Clinical trial NCT02911701
Conditions: Pre-Eclampsia HELLP Syndrome Eclampsia
Sponsor: University of New Mexico
Start date: 2016-09-01; Completion date: 2018-01-10
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
NSAIDs, specifically cyclo-oxygenase (COX) inhibitors, are known to increase blood pressure over time in non-pregnant adults, but the effect of COX-inhibitors on blood pressure in the setting of preeclampsia have not been well studied. This study aims to assess the effect of avoiding COX-inhibitors on postpartum blood pressure control among women diagnosed with preeclampsia with severe features. Eligible women will be randomized to receive either acetaminophen or ibuprofen for postpartum pain control. Both agents are first line therapies for pain control although ibuprofen has better pain control than acetaminophen. The primary outcome will be duration of postpartum severe-range hypertension.

Detailed description:
The proposed study is a randomized, controlled, double-masked trial comparing the effect of postpartum acetaminophen and ibuprofen on blood pressure among women with preeclampsia. Study participants will be randomized to receive either acetaminophen or ibuprofen for mild postpartum pain control. Study participants, study personnel and providers will be blinded to randomization status of study participants.

Potential study participants will be enrolled when they are diagnosed with a severe hypertensive disorder of pregnancy. This will usually occur prior to delivery, but may occur up to 6 hours after delivery. Patients diagnosed with preeclampsia without severe features will also be approached and enrolled at the time of diagnosis in anticipation for possible progression to preeclampsia with severe features. Once enrolled, study participants will not be randomized until delivery, at which time they will be randomized to receive either acetaminophen or ibuprofen for mild postpartum pain. Both groups will have available oxycodone for moderate to severe pain, per our routine. Study group allocation will only be known by the investigational pharmacy. The ibuprofen and acetaminophen will be made to appear identical to each other and will be unmarked through encapsulation. Block randomization will be used to ensure equal allocation to the two study arms.

For the duration of study participation, study participants will undergo postpartum monitoring with vital sign measurements (including blood pressure) every 4 hours, pain assessment with each administration of study medication, as well as daily evaluation of laboratory studies until they have normalized to the satisfaction of their provider. Study participants will receive the study drug every 6 hours from the time of delivery until hospital discharge, unless they refuse. Study participation will be complete upon hospital discharge. Study participants will be contacted by a study team member 6 weeks after delivery to ask about any additional complications or symptoms requiring visits to the emergency department or hospital readmission. Descriptive factors and clinical outcomes will be extracted from the medical record and de-identified by study personnel during each day of study participation.

Arms: arm 1: Study participants randomized to the acetaminophen group will receive 650mg of acetaminophen orally every 6 hours during their postpartum hospital stay. arm 2: Study participants randomized to the ibuprofen group will receive 600mg of ibuprofen orally every 6 hours during their postpartum hospital stay.
Interventions: intervention 1: Acetaminophen intervention 2: Ibuprofen
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
PROTOCOL TITLE: Acetaminophen and Postpartum Blood Pressure in Preeclampsia 
 
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PROTOCOL TITLE: 
Effect of Acetaminophen on Postpartum Blood Pressure Control in Preeclampsia 
with Severe Features 
 
 
PRINCIPAL INVESTIGATOR: 
Luis Izquierdo, MD 
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine 
VERSION NUMBER: 
Version 5 
DATE: 
March 17, 2017. 
REGULATORY FRAMEWORK: 
Please indicate all that apply: 
 
DOD (Department of Defense) 
 
DOE (Department of Energy) 
 
DOJ (Department of Justice) 
 
ED (Department of Education) 
 
EPA (Environmental Protection Agency) 
 
FDA (Food and Drug Administration) 
 
HHS (Department of Health and Human Services) 
 
Other:       
 
Is this a clinical trial under ICH-GCP E6?   
 Yes   
 No 
If yes, please confirm that the research team is familiar with and agrees to comply 
with the investigator requirements cited in ICH-GCP E6.  
 Yes   
 No  
ICH-GCP E6 can be accessed by copying and pasting this URL into your 
browser: http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf 
 
 
 


PROTOCOL TITLE: Acetaminophen and Postpartum Blood Pressure in Preeclampsia 
 
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Table of Contents 
1. 
Objectives ................................................................................................................ 4 
2. 
Background .............................................................................................................. 4 
3. 
Study Design ............................................................................................................ 5 
4. 
Inclusion and Exclusion Criteria ............................................................................... 5 
5. 
Number of Subjects .................................................................................................. 5 
6. 
Study Timelines ....................................................................................................... 6 
7. 
Study Endpoints ....................................................................................................... 6 
8. 
Research Setting ....................................................................................................... 6 
9. 
Resources Available ................................................................................................. 6 
10. 
Prior Approvals .................................................................................................... 8 
11. 
Multi-Site Research .............................................................................................. 8 
12. 
Study Procedures .................................................................................................. 8 
13. 
Data Analysis ....................................................................................................... 9 
14. 
Provisions to Monitor the Data to Ensure the Safety of Subjects ......................... 10 
15. 
Withdrawal of Subjects ....................................................................................... 10 
16. 
Data Management/Confidentiality ...................................................................... 11 
17. 
Data and Specimen Banking ............................................................................... 12 
18. 
Risks to Subjects ................................................................................................. 12 
19. 
Potential Benefits to Subjects .............................................................................. 13 
20. 
Recruitment Methods .......................................................................................... 13 
21. 
Provisions to Protect the Privacy Interests of Subjects......................................... 13 
22. 
Economic Burden to Subjects ............................................................................. 12 
23. 
Compensation ..................................................................................................... 12 
24. 
Compensation for Research-Related Injury ......................................................... 12 
25. 
Consent Process .................................................................................................. 14 
26. 
Documentation of Consent .................................................................................. 15 
27. 
Study Test Results/Incidental Findings ............................................................... 15 
28. 
Sharing Study Progress or Results with Subjects ................................................. 16 
29. 
Inclusion of Vulnerable Populations ................................................................... 16 
30. 
Community-Based Participatory Research .......................................................... 16 
31. 
Research Involving American Indian/Native Populations .................................... 16 
32. 
Transnational Research ....................................................................................... 16 
33. 
Drugs or Devices ................................................................................................ 16 
Checklist Section ........................................................................................................... 17 
References………………………………………………………………………………..30 
Appendix…………………………………………………………………………………32 
 
 


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1. Objectives 
1.1. To compare the duration of post-partum severe range hypertension, the proportion of study 
participants requiring postpartum antihypertensive use, and the length of hospital stay among 
women diagnosed with severe preeclampsia who are randomized to acetaminophen for 
postpartum pain, as compared to women randomized to ibuprofen.  
1.1.1. Compared with those randomized to receive ibuprofen, we hypothesize that women 
randomized to receive acetaminophen for post-partum pain will: 
- 
have a shorter duration of severe range hypertension postpartum 
- 
be less likely to require antihypertensive use 
- 
have similar length of postpartum hospitalization 
1.2. To compare postpartum pain control among women diagnosed with severe preeclampsia who are 
randomized to the ibuprofen arm as compared to women randomized to the acetaminophen arm. 
1.2.1. We hypothesize that women randomized to the ibuprofen arm will have lower mean pain 
scores than those randomized to the acetaminophen arm. 
 
2. Background 
2.1. Hypertensive disorders are significant contributors to maternal morbidity and mortality , and 
many women diagnosed with a hypertensive disorder of pregnancy, or preeclampsia, require 
prolonged postpartum observation or intervention for persistent hypertension.1,2 In addition, 
women with hypertensive disorders of pregnancy are at increased risk for cesarean delivery with 
its attendant need for postoperative pain relief.  Chronic use of non-steroidal anti-inflammatory 
drugs (NSAIDs), particularly cyclo-oxygenase (COX) inhibitors, is known to increase the risk of 
development of hypertension in healthy, non-pregnant women as well as antagonize the effects of 
some antihypertensive drugs in hypertensive patients receiving treatment.3–10 Various 
mechanisms of action have been proposed, including the inhibition of prostaglandin E2-mediated 
sodium excretion, inhibition of prostacyclin-mediated vasodilation, and altered aldosterone 
metabolism.11,12 The American College of Obstetrics and Gynecology (ACOG) suggests avoiding 
the postpartum use of NSAIDs in women diagnosed with preeclampsia, though this 
recommendation is not formally included in its most recent guidelines, likely due to the paucity 
of published data on preeclampsia and NSAID use2. Animal studies are limited to a single 
investigation in a rat model of preeclampsia and showed that indomethacin had no effect on blood 
pressure while rats were still pregnant.13 In humans, the extremely limited data on the influence 
of COX inhibitors on postpartum blood pressure among women with preeclampsia is 
conflicting.14–16 In fact, no prospective studies have been published which examine the effect of 
COX inhibitors on postpartum blood pressure control in patients with preeclampsia. 
 
