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Septic shock after medical abortions with mifepristone (Mifeprex, RU 486) and misoprostol

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Sally Murray
Sally Murray
Sally Murray
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Eric Wooltorton at University of Ottawa
Eric Wooltorton
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PRACTICE
CMAJ • AUG. 30, 2005; 173 (5) 485
© 2005 CMA Media Inc. or its licensors
Reason for posting:
Mifepristone
is used with misoprostol to termi-
nate early pregnancies and has
been taken by more than 460 000
women. The US Food and Drug
Administration (FDA) recently
advised of 4 women in the
United States who died of sepsis
after taking the drugs for medical
abortion. Two of the women had
Clostridium sordellii-related sepsis
(www.fda.gov/cder/drug/advisory
/mifeprex.htm). A Canadian wo-
man died in 2001 of C. sordellii-
related septic shock after taking
the drugs in a clinical trial.1
The drugs:
Mifepristone is a
progesterone receptor antagonist
and abortifacient, but was origi-
nally investigated for its antiglu-
cocorticoid effects as a potential
treatment for Cushing’s syn-
drome. Widely used in Europe
and the United States, it is not li-
censed for use in Canada. Ac-
cording to the FDA-approved
protocol, 600 mg of mifepristone
is taken orally within 49 days af-
ter the start of a woman’s last
menstrual period. Two days later
400 µg of the prostaglandin
misoprostol is taken orally to
soften the cervix and induce uter-
ine contractions if the pregnancy
has not already ended. Ten days
later the woman is followed up
clinically, often with ultrasonog-
raphy, to confirm termination of
her pregnancy. Complete med-
ical abortion occurs in about 92%
of women taking the regimen,
but 5%–8% require a surgical
procedure because of incomplete
abortion, excessive bleeding or
continuing pregnancy. Common
adverse effects of the regimen in-
clude abdominal cramping and
vaginal bleeding, headache, nau-
sea and vomiting, and diarrhea.
Rare but fatal cases of ruptured
ectopic pregnancy have occurred.
Mifepristone is metabolized in
the liver by CYP3A4.
The 4 FDA-reported deaths
occurred between 2003 and 2005
in California and involved women
who had taken the misoprostol
(800 µg) intravaginally. The in-
fective agent was not identified in
2 of the cases. The patients with
C. sordellii infection apparently
had similar presentations (Box 1).
C. sordellii is a gram-positive
anaerobe found ubiquitously in
soil and as part of the human in-
testinal flora. Ten percent of
women’s vaginas are colonized.
Infections are rare but have been
reported in patients of all ages
with both intact and compro-
mised immune systems. Death is
common, and the infections of-
ten occur after transcutaneous,
perineal or gastrointestinal pro-
cedures.2The organism produces
an endotoxin and can produce 2
potent exotoxins. C. sordellii sep-
sis in mifepristone users may oc-
cur through effects on cortisol or
cytokine responses.3
What to do:
Women should be
warned of this rare but poten-
tially fatal adverse effect. They
should seek immediate attention
if they have fever, severe abdom-
inal pain, very heavy bleeding,
syncope or general malaise.
However, clinicians must be
aware that all of the deaths from
C. sordellii sepsis reported here
involved symptoms listed in
Box 1. Prophylactic antibiotic
therapy is not recommended for
all women undergoing medical
abortion; however, for those with
suspected sepsis, complete blood
counts and necessary cultures
should be obtained and aggres-
sive, empirical treatment with
antibiotics started that includes
coverage against C. sordelli.
Sally Murray
Editorial Fellow
Eric Wooltorton
Associate Editor
CMAJ
References
1. Sinave C, Le Templier G, Bluin D,
Leville F, Deland E. Toxic shock syn-
drome due to Clostridium sordellii: a
dramatic postpartum and postabortion
disease. Clin Infect Dis 2002;35:1441-3.
2. Abdulla A, Yee L. The clinical spec-
trum of Clostridium sordellii bacteraemia:
two case reports and a review of the lit-
erature. J Clin Pathol 2000;53:709-12.
3. Miech RP. Pathophysiology of mife-
pristone-induced septic shock due to
Clostridium sordellii. Ann Pharmacother
2005 Jul 26 [Epub ahead of print].
DOI 10.1345/aph.1G189.
