Clinical trial NCT04752475
Conditions: Postpartum Pregnancy-Induced Hypertension Postpartum Preeclampsia Hypertension, Pregnancy-Induced Hypertension
Keywords: De novo postpartum hypertension New-onset postpartum hypertension Lasix Furosemide
Sponsor: Columbia University
Start date: 2021-10-20; Completion date: 2022-05-28
Enrollment: 82 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary objective: To evaluate whether oral furosemide can help prevent de novo postpartum hypertension (new-onset high blood pressure after delivery) by reducing blood pressure after delivery in high-risk women.

Secondary objectives: To evaluate whether oral furosemide administered to high-risk women after delivery can reduce the frequency of postpartum hypertensive episodes, the need for antihypertensive therapy, the risk of postpartum preeclampsia, and the incidence of severe maternal morbidity.

Detailed description:
Hypertensive disorders of pregnancy are one of the leading causes of maternal morbidity and mortality worldwide. The majority of clinical research has focused on pregnancy-related hypertension that develops in the antenatal period, while studies of the incidence, risk factors, and prevention of postpartum hypertension are limited. In particular, there is a paucity of data about the clinical entity known as de novo postpartum hypertension, in which women who are normotensive throughout pregnancy and delivery subsequently go on to develop high blood pressure in the immediate to late postpartum period. Of those with postpartum preeclampsia, 33-69% were normotensive antepartum.

Early identification and treatment of antepartum preeclampsia has been shown to decrease some severe maternal outcomes. Conversely, women with de novo postpartum hypertensive disorders remain among the highest risk for severe maternal morbidity due to decreased surveillance and lack of data regarding preventive therapies and interventions. Evidence from multiple randomized controlled trials have demonstrated a benefit in the use of oral loop-diuretics in decreasing postpartum systolic blood pressure, promoting faster normalization of blood pressure, and decreasing the need for antihypertensive therapy in women with an antenatal diagnosis of preeclampsia. Biological plausibility suggests that loop-diuretic therapy may similarly mitigate the normal physiologic mechanism that has been implicated in the pathogenesis of hypertensive complications after delivery in women at risk for de novo postpartum hypertension.

This study is a double-blind randomized placebo-controlled trial of 82 high-risk women to assess whether treatment with oral Lasix (furosemide) after delivery reduces blood pressure at the time of discharge. Women at high risk for de novo postpartum hypertension will be randomized to a five-day course of either 20 mg oral Lasix (furosemide) or placebo once daily initiated after delivery. Women will be monitored through their routine 2-week and 6-week postpartum visits, during which times hypertensive complications and adverse effects of therapy will be assessed.

Arms: arm 1: Furosemide 20 mg, oral, once daily for 5 days arm 2: Identical-appearing placebo, oral, once daily for 5 days
Interventions: intervention 1: Furosemide intervention 2: Placebo
Intervention descriptions: intervention 1: Furosemide 20 mg pill taken daily for 5 days intervention 2: Identical-appearing placebo pill taken daily for 5 days

Protocol documents:
Prot_SAP_000.pdf: 
Title:  Lasix for the Prevention of De Novo Postpartum Hypertension: A Randomized Control 
Trial (LAPP Trial) 
Version: 06.22.2022 
Applicant: Ukachi Emeruwa, MD, MPH 
Attending Principal Investigators: Cynthia Gyamfi-Bannerman, MD, MSc, Russell S. Miller, 
MD 
1. Proposal abstract
1.1 Scientific abstract 
The overarching goals of our study are to (i) assess whether postpartum administration of 
a loop-diuretic reduces blood pressure prior to discharge in women at high risk for de novo 
postpartum hypertension; (ii) evaluate whether this reduction in blood pressure reduces the need 
for initiation of therapies to treat severe de novo postpartum hypertension; and (iii) evaluate 
whether this reduces the risk of hypertension-associated morbidity in the postpartum period. 
Hypertensive disorders of pregnancy are one of the leading causes of maternal morbidity 
and mortality worldwide.1,2 The majority of clinical research has focused on pregnancy-related 
hypertension that develops in the antenatal period, while studies of the incidence, risk factors, 
and prevention of postpartum hypertension are limited. In particular, there is a paucity of data 
about the clinical entity known as de novo postpartum hypertension, in which women who are 
normotensive throughout pregnancy and delivery subsequently go on to develop high blood 
pressure in the immediate to late postpartum period. Of those with postpartum preeclampsia, 33-
69% were normotensive antepartum. 3-7 
Early identification and treatment of antepartum preeclampsia has been shown to 
decrease some severe maternal outcomes. Conversely, women with de novo postpartum 
hypertensive disorders remain among the highest risk for severe maternal morbidity due to 
decreased surveillance and lack of data regarding identifiable and modifiable risk factors to 
facilitate stratification of monitoring, preventive therapies and intervention.8 Of women admitted 
with postpartum hypertensive complications, for example, two retrospective series estimate rates 
of eclampsia up to 78% in women with no antenatal diagnosis of hypertensive disorders of 
pregnancy, compared to rates ranging from 4.6% to 13.6% in women with antepartum or 
intrapartum diagnoses of hypertensive disorders.3,9 
Over the past two decades, multiple randomized controlled trials have demonstrated a 
benefit in the use of oral loop-diuretics in decreasing postpartum systolic blood pressure, 
promoting faster normalization of blood pressure and decreasing the need for antihypertensive 
therapy in women with an antenatal diagnosis of preeclampsia.10-12 Given the implication of the 
normal physiologic auto-infusion of sequestered extravascular fluid into the intravascular space 
in the pathogenesis of hypertensive disorders in the postpartum period, we propose that this same 
therapy may have benefits in reducing hypertensive episodes and need for therapy in other 
women at high risk for postpartum hypertensive complications – specifically de novo postpartum 
NCT04752475


hypertension. In a randomized placebo-controlled trial design, we propose to use an oral loop 
diuretic (i.e. furosemide) to evaluate whether we can help prevent de novo postpartum 
hypertension by reducing blood pressure after delivery in high-risk women. We hypothesize that 
postpartum administration of the loop diuretic furosemide in women at high risk of developing 
de novo postpartum hypertension will reduce blood pressure at the time of discharge compared 
to placebo. The primary outcome of arterial blood pressure (MAP) will be compared between the 
study groups using student’s t-test. Ultimately, we hypothesize that this will reduce the need for 
therapies to treat severe postpartum hypertension and will reduce hypertension-associated 
morbidity in the postpartum period. For analysis of categorical data in independent samples, the 
Chi-squared test or Fisher exact probability test will be utilized. Continuous data that satisfy the 
assumptions of normality and homoscedasticity (homogeneity of variance) will be analyzed by t-
test. 
 
