Chronic Hypertension and Pregnancy (CHAP) Project

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate whether a blood pressure treatment strategy during pregnancy to achieve targets that are recommended for non-pregnant reproductive-age adults (<140/90 mmHg) compared ACOG- recommended standard during pregnancy (no treatment unless BP is severe) is effective and safe.

Detailed Description
-----------------
During pregnancy, chronic hypertension (CHTN) is the most common major medical disorder encountered, occurring in 2-6%. The substantial negative effect of CHTN on pregnancy includes a consistent 3- to 5-fold increase in superimposed preeclampsia and adverse perinatal outcomes (fetal or neonatal death, preterm birth -PTB, poor fetal growth and placental abruption) and possibly a 5- to10-fold increase in maternal cardiovascular and other complications (death, cerebrovascular accident, pulmonary edema and acute renal failure). Mild CHTN (BP <160/110) contributes to a large proportion of these adverse outcomes. While antihypertensive treatment of CHTN is standard for the general population, it is uncertain whether treatment during pregnancy reduces maternal or fetal complications, and there are concerns that decreased arterial pressure may reduce fetal blood flow and cause poor fetal growth or small-for-gestational-age (SGA) infants. Some authorities, including the American College of Obstetricians and Gynecologists (ACOG) and American Society of Hypertension (ASH) recommend withholding antihypertensive therapy for mild CHTN, particularly if BP is <160/105-110 mmHg. The recommendation to withhold antihypertensive treatment in pregnancy conflicts with the broader public health goal to reduce BP in those with CHTN and there is no evidence that discontinuing therapy during the brief period of pregnancy affects maternal outcomes (other than reducing the severe hypertension). For over a decade, authorities have consistently called for well-designed and powered trials to delineate the benefits and risks of pharmacologic therapy for CHTN during pregnancy. Therefore, our multicenter consortium proposes the Chronic Hypertension and Pregnancy (CHAP) Project, a large pragmatic randomized trial with a primary aim to evaluate the benefits and harms of pharmacologic treatment of mild CHTN in pregnancy.

Official Title
-----------------
A Pragmatic Multicenter Randomized Clinical Trial (RCT) of Antihypertensive Therapy for Mild Chronic Hypertension During Pregnancy: Chronic Hypertension and Pregnancy (CHAP) Project

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Drug: Anti-hypertensive therapy
* Other: No anti-hypertensive therapy (unless BP is severe)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women with chronic hypertension in pregnancy with new or untreated chronic hypertension, blood pressure 140-159 systolic or 90-104 diastolic OR known chronic hypertension on monotherapy and taking any antihypertensive and blood pressure ≤159/104 (including those with blood pressure <140/90); Singleton; and viable pregnancy <23 weeks of gestation. Exclusion Criteria: Blood pressures prior to randomization ≥160 systolic or ≥105 diastolic (with or without treatment); Severe hypertension including patients currently treated with >1 antihypertensive medication (more likely to have severe chronic hypertension); Multi-fetal pregnancy; Known secondary cause of chronic hypertension; High-risk co-morbidities for which treatment may be indicated: Diabetes mellitus diagnosed at age ≤10 years or duration of diagnosis ≥20 years Diabetes mellitus complicated by end organ damage (retinopathy, nephropathy, heart disease, transplant) Chronic kidney disease - including baseline proteinuria (>300mg/24-hr, protein/creatinine ratio ≥0.3, or persistent 1+ proteinuria*) or creatinine >1.2. *If a dipstick value at screening is more than trace, a clean catch or catheter urine should be obtained and re-tested by dipstick. If this shows trace or absence of protein, the patient is included. If it again shows 1+ protein, the patient is excluded until a 24-hr urine <300mg/24hr or p/c ratio is <0.3. If a p/c ratio is >0.3, the patient may be included if a 24-hour urine is < 300 mg. Cardiac disorders: cardiomyopathy, angina, CAD Prior stroke Retinopathy Sickle cell disease Known major fetal anomaly; Known fetal demise; Suspected IUGR; Membrane rupture or planned termination prior to randomization; Plan to deliver outside the consortium centers (unless approved by the Clinical Coordinating Center) or unlikely to follow-up in the opinion of study staff or previous participation in this trial; Contraindication to labetalol and nifedipine (e.g. know hypersensitivity); Current substance abuse or addiction (cocaine, methamphetamine) Participation in another trial without prior approval (CHAP participants will not be enrolled in other trials without prior approval by protocol committee) Physician or provider refusal Patient refusal *The minimum age varies by center

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-hypertensive therapy to goal <140/90 mmHg<br>Labetalol or Nifedipine ER will be used as first-line to achieve goal; if necessary Nifedipine ER or Labetalol will be second-line antihypertensive. Rarely, other antihypertensive medications may also be used | Drug: Anti-hypertensive therapy<br>* 1st line anti-hypertensive (Labetalol or Nifedipine ER) started; escalate to maximum dose and a preferred 2nd line medication if needed (nifedipine ER or Labetalol)<br>* Other names: Adalat;|
| Active Comparator: No anti-hypertensive unless BP is severe (≥160/105 mmHg<br>Antihypertensive therapy given only if BP becomes severe (defined as BP ≥160/105). The lowest dose of anti-hypertensive needed to keep blood pressure below this threshold will be given (1st-line - Labetalol or Nifedipine ER and 2nd-line - Labetalol or Nifedipine ER). Rarely other medications may be used | Other: No anti-hypertensive therapy (unless BP is severe)<br>* Treatment will not be started if blood pressure remains <160/105; for blood pressure ≥160/105, treatment with labetalol or Nifedipine ER will be initiated and maintained at lowest dose needed to keep blood pressure under 160/105.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Adverse Perinatal Outcome | One or more severe outcomes including fetal death or neonatal death up to discharge or 90 days if prior; preeclampsia with severe features up to 2 weeks postpartum (Severe hypertension and proteinuria or hypertension and severe features per ACOG); placental abruption; or indicated PTB <35 weeks (not due to spontaneous preterm labor or membrane rupture). | Up to 2 weeks postpartum for preeclampsia or 90 days for neonatal death | 
| Small for Gestational Age (Safety) | Birth weight less than 10th percentile for gestational age at birth according to accepted national standard | Until delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of Maternal Death or Severe Cardiovascular Morbidity | One or more of maternal death, new heart failure, stroke, encephalopathy, angina, myocardial infarction or ischemia, pulmonary edema, ICU admission/intubation, or renal failure | Up to 6 weeks (4-12 weeks) after delivery | 
| Severe Maternal Hypertension + Components of the Primary Composite Endpoint | Persistent severe hypertension with or without proteinuria + the primary composite | Up to 2 weeks postpartum or 90 days for neonatal death | 
| Preterm Birth and Indicated Preterm Birth (<37 Weeks) | Preterm birth and Indicated preterm birth (<37 weeks) includes any preterm birth less than 37 weeks | Until delivery | 
| Composite of Severe Neonatal Morbidities | One or more of Bronchopulmonary dysplasia (BPD), Retinopathy of prematurity (ROP), Necrotizing enterocolitis (NEC), Intraventricular hemorrhage (VH) grade III/IV | Up to 90 days post delivery | 
| Adherence to Treatment After Delivery | Counts with high adherence to antihypertensive therapy after delivery for those prescribed medications. | 6 weeks (4-12 weeks) after delivery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pregnancy, Chronic hypertension