Clinical trial NCT03904446
Conditions: Uterine Atony With Hemorrhage
Keywords: Methergine Uterine Atony
Sponsor: Cynthia Wong
Start date: 2019-06-08; Completion date: 2021-02-15
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Postpartum hemorrhage remains a leading cause of maternal morbidity and mortality worldwide, even in high income countries. Uterine atony is estimated to cause 70-80% of postpartum hemorrhage. Prolonged labor and augmented labor are known risk factors for postpartum hemorrhage. In attempts to reduce the incidence of postpartum hemorrhage, particularly in patients with known risks factors, it is essential to optimize preventative practices in order to reduce the rates postpartum hemorrhage.

Although oxytocin is considered the first line therapy for preventing and treating uterine atony, early consideration of additional prophylactic uterotonic agents may be indicated in women with prior oxytocin exposure given oxytocin receptor desensitization and down regulation.

As such, investigators sought to examine whether multimodal prophylactic uterotonics (standard oxytocin + methylergonovine), in patients who are increased risk of developing postpartum hemorrhage (specifically laboring patients who ultimately require a cesarean section) would benefit from the addition of prophylactic uterotonics. The clinical rational for administration of multimodal prophylactic uterotonics at the time of cesarean delivery in laboring patients is three-fold: to decrease the incidence of uterine atony, to decrease the incidence of postpartum hemorrhage, decrease the number of uterotonics required at the time of cesarean section.

The primary outcome will be to evaluate the need for additional uterotonic agents (Methylergonovine, Carboprost, Misoprostol) at the time of delivery.

Secondary outcomes will include the incidence of postpartum hemorrhage (quantitative blood loss \>1 liter), surgical assessment of uterine tone four minutes following delivery of the placenta, preoperative and postoperative hemoglobin, the need for a blood transfusion, intensive care unit admission, uterine infection (endometritis).

Detailed description:
All patients who meet eligibility for the study will be consented during their clinic visit or upon arrival to labor and delivery. If patients elect to participate in the study, enrollment in the study will be noted in their sticky note in EPIC (electronic medical record) which will be ready available to all members of the health care team. If patients during the labor process require a cesarean section, the anesthesiologist will pick up a sealed envelope (which will contain the allocation sequence and group assignment). A randomization block design with mixed block sizes will be used to generate the allocation sequence by using the nQuery Advisor computer software.

The sealed envelopes will be readily available to the anesthesiologist and kept in the anesthesia workroom. Following delivery of the infant, the patient will receive the standard oxytocin infusion. Following administration of the oxytocin infusion, the patient will be given either methylergonovine 0.2 mg IM (intramuscular) or placebo (1 ml of normal saline, intramuscular). This will be drawn up and administered by the anesthesiologist. The obstetrician (delivering provider performing the cesarean section) will be blinded to the group assignment. Documentation of the drug will be recorded in epic in the medication administration record.

The delivering provider will be responsible for determining and relaying to the anesthesiologist whether additional uterotonics are needed throughout the procedure. Additional uterotonics will be given in accordance to the current guidelines outlined by the American Congress of Obstetricians and Gynecologists (ACOG). The delivery provider will assess uterine tone at 4 minutes (satisfactory versus unsatisfactory). The registered nurse will be responsible for setting up a timer to let the OB provider know when 4 minutes have passed. Nursing will call out once the 4 minutes have passed and the OB provider will state whether adequate tone was noted. The anesthesiologist will be responsible for documenting whether a placebo/study drug was given and uterine tone after 4 minutes. This documentation will be placed back into the sealed envelope by the anesthesiologist and placed in the anesthesia workroom. Nicole Masse (primary investigator) will be responsible for storing folders in a secured, locked file cabinet within the Maternal Fetal Medicine offices.

As routinely done at the time of cesarean delivery, the registered nurse will be responsible for measuring and documenting the quantitative blood loss. As routinely performed on all are patients who undergo a vaginal or cesarean delivery, preoperative hemoglobin and postoperative day one hemoglobin levels will be collected.

In the event a postpartum hemorrhage was to occur, the obstetrician will then be un-blinded as management of a postpartum hemorrhage will be driven by whether normal saline or methergine was given as part of the study.

The primary outcome, the need for additional uterotonics, will be assessed in the operating room. Other outcome which will be assessed in the operating room include uterine tone and quantitative blood loss. Outcomes which will be assessed in the immediate postpartum period include: postpartum hemoglobin values, need for a blood transfusion, admission to the intensive care unit, endometritis).

No long-term follow will be needed.

Arms: arm 1: Standard Oxytocin Infusion at the time of Cesarean Section plus 0.2 mg of Intramuscular Methergine arm 2: Standard Oxytocin Infusion at the time of Cesarean Section plus 1 milliliter (mL)of normal saline given intramuscular
Interventions: intervention 1: Methylergonovine intervention 2: Normal Saline (placebo)
Intervention descriptions: intervention 1: 0.2 mg of intramuscular methylergonovine at the time of cesarean section following standard IV oxytocin infusion. intervention 2: 1 ml of normal saline intramuscular at the time of cesarean section following standard IV oxytocin infusion

Protocol documents:
ICF_002.pdf: 
Page 1  
 
 
 
 
 
 
 
A Randomized Controlled Trial to Assess the Effectiveness of Multimodal 
Prophylactic Uterotonics in Patients Undergoing Non-Elective Cesarean 
Sections after a Trial of Labor 
 
 
 
NCT Number:  03904446 
 
 
 
Nicole Masse, MD 
 
Document Date:  June 17, 2019 
 


Page 2  
 
 
 
 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
A Randomized Controlled Trial to Assess the Effectiveness of Multimodal 
Prophylactic Uterotonics in Patients Undergoing Non-Elective Cesarean Sections after a Trial of 
Labor 
 
Principal Investigator: 
Research Team Contact: 
Nicole Masse MD 
 
 
This consent form describes the research study to help you decide if you want to participate. This form 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights as a research subject. 
• 
If you have any questions about or do not understand something in this form, you should ask 
the research team for more information. 
• 
You should discuss your participation with anyone you choose such as family or friends. 
• 
Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study. 
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
This is a research study. We are inviting you to participate in this research study because you are a 
candidate for a vaginal trial of labor. 
 
Laboring patients who ultimately require a cesarean section are at increased risk of poor uterine 
contraction and postpartum hemorrhage (excess bleeding at delivery). The purpose of this research study 
is to assess whether laboring patients who ultimately require a cesarean section will benefit from 
prophylactic methylergonovine (a medication that may help poor uterine contraction and postpartum 
hemorrhage). 
 
 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
 
Up to 160 patients who meet criteria for the study will take part in this study conducted by investigators 
at the University of Iowa. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
If you agree to take part in this study, your involvement will last for the duration of the cesarean delivery 
(~ 2 hours). No long -term follow-up is needed.  We will continue to collect your medical data for 
several days after delivery. 
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WHAT WILL HAPPEN DURING THIS STUDY? 
 
Participants undergoing a vaginal trial of labor who ultimately require a cesarean section will be 
randomly assigned to receive one of the two study treatments, either methylergonovine or placebo 
(normal saline). Methylergonovine is a drug commonly administered in the postpartum period to help 
control bleeding and poor uterine contraction after birth. As you will be randomized, this means that 
whichever study treatment you receive will be determined purely by chance, like flipping a coin. You 
will have a 50/50 chance of receiving any one of the study treatments. Enrollment in the study will have 
no impact on your chances of having a successful vaginal delivery . 
 
At the time of cesarean section, following delivery of your baby, the standard dose of oxytocin infusion 
will be administered to you. Following administration of the standard oxytocin infusion, you will then 
receive either 200 micrograms of methylergonovine or placebo (1 ml of normal saline) as a shot in the 
muscle. This will be drawn up and administered by an anesthesiologist. 
 
The obstetrical provider will be responsible for determining and relaying to the anesthesiologist whether 
additional uterotonics (medications for poor uterine contraction) are needed throughout the procedure. 
Additional uterotonics will be given in accordance to the current guidelines outlined by the American 
Congress of Obstetricians and Gynecologists (ACOG). We will evaluate the need for additional 
uterotonic medications at the time of cesarean delivery which include: methylergonovine, carboprost 
and misoprostol. 
 
