Simultaneous Mifepristone and Misoprostol Versus Misoprostol Alone for Induction of Labor of Nonviable Second Trimester Pregnancy: a Pilot Randomized Controlled Trial
Phase: PHASE4
Conditions: Abortion, Second Trimester, PPROM, Rupture, Spontaneous, Fetal Demise, Fetal Death, Fetal Demise From Miscarriage, Fetal Death Before 22 Weeks With Retention of Dead Fetus, Pregnancy Loss, Pregnancy Complications
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
______________________________________________________________________________________ 
 
1 
 
 
Simultaneous 
mifepristone 
and 
misoprostol 
versus misoprostol alone for induction of labor of 
nonviable second trimester pregnancy (MIST):  
a Pilot Randomized Controlled Trial  
 
 
 
Principal Investigator:   
Katherine Bligard, MD MA 
 
 
 
 
 
 
Version Date/Number:  
2/22/2022, Version 3  
 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
2 
TABLE OF CONTENTS 
Introduction 
 
 
 
 
 
 
 
 
3 
 
Study Abstract 
 
 
 
 
 
 
 
3 
 
Primary Hypothesis 
 
 
 
 
 
 
 
3 
 
Background 
 
 
 
 
 
 
 
 
4 
 
Prior Literature and Studies  
 
 
 
 
 
4 
 
Rationale for this Study 
 
 
 
 
 
 
4 
 
Study Objectives  
 
 
 
 
 
 
 
4 
 
Primary Aim 
 
 
 
 
 
 
 
 
4 
 
Secondary Aim 
 
 
 
 
 
 
 
4 
 
 
Rationale for the Selection of Outcome Measures  
 
 
5 
 
Study Design  
 
 
 
 
 
 
 
 
5 
 
Overview 
 
 
 
 
 
 
 
 
5 
 
Subject Selection and Withdrawal 
 
 
 
 
 
5 
 
Study Drug 
 
 
 
 
 
 
 
 
8 
 
Study Procedures  
 
 
 
 
 
 
 
8 
 
Screening for Eligibility 
 
 
 
 
 
 
8 
 
Safety and Adverse Events  
 
 
 
 
 
9 
 
Study Outcome Measurements 
 
 
 
 
 
10 
 
Statistical Plan 
 
 
 
 
 
 
 
 
10 
 
Sample Size Determination and Power 
 
 
 
 
10 
 
Analysis Plan and Statistical Methods 
 
 
 
 
11 
 
Study Timeline 
 
 
 
 
 
 
 
 
11 
 
References  
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
3 
A Introduction 
 
A1 Study Abstract 
Up to 3% of pregnancies in the second trimester are nonviable and require delivery due 
to myriad complications including stillbirth, preterm prelabor rupture of membranes 
(PPROM) at a previable gestational age, fetal anomalies, or risk to maternal life. Stillbirth 
complicates in 1 in 160 deliveries, with over half of these occurring in the second 
trimester.1-3 Additionally, the rate of preterm previable PPROM is estimated to complicate 
up to 1% of all pregnancies.4,5 The rate of neonatal survival after previable PPROM after 
expectant management is reported to be as low as 20% due to complications from 
premature delivery, inadequate fetal lung development, and infectious complications. On 
the other hand, pregnancy continuation in the setting of previable PPROM increases 
maternal risk of bleeding, infection, sepsis, and even death. Most fetal anomalies including 
those that are lethal or associated with severe morbidity are diagnosed after 20 weeks’ 
gestation which is the standard time for the ultrasound assessment of fetal anatomy. 
Lastly, at any time in pregnancy maternal medical complications can arise or worsen that 
make continuation of pregnancy contraindicated due to threat to maternal life.6 Patients in 
these and other complex situations are counseled on options for the pregnancy, and many 
make the decision to proceed with induction of labor with the understanding that the fetus 
will not survive to hospital discharge.  
 
