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Background: Despite therapeutic hypothermia (TH) and neonatal intensive care, 45–50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective therapies are sought, besides TH, to further improve the outcome of affected infants. Allopurinol — a xanthine oxidase inhibitor — reduced the production of oxygen radicals and subsequent brain damage in pre-clinical and preliminary human studies of cerebral ischemia and reperfusion, if administered before or early after the insult. This ALBINO trial aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to (near-)term infants with early signs of HIE. Methods/design: The ALBINO trial is an investigator-initiated, randomized, placebo-controlled, double-blinded, multi-national parallel group comparison for superiority investigating the effect of allopurinol in (near-)term infants with neonatal HIE. Primary endpoint is long-term outcome determined as survival with neurodevelopmental impairment versus death versus non-impaired survival at 2 years. Results: The primary analysis with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be on the intention-to-treat (ITT) population by a generalized logits model according to Bishop, Fienberg, Holland (Bishop YF, Discrete Multivariate Analysis: Therory and Practice, 1975) and."will be stratified for the two treatment groups. Discussion: The statistical analysis for the ALBINO study was defined in detail in the study protocol and implemented in this statistical analysis plan published prior to any data analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Trial registration: ClinicalTrials.gov NCT03162653. Registered on 22 May 2017. [ABSTRACT FROM AUTHOR]

The aim of this study was to analyze signal loss (SL) resulting from low signal quality of pulse oximetry-derived hemoglobin oxygen saturation (SpO2) measurements during prolonged hypoxemic episodes (pHE) in very preterm infants receiving automatic oxygen control (AOC). We did a post hoc analysis of a randomized crossover study of AOC, programmed to set FiO2 to "back-up FiO2" during SL. In 24 preterm infants (median (interquartile range)) gestational age 25.3 (24.6 to 25.6) weeks, recording time 12.7 h (12.2 to 13.6 h) per infant, we identified 76 pHEs (median duration 119 s (86 to 180 s)). In 50 (66%) pHEs, SL occurred for a median duration of 51 s (33 to 85 s) and at a median frequency of 2 (1 to 2) SL-periods per pHE. SpO2 before and after SL was similar (82% (76 to 88%) vs 82% (76 to 87%), p = 0.3)). Conclusion: SL is common during pHE and must hence be considered in AOC-algorithm designs. Administering a "backup FiO2" (which reflects FiO2-requirements during normoxemia) during SL may prolong pHE with SL. Trial registration: The study was registered at www.clinicaltrials.gov under the registration no. NCT03785899. What is Known: • Previous studies examined SpO2 signal loss (SL) during routine manual oxygen control being rare, but pronounced in lower SpO2 states. • Oxygen titration during SL is unlikely to be beneficial as SpO2 may recover to a normoxic range. What is New: • Periods of low signal quality of SpO2 are common during pHEs and while supported with automated oxygen control (SPOC), FiO2 is set to a back-up value reflecting FiO2 requirements during normoxemia in response to SL, although SpO2 remained below target until signal recovery. • FiO2 overshoots following pHEs were rare during AOC and occurred with a delayed onset; therefore, increased FiO2 during SL does not necessarily lead to overshoots. [ABSTRACT FROM AUTHOR]

Choline is an essential nutrient, with high requirements during fetal and postnatal growth. Tissue concentrations of total choline are tightly regulated, requiring an increase in its pool size proportional to growth. Phosphatidylcholine and sphingomyelin, containing a choline headgroup, are constitutive membrane phospholipids, accounting for >85% of total choline, indicating that choline requirements are particularly high during growth. Daily phosphatidylcholine secretion via bile for lipid digestion and very low-density lipoproteins for plasma transport of arachidonic and docosahexaenoic acid to other organs exceed 50% of its hepatic pool. Moreover, phosphatidylcholine is required for converting pro-apoptotic ceramides to sphingomyelin, while choline is the source of betaine as a methyl donor for creatine synthesis, DNA methylation/repair and kidney function. Interrupted choline supply, as during current total parenteral nutrition (TPN), causes a rapid drop in plasma choline concentration and accumulating deficit. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) defined choline as critical to all infants requiring TPN, claiming its inclusion in parenteral feeding regimes. We performed a systematic literature search in Pubmed with the terms "choline" and "parenteral nutrition", resulting in 47 relevant publications. Their results, together with cross-references, are discussed. While studies on parenteral choline administration in neonates and older children are lacking, preclinical and observational studies, as well as small randomized controlled trials in adults, suggest choline deficiency as a major contributor to acute and chronic TPN-associated liver disease, and the safety and efficacy of parenteral choline administration for its prevention. Hence, we call for choline formulations suitable to be added to TPN solutions and clinical trials to study their efficacy, particularly in growing children including preterm infants. [ABSTRACT FROM AUTHOR]

Background: Despite therapeutic hypothermia (TH) and neonatal intensive care, 45–50% of children affected by moderate-to-severe neonatal hypoxic-ischemic encephalopathy (HIE) die or suffer from long-term neurodevelopmental impairment. Additional neuroprotective therapies are sought, besides TH, to further improve the outcome of affected infants. Allopurinol — a xanthine oxidase inhibitor — reduced the production of oxygen radicals and subsequent brain damage in pre-clinical and preliminary human studies of cerebral ischemia and reperfusion, if administered before or early after the insult. This ALBINO trial aims to evaluate the efficacy and safety of allopurinol administered immediately after birth to (near-)term infants with early signs of HIE. Methods/design: The ALBINO trial is an investigator-initiated, randomized, placebo-controlled, double-blinded, multi-national parallel group comparison for superiority investigating the effect of allopurinol in (near-)term infants with neonatal HIE. Primary endpoint is long-term outcome determined as survival with neurodevelopmental impairment versus death versus non-impaired survival at 2 years. Results: The primary analysis with three mutually exclusive responses (healthy, death, composite outcome for impairment) will be on the intention-to-treat (ITT) population by a generalized logits model according to Bishop, Fienberg, Holland (Bishop YF, Discrete Multivariate Analysis: Therory and Practice, 1975) and."will be stratified for the two treatment groups. Discussion: The statistical analysis for the ALBINO study was defined in detail in the study protocol and implemented in this statistical analysis plan published prior to any data analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Trial registration: ClinicalTrials.gov NCT03162653. Registered on 22 May 2017. [ABSTRACT FROM AUTHOR]

Choline is essential for cell membrane formation and methyl transfer reactions, impacting parenchymal and neurological development. It is therefore enriched via placental transfer, and fetal plasma concentrations are high. In spite of the greater needs of very low birth weight infants (VLBWI), choline content of breast milk after preterm delivery is lower (median (p25–75): 158 mg/L (61–360 mg/L) compared to term delivery (258 mg/L (142–343 mg/L)). Even preterm formula or fortified breast milk currently provide insufficient choline to achieve physiological plasma concentrations. This secondary analysis of a randomized controlled trial comparing growth of VLBWI with different levels of enteral protein supply aimed to investigate whether increased enteral choline intake results in increased plasma choline, betaine and phosphatidylcholine concentrations. We measured total choline content of breast milk from 33 mothers of 34 VLBWI. Enteral choline intake from administered breast milk, formula and fortifier was related to the respective plasma choline, betaine and phosphatidylcholine concentrations. Plasma choline and betaine levels in VLBWI correlated directly with enteral choline intake, but administered choline was insufficient to achieve physiological (fetus-like) concentrations. Hence, optimizing maternal choline status, and the choline content of milk and fortifiers, is suggested to increase plasma concentrations of choline, ameliorate the choline deficit and improve growth and long-term development of VLBWI. [ABSTRACT FROM AUTHOR]

