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Antibiotic prophylaxis to prevent postoperative infectious morbidity in low-risk elective cesarean deliveries: a prospective randomized clinical trial a

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Fanzhen Hong , Lei Zhang , Yuan Zhang , Wenjuan Sun , Haijie Hong & Yongping Xu

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Department of Obstetrics & Gynecology, The Second Hospital of Shandong University, Jinan, Shandong, People’s Republic of China and b

Center of Evidence-Based Medicine, The Second Hospital of Shandong University, Jinan, Shandong, People’s Republic of China Published online: 03 Jul 2015.

To cite this article: Fanzhen Hong, Lei Zhang, Yuan Zhang, Wenjuan Sun, Haijie Hong & Yongping Xu (2015): Antibiotic prophylaxis to prevent postoperative infectious morbidity in low-risk elective cesarean deliveries: a prospective randomized clinical trial, The Journal of Maternal-Fetal & Neonatal Medicine To link to this article: http://dx.doi.org/10.3109/14767058.2015.1052397

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http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2015 Informa UK Ltd. DOI: 10.3109/14767058.2015.1052397

ORIGINAL ARTICLE

Antibiotic prophylaxis to prevent postoperative infectious morbidity in low-risk elective cesarean deliveries: a prospective randomized clinical trial Fanzhen Hong1, Lei Zhang1, Yuan Zhang2, Wenjuan Sun1, Haijie Hong1, and Yongping Xu1 Downloaded by [Nanyang Technological University] at 04:12 21 August 2015

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Department of Obstetrics & Gynecology, The Second Hospital of Shandong University, Jinan, Shandong, People’s Republic of China and 2Center of Evidence-Based Medicine, The Second Hospital of Shandong University, Jinan, Shandong, People’s Republic of China Abstract

Keywords

Objective: To determine the effectiveness and cost of antibiotic chemoprophylaxis in reducing infectious morbidity in low-risk women undergoing elective cesarean delivery. Methods: A prospective randomized clinical trial was performed at a single tertiary care center in Jinan, China between November 2012 and December 2013. Women were randomized to receive either antibiotic prophylaxis or no antibiotics prior to elective cesarean delivery at term. The infectious morbidity (fever, surgical site infection – SSI, endometritis and urinary tract infection), routine blood tests and hospital costs were measured. Results: Total of 414 women were enrolled into the study; and 202 women received antibiotic chemoprophylaxis and 212 women received no antibiotics. Demographic and clinical characteristics were similar between the two groups. Total of one case in the treatment group and four case in the non-treatment group developed endometritis, giving the postoperative infection rate of 1.2%, which was not statistically significant between the two groups (2 ¼ 1.679, p ¼ 0.195). The secondary outcomes were also not different between the two groups, except the costs of hospitalization, which was significantly higher in the treatment group (p50.001). Conclusions: In low-risk women undergoing elective cesarean delivery at term, prophylactic antibiotics did not reduce the risk of postoperative infection, but significantly increased the cost of hospitalization.

Antibiotics, cesarean delivery, prophylaxis, surgical site infections

Introduction Puerperal infection remains a significant cause of maternal morbidity and mortality worldwide. The United States has a pregnancy-related mortality rate of 14.5 pregnancy-related deaths per 100 000 live births, with approximately 10% due to puerperal infection [1]. Although, the data are limited, these risks are likely higher in developing countries where less attention is paid to sterile technique and where access to antibiotics may be more restricted. A recent publication out of Shanghai, China reported a pregnancy-related mortality rate of 26.7 pregnancy-related deaths per 100 000 live births, with 9.3% due to puerperal infection [2]. Although, all women are at risk for infection in the postpartum period, not all are at equal risk. A number of antepartum and intrapartum risk factors for puerperal infection have been identified. The most important of these is cesarean delivery, which increased the Address for correspondence: Yongping Xu, M.D., Ph.D., c/o Department of Obstetrics & Gynecology, The Second Hospital of Shandong University, No.247, Bei Yuan Main Street, Tian Qiao District, 250033 Jinan, Shandong, People’s Republic of China. Tel: +86 0531 85875023. Fax: +86 0531 88962544. E-mail: [email protected]

