Oral Combined Hydrochlorothiazide/Lisinopril Versus Oral Nifedipine for Postpartum Hypertension: A Comparative Effectiveness Pilot Randomized Controlled Trial
Phase: PHASE4
Conditions: Hypertension in Pregnancy, Postpartum Preeclampsia
Sponsor: The University of Texas Health Science Center, Houston

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Oral combined Hydrochlorothiazide/Lisinopril versus oral nifedipine for postpartum 
hypertension: A comparative effectiveness pilot randomized 
 
NCT05049616 
 
Version Date: 07/06/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Oral combined Hydrochlorothiazide/Lisinopril versus oral nifedipine for 
postpartum hypertension: A comparative effectiveness pilot randomized 
controlled trial 
Study protocol 
 
Principal investigator: Michal Fishel Bartal, MD 
Co-investigators: 
Baha Sibai, MD 
Sean Blackwell, MD 
Joyce P. Samuel, MD 
 
Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology and 
Reproductive Sciences, The University of Texas Health Science Center at Houston 

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Background and significance: 
 
Hypertensive disorders of pregnancy (HDP) complicate up to 10% of 
pregnancies and are a significant cause of maternal mortality and morbidity.1 
Hypertension may be present before or during pregnancy or in postpartum. Postpartum 
hypertension can be related to the persistence of gestational 
hypertension,preeclampsia, preexisting chronic hypertension, or it could develop de 
novo secondary to other causes. While most research efforts have mainly been focused 
on the antenatal management of hypertension for a maternal and fetal benefit, there is a 
paucity of studies evaluating the behavior of postpartum hypertension and the 
pharmacologic therapies during this period to optimize maternal safety and minimize 
hospital stay. 
Postpartum hypertension results in increased medical costs due to prolonged 
hospitalization, the need for magnesium sulfate and antihypertensive drugs, and 
increased hospital readmission rates. People with hypertensive disorder of pregnancy 
are at increased risk for immediate postpartum complications, including hypertension- 
related complications (i.e., uncontrolled blood pressure, acute cardiovascular disease, 
acute cerebrovascular disease, acute renal insufficiency), and obstetric related 
postpartum complications (i.e., infection, hemorrhage, venous thromboembolism). 2 
Hypertensive disorder of pregnancy, and chronic hypertension are a risk factor for 
stroke during the postpartum period, with the majority of stroke readmission after birth 
occurring in the first 10 days after discharge. 3 Despite the cure for preeclampsia being 
the delivery of the infant, maternal health implications persist well beyond the 
pregnancy. Preeclampsia is associated with maternal cardiovascular dysfunction and 

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long-term cardiovascular risk,4-9 including a 2-fold risk of ischemic heart disease and 
stroke and a 4-fold risk of hypertension in later life.7,8,10-12 The association between 
preeclampsia and future CVD persists, despite accounting for mutual risk factors, 
including age, obesity, and prepregnancy hypertension.13 Cardiovascular disease is not 
only more common in people with preeclampsia, but it tends to occur earlier, with a 
higher fatality rate. 8 
For many asymptomatic women, antenatal care is their first adult 
engagement with the healthcare system. Consequently, pregnancy and the early 
postpartum provide an ideal window for risk screening and primary prevention of 
long-term cardiovascular health and future pregnancy outcomes. 
The American College of Obstetricians and Gynecologists (ACOG) recommends close 
outpatient blood pressure monitoring in all women with preeclampsia 7-10 days (or 
sooner if the patient is symptomatic) after delivery as the standard of care. Blood 
pressure rises progressively over the first five postnatal days, peaking on days three to 
six after delivery. 
Blood pressure medication during the postpartum period: 
 
During the immediate hospital stay after delivery, antihypertensive medications are 
recommended after delivery if systolic BP remains persistently ≥150 mm Hg and/or if 
diastolic BP ≥ 100 mm Hg. 14 However, there are no clear guidelines on optimal blood 
pressure management in the postpartum period. Based on previous data, at least 60- 
70% of women diagnosed with preeclampsia before delivery will require BP medications 
at discharge.15-17 18At three months postpartum, 39% of women still had hypertension 

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(defined as blood pressure ≥140/90), which decreased to 18% at two years postpartum. 
 
17 
 
A case-control study has also found that readmitted patients with HDP were less 
likely to start antihypertensive medications during their initial hospitalization after 
controlling for age, race, and chronic hypertension. 19 Based on previous data during 
readmission for hypertension, more than 50% of patients will start hypertensive 
medications. 20 
Despite the widespread use of antihypertensive drugs in the postpartum period, there is 
limited evidence regarding the preferred antihypertensive agent in that period (Table1). 
Usually, the selection of the antihypertensive agent is based on clinical judgment, as 
there are no standardized management guidelines for specific antihypertensive agents 
or parameters for postpartum medication titration.18 
Table 1: Randomized controlled studies evaluating medications for postpartum 
hypertension 
 
Study/ 
Populatio 
Intervention 
Control 
Primary 
Results 
Year 
n/ 
outcome 
Total 
number of 
patients 
Calcium channel blockers 
Barton21/ 
Severe 
Nifedipine 
Placebo 
MAP 
Reduction in 
1990 
preeclamp 
(oral,10mg) 
MAP with 
sia 
nifedipine 
N=32 
between 18- 
24 hours 
postpartum 
(93.9 versus 
100.2 mm 
Hg; p less 
than 0.05) 

