Antibiotics Added to Regimen for Medical Abortion
Abstract & Commentary
By Jeffrey T. Jensen, MD, MPH, Editor, Professor of Obstetrics and Gynecology, Vice Chair for Research, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: The use of a routine treatment course of doxycycline prevents most cases of serious infection associated with medical abortion.
Source: Fjerstad M, et al. Rates of serious infection after changes in regimens for medical abortion. N Engl J Med 2009;361:145-151.
A large retrospective cohort time series compared strategies to prevent infectious complications of medical abortion at Planned Parenthood Federation of America (PPFA)-affiliated clinics. In 2006, in response to concern about serious infection, PPFA changed the protocol to prohibit the use of vaginal misoprostol in favor of buccal administration, and required that clinics provide routine antibiotics or universal screening and treatment for chlamydia. The rate of serious infection dropped 73% from 0.93/1000 to 0.25/1000 abortions (absolute reduction, 0.67/1000; 95% confidence interval [CI], 0.44-0.94) following this change. In 2007, the protocol was again changed to require routine antibiotic treatment for all medical abortions. With this approach, the rate of serious infection declined an additional 76% from 0.25/1000 to 0.06/1000 (absolute reduction, 0.19/1000; 95% CI, 0.02- 0.34). Taken together, the use of buccal miso-prostol and routine provision of antibiotics accounted for a 93% reduction in the incidence of serious infection.
Commentary
By late 2005, the occurrence of 5 deaths in the United States and Canada that occurred in otherwise healthy medical abortion patients due to infection with an unusual pathogen (but common soil bacterium) Clostridium sordellii shocked the family planning community. In response to these events, the protocol for medical abortion at PPFA was changed. Prior to the switch, PPFA clients received the "evidence-based" protocol: 200 mg oral mifepristone followed in 48 hours by 800 mg of misoprostol dosed vaginally. The "evidence-based" protocol has been shown to be superior to the FDA-approved regimen of 600 mg oral mifepristone followed by 400 mg of oral misoprostol in terms of complete abortion rates, reduced time to expulsion, lower side effects, and lower cost.1,2 However, since there had been no reported cases of C. sordellii infections in Europe (where medical abortion rates are higher but vaginal administration of misoprostol is uncommon), a link between vaginal administration of misoprostol and C. sordellii infection was hypothesized.
More than 600,000 women had been treated with mifepristone/misoprostol by the time PPFA changed its medical abortion protocol, and the vast majority of these received misoprostol by the vaginal route. The estimated case-fatality rate for mifepristone abortion (0.8/100,000 procedures) is statistically no different from that of spontaneous abortion (0.7/100,000 miscarriages) and induced abortion (0.7/100,000 procedures). All of these are much lower than the overall risk of death from pregnancy (12.9/100,000 live births).3 The CDC has continued to investigate reports of toxic shock or death suggestive of Clostridium species infection after medical or spontaneous abortion and the incidence is low.4
Since medical abortion does not require instrumentation of the uterine cavity, rates of infection are low. Most serious infections are related to common gynecologic pathogens such as chlamydia. Clostridium sordellii is an uncommon cause of infection in humans, but can cause toxic shock after pregnancy, injection drug use, trauma, or surgery.4 A related bacterium, Clostridium perfringens, can also cause fulminant septic disease in pregnant women after abortion, and was a leading cause of death associated with illegal abortion. There have been rare case reports of C. perfringens deaths after legal induced abortions, spontaneous abortion, vaginal delivery, cesarean delivery, and amniocentesis.4 While approximately 2%-4% of vaginal cultures reveal C. perfringens, the incidence of vaginal carriage of C. sordellii is not known.4 It is likely that both bacteria ascend from colonized vaginal tracts to cause disease after abortion. Since medical abortion typically results in less complete uterine evacuation than suction abortion, colonization may lead to infection.
Even though the absolute risk of death due to C. sordellii infection is low, I think avoiding vaginal administration of misoprostol makes sense since buccal administration is well tolerated and provides similar efficacy. Misoprostol suppresses local immunity. Studies using a rat model have demonstrated increased mortality from C. sordellii infections with intrauterine compared to gastric administration of misoprostol.5 I believe there will never be a human study of adequate power to compare safety of vaginal and buccal misoprostol for abortion, so the vaginal route should be abandoned in abortion care. Vaginal administration may be appropriate for some indications (gynecologic procedures) where the potentially lethal combination of retained tissue and Clostridium colonization is not a factor.
In addition to abandoning vaginal misoprostol, PPFA health centers were also required to either screen and selectively treat for chlamydia (and other infectious diseases when appropriate) or provide routine antibiotic treatment (doxycycline 100 mg orally twice daily for 7 days starting the same day as the mifepristone administration) to all medical abortion patients. The combined approach reduced the number of serious infections (defined as fever accompanied by pelvic pain treated with intravenous antibiotics in an emergency department or inpatient setting) by 93% from 93 to 6 cases in 100,000 medical abortions. Since many more cases of mild uterine infection are treated as an outpatient, the overall significance of this low-cost intervention is even more impressive. Doxycycline also has in vitro activity against C. sordellii, and while it theoretically might prevent an ascending infection from becoming established, the study did not have adequate power to test this association. No cases of C. sordellii infection occurred during the study period.
Even clinicians that don't provide abortion care need to be aware of the clinical presentation of Clostridium infections during pregnancy and after abortion. Vomiting, diarrhea, and abdominal pain may be the only symptoms before the rapid progress to septic shock seen with C. sordellii infection. Unfortunately, these are all common symptoms associated with mifepristone and misoprostol. A very high WBC is seen in C. sordellii infection. Clinicians should have a high index of suspicion and gather an anaerobic culture of the cervix to aid in diagnosis if they suspect Clostridium species infection. The decision to begin intravenous antibiotics and admit a patient may be insufficient to manage a serious infection. Clostridium species must have an anaerobic environment to survive and multiply, and the older literature suggested that total hysterectomy or surgical debridement is necessary to remove necrotic tissue and prevent death in cases of C. perfringens infection. Interestingly, in the only reported case of C. sordellii infection after pregnancy where the patient survived, testing at the CDC laboratory indicated that the patient was infected with a strain of C. sordellii that did not produce lethal toxin. This patient also did not have a high white blood cell count.4
References
- el-Refaey H, et al. Induction of abortion with mifepristone (RU 486) and oral or vaginal misoprostol. N Engl J Med 1995;332:983-987.
- Honkanen H, et al; WHO Research Group on Post-Ovulatory Methods for Fertility Regulation. WHO multinational study of three misoprostol regimens after mifepristone for early medical abortion. BJOG 2004;111:715-725.
- Grimes DA. Risks of mifepristone abortion in context. Contraception 2005;71:161.
- Cohen AL, et al. Toxic shock associated with Clostridium sordellii and Clostridium perfringens after medical and spontaneous abortion. Obstet Gynecol 2007;110:1027-1033.
- Aronoff DM, et al. Misoprostol impairs female reproductive tract innate immunity against Clostridium sordellii. J Immunol 2008;180:8222-8230.
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