Background: Choline deficiency leads to pathologies particularly of the liver, brain and lung. Adequate supply is important for preterm infants and patients with cystic fibrosis. We analysed the assimilation of four different enterally administered deuterium-labelled (D9-) choline supplements in adults. Methods: Prospective randomised cross-over study (11/2020–1/2022) in six healthy men, receiving four single doses of 2.7 mg/kg D9-choline equivalent each in the form of D9-choline chloride, D9-phosphorylcholine, D9-alpha-glycerophosphocholine (D9-GPC) or D9-1-palmitoyl-2-oleoyl-glycero-3-phosphoryl-choline (D9-POPC), in randomised order 6 weeks apart. Plasma was obtained at baseline (t = − 0.1 h) and at 0.5 h to 7d after intake. Concentrations of D9-choline and its D9-labelled metabolites were analysed by tandem mass spectrometry. Results are shown as median and interquartile range. Results: Maximum D9-choline and D9-betaine concentrations were reached latest after D9-POPC administration versus other components. D9-POPC and D9-phosphorylcholine resulted in lower D9-trimethylamine (D9-TMAO) formation. The AUCs (0-7d) of plasma D9-PC concentration showed highest values after administration of D9-POPC. D9-POPC appeared in plasma after fatty acid remodelling, predominantly as D9-1-palmitoyl-2-linoleyl-PC (D9-PLPC), confirming cleavage to 1-palmitoyl-lyso-D9-PC and re-acylation with linoleic acid as the most prominent alimentary unsaturated fatty acid. Conclusion: There was a delayed increase in plasma D9-choline and D9-betaine after D9-POPC administration, with no differences in AUC over time. D9-POPC resulted in a higher AUC of D9-PC and virtually absent D9-TMAO levels. D9-POPC is remodelled according to enterocytic fatty acid availability. D9-POPC seems best suited as choline supplement to increase plasma PC concentrations, with PC as a carrier of choline and targeted fatty acid supply as required by organs. This study was registered at Deutsches Register Klinischer Studien (DRKS) (German Register for Clinical Studies), DRKS00020498, 22.01.2020. Study registration: This study was registered at Deutsches Register Klinischer Studien (DRKS) (German Register for Clinical Studies), DRKS00020498. [ABSTRACT FROM AUTHOR]

Background: Supply of choline is not guaranteed in current preterm infant nutrition. Choline serves in parenchyma formation by membrane phosphatidylcholine (PC), plasma transport of poly-unsaturated fatty acids (PUFA) via PC, and methylation processes via betaine. PUFA-PC concentrations are high in brain, liver and lung, and deficiency may result in developmental disorders. We compared different deuterated (D9-) choline components for kinetics of D9-choline, D9-betaine and D9-PC. Methods: Prospective study (1/2021–12/2021) in 32 enterally fed preterm infants (28 0/7–32 0/7 weeks gestation). Patients were randomized to receive enterally a single dose of 2.7 mg/kg D9-choline-equivalent as D9-choline chloride, D9-phosphoryl-choline, D9-glycerophosphorylcholine (D9-GPC) or D9-1-palmitoyl-2-oleoyl-PC(D9-POPC), followed by blood sampling at 1 + 24 h or 12 + 60 h after administration. Plasma concentrations were analyzed by tandem mass spectrometry. Results are expressed as median (25th/75th percentile). Results: At 1 h, plasma D9-choline was 1.8 (0.9/2.2) µmol/L, 1.3 (0.9/1.5) µmol/L and 1.2 (0.7/1.4) µmol/L for D9-choline chloride, D9-GPC and D9-phosphoryl-choline, respectively. D9-POPC did not result in plasma D9-choline. Plasma D9-betaine was maximal at 12 h, with lowest concentrations after D9-POPC. Maximum plasma D9-PC values at 12 h were the highest after D9-POPC (14.4 (9.1/18.9) µmol/L), compared to the other components (D9-choline chloride: 8.1 [5.6/9.9] µmol/L; D9-GPC: 8.4 (6.2/10.3) µmol/L; D9-phosphoryl-choline: 9.8 (8.6/14.5) µmol/L). Predominance of D9-PC comprising linoleic, rather than oleic acid, indicated fatty-acyl remodeling of administered D9-POPC prior to systemic delivery. Conclusion: D9-Choline chloride, D9-GPC and D9-phosphoryl-choline equally increased plasma D9-choline and D9-betaine. D9-POPC shifted metabolism from D9-betaine to D9-PC. Combined supplementation of GPC and (PO) PC may be best suited to optimize choline supply in preterm infants. Due to fatty acid remodeling of (PO) PC during its assimilation, PUFA co-supplementation with (PO) PC may increase PUFA-delivery to critical organs. This study was registered (22.01.2020) at the Deutsches Register Klinischer Studien (DRKS) (German Register for Clinical Studies), DRKS00020502. Study registration: This study was registered at the Deutsches Register Klinischer Studien (DRKS) (German Register for Clinical Studies), DRKS00020502. [ABSTRACT FROM AUTHOR]

Background and Objective: Previously, we developed a pharmacokinetic-pharmacodynamic model of allopurinol, oxypurinol, and biomarkers, hypoxanthine, xanthine, and uric acid, in neonates with hypoxic-ischemic encephalopathy, in which high initial biomarker levels were observed suggesting an impact of hypoxia. However, the full pharmacodynamics could not be elucidated in our previous study. The current study included additional data from the ALBINO study (NCT03162653) placebo group, aiming to characterize the dynamics of hypoxanthine, xanthine, and uric acid in neonates with hypoxic-ischemic encephalopathy. Methods: Neonates from the ALBINO study who received allopurinol or placebo mannitol were included. An extended population pharmacokinetic-pharmacodynamic model was developed based on the mechanism of purine metabolism, where synthesis, salvage, and degradation via xanthine oxidoreductase pathways were described. The initial level of the biomarkers was a combination of endogenous turnover and high disease-related amounts. Model development was accomplished by nonlinear mixed-effects modeling (NONMEM®, version 7.5). Results: In total, 20 neonates treated with allopurinol and 17 neonates treated with mannitol were included in this analysis. Endogenous synthesis of the biomarkers reduced with 0.43% per hour because of precursor exhaustion. Hypoxanthine was readily salvaged or degraded to xanthine with rate constants of 0.5 1/h (95% confidence interval 0.33–0.77) and 0.2 1/h (95% confidence interval 0.09–0.31), respectively. A greater salvage was found in the allopurinol treatment group consistent with its mechanism of action. High hypoxia-induced initial levels of biomarkers were quantified, and were 1.2-fold to 2.9-fold higher in neonates with moderate-to-severe hypoxic-ischemic encephalopathy compared with those with mild hypoxic-ischemic encephalopathy. Half-maximal xanthine oxidoreductase inhibition was achieved with a combined allopurinol and oxypurinol concentration of 0.68 mg/L (95% confidence interval 0.48–0.92), suggesting full xanthine oxidoreductase inhibition during the period studied. Conclusions: This extended pharmacokinetic-pharmacodynamic model provided an adequate description of the complex hypoxanthine, xanthine, and uric acid metabolism in neonates with hypoxic-ischemic encephalopathy, suggesting a positive allopurinol effect on these biomarkers. The impact of hypoxia on their dynamics was characterized, underlining higher hypoxia-related initial exposure with a more severe hypoxic-ischemic encephalopathy status. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate body composition at the time of hospital discharge in very preterm infants following rapid transition to full enteral feeding. Study Design: We conducted a prospective, observational, cross-sectional study and included 105 preterm infants <32 gestational age or birth weight <1,500 g, born between April 2015 and December 2020, following rapid transition to full enteral feeding (≥140 mL/kg/day). Fat mass/total body mass (BF%) and fat-free mass (FFM) were measured at the time of hospital discharge using air displacement plethysmography. Results: Median and interquartile range (Q1–Q3) of gestational age at birth (GA) was 27.3 (26.1–28.7) weeks and birth weight 845 (687–990) g. Time to reach full enteral feeding was 5 (5–7) days. At 37.6 weeks (36.1–39.0) postmenstrual age (PMA), BF% was 17.0% (14.9–19.8) and FFM 2,161 g (1,966–2,432). BF% was not associated with GA, and not different between small and appropriate for gestational age infants. FFM was significantly lower in infants born small for gestational age. Conclusions: Following rapid transition to full enteral feeding, FFM and BF% at discharge were similar to other preterm populations. BF% and FFM were not associated with GA at birth but with PMA at measurement. FFM was lower and BF% higher compared to term infants at birth, suggesting diminished parenchymal growth in preterm infants. Continued monitoring of body composition, metabolic health, and neurological development is needed to study long-term effects. [ABSTRACT FROM AUTHOR]