The standard of care for labor induction of a nonviable second trimester pregnancy is the 
use of misoprostol.3 However, mifepristone’s adjunctive use to shorter time to delivery in 
the second trimester has become a topic of interest. Mifepristone, also known as RU-486, 
is a well-tolerated competitive progesterone receptor antagonist. Data has demonstrated 
the safety and efficacy of mifepristone administration followed by misoprostol 1-2 days 
later in medical management of first-trimester pregnancy loss and in first-trimester 
medication abortion.7,8 Newer data suggests that mifepristone administration prior to labor 
induction with misoprostol in nonviable pregnancies decreases total time in labor, with 
optimal time interval between mifepristone and misoprostol administration thought to be 
24-48 hours.9-11 However, when considering the time from first medication administration 
to delivery, the time is longer in those patients receiving mifepristone, owing to the delay 
from mifepristone administration to induction of labor. A retrospective review of our 
patients undergoing induction of labor for nonviable second trimester pregnancies from 
2018 to 2021 revealed an average length of time from first medication administration to 
placental delivery of 13.8 hours in patients receiving misoprostol alone, compared to 43.3 
hours in those receiving mifepristone at least 24 hours prior to induction of labor (p<0.01). 
In the setting of many second trimester pregnancies requiring delivery, shortening the time 
from diagnosis of pregnancy complication and initiation of labor induction to delivery is of 
utmost importance to decrease the risk of maternal morbidity with a continuing pregnancy. 
Currently, given need to expedite delivery, these patients are generally induced with 
misoprostol without adjunctive mifepristone as mifepristone’s effectiveness given 
concurrently with labor induction is unknown. However, pharmacokinetic studies of 
mifepristone demonstrate that peak concentrations are reached within 60-120 minutes 
and remain elevated for at least 48 hours, thus it is reasonable to suspect that mifepristone 
administered at the initiation of labor induction could offer some benefit to patients needing 
urgent delivery.12,13 Thus, we propose a randomized controlled trial investigating the utility 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
4 
of simultaneous mifepristone administration at the time of complicated nonviable labor 
induction with misoprostol in the second trimester. 
 
A2 Primary Hypothesis 
We hypothesize that using simultaneous mifepristone and misoprostol for labor induction 
during the second trimester for nonviable pregnancies will result in higher rates of delivery 
within 12 hours compared to using misoprostol alone and result in lower rates of maternal 
complications. 
 
B Background 
 
B1 Prior Literature and Studies 
Multiple studies published recently have demonstrated that mifepristone administration 
prior to induction of labor in the second trimester decreases time in labor, especially when 
given at least 24 hours prior to labor induction.9,14 However, the total time from first 
medication administration (mifepristone or misoprostol if mifepristone not given) to delivery 
is longer in the mifepristone group, owing to the delay between mifepristone administration 
and initiation of labor. The shortest time interval between mifepristone and misoprostol 
administration that has been studied is 6 hours.15 In this case, mifepristone still appeared 
to have a positive effect on time to delivery. However, this study was performed in first 
trimester abortions so it’s applicability to nonviable second trimester pregnancies is 
uncertain. 
 
A recent retrospective study reported on the time to delivery with same-day mifepristone 
and misoprostol compared to misoprostol alone and found that mifepristone use was 
associated with shorter labor times.16 However, the same-day mifepristone group included 
women who received mifepristone up to 11 hours prior to misoprostol. Another 
retrospective study evaluated time to delivery in second trimester labor induction 
termination with mifepristone administered <12h prior to labor induction compared to those 
receiving mifepristone 12-24h before induction and those receiving mifepristone 24-48h 
before induction.17 This cohort demonstrated shorter total abortion time and similar 
induction time in all groups. There was a statistically higher rate for need for intervention 
for retained placenta in the 12-24h group, compared to the <12h and 24-48h group and a 
trend towards increased risk of chorioamnionitis in the 24-48h group. These studies clearly 
suggest a potential benefit for mifepristone at shorter intervals than 24h but cannot 
comment on simultaneous administration, and given the retrospective nature of these 
studies each group may represent different clinical scenarios. Thus, this data to is limited 
in its ability to guide patient care. 
 
