Elena Maggiora

Context: Bronchopulmonary dysplasia (BPD) is a multifactorial, chronic lung disease affecting preterm infants. Several interventions have been proposed to prevent BPD; a role for specific nutritional practices has also been suggested. Objective: To evaluate, by means of a systematic review of the available literature, which nutritional interventions might prevent BPD in preterm infants. Data Sources: PubMed, The Cochrane Library, and CINAHL were searched using a predefined PICO/PECO strategy for studies recruiting preterm infants (gestational age <37 weeks), examining nutritional interventions, and reporting on BPD. No study design limitation was applied. Articles were included if written in English and published before March 3, 2024. Data Extraction: The literature search yielded 1825 results. After screening, removal of duplicates, and retrieval of additional papers by hand-searching, 135 papers were included in the systematic review and categorized according to their main topic (parenteral nutrition, enteral nutrition, and nutritional supplements). Study quality assessment was performed using the criteria set out by the Cochrane Handbook for Systematic Reviews of Interventions. Data Analysis: Several nutritional interventions appear to reduce the risk of BPD in preterm infants. These include early optimization and balance of fluid, energy, and nutrient intakes through parenteral nutrition, early enteral feeding, and use of own mother’s milk in a dose-dependent fashion. The quality of the examined literature was mixed. Conclusion: The available literature suggests that several nutritional interventions could play a role, together with intensive and respiratory care, to minimize the risk of chronic lung disease in preterm infants. However, the evidence for some interventions is inconclusive and deserves additional, well-designed research. Systematic Review Registration: PROSPERO registration no. CRD42022300524.

Background: Human milk (HM) offers critical short- and long-term benefits for preterm and very low birth weight (VLBW) infants. In 2021, a human milk bank (HMB) was established at the IRCCS Giannina Gaslini Institute, aiming to improve HM feeding rates in this vulnerable population. Methods: We retrospectively analyzed feeding data from 442 VLBW infants (BW < 1500 g) admitted between 2018 and 2024. Data were drawn from the Vermont Oxford Network and Italian Neonatal Network registries. Feeding modalities—exclusive HM, infant formula milk (IM), and mixed feeding (MF)—were recorded and analyzed before and after HMB introduction. Results: Before 2021, MF was predominant, with exclusive HM rates below 10%. Following HMB implementation, exclusive HM feeding increased significantly, reaching 47.2% in 2024 (p < 0.0001). Regression analysis showed a positive trend for HM (+4.84%/year, p = 0.05), and a declining trend for IM (−1.96%/year) and MF (−2.88%/year). Projections suggest HM rates may exceed 58% by 2030. Conclusions: The introduction of the HMB was associated with a significant shift in feeding practices, increasing HM use and reducing IM exposure among VLBW infants. These findings underscore the importance of institutional strategies such as donor milk availability, lactation support, and maternal education in optimizing neonatal nutrition. Ongoing efforts are essential to sustain and extend these improvements beyond NICU discharge, ensuring the long-term benefits of human milk for preterm infants.

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).

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) > 5mg/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.

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: 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 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.

Background : Feeding intolerance, defined as the inability to digest enteral feeding, is a frequent diagnosis in very preterm infants. It is characterized by abdominal distension, delayed gastric emptying and increased frequency and severity of gastroesophageal reflux (GER). 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 ancillary study of the FortiLat trial was to evaluate the effects of using the DF compared with bovine milk-derived fortifier (BF) on GER in VLBW infants.Methods : Over a total of 156 preterm infants enrolled into the FortiLat trial (gestational age <32 weeks and/or birth weight <1500 g) and randomized into BF-arm or DF-arm we selected all infants with clinical signs of GER and cardiorespiratory (CR) symptoms at day 21 of fortification. All the infants underwent CR and multichannel intraluminal impedance and pH (MII/pH) monitoring associated with gastric ultrasound to evaluate GER characteristics, GER-CR temporal associations and gastric emptying time.Results : 10 infants were enrolled, 5 in the DF-arm. At MII/pH infants enrolled into the DF-arm showed a lower GER frequency than BF-arm infants: 2.02(1.95-3.26) vs 4.82(2.84-5.94) GER/hour (p=0.036). No infant had a significant symptom association probability index between GER and CR events. Half gastric emptying time was similar in DF and BF-arm infants: 45.03(42.74-47.02) vs. 48.57(44.73-48.77) min. (p=0.744)Conclusions : The use of donkey derived human milk fortifier reduced the GER frequency and consequently should be recommended in infants with feeding intolerance.Trial Registration : ISRCTN -ISRCTN70022881. Registered 01May 2014 - Retrospectively registered, http://www.isrctn.com/ISRCTN70022881

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. 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. 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. ClinicalTrials.gov, NCT03548324 . Registered on 7 June 2018.

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). 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. 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). 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.