Increasing the dose of ibuprofen with postnatal age to close a hemodynamically significant patent ductus arteriosus in very preterm infants.

Patent ductus arteriosus (PDA) is associated with neonatal morbidities in high-risk preterm infants. Early neonatal treatment by ibuprofen induces the ductus arteriosus (DA) closure in approximatively 60% of infants. Dose escalation of ibuprofen according to postnatal age has been suggested for improving the DA closure rate. The aim of this study was to assess the efficacy and tolerance of an increasing dose regimen of ibuprofen. This single-center retrospective cohort study involved infants hospitalized from 2014 to 2019 in our neonatal unit. Selection criteria were gestational age < 30 weeks, birth weight < 1000 g, and treatment by ibuprofen. Three dose levels were used and consisted of a daily intravenous injection of ibuprofen-tris-hydroxymethyl-aminomethane (ibuprofen-THAM) for three consecutive days: (i) 10 -5 -5 mg/kg before the 70th h of life (H70) (dose level 1), (ii) 14 -7 -7 mg/kg between H70 and H108 (dose level 2), (iii) 18 -9 -9 mg/kg after H108 (dose level 3). The ibuprofen-induced DA closure was compared between ibuprofen schedules, and the Cox proportional-hazard regression was performed to identify factors associated with the ibuprofen efficacy. Tolerance was assessed through renal function, acidosis, and platelet count. One hundred forty-three infants met the inclusion criteria. The ibuprofen-induced DA closure was observed in 67 infants (46.8%). One course of ibuprofen at dose level 1 was more efficient in closing the DA than other schedules (dose level 1, one course (n = 70): 71%, dose level 2 or 3, one course (n = 20): 45%, two-course schedules (n = 53): 15%, p < 0.0001). Independent factors associated with ibuprofen-induced DA closure were a complete antenatal schedule of steroids (p = 0.001), a lower CRIB II score (p = 0.009), and a lower and earlier exposure to ibuprofen (p < 0.0001 and p = 0.002). No severe side effects were observed. Neonatal mortality and morbidities were similar regardless of the infant's response to ibuprofen.  Conclusion: Increasing ibuprofen doses with postnatal age failed to reach an efficacy similar to earlier treatment. Although the infant response to ibuprofen was likely to depend on multiple factors, the optimal use of ibuprofen included its early initiation. What is Known: • Ibuprofen is the current first-line treatment for patent ductus arteriosus during the early neonatal period in very preterm infants. • However, the ibuprofen efficacy rapidly declined with postnatal age during the first week of life. A dose escalation of ibuprofen according to postnatal age has been suggested to improve the ibuprofen-induced ductus arteriosus closure. What is New: • The rapid drop of ibuprofen's ability to close hemodynamically significant patent ductus arteriosus persisted beyond the postnatal day 2 despite the dose adjustment arguing for an early initiation to optimize its efficacy. • The early selection of patients who will suffer from patent ductus arteriosus-related morbidities and who will positively respond to ibuprofen is an issue that could determine the future place of ibuprofen in the patent ductus arteriosus management.

Patent ductus arteriosus, tracheal ventilation, and the risk of bronchopulmonary dysplasia.

BACKGROUND: An increased risk for bronchopulmonary dysplasia (BPD) exists when moderate-to-large patent ductus arteriosus shunts (hsPDA) persist beyond 14 days. GOAL: To examine the interaction between prolonged exposures to tracheal ventilation (≥10 days) and hsPDA on the incidence of BPD in infants <28 weeks gestation. STUDY DESIGN: Predefined definitions of prolonged ventilation (≥10 days), hsPDA (≥14 days), and BPD (room air challenge test at 36 weeks) were used to analyze deidentified data from the multicenter TRIOCAPI RCT in a secondary analysis of the trial. RESULTS: Among 307 infants who survived >14 days, 41 died before 36 weeks. Among survivors, 93/266 had BPD. The association between BPD and hsPDA depended on the length of intubation. In multivariable analyses, prolonged hsPDA shunts were associated with increased BPD (odds ratio (OR) (95% confidence interval (CI)) = 3.00 (1.58-5.71)) when infants required intubation for ≥10 days. In contrast, there was no significant association between hsPDA exposure and BPD when infants were intubated <10 days (OR (95% CI) = 1.49 (0.98-2.26)). A similar relationship between prolonged hsPDA and length of intubation was found for BPD/death (n = 307): infants intubated ≥10 days: OR (95% CI) = 2.41 (1.47-3.95)); infants intubated <10 days: OR (95% CI) = 1.37 (0.86-2.19)). CONCLUSIONS: Moderate-to-large PDAs were associated with increased risks of BPD and BPD/death-but only when infants required intubation ≥10 days. IMPACT: Infants with a moderate-to-large hsPDA that persist beyond 14 days are only at risk for developing BPD if they also receive prolonged tracheal ventilation for ≥10 days. Infants who receive less ventilatory support (intubation for <10 days) have the same incidence of BPD whether the ductus closes shortly after birth or whether it persists as a moderate-to-large shunt for several weeks. Early PDA closure may be unnecessary in infants who require short durations of intubation since the PDA does not seem to alter the incidence of BPD in infants who require intubation for <10 days.

