Emerging neuroprotective interventions in periventricular leukomalacia - A systematic review of preclinical studies.

INTRODUCTION: Periventricular leukomalacia (PVL) is a result of various antenatal, intrapartum, or postnatal insults to the developing brain and is an important harbinger of cerebral palsy in preterm neonates. There is no proven therapy for PVL. This calls for appraisal of targeted therapies that have been investigated in animal models to evaluate their relevance in a clinical research context. AREAS COVERED: This systematic review identifies interventions that were evaluated in preclinical studies for neuroprotective efficacy against PVL. We identified 142 studies evaluating various interventions in PVL animal models (search method is detailed in section 2). EXPERT OPINION: Interventions that have yielded significant results in preclinical research, and that have been evaluated in a limited number of clinical trials include stem cells, erythropoietin, and melatonin. Many other therapeutic modalities evaluated in preclinical studies have been identified, but more data on their neuroprotective potential in PVL must be garnered before they can be considered for clinical trials. Because most of the tested interventions had only a partial efficacy, a combination of interventions that could be synergistic should be investigated in future preclinical studies. Furthermore, since the nature and pattern of perinatal insults to preterm brain predisposing it to PVL are substantially variable, individualized approaches for the choice of appropriate neuroprotective interventions tailored to different subgroups of preterm neonates should be explored.

Decreased Fetal Movements: A Sign of Placental SARS-CoV-2 Infection with Perinatal Brain Injury.

Neonatal COVID-19 is rare and mainly results from postnatal transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, can infect the placenta and compromise its function. We present two cases of decreased fetal movements and abnormal fetal heart rhythm 5 days after mild maternal COVID-19, requiring emergency caesarean section at 29 + 3 and 32 + 1 weeks of gestation, and leading to brain injury. Placental examination revealed extensive and multifocal chronic intervillositis, with intense cytoplasmic positivity for SARS-CoV-2 spike antibody and SARS-CoV-2 detection by RT-qPCR. Vertical transmission was confirmed in one case, and both neonates developed extensive cystic peri-ventricular leukomalacia.

Risk Factors for Periventricular Leukomalacia in Preterm Infants: A Systematic Review, Meta-analysis, and GRADE-Based Assessment of Certainty of Evidence.

BACKGROUND: We analyzed the certainty of evidence (CoE) for risk factors of periventricular leukomalacia (PVL) in preterm neonates, a common morbidity of prematurity. METHODS: Medline, CENTRAL, Embase, and CINAHL were searched. Cohort and case-control studies and randomised randomized controlled trials were included. Data extraction was performed in duplicate. A random random-effects meta-analysis was utilizedused. CoE was evaluated as per Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. RESULTS: One hundred eighty-six studies evaluating 95 risk factors for PVL were included. Of the 2,509,507 neonates assessed, 16,569 were diagnosed with PVL. Intraventricular hemorrhage [adjusted odds ratio: 3.22 (2.52-4.12)] had moderate CoE for its association with PVL. Other factors such as hypocarbia, chorioamnionitis, PPROM >48 hour, multifetal pregnancy reduction, antenatal indomethacin, lack of antenatal steroids, perinatal asphyxia, ventilation, shock/hypotension, patent ductus arteriosus requiring surgical ligation, late-onset circulatory collapse, sepsis, necrotizing enterocolitis, and neonatal surgery showed significant association with PVL after adjustment for confounders (CoE: very low to low). Amongst the risk factors associated with mother placental fetal (MPF) triad, there was paucity of literature related to genetic predisposition and defective placentation. Sensitivity analysis revealed that the strength of association between invasive ventilation and PVL decreased over time (P < 0.01), suggesting progress in ventilation strategies. Limited studies had evaluated diffuse PVL. CONCLUSION: Despite decades of research, our findings indicate that the CoE is low to very low for most of the commonly attributed risk factors of PVL. Future studies should evaluate genetic predisposition and defective placentation in the MPF triad contributing to PVL. Studies evaluating exclusively diffuse PVL are warranted.

Mode of delivery and adverse short- and long-term outcomes in vertex-presenting very preterm born infants: a European population-based prospective cohort study.

