Hernia CC

Cochrane Database of Systematic Reviews
Routes of administration of antibiotic prophylaxis for

preventing infection after caesarean section (Review)
Nabhan AF, Allam NE, Hamed Abdel-Aziz Salama M
Nabhan AF, Allam NE, Hamed Abdel-Aziz Salama M.

Routes of administration of antibiotic prophylaxis for preventing infection after caesarean section.
Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD011876.
DOI: 10.1002/14651858.CD011876.pub2.
www.cochranelibrary.com
Routes of administration of antibiotic prophylaxis for preventing infection after caesarean section (Review)
Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Analysis 1.1. Comparison 1 Intravenous (IV) versus irrigation, Outcome 1 Endometritis. . . . . . . . . . . 40
Analysis 1.2. Comparison 1 Intravenous (IV) versus irrigation, Outcome 2 Wound infection. . . . . . . . . 41
Analysis 1.3. Comparison 1 Intravenous (IV) versus irrigation, Outcome 3 Postpartum febrile morbidity. . . . . 42
Analysis 1.4. Comparison 1 Intravenous (IV) versus irrigation, Outcome 4 Urinary tract infection. . . . . . . . 43
Analysis 1.5. Comparison 1 Intravenous (IV) versus irrigation, Outcome 5 Serious infectious complication. . . . 43
Analysis 1.6. Comparison 1 Intravenous (IV) versus irrigation, Outcome 6 Adverse events (maternal). . . . . . 44
Analysis 1.7. Comparison 1 Intravenous (IV) versus irrigation, Outcome 7 Maternal length of hospital stay (days). . 45
Analysis 2.1. Comparison 2 Intravenous versus irrigation: sensitivity analysis, Outcome 1 Endometritis. . . . . . 46
Analysis 2.2. Comparison 2 Intravenous versus irrigation: sensitivity analysis, Outcome 2 Wound infection. . . . 47
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 48
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Routes of administration of antibiotic prophylaxis for preventing infection after caesarean section (Review) i
[Intervention Review]
Routes of administration of antibiotic prophylaxis for

preventing infection after caesarean section
Ashraf F Nabhan1 , Nahed E Allam2 , Mohamed Hamed Abdel-Aziz Salama3

1 Departmentof Obstetrics and Gynaecology, Faculty of Medicine, Ain Shams University, Cairo, Egypt. 2 Department of Obstetrics
and Gynaecology, Alazhar University, Cairo, Egypt. 3 Faculty of Medicine, Ain Shams University, Cairo, Egypt
Contact address: Ashraf F Nabhan, Department of Obstetrics and Gynaecology, Faculty of Medicine, Ain Shams University, 16 Ali
Fahmi Kamel Street, Heliopolis, Cairo, 11351, Egypt. ashraf.nabhan@gmail.com. anabhan@med.asu.edu.eg.
Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: New, published in Issue 6, 2016.
Review content assessed as up-to-date: 6 January 2016.
Citation: Nabhan AF, Allam NE, Hamed Abdel-Aziz Salama M. Routes of administration of antibiotic prophylaxis for pre-
venting infection after caesarean section. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD011876. DOI:
10.1002/14651858.CD011876.pub2.
ABSTRACT
Background
Post-caesarean section infection is a cause of maternal morbidity and mortality. Administration of antibiotic prophylaxis is recommended
for preventing infection after caesarean delivery. The route of administration of antibiotic prophylaxis should be effective, safe and
convenient. Currently, there is a lack of synthesised evidence regarding the benefits and harms of different routes of antibiotic prophylaxis
for preventing infection after caesarean section.
Objectives
The aim of this review was to assess the benefits and harms of different routes of prophylactic antibiotics given for preventing infectious
morbidity in women undergoing caesarean section.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (31 January 2016), ClinicalTrials.gov, the WHO Inter-
national Clinical Trials Registry Platform (ICTRP) (6 January 2016) and reference lists of retrieved studies.
Selection criteria
We included randomised controlled trials (RCTs) comparing at least two alternative routes of antibiotic prophylaxis for caesarean
section (both elective and emergency). Cross-over trials and quasi-RCTs were not eligible for inclusion.
Data collection and analysis
Two review authors independently assessed trials for inclusion, assessed the risk of bias and extracted data from the included studies.
These steps were checked by a third review author.
Main results
We included 10 studies (1354 women). The risk of bias was unclear or high in most of the included studies.
All of the included trials involved women undergoing caesarean section whether elective or non-elective.
Routes of administration of antibiotic prophylaxis for preventing infection after caesarean section (Review) 1
Intravenous antibiotics versus antibiotic irrigation (nine studies, 1274 women)
Nine studies (1274 women) compared the administration of intravenous antibiotics with antibiotic irrigation. There were no clear
differences between groups in terms of this review’s maternal primary outcomes: endometritis (risk ratio (RR) 0.95, 95% confidence
interval (CI) 0.70 to 1.29; eight studies (966 women) (low-quality evidence)); wound infection (RR 0.49, 95% CI 0.17 to 1.43; seven
studies (859 women) (very low-quality evidence)). The outcome of infant sepsis was not reported in the included studies.
In terms of this review’s maternal secondary outcomes, there were no clear differences between intravenous antibiotic or irrigation
antibiotic groups in terms of postpartum febrile morbidity (RR 0.87, 95% CI 0.48 to 1.60; three studies (264 women) (very low-
quality evidence)); or urinary tract infection (RR 0.74, 95% CI 0.25 to 2.15; five studies (660 women) (very low-quality evidence)). In
terms of adverse effects of the treatment on the women, no drug allergic reactions were reported in three studies (284 women) (very
low-quality evidence), and there were no cases of serious infectious complications reported (very low-quality evidence). There was no
clear difference between groups in terms of maternal length of hospital stay (mean difference (MD) 0.28 days, 95% CI -0.22 to 0.79
days, (random-effects analysis), four studies (512 women). No data were reported for the number of women readmitted to hospital.
For the baby, there were no data reported in relation to oral thrush, infant length of hospital stay or immediate adverse effects of
the antibiotics on the infant.
Intravenous antibiotic prophylaxis versus oral antibiotic prophylaxis (one study, 80 women)
One study (80 women) compared an intravenous versus an oral route of administration of prophylactic antibiotics, but did not report
any of this review’s primary or secondary outcomes.
Authors’ conclusions
There was no clear difference between irrigation and intravenous antibiotic prophylaxis in reducing the risk of post-caesarean en-
dometritis. For other outcomes, there is insufficient evidence regarding which route of administration of prophylactic antibiotics is
most effective at preventing post-caesarean infections. The quality of evidence was very low to low, mainly due to limitations in study
design and imprecision. Furthermore, most of the included studies were underpowered (small sample sizes with few events). Therefore,
we advise caution in the interpretation and generalisability of the results.
For future research, there is a need for well-designed, properly-conducted, and clearly-reported RCTs. Such studies should evaluate the
more recently available antibiotics, elaborating on the various available routes of administration, and exploring potential neonatal side
effects of such interventions.
PLAIN LANGUAGE SUMMARY

What is the most effective and safe way to administer antibiotics to prevent infection for women undergoing caesarean section
What is the issue?
Caesarean delivery increases the risk for infection compared to vaginal birth by five- to 20-fold. Infections can be of the surgical incision,
the lining of the uterus, and inside the pelvis. Clinicians seek to prevent these infections by different measures including prophylactic
(preventative) antibiotics.
Why is this important?
Antibiotics can be given by a number of different routes including by mouth, injection into a vein or by washing inside the uterus and
the surgical site with a saline solution containing the antibiotic. We assessed the benefits and harms of different routes of prophylactic
antibiotics given for preventing infections in women undergoing caesarean section.
What evidence did we find?
We searched for evidence from randomised controlled trials on 6 January 2016 and found 10 studies (involving a total of 1354 women).
Nine studies (1274 women) compared intravenous antibiotic administration with antibiotic irrigation (washing with a saline solution
containing antibiotics). The two routes gave similar results on important outcomes including infection of the uterus/womb (low-quality
evidence) and wound infection (very low-quality evidence). The studies did not report on blood infections in the newborn infant (sepsis).
The numbers of women who had urinary tract infection (very low-quality evidence), serious infectious complications (very low-quality
evidence) or fever after birth (very low-quality evidence) also did not clearly differ between groups. There was no clear difference between
groups in terms of how long women spent in hospital and no data reported on the number of women who were readmitted to hospital.
No women had allergic reactions to the antibiotics (very low-quality evidence) in the three studies that reported this outcome. None of
the studies reported information about whether the babies had any immediate adverse reactions to the antibiotics.
One study (involving 80 women) compared intravenous antibiotics with taking antibiotics orally but it did not report on any of this
review’s outcomes.
What does this mean?
The studies included in this review did not clearly report how they were carried out and outcome data were incomplete. Too few
women were included in each study for sufficient numbers of events to see a clear difference in outcomes between the two groups of
women. This meant the evidence was of low quality. Therefore, we need to exercise caution in the interpretation and generalisability
of the results.
High-quality studies are needed to determine the safest, most effective way of giving preventive antibiotics. Such studies should evaluate
more recently available antibiotics and consider potential side effects that the intervention may have for the baby.
Routes of administration of antibiotic prophylaxis for preventing infection after caesarean section (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Intravenous route compared with irrigation (lavage) for administration of antibiotic prophylaxis for preventing infection after caesarean section
Patient or population: pregnant wom en undergoing caesarean section

Setting: hospital in-patients
Intervention: intravenous route of prophylactic antibiotics
Comparison: irrigation (lavage) containing antibiotics
Outcomes Anticipated absolute effects∗ (95% CI) Relative effect of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Risk with irrigation Risk with Intravenous

route
Endom etritis 142 per 1000 135 per 1000 RR 0.95 966 ⊕⊕
(99 to 183) (0.70 to 1.29) (8 RCTs) LOW 12
Wound inf ection 21 per 1000 10 per 1000 RR 0.49 859 ⊕

(4 to 30) (0.17 to 1.43) (7 RCTs) VERY LOW 13
Postpartum f ebrile 138 per 1000 120 per 1000 RR 0.87 264 ⊕
m orbidity (66 to 222) (0.48 to 1.60) (3 RCTs) VERY LOW 13
Urinary tract inf ection 21 per 1000 15 per 1000 RR 0.74 660 ⊕
(5 to 45) (0.25 to 2.15) (5 RCTs) VERY LOW 13
Serious inf ectious com - 0 per 1000 0 per 1000 not estim able 81 ⊕ No events in one study.
plications (0 to 0) (1 RCT) VERY LOW 14
Adverse events (m ater- 0 per 1000 0 per 1000 not estim able 284 ⊕ No events in three stud-
nal) (0 to 0) (3 RCTs) VERY LOW 15 ies.
Inf ant sepsis (sus- see com m ent see com m ent not estim able - - Not m easured by any of
pected or proven) - not the included studies
m easured
4
Routes of administration of antibiotic prophylaxis for preventing infection after caesarean section (Review)
* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its
95% CI).
CI: Conf idence interval; RR: Risk ratio.
GRADE Working Group grades of evidence

High quality: We are very conf ident that the true ef f ect lies close to that of the estim ate of the ef f ect.
M oderate quality: We are m oderately conf ident in the ef f ect estim ate. The true ef f ect is likely to be close to the estim ate of the ef f ect, but there is a possibility that it is
substantially dif f erent.
Low quality: Our conf idence in the ef f ect estim ate is lim ited. The true ef f ect m ay be substantially dif f erent f rom the estim ate of the ef f ect.
Very low quality: We have very little conf idence in the ef f ect estim ate. The true ef f ect is likely to be substantially dif f erent f rom the estim ate of ef f ect
1 Studies with design lim itations (-1)
2 Optim al inf orm ation size criterion is not m et and the 95% conf idence interval includes no ef f ect (-1)
3 Studies include relatively f ew patients and f ew events and have a wide 95% conf idence interval that includes both appreciable
benef it and appreciable harm (-2)

