Echocardiographic assessment of cardiovascular physiology of preterm miniature piglets supported with a pumped artificial placenta system.

OBJECTIVES: We evaluated fetal cardiovascular physiology and mode of cardiac failure in premature miniature piglets on a pumped artificial placenta (AP) circuit. METHODS: Fetal pigs were cannulated via the umbilical vessels and transitioned to an AP circuit composed of a centrifugal pump and neonatal oxygenator and maintained in a fluid-filled biobag. Echocardiographic studies were conducted to measure ventricular function, umbilical blood flow, and fluid status. In utero scans were used as control data. RESULTS: AP fetuses (n = 13; 102±4d gestational age [term 115d]; 616 ± 139 g [g]; survival 46.4 ± 46.8 h) were tachycardic and hypertensive with initially supraphysiologic circuit flows. Increased myocardial wall thickness was observed. Signs of fetal hydrops were present in all piglets. Global longitudinal strain (GLS) measurements increased in the left ventricle (LV) after transition to the circuit. Right ventricle (RV) and LV strain rate decreased early during AP support compared with in utero measurements but recovered toward the end of the experiment. Fetuses supported for >24 h had similar RV GLS to in utero controls and significantly higher GLS compared to piglets surviving only up to 24 h. CONCLUSIONS: Fetuses on a pump-supported AP circuit experienced an increase in afterload, and redistribution of blood flow between the AP and systemic circulations, associated with elevated end-diastolic filling pressures. This resulted in heart failure and hydrops. These preterm fetuses were unable to tolerate the hemodynamic changes associated with connection to the current AP circuit. To better mimic the physiology of the native placenta and preserve normal fetal cardiovascular physiology, further optimization of the circuit will be required.

Recent advances in the pathophysiology of PIEZO1-related hereditary xerocytosis.

Hereditary xerocytosis is a rare red blood cell disease related to gain-of-function mutations in the FAM38A gene, encoding PIEZO1, in 90% of cases; PIEZO1 is a broadly expressed mechano-transducer that plays a major role in many cell systems and tissues that respond to mechanical stress. In erythrocytes, PIEZO1 adapts the intracellular ionic content and cell hydration status to the mechanical constraints induced by the environment. Until recently, the pathophysiology of hereditary xerocytosis was mainly believed to be based on the "PIEZO1-Gardos channel axis" in erythrocytes, according to which PIEZO1-activating mutations induce a calcium influx that secondarily activates the Gardos channel, leading to potassium and water efflux and subsequently to red blood cell dehydration. However, recent studies have demonstrated additional roles for PIEZO1 during early erythropoiesis and reticulocyte maturation, as well as roles in other tissues and cells such as lymphatic vessels, hepatocytes, macrophages and platelets that may affect the pathophysiology of the disease. These findings, presented and discussed in this review, broaden our understanding of hereditary xerocytosis beyond that of primarily being a red blood cell disease and identify potential therapeutic targets.

Outcomes of haemoglobin Bart's hydrops fetalis following intrauterine transfusion in Ontario, Canada.

OBJECTIVES: With improved access to intrauterine transfusion (IUT), more fetuses with haemoglobin Bart's hydrops fetalis (HBHF; homozygous α0-thalassaemia) will survive. DESIGN: To evaluate the long-term outcome of affected fetuses with and without IUT in Ontario, Canada, we retrospectively collected data on IUTs and pregnancy outcomes in all cases of HBHF, from 1989 to 2014. Clinical outcome and neurocognitive profiles of long-term survivors were also collected and compared with data from 24 patients with transfusion-dependent ß-thalassaemia (TDT-ß). RESULTS: Of the 99 affected pregnancies (93 prenatally diagnosed), 68 resulted in miscarriage or elective termination of pregnancy. Twelve mothers (12%) continued their pregnancies without IUT, and none of those newborns survived the first week of life. All 13 fetuses that received IUT(s) were live-born, but 3 died due to severe hydrops at birth and 1 died due to infection. The remaining nine survivors, in comparison with TDT-ß patients, had earlier iron overload requiring iron chelation therapy. Endocrinopathies and short stature were more frequent in these patients. Neurocognitive outcome was not significantly affected in five patients who were assessed, and none were diagnosed with intellectual impairment. In three patients, MRI studies demonstrated brain white matter changes in keeping with 'silent' ischaemic infarcts. CONCLUSIONS: In patients with HBHF, IUT is associated with improved survival. While acceptable neurocognitive outcome can be expected, these patients have more clinical complications compared with their TDT-ß counterparts. The clinical and neurocognitive outcomes of HBHF should be discussed in detail when counselling and offering IUT for patients.

