Neutropenia in Preterm Infants.

BACKGROUND: The non-specific and antigen-specific components of host defense mechanisms are subject to the adaptation process in the neonate; however, the neutrophil quantitative and qualitative deficiency is one of the most significant causative factors of neonatal-increased vulnerability to infection. OBJECTIVE: To review the incidence and outcome of neutropenia of unknown cause in preterm infants. RESULTS: The incidence of early and late-onset idiopathic neutropenia of prematurity is significant. CONCLUSION: The low neutrophil counts respond quickly to G-CSF treatment; however, due to the low probability of septic complications, particularly in the late-onset neutropenia, a deep diagnostic approach and the potential hematopoietic growth factor treatment should be limited to the severe cases, such as a neutrophil count <500/µL, lasting for more than 2 days.

Neonatal Respiratory Distress and Airway Emergency: Report of Two Cases.

We discuss two cases of congenital airway malformations seen in our neonatal intensive care unit (NICU). The aim is to report extremely rare events characterized by immediate respiratory distress after delivery and the impossibility to ventilate and intubate the airway. The first case is a male twin born at 34 weeks by emergency caesarean section. Immediately after delivery, the newborn was cyanotic and showed severe respiratory distress. Bag-valve-mask ventilation did not relieve the respiratory distress but allowed for temporary oxygenation during subsequent unsuccessful oral-tracheal intubation (OTI) attempts. Flexible laryngoscopy revealed complete subglottic obstruction. Postmortem analysis revealed a poly-malformative syndrome, unilateral multicystic renal dysplasia with a complete subglottic diaphragm, and a tracheo-esophageal fistula (TEF). The second case is a male patient that was vaginally born at 35 weeks. Antenatally, an ultrasound (US) arose suspicion for a VACTERL association (vertebral defects, anal atresia, TEF with esophageal atresia and radial or renal dysplasia, plus cardiovascular and limb defects) and a TEF, and thus, fetal magnetic resonance (MRI) was scheduled. Spontaneous labor started shortly thereafter, before imaging could be performed. Respiratory distress, cyanosis, and absence of an audible cry was observed immediately at delivery. Attempts at OTI were unsuccessful, whereas bag-valve-mask ventilation and esophageal intubation allowed for sufficient oxygenation. An emergency tracheostomy was attempted, although no trachea could be found on cervical exploration. Postmortem analysis revealed tracheal agenesis (TA), renal dysplasia, anal atresia, and a single umbilical artery. Clinicians need to be aware of congenital airway malformations and subsequent difficulties upon endotracheal intubation and must plan for multidisciplinary management of the airway at delivery, including emergency esophageal intubation and tracheostomy.

Sensory Stimulation in the NICU Environment: Devices, Systems, and Procedures to Protect and Stimulate Premature Babies.

Prematurity deprives infants of the prenatal sensory stimulation essential to their correct development; in addition, the stressful environment of the NICU impacts negatively on their growth. The purpose of this review was to investigate the effects of NICU noise pollution on preterm infants and parents. We focused on the systems and projects used to control and modulate sounds, as well as on those special devices and innovative systems used to deliver maternal sounds and vibrations to this population. The results showed beneficial effects on the preterm infants in different areas such as physiological, autonomic, and neurobehavioral development. Although most of these studies highlight positive reactions, there is also a general acknowledgement of the current limits: small and heterogeneous groups, lack of structured variable measurements, systematic control groups, longitudinal studies, and normative values. The mother's presence is always preferred, but the use of music therapy and the devices analyzed, although not able to replace her presence, aim to soften her absence through familiar and protective stimuli, which is a very powerful aid during the COVID-19 pandemic.

Fermented infant formula (with Bifidobacterium breve C50 and Streptococcus thermophilus O65) with prebiotic oligosaccharides is safe and modulates the gut microbiota towards a microbiota closer to that of breastfed infants.