Skin-to-Skin Contact for Transferring Preterm Infants from the Delivery Room to the Neonatal Intensive Care Unit Is Promising Despite Moderate Heat Loss during the Procedure.

OBJECTIVE: The principal aim of this prospective observational study was to assess the feasibility of skin-to-skin contact (SSC) with fathers during the transfer of preterm infants from the delivery room to the neonatal intensive care unit (NICU) in comparison with incubator transfers. STUDY DESIGN: The study population comprised preterm singletons born between May and December 2019 in our maternity ward who did not require invasive ventilation. Physiological parameters (axillary temperature, heart rate, and fraction of inspired oxygen) of the newborns were recorded at prespecified steps during the transfers. The impact of the transfer mode on early blood glucose level, blood gas, and neonatal morbidities and mortality and the delay in the first SSC in the NICU and breastfeeding implementation and maintenance were also analyzed. RESULTS: Twenty-eight preterm infants were transferred in incubators, and 29 infants were transferred using SSC. The SSC transfer induced heat loss (mean, -0.45°C; standard deviation [SD], 0.58). However, the decrease in temperature was similar to that observed during transfer in the incubator (mean, -0.30°C; SD, 0.49; p = 0.3). The transfer using SSC was not an independent factor associated with hypothermia at admission in the NICU (adjusted odds ratio, 2.6 [0.68-9.75]; p = 0.16). Neonatal morbidities and mortality were similar regardless of the transfer mode. The SSC transfer promoted early SSC in the neonatal unit (median hour [range], incubator 26 [2-126] vs SSC 13 [1-136], p = 0.03) and breastfeeding at discharge (incubator 35.7% vs SSC 69%, p = 0.01). CONCLUSION: The SSC transfer of preterm infants was feasible and promoted earlier SSC and breastfeeding. Nevertheless, the SSC transfer, like the transfer in the incubator, induced moderate heat losses that exacerbated hypothermia at admission in the NICU. The improvement of thermal conservation during infant positioning and the continuation of SSC in the unit could help in preventing hypothermia. KEY POINTS: · The SSC transfer was associated with heat loss during the transfer procedure.. · The SSC transfer promoted earlier SSC in the neonatal unit.. · The SSC transfer was likely to encourage breastfeeding..

Effect of Early Targeted Treatment of Ductus Arteriosus with Ibuprofen on Survival Without Cerebral Palsy at 2 Years in Infants with Extreme Prematurity: A Randomized Clinical Trial.

OBJECTIVE: To examine the effects of early echocardiography-targeted ibuprofen treatment of large patent ductus arteriosus (PDA) on survival without cerebral palsy at 24 months of corrected age. STUDY DESIGN: We enrolled infants born at <28 weeks of gestation with a large PDA on echocardiography at 6-12 hours after birth to ibuprofen or placebo by 12 hours of age in a multicenter, double blind, randomized-controlled trial. Open-label ibuprofen was allowed for prespecified criteria of a hemodynamically significant PDA. The primary outcome was survival without cerebral palsy at 24 months of corrected age. RESULTS: Among 337 enrolled infants, 109 had a small or closed ductus and constituted a reference group; 228 had a large PDA and were randomized. The primary outcome was assessed at 2 years in 108 of 114 (94.7%) and 102 of 114 (89.5%) patients allocated to ibuprofen or placebo, respectively. Survival without cerebral palsy occurred in 77 of 108 (71.3%) after ibuprofen, 73 of 102 (71.6%) after placebo (adjusted relative risk 0.98, 95% CI 0.83-1.16, P = .83), and 77 of 101 (76.2%) in reference group. Infants treated with ibuprofen had a lower incidence of PDA at day 3. Severe pulmonary hemorrhage during the first 3 days occurred in 2 of 114 (1.8%) infants treated with ibuprofen and 9 of 114 (7.9%) infants treated with placebo (adjusted relative risk 0.22, 95% CI 0.05-1.00, P = .05). Open-label rescue treatment with ibuprofen occurred in 62.3% of infants treated with placebo and 17.5% of infants treated with ibuprofen (P < .001), at a median (IQR) age of 4 (3, 5) and 4 (4, 12) days, respectively. CONCLUSIONS: Early echocardiography-targeted ibuprofen treatment of a large PDA did not change the rate of survival without cerebral palsy. TRIAL REGISTRATION: Eudract 2011-003063-30 and ClinicalTrials.gov: NCT01630278.