Resolution of Fetal Hydrops Dependent on Sustained Fetal Supraventricular Tachycardia after Digoxin Therapy.

We present a special case of fetal supraventricular tachycardia detected at 34 weeks gestation. Fetal hydrops was noted on ultrasound upon admission. Normal fetal heart rate was maintained for three weeks by maternal administration of digoxin. A live infant was delivered via caesarian section at 37 weeks gestation. This clinical case demonstrated that pharmacological treatment can be effective and helps to prolong pregnancy safely.

Nonimmune Hydrops Fetalis.

Nonimmune hydrops fetalis (NIHF) historically has been considered a lethal fetal condition. Understanding NIHF to be a symptom or an end-stage status of a variety of fetal conditions, along with improved fetal diagnostics and interventions, has changed the landscape for at least some fetuses. Understanding the pathophysiologic mechanisms has led to the development of diagnostic algorithms, improved understanding of cause, and therefore fetal or neonatal treatments. Multidisciplinary counseling and shared decision making are critical to supporting families through pregnancy decisions, potential fetal therapeutic interventions, neonatal management decisions, and at times accepting or transitioning to palliative care.

[Hereditary xerocytosis. Presentation of two pediatric cases]. / Xerocitosis hereditaria. Presentación de dos casos clínicos pediátricos.

Hereditary xerocytosis is a rare disorder caused by defects of red blood cell permeability that are characterized by hemolytic anemia of variable degree and iron overload. Diagnosis is usually late and confused with other hemolytic anemias, which can lead to procedural indications, such as splenectomy, contraindicated in these patients. We report the clinical, haematological, and molecular characteristics of two patients from two unrelated families affected by hereditary xerocytosis. Both patients had dehydrated erythrocytes with a high concentration of mean corpuscular hemoglobin, non-pathognomonic smears, markers of hemolysis and a resistant osmotic fragility curve. The diagnosis was confirmed by the sequencing of the PIEZO gene. We emphasize the importance of recognizing the cause of hemolytic anemia to give an accurate therapeutic approach and give adequate genetic counseling.

La xerocitosis hereditaria es un desorden poco frecuente causado por defectos en la permeabilidad eritrocitaria, que se caracteriza por anemia hemolítica de gravedad variable y sobrecarga de hierro. El diagnóstico suele ser tardío y confundirse con otras anemias hemolíticas, lo que puede llevar a indicaciones de procedimientos, como la esplenectomía, contraindicados en estos pacientes. Se reportan las características clínicas, hematológicas y moleculares de dos pacientes pediátricos no relacionados con diagnóstico de xerocitosis hereditaria. Ambos presentaban eritrocitos deshidratados con alta concentración de hemoglobina corpuscular media, frotis no patognomónico, marcadores de hemólisis y una curva de fragilidad osmótica resistente. El diagnóstico se confirmó por la secuenciación del gen PIEZO. Se resalta la importancia de reconocer la causa de la anemia hemolítica para dar un enfoque terapéutico preciso y dar adecuado consejo genético.

Non-Immune Hydrops, Hypotonia, Encephalopathy, and Liver Failure with Novel Compound Heterozygous AHCY Mutations.

A late-preterm infant with a prenatal diagnosis of non-immune hydrops was born with hypotonia, poor respiratory effort, chylothorax, encephalopathy, coagulopathy, progressive hepatic failure, and refractory pulmonary hypertension. Life support was withdrawn at 7 days of life due to multisystem organ failure. Rapid whole exome sequencing revealed novel compound heterozygous mutations in the gene encoding S-adenosylhomocysteine hydrolase (AHCY); each novel variant was carried by an asymptomatic parent. Reports of neonates with other AHCY mutations describe a pathology of varying severity. AHCY mutations should be considered when seeking an etiology for neonates with the combination of non-immune hydrops, hypotonia, encephalopathy, and liver failure.

