Cervical Ripening in Premature Rupture of Membranes

Study Overview
=================
Brief Summary
-----------------
Premature rupture of membranes (PROM) is diagnosed by demonstrating amniotic fluid in the vaginal canal before the onset of labor. The integrity of the amniotic membrane is compromised thereby increasing the risk of intrauterine infection and compression of the umbilical cord. PROM complicates 3% to 8% of pregnancies in the US and is responsible for 30% of preterm births. Intrauterine infection remains the most significant maternal and neonatal sequelae associated with PROM and this risk increases with the length of time from ruptured membrane to delivery. Induction of labor has been shown to reduce the rates of chorioamnionitis, endometritis and NICU admissions4. Specifically, induction of labor with prostaglandin agents followed by oxytocin, versus oxytocin alone has been shown to be effective for labor induction resulting in vaginal delivery. Management strategies for PROM have been controversial, and published studies on outcomes are over one to two decades old, which does not account for changes in clinical trends and practice patterns. Recently ACOG recommends that patients presenting at 37 weeks gestation or greater with PROM should be induced if not in labor, and generally with oxytocin. In women with PROM without the onset of labor, the cervix is commonly unfavorable and induction with oxytocin alone may lead to an increased risk of cesarean section. With a c-section rate as high as 33%, women undergoing induction of labor have an increased risk of c-section and its associated morbidity and long term sequela. ACOG's recommendation for the use of oxytocin as the induction agent may be meant to avoid a theoretical increased risk of chorioamnionitis in this patient population however it does not take into account the status of the cervix, which may result in a increased risk of c-section. The purpose of the proposed study is to determine whether cervical ripening in women with PROM and an unfavorable cervix is associated with increase rates of vaginal delivery and decreased cesarean section rate compared to induction of labor with oxytocin alone. The investigators aim to determine the incidence of endometritis, and neonatal infection associated with PROM in the current medical environment of antibiotic prophylaxis and antenatal steroid use, taking into account the changes in patient characteristics.

Detailed Description
-----------------
We will perform a prospective randomized control trial involving women with singleton gestation at ≥ 34 weeks gestation who require an induction of labor after diagnosis of PROM with an unfavorable cervix. PROM will be diagnosed and confirmed with sterile speculum examination demonstrating pooling and/or positive ferning or nitrazine. Cervical status will be assessed by visual exam, digital exam or transvaginal ultrasound to assign a Bishop score (dilation, effacement, station, consistency & position). Determination of patient eligibility will be based on the clinical exam and confirmation of PROM. Upon diagnosis, if the patient meets inclusion criteria and accepts to participate in the study, they will be consented by the study investigator and then be randomized to prostaglandin followed by oxytocin or oxytocin alone group. Allocation concealment will be performed via the utilization of pre-sequentially numbered, manila sealed envelopes stapled closed. There are two treatment groups and will be analyzed on an intent-to-treat basis. Randomization will be performed using a computer generated simple randomization sequence. Data safety monitoring will be instituted (see data safety monitoring plan below). Once randomization is completed, the labor and delivery providers will be informed of the treatment arm and this will be placed on the chart. Those randomized to the prostaglandin arm will receive PGE1 (misoprostol) in a dose of 25mcg placed vaginally every 4 hours as per hospital protocol. Those randomized to the oxytocin arm will receive infusion of oxytocin, which will then be titrated per hospital protocol until adequate contractions. Further management after the start of the respective arm will be based on clinical judgment of the provider.

Official Title
-----------------
Cervical Ripening in Premature Rupture of Membranes

Conditions
-----------------
Pregnancy, Premature Rupture of Membranes, Preterm Premature Rupture of Membranes, Unfavorable Cervix

Intervention / Treatment
-----------------
* Drug: Misoprostol
* Drug: Oxytocin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All pregnant women diagnosed with PROM without evidence of labor requiring induction Gestational Age > 34 weeks Bishop score < 6 Category I Fetal heart rate tracing Exclusion Criteria: Contraindication to Induction of Labor Multiple gestation Fetal Anomalies Previous C-Section HIV Positive Patients

Ages Eligible for Study
-----------------
Minimum Age: 15 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Misoprostol<br>Those randomized to the prostaglandin arm will receive PGE1 (misoprostol) in a dose of 25mcg placed vaginally every 4 hours as per hospital protocol. | Drug: Misoprostol<br>* Patients who are randomized to receive misoprostol will have 25mcg placed vaginally. Repeated dosing of misoprostol is based on clinical exam and clinical judgment of the provider.<br>* Other names: Cytotec;|
| Active Comparator: Oxytocin Alone<br>Those randomized to the oxytocin arm will receive infusion of oxytocin, which will then be titrated per hospital protocol or until adequate contractions. | Drug: Oxytocin<br>* Patients who are randomized to receive oxytocin alone will receive intravenous administration of oxytocin as designated by the hospital protocol. Protocol begins with 2 milliunits of oxytocin that is then titrated over time. Titration is based on clinical exam and clinical judgment of the provider and is continued until there are adequate uterine contractions.<br>* Other names: Pitocin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Cesarean Section | Mode of delivery via cesarean section or vaginal delivery | within 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal and Neonatal Infectious Morbidity | Maternal infection defined as fever >100.4 on at least two occasions during labor, continued antibiotic treatment on or after PPD#1, histologic confirmation of chorioamnionitis. Dose of Oxytocin, Tachysystole, Estimated blood loss at delivery, maternal length of stay, Epidural use, Indication for cesarean delivery Neonatal infection defined as WBC <5000 and absolute neutrophil count <1000 or positive blood cultures and neonatal fever, NICU admission, Apgar score less than 7 at 5 minutes, | within 72 hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Misoprostol, Bishop Score, Induction of Labor, Cervical Ripening, Unfavorable Cervix, Mode of Delivery, C-Section, Cesarean Section, Prostaglandin, Prostaglandin E1