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Severity of infection following the introduction of new infection control measures for medical abortion
Contraception 83 (2011) 330 – 335
Original research article
Severity of infection following the introduction of new infection control measures for medical abortion Mary Fjerstada,⁎, James Trussellb,c , E. Steve Lichtenbergd , Irving Sivine , Vanessa Cullinsf a Ipas, Chapel Hill, NC 27514, USA Office of Population Research, Princeton University, Princeton, NJ 08544, USA c The Hull York Medical School, University of Hull, Hull HU6 1RX, England, UK d Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA e Reproductive Health Program, Population Council, New York, NY 10065, USA f Planned Parenthood Federation of America, New York, NY 10001, USA Received 17 June 2010; revised 30 August 2010; accepted 30 August 2010 b
Abstract Background: In response to concerns about serious infections following medical abortion, in early 2006 the Planned Parenthood Federation of America changed the route of misoprostol administration from vaginal to buccal and required either routine antibiotic coverage or universal screening and treatment for chlamydia; in July 2007, the Planned Parenthood Federation of America began requiring routine antibiotic coverage for all medical abortions. We previously reported a pronounced drop in the rate of serious infections following the adoption of these new infection control measures. Our objective in this study was to assess whether the degree of severity of the serious infections differed in the three infection control groups (vaginal misoprostol and no antibiotics; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, to assess whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories. Of particular importance is whether the new infection control measures selectively reduced the least severe serious infections but did not diminish the rate of the most severe infections. Methods: We performed a retrospective analysis assessing the degree of severity of infections before infection controls were implemented and after each of the two new measures was adopted: buccal administration of antibiotics with either screen-and-treat method or routine antibiotic coverage. We ranked the severity of infection from 1 (when treatment occurred in an emergency department) to 4 (when death occurred). We compared the distributions of the severity of serious infections in the three infection control groups (none; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, assessed whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories using the Jonckheere– Terpstra test for a doubly ordered 4×3 table. Results: The distribution of infection by severity was the same for all three infection control groups. Likewise, when the two new infection control groups — buccal misoprostol plus either screen-and-treat method or routine antibiotics — were combined, the distribution of infection by severity was the same before and after the new measures were implemented. Conclusion: The pronounced decline in the rate of serious infections occurred in each category of severity. © 2011 Elsevier Inc. All rights reserved. Keywords: Medical abortion; Infection; Antibiotics; Sepsis
1. Introduction Prompted by the deaths following medical abortion and internal data showing a higher-than-expected serious infection rate, the Planned Parenthood Federation of
⁎ Corresponding author. E-mail address: [email protected] (M. Fjerstad). 0010-7824/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2010.08.022
America (PPFA) changed its medical abortion protocol at the end of March 2006. Vaginal administration of misoprostol delivery was discontinued and replaced by buccal administration (200 mg of oral mifepristone followed 24–48 h later by 800 mcg of buccal misoprostol, 400 mcg in each cheek for 30 min), and all health centers were required to use one of two regimens intended to reduce the risk of infection: routine antibiotic coverage (oral doxycycline 100 mg bid for 7 days, starting the same day as
M. Fjerstad et al. / Contraception 83 (2011) 330–335
mifepristone administration) or universal testing for chlamydia (and for gonorrhea when considered appropriate), with treatment dependent on test results (oral doxycycline 100 mg bid for 7 days for chlamydia and ceftriaxone 125 mg im in a single dose for gonorrhea). After reviewing serious infection rates among health centers using these two infection-reduction regimens, in July 2007 PPFA required all health centers to provide routine preventative antibiotic treatment. In a prior publication, we showed that rates of serious infections dropped significantly after the joint change to buccal misoprostol replacing vaginal misoprostol and either sexually transmitted infection testing or routine antibiotic coverage as part of the medical abortion regimen [73% decline from 0.93/1000 to 0.25/1000, absolute reduction of 0.67/1000 (95% CI=0.44–0.94), pb.001] [1]. The subsequent change to routine antibiotic coverage led to a further significant reduction in the rate of serious infections [76% decline from 0.25/1000 to 0.06/1000, absolute reduction of 0.19/1000 (95% CI=0.02–0.34), p=.03] [1]. Altogether, there was a 93% reduction in the rate of serious infections following the switch to buccal misoprostol and routine antibiotic coverage [absolute decline of 86/ 1000 (95% CI=0.64–1.12), pb.001]; serious infections, originally rare, became extremely rare. Because two interventions were instituted at the same time — route of misoprostol changed from vaginal to buccal and administration of routine antibiotics, it is impossible to know precisely the extent to which either intervention contributed to the drop in the rate of serious infections following medical abortion. In the group that initially adopted the screen-and-treat method, two-thirds of the decline occurred after the switch to buccal administration of misoprostol and screen-and-treat method and one-third occurred after the subsequent switch to routine antibiotic coverage (the serious infection rate fell by 50% after the switch to routine antibiotics). Therefore, the maximum contribution of the change to the buccal route of misoprostol could be as high as 67% (if the screen-and-treat method were completely ineffective) and as low as 0%. It seems unlikely that the screen-and-treat method was completely ineffective because at least some who tested positive would have been treated in time to prevent serious infections. The maximum contribution of routine use of antibiotics could be as high as 100% (if the switch to buccal administration of misoprostol were completely ineffective) and no lower than 33%. In this study, we examined whether the degree of severity of serious infections differed in the three infection control groups (vaginal misoprostol and no antibiotics; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories. Of particular importance is whether the new infection control measures selectively reduced the least severe serious infections.
