Predictors for delayed linguistic skills in very preterm infants.

BACKGROUND: Preterm-born children are at higher risk for impaired linguistic abilities than are their term-born peers. The aim of the current study was to determine early predictors for delayed linguistic skills in very preterm-born preschool children. METHODS: Between January 2005 and November 2010 all very preterm infants born at < 32 weeks gestation in Tyrol were prospectively enrolled (n = 421); 248 of them had a detailed examination at the age of five years including cognitive assessment (Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III) or Snijders-Oomen Nonverbal Intelligence Tests (SON-R)) as well as a screening test for language skills (Bielefelder screening for early diagnosis of reading problems and weak spelling (BISC)). The association between pre-and postnatal factors and poor performance on the BISC assessment was analyzed by means of logistic regression analysis. RESULTS: Of the 248 children 79 (31.8%) showed delayed literacy precursor skills. Male sex, gestational age, retinopathy of prematurity (ROP) grades 3-4 and low maternal education were predictive for delayed linguistic skills at 5 years of age in the multivariate analysis. CONCLUSION: This study identified predictors for delayed literacy precursor skills. These data support the finding that in very preterm infants pre-and perinatal as well as sociodemographic factors account for linguistic skills in the preschool period.

Long-Term Consequences of Fetal Angiotensin II Receptor Antagonist Exposure.

Fetal angiotensin II receptor antagonist exposure is associated with major complications and even death when administered during pregnancy. Neonates frequently require intensive care treatment, and mortality is high. Despite this well-known risk potential, a considerable number of women still receive angiotensin II receptor antagonists during pregnancy to treat arterial hypertension. Although clinical symptoms in the neonatal period are well described, few reports address long-term follow-up after fetal exposure to angiotensin II receptor antagonists. We here report on a patient who was unwittingly exposed to olmesartan medoxomil during pregnancy. After birth, the neonate presented with mild clinical symptoms, mainly affecting the kidneys. However, neurodevelopmental follow-up revealed a delay in motor development with muscular hypotonia and failure to thrive at age 2 years. This case highlights the fact that, despite not causing neurological symptoms in the neonatal period, fetal angiotensin II receptor antagonist exposure during pregnancy might lead to neurodevelopmental impairment in later life.

Amplitude-integrated electroencephalography shows mild delays in electrocortical activity in preterm infants born small for gestational age.

AIM: Being born small for gestational age (SGA) seems to be a relevant risk factor for long-term neurologic deficits. We compared the differences between amplitude-integrated electroencephalography (aEEG) signals in very preterm infants born small for gestational age (SGA) and those in age-matched infants born appropriate size for gestational age (AGA). METHODS: We performed serial aEEG recording on 305 infants: 255 (83.6%) were AGA, and 50 (16.3%) were SGA. RESULTS: The number of bursts per hour decreased over time in both groups, but was higher in the SGA group at every time point. On day one, it was significantly higher in the SGA group (17.4) than in the AGA group (10.1) (p = 0.016). The total Burdjalov score increased with post-natal age and tended to be lower in SGA infants, but did not reach statistical significance at any time point. The percentage of continuous background patterns increased with post-natal age in both groups, with no significant difference between the groups. CONCLUSION: Very preterm infants born SGA showed normal maturation of aEEG signals during post-natal life, but they also showed mild delays in electrocortical activity compared to age-matched AGA infants. The predictive value of these findings on neurodevelopmental outcome needs to be further evaluated.

The common antitussive agent dextromethorphan protects against hyperoxia-induced cell death in established in vivo and in vitro models of neonatal brain injury.

Preterm infants are prematurely subjected to relatively high oxygen concentrations, even when supplemental oxygen is not administered. There is increasing evidence to show that an excess of oxygen is toxic to the developing brain. Dextromethorphan (DM), a frequently used antitussive agent with pleiotropic mechanisms of action, has been shown to be neuroprotective in various models of central nervous system pathology. Due to its numerous beneficial properties, it might also be able to counteract detrimental effects of a neonatal oxygen insult. The aim of the current study was to evaluate its therapeutic potential in established cell culture and rodent models of hyperoxia-induced neonatal brain injury. For in vitro studies pre- and immature oligodendroglial (OLN-93) cells were subjected to hyperoxic conditions for 48 h after pre-treatment with increasing doses of DM. For in vivo studies 6-day-old Wistar rat pups received a single intraperitoneal injection of DM in two different dosages prior to being exposed to hyperoxia for 24h. Cell viability and caspase-3 activation were assessed as outcome parameters at the end of exposure. DM significantly increased cell viability in immature oligodendroglial cells subjected to hyperoxia. In pre-oligodendroglial cells cell viability was not significantly affected by DM treatment. In vivo caspase-3 activation induced by hyperoxic exposure was significantly lower after administration of DM in gray and white matter areas. In control animals kept under normoxic conditions DM did not significantly influence caspase-3-dependent apoptosis. The present results indicate that DM is a promising and safe treatment strategy for neonatal hyperoxia-induced brain injury that merits further investigation.

