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BACKGROUND AND OBJECTIVESThe Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network recently proposed new, severity-based diagnostic criteria for bronchopulmonary dysplasia (BPD). This study provides the first benchmark epidemiological data applying this definition.METHODSRetrospective cohort study of infants born from 22 to 29 weeks’ gestation in 2018 at 715 US hospitals in the Vermont Oxford Network. Rates of BPD, major neonatal morbidities, and common respiratory therapies, stratified by BPD severity, were determined.RESULTSAmong 24 896 infants, 2574 (10.3%) died before 36 weeks’ postmenstrual age (PMA), 12 198 (49.0%) did not develop BPD, 9192 (36.9%) developed grade 1 or 2 BPD, and 932 (3.7%) developed grade 3 BPD. Rates of mortality before 36 weeks’ PMA and grade 3 BPD decreased from 52.7% and 9.9%, respectively, among infants born at 22 weeks’ gestation to 17.3% and 0.8% among infants born at 29 weeks’ gestation. Grade 1 or 2 BPD peaked in incidence (51.8%) among infants born at 25 weeks’ gestation. The frequency of severe intraventricular hemorrhage or cystic periventricular leukomalacia increased from 4.8% among survivors without BPD to 23.4% among survivors with grade 3 BPD. Similar ranges were observed for late onset sepsis (4.8%–31.4%), surgically treated necrotizing enterocolitis (1.4%–17.1%), severe retinopathy of prematurity (1.2%–23.0%), and home oxygen therapy (2.0%–67.5%).CONCLUSIONSMore than one-half of very preterm infants born in the United States died before 36 weeks’ PMA or developed BPD. Greater BPD severity was associated with more frequent development of major neonatal morbidities, in-hospital mortality, and use of supplemental respiratory support at discharge.

Probiotic products in the United States are available for use in the general category of dietary supplements, bypassing the rigor of the US Food and Drug Administration (FDA) approval process in safety, efficacy, and manufacturing standards. As a result, currently available probiotics lack FDA-approved drug labeling and cannot be marketed to treat or prevent disease in preterm infants, including necrotizing enterocolitis and late-onset sepsis. Despite lack of availability of a pharmaceutical-grade product, the number of preterm infants receiving probiotics in the United States and Canada is steadily increasing. According to recent reports from large collaborative databases in the United States, approximately 10% of extremely low gestational age neonates receive a probiotic preparation during their stay in the NICU, with wide variation in practice among units. In sum, more than 10 000 preterm infants have been enrolled in randomized clinical trials of probiotic supplementation worldwide. Methodologic differences among study protocols included different strains and combinations of therapy, masking of trials, and a priori definitions of the primary outcome measure. Large meta-analyses of these trials have demonstrated the efficacy of multiple-strain probiotics in reducing necrotizing enterocolitis and all-cause mortality, whereas the efficacy of single-strain probiotic preparations is less certain. In the absence of an appropriate medical-grade product in the United States, dietary supplement–grade probiotics, some of which have been the subject of recent recalls for contamination, are being prescribed. Given the lack of FDA-regulated pharmaceutical-grade products in the United States, conflicting data on safety and efficacy, and potential for harm in a highly vulnerable population, current evidence does not support the routine, universal administration of probiotics to preterm infants, particularly those with a birth weight of

CONTEXT: Probiotics have proven to be effective in promoting premature infants’ health, but the optimal usage is unknown. OBJECTIVE: To compare probiotic supplements for premature infants. DATA SOURCES: We searched PubMed, Embase, Cochrane, and ProQuest from inception of these databases to June 1, 2020. STUDY SELECTION: Randomized trials of probiotic supplement intervention for preterm infants were screened by 2 reviewers independently. The primary outcomes were mortality and the morbidity of necrotizing enterocolitis (NEC). Secondary outcomes were morbidity of sepsis, time to achieve full enteral feeding, and length of hospital stay. DATA EXTRACTION: The data of primary and secondary outcomes were extracted by 2 reviewers and pooled with a random-effects model. RESULTS: The meta-analysis included 45 trials with 12 320 participants. Bifidobacterium plus Lactobacillus was associated with lower rates of mortality (risk ratio 0.56; 95% credible interval 0.34–0.84) and NEC morbidity (0.47; 0.27–0.79) in comparison to the placebo; Lactobacillus plus prebiotic was associated with lower rates of NEC morbidity (0.06; 0.01–0.41) in comparison to the placebo; Bifidobacterium plus prebiotic had the highest probability of having the lowest rate of mortality (surface under the cumulative ranking curve 83.94%); and Lactobacillus plus prebiotic had the highest probability of having the lowest rate of NEC (surface under the cumulative ranking curve 95.62%). LIMITATIONS: In few studies did authors report the data of infants with a lower birth weight or gestational age. CONCLUSIONS: The efficacy of single probiotic supplements is limited, compared to combined use of probiotics. To achieve optimal effect on premature infant health, combined use of prebiotic and probiotic, especially Lactobacillus or Bifidobacterium, is recommended.

Autism spectrum disorder (ASD) is the most common disability-causing neurodevelopmental disorder in childhood. Although inborn errors of metabolism (IEM) are rare causes of ASD, they are significant for several reasons, including implications in genetic counseling and determination of prognosis. In this article, we present a 6-year-old boy who presented to us with ASD and was diagnosed with creatine transporter deficiency. Physical and neurologic examination of this patient had not previously raised suspicion of IEM, but twin pregnancy, prematurity, NICU stay due to necrotizing enterocolitis, transient infantile hypotonia, gross-motor delay, breath-holding spells, and a single febrile seizure complicated the history. MRI revealed mild T2-hyperintensity in posterior periventricular white matter. Further evaluation with magnetic resonance spectroscopy, which showed a decreased creatine peak, led to diagnostic investigations for disorders of creatine metabolism, revealing increased urinary creatine:creatinine ratio and a de novo, novel hemizygous frameshift variant in SLC6A8. Clinicians are advised to maintain a high index of suspicion for IEM and to evaluate patients with ASD for syndromic features. Although current guidelines from relevant organizations differ in their recommendations regarding the necessity and the extent of metabolic screening in ASD, there is a growing trend toward screening for treatable IEM. In this case report, we present challenges and pitfalls in the diagnostic journey for creatine transporter deficiency and underline the significance of a thorough history and physical examination in the evaluation of a child with ASD.

* Abbreviations: NEC — : necrotizing enterocolitis NMA — : network meta-analysis SUCRA — : surface under the cumulative ranking curve Necrotizing enterocolitis (NEC) and sepsis are major causes of mortality among preterm infants.1,2 Microbial dysbiosis or imbalance in the preterm gut may predispose to NEC, and optimizing the gut microbiome with probiotics is a promising strategy to prevent NEC.3 Multiple previous meta-analyses have reported that enteral supplementation with probiotics, compared to placebo, reduces the risks of NEC, sepsis, and mortality.4 Prebiotics, which support the growth or activity of beneficial bacteria, may also reduce the risks of sepsis and mortality.5 However, there is uncertainty regarding the relative efficacy of different types of probiotics, prebiotics, or synbiotics (combinations of the 2) in preventing morbidity or mortality in preterm infants. In this issue of Pediatrics , Chi et al6 present a systematic review and network meta-analysis (NMA) evaluating the effects of probiotics and synbiotics in preterm infants. The protocol for the systematic review was preregistered, and trials in which authors evaluated both probiotics and synbiotics in preterm infants were searched. The primary outcomes were all-cause mortality and NEC. An NMA was performed … Address correspondence to Ravi Mangal Patel, MD, MSc, Emory Children’s Center, 2015 Uppergate Dr NE, Atlanta, GA 30322. E-mail: rmpatel{at}emory.edu

* Abbreviations: NEC — : necrotizing enterocolitis NIRS — : near-infrared spectroscopy In this issue of Pediatrics, Howarth et al1 report on a completed longitudinal study of 46 preterm infants born at 15 million infants are born preterm (

