By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

Dr. Fischer reports no financial relationships relevant to this field of study.

SYNOPSIS: Adding intravenous azithromycin to “routine” cephalosporin prophylaxis prior to non-elective cesarean section delivery significantly reduces the risk of postpartum endometritis and wound infection.

SOURCE: Tita AT, Szychowski JM, Boggess K, et al. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med 2016;375:1231-1241.

Despite a widespread practice of giving cephalosporin treatment to women undergoing urgent cesarean section delivery, postpartum infections still occur. It has been postulated that Ureaplasma species might be responsible for some of the infections. A total of 1,019 women at 14 U.S. centers were randomized to receive pre-delivery azithromycin or placebo, each in addition to standard prophylaxis mostly cefazolin. Maternal and neonatal outcomes were observed.

Deliveries were by either non-elective cesarean section or by planned elective cesarean section when the membranes had already been ruptured. Eleven percent of deliveries were preterm, and the authors did not stratify outcomes based on whether or not the delivery was preterm. Azithromycin was dosed as 500 mg intravenously prior to skin incision in 88% of subjects and immediately after skin incision in the others.

Interestingly, despite good randomization procedures, smoking was more common in the placebo group (12.3%) than in the azithromycin group (9.5%).

Endometritis was more common in the placebo (6.1%) than in the azithromycin (3.8%) group (P = 0.02). Postoperative wound infection also was more common in women who received placebo (6.6%) than in those who received azithromycin (2.4%, P < 0.001). Infection-related clinic visits and readmissions were more common in placebo-treated women. Statistically, treating 17 women would have prevented at least one case of endometritis or wound infection.

Outcomes were determined during the postpartum admission, at the six-week postpartum visit, and via telephone three months after delivery. Neonatal “complications” included “suspected sepsis” in 12% of newborns and respiratory distress syndrome in 4%. Neonatal outcomes did not differ between the placebo and azithromycin groups.

COMMENTARY

Approximately 32% of births in the United States are via cesarean delivery,1 and, as noted by Tita and colleagues, approximately two-thirds of operative deliveries are not done as planned elective procedures. It is a vitally important and a potentially practice-changing finding that pre-delivery azithromycin administration could halve the rates of endometritis and postoperative wound infection. Of course, effectiveness in this population of women with urgent cesarean section (with 11% of them being preterm at the time of operative delivery) does not necessarily imply that azithromycin would be as effective in women with neither ruptured membranes nor urgent problems during labor. What about the risk of infantile pyloric stenosis with macrolide use?

Idiopathic hypertrophic pyloric stenosis occurs in approximately 1-2 of each 1,000 births.2,3 This risk of pyloric stenosis is much greater in infants who receive a macrolide during the first two weeks of life. Macrolide use between two and six weeks of age also is associated with a risk of pyloric stenosis, although less so.2-4

Tita and colleagues found that treating 17 women with azithromycin would prevent significant postpartum complications in one woman. With reasonable medical care, endometritis, postpartum wound infection, and pyloric stenosis are only very rarely life-threatening. Even if pyloric stenosis rates increased dramatically (from 1-2 per 1,000) due to maternal use of azithromycin, pyloric stenosis still would be very much more rare than the prevented maternal infections.

What about the development of the infant microbiome?

The use of intrapartum antibiotics, whether with cesarean section or vaginal delivery, is associated with variations in the subsequent infant intestinal microbiome.5 These changes in microbiome can persist up to 1 year of age.5 However, the implications of these alterations in infant microbiome have not yet been elucidated.

Thus, Tita and colleagues have provided an excellent randomized, blinded, multicenter large study showing that peripartum intravenous azithromycin is associated with a significant reduction in common postpartum maternal complications. Even pending further studies, it would be reasonable to include azithromycin in the pre-incision prophylaxis provided to women undergoing non-elective cesarean section.

REFERENCES

  1. Martin JA, Hamilton BE, Osterman MJ. Births in the United States, 2014. NCHS Data Brief 2015 Sep;(216):1-8.
  2. Lund M, Pasternak B, Davidsen RB, et al. Use of macrolides in mother and child and risk of infantile hypertrophic pyloric stenosis: Nationwide cohort study. BMJ 2014;348:g1908.
  3. Eberly MD, Eide MB, Thompson JL, Nylund CM. Azithromycin in early infancy and pyloric stenosis. Pediatrics 2015;135:483-488.
  4. Murchison L, De Coppi P, Eaton S. Post-natal erythromycin exposure and risk of infantile hypertrophic pyloric stenosis: A systematic review and meta-analysis. Pediatr Surg Int 2016 Sep 21 [Epub ahead of print].
  5. Azad MB, Konya T, Persaud RR, et al; CHILD Study Investigators. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: A prospective cohort study. BJOG 2016;123:983-993.