Early Effect of Supplemented Infant Formulae on Intestinal Biomarkers and Microbiota: A Randomized Clinical Trial.

BACKGROUND: Post-natal gut maturation in infants interrelates maturation of the morphology, digestive, and immunological functions and gut microbiota development. Here, we explored both microbiota development and markers of gut barrier and maturation in healthy term infants during their early life to assess the interconnection of gut functions during different infant formulae regimes. METHODS: A total of 203 infants were enrolled in this randomized double-blind controlled trial including a breastfed reference group. Infants were fed starter formulae for the first four weeks of life, supplemented with different combination of nutrients (lactoferrin, probiotics (Bifidobacterium animal subsp. Lactis) and prebiotics (Bovine Milk-derived Oligosaccharides-BMOS)) and subsequently fed the control formula up to eight weeks of life. Stool microbiota profiles and biomarkers of early gut maturation, calprotectin (primary outcome), elastase, α-1 antitrypsin (AAT) and neopterin were measured in feces at one, two, four, and eight weeks. RESULTS: Infants fed formula containing BMOS had lower mean calprotectin levels over the first two to four weeks compared to the other formula groups. Elastase and AAT levels were closer to levels observed in breastfed infants. No differences were observed for neopterin. Global differences between the bacterial communities of all groups were assessed by constrained multivariate analysis with hypothesis testing. The canonical correspondence analysis (CCA) at genus level showed overlap between microbiota profiles at one and four weeks of age in the BMOS supplemented formula group with the breastfed reference, dominated by bifidobacteria. Microbiota profiles of all groups at four weeks were significantly associated with the calprotectin levels at 4 (CCA, p = 0.018) and eight weeks of age (CCA, p = 0.026). CONCLUSION: A meaningful correlation was observed between changes in microbiota composition and gut maturation marker calprotectin. The supplementation with BMOS seems to favor gut maturation closer to that of breastfed infants.

Motilin and gastrin secretion and lipid profile in preterm neonates following prebiotics supplementation: a double-blind randomized controlled study.

BACKGROUND: Gut hormones play an important role in the adaptation of the immature neonatal gut, and their secretion may be modulated by prebiotics. Furthermore, prebiotics are well known for their hypolipidemic potentials. We tested the hypothesis that prebiotics could alter motilin and gastrin secretion and reduce lipids in healthy preterms. METHODS: A total of 167 newborns were randomized to either a prebiotics enriched formula containing dietary oligosaccharides (short-chain galacto-oligo-saccharides/long-chain fructo-oligo-saccharides [scGOS/lcFOS]), at a concentration of 0.8 g/100 ml, or a common preterm formula. Day 1 and 16 basal motilin, gastrin concentrations, and lipids were evaluated together with growth parameters, gastric residue, bowel habits, and feeding tolerance. Adverse events including necrotizing enterocolitis (NEC) and septicemia were also recorded. RESULTS: Mean motilin increase and day 16 mean values were greater for the intervention, compared with the control group (P = .001, P = .005, respectively), while gastrin remained high in both groups. Mean cholesterol and low density lipoprotein (LDL) increase were significantly greater in the control, compared with the intervention (P = .037, and P = .001) group. Day 16 LDL levels were significantly higher in the control group. Mean weight was increased in the control group, while gastric residue was less and stool frequency was increased in the intervention group. NEC and septicemia were not statistically different between groups. CONCLUSION: A prebiotics enriched formula resulted in significant surge of motilin relating to reduced gastric residue, compared with a common preterm formula. Mean cholesterol change was lower, while LDL was not increased in the prebiotics group, compared with the control group.

Maternal age demographic trends in Greece from 1980 to 2008.

