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Body composition assessments using air displacement plethysmography (ADP, PEAPOD ® ) have been introduced into clinical practice at a few neonatal units. To allow accurate body composition assessments in term and preterm infants, a workflow for routine testing is needed. The aim of this study was to analyze the feasibility of weekly routine ADP testing. We analyzed (1) postnatal ages at first ADP assessment, (2) the number of weekly routine in-hospital assessments, and (3) the workload of body composition measurements using ADP in clinical practice on the basis of an retrospective analysis of our own clinical operating procedures. The retrospective analysis of weekly routine ADP testing proved feasible at Nuremberg Children's Hospital. The analysis of postnatal age at the first ADP test revealed differences across groups, with extremely preterm infants starting at a mean postmenstrual age of 36.6 weeks, very preterm infants starting at 34.2 weeks, and moderate to late preterm infants starting at 35.3 weeks. The mean number of tests before discharge was significantly greater in the extremely preterm group ( n = 3.0) than in the very preterm ( n = 2.4) and moderate to late preterm groups ( n = 1.7). The workload of the procedure is reasonable, at 8-13 min per test cycle. The study proved that weekly routine ADP assessments in preterm infants are feasible. However, the initiation of routine testing in extremely preterm infants starts at a significantly greater postnatal age than in the more mature population. ADP assessments can be safely and easily integrated into clinical practice and may be valuable tools for providing additional information on nutritional status and infant growth. A standardized routine protocol allowing identical measurement conditions across healthcare institutions and a standardized interpretation tool for age-adapted body composition data, however, would improve comparability and usability.

The quality-initiative analysis of weekly duplicate PEAPOD ® body composition measurements was conducted from clinical practice (January to September 2021) on preterm and term infants without respiratory support. Statistical analysis, including regression analysis, Bland-Altman plots and cv-root-mean-square tests, was performed. A total of 188 duplicate (376 individual) measurements were collected from 119 infants (88 preterm, 31 term). The median absolute difference between duplicates was 31.5 g for fat-free mass (FFM). Linear correlation analysis showed R 2 = 0.97 for FFM. The absolute differences in FFM and fat mass did not significantly correlate with increasing age. The %FFM differed ( p = 0.02) across body weight groups of 1 kg < BW ≤ 2 kg (1.8%; IQR: 0.8, 3.6) and BW > 3 kg (0.9%; IQR: 0.3, 2.1). The median absolute differences were 1 g (IQR: 0.4, 3.1) for body weight and 5.6 mL (IQR: 2.1, 11.8) for body volume. Body volume estimation is charged with a constant absolute error, which is the main factor for differences between repeated body composition assessments. This error becomes more prominent in infants with lower body weights. Nevertheless, reproducibility of weekly PEAPOD testing is sufficient to monitor body compartment changes, offering a foundation for nutritional decisions in both preterm and term infants.

Despite optimized nutrition, preterm-born infants grow slowly and tend to over-accrete body fat. We hypothesize that the premature dissociation of the maternal-placental-fetal unit disrupts the maintenance of physiological endocrine function in the fetus, which has severe consequences for postnatal development. This review highlights the endocrine interactions of the maternal-placental-fetal unit and the early perinatal period in both preterm and term infants. We report on hormonal levels (including tissue, thyroid, adrenal, pancreatic, pituitary, and placental hormones) and nutritional supply and their impact on infant body composition. The data suggest that the premature dissociation of the maternal-placental-fetal unit leads to a clinical picture similar to panhypopituitarism. Further, we describe how the premature withdrawal of the maternal-placental unit, neonatal morbidities, and perinatal stress can cause differences in the levels of growth-promoting hormones, particularly insulin-like growth factors (IGF). In combination with the endocrine disruption that occurs following dissociation of the maternal-placental-fetal unit, the premature adaptation to the extrauterine environment leads to early and fast accretion of fat mass in an immature body. In addition, we report on interventional studies that have aimed to compensate for hormonal deficiencies in infants born preterm through IGF therapy, resulting in improved neonatal morbidity and growth. IMPACT: Preterm birth prematurely dissociates the maternal-placental-fetal unit and disrupts the metabolic-endocrine maintenance of the immature fetus with serious consequences for growth, body composition, and neonatal outcomes. The preterm metabolic-endocrine disruption induces symptoms resembling anterior pituitary failure (panhypopituitarism) with low levels of IGF-1, excessive postnatal fat mass accretion, poor longitudinal growth, and failure to thrive. Appropriate gestational age-adapted nutrition alone seems insufficient for the achievement of optimal growth of preterm infants. Preliminary results from interventional studies show promising effects of early IGF-1 supplementation on postnatal development and neonatal outcomes., (© 2021. The Author(s).)

Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. We assessed the effects of early macronutrient supplements on later growth. We searched databases and clinical trials registers from inception to April 2019. Participant-level data from randomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born preterm or small-for-gestational-age. Co-primary outcomes were cognitive impairment and metabolic risk. Supplementation did not alter BMI in childhood (kg/m 2 : adjusted mean difference (aMD) -0.11[95% CI -0.47, 0.25], p = 0.54; 3 trials, n = 333). Supplementation increased length (cm: aMD 0.37[0.01, 0.72], p = 0.04; 18 trials, n = 2008) and bone mineral content (g: aMD 10.22[0.52, 19.92], p = 0.04; 6 trials, n = 313) in infancy, but not at older ages. There were no differences between supplemented and unsupplemented groups for other outcomes. In subgroup analysis, supplementation increased the height z-score in male toddlers (aMD 0.20[0.02, 0.37], p = 0.03; 10 trials, n = 595) but not in females, and no significant sex interaction was observed ( p = 0.21). Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplementation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls.

Background & Aims: In preterm infants, natural variation of breast milk composition makes it difficult to achieve recommended macronutrient intakes with standard fortification. Evidence suggests that nutritional deficiency induces poor postnatal growth. This study investigates impacts of target fortification on preterm growth and metabolism by adjusting breast milk macronutrients., Methods: This study was conducted as a single-centre, double-blind, randomized controlled trial for infants <30 gestational weeks. The control group received standard fortification and the intervention group received standard plus target fortification adding modular protein, lipids, and carbohydrates. Breast milk content was measured 3x/week using a validated near-infrared bedside spectrometer (NIRS). Modulars were added to achieve recommended values. To assess total nutrient intake, all 2810 native breast milk samples were analyzed - protein and fat using bedside-NIRS, lactose using tandem mass spectrometry (UPLC-MS/MS). Body composition was measured using air displacement plethysmography. Primary outcome was weight gain during the first 21 days of intervention., Results: Baseline characteristics, morbidities, and total fluid intake were not different between groups (intervention n = 52, control n = 51). The intervention group infants had higher macronutrient intakes, weight gain (21.2 ± 2.5 vs 19.3 ± 2.4 g/kg/d, mean difference: 1.9 g/kg/d, 95% CI: 0.9 - 2.9), and body weight. Infants in the intervention group from mothers with below-average breast milk protein content showed greatest impact on weight at 36 weeks (2580 ± 280 g vs 2210 ± 300 g), length, head circumference, fat, and fat-free mass. Also, feeding intolerance was less frequent, blood urea was higher, and triglycerides were lower., Conclusions: This study provides evidence that target fortification of breast milk with low macronutrient content enhances the quality of nutrition and growth and is feasible in clinical routine., Competing Interests: Conflict of interest We declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Preterm infants are increasingly diagnosed as having "extrauterine growth restriction" (EUGR) or "postnatal growth failure" (PGF). Usually EUGR/PGF is diagnosed when weight is <10th percentile at either discharge or 36-40 weeks postmenstrual age. The reasons why the phrases EUGR/PGF are unhelpful include, they: (i) are not predictive of adverse outcome; (ii) are based only on weight without any consideration of head or length growth, proportionality, body composition, or genetic potential; (iii) ignore normal postnatal weight loss; (iv) are usually assessed prior to growth slowing of the reference fetus, around 36-40 weeks, and (v) are usually based on an arbitrary statistical growth percentile cut-off. Focus on EUGR/PGF prevalence may benefit with better attention to nutrition but may also harm with nutrition delivery above infants' actual needs. In this paper, we highlight challenges associated with such arbitrary cut-offs and opportunities for further refinement of understanding growth and nutritional needs of preterm neonates.

