Health care-associated infections occurring in acute care hospitals in the United States included 157,500 cases of surgical site infection in 2011.1 Each surgical site infection after cesarean delivery may add $3,500 in medical costs.2 Surgical site infections have been described as high as 15% within the first 30 days after cesarean delivery.3,4 3,4 A reduction in surgical site infection rates for clean-contaminated surgery when chlorhexidine–alcohol was used as the preoperative skin cleanser instead of a povidone–iodine solution was reported by Darouiche et al.5 In a review of cesarean delivery techniques, one of the most common clean-contaminated surgical procedures, there was no clear recommendation for skin preparation to reduce morbidity.6
Two of the most commonly used skin preparation solutions for cesarean delivery are chlorhexidine and povidone–iodine. Chlorhexidine begins to be effective in decreasing the bacterial load 2 minutes after application but reaches maximum effectiveness at 1 hour.7 Chlorhexidine also must be allowed to dry completely. Povidone–iodine solution has been reported to be completely effective within 4 minutes of application but its effectiveness may wane over time.8 Alcohol has an immediate but brief germicidal action. Both chlorhexidine and povidone–iodine are commercially available in combination with isopropyl alcohol in applicators for use in skin preparation for prevention of surgical site infections associated with cesarean delivery.
Iodine and chlorhexidine have different cellular targets and different mechanisms of action. These differences may prove beneficial when using these two antiseptics in combination.9 We compared skin preparation solutions povidone–iodine with alcohol, chlorhexidine with alcohol, and both (povidone–iodine with alcohol and chlorhexidine with alcohol) applied sequentially to estimate their relative effectiveness in prevention of surgical site infections.
MATERIALS AND METHODS
Women were enrolled into this prospective, randomized clinical trial at two Montefiore Medical Center labor and delivery units. The institutional review board approved the study protocol and written informed consent was obtained from all women before enrollment. Women were eligible if they reached 37 weeks of gestation based on best obstetric estimate and were undergoing scheduled or nonemergent (eg, for labor abnormalities) cesarean delivery. Patients were excluded if they had a urogenital tract infection within 2 weeks of delivery, a 2-week or more history of steroid delivery during their pregnancy, of if they were younger than 18 years old.
Eligible women were randomly allocated to one of the three surgical skin preparation solution groups: povidone–iodine with alcohol (PA group); chlorhexidine with alcohol (CA group); or combination of povidone–iodine with alcohol and chlorhexidine with alcohol used together (povidone–iodine with alcohol was applied first followed immediately by the chlorhexidine with alcohol; BOTH group). Randomization was computer-generated through www.randomization.com with alternating block sizes of six and 12. The randomization allocation was concealed in identical, opaque, sequentially numbered sealed envelopes. The numbered envelope was opened after consent and before the patient entered the operating room for the cesarean delivery. All patients received preoperative prophylactic antibiotics within 1 hour of skin incision. All patients had regional anesthesia, a spinal, epidural, or combined spinal and epidural. The selected skin preparation was applied according to the manufacturer with a minimum of four completed minutes drying time before surgical drapes were placed. If the patient was randomized to the BOTH group, the 4-minute drying time started after application of the second preparation, chlorhexidine with alcohol. Cesarean delivery techniques were according to the attending surgeons' preference.
Demographic features, medical comorbidities, and perioperative factors known to be risk factors for surgical site infections were recorded. Operative time was categorized into a dichotomous variable—above or below 2 standard deviations of the mean of the cohort, which was 79 minutes. Estimated blood loss was also categorized as a dichotomous variable—above or below 1,000 mL.
The primary outcome of surgical site infection was assessed by review of the patient's 2- and 6-week postcesarean outpatient visit and by trial coinvestigator telephone contact at approximately 42 days postcesarean delivery. Surgical site infection was defined according to Horan et al and the Centers for Disease Control and Prevention.10,11 10,11 On telephone interview the patient were asked about any wound complication or infection within the 30 days after discharge from the hospital where the cesarean delivery was performed. A surgical site infection outcome was defined as the patient reporting the requirement of antibiotic use for a wound infection or documented wound infection in the medical record at the outpatient visit within 30 days of discharge.
We assumed a baseline incidence in surgical site infections of 12% and anticipated a 50% reduction in surgical site infections for the combination group relative to either of the single preparation groups.3,12,13 3,12,13 3,12,13 Based on this, 430 women in each group would be enrolled with a power of 0.90 and an α of 0.05 to detect a statistically significant difference in surgical site infections. To account for the possibility of up to a 15% dropout or loss to follow-up, we set a target enrollment of 494 for each of the groups.
Maternal demographics and clinical characteristics were described by study group using mean and standard deviation, median and range, or number and frequency for continuous and categorical variables, respectively. Differences in patient characteristics by skin preparation group were assessed using analysis of variance for continuous variables or the Kruskal-Wallis test for nonnormal distributions and Pearson's χ2 or Fisher's exact test for categorical variables as appropriate. The primary aim of the study was to compare the proportion of surgical site infections of the combination group with the control group (those treated with either iodine or chlorhexidine but not both) using a χ2 test. The odds ratio (OR; with 95% confidence interval [CI]) was accessed for surgical site infections. A global test of differences in surgical site infections between the groups was also performed, a χ2 test of independence (ie, three×two contingency table).
