Cardiotocography alone vs. cardiotocography with ST segment analysis for intrapartum fetal monitoring in women with late-term pregnancy. A randomized controlled trial.

OBJECTIVES: Randomized studies have obtained conflicting results regarding the usefulness of fetal electrocardiographic (ECG) ST-segment analysis, possibly because these studies included non-homogeneous populations. We designed a study to determine whether this monitoring technique is potentially useful for populations at risk for fetal heart rate alterations during labor, i.e. groups of women who share late-term pregnancy as a risk factor. STUDY DESIGN: This randomized clinical trial recruited women whose pregnancy had lasted more than 290 days. The participants were randomly assigned to continuous fetal cardiotocographic monitoring alone (CTG group) or with fetal ECG ST-segment analysis (ECG-F group). In the CTG group fetal heart rate was interpreted according to guidelines from the National Institute of Child Health and Human Development, whereas in the ECG-F group the tracings were interpreted according the original International Federation of Gynecology and Obstetrics (FIGO) guidelines. The primary outcome measure was neonatal outcome, evaluated as arterial blood pH in neonates after abdominal or vaginal operative delivery indicated because of nonreassuring fetal status. RESULTS: A total of 237 women were randomized, of whom 200 were included in the final analysis (100 in each group). The rate of cesarean delivery was the same in both groups (26%), and the rate of operative delivery due to nonreassuring fetal status did not differ significantly (38% in the CTG group vs. 39% in the ECG-F group). Regarding neonatal outcomes, there was no significant difference between groups in neonatal pH (7.27 [7.23-7.29] and 7.25 [7.21-7.27]). CONCLUSIONS: In a population comprising only late-term pregnancies, fetal ECG monitoring had no benefits for the mother or fetus. Additional studies are needed of protocols for using ST waveform analysis in selected population groups.

The Incremental Benefit of Color Tissue Doppler in Fetal Arrhythmia Assessment.

BACKGROUND: Accurate fetal arrhythmia (FA) diagnosis is key for effective management. Currently, FA assessment relies on standard echocardiography-based techniques (M mode and spectral Doppler), which require adequate fetal position and cursor alignment to define temporal relationships of mechanical events. Few data exist on the application of color Doppler tissue imaging (c-DTI) in FA assessment. The aim of this study was to examine the feasibility and clinical applicability of c-DTI in FA assessment in comparison with standard techniques. METHODS: Pregnancies with diagnosed FA were prospectively recruited to undergo c-DTI following fetal echocardiography. Multiple-cycle four-chamber clips in any orientation were recorded (mean frame rate, 180 ± 16 frames/sec). With offline analysis, sample volumes were placed on atrial (A) and ventricular (V) free walls for simultaneous recordings. Atrial and ventricular rates, intervals (for atrial-ventricular conduction and tachyarrhythmia mechanism), and relationships were assessed to decipher FA mechanism. FA diagnosis by c-DTI, conventional echocardiographic techniques, and postnatal electrocardiography and/or Holter monitoring were compared. RESULTS: FA was assessed by c-DTI in 45 pregnancies at 15 to 39 weeks, including 16 with atrial and/or ventricular ectopic beats; 18 with supraventricular tachyarrhythmias, including ectopic atrial tachycardia in 11, atrioventricular reentrant tachycardia in four, atrial flutter in two, and intermittent atrial flutter and junctional ectopic rhythm in one; three with ventricular tachycardias; and eight with bradycardias or atrioventricular conduction pathology, including five with complete atrioventricular block (AVB), one with first-degree AVB evolving into complete AVB, one with second-degree AVB, and one with sinus bradycardia. After training, FA diagnosis by c-DTI could be made irrespective of fetal orientation within 10 to 15 min. FA diagnosis by c-DTI concurred with standard techniques in 41 cases (91%), with additional findings identified by c-DTI in 10. c-DTI led to new FA diagnoses in four cases (9%) not definable by standard techniques. FA diagnosis by c-DTI was confirmed in all 20 with persistent arrhythmias after birth, including three with new diagnoses defined by c-DTI. c-DTI was particularly helpful in deciphering SVT mechanism (long vs short ventricular-atrial interval) in all 18 cases, whereas standard techniques permitted definition in only half. CONCLUSIONS: c-DTI with offline analysis permits rapid and accurate definition of FA mechanism, providing new information in nearly one-third of affected pregnancies.

