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Induction of Labour with Misoprostol—A Review
""'"
'SYMPOS
LJ
M' , , , , , , ,
INDUCTION OF LABOUR WITH MISOPROSTOL-A REVIEW David Young, MD, FRCSC, MSc, Kelly Bennett , MD, Kimberley Butt, MD, William Mundle, MD, Rory Windrim, MD,BS, FRCSC, Department of Obstetrics and Gynaecology, Memorial University of Newfoundland, Department of Obstetrics and Gynaecology, Grace General Hospital, St. John's, Newfoundland
ABSTRACT
Misoprostol is a prostaglandin EI anawgue marke ted far aral prophylaxis of non-steriodal anti-inflammawry drug induced gastric ulcers, and treatment of gastric and duodenal ulcers. Its cost per dose is one hundredth that of cammercial prostaglandin gels used far Iabour induction. I t is listed as being contra-indicated far use in pregnancy . Recent investigations have found that vaginal misoprostol is cast effective far second trimester medical termination of pregnancy. In the first trimester, it is effective only after use of another abortifacient, includingmifepristone ar methotrexate. Vaginal misoprostol, in a much wwer dose, is now being applied as a labour induction agent at term. It is inexpensive and effective, and appears safe far mother and newborn in the reported randomized controlled trials. A concern regarding uterine hyperstimulation exists. Our group has experience with vaginal misoprostol use in the second trimester, and far labour induction. We have now woked at aral administration far Iabour induction. We review our experience and that in the literature . RESUME
Le misoprostol est un anawgue de la prostaglandine EI commercialise ades fins de prophylaxie par voie arale des ulccres gastriques provoques par les anti-inflammatoires non sreroidiens et du traitement des ulceres gastriques et duodenaux. Le cout d' une dose equivaut aun centieme de celui des gels de prostaglandine cammerciaux qui servent adeclencher le travail. Des recherches recentes ont confirme le rapport cout-efficacite avantageux du misoprostol par voie vaginale ades fins d'interruption therapeutique de la grossesse au deuxieme trimestre . Au premier trimestre , il n' est efficace qu' apres I' utilisation d' un autre abortif, notamment la mifepristone ou le methotrexate. Le misoprostol par voie vaginale, adose beaucoup moins elevee, est maintenant applique camme agent de declenchement du travail a terme. Il est bon marche, efficace et semble sur pour la mere et le nouveau-ne, d' apres les essais randomises et contrilles . Cependant, on se preoccupe de l'hyperstimulation uterine.
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NOVEMBER 1996
, , , Notre groupe connai"t l'utilisation du misoprostol par voie vaginale au deuxieme trimestre et ades fins de declenchement du travail. Nous nous inreressons maintenant aI' administration par voie orale afin de declencher le travail. Nous decrivons nos travaux et ceux dont on traite dans la litrerature.
J SOGe
1996;18:1153-57
KEY WORDS
Misoprostol, labor, induction, cost effective. Received on April 17th, 1996. Revised and accepted on June 6th, 1996.
(RCT) has compared misoprostol to dinoprostone. 9 Our group first studied misoprostol in second trimester termination of pregnancy complicated by lethal fetal anomalies. 10 This lead to abstracts presented at FIGO 1994, Montreal, Quebec and the SOGC Annual Clinical Meeting 1995, Calgary, Alberta. This work demonstrated that misoprostol was a cost effective alternative to intra-amniotic hypertonic saline for second trimester pregnancy termination.
WHAT IS MISOPROSTOL? WHY CONSIDER IT?
Misoprostol (Cytotec; Searle, Oakville, Ontario) is a synthetic prostaglandin EI analogue marketed in North America, in an oral tablet form. Two doses, 100pg and 200pg, are available on physician prescription for the prevention and treatment of non-steroidal anti-inflammatory drug induced gastric ulcers, and for the treatment of duodenal ulcers. 1The frequency of gastro-intestinal side effects has been low, with up to 1,600 pg per day in divided doses. Use in pregnancy is contra-indicated in the product monograph because of its uterotonic effects, and risk of miscarriage. There has been no evidence of embryotoxicity, fetotoxicity, teratogenic or carcinogenic effects in animal studies. 2 Misoprostol costs approximately one hundredth the price per dose of commerical prostaglandins currently used in labour induction.
