Azithromycin and Ampicillin for Late PPROM
Trial Snapshot
- Phase
- Phase 4
- Status
- Recruiting
- Sponsor
- Sheba Medical Center
- Enrollment
- 311
- Locations
- 1
- Primary Endpoint
- A composite of neonatal adverse outcomes
Study Overview
Brief Summary
The goal of this clinical trial is to learn whether adding azithromycin to the standard antibiotic treatment (ampicillin) improves newborn outcomes in women with preterm premature rupture of membranes (PPROM) between 34.0 and 36.6 weeks of pregnancy.
The main question it aims to answer is:
Does the combination of ampicillin and azithromycin lower the risk of serious neonatal health problems compared to ampicillin alone?
Researchers will compare two antibiotic regimens:
Ampicillin alone, which is the current standard care Ampicillin with azithromycin, a broader regimen that may better prevent infections and prolong pregnancy
Participants will:
Receive one of the two antibiotic treatments during hospitalization. Be monitored until delivery for signs of infection and labor
All participants will stay in the hospital until delivery. The study also looks at how the antibiotic choice may affect the time between membrane rupture and delivery, maternal infections, and the need for neonatal intensive care.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 50 Years (Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Maternal age 18-50
- •Premature rupture of membranes
- •Gestational age 34.0 and 36.4 weeks
- •Singleton pregnancy
Exclusion Criteria
- •Multiple gestations
- •Individuals in active labor (defined as 3 cm dilatation and 80% effacement or more. or regular uterine construction of more than 4 in 10 minutes)
- •Meconium stain amniotic fluid
- •Non-reassuring fetal heart rate or status
- •Maternal or fetal indication for labor:
- •Suspected Chorioamnionitis
- •Suspected placental abruption
- •Any maternal morbidity requiring labor
- •Cervical cerclage in place.
- •Major fetal malformation or known chromosomal abnormalities.
- •Stillbirth.
- •Sensitivity to Macrolides Antibiotics
Arms & Interventions
Standard antibiotic regimen (Ampicillin and Amoxicillin)
Participants in the control arm receive the standard antibiotic regimen for late PPROM, consisting of intravenous Ampicillin 2g every 6 hours for 48 hours, followed by oral Amoxicillin 500mg every 8 hours for 5 days, administered according to current clinical guidelines
Intervention: Ampicillin/Amoxicillin plus single-dose PO Azithromycin (Drug)
Intervention Arm - Standard Antibiotics with Azithromycin
Participants in this arm will receive the standard antibiotic regimen of intravenous Ampicillin followed by oral Amoxicillin, plus a single dose of 1 gram oral Azithromycin
Intervention: Intravenous Ampicillin followed by Oral Amoxicillin (Drug)
Outcomes
Primary Outcomes
A composite of neonatal adverse outcomes
Time Frame: From the time of birth until 72 hours postpartum
A composite of neonatal adverse outcomes defined as the occurrence of one or more of the following events within 72 hours after birth: use of continuous positive airway pressure (CPAP) or high-flow nasal cannula, supplemental oxygen with a fraction of inspired oxygen (FiO2) ≥0.30 for ≥4 continuous hours, extracorporeal membrane oxygenation (ECMO), mechanical ventilation, neonatal sepsis (defined as positive blood culture), hypoglycemia requiring treatment, hyperbilirubinemia requiring phototherapy, stillbirth, or neonatal death within 72 hours after delivery The composite will be reported as the number of infants who experience at least one of the listed adverse outcomes. Unit of Measure: Number of infants with ≥1 adverse outcome
Secondary Outcomes
- Distribution of Placental Histopathology Lesion Types(Within 6 weeks after delivery, upon receipt of pathology results)
- Number of Infants With Severe Respiratory Morbidity(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first.)
- Number of Infants Requiring Resuscitation at Birth(At birth)
- Number of Infants Diagnosed With Respiratory Distress Syndrome(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first)
- Number of Infants Receiving Surfactant Therapy(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(Within first 72 hours after birth)
- Number of Infants Diagnosed With Necrotizing Enterocolitis(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(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first.)
- Number of Infants With Feeding Intolerance(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first.)
- Number of Infants With NICU Stay Exceeding 3 Days(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first)
- Number of Infants Diagnosed With Pneumothorax(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first)
- Number of Infants Diagnosed With Meconium Aspiration Syndrome(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first)
- Number of Infants Diagnosed With Birth Asphyxia(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first)
- Number of Infants Diagnosed With Periventricular Leukomalacia(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first)
- Number of Neonatal Deaths(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first)
- Number of Participants Completing Full Course of Antenatal Corticosteroids(From randomization until delivery)
- Number of Participants With Placental Abruption(From randomization until delivery)
- Number of Participants With Intrapartum Fever (≥ 38°C)(During labor)
- Number of Participants Diagnosed With Clinical Chorioamnionitis(From randomization until delivery)
- Number of Participants With Bacteremia (Positive Blood Culture)(From randomization until 72 hours postpartum)
- Number of Participants Undergoing Unplanned Cesarean Delivery(From randomization until delivery)
- Number of Participants With Postpartum Endometritis(From delivery until 6 weeks post partum)
- Number of Participants With Postpartum Wound Infection or Dehiscence(from birth and up to 6 weeks postpartum)
- Number of Participants With Composite Adverse Maternal Outcome(From randomization until 6 weeks postpartum)
- Length of Postpartum Hospital Stay(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first)
- Number of Participants Who Initiated Breastfeeding(From delivery through maternal hospital discharge or up to 28 days postpartum, whichever comes first)
- Number of Participants Requiring Hospital Readmission(Up to 6 weeks postpartum)
- Number of Participants With Antepartum Hemorrhage(From randomization until delivery)
- Number of Infants With Neonatal Convulsions(From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first)
- Number of Infants With Positive Placental Cultures(Within 6 weeks after delivery, upon receipt of culture results)
- Latency From Randomization to Delivery(From randomization until delivery)
- Distribution of Bacterial Species in Positive Placental Cultures(Within 4 weeks after delivery, upon receipt of culture results)
- Number of Participants With Uterine Rupture(During labor or delivery)
- Number of Participants With Umbilical Cord Prolapse(From randomization until delivery)