Clinical trial NCT04402385
Conditions: Pre-Eclampsia Stage 1 Hypertension Elevated Blood Pressure
Keywords: Aspirin
Sponsor: Yale University
Start date: 2020-08-06; Completion date: 2022-06-22
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To determine if low dose aspirin reduces the incidence of hypertensive disorders of pregnancy (gestational hypertension, preeclampsia, eclampsia, and HELLP syndrome) in pregnant women with stage 1 hypertension and elevated blood pressure.

Detailed description:
At the baseline visit, women will go through informed consent and review of study eligibility. Objectives of the study, participation requirements, eligibility inclusion and exclusion will be reviewed in detail. If these are not met, the woman is excluded from the study. If she meets inclusion criteria, a checklist of exclusion criteria will be reviewed. If any exclusions are met, the woman is excluded from the study. The consent form will be reviewed in detail. If the woman consents and signs all pages of the form, randomization follows.

Randomization will be done in a 1:1 allocation ratio between the treatment and placebo arms, stratified by blood pressure group (elevated blood pressure and stage 1 hypertension). A computer algorithm will assign participant based on random permuted blocks design with block size between 2-4 within each strata. Each participant will have an assigned Study ID number that is linked to their random assignment.

Participants will be contacted by telephone 1 week after randomization. The purpose of this visit is to ensure the participant has received study medication and initiated the regimen.

The third encounter will be 6 weeks (+/- 1week) after randomization in person to coincide with routine prenatal visit or via telephone. The purpose of this study visit is to review their pregnancy course, use of study medications, any side effects, difficulties with the study, and have opportunities to make comments and/or ask questions. The participants will be asked to bring their study medication for pill count at the time of this encounter, if the study visit is able to be performed in person. Study participants will continue their routine prenatal care with pregnancy management performed routinely per their provider.

The fourth encounter will be 16 weeks (+/- 1week) after randomization in person to coincide with routine prenatal visit or via telephone. If the participant is already delivered by this time, the visit will be performed via telephone postpartum. The purpose of this study visit is to review their pregnancy course, use of study medications, any side effects, difficulties with the study, and have opportunities to make comments and/or ask questions. The participants will be asked to bring their study medication for pill count at the time of this encounter, if the study visit is able to be performed in person.

The rest of the study will be conducted via chart review. Each prenatal visit will be reviewed for blood pressure, evaluation of symptoms, review of any laboratory and/or imaging results. New diagnoses, medications, and hospital admissions will be documented.

Delivery records will be abstracted for outcomes listed below. Neonatal records will be reviewed from birth until 1 year of age. Neonatal and infant chart abstraction will include birthweight, Apgar scores, hospital course, problem visit, diagnoses, medications, emergency department visits, and hospitalizations. Participant's postpartum course will be reviewed for 1 year postpartum, including outpatient visits, emergency department visits, and any hospitalizations.

The study will be performed by an intent-to-treat analysis. Thus, even women who discontinue study medication will be included in final analyses.

Arms: arm 1: Participants randomized to 81 mg of Aspirin daily arm 2: Participants randomized to placebo daily
Interventions: intervention 1: Aspirin 81 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Participants randomized to 81 mg of Aspirin daily intervention 2: Participants randomized to placebo daily

Protocol documents:
Prot_SAP_000.pdf: 
Title: ASPPIRE - Aspirin to Prevent Preeclampsia in Women with Elevated Blood Pressure and Stage 1 
Hypertension 
Date: 12/08/2021 
Clinicaltrials.gov ID: NCT04402385 
Document: Protocol w SAP 


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Page 1 of 23
                   
                                   
HRP-503B – BIOMEDICAL RESEARCH PROTOCOL 
(2017-1)
Protocol Title: ASPPIRE - Aspirin to Prevent Preeclampsia in Women with Elevated Blood Pressure and Stage 1 
Hypertension
Principal Investigator: Olga Grechukhina, MD
Sub-Investigators: Victoria Greenberg, MD; Moeun Son, MD, MSCI; Heather Lipkind, MD, MPH 
Version Date: 12/08/2021
Clinicaltrials.gov Registration #: NCT04402385
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SECTION I: RESEARCH PLAN
1.
Statement of Purpose: State the scientific aim(s) of the study, or the hypotheses to be tested. 
To determine if low dose aspirin reduces the incidence of hypertensive disorders of pregnancy (gestational 
hypertension, preeclampsia, eclampsia, and HELLP syndrome) in pregnant women with stage 1 hypertension 
and elevated blood pressure.
2.
Probable Duration of Project: State the expected duration of the project, including all follow-up and data 
analysis activities.  
5 years
3.
Background: Describe the background information that led to the plan for this project. Provide references to 
support the expectation of obtaining useful scientific data.
New hypertension guidelines proposed in 2017 by the American College of Cardiology/ American Heart 
Association (ACC/AHA) redefined blood pressure (BP) categories as Stage 1 hypertension (systolic 130-139 
mmHg or diastolic 80-89 mmHg), Elevated (systolic 120-129 mmHg and diastolic <80mm) and Normal (<120/<80 
mmHg).  Adaption of these new definitions increases the prevalence of hypertension among adults in the United 
States by approximately 31 million people.  Since publication of the updated guidelines, several studies have 
assessed lower levels of blood pressure elevations and subsequent pregnancy outcomes. 
A secondary analysis of a large, prospective study of nulliparous women evaluated both first trimester 
blood pressure categories and blood pressure trajectories from the first to second trimester. A total of 8,899 
nulliparas were included in this secondary analysis. Increasing first trimester blood pressure category was 
associated with higher risk of all hypertensive disorders of pregnancy. Elevated blood pressure was associated 
with an adjusted relative risk of 1.54 (95% confidence interval, 1.18, 2.02) and stage 1 hypertension was 
associated with adjusted relative risk of 2.16 (95% confidence interval, 1.31, 3.57) of any hypertensive disorder 
of pregnancy. Stage 1 hypertension was associated with the highest risk of preeclampsia with severe features, 
with an adjusted relative risk of 2.48 (95% confidence interval, 1.38,8.74).
In a secondary analysis of a multicenter randomized controlled trial examining the effects of aspirin for 
preeclampsia prophylaxis, women with Stage 1 hypertension (systolic blood pressures 135-139 and/or diastolic 
blood pressure 85-89) were compared with normotensive women. In women randomized to placebo, 15% had 
preeclampsia if they had stage 1 hypertension compared to 5% of those who were normotensive. The study also 
found that women with stage 1 hypertension had increased rates of indicated preterm deliveries and gestational 
diabetes. The women in this study with stage 1 hypertension had a 40% risk reduction of developing 
preeclampsia when they took aspirin 60mg daily compared to placebo. 
In a large study of women with prehypertension, defined as two consecutive elevated blood pressures 
(systolic 120-129 mmHg or diastolic 80-89 mm Hg) in the 12 months prior to last menstrual period up to 12 
weeks gestational age, there was a two-fold increased rate of hypertensive disorders of pregnancy. In a cohort 
of 7,802 women within the Kaiser Permanente health system, 28% had prehypertension. Women with 
prehypertension were 2.65 times more likely to develop a hypertensive disorder of pregnancy, 2.17 times more 
likely to develop preeclampsia, and 1.2 times more likely to develop gestational diabetes as compared to 
normotensive women.
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Studies of reproductive-aged women show that twice as many women will be diagnosed with 
hypertension prior to pregnancy (18.9% vs 10.2%) with the new ACC/AHA guidelines. Lowering the blood 
pressure threshold for hypertension from 140/90 has unknown implications for pregnant women. While the 
new guidelines propose non-pharmacologic management of stage 1 hypertension, pregnancy management 
could be significantly affected by the new guidelines. 
Multiple randomized controlled trials and meta-analyses have demonstrated the beneficial effects of 
preeclampsia prophylaxis with aspirin in women at high risk of developing preeclampsia. High risk factors 
include a prior history of preeclampsia, chronic hypertension, and pre-gestational diabetes. 
Low-dose aspirin is safe for use in pregnancy. Multiple large cohort and case-control studies have not 
found an association with congenital defects, structural, or developmental anomalies in the fetus. Use in the 
third trimester does not cause premature closure of the ductus arteriosus. Maternal use is safe without an 
increased risk of bleeding. There is no increased risk of gastrointestinal bleeding, placental abruption, epidural 
hematoma, and postpartum hemorrhage. Timing of aspirin use to decrease the risk of preeclampsia is 
important. Earlier initiation appears to be beneficial, with a large meta-analysis indicating optimal effects when 
initiated before 16 weeks of pregnancy. The EAGeR trial, which randomized women to low dose aspirin or 
placebo prior to conception, demonstrated similar livebirth rates and no increase in adverse safety events 
between the groups. The ASPRE trial randomized women at high risk for preeclampsia to aspirin versus placebo 
in the first to early second trimester (11-14 weeks’ gestation) with reduction seen in preeclampsia. 
To date, there are no randomized controlled trials of preeclampsia prophylaxis with aspirin in women 
with elevated blood pressure or stage 1 hypertension (by 2017 ACC/AHA guidelines), and no other high-risk 
predictors of preeclampsia. 
Stage 1 Hypertension increases risk of preeclampsia:

