Early-life factors associated with pediatric functional constipation.

OBJECTIVE: This multicenter prospective study aimed to establish possible risk factors for functional constipation (FC) in the first year of life. METHODS: At the infant's age of 3, 6, and 12 months, parents of all included infants completed 2 questionnaires: one about the presence of FC and the other screened the possible risk factors for FC. Parents of 465 infants completed the questionnaires at 3 and 6 months and of 402 infants at 12 months of life. RESULTS: According to the Rome III criteria, FC was found in 11.6% of the infants at 3 months, in 13.7% at 6 months, and in 10.7% at 12 months after birth. Family history of atopy was present in 38.8% and 45.3% of infants with constipation at 3 and 6 months (P = 0.04 and P = 0.02, respectively), but no significant association was found at 12 months (P = 0.80). Breast-feeding was significantly related to a normal evacuation pattern at 3 months (P = 0.05), but not at 6 and 12 months (P = 0.12 and P = 0.9, respectively). Acetaminophen and female sex appeared to be risk factors for FC at 12 months. After the adjustment for all analyzed variables, FC in infants was significantly associated with the use of acetaminophen (odds ratio 6.98, 95% confidence interval 0.82-13.50). CONCLUSIONS: Our results confirmed that breast-feeding is a protective factor for FC in the first 3 months of life and that the female sex is at risk to have FC. We found that the use of acetaminophen was associated with a higher incidence of FC in the first year of life.

Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns.

BACKGROUND AND OBJECTIVES: Gastric acidity is a major nonimmune defense mechanism against infections. The objective of this study was to investigate whether ranitidine treatment in very low birth weight (VLBW) infants is associated with an increased risk of infections, necrotizing enterocolitis (NEC), and fatal outcome. METHODS: Newborns with birth weight between 401 and 1500 g or gestational age between 24 and 32 weeks, consecutively observed in neonatal intensive care units, were enrolled in a multicenter prospective observational study. The rates of infectious diseases, NEC, and death in enrolled subjects exposed or not to ranitidine were recorded. RESULTS: We evaluated 274 VLBW infants: 91 had taken ranitidine and 183 had not. The main clinical and demographic characteristics did not differ between the 2 groups. Thirty-four (37.4%) of the 91 children exposed to ranitidine and 18 (9.8%) of the 183 not exposed to ranitidine had contracted infections (odds ratio 5.5, 95% confidence interval 2.9-10.4, P < .001). The risk of NEC was 6.6-fold higher in ranitidine-treated VLBW infants (95% confidence interval 1.7-25.0, P = .003) than in control subjects. Mortality rate was significantly higher in newborns receiving ranitidine (9.9% vs 1.6%, P = .003). CONCLUSIONS: Ranitidine therapy is associated with an increased risk of infections, NEC, and fatal outcome in VLBW infants. Caution is advocated in the use of this drug in neonatal age.

Diarrhea in neonatal intensive care unit.

AIM: To investigate the frequency, etiology, and current management strategies for diarrhea in newborn. METHODS: Retrospective, nationwide study involving 5801 subjects observed in neonatal intensive care units during 3 years. The main anamnesis and demographic characteristics, etiology and characteristics of diarrhea, nutritional and therapeutic management, clinical outcomes were evaluated. RESULTS: Thirty-nine cases of diarrhea (36 acute, 3 chronic) were identified. The occurrence rate of diarrhea was 6.72 per 1000 hospitalized newborn. Etiology was defined in 29 of 39 newborn (74.3%): food allergy (20.5%), gastrointestinal infections (17.9%), antibiotic-associated diarrhea (12.8%), congenital defects of ion transport (5.1%), withdrawal syndrome (5.1%), Hirschsprung's disease (2.5%), parenteral diarrhea (2.5%), cystic fibrosis (2.5%), and metabolic disorders (2.5%). Three patients died due to complications related to diarrhea (7.7%). In 19 of 39 patients (48.7%), rehydration was performed exclusively by the enteral route. CONCLUSION: Diarrhea in neonates is a challenging clinical condition due to the possible heterogeneous etiologies and severe outcomes. Specific guidelines are advocated in order to optimize management of diarrhea in this particular setting.

