OBJECTIVE: To describe the effect of an extended-spectrum prophylactic antibiotic regimen on postcesarean endometritis.
METHODS: This is a cohort study of trends in postcesarean endometritis using data both from prospective surveillance by the infection control unit and from query of our obstetric computerized database to compare three periods of antibiotic prophylaxis: standard narrow-spectrum with intravenous first- or second-generation cephalosporin (1992–1996), clinical trial of extended-spectrum with addition of intravenous doxycycline and oral azithromycin (1997–1999), and routine use of extended-spectrum with addition of intravenous azithromycin (2001–2006) to standard cephalosporin prophylaxis.
RESULTS: A total of 48,913 deliveries at 24 weeks or more of gestation occurred from 1992 to 2006, of which 10,966 (22.4%) were cesarean deliveries. Annual cesarean rates increased from 16% to 27.5%. Trends in the incidence of postcesarean endometritis revealed a biphasic decrease consistent with the phased introduction of extended-spectrum prophylaxis. Incidence (95% confidence interval [CI]) of endometritis by prospective surveillance dropped from 19.9% (95% CI 18.6–21.3%) to 15.4% (95% CI 13.2–17.9%) during the clinical trial period: relative risk (RR) 0.77 (95% CI 0.66–0.91), P=.002; and then to 6.3% (95% CI 5.0–7.9%) during routine use of extended-spectrum prophylaxis: RR 0.41 (95% CI 0.31–0.54), P<.001. Corresponding incidence by database query dropped from 23% (95% CI 21.5–24.4%) to 16% (95% CI 14.4–17.9%): RR 0.69 (95% CI 0.61–0.79), P<.001; and then to 2.1% (95% CI 1.8–2.6%): RR 0.13 (95% CI 0.11–0.16), P<.001. These findings were unchanged after adjusting for potential confounders.
CONCLUSION: Extended-spectrum antibiotic prophylaxis involving the addition of azithromycin to standard narrow-spectrum prophylaxis was associated with a significant reduction in postcesarean endometritis.
LEVEL OF EVIDENCE: II
The addition of azithromycin to extend the spectrum of standard antibiotic prophylaxis decreases postcesarean endometritis.
From the 1Center for Women’s Reproductive Health & Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, and 2Infection Control Unit, UAB Hospital, University of Alabama at Birmingham, Birmingham, Alabama.
Corresponding author: Alan Thevenet N. Tita, MD, MPH, PhD, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Alabama at Birmingham, 618 20th Street South, Birmingham AL 35233; e-mail: email@example.com.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
Endometritis is the most frequent postcesarean complication, classically reported in up to 50% of patients.1 This rate is reduced to at least 25% or less by perioperative antibiotic prophylaxis.1 The American College of Obstetricians and Gynecologists recommends narrow-spectrum antibiotics, such as a first-generation cephalosporin for prophylaxis.2 This antibiotic regimen, however, does not cover for Ureaplasma, which may be disproportionately isolated from the upper genital tract of women with postcesarean infectious complications as previously demonstrated in our population.3 Among 575 women presenting for cesarean delivery without clinical evidence of chorioamnionitis and membranes intact, chorioamnion colonization with Ureaplasma urealyticum was associated with a threefold increased risk of endometritis in general and almost an eightfold increase in the subgroup with spontaneous onset of labor.3 This observation occurred despite standard narrow-spectrum prophylaxis. A subsequent randomized placebo-controlled clinical trial at our institution, performed from October 1996 to September 1999, revealed that a modified antibiotic prophylaxis regimen with extended spectrum, intended to cover Ureaplasma, reduced the rate of endometritis by a third and also reduced rates of wound infection and duration of hospital stay.4 The study regimen involved administration of intravenous cefotetan and doxycycline at cord clamp and oral azithromycin 6–12 hours after surgery. Because an intravenous preparation of azithromycin (the preferred antibiotic) was not available at the onset of the study, doxycycline was used at cord clamp for rapid intravenous effect and supplemented later with oral azithromycin. The control regimen was intravenous cefotetan and placebo at cord clamp plus oral placebo 6–12 hours later. After these positive findings, routine perioperative antibiotic prophylaxis with intravenous cephalosporin (cefotetan or cefazolin) and newly available intravenous azithromycin at cord clamp was initiated at our institution in August of 2000. Because of the long half-life of azithromycin, intravenous dosing would provide both the rapid effect as well as the extended coverage provided by the oral azithromycin. Although evidence of the regimen’s effect on Ureaplasma (such as cultures) was absent, its effect, regardless of mechanism, was considered sufficiently salutary to warrant the change in policy.
