Individualised dosing of anti-thymocyte globulin in paediatric unrelated allogeneic haematopoietic stem-cell transplantation (PARACHUTE): a single-arm, phase 2 clinical trial.

BACKGROUND: Anti-thymocyte globulin, which is used in the conditioning of haematopoietic stem-cell transplantation (HSCT) to prevent graft-versus-host disease (GVHD) and graft failure, has highly variable pharmacokinetics. Overexposure to anti-thymocyte globulin leads to poor CD4+ T-cell immune reconstitution, which is associated with inferior overall survival. We hypothesised that individualised anti-thymocyte globulin dosing would promote CD4+ immune reconstitution, while still preventing GVHD and graft failure. METHODS: We report the results of a prospective, single-arm, phase 2 clinical trial done at the University Medical Center Utrecht and the Princess Máxima Center for Pediatric Oncology (Utrecht, Netherlands) to investigate individualised dosing of anti-thymocyte globulin for unrelated allogeneic HSCT in paediatric patients. Anti-thymocyte globulin dosing was based on bodyweight, absolute lymphocyte counts before the first dose, and the stem-cell source, with cumulative doses ranging from 2-10 mg/kg. Patients younger than 18 years receiving a first HSCT with a T-cell repleted graft for any indication and a Lansky/Karnofsky performance status of at least 70% were eligible for inclusion. The primary endpoint was CD4+ immune reconstitution (>0·05 × 109 CD4+ T-cells per L twice within 100 days [±3] after transplantation). The primary endpoint needed to be met in 38 of 53 evaluable patients (no death, relapse, or graft failure before day 100). Toxicity was registered according to Common Terminology Criteria for Adverse Events criteria version 4.0. The study is registered with the Dutch Trial Register, NL4836. FINDINGS: Between July 1, 2015, and Aug 22, 2018, 58 patients were included in the study, of whom 51 were evaluable for the primary endpoint. Median follow-up was 25·6 months (IQR 15·0-37·0) and median age was 7·4 years (IQR 2·8-13·2). 29 (50%) of 58 patients were female. CD4+ immune reconstitution was reached in 41 (80%, 95% CI 67-90, in survival analysis) of 51 evaluable patients, hence the study met its primary endpoint. There was no difference in CD4+ immune reconstitution between patients who received different stem-cell sources (87% [95% CI 61-96] in cord blood, 77% [54-89] in bone marrow [p=0·62]). The most common grade 3-5 adverse events were infections (32 [50%] patients had grade 3, two [3%] patients had grade 4, and seven [11%] patients had fatal events) and immunological disorders (seven [11%] patients had grade 3, three [5%] patients had grade 4, and five [8%] patients had fatal events). Two (3%) of 64 patients died of GVHD, which might be indirectly related to the intervention. INTERPRETATION: Individualised dosing of anti-thymocyte globulin led to a significant improvement in early CD4+ immune reconstitution without increasing GVHD and graft failure incidence. Promotion of early CD4+ immune reconstitution by individualising anti-thymocyte globulin dose might improve outcomes of allogeneic HSCT. FUNDING: Sanofi.

Effect of Donor Milk on Severe Infections and Mortality in Very Low-Birth-Weight Infants: The Early Nutrition Study Randomized Clinical Trial.