4 One study with no events (-2)
5 Three studies with no events (-2)
5
BACKGROUND care after leaving the hospital (Maharaj 2007). Other risk factors
include pre-existing operative site infection, breaks in sterile tech-
Caesarean section is probably the most commonly performed ma-
nique, use of electrocautery, advanced maternal age (Magee 1994),
jor obstetric procedure, and rates are increasing globally. Although,
prolonged preoperative admissions, low socioeconomic status, re-
it is mostly a straightforward, uncomplicated surgery, caesarean
peated vaginal examinations during labour (Olsen 2008), inter-
section remains the single most important risk factor for puerperal
nal fetal monitoring, urinary tract infection, development of SC
infection. The incidence of post-caesarean infection varies widely
haematoma, the skill of the operator, method of placental removal
worldwide, ranging from 2.5% to 20.5% (Conroy 2012). Women
and site of uterine repair (Lasley 1997; Magann 1995; Maharaj
undergoing caesarean section have a greater risk of developing in-
2007).
fection compared with women who have a vaginal birth by five-
to 20-fold (Declercq 2007; Leth 2009).
Causative organism
Post-caesarean infections are typically polymicrobial infections
Description of the condition involving a mixture of gram-positive and gram-negative bacte-
ria, anaerobes (including Peptostreptococcus species and Bacteroides
Post-caesarean section infection includes wound infection and en-
species), Gardnerella vaginalis and genital mycoplasmas (Cox
dometritis. Additionally, urinary tract infection may be associated
1989; Maharaj 2007; Roberts 1993).
with caesarean delivery. In rare cases, pelvic abscess, bacteraemia,
septic shock, septic pelvic vein thrombophlebitis, necrotising fasci-
itis, dehiscence of the wound, or evisceration may occur. The im-
pact of post-caesarean infections include additional cost, the use Description of the intervention
of therapeutic antibiotics, additional surgical interventions, longer There are different interventions that aim to reduce the rate of
duration of hospital stay, and in some cases maternal death at- infection after caesarean delivery including preoperative vaginal
tributed to infection (Cantwell 2011; Lamont 2011). preparation with antiseptic solution (Haas 2014) and prophylactic
antibiotics (Chelmow 2001; Dinsmoor 2009; Doss 2012; Eriksen
Postpartum endometritis 2011; Salim 2011; Smaill 2014).
There are different routes of administration of perioperative an-
Postpartum endometritis is one of the commonest complicating
tibiotic prophylaxis including injection, oral, rectal, vaginal lavage
infections, which can follow an aggressive course, progressing into
(Ledger 2006; Liabsuetrakul 2002; Mangram 1999; SIGN 2008;
endomyometritis, up to pelvic abscess or even generalised peri-
Tita 2009). The route of administration of any drug is deter-
tonitis and septicaemia. Caesarean delivery is probably the most
mined by its pharmacological properties and by the therapeutic
important single risk factor for postpartum endometritis, with re-
purposes including the need for a rapid onset of action or long-
ported odds ratios ranging between 5 and 20 (Cox 1989; French
term treatment. Therefore, the route of administration is a deter-
2003; French 2004; Olsen 2010).
minant of the serum and tissue drug levels throughout the proce-
dure that should be adequate to prevent post-caesarean infections.
Wound (surgical site) infection Each route has its advantage and disadvantage (SIGN 2008). Ide-
Wound (surgical site) infection refers to infection of the skin and ally, such a route should be well-tolerated in addition to its effec-
subcutaneous (SC) tissue at the surgical incision site. A post-cae- tiveness.
sarean wound infection detected prior to hospital discharge will Natural orifice routes (oral or rectal), provide less invasive routes,
lead to prolongation of hospital stay and will increase the hospi- but with delayed achievement of target plasma levels. In general,
talisation costs and need readmission (Griffiths 2005; Nice 1996; oral administration is the most convenient with the lowest cost.
Olsen 2008; Roberts 1993; Webster 1988). A rapid delivery can be obtained by breaking the tablets or cap-
sules that come in delayed- or time-release formulations. In some
individuals, the absorption of antibiotics from the gastrointestinal
Risk factors system and thus the effect of oral administration can be unpre-
Post-caesarean section infection is associated with obesity ( dictable. Rectal administration is an easy and relatively painless
Myles 2002), diabetes (Leth 2011), immunosuppressive disorders, route that provides rapid absorption of antibiotics.
chorioamnionitis, rupture of membranes > 18 hours (Chang 1992; Antibiotics can be administered intravenously or by intramuscular
Olsen 2010), corticosteroid therapy, staple suture wound closure, injection. Intravenous administration provides the quickest route
fewer prenatal care visits, repeat caesarean section, emergency cae- to achieve therapeutic plasma levels and has an onset of action of 15
sarean section (Leth 2011), length of surgery > 60 minutes (Killian to 30 seconds. The onset of action for the intramuscular route is 10
2001), a prolonged labour, excessive blood loss during labour, de- to 20 minutes. Most antibiotics have 100% bioavailability when
livery, or surgery, and failure to follow proper steps for wound given by injection. Some antibiotics can only be administered by
injections because they are either poorly absorbed or ineffective antibiotic prophylaxis, which route is most effective at preventing
when given orally. Although intravenous infusion is the mode of post-caesarean infections?
delivery used most often in perioperative prophylaxis, it can cause
complications such as allergic reactions. Injections may cause pain
or discomfort. Injections also require a trained caregiver using
aseptic techniques for administration (Bratzler 2013; SIGN 2008).
OBJECTIVES
The aim of this review is to assess the benefits and harms of differ-
How the intervention might work ent routes of prophylactic antibiotics given to prevent infectious
morbidity in women undergoing caesarean section.
The occurrence of wound infection requires local inoculums (ma-
terial used for inoculation) sufficient to overcome host defences
and establish growth. The process is complex and depends on the
interaction of various hosts, local tissue and microbial virulence METHODS
factors. Antibiotic prophylaxis does not attempt to sterilise tis-
sues, but to reduce the intraoperative microbial burden. There-
fore, the key for effective prophylaxis is to achieve serum and tissue Criteria for considering studies for this review
drug levels that exceed the minimum inhibitory concentration for
the likely causative organisms during the operation (Conte 2002;
Mangram 1999). Types of studies
There is insufficient empirical evidence to show that the parenteral We included all published and unpublished randomised controlled
route is more effective than other routes, whether in prophylaxis trials (RCTs) where the intention was to allocate participants ran-
or treatment in terms of rates of improvement, failure, or relapse domly to one of at least two alternative routes of antibiotic pro-
of infection. The perception that parenteral injections are more phylaxis for caesarean section. Ongoing RCTS and cluster-ran-
effective or have an added effect is not supported by empirical domised RCTs were eligible for inclusion but none were identi-
evidence and is an inadequate reason to choose injection when oral fied. We planned to exclude trials presented only as abstracts where
or rectal antibiotics are less expensive, less painful, and have fewer information on risk of bias and primary or secondary outcomes
serious side effects (Borahay 2011). As the clinical and economic could not be obtained and planned to reconsider these trials for
impact of post-caesarean infections is considerable, an affordable inclusion once the full publication was available. Cross-over trials
convenient route of administration is also required (Chelmow and quasi-RCTs were not eligible for inclusion in this review.
2004; Cooper 2002).
Types of participants
Why it is important to do this review Women undergoing elective or emergency caesarean section.
In view of concerns about post-caesarean section infection as a
cause of direct maternal morbidity and mortality, the specific ques- Types of interventions
tions regarding the best evidence for antibiotic prophylaxis, the Prophylactic antibiotic regimens comparing different routes of an-
class of antibiotic, the dose, the timing, and the route of adminis- tibiotics. We included studies where there was a comparison be-
tration must be answered. The questions regarding antibiotic pro- tween two or more antibiotics from the different classes of an-
phylaxis (Smaill 2014), the class of antibiotics (Gyte 2014), the tibiotics. Different drugs within the same class of antibiotics were
timing of intravenous antibiotics (Mackeen 2014) and regimens used for subgroup analysis.
of penicillin antibiotics (Liu 2014), for caesarean section are tack-
led in other Cochrane reviews. Evidence regarding antibiotic pro-
phylaxis is based on high-quality studies comparing intravenous Types of outcome measures
antibiotics with placebo or no therapy. Currently, there is a lack of
synthesised evidence regarding the benefits and harms of different
routes of administration of antibiotic prophylaxis for preventing Primary outcomes
infection after caesarean section. The route of administration of
antibiotic prophylaxis should be effective, safe, inexpensive, and
convenient for both the woman and her physician. Maternal
Therefore, the current review specifically focuses on the following 1. Endometritis
question: in women undergoing caesarean delivery and receiving 2. Wound infection
Infant 4. monthly searches of CINAHL (EBSCO);
1. Infant sepsis (suspected or proven) 5. handsearches of 30 journals and the proceedings of major
conferences;
6. weekly current awareness alerts for a further 44 journals
Secondary outcomes plus monthly BioMed Central email alerts.
Search results are screened by two people and the full text of all
Maternal relevant trial reports identified through the searching activities de-
scribed above is reviewed. Based on the intervention described,
1. Postpartum febrile morbidity
each trial report is assigned a number that corresponds to a spe-
2. Urinary tract infection
cific Pregnancy and Childbirth Group review topic (or topics),
3. Serious infectious complication (such as bacteraemia, septic
and is then added to the Register. The Trials Search Co-ordinator
shock, septic thrombophlebitis, necrotising fasciitis, or death
searches the Register for each review using this topic number rather
attributed to infection)
than keywords. This results in a more specific search set which has
4. Adverse effects of treatment on the woman (e.g. allergic
been fully accounted for in the relevant review sections (Included
reactions, nausea, vomiting, diarrhoea, skin rashes)
studies; Excluded studies; Studies awaiting classification).
5. Maternal length of hospital stay
In addition, we searched ClinicalTrials.gov and the WHO Interna-
6. Readmissions
tional Clinical Trials Registry Platform (ICTRP) (6 January 2016)
for unpublished, planned and ongoing trial reports (see Appendix
Infant 1 for search strategy).
1. Oral thrush
2. Infant length of hospital stay
3. Immediate adverse effects of antibiotics on the infant Searching other resources
We searched the reference lists of retrieved studies. We did not
apply any language or date restrictions.
Search methods for identification of studies
The following methods section of this review is based on a standard
template used by the Cochrane Pregnancy and Childbirth Group.
The review is based on a published protocol (Nabhan 2015). Data collection and analysis
The following methods section of this review is based on a standard
Electronic searches template used by the Cochrane Pregnancy and Childbirth Group.
We searched the Cochrane Pregnancy and Childbirth Group’s Tri-
als Register by contacting the Trials Search Co-ordinator (31 Jan-
uary 2016). Selection of studies
The Register is a database containing over 21,000 reports of con- Two review authors (NA and MH) independently assessed for
trolled trials in the field of pregnancy and childbirth. For full inclusion all the potential studies we identified as a result of the
search methods used to populate the Pregnancy and Childbirth search strategy. We resolved any disagreement through discussion
Group’s Trials Register including the detailed search strategies for or, if required, we consulted the third review author (AN). We
CENTRAL, MEDLINE, Embase and CINAHL; the list of hand- created a study flow diagram to map out the number of records
searched journals and conference proceedings, and the list of jour- identified, included and excluded.
nals reviewed via the current awareness service, please follow this
link to the editorial information about the Cochrane Pregnancy
and Childbirth Group in the Cochrane Library and select the
Data extraction and management
‘Specialized Register ’ section from the options on the left side of
the screen. We designed a computer form to extract data. For eligible studies,
Briefly, the Cochrane Pregnancy and Childbirth Group’s Trials at least two review authors extracted the data using the agreed
Register is maintained by the Trials Search Co-ordinator and con- form. We resolved discrepancies through discussion or, if required,
tains trials identified from: we consulted the third member of the review team. We entered
1. monthly searches of the Cochrane Central Register of data into Review Manager software (RevMan 2014) and checked
Controlled Trials (CENTRAL); for accuracy. When information regarding any of the above was
2. weekly searches of MEDLINE (Ovid); unclear, we attempted to contact the authors of the original reports
3. weekly searches of Embase (Ovid); to provide further details.
Assessment of risk of bias in included studies We assessed the methods used to blind outcome assessment as:
Two review authors independently assessed risk of bias for each • low, high or unclear risk of bias.
study using the criteria outlined in the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011). We resolved
(4) Incomplete outcome data (checking for possible attrition
any disagreement by discussion or by involving the third review
bias due to the amount, nature and handling of incomplete
author.
outcome data)
We described for each included study, and for each outcome or
(1) Random sequence generation (checking for possible
class of outcomes, the completeness of data including attrition and
selection bias)
exclusions from the analysis. We stated whether attrition and ex-
We described for each included study the method used to generate clusions were reported and the numbers included in the analysis at
the allocation sequence in sufficient detail to allow an assessment each stage (compared with the total randomised participants), rea-
of whether it should produce comparable groups. sons for attrition or exclusion where reported, and whether miss-
We assessed the method as: ing data were balanced across groups or were related to outcomes.
• low risk of bias (any truly random process, e.g. random Where sufficient information was reported, or could be supplied
number table; computer random number generator); by the trial authors, we planned to re-include missing data in the
• high risk of bias (any non-random process, e.g. odd or even analyses which we undertook.
date of birth; hospital or clinic record number); We assessed the methods as:
• unclear risk of bias. • low risk of bias (e.g. no missing outcome data; missing
outcome data balanced across groups);
(2) Allocation concealment (checking for possible selection • high risk of bias (e.g. numbers or reasons for missing data
bias) imbalanced across groups; ‘as treated’ analysis done with
substantial departure of intervention received from that assigned
We described for each included study the method used to con-
at randomisation);
ceal allocation to interventions prior to assignment and assessed
• unclear risk of bias.
whether intervention allocation could have been foreseen in ad-
vance of, or during recruitment, or changed after assignment. For missing data, a cut-off point of 20% was used to assess that a
We assessed the methods as: study was at low risk of bias.
• low risk of bias (e.g. telephone or central randomisation;
consecutively numbered sealed opaque envelopes);
• high risk of bias (open random allocation; unsealed or non- (5) Selective reporting (checking for reporting bias)
opaque envelopes, alternation; date of birth); We described for each included study how we investigated the
• unclear risk of bias. possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
(3.1) Blinding of participants and personnel (checking for • low risk of bias (where it is clear that all of the study’s pre-
possible performance bias) specified outcomes and all expected outcomes of interest to the
We described for each included study the methods used, if any, to review have been reported);
blind study participants and personnel from knowledge of which • high risk of bias (where not all the study’s pre-specified
intervention a participant received. We considered that studies outcomes have been reported; one or more reported primary
were at low risk of bias if they were blinded, or if we judged that outcomes were not pre-specified; outcomes of interest are
the lack of blinding would be unlikely to affect results. We assessed reported incompletely and so cannot be used; study fails to
blinding separately for different outcomes or classes of outcomes. include results of a key outcome that would have been expected
We assessed the methods as: to have been reported);
• low, high or unclear risk of bias for participants; • unclear risk of bias.
• low, high or unclear risk of bias for personnel.
(6) Other bias (checking for bias due to problems not
(3.2) Blinding of outcome assessment (checking for possible covered by (1) to (5) above)
detection bias) We described for each included study any important concerns
We described for each included study the methods used, if any, to we have about other possible sources of bias including: was the
blind outcome assessors from knowledge of which intervention a trial stopped early due to some data-dependent process? Was there
participant received. We assessed blinding separately for different extreme baseline imbalance? Has the study been claimed to be
outcomes or classes of outcomes. fraudulent?
We assessed whether each study was free of other problems that Continuous data
could put it at risk of bias:
For continuous data, we used the mean difference as outcomes
• low risk of other bias;
were measured in the same way between trials. We planned to use
• high risk of other bias;
the standardised mean difference to combine trials that measured
• unclear whether there is risk of other bias.
the same outcome, but used different methods.
(7) Overall risk of bias