The obstetrical provider will assess the tone of your uterus 4 minutes following delivery of your baby 
and report whether uterine tone is satisfactory or unsatisfactory. As routinely done at the time of 
cesarean delivery, the registered nurse will be responsible for measuring and documenting the 
quantitative blood loss. As routinely performed on all are patients who undergo a vaginal or cesarean 
delivery, preoperative hemoglobin and postoperative day one hemoglobin levels will be collected. Other 
outcomes we will be assessing include: the need for a blood transfusion, endometritis, intensive care unit 
admission. 
 
No additional long-term follow up will be needed. 
 
We will collect information from your medical chart about: blood loss from your cesarean section, 
preoperative and postoperative hemoglobin levels, the need for additional uterotonic agents throughout 
the cesarean section, the need for a blood transfusion, the development of postpartum endometritis and 
the need for intensive care unit admission. 
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WHAT ARE THE RISKS OF THIS STUDY? 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study. Rarely observed reactions have included: irritation at injection site, hypersensitivity 
(anaphylaxis), acute myocardial infarction, transient chest pains, vasoconstriction, vasospasm, coronary 
arterial spasm, bradycardia, tachycardia, dyspnea, hematuria, thrombophlebitis , water intoxication , 
seizures, hallucinations, leg cramps, dizziness, tinnitus, nasal congestion, nausea, vomiting, diarrhea, 
diaphoresis, palpitation, rash, and foul taste. 
 
To avoid life threatening risks from the study drug, patients with contraindications to methylergonovine 
have been excluded from the study. Contraindications to methylergonovine include: hypersensitivity to 
the drug, chronic high blood pressure, gestational high blood pressure, preeclampsia and coronary artery 
disease. HIV/AIDS patients on protease inhibitors (Pls) will also be excluded as the use of 
methylergonovine with protease inhibitors has been associated with exaggerated vasoconstrictive 
responses. 
 
You may receive a placebo (an inactive substance) during this study. This means that you would receive 
no active study treatment while participating, thus you may not receive the potential additive benefit of a 
prophylactic uterotonic. However, there is a risk of receiving methylergonovine when the drug itself is 
not necessary. 
 
WHAT ARE THE BENEFITS OF THIS STUDY? 
 
You may not directly benefit from being in this study. 
 
However, we hope that, in the future, other people might benefit from this study because we hope to 
learn whether the administration of prophylactic uterotonic medications will serve to improve poor 
uterine contraction and decrease the incidence of postpartum hemorrhage. 
 
 
WILL IT COST ME ANYTHING TO BE IN THIS STUDY? 
 
You will not have any additional costs for being in this research study. 
 
WILL I BE PAID FOR PARTICIPATING? 
 
You will not be paid for being in this research study. 
 
WHO IS FUNDING THIS STUDY? 
 
The Department of Maternal Fetal Medicine is funding this study. The University and the research team 
are receiving no payments from other agencies, organizations, or companies to conduct this research 
study. 
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WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
 
• 
If you are injured or become ill from taking part in this study, medical treatment is available at the 
University of Iowa Hospitals and Clinics. 
• 
The University of Iowa does not plan to provide free medical care or payment for treatment of any 
illness or injury resulting from this study unless it is the direct result of proven negligence by a 
University employee. 
• 
If you experience a research-related illness or inju ry, you and/or your medical or hospital insurance 
carrier will be responsible for the cost of treatment. 
 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will keep your participation in this research study confidential to the extent permitted by law. 
However, it is possible that other people such as those indicated below may become aware of your 
participation in this study and may inspect and copy records pertaining to this research. Some of these 
records could contain information that personally identifies you. 
• 
federal government regulatory agencies, 
• 
auditing departments of the University of lowa, and 
• 
the University of Iowa Institutional Review Board (a committee that reviews and approves 
research studies) 
 
To help protect your confidentiality, we will be collecting the minimal amount of data needed to answer 
the research question. All records containing protected health information will be transported in a 
manner that no identifiable information is visible. All hard copy material will be kept in a secure office 
within a locked file cabinet. Electronica data will be collected by reviewing your medical chart through 
EPIC. All protected health information obtained will be stored through REDCap (research electric data 
capture) a secure web-based interface for storing study information. At the end of the study, all study 
maternal will be destroyed. If we write a report or article about this study or share the study data set with 
others, we will do so in such a way that you cannot be directly identified. 
 
The University of Iowa Hospitals and Clinics generally requires that we document your participation in 
research occurring in a University of Iowa Health Care facility. This documentation will be in either 
your medical record or a database maintained on behalf of the institution reflecting that you are 
participating in this study. The information included will provide contact information for the research 
team as well as information about the risks associated with this study. We will keep this Informed 
Consent Document in our research files; it will not be placed in your medical record chart. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. A copy of the informed consent document will be available on this website. This website will not 
include information that can identify you. At most, the website will include a summary of the results. 
You can search this website at any time. 
FOR IRB USE ONLY 
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WILL MY HEALTH INFORMATION BE USED DURING THIS STUDY? 
 
The Federal Health Insurance Portability and Accountability Act (HIPAA) requires the University of 
Iowa Health Care to obtain your permission for the research team to access or create " protected health 
information" about you for purposes of this research study. Protected health information is information 
that personally identifies you and relates to your past, present, or future physical or mental health 
condition or care. We will access or create health information about you, as described in this document, 
for purposes of this research study. Once the University of Iowa Health Care has disclosed your 
protected health information to us, it may no longer be protected by the Federal HIPAA privacy 
regulations, but we will continue to protect your confidentiality as described under "Confidentiality." 
 
We may share your health information related to this study with other parties including federal 
government regulatory agencies, the University of Iowa Institutional Review Boards and support staff, 
 
You cannot participate in this study unless you permit us to use your protected health information. If 
you choose not to allow us to use your protected health information, we will discuss any non-research 
alternatives available to you. Your decision will not affect your right to medical care that is not 
research-related. Your signature on this Consent Document authorizes to give us permission to use or 
create health information about you. 
 
Although you may not be allowed to see study information until after this study is over, you may be 
given access to your health care records by contacting your health care provider. Your permission for us 
to access or create protected health information about you for purposes of this study has no expiration 
date. You may withdraw your permission for us to use our health information for this research study by 
sending a written notice to Nicole Masse MD in the department of OBGYN at 200 Hawkins Drive, Iowa 
City 5224.  However, we may still use your health information that was collected before withdrawing 
your permission. Also, if we have sent your health information to a third party, such as the study 
sponsor, or we have removed your identifying information, it may not be possible to prevent its future 
use. You will receive a copy of this signed document. 
 
 
IS BEING IN THIS STUDY VOLUNTARY? 
 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time. If you decide not to be in this 
study, or if you stop participating at any time, you won't be penalized or lose any benefits for which you 
otherwise qualify. 
 
What if I Decide to Drop Out of the Study? 
 
Can Someone Else End my Participation in this Study? 
Under certain circumstances, the researchers might decide to end your participation in this research 
study earlier than planned. This might happen in the event you develop medical condition s which would 
be contraindications to receiving the study drug. For example, in the event you develop gestational 
hypertension or preeclampsia during labor, this would make you ineligible for the study as the 
administration of methylergonovine may worsen hypertensive disorders. 
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WHAT IF I HAVE QUESTIONS? 
 
ou have any questions about the research study itself, please 
. If you experience a research-related injury, please contact: 
 
If you have questions, concerns, or complaints about your rights as a research subject or about research 
related injury, please contact the Human Subjects Office, 105 Hardin Library for the Health Sciences, 
600 Newton Rd, The University of Iowa, Iowa City, IA 52242-1098, (319) 335-6564, or e-mail 
irb@uiowa.edu. General information about being a research subject can be found by clicking "Info for 
Public" on the Human Subjects Office web site, http://hso.research.uiowa.edu/. To offer input about 
your experiences as a research subject or to speak to someone other than the research staff, call the 
Human Subjects Office at the number above. 
 
 
This Informed Consent Document is not a contract. It is a written explanation of what will happen 
during the study if you decide to participate. You are not waiving any legal rights by signing this 
Informed Consent Document. Your signature indicates that this research study has been explained to 
you, that your questions have been answered, and that you agree to take part in this study. You will 
receive a copy of this form. 
 
 
Subject's Name (printed): _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
 
Statement of Person Who Obtained Consent 
 
I have discussed the above points with the subject or, where appropriate, with the subject's legally 
authorized representative. It is my opinion that the subject understands the risks, benefits, and 
procedures involved with participation in this research study. 
 
