Prospective Identification of Long QT Syndrome in Fetal Life
| Status: | Recruiting |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 45 |
| Updated: | 9/20/2018 |
| Start Date: | November 2014 |
| End Date: | December 2020 |
| Contact: | Bettina F Cuneo, MD |
| Email: | bettina.cuneo@childrenscolorado.org |
| Phone: | 720-777-6820 |
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.
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.
Ascertainment of LQTS, an inherited arrhythmia disorder in a group of conditions known as the
channelopathies, is challenging before birth. Recently, in a retrospective study it was
reported that a gestational age dependent bradycardia allows a much higher recognition of
genotype positive LQTS than the standard obstetrical gestational age independent definition
of bradycardia (Mitchell 2012).
However, the fetal heart rate in pregnancies with maternal or paternal LQTS diagnosed prior
to the pregnancy has not been evaluated prospectively from the first trimester to birth. Nor
is it known if the fetal heart rate /gestational age profile might be mutation specific. In
addition, the use of fetal heart rate to successfully distinguish between LQTS and normal
fetuses of pregnancies in which a parent has a known mutation has not been tested.
The investigators believe that fetuses with an LQTS mutation born to families in which the
mother or father has an LQTS mutation will have slower heart compared to fetuses, shown after
birth not to have the family mutation. If the investigators hypothesis is correct, these
findings could be applied to the general population of pregnant women to prospectively
identify fetuses with LQTS and without a known family history. Since a fetal proband has been
led to the identification of unsuspecting family members, prospectively identifying affected
fetuses would increase ascertainment of life-threatening mutations in all ages (Cuneo 2013).
channelopathies, is challenging before birth. Recently, in a retrospective study it was
reported that a gestational age dependent bradycardia allows a much higher recognition of
genotype positive LQTS than the standard obstetrical gestational age independent definition
of bradycardia (Mitchell 2012).
However, the fetal heart rate in pregnancies with maternal or paternal LQTS diagnosed prior
to the pregnancy has not been evaluated prospectively from the first trimester to birth. Nor
is it known if the fetal heart rate /gestational age profile might be mutation specific. In
addition, the use of fetal heart rate to successfully distinguish between LQTS and normal
fetuses of pregnancies in which a parent has a known mutation has not been tested.
The investigators believe that fetuses with an LQTS mutation born to families in which the
mother or father has an LQTS mutation will have slower heart compared to fetuses, shown after
birth not to have the family mutation. If the investigators hypothesis is correct, these
findings could be applied to the general population of pregnant women to prospectively
identify fetuses with LQTS and without a known family history. Since a fetal proband has been
led to the identification of unsuspecting family members, prospectively identifying affected
fetuses would increase ascertainment of life-threatening mutations in all ages (Cuneo 2013).
Inclusion Criteria: (Prospective arm)
1. 18-45 years of age
2. 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.
3. Women at 7-30 weeks of gestation
Exclusion Criteria: (Prospective arm)
1. Phenotype positive but genotype negative pregnant woman or father of the fetus,
2. Fetuses with congenital or chromosomal anomaly identified before or after birth
3. Pregnant women who present beyond 30 weeks of pregnancy.
Inclusion Criteria (Retrospective arm)
1. 18-45 years of age
2. Women with a previous pregnancy and a known LQTS gene or where the father of the baby
had a known LQTS gene
3. Women with a mutation in a known LQTS gene, or
4. 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)
Exclusion Criteria (Retrospective arm)
1. Phenotype positive but genotype negative pregnant woman or father of the fetus,
2. Fetuses with congenital or chromosomal anomaly identified before or after birth
3. Fetal heart rate data unavailable prior to 30 weeks of pregnancy
We found this trial at
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13123 E 16th Ave
Aurora, Colorado 80045
Aurora, Colorado 80045
(720) 777-1234
Phone: 720-777-9514
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