To optimize infant nutrition, the nature of weight gain must be analyzed. This study aims to review publications and develop growth charts for fat and fat-free mass for preterm and term infants. Body composition data measured by air displacement plethysmography (ADP) and dual energy X-ray absorptiometry (DXA) in preterm and term infants until six months corrected age were abstracted from publications (31 December 1990 to 30 April 2019). Age-specific percentiles were calculated. ADP measurements were used in 110 studies (2855 preterm and 22,410 term infants), and DXA was used in 28 studies (1147 preterm and 3542 term infants). At term age, preterm infants had higher percent-fat than term-born infants (16% vs. 11%, p < 0.001). At 52 weeks postmenstrual age (PMA), both reached similar percent-fat (24% vs. 25%). In contrast, at term age, preterm infants had less fat-free mass (2500 g vs. 2900 g) by 400 g. This difference decreased to 250 g by 52 weeks, and to 100 g at 60 weeks PMA (5000 g vs. 5100 g). DXA fat-free mass data were comparable with ADP. However, median percent-fat was up to 5% higher with DXA measurements compared with ADP with PMA > 50 weeks. There are methodological differences between ADP and DXA measures for infants with higher fat mass. The cause of higher fat mass in preterm infants at term age needs further investigation., Competing Interests: The authors declare no conflict of interest.

Background: Preterm infants are at risk of oxidative stress from neonatal intensive care interventions. 8-Oxo-2'-deoxyguanosine (8-oxodG), generated by oxygen radical attack on DNA, is a potential marker of oxidative stress. The aim of the present study was to investigate the impact of quality and source of enteral nutrition (EN) on renal excretion of 8-oxodG in preterm infants., Methods: Spontaneous urine samples were collected on postnatal days 26-31 in 33 preterm infants. Infants were fed either breast milk (BM), formula (FM), or BM/FM mixtures. Daily iron (Fe) supplementation was started day 28 ± 1 postnatally. 8-oxodG was determined by highperformance liquid chromatography-electrochemical detection (HPLC-EC)., Results: The 8-oxodG/creatinine ratio was significantly higher in infants fed FM vs FM/BM (38.7 ± 28.7 vs 16.7 ± 12.2 nmol 8-oxodG/mmol creatinine, P < 0.0001) or BM (11.6 ± 10.4 nmol 8-oxodG/mmol creatinine, P < 0.0001). There was no significant effect of Fe supplementation (P = 0.547). 8-OxodG excretion showed significant interindividual variation but was similar within pairs of twins., Conclusion: Quality and source of EN seem to influence oxidative stress in preterm infants. The underlying pathophysiological mechanism is unclear and needs further investigation. It may be speculated that other mechanisms than Fe supplementation contribute to oxidative stress, such as cow's milk protein-mediated up-regulation of the intestinal inflammatory cascade., (© 2018 American Society for Parenteral and Enteral Nutrition.)

Objective: To evaluate the effect of not relying on prefeeding gastric residual volumes to guide feeding advancement on the time to reach full feeding volumes in preterm infants, compared with routine measurement of gastric residual volumes. We hypothesized that not measuring prefeeding gastric residual volumes can shorten the time to reach full feeds., Study Design: In this single-center, randomized, controlled trial, we included gavage fed preterm infants with birth weights (BW) 1500-2000 g who were enrolled within 48 hours of birth. Exclusion criteria were major congenital malformations, asphyxia, and BW below the third percentile. In the study group, the gastric residual volume was measured only in the presence of bloody aspirates, vomiting, or an abnormal abdominal examination. In the control group, gastric residual volume was assessed routinely, and feeding advancement was based on the gastric residual volume. The primary outcome was the time to reach feeding volumes of 120 mL/kg per day. Secondary outcomes were time to regain BW, episodes of feeding interruptions, sepsis, and necrotizing enterocolitis., Results: Eighty-seven infants were enrolled. There were no differences between the study and control groups with respect to time to reach full feeds (6 days [95% CI, 5.5-6.5] vs 5 days [95% CI, 4.5-5.5]; P = .82), time to regain BW, episodes of feeding interruptions, or sepsis. Two infants in the control group developed necrotizing enterocolitis., Conclusions: Avoiding routine assessment of gastric residual volume before feeding advancement did not shorten the time to reach full feeds in preterm infants with BW between 1500 and 2000 g., Trial Registration: Clinicaltrials.gov: NCT01337622., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aim: To investigate how two different strategies to form larger neonatal intensive care units (NICU) impact neonatal mortality rates., Methods: Cross-sectional study modeling admission volumes and mortality rates of 177,086 VLBW infants aggregated into 862 NICUs. Cumulative 3-year data was abstracted from Vermont Oxford Network. The model simulated a reduction in number of NICUs by stepwise exclusion using either admission volume (VOL) or quality (QUAL) cut-offs. After randomly redirecting infants of excluded to remaining NICUs resulting system mortality rates were calculated with and without adjusting for effects of experience levels (EL) using published data to reflect effects of different team-to-patient exposure., Results: The quality-based strategy is more effective in reducing mortality; while VOL alone was not able to reduce system mortality, QUAL already achieved a 5% improvement after reducing 8% of NICUs and redirecting 6% of infants. Including "EL", a 5% improvement of mortality was achieved by reducing 77% (VOL) vs. 7% (QUAL) of NICUs and redirecting 54% (VOL) vs. 5% (QUAL) of VLBW infants, respectively., Conclusion: While a critical number of admissions is needed to maintain skills this study emphasizes the importance of including quality parameters to restructure neonatal care. The findings can be generalized to other medical fields.