1.2 Lay abstract 
New-onset high blood pressure related to pregnancy is one of the leading causes of 
maternal complications and death worldwide.1,2 Most of what is known about pregnancy-related 
high blood pressure comes from studies of women who develop high blood pressure while they 
are still pregnant. There is little data that exists about the clinical entity known as “de novo 
postpartum hypertension”, in which women who have normal blood pressure throughout 
pregnancy and delivery subsequently go on to develop high blood pressure within two days to 
six weeks after giving birth, also known as the postpartum period. Of all the women who develop 
high blood pressure in the postpartum period, one third to two thirds of them had normal blood 
pressure during pregnancy.3-7 
Early identification and treatment of the complications of pregnancy-related high blood 
pressure while women are still pregnant have been shown to decrease some severe maternal 
outcomes, such as seizures (i.e. eclampsia), strokes, and death. On the other hand, women with 
de novo postpartum hypertension remain among the highest risk for severe maternal 
complications, such as eclampsia.8 This occurs because there is a lack of data to identify who is 
at high risk for de novo postpartum hypertension and may need continued close follow up after 
delivery and what preventive measures or treatments can be provided to reduce the risk of 
complications. Studies of women admitted to the hospital after delivery for high blood pressure-
related complications estimate that the rates of eclampsia were as high as 78% in women who 
had normal blood pressure during pregnancy compared to rates ranging from 4.6% to 13.6% in 
women with were diagnosed with high blood pressure during pregnancy or labor and delivery.  
Over the past two decades, high quality data has shown that for women diagnosed with 
preeclampsia during pregnancy, giving them a medication known as a loop diuretic after they 
deliver reduces their blood pressure, helps their blood pressure to return to normal faster, and 
reduces their need for high blood pressure medication.10-12 This same therapy may have similar 
benefits in women at high risk for new-onset high blood pressure after they give birth, and may 
ultimately reduce their risk of severe complications, such as seizures and strokes.  
 
2. Proposal body 
 


2.1 Background 
Hypertensive disorders of pregnancy are one of the leading causes of maternal morbidity 
and mortality worldwide.1,2 The majority of clinical research has focused on pregnancy-related 
hypertension that develops in the antenatal period, while studies of the incidence, risk factors, 
and prevention of postpartum hypertension are limited. In particular, there is a paucity of data 
about the clinical entity known as de novo postpartum hypertension, in which women who are 
normotensive throughout pregnancy and delivery subsequently go on to develop high blood 
pressure in the immediate to late postpartum period. Of those with postpartum preeclampsia, 33-
69% were normotensive antepartum. 3-7 
Early identification and treatment of antepartum preeclampsia has been shown to 
decrease some severe maternal outcomes. Conversely, women with de novo postpartum 
hypertensive disorders remain among the highest risk for severe maternal morbidity due to 
decreased surveillance and lack of data regarding identifiable and modifiable risk factors to 
facilitate stratification of monitoring, preventive therapies and intervention.8 Of women admitted 
with postpartum hypertensive complications, for example, two retrospective series estimate rates 
of eclampsia up to 78% in women with no antenatal diagnosis of hypertensive disorders of 
pregnancy, compared to rates ranging from 4.6% to 13.6% in women with antepartum or 
intrapartum diagnoses of hypertensive disorders.3,9 
Over the past two decades, multiple randomized controlled trials have demonstrated a 
benefit in the use of oral loop-diuretics in decreasing postpartum systolic blood pressure, 
promoting faster normalization of blood pressure and decreasing the need for antihypertensive 
therapy in women with an antenatal diagnosis of preeclampsia.10-12 The rationale for its efficacy 
is the implication of the normal physiologic auto-infusion of sequestered extravascular fluid into 
the intravascular space in the pathogenesis of hypertensive disorders in the postpartum period. 
Given that this same mechanism may play a role in the pathogenesis of postpartum hypertension, 
we propose that this same therapy may have benefits in reducing hypertensive episodes and 
need for therapy in other women at high risk for postpartum hypertensive complications – 
specifically de novo postpartum hypertension. Therefore, the purpose of this study is to 
evaluate whether furosemide can help prevent de novo postpartum hypertension by 
reducing blood pressure after delivery in high-risk women. 
 
2.2 Specific aims  
Our objective is to trial furosemide in women at high risk for developing de novo 
postpartum hypertension in a randomized control design, with an aim to reduce blood 
pressure at the time of discharge from the delivery hospitalization and thereby reduce the 
frequency of postpartum hypertensive episodes requiring therapy and reduce severe 
morbidity and mortality.  
 
Specific Aim 1. To compare the mean blood pressures over the 24 hours prior to discharge 
or prior to antihypertensive therapy initiation (whichever occurs first) in women who have 
been randomized to a 5-day course of PO furosemide 20 mg daily (study drug) to those who 
have been randomized to a 5-day course of PO placebo daily (placebo). We hypothesize that 
women taking PO furosemide 20 mg daily will have lower mean blood pressure in the 24 hours 


