Conditions: Hypertension, Pregnancy-Induced
Keywords: Postpartum
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 202
Healthy volunteers: no

Brief summary:
This study aims to evaluate whether NSAIDs (Non-steroidal antiinflammatory drugs) administered during the postpartum period influence blood pressure in women with hypertensive disorders of pregnancy. The study design is a prospective double blinded randomized control trial with participants randomized to receive postpartum analgesic regimens with and without NSAIDs.

Detailed description:
Non-steroidal antiinflammatory drugs (NSAIDs) are effective agents for the management of pain in the postpartum period. The addition of NSAIDs to post-cesarean analgesic regimen has been shown to improve post-cesarean pain and reduce opioid requirements. However, concern has been raised over use of NSAIDs in hypertensive pregnant patients, as recent evidence suggests the potential for increased blood pressure in patients with chronic hypertensive disorders receiving these agents. Notably, these studies were conducted on patients with longstanding chronic hypertension, which included males and non-pregnant females, and it is therefore unclear whether this recommendation is appropriate for patients with transient hypertensive disorders of pregnancy.

This protocol describes a randomized trial to evaluate whether NSAIDs influence blood pressure parameters in patients with hypertensive disorders of pregnancy. Patients with severe hypertensive disorders of pregnancy (Severe HDP) will be studied separately from women with mild hypertensive disorders of pregnancy (Mild HDP).

Arms:
arm 1: This arm will be assigned a postpartum analgesic regimen with ibuprofen. arm 2: This arm will be assigned a postpartum analgesic regimen with ibuprofen. arm 3: This arm will be assigned a postpartum analgesic regimen with acetaminophen. arm 4: This arm will be assigned a postpartum analgesic regimen with acetaminophen.

Interventions: intervention 1: Acetaminophen intervention 2: Ibuprofen
Intervention descriptions: intervention 1: Participants will receive acetaminophen for postpartum mild pain relief intervention 2: Participants will receive ibuprofen for postpartum mild pain relief

Protocol document:
Prot_SAP_000.pdf: 
 
1 
A randomized controlled trial on the effects of NSAIDs on postpartum blood pressure in 
patients with hypertensive disorders of pregnancy 
 
Investigators: Christina A. Penfield, Jennifer McNulty, and Michael Nageotte 
 
 
October 13, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
2 
 
 
Background and Rationale: Non-steroidal anti-inflammatory drugs (NSAIDs) are effective 
agents for the management of pain in the postpartum period.1,2 The addition of NSAIDs to post-
cesarean analgesic regimen has been shown to improve post-cesarean pain and reduce opioid 
requirements.1, 3, 4-6  
Concern has been raised over use of NSAIDs in hypertensive pregnant patients, as recent 
evidence suggests the potential for increased blood pressure in patients with chronic hypertensive 
disorders receiving these agents. The mechanism by which NSAIDs have been proposed to 
increase blood pressure is by blocking synthesis of the prostaglandins that regulate vascular tone 
and sodium excretion. Elevated blood pressure in the immediate postpartum period can lead to 
adverse health consequences, particularly hemorrhagic stroke,3,4 as well as pathologic heart 
remodeling that can lead to long-term cardiovascular morbidity and mortality.5,6 Persistent 
postpartum hypertension is also associated with prolonged hospital stays7 and has the potential to 
influence patient satisfaction. Therefore, the American College of Obstetrics and Gynecology has 
suggested that these commonly used postpartum pain relief agents be replaced by other 
analgesics in women with hypertension that persists for more than 1 day postpartum.”8  
However, because of a lack of data, no firm recommendation was provided, no references were 
provided, and no quality or strength of recommendation was provided in the document. 
In fact, limiting use of this analgesic for postpartum women with hypertension may be 
premature. The suggestion from ACOG was extrapolated from studies conducted on patients 
with longstanding chronic hypertension, which included males and non-pregnant females. It is 
therefore unclear whether this recommendation is appropriate for patients with transient 
hypertensive disorders of pregnancy (HDP). These pregnancy-associated disorders, which 
include gestational hypertension and preeclampsia, are diagnosed after 20 weeks of gestation and 
typically resolve by 12 weeks postpartum. Since high blood pressure in these disorders is thought 
to arise as a result of a complex interplay between maternal and placental mechanisms,9-12 
NSAIDs may not produce similar deleterious effects.  
Previous studies on the association of NSAIDs and postpartum blood pressure have been 
inconclusive. One case report describes a postpartum hypertensive crisis in a patient with 
preeclampsia with severe features following rectal indomethacin administration.13 Notably, a 
recent retrospective study suggested that postpartum NSAIDs were not associated with an 
increase in blood pressure in women with severe features of preeclampsia.14 However, limited 
conclusions can be drawn from this study since it is unclear why some subjects had received 
NSAIDs and others did not. Therefore, in order to establish if there is a causal link between 
NSAIDs and elevated blood pressure in hypertensive postpartum women, a prospective trial is 
necessary.   
Currently the use of NSAIDs is not restricted in women with HDP at Miller Children’s and 
Women’s Hospital. We propose a double-blind randomized control trial to test the effects of 
postpartum analgesic medications on blood pressure control in women with HDP. We will also 
assess postpartum analgesic efficacy and patient satisfaction. With this data, we will be able to 
evaluate the safety and efficacy of using NSAIDs in the immediate postpartum period in women 
with HDP. 


