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Objective: To investigate the features of cardiorespiratory events in infants born preterm during the transitional period, and to evaluate whether different neonatal characteristics may correlate with event type, duration, and severity., Study Design: Infants with gestational age (GA) <32 weeks and/or birth weight <1500 g were enrolled in this observational prospective study. Heart rate (HR) and peripheral oxygen saturation (SpO 2 ) were recorded continuously over the first 72 hours. Cardiorespiratory events of ≥10 seconds were clustered into isolated desaturation (SpO 2 <85%), isolated bradycardia (HR <100 bpm or <70% of baseline), or combined desaturation/bradycardia and classified as mild, moderate, or severe. The daily incidences of isolated desaturation, isolated bradycardia, and combined desaturation and bradycardia were analyzed. The effects of relevant clinical variables on cardiorespiratory event type and severity were assessed using generalized estimating equations., Results: Among the 1050 events analyzed, isolated desaturations were the most frequent (n = 625) and isolated bradycardias the least common (n = 171). The number of cardiorespiratory events increased significantly from day 1 to day 2 (P = .028). One in 5 events had severe characteristics; event severity was highest for combined desaturation and bradycardia (P < .001). Compared with other event types, the incidence of combined desaturation and bradycardia was inversely correlated with GA (P = .029) and was higher with the use of continuous positive airway pressure (P = .002). The presence of a hemodynamically significant patent ductus arteriosus was associated with the occurrence of isolated desaturations (P = .001) and with a longer duration of cardiorespiratory events (P = .003)., Conclusions: Cardiorespiratory events during transition exhibit distinct types, duration, and severity. Neonatal characteristics are associated with the clinical features of these events, indicating that a tailored clinical approach may reduce the hypoxic burden in preterm infants aged 0-72 hours., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neonatal encephalopathy (NE), most commonly a result of the disruption of cerebral oxygen delivery, is the leading cause of neurologic disability in term neonates. Given the key role of free radicals in brain injury development following hypoxia-ischemia-reperfusion, several oxidative biomarkers have been explored in preclinical and clinical models of NE. Among these, antioxidant enzyme activity, uric acid excretion, nitric oxide, malondialdehyde, and non-protein-bound iron have shown promising results as possible predictors of NE severity and outcome. Owing to high costs and technical complexity, however, their routine use in clinical practice is still limited. Several strategies aimed at reducing free radical production or upregulating physiological scavengers have been proposed for NE. Room-air resuscitation has proved to reduce oxidative stress following perinatal asphyxia and is now universally adopted. A number of medications endowed with antioxidant properties, such as melatonin, erythropoietin, allopurinol, or N-acetylcysteine, have also shown potential neuroprotective effects in perinatal asphyxia; nevertheless, further evidence is needed before these antioxidant approaches could be implemented as standard care.

Objectives: Human milk (HM) feeding leads to improved outcome for preterm infants. When mother's milk is unavailable, pasteurized donor HM (DHM) is the recommended alternative over formula. The Holder pasteurization (HoP) method is universally performed in HM banks; however, it is known to impair several functional HM components. The aim of this study was to compare the efficacy of HoP with 2 innovative processing methods (high-temperature short-time [HTST] pasteurization and high-pressure processing [HPP]) in preserving some bioactive HM protein components., Methods: HM samples from donors of the Bologna HM bank were collected and divided into 4 subsamples: 1 was kept raw, and each of the others was processed using a different technique (HoP, HTST, and HPP at 600 MPa for 3 minutes). Total protein content, secretory immunoglobulin A (sIgA), and lactoferrin contents were compared., Results: Both HM lactoferrin and sIgA content were negatively affected, but to a different extent, by each method: sIgA was preserved by HTST, with only HPP leading to a significant reduction (-38.8%); lactoferrin content was strongly reduced by HoP (-87.5%) and HTST (-83.5%), and preserved by HPP. Variations in protein profile were seen for all processing methods, being more relevant for HoP, followed by HTST and, finally, by HPP. All the 3 methods lowered the untreated HM microbial counts to undetectable levels, in accordance with national guidelines., Conclusions: Both HTST and HPP better preserved the original HM protein profile, compared to HoP. They, however, affected differently some bioactive HM components involved in immune response and antibacterial activity.

The management of enteral feeds in preterm infants with a hemodynamically significant patent ductus arteriosus (hs-PDA) is a major challenge for neonatologists due to the fear of gastrointestinal (GI) complications. This review aims to analyze the available evidence on the complex relation between the presence and management of PDA, enteral feeding practices, and GI outcomes in the preterm population. There is limited evidence, based on small and heterogeneous trials, that hs-PDA may affect the splanchnic hemodynamic response to enteral feeds. While the presence of PDA seems a risk factor for adverse GI outcomes, the benefits of feeding withholding during pharmacological PDA treatment are controversial. The lack of robust evidence in support of or against a timely feeding introduction or feeding withholding during pharmacological PDA closure in preterm neonates does not allow to draw any related recommendation. While waiting for further data, the feeding management of this population should be carefully evaluated and possibly individualized on the basis of the infants' hemodynamic and clinical characteristics. Large, multicentric trials would help to better clarify the physiological mechanisms underlying the development of gut hypoperfusion, and to evaluate the impact of enteral feeds on splanchnic hemodynamics in relation to PDA features and treatment.

Breastfeeding is considered the gold standard for infants' nutrition, as mother's own milk (MOM) provides nutritional and bioactive factors functional to optimal development. Early life microbiome is one of the main contributors to short and long-term infant health status, with the gut microbiota (GM) being the most studied ecosystem. Some human milk (HM) bioactive factors, such as HM prebiotic carbohydrates that select for beneficial bacteria, and the specific human milk microbiota (HMM) are emerging as early mediators in the relationship between the development of GM in early life and clinical outcomes. The beneficial role of HM becomes even more crucial for preterm infants, who are exposed to significant risks of severe infection in early life as well as to adverse short and long-term outcomes. When MOM is unavailable or insufficient, donor human milk (DHM) constitutes the optimal nutritional choice. However, little is known about the specific effect of DHM on preterm GM and its potential functional implication on HMM. The purpose of this narrative review is to summarize recent findings on HMM origin and composition and discuss the role of HMM on infant health and development, with a specific focus on preterm infants.

Competing Interests: None declared

Because of its possible effect on mesenteric blood flow, the presence of a hemodynamically significant patent ductus arteriosus (PDA) is often of concern for the introduction of enteral feeds in preterm neonates. Near-infrared spectroscopy allows a continuous monitoring of splanchnic oxygenation (SrSO2) and may provide useful hemodynamic information. This observational study evaluated SrSO2 patterns in response to first feed administration in 50 preterm infants <32 weeks' gestation with different ductal status. According to their echocardiographic characteristics, the enrolled infants were divided into the following groups: pulsatile PDA with hemodynamically significant features, restrictive PDA, and no evidence of PDA. The presence of PDA, either with restrictive or hemodynamically significant characteristics, does not significantly affect SrSO2 response to enteral feeding introduction and is not associated with increased rates of gut complications. This finding may provide encouraging evidence in support of early enteral nutrition in very preterm infants with PDA.