prior to discharge or prior to antihypertensive therapy initiation compared with patients taking 
placebo. 
 Sub-aim 1: To compare the rates of diagnosis of postpartum hypertension and 
preeclampsia between those who have been randomized to the study drug and those 
randomized to placebo from the time of delivery to 6 weeks postpartum. We 
hypothesize that women randomized to the study drug will have lower rates of 
postpartum hypertension and preeclampsia.  
 Sub-aim 2: To compare percentage of elevated blood pressures postpartum between 
those who have been randomized to the study drug to those randomized to placebo 
from the time of delivery to 6 weeks postpartum. We hypothesize that women 
randomized to the study drug will have fewer hypertensive episodes.  
 Sub-aim 3: To compare the frequency of postpartum hypertension-related triage 
and emergency department visits between those who have been randomized to the 
study drug to those randomized to placebo from the time of discharge to 6 weeks 
postpartum. We hypothesize that women randomized to the study drug will have fewer 
triage and emergency department visits for hypertension-related complaints episodes 
after discharge. 
 Sub-aim 4: To analyze factors associated with response to therapy. We hypothesize 
that factors such as degree of lower extremity edema and indication for high risk status 
will be associated with greater response to therapy.   
Specific Aim 2. To compare rates of initiation of hypertensive therapies in women 
randomized to the study drug compared to those randomized to placebo. We hypothesize 
that women randomized to the study drug will be less likely to be initiated on hypertensive 
therapies between delivery and 6 weeks postpartum. 
Specific Aim 3. To compare rates of severe maternal morbidity in women randomized to 
the study drug compared to those randomized to placebo from the time of discharge to 6 
weeks postpartum. We hypothesize that women randomized to the study drug will have lower 
rates of severe maternal morbidity between delivery and 6 weeks postpartum compared to those 
randomized to placebo. 
 Sub-aim 1: To compare hypertensive-related unscheduled presentations between 
those who have been randomized to the study drug and those randomized to 
placebo. We hypothesize that women randomized to the study drug will have fewer 
triage and emergency department visits for hypertension-related complaints episodes 
after discharge. 
 Sub-aim 2: To assess adverse effects of therapy in the study group and the control 
group. We hypothesize that there will be no difference in adverse effects, such as 
discontinuation of breastfeeding, hypotension, and electrolyte abnormalities in women 
randomized to the study drug compared to those randomized to placebo. 
 Sub-aim 3: To analyze factors associated with incidence of severe maternal 
morbidity in the study group and the control group. We hypothesize that factors such 
as racial and ethnic identity and age will be associated with increased incidence of severe 
maternal morbidity.   
 


2.3 Methods 
 
2.3.1 Study Design 
This will be a randomized control trial, in which women who are at high risk of developing de 
novo postpartum hypertension will be assigned to either a five-day course of PO furosemide 20 
mg daily or a five-day course of PO placebo after delivery.  
Patients will be informed of the study in the antenatal period, within four weeks of their 
estimated date of delivery or on admission to labor and delivery and will be deemed eligible, 
enrolled and randomized from the postpartum service within 8 hours after delivery. 
Randomization will be performed by the Columbia Research Pharmacy, and the study drug or 
placebo will be dispensed to the postpartum floor to be administered by the patient’s assigned 
postpartum nurse. Blood pressure measurements will occur every six hours (or more if clinically 
indicated) until the time of discharge. Upon discharge, the remainder of the five-day course of 
the study drug or placebo will be dispensed to the patient to complete. Patients in both groups 
will be asked to check their blood pressure twice per day, once in the morning and once in the 
evening, and will receive text message reminders twice a week. In order to check their blood 
pressures after discharge, patients in both groups will be given a Philips Bluetooth-enabled blood 
pressure cuff, which will transmit blood pressure measurements via Bluetooth from the monitor 
to the eCC. These patients will be educated on the use of and enrolled in the software by research 
investigators who have been in-serviced on the devices prior to discharge. The tablets are 
cellular-enabled, so no wireless connection is needed in the patient’s home. Criteria for 
contacting their provider will be reviewed with and provided in writing to the patients upon 
discharged. No changes will be made to standard hypertensive treatment protocols for either 
group. 
Patients in both groups will be given an appointment to follow-up with their obstetric provider in 
the office at approximately 14 days postpartum and at about 6 weeks postpartum. The number of 
measurements total and the number of measurements that were elevated will be ascertained for 
each group at this visit.  
Patients in both groups will also be prompted to answer two electronic surveys (attached as a 
separate document to this IRB application) regarding symptoms of preeclampsia, symptoms of 
volume overload, and breastfeeding continuation at about two weeks postpartum and at the 
conclusion of the study period. A text message reminder will be sent to patients at the time that 
each survey is due. A research coordinator will call to obtain responses to the survey questions if 
patients are unable to complete the survey electronically. 
Patients in both groups will be followed from recruitment until six weeks postpartum. 
 
2.3.2 Inclusion Criteria 
Women who meet the following criteria will be eligible for the study: 
1) Postpartum women 
2) No antenatal diagnosis of hypertensive disorder of pregnancy at the time of admission for 
delivery, defined as existing chronic hypertension diagnosis or documented blood 
pressure of ≥140 systolic OR ≥90 diastolic on at least 2 occasions at least 4 hours apart 


prior to delivery admission who do not go on to get magnesium for seizure prophylaxis 
by the time of delivery 
3) At least 18 years of age 
4) English or Spanish speakers 
5) One or more of the following high risk factors and/or two or more moderate risk factors 
for development of de novo postpartum hypertension: 
a. High risk 
i. Pregestational diabetes mellitus 
ii. Renal disease 
iii. Autoimmune disease (systemic lupus erythematosus, antiphospholipid 
syndrome) 
iv. Multifetal gestation 
v. Gestational diabetes mellitus, A2 (i.e. medication-dependent) 
vi. History of preeclampsia in a prior pregnancy (not including the index 
pregnancy) 
b. Moderate risk 
i. Primiparity 
ii. Obesity (BMI ≥ 35 kg/m2) 
iii. Age ≥ 35 years 
iv. Black or African-American race 
v. Family history of preeclampsia 
2.3.3 Exclusion Criteria 
1) Non-English and Non-Spanish speakers 
 The consent form will only be available in these 2 languages 
2) Women with a contraindication to diuretic therapy 
3) Women who have used diuretics in the two weeks prior to delivery 
 
2.3.4 Recruitment, Screening and Enrollment 
Recruitment and Screening 
A study team member will perform daily chart screen of all women at least 36 weeks of gestation 
who are presenting for prenatal visit with a CUIMC provider and of all women admitted to the 
CUIMC labor and delivery unit (CHONY 10 Tower) for delivery. Permission from healthcare 
providers will be obtained prior to the OB study team member contacting participants. Women 
will be approached at the aforementioned times to be informed of the study and of their 
conditional eligibility. Final eligibility will be determined on admission to labor and delivery and 
eligible women will then be recruited on the postpartum units (CHONY 5 central, 6 central and 
10 central).  
We will abide by the CUMC policy that researchers cannot directly approach a patient for 
recruitment until that patient has been informed of the study by a provider who has ascertained 
that the patient is willing to discuss the study with the investigators. This will be documented in 
the research record.  


