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Research www. AJOG.org OBSTETRICS Administration of cefazolin prior to skin incision is superior to cefazolin at cord clamping in preventing postcesarean infectious morbidity: a randomized, controlled trial Scott A Sullivan, MD, MSCR; Triz Smith, MD; Eugene Chang, MD; Thomas Hulsey, ScD; J. Peter Vandorsten, MD; David Soper, MD OBJECTIVE: The objective of the study was to determine whether the administration of cefazolin prior to skin incision was superior to administration at the time of umb
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  OBSTETRICS Administration of cefazolin prior to skin incision is superior tocefazolin at cord clamping in preventing postcesareaninfectious morbidity: a randomized, controlled trial Scott A Sullivan, MD, MSCR; Triz Smith, MD; Eugene Chang, MD; Thomas Hulsey, ScD; J. Peter Vandorsten, MD;David Soper, MD OBJECTIVE:  The objective of the study was to determine whether theadministration of cefazolin prior to skin incision was superior to ad-ministration at the time of umbilical cord clamping for the preventionof postcesarean infectious morbidity. STUDY DESIGN:  This was a prospective, randomized, double-blind,placebo-controlled trial. Study subjects received cefazolin 15-60 min-utes prior to incision and controls received cefazolin at the time of cordclamping. The occurrence of endomyometritis, wound infection, totalinfectious morbidity, and neonatal complications were compared. RESULTS:  There were 357 subjects enrolled. No demographic differ-ences were observed between groups. There were decreased total in-fectious morbidity in the study group (relative risk [RR]  0.4, 95%confidence interval [CI] 0.18 to 0.87), decreased endometritis (RR  0.2, 95% CI 0.15 to 0.94). No increase in neonatal sepsis ( P   .99),sepsis workups ( P   .96), or length of stay ( P   .17) was observed. CONCLUSION:  Administration of prophylactic cefazolin prior to skinincision resulted in a decrease in both endomyometritis and total post-cesarean infectious morbidity, compared with administration at thetime of cord clamping. This dosing did not result in increased neonatalseptic workups or complications. Key words:  antibiotic prophylaxis, cesarean delivery,endomyometritis Cite this article as: Sullivan SA, Smith T, Chang E, et al. Administration of cefazolin prior to skin incision is superior to cefazolin at cord clamping inpreventing postcesarean infectious morbidity: a randomized, controlled trial. Am J Obstet Gynecol 2007;196;455.e1-455.e5. C esarean delivery is the most com-monly performed surgery in theUnited States, with nearly 1.2 millionprocedures performed in 2004. 1  Infec-tious morbidity, consisting primarily of endomyometritis and wound infection,remains a leading cause of postoperativecomplications. 2  Estimates of postcesar-ean infection rates range from 7% to20%, depending on demographic andobstetric variables. 3,4  Infection followingcesarean delivery results in not only in-creased hospital stay but also increasesthecostofcare.Forexample,diagnosingandtreatingasinglecaseofendometritisis estimated to cost $815. 5 Prophylactic antibiotics can reducethe incidence of postcesarean infectiousmorbidity by as much as 75%. 6  This risk reduction is observed in both plannedand emergent cesareans. 7,8  First-genera-tion cephalosporin antibiotics are themost commonly used agents and areusually administered following delivery of the infant after the cord is clamped. 9 Neither the use of broad-spectrum anti-microbials nor the administration of ad-ditional doses postoperatively has beenshown to be superior to a single-dosecephalosporin regimen. 10,11 Optimal timing for prophylactic anti-biotic administration is based on animalstudies that demonstrate a maximumprotective effect when adequate tissueantibiotic levels are present prior to bac-terial contamination. 12  However, con-cerns about neonatal exposure to antibi-otics and the potential effect on aneonatalsepsisworkuppromptedobste-tricians to delay the administration untilthe time of umbilical cord clamping. 13 Inaddition, there is concern regarding thepotential selection of resistant patho-gens, especially Escherichia coli . 14  Thereis no prospective evidence to supportthese concerns. A recent randomizedtrialfoundnodifferenceinneonatalsep-sis, sepsis workups, or neonatal inten-sive care unit (NICU) admissions be-tween groups administered prophylacticantibiotics preoperatively or at cordclamping. 15 In the majority of surgical proceduresthat require prophylaxis, antibiotics areusuallyadministeredpriortotheskinin-cision. 16  Delay in administration hasbeen associated with increased surgical From the Departments of Obstetrics/Gynecology (Drs Sullivan, Smith,Chang, Vandorsten, and Soper) andBiostatistics, Bioinformatics, andEpidemiology (Dr Hulsey), MedicalUniversity of South Carolina, Charleston,SC 29425. Presented at the 27th Annual Clinical Meetingof the Society for Maternal-Fetal Medicine,San Francisco, CA, Feb. 5-10, 2007.Received Dec. 8, 2006; revised Jan. 25,2007; accepted Mar. 5, 2007.Reprints: Scott A Sullivan, MD, MedicalUniversity of South Carolina, 96 JonathanLucas Street, Charleston, SC 29425;sullivas@musc.edu.Supported by the Department of Obstetricsand Gynecology Research Foundation,Medical University of South Carolina.0002-9378/$32.00© 2007 Mosby, Inc. All rights reserved.doi: 10.1016/j.ajog.2007.03.022 Research  www. AJOG .org  MAY 2007  American Journal of Obstetrics &  Gynecology  455.e1  site infection risk. 17  Such data suggest apotential benefit of preoperative antibi-otic dosing with cesarean procedures.There are limited data to address thetiming of cesarean antibiotic prophy-laxis. In a small randomized trial [n  90], Wax et al 18  concluded that there wasnodifferenceininfectiousmorbiditybe-tweenpreoperativeantibioticsandthosegiven at cord-clamp. Fejgin et al 19  re-porteddecreasedwoundinfections( P   .008) in a prospective trial (n    435)with use of preoperative antibiotic pro-phylaxis. More recently Thigpen et al 15 demonstrated a decrease in total infec-tious morbidity with preoperative anti-biotics but not specifically with the out-comes of endomyometritis or woundinfection.A Cochrane database review from2002 concluded that an adequately powered randomized trial was neededto address this issue. 