 
 
(Signature of Person who Obtained Consent) 
(Date) 
FOR IRB USE ONLY 
$STAMP IRB 
$STAM-P IRS ID 
$STAMP-APPRV OT 
(Signature of Subject) 
(Date) 

Prot_000.pdf: 
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1/17 
 
 
 
 
 
A Randomized Controlled Trial to Assess the Effectiveness of Multimodal 
Prophylactic Uterotonics in Patients Undergoing Non-Elective Cesarean Sections 
after a Trial of Labor 
 
 
 
NCT Number:  03904446 
 
 
 
Nicole Masse, MD 
 
Document Date:  June 17, 2019 
 
 


7/5/22, 8:20 AM 
HawkIRB 
https://hawkirb.research.uiowa.edu/hawkirb/summary/forms.page?mode=pf&OID=64770808 
2/17 
 
 
 
A Randomized Controlled Trial to Assess the Effectiveness of 
Multimodal Prophylactic Uterotonics in Patients Undergoing 
Non-Elective Cesarean Sections after a Trial of Labor 
PI: 
Nicole Masse 
IRB ID #: 201904756 
 
 
Form Content 
I. Project Introduction 
 
I.1 
Project to be reviewed by: 
IRB-01 
 
I.2 
Project Title: 
A Randomized Controlled Trial to Assess the Effectiveness of Multimodal Prophylactic Uterotonics in 
Patients Undergoing Non-Elective Cesarean Sections after a Trial of Labor 
 
I.3 
Short Title (optional): 
I.4 
Provide a short summary of the purpose and procedures of the study proposed in this IRB application. 
DO NOT include information on studies not proposed in this application. 
Use LAY terminology only. This must be easily understandable by IRB community members and 
nonscientists. 
DO NOT cut and paste technical abstracts from funding applications that may not be understood by a 
general audience. 
Postpartum hemorrhage remains a leading cause of maternal morbidity and mortality worldwide, even in high 
income countries. Uterine atony is estimated to cause 70-80% of postpartum hemorrhage. Prolonged labor and 
augmented labor are known risk factors for postpartum hemorrhage. In attempts to reduce the incidence of 
postpartum hemorrhage, particularly in patients with known risks factors, it is essential to optimize    
preventative practices in order to reduce the rates postpartum hemorrhage. 
 
Although oxytocin is considered the first line therapy for preventing and treating uterine atony, early 
consideration of additional prophylactic uterotonic agents may be indicated in women with prior oxytocin 
exposure given oxytocin receptor desensitization and down regulation. 
 
As such, we sought to examine whether multimodal prophylactic uterotonics (standard oxytocin + 
methylergonovine), in patients who are increased risk of developing postpartum hemorrhage (specifically 
laboring patients who ultimately require a cesarean section) would benefit from the addition of prophylactic 
uterotonics. The clinical rational for administration of multimodal prophylactic uterotonics at the time of 
cesarean delivery in laboring patients is three-fold: to decrease the incidence of uterine atony, to decrease the 
incidence of postpartum hemorrhage, decrease the number of uterotonics required at the time of cesarean 
section. 
 
Our primary outcome will evaluate the need for additional uterotonic agents (Methylergonovine, Carboprost, 
Misoprostol). 
Secondary outcomes will include the incidence of postpartum hemorrhage (quantitative blood loss >1 liter), 
surgical assessment of uterine tone four minutes following delivery of the placenta, preoperative and 
postoperative hemoglobin, the need for a blood transfusion, intensive care unit admission, uterine infection 
(endometritis) 
 
Procedures of the Study: 
Written informed consent will be obtained from all study participants. Patients will be consented at the time of 
their clinic visit or upon admission to labor delivery. Nicole Masse MD (or designated members of the    
research team) will be responsible for enrolling study participants. If patients ultimately require a cesarean 
section and meet study criteria, participants will receive routine oxytocin infusion at the time of cesarean   
section and will be randomly allocated to receive 200 mcg of intramuscular methylergonovine or placebo (1    


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ml of intramuscular saline) immediately after delivery of the newborn. 


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As prophylactic methylergonovine at the time of delivery is not currently the standard of care, the 
investigators (Maternal Fetal Medicine Department) will cover the cost of both the study drug (prophylactic 
methylergonovine) and the placebo drug (normal saline). 
 
To detect a 2 fold decrease in the need for additional uterotonics (42% vs 21%) with a 2 sided type 1 error of 
5% and power of 80%, a sample size of 76 patients per group will be necessary. To recruit this number of 
patients, an 18 month inclusion period is anticipated. 
 
Inclusion criteria: patients who are least 18 years of age, laboring patients requiring a cesarean section. 
Reasons for cesarean section would include failure to progress in labor and nonreassuring fetal well-being. 
 
Exclusion criteria: Known placenta or uterine anomalies. Patients with a history of chronic hypertension, 
gestational hypertension or preeclampsia will be excluded as these conditions are contraindications to the 
administration of methergine. HIV/AIDS patients on protease inhibitors (PIs) will be excluded as the 
concomitant use of methergine with PIs have been associated with exaggerated vasoconstrictive responses. 
 
The randomization process will include: 
--1:1 allocation using a randomized block design with mixed block sizes. A computer generated list of random 
numbers will be used to generate the allocation sequence - NQuery Advisor will be used to generate allocation 
sequence. 
--Sealed envelopes will be prepared using the allocation concealment mechanism described above. Once a 
patient has met study criteria, the anesthesiologist will open the envelope to assess whether patient will be 
given study drug (methylergonovine vs placebo). 
 
The allocation sequence and group assignment will be concealed from Nicole Masse (NM) who will be 
enrolling study participants. 
 
The obstetrician (delivery provider) will be blinded to the group assignment. The treatment will be drawn up   
and administered by the anesthesiologist. The delivering provider will be responsible for determining and 
relaying to the anesthesiologist whether additional uterotonics are needed. Additional uterotonics will be given  
in accordance to the dose/routine/frequency recommended by the American College of Obstetricians and 
Gynecologists. The delivery provider will assess uterine tone at 4 minutes (satisfactory versus unsatisfactory).  
As routinely done at the time of cesarean delivery, the registered nurse will be responsible for measuring and 
documenting the quantitative blood loss. As routinely performed on all are patients who undergo a vaginal or 
cesarean delivery, preoperative hemoglobin and postoperative day one hemoglobin levels will be collected. 
 
In the event a delayed postpartum hemorrhage was to occur, the obstetrician will be unblinded at the   
conclusion of the cesarean delivery as management of a delayed hemorrhage will be driven by the uterotonics 
received in the operating room. Although this will be a limitation of the study, the majority of our outcomes  
will be assessed at the time of cesarean section while providers are blinded. 
 
I.5 
Specify your research question(s), study aims or hypotheses (do not indicate "see protocol") 
The aim of this study is to test the hypothesis that multimodal prophylactic uterotonic administration at the 
time of cesarean delivery in laboring patients will be more effective in improving uterine tone, thus reducing 
the incidence of postpartum hemorrhage and reducing the need for additional uterotonic agents. 
 
I.6 
Background and significance and/or Preliminary studies related to this project. 
(do not indicate "see protocol") 
Postpartum hemorrhage remains a significant maternal morbidity at the University of Iowa. From December 
2017 to February 2019, one fourth of our patients (26%) undergoing a cesarean section at the University of 
Iowa had a procedure complicated by a postpartum hemorrhage (blood loss greater than 1 liter). 
 
Laboring patients who ultimately require a cesarean delivery are at increased risk for uterine atony which can 
result in a significant increase in intraoperative blood loss. Within the past twelve months at the University of 
Iowa, 42% of our laboring patients required additional uterotonics agents (methylergonovine, carboprost, 
misoprostol) at the time of cesarean section in addition to the standard oxytocin infusion. At the University of 
Iowa, first line uterotonics agents are given in accordance to recommendations outlined by the American  
College of Obstetricians and Gynecologists: Methergine 0.2 mg is administered as an intramuscular injection 
every 2-4 hours; Hemabate 0.25 mg is given as an intramuscular injection every 15 minutes for a maximum of   
8 doses; misoprostol 600-1000 mcg if typically given rectally as a single dose. 
 
Significant Studies Related to Project: 
Senturk et al demonstrated that routine use of oxytocin with prophylactic methergine during the intraoperative 
and postoperative period to patients undergoing cesarean delivery considerably reduced the level of    
postpartum hemorrhage. No adverse effects were observed in the patients who received prophylactic 
methergine. Although not specifically looked at, Senturk et al believed prophylactic methylergonovine would 


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likely reduce the risk of uterine atony. One of our study outcomes will be looking at uterine tone following 
administration of the study drug to determine whether prophylactic methylergonovine decreased the incidence  
of uterine atony. 
 