Objective: Postnatal tissue accretion in preterm infants differs from those in utero, affecting body composition (BC) and lifelong morbidity. Length normalized BC data allows infants with different body lengths to be compared and followed longitudinally. This study aims to analyze BC of preterm and term infants during the first six months of life., Methods: The BC data, measured using dual energy X-ray absorptiometry, of 389 preterm and 132 term infants from four longitudinal studies were combined. Fat-mass/length² (FMI) and fat-free mass/length² (FFMI) for postmenstrual age were calculated after reaching full enteral feeding, at term and two further time points up to six months corrected age., Results: Median FMI (preterm) increased from 0.4 kg/m² at 30 weeks to 2.5, 4.3, and 4.8 kg/m² compared to 1.7, 4.7, and 6 kg/m² in term infants at 40, 52, and 64 weeks, respectively. Median FFMI (preterm) increased from 8.5 kg/m² (30 weeks) to 11.4 kg/m² (45 weeks) and remained constant thereafter, whereas term FFMI remained constant at 11 kg/m² throughout the tested time points., Conclusion: The study provides a large dataset of length normalized BC indices. Followed longitudinally, term and preterm infants differ considerably during early infancy in the pattern of change in FMI and FFMI for age.

Background: International guidelines suggest that growth of preterm infants should match intrauterine rates. However, the trajectory for extrauterine growth may deviate from the birth percentile due to an irreversible, physiological loss of extracellular fluid during postnatal adaptation to extrauterine conditions. To which "new" physiological growth trajectory preterm infants should adjust to after completed postnatal adaptation is unknown. This study analyzes the postnatal growth trajectories of healthy preterm infants using prospective criteria defining minimal support, as a model for physiological adaptation., Methods: International, multi-center, longitudinal, observational study at five neonatal intensive care units (NICUs). Daily weights until day of life (DoL) 21 of infants with undisturbed postnatal adaptation were analyzed (gestational ages: (i) 25-29 wk, (ii) 30-34 wk)., Results: 981 out of 3,703 admitted infants included. Maximum weight loss was 11% (i) and 7% (ii) by DoL 5, birth weight regained by DoL 15 (i) and 13 (ii). Infants transitioned to growth trajectories parallel to Fenton chart percentiles, 0.8 z-scores below their birth percentiles. The new trajectory after completed postnatal adaptation could be predicted for DoL 21 with R(2) = 0.96., Conclusion: This study provides a robust estimate for physiological growth trajectories of infants after undisturbed postnatal adaptation. In the future, the concept of a target postnatal trajectory during NICU care may be useful.

Purpose of Review: To outline new evidence published from 2013 to 2014 about breast milk fortification in preterm infants., Recent Findings: Breast milk is the feeding choice for preterm infants because of its immunoprotective properties. However, breast milk's nutrient content is not sufficient for preterm infants, and interindividual variation is high. The variation challenges standard fortification, which assumes a standard breast milk composition. Two new fortification strategies (adjustable fortification and target fortification) optimize macronutrient intake and improve growth. Adjustable fortification uses blood urea nitrogen levels to adjust fortifier strength. Target fortification analyzes breast milk and fortifies macronutrients individually to achieve targeted intake. Its feasibility is shown in clinical routine. Current breast milk analyzers used for target fortification achieve acceptable precision for protein and fat but not for lactose and energy. Evidence of benefits for postdischarge breast milk fortification is lacking. Eliminating cow's milk products and feeding exclusively breast milk may decrease the occurrence of feeding intolerance and necrotizing enterocolitis. To facilitate exclusively breast milk diets, a collaboration of prenatal, nutrition and lactation stakeholders is key. Fortification increases osmolality; however, safety cutoffs to prevent necrotizing enterocolitis are unclear. There is also new evidence that composition and structure of various macronutrients and micronutrients affect growth and development, and might play a role in future fortification concepts., Summary: Recent research focuses on the variability of breast milk composition, its impact on postnatal growth patterns and the usefulness of target fortification. As well, diets exclusively composed of human milk are a promising approach to improve feeding tolerance. For safe fortification, osmolality cutoff levels are needed.

