Preeclampsia And Nonsteroidal Drugs for Analgesia (PANDA): a Randomized Non Inferiority Trial
Phase: PHASE2
Conditions: Preeclampsia Severe, Preeclampsia Postpartum
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
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Preeclampsia And Nonsteroidal Drugs for Analgesia (PANDA): a randomized non inferiority trial 
 
 
Principal Investigator:   
Jonathan S. Hirshberg MD 
Department of Obstetrics and Gynecology, Washington University School of Medicine in St. 
Louis, St. Louis, MO 
 
 
 
 
 
 
Version #2.0 
Version Date:  
Version 4.09.19 
 

 
 
 
 
 
 
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TABLE OF CONTENTS 
A 
INTRODUCTION ............................................................................................................................... 3 
A1 
STUDY ABSTRACT ......................................................................................................................... 4 
A2 
PRIMARY HYPOTHESIS ................................................................................................................... 4 
A3 
PURPOSE OF THE STUDY PROTOCOL .............................................................................................. 4 
B 
BACKGROUND .................................................................................................................................. 4 
B1 
PRIOR LITERATURE AND STUDIES .................................................................................................. 5 
B2 
RATIONALE FOR THIS STUDY ......................................................................................................... 7 
C 
STUDY OBJECTIVES........................................................................................................................ 7 
C1 
PRIMARY AIM ................................................................................................................................ 7 
C2 
SECONDARY AIMS ......................................................................................................................... 7 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES ........................................................... 8 
D 
STUDY DESIGN ................................................................................................................................. 8 
D1 
OVERVIEW OR DESIGN SUMMARY ................................................................................................. 8 
D2 
SUBJECT SELECTION AND WITHDRAWAL....................................................................................... 8 
2.a 
Inclusion Criteria ..................................................................................................................... 8 
2.a 
Exclusion Criteria ..................................................................................................................... 9 
2.b 
Ethical Considerations ............................................................................................................. 9 
2.c 
Subject Recruitment Plans and Consent Process ..................................................................... 9 
2.d 
Randomization Method and Blinding ....................................................................................... 9 
2.e 
Risks and Benefits ..................................................................................................................... 9 
2.f 
Early Withdrawal of Subjects ......................................................................................................10 
2.g 
When and How to Withdraw Subjects ......................................................................................10 
2.h 
Data Collection and Follow-up for Withdrawn Subjects .........................................................10 
D3 
STUDY DRUG ................................................................................................................................10 
3.a 
Description ..............................................................................................................................10 
3.b 
Treatment Regimen ..................................................................................................................10 
3.c 
Method for Assigning Subjects to Treatment Groups ..............................................................11 
3.d 
Preparation and Administration of Study Drug .......................................................................11 
3.e 
Subject Compliance Monitoring ..............................................................................................11 
3.f 
Prior and Concomitant Therapy ..................................................................................................11 
3.g 
Packaging ................................................................................................................................11 
3.h 
Blinding of Study Drug ............................................................................................................11 
3.i 
Receiving, Storage, Dispensing and Return .................................................................................11 
E 
STUDY PROCEDURES ....................................................................................................................11 
E1 
SCREENING FOR ELIGIBILITY ........................................................................................................11 
E2 
SCHEDULE OF MEASUREMENTS ....................................................................................................11 
E3 
VISIT 1 ..........................................................................................................................................13 
E4 
VISIT 2. .........................................................................................................................................13 
E5 
SAFETY AND ADVERSE EVENTS ....................................................................................................13 
5.a 
Safety and Compliance Monitoring .........................................................................................13 
5.b 
Medical Monitoring .................................................................................................................13 
i 
Independent Data and Safety Monitoring Board ..................................................................................... 13 
5.c 
Definitions of Adverse Events ..................................................................................................13 
5.d 
Classification of Events ...........................................................................................................14 
i 
Relationship ............................................................................................................................................ 14 
ii 
Severity ................................................................................................................................................... 14 
iii 
Expectedness .......................................................................................................................................... 14 
5.e 
Data Collection Procedures for Adverse Events .....................................................................14 
5.f 
Reporting Procedures ..................................................................................................................14 

 
 
 
 
 
 
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5.g 
Adverse Event Reporting Period ..............................................................................................15 
5.h 
Post-study Adverse Event ........................................................................................................15 
E6 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ..........................................................15 
F 
STATISTICAL PLAN ........................................................................................................................15 
F1 
SAMPLE SIZE DETERMINATION AND POWER .....................................................................................15 
F2 
INTERIM MONITORING AND EARLY STOPPING ..................................................................................15 
F3 
ANALYSIS PLAN ................................................................................................................................15 
F4 
STATISTICAL METHODS ....................................................................................................................16 
F5 
MISSING OUTCOME DATA .................................................................................................................16 
F6 
UNBLINDING PROCEDURES ...............................................................................................................16 
G 
DATA HANDLING AND RECORD KEEPING .............................................................................16 
G1 
CONFIDENTIALITY AND SECURITY ................................................................................................16 
G2 
TRAINING......................................................................................................................................17 
G3 
CASE REPORT FORMS AND SOURCE DOCUMENTS .........................................................................17 
G4 
RECORDS RETENTION ...................................................................................................................17 
H 
STUDY ADMINISTRATION ...........................................................................................................17 
H1 
ORGANIZATION AND PARTICIPATING CENTERS ............................................................................17 
H2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ..........................................................................17 
H3 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................17 
H4 
STUDY TIMETABLE .......................................................................................................................18 
I 
PUBLICATION PLAN ......................................................................................................................18 
J 
ATTACHMENTS ...............................................................................................................................18 
J1 
INFORMED CONSENT DOCUMENTS .....................................................................................................18 
J2 
QUESTIONNAIRES OR SURVEYS .........................................................................................................18 
K 
REFERENCES ...................................................................................................................................19 
 