Background: Allopurinol, an xanthine oxidase (XO) inhibitor, is a promising intervention that may provide neuroprotection for neonates with hypoxic-ischemic encephalopathy (HIE). Currently, a double-blind, placebo-controlled study (ALBINO, NCT03162653) is investigating the neuroprotective effect of allopurinol in HIE neonates. Objective: The aim of the current study was to establish the pharmacokinetics (PK) of allopurinol and oxypurinol, and the pharmacodynamics (PD) of both compounds on hypoxanthine, xanthine, and uric acid in HIE neonates. The dosage used and the effect of allopurinol in this population, either or not undergoing therapeutic hypothermia (TH), were evaluated. Methods: Forty-six neonates from the ALBINO study and two historical clinical studies were included. All doses were administered on the first day of life. In the ALBINO study (n = 20), neonates received a first dose of allopurinol 20 mg/kg, and, in the case of TH (n = 13), a second dose of allopurinol 10 mg/kg. In the historical cohorts (n = 26), neonates (all without TH) received two doses of allopurinol 20 mg/kg in total. Allopurinol and oxypurinol population PK, and their effects on inhibiting conversions of hypoxanthine and xanthine to uric acid, were assessed using nonlinear mixed-effects modelling. Results: Allopurinol and oxypurinol PK were described by two sequential one-compartment models with an autoinhibition effect on allopurinol metabolism by oxypurinol. For allopurinol, clearance (CL) was 0.83 L/h (95% confidence interval [CI] 0.62–1.09) and volume of distribution (Vd) was 2.43 L (95% CI 2.25–2.63). For metabolite oxypurinol, CL and Vd relative to a formation fraction (fm) were 0.26 L/h (95% CI 0.23–0.3) and 11 L (95% CI 9.9–12.2), respectively. No difference in allopurinol and oxypurinol CL was found between TH and non-TH patients. The effect of allopurinol and oxypurinol on XO inhibition was described by a turnover model of hypoxanthine with sequential metabolites xanthine and uric acid. The combined allopurinol and oxypurinol concentration at the half-maximal XO inhibition was 0.36 mg/L (95% CI 0.31–0.42). Conclusion: The PK and PD of allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid in neonates with HIE were described. The dosing regimen applied in the ALBINO trial leads to the targeted XO inhibition in neonates treated with or without TH. [ABSTRACT FROM AUTHOR]

Background: Adequate intake of choline is essential for growth and homeostasis, but its supply does often not meet requirements. Choline deficiency decreases phosphatidylcholine (PC) and betaine synthesis, resulting in organ pathology, especially of liver, lung, and brain. This is of particular clinical importance in preterm infants and cystic fibrosis patients. We compared four different choline supplements for their impact on plasma concentration and kinetics of choline, betaine as a methyl donor and trimethylamine oxide (TMAO) as a marker of bacterial degradation prior to absorption. Methods: Prospective randomized cross-over study (1/2020–4/2020) in six healthy adult men. Participants received a single dose of 550 mg/d choline equivalent in the form of choline chloride, choline bitartrate, α-glycerophosphocholine (GPC), and egg-PC in randomized sequence at least 1 week apart. Blood was taken from t = − 0.1–6 h after supplement intake. Choline, betaine, TMAO, and total PC concentrations were analyzed by tandem mass spectrometry. Results are shown as medians and interquartile range. Results: There was no difference in the AUC of choline plasma concentrations after intake of the different supplements. Individual plasma kinetics of choline and betaine differed and concentrations peaked latest for PC (at ≈3 h). All supplements similarly increased plasma betaine. All water-soluble supplements rapidly increased TMAO, whereas egg-PC did not. Conclusion: All supplements tested rapidly increased choline and betaine levels to a similar extent, with egg-PC showing the latest peak. Assuming that TMAO may have undesirable effects, egg-PC might be best suited for choline supplementation in adults. Study registration: This study was registered at "Deutsches Register Klinischer Studien" (DRKS) (German Register for Clinical Studies), 17.01.2020, DRKS00020454. [ABSTRACT FROM AUTHOR]

This correction notice provides updates to the Recruiting Hospitals and Local Principal Investigator list for the ALBINO study group in the acknowledgement section of the original article. It includes names that were originally missing and removes names that were originally included. The original article has been corrected. [Extracted from the article]

Background: In-utero weight gain can be achieved in very preterm infants through rapid advancement of enteral feeds without increasing risk of necrotizing enterocolitis. There are concerns, however, that such rapid weight gain may lead to an increased childhood adiposity risk, although long-term data are sparse.Design: This retrospective observational study included two well-characterized cohorts comprising 145 infants born at < 28 weeks or with < 1000 g birth weight. We investigated associations between advancing enteral feeding volumes in daily increments of 15-20 ml/kg (Cohort 1, n = 84, born in 2006/2007) vs. 25-30 ml/kg (Cohort 2, n = 61, born in 2010) and growth up to 5 years of age.Results: There was no significant difference in anthropometric parameters post discharge to 5 years between both cohorts. Standard deviation score (SDS) weight and SDS BMI at the age of 5 years remained lower than in the reference population. SDS weight decreased from discharge to about 10-12 months postnatal age and returned to birth values by age 5 years. There was a catch-up for SDS length/height from discharge to 5 years; SDS head circumference decreased from birth to 5 years. Multiple regression analyses revealed that for all anthropometric parameters SDS at birth was the most important predictor for SDS at 5 years. Early parenteral protein intake may be another important factor, at least for head growth.Conclusions: Growth was similar in both cohorts without benefit from more accelerated feeding advancement in cohort 2. In both cohorts, early enteral nutrition was associated with in-hospital weight gain as in utero, a drop in weight SDS post discharge and catch-up to birth SDS until age 5 years, remaining below the reference population. Length showed catch-up form discharge to 5 years, whereas head circumference progressively deviated from the reference population. Increased parenteral protein supplementation may be needed to accompany early enteral feeding advancements. [ABSTRACT FROM AUTHOR]

Background: Therapeutic hypothermia (TH) is an established intervention to improve the outcome of neonates with moderate-to-severe hypoxic-ischemic encephalopathy resulting from perinatal asphyxia. Despite this beneficial effect, TH may further affect drug elimination pathways such as the glomerular filtration rate. Objectives: The objective of this study was to quantify the effect of TH in addition to asphyxia on mannitol clearance as a surrogate for the glomerular filtration rate. Methods: The effect of asphyxia and TH (mild vs moderate/severe) on mannitol clearance was assessed using a population approach, based on mannitol observations collected in the ALBINO (ALlopurinol in addition to TH for hypoxic-ischemic Brain Injury on Neurocognitive Outcome) trial, as some were exposed to a second dose of 10 mg/kg intravenous mannitol as placebo to ensure blinding. Pharmacokinetic analysis and model development were conducted using NONMEM version 7.4. Results: Based on 77 observations from 17 neonates (TH = 13), a one-compartment model with first-order linear elimination best described the observed data. To account for prenatal glomerular filtration rate maturation, both birthweight and gestational age were implemented as clearance covariates using an earlier published three-quarters power function and a sigmoid hyperbolic function. Our final model predicted a mannitol clearance of 0.15 L/h for a typical asphyxia neonate (39.5 weeks, birthweight 3.25 kg, no TH), lower than the reported value of 0.33 L/h for a healthy neonate of similar age and weight. By introducing TH as a binary covariate on clearance, the additional impact of TH on mannitol clearance was quantified (60% decrease). Conclusions: Mannitol clearance was decreased by approximately 60% in neonates undergoing TH, although this is likely confounded with asphyxia severity. Trial Registration: ClinicalTrials.gov identifier NCT03162653. [ABSTRACT FROM AUTHOR]

Background: Offspring of mothers with gestational diabetes mellitus (GDM) have an increased risk of neonatal complications like birth trauma due to macrosomia or postnatal hypoglycemia, as well as long-term metabolic sequelae. Neonatal body composition may be a sensitive marker of metabolic effects on the fetus caused by suboptimal glycemic control during pregnancy.Objective: To determine body composition in offspring of mothers with GDM compared to a reference cohort of healthy term neonates and to assess whether increased body fat would be associated with postnatal hypoglycemia.Methods: This prospective, observational, cross-sectional study included 311 full-term, singleton infants born between June 2014 and July 2015. Body composition was measured within 96 h of birth using air displacement plethysmography. Results are indicated as median (1st Quartile - 3rd Quartile).Results: Of 311 infants, 40 (12.9%) were born to mothers with GDM. Birth weight standard deviation scores (SDS) (0.24 vs. - 0.07, p = 0.04), fat mass (370 g vs. 333 g, p = 0.02) as well as fat mass/total body mass (BF%; 11.4% vs. 10.8%, p = 0.03) were significantly higher in infants following maternal GDM than in controls. In GDM offspring, anthropometric parameters, fat mass or BF% did not differ between infants with or without postnatal hypoglycemia. In this cohort, SDS for birth weight, fat mass, fat free mass, BF% or postnatal hypoglycemia were not associated with maternal blood glucose levels measured at an oral glucose tolerance test.Conclusions: SDS for birth weight, neonatal fat mass, and BF% were significantly higher in newborns following maternal GDM. In these infants born to mothers with GDM, body composition did not differ between those with or without postnatal hypoglycemia. [ABSTRACT FROM AUTHOR]

