Antibiotic Prophylaxis in Obstetric Procedures

Objective: To review the evidence and provide recommendations on antibiotic prophylaxis for obstetrical procedures.Outcomes: Outcomes evaluated include need and effectiveness of antibiotics to prevent infections in obstetrical procedures.Evidence:Published literature was retrieved through searches of Medline and The Cochrane Library on the topic of antibiotic prophylaxis in obstetrical procedures. Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and articles published from January 1978 to June 2009 were incorporated in the guideline. Current guidelines published by the American College of Obstetrics and Gynecology were also incorporated. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

# Introduction
I nfectious complications following obstetric surgical procedures are a significant source of morbidity and potential mortality. They include urinary tract infection, endometritis, wound infection, perineal infection, and sepsis, which lead to prolonged hospital stays and increased health care costs. Much work has been done to study the effect of prophylactic antibiotics in reducing infectious morbidity. A plethora of antibiotic types, dosing schedules, and routes of administration have been investigated. There is evidence to support the use of prophylactic antibiotics for a number of procedures in obstetrics. Unfortunately, few comparative trials have been conducted, leaving the clinician with uncertainty as to which regimen is superior.
The presence of antibiotic resistant organisms is a reality in Canadian health care facilities. [bib_ref] A comparison of infection control program resources, activities, and antibiotic resistant organism..., Zoutman [/bib_ref] These organisms include methicillin resistant Staphylococcus aureus, vancomycin resistant Enterococcus, and extended-spectrum beta-lactamase-producing organisms.
Both morbidity and mortality are increased in infections caused by these organisms, as they may be more virulent and are more difficult to treat because therapeutic options are limited. Antibiotic resistance development results mainly from the inappropriate use of antibiotics. Incomplete courses of antibiotic therapies and the unnecessary use of broader spectrum regimens play a role. [bib_ref] How antibiotics can make us sick: the less obvious adverse effects of..., Dancer [/bib_ref] Adherence to both treatment and prophylaxis guidelines likely assists in reducing infection and antibiotic resistance. Physician adherence to antibiotic prophylaxis guidelines is variable and usually at odds with published guidelines. [bib_ref] Global Network for Perinatal and Reproductive Health. An international survey of practice..., Huskins [/bib_ref] [bib_ref] Use of antimicrobial prophylaxis for major surgery: baseline results from the National..., Bratzler [/bib_ref] In addition to antibiotic prophylaxis, it is essential to review all factors that affect infectious risk reduction in obstetrical care.Adherence to appropriate skin preparation procedure, including hair clipping as opposed to shaving, and effective antisepsis of both patient and staff are required. [bib_ref] Preoperative hair removal to reduce surgical site infection, Tanner [/bib_ref] Sterile surgical fields must be ensured, and ongoing quality assessment of sterilization technique, air ventilation, and postoperative wound care is needed. Consistent infection control surveillance and reporting of infectious complications track ability to minimize these morbidities and possibly to identify clusters of infection and the emergence of antibiotic resistant organisms. This will dictate changes to operative routines to respond to evolving microbial diversity that seems inevitable.

