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The primary purpose of this practical overview is to provide a practical update on appropriate nutritional strategies to improve growth in preterm infants. Current recommendations for improving preterm growth concern both macronutrients and micronutrients, with tailored nutrition since the first days of life, particularly when fetal growth restriction has been reported. Human milk is undoubtedly the best nutrition for all newborns, but, in some populations, if not adequately fortified, it does not adequately support their growth. In all preterms, growth should be correctly monitored weekly to intercept a negative trend of growth and implement nutritional strategies to avoid growth restriction. Similarly, growth should be accurately supported and monitored after discharge to improve long-term health consequences., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 De Rose, Maggiora, Maiocco, Morniroli, Vizzari, Tiraferri, Coscia, Cresi, Dotta, Salvatori and Giannì.)

Background: Particulate contamination due to infusion therapy (administration of parenteral nutrition and medications) carries a potential health risk for infants in neonatal intensive care units (NICUs). This particulate consists of metals, drug crystals, glass fragments, or cotton fibers and can be generated by drug packaging, incomplete reconstitution, and chemical incompatibilities. In-line filters have been shown to remove micro-organisms, endotoxin, air, and particles in critically ill adults and older infants, but its benefits in newborn remain to be demonstrated. Moreover, 50% of inflammatory episodes in the setting of NICUs are blood culture-negative. These episodes could be partly related to the presence of particles in the infusion lines., Methods: A multicenter randomized single-blind controlled trial was designed. All infants admitted to NICUs for which prolonged infusion therapy is expected will be enrolled in the study and randomized to the Filter or Control arm. All patients will be monitored until discharge, and data will be analyzed according to a "full analysis set." The primary outcome is the frequency of patients with at least one sepsis-like event, defined by any association of suspected sepsis symptoms with a level of c-reactive protein (CRP) > 5 mg/L in a negative-culture contest. The frequency of sepsis, phlebitis, luminal obstruction, and the duration of mechanical ventilation and of catheter days will be evaluated as secondary outcomes. The sample size was calculated at 368 patients per arm., Discussion: This is the first multicenter randomized control trial that compares in-line filtration of parenteral nutrition and other intravenous drugs to infusion without filters. Sepsis-like events are commonly diagnosed in clinical practice and are more frequent than sepsis in a positive culture contest. The risk of these episodes in the target population is estimated at 30-35%, but this data is not confirmed in the literature. If the use of in-line filters results in a significant decrease in sepsis-like events and/or in any other complications, the use of in-line filters in all intravenous administration systems may be recommended in NICUs., Trial Registration: ClinicalTrials.gov, NCT05537389, registered on 12 September 2022 ( https://classic., Clinicaltrials: gov/ct2/show/results/NCT05537389?view=results )., (© 2024. The Author(s).)

Introduction: Breastfeeding naturally enables the coordination of sucking, swallowing, and respiration patterns for safe feeding. When breastfeeding is not possible a feeding device that releases milk in response to intra-oral vacuum could potentially offer improved coordination of sucking, swallowing, and breathing patterns compared to conventional devices. The aim of the study is to evaluate the effect of a valved infant-bottle with an ergonomic teat compared to a standard infant-bottle., Methods: This unblinded randomized controlled trial focused on late preterm infants fed by bottle for at least three meals over the day, admitted to the Neonatal Unit of Sant'Anna Hospital (Turin, Italy). Infants were randomized to be fed with a valved infant-bottle with an ergonomic teat (B-EXP arm) or with a standard infant-bottle (B-STD arm). Monitoring included a simultaneous synchronized recording of sucking, swallowing and respiration. The main outcome was the swallowing/breathing ratio., Results: Forty infants (20 B-EXP arm; 20 B-STD arm) with a median gestational age of 35.0 weeks (IQR 35.0-36.0 weeks) completed the study. Four infants were censored for the presence of artifacts in the polygraphic traces. The median swallowing/breathing ratio was 1.11 (1.03-1.23) in the B-EXP arm and 1.75 (1.21-2.06) in the B-STD ( p  = .003). A lower frequency of swallowing events during the inspiratory phase of breathing was observed in B-EXP arm compared with B-STD arm ( p  = 0.013)., Discussion: The valved infant-bottle with an ergonomic teat improves the coordination of sucking-swallowing-respiration and limits the risk of inhalation reducing the frequency of swallowing during the inspiratory phase., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Cresi, Maggiora, Capitanio, Bovio, Borla, Cosimi, Enrietti, Faggiano, Loro, Rovei, Runfola, Scrufari, Taglianti, Vignali, Peila and Coscia.)

