Cesarean delivery, the most common major U.S. surgical procedure,1 is the greatest risk factor for puerperal maternal infection. Compared with vaginal delivery, cesarean delivery is associated with at least a 5- to 10-fold increase in risk for postpartum (surgical site) infections including endometritis and wound infection.2 As many as 60–70% of all cesarean deliveries are unscheduled. Even with standard preincision prophylaxis, surgical site infection occurs in 10–15% of these deliveries.3,4
A systematic review of current published data concluded that among available interventions to further reduce postcesarean surgical site infections, azithromycin-based extended-spectrum prophylaxis (a single intravenous dose of azithromycin in addition to standard prophylaxis) might reduce the risk of postcesarean infection compared with standard cephalosporin alone.5 In a randomized clinical trial of more than 2,000 women undergoing unscheduled and nonelective cesarean delivery, compared with placebo, we found that adding azithromycin to standard preincision prophylaxis reduced surgical site infection by 50% (12% compared with 6.1%), with a relative risk of 0.51 and a 95% confidence interval (CI) of 0.38–0.68 (P<.001).6 In an effort to identify actionable prevention strategies for further clinical trials, the purpose of this secondary analysis was to identify maternal clinical risk factors for postcesarean maternal infection in the context of a trial of azithromycin-based extended-spectrum antibiotic prophylaxis.
MATERIALS AND METHODS
This is a planned secondary analysis of the Cesarean Section Optimal Antibiotic Prophylaxis trial (ClinicalTrials.gov NCT01235546), a double-blind multicenter pragmatic randomized trial conducted at nine clinical centers (14 sites) from 2011 to 2014. Each clinical site provided institutional review board approval, and all participants gave written informed consent. An independent multidisciplinary Data Safety and Monitoring Board monitored the study throughout its implementation for performance and safety.
The details for the primary clinical trial have been published.6 Briefly, women with a singleton pregnancy at 24 weeks of gestation or greater who were undergoing a nonelective cesarean delivery (during labor, defined as ongoing contractions with documented cervical change, or at least 4 hours after membrane rupture) were eligible for randomization. Exclusion criteria were maternal medical complications precluding macrolide use; multiple gestation; known azithromycin or macrolide allergy; vaginal delivery; elective or scheduled cesarean delivery before labor or membrane rupture; use of azithromycin, erythromycin, or other macrolide antibiotic within 7 days of randomization; chorioamnionitis or other active bacterial infection at the time of randomization requiring antibiotic therapy; and fetal demise or known major congenital anomaly. Group B streptococci–positive patients receiving intrapartum antibiotic prophylaxis for this indication were not excluded from participation.
Patients were assigned to receive standard antibiotic prophylaxis with cefazolin, given according to each study site's clinical practice, which was typically before incision and weight-adjusted. Patients with cephalosporin or severe penicillin allergy received the study site-specific alternative (typically clindamycin alone or clindamycin+gentamycin). Patients were randomized to either azithromycin (500 mg) or identical placebo (saline). Study drug was intended to be given up to 1-hour before skin incision and infused over at least 1 hour. Clinical providers gave routine postcesarean care at each center. Study outcomes and other data were abstracted and entered by trained certified study staff.
The primary outcome for this secondary analysis is maternal puerperal infection: a composite of endometritis, wound infection (superficial or deep), or other infections (abdominopelvic abscess, maternal sepsis, pelvic septic thrombophlebitis) occurring up to 6 weeks postpartum. Endometritis was defined as the presence of two or more of the following signs with no other recognized cause: fever greater than 38°C (100.4°F), abdominal pain, uterine tenderness, or purulent drainage from the uterus. Wound infection required the presence of either superficial or deep incisional surgical site infection characterized by cellulitis–erythema and induration around the incision or purulent discharge from the incision site with or without fever and included necrotizing fasciitis (wound hematoma, seroma, or breakdown alone in the absence of the preceding signs did not constitute infection). Abdominal or pelvic abscess required radiologic or surgical confirmation of a purulent fluid collection.
Maternal characteristics examined included demographic, perinatal, and surgical risk factors. These risk factors were collected accordingly: ethnicity was self-reported and then categorized as Hispanic, non-Hispanic black, non-Hispanic white, or other. Body mass index (BMI, calculated as weight (kg)/[height (m)]2 by recorded maternal height and weight at delivery), was categorized according to the National Institutes of Health and World Health Organization obesity classifications7,8: BMI less than 25 as underweight or normal weight, 25–29.9 as overweight, and 30 or greater as obese. Private pay was defined as private insurance compared with those without or with government insurance. Additional maternal characteristics included maternal age at the time of screening, smoking status, primary cesarean delivery, group B streptococci colonization status, diabetes status (further classified into pregestational and gestational diabetes), and steroid use for any reason during pregnancy. Additional perinatal characteristics included intrauterine pressure catheter use, induced labor for any reason, and amnioinfusion. The duration of ruptured membranes was defined as the total number of hours between membrane rupture and newborn delivery. Duration of rupture of membranes was further classified into 6-hour increments: 6 hours or less; 6–12 hours; 12–18 hours; 18–24 hours; and greater than 24 hours. Surgical duration was defined as time from skin incision to skin closure and further categorized as based on quartiles, which corresponded to 38 minutes or less; 38–49 minutes; 49–60 minutes; and greater than 60 minutes.