We will also ensure that if patients are laboring, they are competent to consent to research and 
haven’t received systemic opioids or sedative medications within the past 2 hours. We will also 
ensure the cooperation of the labor room nurse, obstetric care provider, and patient support 
persons in the discussion of proposed research and study informed consent process. Whenever 
practical and feasible, information about research on Labor and Delivery will be made available 
to patients prior to onset of painful labor and/or after placement of epidural analgesia, if such 
analgesia is desired by the patient. 
 
Informed Consent Process 
Research coordinators and study physicians listed on this protocol may obtain informed consent. 
Study personnel will consent participants in person, face-to-face, when they receive notification 
by a provider of an eligible patient. Participants will be consented in English or Spanish by 
personnel fluent in that language or with the use of NYP translators and a full consent in their 
language. Recruitment will occur in a private setting, in a non-coercive manner, with ample time 
to ask questions and receive satisfactory answers.  
 
Patient written informed consent and HIPAA authorization to participate in the study will be 
collected on an iPad or laptop. In-person electronic signature will be captured on the electronic 
informed consent form. Study personnel obtaining consent will be physically present at time of 
signature. A paper copy of the signed informed consent form will be given to the patient. A copy 
of the signed consent form will also be placed in the patient’s inpatient paper chart. The time of 
consent will be documented on the consent form and in the medical record.  
 
Consent forms will be available in both English and Spanish to accommodate our expected 
population. A witness will be required for our non-English speaking patients. 
 
At the time of the consent, the Informed Consent Process will begin with a concise and focused 
presentation of the key information about the research study. The collaborating investigators will 
explain the study, and potential subjects will have an opportunity to discuss the information 
provided. The collaborating investigators will answer any questions. The Informed Consent 
Process as a whole presents information in sufficient detail relating to the research study. 
Consent will be obtained to measure blood pressures postpartum. Consent will be obtained to 
review medical records to abstract pertinent sociodemographic and clinical information and to 
call patients to obtain the aforementioned information if not able to be abstracted from the 
medical record. Consent will be obtained to administer electronic surveys and collect home 
blood pressure measurements at two postpartum study visits. Patients still meeting inclusion 
criteria will be randomized at within eight hours of delivery on the postpartum service. 
 
Enrollment 
After obtaining written informed consent, participants will be randomized to either the study 
drug, as defined above, or placebo. Randomization will occur through the Columbia Research 
Pharmacy in REDCap. The medication intervention will be dispensed to the patient’s postpartum 
unit and administered by the nursing staff once daily beginning within eight hours of delivery. 
The patient, the patient’s nurse, and the patient’s inpatient obstetric provider will not be informed 


of the patient’s randomization group, to avoid potential biases stemming from differences in 
inpatient care. Participants will be enrolled in the study from the time of randomization until 6 
weeks postpartum. 
 
2.3.5 Equipment and Software 
All study participants will receive a Philips Home Telehealth Solution kit, complimentary of 
participating in the study, which includes several FDA/FCC approved devices. NewYork-
Presbyterian has a contract in place with Philips (attached separately to this IRB application 
under “Philips Contract 5.10.21”) which allows the hospital to utilize Philips telehealth programs 
for its patients. The investigators had no role in the signing of this contract and have no 
financial interests in this program. The following equipment is included in the Philips kit: 
 
Device 
US 510(k) 
A&D 
Blood Pressure Meter, regular or small 
cuff version 
UA-767PBT-Ci 
Class II 
K043217 
FCC:POOWML-C40 
eCareCoordinator (eCC) Suite 
K171029 
Samsung Galaxy Tab E 8.0" 
model SM-T377A 
Not a medical device, no associated 510(k) 
FCC: A3LSMT377A 
 
The instructions that patients will receive for use of the tablet and the blood pressure meter are 
attached separately to this IRB application (“Philips A&D Cuff Instructions”).   
At the conclusion of the 6-week study period (in other words, after the scheduled postpartum 
visit or the time when that visit was supposed to occur, if the patient did not present), the patient 
will be expected to return the kit. The full patient terms of use are attached to this IRB 
application as a separate document (“Philips Patient Terms of Use”).  
 
2.3.6 Outcomes 
1) Primary outcome: Our primary outcome will be the difference in mean arterial pressure 
(MAP) averaged over the 24 hours prior to discharge or the 24 hours prior to 
antihypertensive therapy initiation (whichever occurs first).   
2) Secondary outcomes: Secondary outcomes will include: 
1. Rates of de novo postpartum preeclampsia – determined at discharge, at 2 and at 6 
weeks postpartum 
2. Percentage of recorded blood pressure that are elevated (>140 systolic OR >90 
diastolic) – calculated at the time of discharge, at 2 weeks, and at 6 weeks 


3. Rates of magnesium sulfate administration – determined at discharge, at 2 and at 
6 weeks postpartum 
4. Time to discharge 
5. Rates of initiation of antihypertensives – determined at discharge, at 2 and at 6 
weeks postpartum 
6. Rates of severe maternal morbidity (e.g. stroke, seizure, PRES) – determined at 6 
weeks postpartum 
7. Mean frequency of triage or ED presentation/readmission – determined at 2 and at 
6 weeks postpartum 
8. Breastfeeding continuation rates – determined at about 2 weeks and at 6 weeks 
postpartum 
9. Neonatal outcomes 
 