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Vermillion 
22/1998 
Severe BP 
(170/105) 
N=50 
Nifedipine 
(oral,10mg) 
Labetalol 
20mg IV 
Time to 
achieve 
therapeutic 
goal 
(<160/100) 
Time to 
achieve BP 
goal shorter 
with 
nifedipine 
(25 ± 13.6 
min vs. 43.6 
±25.4 min; P 
=.002). 
Arias- 
Hernande 
z23/2020 
Postpartu 
m 
preeclamp 
sia with 
severe 
features 
N=42 
Diltiazem 
(oral,60mg TID) 
Nifedipin 
e 
(oral,10m 
g TID) 
SBP, DBP, 
MAP 
At 6 hours, 
lower SBP 
(133.4±10.2) 
vs. 147.9 
±9.7,p<0.00 
1) and DBP 
(78.5±7.7) 
vs. 90.6 
±5.5, 
p<0.001) 
with 
Diltiazem 
Beta-blocker 
Fidler24/ 
1982 
Postpartu 
m HTN 
(DBP 95- 
105) 
N=80 
Timolol (oral) 
Methyldo 
pa (oral) 
SBP, DBP 
Lower SBP 
with Timolol 
(difference 
5.1mmHg, 
p<0.05) 
Mabie25/ 
1987 
Severe 
Postpartu 
m HTN 
(DBP>110) 
N=60 
Labetalol (IV 20- 
80mg) 
Hydralazi 
ne (IV 
5mg) 
MAP 
Improved in 
the control 
group 
(difference 
5.1mmHg, 
p<0.02) 
Sharma26/ 
2017 
Postpartu 
m HTN 
(>150/100) 
N=50 
Labetalol (oral 
200mg BID) 
Nifedipin 
e (30mg 
daily) 
Time to BP 
control 
No 
difference 
(37.6 hours 
versus 38.2 
hours, p = 
0.51) 
Diuretics 
Matthews2 
7/1997 
Preeclamp 
sia 
N=19 
Furosemide (oral, 
40mg, 7 days) 
Placebo 
Mean BP, 
Max BP 
No 
difference 
Ascarelli28 
/2005 
Preeclamp 
sia 
N=264 
Furosemide (oral, 
20mg, 5 days) + 
Placebo 
SBP 
No benefit 
for patients 
with mild 

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Oral potassium 
preeclampsi 
supplementation 
a (n = 169) 
or 
superimpose 
d 
preeclampsi 
a (n = 25). 
Patients with 
severe 
preeclampsi 
a had lower 
SBP 
(142±13 mm 
Hg vs 
153±19 
mmHg, P < 
.004), and 
required less 
antihyperten 
sive therapy 
during 
hospitalizatio 
n (14% vs 
26%, P = 
.371) 
Venna29/ 
Postpartu 
Furosemide (oral, 
Nifedipin 
SBP,DBP, 
No 
2017 
m HTN 
20mg, 3 days) + 
e (10mg 
MBP, need difference in 
(>150/100) 
Nifedipine (10mg 
TID) 
for 
BP. 
N=108 
TID) 
additional 
Requirement 
HTN drugs 
of additional 
antihyperten 
sive higher 
in in 
Nifedipine 
alone group 
(26.0% vs. 
8.0%, p = 
0.017) 
Viteri30/ 
2018 
Preeclamp 
sia 
N=118 
Torsemide (20 
mg, 5 days) 
Placebo 
BP>150/10 
0 by day 5 
or 
discharge 
No 
difference 
Perdigao3 
Gestational Furosemide (oral, 
Placebo 
persistent 
60% 
1/ 
hypertensi 
20mg, 5 days) 
hypertensi 
reduction in 
2021 
on/preecla 
on 7 days 
the 
mpsia 
postpartum prevalence 

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N= 384 
(at least 2 
consecutiv 
e BP 
readings 
over 48 
hours of 
SBP ≥140 
and DBP 
≥90) 
of persistent 
hypertension 
at 7 days 
(adjusted 
relative risk, 
0.40 [95% 
CI, 0.20– 
0.81]) 
ACE inhibitors 
Ormesher 
32/2020 
Preterm 
preeclamp 
sia 
N= 60 
Enalapril 
5 mg daily 
for 1 week> 10 
mg for 2 weeks 
then 20 mg 
maintenance dose 
for 6 month 
Placebo 
reduction 
in total 
vascular 
resistance 
from 
baseline to 
6 
months 
No 
difference 
Alpha agonists 
Carlos 
Noronha 
Neto33/ 
2017 
Severe 
HTN 
(≥180/110) 
N=90 
Clonidine (oral, 
0.1mg) 
Captopril 
(oral, 
25mg) 
frequency 
of very 
high BP 
episodes 
(≥180/110) 
while in the 
obstetric 
ICU 
No 
difference 
Hydralazine 
Griffis34/ 
1989 
Gestational 
HTN 
N=26 
Hydralazine 
Methyldo 
pa 
MAP 
No 
difference 
Vigil-De 
Gracia35/ 
2007 
Severe 
HTN 
(≥160/110) 
N=82 
Hydralazine (IV, 
5mg) 
Labetalol 
(IV, 
20mg) 
Persistent 
severe BP 
No 
difference 
 
 
 
SBP; systolic blood pressure, DBP; diastolic blood pressure, MAP; mean arterial 
pressure 

