The Use of a Novel Donkey Milk-Derived Human Milk Fortified in the Neonatal Period Had No Effect on the Frequency of Allergic Manifestations During the First Years of Life: The "Fortilat Trial" Follow-Up.

Background: Since human milk contents does not meet the high need of very low birth weight infants, fortification of breast milk is a standard practice for this population. As donkey milk has been long considered for children allergic to cow's milk proteins due to its low allergic properties, a new donkey milk-derived fortifier (DF) has been recently evaluated as a valid alternative to bovine milk-derived fortifier (BF). It seems to improve feeding tolerance when compared with standard BF, with similar neurodevelopmental and auxological outcome at 18 months of age. The aim of this study is to evaluate the development of allergic manifestations occurring in the population of the "Fortilat Trial" at 6-8 years of age. Methods: Allergic manifestations were assessed by an ad hoc questionnaire administered to families. The occurrence of asthma, allergic rhinitis and oculorhinitis, rashes and atopic dermatitis, food allergies, accesses to an emergency department for allergic reactions, and the need of antihistamine have been investigated. Results: In total, 113 infants were enrolled in the study (BF arm: n = 60, DF arm: n = 53). No difference in risk was observed between the two groups for all the considered outcomes. In conclusion, our data suggest that DF does not impact the development of allergic manifestations in the first years of life. Clinical Trial Registration number: ISRCT N70022881.

Effects of a valved infant-bottle with ergonomic teat on the coordination of sucking, swallowing, and respiration in late-preterm infants. The Safe Oral Feeding randomized Trial.

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.

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.

The Gestational Pathologies Effect on the Human Milk Redox Homeostasis: A First Step towards Its Definition.

BACKGROUND: Human Milk (HM) is a dynamic nourishment; its composition is influenced by several conditions such as gestational age, maternal diet and ethnicity. It appears important to evaluate the impact that gestational pathologies have on HM components and if their presence, as a source of oxidative stress in the mother, influence milk's redox homeostasis. To assess the effect of Preeclampsia (PE) and Gestational Diabetes Mellitus (GDM) on some aspects of human milk redox homeostasis, we chose to investigate both oxidative and antioxidant aspects, with, respectively, Lipid hydroperoxides (LOOHs) and Glutathione (GSH). METHODS: Women with PE, GDM and who were healthy were recruited for this study. Colostrum, transitional and mature milk samples were collected. GSH and LOOHs levels were measured using a spectrophotometric test. To investigate the effect of pathology on redox homeostasis, a mixed linear model with unistructural covariance structure was performed. RESULTS: A total of 120 mothers were recruited. The GSH concentration results were significantly lower in GDM women than in healthy women only in colostrum (p < 0.01). No other differences emerged. LOOHs was not detectable in almost all the samples. DISCUSSION: Our study is the first to extensively evaluate these components in the HM of women with these gestational pathologies. The main observation is that GDM can alter the GSH level of HM, mainly in colostrum.

Preeclampsia and Its Impact on Human Milk Activin A Concentration.

BACKGROUND: It is known that preeclampsia affects lactogenesis. However, data on the effects of this pathology on human milk neurobiomarker composition are not available. The aim of this study is to investigate the effects of this gestational pathology on activin A levels, a neurobiomarker known to play an important role in the development and protection of the central nervous system. METHODS: The women recruited were divided in two different study groups: preeclamptic or normotensive women. All the human milk samples were collected using the same procedure. Activin A was quantified using an Enzyme-linked immunosorbent assay (ELISA) test. To investigate the effect of preeclampsia on the activin A concentration in the three lactation phases, a mixed linear model with a unistructural covariance structure, with the mother as the random effect, and fixed effects were performed. RESULTS: Activin A was detected in all samples. There were no significant differences between preeclamptic and normotensive women. The only significant effect is related to the lactation phase: the difference between colostrum and mature milk (p < 0.01) was significant. In conclusion, these results allow us to affirm that breast milk's beneficial properties are maintained even if preeclampsia occurs.

Viruses and Human Milk: Transmission or Protection?

