Cesarean delivery is one of the most common operations performed anywhere. Infection remains its most frequent serious complication, particularly when the operation happens after labor has begun or the waters have broken. This article explains what happened when researchers added a single dose of the antibiotic azithromycin to standard preventive antibiotics in that higher-risk setting. It describes the design and results of the Cesarean Section Optimal Antibiotic Prophylaxis (C/SOAP) trial, published in the New England Journal of Medicine in 2016, and how American obstetric guidance responded. It also covers what the trial did not answer, so that expectant parents can discuss the question knowledgeably with their own physician before the day arrives.
Why infection after cesarean is a real concern
Every cesarean opens the abdomen and uterus, and bacteria normally living in the vagina and cervix can reach tissues that are ordinarily sterile. The two main problems are endometritis, an infection of the uterine lining, and wound infection at the incision. Less often, infection progresses to a pelvic abscess or to sepsis. These complications can mean fever, pain, readmission, further procedures and time away from a newborn during the weeks when mother and baby most need each other.
Risk is not the same for every cesarean. It is substantially higher when the operation is unplanned and occurs during labor or after the membranes have ruptured. By then, vaginal bacteria have had time to ascend into the uterus. Since the 2000s, standard practice has been to give a cephalosporin antibiotic, most commonly cefazolin, before the skin incision. That practice is supported by strong evidence and has greatly reduced infection rates. Even so, infections after unplanned cesareans remained stubbornly common.
The rationale: organisms that cefazolin cannot reach
Cefazolin works by disrupting the construction of the bacterial cell wall. Some organisms frequently found in the lower genital tract, notably Ureaplasma and Mycoplasma species, have no cell wall at all, so cefazolin has no target in them. Research groups, including investigators at the University of Alabama at Birmingham, had identified Ureaplasma in the uterine tissue of women who developed endometritis after cesarean. That finding raised the possibility that these organisms were contributing to infections that standard prophylaxis was missing.
Azithromycin, a macrolide antibiotic, acts on the bacterial ribosome rather than the cell wall and is active against these organisms. It also concentrates well in tissues and persists there for days. Its lineage is a quiet reminder of how much of medicine has been found rather than invented. Azithromycin was developed in the early 1980s by chemically modifying erythromycin, which was isolated in 1952 from a soil bacterium recovered from a sample of earth in the Philippines. There is something fitting in the fact that a remedy protecting mothers at the moment of birth traces back to an organism quietly living in the ground.
Before C/SOAP, the evidence for adding azithromycin came largely from observational work at the Alabama center. When the hospital moved to "extended-spectrum" prophylaxis, post-cesarean infection rates fell. Before-and-after comparisons like this are suggestive, but they cannot rule out other changes in care happening at the same time. A properly randomized trial was needed.
How the C/SOAP trial was designed
C/SOAP was led by Dr. Alan Tita at the University of Alabama at Birmingham and funded by the National Institutes of Health through the Eunice Kennedy Shriver National Institute of Child Health and Human Development. It was a pragmatic, multicenter, randomized, double-blind, placebo-controlled trial conducted at 14 hospitals in the United States. Its key features were:
- Who was enrolled: about 2,000 women carrying a single baby at 24 weeks of pregnancy or later who needed a nonelective cesarean during labor or after membrane rupture.
- What was compared: a single 500 mg intravenous dose of azithromycin versus an identical-appearing placebo, given before the incision where possible.
- Background care: all participants also received standard prophylaxis, which was cefazolin for most women, so the trial tested azithromycin as an addition to standard care, not a replacement.
- Main outcome: a combined measure of endometritis, wound infection or other serious infections, such as abscess or sepsis, within six weeks of delivery.
- Newborn safety: a combined measure of serious neonatal outcomes, including death, suspected or confirmed sepsis and other major complications.
Randomization and blinding mean that neither patients nor clinicians knew who received the active drug. This is the strongest available safeguard against bias. The multicenter design also made the results more applicable beyond a single hospital.
What the trial found
The results were clear and statistically robust. The combined infection outcome occurred in 6.1% of women who received azithromycin, compared with 12.0% of those who received placebo. That is a relative risk of about 0.51, meaning infections were roughly halved. In absolute terms, about one infection was prevented for every 17 women treated. Both major components improved:
- Endometritis: 3.8% with azithromycin versus 6.1% with placebo.