COX inhibitors are ideally suited for postpartum pain control; before issuance of the most recent 
guidelines, they were widely used for postpartum and post-cesarean section pain management 
particularly in bridging from opiate to non-opiate pain relievers.17,18 They are more effective than 
acetaminophen to alleviate pain from postpartum perineal injury, and have also been shown to 
decrease opioid use after Cesarean delivery.15,17–21 Given New Mexico’s high rate of opioid 
addiction and opioid-related deaths, any therapeutic option which may decrease the requirement 
for opioid use is of high value. Additionally, the analgesic alternatives to COX inhibitors have 
significant risks. The use of opioids while breastfeeding is associated with neonatal central 
nervous system (CNS) depression, and acetaminophen use is contraindicated in the setting of 
severe, acute elevation of liver enzymes, a common occurrence among patients with 
preeclampsia22. Whether the theoretical effect of short-term COX inhibitor use on postpartum 
blood pressure is clinically significant remains unclear. Systolic blood pressure has been shown 
to increase by  up to 10mm Hg among both healthy and hypertensive COX inhibitor users, with 
changes in blood pressure appearing with just a few doses per month.23–25 Another study in men 


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found that systemic vascular resistance increased by up to 20% immediately following 
intravenous administration of indomethacin. 12 However, COX inhibitors do not seem to have any 
effect on blood pressure when a patient is already being treated with a calcium channel blocker, 
which is the drug class of choice for postpartum hypertension at UNM.7,8,26   
 
At UNM and many other institutions, COX inhibitors are routinely used for postpartum pain in 
women diagnosed with preeclampsia. It is unclear whether or not to continue their routine use in 
this population as no prospective data exists to guide our practice. The only human study of COX 
inhibitor use in preeclampsia was a retrospective review and found that postpartum COX 
inhibitor use was not associated with any difference in outcomes.16 Overall, the literature is 
mixed on whether short term COX inhibitor use would be expected to affect blood pressure in the 
setting of preeclampsia. Thus, our study is necessary to determine whether avoiding postpartum 
COX inhibitor use is associated with improved outcomes for women diagnosed with 
preeclampsia. 
 
3. Study Design 
3.1. The proposed study is a randomized, controlled double masked trial comparing the effects of 
acetaminophen versus ibuprofen for mild postpartum pain among women with preeclampsia. 
3.2. Study participants, study personnel and providers will be blinded to randomization status of study 
participants. Blinding will occur through the double masked design. The ibuprofen and 
acetaminophen will be made to appear identical to each other and will be unmarked through 
compounding and encapsulation. After delivery, study participants will be randomized by the 
investigational pharmacy to receive either acetaminophen or ibuprofen, and allocation will only 
be known by the investigational pharmacy. Block randomization will be used to ensure equal 
allocation to the two study arms. 
4. Inclusion and Exclusion Criteria 
4.1. All patients admitted to the labor and delivery unit with a diagnosis of a severe hypertensive 
disorder (preeclampsia with severe features, chronic hypertension with superimposed 
preeclampsia with severe features, hemolysis, elevated liver function tests and low platelets 
(HELLP) syndrome, or eclampsia) will be assessed for eligibility.  
4.2. Inclusion criteria include age at least 18, ability to give informed consent, pregnant or recently 
pregnant (< 6 hours postpartum) with a diagnosis of severe hypertensive disorder of pregnancy 
(as defined in 4.1). We will also approach women diagnosed with preeclampsia without severe 
features who are being expectantly managed, anticipating that they may eventually develop 
severe features and be eligible for the study. 
4.3. Exclusion criteria include current incarceration, serum creatinine > 1.0mg/dL or suspicion of 
acute kidney injury, aspartate aminotransferase (AST) > 200 unit/L , alanine aminotransferase 
(ALT) > 200 unit/L, known allergy or sensitivity to NSAIDs or acetaminophen, delivery > 6 
hours prior to enrollment, chronic kidney disease, chronic liver disease, prior liver transplant, 
chronic infectious hepatitis, gastritis, gastro-esophageal reflux disease (GERD), peptic ulcer 
disease, or bleeding disorder. Additionally, a patient may be excluded from participation if their 
provider feels that participation is not in the best interest of the patient. 
4.4. This study will enroll women at the time of their diagnosis of preeclampsia, at which time they 
will most likely still be pregnant. Randomization and study intervention will not occur until they 
are postpartum. Our study will not include minors, prisoners, or adults who are unable to give 
informed consent. 
4.5. The population of interest for this study is post-partum women with preeclampsia, which 
excludes men, as they do not become pregnant and do not suffer from preeclampsia. 
5. Number of Subjects 


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5.1. Total number of subjects to be accrued is 100.  
5.2. Given that we plan to consent patients diagnosed with preeclampsia without severe features in 
anticipation of a possible future diagnosis of preeclampsia with severe features, we plan to 
consent a total of 150 potential subjects. 
5.3. Sample size justification: Based on preliminary data obtained from n=31 patients (as part of 
HRRC Study ID 16-073), the duration of severe-range hypertension was found to follow an 
exponential distribution with mean lifetime = 35 hours (var = 1217 hr2). We performed a sample 
size estimate based on this data to detect a 24-hour difference between patients receiving 
acetaminophen and those receiving ibuprofen. Therefore, we hypothesize that the acetaminophen 
group will have a duration of severe-range hypertension = 35 hours and ibuprofen will have 
duration = 59 hours. Based on the preliminary data and our hypothesis, using a one-sided F-test, 
we require a sample size of n=50 patients per group to detect a mean lifetime difference of 24 
hours between groups with 83% power at a significance level α = 0.05. 
 
6. Study Timelines 
6.1. Describe: 
 
The duration of an individual subject’s participation in the research will be from the time she 
is consented (while admitted to the labor and delivery or OB Special Care units) until her 
discharge from the hospital after her delivery. This may be only a few days if she is enrolled 
just prior to or following delivery, but may last as long as several weeks if she is enrolled 
during a long course of inpatient expectant management prior to delivery. 
 
We anticipate to enroll all study participants over the course of approximately 24 months. 
 
We expect the study to conclude and analysis to be complete within 6 months of completing 
enrollment. 
7. Study Endpoints 
7.1. The primary endpoint will be duration of severe range hypertension (systolic blood pressure ≥ 
160mm Hg, diastolic blood pressure ≥ 110mm Hg) after delivery, measured in hours. Secondary 
outcomes will include: 
- Length of hospitalization 
- Mean arterial pressure over the entire postpartum hospitalization 
- Mean arterial pressure, stratified by postpartum day 1, 2, 3, etc. 
- Mean number of severe range blood pressures 
- Proportion with severe-range hypertension in each group 
- Maximum blood pressure for entire postpartum hospitalization (in mm Hg) 
- The proportion of study participants requiring the use of any scheduled oral 
antihypertensives at discharge 
- Number of scheduled oral antihypertensive agents required at discharge 
- Number of doses of antihypertensives (either oral or intravenous) given for acute 
lowering of blood pressure 
- The proportion of study participants requiring the use of intravenous antihypertensives 
- Mean daily pain level, as reported by patient on scale from 1-10, stratified by postpartum 
days 1, 2, 3. 
- Use of opioid analgesics, measured in morphine milligram equivalents per day, stratified 
by postpartum days 1, 2, 3.  
- Serum creatinine trend from day of delivery to day of discharge 
- Mean drop in hematocrit from pre-delivery to the nadir prior to discharge 
7.2. Primary safety endpoint is a composite of adverse events, and includes: seizure, stroke, posterior 
reversible encephalopathy syndrome (PRES), and repeat course of intravenous magnesium sulfate 
for seizure prophylaxis. Secondary safety endpoints include: new onset elevation of liver function 


