Bettina F Cuneo1, Alexander M Kaizer2, Sally Ann Clur3, Heikki Swan4, Ulrike Herberg5, Annika Winbo5, Annika Rydberg6, Kristina Haugaa7, Susan Etheridge8, Michael J Ackerman9, Federica Dagradi10, Stacy A S Killen11, Annette Wacker-Gussmann12, D Woodrow Benson13, A A M Wilde14, Zhaoxing Pan15, Aimee Lam16, Carla Spazzolini10, Hitoshi Horigome17, Peter J Schwartz10. 1. Colorado Fetal Care Center, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO. Electronic address: Bettina.Cuneo@childrenscolorado.org. 2. Department of Biostatistics and Informatics, University of Colorado, Aurora, CO. 3. Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands. 4. University of Finland, Helsinki, Finland. 5. University of Bonn, Bonn, Germany. 6. Department of Clinical Sciences, Umea University, Umea, Sweden. 7. University of Oslo, Oslo, Norway. 8. Primary Children's Hospital, University of Utah School of Medicine, Salt Lake City, UT. 9. Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN. 10. IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy. 11. Monroe Carell Jr Children's Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN. 12. German Heart Center, Department of Pediatric Cardiology and Congenital Heart Disease, Munich, Germany. 13. Department of Pediatrics Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI. 14. Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands and Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia. 15. Biostatistics Core of the Research Institute, Children's Hospital Colorado, Aurora, CO. 16. Colorado Fetal Care Center, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO. 17. Department of Pediatrics, Tsukuba University, Ibaraki, Japan.
Abstract
BACKGROUND: Most fetal deaths are unexplained. Long QT syndrome is a genetic disorder of cardiac ion channels. Affected individuals, including fetuses, are predisposed to sudden death. We sought to determine the risk of fetal death in familial long QT syndrome, in which the mother or father carries the long QT syndrome genotype. In addition, we assessed whether risk differed if the long QT syndrome genotype was inherited from the mother or father. OBJECTIVE: This was a retrospective review of pregnancies in families with the 3 most common heterozygous pathogenic long QT syndrome genotypes in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3), which occur in approximately 1 in 2000 individuals. The purpose of our study was to compare pregnancy and birth outcomes in familial long QT syndrome with the normal population and between maternal and paternal carriers of the long QT syndrome genotype. We hypothesized that fetal death before (miscarriage) and after (stillbirths) 20 weeks gestation would be increased in familial long QT syndrome compared with the normal population and that the parent of origin would not affect birth outcomes. STUDY DESIGN: Our study was a multicenter observational case series of 148 pregnancies from 103 families (80 mothers, 23 fathers) with familial long QT syndrome (60 with LQT1, 29 with LQT2, 14 with LQT3) who were recruited from 11 international centers with expertise in hereditary heart rhythm diseases, pediatric and/or adult electrophysiology, and high-risk pregnancies. Clinical databases from these sites were reviewed for long QT syndrome that occurred in men or women of childbearing age (18-40 years). Pregnancy outcomes (livebirth, stillbirth, and miscarriage), birthweights, and gestational age at delivery were compared among long QT syndrome genotypes and between maternal vs paternal long QT syndrome-affected status with the use of logistic regression analysis. RESULTS: Most offspring (80%; 118/148) were liveborn at term; 66% of offspring (73/110) had long QT syndrome. Newborn infants of mothers with long QT syndrome were delivered earlier and, when the data were controlled for gestational age, weighed less than newborn infants of long QT syndrome fathers. Fetal arrhythmias were observed rarely, but stillbirths (fetal death at >20 weeks gestation) were 8 times more frequent in long QT syndrome (4% vs approximately 0.5%); miscarriages (fetal death at ≤20 weeks gestation) were 2 times that of the general population (16% vs 8%). The likelihood of fetal death was significantly greater with maternal vs paternal long QT syndrome (24.4% vs 3.4%; P=.036). Only 10% of all fetal deaths underwent postmortem long QT syndrome testing; 2 of 3 cases were positive for the family long QT syndrome genotype. CONCLUSION: This is the first report to demonstrate that mothers with long QT syndrome are at increased risk of fetal death and to uncover a previously unreported cause of stillbirth. Our results suggest that maternal effects of long QT syndrome channelopathy may cause placental or myometrial dysfunction that confers increased susceptibility to fetal death and growth restriction in newborn survivors, regardless of long QT syndrome status.