OBJECTIVES: To compare mortality, morbidity and neurodevelopment by mode of delivery (MOD) for very preterm births with low prelabour risk of caesarean section (CS). METHODS: The study was a population-based prospective cohort study in 19 regions in 11 European countries. Multivariable mixed effects models and weighted propensity score models were used to estimate adjusted odds ratios (aOR) by observed MOD and the unit's policy regarding MOD. Population: Singleton vertex-presenting live births at 24 + 0 to 31 + 6 weeks of gestation without serious congenital anomalies, preeclampsia, HELLP or eclampsia, antenatal detection of growth restriction and prelabour CS for fetal or maternal indications. RESULTS: Main outcome measures: A composite of in-hospital mortality and intraventricular haemorrhage (grade III/IV) or periventricular leukomalacia. Secondary outcomes were components of the primary outcome, 5 min Apgar score <7 and moderate to severe neurodevelopmental impairment at two years of corrected age. The rate of CS was 29.6% but varied greatly between countries (8.0-52.6%). MOD was not associated with the primary outcome (aOR for CS 0.99; 95% confidence interval [CI] 0.65-1.50) when comparing units with a systematic policy of CS or no policy of MOD to units with a policy of vaginal delivery (aOR 0.88; 95% CI 0.59-1.32). No association was observed for two-year neurodevelopment impairment for CS (aOR 1.15; 95% CI 0.66-2.01) or unit policies (aOR 1.04; 95% CI 0.63-1.70). CONCLUSIONS: Among singleton vertex-presenting live births without medical complications requiring a CS at 24 + 0 to 31 + 6 weeks of gestation, CS was not associated with improved neonatal or long-term outcomes.

Severity of Bronchopulmonary Dysplasia Among Very Preterm Infants in the United States.

BACKGROUND AND OBJECTIVES: The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network recently proposed new, severity-based diagnostic criteria for bronchopulmonary dysplasia (BPD). This study provides the first benchmark epidemiological data applying this definition. METHODS: Retrospective cohort study of infants born from 22 to 29 weeks' gestation in 2018 at 715 US hospitals in the Vermont Oxford Network. Rates of BPD, major neonatal morbidities, and common respiratory therapies, stratified by BPD severity, were determined. RESULTS: Among 24 896 infants, 2574 (10.3%) died before 36 weeks' postmenstrual age (PMA), 12 198 (49.0%) did not develop BPD, 9192 (36.9%) developed grade 1 or 2 BPD, and 932 (3.7%) developed grade 3 BPD. Rates of mortality before 36 weeks' PMA and grade 3 BPD decreased from 52.7% and 9.9%, respectively, among infants born at 22 weeks' gestation to 17.3% and 0.8% among infants born at 29 weeks' gestation. Grade 1 or 2 BPD peaked in incidence (51.8%) among infants born at 25 weeks' gestation. The frequency of severe intraventricular hemorrhage or cystic periventricular leukomalacia increased from 4.8% among survivors without BPD to 23.4% among survivors with grade 3 BPD. Similar ranges were observed for late onset sepsis (4.8%-31.4%), surgically treated necrotizing enterocolitis (1.4%-17.1%), severe retinopathy of prematurity (1.2%-23.0%), and home oxygen therapy (2.0%-67.5%). CONCLUSIONS: More than one-half of very preterm infants born in the United States died before 36 weeks' PMA or developed BPD. Greater BPD severity was associated with more frequent development of major neonatal morbidities, in-hospital mortality, and use of supplemental respiratory support at discharge.

Severe Brain Damage in a Moderate Preterm Infant as Complication of Post-COVID-19 Response during Pregnancy.

Current evidence from the COVID-19 pandemic suggests that neonatal SARS-coronavirus-2 infections usually have a mild course. Data on how maternal infection during pregnancy affects fetal development are scarce. We present the unique case of a moderate preterm infant with intracranial bleeding and periventricular leukomalacia as a potential consequence of post-COVID-19 hyperinflammation during pregnancy.

Comparative efficacy of methods for surfactant administration: a network meta-analysis.

