[Prevention of bone mineral deficiency in premature infants: review of the literature with focus on monitoring of urinary calcium and phosphate]. / Knochenmineralmangel bei Frühgeborenen: Prävention mittels Urinmonitoring von Kalzium und Phosphat.

BACKGROUND: Bone mineral deficiency of prematurity (BMDoP) is caused by the lack of simultaneous availability of calcium (Ca) and anorganic phosphate (P) during rapid skeletal growth. METHODS: Review of the literature on the prevention of BMDoP, with specific attention to the limitations of the monitoring of urinary calcium and phosphate concentrations. RESULTS: Intrauterine bone mineral accretion (BMA) can be achieved in preterm infants if urinary concentrations of Ca and P continuously show that the supplementation with these ions slightly exceeds the actual need. An individually adjusted supplementation with Ca and P appears rational because both growth velocity and enteral Ca absorption are highly variable and determine the need for enteral Ca and P administration. If, however, urinary concentrations of Ca and P are used to determine whether Ca and P supplementation is adequate, mechanisms affecting the urinary excretion of these ions other than nutrition have to be taken into account. Specifically, methylxanthines and diuretics increase the renal Ca losses, and the renal P threshold may be lowered in premature infants. A positive effect of physical activity on BMA has been shown in several studies. CONCLUSIONS: An individualized Ca and P supplementation in preterm infants aiming for supplementation in a slight excess of the actual need and guided by urinary Ca and P concentrations appears able to prevent BMDoP. Monitoring of urinary Ca and P concentrations needs to take into account non-nutritional factors affecting these concentrations. BMA may further be improved by physical activity.

The effect of neutral and acidic oligosaccharides on stool viscosity, stool frequency and stool pH in preterm infants.

AIM: To determine the effect of neutral oligosaccharides [small-chain galacto-oligosaccharides/long-chain fructo-oligosaccharides (scGOS/lcFOS)] in combination with acidic oligosaccharides (pAOS) on stool viscosity, stool frequency and stool pH in preterm infants. METHODS: In this explorative RCT, preterm infants with gestational age <32 weeks and/or birth weight <1500 g received enteral supplementation with scGOS/lcFOS/pAOS or placebo (maltodextrin) between days 3 and 30 of life. Stool samples were collected at day 30 after birth. RESULTS: In total, 113 infants were included. Baseline and nutritional characteristics were not different between both groups. Stool viscosity at day 30 was lower in the prebiotics group (16.8N) (3.9-67.8) compared with the placebo group (26.3N) (1.3-148.0) (p = 0.03; 95% CI -0.80 to 0.03). There was a trend towards higher stool frequency in the prebiotics group (3.1 ± 0.8) compared with the placebo group (2.8 ± 0.7) (p = 0.15; 95% CI -0.08 to 0.52). Stool pH at day 30 was lower in the in the prebiotics group (5.9 ± 0.6) compared with the placebo group (6.2 ± 0.3) (p = 0.009; 95% CI 0.08 to 0.53). CONCLUSIONS: Enteral supplementation of a prebiotic mixture consisting of neutral (scGOS/lcFOS) and acidic oligosaccharides (pAOS) decreases stool viscosity and stool pH with a trend towards increased stool frequency in preterm infants. The inclusion of pAOS in a formula containing a mixture of scGOS/lcFOS does not add specific advantages to the formula in terms of stool viscosity, frequency, pH as well as feeding tolerance.

Hydrolysis of casein accelerates gastrointestinal transit via reduction of opioid receptor agonists released from casein in rats.

