Complex and Novel Arrhythmias Precede Stillbirth in Fetuses With De Novo Long QT Syndrome

Background: Long QT syndrome (LQTS) is a leading cause of sudden cardiac death in early life and has been implicated in ≈10% of sudden infant deaths and unexplained stillbirths. The purpose of our study was to use fetal magnetocardiography to characterize the electrophysiology and rhythm phenotypes of fetuses with de novo and inherited LQTS variants and identify risk factors for sudden death before birth. Methods: We reviewed the fetal magnetocardiography database from the University of Wisconsin Biomagnetism Laboratory for fetuses with confirmed LQTS. We assessed waveform intervals, heart rate, and rhythm, including the signature LQTS rhythms: functional 2° atrioventricular block, T-wave alternans, and torsade de pointes (TdP). Results: Thirty-nine fetuses had pathogenic variants in LQTS genes: 27 carried the family variant, 11 had de novo variants, and 1 was indeterminate. De novo variants, especially de novo SCN5A variants, were strongly associated with a severe rhythm phenotype and perinatal death: 9 (82%) showed signature LQTS rhythms, 6 (55%) showed TdP, 5 (45%) were stillborn, and 1 (9%) died in infancy. Those that died exhibited novel fetal rhythms, including atrioventricular block with 3:1 conduction ratio, QRS alternans in 2:1 atrioventricular block, long-cycle length TdP, and slow monomorphic ventricular tachycardia. Premature ventricular contractions were also strongly associated with TdP and perinatal death. Fetuses with familial variants showed a lower incidence of signature LQTS rhythm (6/27=22%), including TdP (3/27=11%). All were live born. Conclusions: The malignancy of de novo LQTS variants was remarkably high and demonstrate that these mutations are a significant cause of stillbirth. Their ability to manifest rhythms not known to be associated with LQTS increases the difficulty of echocardiographic diagnosis and decreases the likelihood that a resultant fetal loss is attributed to LQTS. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT03047161.

Fetal cardiac time intervals in healthy pregnancies – an observational study by fetal ECG (Monica Healthcare System)

Background: Fetal electrocardiogram (fECG) can detect QRS signals in fetuses from as early as 17 weeks’ gestation; however, the technique is limited by the minute size of the fetal signal relative to noise ratio. The aim of this study was to evaluate precise fetal cardiac time intervals (fCTIs) with the help of a newly developed fetal ECG device (Monica Healthcare System). Methods: In a prospective manner we included 15–18 healthy fetuses per gestational week from 32 weeks onwards. The small and wearable Monica AN24 monitoring system uses standard ECG electrodes placed on the maternal abdomen to monitor fECG, maternal ECG and uterine electromyogram (EMG). Fetal CTIs were estimated on 1000 averaged fetal heart beats. Detection was deemed successful if there was a global signal loss of less than 30% and an analysis loss of the Monica AN24 signal separation analysis of less than 50%. Fetal CTIs were determined visually by three independent measurements. Results: A total of 149 fECGs were performed. After applying the requirements 117 fECGs remained for CTI analysis. While the onset and termination of P-wave and QRS-complex could be easily identified in most ECG patterns (97% for P-wave, PQ and PR interval and 100% for QRS-complex), the T-wave was detectable in only 41% of the datasets. The CTI results were comparable to other available methods such as fetal magnetocardiography (fMCG). Conclusions: Although limited and preclinical in its use, fECG (Monica Healthcare System) could be an additional useful tool to detect precise fCTIs from 32 weeks’ gestational age onwards.