Other surgical characteristics included skin incision (vertical or transverse), uterine incision (transverse compared with nontransverse), and skin closure (staples and Dermabond [topical skin adhesive] compared with sutures).
Maternal demographic, perinatal, and surgical characteristics were evaluated individually using logistic regression modeling, controlling for randomization to azithromycin. Characteristics identified as statistically significant at a .05 level or by large effect size (odds ratio [OR] >1.5 or <0.7) were included as covariates in a multivariable logistic regression model. Interaction terms between azithromycin use and individual characteristics were evaluated for significance at the .05 level; if significant, the characteristic and its interaction term were included in the multivariable model. A parsimonious regression model was determined using backward selection, whereby statistically nonsignificant (P>.05) characteristics were sequentially removed from the model. The characteristic with the largest P value was eliminated in each iteration until reaching a final, reduced model where the remaining covariates were statistically significant at the .05 level. SAS 9.2 was used for all statistical analysis.
A total of 2,013 women (Table 1) were randomized to azithromycin (n=1,019) or placebo (n=994), of whom 177 (8.8%) were diagnosed with the composite outcome of maternal infection. Maternal age, race–ethnicity, private pay, membrane rupture duration, surgery duration, intrauterine pressure catheter use, vertical skin incision, nontransverse uterine incision, induced labor, and staple skin closures were all significantly associated with maternal infection after controlling for azithromycin dosing at delivery (Table 2). Only staples and topical skin adhesive use had a significant interaction term, which was carried forward to the multivariable model.
In the final parsimonious logistic regression model (Table 2), maternal age, black race–ethnicity, membrane rupture duration greater than 6 hours, surgery duration greater than 49 minutes, and nontransverse uterine incision remained as significant risk factors for maternal infection, even while controlling for azithromycin assignment. Azithromycin was protective against development of maternal infection.
We identified maternal characteristics associated with postcesarean infection after adjusting for azithromycin extended-spectrum antibiotic prophylaxis. Specifically, black race, duration of membrane rupture, and duration of surgery were associated with increased maternal infection risk. Our findings demonstrate areas that should be studied in the future to identify potentially modifiable risk factors remains critical for development of new prevention strategies for cesarean-associated puerperal infection.
Duration of membrane rupture,9,10 increasing maternal BMI,11–13 incision length, and corticosteroid use14 have been previously reported as a risk factor for postcesarean infection. Studies have reported inconsistent results on risk for maternal infection after classical compared with low-transverse uterine incisions.15,16 Consistent with prior studies, we found that the risk for postcesarean maternal infection was 1.9- to 3.4-fold higher as rupture of membranes increased beyond 6 hours, even after adjusting for azithromycin use. In our analysis, neither incision type nor maternal obesity were independent risk factors for maternal infection.
Strengths of this secondary analysis are that the primary study was a large, double-blind multicenter randomized controlled trial implemented in multiple centers. Outcomes were centrally adjudicated limiting internal bias. A study limitation is that women undergoing a scheduled cesarean delivery and those with chorioamnionitis were excluded in the parent trial; thus, our findings cannot be extrapolated to these groups. In addition, we were not able to assess effect of surgical techniques (blunt compared with sharp entry), surgeon experience, or type of skin disinfectant–antisepsis, because these data were not collected at the individual participant level.
Our findings of risk factors for postcesarean infection must be considered in the context of the patients enrolled in the trial. The majority of participating study sites were tertiary care training centers, and almost 50% of patients reported BMIs greater than 30. Thus, the risk factors for infection identified in this secondary analysis may not be generalizable to all U.S. women undergoing cesarean delivery. In addition, very few maternal infections occurred in women with BMIs less than 25, which creates a wide CI around the OR for infection in this group.
Additional intraoperative doses of antibiotics, at intervals one or two times the half-life of the drug, are recommended to maintain adequate levels throughout the length of the procedure.17,18 Thus, a second dose of cefazolin is recommended for surgeries greater than 3 hours.17 However, these recommendations are not based on obstetric data. We found that the risk for maternal infection was higher despite extended-spectrum prophylaxis with azithromycin for surgery duration greater than 49 minutes. Because the half-life of cefazolin is 1.8 hours and the increased plasma volume in pregnancy may result in lower drug concentrations, it may be reasonable to investigate earlier repeat dosing.
In conclusion, although extended-spectrum prophylaxis as given in the primary study reduced postcesarean infections, black women, and those with ruptured membranes greater than 6 hours, or surgery duration greater than 49 minutes remained at significantly higher risk for infection. Further study and consideration is needed to determine whether alternative timing or dosing of antibiotics for patients with these risk factors can further reduce postcesarean infectious morbidity.
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© 2017 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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