Human milk (HM) is considered the best source of nutrition for infant growth and health. This nourishment is unique and changes constantly during lactation to adapt to the physiological needs of the developing infant. It is also recognized as a potential route of transmission of some viral pathogens although the presence of a virus in HM rarely leads to a disease in an infant. This intriguing paradox can be explained by considering the intrinsic antiviral properties of HM. In this comprehensive and schematically presented review, we have described what viruses have been detected in HM so far and what their potential transmission risk through breastfeeding is. We have provided a description of all the antiviral compounds of HM, along with an analysis of their demonstrated and hypothesized mechanisms of action. Finally, we have also analyzed the impact of HM pasteurization and storage methods on the detection and transmission of viruses, and on the antiviral compounds of HM. We have highlighted that there is currently a deep knowledge on the potential transmission of viral pathogens through breastfeeding and on the antiviral properties of HM. The current evidence suggests that, in most cases, it is unnecessarily to deprive an infant of this high-quality nourishment and that the continuation of breastfeeding is in the best interest of the infant and the mother.

Replication properties and immunomodulatory effects of human cytomegalovirus infection impact the clinical presentation in congenital patients: A case series.

BACKGROUND: Human cytomegalovirus (HCMV) is the leading cause of congenital infections resulting in severe morbidity and mortality among newborns worldwide. Although both the host's and the virus' genetic backgrounds contribute to the outcome of infections, significant gaps remain in our understanding of the exact mechanisms that determine disease severity. OBJECTIVES: In this study, we sought to identify a correlation between the virological features of different HCMV strains with the clinical and pathological features of congenitally infected newborns, therefore proposing new possible prognostic factors. STUDY DESIGN: This short communication presents five newborns with congenital cytomegalovirus infection, whose clinical phenotype during fetal, neonatal, and follow-up periods is correlated with in-vitro growth properties, immunomodulatory abilities and genome variability of HCMV strains isolated from organic samples (urine) of the patients. RESULTS: The five patients described in this short communication displayed a heterogeneous clinical phenotype and different virus replication properties, immunomodulatory abilities, and genetic polymorphisms. Interestingly, we observed that an attenuate viral replication in-vitro influences the immunomodulatory abilities of HCMV, leading to more severe congenital infections and long-term sequelae. Conversely, infection with viruses characterized by aggressive replicative behavior in-vitro resulted in asymptomatic patients' phenotypes. CONCLUSIONS: Overall, this case series suggests the hypothesis that genetic variability and differences in the replicative behavior of HCMV strains result in clinical phenotypes of different severity, most likely due to different immunomodulatory properties of the virus.

Fetal and post-natal growth in infants of mothers with multiple sclerosis: A case-control stud.

BACKGROUND: Multiple sclerosis does not seem to adversely affect fetal and neonatal outcomes, although some studies reported a possible reduction in mean birth weight and length, and a higher incidence of preterm delivery, mainly in relation to the exposure to disease-modifying drugs (DMDs) during pregnancy. Few data are available on intrauterine fetal growth and postnatal somatic development of newborns from mothers with multiple sclerosis compared to those from healthy women. For these reasons, we decided to investigate fetal growth, neonatal anthropometric parameters, and postnatal somatic development up to 12 months of life in offsprings from MS mothers. METHODS: This retrospective cohort study included 211 women with multiple sclerosis, and 384 healthy women paired for maternal age and parity as controls. Fetal biometric parameters (biparietal diameter, head circumference, abdominal circumference, and femur length) measured during the third trimester of pregnancy (30-34 weeks' gestation) were retrieved from the computerized database of the Department (EcoPlus*) where the results of ultrasound exams performed in the hospital are stored. Newborn measurements (weight, length and head circumference) at birth were obtained from the hospital's computerized obstetric and neonatal database (Trackare* and Remote* data base); measurements at 6 and 12 months of life were obtained from the regional database (ECWMED*) of family pediatricians of our region. RESULTS: No differences between the two groups were observed for all the fetal parameters considered, expressed as centiles of growth according to gestational age (biparietal diameter: p = 0.40; head circumference: p = 0.40; abdominal circumference: p = 0.32; femur length: p = 0.32). No differences in gestational age at delivery, birthweight, and in the incidence of low birthweight and small for gestational age newborns were observed between the two groups. In the multiple sclerosis group a significantly higher incidence of caesarean section (p = 0.01) and late preterm delivery (at less than 37 weeks'gestation, p = 0.001) were registered. The trends of postnatal growth in weight (F = 0.53; p-value = 0.590) and length (F = 0.44; p-value = 0.645) were superimposable between the two groups. The trends of growth for head circumference showed a slightly, not significantly greater head circumference of infants from mothers with multiple sclerosis at 6 months of life, but the values at twelve months of life in the two groups were similar (F = 0.85; p-value = 0.427) . Moreover, the trends of postnatal increase of weight (F = 1.016; p-value = 0.331), length (F = 2.001; p-value = 0.146) and head circumference (F = 1.591; p-value = 0.212) of newborns/infants (from birth to twelve months of life) born to mothers with multiple sclerosis who breastfed, mothers who did not, and in the control group were similar. CONCLUSION: Multiple sclerosis in pregnancy does not seem to affect fetal growth and postnatal development during the first year of the offspring life. We think that these results represent an important and reassuring information to provide the patients with during preconception counseling.