Background: Offspring of mothers with gestational diabetes mellitus (GDM) have an increased risk of neonatal complications like birth trauma due to macrosomia or postnatal hypoglycemia, as well as long-term metabolic sequelae. Neonatal body composition may be a sensitive marker of metabolic effects on the fetus caused by suboptimal glycemic control during pregnancy. Objective: To determine body composition in offspring of mothers with GDM compared to a reference cohort of healthy term neonates and to assess whether increased body fat would be associated with postnatal hypoglycemia. Methods: This prospective, observational, cross-sectional study included 311 full-term, singleton infants born between June 2014 and July 2015. Body composition was measured within 96 h of birth using air displacement plethysmography. Results are indicated as median (1st Quartile – 3rd Quartile). Results: Of 311 infants, 40 (12.9%) were born to mothers with GDM. Birth weight standard deviation scores (SDS) (0.24 vs. − 0.07, p = 0.04), fat mass (370 g vs. 333 g, p = 0.02) as well as fat mass/total body mass (BF%; 11.4% vs. 10.8%, p = 0.03) were significantly higher in infants following maternal GDM than in controls. In GDM offspring, anthropometric parameters, fat mass or BF% did not differ between infants with or without postnatal hypoglycemia. In this cohort, SDS for birth weight, fat mass, fat free mass, BF% or postnatal hypoglycemia were not associated with maternal blood glucose levels measured at an oral glucose tolerance test. Conclusions: SDS for birth weight, neonatal fat mass, and BF% were significantly higher in newborns following maternal GDM. In these infants born to mothers with GDM, body composition did not differ between those with or without postnatal hypoglycemia. [ABSTRACT FROM AUTHOR]

Background: Less-invasive surfactant administration (LISA) is increasingly used. We investigated the feasibility of a new LISA-device (Neofact®) in neonates.Design: Prospective observational pilot study with open-label LISA in two tertiary neonatal intensive care units.Patients: 20 infants with a gestational age of ≥26+0/7 weeks and an indication for LISA (Respiratory Severity Score (RSS)≥5 or fraction of inspired oxygen (FiO2) ≥0.30). Infants with respiratory tract malformations or unavailability of an instructed neonatologist were excluded.Main Outcome Measures: Success of LISA, defined as laryngoscopy-confirmed intratracheal catheter position or a decrease in FiO2 by ≥0.05 or to 0.21, accompanied by an RSS decrease of ≥2; number of attempts needed for tracheal catheterisation.Results: 20/57 screened infants were enrolled. Successful application occurred in 19/20 (95%). One application failed after three attempts. No device-related adverse events occurred. The median number of attempts was 2, success rate per attempt 19/31 (61%).Conclusion: LISA via Neofact® appears feasible. [ABSTRACT FROM AUTHOR]

Introduction: Less-invasive surfactant administration (LISA) under continuous positive airway pressure is increasingly used for the treatment of neonatal respiratory distress. Different procedures are described, but data on the optimal catheter insertion depth are sparse.Objective: To generate data for recommending an optimal catheter insertion depth in LISA.Methods: We examined 112 anterior-posterior chest X-rays from intubated infants and determined the carina's vertebral projection, whenever possible. After that, distances between the middle of cervical vertebra 4 (C4) and thoracic vertebra 2 and the middle of C4 to thoracic vertebra 3, respectively, were measured. Results were plotted against infant's weight.Results: A weight-based chart and recommendations for the optimal intratracheal catheter position in infants with a body weight between 350 and 4000 g were created.Conclusions: Generated data offer standardisation and may thus help to find a balance between risk of surfactant reflux and unilateral surfactant administration. [ABSTRACT FROM AUTHOR]

Objective: Severe neonatal growth hormone deficiency (GHD) can cause recurrent hypoglycaemia. Early diagnosis is warranted. The aim of the study was to analyse the GH content in screening cards of 25 affected and 281 healthy newborns. Patients and Measurements: A total of 110 screening cards from ill newborns were sent to us for measuring GH content by a highly sensitive GH ELISA. Clinical information was obtainable in 61 cases. Severe GHD was defined by the presence of recurrent hypoglycaemia with a significant pituitary malformation or two additional pituitary hormone deficiencies. Screening cards from 281 healthy newborns (34.0‐37.9 weeks) were prospectively analysed. Results: In 25 newborns (5 preterm), the definition of severe GHD was fulfilled based on recurrent hypoglycaemia in combination with malformation of the pituitary or midline structures in 21 cases and combined TSH and ACTH deficiency in four cases. The median GH concentration of those affected with severe GHD was 3.9 µg/L (range: 1.1‐11.8), significantly below the previously reported reference range (P <.001). A GH concentration of 7 µg/L was confirmed as the cut‐off for term newborns with the best accuracy (90.0% sensitivity and 98.7% specificity). The 95% reference range for healthy preterm newborns (n = 151) was 7.6‐47.1 µg/L (median: 20.3 µg/L). Conclusions: A GH content <7.0 µg/L in the newborn screening card confirms severe GHD with high accuracy. In preterm newborns, the lower limit of the reference interval was 0.6 µg/L higher than in term newborns. The newborn screening card is a valuable source for the very early diagnosis of GH deficiency. [ABSTRACT FROM AUTHOR]

Importance: Red blood cell transfusions are commonly administered to infants weighing less than 1000 g at birth. Evidence-based transfusion thresholds have not been established. Previous studies have suggested higher rates of cognitive impairment with restrictive transfusion thresholds.Objective: To compare the effect of liberal vs restrictive red blood cell transfusion strategies on death or disability.Design, Setting, and Participants: Randomized clinical trial conducted in 36 level III/IV neonatal intensive care units in Europe among 1013 infants with birth weights of 400 g to 999 g at less than 72 hours after birth; enrollment took place between July 14, 2011, and November 14, 2014, and follow-up was completed by January 15, 2018.Interventions: Infants were randomly assigned to liberal (n = 492) or restrictive (n = 521) red blood cell transfusion thresholds based on infants' postnatal age and current health state.Main Outcome and Measures: The primary outcome, measured at 24 months of corrected age, was death or disability, defined as any of cognitive deficit, cerebral palsy, or severe visual or hearing impairment. Secondary outcome measures included individual components of the primary outcome, complications of prematurity, and growth.Results: Among 1013 patients randomized (median gestational age at birth, 26.3 [interquartile range {IQR}, 24.9-27.6] weeks; 509 [50.2%] females), 928 (91.6%) completed the trial. Among infants in the liberal vs restrictive transfusion thresholds groups, respectively, incidence of any transfusion was 400/492 (81.3%) vs 315/521 (60.5%); median volume transfused was 40 mL (IQR, 16-73 mL) vs 19 mL (IQR, 0-46 mL); and weekly mean hematocrit was 3 percentage points higher with liberal thresholds. Among infants in the liberal vs restrictive thresholds groups, the primary outcome occurred in 200/450 (44.4%) vs 205/478 (42.9%), respectively, for a difference of 1.6% (95% CI, -4.8% to 7.9%; P = .72). Death by 24 months occurred in 38/460 (8.3%) vs 44/491 (9.0%), for a difference of -0.7% (95% CI, -4.3% to 2.9%; P = .70), cognitive deficit was observed in 154/410 (37.6%) vs 148/430 (34.4%), for a difference of 3.2% (95% CI, -3.3% to 9.6%; P = .47), and cerebral palsy occurred in 18/419 (4.3%) vs 25/443 (5.6%), for a difference of -1.3% (95% CI, -4.2% to 1.5%; P = .37), in the liberal vs the restrictive thresholds groups, respectively. In the liberal vs restrictive thresholds groups, necrotizing enterocolitis requiring surgical intervention occurred in 20/492 (4.1%) vs 28/518 (5.4%); bronchopulmonary dysplasia occurred in 130/458 (28.4%) vs 126/485 (26.0%); and treatment for retinopathy of prematurity was required in 41/472 (8.7%) vs 38/492 (7.7%). Growth at follow-up was also not significantly different between groups.Conclusions and Relevance: Among infants with birth weights of less than 1000 g, a strategy of liberal blood transfusions compared with restrictive transfusions did not reduce the likelihood of death or disability at 24 months of corrected age.Trial Registration: ClinicalTrials.gov Identifier: NCT01393496. [ABSTRACT FROM AUTHOR]

