Infection

INFECTION OVERVIEW

What should a patient know about medical abortion infection complications?

Information on infection and sepsis is included in the BOXED WARNING and WARNINGS sections of the Prescribing Information as well as the Medication Guide and the Patient Agreement. ^{(1) (2)}

Infection and hemorrhage are the most frequent serious and life-threatening causes of mifepristone related medical abortion illness and death. ⁽³⁾

If pregnancy tissue or products of conception are retained in a patient’s uterus, the woman may have symptoms such as fever, chills, foul smelling discharge or bleeding and pain in the lower abdomen indicating a possible serious infection. ⁽⁴⁾

Attention must be given to the possible outcome of infectious complications in medical termination of pregnancy. ⁽⁵⁾

Infection may be suspected if a woman: ⁽⁶⁾

• develops a fever of 38^o C (100.4^o F) or higher, that lasts for more than 4 hours, or a fever starts 6−8 hours after she has taken misoprostol
• has severe abdominal pain
• has pelvic tenderness.

Cases of reported of pelvic infections have been reported in recent literature when oral mifepristone was used with oral or vaginal misoprostol for medical abortion. (7)

There is no national system for tracking and reporting complications associated with gynecological procedures, the identification of true rates of reproductive tract infections in women is not readily available. ⁽⁸⁾

FDA does not have sufficient information to recommend the use of prophylactic antibiotics for women having a medical abortion. Prophylactic antibiotic use carries its own risk of serious adverse events such as severe or fatal allergic reactions. ⁽⁷⁾

INFECTION & INCOMPLETE ABORTION

How can incomplete abortion increase the risk of infection?

Incomplete medical abortion may increase the risk of infection and is associated with discomfort as persistent or recurrent bleeding and pain. ⁽⁹⁾

Retention of blood clots and decidual fragments in case of incomplete abortion may increase the likelihood of septic events. ^{(5) (10)}

Incomplete abortion associated with excessive bleeding or infection is an indication for suction curettage. ⁽¹¹⁾

Any woman presenting with an incomplete abortion may also be experiencing one or more life-threatening complications: shock, severe vaginal bleeding, infection and sepsis. ⁽¹²⁾

ATYPICAL INFECTION & SEPSIS

What should patients know about atypical infections and sepsis after medical abortion?

Serious bacterial infection after medical abortion can occur in the absence of the usual signs of typical pelvic infection. ⁽¹³⁾

ATypical Presentation of Infection: Patients with serious bacterial infections (e.g. Clostridium sordellii) and sepsis (a serious infection involving the bloodstream) can present without fever, bacteremia or significant findings on pelvic examination following an abortion. Very rarely, deaths have been reported in patients who presented without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, tachycardia, hemoconcentration, and general malaise. A high index of suspicion is needed to rule out serious infection and sepsis . ⁽¹⁴⁾ (see BOXED WARNINGS)

FDA recommends that healthcare professionals and patients be aware of the following: ⁽¹⁵⁾

• All providers of medical abortion and emergency room health care providers should investigate the possibility of sepsis in patients who are undergoing medical abortion and present with:
  • nausea, vomiting, or diarrhea and
  • weakness with or without abdominal pain, and
  • without fever or other signs of infection more than 24 hours after taking misoprostol.
• To help identify those patients with hidden infection, strong consideration should be given to obtaining a complete blood count.

The most commonly fatal adverse event is sepsis, which may progress rapidly to death. ⁽³⁾

Since the approval of mifepristone (Mifeprex) in September 2000, the FDA has been informed of women who have died from serious infections following medical abortion with mifepristone and misoprostol. ⁽¹⁾

The FDA has concluded that patients who have died from serious infection involving the bloodstream after medical abortion may be possibly related to the use of mifepristone and misoprostol. ⁽¹⁾

The FDA has issued public health advisories to warn health care professionals about the risks of sepsis in medical abortion and to reinforce use of the approved regimen which does not include the vaginal use of misoprostol. ^{(15) (16)}

ALTERATION OF VAGINAL PH & CLOSTRIDIUM SORDELLII INFECTION

How can the alteration of vaginal Ph correlate with fatal Clostridium sordellii infection?

Bacteria vaginosis is the most common vaginal infection during the reproductive years. Vaginosis is characterized by vaginal pH values above 4.5 and is correlated with infections after induced abortions. ⁽⁸⁾

Vaginal pH that correlates with pathogenicity results in the formation of bicarbonate/carbonic acid mixtures required for C. sordellii spore germination. ⁽⁸⁾

The normal vaginal environment of a non-pregnant female lacks the necessary germination signals and is too acidic to allow C. sordellii spore germination. ⁽⁸⁾

Altered vaginal pH conditions could result in a better environment for C. sordellii spores to germinate and establish infections. ⁽⁸⁾

Blood, necrotic tissue and decreased pH enhance clostridial growth and exotoxin production. ⁽¹⁷⁾

IMPAIRED IMMUNE RESPONSE & INFECTION

How can medical abortion drugs impair the innate immune response that may allow for serious or fatal infection?

