Respiratory Support Effects over Time on Regional Lung Ventilation Assessed by Electrical Impedance Tomography in Premature Infants.

Background and objectives: Respiratory distress syndrome (RDS) frequently necessitates respiratory support. While non-invasive methods are typically the preferred approach, mechanical ventilation becomes necessary for patients with insufficient response. Our study aimed to compare two common respiratory support modes, volume-targeted mechanical ventilation and non-invasive ventilation continuous positive airway pressure (CPAP) and high-flow nasal cannula (HFNC), using electrical impedance tomography. Materials and Methods: Infants with very low birth weight and gestational ages of less than 32 weeks were eligible for inclusion in the study. All enrolled infants were beyond the transitional period (>72 h of age). The infants were divided into two groups: infants receiving invasive respiratory support through an endotracheal tube and infants receiving non-invasive respiratory support. We used electrical impedance tomography to assess end-expiratory lung impedance (EELZ), DeltaZ, heterogeneity, and regional ventilation distribution. Patients were evaluated at 0, 30, and 60 min after assuming the supine position to examine potential time-related effects. Results: Our study initially enrolled 97 infants, and the final analysis included a cohort of 72 infants. Ventilated infants exhibited significantly larger EELZ compared to their non-invasive counterparts (p = 0.026). DeltaZ was also greater in the invasive respiratory support group (p < 0.001). Heterogeneity was higher in the non-invasive group and did not change significantly over time. The non-invasive group demonstrated significantly greater ventilation in the dependent lung areas compared to intubated patients (p = 0.005). Regional distribution in the left lung was lower than in the right lung in both groups; however, this difference was significantly more pronounced in intubated patients (p < 0.001). Conclusions: Our study revealed that volume-targeted mechanical ventilation results in higher EELZ and DeltaZ compared to spontaneously breathing infants receiving non-invasive respiratory support. However, lung heterogeneity was lower during mechanical ventilation. Our study also reaffirmed that spontaneous breathing promotes greater involvement of the dependent lung compared to mechanical ventilation.

Cortical activation and oxygen perfusion in preterm newborns during kangaroo mother care: A pilot study.

AIM: This study aimed to assess the functional activation of preterm newborns' cerebral cortex during kangaroo mother care. Possible effects of gestational age and previous kangaroo mother care experience were also considered. METHODS: Fifteen preterm newborns were recruited (gestational age: 24-32 weeks). Cortical activation was assessed in frontal, motor and primary somatosensory cortices after 15 and 30 min of kangaroo mother care by multichannel near-infrared spectroscopy (gestational age at assessment: 30-36 weeks). Both oxy- and deoxy-haemoglobin variations were analysed by t-test. Possible effects of gestational age and previous kangaroo mother care experience on cortical activation were studied by regression analysis. RESULTS: After 15 min, bilateral activations (oxy-haemoglobin increase) were observed in frontal, somatosensory and motor cortices. After 30 min, the right motor and primary somatosensory cortices were found activated. Deoxy-haemoglobin increased after 15 min, returning to baseline at 30 min. After 15 min, there was a positive effect of gestational age at the assessment on both haemoglobin concentrations and a negative effect of previous kangaroo mother care on deoxy-haemoglobin increase. CONCLUSION: Motor and somatosensory cortices, particularly on the right side, showed significant activation during kangaroo mother care. Kangaroo mother care seems to benefit activated cortical areas by improving oxygen supply.

Music in premature infants enhances high-level cognitive brain networks.

Neonatal intensive care units are willing to apply environmental enrichment via music for preterm newborns. However, no evidence of an effect of music on preterm brain development has been reported to date. Using resting-state fMRI, we characterized a circuitry of interest consisting of three network modules interconnected by the salience network that displays reduced network coupling in preterm compared with full-term newborns. Interestingly, preterm infants exposed to music in the neonatal intensive care units have significantly increased coupling between brain networks previously shown to be decreased in premature infants: the salience network with the superior frontal, auditory, and sensorimotor networks, and the salience network with the thalamus and precuneus networks. Therefore, music exposure leads to functional brain architectures that are more similar to those of full-term newborns, providing evidence for a beneficial effect of music on the preterm brain.