9  To this end, weperformed a prospective, double-blinded, randomized clinical trial todetermine whether antibiotic prophy-laxis administered preoperatively wasmore effective in preventing infectiousmorbidity following cesarean delivery than administration following cordclamp. M ATERIALS AND  M ETHODS The Institutional Review Board at theMedical University of South Carolina(MUSC)andtheresearchdivisionoftheDepartment of Obstetrics and Gynecol-ogy approved this project (approval#11120, January 2003). In addition, thetrial was registered with the federal gov-ernment and posted on the ClinicalTrials.gov (Clinical Trials.gov ) clearing- house (NCT00330278).This was a randomized, double-blinded, placebo-controlled trial. Totalpostcesarean infectious morbidity wasthe primary outcome. Power was calcu-latedaprioriusingMUSCinfectioncon-trol data, which indicated a historicalpostcesareaninfectionincidenceof17%.Using a power of 0.80 and an alpha of 0.05, 174 subjects per arm were calcu-lated to be necessary to detect a 50% de-creaseinoverallinfectiousmorbidityforsubjects given preoperative antibioticprophylaxis. Primary and secondary outcomes were defined prior to the be-ginning of enrollment.Subjects were eligible for the trial if they were older than 24 weeks estimatedgestationalageandrequiredcesareande-livery. Exclusion criteria included ceph-alosporin allergy, age less than 18 weeks,exposuretoanyantibioticagentwithin1week of delivery, or the need for emer-gent cesarean delivery. Following in-formed consent, simple randomizationusing a random number table was per-formed by the investigational pharmacy staff. Consolidated Standard of Report-ing Trials (CONSORT) standards forrandomization were followed.Infusion bags were prepared in accor-dance with randomization and the bagslabeled as A or B. One bag contained 1 gof cefazolin mixed with 50 cc of normalsaline. The other bag contained only 50cc of normal saline. Bag A was adminis-teredatleast15minutespriortoskinin-cision but no more than 60 minutes be-fore. This interval was chosen based onpreviously published maternal pharma-cokinetics of cefazolin. 20  Bag B was ad-ministered at the time of cord clampingby the anesthesia staff present for theprocedure. Providers and patients wereblinded to the contents of the bags untilthe conclusion of the study.Subjects were followed through theirhospital course and up to the 6-week postpartum visit. Infectious morbidity was documented using established clini-cal criteria. 21 Endomyometritis was diagnosed if maternal fever greater than 100.4°F on 2separate occasions along with uterinefundaltenderness,tachycardia,orleuko- FIGURE Subject flow through the cefazolin trial TABLE 1 Demographic variable comparison VariableStudy group(n  175)Control group(n  182)  P   value Maternal age 28.3  6.1 28.3  6.0 1.0 .............................................................................................................................................................................................................................................. Maternal weight 225.3  144.5 228.1  152.9 .85 .............................................................................................................................................................................................................................................. Parity 1.4 1.2 .07 .............................................................................................................................................................................................................................................. Race (C/AA/H/other)* 72/77/21/5 82/65/31/4 .45 .............................................................................................................................................................................................................................................. Medicaid   87 (49%) 82 (45%) .61 .............................................................................................................................................................................................................................................. Premature delivery (less than 37 wks) 30 (17%) 46 (25%) .08 .............................................................................................................................................................................................................................................. * Caucasian, African American, Hispanic, other. Research  Obstetrics  www.AJOG.org  455.e2  American Journal of Obstetrics &  Gynecology  MAY 2007  cytosis. Wound infection was diagnosedif there was purulent discharge, ery-thema, and induration of the incisionsite. Hematomas, seromas, or woundbreakdowns in the absence of previously discussed signs were not consideredwoundinfections.Pyelonephritiswasdi-agnosed by maternal temperature, flank pain, and urine culture showing morethan100,000coloniesofagramnegativeuropathogen.Neonatal sepsis was diagnosed by apositive blood culture. Organism, anti-biotic resistances, and clinical coursedata were recorded. Length of stay, ad-mission status, and decision to under-takeasepsisworkupweredeterminedby the staff neonatologists who were alsoblinded to group assignment.Study data were analyzed using SPSSversion 12.0 (Chicago, IL). Normality of the data was tested with Kolmogorov-Smirnov and    2 goodness-of-fit testswhen appropriate.    