Single dose versus multiple dose of antibiotic prophylaxis in caesarean section: a systematic review and meta-analysis

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1 DOI: / Systematic review Single dose versus multiple dose of antibiotic prophylaxis in caesarean section: a systematic review and meta-analysis R Pinto-Lopes, a,b B Sousa-Pinto, a,b LF Azevedo a,b,c a Faculty of Medicine of the University of Porto, Porto, Portugal b Department of Health Information and Decision Sciences (CIDES) of the Faculty of Medicine and Centre for Health Technology and Services Research (CINTESIS), University of Porto, Porto, Portugal c Portuguese Branch of the Iberoamerican Cochrane Centre, Porto, Portugal Correspondence: Rui Miguel dos Reis Cabral Pinto Lopes, R. Dr. Placido da Costa, Porto, Portugal. plopes.rui@gmail.com Accepted 22 August Published Online 24 November Background Prophylactic antibiotics are traditionally given as a single dose for caesarean section. However, inconsistent application of recommendations and recent evidence prompted a literature review. Objectives To assess the optimal regimen for antibiotic prophylaxis in caesarean section by comparing single versus multiple doses of the same intervention. Search strategy MEDLINE, Web of Knowledge, SCOPUS, CENTRAL and ongoing trials databases were searched. Reference lists were reviewed and international groups contacted. Selection criteria Randomised controlled trials (RCT) comparing single with multiple dose regimens of the same antibiotic prophylaxis. Quasi-RCT and abstracts were suitable for inclusion. Data collection and analysis Reviewers independently extracted data and assessed quality of evidence. A random-effects model was used and results presented as risk ratio (RR) with 95% confidence intervals (CI). Main results Sixteen studies were included, involving 2695 women. Nonsignificant differences were observed between single dose and multiple dose antibiotic prophylaxis in the incidence of postpartum infectious morbidity (RR 0.95, 95% CI , I 2 = 25%), endometritis (RR 1.03, 95% CI , I 2 = 0%) and wound infection (RR 1.22, 95% CI , I 2 = 0%). A trend towards lower risk of urinary tract infection was seen with multiple dose (RR 0.65, 95% CI , I 2 = 0%). Conclusions There was insufficient evidence to determine whether there is a difference between single and multiple dose regimens in reducing the incidence of infectious morbidity after caesarean section. The quality of evidence was very low and well-designed RCTs are needed. Keywords Antibiotic prophylaxis, caesarean section, infectious morbidity, multiple dose, single dose. Tweetable abstract Insufficient evidence of difference between dosage regimens of antibiotic prophylaxis in caesarean section. Please cite this paper as: Pinto-Lopes R, Sousa-Pinto B, Azevedo LF. Single dose versus multiple dose of antibiotic prophylaxis in caesarean section: a systematic review and meta-analysis. BJOG 2017;124: Introduction In recent years, the international community has expressed concerns 1 3 about the need to revisit the 1985 recommendation of a 10 15% ideal rate for caesarean sections. 1,4 Over the past decades, caesarean section has become one of the most common major surgical procedures worldwide, given to its continuously rising rates both in developed and developing countries. 5 7 For certain medical indications, caesarean section is advocated as the safest route for delivery when compared with vaginal birth. 8 However, in the absence of medical need, the risks appear to outweigh the benefits. 9,10 In fact, women undergoing caesarean delivery have a 5- to 20-fold greater risk of infectious complications when compared with those who deliver vaginally. 11,12 Fever, endometritis, wound infection and urinary tract infection compose the majority of the complications. 13,14 Given the worrisome trend of increasing caesarean section rates worldwide, measures aimed at reducing postpartum infectious morbidity are an important area of focus. Traditional principles of skin antisepsis, thorough surgical technique and antibiotic prophylaxis have been proven effective for the prevention of infectious complications associated with any surgery. 15 In caesarean sections, the potential of prophylactic antibiotics has been extensively studied both in high-risk and low-risk women, showing a clear benefit 595

