Nasal intermittent positive pressure ventilation during less invasive surfactant administration in preterm infants: An open-label randomized controlled study.

INTRODUCTION: Approximately half of very preterm infants with respiratory distress syndrome (RDS) fail treatment with nasal continuous positive airway pressure (NCPAP) and need mechanical ventilation (MV). OBJECTIVES: Our aim with this study was to evaluate if nasal intermittent positive pressure ventilation (NIPPV) during less invasive surfactant treatment (LISA) can improve respiratory outcome compared with NCPAP. MATERIALS AND METHODS: We carried out an open-label randomized controlled trial at tertiary neonatal intensive care units in which infants with RDS born at 25+0-31+6 weeks of gestation between December 1, 2020 and October 31, 2022 were supported with NCPAP before and after surfactant administration and received NIPPV or NCPAP during LISA. The primary endpoint was the need for a second dose of surfactant or MV in the first 72 h of life. Other endpoints were need and duration of invasive and noninvasive respiratory supports, changes in SpO2/FiO2 ratio after LISA, and adverse effect rate. RESULTS: We enrolled 101 infants in the NIPPV group and 99 in the NCPAP group. The unadjusted odds ratio for the composite primary outcome was 0.873 (95% confidence interval: 0.456-1.671; p = .681). We found that the SpO2/FiO2 ratio was transiently higher in the LISA plus NIPPV than in the LISA plus NCPAP group, while adverse effects of LISA had similar occurrence in the two arms. CONCLUSIONS: The application of NIPPV or NCPAP during LISA in very preterm infants supported with NCPAP before and after surfactant administration had similar effects on the short-term respiratory outcome and are both safe. Our study does not support the use of NIPPV during LISA.

SARS-CoV-2 perinatal transmission and neonatal outcomes across four different waves of COVID-19 pandemic: A nationwide prospective cohort study from the Italian Society of Neonatology.

OBJECTIVES: To describe how SARS-CoV-2 infection at the time of delivery affected maternal and neonatal outcomes across four major waves of the COVID-19 pandemic in Italy. METHODS: This is a large, prospective, nationwide cohort study collecting maternal and neonatal data in case of maternal peripartum SARS-CoV-2 infection between February 2020 and March 2022. Data were stratified across the four observed pandemic waves. RESULTS: Among 5201 COVID-19-positive mothers, the risk of being symptomatic at delivery was significantly higher in the first and third waves (20.8-20.8%) than in the second and fourth (13.2-12.2%). Among their 5284 neonates, the risk of prematurity (gestational age <37 weeks) was significantly higher in the first and third waves (15.6-12.5%). The risk of intrauterine transmission was always very low, while the risk of postnatal transmission during rooming-in was higher and peaked at 4.5% during the fourth wave. A total of 80% of positive neonates were asymptomatic. CONCLUSION: The risk of adverse maternal and neonatal outcomes was significantly higher during the first and third waves, dominated by unsequenced variants and the Delta variant, respectively. Postnatal transmission accounted for most neonatal infections and was more frequent during the Omicron period. However, the paucity of symptoms in infected neonates should lead us not to separate the dyad.

Continuous Fentanyl Infusion in Newborns with Hypoxic-Ischemic Encephalopathy Treated with Therapeutic Hypothermia: Background, Aims, and Study Protocol for Time-Concentration Profiles.

