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Background: Preterm infants are at risk of impaired bone health in later life. Dual-energy X-ray absorptiometry-scan (DXA) is the gold standard to determine bone mineralization. Phalangeal quantitative ultrasound (pQUS) is an alternative technique that is inexpensive, easy to use and radiation-free. The aim of this study was to investigate whether both techniques reveal equivalent results., Materials and Methods: Sixty former preterm infants (31 boys; 29 girls) received a DXA and pQUS at age 9 to 10 years. DXA measured bone mineral content (BMC) and bone mineral density (BMD) for total body and lumbar spine (L1-4), while pQUS measured the amplitude dependent speed of sound (AD-SoS) and bone transit time (BTT) at metacarpals II-IV providing continuous values and Z -scores based on age and sex. Four statistical methods evaluated the association between both techniques: Pearson's correlation coefficients, partial correlation coefficients adjusted for gestational age, height and BMI, Bland-Altman analysis and cross tabulation., Results: Both techniques showed a statistically significant weak correlation for continuous values as well as Z -scores (0.291-0.462, p < 0.05). Boys had significant and relatively high correlations (0.468-0.585, p < 0.05). In comparison, the correlations for girls were not significant. Correlation coefficients further decreased while calculating the partial correlations. The Bland-Altman plots showed poor agreement. Sensitivity ranged from 33% to 92% and specificity from 16% to 68%. Positive and negative predictive values ranged from 4% to 38% and 82% to 97%, respectively., Conclusions: We found statistically significant weak correlations and poor agreement between DXA and pQUS measurements. DXA is not equivalent to pQUS and therefore not replaceable by this technique in former preterm born children at the age of 9 to 10 years.

Preterm infants often have a reduced bone mineral content (BMC) with increased risk of metabolic bone disease. After birth it is difficult to supply calcium (Ca) and phosphorus (P) comparable to the high fetal accretion rate. It is not known whether high supplementation of minerals in the early postnatal period improves growth and bone mineralization. The aim of this study was to evaluate growth and bone mineralization at term corrected age (TCA) in very and extremely preterm infants who received different enteral Ca and P intakes during the first 10 days of life. Infants ( n = 109) with birth weights below 1500 g were randomly assigned to one of three groups that differed in the nutritional protocols delivered until day 10: Group A, mother's own milk (MOM) and donor milk (unfortified); Group B, MOM (unfortified) and preterm formula; Group C, MOM (start fortification >50 mL/day) and preterm formula. Due to the earlier commencement of fortification, Group C received higher intakes of calcium and phosphorus and protein ( p < 0.001) until day 10. At TCA weight, length, BMC and bone mineral density (BMD), measured by dual-X-ray absorptiometry, were not different between the groups. Nutritional intake of P was positively associated with length (β; (95% confidence interval (CI): 0.20 (0.001; 0.393); p -value = 0.048), whereas Ca intake was negatively associated with BMC (-1.94 (-2.78; -1.09); p -value < 0.001). A small interaction between Ca and P intake was only found for BMD (0.003 (0.00002; 0.00006); p -value = 0.036). The volume of human milk per kg provided during the first 10 days was positively associated with BMC (β; (95% CI): 0.013 (0.002; 0.023); p < 0.017). Higher intakes of Ca and P during the first 10 days, as provided in this study, did not improve bone mineralization at term corrected age., Competing Interests: The authors declare no conflict of interest. Johannes B. Van Goudoever reports grants outside the submitted work from Mead Johnson Nutrition, during the conduct of the study, grants from EU, FP-7 programme. Johannes B. Van Goudoever serves as director of the National Human Milk bank and as board member of the National Health Council and the National Breastfeeding Committee.