331
2. Methods We examined the 92 serious infections we previously identified; these were defined as cases in which a patient had fever accompanied by pelvic pain and was treated with intravenous antibiotics either in an emergency department (ED) or in an inpatient unit or where sepsis (a systemic, whole-body infection with positive blood cultures that can become quickly overwhelming despite multiple antibiotics) or death caused by infection was documented. Two of the authors (M.F. and E.S.L.) independently classified the severity of these serious infections (and then reconciled any differences) in one of four categories: 1. infections treated in an ED with intravenous antibiotics; 2. infections requiring hospitalization; 3. infections classified as sepsis or requiring surgery to repair or remove an organ damaged by infection; and 4. infections resulting in death. All authors reviewed and concurred with these classifications. The coding system employed, ranging from 1 (infection treated in the ED with intravenous antibiotics) to 4 (death), is conservative because while it orders the degree of severity, it does not reflect the magnitude of increasing severity of infectious outcomes. We compared the distribution of the severity of serious infections in the three infection control groups (no antibiotics; screen-and-treat method; routine antibiotics) or, equivalently, assessed whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories using the Jonckheere–Terpstra test for a doubly ordered 4×3 table. All calculations were performed in Cytel Studio 8 (Cytel, Boston, MA, USA). The Allendale Investigational Review Board approved the study protocol and design as a retrospective analysis of data routinely collected for quality control. Patient consent was not required to use these data. 3. Results Data about the serious infections in the three infection control groups (none; buccal misoprostol and screen-andtreat method; buccal misoprostol and routine antibiotics) are shown in Tables 1–3. There were 67 serious infections (following 72,195 medical abortions; rate of 93 per 100,000) before the new infection control measures were introduced, 18 (following 40,110 medical abortions; rate of 45 per 100,000) in the clinics that implemented the screen-and-treat method and 7 (following 115,518 medical abortions; rate of 6 per 100,000) in the clinics that added routine antibiotics. Altogether, of the 92 serious infections, 63 were classified as the least serious (category 1), 21 as category 2, 7 as category 3 and 1 as category 4. The distribution of serious infections
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M. Fjerstad et al. / Contraception 83 (2011) 330–335
Table 1 Serious infections before the adoption of buccal misoprostol and screen-and-treat method or routine antibiotics strategy ED/H
Severity
Sepsis
Organism
Notes
H H H H H
4 3 3 3 3
Yes
Clostridium perfringens Not reported to PPFA Not reported to PPFA Escherichia coli Bacteroides
H H H H H H H H H H H H
3 3 2 2 2 2 2 2 2 2 2 2
Yes
Death 5 days after misoprostol administration Hosp×3 days: tube and ovary removed for infection and abscesses, IV antibiotics Hosp×4 days: sepsis, positive blood culture, IV antibiotics Hosp×5 days: GC/CT negative, blood cultures positive for E. coli, IV antibiotics Hosp×5 days: multiple abscesses, hysterectomy and oophorectomy, bacteroides cultured from abdominal fluid, IV antibiotics Hosp×5 days: D&C, positive blood culture, IV antibiotics Hosp×2 days: ovarian thrombosis secondary to pelvic infection, IV antibiotics Hosp×3 days: IV antibiotics Hosp×3 days: IV antibiotics and D&C Hosp×3 days: multiple IV antibiotics Hosp×1 week: D&C, IV antibiotics Hosp×24 h: IV antibiotics Hosp×3 days: D&C, IV antibiotics Hosp×2 days: fever of 105°F, IV antibiotics, D&C Hospitalized overnight: IV antibiotics Hosp×2 days: endometritis, IV antibiotics Hosp×2 days for endometritis: IV antibiotics
H H H H H ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED
2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Yes Yes
Not reported to PPFA Not reported to PPFA
Gram-positive rods from endometrial tissue
CT
CT
Hosp×3 days for endometritis: IV antibiotics Hospitalized overnight: IV antibiotics, infection, pain, fever, high WBC Hosp×5 days: IV antibiotics, severe endometritis Referred to ED for severe pelvic pain/fever, elevated WBC at ED; hosp×24 h: IV antibiotics Hosp×24 h: D&C, IV antibiotics for endometritis, negative GC/CT Endometritis: IV antibiotics in ED IV antibiotics in ED Uterine bacterial infection: IV antibiotics and D&C in ED Fever of 101.3°F: IV antibiotics in ED Pain and fever, D&C: IV antibiotics in ED D&C in ED, IV antibiotics, positive CT identified prior to discharge Pain and fever: IV antibiotics in ED Endometritis: IV antibiotics in ED Endometritis: IV antibiotics in ED Treated for PID in clinic, did not improve: IV antibiotics in ED Severe UTI: IV antibiotics in ED IV antibiotics in ED for endometritis UTI and uterine infection: IV antibiotics in ED Ciprofloxacin and IV metronidazole in ED for endometritis PID treated as outpatient did not improve; referred to ED