History Received 17 January 2015 Revised 14 May 2015 Accepted 14 May 2015 Published online 30 June 2015

risk of puerperal infection by 5–20-fold [3]. For this reason, numerous strategies have been developed in an effort to prevent cesarean-related infectious morbidity, including the administration of prophylactic broad-spectrum antibiotics at the time of cesarean [4–6]. Postoperative infectious morbidity following cesarean delivery can have a variety of sources, including urinary tract infection/pyelonephritis, pneumonia, mastitis, septic pelvic thrombophlebitis and drug fever. But the two most important causes are surgical site infection (SSI) (also referred to as wound infection) and endometritis. SSI refers to infection of the skin and subcutaneous tissue at the surgical incision site and is typically caused by skin flora, such as Streptococcus, Staphylococcus or mixed aerobic/anaerobic bacteria. Endometritis is an infection of the lining of the uterus, which typically results from ascension of vaginal flora through the cervix and into the uterus. Antibiotic prophylaxis given to all women undergoing cesarean delivery has been shown to reduce postoperative infectious morbidity by 60–70% [6,7]. This includes women undergoing cesarean after many hours of labor with ruptured membranes, both of which increase the risk of ascending infection. Whether this

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reduction in infectious morbidity is also true in low-risk women undergoing elective cesarean delivery at term in the absence of labor or ruptured membranes remains contentious [8]. Moreover, increasing concerns about the emergence of resistant strains of common bacteria, the emergence of strains with high virulence and the cost of such antibiotics have resulted in increased scrutiny of the use of antibiotics during pregnancy, particularly in the hospital setting [7]. The purpose of this study is to determine the utility of prophylactic antibiotics in a cohort of low-risk women undergoing elective cesarean delivery at term, including the effect on infectious morbidity and cost.

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Materials and methods This study was carried out in the Department of Obstetrics & Gynecology at the Second Hospital of Shandong University in Jinan, Shandong, China from November 2012 to December 2013. The study was approved by the local Ethics Committee and written informed consent was obtained from all participants. Women presenting for elective cesarean delivery at term were invited to participate. Women were excluded if there was evidence of: (1) labor, (2) ruptured membranes, (3) a preexisting pelvic infection (such as fever, foul vaginal discharge, clinical features suggestive of vaginitis or chorioamnionitis), (4) a preexisting infection in the respiratory or urinary system, (5) placenta previa or placental abruption (since a high blood loss at delivery would be expected to reduce the concentration of the antibiotic and thereby its ability to prevent infection), (6) a preexisting medical or surgical condition that may predispose to infection (such as diabetes, collagen vascular disorder, chronic steroid use, prior bowel surgery), (7) BMI 30 kg/m2 (pre-pregnancy weight) and/or (8) anyone who had received antibiotics in the three days prior to cesarean. The primary outcome measure was infectious morbidity (SSI, endometritis, urinary tract infection). Secondary outcome measures included fever (defined as an axillary temperature 437.5  C), complete blood count parameters (white blood cell count, hematocrit and hemoglobin) and hospital costs. Once the study subjects were identified and consented, they were randomized on the day of surgery using sequentially numbered opaque sealed envelopes containing their group allocation as assigned by the random number table which had been prepared in advance by the study statisticians. Once the envelope was opened, the patient received either: (i) intravenous cefazolin 2 g diluted in 100 mL of 0.9% sodium chloride solution at the time of cord clamping or (ii) no antibiotics. Antibiotics were administered once only. Before the attending doctor order the drugs for the patient, they were blinded to the randomization, but after that, they were not blinded. The surgical procedure was otherwise unaltered. All cases were received combined spinal–epidural anesthesia. All cesarean procedures used a Pfannensteil skin incision and lower uterine segment transverse hysterotomy. The placenta was removed with fundal massage and controlled cord traction. The hysterotomy was closed in two layers using O-vicryl sutures. The peritoneum was closed. The fascia was closed with O-vicryl running sutures. If greater than 2 cm in depth, the subcutaneous tissue was closed

