Hypertension in Pregnancy, Obstetrical Complications
Conditions
Keywords
Preeclampsia, Preterm Delivery, Maternal Morbidity, Neonatal Morbidity, Prevention
Brief summary
This is a phase-III multi-center open-label randomized clinical trial of 4,120 individuals between 23 weeks, 0 days and 35 weeks, 6 days gestation with gestational hypertension or preeclampsia without severe features randomized to antihypertensive medication to a target blood pressure (BP) of \<140/90 mmHg or to no treatment for non-severe hypertension \< 160/110 mmHg (usual care). The primary endpoint is an adverse pregnancy composite comprised of preeclampsia with end-organ damage, medically indicated preterm delivery \<37 weeks 0 days gestation, fetal/neonatal/infant death, or placental abruption.
Detailed description
All women with a diagnosis of gestational hypertension or preeclampsia without severe features at an Maternal-Fetal Medicine Units Network (MFMU) Center outpatient or inpatient setting who are less than 36 weeks and 0 days of gestation will be screened for eligibility and approached for enrollment by the MFMU Research Team. Women who meet study eligibility and want to participate will provide written informed consent. Study participants will be randomized 1:1 to: 1. intervention: antihypertensive medication to achieve a target blood pressure (BP) lower than 140/90 mmHg or 2. usual care: defined as no antihypertensive medication unless BP increases to greater than or equal to 160 mmHg systolic pressure or 110 mmHg diastolic to achieve a target BP of less than 160/110 mmHg. Participants randomized to intervention will be initiated on labetalol or nifedipine extended release (ER). For first line treatment with labetalol, 200 mg twice daily will be initiated and escalated according to institutional protocol to a BP goal of \<140/90 to a maximum dose of 2,400 mg/day (1,200 mg twice daily or 800 mg three time daily). Alternatively, for first line treatment with nifedipine ER, nifedipine ER will be initiated at 30 mg daily and escalated according to institutional protocol to a goal BP \<140/90 to a maximum dose of 120 mg/day (120 mg daily or 60 mg twice daily). Participants will be seen clinically at least weekly until delivery. All participants will have an encounter with research staff twice a week from randomization until delivery. Each encounter (twice a week) should include the following: * Maternal symptom assessment including evaluation for new headaches, changes in vision, abdominal pain, vaginal bleeding, and/or decreased fetal movement * Side effects and adverse events assessment At least one per week, research staff should perform the following: * Record and review all clinic blood pressures and laboratory evaluations * Record changes to antihypertensive medications * Record unscheduled emergency room (ER) visits, Labor and Delivery (L&D) visits or hospitalizations * For participants in the intervention group, research staff should confirm their prescription for study medication will ensure an adequate supply until their next visit, and assess compliance. One to two weeks after randomization, the participant should complete the Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) to assess quality of life. Fetal surveillance (e.g., biophysical profile, or non-stress test with or without amniotic fluid assessment) should be performed clinically at least weekly per local standard of care. Ultrasonographic fetal growth assessment should be performed clinically at least every 4 weeks to assess fetal growth. If fetal growth restriction is identified, increased surveillance with umbilical artery Dopplers will be initiated per institutional protocol. Maternal and neonatal outcomes will be abstracted from the medical records following the delivery hospitalization. Newborn assessment will include the duration of hospitalization up to 6 weeks of life. A single maternal follow-up study visit at 6 weeks (range 4-8) weeks postpartum will be scheduled to ascertain maternal, neonatal, and resource use outcomes.
Interventions
DRUGAnti-hypertensive medication titrated to a BP goal of <140/90 mmHg
Antihypertensive medication titrated to a BP goal of \< 140/90 mmHg initiated on labetalol or nifedipine ER following standard dosing guidelines. For first line treatment with labetalol, 200 mg twice daily will be initiated and escalated to a BP goal of \<140/90 mmHg to a maximum dose of 2,400 mg/day (1,200 mg twice daily or 800 mg three times daily). If a maximum daily dose of 2,400 mg or maximal tolerated dose of labetalol is reached without achieving goal BP \<140/90 mmHg, or at provider discretion, nifedipine ER can be added as a second agent and titrated as per the nifedipine ER algorithm outlined below. For first line treatment with nifedipine ER, dosing will be initiated at 30 mg daily and escalated to a goal BP \<140/90 mmHg to a maximum dose of 120 mg/day (120 mg daily or 60 mg twice daily). If the maximum daily dose or maximal tolerated dose of nifedipine ER is reached without achieving goal BP \<140/90, or at provider discretion, labetalol can be added as described above.
OTHERUsual Care: Anti-hypertensive medication for BP ≥160/110 mmHg titrated to a goal of < 160/110 mmHg
Usual care will not receive anti-hypertensive medication upon randomization. Participants will only be prescribed antihypertensive medication if their BP increases to ≥160/110 mmHg and titrated to a BP goal of \<160/110 mmHg. They will receive IV and/or oral anti-hypertensive medication as per local institutional protocols for management of severe range BP.