INDUCTION OF LABOUR
Encouraged by other reports,11.11 we compared vaginal misoprostol to a standard protocol for induction oflabour at term. In this RCT of 222 patients, our group found a three-hour decrease in time to vaginal delivery in the misoprostol groUp.14 There was less need for oxytocin augmentation with no difference in Caesarean rates, maternal interventions, or substa~tive neonatal adverse outcomes. A much lower dose of 50pg (a 100 pg tablet cut in half) was placed in the vagina as needed to establish labour, but not more frequently than every four hours. Our group is preparing a meta-analysis of the published RCTs (5 papers,"·I3,15.17 3 abstracts,14.18,19 and one letter20 ) of vaginal misoprostol versus concurrent local control groups (most including vaginal and/or cervical commercial prostaglandins). Over 600 subjects receiving vaginal misoprostol have now been observed prospectively in such research. 2J Misoprostol has been effective. There is more frequent vaginal birth within 12 hours (relative risk (RR) 1.60,95% confidence interval (CI) 1.28 to 2.06) and within 24 hours (RR 1.36, CI 1.23 to 1.53). Oxytocin use was less (RR 0.53, CI 0.47 to 0.61). No significant change in low five minute Apgar scores, or rate of neonatal acidosis was found. 21 Misoprostol's usual means of administration for gastrointestinal disorders is oral. Will oral misoprostol be effective, safe, and tolerated by patients, when ingested for
INITIATION OF UTERINE ACTIVITY IN THE 1ST AND 2ND TRIMESTERS
In Europe, misoprostol has been used as a prostagiandin following antiprogesterone (mifepristone, RU 486) administration. This combination is effective for first trimester medical pregnancy termination. 3 Misoprostol has not been effective as a single agent when used in the first trimester, though it has increased intra-uterine pressure. 4 In North America, where mifepristone is not yet available, re cent investigation has demonstrated the value of vaginal misoprostol following parenteral methotrexate, with initiation of uterine activity leading to expulsion of the products of conception. 5 Vaginal misoprostol, in a variety of regimes in divided doses of 400 pg to 2,200 pg per day, has been effective as a single agent for pregnancy termination in the second trimester. 6. 10 A randomized controlled trial
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, , , initation of uterine contractions? Oral administration of other prostaglandins in obstetric practice has been essentially abandoned because of alimentary side effectsemesis and diarrhoea. 22 We obtained ethical approval for a clinical trial of oral misoprostol versus our standard approach to labour induction (physieian chosen combinations of intracervical, or vaginal dinoprostone, dilute intravenous oxytoein infusion, and artifieial membrane rupture). 2J This Rcr of 275 women has been completed. The full report will be submitted for publication. In summary, the time from induction to vaginal birth with oral misoprostol was not significantly different from that with our established protocols. There were no clinically or statistically significant differences in maternal secondary outcome measures (Caesarean rate, frequency of epidural use, perineal trauma, or manual removal of the placenta). Neonatal outcomes, including cord blood acid base analysis, were not different. There was no difference in frequency of maternal gastro-intestinal side effects in the two groups. Oral misoprostol may be a safe, cost effective alternative to standard induction agents with a high degree of patient acceptability. The re cent results of the Term PROM Trial24 have supported the traditional policy of dilute oxytocin infusion labour induction following spontaneous rupture of membranes at term. Induction with commercial vaginal prostaglandins, or conservative observation did not improve outcomes. The comparison of oxytocin infusion for labour induction following term membrane rupture with oral misoprostol warrants studies of effectiveness, safety, and patient satisfaction.
While this terminology is an obvious improvement, it is, nevertheless, arbitrary, particularly with respect to tachysystole or hypertonieity. Although the relationship between continuous electronic fetal heart rate monitoring and fetal weil being is not one to one, non-reassuring changes associated with excessive uterine activity warrant intervention either to reduce uterine activity, to provide more direct assessment of fetal weil being (fetal blood sampling, other biophysical assessment), or to remove the fetus from this environment (delivery), Our meta-analysis 21 of data from existing RCTs has found tachysystole is significantly more frequent with misoprostol protocols (RR 2.21, CI 1.53 to 3.18), with uterine hyperstimulation nearly so (RR 1.84, CI 0.98 to 3.47). This meta-analysis included every vaginal misoprostol protocol. The maximum ineidence of tachysystole in any single report was 37 percent,'6 and uterine hyperstimulation 11 percent. To place this in perspective, contemporary studies with oxytoein inductions report tachysystole and uterine hyperstimulation of similar or greater frequency.26,27 When oxytocin induction results in uterine hyperstimulation with non-reassuring fetal heart rate changes, discontinuing the infusion can reduce oxytocin blood levels quickly. The use of vaginal dinoprostone gels or misoprostol is more problematic. Authors describe vaginal lavage and removing tablet remnants,28 however, intravenous ß-adrenergic agonist regimens have been used with apparent beneficial tocolytic response. 29 Intravenous tocolysis is the approach necessary with oral misoprostol. Forced emesis would likely be ineffective, and distasteful. Despite these concerns of possible uterine hyperstimulation, substantive worrisome newborn outcomes (neonatal aeidosis, meconium aspiration, and ACOG Birth Asphyxia criteria30 ) have been rare, acceptable, and not different between misoprostol and control groups. Ir is imperative that such outcome data be collected in future studies to quantitate more precisely the potential risks of misoprostol (and current approaches).
FETAL SAFETY ISSUES
An issue raised in several reports ' 1,l5,16 using vaginal misoprostol for labour induction has been more frequent uterine hyperstimulation. Is this important? Excessive uterine activity may interfere with uteroplacental perfusion sufficiently to compromise the fetus. Because of confusion stemming from varied definitions of excessive uterine activity, Curtis 25 recommended a standard terminology: hypertonic-a contraction lasting more than 90 seconds; tachysystole-contraction frequency greater than five per ten minutes; hyperstimulation-hypertonic contraction or tachysystole with late fetal heart rate decelerations or fetal tachycardia.
