Fungal microbiota in newborn infants with and without respiratory distress syndrome.

BACKGROUND: Pneumocytis jirovecii infection in preterm newborns has recently been associated with neonatal respiratory distress syndrome and bronchopulmonary dysplasia. Changes in the bacterial microbiota of the airways have also been described in infants with bronchopulmonary dysplasia. However, until now there has been no information on the airway mycobiota in newborns. The purpose of this study was to describe the airway mycobiota in term and preterm newborns and its possible association with respiratory distress syndrome. METHODS: Twenty-six matched preterm newborns with and without respiratory distress syndrome were studied, as well as 13 term babies. The identification of the fungal microbiota was carried out using molecular procedures in aspirated nasal samples at birth. RESULTS: The ascomycota phylum was identified in 89.7% of newborns, while the basidiomycota phylum was found in 33.3%. Cladosporium was the predominant genus in both term and preterm infants 38.4% vs. 73% without statistical differences. Candida sake and Pneumocystis jirovecii were only found in preterm infants, suggesting a potential relationship with the risk of prematurity. CONCLUSIONS: This is the first report to describe the fungal microbiota of the airways in term and preterm infants with and without respiratory distress syndrome. Although no differences have been observed, the number of cases analyzed could be small to obtain conclusive results, and more studies are needed to understand the role of the fungal microbiota of the airways in neonatal respiratory pathology.

Ex-Utero Intrapartum Treatment (EXIT): indications and outcome in fetal cervical and oropharyngeal masses.

BACKGROUND: The "Ex-Utero Intrapartum Treatment" (EXIT) procedure allows to ensure fetal airway before completion of delivery and umbilical cord clamping while keeping uteroplacental circulation. Airway obstruction in fetal oropharyngeal and cervical masses can be life-threatening at birth. In those situations, controlled access to fetal airway performed by a trained multidisciplinary team allows safe airway management, while feto-maternal circulation is preserved. We aim to review the indications and outcome of the EXIT procedure in a case series of fetal cervical and oropharyngeal masses. METHODS: We have carried out a retrospective review of all patients with fetal cervical and oropharyngeal masses who underwent an EXIT procedure between 2008 and 2019. Variables evaluated included indication for EXIT, ultrasound and MRI findings, the need of amnioreduction, gestational age at EXIT, birth weight, complications, operative time, survival rate, pathological findings, and postnatal evolution. Five patients are included in this series. One additional case has already been published. RESULTS: The diagnosis were cervical teratoma (n = 1), epulis (n = 1) and lymphangioma (n = 3). Polyhydramnios was present in 2 patients, requiring amnioreduction in one of them. Mean gestational age at EXIT was 36-37 weeks (range, 34-38 weeks). Median EXIT time in placental support was 9 min (range, 3-22 min). Access to airway was successfully established in EXIT in all cases. All children born by EXIT are currently healthy and without complications. CONCLUSION: The localization and characteristics of the mass, its relationship to the airway, and the presence of polyhydramnios seem to be major factors determining indications for EXIT and clinical outcome.

Topiramate plus Cooling for Hypoxic-Ischemic Encephalopathy: A Randomized, Controlled, Multicenter, Double-Blinded Trial.

BACKGROUND AND OBJECTIVES: Therapeutic interventions to improve the efficacy of whole-body cooling for hypoxic-ischemic encephalopathy (HIE) are desirable. Topiramate has been effective in reducing brain damage in experimental studies. However, in the clinical setting information is limited to a small number of feasibility trials. We launched a randomized controlled double-blinded topiramate/placebo multicenter trial with the primary objective being to reduce the antiepileptic activity in cooled neonates with HIE and assess if brain damage would be reduced as a consequence. STUDY DESIGN: Neonates were randomly assigned to topiramate or placebo at the initiation of hypothermia. Topiramate was administered via a nasogastric tube. Brain electric activity was continuously monitored. Topiramate pharmacokinetics, energy-related and Krebs' cycle intermediates, and lipid peroxidation biomarkers were determined using liquid chromatography-mass spectrometry and MRI for assessing brain damage. RESULTS: Out of 180 eligible patients 110 were randomized, 57 (51.8%) to topiramate and 53 (48.2%) to placebo. No differences in the perinatal or postnatal variables were found. The topiramate group exhibited less seizure burden in the first 24 h of hypothermia (topiramate, n = 14 [25.9%] vs. placebo, n = 22 [42%]); needed less additional medication, and had lower mortality (topiramate, n = 5 [9.2%] vs. placebo, n = 10 [19.2%]); however, these results did not achieve statistical significance. Topiramate achieved a therapeutic range in 37.5 and 75.5% of the patients at 24 and 48 h, respectively. A significant association between serum topiramate levels and seizure activity (p < 0.016) was established. No differences for oxidative stress, energy-related metabolites, or MRI were found. CONCLUSIONS: Topiramate reduced seizures in patients achieving therapeutic levels in the first hours after treatment initiation; however, they represented only a part of the study population. Our results warrant further studies with higher loading and maintenance dosing of topiramate.

