|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||
That original approval included a "black-box" warning that use of the drug could result in incomplete abortion requiring surgical intervention. It advised prescribers to be sure that appropriate provisions were made to provide that care when needed. On November 15, 2004, the FDA strengthened the warning in the black-box labeling of mifepristone to call attention to potentially fatal complications (ruptured ectopic pregnancy and septic shock) associated with its use in terminating early pregnancies. At the same time, the agency updated its Web site (http://www.fda.gov/cder/drug/infopage/mifepristone/default.htm) to reflect the deaths of three U.S. women who had taken the drug since its introduction in the United States; one of these deaths was due to a ruptured ectopic pregnancy, and two were due to septic shock. This updating occurred during the same week that FDA officials were called before a congressional committee investigating the high-profile withdrawal of rofecoxib (Vioxx) in order to respond to charges of lax oversight of the drug industry. Some used the circumstances to call for the withdrawal of mifepristone on the grounds that it, too, posed an undue safety risk.
On July 19, 2005, the agency reported that it was aware of four U.S. deaths due to sepsis in women who had used mifepristone and announced its second revision to the black-box warning in eight months. This revision named Clostridium sordellii as responsible for two of the deaths and specifically called attention to the somewhat unusual and rather distinctive signs and symptoms associated with these infections — an absence of fever but the presence of refractory hypotension, hemoconcentration, effusions in multiple serous cavities, and dramatic leukocytosis. A Canadian woman is also known to have died in 2001 of the same bacterial infection under similar circumstances.
(Figure)
|
Inevitably, the public health question of the safety of this method of pregnancy termination must be addressed. Some critical questions are: How great is the risk? With what is it appropriate to compare this risk? And what are the alternatives?
The manufacturer reports that "more than 460,000" procedures have been performed in the United States since the drug's approval. There is some uncertainty about this number because, although the manufacturer knows how many tablets it has shipped, it is not absolutely certain how many procedures have been performed with those tablets. The FDA-approved dose per procedure is three 200-mg tablets (600 mg total), and the tablets are packaged three to a pack. But on the basis of substantial evidence of equivalent safety and efficacy, the World Health Organization has recommended a dose of 200 mg per procedure. Most providers, including large institutional providers such as Planned Parenthood of America, routinely use the 200-mg dose. The manufacturer's estimate of 460,000 procedures is based on the assumption that most entail use of the lower dose. These figures would suggest that the risk of death from infection is less than 1 per 100,000. In the United States, the risk of death from any cause associated with attempting to carry a pregnancy to term is 8 to 10 times that.
The more appropriate comparison, however, is with the risk associated with other methods of inducing abortion. The overall maternal mortality rate associated with induced abortion in the United States is approximately 1 per 100,000. That overall rate is a "blended" rate including all the procedures performed in the United States at all gestational ages. The gestational-age–specific rate increases exponentially from 0.1 per 100,000 at 8 weeks' gestation to 8.9 per 100,000 at 21 or more weeks' gestation. Mifepristone is approved for the termination of pregnancies at less than seven weeks' gestation. Therefore, the appropriate comparison is with a risk of 0.1 per 100,000 for surgical abortions performed at less than eight weeks' gestation.
As tragic as the deaths of these young, healthy women are, they remain a small number of rare events without a clear pathophysiologic link to the method of termination. Patients should be informed of this risk before they consent to the procedure and should be vigilant for symptoms after the procedure. Providers must be aware of this potential complication and not be reassured by the absence of fever. Regulators should keep this rare complication in perspective and not overreact to scant data by prematurely foreclosing the only approved medical option for pregnancy termination. It may be difficult, however, to maintain equipoise on this issue in the wake of recent perceived regulatory lapses and amid the turbulence created by any discussion about abortion.
Source Information
Dr. Greene is a professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, Boston, director of obstetrics at Massachusetts General Hospital, Boston, and an associate editor of the Journal.
An interview with Dr. Greene can be heard at www.nejm.org.
References
| |||||||||||||||||||||||||||||||||||||||||||||||||||
Related Letters:
Deaths from Clostridium sordellii after Medical Abortion
Baulieu E.-E., Sicard D., Zane S. B., Berg C. J., Fischer M., Reagan S., Zaki S. R.
Extract |
Full Text |
PDF
N Engl J Med 2006;
354:1645-1647, Apr 13, 2006.
Correspondence
This article has been cited by other articles:
HOME | SUBSCRIBE | SEARCH | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | PRIVACY | TERMS OF USE | HELP | beta.nejm.org Comments and questions? Please contact us. The New England Journal of Medicine is owned, published, and copyrighted © 2010 Massachusetts Medical Society. All rights reserved. |
Interview