As early as 1992, it has been suggested that the antiglucocorticoid effect of mifepristone would impair the immune system and favor the occurrence of infections. ⁽¹⁸⁾

It has also been shown in rats that intrauterine misoprostol increases mortality from Clostridium sordellii infection by impairing or altering the immune response. ⁽¹⁹⁾

Mifepristone and misoprostol both induce cervical dilation. Studies in rats show that cervical dilatation with mifepristone may allow for ascending infection of necrotic decidual tissue. ^{(20) (21)}

The opening of the cervical canal due to the antiprogestational effect of mifepristone may favor the migration of bacterial microorganisms that first colonizes the vagina/cervix then gaining access to the uterus. ^{(10) (19)}

In both medical and surgical abortions, vaginal bacteria enter the uterus via the open cervical canal but are removed by phagocytic cells of the innate immune system. ⁽²²⁾

To avoid the establishment of a myometrial infection during the recovery from the abortifacient process, the innate immune system must respond rapidly and appropriately to bacterial incursion of the decidua. ⁽²²⁾

Researchers, Jeanette I. Webster and Esther M. Sternberg have reported on the immune system response of the hypothalamic-pituitary-adrenal (HPA) axis on bacterial infections where interruption of the HPA axis by mifepristone (RU486) can enhance the severity or lethality of the infection. ⁽²³⁾

Interruption of the glucocorticoid response by the antiglucocorticoid (mifepristone) may play role in the pathological sequelae of exposure to a toxin (TcsL) produced by Clostridium sordellii. ⁽²⁴⁾

An important article by Ralph P Miech M.D. demonstrates the likely pathophysiologic basis for mifepristone’s capacity to increase a pregnant woman’s susceptibility to an otherwise rare cause of sepsis. ⁽²⁵⁾

The mechanisms of mifepristone action appears to favor the development of infection that leads to septic shock and intensifies the actions of multiple inflammatory cytokines, resulting in fulminant, lethal septic shock due to Clostridium sordellii. ⁽²⁵⁾

Mifepristone is long-lasting drug that can block steroid stress responses and the inflammation-dampening effects of cortisol. ⁽²⁶⁾

James A. McGregor M.D. and Ozlem Equiles M.D. suggest that mifepristone use impairs hosts responses and may predispose to lethal infection caused by toxigenic C. sordellii, other pathogens, and to reexamine the need for mifepristone use in medical termination of pregnancy. ⁽¹⁷⁾

INFECTIONS ASSOCIATED WITH TOXIC SHOCK AFTER MIFEPRISTONE INDUCED ABORTION

How are Clostridium sordelli infections associated with medical abortion?

The risk of severe, life-threatening, or even lethal adverse events, such as infection and sepsis, has been documented in otherwise healthy young women who have used mifepristone and misoprostol for medical abortion. ^{(3) (7)}

Clostridium sordellii is an emerging bacterial infection associated with toxic shock and has been associated with the medical abortion deaths in North America and Europe. ^{(27) (28) (1) (29)}

Since the approval of Mifeprex (Mifepristone, RU486) in September 2000 in the United States, the FDA has been informed of eight deaths in North America due to serious infections following medical abortion with mifepristone and misoprostol. These women died from sepsis (serious infection involving the bloodstream) and seven women were found to involve infection with bacterium, Clostridium sordellii and one case involved infection with Clostridium perfringens. ^{(1) (27) (28) (30) (31)}

In May of 2011, an additional death of a 16 year old Portuguese girl became the first fatality ever reported in the European community due to clostridium sordellii toxic-shock after medical abortion. ⁽²⁹⁾

Symptoms seen with clostridial infections include weakness, nausea, vomiting or diarrhea with or without abdominal pain that persists after expulsion of the pregnancy. Although patients typically lack a fever, they exhibit rapid pulse, low blood pressure, and very high red and white blood cell counts. ^{(11) (14)}

Clostridium sordellii is present in the vagina in 5% of all women and in up to 29% of women after pregnancy loss. ⁽²⁶⁾

Clostridium sordellii infections as a result of medically induced abortions have a 100% fatality rate. ⁽³²⁾

The risk of fatal sepsis in women is reported to be 10 times greater with medical abortion than surgical abortion (approximately 1 per 100,000 ⁽⁷⁾). ^{(33) (34)}

Women who have died in the United States from sepsis (severe illness caused by infection of the bloodstream) after medical abortion with mifepristone and misoprostol: ⁽⁷⁾

• Most of these women were infected with the same type of bacteria, known as Clostridium sordellii.
• The symptoms in these cases of infection were not the usual symptoms of sepsis.

Although medical termination is thought to be relatively safe, cases of significant infection combined with recently reported deaths highlights the need for enhanced vigilance for infection post medical termination of pregnancy. ⁽¹³⁾

Patients, family planning providers, emergency medical personnel, infectious disease specialists and intensivists/hospitalists should all be made aware of the rare, but rapidly lethal, sepsis syndrome of Clostridium sordelli Associated Toxic Shock (CATS) subsequent to mifepristone (RU486) and misoprostol pregnancy termination. ⁽³⁵⁾

The FDA has concluded that serious or fatal infection involving the bloodstream after medical abortion may be possibly related to the use of mifepristone and misoprostol. ⁽¹⁾

The increased use of mifepristone/misoprostol to terminate early pregnancy may result in the increased risk of Clostridium sordellii infections in women. ⁽⁸⁾