Therapeutic hypothermia (TH) is the standard of care for newborns with moderate to severe hypoxic-ischemic encephalopathy (HIE). Discomfort and pain during treatment are common and may affect the therapeutic efficacy of TH. Opioid sedation and analgesia (SA) are generally used in clinical practice, and fentanyl is one of the most frequently administered drugs. However, although fentanyl's pharmacokinetics (PKs) may be altered by hypothermic treatment, the PK behavior of this opioid drug in cooled newborns with HIE has been poorly investigated. The aim of this phase 1 study protocol (Trial ID: FentanylTH; EUDRACT number: 2020-000836-23) is to evaluate the fentanyl time-concentration profiles of full-term newborns with HIE who have been treated with TH. Newborns undergoing TH receive a standard fentanyl regimen (2 mcg/Kg of fentanyl as a loading dose, followed by a continuous infusion-1 mcg/kg/h-during the 72 h of TH and subsequent rewarming). Fentanyl plasma concentrations before bolus administration, at the end of the loading dose, and 24-48-72-96 h after infusion are measured. The median, maximum, and minimum plasma concentrations, together with drug clearance, are determined. This study will explore the fentanyl time-concentration profiles of cooled, full-term newborns with HIE, thereby helping to optimize the fentanyl SA dosing regimen during TH.

Neurodevelopmental outcomes of very low birth weight preterms in preschool childhood: a prospective cohort study.

BACKGROUND: Preterm birth is a risk factor for a child's neurological development. Preterm children have unusual neurodevelopmental profiles with executive, visual-motor functions, fine and gross motor skills, language and behavior that affect learning. In this study, we analyzed the neurodevelopmental outcomes of a cohort of very low birth weight infants admitted to the Treviso Neonatal Intensive Care Unit (NICU) between 2014 and 2016 and followed up to preschool childhood. METHOD: This is a prospective cohort study. Infants were followed at birth and after NICU discharge at two- and four-year follow-ups. The two-year assessment was conducted with Bayley III, and at four years with the Wechsler Preschool and Primary Scale of Intelligence - III scales and Movement Assessment Battery for Children - 2. RESULTS: The cohort consisted of 207 subjects with a mean gestational age of 28.9 weeks, and a mean birth weight of 1097.2 g. At two years of age, children without disabilities were 90 (59.6%), those with minor disabilities 47 (31.1%), and those with major disabilities 14 (9.3%); at four years, 58.4% of children without previous disabilities, presented problems with verbal tests and manual dexterity: aiming, grasping and balance at movement assessment. There was significant alteration in processing speed (p < 0.001). Furthermore, there was a strong correlation between processing speed and manual dexterity (p < 0.001) and between processing speed and aiming and grasping (p = 0.0059). CONCLUSIONS: We found that more than half the children free of disability at two years, at four years had deficit often involving the oculo-motor coordination and processing speed. These motor profile alterations limit the expression of cognitive abilities and the achievement of expected school performance, thus resulting in behavioral disorders, typical of preterm children. Early professional follow-up could improve the expected educational outcomes.

A Single Dose of Oral Sucrose Is Enough to Control Pain During Venipuncture: A Randomized Controlled Trial.

Sucrose is effective in reducing pain during minor procedures in neonates. We evaluated whether a second dose of sucrose was more effective than a single dose during venipuncture. We performed a randomised, double-blind, controlled trial at the NICU of Padua Hospital (August 2016-October 2017). We randomised 72 preterm infants undergoing venipuncture for routine test to a control group, which received a single standard dose of sucrose 2' before the procedure and a placebo 30″ after the venipuncture, and an experimental group in which they received two doses of 24% sucrose 2' before and 30″ after the venipuncture. No difference in pain perception was found between the groups at 30″, 60″ and 120″. In conclusion, we do not recommend a second dose of sucrose during venipuncture in prematures.

Neonatal Early Onset Sepsis: Impact of Kaiser Calculator in an Italian Tertiary Perinatal Center.

