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Received Date : 18-May-2014 Revised Date : 14-Sep-2014 Accepted Date : 22-Sep-2014 Article type : Main Research Article
Single-dose compared to multiple day antibiotic prophylaxis for cesarean section in low-resource settings, a randomized controlled, non-inferiority trial Running head: Antibiotic prophylaxis for cesarean section. Esther H.M.N. Westen1,2, Pascal R. Kolk1,3, Christine L. van Velzen4, Regine Unkels5,6,
Nicholaus S. Mmuni5, Alex D. Hamisi5, Ritha E. Nakua5, Anne L.M. Vlek7 and Heleen J. van
Beekhuizen5,8.
1
Mkomaindo District Hospital, Masasi, Tanzania.
2
Department of Obstetrics and Gynecology, Máxima Medical Centre, Veldhoven, the
Netherlands.
3
Department of Obstetrics and Gynecology, Radboud University Medical Centre, Nijmegen, the
Netherlands. 4
Department of Obstetrics and Gynecology, VU University Medical Centre, Amsterdam, the
Netherlands. 5
Sokoine Regional Hospital, Lindi, Tanzania.
6
Liverpool School of Tropical Medicine, Liverpool, UK
7
Department of Medical Microbiology, Diakonessen Hospital, Utrecht, the Netherlands.
8
Department of Obstetrics and Gynecology, Erasmus Medical Centre, Rotterdam, the
Netherlands.
Corresponding author: Esther Westen
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/aogs.12517 This article is protected by copyright. All rights reserved.
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Department of Obstetrics and Gynecology, Máxima Medical Centre, P.O. Box 7777, 5500 MB Veldhoven, The Netherlands. E-mail: [email protected].
Conflicts of Interest Statement All authors state explicitly that there are no conflicts of interest.
Abstract
Objective: To investigate the efficacy of a single prophylactic dose of ampicillin combined with
metronidazole to prevent post-cesarean section infections compared with a multiple day regimen in lowresource settings. Design: An evaluator-blinded randomized, controlled, non-inferiority trial. Setting:
Two rural hospitals in Tanzania. Population: Of 181 enrolled eligible women with an indication for cesarean section, information on 176 was analyzed by intention-to-treat. Methods: The women were randomly assigned to either the intervention group who received a single dose of ampicillin and metronidazole, or to the control group who received a multiple day regimen of ampicillin/amoxicillin and metronidazole. Main outcome measures: The primary outcome was maternal post-cesarean infection. Secondary outcomes were severity of these infections, other maternal complications, and the duration of hospital stay. Results: In the intervention group (n = 89), six women (6.7%) developed a wound infection compared to nine (10.3%) in the control group (n = 87) (difference 3.60; 95% CI -4.65 to 11.85) (p = 0.40). Conclusions: A single dose of prophylactic ampicillin and metronidazole is equally effective as a multiple day regimen in preventing post-cesarean wound infections in low-resource settings, therefore it can be considered as a good strategy in low-resource settings. The reduced quantity of prophylactic antibiotics will reduce costs without increasing the risk of maternal infection.
Keywords Antibiotic prophylaxis, cesarean section, infection, ampicillin, metronidazole, low-resource setting, Tanzania, maternal morbidity.
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Key Message Cesarean section is a major risk for postpartum infection and the use of antibiotic prophylaxis has been a major contributor in lowering this risk. In many countries there is no consensus on which antibiotic regimen to use, particularly in low-resource settings where a multiple day regimen is common practice. This randomized controlled multicenter trial shows that a single dose of prophylactic ampicillin and metronidazole is as effective as multiple doses in preventing post-cesarean wound infections in a low-resource setting.
Introduction
Cesarean section is a major risk factor for postpartum infection, with a possible 20-fold increase in infection compared to a vaginal delivery (1-3). Infectious complications that occur after cesarean delivery are an important cause of maternal morbidity and mortality especially in lowresource settings. Known risk factors for post-cesarean infection include emergency delivery, low socio-economic status, long duration of labor and ruptured membranes, obstructed labor, inadequate skills or technique of the surgeon, amongst others (1,3-8). Although general rules to prevent surgical infection, such as good surgical technique and antisepsis are important, the use of antibiotic prophylaxis has been a major contributor in reducing the incidence of post-cesarean infection, and may reduce the incidence by up to two-thirds (4,5,8-11).
In many countries there is no consensus on which antibiotic regimen to use, especially in lowresource settings where surgery is often performed under poor aseptic conditions (12). A
common treatment in Sub-Saharan Africa, is a multiple day regimen of ampicillin and metronidazole for the infection prevention. This is in contrast to many high- and middleresource countries where a single prophylactic dose of antibiotics is common practice. At the time of the study some evidence existed that a single dose regimen would be effective in lowresource settings as well (13). One single intravenous preoperative dose of ampicillin and metronidazole could be just as effective as a multiple day regimen in preventing infections and
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will reduce costs, improve regimen compliance, lead to improved use of scarce resources and lower the incidence of antimicrobial resistance (14).
We investigated the efficacy of the use of a single prophylactic intravenous dose of ampicillin combined with metronidazole prior to cesarean section to prevent postoperative infections and to show its non-inferiority to a multiple day regimen.
Material and methods
An evaluator-blinded randomized, controlled, non-inferiority trial was conducted to compare the efficacy of a single prophylactic intravenous dose of ampicillin and metronidazole prior to cesarean section with a five-day antibiotic regimen in Tanzania. On day one, both groups received the same medication which consisted of 1000 mg of ampicillin and 500 mg of metronidazole intravenously 20 minutes prior to cesarean section. On the following days the intervention group (single dose regimen) did not receive any additional antibiotics. The control group (multiple day regimen) received 500 mg of ampicillin and 500 mg of metronidazole intravenously at 8 and 16 hours post-cesarean, followed by 500 mg of amoxicillin and 400 mg of metronidazole orally three times a day on days two to five. A non-inferiority design was chosen since we intended to determine whether the intervention treatment has the same efficacy as the standard treatment. In order to measure this efficacy the primary outcome was maternal postcesarean infection. Secondary outcomes were severity of infections, other maternal complications, and the duration of hospital stay.
