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.

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.

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.

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.

Xerocytosis is caused by mutations that alter the kinetics of the mechanosensitive channel PIEZO1.

Familial xerocytosis (HX) in humans is an autosomal disease that causes dehydration of red blood cells resulting in hemolytic anemia which has been traced to two individual mutations in the mechanosensitive ion channel, PIEZO1. Each mutation alters channel kinetics in ways that can explain the clinical presentation. Both mutations slowed inactivation and introduced a pronounced latency for activation. A conservative substitution of lysine for arginine (R2456K) eliminated inactivation and also slowed deactivation, indicating that this mutant's loss of charge is not responsible for HX. Fitting the current vs. pressure data to Boltzmann distributions showed that the half-activation pressure, P1/2, for M2225R was similar to that of WT, whereas mutations at position 2456 were left shifted. The absolute stress sensitivity was calibrated by cotransfection and comparison with MscL, a well-characterized mechanosensitive channel from bacteria that is driven by bilayer tension. The slope sensitivity of WT and mutant human PIEZO1 (hPIEZO1) was similar to that of MscL implying that the in-plane area increased markedly, by ∼6-20 nm(2) during opening. In addition to the behavior of individual channels, groups of hPIEZO1 channels could undergo simultaneous changes in kinetics including a loss of inactivation and a long (∼200 ms), silent latency for activation. These observations suggest that hPIEZO1 exists in spatial domains whose global properties can modify channel gating. The mutations that create HX affect cation fluxes in two ways: slow inactivation increases the cation flux, and the latency decreases it. These data provide a direct link between pathology and mechanosensitive channel dysfunction in nonsensory cells.

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.

Etiology of non-immune hydrops fetalis: An update.

Hydrops fetalis is an excessive fluid accumulation within the fetal extra vascular compartments and body cavities. Non-immune hydrops fetalis (NIHF), due to causes other than Rh alloimmunization, is the cause in >85% of all affected individuals. Herein we present an update of our earlier systematic literature review [Bellini et al., 2009] using all publications between 2007 and 2013. We excluded most of the initial 31,783 papers by using strict selection criteria, thus resulting in 24 relevant NIHF publications describing 1,338 individuals with NIHF. We subdivided the affected individuals into 14 classification groups based on the cause of NIHF (percentage of the total group): Cardiovascular (20.1%), Hematologic (9.3%), Chromosomal (9.0%), Syndromic (5.5%), Lymphatic Dysplasia (15.0%), Inborn Errors of Metabolism (1.3%), Infections (7.0%), Thoracic (2.3%), Urinary Tract Malformations (0.9%), Extra Thoracic Tumors (0.7%), TTTF-Placental (4.1%), Gastrointestinal (1.3%), Miscellaneous (3.6%), Idiopathic (19.8%). We discuss the results of the review. There may be some shifts in the percentages of etiological categories as compared to the previous review, but the small numbers within each category make drawing firm conclusions hazardous. We highlight the need for multi-center series of NIHF cases collected and classified using the same schemes in diagnostic work-ups to allow for comparisons of larger numbers of cases.

Mirror syndrome associated with fetal leukemia.

Mirror syndrome describes the association of fetal and placental hydrops with maternal edema. This case is the first reported case of mirror syndrome relative to fetal leukemia. We suggest that fetal leukemia can have a major impact on mirror syndrome, and provide a brief review of the literature related to this syndrome.

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.

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.

Percutaneous in utero thoracoamniotic shunt creation for fetal thoracic abnormalities leading to nonimmune hydrops.

PURPOSE: To describe a transabdominal, transuterine Seldinger-based percutaneous approach to create a shunt for treatment of fetal thoracic abnormalities. MATERIALS AND METHODS: Five fetuses presented with nonimmune fetal hydrops secondary to fetal thoracic abnormalities causing severe mass effect. Under direct ultrasound guidance, an 18-gauge needle was used to access the malformation. Through a peel-away sheath, a customized pediatric transplant 4.5-F double J ureteral stent was advanced; the leading loop was placed in the fetal thorax, and the trailing end was left outside the fetal thorax within the amniotic cavity. RESULTS: Seven thoracoamniotic shunts were successfully placed in five fetuses; one shunt was immediately replaced because of displacement during the procedure, and another shunt was not functioning at follow-up requiring insertion of a second shunt. All fetuses had successful decompression of the thoracic malformation, allowing lung reexpansion and resolution of hydrops. Three of five mothers had meaningful (> 7 d) prolongation of their pregnancies. All pregnancies were maintained to > 30 weeks (range, 30 weeks 1 d-37 weeks 2 d). There were no maternal complications. CONCLUSIONS: A Seldinger-based percutaneous approach to draining fetal thoracic abnormalities is feasible and can allow for prolongation of pregnancy and antenatal lung development and ultimately result in fetal survival.

