Materials and Methods

Patient recruitment in this placebo-controlled double-blind randomized clinical trial was carried out at a single site over a 4-year period (2003 through 2006) and complied with the CONSORT (Consolidated Standards of Reporting Trials) statement. The study was approved by the institutional review board (0239) at the University of Mississippi Medical Center and registered by Clinical Trials.gov ( NCT00830765 ). Women who presented with singleton, vertex gestations to university’s obstetric emergency area with a diagnosis of PPROM at 20-30 weeks’ gestation, typically dated by ultrasound, were eligible for this study. Patients <24 weeks with PPROM were offered induction vs conservative management. These women were counseled and evaluated for pulmonary hypoplasia. Suspected amniorrhexis was confirmed by sonography, visualization of fluid coming from the cervix, and positive ferning. Cervical dilatation was estimated at the time of sterile speculum examination. Cultures for group B streptococcus and aerobic organisms were obtained on admission. All patients had a fetal anatomic scan. Contraindications included severe fetal or placental disease that might bias neonatal outcomes such as intrauterine growth restriction (<5th percentile), suspected placental abruption, and confirmed placenta previa. Also excluded were patients already taking 17P, and some with signs and symptoms of chorioamnionitis, nonreassuring fetal assessments or severe medical/obstetric diseases such as sickle cell disease with the crisis, insulin-dependent diabetes, and severe preeclampsia. Women with oligohydramnios were included providing fetal heart rate tracings were reassuring during observation. Patients who had no such contraindications were counseled about study requirements and eligible women were offered enrollment.

Women were randomized by selecting a sequentially numbered, sealed, opaque envelope generated from a random number table for the 2 groups and opened by a party not involved in the study (University Medical Center pharmacy). Each card was inscribed with either 17P (250 mg) or placebo (castor oil). Both the placebo and 17P were prepared by an independent company (PharmaAmerica, Louisville, KY) and shipped to our pharmacy where the vials were stored per protocol. When a patient was randomized an order was written by the treating physician and faxed to the pharmacy indicating the patient was participating in the progesterone-PPROM trial. The pharmacy performed randomization to the 17P and the placebo which had been prepared by PharmaAmerica into opaque numbered-coded syringes for that specific patient. This code number was recorded in the chart and on a weekly basis a similar order was faxed to the pharmacy so as to receive the medication from the same numbered vial for the duration of the pregnancy. Weekly injections of 17P or placebo injections continued until 34 weeks or delivery, whichever came first. Patients, their families, research personnel, and physicians/nurses were not aware of the study group assignment. Women in both groups were placed on bed rest and monitored in a labor and delivery suite for 12-24 hours to rule out early infection, prolapsed umbilical cord, and nonreassuring fetal heart tracing (NRFT). Randomization occurred after this observation period. Women were given antibiotics per the Eunice Kennedy Shriver National Institute of Child Health and Human Development protocol (ampicillin plus erythromycin intravenously for 48 hours followed by oral amoxicillin and erythromycin for 5 days) and all patients received 2 doses of betamethasone for fetal lung maturation. After their stay in the labor and delivery area, patients were transferred to the high-risk floor. All patients ≥24 ^0/7 weeks had routine fetal testing performed (daily nonstress testing and twice-weekly biophysical profiles) and frequent maternal assessments for infection (fundal tenderness, temperature >100.4°F, white blood cell counts, and maternal-fetal tachycardia). Tocolytics were not used in any of the patients and fetal lung maturity testing was not performed. All patients remained hospitalized until delivery.

The primary study outcome was interval from study entry to delivery. We evaluated maternal demographics, gestational age at birth, route of delivery, and indications for delivery. Selected infant outcomes included birthweight, 5-minute Apgar score, total neonatal intensive care unit (NICU) days, and the occurrence of significant neonatal morbidity such as sepsis and seizures. Respiratory distress syndrome, patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, and death during the neonatal period were also recorded.

Using population data at our institution 80% of PPROM patients deliver within 7 days of amniorrhexis. We estimated a sample size of 56 patients was sufficient to detect a 50% increase in latency, under the assumption of type I error of 5% and a power of 80%. The unpaired t test was used for maternal age, ethnicity, gestational age at birth, reason for delivery, and days spent in the NICU. The Mann-Whitney test was employed for cervical dilatation and gestational age at randomization, interval to delivery in days, and birthweight in grams. The χ ² analysis (relative risk [RR] with 95% confidence interval [CI]) was employed for nulliparity, route of delivery, and neonatal morbidity while the Fisher’s exact test was used for intrauterine fetal deaths and neonatal demise. A Kaplan-Meier survival curve was also constructed.