Duration of mechanical ventilation is more critical for brain growth than postnatal hydrocortisone in extremely preterm infants.

Hydrocortisone is used in preterm infants. However, early disruption of growth velocities was observed in infants exposed to hydrocortisone. This retrospective study aimed to explore the postnatal brain growth of extremely preterm infants requiring hydrocortisone treatment as well as its association with perinatal factors. Extremely preterm infants exposed to hydrocortisone from 2011 to 2016 who survived up to 12 months were included. Each of them was matched with two infants not treated with hydrocortisone exhibiting similar gestational ages and nearly similar birth head circumferences. The outcome variables were brain tissue areas on MRIs performed at term-equivalent age and postnatal head circumference growth up to a corrected age of 12 months. Univariate and multiple regression analyses were performed. Infants treated with hydrocortisone (n=20) were matched with 40 infants not exposed to hydrocortisone. The infants exposed to hydrocortisone exhibited a lower birth weight (p=0.04) and a longer duration of mechanical ventilation (p<0.0001). Infants treated with hydrocortisone exhibited a smaller basal ganglia/thalamus area (p=0.04) at term-equivalent age and a smaller head circumference at a corrected age of 12 months (p=0.003). However, the basal ganglia/thalamus area and the postnatal brain growth were independently associated with the duration of mechanical ventilation and not with hydrocortisone. Interestingly, a significant interaction between hydrocortisone and sex was observed (p=0.04).Conclusion: This study supports previous data that indicated no obvious impact of hydrocortisone on brain growth and highlights the relationship between the severity of the neonatal course and postnatal brain growth in extremely preterm infants. What is Known: • Postnatal hydrocortisone disrupts transiently growth velocities including the head circumference growth. • Postnatal hydrocortisone has less impact on neurodevelopment than dexamethasone. What is New: • Hydrocortisone prescribed for infants in the most severe conditions did not show independent effect on brain growth up to the corrected age of 12 months. However, a different effect of hydrocortisone according to sex can't be excluded and needs further explorations. • Perinatal factors as birth weight and duration of mechanical ventilation were determinant for the subsequent brain growth.

Prematurity alters skin conductance and behavioural scoring after acute stress in term-equivalent age infants.

AIM: The primary objective was to assess the effect of prematurity at term-equivalent age on skin conductance and behavioural responses to acute stress. The secondary objective was to explore the reliability of skin conductance in detecting neonatal discomfort in preterm and full-term populations. METHODS: Very preterm infants at term-equivalent age and healthy full-term neonates, 34 infants in each group, underwent the hip dysplasia screening test. The acute pain in newborn infants (APN) scale was scored before and 15, 45 and 90 seconds after stimulus. Skin conductance was measured in the 30-second time-lap before and after stimulus. RESULTS: The APN score was lower in preterm infants after intervention (term: 5.4 ± 2.8 vs. preterm: 3.9 ± 2.2; p = 0.03). Peaks-per-second, a skin conductance parameter, exhibited lower basal values in preterm infants than in term infants, with similar rise induced by stressful challenge. Peaks-per-second values were correlated to the 15-second APN score in both groups (term: r = 0.55, p < 0.001; preterm: r = 0.43, p = 0.01). CONCLUSION: Preterm birth changed skin conductance signal and behavioural response to stress at term-equivalent age. The skin conductance device may be an objective tool for a continuous monitoring of acute neonatal stress.

Reactive astrocyte COX2-PGE2 production inhibits oligodendrocyte maturation in neonatal white matter injury.