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tests (AST, ALT) above twice the normal limit, acute kidney injury (new onset doubling of serum 
creatinine or serum creatinine > 1.1mg/dL), and delayed postpartum hemorrhage of greater than 
1000mL. 
7.3. There are no exploratory endpoints. 
8. Research Setting 
8.1. Research will take place at University of New Mexico Health Sciences Center.  
8.2. Potential study participants will be identified and approached for participation while admitted to 
either the labor and delivery unit or the OB Special Care (antepartum) unit.  
8.3. Locations of research “procedures” are as follows: 
– screening, recruitment, consenting: Labor and Delivery, OB Special Care (antepartum) 
unit, outpatient Women’s Health Clinic and Women’s Imaging ultrasound suite (for 
women already diagnosed with preeclampsia without severe features and being managed 
as an outpatient) 
– randomization: investigational pharmacy 
- administration of study drug: OB Special Care or Mother-Baby units 
- study monitoring (vital signs, laboratory): OB Special Care or Mother-Baby units 
– data collection: on the UNM campus with an UNM-owned, encrypted computer 
– data analysis: UNM HSC CTSC 
8.4. A community advisory board will not be necessary for this study. 
8.5. No research is planned outside of UNM HSC. 
9. Resources Available 
9.1. The PI, Dr. Luis Izquierdo, has completed residency training in obstetrics and gynecology as well 
as a fellowship in Maternal-Fetal Medicine. He is board-certified in both general OB/GYN and 
Maternal-Fetal Medicine. He has many years’ clinical experience, and as an Associate Professor 
of clinical education, he has the resources necessary to oversee and complete the project. Dr. 
Ellen Mozurkewich, who oversaw the majority of the study design and continues as a co-
investigator, has many years’ experience directing clinical research, including acting as PI for a 
multi-center randomized controlled trial of oral misoprostol versus oxytocin for induction of 
labor among women with pre-labor rupture of members at term as well as a randomized 
controlled trial that compared EPA- and DHA-rich fish oil with soy oil placebo for prevention of 
perinatal depression among women at risk. 
9.2. We will be collaborating with the UNM CTSC for statistical support for the study. Our CTSC 
statistician is Cristina Murray-Crezan. 
9.3. The following licensed providers will be primarily responsible for oversight of the medical 
services to which patients will be admitted: 
- 
Ellen Mozurkewich, MD, MS 
- 
Luis Izquierdo, MD, MBA 
- 
Conrad Chou, MD 
- 
Larry Leeman, MD, MPH 
- 
Sarah Gopman, MD 
- 
Nicole Yonke, MD, MPH 
- 
Mary Beth Sutter, MD 
9.4. Describe other resources available to conduct the research:  
 
Our labor and delivery unit sees an estimate of 3-6 patients with severe preeclampsia per 
week. In order to recruit the necessary number of study participants, we would need to enroll 
approximately 1 subject per week over the course of 24 months. 


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 
One of the co-investigators, Nathan Blue, is a fellow in Maternal-Fetal Medicine at UNM and 
has one full year of dedicated research time over the course of his fellowship (2015-2018), 
during which the majority of the research work will be completed.  
 
No special facilities will be required to conduct the research. 
 
Given that participation in the study involves taking one of two commonly used medicines for 
mild postpartum pain, either of which may be prescribed to patients not participating in the 
study, we do not anticipate the need for additional medical or psychological resources as a 
result of participating in the study. 
 
Prior to involvement in the study, all persons assisting with the research will be oriented by a 
co-investigator, at which point they will review the protocol, consent process, and their 
specific duties in detail. 
10. Prior Approvals 
10.1. Describe any approvals that will be obtained prior to commencing the research. (e.g., school, 
external site. funding agency, laboratory, radiation safety, or biosafety approval.)  
- 
We have applied for internal funding by the UNM department of Obstetrics and 
Gynecology. This funding proposal was submitted on April 1, 2016. 
- 
We obtained our preliminary data with approval by the HRRC, as described in the 
protocol submitted under study number 16-073. 
10.2. The signed “Departmental Review Form” in included in Click under “supporting documents.” 
10.3. If a study includes ionizing radiation, the Radiation Safety Attachment (HUS-FORM_1) must 
be uploaded (attached) in Click with your submission.  The consent should include radiation 
exposure information in the Risks section.  
- 
N/A – this study does not include any ionizing radiation. 
10.4. The signed “Drug Attachment” is included in Click with the submission. 
11. Multi-Site Research 
11.1. If this is a multi-site study where the UNM HSC PI is the lead investigator, or UNM HSC is the 
coordinating site, describe the processes to ensure communication among sites, such as:  
- N/A – UNM is the only site where the study will take place. 
11.2. Describe the method for communicating to engaged participating sites: N/A – see 11.1 
11.3. If the UNM HSC investigator is serving as the “sponsor-investigator” of a FDA-regulated trial, 
describe how sponsor responsibilities will be fulfilled, including, but not limited to: N/A – this 
study is not an FDA-regulated trial 
12. Study Procedures  
12.1. Study participants randomized to the ibuprofen arm will receive oral ibuprofen 600 milligrams 
(mg) every 6 hours starting immediately postpartum and continuing until hospital discharge. 
Participants randomized to the acetaminophen arm will receive oral acetaminophen 650mg 
every 6 hours starting immediately postpartum and continuing until hospital discharge. The 
purpose of the scheduled dosing of either ibuprofen or acetaminophen is to treat mild pain (level 
1-3 on Wong-Baker scale). Around-the-clock, scheduled dosing of either ibuprofen or 
acetaminophen for mild pain is the current practice at UNM. Pain will be assessed and recorded 
in Cerner PowerChart as per the standard protocol for the OB Special care and Mother-Baby 
units by inpatient nursing staff using the Wong-Baker scale. If study participants report a pain 
level of 1-3, no additional medication will be given. If they report a pain level of 4-6, 
oxycodone 5mg will be given as often as every 4 hours, as needed. For a pain level of 7-10, 
oxycodone 10mg will be given as often as every 4 hours, as needed. 


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 
The two agents being compared, ibuprofen and acetaminophen, are both marketed on-label 
for the treatment of pain. 
 
Monitoring: During the first 24 hours postpartum, study participants will receive intravenous 
magnesium sulfate for seizure prophylaxis, which is standard management for preeclampsia 
with severe features. Again, as routine practice for treatment of preeclampsia at our 
institution, vital signs are measured hourly. Once off of magnesium sulfate, vital signs will be 
monitored every 4 hours until discharged from the hospital. Serum studies are routinely sent 
daily as part of normal clinical practice to assess for sequelae of preeclampsia until any 
abnormalities resolve and blood pressures are at goal (< 160 mmHg systolic and 110 mmHg 
diastolic), though they may be checked more often if deemed necessary by her providers. 
They include complete blood count, lactate dehydrogenase, uric acid, prothrombin time, 
partial thromboplastin time, serum creatinine (Cr), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), and total bilirubin. As is our current practice, patients remain 
hospitalized for at least 72 hours postpartum and until they are free of “severe range” blood 
pressure (systolic ≥ 160mm Hg, diastolic ≥ 110mmg Hg) for at least 24 hours.  All of these 
monitoring practices are part of standard of care for women with severe range blood pressures 
and preeclampsia. 
 
Use of antihypertensives: if a study participant had been started or maintained on oral 
labetalol or nifedipine prior to delivery, it will be continued postpartum at the same dose, as is 
our current practice. If not on any oral antihypertensives, study participants will be started on 
either labetalol or extended-release nifedipine, according to their provider’s discretion, if they 
have more than one blood pressure of 150 mmHg systolic or 100 mmHg diastolic, 4-6 hours 
apart, as recommended by recent ACOG guidelines (ACOG 2013).2 Antihypertensives will be 
titrated according to the provider’s discretion to achieve a goal blood pressure of less than 
160mmHg systolic and 110mmHg diastolic. We chose to use these drugs for postpartum 
hypertension as they are first line for hypertension during pregnancy, and thus are the most 
likely agents which enrolled participants will already be on, and they are the first line 
treatment for postpartum hypertension at our institution due to their relative safety while 
breastfeeding.   
 
Demographic data will be collected from study participants at the time of enrollment. 
Outcomes data to be analyzed will be collected from the patient’s electronic medical record in 
PowerChart. 
 
All procedures which are part of the study (including the use of either acetaminophen or 
ibuprofen for mild postpartum pain and serial laboratory studies) would be done if the patients 
were not enrolled in the study, because they are the current standard of care at UNM. 
 