Unit of analysis issues
We made explicit judgements about whether studies were at high
risk of bias, according to the criteria given in the Handbook (
Higgins 2011). With reference to (1) to (6) above, we assessed
the likely magnitude and direction of the bias and whether we Cluster-randomised trials
consider it was likely to impact on the findings. We explored the We did not identify any cluster-randomised trials for inclusion in
impact of the level of bias through undertaking sensitivity analyses this version of the review. In future updates, if we identify any
- see Sensitivity analysis. cluster-randomised trials, we will adjust their sample sizes using
the methods described in the Handbook [Section 16.3.4 or 16.3.6]
using an estimate of the intra-cluster correlation co-efficient (ICC)
Assessing the quality of the evidence using the derived from the trial (if possible), from a similar trial or from a
GRADE approach study of a similar population. If we use ICCs from other sources,
We assessed the quality of the evidence using the GRADE ap- we will report this and conduct sensitivity analyses to investigate
proach as outlined in the GRADE handbook in order to assess the the effect of variation in the ICC. If we identify both cluster-
quality of the body of evidence relating to the following outcomes randomised trials and individually-randomised trials, we plan to
for the main comparisons. synthesise the relevant information. We will consider it reasonable
1. Endometritis to combine the results from both if there is little heterogeneity
2. Wound infection between the study designs and the interaction between the effect
3. Postpartum febrile morbidity of intervention and the choice of randomisation unit is considered
4. Urinary tract infection to be unlikely. We will also acknowledge heterogeneity in the ran-
5. Serious infectious complication domisation unit and perform a sensitivity analysis to investigate
6. Adverse effects of treatment on the woman the effects of the randomisation unit.
7. Infant sepsis (suspected or proven)
We used the GRADEpro Guideline Development Tool to import
data from Review Manager 5.3 (RevMan 2014) in order to create Multi-armed trials
a ’Summary of findings’ table (see Summary of findings for the We anticipated the presence of multi-armed studies, therefore we
main comparison). A summary of the intervention effect and a combined groups of similar routes to create a single pair-wise com-
measure of quality for each of the above outcomes were produced parison.
using the GRADE approach. The GRADE approach uses five con-
siderations (study limitations, consistency of effect, imprecision,
indirectness and publication bias) to assess the quality of the body Dealing with missing data
of evidence for each outcome. The evidence can be downgraded
from ’high quality’ by one level for serious (or by two levels for very For included studies, we noted levels of attrition and contacted
serious) limitations, depending on assessments for risk of bias, in- the study authors, but we failed to obtain additional data. For all
directness of evidence, serious inconsistency, imprecision of effect outcomes, we carried out analyses, as far as possible, on an in-
estimates or potential publication bias. tention-to-treat basis, i.e. we attempted to include all participants
randomised to each group in the analyses, and all participants were
analysed in the group to which they were allocated, regardless of
Measures of treatment effect whether or not they received the allocated intervention. The de-
nominator for each outcome in each trial were the number ran-
domised minus any participants whose outcomes were known to
be missing.
Dichotomous data
Finally, we explored the impact of including studies with high
For dichotomous data, we presented results as summary risk ratio levels of missing data in the overall assessment of treatment effect
with 95% confidence intervals. by using sensitivity analysis.
Assessment of heterogeneity wound infection). We assessed subgroup differences by interaction
We assessed statistical heterogeneity in each meta-analysis using tests available within RevMan (RevMan 2014). We reported the
the Tau², I² and Chi² statistics. We regarded heterogeneity as sub- results of subgroup analyses quoting the Chi2 statistic and P value,
stantial if an I² was greater than 30% and either a Tau² was greater and the interaction test I² value.
than zero, or there was a low P value (less than 0.10) in the Chi² It was not possible to carry out the following planned subgroup
test for heterogeneity. analyses due to insufficient data - these will be performed in future
updates, if appropriate.
1. By type of caesarean delivery: elective versus non-elective
Assessment of reporting biases versus not defined.
In future updates of this review, if we include 10 or more studies in 2. By time of administration: before cord clamping versus
a meta-analysis, we will investigate reporting biases (such as pub- after cord clamping versus not defined.
lication bias) using funnel plots. We will assess funnel plot asym- 3. By type of antibiotic in each class of antibiotics.
metry visually. If asymmetry is suggested by a visual assessment,
we will perform exploratory analyses to investigate it.
Sensitivity analysis
We carried out a sensitivity analysis to explore the effects of trial
Data synthesis
quality assessed by omitting studies rated as ’high risk of bias’ and
We carried out statistical analysis using the Review Manager soft- ’unclear risk of bias’ when considering incomplete outcome data
ware (RevMan 2014). We used fixed-effect meta-analysis for com- (attrition bias). We restricted sensitivity analysis to the primary
bining data where it was reasonable to assume that studies were outcomes. We did not carry out sensitivity analysis considering al-
estimating the same underlying treatment effect: i.e. where trials location concealment (selection bias) since we judged all included
were examining the same intervention, and the trials’ populations trials to be at an unclear risk of bias. In future updates, if we in-
and methods were judged sufficiently similar. If there was clinical clude cluster-RCT trials along with individually-randomised trials
heterogeneity sufficient to expect that the underlying treatment ef- in our analyses, we will carry out sensitivity analysis to investigate
fects differed between trials, or if substantial statistical heterogene- the effect of the randomisation unit.
ity was detected, we used random-effects meta-analysis to produce
an overall summary, if an average treatment effect across trials was
considered clinically meaningful. The random-effects summary
was treated as the average of the range of possible treatment effects
and we discussed the clinical implications of treatment effects dif- RESULTS
fering between trials. If the average treatment effect was not clin-
ically meaningful, we did not combine trials.
Where we used random-effects analyses, the results are presented Description of studies
as the average treatment effect with 95% confidence intervals, and
the estimates of Tau² and I².
Results of the search
Subgroup analysis and investigation of heterogeneity The search of the Cochrane Pregnancy and Childbirth Group’s
Where we identified substantial heterogeneity, we investigated it Trials Register retrieved 16 reports (of 15 studies as two records
using subgroup analyses and sensitivity analyses. We considered reported a single study). We did not identify any additional reports
whether an overall summary was meaningful, and if it was, used through other sources. We did not identify any ongoing or unpub-
random-effects analysis to produce it. lished reports (see: Figure 1). Ten studies are included, excluded
We carried out subgroup analysis by dosage as pre-specified, i.e. four studies and one other study (Wu 1992) is awaiting classifi-
single versus multiple. The following outcomes were used in sub- cation pending translation from Chinese (see Characteristics of
group analysis: maternal primary outcomes (endometritis and studies awaiting classification).
Figure 1. Study flow diagram.
1990; Saravolatz 1985) compared irrigation versus intravenous ad-
Included studies
ministration of antibiotic prophylaxis and one study (Voto 1986)
We included 10 studies (involving 1354 women) (Berkeley 1990; compared oral versus intravenous administration. The studies used
Boothby 1984; Donnenfeld 1986; Elliott 1986; Gonen 1986; different antibiotics and dosages.
Lavery 1986; Leveno 1984; Peterson 1990; Saravolatz 1985; Voto The intravenous route included cephalosporins (cefamandole, ce-
1986). See Characteristics of included studies. fazolin, ceforanide, cefotaxime, and cefoxitin) and penicillins (me-
zlocillin). Studies used different intravenous dosages including sin-
gle dose (Lavery 1986; Peterson 1990; Saravolatz 1985), multiple
Design doses (Berkeley 1990; Boothby 1984; Donnenfeld 1986; Gonen
We included 10 randomised controlled trials. All were superior- 1986; Leveno 1984), or continued antibiotics for two days post-
ity studies. Seven studies used a standard parallel group design operatively (Elliott 1986).
(Berkeley 1990; Boothby 1984; Donnenfeld 1986; Gonen 1986; The irrigation route included cephalosporins (cefamandole, cefa-
Leveno 1984; Saravolatz 1985; Voto 1986) and three were ’multi- zolin, ceforanide, cefotaxime, and cefoxitin) and penicillins (me-
arm’ studies (Elliott 1986; Lavery 1986; Peterson 1990). zlocillin) in 500 mL or 1000 mL normal saline) with the technique
described in the literature by Long 1980.
The oral route used ampicillin in a dose of 2 g/day taken four
Sample sizes times over seven days postoperatively.
The 10 included studies enrolled a total of 1354 women. The
sample size ranged from 64 women to 217 with an average of 135
Outcomes
per study.
The included studies measured the following outcomes: en-
dometritis (or endomyometritis); wound infection (or surgical site
Setting infection); urinary tract infection; serious infectious complications
All studies enrolled women who were admitted to hospitals for included septic pelvic thrombophlebitis and septicaemia; postpar-
delivery. Studies were conducted in Argentina (Voto 1986), Is- tum febrile morbidity; additional antibiotic use; length of post-
rael (Gonen 1986) and the USA (Berkeley 1990; Boothby 1984; partum hospitalisation in days (maternal); adverse events included
Donnenfeld 1986; Elliott 1986; Lavery 1986; Leveno 1984; antibiotic induced allergic reactions; pulmonary complications in-
Peterson 1990; Saravolatz 1985). All studies were conducted and cluded atelectasis and pulmonary infection; and culture included
reported between 1984 and 1990. endometrial, endocervical, subcutaneous, wound and urine cul-
ture. Other outcomes included transfusion reactions.
Participants
Excluded studies
All studies included in this review enrolled women of reproductive
We excluded four studies (reported in five reports). Three
age, whether in labour or not who underwent caesarean delivery.
were quasi-randomised studies (Conover 1984; Itskovitz 1979;
Indications for caesarean delivery reflected the diverse pragmatic
Mathelier 1992) and one was a pharmacokinetic study (Flaherty
practice and included cephalopelvic disproportion, fetal distress,
1983). For further details see the Characteristics of excluded
failure to progress, breech presentation, transverse lie, repeat cae-
studies table.
sarean section, herpes, twins, abruptio placenta, placenta praevia,
pre-eclampsia, and diabetes.
Risk of bias in included studies
We summarised the risk of bias in included studies. Figure 2 is
Interventions and comparisons a ’Risk of bias’ graph depicting the review authors’ judgements
All studies included in this review compared an intravenous route about each ’Risk of bias’ item presented as percentages across all
of administration with other routes. included studies. Figure 3 is a ’Risk of bias’ summary showing
Nine studies (Berkeley 1990; Boothby 1984; Donnenfeld 1986; review authors’ judgements about each ’Risk of bias’ item for each
Elliott 1986; Gonen 1986; Lavery 1986; Leveno 1984; Peterson included study.
Figure 2. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Figure 3. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included
study.
Allocation
Selective reporting
All included studies were reported between 1984 and 1990. The
reporting quality was consistent with the editorial style and stan-
Sequence generation dards existing at the time of publication. We could not identify
In four studies (Berkeley 1990; Boothby 1984; Elliott 1986; any study with prospective registration, or the protocols for the
Saravolatz 1985), the investigators described a random component included studies were not available. In five studies (Boothby 1984;
in the sequence generation process and we judged those studies to Elliott 1986; Gonen 1986; Peterson 1990; Saravolatz 1985), there
be at low risk of selection bias. In the other six studies (Donnenfeld was insufficient information to permit judgement of ’low risk’ or
1986; Gonen 1986; Lavery 1986; Leveno 1984; Peterson 1990; ‘high risk’, and we therefore judged these studies to be at unclear
Voto 1986), there was Insufficient information about the sequence risk of bias.
generation process to permit judgement of ‘low risk’ or ‘high risk’ Although the protocols for the other five studies were not available
and we judged those studies to be at unclear risk of bias. (Berkeley 1990; Donnenfeld 1986; Lavery 1986; Leveno 1984;
Voto 1986), the reports failed to include results for a key outcome
that would be expected to have been reported for such a study,
Allocation concealment and we judged these studies to be at a high risk of reporting bias.
In all included studies, the method of concealment was not de-
scribed or not described in sufficient detail to allow a definite
judgement. Therefore, we judged all included studies to have an Other potential sources of bias
unclear risk of selection bias because there was Insufficient infor- All of the included studies appeared to be free of other forms of
mation to permit judgement of ‘low risk’ or ‘high risk’. bias (low risk of other bias).
Effects of interventions
Blinding
See: Summary of findings for the main comparison Intravenous
Blinding of participants and personnel was reported in three stud-
route compared with irrigation (lavage) for administration of
ies (Gonen 1986; Peterson 1990; Saravolatz 1985) by the use of
antibiotic prophylaxis for preventing infection after caesarean
a double-dummy technique to overcome the different routes of
section
antibiotic administration. In one study (Voto 1986), blinding was
See Summary of findings for the main comparison for the com-
not reported, but we judged that the outcome was not likely to be
parison of Intravenous route versus irrigation for administra-
influenced by lack of blinding. Blinding of participants and per-
tion of antibiotic prophylaxis for preventing infection after
sonnel in the other six studies was not performed and we judged
caesarean section.
those studies (Berkeley 1990; Boothby 1984; Donnenfeld 1986;
We summarised the risk of bias of the included studies in Figure
Elliott 1986; Lavery 1986; Leveno 1984) to be at high risk of per-
2 and Figure 3 and judged many studies to be of ’unclear’ or
formance and detection bias.
’high’ risk of bias. Consequently, we need to exercise caution in
the interpretation and generalisability of the results.
We described two relevant comparisons.
Incomplete outcome data 1. Intravenous verus irrigation
In six studies (Berkeley 1990; Donnenfeld 1986; Lavery 1986; 2. Intravenous versus oral
Leveno 1984; Peterson 1990; Saravolatz 1985) incomplete out-
come data appeared to have been adequately addressed and any
missing outcome data were reasonably well-balanced across inter- Comparison 1: Intravenous antibiotics versus
vention groups with similar reasons for incomplete data across the irrigation with antibiotics (nine studies, 1274 women)
groups. In two of the studies (Boothby 1984; Elliott 1986), there
was insufficient reporting of attrition/exclusions to permit judge-
ment of ‘low risk’ or ‘high risk’ because the number of women Primary outcomes
randomised was not stated (both assessed as unclear risk of bias).
In two of the studies (Gonen 1986; Voto 1986), the proportion
of excluded participants was enough to induce clinically relevant
bias in the intervention effect estimate (high risk of bias). Maternal
Endometritis Urinary tract infection
Eight of the studies (Berkeley 1990; Boothby 1984; Donnenfeld Five of the studies (Boothby 1984; Elliott 1986; Gonen 1986;
1986; Elliott 1986; Gonen 1986; Leveno 1984; Peterson 1990; Peterson 1990; Saravolatz 1985) provided data for this outcome.
Saravolatz 1985) provided data for this outcome. We found no We found no difference between intravenous antibiotics and an-
clear difference between intravenous antibiotics and antibiotic ir- tibiotic irrigation with regard to our outcome ’urinary tract infec-
rigation with regard to our outcome ’endometritis’ (risk ratio (RR) tion’ (RR 0.74, 95% CI 0.25 to 2.15, P = 0.58, 660 caesarean
0.95, 95% confidence interval (CI) 0.70 to 1.29, P = 0.74, 966 sections (very low-quality evidence)). See Analysis 1.4.
women (low-quality evidence)). See Analysis 1.1.
A sensitivity analysis (removing studies that were at a high or
unclear risk of attrition bias), does not change the overall result
(RR 0.87, 95% CI 0.62 to 1.23, five studies, 574 women) See Serious infectious complication
Analysis 2.1. The outcome of septicaemia was reported in one study (81 women)
(Elliott 1986), but there were no events (very low-quality evidence).
See Analysis 1.5.
Wound infection
Seven of the studies (Boothby 1984; Donnenfeld 1986; Elliott
1986; Gonen 1986; Leveno 1984; Peterson 1990; Saravolatz Adverse effects of treatment on the woman
1985) provided data for this outcome. We found no difference Three of the studies (284 women) (Boothby 1984; Donnenfeld
between intravenous antibiotics and antibiotic irrigation with re- 1986; Elliott 1986) reported the outcome of allergic reactions but
gard to our outcome ’wound infection’ (RR 0.49, 95% CI 0.17 there were no events (very low-quality evidence). See Analysis 1.6.
to 1.43, P = 0.19, 859 women (very low-quality evidence)). See
Analysis 1.2.
A sensitivity analysis (removing studies at high or unclear risk of
attrition bias) does not change the overall result (RR 0.42, 95% Maternal length of hospital stay
CI 0.11, 1.61, four studies, 467 women). See Analysis 2.2. Four of the studies (Elliott 1986; Gonen 1986; Lavery 1986;
Saravolatz 1985) provided data for this outcome and there was no
clear difference between the intravenous antibiotics and antibiotic
Infant irrigation groups (average mean difference (MD) 0.28 days, 95%
CI -0.22 to 0.79 days, (random-effects analysis), P = 0.27, 512
women) (Heterogeneity: Tau² = 0.11; Chi² = 5.34, df = 3 (P =
0.15); I² = 44%). See Analysis 1.7.
Infant sepsis (suspected or proven)
This outcome was not reported by any of the studies in this com-
parison.
Readmissions
This outcome was not reported by any of the studies in this com-
Secondary outcomes parison.
Maternal Infant
The included studies did not report on any of this review’s infant
secondary outcomes.
Postpartum febrile morbidity

