Elevated Blood Pressure, Pre-Eclampsia, Stage 1 Hypertension
Conditions
Keywords
Aspirin
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.
Interventions
DRUGAspirin 81 mg
Participants randomized to 81 mg of Aspirin daily
DRUGPlacebo
Participants randomized to placebo daily
Sponsors
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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 criteria
* Chronic hypertension * Pre-gestational diabetes * Chronic renal disease \- 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 (diagnosis made by having 1 or more clinical criteria and 1 or more laboratory criteria) * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Development of Hypertensive Disorder | after 20 weeks gestation until 6 weeks postpartum | This measure is operationally defined as a yes/no response to the development of any hypertensive disorder of pregnancy (gestational hypertension, preeclampsia, eclampsia, or HELLP syndrome). This is defined by American College of Obstetricians and Gynecologists diagnostic criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Development of Preeclampsia | after 20 weeks gestation until 6 weeks postpartum | This measure is operationally defined as a yes/no response to the development of preeclampsia. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria. |
| Development of Preeclampsia- 37 Weeks | up to 37 weeks gestation | This measure is operationally defined as a yes/no response to the development of preeclampsia at less than 37 weeks of pregnancy. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria. |
| Development of Preeclampsia- 34 Weeks | up to 34 weeks gestation | This measure is operationally defined as a yes/no response to the development of preeclampsia at less than 34 weeks of pregnancy. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria. |
| Development of Eclampsia | after 20 weeks gestation until 6 weeks postpartum | This measure is operationally defined as a yes/no response to the development of eclampsia. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria. |
| Development of HELLP Syndrome | after 20 weeks gestation until 6 weeks postpartum | This measure is operationally defined as a yes/no response to the development of HELLP syndrome. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria. |
| Spontaneous Preterm Delivery | Up to 37 weeks | This measure is operationally defined as a yes/no response to a spontaneous preterm delivery up to 37 weeks of pregnancy. |
| Development of Gestational Hypertension | after 20 weeks gestation until 6 weeks postpartum | This measure is operationally defined as a yes/no response to the development of gestational hypertension. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria. |
| Birthweight | day of life 0 | Birthweight small for gestational age (\<10% by sex-specific World Health Organization growth charts) |
| Neonatal ICU Admission | Birth until 1 year of age | Neonatal ICU admission is operationally defined as a yes/no to whether a newborn was admitted to the neonatal ICU admission. |
| Stillbirth | after 20 weeks gestation until delivery | Stillbirth is operationally defined as a fetal death before or during delivery (corrected when results were entered) |
| Neonatal Adverse Events | Birth until 1 year of age | Neonatal adverse events are operationally defined as a composite yes/no response of any of the following: need for respiratory support, necrotizing enterocolitis, neonatal sepsis, retinopathy of prematurity, intraventricular hemorrhage, neonatal death. |
| Placental Abruption | after 20 weeks gestation until delivery | Placental abruption is operationally defined as a yes/no response to a placental abruption verified either clinically or as seen on pathologic placental examination. |
| Fetal Growth Restriction | after 20 weeks gestation until delivery | Fetal growth restriction is estimated fetal weight \<10th percentile for gestational age by Hadlock criteria with Yale New Haven Health practice-specific growth curves. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aspirin Participants randomized to 81 mg of Aspirin daily
Aspirin 81 mg: Participants randomized to 81 mg of Aspirin daily | 20 |
| Placebo Participants randomized to placebo daily
Placebo: Participants randomized to placebo daily | 19 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Aspirin | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 28.0 years STANDARD_DEVIATION 6.4 | 28.9 years STANDARD_DEVIATION 6.5 | 29.8 years STANDARD_DEVIATION 6.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 16 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 23 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 16 Participants | 29 Participants | 13 Participants |
| Region of Enrollment United States | 20 participants | 39 participants | 19 participants |
| Sex: Female, Male Female | 20 Participants | 39 Participants | 19 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 0 / 20 | 0 / 20 | 0 / 19 | 0 / 19 |
| serious Total, serious adverse events | 1 / 20 | 3 / 20 | 0 / 19 | 2 / 19 |
Outcome results
Primary
Development of Hypertensive Disorder
This measure is operationally defined as a yes/no response to the development of any hypertensive disorder of pregnancy (gestational hypertension, preeclampsia, eclampsia, or HELLP syndrome). This is defined by American College of Obstetricians and Gynecologists diagnostic criteria.