Importance: Respiratory distress syndrome and feeding intolerance are common conditions that are often associated with preterm infants. Showing similar efficacy, nasal continuous positive airway pressure (NCPAP) and heated humidified high-flow nasal cannula (HHHFNC) are the most widespread noninvasive respiratory support (NRS) in neonatal intensive care units, but their effect on feeding intolerance is unknown., Objective: To evaluate the effect of NCPAP vs HHHFNC on high-risk preterm infants with respiratory distress syndrome., Design, Setting, and Participants: This multicenter randomized clinical trial involved infants who were born in 1 of 13 neonatal intensive care units in Italy between November 1, 2018, and June 30, 2021. Preterm infants with a gestational age of 25 to 29 weeks, who were suitable for enteral feeding and who proved to be medically stable on NRS for at least 48 hours were enrolled in the study within the first week of life and randomized to receive either NCPAP or HHHFNC. Statistical analysis was performed according to the intention-to-treat approach., Intervention: NCPAP or HHHFNC., Main Outcomes and Measures: The primary outcome was the time to full enteral feeding (FEF), defined as an enteral intake of 150 mL/kg per day. Secondary outcomes were the median daily increment of enteral feeding, signs of feeding intolerance, effectiveness of the assigned NRS, peripheral oxygen saturation (SpO2)-fraction of inspired oxygen (FIO2) ratio at changes of NRS, and growth., Results: Two-hundred forty-seven infants (median [IQR] gestational age, 28 [27-29] weeks; 130 girls [52.6%]) were randomized to the NCPAP group (n = 122) or the HHHFNC group (n = 125). There were no differences in the primary and secondary nutritional outcomes between the 2 groups. The median time to reach FEF was 14 days (95% CI, 11-15 days) in the NCPAP group and 14 days (95% CI, 12-18 days) in the HHHFNC group, and similar results were observed in the subgroup of infants with less than 28 weeks' gestation. On the first NRS change, higher SpO2-FIO2 ratio (median [IQR], 4.6 [4.1-4.7] vs 3.7 [3.2-4.0]; P < .001) and lower rate of ineffectiveness (1 [4.8%] vs 17 [73.9%]; P < .001) were observed in the NCPAP vs HHHFNC group., Conclusions and Relevance: This randomized clinical trial found that NCPAP and HHHFNC had similar effects on feeding intolerance, despite different working mechanisms. Clinicians may tailor respiratory care by selecting and switching between the 2 NRS techniques on the basis of respiratory effectiveness and patient compliance, without affecting feeding intolerance., Trial Registration: ClinicalTrials.gov Identifier: NCT03548324.

Background: The aim of this systematic review is to analyze the available literature on the introduction of allergenic foods and gluten among preterm infants., Methods: A systematic review of published studies concerning the introduction of gluten and allergenic foods in preterm infants was performed on PubMed and on the Cochrane Library., Results: Of the 174 PubMed results, 15 papers were considered suitable for the review. A total of 83 records were identified through the Cochrane Library search; eight papers were included in the review. Additional papers were identified from the reference lists of included studies. A secondary search was conducted on the same databases to find recommendations and advice regarding healthy full-term infants that could be translated to preterm infants. Therefore, 59 additional papers were included in the review., Conclusions: Current guidelines for the introduction of solid food cannot be directly transposed to preterm infants. Further research is needed to provide evidence-based guidelines regarding weaning in preterm infants. To date, we can suggest that in preterm infants allergenic foods and gluten may be introduced when complementary feeding is started, any time after 4 months of corrected age, avoiding delayed introduction and irrespective of infants' relative risk of developing allergy. Avoiding large amounts of gluten during the first few weeks after gluten introduction and during infancy is advised, despite limited evidence to support this recommendation.

