Extended Azithromycin Treatment in Prelabor Rupture of Membranes

Extended Azithromycin Treatment in Peri-viable and Extremely Preterm Prelabor Rupture of Membranes: A Pilot Study

The purpose of this study is to learn whether adding extra doses of azithromycin to the standard antibiotic treatment for preterm prelabor rupture of membranes may improve pregnancy outcomes for patients between 22 weeks and 28 weeks gestational age.

Researchers will compare the standard antibiotic treatment to the standard antibiotic treatment with additional doses of azithromycin.

Participants will:

• Be randomly assigned to one of two groups:
• The standard antibiotic treatment
• The standard antibiotic treatment plus 7 additional doses of oral azithromycin 500 mg every other day.
• Participants will be asked to complete a survey regarding their experience and side effects.

Study Overview

• Status: Not yet recruiting
• Conditions: PPROM; Preterm Prelabor Rupture of Membranes
• Intervention / Treatment: Drug: Standard Azithromycin Dosing; Drug: Azithromycin (Azithro)

Detailed Description

Multiple randomized trials have shown that antibiotic treatment for preterm prelabor rupture of membranes (PPROM) increases pregnancy latency and decreases maternal and neonatal morbidity. However, the optimal dosing schedule for azithromycin in PPROM is not fully understood. This pilot study will assess the feasibility of a non-blinded, randomized-controlled trial comparing maternal and neonatal outcomes between the standard PPROM antibiotic regimen and the standard regimen with extended azithromycin therapy in participants with periviable and extremely preterm PPROM between 22- and 28-weeks gestational age. Preliminary data on pregnancy latency, maternal morbidity, and neonatal outcomes will also be collected. Findings from this feasibility study will inform the design of a future, powered study.

The investigators hypothesize that extended azithromycin therapy may be associated with longer pregnancy latency and decreased rates of maternal and neonatal morbidity compared to standard therapy. This hypothesis is exploratory, and the present feasibility study is not powered to test a hypothesis.

The primary objective is to evaluate the feasibility of conducting a non-blinded, randomized controlled trial of extended azithromycin therapy in participants with periviable and extremely preterm prelabor rupture of membranes (PPROM) who desire expectant management between 22 and 28 weeks gestational age. Specifically, we aim to assess feasibility metrics including recruitment and consent rates, randomization procedures, adherence to the study protocol, and completeness of follow-up.

The secondary objectives of this pilot study are to estimate the variability (standard deviation) of pregnancy latency in this population to inform sample-size calculations for a future definitive trial. The investigators will also collect preliminary data on maternal outcomes (e.g., rates of intra-amniotic infection, endometritis, and placental abruption) and neonatal outcomes (gestational age at delivery, NICU admission, morbidity) for planning purposes. Additionally, the investigators will review placental pathology reports to identify the stage/grade of chorioamnionitis per the Amsterdam criteria. The investigators will obtain an initial estimate of the effect of extended azithromycin on pregnancy latency, recognizing that this pilot study is not powered to detect clinically meaningful differences.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Alexa Henderson, MD; Phone Number: 9136019107; Email: hendersona8@upmc.edu
• Study Contact Backup: Name: Christina Megli, MD, PhD; Email: meglicj@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15217
      • University of Pittsburgh Magee-Womens Hospital
      • Contact: Alexa Henderson, MD; Phone Number: 9136019107; Email: hendersona8@upmc.edu
      • Contact: Christina Megli, MD, PhD; Email: meglicj@upmc.edu
      • Principal Investigator: Christina Megli, MD, PhD
      • Sub-Investigator: Alexa Henderson, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Singleton gestation
• Gestational age at time of PPROM between 22w0d and 28w0d
• Opting for expectant management in the inpatient setting after completion of a maternal-fetal medicine and neonatology consultation (per standard of care)
• Remain pregnant 48 hours after presentation.
• Patients who receive betamethasone, magnesium therapy, and/or a limited course of tocolysis (through the betamethasone window) will be included.
• Pregnant patients below the age of 18 are eligible.