Sutton, Caritis, et al 2018). Maternal outcomes associated with lower range stage 1 hypertension. 
Obstet Gynecol 132(4), 843-849
o
This is a secondary analysis of a randomized controlled trial across 7 centers in the United 
States that enrolled nulliparous women with BP >135/85) to aspirin 60mg or placebo 
between 13-25 weeks of pregnancy
o
This secondary analysis looked at a subset of women (164 of the initial 3,134 were found 
to have stage 1 hypertension) 
o
Among women receiving placebo, preeclampsia occurred significantly more often in 
women with stage 1 hypertension compared with normotensive high-risk women after 
adjustment for maternal age and body mass index (39.1% versus 15.1%; risk ratio, 2.49; 
95% confidence interval, 1.74–3.55). 
o
Women with stage 1 hypertension had a significant risk reduction related to aspirin 
prophylaxis (risk ratio, 0.61; 95% confidence interval, 0.39–0.94) that was not seen in 
normotensive high-risk women (risk ratio, 0.97; 95% confidence interval, 0.70–1.34).

Black MH et al (2015). Prehypertension prior to or during early pregnancy is associated with 
increased risk for hypertensive disorders in pregnancy and gestational diabetes.
o
This study: 10,459 women between 2005-2010 with ICD-9 codes used to identify 
hypertension and pre-hypertension in the 12 months prior to pregnancy and through 12 
weeks gestation 
o
2,156 (27.6%) women had pre-hypertension. More likely to be older, white or black, obese, 
gain excess weight during pregnancy, and to develop GDM 
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
ICD codes used to identify preeclampsia and gestational hypertension 

Women were diagnosed with pre-hypertension if they had 2 consecutive elevated 
BPs (SBP >120 and/or DBP >80)

Results: 653 (8.4%) developed hypertensive disorder of pregnancy 
o
2.65 times more likely to develop hypertensive disorder of pregnancy and 2.17 times more 
likely to have PEC/eclampsia than normotensive women after adjustment 
Aspirin reduces risk of preeclampsia:

Luley D, Meher S, Hunter KE, Seidler AL, & Askie LM (2019). Antiplatelet agents for preventing 
preeclampsia and its complications. Cochrane Database of Systematic Reviews.
o
Meta-analysis of 77 trials including 40,249 women to evaluate placebo versus placebo in 
preeclampsia risk reduction
o
9 of the 77 trials included >1,000 women in each. This contributed to 80% of the included 
patient population.
o
Low dose aspirin dosages varied from 50mg to 150mg daily
o
In total, aspirin reduced the risk of preeclampsia by 18% with a number needed to treat of 
61 women to prevent one case of preeclampsia 

Caritis S, Sibai B et al (1998). Low-dose aspirin to prevent preeclampsia in women at high risk. NEJM, 
338:701-705
o
RCT of aspirin 60mg or placebo begun at 13-26 weeks in women with high risk features 
(prior PEC, cHTN, pre-gestational diabetes, multifetal gestations)
o
Adherence: did 1 week of placebo first, only included women who took >50%. Then had 
phone follow-up with research nurse
o
No improvement with LDA

Odibo AO, Goetzinger KR, Odibo L, & Tuuli MG (2015). Early prediction and aspirin for prevention of 
pre-eclampsia (EPAPP) study: a randomized controlled trial. Ultrasound in Obstetrics and 
Gynecology, 46: 414-418
o
Randomized controlled trial of women receiving low dose aspirin if they had one or more 
high risk factors for developing preeclampsia 
o
Aspirin dispensed by the pharmacy
o
Pill diary done by patients, then asked to return unused pills to be counted by the pharmacy
o
Study concluded early due to clinical equipoise and new societal guidelines recommending 
aspirin in women with at least one high risk factor for preeclampsia
o
Study ended with 53 women, 30 of them randomized to receive aspirin
o
No differences found in rates of preeclampsia between the groups

Byaruhanga RN, Chipato T, & Rusakaniko S (1998). A randomized controlled trial of low-dose aspirin 
in women at risk from pre-eclampsia. International Journal of Obstetrics & Gynecology, 60(2): 129-
135
o
75mg versus placebo in 250 women with prior history of PEC or cHTN
o
Received container with 126 tablets. Asked about adherence at each visit. Monthly count of 
remaining tablets. Total adherence if 80% or more tablets taken 
o
No significant difference found in rates of preeclampsia between the groups
Aspirin timing for preeclampsia prophylaxis

Roberge S, Bujold E, Nicolaides KH. Meta-analysis on the effect of aspirin use for prevention of 
preeclampsia on placental abruption and antepartum hemorrhage. Am J Obstet Gynecol 2018, 
218(5): 483-489
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o
Aspirin dose <100mg daily when initiated prior to 16 weeks decreases risk of placental 
abruption or antepartum hemorrhage compared to initiation after 16 weeks 

Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: 
systematic review and metaanalysis. Am J Obstet Gyneol 2018, 218(3): 287-293
o
Meta-analysis of 16 trials including 18,907 women analyzing outcomes of preeclampsia in 
women randomized to aspirin (at varying doses) versus placebo 
o
No reduction seen in term preeclampsia
o
Reduction in preterm preeclampsia when initiated before 16 weeks’ gestation 

Meher S, Duley L, Hunter K, Askie L. Antiplatelet therapy before or after 16 weeks’ gestation for 
preventing preeclampsia: an individual participant data meta-analysis. Am J Obstet Gynecol 2017, 
216(2): 121-128
o
Individual participant data meta-analysis including 31 randomized controlled trials with 
32,217 women comparing aspirin or other antiplatelet therapy versus placebo for 
preeclampsia prevention
o
Subgroup analysis looking at timing of aspirin initiation (before or after 16 weeks)
o
Found consistent reductions in preeclampsia, preterm birth <34 weeks, small for gestational 
age neonate, and stillbirth regardless of when the dose was initiated 

Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus 
placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017, 377: 613-622
o
Randomized controlled trial of 1,776 women with high risk factors for preeclampsia given 
aspirin 150mg versus placebo daily for preeclampsia prevention
o
Initiated between 11-14 weeks’ gestation 

Committee on Obstetric Practice, Society for Maternal-Fetal Medicine. ACOG Committee Opinion: 
Low-dose aspirin use during pregnancy. Obstet Gynecol 2018, 132(1): e44-e52
o
Society guidelines for initiation of low dose aspirin between 12-28 weeks’ gestation, 
optimally before 16 weeks’ gestation
4.
Research Plan: 
Summarize the study design and research procedures using non-technical language that can be readily 
understood by someone outside the discipline. Be sure to distinguish between standard of care vs. research 
procedures when applicable and include any flowcharts of visits specifying their individual times and lengths. 
Describe the setting in which the research will take place.
Setting: Maternal-Fetal Medicine office at academic center; Women’s Center (academic resident-run obstetric 
clinic); private office for patients with university insurance, and private OBGYN offices that deliver at Yale New 
Haven Hospital  
1. At the baseline visit, women will go through informed consent and review of study eligibility. Objectives of 
the study, participation requirements, eligibility inclusion and exclusion will be reviewed in detail. We will 
complete checklist of inclusion criteria. If these are not met, the woman is excluded from the study. If she 
meets inclusion criteria, a checklist of exclusion criteria will be reviewed. If any exclusions are met, the woman 
is excluded from the study. The consent form will be reviewed in detail. If the woman consents and signs all 
pages of the form, randomization follows. 
Randomization will be done in a 1:1 allocation ratio between the treatment and placebo arms. A computer 
algorithm will assign participant based on random permuted blocks design with block size between 2-4. Each 
participant will have an assigned Study ID number that is linked to their random assignment. Two staff 
members will know the randomization allocation. One staff member will be in the Yale Investigational Drug 
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Services (IDS) and will not have any further part in the study. The second study unblinded study member will be 
Lauren Perley, an experienced research nurse within the Maternal-Fetal Medicine division. Remote dispensing 
has been approved by Jing Lu of the Yale IDS. 
In order to improve patient recruitment, our office will perform remote dispensing as per ASHP guidelines 
(document included in IRB re-submission). This includes temperature monitoring to maintain room 
temperature at 20-25 degrees Celsius utilizing an approved temperature monitoring system and temperature 
logging. We will also maintain drug accountability logs. All logs and regulations are submitted as documents 
to this IRB. 
Yale IDS will continue to compound our study medications and dispense pre-counted and bottled medications 
labeled with study participant ID number as per the randomization scheme. This randomization scheme is 
shared with our staff member, Lauren Perley, who will dispense the pre-bottled study medications to study 
participants as per the study ID number. All allergies and co-morbidities will be verified by research staff. 
Labeling of medications will be performed by Lauren Perley. 
Based on the participant assignment, we will dispense enough medication for the rest of the pregnancy. The 
bottles of study medication are pre-packaged and identical in appearance. 
The patient and the rest of the research staff personnel are blinded to study allocation. The staff members 
who are unblinded will not be involved in data acquisition, statistical analysis, and paper writing. Yale IDS will 
dispense study medication at the time of randomization. Yale IDS will perform pill counting at the beginning 
and completion of study enrollment in order to assess patient adherence with the regimen. Medication 
adherence may be encouraged by helping participants to set a daily reminder on their phone or calendar.
 
2. Participants will be contacted by telephone 1 week after randomization. The purpose of this visit is to ensure 
the participant has received study medication and initiated the regimen. We will then discuss any side effects, 
questions, and/or concerns about the study. Any problems will be discussed and mitigated if possible.
3. The third encounter will be 6 weeks (+/- 1week) after randomization in person to coincide with routine 
prenatal visit or via telephone. The purpose of this study visit is to review their pregnancy course, use of study 
medications, any side effects, difficulties with the study, and have opportunities to make comments and/or ask 
questions. The participants will be asked to bring their study medication for pill count at the time of this 
encounter, if the study visit is able to be performed in person. Study participants will continue their routine 
prenatal care with pregnancy management performed routinely per their provider. 
4. The fourth encounter will be 16 weeks (+/- 1week) after randomization in person to coincide with routine 
prenatal visit or via telephone. If the participant is already delivered by this time, the visit will be performed via 
telephone postpartum. The purpose of this study visit is to review their pregnancy course, use of study 
medications, any side effects, difficulties with the study, and have opportunities to make comments and/or ask 
questions. The participants will be asked to bring their study medication for pill count at the time of this 
encounter, if the study visit is able to be performed in person.
5. The rest of the study will be conducted via chart review. Each prenatal visit will be reviewed for blood 
pressure, evaluation of symptoms, review of any laboratory and/or imaging results. New diagnoses, 
medications, and hospital admissions will be documented. 
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6. Delivery records will be abstracted for outcomes listed below. Neonatal records will be reviewed from birth 
until 1 year of age. Neonatal and infant chart abstraction will include birthweight, Apgar scores, hospital 
course, problem visit, diagnoses, medications, emergency department visits, and hospitalizations. Participant’s 
postpartum course will be reviewed for 1 year postpartum, including outpatient visits, emergency department 
visits, and any hospitalizations. 
The study will be performed by an intent-to-treat analysis. Thus, even women who discontinue study 
medication will be included in final analyses. 
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Visit 1, Trial Eligibility: 

Assessment for trial eligibility with review of 
inclusion and exclusion criteria through checklists  

Informed consent reviewed in detail 
Visit 1, Randomization 

Consent form signed

Randomization 

Distribution of study medication to the participant: 
1 tablet of Aspirin 81mg or placebo orally daily
Visit 2, Telephone Visit: 

1 week after randomization

Ensure receipt and initiation of study medications 

Answer questions and concerns

Assess for medication side effects
Visit 3, Study Visit: 

6 weeks (+/- 1 week) after randomization

In-person if possible to coincide with routine prenatal 
visit. Otherwise, by telephone.

Assessment of ongoing pregnancy, concerns, new 
diagnoses, medications, and preeclampsia symptoms 

Pill count by research personnel
Visit 4, Study Visit: 

16 weeks (+/- 1 week) after randomization

In-person if possible to coincide with routine prenatal 
visit. Otherwise, by telephone.