Background: Infants born at 23-24 weeks' gestation have the highest risk of developing a hemodynamically significant patent ductus arteriosus (hsPDA), that is refractory to pharmacological closure requiring surgical ligation. Thus, these patients might have the greatest benefits from hsPDA closure, although previous studies on PDA closure were not focused on this population., Aim: To compare the occurrence of hsPDA, failure rate of the first course of ibuprofen in closing hsPDA, and need of surgical closure in infants born at 23 +0 -24 +6 weeks' gestation to those in infants born at 25 +0 -28 +6 weeks' gestation., Study Design: This is a retrospective multicenter study including infants born at 23 +0 -28 +6 weeks of gestation admitted to the neonatal care units from January 2013 to December 2017. All infants underwent echocardiographical assessment for hsPDA diagnosis and eventually pharmacological treatment, and surgical closure., Results: We studied a total of 842 infants of which 562 (67%) developed a PDA. Among those with PDA, 511 (91%) received a pharmacological treatment for a hsPDA. We found that a hsPDA occurred in 70% (106/151) of infants born at 23-24 weeks and in 59% (405/691) of infants born at 25-28 weeks of gestation (P < 0.001). Failure of closure with the first-treatment cycle (69 vs. 40%; P < 0.001) and need of surgical closure (19 vs 10%) were more frequent (P < 0.011) in infants born at 23-24 than 25-28 gestational weeks. Paracetamol vs. ibuprofen treatment and gestational age of 23-24 versus 25-28 weeks increased closure failure, while less severe RDS and maternal clinical chorioamnionitis decreased it., Conclusions: Among extremely preterm infants, infants born at 23-24 weeks of gestation have the highest risk of developing a hsPDA refractory to pharmacological treatment requiring surgical closure. Our findings support the need of individualized more careful strategies for hsPDA management in this special population., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study evaluated the effect of a partly fermented infant formula (using the bacterial strains Bifidobacterium breve C50 and Streptococcus thermophilus 065) with a specific prebiotic mixture (short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS; 9:1)) on the incidence of gastrointestinal symptoms, stool characteristics, sleeping and crying behaviour, growth adequacy and safety. Two-hundred infants ≤28 days of age were assigned either to experimental infant formula containing 30% fermented formula and 0.8 g/100 mL scGOS/lcFOS or to non-fermented control infant formula without scGOS/lcFOS. A group of breastfed infants served as a reference. No relevant differences in parent-reported gastrointestinal symptoms were observed. Stool consistency was softer in the experimental versus control group with values closer to the breastfed reference group. Daily weight gain was equivalent for both formula groups (0.5 SD margins) with growth outcomes close to breastfed infants. No clinically relevant differences in adverse events were observed, apart from a lower investigator-reported prevalence of infantile colic in the experimental versus control group (1.1% vs. 8.7%; p < 0.02). Both study formulae are well-tolerated, support an adequate infant growth and are safe for use in healthy term infants. Compared to the control formula, the partly fermented formula with prebiotics induces stool consistencies closer to breastfed infants.

Background: Arachidonic acid (AA) and docosahexaenoic acid (DHA) are crucial for neural and visual development after premature birth. Preterm infants usually require tube feeding (TF) until the achievement of adequate oral feeding skills; the impact of TF on DHA and AA delivery has not been investigated yet. This study aimed to evaluate the effect of different TF techniques on the delivery of AA and DHA contained in human milk (HM)., Methods: HM samples (65 mL each) were collected and divided into three 20-mL aliquots. The remaining 5 mL served as baseline. Three TF techniques were simulated (1 for each aliquot): gravity bolus feeding (BF), 3-hour continuous feeding using a horizontal feeding pump, and 3-hour continuous feeding with the feeding pump angled at 45°. For horizontal continuous feeding (HCF) and 45° angled continuous feeding (ACF), aliquots delivered between 0 and 90 minutes (T1) and 91 and 180 minutes (T2) were collected separately. AA and DHA concentration was analyzed by gas chromatography/mass spectrometry and compared among the TF methods. DHA and AA delivery at T1 and T2 was also evaluated., Results: Fifty-one simulated feeds were performed. DHA and AA amounts after BF and ACF did not differ significantly compared with baseline, whereas HCF resulted in significantly lower DHA and AA concentration. During T2, ACF delivered almost twice the DHA and AA amounts compared with T1., Conclusion: The delivery of HM AA and DHA is significantly affected by TF, with potential clinical implications. When BF is not tolerated, ACF might represent a feasible alternative to reduce TF-related DHA and AA loss., (© 2018 American Society for Parenteral and Enteral Nutrition.)

Mother's own milk represents the optimal source for preterm infant nutrition, as it promotes immune defenses and gastrointestinal function, protects against necrotizing enterocolitis, improves long-term clinical outcome and is hypothesized to drive gut microbiota assembly. Preterm infants at birth usually do not receive their mother's milk directly from the breast, because active suckling and coordination between suckling, swallowing and breathing do not develop until 32-34 weeks gestational age, but actual breastfeeding is usually possible as they grow older. Here, we enrolled moderately preterm infants (gestational age 32-34 weeks) to longitudinally characterize mothers' milk and infants' gut and oral microbiomes, up to more than 200 days after birth, through 16S rRNA sequencing. This peculiar population offers the chance to disentangle the differential contribution of human milk feeding per se vs. actual breastfeeding in the development of infant microbiomes, that have both been acknowledged as crucial contributors to short and long-term infant health status. In this cohort, the milk microbiome composition seemed to change following the infant's latching to the mother's breast, shifting toward a more diverse microbial community dominated by typical oral microbes, i.e., Streptococcus and Rothia. Even if all infants in the present study were fed human milk, features typical of healthy, full term, exclusively breastfed infants, i.e., high percentages of Bifidobacterium and low abundances of Pseudomonas in fecal and oral samples, respectively, were detected in samples taken after actual breastfeeding started. These findings underline the importance of encouraging not only human milk feeding, but also an early start of actual breastfeeding in preterm infants, since the infant's latching to the mother's breast might constitute an independent factor helping the health-promoting assembly of the infant gut microbiome.

The use of probiotics among very low-birth-weight infants is constantly increasing, as probiotics are believed to reduce the incidence of severe diseases such as necrotizing enterocolitis and late-onset sepsis and to improve feeding tolerance. However, despite the enthusiasm towards these products in neonatal medicine, theoretical knowledge and clinical applications still need to be improved. The purpose of this review is to give an overview of the most important gaps in the current literature about potential uses of probiotics in preterm infants, highlighting promising directions for future research. Specifically, further well-designed studies should aim at clarifying the impact of the type of feeding (mother's milk, donor milk, and formula) on the relationship between probiotic supplementation and clinical outcome. Moreover, future research is needed to provide solid evidence about the potential greater efficacy of multi-strain probiotics compared to single-strain products. Safety issues should also be addressed properly, by exploring the potential of paraprobiotics and risks connected to antibiotic resistance in preterm infants. Last, in light of increasing commercial and public interests, the long-term effect of routine consumption of probiotics in such a vulnerable population should be also evaluated.

