Effectiveness of Higher Aspirin Dosing for Prevention of Preeclampsia in High Risk Obese Gravida: An Open Label, Comparative Effectiveness, Randomized Controlled Trial (ASPREO Trial)
Phase: PHASE2
Conditions: Pre-Eclampsia, Hypertension in Pregnancy, Obesity
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
Effectiveness of Higher Aspirin Dosing for Prevention of Preeclampsia in High Risk Obese 
Gravida: An open label, comparative effectiveness RCT (ASPREO Trial) 
 
NCT03961360 
 
Version Date: 03/08/2024 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
Effectiveness of Higher Aspirin Dosing for Prevention of 
Preeclampsia in High Risk Obese Gravida: An open label, 
comparative effectiveness RCT (ASPREO Trial) 
 
 
 
 
 
 
Study Protocol 
 
 
 
 
 
Principal Investigator: Farah Amro, M.D. 
 
 
Co- Investigators: Conisha Holloman , M.D., Claudia Pedroza PhD , Baha Sibai, 
M.D. 
 
 
Division of Maternal-Fetal Medicine 
Department of Obstetrics, Gynecology and Reproductive Sciences 
The University of Texas Health Science Center at Houston 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
1. BACKGROUND AND SIGNIFICANCE 
Hypertensive diseases of pregnancy complicate around 10% of pregnancies. 
Preeclampsia is a pregnancy related hypertensive disorder. In the US during the 
past two decades the incidence of preeclampsia has increased by 25%. 1The 
diagnosis of preeclampsia impacts the gestational age at delivery, with those with 
preeclampsia with severe features being delivered by 34 weeks gestational age, and 
those without being delivered by 37 weeks gestational age.2 Preeclampsia is a major 
contributor to prematurity. Perinatal mortality is higher in infants of preeclamptic 
women regardless of gestational age at delivery. 3Causes are hypothesized as 
placental insufficiency and placental abruption, which in turn cause either 
intrauterine fetal demise, or early delivery. Preeclampsia may also cause serious 
maternal adverse effects including: eclampsia (seizures), posterior reversible 
encephalopathy syndrome, placental abruption leading to disseminated intravascular 
coagulopathy amongst other maternal adverse outcomes. It is also associated with 
long term maternal health consequences, including long-term cardiovascular 
disease risk. 2 
Low dose aspirin was initially reported as having a beneficial effect at preeclampsia 
prevention in a case in 1978.4 Since then there have been large randomized 
controlled trials with conflicting results regarding effectiveness of aspirin for 
preeclampsia prevention, and the optimal dosing. (table 1) 
 
 
 
Table 1: Placebo based randomized trials of ASA ≤100mg for preeclampsia 
prophylaxis 
 
Study 
Location 
Year 
N 
Gestational 
Age At 
Enrollment 
Comparison 
Preeclampsia Outcome 
Wallenburg 
60mg ASA 
Preeclampsia occurred in 30% 
(placebo) vs 0% (ASA), p<0.01. 
et al 
Netherlands 
19865 
46 
28 weeks 
McParland 
et al 
UK 
148 
24 weeks 
75mg ASA 
Preeclampsia occurred in 25% 
(placebo) vs 13% (ASA), not 
19906 
significant. 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
CLASP7 
Multicenter 
1994 
6927 12 -32 
weeks 
60 mg ASA 
A nonsignificant reduction of 
12% in rate of developing 
proteinuric pre-eclampsia. 
ECPPA 8 
Brazil 
1996 
1009 12 – 32 
weeks 
60 mg ASA 
No significant difference in rate 
of preE in both groups. 
 
