The singular case of multiple chorangioma syndrome in an IVF pregnancy. Analysis of the case and review of literature.

The redacted classification of placental lesions identifies in the group of fetal-stromal vascular lesions a subgroup called villous capillary lesions. The causes of villous capillary lesions appear to involve excessive angiogenesis. These conditions include chorangiosis, chorangiomatosis, chorangioma and a rare variant of the latter called multiple chorangioma syndrome where multiple chorangiomas, ranging from very small early precursor lesions to typical macroscopic chorangioma, occupy up to 80% of the total placental parenchyma. We present the first case of multiple chorangioma syndrome in an oncologic patient who obtained the pregnancy by egg donation, comparing the clinical case with ones available in literature. Fifteen cases have been previously published in literature but only 11 were eligible for the present review. We compared clinical characteristics and fetal outcomes with our clinical case, to highlight similarities and differences useful for a better understanding of this rare and partially unknown disease. Multiple chorangioma syndrome is a rare villous capillary lesion associated with poor fetal condition. All cases analyzed have been conceived naturally and our case is the first described in an IVF pregnancy. We believe that in our case the advanced maternal age, the method of conception and the previous chemo-therapeutic treatments might have played an important role in determining the manifestation of this rare placental condition. However, there is not appropriate literature supporting our consideration and, for future studies, it could be reasonable investigate the incidence of this condition, or even the incidence of all cluster of villous capillary lesions, in oncologic and IVF patients.

Oxygen metabolism and oxygenation of the newborn.

The premature infant is to some extent protected from hypoxia, however defense against hyperoxia is poorly developed. The optimal assessment of oxygenation is to measure oxygen delivery and extraction. At the bedside PaO2 and SpO2 are approximations of oxygenation at the tissue level. After birth asphyxia it is crucial to know whether or not to give oxygen supplementation, when, how much, and for how long. Oxygen saturation targets in the delivery room have been studied, but the optimal targets might still be unknown because factors like gender and delayed cord clamping influence saturation levels. However, SpO2 > 80% at 5 min of age is associated with favorable long term outcome in preterm babies. Immature infants most often need oxygen supplementation beyond the delivery room. Predefined saturation levels, and narrow alarm limits together with the total oxygen exposure may impact on development of oxygen related diseases like ROP and BPD. Hyperoxia is a strong trigger for genetic and epigenetic changes, contributing to the development of these conditions and perhaps lifelong changes.

Oxygen and pulmonary vasodilation: The role of oxidative and nitrosative stress.

Respiratory failure complicates up to 2% of live births and contributes significantly to neonatal morbidity and mortality. Under these conditions, supplemental oxygen is required to support oxygen delivery to the brain and other organs, and to prevent hypoxic pulmonary vasoconstriction. However, therapeutic oxygen is also a source of reactive oxygen species that produce oxidative stress, along with multiple intracellular systems that contribute to the production of free radicals in pulmonary endothelium and vascular smooth muscle. These free radicals cause vasoconstriction, act on multiple sites of the nitric oxide pathway to reduce cGMP-mediated vasodilation, and nitrate and inactivate essential proteins such as surfactant. In addition to oxygen, antenatal stressors such as placental insufficiency, maternal diabetes, and fetal growth restriction increase pulmonary and vascular oxidant stress and may amplify the adverse effects of oxygen. Moreover, the effects of free radical damage may extend well beyond infancy as suggested by the increased risk of childhood malignancy after neonatal exposure to hyperoxia. Antioxidant therapy is theoretically promising, but there are not yet clinical trials to support this approach. Targeting the abnormal sources of increased oxidant stress that trigger abnormal pulmonary vascular responses may be more effective in treating disease and preventing long term consequences.

Intermittent hypoxia and long-term neurological outcome: How are they related?

This review looks at data on potential associations between intermittent hypoxia (IH) and impaired neurodevelopment in infants and children. In extremely preterm infants (<28 wk gestation), such an association has been established based on a secondary analysis of Canadian Oxygen Trial data. These showed, in 997 infants, that the odds of developing cognitive or language impairment at 18 months corrected age were 3 times higher in infants who were in the highest decile for %time spent with events where pulse oximeter saturation (SpO2) was <80% for ≥1 min during their first 10 postnatal weeks compared to those who had very few such events after birth. In older term and preterm infants, the occurrence of 5 or more events with prolonged apnea and bradycardia during home monitoring was associated with 5 points less on the mental development index of the Bayley-II scales. For older children, associations between sleep-disordered breathing and impaired cognition/academic achievements have also been established, but not consistently, and it remains unclear whether this association is primarily mediated via IH or via sleep deprivation. Animal data show that IH may cause apoptosis particularly in the hippocampus. Although we need to stress that associations cannot prove causality, current evidence provides support for IH to be detected and prevented early. Future studies should focus on IH rather than on apnea/bradycardia.

