Reevaluating the FDA's warning against the use of probiotics in preterm neonates: A societal statement by ESPGHAN and EFCNI.

The recent advisory issued by the United States Food and Drug Administration, cautioning against the routine administration of probiotics in preterm neonates, has sparked a lively debate within the scientific community. This commentary presents a perspective from members of the Special Interest Group on Gut Microbiota and Modifications within the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and other authors who contributed to the ESPGHAN position paper on probiotics for preterm infants, as well as representatives from the European Foundation for the Care of Newborn Infants. We advocate for a more nuanced and supportive approach to the use of certain probiotics in this vulnerable population, balancing the demonstrated benefits and risks.

Effects of liberalising visiting policy and staff education on parental visiting duration in the neonatal unit.

AIM: The effect of different neonatal unit access hour policies on parental visiting duration is unknown. Therefore, we analysed the effects of access hours policies and parental education on parental visiting duration. METHOD: This prospective longitudinal cohort study was carried out in a level III neonatal unit from October 2020 to May 2022. Three cohorts were compared. The baseline cohort included 51 preterm infants with restricted visiting hours (October 2020 to May 2021). Cohort 1 comprised 35 preterm infants after liberalisation of visiting hours (June 2021 to November 2021). Cohort 2 consisted of 26 preterm infants after an educational program was implemented (December 2021 to May 2022). The primary outcome was the mean daily parental visiting duration. RESULTS: Mean maternal visiting duration was 172 (standard deviation, SD ± 49.2), 195 (SD ± 64.4.), and 258 (SD ± 71.1) minutes/day at baseline and in cohorts 1 and 2 (significant increase from baseline and cohort 1 to cohort 2, p < 0.001). Mean paternal visiting duration did not change significantly across the cohorts: 133 (SD ± 47.2), 135 (SD ± 83.5), and 165 (SD ± 71.3) minutes/day. CONCLUSION: Liberalisation of access hours did not increase parental visiting duration. Parental and staff education significantly increased maternal but not paternal visiting duration.

Multidimensional assessment of infant, parent and staff outcomes during a family centered care enhancement project in a tertiary neonatal intensive care unit: study protocol of a longitudinal cohort study.

BACKGROUND: The therapeutic advances and progress in the care for preterm infants have enabled the regular survival of very immature infants. However, the high burden of lifelong sequelae following premature delivery constitutes an ongoing challenge. Regardless of premature delivery, parental mental health and a healthy parent-child relationship were identified as essential prerogatives for normal infant development. Family centered care (FCC) supports preterm infants and their families by respecting the particular developmental, social and emotional needs in the Neonatal Intensive Care Unit. Due to the large variations in concepts and goals of different FCC initiatives, scientific data on the benefits of FCC for the infant and family outcome are sparse and its effects on the clinical team need to be elaborated. METHODS: This prospective single centre longitudinal cohort study enrols preterm infants ≤ 32 + 0 weeks of gestation and/or birthweight ≤ 1500 g and their parents at the neonatal department of the Giessen University Hospital, Giessen, Germany. Following a baseline period, the rollout of additional FCC elements is executed following a stepwise 6-months approach that covers the NICU environment, staff training, parental education and psychosocial support for parents. Recruitment is scheduled over a 5.5. year period from October 2020 to March 2026. The primary outcome is corrected gestational age at discharge. Secondary infant outcomes include neonatal morbidities, growth, and psychomotor development up to 24 months. Parental outcome measures are directed towards parental skills and satisfaction, parent-infant-interaction and mental health. Staff issues are elaborated with particular focus on the item workplace satisfaction. Quality improvement steps are monitored using the Plan- Do- Study- Act cycle method and outcome measures cover the infant, the parents and the medical team. The parallel data collection enables to study the interrelation between these three important areas of research. Sample size calculation was based on the primary outcome. DISCUSSION: It is scientifically impossible to allocate improvements in outcome measures to individual enhancement steps of FCC that constitutes a continuous change in NICU culture and attitudes covering diverse areas of change. Therefore, our trial is designed to allocate childhood, parental and staff outcome measures during the stepwise changes introduced by a FCC intervention program. TRIAL REGISTRATION: Clinicaltrials.gov, trial registration number NCT05286983, date of registration 03/18/2022, retrospectively registered, http://clinicaltrials.gov .

