Slow Heart Registry of Fetal Immune-mediated High Degree Heart Block

Slow Heart Registry: A Prospective Observational Cohort Study of Fetal Immune-mediated High Degree Heart Block

Few studies are specifically designed to address health concerns that are already relevant during pregnancy. The consequence is a lack of evidence on best clinical practice. This includes mothers and their babies when pregnancy is complicated by an abnormally slow heart rate due to maternal antibody-mediated heart disease in the unborn baby (fetus). Since the late seventies, it has been possible to detect and monitor fetal disease by ultrasound images and to treat selected conditions with pharmaceuticals administered via the mother. To this day, physicians need to make decisions about the management of such pregnancies without evidence from prospective clinical trials on drug efficacy and safety. The SLOW HEART REGISTRY is a multi-centered prospective observational study that will address the knowledge gap to guide future management of high-degree immune-mediated heart block to the best of care. The study seeks to establish an international database of the management and outcome of affected fetuses, to be used to publish information on the results of currently available prenatal care and to evaluate the need for additional research.

Study Overview

• Status: Recruiting
• Conditions: Heart Block Complete; Heart Block Second Degree
• Intervention / Treatment: Drug: Dexamethasone; Other: No Dexamethasone

Detailed Description

The SLOW HEART REGISTRY is a multi-centered prospective observational study of fetuses diagnosed with high-degree immune-mediated atrio-ventricular heart block (AVB). The study seeks to establish an international database of the management and outcome of affected fetuses, to be used to publish information on the results of currently available prenatal care and to evaluate the need for additional research.

The study aims are to document the outcome of patients diagnosed prenatally with immune-mediated 2nd or 3rd degree AVB irrespective of the primary choice of prenatal care.

The primary objective will be to determine the rate of transplant-free survival to 1 year of life of fetuses with AVB based on the prenatal management decision:

• Cohort 1: Fetuses not treated with fluorinated glucocorticoids
• Cohort 2: Fetuses treated with fluorinated glucocorticoids from the time of immune-mediated AVB diagnosis.

Secondary objectives will be to determine:

1. the evolution of clinical findings from AVB diagnosis to birth (AV conduction; fetal heart rate; other NL manifestations; fetal growth; effusions/hydrops) between cohorts;
2. the need of new/additional treatment (steroids; beta-mimetics; IVIG) to birth;
3. gestational age and weight at birth;
4. postnatal management (pacing; steroids; IVIG); and
5. clinical evolution from birth to 1-3 years of life (cardiac function; developmental milestones; infant growth; health).

Prevalence of relevant fetal-maternal events and complications (death; IUGR; morbidity) between the study cohorts will also be determined.

All management is decided by the treating center and physicians in accordance to institutional guidelines and clinical findings. Patient enrollment in the SLOW HEART REGISTRY is possible within up to 8 days of the initial management decision.

Participation in this prospective observational cohort study requires site REB approval and an executed legal contract with the primary investigator/SickKids Hospital, Toronto.

• Study Type: Observational
• Enrollment (Anticipated): 350

Contacts and Locations

• Study Contact: Name: Diana Balmer-Minnes, BSc, CCRP; Phone Number: 228624 416-813-7654; Email: slow.heart@sickkids.ca
• Study Contact Backup: Name: Edgar Jaeggi, MD; Phone Number: 418-813-7466; Email: slow.heart@sickkids.ca

Study Locations

• Canada
  • Toronto, Canada
    • Recruiting
    • The Hospital for Sick Children
    • Contact: Diana Balmer-Minnes, M.Sc; Phone Number: 416-813-7500; Email: slow.heart@sickkids.ca
• Finland
  • Helsinki, Finland, 00260
    • Recruiting
    • Hospital District of Helsinki and Uusimaa
• Germany
  • Bonn, Germany
    • Recruiting
    • University of Bonn
    • Contact: Ulrike Herberg
• Netherlands
  • Leiden, Netherlands
    • Recruiting
    • Leiden University Medical Center - LUMC
    • Principal Investigator: Nico Blom, MD
• Sweden
  • Gothenburg, Sweden
    • Recruiting
    • Queen Silvia Children's Hospital
  • Solna, Sweden
    • Recruiting
    • Karolinska University Hospital, Astrid Lindgen Childrens Hospital
• United States
  • Colorado
    • Denver, Colorado, United States, 80205
      • Recruiting
      • Children's Hospital Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Medical Center
      • Contact: Mary Donofrio, MD
      • Principal Investigator: Mary Donofrio, MD
  • Florida
    • Saint Petersburg, Florida, United States, 33701
      • Recruiting
      • Johns Hopkins All Children's Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: Audrey Dionne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

Enrollment into the SLOW HEART Registry is possible within maximally 8 days of the fetal heart block diagnosis and a management decision to treat or not to treat. If a mother elects participation in the Registry, her treating physician will continue to provide care in accordance with clinical practice at the site and will decide all therapy including close observation without or with immediate steroid treatment.

