Clinical trial NCT03556761
Conditions: Hypertension, Pregnancy-Induced
Keywords: Furosemide Postpartum Hypertension
Sponsor: University of Pennsylvania
Start date: 2018-06-20; Completion date: 2020-02-05
Enrollment: 384 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized, double-blind, placebo-controlled single center investigation of furosemide's effect on postpartum blood pressure control in pregnancies affected by hypertensive disorders of pregnancy

Detailed description:
Hypertensive disorders of pregnancy are recognized causes of significant maternal/fetal morbidity and mortality, accounting for approximately 18% of maternal deaths worldwide. While significant research has been done on the evaluation and management of hypertension during pregnancy, studies of postpartum hypertension (PPHTN) are usually limited by their retrospective design and focus on inpatients in the immediate postpartum period (2-6 days), or patients who were readmitted due to complications related to hypertension. Few studies have investigated the incidence and proper management of hypertension in the postpartum period. Furthermore, in the United Kingdom, a review of maternal deaths determined that 10% were related to hypertensive disorders in pregnancy (HDP) in the postpartum period. Postpartum hypertension is also the cause of approximately 27% of readmissions to the hospital. These studies clearly show that PPHTN is associated with significant morbidity and that it is important to develop interventions that can reduce its effects.

In patients with HDP, postpartum blood pressure has been shown to decrease in the first 48 hours postpartum only to then increase in days 3-6 postpartum. This phenomenon is thought to be secondary to large fluid shifts, both secondary from fluid retention during the pregnant state as well as from fluids given intrapartum. Furthermore, large volumes of sodium are also mobilized into the intravascular compartment at this time. Given the latter, furosemide, a loop diuretic that mobilizes sodium and fluid excretion has been posed as a method to prevent severe range blood pressures and their associated maternal morbidity in the postpartum period.

Arms: arm 1: Oral furosemide 20 mg/day for a total of 5 consecutive doses. arm 2: Placebo once per day for a total of 5 consecutive doses.
Interventions: intervention 1: Oral furosemide intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: Furosemide (Lasix), 20 milligram, PO, PO, daily intervention 2: Placebo, PO, daily

Protocol documents:
Prot_SAP_000.pdf: 
Furosemide for Accelerated Recovery of Blood Pressure Postpartum: a 
randomized controlled trial (FoR BP trial) 
 
A randomized, double-blind, placebo-controlled single center investigation of furosemide’s effect on 
postpartum blood pressure control in pregnancies affected by hypertensive disorders of pregnancy 
 
 
 
 
 
 
 
 
 
 
Protocol date: July 19, 2018 
 
NCT#03556761 
 
 
 
 
 
 
 
 
 
 
 


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i 
Furosemide for Accelerated Recovery of Blood Pressure Postpartum: a 
randomized controlled trial (FoR BP trial) 
 
A randomized, double-blind, placebo-controlled single center investigation of furosemide’s effect on 
postpartum blood pressure control in pregnancies affected by hypertensive disorders of pregnancy 
 
 
 
Principal Investigator:  
Lisa D. Levine, MD, MSCE 
 
 
 
 
Assistant Professor 
 
 
 
 
Division of Maternal Fetal Medicine 
 
 
 
 
Department of Obstetrics and Gynecology 
 
 
 
 
3400 Spruce St 
 
 
 
 
2 Silverstein 
 
 
 
 
Philadelphia, PA 19104 
 
 
 
 
 
 
Sub-Investigator(s): 
 
Joana Lopes Perdigao, MD 
 
 
 
 
Clinical Fellow 
 
 
 
 
Division of Maternal Fetal Medicine 
 
 
 
 
Department of Obstetrics and Gynecology,  
 
 
 
 
 
 
 
 
 
 
Study Drug/Study Device: 
Furosemide (Lasix) 
 
 
 
 
 
 
 
 


 
Page 1 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data and Safety Monitoring Board 
gHTN 
Gestational hypertension 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
HDP 
Hypertensive disorders of pregnancy 
HTN 
Hypertension 
IV (or iv) 
Intravenously 
PI 
Principal Investigator 
PO 
per os/by mouth/orally 
PPHTN 
Postpartum hypertension 
PR 
Partial Response 
SAE 
Serious Adverse Event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STUDY SCHEMA 
 
 
STUDY SUMMARY 
Title 
Furosemide for Accelerated Recovery of Blood Pressure Postpartum: a 
randomized controlled trial 
Short Title 
FoR BP trial 
Methodology 
Double blind, randomized, placebo control design 
Study Duration 
20 months 
Study Center(s) 
Single-center 
Objectives 
To investigate the impact of a short course of furosemide on postpartum 
blood pressure recovery in women with hypertensive disorders of 
pregnancy (HDP). 
Number of Subjects 
385 
Diagnosis and Main 
Inclusion Criteria 
Clinical disease state under study: hypertensive disorder of pregnancy, 
postpartum with delivery >20 weeks EGA, diagnosis of HDP antepartum, 
intrapartum and up to within 1 day of delivery 
Study Product(s), Dose, 
Route, Regimen 
Furosemide (Lasix), 20mg, PO, daily 
Duration of administration 
5 days 
Reference therapy 
Placebo 
Statistical Methodology 
Intention to treat analysis, chi-square tests for categorical variables, two-
sample t-test for continuous variables 
 
 


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1 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Hypertensive disorders of pregnancy are recognized causes of significant maternal/fetal morbidity 
and mortality, accounting for approximately 18% of maternal deaths worldwide. 1 While significant 
research has been done on the evaluation and management of hypertension during pregnancy, 
studies of postpartum hypertension (PPHTN) are usually limited by their retrospective design and 
focus on inpatients in the immediate postpartum period (2-6 days), or patients who were 
readmitted due to complications related to hypertension.2 Few studies have investigated the 
incidence and proper management of hypertension in the postpartum period. PPHTN can present 
either de novo, following a normotensive pregnancy, or as persistent hypertension following a 
pregnancy complicated by preeclampsia or other hypertensive disorders of pregnancy.2,3 Limited 
information is available on the clinical sequelae of PPHTN, but retrospective studies suggest that 
it can lead to death or to potentially life-threatening complications, such as cerebrovascular 
accidents,4,5 seizures,6 congestive heart failure, pulmonary edema, and renal failure.2,7 
Furthermore, in the United Kingdom, a review of maternal deaths determined that 10% were 
related to HDP in the postpartum period.8 Postpartum hypertension is also the cause of 
approximately 27% of readmissions to the hospital.9 These studies clearly show that PPHTN is 
associated with significant morbidity and that it is important to develop interventions that can 
reduce its effects. 
Guidelines from national organizations such as the American College of Obstetrics and 
Gynecology (ACOG) recognize the growing concern with postpartum hypertension and have put 
forth specific guidelines on how to monitor for hypertension postpartum. This includes educating 
patients of signs and symptoms of pre-eclampsia, monitoring blood pressures for 72 hours in the 
hospital prior to discharge, and checking an ambulatory blood pressure within 10 days of 
delivery.10 However, only checking blood pressures 7 to 10 days after delivery is likely missing a 
significant number of patients. Several studies note that only 28 to 57% of patients PPHTN have 
their blood pressure normalize within 3 days12,13 Furthermore, data out of our own institution 
noted that 6% of women with HDP were readmitted within 3 to 14 days for hypertension related 
reasons.11 Therefore, interventions to improve the care of women with PPHTN are urgently 
needed. 
1.2 
Study Agent(s)/Devices Background and Associated Known Toxicities 
 
