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Fortification of human milk (HM) for preterm and very low-birth weight (VLBW) infants is a standard practice in most neonatal intensive care units. The optimal fortification strategy and the most suitable protein source for achieving better tolerance and growth rates for fortified infants are still being investigated. In a previous clinical trial, preterm and VLBW infants receiving supplementation of HM with experimental donkey milk-based fortifiers (D-HMF) showed decreased signs of feeding intolerance, including feeding interruptions, bilious gastric residuals and vomiting, with respect to infants receiving bovine milk-based fortifiers (B-HMF). In the present ancillary study, the urinary metabolome of infants fed B-HMF ( n = 27) and D-HMF ( n = 27) for 21 days was analyzed by 1 H NMR spectroscopy at the beginning (T0) and at the end (T1) of the observation period. Results showed that most temporal changes in the metabolic responses were common in the two groups, providing indications of postnatal adaptation. The significantly higher excretion of galactose in D-HMF and of carnitine, choline, lysine and leucine in B-HMF at T1 were likely due to different formulations. In conclusion, isocaloric and isoproteic HM fortification may result in different metabolic patterns, as a consequence of the different quality of the nutrients provided by the fortifiers.

Breast milk is a complex biofluid that nourishes infants, supports their growth and protects them from diseases. However, at the same time, breastfeeding is a transmission route for human cytomegalovirus (HCMV), with preterm infants being at a great risk of congenital disease. The discrepancy between high HCMV transmission rates and the few reported cases of infants with severe clinical illness is likely due to the protective effect of breast milk. The aim of this study was to investigate the anti-HCMV activity of human preterm colostrum and clarify the role of colostrum-derived extracellular vesicles (EVs). Preterm colostrum samples were collected and the EVs were purified and characterized. The in vitro anti-HCMV activity of both colostrum and EVs was tested against HCMV, and the viral replication step inhibited by colostrum-purified EVs was examined. We investigated the putative role EV surface proteins play in impairing HCMV infection using shaving experiments and proteomic analysis. The obtained results confirmed the antiviral action of colostrum against HCMV and demonstrated a remarkable antiviral activity of colostrum-derived EVs. Furthermore, we demonstrated that EVs impair the attachment of HCMV to cells, with EV surface proteins playing a role in mediating this action. These findings contribute to clarifying the mechanisms that underlie the protective role of human colostrum against HCMV infection.

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.

Aim: To assess the best energy intake in Parenteral Nutrition (PN) for preterm newborns, considering both possible benefits for growth and risk of complications., Methods: Quasi-experimental study comparing two cohorts of newborns, receiving Energy-Enhanced vs. Standard PN (Cohort A, from 1st January 2015 to 31 January 2016 and Cohort B from 1st February 2016 to 31 March 2017; respectively) after implementation of a change in the PN protocol. The primary outcome measure was growth at 24 months of life. The PN associated complications were also measured., Results: We enrolled 132 newborns in two Cohorts, similar for prenatal and postnatal clinical characteristics. Although, body weight and length at 24 months of life were significantly higher (p<0.05) in the Cohort A (11.1, 95% CI 10.6 to 11.6 Kg; 85.0 95% CI 83.8 to 86.2 cm) compared with Cohort B (10.4, 95% CI 9.9 to 10.9 Kg; 81.3 95% CI 79.7 to 82.8 cm), body weight and length Z-Score in the first 24 months of life were similar between the two Cohorts. The rate of PN associated complications was very high in both study Cohorts (up to 98% of enrolments). Multivariate analysis showed that length at 24 months was significantly associated with receiving standard PN (cohort A) in the first week of life and on the energy intake in the first week of life. We also found a marginally insignificant association between Cohort A assignment and body weight at 24 months of life (p = 0.060)., Conclusions: Energy-enhanced PN in early life has not significant effects on long-term growth in preterm newborns. The high prevalence of PN associated complications, poses concerns about the utility of high energy intake recommended by current guidelines for PN., Competing Interests: The authors have declared that no competing interests exist.

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.)

Cytomegalovirus (CMV) is the leading cause of congenital infection. Its occurrence is phenotypically heterogeneous. The type of maternal infection, primary or non-primary, is an important factor related to the symptomatic disease, the primary infection was long considered the only cause of severe neonatal disease. We aimed to analyze the association of primary and non-primary infection with pathological outcomes in infants and with long-term sequelae at follow-up. This was a monocentric retrospective observational study on a population of 91 infants diagnosed with a CMV infection at the Neonatal Care Unit of Neonatology at the Sant'Anna Hospital of Turin during the period of June 2005 to December 2018. Infants underwent clinical, laboratory, and neuroradiological evaluations at birth. Subsequently, the patients were monitored in an auxological, neurodevelopment, and audiological follow-up. Regarding primary vs. non-primary infection, we found a higher percentage of incidence of symptomatic and neurological localized infection, as well as long-term sequelae in the latter. However, no significant difference between the two populations was found. We underline the possibility of re-infection in previously immunized mothers (non-primary infection) with unfavorable neonatal and long-term outcomes.