Estrés oxidativo en la asfixia perinatal y la encefalopatía hipóxico-isquémica / Oxidative stress in perinatal asphyxia and hypoxic-ischaemic encephalopathy

La asfixia intraparto es una de las causas más frecuentes de muerte neonatal precoz pero también puede, en los supervivientes, evolucionar a una encefalopatía hipóxico-isquémica responsable de una elevada morbilidad neurológica. La presencia de episodios de hipoxia-isquemia prolongados conduce a un rápido agotamiento energético en los tejidos exclusivamente dependientes del metabolismo aeróbico, como el sistema nervioso central. El déficit energético conlleva una paralización de las bombas ATP-dependientes y subsiguiente pérdida del potencial neuronal transmembrana. La población neuronal de las regiones más sensibles del SNC mueren por necrosis, mientras que en otras áreas se produce una hiperexcitabilidad neuronal con entrada masiva de calcio iónico, activación de NO-sintasa, generación de radicales libres que alteran el funcionamiento mitocondrial, provocando un fallo energético secundario y muerte neuronal por apoptosis. Recientemente se ha propuesto una tercera fase en la que factores como la inflamación persistente y los cambios epigenéticos causarían un bloqueo de la maduración de los oligodendrocitos, alteración de la neurogénesis, del crecimiento axonal y de la sinaptogénesis. En este contexto, el estrés oxidativo va a tener un papel protagonista como responsable tanto en causar daño directo al SNC como en activar cascadas metabólicas conducentes a la apoptosis e inflamación. La hipotermia moderada precoz, al preservar las reservas energéticas y disminuir la formación de especies reactivas de oxígeno, atenuará el daño cerebral posreanimación. La combinación de la hipotermia con terapias coadyuvantes para modular el estrés oxidativo podría contribuir a mejorar el pronóstico

Birth asphyxia is one of the principal causes of early neonatal death. In survivors it may evolve to hypoxic-ischaemic encephalopathy and major long-term neurological morbidity. Prolonged and intense asphyxia will lead to energy exhaustion in tissues exclusively dependent on aerobic metabolism, such as the central nervous system. Energy deficit leads to ATP-dependent pumps blockage, with the subsequent loss of neuronal transmembrane potential. The most sensitive areas of the brain will die due to necrosis. In more resistant areas, neuronal hyper-excitability, massive entrance of ionic calcium, activation of NO-synthase, free radical generation, and alteration in mitochondrial metabolism will lead to a secondary energy failure and programmed neuronal death by means of the activation of the caspase pathways. A third phase has recently been described that includes persistent inflammation and epigenetic changes that would lead to a blockage of oligodendrocyte maturation, alteration of neurogenesis, axonal maturation, and synaptogenesis. In this scenario, oxidative stress plays a critical role causing direct damage to the central nervous system and activating metabolic cascades leading to apoptosis and inflammation. Moderate whole body hypothermia to preserve energy stores and to reduce the formation of oxygen reactive species attenuates the mechanisms that lead to the amplification of cerebral damage upon resuscitation. The combination of hypothermia with coadjuvant therapies may contribute to improve the prognosis

[Oxidative stress in perinatal asphyxia and hypoxic-ischaemic encephalopathy]. / Estrés oxidativo en la asfixia perinatal y la encefalopatía hipóxico-isquémica.

