Conditions: Induced Vaginal Delivery
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
The purpose of this trial is to explore mifepristone as an option for induction of labor at term by evaluating the efficacy of mifepristone use for cervical preparation. Since the Labor Induction versus Expectant Management in Low-Risk Nulliparous Women (ARRIVE) trial supporting that elective induction after 39 weeks decreases cesarean sections and morbidity, rates of elective term inductions are increasing.

At Lucile Packard Children's Hospital at Stanford University specifically, approximately 40% of spontaneous vaginal deliveries follow induction of labor, with an average induction time of 20 hours. Previous studies have established the maternal and neonatal safety of mifepristone in term inductions, however, this study will assess the difference in overall time from induction to complete cervical dilation, delivery, and the total time on Labor and Delivery.

Detailed description:

Arms:
arm 1: Participants will be given mifepristone with insertion of the cervical Cook balloon for labor induction arm 2: Participants will be given misoprostol with insertion of the cervical Cook balloon for labor induction

Interventions: intervention 1: Mifepristone intervention 2: Misoprostol
Intervention descriptions: intervention 1: Mifepristone 200mg taken orally intervention 2: Misoprostol 50 mcg taken orally, and may receive additional doses of misoprostol 50 - 100 mcg as needed

Protocol document:
Prot_SAP_000.pdf: 
Mifepristone as an Adjunct to Transcervical Balloon for 
Labor Induction (MiLI): A Randomized Clinical Trial 
National Clinical Trial (NCT) Identified Number: 05097326 
Principal Investigators: 
, MD and 
, MD MS 
Research Coordinator: 
 
Funded by: The Division of Maternal-Fetal Medicine 
 May 11, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Mifepristone as an Adjunct to Transcervical Balloon for Labor Induction: A Randomized 
Clinical Trial (MiLI) 
Objective: Our goal is to generate preliminary data on perinatal outcomes, establish recruitment 
feasibility, and medication tolerability among patients who receive mifepristone for labor 
induction for live birth. Our aims are to 1) generate preliminary data on the impact of 
mifepristone use on obstetric and neonatal outcomes and 2) examine recruitment feasibility and 
willingness of participants to be randomized to guide recruitment periods for future studies 
 
Organization: Stanford University School of Medicine, Department of Obstetrics and 
Gynecology 
 
Clinical Center: Stanford/LPCH OB clinic and Labor & Delivery 
 
Design Type: Parallel group, two-arm, non-blinded, randomized control trial 
 
Inclusion Criteria:  
1. Pregnant patients between ages 18 to 45 years  
2. Singleton, live gestation 
3. Nulliparous  
4. Gestational age between 37 weeks 0 days – 42 weeks 0 days  
5. Fetus in cephalic presentation 
6. Patients admitted for labor induction 
7. Patients who are not in labor with intact membranes 
8 Patients with no contraindication for vaginal delivery (placenta previa, vasa previa, active 
genital herpes) 
9. Patients with no contraindications for mifepristone (chronic adrenal failure, concurrent long-
term corticosteroid therapy, history of allergy to mifepristone, or other prostaglandins, 
hemorrhagic disorders or concurrent anticoagulant therapy, inherited porphyria, or an 
intrauterine device (IUD) in place) 
10. Patients with a Bishop score <6 at time of randomization 
11. Transcervical balloon in place <3 hours prior to the time of randomization without prior 
cervical preparation 
 
*For patients who meet the above inclusion criteria 1-10 and who those who decline 
randomization will be offered enrollment for chart review only. 
 
Exclusion Criteria: 
1. Significant cardiac, renal, or hepatic maternal comorbidities, severe gestational hypertension 
or preeclampsia with severe features 
2. Pregnancies complicated by major fetal anomalies 
3. Patients with a uterine scar 
4. Pregnancies complicated by fetal growth restriction (Estimated fetal weight <10%) 
5. Pregnancies complicated by oligohydramnios 
6. Fetuses with an estimated fetal weight >4500 gm by recent ultrasound or Leopold’s exam on 
admission 
7. Patients with class 3 obesity (BMI >40) 


8. Fetuses with a persistent category 2 or 3 fetal heart tracing at labor induction admission 
9. Vaginal bleeding at the time of randomization 
10. Any indication for scheduled cesarean delivery 
11. Hypersensitivity to oxytocin  
12. Uterine contractions ≥ 5 in10 minutes that is sustained for at least 30 minutes  
13. Hypersensitivity to prostaglandins 
 
Interventions:  
1. Active group: Mifepristone 200 mg po + Transcervical (Cook) Balloon 
2. Standard group: Misoprostol 50 mcg po+ Transcervical (Cook) Balloon  
Medications:  
Mifepristone 200mg po  
Misoprostol 50 mcg po  
 
Analysis: Intent to Treat 
 
Outcome Measures:  
Primary outcomes:  
• Generation of preliminary data comparing obstetric and neonatal outcomes among 
patients randomized to misoprostol 50 mcg versus mifepristone 200 mg  
 
Obstetric outcomes:  
o Number of uterine contractions – with and without fetal heart rate decelerations 
during the time the foley is in place 
o Rate of uterine tachysystole (≥ 5 contractions in 10 minutes that is sustained for at 
least 30 minutes) or hypertonus (a single contraction lasting more than 2 minutes) 
during labor  
o Time to delivery  
o Time to complete cervical dilation 
o Total time on the Labor and Delivery unit 
o Rate of cesarean delivery (CD) 
o Rate of failed induction of labor per ACOG guidelines  
o Composite of serious maternal morbidity based on CDC severe maternal 
morbidity and mortality (including acute myocardial infarction, aneurysm, acute 
renal failure, adult respiratory distress syndrome, amniotic fluid embolism, 
cardiac arrest/ventricular fibrillation, conversion of cardiac rhythm, disseminated 
intravascular coagulation, eclampsia, heart failure/arrest during surgery or 
procedure, puerperal cerebrovascular disorders, pulmonary edema/acute heart 
failure, severe anesthesia complications, sepsis, shock, sickle cell disease with 
crisis, air and thrombotic embolism, blood products transfusion, hysterectomy, 
temporary tracheostomy, ventilation) 


• Neonatal outcomes:  
o Comparison of neonatal cord gases (arterial pH) and neonatal APGAR scores at 1 
and 5 minutes 
o Composite of serious neonatal morbidity up to 7 days of life (including perinatal 
death, need for respiratory support within 72 hours after birth, Apgar score of 3 or 
less at 5 minutes, arterial pH, hypoxic-ischemic encephalopathy, seizure, infection 
(confirmed sepsis or pneumonia), meconium aspiration syndrome, intracranial or 
subgaleal hemorrhage, hypotension requiring vasopressor support, admission to 
the neonatal intensive care unit) 
Secondary outcomes 
• Examine recruitment feasibility and willingness of participants to be randomized to guide 
recruitment periods for future studies. 
•  Plan to assess medication tolerability through participant experience surveys at two time 
points (after cervical preparation during the labor process and on postpartum day one)  
 
Sample size: 30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


1.  INTRODUCTION 
This manual gives detailed instructions on procedures for the Mifepristone for Labor Induction 
(MiLI) Trial. It is meant to serve as a reference guide for study staff, including investigators, 
coordinators, study nurses, and data managers.  
 
1.1 Organizational Structure  
 
This study is governed by Stanford Maternal Fetal Medicine Division, Labor and Delivery, and 
the Clinical Translational and Research Unit site. 
 
1.1.1 Steering Committee (SC) 
 
A Maternal-Fetal Medicine Clinical Review Unit (CRU) and the study team that brings together 
the multi-disciplinary will oversee implementation including: finalizing the clinical protocol, 
training and certification, monitoring recruitment, data coordination and quality control, and 
IRB-related issues. The SC will also make final decisions about data analysis and interpretation, 
secondary analyses, presentation at scientific meetings and publications.  
 
