Gut pathogen colonization precedes bloodstream infection in the neonatal intensive care unit.

Bacterial bloodstream infections (BSIs) resulting in late-onset sepsis affect up to half of extremely preterm infants and have substantial morbidity and mortality. Bacterial species associated with BSIs in neonatal intensive care units (NICUs) commonly colonize the preterm infant gut microbiome. Accordingly, we hypothesized that the gut microbiome is a reservoir of BSI-causing pathogenic strains that increase in abundance before BSI onset. We analyzed 550 previously published fecal metagenomes from 115 hospitalized neonates and found that recent ampicillin, gentamicin, or vancomycin exposure was associated with increased abundance of Enterobacteriaceae and Enterococcaceae in infant guts. We then performed shotgun metagenomic sequencing on 462 longitudinal fecal samples from 19 preterm infants (cases) with BSI and 37 non-BSI controls, along with whole-genome sequencing of the BSI isolates. Infants with BSI caused by Enterobacteriaceae were more likely than infants with BSI caused by other organisms to have had ampicillin, gentamicin, or vancomycin exposure in the 10 days before BSI. Relative to controls, gut microbiomes of cases had increased relative abundance of the BSI-causing species and clustered by Bray-Curtis dissimilarity according to BSI pathogen. We demonstrated that 11 of 19 (58%) of gut microbiomes before BSI, and 15 of 19 (79%) of gut microbiomes at any time, harbored the BSI isolate with fewer than 20 genomic substitutions. Last, BSI strains from the Enterobacteriaceae and Enterococcaceae families were detected in multiple infants, indicating BSI-strain transmission. Our findings support future studies to evaluate BSI risk prediction strategies based on gut microbiome abundance in hospitalized preterm infants.

Decreasing Total Medication Exposure and Length of Stay While Completing Withdrawal for Neonatal Abstinence Syndrome during the Neonatal Hospital Stay.

INTRODUCTION: Neonatal abstinence syndrome (NAS) is a rapidly growing public health concern that has considerably increased health-care utilization and health-care costs. In an effort to curtail costs, attempts have been made to complete withdrawal as an outpatient. Outpatient therapy has been shown to prolong exposure to medications, which may negatively impact neurodevelopmental and behavioral outcomes. We hypothesized that the implementation of a modified NAS protocol would decrease total drug exposure and length of stay while allowing for complete acute drug withdrawal during the neonatal hospital stay. METHODS: Data were derived retrospectively from medical records of term (≥37 0/7) infants with NAS who were treated with pharmacologic therapy in the University of Louisville Hospital Neonatal Intensive Care Unit from 2005 to 2015. The pharmacologic protocol (SP1) for infants treated between 2005 and March 2014 (n = 146) dosed oral morphine every 4 h and utilized phenobarbital as adjuvant therapy. Protocol 2 (SP2) initiated after March 2014 (n = 44) dosed morphine every 3 h and used clonidine as adjuvant therapy. Charts were reviewed for demographic information and maternal drug history. Maternal and infant toxicology screens were recorded. The length of morphine therapy and need for adjuvant drug therapy were noted. Length of stay was derived from admission and discharge dates. RESULTS: The length of morphine therapy was decreased by 8.5 days from 35 to 26.5 days (95% CI 4.5-12 days) for infants treated with SP2 vs. SP1 (p < 0.001). The need for adjuvant pharmacologic therapy was decreased by 24% in patients treated with SP2 vs. SP1 (p = 0.004). The length of stay was decreased by 9 days from 42 to 33 days (95% CI 5.1-13 days) for infants treated with SP2 vs. SP1 (p < 0.001). The decreased length of stay resulted in an average reduction of hospital charges by $27,090 per patient in adjusted 2015 US Dollars. CONCLUSION: This study demonstrates that total drug exposure and length of stay can be reduced while successfully completing acute withdrawal during the neonatal hospital stay.

Fortification of human milk for preterm infants.

Human milk is the preferred feeding for all infants, including those of very low birth weight (<1500 g). It has both nutritional and anti-infective properties which are especially important for infants at risk for sepsis and necrotizing enterocolitis. When maternal milk is not available or the amount produced is not sufficient to meet daily needs, donor human milk may (should) be used in its place. However, donor human milk is generally term in quality and likely has insufficient protein to promote appropriate growth. Whether donor or mother's own milk, fortification of human milk is required to meet nutrient requirements for growth and development for these preterm infants who are at high risk for growth faltering during the hospital stay. There are multiple strategies and products that may be employed to support desired growth rates. The advent of human milk analyzers may be helpful in a more customized approach to fortification.

Randomized Controlled Trial of Talactoferrin Oral Solution in Preterm Infants.