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with interrupted 3-0 plain catgut sutures. The skin was closed with 3-0 plain in a subcuticular fashion. Patients who had unexpected excessive blood loss at the time of cesarean (estimated blood loss 42000 mL) were excluded from the final analysis. Following the surgery, patients were followed clinically. Their axillary temperatures were measured at set intervals (immediately after surgery and at 4, 8, 16, 24, 32, 40, 48 h, 3 and 4 d). Blood samples (for complete blood count) were taken routinely on postoperative day 1, and repeated only if patients were febrile. Urinary catheters were moved on postoperative day 1. A midstream urine sample was collected only in febrile or symptomatic patients. Physical examinations were performed daily and abdominal incisions were graded using a standardized classification system (A: healing without adverse reaction; B: poor healing with evidence of redness, induration, hematoma or effusion, but no discharge; C, grossly infected). Endometritis was diagnosed using standard clinical criteria (fever, abdominal pain, uterine tenderness, vaginal discharge). Antibiotics were given to treat proven infections only. The follow-up time for patients was 42 days after cesarean. One doctor was assigned to all follow-ups. All patients were received a phone call one week after discharge from the hospital, and then 4-week postoperatively follow-up in the outpatient setting. All patients were instructed to call doctor if they develop any signs and symptoms of infection. We performed a power analysis to determine the sample size using fever (an increase in axillary temperature of 0.45  C) as a proxy for postoperative infectious morbidity. With an alpha of 0.05 (one-sided test) and 90% power, a sample size of 177 in each group were needed. Assuming a dropout rate of 10%, we determined that 195 cases in each group (or a total of 390 study subjects) would be needed to show a significant difference between the groups. Results were tabulated and analyzed by using SPSS16.0 statistical software. Descriptive statistics was expressed as mean and standard deviation. The t-test was used to evaluate independent variables that are normally distributed. The Chisquare test was used to compare two rates. p50.05 was used to designate a statistically significant difference.

Results During the 14 months of our study, total scheduled cesarean deliveries were 1129. Of these, 552 patients met our inclusion criteria. Of these, 94 patients declined to join the study; 44 patients were excluded, leaving a total of 414 women in the final analysis (202 in the antibiotic group and 212 in the nonantibiotic group). There were no significant differences between the two groups in terms of the women’s demographic and clinical characteristics (Table 1). In terms of the primary outcome measure, there were no cases of SSI or urinary tract infections in either group. There were totally five cases of endometritis (four in the nonantibiotic group and one in the antibiotic group), giving the postoperative infection rate of 1.2% (5/414), which was not statistically different between the two groups (2 ¼ 1.679, p ¼ 0.195). All of these patients received broad-spectrum antibiotic therapy and their infections were resolved.

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Table 1. Demographic and clinical characteristics. Index Age in years Gestational weeks Parity times Delivery times BMI (before delivery) in kg/m2 Operation time in min Amount of bleeding in mL

Non-antibiotic group (n ¼ 212)

Antibiotic group (n ¼ 202)

t

p value

28.92 ± 3.67 39.08 ± 1.13 2.14 ± 1.11 1.38 ± 0.52 29.42 ± 12.06 53.77 ± 10.45 226.37 ± 133.13

28.91 ± 4.40 39.00 ± 1.49 2.28 ± 1.24 1.43 ± 0.55 30.69 ± 17.92 55.23 ± 13.23 247.80 ± 129.15

0.023 0.583 1.215 0.951 0.829 1.249 1.657

0.982 0.560 0.225 0.342 0.408 0.212 0.098

Data are given as mean ± SEM.

