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The human intestinal microbiota, establishing a symbiotic relationship with the host, plays a significant role for human health. It is also well known that a disease status is frequently characterized by a dysbiotic condition of the gut microbiota. A probiotic treatment can represent an alternative therapy for enteric disorders and human pathologies not apparently linked to the gastrointestinal tract. Among bifidobacteria, strains of the species Bifidobacterium breve are widely used in paediatrics. B. breve is the dominant species in the gut of breast-fed infants and it has also been isolated from human milk. It has antimicrobial activity against human pathogens, it does not possess transmissible antibiotic resistance traits, it is not cytotoxic and it has immuno-stimulating abilities. This review describes the applications of B. breve strains mainly for the prevention/treatment of paediatric pathologies. The target pathologies range from widespread gut diseases, including diarrhoea and infant colics, to celiac disease, obesity, allergic and neurological disorders. Moreover, B. breve strains are used for the prevention of side infections in preterm newborns and during antibiotic treatments or chemotherapy. With this documentation, we hope to increase knowledge on this species to boost the interest in the emerging discipline known as “therapeutic microbiology”.

Objective Failure of closure of the patent ductus arteriosus (PDA) may be associated with harm. Early cardiac ultrasound-targeted treatment of a large PDA may result in a reduction in adverse outcomes and need for later PDA closure with no increase in adverse effects. Study design Multicentre, double-blind, placebo-controlled randomised trial. Setting Three neonatal intensive care units in Australia. Patients and interventions Eligible infants born <29 weeks were screened for a large PDA and received indomethacin or placebo before age 12 h. Main outcome Death or abnormal cranial ultrasound. Results The trial ceased enrolment early due to lack of availability of indomethacin. 164 eligible infants were screened before 12 h; of the 92 infants with a large PDA, 44 were randomised to indomethacin and 48 to placebo. There was no difference in the main outcome between groups. Infants receiving early indomethacin had significantly less early pulmonary haemorrhage (PH) (2% vs 21%), a trend towards less periventricular/intraventricular haemorrhage (PIVH) (4.5% vs 12.5%) and were less likely to receive later open-label treatment for a PDA (20% vs 40%). The 72 non-randomised infants with a small PDA were at low risk of pulmonary haemorrhage and had an 80% spontaneous PDA closure rate. Conclusions Early cardiac ultrasound-targeted treatment of a large PDA is feasible and safe, resulted in a reduction in early pulmonary haemorrhage and later medical treatment but had no effect on the primary outcome of death or abnormal cranial ultrasound. Registered Trial Australian New Zealand Clinical Trials Registry (ACTRN12608000295347).

A previous report showed that the use of caffeine to treat apnea of prematurity reduces the risk of bronchopulmonary dysplasia, but whether it has long-term effects on neurodevelopment and growth is unknown. In this placebo-controlled, randomized trial, treatment with caffeine significantly improved the rate of survival without neurodevelopmental disability at 18 to 21 months. Treatment with caffeine significantly improved the rate of survival without neurodevelopmental disability at 18 to 21 months. Apnea of prematurity is one of the most common reasons for the initiation of drug therapy in neonatal medicine. 1 The methylxanthines — aminophylline, theophylline, and caffeine — have been administered to preterm infants as respiratory stimulants for more than 30 years. 2 Caffeine is presently one of the 10 most frequently prescribed medications in neonatal intensive care. 1 Despite their widespread use, caffeine and the other methylxanthines have been evaluated in only a few small, short-term studies. 3 – 5 It has been uncertain whether these drugs might adversely affect the development of the preterm brain and of other organs. Methylxanthines are inhibitors of . . .