Objective: The aim of this observational study was to evaluate the effects of two different protein intake regimes on feeding tolerance, in-hospital growth, anthropometric data and psychomotor outcome up to 24 months corrected age (CA) in extremely low birth-weight (ELBW; birth weight <1000 g) infants. Methods: During the period 2008-2013, 52 ELBW infants admitted at birth to two Neonatal Intensive Care Units of Emilia Romagna (Italy) were fed according to different protocols of protein fortification of human milk: an estimated protein intakes at maximum fortification levels of 3.5 gr/kg/day in the Standard Nutrition Population-SNP group ( n = 26) and 4.8 g/kg/day in the Aggressive Nutrition Population-ANP group ( n = 26). During hospitalization, infants' growth, biochemical indices of nutritional status, enteral intake, feeding tolerance, clinical history and morbidity were evaluated. After discharge, anthropometric data and psychomotor outcome, evaluated by Revised Griffiths Mental Development Scales (GMDS-R) 0-2 years, were assessed up to 24 months CA. Results: During hospitalization, the ANP group showed significantly higher weight (18.87 vs. 15.20 g/kg/day) and head circumference (0.70 vs. 0.52 cm/week) growth rates compared to SNP, less days of parenteral nutrition (7.36 ± 2.7 vs. 37.75 ± 29.6) and of hospitalization (60.0 ± 13.3 vs. 78.08 ± 21.32). After discharge, ANP infants had a greater head circumference compared to SNP (45.64 ± 0.29; 46.80 ± 0.31). Furthermore, the General Quotient of GMDS-R mean scores in the SNP group significantly decreased from 12 to 24 months CA, while no difference was seen in the ANP group. Conclusions: Increased protein intake may provide short and long term benefits in terms of growth and neurodevelopment in human milk-fed ELBW infants.

This review will examine the role of oxidative stress (OS) in the pathogenesis of necrotizing enterocolitis (NEC) and explore potential preventive and therapeutic antioxidant strategies. Preterm infants are particularly exposed to OS as a result of several perinatal stimuli and constitutive defective antioxidant defenses. For this reason, OS damage represents a contributing factor to several complications of prematurity, including necrotizing enterocolitis (NEC). Being NEC a multifactorial disease, OS may act as downstream component of the pathogenetic cascade. To counteract OS in preterm infants with NEC, several antioxidant strategies have been proposed and different antioxidant compounds have been experimented. It is well known that human milk (HM) is an important source of antioxidants. At the same time, the role of an exclusive HM diet is well recognized in the prevention of NEC. However, donor HM (DHM) processing may impair antioxidant properties. As DHM is becoming a common nutritional intervention for high risk PI, the antioxidant status of preterm and DHM and potential ways to preserve its antioxidant capacity may merit further investigation.

Near infrared spectroscopy (NIRS) provides a non-invasive, continuous monitoring of regional tissue oxygenation. NIRS assessment of neonatal splanchnic oxygenation (SrSO 2 ) has gained increasing interest over the last decade, as local hypoxia and ischemia underlie the most feared gut complications in neonates. Current literature provides encouraging evidence in support of SrSO 2 reliability in detecting mesenteric hemodynamic changes related to various physiological and pathological conditions in-term and preterm infants. Even so, while splanchnic NIRS monitoring looks promising for investigating gut physiopathology in research settings, further studies are needed to evaluate its feasibility as a routine monitoring tool in neonatal care and to investigate its potential role in clinical decision making. After a brief introduction to NIRS technical principles, this review aims to provide a complete overview of current neonatal applications for splanchnic NIRS monitoring, to discuss its possible limitations and to suggest future directions for research and clinical applications.

Preterm infants with antenatal absent or reversed end diastolic flow (AREDF) in umbilical arteries are at major risk for gastrointestinal (GI) complications, such as necrotizing enterocolitis, intestinal perforation and feeding intolerance. Near-infrared spectroscopy provides continuous monitoring of splanchnic oxygenation (SrSO2) and may represent a useful tool to predict GI outcomes in this high-risk population. This observational, pilot study assessed feed-related SrSO2 patterns at enteral feeding introduction and full enteral feeding (FEF) achievement in twenty AREDF infants with gestational age ≤34 weeks. Enrolled infants were divided into 2 groups according to the development versus lack of GI complications. Infants developing GI complications showed significantly lower SrSO2 and increased splanchnic oxygen extraction in response to enteral feeds at both enteral feeding introduction and FEF. The potential role of these findings in predicting GI complications in AREDF preterm infants seems promising and deserves further evaluation.

Functional regurgitation (FR) is common in early infancy and represents a major drain on healthcare resources. This double-blind, randomized controlled trial investigated the effects of a formula containing partially hydrolysed, 100% whey protein, starch and Lactobacillus reuteri (DSM 17938) on gastric emptying rate (GErate) and regurgitation frequency in infants with FR. Enrolled infants were randomly allocated to receive either the test formula or a standard starter formula for four weeks. Ultrasound GErate assessment was performed at baseline (week 0) and at week 4; the number of regurgitations, feed volumes and potential adverse events were recorded in a daily diary. Eighty infants aged four weeks to five months were enrolled; 72 (test group = 37; control group = 35) completed the study. Compared to controls, the test group showed greater percentage changes in GErate (12.3% vs. 9.1%, p < 0.01). Mean daily regurgitations decreased from 7.4 (0.8) at week 0 to 2.6 (1.0) at week 4 in the test group and from 7.5 (1.0) to 5.3 (1.0) in controls (between-group difference, p < 0.0001). Compared to a standard formula, a starch-thickened partially hydrolysed whey protein formula supplemented with Lactobacillus reuteri is more effective in decreasing the frequency of regurgitation and improving GErate, and can be of benefit to infants with FR., Competing Interests: Infant formula for the study was supplied by the Nestlé company. The Nestlé Company provided no other funding for the study and had no role in the design of the study. FI serve as a speaker for NNI. The authors declare that they have received no individual funding from Nestlé company, including conference attendance in the past five years.