BACKGROUND AND OBJECTIVES: Vancomycin remains one of the most commonly prescribed antibiotics in NICUs despite recommendations to limit its use for known resistant infections. Baseline data revealing substantially higher vancomycin use in our NICU compared to peer institutions informed our quality improvement initiative. Our aim was to reduce the vancomycin prescribing rate in neonates hospitalized in our NICU by 50% within 1 year and sustain for 1 year. METHODS: In the 60-bed level IV NICU of an academic referral center, we used a quality improvement framework to develop key drivers and interventions including (1) physician education with benchmarking antibiotic prescribing rates; (2) pharmacy-initiated 48-hour antibiotic time-outs on rounds; (3) development of clinical pathways to standardize empirical antibiotic choices for early-onset sepsis, late-onset sepsis, and necrotizing enterocolitis; coupled with (4) daily prospective audit with feedback from the antimicrobial stewardship program. RESULTS: We used statistical process u-charts to show vancomycin use declined from 112 to 38 days of therapy per 1000 patient-days. After education, pharmacy-initiated 48-hour time-outs, and development of clinical pathways, vancomycin use declined by 29%, and by an additional 52% after implementation of prospective audit with feedback. Vancomycin-associated acute kidney injury also declined from 1.4 to 0.1 events per 1000 patient-days. CONCLUSIONS: Through a sequential implementation approach of education, standardization of care with clinical pathways, pharmacist-initiated 48-hour time-outs, and prospective audit with feedback, vancomycin days of therapy declined by 66% over a 1-year period and has been sustained for 1 year.

The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to significant brain injury and permanent cognitive disability. Diazoxide is the first-line and only US Food and Drug Administration–approved, pharmacologic treatment for refractory hyperinsulinism. In recent years, the use of diazoxide in neonates with persistent hyperinsulinemic hypoglycemia has increased in the United States. Known adverse effects of diazoxide include fluid retention, hypertrichosis, neutropenia, thrombocytopenia, and more recently, pulmonary hypertension. It is currently unknown if diazoxide exposure is associated with an increased risk of necrotizing enterocolitis (NEC) in neonates. We reviewed the cases of 24 patients in a level IV NICU at Massachusetts General Hospital who received diazoxide over 12 years (April 2006–April 2018). All 24 patients received enteral diazoxide for refractory hyperinsulinemic hypoglycemia. A total of 5 patients developed NEC after initiation of diazoxide based on clinical and radiographic findings, corresponding to 20% of infants exposed to diazoxide. This is above our baseline incidence of NEC (1% for all inborn infants and 6% for all inborn very low birth weight infants). More research and monitoring are necessary to characterize the potential risk of NEC associated with the use of diazoxide in the neonatal period.

OBJECTIVES: To examine trends in survival without major morbidity and its individual components among very low birth weight infants across California and assess remaining gaps that may be opportune targets for improvement efforts. METHODS: The study population included infants born between 2008 and 2017 with birth weights of 401 to 1500 g or a gestational age of 22 to 29 weeks. Risk-adjusted trends of survival without major morbidity and its individual components were analyzed. Survival without major morbidity was defined as the absence of death during birth hospitalization, chronic lung disease, severe peri-intraventricular hemorrhage, nosocomial infection, necrotizing enterocolitis, severe retinopathy of prematurity or related surgery, and cystic periventricular leukomalacia. Variations in adjusted rates and/or interquartile ranges were examined. To assess opportunities for additional improvement, all hospitals were reassigned to perform as if in the top quartile, and recalculation of predicted numbers were used to estimate potential benefit. RESULTS: In this cohort of 49 333 infants across 142 hospitals, survival without major morbidity consistently increased from 62.2% to 66.9% from 2008 to 2017. Network variation decreased, with interquartile ranges decreasing from 21.1% to 19.2%. The largest improvements were seen for necrotizing enterocolitis and nosocomial infection. Bronchopulmonary dysplasia rates did not change significantly. Over the final 3 years, if all hospitals performed as well as the top quartile, an additional 621 infants per year would have survived without major morbidity, accounting for an additional 6.6% annual improvement. CONCLUSIONS: Although trends are promising, bronchopulmonary dysplasia remains a common and persistent major morbidity, remaining a target for continued quality-improvement efforts.

BACKGROUND AND OBJECTIVES: Preterm infants with necrotizing enterocolitis (NEC) are known to have worse neurodevelopmental outcomes, but there is no substantial evidence to support an underlying pathophysiology. We aimed to examine whether cerebral oxygenation differs in those infants who develop NEC compared to cerebral oxygenation in those who do not. METHODS: We examined 48 infants RESULTS: The median birth weight was 884 g (range of 460–1600 g), the median weeks’ gestational age was 26 + 3/7 (23 + 0/7 to 29 + 6/7), and 52% were girls. In total, 276 NIRS measurements were completed, and 7 infants developed NEC. NIRS measurements from 1 infant with NEC and 4 infants without NEC who developed hemorrhagic parenchymal infarcts were excluded from analysis. Infants who developed NEC had significantly lower cerebral tissue oxygenation index than those who did not (P = .011), even when adjusted for confounders, including gestational age, birth weight, patent ductus arteriosus, enteral feeds, sex, ethnicity, and hemoglobin. CONCLUSIONS: Infants with NEC have significantly lower cerebral tissue oxygenation throughout their neonatal intensive care stay in comparison with those who did not develop NEC. This is a novel finding and could explain their worse neurodevelopmental outcome.

OBJECTIVES: To examine changes in care practices over time by race and ethnicity and whether the decrease in hospital mortality and severe morbidities has benefited infants of minority over infants of white mothers. METHODS: Infants 22 to 29 weeks’ gestation born between January 2006 and December 2017 at a Vermont Oxford Network center in the United States were studied. We examined mortality and morbidity rate differences and 95% confidence intervals for African American and Hispanic versus white infants by birth year. We tested temporal differences in mortality and morbidity rates between white and African American or Hispanic infants using a likelihood ratio test on nested binomial regression models. RESULTS: Disparities for certain care practices such as antenatal corticosteroids and for some in-hospital outcomes have narrowed over time for minority infants. Compared with white infants, African American infants had a faster decline for mortality, hypothermia, necrotizing enterocolitis, and late-onset sepsis, whereas Hispanic infants had a faster decline for mortality, respiratory distress syndrome, and pneumothorax. Other morbidities showed a constant rate difference between African American and Hispanic versus white infants over time. Despite the improvements, outcomes including hypothermia, mortality, necrotizing enterocolitis, late-onset sepsis, and severe intraventricular hemorrhage remained elevated by the end of the study period, especially among African American infants. CONCLUSIONS: Racial and ethnic disparities in vital care practices and certain outcomes have decreased. That the quality deficit among minority infants occurred for several care practice measures and potentially modifiable outcomes suggests a critical role for quality improvement initiatives tailored for minority-serving hospitals.

BACKGROUND: Overuse of antibiotics can facilitate antibiotic resistance and is associated with adverse neonatal outcomes. We studied the association between duration of antibiotic therapy and short-term outcomes of very low birth weight (VLBW) ( METHODS: We included VLBW infants admitted to NICUs in the Canadian Neonatal Network between 2010–2016 who were exposed to antibiotics but did not have culture-proven sepsis in the first week. Antibiotic exposure was calculated as the number of days an infant received antibiotics in the first week of life. Composite primary outcome was defined as mortality or any major morbidity (severe neurologic injury, retinopathy of prematurity, necrotizing enterocolitis, chronic lung disease, or hospital-acquired infection). RESULTS: Of the 14 207 included infants, 21% (n = 2950), 38% (n = 5401), and 41% (n = 5856) received 0, 1 to 3, and 4 to 7 days of antibiotics, respectively. Antibiotic exposure for 4 to 7 days was associated with higher odds of the composite outcome (adjusted odds ratio 1.24; 95% confidence interval [CI] 1.09–1.41). Each additional day of antibiotic use was associated with 4.7% (95% CI 2.6%–6.8%) increased odds of composite outcome and 7.3% (95% CI 3.3%–11.4%) increased odds in VLBW infants at low risk of early-onset sepsis (born via cesarean delivery, without labor and without chorioamnionitis). CONCLUSIONS: Prolonged empirical antibiotic exposure within the first week after birth in VLBW infants is associated with increased odds of the composite outcome. This practice is a potential target for antimicrobial stewardship.