2 comparisons wereperformed for categorical variables andrelative risks (RR) with 95% confidenceintervalwerecalculated.Analysisofvari-ance testing was performed when multi-ple groups of categorical variables wereencountered. Student  t   tests were usedforcontinuousvariableanalysis.Alogis-tic regression was also performed to ob-tain adjusted relative risk values. A  P  value of less than .05 was considered sta-tistically significant. R  ESULTS There were 367 subjects consented forthis trial. Ten subjects did not completerandomization because of either medi-cation delay, previously undiscoveredexclusion criteria, or development of aneed for emergent cesarean delivery.Threehundredfifty-sevensubjectscom-pleted randomization and received thestudy medications. Eight subjects werelostto6-weekpostpartumfollow-upbutwere included in the final analysis be-cause their hospital course data wereavailable. The Figure illustrates the ran-domization scheme. Completion of thetrial was accomplished in 26 months.Table 1 summarizes the demographicvariablesmeasuredinthestudyandcon-trol groups. There were no significantdifferences observed between the study and control groups. Table 2 illustratesthe clinical obstetric variables measuredbetween the two groups. There wereagainnosignificantdifferencesobservedbetween the preoperative or cord-clamping groups. There were no cases of maternal anaphylaxis or other adverseevents related to cefazolin use reportedduring the trial.Infectious morbidity outcomes aresummarized in Table 3. There were more cases of endomyometritis in the controlgroup (n  10) than in the study group(n  2), and this difference was statisti-cally significant (RR   0.2, 95% confi-dence interval [CI] 0.15 to 0.94). Therewere also more cases of wound infectioninthecontrolgroup(n  10)thaninthestudy group (n  5); however, this dif-ference did not reach statistical signifi-cance (RR   0.52, 95% CI 0.18 to 1.5).Seven cases of hematomas or seromasthat did not meet criteria for wound in-fections were noted. There was 1 case of pyelonephritis in the control group and1 case of pneumonia in the study group.Overall, total infectious morbidity in thecontrol (n  21) group was higher thanin the study group (n  8), and this dif-ference was statistically significant (RR   0.4, 95% CI 0.18 to 0.87). A logisticregression model was performed to ad- just for 6 demographic and clinical vari-ables that are associated with infectiousrisk and were noted to trend toward thecontrol group. The adjusted odds ratios TABLE 2 Obstetric variable comparisons VariableStudy group(n  175)Control group(n  182)  P   value Indication for C/S (Arr, NRFS, NL, other) 50/36/51/38 54/39/44/45 .68 .............................................................................................................................................................................................................................................. Diabetes 17 (10%) 29 (16%) .10 .............................................................................................................................................................................................................................................. Multiple gestation 12 (7%) 19 (10%) .31 .............................................................................................................................................................................................................................................. Preeclampsia 18 (10.3%) 25 (13.7%) .4 .............................................................................................................................................................................................................................................. Estimated blood loss (cc) 878  112 895  127 .18 .............................................................................................................................................................................................................................................. ROM time (h) 6.1  5.0 6.8  5.4 .20 .............................................................................................................................................................................................................................................. Internal monitors 23 (13%) 25 (13.7%) .87 .............................................................................................................................................................................................................................................. Subcutaneous drain 6 (3.4%) 13 (7%) .12 .............................................................................................................................................................................................................................................. Operative time (min) 45.3  13.6 48  14.9 .07 .............................................................................................................................................................................................................................................. Arr  , arrest disorders;  C/S  , cesarean section;  NRFS  , nonreassuring fetal status;  NL , not laboring;  ROM  , rupture of membranes. TABLE 3 Infectious morbidity Summary of postcesarean infectious morbidity observedOutcomeStudy group(n  175)Control group(n  182)Relative risk 95% CIAdjusted OR95% CI Endomyometritis 2 (1%) 10 (5%) 0.2 (0.2 to 0.94) 0.22 (0.05 to 