OBJECTIVE: To identify maternal age trends in Greece over a 29-year period from 1980 to 2008. STUDY DESIGN: Data concerning live births after 24 gestational weeks was collected from the Hellenic Vital Statistics records and analyzed. Mothers were categorized into age groups. Data was further sorted according to birth in urban or non-urban areas, and the relative contribution of each group was estimated. RESULTS: In contrast to 1980, when the most prevalent maternal age group was 20-24 years, in 1990 the prevalent maternal age group was 25-29 years. In 2008 the prevalent maternal age group shifted to 30-34 years of age. Adolescent births do not pose a major problem in Greece and present a steadily declining trend throughout the years studied. Urban population exhibited an earlier and more intense shift towards older maternal ages. Demand for assisted reproductive technology methods showed an increase among women > or = 40 years of age. CONCLUSION: Maternal age patterns in Greece over the past 3 decades are described. The differences in birth patterns in women giving birth in urban areas are identified and compared to birth patterns in the rest of the country. The adolescent pregnancy rate in Greece was found to be very low.

Preterm birth trends in Greece, 1980-2008: a rising concern.

OBJECTIVE: To identify preterm birth trends in Greece. DESIGN: Retrospective epidemiological study. SETTING: Women giving birth in Greece from 1980 to 2008. POPULATION: Live births beyond the 24th gestational week. METHODS: Data acquisition from the Hellenic Vital Statistics records. Statistical analysis of preterm birth rate among neonates estimated for each year. MAIN OUTCOME MEASURES: Total number of births and preterm births, as well as rate of preterm birth by gestational week. Stillbirth rates by gestational age. RESULTS: 3 218 463 births occurred during the period under study, 151 594 (4.7%) of which were preterm. A steep rise in preterm births was noted during the final years of the study, reaching 9.6% in 2008. This was mainly due to the "late preterm" sub-group (34(+0) -36(+6) gestational weeks). The rates of stillbirth fell in a constant way regardless of the maturity index. CONCLUSIONS: Although preterm birth etiology is multifactorial, the selective rise in the "late preterm" group possibly was due to an increase in medical reasons necessitating a preterm delivery, changes in obstetric practice, or both. Further studies are needed to estimate the precise effect of each contributing factor.

The impact of oral glutamine supplementation on the intestinal permeability and incidence of necrotizing enterocolitis/septicemia in premature neonates.

OBJECTIVE: To examine the impact of oral glutamine (Gln) supplementation on gut integrity and on the incidence of necrotizing enterocolitis (NEC)/septicemia of premature neonates. METHODS: Preterm neonates (n = 101, gestational age <34 weeks, birth weight <2000 g) were randomly allocated to receive from day 3 to day 30 postpartum, either oral Gln (0.3 g/kg/day, n = 51-Gln group) or placebo (caloreen-isocaloric, n = 50-control group). Intestinal permeability was determined from the urinary lactulose/mannitol recovery (L/M ratio) following their oral administration and assessed at three time points: day 2 (before first administration), day 7 and day 30 of life. The incidence of NEC and septicemia over the study period was also recorded. RESULTS: A decrease of lactulose recovery at days 7 (p = 0.001) and 30 (p < 0.001) and a decrease of L/M ratio at day 7 (p = 0.002) were observed only in the Gln group. Lactulose recovery and L/M ratio at day 7 (p = 0.022 and p = 0.004, respectively), as well as lactulose recovery (p = 0.001), mannitol recovery (p = 0.042), and L/M ratio (p = 0.001) at day 30, were decreased in the Gln group as compared to controls. NEC and septicemia were lower in the Gln group at the end of the first week (p = 0.009 and p = 0.041, respectively) and up to the end of the study (p < 0.001 and p = 0.048, respectively). CONCLUSION: Oral Gln administration may have beneficial effects on intestinal integrity and the overall incidence of NEC/septicemia in preterm infants.

21 Mb deletion in chromosome band 13q22.2q32.1 associated with mild/moderate psychomotor retardation, growth hormone insufficiency, short neck, micrognathia, hypotonia, dysplastic ears and other dysmorphic features.

