Prophylaxis for C-Section: Might Broader Be Better?

Preventing Post-cesarean Infection

Cesarean delivery is the most common major surgical procedure performed. Complications including wound infection and endometritis are five to ten times more common after cesarean as compared with vaginal deliveries.^[1] Periprocedural use of cefazolin is recommended to reduce this risk, yet infections still occur, contributing to maternal morbidity and increased healthcare costs.

Nonelective cesarean section (ie, unscheduled surgery performed during labor, after membrane rupture or for maternal or fetal emergencies) is a particular concern. Postoperative infections occur in up to 12% of these patients despite standard prophylaxis.^[2,3] Previous studies show higher rates of postpartum endometritis in those with genital or placental colonization with Ureaplasma urealyticum,^{[4,5,6,7,8,9]} and single-center studies suggest that a single dose of intravenous azithromycin in addition to standard prophylaxis may reduce the risk for postoperative infection.^[10] A hypothesis for the association is the additional coverage of Ureaplasma species provided by azithromycin; however, the role of Ureaplasma in the pathogenesis of endometritis is debated.

To expand on these findings and assess the benefits and safety of azithromycin in addition to standard prophylaxis, Tita and colleagues^[11] randomly assigned 2013 women at 14 centers across the United States who were undergoing cesarean delivery during labor or after membrane rupture to a single 500-mg dose of intravenous azithromycin (n=1019) or placebo (n=994) in addition to standard preoperative antibiotic prophylaxis. Women undergoing scheduled cesarean section were excluded.

The rate of primary composite outcome (endometritis, wound infection, or other infection within 6 weeks of delivery) was cut nearly in half in the azithromycin group as compared with the placebo group (6.1% vs 12.0%, P<.001). Rates of endometritis (3.8% vs 6.1%, P=.02) and wound infection (2.4% vs 6.6%, P<.001) were lower in the azithromycin group as compared with the placebo group, as were unscheduled return office visits, readmissions, and use of postpartum antibiotics. Neonatal outcomes assessed at 3 months were the same in both groups.

Viewpoint

What is the mechanism for azithromycin-associated reduction in infections? As previously stated, standard prophylaxis with cefazolin or clindamycin would not cover Ureaplasma, suggesting that the benefit comes from this additional coverage.^[12] However, this cannot be confirmed in the absence of any efforts to detect the organism.

Furthermore, more than 70% of participants had a body mass index >30 kg/m², and obesity is a known risk factor for postpartum infections. Although not reported, it is possible that cefazolin was underdosed in these patients, in which case azithromycin would have provided expanded coverage.

Lastly, post hoc analysis found that the addition of azithromycin provided greater benefit when incisions were closed with staples as compared with sutures (P=.02 for the interaction). Staples are discouraged because of increased infection risk (staples were used in 40% of patients in this study), yet it's possible that the concentrations of azithromycin commonly attained in myometrium and adipose tissue in addition to a long half-life explain this finding. Pharmacologic data suggest that minimal azithromycin crosses the placenta into the fetal circulation; however, long-term follow-up is needed to ensure no increased risk for neonatal complications.

Although some questions remain, it's likely that our obstetric colleagues will ask to add azithromycin to surgical prophylaxis guidelines for nonelective cesarean section. This study supports the addition of azithromycin at institutions with high rates of postoperative infections and for patients at higher risk for infection to whom it is likely to provide the most benefit. However, long-term evaluation is needed to monitor for unintended maternal and neonatal consequences.

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