for endometritis: IV antibiotics in ED IV antibiotics in ED Endometritis: IV antibiotics and D&C in ED IV antibiotics and D&C in ED IV antibiotics and D&C in ED IV antibiotics in ED IV antibiotics in ED for uterine tenderness and fever IV antibiotics in ED for abdominal pain and fever IV antibiotics in ED IV antibiotics in ED for endometritis Ciprofloxacin and IV metronidazole in ED IV antibiotics in ED IV antibiotics in ED for endometritis IV antibiotics in ED for endometritis: elevated WBC IV metronidazole for endometritis in ED: positive CT diagnosed in work-up IV antibiotics and D&C in ED IV antibiotics in ED: heavy bleeding 2 weeks after misoprostol administration IV antibiotics in ED IV antibiotics in ED: elevated WBC, fever IV antibiotics in ED IV antibiotics in ED for severe UTI IV antibiotics in ED: fever, pain, high WBC IV antibiotics in ED: fever of 103°F
M. Fjerstad et al. / Contraception 83 (2011) 330–335
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Table 1 (continued) ED/H
Severity
ED ED ED ED ED ED ED ED
1 1 1 1 1 1 1 1
Sepsis
Organism CT
Notes IV antibiotics in ED for endometritis IV antibiotics and ciprofloxacin and doxycycline in ED IV ceftriaxone twice and metronidazole for endometritis: two separate treatments in ED IV metronidazole in ED for endometritis IV antibiotics in ED for endometritis Levofloxacin and IV metronidazole in ED for endometritis: pain, fever, high WBC IV antibiotics in ED: high WBC IV antibiotics in ED for endometritis
Note. ED, treated in emergency department; H, hospitalized; IV, intravenous; WBC, white blood count; GC, gonorrhea; UTI, urinary tract infection; PID, pelvic inflammatory disease; D&C, dilation and curettage; CT, Chlamydia trachomatis. Number of medical abortions=72,195; number of serious infections=67.
by severity category for each infection control group and the reductions in the rates of serious infections for each category are shown in Table 4. These distributions did not differ across the three infection control groups (p=.48), nor did they differ when the screen-and-treat method and routine antibiotics groups were combined and compared with the group not receiving antibiotics (p=.59). The inclusion of one category 2 serious infection in the routine antibiotics group is questionable because the woman was hospitalized after she developed Clostridium difficile, a gut infection, not a reproductive tract infection. The provider did not use the standard doxycycline antibiotic regimen discussed here; she was treated with ciprofloxacin rather than doxycycline, and ciprofloxacin is associated with development of C. difficile [2]. However, the results did not change when this case was eliminated (p=.32 and p=.44, respectively).
Likewise, there were no significant differences in the severity distributions when the one death was reclassified as a category 3, regardless of whether the abovementioned case was included or excluded and regardless of whether the screen-and-treat method and routine antibiotic groups were combined or not. Moreover, all the abovementioned results hold if only severity categories are treated as ordered [using the Kruskal– Wallis test for a singly ordered (by severity of infection) table].
4. Discussion We found reductions in the rates of serious infections after the adoption of new infection control measures of 81% for both severity categories 1 and 2, 92% for severity category 3 and 100% for severity category 4, or a 93% reduction if
Table 2 Serious infections during buccal misoprostol and screen-and-treat strategy ED/H Severity Sepsis Organism Notes on condition and treatment H
3
H H H H H ED ED ED ED ED
2 2 2 2 2 1 1 1 1 1
ED ED ED ED ED ED ED
1 1 1 1 1 1 1
Yes
Unknown Hosp×3 days: IV antibiotics; patient ill the month prior to medical abortion with osteomyelitis of the sternum, which perhaps contributed to \development of sepsis (positive blood cultures, organism not reported despite numerous attempts to get hospital records) Hosp×7 days: high fever, pelvic pain, IV antibiotics Hosp×2 days: fever, pelvic pain, high WBC, IV antibiotics Hosp×3 days: high WBC, pelvic pain, appeared very ill, IV antibiotics Hosp×2 days: pelvic pain, fever, elevated WBC with left shift, IV antibiotics Hospitalized×48 h: fever of 103°F, pain, IV antibiotics IV antibiotics in ED: high fever/pelvic pain IV antibiotics in ED: high fever/pelvic pain CT Treated as outpatient with azithromycin, developed fever, pain did not abate: IV antibiotics in ED IV antibiotics in ED: fever, severe pelvic pain CT Pain/fever developed before patient could be treated for positive CT test: IV antibiotics and azithromycin in ED (CT retested and confirmed) IV antibiotics in ED: fever/pelvic pain IV antibiotics in ED: fever/pelvic pain IV antibiotics in ED: fever/pelvic pain IV antibiotics in ED: fever/pelvic pain IV antibiotics in ED: fever/pelvic pain IV antibiotics in ED: fever/pelvic pain CT Pain/fever developed before patient could be treated for positive CT test: IV antibiotics and azithromycin in ED (CT retested and confirmed)
Note. Number of medical abortions=40,110; number of serious infections=18.