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POTENTIAL MISUSE
Harm to fetus or mother may occur subsequent to misuse of this uterotonic pharmaceutical agent. This has been noted particularly in developing countries where such medication does not require, and is available without physician prescription or supervision. 11 Premeditated patient initiated overdose has been reported in the United States, leading to fetal demise. l2 The compound's
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, , , 11. Sanchez Ramos L, Kaunitz AM, Dei Valle GO, Delke I, Schroeder PA, Briones DK. Labor induction with the prostagiandin E1 methyl analog misoprostol versus oxytocin: a randomized trial. Obstet Gynecol 1993:81 :332-6. 12. Fletcher HM, Mitchell S, Simeon D, Frederick J, Brown D. Intravaginal misoprostol as a cervical ripening agent. Br J Obstet Gynaecol 1993;100:641-4. 13. Fletcher HM, Mitchell S, Frederick J, Simeon D, Brown D. Intravaginal misoprostol versus dinoprostone as cervical ripening and labor-inducing agents. Obstet Gynecol 1994;83:244-7. 14. Mundle W, Young DC. RCT of misoprostol (Cytotec) vs standard therapy for induction of labour. AGM, Society of Obstetricians and Gynaecologists of Canada, Calgary, Alberta, June 1995. 15. Wing DA, Jones MM, Rahall A, Goodwin TM, Paul RH. A comparison of misoprostol and prostagiandin E2 gel for preinduction cervical ripening and labor induction. Am J ObstetGynecoI1995;172:1804-10. 16. Wing DA. Rahall A, Jones MM, Goodwin TM, Paul RH. Misoprostol: an effective agent for cervical ripening and labor induction. Am J Obstet GynecoI1995;172:1811-6. 17. Varaklis K, Gumina R, Stubblefield PG. Randomized controlled trial of vaginal misoprostol and intracervical prostagiandin E2 gel for induction of labor at term. Obstet Gynecol 1995;86:541-4. 18. Chuck F, Huffaker J. Labor induction with intravaginal prostagiandin E1 (PGE1) (misoprostol, Cytotec) versus intracervical prostagiandin E2 (PGE2) (dinoprostone, Prepidil Gel): a randomized comparison. Am J Obstet Gynecol 1995;172:424. 19. Tabor B, Anderson J, Stettler B, Wetwiska N, Howard T. Misoprostol versus prostagiandin E2 gel for cervical ripening. Am J Obstet Gynecol 1995;172:425. 20. Margulies M, Campos Perez G, Voto LS. Misoprostol to induce labour. Lancet 1992;339:64. 21. Young DC, Mundle W, Butt K, Bennett K, Windrim R. Vaginal misoprostol (Cytotec) for term labour induction: a meta-analysis. AGM, Society of Obstetricians and Gynaecologists of Canada, Ouebec City, Ouebec 1996. 22. Keirse MJNC, van Oppen ACe. Preparing the cervix for induction of labour. In: Chalmers I, Enkin M, Keirse MJNC (Eds). Effective care in pregnancy and childbirth. Oxford University Press. 1989:1057-79. 23. Windrim R, Bennett K, Mundle W, Young De. Oral misoprostol for labour induction-RCT. AGM, Society of Obstetricians and Gynaecologists of Canada, Ouebec City, Ouebec, June 1996. 24. Hannah ME, Ohlsson A, Farine D, Hewson SA. Hodnett ED, Myhr TL, Wang EEL, Weston JA. Willan AR, for the Term PROM Study Group. Induction of labor compared with expectant management for prelabor rupture of the membranes at term. N Engl J Med 1996;334: 1005-1 O.
low cost, stable form, and wide availability for gastrointestinal management make misuse in pregnancy a possibility, which must be minimized, and ideally prevented. This concern for possible abuse, issues of use for medical termination, and medico-legalliabilities in intrapartum obstetrics have made the Canadian manufacturer reluctant to participate in any research into the use of this drug for induction oflabour. CONCLUSION
Misoprostol is an effective initiator of uterine contractions. Careful supervision of administration by a physician or another knowledgeable health professonal is required, and essential when fetal safety is an issue. Vaginal misoprostol for second trimester pregnancy termination or with fetal demise is appropriate to consider now. The available evidence for vaginal misoprostol in labour induction at term, although substantial, probably warrants further investigation before becoming standard practice. Oral misoprostol use for induction of uterine contractions is preliminary, though promising. REFERENCES 1.
Garris RE, Kirkwood CF. Misoprostol: a prostagiandin E1 analogue. Clin Pharm 1989; 8:627-44. 2. Product monograph for Cytotec. Searle Canada Inc. June 23,1992. 3. Thong KJ, Baird DT. Induction of abortion with mifepristone and misoprostol in early pregnancy. Br J Obstet GynaecoI1992;99:1004-7. 4. Norman JE, Thong KJ, Baird DT. Uterine contractility and induction of aborti on in early pregnancy by misoprostol and mifepristone. Lancet 1991 Nov; 338:1233-6. 5. Hausknecht RV. Methotrexate and misoprostol to terminate early pregnancy. N Engl J Med 1995;333:537-40. 6. Bugalho A, Bique C, Almeida L, Faundes A. The effectiveness of intravaginal misoprostol (Cytotec) in inducing abortion after eleven weeks of pregnancy. Stud Fam Plann 1993;24:319-23. 7. Bugalho A. Bique C, Almedia L, Bergstrom S. Pregnancy interruption by vaginal misoprostol. Gynecol Obstet Invest 1993;36: 226-9. 8. EI-Refaey H, Calder L, Wheatly DN, Templeton A. Cervical priming with prostagiandin E1 analogues, misoprostol and gemeprost. Lancet 1994;343:1207-9. 9. Jain JK, Mishell DR. A comparison of intravaginal misoprostol with prostagiandin E2 for termination of second-trimester pregnancy. N Engl J Med 1994;331 :290-3. 10. Mundle WR, Young De. Misoprostol versus standard therapy for medical termination of pregnancy. Int J Gynaecol Obstet 1994; SuppI2-46:20.