Rationale for a clinical trial 
Evidence suggests that in preeclamptic patients there is a imbalance in the prostacyclin 
/thromboxane balance favoring thromboxane. Thromboxane is a vasoconstrictor while 
prostacyclin is a vasodilator.9 The pathophysiology of action of aspirin for preeclampsia 
prophylaxis is believed to be due to its preferential inhibition of COX-1 at low doses (60- 
150mg/day)10. 
The American College of Obstetrics and Gynecology in July 2018, published a 
committee opinion supporting the USPSTF guideline criteria for the use of low dose 
aspirin for preeclampsia prophylaxis. The recommended dose is 81mg/day of aspirin, 
and it is to be used in women at high risk for preeclampsia. Women were considered to 
be at high risk if they had at least a 8% incidence of preeclampsia (table 2). The 
initiation of aspirin was to be done at 12-28 weeks gestation, optimally prior to 16 weeks 
gestational age. 10 
Table 2: ACOG recommendations for low dose aspirin (LDA) use for preeclampsia 
prophylaxis 
 
Risk Level 
Risk Factors 
Recommendations 
High 
History of preeclampsia 
LDA if ≥ 1 Risk Factor 
Type 1 or 2 Diabetes 
Chronic Hypertension 
Multifetal Gestation 
Renal Disease 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
Autoimmune Disease (SLE, 
APLS) 
Medium 
BMI ≥ 30 
LDA if > 1 Risk Factor 
Nulliparity 
Fam. Hx of preE (mother or 
sister) 
Sociodemographic 
characteristics (AAF, low SES) 
Age ≥ 35 
Personal Hx factors (hx of SGA , 
prior adverse pregnancy 
outcomes) 
 
As illustrated in table 3 there have been multiple randomized controlled trials that 
support the use of higher aspirin doses for preeclampsia prophylaxis. A recent 
systematic review and metaanalysis of randomized controlled trials, evaluating a 
total of 14,668 patients noted that the incidence of preeclampsia depended on the 
gestational age at initiation of aspirin and the dosing of aspirin used. With a clinically 
significant decrease in rate of preterm preeclampsia noted when the aspirin dose is 
≥ 100 mg/day and when it is initiated at ≤ 16 weeks (table 4)11. 
 
 
Table 3: Randomized Trials with higher dose Aspirin for prevention of 
Preeclampsia 
 
Study 
Location 
Year 
Gestation 
al Age at 
enrollmen 
t 
N 
Comparison 
Preeclamps 
ia      
Outcomes 
Rolnik 
Multicenter 
Europe 
201712 
11-14 
weeks 
177 
6 
150mg ASA 
vs 
placebo 
Preterm 
preeclampsi 
a 4.3% in 
placebo 
group vs 
1.6% in ASA 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
group 
(p=0.0004) 
Yu 
Multicenter 
Internation 
al 
200313 
22-24 
weeks 
844 
150mg ASA 
vs 
placebo 
19% in 
placebo 
group vs 
19% in ASA 
group 
(p=0.6) 
Sureau 
Multicenter 
France 
199114 
15-18 
weeks 
229 
150mg ASA 
vs 
150mg ASA + dipyrimadole 225 
mg/day 
vs 
placebo 
No 
difference 
between 
groups. 
 
 
 
 
 
Table 4: Metaanalysis with Relative Risk of preterm Preeclampsia detailed by 
onset of treatment and dose of aspirin 
 
 
 
Dose 
Trials 
Participants 
Gestational 
Age 
RR (95% CI) 
P-value 
< 100 mg 
10 trials 
11,855 pts 
≤ 16 weeks 
0.59 (0.29- 
1.19) 
0.14 
> 16 weeks 
1.00 (0.80- 
1.25) 
0.99 
≥ 100 mg 
7 trials 
2,813 pts 
≤ 16 weeks 
0.33 (0.19- 
0.57) 
0.001 
> 16 weeks 
0.88 (0.54- 
1.43) 
0.60 
 
 
 
