Correlation of fetal heart rate dynamics to inflammatory markers and brain-derived neurotrophic factor during pregnancy.

OBJECTIVES: This study aims to show the relation between biomarkers in maternal and cord-blood samples and fetal heart rate variability (fHRV) metrics through a non-invasive fetal magnetocardiography (fMCG) technique. METHODS: Twenty-three women were enrolled for collection of maternal serum and fMCG tracings immediately prior to their scheduled cesarean delivery. The umbilical cord blood was collected for measurement of biomarker levels. The fMCG metrics were then correlated to the biomarker levels from the maternal serum and cord blood. RESULTS: Brain-derived neurotrophic factor (BDNF) had a moderate correlation with fetal parasympathetic activity (0.416) and fetal sympathovagal ratios (-0.309; -0.356). Interleukin (IL)-6 also had moderate-sized correlations but with an inverse relationship as compared to BDNF. These correlations were primarily in cord-blood samples and not in the maternal blood. CONCLUSIONS: In this small sample-sized exploratory study, we observed a moderate correlation between fHRV and cord-blood BDNF and IL-6 immediately preceding scheduled cesarean delivery at term. These findings need to be validated in a larger population.

Fetal diagnosis of KCNQ1-variant long QT syndrome using fetal echocardiography and magnetocardiography.

A pregnant woman with KCNQ1 variant long QT syndrome (LQTS) underwent fetal magnetocardiography (fMCG) after atrioventricular (AV) block was noted during fetal echocardiogram-atypical for LQTS type 1. Concern for fetal LQTS on fMCG prompted monitoring of maternal labs, change of maternal beta blocker therapy, and frequent fetal echocardiograms. Collaboration between obstetricians, neonatologists, and pediatric cardiologists ensured safe delivery. Beta blocker therapy was initiated after birth, and postnatal evaluation confirmed genotype and phenotype positive LQTS in the infant. Our experience suggests diagnosis and evaluation of fetal LQTS can alter antenatal management to reduce risk of poor fetal and postnatal outcomes.

Assessment of atrioventricular conduction by echocardiography and magnetocardiography in normal and anti-Ro/SSA-antibody-positive pregnancies.

OBJECTIVES: The objectives of this study were, first, to evaluate the association between fetal echocardiographic atrioventricular (AV) and magnetocardiographic (fMCG) PR intervals at different gestational ages (GAs) in normal and anti-Ro/SSA-antibody-positive pregnancies; second, to determine if PR interval could be predicted by AV interval; and third, to assess the neonatal outcome of fetuses with prolonged AV and PR intervals, with the goal of developing criteria for fetal first-degree AV block (AVB-I). METHODS: This was a retrospective study of anti-Ro/SSA-antibody-positive pregnancies (cases) and controls that underwent fMCG and fetal echocardiography at the same recording session. Cardiac cycle length, GA and AV (by mitral inflow/aortic outflow Doppler) and PR (by fMCG) intervals were measured. We tested for significant differences between AV and PR intervals using generalized estimating equations to account for repeat measurements, and assessed whether PR interval could be predicted reliably by AV interval. After delivery, infants with fetal AV or PR interval Z-score ≥ 3 underwent 12-lead electrocardiography. RESULTS: Thirty-nine controls and 31 cases underwent 46 and 36 simultaneous fMCG and echocardiographic examinations, respectively; 101 controls and nine cases underwent fMCG only. AV and PR intervals increased with GA (P < 0.05 for both). Overall, AV and PR intervals were significantly different from each other (P < 0.001); this difference was not significant when compared between cases and controls (P = 0.222). PR interval could not be predicted accurately from AV interval and GA alone. Three of four cases with AV and PR interval Z-scores > + 3 had postnatal AVB-I despite treatment. The fourth fetus, which had predominately second-degree AVB and rare periods of AVB-I, progressed to third-degree AVB despite treatment with dexamethasone. CONCLUSIONS: The diagnostic threshold for AVB-I, defined by AV interval Z-score, is GA dependent. Based on the observed data, an AV interval Z-score threshold of 3 (AV interval, 151-167 ms) may be appropriate. Echocardiographic AV interval was not predictive of fMCG-PR interval. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Dependencies between maternal and fetal autonomic tone.

