Preterm birth remains a critical challenge in perinatal medicine and a leading cause of neonatal morbidity and mortality worldwide. Painless cervical dilation occurring before 24 weeks of gestation suggests cervical insufficiency, which frequently leads to spontaneous preterm delivery. Examination-indicated cervical cerclage mechanically reinforces the cervix and blocks ascending infection, serving as a key intervention to prolong gestation and improve maternal-fetal outcomes. Previous studies have confirmed that perioperative cefazolin combined with indomethacin effectively extends pregnancy duration. Azithromycin covers pathogens associated with preterm birth—such as Mycoplasmaand Ureaplasma—and theoretically could further reduce this risk. However, high-quality randomized controlled trial (RCT) evidence regarding the routine addition of azithromycin to examination-indicated cerclage has been lacking. To address this, a multicenter RCT published in AJOG MFMevaluated the clinical value of single-dose perioperative azithromycin to guide clinical practice.
(Image Source: AJOG MFM)
01 Antibiotic Selection in Emergency Cervical Cerclage
Painless cervical dilation prior to 24 weeks constitutes an obstetric emergency. Cervical insufficiency directly results in membrane bulging and preterm birth, often leading to poor neonatal prognosis. Examination-indicated cerclage (emergency cerclage) is currently the only effective intervention to prolong gestation by mechanically reinforcing the cervix and preventing ascending infection.
Perioperative management dictates the success of the procedure. Prior RCTs established that cefazolin plus indomethacin increases the rate of pregnancy prolongation ≥28 days from 62.5% to 92.3%, establishing this combination as the clinical standard. Clinically, however, many physicians add azithromycin empirically. The rationale is straightforward: azithromycin targets Mycoplasmaand Ureaplasma(ineffective against cephalosporins), pathogens closely linked to preterm birth and chorioamnionitis. Furthermore, azithromycin has demonstrated benefits in improving infection-related outcomes in cases of PPROM and cesarean delivery.
So, does adding azithromycin to the standard regimen truly provide an additional benefit in emergency cerclage? Due to a lack of high-quality comparative data, this question has remained controversial.
02 Study Design
This open-label, randomized controlled trial was conducted across four tertiary care hospitals in the US between December 2021 and September 2023. Its robust data and high representativeness offer direct guidance for clinical practice.
1. Study Population (Common Clinical Cases)
Singleton pregnancy at <24 weeks gestation.
Diagnosis of painless cervical dilation via physical examination.
No contraindications to cerclage (no uterine contractions, no active bleeding).
Exclusion criteria:Fever, active infection, antibiotic allergy, long QT syndrome, recent use of antibiotics or indomethacin.
2. Grouping and Intervention (Aligned with Clinical Practice)
Fifty-four patients were randomly assigned 1:1 to two groups (n=27 each):
Control Group (Standard Regimen): Preoperative intravenous cefazolin (1–2 g); oral indomethacin 50 mg preoperatively, followed by doses at 8 h and 16 h postoperatively.
Azithromycin Group: Standard regimen + single-dose intravenous azithromycin 1000 mg (administered once perioperatively).3. Primary and Secondary Outcomes
Primary Outcome: Gestational latency (days from cerclage to delivery)—directly reflecting procedural efficacy.
Secondary Outcomes: Rates of preterm birth (<37, <34, and <28 weeks), chorioamnionitis, neonatal birth weight, NICU admission rates, neonatal complications, and mortality.
03 Key Findings
1. Primary Outcome
Azithromycin group: Median gestational latency of 92 days.
Control group: Median gestational latency of 85 days.
P=0.93 (no statistically significant difference).
2. Preterm Birth Rates
Azithromycin group: 66.7%
Control group: 63.0%
No significant differences were observed in the rates of delivery before 34 weeks or 28 weeks.
3. Infection and Neonatal Outcomes
Incidence of chorioamnionitis: No difference between groups.
Birth weight, NICU admission rates, respiratory distress, sepsis, and neonatal mortality were identical between the two cohorts.
4. Inflammatory Markers
Cervicovaginal fluid analysis revealed that higher levels of GM-CSF correlated with earlier gestational age at delivery and higher preterm birth risk, confirming local inflammation as a core driver of premature cervical dilation. However, single-dose azithromycin failed to adequately suppress persistent inflammation, thereby failing to improve outcomes.
04 Why Was Azithromycin "Ineffective"? Clinical Implications
1. Reasons for Ineffectiveness: Suboptimal Dosing and Complex Etiology
Short Duration of Action: Azithromycin concentrations in amniotic fluid and placental tissue decline sharply after 3 days. Since the high-risk period for preterm birth lasts several weeks, a single dose cannot provide sustained protection.
Multifactorial Etiology: Emergency cervical dilation results from mechanical stress, inflammation, and genetic factors. Antibiotics address only the infectious component and cannot repair cervical damage or reverse genetic susceptibility.
Mismatch of Pathogens: While Mycoplasma/Ureaplasmaare associated with preterm birth, the low prevalence of these infections in this study population meant azithromycin had "no target" to act upon, resulting in no observable benefit.
2. Clinical Takeaways: 3 Core Recommendations
Maintain the Standard Regimen: Cefazolin plus indomethacin remains the preferred perioperative protocol for emergency cerclage; routine modification is unnecessary.
Avoid Routine Azithromycin: Current evidence does not support the use of single-dose perioperative azithromycin to improve outcomes. Avoiding its routine use helps prevent unnecessary medication and reduces antimicrobial resistance.
Focus on Precision Medicine: Future research should focus on high-risk subgroups—specifically those with positive cervical secretions for Mycoplasma/Ureaplasmaor significantly elevated inflammatory markers—to explore the potential value of extended-course azithromycin therapy, rather than empirically prescribing it to all patients.
Conclusion
This multicenter RCT demonstrates that adding single-dose perioperative azithromycin to a regimen of cefazolin and indomethacin during examination-indicated cervical cerclage does not prolong gestational latency, reduce preterm birth rates, or improve neonatal outcomes. Current evidence does not support the routine use of azithromycin in this patient population. The standard regimen of cefazolin combined with indomethacin remains the recommended perioperative approach. Future investigations into inflammatory modulation and individualized anti-infective strategies are warranted to optimize maternal and neonatal outcomes.
Source: Jayakumaran J, Khanuja K, Fischer S, et al. Azithromycin to improve latency in examination-indicated cerclage: a multicenter randomized controlled trial. American Journal of Obstetrics & Gynecology MFM. 2025; 8.
Disclaimer: This content is intended for medical professionals for academic exchange only and should not be used as a sole basis for clinical decisions. Clinical practice must integrate individual patient conditions, institutional resources, and the latest guidelines. Multidisciplinary consultation is advised when necessary.
Editor: Lily