Background: Non-invasive ventilation (NIV) has been recommended as the best respiratory support for preterm infants with respiratory distress syndrome (RDS). However, the best NIV technique to be used as first intention in RDS management has not yet been established. Nasal intermittent positive pressure ventilation (NIPPV) may be synchronized (SNIPPV) or non-synchronized to the infant's breathing efforts. The aim of the study is to evaluate the short-term effects of SNIPPV vs. NIPPV on the cardiorespiratory events, trying to identify the best ventilation modality for preterm infants at their first approach to NIV ventilation support., Methods: An unmasked randomized crossover study with three treatment phases was designed. All newborn infants < 32 weeks of gestational age with RDS needing NIV ventilation as first intention or after extubation will be consecutively enrolled in the study and randomized to the NIPPV or SNIPPV arm. After stabilization, enrolled patients will be alternatively ventilated with two different techniques for two time frames of 4 h each. NIPPV and SNIPPV will be administered with the same ventilator and the same interface, maintaining continuous assisted ventilation without patient discomfort. During the whole duration of the study, the patient's cardiorespiratory data and data from the ventilator will be simultaneously recorded using a polygraph connected to a computer. The primary outcome is the frequency of episodes of oxygen desaturation. Secondary outcomes are the number of the cardiorespiratory events, FiO 2 necessity, newborn pain score evaluation, synchronization index, and thoracoabdominal asynchrony. The calculated sample size was of 30 patients., Discussion: It is known that NIPPV produces a percentage of ineffective acts due to asynchronies between the ventilator and the infant's breaths. On the other hand, an ineffective synchronization could increase work of breathing. Our hypothesis is that an efficient synchronization could reduce the respiratory work and increase the volume per minute exchanged without interfering with the natural respiratory rhythm of the patient with RDS. The results of this study will allow us to evaluate the effectiveness of the synchronization, demonstrating whether SNIPPV is the most effective non-invasive ventilation mode in preterm infants with RDS at their first approach to NIV ventilation., Trial Registration: ClinicalTrials.gov NCT03289936 . Registered on September 21, 2017.

Background: Enteral feeding induces mesenteric hemodynamic changes in preterm infants, which may vary according to the milk used. Our aim in this study was to evaluate changes of splanchnic regional oxygenation (rSO 2 S) measured by near-infrared spectroscopy (NIRS) in infants fed with mother's own milk (MOM), fortified human milk (FHM), or preterm formula (PTF)., Methods: Infants born at 25-31 weeks of gestational age (n = 54) received a bolus of MOM, FHM, or PTF. rSO 2 S and splanchnic fractional oxygen extraction ratio (FOES) were recorded 60 min before (T 0 ), and 30 min (T 1 ) and 120 min (T 2 ) after the beginning of bolus feeding., Results: In the MOM group, rSO 2 S and FOES did not change during the study period. In the FBM group, rSO 2 S decreased from T 0 to T 1 and increased from T 1 to T 2 , while FOES changed in reverse. In the PTF group, rSO 2 S decreased from T 0 to T 1 and from T 1 to T 2 , while FOES changed in reverse., Conclusions: Splanchnic oxygenation was not affected by MOM feeding, was transiently decreased by FBM feeding, and was persistently decreased by PTF. These results suggest that preterm infants who received PTF has higher splanchnic tissue oxygen extraction compared to those who received MOM or FBM., Impact: Human milk feeding is associated to a lower splanchnic energy expenditure than preterm formula feeding. Fortified human milk transiently increases splanchnic energy expenditure. Preterm formula should be used only in the absence of human milk.