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, , , 25. Curtis P, Evans 5, Resnick J. Uterine hyperstimulation: the need for standard terminology. J Reprod Med 1987;32:91-5. 26. Lazor LZ, Philipson EH, Ingardia CJ. Kobetitsch ES, Curry SL. A randomized comparison of 15 and 40 minute dosing protocols for labor augmentation and induction. Obstet Gynecol 1993; 82; 1009-12. 27. Satin AJ, Leveno KJ, Sherman ML, Mclntire o. High does oxytocin: 20 versus 40 minute dosage interval. Obstet Gynecol 1994;83:234-8. 28. Egarter CH, Husselein PW, Rayburn WF. Uterine hyperstimulation after low dose prostagiandin E2 therapy: tocolytic treatment in 181 cases. Am J Obstet Gynecol 1990;163:794-6.
29. Sheybany S, Murphy JF, Evans 0, Newcombe RG, Pearson JF. Ritodrine in the management of fetal distress. Br J Obstet Gynaecol 1982;89:723-6. 30. ACOG Committee Opinion. Fetal distress and birth asphyxia. 137 April 1994. The American College of Obstetricians and Gynecologists, Washington, Oe. 31. Schonhofer PS. Brazil: misuse of misoprostol as an abortifacient may induce malformations. Lancet 1991;337:1534-5. 32. Bond GR, Van Zee A. Overdosage of misoprostol in pregnancy. Am J Obstet Gynecol 1994;171 :561-2.
PHYSICIAN HONORED FOR DISTINGUISHED SERVICE With more and more doctors getting ou[ of the baby bu ine Dr. T erry Riley is an anomaly-he not only continue co deliver babie at all hours of the day and night, he loves it. Thrives on it, in fact. For almost 30 years, the family physician has been a familiar face in the OTMH delivery room. And, while his commitment co obstetries may play havoc with his office taff-"l drop everything for babies"-it is gratifying co his patients. Recently the family doccor was honoured for his work with the reception of the Dr. E.P. "Soapy" Soanes Award, honouring a distingui hed Oakville family phy ician. The selection committee chaired by Dr. Gail MacPherson cho e Dr. Riley, in his 29th year of service to the hospital, last month. He was described as "supportive of colleague , a generous, compassionate, involved family physician who always goes the extra mile ... " Dr. Riley is a former chief of paediatries, a prime force behind the creation of the family medicine/obstetries group, and the current chair of the family medicine/obstetries group. He has been one of the key people behind many of the progre ive ob tetrieal practices launched by Oakville Trafalgar Memorial Ho pital (OTMH).
Contacted at his Oakville office, the physician said he was pleasantly urpri ed to leam he was the first recipient of the award. "l'm very flattered CO be cho en. It was very much a surprise to me," said Dr. Riley. He is the only family phy ician member of the Society of Ob tetries and Gynaecologi ts of Canada, a national body whieh ets tandard for the practice of obstetries and gynaecology. He i also a regular pre-natallecturer at Sheridan College. "Ob tetries and paediatries have alway been dose to my heart and I am very encouraged by the recent changes in our own obstetrieal program here in Oakville," he said. As CO the rise in the number ofhis colleagues choo ing not to practiee what has always been considered an integral part of being a doccor, he called it a "critical" problem. But he didn't believe it would be a problem in Oakville. "However, the newer graduates coming out of medieal school may think there is no place for them in this province and we could be looking at a serious fallout down the road," he commented. The Oakville physician remembers the days when fathers were not allowed inco delivery room . When he arrived in Oakville almost 30 years ago, the nation of fathers attending the birth of
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their child wa "greeted with great amusement." lt was another three years until it was routine co have fathers in delivery rooms and another few years that when they were there for Caesarian birth . He wa also a driving force behind key obstetrical pracrices induding labour room birth ,demand feeding, rooming in of infants and as he ays, "the list if long and boring CO anyone nat intere ted in obstetries." Over the past two years the h pital has had a shortage of physicians prepared to provide ob tetrieal ervice and Dr. Riley helped co bridge the gap until two new obstetricians came on the scene thi ummer. At the Board of Govemors meeting, Dr. John Kirby announced the award, adding he was personally very happy with the election, calling Dr. Riley an "obviously worthy choice." Dr. Riley attributes his own dedication for his work co his own belief in family-centred care. "l've always been interested in paediatric and ob tetric and because of the interest, I suppo e, I have worked very hard to provide family-centred eare." The award is in recognition co the hospital's first chief of staff and longtanding member of the department of family medicine at OTMH, Dr. E.P. "Soapy" Soanes.