Inflammation is a major risk factor for neonatal white matter injury (NWMI), which is associated with later development of cerebral palsy. Although recent studies have demonstrated maturation arrest of oligodendrocyte progenitor cells (OPCs) in NWMI, the identity of inflammatory mediators with direct effects on OPCs has been unclear. Here, we investigated downstream effects of pro-inflammatory IL-1ß to induce cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) production in white matter. First, we assessed COX2 expression in human fetal brain and term neonatal brain affected by hypoxic-ischemic encephalopathy (HIE). In the developing human brain, COX2 was expressed in radial glia, microglia, and endothelial cells. In human term neonatal HIE cases with subcortical WMI, COX2 was strongly induced in reactive astrocytes with "A2" reactivity. Next, we show that OPCs express the EP1 receptor for PGE2, and PGE2 acts directly on OPCs to block maturation in vitro. Pharmacologic blockade with EP1-specific inhibitors (ONO-8711, SC-51089), or genetic deficiency of EP1 attenuated effects of PGE2. In an IL-1ß-induced model of NWMI, astrocytes also exhibit "A2" reactivity and induce COX2. Furthermore, in vivo inhibition of COX2 with Nimesulide rescues hypomyelination and behavioral impairment. These findings suggest that neonatal white matter astrocytes can develop "A2" reactivity that contributes to OPC maturation arrest in NWMI through induction of COX2-PGE2 signaling, a pathway that can be targeted for neonatal neuroprotection.

Melatonin modulates neonatal brain inflammation through endoplasmic reticulum stress, autophagy, and miR-34a/silent information regulator 1 pathway.

Maternal infection/inflammation represents one of the most important factors involved in the etiology of brain injury in newborns. We investigated the modulating effect of prenatal melatonin on the neonatal brain inflammation process resulting from maternal intraperitoneal (i.p.) lipopolysaccharide (LPS) injections. LPS (300 µg/kg) was administered to pregnant rats at gestational days 19 and 20. Melatonin (5 mg/kg) was administered i.p. at the same time as LPS. Melatonin counteracted the LPS sensitization to a second ibotenate-induced excitotoxic insult performed on postnatal day (PND) 4. As melatonin succeeded in reducing microglial activation in neonatal brain at PND1, pathways previously implicated in brain inflammation regulation, such as endoplasmic reticulum (ER) stress, autophagy and silent information regulator 1 (SIRT1), a melatonin target, were assessed at the same time-point in our experimental groups. Results showed that maternal LPS administrations resulted in an increase in CHOP and Hsp70 protein expression and eIF2α phosphorylation, indicative of activation of the unfolded protein response consequent to ER stress, and a slighter decrease in the autophagy process, determined by reduced lipidated LC3 and increased p62 expression. LPS-induced inflammation also reduced brain SIRT1 expression and affected the expression of miR-34a, miR146a, and miR-126. All these effects were blocked by melatonin. Cleaved-caspase-3 apoptosis pathway did not seem to be implicated in the noxious effect of LPS on the PND1 brain. We conclude that melatonin is effective in reducing maternal LPS-induced neonatal inflammation and related brain injury. Its role as a prophylactic/therapeutic drug deserves to be investigated by clinical studies.

G protein-coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation-induced sensitization to excitotoxic neurodegeneration.

OBJECTIVE: The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease, and multiple sclerosis. However, mechanisms underpinning this process remain unidentified. METHODS: We combined in vivo systemic lipopolysaccharide-induced or interleukin (IL)-1ß-induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1ß sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models, we assessed metabotropic glutamate receptors (mGluR) signaling and regulation. RESULTS: We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation-induced G protein-coupled receptor kinase 2 (GRK2) downregulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization. INTERPRETATION: Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders.

The role of erythropoietin to prevent red blood cell transfusion in a 2018-2020 two-center cohort of preterm infants.

BACKGROUND: Treatment with recombinant human erythropoietin (rHu-EPO) modestly prevented packed red blood cell transfusions (pRBCTs) in preterm infants in studies performed several years ago. In France, some neonatal units stopped using rHu-EPO, while others continued. The aim of this study was to explore the role of rHu-EPO in the prevention of pRBCTs in a recent cohort of preterm infants. MATERIALS AND METHODS: Preterm infants who met rHu-EPO indications and were hospitalised between 2018 and 2020 in two neonatal units-one that did not use rHu-EPO and another that did-were eligible. Data about the neonatal history, rHu-EPO and iron treatments and pRBCT indications and volumes were collected. Infants exposed and not exposed to rHu-EPO were compared in univariate and multivariate analyses using backward logistic regression and Cox proportional hazards regression. RESULTS: A total of 257 patients exposed to rHu-EPO and 285 patients who were not exposed were included. Three profiles emerged. In the infants with a gestational age <28 weeks, the cumulative pRBCT volume/kg was similar regardless of rHu-EPO exposure (mean difference -2.8 mL, 95% confidence interval -16.1, 10.5, p=0.68). In the infants born between 28 and 30 weeks, a late pRBCT was prevented in the rHu-EPO group (single pRBCT: no rHu-EPO 22.1% vs rHu-EPO 8%, p=0.003). However, rHu-EPO was not independently associated with avoidance of this pRBCT. Finally, the need for pRBCT was low in the infants born after 30 weeks of gestation, making rHu-EPO treatment futile. In contrast, early iron supplementation was revealed to be critical in preventing pRBCT. DISCUSSION: No benefit of rHu-EPO in preventing pRBCT was observed in our cohort. The place of rHu-EPO in future requires careful consideration of the population concerned, adjustment of the therapeutic schedule and evolution of the indications for pRBCT.