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M. Fjerstad et al. / Contraception 83 (2011) 330–335
Table 3 Serious infections during buccal misoprostol and routine antibiotic strategy ED/H
Severity
H
Sepsis
Organism
Notes
2
C. difficile
ED ED ED ED ED
1 1 1 1 1
CT
ED
1
Group D strep
Hosp×4 days: C. difficile, IV antibiotics, ciprofloxacin (instead of doxycycline) for routine antibiotic coverage; not a reproductive tract infection IV antibiotics in ED for severe UTI (not endometritis) IV antibiotics in ED: fever, pain, released on oral meds IV antibiotics in ED: fever, elevated WBC, pelvic pain IV antibiotics in ED: fever, elevated WBC, pelvic pain Pain/fever developed before patient could be treated for positive CT test: IV antibiotics and azithromycin in ED CT retested and confirmed) IV antibiotics in ED: severe pelvic pain/fever, culture of endometrial sample showed Group D Strep.
Note. Number of medical abortions=115,518; number of serious infections=7.
categories 3 and 4 are combined (Table 4). These differences are not statistically significant. Our ability to reach a definitive conclusion is limited, however, by the fact that the number of serious infections was small before (n=67) and was very much smaller after (n=25) the introduction of the new infection control measures. It is noteworthy that there were no deaths or open surgeries among the 155,628 women who received medical abortion since the changes in the regimen were instituted; there was one case of sepsis among the group of affiliates that used the screen-and-treat method, prior to the requirement of routine antibiotics for all women receiving medical abortion. From April 1, 2006, through December 31, 2008, PPFA clinics provided 151,440 medical abortions using buccal misoprostol and routine antibiotics. Although the precise number of medical abortions since the beginning of 2009 to the present is not yet available, adverse events are reported in real time, and up to the present (April 6, 2010), there have been no reports of category 3 or 4 infections (E. Talmont, personal communication, April 2010). The advantage of the screen-and-treat approach is that a woman is likely to become reinfected if she resumes sexual relations with an infected partner and screening allows for identification and treatment of an infected partner. There are disadvantages as well. Because many clinics provide medical abortion without public funding, any costs of screening and treatment must be passed on to the clients.
Chlamydia testing can be expensive, depending on the technology used. In addition, there are inherent delays between the time a woman is tested and that when the test results are reported and between reporting of a positive test and treatment of the individual; in the interim, uterine infection can develop. If screening and routine antibiotic coverage cannot be used simultaneously due to financial constraints, it is therefore logically certain that routine provision of antibiotics alone is an approach to prevent endometritis post-medical abortion caused by chlamydia or gonorrhea superior to the screen-and-treat method alone: it prevents at least as many of these infections at far lower cost (in E.S.L.'s clinic, 14 100-mg doxycycline tablets cost $0.65 and the cost of the screening test alone is $12.50). Another reason the approach of using routine antibiotics was superior to screening and treating positive cases of sexually transmitted infections is that most post-abortal infections are polymicrobial and are not caused by a single sexually transmitted organism for which the client can be tested and treated [3,4]. For all these reasons, providing routine antibiotics is far more cost-effective in preventing serious infections since more serious infections are prevented (50% more in our previous results [1]) at far lower cost. The revised regimen that employed buccal misoprostol and routine antibiotics reduced the rate of serious infections across all levels of severity. The cases of chlamydia and/or gonorrhea and of a variety of other potential pathogens that
Table 4 Serious infections by degree of severity and infection control measure Severity
1 2 3 4 3 and 4 Total Abortions
Infection controls None
Screen-and-treat method and buccal misoprostol
Routine antibiotics and buccal misoprostol
Screen-and-treat method or routine antibiotics and buccal misoprostol
45 (67%) 15 (22%) 6 (9%) 1 (1%) 7 (10%) 67 72,195
12 5 1 0 1 18 40,110
6 1 0 0 0 7 115,518
18 (72%) 6 (24%) 1 (4%) 0 (0%) 1 (4%) 25 155,628
Total
Reduction in the rate of serious infections after introduction of new infection control measures
63 21 7 1 8 92 227,823
81% 81% 92% 100% 93% 83%
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can result in polymicrobial post-abortal infection, but for which there is no feasible testing, were prevented from ascending into the uterine cavity and developing into an upper reproductive tract infection by the broad-spectrum activity of doxycycline. It is possible that even if vaginal colonization of a potentially pathogenic organism is not completely eradicated, the bacterial load is reduced by a course of antibiotics. The action by which doxycycline reduced the rate of infections across all severity levels is almost certainly due to its broad-spectrum activity against multiple organisms, including those that are known sexually transmitted infections that cause post-abortal infection and other organisms that are not usually pathogenic but may become so if they ascend to a uterine cavity containing necrotizing decidua following medical abortion, multiply and result in post-abortal infection. Since the infectionpreventing potency and breadth of doxycycline are not well described in clinical medicine, we were concerned that
335
doxycycline might be less effective in deterring more serious infections associated with medical abortion. The objective of this study was to determine whether the regimen changes reduced the rate of serious infections selectively in certain categories of severity or whether rates were reduced in all categories of severity. Reassuringly, we found that rates of serious infections following medical abortion were reduced in all categories of severity. References [1] Fjerstad M, Trussell J, Sivin I, Lichtenberg ES, Cullins V. Rates of serious infection after changes in regimens for medical abortion. N Engl J Med 2009;361:145–51. [2] Bolon MK. The newer fluoroquinolones. Infect Dis Clin North Am 2009;23:1027–51. [3] Stubblefield P, Grimes D. Septic abortion. N Engl J Med 1994;331:310–3. [4] Sweet RL. Treatment strategies for pelvic inflammatory disease. Expert Opin Pharmacother 2009;10:823–37.