1.1.2 Responsibilities  
 
The responsibilities of these individuals are described briefly here:  
 
PI and co-PIs are responsible for ensuring the proper conduct of the study clinic site including 
recruitment as specified in the protocol and accurate collection of the data. 
Other specific duties include:  
 
a.  Obtaining and maintaining IRB approval and training for study personnel 
b.  Obtaining sufficient study areas for study personnel to interview patients and perform 
study procedures, including storage of study medication and other study supplies.  
c.  Participate in study- related meetings or conference calls 
d.  Familiarity and training for REDCap based data entry system by appropriate staff.  
e.  Screen potential participants for eligibility and consent them. It is important to ensure 
the patient’s primary obstetric provider agrees to follow the study treatment protocol 
during the intrapartum course.   
f.  Randomize per protocol to intervention arms – both arms to receive medication 
g.  Follow participants during the intrapartum period, delivery and 24 hours postpartum: 
with a patient satisfaction survey to evaluate medication side effects and overall 
satisfaction associated with treatment 
h.  Trained research staff will conduct research data abstraction from patient and neonatal 
medical records, and other direct participant contact as required by the protocol.  
i.  Investigators will participate in blinded review of outcomes in order to confirm the 
primary and other key outcomes.  
j. The LPCH pharmacy will be responsible for randomizing the medication 
k.  All newborn outcomes will also be ascertained through birth hospitalization through 
medical records chart review.  


l.  Data collection forms for maternal outcomes, newborn outcomes, NICU outcomes, and 
postpartum patient satisfaction outcomes will be completed by study personnel. These 
forms will be used to enter the clinical data into the study data base.  
 
The Study Coordinator will be responsible for the day-to-day operations of the study at the 
clinical center, including recruitment and data collection processes. This responsibility includes 
the following:  
a.  Establishing a method of training and monitoring to ensure primary obstetric providers 
are following the study treatment protocol during the intrapartum period. 
b.  Establishing a method to ensure that all potential participants receive medications and 
appropriate randomization 
c. Establishing a method that for screening participants who are potentially eligible for 
the study e.g. review of scheduled term inductions at LPCH  
d.  Assures that study drug is available at all times by checking the available drug supply 
at least weekly.  
e. Meeting with Stanford Investigational Drug Pharmacist pharmacy if necessary, to 
understand center specific drug request procedures.  
f. Arranging for the ordering and storage of study supplies.  
g.  Collecting maternal and neonatal information necessary to complete all study forms.  
h.  Will abstract information related to primary and other key outcomes, and assure that 
the PI and IRB (if required by institution) is notified of any primary outcome events and 
adverse events.  
i. Training additional staff as needed in data collection, forms completion and data entry.  
j. Coordinating data entry, including controlling access to the REDCap and study unit as 
applicable, and assuring that required back-up security and confidentiality procedures are 
maintained.  
k. Organizing and maintaining records, including the protocol, data forms, reports and 
correspondence 
 
 
1.2 Procedures for Participant Confidentiality 
 
 The REDCAP database will contain PHI linked to the patient’s clinical data. The MFM 
Research team members are the only people who will be able to access this database. A 
study/screening number will be used to identify each participant. Site will maintain a log of 
participant names and medical record numbers.  
 
1.3 Training and Site Initiation  
 
A training session for study coordinators will be held before recruitment starts. The purpose of 
the training workshop is to review the study design, objectives, procedures, data collection forms 
and a demonstration of the REDCap data base. The coordinators, in turn, are responsible for 
training any additional staff assigned to this study. Clinical site initiation to enroll and randomize 
participants is dependent upon completion of a series of preliminary tasks. These include 
completion of appropriate regulatory approvals (IRBs).  
 


Site staff training, certification, and receipt of all study supplies including medications will need 
to be completed as well as the development of a site recruitment plan. Fulfillment of the 
following are requirements before start of study:  
 
1. Review of the final version of the study protocol, data forms and manual, and study 
medications.  
2. IRB approval and consent forms on file at Stanford. Due to COVID, also consider e-consent 
process.  
3. Completion of training and data entry of forms.  
 
1.4 IRB approval  
 
Approval by an IRB before any participant examination or data collection can begin. Once a 
study has been approved, any additional information about the study that relates to participant 
safety (i.e., protocol changes, significant adverse events, changes in the consent form) also needs 
to be submitted to the IRB.  
 
1.5 Interim IRB Review/Approval  
 
After initial approval, an IRB must be notified any time about:  
• Recruitment Brochures and Advertisements  
• Form Letters or Study information sent to participants 
• Protocol Amendments  
• Protocol Deviations  
• Serious Adverse Events (SAEs)  
• Unanticipated problems 
• Consent Form Revisions  
 
1.5.1 Protocol Amendments  
 
All protocol changes must be sent to an IRB as protocol amendments.  
 
1.5.2 Regulatory Binder  
 
The Study Regulatory Binder is the administrative binder that serves as the regulatory record of 
each clinic’s participation in the MiLI study. It should be kept current and available for review 
by the IRB or in the event of an audit. The binder should include current copies of: 
• Protocol and revisions 
• All protocol amendments  
• IRB submissions and approvals, IRB renewals and any submitted protocol deviations and 
log, IRB correspondence (adverse events reports)  
• Copies of IRB approved informed consent document(s)  
• Research participant advertisements, (e.g. patient brochures, pamphlets) patient education 
materials, newsletters, etc.  
• Current correspondences relating to human subjects research (may keep separate 
correspondence file)  


• Enrolled patient log with pertinent identifier information (randomization number if 
needed)  
• List of study drug formulary and package inserts  
 
Other items that may also be included are: recruitment plans, a set of study forms, CVs or 
biosketches for study staff, staff responsibility logs, essential elements of informed consent 
checklist, protocol deviation logs or other requirements from Stanford institution 
 
 
2.  STUDY INFORMATION 
 
2.1 Study Rationale  
 
The prevalence of labor induction in the US continues to increase, and is considered safe, and 
sometimes critical to the wellbeing of a pregnancy.1 At Lucile Packard Children's Hospital 
(LPCH), specifically, approximately 37% of all spontaneous vaginal deliveries follow labor 
induction. Several methods of cervical preparation have been implemented to expedite a 
successful labor induction and vaginal delivery.1-5 However, due to a rising incidence of 
induction of labor (IOL), particularly induction with an unfavorable cervix (Bishop score <6) 
requiring cervical preparation, the average time a patient occupies a room on Labor and Delivery 
(L&D) has increased, negatively impacting bed availability and healthcare costs.6 Mifepristone is 
an FDA approved medication used in a regimen with misoprostol for first trimester medication 
abortion, and is used off label as a cervical preparation agent for second and third trimester 
pregnancy losses and second trimester abortion.7-10 Previous international studies demonstrated 
that when compared to placebo, mifepristone is safe and efficacious when used as a cervical 
preparation agent in term labor induction in both inpatient and outpatient settings.11-17 No studies 
in the US have assessed mifepristone as a term labor induction agent.  
We propose a pilot study to generate preliminary data, establish recruitment feasibility, 
and medication tolerability to better inform future studies on mifepristone as an adjunct to the 
standard of care for term IOL in both inpatient and outpatient settings. This is a randomized 
control trial (RCT) of nulliparous patients ages 18 to 45 years who are at 37– 42 weeks 
gestational age induced with a transcervical (Cook) balloon, comparing perinatal outcomes 
among patients randomized to receive misoprostol versus mifepristone in the inpatient setting.  
 