Birth weight and head circumference discordance and outcome in preterms: results from the EPIPAGE-2 cohort.

OBJECTIVE: To determine whether the relative measurement of birth weight (BW) and head circumference (HC) in preterm infants is associated with neurological outcomes. METHODS: The EPIPAGE-2 Study included 3473 infants born before 32 weeks' gestation, classified based on their Z-score of BW and HC on the Fenton curves as concordant (≤1 SD apart) or discordant (>1 SD difference). We defined four mutually exclusive categories: discordant smaller BW (sBW) with BW-1SD and concordant small measurement (CsM) with BW and HC concordant and both ≤-1SD. Neurological outcomes at 5.5 years were evaluated with standard tests. RESULTS: 2592 (74.8%) preterm neonates were categorised as CM, 258 (7.4%) CsM, 378 (10.9%) sHC and 239 (6.9%) sBW. Compared with the CM children, those born with CsM had significantly higher risks of cognitive deficiency (adjusted OR (aOR) 1.3, 95% CI (1.0 to 2.0)), developmental coordination disorders (aOR 2.6 (1.5 to 4.4)) and need for special school services (aOR 2.3 (1.5 to 3.7)). Those born with sBW had significantly lower risk of cognitive deficiency (aOR 0.6 (0.4 to 0.9)) and the sHC group significantly higher risk of developmental coordination disorders (aOR 1.8 (1.0 to 3.2)). CONCLUSIONS: The relative discordance of these preterm infants' BW and HC was associated with their neurological outcomes. It merits further exploration as an indirect indicator of development. TRIAL REGISTRATION NUMBER: NCT03078439.

Systemic inflammation disrupts the developmental program of white matter.

OBJECTIVE: Perinatal inflammation is a major risk factor for neurological deficits in preterm infants. Several experimental studies have shown that systemic inflammation can alter the programming of the developing brain. However, these studies do not offer detailed pathophysiological mechanisms, and they rely on relatively severe infectious or inflammatory stimuli that most likely do not reflect the levels of systemic inflammation observed in many human preterm infants. The goal of the present study was to test the hypothesis that moderate systemic inflammation is sufficient to alter white matter development. METHODS: Newborn mice received twice-daily intraperitoneal injections of interleukin-1ß (IL-1ß) over 5 days and were studied for myelination, oligodendrogenesis, and behavior and with magnetic resonance imaging (MRI). RESULTS: Mice exposed to IL-1ß had a long-lasting myelination defect that was characterized by an increased number of nonmyelinated axons. They also displayed a reduction of the diameter of the myelinated axons. In addition, IL-1ß induced a significant reduction of the density of myelinating oligodendrocytes accompanied by an increased density of oligodendrocyte progenitors, suggesting a partial blockade in the oligodendrocyte maturation process. Accordingly, IL-1ß disrupted the coordinated expression of several transcription factors known to control oligodendrocyte maturation. These cellular and molecular abnormalities were correlated with a reduced white matter fractional anisotropy on diffusion tensor imaging and with memory deficits. INTERPRETATION: Moderate perinatal systemic inflammation alters the developmental program of the white matter. This insult induces a long-lasting myelination deficit accompanied by cognitive defects and MRI abnormalities, further supporting the clinical relevance of the present data.

Increased MMP-9 and TIMP-1 in mouse neonatal brain and plasma and in human neonatal plasma after hypoxia-ischemia: a potential marker of neonatal encephalopathy.