2 Pinto-Lopes et al. in reducing the incidence of postpartum infectious morbidity. 16,17 International evidence-based guidelines recommend the preoperative administration of prophylactic antibiotics for all women. 18,19 The current debate focuses on the optimal antibiotic agent to use, with most obstetricians preferring a single agent, frequently a penicillin or a cephalosporin, based on factors such as cost, half-life, safety and antimicrobial spectrum Despite the evidence showing single dose to be as effective as multiple dose regimens, 20,22 recent trials suggest multiple doses of an extended spectrum regimen may reduce infectious morbidity Furthermore, recent surveys report an inconsistent and variable application of antibiotic prophylaxis in caesarean section, worldwide This is probably due to available financial resources, current knowledge of antibiotic resistance and concerns regarding adverse effects on mother and fetus. Therefore, it is important to update the evidence and provide clear recommendations for antibiotic prophylaxis in caesarean section. The purpose of this review was to examine infectious morbidity comparing single and multiple doses of the same intervention to assess the optimal regimen for antibiotic prophylaxis in caesarean section. Methods A protocol was developed, in advance, establishing the search strategy, selection criteria and data analysis methods. This protocol was not formally registered. The PRISMA statement 30 was followed to improve the reporting of this systematic review and meta-analysis. Selection criteria Studies All randomised controlled trials (RCTs) that allocated participants to two distinct groups comparing single dose with multiple doses of the same antibiotic prophylaxis were included. Quasi-RCTs were considered suitable for inclusion, although they were subjected to sensitivity analysis. Abstracts of RCTs that provided useful data as well as adequate information to assess quality, were also eligible for inclusion. Participants Pregnant women, of any age or race, undergoing caesarean section for any medical or non-medical indication were considered. Interventions The intravenous administration of prophylactic antibiotics in a single dose compared with multiple doses, for caesarean section were studied. Trials were considered only if they established direct comparisons between the same drug/combination of drugs. No restrictions as to time of administration, dosage, duration, intensity or frequency were considered. Outcome measures Composite postpartum infectious morbidity encompassing endometritis, wound infection, urinary tract infection and other causes of febrile morbidity of probable infectious origin was considered primary outcome. Endometritis, wound infection and urinary tract infection were considered secondary outcomes. Endometritis was defined as the presence of marked uterine tenderness and/or malodorous discharge associated with fever. Wound infection was defined as the presence of palpable local induration and tenderness associated with purulent or serous discharge from the wound. Urinary tract infection was defined as a positive urine culture, with or without dysuria and fever. Febrile morbidity was defined as a temperature >38.0 C on the first 10 days postpartum, excluding the first 24 hours. Search strategy Electronic searches An electronic database search was performed on MED- LINE, Web of Knowledge, SCOPUS and CENTRAL (last search on 14 December 2015). Broad medical subject headings (MeSH) and subheadings, or the equivalent, were used combining the following: intervention of interest (use of antibiotic prophylaxis) and target population (women undergoing caesarean section). Searches were tailored to the individual databases (see Table S1). There were no language or publication date restrictions. Other resources The ISRCTN registry, ClinicalTrials.gov register, the WHO ICTRP, the UK Clinical Trials Gateway and the EU Clinical Trial Register were searched to retrieve ongoing trials of relevance. To determine the trial stage and whether any pertinent data were available, the authors were contacted. In addition, reference lists from all retrieved articles were analysed for potential studies. Experts in the field and international groups were contacted for unpublished and ongoing trials. Authors of retrieved trials were also contacted to provide additional information when required. Data collection and analysis Study selection All the trials obtained as a result of the search strategy were analysed for exclusion of duplicates. In a first selection phase, two review authors independently assessed the 596