Table 2. Comparison of routine blood tests between the groups.

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Blood count parameter

Non-antibiotic group (n ¼ 212)

Antibiotic group (n ¼ 202)

t

p value

8.4 ± 1.8 9.4 ± 2.5*

8.4 ± 2.0 9.8 ± 2.9#

0.22 1.34

0.83 0.18

6.5 ± 4.8 7.3 ± 2.4*

6.8 ± 7.0 7.9 ± 5.5

0.52 1.13

0.60 0.26

3.8 ± 0.3 3.7 ± 0.5*

3.8 ± 0.4 3.9 ± 2.7

0.72 0.96

0.47 0.34

107.7 ± 11.4 103.5 ± 16.9*

108.0 ± 12.7 103.5 ± 16.7#

0.24 0.02

0.81 0.99

214.8 ± 54.7 229.3 ± 63.7*

217.9 ± 60.3 237.1 ± 62.2#

0.56 1.02

0.58 0.31

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White blood cell count (10 /L) Preoperative Postoperative Neutrophil count (109/L) Preoperative Postoperative Red blood cell count (1012/L) Preoperative Postoperative Hemoglobin concentration (g/L) Preoperative Postoperative Platelet count (109/L) Preoperative Postoperative

Data are given as mean ± SEM. *p50.05, Postoperative compared with preoperative measurements in the non-antibiotic group. p50.05, Postoperative compared with preoperative measurements in the antibiotic group.

#

As regards secondary outcome measures, there was an increase in white blood cell count, neutrophil count and platelet counts on postoperative day 1 compared with bloods drawn prior to the cesarean, but this was not statistically different between the two groups. Similarly, the red blood cell counts and hemoglobin concentrations were decreased following the surgery, but this drop was similar between the two groups (Table 2). As regards temperature, a significant difference was noted at 4 h postoperative with the antibiotic group having a higher mean temperature than the nonantibiotic group (37.2 ± 0.5  C versus 37.0 ± 0.4  C; p ¼ 0.001), but this difference was no longer apparent at 8 h postoperative. This trend is shown in Figure 1. Moreover, this increase in temperature at 4 h did not translate into an increase in overall rates of fever or infectious morbidity. As such, it is of unclear clinical significance. Finally, we compared time and costs of hospitalization between the two groups. As expected, while the time of hospitalization was not different between the two groups (6.0 ± 1.1 versus 6.1 ± 1.1 days; p ¼ 0.68), the cost of medications and the overall cost of the hospitalization were significantly higher in the antibiotic group compared with the non-antibiotic group by about 12% (p50.001), which translates into ¥924 or approximately $147 (Table 3).

Discussion The American College of Obstetricians and Gynecologists (ACOG) recommends the use of a single dose of a narrow spectrum first-generation cephalosporin (cefazolin), or a single dose combination of clindamycin with an aminoglycoside for those with a significant penicillin allergy, as prophylaxis for cesarean delivery [7]. Similar guidelines have been issued by the National Institute for Health and Clinical Excellence (NICE) for use in the UK [9,10]. While broad-spectrum antibiotics have been shown to prevent postoperative infectious morbidity in women after cesarean, antibiotics are not without risks. Allergic reactions to antibiotics, the emergence of antibiotic resistance, increasing costs and potential adverse events suggest that antibiotics can be used only when there is clear evidence of benefit [7,11]. Whether antibiotic chemoprophylaxis is beneficial in healthy women at low risk of infection undergoing elective cesarean delivery prior to labor or rupture of membranes remains controversial [8]. In the current study, total scheduled cesarean deliveries were 1129. Of these, 552 patients (including the 458 recruited cases and 94 rejected cases) met our low risk criteria. The percentage was 48.89%. We randomized 414 healthy women to antibiotic prophylaxis with 2 g cefazolin (202) versus no

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Figure 1. Temperature curve after cesarean delivery.