On the other hand, a randomized controlled trial demonstrated no impact on cervical 
dilation 4-6 hours after simultaneous mifepristone and misoprostol compared to 
misoprostol alone in women undergoing cervical preparation prior to second trimester 
dilation and evacuation. However, as these patients underwent dilation and evacuation, 
this study was unable to comment on whether mifepristone would affect time to delivery 
in those undergoing labor induction in the second trimester.18   
 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
5 
This will be the first RCT to our knowledge to compare simultaneous mifepristone and 
misoprostol to misoprostol alone in nonviable second trimester pregnancies. 
 
B2 Rationale for this Study 
When time allows, administration of mifepristone prior to second trimester induction of 
labor decreases total labor time. However, in the setting of many pregnancy complications, 
decreasing time from diagnosis of nonviable pregnancy to delivery is of utmost importance 
to decrease risk of maternal complications. Previous data has shown that total abortion 
time is longer in the group receiving mifepristone owing to the delay between mifepristone 
administration and initiation of misoprostol induction of labor. Thus, we aim to investigate 
whether simultaneous mifepristone and misoprostol has benefits over misoprostol alone 
when labor induction of a nonviable second trimester cannot be delayed. 
C Study Objectives 
 
C1 Primary Aim:  
Compare the rate of delivery within 12 hours between those receiving simultaneous 
mifepristone and misoprostol versus misoprostol alone for labor induction during the 
second trimester for nonviable pregnancies. 
 
C2 Secondary Aim:  
Compare the rate of delivery complications between those receiving simultaneous 
mifepristone and misoprostol versus misoprostol alone for labor induction during the 
second trimester for nonviable pregnancies. Delivery complications of interest will 
include failed induction of labor (failure of fetal delivery vaginally), retained placenta, 
clinical chorioamnionitis, and postpartum hemorrhage.  
 
C3 Rationale for the Selection of Outcome Measures  
Rate of delivery within 12 hours was selected as the primary outcome because the main 
intention of mifepristone is to shorten time from pregnancy complication diagnosis to 
delivery and the current average time to delivery is 13.8 hours in our population. 
Shortening this interval will hopefully decrease the risk of complications associated with 
pregnancy continuation in the setting of nonviable second trimester pregnancy.  
 
In Aim 2, we will assess the risk of maternal morbidity associated with the intervention as 
the hope to decrease time to delivery is to decrease maternal morbidity. 
 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
6 
D Study Design  
 
D1 Overview or Design Summary 
This is a randomized controlled trial comparing simultaneous mifepristone and misoprostol 
administration to misoprostol alone for induction of labor for a nonviable second trimester 
pregnancy.  
 
D2 Subject Selection and Withdrawal  
 
2.a 
Inclusion Criteria  
Pregnant patients aged 18 years or old admitted to labor and delivery between 14 and 28 
weeks’ gestation undergoing induction of labor of a singleton nonviable fetus, i.e. fetal 
demise or abortion of nonviable fetus. Patients must be eligible for mifepristone 
administration.   
2.b  Exclusion Criteria  
Patients less than 18 years of age, medical contraindication to mifepristone, patients 
undergoing second trimester abortion without an indication to waive Missouri 72 hour 
waiting period, patients undergoing surgical termination of nonviable pregnancy via 
dilation and curettage or dilation and evacuation, patients undergoing induction of labor 
with a viable fetus or with plans to consider neonatal resuscitation after delivery, patients 
undergoing induction of labor with plans to initiate labor induction with any medication, 
device or instrument except misoprostol (i.e. transcervical catheter, oxytocin, 
dinoprostone), patients who decline mifepristone administration, patients with 
contraindication to vaginal delivery of second trimester nonviable fetus (i.e. placenta 
previa, placenta accreta spectrum disorder), patients who elect to wait at least 24 hours 
between mifepristone and misoprostol administration. 
2.c 
Subject Recruitment Plans and Consent Process 
All women admitted to Barnes-Jewish Hospital who require second trimester delivery of a 
nonviable fetus will be screened for eligibility criteria and approached by trained research 
staff for informed consent. Prior to being approached by research team, the patient must 
have an assessment by an obstetrician who has completed an approved Ob/Gyn 
residency who is not a study team member. This clinician must confirm that the pregnancy 
is not viable and that delivery is indicated. The obstetrics team will discuss options for 
delivery which may include dilation and evacuation or labor induction. Only those patients 
desiring induction of labor for a nonviable second trimester pregnancy will be approached. 
If the induction of labor meets criteria for an abortion based on Missouri law, the patient 
will not consented for the study until the appropriate abortion consents are completed by 
the patient and qualified healthcare provider. The Missouri law defines an abortion as: (a) 
The act of using or prescribing any instrument, device, medicine, drug, or any other means 
or substance with the intent to destroy the life of an embryo or fetus in his or her mother's 
womb; or (b) The intentional termination of the pregnancy of a mother by using or 
prescribing any instrument, device, medicine, drug, or other means or substance with an 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
7 
intention other than to increase the probability of a live birth or to remove a dead or dying 
unborn child. 
 