Furosemide (Lasix) is a loop diuretic that is also a known antihypertensive. It exerts its 
mechanism of action by inhibiting reabsorption of sodium and chloride in the ascending loop of 
Henle and distal renal tubule. It also interferes with the chloride-binding cotransport system. 
Accordingly, this causes increased excretion of water, sodium, chloride, magnesium, and 
calcium.  It is known to have onset of action of up to 60 minutes if given by mouth and 5 minutes 
if given by IV for diuresis. Duration is estimated to 6-8 hours when given orally and 2 hours when 
given IV. It is a hepatically metabolized medication with 91-99% protein binding (mostly albumin). 
Bioavailability ranges from 47-64% orally and it has a half-life of 0.5–2 hours. Excretion is through 
the urine with 50% of the PO version 80% of the IV version of the drug excreted within 24 hours.  
Significant side effects are related to the fluid and electrolyte shifts that occur with its lack of 
resorption of electrolytes. These include, but are not completely limited to ototoxicity, mood 
changes, confusion, muscle pain, palpitations, dizziness, syncope, increased thirst, fatigue, 
weakness, decreased appetite, dry mouth, dry eyes, upset stomach, nausea, and emesis.  
 
Prior studies for the prevention and treatment of postpartum hypertension with furosemide had 
mixed results. Three trials (390 women) assessed oral furosemide (20-40 mg/day) in postpartum 
women with preeclampsia.3 In one study, there was a non-statistically significant trend to more 
rapid blood pressure reduction in the group receiving furosemide.14 The second study showed that 
furosemide, given postpartum, was associated with reduced systolic blood pressures only among 
women with severe preeclampsia.15 Meanwhile, the third study found that although furosemide was 
able to reduce the amount of antihypertensive medication given, no significant differences in 


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blood pressures were found in patients with severe preeclampsia.16 Given the inconclusive 
results and little data thus far on the use of postpartum furosemide, a recent Cochrane review 
concluded that more data is needed on substantive outcomes before the practice of postnatal 
furosemide can be recommended.3 
 
Placebo will be given to half of our enrolled patients which will be determined through 
randomization. All placebo will be manufactured and distributed by the Investigational Drug 
Service (IDS) of the University of Pennsylvania. IDS will manufacture the placebo to be similar to 
the furosemide pill. If necessary, IDS will add a coating shell to both the furosemide and placebo 
pills to ensure that all pills look similar.  
1.3 
Rationale 
In patients with HDP, postpartum blood pressure has been shown to decrease in the first 48 
hours postpartum only to then increase in days 3-6 postpartum.17-19 This phenomenon is thought 
to be secondary to large fluid shifts, both secondary from fluid retention during the pregnant state 
as well as from fluids given intrapartum.  Furthermore, large volumes of sodium are also 
mobilized into the intravascular compartment at this time.3 Given the latter, furosemide, a loop 
diuretic that mobilizes sodium and fluid excretion has been posed as a method to prevent severe 
range blood pressures and their associated maternal morbidity in the postpartum period. 
 
2 
STUDY AIMS 
2.1 
AIM 1: To compare the rate of persistently elevated blood pressures 7 days postpartum 
in women that receive a five day furosemide course compared to those that receive 
placebo 
2.2 
AIM 2: To compare the time (days) required to achieve a resolution of elevated blood 
pressure.  
 
2.3 
Endpoints 
2.3.1 
Primary endpoint 
2.3.1.1 
Postpartum hypertension composite outcome, defined as:  
 
Persistently elevated blood pressure (≥140/90) at 7 days 
postpartum OR 
 
Additional 
requirement 
of 
antihypertensive 
agents 
after 
randomization  


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2.3.2 
Secondary endpoints 
2.3.2.1 
Number of readmission/ ER visit that is hypertension related 
2.3.2.2 
Frequency of severe hypertension (SBP>160mmHg or DBP>110mmHg) 
2.3.2.3 
Number of days required until blood pressure resolution (<140/90 for 2 
days) 
2.3.2.4 
Postpartum length of stay 
2.3.2.5 
Complications during hospitalization related to hypertensive disorders of 
pregnancy (acute pulmonary edema, acute kidney injury, disseminated 
intravascular coagulation, stroke or myocardial infarction, eclampsia, ICU 
stay, maternal death) 
2.3.2.6 
Adverse effects secondary to furosemide  
 
 
 
 
 
 
3 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and exclusion criteria to be enrolled to the study. Study 
treatment may not begin until a subject is consented and randomized. 
3.1 
Inclusion Criteria 
3.1.1 
Hypertensive disorder of pregnancy diagnosed antepartum or intrapartum 
  Patients with diagnosis of preeclampsia with severe features, superimposed pre-
eclampsia and gestational hypertension as diagnosed per ACOG guidelines10 
 
o 
Gestational hypertension  
- Two blood pressures at least 4 hours apart > 140/90 with no proteinuria 
or other laboratory abnormalities (detailed below) 
 
o 
Pre-eclampsia with severe features and superimposed pre-eclampsia (any 
of the findings below) 
- Two blood pressures at least 4 hours apart > 160/110 (unless patient 
given antihypertensive therapy before this time)  
- Thrombocytopenia (platelets <100,000/microliter) 
- Liver enzymes at least twice the normal concentration, and/or severe 
right upper quadrant/ epigastric pain 
- Serum creatinine > 1.1 mg/dL or a doubling of baseline serum creatinine 
- Pulmonary edema 
- New-onset cerebral or visual disturbances (headache, blurry vision) 
 


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3.1.2 
New diagnosis of HDP within 1 day from delivery 
3.1.3 
Postpartum, delivery ≥ 20 weeks EGA 
3.1.4 
Age ≥18 years old 
3.1.5 
Have a phone with texting service and be willing to enroll in HUP’s established 
postpartum hypertension texting program, HeartSafe Motherhood 
3.1.6 
Ability to understand and the willingness to sign a written informed consent and 
comply with study procedures 
 
3.2 
Exclusion Criteria 
3.2.1 
History of allergic reaction to furosemide 
3.2.2 
High risk comorbidities for which treatment may be indicated or contraindicated: 
class C or higher diabetes mellitus, chronic kidney disease or baseline creatinine 
>1.2, cardiac disorders including cardiomyopathy, congenital heart disease, angina 
or coronary heart disease, rheumatic disease (lupus), sickle cell disease 
3.2.3 
Baseline labs with K <3 
3.2.4 
Use of furosemide or other diuretics antepartum or intrapartum 
3.2.5 
Use of ototoxic agents including aminoglycosides (ie, Gentamicin for >1 dose), 
cephalosporins (ie Ancef >1 dose),  
3.2.6 
Patient unstable for protocol per investigator’s judgement 
3.3 
Vulnerable patient populations 
Pregnant women are considered a vulnerable population. As the condition of interest is a 
pregnancy-related and specific condition, it is unavoidable to exclude pregnant women from this 
research study. However, all risks to this vulnerable population will be minimized as most of the 
study will occur in the postpartum period.  None of the study medications will be given until the 
patient has been postpartum for at least 6 hours.  
Furthermore, neonates are considered a vulnerable population. We will be collecting data on 
neonatal rates on NICU admission or readmission to the hospital within 6 weeks postpartum to 
determine if there are any adverse effects of furosemide to the neonates. All risks to this 
vulnerable population will be less than minimal risk as furosemide has been used in lactating 
mothers previously with no neonatal adverse events noted at HUP.  Also, no data currently exists 
in the literature to suggest that furosemide would pose any risk to breastfed infants.  
3.4 
Ensuring Necessary Medical Interventions 
Being enrolled in this study will not change patients’ clinical care in regards to antepartum course 
 or delivery decisions. Their intrapartum management will not be different in any way. Regardless 
of randomization, the management will not be different in either arm apart from whether the 
intervention medication is given or not. Any elevations of blood pressure postpartum to greater or 
equal to 150/100 mmHg will receive amlodipine as first-line as an antihypertensive. Patients will 
be provided with prophylaxis against seizures and deep vein thrombosis appropriately as dictated 
by clinical care.   