BACKGROUND & AIMS: Microbiome-modulators can help positively steer early-life microbiota development but their effects on microbiome functionality and associated safety and tolerance need to be demonstrated. We investigated the microbiome impact of a new combination of bioactive compounds, produced by the food-grade microorganisms Bifidobacterium breve C50 and Streptococcus thermophilus ST065 during a fermentation process, and prebiotics in an infant formula. Tolerance and safety were also assessed. METHODS: An exploratory prospective, randomized, double-blind, controlled, multi-centre study was designed to investigate the effect of bioactive compounds and prebiotics (short-chain galacto-oligosaccharides (scGOS)/long-chain fructo-oligosaccharides (lcFOS) 9:1). Experimental formulas containing these bioactive compounds and prebiotics (FERM/scGOS/lcFOS), prebiotics (scGOS/lcFOS), or bioactive compounds (FERM), were compared to a standard cow's milk-based control formula (Control). Exclusively breastfed infants were included as a reference arm since exclusive breastfeeding is considered as the optimal feeding for infants. The study lasted six months and included visits to health care professionals at baseline, two, four and six months of age. Stool SIgA concentration was the primary study outcome parameter. RESULTS: There were 280 infants randomized over the experimental arms and 70 infants entered the breastfed-reference arm. Demographics were balanced, growth and tolerance parameters were according to expectation and adverse events were limited. At four months of age the median SIgA concentration in the FERM/scGOS/lcFOS group was significantly higher compared to the Control group (p = 0.03) and was more similar to the concentrations found in the breastfed-reference group. Bifidobacterium increased over time in all groups. The FERM/scGOS/lcFOS combination resulted in a microbiota composition and metabolic activity closer to the breastfed infants' microbiome. CONCLUSION: The FERM/scGOS/lcFOS combination showed a significant positive effect on SIgA levels. All formulas tested were associated with normal growth and were well-tolerated. Additionally, at four months of age the FERM/scGOS/lcFOS formula brought the microbiome composition and metabolic activity closer towards that of breastfed infants. CLINICAL TRIAL REGISTRY: Registration number NTR2726 (Netherlands Trial Register; www.trialregister.nl/).

Italian inter-society expert panel position on radiological exposure in Neonatal Intensive Care Units.

BACKGROUND: In the recent years, clinical progress and better medical assistance for pregnant women, together with the introduction of new complex technologies, has improved the survival of preterm infants. However, this result requires frequent radiological investigations mostly represented by thoracic and abdominal radiographs in incubators. This document was elaborated by an expert panel Italian inter-society working group (Radiologists, Paediatricians, Medical Physicists) with the aim to assist healthcare practitioners in taking choices involving radiation exposures of new-born infants and to provide practical recommendations about justification and optimization in Neonatal Intensive Care Units. The adherence to these practice recommendations could ensure a high quality and patient safety. More complex and less common radiological practice, such as CT scan or fluoroscopy have been excluded. METHODS: The consensus was reached starting from current good practice evidence shared by four scientific societies panel: AIFM (Italian Association of Physics in Medicine), SIN (Italian Neonatology Society), SIP (Italian Paediatric Society), SIRM (Italian Medical Radiology Society) in order to guarantee good standard practices for every professional involved in Neonatal Intensive Care Units (NICU). The report is divided into clinical and physical-dosimetric sections: clinical Indications, good practice in radiological exposures, devices, exposure parameters and modalities, patient positioning and immobilization, Reference Diagnostic Levels, operators and patient's radiation protection. Another important topic was the evaluation of the different incubators in order to understand if the consequences of the technological evolution have had an impact on the increase of the dose to the small patients, and how to choose the best device in terms of radiation protection. At the end the working group faced the problem of setting up the correct communication between clinicians and parents following the most recent indications of the international paediatric societies. RESULTS: Taking into account the experience and expertise of 10 Italian Centres, the guideline sets out the criteria to ensure a high standard of neonatal care in NICU about procedures, facilities, recommended equipment, quality assurance, radiation protection measures for children and staff members and communication on radiation risk. CONCLUSIONS: This document will allow a standardization of the approach to the exposures in NICU, although oriented to a flexible methodology.

Propranolol 0.2% Eye Micro-Drops for Retinopathy of Prematurity: A Prospective Phase IIB Study.

Background: Oral propranolol reduces retinopathy of prematurity (ROP) progression, although not safely. Propranolol 0.1% eye micro-drops administered to newborns with stage 2 ROP are well-tolerated, but not sufficiently effective. Methods: A multi-center open-label trial was conducted to assess the safety and efficacy of propranolol 0.2% eye micro-drops in newborns with stage 1 ROP. The progression of the disease was evaluated with serial ophthalmologic examinations. Hemodynamic, respiratory, biochemical parameters, and propranolol plasma levels were monitored. Demographic and perinatal characteristics, co-morbidities and co-intervention incidences, together with ROP progression, were compared with a historical control group in the same centers participating in the trial. Results: Ninety-eight newborns were enrolled and compared with the historical control group. Populations were not perfectly homogeneous (as demonstrated by the differences in the Apgar score and the different incidence rate in surfactant administration and oxygen exposure). The progression to ROP stage 2 or 3 plus was significantly lower than the incidence expected on the basis of historical data (Risk Ratio 0.521, 95% CI 0.297- 0.916). No adverse effects related to propranolol were observed and the mean propranolol plasma level was significantly lower than the safety cut-off of 20 ng/mL. Unexpectedly, three newborns treated with oral propranolol before the appearance of ROP, showed a ROP that was unresponsive to propranolol eye micro-drops and required laser photocoagulation treatment. Conclusion: Propranolol 0.2% eye micro-drops were well-tolerated and appeared to reduce the ROP progression expected on the basis of a comparison with a historical control group. Propranolol administered too early appears to favor a more aggressive ROP, suggesting that a ß-adrenoreceptor blockade is only useful during the proliferative phase. Further randomized placebo-controlled trials are required to confirm the current results. Clinical Trial Registration  The trial was registered at ClinicalTrials.gov with Identifier NCT02504944 and with EudraCT Number 2014-005472-29.