Changes Overtime in Perinatal Management and Outcomes of Extremely Preterm Infants in One Tertiary Care Romanian Center.

Background and Objectives: Extremely preterm infants were at increased risk of mortality and morbidity. The purpose of this study was to: (1) examine changes over time in perinatal management, mortality, and major neonatal morbidities among infants born at 250-286 weeks' gestational age and cared for at one Romanian tertiary care unit and (2) compare the differences with available international data. Material and Methods: This study consisted of infants born at 250-286 weeks in one tertiary neonatal academic center in Romania during two 4-year periods (2007-2010 and 2015-2018). Major morbidities were defined as any of the following: severe intraventricular hemorrhage (IVH), severe retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia (BPD). Adjusted logistic regression models examined the association between the mortality and morbidity outcome and the study period. Results: The two cohorts differed with respect to antenatal antibiotics and rates of cesarean birth but had similar exposure to antenatal steroids and newborn referral to the tertiary care center. In logistic regression analyses, infants in the newer compared to the older cohort had a lower incidence of death (OR: 0.19; 95% CI: 0.11-0.35), a lower incidence of IVH (OR: 0.26; 95% CI: 0.15-0.46), and increased incidence of NEC (OR: 19.37; 95% CI: 2.41-155.11). Conclusions: Changes over time included higher use of antenatal antibiotics and cesarean delivery and no change in antenatal steroids administration. Overall mortality was lower in the newer cohort, especially for infants 250-266 weeks' gestation, NEC was higher while BPD and ROP were not different.

Disease modeling following organoid-based expansion of airway epithelial cells.

Air-liquid interface (ALI) cultures are frequently used in lung research but require substantial cell numbers that cannot readily be obtained from patients. We explored whether organoid expansion [three-dimensional (3D)] can be used to establish ALI cultures from clinical samples with low epithelial cell numbers. Airway epithelial cells were obtained from tracheal aspirates (TA) from preterm newborns and from bronchoalveolar lavage (BAL) or bronchial tissue (BT) from adults. TA and BAL cells were 3D-expanded, whereas cells from BT were expanded in 3D and 2D. Following expansion, cells were cultured at ALI to induce differentiation. The impact of cell origin and 2D or 3D expansion was assessed with respect to 1) cellular composition, 2) response to cigarette smoke exposure, and 3) effect of Notch inhibition or IL-13 stimulation on cellular differentiation. We established well-differentiated ALI cultures from all samples. Cellular compositions (basal, ciliated, and goblet cells) were comparable. All 3D-expanded cultures showed a similar stress response following cigarette smoke exposure but differed from the 2D-expanded cultures. Higher peak levels of antioxidant genes HMOX1 and NQO1 and a more rapid return to baseline, and a lower unfolded protein response was observed after cigarette smoke exposure in 3D-derived cultures compared to 2D-derived cultures. In addition, TA- and BAL-derived cultures were less sensitive to modulation by DAPT or IL-13 than BT-derived cultures. Organoid-based expansion of clinical samples with low cell numbers, such as TA from preterm newborns is a valid method and tool to establish ALI cultures.

Distinct innate immune responses between sublethal and lethal models of disseminated candidiasis in newborn BALB/c mice.