OBJECTIVES: To determine neurodevelopmental outcomes at 3 years of age in children born with a birth weight (BW) of ≤500 g. METHODS: Infants who were born with a BW of ≤500 g from 2003 to 2012 in the Neonatal Research Network of Japan and survived to discharge from the NICU were eligible in this study. The study population consisted of 460 children (56.7% of 811 surviving infants) who were evaluated at 36 to 42 months of age. Neurodevelopmental impairment (NDI) was defined as having cerebral palsy, visual impairment, hearing impairment, or a developmental quotient score of RESULTS: The overall proportion of NDI was 59.1% (95% confidence interval [CI]: 54.6%–63.5%). The trend revealed no significant change during the study period. In a multivariate modified Poisson regression analysis, NDI was associated with severe intraventricular hemorrhage (adjusted risk ratio [RR]: 1.42; 95% CI: 1.19–1.68; P < .01), cystic periventricular leukomalacia (adjusted RR: 1.40; 95% CI: 1.13–1.73; P < .01), severe necrotizing enterocolitis (adjusted RR: 1.31; 95% CI: 1.07–1.60; P < .01), surgical ligation for patent ductus arteriosus (adjusted RR: 1.29; 95% CI: 1.09–1.54; P < .01), and male sex (adjusted RR: 1.19; 95% CI: 1.01–2.40; P = .04). CONCLUSIONS: This cohort showed that neurodevelopmental outcomes of infants with a BW of ≤500 g have not improved from 2003 to 2012. Multivariate analysis revealed that severe intracranial hemorrhage and cystic periventricular leukomalacia were the strongest risk factors for NDIs. Our data suggested that measures aimed at reducing neurologic morbidities will be important for improving outcomes of infants with a BW of ≤500 g.

* Abbreviations: AUR — : antibiotic use rate NEC — : necrotizing enterocolitis Antimicrobial stewardship efforts benefit the individual and the community by improving patient-specific outcomes as well as decreasing the overall burden of antimicrobial resistance. Antibiotic stewardship can also save the health care system substantial amounts of money through decreased pharmacy costs, decreased inpatient use for antibiotic-resistant infections, and decreased frequency of antibiotic-associated adverse events.1 In NICUs, infants are frequently exposed to antimicrobial medications as prophylaxis against infection, as empirical treatment of suspected infection, and as targeted treatment of confirmed infection. Most neonatal antibiotic treatment is for suspected rather than proven infection, and researchers in several studies suggest that antibiotics are overused in both term and preterm infants.2–8 Evolving concern for unintended harm from neonatal antibiotic exposures has energized interest in the general principles of antimicrobial stewardship.3,5,9–13 Stewardship recommendations and quality collaborative programs support the appropriate use of antimicrobial agents in the NICU.14–17 Single centers report variably successful impacts of neonatal antibiotic stewardship interventions on the use of antibiotics for term infants who are at risk for early-onset infection, on the overall use of antibiotics across gestational ages, and on appropriate choice and duration of antibiotic therapy.18–21 In recent analyses using large multicenter data sets, researchers find small but significant declines in overall neonatal antibiotic use and in extended use in … Address correspondence to Dustin D. Flannery, DO, Division of Neonatology, Children’s Hospital of Philadelphia, Newborn Care at Pennsylvania Hospital, 800 Spruce St, Philadelphia, PA 19107. E-mail: flanneryd{at}email.chop.edu

CONTEXT: Human and bovine colostrum (HBC) administration has been linked to beneficial effects on morbidity and mortality associated with necrotizing enterocolitis (NEC). OBJECTIVES: To determine the effectiveness and safety of HBC for reducing NEC, mortality, sepsis, time to full-feed and feeding intolerance in preterm infants. DATA SOURCES: We conducted searches through Medline, Embase, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, and gray literature. STUDY SELECTION: Randomized controlled trials comparing human or bovine colostrum to placebo. DATA EXTRACTION: Two reviewers independently did screening, review, and extraction. RESULTS: Eight studies (385 infants) proved eligible. In comparison with placebo, HBC revealed no effect on the incidence of severe NEC (relative risk [RR]: 0.99; 95% confidence interval [CI] 0.48 to 2.02, I2 = 2.2%; moderate certainty of evidence), all-cause mortality (RR: 0.88; 95% CI 0.39 to 1.82, I2 = 0%; moderate certainty), culture-proven sepsis (RR: 0.78; 95% CI 0.53 to 1.14, I2 = 0%; moderate certainty), and feed intolerance (RR: 0.97; 95% CI 0.37 to 2.56, I2 = 55%; low certainty). HBC revealed a significant effect on reducing the mean days to reach full enteral feed (mean difference: −3.55; 95% CI 0.33 to 6.77, I2 = 41.1%; moderate certainty). The indirect comparison of bovine versus human colostrum revealed no difference in any outcome. LIMITATIONS: The number of patients was modest, whereas the number of NEC-related events was low. CONCLUSIONS: Bovine or human colostrum has no effect on severe NEC, mortality, culture-proven sepsis, feed intolerance, or length of stay. Additional research focused on the impact on enteral feeding may be needed to confirm the findings on this outcome.

Neonatal seizures represent a significant health burden on the term and preterm neonatal population and are linked to poor long-term neurodevelopmental outcomes. Currently, there are no US Food and Drug Administration–approved antiepileptic drugs for neonates, and authors of the medical literature have yet to reach a consensus on the most adequate approach to neonatal seizures. Topiramate is readily used in the adult and older pediatric population for the management of migraines and partial-onset seizures. Topiramate continues to gain favor among pediatric neurologists who often recommend this medication as a third-line treatment of neonatal seizures. We report our recent experience with 4 preterm neonates, born between 2015 and 2017, who developed radiographic signs of necrotizing enterocolitis after receiving topiramate for seizures. Each was given oral topiramate for the treatment of electrographic and clinical seizures and developed the subsequent diagnosis of necrotizing enterocolitis, with abdominal distention, hemoccult-positive stools, and radiographic signs of intestinal distention and pneumatosis. More research regarding the risk factors of topiramate use in premature infants is needed.

OBJECTIVES: To determine the cost-effectiveness of supplemental donor human milk (DHM) versus preterm formula (PTF) for very low birth weight (VLBW, METHODS: This prospective cost-effectiveness analysis of 363 VLBW infants was conducted for a randomized control trial. Infants recruited from October 2010 to December 2012 were fed DHM or PTF whenever mother’s milk was unavailable. Formal health care costs for initial hospitalization and readmissions were obtained from standardized cost-accounting systems and physician fees. Informal and nonhealth care sector costs (eg, caregiver transportation, labor market earnings) were calculated from parent reports. RESULTS: Mean infant birth weight was 996 (SD, 272) grams. Incidence of necrotizing enterocolitis (NEC) differed between groups (all stages 3.9% DHM, 11.0% PTF; P = .01). Costs to 18 months did not differ with a mean (95% confidence interval) of 217 624 (197 697–237 551) and 217 245 (196 494–237 995) 2015 Canadian dollars in the DHM and PTF groups. Postdischarge costs were lower in the DHM (46 440 [40 648–52 233]) than PTF group (55 102 [48 269–61 934]) (P = .04), driven by parent lost wages. DHM cost an additional $5328 per case of averted NEC. CONCLUSIONS: In a high mother’s milk use setting, total costs from a societal perspective to 18 months of providing supplemental DHM versus PTF to VLBW infants did not differ, although postdischarge costs were lower in the DHM group. Although supplemental DHM was not cost-saving, it reduced NEC supporting its use over PTF.

