Analysis of Severe Adverse Events Related to the Use of Mifepristone as an Abortifacient

Margaret M. Gary, MD; Donna J. Harrison, MD

Disclosures

The Annals of Pharmacotherapy. 2006;40(2):191-197. 

In This Article

Discussion

The pathophysiology of the rapid onset of sepsis following pregnancy terminations with mifepristone and the unusual afebrile and hemoconcentration presentation is still unclear. An interesting theory was recently published linking the rapid onset of sepsis with mifepristone's blockade of glucocorticoid receptors (mifepristone-induced septic shock).[49] Studies investigating the pathophysiology of septic shock have shown a noncompetitive, dose-dependent repression of the glucocorticoid receptor by both Bacillus anthracis lethal toxin[50] and the Clostridium sordellii lethal toxin.[51] Blockade of glucocorticoid receptors at the endometrial level may allow for ascending infection into a fertile medium of dead fetal tissue surrounded by an endometrium that lacks normal innate immune mechanisms. Further research into glucocorticoid receptor blockade by mifepristone resulting in the loss of the antibacterial role of the innate immune system at the endometrial level should be pursued.

With mifepristone abortions, the rate of failure to cause complete termination of pregnancy increases dramatically, along with hemorrhagic events, as the gestational age and the size of the placenta increases. The US clinical trial demonstrated a failure rate of 8% at 49 days or less from the last menstrual period (LMP), increasing to 17% at 50-56 days from the LMP, and further increasing to a 23% failure at 57-63 days from the LMP, as established by sonographic criteria.[52] Based on the data from this trial, the FDA approved mifepristone for use as an abortifacient up to 49 days from the LMP, but failed to require sonographic data for the accurate determination of gestational age. Furthermore, clinics nationwide routinely advertise mifepristone's use up to 63 days from the LMP, and, thus, would incur a failure rate of 23% or higher in addition to the inaccuracies of the methods used to date the pregnancies.

One serious concern raised by this review of AERs is the suggested fetal malformation rate of at least 23% following mifepristone failures that resulted in continuation of a live pregnancy. Misoprostol is a known teratogen, but the extent of the teratogenicity of mifepristone has yet to be well documented. Fetal malformations were noted in 3 of the 13 women who had pregnancies with known outcome. Another 9 women continued pregnancies without any documentation in the AERs of the outcome of the fetus. It is clear that a mandatory fetal registry should be established to ascertain the true incidence of fetal malformation in pregnancies that are continued after exposure to mifepristone and misoprostol.

Another serious concern is the number of missed diagnoses of ectopic pregnancies that resulted in rupture. Ectopic pregnancy is an absolute contraindication to the use of mifepristone, and failure to rule out ectopic pregnancy resulted in one death, as well as unnecessary morbidity. Requiring ultrasound documentation of intrauterine location of the pregnancy by a qualified ultrasonographer prior to the administration of mifepristone would reduce this life-threatening complication to a minimum.

The incidence of allergic reactions to mifepristone requires closer examination. Assuming that all patients were exposed to mifepristone for the first time, they could not have mounted an immunoglobulin E-mediated mifepristone allergic response. Inflammatory reactions reported as allergic reaction in the AERs are due to the release of proinflammatory mediators, such as histamine, prostaglandins, leukotrienes, and interleukins, which result in urticaria, rhinitis, conjunctivitis, or asthma. Blockade of cortisol receptors by mifepristone can result in an uncontrolled production and release of an excess of these proinflammatory mediators. Mifepristone's ability to block cortisol receptors has been well documented.[53] These proinflammatory reactions reported as allergic reactions in AERs may be due to the action of mifepristone's blockade of cortisol receptors. This potentially serious adverse effect resulting from mifepristone-induced blockade of cortisol receptors deserves further investigation.

Aside from specific safety issues related to mifepristone, studying these reports has been highly instructive for what they reveal about the FDA's Adverse Event Reporting System for all drugs. Michael F Mangano, principal deputy inspector general of the Department of Health and Human Services, stated in testimony before the US Senate:[54]

 

Adverse Event Reporting systems typically detect only a small proportion of events that actually occur. They are passive systems that depend on someone linking an adverse event with the use of a product, then reporting the event.... Rather the system generates signals that FDA must assess to confirm if, in fact, a public health problem exists.... With limited information to draw upon to generate signals, it is not surprising that FDA rarely reaches the point of knowing whether a safety action is warranted to protect consumers.

If our survey of mifepristone AERs is representative of adverse event reporting for all drugs, the American public should be greatly alarmed. In this instance, a majority of the AERs analyzed do not provide enough information to accurately code the severity of the adverse event in question. The deficiencies were so egregious in some instances as to preclude analysis. It is clear that input quality control is necessary for Medwatch to function; this systemic deficiency clearly impairs the FDA's ability to fully assess mifepristone's safety profile because the necessary signals are not being generated.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....