Aspirin resistance is a phenomenon that refers to the inability of aspirin to reduce the 
production of thromboxane A2. It is detected by laboratory tests that either measure 
directly the thromboxane A2 levels, or indirectly the platelet function that depends on 
platelet thromboxane production.15 A recent study evaluated aspirin resistance in 
pregnant patients, and noted that aspirin resistance was decreased as the dosing of 
aspirin increased. With a incidence of 30% , 10% and 5% of aspirin resistance at doses 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
of 81, 121 and 162mg respectively. 16 Moreover, data has emerged in other fields 
linking obesity, female gender, and poor glycemic control to aspirin resistance. 17 
At baseline, obesity is linked to a low grade inflammation state causing lipid 
peroxidation and in turn a persistent platelet activation, causing higher levels of 
thromboxane to be present in this population.18 Also, obesity is a established risk factor 
for preeclampsia. 2In a population-based cohort study including 503,179 nulliparous 
patients, obese patients had a fourfold increase in incidence of preeclampsia in 
comparison to those with a normal BMI.19 
A metaanalysis published in the lancet in 2018 highlighted the effects of the interaction 
between bodyweight and aspirin dose in reducing vascular events.20 This study 
concluded that patients with higher body weights need q higher aspirin dosage for 
secondary cardiovascular prevention. While other fields are also realizing the impact of 
bodyweight on aspirin effectiveness, we argue that this concept should be extended to 
our high risk obese patient population. A population which also inherently has a higher 
incidence of preeclampsia, higher baseline thromboxane levels, and may also have 
higher aspirin resistance. We thus propose that a “one dose fit all” approach may not 
be appropriate in this patient population. To our knowledge, at this time there are no 
randomized controlled trials that have compared aspirin 81mg and 162 mg in the 
pregnant obese patient population. 
Hypothesis 
 
We hypothesize that the administration of a higher dose of aspirin prophylaxis to a high 
risk obese population will result in a clinically significant decrease in rate of developing 
preeclampsia with severe features in comparison to the standard 81mg/day dose. 
 
2. RESEARCH DESIGN AND METHODS 
Objective 
To compare the incidence of preeclampsia with severe features in the 81mg/day 
aspirin group to the 162mg/day aspirin group. Maternal and neonatal outcomes 
will also be compared between the two groups. 
 
Population 
Obese pregnant women with a singleton gestation at less than 20 weeks and either a 
history of preeclampsia in a prior pregnancy or stage I hypertension or pre-gestational 
diabetes. 
Obese is defined as a BMI greater than 30 at time of the first prenatal visit. 
 
Intervention 
Aspirin at a dose of 162mg/day (ie two 81mg/day pills daily) to be started as early as 12 
weeks gestational age till time of delivery 
 
Control 
Women who receive the standard recommended 81 mg/day dosing of aspirin from as 
early as 12 weeks gestational age till time of delivery 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
Outcome (Primary) 
Incidence of preeclampsia 
Preeclampsia with severe features diagnosis will be abstracted from the medical 
charts. This will be used for the primary outcome. The diagnosis will then be 
adjudicated by three maternal fetal medicine specialists, to assess for compliance with 
ACOG established criteria.2 The adjudicated diagnosis will be used for the 
measurement of the secondary outcome. 
 
Other Secondary Outcomes 
- 
Maternal Outcomes 
o Incidence of preterm preeclampsia 
o Gestational Hypertension 
o Abruption 
o Eclampsia 
o HELLP syndrome 
o Postpartum Hemorrhage 
o Other maternal bleeding (?) 
o Need for blood transfusion 
- 
Neonatal Outcomes 
o Gestational age at delivery 
o Delivery at < 37 weeks 
o Apgar score at 5 min ≤ 5 
o Small for gestational age 
o NICU length of stay 
o Intraventricular Hemorrhage Grade III-IV 
o Bronchopulmonary Dysplasia 
o Necrotizing Enterocolitis 
Study Design 
Randomized controlled open-label comparative effectiveness trial. 
 