Music reduces pain perception in healthy newborns: A comparison between different music tracks and recoded heartbeat.

OBJECTIVES: To assess the effect of 3 musical interventions, as compared to no music, on the physiological response of healthy newborns undergoing painful medical procedures (Guthrie test and/or intramuscular antibiotic injections). METHODS: Prospective study of 80 full-term newborns, aged 1 to 3 days, randomly allocated to exposure to Mozart's Sonata for two pianos K.448, Beethoven's Moonlight Sonata, heartbeat sound recordings (70 bpm) or no music. Pain perception (evaluated using the Neonatal Infant Pain Scale), heart rate and oxygen saturation were measured 10 min before (T0), during (T1), 10 (T2) and 20 (T3) minutes after the interventions. RESULTS: Infants who were exposed to the three music interventions displayed a significant reduction in heart rate and in pain perception and an increase in oxygen saturation, as compared to the control group, which showed less modifications on stress measurements after painful medical procedures (F(3,76) = 6.40, p = .001, partial η2 = 0.20). CONCLUSIONS: Exposure to music and heartbeat sound recordings changes short-term physiological parameters in healthy newborns undergoing potentially painful procedures. The similar effect shown by the 3 interventions might be explained by the common characteristics of the sound shared by the various tracks. Further research is needed to investigate the impact of different types of music used in intervention, in order to develop guidelines and include music as a part of evidence-based strategies to promote the outcome for neonates.

Reference intervals of citrated-native whole blood thromboelastography in premature neonates.

BACKGROUND: Bleeding due to acquired coagulation disorders is a common complication in premature neonates. In this clinical setting, standard coagulation laboratory tests might be unsuitable to investigate the hemostatic function as they reflect the concentration of pro-coagulant proteins but not of anti-coagulant proteins. Thromboelastography (TEG), providing a more complete assessment of hemostasis, may be able to overcome some of these limitations. Unfortunately, experience on the use of TEG in premature neonates is very limited and, in particular in this population, reference ranges of TEG parameters have not been yet evaluated. AIMS: To evaluate TEG in preterm neonates, and to assess their reference ranges. METHODS: One hundred and eighteen preterm neonates were analyzed for TEG in a retrospective cohort study. Double-sided 95% reference intervals were calculated using a bootstrap method after Box-Cox transformation. TEG parameters were compared between early-preterm and moderate-/late-preterm neonates and between bleeding and non-bleeding preterm neonates. RESULTS: Comparing early-preterm with moderate-/late-preterm neonates, TEG parameters were not statistically different, except for fibrinolysis which was significantly higher in early preterm neonates. Platelet count significantly correlated with α angle and MA parameters. Bleeding and non-bleeding neonates had similar TEG values. CONCLUSIONS: These results reinforce the concept that in stable preterm neonates, in spite of lower concentration of pro- and anti-coagulants proteins, the hemostasis is normally balanced and well functioning.

Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial.