3 Antibiotic prophylaxis in caesarean section retrieved studies by reviewing titles and abstracts. In a second selection phase, the full text of the selected trials was reviewed, when available. Any disagreement was resolved through discussion or, if required, by consulting a third review author. Data extraction A data collection form was designed, pilot-tested and independently implemented by two review authors to facilitate the extraction, manipulation and comparison of data from eligible trials. Any discrepancies were discussed and, if required, a third review author was consulted. When information regarding a critical topic was unclear, an attempt to contact the authors was made. Quality assessment Risk of bias was independently assessed by two authors according to a domain-based evaluation (sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and other issues). 31 Based on the information reported in each study, authors judged each domain as low risk, high risk or unclear risk of bias. The quality of the evidence was evaluated using the GRADE approach, 32 relating to the following outcomes for the main comparison: postpartum infectious morbidity, endometritis, wound infection and urinary tract infection. GRADEpro GDT 33 was used to import data from REVIEW MANAGER 5 to create a Summary of findings table. Data synthesis Statistical analysis was performed using the software REVIEW MANAGER 5.3 provided by the Cochrane Collaboration. 34 For dichotomous variables, results were presented as summary risk ratio (RR) with 95% confidence interval (CI). Pooled studies were analysed using the Mantel Haenszel method and the DerSimonian and Laird random-effects model for comparison. Statistical heterogeneity was assessed using the I 2 and s 2 or v 2 statistics. Heterogeneity was considered substantial if an I 2 value was >30% and s 2 was greater than zero, or there was a low P value (<0.10) in the v 2 test. The possibility of reporting bias (namely as publication bias) was investigated using funnel plots for the main comparisons and confirmed when asymmetry was detected visually. Subgroup analysis The following subgroup analysis were carried out to address specific questions regarding particular patient characteristics and intervention groups: by antibiotic agent: mezlocillin; piperacillin; cefoxitin; cefotaxime; cefazolin; cefazolin + metronidazole; ampicillin + metronidazole; gentamicin + metronidazole. by antibiotic class: penicillins; cephalosporins; aminoglycosides. by number of antibiotics: single antibiotic; combination of antibiotics. by setting: low resource setting; high resource setting. by type of caesarean section: emergency; elective; both. The subgroup analysis was performed for the outcome of composite postpartum infectious morbidity. Sensitivity analysis A sensitivity analysis was performed to explore the effect of trial quality. This was achieved by sequentially excluding each trial from the analysis to assess the occurrence of any differences in the overall result. A separate sensitivity analysis was executed by excluding the three quasi-rct studies included to determine whether any differences in the overall result would occur. Results Study selection A total of 987 studies were identified in the literature search, of which an initial screening identified 450 duplicates. Concerning the remaining 537 studies, 14 met the inclusion criteria and were therefore included in the metaanalysis. One ongoing trial (IRCT N1) was identified through the International Clinical Trials Registry Platform. However, despite several attempts to contact the listed author, no answer was obtained. Two additional studies were also included through searching reference lists. No additional studies were found after contacting international groups. Figure S1 depicts a flowchart for study selection. Study characteristics Sixteen studies met the inclusion criteria, providing data on 2695 women undergoing caesarean section. Of those, 1339 received multiple doses and 1356 received a single dose of the same antibiotic prophylaxis. One study s full text was not accessible, 35 but relevant data from its online published abstract and additional information obtained through author contact was considered for the meta-analysis. For general characteristics of included studies, see Table S2. Included and excluded participants characteristics are described in detail throughout the studies. The main reasons for exclusion were the presence of fever or evidence of infection, history of allergic reaction to antibiotics (namely penicillins and cephalosporins), recent antibiotic therapy prior to admission, and history of renal or hepatic dysfunction. While most studies included women requiring either emergency or elective caesarean section, some studies were limited to either one or another. 597