In the United States, the Center for Diseases Control and Prevention (CDC) recommends active surveillance of surgical site infections, including postcesarean endometritis.5 Accreditation institutions such as the Joint Commission on Accreditation of Healthcare Organizations require this surveillance. At our institution, infection control practitioners using standard protocols from the CDC perform prospective surveillance. Because this surveillance showed high rates of postcesarean endometritis (more than 20%) in the 1990s, in addition to the introduction of the modified prophylactic antibiotic regimen above, the infection control department undertook a one-time in-service training of all obstetric surgeons and operating room support staff on aseptic technique in 2002. We aim to report the temporal effect of extended-spectrum prophylactic antibiotic coverage on postcesarean endometritis.
MATERIALS AND METHODS
We conducted a retrospective cohort study of temporal trends in postcesarean endometritis based on both prospective infection surveillance and retrospective query of our obstetric computerized database. Ongoing surveillance at our institution is conducted by infection control practitioners for a minimum of 3 months per year. All patients with a cesarean delivery are followed for antibiotic therapy and signs and symptoms of endometritis and wound infections. Criteria of the CDC’s National Healthcare Safety Network (formerly the National Nosocomial Infection Surveillance System) are used to determine hospital-acquired infections, including endometritis.6 The main criteria involve the presence of two or more of the following signs with no other recognized cause: fever (body temperature greater than 100.4ºF [38ºC]), abdominal pain, uterine tenderness, or purulent drainage from uterus.
Independently, physicians or nurse practitioners record the intrapartum and postpartum data from all deliveries on standardized forms, which are entered into our perinatal database by dedicated personnel, who are also responsible for entering antepartum data and conducting audits of the data.
We report annual incidence of postcesarean endometritis using appropriate graphic presentation. Average incidence proportions of endometritis are compared over three chronological time periods: the period of use of standard narrow-spectrum prophylaxis with intravenous first- or second-generation cephalosporin—cefazolin or cefotetan—(up to 1996); the main period of the clinical trial of extended-spectrum prophylaxis to cover for Ureaplasma urealyticum (1997–1999); and the period of routine use of the extended-spectrum regimen (from 2001). Of note, 2000 is excluded from the statistical comparisons because, for most of that year, neither the clinical trial (which had ended) nor the official policy of routine extended-spectrum prophylaxis was active. It is, however, depicted as part of the trial period in graphs because both narrow and extended coverage were used. The χ2 test is applied to compare incidence of endometritis for each time period with the preceding period, and the corresponding relative risks (95% confidence intervals [CIs]) are computed using Stata 9.2 (StataCorp, College Station, TX). Logistic regression (SAS 9.1; SAS Institute, Cary, NC) is used to control for differences in potential confounders in the obstetric database and adjusted odds ratios and 95% confidence intervals are reported. Our institutional review board approved this study.
A total of 48,913 deliveries at 24 weeks or more of gestation were performed at our institution from 1992 to 2006, of which 10,966 (22.4 %) were cesarean deliveries. The number of annual deliveries initially decreased progressively from 4,150 in 1996 to 2,650 in 2003 and then increased sharply to 3,951 in 2006. The annual cesarean delivery rate (including tertiary transfers) ranged from 16.0% to 21.0% from 1992 to 1999 and then increased to 24.0–27.5% from 2000 to 2006. Demographic and other characteristics of women undergoing cesarean delivery are presented in Table 1. The proportions of those who were black, primiparous, undergoing primary cesarean delivery, undergoing labor before cesarean delivery, or diagnosed with chorioamnionitis appeared to decrease over time.