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Angiotensin-converting enzyme inhibitors (ACE inhibitors) in the postpartum 
period. 
A review of the available observational literature concluded that the following 
drugs have minimal milk to maternal plasma ratios to make breastfeeding acceptable: 
methyldopa, beta-blockers with high protein binding, angiotensin-converting enzyme 
inhibitors, and some dihydropyridine calcium channel blockers.36 These drugs are used 
in the postpartum period, but the most common hypertensive treatment for antepartum 
and postpartum hypertension is Nifedipine and Labetalol.37 ACE inhibitors are not used 
during pregnancy due to the higher risk for teratogenic effects but may be used in the 
postpartum period. ACE inhibitors are recommended for those with pregestational 
diabetes mellitus or cardiomyopathy and are the 1st drug of choice by the National 
Institute for Health and Care Excellence (United Kingdom) for postpartum 
hypertension.37-39 
ACE inhibitors play an important role in controlling blood pressure outside of pregnancy. 
There is extensive evidence to support their cardioprotective effects. The HOPE (Heart 
Outcomes Prevention Evaluation) study, during which participants at high risk of 
cardiovascular disease were randomized to ramipril or placebo, was stopped 
prematurely due to the 22% reduction in myocardial infarction, cerebrovascular 
accident, or death from cardiovascular disease.40 
ACE inhibitors may be used in the postpartum period without effect on breastfeeding, 
but the evidence on the effect of ACE inhibitors on postpartum hypertension treatment 
is limited.32,38,41-44 

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Normal pregnancy has been identified as a state of relative resistance to the pressor 
effects of Angiotensin II (Ang II).45 In contrast, pregnant people with new-onset 
hypertension demonstrate increased sensitivity to the pressor effects of Ang II, even 
before the onset of hypertension.45,46 Increased sensitivity to angiotensin II observed 
during pregnancy in women with hypertensive pregnancy was also present 
postpartum.47 There is only one randomized study comparing captopril and clonidine for 
severe range blood pressure in the postpartum period. The above study concluded that 
both clonidine and captopril were safe and effective treatments for severe postpartum 
hypertension.33 There are no studies to date comparing ACE inhibitors to other oral 
medications to control non-severe blood pressure in the postpartum period. 
A recent randomized, double-blind placebo-controlled trial evaluated six months’ 
treatment with enalapril to improve postnatal cardiovascular function in women with 
preterm preeclampsia. The primary clinical outcome was reduction in total vascular 
resistance (TVR) from baseline to 6 months post randomization following treatment with 
enalapril, compared with placebo. There was no difference in the TVR between groups 
at 6 months postpartum. Similarly, there was no difference in systolic function 
(measured by left ventricular ejection fraction/global longitudinal strain). However, 
individuals who were treated with enalaprilhad a significantly better diastolic function 
and improved LV remodeling, compared with placebo at 6 months than those treated 
with placebo. 32 
Our experience with ACE inhibitors in the postpartum period has been favorable, but 
given the lack of data regarding use of ACE inhibitors in the postpartum period, it may 
not be an adequate drug for first-line treatment for persistent postpartum hypertension. 

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Diuretic use in the postpartum: 
 
In individuals with preeclampsia, persistent hypertension and edema result in part from 
the mobilization of up to 8 liters of fluid and sodium from the extravascular to 
intravascular space. The increased urinary sodium excretion on days 3-5 postpartum 
likely results from higher atrial natriuretic peptide concentrations in plasma and 
activation of the renin-angiotensin-aldosterone system. Adding diuretics for postpartum 
hypertension has been associated with better blood pressure control in some of the 
studies.28,29 
Rationale for a Clinical Trial and Hypothesis 
 
o CVD is the leading cause for mortality worldwide. 
 
o Primary prevention is more effective than treating CVD. 
 
o Pregnancy is often the 1st adult engagement with the healthcare system. 
 
o Preeclampsia is a risk factor for long term CVD, even after controlling for mutual 
risk factors. 
o CVD is the leading cause for pregnancy related mortality. 
 
o There is no good data regarding the optimal medications to control blood 
pressure after delivery. 
o ACE inhibitors play an important role in controlling blood pressure outside of 
pregnancy and there is extensive evidence to support their cardioprotective 
effects. 
o The optimal use of diuretics in the postpartum in patients with preeclampsia, 
require further study and clarification to augment current management schemes. 

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Hypothesis: We hypothesize that in postpartum women with hypertensive disorders, 
oral combined Hydrochlorothiazide/Lisinopril will reduce postpartum hypertension at 7 
days after delivery compared to usual care with calcium channel blockers. 
PICO question: 
 
Population: Puerperal women with hypertension within the first 72 hours after delivery. 
Intervention: Hctz/Lisinopril for postpartum management of hypertension 
Comparison: Extended release nifedipine 
Outcome: Stage 2 hypertension at day 7-10 after delivery (defined as SBP ≥ 140 
and/or DBP ≥ 90 mmHg) or admission to the hospital for blood pressure control prior to 
day 10. 
 