BACKGROUND: Protein hydrolysate accelerates gastrointestinal transit (GIT) and feeding advancement in preterm infants compared to native protein. In rat pups, opioid receptor agonists released from casein during digestion such as beta-casomorphins slow down GIT. We hypothesized that hydrolysis of casein reduces the opioid activity released during digestion thereby accelerating GIT compared to native casein. OBJECTIVE: The aim of the present study was to investigate whether casein hydrolysate accelerates GIT compared to native casein and whether pretreatment with naloxone, an opioid receptor blocker, abolishes this difference in rat pups. METHODS: In a randomized controlled trial following a 2 x 2 factorial design, 216 female Wistar rat pups were fed with pellets based on hydrolyzed or native casein. After pretreatment with naloxone or normal saline, carmine red was administered by oro-gastric gavage as a tracer for GIT velocity measurement. Four hours later the animals were sacrificed, their intestine was removed and the length of the colon from the cecocolonic junction to the anus was measured. GIT was recorded as percentage of the total colonic length (percentage of colonic transit) passed by carmine red. Data were given as mean +/- SD. RESULTS: GIT was significantly higher with hydrolyzed casein compared to native casein formula (77.4 +/- 17 and 51.2 +/- 20%), but there was no difference after naloxone pretreatment (77.1 +/- 16 and 76.5 +/- 17%). DISCUSSION: The present data suggest that hydrolysis of casein accelerates GIT via reduction of opioid activity released during digestion. Further studies are required to investigate to which extent these rat pub data apply to preterm infants.

Reference values for urinary calcium and phosphorus to prevent osteopenia of prematurity.

The prevention of osteopenia of prematurity is an important issue in the care of preterm infants. Fetal bone mineral accretion has been achieved in preterm infants by establishing and maintaining a simultaneous slight excretion of calcium (Ca) and phosphorus (P) (urine concentrations of 1-2 mmol/l) by means of an individual supplementation with Ca and/or P, resulting in a slight surplus supply (SSS). In this issue, Aladangady et al. present associations between urinary Ca/Cr and PO(4)/Cr ratios of preterm infants and biochemical variables of bone mineral metabolism. However, to date it has not been proven that these variables are a reliable substitute for direct measurement of bone mineral content (BMC). Before Ca/Cr and PO(4)/Cr ratios can be recommended as a new reference for improving BMC, the following steps are required: (1) direct measurement of BMC, (2) a prospective interventional trial to test and compare this new reference with the existing one (SSS, urinary Ca and P of 1-2 mmol/l) investigating BMC as primary outcome, and (3) adequate proof that Ca and P/Cr ratios are superior to simple urinary Ca and P concentrations.

Transcutaneous bilirubinometry in very low birthweight infants.

AIM: To evaluate whether transcutaneous bilirubinometry (TcB) would be a reliable and efficient screening technique for hyperbilirubinaemia in very low birthweight (VLBW, < or =1500 g) infants in an intensive care unit setting. METHODS: TcB measurements (Minolta Airshield Jaundice Meter JM-102, Osaka, Japan) were obtained immediately before or within 10 min following routine blood sampling for plasma bilirubin concentration measurements in 124 VLBW infants not receiving phototherapy. The relationship between the two techniques was analysed by linear regression analysis. A plasma bilirubin > or =150 micromol/l was defined as hyperbilirubinaemia. The sensitivity and specificity of possible TcB cut-off readings to detect hyperbilirubinaemia was evaluated. RESULTS: There was a significant correlation between the measurements of both techniques (p < 0.0001, r = 0.68). In the present study, a TcB cut-off reading of 14 would have reduced the need for plasma bilirubin measurements by 26% without missing true hyperbilirubinaemia. CONCLUSION: The data suggest that TcB will improve VLBW infant care in an intensive care unit setting by reducing the need for invasive bilirubin concentration measurements.

The abdominal circumference to weight ratio increases with decreasing body weight in preterm infants.

UNLABELLED: Abdominal distension is one of the major clinical indications to withhold feedings in preterm infants. The abdominal circumference (AC) was measured in 42 premature infants on full enteral nutrition in order to establish reference values. AC decreased linearly (r2 = 0.83) with decreasing weight. However, the AC to weight ratio increased substantially (hyperbolically) with decreasing weight. CONCLUSION: The increased AC to weight ratio may be misinterpreted as pathological abdominal distension in the clinical assessment of preterm infants on full enteral nutrition.

Randomized, multicenter trial of two different formulas for very early enteral feeding advancement in extremely-low-birth-weight infants.