The following will be hospital discharge criteria for study participants: 
1.1..1. No blood pressures > 160/110 mm Hg within the last 24 hours prior to discharge 
1.1..2. At least 72 hours of inpatient observation after delivery 
1.1..3. Serum creatinine that is at the patient’s baseline, or trending toward normal 
1.1..4. Serum AST < 250 and ALT < 250 and trending toward normal 
1.1..5. All other postpartum or postoperative discharge criteria (tolerating regular diet, 
ambulating, voiding, etc.) met per the discretion of the provider 
13. Data Analysis 
13.1. Summary statistics will be calculated to describe the patient characteristics. Means and standard 
deviations or medians and quartiles will be reported for continuous data, as appropriate 
(exponential means for times to events or durations of events); frequencies and percentages will 
be reported for categorical data. For all analyses, the intention-to-treat population will be used. 
For the primary analysis, the exponential mean lifetimes (means) and variance will be calculated 
for each group and will be compared via the F test for the ratio of the lifetimes. We will report 
95% confidence intervals for the times and the p-value for the test will be compared to a type I 
error rate of 0.05. All of the secondary outcome measures will be summarized with descriptive 
statistics as reported above and 95% confidence intervals will be calculated for each endpoint by 
group. Graphical tools may be used for visual comparison of the group effect. Exploratory 


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analysis may include linear modeling of the exponential mean duration of severe-range 
hypertension to adjust for potential covariates such as chronic hypertension, chronic pain, 
chronic opioid use, and mode of delivery. 
14. Provisions to Monitor the Data to Ensure the Safety of Subjects 
14.1. A Data Safety Monitoring Board (DSMB) will perform safety monitoring. It will be comprised 
of physicians with a background in obstetrics and gynecology but who will not be enrolling 
patients or supervising the care of potential study participants. The members of the board are 
affiliated with UNM and the department of Obstetrics and Gynecology, and include: 
- 
Valerie Rappapport, MD 
- 
Yuko Komesu, MD 
- 
Sharon Phelan, MD 
Due to the relatively small number of subjects, there will not be interim analysis. The DSMB 
will convene in the event of one of the following sentinel events occurs to determine whether 
the event was attributable to the patient’s randomized intervention: 
- 
stroke 
- 
seizure / eclampsia 
- 
posterior reversible encephalopathy syndrome 
- 
death 
14.2. If a sentinel event occurs, it will be reported to the DSMB within 24 hours, and the DSMB will 
convene within another 48 hours to review the case in detail and determine whether the event is 
attributable to the patient’s study participation. The DSMB will then render advice regarding 
trial continuation on a case-by-case basis. 
14.3. Material Safety Data Sheets (MSDS) will be available for both ibuprofen and acetaminophen, in 
addition to the most recently published guidelines for management of hypertensive disorders of 
pregnancy for review by the DSMB. 
14.4. If the DSMB determines that the sentinel event is attributable to study participation and that 
further enrollment poses undo risk to potential participants, the DSMB will have the power to 
halt the study.  
14.5. When the DSMB convenes following a sentinel event, the conclusion of the board and its 
recommendation to continue or discontinue the study will be distributed to the investigators, the 
sponsor and HRRC in writing within 48 hours of the DSMB convening. 
15. Withdrawal of Subjects 
15.1. Study participants will be withdrawn from treatment allocation and patient and provider 
masking (but not data collection) who experience the following after enrollment: new onset 
seizure activity; stroke; focal neurologic findings necessitating neuroimaging; patient request; 
serum Cr > 1.1 mg/dL; new onset elevation in AST > 250 mg/dL or ALT >250 mg/dL. 
15.1.1. Outlined here is our systematic tracking plan to ensure timely recognition of withdrawal 
criteria and withdrawal from the study. When a patient is recruited for study participation, 
the on-call team will be notified of her study participation status, and the following 
information will be added to the electronic sign-out and census: the patient’s study 
participation status, the withdrawal criteria, and the designated Research Phone number. 
15.1.2. At the time of delivery, the on-call team refers to the Postpartum Orders Checklist when 
writing postpartum orders. The orders will include daily lab studies, including serum 
creatinine and LFTs, to be drawn the following morning at the latest, and earlier if clinically 
indicated. The Postpartum Orders Checklist will also include information to be placed in the 
electronic sign-out and census, as described in 15.1.1. 


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15.1.3. The next morning (postpartum day #1), Dr. Blue (or Dr. Katukuri or Dr. Holbrook, in Dr. 
Blue’s absence) will review the labs with the on-call attending, and will complete a 
checklist documenting the review of lab studies, as outlined above in section 3.2.5 (see 
appendix 1 for daily lab review checklist). On weekends and holidays, this will be done by 
the MFM fellow assigned to rounds (either Dr. Blue, Katukuri, or Holbrook), and reviewed 
with the attending. The on-call attending will decide whether further lab studies are 
indicated the following day. This review and documentation will be completed daily for the 
duration of study participation (until discharge).  
15.1.4. If, at the time of daily lab review, the patient meets criteria for withdrawal, the Daily Lab 
Review Checklist will direct the reviewing fellow and attending to the Study Withdrawal 
Checklist, which outlines and documents the steps needed to withdraw the study subject.  
15.2. As there is no risk related to immediate withdrawal from the study, a patient may be 
immediately withdrawn without special procedures given that all procedures which are part of 
the study would continue (with exception of masking to medication use) because these are the 
routine medications given for postpartum pain at UNM.  
15.3. If a study participant requests withdrawal due to reluctance to continue with the randomization 
allocation or masking procedure but still allows for her data to be collected and analyzed, she 
will then no longer receive the blinding procedure, but will continue to receive ibuprofen or 
acetaminophen for mild postpartum pain, at her provider’s discretion and if the patient is 
amenable.  
16. Data Management/Confidentiality 
16.1. IRB-approved co-investigators will review the study participant’s electronic medical records on 
a daily basis during study participation, and will complete data collection as soon as 
participation in the study is complete in order to collect outcomes data. Demographics data will 
be collected at enrollment or prior to completion of study participation. When accessing 
patients’ charts, research team members will open the chart under the “researcher” designation 
when accessing the chart for this purpose. 
16.2. The data collection does require the maintenance of patient identifiers (name, date of birth, 
medical record number) in order to access the electronic chart to collect the data. 
16.3. The data collection does require the accessing and storage of Protected Health Information, 
including medical comorbidities, elements of medical history, as well as empiric data such as 
vital signs and laboratory study results. 
16.4.  The data collection will included substance abuse information, and thus may be considered 
sensitive.  
16.5. 
A Certificate of Confidentiality will not be used to protect data from forced release (e.g., 
subpoena) and will be applied for once IRB approval is in place.   
16.6. Patient identifiers and collected data will eventually be separated. At the time of enrollment, the 
data collection sheet with patient identifiers will be stored in a locked cabinet until the data are 
collected. No patient identifiers will be on the data collection sheets, and the data will be labeled 
with a case number. In case of need for further review, a file will be maintained linking patient 
identifiers to the case number. This file will be held in a password-protected, encrypted, and 
UNM HSC owned computer under the personal control of one of the coinvestigators. The 
patient identifier file will not be kept on the same computer which will maintain the collected 
data. Only the PI and the coinvestigator to whom the coding file is assigned will be allowed to 
access it. 
16.7. Data collected will be stored in both paper and electronic formats in order to provide backup 
should the electronic form be corrupted or destroyed.  
16.8. If data will be transferred or transmitted to outside locations or entities, describe: N/A – all data 
collection and analysis will take place at UNM. 