 
Inclusion Criteria 
 
• Postpartum women at ≥ 18 years of age 
 
• Postpartum diagnosis of persistent hypertension (2 measurements of Systolic BP 
 
≥150 and/or diastolic BP ≥ 100 or systolic BP ≥140 and/or diastolic BP ≥ 90 for 
people with diabetes) requiring an oral medication based on the ACOG criteria or 
• Hypertensive disorder of pregnancy diagnosed antepartum or intrapartum 
requiring blood pressure medication in the postpartum 
• Chronic hypertension requiring blood pressure medication postpartum 
 
 
Exclusion Criteria 
 
• Urine output < 30 cc/h prior to screening for eligibility 

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• Creatinine > 1.4 during current admission 
 
• End-stage renal disease 
 
• Hypersensitivity to ACE inhibitors or sulfa drugs 
 
• Idiopathic/hereditary angioedema 
 
• Hyperkalemia (serum potassium >5 mEq/L) during current admission 
 
• Pulmonary edema 
 
Randomization: 
 
o Randomization will be achieved by computer-generated random sequences that 
will be created by a non-clinical member of the research team. A permuted block 
randomization with a random fashion will be used to prevent imbalances between 
groups. 
o Randomization will be stratified according to: 
 
1. Primary diagnosis: chronic hypertension or newly diagnosed preeclampsia 
 
2. Recruiting site 
 
Setting: 
 
Recruitment will occur on the Labor and Delivery ward and postpartum ward at: 
 
o Memorial Hermann Hospital-Sowthwest. 
 
o Lyndon B. Johnson Hospital 
 
o Memorial Hermann Hospital-Texas Medical Center. 
 
Recruitment 
o The research staff/MFM physician will approach individuals that meet the 
inclusion and exclusion criteria during their hospital stay before discharge. 

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o The research stuff will Introduce Babyscripts as a health system’s mobile app 
and sign the patients up for Babyscripts. 
o After adding the patient to the system, the patient will receive an email and a text 
message with a personal passcode to complete registration. 
o The patient will download the Babyscripts myJourney app on her smartphone 
and enter the personal passcode under “New User” where it indicates. From 
there, the patient will be prompted to fill in some additional information to 
complete registration. 
o Once the patient completes registration, we will provide her with a BP monitor so 
you can start taking readings through the app. 
o The patients will be instructed to monitor their BP twice daily, in the morning and 
the evening. 
o Of Note, Babyscripts sends daily SMS reminders, twice a day, to remind patients 
to check their blood pressure. 
Intervention and procedures 
 
o Participants will be randomized to Hctz/Lisinopril (brand name: Zestoretic) or 
extended release Nifedipine. Group 1 will be composed of women allocated to 
Hctz/Lisinopril treatment. Group 2 will be composed of women allocated to 
extended release Nifedipine treatment. 
o Hctz/Lisinopril and extended release Nifedipine will be administrated orally in the 
morning for both groups. 
o The allocated study medication will be incrementally increased to achieve blood 
pressure control according to the threshold listed below (Table 2). 

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o If maximum dose of one medication will be reached without blood pressure 
control, oral labetalol will be added at the lowest dose increasing as needed. 
o Hctz/Lisinopril will be started at 10mg/12.5 daily 
 
o Extended release Nifedipine will be starts at 30mg daily 
 
o The use of concomitant intravenous antihypertensive medication (i.e 
Hydralazine, labetalol) for severe hypertension as well as the use of magnesium 
sulfate for seizure prophylaxis will be left to the discretion of the treating medical 
team 
o Following hospital discharge, twice a day (8am and 7pm), patients will receive 
SMS and push notifications to remind them to take their BP through the 
Babyscript app. If patients have three missed readings in a row, they will receive 
a SMS and push notification. 
o information will be collected from the medical record including medical and 
pregnancy history, lab results, delivery and postpartum information. 
Table 2: Dose adjustment plan 
 
Initial 
dose 
Dosing adjustment 
Maximum 
dose/day 
Extended release Nifedipine 
30mg/ 
day 
Increase by 
30mg/day 
90mg/day 
Lisinopril/Hydrochlorothiazide 
10mg/ 
12.5m 
g/day 
Increase by 10mg 
lisinopril/day to 
20mg/12.5 mg 
20/25/day 

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Next increase will be 
with the HCTZ to 
20mg/25 
 
 
Thresholds for action based on raised blood pressure in the postpartum period: 
The following recommendations for blood pressure treatment in the postpartum 
period are based on the ACOG and NICE guidelines38 
• During hospital stay: 
 
o SBP≥160 or DBP≥110, repeat BP in 15 minutes 
 
o If persistent, give intravenous medication to lower blood pressure and 
increase oral medication the next morning 
o SBP ≥150 or DBP≥100, repeat BP in 4 hours 
 
o If persistent, increase oral medication the next morning 
 
• After discharge from the hospital 
 
o SBP≥160 or DBP≥110, repeat BP in 15 minutes 
 
o If persistent, refer for evaluation in the clinic or the emergency department 
 
o SBP≥150 or DBP≥100 in BP monitoring at home or in postpartum clinic, 
increase oral medication the next morning 
Outcome measures: 
 
o All patients will receive a Bluetooth BP cuff at during the hospital course. 
 
o The BP cuff will be connected via Bluetooth to a Babyscripts application and 
available for the research team to review (Figure 1). 

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o The Babyscripts app is a resource for all UT Physicians obstetrical patients 
during their pregnancy and postpartum. 
o The participants will be instructed to measure their BP twice daily until their clinic 
appointment. 
o Following their postpartum clinic appointment the participants will be instructed to 
measure their BP once daily. 
• All patients will be followed in the clinic 7-10 days after delivery and 6 weeks 
postpartum as recommended by the ACOG guidelines 
• Patients will be contacted 3 month, 6 month and 1 year after delivery by 
telephone for information regarding blood pressure control, medication use. 
 