4 Pinto-Lopes et al. The majority of studies were set in developed countries (USA, Canada, Italy, Israel, the Netherlands), whereas only five studies were conducted in developing nations, including Nepal, Pakistan, United Arab Emirates and Tanzania. All studies assessed the use of the same intravenous antibiotic prophylaxis, either in a single dose or a multiple dose. The majority reported the use of monotherapy, 35 45,47,48 whereas three trials compared combined regimens. 46,49,50 The classes of antibiotics addressed included penicillins, cephalosporins and aminoglycosides. Seven trials described the use of mezlocillin, 35,40,42 piperacillin 37,44,47 and the combination of ampicillin with metronidazole. 50 Eight trials demonstrated the use of cefoxitin, 39,43,45 cefotaxime 38,48 and cefazolin, 36,41 one of which used a combination of cefazolin with metronidazole. 49 One trial compared single and multiple doses of gentamicin with metronidazole. 46 The primary outcome, composite postpartum infectious morbidity, was described in the majority of included studies. All outcomes were clinical diagnoses defined by criteria remarkably consistent across studies. Endometritis generally involved uterine tenderness, local malodorous discharge and fever. Wound infection normally included the presence of local induration and tenderness. Urinary tract infection usually required the presence of fever, positive urine culture and symptoms related to the urinary tract. Risk of bias assessment Assessment of risk of bias is portrayed in Figure 1. The methodological quality of the trials was predominately unclear because the majority of studies were performed years ago. Five studies were judged as low risk of selection bias due to adequate methods of randomisation. 36,37,46,47,50 Three studies were classified as quasi-rct and consequently assessed as high risk. 43,48,49 Regarding allocation concealment, only three studies reported in sufficient detail how they addressed selection bias. 39,46,50 The majority failed thoroughly to describe the method used to generate or conceal the allocation sequence. Concerning performance bias, five studies adequately reported all measures used to blind participants and personnel, and were considered to contain a low risk of bias. 35,39,42,46,50 One trial failed to completely describe blinding, with study design suggesting high risk. 43 Two studies described blinding of outcome assessment and were categorised as low risk. 39,46 Most studies did not clearly report performance or detection bias and were judged as having an unclear risk of bias. In most studies, all women allocated to randomisation were included in the data analysis. Where there were Figure 1. Risk of bias assessment: review authors judgements about methodological quality. 598

5 Antibiotic prophylaxis in caesarean section dropouts, sufficient information concerning the reasons for exclusion was presented. However, some studies poorly defined the outcomes of interest and failed accurately to report information concerning women excluded from the analysis, and these wsere therefore deemed to have a high risk of bias. 39,45,47 49 With the exception of one trial, which was judged as low risk, 46 all other studies were judged as unclear risk, as there were no protocols available. No other important sources of bias were identified. Therefore, all trials were judged as low risk. Results for the main comparison Postpartum infectious morbidity was reported by 16 studies, which demonstrated a nonsignificant difference between single dose and multiple dose [pooled risk ratio (RR) 0.95, 95% confidence interval (CI) ; 2695 women; random effects (s 2 = 0.05, v 2 = 20.01, P = 0.17; I 2 = 25%; Figure 2)]. Multiple dose did not significantly affect the risk of endometritis, as demonstrated by eight studies 35,36,38,39,41,43,45,47 [pooled RR 1.03, 95% CI ; 1271 women; random effects (s 2 = 0.00; v 2 = 4.70; P = 0.70, I 2 = 0%; Figure S2)] or the risk of wound infection, as reported by nine studies 35,39,41,43 45,47,48,50 [(pooled RR 1.22, 95% CI ; nine studies, 1294 women; random effects (s 2 = 0.00; v 2 = 6.60; P = 0.58; I 2 = 0%; Figure S3)]. Nine studies 35,39 41,43 45,48,49 demonstrated a trend toward a lower risk of urinary tract infection, displaying a 35% nonsignificant reduction with multiple dose [(pooled RR 0.65, 95% CI ; 1238 women; random effects (s 2 = 0.00, v 2 = 5.23, P = 0.73, I 2 = 0%; Figure S4)] For a