Hypertension, Pregnancy-Induced
Conditions
Keywords
Furosemide, Postpartum, Hypertension
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.
Interventions
DRUGOral furosemide
Furosemide (Lasix), 20 milligram, PO, PO, daily
DRUGPlacebo Oral Tablet
Placebo, PO, daily
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Study medication (furosemide) and placebo will be stored at room temperature at the University of Pennsylvania research pharmacy. Pharmacy will be responsible for labeling and randomizing the medications.
Intervention model description
Double blind, randomized, placebo control design
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Hypertensive disorder of pregnancy diagnosed antepartum or intrapartum * Gestational hypertension * Pre-eclampsia with or without severe features * Superimposed pre-eclampsia with or without severe features * New diagnosis of HDP within 24 hours from delivery * Postpartum, delivery ≥ 20 weeks estimated gestational age * Age ≥18 years old
Exclusion criteria
* History of allergic reaction to furosemide * 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 * Baseline labs with K \<3 * Use of furosemide or other diuretics antepartum or intrapartum * Use of ototoxic agents including aminoglycosides (ie, Gentamicin for \>1 dose), cephalosporins (ie Ancef \>1 dose), * Patient unstable for protocol per investigator's judgement
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Persistently Elevated Blood Pressures 7 Days Postpartum | 0-7 days postpartum | To compare the rate of persistently elevated blood pressures (\>140/90) in women that receive a five day furosemide course compared to those that receive placebo. |
| Time to Resolution | 0-14 days postpartum | To compare the time (days) required to achieve a resolution of elevated blood pressure, adjusted for mode of delivery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Postpartum Length of Stay | 0-6 weeks postpartum | Number of days postpartum participants stayed in the hospital |
| Subjects With Complications During Hospitalization | 0-6 weeks postpartum | Subjects with complications during hospitalization related to hypertensive disorders of pregnancy. |
| Postpartum Readmission | 0-6 weeks postpartum | Number of subjects with one or more readmission/ER visit that were hypertension related |
| Number of Subjects That Required for Additional Antihypertensives | 0 to 6 weeks post-partum | Number of subjects that required additional hypertensive medication after discharge |
| Number of Subjects Experiencing One or More Adverse Effects | 0-6 weeks postpartum | Number of subjects experiencing one or more adverse effects secondary to furosemide |
| Number of Subjects Who Had Severe Hypertension Postpartum | 0-6 weeks postpartum | Number of women who had severe hypertension (systolic blood pressure\>160 millimeters of mercury or diastolic blood pressure\>110 millimeters of mercury) postpartum |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Oral Furosemide Oral tablet of furosemide 20 mg once daily for a total of 5 consecutive doses. | 192 |
| Placebo Oral Tablet Oral tablet of placebo once daily for a total of 5 consecutive doses. | 192 |
| Total | 384 |
Baseline characteristics
| Characteristic | Oral Furosemide | Placebo Oral Tablet | Total |
|---|---|---|---|
| Age, Continuous | 27 years | 27 years | 27 years |
| Cesarean delivery | 55 participants | 38 participants | 93 participants |
| Gestational age at delivery | 38.6 weeks | 38.4 weeks | 38.5 weeks |
| Hypertensive Disorders of Pregnancy (HDP) Non-severe | 128 Participants | 133 Participants | 261 Participants |
| Hypertensive Disorders of Pregnancy (HDP) Severe | 64 Participants | 59 Participants | 123 Participants |
| Race/Ethnicity, Customized Black | 151 Participants | 138 Participants | 289 Participants |
| Race/Ethnicity, Customized Other | 11 Participants | 7 Participants | 18 Participants |
| Race/Ethnicity, Customized White | 30 Participants | 47 Participants | 77 Participants |
| Sex: Female, Male Female | 192 Participants | 192 Participants | 384 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 192 | 0 / 192 |
| other Total, other adverse events | 3 / 192 | 1 / 192 |
| serious Total, serious adverse events | 0 / 192 | 0 / 192 |
Outcome results
Primary
Persistently Elevated Blood Pressures 7 Days Postpartum
To compare the rate of persistently elevated blood pressures (\>140/90) in women that receive a five day furosemide course compared to those that receive placebo.
Time frame: 0-7 days postpartum
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Furosemide | Persistently Elevated Blood Pressures 7 Days Postpartum | 10 Participants |
| Placebo Oral Tablet | Persistently Elevated Blood Pressures 7 Days Postpartum | 23 Participants |
p-value: 0.0395% CI: [0.2, 0.81]Regression, Linear
Primary
Time to Resolution
To compare the time (days) required to achieve a resolution of elevated blood pressure, adjusted for mode of delivery.
Time frame: 0-14 days postpartum
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oral Furosemide | Time to Resolution | 10 days |
| Placebo Oral Tablet | Time to Resolution | 10.5 days |
p-value: 0.1295% CI: [0.95, 1.51]Regression, Cox
Secondary
Number of Subjects Experiencing One or More Adverse Effects
Number of subjects experiencing one or more adverse effects secondary to furosemide
Time frame: 0-6 weeks postpartum
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Furosemide | Number of Subjects Experiencing One or More Adverse Effects | 0 Participants |
| Placebo Oral Tablet | Number of Subjects Experiencing One or More Adverse Effects | 1 Participants |
95% CI: [0.32, 28.59]
Secondary
Number of Subjects That Required for Additional Antihypertensives
Number of subjects that required additional hypertensive medication after discharge
Time frame: 0 to 6 weeks post-partum
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Furosemide | Number of Subjects That Required for Additional Antihypertensives | 25 Participants |
| Placebo Oral Tablet | Number of Subjects That Required for Additional Antihypertensives | 39 Participants |
p-value: 0.0395% CI: [0.39, 0.96]Chi-squared
Secondary
Number of Subjects Who Had Severe Hypertension Postpartum
Number of women who had severe hypertension (systolic blood pressure\>160 millimeters of mercury or diastolic blood pressure\>110 millimeters of mercury) postpartum
Time frame: 0-6 weeks postpartum
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Furosemide | Number of Subjects Who Had Severe Hypertension Postpartum | 81 Participants |
| Placebo Oral Tablet | Number of Subjects Who Had Severe Hypertension Postpartum | 86 Participants |
p-value: 0.3695% CI: [0.64, 1.18]Chi-squared
Secondary
Postpartum Length of Stay
Number of days postpartum participants stayed in the hospital
Time frame: 0-6 weeks postpartum
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oral Furosemide | Postpartum Length of Stay | 2 Days |
| Placebo Oral Tablet | Postpartum Length of Stay | 2 Days |
p-value: 0.7695% CI: [-0.09, 0.13]Regression, Linear
Secondary
Postpartum Readmission
Number of subjects with one or more readmission/ER visit that were hypertension related
Time frame: 0-6 weeks postpartum
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Furosemide | Postpartum Readmission | 9 Participants |
| Placebo Oral Tablet | Postpartum Readmission | 16 Participants |
p-value: 0.1495% CI: [0.25, 1.21]Chi-squared
Secondary
Subjects With Complications During Hospitalization
Subjects with complications during hospitalization related to hypertensive disorders of pregnancy.
Time frame: 0-6 weeks postpartum
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Oral Furosemide | Subjects With Complications During Hospitalization | 3 Participants |
| Placebo Oral Tablet | Subjects With Complications During Hospitalization | 1 Participants |
p-value: 0.62Fisher Exact