Objectives: The purpose of the present randomized controlled clinical trial was to compare the use of donkey milk-derived fortifier (DF) with commercial bovine milk-derived fortifier (BF) in very preterm or very-low-birth-weight newborns, in terms of feeding tolerance., Methods: This trial included 156 newborns born at <32 weeks of gestational age and/or with a birth weight ≤1500 g. Newborns were randomized 1:1 to receive enteral feeding with either a BF-arm, or a new, DF-arm for 21 days. The fortification protocol was the same for both study arms, and the 2 diets were designed to be isoproteic and isocaloric. Feeding tolerance was assessed by a standardized protocol., Results: The risk of feeding intolerance tended to be lower in DF-arm than in BF-arm, with a relative risk reduction of 0.63 (95% confidence interval: -0.29, +0.90). The mean number of episodes per newborn of feeding intolerance and feeding interruptions (any duration) were consistently lower in the DF-arm than in the BF-arm. Episodes of bilious gastric residuals and vomiting were significantly lower in the DF-arm. Time needed to reach full enteral feeding (150 mL · kg · day) and daily weight increase between the first day of exclusive enteral feeding (ie, without administering intravenous fluids) and discharge were similar in the BF- and DF-arms., Conclusions: These results suggest that DF improve feeding tolerance when compared with standard bovine-derived fortifiers, with a similar auxological outcome.

Background: Since populations are becoming increasingly multi-ethnic, the use of local or international charts is a matter of debate. This study aimed to evaluate how the choice of cut-off thresholds affected prevalence of underweight (UW), overweight (OW), obesity (OB) in 1200 11-12-year Italian adolescents, and how their somatic growth depended on parental origin., Methods: The height, weight and body mass index were expressed as standard deviation score (SDS) using Italian (ISPED-2006) and UK (UK-1990) charts. The classification of UW/OW/OB was computed with the IOTF international cut-offs, and thresholds were identified as centiles corresponding to BMI values of 18.5/25.0/30.0 kg/m 2 at 18-year in ISPED-2006 or UK-1990 references., Results: About 30% participants had non-Italian parents, above all from North-Africa and Romania. Referring to the UK-1990 charts, all groups showed negative mean SDS for height, and positive SDS for weight and BMI. Referring to the ISPED-2006 charts, all mean SDS were negative. Percentage of UW individuals was higher in accordance with ISPED-2006 than with UK-1990 charts, whereas percentages of OW/OB were higher with UK-1990 than ISPED-2006 charts. The results obtained using IOFT cut-offs were similar to UK-1990 cut-offs. These results were due to the different shape of age-dependent cut-off centiles. Independently by the parental origin, the percentages of adolescents classified as OW/OB were closer to the expected values using the ISPED-2006 then the UK-1990 cut-offs. The results suggested the use of the Italian references for adolescents with immigrant parents., Conclusion: The use of local charts seems more appropriate at least in Italian adolescents in the age range studied.

Pasteurization, performed at 62.5°C for 30 minutes (holder pasteurization), is currently recommended in all international human milk banks guidelines, but it affects some human milk bioactive and nutritive components. The present systematic review is aimed at critically reviewing evidence on the suitability of human milk processing techniques other than holder pasteurization, both thermal and nonthermal, to ensure microbiological safety, and on the effects of these techniques on biologically active donor milk components. A systematic review of English and non-English articles using Medline, PubMed, Embase, SCOPUS, and CAB Abstracts, with no restriction in publication date was performed. Search terms included: human, breast, donor, or banked milk, breastmilk, breast fed, breastfed, breastfeed; HTST, Flash, High Pressure, UV, ultrasonic or nonthermal; process, pasteuris, pasteuriz. Only primary research articles published in peer-reviewed journals were included, providing or not a comparison with holder pasteurized human milk, provided that the pasteurization technique was clearly described, and not intended for domestic use. Additional studies were identified by searching bibliographies of relevant articles. Twenty-six studies were identified as being relevant. Two examined both High Pressure Processing and High-Temperature-Short-Time pasteurization; 10 only examined High Pressure Processing; 10 only examined High-Temperature-Short-Time; 2 articles examined ultraviolet irradiation; 2 articles examined (thermo-)ultrasonic processing. The results indicate that data about safety for microbiological control are still scarce for most of the novel technologies, and that consensus on processing conditions is necessary for nonthermal technologies, before any conclusions on the qualitative and nutritional advantages of these techniques can be drawn.

