Christoph Fusch

Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition.

The number of surviving children born prematurely has increased substantially during the last 2 decades. The major goal of enteral nutrient supply to these infants is to achieve growth similar to foetal growth coupled with satisfactory functional development. The accumulation of knowledge since the previous guideline on nutrition of preterm infants from the Committee on Nutrition of the European Society of Paediatric Gastroenterology and Nutrition in 1987 has made a new guideline necessary. Thus, an ad hoc expert panel was convened by the Committee on Nutrition of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition in 2007 to make appropriate recommendations. The present guideline, of which the major recommendations are summarised here (for the full report, see http://links.lww.com/A1480), is consistent with, but not identical to, recent guidelines from the Life Sciences Research Office of the American Society for Nutritional Sciences published in 2002 and recommendations from the handbook Nutrition of the Preterm Infant. Scientific Basis and Practical Guidelines, 2nd ed, edited by Tsang et al, and published in 2005. The preferred food for premature infants is fortified human milk from the infants own mother, or, alternatively, formula designed for premature infants. This guideline aims to provide proposed advisable ranges for nutrient intakes for stable-growing preterm infants up to a weight of approximately 1800 g, because most data are available for these infants. These recommendations are based on a considered review of available scientific reports on the subject, and on expert consensus for which the available scientific data are considered inadequate.

Early nasal continuous positive airway pressure treatment reduces the need for intubation in very low birth weight infants

Abstract Nasal continuous positive airway pressure (CPAP) applied shortly after birth is said to be an effective treatment of respiratory distress in very low birth weight infants (VLBW). We tested the hypothesis that the use of early nasal CPAP (applied as soon as signs of respiratory distress occurred, usually within 15 min after birth) reduces the need for intubation, the duration of intermittent mandatory ventilation and the incidence of bronchopulmonary dysplasia. All liveborn VLBW infants (birth weight < 1500 g) admitted to our tertiary neonatal intensive care unit in 1990 (historical controls) and in 1993 (early nasal CPAP group) entered the study. The intubation rate was significantly lower after introduction of nasal CPAP (30% vs 53%, P = 0.016). Median duration of intubation was 4.5 days (interquartile range 3–7 days) before versus 6.0 days (2.8–9 days) after nasal CPAP was introduced (P = 0.73). The incidence of bronchopulmonary dysplasia was not reduced significantly (32% vs 30%, P = 0.94). Survival until discharge was 89.5% before versus 92.9% after introduction of nasal CPAP (P = 0.54). Conclusion Early nasal CPAP is an effective treatment of respiratory distress in VLBW infants, significantly reducing the need for intubation and intermittent mandatory ventilation, without worsening other stan dard measures of neonatal outcome. We found no significant decrease in the incidence of bronchopulmo nary dysplasia.

Structural and neurobehavioral delay in postnatal brain development of preterm infants.

Postnatal brain development of healthy prematurely born infants was assessed to study possible influence of premature birth and early extrauterine environment on structural, biochemical, and functional brain development. Myelination and differentiation of gray and white matter were studied byin vivo magnetic resonance (MR) imaging (MRI), changes in cerebral metabolism by 1H MR spectroscopy (MRS), and changes in early human neurobehavior by the assessment of preterm infants behavior (APIB). The stage of intrauterine and extrauterine brain development in prematurely born infants at term was compared with the stage of mainly intrauterine brain development in a group of full-term infants. Eighteen preterm infants unremarkable with respect to neurologic and medical status were studied at approximately 2 wk of postnatal age [gestational age (GA) 1: 32.5 ± 1.2 wk] and again at term(GA 2: 40.0 ± 1.1 wk). For comparison a group of 13 full-term born infants (GA T: 40.6 ± 2.1 wk) were studied by MR and six by APIB. When GA 2 to GA 1 was compared, significant maturational changes were found with MRI in gray and white matter and myelination, with 1H MRS in the concentration of N-acetylaspartate and with all scores of APIB. In preterm infants at term (GA 2) compared with full-term infants (GA T) significantly less gray and white matter differentiation and myelination was observed as well as significantly poorer performance in four neurobehavioral parameters (autonomic reactivity, motoric reactivity, state organization, attentional availability). We conclude that MRI and 1H MRS can be used to study postnatal brain development in preterm infants. Structural and biochemical maturation is accompanied by functional maturation as shown with the neurobehavior assessment. Preterm infants at term compared with full-term infants show a structural as well as a functional delay in brain development assessed at 40 wk of postconceptional age.

Randomized double-blind study of the nutritional efficacy and bifidogenicity of a new infant formula containing partially hydrolyzed protein, a high β-palmitic acid level, and nondigestible oligosaccharides

Objectives The aim of this study was to evaluate the nutritional efficacy and bifidogenic characteristics of a new infant formula containing partially hydrolyzed whey protein, modified vegetable oil with a high &bgr;-palmitic acid content, prebiotic oligosaccharides, and starch. Methods In a double-blind study, healthy formula-fed term infants aged younger than 2 weeks were randomized to receive either the new infant formula (NF) or a standard formula (SF) until the age of 12 weeks. Anthropometric measurements were taken at enrollment, 6 weeks, and 12 weeks. In a subsample of infants, blood samples were taken at 6 weeks and stool samples were taken at enrollment and 6 weeks. Blood samples were analyzed for biochemical measures of protein status and amino acids, and stools were analyzed for total bacteria and bifidobacteria. Mothers completed a feeding diary and questionnaire at 6 and 10 weeks. Results One hundred fifty-four infants were enrolled in the study; 102 completed the trial. The growth of infants in both formula groups was in line with published growth curves. During the first 6 weeks, NF girls gained more weight and head circumference than the SF girls. These velocity differences were not maintained throughout the 12-week study period. The NF stools had a higher proportion of bifidobacteria at 6 weeks compared with the SF stools, and they were softer. There were no clinically significant differences in the blood biochemical and amino acid values between groups. Both formulas were well tolerated by the infants. Conclusions When compared with a standard infant formula, the new formula supported satisfactory growth, led to higher counts of bifidobacteria in the feces, produced blood bio-chemical values typical of formula-fed infants, and was well tolerated.

EPIDERMAL GROWTH FACTOR-MEDIATED ACTIVATION OF THE MAP KINASE CASCADE RESULTS IN ALTERED EXPRESSION AND FUNCTION OF ABCG2 (BCRP)

Epidermal growth factor (EGF) is a multifunctional growth factor known to play a major role in proliferation and differentiation processes. EGF-induced differentiation is a prerequisite for function of various cell types, among them cytotrophoblasts, a functionally important cellular fraction in human placenta. Stimulation of cytotrophoblasts with EGF results in formation of a multinuclear syncytium representing the feto-maternal interface, which protects the fetus against exogenous substances. It is well established that part of this protection system is based on ATP-binding cassette (ABC) transporters such as ABCG2 (breast cancer resistance protein, BCRP). However, little is known about regulation of transport proteins in the framework of EGF-mediated cellular differentiation. In the present work we show a significant increase of ABCG2 expression by EGF in cytotrophoblasts, BeWo, and MCF-7 cells on both mRNA and protein levels. This increase resulted in decreased sensitivity to the ABCG2 substrates mitoxantrone and topotecan. In each cell type, EGF increases expression of ABCG2 by activation of mitogen-activated protein kinase cascade via phosphorylation of extracellular regulated kinase (ERK)1/2 and c-jun NH-terminal kinase/stress-activated protein kinase (JNK/SAPK). Consequently, the increase of ABCG2 by EGF was abolished by pretreatment of cells with the tyrosine kinase inhibitor 4-(3-chloroanillino)-6,7-dimethoxyquinazoline (AG1478) or the mitogen-activated protein kinase kinase inhibitor 2′-amino-3′methoxyflavone (PD 98059), thereby reestablishing sensitivity toward mitoxantrone. Moreover, analysis of ABCG2 expression during placental development revealed a significant increase in preterm versus term placenta. Taken together, our data show regulation of ABCG2 expression by EGF. In view of EGF signal transduction as a target for drugs (e.g., gefitinib), which are in turn substrates and/or inhibitors of ABCG2, this regulation has therapeutic consequences.

Osteoporosis in pediatric patients suffering from chronic inflammatory bowel disease with and without steroid treatment.

Background: Children and adolescents suffering from inflammatory bowel disease (IBD) are at risk of developing osteoporosis as a result of treatment with corticosteroids as well as of nonsteroidal factors like inflammation and malnutrition. To study the impact of these factors on development of osteopathy, we compared the rate of osteoporosis in steroid-naive and steroid-treated pediatric IBD patients. Methods: In 90 patients (50 girls) with IBD (34 steroid-naive, 53 steroid-treated, 3 not known) aged 8.8 to 19.2 (14.4 ± 2.2) years and 52 controls (27 girls) aged 6.1 to 17.6 (12.9 ± 3.0) years, bone mineral density (BMD) of the lumbar spine was assessed with dual energy x-ray absorptiometry. Areal BMD values were transformed into volumetric densities called bone mineral apparent density (BMAD) and expressed as standard deviation scores (SDS) on the basis of the BMAD values of the controls. Results: The rate of osteoporotic patients (BMAD-SDS < −2) was 8% in girls and 20% in boys. There was a similar proportion of osteoporosis in steroid-naive (12%) and steroid-treated (11%) patients. SDS of body height showed a significant positive correlation with BMD-SDS but not with BMAD-SDS in almost all patient subgroups, indicating an interfering dependency of BMD from bone size. Conclusions: The prevalence of osteoporosis in pediatric patients with IBD is approximately the same as in adult patients. Osteoporosis is already present before steroid treatment. Data of dual energy x-ray absorptiometry measurements should be transformed into volumetric parameters to compensate for short stature. Otherwise, a lot of growth-stunted patients may be falsely diagnosed as osteopenic.

Organic Anion Transporting Polypeptide 2B1 and Breast Cancer Resistance Protein Interact in the Transepithelial Transport of Steroid Sulfates in Human Placenta

The human placenta has both protective and nurturing functions for the fetal organism. Uptake and elimination of xenobiotics and endogenous substances are facilitated by various transport proteins from the solute carrier (SLC) and ABC families, respectively. A functional interaction of uptake and elimination, which is a prerequisite for vectorial transport across cellular barriers, has not been described for placenta. In this study, we examined expression of organic anion transporter (OAT) 4 (SLC22A11), organic anion transporting polypeptide (OATP) 2B1 (SLCO2B1, OATP-B), and breast cancer resistance protein (BCRP) (ABCG2) in human placenta (n = 71) because all three proteins are involved in transmembranal transfer of estrone 3 sulfate (E3S; metabolic product) and dehydroepiandrosterone sulfate (DHEAS; precursor molecule). On the mRNA level, we found a significant correlation of OATP2B1 and BCRP (R2 = 0.534; p < 0.01) but not between OAT4 and BCRP (R2 = –0.104; p > 0.05). Localization studies confirmed basal expression of OATP2B1 and apical expression of BCRP. To study functional interactions between OATP2B1 and BCRP, we developed a Madin-Darby canine kidney cell model expressing both transport proteins simultaneously (OATP2B1 and BCRP in the basal and apical membrane, respectively). Using this cell model in a transwell system resulted in a significantly increased basal to apical transport of both E3S and DHEAS, when both transporters were expressed with no change of transfer in the apical to basal direction. Taken together, these data show the potential for a functional interaction of OATP2B1 and BCRP in transepithelial transport of steroid sulfates in human placenta.

Target Fortification of Breast Milk with Fat, Protein, and Carbohydrates for Preterm Infants

OBJECTIVES Fortification of breast milk is an accepted practice for feeding very low birth weight infants, however, fixed dosage enhancement does not address variations in native breast milk. This could lead to deficiencies in calories and macronutrients. We therefore established the infrastructure for target fortification in breast milk by measuring and adjusting fat, protein, and carbohydrate content daily. We analyzed nutrient intake, growth, and safety variables. STUDY DESIGN Each 12-hour batch of breast milk was analyzed using near-infrared spectroscopy. Macronutrients were individually added to routine fortification to achieve final contents for fat (4.4 g), protein (3 g), and carbohydrates (8.8 g) (per 100 mL). Fully breast milk fed healthy very low birth weight infants (<32 weeks) were fed the fortified breast milk for at least 3 weeks. Matched pair analysis of 20 infants fed routinely fortified breast milk was performed using birth weight, gestational age, and postnatal age. RESULTS All 650 pooled breast milk samples required at least 1 macronutrient adjusted. On average, 0.3 ± 0.4 g of fat, 0.7 ± 0.2 g of protein, and 1.2 ± 0.2 g of carbohydrate were added. Biochemistry was normal in the 10 target fortified infants (birth weight: 860 ± 309 g, 26.3 ± 1.6 weeks gestational age); weight gain was 19.9 ± 2.7 g/kg/d; and milk intake was 147 ± 5 mL/kg/d (131 ± 16 kcal/kg/d). Osmolality of fortified breast milk was 436 ± 13 mOsmol/kg. Matched pair analysis of infants indicated a higher milk intake (155 ± 5 mL/kg/d) but similar weight gain (19.7 ± 3.3 g/kg/d). No adverse event was observed. The linear relationship between milk intake and weight gain observed in study babies but not seen in matched controls may be related to the variable composition of breast milk. CONCLUSIONS Daily target fortification can be safely implemented in clinical routine and may improve growth.

Regional Metabolic Assessment of Human Brain during Development by Proton Magnetic Resonance Spectroscopy In Vivo and by High-Performance Liquid Chromatography/Gas Chromatography in Autopsy Tissue

To study the course of regional metabolite concentrations during early brain development, we measured in vivo metabolites [N-acetyl-aspartate (NAA), choline-containing compounds, and myo-inositol (M-Ino)] in the precentral area of the cerebrum by short echo-time single volume proton magnetic resonance spectroscopy and compared in vivo established spectroscopic data with classic chromatographic data (HPLC) on age-corresponding autopsy tissue in different regions of the brain. In autopsy tissue, regional (frontal lobe, precentral area, basal ganglia, thalamus) and age-dependent differences of the concentration of creatine, NAA, and M-Ino were determined. In vivo measurement of NAA by proton magnetic resonance spectroscopy shows a significant increase of NAA by increasing postconceptional age. M-Ino shows a weak correlation and a nonsignificant decrease with increasing postconceptional age. Choline shows no age-dependent changes. Creatine concentrations measured by HPLC in different regions of the developing brain at autopsy showed an age-dependent increase that was identical for the left and right side and similar for the precentral area and frontal lobe and more pronounced for the basal ganglia and thalamus. Comparison of the results obtained by the two methods shows agreement for the age-dependent changes and the absolute concentration of M-Ino. NAA determined in autopsy tissue by HPLC is significantly lower than that measured in vivo by proton magnetic resonance spectroscopy. A comparison of the concentrations measured by HPLC in frontal lobe, basal ganglia, and thalamus with the results obtained from the precentral area showed significant regional differences in all measured metabolites. These results define important age-dependent changes detected with both methods and further indicate limitations of both methods that have to be considered when presenting absolute concentration values.

Neonatal body composition : Dual-energy X-ray absorptiometry, magnetic resonance imaging, and three-dimensional chemical shift imaging versus chemical analysis in piglets

An animal study to evaluate dual-energy x-ray absorptiometry (DXA) and magnetic resonance (MR) imaging and spectroscopy for measurement of neonatal body composition was performed. Twenty-three piglets with body weights ranging from 848 to 7550 g were used. After measuring total body water, animals were killed and body composition was assessed using DXA and MR (1.5 T; MR imaging, T1-weighted sagittal spin-echo sequence; MR spectroscopy, three-dimensional chemical shift imaging) as well as chemical carcass analysis (standard methods) after homogenization. Body composition by chemical analysis (percent of body weight, mean ± SD) was as follows: body water, 75.3 ± 3.9%; total protein, 13.9 ± 8.8%; and total fat, 6.5 ± 3.7%. Absolute content of fat and total ash was 7–674 and 35–237 g, respectively. Mean hydration of fat-free mass was 0.804 ± 0.011 g/kg and decreased with increasing body weight (r2 = 0.419) independent of age. Using DXA, bone mineral content was highly correlated with calcium content (r2= 0.992), and calcium per bone mineral content was 44.1 ± 4.2%. DXA fat mass correlated with total fat (r2 = 0.961). Using MR, spectroscopy and chemical analysis were highly correlated with fat-to-water ratio (r2 = 0.984) and absolute fat content (r2 = 0.988). Total fat by MR imaging volumetry showed a lower correlation (r2 = 0.913) and overestimated total fat by a factor of 2.46. Conversion equations for DXA were developed (total fat = 1.31 × fat mass measured by DXA − 68.8; calcium = 0.402 × bone mineral content + 1.7), which improved precision and accuracy of DXA measurements. In conclusion, both DXA and MR spectroscopy give accurate and precise estimates of neonatal body composition and may become valuable tools for the noninvasive assessment of neonatal growth and nutritional status.