Invasive candidiasis is associated with a high incidence and mortality rates in infants, especially in preterm newborns. The immunopathogenesis of the mycosis during the neonatal period is poorly understood. Although several in vivo models exist to study invasive candidiasis, the majority of studies employ distinct routes of infection and use 2 to 6 day-old mice that could be less comparable in studying candidiasis in preterm infants. In this study, by using 0-days-old mice we developed a new neonatal murine model of intravenous Candida albicans infection. Using different inoculums of Candida albicans we evaluated survival, dissemination of the fungus, frequency of CD45+ cells, and cytokine production in the liver, brain, and kidneys of newborn and adult BALB/c mice. Unexpectedly, the newborn mice infected with a low inoculum (1×105 cfu per mouse) of Candida albicans survive to the infection. Compared to adult mice, the liver and brain of newborn animals had the greatest fungal burden, fungal invasion and leukocyte infiltrate. A moderate production of TNFα, IL-1ß, IL-6 and IFNγ was detected in tissues of newborn mice infected with a non-lethal inoculum of Candida albicans. In contrast, overproduction of TNFα, IL-1ß, IL-6 and IL-10 was determined when injecting with a lethal inoculum. In agreement, flow cytometry of brain and liver showed an inoculum-dependent CD45+ leukocyte infiltration in newborn mice infected with Candida albicans. Overall, our data shows that Candida albicans infection in newborn mice affects mainly the brain and liver and a 2-fold increase of the inoculum rapidly becomes lethal probably due to massive fungal invasion and exacerbated CD45+ leukocyte infiltrate and cytokine production. This study is the first analysis of innate immune responses in different tissues during early neonatal disseminated candidiasis.

Distribution of proteinuria- and albuminuria-to-creatinine ratios in preterm newborns.

BACKGROUND: Urine protein assessment is important when glomerular disease or injury is suspected. Normal values of proteinuria already published for preterm newborns suffer from limitation, with small cohorts of patients. This prospective study was conducted to update the urine total protein- and albumin-to-creatinine ratio values. METHODS: Urine samples were collected from 231 preterm newborns within the first 48 h (D0-1) and/or between 72-120 h of life (D3-4). Total protein, albumin, and creatinine were measured, their distribution and upper-limit values determined. RESULTS: At D0-1 and D3-4, respectively, the median for the total protein-to-creatinine ratio were 80 and 107 mg/mmol (upper-limit values 223 and 289 mg/mmol) in the whole studied population, 149 and 214 mg/mmol in children born before 29 weeks of gestational age, 108 and 130 mg/mmol in those born between 29 and 33 weeks, and 61 and 93 mg/mmol in those born after 33 weeks. For the albumin-to-creatinine ratio, the median were 12 and 17 mg/mmol (upper-limit values 65 and 62 mg/mmol) in the whole studied population, 22 and 50 mg/mmol in children born before 29 weeks, 21 mg/mmol in those born between 29 and 33 weeks, and 8 and 12 mg/mmol in those born after 33 weeks. The use of nephrotoxic drugs and mechanical ventilation seems to influence proteinuria and albuminuria values. CONCLUSIONS: We report distribution of proteinuria- and albuminuria-to-creatinine in preterm newborns, including the upper-limit values. These values should be taken into account in the detection and diagnosis of glomerular disease and/or injury in daily clinical practice. Graphical abstract.

Differential Secretion of Angiopoietic Factors and Expression of MicroRNA in Umbilical Cord Blood from Healthy Appropriate-For-Gestational-Age Preterm and Term Newborns-in Search of Biomarkers of Angiogenesis-Related Processes in Preterm Birth.