Objective: Closed-loop automatic control (CLAC) of the fractional inspired oxygen (FiO2) improved oxygen administration to preterm infants on respiratory support. We investigated whether a revised CLAC algorithm (CLACfast, ≤2 FiO2 adjustments/min), compared with routine manual control (RMConly), increased the proportion of time with arterial haemoglobin oxygen saturation measured by pulse oximetry within prespecified target ranges (Target%) while not being inferior to the original algorithm (CLACslow: ≤0.3 FiO2 adjustments/min).Design: Unblinded randomised controlled crossover study comparing three modes of FiO2 control in random order for 8 hours each: RMC supported by CLACfast was compared with RMConly and RMC supported by CLACslow. A computer-generated list of random numbers using a block size of six was used for the allocation sequence.Setting: Two German tertiary university neonatal intensive care units.Patients: Of 23 randomised patients, 19 were analysed (mean±SD gestational age 27±2 weeks; age at randomisation 24±10 days) on non-invasive (n=18) or invasive (n=1) respiratory support at FiO2 >0.21.Main Outcome Measure: Target%.Results: Mean±SD [95% CI] Target% was 68%±11% [65% to 71%] for CLACfast versus 65%±11% [61% to 68%] for CLACslow versus 58%±11% [55% to 62%] for RMConly. Prespecified hypothesis tests of: (A) superiority of CLACfast versus RMConly and (B) non-inferiority of CLACfast versus CLACslow with margin of 5% yielded one-sided p values of <0.001 for both comparisons.Conclusions: This revised and faster CLAC algorithm was still superior to routine care in infants on respiratory support and not inferior to a previously tested slower algorithm.Trial Registration Number: NCT03163108. [ABSTRACT FROM AUTHOR]

Background: Respiratory distress syndrome (RDS) is a frequent complication of premature birth. Treating RDS by continuous positive airway pressure and less invasive surfactant administration (LISA) may reduce bronchopulmonary dysplasia. Surfactant, however, can be inactivated by bacterial infection. Therefore, potential routes of microbe transmission into the airway are of interest. The aim of this study was to evaluate microbiological contamination of catheters used for LISA procedures and its association with postnatal age.Methods: Catheter tips used for LISA procedures via the nasal route (LISA-n) in infants with RDS were placed into a sterile eSwab container directly after the procedure, cultured and examined for microbiological contamination.Results: Interpretable results could be collected from 20 catheter tips. Four showed positive culture results (20%) with microbes potentially associated with the development of early onset neonatal sepsis. Risk of positive microbe detection increased with postnatal age (< 4 h: 10%; 4-18 h: 20%; > 18 h: 40%).Conclusions: In this pilot study, the risk of tracheal microbe transmission following the LISA-n procedure increased with postnatal age. Although the clinical relevance of this finding is unclear, earlier surfactant administration might reduce the risk of catheter contamination.Trial Registration Number: Substudy of the registered Trial: feasibility study - Neofact: NCT04086095, www.ClinicalTrials.gov, September 11, 2019. [ABSTRACT FROM AUTHOR]

Objective: Choline and docosahexaenoic acid (DHA) are essential nutrients for preterm infant development. They are metabolically linked via phosphatidylcholine (PC), a constitutive plasma membrane lipid and the major transport form of DHA in plasma. Plasma choline and DHA-PC concentrations rapidly decline after preterm birth. To improve preterm infant nutrition, we evaluated combined compared to exclusive choline and DHA supplementation, and standard feeding. Design: Randomized partially blinded single-center trial. Setting: Neonatal tertiary referral center in Tübingen, Germany. Patients: 24 inborn preterm infants < 32 week postmenstrual age. Interventions: Standard nutrition (control) or, additionally, enteral choline (30 mg/kg/day), DHA (60 mg/kg/day), or both for 10 days. Single enteral administration of 3.6 mg/kg [methyl-D9-] choline chloride as a tracer at 7.5 days. Main outcome measures: Primary outcome variable was plasma choline following 7 days of supplementation. Deuterated and unlabeled choline metabolites, DHA-PC, and other PC species were secondary outcome variables. Results: Choline supplementation increased plasma choline to near-fetal concentrations [35.4 (32.8–41.7) µmol/L vs. 17.8 (16.1–22.4) µmol/L, p < 0.01] and decreased D9-choline enrichment of PC. Single DHA treatment decreased DHA in PC relative to total lipid [66 (60–68)% vs. 78 (74–80)%; p < 0.01], which was prevented by choline. DHA alone increased DHA-PC only by 35 (26–45)%, but combined treatment by 63 (49–74)% (p < 0.001). D9-choline enrichment showed preferential synthesis of PC containing linoleic acid. PC synthesis via phosphatidylethanolamine methylation resulted in preferential synthesis of DHA-containing D3-PC, which was increased by choline supplementation. Conclusions: 30 mg/kg/day additional choline supplementation increases plasma choline to near-fetal concentrations, dilutes the D9-choline tracer via increased precursor concentrations and improves DHA homeostasis in preterm infants. Trial registration: clinicaltrials.gov. Identifier: NCT02509728. [ABSTRACT FROM AUTHOR]

Background: There is increasing evidence that intrauterine environment and, consequently, growth in utero have both immediate and far-reaching consequences for health. Neonatal body composition might be a more sensitive marker of intrauterine environment and neonatal adiposity than birth weight and could serve as a predictor for non-communicable diseases later in life.Methods: To perform a systematic literature review on neonatal body composition determined by air displacement plethysmography in healthy infants. The systematic review was performed using the search terms "air displacement plethysmography", "infant" and "newborn" in Pubmed. Data are displayed as mean (Standard deviation).Results: Fourteen studies (including n = 6231 infants) using air displacement plethysmography fulfilled inclusion criteria for meta-analysis. In these, weighted mean body fat percentage was 10.0 (4.1) % and weighted mean fat free mass was 2883 (356) g in healthy term infants. Female infants had a higher body fat percentage (11.1 (4.1) % vs. 9.6 (4.0) %) and lower fat free mass (2827 (316) g vs. 2979 (344) g). In the Caucasian subpopulation (n = 2202 infants) mean body fat percentage was 10.8 (4.1), whereas data for reference values of other ethnic groups are still sparse.Conclusions: Body composition varies depending on gender and ethnicity. These aggregated data may serve as reference for body composition in healthy, term, singletons at least for the Caucasian subpopulation. [ABSTRACT FROM AUTHOR]

Background: During pregnancy, a variety of factors can influence fetal growth and development. Intrauterine growth may impact on later life and health. Neonatal body composition may be a more sensitive marker for the intrauterine environment than established anthropometric parameters at birth.Methods: To study neonatal body composition determined by air displacement plethysmography in healthy, term singletons as national reference data, and to establish factors impacting on neonatal body composition in this population. This prospective cross-sectional observational study included 271 healthy, full-term, singletons born between June 2014 and July 2015. Body composition was measured within 96 h of birth using air displacement plethysmography.Results: Median (Q1, Q2) fat mass / total body mass (BF%) in German singletons was 10.8% (7.7-13.4) and fat free mass (FFM) 2843 g (2606-3099). Female infants had significantly increased BF% compared to male infants (11.2% (8.7-14.0) vs. 9.6% (7.2-12.1)). On multiple regression analysis, BF% and fat mass increased with female gender, maternal pre-pregnancy body mass index, non-smoking mother and parity, whereas FFM increased with male gender and increasing gestational age at birth. Gestational weight gain category, birth mode, and postnatal age at measurement were not associated with BF%, FFM or fat mass.Conclusions: We generated BF% and FFM centiles for healthy, term, singletons born in Germany; these are similar to those found in other European countries. Infant body composition at birth was associated with modifiable (pre-pregnancy body mass index, smoking), and given factors (gender, gestational age at birth, parity). [ABSTRACT FROM AUTHOR]

Background: We conducted a monthly epidemiological survey in Germany to detect the prevalence of volvulus without malrotation (VWM) in very low birthweight (VLBW) infants and to identify factors for a better distinction between this rare and life-threatening event and other acute abdominal diseases in preterm infants.Methods: Throughout 2014 and 2015, every paediatric department in Germany was asked to report cases of VWM in infants with birth weights <1500 g to the Surveillance Unit for Rare Paediatric Conditions in Germany. Hospitals reporting a case were asked to return an anonymised questionnaire and discharge letter.Results: Of 36 cases reported, detailed information was submitted on 29, with 26 meeting entry criteria. With 9896 and 10 140 VLBW infants born in Germany in 2014 and 2015, respectively, we estimated a prevalence of 1.52/1000 VLBW infants for 2014 and 1.08/1000 in 2015. No specific early symptom could be determined. 10% died, and 21% of infants developed short bowel syndrome. Calculated from all verified VWM arise death in 8% and a short bowel syndrome in 15%.Conclusion: VWM is a rare source of acute abdomen in VLBW infants. No specific signs and symptoms potentially facilitating an early recognition of VWM could be found from this survey. Because the rates of death and short bowel syndrome are high, VWM should always be considered early in an acute abdomen in a VLBW infant. [ABSTRACT FROM AUTHOR]