Septic shock after medical abortions with mifepristone
(Mifeprex, RU 486) and misoprostol
HEALTH AND DRUG ALERTS
DOI:10.1503/cmaj.050980
Canadian Adverse Reaction Newsletter
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Box 1: Characteristics of
Clostridium
sordellii
septic shock after medical abortion
with mifepristone and misoprostol
•Little or no fever
•Variable nausea, vomiting, weakness and
abdominal pain (often little)
•Rapid deterioration (within hours or days)
•Tachycardia and refractory hypotension
•Multiple effusions
•Elevated hematocrit
•Elevated leukocyte count, neutrophilia
Early release
All Health and Drug Alerts
are posted online ahead of
print and are available at
www.cmaj.ca. This article
was posted on Aug. 10,
2005.
... In humans, C. sordellii has been associated with fulminant necrotizing omphalitis in babies, 1,17,19 and endometritis and toxic shock syndrome in women. 21 The cause of death of humans with C. sordellii infection is thought to be septic shock, including disseminated intravascular coagulation. The toxins generated by the microorganism at the site of infection are thought to spread systemically, leading to septic shock. ...
Clostridium sordellii– associated gas gangrene in eight horses, 1998–2019
Article
  • Oct 2019
Gas gangrene occurs in several animal species and is caused by one or more clostridial species. In horses, the disease is most often caused by Clostridium perfringens type A. Although Clostridium sordellii has been associated with gas gangrene in ruminants and humans, cases of the disease associated with this microorganism have not been described in horses, to our knowledge. We report herein 8 cases of gas gangrene caused by C. sordellii in horses. These cases were characterized by myonecrosis and cellulitis, associated with systemic changes suggestive of toxic shock. The diagnosis was confirmed by gross and microscopic changes combined with anaerobic culture, fluorescent antibody test, immunohistochemistry, and/or PCR. The predisposing factor in these cases was an injection or a traumatic skin injury. C. sordellii should be considered as a possible etiologic agent in cases of gas gangrene in horses.
View
... 2 Although medical abortion is associated with less anxiety and pain than surgical abortion, 3 there are potential risks of incomplete abortion, excessive bleeding and still ongoing pregnancy. 4 On the other hand, surgical abortion is associated with high rates of complete abortion and short postoperative vaginal bleeding. Therefore, it is widely used in China. ...
Pain management of surgical abortion using transcutaneous acupoint electrical stimulation: An orthogonal prospective study
Article
Full-text available
  • Jul 2018
  • J OBSTET GYNAECOL RE
Aim: This study aimed to evaluate the optimal combination of parameters for the management of pain during surgical abortion using transcutaneous acupoint electrical stimulation (TEAS). Methods: This study recruited patients scheduled for surgical abortion between October 2014 and August 2015. The treatment protocol was created using three levels for each factor (stimulating time, acupoints, age, and parity). The primary outcomes were intraoperative visual analog scale (VAS), postoperative VAS, cervical relaxation degree and intraoperative blood loss. The secondary outcomes were the vital signs. Results: Stimulation time was associated with intraoperative VAS scores (P < 0.001), acupoints were associated with postoperative VAS scores (P = 0.037), and age was associated with postoperative VAS scores (P < 0.043). Parity (P = 0.025) was associated with heart rate. A comprehensive analysis of the parameters revealed the best levels for each (stimulation time: from 15 min before operation to immediate postoperative; acupoints: SP 6 and LR 3; patient age 25.1-30.0 years; and parity: G≥2 P0 A≥1 ). Seven patients did not complete follow-up. The remaining 135 subjects did not show continuous vaginal bleeding, abdominal pain, fever or any other adverse effect. Conclusion: During surgical abortion, TEAS stimulation from 15 min before operation to immediate postoperative, SP 6 and LR 3, age 25.1-30.0 years and G≥2 P0 A≥1 were associated with the best analgesic effect.
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... The combination has an acceptable safety profile in clinical practice (Goldstone et al., 2012;Cleland et al.,2013) and controlled administration for abortion in outpatient and home settings has also been successfully performed even prior to formal registration of these drugs in Australia (de Costa et al., 2007;Mulligan and Messenger, 2011). Nevertheless, significant adverse events including incomplete abortion, sepsis and death have all been reported (Murray and Wooltorton, 2005;Goldstone et al., 2012). The recommendation from the Royal contents of a gravid uterus, in both miscarriage and abortion have also been described (Gomez Ponce de Leon et al., 2007) and evaluated (Dodd and Crowther, 2010). ...