Notably, administration of mifepristone for pregnancy termination for any indication does 
require 
the 
patient 
to 
sign 
a 
Patient 
Agreement 
Form 
(https://www.plannedparenthood.org/uploads/filer_public/95/87/9587109f-4848-4ceb-
97f2-369bff70f5b7/mifeptagree-e.pdf). All patients willing to participate in the study will 
need to review this form with their healthcare provider and be willing to sign it if randomized 
to the mifepristone group in order to be eligible for the study. 
 
The study staff will review the informed consent with the patient in a private setting free of 
coercion and undue influence. The study staff are not directly involved in the patient’s 
care. When the study staff believes the patient understands fully about the study, the staff 
will ask the patient if he or she accepts to be enrolled in the study. The patient will be 
notified and made aware that her decision to enroll or decline will not impact her clinical 
care.  If the patient agrees to be in the study: the study staff will obtain the patient’s 
signature and current date on the consent form.  The study staff will sign his or her own 
name on the consent form, and write the current date on the consent form.  A copy of the 
signed consent form will be given to the patient. If the patient does not agree to be in the 
study: The study staff will end the discussion, and thank the patient for her time, the patient 
will not be enrolled in the study, the study staff will emphasize that the patient’s access to 
medical care and/or other services provided will not be affected by her decision whether 
or not to screen for or take part in the study. Furthermore, she will be notified that she has 
the right to withdraw from the study at any point.  
2.e  
Randomization Method and Masking 
After informed consent is obtained, the research team will proceed with randomization. 
Using a computer-generated sequence in variable block sizes, a list of randomized 
assignments will be created and uploaded to REDCap. Patients will be randomized to 
simultaneous administration of mifepristone and misoprostol or misoprostol alone.  
 
Multiple factors make masking this study impossible, most notably the separate patient 
consent required to use mifepristone in pregnancy. Thus, the patient and staff will not be 
blinded to the study group. However, to minimize bias, perinatal data assessors will be 
masked to the allocation of the patients and allocation will be concealed within our 
database. Our research staff is experienced in screening, consenting, and enrolling 
patients with multiple prior large randomized trials at our institution and are well-trained to 
minimize bias in their approaches. 
2.f  
Risks and Benefits 
The proposed study involves potentially rare risks to the subjects, including loss of 
confidential health information and provision of poor feedback to families regarding 
outcome. Mifepristone administration is generally well-tolerated.  The most common side 
effects of mifepristone are all also commonly seen with misoprostol which every patient in 
the study will receive. These include vaginal bleeding, nausea, vomiting, diarrhea, 
dizziness, and fatigue. Severe allergic reaction to mifepristone is exceedingly rare. We 
anticipate minimal additional risks or side effects with the administration of mifepristone. 
 
In the rare event that a patient undergoing termination of pregnancy with a living fetus 
decides to stop her induction of labor with the goal to continue the pregnancy to a point at 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
8 
which the fetus would be viable, there is a risk of fetal anomalies and demise. Both 
misoprostol and mifepristone have been implicated in fetal anomalies when given to a 
continuing pregnancy in the first trimester. The risk is lower in this population as fetal 
organogenesis is complete by the second trimester. More likely is the risk of delivery or 
fetal demise after administration of either medication as these medications are intended 
to end the pregnancy. To decrease the risk of this occurrence, patients will be thoroughly 
counseled by an OB provider and will have decided and consented for termination of 
pregnancy prior to being approached for participation in the study. 
 