Necrotizing enterocolitis (NEC) is a severe form of bowel disease that develops in premature infants. Although animal data and human studies suggest that aberrant activation of the intestinal immune system contributes to NEC, the pathogenesis remains unclear. We hypothesized that inherited defects in the regulation of Toll-like receptor signaling can contribute to NEC susceptibility in premature infants. A forward genetic screen done in an infant with lethal NEC using exome sequencing identified a novel stop mutation (p.Y168X) and a rare missense variant (p.S80Y) in SIGIRR, a gene that inhibits intestinal Toll-like receptor signaling. Functional studies carried out in human embryonic kidney cells and intestinal epithelial cells demonstrated that SIGIRR inhibited inflammation induced by lipopolysaccharide, a cell wall component of Gram-negative bacteria implicated in NEC. The genetic variants identified in the infant with NEC resulted in loss of SIGIRR function and exaggerated inflammation in response to lipopolysaccharide. Additionally, Sanger sequencing identified missense, stop, or splice region SIGIRR variants in 10 of 17 premature infants with stage II+ NEC. To the best of our knowledge, this is one of the first reports of a phenotype associated with SIGIRR in humans. Our data provide novel mechanistic insight into the probable causation of NEC and support additional investigation of the hypothesis that inherited defects in the regulation of innate immune signaling can contribute to NEC susceptibility in premature infants.

OBJECTIVE:To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (≤1500 g) infants.METHODS:We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobic antimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infants exposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity score stratified by NEC severity (medical and surgical). The primary composite outcome was in-hospital death or intestinal stricture. We assessed the relationship between anaerobic antimicrobial therapy and outcome by using a conditional logistic regression on the matched cohort.RESULTS:A total of 1390 infants exposed to anaerobic antimicrobial therapy were matched with 1390 infants not exposed. Mean gestational age and birth weight were 27 weeks and 946 g, respectively, and were similar in both groups. We found no significant difference in the combined outcome of death or strictures, but strictures as a single outcome were more common in the anaerobic antimicrobial therapy group (odds ratio 1.73; 95% confidence interval, 1.11–2.72). Among infants with surgical NEC, mortality was less common with anaerobic antimicrobial therapy (odds ratio 0.71; 95% confidence interval, 0.52–0.95).CONCLUSIONS:Anaerobic antimicrobial therapy was not associated with the composite outcome of death or strictures but was associated with an increase in intestinal strictures. This higher incidence of intestinal strictures may be explained by the fact that death is a competing outcome for intestinal strictures, and mortality was slightly lower in the anaerobic cohort. Infants with surgical NEC who received anaerobic antimicrobial therapy had lower mortality.

OBJECTIVE: Prophylactic indomethacin reduces severe intraventricular hemorrhage but may increase spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants. Early feedings improve nutritional outcomes but may increase the risk of SIP. Despite their benefits, use of these therapies varies largely by physician preferences in part because of the concern for SIP. METHODS: This was a cohort study of 15 751 ELBW infants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from 1999 to 2010 who survived beyond 12 hours after birth. The risk of SIP was compared between groups of infants with and without exposure to prophylactic indomethacin and early feeding in unadjusted analyses and in analyses adjusted for center and for risks of SIP. RESULTS: Among infants exposed to prophylactic indomethacin, the risk of SIP did not differ between the indomethacin/early-feeding group compared with the indomethacin/no-early-feeding group (adjusted relative risk [RR] 0.74, 95% confidence interval [CI] 0.49–1.11). The risk of SIP was lower in the indomethacin/early-feeding group compared with the no indomethacin/no-early-feeding group (adjusted RR 0.58, 95% CI 0.37–0.90, P = .0159). Among infants not exposed to indomethacin, early feeding was associated with a lower risk of SIP compared with the no early feeding group (adjusted RR 0.53, 95% CI 0.36–0.777, P = .0011). CONCLUSIONS: The combined or individual use of prophylactic indomethacin and early feeding was not associated with an increased risk of SIP in ELBW infants.

BACKGROUND AND OBJECTIVES: It is unknown how gestational age (GA) impacts neonatal morbidities in infants with critical congenital heart disease (CCHD). We aim to quantify GA-specific mortality and neonatal morbidity in infants with CCHD. METHODS: Cohort study using a database linking birth certificate, infant hospital discharge, readmission, and death records, including infants 22 to 42 weeks’ GA without chromosomal anomalies (2005–2012, 2 988 925 live births). The International Classification of Diseases, Ninth Revision diagnostic and procedure codes were used to define CCHD and neonatal morbidities (intraventricular hemorrhage, retinopathy, periventricular leukomalacia, chronic lung disease, necrotizing enterocolitis). Adjusted absolute risk differences (ARDs) with 95% confidence intervals (CIs) were calculated. RESULTS: We identified 6903 out of 2 968 566 (0.23%) infants with CCHD. The incidence of CCHD was highest at 29 to 31 weeks’ GA (0.9%) and lowest at 39 to 42 weeks (0.2%). Combined neonatal morbidity or mortality in infants with and without CCHD was 82.8% and 57.9% at CONCLUSIONS: Infants born with CCHD are at high risk of neonatal morbidity. Morbidity remains increased across all GA groups in comparison with infants born at 39 to 42 weeks. This substantial risk of neonatal morbidity is important to consider when caring for this patient population.

* Abbreviations: PDA — : patent ductus arteriosus VLBW — : very low birth weight At a meeting of the Section of Pediatrics of the Royal Society of Medicine in October 1958, Dr Burnard1 reported the first observation that prematurity is associated with persistence of the murmur of patent ductus arteriosus (PDA), and that the latter is associated with dyspnea. Reinforced by subsequent confirmation, the concept developed that prolonged ductal patency in preterm infants is pathologic and therefore requires treatment. The hypothesis that left-to-right ductal shunting associated with persistent PDA is a direct cause of the various adverse outcomes overrepresented in preterm infants with PDA has become deeply ingrained in theory and practice, despite absence of supporting evidence. Randomized controlled trials over 4 decades have demonstrated that early, routine intervention to close the PDA in preterm infants fails to ameliorate risk of those outcomes, casting doubt on this hypothesis.2 The pervasive conviction that it is correct, however, resulted in open-label treatment of at least some control subjects in most treatment trials and in nearly all recent case series of observational management. The available data, … Address correspondence to William E. Benitz, MD, Division of Neonatal and Developmental Medicine, Stanford University, 750 Welch Rd, Suite 315, Palo Alto, CA 94304. E-mail: benitzwe{at}stanford.edu

* Abbreviations: CFU — : colony-forming unit IAP — : intrapartum antibiotic prophylaxis Sepsis is a major cause of morbidity and mortality among infants in the NICU. Because septic infants present with nonspecific clinical findings, providers are justifiably concerned about missing sepsis. Blood cultures are the gold standard for diagnosis of sepsis, and when adequate volumes are obtained, cultures have excellent sensitivity even when the infant has very low levels of bacteremia.1 However, many providers view sterile culture results with skepticism, especially when the infant appears ill or received antibiotics before cultures were obtained. Therefore, we have developed a culture (no pun intended) of acceptance in treating “culture-negative” sepsis. Recent reports suggest that up to 10 times as much antibiotic is used for culture-negative sepsis as for culture-proven sepsis.2,3 This practice must stop. The evidence for unintended harm caused by prolonged or unnecessary antibiotic exposure continues to mount and includes increased risk for obesity, atopy, and, for preterm infants, necrotizing enterocolitis, sepsis, bronchopulmonary dysplasia, and death.4 Why then do providers view sterile cultures with such skepticism? The first reason is that providers have all-too-frequent experiences with cultures that are obtained incorrectly. Blood cultures collected inappropriately cannot be trusted, but such cultures, unfortunately, are a common problem. The recommendation is that a minimum of 1 mL of blood, either in 1 culture or divided into 2 0.5 mL cultures, be obtained from infants … Address correspondence to Joseph B. Cantey, MD, Department of Pediatrics, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229. E-mail: cantey{at}uthscsa.edu

OBJECTIVE: Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects. METHODS: Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994–2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18. RESULTS: Of 52 262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis. CONCLUSIONS: In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.