Off-label use of misoprostol in gynaecology
Article
Full-text available
  • Dec 2015
Clinical use of drugs is approved for specified clinical indication, route of administration, dose and population group. Off-label prescribing of a registered medicine occurs outside of these parameters and may be justified by pharmacology and physiology, as well as sufficient evidence from published clinical trials and reviews. Misoprostol and mifepristone in combination have recently been registered in Australia for medical termination of pregnancy in women of child-bearing age. There is good clinical evidence for efficacy and safety of misoprostol in uterine evacuation in both miscarriage and termination of pregnancy. The pharmacological effects of misoprostol on the uterus and clinical outcomes in both early miscarriage and abortion are comparable. Medical management of miscarriage with misoprostol in Australia is performed off-label. A woman presenting with first trimester miscarriage must be clearly informed that use of misoprostol in her case is for a non-approved indication. This raises the issue of inequity in her management compared with that of first trimester medical abortion, including being treated off-label and the potential cost of non-subsidised medication. The clinician must also be careful to use an evidence-based protocol that would withstand medicolegal challenge in the case of an adverse outcome.
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... En el 2005 la FDA señala 4 casos de muerte por sepsis después de toma de RU486, entre septiembre de 2003 y junio de 2005 119 . Otra señal de deceso por choque séptico es referida en Canadá siempre en el 2005 120 . En el 2006 otras 2 notificaciones de decesos después de aborto químico con RU486, de las cuales una claramente atribuible al RU486. ...
Ru486: del aborto químico a la contracepción de emergencia
Article
Full-text available
  • Jun 2009
El uso del mifepriston (RU486), en combinación con análogos de las prostaglandinas, en la inducción del aborto químico requiere una específica reflexión en relación a los principales aspectos farmacológicos y toxicológicos. La actual dialéctica bioética y biopolítica, a menudo ideologizada, impone aún más un tratamiento riguroso basado en evidencias científicas, para aclarar sobre todo los mecanismos de acción y de los eventos adversos. Estos últimos a veces también subvalorados o minimizados. Considerada la iniquidad del aborto voluntario, el artículo se propone también el objetivo de aclarar cómo, a la luz de una reciente bibliografía, el recurso al RU486 representa un significativo riesgo para la salud de las mujeres. Una particular atención está reservada a la aclaración etiopatogenética de las hemorragias y de las sepsis, en las cuales se han evidenciado también distintos decesos. En el artículo están presentes, además, los más actuales desarrollos de la investigación con RU486 sea para el tratamiento experimental de patologías –ginecológicas y no– como para el uso de la molécula de la contracepción hormonal y la “contracepción de emergencias”.
View
... A fulminant toxic shock syndrome (irreversible hypotension, apyrexia, haemoconcentration with hyperproteinemia, leukocytosis, high haematocrit and pleural effusion) accompanies the local infection of uterus or perineum (Soper, 1986;McGregor et al., 1989;Bitti et al., 1997;Rorbye et al., 2000;Sinave et al., 2002;Centers for Disease Control and Prevention, 2005;Ho et al., 2009;Zane and Guarner, 2011;Agrawal and Garg, 2012). In the recent period, several cases of fatal toxic shock syndrome due to C. sordellii were reported following medical abortion (Wiebe et al., 2004;Fischer et al., 2005;Greene, 2005;Miech, 2005;Murray and Wooltorton, 2005;Couzin, 2006;Winikoff, 2006;Cohen et al., 2007;Soper, 2007;Meites et al., 2010;Agrawal and Garg, 2012). In addition, C. sordellii is responsible for bacteraemia and arthritis resulting in a high rate of mortality (Abdulla and Yee, 2000;Gredlein et al., 2000). ...
The catalytic domains of C lostridium sordellii lethal toxin and related large clostridial glucosylating toxins specifically recognize the negatively charged phospholipids phosphatidylserine and phosphatidic acid: LCGT catalytic domains specifically bind to anionic phospholipids
Article
Clostridium sordellii lethal toxin is a potent virulence factor belonging to the large clostridial glucosylating toxin family. TcsL enters target cells via receptor-mediated endocytosis and delivers the N-terminal catalytic domain (TcsL-cat) into the cytosol upon an autoproteolytic process. TcsL-cat inactivates small GTPases including Rac and Ras by glucosylation with UDP-glucose as cofactor leading to drastic changes in cytoskeleton and cell viability. TcsL-cat was found to preferentially bind to phosphatidylserine (PS) containing membranes and to increase the glucosylation of Rac anchored to lipid membrane (Mesmin et al., 2004). We here report binding affinity measurements of TcsL-cat for brain PS containing membranes by SPR and ELISA. In addition, TcsL-cat bound to phosphatidic acid (PA) and to a lesser extent to other anionic lipids, but not to neutral lipids, sphingolipids or sterol. We further show that the lipid unsaturation status influenced TcsL-cat binding to phospholipids, PS with unsaturated acyl chains and PA with saturated acyl chains being the preferred binding substrates. Phospholipid binding site is localized at the N-terminal four helical bundle structure (1-93 domain). However, TcsL-1-93 bound to a broad range of substrates, whereas TcsL-cat, which is the active domain physiologically delivered into the cytosol, selectively bound to PS and PA. Similar findings were observed with the other LCGTs from Clostridium difficile, Clostridium novyi and Clostridium perfringens. This article is protected by copyright. All rights reserved.