BACKGROUND: In extremely-low-birth-weight (ELBW) infants, formula feeding is required if human milk is not available. The tolerance of a new 'high' lactose (55 g/L), low protein, low phosphate, hydrolyzed protein formula (HLF) for early enteral feeding advancement of ELBW infants was compared with that of a low lactose (1 g/L) hydrolyzed protein formula (LLF). METHODS: In a randomized multicenter trial, 99 ELBW infants were fed according to a standardized protocol beginning at 48 hours of age with 12 ml/kg daily increments. Primary outcome was the cumulative milk feeding volume (CFV) from days 3 to 14. The authors hypothesized that feeding HLF as a supplement to human milk would increase the CFV at least by 20% in at least 60% of matched pairs compared with LLF. A secondary issue was to investigate whether human milk would increase the CFV compared with formula. RESULTS: The CFV was 720 mL/kg (range, 0-962 mL/kg) with HLF and 613 mL/kg (range, 3-1,283 mL/kg) with LLF feeding. There was no 20% difference. On day 14, the median feeding volume was 103 mL/kg. The CFV was 533 mL/kg (range, 0-962 mL/kg) in infants who received less than 10% of human milk and 832 mL/kg (range, 74-1,283 mL/kg) in infants who received more than 10%. Necrotizing enterocolitis (Bell stage > or =2) occurred only with LLF feeding (n = 5; P < 0.05). CONCLUSIONS: The study failed to find the hypothesized 20% advantage of the new HLF. The observed advantage of human milk supports the hypothesis that it should be the first diet in ELBW infants; however, this hypothesis still must be confirmed in a controlled, randomized trial.

Meconium passage in extremely low birthweight infants and its relation to very early enteral nutrition.

UNLABELLED: The aim of this study was to evaluate the correlation between the timing of the first and last meconium and feeding tolerance in the very early enteral nutrition of extremely low birthweight (ELBW) infants. Forty-one ELBW infants were fed following a standardized protocol (day 3-14). At 48 h of age bolus gavage feeding with milk was started (12 ml kg(-1) d(-1) increments, 12 meals per day). Gastric residuals up to 2 ml or up to 3 ml were tolerated in infants with a birthweight of < or = 750 g or > 750 g, respectively. No enemas or laxatives were given during the study. The impact of the time until the passage of the first (M-1) and last (M-last) meconium on the feeding volume on day 14 (V14) was evaluated by linear regression analysis. Data are presented as median (range). M-1 was 31 h (0.5-77 h), M-last was 6 d (1.4-22 d) and V14 was 99 (0-156) ml kg(-1). V14 increased with decreasing M-last (p < 0.001) but there was no correlation between V14 and M-1. V14 was 112 (0-156) ml kg(-1) if M-last was shorter than 6 d and 37 (0-147) ml kg(-1) if M-last was longer than 6 d. CONCLUSION: Rapid meconium evacuation appeared to be a key factor for the feeding tolerance of ELBW infants during the first 14 d of life. Further studies needed to investigate whether meconium passage can be accelerated and whether acceleration of the meconium passage will improve the early feeding tolerance in ELBWW infants.

Hydrolysed protein accelerates the gastrointestinal transport of formula in preterm infants.

UNLABELLED: Vomiting, large gastric residuals and abdominal distension are common in very immature infants on formula feeding. The present trial investigated whether a protein hydrolysate formula reduces the gastrointestinal transit time in preterm infants. Fifteen preterm infants (median gestational age 29 (24-32) wk, birthweight 1241 (660-1900) g, postnatal age 18 (5-54) d) on full enteral feeds (>150 ml/kg*d) were enrolled. It was hypothesized that the gastrointestinal transit time is at least 2 h shorter when protein hydrolysate formula is fed compared with standard preterm formula. In a randomized cross-over design study, each formula was fed for 5 d. On days 4 and 9 the gastrointestinal transit time was estimated using carmine red. The protein hydrolysate formula had a markedly shorter gastrointestinal transit time (9.8 h) than the standard formula (19 h) (p = 0.0022, two-sided Mann-Whitney U test). CONCLUSION: The hydrolysate protein formula accelerated gastrointestinal transit of milk and stools, but whether hydrolysate formulas enable a more rapid establishment of full enteral feeding in preterm infants needs to be investigated.

Prospective randomized trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams.

