Immature brain structures were associated with poorer eye movement performance at 8 years of age in preterm born children.

AIM: Eye movements have rarely been explored in preterm born children. The aim of this study was to compare horizontal eye movements in children born preterm and full term when they reached 8 years of age. METHODS: Eye movements were recorded in 24 preterm born children (18 boys) and 26 matched controls (19 boys), recruited by a French hospital, using an eye tracker. This identified different types of visually guided saccades, namely step, gap, overlap and antisaccades and pursuit eye movements. The saccades task measured the latency and the percentage of anticipatory and express saccades and errors. The pursuit task measured the gain and percentage of intrusive saccades. RESULTS: This study confirmed that children born at 24-28 weeks of gestation demonstrated a global deficit in inhibitory processes compared to children born full term. The saccades were less precise in the preterm group, anticipatory and express saccades were elevated and there was a high occurrence of intrusive saccades during pursuit movements. CONCLUSION: These findings suggest that preterm born children have immature brain structures, particularly the parietal and frontal cortexes that are responsible for both saccade and pursuit performance. These could have been the cause of the abnormal inhibitory control measured in this study.

Oxytocin receptor agonist reduces perinatal brain damage by targeting microglia.

Prematurity and fetal growth restriction (FGR) are frequent conditions associated with adverse neurocognitive outcomes. We have previously identified early deregulation of genes controlling neuroinflammation as a putative mechanism linking FGR and abnormal trajectory of the developing brain. While the oxytocin system was also found to be impaired following adverse perinatal events, its role in the modulation of neuroinflammation in the developing brain is still unknown. We used a double-hit rat model of perinatal brain injury induced by gestational low protein diet (LPD) and potentiated by postnatal injections of subliminal doses of interleukin-1ß (IL1ß) and a zebrafish model of neuroinflammation. Effects of the treatment with carbetocin, a selective, long lasting, and brain diffusible oxytocin receptor agonist, have been assessed using a combination of histological, molecular, and functional tools in vivo and in vitro. In the double-hit model, white matter inflammation, deficient myelination, and behavioral deficits have been observed and the oxytocin system was impaired. Early postnatal supplementation with carbetocin alleviated microglial activation at both transcriptional and cellular levels and provided long-term neuroprotection. The central anti-inflammatory effects of carbetocin have been shown in vivo in rat pups and in a zebrafish model of early-life neuroinflammation and reproduced in vitro on stimulated sorted primary microglial cell cultures from rats subjected to LPD. Carbetocin treatment was associated with beneficial effects on myelination, long-term intrinsic brain connectivity and behavior. Targeting oxytocin signaling in the developing brain may be an effective approach to prevent neuroinflammation - induced brain damage of perinatal origin.

Transcriptomic regulations in oligodendroglial and microglial cells related to brain damage following fetal growth restriction.

Fetal growth restriction (FGR) is a major complication of human pregnancy, frequently resulting from placental vascular diseases and prenatal malnutrition, and is associated with adverse neurocognitive outcomes throughout life. However, the mechanisms linking poor fetal growth and neurocognitive impairment are unclear. Here, we aimed to correlate changes in gene expression induced by FGR in rats and abnormal cerebral white matter maturation, brain microstructure, and cortical connectivity in vivo. We investigated a model of FGR induced by low-protein-diet malnutrition between embryonic day 0 and birth using an interdisciplinary approach combining advanced brain imaging, in vivo connectivity, microarray analysis of sorted oligodendroglial and microglial cells and histology. We show that myelination and brain function are both significantly altered in our model of FGR. These alterations, detected first in the white matter on magnetic resonance imaging significantly reduced cortical connectivity as assessed by ultrafast ultrasound imaging. Fetal growth retardation was found associated with white matter dysmaturation as shown by the immunohistochemical profiles and microarrays analyses. Strikingly, transcriptomic and gene network analyses reveal not only a myelination deficit in growth-restricted pups, but also the extensive deregulation of genes controlling neuroinflammation and the cell cycle in both oligodendrocytes and microglia. Our findings shed new light on the cellular and gene regulatory mechanisms mediating brain structural and functional defects in malnutrition-induced FGR, and suggest, for the first time, a neuroinflammatory basis for the poor neurocognitive outcome observed in growth-restricted human infants. GLIA 2016;64:2306-2320.

