Low Baseline Fetal Heart Rate Leads to Diagnosis of Long QT Syndrome Type 1.

A low baseline fetal heart rate at 20 weeks' gestation was detected in a fetus without cardiac structural anomalies. Fetal echocardiography and magnetocardiography were used to diagnose congenital long QT syndrome. It was confirmed in the neonate, and the same pathogenic variant in KCNQ1 was subsequently identified in the mother.

Fetal Congenital Complete Heart Block: A Rare Case with an Extremely Low Ventricular Rate and Review of Current Management Strategies.

Congenital complete heart block (CCHB) is associated with high intrauterine and post-natal mortality. Prenatal detection and management, as well as appropriate delivery planning, may improve the outcomes in CCHB. We describe a rare case of CCHB that initially presented with fetal ascites and high-grade second-degree heart block noted on fetal echocardiography. The mother was noted to be positive for anti-SSA antibodies, and treatment with maternal steroids was started in an effort to reverse the fetal cardiac conduction abnormality. However, the fetal cardiac rhythm progressed to complete heart block by the follow up evaluation and the fetus had a continual declination of heart rate throughout the pregnancy to a low fetal heart rate of 25 beats per minute (bpm). This case demonstrates the lowest fetal ventricular rate documented in the literature and illustrates a severe presentation of a rare disease process. An overview of the existing knowledge related to etiology, prenatal evaluation with fetal echocardiography and fetal magnetocardiography, prenatal management, and delivery planning in fetuses with prenatally detected CCHB is included.

A Small Scale Optically Pumped Fetal Magnetocardiography System.

INTRODUCTION: Fetal magnetocardiography (fMCG) is considered the best technique for diagnosis of fetal arrhythmia. It is superior to more widely used methods such as fetal, fetal electrocardiography, and cardiotocography for evaluation of fetal rhythm. The combination of fMCG and fetal echocardiography can provide a more comprehensive evaluation of fetal cardiac rhythm and function than is currently possible. In this study, we demonstrate a practical fMCG system based on optically pumped magnetometers (OPMs). METHODS: Seven pregnant women with uncomplicated pregnancies underwent fMCG at 26-36 weeks' gestation. The recordings were made using an OPM-based fMCG system and a person-sized magnetic shield. The shield is much smaller than a shielded room and provides easy access with a large opening that allows the pregnant woman to lie comfortably in a prone position. RESULTS: The data show no significant loss of quality compared to data acquired in a shielded room. Measurements of standard cardiac time intervals yielded the following results: PR = 104 ± 6 ms, QRS = 52.6 ± 1.5 ms, and QTc = 387 ± 19 ms. These results are compatible with those from prior studies performed using superconducting quantum interference device (SQUID) fMCG systems. CONCLUSIONS: To our knowledge, this is the first European fMCG device with OPM technology commissioned for basic research in a pediatric cardiology unit. We demonstrated a patient-friendly, comfortable, and open fMCG system. The data yielded consistent cardiac intervals, measured from time-averaged waveforms, compatible with published SQUID and OPM data. This is an important step toward making the method widely accessible.

Ferrite Shield to Enhance the Performance of Optically Pumped Magnetometers for Fetal Magnetocardiography.

Fetal magnetocardiography (fMCG) has proven to be an important tool for the prenatal monitoring of electrical cardiac activity; however, the high cost of superconducting quantum instrumentation (SQUID) poses a limitation for the dissemination of fMCG as a routine clinical technique. Recently, optically pumped magnetometers (OPMs) operating within person-sized, cylindrical shields have made fMCG more practical, but environmental magnetic interference entering through the shield opening substantially degrades the quality of fMCG signals. The goal of this study was to further attenuate these interferences by placing the OPM array within a small ferrite shield. FMCG recordings were made with and without the ferrite shield in ten subjects inside a person-sized, three-layer mu-metal cylindrical shield. Although the fetal signal was slightly attenuated, the environmental interference was reduced substantially, and maternal interference was also diminished. This increased the signal-to-noise ratio significantly and improved the resolution of the smaller waveform components. The performance improvement was highest in the axial direction and compensated for a major weakness of open-ended, person-sized shields. The ferrite shield is especially beneficial for the deployment of triaxial OPM sensors, which require effective shielding in all directions.