2.3.7 Measures 
The following data will be collected for analysis. 
1) To be collected on enrollment/prior to hospital discharge: 
1. Demographic and social factors. Date of birth, self-reported race/ethnicity, 
cultural background [place of birth (US or not), years living in the US, and 
primary language spoken in the home], marital status, highest level of maternal 
education attained, employment status, household income, and insurance status 
will be elicited from the patients on enrollment 
2. Pregnancy history. On enrollment, participants will be asked about the number 
and outcomes of prior pregnancies 
3. Prenatal care history. Location of prenatal care, gestational age on initiation of 
prenatal care and number of prenatal visits will be extracted from the EHR when 
possible and verified by the participant on enrollment.  
4. Delivery history. Mode of delivery and baby’s disposition will be collected on 
enrollment 
5. Medical history. Other medical history will be extracted from the EHR and 
verified by the participant on enrollment 
6. Health behaviors. Current and prior smoking, alcohol, and illicit drug use will be 
elicited on enrollment. 
7. Weight and height. Height, pre-pregnancy weight, first documented weight 
during the pregnancy, and weight at enrollment, will be obtained on enrollment 
and extracted from the EHR. Body mass index (BMI) will be calculated as height 
(cm)/weight (kg)2. 
8. Hospital length of stay. defined as days AFTER delivery that the patient is 
admitted to the hospital; this will be ascertained upon hospital discharge 
9. Medications. discharge antihypertensive medications will be collected upon 
discharge  
2) To be collected throughout the study period: 
1. Blood pressures. Blood pressure recordings on the postpartum unit will be 
abstracted from the chart. Mean arterial pressure will be calculated for each blood 
pressure measured within the 24 hours prior to discharge or prior to 


antihypertensive therapy initiation (whichever comes first) and will be averaged 
over that time period. Participants will be asked to provide a record of the blood 
pressures they are recording at home, and the blood pressures from their office 
visits will be recorded as well. Percentage of scheduled blood pressure readings 
that are recorded will be compared between groups. Incidence of elevated blood 
pressures during this time will also be compared between groups.  
2. Adherence. For both groups, proportion of medication course completed will be 
recorded 
3. Time to initiation of medications. For both groups, time to initiation of anti-
hypertensive medications will be tracked 
4. Final plan at 6 weeks. For both groups, continuing medication regimens at 6 
weeks will be collected.  
5. Hospital readmissions. Hospital readmission for any indication will be collected 
for both groups 
6. Triage/ED visits. Presentation to the obstetric triage unit or the emergency 
department for any indication will be collected for both groups 
7. Maternal morbidity and mortality. Incidences of eclampsia, stroke, PRES, 
maternal death will be collected for both groups 
8. Breastfeeding continuation. Rates of breastfeeding continuation will be 
collected for both groups 
9. Adverse effects. Incidences of hypotension, electrolyte abnormalities, and 
development of renal insufficiency will be collected for both groups. 
 
2.3.8 Definitions 
Chronic hypertension will be defined according to ACOG guidelines as blood pressure 
measurement of EITHER ≥140 mm Hg OR diastolic ≥90 mm Hg on at least 2 occasions, at least 
4 hours apart, prior to 20 weeks gestation.2 
Hypertensive disorders of pregnancy will be defined according to ACOG guidelines.2 The 
minimum criteria for a diagnosis of HDP are as follows: 
 Blood pressure measurement of EITHER systolic ≥140 mm Hg OR diastolic ≥90 mm Hg 
on at least 2 occasions, at least 4 hours apart, between 20 weeks gestation and delivery 
 Blood pressure measurement of EITHER systolic ≥160 mm Hg OR diastolic ≥110 mm 
Hg on at least 2 occasions qualifies as severe features 
Diagnosis of hypertensive disorder of pregnancy will be determined at the time of admission for 
delivery. 
The following investigations are routinely undertaken in the clinical setting once HDP is 
identified in order to further categorize HDP into more specific diagnoses. These results will be 
reviewed for each patient to ensure the correct diagnosis has been assigned to the patient. Blood 
pressure findings as above with none of the findings listed in the table below satisfies a diagnosis 
of gestational hypertension. 
Type of test
Cutoffs
Diagnosis


  
De novo postpartum hypertensive disorders of pregnancy will be defined according to the 
aforementioned criteria and definitions, except for their timing of occurrence after delivery, and 
in the absence of any antenatal diagnosis of a hypertensive disorder of pregnancy. 
 
2.4 Statistical Analyses 
 
2.4.1 Sample size and statistical power 
Urine 
-24-hour protein 
concentration > 300 mg 
OR 
-Protein/Creatinine ratio > 0.3 
Preeclampsia  
Serum 
-Platelets <100,000/microliter 
OR 
-Creatinine >1.1 mg/dL, or 
doubling from baseline 
OR 
-LFTs > twice the upper limit 
of normal concentration or 
twice baseline 
Preeclampsia with severe 
features  
Signs/symptoms: any of the 
following, if not accounted 
for by another diagnosis 
-New-onset, refractory 
cerebral or visual 
disturbances 
-Severe persistent right upper 
quadrant or epigastric pain 
unresponsive to medication  
-Pulmonary edema 
-Blood pressure ≥ 160 
systolic OR ≥110 diastolic
Preeclampsia with severe 
features 
Serum 
-Platelets <100,000/microliter 
AND 
-Evidence of hemolysis 
AND 
-LFTs > twice the upper limit 
of normal concentration or 
twice baseline 
Hemolysis, elevated liver 
enzymes and low platelet 
count (HELLP) syndrome 
Signs/symptoms 
New-onset, grand mal 
seizure, with no history of 
seizure disorder and not 
accounted for by any other 
diagnosis
Eclampsia 


A case-control study of women who were normotensive at delivery but who were later 
hospitalized with a diagnosis of severe preeclampsia compared to women who remained 
normotensive in the postpartum period and women who were diagnosed with preeclampsia in the 
antenatal period determined that differences in mean arterial blood pressure could be detected 
following delivery. This retrospective review determined that women who developed de novo 
postpartum preeclampsia had a greater increase in MAP after delivery than normotensive women 
(5.0 ± 6.4 mm Hg vs 0.2 ± 6.0 mm Hg, p < 0.004). 13 Though data is scarce on whether a change 
in MAP can be detected in women with a broader diagnosis of de novo postpartum hypertension, 
using this reference data to assign an effect size of 5 mm Hg with standard deviation of 6.4 mm 
Hg and a baseline MAP of 83 mm Hg will provide a conservative estimate of a clinically 
meaningful change. For a power of 90%, a significance level 5%, and anticipated post-
randomization losses of 10%, 41 patients will be needed for each group, or 82 patients total. 
  
