Chronic Hypertension and Pregnancy (CHAP) Project

Phase 4

Completed

• Conditions: Hypertension
• Interventions: Other: No anti-hypertensive therapy (unless BP is severe); Drug: Anti-hypertensive therapy

• Registration Number: NCT02299414
• Lead Sponsor: University of Alabama at Birmingham

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.

Study Timeline

• Study First Submitted: 2014-10-28
• Study First Submitted QC: 2014-11-19
• Study First Posted: 2014-11-24
• Study Start: 2015-06
• Primary Completion: 2022-04-01
• Study Completion: 2022-12-16
• Results First Submitted: 2023-04-04
• Status Verified: 2023-05
• Results First Submitted QC: 2023-05-16
• Last Update Submitted: 2023-05-16
• Results First Posted: 2023-05-17
• Last Update Posted: 2023-05-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 2408

Inclusion Criteria

1. 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);
2. Singleton; and
3. viable pregnancy <23 weeks of gestation.

Exclusion Criteria

1. Blood pressures prior to randomization ≥160 systolic or ≥105 diastolic (with or without treatment);

2. Severe hypertension including patients currently treated with >1 antihypertensive medication (more likely to have severe chronic hypertension);

3. Multi-fetal pregnancy;

4. Known secondary cause of chronic hypertension;

5. 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

6. Known major fetal anomaly;

7. Known fetal demise;

8. Suspected IUGR;

9. Membrane rupture or planned termination prior to randomization;

10. 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;

11. Contraindication to labetalol and nifedipine (e.g. know hypersensitivity);

12. Current substance abuse or addiction (cocaine, methamphetamine)

13. Participation in another trial without prior approval (CHAP participants will not be enrolled in other trials without prior approval by protocol committee)

14. Physician or provider refusal

15. Patient refusal *The minimum age varies by center

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
No anti-hypertensive unless BP is severe (≥160/105 mmHg	No anti-hypertensive therapy (unless BP is severe)	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
Anti-hypertensive therapy to goal <140/90 mmHg	Anti-hypertensive therapy	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

Primary Outcome Measures

Name	Time	Method
Small for Gestational Age (Safety)	Until delivery	Birth weight less than 10th percentile for gestational age at birth according to accepted national standard
Composite Adverse Perinatal Outcome	Up to 2 weeks postpartum for preeclampsia or 90 days for neonatal death	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).

Secondary Outcome Measures

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

Trial Locations

Locations (72)

University of Alabama at Birmingham, Clinical Coordinating Center; 🇺🇸 Birmingham, Alabama, United States

University of Alabama at Birmingham, Data Coordinating Center; 🇺🇸 Birmingham, Alabama, United States

University of South Alabama; 🇺🇸 Mobile, Alabama, United States

University of Arkansas for Medical Sciences; 🇺🇸 Little Rock, Arkansas, United States

Arrowhead Regional Medical Center; 🇺🇸 Colton, California, United States

University of California, San Diego; 🇺🇸 San Diego, California, United States

General Hospital of San Francisco; 🇺🇸 San Francisco, California, United States

University of California San Francisco; 🇺🇸 San Francisco, California, United States

Stanford University; 🇺🇸 Stanford, California, United States

University of Colorado; 🇺🇸 Boulder, Colorado, United States

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