2.2 Background  
Approximately 29% of US births follow induction of labor (IOL), more than doubling since 
1990.18 In 2018, a national multicenter randomized trial, Labor Induction versus Expectant 
Management in Low-Risk Nulliparous Women (ARRIVE), supported that elective induction 
after 39 weeks decreases cesarean delivery (CD) and morbidity.19 Since the ARRIVE trial, the 
incidence of IOL has increased nationally and institutionally.6 At LPCH, approximately 37% of 
vaginal deliveries currently follow IOL, with an average of 20 hours from admission time to 
delivery, compared to an average of 12-18 hours among those in spontaneous labor.4,5 As the 
number of patients electing IOL increases, L&D beds are occupied for a longer duration with a 
subsequent increase in hospital costs and a decrease in bed availability.6 IOL frequently begins 
with cervical preparation when the cervix is not dilated.1 At LPCH cervical preparation typically 
begins with prostaglandins (misoprostol and dinoprostone), 12-hours of transcervical (Cook) 


balloon placement, or misoprostol and Cook balloon used concurrently. Several studies have 
compared the cervical preparation methods that achieve the safest, most efficacious, and fastest 
method that led to spontaneous vaginal delivery.1-5 With increasing rates of IOL, there is a need 
for new methods to decrease the hospital induction times and to safely and expeditiously 
facilitate vaginal delivery.  
Misoprostol, a PGE2 prostaglandin, is among one of the most highly utilized cervical 
preparation agents for term labor induction.1 Misoprostol is FDA approved for the use of peptic 
ulcer disease but is widely used off label for term IOL.1 However, oral misoprostol may cause 
uterine hyperstimulation due to its effects on uterine contractility or may fail to produce 
sufficient cervical ripening for labor induction to proceed.18 Misoprostol is also FDA approved 
for its use in conjunction with mifepristone, a progesterone antagonist, as a regimen for first 
trimester medical abortion.7 Mifepristone, in conjunction with misoprostol, is used off label for 
second trimester IOL, and induction for second and third trimester pregnancy loss due to its 
efficacy as a cervical preparation agent.7,8 Based on the clinical trials in the second trimester, 
mifepristone reduces the time to delivery 40-50% while decreasing overall maternal 
morbidity.9,10 Although preexisting data exists on the safety and efficacy of mifepristone for 
cervical preparation used in both inpatient and outpatient settings outside the US,11-19 there are 
no studies in the US that assess the safety or the efficacy of mifepristone on IOL among term 
pregnancies.  
Specifically, several studies have focused on assessment of maternal and neonatal 
outcomes. Previous studies have demonstrated that when compared to expectant management, 
those treated with mifepristone are more likely to be in labor or have a favorable cervix (Bishop 
score >6) at 24 and 48 hours, are less likely to need augmentation with oxytocin, and less likely 
to undergo CD.11-17 In a large Cochrane Review, neonates were more likely to have abnormal 
fetal heart tracing, however, abnormal tracings did not correlate with difference in objective 
neonatal outcomes including NICU admission, cord blood gas, and APGAR scores.12 
Specifically in a randomized control trial comparing placebo to different doses of mifepristone, 
neonatal outcomes did not differ on the Apgar score at 1 and 5 minutes, the proportion of 
children requiring resuscitation, the transfer rate to neonatal intensive care units, cord artery 
blood pH, cord artery blood gas values, and neonatal hypoglycemia. Likewise, there was no 
significant difference in neonatal systolic or diastolic blood pressure on days 1 and 2.13 Studies 
have shown that mifepristone crosses the placenta and the fetus is exposed to maternal  
mifepristone intake and is maternal dose dependent with fetal levels at about one third of 
maternal levels. Maximum fetal plasma concentrations of mifepristone occur 4 hours after 
treatment with a subsequent decrease at 24 and 48 hours.11,13 Despite low neonatal plasmas 
concentration, there were no signs of peripheral cortisol deprivation in the neonates  
or differences in the above neonatal outcomes.13 
Based on previous studies and pharmacokinetics, we hypothesize that mifepristone 
prepares the cervix for IOL without causing increased uterine contractions or fetal heart rate 
abnormalities, compared to misoprostol.11-19 This pilot study would provide preliminary data for 
future studies of mifepristone as an outpatient induction agent to reduce time on L&D and 
improve perinatal outcomes as the incidence of IOL increases. 
2.3 Risk/Benefit Assessment  
 
Mifepristone 200mg, oral use 
 


2.3.1 Known Potential Benefits  
 
Mifepristone is a progesterone receptor antagonist that has been used off-label for second-
trimester induction of labor. It has been shown to reduce the time to delivery 40-50% while 
decreasing overall morbidity in second-trimester induction.9,10 Induction of labor is used as a 
therapeutic option when the benefits of delivery outweigh the risks of continuing the pregnancy.1 
Prolonged pregnancy is associated with significantly increased risks of perinatal and maternal 
complications.1 To successfully, safely and expeditiously induce labor and vaginal delivery 
without increasing the CD rate, ACOG endorses cervical preparation methods to facilitate 
cervical softening, thinning, and dilation. Several methods of cervical preparation have been 
implemented to expedite a successful labor induction and vaginal delivery, and ultimately 
decrease hospital stays and healthcare costs.1 
 
2.3.2 Assessment of potential risks  
 
Mifepristone is an FDA-approved drug for medical termination of intrauterine pregnancy 
through 70 days gestation. It is used off-label labor for cervical preparation for second trimester 
induction of labor.  
 
Most common adverse reactions (>15%) are nausea, weakness, fever/chills, vomiting, headache, 
diarrhea, and dizziness.  
It is contraindicated to use this medication among patients who have a confirmed/suspected 
ectopic pregnancy (not applicable to term pregnancies), chronic adrenal failure, concurrent long-
term corticosteroid therapy, history of allergy to mifepristone, misoprostol, or other 
prostaglandins, hemorrhagic disorders or concurrent anticoagulant therapy, inherited porphyria, 
or an intrauterine device (IUD) in place.   
When taken with misoprostol, risk of fetal malformations in ongoing pregnancy (if not 
terminated) is unknown. However, mifepristone will be administered to term pregnant 
participants and will be far outside of the window of organogenesis (fetal development), thus risk 
for teratogenicity is nullified by the fact that the study will take place in term pregnancies long 
after fetal development is completed. 
As with other pregnancies, cases of serious bacterial infection, including very rare cases of fatal 
septic shock, have been reported following the use of mifepristone. No causal relationship 
between mifepristone and misoprostol use and an increased risk of infection or death has been 
established.  
Mifepristone is present in human milk. Limited data demonstrate undetectable to low levels of 
the drug in human milk. 
Animal studies:  
Mifepristone has been shown to induce labor in rats,20 through opposition to progesterone‐
induced suppression of oxytocin receptors, and enhanced synthesis of prostaglandins. 


Mifepristone has also been shown to induce preterm birth in mice, associated with a rise in 
prostaglandins and cytokines.21 A randomized‐controlled trial in beef heifers found a mean time 
to delivery of 43 hours after mifepristone administration, compared to 182 hours in placebo 
treated controls.22 In a primate model (the macaque), mifepristone administration induced 
prostaglandin F2 alpha production by decidua, but not prostaglandin E2 production by amnion.23 
The FDA Mifeprex (mifepristone) information describes teratology studies in mice, rats and 
rabbits at doses of 0.25 to 4.0 mg/kg (less than 1/100 to approximately 1/3 the human exposure 
based on body surface area), stating that because of the antiprogesterone activity of mifepristone, 
fetal losses were much higher than in control animals. Skull deformities were detected in rabbit 
studies at approximately 1/6 the human exposure, although no teratogenic effects of mifepristone 
have been observed to date in rats or mice. These deformities were most likely due to the 
mechanical effects of uterine contractions resulting from inhibition of progesterone action. As 
stated above, mifepristone will be administered to term pregnant participants and will be far 
outside of the window of organogenesis (fetal development), thus risk for teratogenicity is 
nullified by the fact that the study will take place in term pregnancies long after fetal 
development is completed. 
 
Safety measures for this study include the following:  
- 
Obtain VITALS (blood pressure, mean arterial blood pressure, heart rate, respiratory rate) 
throughout labor induction, every 15 minutes for the first hour of the induction process 
and then hourly during the first 4 hours of the induction process. (see table below for 
reference range in pregnancy). In addition, oral temperature will be taken per standard 
protocol 
- 
Pregnant patients in this study may receive up to a maximum dose of 200 mg 
mifepristone only; this is the max dose per course as outlined by the package label 
instructions. Each dose will be given as 200 mg orally, once at the induction initiation 
- 
Monitor patients for adverse symptoms of mifepristone 
- 
All patients will undergo continuous electronic fetal heart rate monitoring and tocometry 
until the time of delivery 
 


 
Source: Williams Obstetrics and Gynecology, 25th Edition 
 
Vital signs which suggest hemodynamic instability or suspicion for sepsis 
- 
Oral Temperature <36 °C (96.8 °F) or >38°C (100.4°F)   
- 
Heart rate > 110 beats per minute or <50 beats per minute 
- 
MAP <65 mm Hg 
- 
Respiratory rate > 24 breaths per minute or less than < 10 breaths per 
minute  
 
If the patient experiences 2 vital signs that are outside of normal parameters, the standard of care 
work up will be initiated. 
 
If the patient experiences a fever in labor, per standard of care, antibiotics are started, and an 
infectious workup is initiated. If the patient has a fever with abnormal vital signs per CMQCC 
guidelines (see below), assessment for infection is initiated per standard of care. 


 
2.3.3 Risk Benefit/Ratio 
 
As the incidence of labor induction increases, the average time a patient is occupying a room on 
Labor & Delivery increases, impacting bed availability and cost. There is an urgent need for new 
methods and models to decrease the labor induction times. Studies have determined maternal and 
neonatal safety when using mifepristone as a cervical preparation agent. Assessment of outcomes 
in this study will determine how treatment can improve maternal and neonatal outcomes. 
 


Any serious adverse event or unanticipated problem will be reported to the Stanford IRB. The 
study team encompasses the responsibility to monitor all aspects of the study and monitor data 
and oversee participant safety. 
 
We satisfy all requirements for this to be IND exempt.  
 
Misoprostol 50 micrograms po  
 
2.3.4 Assessment of potential benefits 
 
Misoprostol can induce or augment uterine contractions and is used as part of the standard of 
care for labor induction. Vaginal and oral administration of misoprostol, outside of its approved 
indication, has been used as a cervical ripening agent, for the induction of labor and for treatment 
of serious postpartum hemorrhage in the presence of uterine atony. Misoprostol is well studied 
for obstetric use and is used as a standard of care for labor induction internationally.1-5 
 
According to ACOG, misoprostol, a synthetic PGE1 analogue, can be administered 
intravaginally, orally, or sublingually and is used for both cervical ripening and induction of 
labor. It currently is available in a 100-mcg (unscored) or a 200- mcg tablet, and can be broken to 
provide 25-mcg or 50- mcg doses. There is extensive clinical experience with this agent and a 
large body of published reports supporting its safety and efficacy when used appropriately.1 
 
 
2.3.5 Assessment of potential risks  
 
No studies indicate that intrapartum exposure to misoprostol (or other prostaglandin cervical 
ripening agents) has any long-term adverse health consequences to the fetus in the absence of 
fetal distress, nor is there a plausible biologic basis for such a concern. Although misoprostol 
currently is approved by the U.S. Food and Drug Administration (FDA) for the prevention of 
peptic ulcers, the FDA in 2002 approved a new label on the use of misoprostol during pregnancy 
for cervical ripening and for the induction of labor. This labeling does not contain claims 
regarding the efficacy or safety of misoprostol, nor does it stipulate doses or dose intervals.1 
 
According to the FDA, the major adverse effect of the obstetrical use of misoprostol is 
hyperstimulation of the uterus which may progress to uterine tetany. There is an increase in 
uterine rupture (requiring surgical repair, hysterectomy, and/or salpingo-oophorectomy) among 
patients with a known history of a previous uterine surgery. 
 
There may be an increased risk of uterine tachysystole, meconium passage, meconium staining 
of amniotic fluid, and Cesarean delivery due to uterine hyperstimulation with the use of higher 
doses of misoprostol. In this study, the standard dose of 50 mcg and 100 mcg as the second dose 
if indicated will be used. It is established that oral misoprostol reduces risk for cesarean section 
rate and has a low incidence of uterine hyperstimulation.5 The risk of uterine rupture increases 
with advancing gestational ages and with prior uterine surgery, including cesarean birth and 
these patients are excluded from this study.  
 


The following have been reported as adverse events in subjects receiving misoprostol: 
Gastrointestinal: In subjects receiving misoprostol 400 or 800 mcg daily in clinical trials, the 
most frequent gastrointestinal adverse events were diarrhea and abdominal pain. The incidence 
of diarrhea at 800 mcg in controlled trials in patients on NSAIDs ranged from 14-40% and in all 
studies (over 5,000 patients) averaged 13%. Abdominal pain occurred in 13-20% of patients in 
NSAID trials and about 7% in all studies, but there was no consistent difference from placebo. 
However, patients will not receive doses greater than 100 micrograms, minimizing the risk for 
gastrointestinal side effects.  
 
Due to potential risks of misoprostol, the same safety guidelines as stated in 2.3.2 will remain in 
this study group.  
 
2.3.6 Risk Benefit/Ratio 
 
As stated above, the incidence of labor induction increases, the average time a patient is 
occupying a room on Labor & Delivery increases, impacting bed availability and cost. There is 
an urgent need for new methods and models to decrease the labor induction times. Studies have 
determined maternal and neonatal safety when using misoprostol as a cervical preparation agent. 
Misoprostol is among one of the most common medications used for labor induction at LPCH 
and internationally. The benefits of improving labor induction success and decreasing rates of 
cesarean birth outweigh the potential of uterine tachysystole with continuous external fetal 
monitoring. Our study population excludes patients with uterine scars, including cesarean birth, 
and this mitigates the risk of uterine rupture.  
 
Any serious adverse event or unanticipated problem will be reported to the Stanford IRB. The 
study team encompasses the responsibility to monitor all aspects of the study and monitor data 
and oversee participant safety. 
 