Adherence to Mediterranean Diet of Breastfeeding Mothers and Fatty Acids Composition of Their Human Milk: Results From the Italian MEDIDIET Study.

Background and Aims: The content of fatty acids (FA) in human milk may be influenced by maternal nutrition. We evaluated the role of a Mediterranean diet in influencing the content of FA in human milk among 282 breastfeeding mothers participating in the MEDIDIET study. Materials and Methods: Mediterranean Diet Score (MDS), a composite index, was used to evaluate adherence to the Mediterranean diet. It includes 9 components (i.e., vegetables, fruit, cereals, legumes, monounsaturated to saturated FA ratio - MUFA/SFA, fish, dairy products, meat, and alcohol) and therefore potentially ranges from 0 (no adherence) to 9 (complete adherence) points. None of the mothers obtained the highest score due to the low alcohol consumption in the study population. Mothers were categorized in approximate tertiles of adherence: 0-3 (34.4%), 4 (26.2%), and 5-8 points (39.4%). The mean content of FA across categories of MDS was compared using ANOVA and test for trend. Results: A high adherence of breastfeeding mothers to the Mediterranean diet was associated with lower content of SFA in human milk (42.58 ± 4.36 for MDS = 0-3, 42.58 ± 4.89 for MDS = 4, and 40.92 ± 5.22% of fats for MDS = 5-8 points; p ANOVA and p for trend = 0.02). Conversely, a high adherence was associated with higher content of MUFA in human milk (43.27 ± 4.27 for MDS = 0-3, 43.27 ± 4.47 for MDS = 4, and 45.24 ± 5.22% of fats for MDS = 5-8 points; p ANOVA and p for trend < 0.01), ω-3 FA (1.07 ± 0.25 for MDS = 0-3, 1.22 ± 0.49 for MDS = 4, and 1.31 ± 0.51% of fats for MDS = 5-8 points; p ANOVA and p for trend < 0.01), and the major types of ω-3 FA (i.e., α-linolenic acid - ALA, eicosapentaenoic acid - EPA, docosahexaenoic acid - DHA, docosapentaenoic acid - DPA). These associations were mainly driven by the adherence to the vegetables, MUFA/SFA, fish, and dairy products components of the Mediterranean diet. Conclusion: A high adherence to the Mediterranean diet was associated with human milk showing a lower content of SFA and higher content of MUFA and ω-3 FA, including DHA. The Mediterranean diet may contribute in human milk production with higher content of specific FA which is directly involved in infant's neural and visual development, as reported by previous studies.

The Donkey Milk in Infant Nutrition.

In the history of the world, the donkey has always had a special place next to humans since the time of its domestication, about 10,000 years ago [...].