Background/aims: Combined multichannel intraluminal impedance and pH monitoring (MII/pH) is considered the most accurate test to detect gastroesophageal reflux (GER), however lacking reference values. We aim to determine reference values for the pediatric population and to correlate these values with age and postprandial/fasting period., Methods: We evaluated MII/pH traces from patients (newborns, infants, and children) admitted to 3 Italian hospitals and who underwent MII/ pH for suspected GER disease. Patients with MII/pH traces that showed significant symptom-reflux associations and/or a pathological reflux index (> 6% for newborns and infants, > 3% for children) were excluded. Traces were analysed in their entirety, and in the postprandial period (first hour after a meal) and the fasting period (the following hours before the next meal) separately., Results: A total of 195 patients (46 newborns, 83 infants, and 66 children) were included. Age positively correlated with frequency of acidic GER events ( r = 0.37, P < 0.05) and negatively associated with weakly acidic GER events ( r = 0.46, P < 0.05)., Conclusions: This study describes the distribution of MII/pH values in a pediatric population with normally acidic GER exposure and no significant association between GER events and symptoms. These MII/pH values may be used as reference values in clinical practice for a corrected GER disease diagnosis in the pediatric population.

Background: Feeding intolerance is a frequent diagnosis in very preterm infants. As seen in the FortiLat trial, human milk fortification with the new donkey milk-derived human milk fortifier (DF) seems to improve feeding tolerance in these infants. The aim of this study was to evaluate the effects of using the DF compared with bovine milk-derived fortifier (BF) on gastroesophageal reflux (GER) in very low birth weight (VLBW) infants., Methods: Over a total of 156 preterm infants were enrolled into the FortiLat trial (GA <32 weeks and birth weight <1500 g) and randomized into the BF arm or DF arm, and we selected all infants with clinical signs of GER and cardiorespiratory (CR) symptoms. All the infants underwent CR and multichannel intraluminal impedance and pH (MII/pH) monitoring associated with gastric ultrasound to evaluate GER and gastric emptying time., Results: 10 infants were enrolled, and 5 were in the DF arm. At MII/pH, infants enrolled into the DF arm showed a lower GER frequency than BF arm infants ( p = 0.036). Half gastric emptying time was similar in DF and BF arm infants ( p = 0.744)., Conclusion: The use of donkey-derived human milk fortifier reduced the GER frequency and consequently should be recommended in infants with feeding intolerance.

Objective: Ensuring cardiorespiratory (CR) stability is essential for a safe discharge. The aim of this study was to assess the impact of a new pre-discharge protocol named CORE on the risk of hospital readmission (RHR). Methods: Preterm infants admitted in our NICU between 2015 and 2018 were randomly assigned to CORE (exposed) or to standard (not-exposed) discharge protocol. CORE included 24 h-clinical observation, followed by 24 h-instrumental CR monitoring only for high-risk infants. RHR 12 months after discharge and length of stay represent the primary and secondary outcomes, respectively. Results: Three hundred and twenty three preterm infants were enrolled. Exposed infants had a lower RHR (log-rank p < 0.05). The difference was especially marked 3 months after discharge (9.09 vs. 21.6%; p = 0.004). The hospital length of stay in exposed and not-exposed infants was 39(26-58) and 43(26-68) days, respectively ( p = 0.16). Conclusions: The CORE protocol could help neonatologists to define the best timing for discharge reducing RHR without lengthening hospital stay., (Copyright © 2020 Cresi, Cocchi, Maggiora, Pirra, Logrippo, Ariotti, Peila, Bertino and Coscia.)

Background: Respiratory distress syndrome (RDS) and feeding intolerance are common conditions in preterm infants and among the major causes of neonatal mortality and morbidity. For many years, preterm infants with RDS have been treated with mechanical ventilation, increasing risks of acute lung injury and bronchopulmonary dysplasia. In recent years non-invasive ventilation techniques have been developed. Showing similar efficacy and risk of bronchopulmonary dysplasia, nasal continuous positive airway pressure (NCPAP) and heated humidified high-flow nasal cannula (HHHFNC) have become the most widespread techniques in neonatal intensive care units. However, their impact on nutrition, particularly on feeding tolerance and risk of complications, is still unknown in preterm infants. The aim of the study is to evaluate the impact of NCPAP vs HHHFNC on enteral feeding and to identify the most suitable technique for preterm infants with RDS., Methods: A multicenter randomized single-blind controlled trial was designed. All preterm infants with a gestational age of 25-29 weeks treated with NCPAP or HHHFNC for RDS and demonstrating stability for at least 48 h along with the compliance with inclusion criteria (age less than 7 days, need for non-invasive respiratory support, suitability to start enteral feeding) will be enrolled in the study and randomized to the NCPAP or HHHFNC arm. All patients will be monitored until discharge, and data will be analyzed according to an intention-to-treat model. The primary outcome is the time to reach full enteral feeding, while parameters of respiratory support, feeding tolerance, and overall health status will be evaluated as secondary outcomes. The sample size was calculated at 141 patients per arm., Discussion: The identification of the most suitable technique (NCPAP vs HHHFNC) for preterm infants with feeding intolerance could reduce gastrointestinal complications, improve growth, and reduce hospital length of stay, thus improving clinical outcomes and reducing health costs. The evaluation of the timing of oral feeding could be useful in understanding the influence that these techniques could have on the development of sucking-swallow coordination. Moreover, the evaluation of the response to NCPAP and HHHFNC could clarify their efficacy as a treatment for RDS in extremely preterm infants., Trial Registration: ClinicalTrials.gov, NCT03548324 . Registered on 7 June 2018.