Probiotics for the Management of Pediatric Gastrointestinal Disorders: Position Paper of the ESPGHAN Special Interest Group on Gut Microbiota and Modifications.

BACKGROUND: Probiotics, defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, are widely used despite uncertainty regarding their efficacy and discordant recommendations about their use. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Special Interest Group on Gut Microbiota and Modifications provides updated recommendations for the use of probiotics for the management of selected pediatric gastrointestinal disorders. METHODS: All systematic reviews and/or meta-analyses, as well as subsequently published randomized controlled trials (RCTs) (until December 2021), that compared the use of probiotics in all delivery vehicles and formulations, at any dose, with no probiotic (ie, placebo or no treatment), were eligible for inclusion. The recommendations were formulated only if at least 2 RCTs on a similar well-defined probiotic strain were available. The modified Delphi process was used to establish consensus on the recommendations. RESULTS: Recommendations for the use of specific probiotic strains were made for the management of acute gastroenteritis, prevention of antibiotic-associated diarrhea, nosocomial diarrhea and necrotizing enterocolitis, management of Helicobacter pylori infection, and management of functional abdominal pain disorders and infant colic. CONCLUSIONS: Despite evidence to support the use of specific probiotics in some clinical situations, further studies confirming the effect(s) and defining the type, dose, and timing of probiotics are still often required. The use of probiotics with no documented health benefits should be discouraged.

Research priorities in pediatric parenteral nutrition: a consensus and perspective from ESPGHAN/ESPEN/ESPR/CSPEN.

Parenteral nutrition is used to treat children that cannot be fully fed by the enteral route. While the revised ESPGHAN/ESPEN/ESPR/CSPEN pediatric parenteral nutrition guidelines provide clear guidance on the use of parenteral nutrition in neonates, infants, and children based on current available evidence, they have helped to crystallize areas where research is lacking or more studies are needed in order to refine recommendations. This paper collates and discusses the research gaps identified by the authors of each section of the guidelines and considers each nutrient or group of nutrients in turn, together with aspects around delivery and organization. The 99 research priorities identified were then ranked in order of importance by clinicians and researchers working in the field using a survey methodology. The highest ranked priority was the need to understand the relationship between total energy intake, rapid catch-up growth, later metabolic function, and neurocognitive outcomes. Research into the optimal intakes of macronutrients needed in order to achieve optimal outcomes also featured prominently. Identifying research priorities in PN should enable research to be focussed on addressing key issues. Multicentre trials, better definition of exposure and outcome variables, and long-term metabolic and developmental follow-up will be key to achieving this. IMPACT: The recent ESPGHAN/ESPEN/ESPR/CSPEN guidelines for pediatric parenteral nutrition provided updated guidance for providing parenteral nutrition to infants and children, including recommendations for practice. However, in several areas there was a lack of evidence to guide practice, or research questions that remained unanswered. This paper summarizes the key priorities for research in pediatric parenteral nutrition, and ranks them in order of importance according to expert opinion.

Editorial: Light shielding of bags and tubing used for parenteral nutrition of infants.

PURPOSE OF REVIEW: In July 2019, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recommended light protection of all parenteral nutrition (PN) solutions containing amino acids (AA) and/or lipids, with or without admixture of vitamins or trace elements, during administration for preterm infants, term infants and children less than 2 years of age. The aim of the present paper was to review the available evidence and to provide recommendations for in hospital and home PN light protection in children. RECENT FINDINGS: Lipid emulsions and multivitamins are susceptible to photooxidation and generation of oxidation products. There is no conclusive evidence to justify recommending light protection for PN solutions without lipid emulsions and/or vitamins during administration (solutions containing e.g. AA, glucose, electrolytes, or trace elements). SUMMARY: Lipid emulsions and/or vitamins containing PN solutions should be protected from light during administration (bags and tubing) to reduce the generation of oxidation products.