 
 
3. OBJECTIVES 
 
3.1 Primary Outcome  
Generation of preliminary data comparing obstetric and neonatal outcomes among patients 
randomized to misoprostol 50 mcg versus mifepristone 200 mg  
 
Obstetric outcomes:  
o Number of uterine contractions – with and without fetal heart rate decelerations 
during the time the foley is in place 
o Rate of uterine tachysystole (≥ 5 contractions in 10 minutes that is sustained for at 
least 30 minutes) or hypertonus (a single contraction lasting more than 2 minutes) 
during labor  
o Time to delivery  


o Time to complete cervical dilation 
o Total time on the Labor and Delivery unit 
o Rate of cesarean delivery (CD) 
o Rate of failed induction of labor per ACOG guidelines  
o Composite of serious maternal morbidity based on CDC severe maternal 
morbidity and mortality (including acute myocardial infarction, aneurysm, acute 
renal failure, adult respiratory distress syndrome, amniotic fluid embolism, 
cardiac arrest/ventricular fibrillation, conversion of cardiac rhythm, disseminated 
intravascular coagulation, eclampsia, heart failure/arrest during surgery or 
procedure, puerperal cerebrovascular disorders, pulmonary edema/acute heart 
failure, severe anesthesia complications, sepsis, shock, sickle cell disease with 
crisis, air and thrombotic embolism, blood products transfusion, hysterectomy, 
temporary tracheostomy, ventilation) 
• Neonatal outcomes:  
o Comparison of neonatal cord gases (arterial pH) and neonatal APGAR scores at 1 
and 5 minutes 
o Composite of serious neonatal morbidity up to 7 days of life (including perinatal 
death, need for respiratory support within 72 hours after birth, Apgar score of 3 or 
less at 5 minutes, arterial pH, hypoxic-ischemic encephalopathy, seizure, infection 
(confirmed sepsis or pneumonia), meconium aspiration syndrome, intracranial or 
subgaleal hemorrhage, hypotension requiring vasopressor support, admission to 
the neonatal intensive care unit) 
Secondary outcomes 
• Examine recruitment feasibility and willingness of participants to be randomized to guide 
recruitment periods for future studies. 
 Plan to assess medication tolerability through participant experience surveys at two time 
points (after cervical preparation during the labor process and on postpartum day one)  
 
4.  STUDY DESIGN 
 
4.1 Overall Design  
We will perform a parallel group, two-arm, non-blinded, randomized control trial comparing 
mifepristone to misoprostol in pregnant patients at term delivering their first neonate. 
 
4.2 Justification for Dose  
The FDA has approved mifepristone in a regimen with misoprostol, for the medical termination 
of intrauterine pregnancy through 70 days gestation. Historically mifepristone 600 mg followed 
by a prostaglandin were used, however, preferred dosing of mifepristone 200 mg is the current 
FDA approved dose due to its equal efficacy and safety as compared to 600 mg (Poppema, 1999 
and Raymond, 2013). 
 
Mifepristone 200 mg in adjunct to misoprostol is used off-label for management of pregnancy 
loss before 20 weeks and second trimester abortion, including induction of labor and dilation and 


evacuation. Mifepristone used with misoprostol reduces time to delivery and leads to fewer 
adverse effects when compared to misoprostol alone. 7,8 
 
Mifepristone 200 mg dosing received FDA approval in 2016 and is used as the standard dose in 
conjunction with misoprostol. Mifepristone 200 mg dose was used as the standard dose among 
studies of inducing labor at term.11,12 However, one study compared mifepristone 50 mg, 100 mg, 
200 mg, 400 mg, and 600 mg and found no difference in maternal or neonatal outcomes among 
dosing.13 
 
The recommended FDA approved adult oral dose of misoprostol for reducing the risk for 
NSAID-induced gastritis is 200 mcg four times daily, however, the dose varies for labor 
induction.  
 
According to ACOG, one quarter of an unscored 100-mcg tablet (ie, approximately 25 mcg) of 
misoprostol should be considered as the initial dose for cervical ripening and labor induction. 
However, this is based on a vaginal route. The standard of care at LPCH is 50 mcg orally, based 
on previous literature that suggests stepwise oral misoprostol (50 mg followed by 100 mg) 
appears to be as effective as vaginal misoprostol (25 mg) for cervical ripening with a low 
incidence of hyperstimulation, no increase in side effects, a high rate of patient satisfaction, and 
is associated with a lower cesarean section rate.5 
 
The frequency of administration should not be more than every 3–6 hours. In hour study, we 
have chosen repeat dosing at 4 hour intervals based on routine management at LPCH. In 
addition, oxytocin should not be administered less than 4 hours after the last misoprostol dose. 
Misoprostol in higher doses (50 mcg every 6 hours) may be appropriate in some situations, 
although higher doses are associated with an increased risk of complications, including uterine 
tachysystole with FHR decelerations. 
 
4.3  End of Study Definition  
 
The study will be complete once enrollment has been completed. The goal is 30 patients with 15 
in each arm.  
 
4.4  Sample Size  
 
We plan to recruit 15 patients per group (30 total) based on the “rule of 12” that is recommended 
for pilot studies that aim to estimate average values and variability to plan larger studies,24 and to 
accommodate an estimated 25% intrapartum cesarean rate. Based on 80% power, a two-sided 
alpha of 0.05, and prior data, we estimate that this sample size would enable us to detect a 
difference of at least 25 uterine contractions between the two study groups (140-150 on average 
during labor for patients induced with misoprostol and Cook balloon). The analysis plan and 
sample size calculation were developed in consultation with Maternal-Fetal Medicine Senior 
Biostatistician, Stephanie Leonard, PhD (Co-I).  
 
4.5  Timeline  


 
Year 1 
July-
22 
Aug-
22 
Sept-
22 
Oct-
22 
Nov-
22 
Dec-
22 
Jan-
23 
Feb- 
23 
Mar-
23 
April- 
23 
May-
23 
June-
23 
Recruitment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Data collection 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Data analysis 
 
 
 
 
 
 
 
 
x 
x 
 
 
Manuscript 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
5.  STUDY POPULATION 
 
(see  Study Design Figure below) 
 
5.1. Screening and Inclusion/Exclusion Criteria  
General Screening guidelines  
 
I. 
We will recruit patients receiving prenatal care at San Mateo County Health Clinics, 
LPCH, and private practices who deliver at LPCH at LPCH OB clinic and Labor and 
Delivery 
a. Patients will be eligible for the study if they are scheduled for or admitted for 
induction of labor at LPCH  
b. All other eligibility criteria must me bet to be included in the study 
c. Among those screened and meeting eligibility at LPCH OB clinic, will require 
rescreening once admitted for labor induction to confirm the participant meets all 
study eligibility criteria 
d. Gestational age must be validated prior to enrollment using the latest ACOG 
criteria that compares LMP derived gestational age with ultrasound parameters. 
The ACOG criteria for gestational age determination based on ultrasound is as 
follows:  
 
 
Source: ACOG Committee Opinion No 700: Methods for Estimating the Due 
Date 
 


II. 
Patients admitted for scheduled labor induction or admitted from Labor and Delivery 
triage will be screened by chart review 
a. Patients will need to be scheduled or admitted for a term labor induction at LPCH 
b. Review of electronic medical record will include pregnancy dating information 
using the initial ultrasound, and medical history information taken at the prenatal 
visits or time of admission. Baseline information, including contact information, 
vitals, demographics, pregnancy history information, and maternal and neonatal 
medical information will be reviewed to assess eligibility for study participation.  
c. Patients will undergo a fetal non-stress test at time of admission as part of 
standard of care. The OB provider or PI’s will review the non-stress test. 
Category 1 or not a persistently Category 2 or 3 fetal heart tracing, according to 
ACOG criteria is required for eligibility.  
d. Patients will undergo a cervical exam by the OB provider at time of admission as 
part of standard of care, to assess for eligibility.  
 
III. 
Patients screened at LPCH OB clinic will be screened by chart review 
a. Patients will need to be scheduled for a term labor induction at LPCH 
b. Review of electronic medical record will include pregnancy dating information 
using the initial ultrasound, and medical history information taken at the prenatal 
visits or time of admission. Baseline information, including contact information, 
vitals, demographics, pregnancy history information, and maternal and neonatal 
medical information will be reviewed to assess eligibility for study participation.  
 
Throughout screening period we will record number of patients screened, eligible, and 
approached in the REDCap database.  
 