Intermittent hypoxia and bronchial hyperreactivity.

The premature neonate is at high risk for childhood airway hyperreactivity and episodes of wheezing. Intermittent hypoxic events are frequently observed during the first weeks and months of life in these infants. Intermittent hypoxemia has been associated with adverse outcomes in extremely premature infants; including the diagnosis of bronchopulmonary dysplasia, reported wheezing, and use of prescription asthma medications. We review the incidence of intermittent hypoxia, their potential role in short and longer term respiratory morbidity, and the translational newborn models now being used to investigate common pathways by which intermittent hypoxia contributes to respiratory disease.

Superior explicit memory despite severe developmental amnesia: In-depth case study and neural correlates.

The acquisition of new semantic memories is sometimes preserved in patients with hippocampal amnesia. Robust evidence for this comes from case reports of developmental amnesia suggesting that low-to-normal levels of semantic knowledge can be achieved despite compromised episodic learning. However, it is unclear whether this relative preservation of semantic memory results from normal acquisition and retrieval or from residual episodic memory, combined with effortful repetition. Furthermore, lesion studies have mainly focused on the hippocampus itself, and have seldom reported the state of structures in the extended hippocampal system. Preserved components of this system may therefore mediate residual episodic abilities, contributing to the apparent semantic preservation. We report an in-depth study of Patient KA, a 27-year-old man who had severe hypoxia at birth, in which we carefully explored his residual episodic learning abilities. We used novel speeded recognition paradigms to assess whether KA could explicitly acquire and retrieve new context-free memories. Despite a pattern of very severe amnesia, with a 44-point discrepancy between his intelligence and memory quotients, KA exhibited normal-to-superior levels of knowledge, even under strict time constraints. He also exhibited normal-to-superior recognition memory for new material, again under strict time constraints. Multimodal neuroimaging revealed an unusual pattern of selective atrophy within each component of the extended hippocampal system, contrasting with the preservation of anterior subhippocampal cortices. A cortical thickness analysis yielded a pattern of thinner but also thicker regional cortices, pointing toward specific temporal lobe reorganization following early injury. We thus report the first case of superior explicit learning and memory in a severe case of amnesia, raising important questions about how such knowledge can be acquired.

A prospective observational cohort study of exposure to womb-like sounds to stabilize breathing and cardiovascular patterns in preterm neonates.

PURPOSE: We exposed premature infants to womb-like sounds to evaluate such exposure on breathing and cardiovascular patterns. We hypothesized that these sounds would reduce apnea and intermittent hypoxemia, enhance parasympathetic outflow, and improve cardiovascular patterns. METHODS: A total of 20 cases and 5 control infants at ≤32-36 weeks corrected gestational age participated in a prospective observational cohort study. Twenty-four hours of continuous ECG, respiratory and oxygen saturation data were collected in all infants. Womb-like sounds were played intermittently in 6-hour blocks. Salivary samples were collected at study beginning and end for cortisol. Apnea, intermittent hypoxemia, and bradycardia were evaluated, and heart rate variability was assessed by time domain and spectral techniques. RESULTS: Intermittent hypoxemia and bradycardia significantly declined after sound exposure. No significant differences in apnea, cortisol levels, or heart rate variability were evident among the study infants. CONCLUSIONS: Exposing premature infants to womb-like sounds has the potential to reduce hypoxemic and bradycardic events, and be used as an intervention to stabilize breathing and cardiac control in preterm infants.

Hypoxic/ischemic and infectious events have cumulative effects on the risk of cerebral palsy in very-low-birth-weight preterm infants.

