Comparison of Pre-Induction Cervical Ripening

• Route of Delivery [ Time Frame: Gestational age 26-42 weeks ] [ Designated as safety issue: No ]
  The primary outcome of this study is vaginal delivery of a liveborn singleton pregnancy. The outcome is considered a vaginal delivery if accomplished by spontaneous vaginal delivery, operative forceps or vacuum forceps. The alternate outcome is delivery by cesaeran section.
  
  

• Time from initiation of induction to delivery [ Time Frame: Time from induction to delivery (up to 72 hours) ] [ Designated as safety issue: No ]
  One of several secondary outcomes to be studied is time from initiation of induction to delivery.
  
  
• Newborn Outcome [ Time Frame: 30 days after delivery ] [ Designated as safety issue: No ]
  One of several secondary outcomes to be studied is infant outcome, including birth weight, Apgar score, admission to Special Care/NICU, and others.
  
  
• Maternal complications. [ Time Frame: 42 days after delivery ] [ Designated as safety issue: No ]
  One of several secondary outcomes to be studied is maternal complications, including infection, excessive bleeding, need for transfusion and unexpected hospital re-admission.
  
  

Title: Comparison of pre-induction cervical ripening using Prepidil gel administered through a urinary balloon catheter

Precis- This study is designed to assess the effectiveness of a combination method of induction of labor using a urinary balloon catheter and prostaglandin gel.

Background

Induction of labor is a common intervention during pregnancy1. The frequency of hospital admissions for induction of labor is increasing in the United States. Indications for induction of labor include maternal disease, fetal complications and social/geographical issues. Obstetricians may also choose elective induction, to facilitate delivery at term for the physician or patient who does not have a medical indication for delivery.

The vaginal delivery rate for medical induction of labor is lower than the vaginal delivery rate for spontaneous labor. As a consequence, the frequency of cesarean section for failed induction in the United States is rising2. This has led to a renewed effort to examine the effectiveness of the varied methods of induction3-5.

The vaginal delivery rate for induction of labor can be predicted by assessing the patient's cervical examination prior to induction. The Bishop Score uses the cervical examination components to predict the vaginal delivery rate for a particular patient. A low or poor Bishop score predicts a low success rate for vaginal delivery.

There are 3 common methods used to induce labor. The first are physiological methods such as breaking the patient's water or causing contractions by nipple stimulation. Breaking the patient's water requires a high (favorable) Bishop Score and cannot be safely performed with a low (poor) Bishop score. This method has a higher success rate in patients who have had a prior vaginal delivery. Nipple stimulation has been associated with an increased risk of tachysystole (too frequent contractions) and non-reassuring fetal heart rate patterns. It is not considered an acceptable method of induction in the United States.

Physical methods include pre-induction cervical ripening with laminaria or urinary balloon catheter6. Both of these methods are designed to force the cervix to open mechanically. Laminaria are small sticks of dehydrated seaweed which are placed in the cervical canal. As the sticks hydrate, the cervical canal dilates. Balloon urinary catheters are inserted into the cervical canal. The balloon is inflated in the lower uterine segment. A weight is placed on the catheter to apply traction which forces the fluid-filled balloon to dilate the cervical canal. Urinary balloon catheters have been used alone7,8, with saline infusion9-11 or with prostaglandin infusion12-16.

Pharmacological methods include ergot alkaloids, prostaglandin E and F series and oxytocin. Ergot alkaloids cause forceful uterine contractions and have been used to treat postpartum hemorrhage. Ergot alkaloids may cause severe hypertension during induction of labor and are not used in the United States. Prostaglandin E and F series cause increased uterine muscle tone (tonic contractions). They are used for pre-induction cervical ripening. The different prostaglandins have varying complications which may include nausea, vomiting, diarrhea and fever. Use of misoprostol for pre-induction cervical ripening has been associated with an increased risk of uterine rupture both in normal patients and in patients who have had previous cesarean sections17. The method of drug delivery for prostaglandin medications has varied. It can be administered as an oral tablet, a vaginal suppository, a vaginal gel, or by infusion into the lower uterine segment via a urinary balloon catheter. It is unclear, based on evidence-based medicine, whether any particular method of delivery is superior to another. The Food and Drug Administration of the United States (FDA) has approved the use of Prepidil gel (prostaglandin E2) for pre-induction cervical ripening18,19. Prepidil gel is administered as a gel into the vaginal fornix using a syringe. Oxytocin is a pituitary hormone which can be used to augment spontaneous labor or to induce labor. It results in both increased uterine tone (tonic contractions) and increased contraction frequency (clonic contractions). It is considered the most physiologic method of pre-induction cervical ripening. Oxytocin is administered by intravenous infusion.

Methods of induction can be used individually or in combination. The most common combination method for induction of labor is the use of prostaglandin for pre-induction cervical ripening followed by oxytocin.

