Cardiovascular and cerebrovascular effects of caffeine maintenance in preterm infants during the transitional period.

BACKGROUND AND AIM: Caffeine is routinely used for the prophylaxis of prematurity-related apnoeas. We aimed to evaluate the effect of caffeine maintenance on cardiovascular and cerebrovascular haemodynamics using a non-invasive multimodal monitoring in preterm infants during the transitional period. METHODS: Infants <32 weeks' gestational age (GA) were enrolled in this observational prospective study. The following parameters were recorded before and after the administration of caffeine citrate 5 mg/kg using near-infrared spectroscopy, pulse oximetry and electrical velocimetry: heart rate, cardiac output, stroke volume, cardiac contractility, systemic vascular resistance (SVR), perfusion index, peripheral and cerebral oxygenation, cerebral fractional oxygen extraction, correlation index between cerebral oxygenation and heart rate (TOHRx, marker of cerebrovascular reactivity). Multilevel mixed-effects linear models were used to assess the impact of caffeine and of relevant clinical covariates on each parameter. RESULTS: Seventy-seven infants (mean GA 29.3 ± 2.5 weeks, mean birthweight 1148 ± 353 g) were included. Caffeine administration was associated with increased SVR (B = 0.623, p = 0.004) and more negative TOHRx values (B = -0.036, p = 0.022), which suggest improved cerebrovascular reactivity. CONCLUSIONS: Caffeine administration at maintenance dosage during postnatal transition is associated with increased systemic vascular tone and improved cerebrovascular reactivity. A possible role for caffeine-mediated inhibition of adenosine receptors may be hypothesized. IMPACT: This study provides a thorough and comprehensive overview of multiple cerebrovascular and cardiovascular parameters, monitored non-invasively by combining near-infrared spectroscopy, electrical velocimetry and pulse oximetry, before and after the administration of caffeine at maintenance dosage in preterm infants during postnatal transition. Caffeine was associated with an improvement in cerebrovascular reactivity and with a slight but significant increase in systemic vascular resistance, with no additional effects on other cardiovascular and cerebrovascular parameters. Our results support the safety of caffeine treatment even during a phase at risk for haemodynamic instability such as postnatal transition and suggest potential beneficial effects on cerebral haemodynamics.

Neurodevelopmental Correlates of Brain Magnetic Resonance Imaging Abnormalities in Extremely Low-birth-weight Infants.

OBJECTIVE: To evaluate the relationship between impaired brain growth and structural brain abnormalities at term-equivalent age (TEA) and neurodevelopment in extremely low-birth-weight (ELBW) infants over the first 2 years. METHODS: ELBW infants born from 2009 through 2018 and undergoing brain magnetic resonance imaging (MRI) at TEA were enrolled in this retrospective cohort study. MRI scans were reviewed using a validated quali-quantitative score, including several white and gray matter items. Neurodevelopment was assessed at 6, 12, 18, and 24 months using the Griffiths scales. The independent associations between MRI subscores and the trajectories of general and specific neurodevelopmental functions were analyzed by generalized estimating equations. RESULTS: One hundred-nine ELBW infants were included. White matter volume reduction and delayed myelination were associated with worse general development (b = -2.33, P = .040; b = -6.88, P = .049 respectively), social skills (b = -3.13, P = .019; b = -4.79, P = .049), and eye-hand coordination (b = -3.48, P = .009; b = -7.21, P = .045). Cystic white matter lesions were associated with poorer motor outcomes (b = -4.99, P = .027), while white matter signal abnormalities and corpus callosum thinning were associated with worse nonverbal cognitive performances (b = -6.42, P = .010; b = -6.72, P = .021, respectively). Deep gray matter volume reduction correlated with worse developmental trajectories. CONCLUSIONS: Distinctive MRI abnormalities correlate with specific later developmental skills. This finding may suggest that TEA brain MRI may assist with neurodevelopmental prediction, counseling of families, and development of targeted supportive interventions to improve neurodevelopment in ELBW neonates.

Clinical determinants of cerebrovascular reactivity in very preterm infants during the transitional period.