Objectives: Premature birth, defined as less than 37 weeks gestation, affects approximately 12% of all live births around the world. Advances in neonatal care have resulted in the increased survival of infants born prematurely. Although prematurity is a known risk factor for different cardiovascular diseases, little is known about the pathophysiology of vasculature during premature gestation and angiopoietic factors network during premature birth. Aims: The objective of this study was to determine whether the profile of several pro-angiogenic and anti-angiogenic factors in umbilical cord blood (UCB) is different in healthy appropriate-for-gestational-age preterm newborns and normal term babies. The second aim of this study was to investigate the microRNA (miRNAs) expression profile in UCB from preterm labor and to detect miRNAs potentially taking part in control of angogenesis-related processes (Angio-MiRs). Methods: Using an immunobead Luminex assay, we simultaneously measured the concentration of Angiogenin, Angiopoietin-1, FGF-acidic, FGF-basic, PDGF-aa, PlGF, VEGF, VEGF-D, Endostatin, Thrombospondin-2, NGF, BDNF, GDNF, and NT-4 in UCB samples collected from the preterm (n = 27) and term (n = 52) delivery. In addition, the global microRNA expression in peripheral blood mononuclear cells (PBMCs) circulating in such UCB samples was examined in this study using microarray MiRNA technique. Results: The concentrations of five from eight measured pro-angiogenic factors (VEGF, Angiopoietin-1, PDGF-AA, FGF-a, and FGF-b) were significantly lower in UCB from preterm newborns. On the contrary, two angiostatic factors (Endostatin and Thrombospondin-2) were significantly up-regulated in preterm UCB. Among analyzed neurotrophins in preterm newborns, the elevated UCB concentration was found only in the case of GDNF, whereas BDNF was significantly reduced. Moreover, two angiopoietic factors, VEGF-D and PlGF, and two neurotrophins, NT4 and NGF, did not differ in concentration in preterm and term babies. We also discovered that among the significantly down-regulated miRNAs, there were several classical Angio-MiRs (inter alia MiR-125, MiR-126, MiR-145, MiR-150, or MiR155), which are involved in angiogenesis regulation in newborn after preterm delivery. Conclusions: This is the first report of simultaneous measurements of several angiopoietic factors in UCB collected from infants during preterm and term labor. Here, we observed that several pro-angiogenic factors were at lower concentration in UCB collected from preterm newborns than term babies. In contrast, the two measured angiostatic factors, Endostatin and Thrombospondin-2, were significantly higher in UCB from preterm babies. This can suggest that distinct pathophysiological contributions from differentially expressed various angiopoietic factors may determine the clinical outcomes after preterm birth. Especially, our angiogenesis-related molecules analysis indicates that preterm birth of healthy, appropriate-for-gestational-age newborns is an "anti-angiogenic state" that may provide an increased risk for improper development and function of cardiovascular system in the adulthood. This work also contributes to a better understanding of the role of miRNAs potentially involved in angiogenesis control in preterm newborns.

Music processing in preterm and full-term newborns: A psychophysiological interaction (PPI) approach in neonatal fMRI.

Neonatal Intensive Care Units (NICU) provide special equipment designed to give life support for the increasing number of prematurely born infants and assure their survival. More recently NICU's strive to include developmentally oriented care and modulate sensory input for preterm infants. Music, among other sensory stimuli, has been introduced into NICUs, but without knowledge on the basic music processing in the brain of preterm infants. In this study, we explored the cortico-subcortical music processing of different types of conditions (Original music, Tempo modification, Key transposition) in newborns shortly after birth to assess the effective connectivity of the primary auditory cortex with the entire newborn brain. Additionally, we investigated if early exposure during NICU stay modulates brain processing of music in preterm infants at term equivalent age. We approached these two questions using Psychophysiological Interaction (PPI) analyses. A group of preterm infants listened to music (Original music) starting from 33 weeks postconceptional age until term equivalent age and were compared to two additional groups without music intervention; preterm infants and full-term newborns. Auditory cortex functional connectivity with cerebral regions known to be implicated in tempo and familiarity processing were identified only for preterm infants with music training in the NICU. Increased connectivity between auditory cortices and thalamus and dorsal striatum may not only reflect their sensitivity to the known music and the processing of its tempo as familiar, but these results are also compatible with the hypothesis that the previously listened music induces a more arousing and pleasant state. Our results suggest that music exposure in NICU's environment can induce brain functional connectivity changes that are associated with music processing.

