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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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard Antibiotic Regimen | Active Comparator | 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. |
|
| Extended Azithromycin Regimen | Experimental | The standard antibiotic regimen will be given in addition to Azithromycin 500g every other day for 7 additional doses. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Azithromycin (Azithro) | Drug | Azithromycin 500 mg every other day for 7 additional doses will be given in addition to the standard antibiotic regimen. |
|
| 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. |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Alexa Henderson, MD | Contact | 9136019107 | hendersona8@upmc.edu | |
| Christina Megli, MD, PhD | Contact | meglicj@upmc.edu |
| Name | Affiliation | Role |
|---|---|---|
| Christina Megli, MD/PhD | University of Pittsburgh Magee-Womens Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Pittsburgh Magee-Womens Hospital | Pittsburgh | Pennsylvania | 15217 | United States |
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.
Beginning 3 months after publication without end.
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.
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| ID | Term |
|---|---|
| C563032 | Preterm Premature Rupture of the Membranes |
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| ID | Term |
|---|---|
| D017963 | Azithromycin |
| ID | Term |
|---|---|
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009930 |
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| Standard Azithromycin Dosing | Drug | Oral Azithromycin 1g once. |
|
| 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. |
| 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. |
| Organic Chemicals |