Azithromycin and Ampicillin for Late PPROM

Preterm premature rupture of membranes (PPROM) occurs in 1-3% of all pregnancies and accounts for approximately 30% of all preterm births. It is associated with significant maternal, fetal, and neonatal risks, including infections, respiratory complications, and adverse neurodevelopmental outcomes. The management of PPROM before 34 weeks is well established and includes corticosteroids and antibiotic therapy to prolong latency and reduce infectious complications. However, optimal management of PPROM in the late preterm period (34.0 to 36.6 weeks) remains under debate.

Historically, immediate delivery was recommended after PPROM at 34 weeks or later. More recent evidence, however, suggests that expectant management may reduce neonatal respiratory morbidity, mechanical ventilation, and NICU stays, even in the late preterm period. As a result, expectant management has become more accepted. In this setting, prophylactic antibiotics are commonly used to reduce maternal and neonatal infections. While ampicillin is the standard agent used for GBS prophylaxis, it is unclear whether broader antibiotic coverage might lead to better neonatal outcomes by delaying delivery or preventing ascending infections.

In early preterm PPROM (\<32 weeks), a combination of ampicillin and erythromycin (or azithromycin) has demonstrated improved outcomes in large trials. However, few studies have addressed the benefits of such regimens in late PPROM, and no randomized controlled trials to date have compared different antibiotic regimens in this specific population.

This multicenter randomized controlled trial will compare two antibiotic regimens in women with PPROM between 34.0 and 36.6 weeks of gestation:

Control group (standard care): Intravenous ampicillin 2 g every 6 hours for 48 hours, followed by oral amoxicillin 500 mg every 8 hours for 5 days.

Intervention group: Same regimen as the control group, with the addition of a single dose of PO azithromycin 1 g administered at the start of treatment.

The primary outcome is a composite of neonatal adverse outcomes, including:

Use of respiratory support (CPAP, HFNC, mechanical ventilation, ECMO) Neonatal sepsis (confirmed by positive blood culture) Hypoglycemia requiring treatment Hyperbilirubinemia requiring phototherapy Stillbirth or neonatal death within 72 hours

Secondary neonatal outcomes include:

Components of the primary outcome analyzed individually RDS, need for resuscitation, surfactant use, TTN, IVH, NEC, NICU stay duration, pneumothorax, asphyxia, convulsions, placental pathology, and others Maternal outcomes include Latency from randomization to delivery Chorioamnionitis, fever, bacteremia, placental abruption, cesarean delivery Composite maternal morbidity Postpartum infections, need for ICU admission, wound complications Length of postpartum hospital stay and breastfeeding initiation

Participants will be hospitalized from diagnosis until delivery. Management will include:

Regular maternal vital signs and infection monitoring Twice-daily fetal heart rate monitoring Corticosteroids for fetal lung maturation (in selected patients) Ultrasound to assess fetal well-being No tocolysis will be administered Labor will be induced at 37 weeks or earlier if indicated

Inclusion criteria:

Women aged 18-50 years with singleton pregnancy PPROM diagnosed between 34.0 and 36.6 weeks No active labor or signs of infection at presentation

Exclusion criteria:

Multiple gestation, chorioamnionitis, abnormal fetal heart rate, cerclage, meconium-stained amniotic fluid, fetal malformations, or GBS macrolide allergy Diagnosis of PPROM will be based on history and physical exam, including pooling seen on sterile speculum exam. When necessary, AmniSure testing will confirm membrane rupture.

Eligible women will be approached within 24 hours of admission. After obtaining informed consent, participants will be randomized (1:1) and stratified by center and gestational age (\<35 weeks or ≥35 weeks). Women will remain inpatients until delivery, and labor will be induced no later than 37.0 weeks, unless earlier delivery is indicated.

Placental pathology and culture will be performed in all participants after delivery.

The sample size is based on an expected 50% rate of the composite neonatal outcome in the control group. A total of 296 women will provide 80% power to detect a 33% relative reduction in the primary outcome (from 50% to 33.5%) with a 5% alpha level. Including a 5% loss to follow-up, 311 women will be enrolled.

Data will be collected using REDCap, and participant confidentiality will be maintained through study ID numbers. Results may be used in future research but will remain de-identified.

Ethics approval will be obtained at each participating site. All participants will provide written informed consent, and the study will be conducted under standard GCP (Good Clinical Practice) guidelines.

This trial aims to provide the first direct comparison of two antibiotic regimens in the setting of late preterm PPROM, potentially impacting future recommendations on latency antibiotic therapy and neonatal outcomes.

• Number of Infants With Severe Respiratory Morbidity [Срок оценки: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first.]
• Number of Infants Requiring Resuscitation at Birth [Срок оценки: At birth]
• Number of Infants Diagnosed With Respiratory Distress Syndrome [Срок оценки: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first]
• Number of Infants Receiving Surfactant Therapy [Срок оценки: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first.]
• Number of Infants Diagnosed With Transient Tachypnea of the Newborn [Срок оценки: Within first 72 hours after birth]
• Number of Infants Diagnosed With Necrotizing Enterocolitis [Срок оценки: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first.]
• Number of Infants With Grade 3 or 4 Intraventricular Hemorrhage [Срок оценки: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first.]
• Number of Infants With Feeding Intolerance [Срок оценки: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first.]
• Number of Infants With NICU Stay Exceeding 3 Days [Срок оценки: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first]
• Number of Infants Diagnosed With Pneumothorax [Срок оценки: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first]
• Number of Infants Diagnosed With Meconium Aspiration Syndrome [Срок оценки: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first]
• Number of Infants Diagnosed With Birth Asphyxia [Срок оценки: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first]