BACKGROUND: Hypoxia/ischemia and inflammation are two major mechanisms for cerebral palsy (CP) in preterm infants. OBJECTIVE: To investigate whether hypoxia/ischemia- and infection-related events in the perinatal and neonatal periods had cumulative effects on CP risk in very-low-birth-weight (VLBW) premature infants. METHODS: From 1995 to 2005, 5,807 VLBW preterm infants admitted to Taiwan hospitals were enrolled. The cumulative effects of hypoxic/ischemic and infectious events during the perinatal and neonatal periods on CP risk at corrected age 24 months were analyzed. RESULTS: Of the 4,355 infants with 24-month follow-up, 457 (10.5%) had CP. The CP group had significantly higher incidences of hypoxia/ischemia-related events in the perinatal and neonatal periods, and sepsis in the neonatal period than the normal group. Three hypoxic/ischemic events, including birth cardiopulmonary resuscitation (OR 2.25; 95% CI 1.81-2.82), patent ductus arteriosus (PDA) ligation (2.94; 1.35-5.75) and chronic lung disease (3.14; 2.61-3.85) had the most significant contribution to CP. Relative to CP risk for infants with neither the three hypoxic/ischemic events nor sepsis, the CP odds increased 1.98-, 2.26- and 2.15-fold for infants with birth cardiopulmonary resuscitation, PDA ligation and chronic lung disease, respectively; while the combination with sepsis further increased the odds to 3.18-, 3.83- and 3.25-fold, respectively. Using the three hypoxic/ischemic events plus sepsis, CP rates were 10.0, 16.7, 26.7, 40.0 and 54.7% for infants with none, one, two, three and four events, respectively. CONCLUSIONS: Hypoxic/ischemic and infectious events across the perinatal and neonatal periods exerted cumulative effects on CP risk in VLBW premature infants.

The specific characteristics of DIC syndrome vary with different clinical settings in the newborn.

Abstract Two hundred fourteen newborns with serious perinatal pathology (posthypoxic syndrome, sepsis, surgical intervention, etc.) were examined in progress, according to 27 parameters including coagulative, trombocitic, anti-coagulative and fibrinolitic parts of hemostasis system. It was proved, that neonatal disseminated intravascular coagulation (DIC) syndrome had different hemostasiological patterns, which were connected with the genesis: sepsis, surgical intervention or posthypoxic syndrome. Precise periods of DIC syndrome are not always presented in newborns. DIC syndrome with neonatal sepsis has two different patterns (overcompensated and decompensated). The manifestation of trombo-hemorrhagic disorders and their characteristics depend on the genesis of DIC syndrome (e.g. an infection process and hyperbilirubinemia can provide the appearance of hemorrhagic syndrome).

Increased myocardial methionine-enkephalin with reduced arterial oxygenation in congenital heart disease.

BACKGROUND: Cardiac opioid peptides have been identified to exert important adaptive metabolic signalling for cardioprotection against ischaemia or hypoxia-related injury. AIMS: To determine myocardial methionine-enkephalin content in children with hypoxemic congenital heart defects and to correlate myocardial content of methionine-enkephalin with the extent of arterial oxygen desaturation. METHODS: Children (n= 20, median age of 16 months), undergoing cardiac surgical repair (tetralogy of Fallot, 17/20), were included in this study. Arterial oxygen saturation was measured on admission. Myocardial samples obtained during surgery were assayed via radioimmunochemistry for methionine-enkephalin content. RESULTS: Greater methionine-enkephalin content was measured in the right ventricles of the patients suffering from recent cyanotic spells compared with those with no recent spells (cyanotic spells: 2418 ± 844 pg/g wet weight tissue, n= 6; no spells: 1175 ± 189 pg/g wet weight tissue, n= 14, P= 0.04). An inverse correlation was evident between the arterial oxygen saturation and myocardial methionine-enkephalin content. CONCLUSION: Myocardial methionine-enkephalin levels increase with the severity of hypoxic stress in congenital cardiac disease and may play an important adaptive role in countering adrenergic over-activity and related excess demand on myocardial metabolic capacity.

The assessment of time-dependent myocardial changes in infants with perinatal hypoxia.

OBJECTIVE: The aim of the study was to assess myocardial damage in infants due to perinatal hypoxia. METHODS: The findings of 29 infants with perinatal hypoxia and 20 healthy infants were compared. Blood gas analysis, serum lactate, cardiac troponin I (cTnI), troponin T (cTnT), creatine kinase-MB (CK-MB) and B-type natriuretic peptide (BNP) were evaluated. Echocardiography together with tissue Doppler imaging was performed. RESULTS: cTnT, CK-MB and BNP were higher in patients at the first day. There were positive correlations between the left ventricular (LV) myocardial performance index (MPI) and cTnT at first day and also at first month. LV ejection fraction and fractional shortening were lower at first day and at first month in patients. Myocardial systolic (Sm) and diastolic (Em and Am) velocities at all segments were lower at first day, and interventricular septum Sm, LV Sm, LV Em, right ventricular Em and LV Am were still lower at first month in patients. Isovolumic relaxation time at all segments together with LV MPI was higher at first day, ejection time values were lower and MPI values were higher at all segments at first month in patients. CONCLUSIONS: These findings demonstrated that the signs of myocardial damage due to perinatal hypoxia still present at first month.