OBJECTIVE: To determine 1-year survival and major neonatal morbidities (intracranial hemorrhage grade >2, cystic periventricular leukomalacia, retinopathy of prematurity grade >2, necrotizing enterocolitis, severe bronchopulmonary dysplasia) among extremely preterm infants in Norway in 2013–2014, and to compare the results to the first Norwegian Extreme Prematurity Study 1999–2000 and similar contemporary European population-based studies. METHODS: Population-based study of all infants born at 22 through 26 weeks’ gestation in Norway in 2013–2014. Prospectively collected data were obtained by linking data in the Norwegian Neonatal Network to the Medical Birth Registry of Norway. RESULTS: Of 420 infants (incidence 3.5 per 1000 births), 145 were stillborn (34.5%), 275 were live-born (82.3% of the 334 fetuses alive at admission for obstetrical care), and 251 (91.3% of live-born infants) were admitted to a neonatal unit. The survival among live-born infants was 18% at 22 weeks, 29% at 23 weeks, 56% at 24 weeks, 84% at 25 weeks and 90% at 26 weeks (for each week increment in gestational age: odds ratio 3.3; 95% confidence interval, 2.4–4.4). Among infants surviving to 1 year of age, major neonatal morbidity was diagnosed in 55%. Decreasing gestational age was moderately associated with rates of major morbidity (odds ratio 1.6; 95% confidence interval, 1.2–2.2). CONCLUSIONS: Compared to the previous 1999–2000 cohort, the rate of stillbirth before admission to an obstetrical unit increased, whereas the survival rate among live born infants was similar in our 2013–2014 cohort. Neonatal morbidity rates remain high among extremely preterm infants.

* Abbreviations: GER — : gastroesophageal reflux H2 — : histamine-2 NEC — : necrotizing enterocolitis VLBW — : very low birth weight Medications are frequently used to treat gastroesophageal reflux (GER) in premature infants.1–4 However, diagnostic modalities for GER are poor and clinical diagnosis is highly variable. Like all medications, GER medications have side effects specific to their drug class. In addition, a number of these medications have been associated with significant harm (eg, sepsis, necrotizing enterocolitis [NEC]) in large cohort studies.2,5–7 In this issue of Pediatrics , D’Agostino et al use an electronic health record from 30 sites in Pennsylvania and New Jersey to document the use of GER medications in infants ≤35 weeks’ gestation at birth born between January 2005 and January 2009.8 They find that 37% (812 of 2217) of the cohort was treated with GER medications in the first year of life. Strikingly, in >75% of cases, these medications were started after the initial presentation to the ambulatory setting. The length of exposure to these medications was prolonged: 375 days (interquartile range: 165–515) for … Address correspondence to P. Brian Smith, MD, MPH, MHS, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. E-mail: brian.smith{at}duke.edu

Human cytomegalovirus (CMV) infection may be acquired in very low birth weight and extremely low birth weight (ELBW) infants from breast milk. The clinical relevance of such infections is uncertain. There is no consensus on whether screening breast milk for CMV, freezing/pasteurizing milk before feeding, or performing virological monitoring on at-risk infants is warranted. We describe an ELBW infant who acquired CMV postnatally from breast milk and developed CMV sepsis syndrome and clinical evidence of necrotizing enterocolitis (NEC) at ∼5 weeks of age. The availability of serial dried blood spots from day of life (DOL) 4 to 21, coincidentally obtained for a metabolic study, provided the novel opportunity to retrospectively test for and quantify the magnitude of CMV DNAemia. DNAemia was present for several weeks before the onset of severe CMV disease, first being noted on DOL 18 and increasing in magnitude daily to 4.8 log10 genomes/mL on DOL 21, approximately 8 days before the onset of abdominal distension and 15 days before the onset of CMV sepsis syndrome and NEC. After surgical resection, supportive care, and ganciclovir therapy, the infant recovered. This case underscores the importance of including CMV infection in the differential diagnosis of sepsis and NEC in premature infants. This case also suggests the value of prospective virological monitoring in at-risk low birth weight and ELBW infants. Future studies should examine the potential utility of preemptive monitoring for, and possibly treatment of, CMV DNAemia in premature infants, which may herald the onset of serious disease.

BACKGROUND: There is currently no clear evidence that nasal-biphasic positive airway pressure (n-BiPAP) confers any advantage over nasal-continuous positive airway pressure (n-CPAP). Our hypothesis was that preterm infants born before 30 weeks' gestation and METHODS: We conducted an unblinded multicenter randomized trial comparing n-CPAP with n-BiPAP in infants born RESULTS: A total of 540 infants (270 in each group) were eligible to be included in the statistical analysis; 57 (21%) of n-BiPAP group and 55 (20%) of n-CPAP group failed extubation at 48 hours postextubation (adjusted odds ratio 1.01; 95% confidence interval 0.65–1.56; P = .97). Subgroup analysis of infants born before and after 28 weeks’ gestation showed no significant differences between the 2 groups. There were no significant differences between arms in death; oxygen requirement at 28 days; oxygen requirement at 36 weeks' corrected gestation; or intraventricular hemorrhage, necrotizing enterocolitis requiring surgery, or pneumothorax. CONCLUSIONS: This trial shows that there is no added benefit to using n-BIPAP over n-CPAP at equivalent mean airway pressure in preventing extubation failures in infants born before 30 weeks' gestation and

BACKGROUND AND OBJECTIVE: Little is known about in-hospital morbidities and neurodevelopmental outcomes among extremely preterm infants born to women with insulin-dependent diabetes mellitus (IDDM). We examined risks of mortality, in-hospital morbidities, and neurodevelopmental outcomes at 18 to 22 months’ corrected age between extremely preterm infants of women with insulin use before pregnancy (IBP), with insulin use started during pregnancy (IDP), and without IDDM. METHODS: Infants 22 to 28 weeks’ gestation born or cared for at a Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network center (2006–2011) were studied. Regression models compared the association between maternal IDDM and timing of insulin use and the outcomes of the 3 groups. RESULTS: Of 10 781 infants, 536 (5%) were born to women with IDDM; 58% had IBP, and 36% had IDP. Infants of mothers with IBP had higher risks of necrotizing enterocolitis (adjusted relative risk [RR] = 1.55 [95% confidence interval (CI) 1.17–2.05]) and late-onset sepsis (adjusted RR = 1.26 [95% CI 1.07–1.48]) than infants of mothers without IDDM. There was some indication of higher in-hospital mortality risk among infants of mothers with IBP compared with those with IDP (adjusted RR = 1.33 [95% CI 1.00–1.79]). Among survivors evaluated at 18 to 22 months’ corrected age, average head circumference z score was lower for infants of mothers with IBP compared with those without IDDM, but there were no differences in risk of neurodevelopmental impairment. CONCLUSIONS: In this cohort of extremely preterm infants, infants of mothers with IBP had higher risks of necrotizing enterocolitis, sepsis, and small head circumference.

OBJECTIVES: To examine the availability of donor human milk (DHM) in a population-based cohort and assess whether the availability of DHM was associated with rates of breast milk feeding at NICU discharge and rates of necrotizing enterocolitis (NEC). METHODS: Individual patient clinical data for very low birth weight infants from the California Perinatal Quality Care Collaborative were linked to hospital-level data on DHM availability from the Mothers’ Milk Bank of San José for 2007 to 2013. Trends of DHM availability were examined by level of NICU care. Hospitals that transitioned from not having DHM to having DHM availability during the study period were examined to assess changes in rates of breast milk feeding at NICU discharge and NEC. RESULTS: The availability of DHM increased from 27 to 55 hospitals during the study period. The availability increased for all levels of care including regional, community, and intermediate NICUs, with the highest increase occurring in regional NICUs. By 2013, 81.3% of premature infants cared for in regional NICUs had access to DHM. Of the 22 hospitals that had a clear transition to having availability of DHM, there was a 10% increase in breast milk feeding at NICU discharge and a concomitant 2.6% decrease in NEC rates. CONCLUSIONS: The availability of DHM has increased over time and has been associated with positive changes including increased breast milk feeding at NICU discharge and decrease in NEC rates.