NMR Metabonomic Profile of Preterm Human Milk in the First Month of Lactation: From Extreme to Moderate Prematurity.

Understanding the composition of human milk (HM) can provide important insights into the links between infant nutrition, health, and development. In the present work, we have longitudinally investigated the metabolome of milk from 36 women delivering preterm at different gestational ages (GA): extremely (<28 weeks GA), very (29-31 weeks GA) or moderate (32-34 weeks GA) premature. Milk samples were collected at three lactation stages: colostrum (3-6 days post-partum), transitional milk (7-15 days post-partum) and mature milk (16-26 days post-partum). Multivariate and univariate statistical data analyses were performed on the 1H NMR metabolic profiles of specimens in relation to the degree of prematurity and lactation stage. We observed a high impact of both the mother's phenotype and lactation time on HM metabolome composition. Furthermore, statistically significant differences, although weak, were observed in terms of GA when comparing extremely and moderately preterm milk. Overall, our study provides new insights into preterm HM metabolome composition that may help to optimize feeding of preterm newborns, and thus improve the postnatal growth and later health outcomes of these fragile patients.

Perinatal asphyxia partly affects presepsin urine levels in non-infected term infants.

OBJECTIVES: Standard of care sepsis biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT) can be affected by several perinatal factors, among which perinatal asphyxia (PA) has a significant role. In this light, new early sepsis biomarkers such as presepsin (P-SEP) are needed to enact therapeutic strategies at a stage when clinical and laboratory patterns are still silent or unavailable. We aimed at investigating the potential effects of PA on longitudinal P-SEP urine levels. METHODS: We conducted an observational case-control study in 76 term infants, 38 with PA and 38 controls. Standard clinical, laboratory, radiological monitoring procedures and P-SEP urine measurement were performed at four time-points (first void, 24, 48, 96 h) after birth. RESULTS: Higher (p<0.05) CRP and PCT blood levels at T1-T3 were observed in PA than control infants whilst no differences (p>0.05, for all) at T0 were observed between groups. P-SEP urine levels were higher (p<0.05) in PA at first void and at 24 h while no differences (p>0.05) at 48 and 96 h were observed. No significant correlations were found (p>0.05) between P-SEP and urea (R=0.11) and creatinine (R=0.02) blood levels, respectively. CONCLUSIONS: The present results, showed that PA effects on P-SEP were limited up to the first 24 h following birth in absence of any kidney function bias. Data open the way to further investigations aimed at validating P-SEP assessment in non-invasive biological fluids as a reliable tool for early EOS and LOS detection in high-risk infants.

Prolonged refrigeration does not alter isoprostanes concentration in human milk.

BACKGROUND: The Academy of Breastfeeding Medicine published a clinical protocol for Human Milk storage, recommending refrigeration at a temperature of 4 °C up to 4 d as the optimal conditions for the safety and bactericidal capacity of Human Milk. However, few studies were conducted to evaluate the change in milk composition during this type of refrigeration storage. AIM: To elucidate some uncertainties regarding the Human Milk composition and prolonged cold storage, we have investigated the effects of storage at 4 °C up to 96 h on an important category of oxidative stress markers: the Isoprostanes (F2-isoprostanes, F4-neuroprostanes and F3-isoprostanes). MATERIAL AND METHOD: The experiment was repeated 3 times to ensure reproducibility of the results. We enrolled 3 donating healthy mothers for each time (total: 9 mothers). Milk was collected with standard extraction methods. Immediately after collection, each Human Milk sample from each mother was pooled and then divided into 5 aliquots. One aliquot (0 h) was immediately frozen at -80 °C until the analysis. The other aliquots (24 h, 48 h, 72 h, 96 h) were stored in a refrigerator at 4 °C respectively for 24, 48, 72 and 96 h, then immediately frozen at -80 °C until the analysis. Milk samples were then used to determine concentration of Isoprostanes in Liquid Chromatography - Mass Spectrometry and Liquid Chromatography - Tandem Mass Spectrometry. RESULTS: Isoprostanes were detectable in all Human Milk samples. There was no significant trend of the concentration of the tested analytes over time. DISCUSSION AND CONCLUSION: This study provides evidence of the presence in human milk of all the tested isoprostanes: in particular, F2-isoprostanes, F4-neuroprostanes and F3-isoprostanes. Refrigeration and storage of fresh Human Milk in controlled conditions for 96 h did not significantly affect its bioactivity and nutritional quality related with these biomarkers.

