Mifepristone Induction for Fetal Demise, a Randomized Control Trial
Phase: PHASE4
Conditions: Intrauterine Fetal Demise, Fetal Death
Sponsor: Montefiore Medical Center

 
 
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Mifepristone Induction forFetal Demise 
(MIFD) 
 
A Randomized Control Trial 
 
Final Study and Analysis Protocol 
 
 
Principal Investigator JessicaAtrio, MD MSc 
Co-Investigator Nerys Benfield MD 
Saila Moni MD 
Faina Gelman MD 
 
 
 
 
Funded by the Department of Family Planning 
Department of Obstetrics & Gynecology  
Montefiore Medical Center  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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I Introduction 
 
1.1 Background 
The diagnosis of an intrauterine fetal demise is in itself a challenging moment. A patient can tell, 
almost immediately, that something is gravely wrong as the medical team is working to confirm the 
diagnosis and gather more information. Once diagnosed, a provider’s goals are two-fold: first to provide 
appropriate emotional grievance support to the patient and her family; the second is to deliver the fetus in 
the safest and most expeditious matter [1, 2].  
 
Current methods applied to the management of a late second and third trimester fetal demise 
incorporate similar techniques and pharmaceuticals that are utilized for the induction of a term viable 
pregnancy such as prostaglandin analogues, dilute oxytocin, mechanical cervical dilation with foley 
balloon, and amniotomy [3]. Despite the need for a safe and swift delivery, there have been few 
innovations that focus on the delivery of a non-viable fetus or practices that see to enhance the standard 
management of these patients over the last several decades [4, 5].  New research involving mifepristone 
has shown to be a promising addition to third trimester labor augmentation [6].  
 
Mifepristone is a progesterone receptor modulator that is currently recommended by ACOG for 
use in management of first and second trimester medical abortions [27, 28]. Numerous publications have 
demonstrated the safety of this competitive progesterone receptor antagonist when utilized to induce labor 
in the second trimester or for cervical ripening and preparation prior to surgical dilation and evacuation[7-
9]. The use of mifepristone, in addition to misoprostol, in second trimester medical abortions has shown 
that the addition of mifepristone decreases time to completion of abortion by 8 hours compared to 
misoprostol alone (p<0.01) [26].   Mifepristone has been shown to augment the effects of misoprostol not 
only in the first and second trimesters, but in the third trimester as well [26].  
 
A recent study in India randomized women at a gestational age of 28weeks and greater, with 
diagnosed intrauterine fetal demise, to either receiving 200mg of mifepristone 24hours prior to initiation 
of induction with 100mcg of misoprostol every 4 hours or to receiving the misoprostol induction regimen 
alone. Results showed that induction to delivery in the combination group was 6.54 hours shorter than in 
the misoprostol group (p<0.001) and that significantly fewer doses of misoprostol were required for 
delivery completion in the combination group [30].  
 
The delayed dosage intervals of >24 hours between mifepristone and misoprostol in previous publications 
does not reflect the care implemented at most United States hospitals [6, 13].  At the time of diagnosis of 
fetal demise, a woman is typically offered and requests same-day admission to the hospital and definitive 
management via an induction of labor.  Utilization of mifepristone at the time of admission and initiation 
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of induction has not been studied in a prospective randomized trail. This is clinically relevant for the 
typical and practical management of fetal demise in the late second and third trimester where the standard 
of care in the United States is to ascertain the diagnosis and then implement management during that 
same day or admission. The information gained from physical exam and ultrasound are rarely able to 
identify exactly at what point in time thefetal death had occurred.  However, ultrasound is a powerful and 
specific diagnostic tool, which can assure the veracity of the diagnosis when made.  Women are 
offeredinduction of labor at the time of diagnosis to minimize their suffering, and mitigate potential 
complications such as: coagulopathy, sepsis, and hemorrhage [22].  
 