The study is not designed to provide direct benefits to research participants. Nonetheless, 
if our hypothesis that simultaneous mifepristone administration at time of misoprostol 
induction of labor reduces the time to delivery is correct, then subjects randomized to 
mifepristone will have the benefits of decreased time in labor and decreased risks 
associated with pregnancy prolongation.  More importantly, results from this study have 
the potential to improve outcomes for women undergoing induction of labor of a nonviable 
second trimester pregnancy. Because the anticipated risk to participants is minimal, the 
risks-benefit ratio is very favorable. 
2.g  Protection Against Risk 
Pre-screening for eligibility criteria via medical record review will be conducted, and 
potential participants will be approached on Labor and Delivery. The study design, 
expectations, and risks/benefits will be explained, and potential subjects will be given a 
written informed consent form by a study team member. Consent will be documented by 
using a signed consent form. Trained study team members will have sufficient time to 
explain the study and the informed consent carefully in a private room, and eligible patients 
may decide to enroll at any time as long as they still meet eligibility criteria.  
 
Informed consent will always be obtained before a subject participates in any component 
of the protocol. For all participants, the consent form will be explained to participants as 
well as having them read the consent themselves. This consent will contain a detailed 
description of all study procedures, as well as any possible risks and/or benefits. Patients 
will be asked to sign the consent form. It will be clearly communicated to the patients 
during the consent process that their decision to participate will not affect their obstetric 
care. A copy of the consent forms will be kept in a locked cabinet in the research office 
and participants will be given a copy of the consent forms for their own records.  
 
Clinical data will be entered into REDCap, a secure, web-based application. Access to the 
data username/password keys is restricted in accordance with our University’s HIPAA 
policy. Data will be anonymized with study identifier only.  
 
Given the particular vulnerability of pregnant patients, especially those potentially pursuing 
a termination of pregnancy, patients will not be approached for this study until the following 
has been confirmed by a residency-trained obstetrician: 
1. Fetus is not viable (intrauterine fetal demise, gestational age less than 22 weeks’ 
gestation, lethal fetal anomalies, etc.) 
2. Delivery is indicated at current gestational age. Indications for delivery will be 
determined by clinician 
3. Patient-desired mode of delivery (dilation and evacuation, labor induction, 
cesarean delivery)  

 
 
 
 
 
 
______________________________________________________________________________________ 
 
9 
4. Appropriate consents of delivery are completed. This includes completion of 
Missouri Termination of Pregnancy consents, if applicable.  
 
Adverse events will be monitored by a data and safety monitoring board (see separate 
section).  
2.h  Withdrawal of Subjects  
Patients or their primary obstetric providers may choose to withdraw their patients at any 
point in the study. The study staff will be notified and all study interventions not yet 
administered will be withdrawn appropriately (or randomization will be held if this decision 
is made prior to randomization). Patients will be notified of this process at the time of 
consent. Notably, while there have been case reports of patients deciding to continue a 
pregnancy after mifepristone or misoprostol administration, these reports are all after 
administration in the first trimester. Data does suggest that both medications are 
associated with increased risk for fetal anomalies; however, as organogenesis is complete 
in all patients we plan to enroll, we feel this risk is less likely. More likely is the risk of 
delivery or fetal demise after administration of either medication as these medications are 
intended to end the pregnancy. To decrease the risk of this occurrence, patients will be 
thoroughly counseled by an OB provider and will have decided and consented for 
termination of pregnancy prior to being approached for participation in the study.  
 
For patients that withdraw after randomization, clinical outcomes will be followed and 
recorded securely. For patients that withdraw before randomization, no clinical data will 
be followed or recorded.  
 