Simulated dynamic digestion reveals different peptide releases from human milk processed by means of holder or high temperature-short time pasteurization.

High Temperature-Short Time (HTST) pasteurization was proposed as an alternative to Holder pasteurization (HOP) to increase the retention of specific human milk (HM) bioactive proteins. The present study explored whether HTST and HOP differently affect peptide release during simulated preterm infant gastrointestinal digestion. Raw (RHM), HOP- and HTST- pasteurized HM were digested using an in vitro dynamic system, and the identified peptides were analyzed by mass spectrometry and multivariate statistics. Before digestion, 158 peptides were identified in either RHM, HTST- or HOP- HM, mostly (84.4%) originating from ß-casein (CASB). During gastric digestion, HOP-HM presented a greater number and more abundant specific CASB peptides. A delayed release of peptides was observed in RHM during the intestinal phase, with respect to both pasteurized HM. Although limited to gastric digestion, the HM peptidomic profile differed according to the pasteurization type, and the pattern of the HTST peptides showed a greater similarity with RHM.

Interactions between preeclampsia and composition of the human milk: what do we know?

Purpose: Preeclampsia (PE) is a gestational hypertensive syndrome characterized by a complex disease with variable clinical manifestation. An aspect of increased interest is the possible effect of PE on the mammary gland (and therefore on breast milk composition) considering that a mother's own milk is always considered the first choice for the nutrition of all neonates. Human milk (HM) is a unique food believed to contain biological factors involved in both short and long-term benefits. This article aims to review the published papers on this topic and to offer additional insights on the role of this gestational pathology on the composition of HM.Materials and methods: This review was performed by searching the MEDLINE, EMBASE, CINHAL, and Cochrane Library databases.Results: A total of 15 articles were selected.Conclusions: Overall, the findings from the literature suggest that PE can alter the composition of HM milk. Nevertheless, the number of studies in this field are scarce, and the related protocols present some limitation, for example, evaluating the variability of just a few specific milk biochemical markers in association with this syndrome.

Complementary Feeding: Recommendations for the Introduction of Allergenic Foods and Gluten in the Preterm Infant.

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.

Short-term effects of synchronized vs. non-synchronized NIPPV in preterm infants: study protocol for an unmasked randomized crossover trial.

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, FiO2 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.

Evaluation of Extrauterine Head Growth From 14-21 days to Discharge With Longitudinal Intergrowth-21st Charts: A New Approach to Identify Very Preterm Infants at Risk of Long-Term Neurodevelopmental Impairment.

Background: ExtraUterine Growth Restriction (EUGR) is a common definition for in-hospital growth failure of very preterm infants. Wide heterogeneity is found in definitions and anthropometric charts used to describe EUGR. Aim: We aim to compare two traditional definitions of EUGR with a newly proposed one, based on a longitudinal evaluation, that takes into account the physiological period of fluid loss after birth. We also wish to detect which definition could better predict neurodevelopmental impairment at 24 months of corrected age (CA). Methods: A total of 195 infants with GA < 30 were included. EUGR was calculated both for weight and head circumference (HC). Cross-sectional EUGR was defined as measurements < 10th percentile at discharge; longitudinal EUGR was defined as Δz-score < -1 between birth and discharge measurements. The new longitudinal "post-loss" EUGR definition was proposed as Δz-score < -1 between measurements taken at 14-21 days of life and at discharge. Longitudinal postnatal Intergrowth-21st charts specifically built on preterm infants were used. Association with major and minor neurodevelopmental impairment at 24-month CA was assessed for each definition. K coefficient and ROC curve were evaluated. Results: Longitudinal "post-loss" definition of EUGR for HC is the one predicting minor neurodevelopmental impairment at the multivariate analysis (OR = 3.94), and it is also associated with a worse General Quotient. The chosen cut-off (Δz-score < -1) is the proper one. Conclusion: HC in-hospital growth could be a more accurate tool than weight to predict neurodevelopmental outcomes and especially minor neurological impairment. Longitudinal "post-loss" definition of EUGR assessed on longitudinal charts for preterm infants could be the most appropriate definition from the methodological, clinical, and prognostic point of view.