Objective: To evaluate the relationship between multichannel intraluminal impedance and pH monitoring (MII/pH) values in newborns with symptoms of gastroesophageal reflux disease (GERD) and clinical history in their first 3 years of life., Study Design: Sixty-four newborns with GERD symptoms who underwent MII/pH in the first weeks of life were enrolled into a clinical follow-up program. Follow-up visits were programmed at 1, 3, 6, 9, 12, 18, 24, and 36 months. Patients were divided into 3 groups according to duration of symptoms: short (1-3 months), medium (4-9 months), and long (>9 months), and MII/pH values in these groups were compared., Results: Fifty-three patients completed the 3-year follow-up. The number of patients with GERD symptoms decreased each month. A comparison of MII/pH values of the 3 lifetime symptom groups revealed differences in the impedance bolus exposure index (F = 83; P = .012) and proximal reflux frequency (F = 410; P = .022). These 2 MII variables showed an increasing trend from the short lifetime symptom group to the long lifetime symptom group. Weakly acidic reflux events, but not acidic events, were responsible for these differences., Conclusion: MII/pH in newborns has prognostic value regarding the duration of GERD symptoms and provides useful information that clinicians may give parents about the prognosis of symptomatic infants. Impedance bolus exposure index and proximal reflux frequency seem to be the variables with the highest predictive value. Weakly acidic reflux events play an important role in determining the duration of GERD symptoms in newborns., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background: Despite the increasing prevalence of food allergy, few studies have assessed the prevalence of perceived food-induced symptoms among school-aged children. There is also a paucity of data on how children with food reactions are managed. We investigated the frequency and characteristics of perceived food reactions in school-aged children., Methods: Children aged 5-14 years were included in this cross-sectional study. A standardized self-administered questionnaire on food reactions was handed out to 900 parents., Results: We achieved a response rate of 69%. The lifetime prevalence of parental perceived allergic reactions to food was 10.5%; the point prevalence was 1.6%. Medical care included a call to a general practitioner in 54% of cases, self-management in 37%, an emergency call in 6%, and hospitalization in 3%. Antihistamines were administered in 45% of food reactions, topical steroids in 24%, oral or parenteral steroids in 16%, and epinephrine in 1.5%. In children who reported food reactions, skin prick tests for foods were performed in 54% of cases; the oral food challenge test was performed in 7.5%., Conclusion: Parent perception of food allergic disorders is common in school-aged children. Few children have undergone diagnostic tests to ascertain clinical food hypersensitivity. This is warranted to avoid unnecessarily restricted diets. Efforts should be made to train primary care physicians to manage food-allergic children., (© 2011 The Authors. Pediatrics International © 2011 Japan Pediatric Society.)

The Holder method is the recommended pasteurization method for human milk banks, as it ensures the microbiological safety of human milk (HM). The loss of some biologically active milk components, due to the heat treatment, is a main limit to the diffusion of donor HM. High-temperature short-time (HTST) pasteurization may be an alternative to maintain the nutritional and immunological quality of HM. The aim of the present study was to compare the impact of Holder and HTST pasteurization on the HM protein profile. The protein patterns of HTST-treated milk and raw milk were similar. The Holder method modified bile salt-stimulated lipase, lactoferrin and components of the immune system. The HTST method preserved the integrity of bile salt-stimulated lipase, lactoferrin and, to some extent, of IgAs. Holder pasteurization decreased the amount of bile salt-stimulated lipase and inactivated the remaining molecules, while the HTST method did not alter its activity. Pasteurization increased the bioavailable lysine quantity. HTST pasteurization seems to better retain the protein profile and some of the key active components of donor HM.

Successful therapy in cow milk (CM) protein allergy rests upon completely eliminating CM proteins from the child's diet: it is thus necessary to provide a replacement food. Donkey milk (DM) has recently aroused scientific and clinical interest, above all among paediatric allergologists. A deeper knowledge of proteins in DM is necessary to evaluate the immunological and physiological properties of this natural substitute for cow's milk. The paper offers a detailed comparative analysis among the protein fractions of DM, CM and human milk, following an extensive proteomic study of the casein and whey proteins of DM performed by narrow pH range 2-DE. The detailed protein composition and structural features reported in this study provide insight into the molecular reasons for the hypoallergenicity of DM. Whole DM might constitute a valid substitute of CM in feeding children with CM protein allergy and it might also constitute the basis for formulas suitable for allergic subjects in the first year of life.

Allergy is believed to play a role in the pathogenesis of irritable bowel syndrome (IBS) and constipation. We investigated whether allergic patients are more prone to constipation or IBS. In a multicenter study, two groups of outpatient children aged 3-13 years were included. In group 1, children with allergic symptoms were enrolled. Group 2 consisted of nonallergic children. In both groups, the assessment of IBS and constipation was carried out using a questionnaire based on the Rome criteria for functional gastrointestinal disorders. All children were examined and underwent skin prick tests (SPT) to foods and aeroallergens. The allergic group (n=196) and controls (n=127) were comparable with respect to sex, age, and anthropometric parameters. IBS was found in 6.6% of the allergic children and in 6.3% of the controls (p=0.581). The frequency of constipation was similar in the two groups. In allergic children, positive SPTs to food and self-reported reactions to food were associated with IBS. Our results show that evaluation of constipation comorbidity is not required in allergic children. In allergic children with positive SPT to foods attention may be paid to IBS symptoms.