 
Inclusion Criteria 
- 
A singleton gestation at less than 20 weeks at time of enrollment, with a BMI 
greater than or equal to 30 and one of the following: 
 
1. History of preeclampsia in a prior pregnancy 
-Diagnosis will be obtained by review of records, and if unavailable then 
patient history. Preeclampsia diagnosis may be made in antepartum or 
postpartum period. 
OR 
2. At least stage I hypertension during pregnancy 
-Stage I hypertension is defined as a systolic blood pressure between 130- 
139 mm Hg or diastolic blood pressure between 80-89 mm Hg21 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
-This blood pressure criteria is met regardless of medication usage 
- The patient must have a blood pressure reading ≥ 130-139/80-89 mm Hg at least 
during 1 clinic visit during the current pregnancy; before or at time of enrollment 
 
OR 
 
3. Pre-gestational diabetes 
-Type 1 and Type 2 diabetics are included 
-Gestational diabetes mellitus diagnosed prior to 20 weeks gestational age 
will also be included 
 
 
Exclusion Criteria 
- 
Known allergy/prior adverse reaction/any medical condition where aspirin 
is contraindicated 
- 
Already on aspirin prior to pregnancy 
- 
Baseline renal Disease 
- 
Baseline Proteinurea identified at time of enrollment, defined as urine 
analysis with 3+ protein, or urine protein to creatinine ratio ≥ 0.3 
- 
Seizure disorder on medications 
- 
Known major fetal anomalies 
- 
Multifetal gestation 
Recruitment 
Patients will be recruited from the following locations: 
- 
Texas Medical center Ross Clinic in the UT Professional Building (Suite 350) 
- 
Texas Medical center High Risk OB Clinic in the UT Professional Building (Suite 
350) 
- 
UT Obstetrics office at Bellaire 
- 
Harris Health Obstetrics Clinic at LBJ Hospital 
Randomization 
Randomization will be achieved by computer-generated random sequences, using 
RedCap. Permuted block randomization will be performed. Women will be randomized 
to 81mg/day of aspirin or 162 mg/day of aspirin. 
 
 
Interventions and Procedures 
Women with singleton gestations that are less than twenty weeks gestational age and 
meet inclusion criteria will be approached by the research staff after the study is 
introduced by the patient’s provider. Written informed consent will be obtained from 
participating women at the outpatient clinic. If the patient consents, then randomization 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
will be performed. The results of randomization will be shared with the obstetric provider 
and the patient prior to starting aspirin. If the patient had already been started on 
81mg/day aspirin in a prior visit then she will be informed of whether she should 
continue with the same dose or if she would need a higher dose based on the 
randomization. 
After randomization, patients will then be prescribed the medication. Which will be 
started between 12 and 20 weeks gestational age and continued till time of delivery. 
The primary provider will dictate all other aspects of care. 
A medication adherence survey (Morisky medication adherence survey) will be performed 
to assess for compliance at 16-24 weeks of gestational age, and again at 32- 36 weeks 
gestational age. At the time of administration of medication adherence surveys, 
participants will be asked about medication side effects. 22-24 
Blood samples (3-4 cc) and urine samples (3-4 cc) will be obtained at the time of 
enrollment (with the routine blood tests that are sent), to test for baseline aspirin, 
thromboxane and prostacyclin levels. At the time of delivery, blood samples (3-4 cc) and 
urine samples (3-4 cc) (with routine blood samples that are sent at time of labor 
admission), placental 1x1 cm specimens and cord blood will be obtained. These samples 
will be used for biochemical correlation with the clinical data. 
The primary outcome (incidence of preeclampsia with severe features) will be 
determined based on clinician diagnosis, with the use of ACOG diagnostic criteria. 
Secondary outcomes will be determined by following the mother and the neonate 
clinically until the time of discharge. Patients will not be contacted after discharge from 
the hospital. 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
Allocated to ASA 162 mg 
N = 110 
Allocated to ASA 81mg 
N =110 
Exclusion criteria 
GA <20wk with BMI ≥ 30 
& (one of following) 
1. History of prior preeclampsia 
2. Stage I HTN 
3. Pregestational Diabetes 
 
Figure 1. Flow Diagram 
 
 
 