INTRODUCTION: To implement neuroprotective strategies in newborns, sensitive and specific biomarkers are needed for identifying those who are at risk for brain damage. We evaluated the effectiveness of matrix metalloproteinases (MMPs) and their naturally occurring tissue inhibitors of metalloproteinases (TIMPs) in predicting neonatal encephalopathy (NE) damage in newborns. RESULTS: Plasma MMP-9 and TIMP-1 levels were upregulated as early as 1 h after the HI insult but not did not show such elevations after other types of injury (ibotenate-induced excitotoxicity, hypoxia, lipopolysaccharide-induced inflammation), and brain levels reflected this increase soon thereafter. We confirmed these results by carrying out plasma MMP-9 and TIMP-1 measurements in human newborns with NE. In these infants, protein levels of MMP-9 and TIMP-1 were found to be elevated during a short window up to 6 h after birth. DISCUSSION: This feature is particularly useful in identifying newborns in need of neuroprotection. A second peak observed 72 h after birth is possibly related to the second phase of energy failure after a HI insult. Our data, although preliminary, support the use of MMP-9 and TIMP-1 as early biomarkers for the presence and extent of perinatal brain injury in human term newborns. METHODS: We first used a mouse model of neonatal HI injury to explore mechanistic aspects such as the time course of these markers after the hypoxia-ischemia event, and the correlation between the levels of these candidate markers in brain and plasma.

Alteration of the Oligodendrocyte Lineage Varies According to the Systemic Inflammatory Stimulus in Animal Models That Mimic the Encephalopathy of Prematurity.

Preterm birth before the gestational age of 32 weeks is associated with the occurrence of specific white matter damage (WMD) that can compromise the neurological outcome. These white matter abnormalities are embedded in more global brain damage defining the encephalopathy of prematurity (EoP). A global reduction in white matter volume that corresponds to chronic diffuse WMD is the most frequent form in contemporary cohorts of very preterm infants. This WMD partly results from alterations of the oligodendrocyte (OL) lineage during the vulnerability window preceding the beginning of brain myelination. The occurrence of prenatal, perinatal and postnatal events in addition to preterm birth is related to the intensity of WMD. Systemic inflammation is widely recognised as a risk factor of WMD in humans and in animal models. This review reports the OL lineage alterations associated with the WMD observed in infants suffering from EoP and emphasizes the role of systemic inflammation in inducing these alterations. This issue is addressed through data on human tissue and imaging, and through neonatal animal models that use systemic inflammation to induce WMD. Interestingly, the OL lineage damage varies according to the inflammatory stimulus, i.e., the liposaccharide portion of the E.Coli membrane (LPS) or the proinflammatory cytokine Interleukin-1ß (IL-1ß). This discrepancy reveals multiple cellular pathways inducible by inflammation that result in EoP. Variable long-term consequences on the white matter morphology and functioning may be speculated upon according to the intensity of the inflammatory challenge. This hypothesis emerges from this review and requires further exploration.

Early Plasma Magnesium in Near-Term and Term Infants with Neonatal Encephalopathy in the Context of Perinatal Asphyxia.

Magnesium ions are implicated in brain functioning. The disruption of brain metabolism subsequent to a perinatal hypoxic-ischaemic insult may be reflected by plasma magnesium. Infants at 36 weeks after birth or later with neonatal encephalopathy and who were admitted to our neonatal unit from 2011 to 2019 were retrospectively included. The kinetics of plasma magnesium were investigated for the first 72 h of life and correlated to the Barkovich MRI score. Among the 125 infants who met the inclusion criteria, 45 patients (36%) had moderate to severe brain lesions on neonatal MRI. Plasma magnesium values were not strongly associated with the severity of clinical encephalopathy, initial EEG background and brain lesions. Intriguingly, higher plasma magnesium values during the 0−6 h period were linked to the presence of brain injuries that predominated within the white matter (p < 0.001) and to the requirement of cardiac resuscitation in the delivery room (p = 0.001). The occurrence of seizures was associated with a lower mean magnesium value around the 24th hour of life (p = 0.005). This study supports that neonatal encephalopathy is a complex and multifactorial condition. Plasma magnesium could help to better identify the subtypes of neonatal encephalopathy. Further studies are needed to confirm these results in this prospect.

Evaluation of Maturation in Preterm Infants Through an Ensemble Machine Learning Algorithm Using Physiological Signals.