 
 
 
 
 
 
 
A Introduction 
 

 
 
 
 
 
 
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A1 Study Abstract 
Recently published clinical guidelines for the care of women with hypertensive disorders 
recommended that nonsteroidal anti-inflammatory drugs (NSAIDs) should be withheld from 
patients with hypertension that persists for more than one day postpartum. There has been a 
paucity of data from the obstetric literature to support or rebuff this recommendation. As the 
opioid crisis worsens in the United States, additional attention and resources have focused on 
limiting the use of narcotic medications. The effective employment of non-opioid analgesics has 
been shown to reduce narcotic use. Ibuprofen and other NSAIDs are the most effective and 
most commonly prescribed analgesics for postpartum pain, but clinicians now find themselves 
stuck between these recommendations and their efforts to limit unnecessary opioid 
prescriptions. We propose a randomized controlled non-inferiority trial of women with 
preeclampsia comparing a postpartum analgesic protocol that includes NSAIDs, to one that 
excludes them. Our central hypothesis is that NSAID use does not worsen hypertensive diseases 
of pregnancy. Our primary aim is to determine the effect of NSAIDs on postpartum 
antihypertensive requirements. 
 
A2 Primary Hypothesis 
Our central hypothesis is that NSAID use does not worsen hypertensive diseases of pregnancy. 
A3 Purpose of the Study Protocol 
Recently published clinical guidelines for the care of women with hypertensive disorders 
recommended that nonsteroidal anti-inflammatory drugs (NSAIDs) should be withheld from 
patients with hypertension that persists for more than one day postpartum (1). This 
recommendation is based in data from the general medicine literature, which suggests a role of 
NSAIDs in precipitating hypertension in non-pregnant adults (2,3). It may also draw from 
previously published case reports of post-partum hypertension that were thought to be NSAID 
induced (4). There has been a paucity of data from the obstetric literature to support or rebuff 
this recommendation. As the opioid crisis worsens in the United States, additional attention and 
resources have focused on limiting the use of narcotic medications. The effective employment 
of non-opioid analgesics has been shown to reduce narcotic use (5). Ibuprofen and other NSAIDs 
are the most effective and most commonly prescribed analgesics for postpartum pain, but 
clinicians now find themselves stuck between these recommendations and their efforts to limit 
unnecessary opioid prescriptions. 
 
We propose a randomized controlled non-inferiority trial of women with preeclampsia 
comparing a postpartum analgesic protocol that includes NSAIDs, to one that excludes them. 
Our central hypothesis is that NSAID use does not worsen hypertensive diseases of pregnancy. 
 
 
B Background 
 

 
 
 
 
 
 
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B1 Prior Literature and Studies 
Burden of postpartum hypertension: Hypertensive disorders effect up to 10% of pregnancies.  
They are a significant contributor to maternal and perinatal morbidity and mortality worldwide. 
Maternal morbidity from severe hypertension can be significant and potentially life-threatening. 
Stroke, cerebral hemorrhage, heart failure, pulmonary edema, and renal failure can occur from 
end organ damage with uncontrolled hypertension. Maternal mortality was attributed to 
hypertensive disorders in 13% of women in the Confidential Enquiries into Maternal Deaths [2]. 
Hypertensive disease that originates or persists into the postpartum period contribute to 
prolonged hospitalizations and hospital readmissions. Presence of these conditions in the 
peripartum period has also been linked to lifelong cardiovascular risk.  
The American College of Obstetrician and Gynecologists Task Force on Hypertension in 
Pregnancy released guidelines for the clinical care of hypertension in pregnancy in 2013.  These 
guidelines included a statement which suggested that nonsteroidal anti-inflammatory drugs 
(NSAIDs) should be withheld from patients with hypertension that persists for more than one 
day postpartum.  There are two sources for this recommendation.  The first is based in data 
from the general medicine literature, which suggests a role of NSAIDs in precipitating 
hypertension in non-pregnant adults.  The second may draw from previously published case 
reports of post-partum hypertension that were thought to be NSAID induced. 
Biologic feasibility:  There are multiple mechanisms which contribute to a biologic possibility 
that NSAIDs negatively impact postpartum hypertension. In Vivo studies have demonstrated 
that NSAIDs inhibit aldosterone and prostaglandin metabolism, potentially worsening 
vasoconstriction. Nonsteroidal medications produce vasoconstriction of the afferent renal 
arteriole, reducing GFR, and obstruct sodium excretion, with a combined effect of inhibiting 
diuresis.  Cytochrome-450 induction and Cox inhibition may lead to the accumulation of 
vasoactive metabolites of arachidonic acid.  
Related Research: Recent attention to this clinical question has generated data from multiple 
retrospective cohorts. Vieri et al found no difference in clinically significant hypertensive 
episodes in their 399 patients regardless of NSAID exposure.  Of note, they also found no 
difference between rates of renal injury, pulmonary edema, and intensive care unit admission. 
This replicates the findings of Wasden Et al, who in addition, showed that there were no 
increased antihypertensive requirements in those who received NSAIDs.   
A prospective trial was completed in Panama and published in 2017.  Vigil-De Gracia and 
colleagues randomized women with severe preeclampsia to acetaminophen or Ibuprofen for 
postpartum pain control.  The cohort, limited to women after vaginal birth, showed a 
statistically higher rate of hypertension (systolic BP>150 or diastolic >100) after the first 24 hour 
postpartum in those who received ibuprofen.  There was no difference in rates of severe range 
blood pressures (>160/110).  This study was limited by its small sample size (n=113), exclusion of 
those delivered by cesarean section, and open label- randomization. 
A double masked, randomized controlled trial completed by Blue et al in 2018, did not replicate 
these findings.  Key results from this study showed no difference in the duration of severe range 
blood pressures in the ibuprofen vs acetaminophen groups, no difference in mean arterial 
pressures, need for antihypertensives, or laboratory evidence of end organ dysfunction between 
the treatment groups.  Follow-up was carried out to 6 weeks postpartum, and while 23% of the 
cohort was lost to follow-up by 6 weeks, the remaining patients showed no difference between 
treatment groups. The study was designed and powered as a superiority trial.  Thus, its findings 
suggested that acetaminophen is not superior to Ibuprofen, but cannot be used to draw 
conclusions of equivalence or non-inferiority. 