Background Disturbances in maternal physiology can cause changes in the fetal condition that may lead to impaired fetal development. Synchronous monitoring of cardiac autonomic tone via the assessment of the fetal and maternal heart rate (HR) and heart rate variability (HRV) may provide an appropriate diagnostic window. Methods Partial rank correlation coefficients between the maternal and fetal HR and HRV indices were calculated and verified by testing surrogate data in 315 magnetocardiographic (MCG) recordings from 141 healthy women pregnant with singleton fetuses [18+6 to 39+2 weeks gestational age (WGA)]. We assessed maternal self-perceived depression, anxiety and stress by means of the Depression, Anxiety, Stress Scales self-reporting instrument (DASS42G) questionnaire. Results The maternal HRV correlated positively with the fetal HRV, but negatively with the fetal HR. Correlation was |r|<0.2 in state-independent and gestational age (GA) <32 weeks, but |r|>0.2 in active sleep and GA ≥32 weeks. The DASS42G results correlated with the maternal HRV and HR, while the fetal HR and HRV were not influenced. Conclusion Correlations between maternal and fetal autonomic activation were statistically confirmed. They depend on the GA and active fetal state. As far as healthy subjects are concerned, maternal self-perceived stress, anxiety or depression is mirrored in maternal but not in fetal autonomic tone.

Fetal magnetocardiography (fMCG) to monitor cardiac time intervals in fetuses at risk for isoimmune AV block.

OBJECTIVE: The objective of this report is to detect cardiac time intervals (CTIs) in fetuses exposed to SSA/Ro-SSB/La antibodies in relation to gestational age (GA) and fetal weight and compared them with a control cohort. METHODS: Fetal magnetocardiography (fMCG) recordings were conducted on a biomagnetic device dedicated to obstetrical measurement starting in the second trimester. Fetal cardiac time intervals of 87 healthy fetuses of normal gestation (control group) were compared to 11 fetuses exposed to maternal SSA/Ro-SSB/La antibodies (study group). RESULTS: fCTIs were analyzed starting at 17 weeks of GA. Atrial and ventricular depolarization times increased with GA in both groups. PQ segments were significantly longer in the study group (50.8 ms vs. 60.2 ms; p < 0.001) independent of GA or fetal weight. PQ segment prolongation was more obvious in the study group prior to 30 weeks of GA. CONCLUSION: PQ segment prolongation can be interpreted as early AV-node involvement caused by maternal SSA/Ro-SSB/La antibodies. The age dependency of the PQ segment should be taken into account in further studies.

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.

Diagnosis and Management of Fetal Arrhythmias in the Current Era.

Diagnosis and management of fetal arrhythmias have changed over the past 40-50 years since propranolol was first used to treat fetal tachycardia in 1975 and when first attempts were made at in utero pacing for complete heart block in 1986. Ongoing clinical trials, including the FAST therapy trial for fetal tachycardia and the STOP-BLOQ trial for anti-Ro-mediated fetal heart block, are working to improve diagnosis and management of fetal arrhythmias for both mother and fetus. We are also learning more about how "silent arrhythmias", like long QT syndrome and other inherited channelopathies, may be identified by recognizing "subtle" abnormalities in fetal heart rate, and while echocardiography yet remains the primary tool for diagnosing fetal arrhythmias, research efforts continue to advance the clinical envelope for fetal electrocardiography and fetal magnetocardiography. Pharmacologic management of fetal arrhythmias remains one of the most successful achievements of fetal intervention. Patience, vigilance, and multidisciplinary collaboration are key to successful diagnosis and treatment.

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.

Impact of maternal emotional state during pregnancy on fetal heart rate variability.