Non-Immune Hydrops Fetalis: Do Placentomegaly and Polyhydramnios Matter?

OBJECTIVES: Polyhydramnios and placentomegaly are commonly observed in nonimmune hydrops fetalis (NIHF); however, whether their ultrasonographic identification is relevant for prognosis is controversial. We evaluated outcomes of fetal or neonatal death and preterm birth (PTB) in cases of NIHF alone and in those with polyhydramnios and/or placentomegaly (P/PM). METHODS: We conducted a retrospective cohort of singletons with NIHF evaluated between 1994 and 2013. Nonimmune hydrops fetalis was defined as 2 or more abnormal fluid collections, including ascites, pericardial effusion, pleural effusion, and skin edema. Primary outcomes were intrauterine fetal demise (IUFD) and neonatal death. Secondary outcomes were PTB (<37, < 34, and <28 weeks) and spontaneous PTB. Outcomes were compared between cases of NIHF alone and NIHF with P/PM. RESULTS: A total of 153 cases were included; 21% (32 of 153) had NIHF alone, and 79% (121 of 153) had NIHF with P/PM. There was no significant difference in neonatal death (38.1% versus 43.0%; P = .809) between the groups. Intrauterine fetal demise was seen more frequently in NIHF alone (34.4% versus 17.4%; P = .049). Nonimmune hydrops fetalis-with-P/PM cases were more likely to deliver before 37 weeks (80.0% versus 57.1%; P = .045) and before 34 weeks (60.0% versus 28.6%; P = .015) and to have spontaneous PTB (64.4% versus 33.3%; P = .042). Adjusted odds ratios accounting for the etiology of NIHF supported these findings, with the exception of IUFD. CONCLUSIONS: Compared to NIHF alone, pregnancies with NIHF and P/PM had a lower risk of IUFD and were at increased risk of PTB (<37 and <34 weeks) and spontaneous PTB. This information may help providers in counseling patients with NIHF and supports the need for close antenatal surveillance.

Fetal hemoglobin Bart's hydrops fetalis: pathophysiology, prenatal diagnosis and possibility of intrauterine treatment.

This review aimed at comprehensively summarizing current available reports regarding the ultrasound markers and biomarkers in predicting fetal Hb Bart's disease and evaluate the potential role of cardiac function assessment in a clinical practice. This review involves various methods in prenatal predicting fetal Hb Bart's disease or alpha-thalassemia major and attempts to provide valuable insights regarding the underlying mechanisms responsible for heart failure in Hb Bart's fetuses. Moreover, this information may be used to predict the cardiac function before the development of hydrops fetalis. Finally, the affected Hb Bart's fetus could be the best model of the study on cardiovascular response to fetal anemia, thus the cardiovascular ultrasound and molecular assessment may be helpful in predicting the prognosis or in making a choice in the management of the fetal anemia condition. In conclusion, ultrasound findings especially cardiomegaly and an increase in peak systolic velocity of the middle cerebral artery (MCA-PSV) are helpful in predicting the future hydrops fetalis and ultrasound assessment of fetal cardiac function is potentially helpful in clinical practice. Finally, this review highlights the pathogenesis of hydropic changes secondary to fetal anemia.

A novel method to estimate safety factor of capture by a fetal micropacemaker.

We have developed a rechargeable fetal micropacemaker in order to treat severe fetal bradycardia with comorbid hydrops fetalis, a life-threatening condition in pre-term non-viable fetuses for which there are no effective treatment options. The small size and minimally invasive form factor of our design limit the volume available for circuitry and a power source. The device employs a fixed-rate and fixed-amplitude relaxation oscillator and a tiny, rechargeable lithium ion power cell. For both research and clinical applications, it is valuable to monitor the electrode-myocardium interface in order to determine that adequate pacemaker output is being provided. This is typically accomplished by observing the minimal stimulus strength that achieves threshold for pacing capture. The output of our simple micropacemaker cannot be programmatically altered to determine this minimal capture threshold, but a safety factor can be inferred by determining the refractory period for ventricular capture at a given stimulus strength. This is done by measuring the minimal timing between naturally occurring QRS complexes and pacing stimuli that successfully generate a premature ventricular contraction. The method was tested in a pilot study in four fetal sheep and the data demonstrate that a relative measure of threshold is obtainable. This method provides valuable real-time information about the electrode-tissue interface.