Three of the studies (Berkeley 1990; Boothby 1984; Saravolatz Oral thrush
1985) provided data for this outcome. We found no difference be-
tween intravenous antibiotics and antibiotic irrigation with regard
to our outcome ’postpartum febrile morbidity’ (RR 0.87, 95% CI
0.48 to 1.60, P = 0.66, 264 women (very low-quality evidence)).
Infant length of hospital stay
See Analysis 1.3.
Immediate adverse effects of antibiotics on the infant. our review, there was no synthesised evidence comparing different
routes of antibiotic prophylaxis for preventing infection after cae-
sarean section. With this in mind, we conducted this review. Sev-
Comparison 2: Intravenous antibiotics versus oral eral randomised controlled trials (RCTs) included in our review
antibiotics (one study, 80 women) did not compare the outcome data between different routes of
One study compared intravenous antibiotics versus oral antibiotics antibiotic administration. Furthermore, one of our pre-specified
(Voto 1986), but did not report on any of this review’s primary or primary outcomes, infant sepsis, was not measured or reported by
secondary outcomes. The study enrolled 80 women and compared any of the studies. Irrigation with antibiotics was compared with
intravenous cefoxitin (2 g administered through an intravenous intravenous antibiotics in nine trials. We found only one RCT
drip immediately after the umbilical cord had been cut; thereafter, trial involving 80 women comparing another route of antibiotic
two doses, 2 g each dose, were administered at four and eight hours prophylaxis (oral) versus intravenous antibiotics, however it did
after the first dose) versus oral ampicillin (2 g/day taken four times not report on any of this review’s primary or secondary outcomes.
over seven days). Only 53 women were analysed due to errors in
collection of the samples for culture. The study reported the results
of cultures of the wound, urine, endocervix and uterine incision. Quality of the evidence
All studies included in this review were categorised as having an
’unclear’ risk of bias for allocation concealment and six of the 10
included studies were categorised as having an ’unclear’ risk of
DISCUSSION bias for random sequence generation. Therefore caution is advised
when interpreting the results. Furthermore, the total number of
all women enrolled was 1354 in 10 studies. Most of the included
Summary of main results studies were underpowered for the primary outcomes and for ad-
verse events.
We included 10 studies that compared different routes of adminis-
For the main comparison of intravenous antibiotics versus antibi-
tering prophylactic antibiotics: intravenous versus irrigation (nine
otic irrigation, the quality of evidence was low for endometritis
studies) and intravenous versus oral (one study).
(Summary of findings for the main comparison). This provides
The main findings indicate that there is no difference between
some indication of the likely effect. However, the likelihood that
intraoperative irrigation of the uterus and intravenous prophylac-
it will be substantially different (a large enough difference that it
tic antibiotics in reducing the risk of post-caesarean endometri-
might have an effect on a decision) is high. The quality of evidence
tis, as shown in Summary of findings for the main comparison.
was very low for all other outcomes including wound infection,
However, this is based on low-quality evidence due to study de-
urinary tract infection, postpartum febrile morbidity, serious in-
sign limitations and imprecision. The results for all other reported
fectious complications, and maternal allergic reactions (Summary
outcomes: wound infection, urinary tract infection, serious infec-
of findings for the main comparison). This does not provide a re-
tious complications, postpartum febrile morbidity, maternal aller-
liable indication of the likely effect. The likelihood that the effect
gic reactions and maternal length of hospital stay, are based on
will be substantially different is very high.
a very low-quality evidence. We downgraded the quality of evi-
The quality of the evidence was very low to low. The main reasons
dence for limitations of study design and for imprecision. Studies
for downgrading the evidence included study design limitations
included relatively few patients and few events and have wide 95%
and imprecision.
confidence intervals that include both appreciable benefit and ap-
preciable harm, as shown in Summary of findings for the main
comparison. It is notable that we could not find any study that
has measured or reported neonatal or infant outcomes. Potential biases in the review process
This summary of our main results underscores the outstanding We used rigorous steps to eliminate bias during conducting and
uncertainties regarding the effectiveness of different routes of pro- reporting our review. However, it is possible that trials may have
phylactic antibiotics in preventing post-caesarean infections. been overlooked. Furthermore, we have explicitly indicated that
some outcomes were not reported and we could not obtain data
regarding the unreported points in methods and outcomes by
Overall completeness and applicability of directly contacting the trial investigators.
evidence
In current practice, evidence regarding antibiotic prophylaxis is
based on high-quality studies comparing intravenous antibiotics
Agreements and disagreements with other
with placebo or no therapy. Prior to conducting and reporting
studies or reviews
The recently published World Health Organization (WHO) ev- Implications for research
idence-based guidance for preventing peripartum infections rec-
Having reviewed studies addressing an issue as important as com-
ommended routine antibiotic prophylaxis for women undergo-
paring the different routes of administration of antibiotic prophy-
ing elective or emergency caesarean section (WHO 2015). For
laxis for the most commonly practised obstetric major surgery, the
caesarean section, prophylactic antibiotics should be given prior
number of high quality randomised controlled trials (RCTs) at-
to skin incision, rather than intraoperatively after umbilical cord
tempting to answer this clinical question was small. Furthermore,
clamping. For antibiotic prophylaxis for caesarean section, a single
methodological flaws in designing, conducting and reporting the
dose of first-generation cephalosporin or penicillin should be used
few available studies, affected the quality of evidence extracted
in preference to other classes of antibiotics. The WHO guideline
from the included studies. This calls for investigators to work on
development group added in a remark that the intravenous route
improving the methodological infrastructure of future attempted
should be used for antibiotic administration given that the evi-
RCTs. The latest included study in this review dates back to 1990,
dence underpinning this recommendation was based on findings
and obviously, over more than quarter of a century, novel antibi-
from trials where the majority used this route (WHO 2015). This
otics, available through more varied routes, have been introduced
clearly shows there are insufficient head-to-head comparisons be-
into clinical practice. Hence, clinicians should embark on putting
tween different routes to formulate a direct recommendation.
those newer agents into clinical trials, comparing their efficacies
To our knowledge this is the first systematic review assessing the
and safety profiles.
benefits and harms of different routes of antibiotic administration
for prevention of infection after caesarean section. We have noted Additionally, not all available routes of antibiotic administration
that it was only in 1980 when a preliminary report (Long 1980) de- have been included in the reviewed studies. Trans-rectal adminis-
scribed the use of Intrauterine irrigation with cefamandole nafate tration, for example, has not been studied. It might prove to be of
in reducing the incidence of endometritis after caesarean section. value, especially considering the gastro-intestinal upset surround-
The technique of irrigation was later replicated by the randomised ing caesarean delivery. The intravenous route is the standard route
controlled trials included in this review. of prophylactic antibiotic administration, but more studies are
Regarding the different routes of prophylactic antibiotics, the ma- needed to evaluate the uterine lavage route, which showed com-
jority of the studies compared intravenous administration with parable effect and seems more suitable for emergency caesarean
the peritoneal and uterine lavage. One excluded trial considered section; and the oral route as it has not been thoroughly examined,
the intravenous route the most effective means (Conover 1984), although it is very simple, convenient and suitable for women who
another trial considered the intrauterine antibiotic lavage more receive regional anaesthesia. Future research should evaluate the
safe and cost-effective than intravenous route (Donnenfeld 1986), most effective and safe route of administration to inform policy-
whereas (Gonen 1986) could not find a difference in benefits and making.
harms.
It is noteworthy that, in agreement with our observation, two Lastly, the possible neonatal effects of maternal administration of
Cochrane systematic reviews on antibiotic prophylaxis versus no antibiotics were not reported in any of the included studies. Such
prophylaxis for preventing infection after caesarean section (Smaill effects might include change of neonatal infection rates, possible
side effects of drugs, potentially causing neonatal jaundice, or drug
2014) and on the different classes of antibiotics for preventing
infection at caesarean section (Gyte 2014), also reported that there reactions.
was incomplete information collected about the potential adverse We, therefore, suggest that well-designed, properly-conducted,
effects, especially on the baby, further complicating the assessment and clearly-reported RCT’s be considered a research priority for
of overall benefits and harms of prophylactic antibiotics given for investigators in the field of childbirth. Such studies should evaluate
prevention of infection at caesarean section. the more recently available antibiotics, elaborating on the various
available routes of administration, and exploring potential neona-
tal side effects of such interventions.
AUTHORS’ CONCLUSIONS
Implications for practice

