytocicson PPH be based on peripartum hemoglobin© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 26

delivered by controlled cordtraction. Irrespective of theallocation, an additional dose ofsyntometrine was given if theuterus was not well contractedor if there was excessivevaginal bleeding as assessed bythe midwife or doctor attendingthe delivery-Sample size was based on1000 subjects per study groupin order to detect a 2%difference in the incidence ofPPH with an 80% power at α =0.05 (incidence of PPH is 4%which is similar among the 3hospitals; incidence of PPHassociated with oralmisoprostol was reported to be6%)-Statistic tests used : chi-squaretest, Student’s t testGoals:• To compare the efficacy andsafety of oral misoprostol withIM syntometrine in themanagement of the 3 rd stage oflabor[95% CI 1.34 – 1.96] P < 0.05)- The incidence of side effects(nausea, vomiting, headache, chestpain) was low and similar in bothgroups; shivering was significantlyhigher in the misoprostol group(30.2% in the misoprostol group vs9.9%, RR 3.06 [95% CI 2.49 –3.76] P < 0.05)Conclusion:• Misoprostol may be used as analternative to IM syntometrine in themanagement of the third stage oflabor, especially in situations inwhich syntometrine iscontraindicated or where storageand parenteral administration ofoxytocics is a potential problemchange rather than on clinical estimate ofblood lossKEY:> = greater than< = less than≥ = greater than or equal toPPH = postpartum hemorrhageBP = blood pressureDIC = disseminated intravascular coagulationIM = intramuscularIU = international unitsIV =intravenousL = litermcg = microgrammL = milliliterdL = deciliterCS = cesarean sectionmin = minutesIntl = international© 2001 The United States Pharmacopeial Convention, Inc. All rights reserved 27