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3.5 
Potential Benefit to Participants 
The potential benefit will be prevention of elevation of blood pressures to levels that are associated 
with high maternal among individuals randomized to the intervention arm. This will lead to a possible 
increased reduction in hypertension related morbidity, improved patient outcomes, and possibly 
decreased need for readmission or emergency room visits as compared to placebo. All efforts will 
be taken to minimize the risks associated with this study and the risks overall are considered 
minimal; therefore, the risk to subjects is reasonable compared to the benefit to patients and to 
society in general. 
 
4 
TREATMENT PLAN 
4.1 
Treatment Dosage and Administration 
4.1.1 
Oral furosemide 20 mg/day OR placebo for a total of 5 consecutive doses.   
- Missed or vomited doses will be noted and attempts made to provide them 
immediately when recognized for missed doses when inpatient.  After discharge, 
patients will be instructed to take a dose as soon as possible if they have missed 
one.  Furthermore, in the unlikely event that patients are discharged without a 
supply of their medications, we will ensure that the medication will be shipped to 
their house within 24 hours. 
4.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment will be evaluable for toxicity. Each patient will be 
assessed for the development of toxicity according to development of ototoxicity or 
symptomatic derangements in electrolytes as determined by symptoms and 
corresponding daily basic metabolic profiles. In the event of the development of either, 
the medication will be discontinued.  
4.3 
Concomitant Medications/Treatments 
To maintain adequate blood pressure control postpartum (goal SBP < 150 mmHg and 
DBP < 100 mmHg ) additional antihypertensive medications may be necessary, and 
should be used at any time in the postpartum period regardless of enrollment time and 
first study drug administration: 
 
1) Any patient with persistent postpartum blood pressures, ≥150 mmHg 
systolic and/or ≥100 mmHg diastolic, will be started on 5 mg of amlodipine PO regardless 
of study arm or whether they are already taking another antihypertensive maintained from 
their antepartum period. 
 
2)  Any patient with persistent postpartum blood pressures, ≥160 mmHg 
systolic and/or 100 mmHg diastolic,  will be started on 10 mg of amlodipine PO.  
 
3) If blood pressures are still higher than the stated goal above, providers 
should utilize additional non-diuretic antihypertensive* medications known to be effective 
in managing elevated peripartum blood pressures. 
*Providers will be asked to use non-diuretic medications first, however, if deemed 
medically necessary, furosemide will be allowed any time in the postpartum period.  All 
uses of diuretic use for medically necessary reasons after enrollment of patient into the 
trial will be noted.   
4.4 
Duration of Therapy 
Therapy with furosemide will continue daily for 5 days unless there is the development of 
intercurrent illness that prevents further administration of treatment, unacceptable 
adverse events, patient withdrawal from the study, or general or specific changes in the 
patient’s condition render continued treatment unacceptable.  


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4.5 
Duration of Follow Up 
Patients will be followed for 10 days after discharge.  All patients that consent to the 
study will be expected to enroll at an established program at the Hospital of the University 
of Pennsylvania to monitor blood pressures postpartum through daily texting. Patients will 
be expected to measure their blood pressures at least once daily and text them to a 
physician through the program. The program, Heart Safe Motherhood, has been utilized 
successfully over the past year to follow-up women after discharge and be more readily 
available to monitor blood pressures and give advice. Patients removed from treatment 
for unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event.  
4.6 
Removal of Patients from Protocol Therapy 
Patients will be removed from therapy when any of the criteria listed in Section 4.2 and 
5.5 apply. The Principal Investigator will be notified and document the reason for study 
removal and the date the patient was removed in the Case Report Form. The patient will 
be followed-up per protocol.  
4.7 
Management of blinding 
This is a double blind study and therefore physicians, staff, and patients will be blinded to 
the patient’s allocated treatment group. In the event of a potential suspected unexpected 
serious adverse reaction, unblinding will be undertaken by the PI. Unblinding may also be 
performed at the request of a senior clinician responsible for the care of a trial participant 
but such requests are likely to occur only in the case of an adverse clinical event and are 
expected to be rare.  Any request to unblind treatment allocation for clinical reasons will 
be made directly to IDS and the treatment allocation will be reported to the relevant 
clinician. The PI and main trial manager will be kept informed of all instances of unblinding 
but remain blind to treatment allocations themselves wherever possible. All requests for 
unblinding will be recorded by research staff and IDS.  
5 
STUDY PROCEDURES 
5.1 
Screening for Recruitment and Recruitment Process 
The labor and delivery board and patient list will be screened daily to identify eligible 
patients. Women identified as having a hypertensive disorder of pregnancy will be invited to 
participate in the study and written informed consent will be obtained from those who choose 
to participate in the postpartum period. All screening procedures must be performed within 
24 hours of delivery. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
  
 
Complete medical and surgical history 
5.1.3 Demographics 
  
 
Age, gender, race, ethnicity 
5.1.4 Review subject eligibility criteria 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height and weight 
 
 
Vital signs (temperature, pulse, respirations, blood pressure),  
 
 
height, weight 


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5.1.7 Adverse event assessment 
Baseline adverse events will be assessed. See section 6 for 
Adverse Event monitoring and reporting. 
5.2 
Randomization 
If the patient is eligible, after informed consent the patient will be randomized by IDS. We 
plan to randomize through a computer generated sequence in blocks of 4 and stratify 
randomization blocks by whether severe features are present or not (ie., gestational 
hypertension and pre-eclampsia without severe features vs. pre-eclampsia with severe 
features).  IDS will then dispense the furosemide or placebo accordingly. 
5.3 
Procedures During Treatment  
After enrollment and consent, a specific order will be placed in the electronic medical 
record for this study’s purposes.  This order will alert IDS that a patient has been enrolled 
and the patient will be randomized accordingly. After randomization, IDS will send to the 
floor either 5 doses of placebo or furosemide clearly marked for the specific patient. A 
research coordinator will be present at this time and ensure that there are 5 doses of 
furosemide/placebo and that the patient’s nurse is aware that the patient is enrolled in the 
study. The research coordinator will also ensure that the medication order is given by 
postpartum day 1 and ensures that the first pill is given after 6 hours from delivery.  
Patients in the furosemide arm will be assigned to receive oral furosemide 20 mg/day for 
a total of 5 consecutive days during hospitalization and after discharge. This dose of 
furosemide is based on prior studies,3 which have shown it to be safe with breast 
feeding.2For those randomized to the placebo group, they will be given placebo pills for a 
total of 5 consecutive days. The time of initiation of first pill given will be recorded by the 
research coordinator.  Each time a pill is given in the hospital, it will be accounted for in 
the medical administration record (MAR) in the EMR.  Pills should be given approximately 
24 hours apart, and the Epic order placed after enrollment will have this distinction. 
 