Mesenchymal stem cells from preterm to term newborns undergo a significant switch from anaerobic glycolysis to the oxidative phosphorylation.

We evaluated the energy metabolism of human mesenchymal stem cells (MSC) isolated from umbilical cord (UC) of preterm (< 37 weeks of gestational age) and term (≥ 37 weeks of gestational age) newborns, using MSC from adult bone marrow as control. A metabolic switch has been observed around the 34th week of gestational age from a prevalently anaerobic glycolysis to the oxidative phosphorylation. This metabolic change is associated with the organization of mitochondria reticulum: preterm MSCs presented a scarcely organized mitochondrial reticulum and low expression of proteins involved in the mitochondrial fission/fusion, compared to term MSCs. These changes seem governed by the expression of CLUH, a cytosolic messenger RNA-binding protein involved in the mitochondria biogenesis and distribution inside the cell; in fact, CLUH silencing in term MSC determined a metabolic fingerprint similar to that of preterm MSC. Our study discloses novel information on the production of energy and mitochondrial organization and function, during the passage from fetal to adult life, providing useful information for the management of preterm birth.

Breast Milk for Preterm Multiples: More Proteins, Less Lactose.

Exclusive breastfeeding is currently recommended until at least 6 months of postnatal age, due to maternal breast milk (BM) unique composition and beneficial properties. In fact, BM modifies itself according to gestational age (GA) at birth, adapting its composition to neonatal requests during lactation. Multiple births represent about 3% of the whole pregnancies; such neonates result more vulnerable than full-term newborns, due to lower GA and birth weight (BW) and the higher incidence of perinatal complications. Although an adequate nutrition is fundamental for twins and other multiples, studies on this topic are lacking. We collected and analyzed BM from mothers of 19 twins and 5 triplets showing GA < 33 weeks and BW < 1500 g, comparing it to a control group of 28 preterm singletons. As a result, at GA ≤ 28 weeks, we observed that protein content is higher in BM for multiples (1.53 vs. 1.29 g per 100 ml), lactose concentration is greater in BM for singletons (6.72 vs. 6.34 g per 100 ml) and GA results the most relevant factor influencing BM protein composition. BM for multiples results higher in proteins and lower in lactose, if compared with singleton's samples; this could promote and sustain growth and organ development in this vulnerable category. BM from multiples shows a trophic and immunologic role, since these neonates often show lower GA and BW instead of singletons. These findings could help in optimizing nutritional strategies and improving BM individualized fortification.

Evaluation of the Induction of Cell-Mediated Immunity Against Candida albicans in a Model of Cutaneous Infection in Newborn 0-Day-Old Mice.

Candida albicans is a commensal fungus of the skin and mucous membranes in humans, but it is also responsible for mucocutaneous and systemic infections in immunocompromised patients like low birth weight neonates and premature newborns. The epicutaneous application of C. albicans is widely used to study the immune response against this pathogen in adult mice models. However, the immune response of newborns against infections caused by the genus Candida is poorly understood. In order to mimic premature human infection, we developed a model of C. albicans epicutaneous infection in newborn mice. We found that yeasts were able to colonize while the pseudohyphae invaded the epidermis. Recruitment of polymorphonuclear and mononuclear cells at the infection zone was observed. Fungal invasion, fungal burden and cellular infiltration displayed a time- and dose-dependent response. Interestingly, newborn mice were able to control C. albicans primary infection. Finally, we showed that the epicutaneous infection of C. albicans in newborn mice at birth results in the induction of cell-mediated immunity as evinced by delayed-type hypersensitivity assays.

Surfactant Components and Tracheal Aspirate Inflammatory Markers in Preterm Infants with Respiratory Distress Syndrome.

In 93 preterm infants ≤32 weeks of gestational age and 12 control infants, epithelial lining fluid disaturated-phosphatidylcholine, surfactant protein A and B, albumin, and myeloperoxidase activity were assessed after intubation and before exogenous surfactant administration. We found that disaturated-phosphatidylcholine, surfactant protein B, and myeloperoxidase were significantly higher in preterms with chorioamnionitis.