D3 Study Drug  
 
3.a 
Description  
The current standard of care is misoprostol use for nonviable second trimester induction 
of labor; however, recent data suggests that mifepristone administration prior to induction 
decreases time to delivery, but if simultaneous mifepristone administration at time of 
induction of labor offers benefits in patients with a contraindication to delaying induction 
of labor is unclear. Therefore, the intervention being tested is mifepristone given at the 
same time as the first dose of misoprostol for labor induction. There will not be a placebo 
in this trial as it is a pilot study.  
3.b 
Treatment Regimen  
The dose of mifepristone will be 200mg orally. This medication will be given to the patient 
under the direct supervision of the physician that counseled the patient on the use of 
mifepristone and reviewed the Mifepristone Patient Agreement Form with the patient. 
Legally, if this induction of labor is an abortion by Missouri state laws, the mifepristone 
must be administered by the provider who consented the patient for the abortion 
procedure. Immediately after the administration of mifepristone, the patient’s induction of 
labor will be started with misoprostol. The dosing and route of administration of the initial 
misoprostol and the continued labor induction management will be left to the discretion of 
the obstetrician. 
 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
10
Patients randomized to the misoprostol alone group will have their labor induction started 
with misoprostol. The dosing and route of administration of the initial misoprostol and the 
continued labor induction management will be left to the discretion of the obstetrician. 
3.c 
Medication Dispensing and Return  
Patients randomized to the mifepristone study group will have an order for mifepristone 
200mg orally placed in Epic and dispensed by the BJH pharmacy. In the event that the 
medication needs to be returned to the pharmacy, the medication will be returned using 
standard protocols for any medication administered in the hospital. 
 
E Study Procedures  
 
E1 Screening for Eligibility 
 
Study staff will screen potential subjects who are admitted to Labor and Delivery with a 
nonviable second trimester pregnancy against our inclusion/exclusion criteria.  Eligible 
patients will be approached to see if they are interested in learning more about the 
research study.  If a patient declines to learn more, she will be thanked for her time. 
 
E2 Safety and Adverse Events  
2.a 
Safety and Compliance Monitoring 
If subjects have any issues or concerns, or feel as though they were harmed in any way 
they will be instructed to contact the PI or a member of the research team.  Contact 
information will be provided in the informed consent document.   
 
Data and research monitoring will be undertaken annually by the study’s PIs and the 
WUSM IRB.  
 
All maternal adverse events will be reviewed by a data and safety monitoring board 
(DSMB) composed of three individuals with expertise in obstetrics and clinical trials 
(Whitney Ross, MD, Ashley Veade, MD, and Lindsay Kuroki, MD). The DSMB receive a 
report of any severe and/or non-severe adverse neonatal or maternal outcomes within 72 
hours of occurrence.  
 
For confidentiality, only members of the research team will have access to the study 
information.  Subjects will be assigned a unique study ID that will be used.  This data base 
is in REDCap, which is a HIPAA-compliant, encrypted, WU-approved, password protected 
database.  Any hard copies will be maintained in a locked cabinet in a locked office by a 
member of the study team.  Work will only be done on secure WUSTL computers.  
Specimens will be marked with the subject ID and transported securely to the lab by 
research staff.  Specimens will be processed and stored per research protocols.  
 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
11
The PI and study staff will meet monthly to review compliance and protocol adherence. 
Nursing staff are encouraged to communicate openly with the study team with concerns 
regarding the protocol.  
2.b 
Definitions of Adverse Events 
Detailed information concerning reportable adverse events will be collected and evaluated 
throughout the conduct of the protocol (Table 1 a and b). 
 
 
 
The DSMB will review all Adverse Event Reports and other interim safety data and will 
report back to the study PI. The Study PI will then report findings to the IRB. If a participant 
develops a serious adverse event, the safety of continuing the intervention will be 
ascertained by the participant’s obstetric care provider.  
2.c 
Adverse Event Reporting Period 
Adverse events will be reported to the DSMB and PI within 72 hours.  
 