Contribution of Fetal Magnetocardiography to Diagnosis, Risk Assessment, and Treatment of Fetal Arrhythmia.

Background Fetal echocardiography has been the mainstay of fetal arrhythmia diagnosis; however, fetal magnetocardiography (fMCG) has recently become clinically available. We sought to determine to what extent fMCG contributed to the precision and accuracy of fetal arrhythmia diagnosis and risk assessment, and in turn, how this altered pregnancy management. Methods and Results We reviewed fMCG tracings and medical records of 215 pregnancies referred to the Biomagnetism Laboratory, UW-Madison, over the last 10 years, because of fetal arrhythmia or risk of arrhythmia. We compared referral diagnosis and treatment with fMCG diagnosis using a rating scale and restricted our review to the 144 subjects from the tachycardia, bradycardia/AV block, and familial long QT syndrome categories. Additional fMCG findings beyond those of the referring echocardiogram, or an alternative diagnosis were seen in 117/144 (81%), and 81 (56%) were critical changes. Eight (5.5%) had resolution of arrhythmia before fMCG. At least moderate changes in management were seen in 109/144 (76%) fetuses, of which 35/144 (24%) were major. The most diverse fMCG presentation was long QT syndrome, present in all 3 referral categories. Four of 5 stillbirths were seen with long QT syndrome. Nine fetuses showed torsades de pointes ventricular tachycardia, of which only 2 were recognized before fMCG. Conclusions FMCG has a significant impact on prenatal diagnosis and management of arrhythmias or familial arrhythmia risk, which cannot be fully met by existing technology. The combination of fMCG and fetal echocardiography in fetal care centers will be needed in the future to optimize care.

Genotype Predicts Outcomes in Fetuses and Neonates With Severe Congenital Long QT Syndrome.

OBJECTIVES: This study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs). BACKGROUND: LQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown. METHODS: A retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death. RESULTS: A total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p < 0.001), and LQT3, relative to LQT2, genotype predicted death and/or cardiac transplant (p < 0.001). CONCLUSIONS: In this large multicenter study, fetuses and/or neonates with LQT3 but not those with LQT1 or LQT2 presenting with severe arrhythmias were at high risk of not only frequent, but lethal CEs.

Dynamics of the use of magnetocardiography in the study of the cardiac conduction system of the chick embryo.

INTRODUCTION: Human fetal magnetocardiography (fMCG) has been done for several decades to evaluate fetal arrhythmias using a superconducting quantum interference device (SQUID) magnetometer, but there is little work in embryonic/fetal animal models. This study uses an optically-pumped magnetometer (OPM) to obtain an fMCG in the chick embryo. METHODS: White Leghorn chick embryos were examined from incubation Day #10-19. Different examination chambers were tested to optimize embryonic thermal stability and magnetic signal acquisition. All examinations were done with magnetic shielding. The OPM sensors were placed next to the egg shell. The embryo's position was localized by transilluminating the intact egg or ultrasound imaging the egg with an open air cell to optimize sensor placement. The raw data for each embryo was postprocessed to obtain a fMCG composite waveform. RESULTS: fMCG's were obtained in embryos from Day #12 to 19. The best success with intact eggs was obtained using five sensors; one at the bottom and four around the lower perimeter of the egg at 90° intervals with the egg oriented vertically and the air cell up. Using ultrasound imaging with the air cell open only two sensors were necessary, one at the bottom and one laterally next to the embryo. fMCGs were analyzed for heart rate and rhythm, each portion of the PQRST waveform, and the PR interval, QRS complex, RR interval, and QT interval. CONCLUSIONS: This study validates the chick embryo as an animal model to study in a longitudinal and noninvasive fashion the fetal cardiac conduction system by using OPM magnetocardiography.

Noninvasive Fetal Electrocardiography in the Diagnosis of Long QT Syndrome: A Case Series.