This study was designed to test if heart rate variability (HRV) data from preterm and full-term infants could be used to estimate their functional maturational age (FMA), using a machine learning model. We propose that the FMA, and its deviation from the postmenstrual age (PMA) of the infants could inform physicians about the progress of the maturation of the infants. The HRV data was acquired from 50 healthy infants, born between 25 and 41 weeks of gestational age, who did not present any signs of abnormal maturation relative to their age group during the period of observation. The HRV features were used as input for a machine learning model that uses filtering and genetic algorithms for feature selection, and an ensemble machine learning (EML) algorithm, which combines linear and random forest regressions, to produce as output a FMA. Using HRV data, the FMA had a mean absolute error of 0.93 weeks, 95% CI [0.78, 1.08], compared to the PMA. These results demonstrate that HRV features of newborn infants can be used by an EML model to estimate their FMA. This method was also generalized using respiration rate variability (RRV) and bradycardia data, obtaining similar results. The FMA, predicted either by HRV, RRV or bradycardia, and its deviation from the true PMA of the infants, could be used as a surrogate measure of the maturational age of the infants, which could potentially be monitored non-invasively and in real-time in the setting of neonatal intensive care units.

Partial protective effects of melatonin on developing brain in a rat model of chorioamnionitis.

Melatonin has shown promising neuroprotective effects due to its anti-oxidant, anti-inflammatory and anti-apoptotic properties, making it a candidate drug for translation to humans in conditions that compromise the developing brain. Our study aimed to explore the impact of prenatal melatonin in an inflammatory/infectious context on GABAergic neurons and on oligodendrocytes (OLs), key cells involved in the encephalopathy of prematurity. An inflammatory/infectious agent (LPS, 300 µg/kg) was injected intraperitoneally (i.p.) to pregnant Wistar rats at gestational day 19 and 20. Melatonin (5 mg/kg) was injected i.p. following the same schedule. Immunostainings focusing on GABAergic neurons, OL lineage and myelination were performed on pup brain sections. Melatonin succeeded in preventing the LPS-induced decrease of GABAergic neurons within the retrospenial cortex, and sustainably promoted GABAergic neurons within the dentate gyrus in the inflammatory/infectious context. However, melatonin did not effectively prevent the LPS-induced alterations on OLs and myelination. Therefore, we demonstrated that melatonin partially prevented the deleterious effects of LPS according to the cell type. The timing of exposure related to the cell maturation stage is likely to be critical to achieve an efficient action of melatonin. Furthermore, it can be speculated that melatonin exerts a modest protective effect on extremely preterm infant brains.

Early bradycardia detection and therapeutic interventions in preterm infant monitoring.

In very preterm infants, cardio-respiratory events and associated hypoxemia occurring during early postnatal life have been associated with risks of retinopathy, growth alteration and neurodevelopment impairment. These events are commonly detected by continuous cardio-respiratory monitoring in neonatal intensive care units (NICU), through the associated bradycardia. NICU nurse interventions are mainly triggered by these alarms. In this work, we acquired data from 52 preterm infants during NICU monitoring, in order to propose an early bradycardia detector which is based on a decentralized fusion of three detectors. The main objective is to improve automatic detection under real-life conditions without altering performance with respect to that of a monitor commonly used in NICU. We used heart rate lower than 80 bpm during at least 10 sec to define bradycardia. With this definition we observed a high rate of false alarms (64%) in real-life and that 29% of the relevant alarms were not followed by manual interventions. Concerning the proposed detection method, when compared to current monitors, it provided a significant decrease of the detection delay of 2.9 seconds, without alteration of the sensitivity (97.6% vs 95.2%) and false alarm rate (63.7% vs 64.1%). We expect that such an early detection will improve the response of the newborn to the intervention and allow for the development of new automatic therapeutic strategies which could complement manual intervention and decrease the sepsis risk.

Automated brain MRI metrics in the EPIRMEX cohort of preterm newborns: Correlation with the neurodevelopmental outcome at 2 years.

PURPOSE: The purpose of this study was to identify in the EPIRMEX cohort the correlations between MRI brain metrics, including diffuse excessive high signal intensities (DEHSI) obtained with an automated quantitative method and neurodevelopmental outcomes at 2 years. MATERIALS AND METHODS: A total of 390 very preterm infants (gestational age at birth≤32 weeks) who underwent brain MRI at term equivalent age at 1.5T (n=338) or 3T (n=52) were prospectively included. Using a validated algorithm, automated metrics of the main brain surfaces (cortical and deep gray matter, white matter, cerebrospinal fluid) and DEHSI with three thresholds were obtained. Linear adjust regressions were performed to assess the correlation between brain metrics with the ages and stages questionnaire (ASQ) score at 2 years. RESULTS: Basal ganglia and thalami, cortex and white matter surfaces positively and significantly correlated with the global ASQ score. For all ASQ sub-domains, basal ganglia and thalami surfaces significantly correlated with the scores. DEHSI was present in 289 premature newborns (74%) without any correlation with the ASQ score. Metrics of DEHSI were greater at 3T than at 1.5T. CONCLUSION: Brain MRI metrics obtained in our multicentric cohort correlate with the neurodevelopmental outcome at 2 years of age. The quantitative detection of DEHSI is not predictive of adverse outcomes. Our automated algorithm might easily provide useful predictive information in daily practice.

