LAUSR

BACKGROUND Most fetal deaths are unexplained. Long QT syndrome (LQTS) 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 LQTS, in which the mother or father carries LQTS genotype. In addition, we assessed whether risk differed if the LQTS genotype was inherited from the mother or father. OBJECTIVE (s): This was a retrospective review of pregnancies in families with the 3 most common heterozygous pathogenic LQTS genotypes in KCNQ1 (LQT1), KCNH2 (LQT2) or SCN5A (LQT3), which occur in ∼1/2000 individuals. The purpose of our study was to compare pregnancy and birth outcomes in familial LQTS with the normal population and between maternal and paternal carriers of the LQTS genotype. We hypothesized that fetal death before (miscarriage) and after (stillbirths) 20 weeks gestation would be increased in familial LQTS compared to the normal population, and 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 LQTS (60 LQT1, 29 LQT2, 14 LQT3) 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 LQTS occurring in men or women of childbearing age (18-40 years). Pregnancy outcomes (livebirth, stillbirth and miscarriage), birthweights and gestational age at delivery were compared between LQTS genotypes and between maternal vs. paternal LQTS-affected status using logistic regression analysis. RESULTS Most offspring (80%, 118/148) were term live born, and 66% (73/110) had LQTS. Newborns of LQTS mothers were delivered earlier and, when controlling for gestational age, weighed less than newborns of LQTS fathers. Fetal arrhythmias were rarely observed, but stillbirths (fetal death > 20 weeks) were 8 times more frequent in LQTS (4% vs.∼ 0.5%) while miscarriages (fetal death ≤ 20 weeks) were 2 times that of the general population (16% vs. 8%). The likelihood of fetal death was significantly greater with maternal vs. paternal LQTS (24.4% vs. 3.4%, P=0.036). Only 10% of all fetal deaths underwent postmortem LQTS testing; 2 of 3 were positive for the family LQTS genotype. CONCLUSION (s): This is the first report demonstrating that mothers with LQTS are at increased risk of fetal death and uncovers a previously unreported etiology of stillbirth. Our results suggest that maternal effects of LQTS channelopathy may cause placental or myometrial dysfunction conferring increased susceptibility to fetal death and growth restriction in newborn survivors, regardless of LQTS status.