 
 
Figure: 

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Primary outcome: 
 
Stage 2 hypertension at day 7-10 after delivery (defined as SBP ≥ 140 and/or DBP ≥ 90 
mmHg) or admission to the hospital for blood pressure control prior to day 10. 
Primary outcome will be calculated as the average BP reading for day 7-10 after 
delivery. 
 
 
Secondary outcomes: 
 
• Occurrence of severe postpartum hypertension (SBP≥160 and/or DBP≥110 
 
mmHg on 2 occasions, 15 minutes apart) 
• Receipt of additional antihypertensive during admission, at 7-10 postpartum, and 
at 6 weeks postpartum. 

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• Postpartum length of stay 
 
• Postpartum readmission 
 
• Time from delivery to BP control (i.e time from delivery to last BP <150/100). 
 
• Incidence of persistent postpartum hypertension 6 weeks postpartum (SBP ≥ 140 
and/or DBP ≥ 90 mmHg). 
• Proteinuria at 7-10 days, and 6 weeks postpartum (measured by urine protein 
creatinine ratio). 
• Labs abnormality including hyperkalemia or creatinine increase at 7-10 day visit 
and 6 weeks postpartum. 
• Compliance with medications at postpartum visit at 7-10 days after delivery and 6 
weeks postpartum. The patient will be asked to bring their medication bottle with 
them and the compliance will be measured by counting pills at each postpartum 
visit. 
• Blood pressure control at 3 month, 6 month, 9 month, 1 year after delivery and 
need for BP medications. 
• % of patients receiving primary care with BP measurement at 1 year. 
 
• Postpartum complications captured as Severe composite maternal morbidity: 
 
o Need for ICU admission 
 
o HELLP 
 
o Eclampsia 
 
o Stroke 
 
o Renal failure 
 
o Pulmonary edema 

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o Cardiomyopathy 
 
o Maternal death 
 
• Blood pressure control at 3 month, 6 month, 9 month, 1 year after delivery and 
need for BP medications 
• % of patients receiving primary care with BP measurement at 1 year 
 
Sample size: 
 
Due to lack of information regarding the prevalence of persistent hypertension 7 days 
after delivery, and the limited information regarding the use of ACE inhibitors in the 
postpartum period, this will be a pilot study that will include 70 patients. That sample 
size will allow us to gather information regarding feasibility, compliance, rate of the 
primary outcome, dosing of medications, and side effects. 
Feasibility: 
 
Based on data from our center, in the 3 participating centers there are 6,574 deliveries 
per year. With 10% rate of preeclampsia, 657 people per year will be eligible to 
participate in this trial. Assuming 30-50% of patients will decline to participate, we will 
expect to recruit 70 patients in 6-9 month. 
Blinding: 
 
• We will not be able to blind the treating physician or patient to the study 
medication due to different dose adjustment, side effects, etc 
• However, the research person who would review the 7-10 day BP measurements 
will be blinded to treatment assignment 
Procedures for safety monitoring: 

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• A review of the available observational literature concluded that extended release 
nifedipine and ACEI have minimal milk to maternal plasma ratios to make 
breastfeeding acceptable. 
• Additionally Severe BP (SBP≥160/DBP ≥110) will be reported by the babyscript 
app to the physician via text and email, and the team will contact the patient for 
further management 
 
 
Statistical tests: 
 
• An intent-to-treat analysis will be conducted. Outcomes will be evaluated using 
the independent t-test for continuous variables and the x2 or fisher’s exact test for 
categorical variables as appropriate. Mann-Whitney U test will be used for non- 
parametric comparisons. We will report RR and 95% confidence intervals. 
Secondary outcome measures will be compared. 
• We will conduct a Bayesian analysis to calculate the probability of treatment 
benefit or hram. The probability of at least 20% reduction in the rate of the 
primary outcome will be considered clinically significant. we conservatively set a 
neutral prior probability centered at a relative risk (RR) of 1.0 (i.e., a priori no 
effect on the outcome) and a 95% credible interval of 0.25 – 4.0. 
 
 
 
Ancillary Studies 
 
1. Medication adherence survey: Medication non- adherence is an important public 
health issue that clinicians encounter. Approximately 78% of e-prescriptions are 

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actually filled; only 72% of new prescriptions are filled.48 Non-compliance is most 
common among new prescriptions for chronic conditions including 
hypertension(31.4%). Adherence to medications can be affected by a variety of 
factors in patients with hypertension; the perception that drugs are only needed 
when blood pressure levels are high, concerns regarding adverse effects, and lack 
of self-confidence in their self-treatment. Medications are commonly used in 
pregnancy and postpartum, with at least 81.2-96.9% of women using at least one 
medication, either prescribed or over-the-counter.49,50 The attitudes regarding drug 
use in pregnancy and obtaining drug information play an essential role in medication 
adherence51. The MMAS-8 validated survey (attached as Figure 1) will be given to 
women to complete their routine postpartum care during their clinic visit if they meet 
study criteria and agree to the study. This survey will be supplemented with other 
questions about demographics and challenges with prescription error and pick-up 
problems. It takes less than 10 minutes to complete. The answers will not be 
available to the managing health care provider but will be kept in the locked research 
office until after the delivery of the subject. Based on the survey scores, the subject 
will be divided into groups based on high, medium and low adherence. Outcomes 
between groups will be compared. 
2. Social determinants of health (SDH) Survey (SDH)- while our approach to clinical 
care is rooted in biology, an increasingly interdisciplinary approach is being employed 
that acknowledges SDH, i.e., the social and structural aspects of a ‘patient’s life that can 
influence health. Social determinants of health (SDH) include but are not limited to basic 
resources, educational opportunities and economic stability, access to health care, 

