International Journal of Gynecology and Obstetrics (2006) 94 (Supplement 2), S149-- S150
The safety of misoprostol
Anke Hemmerling *
University of California, Berkeley, School of Public Health, 513 Warren Hall, Berkeley,CA 94720-6390, USA Misoprostol is currently on the WHO Essential Drug with supportive care within 12 hours. Bentov [7] List for treatment of gastric ulcers, for induced concludes that his case of overdose with 42 tablets abortion in combination with mifepristone, and (8.4 mg) over three days "illustrates the relative more recently for induction of labor. The WHO will review its role as an essential drug for control of The literature also reports one case of severe postpartum hemorrhage (PPH) in early 2007. Rel- hyperthermia postpartum reaching 41.9°C follow- evant data on the safety of misoprostol has accu- ing a normal dose of 800 mcg of oral misopros- mulated since the introduction of the drug in the tol and requiring intensive supportive care [9]. Al- late 1980s. Since then, millions of individuals world- though no other extreme cases of pyrexia are re- wide have used up to four tablets (800 mcg) daily for ported, several studies on PPH using oral misopros- treatment and prevention of gastric ulcer.
tol of 400-- 600 mcg describe transient pyrexia of Multi-center trials following thousands of users 38°C (100.4°F) or higher [10-- 14]. In these trials [1,2], as well as a review of the worldwide safety a limited number of parturients (5--28%) were af- data [3] and a Cochrane Review in 2002 [4] failed to fected and very few sustained a fever of 39--40°C.
report any misoprostol related deaths or side effects The temperature elevations generally last 1-- 2 hours severe enough to demand the cessation of treat- and then rapidly cease with minor or no interven- ment. Common side effects for long term misopros- tion. Oral and sublingual routes of administration tol users with gastric ulcers were the same as seen seem to trigger pyrexia more frequently than the in some women treated for PPH -- and include chills, Interestingly, pyrexia after misoprostol adminis- Four cases of acute toxicity after accidental or tration also seems to occur in women using the drug intentional overdose with misoprostol are described late in gestation and at delivery but rarely in ulcer in the peer-reviewed literature, two of them in patients or women in early pregnancy. The author is women beyond 30 weeks of pregnancy [5--8]. Af- not aware of a conclusive explanation for this phe- ter ingesting a large number of misoprostol tablets, nomenon at this time. Including careful monitoring sometimes mixed with other medication, tachycar- of body temperature into the design of future miso- dia, nausea and abdominal pain and, in some cases, prostol studies would be helpful, and users should hyperthermia was reported, although the authors be taught simple techniques of diagnosing and treat- of these reports emphasize the complete resolution ing transient fevers associated with misoprostol use.
Among more than two dozen studies of the use * Corresponding author. Tel.: +1 510 643-7627.
of misoprostol for PPH, death was not reported to E-mail: (A. Hemmerling).
have occurred during these trials. In four other stud- 0020-7292/$ -- see front matter 2006 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd.
All rights reserved.
ies, deaths were reported, and for six of the total intestinal complications in patients with rheumatoid of eight cases detailed information was presented.
arthritis receiving nonsteroidal anti-inflammatory drugs.
One woman died of a malaria-related disseminated A randomized, double-blind, placebo-controlled trial. AnnIntern Med 1995;123(4):241-- 9.
intravascular coagulation after average blood loss.
[2] Herting RL and Clay GA. Overview of clinical safety with A high risk multiparous woman with a low prena- misoprostol. Dig Dis Sci 1985;30(11 Suppl):185S-- 93S.
tal hemoglobin level died of severe PPH before she [3] Wildeman RA. Focus on misoprostol: review of worldwide reached the hospital [14]. One woman died sec- safety data. Clin Invest Med 1987;10(3):243-- 5.
ondary to a coagulopathy after hysterectomy and [4] Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, et al. Prevention of NSAID-induced gastroduodenal ulcers.
consequent re-laparotomy 48 hours after delivery.
Cochrane Database Syst Rev 2002(4): CD002296.
Another woman with a previous C-section died of [5] Graber DJ and Meier KH. Acute misoprostol toxicity. Ann PPH and did not receive an autopsy to evaluate the possibility of a ruptured scar. A third woman in the [6] Bond GR and Van Zee A. Overdosage of misoprostol in preg- same trial died of severe blood loss caused by a torn nancy. Am J Obstet Gynecol 1994;171(2):561-- 2.
[7] Bentov Y, Sheiner E and Katz M. Misoprostol overdose dur- cervix after labor induction and postpartum appli- ing the first trimester of pregnancy. Eur J Obstet Gynecol cation of several uterotonics [12]. In another trial, a woman died suddenly after severe blood loss 90 [8] Austin J, Ford MD, Rouse A and Hanna E. Acute intravagi- minutes after delivery of an inconclusive cause of nal misoprostol toxicity with fetal demise. J Emerg Med death [15]. In a fourth trial with two cases no reason [9] Chong YS, Chua S and Arulkumaran S. Severe hyperther- for death was specified by the authors [11]. None of mia following oral misoprostol in the immediate postpar- the cases with fatal complications were associated tum period. Obstet Gynecol 1997;90(4 Pt 2):703-- 4.
with misoprostol side effects such as severe hyper- [10] Chandhiok N., Dhillon BS, Datey S, Mathur A and Saxena NC. Oral misoprostol for prevention of postpartum hem- In conclusion, there have been no serious side ef- orrhage by paramedical workers in India. Int J GynaecolObstet 2006;92(2):170-- 5.
fects among millions of ulcer patients using miso- [11] Gulmezoglu AM, Villar J, Ngoc NT, Piaggio G, Carroli G, prostol. The few reported cases of extreme over- Adetoro L, et al. WHO multicentre randomised trial of dose experienced a rapid recovery. None of the fatal misoprostol in the management of the third stage of cases among misoprostol recipients in PPH trials is labour. Lancet 2001;358(9283):689-- 95.
definitively linked to a misoprostol side effect. The [12] Hofmeyr GJ, Ferreira S, Nikodem VC, Mangesi L, Singata M, Jafta Z, et al. Misoprostol for treating postpartum haem- occurrence of transient pyrexia of 38--40°C among orrhage: a randomized controlled trial [ISRCTN72263357].
a minority of women receiving misoprostol for PPH BMC Pregnancy Childbirth 2004;4(1):16.
should be monitored in the future and clearly ad- [13] Lumbiganon P, Hofmeyr J, Gulmezoglu AM, Pinol A and Vil- dressed during the training of community health lar J. Misoprostol dose-related shivering and pyrexia in the workers. The data from several dozen trials com- third stage of labour. WHO Collaborative Trial of Misopros-tol in the Management of the Third Stage of Labour. Br J pleted at this time -- combining the experience of Obstet Gynaecol 1999;106(4):304-- 8.
more than 17,000 women who have used misoprostol [14] Walraven G, Blum J, Dampha Y, Sowe M, Morison L, to control PPH -- shows that the drug has a remark- Winikoff B, et al. Misoprostol in the management of the ably benign safety profile and would appear safe to third stage of labour in the home delivery setting in rural use outside of hospital settings. This stable, low cost Gambia: a randomised controlled trial. Bjog 2005;112(9):1277-- 83.
and easy-to-use medication has the potential to im- [15] Hoj L, Cardoso P, Nielsen BB, Hvidman L, Nielsen J prove significantly the control of postpartum hem- and Aaby P. Effect of sublingual misoprostol on severe postpartum haemorrhage in a primary health centre inGuinea-Bissau: randomised double blind clinical trial. BMJ2005;331(7519):723.
[1] Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, et al. Misoprostol reduces serious gastro-



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