Nonisolated diaphragmatic hernia in Simpson-Golabi-Behmel syndrome.

OBJECTIVE: Congenital diaphragmatic hernia (CDH) is associated with Simpson-Golabi-Behmel syndrome (SGBS), but few cases diagnosed prenatally have been reported. The aim of this series is to highlight the association of nonisolated CDH with SGBS type I on prenatal ultrasound and emphasize the importance of genetic testing, fetal autopsy, and family history in confirming this diagnosis. METHOD: Retrospective review of 3 cases of SGBS type I in a single tertiary care centre. Family history, fetal ultrasound, autopsy findings, and genetic testing for GPC3 was performed for each case. RESULTS: Fetal ultrasound findings in the second trimester were CDH, omphalocele, increased nuchal fold, renal anomaly, and cleft lip and palate. Fetal autopsy confirmed the prenatal ultrasound findings and also showed dysmorphic facial features and premalignant lesions on renal and gonadal histology. Microarray and DNA analysis of the GPC3 gene confirmed the diagnosis of SGBS type I in each case. CONCLUSION: Nonisolated CDH in a male fetus suggests a diagnosis of SGBS type I. Fetal autopsy, pedigree analysis, and genetic testing for GPC3 are all essential to confirming the diagnosis. The histological findings of ovotestes and nephroblastomatosis indicate that cancer predisposition is established early in fetal life.

First-Line Antiarrhythmic Transplacental Treatment for Fetal Tachyarrhythmia: A Systematic Review and Meta-Analysis.

BACKGROUND: There is no consensus on the most effective and best tolerated first-line antiarrhythmic treatment for fetal tachyarrhythmia. The purpose of this systematic review and meta-analysis was to compare the efficacy, safety, and fetal-maternal tolerance of first-line monotherapies for fetal supraventricular tachycardia and atrial flutter. METHODS AND RESULTS: A comprehensive search of several databases was conducted through January 2017. Only studies that made a direct comparison between first-line treatments of fetal tachyarrhythmia were included. Outcomes of interest were termination of fetal tachyarrhythmia, fetal demise, and maternal complications. Ten studies met inclusion criteria, with 537 patients. Overall, 291 patients were treated with digoxin, 137 with flecainide, 102 with sotalol, and 7 with amiodarone. Digoxin achieved a lower rate of supraventricular tachycardia termination compared with flecainide (odds ratio [OR]: 0.773; 95% confidence interval [CI], 0.605-0.987; I2=34%). In fetuses with hydrops fetalis, digoxin had lower rates of tachycardia termination compared with flecainide (OR: 0.412; 95% CI, 0.268-0.632; I2=0%). There was no significant difference in the incidence of maternal side effects between digoxin and flecainide groups (OR: 1.134; 95% CI, 0.129-9.935; I2=80.79%). The incidence of maternal side effects was higher in patients treated with digoxin compared with sotalol (OR: 3.148; 95% CI, 1.468-6.751; I2=0%). There was no difference in fetal demise between flecainide and digoxin (OR: 0.767; 95% CI, 0.140-4.197; I2=44%). CONCLUSIONS: Flecainide may be more effective treatment than digoxin as a first-line treatment for fetal supraventricular tachycardia.

Cardiac Etiologies of Hydrops Fetalis.

Cardiac etiologies of hydrops fetalis have been a topic of concern due to challenging perinatal management. The common cardiac etiologies leading to hydrops fetalis include structural cardiac anomalies, cardiac dysrhythmias, cardiac tumors, cardiomyopathy and myocarditis. The mechanisms of cardiogenic hydrops fetalis may be: 1) elevation of atrial pressure and volume overload, 2) decrease of cardiac output, and 3) development of congestive heart failure. The diagnosis of hydrops fetalis was usually made at 19-36 gestational weeks, when ultrasound is a highly effective diagnostic method. Intrauterine interventions for certain congenital heart defects, maternal transplacental or direct fetal medications and fetal pacing placement for cardiac arrhythmias, and fetal or postnatal tumor resections are important progressions of etiologic treatment for hydrops fetalis. Treatment strategies for hydrops fetalis per se are usually ultrasound-guided pericardiocentesis and feto-amniotic shunting, whereas reaccumulation may require further interventions in utero or postnatally. Hydrops fetalis often carries a poor prognosis, and mortality remains high. Current developments in the management of hydrops fetalis should encourage physicians to attempt further fetal interventions.