Patients in both groups will undergo similar postpartum surveillance, including blood 
pressure and pulse assessment every 4 hours and urinary output measurements while 
hospitalized. Proper treatment for elevated blood pressures will be initiated immediately 
as soon as the elevated blood pressures are recognized, and will not be delayed for any 
study purposes including study drug administration. For this study, antihypertensive 
therapy will be initiated for persistently elevated postpartum blood pressures (BP) of > 150 
systolic or >100 mg Hg diastolic with 5 mg of amlodipine PO. Persistent severe range 
blood pressures (BP >160 mm Hg systolic or >110 mm Hg diastolic) will be treated with IV 
antihypertensives if needed, as well as 10 mg of amlodipine PO. If further 
antihypertensive medications are needed to maintain blood pressures <150/100, these 
will be per the discretion of the clinical staff in both arms. All physicians and clinical staff in 
Labor and Delivery as well the postpartum unit will be educated extensively to avoid 
diuretic antihypertensive medications unless deemed medically necessary. Furthermore, 
diagnostic and laboratory tests will be per the discretion of the clinical staff in both arms 
as well. Routinely, all patients undergoing cesarean section remain hospitalized for at 
least 3 days and all patients with preeclampsia with severe features are kept in the 
hospital for 3 days (per the recommendations of the ACOG Task Force on Hypertension 
in Pregnancy).10 All patients will be followed at for 10 days after discharge as detailed 
below. Being enrolled in the study will not change the patient’s clinical care at any time. 
Physicians, staff, and patients will be blinded to the intervention administered, unless a 
break in blinding is required for medical intervention of adverse effects.  
5.4 
Follow-up Procedures 
Prior to patient discharge, a research coordinator will ensure that the patient has the 
correct amount of pills left and will review instructions about taking the pill daily for 
however many remaining doses there are. If patients are breastfeeding exclusively, the 


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research coordinators will ask the patients upon discharge if they encountered any 
difficulties with breastfeeding while in the hospital. Patients will be followed for 10 days 
after discharge through Heart Safe Motherhood, a texting program offered at the Hospital 
of University of Pennsylvania in which women with HDP take their own blood pressures at 
home, and report those blood pressures through a texting service.  A physician who is 
part of the study, will review the blood pressures daily and notify patients if more blood 
pressures, medications, or medical attention are needed. All patients in the study will be 
asked to text through the program their daily blood pressure and an affirmation that they 
are taking the remaining daily doses of furosemide/placebo at home. All patients, 
regardless of whether they are in the study or not, are expected to have a 6 week 
postpartum appointment.  Participants will be asked to bring any remaining pills with them 
to that appointment at which time a research coordinator will collect the remaining pills, 
and record how many doses were missed. Any pills brought back by the patient will be 
given back to IDS to dispose of them. The research coordinator will also ask questions 
regarding any breastfeeding issues at this time. Furthermore, the charts of breastfed 
neonates will be followed to determine NICU admission or readmission during the first 6 
weeks postpartum. 
5.5 
Study schedule 
Procedure 
At 
Enrollment 
Within 1 
day of 
delivery 
Postpartum, 
in house 
Postpartum, 
at home 
Up to 10 
days after 
discharge 
Postpartum 
6 weeks 
Inclusion/exclusion 
and demographics 
X 
X 
 
 
 
 
Randomization 
X 
X 
 
 
 
 
Start intervention/ 
placebo 
 
X 
 
 
 
 
Intervention/placebo 
 
 
X 
X 
 
 
Blood pressure 
collection 
X 
 
X 
X 
X 
X 
Maternal outcomes 
 
 
 
 
 
X 
 
5.6 
Removal of Subjects from Study 
Patients can be taken off the study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative 
reasons. The reason(s) for discontinuation will be documented and may include: 
5.4.1 
Patient voluntarily withdraws from treatment (follow-up permitted);  
5.4.2 
Patient withdraws consent (termination of treatment and follow-up); 
5.4.3 
Patient is unable to comply with protocol requirements; 
5.4.4 
Patient experiences toxicity that makes continuation in the protocol unsafe; 
5.4.5 
Treating physician judges continuation on the study would not be in the patient’s 
best interest; 
5.4.6 
Lost to follow-up.  
 
If a research subject cannot be located to document outcomes after a period of 2 
weeks, the subject may be considered “lost to follow-up.” All attempts to contact 
the subject during the first 2 weeks after discharge will be documented and will 
not exceed more than 2 phone texting messages and 1 phone call with or without 
voicemails. 
5.4.6 
The study is stopped. 


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5.7 
Protections Against Physical Risk 
There is minimal risk to use of furosemide in the postpartum period. Furosemide is a 
commonly used drug in postpartum period and prior studies have not shown any adverse 
effects in this patient population. At the Hospital of University of Pennsylvania, 
furosemide has been used frequently as part of a postpartum hypertension protocol. A 
DSMB comprised of individuals who are not investigators on the trial will be utilized to 
monitor for adverse outcomes. A list of mandatory events that should be reported to the 
DSMB within 24 hours of occurrence will be supplied to all clinicians and research 
coordinators managing trial patients. The DSMB will stop the trial if there is a 20% 
increase in the rates of adverse outcomes (a composite outcome). The DSMB will review 
the data every 6 months. Also all serious adverse effect will be recorded and reported to 
the institutional review board. 
5.8 
Protection against Loss of Privacy/Breech of Confidentiality 
In order to protect a potential subject’s privacy, study staff will only approach potential 
subjects in a private setting. Once consented, we will take multiple steps to protect the 
study subject from breach of confidentiality. The list linking the subject’s name and 
medical record number will be kept behind the hospital firewall in a password-protected 
file. This file is only accessible through the hospital server to those individuals given 
password approval to access the file. Furthermore, the electronic database (REDCap) 
will be coded with a unique study identifier rather than with any individually identifiable 
private information. No PHI will be shared with anyone outside the institution.  
6 
Response Criteria 
6.1 
Criteria for initiation of therapy 
Therapy will be given after 6 hours from delivery. 
Safety/tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study 
drug.  
7 
ADVERSE EVENTS 
7.1 
Adverse Event Monitoring 
Adverse event data collection and reporting will be done to ensure the safety of subjects 
who will enroll be enrolled in thus study. Adverse events will be reported in a routine 
manner at scheduled times during the trial. Additionally, certain adverse events will be 
reported in an expedited manner to allow for optimal monitoring of patient safety and 
care.  
 
All patients experiencing an adverse event, regardless of its relationship to study 
drug/device, will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 


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7.2 
Definitions 
7.2.1 
Definition of Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.  
7.2.2 Severity of Adverse Events 
The severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
Fatal (grade 5): the event caused death. 
7.2.3 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
7.2.3.1 
Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
7.2.3.2 
Is life-threatening (i.e. the patient was at risk of death at the time of 
the event). 
7.2.3.3 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
7.2.3.4 
Results in persistent or significant disability or incapacity. 
7.2.3.5 
Is an important medical event. Essentially, any event that does not 
meet the above criteria, but that in the judgment of the investigator 
jeopardizes the patient, may be considered for reporting as a serious 
adverse event.  
 
