Prospective Identification of Long QT Syndrome in Fetal Life

NCT02876380 | Completed

• 1 other identifier: 13-3129
• Study Type: observational
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

The postnatal diagnosis of Long QT Syndrome (LQTS) is suggested by a prolonged QT interval on 12 lead electrocardiogram (ECG), strengthened by a positive family history and/or characteristic arrhythmias and confirmed by genetic testing. However, for several reasons such LQTS testing cannot be performed successfully before birth. First, fetal ECG is not possible and direct measure of the fetal QT interval by magnetocardiography is limited to fewer than 10 sites world-wide. Second, while genetic testing can be performed in utero, there is risk to the pregnancy and the fetus. Third, although some fetuses present with arrhythmias easily recognized as LQTS (torsade des pointes (TdP) and/or 2° atrioventricular (AV) block, this is uncommon, occurring in \<25% of fetal LQTS cases. Rather, the most common presentation of fetal LQTS is sinus bradycardia, a subtle rhythm disturbance that often is unappreciated to be abnormal. Consequently, the majority of LQTS cases are unsuspected and undiagnosed during fetal life, with dire consequences. For example, maternal medications commonly used during pregnancy can prolong the fetal QT interval and may provoke lethal fetal ventricular arrhythmias. But the most significant consequence is the missed opportunity for primary prevention of life threatening ventricular arrhythmias after birth because the infant is not suspected to have LQTS before birth. The over-arching goal of the study is to overcome the barriers to prenatal detection of LQTS. The investigators plan to do so by developing an algorithm using fetal heart rate (FHR) which will discriminate fetuses with or without LQTS. Immediate Goal: The investigators propose a multicenter pre-birth observational cohort study to develop a Fetal Heart Rate (FHR)/Gestational Age (GA) algorithm from a cohort of fetuses recruited from 13 national and international centers where one parent is known by prior genetic testing to have a mutation in one of the common LQTS genes: potassium voltage-gated channel subfamily Q member 1 (KCNQ1), potassium voltage-gated channel subfamily H member 2 (KCNH2), or sodium voltage-gated channel alpha subunit 5 (SCN5A). The investigators have chosen this population because 1) These mutations are the most common genetic causes of LQTS, and 2) Offspring will have high risk of LQTS as inheritance of these LQTS gene mutations is autosomal dominant. Thus, progeny of parents with a known mutation are at high (50%) risk of having the same parental LQTS mutation. The algorithm will be developed using FHR measured serially throughout pregnancy. All offspring will undergo postnatal genetic testing for the parental mutation as the gold standard for diagnosing the presence or absence of LQTS.

Conditions

Long QT Syndrome

Outcome Measures

Primary Outcomes (2)

• Effectiveness of an Fetal Heart Rate/Gestational Age, FHR/GA, Algorithm

  The investigators hypothesize that from this fetal cohort, they can construct a FHR/GA algorithm that will discriminate fetuses who inherit the parental LQTS mutation from those who do not, with an area under the ROC ≥0.75.

  5 years

• Differences in the Receiver Operating Characteristic (ROC) of FHR/GA vs gold standard of genetic testing

  The area under the ROC of the FHR/GA algorithm compared to a gold standard of genetic testing will remain ≥0.75 across mutation types and offspring sex. Based on power calculations using preliminary studies, the investigators estimate they can test this hypothesis by study of 200 fetal subjects.

  5 years

Study Arms (2)

Prospective cohort

These are women who are currently pregnant and who have a LQTS mutation. This also includes women whose partner/father of the baby has a LQTS mutation. If the father of the child has the LQTS mutation, the father will also be enrolled.

Retrospective cohort

In this cohort the investigators will collect information about previous pregnancies affected by the LQTS mutation. Parents may enroll in both retrospective and prospective cohorts

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Up to 500 total subjects will be enrolled globally. Up to 303 subjects will be enrolled locally. This number includes mothers, fetuses, and fathers who have long QT syndrome.

You may qualify if:

• years of age
• Pregnant women with a previously identified mutation in a known LQTS gene or pregnant women whose partner (and the father of the baby) has a previously identified mutation in a known LQTS gene will be invited to participate. If the pregnant partner of a man with a LQTS gene is enrolled, then the man/father of child will be enrolled as well.
• Women at 7-30 weeks of gestation

You may not qualify if:

• Phenotype positive but genotype negative pregnant woman or father of the fetus,
• Fetuses with congenital or chromosomal anomaly identified before or after birth
• Pregnant women who present beyond 30 weeks of pregnancy.
• years of age
• Women with a previous pregnancy and a known LQTS gene or where the father of the baby had a known LQTS gene
• Women with a mutation in a known LQTS gene, or
• Women whose partner/father of the baby has a mutation in a known LQTS gene (The father of the child will be enrolled if mother of child is enrolled)
• Phenotype positive but genotype negative pregnant woman or father of the fetus,
• Fetuses with congenital or chromosomal anomaly identified before or after birth
• Fetal heart rate data unavailable prior to 30 weeks of pregnancy

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Children's Hospital Colorado: collaborator
• University of Pavia: collaborator
• University of Utah: collaborator
• Mayo Clinic: collaborator
• University of Helsinki: collaborator
• University of Amsterdam: collaborator
• University of Oslo: collaborator
• University Hospital, Umeå: collaborator
• Deutsches Herzzentrum Muenchen: collaborator
• Vanderbilt University: collaborator
• University of Bonn: collaborator
• University of Tsukuba: collaborator
• Eastern Virginia Medical School: collaborator

Study Sites (1)

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

MeSH Terms

Conditions

Long QT Syndrome

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Bettina F Cuneo, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: OTHER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 8, 2016
• First Posted: August 23, 2016
• Study Start: November 1, 2014
• Primary Completion: July 8, 2019
• Study Completion: July 8, 2019
• Last Updated: February 21, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)