Safety and Parental Satisfaction With Early Discharge of Preterm Infants on Nasogastric Tube Feeding and Outpatient Clinic Follow-Up.

Aim: To evaluate our early discharge program of preterm infants with nasogastric tube feeding (NTF) and close outpatient clinic follow-up with regard to safety, parent satisfaction and parental stress level. Methods: 119 preterm infants were discharged on NTF from our tertiary care neonatal unit (median gestational age 31.0 weeks, median birthweight 1,650 g). Parental satisfaction was evaluated by a standardized questionnaire. For safety assessment growth until term equivalent age and re-hospitalizations within 2 months after discharge were evaluated. Results: Infants were discharged home at a median gestational age of 35.4 weeks after a median hospital stay of 22 days. Follow up was attained in 95 of 104 parent-infant dyads. The majority of parents (94%) reported that they had made the right decision in taking their infant home on NTF. At the time of discharge 86% of parents felt very well-prepared to perform NTF. 70% Of parents rated their stress level at home as low (≤2 out of 5). There were no NTF associated readmissions and no growth faltering until term equivalent age. Conclusion: Early discharge of preterm infants with NTF together with outpatient clinic follow-up is very well-accepted by parents and appears to be safe.

Probiotics and Preterm Infants: A Position Paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics.

More than 10,000 preterm infants have participated in randomised controlled trials on probiotics worldwide, suggesting that probiotics in general could reduce rates of necrotising enterocolitis (NEC), sepsis, and mortality. Answers to relevant clinical questions as to which strain to use, at what dosage, and how long to supplement are, however, not available. On the other hand, an increasing number of commercial products containing probiotics are available from sometimes suboptimal quality. Also, a large number of units around the world are routinely offering probiotic supplementation as the standard of care despite lacking solid evidence. Our recent network meta-analysis identified probiotic strains with greatest efficacy regarding relevant clinical outcomes for preterm neonates. Efficacy in reducing mortality and morbidity was found for only a minority of the studied strains or combinations. In the present position paper, we aim to provide advice, which specific strains might potentially be used and which strains should not be used. In addition, we aim to address safety issues of probiotic supplementation to preterm infants, who have reduced immunological capacities and occasional indwelling catheters. For example, quality reassurance of the probiotic product is essential, probiotic strains should be devoid of transferable antibiotic resistance genes, and local microbiologists should be able to routinely detect probiotic sepsis. Provided all safety issues are met, there is currently a conditional recommendation (with low certainty of evidence) to provide either Lactobacillus rhamnosus GG ATCC53103 or the combination of Bifidobacterium infantis Bb-02, Bifidobacterium lactis Bb-12, and Streptococcus thermophilus TH-4 in order to reduce NEC rates.

Prevention of Vitamin K Deficiency Bleeding in Newborn Infants: A Position Paper by the ESPGHAN Committee on Nutrition.

Vitamin K deficiency bleeding (VKDB) due to physiologically low vitamin K plasma concentrations is a serious risk for newborn and young infants and can be largely prevented by adequate vitamin K supplementation. The aim of this position paper is to define the condition, describe the prevalence, discuss current prophylaxis practices and outcomes, and to provide recommendations for the prevention of VKDB in healthy term newborns and infants. All newborn infants should receive vitamin K prophylaxis and the date, dose, and mode of administration should be documented. Parental refusal of vitamin K prophylaxis after adequate information is provided should be recorded especially because of the risk of late VKDB. Healthy newborn infants should either receive 1 mg of vitamin K1 by intramuscular injection at birth; or 3 × 2 mg vitamin K1 orally at birth, at 4 to 6 days and at 4 to 6 weeks; or 2 mg vitamin K1 orally at birth, and a weekly dose of 1 mg orally for 3 months. Intramuscular application is the preferred route for efficiency and reliability of administration. The success of an oral policy depends on compliance with the protocol and this may vary between populations and healthcare settings. If the infant vomits or regurgitates the formulation within 1 hour of administration, repeating the oral dose may be appropriate. The oral route is not appropriate for preterm infants and for newborns who have cholestasis or impaired intestinal absorption or are too unwell to take oral vitamin K1, or those whose mothers have taken medications that interfere with vitamin K metabolism. Parents who receive prenatal education about the importance of vitamin K prophylaxis may be more likely to comply with local procedures.