Association Between Early Amino Acid Intake and Full-Scale IQ at Age 5 Years Among Infants Born at Less Than 30 Weeks' Gestation.

Importance: An international expert committee recently revised its recommendations on amino acid intake for very preterm infants, suggesting that more than 3.50 g/kg/d should be administered only to preterm infants in clinical trials. However, the optimal amino acid intake during the first week after birth in these infants is unknown. Objective: To evaluate the association between early amino acid intake and cognitive outcomes at age 5 years. Design, Setting, and Participants: Using the EPIPAGE-2 (Epidemiologic Study on Small-for-Gestational-Age Children-Follow-up at Five and a Half Years) cohort, a nationwide prospective population-based cohort study conducted at 63 neonatal intensive care units in France, a propensity score-matched analysis was performed comparing infants born at less than 30 weeks' gestation who had high amino acid intake (3.51-4.50 g/kg/d) at 7 days after birth with infants who did not. Participants were recruited between April 1 and December 31, 2011, and followed up from September 1, 2016, to December 31, 2017. Full-scale IQ (FSIQ) was assessed at age 5 years. A confirmatory analysis used neonatal intensive care unit preference for high early amino acid intake as an instrumental variable to account for unmeasured confounding. Statistical analysis was performed from January 15 to May 15, 2021. Exposures: Amino acid intake at 7 days after birth. Main Outcomes and Measures: The primary outcome was an FSIQ score greater than -1 SD (ie, ≥93 points) at age 5 years. A complementary analysis was performed to explore the association between amino acid intake at day 7 as a continuous variable and FSIQ score at age 5 years. Data from cerebral magnetic resonance imaging at term were available for a subgroup of preterm infants who participated in the EPIRMEX (Cerebral Abnormalities Detected by MRI, Realized at the Age of Term and the Emergence of Executive Functions) ancillary study. Results: Among 1789 preterm infants (929 boys [51.9%]; mean [SD] gestational age, 27.17 [1.50] weeks) with data available to determine exposure to amino acid intake of 3.51 to 4.50 g/kg/d at 7 days after birth, 938 infants were exposed, and 851 infants were not; 717 infants from each group could be paired. The primary outcome was known in 396 of 646 exposed infants and 379 of 644 nonexposed infants who were alive at age 5 years and was observed more frequently among exposed vs nonexposed infants (243 infants [61.4%] vs 206 infants [54.4%], respectively; odds ratio [OR], 1.33 [95% CI, 1.00-1.71]; absolute risk increase in events [ie, the likelihood of having an FSIQ score >-1 SD at age 5 years] per 100 infants, 7.01 [95% CI, 0.06-13.87]; P = .048). In the matched cohort, correlation was found between amino acid intake per 1.00 g/kg/d at day 7 and FSIQ score at age 5 years (n = 775; ß = 2.43 per 1-point increase in FSIQ; 95% CI, 0.27-4.59; P = .03), white matter area (n = 134; ß = 144 per mm2; 95% CI, 3-285 per mm2; P = .045), anisotropy of the corpus callosum (n = 50; ß = 0.018; 95% CI, 0.016-0.021; P < .001), left superior longitudinal fasciculus (n = 42; ß = 0.018; 95% CI, 0.010-0.025; P < .001), and right superior longitudinal fasciculus (n = 42; ß = 0.014 [95% CI, 0.005-0.024; P = .003) based on magnetic resonance imaging at term. Confirmatory and sensitivity analyses confirmed these results. For example, the adjusted OR for the association between the exposure and the primary outcome was 1.30 (95% CI, 1.16-1.46) using the instrumental variable approach among 978 participants in the overall cohort, and the adjusted OR was 1.35 (95% CI, 1.05-1.75) using multiple imputations among 1290 participants in the matched cohort. Conclusions and Relevance: In this cohort study, high amino acid intake at 7 days after birth was associated with an increased likelihood of an FSIQ score greater than -1 SD at age 5 years. Well-designed randomized studies with long-term follow-up are needed to confirm the benefit of this nutritional approach.