Minimal enteral feeding reduces the risk of sepsis in feed-intolerant very low birth weight newborns.

AIMS: To evaluate the efficacy and safety of minimal enteral feeding (MEF) nutritional practice in feed-intolerant very low birth weight (VLBW) infants. METHODS: A retrospective design using data reported in the clinical charts of VLBW newborns consecutively observed in neonatal intensive care units (NICU) that presents feed intolerance. During the study period, two feeding strategies were adopted: total parenteral nutrition (PN) (group 1) or PN plus MEF (group 2), for at least 24 h. Primary outcome was the time to reach full enteral feeding; secondary outcomes were the occurrence of sepsis, the time to regain birth weight, the length of hospitalization, the occurrence of necrotizing enterocolitis (NEC) Bell stage >II and death. RESULTS: In total, 102 newborns were evaluated: 51 in group 1, and 51 in group 2. Neonates in group 2 achieved full enteral nutrition earlier (8 days, interquartile range [IQR] 5) compared with subjects receiving total PN (11 days, IQR 5, p < 0.001). A reduction of sepsis episodes was observed in group 2 (15.7%) compared with group 1 (33.3%, p = 0.038). Additionally, subjects in group 2 regained their birth weight and were discharged earlier. The occurrence of NEC and death were similar in the two groups. CONCLUSION: Minimal enteral feeding in very low birth weight infants presenting feed intolerance reduces the time to reach full enteral feeding and the risk of sepsis. This feeding practice does not increase the risk of necrotizing enterocolitis and death.

Neonatal onset intestinal failure: an Italian Multicenter Study.

OBJECTIVE: To describe the natural course of intestinal failure with onset in the neonatal period to provide data regarding the occurrence and to provide a population-based survey regarding the spectrum of underlying diseases. STUDY DESIGN: We performed a retrospective chart review including infants admitted to the neonatal intensive care unit of 7 Italian tertiary care centers. Intestinal failure was defined as a primary intestinal disease that induces the need of total parenteral nutrition (PN) for more than 4 weeks or the need of partial PN for more than 3 months. RESULTS: The total number of live births during the study time within the enrolled institutions was 30 353, and the number of newborns admitted to the neonatal intensive care unit was 5088. Twenty-six patients satisfied the definition of intestinal failure; thus the occurrence rate of intestinal failure was 0.1% among live-birth newborns and 0.5% among infants at high risk. The main underlying diseases leading to intestinal failure in neonatal age were congenital intestinal defects (42.3%), necrotizing enterocolitis (30.8%), severe intestinal motility disorder (11.5%), intestinal obstruction (7.7%), structural enterocyte defects (3.8%), and meconium peritonitis (3.8%). After a follow-up of 36 months, 84.6% of patients achieved intestinal competence, 1 patient was still receiving home PN, 1 patient underwent transplantation, and 2 patients died. Cholestatic liver disease was diagnosed in 54% of observed children. CONCLUSION: An understanding of the incidence, causes, and natural history of intestinal failure would be helpful to appropriately allocate resources and to plan clinical trials.

Neonatal hyperbilirubinemia increases intestinal protein permeability and the prevalence of cow's milk protein intolerance.

AIMS: Bilirubin is a newly discovered modulator of the gut barrier in vitro and in vivo. We studied the effect of bilirubin on the serosal to mucosal intestinal permeability in vivo. We also investigated the prevalence of cow's milk protein intolerance (CMPI) in infants with moderate hyperbilirubinemia versus matched controls. METHODS: Faecal alpha 1 antitrypsin (a1AT) was used to monitor intestinal protein loss; a large cohort was prospectively followed for 12 months for sign and symptoms of CMPI. RESULTS: Neonates with hyperbilirubinemia had higher stool excretion of a1AT than controls (0.68 +/- 0.28 mg/g vs. 0.25 +/- 0.11 mg/g; p < 0.01). Faecal a1AT correlates with total serum bilirubin (TSB) (r = 0.85; p < 0.01). Also, in the first 12 months of life, formerly hyperbilirubinemic infants had an higher prevalence of CMPI (14/353 vs. 4/339; chi2= 4.018, p = 0.045). CONCLUSIONS: Neonatal hyperbilirubinemia increases stool protein loss and is also a mild risk factor for CMPI.