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... Pleural effusions and serosanguineous ascites have been reported in almost all of the cases (15)(16)(17)(18)(19)(20)(21)(22)(23). In the recent period, several cases of fatal toxic shock syndrome due to C. sordellii were reported following medical abortion (15,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). From a series of 45 cases of C. sordellii infections, 8 (18%) were associated with normal childbirth, 5 (11%) with medical abortion, 2 (0.4%) with spontaneous abortion, 10 (22%) with drug injection, and 19 (43%) occurred after trauma or surgery. ...
Foot Infection by Clostridium sordellii: Case Report and Review of 15 Cases in France
Article
Full-text available
We report a case of foot infection by Clostridium sordellii and review 15 human infections registered at a Reference Center in France during the period 1998-2011. All the strains were found non-toxigenic, lacking the lethal toxin gene TcsL. Like Clostridium septicum, several C. sordellii infections were associated with intestinal neoplasms. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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Entre la indolencia y el sesgo: el derecho de las mujeres a beneficiarse de los avances científicos en materia reproductiva
Article
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  • Feb 2017
“Entre la indolencia y el sesgo” expresa de manera muy clara la arbitraria negativa que actualmente enfrentan las mujeres en nuestra región, al negárseles explícitamente el acceso a los insumos, que tienen la potencialidad de reducir complicaciones para su salud y, sobre todo, permiten -en contextos donde está permitido- la interrupción de embarazos de manera digna, segura y con los mismos estándares que se exigiría en cualquier otra intervención sanitaria. Si bien es cierto que en América Latina y el Caribe la mayoría de países contemplan alguna forma de aborto legal -y en América del Sur, a la fecha solo un país (Chile) mantiene la prohibición absoluta- lo real es que el avance en términos de oferta aun no alcanza a todas las mujeres que requieren este tipo de atención. Y para quienes sí acceden, no se pone a su alcance insumos y tecnologías, que son costo efectivas, que ofrecen opciones y, ante todo, que protegen la salud de la mujer. El Estudio que Agustina Ramón Michel y Sonia Ariza Navarrete han desarrollado para el Consorcio Latinoamericano Contra el Aborto Inseguro, nos permite tener un análisis que da cuenta de que la falta de disponibilidad del misoprostol obstétrico y de la mefiprestona, que prevalece en la Región, no es un hecho casual. Está determinada por factores económicos o de propiedad que influyen en las políticas de medicamentos e insumos, así como en cuestiones de orden ideológicos y prejuicios, a través de las cuales, se instrumentaliza la negativa de acceso al aborto seguro. Lo que es peor, se incrementa de forma adrede la peligrosidad, al dejar como única opción el uso de técnicas o insumos obsoletos, hechos que en sí mismos constituyen un atentado al derecho a la salud, a la integridad sexual y reproductiva de las mujeres y a la propia competencia de los profesionales de salud, quienes difícilmente podrían atender con estándares de calidad si carecen de tecnología y de insumos. Con este estudio, CLACAI entrega a las organizaciones defensoras de los derechos de las mujeres, a la comunidad médica, a las organizaciones que trabajan en el marco del derecho a la salud y a quienes luchan por el acceso a medicamentos, información clave que permitirá acercarse a una comprensión más amplia y al desarrollo de argumentos sólidos del derecho que tienen todas las personas a disponer del alcance al desarrollo científico y, sobre todo, a estar alertas de las motivaciones ajenas a los procedimientos, pero muy propias de quienes hacen de su ejercicio profesional un canal para aplicar sus concepciones privadas y afectar la política pública que, por lo general, perjudica principalmente a las mujeres que dependen de los servicios del Estado.