Exclusion Criteria:

• Contraindications to expectant management (clinical intra-amniotic infection, active preterm labor, or acute placental abruption)
• Lethal congenital defects
• Multiple gestation
• Ongoing alternative antibiotic treatment
• Known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic
• History of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin
• Known prolongation of QT interval
• History of torsades de pointes
• Congenital long QT syndrome
• Bradyarrhythmia
• Decompensated heart failure
• Drugs known to significantly prolong the QT interval including Class 1A and Class III antiarrhythmic agents
• Impaired hepatic function
• GFR<10 mL/min
• Diagnosis of myasthenia gravis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard Antibiotic Regimen; A single dose of oral azithromycin 1 gram which is given at the time of presentation in addition to the standard intravenous ampicillin 2g q6h for 48 hours followed by oral amoxicillin 250 mg q8 hours for 5 days.	Drug: Standard Azithromycin Dosing; Oral Azithromycin 1g once.
Experimental: Extended Azithromycin Regimen; The standard antibiotic regimen will be given in addition to Azithromycin 500g every other day for 7 additional doses.	Drug: Standard Azithromycin Dosing; Oral Azithromycin 1g once.; Drug: Azithromycin (Azithro); Azithromycin 500 mg every other day for 7 additional doses will be given in addition to the standard antibiotic regimen.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recruitment Capability	Number of participants recruited per week/month	From recruitment to enrollment, up to 3 days.
Participant Eligibility	Percentage of eligible participants who agree to participate, reasons for refusal or ineligibility	From recruitment until enrollment, up to 3 days.
Retention and Dropout Rates	Percentage of patients who complete study and reasons for withdrawal from study.	From recruitment to completion of the study, up to 4 months.
Intervention Delivery	Percentage of interventions delivered as intended	From recruitment to completion of intervention, up to 15 days.
Participant Acceptability	Likert-scale survey evaluating the participant's perceived affective attitude, burden, ethicality, intervention coherence, confidence, opportunity costs, general acceptability, and side effects related to the study.	At completion of study (either after Day 14 of study or after delivery if does not complete study) prior to hospital discharge.
Data Collection Procedures	Data completeness measured as number of participants with complete data entry.	From recruitment to completion of postpartum period, up to 6 months.
Resource Use and Cost	Total cost versus planned budget, time and staffing required.	From recruitment to postpartum period, up to 6 months.
Incidence of Treatment-Related Adverse Events [Safety and Tolerability]	Adverse events associated with antibiotic usage, maternal and neonatal outcomes, bacterial resistance profiles. Assessed using previously validated Medication Side Effect survey.	Ongoing during treatment from Day 2 through Day 14. Formally assessed with surveys as above on Day 8 and Day 14 (or earlier if delivers prior to completion of study period).
Protocol Deviations	Incidence of protocol deviation, indications for protocol deviation.	From recruitment to completion of intervention, up to 15 days.
Time for Delivery	Amount of study team time needed for delivery.	From recruitment to completion of postpartum period, up to 6 months.
Financial Resources	Amount of monetary resources needed for study delivery.	From recruitment to postpartum period, up to 6 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pregnancy Latency	Number of days participants remain pregnant after PPROM until delivery	From time of PPROM diagnosis (D0) until day of delivery, up to 3 months.
Pregnancy Outcome	Intrauterine fetal demise, neonatal demise while in NICU, living infant to NICU discharge.	From time of PPROM diagnosis (D0) until day of delivery, up to 3 months.
NICU Admission	Requirement for NICU admission.	From day of delivery through neonatal discharge, up to 4 months.
Neonatal Ventilatory Support	Level of ventilatory support required for neonate (none, bubble CPAP, intubation).	From day of delivery through neonatal discharge, up to 4 months.
Neonatal Sepsis	Rates of early-onset sepsis, late-onset sepsis (including culture positive sepsis and culture-negative, clinically suspected sepsis)	From day of delivery through neonatal discharge, up to 4 months.
Neonatal Intraventricular Hemorrhage (IVH)	Grade of IVH if present.	From day of delivery through neonatal discharge, up to 4 months.