Changes in echocardiography and blood variables during and after development of Ballantyne syndrome.

We report a pregnant woman who was monitored by echocardiography and determination of blood variables, including components of the renin-angiotensin-aldosterone system (RAAS), cardiac biomarkers and soluble fms-like tyrosine kinase-1 (sFlt-1), during and after the development of Ballantyne syndrome. Generalised maternal oedema with dyspnoea following fetal and placental hydrops necessitated a caesarean section at 33 weeks of gestation. Changes in blood variables and simultaneous echocardiography changes indicated acutely enhanced RAAS and hyperdynamic left ventricular function in response to excessive volume overload (as evidenced by brain-type natriuretic peptide level of 523 pg/mL) in the absence of increased systemic vascular resistance. Elevated sFlt-1 (15 600 pg/mL) and human chorionic gonadotrophin (404 000 IU/L) levels were also noted. The increased plasma aldosterone concentration (2070 pg/mL) may have been responsible for the increase in circulating plasma volume, and the increased sFlt-1 level was responsible for generalised maternal oedema. It remains unclear which factor(s) triggered RAAS activation.

Two cases of RIT1 associated Noonan syndrome: Further delineation of the clinical phenotype and review of the literature.

Mutations in RIT1, involved in the RAS-MAPK pathway, have recently been identified as a cause for Noonan syndrome. We present two patients with Noonan syndrome caused by a RIT1 mutation with novel phenotypic manifestations, severe bilateral lower limb lymphedema starting during puberty, and fetal hydrops resulting in intrauterine fetal death, respectively. Including our patients, a total of 52 patients have been reported with Noonan syndrome caused by a RIT1 mutation. Our report contributes to the delineation of the phenotype associated with RIT1 mutations and underlines that lymphatic involvement is part of this spectrum. In addition, we provide an overview of the currently described Noonan syndrome patients with RIT1 mutations in literature. © 2016 Wiley Periodicals, Inc.

High-dose flecainide is the most effective treatment of fetal supraventricular tachycardia.

BACKGROUND: Fetal tachyarrhythmia can lead to fetal hydrops due to heart failure. Flecainide is often considered as second-line therapy when digoxin monotherapy fails, which is more likely in hydropic fetuses. Time to conversion to sinus rhythm (SR) is critical in cases presenting with hydrops. OBJECTIVE: The aim of this study was to evaluate the efficacy and time to conversion to SR of transplacental treatment, especially flecainide. METHODS: This is a retrospective observational study of 46 fetuses with fetal tachyarrhythmia. Treatment was either flecainide (n = 28, 60.9%), digoxin+flecainide combination (n = 4, 8.7%), or digoxin (n = 10, 21.7%). In 4 fetuses (8.7%), no treatment was necessary. RESULTS: In our study population, 26 of the 32 fetuses (81.2%) that were treated with flecainide as a first-line therapy (flecainide or digoxin+flecainide) converted to SR. The median time to conversion to SR was 3 days (range 1-7 days) with flecainide monotherapy and 11.5 days (range 3-14 days) with a combination therapy. Seventy-two percent (13/18) of hydropic fetuses and 90% (9/10) of nonhydropic fetuses converted to SR when treated with flecainide monotherapy. There was no statistical difference in rates of conversion to SR in hydropic and nonhydropic fetuses (P = .37) or time to conversion to SR in the 2 groups (P = .9). In the majority of the remaining fetuses, there was a partial response with decreased ventricular heart rates that were well tolerated. CONCLUSION: Flecainide is highly effective in achieving SR in hydropic and nonhydropic fetuses with supraventricular tachycardia in a median time of 3 days. In our opinion, flecainide should be considered as first-line therapy in fetal supraventricular tachycardia with and without hydrops.

Ventricular Diastolic Function in Normal Fetuses and Fetuses with Hb Bart's Disease Assessed by Color M-Mode Propagation Velocity using Cardio-STIC-M (Spatio-Temporal Image Correlation M-Mode).