Time frame: after 20 weeks gestation until 6 weeks postpartum
Population: All enrolled participants that successfully delivered.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Development of Hypertensive Disorder | Yes | 5 Participants |
| Aspirin | Development of Hypertensive Disorder | No | 15 Participants |
| Placebo | Development of Hypertensive Disorder | Yes | 4 Participants |
| Placebo | Development of Hypertensive Disorder | No | 15 Participants |
Secondary
Birthweight
Birthweight small for gestational age (\<10% by sex-specific World Health Organization growth charts)
Time frame: day of life 0
Population: All infants born from enrolled participants that successfully delivered while on study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Birthweight | 3320.95 weight in grams | Standard Deviation 390.47 |
| Placebo | Birthweight | 3271.57 weight in grams | Standard Deviation 609.29 |
Secondary
Development of Eclampsia
This measure is operationally defined as a yes/no response to the development of eclampsia. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria.
Time frame: after 20 weeks gestation until 6 weeks postpartum
Population: All enrolled participants that successfully delivered while on study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Development of Eclampsia | Yes | 0 Participants |
| Aspirin | Development of Eclampsia | No | 20 Participants |
| Placebo | Development of Eclampsia | Yes | 0 Participants |
| Placebo | Development of Eclampsia | No | 19 Participants |
Secondary
Development of Gestational Hypertension
This measure is operationally defined as a yes/no response to the development of gestational hypertension. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria.
Time frame: after 20 weeks gestation until 6 weeks postpartum
Population: All enrolled participants that successfully delivered.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Development of Gestational Hypertension | Yes | 3 Participants |
| Aspirin | Development of Gestational Hypertension | No | 17 Participants |
| Placebo | Development of Gestational Hypertension | Yes | 4 Participants |
| Placebo | Development of Gestational Hypertension | No | 15 Participants |
Secondary
Development of HELLP Syndrome
This measure is operationally defined as a yes/no response to the development of HELLP syndrome. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria.
Time frame: after 20 weeks gestation until 6 weeks postpartum
Population: All enrolled participants that successfully delivered while on study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Development of HELLP Syndrome | Yes | 0 Participants |
| Aspirin | Development of HELLP Syndrome | No | 20 Participants |
| Placebo | Development of HELLP Syndrome | Yes | 0 Participants |
| Placebo | Development of HELLP Syndrome | No | 19 Participants |
Secondary
Development of Preeclampsia
This measure is operationally defined as a yes/no response to the development of preeclampsia. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria.
Time frame: after 20 weeks gestation until 6 weeks postpartum
Population: All enrolled participants that successfully delivered.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Development of Preeclampsia | Yes | 2 Participants |
| Aspirin | Development of Preeclampsia | No | 18 Participants |
| Placebo | Development of Preeclampsia | Yes | 0 Participants |
| Placebo | Development of Preeclampsia | No | 19 Participants |
Secondary
Development of Preeclampsia- 34 Weeks
This measure is operationally defined as a yes/no response to the development of preeclampsia at less than 34 weeks of pregnancy. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria.
Time frame: up to 34 weeks gestation
Population: All enrolled participants that successfully delivered while on study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Development of Preeclampsia- 34 Weeks | Yes | 0 Participants |
| Aspirin | Development of Preeclampsia- 34 Weeks | No | 20 Participants |
| Placebo | Development of Preeclampsia- 34 Weeks | Yes | 0 Participants |
| Placebo | Development of Preeclampsia- 34 Weeks | No | 19 Participants |
Secondary
Development of Preeclampsia- 37 Weeks
This measure is operationally defined as a yes/no response to the development of preeclampsia at less than 37 weeks of pregnancy. This is defined by American College of Obstetricians and Gynecologists diagnostic criteria.