ACKNOWLEDGEMENTS
There was a low-quality evidence of no difference between irriga-
tion and intravenous administration of antibiotic prophylaxis in We would like to acknowledge the valuable input of Lynn Hamp-
reducing the risk of endometritis after caesarean section. For other son in the development of the search strategy. We would also like
outcomes, there is insufficient evidence regarding which route of to thank all members of the Pregnancy and Childbirth Group
administration of prophylactic antibiotics is most effective at pre- Editorial base at the University of Liverpool, UK, led by Frances
venting post-caesarean infections. Kellie, for their kind assistance with preparation of the protocol.
As part of the pre-publication editorial process, this review has been
commented on by two peers (an editor and referee who is external
to the editorial team), a member of the Pregnancy and Childbirth
Group’s international panel of consumers and the Group’s Statis-
tical Adviser.
This project was supported by the National Institute for Health
Research, via Cochrane Infrastructure funding to Cochrane Preg-
nancy and Childbirth. The views and opinions expressed therein
are those of the authors and do not necessarily reflect those of the
Systematic Reviews Programme, NIHR, NHS or the Department
of Health.
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Peterson CM, Medchill M, Gordon DS, Chard HL.
Berkeley 1990 {published data only} Cesarean prophylaxis: a comparison of cefamandole and
Berkeley AS, Hirsch JC, Freedman KS, Ledger WJ. cefazolin by both intravenous and lavage routes, and risk
Cefotaxime for cesarean section prophylaxis in labor. factors associated with endometritis. Obstetrics & Gynecology
Intravenous administration vs. lavage. Journal of 1990;75:179–82.
Reproductive Medicine 1990;35(3):214–8. Saravolatz 1985 {published data only}
Saravolatz LD, Lee C, Drukker B. Comparison of
Boothby 1984 {published data only}
intravenous administration with intrauterine irrigation with
Boothby R, Benrubi G, Ferrell E. Comparison of
ceforanide for nonelective cesarean section. Obstetrics &
intravenous cefoxitin prophylaxis with intraoperative
Gynecology 1985;66:513–6.
cefoxitin irrigation for the prevention of post-cesarean-
section endometritis. Journal of Reproductive Medicine 1984; Voto 1986 {published data only}
29:830–2. Voto LS, Benoliel LA, Amadora Muñiz A, Trepat A, Balsechi
EE, Margulies M. Prophylaxis of post cesarean section
Donnenfeld 1986 {published data only}
puerperal infection with the using of cefoxitin antibiotics
Donnenfeld AE, Otis C, Weiner S. Antibiotic prophylaxis
[Profilaxis de la infección puerperal post–cesarea mediante
in cesarean section. Comparison of intrauterine lavage
el uso del antibiótico cefoxitina: I – Resultados de su
and intravenous administration. Journal of Reproductive
empleo valorados a través del cultivo sistemático pre, intra y
Medicine 1986;31:15–8.
postquirúrgico]. Obstetricia y Ginecologia Latino-Americanas
Elliott 1986 {published data only} 1986;44:419–24.
Elliott JP, Flaherty JF. Comparison of lavage or intravenous
antibiotics at cesarean section. Obstetrics & Gynecology References to studies excluded from this review
1986;67:29–32.
Conover 1984 {published data only}
Gonen 1986 {published data only} Conover WB, Moore TR. Comparison of irrigation and
Gonen R, Samberg I, Levinski R, Levitan Z, Sharf M. intravenous antibiotic prophylaxis at cesarean section.
Effect of irrigation or intravenous antibiotic prophylaxis Obstetrical and Gynecological Survey 1984;39:692–3.
on infectious morbidity at cesarean section. Obstetrics & ∗
Conover WB, Moore TR. Comparison of irrigation and
Gynecology 1986;67:545–8. intravenous antibiotic prophylaxis at cesarean section.
Obstetrics & Gynecology 1984;63(6):787–91.
Lavery 1986 {published data only}
Lavery JP, Huang KC, Koontz WL, Reinstine J, Marcell C, Flaherty 1983 {published data only}
Rosenberg N. Mezlocillin prophylaxis against infection after Flaherty JF, Boswell GW, Winkel CA, Elliott JP.
cesarean section: a comparison of techniques. Southern Pharmacokinetics of cefoxitin in patients at term gestation:
Medical Journal 1986;79:1248–51. lavage versus intravenous administration. American Journal
of Obstetrics and Gynecology 1983;146(7):760–6.
Leveno 1984 {published data only}
Leveno KJ, Quirk JG, Cunningham FG, Nelson S, Bawdon Itskovitz 1979 {published data only}
RE. Perioperative antimicrobials at cesarean section: lavage Itskovitz J, Paldi E, Katz M. The effect of prophylactic
vs three intravenous doses. American Journal of Obstetrics antibiotics on febrile morbidity following cesarean section.
and Gynecology 1984;149:463–4. Obstetrics & Gynecology 1979;53(2):162–5.
Mathelier 1992 {published data only} Conte 2002
Mathelier AC. A comparison of postoperative morbidity Conte JE. Manual of Antibiotics and Infectious Diseases:
following prophylactic antibiotic administration by Treatment and Prevention. Philadelphia: Lippincott,
combined irrigation and intravenous route or by intravenous Williams & Wilkins, 2002.
route alone during cesarean section. Journal of Perinatal Cooper 2002
Medicine 1992;20(3):177–82. Cooper NJ, Sutton AJ, Abrams KR. Decision analytical
References to studies awaiting assessment economic modelling within a Bayesian framework:
application to prophylactic antibiotics use for caesarean
Wu 1992 {published data only} section. Statistical Methods in Medical Research 2002;11:
Wu Y. Prevention of post-operative infection by using 491–512.
antibiotics of 217 cases of cesarean section. Chung-Hua Cox 1989
Fu Chan Ko Tsa Chih [Chinese Journal of Obstetrics & Cox SM, Gilstrap LC 3rd. Postpartum endometritis.
Gynecology] 1992;27(2):73–5. Obstetrics and Gynecology Clinics of North America 1989;16:
363–71.
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Berkeley 1990
Methods Parallel randomised controlled trial.
Participants Inclusion criteria: women in labour, with or without ruptured membranes

Exclusion criteria: participants < 18 years of age, had a known allergy to penicillin
or cephalosporin antibiotics, had received other antibiotics in the 72 hours prior to
admission, required prophylactic antibiotics for medical indications, had received steroid
therapy for either underlying medical illness or enhancement of fetal lung maturity, had
severe renal or hepatic dysfunction, or had clinical evidence of chorioamnionitis at the
time of caesarean section
Interventions Number of women randomised: 107.