Description

Inclusion Criteria:

• Written informed maternal consent to participate in the Slow Heart Registry
• High-degree (2nd; 2:1; 2nd-3rd or 3rd degree) AVB diagnosed ≤ 32+0 weeks with or without hydrops
• Enrollment within maximally 8 days of high-degree AVB diagnosis
• Positive or pending anti-Ro/La antibody test results at the time of enrollment

Exclusion Criteria:

• AVB associated with major CHD (e.g. left atrial isomerism, cc-TGA)
• AVB with known negative anti-Ro and/or La antibody test result at enrollment
• 1st degree AVB
• Sinus bradycardia with normal 1:1 AV conduction
• Blocked atrial bigeminy (irregular atrial rate with failure of AV conduction of the premature atrial beat)
• Primary delivery for postnatal treatment
• Maternal-fetal conditions (other than cardiac NL) associated with high odds of premature delivery or death (e.g. renal failure, significant infectious diseases, major extracardiac anomalies, PROM, etc.)
• Preexisting maternal mental disorder (e.g. bipolar, mania, severe depression, substance abuse)
• Poorly controlled insulin-dependent diabetes (HbA1c >7%) at CAVB diagnosis
• Oligohydramnios (deepest/maximal vertical pocket <2 cm)
• Severe IUGR (estimated fetal weight <3rd percentile)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Prospective observational cohort 1; Complete AVB (3rd degree) diagnosed ≤ 32+0 weeks with or without hydrops	Drug: Dexamethasone; All management decisions are made by the primary physician and may include: 1) no treatment with dexamethasone or 2) treatment with dexamethasone from the time of enrollment; Other: No Dexamethasone; All management decisions are made by the primary physician and may include: 1) no treatment with dexamethasone or 2) treatment with dexamethasone from the time of enrollment
Prospective observational cohort 2; Incomplete AVB (2nd; 2:1; 2nd-3rd degree) diagnosed ≤ 32+0 weeks with or without hydrops	Drug: Dexamethasone; All management decisions are made by the primary physician and may include: 1) no treatment with dexamethasone or 2) treatment with dexamethasone from the time of enrollment; Other: No Dexamethasone; All management decisions are made by the primary physician and may include: 1) no treatment with dexamethasone or 2) treatment with dexamethasone from the time of enrollment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Freedom from cardiac death ≥1 year of life	up to 12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of participants with fetal and neonatal death and their causes/factors	1 month
Proportion of participants with change in prenatal treatment	up to 6 months
Proportion of secondarily treated patients (initially untreated group 1 cases)	up to 6 months
Proportion of serious pregnancy outcomes (IUFD, IUGR <3rd percentile, delivery <35 weeks)	up to 6 months
Proportion of patients/group with progression from incomplete to complete AVB by 1 year	Fetal diagnosis to 12 months
Proportion of maternal serious adverse events and outcomes	Fetal diagnosis to 12 months
Average gestational age at birth	Birth
Average birth weight	Birth
Freedom from permanent pacemaker implantation from birth to 1 year of life	Birth to 12 months
Prevalence of significant heart failure (HF score, echo, HF treatment) at 1 year of life	12 months
Proportion of children with moderate/severe neuro-developmental delay at 12-18 months	12-18 months

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Investigators: Principal Investigator: Edgar Jaeggi, MD, The Hospital for Sick Children, Toronto

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2020
• Primary Completion (Anticipated): December 31, 2027
• Study Completion (Anticipated): December 31, 2029

Study Registration Dates

• First Submitted: September 11, 2020
• First Submitted That Met QC Criteria: September 21, 2020
• First Posted (Actual): September 22, 2020

Study Record Updates

• Last Update Posted (Actual): June 14, 2021
• Last Update Submitted That Met QC Criteria: June 10, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: outcome; fetal; steroids; heart block; anti-Ro antibodies
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Heart Block; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Dexamethasone; Dexamethasone acetate; BB 1101
• Other Study ID Numbers: 1000065121

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No