'SYMPOS
LJ
M' , , , , , , ,
INDUCTION OF LABOUR WITH MISOPROSTOL-A REVIEW David Young, MD, FRCSC, MSc, Kelly Bennett , MD, Kimberley Butt, MD, William Mundle, MD, Rory Windrim, MD,BS, FRCSC, Department of Obstetrics and Gynaecology, Memorial University of Newfoundland, Department of Obstetrics and Gynaecology, Grace General Hospital, St. John's, Newfoundland
ABSTRACT
Misoprostol is a prostaglandin EI anawgue marke ted far aral prophylaxis of non-steriodal anti-inflammawry drug induced gastric ulcers, and treatment of gastric and duodenal ulcers. Its cost per dose is one hundredth that of cammercial prostaglandin gels used far Iabour induction. I t is listed as being contra-indicated far use in pregnancy . Recent investigations have found that vaginal misoprostol is cast effective far second trimester medical termination of pregnancy. In the first trimester, it is effective only after use of another abortifacient, includingmifepristone ar methotrexate. Vaginal misoprostol, in a much wwer dose, is now being applied as a labour induction agent at term. It is inexpensive and effective, and appears safe far mother and newborn in the reported randomized controlled trials. A concern regarding uterine hyperstimulation exists. Our group has experience with vaginal misoprostol use in the second trimester, and far labour induction. We have now woked at aral administration far Iabour induction. We review our experience and that in the literature . RESUME
Le misoprostol est un anawgue de la prostaglandine EI commercialise ades fins de prophylaxie par voie arale des ulccres gastriques provoques par les anti-inflammatoires non sreroidiens et du traitement des ulceres gastriques et duodenaux. Le cout d' une dose equivaut aun centieme de celui des gels de prostaglandine cammerciaux qui servent adeclencher le travail. Des recherches recentes ont confirme le rapport cout-efficacite avantageux du misoprostol par voie vaginale ades fins d'interruption therapeutique de la grossesse au deuxieme trimestre . Au premier trimestre , il n' est efficace qu' apres I' utilisation d' un autre abortif, notamment la mifepristone ou le methotrexate. Le misoprostol par voie vaginale, adose beaucoup moins elevee, est maintenant applique camme agent de declenchement du travail a terme. Il est bon marche, efficace et semble sur pour la mere et le nouveau-ne, d' apres les essais randomises et contrilles . Cependant, on se preoccupe de l'hyperstimulation uterine.
JOURNAL SOGe
1153
NOVEMBER 1996
, , , Notre groupe connai"t l'utilisation du misoprostol par voie vaginale au deuxieme trimestre et ades fins de declenchement du travail. Nous nous inreressons maintenant aI' administration par voie orale afin de declencher le travail. Nous decrivons nos travaux et ceux dont on traite dans la litrerature.
J SOGe
1996;18:1153-57
KEY WORDS
Misoprostol, labor, induction, cost effective. Received on April 17th, 1996. Revised and accepted on June 6th, 1996.
(RCT) has compared misoprostol to dinoprostone. 9 Our group first studied misoprostol in second trimester termination of pregnancy complicated by lethal fetal anomalies. 10 This lead to abstracts presented at FIGO 1994, Montreal, Quebec and the SOGC Annual Clinical Meeting 1995, Calgary, Alberta. This work demonstrated that misoprostol was a cost effective alternative to intra-amniotic hypertonic saline for second trimester pregnancy termination.
WHAT IS MISOPROSTOL? WHY CONSIDER IT?
Misoprostol (Cytotec; Searle, Oakville, Ontario) is a synthetic prostaglandin EI analogue marketed in North America, in an oral tablet form. Two doses, 100pg and 200pg, are available on physician prescription for the prevention and treatment of non-steroidal anti-inflammatory drug induced gastric ulcers, and for the treatment of duodenal ulcers. 1The frequency of gastro-intestinal side effects has been low, with up to 1,600 pg per day in divided doses. Use in pregnancy is contra-indicated in the product monograph because of its uterotonic effects, and risk of miscarriage. There has been no evidence of embryotoxicity, fetotoxicity, teratogenic or carcinogenic effects in animal studies. 2 Misoprostol costs approximately one hundredth the price per dose of commerical prostaglandins currently used in labour induction.