Purpose: To determine whether ventricular diastolic dysfunction contributes to the pathogenesis of fetal cardiac failure due to fetal anemia using fetal Hb Bart's disease as a live model and cardio-STIC-M as a diagnostic tool. Materials and Methods: Color cardio-STIC volume datasets were acquired from fetuses at risk for Hb Bart's disease during 18 - 22 weeks of gestation and normal pregnancies and pregnancies with hydrops fetalis caused by Hb Bart's disease at 28 - 32 weeks. The volumes were analyzed off-line for velocity propagation (Vp) of the right and left ventricles to assess ventricular diastolic function using color cardio-STIC-M. Results: The Vp for the right and left ventricles was studied in fetuses at 18 - 22 weeks, including 64 normal fetuses (group 1) and 22 fetuses with Hb Bart's disease (group 2), and in fetuses at 28 - 32 weeks, including 22 normal fetuses (group 3) and 16 fetuses with Hb Bart's hydrops fetalis (group 4). The Vp of the fetuses in group 1 and group 2 was not significantly different. However, the Vp for the right and left ventricles in group 4 was significantly lower than in group 3 (19.02 vs. 9.78, p < 0.001; and 20.24 vs. 13.40, p < 0.001, respectively). The inter-observer variability had fair agreement with the intra-class correlation coefficient of 0.531 (95 % CI 0.393 - 0.646, p < 0.001). Conclusion: Hydrops fetalis secondary to fetal anemia is initially caused by hypervolemia rather than ventricular diastolic dysfunction while ventricular diastolic compromise is a late occurring consequence of persistent hypervolemia, different from the mechanism of hydropic changes caused by cardiac causes.

Clinical Features of Neonates with Hydrops Fetalis.

OBJECTIVE: The objective of this study was to evaluate the clinical characteristics of neonates with hydrops fetalis to improve recognition of the disease. PATIENTS AND METHODS: The clinical data of 10 neonates with hydrops fetalis were retrospectively studied. Prenatal characteristics, causes, clinical features, and prognosis were explored. RESULTS: Eight neonates presenting abnormal nonstress test suffered from severe neonatal asphyxia at birth and were resuscitated by endotracheal intubation. Nine had skin edema, eight had pleural effusions with one unilateral and seven bilateral. Six had ascites, eight had polyhydramnios, one had multiple malformations and one had chromosome abnormalities. One survived and nine died. Six died due to resuscitation failure in delivery room, two died due to giving up after 1 day and one died due to the treatment failure after 6 months. Causes of hydrops fetalis were a congenital diaphragmatic hemangioma, recurrent atrial premature beats, genetic syndrome suspicious, Down syndrome, congenital pulmonary lymphangiectasia, anemia, paroxysmal supraventricular tachycardia, placental chorioangioma, and idiopathic edema. CONCLUSION: The prognosis varied because of different etiologies of hydrops fetalis. Severe cases frequently had skin edema and high rate of asphyxia at birth and difficult resuscitation. Timely intrauterine interventions were helpful for successful resuscitation. A well-prepared resuscitation team and the effectiveness of resuscitation could correlate to increasing survival rate.

Fetal critical aortic stenosis with natural improvement of hydrops fetalis due to spontaneous relief of severe restrictive atrial communication.

We describe a rare case of fetal critical aortic stenosis with spontaneous relief of severe restrictive atrial communication, resulting in complete resolution of hydrops fetalis in utero. Fetal ultrasonography showed hydrops fetalis caused by critical aortic stenosis with a severely restrictive foramen ovale and severe mitral regurgitation at 23 weeks of gestation. Hydrops fetalis, however, spontaneously resolved, showing an obvious increase of flow through the foramen ovale and pulmonary vein at 26 weeks of gestation. The neonate required balloon dilation of the aortic valve and balloon atrioseptostomy immediately after birth and also received bilateral pulmonary artery banding and arterial duct stenting 1 week later. The patient was in good condition after conversion to biventricular circulation via Ross procedure at 8 months old. The present case suggests that atrioseptostomy as a fetal intervention may improve outcome in even a hydropic condition.