N-acetyl-cysteine prevents pyramidal cell disarray and reelin-immunoreactive neuron deficiency in CA3 after prenatal immune challenge in rats.

BACKGROUND: Prenatal infection is a major risk factor for the occurrence of neuropsychiatric disorders. These have been associated with hippocampal neuroanatomical and functional abnormalities. In the present study, we evaluated the occurrence of pyramidal cell disarray and reelin neuronal deficit in the hippocampus, and the protective role of N-acetyl-cysteine (NAC) in a rodent experimental model of prenatal immune challenge. METHODS: Sprague-Dawley rats received either 500 µg/kg of endotoxin (lipopolysaccharide, LPS) or 2 ml/kg of isotonic saline by i.p. injection on day 19 of gestation. After LPS injection, rats were or were not maintained on a preventive treatment of NAC (5 g/l in tap water), up to delivery. The pyramidal cell orientation and the number and type of reelin-expressing neurons were determined in male offspring. RESULTS: Prenatal LPS challenge led to permanent pyramidal cell disarray and to an early and transient decreased density of reelin-immunoreactive neurons. These disorders, more pronounced in the CA3 area, were prevented by NAC. CONCLUSION: Hippocampal cytoarchitectural alterations and reelin deficiency may be involved in the development of remote cognitive impairments in this model. The antioxidant NAC is an efficient neuroprotective drug that underlines the role of oxidative stress in prenatal infection and associated neurodevelopmental damage.

Hyperventilation during exercise in very low birth weight school-age children may implicate inspiratory muscle weakness.

OBJECTIVES: To study the ventilatory response during exercise in 8- to 10-year-old children born in 1998 to 2000 with a birthweight <1500 g (very low birthweight [VLBW]). STUDY DESIGN: We studied 19 VLBW children and 20 full-term children paired for age and sex. A physical activity questionnaire was administered. Lean body mass, spirometry, and maximal inspiratory pressure were assessed at rest. Gas exchange, breathing pattern, and the tension-time index of the inspiratory muscles, a noninvasive indicator of inspiratory muscle effort, were evaluated during a continuous incremental cycling protocol. RESULTS: VLBW children had lower weight, height, lean body mass, and maximal inspiratory pressure than control subjects. Their physical activity level was not different. During exercise, they had a higher respiratory rate and minute ventilation for the same metabolic level (VCO(2)/kg) and a higher tension-time index of the inspiratory muscles for the same exercise level (percentage of maximal oxygen consumption). CONCLUSIONS: The lower inspiratory muscle strength observed in school-age VLBW children resulted in a higher inspiratory effort during incremental exercise. The rapid but not shallow breathing pattern adopted by this population during exercise may have been in response to their lower inspiratory muscle resistance to fatigue. VLBW children complaining of dyspnea should be investigated with exercise testing.

Immaturity of Oculomotor Capabilities During a Reading Task in Children Born Prematurely: An Eye Tracker Study.

To our knowledge, there are no studies recording the reading eye movements of children born prematurely. We examined the oculomotor patterns during reading of 23 children born prematurely (M age = 7.8, SD = 0.2 years) to compare them with those from two groups of children born at full-term who were matched for chronological age or reading age, respectively. We found the oculomotor reading pattern in children who were preterm to be similar to that of children who were full-term and matched for reading age; this shared pattern was characterized by longer duration of fixations, frequent prosaccades of smaller amplitude and several backward saccades. In contrast, when these two groups were compared to full-term children matched for chronological age, the latter group showed significantly shorter duration of fixations, less frequent saccades and larger amplitude prosaccades. Thus, the oculomotor pattern we observed in 7-year-old children who were either preterm or reading-delayed, relative to their age-matched peers, reflected delayed development of brain areas involved in reading-related eye movements.