Sponsors
The George Washington University Biostatistics Center
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Alabama at Birmingham
University of Utah
Brown University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Individuals will be randomized between 23 weeks, 0 days and 35 weeks, 0 days gestation to either antihypertensive medication (labetalol or nifedipine extended release) titrated to a BP goal of \<140/90 or to usual care - no treatment of non-severe hypertension (i.e. no anti-hypertensive medication unless BP ≥160/110 to a goal BP \<160/110 mmHg).
Eligibility
Sex/Gender
FEMALE
Age
14 Years to 56 Years
Healthy volunteers
Yes
Inclusion criteria
* Singleton or di-chorionic twin gestation. * Gestational age at randomization from 23 weeks 0 days through 35 weeks 6 days based on clinical information and evaluation of the earliest ultrasound * Diagnosis of gestational hypertension or preeclampsia without severe features within 10 days prior to randomization. * Gestational hypertension or preeclampsia is defined as new onset systolic blood pressure 140-159 or diastolic blood pressure 90-109 (or both) on two occasions at least four hours apart on or after 20 weeks 0 days gestation with normal end-organ labs, with or without proteinuria. * Blood pressure measurements used for the diagnosis must occur during a formal clinical assessment in the outpatient, inpatient, or emergency care setting and be documented in the medical record. The diagnosis is made on the date of the second qualifying blood pressure. * At least 1 elevated blood pressure (systolic blood pressure 140-159 and/or diastolic blood pressure 90-109) must be documented at the recruitment site
Exclusion criteria
* Known allergy or hypersensitivity to both labetalol and nifedipine ER * Two blood pressure measurements ≥ 140/90 at least 4 hours apart prior to 20 weeks 0 days in the current pregnancy * History or current use of anti-HTN medication defined as any of the following: * Prescribed anti-HTN medication for the indication of lowering blood pressure within 12 months prior to conception or prior to 20 weeks 0 days in the current pregnancy. Use during a prior pregnancy and through 12 weeks postpartum, or use for stage 1 chronic hypertension is not an exclusion. * Current use of anti-HTN medication. Participants on anti-HTN medication for the purpose of treating non-severe hypertensive disorders of pregnancy, or for indications other than hypertension, who are willing to go through a 48 hour washout before randomization would be eligible. * High-risk co-morbidities for which treatment at a lower blood pressure level (i.e., below the standard cutoff of 160/110) may be indicated * Chronic kidney disease including any of the following lab values prior to 20 weeks gestation: proteinuria ≥ 300mg/24 hr, clean catch protein creatinine ratio ≥ 0.3, or serum creatinine \>1.1 * Cardiac disorders including cardiomyopathy, angina, and coronary artery disease * Prior stroke * Retinopathy * Sickle cell disease Preeclampsia with severe features defined as any of the following: * Severe hypertension defined as new onset systolic blood pressure ≥ 160 or diastolic blood pressure ≥ 110 on two occasions at least 4 hours apart (unless antihypertensive medication is initiated before this time) on or after 20 weeks 0 days gestation. * Severe features of preeclampsia as evidenced by end organ damage defined as any of the following on or after 20 weeks 0 days gestation: * Thrombocytopenia defined as a platelet count \<100,000 * Renal insufficiency defined as a serum creatinine \>1.1 mg/dL or a doubling of the concentration in the absence of other renal disease * Impaired liver function defined as an elevated blood concentration of liver transaminases to twice normal concentration, or by severe persistent right upper quadrant or epigastric pain * Pulmonary edema * New onset headache unresponsive to medication and not accounted for by alternative diagnoses * Visual disturbances * Eclampsia * Oligohydramnios defined as a maximum vertical pocket (MVP) \<2 cm or an amniotic fluid index (AFI) \< 5 cm * Fetal growth restriction defined as estimated fetal weight \< 5th percentile, or fetal growth restriction \<10th percentile (estimated fetal weight \<10th percentile or abdominal circumference \< 10th percentile) with abnormal umbilical artery dopplers (elevated (S/D ratio \>95th percentile for gestational age), absent or reversed end diastolic flow) * Known fetal genetic disease or major malformations * Fetal demise or planned termination of pregnancy. * Planned indicated delivery prior to 37 weeks 0 days * Participation in another interventional study that influences the primary outcome in this study. This may not apply to comparative effectiveness studies evaluating treatments that are available and used as part of clinical practice. Such cases will be adjudicated by the Concurrent Research Committee and Protocol Subcommittee. * Plan to deliver at a non-participating site * Participation in this trial in a previous pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with the adverse pregnancy composite | Randomization to 6 weeks postpartum / 6 weeks of life (a period of up to 23 weeks) | Number of participants with preeclampsia with severe features (excluding severe hypertension), medically indicated preterm birth less than 37 weeks 0 days, fetal or neonatal death, placental abruption. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with the adverse perinatal composite outcome | Randomization to 6 weeks of life (a period of up to 23 weeks) | Adverse perinatal composite defined as any one of the following: respiratory distress syndrome, 5-minute Apgar score less than or equal to 3, seizure, confirmed sepsis, Intraventricular hemorrhage (Grade 3-4), Bronchopulmonary dysplasia (Grade 3 or higher), necrotizing enterocolitis (Bell Stage greater than or equal to 2A), treated hyperbilirubinemia, treated hypoglycemia, hypoxic ischemic encephalopathy, fetal/neonatal/infant death |