Assessment of ongoing pregnancy, concerns, new 
diagnoses, medications, and preeclampsia symptoms 

Pill count by research personnel
Chart Abstraction: 

Participant chart review 
including antepartum, 
intrapartum, and postpartum 
course until 1-year post delivery

Neonatal chart review until 1 
year of age
Yale IDS 

Pill count at conclusion of 
participant enrollment 
Exclude if inclusion criteria not met or 
has any exclusion criteria 
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5.
Genetic Testing   
N/A ☒
6.
Subject Population: Provide a detailed description of the types of human subjects who will be recruited into 
this study.
Pregnant women ages ≥ 18 years with live, singleton pregnancies enrolled prior to 20 weeks gestational age. 
These women will receive prenatal care through a Yale New Haven Hospital (YNHH)-associated obstetric and/or 
midwifery practice. They will plan to deliver at a hospital within the YNHH system. 
7. Subject classification: Check off all classifications of subjects that will be specifically recruited for enrollment in 
the research project. Will subjects who may require additional safeguards or other considerations be enrolled 
in the study? If so, identify the population of subjects requiring special safeguards and provide a justification 
for their involvement.
☐Children
☐ Healthy 
☐Fetal material, placenta, or dead fetus
☒Non-English Speaking
☐ Prisoners
☐Economically disadvantaged persons
☐Decisionally Impaired
☐ Employees
☒Pregnant women and/or fetuses
☐Yale Students 
☒ Females of childbearing potential
NOTE: Is this research proposal designed to enroll children who are wards of the state as potential subjects?
Yes ☐  No ☒ 
8. Inclusion/Exclusion Criteria: What are the criteria used to determine subject inclusion or exclusion?
Inclusion: 

Age  18 years

Singleton pregnancy 

Elevated blood pressure (At least 2 systolic BP 120-129 mm Hg within 1 year pre-
pregnancy until 20 weeks gestational age on at least 2 separate healthcare encounters) 
or Stage 1 hypertension (At least 2 systolic BP 130-139 and/or diastolic BP 80-89 within 
1 year pre-pregnancy until 20 weeks gestational age on at least 2 separate healthcare 
encounters)

Speaks English or Spanish 

Informed and written consent 

Confirmed single live intrauterine pregnancy (confirmed by positive cardiac motion by 
transvaginal or transabdominal ultrasound)
Exclusion: 

Chronic hypertension 

Pre-gestational diabetes, defined as diabetes diagnosed prior to pregnancy (type 1, 1.5, 
or 2)

Chronic renal disease 
o
diagnosis of stage 1 chronic kidney disease or higher and/or GFR <60 mL/min 
with duration at least 3 months and/or history of kidney transplantation and/or 
undergoing peritoneal or hemodialysis

Systemic lupus erythematous 

Antiphospholipid antibody syndrome 
o
diagnosis made by having 1 or more clinical criteria and 1 or more laboratory 
criteria
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
Clinical criteria: venous thrombosis, arterial thrombosis, obstetric 
complications (3 or more unexplained consecutive spontaneous 
abortions <10 weeks gestation, 1 or more unexplained deaths of a 
morphologically normal fetus after 10 weeks gestation, 1 or more 
premature births before 34 weeks gestation attributable to placental 
insufficiency, including severe preeclampsia or fetal growth restriction)

Laboratory criteria: lupus anticoagulant, anti-cardiolipin IgG or IgM with 
titer >99th percentile, anti-beta 2 glycoprotein IgG or IgM with titer >99th 
percentile. Laboratory result must be positive twice at least 12 weeks 
apart 

Multifetal gestation

 20 weeks gestation at time of randomization based on American College of 
Obstetricians and Gynecologists dating criteria. Dating will be based on last menstrual 
period (LMP) if regular, sure LMP is available that agrees with ultrasound dating. 
Otherwise, earliest ultrasound will be used for dating purposes. 

Prior history of hypertensive disorder of pregnancy 

Current pregnancy with known chromosomal, genetic, major malformations or fetal 
demise, or planned termination of pregnancy

Women with contraindications to taking aspirin (bleeding diathesis such as Von 
Willebrand’s disease, peptic ulcer disease, aspirin hypersensitivity, nasal polyps, asthma 
with aspirin-induced bronchospasm, severe liver disease). 

Concurrent participation in another study that influences risk of preeclampsia

Women who do not plan to deliver within the YNHH system 
Write here
9. How will eligibility be determined, and by whom? Write here
Eligibility will be determined by study personnel with human subject protection training and ability to 
randomize patients. Patients will be approached and asked about eligibility criteria utilizing a checklist. If any 
exclusion criteria are met, the patient will not be eligible to participate in the study. 
An MFM or OBGYN attending will confirm that the woman has a single, live intrauterine pregnancy by 
transvaginal or transabdominal ultrasound as part of standard of care. This ultrasound typically occurs 
between 8-14 weeks gestational age. The results of this ultrasound will be recorded in the woman’s electronic 
medical record and this documentation will serve to confirm that this eligibility criterion has been met.
Women will be deemed to have elevated blood pressure if they have at least 2 systolic blood pressure 
measurements of 120-129 mm Hg within 1 year prior to pregnancy until 20 weeks gestational age on at least 
2 separate healthcare encounters. Women will be deemed to have stage 1 hypertension if they have had at 
least 2 systolic blood sure measurements of 130-139 mm Hg and/or diastolic blood pressures of 80-89 mm Hg 
within 1 year prior to pregnancy until 20 weeks gestational age on at least 2 separate healthcare encounters.
Enrolled participants will be randomized after a single, live intrauterine pregnancy is determined by 
ultrasound. They must then be randomized prior to 20 weeks’ gestation.
10. Risks: Describe the reasonably foreseeable risks, including risks to subject privacy, discomforts, or 
inconveniences associated with subjects participating in the research. 
Risks of aspirin:

Most common: stomach upset, heartburn, nausea, vomiting (likelihood: 1-3/100 people)
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
Uncommon: Gastrointestinal bleeding (likelihood: 0.5-3/1,000 people)

Rare but serious: Acute renal failure, hives or facial swelling (likelihood: 7-20/10,000 
people), bleeding in the brain (likelihood: 4/10,000 people)

Contraindicated in people with: bleeding disorders (such as Von Willebrand’s Disease), 
peptic ulcer disease, nasal polyps, asthma with aspirin-induced bronchospasm, severe 
liver disease, and aspirin or salicylate allergy or hypersensitivity. 