 
3 
Study Objectives 
This study aims to investigate the effects of ibuprofen on blood pressure in postpartum women 
with hypertensive disorders of pregnancy (HDP).  
Women with HDP are often considered to have a distinct clinical course and risk of adverse 
outcomes if their hypertension is mild or severe. We will therefore consider these two subgroups 
as distinct study populations with different primary endpoints. 
Specific Aims:  
1) In women with severe hypertension prior to delivery, we will compare the incidence of 
severe postpartum blood pressures in patients receiving ibuprofen versus acetaminophen. 
 
Hypotheses: 
• There will be no difference in the proportion of women with an episode of severe 
hypertension in the two study groups. 
 
2) In women with mild hypertension prior to delivery, we will compare average postpartum 
blood pressure in patients receiving ibuprofen versus acetaminophen. 
 
Hypotheses: 
• There will be no difference in average postpartum blood pressure between study 
groups.  
Study Population 
Potential subjects will be patients admitted for medical care at Miller’s Children’s and Women’s 
Hospital.  
Inclusion Criteria 
1. Postpartum females at least 18 years old 
2. Delivery occurred at equal to or greater than 24 0/7 weeks gestational age 
3. Patient receiving care with the Women’s Perinatal Group (Maternal Fetal Medicine practice) 
or Obstetric Clinic resident services  
4. Diagnosis of a hypertensive disorder of pregnancy (HDP), including the following: 
• Gestational hypertension 
• Preeclampsia without severe features 
• Preeclampsia with severe features  
• Hemolysis, Elevated Liver Enzymes, Low Platelet (HELLP) Syndrome  
• Eclampsia 
Exclusion Criteria 
1. Diagnosis of chronic hypertension or documentation of elevated blood pressures before 20 
weeks gestational age.  


 
4 
2. Renal dysfunction (Serum creatinine measurement >1.3mg/dL during the current pregnancy) 
3. Low platelet count (recorded measurement <50,000 during hospital admission) 
4. Significant liver dysfunction (AST or ALT >500) 
5. Known sensitivities to ibuprofen or acetaminophen 
7. Use of therapeutic doses of anticoagulation (low dose anticoagulation used for routine 
prophylaxis of venous thromboembolism is acceptable) 
8. Postpartum hemorrhage requiring transfusion 
 
Subgroups of HDP 
Enrollment will be stratified into two groups of hypertensive patients based on the degree of 
elevation of blood pressures.  
 
• Group 1: “HDP-Severe” 
o Patients with at least one severe blood pressure measurement (systolic 
>160mmHg or diastolic >105mmHg) prior to randomization will be classified as 
having a severe hypertensive disorder of pregnancy. 
• Group 2: “HDP-Mild” 
o Patients without a severe-range blood pressure prior to randomization will be 
classified as having a mild hypertensive disorder of pregnancy.  
 
The definition of severe hypertension is adopted from the definitions of the American College of 
Obstetrics and Gynecology8 and the California Maternal Quality Care Collaborative. 
 