Birth asphyxia is one of the principal causes of early neonatal death. In survivors it may evolve to hypoxic-ischaemic encephalopathy and major long-term neurological morbidity. Prolonged and intense asphyxia will lead to energy exhaustion in tissues exclusively dependent on aerobic metabolism, such as the central nervous system. Energy deficit leads to ATP-dependent pumps blockage, with the subsequent loss of neuronal transmembrane potential. The most sensitive areas of the brain will die due to necrosis. In more resistant areas, neuronal hyper-excitability, massive entrance of ionic calcium, activation of NO-synthase, free radical generation, and alteration in mitochondrial metabolism will lead to a secondary energy failure and programmed neuronal death by means of the activation of the caspase pathways. A third phase has recently been described that includes persistent inflammation and epigenetic changes that would lead to a blockage of oligodendrocyte maturation, alteration of neurogenesis, axonal maturation, and synaptogenesis. In this scenario, oxidative stress plays a critical role causing direct damage to the central nervous system and activating metabolic cascades leading to apoptosis and inflammation. Moderate whole body hypothermia to preserve energy stores and to reduce the formation of oxygen reactive species attenuates the mechanisms that lead to the amplification of cerebral damage upon resuscitation. The combination of hypothermia with coadjuvant therapies may contribute to improve the prognosis.

Evolution of Energy Related Metabolites in Plasma from Newborns with Hypoxic-Ischemic Encephalopathy during Hypothermia Treatment.

Therapeutic hypothermia (TH) initiated within 6 h from birth is the most effective therapeutic approach for moderate to severe hypoxic-ischemic encephalopathy (HIE). However, underlying mechanisms and effects on the human metabolism are not yet fully understood. This work aims at studying the evolution of several energy related key metabolites in newborns with HIE undergoing TH employing gas chromatography - mass spectrometry. The method was validated following stringent FDA requirements and applied to 194 samples from a subgroup of newborns with HIE (N = 61) enrolled in a multicenter clinical trial (HYPOTOP) for the determination of lactate, pyruvate, ketone bodies and several Krebs cycle metabolites at different sampling time points. The analysis of plasma samples from newborns with HIE revealed a decrease of lactate, pyruvate and ß-hydroxybutyrate concentrations, whereas rising malate concentrations were observed. In healthy control newborns (N = 19) significantly lower levels of pyruvate and lactate were found in comparison to age-matched newborns with HIE undergoing TH, whereas acetoacetate and ß-hydroxybutyrate levels were clearly increased. Access to a validated analytical method and a controlled cohort of newborns with HIE undergoing hypothermia treatment for the first time allowed the in-depth study of the evolution of key metabolites of metabolic junctions in this special population.

Early Acquisition of Pneumocystis jirovecii Colonization and Potential Association With Respiratory Distress Syndrome in Preterm Newborn Infants.

BACKGROUND: Pneumocystis pneumonia is a well-recognized lung disease of premature and malnourished babies. Even though serologic studies have shown that children are exposed to Pneumocystis jirovecii early in life, the epidemiology of human P. jirovecii infection and the host-microorganism relationship in infancy remain poorly understood. The aim of the present study was to investigate the prevalence of P. jirovecii colonization in preterm infants and its possible association with medical complications. METHODS: A prospective observational study of preterm infants (birth weight <1500 g and/or gestational age <32 weeks) was carried out. Identification of P. jirovecii colonization was performed by means of molecular techniques in nasal aspirated samples at birth. RESULTS: A total of 128 preterm infants were included during the study period. Pneumocystis DNA was identified in 25.7% (95% confidence interval [CI], 17.8%-33.7%) of newborns studied. A significant increase of respiratory distress syndrome in colonized group, even after adjusting for confounding factors (odds ratio, 2.7 [95% CI, 1.0-7.5]; P = .04), was observed. No differences were observed in other medical conditions between the 2 groups. CONCLUSIONS: Pneumocystis jirovecii colonization is frequent in preterm births and could be a risk factor to develop respiratory distress syndrome among preterm infants.

NT-proBNP as Marker of Ventricular Dilatation and Pulmonary Regurgitation After Surgical Correction of Tetralogy of Fallot: A MRI Validation Study.