summary of findings for the main comparison, see Table 1. Subgroup analysis for the primary outcome For an overview of the results regarding the subgroup analysis, see Table 2. Subgroup analysis by antibiotic agent All subgroups based on antibiotic agent demonstrated nonsignificant differences when comparing single dose and multiple dose (Figure S5). With the exception of cefoxitin, which displayed a trend towards lower risk of postpartum infectious morbidity with multiple dose [pooled RR 0.55, 95% CI ; three studies, 39,43,45 79 women; random effects (s 2 = 0.16; v 2 = 3.86, P = 0.15, I 2 = 48%)], all other antibiotic agents reported nonsignificant increases. The largest risk increase was noted with piperacillin [(pooled RR 1.17, 95% CI ; three studies, 37,44, women; random effects (s 2 = 0.00; v 2 = 0.60; P = 0.74; I 2 = 0%)]. Three studies reported on mezlocillin 35,40,42 [pooled RR 1.08, 95% CI ; 328 women; random effects (s 2 = 0.00; v 2 = 1.95; P = 0.38; I 2 = 0%)]. Two studies addressed the use of cefotaxime 38,48 [pooled RR 1.12, 95% CI ; 200 women; random effects (s 2 = 0.00; v 2 = 0.25; P = 0.62; I 2 = 0%)]. The smallest risk increase was observed with cefazolin [pooled RR 1.03, 95% CI ; two studies, 36, women; random effects (s 2 = 0.00; v 2 = 0.93; P = 0.33; I 2 = 0%)]. The combination regimens of cefazolin, ampicillin, gentamicin, with metronidazole, were reported by one study each. 46,49,50 Figure 2. Forest plot for main comparison showing results for the outcome Postpartum Infectious Morbidity. 599

6 Pinto-Lopes et al. Table 1. Summary of findings for main comparison Single dose versus multiple dose of antibiotic prophylaxis in cesarean section: a systematic review and meta-analysis Patient or population: women undergoing cesarean section Setting: Hospitals in the Netherlands, Italy, USA, Canada, Israel, United Arab Emirates, Nepal, Pakistan, Tanzania. Intervention: multiple dose; Comparison: single dose Outcomes Anticipated absolute effects* (95% CI) Relative effect No. of participants Quality of the evidence Risk with single dose Risk with multiple dose (95% CI) (studies) (GRADE) Composite postpartum Study population RR infectious morbidity 141 per per 1000 ( ) ( ) (16 RCTs) VERY LOW**, ***, **** Moderate 138 per per 1000 ( ) Endometritis Study population RR per per 1000 (81 156) ( ) (8 RCTs) VERY LOW**, ***, **** Moderate 68 per per 1000 (50 97) Wound infection Study population RR per per 1000 (30 88) ( ) (9 RCTs) VERY LOW**, ***, **** Moderate 22 per per 1000 (16 46) Urinary tract infection Study population RR per per 1000 (15 55) ( ) (9 RCTs) VERY LOW**, ***, **** Moderate 46 per per 1000 (16 57) *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect **Most studies contributing data had design limitations. ***Wide confidence interval crossing the line of no effect. ****Visual inspection of funnel plot reveals asymmetry. Subgroup analysis by antibiotic class Overall, three major antibiotic classes were identifiable penicillins, cephalosporins and aminoglycosides (Figure S6). Seven studies reported a nonsignificant risk increase with multiple dose of penicillins 35,37,40,42,44,47,50 [pooled RR 1.15, 95% CI ; 919 women; random effects (s 2 = 0.00; v 2 = 2.98; P = 0.81, I 2 = 0%)]. On the other hand, a 21% nonsignificant risk reduction was noted with multiple dose of cephalosporins [pooled RR 0.79, 95% CI ; eight studies, 36,38,39,41,43,45,48, women; random effects (s 2 = 0.13; v 2 = 13.16; P = 0.07; I 2 = 47%)]. Only one study reported on an aminoglycoside. 46 Subgroup analysis by number of antibiotics Regarding the number of antibiotics used for prophylaxis, a trend towards a risk reduction using multiple dose was demonstrated with monotherapy [pooled RR 0.90, 95% CI ; 13 studies, 35 45,47, women; random effects (s 2 = 0.07; v 2 = 17.95; P = 0.12; I 2 = 33%)] (Figure S7). On the other hand, the combinations of antibiotics 600