Study Design  
An outline of the study design can be found in Appendix I. This study will be a prospective 
double blinded randomized control trial with participants randomized to receive one of two oral 
postpartum study analgesic regimens: 
o Ibuprofen 600mg every 6 hours  
o Acetaminophen 650mg every 6 hours  
Participants will be randomized by computer-generated random numbers using consecutively 
numbered opaque sealed envelopes. The HDP-mild and HDP-severe subgroups will be 
randomized separately to ensure a balanced number of subjects in these two categories.  
Participants will receive the first dose of study analgesic (either oral ibuprofen or oral 
acetaminophen) no later than 8 hours after delivery, which will be continued until the time of 
discharge from the hospital. The medication will be offered to the patient every 6 hours, but they 
will have the option to skip a dose if they prefer. On the other hand, if after taking the scheduled 
study analgesic medication more analgesic medication is desired, every participant can request 
additional analgesic medications (i.e. hydrocodone, oxycodone) that are part of the standard 
options available for postpartum patients at Miller Children’s and Women’s Hospital.  


 
5 
Blood pressure measurements will be included in the study starting from the time of 
administration of the study medication until discharge. Blood pressures will be measured at least 
every 4 hours and recorded in the electronic medical record. Measurements can be taken more 
frequently, as clinically indicated. Blood pressure cutoffs will be established for physician 
notification by the RN (see study protocol order set).  
Intravenous (IV) antihypertensive medications will be administered according to the previously 
established management guidelines at Miller Children’s and Women’s Hospital (see Acute 
Hypertension Protocol, Appendix II) and the need for such treatment, if any, will be recorded. 
Oral antihypertensive therapy will be started to treat non-severe hypertension to keep blood 
pressure <150/100mmHg.  Oral antihypertensive medication regimens will be limited to 
nifedipine and labetalol which are considered first line oral antihypertensive agents for treating 
postpartum hypertension associated with hypertensive diseases of pregnancy. After initiation of a 
regimen, subsequent increased dosing of medications will be managed at the treating physician’s 
discretion.  
Pain scores will be assessed and recorded at least every 12 hours using visual (Wong-Baker 
facial grimace scale, Appendix III) or verbal numeric analog scale with scores 1-10 (Appendix 
IV). Pain measurements can be recorded more frequently as clinically indicated.  
A 3-item survey will be administered to patients prior to discharge (Appendix V). The survey 
will include one item from the HCAHPS survey (Appendix VI), an item to assess patient 
satisfaction, and an item to assess side effects of the medication. The survey will be administered 
by research staff and identified with the patient’s study ID number.  
An interim analysis will be performed for both the "HDP-severe" and "HDP-mild" study groups. 
The interim analysis will be performed on the primary endpoint when 50% of patients have been 
randomized and have completed the study including the 3-day outpatient blood pressure check 
follow-up. The interim analysis will be conducted by an independent group of 2-3 clinicians or 
researchers in conjunction with the research office who will be blinded to the treatment 
allocation. 
Outpatient Protocol 
At the time of discharge, if the patient is being prescribed oral antihypertensive medication as an 
outpatient, or if she had a blood pressure measurement systolic >140mmHg or diastolic 
>90mmHg in the prior 24 hours, then she will be advised to avoid ibuprofen as an outpatient. 
These patients will also receive a prescription for acetaminophen for mild analgesia, as well as 
additional opioid medications as necessary, with attention to avoiding more than the 
recommended 4g of acetaminophen from all sources in 24 hours. For example, postoperative 
patients could be prescribed hydrocodone or oxycodone 5/325 every 4 hours PRN, and 
acetaminophen 650mg every 8 hours PRN. If every pill is taken in the regimen, the total 
acetaminophen dose will be 3900mg in 24 hours. 
Within 3 days after discharge, the patient will have a visit scheduled at the WPG office or the 
Obstetric Resident Clinic for a blood pressure check.  
Study recruitment for each arm of the study will end when the number of enrolled patients meets 
the criteria specified by the power analysis for that arm of the study.  


