Mothers with Long QT Syndrome Face an Increased Risk for Fetal Death

Key takeaways

• Children’s Hospital Colorado researchers led an international multicenter study on outcomes of 148 pregnancies from 103 LQTS families.
• The risk of miscarriage or stillbirth was significantly higher than the general population and occurred primarily when the mother rather than the father carried the pathogenetic LQTS variant.
• This suggests that pregnant women with LQTS may benefit from high-risk obstetrical and fetal cardiology care

Research background: understanding familial long QT syndrome (LQTS) and its effects on pregnancy outcome

LQTS is the most common cardiac channelopathy, which predisposes the affected individual to an increased risk of death from ventricular tachycardia.

• About 90% of people with LQTS inherit the genotype.
  • 10% occur de novo
• About 80% of all LQTS are one of three genetic subtypes (LQT1, LQT2, LQT3).
• LQTS is often found to be causative in sudden unexplained death of the young.
  • 3 to 10% of sudden infant death syndrome victims
  • 8% purportedly normal stillbirths

Before this study, little was known about pregnancy outcomes of inherited long QT syndrome. Bettina F. Cuneo, MD, former director of Perinatal Cardiology in the Colorado Fetal Care Center at Children’s Hospital Colorado, served as the lead author. She led the international multicenter study aimed to understand the pregnancy outcomes of familial LQTS. Familial LQTS is when the mother or father carries the LQTS genotype.

The study looked at the three most common types of familial LQTS to determine if stillbirths and/or miscarriages occurred more frequently in familial long QT syndrome than in the normal population. Researchers also examined if the risk differed based on the parent of LQTS origin.

Research methods: a multicenter, retrospective study of LQTS

The retrospective study recruited subjects from 11 international centers, known collectively as the Fetal LTQS Consortium. Each center reviewed their patient databases for 18- to 40-year old men and women with LQT1, LQT2 or LQT3. Pregnancies in which the mother or father had a positive genetic test for LQT1, LQT2, or LQT3 were included in the study. Researchers also evaluated pregnancy outcomes, including gestational age at delivery, birthweight and whether the infant inherited the family LQT variant.

Research results: familial origin and rate of death

Research data from the 11 centers included 148 pregnancies from 103 families:

• 80 mothers with long QT
  • 119 pregnancies
    • 65 LTQ1
    • 41 LQT2
    • 5 LQT3
• 23 fathers with long QT
  • 29 pregnancies
    • 20 LQT1
    • 4 LQT2
    • 5 LQT3

Live births: 118

Fetal deaths: 30

• 24 miscarriages (all in maternal LQTS families)
  • Occurrence is two times greater than general population
• 6 stillbirths (5/6 in maternal LQTS families)
  • Occurrence is eight times greater than general population

Effect of parental origin of long QT syndrome

The overall chance of fetal death was 24.4% vs. 3.5% if the mother, rather than the father, had LQTS. Unfortunately, only 10% of fetal deaths were tested for LQTS, but of those tested not all had inherited LQTS.

Effect of beta-blocker treatment on pregnancy outcome

Of the 80 long QT syndrome-positive mothers, 71% (57) were treated with beta blockers.

• LQT1: 78%
• LQT2: 84%
• LQT3: 10%

A total of 20 mothers with LQTS experienced one or more fetal deaths; 11 had a history of beta-blocker treatment during pregnancy.

Effect of long QT syndrome on obstetrical outcomes

Mothers with LQTS delivered earlier and, when the data were controlled for gestational age, their newborns weighed less than those who had fathers with LQTS. Fetal arrhythmias other than sinus bradycardia were rare.

Research conclusion: greater risk of fetal death, lower birth weight associated with maternal long QT syndrome

Mothers with LQTS should be considered high risk and followed by maternal fetal medicine specialists and fetal cardiologists as well as their obstetricians. Dr. Cuneo, along with the participating institutions’ researchers, are the first to demonstrate that mothers with LQTS are at an increased risk of poor pregnancy outcome.

This study also unveiled a previously unreported cause of stillbirth and encouraged the use of postmortem molecular autopsy (testing for a LQTS pathogenic variant in unexplained stillbirth). The results suggest that the channelopathy is not limited to the heart but may also cause placental dysfunction leading to increased susceptibility to fetal death and growth restriction in maternal LQTS pregnancies.