Trial arm 1: 53 women were randomised to 2 g of cefotaxime in 1000 mL of normal
saline through uterine lavage
Trial arm 2: 54 women were randomised to 1 g of cefotaxime intravenously at the time
of cord clamping followed by a dose of 1 g 6 and 12 hours after the initial dose
The investigators added a third group to establish a baseline postoperative infection rate in
their facility. The first 50 women in calendar year 1982 who underwent caesarean section
in labour and did not receive prophylactic antibiotics by any method were evaluated by
chart review using the same criteria as those used in the trial
Outcomes Febrile morbidity.

Endomyometritis.
Notes Centre: Department of obstetrics and gynaecology, New York Hospital, Cornell Medical
Center
Country: USA.
Language: English.
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Low risk A computer-generated randomisation code sup-
bias) plied by the sponsor
Allocation concealment (selection bias) Unclear risk Insufficient information to permit judgement of
‘Low risk’ or ‘High risk’
Blinding of participants and personnel High risk Given that the control arm was easily distin-
(performance bias) guished from the treatment arm during treat-
All outcomes ment, participants and personnel were not
blinded. We judge that the outcome is likely to
be influenced by lack of blinding
Berkeley 1990 (Continued)
Blinding of outcome assessment (detection High risk The trial was not blinded. We judge that the out-
bias) come is likely to be influenced by lack of blinding
All outcomes
Incomplete outcome data (attrition bias) Low risk Incomplete outcome data balanced in numbers
All outcomes across intervention groups, with similar reasons
(protocol violations) across groups
107 participants who signed consent forms at
the time of admission to the obstetric service ul-
timately underwent caesarean section in labour.
7 participants were excluded; 3 received steroid
therapy for induction of fetal lung maturity, 1
had no chart available for subsequent review, 1
did not undergo the lavage to which she was ran-
domised, and 2, both in the intravenous group,
had protocol violations related to errors in the
administration of the second and third prophy-
lactic doses
Selective reporting (reporting bias) High risk The study protocol is not available and the study
report fails to include results for a key outcome
that would be expected to have been reported for
such a study
Other bias Low risk The study appears to be free of other sources of
bias.
Boothby 1984
Participants All women who underwent primary caesarean section at University Hospital during the
6-month study period were included
Exclusion criteria: women were excluded if they had a history of penicillin or
cephalosporin allergy or a known infectious process or had recently used antibiotics

Trial arm 1: 53 women were randomised to intraoperative irrigation with a cefoxitin
solution. The antibiotic irrigation solution contained 2 g of cefoxitin dissolved in 1 L of
normal saline. After delivery of the Infant, placenta and membranes, the open uterus,
wound margins and endometrial cavity were irrigated with a bulb syringe, creating a jet-
like action on the tissues. The closed uterine incision was then irrigated. Both gutters
were irrigated and cleared of any blood clots. After closure of the peritoneum the wound
was irrigated, and a final irrigation was performed in the subcutaneous tissue after closure
of the fascia. Approximately 200 mL of solution was used during each irrigation step.
Trial arm 2: 50 women were randomised to intravenous prophylaxis with cefoxitin and
saline irrigation. Women receiving intravenous prophylaxis were given 2 g of cefoxitin
after cord clamping by the anaesthesiologist or nurse-anaesthetist and then 2 g at 6, 12
Boothby 1984 (Continued)
and 18 hours after surgery
Outcomes Febrile morbidity.

Postpartum endometritis.
Urinary tract infection.
Wound infection.
Drug allergy.
Notes Centre: Department of Obstetrics and Gynecology, University Hospital of Jacksonville

Country: USA.
Language: English.
Risk of bias
Random sequence generation (selection Low risk Using a randomisation table.

bias)
Blinding of outcome assessment (detection High risk The study was not blinded. We judge that the
bias) outcome is likely to be influenced by lack of
All outcomes blinding
Incomplete outcome data (attrition bias) Unclear risk Insufficient information to permit judgement of
All outcomes ‘Low risk’ or ‘High risk’
Selective reporting (reporting bias) Unclear risk The study protocol is not available. There is insuf-
ficient information to permit judgement of ‘Low
risk’ or ‘High risk’
bias.
Donnenfeld 1986
Participants The study enrolled 103 women. All women in the clinic who were in labour immediately
prior to caesarean section were entered into the study
Exclusion criteria: known penicillin or cephalosporin allergies, those taking antibiotics,
those requiring prophylaxis against bacterial endocarditis and those with ongoing infec-
tions

Trial arm 1: 53 women were randomised to 1 g intravenous cefazolin solution immedi-
ately after cord clamping, followed by 2 subsequent doses given at 8-hour intervals
Trial arm 2: 50 women were randomised to an intrauterine lavage of 1 g cefazolin in
500 mL normal saline. A bulb syringe was used to administer 300 mL directly into the
uterine cavity as well as to thoroughly irrigate the margins of the entire uterine incision,
creating a jet-like effect. After closure of the uterus, 100 mL was used for lavage of
the vesicouterine peritoneum. The final 100 mL was used to irrigate the subcutaneous
adipose tissue. The excess run-off of irrigant was suctioned at the time of application
Outcomes Endometritis.
Postpartum hospital stay.
Notes Centre: Section on perinatology, Department of Obsterics and Gynecology, Pennsylvania

Hospital
Country: USA.
Language: English.
Risk of bias
Random sequence generation (selection Unclear risk Insufficient information to permit judgement of
bias) ‘Low risk’ or ‘High risk’
Blinding of outcome assessment (detection High risk The study was not blinded. We judge that the
bias) outcome is likely to be influenced by lack of
All outcomes blinding
Incomplete outcome data (attrition bias) Low risk Incomplete outcome data balanced in numbers
All outcomes across intervention groups, with similar reasons
for incomplete data across groups
Donnenfeld 1986 (Continued)
2 women were excluded due to administration of

the intravenous antibiotic at improper intervals.
1 woman was excluded due to deviation from the
intrauterine lavage protocol at the time of surgery
Selective reporting (reporting bias) High risk The study protocol is not available and study re-
port fails to include results for a key outcome that
would be expected to have been reported for such
a study
bias.
Elliott 1986
Methods Multi-arm randomised controlled trial.
Participants The study included 158 women who were to be delivered by caesarean section and who
were in active labour or had ruptured membranes and had at least 1 digital vaginal
examination.
Criteria for exclusion from the study included: any known allergy to cephalosporins
or penicillin, the presence of a fever greater than or equal to 37.8o C during labour
with suspicion of chorioamnionitis, or maternal use of any antibiotic during the 2-week
period before delivery

Trial arm 1: 39 women, a control group that received no prophylactic antibiotic therapy
Trial arm 2: 39 women were randomised to 2 g of cefoxitin by intravenous injection over
a 3- to 5-minute period after the fetal umbilical cord was clamped. 7 additional doses of
2 g of cefoxitin were administered every 6 hours for a 2-day course of therapy
Trial arm 3: 42 women were randomised to uterine and peritoneal lavage with 2 g of
cefoxitin in 1 L of normal saline. After delivery of the placenta, the fundus of the uterus
was irrigated with approximately 300 mL of antibiotic solution, the uterine incision was
irrigated with 150 mL, after closure of the first layer 150 mL, and bladder flap 150 mL,
then the remainder was used to irrigate the peritoneal cavity. Any remaining irrigating
solution was suctioned from the peritoneal cavity before closing the abdomen. No further
antibiotic therapy was administered
Trial arm 4: 38 women were randomised to irrigation plus intravenous treatment. This
group was given antibiotics as described for both group 2 and group 3
Outcomes Endomyometritis.
Wound infection.
Pulmonary infection.
Septicemia.
Total febrile morbidity.
Seroma.
Transfusion reaction.
Atelectasis.
Elliott 1986 (Continued)
Fever index (degree-h).

Hospital stay (d).
Notes Centres: Letterman Army Medical Center and Womack Army Community Hospital
under a protocol approved by the hospital Research and Human Use Committees
Country: USA.
Language: English.
Risk of bias
Random sequence generation (selection Low risk Randomisation into 1 of 4 treatment groups
bias) was performed by using a table of random
numbers
Allocation concealment (selection bias) Unclear risk Insufficient information to permit judgement
of ‘Low risk’ or ‘High risk’
Blinding of participants and personnel High risk No blinding and the outcome is likely to be
(performance bias) influenced by lack of blinding
All outcomes The investigators indicated that the intra-
venous antibiotic protocols involved 2 days of
therapy due to the investigators’ impression
that the incidence of subclinical infection is
high and a treatment course of antibiotics is
appropriate
Blinding of outcome assessment (detection High risk No blinding and the outcome is likely to be
bias) influenced by lack of blinding
All outcomes
Incomplete outcome data (attrition bias) Unclear risk Insufficient information to permit judgement
All outcomes of ‘Low risk’ or ‘High risk’
Selective reporting (reporting bias) Unclear risk The study protocol is not available. There is
insufficient information to permit judgement
Other bias Low risk The study appears to be free of other sources
of bias.
Gonen 1986
Participants The study included 217 women who underwent caesarean section
Exclusion criteria: fever or other infection during labour, using antibiotics within 48
hours, a separate indication for using prophylactic antibiotics, allergy to penicillin or
cephalosporin

Trial arm 1: 107 women were randomised to intravenous cefamandole 6 vials of 1 g
cefamandole. First dose given after cord clamping, followed by 5 doses 6 hours apart
Trial arm 2: 110 women were randomised to irrigation with 2 g cefamandole in 1000
mL normal saline. The uterine cavity and incision irrigated by 300 mL, 150 after closure
of the first layer, and 150 for the bladder flap, gutters and subcutaneous layer
Wound infection.
Fever above 38o C.
Additional days in hospital.
Notes Centre: Department of Obstetrics and Gynecology, Haifa Medical Center (Rothschild)
Country: Israel.
Language: English.
Risk of bias
Blinding of participants and personnel Low risk All irrigant and intravenous solutions assigned to
(performance bias) women were blinded and similarly coded so that
All outcomes women treated with antibiotic irrigation (study
group) would be administered with intravenous
placebo, and women treated with intravenous an-
tibiotic (control group) would be irrigated with
placebo
Blinding of outcome assessment (detection Low risk Blinding of outcome assessment ensured, and un-
bias) likely that the blinding could have been broken
All outcomes
Incomplete outcome data (attrition bias) High risk The study enrolled 217 women. 9 were excluded
All outcomes from the analysis due to deviation from the pro-
tocol of irrigation. Number analysed 208 (intra-
Gonen 1986 (Continued)
venous 107 women and irrigation 101 women)
Selective reporting (reporting bias) Unclear risk Insufficient information to permit judgement of
bias.
Lavery 1986
Participants The study included 212 women requiring emergency caesarean section who were either
in labour or had membranes ruptured at the time of admission
Exclusion criteria: elective, primary or repeat caesarean section, signs of infection, if
antibiotic had been administered within 1 week, a known allergy to penicillin