Intestinal mucosal defense system, Part 1. Consensus recommendations for immunonutrients.

When microbial communities colonize in the developing intestinal tract after birth, microorganisms interact with specific apical surface receptors on the enterocytes. This interaction triggers a response that prevents overexpression of inflammatory cytokines, thus providing protection from pathogen-induced mucosal damage. Multiple immune modulatory factors in human milk and innate humoral factors also control inflammatory responses, providing additional protective effects. Our understanding of the role of the luminal microbial communities or microbiota is growing rapidly as novel technologies provide new insights into their taxonomy, function during early development, and impact on life-long health. Multiple studies have evaluated the effects of the specific nutrients, glutamine, arginine, nucleotides, polyunsaturated fatty acids, and lactoferrin, on disease outcomes in premature infants. These studies support a role for nutrients to modulate host defense mechanisms in premature infants, to develop normal digestive function, to protect from bacterial translocation, and to preserve mucosal barrier integrity. These effects are clearly important. However, not enough is yet known to design specific clinical care practices that support a healthy microbiota.

Intestinal mucosal defense system, Part 2. Probiotics and prebiotics.

The interplay between microorganisms and the intestine of newborn infants is associated with diverse functional and clinical outcomes that result from the specific interactions among microbial communities, their products, and the unique characteristics of the gastrointestinal tract. Multiple mechanisms of action for infant formula ingredients with probiotic activity appear to exist. These mechanisms are thought to protect the host not only from intestinal diseases but also from systemic infection. However, questions about the safety of probiotics for preterm infants remain unanswered, particularly with regard to sepsis, immunomodulatory effects, and microbial resistance. Few well-designed studies have been conducted to evaluate the effects of probiotic, prebiotic, and synbiotic ingredients on relevant clinical outcomes in preterm infants. Although existing data are encouraging, there is insufficient evidence to recommend the routine use of these ingredients in all preterm infants.

Critical systematic review of the level of evidence for routine use of probiotics for reduction of mortality and prevention of necrotizing enterocolitis and sepsis in preterm infants.

BACKGROUND & AIMS: Probiotics have been suggested to prevent severe necrotizing enterocolitis (NEC) and decrease mortality in preterm infants. The aim of this paper was to systematically analyze the level of evidence (LoE) of published controlled randomized trials (RCTs) on probiotics in preterm infants. METHODS: Literature searches were made up to November 2010. LoE of recommendations based on single trials or meta-analyses were scored following the Oxford Center for Evidence based Medicine approach (1a - meta-analyses of 1b LoE studies; 1b - well designed RCT; 2a - meta-analyses which include 2b LoE studies; 2b - lesser quality RCT). RESULTS: Fifteen trials were included (Two 1b LoE trials and thirteen 2b LoE trials). Methodological assessment revealed considerable heterogeneity. Some probiotics may be beneficial in relation to reduction of severe NEC (2b LoE) and reduction of mortality (2b LoE). Probiotics do not accelerate feeding advancement (1b and 2b LoE). There was no convincing benefit with regard to prevention of sepsis (1b and 2b LoE). CONCLUSION: There is insufficient evidence to recommend routine probiotics. However, there is encouraging data (2b LoE) which justifies the further investigation regarding the efficacy and safety of specific probiotics in circumstances of high local incidence of severe NEC.

What is the power of evidence recommending routine probiotics for necrotizing enterocolitis prevention in preterm infants?

