Mothers with long QT syndrome are at increased risk for fetal death: findings from a multicenter international study

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Publisher: Elsevier B.V.
Document Type: Article
Length: 949 words

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for the Fetal LQTS Consortium Key words channelopathy; fetal arrhythmia; growth restriction; long QT syndrome; pregnancy outcome; stillbirth 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 [less than or equal to]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. Author Affiliation: (a) Colorado Fetal Care Center, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO (b) Department of Biostatistics and Informatics, University of Colorado, Aurora, CO (c) Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands (d) University of Finland, Helsinki, Finland (e) University of Bonn, Bonn, Germany (f) Department of Clinical Sciences, Umea University, Umea, Sweden (g) University of Oslo, Oslo, Norway (h) Primary Children's Hospital, University of Utah School of Medicine, Salt Lake City, UT (i) 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 (j) IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin, Milan, Italy (k) Monroe Carell Jr Children's Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN (l) German Heart Center, Department of Pediatric Cardiology and Congenital Heart Disease, Munich, Germany (m) Department of Pediatrics Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI (n) 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 (o) Biostatistics Core of the Research Institute, Children's Hospital Colorado, Aurora, CO (p) Department of Pediatrics, Tsukuba University, Ibaraki, Japan * Corresponding author: Bettina F. Cuneo, MD. Article History: Received 13 May 2019; Revised 3 September 2019; Accepted 4 September 2019 (footnote) M.J.A. is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medronic, MyoKardia, and St. Jude Medical; Mayo Clinic and M.J.A. have an equity/royalty relationship (without remuneration thus far) with AliveCor, Blue Ox Health, and StemoniX (none of which were involved in this study in any way). The remaining authors report no conflict of interest. (footnote) Cite this article as: Cuneo BF, Kaizer AM, Clur SA, et al. Mothers with long QT syndrome are at increased risk for fetal death: findings from a multicenter international study. Am J Obstet Gynecol 2020;222:263.e1-11. Byline: Bettina F. Cuneo, MD [] (a,*), Alexander M. Kaizer, PhD (b), Sally Ann Clur, MBBCH, MSc(MedFCP) (SA)Paeds, PhD (c), Heikki Swan, MD, PhD (d), Ulrike Herberg, MD (e), Annika Winbo, MD (e), Annika Rydberg, MD (f), Kristina Haugaa, MD (g), Susan Etheridge, MD (h), Michael J. Ackerman, MD, PhD (i), Federica Dagradi, MD (j), Stacy A.S. Killen, MD (k), Annette Wacker-Gussmann, MD (l), D. Woodrow Benson, MD, PhD (m), A.A.M. Wilde, MD, PhD (n), Zhaoxing Pan, MD, PHD (o), Aimee Lam, BS (a), Carla Spazzolini, DVM, MS (j), Hitoshi Horigome, MD (p), Peter J. Schwartz, MD (j)

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Gale Document Number: GALE|A615695130