Off-label mesenchymal stromal cell treatment in two infants with severe bronchopulmonary dysplasia: clinical course and biomarkers profile.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most prevalent sequelae of premature birth, for which therapeutic options are currently limited. Mesenchymal stromal cells (MSCs) are a potential therapy for prevention or reversal of BPD. SERIES OF CASES: We report on two infants with severe BPD in whom off-label treatment with repeated intravenous doses of allogeneic bone marrow-derived MSCs were administered. We analyzed the temporal profile of serum and tracheal cytokines and growth factors as well as safety, tolerability and clinical response. The administration of repeated intravenous doses of MSCs in two human babies with severe and advanced BPD was feasible and safe and was associated with a decrease of pro-inflammatory molecules and lung injury biomarkers. Both patients were at very advanced stages of BPD with very severe lung fibrosis and did not survive the disease. CONCLUSIONS: MSCs are a promising therapy for BPD, but they should be administered in early stages of the disease.

Mother's voice and heartbeat sounds elicit auditory plasticity in the human brain before full gestation.

Brain development is largely shaped by early sensory experience. However, it is currently unknown whether, how early, and to what extent the newborn's brain is shaped by exposure to maternal sounds when the brain is most sensitive to early life programming. The present study examined this question in 40 infants born extremely prematurely (between 25- and 32-wk gestation) in the first month of life. Newborns were randomized to receive auditory enrichment in the form of audio recordings of maternal sounds (including their mother's voice and heartbeat) or routine exposure to hospital environmental noise. The groups were otherwise medically and demographically comparable. Cranial ultrasonography measurements were obtained at 30 ± 3 d of life. Results show that newborns exposed to maternal sounds had a significantly larger auditory cortex (AC) bilaterally compared with control newborns receiving standard care. The magnitude of the right and left AC thickness was significantly correlated with gestational age but not with the duration of sound exposure. Measurements of head circumference and the widths of the frontal horn (FH) and the corpus callosum (CC) were not significantly different between the two groups. This study provides evidence for experience-dependent plasticity in the primary AC before the brain has reached full-term maturation. Our results demonstrate that despite the immaturity of the auditory pathways, the AC is more adaptive to maternal sounds than environmental noise. Further studies are needed to better understand the neural processes underlying this early brain plasticity and its functional implications for future hearing and language development.

Is early breast milk fortification more effective in preterm infants?: a clinical trial.

OBJECTIVE: Breast feeding alone does not provide adequate nutrition for growth in preterm infants; therefore, fortifiers are added when over 70-80 cc/kg/day of breast milk is tolerated. As there are few studies comparing early and late breast milk fortification, the following study was conducted. STUDY DESIGN: This double-blind clinical trial was performed on 80 preterm infants (gestational age of 28-34 weeks, birth weight <2 kg). The newborns were randomly divided into two groups to receive either early or late fortification. The primary and secondary outcomes were the difference in growth indices and complications (including feeding intolerance, necrotizing enterocolitis (NEC), and septicemia) between the two groups, respectively. RESULTS: Both groups showed increases in growth indices; however, there was no statistically significant difference in increments of growth indices and complications between the two groups. CONCLUSION: Our findings suggest that early fortification from the first feeding in neonates with exclusive breast feeding did not improve growth in the first 4 weeks in preterm neonates in comparison with late fortification; so early fortification may not be cost effective.

Congenital erosive and vesicular dermatosis with reticulated supple scarring.