BACKGROUND: Suspected early-onset sepsis (EOS) results in antibiotic treatment and blood withdraw of a substantial number of neonates who are uninfected. We evaluated if the EOS calculator can reduce antibiotic exposure and invasive procedures for suspected EOS in term and late preterm neonates, without any significant increase in adverse outcomes. METHODS: The proportion of EOS risk in neonates ≥35 weeks gestation exposed to antibiotics, intensive monitoring and blood withdrawal was compared between a baseline period (January 2018-May 2018), when Centers for Disease Control guidelines approach was used, and a post-EOS calculator-implementation period (June 2018-December 2019). RESULTS: We included 4363 newborn infants with gestational age ≥35 weeks, respectively 824 in baseline period and 3539 in the EOS calculator period. Among them, 1021 (23.4%) infants presented risk factors for neonatal sepsis. There was a halving in empirical antibiotics exposure: 3% in the baseline and 1.4% in the post-EOS-implementation period, P < 0.05. Blood culture and laboratory evaluations had fallen from 30.6% to 15.4% (P < 0.05). Close monitoring of vital parameters decreased from 25.4% to 4.8% (P < 0.05). The number of antibiotic days per 100 live births decreased from 15.05 to 6.36 days (P <0.05). The incidence of culture-confirmed sepsis and clinical sepsis was very low in 2 periods. Only one infant identified at low-risk by Kaiser calculator at birth developed symptoms after 12 h from birth. We had no readmissions for EOS. CONCLUSIONS: Application of the EOS calculator more than halved the burden of intensive monitoring and antibiotic exposure, without compromising safety in a population with a relatively low incidence of culture-proven EOS and good access to follow-up care.

Fentanyl analgesia in asphyxiated newborns treated with therapeutic hypothermia.

INTRODUCTION: Therapeutic hypothermia is the standard care for asphyxiated newborns. Discomfort and pain during treatment are common and may affect therapeutic efficacy of hypothermia. Opioid analgosedation is commonly used in the clinical setting, but its effects in the cooled newborns is poorly investigated. OBJECTIVE: The aim of this study was to assess the safety of fentanyl analgosedation during therapeutic hypothermia, by evaluating severe adverse effects and possible correlation with the neurodevelopmental outcome. METHODS: We analyzed asphyxiated newborns treated with hypothermia receiving fentanyl intravenous infusion (years 2013-2018). Severe neurodevelopmental outcome was defined as cerebral palsy or Griffith's developmental quotient <70 or major sensorineural deficit. Severe brain lesions were defined as cortical or/and basal ganglia extensive involvement. RESULTS: Fentanyl cumulative dose was variable (61.7 ± 18.5 µg/kg; range 34.3-120.3 µg/kg) among 45 enrolled patients. Respiratory depression was recorded in 13.3% cases of 30 spontaneously breathing patients. Severe brain lesions and severe neurodevelopmental disability were found in 24.4 and 11.1% of all included cases, respectively. Higher cumulative fentanyl dose was not associated with poor outcome. CONCLUSIONS: Fentanyl treatment during therapeutic hypothermia does not negatively affect the neurodevelopmental outcome, thus on the contrary, it may contribute to ameliorate neuroprotection in the asphyxiated cooled newborns.

Surfactant Treatment of Late Preterm Infants during Emergency Transport: A Retrospective, Observational Study.

BACKGROUND: In late preterm infants born in nontertiary hospitals, the occurrence of respiratory distress syndrome requires postnatal transport. This study aimed to investigate the impact of the timing of surfactant administration in late preterm infants needing postnatal transport. METHODS: This is a retrospective study evaluating surfactant administration in late preterm infants during emergency transports by the Eastern Veneto Neonatal Emergency Transport Service between January 2005 and December 2019. The outcome measures included short-term clinical complications, stabilization time, oxygen concentration, duration of mechanical ventilation and noninvasive respiratory support, length of hospital stay, bronchopulmonary dysplasia, intraventricular hemorrhage, and sepsis. RESULTS: Surfactant was administered to 155/303 neonates (51.1%) at 3 different time points: at a referring hospital (50 neonates), when the transport team arrived (25 neonates), or at a referral hospital (80 neonates). Stabilization time was longer in neonates receiving surfactant by the transport team (adjusted mean difference 17 min, 95% confidence interval, 4-29 min; p = 0.01). Decrease in oxygen concentrations during the transport was larger in neonates receiving surfactant at a referring hospital (adjusted mean difference -11%, 95% confidence interval, -15 to -3%; p = 0.01). The other outcome measures were not statistically different according to the timing of surfactant administration. CONCLUSIONS: In late preterm infants with respiratory distress needing postnatal transfer, stabilization time was longer when the first surfactant was administered by the transport team, but such delay did not affect safety and clinical outcomes.