BACKGROUND: Because greater percentages of women deliver at hospitals without high-level NICUs, there is little information on the effect of delivery hospital on the outcomes of premature infants in the past 2 decades, or how these effects differ across states with different perinatal regionalization systems. METHODS: A retrospective population-based cohort study was constructed of all hospital-based deliveries in Pennsylvania and California between 1995 and 2005 and Missouri between 1995 and 2003 with a gestational age between 23 and 37 weeks (N = 1 328 132). The effect of delivery at a high-level NICU on in-hospital death and 5 complications of premature birth was calculated by using an instrumental variables approach to control for measured and unmeasured differences between hospitals. RESULTS: Infants who were delivered at a high-level NICU had significantly fewer in-hospital deaths in Pennsylvania (7.8 fewer deaths/1000 deliveries, 95% confidence interval [CI] 4.1–11.5), California (2.7 fewer deaths/1000 deliveries, 95% CI 0.9–4.5), and Missouri (12.6 fewer deaths/1000 deliveries, 95% CI 2.6–22.6). Deliveries at high-level NICUs had similar rates of most complications, with the exception of lower bronchopulmonary dysplasia rates at Missouri high-level NICUs (9.5 fewer cases/1000 deliveries, 95% CI 0.7–18.4) and higher infection rates at high-level NICUs in Pennsylvania and California. The association between delivery hospital, in-hospital mortality, and complications differed across the 3 states. CONCLUSIONS: There is benefit to neonatal outcomes when high-risk infants are delivered at high-level NICUs that is larger than previously reported, although the effects differ between states, which may be attributable to different methods of regionalization.

OBJECTIVE: We sought to determine if a center’s approach to care of premature infants at the youngest gestational ages (22–24 weeks’ gestation) is associated with clinical outcomes among infants of older gestational ages (25–27 weeks’ gestation). METHODS: Inborn infants of 401 to 1000 g birth weight and 22 0/7 to 27 6/7 weeks’ gestation at birth from 2002 to 2008 were enrolled into a prospectively collected database at 20 centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Markers of an aggressive approach to care for 22- to 24-week infants included use of antenatal corticosteroids, cesarean delivery, and resuscitation. The primary outcome was death before postnatal day 120 for infants of 25 to 27 weeks’ gestation. Secondary outcomes were the combined outcomes of death or a number of morbidities associated with prematurity. RESULTS: Our study included 3631 infants 22 to 24 weeks’ gestation and 5227 infants 25 to 27 weeks’ gestation. Among the 22- to 24-week infants, use of antenatal corticosteroids ranged from 28% to 100%, cesarean delivery from 13% to 65%, and resuscitation from 30% to 100% by center. Centers with higher rates of antenatal corticosteroid use in 22- to 24-week infants had reduced rates of death, death or retinopathy of prematurity, death or late-onset sepsis, death or necrotizing enterocolitis, and death or neurodevelopmental impairment in 25- to 27-week infants. CONCLUSIONS: This study suggests that physicians’ willingness to provide care to extremely low gestation infants as measured by frequency of use of antenatal corticosteroids is associated with improved outcomes for more-mature infants. * Abbreviations: BPD — : bronchopulmonary dysplasia CI — : confidence interval ELBW — : extremely low birth weight GDB — : Generic Database GMFCS — : gross motor function classification system IVH — : intraventricular hemorrhage LOS — : late-onset sepsis NDI — : neurodevelopmental impairment NEC — : necrotizing enterocolitis NICHD — : National Institute of Child Health and Human Development NRN — : Neonatal Research Network OR — : odds ratio PVL — : periventricular leukomalacia ROP — : retinopathy of prematurity

With improved obstetrical management and evidence-based use of intrapartum antimicrobial therapy, early-onset neonatal sepsis is becoming less frequent. However, early-onset sepsis remains one of the most common causes of neonatal morbidity and mortality in the preterm population. The identification of neonates at risk for early-onset sepsis is frequently based on a constellation of perinatal risk factors that are neither sensitive nor specific. Furthermore, diagnostic tests for neonatal sepsis have a poor positive predictive accuracy. As a result, clinicians often treat well-appearing infants for extended periods of time, even when bacterial cultures are negative. The optimal treatment of infants with suspected early-onset sepsis is broad-spectrum antimicrobial agents (ampicillin and an aminoglycoside). Once a pathogen is identified, antimicrobial therapy should be narrowed (unless synergism is needed). Recent data suggest an association between prolonged empirical treatment of preterm infants (≥5 days) with broad-spectrum antibiotics and higher risks of late onset sepsis, necrotizing enterocolitis, and mortality. To reduce these risks, antimicrobial therapy should be discontinued at 48 hours in clinical situations in which the probability of sepsis is low. The purpose of this clinical report is to provide a practical and, when possible, evidence-based approach to the management of infants with suspected or proven early-onset sepsis.

BACKGROUND: Data are limited on the impact of methicillin-resistant Staphylococcus aureus (MRSA) on morbidity and mortality among very low birth weight (VLBW) infants with S aureus (SA) bacteremia and/or meningitis (B/M). METHODS: Neonatal data for VLBW infants (birth weight 401–1500 g) born January 1, 2006, to December 31, 2008, who received care at centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network were collected prospectively. Early-onset (≤72 hours after birth) and late-onset (>72 hours) infections were defined by blood or cerebrospinal fluid cultures and antibiotic treatment of ≥5 days (or death 3 days, 316 (3.7%) had SA B/M. Eighty-eight had MRSA (1% of all infants, 28% of infants with SA); 228 had MSSA (2.7% of all infants, 72% of infants with SA). No infant had both MRSA and MSSA B/M. Ninety-nine percent of MRSA infections were late-onset. The percent of infants with MRSA varied by center ( P < .001) with 9 of 20 centers reporting no cases. Need for mechanical ventilation, diagnosis of respiratory distress syndrome, necrotizing enterocolitis, and other morbidities did not differ between infants with MRSA and MSSA. Mortality was high with both MRSA (23 of 88, 26%) and MSSA (55 of 228, 24%). CONCLUSIONS: Few VLBW infants had SA B/M. The 1% with MRSA had morbidity and mortality rates similar to infants with MSSA. Practices should provide equal focus on prevention and management of both MRSA and MSSA infections among VLBW infants. * Abbreviations: B/M — : bacteremia and/or meningitis BPD — : bronchopulmonary dysplasia BW — : birth weight CI — : confidence interval CSF — : cerebrospinal fluid GA — : gestational age IVH — : intraventricular hemorrhage MRSA — : methicillin-resistant Staphylococcus aureus MSSA — : methicillin-susceptible Staphylococcus aureus NEC — : necrotizing enterocolitis NICHD — : Eunice Kennedy Shriver National Institute of Child Health and Human Development NRN — : Neonatal Research Network PMA — : postmenstrual age PVL — : periventricular leukomalacia RDS — : respiratory distress syndrome ROP — : retinopathy of prematurity RR — : relative risk SA — : Staphylococcus aureus SGA — : small for gestational age VLBW — : very low birth weight