Objectives-

The current study is a randomized, unblinded trial of urinary balloon catheter and prostaglandin gel for induction of labor in term pregnant patients. The primary outcome to be studied is vaginal delivery rate for urinary balloon catheter alone, prostaglandin gel alone and a combination of urinary balloon catheter and prostaglandin gel. Secondary outcomes to be studied include the safety of the method, composite maternal morbidity and composite neonatal morbidity.

The null hypothesis is that there is no difference in the vaginal delivery rate between the three study protocols.

Study Design and Methods-

Pregnant women presenting to the Palmetto Health Richland for a scheduled induction of labor will be offered enrollment in the trial.

Eligible patients will undergo an interview with the investigator. Enrollment pre-requisites and exclusions will be reviewed with the patient. The patient will also be provided with written information regarding the safety of prepidil as an pre-induction cervical ripening agent and the safety of urinary balloon catheters as a pre-induction cervical ripening agent. The investigator will review general information on the trial and an informed consent. Patients who decline enrollment in the trial will have the method of pre-induction cervical ripening chosen by their physician.

Inclusion Criteria:

1. Single, live fetus
2. Cephalic (head-first) presentation
3. Reassuring fetal health assessment
4. Gestational age between 26 and 42 weeks
5. Maternal age 18 and above
6. Bishop score less than 5

Exclusion Criteria:

1. Multiple Gestation (twins, triplets, quadruplets)
2. Fetal demise
3. Fetal malpresentation
4. Estimated fetal weight less than 500 grams or more than 4000 grams
5. Placenta previa
6. Non-reassuring fetal health assessment
7. Maternal asthma
8. Latex allergy
9. Spontaneous labor
10. Other contraindication to vaginal delivery

Patients who enroll in the study will be randomized into 3 study arms: urinary balloon catheter only, prostaglandin gel only and combination urinary balloon catheter and prostaglandin gel. Randomization will be made by choosing a sealed envelope from the locked nurse medication storage area (Pyxis) located on Labor and Delivery at Palmetto Health Richland. Randomization will be 1:1:1 with randomization envelopes prepared by statisticians at the University of South Carolina Arnold School of Public Health. The investigator will be given the next sequentially numbered study envelope by the patient's nurse. The randomization included will be unblinded to the patient and her physicians.

URINARY BALLLOON CATHETER ONLY ARM

The patient will be placed in the lithotomy position, either in the bed or in stirrups. A baseline digital exam of the cervix will be performed by the physician and a Bishop score recorded. A urinary balloon catheter will be placed through the cervix into the lower uterine segment, either digitally or with the aid of a speculum. Once the catheter is properly positioned, the bulb will be inflated with 40ml of normal saline. The urinary balloon catheter will then be secured to the patient's thigh using tape. The catheter will then be placed under traction by attaching it to a liter bag of saline.

The catheter will be deflated and removed after 6 hours, with the time of removal recorded in the medical record. If the catheter is spontaneously expelled from the uterus, the time of expulsion will be noted by the nurse. Six (6) hours after insertion of the catheter, the physician will perform a digital cervical exam and a Bishop score recorded.

If the patient is not in active labor at the time of catheter removal or expulsion, a standardized protocol of oxytocin will commence. Labor management will be at the discretion of the physician. Artificial rupture of membranes may also be carried out at the physician's discretion.

PREPIDIL ONLY ARM

The patient will be placed in the lithotomy position, either in the bed or in stirrups. A baseline digital exam of the cervix will be performed by the physician and a Bishop score recorded in the medical record.

Prepidil gel will be inserted into the vaginal fornix according to the manufacturer's direction. No oxytocin or other intervention will commence until 6 hours after insertion of the gel. Six (6) hours after insertion of the gel, the physician will perform a digital cervical exam and a Bishop score recorded.

If the patient is not in active labor 6 hours after the administration of Prepidil gel, a standardized protocol of oxytocin will commence. Labor management will be at the discretion of the physician. Artificial rupture of membranes may also be carried out at the physician's discretion.

COMBINED URINARY BALLOON CATHETER AND PREPIDIL GEL ARM

The patient will be placed in the lithotomy position, either in the bed or in stirrups. A baseline digital exam of the cervix will be performed by the physician and a Bishop score recorded. A urinary balloon catheter will be placed through the cervix into the lower uterine segment, either digitally or with the aid of a speculum. Once the catheter is properly positioned, the bulb will be inflated with 40ml of normal saline. The urinary balloon catheter will then be secured to the patient's thigh using tape. The catheter will then be placed under traction by attaching it to a liter bag of saline.

Prepidil gel will be inserted through the urinary balloon catheter into the lower uterine segment, in a dose equivalent to the manufacturer's recommendation. No oxytocin or other intervention will commence until 6 hours after insertion of the catheter and prepidil gel (even if the catheter is spontaneously expelled prior to that time). Six (6) hours after insertion of the catheter and gel, the physician will perform a digital cervical exam and a Bishop score recorded.

The catheter will be deflated and removed after 6 hours, with the time of removal noted by the nurse. If the catheter is spontaneously expelled from the uterus, the time of expulsion will be noted by the nurse. If the patient is not in active labor 6 hours after insertion of prepidil gel, a standardized protocol of oxytocin will commence. Labor management will be at the discretion of the physician. Artificial rupture of membranes may also be carried out at the physician's discretion.