OBJECTIVES: To examine whether early enteral iron supplementation (EI) would improve serum ferritin as a measure of nutritional iron status at 2 months of age and would prevent definite iron deficiency (ID) in infants with a birth weight of <1301 g. METHODS: Infants were randomly assigned to receive enteral iron supplementation of 2 to 6 mg/kg/day as soon as enteral feedings of >100 mL/kg/day were tolerated (EI) or at 61 days of life (late enteral iron supplementation [LI]). Nutritional iron status was assessed: 1) at birth, 2) at 61 days of life, 3) when the infants reached a weight of 1.6 times birth weight, and 4) before blood was transfused at a hematocrit of <.25. ID was defined by any one of the following criteria: ferritin, <12 microg/L; transferrin saturation, <17%; or increase of absolute reticulocyte counts by >50% one week after the onset of enteral iron supplementation. Restrictive red cell transfusion guidelines were followed and all transfusions were documented. Erythropoietin was not administered. The primary outcome variables were: 1) ferritin at 61 days and 2) the number of infants with ID. RESULTS: Ferritin at 61 days was not different between the groups. Infants in the LI group were more often iron-deficient (26/65 vs 10/68) and received more blood transfusions after day 14 of life. No adverse effects of EI were noted. CONCLUSIONS: EI is feasible and probably safe in infants with birth weight <1301 g. EI may reduce the incidence of ID and the number of late blood transfusions. ID may occur in very low birth weight infants despite early supplementation with iron and should be considered in the case of progressive anemia.preterm infant, iron supplementation, iron deficiency, blood transfusion.

Protein hydrolysate formula maintains homeostasis of plasma amino acids in preterm infants.

BACKGROUND: Plasma amino acid concentrations were measured in preterm infants who were fed either a new hydrolyzed cow's milk protein formula or a standard preterm infant formula. It was hypothesized that feeding with the hydrolysate results in preprandial amino acid concentrations that are significantly different from the concentrations found when feeding with the standard formula. METHODS: Fifteen preterm infants, median gestational age, 29 weeks (range, 24-32 weeks); birth weight, 1241 g (range, 660-1900 g); and postnatal age, 18 days (range, 7-54 days) receiving full enteral feedings (>150 ml/kg x day), were enrolled. The intervention was randomized allocation to the formula with hydrolyzed or natural cow's milk protein (the whey/casein ratio was 60:40 in both formulas). In a crossover design, each formula was fed for 5 days, and plasma amino acids were analyzed on day 4 or 5 of each 5-day period. RESULTS: In spite of the 12% higher amino acid intake with hydrolysate formula, the median individual plasma amino acid concentrations were virtually identical with both formulas, and they were within the 10th and the 90th percentile of the reference of levels in the umbilical cord artery after elective cesarean delivery or of breast-fed newborn infants. The median concentrations of lysine and aspartic acid were higher with hydrolyzed formula feeding (p<0.05; two-tailed Mann-Whitney test). With both formulas, single amino acid concentrations were out of the reference values. CONCLUSION: Virtually identical plasma amino acid concentration patterns were measured with the new hydrolyzed preterm infant formula and the standard preterm infant formula, but longitudinal studies are required before the studied protein hydrolysate can be recommended for preterm feeding in general.

The renal phosphate threshold decreases with increasing postmenstrual age in very low birth weight infants.

Our objective was the study of the renal phosphate threshold (TP/GFR) in very low birth weight infants with increasing postmenstrual (pm) age (gestational age plus postnatal age). The case notes of 62 very low birth weight infants were reviewed. Plasma and urine phosphate concentrations (PP, UP) determined on the same day together with the corresponding creatinine concentrations (PCrea, UCrea) built up a data set. Data sets obtained from 29 to 36 wk of pm age were included in the study. UP > or = 1 mmol/L was defined as phosphaturia. TP/GFR = PP - (UP x PCrea/ UCrea). In infants without phosphaturia, maximum PP is a lower limit of TP/GFR and was used as a censored TP/GFR value. We found that in phosphaturic infants, maximum PP (median and range) decreased from 2.8 (1.2-4.6) to 2.0 (1.4-2.7) mmol/L from 29-30 to 35-36 wk of pm age (p < 0.001), and censored TP/GFR (median and 95% confidence interval) decreased from 2.13 (1.95-2.33) to 1.57 (1.31-1.77) mmol/L (p < 0.001). We speculate that the renal phosphate threshold declines with increasing postmenstrual age because tubular reabsorption capacity increases more slowly than GFR.