PURPOSE OF REVIEW: There is a lively discussion in literature whether routine use of probiotics should be recommended to reduce the incidence of severe necrotizing enterocolitis (NEC) and mortality in preterm infants. The aim of the present review is to analyze the level of evidence of published randomized controlled trials (RCTs) that different probiotic products reduce the incidence of severe NEC and mortality in preterm infants following Oxford Center for Evidence-based Medicine approach. RECENT FINDINGS: Application of probiotics is not a homogeneous intervention and meta-analyses across the available trials may be misleading with the risk that generalized conclusions are erroneously extrapolated to other probiotics. Each individual probiotic intervention should be analyzed separately. Currently, there are 16 RCTs studying 12 different probiotic preparations in preterm infants which report data on clinically important outcomes such as NEC, mortality, sepsis, or feeding advancement. Certain probiotics may be beneficial in relation to severe NEC (level of evidence, LoE 2b). SUMMARY: In circumstances of high local incidence of severe NEC, there is encouraging data (LoE 2b) for the use of probiotics. However, currently there is no level 1a evidence to recommend that all preterm infants should be fed probiotics routinely. Further, well designed RCTs on specific probiotics are required.

Effect of Bifidobacterium lactis on the incidence of nosocomial infections in very-low-birth-weight infants: a randomized controlled trial.

BACKGROUND: Nosocomial infections endanger preterm infants. OBJECTIVE: The aim of the present controlled randomized trial was to investigate whether Bifidobacterium lactis reduces the incidence of nosocomial infections in infants with very low birth weight (VLBW; <1,500 g) <30 weeks of gestation. PATIENTS AND METHODS: In a randomized controlled trial, 183 VLBW infants <30 weeks of gestation were stratified according to gestational age (23-26 and 27-29 weeks) and early antibiotic therapy (days 1-3, yes or no) and randomly assigned to have their milk feedings supplemented with B. lactis (6 x 2.0 x 10(9) CFU/kg/day, 12 billion CFU/kg/day) or placebo for the first 6 weeks of life. Primary outcome was the 'incidence density' of nosocomial infections defined as periods of elevated C-reactive protein (>10 mg/l) from day 7 after initiation of milk feedings until the 42nd day of life (number of nosocomial infections/total number of patient days). The main secondary outcome was necrotizing enterocolitis (NEC; >or=stage 2). RESULTS: There were 93 infants in the B. lactis group and 90 in the placebo group. There was no significant difference between the two groups with regard to the incidence density of nosocomial infections (0.021 vs. 0.016; p = 0.9, chi(2) test). There were 2 cases of NEC in the B. lactis group and 4 in the placebo group. None of the blood cultures grew B. lactis. CONCLUSION: In the present setting, B. lactis at a dosage of 6 x 2.0 x 10(9) CFU/kg/day (12 billion CFU/kg/day) did not reduce the incidence density of nosocomial infections in VLBW infants. No adverse effect of B. lactis was observed.

Intrauterine, early neonatal, and postdischarge growth and neurodevelopmental outcome at 5.4 years in extremely preterm infants after intensive neonatal nutritional support.

OBJECTIVE: Extremely preterm infants are at risk for poor growth and impaired neurodevelopment. The objective of this study was to determine whether intrauterine, early neonatal, or postdischarge growth is associated with neurocognitive and motor-developmental outcome in extremely preterm infants. METHODS: Surviving children who were born between July 1996 and June 1999 at <30 weeks' gestation and with a birth weight <1500 g were evaluated at the age of school entry by application of (1) a standardized neurologic evaluation, (2) the Kaufmann Assessment Battery for Children, and (3) the Gross Motor Function Classification Scale. Growth was assessed on the basis of SD scores of weight and head circumference measured at birth, at discharge, and at the time of the follow-up examination. All infants had received intensive early nutritional support. RESULTS: A total of 219 (83%) of 263 long-term survivors were evaluated at a median corrected age of 5.4 years. Increasing SD scores for weight and head circumference from birth to discharge were associated with a reduced risk for an abnormal neurologic examination. Catch-up growth of head circumference from birth to discharge was also associated with a reduced risk for impaired mobility. Weight SD score at birth, an increase of weight SD score from birth to discharge, and an increase of head circumference SD score from discharge to follow-up had an effect on the mental processing composite score. The effects of growth on neurodevelopment were by far exceeded by the consequences of intraventricular and periventricular hemorrhage. CONCLUSIONS: Growth from birth to discharge seemed to be associated with long-term motor development. Cognitive development was associated with intrauterine growth measured as weight at birth, early neonatal weight gain, and postdischarge head circumference growth. Improving particularly early neonatal growth may improve long-term outcome in extremely preterm infants, but the effects of improved growth may only be small.