BACKGROUND: Most fetal deaths are unexplained. Long QT syndrome is a genetic disorder of cardiac ion channels. Affected individuals, including fetuses, are predisposed to sudden death. We sought to determine the risk of fetal death in familial long QT syndrome, in which the mother or father carries the long QT syndrome genotype. In addition, we assessed whether risk differed if the long QT syndrome genotype was inherited from the mother or father. OBJECTIVE: This was a retrospective review of pregnancies in families with the 3 most common heterozygous pathogenic long QT syndrome genotypes in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3), which occur in approximately 1 in 2000 individuals. The purpose of our study was to compare pregnancy and birth outcomes in familial long QT syndrome with the normal population and between maternal and paternal carriers of the long QT syndrome genotype. We hypothesized that fetal death before (miscarriage) and after (stillbirths) 20 weeks gestation would be increased in familial long QT syndrome compared with the normal population and that the parent of origin would not affect birth outcomes. STUDY DESIGN: Our study was a multicenter observational case series of 148 pregnancies from 103 families (80 mothers, 23 fathers) with familial long QT syndrome (60 with LQT1, 29 with LQT2, 14 with LQT3) who were recruited from 11 international centers with expertise in hereditary heart rhythm diseases, pediatric and/or adult electrophysiology, and high-risk pregnancies. Clinical databases from these sites were reviewed for long QT syndrome that occurred in men or women of childbearing age (18-40 years). Pregnancy outcomes (livebirth, stillbirth, and miscarriage), birthweights, and gestational age at delivery were compared among long QT syndrome genotypes and between maternal vs paternal long QT syndrome-affected status with the use of logistic regression analysis. RESULTS: Most offspring (80%; 118/148) were liveborn at term; 66% of offspring (73/110) had long QT syndrome. Newborn infants of mothers with long QT syndrome were delivered earlier and, when the data were controlled for gestational age, weighed less than newborn infants of long QT syndrome fathers. Fetal arrhythmias were observed rarely, but stillbirths (fetal death at >20 weeks gestation) were 8 times more frequent in long QT syndrome (4% vs approximately 0.5%); miscarriages (fetal death at ≤20 weeks gestation) were 2 times that of the general population (16% vs 8%). The likelihood of fetal death was significantly greater with maternal vs paternal long QT syndrome (24.4% vs 3.4%; P=.036). Only 10% of all fetal deaths underwent postmortem long QT syndrome testing; 2 of 3 cases were positive for the family long QT syndrome genotype. CONCLUSION: This is the first report to demonstrate that mothers with long QT syndrome are at increased risk of fetal death and to uncover a previously unreported cause of stillbirth. Our results suggest that maternal effects of long QT syndrome channelopathy may cause placental or myometrial dysfunction that confers increased susceptibility to fetal death and growth restriction in newborn survivors, regardless of long QT syndrome status.
Authors: Peter J Schwartz; Michael J Ackerman; Charles Antzelevitch; Connie R Bezzina; Martin Borggrefe; Bettina F Cuneo; Arthur A M Wilde Journal: Nat Rev Dis Primers Date: 2020-07-16 Impact factor: 52.329
Authors: Lee L Eckhardt; Elizabeth S Kaufman; Michael J Ackerman; Peter F Aziz; Elijah R Behr; Marina Cerrone; Mina K Chung; Michael J Cutler; Susan P Etheridge; Andrew D Krahn; Steven A Lubitz; Marco V Perez; Silvia G Priori; Jason D Roberts; Dan M Roden; Eric Schulze-Bahr; Peter J Schwartz; Wataru Shimizu; M Benjamin Shoemaker; Raymond W Sy; Jeffrey A Towbin; Sami Viskin; Arthur A M Wilde; Wojciech Zareba Journal: Circ Arrhythm Electrophysiol Date: 2021-07-09
Authors: Elizabeth A Streeten; Vincent Y See; Linda B J Jeng; Kristin A Maloney; Megan Lynch; Andrew M Glazer; Tao Yang; Dan Roden; Toni I Pollin; Melanie Daue; Kathleen A Ryan; Cristopher Van Hout; Nehal Gosalia; Claudia Gonzaga-Jauregui; Aris Economides; James A Perry; Jeffrey O'Connell; Amber Beitelshees; Kathleen Palmer; Braxton D Mitchell; Alan R Shuldiner Journal: Circ Genom Precis Med Date: 2020-11-03