The trial was conducted between March 2008 and February 2009 in two rural hospitals:
Sokoine Regional Hospital, Lindi and Mkomaindo District Hospital Masasi, both in Southeastern Tanzania. This trial was approved by the National Institute for Medical Research in Dar es Salaam, Tanzania (NIMR/HQ/R.8a/Vol.IX/633). This study is registered under number ISRCTN06127083.
All women with an indication for cesarean section were assessed for eligibility and were included after informed consent before cesarean section. Informed consent was obtained after
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verbal and written information was given in the local language (Kiswahili). Exclusion criteria were: use of antibiotics in the preceding week, known allergy to any of the study antibiotics, ruptured membranes for more than 24 hours, evidence of infection or fever, preoperatively or during surgery. Enrolment was carried out by the doctor on call at the delivery ward.
The following demographics were obtained and assessed: age, parity, gestational age, weight, preoperative hemoglobin, voluntary tested HIV-status, number of vaginal examinations, duration
of ruptured membranes, indication for cesarean section, repeat cesarean section, type of anesthesia, type of incision and skin suture used, type of suture material , surgeon (gynecologist, medical officer or assistant medical officer), number of in-patient postoperative days and additional need for antibiotics.
Eligible women were randomly assigned. Permuted block randomization with block size of four and concealed allocation were accomplished by numbered and sealed opaque envelopes which contained the randomization code together with protocol forms for the respective groups and were opened after surgery, as the preoperative prophylaxis was the same for both groups. All women received a standardized preoperative preparation. A urinary catheter was placed and the preoperative dose of study medication administered in the labor room. In Sokoine Hospital the patients had spinal anesthesia with bupivacaine or general anesthesia with ketamine as indicated. In Mkomaindo Hospital only ketamine was available. Iodine for skin disinfection and sterile reusable cotton sheets for draping were used in both hospitals according to national guidelines. Surgical instruments used were autoclaved prior to surgery. The theatre was a closed room but windows were open for ventilation and fly wire was not completely intact. General rules of sterility were respected but dust and regularly flying or crawling insects were present. The skin incision technique was done with respect to any previous scar and surgeon´s preference. Wounds were dressed directly after surgery with an autoclaved gauze. The urinary catheter was removed on the first postoperative day, unless contraindicated. Dressings were removed after 24 hours. The ward doctor inspected the wound during daily ward rounds and patients were monitored for any signs of infection. On either day five in case of a low transverse incision, or on day seven in case of midline incision, the sutures were removed, the patient was clinically assessed and the wound scored by a treatment-blinded doctor and discharged if possible. The
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doctor who discharged the patient was not the same one who carried out the randomization or surgery. Infections after discharge were documented and scored until 30 days after surgery, if patients returned in case of a postoperative infection. The list shown in Table 1 was used to examine the patient. From score four and upwards, the patient was regarded as having a postoperative infection. In case multiple features were scored, the highest score found was used in the analysis (Table 1). Prior to the study, a retrospective analysis of wound infections in the past year took place: 7% of the women had a wound infection after cesarean section. The study was designed as a non-inferiority trial with the assumption that the success rate in both the intervention and control group would be around 93%. Success was defined as absence of infection under the allocated treatment of either group.
Statistical analysis To indicate non-inferiority we selected a 10% difference between the two treatment groups as maximum acceptable value. We used a two-sided test of equivalence with a significance level of 0.05. At least 160 women were needed for the study to achieve a statistical power of 80%. Study outcomes were assessed by intention-to-treat analysis. Results for continuous variables are expressed as means with standard deviation (SD) or as median with inter-quartile range (IQR) when not normally distributed, and for categorical variables as absolute numbers with the percentage between parentheses. Summary data were calculated using a Student’s t-test (normal distribution) or Mann Whitney U test (skewed distribution). Differences in infection rate
between groups were expressed as risk difference with 95% confidence intervals. Associations between duration of ruptured membranes, duration of labor, technique of incision and the
occurrence of maternal infection were evaluated using logistic regression analysis, resulting in an odds ratio with a 95% confidence interval. Data were analyzed using IBM SPSS Statistics, v 20 (IBM Corp, Armonk, NY, USA).
Results
Of the women who were enrolled, three women were excluded because they were incorrectly recruited with a duration of ruptured membranes exceeding 24 hours. Due to lost data of two
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women, the data of 176 women were actually analyzed in this study. The intervention group consisted of 89 women and the control group consisted of 87 women (Figure 1). Demographic and clinical characteristics of both groups were comparable, except for a significant difference in the occurrence of ruptured membranes prior to surgery (Table 2). In the intervention group 63 patients (70.8%) had ruptured membranes compared to 52 (59.8%) in the control group (p = 0.03). However, the duration of ruptured membranes did not differ significantly (p = 0.09).
In total 15 cases of maternal wound infection were recorded during 1215 hospitalization days. In the intervention group, six women (6.7%) developed a wound infection compared to nine (10.3%) (difference 3.60; 95% CI -4.65 to 11.85) (p = 0.40) in the control group. The infection rate was 9.95/1000 hospitalization days at risk for the intervention group compared to 14.71/1000 hospitalization days at risk for the control group (infection rate difference -4.76; 95% CI -17.23 to 7.72).
No significant difference in the type or severity of wound infections was observed between both groups (Table 3). No cases of endometritis were observed and one case of urinary tract infection occurred. The mean duration of hospital admission was 7.0 ± 2.0 days in the intervention group and 7.2 ± 4.1 days in the control group (difference 0.20; 95% CI -0.76 to 1.16) (p = 0.67). No maternal deaths occurred. There were three women with malaria. Neonatal sepsis was present in 10 babies (11.2%) whose mothers received a single dose of amoxicillin and metronidazole and in 11 babies (12.6%) whose mothers received the multiple day regimen (difference 1.40; 95% CI 8.17 to 10.99) (p = 0.77). Perinatal mortality rate was similar in both groups (six neonates in the
intervention group and five neonates in the control group) (difference -1.00; 95% CI -8.14 to 6.15) (p = 0.77). Amongst them, there were four cases of neonatal sepsis, two in the intervention group and two in the control group. Unfortunately the primary causes of perinatal mortality were not recorded. Furthermore, in this study the duration of ruptured membranes did not significantly influence occurrence of maternal infection in this population (OR 0.97, 95% CI 0.87-1.07), nor did the duration of labor (OR 0.99, 95% CI 0.93-1.05). Also the technique of incision and type of suture were not associated with maternal infection (OR for incision 0.98, 95% CI 0.37-2.59; OR for suture 0.86, 95% CI 0.32-2.35).