 
6 
Study Procedures 
Study Setting  
The study will take place at Miller’s Women’s and Children’s Hospital, a tertiary academic 
community hospital with 6000 deliveries annually.  
Patient Identification and Enrollment 
Residents, maternal fetal medicine (MFM) fellows, attending physicians, and research 
coordinators will screen patients for eligibility. The physician members of the team will screen 
for patients under their direct care, while research staff will review electronic medical records of 
patients to screen for potential candidates. The patient can be approached about enrollment in the 
study after admission to the hospital and diagnosis with a HDP. Recruitment will be completed 
before the initiation of the postpartum order set. Study personnel will be available 24/7 to answer 
all questions or concerns regarding the study. This team will be available to assist with the study 
until its completion.  
Research coordinators will obtain and maintain data on patient outcomes. All members of the 
research team will complete the appropriate human subjects research training and provide 
documentation to the IRB before participating in the study. 
Study Protocol Postpartum Order Set 
A specific study protocol postpartum order set will be used for all study participants.   
The order set will include the following: 
• Indication of assigned randomization group (study medication A or B) 
• Study drug to be administered every 6 hours, with the first dose prior to 8 hours after 
delivery 
• Vital signs to be recorded every 4 hours minimum per unit standard procedure,  
• Management of severe hypertension (defined as systolic BP of >160 OR diastolic BP 
>105 per unit standard protocol as described in the standard Miller's Women's and 
Children's Hospital acute hypertension order set: 
o Notify MD if systolic BP >160 mmHg or diastolic BP >105 mmHg and initiate 
acute hypertension protocol (Appendix II) 
• Pain score assessment at least every 12 hours as per unit policy 
• Do not administer NSAID medications   
• Do not exceed 1400mg/day of acetaminophen from all sources while on study protocol. 
• Any serum creatinine measurement >1.1 will have serum creatinine measured again at 
least every 24 hours until the measurement is less than 1.1. A study representative should 
be contacted. 
• Orders for additional PRN pain management:  
o Norco 5/325mg or 10/325mg 1 tab PO q6 hours PRN pain 
o Percocet 5/325mg or 10/325mg 1 tab PO q6 hours PRN pain 
o Additional orders can be activated by the managing physician if needed 
§ Hydromorphone 1mg IV q2-4 hours PRN breakthrough pain 


 
7 
§ Morphine 5mg IV q2-4 hours PRN breakthrough pain 
§ Oxycodone 5mg or 10mg 1 tab PO q4-6 hours PRN breakthrough pain 
 
Study Drug Maintenance and Concealment 
 
The pharmacist will individually prepare each dose of the study drug and label it as “study 
medication A” or “study medication B” with the necessary lot number and expiration date. The 
study medication will be dispensed as an oral solution to maintain blinding of patients, nursing, 
and patients. Only the pharmacist will know the identity of study medication A and B. The 
pharmacy staff will maintain a master inventory with logs of lot numbers and information on the 
study drug administered to participants.  
Randomization 
Participants will be randomized by computer-generated random assignments of group “A” and 
“B”. These assignments will be placed in consecutively numbered opaque sealed envelopes. The 
HDP-mild and HDP-severe subgroups will be randomized separately to ensure a balanced 
number of subjects in each of these two categories. The physician will indicate the assigned 
study group “A” or “B” in the study postpartum order set to indicate to pharmacy staff which 
study medication should be administered.  
Data Collection 
The following information will be collected for analysis. Please see Appendix VII for the data 
collection tool. 
Patient demographic information: 
• Age 
• BMI  
• Race/ethnicity  
• Parity 
• Tobacco or substance use in pregnancy 
• Pregestational or gestational diabetes 
Patient clinical information 
• Gestational age at delivery 
• IV magnesium use 
• Mode of delivery 
• Neonatal outcomes: Apgar scores, birthweight, NICU admission 
 
Outcome variables 
Outcomes in the HDP-severe subgroup  
The primary clinical concern for postpartum patients with HDP-severe is further postpartum 
episodes of severe hypertension, which are associated with adverse health outcomes such as 


