PPROM, Preterm Prelabor Rupture of Membranes
Conditions
Keywords
azithromycin, peri-viability
Brief summary
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.
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.
Interventions
Azithromycin 500 mg every other day for 7 additional doses will be given in addition to the standard antibiotic regimen.
DRUGStandard Azithromycin Dosing
Oral Azithromycin 1g once.
Sponsors
Alexa Henderson
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recruitment Capability | From recruitment to enrollment, up to 3 days. | Number of participants recruited per week/month |
| Participant Eligibility | From recruitment until enrollment, up to 3 days. | Percentage of eligible participants who agree to participate, reasons for refusal or ineligibility |
| Retention and Dropout Rates | From recruitment to completion of the study, up to 4 months. | Percentage of patients who complete study and reasons for withdrawal from study. |
| Intervention Delivery | From recruitment to completion of intervention, up to 15 days. | Percentage of interventions delivered as intended |
| Participant Acceptability | At completion of study (either after Day 14 of study or after delivery if does not complete study) prior to hospital discharge. | 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. |
| Data Collection Procedures | From recruitment to completion of postpartum period, up to 6 months. | Data completeness measured as number of participants with complete data entry. |
| Resource Use and Cost | From recruitment to postpartum period, up to 6 months. | Total cost versus planned budget, time and staffing required. |
| Incidence of Treatment-Related Adverse Events [Safety and Tolerability] | 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). | Adverse events associated with antibiotic usage, maternal and neonatal outcomes, bacterial resistance profiles. Assessed using previously validated Medication Side Effect survey. |
| Protocol Deviations | From recruitment to completion of intervention, up to 15 days. | Incidence of protocol deviation, indications for protocol deviation. |
| Time for Delivery | From recruitment to completion of postpartum period, up to 6 months. | Amount of study team time needed for delivery. |
| Financial Resources | From recruitment to postpartum period, up to 6 months. | Amount of monetary resources needed for study delivery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pregnancy Latency | From time of PPROM diagnosis (D0) until day of delivery, up to 3 months. | Number of days participants remain pregnant after PPROM until delivery |
| Pregnancy Outcome | From time of PPROM diagnosis (D0) until day of delivery, up to 3 months. | Intrauterine fetal demise, neonatal demise while in NICU, living infant to NICU discharge. |
| NICU Admission | From day of delivery through neonatal discharge, up to 4 months. | Requirement for NICU admission. |
| Neonatal Ventilatory Support | From day of delivery through neonatal discharge, up to 4 months. | Level of ventilatory support required for neonate (none, bubble CPAP, intubation). |
| Neonatal Sepsis | From day of delivery through neonatal discharge, up to 4 months. | Rates of early-onset sepsis, late-onset sepsis (including culture positive sepsis and culture-negative, clinically suspected sepsis) |
| Neonatal Intraventricular Hemorrhage (IVH) | From day of delivery through neonatal discharge, up to 4 months. | Grade of IVH if present. |
| Neonatal respiratory distress syndrome | From day of delivery through neonatal discharge, up to 4 months. | Documented respiratory distress syndrome by neonatology providers. |
| Necrotizing enterocolitis | From day of delivery through neonatal discharge, up to 4 months. | Rate of documented necrotizing enterocolitis by neonatology team. |
| Mode of delivery | From day of PPROM (D0) through day of delivery, up to 3 months. | Cesarean section, vaginal delivery, or operative delivery. |
| Indication for delivery | From day of PPROM (D0) through day of delivery, up to 3 months. | Non-reassuring fetal status, labor, intra-uterine infection, placental abruption, cord prolapse. |
| Maternal group B streptococcus status | From day of PPROM (D0) through day of delivery, up to 3 months. | Positive or negative group B streptococcus maternal rectovaginal culture. |
| Maternal postpartum hemorrhage | From day of PPROM (D0) through 6 weeks postpartum, up to 4 months. | Estimated blood loss greater than 1000mL after delivery. |
| Suspected intraamniotic infection | From day of PPROM (D0) through day of delivery, up to 3 months. | 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. |
| Confirmed intraamniotic infection | From day of PPROM (D0) through delivery with postpartum placental pathology result, up to 3 months. | Positive amniotic fluid test result OR placental pathology demonstrating histologic evidence of infection or inflammation. |
| Maternal sepsis | From day of PPROM (D0) through 6 weeks postpartum, up to 4 months. | Suspected sepsis documented by clinical provider in chart or culture proven sepsis. |
| Maternal placental abruption | From day of PPROM (D0) through day of delivery, up to 3 months. | Clinical evidence of placental abruption documented by OBGYN provider. |
| Maternal ICU Admission | From day of PPROM (D0) through 6 weeks postpartum, up to 4 months. | Required admission to adult ICU prior to or after delivery. |
| Maternal postpartum endomtritis | From day of delivery through 6 weeks postpartum. | Documented clinical diagnosis of endometritis in participant chart. |
| Maternal retained products of conception | From day of delivery through 6 weeks postpartum. | Clinical documentation of retained products of conception in participant chart. |
| Additional maternal surgical procedures | From day of delivery through 6 weeks postpartum. | Requirement of additional surgical procedures following delivery (suction dilation and curettage, hysterectomy). |
| Maternal blood transfusion | From day of PPROM (D0) through 6 weeks postpartum, up to 4 months. | Documented maternal blood transfusion following delivery. |
| Maternal antibiotic course completion | From day of PPROM (D0) through day of delivery, up to D14. | Number of participants in intervention arm who completed the extended antibiotic course. |
| Additional maternal antibiotic administration | From day of PPROM (D0) through day of delivery, up to 3 months. | Maternal antibiotics administered for other indications after enrollment in the study. |
| Maternal placental pathology | From day of PPROM (D0) through delivery with postpartum placental pathology result, up to 3 months. | Maternal and fetal inflammation stage/grade as defined by the Amsterdam Criteria. |
Countries
United States
Contacts
CONTACTAlexa Henderson, MD
CONTACTChristina Megli, MD, PhD
PRINCIPAL_INVESTIGATORChristina Megli, MD/PhD
University of Pittsburgh Magee-Womens Hospital
Outcome results
None listed