A Phase 4 interventional study of Intravenous Ampicillin followed by Oral Amoxicillin and Ampicillin/Amoxicillin plus single-dose PO Azithromycin in Pregnancy Complications, Infectious, Premature Birth and Neonatal Diseases and Abnormalities, sponsored by Sheba Medical Center. Recruiting at 1 site in Israel. Open to female participants aged 18 Years to 50 Years. Per ClinicalTrials.gov, last updated 2025-12-18.
Sponsored by Sheba Medical Center · Phase 4, Interventional, and Treatment
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.
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.
Exclusion Criteria:
Maternal or fetal indication for labor:
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
Drug: Ampicillin/Amoxicillin plus single-dose PO 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
Drug: Intravenous Ampicillin followed by Oral Amoxicillin
This intervention consists of intravenous Ampicillin 2 grams every 6 hours for 48 hours, followed by oral Amoxicillin 500 mg every 8 hours for 5 days
This intervention includes intravenous Ampicillin 2 grams every 6 hours for 48 hours, followed by oral Amoxicillin 500 mg every 8 hours for 5 days, plus a single dose of oral Azithromycin 1 gram administered once at the start of treatment
A composite of neonatal adverse outcomes
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
Time frame: From the time of birth until 72 hours postpartum
Number of Infants With Severe Respiratory Morbidity
Includes infants requiring CPAP or high-flow nasal cannula for ≥12 hours or mechanical ventilation, or neonatal death
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first.
Number of Infants Requiring Resuscitation at Birth
Any newborn requiring active resuscitation immediately after birth
Time frame: At birth
Number of Infants Diagnosed With Respiratory Distress Syndrome
Based on clinical signs, FiO₂ \>0.21, and characteristic chest X-ray findings
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first
Number of Infants Receiving Surfactant Therapy
Administration of surfactant during hospitalization
Time frame: 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
Tachypnea resolving within 72 hours after birth
Time frame: Within first 72 hours after birth
Number of Infants Diagnosed With Necrotizing Enterocolitis
Clinical diagnosis of NEC during hospitalization
Time frame: 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
Diagnosed by cranial ultrasound or imaging during hospitalization
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first.
Number of Infants With Feeding Intolerance
Clinical diagnosis of feeding intolerance during hospitalization
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first.
Number of Infants With NICU Stay Exceeding 3 Days
Length of NICU admission greater than three days
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first
Number of Infants Diagnosed With Pneumothorax
Radiologically confirmed pneumothorax during hospitalization
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first
Number of Infants Diagnosed With Meconium Aspiration Syndrome
Clinical diagnosis during hospitalization
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first
Number of Infants Diagnosed With Birth Asphyxia
Clinical diagnosis of perinatal asphyxia during hospitalization
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first
Number of Infants Diagnosed With Periventricular Leukomalacia
Diagnosed by imaging during hospitalization
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first
Number of Infants With Neonatal Convulsions
Clinically diagnosed seizures during hospitalization
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first
Number of Neonatal Deaths
Death of the newborn during hospitalization
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first
Distribution of Placental Histopathology Lesion Types
Classification of placental lesions according to standardized pathology criteria, including maternal vascular malperfusion lesions, fetal vascular malperfusion lesions, inflammatory lesions, and other abnormalities. Each placenta will be categorized based on pathology report
Time frame: Within 6 weeks after delivery, upon receipt of pathology results
Number of Infants With Positive Placental Cultures
Number of infants whose placental tissue culture was positive for bacterial growth
Time frame: Within 6 weeks after delivery, upon receipt of culture results
Distribution of Bacterial Species in Positive Placental Cultures
Identification and classification of bacterial species isolated from positive placental tissue cultures. Each positive culture will be categorized by bacterial genus and speciesWithin 4 weeks after delivery, upon receipt of culture results
Time frame: Within 4 weeks after delivery, upon receipt of culture results
Latency From Randomization to Delivery
Number of days from randomization until delivery
Time frame: From randomization until delivery
Number of Participants Completing Full Course of Antenatal Corticosteroids
Completion of full corticosteroid course for fetal lung maturity
Time frame: From randomization until delivery
Number of Participants With Placental Abruption
Clinically diagnosed placental abruption
Time frame: From randomization until delivery
Number of Participants With Intrapartum Fever (≥ 38°C)
Maternal fever occurring during labor
Time frame: During labor
Number of Participants Diagnosed With Clinical Chorioamnionitis
Diagnosis based on uterine tenderness and/or maternal fever related to suspected uterine infection
Time frame: From randomization until delivery
Number of Participants With Bacteremia (Positive Blood Culture)
Positive maternal blood cultures indicating bacteremia
Time frame: From randomization until 72 hours postpartum
Number of Participants Undergoing Unplanned Cesarean Delivery
Cesarean delivery not planned before labor onset
Time frame: From randomization until delivery
Number of Participants With Postpartum Endometritis
Clinical diagnosis of postpartum endometritis
Time frame: From delivery until 6 weeks post partum
Number of Participants With Postpartum Wound Infection or Dehiscence
Clinical diagnosis of wound infection or dehiscence after delivery
Time frame: from birth and up to 6 weeks postpartum
Number of Participants With Composite Adverse Maternal Outcome
A composite of maternal adverse outcomes defined as the occurrence of one or more of the following events within 6 weeks postpartum: bacteremia, ICU admission, hysterectomy, or need for drainage or relaparotomy
Time frame: From randomization until 6 weeks postpartum
Length of Postpartum Hospital Stay
Number of days hospitalized postpartum
Time frame: From delivery through neonatal hospitalization or up to 28 days of life, whichever comes first
Number of Participants Who Initiated Breastfeeding
Initiation of breastfeeding during hospital stay
Time frame: From delivery through maternal hospital discharge or up to 28 days postpartum, whichever comes first
Number of Participants Requiring Hospital Readmission
Any hospital readmission within 6 weeks postpartum
Time frame: Up to 6 weeks postpartum
Number of Participants With Antepartum Hemorrhage
Clinically diagnosed bleeding before delivery
Time frame: From randomization until delivery
Number of Participants With Uterine Rupture
Clinically diagnosed uterine rupture during labor or delivery
Time frame: During labor or delivery
Number of Participants With Umbilical Cord Prolapse
Clinically diagnosed cord prolapse
Time frame: From randomization until delivery
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