Bile acids modulate tight junction structure and barrier function of Caco-2 monolayers via EGFR activation.

Intestinal and systemic illnesses have been linked to increased gut permeability. Bile acids, whose luminal profile can be altered in human disease, modulate intestinal paracellular permeability. We investigated the mechanism by which selected bile acids increase gut permeability using a validated in vitro model. Human intestinal Caco-2 cells were grown in monolayers and challenged with a panel of bile acids. Transepithelial electrical resistance and luminal-to-basolateral fluxes of 10-kDa Cascade blue-conjugated dextran were used to monitor paracellular permeability. Immunoprecipitation and immunoblot analyses were employed to investigate the intracellular pathway. Redistribution of tight junction proteins was studied by confocal laser microscopy. Micromolar concentrations of cholic acid, deoxycholic acid (DCA), and chenodeoxycholic acid (CDCA) but not ursodeoxycholic acid decreased transepithelial electrical resistance and increased dextran flux in a reversible fashion. Coincubation of 50 muM CDCA or DCA with EGF, anti-EGF monoclonal antibody, or specific src inhibitor 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP-2) abolished the effect. A concentration of 50 muM of either CDCA or DCA also induced EGF receptor phosphorylation, occludin dephosphorylation, and occludin redistribution at the tight junction level in the same time frame and in a reversible fashion. We conclude that selected bile acids modulate intestinal permeability via EGF receptor autophosphorylation, occludin dephosphorylation, and rearrangement at the tight junction level. The effect is mediated by the src family kinases and is abolished by EGF treatment. These data also support the role of bile acids in the genesis of necrotizing enterocolitis and the protective effect of EGF treatment.

Intravenous magnesium sulphate vs. inhaled nitric oxide for moderate, persistent pulmonary hypertension of the newborn. A Multicentre, retrospective study.

We have compared intravenous magnesium sulphate vs. inhaled nitric oxide in the therapy of moderate persistent pulmonary hypertension of the neonate. A retrospective collection of clinical data from 58 neonates was carried out in six neonatal intensive care units of Southern Italy sharing the same operational protocols. In our setting, both drugs were effective in treating moderate persistent pulmonary hypertension of the neonate but nitric oxide (NO) treatment resulted in much faster amelioration of oxygenation index, taken as a marker of the underlying condition. No significant difference was recorded in immediate or long-term complications. We conclude that, wherever NO facilities are not readily available, magnesium sulphate is a safe and cheaper alternative for first-line treatment of moderate persistent pulmonary hypertension of the neonate.

Neonatal urinary cotinine correlates with behavioral alterations in newborns prenatally exposed to tobacco smoke.

Altered behavior due to prenatal smoke exposure was examined in 25 neonates born from smoking mothers who consumed at least 5 cigarettes/d during the entire gestation. Data were compared with 25 matched neonates born from nonsmoking mothers. Neonatal behavior was evaluated using the Brazelton Neonatal Behavioral Assessment Scale (BNBAS). Antenatal exposure to tobacco smoke at the end of the pregnancy was determined by measurement of urinary cotinine. Newborns from smoking mothers showed significant lower scores in various BNBAS items compared with neonates from nonsmoking mothers. A strong correlation was observed between infant irritability and urinary cotinine in newborns from smoker and nonsmoking mothers and with number of daily smoked cigarettes and maternal nicotine daily intake of infants exposed to active maternal smoking. Linear regression analysis showed that urinary cotinine was the best predictor of infant irritability (r(2) = 0.727). The latter was also associated to the neonate's low level of attention and poor response to inanimate auditory stimuli. Among infants from nonsmoking mothers, paternal smoking significantly correlated with infant urinary cotinine and infant irritability, being also the best predictor of irritability (r(2) = 0.364). Neonatal behavior can be significantly altered in a dose-dependent manner even after modest prenatal exposure to tobacco smoke.