Diagnóstico por imagem e aspectos clínicos da trombose venosa cerebral em recém-natos a termo sem dano cerebral: revisão em 10 anos / Imaging diagnosis and clinical findings of cerebral venous thrombosis in full-term neonateswithout brain damage: a ten-year review

OBJETIVO: Descrever e comparar os métodos de imagem e os aspectos clínicos em quatro recém-natos a termo diagnosticados como trombose venosa cerebral, sem dano encefálico, adscritos a uma unidade de terapia intensiva neonatal. MATERIAIS E MÉTODOS: Revisão em 10 anos com quatro casos diagnosticados como trombose venosa cerebral por meio de ultrassonografia transfontanela com Doppler e confirmados por ressonância magnética/angiorressonância, correlacionados aos aspectos clínicos e evolução neurológica. RESULTADOS: A ultrassonografia foi normal em 75 por cento dos casos e a ressonância magnética, em 100 por cento. No caso alterado, a dilatação venosa foi identificada. O Doppler e a angiorressonância estavam alterados em 100 por cento dos casos. Dos aspectos clínicos, a hipóxia (100 por cento) e a convulsão precoce (100 por cento) predominaram, com potencial evocado alterado em 50 por cento dos casos. Na avaliação do neurodesenvolvimento, todas as áreas estiveram dentro da normalidade até a última avaliação. CONCLUSÃO: A ultrassonografia associada ao Doppler é capaz de identificar as alterações da trombose venosa cerebral, devendo ser complementada com a ressonância magnética, que é o padrão ouro de diagnóstico.

OBJECTIVE: To describe and compare imaging methods and clinical findings of cerebral venous thrombosis in four full-term neonates without brain damage, admitted to a neonatal intensive care unit. MATERIALS AND METHODS: Ten-year review of four cases diagnosed with cerebral venous thrombosis by transfontanellar ultrasonography associated with Doppler fluxometry and confirmed by magnetic resonance imaging/magnetic resonance angiography in correlation with clinical findings and neurological progression. RESULTS: Ultrasonography presented normal results in 75 percent of cases and magnetic resonance imaging in 100 percent. Doppler fluxometry and magnetic resonance angiography were abnormal in 100 percent of cases. Hypoxia (100 percent) and early seizures (100 percent) were predominant among clinical findings with evoked potential changes in 50 percent of cases. In the assessment of the neurodevelopment all the areas remained within normality parameters up to the conclusion of the present study. CONCLUSION: Ultrasonography in association with Doppler can identify changes related to cerebral venous thrombosis and should be complemented with magnetic resonance imaging that is the gold standard for diagnosis in these cases.

Attenuation of lipopolysaccharide-induced oxidative stress and apoptosis in fetal pulmonary artery endothelial cells by hypoxia.

Pulmonary vascular endothelial injury resulting from lipopolysaccharide (LPS) and oxygen toxicity contributes to vascular simplification seen in the lungs of premature infants with bronchopulmonary dysplasia. Whether the severity of endotoxin-induced endothelial injury is modulated by ambient oxygen tension (hypoxic intrauterine environment vs. hyperoxic postnatal environment) remains unknown. We posited that ovine fetal pulmonary artery endothelial cells (FPAEC) will be more resistant to LPS toxicity under hypoxic conditions (20-25 Torr) mimicking the fetal milieu. LPS (10 microg/ml) inhibited FPAEC proliferation and induced apoptosis under normoxic conditions (21% O(2)) in vitro. LPS-induced FPAEC apoptosis was attenuated in hypoxia (5% O(2)) and exacerbated by hyperoxia (55% O(2)). LPS increased intracellular superoxide formation, as measured by 2-hydroxyethidium (2-HE) formation, in FPAEC in normoxia and hypoxia. 2-HE formation in LPS-treated FPAEC increased in parallel with the severity of LPS-induced apoptosis in FPAEC, increasing from hypoxia to normoxia to hyperoxia. Differences in LPS-induced apoptosis between hypoxia and normoxia were abolished when LPS-treated FPAEC incubated in hypoxia were pretreated with menadione to increase superoxide production. Apocynin decreased 2-HE formation, and attenuated LPS-induced FPAEC apoptosis under normoxic conditions. We conclude that ambient oxygen concentration modulates the severity of LPS-mediated injury in FPAEC by regulating superoxide levels produced in response to LPS.

Can inhaled prostacyclin stimulate surfactant in ELBW infants?

Respiratory distress syndrome (RDS) causes significant hypoxia in extremely low birth weight (ELBW) infants. We report an ELBW infant with RDS and pulmonary hypertension whose hypoxia did not respond to inhaled nitric oxide but improved with inhaled prostacyclin. We propose that inhaled prostacyclin alleviated the hypoxia by stimulating surfactant secretion.