OBJECTIVES: To compare surfactant administration via thin catheters, laryngeal mask, nebulisation, pharyngeal instillation, intubation and surfactant administration followed by immediate extubation (InSurE) and no surfactant administration. DESIGN: Network meta-analysis. SETTING: Medline, Scopus, CENTRAL, Web of Science, Google-scholar and Clinicaltrials.gov databases were systematically searched from inception to 15 February 2020. PATIENTS: Preterm neonates with respiratory distress syndrome. INTERVENTIONS: Less invasive surfactant administration. MAIN OUTCOME MEASURES: The primary outcomes were mortality, mechanical ventilation and bronchopulmonary dysplasia. RESULTS: Overall, 16 randomised controlled trials (RCTs) and 20 observational studies were included (N=13 234). For the InSurE group, the median risk of mortality, mechanical ventilation and bronchopulmonary dysplasia were 7.8%, 42.1% and 10%, respectively. Compared with InSurE, administration via thin catheter was associated with significantly lower rates of mortality (OR: 0.64, 95% CI: 0.54 to 0.76), mechanical ventilation (OR: 0.43, 95% CI: 0.29 to 0.63), bronchopulmonary dysplasia (OR: 0.57, 95% CI: 0.44 to 0.73), periventricular leukomalacia (OR: 0.66, 95% CI: 0.53 to 0.82) with moderate quality of evidence and necrotising enterocolitis (OR: 0.67, 95% CI: 0.41 to 0.9, low quality of evidence). No significant differences were observed by comparing InSurE with administration via laryngeal mask, nebulisation or pharyngeal instillation. In RCTs, thin catheter administration lowered the rates of mechanical ventilation (OR: 0.39, 95% CI: 0.26 to 0.60) but not the incidence of the remaining outcomes. CONCLUSION: Among preterm infants, surfactant administration via thin catheters was associated with lower likelihood of mortality, need for mechanical ventilation and bronchopulmonary dysplasia compared with InSurE. Further research is needed to reach firm conclusions about the efficacy of alternative minimally invasive techniques of surfactant administration.

Intraventricular Hemorrhage and White Matter Injury in Preclinical and Clinical Studies.

Germinal matrix-intraventricular hemorrhage (IVH) occurs in nearly half of infants born at less than 26 weeks' gestation. Up to 50% of survivors with IVH develop cerebral palsy, cognitive deficits, behavioral disorders, posthemorrhagic ventricular dilatation, or a combination of these sequelae. After the initial bleeding and the primary brain injury, inflammation and secondary brain injury might lead to periventricular leukomalacia or diffuse white matter injury. Potential factors that are involved include microglia and astrocyte activation, degradation of blood components with release of "toxic" products, infiltration of the brain by systemic immune cells, death of neuronal and glial cells, and arrest of preoligodendrocyte maturation. In addition, impairment of the blood-brain barrier may play a major role in the pathophysiology. A wide range of animal models has been used to explore causes and mechanisms leading to IVH-induced brain injury. Preclinical studies have identified potential targets for enhancing brain repair. However, little has been elucidated about the effectiveness of potential interventions in clinical studies. A systematic review of available preclinical and clinical studies might help identify research gaps and which types of interventions may be prioritized. Future trials should report clinically robust and long-term outcomes after IVH.

[Mechanisms of brain injury of the premature baby]. / Mecanismos de lesión cerebral en niños prematuros.

Preterm birth is one of the main country health indicators. It is associated with high mortality and significant morbidity in preterm newborns with cerebral palsy and potential long-term neurodevelopmental disabilities like cognitive and learning problems. The main lesions could be: a) white matter injuries, generally associated with cortical and other regions of grey matter neuronal-axonal disturbances; b) intracranial hemorrhage that includes germinal matrix, intraventricular and parenchymal, c) cerebellum injuries. The white matter lesions include cystic and non-cystic (with microscopic focal necrosis) periventricular leukomalacia and non-necrotic diffuse white matter injury. Multiple etiologic factors are associated with these injuries. Anatomical and physiological characteristics of periventricular vascular structures predispose white matter to cerebral ischemia and, interacting with infection/inflammation factors, activate microglia, generating oxidative stress (mediated by free oxygen and nitrogen radicals), pro-inflammatory cytokine and glutamate toxicity, energetic failure and vascular integrity disturbances. All these factors lead to a particular vulnerability of pre-oligodendrocytes that will affect myelination. Hypoxia-ischemia also may produce selective neuronal necrosis in different cerebral regions. Germinal matrix is a highly vascularized zone beneath ependymal or periventricular region that constitutes a capillary bed with a particular structural fragility that predispose it to hemorrhage.

