Chronic Hypertension and Pregnancy (CHAP) Project

Overview

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.

Full Title of Study: “A Pragmatic Multicenter Randomized Clinical Trial (RCT) of Antihypertensive Therapy for Mild Chronic Hypertension During Pregnancy: Chronic Hypertension and Pregnancy (CHAP) Project”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 2021

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.

Interventions

  • Drug: Anti-hypertensive therapy
    • 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)
  • Other: No anti-hypertensive therapy (unless BP is severe)
    • 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.

Arms, Groups and Cohorts

  • Experimental: Anti-hypertensive therapy to goal <140/90 mmHg
    • 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
  • Active Comparator: No anti-hypertensive unless BP is severe (≥160/105 mmHg
    • 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

Clinical Trial Outcome Measures

Primary Measures

  • Composite adverse perinatal outcome
    • Time Frame: Up to 2 weeks after delivery
    • One of more severe outcomes including fetal or neonatal death up to 2 weeks; preeclampsia with severe features (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).
  • Small for Gestational Age
    • Time Frame: Until delivery
    • Birth weight less than 10th percentile for gestational age at birth according to accepted national standard

Secondary Measures

  • Composite of maternal death or severe cardiovascular morbidity
    • Time Frame: Up to 6 weeks (4-12 weeks) after delivery
    • One or more of maternal death, heart failure, stroke, encephalopathy, Myocardial infarction or ischemia, pulmonary edema, ICU admission, or renal failure
  • Composite of severe adverse perinatal outcome
    • Time Frame: Up to 6 weeks (4-12 weeks) after delivery
    • One or more of perinatal death, IVH III or IV, BPD or chronic lung disease, NEC, ROP, Seizures, Proven sepsis
  • Adherence to treatment after delivery
    • Time Frame: Up to 6 weeks (4-12 weeks) after delivery
    • Adherence to antihypertensive therapy after delivery

Participating in This Clinical Trial

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. 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:

  • Class C or higher diabetes mellitus
  • Chronic kidney disease – including baseline proteinuria (>300mg/24-hr, p/c 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.

  • 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 or nifedipine (e.g. know hypersensitivity); and (12) Current substance abuse or addiction (cocaine, methamphetamine) *The minimum age varies by center

Gender Eligibility: Female

Minimum Age: 12 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Alabama at Birmingham
  • Collaborator
    • Columbia University
  • Provider of Information About this Clinical Study
    • Principal Investigator: Alan Tita, Principal Investigator – University of Alabama at Birmingham
  • Overall Official(s)
    • Alan Tita, MD, PhD, Principal Investigator, University of Alabama at Birmingham – Clinical Coordinating Center
    • Gary Cutter, PhD, Principal Investigator, University of Alabama at Birmingham-Data Coordinating Center
  • Overall Contact(s)
    • Alan Tita, MD, PhD, 205-934-5612, atita@uabmc.edu

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