INDUCTION OF LABOUR
Encouraged by other reports,11.11 we compared vaginal misoprostol to a standard protocol for induction oflabour at term. In this RCT of 222 patients, our group found a three-hour decrease in time to vaginal delivery in the misoprostol groUp.14 There was less need for oxytocin augmentation with no difference in Caesarean rates, maternal interventions, or substa~tive neonatal adverse outcomes. A much lower dose of 50pg (a 100 pg tablet cut in half) was placed in the vagina as needed to establish labour, but not more frequently than every four hours. Our group is preparing a meta-analysis of the published RCTs (5 papers,"·I3,15.17 3 abstracts,14.18,19 and one letter20 ) of vaginal misoprostol versus concurrent local control groups (most including vaginal and/or cervical commercial prostaglandins). Over 600 subjects receiving vaginal misoprostol have now been observed prospectively in such research. 2J Misoprostol has been effective. There is more frequent vaginal birth within 12 hours (relative risk (RR) 1.60,95% confidence interval (CI) 1.28 to 2.06) and within 24 hours (RR 1.36, CI 1.23 to 1.53). Oxytocin use was less (RR 0.53, CI 0.47 to 0.61). No significant change in low five minute Apgar scores, or rate of neonatal acidosis was found. 21 Misoprostol's usual means of administration for gastrointestinal disorders is oral. Will oral misoprostol be effective, safe, and tolerated by patients, when ingested for
INITIATION OF UTERINE ACTIVITY IN THE 1ST AND 2ND TRIMESTERS
In Europe, misoprostol has been used as a prostagiandin following antiprogesterone (mifepristone, RU 486) administration. This combination is effective for first trimester medical pregnancy termination. 3 Misoprostol has not been effective as a single agent when used in the first trimester, though it has increased intra-uterine pressure. 4 In North America, where mifepristone is not yet available, re cent investigation has demonstrated the value of vaginal misoprostol following parenteral methotrexate, with initiation of uterine activity leading to expulsion of the products of conception. 5 Vaginal misoprostol, in a variety of regimes in divided doses of 400 pg to 2,200 pg per day, has been effective as a single agent for pregnancy termination in the second trimester. 6. 10 A randomized controlled trial
JOURNAL SOGC
1154
NOVEMBER 1996
, , , initation of uterine contractions? Oral administration of other prostaglandins in obstetric practice has been essentially abandoned because of alimentary side effectsemesis and diarrhoea. 22 We obtained ethical approval for a clinical trial of oral misoprostol versus our standard approach to labour induction (physieian chosen combinations of intracervical, or vaginal dinoprostone, dilute intravenous oxytoein infusion, and artifieial membrane rupture). 2J This Rcr of 275 women has been completed. The full report will be submitted for publication. In summary, the time from induction to vaginal birth with oral misoprostol was not significantly different from that with our established protocols. There were no clinically or statistically significant differences in maternal secondary outcome measures (Caesarean rate, frequency of epidural use, perineal trauma, or manual removal of the placenta). Neonatal outcomes, including cord blood acid base analysis, were not different. There was no difference in frequency of maternal gastro-intestinal side effects in the two groups. Oral misoprostol may be a safe, cost effective alternative to standard induction agents with a high degree of patient acceptability. The re cent results of the Term PROM Trial24 have supported the traditional policy of dilute oxytocin infusion labour induction following spontaneous rupture of membranes at term. Induction with commercial vaginal prostaglandins, or conservative observation did not improve outcomes. The comparison of oxytocin infusion for labour induction following term membrane rupture with oral misoprostol warrants studies of effectiveness, safety, and patient satisfaction.
While this terminology is an obvious improvement, it is, nevertheless, arbitrary, particularly with respect to tachysystole or hypertonieity. Although the relationship between continuous electronic fetal heart rate monitoring and fetal weil being is not one to one, non-reassuring changes associated with excessive uterine activity warrant intervention either to reduce uterine activity, to provide more direct assessment of fetal weil being (fetal blood sampling, other biophysical assessment), or to remove the fetus from this environment (delivery), Our meta-analysis 21 of data from existing RCTs has found tachysystole is significantly more frequent with misoprostol protocols (RR 2.21, CI 1.53 to 3.18), with uterine hyperstimulation nearly so (RR 1.84, CI 0.98 to 3.47). This meta-analysis included every vaginal misoprostol protocol. The maximum ineidence of tachysystole in any single report was 37 percent,'6 and uterine hyperstimulation 11 percent. To place this in perspective, contemporary studies with oxytoein inductions report tachysystole and uterine hyperstimulation of similar or greater frequency.26,27 When oxytocin induction results in uterine hyperstimulation with non-reassuring fetal heart rate changes, discontinuing the infusion can reduce oxytocin blood levels quickly. The use of vaginal dinoprostone gels or misoprostol is more problematic. Authors describe vaginal lavage and removing tablet remnants,28 however, intravenous ß-adrenergic agonist regimens have been used with apparent beneficial tocolytic response. 29 Intravenous tocolysis is the approach necessary with oral misoprostol. Forced emesis would likely be ineffective, and distasteful. Despite these concerns of possible uterine hyperstimulation, substantive worrisome newborn outcomes (neonatal aeidosis, meconium aspiration, and ACOG Birth Asphyxia criteria30 ) have been rare, acceptable, and not different between misoprostol and control groups. Ir is imperative that such outcome data be collected in future studies to quantitate more precisely the potential risks of misoprostol (and current approaches).
FETAL SAFETY ISSUES
An issue raised in several reports ' 1,l5,16 using vaginal misoprostol for labour induction has been more frequent uterine hyperstimulation. Is this important? Excessive uterine activity may interfere with uteroplacental perfusion sufficiently to compromise the fetus. Because of confusion stemming from varied definitions of excessive uterine activity, Curtis 25 recommended a standard terminology: hypertonic-a contraction lasting more than 90 seconds; tachysystole-contraction frequency greater than five per ten minutes; hyperstimulation-hypertonic contraction or tachysystole with late fetal heart rate decelerations or fetal tachycardia.