Table 3. Effect of antibiotic prophylaxis on hospitalization. Characteristics Total costs for hospitalization (CNY) Total cost of medications (CNY) Total time in hospital (days)

Non-antibiotic group (n ¼ 212)

Antibiotic group (n ¼ 202)

t

p value

7546.44 ± 1081.17 1514.56 ± 365.30 6.0 ± 1.1

8469.91 ± 1119.01 2091.83 ± 471.51 6.1 ± 1.1

8.54 13.96 0.42

50.001 50.001 0.68

CNY ¼ Chinese yuan (renminbi); current exchange rate is 1 CNY & $0.16.

antibiotics (212) at the time of elective cesarean delivery. The overall rate of infectious morbidity was low (1.2%) and there was no difference between the two groups. While there was a significant increase in oral temperature 4 h after surgery in those women who received antibiotics, this was transient and likely clinically insignificant. Moreover, it did not translate into a difference in white cell count, wound healing or infection rates. The overall low rate of infection was likely due to the fact that the patients were otherwise healthy, not obese or diabetic, without labor or ruptured membranes and that careful attention was paid to aseptic technique at the time of surgery. In this study, antibiotics were administered at the time of cord clamping, which complied with the Chinese newest guideline on the use of antibiotics for cesarean (2011). While both the ACOG [7] and NICE guidelines [10] recommend that antibiotics should be given within 60 min prior to skin incision, a similar reduction in postoperative infectious morbidity has been documented in patients receiving antibiotics preoperatively or at cord clamping in some metaanalyses [6]. In our study, a significant reduction in hospitalization costs was demonstrated in those women randomized to receive no antibiotic at the time of cesarean, without changing the length of time spent in hospital. Although, the absolute cost reduction may appear modest by US standards (an average of $147 per patient), this represented 12% of the overall cost of hospitalization and, as such, should be viewed as significant in the setting in which this study was conducted. Based on our findings, a large number of women could avoid prophylactic antibiotics for elective cesarean deliveries.

The overall postoperative infection rate in our study population was very low (1.2%), which might be the reason that we did not see the significant reduction of infectious morbidity in the antibiotics treatment group. The other limitation of our study is that the possibility of bias since this was not a totally blinded study. In summary, the results of this prospective randomized clinical study show that, in a cohort of healthy women at low risk of postoperative infectious morbidity undergoing elective cesarean delivery at term, prophylactic broad-spectrum antibiotics did not reduce the risk of postoperative infectious morbidity, but was associated with increased cost.

Acknowledgements The authors would like to thank Dr. Errol R. Norwitz (Chairman, Department of Obstetrics & Gynecology, Tufts Medical Center, Boston, MA, USA) for his assistance in reviewing and editing the manuscript.

Declaration of interest The authors report no declarations of interest. Clinical Trial Number: ChiCTR-OPC-15005817 (see www.chictr.org.cn).

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8. Bagratee JS, Moodley J, Kleinschmidt I, Zawilski W. A randomized controlled trial of antibiotic prophylaxis in elective caesarean delivery. Br J Obstet Gynaecol 2001;108:143–8. 9. Gholitabar M, Ullman R, James D, Griffiths M; Guideline Development Group of the National Institute for Health and Clinical Excellence. Caesarean section: summary of updated NICE guidance. BMJ 2011;343:d7108. 10. National Institute for Health and Clinical Excellence. Caesarean section (update). (Clinical guideline 132). 2011. Available from: http://guidance.nice.org.uk/CG132 [last accessed 22 Dec 2014]. 11. Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 2008;372:1319–27.

Antibiotic prophylaxis to prevent postoperative infectious morbidity in low-risk elective cesarean deliveries: a prospective randomized clinical trial.

To determine the effectiveness and cost of antibiotic chemoprophylaxis in reducing infectious morbidity in low-risk women undergoing elective cesarean...
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