## Antibiotic prophylaxis in obstetric procedures
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## Principles of antibiotic prophylaxis
The purpose of antibiotic prophylaxis in surgical procedures is not to sterilize tissues but to reduce the colonization pressure of microorganisms introduced at the time of operation to a level that the patient's immune system is able to overcome. [bib_ref] Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory..., Mangram [/bib_ref] Prophylaxis does not prevent infection caused by postoperative contamination. Prophylactic antibiotic use differs from treatment with antibiotics 5 in that the former is intended to prevent infection, whereas the latter is intended to resolve an established infection, typically requiring a longer course of therapy. Prophylaxis is intended for elective procedures when the incision will be closed in the operating room.
Before an agent can be considered for use as a prophylactic antibiotic, there must be evidence that it reduces postoperative infection. It must also be safe and inexpensive, and it must be effective against organisms likely to be encountered in the surgical procedure. The agent must be administered in a way that ensures that serum and tissue levels are adequate before an incision is made and that therapeutic levels of the agent can be maintained in serum and tissue during surgery and for a few hours (at most) after the incision is closed. [bib_ref] Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory..., Mangram [/bib_ref] Wound infections-surgical site infections-in the form of cellulitis, abscess, or dehiscence can occur following laparotomy. Pelvic infections, such as an abscess or infected hematoma, are a risk with any surgical procedure that enters the abdominal cavity. Cuff cellulitis is a specific risk for hysterectomy. Endometritis can result from Caesarean section or surgical abortion. Urinary tract infections can occur as a result of any procedure that involves catheterization of the bladder. A 1999 guideline published by the US Centers for Disease Control and Prevention lists the specific and stringent criteria that must be met for diagnosis of a surgical site infection. [bib_ref] Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory..., Mangram [/bib_ref] Accurate surveillance for SSI monitoring requires followup for 30 days postoperatively, and the trend towards early discharge from hospital makes surveillance a challenge. It is estimated that up to 84% of surgical site infections occur following discharge from hospital. [bib_ref] Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory..., Mangram [/bib_ref] If prophylactic antibiotics are to be given, they should be administered shortly prior to or at bacterial inoculation. [bib_ref] The timing of prophylactic administration of antibiotics and the risk of surgical-wound..., Classen [/bib_ref] The majority of studies suggest that a single dose is effective, but for lengthy procedures (> 3 hours) the dose should be repeated at intervals 1or 2 times the half-life of the drug. It has also been suggested that with large blood loss (> 1500 mL), a second dose should be given. 10

## Use of antibiotic prophylaxis in obstetrics
Procedures reviewed in this section include Caesarean section, operative vaginal delivery, manual removal of placenta, repair of third or fourth degree perineal laceration, cervical cerclage, and postpartum dilatation and curettage. Recent changes to endocarditis prophylaxis guidelines are also be reviewed.

## Caesarean section
The single most important risk factor for postpartum maternal infection is Caesarean section. [bib_ref] Clinical risk factors for puerperal infection, Gibbs [/bib_ref] Women having Caesarean section have a 5-to 20-fold greater risk of infection than women having vaginal delivery. Rates of wound infection and serious infectious complications can be as high as 25%. [bib_ref] Incidence of hospital-acquired infections associated with caesarean section, Henderson [/bib_ref] There is no consistent application of definitions for SSI, and the practice of post-discharge surveillance varies widely. [bib_ref] Forum: surveillance of surgical site infections, Lee [/bib_ref] There has been debate about the benefit of prophylactic antibiotics for a woman who has an elective Caesarean section with intact membranes and without labour. A meta-analysis of 4 studies found that antibiotic prophylaxis resulted in a decrease in postoperative fever (RR 0.25; 95% CI 0.14 to 0.44) and endometritis (RR 0.05; 95% CI 0.01 to 0.38). [bib_ref] Prophylactic use of antibiotics for nonlaboring patients undergoing cesarean delivery with intact..., Chelmow [/bib_ref] Taken together, these data support the recommendation to use prophylactic antibiotics for all women undergoing Caesarean section.
Controversy also exists about whether prophylactic antibiotics in Caesarean section should be given prior to skin incision or at the time of the umbilical cord clamping. Traditionally, prophylaxis has been delayed in an effort to avoid masking a neonatal infection and to prevent an unnecessary septic work-up. However, recent evidence may change this practice. A randomized trial compared maternal infectious and neonatal outcomes in women randomized to receive cefazolin 15 to 60 minutes before incision versus at cord clamp. Three hundred fifty-seven women were enrolled. Overall maternal infectious morbidity was reduced in the pre-treatment group (RR 0.4; 95% CI 0.18 to 0.87); in particular, endometritis was reduced (RR 0.2; 95% CI 0.15 to 0.94).
No increase in neonatal sepsis, investigation, or length of stay was observed. [bib_ref] Administration of cefazolin prior to skin incision is superior to cefazolin at..., Sullivan [/bib_ref] A recent meta-analysis supports the use of prophylactic antibiotics prior to Caesarean incision to prevent total infectious morbidity (RR 50; 95% CI 0.33 to 0.78, P = 0.002). Neonatal outcomes were not affected. [bib_ref] Timing of perioperative antibiotics for cesarean delivery: a metaanalysis, Costantine [/bib_ref] The most widely studied antibiotics for surgical prophylaxis are cephalosporins. Cefazolin is a first-generation cephalosporin and is a Pregnancy Category B drug. When given intravenously, its half-life is 1.8 hours. It provides good coverage for gram positive organisms and has modest gram negative coverage. In a 1999 guideline, the US Centers for Disease Control and Prevention recommended its use at Caesarean section. [bib_ref] Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory..., Mangram [/bib_ref] It is recommended that 1 to 2 grams should be administered intravenously not more than 30 minutes before the skin is cut. An additional dose can be considered if blood loss exceeds 1500 mL or at 4 hours if the procedure lasts more than 4 hours (i.e., up to 2 half-lives of the drug). [bib_ref] Antibiotic prophylaxis against postoperative wound infections, Gordon [/bib_ref] Trials have shown that broader spectrum antibiotics for Caesarean section do reduce infectious morbidity. Superiority trials with cefazolin have not been conducted. Given the potential for antibiotic resistance in both mother and neonate, recommendations for the use of broader spectrum antibiotics require further study. 20