5.2  Inclusion Criteria  
 
Nulliparous patients aged 18 to 45 years, with singleton live pregnancies of gestational age 37 
weeks 0 days – 42 weeks 0 days, with a planned labor induction, not in labor, with intact 
membranes with no contraindication for vaginal delivery, misoprostol or mifepristone, and a 
Bishop score <6 with transcervical balloon in place <3 hours prior to the time of 
randomization, without prior cervical preparation. 
 
For patients who meet the above inclusion criteria 1-10 and who those who decline 
randomization will be offered enrollment for chart review only. 
 
5.3  Exclusion Criteria  
 
If the basic screening criteria are met, the next step is to review the exclusion criteria. Those 
without exclusions should be approached for study participation.  
 
Assess the following exclusions:  
1. Significant cardiac, renal, or hepatic maternal comorbidities, severe gestational hypertension 
or preeclampsia with severe features 
2. Pregnancies complicated by major fetal anomalies 
3. Patients with a uterine scar 


4. Pregnancies complicated by fetal growth restriction (estimated fetal weight <10%) 
5. Pregnancies complicated by oligohydramnios 
6. Fetuses with an estimated fetal weight >4500 gm by recent ultrasound or Leopold’s exam on 
admission 
7. Patients with class 3 obesity (BMI >40) 
8. Fetuses with a persistent category 2 or 3 fetal heart tracing at labor induction admission 
9. Vaginal bleeding at the time of randomization 
10. Any indication for scheduled CD 
11. Hypersensitivity to oxytocin  
12. Uterine contractions ≥ 3 in10 minutes 
13. Hypersensitivity to prostaglandins  
 
Patients who meet inclusion criteria and do not have exclusion criteria may be approached for 
the informed consent process.  
 
5.4 Screening/Re-screening 
 
Patients may be included in the study up to 42 weeks gestation. If the above inclusion criteria are 
met and exclusion criteria are absent, patients should be approached for study participation. The 
screening number will be generated electronically with REDCap is accessed and participant 
information is entered.  
 
The patients screened at LPCH OB clinic will require re-screening at the time of labor induction 
admission.  
 
5.5 Gestational Age Determination  
 
Gestational age will be determined by the most recent ACOG criteria (see table in Section 5.1) 
with ultrasound required prior to randomization. If no ultrasound examination has been 
performed previously, one will be performed before the patient is randomized. Only pregnant 
patients with gestational age > 37 0/7 weeks will be included.  
 
5.6 Informed Consent Process  
 
An informed consent must be obtained before entry into the randomized trial. Full disclosure of 
the nature and potential risks of participating in the trial including the risks of being in the 
standard care group will be made. All potential participants will undergo the informed consent 
process as approved by the Institutional Review Board at each participating center. Any person 
who is potentially eligible will be told about the study and asked if they are willing to participate. 
The point in the screening process at which a signed informed consent is required will be prior to 
randomization. The study personnel conducting the informed consent process should emphasize 
the following study criteria during the informed consent process:  
 
• Randomization to a treatment arm with mifepristone for a cervical preparation agent, 
with 50% chance to be assigned to either arm: 
o One group will receive mifepristone 


o One group will receive misoprostol  
• Participants to sign medical release 
• American College of Obstetrics and Gynecology recommends cervical preparation for 
labor induction, including the use of a transcervical (Cook) balloon 
• Follow up to occur through a numerical rating scale patient satisfaction survey on 
postpartum day one to evaluate medication side effects and overall satisfaction associated 
with treatment 
 
Patients who did not give informed consent for randomization but meet eligibility criteria 1-10, 
or who are unable to receive a Cook balloon based on their initial exam will be offered 
enrollment for chart review only. Patients undergoing induction with a Cook balloon alone will 
be offered enrollment for chart review. These patients will consent to chart review without 
participating in the study’s randomization, they will receive standard of care at LPCH.  
 
Due to a large proportion of Spanish speaking patients at LPCH, we will also have consents and 
short form consents available in Spanish, and translators will be available for the consent 
process. A short form consent may also be used depending on the participant’s preferred 
language. 
 
All patients who are considered for participation in the study (consent for randomization, consent 
for chart review, decline or ineligible) should have a data entry form and entered into the 
electronic data system even if not randomized. Patients who do not meet criteria at the LPCH OB 
clinic screening, may be re-screened at the labor induction.  
 
5.7 Requesting Medical Release Forms  
 
In order to obtain medical records from participants, each participant should sign a “Release of 
Medical Information” form. A signed Release of Medical Information form should be obtained at 
the time of, and preferably before, randomization. Clinical Site staff will be able to answer any 
questions about the procedure at the very beginning of their participation in the study. Also, 
reluctance to supply medical records may serve as a potential “red flag” that a potential 
participant may be an adherence or retention risk.  
If a participant refuses to sign a Medical Release Form, probe for reasons for the refusal. Explain 
the importance of the records for the study and why they are needed. Some participants may be 
willing to sign a release that is specific to information needed for a particular outcome. If the 
participant continues to refuse, note the refusal in the participant’s chart and continue to follow 
them according to the protocol if they consent to the study at labor induction admission. 
 
6. RANDOMIZATION 
 
Randomization will occur at the time of labor induction admission.  
Randomization may occur upon confirmation that all exclusion/inclusion criteria are satisfied, 
after verification of participant consent and HIPAA authorization, and a transcervical balloon is 
placed by the OB provider. Of particular importance, careful consideration will be given to the 
patient’s history and fetal status to determine final eligibility. Study staff will also verify 
participant contact information and obtain a Release of Information. 


 
The MFM Research team will review the following before randomization:  
• Complete review of all exclusion and inclusion criteria  
• Informed consent obtained  
• Fetal status and cervical exam to confirm eligibility 
• Verification by OB provider that transcervical balloon is in place  
 
Pharmacy randomization: 
 
• The LPCH pharmacy will randomize the study medication and dispense to the Labor and 
Delivery medication dispense system, Pyxis.  
• The L&D nurse caring for the participant will provide the medication and instructions  
 
The LPCH pharmacy will attain records of randomization. 
 
Both groups, will undergo continuous external fetal monitoring and tocometry throughout the 
entirety of labor induction per standard of care.  
 
The categories of patients randomized:  
 
Patients consenting to the study will be randomized in 1:1 blocks to two treatment groups  
 
Group 1: Patients randomized to the mifepristone group will receive mifepristone 200 mg po 
treatment. 
Group 2: Patients randomized to the misoprostol group will receive misoprostol 50 mcg po 
treatment.  
Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligible patients screened and 
enrolled at LPCH OB clinic 
Cook balloon in place 
Cook balloon 
+ 
Misoprostol 
Cook balloon 
+ 
Mifepristone 
Randomization 
Eligibility screening/re-screening 
at labor induction admission 
• Non-stress test 
• Cervical exam 
• Rescreen enrolled 
patients  
Patients induced with Cook balloon 
alone or balloon unable to be placed 
• Consented for chart review 
• Study participation declined  
Patients who decline randomization:  
• Consented for chart review 
• Study participation declined  


6.1 Informed Consent  
 
No study activities will be conducted until an IRB approval is obtained. Potential participants 
who may be eligible will be approached by the research staff. The research staff will only 
introduce the study with the patients after a member of the clinical care team acquires permission 
from the potential participant that they can be approached for a study. If interested, the research 
staff will discuss the study and obtain an informed consent from the participant. 
 
Sufficient time will be given to participants to read the consent form, and to ask questions to 
ensure understanding. 
 
An IRB-approved study brochure may be given to potential participants to provide more 
information about the study and the procedures involved. 
 
6.2 Induction of Labor: Study Groups  
 
At LPCH cervical preparation typically begins with prostaglandins (misoprostol and 
dinoprostone), 12-hours of transcervical (Cook) balloon placement, or misoprostol and Cook 
balloon used concurrently. For the purposes of our study, all patients will receive the standard of 
care for labor induction at LPCH, starting with mechanical induction of labor with the 
transcervical (Cook) balloon. The Cook balloon will remain in place for a maximum of 12 hours. 
After 12 hours of Cook balloon placement, the OB provider will deflate the Cook balloon and 
perform a cervical exam. If the balloon spontaneously expels prior to 12 hours, the time will be 
noted and a cervical exam performed. The balloon will be removed at any point in the setting of 
spontaneous rupture of membranes (SROM) per standard of care, to minimize risk of 
intraamniotic infection. After a balloon expulsion, balloon removal in the setting of SROM or 
after 12 hours of balloon placement and removal, the provider will manage the labor induction 
based on standard of care practice, including using up-titration of oxytocin, amniotomy when 
deemed safe and appropriate, and transitioning to cesarean or operative birth if deemed necessary 
by the provider.  Patients who receive misoprostol will be eligible to receive additional doses of 
misoprostol 50 – 100 mcg, because of its known safety. Patients who receive mifepristone will 
not be eligible for additional doses of misoprostol because based on the pharmacokinetics of 
mifepristone, the ripened cervix could potentiate uterine tachysystole.  
 
Once the patient achieves complete cervical dilation, time spent in the second stage of labor will 
be at the discretion of the OB provider given variability among patients and providers. 
 
As the standard of care, oxytocin is indicated when a modified Bishop score of 8 or greater is 
observed or if spontaneous rupture of membranes occurs during the ripening process. 
Intravenous oxytocin will begin at 1 milliunits per minute about 12 hours after mifepristone 
dispense and will be titrated per LPCH protocol. Amniotomy will performed at the discretion of 
the provider.  
 
Maternal pulse and blood pressure will be recorded during the ripening process to assess for the 
incidence of maternal blood pressure or maternal heart rate changes; mean arterial pressures and 


pulse measurements will be recorded every 15 minutes for the first hour of the induction process 
and then hourly during the first 4 hours of the induction process. If 2 vital sign abnormalities are 
noted during this period, the OB provider will be notified, and the standard of care work up will 
be initiated. (See section 2.3.2) Abnormal vital signs include Heart rate > 110 beats per minute or 
<50 beats per minute, systolic blood pressure (mm Hg) > 160 or < 45 or diastolic blood pressure 
> 110 or < 85 or MAP <65 mm Hg. Patients will assessed for the presence of known potential 
side effects from mifepristone or misoprostol by patient interview on postpartum day one. All 
patients will undergo continuous electronic fetal heart rate monitoring and tocometry until the 
time of delivery.  
 
Cervical exams will be performed per standard of care by OB providers and recorded. The 
primary outcome is time to complete cervical dilation. Once the patient achieves complete 
cervical dilation, time spent in the second stage of labor will be at the discretion of the provider. 
 
Placentas will be sent out to Pathology after delivery if deemed indicated for both groups by the 
provider. Both groups will have their placentas analyzed if there are clinical indications for the  
test.  
 
Time and mode of delivery will be recorded into the REDCap database. 
 
6.3. Standard Dose of Medications  
The FDA has approved mifepristone in a regimen with misoprostol, for the medical termination 
of intrauterine pregnancy through 70 days gestation. Historically mifepristone 600 mg followed 
by a prostaglandin were used, however, preferred dosing of mifepristone 200 mg is the current 
FDA approved dose due to its equal efficacy and safety as compared to 600 mg.26,27 
 
Mifepristone 200 mg in adjunct to misoprostol is used off-label for management of pregnancy 
loss before 20 weeks and second trimester abortion, including induction of labor and dilation and 
evacuation. Mifepristone used with misoprostol reduces time to delivery and leads to fewer 
adverse effects when compared to misoprostol alone.7,8 
 
Mifepristone 200 mg dosing received FDA approval in 2016 and is used as the standard dose in 
conjunction with misoprostol. Mifepristone 200 mg dose was used as the standard dose among 
studies of inducing labor at term.11,12 However, one study compared mifepristone 50 mg, 100 mg, 
200 mg, 400 mg, and 600 mg and found no difference in maternal or neonatal outcomes among 
dosing.13 
 
According to ACOG, one quarter of an unscored misoprostol 100-mcg tablet (ie, approximately 
25 mcg) of misoprostol should be considered as the initial dose for cervical ripening and labor 
induction. However, this is based on a vaginal route. The standard of care at LPCH is 50 mcg 
orally, based on previous literature that suggests stepwise oral misoprostol (50 mg followed by 
100 mg) appears to be as effective as vaginal misoprostol (25 mg) for cervical ripening with a 
low incidence of hyperstimulation, no increase in side effects, a high rate of patient satisfaction, 
and is associated with a lower cesarean section rate.5 
 


Frequency of dosing varies between every 3-6 hours. At LPCH standard of care is every 4 hours. 
Repeat doses of misoprostol 50-100 mcg orally will be given if indicated starting 4 hours after 
first dose.  
 
7.  POST RANDOMIZATION  
 
7.1 Post Randomization Patient Satisfaction Survey 
 
All patients will complete a numerical rating scale patient satisfaction survey after balloon 
removal and on postpartum day one to evaluate medication side effects and overall satisfaction 
associated with treatment.  
 
7.2 Management of patient’s intolerance to study intervention  
  
Most common adverse reactions (>15%) to mifepristone include nausea, weakness, fever/chills, 
vomiting, headache, diarrhea, and dizziness.  
 
If the patient experiences side effects, the standard of care medications will be used for the 
patients: 
.  
 
For nausea and vomiting the patient will be offered Zofran 4 milligrams IV or po every 6 
hours as needed, Compazine 10 milligrams IV or po every 6 hours as needed, Reglan 10 
milligrams IV or po every 6 hours as needed.  
For headache the patient will be offered Tylenol 1 gram po every 8 hours as needed.  
For diarrhea the patient will be offered Lomotil 5 milligrams every 6 hours as needed.  
For dizziness and weakness, a comprehensive workup will be established to ensure the 
etiology is neither infectious or neurological.   
 
As stated in 2.3.2, if the patient experiences 2 vital signs that are outside of normal parameters, 
the standard of care work up will be initiated. 
 
If the patient experiences a fever in labor, per standard of care, antibiotics are started, and an 
infectious workup is initiated. If the patient has a fever with abnormal vital signs per CMQCC 
guidelines (see 2.3.2), assessment for infection is initiated per standard of care. 
 
 
7.8 Study Drug, Dispensing 
 
Stanford’s investigational pharmacy will dispense either mifepristone or to LPCH pharmacy. 
LPCH pharmacy will dispense/administer study drug to research participant’s nurse via the 
Pyxis. The nurse will dispense the medication to the participant.  
 
7.9 Biospecimens  
 
Placentas will be sent out to Pathology after delivery if deemed indicated for both groups by the 
provider. Both groups will have their placentas analyzed if there are clinical indications for the  


test. Assessment will be performed with the standard of care for all LPCH delivering 
participants.  
 
 
8. POST-DELIVERY 
 
Outcome Data Collection and Chart Review Delivery Outcomes will be ascertained on an 
ongoing basis until discharge.  
Study personnel will abstract the hospital charts and complete information for REDCap entry: 
- 
Labor and Delivery Data 
- 
Neonatal Outcome Data 
- 
Placental Pathology (if obtained) 
- 
NICU admission form (if indicated)  
- 
Adverse Event  
- 
Study Intervention Discontinuation and Participation 
discontinuation/withdrawal  
 
9.  PROCEDURES FOR INACTIVE/ LOST/ REFUSED PARTICIPANTS AND MISSED 
VISITS  
 
9.1  Overview  
 
Staff will use a systematic approach in attempting to recover reluctant participants, i.e., those 
who have either expressed interest in dropping out of the study or appear to be likely to drop-out 
with any aspect of the study. 
 
The goals to avoid drop-out and accomplish drop-out recovery include the following:  
1. to ensure that participants are not pushed to the point that they refuse to participate further 
2. to continue to engage participants through some form of contact (e.g., phone, e-mail) and 
allow an opportunity to determine participants’ concerns and problem-solve for solutions to 
concerns and barriers to participation,  
3. to foster some form of continued participation  
 
The general approach to drop-out recovery will involve contact by the study coordinator in an 
attempt to:  
1. identify barriers to participation  
2. problem-solve for solutions to overcome identified barriers  
3. apply motivational enhancement methods 
 
In situations where a participant’s behavior suggests that they do not wish to participate, the 
participant can be removed from the study.  
 
9.2 Definition of Participant Status. 
 
 For purposes of the study, we define the following terms related to trial participation status: 
 


 • Active status – active if medication therapy is managed according to the study algorithm. The 
participant continues labor induction per study protocol, which is the standard of care at LPCH.  
 
• Inactive status – participant consents to chart review for study purposes, but does not consent 
to randomization.   
 
• Lost status –lost-to-follow-up if the participant does not arrive for planned labor induction and 
cannot be contacted by any ordinary means (e.g., home phone, cell phone, mail, email, fax, etc.), 
clinic staff does not know the participant’s whereabouts, and alternative contacts either do not 
know where the participant is or cannot be contacted themselves.  
 
• Withdrawn/Refused status –participant is considered to be withdrawn if they have withdrawn 
consent to participate in the study and refuses further contact for any reason or if the participant 
consented and no longer meets study eligibility criteria at any point in the study. 
 
10. ADVERSE EVENT REPORTING 
Serious adverse events that meet any of the following criteria: 
• fatal or life-threatening 
• result in significant or persistent disability, 
• require or prolong hospitalization, 
• neonatal death, 
• are important medical events that investigators judge to represent significant hazards or harm to 
research participants.  
 
Specifically, any AE that meets any of these criteria (maternal death, ICU admission stroke, 
myocardial infarction, cardiomyopathy, fetal death or neonatal death) will be documented and 
reported as a SAE.  
In addition, any unexpected event/ unanticipated problems which the investigator identifies will 
be reported.  
10.1 Data Safety Monitoring Plan  
A DSMP will be in place to ensure the safety of participants by analyzing data and to 
oversee the validity and integrity of the data.  
Any serious adverse event or unanticipated problem will be reported to the Stanford IRB. A Data 
Safety Monitoring Plan (DSMP) will be established to guide all aspects of the study and oversee 
participant safety. DSMP participants include the research team. The DSMP will be implemented 
to monitor safety, to advise on study progress and performance, protocol modification, or 
whether there should be early termination. 
The outcome of reviews will be relayed to the IRB and protocol director.  


10.2 Reporting of Adverse Events  
In addition, the following maternal or neonatal events are examples of adverse events to be 
reported:   
• Maternal or perinatal allergic reaction 
• Angioedema, anaphylaxis or generalized skin rash  
• Transfer to Chronic Care facility (neonatal)  
• Maternal arrhythmia (especially QT prolongation) or congestive cardiac failure 
(EF<45%) 
• Neonatal arrhythmia (especially QT prolongation)  
• Any adverse event leading to discontinuation of study medication or suspected to be due 
to the medication  
• Maternal pulmonary thromboembolism  
• Maternal admission to ICU  
• Neonatal IVH Grade III or IV  
• Prolonged maternal or term neonatal hospitalized 
11.  QUALITY CONTROL  
Quality control and assurance are the responsibility of every member of the MiLI trial. 
 
All clinic personnel are responsible for understanding the protocol procedures.  
 
Research Staff responsibilities: 
 
• Maintaining the integrity of the protocol and regulatory document binder. 
• 
Developing a data entry system that incorporates real-time data quality assurance 
features, such as range and logic checks  
• Monitoring site initiation requirements.  
• Monitoring the screening and randomization processes to ensure randomization of 
eligible participants and appropriate randomization allocation of participants.  
• Generating timely web-based reports describing clinic and study performance, including 
but not limited to: a) recruitment b) visit adherence and visit completeness c) study 
intervention) data entry e) data completeness f) outcomes documentation 
• Monitoring documentation of 100% of potential outcomes  
 
 
12.  STATISTICAL ANALYSIS 
  
12.1 Statistical Considerations  
 
Efficacy Endpoint(s): The primary outcomes include generation of preliminary data comparing 
obstetric and neonatal outcomes among patients randomized to misoprostol 50 mcg versus 
mifepristone 200 mg a) obstetric outcomes: number of uterine contractions– with and without 


fetal heart rate decelerations in labor, uterine tachysystole (more than 5 contractions in 10 
minutes with and without fetal heart rate decelerations) or hypertonus (a single contraction 
lasting more than 2 minutes) during the time the foley is in place. We will also be assessing time 
to complete dilation and delivery, total time on L&D, rate of cesarean delivery, number of 
patients able to achieve active labor, and severe maternal morbidity- composite of 21 indicators, 
such as hysterectomy, eclampsia, sepsis, and blood products transfusion and b) neonatal 
outcomes: neonatal cord gases (arterial pH), neonatal Apgar scores at 1 and 5 minutes, and a 
composite of serious neonatal morbidity up to 7 days of life defined as need for respiratory 
support within 72 hours after birth, hypoxic-ischemic encephalopathy, seizure, infection, 
meconium aspiration syndrome, intracranial or subgaleal hemorrhage, hypotension requiring 
vasopressor support, admission to neonatal intensive care unit. 
Secondary Efficacy Endpoint(s): The secondary outcomes are to examine recruitment feasibility, 
willingness of participants to be randomized to guide recruitment periods for future studies, and 
to assess medication tolerability through participant experience surveys. 
 
12.2  Sample size determination  
 
We plan to recruit 15 patients per group (30 total) based on the “rule of 12” that is recommended 
for pilot studies that aim to estimate average values and variability to plan larger studies,24 and to 
accommodate an estimated 25% intrapartum cesarean rate. Based on 80% power, a two-sided 
alpha of 0.05, and prior data, we estimate that this sample size would enable us to detect a 
difference of at least 25 uterine contractions between the two study groups (140-150 on average 
during labor for patients induced with misoprostol and Cook balloon). 
 
There were approximately 800 inductions among nulliparous patients at LPCH in 2020. We 
anticipate excluding ~200 patients based on eligibility criteria. Based on previous institutional 
studies and institutional practices, we expect 50% of patients to be approached for enrollment 
based on our experience and approximately 50% of patients who are approached to agree to 
participate in research study. This will result in approximately 150 patients who would agree to 
participate during one year.  
 
The analysis plan and sample size calculation were developed in consultation with Maternal-
Fetal Medicine Senior Biostatistician, Stephanie Leonard, PhD (Co-I).  
 
12.3  Analyses  
 
We will compare the number of uterine contractions and other continuous variables using Mann-
Whitney U test and will use Fisher’s exact test for categorical variables. Differences will be 
considered statistically significant using two-sided tests (P<0.05). 
 
13. POTENTIAL CONTINGENCY PLANS  
 
There may be slower than expected enrollment in the study, thus we plan to seek approval to 
advertise in all practices delivering at LPCH. We plan to recruit additional research staff support 
to assist in recruitment in the case of slower than expected enrollment.