Postnatal ductal closure is stimulated by rising oxygen tension and withdrawal of vasodilatory mediators (prostaglandins, nitric oxide, adenosine) and by vasoconstrictors (endothelin-1, catecholamines, contractile prostanoids), ion channels, calcium flux, platelets, morphologic maturity, and a favorable genetic predisposition. A persistently patent ductus arteriosus (PDA) in preterm infants can have clinical consequences. Decreasing pulmonary vascular resistance, especially in extremely low gestational age newborns, increases left-to-right shunting through the ductus and increases pulmonary blood flow further, leading to interstitial pulmonary edema and volume load to the left heart. Potential consequences of left-to-right shunting via a hemodynamically significant patent ductus arteriosus (hsPDA) include increased risk for prolonged ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis or focal intestinal perforation, intraventricular hemorrhage, and death. In the last decade, there has been a trend toward less aggressive treatment of PDA in preterm infants. However, there is a subgroup of infants who will likely benefit from intervention, be it pharmacologic, interventional, or surgical: (1) prophylactic intravenous indomethacin in highly selected extremely low gestational age newborns with PDA (

OBJECTIVE: The survival rates after pediatric intestinal transplant according to underlying disease are unknown. The objective of our study was to describe the population of pediatric patients receiving an intestinal transplant and to evaluate survival according to specific disease condition. PATIENTS: Pediatric patients (≤21 years of age) with intestinal failure meeting criteria for intestinal transplant were included in the study. METHODS: A retrospective review of the United Network for Organ Sharing intestinal transplant database (January 1, 1991, to May 16, 2008), including all pediatric transplant centers participating in the United Network for Organ Sharing, was conducted. The main outcome measures were survival and mortality. RESULTS: Eight hundred fifty-two children received an intestinal transplant (54% male). Median age and weight at the time of transplant were 1 year (interquartile rage: 1–5) and 10.7 kg (interquartile rage: 7.8–21.7). Sixty-nine percent of patients also received a simultaneous liver transplant. The most common diagnoses among patients who received a transplant were gastroschisis (24%), necrotizing enterocolitis (15%), volvulus (14%), other causes of short-gut syndrome (19%), functional bowel syndrome (16%), and Hirschsprung disease (7%). The Kaplan-Meier curves demonstrated variation in patient survival according to diagnosis. Cox regression analysis confirmed a survival difference according to diagnosis (P < .001) and demonstrated a survival advantage for those patients listed with a diagnosis of volvulus (P < .01) compared with the reference gastroschisis. After adjusting for gender, recipient weight, and concomitant liver transplant, children with volvulus had a lower hazard ratio for survival and a lower risk of mortality. CONCLUSIONS: Survival after intestinal transplant was associated with the underlying disease state. The explanation for these findings requires additional investigation into the differences in characteristics of the population of children with intestinal failure.

OBJECTIVES: Necrotizing enterocolitis (NEC) with multiple organ dysfunction syndrome (MODS) carries significant morbidity and mortality. There is extensive experimental evidence to support investigation of therapeutic hypothermia in infants with these conditions. We aimed to establish the feasibility and safety of mild hypothermia in preterm neonates with NEC and MODS as a prelude to a randomized trial. METHODS: This was a prospective, nonrandomized pilot study of 15 preterm infants who were referred for surgical intervention of advanced NEC and failure of at least 3 organs. Whole-body cooling was achieved by ambient temperature adjustment with or without cooling mattress. Three groups (n = 5 per group) were cooled to core temperatures of 35.5°C (±0.5°C), 34.5°C, and 33.5°C, respectively, for 48 hours before rewarming to 37°C. Infants were carefully assessed to identify adverse effects that potentially were related to cooling and rewarming. A noncooled group (n = 10) with advanced surgical NEC and MODS was used for comparison. Data are medians (interquartile range). RESULTS: Gestational age at birth was 27 weeks (26–30), admission weight was 1.1 kg (1.0–1.7), and admission age was 31 days (12–45). Core temperature was maintained within target range for 90% (88%–97%) of the intended time. Statistically significant relationships were identified between core temperature and heart rate (P < .0001), pH (P < .0001), base excess (P = .003), and blood clot dynamics (longer time to initial clot formation, slower rate of clot formation, and decrease in clot strength; all P < .001) as assessed by thromboelastography. No major clinical problems or adverse events were noted during cooling or rewarming. Comparison with the noncooled group revealed no increase in mortality, bleeding, infection, or need for inotropes in infants who were cooled. CONCLUSIONS: Mild hypothermia for 48 hours in preterm neonates with severe NEC seems both feasible and safe. Additional investigation of the efficacy of this therapeutic intervention in this population is warranted.

BACKGROUND: As extremely preterm infant mortality rates have decreased, concerns regarding resource use have intensified. Accurate models for predicting time to hospital discharge could aid in resource planning, family counseling, and stimulate quality-improvement initiatives. OBJECTIVES: To develop, validate, and compare several models for predicting the time to hospital discharge for infants PATIENTS AND METHODS: We conducted a retrospective analysis of infants RESULTS: Data from 2254 infants were included. Prediction of postmenstrual age at discharge was poor. However, models that incorporated later clinical characteristics were more accurate in predicting early or late discharge (AUC: 0.76–0.83 [full models] vs 0.56–0.69 [perinatal factor models]). In simplified key-risk-factors models, the predicted probabilities for early and late discharge compared favorably with the observed rates. Furthermore, the AUC (0.75–0.77) was similar to those of the models that included the full factor set. CONCLUSIONS: Prediction of early or late discharge is poor if only perinatal factors are considered, but it improves substantially with knowledge of later-occurring morbidities. Predictive models that use a few key risk factors are comparable to the full models and may offer a clinically applicable strategy.

BACKGROUND. The most common congenital heart disease in the newborn population, patent ductus arteriosus, accounts for significant morbidity in preterm newborns. In addition to prematurity and environmental factors, we hypothesized that genetic factors play a significant role in this condition. OBJECTIVE. The objective of this study was to quantify the contribution of genetic factors to the variance in liability for patent ductus arteriosus in premature newborns. PATIENTS AND METHODS. A retrospective study (1991–2006) from 2 centers was performed by using zygosity data from premature twins born at ≤36 weeks' gestational age and surviving beyond 36 weeks' postmenstrual age. Patent ductus arteriosus was diagnosed by echocardiography at each center. Mixed-effects logistic regression was used to assess the effect of specific covariates. Latent variable probit modeling was then performed to estimate the heritability of patent ductus arteriosus, and mixed-effects probit modeling was used to quantify the genetic component. RESULTS. We obtained data from 333 dizygotic twin pairs and 99 monozygotic twin pairs from 2 centers (Yale University and University of Connecticut). Data on chorioamnionitis, antenatal steroids, gestational age, body weight, gender, respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, oxygen supplementation, and bronchopulmonary dysplasia were comparable between monozygotic and dizygotic twins. We found that gestational age, respiratory distress syndrome, and institution were significant covariates for patent ductus arteriosus. After controlling for specific covariates, genetic factors or the shared environment accounted for 76.1% of the variance in liability for patent ductus arteriosus. CONCLUSIONS. Preterm patent ductus arteriosus is highly familial (contributed to by genetic and environmental factors), with the effect being mainly environmental, after controlling for known confounders.

OBJECTIVE. A count of 3 neonatal morbidities (bronchopulmonary dysplasia, brain injury, and severe retinopathy of prematurity) strongly predict the risk of death or neurosensory impairment in extremely low birth weight infants who survive to 36 weeks' postmenstrual age. Neonatal infection has also been linked with later impairment. We examined whether the addition of infection to the count of 3 neonatal morbidities further improves the prediction of poor outcome. METHODS. We studied 944 infants who participated in the Trial of Indomethacin Prophylaxis in Preterms and survived to 36 weeks' postmenstrual age. Culture-proven sepsis, meningitis, and stage II or III necrotizing enterocolitis were recorded prospectively. We investigated the incremental prognostic importance of neonatal infection by adding terms for the different types of infection to a logistic model that already contained terms for the count of bronchopulmonary dysplasia, brain injury, and severe retinopathy. Poor outcome at 18 months of age was death or survival with 1 or more of the following: cerebral palsy, cognitive delay, severe hearing loss, and bilateral blindness. RESULTS. There were 414 (44%) infants with at least 1 episode of infection or necrotizing enterocolitis. Meningitis and the presence of any type of infection added independent prognostic information to the morbidity-count model. The odds ratio associated with infection or necrotizing enterocolitis in this model was 50% smaller than the odds ratio associated with each count of the other 3 neonatal morbidities. Meningitis was rare and occurred in 22 (2.3%) of 944 infants. CONCLUSIONS. In this cohort of extremely low birth weight infants who survived to 36 weeks' postmenstrual age, neonatal infection increased the risk of a late death or survival with neurosensory impairment. However, infection was a weaker predictor of poor outcome than bronchopulmonary dysplasia, brain injury, and severe retinopathy.