 
8 
cerebrovascular events and seizures. As a result, these patients must be treated with a 
combination of oral and IV antihypertensive medications to maintain blood pressure control 
below this threshold. Additionally, the presence of severe hypertension is important because 
patients cannot be discharged if blood pressures are at this level, which can result in prolonged 
postpartum hospital stays. By using these endpoints, we will be able to evaluate if there is a 
difference in these postpartum complications in patients taking ibuprofen or acetaminophen. 
Additionally, pain scores will be regularly measured and recorded to assess adequacy of pain 
control with the two study medications.  
Primary outcome for HDP-severe subgroup 
Evaluate the incidence of severe blood pressures in women randomized to ibuprofen versus 
acetaminophen. 
o Null hypothesis: There is no difference in incidence of postpartum severe 
hypertension between the two study groups. 
o Primary endpoint: Proportion of women with at least one episode of severe blood 
pressure postpartum (systolic >160mmHg or diastolic >105mmHg). 
     Secondary outcomes for HDP-severe subgroup 
I. Blood Pressure Measurements 
• Total number of blood pressures that are severe-range (systolic >160mmHg or 
diastolic >105mmHg) 
• Average MAP using “per protocol” approach (including patients who were treated)  
• Average MAP in 24 hour intervals (postpartum day 1, day 2, day 3) and summative 
over the first 4 days of the postpartum period. 
• Outpatient postpartum blood pressure measurement within 3 days after discharge  
II. Antihypertensive treatment  
• Administration of an antihypertensive medication (yes/no)  
• Administration of an acute IV antihypertensive medication (yes/no) 
• Administration of an oral antihypertensive medication (yes/no) 
o Need to increase dosing of antihypertensive medication (yes/no) 
• Summation of all antihypertensive medications and doses administered  
III. Pain control 
• Average pain score using numeric analog scale 1-10 
o Visual pain scores with Wong-Baker facial grimace scale will be translated 
into 1-10 scores 
• Use of additional analgesic medications (yes/no) 
o Total number and dosing of analgesic medications 
• HCAHPS patient survey at time of discharge  
o “During this hospital stay, how often was your pain well controlled?” 
§ Never, sometimes, usually, always 


 
9 
IV. Patient satisfaction/Side effects 
• “Were you satisfied with the pain medications you received postpartum?” 
- Definitely no, sometimes, usually, always 
• Patient survey for side effects from analgesic medications: GI irritation/sedation 
• Length of hospital stay 
o Number of cases where hospital stay in prolonged due to uncontrolled blood 
pressures  
Outcomes in the HDP-mild subgroup 
For the HDP-mild subgroup, we are primarily interested in average blood pressure during 
postpartum stay. Since this group rarely receives antihypertensive treatment, we will be able to 
isolate the effect of ibuprofen and acetaminophen on average postpartum blood pressure. We will 
also evaluate if there is a difference in incidence of severe hypertension and need for treatment 
between the two medication study groups. 
Additionally, pain scores will be regularly measured and recorded to assess adequacy of pain 
control with the two study medications.  
Primary Outcome for HDP-mild subgroup 
Evaluate average blood pressure in postpartum women randomized to acetaminophen 
versus ibuprofen. 
o Null hypothesis: There is no difference in blood pressure between the two study 
groups. 
o Primary Endpoint: Average mean arterial pressure (MAP) during postpartum hospital 
stay. 
§ We will exclude any patient who received antihypertensive medications 
postpartum from this primary analysis 
 
Secondary Outcomes for HDP-mild subgroup 
I. Blood Pressure Measurements 
• Average MAP using “per protocol” approach (including patients who were treated) 
• Average MAP in 24 hour intervals (postpartum day 1, day 2, day 3)  
• Incidence and total number of blood pressures that are severe-range (systolic 
>160mmHg or diastolic >105mmHg) 
• Outpatient postpartum blood pressure measurement within 3 days after discharge  
II. Antihypertensive treatment  
• Administration of an antihypertensive medication (yes/no)  
• Administration of an acute IV antihypertensive medication (yes/no) 
• Administration of an oral antihypertensive medication (yes/no) 
o Need to increase dosing of antihypertensive medication (yes/no) 
• Summation of all antihypertensive medications and doses administered  


 
10 
III. Pain control 
• Average pain score using numeric analog scale 1-10 
o Visual pain scores with Wong-Baker facial grimace scale will be translated 
into 1-10 scores 
• Use of additional analgesic medications (yes/no) 
o Total number and dosing of analgesic medications 
• HCAHPS patient survey at time of discharge  
o “During this hospital stay, how often was your pain well controlled?” 
§ Never, sometimes, usually, always 
IV. Patient satisfaction/Side effects 
• “Were you satisfied with the pain medications you received postpartum?” 
- Definitely no, sometimes, usually, always 
• Patient survey for side effects from analgesic medications: GI irritation/sedation 
• Length of hospital stay 
o Number of cases where hospital stay in prolonged due to uncontrolled blood 
pressures  
 
Privacy 
Research staff and the investigators will ensure that the consent process, protocol compliance, 
documentation of CRFs, source document storage, and standards of privacy and confidentiality 
are maintained throughout the study by the research coordinator and research staff. 
Statistical Considerations 
The outcome data from the two subgroups of HDP-severe and HDP-mild will be analyzed 
separately.  
 