Non-immune hydrops fetalis: A prospective study of 53 cases.

Non-immune hydrops fetalis (NIHF) is a symptom caused by a heterogeneous group of conditions. Diagnostic investigations may constitute a real challenge. This study aimed to evaluate prospectively and systematically a series of NIHF cases using a research protocol expanded for studying inborn errors of metabolism (IEM) during 2 years-2010 and 2011. We also reviewed the frequency of IEM among the NIHF reported in literature. A clinical or etiopathogenic diagnosis was reached in 46 (86.8%) of the 53 studied cases. The main diagnostic groups were chromosomal anomalies (28.3%), syndromic (18.9%), isolated cardiovascular anomaly (7.5%) and congenital infection (7.5%). Metabolic causes were found in 5.7%, all lysosomal storage disorders (LSD). In seven (13.2%), no diagnosis was found in part because of incomplete evaluation. The hydrops was identified prenatally in 90.5% of cases. In 5.7% a spontaneous and complete resolution of the hydrops occurred during pregnancy. Overall mortality was 75.5%. The IEM frequency in the present study (5.7%) was higher than that usually reported. We suggest performing studies directed to IEMs if the more common causes are excluded.

Fluid shift from intravascular compartment during fetal red blood cell transfusion.

OBJECTIVES: Intrauterine transfusion imposes a considerable burden on the fetal circulation by increasing volume and pressure, and a fluid shift from the fetal circulation occurs even during the procedure. The aim of this study was to quantify the intraprocedural fluid shift and to investigate the effect of procedural and fetal characteristics on this fluid shift. METHODS: In 95 alloimmunized pregnancies, we calculated fluid shift at the first intrauterine transfusion by determining initial and final blood volumes. We evaluated the association of the fluid shift with the speed and volume of the transfusion, the severity of anemia and the presence of hydrops. RESULTS: Of the included fetuses, 11 were mildly hydropic and four were severely hydropic. A mean fluid shift of 36% of the transfused volume was found. Fluid shift related positively to transfused volume (P < 0.001). The percentage fluid shift of transfused volume was inversely related to the speed of transfusion (mL/kg/min) (P < 0.041) and was not related to the severity of anemia (P = 0.55) or to hydrops (P = 0.66). It was found that younger fetuses had been unintentionally subject to high volumes and speeds of transfusion relative to their size. CONCLUSIONS: Around one-third of the transfused volume is lost from the intravascular compartment during the procedure of intrauterine transfusion. There is a large variation between fetuses, partly explained by the volume and speed of the transfusion. Neither severity of anemia nor hydrops plays a clear-cut role, and thus other factors may explain the variation in fluid shift. The probability that hematocrit will still increase after transfusion, as a result of a continuing fluid shift, should be considered in transfusion policy. Advice is given on gestational age-adjusted speed of transfusion.

Association of nonimmune hydrops fetalis with familial hemophagocytic lymphohistiocytosis in identical twin neonates with perforin His222Arg (c665A>G) mutation.

BACKGROUND: This is the first study demonstrating that nonimmune hydrops fetalis (NIHF) in identical twin neonates is associated with biallelic gene defect causing familial hemophagocytic lymphohistiocytosis. OBSERVATIONS: Preterm male twins (31(4/7) wk) with NIHF and hepatosplenomegaly gradually developed pancytopenia, hyperferritinemia, hyponatremia, hypoalbuminemia, and elevated alanine aminotransferase, aspartate aminotransferase, bilirubin, and lactate dehydrogenase levels. Suspected sepsis led to antibiotic therapy. Upon detection of hemophagocytosis in bone marrow, multiorgan failure and pulmonary bleeding led to death. Homozygous His222Arg (c665A>G) mutation was identified in Perforin. CONCLUSIONS: Familial hemophagocytic lymphohistiocytosis should be considered in first days of NIHF cases to have chance for HLH-2004 therapy. Missense mutations of Perforin codon His222 may lead to intrauterine presentation.