Lavioe et al demonstrated that women with prior exposure to exogenous oxytocin required a higher initial 
infusion rate of oxytocin to prevent uterine atony after cesarean delivery than women without prior exposure. 
Their group also found that laboring patients requiring a cesarean section required additional uterotonic agents 
compared to a scheduled cesarean/nonlaboring patients (34% vs 8%). This is likely secondary to oxytocin 
desensitization and down regulation in patients exposed to oxytocin prior to their cesarean delivery. Our study 
intends on administering multimodal prophylactic uterotonic agents in laboring patients undergoing a cesarean 
section as this may be more effective in improving uterine tone by using different medications which 
mechanisms are not affected by potential oxytocin desensitization and down regulation. 
 
I.7 
Literature cited / references (if attaching a grant or protocol enter N/A). 
References: 
 
1. The American College of Obstetricians and Gynecologists. “Postpartum Hemorrhage.” Practice Bulletin, 
Number 183. October 2017. 
 
2. Lavoie A, McCarthy RJ, Wong C. The ED90 of Prophylactic Oxytocin Infusion After Delivery of the 
Placenta During Cesarean Delivery in Laboring Compared with Nonlaboring Women: An Up-Down 
Sequential Allocation Dose-Response Study. Anesth Analg. 2015; 121:159-64. 
 
3. Khan KS, Wojdyla D, Say L et al. WHO analysis causes of maternal death: a systemic review. Lancet 2006; 
367:1066-74. 
 
4. Senturk S, Kagitci M, Baluk G et al. The Effect of the Combined Use of Methylergonovine and Oxytocin 
during Cesarean Section in the Prevention of Post-partum Hemorrhage. Basin Clin Pharmacol Toxicol. 2016; 
118(5)338-43. 
 
5. U.S. Department of Health and Human Services (2018, December 7). Recommendations for the Use of 
Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV 
Transmission in the United States. Retrieved from 
https://aidsinfo.nih.gov/guidelines/html/3/perinatal/183/other-intrapartum-management-considerations 
 
 
 
 
 
 
II. Research Team 
 
II.2 
Team Members 
UI Team Members 
 
 
Key 
 
 
UI VAMC 
 
 
Consent 
Name 
E-mail 
College Contact Prsn COI 
COI 
Process 
Involvement 
Deactivated 
 
Nicole Masse, MD 
 nicole- 
 masse@uiowa.edu 
 
 mildrede- 
Carver 
College of 
Medicine 
Carver 
Mildrede Bonglack, MD bonglack@uiowa.edu 
Rebecca Chung, BS 
 rebecca- 
 chung@uiowa.edu 
 colette- 
College of 
Medicine 
University 
Hospitals 
Carver 
Colette  Gnade, MD 
 
 
Shelby  Green, MD 
gnade@uiowa.edu 
 
 shelby-r- 
green@uiowa.edu 
College of 
Medicine 
Carver 
College of 
Medicine 
Yes 
Yes No 
Yes 
Yes 
No 
No No 
Yes 
No 
No 
No No 
Yes 
Yes 
No 
No No 
Yes 
Yes 
No 
No No 
Yes 
No 


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Key UI VAMC 
Consent 
Name 
E-mail 
College Contact Prsn COI 
Carver 
COI 
Process 
Involvement 
Deactivated 
Leigh Hess, MD 
 leigh-hess@uiowa.edu 
 
 danielle- 
Danielle Ikoma, MD 
 
 
Emily Jacobs, MD, MS 
 
 
Jordan Mattson, MD 
 
 
Laura Rasmussen, MD 
 
 
Hope Richards, MD 
 ikoma@uiowa.edu 
 
 emily- 
jacobs@uiowa.edu 
 
jordan- 
 mattson@uiowa.edu 
 
 laura- 
 rasmussen@uiowa.edu 
 
 hope- 
 richards@uiowa.edu 
 
Keely Ulmer, MD 
 keely-ulmer@uiowa.edu 
 
 vincent- 
Vincent Wagner, MD 
 wagner@uiowa.edu 
 
 noelle- 
Noelle Waldschmidt, BS waldschmidt@uiowa.edu 
 heather- 
Heather Winn, MD 
 
 
Cynthia  Wong, MD 
 winn@uiowa.edu 
 
cynthia- 
 wong@uiowa.edu 
 
Non-UI Team Members 
Name  Institution  Location  FWA  Role  DHHS  Contact Key 
Prsn 
 
UI 
COI 
 
VAMC 
COI 
 
Consent Process 
Involvement 
 
 
Email 
Nothing found to display. 
 
II.3 
The Principal Investigator of this study is: 
Fellow or Research Scholar 
 
II.3.a 
Select the mentor or faculty advisor: 
Cynthia Wong 
 
II.6 
Identify the key personnel. The system will automatically designate the PI and all faculty members on the project  
as “key personnel.” For information about other team members who should be designated as “key personnel” 
please click on the help information. 
Name 
Is Key Personnel 
Nicole Masse, MD 
Yes 
Mildrede Bonglack, MD 
No 
Rebecca Chung, BS 
No 
Colette Gnade, MD 
No 
Shelby Green, MD 
No 
Leigh Hess, MD 
No 
Danielle Ikoma, MD 
No 
Emily Jacobs, MD, MS 
No 
College of 
Medicine 
No 
No No 
Yes 
Yes 
Carver 
College of 
No 
No No 
Yes 
No 
Medicine 
Carver 
College of 
No 
No No 
Yes 
No 
Medicine 
Carver 
College of 
No 
No No 
Yes 
Yes 
Medicine 
Carver 
College of 
No 
No No 
Yes 
No 
Medicine 
Carver 
College of 
No 
No No 
Yes 
Yes 
Medicine 
Carver 
College of 
No 
No No 
Yes 
No 
Medicine 
Carver 
College of 
No 
No No 
Yes 
Yes 
Medicine 
Carver 
College of 
Medicine 
No 
No No 
Yes 
No 
Carver 
College of 
No 
No No 
Yes 
Yes 
Medicine 
Carver 
College of 
Yes 
Yes No 
No 
No 
Medicine 


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Name 
Is Key Personnel 
Jordan Mattson, MD 
No 
Laura Rasmussen, MD 
No 
Hope Richards, MD 
No 
Keely Ulmer, MD 
No 
Vincent Wagner, MD 
No 
Noelle Waldschmidt, BS 
No 
Heather Winn, MD 
No 
Cynthia Wong, MD 
Yes 
 
II.5 
Select research team member who is the primary contact for study participants. 
Nicole Masse 
 
 
III. Funding/Other Support 
 
III.1 
Funding Sources 
Source Entered as Text  DSP Link 
Type 
Source Grant Title Name of PI on Grant 
Source is entered as text no 
Departmental / PI Discretionary 
* new source name 
 
III.3 
Does any member of the research team have a financial conflict of interest related to this project according to the 
 Conflict of Interest in Research policy? If yes, please indicate which members below. 
Name 
Has Conflict of Interest 
Nicole Masse, MD 
No 
Mildrede Bonglack, MD 
No 
Rebecca Chung, BS 
No 
Colette Gnade, MD 
No 
Shelby Green, MD 
No 
Leigh Hess, MD 
No 
Danielle Ikoma, MD 
No 
Emily Jacobs, MD, MS 
No 
Jordan Mattson, MD 
No 
Laura Rasmussen, MD 
No 
Hope Richards, MD 
No 
Keely Ulmer, MD 
No 
Vincent Wagner, MD 
No 
Noelle Waldschmidt, BS 
No 
Heather Winn, MD 
No 
Cynthia Wong, MD 
No 
 
IV. Project Type 
IV.1 
Do you want the IRB to give this project 
Regular (expedited or full board) review 
 
IV.2 
Enter the date you will be ready to begin screening subjects/collecting data for this project. (If you do not 
have a specified date, add "upon IRB approval") 
upon IRB approval 
 
IV.3 
Are you requesting a waiver of informed consent/authorization (subjects will not be given any oral or 
written information about the study)? 
No 


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V. Other Committee Review 
 
V.1 
Does this project involve any substance ingested, injected, or applied to the body? 
Do not answer yes, if the involvement includes a device, wire, or instrument 
Yes 
 
V.1.a 
What is/are the substance(s): 
Intramuscular Methylergonovine 0.2 mg (study drug) 
Intramuscular Normal Saline 1 ml (placebo) 
 