ObjectiveTo test whether azithromycin eradicates Ureaplasma from the respiratory tract in preterm infants.DesignProspective, phase IIb randomised, double-blind, placebo-controlled trial.SettingSeven level III–IV US, academic, neonatal intensive care units (NICUs).PatientsInfants 240–286 weeks’ gestation (stratified 240–266; 270–286 weeks) randomly assigned within 4 days following birth from July 2013 to August 2016.InterventionsIntravenous azithromycin 20 mg/kg or an equal volume of D5W (placebo) every 24 hours for 3 days.Main outcome measuresThe primary efficacy outcome was Ureaplasma-free survival. Secondary outcomes were all-cause mortality, Ureaplasma clearance, physiological bronchopulmonary dysplasia (BPD) at 36 weeks’ postmenstrual age, comorbidities of prematurity and duration of respiratory support.ResultsOne hundred and twenty-one randomised participants (azithromycin: n=60; placebo: n=61) were included in the intent-to-treat analysis (mean gestational age 26.2±1.4 weeks). Forty-four of 121 participants (36%) were Ureaplasma positive (azithromycin: n=19; placebo: n=25). Ureaplasma-free survival was 55/60 (92% (95% CI 82% to 97%)) for azithromycin compared with 37/61 (61% (95% CI 48% to 73%)) for placebo. Mortality was similar comparing the two treatment groups (5/60 (8%) vs 6/61 (10%)). Azithromycin effectively eradicated Ureaplasma in all azithromycin-assigned colonised infants, but 21/25 (84%) Ureaplasma-colonised participants receiving placebo were culture positive at one or more follow-up timepoints. Most of the neonatal mortality and morbidity was concentrated in 21 infants with lower respiratory tract Ureaplasma colonisation. In a subgroup analysis, physiological BPD-free survival was 5/10 (50%) (95% CI 19% to 81%) among azithromycin-assigned infants with lower respiratory tract Ureaplasma colonisation versus 2/11 (18%) (95% CI 2% to 52%) in placebo-treated infants.ConclusionA 3-day azithromycin regimen effectively eradicated respiratory tract Ureaplasma colonisation in this study.Trial registration number NCT01778634.

ObjectiveTo determine survival and neurodevelopmental outcomes in the Hypotension in Preterm (HIP) trial.DesignProspective follow-up of infants enrolled in randomised controlled trial.Participants58 infants born before 28 weeks of gestation with low mean arterial blood pressure.InterventionRandom allocation to treatment of low blood pressure values with infusion of dopamine or placebo.Primary outcomeSurvival without neurodevelopmental impairment to 24 months corrected age (CA).ResultsThe HIP trial stopped early due to logistic and recruitment difficulties. Outcomes were determined for 55 infants (27 in the dopamine group and 28 in the placebo group) at 24 months CA. Survival without impairment was present in 13 (48%) infants in the dopamine group and 7 (25%) infants in the placebo group (OR 2.79 (95% CI 0.89, 8.72); p=0.078). The components of the primary outcome were similarly distributed between the two arms. Mean Bayley composite scores and the frequency of somatic impairments did not differ significantly between groups but infants were shorter and lighter at 2 years of age after dopamine administration.ConclusionIn this placebo-controlled trial of the treatment of hypotension in extremely preterm infants, dopamine administration did not increase survival without impairment at 2 years CA. However, the study was not sufficiently powered and a clinically important effect cannot be excluded. The role of inotropic medication in facilitating good outcomes requires further study.

Abstract Rationale Caffeine in the newborn period shortens the duration of assisted ventilation and reduces the incidence of bronchopulmonary dysplasia, but its effects on respiratory function in later childhood are unknown. Objectives To determine if children born with birth weight less than 1,251 g who were treated with neonatal caffeine had improved respiratory function at 11 years of age compared with children treated with placebo. Methods Children enrolled in the CAP (Caffeine for Apnea of Prematurity) randomized controlled trial and assessed at the Royal Women’s Hospital in Melbourne at 11 years of age had expiratory flow rates measured according to the standards of the American Thoracic Society. Values were converted to z-scores predicted for age, height, ethnicity, and sex. Parents completed questionnaires related to their child’s respiratory health. Measurements and Main Results A total of 142 children had expiratory flows measured. Expiratory flows were better in the caffeine group, by approximately 0.5 SD for most variables (e.g., FEV1; mean z-score, −1.00 vs. −1.53; mean difference, 0.54; 95% confidence interval, 0.14–0.94; P = 0.008). Fewer children in the caffeine group had values for FVC below the fifth centile (11% vs. 28%; odds ratio, 0.31; 95% confidence interval, 0.12–0.77; P = 0.012). When adjusted for bronchopulmonary dysplasia, the difference in flow rates between groups diminished. Conclusions Caffeine treatment in the newborn period improves expiratory flow rates in midchildhood, which seems to be achieved by improving respiratory health in the newborn period. Follow-up lung function testing in adulthood is vital for these individuals. Future placebo-controlled randomized trials of neonatal caffeine are unlikely. Clinical trial registered with www.clinicaltrials.gov (NCT00182312).