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community resources, literacy, socioeconomics, and safety.52 By understanding SDH, 
interventions can be pursued that can improve individual and population health. For 
patients living with hypertension, there is a correlation between social determinants of 
health and blood pressure control. SDH also impacts many obstetrical conditions. 53 
Using this broader context to understand ‘patients’ health care decision-making and 
health literacy facilitates the intersections of social identity and their associated patterns 
of structural oppression and fosters a creative approach to overcoming potential 
barriers. The PRAPARE Assessment (The Protocol for Responding to and Assessing’ 
Patients’ Assets, Risks, and Experiences) is an established tool to assess SDH briefly. 
Core measures of this tool include race, ethnicity, education, employment, insurance, 
income, material security, transportation, social integration and support, stress and 
migrant, veteran and housing status. It will provide insight by which we can understand 
correlations between SDH and health care outcomes in our population as a springboard 
to improving both the outcomes and the pathways leading to them. The brevity of 
questions covering numerous social domains can help target particular social features 
that may be correlated with blood pressure control as well as target resource referrals 
and utilization, thereby translating into actionable items. 
Ethical considerations 
Informed consent 
All study candidates will be given a full explanation of study, allowed to read the 
informed consent, and be provided the opportunity to ask any questions. Once all 
questions have been answered and the investigator is assured that the individual 

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23 
 
 
understands the requirements of the study, the subject will be signing an informed 
consent. The investigator shall provide a copy of the informed consent. 
Institutional review board 
 
Before initiation of the study, the PI will obtain approval of the research protocol from 
the IRB. The study will be registered in www.clinicaltrials.gov as required by US law for 
public access. 
 
Subject confidentially 
 
Each study’s subject anonymity will be maintained throughout the study. Before 
collecting the data, a unique study number will be assigned to each case, thus de- 
identifying the individual subject. There will be a log of the study subject to the assigned 
study number in the study site. 
Research assistants are in compliance with required CITI training. When the results of 
this research study are reported in medical journals or at scientific meetings, the 
subjects who take part will not be named or identified. The Federal Privacy Act protects 
the confidentiality of medical records and any private health information collected. 
Access to personal data will be limited to the investigators only. However, these 
individuals are required to keep all information confidential. 
Data handling and record-keeping 
 
Access to source documents: 

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Research personal will perform data collection manually from patient charts at the 
different sites. Please refer to the attached data collection sheet for detail on variables 
to be collected. Data will be collected from randomization until one year postpartum. 
Records retention: Data will be digitally encrypted and stored in the UTHealth Redcap 
system. After the study, the principal investigator will retain copies of the approved 
protocol and all other supporting documentation related to the project. De-identified 
patient information may be used for future research projects. 
Quality control Assurance: the principal investigator and co-investigators will go 
through all the files to assure that data is reliable and complete. The verification will be 
by self-assessment. 
 
 
 
 
 
 
Figure 1: Morisky Medication Adherence Questions (MMAS-8). 
 
 
 
These are questions about your medication adherence. Please circle or select one 
option. 
 
 
 
1. Do you sometimes forget to take your medicine? 
No 
Yes 
 
 
 
 
2. People sometimes miss taking their medicines 
No 
Yes 

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for reasons other than forgetting. Were there 
any days when you did not take your medicine? 
 
 
3. Have you ever cut back or stopped taking your 
No 
Yes 
medicine without telling your doctor because you 
felt worse when you took it? 
 
 
 
 
4. When you travel or leave home, do you sometimes 
No 
Yes 
forget to bring along your medicine? 
 
 
5. Did you take all your medicines yesterday? 
No 
Yes 
 
 
 
 
6. When you feel like your symptoms are under control, 
No 
Yes 
do you sometimes stop taking your medicine? 
 
 
7. Taking medicine every day is a real inconvenience 
No 
Yes 
for some people. Do you ever feel hassled about 
sticking to your treatment plan? 

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8. How often do you have difficulty remembering to 
take all your blood pressure medication? 
  
A. Never/rarely 
 
  
B. Once in a while 
 
  
C. Sometimes 
 
  
D. Usually 
 
  
E. All the time 
 
 
 
 
References: 
 
1. 
Umesawa M, Kobashi G. Epidemiology of hypertensive disorders in pregnancy: 
prevalence, risk factors, predictors and prognosis. Hypertens Res. 
2017;40(3):213-220. 
2. 
Murray Horwitz ME, Rodriguez MI, Dissanayake M, Carmichael SL, Snowden 
JM. Postpartum health risks among women with hypertensive disorders of 
pregnancy, California 2008-2012. J Hypertens. 2020. 
3. 
Too G, Wen T, Boehme AK, et al. Timing and Risk Factors of Postpartum Stroke. 
Obstet Gynecol. 2018;131(1):70-78. 
4. 
Evans CS, Gooch L, Flotta D, et al. Cardiovascular system during the postpartum 
state in women with a history of preeclampsia. Hypertension. 2011;58(1):57-62. 
5. 
Melchiorre K, Sutherland GR, Liberati M, Thilaganathan B. Preeclampsia is 
associated with persistent postpartum cardiovascular impairment. Hypertension. 
2011;58(4):709-715. 
6. 
Arnott C, Nelson M, Alfaro Ramirez M, et al. Maternal cardiovascular risk after 
hypertensive disorder of pregnancy. Heart. 2020;106(24):1927-1933. 
7. 
Grandi SM, Filion KB, Yoon S, et al. Cardiovascular Disease-Related Morbidity 
and Mortality in Women With a History of Pregnancy Complications. Circulation. 
2019;139(8):1069-1079. 
8. 
Leon LJ, McCarthy FP, Direk K, et al. Preeclampsia and Cardiovascular Disease 
in a Large UK Pregnancy Cohort of Linked Electronic Health Records: A 
CALIBER Study. Circulation. 2019;140(13):1050-1060. 