Background: Choline is an essential nutrient, with increased requirements during development. It forms the headgroup of phosphatidylcholine and sphingomyelin in all membranes and many secretions. Phosphatidylcholine is linked to cell signaling as a phosphocholine donor to synthesize sphingomyelin from ceramide, a trigger of apoptosis, and is the major carrier of arachidonic and docosahexaenoic acid in plasma. Acetylcholine is important for neurodevelopment and the placental storage form for fetal choline supply. Betaine, a choline metabolite, functions as osmolyte and methyl donor. Their concentrations are all tightly regulated in tissues. Clincal impact: During the fetal growth spurt at 24–34-week postmenstrual age, plasma choline is higher than beyond 34 weeks, and threefold higher than in pregnant women [45 (36–60) µmol/L vs. 14 (10–17) µmol/L]. The rapid decrease in plasma choline after premature birth suggests an untimely reduction in choline supply, as cellular uptake is proportional to plasma concentration. Supply via breast milk, with phosphocholine and α-glycerophosphocholine as its major choline components, does not prevent such postnatal decrease. Moreover, high amounts of liver PC are secreted via bile, causing rapid hepatic choline turnover via the enterohepatic cycle, and deficiency in case of pancreatic phospholipase A2 deficiency or intestinal resection. Choline deficiency causes hepatic damage and choline accretion at the expense of the lungs and other tissues. Conclusion: Choline deficiency may contribute to the impaired lean body mass growth and pulmonary and neurocognitive development of preterm infants despite adequate macronutrient supply and weight gain. In this context, a reconsideration of current recommendations for choline supply to preterm infants is required. [ABSTRACT FROM AUTHOR]

Background: Adjusting the fraction of inspired oxygen (FiO2) delivered to preterm infants to keep their oxygen saturation within target range remains challenging. Closed-loop automated FiO2 control increases the time infants spend within the assigned target range. The delay with which FiO2 adjustments at the ventilator result in a change in the inspired gas limits the performance of both manual and automated controls.Objective: To evaluate the equilibration time (Teq) between FiO2 adjustments and changes in FiO2 reaching the patient.Methods: In vitro determination of the delay in FiO2 adjustments at the ventilator at 5 and 8 L/min of gas flow and two different humidifier/ventilator circuit volumes (840 and 432 mL).Results: Teq values were 31, 23, 20 and 17 s for the volume-flow combinations 840 mL+5 L/min, 840 mL+8 L/min, 432 mL+5 L/min and 432 mL+8 L/min, respectively.Conclusion: The identified delay seems clinically relevant and should be taken into account during manual and automatic control of FiO2. [ABSTRACT FROM AUTHOR]

Aim: Data on the depth of nasal intubation in neonates are rare, although this is the preferred route in some countries. Therefore, recommendations on optimal nasal intubation depths based on gestational age (GA) and weight are desirable.Methods: We determined the distances between the middle of thoracic vertebrae 2 (T2) and the tip of the endotracheal tube in 116 X-rays from nasally intubated neonates. The intubation depth (tip to nostril distance) that was documented in the digital patient's file was then corrected for this distance to reach an optimal nasal insertion depth. Results were plotted against the infant's GA and weight.Results: GA-based and birthweight-based charts and formulas for the nasal intubation depth in infants with a GA between 24 and 43 weeks and body weight between 400 and 4500 g were created.Conclusions: Generated data may help in predicting optimal insertion depths for nasal intubation in neonates. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of pancreatic enzyme substitution (PES) in selected very low birthweight (VLBW) infants with poor postnatal growth despite intensified nutritional support.Design: Retrospective historic cohort study with matched controls.Setting: Single level III neonatal intensive care unit.Patients: Infants with a gestational age at birth <32 weeks and birth weight <1500 g born between 1 January 2005 and 31 December 2014 (n=26) who received PES for restricted postnatal growth despite intensified enteral nutritional support in comparison with infants matched for birth weight, birth year, gestational and postnatal age (n=52).Interventions: PES 15-93 mg/g fat with enteral feeds.Main Outcome Measures: The difference in SD score (SDS) differences for weight during the 7 days before and after onset of PES and weight gain in g/kg/d. Data are presented as median (P10-P90).Results: Gestational age was 26.6 (24.4-29.9) weeks in enzyme substituted versus 26.4 (24.7-29.9) weeks in matched controls, and birth weight was 648(420-950)g versus 685(453-949)g. SDS differences for weight improved after onset of PES by 0.18(-0.12 to 0.53) in PES infants versus -0.04(-0.31 to 0.44) in controls. Weight gain increased in the PES group from 13.6 (4.2-22.9) g/kg/day in the week before to 19.0 (10.9-29.1) g/kg/day in the week after the onset of PES. There was no difference in weight gain in substituted subgroups receiving formula/pasteurised human milk versus unpasteurised human breast milk or who had pancreatic-specific elastase-1 concentrations in stool >200 µg/g versus≤200 µg/g. No adverse effects were noted.Conclusions: PES in selected VLBW infants with growth failure despite intensified enteral nutritional support was associated with a significant increase in weight gain in the first 7 days of PES.k. [ABSTRACT FROM AUTHOR]

Background: Docosahexaenoic (C22:6) and arachidonic (C20:4) acids are long-chain polyunsaturated fatty acids (LC-PUFA) essential to neonatal development, being present in the glycerophospholipids of all organs, particularly the brain. In plasma, LC-PUFAs are mainly present in lipoprotein lipids, which are neutral lipids (triglycerides and cholesterol esters) and glycerophospholipids, like choline containing phosphatidylcholine (PC).Purpose: To guide future supplementation strategies of C22:6 and C20:4 in combination with choline, we determined the distribution of C20:4 and C22:6 between PC and neutral lipid.Methods: Preterm infant plasma (N = 59, postmenstrual age [PMA] 33.9 wk (32.4-36.0)) and cord plasma (N = 34, PMA 34.0 wk (30.86-38.4)) were investigated. PC and neutral lipids were extracted and analyzed using tandem mass spectrometry and gas chromatography, respectively. Data are reported as medians and 25th/75th percentiles.Results: In cord blood, C20:4-PC and C22:6-PC comprised 36.1% (34.2-38.6) and 10.2% (8.8-12.8) of total PC, respectively. In preterm infant plasma, values were only 20.8% (19.2-23.1) and 5.7% (5.2-6.0), respectively (p < 0.001 each). Nevertheless, in preterm infant plasma, 80.6% (77.6-83.0) of C20:4 and 86.0% (83.0-88.9) of C22:6 were found in PC. These values exceeded the proportions of C20:4 and C22:6 in PC of cord plasma [71.3% (67.8-72.9) and 79.2% (75.2-85.4), respectively] (p < 0.0001 each).Conclusion: Irrespective of the low proportions of C20:4-PC and C22:6-PC in preterm infant plasma lipids, PC is the major transporter for C20:4 and C22:6. Our data support the hypotheses that choline deficiency may impair end-organ availability of these LC-PUFA in preterm infants. Therefore, supplementation of C20:4 and C22:6 might better be accompanied by choline supplementation. [ABSTRACT FROM AUTHOR]

Background: Reticulocyte haemoglobin content, i.e., the reticulocyte equivalent (Ret-He ), seems to be a promising parameter for the detection of iron deficiency (ID) in neonates because it can be obtained as part of a reticulocyte count, with no additional blood loss and at no extra cost. Due to the short life span of reticulocytes, Ret-He reflects current iron availability for erythropoiesis more accurately than other common erythrocyte indices. Objective: We aimed to evaluate postnatal changes in Ret-He within the first days after birth in term and preterm infants with the hypothesis that preterm infants experience a more pronounced postnatal reduction in Ret-He when compared to term infants. Methods: We conducted retrospective analyses of clinically indicated blood samples. Paired t test and mixed regression modelling were used. Results: In total, 805 blood samples obtained from 207 term and 295 preterm infants were analysed. Ret-He decreased by 1.5 pg per day (regression coefficient [95% CI] -1.5 [-1.8 to -1.2] pg, p < 0.0001). This drop was more significant in preterm infants (regression coefficient -2.2 [-2.6 to -1.8] pg, p < 0.0001) than in term infants (regression coefficient -0.8 [-1.3 to -0.2] pg, p < 0.01, p interaction < 0.0001). Conclusion: Ret-He declined within the first days after birth. The observed changes with postnatal age were more pronounced in preterm than in term infants. Further studies are needed to evaluate if these changes are due to developing ID or other causes. [ABSTRACT FROM AUTHOR]