- Wound infection: 2.4% versus 6.6%, the largest proportional reduction.
- Serious maternal adverse events: also less frequent in the azithromycin group, at roughly 1.5% versus 2.9%.
Readmissions and unscheduled visits were also lower in the azithromycin group. The benefit appeared consistent across the subgroups the investigators examined. For newborns, the combined serious outcome did not differ meaningfully between groups, at roughly 14% in each. So the trial found no signal of harm to babies, and also no direct benefit to them.
A later economic analysis by members of the research group concluded that adding azithromycin was likely to reduce overall costs. The drug is inexpensive, and treating infections is not. Cost matters less than a mother's health, but it bears on whether hospitals adopt a practice.
Why is this evidence considered strong? The trial was large, randomized, blinded and placebo-controlled. It was conducted across many centers, used a clinically meaningful outcome and produced a large effect with a narrow margin of uncertainty. It also built on a plausible biological rationale and prior observational data pointing the same way. Few questions in obstetrics are answered this cleanly.
How obstetric guidance responded
The American College of Obstetricians and Gynecologists (ACOG) addressed the findings in its 2018 Practice Bulletin on prophylactic antibiotics in labor and delivery. The College advised that, for women undergoing nonelective cesarean during labor or after membrane rupture, clinicians should consider adding a single 500 mg intravenous dose of azithromycin to standard prophylaxis. The Society for Maternal-Fetal Medicine has likewise supported this approach. Many American hospitals incorporated azithromycin into their standard order sets for unplanned cesareans.
Note the wording: "consider," not "must." The guidance leaves room for the physician's judgment and the patient's circumstances. That is appropriate, since a recommendation from a professional body is a starting point for a conversation between a woman and her own doctor, not a substitute for it. Readers should also know that azithromycin's labeled indications are for treating specific infections. Its use to prevent surgical infection at cesarean is off-label, a common and lawful practice when supported by good evidence, but worth understanding.
The same research network later tested azithromycin in a different setting. The A-PLUS trial, published in the New England Journal of Medicine in 2023, gave a single oral dose to women planning vaginal birth in several low- and middle-income countries. It found a reduction in maternal sepsis or death but no reduction in newborn sepsis or death. That result concerns a different population and route of delivery, and it should not be read as applying directly to cesarean practice in the United States.
Limits, open questions and sensible cautions
Strong evidence is not unlimited evidence. Several boundaries deserve plain statement:
- Scheduled cesareans were not studied. C/SOAP enrolled only women in labor or with ruptured membranes. Planned cesareans before labor carry lower infection risk, and the trial does not show that azithromycin helps in that setting.
- Rare newborn effects cannot be excluded. Azithromycin crosses the placenta. The trial was not large enough to detect uncommon problems, and macrolide exposure in early infancy has been associated in other studies with infantile hypertrophic pyloric stenosis, a narrowing of the stomach outlet. Most of that association involves antibiotics given directly to infants, and a single maternal dose has not been shown to cause it, but the question has not been definitively closed.
- Antibiotic stewardship. Every additional antibiotic dose, multiplied across millions of births, adds pressure toward bacterial resistance. Professional guidance reflects a judgment that the benefit in this higher-risk group justifies one targeted dose. That judgment is reasonable, but it should not be extended casually to lower-risk situations.
- Individual factors. Allergy to macrolides is an obvious reason not to give the drug. Azithromycin can also affect heart rhythm, specifically the QT interval, in susceptible people, so women with known rhythm disorders or those taking interacting medications should raise this with their physician.
For families, the practical lesson is preparedness. Most cesareans that happen during labor were not planned, and decisions are made quickly. A woman who has asked her obstetrician beforehand which antibiotics are used if an unplanned cesarean becomes necessary, and why, can give genuinely informed consent instead of being caught unawares. Caring well for one's own family begins with understanding the options, and both a mother and her child are worth that effort.
Key takeaway: In a large, rigorous NIH-funded trial, adding one dose of azithromycin to standard antibiotics before an unplanned cesarean roughly halved maternal infections without evident harm to newborns, and ACOG now advises that it be considered, a decision best made in advance by an informed mother and her own physician.