27 
IRB NUMBER: HSC-MS-21-0476 
IRB APPROVAL DATE: 07/06/2022 
27 
 
 
9. 
Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. 
Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and 
type 2 diabetes mellitus in the mother. Hypertension. 2009;53(6):944-951. 
10. 
McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ. Cardiovascular 
sequelae of preeclampsia/eclampsia: a systematic review and meta-analyses. 
Am Heart J. 2008;156(5):918-930. 
11. 
Wikstrom AK, Haglund B, Olovsson M, Lindeberg SN. The risk of maternal 
ischaemic heart disease after gestational hypertensive disease. BJOG. 
2005;112(11):1486-1491. 
12. 
Giorgione V, Ridder A, Kalafat E, Khalil A, Thilaganathan B. Incidence of 
postpartum hypertension within 2 years of a pregnancy complicated by 
preeclampsia: a systematic review and meta-analysis. BJOG. 2020. 
13. 
Bellamy L, Casas JP, Hingorani AD, Williams DJ. Preeclampsia and risk of 
cardiovascular disease and cancer in later life: systematic review and meta- 
analysis. BMJ. 2007;335(7627):974. 
14. 
American College of O, Gynecologists, Task Force on Hypertension in P. 
Hypertension in pregnancy. Report of the American College of Obstetricians and 
Gynecologists’ Task Force on Hypertension in Pregnancy. Obstet Gynecol. 
2013;122(5):1122-1131. 
15. 
Blue NR, Murray-Krezan C, Drake-Lavelle S, et al. effect of ibuprofen vs 
acetaminophen on postpartum hypertension in preeclampsia with severe 
features: a double-masked, randomized controlled trial. Am J Obstet Gynecol. 
2018;218(6):616 e611-616 e618. 
16. 
Goel A, Maski MR, Bajracharya S, et al. Epidemiology and Mechanisms of De 
Novo and Persistent Hypertension in the Postpartum Period. Circulation. 
2015;132(18):1726-1733. 
17. 
Berks D, Steegers EAP, Molas M, Visser W. Resolution of hypertension and 
proteinuria after preeclampsia. Obstet Gynecol. 2009;114(6):1307-1314. 
18. 
Cairns AE, Pealing L, Duffy JMN, et al. Postpartum management of hypertensive 
disorders of pregnancy: a systematic review. BMJ Open. 2017;7(11):e018696. 
19. 
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(5):405-409. 
20. 
Matthys LA, Coppage KH, Lambers DS, Barton JR, Sibai BM. Delayed 
postpartum preeclampsia: an experience of 151 cases. Am J Obstet Gynecol. 
2004;190(5):1464-1466. 
21. 
Barton JR, Hiett AK, Conover WB. The use of nifedipine during the postpartum 
period in patients with severe preeclampsia. Am J Obstet Gynecol. 
1990;162(3):788-792. 
22. 
Vermillion ST, Scardo JA, Newman RB, Chauhan SP. A randomized, double- 
blind trial of oral nifedipine and intravenous labetalol in hypertensive 
emergencies of pregnancy. Am J Obstet Gynecol. 1999;181(4):858-861. 
23. 
Arias-Hernandez G, Vargas-De-Leon C, Calzada-Mendoza CC, Ocharan- 
Hernandez ME. Efficacy of Diltiazem for the Control of Blood Pressure in 
Puerperal Patients with Severe Preeclampsia: A Randomized, Single-Blind, 
Controlled Trial. Int J Hypertens. 2020;2020:5347918. 