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Discussion
According to the non-inferiority criteria that were set prior to the trial, this study showed that a single dose of prophylactic ampicillin and metronidazole is non-inferior to a regimen of multiple
doses in preventing post-cesarean wound infections in a low-resource setting. The reduced quantity of prophylactic antibiotics will reduce the costs of treatment and workload for medical staff. It will also increase the patient compliance and might protect against antimicrobial resistance.
In our study the majority of post-cesarean infectious complications consisted of wound infections during hospital stay. However, it is known that up to 36% of post-cesarean infections may actually occur after initial discharge, therefore underestimation of the incidence is pervasive, particularly when based solely on inpatient data (5). The setting of the study made it difficult to assess the long term outcomes, as follow up is complex in rural Tanzania, since most women do not return for a postpartum check.
The strength of this study is the study design, a randomized controlled multicenter trial in rural low-resource settings and the fact that it assessed the same type of antibiotics in a single or multiple day regimen in both elective and emergency cesarean sections.
The efficacy of different prophylactic antibiotic regimens in cesarean section has been studied in other low-resource, mainly urban settings. A randomized controlled trial conducted in Mozambique, compared a single preoperative dose of gentamycin and metronidazole versus a seven day post-cesarean scheme consisting of a combination of crystalline penicillin , metronidazole and erythromycin. The two regimens were clinically equivalent in their setting (13). Alekwe in Nigeria compared a single dose of ceftriaxone with a triple drug regimen consisting of Ampiclox, gentamycin and metronidazole. This study concluded that a single dose was as effective as the multiple combination dose (15). In Nepal, Shakya et al conducted a research to compare intraoperative single dose cefazolin and metronidazole with a multiple day regimen of the same antibiotics. This group did not find a difference between the two regimens (16). More recently, a study performed by Lyimo et al in an urban setting in Tanzania, compared
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a single dose of gentamycin and metronidazole with the same preoperative regimen followed by multiple doses of metronidazol. The authors recommend the administration of a single dose of antibiotic prophylaxis (17). The weaknesses of these previous studies, compared to our study, are that the timing of administration and type of antibiotics used differed, that some of the antibiotics they used are too expensive for many low-resource settings or are not considered as first choice medication in prophylaxis. Furthermore some of these studies only included elective cesarean sections or excluded patients with ruptured membranes or prolonged labor, which do not reflect the average daily practice in a rural low-resource setting.
Generally, post-cesarean infections are polymicrobial (6,18-20). Several classes of antibiotics are effective against the majority of the relevant microorganisms (4,21,22). Worldwide there is no consensus on which prophylactic regimen to use to prevent infection after cesarean section. We chose a drug combination that is available, appropriate according to National guidelines, cheap and effective in literature (20,21). Preoperative administration of antibiotics is more effective in preventing postoperative wound infections compared to administration in the intraoperative or postoperative period (23-25).
Given the known risk factors for post-cesarean infection our study population could be considered to have a high risk for infection a priori, because of the low socio-economic status of women, in general low number of prenatal visits and a high chance of long duration of labor before operation. Furthermore, a large number of cesarean sections in low-resource settings can be classified as emergency cesareans with an increased risk for infection compared to elective operation, as most women only come to the hospital when in labor. In this study we could not determine that duration of ruptured membranes, duration of labor, or any other possible risk factor recorded, made a significant difference in maternal infection rate. The length of hospital stay was not significantly different for both groups. In terms of cost-effectiveness including indirect and opportunity costs, it would be desirable to reduce the postoperative period through a shorter antibiotic regimen. However, national guidelines included five days clinical postcesarean follow-up. In addition, the reduction in medicine costs in the intervention group is 66%, as a single dose of antibiotics cost 1003 Tanzanian Shillings (0.48 Euro) at time of study, compared to 3044 Tanzanian Shillings (1.46 Euro) for multiple doses.
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In conclusion we have shown that one prophylactic dose of ampicillin and metronidazole prior to cesarean section is non-inferior to a multiple day regimen and can be prescribed safely in lowresource settings in prevention of post-cesarean wound infection. Moreover, shorter regimens of antibiotics are cheaper and therapy compliance is ensured.
Acknowledgements We thank Professor J.L.H. Evers for reviewing the manuscript. We are grateful to the medical personnel in Sokoine Regional Hospital in Lindi and Mkomaindo District Hospital in Masasi.
Funding Statement Costs for drugs, ethical clearance and trial registration where provided by Tanzanian German Programme to Support Health (TGPSH).
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7
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Kayihura V, Bique Osman N, Bugalho A, Bergstrom S. Choice of antibiotics for infection prophylaxis in emergency cesarean sections in low-income countries: A costbenefit study in Mozambique. Acta Obstet Gynecol Scand. 2002; 82: 636–641.
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Shlaes DM, Gerding DN, John JF Jr, Craig WA, Bornstein DL, Duncan RA et al. Society for Healthcare Epidemiology of America and Infectious Diseases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hospitals. Clin Infect Dis 1997; 25: 584–99.
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Alekwe LO, Kuti O, Orji EO, Ogunniyi SO. Comparison of ceftriaxone versus triple drug regimen in the prevention of cesarean section infectious morbidities. J Matern Fetal Neonatal Med 2008; 21: 638–42.
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Shakya A, Sharma J. Comparison of single versus multiple doses of antibiotic prophylaxis in reducing post-elective Caesarean section infectious morbidity. Kathmandu Univ Med J 2010; 8: 179–84.