Power analysis 
I. HDP-Severe Subgroup 
The study will be powered to detect a difference in the proportion of patients who have an 
episode of severe postpartum blood pressure between the two study groups. Based on a prior 
study of women with preeclampsia with severe features exposed to NSAIDs postpartum, 59% of 
women require treatment with antihypertensive medications.9 Another study reported an 88% 
rate of antihypertensive treatment postpartum in women with HDP, although they did not 
indicate if NSAIDs were prescribed.15 We therefore estimate that 75% of HDP-severe patients 
taking NSAIDs will have at least one severe blood pressure postpartum. 
Since NSAIDs have the potential to contribute to postpartum pain control, we anticipate that we 
would need to demonstrate a large clinical effect on blood pressure in order to influence current 
prescribing practices. We therefore would like to detect a 35% decrease in number of patients 
with at least one severe blood pressure postpartum in the acetaminophen study group, to a rate of 
49%. With a statistical significance level of 0.05 and power set at 0.80 in a two-sided test, we 


 
11 
will need to enroll 122 participants. To account for potential dropout in our study groups, we 
plan to enroll 10% more patients, for a total of 140 HDP-severe patients. 
II. HDP-mild patients 
In women with mild HDP, we would like to detect a change in postpartum mean arterial pressure 
(MAP) between the two study groups. In several studies of non-pregnant patients, NSAID use 
led to a MAP increase of 4-6mmHg compared to acetaminophen and placebo groups.10-11 
Therefore, to maximize clinical significance, we will aim to detect a difference in MAP of 6 
mmHg between study groups. Previous studies have suggested the standard deviation for average 
MAP during postpartum stay in women with HDP is 7.9mmHg.9 
Assuming an average blood pressure of 140/90 in mild hypertensive patients, we will predict a 
MAP of 107mmHg in the NSAID group, and expect to see a 6 mmHg decrease to a MAP of 101 
mmHg in the acetaminophen group. By setting statistical significance at 0.05 and power at 0.80 
in a two-sided test, we will need to enroll 56 study participants. To account for potential dropout 
in our study groups, we plan to enroll 10% more patients, for a total of 62 HDP-mild patients. 
 
Data Analysis 
STATA 11.0 software 
Comparison of mean arterial blood pressure between groups:  
- 
Student’s t-test (comparison of means, assuming data is parametric) 
- 
Logistic regression for all postpartum blood pressure measurements as a continuous 
variable 
Comparisons of frequency of severe blood pressures: difference in median frequency between 
groups, nonparametric distribution. 
- 
Mann-Whitney U test 
Difference in pain score median averages, nonparametric data:  
- 
Mann-Whitney U Test 
Other categorical variables: use of antihypertensive meds, need to increase antihypertensive 
medications, patient satisfaction/side effects 
- 
Chi-squared analysis, Fischer’s exact test  
 
 
Schedule of Study Visits 
The patients will be scheduled for one outpatient postpartum blood pressure evaluation within 3 
days after discharge. 
 
Risks and Benefits Associated with the Study Procedure 
Benefits: There are no benefits to the study participants. 


 
12 
Risks: There are no additional risks over standard current care to participating in the study, since 
both study drugs are routinely administered for postpartum analgesia at Miller’s Children’s and 
Women’s Hospital, regardless of the diagnosis of hypertensive diseases of pregnancy. The 
frequency and dosing of these medications are also consistent with the current standard of care at 
our hospital. These medications are well tolerated, have minimal side effects, and are available 
over the counter.  
If the assigned treatment regimen does not control pain adequately, several alternative pain 
medications will be available to the participant. However, the patient would not be able to 
receive the alternative non-narcotic treatment for mild pain control unless they withdraw from 
the study.  
Monitoring Plan 
Research staff and the investigators will ensure that the consent process, protocol compliance, 
documentation of CRFs, source document storage, and standards of privacy and confidentiality 
are maintained throughout the study by the research coordinator and research staff. 
Additionally, storage of all sensitive material will be in a locked file cabinet and there will be no 
storage of data with protected health information (PHI) on laptop computers. No PHI will leave 
the LBMMC premises or be transmitted on personal emails. 
Research staff will audit the consent binders to assess that all protocols have been adhered to. 
Study personnel will be available 24/7 to answer all questions or concerns regarding the study.  
Safety Considerations 
 
Pharmacy and study personnel will ensure all safety procedures will be maintained throughout 
the study. If a significant unanticipated adverse event or other unanticipated problem is 
identified, the investigators or designee will report them within 7 days (if the event is serious) or 
within 14 days (for any other unanticipated problems) of becoming aware of the problem and 
records will be maintained in the research coordinator’s file.  All data will be kept in the research 
coordinator office, which has a locked door and in a cabinet that is double locked.  
Potential complications of high blood pressure during pregnancy include stroke and seizures. 
Complications from antihypertensive medications include sudden symptomatic low blood 
pressure. Potential complications from the study medications include gastrointestinal bleeding 
and renal dysfunction (ibuprofen) and liver dysfunction (acetaminophen), although neither study 
drug will be administered in the high doses that are associated with these complications. 
However, as a precaution we will have a serum creatinine monitoring protocol in place. 
Currently, as part of routine of care, every hypertensive obstetric patient receives a measurement 
of creatinine (along with liver function enzymes and complete blood count) when admitted to the 
hospital. If serum creatinine measurement is >1.1mg/dl, we will monitor creatinine levels every 
24 hours until the measurement is less than 1.1mg/dL. A study representative will be contacted 
to ensure that these levels are monitored appropriately. If the creatinine increases to 1.4 mg/dl or 
above, the patient will be the study medication will be unmasked. If the patient was assigned to 
ibuprofen, the medication will be discontinued and this unanticipated problem will be reported to 
the IRB. 


 
13 
An interim analysis will be performed for both the "HDP-severe" and "HDP-mild" study groups.  
The interim analysis will be performed on the primary endpoint when 50% of patients have been 
randomized and have completed the study including the 3-day outpatient blood pressure check 
follow-up. The interim analysis will be conducted by an independent group of 2-3 clinicians or 
researchers in conjunction with the research office who will be blinded to the treatment 
allocation. The validated Peto approach will be used: the trial will be ended if a significant 
difference in primary outcomes is found between the two study groups using symmetric stopping 
boundaries at p<0.001. Additionally, the study will be halted if there are significant differences 
in numbers of patients in each group with serum creatinine that exceeds >1.4mg/dl while using 
the study drug using symmetric stopping boundaries at p<0.001. 
Confidentiality 
Throughout the study, only study personnel will have access to collected subject data. Please see 
application for description of who will have access to data. Additionally, storage of all sensitive 
material will be in a locked file cabinet and there will be no storage of data with protected health 
information (PHI) on laptop computers. No PHI will leave the LBMMC premises or be 
transmitted on personal emails. 
The data will be collected until the predefined number of patients have been enrolled and 
completed the study. After the study’s closure, the data will be stored for thirty years, and 
subsequently destroyed. 
Please see HIPAA subject authorization form for more details (Appendix VIII). 
Appendices:  
I. Study design flow diagram 
II. Hypertension Protocol  
III. Visual Analog Pain Scale 
IV. Verbal Numeric Analog Pain Scale 
V. Discharge Assessment Patient Survey 
VI. HCAHPS Survey 
VII. Data Collection Tool 
VIII. HIPAA Subject Authorization Form 
 
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doi:10.1213/01.ANE.0000024266.92933.87. 


 
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2. 
Deussen AR APMR. Analgesia for relief of pain due to uterine cramping/involution after 
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3. 
Martin JN Jr, Thigpen BD, Moore RC, Rose CH, Cushman J, May W. Stroke and Severe 
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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. 
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8. 
American College of Obstetricians and Gynecologists. Task Force on Hypertension in 
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9. 
Wagner SJ, Craici IM, Grande JP, Garovic VD. From placenta to podocyte: vascular and 
podocyte pathophysiology in preeclampsia. Clin Nephrol. 2012;78(3):241-249. 
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Herse F, LaMarca B. Angiotensin II Type 1 Receptor Autoantibody (AT1-AA)-Mediated 
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