Jacobsen syndrome and neonatal bleeding: report on two unrelated patients.

INTRODUCTION: In 1973, Petrea Jacobsen described the first patient showing dysmorphic features, developmental delay and congenital heart disease (atrial and ventricular septal defect) associated to a 11q deletion, inherited from the father. Since then, more than 200 patients have been reported, and the chromosomal critical region responsible for this contiguous gene disorder has been identified. PATIENTS' PRESENTATION: We report on two unrelated newborns observed in Italy affected by Jacobsen syndrome (JBS, also known as 11q23 deletion). Both patients presented prenatal and postnatal bleeding, growth and developmental delay, craniofacial dysmorphisms, multiple congenital anomalies, and pancytopenia of variable degree. Array comparative genomic hybridization (aCGH) identified a terminal deletion at 11q24.1-q25 of 12.5 Mb and 11 Mb, in Patient 1 and 2, respectively. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletion for Patient 1; parents of Patient 2 refused further genetic investigations. CONCLUSIONS: Present newborns show the full phenotype of JBS including thrombocytopenia, according to their wide 11q deletion size. Bleeding was particularly severe in one of them, leading to a cerebral hemorrhage. Our report highlights the relevance of early diagnosis, genetic counselling and careful management and follow-up of JBS patients, which may avoid severe clinical consequences and lower the mortality risk. It may provide further insights and a better characterization of JBS, suggesting new elements of the genotype-phenotype correlations.

Ibuprofen enantiomers in premature neonates with patent ductus arteriosus: Preliminary data on an unexpected pharmacokinetic profile of S(+)-ibuprofen.

S(+)-ibuprofen (S-IBU) and R(-)-ibuprofen (R-IBU) concentrations were measured in 16 neonates with patent ductus arteriosus during a cycle of therapy (three intravenous doses of 10-5-5 mg kg-1 at 24-h intervals), at the end of the first infusion and 6, 24, 48, and 72 h later. Data were analyzed with a PK model that included enantiomer elimination rate constants and the R- to S-IBU conversion rate constant. The T½ of S-IBU in the newborn was much longer than in adults (41.8 vs. ≈2 h), whereas the T½ of R-IBU appeared to be the same (2.3 h). The mean fraction of R- to S-IBU conversion was much the same as in adults (0.41 vs. ≈0.60). S-IBU concentrations measured 6 h after the first dose were higher than at the end of the infusion in 10 out of 16 cases, and in five cases, they remained higher even after 24 h. This behavior is unprecedented and may be attributable to a rapid R-to-S conversion overlapping with a slow S-IBU elimination rate. In 13 of the 16 neonates, S-IBU concentrations at 48 and/or 72 h were lower than expected, probably due to the rapid postnatal maturation of the newborn's liver metabolism.

Early onset food protein-induced enterocolitis syndrome in two breastfed newborns masquerading as surgical diseases: case reports and literature review.

Background: Food protein-induced enterocolitis syndrome (FPIES) is a non-immunoglobulin E cell-mediated gastrointestinal food allergy that primarily presents in infancy, as early as the first hours of life. FPIES is often misdiagnosed as sepsis, severe gastroenteritis, abdominal surgical emergency or even metabolic, neurologic, or cardiac disorders.Methods: We report two neonatal cases of cow's milk protein (CMP)-induced FPIES masquerading as surgical diseases. Our purpose is to highlight the diagnostic difficulties in FPIES in this age group and to provide further evidence of the important role played by the prenatal environment in the development of allergic diseases.Results: Case 1 is a 2-day-old boy born at 35th + 5 weeks of gestation admitted to our Neonatal Intensive Care Unit (NICU) for bloody diarrhea who started presenting apnea, crying, pallor, jaundice, and abdominal tenderness. Case 2 is a 3-day-old boy born at 38th +5 weeks of gestation admitted to our NICU for repeated bilious vomiting. Both patients were administered infant formula in the first hours of life, thereafter they received only breast milk. In both cases, CMP allergy was finally suspected and an extensively hydrolyzed formula was administered with the resolution of symptoms. A diagnosis of CMP-induced FPIES was made.Conclusions: FPIES is a heterogeneous disorder. Severe forms of FPIES could be mistaken for surgical diseases, such as necrotizing enterocolitis. A trial of food elimination should be considered whenever diagnostic tests are inconclusive. FPIES must be suspected even in breastfed infants.