The goal of this study is to evaluate whether NT-proBNP plasma levels may help as a screening biomarker for monitoring right ventricular dilatation, pulmonary regurgitation and the onset of heart failure in patients with repaired Tetralogy of Fallot. Our single-centre observational prospective study involved 43 patients (15.1 years, SD = 8) with corrected Tetralogy of Fallot. Data collection included: clinical parameters (electrocardiogram, chest X-ray, NYHA scale, time since last surgery), biochemistry (NT-proBNP levels) and MRI values (ventricular volumetry, pulmonary flow assessment). Mean time since last surgery was 13.5 years (SD = 7.8). There was a statistically significant correlation between the NT-proBNP levels (187.4 pg/ml, SD = 154.9) and right ventricular dilatation for both the right ventricular end-diastolic volume (124.9 ml/m2, SD = 31.2) (Pearson = 0.19, p < 0.01) and end-systolic volume (56.1 ml/m2, SD = 18.8) (Pearson = 0.21, p < 0.01) and also with the pulmonary regurgitation fraction (36.5%, SD = 16, Pearson = 0.12, p < 0.01). No significant correlation was found between NT-proBNP and right ventricular ejection fraction (54.6%, SD = 10.6, Pearson = -0.07), left ventricular ejection fraction (59.9%, SD = 7.1, Pearson = -0.18) or any clinical parameters. The receiver operating curve analysis evidenced that a NT-proBNP cut-off value above 133.2 pg/ml predicted the presence of dilated right ventricular end-diastolic and end-systolic volumes over centile 95 (sensitivity 82 and 83% and specificity 93 and 79%, respectively). In conclusion, in patients with surgically corrected Tetralogy of Fallot, NT-proBNP levels correlate with right ventricular dilatation and the degree of pulmonary regurgitation. Ambulatory determination of NT-proBNP might be an easy, readily available and cost-effective alternative for MRI follow-up evaluation of these patients.

EXIT procedure in twin pregnancy: a series of three cases from a single center.

BACKGROUND: Indications for the ex utero intrapartum therapy (EXIT) procedure have evolved and nowadays in addition to secure the airway, obtain vascular access, administer surfactant and other resuscitation medications, EXIT is used to resect cervical or thoracic masses, for extracorporeal membrane circulation (ECMO) cannulation, as well as to rescue maximum intra-thoracic space for ventilation of the remaining functional lung tissue or in cases in which resuscitation of the neonate may be compromised. EXIT procedure in twin pregnancy has been rarely reported and some doubts have been raised about its strategy and safety in such cases. METHODS: We reviewed the medical records of 3 twin pregnancy cases where the EXIT procedure have been performed in our center. RESULTS: The mean gestational age at EXIT procedure was 34 + 4 weeks. In two out the three EXIT procedures, the affected twin was delivered first. The average time on placental bypass was 9 minutes. There were no fetal or maternal complications related to the EXIT procedure. All newborns are currently doing well. CONCLUSION: In twin pregnancies, prenatal diagnosis combined with the EXIT procedure permits the formulation of a controlled delivery strategy to secure both newborns outcome. In those pregnancies, if intervention can be accomplished without compromise of the normal twin, EXIT can be considered. Our results support that EXIT procedure, if properly planned, safely provides a good outcome for both the fetuses as well as the mother.

Immunolocalization of substance P and NK-1 receptor in Hofbauer cells in human normal placenta.

Substance P (SP) after binding to the neurokinin-1 (NK-1) receptor regulates many biological functions. Both SP and the NK-1 receptor are expressed in human normal placenta cells, monocytes, and macrophages. However, to our knowledge, the presence of both SP and the NK-1 receptor in macrophages of the placenta, the Hofbauer cells, is unknown. We demonstrate by immunohistochemistry in human normal placenta samples the presence of both SP and NK-1 receptors in the cytoplasm and in the nucleus of Hofbauer cells. The findings suggest a functional role of the SP/NK-1 receptor system in the physiology and pathophysiology of Hofbauer cells in the human placenta.

Association of human beta-defensin-2 serum levels and sepsis in preterm neonates*.

OBJECTIVES: To determine human beta-defensin-2 levels in term and preterm neonates at birth and to evaluate its impact on sepsis. DESIGN: Observational study. SETTING: Single tertiary care hospital. PATIENTS: Term neonates and preterm neonates were recruited and divided in groups according to important clinical events. INTERVENTIONS: Cord blood samples were drawn from all newborns immediately after birth. Human beta-defensin-2 levels were determined using enzyme-linked immunosorbent assay technology. All neonates were followed clinically during the first 30 days of life. MEASUREMENTS AND MAIN RESULTS: Forty-two term and 31 preterm neonates were enrolled. Human beta-defensin-2 levels in term neonates were higher compared with preterm infants (median, 1,882 vs 918 pg/mL; p = 0.003) and correlated with gestational age and birth weight. Of 31 preterm neonates, seven suffered from late-onset sepsis, and this was associated with lower human beta-defensin-2 levels (median, 513 vs 1,411 pg/mL; p = 0.006). CONCLUSION: Preterm neonates show lower human beta-defensin-2 levels in cord blood compared with term neonates. Low human beta-defensin-2 levels in preterm neonates might be associated with an increased risk of late-onset sepsis.