In July of 2015, the CDC released the most updated statistical report on fetal and perinatal 
mortality.  There were 23,595 documented fetal deaths in the year 2013, gestational age 20weeks and 
greater. Minority and marginalized women are disproportionately affected; with 
blackwomencomprising26% and Hispanic women comprising20% of the reported cases [34]. Our Bronx 
population includes these vulnerable populations, who stand to gain the most from evidence based 
protocols and improvements in the management of fetal demise.  The community surrounding our 
Montefiore Weilerand Wakefield labor and delivery is identified as 45.3% Black and 58.4% Hispanic by 
US Census data [35]. Safely shortening the length of labor induction can greatly benefit the emotional and 
medical safety of our patients.  A prolonged induction puts a woman at increased risk for:coagulopathy, 
sepsis, hemorrhage, and complications that require surgical intervention [22]. Mifepristone has a well-
tested and known safety profile and has been proven to optimizethe effects of misoprostol, which is the 
standard medication for induction of labor in the setting of fetal demise [6].  
 
 
1.2 Hypothesis: 
The addition of mifepristone, when compared to placebo, to the standard accepted methods of induction 
of laborwill expedite time to delivery of the fetus in womenwith intra-uterine fetal demise at 20 weeks 
gestational age and greater. 
 
1.3 Objectives: 
1. To compare time to delivery of fetus after administration of mifepristone or placebo at the onset of 
labor induction. 
2. To calculate the duration of induction and hospitalization time among the two groups including time to 
delivery of placenta, duration of time on labor and delivery, time as an inpatient, and number of nights in 
the hospital.  
3.  To determine the number of women, in each arm of the study, who require surgical interventions due 
to a failed induction or retained products of conception. 
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4. To determine if administration of mifepristone augments misoprostol, oxytocin and mechanical 
cervical dilation. 
5. To explore the overall incidence of complications and their association with mifepristone use, such as 
febrile morbidity, infection requiring antibiotics, or transfusion. 
6. To assess whether simultaneous start of induction of labor with misoprostol after mifepristone 
administration versus subsequent administration or delays in the administration of misoprostol after 
mifepristone administration makes a difference in the time to delivery of the fetus and to assess the 
optimal lag time between the two medications.   
 
1.4 Expected Outcomes: 
 
It is expected that the addition of mifepristone will allow for more an expeditious delivery of the 
fetus among women who present with fetal demise greater than 20 weeks gestation age.  It is the intention 
of the researchers that our results will be submitted for internal quality improvement assessment, 
scientific meeting presentation and peer review publication.  We hope to impact our institutional practice 
as well as regional and national guidelines regarding the management of second and third trimester fetal 
demise.   
 
 
II Study Design  
 
2.1 Proposed Protocol: 
 
We propose a double blinded, randomized, placebo-controlled clinical trial at the time of initiation of 
induction of labor for fetal demise at 20 weeks gestational age or greater. 
1. Diagnose fetal demise: confirm absence of fetal heart motion by attending physician as per the 
institutional standards and protocols.  
2. Confirm gestational age at presentation to labor and delivery based on available medical records 
and/or ultrasonography as per standard practice and institutional protocols.  
3. Based on inclusion and exclusion criteria potential participants will be informed about the 
research, offered the opportunity to contribute, and trained research staff will complete the 
informed consent process.  After documentation of consent and discussion of the research as 
indicated the participants will be randomized to the intervention or control arm.  Both groups will 
receive emotional and physical support with induction of labor as per practice guidelines and 
standard of care by Montefiore physicians, faculty and staff irrespective of participation or 
assignment. 
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4. Interventional Arm: Ingest 200mg tab of mifepristone orally.  This will coincide with or be 
implemented prior to the initiation of the induction of labor plan as delineated by the attending 
physician.  The timing will be sensitive to the needs of the participant and the labor and delivery 
room staff.  
5. Control Arm: Ingest a placebo tab orally with similar physical properties.  This will coincide with 
or be implemented prior to the initiation of the induction of labor plan as delineated by the 
attending physician.  The timing will be sensitive to the needs of the participant and the labor and 
delivery room staff.  
6. Montefiore protocol for induction of labor:  
a. 12w0d-23w6d: Misoprostol 400 micrograms vaginally every 3 hours for 5 doses.  
b. 24w0d-28w6d: Misoprostol 400micrograms vaginally every 6 hours for 5 doses. 
c. 29w0d and older: Misoprostol 25-50mcg vaginally every 4 hours for 4 doses OR 100mcg 
vaginally every 12 hours for 4 doses.   
d. Induction methods and protocols will be at the discretion of the physician team and 
tailored to the clinical context. 
7. Data: Patient data will be collected by the Labor and Delivery staff via electronic medical record 
or paper record that will be scanned into the electronic medical record. The investigators will use 
data abstraction tools to collect information such astime of medication administration, 
medications administered, time of delivery of fetus,duration of admittance to labor and delivery, 
and postpartum course, or complications from the electronic medical record.  
 