We report on a 9-month old boy carrying a 21 Mb de novo 13q interstitial deletion. The imbalance was detected by chromosomal analysis and investigated by Fluorescence In Situ Hybridization (FISH) and Comparative Genomic Hybridization (array-CGH) using two different platforms: a BAC microarray with 516 kb resolution (Cytochip) and a 15 kb resolution oligonucleotide microarray (Agilent 244K). The deletion has been estimated to span 21.46 Mb on chromosomal bands 13q22.2-13q32.1. The patient has mild/moderate psychomotor retardation, growth hormone insufficiency, hypertelorism, short neck, micrognathia, hypotonia, dysplastic ears and other dysmorphic features. Further investigation revealed that the abnormality is de novo and causative of the patient's phenotype. The described patient is unique among similar rare cases with different deletion breakpoints. It is the first case of 13q22.2q32.1 deletion where the breakpoints are clearly defined, indicating the importance of detailed clinical description and high-resolution genomic analysis for characterization of rare genetic syndromes.

The effect of a fructo-oligosaccharide supplemented formula on gut flora of preterm infants.

AIM: The intestinal flora of breast-fed infants is generally dominated by bifidobacteria which have beneficial properties. Their presence is due to various components of breast milk, including prebiotic substances. This prospective double-blind study compared the numbers of bifidobacteria in the stool flora of bottle-fed preterm infants randomized to receive for 14 days either a formula with prebiotic fructo-oligosaccharides at a concentration of 0.4 g/dL or the same formula with maltodextrin as a placebo. METHODS: Within 0-14 days after birth, 56 healthy bottle-fed infants were enrolled to receive either the prebiotic or placebo. Faecal samples were taken at inclusion day and at study day 7. The number of bifidobacteria in the stools, stool characteristics and somatic growth were recorded during the study. RESULTS: In the group fed fructo-oligosaccharides, both the numbers of bifidobacteria in the stools and the proportion of infants colonized with them were significantly higher as compared to the placebo group (p=0.032 and p=0.030 respectively). There was also a higher number of bacteroids in the fructo-oligosaccharide group as compared to the placebo (p=0.029). At the same time, reduction was noted in the numbers of Escherichia coli and enterococci. (p=0.029, and p=0.025, respectively). Supplementation had also significant influence on stool frequency per day (p=0.0080). CONCLUSION: An infant formula containing a small quantity of prebiotic oligosaccharides is well accepted and leads to rapid growth of bifidobacteria in the gut of bottle-fed preterm infants while decreasing the numbers of pathogenic microorganisms.

Immunologic markers in the neonatal period: diagnostic value and accuracy in infection.

Diagnosis of early-onset neonatal infection has led to the development of several screening tests including C-reactive protein, a very commonly used marker, and cytokines (mainly interleukin-6 and -8), alone or in combination with C-reactive protein, based on the premise that their increases in response to infection may precede that of C-reactive protein. In recent years the search for diagnostic tests has turned to procalcitonin, a propeptide of calcitonin, which appears to be a promising marker of infection in newborn infants. Additionally, specific leukocyte cell surface antigens (mainly CD11b and CD64), detected by flow cytometry, are evaluated as markers of neonatal infection, since their expression on the cell membrane increases in substantial quantities after leukocyte activation by bacteria or their cellular products. This review aims to examine the role of these newly available immunologic indices and to assess their validity as diagnostic markers of infection during the neonatal period.

Gastric emptying in very-low-birth-weight infants treated with nasal continuous positive airway pressure.

OBJECTIVE: Nasal continuous positive airway pressure (NCPAP) is frequently used for prolonged periods in very low birth weight infants. We asked if NCPAP affects gastric emptying. STUDY DESIGN: Preterm newborn infants (n = 16) with a mean body weight of 935 g (SD, 155) and a mean gestational age of 27.7 weeks (SD, 1.9) were treated with NCPAP and fed by orogastric tube. A comparison group of 20 newborn infants with a mean body weight of 1090 grams (SD, 130) and a mean gestational age of 28.2 weeks (SD, 1.2) were not receiving NCPAP. All newborn infants received a milk formula containing 81 kcal/dL given in similar quantities. The antral cross-sectional area was measured by means of an ultrasound technique. RESULTS: Mean half-time of antral cross-sectional area was 28 minutes (SD, 12) in the NCPAP group and 40 minutes (SD, 17) in the comparison group ( P < .05). There were no differences in gastrointestinal complications between the two groups. CONCLUSIONS: The gastric emptying time was shorter for newborn infants treated with NCPAP.