The "Fortilat" Randomized Clinical Trial Follow-Up: Neurodevelopmental Outcome at 18 Months of Age.

Adequate nutrition is fundamental to neonatal survival and short-term outcomes, but it also has long-term consequences on quality of life and neurologic development of preterm infants. Donkey milk has been suggested as a valid alternative for children allergic to cows' milk proteins, due to its biochemical similarity to human milk; we, hence, hypothesized that donkey milk could be a suitable basis for developing an innovative human milk fortifier for feeding preterm infants. The aim of the current study was to extend the findings and to evaluate the neurodevelopmental outcomes at 18 months of corrected age of the infants enrolled in the clinical trial named "Fortilat". Infants born ≤1500 g and <32 weeks of gestational age were randomized to receive either a combination of bovine milk-based multicomponent fortifier and protein supplement or a combination of a novel multicomponent fortifier and protein supplement derived from donkey milk. The followed fortification protocol was the same for the two groups and the two diets were designed to be isoproteic and isocaloric. All infants enrolled were included in a developmental assessment program. The neurodevelopmental assessment was performed at 18 ± 6 months of corrected age. Minor and major neurodevelopmental impairment and General Quotient (GQ) at the Griffiths-II Mental Development Scale were considered. The GQ was considered both in continuous and as two classes: lower than and higher than (or equal to) a defined cutoff (GQcl). The difference in GQ and GQcl between the two arms was estimated using Mann-Whitney-Wilcoxon test or Fischer exact test, respectively, on the assumption of casual loss at follow-up. A further analysis was performed using generalized linear models. There were 103 children (bovine milk-derived fortifier arm = 54, donkey milk-derived fortifier arm = 49) included for the neurodevelopmental follow-up. All observations were included in the interval of 18 ± 6 months of corrected age. No significant difference was observed between the two arms in the incidence of neurologic sequelae and the GQs were similar in the two arms. Our results demonstrated no difference for the donkey milk-derived fortifier compared to standard bovine-derived fortifier regarding long-term neurodevelopmental outcomes.

The "Fortilat" Randomized Clinical Trial Follow-Up: Auxological Outcome at 18 Months of Age.

Human milk fortification is a routine clinical practice for feeding preterm infants. We hypothesized that donkey milk can be a suitable basis for developing an innovative human milk fortifier. Our randomized controlled single-blind clinical trial, named "Fortilat", evaluated the feeding tolerance, growth and clinical short-term outcomes in a population of preterm infants fed with a novel multi-component fortifier and a protein concentrate derived from donkey milk. The aim of the current study is to extend the previous findings and to evaluate the auxological outcomes of the infants enrolled in the "Fortilat" trial at 18 months of age. In the previous trial "Fortilat", the fortification protocol followed was the same for the two groups, and the two diets were designed to be isoproteic and isocaloric. All infants enrolled in the trial were included in a premature infant developmental evaluation program consisting of hospital visits at 40 ± 1 weeks of postmenstrual age, and at 6, 12 and 18 months of corrected age. Weight, head circumference and length were expressed in z-score using neonatal Intergrowth21st and INeS charts at birth, and WHO 0-5 years growth charts at 18 months. 122 children (Bovine-arm = 62, Donkey-arm = 60) were included in this study. All the observations were recorded in the interval of 18 ± 3 months of the correct age. The two groups did not differ for head circumference, length or weight at 18 months of age. Our data show that fortifiers derived from donkey milk had not different long term auxological outcomes of standard bovine-derived fortifier, but the new donkey milk fortifier was well tolerated in our population.