JOURNAL SOGC
POTENTIAL MISUSE
Harm to fetus or mother may occur subsequent to misuse of this uterotonic pharmaceutical agent. This has been noted particularly in developing countries where such medication does not require, and is available without physician prescription or supervision. 11 Premeditated patient initiated overdose has been reported in the United States, leading to fetal demise. l2 The compound's
1155
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, , , 11. Sanchez Ramos L, Kaunitz AM, Dei Valle GO, Delke I, Schroeder PA, Briones DK. Labor induction with the prostagiandin E1 methyl analog misoprostol versus oxytocin: a randomized trial. Obstet Gynecol 1993:81 :332-6. 12. Fletcher HM, Mitchell S, Simeon D, Frederick J, Brown D. Intravaginal misoprostol as a cervical ripening agent. Br J Obstet Gynaecol 1993;100:641-4. 13. Fletcher HM, Mitchell S, Frederick J, Simeon D, Brown D. Intravaginal misoprostol versus dinoprostone as cervical ripening and labor-inducing agents. Obstet Gynecol 1994;83:244-7. 14. Mundle W, Young DC. RCT of misoprostol (Cytotec) vs standard therapy for induction of labour. AGM, Society of Obstetricians and Gynaecologists of Canada, Calgary, Alberta, June 1995. 15. Wing DA, Jones MM, Rahall A, Goodwin TM, Paul RH. A comparison of misoprostol and prostagiandin E2 gel for preinduction cervical ripening and labor induction. Am J ObstetGynecoI1995;172:1804-10. 16. Wing DA. Rahall A, Jones MM, Goodwin TM, Paul RH. Misoprostol: an effective agent for cervical ripening and labor induction. Am J Obstet GynecoI1995;172:1811-6. 17. Varaklis K, Gumina R, Stubblefield PG. Randomized controlled trial of vaginal misoprostol and intracervical prostagiandin E2 gel for induction of labor at term. Obstet Gynecol 1995;86:541-4. 18. Chuck F, Huffaker J. Labor induction with intravaginal prostagiandin E1 (PGE1) (misoprostol, Cytotec) versus intracervical prostagiandin E2 (PGE2) (dinoprostone, Prepidil Gel): a randomized comparison. Am J Obstet Gynecol 1995;172:424. 19. Tabor B, Anderson J, Stettler B, Wetwiska N, Howard T. Misoprostol versus prostagiandin E2 gel for cervical ripening. Am J Obstet Gynecol 1995;172:425. 20. Margulies M, Campos Perez G, Voto LS. Misoprostol to induce labour. Lancet 1992;339:64. 21. Young DC, Mundle W, Butt K, Bennett K, Windrim R. Vaginal misoprostol (Cytotec) for term labour induction: a meta-analysis. AGM, Society of Obstetricians and Gynaecologists of Canada, Ouebec City, Ouebec 1996. 22. Keirse MJNC, van Oppen ACe. Preparing the cervix for induction of labour. In: Chalmers I, Enkin M, Keirse MJNC (Eds). Effective care in pregnancy and childbirth. Oxford University Press. 1989:1057-79. 23. Windrim R, Bennett K, Mundle W, Young De. Oral misoprostol for labour induction-RCT. AGM, Society of Obstetricians and Gynaecologists of Canada, Ouebec City, Ouebec, June 1996. 24. Hannah ME, Ohlsson A, Farine D, Hewson SA. Hodnett ED, Myhr TL, Wang EEL, Weston JA. Willan AR, for the Term PROM Study Group. Induction of labor compared with expectant management for prelabor rupture of the membranes at term. N Engl J Med 1996;334: 1005-1 O.
low cost, stable form, and wide availability for gastrointestinal management make misuse in pregnancy a possibility, which must be minimized, and ideally prevented. This concern for possible abuse, issues of use for medical termination, and medico-legalliabilities in intrapartum obstetrics have made the Canadian manufacturer reluctant to participate in any research into the use of this drug for induction oflabour. CONCLUSION
Misoprostol is an effective initiator of uterine contractions. Careful supervision of administration by a physician or another knowledgeable health professonal is required, and essential when fetal safety is an issue. Vaginal misoprostol for second trimester pregnancy termination or with fetal demise is appropriate to consider now. The available evidence for vaginal misoprostol in labour induction at term, although substantial, probably warrants further investigation before becoming standard practice. Oral misoprostol use for induction of uterine contractions is preliminary, though promising. REFERENCES 1.
Garris RE, Kirkwood CF. Misoprostol: a prostagiandin E1 analogue. Clin Pharm 1989; 8:627-44. 2. Product monograph for Cytotec. Searle Canada Inc. June 23,1992. 3. Thong KJ, Baird DT. Induction of abortion with mifepristone and misoprostol in early pregnancy. Br J Obstet GynaecoI1992;99:1004-7. 4. Norman JE, Thong KJ, Baird DT. Uterine contractility and induction of aborti on in early pregnancy by misoprostol and mifepristone. Lancet 1991 Nov; 338:1233-6. 5. Hausknecht RV. Methotrexate and misoprostol to terminate early pregnancy. N Engl J Med 1995;333:537-40. 6. Bugalho A, Bique C, Almeida L, Faundes A. The effectiveness of intravaginal misoprostol (Cytotec) in inducing abortion after eleven weeks of pregnancy. Stud Fam Plann 1993;24:319-23. 7. Bugalho A. Bique C, Almedia L, Bergstrom S. Pregnancy interruption by vaginal misoprostol. Gynecol Obstet Invest 1993;36: 226-9. 8. EI-Refaey H, Calder L, Wheatly DN, Templeton A. Cervical priming with prostagiandin E1 analogues, misoprostol and gemeprost. Lancet 1994;343:1207-9. 9. Jain JK, Mishell DR. A comparison of intravaginal misoprostol with prostagiandin E2 for termination of second-trimester pregnancy. N Engl J Med 1994;331 :290-3. 10. Mundle WR, Young De. Misoprostol versus standard therapy for medical termination of pregnancy. Int J Gynaecol Obstet 1994; SuppI2-46:20.