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16.9. The de-identified/coded data will be transmitted via email only after being encrypted, but not 
stored on the internet. The coding file, which will be maintained on a separate computer, will 
not be transmitted via email or the internet. It will remain on the computer to which it is 
assigned. 
16.10. 
Data will not be collected by audio or video recording.  
16.11. 
Data will not include photographs.  
17. Data and Specimen Banking 
17.1. De-identified study data will be stored for 5 years after study completion, and then destroyed. ] 
17.2. No data or specimens will be banked or archived elsewhere.  
18. Risks to Subjects 
18.1. COX inhibitors are known to contribute to acute kidney injury. Even though suspicion for acute 
kidney injury is one of the exclusion criteria, a patient may have sub-clinical or evolving acute 
kidney injury at the time of enrollment, which may become apparent only after randomization. 
The same possibility exists for randomization to the acetaminophen arm and the possibility of 
evolving subclinical liver injury not identified until after randomization. Should acute kidney or 
liver injury occur, it will be identified on the serial laboratory studies which are part of the study 
procedure, the providers will be unmasked to the patient’s allocation (per criteria for 
withdrawal, as described above), and therefor able to withdraw the study medication if needed. 
Acute kidney injury and acute liver injury are both virtually always temporary in association 
with preeclampsia, and can both occur in the absence of the use of COX inhibitors. The risk of 
one of these occurrences is unlikely to be increased by participation in the study because our 
standard practice is currently to use either ibuprofen or acetaminophen (or sometimes both) for 
mild postpartum pain in the setting of preeclampsia. Risks could include worse control of 
hypertension if assigned to the COX inhibitor arm, but this is theoretical in this population and 
this question is the purpose of the experiment. COX inhibitor use is also known to exacerbate or 
contribute to GERD.  
There is also a risk of accidental breach of confidentiality by inappropriate transmission of 
identifying information or protected health information 
18.2. There is a possibility unforeseen risks/adverse events to patients as a result of participation in 
this study. 
18.3. The only part of the process which will take place during pregnancy is the consent and 
collection of demographics information. Once she has delivered, she will be randomized and the 
remaining study procedures will begin. 
18.4. There are no risks to others who are not subjects 
18.5. Describe the steps being taken to minimize the probability or magnitude of risks. 
- 
Risk of acute kidney injury in those randomized to ibuprofen: only subjects with 
normal renal function will be enrolled. Daily serum BUN and creatinine will be 
collected (in addition to other preeclampsia labs) and study participants will be 
withdrawn and providers un-masked to their randomization status if evidence of acute 
kidney injury develops. 
- 
Risk of GERD in those randomized to ibuprofen: only subjects without gastritis will be 
enrolled.  
- 
Risk of acute liver injury in those randomized to acetaminophen: only subjects with 
normal liver function will be enrolled. Daily serum AST and ALT will be collected (in 
addition to other preeclampsia labs) and study participants will be withdrawn and 
providers un-blinded to their randomization status if evidence of acute liver injury 
develops. 


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19. Potential Benefits to Subjects 
19.1. Describe the potential benefits that individual subjects may experience from taking part in the 
research. Include as may be useful for the IRB’s consideration, the probability, magnitude, and 
duration of the potential benefits. 
- 
If randomized to the ibuprofen arm, study participants may have better pain control. If 
randomized to the acetaminophen arm, study participants may have better blood 
pressure control. Again, this is the principle question of the study. Otherwise, there is 
no direct benefit to study participants. 
20. Recruitment Methods 
20.1. Potential study participants will be identified by labor and delivery providers while admitted to 
the labor and delivery unit. Charts may also be reviewed by study personnel to identify 
potentially eligible subjects. They will be approached by study personnel while admitted to 
labor and delivery, either during a period of initial observation following the diagnosis, during 
labor, or within the first 6 hours postpartum. Potential study participants may also be 
approached for recruitment after transfer from labor and delivery to our antepartum inpatient 
unit if the plan is for expectant management until delivery at a later time.   
20.2. Potential study participants will be identified by their providers, who will notify study 
personnel. The study personnel will then determine whether the patient is a study candidate. 
20.3. To assist in recruitment of potential study participants, we will make use of a study fact sheet 
which will review the basic information in plain language, in a bullet point fashion. . 
21. Provisions to Protect the Privacy Interests of Subjects 
21.1. The only settings in which potential study participants will be approached for participation are 
private: either their labor and delivery room, their private room while undergoing expectant 
management on the antepartum service, or in an outpatient clinic exam room. Additionally, all 
research procedures will occur in the privacy of a participant’s hospital room. 
21.2. Encounters with patients during study recruitment, consent and participation all will occur in a 
private setting of a patient’s hospital room and will be executed by either qualified study 
personnel or providers who would otherwise already be involved in their care. Documentation 
of consent will be stored initially in the provider workroom on the labor and delivery unit and 
will be collected at periodically, usually every 2-3 days, for storage in a locked cabinet 
accessible only to study personnel.  Issues related to data are addressed in the Data 
Management/Confidentiality Section.  
22. Economic Burden to Subjects 
22.1. Study participants will not be responsible for any additional cost because of participation in the 
study. 
22.2. The patients’ insurers will be responsible for paying for adverse events. If the patient is 
uninsured, or “self-pay”, then the study participants will be financially responsible. Because the 
medications being studied are both already the standard of care for mild postpartum pain, an 
adverse even likely would have occurred whether or not a patient is a participant of the study. 
23. Compensation 
23.1. Upon completion of the study (at the time of hospital discharge) research participants will be 
compensated with a $15 gift card to a local retailer, such as Target™. This dollar amount was 
chosen because it is enough to serve as an incentive to complete the trial, but is not so large as 
to compel potential participants who are economically disadvantaged to participate due to 
financial need. 
24. Compensation for Research-Related Injury 


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24.1. Study participants will be responsible for their own medical care following a research-related 
injury, and no compensation plan will be in place. 
24.2. Study participants will be informed of their responsibility for seeking their own care for 
research-related injury at the time obtaining consent. Available care options include care options 
available under an existing insurance plan or any other options which the participant desires to 
pursue at their own cost. 
25. Consent Process 
25.1. Prior to study participation, consent will be obtained from each participant.  
25.1.1. Coinvestigators or study personnel will be responsible for obtaining consent. Their 
minimum qualifications include completion of the following online training modules: 
- Collaborative Institutional Training Initiative (CITI) Program: Biomedical Responsible 
Conduct of Research 
- CITI Program: Human Research 
- UNM Conflict of Interest training 
25.1.2. The consent process will take place in the patient’s hospital room or outpatient exam 
room. Other patients, or persons unknown to the patient will not be present for the 
consent process. 
25.1.3. In order to minimize coercion or undue influence, potential study participants will be 
given the option of reviewing study contents alone or with the provider or study 
personnel. 
25.1.4. After being approached, potential study participants will have the option for a waiting 
period of at least 30 minutes for review of consent materials prior to the obtaining of 
consent. 
25.1.5. In order to ensure ongoing consent throughout the study, study participants will be asked 
by care providers administering the medication whether they continue to give consent for 
participation, or whether they have any reservations or questions about study 
participation. If patients express concerns or have questions, study personnel will be 
contacted immediately to address the questions or concerns.  
25.1.6. In order to ensure that the consent is understood by the potential study participant, the 
provider or study personnel will ask that the patient repeat back the general nature of the 
study and the potential treatments to which she may be randomized. Consent will not be 
complete until this step is accomplished. 
Subjects not fluent in English 
25.1.7. Study participants speaking primarily Spanish may also be recruited and enrolled. 
25.1.8. For patients who speak primarily Spanish and have a poor understanding of English 
language communication, oral consent will either be obtained in Spanish by study 
personnel who speak Spanish fluently, or through the use of interpreters. Spanish 
language translations of consent documents will also be used and provided to the patients 
for review. 
25.1.9. Patients not understanding either English or Spanish will not be recruited for 
participation, thus short-form consent documents will not be used. 
 
Cognitively Impaired Adults/Adults Unable to Consent/Use of a Legally 
Authorized Representative 