0.9) ................................................................................................................................................................................................................................................................................................................................................................................ Wound infections 5 (3%) 10 (5%) 0.52 (0.18 to 1.5) 0.4 (0.1 to 1.3) ................................................................................................................................................................................................................................................................................................................................................................................ Total infectious morbidity 8 (4.5%) 21 (11.5%) 0.4 (0.18 to 0.87) 0.35 (0.14 to 0.82) ................................................................................................................................................................................................................................................................................................................................................................................ OR  , odds ratio.  www.AJOG.org   Obstetrics  Research MAY 2007  American Journal of Obstetrics &  Gynecology  455.e3  are reported in Table 3 and were not sig- nificantly different from the crude rela-tive risks.Theneonataloutcomevariablesareil-lustrated in Table 4. There were no sig-nificant differences observed betweenthe2groupsinneonatalsepsis( P   .99),NICUadmission( P   .4),totallengthof stay ( P   .17), metabolic acidosis ( P   .88), or sepsis workups ( P   .96). Therewere significantly fewer NICU admis-sion days in the preoperative antibioticgroup ( P   .01).In addition, the neonatal cases of sep-sis did not demonstrate different caus-ativeorganismsbetweengroupsoranin-creased incidence of antibiotic resistantorganisms. Table 5 lists the causative or- ganisms and their resistance profiles. C OMMENT Postcesarean infectious morbidity iscommon and costly and rarely can leadto life-threatening conditions such asnecrotizing fasciitis. 22  Cesarean infec-tious rates have been shown to behigher than in comparable surgicalprocedures. 23  Whereas it is impossibleto compare outcomes across differentprocedures, 1 possible explanation forthis difference is the common practiceof delaying prophylactic antibioticsuntil cord clamping for neonatal con-cerns. The neonatal concerns oftencited to justify this practice have notbeen validated by prospective trials.On the contrary, previous studies havedemonstrated no increase in neonatalsepsis or sepsis workups when prophy-lactic antibiotic are given preopera-tively. 15  Our study confirms these find-ings and, in fact, revealed a trendtoward decreased NICU admissionand length of stay in the preoperativeantibiotic group. We do not believethis is causative but merely more evi-dence of no neonatal harm.Ourstudyconfirmsthefindingsintheanimal models of antibiotic prophylaxisof Burke. 12  He demonstrated that thesize of   Staphylococcus -induced lesionswere reduced when antibiotic tissue lev-elswerepresentbeforebacterialcontam-ination.Itisprobablethatitisthismech-anism that explains the benefit of preoperative antibiotics. Waiting untilcord clamping to administer antibioticsallows bacterial contamination of theuterus and subcutaneous tissues well be-fore adequate tissue levels can beachieved.Strengths of this study include its de-sign as a randomized, double-blind, pla-cebo trial. The a priori power was TABLE 4 Neonatal outcomes VariableStudy group(n  185)Control group(n  194)  P   value Birthweight 3034  732 2947  989 .35 .............................................................................................................................................................................................................................................. Gestational age 37.5  2.8 37  3.1 .11 .............................................................................................................................................................................................................................................. Sepsis 6 (3%) 7 (3.6%) .99 .............................................................................................................................................................................................................................................. Septic workup 35 (19%) 36 (18.5%) .96 .............................................................................................................................................................................................................................................. NICU admission 25 (13.5%) 33 (17%) .40 .............................................................................................................................................................................................................................................. Intermediate admission 35 (19%) 32 (16.4%) .65 .............................................................................................................................................................................................................................................. NICU days 14.2  15.8 19.7  24.9  .01 .............................................................................................................................................................................................................................................. Length of stay 6.6  9.9 8.5  15.8 .17 .............................................................................................................................................................................................................................................. pH less than 7.1 10 (5%) 12 (6%) .88 TABLE 5 Neonatal sepsis organisms Subject Treatment group Cultured organism Day of life Resistances 1 1  Staphylococcus aureus   14 None ................................................................................................................................................................................................................................................................................................................................................................................ 