28 
IRB NUMBER: HSC-MS-21-0476 
IRB APPROVAL DATE: 07/06/2022 
28 
 
 
24. 
Fidler J, Smith V, De Swiet M. A randomized study comparing timolol and 
methyldopa in hospital treatment of puerperal hypertension. Br J Obstet 
Gynaecol. 1982;89(12):1031-1034. 
25. 
Mabie WC, Gonzalez AR, Sibai BM, Amon E. A comparative trial of labetalol and 
hydralazine in the acute management of severe hypertension complicating 
pregnancy. Obstet Gynecol. 1987;70(3 Pt 1):328-333. 
26. 
Sharma KJ, Greene N, Kilpatrick SJ. Oral labetalol compared to oral nifedipine 
for postpartum hypertension: A randomized controlled trial. Hypertens 
Pregnancy. 2017;36(1):44-47. 
27. 
Matthews G, Gornall R, Saunders NJ. A randomised placebo controlled trial of 
loop diuretics in moderate/severe preeclampsia, following delivery. J Obstet 
Gynaecol. 1997;17(1):30-32. 
28. 
Ascarelli MH, Johnson V, McCreary H, Cushman J, May WL, Martin JN, Jr. 
Postpartum preeclampsia management with furosemide: a randomized clinical 
trial. Obstet Gynecol. 2005;105(1):29-33. 
29. 
Veena P, Perivela L, Raghavan SS. Furosemide in postpartum management of 
severe preeclampsia: A randomized controlled trial. Hypertens Pregnancy. 
2017;36(1):84-89. 
30. 
Viteri OA, Alrais MA, Pedroza C, et al. Torsemide for Prevention of Persistent 
Postpartum Hypertension in Women With Preeclampsia: A Randomized 
Controlled Trial. Obstet Gynecol. 2018;132(5):1185-1191. 
31. 
Lopes Perdigao J, Lewey J, Hirshberg A, et al. Furosemide for Accelerated 
Recovery of Blood Pressure Postpartum in women with a hypertensive disorder 
of pregnancy: A Randomized Controlled Trial. Hypertension. 
2021:HYPERTENSIONAHA12016133. 
32. 
Ormesher L, Higson S, Luckie M, et al. Postnatal Enalapril to Improve 
Cardiovascular Function Following Preterm Preeclampsia (PICk-UP):: A 
Randomized Double-Blind Placebo-Controlled Feasibility Trial. Hypertension. 
2020;76(6):1828-1837. 
33. 
Noronha Neto C C, Maia SS, Katz L, Coutinho IC, Souza AR, Amorim MM. 
Clonidine versus Captopril for Severe Postpartum Hypertension: A Randomized 
Controlled Trial. PLoS One. 2017;12(1):e0168124. 
34. 
Griffis KR, Jr., Martin JN, Jr., Palmer SM, Martin RW, Morrison JC. Utilization of 
hydralazine or alpha-methyldopa for the management of early puerperal 
hypertension. Am J Perinatol. 1989;6(4):437-441. 
35. 
Vigil-De Gracia P, Ruiz E, Lopez JC, de Jaramillo IA, Vega-Maleck JC, Pinzon J. 
Management of severe hypertension in the postpartum period with intravenous 
hydralazine or labetalol: a randomized clinical trial. Hypertens Pregnancy. 
2007;26(2):163-171. 
36. 
Beardmore KS, Morris JM, Gallery ED. Excretion of antihypertensive medication 
into human breast milk: a systematic review. Hypertens Pregnancy. 
2002;21(1):85-95. 
37. 
Sibai BM. Etiology and management of postpartum hypertension-preeclampsia. 
Am J Obstet Gynecol. 2012;206(6):470-475. 
38. 
In: Hypertension in pregnancy: diagnosis and management. London2019. 

29 
IRB NUMBER: HSC-MS-21-0476 
IRB APPROVAL DATE: 07/06/2022 
29 
 
 
39. 
Podymow T, Joseph G. Preconception and pregnancy management of women 
with diabetic nephropathy on angiotensin converting enzyme inhibitors. Clin 
Nephrol. 2015;83(2):73-79. 
40. 
Heart Outcomes Prevention Evaluation Study I, Yusuf S, Sleight P, et al. Effects 
of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events 
in high-risk patients. N Engl J Med. 2000;342(3):145-153. 
41. 
Magee L, von Dadelszen P. Prevention and treatment of postpartum 
hypertension. Cochrane Database Syst Rev. 2013(4):CD004351. 
42. 
Redman CW, Kelly JG, Cooper WD. The excretion of enalapril and enalaprilat in 
human breast milk. Eur J Clin Pharmacol. 1990;38(1):99. 
43. 
Bramham K, Nelson-Piercy C, Brown MJ, Chappell LC. Postpartum management 
of hypertension. BMJ. 2013;346:f894. 
44. 
Shannon ME, Malecha SE, Cha AJ. Angiotensin converting enzyme inhibitors 
(ACEIs) and angiotensin II receptor blockers (ARBs) and lactation: an update. J 
Hum Lact. 2000;16(2):152-155. 
45. 
Chesley LC. Vascular reactivity in normal and toxemic pregnancy. Clin Obstet 
Gynecol. 1966;9(4):871-881. 
46. 
Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC. A study of 
angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest. 
1973;52(11):2682-2689. 
47. 
Saxena AR, Karumanchi SA, Brown NJ, Royle CM, McElrath TF, Seely EW. 
Increased sensitivity to angiotensin II is present postpartum in women with a 
history of hypertensive pregnancy. Hypertension. 2010;55(5):1239-1245. 
48. 
Fischer MA, Stedman MR, Lii J, et al. Primary medication non-adherence: 
analysis of 195,930 electronic prescriptions. J Gen Intern Med. 2010;25(4):284- 
290. 
49. 
Lupattelli A, Spigset O, Nordeng H. Adherence to medication for chronic 
disorders during pregnancy: results from a multinational study. Int J Clin Pharm. 
2014;36(1):145-153. 
50. 
Refuerzo JS, Blackwell SC, Sokol RJ, et al. use of over-the-counter medications 
and herbal remedies in pregnancy. Am J Perinatol. 2005;22(6):321-324. 
51. 
Morisky DE, Green LW, Levine DM. Concurrent and predictive validity of a self- 
reported measure of medication adherence. Med Care. 1986;24(1):67-74. 
52. 
Braveman P, Gottlieb L. The social determinants of health: it’s time to consider 
the causes of the causes. Public Health Rep. 2014;129 Suppl 2:19-31. 
53. 
Committee on Health Care for Underserved W. ACOG Committee Opinion No. 
729: Importance of Social Determinants of Health and Cultural Awareness in the 
Delivery of Reproductive Health Care. Obstet Gynecol. 2018;131(1):e43-e48.