OBJECTIVE: To evaluate the safety and explore the efficacy of recombinant human lactoferrin (talactoferrin [TLf]) to reduce infection. STUDY DESIGN: We conducted a randomized, double blind, placebo-controlled trial in infants with birth weight of 750-1500 g. Infants received enteral TLf (n = 60) or placebo (n = 60) on days 1 through 28 of life; the TLf dose was 150 mg/kg every 12 hours. Primary outcomes were bacteremia, pneumonia, urinary tract infection, meningitis, and necrotizing enterocolitis (NEC). Secondary outcomes were sepsis syndrome and suspected NEC. We recorded clinical, laboratory, and radiologic findings, along with diseases and adverse events, in a database used for statistical analyses. RESULTS: Demographic data were similar in the 2 groups of infants. We attributed no enteral or organ-specific adverse events to TLf. There were 2 deaths in the TLf group (1 each due to posterior fossa hemorrhage and postdischarge sudden infant death), and 1 death in the placebo group, due to NEC. The rate of hospital-acquired infections was 50% lower in the TLf group compared with the placebo group (P < .04), including fewer blood or line infections, urinary tract infections, and pneumonia. Fourteen infants in the TLf group weighing <1 kg at birth had no gram-negative infections, compared with only 3 of 14 such infants in the placebo group. Noninfectious outcomes were not statistically significantly different between the 2 groups, and there were no between-group differences in growth or neurodevelopment over a 1-year posthospitalization period. CONCLUSION: We found no clinical or laboratory toxicity and a trend toward less infectious morbidity in the infants treated with TLf. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00854633.

Gut bacteria dysbiosis and necrotising enterocolitis in very low birthweight infants: a prospective case-control study.

BACKGROUND: Gut bacteria might predispose to or protect from necrotising enterocolitis, a severe illness linked to prematurity. In this observational prospective study we aimed to assess whether one or more bacterial taxa in the gut differ between infants who subsequently develop necrotising enterocolitis (cases) and those who do not (controls). METHODS: We enrolled very low birthweight (1500 g and lower) infants in the primary cohort (St Louis Children's Hospital) between July 7, 2009, and Sept 16, 2013, and in the secondary cohorts (Kosair Children's Hospital and Children's Hospital at Oklahoma University) between Sept 12, 2011 and May 25, 2013. We prospectively collected and then froze stool samples for all infants. Cases were defined as infants whose clinical courses were consistent with necrotising enterocolitis and whose radiographs fulfilled criteria for Bell's stage 2 or 3 necrotising enterocolitis. Control infants (one to four per case; not fixed ratios) with similar gestational ages, birthweight, and birth dates were selected from the population after cases were identified. Using primers specific for bacterial 16S rRNA genes, we amplified and then pyrosequenced faecal DNA from stool samples. With use of Dirichlet multinomial analysis and mixed models to account for repeated measures, we identified host factors, including development of necrotising enterocolitis, associated with gut bacterial populations. FINDINGS: We studied 2492 stool samples from 122 infants in the primary cohort, of whom 28 developed necrotising enterocolitis; 94 infants were used as controls. The microbial community structure in case stools differed significantly from those in control stools. These differences emerged only after the first month of age. In mixed models, the time-by-necrotising-enterocolitis interaction was positively associated with Gammaproteobacteria (p=0·0010) and negatively associated with strictly anaerobic bacteria, especially Negativicutes (p=0·0019). We studied 1094 stool samples from 44 infants in the secondary cohorts. 18 infants developed necrotising enterocolitis (cases) and 26 were controls. After combining data from all cohorts (166 infants, 3586 stools, 46 cases of necrotising enterocolitis), there were increased proportions of Gammaproteobacteria (p=0·0011) and lower proportions of both Negativicutes (p=0·0013) and the combined Clostridia-Negativicutes class (p=0·0051) in infants who went on to develop necrotising enterocolitis compared with controls. These associations were strongest in both the primary cohort and the overall cohort for infants born at less than 27 weeks' gestation. INTERPRETATION: A relative abundance of Gammaproteobacteria (ie, Gram-negative facultative bacilli) and relative paucity of strict anaerobic bacteria (especially Negativicutes) precede necrotising enterocolitis in very low birthweight infants. These data offer candidate targets for interventions to prevent necrotising enterocolitis, at least among infants born at less than 27 weeks' gestation. FUNDING: National Institutes of Health (NIH), Foundation for the NIH, the Children's Discovery Institute.

A modified Bilirubin-induced neurologic dysfunction (BIND-M) algorithm is useful in evaluating severity of jaundice in a resource-limited setting.