INTRODUCTION: Early detection and monitoring for malignant arrhythmias is fundamental to prenatal care in long QT syndrome (LQTS). Recently, we studied the feasibility of isolating the fetal electrocardiogram (fECG) and measuring electrocardiographic intervals with a noninvasive fECG device using blind source separation with reference signal. Our aim was to evaluate the ability of fECG to diagnose LQTS. CASE PRESENTATIONS: We identified 3 cases of clinically suspected LQTS based on fetal echocardiogram (2 had sinus bradycardia, 1 had second-degree atrioventricular block with negative maternal anti-SSA/SSB antibody titers). With institutional review board approval, these patients were prospectively enrolled for fECG acquisition. Offline post-processing generated fECG waveforms and calculated QT intervals. Case 1 and 3 had a maternal history of LQTS. Two of the three fetuses with suspected LQTS had confirmed LQTS by postnatal ECG and genetic testing. FECG was able to identify a prolonged corrected QT interval in both cases. One of these also had fetal magnetocardiography (fMCG), which yielded similar findings to the fECG. The third fetus had a normal fECG; fMCG and postnatal ECG were also normal. CONCLUSIONS: In 3 cases, fECG findings corroborated the diagnosis of LQTS. Noninvasive fECG may offer a novel method for fECG that is portable and more clinically accessible.

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.

Repolarization Predictors of Fetal Long QT Syndrome.

BACKGROUND: Diagnosis of fetal long QT syndrome (LQTS) using fetal magnetocardiography (fMCG) is straightforward in cases of overt QTc prolongation accompanied by LQTS rhythms; however, cases of isolated QTc prolongation can be challenging. OBJECTIVE: To characterize repolarization in normal and phenotype-positive LQTS fetuses with the goal of utilizing additional parameters of repolarization to improve the accuracy of fMCG diagnosis of LQTS. METHODS: FMCG recordings were taken from 37 phenotype-positive fetuses with confirmed LQTS and 132 normal controls. The normal fetuses were grouped into those with T-and U-waves and those with only T-waves. We compared the repolarization characteristics of normal fetuses with only T-waves with those of LQTS fetuses. We also compared the repolarization characteristics of normal fetuses with T-and U-waves with those of LQTS fetuses with two-component T-waves. RESULTS: Late-peaking T-waves were strongly associated (35/37= 95%) with LQTS. No normal fetuses showed both QTc prolongation (QTc> 500 ms) and a late-peaking T-wave. U-waves were seen in 11 normal fetuses (8%) and resulted in waveforms that often mimicked those of the 19 LQTS fetuses with two-component T-waves; however, in normal fetuses the polarities of the T-and U-waves were the same, whereas in LQTS fetuses with two-component T-waves the polarity of the components was usually opposite. CONCLUSION: A late-peaking T-wave in association with QTc prolongation is a distinctive, reliable indicator of fetal LQTS. U-waves confound assessment of QTc; however, normal U-waves can usually be distinguished from LQTS T-waves based on polarity.

Low-Cost Fetal Magnetocardiography: A Comparison of Superconducting Quantum Interference Device and Optically Pumped Magnetometers.

Background Fetal magnetocardiography (fMCG) is a highly effective technique for evaluation of fetuses with life-threatening arrhythmia, but its dissemination has been constrained by the high cost and complexity of Superconducting Quantum Interference Device (SQUID) instrumentation. Optically pumped magnetometers (OPMs) are a promising new technology that can replace SQUIDs for many applications. This study compares the performance of an fMCG system, utilizing OPMs operating in a person-sized magnetic shield, to that of a conventional fMCG system, utilizing SQUID magnetometers operating in a magnetically shielded room. Methods and Results fMCG recordings were made in 24 subjects using the SQUID system with the mother lying supine in a magnetically shielded room and the OPM system with the mother lying prone in a person-sized, cylindrical shield. Signal-to-noise ratios of the OPM and SQUID recordings were not statistically different and were adequate for diagnostic purposes with both technologies. Although the environmental noise was higher using the small open-ended shield, this was offset by the higher signal amplitude achieved with prone positioning, which reduced the distance between the fetus and sensors and improved patient comfort. In several subjects, fMCG provided a differential diagnosis that was more precise and/or definitive than was possible with echocardiography alone. Conclusions The OPM-based system was portable, improved patient comfort, and performed as well as the SQUID-based system at a small fraction of the cost. Electrophysiological assessment of fetal rhythm is now practical and will have a major impact on management of fetuses with long QT syndrome and other life-threatening arrhythmias.