Breach of confidentiality. This is mitigated by having name and phone number of the 
patient visible to only two research staff members. After completion of the study and 
information collection, identifiers will be removed and be exchanged with a code 
number. The information is kept in a password-protected database via Yale’s RedCap 
system. These files will only be accessed by a small group of research staff. Consent form 
documents will be kept in a locked cabinet in our research office, accessible only by Yale 
Maternal-Fetal Medicine research staff. Publications and presentations will not include 
any names or identifying information.
11. Minimizing Risks: Describe the manner in which the above-mentioned risks will be minimized.
We will ensure that patients with the listed contraindications to aspirin therapy are not enrolled in the study. 
Low dose aspirin (81mg) with enteric coating will be used, which will reduce the gastrointestinal side effects. 
While gastrointestinal bleeding is possible, it is very unlikely at this low dose. 
Patients will be provided a list of medications containing salicylic acid so they do not take any in addition to 
the low dose aspirin.
12. Data and Safety Monitoring Plan: Include an appropriate Data and Safety Monitoring Plan (DSMP) based on 
the investigator’s risk assessment stated below. (Note: the HIC will make the final determination of the risk to 
subjects.)
a. 
What is the investigator’s assessment of the overall risk level for subjects participating in this 
study? Greater than minimal risk 
b.
If children are involved, what is the investigator’s assessment of the overall risk level for the 
children participating in this study? N/A
c.
Include an appropriate Data and Safety Monitoring Plan:
Greater Than Minimal Risk DSMP
1. Personnel responsible for the safety review and its frequency:
The principal investigator will be responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews at the specified frequency, which will be conducted 
every 6 months. The first DSMB is scheduled for May 2021. During the review process, the 
principal investigator (monitor) will evaluate whether the study should continue unchanged, 
require modification/amendment, or close to enrollment. 
An independent data safety monitoring board will be constructed, consisting of three members 
outside of Yale University who are not co-investigators on the trial. Two of these members will be 
obstetricians and one a biostatistician. 
Either the principal investigator or the IRB have the authority to stop or suspend the study or 
require modifications.
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2. The risks associated with the current study are deemed greater than minimal for the following 
reasons: 
1.
We do not view the risks associated with the experimental arm as minimal risks.
Although we have assessed the proposed study as one of greater than minimal risk, the potential 
exists for anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is 
not possible to predict with certainty the absolute risk in any given individual or in advance of first-
hand experience with the proposed study methods. Therefore, we provide a plan for monitoring 
the data and safety of the proposed study as follows:
3. Attribution of Adverse Events:
Adverse events will be monitored for each subject participating in the study and attributed to the 
study procedures / design by the principal investigator and Victoria Greenberg, MD according to 
the following categories:
a.) Definite: Adverse event is clearly related to investigational procedures(s)/agent(s).
b.) Probable: Adverse event is likely related to investigational procedures(s)/agent(s).
c.) Possible: Adverse event may be related to investigational procedures(s)/agent(s).
d.) Unlikely: Adverse event is likely not to be related to the investigational procedures(s)/agent(s).
e.) Unrelated: Adverse event is clearly not related to investigational procedures(s)/agent(s).
4. Plan for Grading Adverse Events:
The following scale will be used in grading the severity of adverse events noted during the study:
1.
Mild adverse event
2.
Moderate adverse event
3.
Severe 
5. Plan for Determining Seriousness of Adverse Events:
Serious Adverse Events:
In addition to grading the adverse event, the PI will determine whether the adverse event meets 
the criteria for a Serious Adverse Event (SAE).  An adverse event is considered serious if it results in 
any of the following outcomes:
1.
Death;
2.
A life-threatening experience in-patient hospitalization or prolongation of existing 
hospitalization; 
3.
A persistent or significant disability or incapacity; 
4.
A congenital anomaly or birth defect; OR
5.
Any other adverse event that, based upon appropriate medical judgment, may jeopardize 
the subject’s health and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. 
An adverse event may be graded as severe but still not meet the criteria for a Serious Adverse 
Event.  Similarly, an adverse event may be graded as moderate but still meet the criteria for an 
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SAE.  It is important for the PI to consider the grade of the event as well as its “seriousness” when 
determining whether reporting to the IRB is necessary.
6. Plan for reporting UPIRSOs (including Adverse Events) to the IRB
The principal investigator will report the following types of events to the IRB: 
Any incident, experience or outcome that meets ALL 3 of the following criteria:
1.
Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the research 
procedures described in the protocol-related documents, such as the IRB-approved protocol and 
informed consent document and (b) the characteristics of the subject population being studied; 
AND 
2.
Is related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); AND
3.
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, legal, or social harm) than was previously known or recognized.
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) may be medical or non-
medical in nature, and include – but are not limited to – serious, unexpected, and related adverse 
events and unanticipated adverse device effects.  Please note that adverse events are reportable 
to the IRB as UPIRSOs only if they meet all 3 criteria listed above.
These UPIRSOs/SAEs will be reported to the IRB in accordance with IRB Policy 710, using the 
appropriate forms found on the website. All related events involving risk but not meeting the 
prompt reporting requirements described in IRB Policy 710 should be reported to the IRB in 
summary form at the time of continuing review. If appropriate, such summary may be a simple 
brief statement that events have occurred at the expected frequency and level of severity as 
previously documented.  In lieu of a summary of external events, a current DSMB report can be 
submitted for research studies that are subject to oversight by a DSMB (or other monitoring entity 
that is monitoring the study on behalf of an industry sponsor).
7. Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol’s 
research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and Safety Monitoring 
Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study sponsors, funding and 
regulatory agencies, and regulatory and decision-making bodies.
For the current study, the following individuals, funding, and/or regulatory agencies will be 
notified:
•
All Co-Investigators listed on the protocol.
•
Yale IRB
•
Independent Data Safety Monitoring Board 
•
Yale Investigational Drug Services 
•
National Institutes of Health