Trial arm 1: 59 women were randomised to intravenous single dose: intravenous admin-
istration of 4 g of mezlocillin after cord clamping
Trial arm 2: 49 women were randomised to irrigation using 4 g mezlocillin in 1 L of
normal saline, of uterine cavity, pelvic gutters, uterine incision and fascia during the
closure
Trial arm 3: 54 women were randomised to intravenous triple dose: intravenous admin-
istration of 4 g of mezlocillin followed by 4 g given 4 and 8 hours after procedure
Trial arm 4: 50 women were randomised to pelvic irrigation (as described in trial arm 2)
with 2 g of mezlocillin in 1000 mL of normal saline, combined with a single dose of 2
g of mezlocillin given intravenously after clamping of the cord
Outcomes Surgically-related infection a composite outcome (endomyometritis, septicaemia, wound

infection, phlegmon, or abscess)
Hospital stay (days).
Women requiring additional antibiotics.
Notes Centre: Department of Obstetrics and Gynecology university of Louisville School of

Medicine
Country: USA.
Language: English.
Risk of bias
Random sequence generation (selection Unclear risk Insufficient information to permit judgement
bias) of ‘Low risk’ or ‘High risk’
“randomised by the anaesthesia staff.”
Lavery 1986 (Continued)
“unidentified envelops at surgery.”
Blinding of participants and personnel High risk No blinding and the outcome is likely to be
(performance bias) influenced by lack of blinding
All outcomes
Blinding of outcome assessment (detection High risk No blinding and the outcome is likely to be
bias) influenced by lack of blinding
All outcomes
Incomplete outcome data (attrition bias) Low risk No missing outcome data.
All outcomes
Selective reporting (reporting bias) High risk The study protocol is not available and study
that would be expected to have been reported
for such a study
of bias.
Leveno 1984
Participants The study included 103 nulliparous women who had ruptured membranes for > 6 hours
and who were delivered by caesarean section due to cephalopelvic disproportion
The investigators did not report any exclusion criteria.

Trial arm 1: 52 women were randomised to 3 doses of intravenous cephamandole at 6-
hour intervals starting after cord clamping
Trial arm 2: 51 women were randomised to irrigation using 2 g cephamandole in 1 L of
normal saline for lavage
Phlegmon.
Notes Centre: Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology,
University of Texas
Country: USA.
Language: English.
Partially supported by grant from Eli Lilly.
Risk of bias
Leveno 1984 (Continued)
Blinding of participants and personnel High risk No blinding and the outcome is likely to be in-
(performance bias) fluenced by lack of blinding
All outcomes
Blinding of outcome assessment (detection High risk No blinding and the outcome is likely to be in-
bias) fluenced by lack of blinding
All outcomes
All outcomes
Selective reporting (reporting bias) High risk The study protocol is not available and study re-
port fails to include results for a key outcome that
would be expected to have been reported for such
a study
bias.
Peterson 1990
Participants The study included 207 women undergoing non-elective caesarean section (all women
were in labour with ruptured membranes)
Exclusion criteria: those allergic to penicillin or cephalosporins, those already on antibi-
otics, those with ongoing infection, and those requiring bacterial endocarditis prophy-
laxis

Trial arm 1: 47 women were randomised to 2 g of cefazolin intravenous with normal
saline intraoperative lavage
Trial arm 2: 47 women were randomised to 2 g cefamandole intravenous with normal
saline intraoperative lavage
Trial arm 3: 59 women were randomised to 2 g cefazolin by intraoperative lavage with
intravenous normal saline
Trial arm 4: 54 women were randomised to 2 g cefamandole by intraoperative lavage
with intravenous normal saline
Peterson 1990 (Continued)
Wound infection.
Notes Centre: Department of Obsterics and Gynecology, Maricopa Medical Center

Country: USA.
Language: English.
Risk of bias
Random sequence generation (selection Unclear risk Insufficient information to permit judgement
bias) of ‘Low risk’ or ‘High risk’
Blinding of participants and personnel Low risk A double-blind study. All surgeons and
(performance bias) women were blinded.
All outcomes
Blinding of outcome assessment (detection Low risk A double-blind study.

bias)
All outcomes
All outcomes
Selective reporting (reporting bias) Unclear risk Insufficient information to permit judgement
of bias.
Saravolatz 1985
Participants The study included 64 women who were 18 years or older and underwent caesarean
section and had ruptured membranes for 3 hours or longer
Exclusion criteria: Those women who had received antimicrobial therapy within 72
hours before caesarean section, were hypersensitive for cephalosporins, were likely to
receive other antimicrobial agents, or they had evidence of intrapartum infection

Trial arm 1: 34 women were randomised to 2 g of ceforanide intravenously in 50 mL
normal saline immediately after cord clamping, in addition 1000 mL normal saline was
Saravolatz 1985 (Continued)
administered by intrauterine irrigation

Trial arm 2: 27 women were randomised to 2 g ceforanide in 1000 mL of normal
saline by intrauterine irrigation, with 5 mL of normal saline was simultaneously infused
immediately after cord clamping
Wound infection.
Notes Centre: Henry Ford Hospital, Detriot, Michigan Michigan State University
Country: USA.
Language: English.
Risk of bias
Random sequence generation (selection Low risk A computer-generated random table.

bias)
Blinding of participants and personnel Low risk A double-blind study. Neither the woman nor her
(performance bias) primary obstetrician was informed as to which
All outcomes group she had been assigned
Blinding of outcome assessment (detection Low risk A double-blind study.

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk 3 of the 64 women were excluded from evalu-
All outcomes ation because they met the exclusion criteria (2
because they were receiving other antimicrobial
agents and 1 because she had a pre-existing in-
fection)
Selective reporting (reporting bias) Unclear risk Insufficient information to permit judgement of
bias.
Voto 1986
Participants The study included 80 women who were admitted to the maternity ward for caesarean
section
Before the operation began, a sample of the endocervical was extracted for culture through
use of a cotton swab and a sample of urine was also collected. This was repeated 48 hours
after the operation.
During the operation, samples of uterine incision, peritoneum, amniotic fluid, subcu-
taneous cellular tissue and skin were taken for culture

Trial arm 1: 40 women were randomised to 2 g of cefoxitin. Cefoxitin was administered
through an intravenous drip immediately after the umbilical cord had been cut. There-
after, 2 doses, 2 g each dose, were administered in the same place at 4 and 8 hours after
the first dose.
Trial arm 2: 40 women were randomised to ampicillin, which was administered orally
with a dosage of 2 g/day taken 4 times over 7 days
Outcomes 1. Wound culture.

2. Urine culture.
3. Endocervical culture.
4. Uterine incision culture.
Notes Centre: The Hospital Juan A. Fernández, Buenos Aires.

Country: Argentina.
Language: Spanish. We used a translated version of the study report
Risk of bias
Blinding of participants and personnel Low risk Given that the control arm was easily distin-
blinded. We judge that the outcome is not likely
to be influenced by lack of blinding
Blinding of outcome assessment (detection Unclear risk It is unclear whether blinding of outcome assess-
bias) ment was done
All outcomes
Incomplete outcome data (attrition bias) High risk Number of participants randomised = 80 (40 par-
All outcomes ticipants per trial arm), number analysed = 37/
Voto 1986 (Continued)
40 and 16/40. Exclusion was due to errors in col-

lection of samples
Selective reporting (reporting bias) High risk The study protocol is not available and the study
that would be expected to have been reported for
such a study
bias.
degree-h: this relates to a fever index (degree-h), a quantitative measure of the total amount of fever in degree hours.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Conover 1984 It is a quasi-random study. Women were assigned to receive irrigation or intravenous prophylaxis based on the last
digit of the woman sponsor’s social security number,
Flaherty 1983 The study compared pregnant and non-pregnant women regarding the pharmacokinetics of cefoxitin administered
by intravenous route and lavage
Itskovitz 1979 It is a quasi-random study. Women were allocated to each of the 2 wings of the department according to the day
of their admission
Mathelier 1992 It is a quasi-random study. Women were alternatively assigned to 1 of 2 regimens of prophylaxis
Characteristics of studies awaiting assessment [ordered by study ID]
Wu 1992
Methods A prospective study was undertaken to compare the efficacy of local antibiotics irrigation with that of systemic
antibiotics for the prophylaxis of postoperative infection in women undergoing caesarean section. Women were
randomly divided into 3 groups
Participants The study included 217 women delivered by caesarean section.
Interventions Trial arm (1): intrauterine and pelvic irrigation with ampicillin
Trial arm (2): systemic use of penicillin + gentamycin (intravenously and intramuscularly)
Trial arm (3): no antibiotics given.
Outcomes Postoperative infection.
Wu 1992 (Continued)
Notes Centre: Third Hospital, Beijing Medical University.

Country: China.
Language: Chinese (Awaiting translation).
Abstract: English.
DATA AND ANALYSES
Comparison 1. Intravenous (IV) versus irrigation
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Endometritis 8 966 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.70, 1.29]
1.1 Single IV dose 2 268 Risk Ratio (M-H, Fixed, 95% CI) 1.17 [0.59, 2.32]
1.2 Multiple IV doses 6 698 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.64, 1.26]
2 Wound infection 7 859 Risk Ratio (M-H, Fixed, 95% CI) 0.49 [0.17, 1.43]
2.1 Single IV dose 2 264 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.03, 2.20]
2.2 Multiple IV doses 5 595 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.19, 2.28]
3 Postpartum febrile morbidity 3 264 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.48, 1.60]
4 Urinary tract infection 5 660 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.25, 2.15]
5 Serious infectious complication 1 81 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6 Adverse events (maternal) 3 284 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
6.1 Allergic reactions 3 284 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
7 Maternal length of hospital stay 4 512 Mean Difference (IV, Random, 95% CI) 0.28 [-0.22, 0.79]
(days)
Comparison 2. Intravenous versus irrigation: sensitivity analysis
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Endometritis 5 574 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.62, 1.23]
2 Wound infection 4 467 Risk Ratio (M-H, Fixed, 95% CI) 0.42 [0.11, 1.61]
Analysis 1.1. Comparison 1 Intravenous (IV) versus irrigation, Outcome 1 Endometritis.
Review: Routes of administration of antibiotic prophylaxis for preventing infection after caesarean section
Comparison: 1 Intravenous (IV) versus irrigation
Outcome: 1 Endometritis
Study or subgroup Intravenous Irrigation Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 Single IV dose
Peterson 1990 11/94 11/113 14.4 % 1.20 [ 0.55, 2.65 ]
Saravolatz 1985 4/34 3/27 4.8 % 1.06 [ 0.26, 4.33 ]
Subtotal (95% CI) 128 140 19.3 % 1.17 [ 0.59, 2.32 ]

Total events: 15 (Intravenous), 14 (Irrigation)
Heterogeneity: Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0%
Test for overall effect: Z = 0.44 (P = 0.66)
2 Multiple IV doses
Berkeley 1990 6/50 6/50 8.7 % 1.00 [ 0.35, 2.89 ]
Boothby 1984 2/50 2/53 2.8 % 1.06 [ 0.16, 7.24 ]
Donnenfeld 1986 15/53 18/50 26.8 % 0.79 [ 0.45, 1.38 ]
Elliott 1986 2/39 2/42 2.8 % 1.08 [ 0.16, 7.28 ]
Gonen 1986 15/107 11/101 16.4 % 1.29 [ 0.62, 2.67 ]
Leveno 1984 11/52 16/51 23.3 % 0.67 [ 0.35, 1.31 ]
Subtotal (95% CI) 351 347 80.7 % 0.90 [ 0.64, 1.26 ]