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25.1.10. Patients with limited decisional capacity (either due to long-term cognitive impairment or 
short-term medical etiology) will not be approached for study participation. 
25.1.11. Potential study participants will only be approached for participation in the study if the 
assessment of the providers administering their care is that their decisional capacity is 
intact. Documentation of a potential study participant’s decisional capacity will be 
included on the consent form. 
25.1.12. Prior to approaching a potential study participant for recruitment, study personnel will 
review with the patient’s providers whether she has demonstrated intact decisional 
capacity during her hospital admission so far. If not, the potential participant will not be 
approached for recruitment. If the patient has demonstrated intact decisional capacity and 
meets other inclusion criteria, she will be approached. The study personnel reviewing the 
consent with the potential participant will assess her decisional capacity by requiring her 
to repeat not only the general nature of the study (as noted in section 25.1.6 above), but 
also the potential risk and benefit of each randomization arm (randomization to 
acetaminophen may have risk of worse pain control, whereas randomization to ibuprofen 
may have risk of higher blood pressure). If the potential participant is unable to articulate 
this, then she will not be enrolled for participation. Intact decisional capacity will be 
documented with a checkbox on the consent form. 
25.1.13. Decisional capacity will be evaluated on a daily basis by the providers administering 
medical care. If a participant’s decisional capacity becomes affected and she is unable to 
provide ongoing consent, she will be withdrawn from the study. Given the short duration 
of the study, participants regaining decisional capacity will not be re-consented for 
continued participation. 
25.1.14. Potential participants unable or unauthorized to give their own consent (as determined 
either by age or lack of decisional capacity) will not be enrolled in the study. 
25.1.15. Given that only potential participants who are able to provider their own consent will be 
enrolled, obtaining assent is not applicable. 
Subjects who are not yet adults (infants, children, teenagers): All study 
subjects will be a minimum age of 18. 
Waiver or Alteration of Consent Process (consent will not be obtained, 
required element of consent will not be included, or one or more required 
elements of consent will be altered): N/A  
26. Documentation of Consent 
26.1. Full written informed consent will be documented on all participants. 
26.2. Consent will be obtained verbally with the use of both a script and an information sheet. An 
information sheet summarizing the salient points of the consent will be provided for use by the 
consenting provider or study personnel and for review by the potential study participant. 
27. Study Test Results/Incidental Findings 
27.1. Individual Results: Individual test results obtained as part of the study protocol (i.e. daily 
preeclampsia labs) will be shared with the study participant by her team of medical providers as 
part of her ongoing medical care (as would normally be the routine). 
27.2. Incidental Findings: No experimental tests will be used as part of the study protocol. All tests 
that will be performed as part of the study protocol are relevant to the care of the study 
participant and would be performed anyway as part of her care and will be reviewed by her team 
of medical providers. Thus, any incidental findings will be communicated to the study 
participant by her medical provider(s).   


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28. Sharing Study Progress or Results with Subjects 
28.1. As the study data will not be analyzed until the completion of enrollment and because duration 
of participation is relatively short, study progress will not be reviewed with study participants 
while the study is underway. 
28.2. We do not intend to provide subjects with a summary of the study results after the study is 
complete.   
29. Inclusion of Vulnerable Populations 
29.1. 
The study will not exclude economically disadvantaged persons from participation, as there is 
no anticipated economic burden associated with participation. As the compensation for 
participation is of small value, they are not vulnerable to economic coercion. 
29.2. 
The study will not exclude educationally disadvantaged persons from participation. If a 
potential participant’s educational disadvantage is significant enough that they are unable to 
understand and articulate back the general nature of the study and the risks associated with 
randomization to each arm, they will not be enrolled in the study. 
29.3. All study participants will be recently pregnant.   
30. Community-Based Participatory Research  
30.1. N/A 
31. Research Involving American Indian/Native Populations 
31.1. American Indian/Native populations are not the focus of this study, so no additional tribal 
approval or review will be pursued. Potential study participants of American Indian or Native 
background who are eligible for the study will be approached for participation in the same 
manner as all non-Native potential participants. 
32. Transnational Research 
32.1. N/A 
33. Drugs or Devices 
33.1. The ibuprofen and acetaminophen administered as part of the study protocol will be stored and 
distributed by the research pharmacy and administered by the nurse caring for the participant. 
Both medications are already FDA approved for use to control pain, thus an IND is not 
necessary. 
33.2. Update to study drug preparation process: at the time the study was initiated the investigational 
pharmacy was unable to source both acetaminophen and ibuprofen in powdered form. As an 
alternative and to ensure uniformity between the two types of capsules, commercially prepared 
tablets were obtained for use in preparing blinded capsules. These tablets were broken into 
pieces which were placed inside a size “00” capsule shell in the required quantity. Subjects 
numbered 1 through 50 were enrolled in the study between September 29, 2016 and March 10, 
2017. In late February 2017, IDS was able to procure both acetaminophen and ibuprofen in 
powdered form. For the second half of the study, IDS proposes switching from the use of tablet 
fragments to an equivalent dosage of a powdered formulation when preparing blinded capsules. 
The reformulated capsules will be smaller and less odorous, resulting in a formulation more 
agreeable to study subjects receiving the medication. The amount of active ingredient in each 
capsule will remain the same with a calculated minimum amount of inert filler (microcrystalline 
cellulose) added to ensure uniform distribution of active ingredients among capsules. 


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Checklist Section 
This section contains checklists to provide information on a variety of topics that require special 
determinations by the IRB.  Please complete all checklists relevant to your research. 
 
I. Waivers or Alterations of Consent, Assent, and HIPAA Authorization 
A. Partial Waiver of Consent for Screening/Recruitment 
Complete this checklist if you are requesting a partial waiver of consent so that you 
can review private information to identify potential subjects and/or determine 
eligibility prior to approaching potential subjects for consent or parental permission. 
1. Describe the data source that you need to review (e.g., medical records): 
Labor and Delivery workroom monitor and electronic medical records. 
2. Describe the purpose for the review (e.g., screening): 
Screening for eligibility. 
3. Describe who will conducting the reviews (e.g., investigators, research staff): 
Medical providers, investigators. 
4. Do all persons who will be conducting the reviews already have permitted 
access to the data source? 
 Yes 
 No. Explain:       
5. Verify that each of the following are true or provide an alternate justification 
for the underlined regulatory criteria: 
a) The activity involves no more than minimal risk to the subjects 
because the records review itself is non-invasive and the results of the 
records review will not be used for any purposes other than those 
described above. 
 True 
 Other justification:       
b) The waiver or alteration will not adversely affect the rights and 
welfare of the subjects because eligible subjects will be approached for 
consent to participate in the research and are free to decline.  Further, 
the information accessed during the records review will not be 
disclosed to anyone without a legitimate purpose (e.g., verification of 
eligibility). 
 True 


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 Other justification:       
c) The research could not practicably be carried out without the waiver or 
alteration because there is no other reasonably efficient and effective 
way to identify who to approach for possible participation in the 
research.   
 True 
 Other justification:       
d) Whenever appropriate, potentially eligible subjects will be presented 
with information about the research and asked to consider 
participation.  (Regulatory criteria: Whenever appropriate, the 
subjects will be provided with additional pertinent information after 
participation.) 
 True 
 Other justification:       
Partial Waiver of HIPAA Authorization for Screening/Recruitment 
Complete the following additional questions/attestations if the records you will 
review to identify potential subjects and/or determine eligibility include Protected 
Health Information (PHI). 
6. Will you be recording any PHI when conducting the records review to identify 
potential subjects and/or determine eligibility? 
 Yes. Describe:       
 No 
7. If you answered “Yes” to question 6 above, please describe when you will 
destroy identifiers (must be the earliest opportunity consistent with the 
conduct of the research) or provide justification for why they must be 
retained: 
      
8. The PHI accessed or recorded for identification/screening purposes will not be 
reused or disclosed to (shared with) any other person or entity, except as 
required by law, for authorized oversight of the research study, or for other 
research for which the use or disclosure of the PHI would be permitted under 
the Privacy Rule. 
 True 
 False 


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B. Waiver of Documentation of Consent 
Complete this checklist if you intend to obtain consent verbally but will not be 
obtaining signatures from subjects on a consent form to document consent.  Waivers 
of documentation of consent are commonly requested when using scripts, information 
sheets, or email or survey introductions to present the elements of consent instead of 
using a traditional consent form. 
1. Are you requesting a waiver of documentation of consent for some or all 
subjects? 
 All 
 Some. Explain:       
2. Provide justification for one of the following: 
a) That the only record linking the subject and the research would be the 
consent document and the principal risk would be potential harm 
resulting from a breach of confidentiality. Each subject will be asked 
whether the subject wants documentation linking the subject with the 
research, and the subject's wishes will govern. 
      
b) That the research presents no more than minimal risk of harm to 
subjects and involves no procedures for which written consent is 
normally required outside of the research context. 
      
3. Do you intend to provide subjects with a written statement regarding the 
research in lieu of a traditional consent form? 
 Yes. Please attach a copy to your submission in Click. 
 No 
C. Alteration of Consent 
Complete this checklist if you intend to obtain consent but will be eliminating or 
altering one or more of the required elements of consent. Alterations of consent are 
commonly requested for research involving deception or for minimal risk research 
when an abbreviated consent is desired and one or more of the required element are 
not relevant to the research. 
Note: FDA-regulated research is not eligible for an alteration of consent. 
1. Which element(s) of consent do you wish to eliminate and why? 
      


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2. Which element(s) of consent do you wish to alter and why? 
      