Original research article
Severity of infection following the introduction of new infection control measures for medical abortion Mary Fjerstada,⁎, James Trussellb,c , E. Steve Lichtenbergd , Irving Sivine , Vanessa Cullinsf a Ipas, Chapel Hill, NC 27514, USA Office of Population Research, Princeton University, Princeton, NJ 08544, USA c The Hull York Medical School, University of Hull, Hull HU6 1RX, England, UK d Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA e Reproductive Health Program, Population Council, New York, NY 10065, USA f Planned Parenthood Federation of America, New York, NY 10001, USA Received 17 June 2010; revised 30 August 2010; accepted 30 August 2010 b
Abstract Background: In response to concerns about serious infections following medical abortion, in early 2006 the Planned Parenthood Federation of America changed the route of misoprostol administration from vaginal to buccal and required either routine antibiotic coverage or universal screening and treatment for chlamydia; in July 2007, the Planned Parenthood Federation of America began requiring routine antibiotic coverage for all medical abortions. We previously reported a pronounced drop in the rate of serious infections following the adoption of these new infection control measures. Our objective in this study was to assess whether the degree of severity of the serious infections differed in the three infection control groups (vaginal misoprostol and no antibiotics; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, to assess whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories. Of particular importance is whether the new infection control measures selectively reduced the least severe serious infections but did not diminish the rate of the most severe infections. Methods: We performed a retrospective analysis assessing the degree of severity of infections before infection controls were implemented and after each of the two new measures was adopted: buccal administration of antibiotics with either screen-and-treat method or routine antibiotic coverage. We ranked the severity of infection from 1 (when treatment occurred in an emergency department) to 4 (when death occurred). We compared the distributions of the severity of serious infections in the three infection control groups (none; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, assessed whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories using the Jonckheere– Terpstra test for a doubly ordered 4×3 table. Results: The distribution of infection by severity was the same for all three infection control groups. Likewise, when the two new infection control groups — buccal misoprostol plus either screen-and-treat method or routine antibiotics — were combined, the distribution of infection by severity was the same before and after the new measures were implemented. Conclusion: The pronounced decline in the rate of serious infections occurred in each category of severity. © 2011 Elsevier Inc. All rights reserved. Keywords: Medical abortion; Infection; Antibiotics; Sepsis
1. Introduction Prompted by the deaths following medical abortion and internal data showing a higher-than-expected serious infection rate, the Planned Parenthood Federation of
⁎ Corresponding author. E-mail address: [email protected] (M. Fjerstad). 0010-7824/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2010.08.022
America (PPFA) changed its medical abortion protocol at the end of March 2006. Vaginal administration of misoprostol delivery was discontinued and replaced by buccal administration (200 mg of oral mifepristone followed 24–48 h later by 800 mcg of buccal misoprostol, 400 mcg in each cheek for 30 min), and all health centers were required to use one of two regimens intended to reduce the risk of infection: routine antibiotic coverage (oral doxycycline 100 mg bid for 7 days, starting the same day as
M. Fjerstad et al. / Contraception 83 (2011) 330–335
mifepristone administration) or universal testing for chlamydia (and for gonorrhea when considered appropriate), with treatment dependent on test results (oral doxycycline 100 mg bid for 7 days for chlamydia and ceftriaxone 125 mg im in a single dose for gonorrhea). After reviewing serious infection rates among health centers using these two infection-reduction regimens, in July 2007 PPFA required all health centers to provide routine preventative antibiotic treatment. In a prior publication, we showed that rates of serious infections dropped significantly after the joint change to buccal misoprostol replacing vaginal misoprostol and either sexually transmitted infection testing or routine antibiotic coverage as part of the medical abortion regimen [73% decline from 0.93/1000 to 0.25/1000, absolute reduction of 0.67/1000 (95% CI=0.44–0.94), pb.001] [1]. The subsequent change to routine antibiotic coverage led to a further significant reduction in the rate of serious infections [76% decline from 0.25/1000 to 0.06/1000, absolute reduction of 0.19/1000 (95% CI=0.02–0.34), p=.03] [1]. Altogether, there was a 93% reduction in the rate of serious infections following the switch to buccal misoprostol and routine antibiotic coverage [absolute decline of 86/ 1000 (95% CI=0.64–1.12), pb.001]; serious infections, originally rare, became extremely rare. Because two interventions were instituted at the same time — route of misoprostol changed from vaginal to buccal and administration of routine antibiotics, it is impossible to know precisely the extent to which either intervention contributed to the drop in the rate of serious infections following medical abortion. In the group that initially adopted the screen-and-treat method, two-thirds of the decline occurred after the switch to buccal administration of misoprostol and screen-and-treat method and one-third occurred after the subsequent switch to routine antibiotic coverage (the serious infection rate fell by 50% after the switch to routine antibiotics). Therefore, the maximum contribution of the change to the buccal route of misoprostol could be as high as 67% (if the screen-and-treat method were completely ineffective) and as low as 0%. It seems unlikely that the screen-and-treat method was completely ineffective because at least some who tested positive would have been treated in time to prevent serious infections. The maximum contribution of routine use of antibiotics could be as high as 100% (if the switch to buccal administration of misoprostol were completely ineffective) and no lower than 33%. In this study, we examined whether the degree of severity of serious infections differed in the three infection control groups (vaginal misoprostol and no antibiotics; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories. Of particular importance is whether the new infection control measures selectively reduced the least severe serious infections.