Total (95% CI) 479 487 100.0 % 0.95 [ 0.70, 1.29 ]
Test for subgroup differences: Chi2 = 0.45, df = 1 (P = 0.50), I2 =0.0%
0.01 0.1 1 10 100

Favours Intravenous Favours Irrigation
Analysis 1.2. Comparison 1 Intravenous (IV) versus irrigation, Outcome 2 Wound infection.
Outcome: 2 Wound infection

1 Single IV dose
Peterson 1990 0/94 2/109 23.1 % 0.23 [ 0.01, 4.76 ]
Saravolatz 1985 0/34 1/27 16.6 % 0.27 [ 0.01, 6.30 ]
Subtotal (95% CI) 128 136 39.7 % 0.25 [ 0.03, 2.20 ]

2 Multiple IV doses
Boothby 1984 1/50 1/53 9.7 % 1.06 [ 0.07, 16.49 ]
Donnenfeld 1986 0/51 0/49 Not estimable
Elliott 1986 0/39 0/42 Not estimable
Gonen 1986 1/107 2/101 20.5 % 0.47 [ 0.04, 5.13 ]
Leveno 1984 2/52 3/51 30.2 % 0.65 [ 0.11, 3.75 ]
Subtotal (95% CI) 299 296 60.3 % 0.66 [ 0.19, 2.28 ]

Total (95% CI) 427 432 100.0 % 0.49 [ 0.17, 1.43 ]
Test for subgroup differences: Chi2 = 0.58, df = 1 (P = 0.45), I2 =0.0%
0.01 0.1 1 10 100

Analysis 1.3. Comparison 1 Intravenous (IV) versus irrigation, Outcome 3 Postpartum febrile morbidity.
Outcome: 3 Postpartum febrile morbidity

Berkeley 1990 8/50 9/50 48.4 % 0.89 [ 0.37, 2.12 ]
Boothby 1984 2/50 3/53 15.7 % 0.71 [ 0.12, 4.05 ]
Saravolatz 1985 7/34 6/27 36.0 % 0.93 [ 0.35, 2.43 ]
Total (95% CI) 134 130 100.0 % 0.87 [ 0.48, 1.60 ]

Test for subgroup differences: Not applicable
0.01 0.1 1 10 100

Analysis 1.4. Comparison 1 Intravenous (IV) versus irrigation, Outcome 4 Urinary tract infection.
Outcome: 4 Urinary tract infection

Boothby 1984 0/50 1/53 18.5 % 0.35 [ 0.01, 8.47 ]
Elliott 1986 0/39 1/42 18.3 % 0.36 [ 0.02, 8.54 ]
Gonen 1986 2/107 2/101 26.1 % 0.94 [ 0.14, 6.58 ]
Peterson 1990 1/94 2/113 23.0 % 0.60 [ 0.06, 6.53 ]
Saravolatz 1985 2/34 1/27 14.1 % 1.59 [ 0.15, 16.60 ]
Total (95% CI) 324 336 100.0 % 0.74 [ 0.25, 2.15 ]

0.01 0.1 1 10 100

Analysis 1.5. Comparison 1 Intravenous (IV) versus irrigation, Outcome 5 Serious infectious complication.
Outcome: 5 Serious infectious complication

Total (95% CI) 39 42 Not estimable

Heterogeneity: not applicable
Test for overall effect: not applicable
0.01 0.1 1 10 100

Analysis 1.6. Comparison 1 Intravenous (IV) versus irrigation, Outcome 6 Adverse events (maternal).
Outcome: 6 Adverse events (maternal)

1 Allergic reactions
Boothby 1984 0/50 0/53 Not estimable
Total (95% CI) 140 144 Not estimable

Heterogeneity: not applicable
Test for overall effect: not applicable
Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%
0.01 0.1 1 10 100

Analysis 1.7. Comparison 1 Intravenous (IV) versus irrigation, Outcome 7 Maternal length of hospital stay
(days).
Outcome: 7 Maternal length of hospital stay (days)
Mean Mean
Study or subgroup Intravenous Irrigation Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
Elliott 1986 39 4.8 (1.1) 42 4.9 (1) 39.6 % -0.10 [ -0.56, 0.36 ]
Gonen 1986 107 2.7 (3.5) 101 1.9 (2.2) 24.1 % 0.80 [ 0.01, 1.59 ]
Lavery 1986 113 5.4 (2.3) 49 5.3 (2) 27.5 % 0.10 [ -0.60, 0.80 ]
Saravolatz 1985 34 7.7 (4.07) 27 6.55 (1.95) 8.9 % 1.15 [ -0.40, 2.70 ]
Total (95% CI) 293 219 100.0 % 0.28 [ -0.22, 0.79 ]

Heterogeneity: Tau2 = 0.11; Chi2 = 5.34, df = 3 (P = 0.15); I2 =44%
-100 -50 0 50 100

Analysis 2.1. Comparison 2 Intravenous versus irrigation: sensitivity analysis, Outcome 1 Endometritis.
Comparison: 2 Intravenous versus irrigation: sensitivity analysis
Outcome: 1 Endometritis

Berkeley 1990 6/50 6/50 11.1 % 1.00 [ 0.35, 2.89 ]
Donnenfeld 1986 15/53 18/50 34.3 % 0.79 [ 0.45, 1.38 ]
Leveno 1984 11/52 16/51 29.9 % 0.67 [ 0.35, 1.31 ]
Peterson 1990 11/94 11/113 18.5 % 1.20 [ 0.55, 2.65 ]
Saravolatz 1985 4/34 3/27 6.2 % 1.06 [ 0.26, 4.33 ]
Total (95% CI) 283 291 100.0 % 0.87 [ 0.62, 1.23 ]

0.01 0.1 1 10 100

Analysis 2.2. Comparison 2 Intravenous versus irrigation: sensitivity analysis, Outcome 2 Wound infection.
Comparison: 2 Intravenous versus irrigation: sensitivity analysis
Outcome: 2 Wound infection

Leveno 1984 2/52 3/51 43.2 % 0.65 [ 0.11, 3.75 ]
Peterson 1990 0/94 2/109 33.0 % 0.23 [ 0.01, 4.76 ]
Saravolatz 1985 0/34 1/27 23.8 % 0.27 [ 0.01, 6.30 ]
Total (95% CI) 231 236 100.0 % 0.42 [ 0.11, 1.61 ]

0.01 0.1 1 10 100

APPENDICES
Appendix 1. Search terms

(cesarean OR caesarean OR caesarian OR cesarian) AND (antibio*)
CONTRIBUTIONS OF AUTHORS
Nahed Allam (NA) and Mohamed Hamed (MH) independently assessed trials for inclusion, extracted data, assessed the risk of bias,
and entered data into Revman. All steps were checked for accuracy and reviewed by Ashraf Nabhan (AN). Both review authors NA and
MH contributed to the analysis conducted by AN. All authors contributed to the interpretation of results and drawing conclusions.
All review authors carefully reviewed and approved the content of the full review before submission to the Pregnancy and Childbirth
Group Editors.
DECLARATIONS OF INTEREST
Nahed Allam - none known.
Mohamed Hamed - none known.
Ashraf Nabhan - none known.
SOURCES OF SUPPORT
Internal sources
• Egyptian Center for Evidence Based Medicine, Egypt.
Author Training
External sources
• No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

Erratum: Infant sepsis was added to the outcomes included in the GRADE ’Summary of findings’ table. It was one of our pre-specified
primary outcomes.
The following aspects of the protocol were planned but not implemented, but will be implemented in future updates of the review if
relevant data become available.
Types of studies
“Cluster-randomised RCTs will be included. We will exclude trials presented only as abstracts where information on risk of bias and
primary or secondary outcomes cannot be obtained; we will reconsider these trials for inclusion once the full publication is available.”
Measures of treatment effects
Continuous data
“We will calculate standardised mean differences (SMDs) to combine trials that measure the same outcome but with different methods.”
NOTES
Alfirevic 2010 describes plans for that review to be separated into three reviews and a further two reviews prepared in order to provide
comprehensive coverage of the review topic. These five reviews are listed below.
1. Different classes of antibiotics given to women routinely for preventing infection after caesarean section (Gyte 2014).
2. Different regimens of penicillin antibiotic given to women routinely for preventing infection after caesarean section (Liu 2014).
3. Different regimens of cephalosporin antibiotic given to women routinely for preventing infection after caesarean section
(protocol in preparation).
4. Timing of prophylactic antibiotics for preventing infectious morbidity in women undergoing caesarean section (Mackeen 2014).
5. Routes of administration of antibiotic prophylaxis for preventing infection after caesarean section (this review).

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Cochrane Database of Systematic Reviews

Routes of administration of antibiotic prophylaxis for

Nabhan AF, Allam NE, Hamed Abdel-Aziz Salama M

Nabhan AF, Allam NE, Hamed Abdel-Aziz Salama M.

Routes of administration of antibiotic prophylaxis for

Ashraf F Nabhan1 , Nahed E Allam2 , Mohamed Hamed Abdel-Aziz Salama3

Editorial group: Cochrane Pregnancy and Childbirth Group.

PLAIN LANGUAGE SUMMARY

Patient or population: pregnant wom en undergoing caesarean section

Risk with irrigation Risk with Intravenous

Wound inf ection 21 per 1000 10 per 1000 RR 0.49 859 ⊕

CI: Conf idence interval; RR: Risk ratio.

GRADE Working Group grades of evidence

benef it and appreciable harm (-2)

(7) Overall risk of bias

Postpartum febrile morbidity

Implications for practice

Characteristics of included studies [ordered by study ID]

Methods Parallel randomised controlled trial.

Participants Inclusion criteria: women in labour, with or without ruptured membranes

Interventions Number of women randomised: 107.

Outcomes Febrile morbidity.

Bias Authors’ judgement Support for judgement

Methods Parallel randomised controlled trial.

Interventions Number of women randomised: 103.

and 18 hours after surgery

Outcomes Febrile morbidity.

Notes Centre: Department of Obstetrics and Gynecology, University Hospital of Jacksonville

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Using a randomisation table.

Methods Parallel randomised controlled trial.

Interventions Number of women randomised: 103.

Notes Centre: Section on perinatology, Department of Obsterics and Gynecology, Pennsylvania

Bias Authors’ judgement Support for judgement

2 women were excluded due to administration of

Methods Multi-arm randomised controlled trial.

Interventions Number of women randomised: 158.

Fever index (degree-h).

Bias Authors’ judgement Support for judgement

Methods Parallel randomised controlled trial.

Interventions Number of women randomised: 217.

Bias Authors’ judgement Support for judgement

venous 107 women and irrigation 101 women)

Methods Multi-arm randomised controlled trial.

Interventions Number of women randomised: 212.

Outcomes Surgically-related infection a composite outcome (endomyometritis, septicaemia, wound

Notes Centre: Department of Obstetrics and Gynecology university of Louisville School of

Bias Authors’ judgement Support for judgement

Methods Parallel randomised controlled trial.

Interventions Number of women randomised: 103.

Bias Authors’ judgement Support for judgement

Methods Multi-arm randomised controlled trial.

Interventions Number of women randomised: 207.

Notes Centre: Department of Obsterics and Gynecology, Maricopa Medical Center

Bias Authors’ judgement Support for judgement

Blinding of outcome assessment (detection Low risk A double-blind study.

Methods Parallel randomised controlled trial.

Interventions Number of women randomised: 64.

administered by intrauterine irrigation

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk A computer-generated random table.

Blinding of outcome assessment (detection Low risk A double-blind study.

Methods Parallel randomised controlled trial.