BACKGROUND: Severe neonatal jaundice with associated acute bilirubin encephalopathy occurs frequently in low- and middle-income countries, where advanced diagnostic technology is in short supply. In an effort to facilitate the physical diagnosis of acute bilirubin encephalopathy, we pilot-tested a modified bilirubin induced neurologic dysfunction scoring algorithm in a group of pediatric trainees (residents) and their mentors (consultants) in a resource-constrained setting. METHODS: Jaundiced Nigerian infants were examined by consultant and resident pediatricians. The modified bilirubin induced neurologic dysfunction score assigned by residents was compared with the clinical diagnosis of acute bilirubin encephalopathy by expert consultants. Demographic information was obtained. Known risk factors were also evaluated among infants with and without acute bilirubin encephalopathy in addition to exploratory analyses. Data were analyzed by Statistical Analysis System; statistical significance was set at p < 0.05. RESULTS: Three hundred and thirty three paired modified bilirubin induced neurologic dysfunction scores (333) were analyzed and showed excellent agreement (weighted Kappa coefficient 0.7969) between residents and consultants. A modified bilirubin induced neurologic dysfunction score greater than or equal to 3 was highly predictive of a clinical diagnosis of acute bilirubin encephalopathy, with sensitivity of 90.7%, specificity of 97.7%, positive predictive value of 88.9%, and negative predictive value of 98.2%. Exposure to mentholated products was strongly associated with increased risk of acute bilirubin encephalopathy among those with known glucose-6-phosphate dehydrogenase deficiency (odds ratio = 73.94; 95% confidence interval = 5.425-infinity) as well as among those whose G6PD phenotype was unknown (odds ratio = 25.88; 95% confidence interval = 2.845-235.4). CONCLUSIONS: The modified bilirubin induced neurologic dysfunction score for neonatal jaundice can be assigned reliably by both residents and experienced pediatricians in resource-limited settings as reflected in the algorithm's sensitivity and specificity. It may be useful for predicting the development and severity of acute bilirubin encephalopathy in neonates.

Fortification of human milk in very low birth weight infants (VLBW <1500 g birth weight).

The American Academy of Pediatrics supports the feeding of human milk for all infants. Very-low-birth-weight and extremely low-birth-weight infants especially can benefit from the immune and neurodevelopmental effects of human milk. However, human milk alone is nutritionally inadequate for the rapid growth of the very-low-birth-weight infant during a critical window for brain development and requires fortification to meet current recommendations. There are a variety of products, devices, and strategies that can be used to fine tune nutritional support of these very vulnerable infants.

Creamatocrit analysis of human milk overestimates fat and energy content when compared to a human milk analyzer using mid-infrared spectroscopy.

BACKGROUND AND OBJECTIVE: Human milk (HM) is the preferred feeding for human infants but may be inadequate to support the rapid growth of the very-low-birth-weight infant. The creamatocrit (CMCT) has been widely used to guide health care professionals as they analyze HM fortification; however, the CMCT method is based on an equation using assumptions for protein and carbohydrate with fat as the only measured variable. The aim of the present study was to test the hypothesis that a human milk analyzer (HMA) would provide more accurate data for fat and energy content than analysis by CMCT. METHODS: Fifty-one well-mixed samples of previously frozen expressed HM were obtained after thawing. Previously assayed "control" milk samples were thawed and also run with unknowns. All milk samples were prewarmed at 40°C and then analyzed by both CMCT and HMA. CMCT fat results were substituted in the CMCT equation to reach a value for energy (kcal/oz). Fat results from HMA were entered into a computer model to reach a value for energy (kcal/oz). Fat and energy results were compared by paired t test with statistical significance set at P < 0.05. An additional 10 samples were analyzed locally by both methods and then sent to a certified laboratory for quantitative analysis. Results for fat and energy were analyzed by 1-way analysis of variance with statistical significance set at P < 0.05. RESULTS: Mean fat content by CMCT (5.8 ± 1.9 g/dL) was significantly higher than by HMA (3.2 ± 1.1 g/dL, P < 0.001). Mean energy by CMCT (21.8 ± 3.4 kcal/oz) was also significantly higher than by HMA (17.1 ± 2.9, P < 0.001). Comparison of biochemical analysis with HMA of the subset of milk samples showed no statistical difference for fat and energy, whereas CMCT was significantly higher than for both fat (P < 0.001) and energy (P = 0.002). CONCLUSIONS: The CMCT method appears to overestimate fat and energy content of HM samples when compared with HMA and biochemical methods.

Psychotropic medication use in children with autism in the Kentucky Medicaid population.

This study reviewed Kentucky Medicaid claims data for children with autism spectrum disorders to determine psychotropic drug (PTD) use in this population. Children with autism spectrum disorders (ICD-9 code 299.XX) in 3 different age-groups from 2005 to 2008 were identified; PTD use was defined as at least 1 prescription per year. PTD use in all age ranges was higher than in previously reported studies. High PTD use in children between 1 and 5 years is particularly of concern and may reflect perceived inadequacies of comprehensive educational/behavioral services for these children.

Natural course of cholestasis in neonates on extracorporeal membrane oxygenation (ECMO): 10-year experience at a single institution.