E3 Study Outcome Measurements  
 
Aim 1: Primary Outcome: Completion of delivery (including placenta) within 12 hours. 
Secondary Outcome: Completion of delivery (including placenta) within 18 and 24 hours, 
time to delivery of placenta, time to delivery of fetus 
 
Aim 2: Primary Outcome: Composite obstetric morbidity score of failed induction of labor 
(failure of fetal vaginal delivery), postpartum hemorrhage, chorioamnionitis, and retained 
placenta.   
Secondary Outcomes: Estimated/quantitative blood loss, total dose of misoprostol, 
hospital 
length 
of 
stay, 
need 
for 
surgical 
procedure, 
use 
of 
other 
Table 1a: Adverse events (Less likely/less common)  
Adverse Event 
Definition 
Severe 
postpartum 
hemorrhage 
Estimated blood loss >1000ml for vaginal delivery and >2000ml 
for cesarean 
Failed induction of labor 
Need for cesarean delivery, dilation and curettage, or dilation 
and evacuation for fetus and placenta 
Table 1b: Serious adverse events (Rare)  
Serious adverse event 
Definition 
Maternal 
Maternal death 
Any maternal death  
Life-threatening 
maternal 
event 
Life threatening events in the mother are defined as those that 
in the view of the research staff and PI put the individual patient 
at imminent substantial risk of dying, or if continued participation 
in the study might have resulted in death 
Maternal admission to the 
intensive care unit 
Maternal admission to the intensive care unit for any indication 
Unplanned hysterectomy 
Unplanned hysterectomy performed during cesarean or 
following a vaginal delivery 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
12
medications/instruments/devices for labor induction/augmentation, readmission of 
pregnancy complication within 30 days of delivery 
 
These outcomes will assessed by review of electronic medical records by trained study 
staff.  
 
F Statistical Plan  
 
F1  Sample Size Determination and Power 
As this is a pilot trial to assess feasibility of a larger scale trial, we plan to enroll 30 patients 
(15 mifepristone/misoprostol and 15 misoprostol alone). Assuming a 34.0% delivery 
rate within 12 hours with misoprostol alone,16 we will be powered to detect an increase to 
82.0% delivery rate within 12 hours with a power of 80% and alpha of 0.05. This high rate 
of delivery by 12 hours has been seen in prior studies utilizing mifepristone.9 More 
importantly, the data will be used to inform sample size for a larger trial. The data collected 
from this study will be used to determine the number of patients needed to enroll in a larger 
trial. We do not anticipate loss to follow up as all patients will deliver on our Labor and 
Delivery unit during the same hospitalization as randomization. We deliver approximately 
60-75 patients with second trimester nonviable pregnancies per year at Barnes-Jewish 
Hospital. We have experience with consent rates of approximately 50-75% in prior trials 
in patients on Labor and Delivery. Therefore, we anticipate meeting this sample size within 
1 year.  
 
F2 Analysis Plan and Statistical Methods  
 
Baseline characteristics will be compared between groups using appropriate descriptive 
statistics. The primary analysis will be by intention-to-treat. Primary and secondary 
outcomes will be compared between groups using the Chi-squared, Fisher’s exact, Mann-
Whitney U or student’s t-tests, as appropriate.  A p-value of <0.05 will be considered 
significant. We will calculate relative risks and 95% confidence intervals for the primary 
outcome. 
 
If there is an imbalance in baseline characteristics, we will perform adjusted analyses to 
account for relevant covariates using multivariable logistic or linear regression. We will 
perform the following prespecified subgroup analyses for the primary outcome: parity 
(nulliparous vs multiparous) membrane status (ruptured vs intact), and cervical dilation at 
time of induction of labor (less than 2 cm vs 2 cm or more). 
 
 
 
 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
13
G Study Timeline  
 
 
 
 
 
 
 
 
 
 
 
 
 