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, , , 25. Curtis P, Evans 5, Resnick J. Uterine hyperstimulation: the need for standard terminology. J Reprod Med 1987;32:91-5. 26. Lazor LZ, Philipson EH, Ingardia CJ. Kobetitsch ES, Curry SL. A randomized comparison of 15 and 40 minute dosing protocols for labor augmentation and induction. Obstet Gynecol 1993; 82; 1009-12. 27. Satin AJ, Leveno KJ, Sherman ML, Mclntire o. High does oxytocin: 20 versus 40 minute dosage interval. Obstet Gynecol 1994;83:234-8. 28. Egarter CH, Husselein PW, Rayburn WF. Uterine hyperstimulation after low dose prostagiandin E2 therapy: tocolytic treatment in 181 cases. Am J Obstet Gynecol 1990;163:794-6.
29. Sheybany S, Murphy JF, Evans 0, Newcombe RG, Pearson JF. Ritodrine in the management of fetal distress. Br J Obstet Gynaecol 1982;89:723-6. 30. ACOG Committee Opinion. Fetal distress and birth asphyxia. 137 April 1994. The American College of Obstetricians and Gynecologists, Washington, Oe. 31. Schonhofer PS. Brazil: misuse of misoprostol as an abortifacient may induce malformations. Lancet 1991;337:1534-5. 32. Bond GR, Van Zee A. Overdosage of misoprostol in pregnancy. Am J Obstet Gynecol 1994;171 :561-2.
PHYSICIAN HONORED FOR DISTINGUISHED SERVICE With more and more doctors getting ou[ of the baby bu ine Dr. T erry Riley is an anomaly-he not only continue co deliver babie at all hours of the day and night, he loves it. Thrives on it, in fact. For almost 30 years, the family physician has been a familiar face in the OTMH delivery room. And, while his commitment co obstetries may play havoc with his office taff-"l drop everything for babies"-it is gratifying co his patients. Recently the family doccor was honoured for his work with the reception of the Dr. E.P. "Soapy" Soanes Award, honouring a distingui hed Oakville family phy ician. The selection committee chaired by Dr. Gail MacPherson cho e Dr. Riley, in his 29th year of service to the hospital, last month. He was described as "supportive of colleague , a generous, compassionate, involved family physician who always goes the extra mile ... " Dr. Riley is a former chief of paediatries, a prime force behind the creation of the family medicine/obstetries group, and the current chair of the family medicine/obstetries group. He has been one of the key people behind many of the progre ive ob tetrieal practices launched by Oakville Trafalgar Memorial Ho pital (OTMH).
Contacted at his Oakville office, the physician said he was pleasantly urpri ed to leam he was the first recipient of the award. "l'm very flattered CO be cho en. It was very much a surprise to me," said Dr. Riley. He is the only family phy ician member of the Society of Ob tetries and Gynaecologi ts of Canada, a national body whieh ets tandard for the practice of obstetries and gynaecology. He i also a regular pre-natallecturer at Sheridan College. "Ob tetries and paediatries have alway been dose to my heart and I am very encouraged by the recent changes in our own obstetrieal program here in Oakville," he said. As CO the rise in the number ofhis colleagues choo ing not to practiee what has always been considered an integral part of being a doccor, he called it a "critical" problem. But he didn't believe it would be a problem in Oakville. "However, the newer graduates coming out of medieal school may think there is no place for them in this province and we could be looking at a serious fallout down the road," he commented. The Oakville physician remembers the days when fathers were not allowed inco delivery room . When he arrived in Oakville almost 30 years ago, the nation of fathers attending the birth of
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their child wa "greeted with great amusement." lt was another three years until it was routine co have fathers in delivery rooms and another few years that when they were there for Caesarian birth . He wa also a driving force behind key obstetrical pracrices induding labour room birth ,demand feeding, rooming in of infants and as he ays, "the list if long and boring CO anyone nat intere ted in obstetries." Over the past two years the h pital has had a shortage of physicians prepared to provide ob tetrieal ervice and Dr. Riley helped co bridge the gap until two new obstetricians came on the scene thi ummer. At the Board of Govemors meeting, Dr. John Kirby announced the award, adding he was personally very happy with the election, calling Dr. Riley an "obviously worthy choice." Dr. Riley attributes his own dedication for his work co his own belief in family-centred care. "l've always been interested in paediatric and ob tetric and because of the interest, I suppo e, I have worked very hard to provide family-centred eare." The award is in recognition co the hospital's first chief of staff and longtanding member of the department of family medicine at OTMH, Dr. E.P. "Soapy" Soanes.