BACKGROUND: Preterm infants are at enhanced risk of brain injury due to altered cerebral haemodynamics during postnatal transition. This observational study aimed to assess the clinical determinants of transitional cerebrovascular reactivity and its association with intraventricular haemorrhage (IVH). METHODS: Preterm infants <32 weeks underwent continuous monitoring of cerebral oxygenation and heart rate over the first 72 h after birth. Serial cranial and cardiac ultrasound assessments were performed to evaluate the ductal status and to diagnose IVH onset. The moving correlation coefficient between cerebral oxygenation and heart rate (TOHRx) was calculated. Linear mixed-effect models were used to analyse the impact of relevant clinical variables on TOHRx. The association between TOHRx and IVH development was also assessed. RESULTS: Seventy-seven infants were included. A haemodynamically significant patent ductus arteriosus (hsPDA) (ß = 0.044, 95% CI: 0.007-0.081) and ongoing dopamine treatment (ß = 0.096, 95% CI: 0.032-0.159) were associated with increasing TOHRx, indicating impaired cerebrovascular reactivity. A significant association between TOHRx, mean arterial blood pressure (ß = -0.004, 95% CI: -0.007, -0.001) and CRIB-II score (ß = 0.007, 95% CI: 0.001-0.015) was also observed. TOHRx was significantly higher in infants developing high-grade IVH compared to those without IVH. CONCLUSIONS: Dopamine treatment, low blood pressure, hsPDA and high CRIB-II are associated with impaired cerebrovascular reactivity during postnatal transition, with potential implications on IVH development. IMPACT: The correlation coefficient between cerebral oxygenation and heart rate (TOHRx) provides a non-invasive estimation of cerebrovascular reactivity, whose failure has a potential pathogenic role in the development of IVH in preterm infants. This study shows that cerebrovascular reactivity during the transitional period improves over time and is affected by specific clinical and therapeutic factors, whose knowledge could support the development of individualized neuroprotective strategies in at-risk preterm infants. The evidence of increased TOHRx in infants developing high-grade compared to low-grade or no IVH during the transitional period further supports the role of impaired cerebrovascular reactivity in IVH pathophysiology.

Diagnostic challenges of an incidental finding: case report of definitely-congenital glioblastoma multiforme in a very preterm infant.

BACKGROUND: Congenital brain tumors are extremely rare in the neonatal population, and often associated with a poor prognosis. The diagnostic suspicion is often aroused at antenatal scans or postnatally, if clinical signs and symptoms of increased intracranial pressure become evident. We present a case of definitely congenital glioblastoma multiforme incidentally diagnosed in a preterm infant, aiming to raise clinical awareness on this condition and to highlight the challenges of the related diagnostic work-up. CASE PRESENTATION: This female infant was born at 31 weeks' gestation after an uneventful pregnancy. No abnormalities were detected at antenatal ultrasound scans and genetic tests. Head circumference at birth was on the 25th centile. A routine brain ultrasound scan performed on day 1 revealed a large, inhomogeneous lesion in the right cerebral hemisphere, with contralateral midline shift, which was confirmed by brain magnetic resonance imaging (MRI). Eye fundus and routine blood exams, including platelets count, coagulation screening and C-reactive protein, were normal. Given the high risk of complications, surgical biopsy of the lesion was temporarily hold and a daily sonographic follow-up was undertaken. Although head circumference growth was steady on the 25th centile, progressive changes of the lesion were detected by cranial ultrasound. The repeat MRI scans showed a significant enlargement of the mass, with contralateral midline shift and signs of intralesional and intraventricular bleeding. In view of this worsening, surgical resection was performed. The histological examination of the lesion biopsy documented a GFAP+ highly cellular neoplasm, with no mutation on SMARCB1 gene. At the molecular analysis, mutations on IDH and H3F3A genes were absent, whereas MGMT promoter was unmethylated. The diagnosis was grade IV glioblastoma IDH wild-type. CONCLUSIONS: Congenital glioblastoma multiforme is an extremely rare but highly aggressive neoplasm. Since intralesional biopsy is not often feasible in affected neonates, knowledge of the associated clinical and neuroradiological features is particularly important, as they can also add useful information on the neoplasm behavior. Specimens from open surgical resection allow to perform a definite histological analysis and an extended molecular characterization, with relevant prognostic implications.