Growing evidence supports the role of probiotics in reducing the risk of necrotizing enterocolitis, time to achieve full enteral feeding, and late-onset sepsis (LOS) in preterm infants. As reported for several neonatal clinical outcomes, recent data have suggested that nutrition might affect probiotics' efficacy. Nevertheless, the currently available literature does not explore the relationship between LOS prevention and type of feeding in preterm infants receiving probiotics. Thus, the aim of this systematic review and meta-analysis was to evaluate the effect of probiotics for LOS prevention in preterm infants according to type of feeding (exclusive human milk (HM) vs. exclusive formula or mixed feeding). Randomized-controlled trials involving preterm infants receiving probiotics and reporting on LOS were included in the systematic review. Only trials reporting on outcome according to feeding type were included in the meta-analysis. Fixed-effects models were used and random-effects models were used when significant heterogeneity was found. The results were expressed as risk ratio (RR) with 95% confidence interval (CI). Twenty-five studies were included in the meta-analysis. Overall, probiotic supplementation resulted in a significantly lower incidence of LOS (RR 0.79 (95% CI 0.71-0.88), p < 0.0001). According to feeding type, the beneficial effect of probiotics was confirmed only in exclusively HM-fed preterm infants (RR 0.75 (95% CI 0.65-0.86), p < 0.0001). Among HM-fed infants, only probiotic mixtures, and not single-strain products, were effective in reducing LOS incidence (RR 0.68 (95% CI 0.57-0.80) p < 0.00001). The results of the present meta-analysis show that probiotics reduce LOS incidence in exclusively HM-fed preterm infants. Further efforts are required to clarify the relationship between probiotics supplementation, HM, and feeding practices in preterm infants., Competing Interests: The authors declare no conflict of interest.

Epigenetic modifications are among the most important mechanisms by which environmental factors can influence early cellular differentiation and create new phenotypic traits during pregnancy and within the neonatal period without altering the deoxyribonucleic acid sequence. A number of antenatal and postnatal factors, such as maternal and neonatal nutrition, pollutant exposure, and the composition of microbiota, contribute to the establishment of epigenetic changes that can not only modulate the individual adaptation to the environment but also have an influence on lifelong health and disease by modifying inflammatory molecular pathways and the immune response. Postnatal intestinal colonization, in turn determined by maternal flora, mode of delivery, early skin-to-skin contact and neonatal diet, leads to specific epigenetic signatures that can affect the barrier properties of gut mucosa and their protective role against later insults, thus potentially predisposing to the development of late-onset inflammatory diseases. The aim of this review is to outline the epigenetic mechanisms of programming and development acting within early-life stages and to examine in detail the role of maternal and neonatal nutrition, microbiota composition, and other environmental factors in determining epigenetic changes and their short- and long-term effects.

The progressive building of the infants' gut microbiota is pivotal for educating their immune system. Human breast milk is among the first sources of microbes for the assembly of the infant's microbiota, but research struggles to give a demonstration for the origin of bacteria in milk. Aiming at contributing to the knowledge on assembly of the mother's milk and infant's microbiome, here we characterized the oral, gut and milk ecosystems in a homogeneous cohort of 36 healthy mother-infants pairs, by 16S rRNA next-generation sequencing. A limited number of operational taxonomic units (OTUs) was shared among the three ecosystems, including not only OTUs assigned to the well-known immune-modulating Bifidobacterium genus, but also specific Streptococcus and Staphylococcus OTUs, which were dominant in the infant's mouth ecosystem. The high conservation of these OTUs among the three ecosystems seems to call for a worth exploring ecological role through targeted and/or culture-dependent techniques. Notwithstanding the limitations of a 16S rRNA gene-based molecular characterization, we might hypothesize that the baby's mouth, being the transition point for the milk to reach the intestine, could play a role in both the gut microbiota assembly, via deglutition, and mother's milk duct colonization, during suction.

Preterm infants are at risk of developing gastrointestinal complications such as feeding intolerance and necrotizing enterocolitis. Near-infrared spectroscopy (NIRS) provides continuous monitoring of abdominal oxygenation (ArSO2) and could help to predict gastrointestinal complications in preterm neonates. In this prospective observational study, ArSO2 patterns at first enteral feed were evaluated by NIRS in 61 clinically stable preterm infants. Splanchnic-cerebral oxygenation ratio, which is a marker of gut hypoxia, was also calculated. ArSO2 and splanchnic-cerebral oxygenation ratio were significantly lower both at baseline and after feeding administration in infants who later developed feeding intolerance (n = 23). NIRS could help the early prediction of gastrointestinal complications in high-risk preterm infants.

Necrotizing enterocolitis (NEC) is the most severe gastrointestinal complication of prematurity. Surgery, either peritoneal drainage placement or laparotomy with resection of the intestinal necrotic tracts, is the definitive treatment of perforated NEC; however, when clinical conditions contraindicate surgical approaches, little is known about medical treatments adjuvant or alternative to surgery. Octreotide is a synthetic somatostatin analog that inhibits pancreatic secretion and leads to splanchnic vasoconstriction. In preterm neonates, it is mainly used off-label for chylothorax and congenital hyperinsulinism, whereas gastrointestinal indications are limited. We describe the case of a critically ill extremely low birth weight infant with perforated NEC, who had unsuccessfully undergone peritoneal drainage placement and laparotomy. Her unstable condition contraindicated a further laparotomy, thus off-label treatment with octreotide was attempted. No adverse events occurred. The infant's condition gradually improved and progressive reduction of peritoneal outputs and successful resolution of pneumoperitoneum were achieved, with no relapse after octreotide discontinuation., (Copyright © 2016 by the American Academy of Pediatrics.)

Probiotics have been linked to a reduction in the incidence of necrotizing enterocolitis and late-onset sepsis in preterm infants. Recently, probiotics have also proved to reduce time to achieve full enteral feeding (FEF). However, the relationship between FEF achievement and type of feeding in infants treated with probiotics has not been explored yet. The aim of this systematic review and meta-analysis was to evaluate the effect of probiotics in reducing time to achieve FEF in preterm infants, according to type of feeding (exclusive human milk (HM) vs. formula). Randomized-controlled trials involving preterm infants receiving probiotics, and reporting on time to reach FEF were included in the systematic review. Trials reporting on outcome according to type of feeding (exclusive HM vs. formula) were included in the meta-analysis. Fixed-effect or random-effects models were used as appropriate. Results were expressed as mean difference (MD) with 95% confidence interval (CI). Twenty-five studies were included in the systematic review. In the five studies recruiting exclusively HM-fed preterm infants, those treated with probiotics reached FEF approximately 3 days before controls (MD -3.15 days (95% CI -5.25/-1.05), p = 0.003). None of the two studies reporting on exclusively formula-fed infants showed any difference between infants receiving probiotics and controls in terms of FEF achievement. The limited number of included studies did not allow testing for other subgroup differences between HM and formula-fed infants. However, if confirmed in further studies, the 3-days reduction in time to achieve FEF in exclusively HM-fed preterm infants might have significant implications for their clinical management.