Univariable and multivariable logistic regression models were fit to assess associations between skin preparation groups and additional risk factors for surgical site infections. The skin preparation group was a priori included in the multivariable model and other risk factors were included if they had a P<.1 on univariable analysis. Surgical skin preparation was maintained as the primary factor of interest and additional factors that were considered in the model included age, gestational age, site, number of prior cesarean deliveries, indication for delivery, surgical time, estimated blood loss, preoperative and postoperative hematocrit, closure, subcutaneous reapproximation, chronic hypertension, preeclampsia, pregestational or gestational diabetes, chorioamnionitis, and transfusion. Probability for entry and removal from the model were P=.2 and P=.3, respectively. All P values were two-sided and a P value <.05 was deemed statistically significant. Statistical analysis was performed using STATA 13.0. The study was approved by the institutional review board and registered with ClinicalTrials.gov number NCT01870583.
From January 2013 through July 2014 a total of 1,404 patients were randomly assigned to one of the three study groups: 463 to the PA group, 474 to the CA group, and 467 to the BOTH group. Of the 1,404 patients, eight women (less than 1%) were protocol breaches: four patients were less than 37 weeks of gestation at the time of delivery, one patient had a vaginal birth, one patient had an active urinary tract infection, one received the wrong preparation solution, and one patient was using chronic steroids (Fig. 1). None of these women had a surgical site infection. Overall, 97% (1,367/1,404) of the women recruited completed 30 days follow-up required in the definition of surgical site infection.
Randomization resulted in groups that were demographically comparable with similar risks for surgical site infection (Table 1). The overall rate of surgical site infection for the study was 4.3% (60/1,404) and was similar among groups (4.6% in PA group, 4.5% in the CA group, and 3.9% in the BOTH group; P=.85; Table 2). In classifying the surgical site infections, 76% (46/60) were superficial site infection, 12% (7/60) were deep space infections, and 12% (7/60) were organ space infections. Again there were no differences across groups in the type of surgical site infection.
In both univariate and multivariate analysis, there were no differences among the three groups in the incidence of surgical site infection (CA group OR 0.99, CI 0.53–1.84, BOTH group OR 0.85, CI 0.44–1.61, PA group 1.00 reference) (Table 3). In univariate analysis the following risk factors for surgical site infection were identified: body mass index (BMI, calculated as weight (kg)/[height (m)]2) (OR 1.05, CI 1.02–1.09), preeclampsia (OR 3.72, CI 1.90–7.27), blood transfusion (OR 2.75, CI 1.20–6.30), and estimated blood loss greater than 1,000 mL (OR 3.24, CI 1.82–5.76) (Table 3). Scheduled cesarean deliveries, either primary (OR 0.31 CI 0.12–0.79) or repeat (OR 0.34, CI 0.18–0.63), were negatively associated with surgical site infection. In multivariate analysis, BMI (OR 1.04, CI 1.00–1.08), estimated blood loss greater than 1,000 mL (OR 2.44, CI 1.29–4.62), and preeclampsia (OR 2.61, CI 1.25–5.44) remained risk factors for surgical site infection (Table 3). Historical risk factors, pregestational diabetes mellitus (P=.54), gestational diabetes mellitus (P=.62), and chorioamnionitis (P=.55) were not risk factors for development of surgical site infection.
We also performed subgroup analysis in further evaluation of potential associations of skin preparation solution and surgical site infection. There were 423 (30.1%) women who underwent a nonscheduled cesarean delivery, labor before cesarean delivery, and there were similar surgical site infection rates among groups (Table 4). Additionally, a subanalysis was performed based on BMI with 283 (20.2%) of women meeting criteria for class III obesity (Table 5). In class III obesity, the use of sequential application of both solutions demonstrated a reduction in surgical site infection in multivariate regression analysis (OR 0.17, CI 0.04–0.77) (Table 6).
There were no differences in surgical site infection rates when comparing skin preparation solutions povidone–iodine with alcohol or chlorhexidine with alcohol to the sequential combination of povidone–iodine with alcohol and chlorhexidine with alcohol. The study of topical antimicrobial solutions before cesarean delivery has been limited to small prospective and retrospective studies. Guidance has followed randomized controlled trials and retrospective cohorts in clean-contaminated abdominal surgery.5,14 5,14 Dahlke et al systematically reviewed cesarean delivery and a recent Cochrane review stated that the quality of evidence surrounding preoperative skin preparation was low.6,15 6,15 Chlorhexidine with alcohol has been suggested as a superior agent; however, chlorhexidine with alcohol has not been compared with iodine with alcohol in a meaningful way.15 Our evaluation has removed the alcohol bias by comparing currently commercially available agents containing alcohol.
The limitations of our study include an unanticipated low incidence of surgical site infections. The observed 4.3% overall rate of surgical site infections was lower than we anticipated. At this rate, a sample size of 3,000 would be required to detect a 50% reduction in surgical site infections. An additional limitation is that our study specifically excluded emergency cesarean deliveries, principally because of the lack of informed consent discussions as well as the potential fire hazard presented by the alcohol component if not allowed adequate time to evaporate before surgery.
We identified several independent risk factors for surgical site infections, which is consistent with prior published studies including obesity, preeclampsia, blood loss of greater than 1,000 cc, blood transfusion, surgical time, and dysfunctional labor.12,16–19 12,16–19 12,16–19 12,16–19 12,16–19 Risk factors that were not associated with surgical site infections in this trial that have been previously reported as significant included: pregestational and gestational diabetes mellitus, and chorioamnionitis.20 Our study's incidence of chorioamnionitis does not differ from other published reports, but chorioamnionitis is treated aggressively at our center with continued use of intravenous antibiotics after cesarean delivery until afebrile for 24 hours and clinically no uterine tenderness on examination.21 A scheduled cesarean delivery was negatively associated with the risk of surgical site infection.
In summary, our study provides no support for a particular method of skin preparation before cesarean delivery. In class III obesity, the use of sequential application of both solutions may have potential benefit, which requires further investigation.
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© 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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