17
Lyimo FM, Massinde AN, Kidenya BR, Konje ET, Mshana SE. Single dose of gentamicin in combination with metronidazole versus multiple doses for prevention of
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post-caesarean infection at Bugando Medical Centre in Mwanza, Tanzania: a randomized, equivalence, controlled trial. BMC Pregnancy Childbirth. 2013;13:123.
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Roberts S, Maccato M, Faro S, Pinell P. The microbiology of post-cesarean wound morbidity. Obstet Gynecol 1993; 81: 383–6.
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Watts DH, Hillier SL, Eschenbach DA. Upper genital tract isolates at delivery as predictors of post-cesarean infections among women receiving antibiotic prophylaxis. Obstet Gynecol 1991; 77: 287–92.
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Watts DH, Krohn MA, Hillier SL, Eschenbach DA. Bacterial vaginosis as a risk factor for post-cesarean endometritis. Obstet Gynecol 1990; 75: 52–8.
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Faro S, Martens MG, Hammill HA, Riddle G, Tortolero G. Antibiotic prophylaxis: is there a difference? Am J Obstet Gynecol 1990; 162: 900–7.
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Alfirevic Z, Gyte GM, Dou L. Different classes of antibiotics given to women routinely for preventing infection at caesarean section. Cochrane Database Syst Rev 2010; 10: CD008726.
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Table 1. Score list wound and infection.
1. No sign of infection: wound closed without gaping 2. No signs of infection, but some gaping in wound 3. Presence of serous discharge 4. Presence of erythema 5. Presence of purulent discharge 6. Presence of cellulitis, symptoms: painful and tender wound and erythema and oedema beyond edge of incision 7. Wound abscess, symptoms: unusually tender wound with bloody or serous discharge. 8. Peritonitis, symptoms: low-grade fever/chills, lower abdominal pain, absent bowel sounds and sometimes rebound tenderness, abdominal distension, nausea/vomiting, anorexia, shock 9. Pelvic abscess, symptoms: lower abdominal pain and distension, persistent spiking fever/chills, tender uterus and sometimes poor response to antibiotics, swelling in adnexa or pouch of Douglas 10. Wound dehiscence: the sutures of fascia (and skin) burst open
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Table 2: Demographic and clinical characteristic of the study groups. Characteristics
Single dose (n=89)
Multiple doses (n=87)
p-value
Age in years ± SD
26.4 ± 7.4
26.2 ± 7.0
0.94
Weight in kilograms ± SD
56.9 ± 11.6
56.3 ± 11.5
0.96
Gravidity in numbers (IQR)
2.0 (1.0-3.0)
2.0 (1.0-3.0)
0.75
Parity in numbers (IQR)
1.0 (0.0-2.0)
1.0 (0.0-2.0)
0.6
Gestational age in weeks ± SD
38.9 ± 1.8
38.5 ± 2.0
0.46
Repeat cesarean
21 (23.6)
24 (27.6)
0.49
23 (25.8)
15 (17.2)
0.17
8 (9.0)
8 (9.2)
0.96
20 (22.5)
19 (21.8)
0.92
Placenta previa
3 (3.4)
1 (1.1)
0.32
Malpresentation
7 (7.9)
7 (8.0)
0.97
Protracted labor
24 (27.0)
25 (28.7)
0.79
Elective
1 (1.1)
-
1.0
Other
2 (2.2)
9 (10.3)
0.03
Not stated
1 (1.1)
3 (3.4)
0.30
59 (66.3) vs 30 (33.7)
59 (67.8) vs 28 (32.2)
0.83
5 (5.6)
5 (5.7)
0.83
63 (70.8)
52 (59.8)
0.03
2.9 (0.0-4.9)
3.3 (0.0-7.1)
0.09
13.6 (0.0-12.9)
13.0 (1.0-15.3)
0.79
Indication for cesarean: Fetal distress ≥ 2 previous scars Cephalo-pelvic disproportion
Sokoine versus Mkomaindo Hospital HIV-positive (voluntary tested) Membranes ruptured prior to cesarean Duration of ruptured membranes in hours (IQR) Duration of labor in hours (IQR)
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3.3 ± 1.2
3.4 ± 1.3
46 (51.7) vs 43 (48.3)
41 (47.1) vs 46 (52.9)
30 (33.7) vs 59 (66.3)
33 (37.9) vs 54 (62.1)
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Vaginal examinations in number ± SD Technique of skin incision: lower transverse abdomen (Pfannenstiel or Joel Cohen) versus midline incision Intracutaneous versus interrupted suture
0.93 0.55
0.56
Note: data are presented as n(%) except when stated otherwise
Table 3: Results. Single dose
Multiple
(n=89)
doses (n=87)
6 (6.7)
9 (10.3)
3.60 (-4.65 to 11.85; 0.40)
1. no sign of infection, wound closed
72 (80.9)
65 (74.7)
-6.2 (-18.44 to 6.07; 0.32)
2. no sign of infection, wound gaping
10 (11.2)
11 (12.6)
1.40 (-8.17 to 10.99; 0.82)
3. serous discharge
1 (1.1)
2 (2.3)
1.20 (-2.66 to 5.01; 0.56)
4. erythema
-
1 (1.1)
1.10 (-1.09 to 3.39; 0.70)
5. purulent discharge
3 (3.4)
4 (4.6)
1.20 (-4.55 to 7.01; 0.73)
6. cellulitis
-
3 (3.4)
3.40 (-0.39 to 7.28; 0.81)
7. wound abscess
2 (2.2)
1 (1.1)
-1.10 (-4.91 to 2.71; 0.56)
8. peritonitis
-
-
-
9. pelvic abscess
-
-
-
10. wound dehiscence/ burst abdomen
1 (1.1)
-
-1.10 (-3.31 to 1.07; 0.32)
Urinary tract infection
1 (1.1)
-
-1.10 (-3.31 to 1.07; 0.32)
Endometritis
-
-
-
Duration of hospital stay in days ±SD
7.0 ± 2.0
7.2 ± 4.1
0.20 (-0.76 to 1.16; 0.67)
(Wound) infection (category 4-10)
Difference (95% CI; p-value)
Classification:
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Neonatal sepsis Neonatal mortality
10 (11.2)
11 (12.6)
1.40 (-8.17 to 10.99; 0.77)
6 (6.7)
5 (5.7)
-1.00 (-8.14 to 6.15; 0.77)
Note: data are presented as n(%) except when stated otherwise
Figure 1: Flow diagram of trial profile.