Time-interval changes of cardiac cycles in fetal growth restriction.

OBJECTIVE: The aims of this study were to investigate the time intervals of each component of cardiac flow velocity waveforms (FVWs) in fetuses with fetal growth restriction (FGR) and to compare these with those of normal fetuses using reference ranges. METHODS: The durations of atrioventricular (AV) valve opening (AVVO), AV valve closure (AVVC), total E- (total-E) and A- (total-A) waves, total ejection time (total-ET), acceleration time (acc-E for E-wave, acc-A for A-wave, and acc-ET for ejection time), and deceleration time (dec-E for E-wave, dec-A for A-wave, and dec-ET for ejection time) were measured in fetuses with FGR. All variables were analyzed using z-scores. RESULTS: Measurements of 17 growth-restricted fetuses were obtained. The time intervals between the last Doppler examination and delivery ranged from 0 to 6 days, with a median of 1 day. Significant increases were observed in AVVO, total-E, dec-E, and acc-A of the left heart. acc-E, acc-ET and AVVC of the left heart were significantly decreased. In the right heart, AVVO, total-E and dec-E were significantly increased. CONCLUSION: A prolonged time interval between early ventricular inflow and atrial contraction, as well as increased duration of AV valve opening, may reflect hemodynamic alterations in FGR fetuses.

Comparative analysis of cardiovascular effects of selenium nanoparticles and sodium selenite in zebrafish embryos.

Selenium acts as an important element in the prevention and treatment of cardiovascular diseases but their health-related effects have not been fully explored. As a novel attempt, zebrafish embryos were treated separately with SeNPs (5-25 µg/ml) and sodium selenite (5-25 µg/ml) starting at early blastula stage. Abnormalities were also observed in the morphology of the zebrafish embryos. The SeNPs-treated embryos exhibited concentration-dependent increased in mortality, pericardial edema, and cardiac arrhythmia. In contrast, sodium selenite showed no significant malformation effect in developing zebrafish embryos. The results of the present study conclude that the SeNPs were more toxic than sodium selenite. The results also suggest that lower concentrations of SeNPs and sodium selenite can be used as possible therapeutic agents for cardiovascular-related problems.

Pediatric prenatal diagnosis of congenital heart disease.

PURPOSE OF REVIEW: Fetal cardiology is a rapidly evolving field. Imaging technology continues to advance as do approaches to in-utero interventions and care of the critically ill neonate, with even greater demand for improvement in prenatal diagnosis of congenital heart disease (CHD) and arrhythmias. RECENT FINDINGS: Reviewing the advances in prenatal diagnosis of CHD in such a rapidly developing field is a broad topic. Therefore, we have chosen to focus this review of recent literature on challenges in prenatal detection of CHD, challenges in prenatal counseling, advances in fetal arrhythmia diagnosis, and potential benefits to patients with CHD who are identified prenatally. SUMMARY: As methods and tools to diagnose and manage CHD and arrhythmias in utero continue to improve, future generations will hopefully see a reduction in both prenatal and neonatal morbidity and mortality. Prenatal diagnosis can and should be used to optimize location and timing of delivery and postnatal interventions.

NADPH oxidase 4 induces cardiac arrhythmic phenotype in zebrafish.