Placental Findings and Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants.

OBJECTIVES: To investigate the relationship between histologic findings of the placenta and response to early postnatal hydrocortisone treatment used to prevent bronchopulmonary dysplasia (BPD) in extremely preterm infants. METHODS: In an exploratory analysis of the Early Low-Dose Hydrocortisone to Improve Survival Without Bronchopulmonary Dysplasia in Extremely Preterm Infants (PREMILOC) trial, detailed placental analyses were performed on the basis of standardized macroscopic and histologic examinations. Placental histology, categorized into 3 groups, was correlated to neonatal outcomes and response to hydrocortisone treatment. RESULTS: Of 523 randomly assigned patients, 457 placentas were analyzed. In total, 125 out of 457 (27%) placentas were classified as normal, 236 out of 457 (52%) placentas were classified as inflammatory, and 96 out of 457 (21%) placentas were classified as vascular. Placental inflammation was associated with a significant, increased rate of BPD-free survival at 36 weeks' postmenstrual age, independent of gestational age, treatment group, and sex (adjusted odds ratio: 1.72, 95% confidence interval [CI]: 1.05 to 2.82, P = .03). Regarding the response to treatment, the strongest benefit of hydrocortisone compared with placebo was found in infants born after placental vascular disease, with significantly more patients extubated at day 10 (risk difference: 0.32, 95% CI: 0.08 to 0.56, P = .004) and similar positive direction on survival without BPD (risk difference: 0.23, 95% CI: 0.00 to 0.46, P = .06). Adjusted to gestational age and treatment groups, placental inflammation was associated with significantly fewer patent ductus arteriosus ligation (adjusted hazard ratio: 0.58, 95% CI: 0.36 to 0.95, P = .03). Placental histology was not found to be associated with other adverse events related to preterm birth. CONCLUSIONS: With these findings, we confirm that early low-dose hydrocortisone confers benefits in extremely preterm infants overall and we suggest there is a higher treatment effect in those born after placental vascular disease.

Intubation in the delivery room: experience with nasal midazolam.

BACKGROUND: Neonates are often intubated in the delivery room (DR) without anesthesia because vascular access is impossible. AIMS: To assess neonatal comfort and adverse events after use of nasal midazolam (nMDZ) for intubation in the DR. STUDY DESIGN: Prospective data collection over 6months on the intubation of neonates with respiratory distress requiring tracheal instillation of surfactant. SUBJECTS: Twenty-seven neonates with median (Q25-75) gestational age and birthweight of, respectively, 29 (27-33)weeks and 1270 (817-1942)g received a 0.1mg/kg dose of nMDZ, and intubation was performed at the onset of tonus resolution or apnea. OUTCOME MEASURES: Comfort was assessed with a scale of hetero-pain assessment and electrical skin conductance monitoring. Continuous pulse oximetry was recorded in the first postnatal hour, with oscillometric blood pressure measurement every 10min. RESULTS: Seventy percent of the patients required a single dose, with intubation performed 4.8 (3-9)min after administration. Combined electro-clinical assessment found adequate comfort during the procedure in 68% of neonates. Mean blood pressure decreased from 39 (34-44)mmHg before to 31 (25-33)mmHg 1h following nMDZ (p=0.011). CONCLUSION: nMDZ provided rapid and effective sedation to intubate neonates in the DR but potentially exposed them to hypotension, thus requiring close hemodynamic monitoring.

Validation of nosocomial infection in neonatology: a new method for standardized surveillance.