Unconjugated bilirubin modulates the intestinal epithelial barrier function in a human-derived in vitro model.

Unconjugated bilirubin promotes intestinal secretion without affecting nutrient digestion or absorption. In the current study, the effects of unconjugated bilirubin (UCB) on the barrier function of the intestinal epithelium were investigated. The apical side of human intestinal cell line Caco-2 monolayers was challenged with purified UCB. Transepithelial electrical resistance and paracellular fluxes of 10 kD Cascade blue conjugate dextran were measured. Cell monolayer viability was studied using LDH release and trypan blue exclusion tests. Redistribution of enterocyte tight junction occludin was studied by confocal microscopy. Bilirubin induced a dose-dependent decrease of transepithelial electrical resistance (TEER). This effect was maximal at 6 h and tended to be reversed at 48 h. Oxidated bilirubin was ineffective. Bilirubin significantly increased fluorescent dextran paracellular passage. Cell viability was not affected by UCB over the 5-200 nmol/L concentration range. Finally, bilirubin triggered a reversible redistribution of tight junctional occludin. UCB increases the permeability of intestinal epithelium. This effect is reversible, dependent on the redox status of the molecule and the rearrangement of the tight junction. These data attribute to bilirubin a novel role of functional modulator of intestinal paracellular permeability in vitro.

A randomized trial comparing oxygen delivery on intermittent positive pressure with nasal cannulae versus facial mask in neonatal primary resuscitation.

AIM: To compare, in a prospective clinical trial, oxygen delivery on intermittent positive pressure with nasal cannulae versus facial mask in primary resuscitation of the newborn with moderate asphyxia. METHODS: 617 neonates with moderate asphyxia at birth were randomized: 303 were resuscitated by oxygen on intermittent positive pressure with nasal cannuale and 314 neonates by mask. Resuscitation followed the Neonatal Resuscitation Program guidelines of the American Academy of Pediatrics, 3rd edition. RESULTS: Resuscitation through the nasal route less frequently requires chest compressions and intubations (26 neonates needed chest compression and 20 needed intubation out of 314 resuscitated by mask; five neonates needed chest compression and two needed intubation out of 303 resuscitated by nasal cannulae). Apgar scores, admission rates to neonatal intensive care units, air-leak syndromes, birthweight, gestational age, use of prenatal steroids and deaths did not differ between groups. CONCLUSION: Oxygen delivery on intermittent positive pressure with nasal cannulae in primary resuscitation of the newborn with moderate asphyxia is a less aggressive and potentially advantageous alternative to the traditional oral route.

Brain damage in glycogen storage disease type I.

OBJECTIVE: To investigate brain morphology and function in patients with glycogen storage disease type I (GSDI). STUDY DESIGN: Nineteen patients (13 females and 6 males, aged 0.9-22.6 years) and 38 sex- and age-matched controls entered the study. Neurological examinations, psychometric tests (IQ, tests of performance and verbal abilities), standard electroencephalogram (EEG), somatosensory (SEPs), visual (VEPs), and brain-stem auditory evoked potentials (BAEPs), and brain magnetic resonance imaging (MRI) were performed. RESULTS: The results of tests of performance ability were lower in patients than in controls (P <.05). The prevalence of abnormal EEG findings (26.3% versus 2.6%), VEPs (38.4% versus 7.7%), SEPs (23.0% versus 0%), and BAEPs abnormalities (15.7% versus 0%) was higher in patients than in controls (P <.05). MRI pattern was altered in 57.1% of patients and was normal in all controls (P <.05). Both results of tests of performance ability and BAEPs abnormalities significantly correlated with the frequency of admissions for hypoglycemia, whereas EEG abnormalities correlated with dietary compliance (P <.05). CONCLUSIONS: Brain damage, probably caused by recurrent severe hypoglycemia, may be present in patients with GSDI.