OBJECTIVES. Our objectives were to identify factors associated with the duration of the first antibiotic course initiated in the first 3 postnatal days and to assess associations between the duration of the initial antibiotic course and subsequent necrotizing enterocolitis or death in extremely low birth weight infants with sterile initial postnatal culture results. METHODS. We conducted a retrospective cohort analysis of extremely low birth weight infants admitted to tertiary centers in 1998–2001. We defined initial empirical antibiotic treatment duration as continuous days of antibiotic therapy started in the first 3 postnatal days with sterile culture results. We used descriptive statistics to characterize center practice, bivariate analyses to identify factors associated with prolonged empirical antibiotic therapy (≥5 days), and multivariate analyses to evaluate associations between therapy duration, prolonged empirical therapy, and subsequent necrotizing enterocolitis or death. RESULTS. Of 5693 extremely low birth weight infants admitted to 19 centers, 4039 (71%) survived >5 days, received initial empirical antibiotic treatment, and had sterile initial culture results through the first 3 postnatal days. The median therapy duration was 5 days (range: 1–36 days); 2147 infants (53%) received prolonged empirical therapy (center range: 27%–85%). Infants who received prolonged therapy were less mature, had lower Apgar scores, and were more likely to be black. In multivariate analyses adjusted for these factors and center, prolonged therapy was associated with increased odds of necrotizing enterocolitis or death and of death. Each empirical treatment day was associated with increased odds of death, necrotizing enterocolitis, and the composite measure of necrotizing enterocolitis or death. CONCLUSION. Prolonged initial empirical antibiotic therapy may be associated with increased risk of necrotizing enterocolitis or death and should be used with caution.

SHORT BOWEL SYNDROME (SBS) is a devastating clinical problem that affects an estimated 20 000 Americans (children and adults). Although not consistently fatal, complications that are associated with this disorder include dehydration, malnutrition, sepsis, poor growth, and impaired neurodevelopment.1-5 SBS is defined as insufficient bowel length to digest and absorb adequately nutrients that are needed to promote appropriate growth of the infant. SBS is often the result of massive small intestinal resection in infants as a result of necrotizing enterocolitis (NEC).6,7 Overall, the number of children with this disorder seems to be increasing, likely as a result of reductions in neonatal mortality in both term and preterm neonates, putting more infants at risk for developing diseases that predispose to SBS.8,9 The related health care costs that result from treating patients with SBS and its complications are very high. The quality-of-life burden on these children and their families is also very high.1,3 The most common cause of SBS in infants is NEC.10 The incidence of NEC in extremely low birth weight (ELBW) infants is ~10%, and the associated mortality is 30%.11,12 Infants who have NEC and are surgically treated have hospital lengths of stay that exceed those of gestational age (GA)-matched infants by 60 days. On the basis of this length of stay in 1 US hospital, the estimated hospital charges for infants with NEC exceeded those of matched control subjects by more than $186 000, and the yearly additional charges related to NEC were $6.5 million.13 Multiple factors have been identified as predictors of morbidity and mortality in patients with SBS14-16; however, SBS continues to constitute a major clinical challenge for neonatologists, gastroenterologists, and nutritionists, who often collectively treat these patients. It is associated with high morbidity and mortality because of chronic malabsorption that results from reduced bowel absorptive surface area and diminished mucosal function, including gut barrier dysfunction, frequent infections, and complications that are associated with specialized parenteral and enteral feeding.2,17 In children, SBS may lead to poor growth, nutritional deficiencies, delayed neurodevelopment, and ultimately death.18-20 Data illustrating the effect of SBS on subsequent growth and neurologic development in preterm infants are sparse.20-22 We determined the incidence of surgical SBS and examined morbidity, mortality, and growth outcomes of children with and without surgical SBS in a large cohort of very low birth weight (VLBW) infants who were born between 2002 and 2005.

Background And Objective: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.

Despite dramatic improvements in survival rates of preterm infants over the last 50 years, there have been no significant further improvements in survival or morbidity rates over the most recent 10 years.1,2 Survival rates among infants with a birth weight of 500 to 1500 g in participating centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network of the United States were 84% in 1995–1996 and 85% in 1997–2002; the survival rate without major neonatal morbidity (which included bronchopulmonary dysplasia [BPD], intraventricular hemorrhage, and necrotizing enterocolitis) was unchanged (70%) between these 2 time periods.1 Similar findings were observed in epidemiologic data from Norway and Germany, which were published almost coincidentally.2,3 New paradigms for addressing care of extremely preterm infants may be necessary to achieve further improvements in outcome. Before the last decade, increased survival rates of preterm infants had been attributed to regionalization of high-risk pregnancies, use of prenatal corticosteroids, and an aggressive approach to perinatal therapy.4 Birth in a high-risk perinatal center with a higher level of neonatal care is associated with better survival rates than birth in a center that provides a lower level of care,5 and mortality and morbidity rates are increased for the most immature infants who require transport after birth.6 Some of the major morbidities associated with extreme prematurity such as BPD and intraventricular/periventricular hemorrhage could potentially be affected by management in the first minutes of life. However, the principles of care that occur in the NICU are not always used in the delivery room (DR). Care of the smallest preterm infants in the DR has received very little attention in newborn-resuscitation protocols. It is only with the most recent edition of the Neonatal Resuscitation Program textbook7 … Address correspondence to Maximo Vento, PhD, MD, Hospital Universitario Materno Infantil La Fe, Neonatal Research Unit, Division of Neonatology, Avenida de Campanar, 21, E46009 Valencia, Spain. E-mail: maximo.vento{at}uv.es or maximovento{at}telefonica.net

OBJECTIVE. This study compared the effects of immediate (ICC) and delayed (DCC) cord clamping on very low birth weight (VLBW) infants on 2 primary variables: bronchopulmonary dysplasia (BPD) and suspected necrotizing enterocolitis (SNEC). Other outcome variables were late-onset sepsis (LOS) and intraventricular hemorrhage (IVH).STUDY DESIGN. This was a randomized, controlled unmasked trial in which women in labor with singleton fetuses RESULTS. Seventy-two mother/infant pairs were randomized. Infants in the ICC and DCC groups weighed 1151 and 1175 g, and mean gestational ages were 28.2 and 28.3 weeks, respectively. Analyses revealed no difference in maternal and infant demographic, clinical, and safety variables. There were no differences in the incidence of our primary outcomes (BPD and suspected NEC). However, significant differences were found between the ICC and DCC groups in the rates of IVH and LOS. Two of the 23 male infants in the DCC group had IVH versus 8 of the 19 in the ICC group. No cases of sepsis occurred in the 23 boys in the DCC group, whereas 6 of the 19 boys in the ICC group had confirmed sepsis. There was a trend toward higher initial hematocrit in the infants in the DCC group.CONCLUSIONS. Delayed cord clamping seems to protect VLBW infants from IVH and LOS, especially for male infants.

Present evidence seems to suggest increasingly that fresh human milk has a protective role in the syndrome of acute necrotizing enterocolitis. For this reason (and many others), there appears to be an understandable increase in interest in the development of breast-milk banks. Considerable information already exists concerning the organization of such banks in the early decades of the present century and prior to that time. However, the milk stored in such earlier banks was not usually fresh, as it was primarily required for feeding rather than for the control of bacterial colonization of the intestine.