Los nacimientos prematuros son uno de los principales indicadores de salud de un país. Están asociados a una alta mortalidad e importante morbilidad en niños con parálisis cerebral y otros trastornos del neurodesarrollo, incluyendo problemas cognitivos y del aprendizaje. Los principales tipos de lesión encefálica en los recién nacidos prematuros son: a) las lesiones de la sustancia blanca, generalmente asociadas a alteraciones neuronales y axonales en la corteza cerebral y otras zonas de sustancia gris; b) hemorragias intracraneanas que incluyen las de la matriz germinal, intraventriculares e intraparenquimatosas y c) del cerebelo. Las lesiones de sustancia blanca incluyen la leucomalacia periventricular quística, no quística (con focos de necrosis microscópicos) y lesiones difusas de sustancia blanca, no necróticas. Estas lesiones tienen múltiples factores etiológicos. Las características anatómicas y fisiológicas de las estructuras vasculares periventriculares predisponen a la sustancia blanca a ser muy vulnerable a las situaciones de isquemia cerebral y, en interacción con factores infecciosos/inflamatorios, activan a las microglías generando estrés oxidativo (por liberación de radicales libres del oxígeno y del nitrógeno), liberación de citoquinas proinflamatorias, liberación de glutamato, fallo energético y alteración de la integridad vascular. Todo lo anteriormente mencionado genera una particular vulnerabilidad de los pre-oligodendrocitos que termina alterando la mielinización. La hipoxia-isquemia también puede producir necrosis neuronal selectiva en diferentes regiones encefálicas. La matriz germinal es un área altamente vascularizada en la región subependimaria periventricular con una estructura capilar muy frágil que la predispone a las hemorragias.

Beyond Anesthesia Toxicity: Anesthetic Considerations to Lessen the Risk of Neonatal Neurological Injury.

Infants who undergo surgical procedures in the first few months of life are at a higher risk of death or subsequent neurodevelopmental abnormalities. Although the pathogenesis of these outcomes is multifactorial, an understanding of the nature and pathogenesis of brain injury in these infants may assist the anesthesiologist in consideration of their day-to-day practice to minimize such risks. This review will summarize the main types of brain injury in preterm and term infants and their key pathways. In addition, the review will address key potential pathogenic pathways that may be modifiable including intraoperative hypotension, hypocapnia, hyperoxia or hypoxia, hypoglycemia, and hyperthermia. Each of these conditions may increase the risk of perioperative neurological injury, but their long-term ramifications are unclear.

Mecanismos de lesión cerebral en niños prematuros / Mechanisms of brain injury of the premature baby

Los nacimientos prematuros son uno de los principales indicadores de salud de un país. Están asociados a una alta mortalidad e importante morbilidad en niños con parálisis cerebral y otros trastornos del neurodesarrollo, incluyendo problemas cognitivos y del aprendizaje. Los principales tipos de lesión encefálica en los recién nacidos prematuros son: a) las lesiones de la sustancia blanca, generalmente asociadas a alteraciones neuronales y axonales en la corteza cerebral y otras zonas de sustancia gris; b) hemorragias intracraneanas que incluyen las de la matriz germinal, intraventriculares e intraparenquimatosas y c) del cerebelo. Las lesiones de sustancia blanca incluyen la leucomalacia periventricular quística, no quística (con focos de necrosis microscópicos) y lesiones difusas de sustancia blanca, no necróticas. Estas lesiones tienen múltiples factores etiológicos. Las características anatómicas y fisiológicas de las estructuras vasculares periventriculares predisponen a la sustancia blanca a ser muy vulnerable a las situaciones de isquemia cerebral y, en interacción con factores infecciosos/inflamatorios, activan a las microglías generando estrés oxidativo (por liberación de radicales libres del oxígeno y del nitrógeno), liberación de citoquinas proinflamatorias, liberación de glutamato, fallo energético y alteración de la integridad vascular. Todo lo anteriormente mencionado genera una particular vulnerabilidad de los pre-oligodendrocitos que termina alterando la mielinización. La hipoxia-isquemia también puede producir necrosis neuronal selectiva en diferentes regiones encefálicas. La matriz germinal es un área altamente vascularizada en la región subependimaria periventricular con una estructura capilar muy frágil que la predispone a las hemorragias.

Preterm birth is one of the main country health indicators. It is associated with high mortality and significant morbidity in preterm newborns with cerebral palsy and potential long-term neurodevelopmental disabilities like cognitive and learning problems. The main lesions could be: a) white matter injuries, generally associated with cortical and other regions of grey matter neuronal-axonal disturbances; b) intracranial hemorrhage that includes germinal matrix, intraventricular and parenchymal, c) cerebellum injuries. The white matter lesions include cystic and non-cystic (with microscopic focal necrosis) periventricular leukomalacia and non-necrotic diffuse white matter injury. Multiple etiologic factors are associated with these injuries. Anatomical and physiological characteristics of periventricular vascular structures predispose white matter to cerebral ischemia and, interacting with infection/inflammation factors, activate microglia, generating oxidative stress (mediated by free oxygen and nitrogen radicals), pro-inflammatory cytokine and glutamate toxicity, energetic failure and vascular integrity disturbances. All these factors lead to a particular vulnerability of pre-oligodendrocytes that will affect myelination. Hypoxia-ischemia also may produce selective neuronal necrosis in different cerebral regions. Germinal matrix is a highly vascularized zone beneath ependymal or periventricular region that constitutes a capillary bed with a particular structural fragility that predispose it to hemorrhage.