Fetal myocardial performance (Tei) index in fetal hemoglobin Bart's disease.

PURPOSE: To assess the effectiveness of Tei index in differentiating fetal Hb Bart's disease in pregnancies at risk in the first half of pregnancy. MATERIALS AND METHODS: Pregnancies meeting the inclusion criteria were consecutively recruited to the study. The inclusion criteria were as follows: 1) singleton pregnancies, 2) gestational age of 12 - 20 weeks, 3) at risk of Hb Bart's disease, 4) confirmed fetal diagnosis of Hb Bart's disease. Fetuses with frank hydrops fetalis or fetuses with chromosomal abnormalities or structural anomalies were excluded. Tei index was performed and immediately recorded before invasive prenatal diagnosis was performed. RESULTS: Of 152 fetuses, 50 were finally proven to be affected by Hb Bart disease, and the remainder was unaffected. Mean (± SD) Tei index were 0.48 ± 0.07 and 0.54 ± 0.08 in group of unaffected and affected fetuses, respectively. The mean difference was 0.05 which was statistically significant (p < 0.001). Likewise, mean (± SD) isovolumetric contraction time (ICT) in normal fetuses were also significantly different from that of affected fetuses. CONCLUSION: In the first half of pregnancy, Tei index in the fetuses with Hb Bart's disease was significantly higher than that in normal fetuses implying that Tei index may be a novel useful and non-invasive tool for early detection of fetal Hb Bart's disease among pregnancies at risk.

Non-immune hydrops fetalis.

BACKGROUND: Non-immune hydrops fetalis (NIHF) is a rare fetal condition with a very high mortality in spite of advances in prenatal diagnostic techniques, early detection, and individualized management. Despite advancement in fetal therapy and rapidly developing new knowledge about the aetiology and prenatal diagnosis, its management has remained controversial. METHODS: This is a descriptive review ofNIHF. RESULTS: NIHF is a rare fetal condition that presents in an extremely acute manner with almost 90% mortality. Fetal cardiac anomalies are the most common cause and chromosome anomalies are the second-most-common cause. The worst prognosis was related to prematurity, severe hydrops, anaemia, cardiac malformations, chromosomal disorders and congenital infections. Fetal interventions includeboth medical and surgical modalities. CONCLUSION: NIHF is a rare condition with high prenatal mortality. The exact pathophysiology is still poorly understood. It is important to detect NIHF early, diagnose the underlying cause and institute appropriate treatment. There is need for autopsy of all fetuses or neonates who die from NIHF.

Non-immune hydrops fetalis: a short review of etiology and pathophysiology.

Hydrops fetalis is an excessive accumulation of fetal fluid. Hydrops is traditionally classified into either immune or non-immune hydrops (NIHF), but in practice, nowadays in the Western world >90% of hydrops is of non-immune origin. The basis of the disorder is an imbalance in the regulation of fetal fluid movement between the vascular and interstitial space. We previously suggested a diagnostic flow-chart for NIHF. In this short review we describe the main mechanisms leading to NIHF.

Circulating N-terminal pro-B-type natriuretic peptide in fetal anemia before and after treatment.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (ntproBNP) is an established marker of heart failure in adult cardiology. We analyzed nt-proBNP in the circulation of fetuses with increased volume load secondary to anemia and investigated the effect of treatment on nt-proBNP concentration. METHODS: Fetuses undergoing intrauterine transfusion (IUT) were examined. nt-proBNP was measured before IUT and correlated with hemoglobin concentrations, ultrasonographic findings, and Doppler measurements of the peak systolic velocity of the middle cerebral artery (MCA-PSV). RESULTS: A total of 27 patients (7 with hydrops) and 78 controls were examined. nt-proBNP was markedly elevated in anemia (P < 0.001). Concentrations were highest in hydropic fetuses (P < 0.03); no differences were present in hemoglobin and MCA-PSV values between hydropic and nonhydropic cases. In fetuses undergoing multiple IUTs nt-proBNP normalized after the third IUT, whereas hemoglobin and MCA-PSV remained abnormal. CONCLUSION: Levels of circulating nt-proBNP correlate well with the degree of myocardial workload in the hyperdynamic state of fetal anemia. We hypothesize that normalization of nt-proBNP after serial transfusions is an indicator of myocardial adjustment to chronic anemia. nt-proBNP measurement may be useful in the management of fetal anemia, particularly in cases at risk of hydrops and fetuses requiring multiple transfusions.