[Pneumothorax during mechanical ventilation--therapeutic options in term and preterm neonates]. / Pneumothorax unter Beatmung--ein Vergleich möglicher Therapieoptionen bei Reif- und Frühgeborenen.

A pneumothorax (PTX) is a potentially life threatening event during mechanical ventilation. Aim of this study was to analyse 3 different ways of management: expectant treatment, once-only pleural puncture and thoracic drainage.Retrospective data analysis in term and preterm neonates admitted to the NICU of the Medical University of Graz (between 2000-2010) and Innsbruck (2002-2010) who suffered from a PTX during continuous positive airway pressure (CPAP) or conventional mechanical ventilation (CMV).104 neonates, 33 term and 71 preterm neonates with PTX were included. 33 term neonates: 52% were treated expectantly, 36% with thoracic drainage and 12% with once-only pleural puncture (100% thoracic drainage after pleural puncture). 71 preterm neonates: 25% were treated expectantly, 52% with thoracic drainage and 23% with pleural puncture (63% thoracic drainage after pleural puncture). In CPAP-subgroup (n=64), term neonates were treated in 60% expectantly and in 40% with thoracic drain-age, preterm neonates in 33% expectantly, in 47% with thoracic drainage and in 20% with pleural puncture (50% thoracic drainage after pleural puncture). In CMV-subgroup (n=40), term neonates were treated in 44% expectantly, in 33% with thoracic drainage and in 22% with pleural puncture (100% thoracic drainage after pleural puncture), preterm neonates in 9% expectantly, in 64% with thoracic drainage and in 27% with pleural puncture (83% thoracic drain-age after pleural puncture).Present data show that expectant treatment is feasible. If invasive intervention is needed, once-only pleural puncture was not successful, as often thoracic drainage was necessary in addition.

Neuroprotective effects of the sigma-1 receptor ligand PRE-084 against excitotoxic perinatal brain injury in newborn mice.

Excessive glutamate release followed by N-methyl-D-aspartate receptor (NMDAR) activation plays a crucial role in perinatal brain injury. We have previously shown that dextromethorphan, a low-affinity NMDAR antagonist with anti-inflammatory properties, is neuroprotective against neonatal excitotoxic brain injury. Of interest, dextromethorphan is also a sigma-1 receptor (σ1R) agonist. The pharmacologic class of σ1R agonists has yielded propitious results in various animal models of adult central nervous system pathology. In an established neonatal mouse model of excitotoxic brain injury, we evaluated the effect of the selective σ1R agonist 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate (PRE-084). A single intraperitoneal injection of 0.1 µg/g (low dose) or 10 µg/g (high dose) bodyweight (bw) PRE-084, given 1h after the excitotoxic insult, significantly reduced lesion size in cortical gray matter 24 h and 120 h after the insult. Repetitive injections of 0.1 µg/g PRE-084 proved to be equally effective. PRE-084 treatment resulted in a decrease in cell death indicated by reduced TUNEL positivity and caspase-3 activation. Furthermore, it lowered the number of isolectin B4-positive, activated microglial cells. PRE-084 had no effect on developmental apoptosis in the undamaged brain. In vitro findings in primary hippocampal neurons suggest that PRE-084 treatment provides partial protection against glutamate induced morphological and functional changes. For excitotoxicity as playing a crucial role in the pathogenesis of perinatal brain injury, we demonstrate for the first time that systemic treatment with the highly selective σ1R agonist PRE-084 protects against NMDAR-mediated excitotoxic brain damage.

Feasibility of cerebral MRI in non-sedated preterm-born infants at term-equivalent age: report of a single centre.