BACKGROUND: Retinopathy of prematurity (ROP) still represents one of the leading causes of visual impairment in childhood. Systemic propranolol has proven to be effective in reducing ROP progression in preterm newborns, although safety was not sufficiently guaranteed. On the contrary, topical treatment with propranolol eye micro-drops at a concentration of 0.1% had an optimal safety profile in preterm newborns with ROP, but was not sufficiently effective in reducing the disease progression if administered at an advanced stage (during stage 2). The aim of the present protocol is to evaluate the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns at a more precocious stage of ROP (stage 1). METHODS: A multicenter, open-label, phase II, clinical trial, planned according to the Simon optimal two-stage design, will be performed to analyze the safety and efficacy of propranolol 0.2% eye micro-drops in preterm newborns with stage 1 ROP. Preterm newborns with a gestational age of 23-32 weeks, with a stage 1 ROP will receive propranolol 0.2% eye micro-drops treatment until retinal vascularization has been completed, but for no longer than 90 days. Hemodynamic and respiratory parameters will be continuously monitored. Blood samplings checking metabolic, renal and liver functions, as well as electrocardiogram and echocardiogram, will be periodically performed to investigate treatment safety. Additionally, propranolol plasma levels will be measured at the steady state, on the 10th day of treatment. To assess the efficacy of topical treatment, the ROP progression from stage 1 ROP to stage 2 or 3 with plus will be evaluated by serial ophthalmologic examinations. DISCUSSION: Propranolol eye micro-drops could represent an ideal strategy in counteracting ROP, because it is definitely safer than oral administration, inexpensive and an easily affordable treatment. Establishing the optimal dosage and treatment schedule is to date a crucial issue. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02504944, registered on July 19, 2015, updated July 12, 2016. EudraCT Number 2014-005472-29.

Numerical assessment of a criterion for the optimal choice of the operative conditions in magnetic nanoparticle hyperthermia on a realistic model of the human head.

PURPOSE: This paper presents a numerical study aiming at assessing the effectiveness of a recently proposed optimisation criterion for determining the optimal operative conditions in magnetic nanoparticle hyperthermia applied to the clinically relevant case of brain tumours. MATERIALS AND METHODS: The study is carried out using the Zubal numerical phantom, and performing electromagnetic-thermal co-simulations. The Pennes model is used for thermal balance; the dissipation models for the magnetic nanoparticles are those available in the literature. The results concerning the optimal therapeutic concentration of nanoparticles, obtained through the analysis, are validated using experimental data on the specific absorption rate of iron oxide nanoparticles, available in the literature. RESULTS: The numerical estimates obtained by applying the criterion to the treatment of brain tumours shows that the acceptable values for the product between the magnetic field amplitude and frequency may be two to four times larger than the safety threshold of 4.85 × 10(8)A/m/s usually considered. This would allow the reduction of the dosage of nanoparticles required for an effective treatment. In particular, depending on the tumour depth, concentrations of nanoparticles smaller than 10 mg/mL of tumour may be sufficient for heating tumours smaller than 10 mm above 42 °C. Moreover, the study of the clinical scalability shows that, whatever the tumour position, lesions larger than 15 mm may be successfully treated with concentrations lower than 10 mg/mL. The criterion also allows the prediction of the temperature rise in healthy tissue, thus assuring safe treatment. CONCLUSIONS: The criterion can represent a helpful tool for planning and optimising an effective hyperthermia treatment.

Lung Ultrasound for Diagnosing Pneumothorax in the Critically Ill Neonate.

OBJECTIVES: To evaluate the accuracy of lung ultrasound for the diagnosis of pneumothorax in the sudden decompensating patient. STUDY DESIGN: In an international, prospective study, sudden decompensation was defined as a prolonged significant desaturation (oxygen saturation <65% for more than 40 seconds) and bradycardia or sudden increase of oxygen requirement by at least 50% in less than 10 minutes with a final fraction of inspired oxygen ≥0.7 to keep stable saturations. All eligible patients had an ultrasound scan before undergoing a chest radiograph, which was the reference standard. RESULTS: Forty-two infants (birth weight = 1531 ± 812 g; gestational age = 31 ± 3.5 weeks) were enrolled in 6 centers; pneumothorax was detected in 26 (62%). Lung ultrasound accuracy in diagnosing pneumothorax was as follows: sensitivity 100%, specificity 100%, positive predictive value 100%, and negative predictive value 100%. Clinical evaluation of pneumothorax showed sensitivity 84%, specificity 56%, positive predictive value 76%, and negative predictive value 69%. After sudden decompensation, a lung ultrasound scan was performed in an average time of 5.3 ± 5.6 minutes vs 19 ± 11.7 minutes required for a chest radiography. Emergency drainage was performed after an ultrasound scan but before radiography in 9 cases. CONCLUSIONS: Lung ultrasound shows high accuracy in detecting pneumothorax in the critical infant, outperforming clinical evaluation and reducing time to imaging diagnosis and drainage.

Ventilation strategies for preventing oxidative stress-induced injury in preterm infants with respiratory disease: an update.