OBJECTIVE Hydrocephalus treatment in extremely low-birth-weight (ELBW) infants still represents a challenge for the pediatric neurosurgeon, particularly when the patient weighs far less than 1000 g. In such cases, the benefits in terms of neurological outcome following early treatment do not always outweigh the surgical risks, especially considering the great difference in the surgical risk before patient weight increases. To assess the efficacy and reliability of a percutaneous-tunneled, transfontanellar external ventricular drain (PTTEVD) in ELBW infants, the authors started a new protocol for the early surgical treatment of hydrocephalus. METHODS Ten cases of posthemorrhagic hydrocephalus (PHH) in ELBW infants (5 cases < 700 g, range for all cases 550-1000 g) were treated with a PTTEVD that was implanted at bedside as the first measure in a stepwise approach. RESULTS The average duration of the procedure was 7 minutes, and there was no blood loss. The drain remained in place for an average of 24 days (range 8-45 days). In all cases early control of the hydrocephalus was achieved. One patient had a single episode of CSF leakage (due to insufficient CSF removal). In another patient Enterococcus in the CSF sample was detected the day after abdominal surgery with ileostomy (infection resolved with intrathecal vancomycin). One patient died of Streptococcus sepsis, a systemic infection existing prior to drain placement that never resolved. One patient had Pseudomonas aeruginosa sepsis prior to drain insertion; a PTTEVD was implanted, the infection resolved, and the hydrocephalus was treated in the same way as with a traditional EVD, while the advantages of a quick, minimally invasive, bedside procedure were maintained. Once a patient reached 1 kg in weight, when necessary, a ventriculoperitoneal shunt was implanted and the PTTEVD was removed. CONCLUSIONS The introduction of PTTEVD placement in our standard protocol for the management of PHH has proved to be a wise option for small patients.

Unlabelled: This crossover study showed that non-nutritive sucking, provided with a pacifier in 30 preterm infants, had no effect on acid and nonacid gastro-esophageal reflux evaluated by esophageal pH-impedance, and thus may be reasonably used in preterm neonates with symptoms of gastro-esophageal reflux., Trial Registration: ClinicalTrials.gov: NCT02023216., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The effect of intrapartum antibiotic prophylaxis (IAP) for group B Streptococcus (GBS) on bacterial colonization of the infant's gut has not been investigated extensively. We aimed to evaluate the effect of IAP on gut microbiota in healthy term infants, also exploring the influence of type of feeding., Methods: Healthy term infants, whose mothers had been screened for GBS in late gestation, were divided into 2 groups: infants born to GBS-positive mothers who had received IAP versus controls. Neonatal fecal samples were collected at 7 and 30 days of life; DNA was extracted, and quantification of selected microbial groups (Lactobacillus spp, Bifidobacterium spp, and Bacteroides fragilis group) was performed by real-time PCR., Results: A total of 84 infant-mother pairs were recruited. Bifidobacteria count was significantly lower in the IAP group at 7 days of life (median [interquartile range] 6.01 Log colony-forming unit per gram [5.51-6.98] vs 7.80 [6.61-8.26], P = 0.000). No differences in Bifidobacteria count at 30 days or in Lactobacilli and B fragilis counts at any time point were documented. Furthermore, at 7 days of life, infants who had not received IAP and were exclusively human milk-fed had higher counts of Bifidobacteria. Regardless of IAP treatment, infants fed exclusively human milk had higher Lactobacillus spp counts both at 7 and 30 days of life., Conclusions: IAP alters gut microflora by reducing the count of Bifidobacteria, which is further affected in infants receiving formula feeding. Whether these alterations could have long-term consequences on health and disease requires further investigation.

Background . The neonatal immune system is not fully developed at birth; newborns have adequate lymphocytes counts but these cells lack function. Objective . To assess the activity of T-cells and the influence of the main perinatal factors in very preterm infants (birth weight < 1500 g). Design . Blood samples from 59 preterm infants (21/59 were dizygotic twins) were collected at birth and at 30 days of life to measure CD4+ T-cell activity using the ImmuKnow™ assay. Fifteen healthy adults were included as a control group. Results . CD4+ T-cell activity was lower in VLBW infants compared with adults ( p < 0.001). Twins showed lower immune activity compared to singletons ( p = 0.005). Infants born vaginally showed higher CD4+ T-cell activity compared to those born by C-section ( p = 0.031); infants born after prolonged Premature Rupture of Membranes (pPROM) showed higher CD4+ T-cell activity at birth ( p = 0.002) compared to infants born without pPROM. Low CD4+ T-cell activity at birth is associated with necrotizing enterocolitis (NEC) in the first week of life ( p = 0.049). Conclusions . Preterm infants show a lack in CD4+ T-cell activity at birth. Perinatal factors such as intrauterine inflammation, mode of delivery, and zygosity can influence the adaptive immune activation capacity at birth and can contribute to exposing these infants to serious complications such as NEC., Competing Interests: All the authors declare that they have no conflict of interests in connection with this paper.

Necrotizing enterocolitis (NEC) affects predominantly preterm infants, who have specific risk factors leading to intestinal dysbiosis. Manipulations of gut microbiota through probiotics have the potential to prevent NEC.The aim of this systematic review and meta-analysis was to evaluate the effect of probiotics for NEC prevention in preterm infants, with a focus on specific strains, microbiological strength of currently available studies, and high-risk populations. PubMed and the Cochrane Library were searched for trials published within 4th February 2015. Randomized-controlled trials reporting on NEC and involving preterm infants who were given probiotics in the first month of life were included in the systematic review.Twenty-six studies were suitable for inclusion in the meta-analysis.Data about study design, population, intervention and outcome were extracted and summarized independently by two observers. Study quality and quality of evidence were also evaluated.Fixed-effects models were used and random-effects models where significant heterogeneity was present. Subgroup analyses were performed to explore sources of heterogeneity among studies. Results were expresses as risk ratio (RR) with 95 % confidence interval (CI). The main outcome was incidence of NEC stage ≥2 according to Bell's criteria. Probiotics prevented NEC in preterm infants (RR 0.47 [95 % CI 0.36-0.60], p < 0.00001). Strain-specific sub-meta-analyses showed a significant effect for Bifidobacteria (RR 0.24 [95 % CI 0.10-0.54], p = 0.0006) and for probiotic mixtures (RR 0.39 [95 % CI 0.27-0.56], p < 0.00001). Probiotics prevented NEC in very-low-birth-weight infants (RR 0.48 [95 % CI 0.37-0.62], p < 0.00001); there were insufficient data for extremely-low-birth-weight infants. The majority of studies presented severe or moderate microbiological flaws.Probiotics had an overall preventive effect on NEC in preterm infants. However, there are still insufficient data on the specific probiotic strain to be used and on the effect of probiotics in high-risk populations such as extremely-low-birth-weight infants, before a widespread use of these products can be recommended.