V.1.b 
Are any of these substances defined as a Schedule I - V Controlled Substance? 
No 
 
V.2 
Are any contrast agents used for any purpose in this study? 
No 
 
V.4 
Are all drugs or substances in this study being used within the FDA approved population (i.e., children, 
adults)? 
Yes 
 
V.5 
Are all drugs or substances in this study being used within the FDA approved indication (i.e., disease, 
condition)? 
Yes 
 
V.6 
Are all drugs or substances in this study being used within the FDA approved dose? 
Yes 
 
V.7 
Are all drugs or substances in this study being used within the FDA approved route of administration? 
Yes 
 
V.9 
Will any subject be asked to undergo a diagnostic radiation procedure (including radiographic, nuclear medicine, 
DEXA)? 
No 
 
V.14 
Will any subject be asked to undergo a radiation therapy procedure (including external beam therapy, 
brachytherapy, or nuclear medicine therapy)? 
No 
 
V.20 
Does this project involve the deliberate transfer of recombinant or synthetic nucleic acid molecules, or DNA or 
RNA derived from recombinant or synthetic nucleic acid molecules, into one or more human research 
participant? 
No 
 
V.21 
Will any portion of this project be conducted in the CRU, or does it use any CRU resources? 
No 
 
V.22 
Will this project use: 
any resource/patients of the Holden Comprehensive Cancer Center 
involve treatment, detection, supportive care, or prevention of cancer 
 
No 
 
V.25.a 
Will the study involve any of the following activity at UI Health Care, even if subjects or their insurance will not  
be billed for the item or service, and regardless of the study funding source (including studies with departmental 
or no funding)? 
Procedures, tests, examinations, hospitalizations, use of Pathology services, use of clinic facilities or 
clinical equipment, or any patient care services, including services conducted in the Clinical Research 
Unit; or 
Physician services or services provided by non-physicians who are credentialed to bill (ARNPs, Physician 
Assistants, etc.) 


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Yes 
 
V.25.b 
Will there be any procedures or services that may happen as part of a subject’s regular medical care 
and as part of the study? 
Yes 
 
V.25.c 
Will any study equipment or devices be supplied by a study sponsor? 
Yes 
 
V.25.d 
Please describe the equipment or device(s) being provided and what it will be used for 
As prophylactic methylergonovine prior to a cesarean section is not the standard of care - the 
department of maternal fetal medicine will be covering the costs of both methyergonovine and 
normal saline (placebo drug). 
 
This will come out of an MLF account set up by Nicole Masse 
 
V.25.e 
Is there or will there be an internal budget for this study? 
Yes 
 
V.25.f 
Is there or will there be an external budget for this study? 
No 
 
V.26 
The study involves Department of Nursing Services and Patient Care nursing, nursing resources or 
evaluates nursing practices at UI Health Care. 
No 
 
 
VI. Subjects 
 
VI.1 
How many adult subjects do you expect to consent or enroll for this project? 
3000 
 
VI.2 
What is the age of the youngest adult subject? 
18.0 
 
VI.3 
What is the age of the oldest adult subject? 
50.0 
 
VI.4 
What is the percentage of adult male subjects? 
0 
 
VI.5 
What is the percentage of adult female subjects? 
100 
 
VI.6 
How many minor subjects do you expect to consent or enroll for this project? 
0 
 
VI.13 
Describe EACH of your subject populations 
Include description of any control group(s) 
Specify the Inclusion/Exclusion criteria for EACH group 
Control Group: at the time of cesarean section, patients in the control group will receive the standard oxytocin 
infusion plus 1 ml of normal saline following delivery of the infant 
Study Group: at the time of cesarean section, patients in the study group will receive the standard oxytocin infusion 
plus 0.2 mg of intramuscular methylergonovine following delivery of the infant 
 
Inclusion: Pregnant patients who are least 18 years of age, laboring patients requiring a cesarean section. 
Exclusion: Known placenta or uterine anomalies. Patients with a history of chronic hypertension, gestational 
hypertension or preeclampsia will be excluded as these conditions are contraindications to the administration of 
methylergonovine given the risk of hypertension associated with administration. HIV/AIDS patients on protease 
inhibitors (PIs) will be excluded as the concomitant use of administration with PIs have been associated with 
exaggerated vasoconstrictive responses. 


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VI.14 
Provide an estimate of the total number of subjects that would be eligible for inclusion in each of your study 
populations (include your control population if applicable) 
With the exception of patients scheduled for a cesarean delivery and patients who have a contraindication to the    
study drug, all patients will be consented during their prenatal visit or at the time of arrival to labor and delivery. We 
chose to consent patients on arrival or at their prenatal visit to avoid consenting patients in labor at the time the 
cesarean section is called as this can be a stress provoking time for patients. 
 
Of the patients consented (~3000), 160 patients will undergo a cesarean section. 80 patients will be enrolled in the 
control group, 80 in the experimental group. 
 
 
VI.15 
Describe how you will have access to each of your study populations in sufficient number to meet your 
recruitment goals. 
These patients will be identified by chart review to see if they meet inclusion for our study. 
 
VI.16 
Do you plan to recruit/enroll non-English speaking people? 
No 
 
VI.18 
Do you propose to enroll any of the following in this study as subjects? 
Employee of the PI or employee of a  research  team  member 
Individual supervised by PI or supervised by member of research team 
Individual subordinate to the PI or subordinate to any member of the research team 
Student or trainee under the direction of the PI or under the direction of a member of the research team 
No 
 
VI.20 
Will subjects provide any information about their relatives? 
No 
 
VI.23 
Will anyone (other than the subject) provide you with information about the subject (e.g. proxy interviews)? 
No 
 
VI.26 
Is this project about pregnant women? 
Yes 
 
VI.27 
Will this project involve fetuses? 
No 
 
VI.28 
Does this project involve adult subjects who may be incompetent or have limited decision-making capacity on 
initial enrollment into the study? 
No 
 
VI.32 
Does this project involve subjects whose capacity to consent may change over the course of the study? 
No 
 
VI.37 
Does this project involve prisoners as subjects? 
No 
 
 
VII.A. Project Description (A) 
 
VII.A.1 
Where will project procedures take place (check all that apply)? 
UIHC - Labor and Delivery, UIHC Clinics 
 
 
VII.A.2 
Is this project also being conducted by other researchers at their own sites (e.g. a multi-site collaborative project)? 
No 
 
 
VII.B. Project Description (B) 


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VII.B.1 
Does this project involve any of the following (Check all that apply): 
    Registry – The collection and maintenance of data (not including biologic samples) in which: (1) the 
individuals in the registry have a common or related condition(s), and/or (2) the individuals in the registry 
are interested in being contacted for future studies by investigators other than those listed in Section II of 
this project.(UI Guide) 
    Repository – The collection, storage, and distribution of human biologic samples and/or data materials for 
research purposes. Repository activities involve three components: (i) the collection of data and/or 
specimens such as blood, tissue, saliva, etc.; (ii) the storage of data or specimens, and data management 
function; and (iii) the sharing of data/specimens with recipient investigators other than the original 
investigators. (paraphrased from OHRP) 
    Expanded Access – A process regulated by the Food and Drug Administration (FDA) that allows 
manufacturers to provide investigational new drugs to patients with serious diseases or conditions who 
cannot participate in a clinical trial. Examples of expanded access include non-protocol access to 
experimental treatments, including protocol exception, single-patient IND, treatment IND, compassionate 
use, emergency use, continued access to investigational drug, and parallel track (ClinicalTrials.gov & 
 FDA). 
    Clinical (or Treatment) trial – A prospective biomedical or behavioral research study of new treatments, 
new drug or combinations of drugs, new devices, or new approaches to surgery or radiation therapy. (NIH 
and ClinicalTrials.gov & FDA) 
    Physiology intervention/study – A pharmacologic or measurement study aimed at understanding basic 
mechanisms of disease and/or of normal human physiology, often without any therapeutic intent (though a 
clinical trial could include such components, often labeled as “translational” or “basic science” aims.) 
Measurements in such studies could include, but are not limited to, a blood draw, EKG, EEG, MRI,   
auditory or sensory testing, checking vital signs, DEXA scans, eye tracking, specimen collection, exercise, 
fasting, special diets, etc. 
    Behavioral intervention/study – May be used to refer to studies of individual or group behavior. This 
option does not include drugs, biologics, or devices but could include psychotherapy, lifestyle counseling, 
behavior modification, etc. 
    Diagnostic trial – Protocol designed to evaluate one or more interventions aimed at identifying a disease 
or health condition (ClinicalTrials.gov & FDA) 
    Non-clinical – any college/department that would regularly submit to IRB-02 
    Other 
 