Prebiotic oligosaccharides reduce stool viscosity and accelerate gastrointestinal transport in preterm infants.

AIM: To investigate whether a mixture of prebiotic non-digestible oligosaccharides (GosFos; referring to galacto- and fructo-oligosaccharides) would improve feeding tolerance in preterm infants on full enteral formula feeding. We hypothesized that GosFos would: (1) reduce stool viscosity and (2) accelerate gastrointestinal transport. METHODS: In a placebo-controlled double-blind trial 20 preterm infants on full enteral nutrition (gestational age 27 (24-31) weeks, postnatal age 42 (11-84) days, and weight at study entry 1570 (1080-2300) g were randomly allocated to have their feedings supplemented with either GosFos (1 g/100 mL) or placebo for 14 days. Stool viscosity was measured by high-pressure capillary rheometry. Gastrointestinal transport time was assessed as the time from feeding carmine red to its appearance in the diaper. The hypotheses were tested as a priori ordered hypotheses. Data are shown as median (range). RESULTS: Birth weight, gestational age, postnatal age, and weight at study entry did not differ between groups. GosFos significantly reduced both stool viscosity, as measured by extrusion force (32 (2-67) versus 158 (24-314) N), and gastrointestinal transit time (12 (4-33) versus 26 (5-52) h). No adverse effects were observed. CONCLUSION: Formula supplementation with GosFos reduced stool viscosity and accelerated gastrointestinal transport. Further trials are required to investigate whether GosFos facilitates enteral feeding advancement and early enteral nutrition thereby eventually reducing the incidence of catheter-related nosocomial infections and improving long-term outcome.

Hydrolyzed protein accelerates feeding advancement in very low birth weight infants.

BACKGROUND: Feeding intolerance is common in very low birth weight (VLBW; <1500 g) infants. Hydrolyzed protein preterm infant formula (HPF) has been shown to accelerate the gastrointestinal transit of formula. The aim of this study was to investigate whether HPF improves early feeding tolerance compared with standard preterm infant formula (SPF). We hypothesized that HPF would accelerate early enteral feeding advancement. METHODS: Primary outcome was the time from initiation of milk feeds until full feeds (150 mL/kg birth weight/d) were achieved in infants who received <10% human milk (HM) to exclude HM as a confounder. Because the availability of HM was not predictable at the time of enrollment, all eligible VLBW infants (n = 129) were randomly assigned in a randomized, controlled trial to receive HPF or SPF if HM was not available. Infants who received >10% HM (n = 42) were excluded. Milk bolus feeding every 2 to 3 hours was started at the discretion of the attending physician and advanced by 16 mL/kg/d. Preprandial gastric residuals were tolerated up to 5 mL/kg; otherwise, feedings were reduced or withheld. Data are shown as median (5th and 95th percentile). RESULTS: Forty-six and 41 (HPF vs SPF) infants received <10% HM. There was no significant difference with regard to birth weight, gestational age, and onset of milk feeds (day 3 [1-8] vs 4 [2-6]). The time from initiation of milk feeds to full feeds was significantly shorter with HPF feeding (10 [9-27] vs 12 [9-28] days). CONCLUSION: HPF improved the feeding tolerance and enabled a more rapid establishment of full enteral feeding in VLBW infants compared with SPF.