The principal investigator and Victoria Greenberg, MD will conduct a review of all adverse events 
upon completion of every study subject. The principal investigator and Victoria Greenberg, MD will 
evaluate the frequency and severity of the adverse events and determine if modifications to the 
protocol or consent form are required.
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A P P R O V E D B Y T H E Y A L E U NI V E R SI T Y I R B 1 2/ 8/ 2 0 2 1
Pa ge 1 4  of 2 3
d. F or m ulti-sit e st u di es f or w hic h t h e Y al e PI s erv es as t h e l e a d i nv esti g at or: N/ A
1 3. St atistic al C o nsi d er ati o ns:
St atistic al C o nsi d er ati o ns:  D escri b e t h e st atistic al a n alys es t h at s u p p ort t h e st u dy d esi g n. 
O ur s a m pl e siz e c alc ul ati o n is b as e d o n a s ec o n d ary a n alysis of a M at er n al- F et al M e dici n e U nits ( M F M U) 
r a n d o miz e d c o ntr oll e d tri al a n d o ur o w n r etr os p ectiv e a n alysis of Y N H H d at a. T h e s ec o n d ary a n alysis a n alyz e d 
a s u bs et of w o m e n wit h st a g e 1 hy p ert e nsi o n r a n d o miz e d t o as piri n 6 0 m g d aily v ers us pl ac e b o. I n t his st u dy, 
t h e i nci d e nc e of st a g e 1 hy p ert e nsi o n w as 1 9 %. T h e i nci d e nc e of pr e ecl a m psi a i n w o m e n wit h st a g e 1 
hy p ert e nsi o n w as 3 9 % i n t ot al. T h er e w as a 4 0 % d ecr e as e i n r el ativ e risk of d ev el o pi n g pr e ecl a m psi a i n w o m e n 
w h o t o ok as piri n 6 0 m g d aily v ers us pl ac e b o. 
A r etr os p ectiv e c o h ort st u dy d o n e at Y N H H f o u n d a 2 9 % i nci d e nc e of hy p ert e nsiv e dis or d ers of pr e g n a ncy i n 
w o m e n wit h st a g e 1 hy p ert e nsi o n. W e a ntici p at e a 4 0 % risk r e d ucti o n i n t h e pr ev al e nc e of pr e ecl a m psi a fr o m 
2 9 % i n t h e pl ac e b o gr o u p t o 1 8 % i n t h e as piri n gr o u p. T o d et ect t his diff er e nc e wit h a p o w er of 8 0 % a n d  
0. 0 5, w e will n e e d t o r a n d o miz e a t ot al of 4 6 6 w o m e n wit h el ev at e d bl o o d pr ess ur e or st a g e 1 hy p ert e nsi o n, 
2 3 3 i n e ac h of t h e as piri n a n d pl ac e b o ar ms.
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SECTION II: RESEARCH INVOLVING DRUGS, BIOLOGICS, RADIOTRACERS, PLACEBOS AND DEVICES
If this section (or one of its parts, A or B) is not applicable, check off N/A and delete the rest of the section.
A.  RADIOTRACERS
☒N/A
B.  DRUGS/BIOLOGICS    ☐N/A
1.
If an exemption from IND filing requirements is sought for a clinical investigation of a drug product that is 
lawfully marketed in the United States, review the following categories and complete the category that 
applies (and delete the inapplicable categories):
Exempt Category 1: The clinical investigation of a drug product that is lawfully marketed in the United States 
can be exempt from IND regulations if all of the following are yes: 
1.
The intention of the investigation is NOT to report to the FDA as a well-controlled study in support 
of a new indication for use or to be used to support any other significant change in the labeling for 
the drug.
☒
2.
The drug that is undergoing investigation is lawfully marketed as a prescription drug product, and 
the intention of the investigation is NOT to support a significant change in the advertising for the 
product.
☒
3.
The investigation does NOT involve a route of administration or dosage level or use in populations 
or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with the use of the drug product
☒
2.
The investigation will be conducted in compliance with the requirements for institutional (HIC) 
review and with the requirements for informed consent of the FDA regulations (21 CFR Part 50 and 
21 CFR Part 56).
☒
3.
The investigation will be conducted in compliance with the requirements regarding promotion and 
charging for investigational drugs.
☒
2. 
Background Information: Provide a description of previous human use, known risks, and data addressing 
dosage(s), interval(s), route(s) of administration, and any other factors that might influence risks. If this is the first 
time this drug is being administered to humans, include relevant data on animal models. 
Low-dose aspirin is safe for use in pregnancy. Multiple large cohort and case-control studies have not 
found an association with congenital defects, structural, or developmental anomalies in the fetus. Several 
randomized controlled trials including thousands of women have demonstrated no increase in adverse fetal 
outcomes in doses less than 150mg per day.1,3,6  A meta-analysis of 22 studies women demonstrated no increase in 
birth defects.4Use in the third trimester does not cause premature closure of the ductus arteriosus.7 
Maternal use is safe without an increased risk of bleeding. There is no increased risk of gastrointestinal 
bleeding, placental abruption, epidural hematoma, and postpartum hemorrhage.1 This was determined by several 
meta-analyses including over 20,000 pregnant women. 2
Low dose aspirin is recommended for use during pregnancy to reduce risk of developing preeclampsia in 
women with at least one high risk factor or at least two moderate risk factors for developing preeclampsia. This 
management plan is recommended by numerous sources, including the United States Preventive Task Forces and 
the American College of Obstetricians and Gynecologists.5 Aspirin will not be withheld from women who have 
indications for aspirin prophylaxis in pregnancy.
References:
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1.
CLASP Collaborative Group (1994). CLASP: a randomized trial of low-dose aspirin for the 
prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet, 
343(8898):619-629
2.
Duley L, Henderson-Smart DJ, Meher S, & King JF (2007). Antiplatelet agents for preventing 
pre-eclampsia and its complications. Cochrane Database Systematic Review. 
3.
Golding J (1998). A randomized trial of low dose aspirin for primiparae in pregnancy: the 
Jamaica low dose aspirin study. British Journal of Obstetrics and Gynecology, 105:293-299
4.
Kozer E et al (2002). Aspirin consumption during the first trimester of pregnancy and 
congenital anomalies: a meta-analysis. American Journal of Obstetrics and Gynecology, 
187(6): 1623-1630
5.
LeFevre ML, U.S. Preventive Services Task Force (2014). Low-dose aspirin use for the 
prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task 
Force recommendation statement. Annals of Internal Medicine, 161(11):819-826
6.
Pattison NS et al (2000). Does aspirin have a role in improving pregnancy outcome for 
women with the antiphoshoplipid syndrome? A randomized controlled trial. American 
Journal of Obstetrics and Gynecology, 183:1008-1012
7.
Grab D, Paulus WE, Erdmann M, Terinde R, Oberhoffer R, Lang D, et al (2000). Effects of 
low-dose aspirin on uterine and fetal blood flow during pregnancy: results of a randomized, 
placebo-controlled, double-blind trial. Ultrasound in Obstetrics and Gynecology, 15: 19-27
3. 
Source:  Identify the source of the drug or biologic to be used. Write here
Yale Investigational Drug Services will provide both the low dose aspirin and placebo. 
a)
Is the drug provided free of charge to subjects? ☒YES 
☐NO 
If yes, by whom? Study investigator in conjunction with Yale Investigation Drug Services 
1.
Storage, Preparation and Use: Describe the method of storage, preparation, stability information, and for 
parenteral products, method of sterilization and method of testing sterility and pyrogenicity.
 Drug accountability:
Storage:

Aspirin is kept stored at room temperature (20-25 degrees Celsius). Study medications will be compounded 
by the Yale IDS. A weekly supply of pre-bottled medications will be stored at the Maternal-Fetal Medicine 
office located at 1 Long Wharf Drive, 2nd Floor, New Haven, CT. Temperature will be monitored 
continuously utilizing a NIST-approved temperature monitoring system. Patients will be dispensed once 
daily aspirin or placebo tablets monthly by our unblinded staff member Lauren Perley in accordance with 
the randomization scheme shared between herself and Yale IDS staff.

Aspirin and placebo are individually encapsulated and packaged into childproof IDS bottles
Preparation: 

Study medication and placebo will be compounded and encapsulated by the Yale IDS 

Aspirin tablets will contain aspirin only and be encapsulated in cellulose

Placebo will be cellulose only 

Aspirin and placebo tablets will be identical, as the aspirin will be encapsulated in cellulose to appear 
identical to the placebo tablets 
Stability: 

Aspirin and placebo are stable at room temperature 

The aspirin and placebo tablets expire after 6 months. These expiration dates are clearly labeled and 
discussed with the patient. 
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
Unused study medication is collected at the completion of the study (after delivery of their baby) and 
returned to IDS
Check applicable Investigational Drug Service utilized:
    ☒  YNHH IDS                                                        ☐  CMHC Pharmacy                                           ☐ West Haven VA
    ☐  PET Center                                                      ☐    None      
    ☐  Other: 
Note: If the YNHH IDS (or comparable service at CMHC or WHVA) will not be utilized, explain in detail how the PI 
will oversee these aspects of drug accountability, storage, and preparation.  
2.
Use of Placebo: 
☐Not applicable to this research project
If use of a placebo is planned, provide a justification which addresses the following:
a)
Describe the safety and efficacy of other available therapies. If there are no other available therapies, state 
this. 
No other available therapies.  
b)
State the maximum total length of time a participant may receive placebo while on the study. 
Total length is from randomization until delivery (maximum 36 weeks). Aspirin will not be withheld from 
patients that would have otherwise received it as part of the standard of care were they not in this study.  
Women with any single high-risk factor or 2+ moderate risk factors will be offered aspirin as part of their 
clinical care and are not included in this study; this study only enrolls women with elevated blood pressure or 
stage 1 hypertension +/- only one other moderate risk factor.
c)
Address the greatest potential harm that may come to a participant as a result of receiving placebo. 
Greatest harm would be hypersensitivity to any included ingredient in the placebo
d)
Describe the procedures that are in place to safeguard participants receiving placebo. 
Use of Yale IDS for preparation of placebo
Data Safety Monitoring Committee will review both the aspirin and placebo arms for any adverse events
3.
Continuation of Drug Therapy After Study Closure   ☒Not applicable to this project
Are subjects provided the opportunity to continue to receive the study drug(s) after the study has ended?
☐ Yes   If yes, describe the conditions under which continued access to study drug(s) may apply as well as 
conditions for termination of such access.  Write here
☒ NO   If no, explain why this is acceptable. 
Use of low dose aspirin is beneficial during pregnancy to reduce the risk of preeclampsia. The American College of 
Obstetricians and Gynecologists does not currently endorse postpartum use. 
 B.  DEVICES
 ☒N/A
SECTION III: RECRUITMENT/CONSENT AND ASSENT PROCEDURES 
1. Targeted Enrollment: Give the number of subjects: 
a.
Targeted for enrollment at Yale for this protocol: 466
b.
If this is a multi-site study, give the total number of subjects targeted across all sites: N/A
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2.
Indicate recruitment methods below.  Attach copies of any recruitment materials that will be used.
☐Flyers
☐ Internet/web postings
☐ Radio
☒ Posters
☐ Mass email solicitation
☐ Telephone
☐ Letter
☐ Departmental/Center website
☐ Television
☒ Medical record review* 
☐ Departmental/Center research boards
☐ Newspaper
☐ Departmental/Center newsletters
☐ Web-based clinical trial registries
☒ Clinicaltrails.gov 
☐ YCCI Recruitment database
☐ Social Media (Twitter/Facebook): 
☐ Other: 
* Requests for medical records should be made through JDAT as described at 
http://medicine.yale.edu/ycci/oncore/availableservices/datarequests/datarequests.aspx
3.  Recruitment Procedures: 
a. Describe how potential subjects will be identified. 
Subjects will be identified through routine prenatal visits at Yale-associated OBGYN offices (maternal-fetal 
medicine office, Women’s Center, Yale Health Plan, and private obstetric offices that deliver at YNHH). Blood 
pressures will be observed for the year preceding pregnancy and up to 20 weeks gestation through chart 
review. 
b. Describe how potential subjects are contacted. 
Subjects will be contacted in person during the time of a routine prenatal visit.
c. Who is recruiting potential subjects? 
All research staff personnel. Potential subjects may also be referred to research staff by clinical staff at the 
above-mentioned clinic locations.
4. Assessment of Current Health Provider Relationship for HIPAA Consideration:
Does the Investigator or any member of the research team have a direct existing clinical relationship with any 
potential subject? 
☐Yes, all subjects
☒Yes, some of the subjects
☐No
If yes, describe the nature of this relationship. 
Primary investigator may be the physician in charge of care for a subset of these women, if they are recruited 
from the maternal-fetal medicine office or present to labor and delivery at Yale’s York Street campus. 
5. Request for waiver of HIPAA authorization: (When requesting a waiver of HIPAA Authorization for either the 
entire study, or for recruitment purposes only.  Note: if you are collecting PHI as part of a phone or email 
screen, you must request a HIPAA waiver for recruitment purposes.)
Choose one: 
☐ For entire study 
☒ For recruitment/screening purposes only
☐ For inclusion of non-English speaking subject if short form is being used and there is no translated HIPAA 
research authorization form available on the University’s HIPAA website at hipaa.yale.edu.
i.
Describe why it would be impracticable to obtain the subject’s authorization for use/disclosure of this 
data: We will need to review the potential subject’s medical record prior to approaching her about the 
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study in order to confirm that she is medically eligible. It is impractical to approach patients about the 
study if they are not medically eligible, given the time involved in approaching patients and the volume 
of patients seen at the clinics. Once we have determined initial medical eligibility, we will then screen 
those patients in-person to confirm all eligibility criteria has been met.
ii.
If requesting a waiver of signed authorization, describe why it would be impracticable to obtain the 
subject’s signed authorization for use/disclosure of this data: N/A
The investigator assures that the protected health information for which a Waiver of Authorization has been 
requested will not be reused or disclosed to any person or entity other than those listed in this application, except 
as required by law, for authorized oversight of this research study, or as specifically approved for use in another 
study by an IRB.
Researchers are reminded that unauthorized disclosures of PHI to individuals outside of the Yale HIPAA-Covered 
entity must be accounted for in the “accounting for disclosures log”, by subject name, purpose, date, recipients, 
and a description of information provided.  Logs are to be forwarded to the Deputy HIPAA Privacy Officer.
6.
Process of Consent/Assent: Describe the setting and conditions under which consent/assent will be obtained, 
including parental permission or surrogate permission and the steps taken to ensure subjects’ independent 
decision-making. 
The entire consent form will be reviewed with interested women who meet study inclusion criteria and do not 
have any exclusion criteria. The consent form will be summarized verbally by research staff personnel, with 
time for questions at each section of the consent form. Women will then be asked to read the consent form. 
Any questions or concerns will be reviewed. Women ages 18+ will be enrolled, so parental permission is not 
required. Women will only be included if they are English or Spanish-speaking. If another person is with the 
woman during her routine prenatal visit, she will be asked if she would like to discuss the study on her own or 
together with the accompanying person or people.
The consent form has been translated into Spanish by the Yale Center for Clinical Investigation’s translation 
services. Spanish-speaking patients will be consented by utilizing Yale language services. 
7.
Evaluation of Subject(s) Capacity to Provide Informed Consent/Assent: Indicate how the personnel obtaining 
consent will assess the potential subject’s ability and capacity to consent to the research being proposed. 
Women will be assumed to have capacity to provide informed consent for research unless there is indication to 
the contrary. These indications include: known cognitive impairment, altered mental status, difficulties in 
communication observed during research staff interaction, psychotic symptoms, bizarre behavior. Women 
with these indications will not be included in the research study. If any of these symptoms or behaviors are 
new, their medical provider will be informed immediately for further assessment.
8.
Non-English Speaking Subjects: Explain provisions in place to ensure comprehension for research involving 
non-English speaking subjects. If enrollment of these subjects is anticipated, translated copies of all consent 
materials must be submitted for approval prior to use. 
Spanish speakers will be included. The consent form has been translated by the Yale Center for Clinical 
Investigation’s official translation services. Spanish speaking participants will be counseled utilizing Yale 
language services for all discussions and study visits.
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As a limited alternative to the above requirement, will you use the short form* for consenting process if you 
unexpectedly encounter a non-English speaking individual interested in study participation and the translation of 
the long form is not possible prior to intended enrollment?  YES ☐  NO ☒
Note* If more than 2 study participants are enrolled using a short form translated into the same language, then 
the full consent form should be translated into that language for use the next time a subject speaking that 
language is to be enrolled.
Several translated short form templates are available on the HRPP website (yale.edu/hrpp) and translated HIPAA 
Research Authorization Forms are available on the HIPAA website (hipaa.yale.edu). If the translation of the short 
form is not available on our website, then the translated short form needs to be submitted to the IRB office for 
approval via modification prior to enrolling the subject.   Please review the guidance and presentation on use of 
the short form available on the HRPP website.
If using a short form without a translated HIPAA Research Authorization Form, please request a HIPAA waiver in 
the section above. 
9.
Consent Waiver: In certain circumstances, the HIC may grant a waiver of signed consent, or a full waiver 
of consent, depending on the study. If you will request either a waiver of consent, or a waiver of signed consent 
for this study, complete the appropriate section below.  
☒Not Requesting any consent waivers 
 
SECTION IV: PROTECTION OF RESEARCH SUBJECTS
    Confidentiality & Security of Data:
1.
What protected health information (medical information along with the HIPAA identifiers) about subjects will 
be collected and used for the research?   
•
Past medical and surgical history, allergies, family history 
•
Medication list
•
The rest of the participant’s medical record held by Yale New Haven Health created from the start of 
pregnancy and up to 1 year after delivery 
•
Records about phone calls made as part of this research
•
Records about study visits
•
Information obtained during this research regarding