Background: The fetal autonomic nervous system (ANS) is believed to be negatively affected by maternal adverse emotional states. In this study, we evaluated how depression, anxiety and stress during pregnancy are related to fetal heart rate variability (HRV) as recorded with magnetocardiography (MCG). We also considered metabolic factors such as maternal adiposity and circulating levels of cortisol during gestation. Furthermore, we followed up these fetuses after birth, recording HRV and saliva levels of cortisol in these infants to establish any effects postpartum. Methods: We calculated HRV in spontaneous MCG recordings from 32 healthy fetuses between 32 and 38 weeks of gestational age. Maternal emotional state was assessed using standardized questionnaires about anxiety, depression and stress. An overall indicator of maternal well-being was calculated by z-scoring each individual questionnaire and summation. We used a median split to divide the group into high and low z-scores (HZS and LZS), respectively. Standard HRV measures were determined in the time and frequency domain. T-test analyses were performed between LZS and HZS, with the HRV and the metabolic measures as the dependent variables. Results: We found an impaired HRV in the HZS group both during pregnancy and after birth. No differences were observed between LZS and HZS for metabolic factors. Depression and anxiety symptoms seem to affect HRV differently. No relationship was found between maternal and infant cortisol levels. Conclusions: On the basis of our results on different HRV parameters, we propose that maternal emotional state might affect the development of the fetal nervous system in utero.

Fetal Arrhythmia Diagnosis and Pharmacologic Management.

One of the most successful achievements of fetal intervention is the pharmacologic management of fetal arrhythmias. This management usually takes place during the second or third trimester. While most arrhythmias in the fetus are benign, both tachy- and bradyarrhythmias can lead to fetal hydrops or cardiac dysfunction and require treatment under certain conditions. This review will highlight precise diagnosis by fetal echocardiography and magnetocardiography, the 2 primary means of diagnosing fetuses with arrhythmia. Additionally, transient or hidden arrhythmias such as bundle branch block, QT prolongation, and torsades de pointes, which can lead to cardiomyopathy and sudden unexplained death in the fetus, may also need pharmacologic treatment. The review will address the types of drug therapies; current knowledge of drug usage, efficacy, and precautions; and the transition to neonatal treatments when indicated. Finally, we will highlight new assessments, including the role of the nurse in the care of fetal arrhythmias. The prognosis for the human fetus with arrhythmias continues to improve as we expand our ability to provide intensive care unit-like monitoring, to better understand drug treatments, to optimize subsequent pregnancy monitoring, to effectively predict timing for delivery, and to follow up these conditions into the neonatal period and into childhood. Coordinated initiatives that facilitate clinical fetal research are needed to address gaps in knowledge and to facilitate fetal drug and device development.

The Relationship between Gestational Diabetes Metabolic Control and Fetal Autonomic Regulation, Movement and Birth Weight.

(1) Background: Maternal metabolic control in gestational diabetes is suggested to influence fetal autonomic control and movement activity, which may have fetal outcome implications. We aimed to analyze the relationship between maternal metabolic control, fetal autonomic heart rate regulation, activity and birth weight. (2) Methods: Prospective noninterventional longitudinal cohort monitoring study accompanying 19 patients with specialist clinical care for gestational diabetes. Monthly fetal magnetocardiography with electro-physiologically-based beat-to-beat heart rate recording for analysis of heart rate variability (HRV) and the 'fetal movement index' (FMI) was performed. Data were compared to 167 healthy pregnant women retrieved from our pre-existing study database. (3) Results: Fetal vagal tone was increased with gestational diabetes compared to controls, whereas sympathetic tone and FMI did not differ. Within the diabetic population, sympathetic activation was associated with higher maternal blood-glucose levels. Maternal blood-glucose levels correlated positively with birth weight z scores. FMI showed no correlation with birth weight but attenuated the positive correlation between maternal blood-glucose levels and birth weight. (4) Conclusion: Fetal autonomic control is altered by gestational diabetes and maternal blood-glucose level, even if metabolic adjustment and outcome is comparable to healthy controls.

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.

Successful trans-maternal nadolol pharmacotherapy in a fetus presenting with long QT syndrome type 2 complicated by torsade de pointes.

Fetuses with congenital long QT syndrome (LQTS) may experience life-threatening arrhythmias, such as torsade de pointes (TdP), and/or functional atrioventricular block. However, trans-maternal pharmacotherapy for these cases is rarely reported and management practices have yet to be established. The fetus of a mother with genetically-confirmed LQTS type 2 (LQT2) presented with complex arrhythmias, diagnosed via magnetocardiography as ventricular arrhythmias (including TdP), at 28 weeks of gestation. After initiation of trans-maternal nadolol administration at 15 mg/d initial dosage and 30 mg/d subsequent dosage, the frequency of fetal ventricular arrhythmias decreased and almost disappeared within several days. The mother gave birth to the baby at full term without significant complications in either the mother or fetus. This is the first report that demonstrates the efficacy and safety of trans-maternal administration of nadolol for treatment of symptomatic LQT2 fetuses with TdP. .