 
 
 
 
 
 
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Using internal data, we completed a planned secondary analysis of a prospective cohort study of 
consecutive term patients meeting diagnostic criteria for preeclampsia with severe features. 
Ibuprofen dose, frequency and time of administration were collected during the postpartum 
course.  Noninvasive measurements of systolic and diastolic blood pressures (NIBP) were used 
to calculate daily mean arterial pressure (MAP).  Of the 335 patients in our analysis, 94% 
received Ibuprofen postpartum.  For those that received Ibuprofen, there was no association 
between daily Ibuprofen dose and mean postpartum MAP. The median total dose of ibuprofen 
was 3g during the post-partum hospitalization.  Patients who received more than 3g of 
ibuprofen had an average MAP of 100.5+9.1 mmHg, which did not differ significantly from those 
who received less than 3g (99.4+9.4 mmHg, p= 0.28).  
Table 1. MAPs postpartum across median ibuprofen dosage group   
Ibuprofen dose > 3g 
(n=132) 
Ibuprofen dose ≤ 3g  
(n= 183) 
P 
Overall mean 
MAPs postpartum 
100.5 ± 9.1 
99.4 ± 9.4 
0.28 
Mode of delivery 
 Vaginal 
101.0 ± 9.0 
99.1 ± 9.5 
0.16 
 Cesarean  
100.0 ±  9.4 
101.6 ± 7.5 
0.49 
 
We then examined the relationship between ibuprofen dose and the need for antihypertensive 
medications while hospitalized or at time of discharge. In this same cohort, antihypertensive 
medications were required in 42% of patients postpartum and 33% of patients at time of 
discharge.  Mean total Ibuprofen doses were higher in those who required antihypertensive 
medication compared to those who did not, but this was not significant after controlling for 
length of hospital stay and admission BP severity (aOR 1.03, 95% CI 0.92 – 1.15).  Those who 
required antihypertensive medications on discharge did not have a significantly higher mean 
total Ibuprofen doses while inpatient (aOR 1.06, 95% CI 0.95 – 1.18). 
 
Table 2. Association between ibuprofen dose and blood pressure medications postpartum and 
at time of discharge  
BP Meds PP 
(n= 141) 
No BP Meds PP 
(n= 194) 
P 
aOR* 
(95% CI) 
Ibuprofen dose, mg 
3664 ± 2021 
2836 ± 1474 
<0.01 
1.03 (0.92, 1.15) 
BP Meds at Discharge 
(n= 110) 
No BP Meds at Discharge 
(n= 225) 
Ibuprofen dose, mg 
3706 ± 1835 
2932 ± 1685 
<0.01 
1.06 (0.95, 1.18) 
*Adjusted for number of days inpatient postpartum, admission MAP   
 
NSAID analgesic effects and opioid use: As the opioid crisis worsens in the United States, 
additional attention and resources have focused on limiting the use of narcotic medications. The 
effective employment of non-opioid analgesics has been shown to reduce narcotic use (5).  
NSAIDs are the most commonly prescribed, and the most effective, medication for postpartum 
pain (12). Blue et al found no difference in pain scores or opioid use between the Ibuprofen and 
Acetaminophen groups. To date, there are no randomized controlled trials comparing opioid use 
in patients with and without NSAID analgesia. 

 
 
 
 
 
 
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B2 Rationale for this Study 
There is currently a paucity of data examining the impact of NSAIDs on postpartum 
preeclampsia.  Safety concerns have led to recommendations limiting their use, but these 
concerns have not yet been born out in the literature.  Retrospective analysis, including from 
our internal data, have displayed relative safety.  These studies are prone to the bias and 
limitations of any retrospective cohort.  The two published prospective trials had conflicting 
findings and significant limitations.  The proposed trial has several features that make it an 
innovative and unique approach to the clinical question of what role NSAIDs have in postpartum 
analgesia for patients with preeclampsia with severe features.  First, as proposed, this trial 
would be the largest to date examining this question.  Second, our trial is powered and designed 
as a non-inferiority trial, expanding its potential impact on clinical care.  Lastly, this trial is 
designed to mimic actual clinical practice. Where previous studies have compared 
acetaminophen alone to Ibuprofen alone, it is the practice at our institution, and we assume 
many others, to use both acetaminophen and ibuprofen in combination for post-partum 
analgesia.  Our trial is designed to determine the effect of prescribing vs withholding NSAIDs in 
addition to the standard analgesic care. This becomes important as we understand that 
acetaminophen is also a COX-2 inhibitor and has some inhibitory effect on prostaglandin 
synthesis.  Findings from this study have potential to impact the over 300,000 births each year 
effected by preeclampsia.  These findings will be vital to establishing the standard of care in 
these patients, promoting safe analgesia while decreasing opioid use in the postpartum period.      
 