Perinatal palliative care: a dedicated care pathway.

OBJECTIVE: Ensure access to perinatal palliative care (PnPC) to all eligible fetuses/infants/parents. DESIGN: During 12 meetings in 2016, a multidisciplinary work-group (WG) performed literature review (Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method was applied), including the ethical and legal references, in order to propose shared care pathway. SETTING: Maternal-Infant Department of Padua's University Hospital. PATIENTS: PnPC eligible population has been divided into three main groups: extremely preterm newborns (first group), newborns with prenatal/postnatal diagnosis of life-limiting and/or life-threatening disease and poor prognosis (second group) and newborns for whom a shift to PnPC is appropriate after the initial intensive care (third group). INTERVENTIONS: The multidisciplinary WG has shared care pathway for these three groups and defined roles and responsibilities. MAIN OUTCOME MEASURES: Prenatal and postnatal management, symptom's treatment, end-of-life care. RESULTS: The best care setting and the best practice for PnPC have been defined, as well as the indications for family support, corpse management and postmortem counselling, as well suggestion for conflicts' mediation. CONCLUSIONS: PnPC represents an emerging field within the paediatric palliative care and calls for the development of dedicated shared pathways, in order to ensure accessibility and quality of care to this specific population of newborns.

Summary of the Key Concepts on How to Develop a Perinatal Palliative Care Program.

Purpose of review: The aim of this study is to assess the most significant Perinatal Palliative Care (PnPC) development projects in the literature and summarize the shared key principles. Recent findings: PnPC is a new concept in neonatal intensive care approach. Advancements in perinatal diagnostics and medical technology have changed the landscape of the perinatal world. The threshold of viability continues to decrease, and diagnostic information is available earlier in pregnancy and more rapidly at the bedside; overall outcomes continue to improve. This rapid technological improvement brings ethical debates on the quality of life of patients with life-limiting and life-threatening conditions and the need to involve the family in the decision-making process, according to their wishes and cultural beliefs. Although the Perinatal Hospice concept was developed in the 1980s in the US, the first recommendations on how to develop a PnPC pathway were published in the early 2000s. We considered the most relevant position statements or guidelines on PnPC published in the last two decades. Some of them were more pertinent to pediatrics but still useful for the fundamental concepts and PnPC project's development. Summary: Health care providers and institutions are encouraged to develop PnPC programs, which have the goal of maximizing the quality of life of infants with non-curable conditions. These may generally include the following: a formal prenatal consultation; development of a coordinated birth plan between obstetrician, newborn care, and family; access to other neonatal and pediatric specialties, as needed; comfort palliative care during the prenatal, birth, and postnatal periods; and psychosocial and spiritual support for families, siblings, and staff.

COnsensus on Pediatric Pain in the Emergency Room: the COPPER project, issued by 17 Italian scientific societies.

In the pediatric setting, management of pain in the emergency department - and even in common care - is a challenging exercise, due to the complexity of the pediatric patient, poor specific training of many physicians, and scant resources.A joint effort of several Italian societies involved in pediatrics or in pain management has led to the definition of the PIPER group and the COPPER project. By applying a modified Delphi method, the COPPER project resulted in the definition of 10 fundamental statements. These may represent the basis for improving the correct management of children pain in the emergency department.