 
 
For the purposes of this study, the adverse events that would meet any of these 
criteria are: maternal death, ICU admission, stroke, seizure, myocardial 
infarction, and cardiomyopathy will be documented and reported as a SAE. In 
addition, any unexpected event which the PI believes to have been cause or 
contributed to by the intervention, regardless of whether it resulted in 
hospitalization, will also be considered an AE or SAE (e.g., severe allergy or 
anaphylaxis due to furosemide).   


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7.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event   
 
Step 2: Grade the adverse event  
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
Step 4:  Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
 
the drug package insert; 
 
the current Investigator’s Brochure 
7.4 
Reporting Requirements for Adverse Events 
7.4.1 
Expedited Reporting 
 
The Principal Investigator will be notified within 24 hours of learning of any 
serious adverse events, regardless of attribution, occurring during the study 
or within 30 days of the last administration of the study drug.  
 
The University of Pennsylvania IRB must be notified within 10 business 
days of “any unanticipated problems involving risk to subjects or others” 
(UPR/UPIRSO). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), 
which in the opinion of the Principal Investigator was unanticipated, 
involved risk to subjects or others, and was possibly related to the 
research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved 
protocol that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated 
sponsor safety report), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or 
others. 
6. Any complaint of a subject that indicates an unanticipated risk or that 
cannot be resolved by the Principal Investigator. 


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7.4.2 
Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or definitely not 
related to the study participation- are to be reported annually as part of regular data 
submission. 
7.5 Stopping Rules  
This study does not have a primary safety endpoint or place study subjects at high risk. 
Please refer to section 11.2 for further discussion of Data Safety Monitoring. 
 
8 
DRUG/DEVICE INFORMATION 
8.1 
Furosemide 
 
Other names for the drug: Lasix 
 
Classification - type of agent: Loop diuretic; Antihypertensive 
 
Mode of action: inhibits reabsorption of sodium and chloride in the ascending loop of 
Henle and distal renal tubule, interfering with the chloride-binding co-transport 
system, thus causing increased excretion of water, sodium, chloride, magnesium, 
and calcium 
 
Protocol dose: 20 mg, daily 
 
Route of administration for this study: Oral 
 
Incompatibilities: NSAIDs may diminish the diuretic effect of loop diuretics. Loop 
diuretics may enhance the nephrotoxic effect of NSAIDs. Monitoring for evidence of 
kidney injury or decreased therapeutic effects of loop diuretics with concurrent use of 
an NSAID. 
 
Availability: commercially available, on formulary 
 
Side effects: ototoxicity, mood changes, confusion, muscle pain, palpitations, 
dizziness, syncope, increased thirst, fatigue, weakness, decreased appetite, dry 
mouth, dry eyes, upset stomach, nausea, and emesis associated with fluid and 
electrolyte problems (Please refer to the manufacturer’s package insert for a 
complete list of adverse events) 
 
Nursing implications: PO administration should be on empty stomach 
8.1.1 Product Preparation/Packaging, Receipt and Storage 
Investigational Drug Service (IDS) of the University of Pennsylvania will purchase 
commercial furosemide 20mg tablets. These will be over-encapsulated into gelatin 
capsule shells and backfilled with Lactose Monohydrate, NF. The finished furosemide 
capsules will be placed in a light protected Type 2 HDPE plastic container with a tightly 
sealing lid. An internal lot number and use-by date will be assigned. The use-by date will 
be 12 month or the remaining expiration of any component (whichever is less). 
Visually-matching placebo capsules will be prepared by backfilling Lactose Monohydrate, 
NF into gelatin capsule shells. The finished placebo capsules will be placed in a light 
protected Type 2 HDPE plastic container with a tightly sealing lid. An internal lot number 
and use-by date will be assigned. The use-by date will be 12 month or the remaining 
expiration of any component (whichever is less). 
 
IDS will dispense patient-specific study medication. IDS will package and deliver the 
drugs or study coordinators will pick them up as needed for participants. Drug 
accountability will be maintained by IDS and study coordinators. 
 
Study medication (furosemide) will be stored at room temperature at IDS research 
pharmacy.  Temperature is monitored in the investigational pharmacy daily. Once the 


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study medication or placebo are up on the floor, they will be stored at room temperature 
at a secure area for medications only accessible by floor and research staff.  
 
9 
STUDY DESIGN/STUDY ENDPOINTS 
This will be a prospective, randomized, double-blinded, single center study of the impact of a 
short course of furosemide on postpartum blood pressure recovery in women with hypertensive 
disorders of pregnancy (HDP). Please refer to Section 2.4 for end points.   
Regarding stopping rules for safety or efficacy, we do not anticipate early termination of the study 
for either. Issues that would be of concern would be persistent hypokalemia (< 3.0) with therapy, 
ineffectiveness of therapy (as defined by the use of the same dosing of other antihypertensive 
agents for blood pressure control), and unexpected events (admission to ICU).  Other findings 
that could trigger a safety review include the number of SAEs overall, the number of occurrences 
of a particular type of SAE, severe AEs, or increased frequency of events. 
9.1 
Sample Size and Accrual 
 
The sample size is based on a current ongoing study at HUP in which 45.6% of patients had 
persistently elevated blood pressures 7 days after delivery. For a power of 80% and a statistical 
significance level of 5%, 175 patients would be needed to find a 40% reduction in blood 
pressures with the use of furosemide. In anticipation of possible post-randomization losses of 
approximately 10% of patients, we plan to recruit 385 participants for randomization in the two 
groups.  
 
9.2 
Data Analyses Plans 
To account for the multiple measurements per patient, we will employ repeated measure 
regression techniques. Measures of relative risk will include 95% confidence intervals. Descriptive 
statistics will be presented as mean with standard deviation, median with interquartile range, or 
proportion with 95% confidence interval based on data type and distribution.  Comparisons 
between groups will be performed using a Chi-square or Fisher’s exact test for categorical 
variables and parametric or non-parametric tests for continuous variables, as appropriate. 
Bivariable analysis will be used to determine variables (risk factors) that are independently 
associated with PPHTN. Intention-to-treat analyses will be conducted such that all patients with 
available follow-up measures will be included in the analysis. Blood-pressure measurements after 
randomization will be compared between groups with the use of a mixed-effects logistic-
regression model, which will account for participants having different numbers of observations 
over a varying time span. Statistical analyses were conducted in SAS, version 9.4 (SAS Institute, 
Cary, NC). Two-tailed P values of <0.05 will be considered statistically significant. 
 
 
10 STUDY MANAGEMENT 
10.1 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the PI and the IRB.  All investigators will follow the University’s 
conflict of interest policy. 
10.2 Collection of data 
We will record data on each patient regarding their demographics, obstetrical and 
medical history, labor and delivery admission and any readmission information within 6 
weeks postpartum. 