2.2 Definitions: 
1. Intrauterine Demise: Absence of fetal heart motion on bedside ultrasound; confirmed by two 
separate providers and the attending physician. 
2. Mifepristone: A19-nor-steroid derivative of norethindrone that competitively binds to 
progesterone and glucocorticoid receptors, with antagonist effect. Mifepristone administration is 
the standard of care when providing medical management for first and second trimester 
terminations/abortions as per the American Congress of Obstetricians and Gynecologists. 
3. Induction of Labor: The use of medications and other techniques to induce contractions and 
cervical change with the goal of effecting delivery and evacuation of all uterine contents. 
 
2.3 Protocol Amendments: 
 
 
All amendments to the protocol by the primary research team will be delineated on handouts and 
distributed at participating Labor and Delivery Units at 8AM the following day. The same information 
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will be electronically mailed to resident physicians, attending physicians, physician assistants and nurse 
managers currently staffing the participating Labor and Delivery units.  
 
III Drug Information 
 
3.1 Study Drug Information 
Mifepristone is a 19-nor-steroid derivative of norethindrone that competitively binds to 
progesterone and glucocorticoid receptors, with antagonist effect.  The majority of the drug is absorbed 
through the gut (70%), it then undergoes demethylation and hydroxylation in P-450 microenzyme 
systems, namely CYP3A4 [18].  Subsequent monodemethylated, didemethylated and hydroxylated 
metabolites all maintain significant receptor activity[19].  Mifepristone and its metabolites are bound to 
alpha 1 acid glycoprotein in serum (AAG); saturation is reached with 100 mg of mifepristone. Peak 
plasma concentrations are reached within 1-2 hours of ingestion, with rapid distribution, alpha half-life of 
1.4 hours, and a long beta half-life, elimination time of 20-30 hours [18].  Dosage regimens of 200 mg or 
more quickly saturate AAG and with the elaboration of metabolites nonlinear pharmacokinetics results in 
a large pool of biologically active substrates [19].   The physiologic effects of mifepristone include 
decidual detachment, necrosis, capillary regression, cervical softening and potentiation of myometrial 
contractions through the loss of progesterone’s inhibitory effects [20].  This profile lends compelling 
support that mifepristone can confer tissue changes and procedural benefit within hours of 
administration.Of note, since Mifepristone is mainly metabolized by microenzyme CP3A4, the study will 
thoroughly review patients’ medications/substances that may have the potential to induce/inhibit this 
enzyme. The safety and toxicity profiles of mifepristone are excellent.  The FDA approved regimens for 
medication abortion in the US includes a dose of 800 mg and does not require any consideration or 
contraindication for women who are taking cytochrome inducing or inhibiting agents.  It is not anticipated 
that many young, pregnant patients will be on such drugs; however, if a significant difference of patients’ 
intake of such medications is noticed among the study arm compared to the control arm, the analysis of 
the outcomes will take that into account as a possible confounder, ie. exclude such patients in sub-analysis 
or control for this as a confounder.      
 
The American Congress of Obstetricians and Gynecologists recommends the use of mifepristone 
in the management of labor induction for a woman with a first or second trimester fetal demise [27,28]. 
Clinical trials have proven mifepristone to be effective for cervical ripening for labor induction, 
shortening operative time in dilation and curettage procedures, decreasing length of completion of 
induced abortions, and augmenting the effects of misoprostol [26, 30-33].  These effects of mifepristone 
have not yet been studied in a real-time practical management of second and third trimester fetal demise. 
There is a dearth of information on how quickly the mifepristone augments the effects of cervidil, 
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oxytocin, and mechanical cervical dilation – all methods currently known to be safe and effective in 
augmentation of late second and third trimester fetal demise in medical institutions. The following 
proposed study will investigate if administration of mifepristone at the time of induction of labor will 
expedite delivery of a demised fetus.  This finding would be a significant improvement to the existing 
management of fetal demise and a compelling surrogate for the potential morbidity associated with a 
protracted or failed induction of labor.  
 