An enhanced frequency dependent subtraction algorithm for removal of cardiac interference from fMEG by using minimum norm projection operator.

BACKGROUND: A frequency dependent subtraction method, SUBTR, is developed to remove maternal and fetal magnetocardiography (mMCG and fMCG) interference from fetal magnetoencephalography (fMEG). But channels close to fetal head cannot be used as references for SUBTR in order to protect fMEG from subtraction and this results in cardiac residual when these channels have important fMCG frequency components. Cardiac residual creates noise in evoked response (ER) which results in poor ER detection. NEW METHOD: We developed an enhanced SUBTR algorithm, which we call SUBTR with minimum norm projection operator (SUBTRwMNPO), by employing covariance based minimum norm projection operators (MNPO). mMCG and fMCG signals are extracted from the raw data using MNPO and they are subtracted in the frequency domain from raw data to extract fetal Evoked Response (fER). RESULTS: When tested on 87 datasets, SUBTRwMNPO is shown to attenuate cardiac interference almost totally resulting in a clean fER signal. COMPARISON WITH EXISTING METHODS: Cardiac attenuation with SUBTRwMNPO is either as good as or better than SUBTR. SUBTRwMNPO has higher attenuation rate for the datasets where SUBTR leaves cardiac residual. CONCLUSIONS: SUBTRwMNPO is successful in removing cardiac interference regardless of the orientation of fMCG and fMEG signal spaces. It can also be used to remove cardiac interference when there is no prior knowledge of fetal head location.

A Comparison of Five Algorithms for Fetal Magnetocardiography Signal Extraction.

Fetal magnetocardiography (fMCG) provides accurate and reliable measurements of electrophysiological events in the fetal heart and is capable of studying fetuses with congenital heart diseases. A variety of techniques exist to extract the fMCG signal with the demand for non-invasively obtained fetal cardiac information. To the best of our knowledge, there is no comparative study published in the field as to how the various extraction algorithms perform. We perform a comparative study of the ability of five methods to extract the fMCG using real biomagnetic signals, two of those methods are applied to real fMCG data for the first time. Biomagnetic signals were recorded and processed with each of the five methods to obtain fMCG. The R peaks of the fMCG traces were obtained via a peak-detection algorithm. From whole recording for each method, the fetal heart rate (FHR) was calculated and used to perform FHR variability (FHRV) analysis. Additionally, we calculated durations from the PQRST complex from time-averaged data during sinus rhythm. The five methods recovered the fMCG signals, but two of them were able to extract cleaner fMCG and the morphology was observed from the continuous data. The time-averaged data showed very similar morphologies between methods, but two of them displayed a signal amplitude reduction on the R-waves and T-waves. Values of PQRST durations, FHR and FHRV were in the range of previous fetal cardiac studies. We have compared five methods for fMCG extraction and showed their ability to perform fMCG analysis.

Fetal Atrial Flutter: Electrophysiology and Associations With Rhythms Involving an Accessory Pathway.

BACKGROUND: Atrial flutter (AFl) accounts for up to one third of all fetal tachyarrhythmias and can result in premature delivery, hydrops, and fetal death in 10% of cases; however, the electrophysiology of AFl in utero is virtually unstudied. METHODS AND RESULTS: In this observational study, we reviewed 19 fetal magnetocardiography studies from 16 fetuses: 15 fetuses (21-38 weeks' gestation) referred with an echocardiographic diagnosis of AFl and 1 fetus (20 weeks' gestation) referred with a diagnosis of tachycardia that was shown by fetal magnetocardiography to have transient AFl in addition to atrioventricular reciprocating tachycardia. Thirteen fetuses showed AFl during the fetal magnetocardiography session, including 4 that presented prior to the third trimester. Five fetuses had incessant AFl; all but 1 of the others with AFl showed additional significant rhythms. Specifically, AFl showed a strong association with rhythms involving an accessory pathway: atrioventricular reciprocating tachycardia, blocked reentrant premature atrial contractions, and ventricular preexcitation. The observed initiations and terminations of AFl most often involved reentrant premature atrial contractions. Spontaneous termination of AFl showed AFl cycle length oscillations. Nine fetuses with 2:1 AFl also showed periods of 4:1 conduction or variable conduction that oscillated between 2:1 and 4:1; however, 3:1 AFl was relatively rare. CONCLUSIONS: Fetal AFl can occur as early as midgestation and is often accompanied by atrioventricular reciprocating tachycardia and other rhythms associated with an accessory pathway. The findings depict critical differences in the electrophysiology of AFl in the fetus versus the neonate.