Neonatal respiratory distress syndrome	Documented respiratory distress syndrome by neonatology providers.	From day of delivery through neonatal discharge, up to 4 months.
Necrotizing enterocolitis	Rate of documented necrotizing enterocolitis by neonatology team.	From day of delivery through neonatal discharge, up to 4 months.
Mode of delivery	Cesarean section, vaginal delivery, or operative delivery.	From day of PPROM (D0) through day of delivery, up to 3 months.
Indication for delivery	Non-reassuring fetal status, labor, intra-uterine infection, placental abruption, cord prolapse.	From day of PPROM (D0) through day of delivery, up to 3 months.
Maternal group B streptococcus status	Positive or negative group B streptococcus maternal rectovaginal culture.	From day of PPROM (D0) through day of delivery, up to 3 months.
Maternal postpartum hemorrhage	Estimated blood loss greater than 1000mL after delivery.	From day of PPROM (D0) through 6 weeks postpartum, up to 4 months.
Suspected intraamniotic infection	Defined as maternal temperature greater than 39 degrees Celsius OR maternal temperature between 38.0-38.9 degrees Celsius plus one or more additional clinical risk factors: maternal leukocytosis greater than 15,000/mm^3, purulent cervical drainage, or fetal tachycardia.	From day of PPROM (D0) through day of delivery, up to 3 months.
Confirmed intraamniotic infection	Positive amniotic fluid test result OR placental pathology demonstrating histologic evidence of infection or inflammation.	From day of PPROM (D0) through delivery with postpartum placental pathology result, up to 3 months.
Maternal sepsis	Suspected sepsis documented by clinical provider in chart or culture proven sepsis.	From day of PPROM (D0) through 6 weeks postpartum, up to 4 months.
Maternal placental abruption	Clinical evidence of placental abruption documented by OBGYN provider.	From day of PPROM (D0) through day of delivery, up to 3 months.
Maternal ICU Admission	Required admission to adult ICU prior to or after delivery.	From day of PPROM (D0) through 6 weeks postpartum, up to 4 months.
Maternal postpartum endomtritis	Documented clinical diagnosis of endometritis in participant chart.	From day of delivery through 6 weeks postpartum.
Maternal retained products of conception	Clinical documentation of retained products of conception in participant chart.	From day of delivery through 6 weeks postpartum.
Additional maternal surgical procedures	Requirement of additional surgical procedures following delivery (suction dilation and curettage, hysterectomy).	From day of delivery through 6 weeks postpartum.
Maternal blood transfusion	Documented maternal blood transfusion following delivery.	From day of PPROM (D0) through 6 weeks postpartum, up to 4 months.
Maternal antibiotic course completion	Number of participants in intervention arm who completed the extended antibiotic course.	From day of PPROM (D0) through day of delivery, up to D14.
Additional maternal antibiotic administration	Maternal antibiotics administered for other indications after enrollment in the study.	From day of PPROM (D0) through day of delivery, up to 3 months.
Maternal placental pathology	Maternal and fetal inflammation stage/grade as defined by the Amsterdam Criteria.	From day of PPROM (D0) through delivery with postpartum placental pathology result, up to 3 months.

Collaborators and Investigators

• Sponsor: Alexa Henderson
• Investigators: Principal Investigator: Christina Megli, MD/PhD, University of Pittsburgh Magee-Womens Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: May 29, 2026
• First Submitted That Met QC Criteria: June 21, 2026
• First Posted (Actual): June 25, 2026

Study Record Updates

• Last Update Posted (Actual): June 25, 2026
• Last Update Submitted That Met QC Criteria: June 21, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: azithromycin; peri-viability
• Additional Relevant MeSH Terms: Preterm Premature Rupture of the Membranes; Organic Chemicals; Macrolides; Lactones; Erythromycin; Polyketides; Azithromycin
• Other Study ID Numbers: STUDY25110085

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD collected throughout the study will potentially be shared with future collaborating sites if the feasibility trial is expanded to a multi-center trial.
• IPD Sharing Time Frame: Beginning 3 months after publication without end.
• IPD Sharing Access Criteria: Collaborating principal investigators will have access to IPD. The information will be shared upon request via secure email or to advance further research efforts in the case of a multi-site trial.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No