Early cord clamping protects at-risk neonates from polycythemia.

UNLABELLED: Neonatal polycythemia is a potentially lethal, multi-organ disease. We have performed a prospective, open-label study to test the hypothesis that an early cord clamping proximally to the neonate's abdomen could avert from the neonatal circulation a blood volume critical to the occurrence of polycythemia in at-risk neonates. Newborns were divided into group 1 (clamping time within 10 s) and group 2 (clamping time 11-120 s). Group 1 had statistically significant more blood volume sequestered in the cord and less manifestations of polycythemia. CONCLUSION: An early cord clamping is an effective and zero-cost way to prevent polycythemia in at-risk neonates.

Moderate hyperbilirubinemia induces a transient alteration of neonatal behavior.

OBJECTIVE: To investigate the behavioral changes induced by moderate hyperbilirubinemia in the otherwise healthy, untreated newborn infant. METHODS: Fifty term neonates (23 boys) with untreated moderate hyperbilirubinemia (median: 14.3 mg/dL; range: 13.2-20 mg/dL) and 50 matched control subjects with lower bilirubin concentrations (median: 9.1 mg/dL; range: 5.3-12 mg/dL) were administered the Brazelton Neonatal Behavioral Scale at 87 hours of life (range: 72-110 hours). A subgroup analysis was also performed at 104 hours of life (range: 96-134 hours) and at 3 weeks of age. RESULTS: At the first examination, all behavioral clusters were significantly altered in the group with moderate hyperbilirubinemia. The visual and auditory capabilities of the hyperbilirubinemic infant were especially compromised. Although social-interactive cluster scores significantly correlated both with serum bilirubinemia and birth weight, the former accounted for 8.7% of the variance and the latter accounted for only 4.7%. The moderate hyperbilirubinemia neonates' scores also showed a negative correlation with the autonomic system and more frequent presence of tremors. After 24 hours, a decrease in serum bilirubin within the moderate hyperbilirubinemic group was associated with improved scores. At 3 weeks of age, the behavioral assessment of the 2 groups did not show significant differences. CONCLUSIONS: Untreated moderate hyperbilirubinemia is associated with a transient and apparently reversible alteration of neonatal behavior, particularly in the social-interactive area.

Unconjugated bile acids modulate adult and neonatal neutrophil chemotaxis induced in vitro by N-formyl-met-leu-phe-peptide.

In this study, we have investigated the effect of hydrophobic and hydrophilic unconjugated bile acids (UBAs)-ursodeoxycholic acid (UDCA), chenodeoxycholic acid (CDCA), lithocholic acid, and colic acid-on chemotaxis in adult and neonatal human polymorphonuclear leukocytes (PMNs). The trypan blue exclusion dye test was preliminarily performed to determine the toxicity of the studied UBAs on PMNs. N-formyl-methionyl-leucyl-phenylalanine (100 nM) was used as a chemoattractant. Chemotaxis (1 x 10(6)cells/mL) was analyzed in the presence or absence of UBAs (10 microM) by blind well chambers. The antioxidants vitamin E and vitamin C were tested for their ability to reduce the inhibitory effect of UBAs. We found that only CDCA was able to induce damage in PMNs in the range of 1-40 microM. Both CDCA and UDCA were able to inhibit chemotaxis in PMNs, whereas lithocholic acid and colic acid were ineffective. The inhibitory effect was reversible inasmuch as PMNs incubated with either CDCA or UDCA and subsequently washed showed normal chemotaxis. Concomitant incubation of PMNs with UBAs and vitamins C or E reversed the inhibition. We did not find substantial differences between PMNs from adults or newborns. In conclusion, CDCA and UDCA are able to reduce, in a specific and reversible fashion, both adult and newborn neutrophil chemotaxis. As concomitant incubation of UBAs and electron scavengers restores PMN chemotaxis to control values, we conclude that free radicals may be involved in the mechanism of inhibition. We speculate that this defect may contribute to the impaired host response described in cholestatic patient.