IMPORTANCE: Infections and necrotizing enterocolitis, major causes of mortality and morbidity in preterm infants, are reduced in infants fed their own mother's milk when compared with formula. When own mother's milk is not available, human donor milk is considered a good alternative, albeit an expensive one. However, most infants at modern neonatal intensive care units are predominantly fed with own mother's milk. The benefits of add-on donor milk over formula are not clear. OBJECTIVE: To determine whether providing donor milk instead of formula as supplemental feeding whenever own mother's milk is insufficiently available during the first 10 days of life reduces the incidence of serious infection, necrotizing enterocolitis, and mortality. DESIGN, SETTINGS, AND PARTICIPANTS: The Early Nutrition Study was a multicenter, double-blind randomized clinical trial in very low-birth-weight infants (birth weight <1500 g) admitted to 1 of 6 neonatal intensive care units in the Netherlands from March 30, 2012, through August 17, 2014. Intent-to-treat analysis was performed. INTERVENTIONS: Infants received pasteurized donor milk or preterm formula during the first 10 days of life if own mother's milk was not (sufficiently) available. MAIN OUTCOMES AND MEASURES: The primary end point was cumulative occurrence of serious infection (sepsis or meningitis), necrotizing enterocolitis, or mortality during the first 60 days of life. RESULTS: A total of 930 infants were screened for inclusion; 557 were excluded, resulting in 373 infants (183 receiving donor milk and 190 receiving formula) who were evaluated by intent-to-treat analysis (median birth weight, 1066 g; mean gestational age, 28.4 weeks). Own mother's milk comprised 89.1% and 84.5% of total mean intake during the intervention period for the donor milk and formula groups, respectively. The incidence of the combined outcome was not different (85 [44.7%] [formula] vs 77 [42.1%] [donor milk]; mean difference, 2.6%; 95% CI, -12.7% to 7.4%). The adjusted hazard ratio was 0.87 (95% CI, 0.63-1.19; P = .37). CONCLUSIONS AND RELEVANCE: In the current study, pasteurized donor milk and preterm formula as supplemental feeding during the first 10 days of life yielded similar short-term outcomes in very low-birth-weight infants regarding safety and efficacy when own mother's milk availability was insufficient. Future studies investigating longer duration of use of human donor milk on short-term and long-term outcomes are necessary. TRIAL REGISTRATION: trialregister.nl Identifier: NTR3225.

The bilirubin albumin ratio in the management of hyperbilirubinemia in preterm infants to improve neurodevelopmental outcome: a randomized controlled trial--BARTrial.

BACKGROUND AND OBJECTIVE: High bilirubin/albumin (B/A) ratios increase the risk of bilirubin neurotoxicity. The B/A ratio may be a valuable measure, in addition to the total serum bilirubin (TSB), in the management of hyperbilirubinemia. We aimed to assess whether the additional use of B/A ratios in the management of hyperbilirubinemia in preterm infants improved neurodevelopmental outcome. METHODS: In a prospective, randomized controlled trial, 615 preterm infants of 32 weeks' gestation or less were randomly assigned to treatment based on either B/A ratio and TSB thresholds (consensus-based), whichever threshold was crossed first, or on the TSB thresholds only. The primary outcome was neurodevelopment at 18 to 24 months' corrected age as assessed with the Bayley Scales of Infant Development III by investigators unaware of treatment allocation. Secondary outcomes included complications of preterm birth and death. RESULTS: Composite motor (100 ± 13 vs. 101 ± 12) and cognitive (101 ± 12 vs. 101 ± 11) scores did not differ between the B/A ratio and TSB groups. Demographic characteristics, maximal TSB levels, B/A ratios, and other secondary outcomes were similar. The rates of death and/or severe neurodevelopmental impairment for the B/A ratio versus TSB groups were 15.4% versus 15.5% (P = 1.0) and 2.8% versus 1.4% (P = 0.62) for birth weights ≤ 1000 g and 1.8% versus 5.8% (P = 0.03) and 4.1% versus 2.0% (P = 0.26) for birth weights of >1000 g. CONCLUSIONS: The additional use of B/A ratio in the management of hyperbilirubinemia in preterm infants did not improve their neurodevelopmental outcome. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN74465643.

Branched-chain amino acid requirements for enterally fed term neonates in the first month of life.

BACKGROUND: Knowledge of essential amino acid requirements in infants is important because excessive intake of protein can lead to increased long-term morbidity such as obesity. A deficient intake may lead to suboptimal growth and impaired neurodevelopment. The current recommended branched-chain amino acid requirements in infants aged 0-1 mo are based on the amino acid content of human milk. OBJECTIVE: We quantified the requirements for isoleucine, leucine, and valine for term neonates by using the indicator amino acid oxidation method with [1-(13)C]phenylalanine as the indicator. DESIGN: Fully enterally fed term infants received randomly graded amounts of isoleucine (5-216 mg · kg(-1) · d(-1)), leucine (5-370 mg · kg(-1) · d(-1)), or valine (5-236 mg · kg(-1) · d(-1)) as part of an elemental formula. Data are expressed as means ± SDs. RESULTS: Eighty-three Asian, term neonates (mean ± SD birth weight: 3.3 ± 0.4 kg; gestational age: 39.4 ± 1.3 wk) were studied at a postnatal age of 13 ± 5 d. Mean requirements for isoleucine, leucine, and valine (measured in boys only) were 105 mg · kg(-1) · d(-1) (r(2) = 0.61, P < 0.001), 140 mg · kg(-1) · d(-1) (r(2) = 0.26, P < 0.01), and 110 mg · kg(-1) · d(-1) (r(2) = 0.35, P = 0.001), respectively. CONCLUSIONS: Current human milk-based recommendations for isoleucine and valine in term infants aged 0-1 mo are correct. However, the current recommendation for leucine (166 mg · kg(-1) · d(-1)) is higher than the mean requirement of 140 mg · kg(-1) · d(-1) that we determined in this study. This trial was registered at www.trialregister.nl as NTR1610.