VII.B.1.a 
Does this project involve any of the following (Check all that apply): 
    Phase I trials – include initial studies to determine the metabolism and pharmacologic actions of 
drugs in humans, the side effects associated with increasing doses, and to gain early evidence of 
effectiveness; may include healthy participants and/or patients (ClinicalTrials.gov & FDA) 
    Phase II trials – include controlled clinical studies conducted to evaluate the effectiveness of the 
drug for a particular indication or indications in patients with the disease or condition under study 
and to determine the common short-term side effects and risks(ClinicalTrials.gov & FDA) 
    Phase III trials – include expanded controlled and uncontrolled trials after preliminary evidence 
suggesting effectiveness of the drug has been obtained, and are intended to gather additional 
information to evaluate the overall benefit-risk relationship of the drug and provide an adequate basis 
for physician labeling(ClinicalTrials.gov & FDA) 
    Phase IV trials – studies of FDA-approved drugs to delineate additional information including the 
drug’s risks, benefits, and optimal use(ClinicalTrials.gov & FDA) 
 
VII.B.1.b 
Provide the NCT (National ClinicalTrials.gov Identifier) number 
NCT03904446 
 
VII.B.2 
Does this project involve a drug washout (asking subject to stop taking any drugs s/he is currently taking)? 
No 
 
VII.B.6 
Will any subjects receive a placebo in this study when, if they were not participating, they could be receiving 
an FDA-approved treatment for their condition? 
No 
 
VII.B.11 
Is there a separate, written protocol that will be submitted in addition to this IRB New Project form? (Note: a 
grant application is not considered to be a protocol) 


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No 
 
VII.B.18 
Does this project involve testing the safety and/or efficacy of a medical device? 
No 
 
 
VII.C. Project Description (C) 
 
VII.C.1 
Does this project involve any research on genes or genetic testing/research? 
No 
 
 
VII.D. Project Description (D) 
 
VII.D.1 
Check all materials/methods that will be used in recruiting subjects (you will need to attach copies of all materials  
at the end of the application): 
Use of any information available to the researchers or their colleagues because this person is a patient OR use  
of any information considered to be Protected Health Information (PHI) OR review of patient/clinic records - 
EPIC would be used to review medical and surgical history to see whether patients meet inclusion/exclusion 
criteria for the study. 
 
 
VII.D.2 
List the individual data elements you will need to access/use from the patient or clinic records to identify 
potential subjects for recruitment 
The obstetrical history (vaginal versus cesarean section) will need to be reviewed. Patients scheduled for a 
planned cesarean delivery would be excluded from the study. 
The medical history would also need to be reviewed as patients with hypertension (chronic hypertension, 
gestational hypertension, preeclampsia) would be excluded from the study as methylergonovine (study drug) 
can lead to vasoconstriction and worsen hypertension. 
 
VII.D.3 
Describe why you could not practicably recruit subjects without access to and use of the information 
described above 
As the study drug methylergonovine should be avoided in patients with hypertensive disorders, the chart will 
need to be reviewed to exclude these patients from the study. 
 
Patients scheduled for a cesarean section (either elective or medically indicated) will be excluded, thus the 
chart will need to be reviewed beforehand to exclude these patients. 
 
VII.D.4 
Describe why you could not practicably obtain authorization from potential subjects to review their patient 
or clinic records for recruitment purposes. 
Patient identifiers are needed to determine eligibility for the study. As ~ 1/4 of the patients will likely not meet 
study criteria, reviewing charts a head of time is more practicable. In addition, reviewing patients charts to  
assess eligibility involves no more than minimal risk to the privacy of individuals. 
 
VII.D.5 
Describe plans to protect the identifiers from improper use or disclosure 
After cesarean delivery, the envelope which contains the patients information and which study drug was given 
will be placed in a secure location in the anesthesia work room. The envelope will be picked up by Nicole  
Masse (NM). Information will then be stored in RedCap. The envelope with patients information will then be 
destroyed by NM. 
 
Subjects will be de-identified with the use of a separate document correlating subjects medical record number 
with the study ID number. At the conclusion of the research project, the key will be destroyed. 
 
Files will not be shared with non-study personnel. 
 
VII.D.6 
Describe plans to destroy identifiers at the earliest opportunity consistent with  conduct  of  the  research 
When the pregnancy is over, the sticky note (in EPIC) which will be used to document whether the patient was 
enrolled in the study disappears after the patient delivers therefore will not remain part of the medical record. 
 
Additionally, at the conclusion of the research study, all data collected will be destroyed by Nicole Masse. 
 
VII.D.7 
Does the research team agree that the requested information will not be reused or disclosed to any other 
person or entity, except as required by law, for authorized oversight of the study, or for other research for 
which the use or disclosure of the requested information would be permitted by the HIPAA Privacy Rule 


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Yes 
 
VII.D.8 
Will a member of the research team discuss the study with the subject in person prior to the subject agreeing to 
participate? 
Yes 
 
VII.D.9 
Describe the physical location where the consent process will take place: 
Nicole Masse (or designated members of her research team) will be responsible for discussing the study and 
reviewing consent with all patients. The consent process will take place at both clinic visits (UIHC clinics) 
and on labor and delivery. 
 
VII.D.10 
Will a member of the research team discuss the study with the subject by phone prior to the subject agreeing to 
participate? 
No 
 
VII.D.12 
Who will be involved in the consent process (including review of consent document, answering subjects' 
questions)? 
Name 
Consent Process Involvement 
Nicole Masse, MD 
Yes 
Mildrede Bonglack, MD 
Yes 
Rebecca Chung, BS 
Yes 
Colette Gnade, MD 
Yes 
Shelby Green, MD 
Yes 
Leigh Hess, MD 
Yes 
Danielle Ikoma, MD 
Yes 
Emily Jacobs, MD, MS 
Yes 
Jordan Mattson, MD 
Yes 
Laura Rasmussen, MD 
Yes 
Hope Richards, MD 
Yes 
Keely Ulmer, MD 
Yes 
Vincent Wagner, MD 
Yes 
Noelle Waldschmidt, BS 
Yes 
Heather Winn, MD 
Yes 
Cynthia Wong, MD 
No 
 
VII.D.15 
Check all materials that will be used to obtain/document informed consent: 
Consent Document 
 
 
VII.D.16 
Are you requesting a waiver of documentation of consent (either no subject signature or no written document)? 
No 
 
VII.D.19 
 Before the subject gives consent to participate are there any screening questions that you need to directly ask the 
potential subject to determine eligibility for the study? 
Yes 
 
VII.D.20 
List any screening questions you will directly ask the potential subject to determine eligibility. 
Prior to consenting patients to the study I will confirm they do not have any contraindications to the study 
drug (i.e. hypertension, preeclampsia, gestational hypertension, HIV, cardiac disease). 
 
VII.D.21 
Will you keep a screening log or other record that would include information on people who do not enroll  
in the study? 
Yes 
 
VII.D.22 
Describe the information being collected and the purpose for keeping this information. 
This information will only be used to look at enrollment and how many patients assessed for eligibility 
were excluded from the study after declining to participate. 
 
This information will be kept in a secure platform - RedCap. I plan on recording patients medical record 
number. This information will be destroyed at the completion of the study. 


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VII.D.23 
Will this information be shared with anyone outside the UI research team members? 
No 
 
VII.D.25     After the subject agrees to participate (signs consent), are there any screening procedures, tests, or studies that    
need to be done to determine if the subject is eligible to continue participating? 
No 
 
VII.D.27 
Discuss how much time a potential subject will have to agree to consider participation and whether or not they 
will be able to discuss the study with family/friends before deciding on participation. 
The potential subject would have from the time they are approached up until the time a cesarean section is required.  
As patients will be approached both in clinic and upon arrival to labor and delivery, patients will have weeks to days  
to discuss study with family and friends prior to deciding on participation. 
 
VII.D.28 
How long after the subject agrees to participate do study procedures begin? 
If patients are consented in clinic, study procedures may take weeks as the study procedure will not take place until 
the patient arrives for delivery. 
If patients are consented upon arrival to labor and delivery, many patients are in labor for 24-72 hours before 
deeming a cesarean section necessary. 
 