Free Radicals and Neonatal Brain Injury: From Underlying Pathophysiology to Antioxidant Treatment Perspectives.

Free radicals play a role of paramount importance in the development of neonatal brain injury. Depending on the pathophysiological mechanisms underlying free radical overproduction and upon specific neonatal characteristics, such as the GA-dependent maturation of antioxidant defenses and of cerebrovascular autoregulation, different profiles of injury have been identified. The growing evidence on the detrimental effects of free radicals on the brain tissue has led to discover not only potential biomarkers for oxidative damage, but also possible neuroprotective therapeutic approaches targeting oxidative stress. While a more extensive validation of free radical biomarkers is required before considering their use in routine neonatal practice, two important treatments endowed with antioxidant properties, such as therapeutic hypothermia and magnesium sulfate, have become part of the standard of care to reduce the risk of neonatal brain injury, and other promising therapeutic strategies are being tested in clinical trials. The implementation of currently available evidence is crucial to optimize neonatal neuroprotection and to develop individualized diagnostic and therapeutic approaches addressing oxidative brain injury, with the final aim of improving the neurological outcome of this population.

Neuroprem: the Neuro-developmental outcome of very low birth weight infants in an Italian region.

INTRODUCTION: The survival of preterm babies has increased worldwide, but the risk of neuro-developmental disabilities remains high, which is of concern to both the public and professionals. The early identification of children at risk of neuro-developmental disabilities may increase access to intervention, potentially influencing the outcome. AIMS: Neuroprem is an area-based prospective cohort study on the neuro-developmental outcome of very low birth weight (VLBW) infants that aims to define severe functional disability at 2 years of age. METHODS: Surviving VLBW infants from an Italian network of 7 neonatal intensive care units (NICUs) were assessed for 24 months through the Griffiths Mental Developmental Scales (GMDS-R) or the Bayley Scales of Infant and Toddler Development (BSDI III) and neuro-functional evaluation according to the International Classification of Disability and Health (ICF-CY). The primary outcome measure was severe functional disability at 2 years of age, defined as cerebral palsy, a BSDI III cognitive composite score < 2 standard deviation (SD) or a GMDS-R global quotients score < 2 SD, bilateral blindness or deafness. RESULTS: Among 211 surviving VLBW infants, 153 completed follow-up at 24 months (72.5%). Thirteen patients (8.5%) developed a severe functional disability, of whom 7 presented with cerebral palsy (overall rate of 4.5%). Patients with cerebral palsy were all classified with ICF-CY scores of 3 or 4. BSDI III composite scores and GMDS-R subscales were significantly correlated with ICF-CY scores (p < 0.01). CONCLUSION: Neuroprem represents an Italian network of NICUs aiming to work together to ensure preterm neuro-developmental assessment. This study updates information on VLBW outcomes in an Italian region, showing a rate of cerebral palsy and major developmental disabilities in line with or even lower than those of similar international studies. Therefore, Neuroprem provides encouraging data on VLBW neurological outcomes and supports the implementation of a preterm follow-up programme from a national network perspective.

Standard fortification of preterm human milk fails to meet recommended protein intake: Bedside evaluation by Near-Infrared-Reflectance-Analysis.