Intake of own mother's milk during the first days of life is associated with decreased morbidity and mortality in very low birth weight infants during the first 60 days of life.

BACKGROUND: The incidence of necrotizing enterocolitis (NEC) and possibly also of sepsis is lower in preterm infants fed their own mother's milk (hereafter 'mother's milk') compared with formula-fed infants. It is unclear whether this is caused by the protective properties of breast milk or by the absence of cow's milk. Especially in early life, mother's milk is often unavailable to preterm infants, while minimal enteral nutrition is initiated immediately. OBJECTIVES: To determine whether there is an association between intake of mother's milk during the first days of life and the combined outcome of sepsis, NEC and death over a prolonged period. METHODS: Retrospective study in infants with a birth weight <1,500 g. Intake of mother's milk and formula during the first 10 days of life was recorded. The occurrence of sepsis, NEC and death was registered during the first 60 days. Data were analysed using Cox regression analysis, taking confounders into account. RESULTS: In total, 349 infants were included. Intake of mother's milk during the first 5 days of life was associated with a lower incidence of NEC, sepsis and/or death during the first 60 days of life (hazard ratio (HR) in the category 0.01-50% intake of mother's milk: 0.49, 95% confidence interval (CI) 0.28, 0.87; HR in the category 50.01-100% intake of mother's milk: 0.50, 95% CI 0.31, 0.83, both compared to no mother's milk). During days 6-10, the protective effect was only present if >50% of the total intake was mother's milk (HR = 0.37, 95% CI 0.22, 0.65). CONCLUSION: The type of enteral nutrition during the first 10 days of life is associated with the risk of NEC, sepsis and/or death during the first 60 days of life.

Human milk banking-facts and issues to resolve.

The number of human milk banks is increasing worldwide. Although the beneficial effects of feeding premature infants with their mother's milk are well documented, less is known about the effects of feeding these infants with pasteurized donor milk. We propose a randomized trial comparing the effects of a 100% human milk-based diet (human milk supplemented with a human milk-derived fortifier) and a diet (partially) based on bovine milk. In theory, human milk has a beneficial effect on various aspects of human physiology, most of which become apparent after infancy. We therefore propose an extensive follow-up program that takes this aspect into consideration. Other issues concerning the practice of human milk banks need to be addressed as well as optimization of the feeding strategies for preterm infants.

Effect of enteral IGF-1 supplementation on feeding tolerance, growth, and gut permeability in enterally fed premature neonates.

OBJECTIVES: The gastrointestinal tract of the premature newborn functions suboptimally with regard to digestion, absorption, and feeding tolerance. Human milk contains trophic factors, such as insulin-like growth factor-1 (IGF-1), that are believed to stimulate gut growth and function. The objective of this double blind, randomized, controlled trial was to assess the effects of enteral IGF-1 supplementation on whole body growth measured by weight gain (in grams per kilogram per day), days to regain birth weight, and anthropometrical characteristics, and gut maturation and permeability (measured by sugar absorption tests). PATIENTS AND METHODS: The study included 60 premature infants (birth weight 750-1250 g) during the first month of life. Patients received either standard infant formula or standard infant formula supplemented with IGF-1 in a concentration twice that of human colostrum (10 microg/100 mL of formula). Primary endpoints were days to full enteral feeding, days to regain birth weight, and growth rate. Sugar absorption tests were performed weekly to assess the secondary endpoints gut permeability and maturation. RESULTS: None of the primary endpoints differed to statistical significance between groups at any point. However, gut permeability was significantly lower in the IGF-1 supplement group on day 14 compared with the control group. At day 21, lactulose/mannitol excretion ratios were (again) comparable between the groups. CONCLUSIONS: Although gut permeability showed a faster decrease in the IGF-1 supplement group, our data do not support IGF-1 supplementation to infant formula.