Predictors of Severe Neurologic Injury on Ultrasound Scan of the Head and Risk Factor-based Screening for Infants Born Preterm.

OBJECTIVE: To identify risk factors for severe neurologic injury (intraventricular hemorrhage grade 3 or greater and/or periventricular leukomalacia) diagnosed by ultrasound scan of the head among infants born at 300-326 weeks of gestation and compare different screening strategies. STUDY DESIGN: This was a retrospective cohort study of infants born at 300-326 weeks or >326 weeks of gestation with a birth weight <1500 g admitted to neonatal intensive care units in the Canadian Neonatal Network from 2011 to 2016. Stepwise logistic regression analysis was used to identify significant risk factors and calculate aORs and 95% CIs. Risk factor-based screening strategies were compared. RESULTS: The rate of severe neurologic injury was 3.1% among infants screened (285/9221). Significant risk factors included singleton birth (aOR 1.96, 95% CI 1.35-2.85), 5-minute Apgar <7 (aOR 1.81, 95% CI 1.30-2.50), mechanical ventilation on day 1 (aOR 2.65, 95% CI 1.88-3.71), and treatment with vasopressors on day 1 (aOR 3.23, 95% CI 2.19-4.75). Risk categories were low (no risk factor, 1.2%, 25/2137), moderate (singleton with no other risk factor: 1.8%, 68/3678), and high (≥1 risk factor among 5-minute Apgar <7, receipt of vasopressors or mechanical ventilation on day 1: 5.6%, 192/3408). Screening moderate- to high-risk infants identified 91% (260/285) of infants with severe neurologic injury and would require screening fewer infants (1647 infants per year) than screening all infants <33 weeks of gestation (2064 infants screened per year, 93% [265/285] of cases identified). CONCLUSIONS: Risk factor-based ultrasound scan of the head screening among infants born at 30-32 weeks of gestation could help optimize resources better than gestational age based screening.

Inhibition of microglial activation by minocycline reduced preoligodendrocyte injury in a neonatal rat brain slice model.

BACKGROUND: Periventricular leukomalacia is a common white-matter injury after neonatal cardiac surgery; however, its potential cellular mechanism remains uncertain. There is limited study regarding periventricular leukomalacia treatment. METHODS: A neonatal rat brain slice perfusion model was used for reproducing the condition of cardiopulmonary bypass, and oxygen glucose deprivation simulated circulatory arrest. Seven-day-old Sprague-Dawley rats were randomly divided into 7 groups: (1) control group with 36°C; (2) 60 minutes of oxygen glucose deprivation group on 15°C, 25°C, 36°C, respectively; and (3) 60 minutes of oxygen glucose deprivation group on 15°C, 25°C, 36°C, plus minocycline (10 µmol/L), respectively. Immunohistochemistry, Western blot, and inflammatory mediators were compared after the perfusion procedures in the different groups. RESULTS: This neonatal rat brain slice perfusion with oxygen glucose deprivation model could replicate the pathophysiologic process and injury after cardiopulmonary bypass and hypothermic circulatory arrest. With the increase of oxygen glucose deprivation perfusion temperature, we found that both microglia activation and preoligodendrocyte loss increased. The application of minocycline can significantly inhibit microglial activation and preoligodendrocyte cells loss in the normothermic (36°C) and moderate hypothermia (25°C) oxygen glucose deprivation groups (P < .05), with accompanying significant decreasing microglial inflammatory productions; however, no significant improvement was found in the deep hypothermia (15°C) group. CONCLUSIONS: The microglial activation may play a key role in preoligodendrocyte injury in the ex vivo neonatal rat brain slice perfusion and circulatory arrest model. Inhibition of microglial activation with minocycline may be an attractive target for white-matter protection during cardiopulmonary bypass and hypothermic circulatory arrest.

Neuronalinjury and roles of apoptosis and autophagy in a neonatal rat model of hypoxia-ischemia-induced periventricular leukomalacia.