BACKGROUND: Protein content of preterm human milk (HM) is relatively low and extremely variable among mothers: thus, recommended protein intake is rarely met. OBJECTIVES: To evaluate in a NICU setting if HM protein content after standard fortification meets the recommended intake, and also to check the effect of fortification on the osmolality of HM, as an index of feeding intolerance. METHODS: Protein content of 34 preterm HM samples was evaluated by a bedside technique (Near-Infrared-Reflectance-Analysis - NIRA); osmolality was also checked. Seventeen samples were fortified with Aptamil BMF, Milupa (Group A) and 17 with FM85, Nestlé (Group B). Fortification was performed as recommended by the manufacturer ("full fortification [FF]") and also with a lower amount of fortifier ("low-dose fortification [LF]"). After fortification, actual protein content was calculated and compared to that needed to meet recommended intake (2.33-3g/dl), and osmolality was measured. RESULTS: After FF, protein content was above 3g/dl in none of the samples, and below 2.33 g/dl in 16/34 samples (11 in Group A, 5 in Group B). After LF, protein content was above 3g/dl in none of the samples and below 2.33 g/dl in 32/34 samples (15 in Group A, 17 in Group B). Osmolality exceeded 400 mOsm/kg in 19 samples after FF (10 in Group A, 9 in Group B) and in 2/34 samples after LF (1 in each group). CONCLUSION: HM protein content after standard fortification fails to meet the recommended intake for preterm infants in approximately half of the cases.

Protein content and fortification of human milk influence gastroesophageal reflux in preterm infants.

OBJECTIVES: : Preterm human milk (HM) may provide insufficient energy and nutrients and thus may need to be fortified. Our aim was to determine whether fat content, protein content, and osmolality of HM before and after fortification may affect gastroesophageal reflux (GER) in symptomatic preterm infants. METHODS: : Gastroesophageal reflux was evaluated in 17 symptomatic preterm newborns fed naïve and fortified HM by combined pH/intraluminal-impedance monitoring (pH-MII). Human milk fat and protein content was analysed by a near-infrared reflectance analysis. Human milk osmolality was tested before and after fortification. Gastroesophageal reflux indexes measured before and after fortification were compared and were also related to HM fat and protein content and osmolality before and after fortification. RESULTS: : An inverse correlation was found between naïve HM protein content and acid reflux index (RIpH: P = 0.041, rho =-0.501). After fortification, osmolality often exceeded the values recommended for infant feeds; furthermore, a statistically significant (P < 0.05) increase in nonacid reflux indexes was observed. CONCLUSIONS: : Protein content of naïve HM may influence acid GER in preterm infants. A standard fortification of HM may worsen nonacid GER indexes and, due to the extreme variability in HM composition, may overcome both recommended protein intake and HM osmolality. Thus, an individualised fortification, based on the analysis of the composition of naïve HM, could optimise both nutrient intake and feeding tolerance.

Lack of correlation between fecal elastase-1 levels and fecal nitrogen excretion in preterm infants.

We measured fecal elastase-1 (FE1) levels in 34 preterm newborns (15 small-for-gestational-age and 19 appropriate-for-gestational-age) during the first 2 months of life and evaluated whether they were correlated with nitrogen loss in stools. FE1 increased over time, and values were similar in both groups of newborns. Fecal nitrogen was significantly higher in small-for-gestational-age infants. There was no correlation between FE1 levels and fecal nitrogen excretion. Pancreatic proteolytic function was efficient at an early stage in enterally fed preterm newborns. Despite the similar FE1 values, fecal nitrogen loss was significantly higher in small-for-gestational-age preterm infants than in appropriate-for-gestational-age preterm infants.

Starch thickening of human milk is ineffective in reducing the gastroesophageal reflux in preterm infants: a crossover study using intraluminal impedance.

We evaluated the efficacy of the thickening of human milk by precooked starch in reducing gastroesophageal reflux in preterm infants. Five preterm infants with frequent regurgitations (median gestational age, 28 weeks; range, 27 to 32 weeks; median birth weight, 990 g; range, 570 to 1900 g) were fed alternately during 24 hours with four meals of fortified maternal milk (milk A) and four meals of fortified maternal milk thickened by 1.5 g of precooked starch per 100 mL of milk (milk B). The acidic and buffered refluxes were detected by simultaneous pH monitoring and multiple intraluminal impedance. Eight feeding periods for each baby were recorded. The number of the acidic (34 after milk A vs 36 after milk B) and buffered (112 after milk A vs 134 after milk B) episodes of gastroesophageal reflux did not differ. Thickening human milk by precooked starch is ineffective in reducing gastroesophageal reflux in premature infants.