2 1  Staphylococcus aureus   24 Methicillin ................................................................................................................................................................................................................................................................................................................................................................................ 3 2  Enterobacter cloacae   14 None ................................................................................................................................................................................................................................................................................................................................................................................ 4 2  Staphylococcus aureus   3 Methicillin ................................................................................................................................................................................................................................................................................................................................................................................ 5 2  Enterobacter cloacae   7 None ................................................................................................................................................................................................................................................................................................................................................................................ 6 1  Escherichia coli   10 Ampicillin ................................................................................................................................................................................................................................................................................................................................................................................ 7 2  Pseudomonas aeriginosa   35 None ................................................................................................................................................................................................................................................................................................................................................................................ 8 2  Staphylococcus aureus   26 Methicillin ................................................................................................................................................................................................................................................................................................................................................................................ 9 1  Serratia marcesens   3 None ................................................................................................................................................................................................................................................................................................................................................................................ 10 2  Staphylococcus aureus   11 Methicillin ................................................................................................................................................................................................................................................................................................................................................................................ 11 1  Staphylococcus aureus   11 None ................................................................................................................................................................................................................................................................................................................................................................................ 12 2  Staphylococcus aureus   5 None ................................................................................................................................................................................................................................................................................................................................................................................ 13 1  Klebsiella pneumoniae   23 None ................................................................................................................................................................................................................................................................................................................................................................................ Treatment groups: 1, study group; 2, control group. Research  Obstetrics  www.AJOG.org  455.e4  American Journal of Obstetrics &  Gynecology  MAY 2007

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