2.4.2 Statistical analysis 
For analysis of discrete (categorical) data in independent samples, the Chi-squared test or Fisher 
exact probability test will be utilized. For group comparisons, continuous data that satisfy the 
assumptions of normality and homoscedasticity (homogeneity of variance) will be analyzed by t-
test (for 2 independent samples) or analysis of variance (>2 groups, ANOVA) with post hoc 
comparisons by Scheffe tests. When possible, continuous data that do not fulfill the 
aforementioned assumptions will be mathematically transformed (e.g., logarithmic 
transformation) before performing t-tests or ANOVA. In some cases, data that do not satisfy 
these assumptions will be analyzed by nonparametric methods [Mann-Whitney U Test (for two 
independent samples) or Kruskal-Wallis One-Way ANOVA (for more than two independent 
samples)]. Significant Kruskal-Wallis ANOVAs will be followed by Dunn tests for post hoc 
analysis. The degree of linear association between variables will be measured by the Pearson 
product moment correlation coefficient or the Spearman rank-order correlation coefficient and 
their corresponding tests of significance. Multivariate linear or logistic regression will be utilized 
where appropriate. In all cases, statistical significance will be assumed when p<0.05. Propensity 
score analysis will be used as a balancing score as deemed necessary. 
 
2.4.3 Strengths and limitations 
Strengths of our study include a randomized control design, as well as a large cohort of patients 
who will be eligible for enrollment. CUIMC has 9 obstetric clinics which annually experience 
27,612 deliveries, of which only 2,853 would be excluded based on an antenatal diagnosis of 
HDP.   
Project limitations include potential fear among patients of a medication that is not standardly 
used in postpartum management that could limit enrollment. Additionally, patients are being 
discharged earlier than prior to the start of the COVID-19 pandemic, which would limit the 
amount of blood pressure data that can be collected and may limit the amount of time necessary 
to be able to see the effect of the diuresis; however, extended follow up and secondary outcomes 
included in the analysis, particularly review of logs at 10-14 days postpartum may assist in 
capturing the effect of the intervention after discharge.  


 
2.5. Anticipated outcomes  
The primary outcome will be the difference in the mean arterial blood pressure in the 24 hours 
prior to discharge or antihypertensive therapy initiation (whichever occurs first) between patients 
in the study drug group and those in the placebo group. We anticipate that the patients 
randomized to the study drug will have a significantly lower mean arterial blood pressures than 
those randomized to placebo. We propose that this will lead to faster normalization of blood 
pressures, reduce the rate of development of de novo hypertension, specifically preeclampsia, 
and reduce the morbidity and mortality associated with de novo postpartum hypertension without 
adverse effect.  
 
2.6 Significance  
There are several knowledge gaps in the postpartum management of women with pregnancy-
related hypertension. Specifically, no management recommendations or interventions for women 
at risk for developing de novo postpartum hypertension have been described, despite the 
evidence for their high risk of morbidity. These knowledge gaps have important clinical 
implications and answering them will provide valuable information regarding the low-cost 
interventions to reduce morbidity. The overall goal of this project is to collect empiric data for 
future guidelines on the use of diuretic therapy among postpartum women at risk for de novo 
postpartum hypertension. 
 
2.7 Timeline  
Enrollment is planned to begin in July of 2021, as soon as IRB approval is granted. The sample 
size required is 41 patients per group for a total of 82 patients. We anticipate that these patients 
will be successfully recruited into the study within a 12-month period, ending approximately in 
July of 2022. These patients will need to be followed until 6 weeks postpartum. We anticipate 
that the study will be completed by August 2022. 
 
2.8 Environment 
The Columbia Department of OB/GYN brings substantial experience and skill in organizing and 
participating in clinical research.  We have a strong track record in all areas of collaborative 
research including protocol design, implementation, data analysis and dissemination of findings.  
Our productivity is facilitated by a number of factors: (1) A critical mass of academic full time 
faculty with sufficient time and skill to perform clinical research, (2) the presence of a diverse 
patient population willing to participate in research initiatives, and (3) an established research 
environment in which clinicians accept participation in research initiatives as a major role of a 
teaching institution.  This has led to a longstanding reputation for excellence in clinical research. 
 
Of utmost importance is our research infrastructure with a proven record of success, which is 
embedded in the elaborate system of prenatal clinics and obstetric services and complemented by 
our large and diverse population of over 6,600 deliveries per year, advanced support systems, 


strong division of Neonatology, outstanding follow-up programs and a patient population proven 
to be receptive to participation in research.  The research staff is trained and certified in Good 
Clinical Practice, HIPPA, Blood Borne Pathogen Handling, and IATA Shipping Regulations. All 
staff is capable of collecting patient samples, cord blood and placental processing (including 
RNA, proteomics and DNA). Our research staff of over 25 individuals are trained and certified 
in each ongoing project.  This maximizes efficiencies in recruitment and the performance of 
study procedures and also allows staff to share the responsibility of on-call coverage. 
 
The Department of OB/GYN maintains a centralized administrative research office that manages 
pre- and post-award grant administration, and oversees roughly $10 million in sponsored 
research funding annually. The Office analyzes, monitors, and evaluates the Department’s 
research activities including all federal and non-federal sponsored awards and contracts. They 
ensure the efficient, cost-effective administration and financial management and ensure 
compliance with internal and external policies and procedures.  
 