Congenital erosive and vesicular dermatosis with reticulated supple scarring is a rare cutaneous disorder of unknown aetiology first described by Cohen and colleagues in 1985. It classically presents in the neonate as erosions and vesicles that heal within the first months of life, with supple scarring of a reticulated pattern. Along with a review of the literature, this article presents two atypical cases of congenital erosive and vesicular dermatosis with reticulated supple scarring. Patient one presented with neither erosions nor vesicles at birth, yet continued to experience sporadic blistering at the age of 15 months and patient two is the second documented case to develop congenital erosive and vesicular dermatosis after birth.

Intraventricular hemorrhage in premature infants with Respiratory Distress Syndrome treated with surfactant: incidence and risk factors in the prospective cohort study.

BACKGROUND: Intraventricular hemorrhage (IVH) is a common pathology in preterm infants with extremely and very low birth weight. It is particularly often seen in newborns with Respiratory Distress Syndrome (RDS). AIM: To assess the incidence of IVH in preterm newborns with RDS treated with surfactant, and to identify factors that might reduce the risk of IVH in this population. MATERIAL AND METHODS: This multicenter, prospective cohort study is part of the "Neo-pro" study project. The investigations were carried out in 936 newborns, including 652 survivors. We enrolled a consecutive sample of infants born before 32 weeks' gestation. IVH was diagnosed with trans-fontanel ultrasonography, performed according to the approved standards and classified according to Papile's grading system. RESULTS: Intraventricular hemorrhage was diagnosed in 462/936 infants (49.4%), and in 43.3% of the survivors. Grade 3 and 4 IVH occurred in 14.8% and 13.8% of the infants, respectively, and in 10.6% and 5.7% of the survivors. Lack of antenatal application in mothers of corticosteroids increased the incidence rate of severe IVH from 14.2% to 22.1% (p=0.0087). The risk of IVH was reduced with early (from the first day of life) initiation of caffeine citrate (OR: 0.63, 95% CI: 0.45-0.88), delivery by cesarean section (OR: 0.50, 95% CI: 0.36-0.69), and the risk of severe IVH - from treatment with antenatal corticosteroids (OR: 0.58, 95% CI: 0.39-0.87). The most significant factor which increased the risk of hemorrhage was invasive mechanical ventilation (OR: 2.90, 95% CI: 2.07-4.07). The risk was further increased if the duration of mechanical ventilation was greater than seven days (OR: 3.02, 95% CI: 2.21-4.12). CONCLUSIONS: The incidence of IVH in newborns with RDS is significant and the risk of IVH is increased by mechanical ventilation. Antenatal exposure to corticosteroids and delivery by cesarean section have a protective effect, and the former also reduces the risk of the most severe manifestations of IVH. Caffeine citrate initiated from the first day of life is another protective strategy.

Hindbrain regional growth in preterm newborns and its impairment in relation to brain injury.

Premature birth globally affects about 11.1% of all newborns and is a risk factor for neurodevelopmental disability in surviving infants. Histology has suggested that hindbrain subdivisions grow differentially, especially in the third trimester. Prematurity-related brain injuries occurring in this period may selectively affect more rapidly developing areas of hindbrain, thus accompanying region-specific impairments in growth and ultimately neurodevelopmental deficits. The current study aimed to quantify regional growth of the cerebellum and the brainstem in preterm neonates (n = 65 with individually multiple scans). We probed associations of the regional volumes with severity of brain injury. In neonates with no imaging evidence of injury, our analysis using a mixed-effect linear model showed faster growth in the pons and the lateral convexity of anterior/posterior cerebellar lobes. Different patterns of growth impairment were found in relation to early cerebral intraventricular hemorrhage and cerebellar hemorrhage (P < 0.05), likely explaining different mechanisms through which neurogenesis is disrupted. The pattern of cerebellar growth identified in our study agreed excellently with details of cerebellar morphogenesis in perinatal development, which has only been observed in histological data. Our proposed analytic framework may provide predictive imaging biomarkers for neurodevelopmental outcome, enabling early identification and treatment of high-risk patients. Hum Brain Mapp 37:678-688, 2016. © 2015 Wiley Periodicals, Inc.