331
2. Methods We examined the 92 serious infections we previously identified; these were defined as cases in which a patient had fever accompanied by pelvic pain and was treated with intravenous antibiotics either in an emergency department (ED) or in an inpatient unit or where sepsis (a systemic, whole-body infection with positive blood cultures that can become quickly overwhelming despite multiple antibiotics) or death caused by infection was documented. Two of the authors (M.F. and E.S.L.) independently classified the severity of these serious infections (and then reconciled any differences) in one of four categories: 1. infections treated in an ED with intravenous antibiotics; 2. infections requiring hospitalization; 3. infections classified as sepsis or requiring surgery to repair or remove an organ damaged by infection; and 4. infections resulting in death. All authors reviewed and concurred with these classifications. The coding system employed, ranging from 1 (infection treated in the ED with intravenous antibiotics) to 4 (death), is conservative because while it orders the degree of severity, it does not reflect the magnitude of increasing severity of infectious outcomes. We compared the distribution of the severity of serious infections in the three infection control groups (no antibiotics; screen-and-treat method; routine antibiotics) or, equivalently, assessed whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories using the Jonckheere–Terpstra test for a doubly ordered 4×3 table. All calculations were performed in Cytel Studio 8 (Cytel, Boston, MA, USA). The Allendale Investigational Review Board approved the study protocol and design as a retrospective analysis of data routinely collected for quality control. Patient consent was not required to use these data. 3. Results Data about the serious infections in the three infection control groups (none; buccal misoprostol and screen-andtreat method; buccal misoprostol and routine antibiotics) are shown in Tables 1–3. There were 67 serious infections (following 72,195 medical abortions; rate of 93 per 100,000) before the new infection control measures were introduced, 18 (following 40,110 medical abortions; rate of 45 per 100,000) in the clinics that implemented the screen-and-treat method and 7 (following 115,518 medical abortions; rate of 6 per 100,000) in the clinics that added routine antibiotics. Altogether, of the 92 serious infections, 63 were classified as the least serious (category 1), 21 as category 2, 7 as category 3 and 1 as category 4. The distribution of serious infections
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M. Fjerstad et al. / Contraception 83 (2011) 330–335
Table 1 Serious infections before the adoption of buccal misoprostol and screen-and-treat method or routine antibiotics strategy ED/H
Severity
Sepsis
Organism
Notes
H H H H H
4 3 3 3 3
Yes
Clostridium perfringens Not reported to PPFA Not reported to PPFA Escherichia coli Bacteroides
H H H H H H H H H H H H
3 3 2 2 2 2 2 2 2 2 2 2
Yes
Death 5 days after misoprostol administration Hosp×3 days: tube and ovary removed for infection and abscesses, IV antibiotics Hosp×4 days: sepsis, positive blood culture, IV antibiotics Hosp×5 days: GC/CT negative, blood cultures positive for E. coli, IV antibiotics Hosp×5 days: multiple abscesses, hysterectomy and oophorectomy, bacteroides cultured from abdominal fluid, IV antibiotics Hosp×5 days: D&C, positive blood culture, IV antibiotics Hosp×2 days: ovarian thrombosis secondary to pelvic infection, IV antibiotics Hosp×3 days: IV antibiotics Hosp×3 days: IV antibiotics and D&C Hosp×3 days: multiple IV antibiotics Hosp×1 week: D&C, IV antibiotics Hosp×24 h: IV antibiotics Hosp×3 days: D&C, IV antibiotics Hosp×2 days: fever of 105°F, IV antibiotics, D&C Hospitalized overnight: IV antibiotics Hosp×2 days: endometritis, IV antibiotics Hosp×2 days for endometritis: IV antibiotics
H H H H H ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED
2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Yes Yes
Not reported to PPFA Not reported to PPFA
Gram-positive rods from endometrial tissue
CT
CT
Hosp×3 days for endometritis: IV antibiotics Hospitalized overnight: IV antibiotics, infection, pain, fever, high WBC Hosp×5 days: IV antibiotics, severe endometritis Referred to ED for severe pelvic pain/fever, elevated WBC at ED; hosp×24 h: IV antibiotics Hosp×24 h: D&C, IV antibiotics for endometritis, negative GC/CT Endometritis: IV antibiotics in ED IV antibiotics in ED Uterine bacterial infection: IV antibiotics and D&C in ED Fever of 101.3°F: IV antibiotics in ED Pain and fever, D&C: IV antibiotics in ED D&C in ED, IV antibiotics, positive CT identified prior to discharge Pain and fever: IV antibiotics in ED Endometritis: IV antibiotics in ED Endometritis: IV antibiotics in ED Treated for PID in clinic, did not improve: IV antibiotics in ED Severe UTI: IV antibiotics in ED IV antibiotics in ED for endometritis UTI and uterine infection: IV antibiotics in ED Ciprofloxacin and IV metronidazole in ED for endometritis PID treated as outpatient did not improve; referred to ED for endometritis: IV antibiotics in ED IV antibiotics in ED Endometritis: IV antibiotics and D&C in ED IV antibiotics and D&C in ED IV antibiotics and D&C in ED IV antibiotics in ED IV antibiotics in ED for uterine tenderness and fever IV antibiotics in ED for abdominal pain and fever IV antibiotics in ED IV antibiotics in ED for endometritis Ciprofloxacin and IV metronidazole in ED IV antibiotics in ED IV antibiotics in ED for endometritis IV antibiotics in ED for endometritis: elevated WBC IV metronidazole for endometritis in ED: positive CT diagnosed in work-up IV antibiotics and D&C in ED IV antibiotics in ED: heavy bleeding 2 weeks after misoprostol administration IV antibiotics in ED IV antibiotics in ED: elevated WBC, fever IV antibiotics in ED IV antibiotics in ED for severe UTI IV antibiotics in ED: fever, pain, high WBC IV antibiotics in ED: fever of 103°F