Reactive oxygen and nitrogen species are produced by several inflammatory and structural cells of the airways. The lungs of preterm newborns are susceptible to oxidative injury induced by both reactive oxygen and nitrogen species. Increased oxidative stress and imbalance in antioxidant enzymes may play a role in the pathogenesis of inflammatory pulmonary diseases. Preterm infants are frequently exposed to high oxygen concentrations, infections or inflammation; they have reduced antioxidant defense and high free iron levels which enhance toxic radical generation. Multiple ventilation strategies have been studied to reduce injury and improve outcomes in preterm infants. Using lung protective strategies, there is the need to reach a compromise between satisfaction of gas exchange and potential toxicities related to over-distension, derecruitment of lung units and high oxygen concentrations. In this review, the authors summarize scientific evidence concerning oxidative stress as it relates to resuscitation in the delivery room and to the strategies of ventilation.

Neonatal morbidity after cesarean section before labor at 34(+0) to 38(+6) weeks: a cohort study.

OBJECTIVE: To describe morbidity in neonates born by cesarean section (CS) before labor between 34(+0) and 38(+6) weeks, stratified by gestational age. METHODS: Cohort study from five Italian tertiary care hospitals. Consecutive singleton pregnancies delivered by CS before labor between 34(+0) and 38(+6) weeks of gestation from January 2010 to August 2011 were included. Women in labor, with premature rupture of membranes, or with previous administration of steroids were excluded. The incidence of neonatal complication by gestational week was calculated. RESULTS: A total of 1135 cases were analyzed. Composite adverse neonatal outcomes, respiratory distress syndrome, transient tachypnea and use of continuous airway positive pressure decreased from 50%, 28%, 5% and 22% at 34 weeks of gestation, to 4.7%, 1.0%, 0.9% and 0.3% at 38 weeks of gestation. Multivariate analysis showed that the only variable independently associated with composite adverse neonatal outcome was gestational age at delivery (adjusted odds ratio 0.49; 95% confidence interval 0.39-0.61). CONCLUSIONS: The prevalence of neonatal complications in newborns delivered by CS before labor halves at each week of gestation from 34 to 38 weeks. Nonetheless complications, and mainly respiratory problems, are still present at early term gestation.

Revised recommendations concerning palivizumab prophylaxis for respiratory syncytial virus (RSV).

Respiratory Syncytial Virus infections are one of the leading causes of severe respiratory diseases that require hospitalization and, in some cases, intensive care. Once resolved, there may be respiratory sequelae of varying severity. The lack of effective treatments for bronchiolitis and the lack of vaccines for RSV accentuate the role of prevention in decreasing the impact of this disease. Prevention of bronchiolitis strongly relies on the adoption of environment and the hygienic behavior measures; an additional prophylactic effect may be offered, in selected cases, by Palivizumab, a humanized monoclonal antibody produced by recombinant DNA technology, able to prevent RSV infection by blocking viral replication.After many years the Italian Society of Neonatology, on the basis of the most recent scientific knowledge, has decided to revise recommendations for the use of palivizumab in the prevention of RSV infection.

Fresh Frozen Plasma Administration in the Neonatal Intensive Care Unit: Evidence-Based Guidelines.

Neonates receiving fresh frozen plasma (FFP) should do so according to evidence-based guidelines so as to reduce inappropriate use of this life-saving and costly blood product and to minimize associated adverse effects. The consensus-based uses of FFP in neonatology involve neonates with active bleeding and associated coagulopathy. However, because of limited and poor-quality evidence, considerable FFP utilization occurs outside these recommendations. In this review, we describe what we conclude are currently the best practices for the use of FFP in neonates, including interpreting neonatal coagulation tests and strategies for reducing unnecessary FFP transfusions.

Similar Occurrence of Febrile Episodes Reported in Non-Atopic Children at Three to Five Years of Age after Prebiotics Supplemented Infant Formula.

This is a follow up study of a multicenter randomised placebo-controlled trial in seven centres in five West European countries. The RCT assessed the effect of infant formula supplemented with a mixture of prebiotics (with neutral short-chain and long-chain oligosaccharides and pectin-derived acidic oligosaccharides) during infancy in term-born children (n=1130). In the follow-up study 672 children (60% of the study population) participated: 232 (56%) from the prebiotics group (PG), 243 (58%) from the control group (CG), and 197 (66%) from the non-randomised breast-fed group (BG). The primary outcome was the occurrence of febrile episodes at three to five years of age prospectively documented by the parents: in the PG 1.17 (interquartile range 0.50-2.08) episodes per year versus 1.20 (0.52-2.57) in the CG; and 1.48 (0.65-2.60) in the BG. This specific prebiotics mixture given during infancy in healthy non-atopic subjects does not decrease febrile episodes and therefore seems not to prevent infection between their third and fifth birthday.