3.2 Study Drug Side Effects 
The side effects of misoprostol are similar to those one would experience during a labor course: 
bleeding, abdominal cramping, diarrhea, nausea, vomiting, headache, dizziness, back pain, and tiredness. 
Any drug can cause an allergic reaction, which could be mild or more serious and can even result in 
death. Common symptoms of an allergic reaction are rash, itching, skin problems, swelling of the face 
and throat or trouble breathing.  
 
IV Participant Selection 
4.1 Recruitment 
Patients will be recruited at the time of admission to the Labor and Delivery units at the Montefiore 
Hospitals – Einstein Campus at Weiler and Montefiore North, at which there are approximately 60 and 
30, respectively, fetal demises diagnosed annually. Firstly the diagnosis of fetal death will be ascertained 
as per the standards of the unit by the attending physician.  The medical team will counsel the patient on 
the induction of labor plan.  Based on inclusion and exclusion criteria potential participants will be 
informed about the research, offered the opportunity to voluntarily contribute, and trained research staff 
will complete the informed consent process.The timing of consent will be sensitive to the needs of the 
participant. The research and therefore voluntary aspect of care will be clearly delineated.  After 
documentation of consent and discussion of the research as indicated the participants will be randomized 
to the intervention or control arm.  Both groups will receive emotional and physical support with 
induction of labor as per practice guidelines and standard of care by Montefiore physicians, faculty and 
staff irrespective of participation or assignment. 
Patients in the interventional arm will ingest 200mg tab of mifepristone orally.  This will coincide with or 
be implemented prior to the initiation of the induction of labor plan as delineated by the attending 
physician.  The timing will be sensitive to the needs of the participant and the labor and delivery room 
staff.  
Similarly, patients in the control arm will ingest a placebo tab orally with similar physical properties 
without the active ingredient.  This will coincide with or beimplemented prior to the initiation of the 
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induction of labor plan as delineated by the attending physician.  The timing will be sensitive to the needs 
of the participant and the labor and delivery room staff.  
In an effort to optimize recruitment, participation and the diversity of the participants, no parental 
consent will be obtained. This is consistent with other research that involves youth and addresses 
reproductive health needs, with the goal of protecting privacy and eliminating a potential sampling 
bias (Martinez-Garcia 2014, Reed 2008). The National Commission for the Protection of Human 
Subjects of Biomedical and Behavioral Research and the Society of Adolescent Medicine have 
advised that parental consent can be waived for minimal risk research that involves care that is 
legally rendered in the state (reproductive health services) and it is difficult to obtain parental 
consent (National Commission 1997, Santelli 2003).  Pregnant teens are emancipated in New York 
State and are often faced with socially complex and unstable home environments (Alperen 2013, 
Malee 2013). They may not have a guardian who accompanies them to their clinic visits or 
accompany is present with them in the hospital during the admission for management of fetal 
demise. 
4.2 Inclusion Criteria 
1. Women ages 16-50 
2. Women whose primary language is English 
3. Intrauterine fetal death as confirmed by absence of cardiac motion on ultrasound by 
Attending physician at the time of admission to the hospital. 
4. Estimated gestational age greater than 20 weeks  
5. Hemodynamically stable 
6. Women with one prior low transverse cesarean delivery 
 
4.3 Exclusion Criteria  
1. History of 2 or more low transverse cesarean deliveries 
2. Prior classical cesarean delivery 
3. History of abdominal myomectomy   
4. Known or suspected allergic reaction to mifepristone  
5. Known or suspected adrenal gland disease 
6. Known or suspected bleeding diatheses or coagulopathies   
7. Known or suspected use of QTc-prolonging medication  
8. Known maternal medical or physical conditions that prohibits vaginal delivery  
9. Patients in active labor, with cervical dilation greater than 6 cm. 
 
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4.4 Participant Timeline 
1. The patient receives a diagnosis of intrauterine fetal demise at 20 weeks gestational age or 
greater. 
2. Patient must meet inclusion and exclusion criteria of study. 
3. Patient verbally consents to the delivery plan and is a candidate for induction at a Montefiore 
labor and delivery (Wakefield or Weiler-Einstien Hospitals). 
4. Participants will be informed about the research, offered the opportunity to contribute, and trained 
research staff will complete the informed consent process.   
5. After documentation of consent and discussion of the research as indicated the participants will 
be randomized to the intervention or control arm.  Both groups will receive emotional and 
physical support with induction of labor as per practice guidelines and standard of care by 
Montefiore physicians, faculty and staff irrespective of participation or assignment. 
6.  With prior assignment based on the randomization scheme medications will be maintained in 
secure medical dispensing equipment consistent with Montefiore standards (labor and delivery Pyxis 
will be used).  Medications will be individually placed in sequentially numbered, sealed opaque 
containers.   Research team will source and dispense medication to participants. 
6. Patient’s labor course is routinely monitored and documented in EMR by all participating 
providers. 
 
V Randomization  
Allocation methods will be variable block randomization (blocks of 2&6, by computer generated random 
number sequence.  Best practices will be implemented to assure the maintenance of randomization and 
blinding.  The randomization scheme will be kept at a separate secure research site and researchers will 
not have access to this scheme until the analysis phase, following completion of the data collection 
process and enrollment.  The Montefiore research pharmacy will be involved in the storage, packaging, 
monitoring and utilization of both placebo and study medications.  The placebo and study medications 
will be maintained in secure medical dispensing equipment consistent with Montefiore standards (labor 
and delivery Pyxis).  Medications will be individually placed in sequentially numbered, sealed opaque 
containerswith a unique participant identifier that will correspond with the patient identifier the 
participant receives upon enrollment.  Participants, research staff, and the data collection and analysis 
teamswill be blinded to contents of each pill. The mifepristone and placebo tablets will be obtained from 
Danco pharmacies where the placebo has been specifically developed to have similar physical properties 
to the mifepristone tablet. 
 
 
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VI Data Collection 
The hospital staff will maintain medical records as per standard of care.   The research team will assigna 
unique numerical participant identifier with enrollment and allocation of participants.  As previously 
mentioned this identifier will correspond with the information on the sealed medication envelop.  Case 
report forms (CRF) will capture relevant data such as: medication administration time points, clinical 
events and secondary outcomes.  Nursing, pharmacy and medical records will be reviewed to assure 
accuracy and completeness.   Data proofing and collection will be completed by persons blinded to 
treatment assignment.  Intake measures will include: age, socio-economic status, gestational age, method 
of attainment of gestational age, insurance, gravidity and parity, previous cesarean deliveries, medical 
history, most recent hemoglobin and hematocrit.  Admission data will include cervical exam, membrane 
intact or rupture status, and vital signs.  Secondary outcomes, additional interventions, and adverse events 
will be captured on the CRF.  Due to the fact that participants will be inpatient for the duration of their 
induction and post-partum course, we do not anticipate any significant withdrawals, deviations or 
incomplete data sets.   Patient identifiers will be secured in locked and protected environments.  The CRF 
and abstracted data will not have any patient identifiers. 
 
VII Statistical Guidelines 
7.1 Sample Size:  
 
Based on a review of the literature, institutional charts and clinician experience, the mean time to 
delivery of fetus is projected to be 24 hours with a standard deviation of 6 hours.  To detect a change in 4 
hours, with a two-sided alpha of 0.05 and power of 0.8: 37 persons would be needed in each group for a 
total of 74 persons enrolled in the study.The effect of 4-hour reduction is chosen because it is considered 
a clinically significant reduction. 
 
7.2 Analysis: 
 
An intention to treat analysis will be completed.  Two sample t-test and Wilcoxon rank sum test 
will be calculated for the primary outcome of time to delivery of fetus. Other secondary outcomes will be 
described with descriptive statistics and compared with ANOVA or Chi square analysis.  
 
VIII Ethical Consideration 
8.1 Confidentiality:  
 
The participants, providers, and research team will all be blinded for the duration of the study. 
The patients’ medical information is protected under HIPAA, therefore only staff directly involved in the 
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patients’ care and the primary research team will access the participants’ medical records. All personal 
identify information will be removed from CRF.  A unique participant identifier will be utilized for all 
data collection and analysis.  In a separate locked and secured location the consent forms will be secured 
with a log of participants enrolled in the research.  
 