7 Antibiotic prophylaxis in caesarean section Table 2. Subgroup analysis postpartum infectious morbidity RR CI I 2 s 2 By antibiotic agent Mezlocillin (3 trials) % 0 Piperacillin (3 trials) % 0 Cefoxitin (3 trials) % 0.16 Cefotaxime (2 trials) % 0 Cefazolin (2 trials) % 0 Cefazolin + metronidazole NA NA (1 trial) Ampicillin + metronidazole NA NA (1 trial) Gentamicin + metronidazole NA NA (1 trial) By antibiotic class Penicillins (7 trials) % 0 Cephalosporins (8 trials) % 0.13 Aminoglycosides (1 trial) NA NA By number of antibiotics Single antibiotic (13 trials) % 0.07 Combination of % 0 antibiotics (3 trials) By setting Low resource setting (5 trials) % 0 High resource setting (11 trials) % 0.1 By type of caesarean section Emergency CS (5 trials) % 0 Elective CS (3 trials) % 0 Both types of CS (8 trials) % 0.17 CI, confidence interval; CS, caesarean section; I 2, I-squared; NA, not applicable; RR, risk ratio; s 2, tau-squared. demonstrated a nonsignificant risk increase with multiple dose [pooled RR 1.34, 95% CI ; three studies, 46,49, women; random effects (s 2 = 0.00; v 2 = 0.21; P = 0.90; I 2 = 0%)]. Subgroup analysis by setting Concerning the setting in which the studies occur, a 12% nonsignificant risk reduction with multiple dose was demonstrated in the high resource setting subgroup [pooled RR 0.88, 95% CI ; 11 studies, women; random effects (s 2 = 0.10; v 2 = 16.97; P = 0.07; I 2 = 41%)] (Figure S8). However, the low resource setting subgroup demonstrated a trend towards an increased risk with multiple dose [pooled RR 1.26, 95% CI ; five studies, women; random effects (s 2 = 0.00; v 2 = 0.87; P = 0.93; I 2 = 0%)]. Subgroup analysis by type of caesarean In both the emergency and elective caesarean section subgroups there was a nonsignificant difference in the risk of postpartum infectious morbidity (Figure S9). Five studies reported on emergency caesarean section 40 43,46 [pooled RR 1.13, 95% CI ; 1081 women; random effects (s 2 = 0.00; v 2 = 1.91; P = 0.75; I 2 = 0%)]. Three studies addressed elective caesarean section [pooled RR 1.11, 95% CI ; 293 women; random effects (s 2 = 0.00; v 2 = 0.54; P = 0.76; I 2 = 0%)]. In addition, the both types of caesarean section subgroup displayed a 14% nonsignificant decrease in the risk of postpartum infectious morbidity [pooled RR 0.86, 95% CI ; eight studies, 35 39,44,45, women; random effects (s 2 = 0.17; v 2 = 15.29; P = 0.03; I 2 = 54%)]. Publication bias There was potential for publication bias, for all outcomes assessed, given the asymmetry of the corresponding funnel plots (see Figure S10). Quality of the body of evidence The GRADE approach was used to assess the quality of the body of evidence (for each individual outcome) considering risk of bias, heterogeneity, directness of evidence, precision of effect estimates and risk of publication bias. 32 Among the four possible levels of quality (high, moderate, low and very low), all outcomes evaluated were downgraded one level for risk of bias, one level for imprecision and one level for risk of publication bias. Ultimately, the quality of evidence was classified as very low for all outcomes. Sensitivity analysis Two separate sensitivity analysis were performed for the primary outcome. The first sensitivity analysis, which consisted of sequentially omitting studies, reported a significant improvement of heterogeneity when omitting one study 45 (see Table S3). The second analysis considered study quality, therefore excluding the three quasi- RCTs. 43,48,49 The overall findings did not change appreciably in either direction, with the exception of an increase in heterogeneity (see Table S4). Discussion Main findings This review included 16 studies, encompassing 2695 women, which addressed the use of antibiotic prophylaxis in caesarean section. In conformity with the literature, this review demonstrated no significant difference between single and multiple dose regimens of antibiotic prophylaxis in the incidence of composite postpartum infectious morbidity, endometritis, wound infection or urinary tract infection. However, a trend towards a decreased risk of urinary tract infection was noted when using a multiple dose regimen. See Summary of findings for the main comparison (Table 1). Considering the effect of specific antibiotic 601

8 Pinto-Lopes et al. agents, a nonsignificant risk decrease in postpartum infectious morbidity with second generation cephalosporin, cefoxitin, contrasted with an overall increase in other classes and agents studied, when using multiple dose regimens. Although nonsignificant, opposite effects were seen when the antibiotics were administered in monotherapy or in combination, with multiple dose associated with lower incidence of postpartum infectious morbidity when given in monotherapy. Similar estimates of effect when comparing high and low resource settings were demonstrated, with decreased risk of the primary outcome occurring with multiple doses. No overall differences were identified between single and multiple dose regimens when considering the type of caesarean section. Strengths and limitations This review was based upon a rigorous methodology which followed the recommended guidelines. 