Fetal magnetocardiogram waveform characteristics.

BACKGROUND: Fetal magnetocardiography (fMCG) is the most direct and precise method of assessing fetal rhythm and conduction. Although the utility of fMCG for evaluation of fetuses with serious arrhythmia is generally acknowledged, many aspects of fetal rhythm and conduction are relatively unstudied. OBJECTIVE: To record fMCG in a large group of normal fetuses in order to provide a more comprehensive evaluation of fMCG waveform characteristics, including waveform intervals, amplitudes, and morphology. METHODS: The subjects were 132 healthy women with uncomplicated singleton pregnancies, studied at 15.7-39.9 (mean 28.9) weeks' gestation in 259 sessions. The P, PR, QRS, QT, QTc, and RR intervals and the P/QRS and T/QRS amplitude ratios were measured. MAIN RESULTS: The P, PR, QRS, and RR intervals increased with gestational age, but QT and QTc did not. U-waves were seen in 11% of fetuses. The T-waves were often flat with low T/QRS amplitude ratios. Equiphasic QRS complexes were associated with tall P-waves. The PR, QRS, and QT intervals showed a power law dependence on RR interval with power law exponents 0.445, 0.363, and 0.381, respectively. SIGNIFICANCE: The data establish prediction intervals for fMCG waveform intervals and amplitudes in normal fetuses. This is critical for identification of fetuses with abnormal rhythm. Our study is the first to document the incidence of U-waves and flat T-waves in the fetus, both of which are uncommon postnatally. The association of tall P-waves with equiphasic QRS complexes provides a useful means of improving the resolution of fetal P-waves.

Fetal QT Interval Estimation Using Sequential Hypothesis Testing.

Objective: Recent studies utilizing fetal magnetocardiography have demonstrated the efficacy of corrected QT interval (QTc) measurement for in utero diagnosis and prognosis of long QT syndrome, a leading cause of sudden death in early life. The objective of the study was to formulate and test a novel statistical estimation method to detect the end of the fetal T-wave and thereby improve the accuracy of fetal QT interval measurement. Methods: To detect the end of the T-wave, we apply a sequential composite hypothesis test to decide when the T-wave has returned to baseline. The method uses the generalized likelihood ratio test in conjunction with a low-rank spatiotemporal model that exploits the repetitive nature of cardiac signals. The unknown model parameters are determined using maximum likelihood estimation. Results: In realistic simulations, the detector was shown to be accurate to within 10 ms (95% prediction interval), even at noise-to-signal ratios as high as 6. When applied to real data from normal fetuses, the detector agreed well with measurements made by cardiologists ( 1.4 6.9 ms). Conclusions: The method was effective and practical. Detector performance was excellent despite the continual presence of strong maternal interference. Significance: This detector serves as a valuable adjunct to traditional measurement based on subjective assessment.Objective: Recent studies utilizing fetal magnetocardiography have demonstrated the efficacy of corrected QT interval (QTc) measurement for in utero diagnosis and prognosis of long QT syndrome, a leading cause of sudden death in early life. The objective of the study was to formulate and test a novel statistical estimation method to detect the end of the fetal T-wave and thereby improve the accuracy of fetal QT interval measurement. Methods: To detect the end of the T-wave, we apply a sequential composite hypothesis test to decide when the T-wave has returned to baseline. The method uses the generalized likelihood ratio test in conjunction with a low-rank spatiotemporal model that exploits the repetitive nature of cardiac signals. The unknown model parameters are determined using maximum likelihood estimation. Results: In realistic simulations, the detector was shown to be accurate to within 10 ms (95% prediction interval), even at noise-to-signal ratios as high as 6. When applied to real data from normal fetuses, the detector agreed well with measurements made by cardiologists ( 1.4 6.9 ms). Conclusions: The method was effective and practical. Detector performance was excellent despite the continual presence of strong maternal interference. Significance: This detector serves as a valuable adjunct to traditional measurement based on subjective assessment.