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10.2.1 Private information 
Only the study staff listed on the protocol approved by the Institutional Review Board will 
have access to individually identifiable private information about human subjects. The 
only individually identifiable private information about human subjects that will be 
collected for research purposes is the subject’s name and medical record number for the 
purpose of linking the subject to their unique study identifier. 
10.2.2 Data Protection 
The individually identifiable private information that will be collected is name and medical 
record number for the purposes on linking the subject to their unique study number for 
chart review. We will collect phone numbers as well in order to be able to text with 
patients in the postpartum period to collect their daily blood pressures. The file linking the 
study number to the name, medical record number and phone number will be kept in a 
password-protected file on a secure server. Data will be collected primarily by the 
research team. The electronic database (REDCap) will be stored behind the institution’s 
firewall in a password-protected file. 
10.3 Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion. 
10.4 
Data Management and Monitoring/Auditing 
10.4.1 Data Safety and Monitoring Plan 
Safety monitoring will be performed periodically by the principal investigator. This will 
include assessment of accuracy of data recording, assuring de-identification of data, and 
that there is appropriate locked storage of data material. There will be no planned interim 
analyses. An advisory board will be created for continual oversight of the project. It will be 
comprised of faculty members within the department with extensive experience in 
prospective clinical trials. They will perform periodic reviews of safety data from this 
study. The DSMB that will be created is attached.  
10.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  


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10.5.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, a IRB modification form 
must be completed within five (5) business days of making the change.  
10.5.2 Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the IRB. According to the IRB, a protocol deviation is 
any unplanned variance from an IRB approved protocol that:  
 
Is generally noted or recognized after it occurs 
 
Has no substantive effect on the risks to research participants 
 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
 
Has harmed or increased the risk of harm to one or more research 
participants. 
 
Has damaged the scientific integrity of the data collected for the study. 
 
Results from willful or knowing misconduct on the part of the investigator(s). 
 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, the ensuing guidelines will be followed: 
 
Protocol Deviations: Personnel will report to any sponsor or data and safety 
monitoring committee in accordance with their policies. Deviations should be 
summarized and reported to the IRB at the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within one (1) 
week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.  
10.6 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator must 
retain all study documentation pertaining to the conduct of a clinical trial. In all other 
cases, study documents should be kept on file until three years after the completion and 
final study report of this investigational study. 


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10.7 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator will be responsible for assuring that all the required data will be 
collected and entered onto the Case Report Forms. Periodically, monitoring visits will be 
conducted and the Principal Investigator will provide access to his/her original records to 
permit verification of proper entry of data. At the completion of the study, all case report 
forms will be reviewed by the Principal Investigator and will require his/her final signature 
to verify the accuracy of the data. 
 
 
11 REFERENCES 
 
1. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO analysis of causes of maternal 
death: a systematic review. Lancet 2006;367:1066-74. 
2. Sibai BM. Etiology and management of postpartum hypertension-preeclampsia. Am J Obstet 
Gynecol 2012;206:470-5. 
3. Magee L, von Dadelszen P. Prevention and treatment of postpartum hypertension. Cochrane 
Database Syst Rev 2013;4:CD004351. 
4. Bateman BT, Schumacher HC, Bushnell CD, et al. Intracerebral hemorrhage in pregnancy: 
frequency, risk factors, and outcome. Neurology 2006;67:424-9. 
5. Kuklina EV, Tong X, Bansil P, George MG, Callaghan WM. Trends in pregnancy hospitalizations 
that included a stroke in the United States from 1994 to 2007: reasons for concern? Stroke 
2011;42:2564-70. 
6. Chames MC, Livingston JC, Ivester TS, Barton JR, Sibai BM. Late postpartum eclampsia: a 
preventable disease? Am J Obstet Gynecol 2002;186:1174-7. 
7. Ojogwu LI, Ofili UG. Morbidity and mortality from postpartum hypertension in Nigerian women. Afr 
J Med Med Sci 1993;22:11-6. 
8. Department of Health. Why mothers die. Report on confidential inquiries into maternal deaths in 
the United Kingdom 1994-96. London: HMSO, 1999. 
9. American Hospital Association. Reducing avoidable obstetrical and neonatal readmissions. 
Available from http://www.aha.org/content/11/Perinatalreadmissionscall1.pdf retrieved December 
12, 2017. 
10. American College of Obstetricians and Gynecologists; Task Force on Hypertension in 
Pregnancy.Hypertension in pregnancy: report from the American College of Obstetricians and 
GynecologistsTask Force on Hypertension in Pregnancy. Obstet Gynecol 2013; 122: 1122-1131. 
11. Hirshberg A, Levine LD, Srinivas SK. Clinical factors associated with readmission for postpartum 
hypertension in women with pregnancy-related hypertension: a nested case control study. J 
Perinatol 2016; 36: 405-9. 
12. Makkonen N, Harju M, Kirkinen P. Postpartum recovery after severe pre-eclampsia and HELLP-
syndrome. J Perinat Med 1996;24:641-9. 
13. Stepan H, Nordmeyer AK, Faber R. Proteinuria in hypertensive pregnancy diseases is associated 
with a longer persistence of hypertension postpartum. J Hum Hypertens 2006;20:125-8. 
14. Matthews G, Gornall R, Saunders NJ. A randomized placebo controlled trial of loop diuretics in 
moderate/ severe pre-elcmpais, flowing delivery. J Obstet Gynaecol 1997; 17: 30-2. 
15. Ascarelli MH, Johnson V, McCreary H, Cushman J, May Wl, Martin JN Jr. Posptarum 
preeclampsia management with furosemide: a randomized clinical trial. Obstet Gynecol 2005: 
105:29-33.  


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16. Veena P, Perivela L, Soundara Raghavan S. Furosemide in postpartum management of severe 
preeclampsia: a randomized controlled trial. Hypertens Pregnancy 2017; 36: 84-89. 
17. Podymow T, August P. Postpartum course of gestational hypertension and preeclampsia. 
Hypertens Pregnancy 2010;29:294–300. 
18. Walters BN, Walters T. Hypertension in the puerperium. Lancet 1987; 2: 330.  
19. Robson SC, Boys RJ, Hunter S, Dunlop W. Maternal hemodynamics after normal delivery and 
delivery complicated by postpartum hemorrhage. Obstet Gynecol 1989;74:234-9 
 
 
 

ICF_001.pdf: 
Furosemide for Accelerated Recovery of Blood Pressure Postpartum: a 
randomized controlled trial (FoR BP trial) 
 
A randomized, double-blind, placebo-controlled single center investigation of furosemide’s effect on 
postpartum blood pressure control in pregnancies affected by hypertensive disorders of pregnancy 
 
 
 
 
 
 
 
 
 
 
Consent date: September 13, 2018 
 
NCT#03556761 
 
 
 
 
 
 
 
 
 
 
 


FOR BP TRIAL 
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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT  
INFORMED CONSENT AND HIPAA 
AUTHORIZATION FORM 
 
 
Protocol Title:   
Furosemide for Accelerated Recovery of Blood Pressure 
Postpartum: a randomized controlled trial  (FoR BP trial) 
Principal 
Investigator: 
 
 
Co-investigator:  
Lisa D. Levine, MD, MSCE 
3400 Spruce Street, 2 Silverstein 
Philadelphia, PA 19104 
215-662-6913 
 
Joana Lopes Perdigao, MD 
3400 Spruce Street, 2 Silverstein  
Philadelphia, PA 19104  
215-662-6913 
Emergency 
Contact: 
24 hour Labor & Delivery Phone: (215) 662-3815 
 
 
 
 
 
Why am I being asked to volunteer? 
 
You are being invited to participate because you recently delivered a baby and 
also have high blood pressure. Your participation is voluntary which means you 
can choose whether or not you want to participate. If you choose not to participate, 
there will be no loss of benefits to which you are otherwise entitled. Before you can 
make your decision, you will need to know what the study is about, the possible 
risks and benefits of being in this study, and what you will have to do in this study. 
The research team is going to talk to you about the research study, and they will 
give you this consent form to read. You may also decide to discuss it with your 
family, friends, or family doctor. You may find some of the medical language 
difficult to understand. Please ask the study doctor and/or the research team about 
this form. If you decide to participate, you will be asked to sign this form.   
 