2.9 Investigators  
We are uniquely qualified to perform this project, as we are in a large medical center, with a 
diverse patient population. Our research study will take place at Columbia University, a large 
academic center actively involved in a myriad of academic studies. The co-principal 
investigators, Dr. Cynthia Gyamfi-Bannerman and Dr. Russell S. Miller, completed their 
fellowship in Maternal-Fetal Medicine. Dr. Gyamfi-Bannerman is the Chair of Obstetrics, 
Gynecology, and Reproductive Sciences at University of California San Diego. Prior to that, she 
served as the Columbia Center PI for the Maternal-Fetal Medicine Unit Network, overseeing 
multiple randomized controlled trials. Dr. Miller is the Sloane Hospital for Women Associate 
Professor of Prenatal Pediatrics (in Obstetrics and Gynecology) and Medical Director of the 
Carmen and John Thain Center for Prenatal Pediatrics at Columbia University. Additionally, he 
has overseen multiple clinical trials. He is also the Director of the Maternal-Fetal Medicine 
fellowship program at Columbia University and a dedicated teacher and mentor in the residency 
program, as well. Dr. Ukachi Emeruwa, a fellow in Maternal-Fetal Medicine, has professional 
interests geared toward system-based program implementation, as well as behavioral health 
interventions centered around improvements in maternal health. Her research has begun to focus 
on investigations of clinical evidence that will inform systems-based practices for improvement 
of outcomes related to high-risk obstetrical issues, such as hypertensive disorders of pregnancy 
in particular. 
 
Support for database construction and management will primarily come from Cynthia Masson, 
Director of Clinical Information System Design and Innovation and head of the Columbia 
University’s Department of Obstetrics and Gynecology Interdepartmental CORE Data Team. 
She has assisted multiple single and multi-center funded and unfunded studies in obtaining and 
capturing research, clinical and operational data and providing a stream-lined process for 
building complex databases and translating complex data for seamless data analysis.  
 


As part of a major academic research center, we additionally have the continued support of 
medical students, residents and experienced research assistants. 
 
2.10 Risks, Benefits, and Monitoring 
 
2.10.1 Risks 
Lasix (furosemide) is in a class of drugs call diuretics and is commonly used to treat edema 
(swelling) and hypertension. Lasix is considered safe for use in adults and pediatric patients. If 
given in excessive amounts, Lasix can cause dehydration and electrolyte imbalances. Other 
possible side effects include dryness of mouth, thirst, weakness, lethargy, drowsiness, 
restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, 
arrhythmia, or gastrointestinal disturbances such as nausea and vomiting. Increases in blood 
glucose and alterations in glucose tolerance tests (with abnormalities of the fasting and 2-hour 
postprandial sugar) have been observed, and rarely, precipitation of diabetes mellitus has been 
reported.  
In patients with severe symptoms of urinary retention (because of bladder emptying disorders, 
prostatic hyperplasia, urethral narrowing), the administration of furosemide can cause acute 
urinary retention related to increased production and retention of urine. Thus, these patients 
require careful monitoring, especially during the initial stages of treatment. 
 
Lasix is contraindicated in patients with anuria and in patients with a history of hypersensitivity 
to furosemide. Therefore, if you do not produce urine or if you have ever had an allergic reaction 
to furosemide, you will not be able to participate in the study. 
  
A very small amount of Lasix may pass to the baby through breast milk. Lasix may also inhibit 
lactation. 
 
Since the use of the study drug is investigational, there may be other risks that are unknown. 
These may be minor or severe. They may find out new risks while the study is going on. If this 
happens, the research staff will tell the participants any new information, whether it may affect 
her, and what, if anything, to expect. 
 
Another risk of taking part in this study is the possibility of a loss of confidentiality. All efforts 
will be made to maintain confidentiality, including storage of data on secure servers and 
deidentification of data after it is collected. 
 
2.10.2 Benefits 
Participants may benefit from a reduction in blood pressure that could lead to lower rates of 
serious complications (e.g. seizure or stroke) as a result of participation in this study. There is, 
however, no guarantee that they will benefit from participation in this study. 
Information learned from the study may help other people in the future. 


 
2.10.3 Alternatives 
Alternatives to participating in this study include non-participation. 
 
2.10.4 Monitoring 
To ensure safety of the subjects, local monitoring will be completed by the Quality Assurance 
Monitor for the Department of Obstetrics and Gynecology for this Investigator/Peer study. At 
each scheduled monitoring visit, the QA Monitor will randomly select a representative number 
of study subject charts to be reviewed. He/she will perform a data query and review 
electronically uploaded source records (admission/hospital note). Additional monitoring will be 
based on the initial monitoring review. Upon completion of monitoring, the QA Monitor will 
submit a report of his/her findings to Dr. Russell S. Miller (Principal Investigator), Dr. Ukachi 
Emeruwa (Lead Co-Investigator), Dr. Ronald Wapner (Vice Chair of Research/Innovation) and 
Michelle DiVito RN, MSN (Senior Director of Research Administration), with corrective actions 
if necessary.  
 
The study will also be monitored by a Data Safety Monitoring Board (DSMB). The individuals 
responsible for monitoring data safety include:  
1) Alexander Friedman MD, MPH, Associate Professor of Obstetrics & Gynecology and 
Maternal-Fetal Medicine specialist with expertise in large scale obstetrics outcomes-
based research and care quality assessments  
2) Dani Dumitriu MD, PhD Assistant Professor of Pediatrics (in Psychology) with expertise 
in basic science research, as well as Principal Investigator of multiple large scale and 
multidisciplinary studies investigating mother and baby outcomes  
3) Alexander Melamed, MD, MPH, Assistant Professor of Obstetrics & Gynecology and 
Gynecologic Oncology specialist with expertise in harnessing large datasets to learn how 
to improve outcomes. 
No member of the DSMB will have direct involvement in the conduct of the study, nor any 
financial or other interests with any of the collaborating organizations involved in the study that 
constitute a potential conflict of interest.  
 
Meetings  
The DSMB will convene as often as necessary, but at least three times annually (at 25%, 50%, 
and 75% enrollment), to examine the accumulated safety and enrollment data, review study 
progress, and discuss other factors (internal or external to the study) that might necessitate a 
protocol modification or impact continuation of the study as designed. A DSMB meeting may be 
requested by DSMB members, IRB, or study Principal Investigator at any time to discuss safety 
concerns (ad hoc meetings.) Meetings may be held by conference calls or videoconferences or as 
face-to-face meetings. In the event a DSMB member cannot attend a meeting, he/she may 
receive the DSMB report (see below) and either participate by conference call or provide written 
comments to the DSMB Chair for consideration at the meeting.  
 