## Operative vaginal delivery
A 2004 Cochrane review investigated the use of prophylactic antibiotics for operative vaginal delivery, with either forceps or vacuum assisted deliveries, to determine if prophylaxis reduces the incidence of postpartum infections. [bib_ref] Antibiotic prophylaxis for operative vaginal delivery, Liabsuetrakul [/bib_ref] The review identified only one trial of 393 women, and only 2 of 9 outcomes deemed appropriate by the reviewers were assessed in this study: endometritis and length of hospital stay. These did not differ between those who received prophylaxis and those who received no treatment. The review concluded there were insufficient data on which to base recommendations for practice and that further research is needed. No additional studies addressing this issue have been published to date.

## Manual removal of placenta
There is limited information regarding the use of prophylactic antibiotics to reduce the development of postpartum endometritis following manual removal of the placenta. A Cochrane review, updated in April 2009, did not identify any randomized controlled trials. [bib_ref] Prophylactic antibiotics for manual removal of retained placenta in vaginal delivery, Chongsomchai [/bib_ref] The World Health Organization suggests that prophylaxis should be offered but recognizes that there is no direct evidence of the value of antibiotic prophylaxis after manual removal of the placenta and bases the recommendation on studies involving Caesarean section and abortion and on observational studies of other intrauterine manipulations.The effect of operator glove change before manual removal of the placenta at Caesarean section was studied in a group of 228 women, with operators changing gloves in one half of the cases. No difference in post-Caesarean endometritis was noted between the 2 groups. [bib_ref] Effect of changing gloves before placental extraction on incidence of postcesarean endometritis, Turrentine [/bib_ref] However, the incidence of endometritis was decreased when the placenta delivered spontaneously rather than being manually removed at Caesarean section in a study of 333 women, all of whom received prophylactic antibiotics (15% vs. 26%, RR 0.6; P = 0.01). 25

## Third or fourth degree perineal laceration
A 2005 Cochrane review 26 on this subject found there were no randomized trials comparing prophylactic antibiotics with placebo or no treatment in fourth degree perineal tears during vaginal birth. A well-designed randomized trial was recommended. This was undertaken by Duggal et al. [bib_ref] Antibiotic prophylaxis for prevention of postpartum perineal wound complications: a randomized controlled..., Duggal [/bib_ref] and published in 2008. This prospective trial followed 107 women post third or fourth degree laceration repair for 2 weeks; the women had been randomly assigned to receive a single intravenous dose of cefotetan, cefoxitin, or placebo. Four of 49 (8%) who received antibiotics and 14 of 58 (24%) who received placebo developed perineal wound complication (P = 0.037). This suggests a benefit to using prophylactic antibiotics to reduce morbidity following significant perineal laceration. 27

## Elective and emergency cerclage, with or without exposed membranes
There is insufficient evidence to support the use of prophylactic antibiotics with the placement of cervical cerclage in any clinical setting. One study [bib_ref] Continuous low-dose antibiotics and cerclage for recurrent second-trimester pregnancy loss, Shiffman [/bib_ref] investigated the use of continuous low-dose antibiotics in women with a history of second trimester pregnancy loss with the placement of cerclage at 14 to 24 weeks' gestation on the basis of transvaginal sonographic findings of cervical funnelling. Each of the 10 patients had a live birth, and pregnancy was prolonged by a mean of 13.4  4.2 weeks beyond the previous pregnancy. There was no control group. [bib_ref] Continuous low-dose antibiotics and cerclage for recurrent second-trimester pregnancy loss, Shiffman [/bib_ref] In a second retrospective study of 116 mid-trimester cerclage placements, antibiotic use was not associated with a decreased risk of delivery before 28 weeks' gestation. [bib_ref] Factors associated with success of emergent second-trimester cerclage, Terkildsen [/bib_ref] Randomized clinical trials are needed to confirm the role of antibiotics in these high-risk pregnancies.