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Received Date : 18-May-2014 Revised Date : 14-Sep-2014 Accepted Date : 22-Sep-2014 Article type : Main Research Article
Single-dose compared to multiple day antibiotic prophylaxis for cesarean section in low-resource settings, a randomized controlled, non-inferiority trial Running head: Antibiotic prophylaxis for cesarean section. Esther H.M.N. Westen1,2, Pascal R. Kolk1,3, Christine L. van Velzen4, Regine Unkels5,6,
Nicholaus S. Mmuni5, Alex D. Hamisi5, Ritha E. Nakua5, Anne L.M. Vlek7 and Heleen J. van
Beekhuizen5,8.
1
Mkomaindo District Hospital, Masasi, Tanzania.
2
Department of Obstetrics and Gynecology, Máxima Medical Centre, Veldhoven, the
Netherlands.
3
Department of Obstetrics and Gynecology, Radboud University Medical Centre, Nijmegen, the
Netherlands. 4
Department of Obstetrics and Gynecology, VU University Medical Centre, Amsterdam, the
Netherlands. 5
Sokoine Regional Hospital, Lindi, Tanzania.
6
Liverpool School of Tropical Medicine, Liverpool, UK
7
Department of Medical Microbiology, Diakonessen Hospital, Utrecht, the Netherlands.
8
Department of Obstetrics and Gynecology, Erasmus Medical Centre, Rotterdam, the
Netherlands.
Corresponding author: Esther Westen
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/aogs.12517 This article is protected by copyright. All rights reserved.
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Department of Obstetrics and Gynecology, Máxima Medical Centre, P.O. Box 7777, 5500 MB Veldhoven, The Netherlands. E-mail: [email protected].
Conflicts of Interest Statement All authors state explicitly that there are no conflicts of interest.
Abstract
Objective: To investigate the efficacy of a single prophylactic dose of ampicillin combined with
metronidazole to prevent post-cesarean section infections compared with a multiple day regimen in lowresource settings. Design: An evaluator-blinded randomized, controlled, non-inferiority trial. Setting:
Two rural hospitals in Tanzania. Population: Of 181 enrolled eligible women with an indication for cesarean section, information on 176 was analyzed by intention-to-treat. Methods: The women were randomly assigned to either the intervention group who received a single dose of ampicillin and metronidazole, or to the control group who received a multiple day regimen of ampicillin/amoxicillin and metronidazole. Main outcome measures: The primary outcome was maternal post-cesarean infection. Secondary outcomes were severity of these infections, other maternal complications, and the duration of hospital stay. Results: In the intervention group (n = 89), six women (6.7%) developed a wound infection compared to nine (10.3%) in the control group (n = 87) (difference 3.60; 95% CI -4.65 to 11.85) (p = 0.40). Conclusions: A single dose of prophylactic ampicillin and metronidazole is equally effective as a multiple day regimen in preventing post-cesarean wound infections in low-resource settings, therefore it can be considered as a good strategy in low-resource settings. The reduced quantity of prophylactic antibiotics will reduce costs without increasing the risk of maternal infection.
Keywords Antibiotic prophylaxis, cesarean section, infection, ampicillin, metronidazole, low-resource setting, Tanzania, maternal morbidity.
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Key Message Cesarean section is a major risk for postpartum infection and the use of antibiotic prophylaxis has been a major contributor in lowering this risk. In many countries there is no consensus on which antibiotic regimen to use, particularly in low-resource settings where a multiple day regimen is common practice. This randomized controlled multicenter trial shows that a single dose of prophylactic ampicillin and metronidazole is as effective as multiple doses in preventing post-cesarean wound infections in a low-resource setting.
Introduction
Cesarean section is a major risk factor for postpartum infection, with a possible 20-fold increase in infection compared to a vaginal delivery (1-3). Infectious complications that occur after cesarean delivery are an important cause of maternal morbidity and mortality especially in lowresource settings. Known risk factors for post-cesarean infection include emergency delivery, low socio-economic status, long duration of labor and ruptured membranes, obstructed labor, inadequate skills or technique of the surgeon, amongst others (1,3-8). Although general rules to prevent surgical infection, such as good surgical technique and antisepsis are important, the use of antibiotic prophylaxis has been a major contributor in reducing the incidence of post-cesarean infection, and may reduce the incidence by up to two-thirds (4,5,8-11).
In many countries there is no consensus on which antibiotic regimen to use, especially in lowresource settings where surgery is often performed under poor aseptic conditions (12). A
common treatment in Sub-Saharan Africa, is a multiple day regimen of ampicillin and metronidazole for the infection prevention. This is in contrast to many high- and middleresource countries where a single prophylactic dose of antibiotics is common practice. At the time of the study some evidence existed that a single dose regimen would be effective in lowresource settings as well (13). One single intravenous preoperative dose of ampicillin and metronidazole could be just as effective as a multiple day regimen in preventing infections and
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will reduce costs, improve regimen compliance, lead to improved use of scarce resources and lower the incidence of antimicrobial resistance (14).
We investigated the efficacy of the use of a single prophylactic intravenous dose of ampicillin combined with metronidazole prior to cesarean section to prevent postoperative infections and to show its non-inferiority to a multiple day regimen.