Magnesium (Mg) is an essential mineral in the body, impacting the synthesis of biomacromolecules, bone matrix development, energy production, as well as heart, nerve, and muscle function. Although the importance of Mg is evident, reference values for serum Mg (sMg) in pediatric patients (more specifically, in neonates) are not well established. This systematic literature review and meta-analysis (using 47 eligible studies) aims to quantify normal and tolerable ranges of sMg concentrations during the neonatal period and to highlight the factors influencing Mg levels and the importance of regulating sMg levels during pregnancy and birth. In newborns without Mg supplementation during pregnancy, magnesium levels at birth (0.76 (95% CI: 0.52, 0.99) mmol/L) were similar to that of mothers during pregnancy (0.74 (95% CI: 0.43, 1.04) mmol/L), but increased during the first week of life (0.91 (95% CI: 0.55, 1.26) mmol/L) before returning to adult levels. This pattern was also seen in newborns with Mg supplementation during pregnancy, where the average was 1.29 (95% CI: 0.50, 2.08) mmol/L at birth and 1.44 (95% CI: 0.61, 2.27) mmol/L during the first week of life. Factors influencing these levels include prenatal Mg supplementation, gestational age, birth weight, renal maturity/function, and postnatal Mg intake. Elevated Mg levels (>2.5 mmol/L) have been associated with an increased risk of mortality, admission into intensive care, hypotonia, hypotension, and respiratory depression but sMg concentrations up to 2.0 mmol/L appear to be well tolerated in neonates, requiring adequate survey and minimal intervention., Competing Interests: Jacques Rigo participated in the design and coordinated the multi-centric study on the multi-chamber bags of parenteral nutrition for preterm infants initiated by Baxter Healthcare Corporation. He received financial support from Baxter Healthcare Corporation for travel and conferencing related to this work. Sissel J. Moltu has participated as a speaker at the Baxter iCAN program. Catherine Pieltain, Viola Christmann, Francesco Bonsante, Silvia Iacobelli, and Stéphane Marret declare no conflicts of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; and in the decision to publish the results.

Aim: This study assessed whether increased amino acid and energy intake in preterm infants during the first week of life was associated with improved neurodevelopment at the corrected age (CA) of 24 months., Methods: We evaluated preterm infants from two consecutive cohorts in 2004 (Cohort 1) and 2005 (Cohort 2) with different nutritional intakes in the Netherlands. Nutritional intake and growth were recorded until week 5 and after discharge. Neurodevelopment was determined using the Bayley Scales of Infant Development - Second Edition at a CA of 24 months., Results: Compared to Cohort 1 (n = 56), Cohort 2 (n = 56) received higher nutritional intake during week 1 (p < 0.001). The weight gain in Cohort 2 was higher until week 5, especially among boys (p < 0.002). The mean Mental Developmental Index (MDI) scores did not differ, but Cohort 2 was associated with an increased chance of having an MDI ≥ 85, with an odds ratio of 6.4 and 95% confidence interval (CI) of 1.5-27.4, among all girls with a higher protein intake (5.3, 1.2-23.3). The Psychomotor Developmental Index increased with increasing nutritional intake, especially among boys (β-coefficient 3.1, 95% CI 0.2-6.0)., Conclusion: Higher nutritional intake was associated with different improvements in growth and neurodevelopment in boys and girls., (©2016 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Preterm infants are at significant risk to develop reduced bone mineralization based on inadequate supply of calcium and phosphorus (Ca-P). Biochemical parameters can be used to evaluate the nutritional intake. The direct effect of nutritional intake on changes in biochemical parameters has not been studied. Our objective was to evaluate the effect of Ca-P supplementation on biochemical markers as serum (s)/urinary (u) Ca and P; alkaline phosphatase (ALP); tubular reabsorption of P (TrP); and urinary ratios for Ca/creatinin (creat) and P/creatinin in Very-Low-Birth-Weight infants on Postnatal Days 1, 3, 5, 7, 10, and 14. This observational study compared two groups with High ( n = 30) and Low ( n = 40) intake of Ca-P. Birth weight: median (IRQ) 948 (772-1225) vs. 939 (776-1163) grams; and gestational age: 28.2 (26.5-29.6) vs. 27.8 (26.1-29.4) weeks. Daily median concentrations of biochemical parameter were not different between the groups but linear regression mixed model analyses showed that Ca intake increased the uCa and TrP ( p = 0.04) and decreased ALP ( p = 0.00). Phosphorus intake increased sP, uP and uP/creat ratio and ALP ( p ≤ 0.02) and caused decrease in TrP ( p = 0.00). Protein intake decreased sP ( p = 0.000), while low gestational age and male gender increased renal excretion of P ( p < 0.03). Standardized repeated measurements showed that biochemical parameters were affected by nutritional intake, gestational age and gender., Competing Interests: The authors declare no conflict of interest. J.B.v.G. reports grants outside the submitted work from Mead Johnson Nutrition, during the conduct of the study, grants from Danone, grants and non-financial support from Hipp, personal fees and non-financial support from Nestle Institute and non-financial support from Baxter.