In infants with very low birth weight who have apnea of prematurity, caffeine therapy reduced the risk of bronchopulmonary dysplasia assessed at 36 weeks of postmenstrual age. Caffeine temporarily reduced weight gain; it did not affect the rates of death, ultrasonographic signs of brain injury, or necrotizing enterocolitis. These short-term data demonstrate an important benefit of caffeine therapy in this population, but a definitive assessment of its benefits and risks awaits results of long-term follow-up of this cohort. In infants with very low birth weight who have apnea of prematurity, caffeine therapy reduced the risk of bronchopulmonary dysplasia. Caffeine temporarily reduced weight gain; it did not affect the rates of death. Apnea of prematurity — defined as cessation of breathing that lasts for more than 15 seconds and is accompanied by hypoxia or bradycardia — occurs in at least 85 percent of infants who are born at less than 34 weeks of gestation. 1 Widely used treatments include the application of continuous positive airway pressure and the prescription of a methylxanthine. 2 The methylxanthines — aminophylline, theophylline, and caffeine — reduce the frequency of apnea and the need for mechanical ventilation during the first seven days of therapy. 3 However, it has remained uncertain whether methylxanthines have any additional short- and long-term benefits or . . .

Background Intraventricular hemorrhage (IVH) is a common complication in preterm infants that has poor outcomes, especially in severe cases, and there are currently no widely accepted effective treatments. Erythropoietin has been shown to be neuroprotective in neonatal brain injury. Objective The objective of this study was to evaluate the protective effect of repeated low-dose recombinant human erythropoietin (rhEPO) in preterm infants with IVH. Methods This was a single-blinded prospective randomized controlled trial. Preterm infants ≤ 32 weeks gestational age who were diagnosed with IVH within 72 h after birth were randomized to receive rhEPO 500 IU/kg or placebo (equivalent volume of saline) every other day for 2 weeks. The primary outcome was death or neurological disability assessed at 18 months of corrected age. Results A total of 316 eligible infants were included in the study, with 157 in the rhEPO group and 159 in the placebo group. Although no significant differences in mortality ( p  = 0.176) or incidence of neurological disability ( p  = 0.055) separately at 18 months of corrected age were seen between the rhEPO and placebo groups, significantly fewer infants had poor outcomes (death and neurological disability) in the rhEPO group: 14.9 vs. 26.4%; odds ratio (OR) 0.398; 95% confidence interval (CI) 0.199–0.796; p  = 0.009. In addition, the incidence of Mental Development Index scores of < 70 was lower in the rhEPO group than in the placebo group: 7.2 vs. 15.3%; OR 0.326; 95% CI 0.122–0.875; p  = 0.026. Conclusions Treatment with repeated low-dose rhEPO improved outcomes in preterm infants with IVH. Trial Registration The study was retrospectively registered on ClinicalTrials.gov on 16 April 2019 (NCT03914690).

ObjectiveEarly hypoglycaemia at the time of neonatal intensive care unit (NICU) admission is common in very/extreme preterm infants. This study aimed to determine whether buccal dextrose gel in the delivery room (DR) would improve rates of early hypoglycaemia in this population.DesignRandomised, blinded, placebo-controlled trial.SettingFour level-3 and one level-2 neonatal units.PatientsInborn infants≤32+0 weeks gestational age (GA).InterventionsInfants were randomised to 40% dextrose or placebo gel in the DR (≤29+0 GA: 0.5 mL gel, ≥29+1 GA: 1 mL gel).Main outcome measureHypoglycaemia (<1.8 mmol/L) measured at the time of first intravenous access at NICU admission.ResultsBetween November 2020 and August 2022, the recruitment rate was slow (impacted by the requirement for antenatal consent). This fact, coupled with finite research resources, led to a decision to end recruitment early. Data analysis of 169 newborns (33% of target sample size) showed no significant difference in the frequency of the primary outcome between dextrose 24/84 (29%) and placebo 25/85 (29%) groups (OR 0.95; 95% CI 0.49 to 1.86; p=0.88). A post-hoc analysis indicated that the trial had a low (47% conditional power) chance of detecting a statistically significant benefit from the intervention (had the target sample been achieved).ConclusionsThis study showed no evidence of benefit of 40% dextrose gel on rates of hypoglycaemia at NICU admission. Management of these vulnerable newborns should continue to focus on vascular access and commencement of dextrose-containing intravenous fluids as early as possible.Trial registration number NCT04353713.

Background Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28 weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking. Methods This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h postnatal age) with the cyclooxygenase inhibitor (COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36 weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis. Discussion As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28 weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36 weeks. Trial registration This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017–001376-28 .