Material and methods
An evaluator-blinded randomized, controlled, non-inferiority trial was conducted to compare the efficacy of a single prophylactic intravenous dose of ampicillin and metronidazole prior to cesarean section with a five-day antibiotic regimen in Tanzania. On day one, both groups received the same medication which consisted of 1000 mg of ampicillin and 500 mg of metronidazole intravenously 20 minutes prior to cesarean section. On the following days the intervention group (single dose regimen) did not receive any additional antibiotics. The control group (multiple day regimen) received 500 mg of ampicillin and 500 mg of metronidazole intravenously at 8 and 16 hours post-cesarean, followed by 500 mg of amoxicillin and 400 mg of metronidazole orally three times a day on days two to five. A non-inferiority design was chosen since we intended to determine whether the intervention treatment has the same efficacy as the standard treatment. In order to measure this efficacy the primary outcome was maternal postcesarean infection. Secondary outcomes were severity of infections, other maternal complications, and the duration of hospital stay.
The trial was conducted between March 2008 and February 2009 in two rural hospitals:
Sokoine Regional Hospital, Lindi and Mkomaindo District Hospital Masasi, both in Southeastern Tanzania. This trial was approved by the National Institute for Medical Research in Dar es Salaam, Tanzania (NIMR/HQ/R.8a/Vol.IX/633). This study is registered under number ISRCTN06127083.
All women with an indication for cesarean section were assessed for eligibility and were included after informed consent before cesarean section. Informed consent was obtained after
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verbal and written information was given in the local language (Kiswahili). Exclusion criteria were: use of antibiotics in the preceding week, known allergy to any of the study antibiotics, ruptured membranes for more than 24 hours, evidence of infection or fever, preoperatively or during surgery. Enrolment was carried out by the doctor on call at the delivery ward.
The following demographics were obtained and assessed: age, parity, gestational age, weight, preoperative hemoglobin, voluntary tested HIV-status, number of vaginal examinations, duration
of ruptured membranes, indication for cesarean section, repeat cesarean section, type of anesthesia, type of incision and skin suture used, type of suture material , surgeon (gynecologist, medical officer or assistant medical officer), number of in-patient postoperative days and additional need for antibiotics.
Eligible women were randomly assigned. Permuted block randomization with block size of four and concealed allocation were accomplished by numbered and sealed opaque envelopes which contained the randomization code together with protocol forms for the respective groups and were opened after surgery, as the preoperative prophylaxis was the same for both groups. All women received a standardized preoperative preparation. A urinary catheter was placed and the preoperative dose of study medication administered in the labor room. In Sokoine Hospital the patients had spinal anesthesia with bupivacaine or general anesthesia with ketamine as indicated. In Mkomaindo Hospital only ketamine was available. Iodine for skin disinfection and sterile reusable cotton sheets for draping were used in both hospitals according to national guidelines. Surgical instruments used were autoclaved prior to surgery. The theatre was a closed room but windows were open for ventilation and fly wire was not completely intact. General rules of sterility were respected but dust and regularly flying or crawling insects were present. The skin incision technique was done with respect to any previous scar and surgeon´s preference. Wounds were dressed directly after surgery with an autoclaved gauze. The urinary catheter was removed on the first postoperative day, unless contraindicated. Dressings were removed after 24 hours. The ward doctor inspected the wound during daily ward rounds and patients were monitored for any signs of infection. On either day five in case of a low transverse incision, or on day seven in case of midline incision, the sutures were removed, the patient was clinically assessed and the wound scored by a treatment-blinded doctor and discharged if possible. The
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doctor who discharged the patient was not the same one who carried out the randomization or surgery. Infections after discharge were documented and scored until 30 days after surgery, if patients returned in case of a postoperative infection. The list shown in Table 1 was used to examine the patient. From score four and upwards, the patient was regarded as having a postoperative infection. In case multiple features were scored, the highest score found was used in the analysis (Table 1). Prior to the study, a retrospective analysis of wound infections in the past year took place: 7% of the women had a wound infection after cesarean section. The study was designed as a non-inferiority trial with the assumption that the success rate in both the intervention and control group would be around 93%. Success was defined as absence of infection under the allocated treatment of either group.
Statistical analysis To indicate non-inferiority we selected a 10% difference between the two treatment groups as maximum acceptable value. We used a two-sided test of equivalence with a significance level of 0.05. At least 160 women were needed for the study to achieve a statistical power of 80%. Study outcomes were assessed by intention-to-treat analysis. Results for continuous variables are expressed as means with standard deviation (SD) or as median with inter-quartile range (IQR) when not normally distributed, and for categorical variables as absolute numbers with the percentage between parentheses. Summary data were calculated using a Student’s t-test (normal distribution) or Mann Whitney U test (skewed distribution). Differences in infection rate
between groups were expressed as risk difference with 95% confidence intervals. Associations between duration of ruptured membranes, duration of labor, technique of incision and the
occurrence of maternal infection were evaluated using logistic regression analysis, resulting in an odds ratio with a 95% confidence interval. Data were analyzed using IBM SPSS Statistics, v 20 (IBM Corp, Armonk, NY, USA).
Results
Of the women who were enrolled, three women were excluded because they were incorrectly recruited with a duration of ruptured membranes exceeding 24 hours. Due to lost data of two
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women, the data of 176 women were actually analyzed in this study. The intervention group consisted of 89 women and the control group consisted of 87 women (Figure 1). Demographic and clinical characteristics of both groups were comparable, except for a significant difference in the occurrence of ruptured membranes prior to surgery (Table 2). In the intervention group 63 patients (70.8%) had ruptured membranes compared to 52 (59.8%) in the control group (p = 0.03). However, the duration of ruptured membranes did not differ significantly (p = 0.09).
In total 15 cases of maternal wound infection were recorded during 1215 hospitalization days. In the intervention group, six women (6.7%) developed a wound infection compared to nine (10.3%) (difference 3.60; 95% CI -4.65 to 11.85) (p = 0.40) in the control group. The infection rate was 9.95/1000 hospitalization days at risk for the intervention group compared to 14.71/1000 hospitalization days at risk for the control group (infection rate difference -4.76; 95% CI -17.23 to 7.72).