The temporal trend in postcesarean endometritis ascertained by prospective infection-control surveillance from 1992 to 2006 is presented in Figure 1. Before 1998, infection surveillance was conducted on a continuous basis throughout the year. In 1998 and 2001, surveillance was not performed. From 1999, surveillance was conducted for at least 3 months per year (including the month of July because of its association with a seasonal peak in endometritis). The figure indicates high rates of postcesarean endometritis from 1992 to 1996, before the trial of the modified antibiotic prophylaxis regimen ranging from 19% to 22%, with average incidence of 19.9% (95% CI 18.6–21.3)%. During the main trial period from 1997 to 1999, the incidence of endometritis dropped modestly but significantly to the 12–17% range, with average incidence of 15.4% (95% CI 13.2–17.9%). The risk ratio (RR) relative to the preceding period was 0.77 (95% CI 0.66–0.91), P=.002. The incidence of 14.5% in 2000 represents the average for 2 months (June and July) following the end of the study and the first month (August) of official initiation of routine extended-spectrum prophylaxis. With the routine use of the modified antibiotic regimen for all cesarean deliveries from 2001 forward, the incidence of endometritis once again dropped significantly to the 4–8.5% range, with cumulative incidence of 6.3% (95% CI 5.0–7.9%); RR 0.41 (95% CI 0.31–0.54), P<.001.
Annual incidence of endometritis based on data collated in our obstetric database for all cesarean deliveries at our institution is presented in Figure 2. Outcome information was unknown or missing only for 170 cesarean deliveries (1.6%). The pattern more clearly indicates a decrease in endometritis coincident with the clinical trial of extended-spectrum prophylaxis and a further drop after its routine use. The corresponding incidence proportions fell, respectively, from the 20–25% range and average incidence of 23.0% (95% CI 21.5–24.4%), to 14–17%, with average incidence of 16.0% (95% CI 14.4–17.9%): RR 0.69 (95% CI 0.61–0.79), P<.001; and then drastically to 1–2%, with average incidence of 2.1% (95% CI 1.8–2.6%): RR 0.13 (95% CI 0.11–0.16), P<.001. When restricted to the subgroups of cesarean deliveries performed before the onset of labor (mostly elective repeat cesarean deliveries), an identical biphasic decrease in endometritis was observed, with the following average incidence proportions: 12.5% before, 8.3% during the clinical trial, and 0.9% with routine use of extended-spectrum prophylaxis. The corresponding results for the comparison of successive time periods were RR 0.67 (95% CI 0.48–0.92), P=.01, and RR 0.11 (95% CI 0.06–0.19), P<.001.
In Table 2 we present data from two multivariable logistic regression models of endometritis: period of the trial of extended antibiotic prophylaxis relative to the period of standard prophylaxis and for the period of routine extended prophylaxis relative to the trial period, each adjusted for covariates including race, parity, primary cesarean delivery, labor before cesarean delivery, and chorioamnionitis. The protective effect of trial of extended prophylaxis and routine extended prophylaxis relative to the preceding period is confirmed: adjusted odds ratios were 0.65 (95% CI 0.5–0.9) and 0.11 (95% CI 0.1–0.2), respectively.
We demonstrate a biphasic drop in incidence of postcesarean endometritis, coincident and consistent with the phased introduction of extended-spectrum antibiotic prophylaxis intended to cover for Ureaplasma at our institution. The exact underlying mechanism cannot be affirmed because of the lack of culture information on the effect on Ureaplasma or other microbes. The initial modest drop coincided with the period of the clinical trial when only about 20% of all cesarean deliveries were exposed to extended-spectrum prophylaxis after randomization. Rates of postcesarean endometritis plummeted sharply once the new antibiotic regimen became routine. Review of baseline characteristics revealed changing patterns in potential confounders. The drop in the proportion of black women is related to a significant increase in our Hispanic population. Analyses of pregnant patients in our system indicated a remarkable ongoing increase in the proportion of obese patients up to 2000.7 The drop in mean weight from 2001 may be related to the higher proportion of Hispanics, who tend to be of shorter stature, and not due to a decrease in obesity. The presence of a consistent biphasic pattern in endometritis in the subgroup of cesarean deliveries performed before labor or elective repeats (and the lack of a similar pattern in rates of precesarean chorioamnionitis in additional analyses) suggests that the pattern is related to the performance of a cesarean delivery. Furthermore, effect of extended-spectrum prophylaxis remained steady after controlling for apparent differences over time in several baseline characteristics, including labor preceding cesarean delivery and chorioamnionitis, which were consistent independent risk factors for endometritis in our population. After 2000, the rates of endometritis ascertained by infection surveillance were higher than the rates from our perinatal database. Infection surveillance occurred for 3 months per year, including July with the highest rates of endometritis annually. The lower database rates involved all cesarean deliveries each year and, therefore, may better reflect the true annual incidence of endometritis.