As research into periventricular leukomalacia (PVL) gradually increases, concerns are emerging about long­term neuron injury. The present study aimed to investigate neuronal injury and the relevant alterations in apoptosis and autophagy in a PVL model established previously. A rat model of hypoxia­ischemia­induced PVL was established. In the model group, Sprague­Dawley (SD) rats [postnatal day 3 (P3)] were subjected to right common carotid artery ligation followed by suturing and exposed to 6­8% oxygen for 2 h; in the control group, SD rats (P3) were subjected to right common carotid artery dissection followed by suturing, without ligation and hypoxic exposure. At 1, 3, 7 and 14 days following modeling, brain tissue samples were collected and stained with hematoxylin and eosin. Cellular apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and the protein and mRNA expression alterations of neuronal nuclei (NeuN), caspase­3 and Beclin 1 in the model group were detected by western blot analysis and reverse transcription­quantitative polymerase chain reaction (RT­qPCR) analyses. Compared with the control group, the protein and mRNA expression levels of NeuN (a marker of mature neurons) were markedly reduced, the number of positive cells was increased as detected by TUNEL, and the protein and mRNA expression levels of caspase­3 and Beclin 1 were elevated in the model group. In the rat model of hypoxia­ischemia­induced PVL, oligodendrocyte injury and myelinization disorders were observed, in addition to neuron injury, a decrease in mature neurons and the co­presence of apoptosis and autophagy. However, apoptosis and autophagy exist in different phases: Apoptosis is involved in neuron injury, while autophagy is likely to have a protective role.

Pretreatment with magnesium sulfate attenuates white matter damage by preventing cell death of developing oligodendrocytes.

AIM: Antenatal maternal administration of magnesium sulfate (MgSO4 ) reduces cerebral palsy in preterm infants. However, it remains controversial as to whether it also reduces occurrence of white matter damage, or periventricular leukomalacia. We assessed the effect of MgSO4 against white matter damage induced by hypoxic-ischemic insult using a neonatal rat model and culture of premyelinating oligodendrocytes (pre-OL). METHODS: Rat pups at postnatal day (P) 6 were administered either MgSO4 or vehicle intraperitoneally before hypoxic-ischemic insult (unilateral ligation of the carotid artery followed by 6% oxygen for 1 h). The population of oligodendrocyte (OL) markers and CD-68-positive microglia at P11, and TdT-mediated biotin-16-dUTP nick-end labeling (TUNEL)-positive cells at P8 were evaluated in pericallosal white matter. Primary cultures of mouse pre-OL were subjected to oxygen glucose deprivation condition, and the lactate dehydrogenase release from culture cells was evaluated to assess cell viability. RESULTS: Pretreatment with MgSO4 attenuated the loss of OL markers, such as myelin basic protein and Olig2, in ipsilateral pericallosal white matter and decreased the number of CD-68-positive microglia and TUNEL-positive cells in vivo. Pretreatment with MgSO4 also inhibited lactate dehydrogenase release from pre-OL induced by oxygen glucose deprivation in vitro. CONCLUSION: Pretreatment with MgSO4 attenuates white matter damage by preventing cell death of pre-OL.

Efficacy of antenatal corticosteroids in preterm twins: the EPIPAGE-2 cohort study.

OBJECTIVES: To investigate the efficacy of antenatal corticosteroid (ACS) therapy on short-term neonatal outcomes in preterm twins, and further document the influence of the ACS-to-delivery interval. DESIGN: EPIPAGE-2 is a nationwide observational multicentre prospective cohort study of neonates born between 22 and 34 completed weeks of gestation. SETTING: All French maternity units, except in a single administrative region, between March and December 2011. POPULATION: A total of 750 twin neonates born between 24 and 31 weeks of gestation. METHODS: Exposure to ACSs was examined in four groups: single complete course, with an ACS administration-to-delivery interval of ≤7 days; single complete course, with an ACS-to-delivery interval of >7 days; repeated courses; or no ACS treatment. MAIN OUTCOME MEASURES: Neonatal outcomes analysed were severe bronchopulmonary dysplasia, periventricular leukomalacia or intraventricular haemorrhage grade III/IV, in-hospital mortality, and a composite indicator of severe outcomes. RESULTS: Compared with no ACSs, in multivariable analysis, a single course of ACSs with an administration-to-delivery interval of ≤7 days was significantly associated with a reduced rate of periventricular leukomalacia or intraventricular haemorrhage grade III/IV (aOR 0.2; CI 95% 0.1-0.5), in-hospital mortality (0.3; 0.1-0.6), and the composite indicator (0.1; 0.1-0.3), whereas a single course of ACDs with an administration-to-delivery interval of >7 days did not significantly reduce the frequency of in-hospital mortality (0.7; 0.3-1.8). No significant differences in terms of benefit or risk were found when comparing repeated courses with a single complete course. CONCLUSION: In preterm twins, a single complete course of antenatal corticosteroids was associated with an improvement of severe neurological outcome, whereas reduced in-hospital mortality was seen only when the ACS-to-delivery interval was ≤7 days. TWEETABLE ABSTRACT: A single complete course of antenatal steroids reduced severe neurological morbidity in preterm twins (24-31 weeks).

