Choline and Betaine Levels in Plasma Mirror Choline Intake in Very Preterm Infants.

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.

Body Composition of Preterm Infants following Rapid Transition to Enteral Feeding.

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.

Enteral feeding advancement and growth until 5 years in extremely preterm infants.

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.

Calculating Protein Content of Expressed Breast Milk to Optimize Protein Supplementation in Very Low Birth Weight Infants with Minimal Effort-A Secondary Analysis.

Breast milk does not meet the nutritional needs of preterm infants, necessitating fortification. Breast milk is particularly variable in protein content, hence standardized (fixed dosage) supplementation results in inadequate supply. This was a secondary analysis of 589 breast milk protein content measurements of 51 mothers determined by mid-infrared spectroscopy during a clinical trial of higher versus lower protein supplementation in very low birth weight infants. Mothers (and breast milk samples) were divided into a test (41 mothers) and a validation cohort (10 mothers). In the test cohort, the decrease in protein content by day of lactation was modeled resulting in the breast milk-equation (BME)). In the validation cohort, five supplementation strategies to optimize protein supply were compared: standardized supplementation (adding 1.0 g (S1) or 1.42 g protein/100 mL (S2)) was compared with 'adapted' supplementation, considering variation in protein content (protein content according to Gidrewicz and Fenton (A1), to BME (A2) and to BME with adjustments at days 12 and 26 (A3)). S1 and S2 achieved 5% and 24% of adequate protein supply, while the corresponding values for A1-A3 were 89%, 96% and 95%. Adapted protein supplementation based on calculated breast milk protein content is easy, non-invasive, inexpensive and improves protein supply compared to standardized supplementation.

Combined choline and DHA supplementation: a randomized controlled trial.

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.

Neonatal body composition: crossectional study in healthy term singletons in Germany.

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).

Neonatal body composition by air displacement plethysmography in healthy term singletons: a systematic review.

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.

Epidemiological study on intestinal volvulus without malrotation in VLBW infants.

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.

Effect of increased enteral protein intake on plasma and urinary urea concentrations in preterm infants born at < 32 weeks gestation and < 1500 g birth weight enrolled in a randomized controlled trial - a secondary analysis.

BACKGROUND: Feeding breast milk is associated with reduced morbidity and mortality, as well as improved neurodevelopmental outcome but does not meet the high nutritional requirements of preterm infants. Both plasma and urinary urea concentrations represent amino acid oxidation and low concentrations may indicate insufficient protein supply. This study assesses the effect of different levels of enteral protein on plasma and urinary urea concentrations and determines if the urinary urea-creatinine ratio provides reliable information about the protein status of preterm infants. METHODS: Sixty preterm infants (birthweight < 1500 g; gestational age < 32 weeks) were enrolled in a randomized controlled trial and assigned to either a lower-protein group (median protein intake 3.7 g/kg/d) or a higher-protein group (median protein intake 4,3 g/kg/d). Half the patients in the higher-protein group received standardized supplementation with a supplement adding 1.8 g protein/100 ml milk, the other half received individual supplementation depending on the respective mother's milk macronutrient content. Plasma urea concentration was determined in two scheduled blood samples (BS1; BS2); urinary urea and creatinine concentrations in weekly spot urine samples. RESULTS: The higher-protein group showed higher plasma urea concentrations in both BS1 and BS2 and a higher urinary urea-creatinine-ratio in week 3 and 5-7 compared to the lower-protein group. In addition, a highly positive correlation between plasma urea concentrations and the urinary urea-creatinine-ratio (p < 0.0001) and between actual protein intake and plasma urea concentrations and the urinary urea-creatinine-ratio (both p < 0.0001) was shown. CONCLUSIONS: The urinary urea-creatinine-ratio, just like plasma urea concentrations, may help to estimate actual protein supply, absorption and oxidation in preterm infants and, additionally, can be determined non-invasively. Further investigations are needed to determine reliable cut-off values of urinary urea concentrations to ensure appropriate protein intake. TRIAL REGISTRATION: Clinicaltrials.gov; NCT01773902 registered 15 January 2013, retrospectively registered.

Retrospective cohort analysis on pancreatic enzyme substitution in very low birthweight infants with postnatal growth failure.

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.

Growth and morbidity of extremely preterm infants after early full enteral nutrition.

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.

Transport of long-chain polyunsaturated fatty acids in preterm infant plasma is dominated by phosphatidylcholine.

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.

Multicenter study on the effectiveness of the pre-epiglottic baton plate for airway obstruction and feeding problems in Robin sequence.

BACKGROUND: Treatment of Robin sequence is often either invasive or of unproven effectiveness. The pre-epiglottic baton plate (PEBP) is a well-studied alternative, yet is not widely applied internationally. We report on a prospective 3-center cohort study investigating this treatment. Based on an agreed protocol, parents of infants with Robin sequence referred to participating centers were offered enrollment, which involved taking a maxillary cast followed by endoscopy to fit the plate and sleep studies to monitor its effectiveness. Recordings were centrally analyzed by sleep specialists blinded to timing and center. Primary outcome was the mixed-obstructive apnea index, defined as the number of such apneas/h of sleep; secondary outcomes included the desaturation index to <80% pulse oximeter saturation and weight gain. RESULTS: Of 75 infants referred, 49 could be included; 1 center failed to perform appropriate sleep studies. Within a mean hospitalization of 3 weeks, the mixed-obstructive apnea index decreased (median; interquartile range) from 15.9 (6.3-31.5) to 2.3 (1.2-5.4); it decreased further to 0.7 (0.1-2.4) in the 32 infants who had a successful 3-month follow-up sleep study performed. The desaturation index normalized (from 0.38 (0-2.7) to 0.0 (0-0.1)). Mean standard deviation score for weight remained unchanged between admission and follow-up, while the proportion of tube-fed infants decreased from 74 to 14%. CONCLUSIONS: This prospective multi-center cohort study confirms retrospective audits on the effectiveness of PEBP treatment in improving upper airway obstruction and feeding problems, the main clinical problems of infants with Robin sequence. International collaboration is required to compare this with other treatment approaches. TRIAL REGISTRATION: Number NCT02266043 , Registered 30/09/2014; registered partially retrospectively.

Effect of Increased Enteral Protein Intake on Growth in Human Milk-Fed Preterm Infants: A Randomized Clinical Trial.

Importance: Protein, supplied in currently available commercial fortifiers, may be inadequate to meet the requirements of very preterm infants; in addition, intraindividual and interindividual variability of human milk protein and energy content potentially contribute to unsatisfactory early postnatal growth. Objective: To determine effects on growth of different levels of enteral protein supplementation in predominantly human milk-fed preterm infants. Design, Setting, and Participants: This randomized clinical and partially blinded single-center trial was conducted in a neonatal tertiary referral center in Germany. Sixty preterm infants (gestation <32 weeks and weight <1500 g at birth) were recruited from October 2012 to October 2014 and included 35% of 173 eligible infants. Median (interquartile range [IQR]) gestational age at birth was 29.9 (28.7-31.2) weeks. All analyses were conducted in an intention-to-treat population. Interventions: Infants were randomly assigned to either a lower-protein (adding 1 g of bovine protein/100 mL of breast milk through a commercial human milk fortifier; n = 30) or a higher-protein group at a median (IQR) postnatal age of 7 (6-8) days. The higher-protein group (n = 30) received either standardized higher-protein supplementation (study fortifier adding 1.8 g of bovine protein/100 mL of breast milk [n = 15]) or individualized high-protein supplementation based on protein and fat content of administered breast milk (n = 15). Study interventions were continued for a median (IQR) of 41 (30-57) days and until definite discharge planning. Main Outcomes and Measures: Primary outcome was weight gain (g/kg/d) from birth to the end of intervention. Results: Sixty preterm infants (gestation <32 weeks and weight <1500 g at birth), 33 girls, were recruited from October 2012 to October 2014 and included 35% of 173 eligible infants. Median (IQR) gestational age at birth was 29.9 (28.7-31.2) weeks. Demographic characteristics and hospital courses were similar in both groups, and birth weights ranged from 580 to 1495 g in the lower-protein group and 490 to 1470 g in the higher-protein group. Weight gain was similar in the lower- and higher-protein groups: mean (95% CI), 16.3 g/kg/d (15.4-17.1 g/kg/d) in the lower-protein group vs 16.0 g/kg/d (15.1-16.9 g/kg/d) in the higher-protein group) (P = .70), despite an increase in actual protein intake by 0.6 g/kg/d (0.4-0.7 g/kg/d) (P < .001). Head circumference and lower leg longitudinal growth were also similar, as was the proportion of cumulative total enteral feeding volume provided as breast milk: median (IQR) proportion of breast milk, 92% (79%-98%) in the lower-protein group vs 94% (62%-99%) in the higher-protein group (P = .89). Conclusions and Relevance: An increase in protein intake by 0.6 g/kg/d to a mean intake of 4.3 g/kg/d did not further enhance growth of very preterm infants with a median birth weight of 1200 g, who achieved near-fetal growth rates. This might point to a ceiling effect for enteral protein intake with respect to its influence on growth. Trial Registration: clinicaltrials.gov Identifier: NCT01773902.

Choline and polyunsaturated fatty acids in preterm infants' maternal milk.

BACKGROUND: Choline, docosahexaenoic acid (DHA), and arachidonic acid (ARA) are essential to fetal development, particularly of the brain. These components are actively enriched in the fetus. Deprivation from placental supply may therefore result in impaired accretion in preterm infants. OBJECTIVE: To determine choline, choline metabolites, DHA, and ARA in human breast milk (BM) of preterm infants compared to BM of term born infants. DESIGN: We collected expressed BM samples from 34 mothers (N = 353; postnatal day 6-85), who had delivered 35 preterm infants undergoing neonatal intensive care (postmenstrual age 30 weeks, range 25.4-32.0), and from mothers after term delivery (N = 9; postnatal day 6-118). Target metabolites were analyzed using tandem mass spectrometry and gas chromatography and reported as medians and 25th/75th percentiles. RESULTS: In BM, choline was mainly present in the form of phosphocholine and glycerophosphocholine, followed by free choline, phosphatidylcholine, sphingomyelin, and lyso-phosphatidylcholine. In preterm infants' BM total choline ranged from 61 to 360 mg/L (median: 158 mg/L) and was decreased compared to term infants' BM (range 142-343 mg/L; median: 258 mg/L; p < 0.01). ARA and DHA comprised 0.81 (range: 0.46-1.60) and 0.43 (0.15-2.42) % of total preterm BM lipids, whereas term BM values were 0.68 (0.52-0.88) and 0.35 (0.18-0.75) %, respectively. Concentrations of all target parameters decreased after birth, and frequently 150 ml/kg/d BM did not meet the estimated fetal accretion rates. CONCLUSIONS: Following preterm delivery, BM choline concentrations are lower, whereas ARA and DHA levels are comparable versus term delivery. Based on these findings we suggest a combined supplementation of preterm infants' BM with choline, ARA and DHA combined to improve the nutritional status of preterm infants. STUDY REGISTRATION: This study was registered at www.clinicaltrials.gov. Identifier: NCT01773902.

Developmental changes in polyunsaturated fetal plasma phospholipids and feto-maternal plasma phospholipid ratios and their association with bronchopulmonary dysplasia.

BACKGROUND: Docosahexaenoic (C22:6) and arachidonic acid (C20:4) are long-chain polyunsaturated fatty acids (LC-PUFA), essential to fetal development, and preferentially transported by plasma phospholipids. OBJECTIVE: To characterize fetal and maternal plasma phospholipid changes during gestation, and to investigate whether LC-PUFA phospholipid profiles are associated with bronchopulmonary dysplasia (BPD). DESIGN: Cord plasma and parturient serum from N = 108 pregnancies [24-42 week postmenstrual age (PMA)] were collected. Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were analyzed with tandem mass spectrometry. PMA-associated changes were quantified, and break point analyses served to describe nonlinear changes during gestation. RESULTS: PC and PE were lower in cord than in parturient samples. In parturients, PC decreased until 33 week PMA, but then re-increased, whereas in cord plasma, concentrations linearly decreased. Fetal PC and PC sub-group values correlated with maternal values. C20:4-PC was twofold higher in cord than in maternal samples throughout gestation. C22:6-PC values, however, exceeded maternal values only beyond 33 week PMA. Consequently, early preterm C20:4-PC-to-C22:6-PC ratio largely exceeded term infant values. In infants born before 28 week PMA, a low C20:4-PC-to-C22:6-PC ratio was associated with BPD severity. CONCLUSIONS: Fetal plasma LC-PUFA-PC composition correlates with maternal values. Fetal C20:4-PC exceeds maternal values throughout gestation, whereas C22:6-PC exceeds maternal values only beyond 33 week PMA, resulting in a low fetal C20:4-PC/C22:6-PC ratio only toward end gestation. A low C20:4-PC/C22:6-PC ratio before 28 week PMA is associated with BPD severity. These data point to a concept of PMA-adjusted ARA and DHA supplementation and, potentially, cord plasma phospholipid analysis for BPD prediction.

Piccolo Directs Activity Dependent F-Actin Assembly from Presynaptic Active Zones via Daam1.

The dynamic assembly of filamentous (F) actin plays essential roles in the assembly of presynaptic boutons, the fusion, mobilization and recycling of synaptic vesicles (SVs), and presynaptic forms of plasticity. However, the molecular mechanisms that regulate the temporal and spatial assembly of presynaptic F-actin remain largely unknown. Similar to other F-actin rich membrane specializations, presynaptic boutons contain a set of molecules that respond to cellular cues and trans-synaptic signals to facilitate activity-dependent assembly of F-actin. The presynaptic active zone (AZ) protein Piccolo has recently been identified as a key regulator of neurotransmitter release during SV cycling. It does so by coordinating the activity-dependent assembly of F-Actin and the dynamics of key plasticity molecules including Synapsin1, Profilin and CaMKII. The multidomain structure of Piccolo, its exquisite association with the AZ, and its ability to interact with a number of actin-associated proteins suggest that Piccolo may function as a platform to coordinate the spatial assembly of F-actin. Here we have identified Daam1, a Formin that functions with Profilin to drive F-actin assembly, as a novel Piccolo binding partner. We also found that within cells Daam1 activation promotes Piccolo binding, an interaction that can spatially direct the polymerization of F-Actin. Moreover, similar to Piccolo and Profilin, Daam1 loss of function impairs presynaptic-F-actin assembly in neurons. These data suggest a model in which Piccolo directs the assembly of presynaptic F-Actin from the AZ by scaffolding key actin regulatory proteins including Daam1.

Avoiding postnatal undernutrition of VLBW infants during neonatal intensive care: evidence and personal view in the absence of evidence.

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.

Choline concentrations are lower in postnatal plasma of preterm infants than in cord plasma.

BACKGROUND: Choline is essential to human development, particularly of the brain in the form of phosphatidylcholine, sphingomyelin and acetylcholine, for bile and lipoprotein formation, and as a methyl group donator. Choline is actively transported into the fetus, and maternal supply correlates with cognitive outcome. Interruption of placental supply may therefore impair choline homeostasis in preterm infants. OBJECTIVE: Determination of postnatal plasma concentrations of choline and its derivatives betaine and dimethylglycine (DMG) in preterm infants compared to cord and maternal blood matched for postmenstrual age (PMA). DESIGN: We collected plasma of very low-birth-weight infants undergoing neonatal intensive care (n = 162), cord plasma of term and preterm infants (n = 176, 24-42-week PMA), serum of parturients (n = 36), and plasma of healthy premenopausal women (n = 40). Target metabolites were analyzed with tandem mass spectrometry and reported as median (25th/75th percentiles). RESULTS: Cord plasma choline concentration was 41.4 (31.8-51.2) µmol/L and inversely correlated with PMA. In term but not in preterm infants, cord plasma choline was lower in girls than in boys. Prenatal glucocorticoid treatment did not affect choline levels in cord plasma, whereas betaine was decreased and DMG increased. In parturients and non-pregnant women, choline concentrations were 14.1 (10.3-16.9) and 8.8 (5.7-11.2) µmol/L, respectively, whereas betaine was lowest in parturients. After delivery, preterm infant plasma choline decreased to 20.8 (16.0-27.6) µmol/L within 48 h. Betaine and DMG correlated with plasma choline in all groups. CONCLUSIONS: In preterm infants, plasma choline decreases to 50 % of cord plasma concentrations, reflecting choline undernourishment and postnatal metabolic adaptation, and potentially contributing to impaired outcome.

Late-onset volvulus without malrotation in extremely preterm infants--a case-control-study.

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.