BACKGROUND: Nosocomial infections (NIs) are a leading cause of mortality and morbidity in premature infants. We present a new method for detecting and confirming NIs in a neonatal intensive care unit. METHODS: Newborns with birth weight < 1,500 g or gestational age (GA) < 33 weeks were included prospectively over 2 years in a single-center tertiary neonatal intensive care unit. The computerized physician order entry system (CPOE) generated alerts when antibiotics were prescribed for at least 5 consecutive days and these cases were reviewed by an expert group following international recommendations. RESULTS: Four hundred sixty-one neonates were included, with a mean GA of 30 weeks (range, 26-32 weeks) and mean birth weight 1,270 g (range, 950-1600 g). The CPOE flagged 158 cases of potential NI, 85.1% of which were classified as true NI and 14.9% of which were false positive. Incidence and device-associated nosocomial bloodstream infection rates were 21.9% and 10.8 per 1,000 central venous catheter days, respectively. GA ≤ 28 weeks (odds ratio, 2.18; 95% confidence interval, 1.2-4) and > 7 central venous catheter days (odds ratio, 1.47; 95% confidence interval, 1.3-1.7) were independently associated with the risk of nosocomial bloodstream infection. CONCLUSION: Combining CPOE and interdisciplinary review may improve the accuracy of NI recording in a neonatal intensive care unit.

Tiagabine improves hippocampal long-term depression in rat pups subjected to prenatal inflammation.

Maternal inflammation during pregnancy is associated with the later development of cognitive and behavioral impairment in the offspring, reminiscent of the traits of schizophrenia or autism spectrum disorders. Hippocampal long-term potentiation and long-term depression of glutamatergic synapses are respectively involved in memory formation and consolidation. In male rats, maternal inflammation with lipopolysaccharide (LPS) led to a premature loss of long-term depression, occurring between 12 and 25 postnatal days instead of after the first postnatal month, and aberrant occurrence of long-term potentiation. We hypothesized this would be related to GABAergic system impairment. Sprague Dawley rats received either LPS or isotonic saline ip on gestational day 19. Male offspring's hippocampus was studied between 12 and 25 postnatal days. Morphological and functional analyses demonstrated that prenatal LPS triggered a deficit of hippocampal GABAergic interneurons, associated with presynaptic GABAergic transmission deficiency in male offspring. Increasing ambient GABA by impairing GABA reuptake with tiagabine did not interact with the low frequency-induced long-term depression in control animals but fully prevented its impairment in male offspring of LPS-challenged dams. Tiagabine furthermore prevented the aberrant occurrence of paired-pulse triggered long-term potentiation in these rats. Deficiency in GABA seems to be central to the dysregulation of synaptic plasticity observed in juvenile in utero LPS-challenged rats. Modulating GABAergic tone may be a possible therapeutic strategy at this developmental stage.

Implementation of a neonatal pain management module in the computerized physician order entry system.

BACKGROUND: Despite the recommended guidelines, the neonatal management of pain and discomfort often remains inadequate. The purpose of the present study was to determine whether adding a pain and discomfort module to a computerized physician order entry (CPOE) system would improve pain and discomfort evaluation in premature newborns under invasive ventilation. METHODS: All newborns <37 weeks gestational age (GA) and requiring invasive ventilation were included in a prospective study during two 6-month periods: before and after the inclusion of the pain and discomfort evaluation module. The main outcome measure was the percentage of patients having at least one assessment of pain and discomfort per day of invasive ventilation using the COMFORT scale. RESULTS: A total of 122 patients were included: 53 before and 69 after the incorporation of the module. The mean age was 30 (3) weeks GA. After the module was included, the percentage of patients who benefited from at least one pain and discomfort assessment per day increased from 64% to 88% (p < 0.01), and the mean number (SD) of scores recorded per day increased from 1 (1) to 3 (1) (p < 0.01). When the score was not within the established range, the nursing staff adapted analgesia/sedation doses more frequently after module inclusion (53% vs. 34%, p < 0.001). Despite higher mean doses of midazolam after module introduction [47 (45) vs. 31 (18) µg/kg/hr, p < 0.05], the durations of invasive ventilation and hospital stay, and the number of nosocomial infections, were not significantly modified. CONCLUSIONS: Adding a pain and discomfort tool to the CPOE system was a simple and effective way to improve the systematic evaluation of premature newborns who required ventilatory assistance.