AIM: MRI is gaining in importance as an imaging tool for brain development and injury in preterm infants. The aim of this study was to evaluate the feasibility of performing MRI in non-sedated preterm-born infants at term-equivalent age (TEA). METHODS: A total of 89 infants born before 32 gestational weeks were recruited. Infants were scanned without sedation. Duration of the entire examination including scan repetition and interruptions was registered. RESULTS: Of the 89 infants, 56 (63%) underwent MRI at TEA. Out-patients required a significantly shorter total MR examination time than did in-patients (32 ± 12 vs. 54 ± 10 min, p < 0.01). Of the 56 infants, 39 (69.6%) were examined without interruption. Only four (7.2%) of the 56 scans were unusable because of motion artefacts. Mean duration of all scans was 36 ± 14 min. In cases with no interruptions, sessions were completed within 32 ± 12 min; MR sessions with interruption lasted 45 ± 13 min. CONCLUSION: A well-trained team is indispensable in obtaining best-quality images as a prerequisite for good counselling. From our experience, we worked out a guideline to ensure that scans in stable non-sedated preterm-born infants at TEA run smoothly and provide high-quality images.

Systemic G-CSF treatment does not improve long-term outcomes after neonatal hypoxic-ischaemic brain injury.

Hypoxia-ischaemia (HI) is a major factor in the pathogenesis of developmental brain injury, leading to cognitive deficits and motor disabilities in preterm infants. The haematopoietic growth factor granulocyte colony-stimulating factor (G-CSF) has been shown to exert a neuroprotective activity in rodent models of ischaemic stroke and is currently subject to phase I/II clinical trials in adults. Results of studies examining the effect of G-CSF in perinatal brain damage have been contradictory. We have previously shown that G-CSF increases NMDAR-mediated excitotoxic brain injury in the neonatal mouse brain. In this study, we evaluated the effect of G-CSF on long-term outcomes after HI. On postnatal day 5, mice pubs were first randomly assigned to a sham operation or HI and then divided into four treatment groups: i) G-CSF; ii) phosphate buffered saline (PBS) 1h after injury; iii) G-CSF and iv) PBS 60 h after injury. G-CSF (200 µg/kg BW) was administered five times within a 24h interval. Neuromotor and cognitive outcomes were assessed by open-field, novel object recognition tests and rotarod tests starting on P90, with subsequent histological analyses of brain injury. G-CSF treatment did not improve either neurobehavioural outcomes or brain injuries. Interestingly, the application of PBS and G-CSF in the acute phase increased brain damage in the hippocampus. We could not confirm the neuroprotective properties of G-CSF in neonatal HI brain damage. The exacerbation of injury by the administration of substances in the acute phase might indicate a heightened state of neurological sensitivity that is specific to mechanisms of secondary neurodegeneration and influenced by unidentified external factors possibly associated with the treatment protocol during the acute phase. This article is part of a Special Issue entitled "Interaction between repair, disease, & inflammation."

Neurodevelopmental outcome following congenital cytomegalovirus infection in preterm infants with twin-to-twin transfusion syndrome: a case report.

Twin-to-twin transfusion syndrome and conital cytomegalovirus infection bear the risk of brain damage. In the 27th week of gestation of a twin pregnancy a Caesarean section was performed because of pathological cardiotocogram and Doppler ultrasonography of the second twin (recipient). Both infants presented with severe, persistent thrombocytopenia, elevated liver enzymes and direct hyperbilirubinemia. Primary congenital CMV infection was diagnosed. Both twins showed severe neuropathological symptoms, pathological aEEG with seizure activity and severe neurodevelopmental delay at corrected age of 12 months. The severity of brain pathology, the complex etiology, its consequence for neurotion with extreme prematurity make this case of special interest.

Smoking in pregnancy: a risk factor for adverse neurodevelopmental outcome in preterm infants?

AIM: To assess whether smoking in pregnancy influences neurodevelopmental outcome at 2-years of age in preterm infants with a gestational age <32 weeks. METHODS: Between January 2003 and December 2005 we prospectively enrolled 181 infants born alive between 23 and 32 weeks of gestation; 142 infants (78.5%) completed the follow-up visit. The association between candidate risk factors and delayed motor or mental development (Bayley Scales of Infant Development II; psychomotor or mental developmental index <85) was analysed by means of logistic regression analysis. RESULTS: Low maternal age, smoking in pregnancy, low gestational age, low birth weight, small for gestational age, chronic lung disease, intracerebral haemorrhage, periventricular leucomalacia, and retinopathy of prematurity (stages 3 and 4) all were associated with an increased risk for delayed development (p < 0.05, each). Smoking in pregnancy, small for gestational age and chronic lung disease maintained significance in a multivariable analysis. CONCLUSION: Smoking in pregnancy emerged as a risk predictor for adverse neurodevelopmental outcome in our study. Strategies to reduce smoking in pregnancy should be further endorsed.