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Bacterial intracellularly active toxins: Membrane localisation of the active domain
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  • Apr 2020
Numerous bacterial toxins exert their activity by inactivating or modulating a specific intracellular host target. For this purpose, these toxins have developed efficient strategies to overcome the different host cell defenses including specific binding to cell surface, internalization, passage through the endosome or plasma membrane, exploiting intracellular trafficking and addressing to intracellular targets. Several intracellularly active toxins deliver an active domain into the cytosol that interacts with a target localized to the inner face of the plasma membrane. Thus, the large clostridial glucosylating toxins (LCGTs) target Rho/Ras‐GTPases, certain virulence factors of Gram negative bacteria, Rho‐GTPases, while Pasteurella multocida toxin (PMT) targets trimeric G‐proteins. Others such as botulinum neurotoxins and tetanus neurotoxin have their substrate on synaptic vesicle membrane. LCGTs, PMT, and certain virulence factors from Vibrio sp. show a particular structure constituted of a 4 α‐helices bundle (4HBM) protruding from the catalytic site that specifically binds to the membrane phospholipids and then trap the catalytic domain at the proximity of the membrane anchored substrate. Structural and functional analysis indicate that the 4HBM tip of the Clostridium sordellii lethal toxin (TcsL) from the LCGT family contain two loops forming a cavity that mediates the binding to phospholipids and more specifically to phosphatidylserine. This article is protected by copyright. All rights reserved.
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Untersuchungen zur Aufnahme clostridialer glucosylierender Toxine in Zielzellen
Thesis
  • Jan 2013
Zielsetzung dieser Arbeit ist die Aufklärung der Aufnahmemechanismen der clostridialer glucosylierender Toxine (CGT) in Zielzellen. Für diese Untersuchungen sollten verschiedene Endozytosewege durch pharmakologische und genetische Methoden blockiert werden. Folgend wurde untersucht, ob diese Hemmung einen Einfluss auf die Intoxikation der Zellen durch die CGTs ausübt. Es stellte sich heraus, dass die CGTs Clathrin-abhängig in Ihre Zielzellen gelangen
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The clinical spectrum of Clostridium sordellii bacteraemia: Two case reports and a review of the literature
Article
Full-text available
  • Oct 2000
Clostridium sordellii is rarely associated with disease in humans. Since its first report in 1922 only a few cases of bacteraemia have been reported. This report describes two cases of C sordellii bacteraemia; the oldest and youngest patients reported to date. The first, is a previously well 81 year old woman presented with perianal infection, which was later complicated by thrombosis of the aorta, and the second is a 12 year old boy with epilepsy who presented with an ear infection. These cases are also highlighted to demonstrate the wide spectrum of presentation of sordellii bacteraemia.
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Toxic Shock Syndrome Due to Clostridium sordellii: A Dramatic Postpartum and Postabortion Disease
Article
Full-text available
  • Dec 2002
  • CLIN INFECT DIS
We describe a young woman who developed Clostridium sordellii toxic shock syndrome after having had an abortion medically induced by mifepristone (RU-486; Mifeprex [Danco Laboratories]) 7 days before admission to our hospital. Although the patient was aggressively treated, death occurred <3 days after admission. It is hoped that very early recognition of this disease will decrease the mortality associated with this rarely reported ailment that occurs among young, otherwise healthy women.
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Pathophysiology of Mifepristone-Induced Septic Shock Due to Clostridium sordellii
Article
Full-text available
  • Oct 2005
To explain the role of mifepristone in medical abortions that results in fulminant and lethal septic shock due to Clostridium sordellii. MEDLINE, PubMed, and Google Scholar databases were searched (1984-March 2005). Key search terms were mifepristone, RU38486, RU486, Mifeprex, medical abortion, septic shock, innate immune system, cytokines, and Clostridium sordellii. All articles identified from the data sources were evaluated and all information deemed relevant was included for the information related to the development of the understanding of the pathophysiology of mifepristone-induced septic shock due to C. sordellii. The mechanisms of action of mifepristone were incorporated into the pathophysiology of septic shock due to C. sordellii. Mifepristone, by blocking both progesterone and glucocorticoid receptors, interferes with the controlled release and functioning of cortisol and cytokines. Failure of physiologically controlled cortisol and cytokine responses results in an impaired innate immune system that results in disintegration of the body's defense system necessary to prevent the endometrial spread of C. sordellii infection. The abnormal cortisol and cytokine responses due to mifepristone coupled to the release of potent exotoxins and an endotoxin from C. sordellii are the major contributors to the rapid development of lethal septic shock. Theoretically, it appears that the mechanisms of mifepristone action favor the development of infection that leads to septic shock and intensifies the actions of multiple inflammatory cytokines, resulting in fulminant, lethal septic shock.
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Toxic shock syndrome due to Clostridium sordellii: a dramatic postpartum and postabortion disease
  • Jan 2002
  • CLIN INFECT DIS
  • 1441-1443
  • C Sinave
  • Le Templier
  • G Bluin
  • D Leville
  • F Deland
Sinave C, Le Templier G, Bluin D, Leville F, Deland E. Toxic shock syndrome due to Clostridium sordellii: a dramatic postpartum and postabortion disease. Clin Infect Dis 2002;35:1441-3.