It might be argued that the observed trend is attributable to the effect of another coincident period effect or intervention. However, we could not identify any other ongoing intervention, system change, or innovation that would explain the biphasic drop. Operative technique is largely standardized (for consistency in the training of residents) and has not undergone any modifications that would likely affect rates of endometritis. Review of infection control activities revealed the one-time in-service training of operating room staff on aseptic techniques in 2002. This would not account for the initial drop in rates during the clinical trial (1997–1999) and the drop observed in 2001 (Fig. 2) after initiation of routine extended-spectrum prophylaxis. Pertinently, current incidence proportions are far lower than the rate of 17% observed in the antibiotic arm during the clinical trial. It is, therefore, possible that the aseptic technique intervention in 2002 may have contributed to these low rates. Although there was an existing policy for routine antibiotic prophylaxis, we do not have data on actual compliance. This has been reported to be an issue in some settings.1 It is, therefore, unknown whether the evaluation in the clinical trial and modification of the antibiotic regimen might have led to an overall increase in compliance rates. Alternatively, extended prophylaxis with intravenous azithromycin during surgery may be more efficacious than the extended regimen of doxycycline during surgery and oral azithromycin afterward.
Published rates of postcesarean endometritis with antibiotic prophylaxis vary widely from less than 5% to over 25%.1,4,8 In spite of some differences in clinical definition, population characteristics, especially socioeconomic profile, account for a major portion of this variation, with indigent populations carrying the highest rates.9 Our institution serves a predominantly inner-city Medicaid-funded population that is about 70% African American, considering all deliveries. However, our patients now experience rates of endometritis that are equal to or lower than those observed in more affluent populations.8 We demonstrate in this report that routine extended-spectrum prophylaxis (intended to cover for Ureaplasma although it could have affected other pathogens) was responsible, at least in part, for the remarkable reduction in this postcesarean complication. A systematic review of antibiotic prophylaxis regimens and drugs for cesarean delivery suggested that there is no evidence that a more broad-spectrum agent produces greater efficacy in the reduction of infectious morbidity after cesarean delivery.10 This was, however, based on limited data because studies of extended-spectrum prophylaxis generally compared narrow-spectrum with extended-spectrum, single-agent, penicillins or cephalosporins.10 Apart from our prior clinical trial,4 there is a paucity of studies examining the effect of extended-spectrum regimens based on the addition, to standard protocols, of agents of a different class (such as azithromycin to cover for Ureaplasma, which is particularly predominant in the lower genital tract). In one clinical trial involving 224 cesarean deliveries in which extended coverage was provided by the addition of 5 g of vaginal metronidazole as compared with placebo, postcesarean endometritis was significantly lower in the metronidazole group (7% compared with 17%).11 In another trial of standard intravenous cefazolin compared with intravenous cefazolin and metronidazole involving 160 cesarean deliveries, incidence of endometritis was lower in the extended-prophylaxis group (14% compared with 32%), which was also found to be associated with lower overall cost per person. It has also been reported that administration of standard prophylaxis before skin incision (as opposed to after clamping the cord) also further reduces postcesarean infectious complications,13 although original concerns regarding effect on neonatal infections have not been adequately dispelled. Therefore, in addition to timing of administration, extended-spectrum prophylaxis should be considered among innovations that might achieve further reductions in postcesarean infectious morbidity and costs compared with standard narrow-spectrum prophylaxis given at cord clamp.
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