 
What is the purpose of this research study? 
 
About 10% of pregnant women have high blood pressure that affects their 
pregnancy.   Many women have well controlled blood pressures after their baby 
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delivers (postpartum), however some require more blood pressure medications 
than others.  Furthermore, about 30% of women with high blood pressure in 
pregnancy need to be seen or readmitted a couple of days after they deliver their 
baby due to very high blood pressures. To treat these high blood pressures, there 
are many medications that are breastfeeding friendly.  
 
This study wants to determine the effect of a short course of a common blood 
pressure medication, furosemide (also known as Lasix), to see if it prevents very 
high blood pressures after you deliver your baby and if it reduces your chances of 
being readmitted.    If you decide to participate, you will be in one of two groups –
in one arm you will be given a low dose of furosemide, in the other you will be given 
placebo which is an inactive pill with no medication in it (like a sugar pill).  These 
methods are described in more detail later in this form. 
 
We are asking women who are at least 18 years of age and who just delivered at 
the Hospital of the University of Pennsylvania if they would be interested in 
volunteering for our research study.  
 
  
How long will I be in the study? How many other people will be in the study? 
 
You will be involved in the study from delivery of your baby until 10 days after 
discharge.  The study is expected to take approximately 20 months to enroll 385 
subjects.   
 
What am I being asked to do? 
 
You are being asked to provide us with some general background personal 
information, including information on the number and outcomes of previous 
pregnancies, any medical or gynecologic conditions you have, surgeries you have 
had, and personal habits of yours.     
 
We will gather information surrounding the outcome of your pregnancy by 
reviewing your electronic medical record. If you are breastfeeding, we also ask 
your permission to gather information from your baby’s medical record. 
 
You are being asked to allow us to randomly assign you, like flipping a coin, to one 
of 2 groups after you deliver: 
 
• Group 1: Furosemide, you will take one 20 mg pill daily for 5 days 
• Group 2: Placebo (sugar pill), you will take one pill daily for 5 days 
 
Neither you nor the doctors working on the study will have any control over which 
group you are assigned to or know which group you are assigned to.  In the case 
of an emergency, your study doctor can find out what medication you received. 
 
The blood pressure medication that we are studying, furosemide, has been used 
very often at this hospital for blood pressure control after the baby delivers as 
standard of care.  It is safe with breastfeeding, however there are concerns that it 
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may decrease breastmilk when taken at high doses. We will monitor how you are 
doing in terms of breastfeeding, and, as per the usual standard of care in our 
postpartum floor, you will have our lactation consultants available to you at any 
time.   We will be giving you the smallest dose possible to treat your condition in 
this study.  
 
 
If your blood pressure is well controlled after your delivery, you will: 
• Continue on the same type of blood pressure medication you were already 
taking while pregnant. 
• Receive no additional blood pressure medications (apart from the pill 
mentioned above). 
 
 
If your blood pressure is high after delivery, you will:  
• Be started on additional blood pressure medications (first line will be 
amlodipine) as deemed necessary by your doctors that have been proven 
safe with breastfeeding.   
• Your doctors will be instructed to not give you additional diuretic type 
medications while you are on this study, unless they think it is medically 
necessary. 
 
 
 
 
Standard of care at our hospital for women with high blood pressures is to check 
certain lab work to determine the severity of your disease.  We will also be looking 
at these lab values as part of the study as well.  
 
Furosemide can also lower your potassium; therefore, we will be paying attention 
to your potassium levels (a potassium level is part of your laboratory tests when 
Diagnosis of high blood pressure in pregnancy-
What medications will I have to take in this study?
Well controlled blood 
pressures 
Study medication only 
(if you're not taking blood 
pressure medication in 
pregnancy)
Study medication 
+ medication you are already 
on in pregnancy
Very high blood 
pressures
Moderate high blood pressures: 
study medication 
+ amlodipine 5 mg
Severely high blood pressures: 
Study medication 
+ amlodipine 10 mg, and other 
medications as necessary
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you have high blood pressures in pregnancy).  If you are noted to have a low 
potassium, your doctor may give you a potassium supplement. 
 
After discharge from the hospital, we ask that you send in daily blood pressures 
through our texting program, Heart Safe Motherhood.  All women with high blood 
pressures in pregnancy are enrolled in this program at the Hospital of the 
University of Pennsylvania.  This would be the same level of care you would get 
even if not enrolled in this study..  To be enrolled in this study, you must also agree 
to participate in this texting program..  
 
What are the possible risks or discomforts?  
 
Common and Mild: 
• dehydration 
• dizziness 
• nausea/vomiting 
• abdominal pain  
• diarrhea 
• weight loss  
 
Rare and Not Common: 
• confusion 
• muscle pain/spams 
• palpitations  
• dry mouth/increased thirst 
• weakness 
• vertigo, headache, blurred vision 
• lab abnormalities 
• rash/skin conditions 
• Fainting and fatigue due to hypotension (low blood pressure) are possible, 
but rare, and will be monitored.   
 
 
Always report any side effect you are experiencing to the study doctor. 
 
As mentioned above, we believe that furosemide is safe for breastfeeding women. 
However, furosemide can be excreted in breastmilk.  In infants that received 
furosemide, cases of kidney stones were noted, and furosemide has been noted 
to increase the risk of persistent patent ductus arteriosus in premature infants in 
the neonatal period. However, this was noted when the medication was given 
directly to babies; therefore, the doses were much higher than your baby will be 
exposed to in this study.  
 
What if new information becomes available about the study? 
 
During the course of this study, we may find more information that could be 
important to you.  This includes information that, once learned, might cause you to 
change your mind about being in the study.  We will notify you as soon as possible 
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if such information becomes available. However, based upon the nature of this 
study, we do not anticipate that this will happen. 
 
What are the possible benefits of the study?  
 
Participation in this study is for research purposes and no health benefit is 
guaranteed for you. The results of this study could also benefit future patients. 
 
What other choices do I have if I do not participate?  
 
You may choose not to participate in this study without affecting your present or 
future care at the University of Pennsylvania Health System. Your alternative to 
providing your consent is to not participate in this study, in which case you would 
continue to have your blood pressures treated with other medications as deemed 
necessary by your doctors.   
 
Will I be paid for being in this study? 
 
You will not be paid for being in this study.  
 
Will I have to pay for anything? 
 
You / your insurance will have to pay for any routine medical care that you receive, 
including all costs related to your delivery and postpartum course.  You will not be 
billed for any medications given for research purposes. 
 
What happens if I am injured from being in the study?  
 
You will receive the same care regardless of whether you participate in the study. 
We will offer you the care needed to treat injuries directly resulting from taking part 
in this research.  We may bill your insurance company or other third parties, if 
appropriate, for the costs of the care you get for the injury, but you may also be 
responsible for some of them. 
 
There are no plans for the University of Pennsylvania to pay you or give you other 
compensation for the injury.  You do not give up your legal rights by signing this 
form.   
 
If you think you have been injured as a result of taking part in this research study, 
tell the person in charge of the research study as soon as possible.  The 
researcher’s name and phone number are listed on page 1 of this consent form. 
 
When is the study over?  Can I leave the study before it ends? 
 