VII.D.29 
Provide a description of the enrollment and consent process for adult subjects 
Describe each study population separately including control population 
Include when recruitment and consent materials are used 
Use 3rd person active voice “The Principal Investigator will identify subjects. For example, the principal 
investigator will identify potential subjects, the study coordinator will discuss the study with subjects over 
the telephone and schedule the first study visit, etc...” 
Describe the steps that will be taken by the research team to minimize the possibility of coercion or undue 
influence during the consent process 
Nicole Masse (NM) or designated members of her research team will be responsible for reviewing patients charts 
through EPIC to determine eligibility. If patients are found to meet study criteria, NM or members of the research 
team will review both consent form and consent summary and obtain consent if patients wish to participate in the 
study. Patients will be consented in clinic or upon arrival to labor and delivery. This will avoid consenting patients 
prior to when a cesarean section is deemed necessary during the labor process as this can be an anxiety provoking 
time for patients. Patients will be given the opportunity to discuss enrollment with their family and friends. 
 
NM (primary investigator) will meet with all members of the research team prior to the start of the study to review 
the consent process. NM will make herself available at all times (through cell phone and pager), in the event 
questions were to arise. 
 
VII.D.37 
Does the study include any form of deception (e.g., providing participants with false information, misleading 
information, or withholding information about certain study procedures)? 
Examples: 
 
Procedure includes a cover story that provides a plausible but inaccurate account of the purposes of the 
research. 
Participants will be provided with false information regarding the particular behaviors of interest in the 
research. 
Procedures include a confederate pretending to be another participant in the study. 
Participants will be told that the research includes completion of a particular task, when in fact, that task 
will not be administered. 
Study is designed to introduce a new procedure (or task) that participants are not initially told about.  
If yes, a waiver of informed consent must be requested under question IV.3. 
No 
 
 
VII.E. Project Description (E) 
 
VII.E.1 
Will subjects be randomized? 
Yes 
 
VII.E.1.a 
Will any subjects be blinded to which study arm they have been assigned? 
Yes 


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VII.E.1.b 
Does the protocol permit telling subjects their treatment assignment at the end of the entire 
study? 
No 
 
VII.E.1.d 
Justify why subjects cannot be told what study arm they have been assigned. You will 
need to disclose to subjects in the consent document that they cannot receive this 
information. 
Knowledge of whether patients received study drug/placebo might impact one of our 
secondary outcomes - the need for blood transfusion. 
 
Determination of the need for a blood transfusion is dependent on hemoglobin levels and 
maternal symptoms concerning for anemia (fatigue, heart palpitations, shortness of breath).   
If the patient is aware of whether they received the  treatment  drug/placebo  this  could 
impact the results of this outcome as patients reported symptoms could be impacted by their 
knowledge of whether study drug/placebo was given. 
 
Additionally, in our current practice, it is not standard of care to disclose if uterotonics were 
given in the procedure to assist with uterine atony or hemorrhage. 
 
If a patient requests to know which treatment assignment she was randomized to, she will 
be given the option of receiving a letter (either emailed or mailed to her home address) at 
the completion of the study. 
 
VII.E.2 
Describe randomization scheme/assignment including ratio such as 1:1, 2:1 etc. 
A 1:1 allocation ratio with randomized block design using mixed block sizes. A computer generated list of 
random numbers will be used to generate the allocation sequence using nQuery Advisor. 
 
VII.E.3 
Will any questionnaires, surveys, or written assessments be used to obtain data directly from subjects in this 
study? 
No 
 
VII.E.5 
Does this project involve creating any audiotapes, videotapes, or photographs? 
No 
 
VII.E.6 
Provide a detailed description in sequential order of the study procedures following the consent process - DO 
NOT cut and paste from the Consent Document. 
 
Describe study populations separately if they will be participating in different procedures - include CONTROL 
population if applicable. 
 
DESCRIBE: 
What subjects will be asked to do/what happens in the study (in sequential order) 
The time period over which procedures will occur 
The time commitment for the subject for individual visits/procedures 
Long-term followup and how it occurs 
All patients who meet eligibility for the study will be consented during their clinic visit or upon arrival to labor and 
delivery. If patients elect to participate in the study, enrollment in the study will be noted in their sticky note in EPIC 
which will be ready available to all members of the health care team. 
 
If patients during the labor process require a cesarean section, the anesthesiologist will pick up a sealed envelope 
(which will contain the allocation sequence and group assignment). The sealed envelopes will be readily available to 
the anesthesiologist and kept in the anesthesia workroom. Following delivery of the infant, the patient will receive    
the standard oxytocin infusion. Following administration of the oxytocin infusion, the patient will be given either 
methylergonovine 0.2 mg IM (intramuscular) or placebo (1 ml of normal saline, intramuscular). This will be drawn   
up and administered by the anesthesiologist. The obstetrician (delivering provider performing the cesarean section)  
will be blinded to the group assignment. Documentation of the drug will be recorded in epic in the medication 
administration record. 
 
The delivering provider will be responsible for determining and relaying to the anesthesiologist whether additional 
uterotonics are needed throughout the procedure. Additional uterotonics will be given in accordance to the current 
guidelines outlined by the American Congress of Obstetricians and Gynecologists (ACOG). The delivery provider  
will assess uterine tone at 4 minutes (satisfactory versus unsatisfactory). The registered nurse will be responsible for 


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setting up a timer to let the OB provider know when 4 minutes have passed. Nursing will call out once the 4 minutes 
have passed and the OB provider will state whether adequate tone was noted. The anesthesiologist will be    
responsible for documenting whether a placebo/study drug was given and uterine tone after 4 minutes. This 
documentation will be placed back into the sealed envelope by the anesthesiologist and placed in the anesthesia 
workroom. Nicole Masse will pick up folders on a regular basis (every 1-3 days) and store folders in a secured,   
locked file cabinet within the Maternal Fetal Medicine offices. 
 
As routinely done at the time of cesarean delivery, the registered nurse will be responsible for measuring and 
documenting the quantitative blood loss. As routinely performed on all are patients who undergo a vaginal or 
cesarean delivery, preoperative hemoglobin and postoperative day one hemoglobin levels will be collected. 
 
In the event a delayed postpartum hemorrhage was to occur, the obstetrician will be un-blinded at the conclusion of 
the cesarean delivery as management of a delayed hemorrhage will be driven by the uterotonics received in the 
operating room. Because all drugs administered during the procedure will be documented in the patients medical 
record, the obstetrician will have access to the medications given during the cesarean section. 
 
The majority of our outcomes (including a primary outcome - need for additional uterotonics) will be assessed in the 
operating room. The outcomes we plan on assessing in the operating room include uterine tone, quantitative blood 
loss). Outcomes we plan on assessing in the immediate postpartum period include: postpartum hemoglobin values, 
need for a blood transfusion, admission to the intensive care unit, endometritis). 
 
No long-term follow will be needed. 
 
 
VII.E.7 
Will you attempt to recontact subjects who are lost to follow-up? 
No - followup is not required in this study 
 
VII.E.9 
Will subjects be provided any compensation for participating in this study? 
No 
 
 
VIII. Risks 
 
VIII.1 
What are the risks to subjects including 
- emotional or psychological 
- financial 
- legal or social 
- physical? 
Discomfort at the injection site. 
The risk of giving the drug when not necessary. 
Rarely observed reactions have included: acute myocardial infarction, transient chest pains, vasoconstriction, 
vasospasm, hypertension, coronary arterial spasm, bradycardia, tachycardia, dyspnea, hematuria, thrombophlebitis, 
water intoxication, hallucinations, seizures, leg cramps, dizziness, tinnitus, nasal congestion, diarrhea, diaphoresis, 
palpitation, rash, and foul taste 
 
There will be no financial risks to the patient as the Department of Maternal Fetal Medicine we will be covering both 
the costs of the study drug and the placebo. 
 
VIII.2 
What have you done to minimize the risks? 
If applicable to this study ALSO include: 
How you (members of your research team at Iowa) will monitor the safety of individual subjects. 
Include a description of the availability of medical or psychological resources that subjects might 
require as a consequence of participating in this research and how referral will occur if necessary 
(e.g. availability of emergency medical care, psychological counseling, etc.) 
We have minimized risks by excluding patients with a documented hypersensitivity to methylergonovine or patients 
with contraindications to the drug (i.e. hypertension, preeclampsia, coronary artery disease, HIV on a protease 
inhibitor). 
 