Repeating a dose of sucrose for heel prick procedure in preterms is not effective in reducing pain: a randomised controlled trial.

Oral sucrose is included in almost all recommendations for treatment of pain in newborns, but evidence if multiple doses might be more effective than a single standard dose is lacking. We designed a single-centre, double-blind, randomised, controlled trial. We enrolled preterm infants needing the heel prick procedure. Each enrolled infant was randomised to receive a single standard dose of sucrose 2 min before or a double dose of sucrose 2 min before, and 30 s after heel prick. Primary outcome was the efficacy of the two interventions tested by the premature infant pain profile-PIPP scale obtained at 30 s, 60 s, and 120 s after heel prick. Secondary outcome was the evaluation of the concordance between the PIPP scale and other pain scores more feasible in clinical practice. Seventy-two infants were randomised. No difference in pain perception as measured by the PIPP scale was found between the groups: median PIPP values 4.0(IQR 3.0-4.0) vs 3.0(IQR 3.0-4.0) at baseline; 6.0(IQR 5.0-10.0) vs 6.0(IQR 4.0-8.5) at 30 s; 6.0(IQR 4.0-7.0) vs 5.0(IQR 4.0-8.5) at 60 s and 5.0(IQR 4.0-7.0) vs 5.0(IQR 4.0-7.5) at 2 min, in the experimental and standard treatment groups, respectively (p = 0.9020). There was no correlation between PIPP scores and other pain scales.Conclusion: We do not recommend doubling the dose during heel prick.What is Known:• Oral sucrose is included in almost all international position papers and recommendations for the treatment of mild to moderate pain in newborns, associated with non-nutritive sucking and facilitated tucking• Premature infant pain profile (PIPP) scale is the gold standard for evaluation of pain in preterms but it is difficult to use in clinical practiceWhat is New:• Repeating a dose of 24% sucrose is not effective in reducing pain during the recovery phase of a skin breaking procedure• Other pain scales, easier to use in clinical practice, are not comparable with PIPP for the evaluation of procedural pain in preterms.

Patent ductus arteriosus in preterm infants born at 23-24 weeks' gestation: Should we pay more attention?

BACKGROUND: Infants born at 23-24 weeks' gestation have the highest risk of developing a hemodynamically significant patent ductus arteriosus (hsPDA), that is refractory to pharmacological closure requiring surgical ligation. Thus, these patients might have the greatest benefits from hsPDA closure, although previous studies on PDA closure were not focused on this population. AIM: To compare the occurrence of hsPDA, failure rate of the first course of ibuprofen in closing hsPDA, and need of surgical closure in infants born at 23+0-24+6 weeks' gestation to those in infants born at 25+0-28+6 weeks' gestation. STUDY DESIGN: This is a retrospective multicenter study including infants born at 23+0-28+6 weeks of gestation admitted to the neonatal care units from January 2013 to December 2017. All infants underwent echocardiographical assessment for hsPDA diagnosis and eventually pharmacological treatment, and surgical closure. RESULTS: We studied a total of 842 infants of which 562 (67%) developed a PDA. Among those with PDA, 511 (91%) received a pharmacological treatment for a hsPDA. We found that a hsPDA occurred in 70% (106/151) of infants born at 23-24 weeks and in 59% (405/691) of infants born at 25-28 weeks of gestation (P < 0.001). Failure of closure with the first-treatment cycle (69 vs. 40%; P < 0.001) and need of surgical closure (19 vs 10%) were more frequent (P < 0.011) in infants born at 23-24 than 25-28 gestational weeks. Paracetamol vs. ibuprofen treatment and gestational age of 23-24 versus 25-28 weeks increased closure failure, while less severe RDS and maternal clinical chorioamnionitis decreased it. CONCLUSIONS: Among extremely preterm infants, infants born at 23-24 weeks of gestation have the highest risk of developing a hsPDA refractory to pharmacological treatment requiring surgical closure. Our findings support the need of individualized more careful strategies for hsPDA management in this special population.