H References 
 
 
1. 
Hoyert DL, Gregory EC. Cause of Fetal Death: Data From the Fetal Death Report, 
2014. Natl Vital Stat Rep. 2016;65(7):1-25. 
2. 
Hoyert DL, Gregory ECW. Cause-of-death Data From the Fetal Death File, 2015-
2017. Natl Vital Stat Rep. 2020;69(4):1-20. 
3. 
American College of O, Gynecologists, Society for Maternal-Fetal M. Management 
of Stillbirth: Obstetric Care Consensus No, 10. Obstet Gynecol. 2020;135(3):e110-
e132. 
4. 
LeMoine F, Moore RC, Chapple A, Moore FA, Sutton E. Neonatal Survivability 
following Previable PPROM after Hospital Readmission for Intervention. AJP Rep. 
2020;10(4):e395-e402. 
5. 
Sim WH, Araujo Júnior E, Da Silva Costa F, Sheehan PM. Maternal and neonatal 
outcomes following expectant management of preterm prelabour rupture of 
membranes before viability. J Perinat Med. 2017;45(1):29-44. 
6. 
Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 
222. Obstet Gynecol. 2020;135(6):e237-e260. 
7. 
Abubeker FA, Lavelanet A, Rodriguez MI, Kim C. Medical termination for 
pregnancy in early first trimester (≤ 63 days) using combination of mifepristone and 
misoprostol or misoprostol alone: a systematic review. BMC Womens Health. 
2020;20(1):142. 
8. 
Chu JJ, Devall AJ, Beeson LE, et al. Mifepristone and misoprostol versus 
misoprostol alone for the management of missed miscarriage (MifeMiso): a 
randomised, double-blind, placebo-controlled trial. Lancet. 2020;396(10253):770-
778. 
9. 
Allanson ER, Copson S, Spilsbury K, et al. Pretreatment With Mifepristone 
Compared With Misoprostol Alone for Delivery After Fetal Death Between 14 and 
28 Weeks of Gestation: A Randomized Controlled Trial. Obstet Gynecol. 
2021;137(5):801-809. 
10. 
Chaudhuri P, Datta S. Mifepristone and misoprostol compared with misoprostol 
alone for induction of labor in intrauterine fetal death: A randomized trial. J Obstet 
Gynaecol Res. 2015;41(12):1884-1890. 
 
0-2 
months 
3-6 
months 
7-9 
months 
10-12 
months 
12-18 
months 
Protocol development 
x 
 
 
 
 
Trial registration 
x 
 
 
 
 
Staff training 
x 
 
 
 
 
Study forms and database  
x 
 
 
 
 
Data collection & management 
 
x 
x 
x 
 
Protocol & IRB finalized 
x 
 
 
 
 
Recruitment start 
 
x 
 
 
 
50% recruitment 
 
 
x 
 
 
100% recruitment 
 
 
 
x 
 
Data analysis complete 
 
 
 
 
x 

 
 
 
 
 
 
______________________________________________________________________________________ 
 
14
11. 
Abbas DF, Blum J, Ngoc NT, et al. Simultaneous Administration Compared With a 
24-Hour Mifepristone-Misoprostol Interval in Second-Trimester Abortion: A 
Randomized Controlled Trial. Obstet Gynecol. 2016;128(5):1077-1083. 
12. 
Heikinheimo O. Clinical pharmacokinetics of mifepristone. Clin Pharmacokinet. 
1997;33(1):7-17. 
13. 
Sarkar NN. Mifepristone: bioavailability, pharmacokinetics and use-effectiveness. 
Eur J Obstet Gynecol Reprod Biol. 2002;101(2):113-120. 
14. 
Chai J, Tang OS, Hong QQ, et al. A randomized trial to compare two dosing 
intervals of misoprostol following mifepristone administration in second trimester 
medical abortion. Hum Reprod. 2009;24(2):320-324. 
15. 
Creinin MD, Fox MC, Teal S, et al. A randomized comparison of misoprostol 6 to 
8 hours versus 24 hours after mifepristone for abortion. Obstet Gynecol. 
2004;103(5 Pt 1):851-859. 
16. 
Shay RL, Benson LS, Lokken EM, Micks EA. Same-day mifepristone prior to 
second-trimester induction termination with misoprostol: A retrospective cohort 
study. Contraception. 2022;107:29-35. 
17. 
Henkel A, Lerma K, Blumenthal PD, Shaw KA. Evaluation of shorter mifepristone 
to misoprostol intervals for second trimester medical abortion: a retrospective 
cohort study. Contraception. 2020;102(5):327-331. 
18. 
Casey FE, Ye PP, Perritt JD, Moreno-Ruiz NL, Reeves MF. A randomized 
controlled trial evaluating same-day mifepristone and misoprostol compared to 
misoprostol alone for cervical preparation prior to second-trimester surgical 
abortion. Contraception. 2016;94(2):127-133.