VIII.3 
Does this study have a plan to have an individual or committee review combined data from all subjects on a 
periodic basis (such as summary or aggregate safety and/or efficacy data)? 
Yes 
 
VIII.4 
Describe the plan to review combined data from all subjects, such as summary or aggregate safety and/or 


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efficacy data. Include the following: 
Describe what data will be summarized and reviewed 
Describe how frequently data will be reviewed. 
Andrea Greiner MD will review aggregate data every for every 25 randomized subjects to check for any 
unexpected safety findings related to either study arm 
 
VIII.5 
Will overall safety monitoring be performed by individual(s)/committee at The University of Iowa. (NOTE:  
If this study involves more than minimal risk, in most cases these should be individuals who are not 
members of the study research team.)? 
Yes 
 
VIII.6 
List names: 
Andrea Greiner MD (MFM Fellowship Director) 
 
VIII.7 
Will overall safety monitoring be performed by individuals or committee not associated with The University 
of Iowa (such as a study Data Safety Monitoring Board)? 
No 
 
 
IX. Benefits 
 
IX.1 
What are the direct benefits to the subject (do not include compensation or hypothesized results)? 
No direct benefit to patients 
 
IX.2 
What are the potential benefits to society in terms of knowledge to be gained as a result of this project? 
Uterine atony is the leading cause of postpartum hemorrhage. Postpartum hemorrhage is the leading cause of  
maternal mortality worldwide. It is well known that laboring patients who ultimately require cesarean delivery are a 
subset of women who are at increased risk for uterine atony. We anticipate the use of multimodal prophylactic 
uterotonics in these patients at the time of cesarean section will serve to prevent uterine atony, therefore reduce the 
morbidity and mortality associated with postpartum hemorrhage. 
 
 
 
X. Privacy & Confidentiality 
 
X.1 
What are you doing to protect the privacy interests of the subjects? 
All discussion of the study will take place in a private room - either in clinic or in a labor and delivery room. 
We also plan on collecting the minimal amount of data needed to answer the research questions. 
X.2 
Are you collecting the Social Security Number of any subjects for any purpose? 
No 
 
X.4 
How will information/data be collected and stored for this study (check all that apply): 
Paper/hard copy records (hard copy surveys, questionnaires, case report forms, pictures, etc.) - All records 
containing protected health information will be transported in a manner that no identifiable information is 
visible. All hard copy material will be kept in Nicole Masse's office within a locked file cabinet. 
Electronic records (computer files, electronic databases, etc.) - Electronica data will be collected by reviewing 
patients medical chart through EPIC. All protected health information obtained will be stored through    
REDCap (research electric data capture) a secure web based interface for storing study information. 
Name - Nicole Masse 
Title - Physician 
University Job Classification - Maternal Fetal Medicine Fellow 
 
 
X.5 
Do the confidentiality protections indicated above allow only members of the research team to access the 
data/specimens? 
Yes 
 
X.7 
Does your study meet the NIH criteria for a Certificate of Confidentiality or will you be applying for Certificate of 
Confidentiality? 
No 


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XI. Data Analysis 
 
XI.1 
Describe the analysis methods you will use, including, if applicable, the variables you will analyze 
Continuous variables will be analyzed using a fishers exact t-test (i.e. hemoglobin value). Categorical variables will  
be compared using a chi square analysis (i.e need for additional uterotonics). 
 
Multiple logistic regression will be used to model the relationship between the group assignment (methylergonovine  
vs placebo) and the need for additional uterotonic agents while controlling for potential confounders. P < .05 will be 
considered statistically significant. 
 
XI.2 
Provide the rationale or power analysis to support the number of subjects proposed to complete this study. 
Preliminary data demonstrated 42% of laboring patients requiring a cesarean section at the University of Iowa over 
the past 12 months required additional uterotonics at delivery in addition to the standard oxytocin infusion. 
 
To detect a 2 fold decrease in the need for additional uterotonics (42% vs 21%) with a type 1 error of 5% and power  
of 80%, a sample size of 76 patients per group will be necessary. To account for missing information (i.e. failure to 
document uterine tone, failure to document in quantitative blood loss in the medical record), we plan to recruit 80 
patients per group. 
 
 
 
XII. Future Research 
 
XII.1 
Do you wish to keep any information about subjects involved with this research project so that members of the 
current research team may contact them in the future for your own research projects? 
No 
 
XII.2 
Do you wish to keep any information about subjects involved with this research project so that other researchers 
may contact them for future research? 
No 
 
XII.4 
Does this project involve storing any data, tissues or specimens for future research? 
No 
 
 
ROC. Record of Consent 
 
ROC.1 
Select which option applies to address the University of Iowa Health Care policy IM-MR-06.21 titled 
 “Documentation of patient participation as a subject in a research protocol or use of an investigational 
 medication, study medication, investigational device, or biologic.” 
The research related activities proposed in this study does meet the registration requirements under the University of 
Iowa Health Care policy IM-MR-06.21 titled “Documentation of patient participation as a subject in a research 
protocol or use of an investigational medication, study medication, investigational device, or biologic.” The below 
information must be completed and approved as part of the IRB application. This information contained   
within this page will be used to create the Epic Research Study Application Form. 
 
ROC.2 
Select a publicly viewable title for this study. (This title will be visible in EPIC) 
Release full title 
 
ROC.3 
Select research team member who has taken Epic Training 
Nicole Masse 
 
ROC.4 
Who is a 24/7 contact person for projects involving treatment(s) or procedures that result in complications 
or side effects? 
Nicole Masse 
Other contact information that may be relevant to a subject’s clinical care (i.e. may be important if the 
contact person is not available 24/7 or an alternate contact may be required.) 
708-466-2034 (cell phone) 
 
ROC.5 
Describe the key complications from the study drug(s) listed below or study procedure(s): 
A complication of methlyergonovine is hypertension. As such, patients with hypertensive disorders will be 


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excluded to avoid exacerbation of a hypertensive disorder. Patients with a history of a hypersensitivity reaction  
to methyergonovine will also be excluded. 
 
By elimination of relative contraindications to the administration of methylergonovine, I anticipate the risks to 
patients to be minimal. Methlyergonovine is a medication commonly given on labor and delivery for the 
treatment of uterine atony. Provided contraindications to medication administration is avoided, patients   
typically tolerate the drug well. 
 
ROC.6 
Any other information that may be important to emergency personnel: 
None 
 
ROC.7 
Would you like to advertise this study on the Iowa Clinical Research & Trials website? 
No 
 
 
New Project Form Attachments 
 
Attachment Name 
 Multimodal Uterotonics Infomred Consent May 3.rtf 
Category 
Informed 
Ver 
Size 
6  191 k 
Type 
E 
Attached 
06/17/19 
Consent 
 Multimodal Uterotonics Trial Consent Summary Final.rtf 
Other 
2 66 k 
E 
05/03/19 
Consent 
Document 
 Screening Log Multimodal Uterotonics Study.xlsx 
Screening: 
Screening 
Log 
1 
8 k 
E 
03/26/19 
 SKMBT_C454e19040111111.pdf 
Assurance 
Document 
1 808 k 
E 
04/01/19 
 

SAP_001.pdf: 
 
A Randomized Controlled Trial to Assess the Effectiveness of 
Multimodal Prophylactic Uterotonics in Patients Undergoing 
Non-Elective Cesarean Sections after a Trial of Labor 
 
 
 
NCT Number:  03904446 
 
 
 
Nicole Masse, MD 
 
Document Date:  June 17, 2019 
 
 


Continuous variables will be analyzed using a fishers exact t-test (i.e. hemoglobin value). 
Categorical variables will be compared using a chi square analysis (i.e. need for additional 
uterotonics). Multiple logistic regression will be used to model the relationship between the 
group assignment (methylergonovine vs placebo) and the need for additional uterotonic agents 
while controlling for potential confounders. P < .05 will be considered statistically significant.  
Provide the rationale or power analysis to support the number of subjects proposed to 
complete this study. Preliminary data demonstrated 42% of laboring patients requiring a 
cesarean section at the University of Iowa over the past 12 months required additional 
uterotonics at delivery in addition to the standard oxytocin infusion.  To detect a 2-fold 
decrease in the need for additional uterotonics (42% vs 21%) with a type 1 error of 5% and 
power of 80%, a sample size of 76 patients per group will be necessary. To account for missing 
information (i.e. failure to document uterine tone, failure to document in quantitative blood 
loss in the medical record), we plan to recruit 80patients per group.