Oxidative stress has been implicated in cardiac arrhythmia, although a causal relationship remains undefined. We have recently demonstrated a marked up-regulation of NADPH oxidase isoform 4 (NOX4) in patients with atrial fibrillation, which is accompanied by overproduction of reactive oxygen species (ROS). In this study, we investigated the impact on the cardiac phenotype of NOX4 overexpression in zebrafish. One-cell stage embryos were injected with NOX4 RNA prior to video recording of a GFP-labeled (myl7:GFP zebrafish line) beating heart in real time at 24-31 h post-fertilization. Intriguingly, NOX4 embryos developed cardiac arrhythmia that is characterized by irregular heartbeats. When quantitatively analyzed by an established LQ-1 program, the NOX4 embryos displayed much more variable beat-to-beat intervals (mean S.D. of beat-to-beat intervals was 0.027 s/beat in control embryos versus 0.038 s/beat in NOX4 embryos). Both the phenotype and the increased ROS in NOX4 embryos were attenuated by NOX4 morpholino co-injection, treatments of the embryos with polyethylene glycol-conjugated superoxide dismutase, or NOX4 inhibitors fulvene-5, 6-dimethylamino-fulvene, and proton sponge blue. Injection of NOX4-P437H mutant RNA had no effect on the cardiac phenotype or ROS production. In addition, phosphorylation of calcium/calmodulin-dependent protein kinase II was increased in NOX4 embryos but diminished by polyethylene glycol-conjugated superoxide dismutase, whereas its inhibitor KN93 or AIP abolished the arrhythmic phenotype. Taken together, our data for the first time uncover a novel pathway that underlies the development of cardiac arrhythmia, namely NOX4 activation, subsequent NOX4-specific NADPH-driven ROS production, and redox-sensitive CaMKII activation. These findings may ultimately lead to novel therapeutics targeting cardiac arrhythmia.

Effects of macrolide antibiotics on rat embryonic heart function in vitro.

The Swedish Medical Product Agency (MPA) has listed erythromycin as a suggested human teratogen, causing cardiovascular malformations. It is further suggested that this may be a class effect of macrolide antibiotics. The proposed teratogenic mechanism is blockade of the human ether-á-go-go-related (hERG)/IKr current in the embryonic heart causing bradycardia and arrhythmia resulting in altered cardiac blood flow and/or embryonic hypoxia. To test this hypothesis, we examined the effect of three macrolide antibiotics on the function of the rat embryonic heart. Gestational day 13 rat embryos in vitro were exposed to erythromycin (25-500 µM), clarithromycin (25-500 µM), or azithromycin (100 µM to 1 mM) for 3 hr. The effect on the embryonic heart was monitored every hour. The results showed that erythromycin and clarithromycin caused a concentration-dependent bradycardia. Twenty-five micromolar was a no-effect concentration for erythromycin and was close to a no-effect concentration for clarithromycin. Azithromycin only caused significant bradycardia at 1 mM. Additional studies were performed with the embryos cultured at 40°C instead of 38°C, to mimic fever. The increased temperature increased the number of arrhythmias but did not worsen the drug-induced bradycardia. The results support the concept that erythromycin and clarithromycin can adversely affect the embryonic heart but only at concentrations well outside expected embryonic exposure in the human.

Genetically encoded probes provide a window on embryonic arrhythmia.

Supraventricular tachycardias are the most prevalent group of arrhythmias observed in the fetus and infant and their incidence increases through early childhood. The molecular pathogenesis of embryonic cardiac dysfunction is poorly understood, due in part to the absence of imaging techniques that provide functional information at the cellular and molecular levels in the developing mammalian heart, particularly during early heart formation. The combination of protein engineering, genetic specification, and high-resolution optical imaging enables new insights into cardiac function and dysfunction during cardiac development. Here we describe the use of GCaMP2, a genetically encoded Ca(2+) indicator (GECI), to determine the processes of cardiac electrical activation during cardiac organogenesis. Transgenic specification of GCaMP2 in mice allows sufficient expression for Ca(2+) imaging as early as embryonic day (e.d.) 9.5, just after the heart begins to function at e.d. 8.5. Crosses with knockout lines in which lethality occurs due to cardiac dysfunction will enable precise determination of the conduction or excitation-contraction coupling phenotypes and thereby improve the understanding of the genetic basis of heart development and the consequence of gene mutations. Moreover, lineage-specific targeting of these sensors of cell signaling provides a new window on the molecular specification of the heart conduction system. We describe mouse lines and imaging methods used to examine conduction in the pre-septated heart (e.d. 10.5), which occurs through dramatically slowed atrioventricular (AV) canal conduction, producing a delay between atrial and ventricular activation prior to the development of the AV node. Genetic constructs including single and bi-allelic minimal promoter systems, and single allele BAC transgenes, enable general or lineage-specific targeting of GCaMP2. High-resolution imaging of embryonic heart conduction provides a new window on one of the most complex events in the mammalian body plan.