| Number of participants with preeclampsia with severe features | Randomization to 6 weeks postpartum (a period of up to 23 weeks) | Number of participants with preeclampsia with severe features defined using American College of Obstetricians and Gynecologists 2020 criteria through 6 weeks postpartum. |
| Number of perinatal deaths | Randomization to 28 days of life (a period of up to 147 days) | Number of fetal or neonatal deaths through 28 days of life |
| Number of neonates who were small for gestational age <3rd percentile | At birth | Number of neonates who were small for gestational age (SGA) defined as a birth weight \<3rd and \<10th percentile for gestational age as defined by Aris et al. |
| Number of neonates who were small for gestational age <10th percentile for gestational age | At birth | Number of neonates who were small for gestational age (SGA) defined as a birth weight \<10th percentile for gestational age as defined by Aris et al. |
| Number of neonates with low birth weight | At birth | Number of neonates with birth weight \<2,500g |
| Number of participants with preterm births | From randomization to birth (a period of up to 14 weeks) | Number of participants with delivery of a fetus at less than 37 weeks for any reason or indication, includes spontaneous and iatrogenic preterm birth |
| Number of participants with spontaneous preterm birth | From randomization to birth (a period of up to 14 weeks) | Spontaneous delivery at less than 37 weeks 0 days gestation |
| Number of participants with severe hypertension | Randomization to 6 weeks postpartum (a period of up to 23 weeks) | Number of participants with systolic blood pressure greater than or equal to 160 mmHg or diastolic blood pressure greater than or equal to 110 mmHg confirmed by at least one repeated measure within 4 hours unless antihypertensive medication was already initiated. |
| Number of participants with cesarean delivery | At delivery | Number of participants who had delivery of a fetus via an abdominal incision and hysterotomy |
| Number of participants with postpartum hemorrhage | Randomization to 6 weeks postpartum (a period of up to 23 weeks) | Number of participants with cumulative blood loss ≥ 1,000mL or any blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after delivery, regardless of delivery route |
| Number of maternal deaths | Randomization to 6 weeks postpartum (a period of up to 23 weeks) | Death of the mother for any reason through 6 weeks postpartum |
| Number of antepartum and postpartum clinic visits | Randomization to 6 weeks postpartum (a period of up to 23 weeks) | The number of antepartum and postpartum clinic visits (scheduled and unscheduled) |
| Number of Obstetric (OB) Triage / Emergency Room (ER) visits | Randomization to 6 weeks postpartum (a period of up to 23 weeks) | The number of times the participant sought care in the obstetric triage or emergency department through 6 weeks postpartum |
| Number of postnatal hospitalization days | From delivery to hospital discharge (no maximum time frame) | The number of days the participant was admitted to the hospital from delivery to discharge |
| Number of postpartum readmissions | From discharge from the delivery-associated hospitalization through 6 weeks postpartum (a period of up to 23 weeks) | The number of times a participant is admitted to the hospital after she is discharged from the delivery-associated hospitalization through 6 weeks postpartum |
| Number of antepartum hospitalization days | Randomization to delivery (a period of up to 17 weeks) | The number of days the participant was admitted to the hospital from randomization to delivery |
| Number of participants admitted to intensive care unit (ICU) | Randomization to 6 weeks postpartum (a period of up to 23 weeks) | Admission of the mother to an intensive care unit (ICU) through 6 weeks postpartum |
| Number of neonates admitted to neonatal intensive care unit (NICU) | Birth to 6 weeks of life | Admission of the neonate to an intensive care unit admission greater than or equal to 2 days through 6 weeks of life |
| Neonatal length of hospital stay | Birth to hospital discharge (no maximum timeframe) | Number of days from delivery to discharge |
| Number of neonatal hospital readmissions | Hospital discharge to 6 weeks of life | Number of times the neonate is admitted to the hospital from discharge to 6 weeks of life |
| Number of neonatal clinic visits | Hospital discharge to 6 weeks of life | Number of neonatal clinic visits |
| Number of neonatal emergency room (ER) visits | Hospital discharge to 6 weeks of life | Number of neonatal emergency room (ER) visits |
Countries
United States
Contacts
CONTACTRebecca G Clifton, PhD
CONTACTRoja Kambhampati, MSHS
PRINCIPAL_INVESTIGATORRebecca G Clifton, PhD
The George Washington University Biostatistics Center
STUDY_CHAIRRachel G Sinkey, MD
University of Alabama at Birmingham
STUDY_CHAIRLaurie B Griffin, MD
University of Utah Health Sciences
PRINCIPAL_INVESTIGATORDwight J Rouse, MD
Brown University
PRINCIPAL_INVESTIGATORAlan TN Tita, MD PHD
University of Alabama at Birmingham
Outcome results
None listed