Respiratory insufficiency is a major cause of neonatal mortality and long-term morbidity, especially in very low birth weight infants. Today, non-invasive and mechanical ventilation are commonly accepted procedures to provide respiratory support to newborns, but they can reach their limit of efficacy. To overcome this technological plateau and further reduce mortality rates, the technology of an "artificial placenta", which is a pumpless lung assist device connected to the umbilical vessels, would serve to expand the therapeutic spectrum when mechanical ventilation becomes inadequate to treat neonates with severe respiratory insufficiency.
The first attempts to create such an artificial placenta took place more than 60 years ago. However, there has been a recent renaissance of this concept, including developments of its major components like the oxygenator, vascular access via umbilical vessels, flow control, as well as methods to achieve hemocompatibility in extracorporeal circuits. This paper gives a review of past and current development, animal experiments and human case studies of artificial placenta technology.

Objective: Birth weight percentiles based on weekly measurements are used to assess the nutritional status of preterm infants. However, as preterm infants exhibit a rapid growth rate (up to 20 g/kg/day), their body weight can increase by 15% per week. We calculated birth weight percentiles based on daily measurements, to more precisely classify very preterm infants (gestational age of 154-223 days)., Methods: Data of 23,864 (10,720 females and 13,144 males) very preterm singleton infants with a gestational age of 154-223 days (22-31 completed weeks) were retrieved from the German perinatal statistics of 1995-2000. Percentile curves based on the empirical birth weight data were subjected to three statistical smoothing procedures: cubic regression, local regression (LOESS smoothing), and the LMS method., Results: Smoothing of the birth weight percentiles using cubic regression produced the smallest residual variance., Conclusion: Birth weight percentiles based on daily averages allow a more precise assessment of the somatic development of preterm infants.

Background: Actual recommendations in preterm infants limit parenteral fat intake to 3-4 g/kg/d. This is based on clinical studies where fat administration was adjusted to achieve levels close to those recommended in adults for atherosclerosis prevention. Data about lipid profiles of breast fed preterm infants who may have fat intakes of up to 7 g/kg/d and could serve as reference are not available., Objective: To establish full lipid profiles in healthy fully breast fed preterm infants and to test the hypothesis that breast milk fat intake leads to serum triglycerides higher than those achieved under full parenteral fat administration., Design: Serum triglycerides, cholesterol, VLDL, LDL, HDL (all pre- and postprandial), as well as triglycerides in breast milk were measured in 65 healthy, fully breast fed, stable growing preterm infants stratified in 500 g intervals (mean gestational age: 31+/-4 weeks, birth weight: 1500+/-600 g, age at study: 25+/-16 d)., Results: Median fat intake was 7.0 g/kg/d (interquartile range: 5.8;8.1) and led to the following serum levels: triglycerides 0.9 (0.6;1.1), cholesterol 3.1 (2.6;3.5), VLDL 0.5 (0.3;0.6), LDL 1.3 (1.1;1.6), HDL 1.1 (0.8;1.4)mmol/L. Small for gestational age infants showed higher triglycerides (p=0.005). Triglycerides (r2=0.08, p=0.023), postprandial triglyceride increase (r2=0.21, p<0.001), cholesterol (r2=0.16, p<0.001) and HDL (r2=0.16, p<0.001) were correlated with weight at study., Conclusion: Though higher by a factor of two, fat intake by breast milk leads to considerably lower lipid levels when compared to published values obtained under parenteral fat intake. Results suggest that either fat absorption is reduced in preterm infants, or the composition of breast milk supports a lower profile of fat levels when compared to commercially available parenteral fat emulsions., (Copyright 2009 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)