Neonatal necrotizing enterocolitis: an overview.

PURPOSE OF REVIEW: Necrotizing enterocolitis represents a disease entity that remains quite challenging for neonatologists all around the world, in that its aetiology has yet to be revealed, but it is the cause of death for many premature infants each year, affecting up to 28% of very low birthweight infants. This is an attempt to improve the management of affected babies and stimulate more research concerning new diagnostic tools. RECENT FINDINGS: Current trends in the field of (early) diagnosis, such as: (1) imaging techniques, e.g. contrast radiography, portal vein ultrasonography, magnetic resonance, radionuclide scanning; (2) gastrointestinal tonometry; (3) the detection of biochemical markers, cytokines, growth factors; and (4) the determination of the mean peak hydrogen: carbon dioxide ratio excreted in breath, are only some of those mentioned. Various novel preventive techniques are also presented, among which platelet-activating factor acetyl hydrolase activity enhancement, platelet-activating factor receptor antagonists and probiotics, such as Bifidobacterium infantis and Lactobacillus acidophilus, seem quite promising. Regarding treatment, the use of oxygenated perfluorocarbon has added to the limited alternatives available. These data along with other recent discoveries concerning the risk factors and pathogenesis of this disease create a full picture of the current opinion on this topic. SUMMARY: Keeping in mind that the key to confronting such a devastating disorder as necrotizing enterocolitis is early diagnosis and prevention, both clinically applicable and experimental advances are presented with the hope of improving the survival rates of patients affected.

The effect of neonatal jaundice on biotinidase activity.

BACKGROUND: Jaundice is one of the most common and one of the vexing problems that can occur in newborns. A newborn screening test for biotinidase deficiency has been added to many national screening programmes. AIM: To clarify the problem of false-positive screening tests in neonates, especially in term babies, we evaluated the biotinidase activity in the serum of fullterm, premature and small-for-dates newborn infants with jaundice. METHODS: 1296 fullterms (controls N=426), 246 prematures (controls N=86) and 156 small-for-dates babies (controls N=38) aged 2-3 days with jaundice were included in the study. In jaundiced neonates and controls, 3.0 ml of blood was drawn for the evaluation of total bilirubin (t.bil), liver enzymes and biotinidase activity in the serum using a fluorimetric method. In order to test whether or not t.bil causes an artifact in the previous method, biotinidase activity was also evaluated in a number of jaundiced newborns using an HPLC method. Additionally, a preliminary in vitro experiment was carried out to test whether t.bil is an inhibitor of the enzyme. RESULTS: Biotinidase activities in the group of controls of prematures (3.30+/-1.2 mmol/min/l) and small-for-dates babies (3.34+/-0.8 mmol/min/l) were lower than those of term babies (4.99+/-1.1 mmol/min/l, p<0.001). T.bil and liver enzymes showed a statistically significant inverse correlation with biotinidase activity (p<0.001) in all the jaundiced infants of this study. Additionally, biotinidase activity, evaluated in a number of neonates with both fluorimetric and HPLC methods showed similar results. Preincubation of the serum enzyme with t.bil (>10 mg/dl) resulted in a 50% or more inhibition. CONCLUSIONS: (a) Low biotinidase activity was found in term babies, prematures and small-for-dates with jaundice. (b) The low activity of the enzyme could be due to their impaired liver function. (c) The high t.bil levels in the studied groups may play the role of an "inhibitor" of the enzyme. (d) Gestational age as well as t.bil levels should always be written on Guthrie cards for a correct evaluation of biotinidase activity.

Comparison of three treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome.