DATA COLLECTION

Standard data points will be collected during the labor of each patient enrolled in the study:

1. Date of admission
2. Pre-induction Bishop score and post-induction Bishop score to be recorded 6 hours after initiation of assigned randomized treatment
3. Start time for induction
4. Time of membrane rupture (spontaneous or artificial)
5. Time of onset of second stage labor
6. Time of delivery of fetus
7. Time of delivery of placenta
8. Birth weight of fetus
9. Apgar score of fetus (1 minute and 5 minute)
10. Type of nursery admission (newborn or NICU)
11. Type of delivery (vaginal, vacuum forceps, operative forceps, cesarean)
12. Time of decision to perform cesarean section (if applicable)
13. Date of hospital discharge
14. Maternal complications

a. Postpartum Fever (temperature greater than 100.3 F) b. Blood loss more than 500 ml c. Lowest postpartum hematocrit d. Transfusion e. Readmission to hospital following discharge o. Newborn complications

1. Requirement for oxygen therapy
2. Requirement for transfusion
3. Requirement for antibiotic therapy
4. Lowest hematocrit
5. Fever (temperature greater than 100.3 C)
6. Date of discharge

WITHDRAWAL FROM STUDY

Patients may choose to withdraw from the study at any time. If a patient develops an Adverse Event (AE), the Investigator will discuss whether the patient wishes to withdraw from the study or continue in the study. Treatment will be withdrawn from all patients who develop a Serious Adverse Event (SAE).

Safety Monitoring

Prepidil is approved by the FDA for pre-induction cervical ripening. "Adverse Reactions" of Prepidil are outlined in the Package insert (attached). Unexpected Adverse Events (AE) or Serious Adverse Events (SAE) are defined by the FDA and will be reported for all patients enrolled in the study in accordance with IRB guidelines and FDA regulations.

All patients will be monitored during induction of labor, based on current Palmetto Health Richland protocols. Clinical Adverse Events (AE) or side effects from induction agents are possible during labor and delivery regardless of the method of induction. AE and side effects may include any of the following listed below in normal labor or as a result of our study protocol.

Unexpected Adverse Events or Serious Adverse Events will be reported for all patients enrolled in the study in accordance with the local IRB guidelines and federal regulations. The possible relationship of the AE or the SAE to the study drug will be assessed. An SAE is defined by the FDA as an event which results in death or is life threatening, results in prolonged hospitalization or disability, causes a congenital anomaly, or requires intervention to prevent permanent impairment or damage.

An abnormal rate of AE/SAE will be established at 10% (see Appendix A). If more than 9 patient enrolled in the study have an AE/SAE, enrollment in the study will be stopped pending an evaluation of the frequency of AE/SAE.

Side Effects

Prepidil is generally well tolerated. All patients will be monitored for side effects. If a patient enrolled in the study experiences a Side effect, appropriate clinical action will be taken by the physician. Side effects may include:

1. Discomfort from urinary balloon catheter
2. Discomfort from Prepidil gel
3. Tachysystole (more than 4 contractions in 10 minutes)
4. Vaginal bleeding
5. Maternal temperature greater than 100.3 C.
6. Nausea
7. Diarrhea

Serious Adverse Event

All patients will be monitored for Serious Adverse Events (SAE). Any patient who is diagnosed with a Serious Adverse Event (SAE) will immediately be withdrawn from the study protocol. Appropriate physician intervention will be initiated. Serious Adverse Events (SAE) include the below conditions and are not anticipated to be increased in relation to our study protocol:

1. Uterine rupture
2. Patient death
3. Cardio-respiratory arrest
4. Status asthmaticus
5. Non-reassuring fetal heart rate tracing (Category III tracing)
6. Severe vaginal bleeding
7. Abruptio placenta
8. Chorioamnionitis

DATA ANALYSIS

The goal of the pilot study will be to enroll 90 patients.

Data will be collected on standardized data sheets. The patient will be assigned a study number during the randomization process. The patient's study number will be recorded on the consent and on the standardized data collection sheet. During the data collection and analysis, only the study number will be used to identify the patient. No Protected Health Information (PHI) will be used to identify the patient following the completion of the consent and randomization.

The completed data sheets will be given to the study coordinator. The study coordinator will be responsible for entering data into an electronic database. The database entry will require a login and password. A Secure Socket Layer (SSL) encryption will be used to prevent unauthorized access to study data.

The null hypothesis will be that there is no difference in the vaginal delivery success rate when comparing urinary balloon catheter only, Prepidil gel only and combination of urinary balloon catheter and Prepidil gel.

A success rate of vaginal delivery for each arm of the study will be estimated at 70%, based on the literature3, 20-33 and on the current cesarean section rates at Palmetto Health Richland (see Appendix B)

In comparing discrete data points such as method of delivery, analysis will be performed using logistic regression. For continuous variable such as time (minutes), a Student's T-Test will be used for analysis.