Vital signs, in including blood pressure 

Physical exams

Laboratory, x-ray, and other test results

Diaries and questionnaires

The diagnosis and treatment of any physical or mental health condition

Records about any study drug received
•
Neonatal and infant records until 1 year of age 
o
Information obtained during this research regarding

Birthweight

Apgar scores

Delivery records

Laboratory, x-ray, and other test results
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
Diagnosis and treatment of any physical or mental health condition

Outpatient, emergency department, and hospital visits/admissions until 1 year of age
2.
How will the research data be collected, recorded and stored? 
Data will be collected from the patients’ medical records (including the medical record of their 
baby) and from self-report. It will be recorded/stored in REDCap, OnCore and on a Yale server accessible only to 
members of the research team. This server is on a secure, encrypted hospital-issued computer.
3.
How will the digital data be stored? ☐CD  ☐DVD  ☐Flash Drive  ☐Portable Hard Drive   ☒Secured Server  ☐
Laptop Computer  ☒Desktop Computer  ☐Other
4.
What methods and procedures will be used to safeguard the confidentiality and security of the identifiable 
study data and the storage media indicated above during and after the subject’s participation in the study? 
All subjects will be assigned a unique study ID code upon enrollment. Documents linking the 
patient to their ID code will be kept on a Yale server accessible only to members of the research team. This server 
is on a secure, encrypted hospital-issued computer. All data will be de-identified at the conclusion of chart 
review. Data analysts will have access to only de-identified information. Patient consent forms and chart 
abstraction forms will be kept in a locked cabinet in a locked research office at the Yale Maternal-Fetal Medicine 
office. This locked cabinet may only be accessed by research personnel. 
All portable devices must contain encryption software, per University Policy 5100.  If there is a technical reason a 
device cannot be encrypted please submit an exception request to the Information Security, Policy and Compliance 
Office by clicking on url http://its.yale.edu/egrc or email it.compliance@yale.edu
5.
What will be done with the data when the research is completed? Are there plans to destroy the identifiable 
data? If yes, describe how, by whom and when identifiers will be destroyed. If no, describe how the data and/or 
identifiers will be secured. 
Data will remain on an encrypted server through Yale University. If research personnel leave the 
university, data will not travel with them. 
6.
If appropriate, has a Certificate of Confidentiality been obtained? 
N/A
SECTION V: POTENTIAL BENEFITS
Potential Benefits: Identify any benefits that may be reasonably expected to result from the research, either to 
the subject(s) or to society at large. (Payment of subjects is not considered a benefit in this context of the risk 
benefit assessment.) 
There may be reduction in rates of hypertensive disorders of pregnancy (gestational hypertension, 
preeclampsia, HELLP syndrome, eclampsia) both to study participants and future pregnant women with elevated 
BP and stage 1 hypertension. 
         SECTION VI: RESEARCH ALTERNATIVES AND ECONOMIC CONSIDERATIONS
1.
Alternatives: What other alternatives are available to the study subjects outside of the research? 
If women do not want to participate in the study, they will continue routine prenatal care. 
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2.
Payments for Participation (Economic Considerations): Describe any payments that will be made to subjects, 
the amount and schedule of payments, and the conditions for receiving this compensation.
N/A
3.
Costs for Participation (Economic Considerations): Clearly describe the subject’s costs associated with 
participation in the research, and the interventions or procedures of the study that will be provided at no cost 
to subjects. 
There are no costs to study participants. Study medications (whether low dose aspirin or placebo)
will be provided at no cost. No further interventions or procedures will be required.
4.
In Case of Injury: This section is required for any research involving more than minimal risk, and for minimal 
risk research that presents the potential for physical harm (e.g., research involving blood draws).
a.
Will medical treatment be available if research-related injury occurs? 
Medical treatment will not be available from research staff.
b.
Where and from whom may treatment be obtained? 
Medical treatment will be through the participant’s usual provider, emergency room, and 
any other health professionals as needed. 
c.
Are there any limits to the treatment being provided? 
No.
d.
Who will pay for this treatment? 
Insurance will be billed for any treatment and the participants will be responsible for any 
co-pays required by the insurance company for standard treatment.
 
e.
How will the medical treatment be accessed by subjects? 
If needed, medical treatment will be sought through usual avenues—either through the 
patient’s usual healthcare provider (whether obstetrician or primary care physician) or emergency 
department. Participants will be asked to report any side effects of study medication (whether 
aspirin or placebo). If any side effects are reported, research personnel will encourage and help set 
up medical diagnosis and treatment services. 
During the study visits (whether conducted in person or by telephone), we will ask women 
questions about their blood pressure and symptoms of preeclampsia. If any study participant 
notes onset of preeclampsia symptoms (headache, vision changes, right upper quadrant pain, 
and/or dyspnea) or new onset of systolic blood pressure 140 mm Hg and/or diastolic blood 
pressure  90 mm Hg, she will be asked to contact her primary obstetrician immediately. 
IMPORTANT REMINDERS
Will this study have a billable service?  Yes ☒ 
 No☐
A billable service is defined as any service rendered to a study subject that, if he/she was not on a study, would 
normally generate a bill from either Yale-New Haven Hospital or Yale Medical Group to the patient or the patient’s 
insurer. The service may or may not be performed by the research staff on your study, but may be provided by 
professionals within either Yale-New Haven Hospital or Yale Medical Group (examples include x-rays, MRIs, CT 
scans, specimens sent to central labs, or specimens sent to pathology). Notes: 1. There is no distinction made 
whether the service is paid for by the subject or their insurance (Standard of Care) or by the study’s funding 
mechanism (Research Sponsored). 2. This generally includes new services or orders placed in EPIC for research 
subjects. 
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If answered, “yes”, this study will need to be set up in OnCore, Yale’s clinical research management system, for 
Epic to appropriately route research related charges. Please contact oncore.support@yale.edu
Are there any procedures involved in this protocol that will be performed at YNHH or one of its affiliated entities?  
Yes ☒  No ☐ 
If Yes, please answer questions a through c and note instructions below.  
a. Does your YNHH privilege delineation currently include the specific procedure that you will perform? Yes ☒  No 
☐
b. Will you be using any new equipment or equipment that you have not used in the past for this procedure? Yes 
☐  No ☒
c. Will a novel approach using existing equipment be applied? Yes ☐  No ☒
 
If you answered “no” to question 4a, or "yes" to question 4b or c, please contact the YNHH Department of 
Physician Services (688-2615) for prior approval before commencing with your research protocol.
IMPORTANT REMINDER ABOUT RESEARCH AT YNHH 
Please note that if this protocol includes Yale-New Haven Hospital patients, including patients at the HRU, the 
Principal Investigator and any co-investigators who are physicians or mid-level practitioners (includes PAs, APRNs, 
psychologists and speech pathologists) who may have direct patient contact with patients on YNHH premises 
must have medical staff appointment and appropriate clinical privileges at YNHH. If you are uncertain whether 
the study personnel meet the criteria, please telephone the Physician Services Department at 203-688-2615. By 
submitting this protocol as a PI, you attest that you and any co-investigator who may have patient contact has a 
medical staff appointment and appropriate clinical privileges at YNHH.
APPROVED BY THE YALE UNIVERSITY IRB 12/8/2021