No significant difference in the type or severity of wound infections was observed between both groups (Table 3). No cases of endometritis were observed and one case of urinary tract infection occurred. The mean duration of hospital admission was 7.0 ± 2.0 days in the intervention group and 7.2 ± 4.1 days in the control group (difference 0.20; 95% CI -0.76 to 1.16) (p = 0.67). No maternal deaths occurred. There were three women with malaria. Neonatal sepsis was present in 10 babies (11.2%) whose mothers received a single dose of amoxicillin and metronidazole and in 11 babies (12.6%) whose mothers received the multiple day regimen (difference 1.40; 95% CI 8.17 to 10.99) (p = 0.77). Perinatal mortality rate was similar in both groups (six neonates in the
intervention group and five neonates in the control group) (difference -1.00; 95% CI -8.14 to 6.15) (p = 0.77). Amongst them, there were four cases of neonatal sepsis, two in the intervention group and two in the control group. Unfortunately the primary causes of perinatal mortality were not recorded. Furthermore, in this study the duration of ruptured membranes did not significantly influence occurrence of maternal infection in this population (OR 0.97, 95% CI 0.87-1.07), nor did the duration of labor (OR 0.99, 95% CI 0.93-1.05). Also the technique of incision and type of suture were not associated with maternal infection (OR for incision 0.98, 95% CI 0.37-2.59; OR for suture 0.86, 95% CI 0.32-2.35).
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Discussion
According to the non-inferiority criteria that were set prior to the trial, this study showed that a single dose of prophylactic ampicillin and metronidazole is non-inferior to a regimen of multiple
doses in preventing post-cesarean wound infections in a low-resource setting. The reduced quantity of prophylactic antibiotics will reduce the costs of treatment and workload for medical staff. It will also increase the patient compliance and might protect against antimicrobial resistance.
In our study the majority of post-cesarean infectious complications consisted of wound infections during hospital stay. However, it is known that up to 36% of post-cesarean infections may actually occur after initial discharge, therefore underestimation of the incidence is pervasive, particularly when based solely on inpatient data (5). The setting of the study made it difficult to assess the long term outcomes, as follow up is complex in rural Tanzania, since most women do not return for a postpartum check.
The strength of this study is the study design, a randomized controlled multicenter trial in rural low-resource settings and the fact that it assessed the same type of antibiotics in a single or multiple day regimen in both elective and emergency cesarean sections.
The efficacy of different prophylactic antibiotic regimens in cesarean section has been studied in other low-resource, mainly urban settings. A randomized controlled trial conducted in Mozambique, compared a single preoperative dose of gentamycin and metronidazole versus a seven day post-cesarean scheme consisting of a combination of crystalline penicillin , metronidazole and erythromycin. The two regimens were clinically equivalent in their setting (13). Alekwe in Nigeria compared a single dose of ceftriaxone with a triple drug regimen consisting of Ampiclox, gentamycin and metronidazole. This study concluded that a single dose was as effective as the multiple combination dose (15). In Nepal, Shakya et al conducted a research to compare intraoperative single dose cefazolin and metronidazole with a multiple day regimen of the same antibiotics. This group did not find a difference between the two regimens (16). More recently, a study performed by Lyimo et al in an urban setting in Tanzania, compared
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a single dose of gentamycin and metronidazole with the same preoperative regimen followed by multiple doses of metronidazol. The authors recommend the administration of a single dose of antibiotic prophylaxis (17). The weaknesses of these previous studies, compared to our study, are that the timing of administration and type of antibiotics used differed, that some of the antibiotics they used are too expensive for many low-resource settings or are not considered as first choice medication in prophylaxis. Furthermore some of these studies only included elective cesarean sections or excluded patients with ruptured membranes or prolonged labor, which do not reflect the average daily practice in a rural low-resource setting.
Generally, post-cesarean infections are polymicrobial (6,18-20). Several classes of antibiotics are effective against the majority of the relevant microorganisms (4,21,22). Worldwide there is no consensus on which prophylactic regimen to use to prevent infection after cesarean section. We chose a drug combination that is available, appropriate according to National guidelines, cheap and effective in literature (20,21). Preoperative administration of antibiotics is more effective in preventing postoperative wound infections compared to administration in the intraoperative or postoperative period (23-25).
Given the known risk factors for post-cesarean infection our study population could be considered to have a high risk for infection a priori, because of the low socio-economic status of women, in general low number of prenatal visits and a high chance of long duration of labor before operation. Furthermore, a large number of cesarean sections in low-resource settings can be classified as emergency cesareans with an increased risk for infection compared to elective operation, as most women only come to the hospital when in labor. In this study we could not determine that duration of ruptured membranes, duration of labor, or any other possible risk factor recorded, made a significant difference in maternal infection rate. The length of hospital stay was not significantly different for both groups. In terms of cost-effectiveness including indirect and opportunity costs, it would be desirable to reduce the postoperative period through a shorter antibiotic regimen. However, national guidelines included five days clinical postcesarean follow-up. In addition, the reduction in medicine costs in the intervention group is 66%, as a single dose of antibiotics cost 1003 Tanzanian Shillings (0.48 Euro) at time of study, compared to 3044 Tanzanian Shillings (1.46 Euro) for multiple doses.
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In conclusion we have shown that one prophylactic dose of ampicillin and metronidazole prior to cesarean section is non-inferior to a multiple day regimen and can be prescribed safely in lowresource settings in prevention of post-cesarean wound infection. Moreover, shorter regimens of antibiotics are cheaper and therapy compliance is ensured.
Acknowledgements We thank Professor J.L.H. Evers for reviewing the manuscript. We are grateful to the medical personnel in Sokoine Regional Hospital in Lindi and Mkomaindo District Hospital in Masasi.
Funding Statement Costs for drugs, ethical clearance and trial registration where provided by Tanzanian German Programme to Support Health (TGPSH).
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7
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Alekwe LO, Kuti O, Orji EO, Ogunniyi SO. Comparison of ceftriaxone versus triple drug regimen in the prevention of cesarean section infectious morbidities. J Matern Fetal Neonatal Med 2008; 21: 638–42.
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Shakya A, Sharma J. Comparison of single versus multiple doses of antibiotic prophylaxis in reducing post-elective Caesarean section infectious morbidity. Kathmandu Univ Med J 2010; 8: 179–84.