## Postpartum dilatation and curettage
No studies were identified that investigated the use of prophylactic antibiotics for postpartum dilatation and curettage.

## Dosage of antibiotic prophylaxis in obesity
Increased BMI is associated with higher rates of both obstetric and infectious complications. [bib_ref] The impact of maternal BMI status on pregnancy outcomes with immediate short-term..., Heslehurst [/bib_ref] Controlled trials assessing the required dosage for antibiotic prophylaxis based on patient BMI have not been assessed in our specialty. Expert opinion recommends twice the normal dose of prophylaxis for morbidly obese patients, who have a BMI > 35. [bib_ref] Antibiotic prophylaxis against postoperative wound infections, Gordon [/bib_ref] Future research in this area is needed.

## Recommendations for penicillin / cephalosporin allergy
Penicillin allergy is self-reported by up to 10 % of patients, yet only 10 % of those are actually allergic when skin testing is performed. [bib_ref] The incidence of antimicrobial allergies in hospitalized patients: implications regarding prescribing patterns..., Lee [/bib_ref] [bib_ref] Results of the National Institute of Allergy and Infectious Diseases collaborative clinical..., Sogn [/bib_ref] [bib_ref] Penicillin skin testing in patients with a history of beta-lactam allergy, Del Real [/bib_ref] True anaphylactic response to penicillin is rare, occurring in 1 to 4 of 10 000 administrations.An allergic reaction to cephalosporins in those with a penicillin allergy occurs at rates of 0.17% to 8.4%. [bib_ref] Penicillin allergy and the cephalosporins, Dash [/bib_ref] [bib_ref] Safety of cephalosporin administration to patients with histories of penicillin allergy, Daulat [/bib_ref] [bib_ref] Adverse drug reactions to a cephalosporins in hospitalized patients with a history..., Fonacier [/bib_ref] An alternative to cephalosporins should be given only to individuals with a history of penicillin anaphylaxis (shortness of breath or evidence of airway edema rather than just rash or other allergic reaction) or cephalosporin allergy. Alternative prophylactic antibiotics include clindamycin 600 mg IV or erythromycin 500 mg IV.

## Prevention of infective endocarditis
An American Heart Association guidelinepublished in 2007 found no evidence that genitourinary procedures cause IE or that administration of antibiotics prevents IE following such procedures. The American Heart Association therefore does not recommend prophylactic antibiotics for patients undergoing genitourinary procedures; this is a change from their 1997 guideline. They identified 4 conditions that are at highest risk of adverse outcome . For patients with the conditions listed in who have an established gastrointestinal or genitourinary tract infection or for those who receive antibiotic therapy for another reason (e.g., to prevent wound infection), they suggest it may be reasonable that the choice of antibiotic also be active against enterococci (i.e., ampicillin, piperacillin, or vancomycin).
They also suggest that it may be reasonable for patients at high risk of IE who have a known enterococcal urinary tract infection or colonization to receive antibiotic treatment prior to any urinary tract manipulation. A review on this recommendation change has been recently published. 39
[table] Table 1: Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care [/table]
[table] Table 2 Table 3: Cardiac conditions associated with the highest risk of adverse outcome from endocarditis Prosthetic cardiac valve or prosthetic material used for cardiac valve repair Previous infective endocarditis Congenital heart disease (CHD) Unrepaired cyanotic CHD (including palliative shunts and conduits) Completely repaired CHD with prosthetic material < 6 months after procedure Repaired CHD with residual defects at/near site of prosthetic material Cardiac transplant recipient with cardiac valvulopathy Adapted from Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, et al. 38 Prophylactic antibiotic recommendations for obstetrical procedures [/table]