31 An extensive and well-designed literature search to identify all relevant trials, with no language restrictions, was conducted. Two review authors independently determined eligibility for inclusion, carried out data extraction and assessed quality, using validated methods. Reproducible statistical techniques were used for the meta-analysis and results were thoroughly reported. Nonetheless, this study is subject to several limitations. Like any systematic review and meta-analysis, its quality depends upon the quality of the original data included. Most studies were conducted several years ago and failed to describe the methods used for allocation, concealment or blinding. These design limitations ultimately affected the quality of the body of evidence for all outcomes assessed. The possibility of publication bias, which could not be rejected, further downgraded this quality. In addition, we were unable to contact authors of older studies when clarifications were needed. Interpretation The beneficial effect of antibiotic prophylaxis in caesarean section has long been established in the literature 16,17 and current international guidelines recommend its use for all women undergoing this procedure. 18,19 Several studies have already addressed the use of single versus multiple doses of antibiotic prophylaxis in caesarean section, reporting equivalent efficacy with both regimens. 20,22 Traditionally, a single dose of a first-generation cephalosporin is the agent of choice. The rationale for this recommendation is that this agent is considered cost-effective when compared with broad-spectrum antibiotics or multiple dose regimens However, there is considerable inconsistency in the implementation of this recommendation This is driven by concerns regarding the drug of choice, optimal regimen, adverse effects, bacterial resistance and economic resources. 20 The purpose of this review was to update current recommendations in light of the recent published data in the literature. Andrews et al. 23 reported lower endometritis and wound infection rates when administering multiple dose versus single dose antibiotics. Follow-up observational studies confirmed these findings. 24,25 Despite recent evidence, we found no significant difference between single and multiple dose of antibiotic prophylaxis in caesarean section. Limiting the included studies to comparisons of the same antibiotic agents explains the absence of recent quality trials, comparing different regimens, which might have significantly affected the results. The goal of antibiotic prophylaxis is to achieve effective tissue levels at the time of contamination, and therefore the optimal agent should be long-acting. 20 One would expect that multiple dose regimens would be, at some level, associated with lower rates of infection. Although nonsignificant, we frequently noticed higher risks of infection with multiple dose regimens. Given the overall unclear risk of bias of the included studies, impaired randomisation with loss of comparable groups could explain this result. Urinary catheters are routinely used in caesarean sections to prevent postoperative urinary retention. 19 As invasive medical devices, their presence is associated with higher incidence of urinary tract infections. Considering the lower genital tract to be the main source of infection after a caesarean section, 20 as long as the urinary catheter is in place, a potential entry site for microorganisms persists. Therefore, the observed trend towards a lower incidence of urinary tract infection with multiple dose antibiotics is presumably explained by the maintenance of adequate tissue levels for longer periods of time, better achieved with multiple dose than single dose regimens. Among the included studies, Roex et al. 45 significantly increased heterogeneity, producing a plausible explanation for the reported trend of lower rates of infectious morbidity with multiple doses of the second-generation cephalosporin, cefoxitin. Conclusion Considerations based on data presented in this review should take into account the very low quality of the body of evidence for all outcomes assessed. This meta-analysis found insufficient evidence to determine whether there is a difference between single dose and multiple dose regimens of antibiotic prophylaxis in reducing the incidence of infectious morbidity in women undergoing caesarean section. Despite not reaching statistical significance, a trend towards a lower incidence of urinary tract infection was observed with multiple dose regimens of antibiotic prophylaxis. 602