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Lyimo FM, Massinde AN, Kidenya BR, Konje ET, Mshana SE. Single dose of gentamicin in combination with metronidazole versus multiple doses for prevention of
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post-caesarean infection at Bugando Medical Centre in Mwanza, Tanzania: a randomized, equivalence, controlled trial. BMC Pregnancy Childbirth. 2013;13:123.
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Roberts S, Maccato M, Faro S, Pinell P. The microbiology of post-cesarean wound morbidity. Obstet Gynecol 1993; 81: 383–6.
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Watts DH, Hillier SL, Eschenbach DA. Upper genital tract isolates at delivery as predictors of post-cesarean infections among women receiving antibiotic prophylaxis. Obstet Gynecol 1991; 77: 287–92.
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Watts DH, Krohn MA, Hillier SL, Eschenbach DA. Bacterial vaginosis as a risk factor for post-cesarean endometritis. Obstet Gynecol 1990; 75: 52–8.
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Table 1. Score list wound and infection.
1. No sign of infection: wound closed without gaping 2. No signs of infection, but some gaping in wound 3. Presence of serous discharge 4. Presence of erythema 5. Presence of purulent discharge 6. Presence of cellulitis, symptoms: painful and tender wound and erythema and oedema beyond edge of incision 7. Wound abscess, symptoms: unusually tender wound with bloody or serous discharge. 8. Peritonitis, symptoms: low-grade fever/chills, lower abdominal pain, absent bowel sounds and sometimes rebound tenderness, abdominal distension, nausea/vomiting, anorexia, shock 9. Pelvic abscess, symptoms: lower abdominal pain and distension, persistent spiking fever/chills, tender uterus and sometimes poor response to antibiotics, swelling in adnexa or pouch of Douglas 10. Wound dehiscence: the sutures of fascia (and skin) burst open
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Table 2: Demographic and clinical characteristic of the study groups. Characteristics
Single dose (n=89)
Multiple doses (n=87)
p-value
Age in years ± SD
26.4 ± 7.4
26.2 ± 7.0
0.94
Weight in kilograms ± SD
56.9 ± 11.6
56.3 ± 11.5
0.96
Gravidity in numbers (IQR)
2.0 (1.0-3.0)
2.0 (1.0-3.0)
0.75
Parity in numbers (IQR)
1.0 (0.0-2.0)
1.0 (0.0-2.0)
0.6
Gestational age in weeks ± SD
38.9 ± 1.8
38.5 ± 2.0
0.46
Repeat cesarean
21 (23.6)
24 (27.6)
0.49
23 (25.8)
15 (17.2)
0.17
8 (9.0)
8 (9.2)
0.96
20 (22.5)
19 (21.8)
0.92
Placenta previa
3 (3.4)
1 (1.1)
0.32
Malpresentation
7 (7.9)
7 (8.0)
0.97
Protracted labor
24 (27.0)
25 (28.7)
0.79
Elective
1 (1.1)
-
1.0
Other
2 (2.2)
9 (10.3)
0.03
Not stated
1 (1.1)
3 (3.4)
0.30
59 (66.3) vs 30 (33.7)
59 (67.8) vs 28 (32.2)
0.83
5 (5.6)
5 (5.7)
0.83
63 (70.8)
52 (59.8)
0.03
2.9 (0.0-4.9)
3.3 (0.0-7.1)
0.09
13.6 (0.0-12.9)
13.0 (1.0-15.3)
0.79
Indication for cesarean: Fetal distress ≥ 2 previous scars Cephalo-pelvic disproportion
Sokoine versus Mkomaindo Hospital HIV-positive (voluntary tested) Membranes ruptured prior to cesarean Duration of ruptured membranes in hours (IQR) Duration of labor in hours (IQR)
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3.3 ± 1.2
3.4 ± 1.3
46 (51.7) vs 43 (48.3)
41 (47.1) vs 46 (52.9)
30 (33.7) vs 59 (66.3)
33 (37.9) vs 54 (62.1)
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Vaginal examinations in number ± SD Technique of skin incision: lower transverse abdomen (Pfannenstiel or Joel Cohen) versus midline incision Intracutaneous versus interrupted suture
0.93 0.55
0.56
Note: data are presented as n(%) except when stated otherwise
Table 3: Results. Single dose
Multiple
(n=89)
doses (n=87)
6 (6.7)
9 (10.3)
3.60 (-4.65 to 11.85; 0.40)
1. no sign of infection, wound closed
72 (80.9)
65 (74.7)
-6.2 (-18.44 to 6.07; 0.32)
2. no sign of infection, wound gaping
10 (11.2)
11 (12.6)
1.40 (-8.17 to 10.99; 0.82)
3. serous discharge
1 (1.1)
2 (2.3)
1.20 (-2.66 to 5.01; 0.56)
4. erythema
-
1 (1.1)
1.10 (-1.09 to 3.39; 0.70)
5. purulent discharge
3 (3.4)
4 (4.6)
1.20 (-4.55 to 7.01; 0.73)
6. cellulitis
-
3 (3.4)
3.40 (-0.39 to 7.28; 0.81)
7. wound abscess
2 (2.2)
1 (1.1)
-1.10 (-4.91 to 2.71; 0.56)
8. peritonitis
-
-
-
9. pelvic abscess
-
-
-
10. wound dehiscence/ burst abdomen
1 (1.1)
-
-1.10 (-3.31 to 1.07; 0.32)
Urinary tract infection
1 (1.1)
-
-1.10 (-3.31 to 1.07; 0.32)
Endometritis
-
-
-
Duration of hospital stay in days ±SD
7.0 ± 2.0
7.2 ± 4.1
0.20 (-0.76 to 1.16; 0.67)
(Wound) infection (category 4-10)
Difference (95% CI; p-value)
Classification:
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Neonatal sepsis Neonatal mortality
10 (11.2)
11 (12.6)
1.40 (-8.17 to 10.99; 0.77)
6 (6.7)
5 (5.7)
-1.00 (-8.14 to 6.15; 0.77)
Note: data are presented as n(%) except when stated otherwise
Figure 1: Flow diagram of trial profile.
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