3. Provide justification for each of the following regulatory criteria: 
a) The research involves no more than minimal risk to the subjects: 
      
b) The waiver or alteration will not adversely affect the rights and 
welfare of the subjects: 
      
c) The research could not practicably be carried out without the waiver or 
alteration: 
      
d) Whenever appropriate, the subjects will be provided with additional 
pertinent information after participation: 
      
D. Full Waiver of Consent/Parental Permission 
Complete this checklist if you are requesting a full waiver of consent for all subjects 
or certain subject groups (e.g., retrospective cohort).  Full waivers of consent are 
commonly requested when the research does not include any opportunity for 
interaction with subjects (e.g., chart review). 
Note: FDA-regulated research is not eligible for a full waiver of consent using these 
criteria.  If you believe that your FDA-regulated research may be eligible for a waiver 
under another mechanism, such as planned emergency research, contact the HRPO 
for assistance in determining what information to provide to the HRRC. 
1. Are you requesting a waiver for some or all subjects? 
 All 
 Some. Explain:       
2. Provide justification for each of the following regulatory criteria: 
a) The research involves no more than minimal risk to the subjects: 
      
b) The waiver or alteration will not adversely affect the rights and 
welfare of the subjects: 
      


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c) The research could not practicably be carried out without the waiver or 
alteration: 
      
d) Whenever appropriate, the subjects will be provided with additional 
pertinent information after participation: 
      
E. Full Waiver of Consent/Parental Permission (Public Benefit or Service 
Programs) 
Complete this checklist if you are requesting a full waiver of consent for all subjects 
or certain subject groups (e.g., retrospective cohort) and the research involves the 
evaluation of a public benefit or service program.   
1. Are you requesting a waiver for some or all subjects? 
 All 
 Some. Explain:       
2. Provide justification for each of the following regulatory criteria: 
a) The research or demonstration project is to be conducted by or subject 
to the approval of state or local government officials and is designed to 
study, evaluate, or otherwise examine: (i) public benefit or service 
programs; (ii) procedures for obtaining benefits or services under those 
programs; (iii) possible changes in or alternatives to those programs or 
procedures; or (iv) possible changes in methods or levels of payment 
for benefits or services under those programs: 
      
b) The research could not practicably be carried out without the waiver or 
alteration. 
      
F. Full Waiver of HIPAA Authorization 
Complete this checklist if you are requesting a full waiver of the requirement to 
obtain HIPAA authorization for all subjects or certain subject groups (e.g., 
retrospective cohort).  Full waivers of HIPAA authorization are commonly requested 
when the research does not include any opportunity for interaction with subjects 
(e.g., chart review). 
1. Are you requesting a waiver of authorization for some or all subjects? 
 All 
 Some. Explain:       


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2. Describe your plan to protect health information identifiers from improper use 
and disclosure: 
      
3. Describe your plan to destroy identifiers at the earliest opportunity consistent 
with conduct of the research (absent a health or research justification for 
retaining them or a legal requirement to do so): 
      
4. Describe why the research could not practicably be conducted without the 
waiver or alteration: 
      
5. The PHI accessed or recorded for identification/screening purposes will not be 
reused or disclosed to (shared with) any other person or entity, except as 
required by law, for authorized oversight of the research study, or for other 
research for which the use or disclosure of the PHI would be permitted under 
the Privacy Rule. 
 True 
 False 
G. Other Waiver Types 
If you are seeking another waiver type (e.g., Planned Emergency Research, Waiver of 
Parental Permission to Protect Child Participants, Enforcement Discretion for In 
Vitro Diagnostics, etc. contact the HRPO office for assistance in determining what 
information to submit for the HRRC’s consideration. 
 
II. Vulnerable Populations 
A. Adults with Cognitive Impairments 
Complete this checklist if the subject population will include adults with cognitive 
impairments.   
This checklist does not need to be completed if the research doesn’t involve 
interactions or interventions with subjects and will be conducted under a waiver of 
consent. 
1. Describe why the objectives of the study cannot be met without inclusion of 
adults with cognitive impairments. 
      
2. Describe how capacity to consent will be evaluated. 


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3. If subjects may regain capacity to consent, or if subjects may have fluctuating 
capacity to consent, describe your plans to evaluate capacity to consent 
throughout the research and to obtain consent to continue participation if 
capacity is regained. 
      
4. Describe your plans, if any, to provide information about the research to 
subjects and the steps you will take to assess understanding. 
      
5. Describe your plans to obtain assent, including whether assent will be 
obtained from none, some, or all subjects. 
      
6. Describe why risks to subjects are reasonable in relation to anticipated 
benefits to the subjects. 
      
7. If this study involves a health or behavioral intervention, describe why the 
relation of the anticipated benefit to the risk of the research is at least as 
favorable to the subjects as that presented by alternative procedures. 
      
8. Describe your plans for monitoring the well-being of subjects including any 
plans to withdraw subjects from the research if they appear to be unduly 
distressed. 
      
B. Children 
Complete this checklist if the subject population will include children. 
1. Select the category of research that you believe this research falls within and 
provide justification for any associated criteria.  If there are different 
assessments for different groups of children or arms (e.g., placebo vs. drug), 
include a memo to provide an assessment for each group.   
 Research not involving greater than minimal risk. (Minimal risk means 
that the probability and magnitude of harm or discomfort anticipated 
in the research are not greater in and of themselves than those 
ordinarily encountered in daily life or during the performance of 
routine physical or psychological examinations or tests.) 


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 Research involving greater than minimal risk but presenting the 
prospect of direct benefit to the individual subjects. 
Provide justification for each of the following criteria: 
(1) The risk is justified by the anticipated benefit to the subjects: 
      
(2) The relation of the anticipated benefit to the risk is at least as 
favorable to the subjects as that presented by available 
alternative approaches: 
      
 Research involving greater than minimal risk and no prospect of direct 
benefit to individual subjects, but likely to yield generalizable 
knowledge about the subject's disorder or condition. 
Provide justification for each of the following criteria: 
(1) The risk represents a minor increase over minimal risk: 
      
(2) The intervention or procedure presents experiences to subjects 
that are reasonably commensurate with those inherent in their 
actual or expected medical, dental, psychological, social, or 
educational situations: 
      
(3) The intervention or procedure is likely to yield generalizable 
knowledge about the subjects' disorder or condition which is of 
vital importance for the understanding or amelioration of the 
subjects' disorder or condition 
      
C. Pregnant Women and Fetuses 
Complete this checklist if the subject population will include pregnant women and 
fetuses. 
Besides obtaining consent and obtaining demographic information, no study 
procedures will take place while the patient is still pregnant. Randomization, 
administration of study medication, and monitoring will only begin after delivery.  
Provide justification for each of the following: 
1. Where scientifically appropriate, preclinical studies, including studies on 
pregnant animals, and clinical studies, including studies on non-pregnant 
women, have been conducted and provide data for assessing potential risks to 
pregnant women and fetuses. 


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Numerous studies have been carried out on non-pregnant (mostly non-
reproductive age) humans, and at least one study in pregnant rats assessing the 
effect of NSAIDs on blood pressure, with varying results. Our goal is not to 
assess the effect of NSAIDs on blood pressure during pregnancy but rather in 
the postpartum period. Thus, patients will no longer be pregnant while 
participating in the study protocol. They will, however, be consented while 
pregnant.  
2. The risk to the fetus is caused solely by interventions or procedures that hold 
out the prospect of direct benefit for the woman or the fetus; or, if there is no 
such prospect of benefit, the risk to the fetus is not greater than minimal and 
the purpose of the research is the development of important biomedical 
knowledge which cannot be obtained by any other means. 
Given that randomization and the study interventions occur after delivery, 
there is no risk to the fetus. Additionally, both study medications are first line 
agents for postpartum pain control in the setting of breastfeeding and are 
considered safe for mothers and neonates who are breastfeeding.  
3. Any risk is the least possible for achieving the objectives of the research. 
The interventions in each randomization arm are both first line treatments for 
mild postpartum pain and are used ubiquitously in postpartum patients, 
including those with preeclampsia. Besides being randomized to either 
ibuprofen or acetaminophen, all study procedures effectively mirror the 
standard of care that would be delivered even if patients were not participating 
in the study. Additionally, because study participation only occurs while 
admitted to the hospital, participants undergo very close observation and 
monitoring in the form of lab tests, symptom checks and vital signs 
measurements as part of routine care.  
D. Neonates of Uncertain Viability or Nonviable Neonates 
Complete this checklist if the subject population will include neonates of uncertain 
viability. 
Provide justification for each of the following: 
1. Where scientifically appropriate, preclinical and clinical studies have been 
conducted and provide data for assessing potential risks to neonates. 
      