Specifically, the DSMB will review:  
 any specific events that would preclude a participant from continuing the intervention  
 any procedures in place for managing any medication-related issues – though this is a 
minimal risk study and we do not expect the following (e.g. allergic reactions, drug 
interactions, discontinuation/stoppage of medication)  
 trial stopping rules for the study, if any (e.g. safety concerns, futility)  
 any adverse events (non-serious and serious), unexpected safety events and unanticipated 
problems that occurred during study period  
 
Reports and Recommendations  
The DSMB will provide written minutes that identify topics discussed by the DSMB and 
describe its individual findings, overall safety assessment, and recommendations to the PI within 
a week of the meeting. Recommendations to discontinue or substantially modify the design or 
conduct of a study must be conveyed in a written, confidential report that may contain unmasked 
supporting data and include the DSMB member's rationale for their recommendations. It is the 
responsibility of the PI to forward the distributed communications from the DSMB to the IRB 
and other applicable entities.  
 
The Principal Investigator and Lead Co-Investigator will also be responsible for monitoring the 
trial, starting at the point the patient begins the study drug in the hospital, the day of delivery. 
The patient will be given the research team contact information on the consent and instructed to 
report any concerns about or adverse effects from the study drug (Lasix/furosemide or placebo). 
Of course, in the case of any medical emergency, the patient will be cautioned to call 911. The 
medical members of the research team will make the determination of relationship of each 
adverse effect to the Lasix (furosemide). During the study, the Principal Investigator or study site 
personnel will be responsible for querying and recording adverse events and serious adverse 
events. All adverse events – regardless of seriousness or relationship to the study drug – 
occurring from the signature of informed consent through the period of study drug intake (within 
eight hours after delivery up to 5 days after delivery), should be recorded.  
 
The research team will be keeping track of the patient’s progress while she is recovering post-
delivery, including blood pressures, labs, and post-procedural complications. If the patient 
develops any significant hypokalemia or severe renal dysfunction, which will be reflective in her 
labs, she will discontinue the drug. When the patient returns for her routine follow-up visit 
around 2 weeks and 6 weeks, the research team will follow up her postpartum course and 
monitor for any adverse events. If the patient is readmitted prior to her research follow-up visit, 
the research team will be notified by her clinical providers. The total monitoring period will last 
6 weeks from the time of delivery. The entire clinical trial will be stopped if there is greater than 
expected morbidity from the study drug – that is, if multiple patients have to withdraw from the 
trial due to adverse effects from the Lasix (furosemide).  
 
Once a mild adverse event is noted, the Principal Investigator will be notified by email within 1 
to 2 days. If a moderate or serious adverse event or unanticipated problem arises involving risk 
to subjects or others, the Principal Investigator will be notified immediately by email. This 
information will then be relayed by the Principal Investigator to the appropriate monitoring and 


regulatory entities, if needed. However, this is a minimal-risk study and such events are 
anticipated to occur very rarely. 
 
 
2.11 Privacy and Data Security 
 
2.11.1 Confidentiality of Study Data 
Study subject numbers linked to patient MRNs will be stored on an excel file which will require 
a password to open, on the RedCap Server until the completion of data collection, after which all 
patient identifiers will be removed from the excel file. This password will only be known to 
Research Personnel. No hard copy will exist. 
 
Data and research records will be primarily stored electronically in a study database on REDCap. 
This study database will be developed and maintained with support from Columbia University’s 
Department of Obstetrics and Gynecology CORE Data Team.  
 
REDCap (Research Electronic Data Capture) is a secure, web-based application designed to 
support data capture for research studies. The system was developed by a multi-institutional 
consortium initiated at Vanderbilt University. REDCap data collection projects rely on a 
thorough study-specific data dictionary defined in an iterative self- documenting process by all 
members of the research team with planning assistance from the OB/GYN Division of Research 
Informatics Support Team. The iterative development and testing process results in a well-
planned data collection strategy for individual studies. With the assistance of the OB/GYN 
Division of Research Informatics, the research team work to maintain a software toolset and 
workflow methodology for electronic collection and management of research and clinical trial 
data.  
 
REDCap servers are securely housed in an on-site limited access data center and is managed by 
the OB/GYN IT Division. The data is all stored on a private, protected university managed 
server. All users are authenticated via the CU and NYP LDAP servers and their access is 
restricted on a role-specific basis. Access can only be granted by administrators of the system. 
REDCap@OBGYN was developed specifically around HIPAA-Security guidelines and is 
implemented and maintained according to Columbia University and New York Presbyterian 
guidelines. All collected data are backed up daily. REDCap@OBGYN system id is 4283. 
 
REDCap Reference:  
P.A. Harris, R. Thielke, R. Taylor, J. Payne, N. Gonzalez, J.G. Conde. Research Electronic Data 
Capture (REDCap) - A metadata-driven methodology and workflow process for providing 
translational research informatics support. Journal of Biomedical Informatics, 2008 
(doi:10.1016/j.jbi.2008.08.010).  
 
Source data will be stored on encrypted, password-protected servers maintained by OBGYN IT 
at the CUMC server farm; system id is 3959. 
 


2.11.2 Privacy Protections 
Patient information will be collected by trained research personnel in a private setting. Patient 
confidentiality will be maintained following HIPAA rules and regulations. Patients medical 
records will be accessed in a secure location by one of the research personnel. The MRN, name, 
study ID, and data variables will be recorded on the secure excel file mentioned above to obtain 
all data variables. At the completion of data collection all identifiable data will be removed from 
the research database. No patient identifiers (names, numbers etc.) will be recorded on hard copy 
paper. 
 
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Bigelow CA, Pereira GA, Warmsley A, et al. Risk factors for new-onset late postpartum 
preeclampsia in women without a history of preeclampsia. Am J Obstet Gynecol. 
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