Heart rate variability parameters and fetal movement complement fetal behavioral states detection via magnetography to monitor neurovegetative development.

Fetal behavioral states are defined by fetal movement and heart rate variability (HRV). At 32 weeks of gestational age (GA) the distinction of four fetal behavioral states represented by combinations of quiet or active sleep or awakeness is possible. Prior to 32 weeks, only periods of fetal activity and quiesence can be distinguished. The increasing synchronization of fetal movement and HRV reflects the development of the autonomic nervous system (ANS) control. Fetal magnetocardiography (fMCG) detects fetal heart activity at high temporal resolution, enabling the calculation of HRV parameters. This study combined the criteria of fetal movement with the HRV analysis to complete the criteria for fetal state detection. HRV parameters were calculated including the standard deviation of the normal-to-normal R-R interval (SDNN), the mean square of successive differences of the R-R intervals (RMSSD, SDNN/RMSSD ratio, and permutation entropy (PE) to gain information about the developing influence of the ANS within each fetal state. In this study, 55 magnetocardiograms from healthy fetuses of 24-41 weeks' GA were recorded for up to 45 min using a fetal biomagnetometer. Fetal states were classified based on HRV and movement detection. HRV parameters were calculated for each state. Before GA 32 weeks, 58.4% quiescence and 41.6% activity cycles were observed. Later, 24% quiet sleep state (1F), 65.4% active sleep state (2F), and 10.6% active awake state (4F) were observed. SDNN increased over gestation. Changes of HRV parameters between the fetal behavioral states, especially between 1F and 4F, were statistically significant. Increasing fetal activity was confirmed by a decrease in PE complexity measures. The fHRV parameters support the differentiation between states and indicate the development of autonomous nervous control of heart rate function.

Magnetophysiologic and echocardiographic comparison of blocked atrial bigeminy and 2:1 atrioventricular block in the fetus.

BACKGROUND: Blocked atrial bigeminy (BAB) and second-degree atrioventricular block with 2:1 conduction block (2:1 AVB) both present as ventricular bradycardia and can be difficult to distinguish by echocardiography. Since the prognosis and clinical management of these rhythms are different, an accurate diagnosis is essential. OBJECTIVE: To identify magnetic and mechanical heart rate and rhythm parameters that could reliably distinguish BAB from 2:1 AVB. METHODS: A retrospective study of ten BAB and seven 2:1 AVB subjects was performed, using fMCG and pulsed Doppler ultrasound. RESULTS: Distinguishing BAB from 2:1 AVB by using fMCG was relatively straightforward because in BAB the ectopic P wave (P') occurred early, resulting in a bigeminal (short-long) atrial rhythm. The normalized coupling interval of the ectopic beat (PP' of the blocked beat to PP of the conducted beat) was 0.29 ± 0.03. In contrast, the echocardiographic assessment of inflow-outflow gave a normalized mechanical coupling interval (AA'/AA) near 0.5, which made it difficult to distinguish BAB from 2:1 AVB. Heart rate distinguished most subjects with BAB from those with 2:1 AVB (82 ± 5.7 beats/min vs 69 ± 4.2 beats/min), but was not a completely reliable indicator. In most subjects, BAB alternated with sinus rhythm or other rhythms, resulting in complex heart rate and rhythm patterns. CONCLUSIONS: Fetal BAB and 2:1 AV block can be difficult to distinguish using echocardiography because in many fetuses with BAB the mechanical rhythm does not accurately reflect the magnetic rhythm. fMCG provides a more reliable means of making a differential diagnosis.