C Study Objectives 
 
C1 Primary Aim 
Determine the effect of NSAIDs on postpartum antihypertensive requirements  
Hypothesis: Analgesic bundles that include NSAIDS, compared to those that exclude them, 
are not associated with antihypertensive requirements in the postpartum period. 
 
C2 Secondary Aims 
Secondary Aim #1: Characterize the effect of NSAID use on preeclampsia related end 
organ injury. 
Hypothesis: NSAID administration will be associated with a rate of renal and hepatic 
injury that is not different from those not exposed to NSAIDs. 
 
Secondary Aim #2: Evaluate the effect of NSAIDs on patient perception of pain, and 
opioid analgesic requirements. 
Hypothesis: NSAID administration will be associated with decreased patient perception 
of pain and decreased use of opioid analgesics. 
 
 

 
 
 
 
 
 
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C3 Rationale for the Selection of Outcome Measures 
The expected outcome of this study is high-quality evidence for management of postpartum 
pain in patients with preeclampsia with severe features to reduce opioid use and improve 
maternal outcomes. Achievement of the specific aims of the study will thus have an important 
impact on clinical management of this at-risk patient population and decrease maternal 
morbidities.  
 
D Study Design  
 
D1 Overview or Design Summary 
This will be a randomized noninferiority trial aimed at determining the efficacy of NSAIDs for 
management of postpartum pain in patients with severe postpartum preeclampsia. The 
randomized control trial is the ‘gold standard’ for research design. A case control or cohort 
study may be limited by selection bias and confounding. Random allocation of patients to 
interventions will minimize selection bias and confounding by both measured and unmeasured 
factors. Noninferiority trials test whether a new experimental treatment is not unacceptably less 
efficacious than a treatment already in use.  They are used when the treatment may offer 
advantages over standard treatments, in terms of improved safety, convenience, better 
compliance, or cost.  This study design requires a larger sample size, and specific statistical 
analysis, but is required to draw a conclusion such as: NSAIDs are not inferior to other analgesics 
in their effect on hypertension.  We will follow the Consolidated Standards of Reporting Trials 
(CONSORT) guidelines wherever appropriate in the conduct and reporting of this trial. We will 
use broad inclusion criteria and computer-generated random sequences to assign participants 
to the two interventions. Postpartum management will be similar in the two groups except for 
the analgesics available. Analysis will follow the intention-to-treat principle. The use of broad 
inclusion criteria and intention-to-treat analysis will allow a more conservative estimate of 
differences in outcomes between the two regimens and allow a better estimate of effectiveness 
and public health implications of practice change than would pure estimate of efficacy alone. 
D2 Subject Selection and Withdrawal  
 
2.a 
Inclusion Criteria  
Women at > 23 weeks gestational age undergoing vaginal or cesarean delivery at Barnes-Jewish 
Hospital with: 
i) An antepartum diagnosis of preeclampsia with severe features  
[Pre-eclampsia with severe features will be defined as elevated blood pressure ≥ 160/110, or 
pre-eclampsia in the setting of thrombocytopenia (platelet count < 100,000), impaired liver 
function (AST elevated to twice upper limit of normal) or persistent epigastric pain, renal 
insufficiency (serum creatinine of 1.1 mg/dl or doubling of prior value), pulmonary edema, or 
new onset visual disturbance or headache unresponsive to therapy.] 
 

 
 
 
 
 
 
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2.a 
Exclusion Criteria  
Women with NSAID allergy, an allergy to acetaminophen, Antihypertensive use in this 
pregnancy prior to 20 weeks gestation, chronic kidney disease or Acute kidney injury with 
Creatine clearance less than 60 mL/min, inability to obtain consent, Opioid abuse disorder, or 
peptic ulcer disease. 
2.b 
Ethical Considerations  
As this study addresses issues of analgesia and pain control, ethical considerations are of utmost 
importance.  Pain control in the postpartum period is an important factor in patient perceived 
autonomy and overall satisfaction with the birthing process.  In addition, physician prescribed 
opiod use has a known association with later opiod abuse disorders.  This study has potential 
ethical considerations for its participants and its future findings have the potential to impact 
ethical considerations for many poatpartum patient’s.   
 
This study will seek to balence concerns for beneficence and nonmaleficence while maintaining 
patient autonomy.  First, out goal is do no harm.  The existing data reviewed above in this 
protocol suggests that NSAIDs are safe in the poastpartum period and that withholding NSAIDs 
does not increase patient reliance on narcotic medications.  Second, our goal is to use the data 
collected and published from this study to improve patient safety and satisfaction for all women 
in the postpartum period.  Lastly, it is of utmost importance that we protect patient autonomy 
in this study.  Patients will be allowed to exit the study at any time, before or after 
randomization.  We have taken this crossover into account in our power calculations.   
2.c 
Subject Recruitment Plans and Consent Process 
We will employ familiar efficient recruitment techniques we have used in recent randomized 
trials in the same settings. All women admitted to the labor and delivery units of the 
participating medical centers will be screened against inclusion and exclusion criteria. Eligible 
subjects will be approached for written consent to participate in the study once they are 
diagnosed with preeclampsia with severe features.  
 
2.d 
Randomization Method and Blinding 
Although consent to participate will be obtained irrespective of mode of delivery, randomization 
will be performed only when delivery is complete. This is necessary to allow stratification by 
mode of delivery and eliminate any bias mode of delivery might introduce into our moderate 
sample size. 
 
Because of the ethical concerns of blinding patients or providers to analgesic treatments, 
neither patients nor physicians will be blinded to the group assignment of the subjects. Treating 
physicians will make decisions on escalation of analgesic medications on a case by case basis, 
with a goal of maintaining the patient in their treatment group unless they request to end their 
participation in the study. 
2.e 
Risks and Benefits 
The risks associated with study participation are theoretical as they have not been consistently 
described in the existing literature.  There is no clear link between NSAID use and worsening 
hypetension in patients with preeclampsia, but there is a theoretical risks described in the 

 
 
 
 
 
 
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introduction above.  There is also the known risks associated with Ibuprofen use as described in 
its FDA approval documentation. These risks include: Cardiovascular (CV) thrombotic events, 
myocardial infarction, and stroke, Gastrointestinal ulceration, perforation and bleeding, 
Hypertension, Congestive heart failure and Renal Injury.  These risks are described in low rates 
in chronic Ibuprofen users.  Ibuprofen is generally accepted as a safe medication for use in acute 
pain setting and for treatment of postpartum and postoperative pain. 
 
Benefits of study participation for those enrolled include the benefits of routine postpartum 
care and analgesia.  This includes pain score monitoring and blood pressure monitoring.  
Compensation of $25 will be provided at the end of participation.  Benefits of this work extend 
beyond the study population as its findings will be applicable to upwards of 15% of postpartum 
women. 
2.f 
Early Withdrawal of Subjects  
Patients will be able to withdrawl from study participation at any time.   
2.g 
When and How to Withdraw Subjects  
Patients can withdraw from the study by informing any member of their medical care team.  
This information will be passed from those team members to the research staff. 
2.h 
Data Collection and Follow-up for Withdrawn Subjects  
This study will be completed as an intent to treat analysis.  Crossover from one study group to 
the other, or withdrawl from study in its entirely will be documented so that the already existing 
data on that patient can be collated appropriately.   
 
D3 Study Drug  
 
3.a 
Description  
Ibuprofen is a Nonsteroidal Anti-Inflamitory Drug (NSAID) used for analgesia in the postpartum 
and postoperative period.  It is an FDA approved medication with excellent patient safety and 
tolerance data.   
3.b 
Treatment Regimen  
Patients will be randomized to one of the following: 
1. Standard Analgesic bundle: Ibuprofen 600mg PO q 6 hrs as needed for pain, 
Acetaminophen 1000mg q 8 hrs as needed for pain, and Oxycodone 5 to 10 mg q 4 hrs 
as needed for pain 
a. In patients undergoing cesarean section, ketorolac 30mg IV q 6 hrs may be 
substituted as an IV alternative to ibuprofen for the first 24 hours after 
surgery  
2. NSAID free analgesic bundle: Acetaminophen 1000mg q 8 hrs as needed for pain, and 
Oxycodone 5 to 10 mg q 4 hrs as needed for pain 
 

 
 
 
 
 
 
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3.c 
Method for Assigning Subjects to Treatment Groups  
Enrolled patients will be randomly assigned in a 1:1 ratio using computer-generated 
randomization sequence, stratified by mode of delivery.   
3.d 
Preparation and Administration of Study Drug  
As Ibuprofen is a standard medication used in postpartum pain, it will be prepared and 
administered in the usual fashion.  Preparation will be by the BJH pharmacy and administration 
will be per the Nursing staff. 
3.e 
Subject Compliance Monitoring  
Daily review of analgesic protocol adhearance will be performed by the study staff and the labor 
and delivery clinical pharmacists. 
3.f 
Prior and Concomitant Therapy  
Prior therapy will not be considered for this over the counter FDA approved medication.  
Concominant therapy will not be allowed and will be avoided as all duplicate therapies are 
monitored for inpatients, by BJH medical and pharmacy staff. 
3.g 
Packaging  
As this medication is being used according to its FDA approved role, no additional packaging will 
be used. 
3.h 
Blinding of Study Drug  
This is an unblinded study protocol. 
3.i 
Receiving, Storage, Dispensing and Return  
Ibuprofen will be used in accordance with existing BJH pharmacy guidelines.  No additional 
protocols are required for this use. 
E Study Procedures  
 
E1 Screening for Eligibility 
We will employ familiar efficient recruitment techniques we have used in recent randomized 
trials in the same settings. All women admitted to the labor and delivery units of the 
participating medical centers will be screened against inclusion and exclusion criteria.  
 
E2 Schedule of Measurements 
We will collect extensive antepartum, intrapartum, and postpartum data up to the 6 week 
postpartum clinic visit (Table 3). Data will be extracted from the medical record by trained 
research assistants.  Surveys will be obtained at the 6 weeks postpartum visit by trained 
research staff. A CMP will be obtained during the inpatient postpartum period only if clinically 
indicated to asses renal and hepatic function. 

 
 
 
 
 
 
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Table 3: Data to be collected
Antepartum Data 
 
Demographic characteristics: age, race, tobacco 
 
Medical history: diabetes, chronic hypertension, maternal body mass index 
 
Obstetric history: gestational age at delivery, pregnancy complications (gestational diabetes, 
preeclampsia, gestational hypertension)  
Intrapartum Data 
 
Labor type (spontaneous, induced, augmented) 
 
Labor duration 
 
Delivery type: cesarean, instrumental vaginal, spontaneous vaginal 
 
Vaginal laceration grade, if applicable 
Postpartum Data
 
MAPs prior to discharge 
 
Renal and hepatic function prior to discharge (CMP) 
 
Antihypertensive medication requirements prior to discharge 
 
Antihypertensive medications at time of discharge 
 
Hypertension-related outpatient visits during the postpartum period  
 
Hospital readmissions, indication, length of stay on readmission, treatments on readmission 
 
Patient reported pain scores while inpatient 
 
Opioid requirements while inpatient and at time of discharge 
 
MAP at 6 weeks postpartum visit 
 
Patient reported pain scores, opioid use and analgesia satisfaction at 6 weeks postpartum 
 
 

 
 
 
 
 
 
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E3 Visit 1  
Visit 1 will be defined as the patient’s inpatient admission for delivery until the time of hospital 
discharge. The data collected during this visit is defined above.   
E4 Visit 2  
Visit 2 will be the patient’s postpartum visit at 6 weeks after delivery.  This is a clinically 
indicated visit and is standard of care for all delivering women in the United States.  In person 
visits that occur in Washington University School of Medicine or Barnes Jewish Hospital 
outpatient spaces will proceed as typically scheduled and conducted.  Enrolled study patients 
will have their visit augmented by a brief survey administered by study staff via secured tablet.  
Please see the addendum for a copy of this questionnaire.  Patients who do not have follow up 
scheduled in either of these two clinical spaces will have their survey administered by trained 
study staff via telephone.  
 
Some subjects may be contacted 12 months following the completion of the follow up survey, if 
they consent.  This contact will be done to collect additional information regarding their medical 
history, if needed.  
 
E5 Safety and Adverse Events  
 
5.a 
Safety and Compliance Monitoring 
Safety and compliance monitoring will be performed by two separate review systems.  
Compliance will be monitored at regular intervals throughout patient participation.  Monitoring 
will be performed by the PI, trained study staff and our clinical pharmacy specialist.  Compliance 
will be monitored daily and any compliance issues will be reported to the PI who will assess and 
address systematic issues.  Safety will be monitored by an independent Data Safety and 
Monitoring Board as described below in section E5.5.b.i. 
5.b 
Medical Monitoring  
i 
Independent Data and Safety Monitoring Board 
An independent Data Safety and Monitoring Board is being recruited from within the 
Department of Obstetrics and Gynecology at Washington University in St. Louis.  This board will 
be made up of three faculty members without direct study interaction or responsibilities.  
Faculty will include maternal fetal medicine (MFM) specialists, and non MFM personnel. The 
board will be given direct reports from study staff on adverse events and data accrual.  The 
board will have direct access to deidentified data. The safety review board will meet annually or 
earlier as indicated by specific adverse events. 
5.c 
Definitions of Adverse Events 
Adverse events will be defined as outcomes outside of the typical clinical findings associated 
with preeclampsia with severe features.  This will include rare complications that are known to 
be risks intrinsic to preeclampsia, but that may be modified in their frequency by study group.  
This definition should capture both expected and unexpected adverse events.  This will include 

 
 
 
 
 
 
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maternal death, maternal seizure, persistantly uncontrolled hypertension greater than 4 days 
after delivery, acute kidney injury, and postpartum readmission.    
 
 
 
 
 
5.d 
Classification of Events 
 
i 
Relationship 
Associated events will be defined as those that are temporarily related to the study protocol 
without other explanatory etiologies.  Events will be considered Not Associated if the event is 
temporarily independent of the study protocol and appear to be explained by another etiology.  
 
ii 
Severity 
Adverse events (AEs) will be categorized into the following catagories. 
 
Mild: Transient (<48 hrs) or mild discomfort with no medical intervention or therapy required. 
Moderate: Mild to moderate limitation in activity outside of those typically seen in postpartum 
care.  Some assistance or minimal medical therapy required. 
Severe: Marked limitation in activity with medical intervention or therapy required. 
Life Threatening: Extreme limitation in activity with significant medical intervention required. 
iii 
Expectedness 
Defining adverse events as outcomes outside of the typical clinical findings associated with 
preeclampsia and rare complications that are known to be risks intrinsic to preeclampsia, will 
capture both expected and unexpected adverse events. 
5.e 
Data Collection Procedures for Adverse Events 
Study staff will perform ongoing adverse event collection.  Adverse events will be categorized as 
associated vs non associated and by their severity as defined in sections E5.5.d.i and E5.5.d.ii.  In 
addition to the real time collection and reporting of severe adverse events, patients will be 
evaluated for any adverse events at the time of hospital discharge and at the time of study visit 
2 as defined above. AE forms will be collected for any event. 
5.f 
Reporting Procedures 
All adverse events will be reported directly to the PI and separately to the Independent Review 
Board.  Non-serious AE’s will under go routine reporting via bianual reports to the Review Board.  
Any Serious AE will be reported to the PI and Review Board within 72 hours of awareness.  Life 
threatening AEs will be reported within 24 hours of awareness. Serious events will be defined by 
any AE that includes death, life threatening illness, hospital readmission, or any event that 
causes persistent or significant disability. 

 
 
 
 
 
 
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15
5.g 
Adverse Event Reporting Period 
Adverse events will be collected and reported throughout the study duration from 
randomization until 6 weeks postpartum. 
5.h 
Post-study Adverse Event 
Adverse events that take place outside of the study period, which extends through the entire 
postpartum period, and 6 weeks after medication administration,  will not be collected or 
reported.  
E6 Study Outcome Measurements and Ascertainment 
See Table 3 in section E2. 
F Statistical Plan  
 
F1  Sample Size Determination and Power 
A sample size estimate was performed for a non-inferiority trial with a binary outcome 
(antihypertensive needed at time of discharge, yes/no). Preliminary data from our retrospective 
cohort (see 2B) was used to estimate that 38% of preeclampsia patients require 
antihypertensives at time of discharge (62% ‘success’ rate). The non-inferiority limit of 0.2 was 
selected so that the study could detect any difference between the treatment groups of up to 
20% (Table 5). This was chosen given the clinical scenario in which NSAID medications have 
moderate data to support both their safety and efficacy. Calculations used an alpha of 0.025 and 
a power of 90%. In other words, if there is truly no difference between the NSAID-containing 
and NSAID-free analgesic bundle, then 286 total patients are required to be 90% sure that the 
upper limit of a 95% confidence interval will exclude a difference in favor of the standard group 
of more than 20%. The sample size estimate accounts for a 15% crossover rate. 
  
Table 5. Sample size estimation (Power 90%, α=0.025)
Non-inferiority limit
Detectable rate
w/NSAIDs 
Detectable rate w/o
NSAIDS 
Sample size
10%
56%
62%
1142
20%
50%
62%
286
30%
44%
62%
130
  
F2  Interim Monitoring and Early Stopping 
Given the short duration of this study, the only interim monitoring that will be performed is 
safety monitoring as described in section 5e.  There is no plan for interim analysis and thus no 
plan to terminate the study early. 
F3  Analysis Plan 
Comparisons will be made between the two treatment groups in an intention-to-treat analysis. 
Objective markers of hypertension and its sequelae will be recorded and coded by trained 

 
 
 
 
 
 
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16
research staff. Subjective reports of pain perception and analgesia satisfaction will be collected 
and compared. 
F4  Statistical Methods  
Data analysis will adhere closely to the Consolidated Standards of Reporting Trials guidelines. 
Analysis will follow the intention-to-treat principle in which subjects will be analyzed in the 
group to which they were randomized, regardless of whether or not they received the assigned 
intervention. This is important because analysis according to the intention-to- treat principle is 
accepted as the most unbiased assessment of the true therapeutic benefits of a treatment.  
 
We will first employ descriptive statistics to characterize the group of individuals recruited and 
to investigate comparability of the two groups at baseline. Formal statistical testing will be 
limited to selected baseline characteristics considered to be prognostic factors for the primary 
outcome such as mode of delivery, antepartum blood pressures, and presence or absence of 
chronic hypertension. The Chi-squared or Fisher’s exact tests will be used as appropriate to 
compare the primary outcome (proportion of subjects requiring antihypertensive medications at 
discharge) and other categorical secondary outcomes and prognostic factors between trial 
groups. Relative risks and confidence intervals associated with the primary and categorical 
secondary outcomes will be calculated and reported. Distribution of continuous prognostic 
factors and secondary outcome measures will be assessed by visual inspection of histograms 
and the Kolmogorov-smirnov test. Normally distributed variables will be compared by using the 
two-group independent t-test. If variables are not normally distributed, the Mann-Whitney U 
test will be used to make comparisons between the trial groups 
F5  Missing Outcome Data 
Missing outcome data will be coded as missing at the time of data collection.  Patient with 
missing data will remain in the study given our analytic plan of intention to treat. The statistical 
methods noted in section F4 will be used to account for missing data and minimize their effect 
on type I and type II error.  
F6  Unblinding Procedures  
This is an unblinded trial. 
 
G Data Handling and Record Keeping  
 
G1 Confidentiality and Security 
Participants will be recruited and consented in a private exam room on the Labor and Delivery 
floor of Barnes Jewish Hospital.  Study follow up will take place in Washington University School 
of Medicine or Barnes Jewish Hospital outpatient spaces, in a private room.   If a subject cannot 
return to the clinic for the 6 week follow up, the survey will be conducted via phone.  The 
research staff will call from a private office setting in a research area.  Study IDs will be provided 
to each subject to further protect their privacy.   
 

 
 
 
 
 
 
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17
For confidentiality, only members of the research team will have access to the study 
information.  Any information collected will be coded using the unique study ID.  The master list 
that links the study ID to the participant will be kept separately from the research documents 
and will only be available to research staff. 
G2 Training  
Research staff are CITI trained, and well versed in conducting clinical research and HIPAA 
compliance.   
G3 Case Report Forms and Source Documents 
All paper documents will be stored in a locked drawer in a locked office of the study PI.  Access 
will be limited to only members of the research team. 
 
The master list that links the patient ID to the name of the subject will be kept separate from 
the study documents.  Electronic data will be stored in a REDCap database, which is WU 
approved, HIPAA compliant, and requires a unique password to login.  All electronic work will be 
done on WU computers, which are encrypted, firewall-protected, and password protected.  
Only research team members will be able to access electronic data.  
G4 Records Retention 
Hard copies will be stored in a locked drawer in a locked office of the study PI.  We will store 
these records per the HRPO guidelines consistent with research.  Electronic data will be stored 
in a REDCap database, which is HIPAA compliant and accessible only by unique password login.  
H Study Administration 
 
H1 Organization and Participating Centers 
This is a single center trial, with all inpatient clinical care taking place at Barnes Jewish Hospital 
and all outpatient care taking place at Barnes Jewish Hospital and Washington University School 
of Medicine Center for outpatient Health. 
H2 Funding Source and Conflicts of Interest 
This trial will be funded by departmental research funds.  This does not preclude the possibility 
of grant funding in the future.  Any applications for grant funding will be updated immediately 
with the Insitutional Review Board. 
H3 Subject Stipends or Payments  
Patients will be compensated a total of $25 at the completion of their study participation.This 
compensation will come in the form of a gift card to local merchants.     
 
 
 
 
 

 
 
 
 
 
 
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18
 
 
 
 
 
 
 
H4  Study Timetable 
 
Project Period 
0-3 
months  
3-6 months 
 
6-9 
months  
9-12 
months 
12-15 
months  
15-18 
months 
18 -21 
months  
21-24 
months 
ACTIVITIES 
Protocol Development 
x
Trial registration 
x
Staff recruitment and 
training  
x
Study forms and database 
x
Subject recruitment 
x
x
x
x
x
x
x
Data collection & 
management  
x
x
x
x
x
x
x
Data analysis 
x
Drafting of manuscript & 
reports  
x
MILESTONES 
Protocol & IRB finalized 
x 
Recruitment start 
x
50% recruitment 
x
75% recruitment 
x
100% recruitment 
x
Data analysis complete 
x
 
I 
Publication Plan  
After completion of this trial and data analysis, we will publish our findings in a peer reviewed 
medical journal. 
 
 
J  Attachments  
 
J1  Informed consent documents 
 
J2  Questionnaires or surveys 
 
 
 
 
 

 
 
 
 
 
 
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19
 
 
 
 
 
K References 
 
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Gynecologists Women's Health Care Physicians; 2013  
2) Lo JO, Mission JF, Caughey AB. Hypertensive disease of pregnancy and maternal mortality. 
Curr Opin Obstet Gynecol. 2013;25(2):124-32.  
3) Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365: 785–799.  
4) Mogos MF, Salemi JL, Spooner KK, Mcfarlin BL, Salihu HH. Hypertensive disorders of 
pregnancy and postpartum readmission in the United States: national surveillance of the 
revolving door. J Hypertens. 2018;36(3):608-618.  
5) Viteri OA, England JA, Alrais MA, et al. Association of Nonsteroidal Antiinflammatory Drugs 
and Postpartum Hypertension in Women With Preeclampsia With Severe Features. Obstet 
Gynecol. 2017;130(4):830-835.  
6) Wasden SW, Ragsdale ES, Chasen ST, Skupski DW. Impact of non-steroidal anti-inflammatory 
drugs on hypertensive disorders of pregnancy. Pregnancy Hypertens. 2014;4(4):259-63.  
7) Vigil-de gracia P, Solis V, Ortega N. Ibuprofen versus acetaminophen as a post-partum 
analgesic for women with severe pre-eclampsia: randomized clinical study. J Matern Fetal 
Neonatal Med. 2017;30(11):1279-1282.  
8) 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  
9) Johnson AG, Nguyen TV, Day RO. Do non-steroidal anti-inflammatory drugs affect blood 
pressure? A meta-analysis. Ann Intern Med. 1994;121:289 –300.  
10) Snowden S and Nelson R. The Effects of Nonsteroidal Anti-Inflammatory Drugs on Blood 
Pressure in Hypertensive Patients. Cardiology in Review. 2011. 19:184-191  
11) Makris A, Thornton C, Hennessy A. Postpartum hypertension and nonsteroidal analgesia. Am 
J Obstet Gynecol. 2004;190(2):577-8.  
12) Knights KM, Mangoni AA, Miners JO. Non-selective nonsteroidal anti-inflammatory drugs 
and cardiovascular events: is aldosterone the silent partner in crime?. Br J Clin Pharmacol. 
2006;61(6):738-40.  
13) Scaife PJ, Mohaupt MG. Salt, aldosterone and extrarenal Na- sensitive responses in 
pregnancy. Placenta. 2017;56:53-58.  
14) Hörl WH. Nonsteroidal Anti-Inflammatory Drugs and the Kidney. Pharmaceuticals (Basel). 
2010;3(7):2291-2321.  
15) Rahman M, Wright JT Jr, Douglas JG. The role of the cytochrome P450- dependent 
metabolites of arachidonic acid in blood pressure regulation and renal function: a review. Am J 
Hypertens. 1997;10:356–365.  
16) White PF. The changing role of non-opioid analgesic techniques in the management of 
postoperative pain. Anesth Analg. 2005;101(5 Suppl):S5-22.  
17) Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther. 2005;12(1):46-55. 
 

 
 
 
 
 
 
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