Neurally adjusted ventilatory assist compared to other forms of triggered ventilation for neonatal respiratory support.

BACKGROUND: Effective synchronisation of infant respiratory effort with mechanical ventilation may allow adequate gas exchange to occur at lower peak airway pressures, potentially reducing barotrauma and volutrauma and development of air leaks and bronchopulmonary dysplasia. During neurally adjusted ventilatory assist ventilation (NAVA), respiratory support is initiated upon detection of an electrical signal from the diaphragm muscle, and pressure is provided in proportion to and synchronous with electrical activity of the diaphragm (EADi). Compared to other modes of triggered ventilation, this may provide advantages in improving synchrony. OBJECTIVES: Primary• To determine whether NAVA, when used as a primary or rescue mode of ventilation, results in reduced rates of bronchopulmonary dysplasia (BPD) or death among term and preterm newborn infants compared to other forms of triggered ventilation• To assess the safety of NAVA by determining whether it leads to greater risk of intraventricular haemorrhage (IVH), periventricular leukomalacia, or air leaks when compared to other forms of triggered ventilation Secondary• To determine whether benefits of NAVA differ by gestational age (term or preterm)• To determine whether outcomes of cross-over trials performed during the first two weeks of life include peak pressure requirements, episodes of hypocarbia or hypercarbia, oxygenation index, and the work of breathing SEARCH METHODS: We performed searches of the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cohrane Library; MEDLINE via Ovid SP (January 1966 to March 2017); Embase via Ovid SP (January 1980 to March 2017); the Cumulative Index to Nursing and Allied Health Literature (CINAHL) via EBSCO host (1982 to March 2017); and the Web of Science (1985 to 2017). We searched abstracts from annual meetings of the Pediatric Academic Societies (PAS) (2000 to 2016); meetings of the European Society of Pediatric Research (published in Pediatric Research); and meetings of the Perinatal Society of Australia and New Zealand (PSANZ) (2005 to 2016). We also searched clinical trials databases to March 2017. SELECTION CRITERIA: We included randomised and quasi-randomised clinical trials including cross-over trials comparing NAVA with other modes of triggered ventilation (assist control ventilation (ACV),synchronous intermittent mandatory ventilation plus pressure support (SIMV ± PS), pressure support ventilation (PSV), or proportional assist ventilation (PAV)) used in neonates. DATA COLLECTION AND ANALYSIS: Primary outcomes of interest from randomised controlled trials were all-cause mortality, bronchopulmonary dysplasia (BPD; defined as oxygen requirement at 28 days), and a combined outcome of all-cause mortality or BPD. Secondary outcomes were duration of mechanical ventilation, incidence of air leak, incidence of IVH or periventricular leukomalacia, and survival with an oxygen requirement at 36 weeks' postmenstrual age.Outcomes of interest from cross-over trials were maximum fraction of inspired oxygen, mean peak inspiratory pressure, episodes of hypocarbia, and episodes of hypercarbia measured across the time period of each arm of the cross-over. We planned to assess work of breathing; oxygenation index, and thoraco-abdominal asynchrony at the end of the time period of each arm of the cross-over study. MAIN RESULTS: We included one randomised controlled study comparing NAVA versus patient-triggered time-cycled pressure-limited ventilation. This study found no significant difference in duration of mechanical ventilation, nor in rates of BPD, pneumothorax, or IVH. AUTHORS' CONCLUSIONS: Risks and benefits of NAVA compared to other forms of ventilation for neonates are uncertain. Well-designed trials are required to evaluate this new form of triggered ventilation.

Association between perinatal hypoxic-ischemia and periventricular leukomalacia in preterm infants: A systematic review and meta-analysis.