8.2 Dissemination Policy:  
 
Data collected during the study by labor and delivery team is confidential and protected by 
HIPPA. Abstracted data without patient identifier will be entered into CRF. The data will then be 
analyzed and reported. 
 
8.3Declaration of Interest:  
 
The investigatorshave nothing to declare. Our purpose is to enrich the current body of knowledge 
on induction of labor for an intrauterine fetal demise in the second and third trimester.  
 
8.4 Potential Benefits: 
If Mifepristone expedites the delivery of the demised fetus, women in the control of the arm of the study 
will benefit tremendously from participating in the study as their induction will be shorter. This outcome 
has important consequences as it will avoid secondary complications from long inductions such as 
maternal infections and surgery. Additionally, a quicker induction time may ameliorate the emotional 
suffering of the patients.  
 
8.5Adverse Event and Safety Monitoring Board: 
 
A safety monitoring board will be identified consisting of two clinician scientists who are 
familiar with scope of clinical practice but are not directly involved in the research.  These 
physicians will review adverse events and work closely with the principle investigator and research 
team to assure that safety and reporting standards are maintained at a high level.  The principle 
investigator will also actively review all outcomes for the patients throughout the course of the 
study, and will remained blinded to their treatment.Data will be abstracted within 72 hours of 
enrollment from the electronic medical record onto case report forms for the majority of 
participants.  Timing regarding abstraction of serious adverse events onto case report forms is 
delineated below.  The PI will review all CRFs and cross check to the medical record for accuracy 
every 6 weeks.  There will be quarterly communications between the PI and monitoring board 
regarding adverse events and a written annual reports of these communications will be compiled 
regarding the review and assessments by the monitoring board.  The PI and research team will 
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convene weekly for the first few months and then monthly thereafter to assure that the application 
of the protocol, recruitment and data collection practices are all in compliance.  All adverse event 
and case report forms will be available to the monitoring board, and reports of this information will  
 
An adverse event is any symptoms, sign, illness or experience that develops or worsens in 
severity during the course of the study.  A number of adverse events are expected in the course of the 
management of fetal demise and induction of labor including, painand bleeding.  Information as noted in 
the medical records will be abstracted in the CRF and compiled as secondary outcomes.  Events that are 
determined to be both unexpected and related to the study medication will be entered into the CRF as well 
as a separate adverse event form.  All serious adverse events will be reviewed by the PI, data safety 
monitoring board and submitted to the IRB within 48 hours.  Other adverse events will be reviewed by 
the PI, data safety monitoring board, and submitted within one week.  Events that meet International 
Conference on Harmonization (ICH) criteria for a serious adverse event include volunteers who 
experience any of the following during the course of their enrollment: death, life-threatening event, 
inpatient hospitalization or prolongation of existing hospitalization, occurrence that results in persistent or 
significant disability in capacity, congenital anomaly/birth defect, or other important medical event (may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the events listed above).An important medical event is one that 
may not be immediately life threatening, but is clearly of major medical significance. It may jeopardize 
the subject, and may require intervention to prevent one of the other serious outcomes noted above. All 
serious adverse events will be reviewed by the PI, regardless of causality assessment. Serious adverse 
events will be reported to Montefiore Medical Center, the FDA, and Danco Laboratories, Inc.   All 
information related to data and adverse events will be monitored by the principle investigator, Jessica 
Atrio.   
 
 
XI Consent 
 Following diagnosis, counseling and support patients will be offered the opportunity to go through the 
informed consent. Physician researchers will be sensitive to the context for some women this may be a 
relatively short interval (closer to 30 minutes) and for others who need time to process the diagnosis with 
family and in consultation with other persons they may be offered participation after a more lengthy 
counseling process (closer to several hours). Women will be approached during their admission for their 
induction while in the obstetric triage area or in labor and delivery. Standard of care will be maintained. 
When women are given this diagnosis, the standard recommendation is to admit to the hospital for 
induciton of labor. All physician researchers will respect the emotional needs of women and will offer 
participation and informed consent after women have received counseling and support. 
 
 
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IRB NUMBER: 2015-5689
IRB APPROVAL DATE: 02/11/2016