Time frame: up to 37 weeks gestation
Population: All enrolled participants that successfully delivered.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Development of Preeclampsia- 37 Weeks | Yes | 0 Participants |
| Aspirin | Development of Preeclampsia- 37 Weeks | No | 20 Participants |
| Placebo | Development of Preeclampsia- 37 Weeks | Yes | 0 Participants |
| Placebo | Development of Preeclampsia- 37 Weeks | No | 19 Participants |
Secondary
Fetal Growth Restriction
Fetal growth restriction is estimated fetal weight \<10th percentile for gestational age by Hadlock criteria with Yale New Haven Health practice-specific growth curves.
Time frame: after 20 weeks gestation until delivery
Population: All infants born to enrolled participants that successfully delivered while on study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Fetal Growth Restriction | Yes | 0 Participants |
| Aspirin | Fetal Growth Restriction | No | 20 Participants |
| Placebo | Fetal Growth Restriction | Yes | 2 Participants |
| Placebo | Fetal Growth Restriction | No | 17 Participants |
Secondary
Neonatal Adverse Events
Neonatal adverse events are operationally defined as a composite yes/no response of any of the following: need for respiratory support, necrotizing enterocolitis, neonatal sepsis, retinopathy of prematurity, intraventricular hemorrhage, neonatal death.
Time frame: Birth until 1 year of age
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Neonatal Adverse Events | Yes | 3 Participants |
| Aspirin | Neonatal Adverse Events | No | 17 Participants |
| Placebo | Neonatal Adverse Events | Yes | 2 Participants |
| Placebo | Neonatal Adverse Events | No | 17 Participants |
Secondary
Neonatal ICU Admission
Neonatal ICU admission is operationally defined as a yes/no to whether a newborn was admitted to the neonatal ICU admission.
Time frame: Birth until 1 year of age
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Neonatal ICU Admission | NICU Admission = Yes | 1 Participants |
| Aspirin | Neonatal ICU Admission | NICU Admission = No | 19 Participants |
| Placebo | Neonatal ICU Admission | NICU Admission = Yes | 3 Participants |
| Placebo | Neonatal ICU Admission | NICU Admission = No | 16 Participants |
Secondary
Placental Abruption
Placental abruption is operationally defined as a yes/no response to a placental abruption verified either clinically or as seen on pathologic placental examination.
Time frame: after 20 weeks gestation until delivery
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Placental Abruption | Yes | 0 Participants |
| Aspirin | Placental Abruption | No | 20 Participants |
| Placebo | Placental Abruption | Yes | 0 Participants |
| Placebo | Placental Abruption | No | 19 Participants |
Secondary
Spontaneous Preterm Delivery
This measure is operationally defined as a yes/no response to a spontaneous preterm delivery up to 34 weeks of pregnancy.
Time frame: Up to 34 weeks
Population: All enrolled participants that successfully delivered while on study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Spontaneous Preterm Delivery | Yes | 0 Participants |
| Aspirin | Spontaneous Preterm Delivery | No | 20 Participants |
| Placebo | Spontaneous Preterm Delivery | Yes | 1 Participants |
| Placebo | Spontaneous Preterm Delivery | No | 18 Participants |
Secondary
Spontaneous Preterm Delivery
This measure is operationally defined as a yes/no response to a spontaneous preterm delivery up to 37 weeks of pregnancy.
Time frame: Up to 37 weeks
Population: All enrolled participants that successfully delivered while on study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Spontaneous Preterm Delivery | Yes | 0 Participants |
| Aspirin | Spontaneous Preterm Delivery | No | 20 Participants |
| Placebo | Spontaneous Preterm Delivery | Yes | 2 Participants |
| Placebo | Spontaneous Preterm Delivery | No | 17 Participants |
Secondary
Stillbirth
Stillbirth is operationally defined as a fetal death before or during delivery (corrected when results were entered)
Time frame: after 20 weeks gestation until delivery
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aspirin | Stillbirth | Yes | 0 Participants |
| Aspirin | Stillbirth | No | 20 Participants |
| Placebo | Stillbirth | Yes | 0 Participants |
| Placebo | Stillbirth | No | 19 Participants |