The study objectives were to confirm the incidence of cholestasis and determine factors that contribute to its development and the natural course of cholestasis in neonates treated with extracorporeal membrane oxygenation (ECMO). This was a retrospective chart review including all patients receiving ECMO between 1995 and 2005 at Kosair Children's Hospital. Neonates were grouped as having cholestasis or no cholestasis. A total of 211 patients underwent ECMO between 1995 and 2005. Thirty patients (14%) developed cholestasis. There was no difference in demographics or diagnoses between patients developing cholestasis on ECMO vs. those who did not. The development of cholestasis on ECMO was related to run time, 148 hours +/- 111 (no cholestasis group) vs. 252.8 hours +/- 187 (cholestasis group), p < 0.001 respectively. The majority of patients received veno-arterial ECMO, but there was no difference in cholestasis related to type of ECMO support. Direct hyperbilirubinemia and elevation of hepatic enzymes resolved in all but one patient by the time of discharge. Our incidence of cholestasis (14%) on ECMO is lower than previously reported series. Longer duration of ECMO and other complications on ECMO (renal, infectious, and metabolic) are more likely in the patients developing cholestasis. Follow-up showed resolution of cholestasis in all patients without hepatic sequelae.

Scapular thickness--implications for fracture fixation.

The purpose of this study was to measure and map scapula osseous thickness to identify the optimal areas for internal fixation. Eighteen (9 pairs) scapulae from 2 female and 7 male cadavers were used. After harvest and removal of all soft tissues, standardized measurement lines were made based on anatomic landmarks. For consistency among scapulae, measurements were taken at standard percentage intervals along each line approximating the distance between two consecutive reconstruction plate screw holes. Two-mm-diameter drill holes were made at each point, and a standard depth gauge was used to measure thickness. The glenoid fossa (25 mm) displayed the greatest mean osseous thickness, followed by the lateral scapular border (9.7 mm), the scapula spine (8.3 mm), and the central portion of the body of the scapula (3.0 mm). To optimize screw purchase and internal fixation strength, the lateral border, the lateral aspect of the base of the scapula spine, and the scapula spine itself should be used for anatomic sites of internal fixation of scapula fractures.

Postnatal malnutrition of extremely low birth-weight infants with catch-up growth postdischarge.

OBJECTIVE: To assess nutritional intakes and subsequent growth of extremely low birth-weight (BW) infants. STUDY DESIGN: Chart review of 69 extremely low BW infants stratified into two groups by BW: < or =750 g (group 1; n=27) or 751 to 1000 g (group 2; n=42). Dietary intakes, weights, and head circumferences (HC) were collected through discharge and at 1 month postdischarge. The differences between goals and intakes were calculated weekly during hospitalization. Descriptive comparisons were made between growth parameters at birth, discharge, and follow-up. RESULTS: Total energy and protein deficits were inversely related to BW. Both groups exhibited extrauterine growth retardation while hospitalized. After discharge, the rates of weight gain and HC growth increased, leading to some growth recovery at follow-up. CONCLUSIONS: Existing feeding methods resulted in sizeable deficits in energy and protein, particularly for the smallest infants. Changing current practices to limit these deficits is essential to improving postnatal growth.

Prediction of extrauterine growth retardation (EUGR) in VVLBW infants.

BACKGROUND: Long-term growth failure in very very low birth weight (VVLBW) infants is a common complication of extreme prematurity. Critical illnesses create challenges to adequate nutriture. PURPOSE: To identify predictors of extrauterine growth retardation (EUGR) in VVLBW infants and to evaluate their nutritional intake and subsequent growth. STUDY DESIGN: A 4-year retrospective chart review of 221 infants

Hidden morbidity with "successful" early discharge.

OBJECTIVE: This study was conducted to determine if early postnatal discharge (EDC; < or =48 hours) in well newborns had an effect on the rate of hospital readmission within the first week after hospital discharge when compared to infants who remained >48 hours after birth (later discharge, LDC). STUDY DESIGN: This was a retrospective medical chart review. Charts of infants born between January 1994 and December 1998, discharged as "well newborns" and treated subsequently at a primary children's hospital within 7 days of neonatal discharge, were reviewed. Infants were categorized by length of neonatal hospital stay, level of medical intervention (emergency department treatment or hospital admission), and final diagnosis. RESULTS: There was a significant increase in hospital readmission rate for LDC infants when compared to EDC infants. When considering jaundice alone as an admitting diagnosis, EDC infants were admitted at a higher rate than LDC infants and with higher serum bilirubin concentrations. Readmitted, jaundiced infants had been almost always breast-fed. CONCLUSION: Overall, EDC of well newborns appears to be a safe and reasonable practice. However, the risk for severe jaundice is an unresolved issue that requires a discharge strategy and early follow-up to prevent serious morbidity.