This study is expected to end after all participants have been recruited and all 
information has been collected. The study is expected to take 20 months.  This 
study may also be stopped at any time by your physician, the study Sponsor, or 
the Department of Obstetrics and Gynecology without your consent because: 
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• 
The Primary Investigator feels it is necessary for your health or safety.  Such 
an action would not require your consent, but you will be informed if such a 
decision is made and the reason for this decision. 
• 
You have not followed study instructions.  
• 
The study Principal Investigator, or the Department of Obstetrics and 
Gynecology has decided to stop the study. 
 
If you decide to participate, you are free to leave the study at any time.  
Withdrawal will not interfere with your future care.   
 
Who can see or use my information?  How will my personal information be 
protected?    
 
We will do our best to make sure that the personal information obtained during 
the course of this research study will be kept private.  However, we cannot 
guarantee total privacy.  Your personal information may be given out if required 
by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.   
 
Your information will be held in a research database on a password protected 
computer in a locked office in the Department of Maternal Fetal Medicine. Only 
the principal investigator or study staff will have access to these files.  
 
Electronic Medical Records and Research Results  
 
What is an Electronic Medical Record and/or a Clinical Trial Management 
System?  
 
An Electronic Medical Record (EMR) is an electronic version of the record of your 
care within a health system. An EMR is simply a computerized version of a paper 
medical record.  
 
A clinical trial management system (CTMS) is used to register your information 
as a participant in a study and to allow for your research data to be 
entered/stored for the purposes of data analysis and any other required activity 
for the purpose of the conduct of the research.  
 
If you are receiving care or have received care within the University of 
Pennsylvania Health System (UPHS) (outpatient or inpatient) and are 
participating in a University of Pennsylvania research study, information related 
to your participation in the research (i.e. laboratory tests, imaging studies and 
clinical procedures) may be placed in your existing EMR maintained by UPHS. 
Information related to your participation in clinical research will also be contained 
in the CTMS. 
 
If you have never received care within UPHS and are participating in a University 
of Pennsylvania research study that uses UPHS services, an EMR will be 
created for you for the purpose of maintaining any information produced from 
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your participation in this research study.  The creation of this EMR is required for 
your participation in this study. In order to create your EMR, the study team will 
need to obtain basic information about you that would be similar to the 
information you would provide the first time you visit a hospital or medical facility 
(i.e. your name, the name of your primary doctor, the type of insurance you 
have). Information related to your participation in the study (i.e. laboratory tests, 
imaging studies and clinical procedures) may be placed in this EMR.  
Once placed in your EMR or in the CTMS, your information may be accessible to 
appropriate UPHS workforce members that are not part of the research team.  
Information within your EMR may also be shared with others who are determined 
by UPHS to be appropriate to have access to your EMR (e.g. health insurance 
company, disability provider, etc.). 
 
What information about me may be collected, used or shared with others? 
 
The following personal health information will be collected and used for research: 
  
• Name, date of birth, medical 
record number 
• Phone number 
• Personal medical and 
obstetric history, general 
information regarding medical 
condition of the newborn after 
delivery 
 
• Information from your and your child’s 
medical records regarding your labor 
and delivery, and the health of your 
child.    
• Information from a physical 
examination including cervical exams 
• Results of tests and procedures you 
will undergo during this research 
study as described in the informed 
consent form.  
Why is my information being used? 
 
Your information and results of tests and procedures are used to: 
• 
Do the research 
• 
Oversee the research to see if the research was done right.   
 
Who may use and share information about me? 
 
The following individuals may use your personal health information for this 
research study: 
• The Principal Investigator and the Investigator’s study team 
• Authorized members of the workforce of the UPHS and the School of 
Medicine, and University of Pennsylvania support offices, who may need to 
access your information in the performance of their duties (for example: for 
research oversight and monitoring, to provide treatment, to manage 
accounting or billing matters, etc.).  
• Other research personnel with access to the databases for research and/or 
study coordination and as otherwise approved by the IRB. 
 
At this time there are no plans to disclose specific information to anyone besides 
those persons listed above. 
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Who, outside of UPHS and the School of Medicine, might receive my 
personal health information?  
 
As part of the study, the Principal Investigator and the study team may review your 
personal health information, including the results of the research study tests.  This 
information may be disclosed to those listed below upon request: 
 
Individuals or organizations responsible for administering the study: 
At this time, there are no plans for anyone besides the researchers involved at the 
Hospital of the University of Pennsylvania to receive your personal health 
information. 
 
Regulatory and safety oversight organizations 
• 
University of Pennsylvania Institutional Review Board 
• 
Perelman School of Medicine’s Office of Human Research 
• 
The Food and Drug Administration 
• 
The Office of Human Research Protections 
• 
The study data and safety monitoring board 
 
Once your personal health information is disclosed to others outside of UPHS or 
the School of Medicine, it may no longer be covered by federal privacy protection 
regulations.   
 
The Principal Investigator or study staff will inform you if there are any additions to 
the list above during your active participation in the trial. Any additions will be 
subject to University of Pennsylvania procedures developed to protect your 
privacy. 
 
How long may UPHS and the School of Medicine be able to use or disclose 
my personal health information?   
 
Your authorization for use of your personal health information for this specific study 
does not expire.  
 
Your information may be held in a research repository (database).  However, 
UPHS and the School of Medicine may not re-use or re-disclose information 
collected in this study for a purpose other than this study unless: 
You have given written authorization to do so  
The University of Pennsylvania’s Institutional Review Board grants permission 
after ensuring that appropriate privacy safeguards are in place  
As permitted by law  
 
Can I change my mind about giving permission for use of my information? 
 
Yes, at any time you may withdraw your approval to allow the use and disclosure 
of your personal health information as described here.  You must do so in writing 
to the Principal Investigator at the address on the first page.  Even if you withdraw 
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your permission, your personal health information that was collected before we 
received your written request may still be used and disclosed, as necessary for the 
study.  If you withdraw your permission to use your personal health information, 
you will also be withdrawn from the research study. 
 
What if I decide not to give permission to use and give out my health 
information? 
 
Then you will not be able to be in this research study. 
 
Who can I call with questions, complaints or if I’m concerned about my 
rights as a research subject? 
 
If you have questions, concerns or complaints regarding your participation in this 
research study or if you have any questions about your rights as a research 
subject, you should speak with the Principal Investigator listed on page one of this 
form.  If a member of the research team cannot be reached or you want to talk to 
someone other than those working on the study, you may contact the Office of 
Regulatory Affairs with any question, concerns or complaints at the University of 
Pennsylvania by calling (215) 898-2614. 
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as 
required by U.S. law. This web site will not include information that can identify 
you. At most, the web site will include a summary of the results. You can search 
this web site at any time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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When you sign this form, you are agreeing to take part in this research study. 
This means that you have read the consent form, your questions have been 
answered, and you have decided to volunteer.  Your signature also means that 
you are permitting the University of Pennsylvania to use your personal health 
information collected about you for research purposes within our institution. 
You are also allowing the University of Pennsylvania to disclose that personal 
health information to outside organizations or people involved with the 
operations of this study. 
 
A copy of this consent and HIPAA authorization form will be given to you.  
 
 
________________________       ____________________________________ 
Name of Subject (Please Print)  Signature of Subject  
 
           Date 
 
 
 
________________________ 
_____________________________________ 
Name of Person Obtaining 
Signature                                  
 
Date 
Consent (Please Print) 
 
        Please initial here if you are willing to be contacted about future research 
opportunities. 
 
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