Growing evidence underlines the pivotal role of infant gut colonization in the development of the immune system. The possibility to modify gut colonization through probiotic supplementation in childhood might prevent atopic diseases. The aim of the present systematic review and meta-analysis was to evaluate the effect of probiotic supplementation during pregnancy and early infancy in preventing atopic diseases. PubMed, Embase and Cochrane Library were searched for randomized controlled trials evaluating the use of probiotics during pregnancy or early infancy for prevention of allergic diseases. Fixed-effect models were used, and random-effects models where significant heterogeneity was present. Results were expressed as risk ratio (RR) with 95% confidence interval (CI). Seventeen studies, reporting data from 4755 children (2381 in the probiotic group and 2374 in the control group), were included in the meta-analysis. Infants treated with probiotics had a significantly lower RR for eczema compared to controls (RR 0.78 [95% CI: 0.69-0.89], P = 0.0003), especially those supplemented with a mixture of probiotics (RR 0.54 [95% CI: 0.43-0.68], P < 0.00001). No significant difference in terms of prevention of asthma (RR 0.99 [95% CI: 0.77-1.27], P = 0.95), wheezing (RR 1.02 [95% CI: 0.89-1.17], P = 0.76) or rhinoconjunctivitis (RR 0.91 [95% CI: 0.67-1.23], P = 0.53) was documented. The results of the present meta-analysis show that probiotic supplementation prevents infantile eczema, thus suggesting a new potential indication for probiotic use in pregnancy and infancy., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Methicillin-resistant Staphylococcus aureus (MRSA) is an established nosocomial pathogen with frequent multidrug resistance. The immaturity of the immune system along with intravascular lines and empirical antibiotic treatments place hospitalized preterm infants at major risk of MRSA infection.We report a case of MRSA mandibular osteomyelitis complicating a persistent S. aureus bacteremia in a 23-week preterm infant. From the first weeks of life, the infant showed recurrent C-reactive protein (CRP) elevation, associated with S. aureus bacteremia. Antibiotic courses, including vancomycin and linezolid, were performed with transitory normalization of blood parameters. On day 74, the infant suddenly deteriorated and showed a significant increase of both CRP and procalcitonin. Empiric vancomycin and piperacillin-tazobactam treatment was started; nevertheless, she developed a progressive hard swelling of neck and mandible. Radiological evaluation revealed a mandibular osteomyelitis complicated by an abscess, whose culture grew MRSA. Vancomycin was thus changed to teicoplanin and complete clinical and radiological healing was gradually achieved.In the presence of major risk factors, persistent bacteremia and nonspecific symptoms, a localized focus of infection should be suspected. Microbiological diagnosis should always be attempted and antibiotic treatment should be guided by both susceptibility results and clinical response.

The aim of this study was to determine the effect of human milk feeding during NICU hospitalization on neurodevelopment at 24 months of corrected age in very low birth weight infants. A cohort of 316 very low birth weight newborns (weight ≤ 1500 g) was prospectively enrolled in a follow-up program on admission to the Neonatal Intensive Care Unit of S. Orsola Hospital, Bologna, Italy, from January 2005 to June 2011. Neurodevelopment was evaluated at 24 months corrected age using the Griffiths Mental Development Scale. The effect of human milk nutrition on neurodevelopment was first investigated using a multiple linear regression model, to adjust for the effects of gestational age, small for gestational age, complications at birth and during hospitalization, growth restriction at discharge and socio-economic status. Path analysis was then used to refine the multiple regression model, taking into account the relationships among predictors and their temporal sequence. Human milk feeding during NICU hospitalization and higher socio-economic status were associated with better neurodevelopment at 24 months in both models. In the path analysis model intraventricular hemorrhage-periventricular leukomalacia and growth restriction at discharge proved to be directly and independently associated with poorer neurodevelopment. Gestational age and growth restriction at birth had indirect significant effects on neurodevelopment, which were mediated by complications that occurred at birth and during hospitalization, growth restriction at discharge and type of feeding. In conclusion, our findings suggest that mother's human milk feeding during hospitalization can be encouraged because it may improve neurodevelopment at 24 months corrected age.

We evaluated the effects of bolus vs continuous tube feeding on cardiorespiratory events, detected by polysomnographic monitoring, in healthy preterm infants. Continuous tube feeding resulted in a significant increase of apneas and apneas-related hypoxic episodes compared with bolus feeding., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Intermittent and continuous tube feeding modes are commonly used to feed preterm infants. However, there is no clear evidence regarding which method is better tolerated. We investigated the differences between bolus and continuous feeding in terms of cerebral and splanchnic oxygenation in healthy preterm infants., Methods: Thirty preterm infants underwent a simultaneous 6-h near-infrared-spectroscopy monitoring of cerebral and splanchnic oxygenation, during which they were fed twice through an orogastric tube: one meal was given as a 10-min bolus, and the other was given continuously over a period of 3 h. Oxygenation trends over time were evaluated and compared between bolus and continuous feeding modes., Results: Cerebral oxygenation did not change over time and did not differ between the two feeding techniques. Splanchnic oxygenation changed significantly over time and differed between the two feeding techniques, with a significant increase after bolus feeding and a remarkable reduction during continuous feeding., Conclusion: Bolus and continuous feeding modes influence splanchnic oxygenation in healthy preterm infants differently. Further studies are needed to investigate possible underlying mechanisms and potential effects on feeding tolerance.

Background: To elucidate the role of prenatal, neonatal and early postnatal variables in influencing the achievement of full enteral feeding (FEF) in very low birth weight (VLBW) infants and to determine whether neonatal intensive care units (NICUs) differ in this outcome., Methods: Population-based retrospective cohort study using data on 1,864 VLBW infants drawn from the "Emilia-Romagna Perinatal Network" Registry from 2004 to 2009. The outcome of interest was time to FEF achievement. Eleven prenatal, neonatal and early postnatal variables and the study NICUs were selected as potential predictors of time to FEF. Parametric survival analysis was used to model time to FEF as a function of the predictors. Marginal effects were used to obtain adjusted estimates of median time to FEF for specific subgroups of infants., Results: Lower gestational age, exclusive formula feeding, higher CRIB II score, maternal hypertension, cesarean delivery, SGA and PDA predicted delayed FEF. NICUs proved to be heterogeneous in terms of FEF achievement. Newborns with PDA had a 4.2 days longer predicted median time to FEF compared to those without PDA; newborns exclusively formula-fed had a 1.4 days longer time to FEF compared to those fed human milk., Conclusions: The results of our study suggest that time to FEF is influenced by clinical variables and NICU-specific practices. Knowledge of the variables associated with delayed/earlier FEF achievement could help in improving specific aspects of routine clinical management of VLBW infants and to reduce practice variability.