M. Fjerstad et al. / Contraception 83 (2011) 330–335
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Table 1 (continued) ED/H
Severity
ED ED ED ED ED ED ED ED
1 1 1 1 1 1 1 1
Sepsis
Organism CT
Notes IV antibiotics in ED for endometritis IV antibiotics and ciprofloxacin and doxycycline in ED IV ceftriaxone twice and metronidazole for endometritis: two separate treatments in ED IV metronidazole in ED for endometritis IV antibiotics in ED for endometritis Levofloxacin and IV metronidazole in ED for endometritis: pain, fever, high WBC IV antibiotics in ED: high WBC IV antibiotics in ED for endometritis
Note. ED, treated in emergency department; H, hospitalized; IV, intravenous; WBC, white blood count; GC, gonorrhea; UTI, urinary tract infection; PID, pelvic inflammatory disease; D&C, dilation and curettage; CT, Chlamydia trachomatis. Number of medical abortions=72,195; number of serious infections=67.
by severity category for each infection control group and the reductions in the rates of serious infections for each category are shown in Table 4. These distributions did not differ across the three infection control groups (p=.48), nor did they differ when the screen-and-treat method and routine antibiotics groups were combined and compared with the group not receiving antibiotics (p=.59). The inclusion of one category 2 serious infection in the routine antibiotics group is questionable because the woman was hospitalized after she developed Clostridium difficile, a gut infection, not a reproductive tract infection. The provider did not use the standard doxycycline antibiotic regimen discussed here; she was treated with ciprofloxacin rather than doxycycline, and ciprofloxacin is associated with development of C. difficile [2]. However, the results did not change when this case was eliminated (p=.32 and p=.44, respectively).
Likewise, there were no significant differences in the severity distributions when the one death was reclassified as a category 3, regardless of whether the abovementioned case was included or excluded and regardless of whether the screen-and-treat method and routine antibiotic groups were combined or not. Moreover, all the abovementioned results hold if only severity categories are treated as ordered [using the Kruskal– Wallis test for a singly ordered (by severity of infection) table].
4. Discussion We found reductions in the rates of serious infections after the adoption of new infection control measures of 81% for both severity categories 1 and 2, 92% for severity category 3 and 100% for severity category 4, or a 93% reduction if
Table 2 Serious infections during buccal misoprostol and screen-and-treat strategy ED/H Severity Sepsis Organism Notes on condition and treatment H
3
H H H H H ED ED ED ED ED
2 2 2 2 2 1 1 1 1 1
ED ED ED ED ED ED ED
1 1 1 1 1 1 1
Yes
Unknown Hosp×3 days: IV antibiotics; patient ill the month prior to medical abortion with osteomyelitis of the sternum, which perhaps contributed to \development of sepsis (positive blood cultures, organism not reported despite numerous attempts to get hospital records) Hosp×7 days: high fever, pelvic pain, IV antibiotics Hosp×2 days: fever, pelvic pain, high WBC, IV antibiotics Hosp×3 days: high WBC, pelvic pain, appeared very ill, IV antibiotics Hosp×2 days: pelvic pain, fever, elevated WBC with left shift, IV antibiotics Hospitalized×48 h: fever of 103°F, pain, IV antibiotics IV antibiotics in ED: high fever/pelvic pain IV antibiotics in ED: high fever/pelvic pain CT Treated as outpatient with azithromycin, developed fever, pain did not abate: IV antibiotics in ED IV antibiotics in ED: fever, severe pelvic pain CT Pain/fever developed before patient could be treated for positive CT test: IV antibiotics and azithromycin in ED (CT retested and confirmed) IV antibiotics in ED: fever/pelvic pain IV antibiotics in ED: fever/pelvic pain IV antibiotics in ED: fever/pelvic pain IV antibiotics in ED: fever/pelvic pain IV antibiotics in ED: fever/pelvic pain IV antibiotics in ED: fever/pelvic pain CT Pain/fever developed before patient could be treated for positive CT test: IV antibiotics and azithromycin in ED (CT retested and confirmed)
Note. Number of medical abortions=40,110; number of serious infections=18.
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Table 3 Serious infections during buccal misoprostol and routine antibiotic strategy ED/H
Severity
H
Sepsis
Organism
Notes
2
C. difficile
ED ED ED ED ED
1 1 1 1 1
CT
ED
1
Group D strep
Hosp×4 days: C. difficile, IV antibiotics, ciprofloxacin (instead of doxycycline) for routine antibiotic coverage; not a reproductive tract infection IV antibiotics in ED for severe UTI (not endometritis) IV antibiotics in ED: fever, pain, released on oral meds IV antibiotics in ED: fever, elevated WBC, pelvic pain IV antibiotics in ED: fever, elevated WBC, pelvic pain Pain/fever developed before patient could be treated for positive CT test: IV antibiotics and azithromycin in ED CT retested and confirmed) IV antibiotics in ED: severe pelvic pain/fever, culture of endometrial sample showed Group D Strep.