Development and application of an automated extraction algorithm for fetal magnetocardiography - normal data and arrhythmia detection.

INTRODUCTION: Current standard methods of monitoring fetal heart function are mainly based on echocardiography, which provides indirect information (through mechanical assessment) of the fetal heart rhythm. Fetal magnetocardiography (fMCG) allows a reliable quantification of the temporal structure of fetal heart signals. However, its application in clinical studies is difficult because extracting the fetal heart signal for most current applications requires user intervention. To overcome this limitation, we developed a completely automated extraction algorithm. PATIENTS AND METHODS: The fMCG recordings were acquired using a 156-channel biomagnetic system. To perform an automated analysis, a combination of orthogonal projection and independent component analysis was used. fMCG recordings from 69 healthy uncomplicated singleton pregnancies with normally developing fetuses were included in the study. RESULTS: The normal values achieved by the automated algorithm were comparable to previously published data. The majority of the cardiac time intervals were positively correlated with gestational age (GA). The ST segment, T wave and QT interval did not show any correlation. CONCLUSIONS: The automated detection of fetal heart signals was possible beginning at a GA of 19 weeks. This automated analysis of fMCG recordings might be an objective and easily applicable approach for clinicians to analyze fetal heart signals.

The teratogenic effect of dofetilide during rat limb development and association with drug-induced bradycardia and hypoxia in the embryo.

BACKGROUND: Dofetilide is an antiarrhythmic drug that blocks the cardiac repolarizing current IKr ((IKr, rapid component of the delayed rectifying potassium current). Previous studies have shown that (a) IKr is essential for normal cardiac function of the embryonic heart and (b) dofetilide is teratogenic in rodents. This study was undertaken to examine the mechanism by which dofetilide causes limb defects on gestational day 13 (GD 13) in the rat. METHODS: Rats were treated with dofetilide (single oral dose, 5 mg/kg) on GD 13 and embryonic heart rates assessed by ultrasound (Vevo770, VisualSonics, Toronto, Ontario, Canada) 2 hr later. Fetuses were examined for malformations on GD 20. In a separate experiment, dofetilide treatment of GD 13 rats was followed 2, 4, 12, or 24 hr with iv dosing with the hypoxia marker, pimonidazole (60 mg/kg). Embryos were collected and heart rates were assessed in vitro and hypoxia in embryo limbs analyzed. RESULTS: A teratogenic dose of dofetilide at a susceptible stage of development (GD 13) resulted in a period of bradycardia and arrhythmia of the embryonic heart and hypoxia in the developing limbs (GD 13) resulting in limb malformations (GD 20). CONCLUSIONS: Drugs that induce periods of bradycardia and/or arrhythmia of the embryonic heart and cause the embryo to become hypoxic are potential human teratogens.

Insights from cardiac development relevant to congenital defects and adult clinical anatomy.

Advances made in understanding temporal changes in structure of the developing heart, along with advances in knowledge of the lineage of cardiomyocytes forming the components of cardiac chambers, permit us to draw inferences concerning substrates for arrhythmias such as atrial fibrillation and outflow tract tachycardias. We frame these insights in our description of the formation of cardiac chambers. Adult-like electrocardiograms can be generated by developing hearts before it is possible to recognize an anatomically discrete conduction system. Working components of the atrial and ventricular chambers, which are rapidly conducting, balloon from walls of the primary heart tube, themselves slowly conducting. Recognition of the locations of these populations of primary and secondary myocardial pools suggests that some potential myocardial substrates (those producing outflow tract tachycardias) initially had a primary phenotype. In contrast, cardiomyocytes forming pulmonary venous sleeves, substrates for many cases of atrial fibrillation, have never possessed a primary phenotype. This article is part of a JCTR special issue on Cardiac Anatomy.