Purpose: To assess the diagnostic and prognostic value of cerebral magnetic resonance imaging (cMRI) in comparison with that of cerebral ultrasound (cUS) in predicting neurodevelopmental outcome in newborns with congenital cytomegalovirus (CMV) infection., Methods: Forty CMV-congenitally infected newborns underwent cUS and cMRI within the first month of life. Clinical course, laboratory findings, visual/hearing function and neurodevelopmental outcome were documented., Results: Thirty newborns showed normal cMRI, cUS and hearing/visual function in the first month of life; none showed CMV-related abnormalities at follow-up. Six newborns showed pathological cMRI and cUS findings (pseudocystis, ventriculomegaly, calcifications, cerebellar hypoplasia) but cMRI provided additional information (white matter abnormalities in three cases, lissencephaly/polymicrogyria in one and a cyst of the temporal lobe in another one); cerebral calcifications were detected in 3/6 infants by cUS but only in 2/6 by cMRI. Four of these 6 infants showed severe neurodevelopmental impairment and five showed deafness during follow-up. Three newborns had a normal cUS, but cMRI documented white matter abnormalities and in one case also cerebellar hypoplasia; all showed neurodevelopmental impairment and two were deaf at follow-up. One more newborn showed normal cUS and cMRI, but brainstem auditory evoked responses were abnormal; psychomotor development was normal at follow-up., Conclusions: Compared with cUS, cMRI disclosed additional pathological findings in CMV-congenitally infected newborns. cUS is a readily available screening tool useful in the identification of infected newborns with major cerebral involvement. Further studies with a larger sample size are needed to determine the prognostic role of MRI, particularly regarding isolated white matter lesions., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Importance: Infantile colic, gastroesophageal reflux, and constipation are the most common functional gastrointestinal disorders that lead to referral to a pediatrician during the first 6 months of life and are often responsible for hospitalization, feeding changes, use of drugs, parental anxiety, and loss of parental working days with relevant social consequences., Objective: To investigate whether oral supplementation with Lactobacillus reuteri DSM 17938 during the first 3 months of life can reduce the onset of colic, gastroesophageal reflux, and constipation in term newborns and thereby reduce the socioeconomic impact of these conditions., Design: A prospective, multicenter, double-masked, placebo-controlled randomized clinical trial was performed on term newborns (age <1 week) born at 9 different neonatal units in Italy between September 1, 2010, and October 30, 2012., Setting: Parents were asked to record in a structured diary the number of episodes of regurgitation, duration of inconsolable crying (minutes per day), number of evacuations per day, number of visits to pediatricians, feeding changes, hospitalizations, visits to a pediatric emergency department for a perceived health emergency, pharmacologic interventions, and loss of parental working days., Participants: In total, 589 infants were randomly allocated to receive L reuteri DSM 17938 or placebo daily for 90 days., Interventions: Prophylactic use of probiotic., Main Outcomes and Measures: Reduction of daily crying time, regurgitation, and constipation during the first 3 months of life. Cost-benefit analysis of the probiotic supplementation., Results: At 3 months of age, the mean duration of crying time (38 vs 71 minutes; P < .01), the mean number of regurgitations per day (2.9 vs 4.6; P < .01), and the mean number of evacuations per day (4.2 vs 3.6; P < .01) for the L reuteri DSM 17938 and placebo groups, respectively, were significantly different. The use of L reuteri DSM 17938 resulted in an estimated mean savings per patient of €88 (US $118.71) for the family and an additional €104 (US $140.30) for the community., Conclusions and Relevance: Prophylactic use of L reuteri DSM 17938 during the first 3 months of life reduced the onset of functional gastrointestinal disorders and reduced private and public costs for the management of this condition., Trial Registration: clinicaltrials.gov Identifier: NCT01235884.

Introduction: MRI, proton magnetic resonance spectroscopy (¹H-MRS), and diffusion tensor imaging (DTI) have been shown to be of great prognostic value in term newborns with moderate-severe hypoxic-ischemic encephalopathy (HIE). Currently, no data are available on ¹H-MRS and DTI performed in the subacute phase after hypothermic treatment. The aim of the present study was to assess their prognostic value in newborns affected by moderate-severe HIE and treated with selective brain cooling (BC)., Methods: Twenty infants treated with BC underwent conventional MRI and (1)H-MRS at a mean (SD) age of 8.3 (2.8) days; 15 also underwent DTI. Peak area ratios of metabolites and DTI variables, namely mean diffusivity (MD), axial and radial diffusivity, and fractional anisotropy (FA), were calculated. Clinical outcome was monitored until 2 years of age., Results: Adverse outcome was observed in 6/20 newborns. Both ¹H-MRS and DTI variables showed higher prognostic accuracy than conventional MRI. N-acetylaspartate/creatine at a basal ganglia localisation showed 100% PPV and 93% NPV for outcome. MD showed significantly decreased values in many regions of white and gray matter, axial diffusivity showed the best predictive value (PPV and NPV) in the genu of corpus callosum (100 and 91%, respectively), and radial diffusivity was significantly decreased in fronto white matter (FWM) and fronto parietal (FP) WM. The decrement of FA showed the best AUC (0.94) in the FPWM., Conclusion: Selective BC in HIE neonates does not affect the early and accurate prognostic value of ¹H-MRS and DTI, which outperform conventional MRI.

Background: Gastro-esophageal reflux (GER) is diagnosed frequently in preterm infants. Pharmacological treatment of GER has some potential side effects. Conservative treatment of GER should be the first-line approach and should include body positioning and diet modifications. Formula-fed preterm infants experience frequently symptoms of feeding intolerance. Hydrolyzed protein formula (HPF) is often used in these infants due to their effects on gastrointestinal motility., Aims: To investigate the role of an extensively HPF (eHPF) on GER indexes in formula-fed preterm infants with symptoms of both GER and feeding intolerance., Study Design: Randomized crossover trial., Subjects: Preterm infants (gestational age ≤33 weeks) with symptoms of feeding intolerance (large gastric residuals, abdominal distension and constipation) and GER (frequent regurgitations and/or postprandial desaturations)., Outcome Measures: GER indexes detected by 24-h combined multichannel intraluminal impedance and pH monitoring. GER indexes detected after 4 feeds of an eHPF were compared to those detected after 4 feeds of a standard preterm formula (SPF) by Wilcoxon signed ranks test. A p<0.05 was considered statistically significant., Results: eHPF significantly reduced the number of GERs detected by pH monitoring (p=0.036) and also the reflux index (p=0.044) compared to SPF. No differences in impedance bolus exposure indexes nor in GER height were detected., Conclusions: The use of an eHPF should be evaluated for reducing esophageal acid exposure in preterm infants with feeding intolerance and symptoms of GER. Future research should focus on the evaluation of an eHPF adequate for preterm infants in improving clinical symptoms of GER., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Respiratory Syncytial Virus (RSV) is the most important cause of severe respiratory infections in infants with seasonal epidemics. Environmental factors (temperature, humidity, air pollution) could influence RSV epidemics through their effects on virus activity and diffusion., Methods: We conducted a retrospective study on a paediatric population who referred to our Paediatric Emergency Unit in order to analyze the correlation between weekly incidence of RSV positive cases during winter season in Bologna and meteorological factors and air pollutants concentration., Results: We observed a significant correlation between the incidence of RSV infections and the mean minimum temperature registered during the same week and the previous weeks.The weekly number of RSV positive cases was also correlated to the mean PM10 concentration of the week before., Conclusions: RSV epidemic trend in Bologna (Italy) is related to the mean minimum temperature, and the mean PM10 concentration.