Phospholipid composition of myocardium in children with normoxemic and hypoxemic congenital heart diseases.

Samples of myocardial tissue were obtained during cardiac surgery from children operated for different types of normoxemic and hypoxemic congenital heart diseases. The phospholipid composition was analyzed by thin layer chromatography. The concentration of total phospholipids (PL), phosphatidylcholine and phosphatidylethanolamine (PE) was found lower in atrial tissue of both normoxemic and hypoxemic groups in comparison with the ventricles. When comparing the difference between hypoxemic and normoxemic defects, hypoxemia was found to increase the concentration of total PL, PE and phosphatidylserine in ventricles and total PL and PE in the atria. The increased level of particular phospholipid species may represent adaptive mechanisms to hypoxemia in children with congenital heart diseases.

Sensitivity and specificity of prenatal features of physiological shunts to predict neonatal clinical status in transposition of the great arteries.

BACKGROUND: Although prenatal diagnosis of transposition of the great arteries (TGA) reduces neonatal mortality, the preoperative course can be complicated in infants with a restrictive foramen ovale (FO) or a ductus arteriosus (DA) constriction. We sought to determine the specificity and sensitivity of prenatal features of physiological shunts in predicting postnatal clinical status in prenatally diagnosed TGA in babies delivered in a tertiary care center providing all facilities for neonatal urgent care. METHODS AND RESULTS: The outcomes of 130 fetuses with TGA were reviewed over a period of 5.5 years. Restriction of the FO and/or constriction of the DA could be analyzed in 119/130 fetuses at 36+/-2.7 weeks of gestation. Twenty-four out of 119 had at least 1 abnormal shunt (23 FO, 5 DA, and 4 both). Thirteen of 130 neonates had profound hypoxemia (PaO2<25 mm Hg) and metabolic acidosis (pH <7.15) in the first 30 minutes and required immediate balloon atrioseptostomy. Two who had abnormal FO and DA died despite aggressive resuscitation. The specificity and sensitivity of the fetal echo in predicting neonatal emergency were 84% and 54%, respectively. The specificity and sensitivity of a combination of restrictive FO and DA constriction were 100% and 31%, respectively. CONCLUSIONS: Restriction of the FO and/or of the DA has a high specificity to predict the need for emergency neonatal care in fetuses with TGA, but the sensitivity is too low to detect all high-risk fetuses. Exceptional procedures should be considered for fetuses that have a combination of restrictive FO and DA constriction.

New concepts in abnormalities of respiratory control in children.

PURPOSE OF REVIEW: Respiratory control disorders such as apnea of prematurity, apparent life-threatening events, sudden infant death syndrome, and central hypoventilation are relatively frequent conditions in the pediatric age range and are associated with substantial morbidity and mortality. The explosion of technological breakthroughs in biology and medicine has facilitated our understanding of the fundamental mechanisms that govern the development of brain regions underlying respiratory control functions. RECENT FINDINGS: Recent critically important discoveries encompass the identification of neurons that constitute the central respiratory rhythm generator in the brainstem, the conceptual framework allowing for many neurons located in multiple strategic regions within the brain to coordinate central chemosensitivity, the discovery of long-term and short-term plasticity in hypoxic ventilatory regulation, and the recent uncovering of specific gene mutations in children affected with congenital central hypoventilation syndrome. SUMMARY: While the developmental aspects of control breathing are only now being actively explored in the context of our current understanding, it is likely that such efforts will yield important novel approaches to the clinical and pharmacologic management of these disorders in the near future.

Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors.

Adaptation to hypoxia is critical for survival and regulates multiple processes, including erythropoiesis and vasculogenesis. Chuvash polycythemia is a hypoxia-sensing disorder characterized by homozygous mutation (598C>T) of von Hippel-Lindau gene (VHL), a negative regulator of hypoxia sensing. Although endemic to the Chuvash population of Russia, this mutation occurs worldwide and originates from a single ancient event. That VHL 598C>T homozygosity causes elevated normoxic levels of the transcription factor hypoxia inducible factor-1alpha (HIF-1alpha), serum erythropoietin and hemoglobin is known, but the disease phenotype has not been documented in a controlled manner. In this matched cohort study, VHL 598C>T homozygosity was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum vascular endothelial growth factor (VEGF) concentrations (P <.0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classical VHL syndrome were not found, suggesting that overexpression of HIF-1alpha and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in VHL 598C>T homozygotes than in controls, erythropoietin response to hypoxia was identical. Thus, Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes.