Correspondence
Deaths from Clostridium sordellii after Medical Abortion
N Engl J Med 2006; 354:1645-1647April 13, 2006
- Article
To the Editor:
Since its approval in France in 1988, a regimen of mifepristone (RU 486) and a prostaglandin has been used to terminate more than 1.2 million pregnancies of up to seven weeks of gestation. Most women have received oral mifepristone (at a dose of 600 mg), followed by oral misoprostol (at 400 or 800 μg).1,2 Success rates have exceeded 95 percent, and uterine infection (endometritis) has been rare (≤1 percent), less than the rate of infection after surgical abortion.3 No case of Clostridium sordellii has been reported. Mifepristone has also appeared to be safe when it has been used (without misoprostol) for long-term treatment of other indications (i.e., Cushing's syndrome and meningiomas).
In the cases reported by Fischer et al. (Dec. 1 issue)4 and discussed in the accompanying Perspective article by Greene,5 misoprostol was vaginally administered. This method has been shown to be highly efficacious (more effective than oral administration for the termination of pregnancy from day 49 to day 63),6,7 and its use after the administration of 200 mg of mifepristone has been recommended by the World Health Organization. However, such use has not been approved by any regulatory agency. It is possible that this regimen (which involves vaginal insertion under nonsterile conditions) may predispose patients to infection with C. sordellii or other bacteria while the cervix is open. In the United Kingdom and Sweden, antibiotic prophylaxis is routinely prescribed when this regimen is used, and no severe infection has been reported after approximately 350,000 cases of use (data provided by Exelgyn).
One additional precaution should be noted. Early studies (without secondary administration of a prostaglandin) showed that 200 mg of mifepristone was much less effective than 600 mg (63 percent success rate vs. 89 percent) (data provided by Roussel and Exelgyn). These findings indicate that the risk of incomplete abortion is greater in women receiving a lower dose of mifepristone who do not take a prostaglandin. I recommend the systematic use of 600 mg of mifepristone, followed by the administration of misoprostol, with oral administration up to day 49 of gestation or vaginal administration up to day 63, with prophylactic antibiotics.
Etienne-Emile Baulieu, M.D., Ph.D.
INSERM Unité 788, 94276 Le Kremlin Bicêtre, France
baulieu@kb.inserm. fr Dr. Baulieu reports having received honoraria from Exelgyn.
7 References1
Peyron R ,Aubeny E ,Targosz V , et al. Early pregnancy interruption with RU 486 (mifepristone) and misoprostol, an orally active prostaglandin analogue. N Engl J Med 1993;328:1509-1513
Full Text | Web of Science | Medline2
Aubeny E . A two-stage increase in the dose of misoprostol improves the efficacy of medical abortion with mifepristone and prostaglandins. Eur J Contracept Reprod Health Care 2001;6:54-55
Web of Science | Medline3
Sitruk-Ware R. Mifepristone and misoprostol: sequential regimen side-effects, complications and safety. Contraception (in press).
4
Fischer M ,Bhatnagar J ,Guarner J , et al. Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med 2005;353:2352-2360
Full Text | Web of Science | Medline5
Greene MF . Fatal infections associated with mifepristone-induced abortion. N Engl J Med 2005;353:2317-2318
Full Text | Web of Science | Medline6
Ashok PW ,Templeton A ,Wagaarachchi PT ,Flett GM . Factors affecting the outcome of early medical abortion: a review of 4132 consecutive cases. BJOG 2002;109:1281-1289
CrossRef | Web of Science | Medline7
Fiala C. Improving medical abortion: using mifepristone in combination with a prostaglandin analogue. (Ph.D. thesis. Stockholm: Department of Woman and Child Health, Division for Obstetrics and Gynaecology, Karolinska Institutet, October 2005.)
To the Editor:
The article by Fischer et al. and the Perspective by Greene are of utmost interest to me, since Patient 4 was my eldest daughter, the mother of two young children.
I would call attention to two factors that may have contributed to the lethal complications reported in this study. One of the factors is the recognized activity of mifepristone as an antagonist to glucocorticoids. After all, mifepristone was initially developed for its effects on the adrenal gland. Another factor was the vaginal use of misoprostol (a route of administration that is prohibited in France) and at a dose that was higher than the typical oral dose.
Strong consideration should be given to routine prophylactic use of antibiotics for two days in women treated with a regimen of mifepristone and misoprostol in order to eradicate possible infection with C. sordellii and to the use of oral misoprostol (at a dose of 400 μg), rather than 800 μg of the drug administered vaginally, as was used in the cases described. In addition, careful surveillance of patients is warranted for at least two or three days after treatment.
The response to these tragedies should not be to prohibit the use of mifepristone but to be extremely cautious, recognizing the potential risk of infection.
Didier Sicard, M.D.
Hôpital Cochin, 75679 Paris, France
didier.sicard@cch. ap-hop-paris. fr To the Editor:
Fischer et al. report four deaths associated with C. sordellii after medically induced abortion and review 10 published case reports of previous deaths associated with C. sordellii infection of the genital tract. The Division of Reproductive Health at the Centers for Disease Control and Prevention (CDC), through the Pregnancy Mortality Surveillance System, receives information, mainly from state health departments, on deaths attributed to complications of pregnancy.1 We reviewed all pregnancy-related deaths caused by infection from 1986 through 2001, the most recent year for which complete data have been received and coded. We found two deaths for which C. sordellii was identified as a causative organism; both deaths occurred after spontaneous abortion in the second trimester of pregnancy. One case involved the death of a woman with gas gangrene of the uterus and viscera; multiple postmortem cultures yielded C. sordellii and C. perfringens. The second case involved a death from acute endometritis and chorioamnionitis associated with C. sordellii. These cases are the first reported isolations of C. sordellii associated with death among women with spontaneous abortion.
The only sources of information for almost all cases reported to the Pregnancy Mortality Surveillance System are certificates of death, birth, and fetal death. Such certificates usually do not indicate specific causative organisms for deaths from infection, and information that would confirm causation is not available. On the basis of information that is available to us, these two cases in which C. sordellii was identified as a causative organism are a minimum number, and the frequency of fatal infection from this organism in pregnancy remains unknown.
1 ReferencesSuzanne B. Zane, D.V.M.
Cynthia J. Berg, M.D., M.P.H.
Centers for Disease Control and Prevention, Atlanta, GA 30341
saz3@cdc.gov 1
Chang J ,Elam-Evans L ,Berg C , et al. Pregnancy-related mortality surveillance -- United States, 1991-1999. MMWR Surveill Summ 2003;52:1-8
Medline
Author/Editor Response
Dr. Baulieu and Dr. Sicard both suggest that prophylactic antimicrobial agents should be given to women to prevent C. sordellii infection after medically induced abortion, particularly when mifepristone is administered after 49 days of gestation or when misoprostol is administered vaginally. Although this idea warrants evaluation and discussion, we are not aware of any direct evidence that prophylactic antimicrobial agents would prevent C. sordellii infection. To date, reports of fatal sepsis in women undergoing medical abortion are relatively uncommon (approximately 1 in 100,000), and antimicrobial agents carry their own risk of adverse events, including serious allergic reactions. In the United States, the Food and Drug Administration (FDA) has approved mifepristone only for the termination of intrauterine pregnancy of up to 49 days of gestation.1 The approved regimen consists of 600 mg of mifepristone, followed by 400 μg of misoprostol, both administered orally. Modified regimens of mifepristone and misoprostol have been studied and are commonly used2-4; however, their safety and effectiveness have not been established by the FDA.
Researchers have speculated about possible mechanisms by which oral mifepristone or intravaginal misoprostol could potentiate C. sordellii infection or the toxic shock syndrome. However, additional data are needed to evaluate these hypotheses. The information provided by Drs. Zane and Berg demonstrates that serious C. sordellii infection can occur after spontaneous abortion, just as it has occurred after childbirth and medical abortion. The CDC, the FDA, and state and local health agencies are working to investigate other possible cases of pregnancy-associated C. sordellii toxic shock syndrome and establish a research agenda to reduce further the risks of C. sordellii infection.
Clinicians should be aware of the distinctive features of C. sordellii toxic shock syndrome, including tachycardia, hypotension, edema, hemoconcentration, and profound leukocytosis, with or without fever. Patients with possible C. sordellii infection after induced abortion, spontaneous abortion, or childbirth should be evaluated thoroughly, including obtaining a complete blood count and appropriate cultures. If indicated, empirical antimicrobial therapy should include coverage of toxin-producing anaerobic bacteria. Health care providers are asked to report any suspected cases of pregnancy-associated C. sordellii infection to their state or local health department. Cases associated with the use of mifepristone or misoprostol should also be reported through the FDA MedWatch system.5
5 ReferencesMarc Fischer, M.D., M.P.H.
Sarah Reagan, M.P.H.
Sherif R. Zaki, M.D., Ph.D.
Centers for Disease Control and Prevention, Atlanta, GA 30333
mfischer@cdc.gov 1
Center for Drug Evaluation and Research. Mifeprex (mifepristone) information. Rockville, Md.: Food and Drug Administration, July 2005. (Accessed March 23, 2006, at http://www.fda.gov/cder/drug/infopage/mifepristone/default.htm.)
2
Shannon C ,Brothers LP ,Philip NM ,Winikoff B . Infection after medical abortion: a review of the literature. Contraception 2004;70:183-190
CrossRef | Web of Science | Medline3
von Hertzen H ,Honkanen H ,Piaggio G , et al. WHO multinational study of three misoprostol regimens after mifepristone for early medical abortion. I. Efficacy. BJOG 2003;110:808-818
Web of Science | Medline4
Kulier R ,Gulmezoglu AM ,Hofmeyr GJ ,Cheng LN ,Campana A . Medical methods for first trimester abortion. Cochrane Database Syst Rev 2004;1:CD002855-CD002855
Medline5
Food and Drug Administration. MedWatch: the FDA safety information and adverse events reporting program. (Accessed March 23, 2006, at http://www.fda.gov/medwatch/index.html.)
- Citing Articles (2)
Citing Articles
1
Eric A. Schaff. (2010) Mifepristone: ten years later. Contraception 81:1, 1-7
CrossRef2
Irving M Spitz. (2007) Progesterone receptor antagonists and selective progesterone receptor modulators: proven and potential clinical applications. Expert Review of Obstetrics & Gynecology 2:2, 227-242
CrossRef