BACKGROUND: Although investigators have implicated hypoxic-ischemia (HI) as a potential cause of periventricular leukomalacia (PVL), the role of clinical risk factors or markers for HI in the development of PVL remains controversial. The aim of this study was to identify perinatal HI-related factors associated with PVL. METHOD: The PubMed, EMBASE, and Cochrane Library databases were searched. The last search was performed on January 2017. Summary effect estimates (pooled odds ratios [ORs]) were calculated for each risk factor using fixed or random effects models with tests for heterogeneity and publication bias. RESULTS: Fifteen studies with a total of 12,851 participants were included in this meta-analysis, and 14 potential risk factors were analyzed. The pooled results showed that mothers with oligohydramnios (OR, 1.55; 95% confidence interval [CI], 1.05 to 2.30), preterm infants with acidemia (OR, 1.87; 95% CI, 1.18 to 2.97), 1-minute Apgar score <7 (OR 2.69; 95% CI, 1.13 to 6.41), 5-minute Apgar score <7 (OR, 1.89; 95% CI, 1.39 to 2.56), apnea (OR, 1.76; 95% CI, 1.07 to 2.90), respiratory distress syndrome (OR, 1.46; 95% CI, 1.04 to 2.03), and seizures (OR, 4.60; 95% CI, 2.84 to 7.46) were associated with increased risk of PVL. CONCLUSION: This study identified perinatal HI-related risk factors for the development of PVL in preterm infants. Future large-scale prospective clinical studies are required to validate and extend these findings.

[Prevalence and risk factors for periventricular leukomalacia in preterm infants. A systematic review]. / Prevalencia y factores de riesgo de leucomalacia periventricular en recien nacidos prematuros. Revision sistematica.

INTRODUCTION: There is a huge disparity in the description of the prevalence and risk factors of periventricular leukomalacia in preterm infants. AIMS: To describe and compare, through a systematic review of the literature, the prevalence of periventricular leukomalacia in preterm infants, as well as to determine the main risk factors associated with its presentation. SUBJECTS AND METHODS: A systematic review was conducted consulting multiple databases of the last 20 years. The search terms were: periventricular leukomalacia, prevalence, risk factors and premature birth. We included all studies that mention or led to the prevalence of periventricular leukomalacia and those that referred to its risk factors. RESULTS: Of the 209 studies identified, we selected 107 studies in which the prevalence of periventricular leukomalacia was mentioned or the risk factors were described. A stratified analysis was performed for the diagnostic technique and gestational age, in addition to a narrative synthesis. Ultrasound detected a prevalence of 14.7% and magnetic resonance of 32.8%. Prevalence in children under 28 weeks was 39.6%; 27.4% in children under 32 weeks and 7.3% in children under 37 weeks. Risk factors include gestational age, intrauterine infection, premature rupture of membranes and chorioamnionitis. CONCLUSIONS: The prevalence of periventricular leukomalacia in preterm infants is heterogeneous, increases according to the degree of prematurity and is better detected by magnetic resonance. There are multiple factors related to its presentation, the main factor is gestational age.

TITLE: Prevalencia y factores de riesgo de leucomalacia periventricular en recien nacidos prematuros. Revision sistematica.Introduccion. Existe una enorme disparidad en cuanto a la descripcion de la prevalencia y los factores de riesgo de la leucomalacia ventricular en los prematuros. Objetivos. Describir y comparar, a traves de una revision sistematica de la bibliografia, la prevalencia y los factores de riesgo de la leucomalacia periventricular en los prematuros. Sujetos y metodos. Se realizo una revision sistematica consultando multiples bases de datos de los ultimos 20 anos. Los terminos de busqueda fueron: leucomalacia periventricular, prevalencia, factores de riesgo y recien nacidos prematuros. Se incluyeron todos los estudios que senalaran o condujeran a la obtencion de la prevalencia de la leucomalacia periventricular y los que hicieran referencia a sus factores de riesgo. Resultados. Se seleccionaron 107 estudios en los que se menciono o condujo a la obtencion de la prevalencia de la leucomalacia periventricular o en los que se describian los factores de riesgo. Se efectuo un analisis estratificado para la tecnica de diagnostico y la edad gestacional, ademas de una sintesis narrativa. Ecograficamente se detecto una prevalencia del 14,7%, y con resonancia magnetica, del 32,8%. La prevalencia en menores de 28 semanas fue del 39,6%; en menores de 32 semanas, del 27,4%; y en menores de 37 semanas, del 7,3%. Entre los factores de riesgo destacan la edad gestacional, infeccion intrauterina, ruptura prematura de membranas y corioamnionitis. Conclusiones. La prevalencia de la leucomalacia periventricular en prematuros es heterogenea, aumenta segun el grado de prematuridad y se detecta mejor con resonancia magnetica; existen multiples factores relacionados con su presentacion, y el principal es la edad gestacional.