2. Each individual providing consent is fully informed regarding the reasonably 
foreseeable impact of the research on the neonate. 
      
3. Individuals engaged in the research will have no part in determining the 
viability of a neonate. 


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4. The research holds out the prospect of enhancing the probability of survival of 
the neonate to the point of viability, and any risk is the least possible for 
achieving that objective, or, the purpose of the research is the development of 
important biomedical knowledge which cannot be obtained by other means 
and there will be no added risk to the neonate resulting from the research 
      
E. Nonviable Neonates 
Complete this checklist if the subject population will include nonviable neonates. 
Provide justification for each of the following: 
1. Where scientifically appropriate, preclinical and clinical studies have been 
conducted and provide data for assessing potential risks to neonates. 
      
2. Each individual providing consent is fully informed regarding the reasonably 
foreseeable impact of the research on the neonate. 
      
3. Individuals engaged in the research will have no part in determining the 
viability of a neonate. 
      
4. The purpose of the research is the development of important biomedical 
knowledge that cannot be obtained by other means. 
 
      
Verify each of the following: 
5. Vital functions of the neonate will not be artificially maintained 
 True 
 False 
6. The research will not terminate the heartbeat or respiration of the neonate 
 True 
 False 
7. There will be no added risk to the neonate resulting from the research 
 True 
 False 


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F. Biomedical and Behavioral Research Involving Prisoners 
Complete this checklist if the subject population will include prisoners. 
Note: Minimal risk for research involving prisoners is the probability and magnitude 
of physical or psychological harm that is normally encountered in the daily lives, or 
in the routine medical, dental, or psychological examination of healthy persons. 
1. Select and justify which allowable category of research involving prisoners 
this research falls within: 
 Study of the possible causes, effects, and processes of incarceration, and of 
criminal behavior, provided that the study presents no more than minimal 
risk and no more than inconvenience to the subjects 
      
 Study of prisons as institutional structures or of prisoners as incarcerated 
persons, provided that the study presents no more than minimal risk and 
no more than inconvenience to the subjects 
      
 Research on conditions particularly affecting prisoners as a class (for 
example, vaccine trials and other research on hepatitis which is much 
more prevalent in prisons than elsewhere; and research on social and 
psychological problems such as alcoholism, drug addiction, and sexual 
assaults) 
      
 Research on practices, both innovative and accepted, which have the intent 
and reasonable probability of improving the health or well-being of the 
subject 
      
 Epidemiologic studies in which the sole purpose is to describe the 
prevalence or incidence of a disease by identifying all cases or to study 
potential risk factor associations for a disease, the research presents no 
more than Minimal Risk and no more than inconvenience to the subjects, 
and Prisoners are not a particular focus of the research. 
      
2. Provide justification for each of the following regulatory criteria: 
a) Any possible advantages accruing to the prisoner through his or her 
participation in the research, when compared to the general living 
conditions, medical care, quality of food, amenities and opportunity 
for earnings in the prison, are not of such a magnitude that his or her 


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ability to weigh the risks of the research against the value of such 
advantages in the limited choice environment of the prison is impaired 
      
b) The risks involved in the research are commensurate with risks that 
would be accepted by nonprisoner volunteers 
      
c) Procedures for the selection of subjects within the prison are fair to all 
prisoners and immune from arbitrary intervention by prison authorities 
or prisoners. Unless justification is provided, control subjects must be 
selected randomly from the group of available prisoners who meet the 
characteristics needed for that particular research project 
      
d) The information is presented in language which is understandable to 
the subject population 
      
e) Adequate assurance exists that parole boards will not take into account 
a prisoner's participation in the research in making decisions regarding 
parole, and each prisoner is clearly informed in advance that 
participation in the research will have no effect on his or her parole 
      
f) When appropriate, adequate provision has been made for follow up 
examination or care after research participation, taking into account 
the varying lengths of individual prisoners' sentences, and for 
informing participants of this fact 
      
 
III. Medical Devices 
Complete this checklist if the research evaluates the safety or effectiveness of a medical device.  
If more than one medical device is being evaluated, provide the requested information for each. 
A. Device Name:        
B. Manufacturer:        
C. Does the research involve a Significant Risk Device under an IDE? 
 Yes. Include documentation of the FDA approval of the IDE with your submission.  
Acceptable methods of documentation include: (1) FDA letter noting IDE number 


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and approval status; (2) Industry sponsor letter noting IDE number and FDA 
approval status; or (3) FDA-approved industry sponsor protocol with IDE number 
noted  
 No 
D. Is the research IDE-exempt? 
 Yes. Include a FDA letter with your submission noting the determination that the 
research is IDE-exempt or a letter from the sponsor (or sponsor-investigator) 
justifying why they believe the research is IDE-exempt*.   
 No 
E. Does the research involve a Non-Significant Risk (NSR) Device? 
 Yes. Include a FDA letter with your submission noting the determination that the 
research is NSR or a letter from the sponsor (or sponsor-investigator) justifying why 
they believe the research is NSR**.   
 No 
* This FDA guidance includes a description for when a device study is exempt from the 
IDE requirements: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127067.pdf  
**This FDA guidance includes information on how to differentiate between Significant 
Risk and Non-Significant Risk device studies: 
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.1097/01.AOG.0000437382.03963.88. 
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Floor-Schreudering A, De Smet PAGM, Buurma H, et al. NSAID-antihypertensive drug interactions: which 
outpatients are at risk for a rise in systolic blood pressure? Eur J Prev Cardiol. 2015. 
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White WB. Cardiovascular effects of the cyclooxygenase inhibitors. Hypertension. 2007;49(3):408-418. 
doi:10.1161/01.HYP.0000258106.74139.25. 
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Nowak J, Wennmalm A. Influence of indomethacin and of prostaglandin E1 on total and regional blood 
flow in man. Acta Physiol Scand. 1978;102(4):484-491. doi:10.1111/j.1748-1716.1978.tb06097.x. 
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Zlatnik MG, Buhimschi I, Chwalisz K, Liao QP, Saade GR, Garfield RE. The effect of indomethacin and 
prostacyclin agonists on blood pressure in a rat model of preeclampsia. Am J Obstet Gynecol. 
1999;180(5):1191-1195. doi:S0002937899002999 [pii]. 
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Makris A, Thornton C, Hennessy A. Postpartum hypertension and nonsteroidal analgesia. Am J Obstet 
Gynecol. 2004;190(2):577-578. doi:10.1016/j.ajog.2003.08.030. 
15.  
Schachtel BP, Thoden WR, Baybutt RI. Ibuprofen and acetaminophen in the relief of postpartum episiotomy 
pain. J Clin Pharmacol. 1989;29(6):550-553. http://www.ncbi.nlm.nih.gov/pubmed/2666455. 
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Wasden SW, Ragsdale ES, Chasen ST, Skupski DW. Impact of non-steroidal anti-inflammatory drugs on 
hypertensive disorders of pregnancy. Pregnancy Hypertens An Int J Women’s Cardiovasc Heal. 
2014;4(4):259-263. doi:10.1016/j.preghy.2014.06.001. 
17.  
Lowder JL, Shackelford DP, Holbert D, Beste TM. A randomized, controlled trial to compare ketorolac 
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Sammour RN, Ohel G, Cohen M, Gonen R. Oral naproxen versus oral tramadol for analgesia after cesarean 
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Bhounsule SA(1), Nevreker PR, Agshikar NV, Pal MN DV. A comparison of four analgesics in post-
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Wilasrusmee S, Chittachareon A, Jirasiritum S, Srisangchai P. Naproxen suppository for perineal pain after 
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Hinz B, Dormann H, Brune K. More pronounced inhibition of cyclooxygenase 2, increase in blood pressure, 
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Appendix 
 
Listed in the Appendix are the supporting documents, including data collection tools and recruitment materials, 
which are uploaded into Click: 
 
1. 
Data Collection Postpartum Day #1 
2. 
Data Collection Postpartum Day #2 
3. 
Data Collection Postpartum Day #3 
4. 
Data Collection Postpartum Day #4 and beyond 
5. 
Eligibility log sheet 
6. 
Enrollment Data Collection 
7. 
6 week post-study questionnaire 
8. 
Patient Fact Sheet