Note. Number of medical abortions=115,518; number of serious infections=7.
categories 3 and 4 are combined (Table 4). These differences are not statistically significant. Our ability to reach a definitive conclusion is limited, however, by the fact that the number of serious infections was small before (n=67) and was very much smaller after (n=25) the introduction of the new infection control measures. It is noteworthy that there were no deaths or open surgeries among the 155,628 women who received medical abortion since the changes in the regimen were instituted; there was one case of sepsis among the group of affiliates that used the screen-and-treat method, prior to the requirement of routine antibiotics for all women receiving medical abortion. From April 1, 2006, through December 31, 2008, PPFA clinics provided 151,440 medical abortions using buccal misoprostol and routine antibiotics. Although the precise number of medical abortions since the beginning of 2009 to the present is not yet available, adverse events are reported in real time, and up to the present (April 6, 2010), there have been no reports of category 3 or 4 infections (E. Talmont, personal communication, April 2010). The advantage of the screen-and-treat approach is that a woman is likely to become reinfected if she resumes sexual relations with an infected partner and screening allows for identification and treatment of an infected partner. There are disadvantages as well. Because many clinics provide medical abortion without public funding, any costs of screening and treatment must be passed on to the clients.
Chlamydia testing can be expensive, depending on the technology used. In addition, there are inherent delays between the time a woman is tested and that when the test results are reported and between reporting of a positive test and treatment of the individual; in the interim, uterine infection can develop. If screening and routine antibiotic coverage cannot be used simultaneously due to financial constraints, it is therefore logically certain that routine provision of antibiotics alone is an approach to prevent endometritis post-medical abortion caused by chlamydia or gonorrhea superior to the screen-and-treat method alone: it prevents at least as many of these infections at far lower cost (in E.S.L.'s clinic, 14 100-mg doxycycline tablets cost $0.65 and the cost of the screening test alone is $12.50). Another reason the approach of using routine antibiotics was superior to screening and treating positive cases of sexually transmitted infections is that most post-abortal infections are polymicrobial and are not caused by a single sexually transmitted organism for which the client can be tested and treated [3,4]. For all these reasons, providing routine antibiotics is far more cost-effective in preventing serious infections since more serious infections are prevented (50% more in our previous results [1]) at far lower cost. The revised regimen that employed buccal misoprostol and routine antibiotics reduced the rate of serious infections across all levels of severity. The cases of chlamydia and/or gonorrhea and of a variety of other potential pathogens that
Table 4 Serious infections by degree of severity and infection control measure Severity
1 2 3 4 3 and 4 Total Abortions
Infection controls None
Screen-and-treat method and buccal misoprostol
Routine antibiotics and buccal misoprostol
Screen-and-treat method or routine antibiotics and buccal misoprostol
45 (67%) 15 (22%) 6 (9%) 1 (1%) 7 (10%) 67 72,195
12 5 1 0 1 18 40,110
6 1 0 0 0 7 115,518
18 (72%) 6 (24%) 1 (4%) 0 (0%) 1 (4%) 25 155,628
Total
Reduction in the rate of serious infections after introduction of new infection control measures
63 21 7 1 8 92 227,823
81% 81% 92% 100% 93% 83%
M. Fjerstad et al. / Contraception 83 (2011) 330–335
can result in polymicrobial post-abortal infection, but for which there is no feasible testing, were prevented from ascending into the uterine cavity and developing into an upper reproductive tract infection by the broad-spectrum activity of doxycycline. It is possible that even if vaginal colonization of a potentially pathogenic organism is not completely eradicated, the bacterial load is reduced by a course of antibiotics. The action by which doxycycline reduced the rate of infections across all severity levels is almost certainly due to its broad-spectrum activity against multiple organisms, including those that are known sexually transmitted infections that cause post-abortal infection and other organisms that are not usually pathogenic but may become so if they ascend to a uterine cavity containing necrotizing decidua following medical abortion, multiply and result in post-abortal infection. Since the infectionpreventing potency and breadth of doxycycline are not well described in clinical medicine, we were concerned that
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doxycycline might be less effective in deterring more serious infections associated with medical abortion. The objective of this study was to determine whether the regimen changes reduced the rate of serious infections selectively in certain categories of severity or whether rates were reduced in all categories of severity. Reassuringly, we found that rates of serious infections following medical abortion were reduced in all categories of severity. References [1] Fjerstad M, Trussell J, Sivin I, Lichtenberg ES, Cullins V. Rates of serious infection after changes in regimens for medical abortion. N Engl J Med 2009;361:145–51. [2] Bolon MK. The newer fluoroquinolones. Infect Dis Clin North Am 2009;23:1027–51. [3] Stubblefield P, Grimes D. Septic abortion. N Engl J Med 1994;331:310–3. [4] Sweet RL. Treatment strategies for pelvic inflammatory disease. Expert Opin Pharmacother 2009;10:823–37.