Background: Despite iron supplementation, some preterm infants develop iron deficiency (ID). The optimal iron status parameter for early detection of ID has yet to be determined. Objective: To establish reference ranges for reticulocyte haemoglobin content (Ret-He) in preterm and term infants and to identify confounding factors. Methods: Retrospective analyses of Ret-He and complete blood count in infants with a clinically indicated blood sample obtained within 24 h after birth. Results: Mean (SD) Ret-He was 30.7 (3.0) pg in very preterm infants with a gestational age (GA) of <30 weeks (n = 55), 31.2 (2.6) pg in moderately preterm infants (GA 30-- 36 weeks, n = 241) and 32.0 (3.2) pg in term infants (GA ≥ 37 weeks, n = 216). The 2.5th percentile of Ret-He across all GA groups was 25 pg, with a weak correlation between Ret-He and GA (r = 0.18). Moreover, only weak/no correlations were found between Ret-He and C-reactive protein (r = 0.18), interleukin 6 (IL-6) (r = 0.03) and umbilical artery pH (r = --0.07). There was a slight variation in Ret-He with mode of delivery [normal vaginal delivery: 32.3 (3.2) pg, secondary caesarean section (CS): 31.4 (3.0) pg, instrumental delivery: 31.3 (2.7) pg and elective CS: 31.2 (2.8) pg]. Conclusion: GA at birth has a negligible impact on Ret-He, and the lower limit of the normal reference range in newborns within 24 h after birth can be set to 25 pg. Moreover, Ret-He seems to be a robust parameter which is not influenced by perinatal factors within the first 24 h after birth. [ABSTRACT FROM AUTHOR]

Recipients of severe twin-to-twin transfusion syndrome (TTTS) may suffer from low cardiac output caused by myocardial hypertrophy and sudden postnatal drop in preload. Our hypothesis was that selective beta-1 adrenergic blockers improve cardiac function in TTTS recipients with left ventricular outflow tract obstruction. We analysed data from two TTTS recipients treated with esmolol/metoprolol. Despite intense circulatory support, both patients showed severe hypotension and tachycardia before therapy. Echocardiographic findings included hypertrophic ventricles with thickened intraventricular septum, reduced aortic valve velocity time integral (AV-VTI), left ventricular outflow tract obstruction and collapsing ventricles in systole. Beta blocker improved blood pressure as well as AV-VTI, which served as a surrogate parameter for left ventricular stroke volume, reduced heart rate and need for circulatory support. In conclusion, beta blockade may improve left ventricular function in TTTS recipients with low cardiac output due to myocardial hypertrophy. [ABSTRACT FROM AUTHOR]

Background: The hemodynamically relevant patent ductus arteriosus in preterm infants is not well defined. Different clinical and echocardiographic parameters are used and the diagnostic accuracy is unknown because of the lack of a gold standard definition. Our study evaluates the inter-observer repeatability of echocardiographic and Doppler-ultrasound parameters.Methods: This prospective observational study included 19 very low birth weight preterm infants (median [interquartile range]: gestational age 28.0 (28.0-29.0) weeks, birth weight 1130 (905-1321) g, postnatal age at measurement 8.7 (4.8-23.5) d) with a clinical suspicion of ductal patency in whom 27 repeated echocardiographic and Doppler-ultrasound examinations were performed within 30 min by 2 of 3 independent observers (54 measurements overall). The repeatability index (=2 times the standard deviation of the differences/mean of all measurements) according to Bland and Altman was used to assess repeatability of different parameters.Results: The repeatability indices of the echocardiographic parameters (left Atrium-to-Aortic root-ratio, diameter of the patent ductus arteriosus at its narrowest part, the left-ventricular-preejection-period-to-ejection-time-ratio and the ratio of the velocity time integrals in the large vessels were 16, 21, 23 and 26 % respectively. The repeatability indices of Doppler-ultrasound measurements (resistance index in celiac artery and anterior cerebral artery) were 11 and 14 %, respectively.Conclusions: The inter-observer repeatability of all echocardiographic parameters was poor compared to that of resistance indices in peripheral vessels. Therefore, interventions for ductal patency should be indicated based on averaged repeated rather than single measurements, especially when measured values are close to their cut-off value - both in clinical routine and for study purposes. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate feasibility and consequences of accelerated feeding advancement on short-term outcomes in extremely low gestational age neonates (ELGANs) who stayed in our institution for >28 days.Methods: Retrospective single-centre cohort analysis covering the years 2011-2013. Data are presented as median (IQR).Results: Infants '(n=77) birth weight was 745 (640 to 960) g and gestational age at birth 26.7 (25.1 to 27.4) weeks. Full enteral feeds were attained by postnatal day 7 (5 to 11). Weight gain from birth to discharge was 14.3 (13.3 to 16.1) g/kg/day, change in SD score for weight -0.03 (-0.55 to 0.46) and 0.09 (-0.78 and 0.82) for head circumference. Rates of necrotising enterocolitis and spontaneous intestinal perforation in all ELGANs admitted during the study period were 3.1% and 9.4%, respectively.Conclusions: This cohort of ELGANs showed good weight gain and head growth after early full enteral nutrition. The impact of this feeding practice on neonatal morbidity and long-term outcome remains to be tested in adequately powered randomised trials. [ABSTRACT FROM AUTHOR]

Background: Hepcidin, a key regulatory peptide hormone in iron homeostasis, may in future serve as a non-invasive iron status parameter for monitoring iron supplementation in preterm infants. For this, coexisting influencing factors should be taken into account. Objectives: To evaluate the short-term effects of red blood cell (RBC) transfusions on hepcidin concentrations in serum (HepS) and urine (HepU) of preterm infants. Methods: This was a prospective, observational study conducted between May 2009 and September 2010 at a single neonatal unit (Tübingen University Hospital, Tübingen, Germany) in very preterm infants, i.e. with a gestational age (GA) of <32 weeks, who received clinically indicated RBC transfusions. The concentration of the mature, 25 amino-acid form of hepcidin was determined in serum und urine by competitive enzyme-linked immunosorbent assay together with cellular indices before and after transfusion. Results: Twenty preterm infants born at a median GA of 26 + 0/7 (interquartile range: 24 + 6/7 to 27 + 3/7) weeks received 27 RBC transfusions at a median corrected age of 31 + 3/7 (29 + 6/7 to 34 + 5/7) weeks. When measured shortly after transfusion (mean time: 10 h), haematocrit values increased from a mean of 26.6% (SD 2.8) to 40.9% (SD 3.2); p < 0.0001. HepS also increased [geometric mean: 44.3 (95% confidence interval 30.8-63.8) ng/ml vs. 58.0 (35.7-94.3) ng/ml; p < 0.05] but HepU remained unaffected. Conclusion: The data indicate that HepS concentrations increase shortly after RBC transfusion in preterm infants. Long-term observational studies are needed to understand the dynamics of hepcidin regulation in preterm infants. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective To evaluate reticulocyte haemoglobin content (CHr), compared with ferritin, transferrin saturation (TS) and mean corpuscular volume (MCV), as a marker of iron deficiency (ID). Design Retrospective analysis of clinically indicated blood samples taken between February 2010 and October 2012. Setting Single-centre neonatal care unit. Patients 210 very preterm (gestational age <32 weeks) or very low birthweight infants (birth weight <1500 g) at 3-4 months corrected age. Main outcome measures Complete blood count, CHr, ferritin and TS determined as part of a standard follow-up examination. To detect the optimal CHr cutoff, ID was defined by the presence of more than two of the following three criteria: MCV <75 fL, TS <10%, ferritin <30 µg/L. Results 210 preterm infants were included at a corrected age of (median (IQR)) 3.5 (3.0-4.0) months and with a CHr of 29.7 (28.6-30.7) pg. There were correlations between CHr and MCV (r=0.54, p <0.0001) and between CHr and TS (r=0.44, p <0.0001). There were 27 (13.4%) iron-deficient infants, and two infants (1%) fulfilled criteria of ID-anaemia. CHr was lower in infants with ID (26.4 (23.8-28.7) pg) than in those without (29.9 (29.0-30.8) pg, p <0.0001). The optimal CHr cut-off for detecting ID was 29 pg (sensitivity 85%, specificity 73%). Areas under the receiver operating characteristic curve for detection of ID tended to be higher for CHr compared with ferritin (0.92 vs 0.75), TS (0.90 vs 0.82) and MCV (0.81 vs 0.72). Conclusions CHr seems to be a suitable marker for latent ID in preterm infants at 3-4 months corrected age and may be superior to ferritin, TS and MCV. [ABSTRACT FROM AUTHOR]