9 Antibiotic prophylaxis in caesarean section Practical and research recommendation Given current evidence, the policy of single dose antibiotic prophylaxis in caesarean section should not be modified. Whereas not a data-driven practice, this minimalistic approach complies with pharmacological and microbiological principles of optimising drug exposure to minimise selection of multiresistant organisms. Nonetheless, the choice of optimal regimen should be made on an individual basis, according to factors inherent to the mother, infant and setting. The judicious use of antibiotics is becoming acutely relevant nowadays. There is a critical need for better designed randomised controlled trials that determine the most effective antibiotic regimen for caesarean section. It is of great importance to confirm the recent published data showing a lower infectious morbidity with multiple dose antibiotics, especially in a subset of high-risk women Further research investigating the impact of current practices in bacterial resistance is urgent. Future trials should evaluate optimal timing for administration and the adverse outcomes on mother and infant. Other interventions to further reduce infection rates in caesarean deliveries should also be investigated. Disclosure of interests None declared. Completed disclosure of interests form available to view online as supporting information. Contribution to authorship RP-L and LFA conceived the review question for this study. RP-L developed the search strategy and conducted the literature review. Both RP-L (as first reviewer) and BS-P (as second reviewer) independently screened the title and abstract of identified studies, carried out data extraction from included studies and assessed trial quality. RP-L performed the statistical analysis and interpreted the results. LFA provided statistical guidance and contributed to the interpretation of data. RP-L drafted the manuscript and LFA critically reviewed it, approving the final version. Details of ethics approval Ethics approval was not required, as this is a systematic review of published studies. Funding No funding was received. Acknowledgements The authors would like to thank Daniel Lima Moura, M.D. Ph.D., for his valuable contribution and insight during the initial development of this review. Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1. Preferred reporting items for Systematic Reviews and Meta- Analyses (PRISMA) flow diagram showing study selection process. Figure S2. Forest plot for main comparison showing results for the outcome Endometritis. Figure S3. Forest plot for main comparison showing results for the outcome Wound infection. Figure S4. Forest plot for main comparison showing results for the outcome Urinary tract infection. Figure S5. Forest plot for subgroup analysis by antibiotic agent showing results for outcome Postpartum Infectious Morbidity. Figure S6. Forest plot for subgroup analysis by antibiotic class showing results for outcome Postpartum Infectious Morbidity. Figure S7. Forest plot for subgroup analysis by number of antibiotics showing results for outcome Postpartum Infectious Morbidity. Figure S8. Forest plot for subgroup analysis by setting showing results for outcome Postpartum infectious Morbidity. Figure S9. Forest plot for subgroup analysis by type of caesarean showing results for outcome Postpartum Infectious Morbidity. Figure S10. Funnel plots for main comparison showing results for all outcomes (A Postpartum Infectious Morbidity; B Endometritis; C Wound Infection D Urinary tract Infection). Table S1. Search strategy tailored to specific database. Table S2. General characteristics of included studies. Table S3. Sensitivity analysis. Table S4. Sensitivity Analysis for Quasi-RCTs. & References 1 Victora CG, Barros FC. Beware: unnecessary caesarean sections may be hazardous. Lancet 2006;367: Steer PJ, Modi N. Elective caesarean sections risks to the infant. Lancet 2009;374: Mi J, Liu F. Rate of caesarean section is alarming in China. Lancet 2014;383: Hall MH. Editorial: what is the right number of caesarean sections? Lancet 1997;349: OECD. Health at a Glance 2015: OECD Indicators. Paris: OECD Publishing, Osterman MJ, Kochanek KD, MacDorman MF, Strobino DM, Guyer B. Annual summary of vital statistics: Pediatrics 2015;135: Vogel JP, Betran AP, Vindevoghel N, Souza JP, Torloni MR, Zhang J, et al. Use of the Robson classification to assess caesarean section trends in 21 countries: a secondary analysis of two WHO multicountry surveys. Lancet Glob Health 2015;3:e

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