Background: Apnea of prematurity (AOP) occurs frequently in preterm infants and a variable proportion of AOP can be induced by gastroesophageal reflux (GER). Conservative treatment, including dietary modifications, should be the first-line approach for both GER and GER-related apneas in this population., Objectives: To evaluate the efficacy of a starch-thickened preterm formula (PF) in reducing the frequency of apneas related to GER., Methods: Preterm infants with AOP were studied by combined impedance and pH monitoring and polysomnography. The 6-hour study period included two feeds, one of a commercially available PF and one of the same formula thickened with amylopectin (TPF). GER indexes, apneas and GER-related apneas detected after TPF and PF feeds were compared by Wilcoxon signed-rank test., Results: 24 infants were studied. During 140 h of registration, 289 apneas (147 after TPF and 142 after PF; p = 0.876), and 861 GER episodes (400 after TPF and 461 after PF; p = 0.465) were recorded. No difference in the number of AOP was found between TPF and PF. A significant reduction in acid exposure was found after TPF; there was no influence on non-acid GER indexes. The frequency of GER-related apneas did not differ between TPF and PF., Conclusions: A formula thickened with amylopectin did not reduce the number of AOP or GER-related apneas. It reduced acid GER features but had no effect on non-acid GER indexes. Future research should focus on exploring different conservative strategies to treat GER-related apneas in preterm infants., (Copyright © 2012 S. Karger AG, Basel.)

Gastroesophageal reflux (GOR) is very common among preterm infants, due to several physiological mechanisms. Although GOR should not be usually considered a pathological condition, its therapeutic management still represents a controversial issue among neonatologists; pharmacological overtreatment, often unuseful and potentially harmful, is increasingly widespread. Hence, a stepwise approach, firstly promoting conservative strategies such as body positioning, milk thickening, or changes of feeding modalities, should be considered the most advisable choice in preterm infants with GOR. This review focuses on the conservative management of GOR in the preterm population, aiming to provide a complete overview, based on currently available evidence, on potential benefits and adverse effects of nonpharmacological measures. Nonpharmacological management of GOR might represent a useful tool for neonatologists to reduce the use of antireflux medications, which should be limited to selected cases of symptomatic babies.

Although gastroesophageal reflux (GER) is a very common phenomenon among preterm infants, its therapeutic management is still an issue of debate among neonatologists. A step-wise approach should be advisable, firstly promoting nonpharmacological interventions and limiting drugs to selected infants unresponsive to the conservative measures or who are suffering from severe GER with clinical complications. Despite of this, a concerning pharmacological overtreatment has been increasingly reported. Most of the antireflux drugs, however, have not been specifically assessed in preterm infants; moreover, serious adverse effects have been noticed in association to their administration. This review mainly aims to draw the state of the art regarding the pharmacological management of GER in preterm infants, analyzing the best piecies of evidence currently available on the most prescribed anti-reflux drugs. Although further trials are required, sodium alginate-based formulations might be considered promising; however, data regarding their safety are still limited. Few piecies of evidence on the efficacy of histamine-2 receptor blockers and proton pump inhibitors in preterm infants with GER are currently available. Nevertheless, a significantly increased risk of necrotizing enterocolitis and infections has been largely reported in association with their use, thereby leading to an unfavorable risk-benefit ratio. The efficacy of metoclopramide in GER's improvement still needs to be clarified. Other prokinetic agents, such as domperidone and erythromycin, have been reported to be ineffective, whereas cisapride has been withdrawn due to its remarkable cardiac adverse effects.

Background: Gastro-oesophageal reflux (GOR) is common in preterm infants; conservative interventions (i.e. dietary changes) should represent the first-line approach., Aim: To evaluate by combined pH and impedance monitoring (pH-MII) the effect of a new preterm formula thickened with amylopectin (TPF) on GOR features in symptomatic preterm infants., Methods: Twenty-eight symptomatic preterm newborns underwent a 24-hour pH-MII; each baby received eight meals (four of TPF and four of a preterm formula [PF]). GOR indexes (number, acidity, duration and height of GORs) after TPF and PF meals were compared by Wilcoxon Signed Ranks Test. Viscosity of PF and TPF was measured., Results: TPF significantly decreased the number of acid GORs detected by pH-monitoring (TPF vs. PF: median 20 vs. 24.5, p = 0.009), while it had no influence on Reflux Index (RIpH), nor on acid and non-acid GOR indexes detected by MII, GOR physical features, and GOR height. TPF's viscosity was extremely higher than PF's, and further increased at pH 3 after the addition of pepsin., Conclusions: The new formula was found to reduce the number of acid GORs detected by pH-monitoring; it did not reduce neither total oesophageal acid exposure nor non-acid GORs. At present its extended clinical use cannot be recommended.

Objective: To compare the efficacy of intravenous immunoglobulin (IVIg) and exchange transfusion (EXT) on rhesus haemolytic disease of the newborn (Rh-HDN) and evaluate treatment-related side effects., Methods: Retrospective chart review of two cohorts of newborns with Rh-HDN, treated with (Group 2) or without (Group 1) IVIg. Length of phototherapy, number of EXT, IVIg infusions, intrauterine and top-up red blood cells transfusions, need and permanence of umbilical venous catheter, and length of hospital stay, as well as treatment-related adverse events, were evaluated., Results: Charts of 88 newborns were reviewed (34 in Group 1, 54 in Group 2). Infants in Group 2 received a significantly lower number of EXT, had a lower risk of neurological impairment and needed an umbilical venous catheter for shorter, but required longer phototherapy, longer length of hospital stay, and more top-up transfusions. EXT was associated with a high number of adverse events. Two newborns treated with IVIg developed necrotizing enterocolitis (NEC)., Conclusions: IVIg appear as an effective alternative to EXT, reducing the risk of neurological impairment and complications related to EXT. However, side effects of IVIg treatment (higher need of top-up transfusions and longer hospital stay) should be taken into account and the risk of NEC should be carefully monitored during treatment.

Background: Apnoea of prematurity (AOP) frequently recurs in preterm infants. We have previously shown that a significant but variable proportion of AOP is induced by gastro-oesophageal reflux (GOR)., Aim: The aim of this study is to evaluate the efficacy of sodium alginate in reducing the frequency of GOR-related AOP., Subjects: Twenty-eight preterm infants with AOP were studied by a six-hour recording of combined multichannel intraluminal impedance and pH monitoring and polysomnography, including two three-hour postprandial periods: sodium alginate was given after one single meal named as drug-given (DG) meal, while the other as drug-free (DF)., Results: During 165h of registration, 715 apnoeas were recorded, 368 after-DG and 347 after-DF (p=.99); furthermore, 851 GOR episodes were detected, 315 after-DG and 536 after-DF (p=.001). No differences in the number of AOP were found between DG and DF. A significant reduction in the number of acid GORs and in acid exposure was found during DG, while the administration of sodium alginate didn't influence non-acid GOR indexes. The frequency of GOR-related apnoeas didn't differ between DG and DF., Discussion: Sodium alginate doesn't reduce the total number of AOP nor GOR-related apnoeas. On the other hand, it reduces acid GOR features, while it had no effect on non-acid GOR indexes., (Copyright © 2011 Elsevier Ltd. All rights reserved.)