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

Objectives: Bone mineralisation in preterm infants is related to the supply of calcium (Ca) and phosphorus (P). We increased the amount of minerals in parenteral nutrition (PN) for preterm infants and evaluated postnatal Ca and P metabolism in relation to mineral and vitamin D (vitD) intake., Methods: Preterm infants, included on their first day of life, received standard PN, providing a maximum Ca/P intake of 3/1.92 mmol · kg(-1) · day(-1) on day 3. Ca/P content of formula was 2.5/1.6 mmol/dL, and fortified human milk was 2.4/1.95 mmol/dL. PN supplied 80 IU · kg(-1) · day(-1) vitD. Formula and fortified human milk contained 200 IU/dL of vitD. During a 5-week period, serum concentrations and urinary excretion of Ca/P were registered and related to the intake of minerals and vitD., Results: During 12 months, 79 infants (mean gestational age 29.8 ± 2.2 weeks, mean birth weight 1248 ± 371 g) were included. The recommended intake for minerals was achieved by day 5 and for vitD by 4 weeks. Infants developed hypercalcaemia, hypercalciuria, and hypophosphataemia during the first postnatal week, leading to the additional P supplementation in 49 infants. The renal tubular reabsorption of P was >95% until day 9 but decreased <70% after the second week. Alkaline phosphatase was normal at birth, increased to a maximum of 450 IU/L by day 14, and remained above the normal range for the remaining period., Conclusions: Parenteral intake of P appeared to be too low, leading to mineral imbalances in the early postnatal period, and vitD intake was also below recommendations.

Unlabelled: Vasoconstriction induced by bolus injection of indomethacin reduces organ perfusion and has been related to the well-known side effects of indomethacin given for closure of the patent ductus arteriosus (PDA). The aim of the study was to compare the changes in cerebral, renal and mesenteric blood flow velocities after continuous infusion versus bolus injection of indomethacin for closure of the PDA. Thirty-two preterm infants (range 26-35 wk gestational age) with PDA were randomly assigned to receive the same amount of indomethacin either as three bolus injections (n = 14) or as a continuous infusion (n = 18) over 36 h. Blood flow velocities were measured in the internal carotid, right renal and superior mesenteric arteries at baseline and serially at 10, 30, 60 and 120 min and 12, 24, 36 and 48 h after the start of indomethacin treatment. There were no differences in blood flow velocities between both groups at baseline. During continuous infusion of indomethacin there was no significant change in the cerebral, renal and mesenteric blood flow velocities, whereas the flow velocities in the infants receiving bolus injections decreased significantly during the first 2 h after indomethacin administration in all arteries measured. There was a transient, but significant reduction in urine output after bolus injection of indomethacin., Conclusion: In contrast to bolus injections, decrease of organ blood flow and impairment of urine output do not accompany continuous infusion of indomethacin over 36 h.

Purpose: Bioavailability of orally administered drugs is much influenced by the behavior, performance and fate of the dosage form within the gastrointestinal (GI) tract. Therefore, MRI in vivo methods that allow for the simultaneous visualization of solid oral dosage forms and anatomical structures of the GI tract have been investigated., Methods: Oral contrast agents containing Gd-DTPA were used to depict the lumen of the digestive organs. Solid oral dosage forms were visualized in a rat model by a 1H-MRI double contrast technique (magnetite-labelled microtablets) and a combination of 1H- and 19F-MRI (fluorine-labelled minicapsules)., Results: Simultaneous visualization of solid oral dosage forms and the GI environment in the rat was possible using MRI. Microtablets could reproducibly be monitored in the rat stomach and in the intestines using a 1H-MRI double contrast technique. Fluorine-labelled minicapsules were detectable in the rat stomach by a combination of 1H- and 19F-MRI in vivo., Conclusions: The in vivo 1H-MRI double contrast technique described allows solid oral dosage forms in the rat GI tract to be depicted. Solid dosage forms can easily be labelled by incorporating trace amounts of non-toxic iron oxide (magnetite) particles. 1H-MRI is a promising tool for observing such pharmaceutical dosage forms in humans. Combined 1H- and 19F-MRI offer a means of unambiguously localizing solid oral dosage forms in more distal parts of the GI tract. Studies correlating MRI examinations with drug plasma levels could provide valuable information for the development of pharmaceutical dosage forms.