Introduction: The role of CD64 in late onset sepsis (LOS) in preterm infants has been described in several studies. Aim of this study was to investigate whether CD64 expression is increased in the days before clinical manifestation of LOS. Methods: Patients with birth weight below 1,500g were eligible for study participation. During routine blood sampling CD64 index was determined between day of life 4 and 28. Patients were allocated to one of four groups: (1) blood-culture positive sepsis, (2) clinical sepsis, (3) symptoms of infection without biochemical evidence of infection, or (4) patients without suspected infection. Kinetics of CD64 expression were compared during a period before and after the day of infection in the respective groups. Results: 50 infants were prospectively enrolled and allocated to each group as follows: group (1) n = 7; group (2) n = 10; group (3) n = 8; and group (4) n = 25. CD64 index was elevated in 57% of patients in group (1) at least two days before infection. In contrast only 20% in the clinical sepsis group and 0% in group (3) had an elevated CD64 index in the days before infection. 10 of the 25 patients in the control group (4) presented increased CD64 index values during the study period. Conclusions: The CD64 index might be a promising marker to detect LOS before infants demonstrate signs or symptoms of infection. However, larger prospective studies are needed to define optimal cut-off values and to investigate the role of non-infectious inflammation in this patient group. [ABSTRACT FROM AUTHOR]

Background Congenital chylothorax (CCT) is a rare disease of unknown aetiology. Treatment approaches vary; none has been evaluated prospectively. Objective To prospectively determine incidence, treatment and outcome of infants with CCT born in Germany in 2012. Design CCT was defined as non-traumatic chylous pleural effusion within 28 days after birth. As part of the Surveillance Unit for Rare Pediatric Conditions in Germany (Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland), all paediatric departments (n=432) received monthly reporting cards to notify the study centre of CCT cases, which were analysed based on anonymised questionnaires and discharge summaries. Data are shown as median (range) or n/N. Results Of 37 cases reported, 28 met inclusion criteria. Questionnaires and/or discharge summaries were available for 27/28. Assuming complete reporting, the incidence of CCT was 1:24 000. Nine infants suffered from proven or suspected syndromal anomalies, most frequently Noonan syndrome (5/9). Postnatally, 23 required mechanical ventilation, 3 continuous positive airway pressure; only 1 had no respiratory support. 17 infants were treated with inotropes/vasopressors, 25 required pleural drainage for 11 (1-36) days. In 13 infants, enteral feeds were withheld initially; 25 received medium-chain triglyceride diet at some time, 9 were treated with octreotide or somatostatin. 18 infants survived without, 6 with sequelae attributable to the underlying disorder; 3 infants died (median age at death 37 (2-144) days). Duration of hospital stay in survivors was 51 (20-127) days. Infants treated with octreotide or somatostatin had similar outcomes compared with those not treated. Conclusions Based on this small observational study, CCT seems to have a favourable prognosis if not associated with genetic disorders. [ABSTRACT FROM AUTHOR]

Inadequate nutrient intakes in the first postnatal weeks play a crucial role in the aetiology of postnatal growth restriction of very low birthweight (VLBW) infants. Efforts to improve early nutrition in these infants led to a significant reduction in postnatal growth failure. Initiation of enhanced parenteral nutrition immediately after birth and utilisation of the large potential of early enteral nutrition seem pivotal. Nevertheless, it remains challenging to further reduce the initial drop in weight and head circumference z-score and to improve body composition and linear growth. This review will summarise data on how near-fetal postnatal weight gain in VLBW infants can be achieved and makes suggestions for early nutrition of VLBW infants. [ABSTRACT FROM AUTHOR]

Background: Volvulus without malrotation in preterm infants is a rare but potentially life-threatening event of unknown aetiology. Confusion with necrotising enterocolitis may delay surgical intervention thereby aggravating morbidity and mortality. We aimed at elucidating potential risk factors for, and characteristic clinical signs of, volvulus without malrotation in preterm infants. Methods: Retrospective, single-centre case–control study (2007–2011). For every index patient, five infants of similar gestational age, birth weight and birth year were evaluated. Additionally, all 9 cases of necrotising enterocolitis occurring during the above period were evaluated. Data are presented as median (interquartile range). Results: Five extremely premature infants suffering from volvulus without malrotation were identified (gestational age at birth 24.4 (23.6-25.5) weeks, birth weight 480 (370–530) g). All were small for gestational age and female; three out of five died. Volvulus occurred several weeks after birth, whereas necrotising enterocolitis occurred significantly earlier. Beyond that, no striking differences in clinical or laboratory presentation of volvulus without malrotation and necrotising enterocolitis were found. Infants with volvulus had significantly more frequent manipulations with rectal tubes for flatulence, but there were no differences in the frequency of enemas, abdominal massage or defecation. In infants with volvulus, nasal high-frequency oscillation was used more frequently for respiratory support, and PEEP-level tended to be higher. Conclusions: In extremely premature infants volvulus without malrotation represents a life-threatening event that occurs typically several weeks after birth with an acute abdomen and seems to affect predominantly girls. Infants requiring intensive non-invasive respiratory support might be at highest risk. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency (ID) contributes to anaemia of prematurity, and hence the reliable assessment of iron nutrition status appears to be mandatory. Objective: To establish gestational age (GA)-specific reference ranges for hepcidin concentrations in cord blood [Hep(CB)] of preterm and term infants and to identify pre- and perinatal confounding factors. Methods: This is a prospective observational study including 221 infants (GA at birth: 24-42 weeks). Hep(CB) along with complete blood counts, ferritin and parameters of inflammation and clinical data were recorded. Data are presented as medians (IQR). Results: The Hep(CB) of very preterm infants (GA <30 weeks, n = 40) was 26.9 ng/ml (13.5-63.1), for moderately preterm infants (GA 30-36 weeks, n = 81) it was 45.9 ng/ml (24.7-74.5) and for term infants (GA ≥37 weeks, n = 100) it was 103.9 ng/ml (61.4-149.2). The Hep(CB) of infants with ID was lower [36.9 ng/ml (18.0-58.3)] than that of iron-replete infants [86.6 ng/ml (51.9-143.8)]. The Hep(CB) of infants delivered by elective caesarean section was lower [38.3 ng/ml (15.5-73.7)] than that of infants after spontaneous vaginal delivery or secondary caesarean section [80.3 ng/ml (48.5-137.6)]. Infants with a standard deviation score for birth weight (SDSBW) <-2 had a lower Hep(CB) [23.1 ng/ml (11.7-61.5)] compared to infants with SDSBW ≥-2 [71.1 ng/ml (34.0-121.7)]. The highest Hep(CB) (437.6 ng/ml) was recorded in an infant with Enterococcus faecalis sepsis. Multiple logistic regression analysis confirmed ferritin, GA and mode of delivery as important factors associated with Hep(CB). Conclusion: This is the first report on GA-specific reference ranges for Hep(CB) in preterm infants. Whereas iron stores, GA and mode of delivery were associated with Hep(CB), the association with inflammation and intra-uterine growth retardation was less clear. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Near-infrared spectroscopy (NIRS) is increasingly used in neonatal intensive care. We investigated the impact of skin, bone, and cerebrospinal fluid (CSF) layer thickness in term and preterm infants on absorption- (µa) and/or reduced scattering coefficients (µ's) measured by multidistance frequency-domain (FD)-NIRS. Transcranial ultrasound was performed to measure the layer thicknesses. Correlations were only statistically significant for µa at 692 nm with bone thickness and µ's at 834 nm with skin thickness. There is no evidence that skin, bone, or CSF thickness have an important effect on µa and µ's. Layer thicknesses of skin, bone, and CSF in the range studied do not seem to affect cerebral oxygenation measurements by multidistance FD-NIRS significantly. [ABSTRACT FROM AUTHOR]