UNLABELLED: The aim of the study was to compare the treatment regimen of three natural surfactants of different extraction and formulation (Alveofact [Surfactant A = SA], Poractant [Surfactant B = SB] and Beractant [Surfactant C = SC]) in neonatal respiratory distress syndrome (RDS). Premature infants of /=0.3 were randomly assigned to receive at least two doses of SA, SB or SC (100 mg/kg per dose). Infants who remained dependent on artificial ventilation with a FiO2 >/=0.3 received up to two additional doses. There were no differences among the groups regarding the necessity for more than two doses. The SA and the SB groups spent fewer days on a ventilator (p-value SA/SB 0.7, SA/SC 0.05, SB/SC 0.043) compared with the SC group, needed fewer days of oxygen administration (p-value SA/SB 0.14, SA/SC 0.05, SB/SC 0.04) and spent fewer days in hospital (p-value SA/SB 0.65, SA/SC 0.04, SB/SC 0.027). There were no statistically significant differences in the incidence of mortality, chronic lung disease, air leaks, necrotising enterocolitis, retinopathy of prematurity and intraventricular haemorrhage among the three groups. CONCLUSION: The Alveofact and Poractant groups spent fewer days on the ventilator, needed fewer days of oxygen administration and spent fewer days in hospital compared with the Beractant group but no differences were observed among the three groups with regards to mortality and morbidity.

Levels of soluble ICAM-1 in premature and full-term neonates with infection.

BACKGROUND: Infection in the neonatal period is an extremely serious condition and diagnosis is difficult. C-reactive protein (CRP) is widely used as a marker of infection; however, its usefulness is limited in the early phase. The role of soluble intracellular adhesion molecule-1 (sICAM-1), an adhesion molecule, has been examined in recent studies as an early marker of neonatal infection with controversial results. AIM: Assessment of sICAM-1 concentrations and correlation with CRP, which is the currently used marker of infection, in order to use sICAM as an early diagnostic tool in neonates suspected for infection METHODS: Blood samples and blood cultures were obtained from two groups of pre-term and full-term neonates with clinical suspicion of infection prior to the initiation of antibiotics. The sICAM-1 and CRP values were compared with the corresponding noninfected ones (n = 10 each). RESULTS: The sICAM-1 levels were found increased in the group of both premature and term neonates with infection compared with the corresponding healthy ones (P < 0.0001). Prematurity combined with infection resulted in excessive increase of the levels of sICAM-1 in comparison with full-term infected newborns (p < 0.001). CRP values were normal in all samples except one in both full-term and premature infected neonates on day 1 of clinically suspected infection. Serial detection of CRP values on days 2 and 4 of infection revealed a pattern according to which CRP values in premature neonates continued rising, while in the group of full terms these values, after rising on the second day, lowered on day 4. CONCLUSIONS: Increased sICAM-1 levels can be detected early in both full-term and premature neonates with sepsis while CRP levels are within normal range at the same time. Assessment of sICAM-1 concentrations may be used as a diagnostic tool in neonates suspected for infection, resulting in earlier initiation of antibiotic therapy and therefore improving their outcome.

Erythromycin as a prokinetic agent in preterm infants.

BACKGROUND: The macrolide antibiotic erythromycin is a prokinetic agent that stimulates gastrointestinal motility. The aim of the study was to determine the effect of erythromycin on the gastrointestinal motility of preterm infants. METHODS: Erythromycin 10 mg/kg, 8 hourly or a placebo, was given orally for 7 days in a double-blind randomized, crossover study of 20 preterm infants with a median gestational age of 32 weeks (range, 26-34 weeks). Antral contractility was determined by using ultrasonography to measure the decrease in the gastric antral cross-sectional area after a feed. The whole gut transit time was assessed by timing the transit of carmine red through the gut. RESULTS: Antral contractility lasted for a shorter period of time during erythromycin treatment than during placebo treatment (mean [standard deviation], 31 minutes [9.9 minutes] vs. 70 minutes [13 minutes]; P < 0.01). Whole gut transit time was also shorter during erythromycin treatment (mean, 23.1 hours [12.9 hours] vs. 49.3 hours [29 hours]; P < 0.01). All infants tolerated the drug well. CONCLUSIONS: Oral erythromycin in food-intolerant preterm infants enhances both antral contractility and whole gut transit time.