Sample Size and Feasibility 
An intent-to-treat principle will be applied to all analysis. To calculate Bayesian 
statistical power we assumed a baseline incidence of preeclampsia in our population to 
be 20%. We investigated effects sizes of 50%, 40%, and 30% reduction (corresponding 
relative risk [RR] of 0.5, 0.6, and 0.7). We also varied the level of certainty (probability 
threshold for declaring benefit) from 70% to 85%. For all scenarios, we assumed a 
neutral prior centered at RR of 1.0 with 95% credible interval of 0.33-3.0 (excludes 
implausible large treatment effects). Tables 5 and 6 present the power for two total 
sample sizes. We will use the number of patients required to detect a 40% reduction in 
incidence of preeclampsia with 75% certainty and power (1 – β) = 0.80 is 220 (110 
patients in each arm). 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
Table 5: Bayesian power for sample size N=290 using different levels of certainty 
Level of Certainty 
Assumed RR 
70% 
75% 
80% 
85% 
0.50 
0.97 
0.95 
0.93 
0.89 
0.60 
0.91 
0.88 
0.83 
0.76 
0.70 
0.80 
0.75 
0.68 
0.59 
 
 
Table 6: Bayesian power for sample size N=220 using different levels of certainty 
Level of Certainty 
Assumed RR 
70% 
75% 
80% 
85% 
0.50 
0.93 
0.9 
0.86 
0.81 
0.60 
0.84 
0.80 
0.74 
0.67 
0.70 
0.71 
0.66 
0.59 
0.5 
 
In the week of November 5-9 2018, 10 patients that attended the UT Women’s clinic 
and UT Bellaire Clinic, met inclusion criteria. Assuming a 50% enrollment rate, the study 
would take 12.5 months. 
Statistical Tests 
Selected baseline characteristics and outcome measures will be collected for each 
group. Descriptive statistics will be used to summarize all variables. An intent-to-treat 
analysis will be conducted. The rate of the primary outcome, preeclampsia, will be 
compared between the intervention and control group using a log binomial (or Poisson in 
case of nonconvergence) model to estimate relative risk and 95% confidence interval (CI). 
Each secondary outcome will be similarly analyzed using the best fitting generalized linear 
model with intervention group as the covariate. For all outcomes, we will report relative 
risks or differences and 95% CIs. 
We will also conduct a Bayesian analysis of the primary outcome to calculate 
probability of treatment benefit or harm. We will use a neutral prior distribution for the 
intervention effect that excludes implausible large treatment effects: Normal(0, SD=0.57) 
in the log RR scale (prior 95% interval for the RR of 0.33-3) 25. We will report posterior 
median and 95% credible interval and probability of treatment benefit. 
 
Subgroup Analysis. To investigate treatment effect modifier for the primary 
outcome, we will use a Bayesian hierarchical model with terms of interaction between 
treatment group (162 mg, 81 mg) and the prespecified potential moderator of BMI (30- 
40; >40). The conservative Bayesian approach of Dixon and Simon 26 allows us to specify 
a priori how likely (or unlikely) it is for subgroup differences to be present and to shrinkthe 
subgroup estimates to the overall mean treatment effect. A neutral prior will be used for 
the interaction term. Point estimates of treatment effect and 95% credible intervals will be 
reported along with probability of treatment benefit/harm. 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
3. SAFETY ASSESSMENT 
A. Maternal Risk 
According to a USPSTF report discussing low-dose aspirin use for the prevention of 
preeclampsia, there was no increased risk of placental abruption (RR: 1.17; CI, 0.93-1.48) 
in 11 trials (23,332 women). No increased risk of postpartum hemorrhage (RR: 1.02; CI 
0.96-1.09) in 9 trials (22,760 women) and no difference in mean blood loss (5 trials; 2,478 
women). 27 
In the EPREDA trial (150mg ASA administered) they noted no abnormal bleeding in 
mothers nor babies. 28 In the multicenter RCT done by Yu et al, with administration of 150 
mg ASA in comparison to placebo, no statistically significant differences in the rates of 
placental abruption (4% vs 2%, p=0.12), postpartum hemorrhage (25% vs 26%, p=0.67) 
and blood transfusions (2.5 vs 2.2%, p=0.81) were observed between the groups. 
 