Mother's own milk is the first choice for the feeding and nutrition of preterm and term newborns. When mother's own milk is unavailable or in short supply donor human milk (DM) could represent a solution. Heat treatment and cold storage are common practices in Human Milk Banks (HMBs). Currently, Holder pasteurization process is the recommended heat treatment in all international guidelines. This method is thought to lead to a good compromise between the microbiological safety and nutritional/biological quality of DM. Moreover, storage of refrigerated milk is a common practice in HMBs and in NICUs. Depending on the length and on the type of storage, human milk may lose some important nutritional and functional properties. The available data on oxidative stress markers confirm that pasteurization and refrigeration affected this important elements to variable degrees, even though it is rather difficult to quantify the level of deterioration. Nonetheless, clinical practice demonstrates that many beneficial properties of human milk are preserved, even after cold storage and heat treatment. Future studies should be focused on the evaluation of new pasteurization techniques, in order to achieve a better compromise between biological quality and safety of DM.

Purpose: The aim of this study was to evaluate bolus transit during esophageal swallow (ES) and gastroesophageal reflux (GER) events and to investigate the relationship between the characteristics of ES and GER events in a population of term and preterm newborns with symptoms of gastroesophageal reflux disease (GERD)., Methods: The study population consisted of term and preterm newborns referred to combined multichannel intraluminal impedance (MII) and pH monitoring for GERD symptoms. The frequency and characteristics of ES and GER events were assessed by two independent investigators. Statistical significance was set at p<0.05., Results: Fifty-four newborns (23 preterm) were included in the analyses. Median bolus head advancing time corrected for esophageal length (BHATc) was shorter during mealtime than during the postprandial period (median, interquartile range): 0.20 (0.15-0.29) s/cm vs. 0.47 (0.39-0.64) s/cm, p<0.001. Median bolus presence time (BPT) was prolonged during mealtime: 4.71(3.49-6.27) s vs. 2.66 (1.82-3.73) s, p<0.001. Higher BHATc (p=0.03) and prolonged BPT (p<0.001) were observed in preterm newborns during the postprandial period. A significant positive correlation between BHATc and bolus clearance time was also observed (ρ=0.33, p=0.016)., Conclusion: The analysis of ES and GER events at the same time by MII provides useful information to better understand the physiopathology of GERD. In particular, the analysis of BHATc during the postprandial period could help clinicians identify newborns with prolonged esophageal clearance time due to impaired esophageal motility, which could allow for more accurate recommendations regarding further tests and treatment.

The state of sleep/wakefulness is well known to influence esophageal acid exposure and the number of acid refluxes whereas it is uncertain whether the same is true of the non-acid refluxes that predominate in the newborns. To investigate the relationship between sleep/wakefulness and refluxes 45 newborns with gastroesophageal reflux symptoms were studied with combined multichannel intraluminal impedance and pH monitoring. We found that sleep/wakefulness influenced acid and weakly acidic reflux frequency (awake 2.6+/-0.8; asleep 2.1+/-1.1; p=0.006). A negative correlation was found between sleepness periods and the mean reflux duration for both acid (R=0.55;p < 0.001) and weackly acidic (R=0.51;p < 0.001) refluxes. This finding may raise some concerns about the over-prescription of antacid drugs in newborns.