B. Fetal Risk 
 
A review of 11 trials (which included 23,332 participants), noted no significant harm of 
perinatal death or abruption to those receiving aspirin in comparison to those that did 
not. Of the 10 trials reporting on neonatal intracranial hemorrhage, the fixed-affects 
pooled risk ratio was 0.84 (CI, 0.61 to 1.16). 29 In a cohort of 15,000 women that 
reported aspirin use in the first trimester, there was no increased risk of congenital 
malformations. 30 Furthermore, the use of low dose aspirin in the third trimester, has not 
been found to be associated with early ductal closure. 31 A 2007 cochrane meta- 
analysis which reviewed 10 trials (including 26, 148 infants) did not find an increased 
risk of neonatal intracranial hemorrhage, in relation to the use of low dose aspirin in the 
third trimester.32 
 
Management of Adverse Events 
Any adverse events will be reported to the Committee for the Protection of Human 
Subjects (CPHS). Because this study involves the use of aspirin at low doses there is no 
increased anticipation of severe adverse events. 
Procedures in the Event of Abnormal Clinical Findings 
In the event of an abnormal clinical finding, the health care provider caring for the 
participant will be notified to allow treatment in the usual clinical manner. 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
Institutional Review Board 
Before initiation of the study, the PI will obtain approval of the research protocol from the 
IRB. The study will be registered in www.clinicaltrials.gov as required by US law for public 
access. 
Specification of Safety Parameters 
The proposed trial is intended to evaluate the impact of different low doses of aspirin on 
rates of preeclampsia. Aspirin at the desired doses have been used safely during 
pregnancy. 
The PI, who will also determine the safety parameters, will carefully monitor patient safety. 
The PI or designee will notify the IRB of applicable events according to institutional 
guidelines. 
 
 
4. ETHICAL CONSIDERATIONS 
Informed Consent 
The study will be introduced to potentialsubjects from their care providers. Research staff will be 
present to answer any questions about the study. Both verbal and written subject consent will be 
obtained prior to the commencement of any study procedures. Consent will be obtained by a 
person fluent in their language, English or Spanish. A patient research authorization form (as 
required by the HIPAA Privacy Rule) will also be obtained in the same manner. A copy of the 
signed consent form and patient research authorization form will be provided to the patient and 
placed in the hospital EMR. 
All prospective study candidates will be given a full explanation of the consent form, allowed to 
read the approved form, and be provided the opportunity to ask any questions. Once all questions 
have been answered and the Investigator is assured that the individual understands the 
requirements of the study, the subject will be asked to sign the consent. The Investigator shall 
provide a copy of the signed and dated informed consent to the patient and the original shall be 
maintained in the patient’s study files. Patients who do not sign the consent form will not be 
permitted to participate in the study. 
Data Collection 
For this protocol, web data entry screens corresponding to the data collection forms will be 
entered electronically in the REDCap Database. 
Institutional Review Board 
Before initiation of the study, the PI will obtain approval of the research protocol and from the IRB. 
The study will be registered in www.clinicaltrials.gov as required by the US law for publicaccess. 
Subject Confidentiality 
A linking log will be created that will link patients with a patient number. Strict confidentiality of 
their patient data may be reviewed for study purposes by authorized individuals other than their 
treating physician. Patient, neonatal and delivery information will be recorded on datasheets that 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
will be stored in a locked file cabinet in the PI’s office, which is also locked. Information will be 
entered into a secured REDCap database that is password protected and maintained on a UT 
computer, which are password protected. 

IRB NUMBER: HSC-MS-18-1073 
IRB APPROVAL DATE: 03/08/2024 
 
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