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Background: Growth and nutrition are critical aspects of care for all infants in the neonatal intensive care unit, especially for infants considered very low birth weight (VLBW; birth weight less than 1500 grams). These infants are at increased risk for prematurity-related morbidities, including bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, and late-onset sepsis. Human milk has been shown to reduce the incidence and severity for some of these morbidities. In 2017, our unit had only 19% of VLBW infants receiving maternal milk at the time of discharge. The …

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.

Chylothorax and chyloperitoneum are rare in infants and challenging to definitively diagnose by using current criteria extrapolated from the adult population. They can be of primary or secondary etiologies, including congenital lymphatic malformations and postoperatively, after cardiothoracic or abdominal surgery. Current first-line management consists of bowel rest, parenteral nutrition, and a modified diet of medium-chain triglycerides but can often take weeks to be effective. Off-label use of octreotide has been reported in numerous case studies for the management of chylous effusions. However, there are no definitive neonatal data available regarding dosing, safety, and efficacy; moreover, octreotide has a side effect profile that been linked to serious morbidities, such as pulmonary hypertension and necrotizing enterocolitis. Propranolol, commonly used for the treatment of infantile hemangiomas, is currently gaining interest as a novel therapy for chylous effusions. In this case series review, we describe the use of propranolol in 4 infants with presumed chylous effusions: 1 with congenital pleural effusions and 3 infants who developed postoperative chylothorax and/or chylous ascites. Clinical improvement was noted within a few days of initiating oral propranolol, and the maximum dose used in our cases was 6 mg/kg per day. In previous case reports, researchers describe the use of oral propranolol in infants with chylous effusions, with the dose used ranging from 0.5 to 4 mg/kg per day. However, this is the first case series in which researchers report its use exclusively in infants with chylothorax and chyloperitoneum. Although further research is needed to establish safety and efficacy, our experiences suggest that propranolol could be an acceptable treatment option for chylous effusions in infants.

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

In rare instances, severe respiratory syncytial virus (RSV) infections of the lower respiratory tract can cause life-threatening extrapulmonary complications. In this report, we describe 4 previously healthy, term and late-preterm infants admitted to the PICU with respiratory failure due to RSV bronchiolitis who developed necrotizing enterocolitis shortly after admission. All infants exhibited progressive abdominal distention, had typical radiographic findings, and developed simple or complex ascites. In addition to being managed with broad-spectrum antibiotics and bowel rest, 1 infant was treated with colon resection and ileostomy, 2 had peritoneal drainage procedures for ascites, and one of those later developed small bowel strictures treated with delayed resection and anastomosis. Three were discharged from the hospital without further complications; 1 died of septic shock. In this case series, we describe development of necrotizing enterocolitis in otherwise healthy neonates with severe RSV disease in the absence of traditional risk factors. We hypothesize that a dysregulated proinflammatory response associated with severe RSV disease may alter intestinal blood flow and compromise barriers to bacterial translocation. Enteral feeding intolerance, septic ileus, and/or complex ascites may represent important clinical corollaries in these patients.

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.

Introduction and Objective Enteral nutrition (EN) is often withheld from neonates with congenital heart disease due to concerns of necrotizing enterocolitis (NEC), despite limited evidence showing no association between the two in this population. This study sought to confirm the association between EN and NEC and determine if this relationship was influenced by feeding practices. Methods This single-center retrospective study included all neonates with congenital heart disease admitted to the Cardiac Critical Care Unit (CCCU) at the Hospital for Sick Children, Toronto between July 1, 2016 and …

* 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.

BACKGROUND AND OBJECTIVES: Treatment of suspected infection is a mainstay of the daily work in the NICU. We hypothesized that NICU antibiotic prescribing practice variation correlates with rates of proven infection, necrotizing enterocolitis (NEC), mortality, inborn admission, and with NICU surgical volume and average length of stay. METHODS: In a retrospective cohort study of 52 061 infants in 127 NICUs across California during 2013, we compared sample means and explored linear and nonparametric correlations, stratified by NICU level of care and lowest/highest antibiotic use rate quartiles. RESULTS: Overall antibiotic use varied 40-fold, from 2.4% to 97.1% of patient-days; median = 24.5%. At all levels of care, it was independent of proven infection, NEC, surgical volume, or mortality. Fifty percent of intermediate level NICUs were in the highest antibiotic use quartile, yet most of these units reported infection rates of zero. Regional NICUs in the highest antibiotic quartile reported inborn admission rate 218% higher (0.24 vs 0.11, P = .03), and length of stay 35% longer (90.2 days vs 66.9 days, P = .03) than regional NICUs in the lowest quartile. CONCLUSIONS: Forty-fold variation in NICU antibiotic prescribing practice across 127 NICUs with similar burdens of proven infection, NEC, surgical volume, and mortality indicates that a considerable portion of antibiotic use lacks clear warrant; in some NICUs, antibiotics are overused. Additional study is needed to establish appropriate use ranges and elucidate the determinants and directionality of relationships between antibiotic and other resource use.

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.

BACKGROUND AND OBJECTIVES: There is evidence that new methods of noninvasive ventilation (NIV) support have significantly changed respiratory distress syndrome (RDS) management in preterm infants. Further perspectives for neonatologists involve the assessment of different NIV strategies in terms of availability, effectiveness, and failure. This study evaluates the efficacy of 2 different NIV strategies for RDS treatment in very low birth weight (VLBW) infants: nasal synchronized intermittent positive pressure ventilation (NSIPPV), which is a modality of conventional ventilation with intermittent peak inspiratory pressure, and bilevel continuous positive airway pressure (BiPAP), not synchronized, with 2 alternate levels of continuous positive airway pressure. METHODS: We conducted a 2-center randomized control study in 124 VLBW infants ( RESULTS: The number of failures and duration of ventilation support did not differ between NSIPPV and BiPAP strategies (P > .05 for both). Moreover, no differences between groups were found regarding secondary outcomes (P > .05 for all). CONCLUSIONS: The present data show no statistically significant differences between NSIPPV and BiPAP strategies in terms of duration of ventilation and failures, suggesting that both NIV techniques are effective in the early treatment of RDS in VLBW infants. Further randomized investigations on wider populations are needed to evaluate the effect of NIV techniques on long-term outcomes.

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: 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

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.

* Abbreviations: NEC — : necrotizing enterocolitis VLBW — : very low birth weight Dr Kantarowska and colleagues have brought welcome attention to the benefits of donor human milk for very low birth weight (VLBW, birth weight 90% of VLBW infants in California, the state with the highest (current) number of births over a 6 year period (2007–2013). This treasure trove of information produced the welcome and … Address correspondence to Lydia Furman, MD, Division of General Academic Pediatrics, Department of Pediatrics, Room 784, MS 6019, Rainbow Babies and Children’s Hospital, 11100 Euclid Avenue, Cleveland, OH 44016. E-mail: lydia.furman{at}uhhospitals.org

OBJECTIVE: To reduce the incidence of necrotizing enterocolitis (NEC) among very low birth weight (VLBW) infants admitted to 8 intensive care nurseries from a 2010 baseline of 8.0% to METHODS: A multidisciplinary NEC QI team used the Vermont Oxford Network definition of NEC and the Institute for Healthcare Improvement model. The specific aims were evidenced based and included (1) standardized early human milk feedings, (2) conservative feeding guidelines during blood transfusions and indomethacin treatment, and (3) restriction of ranitidine use in VLBW infants. Inclusion criteria included VLBW infants admitted within the study period without NEC. Exclusion criteria included established NEC or spontaneous intestinal perforation unrelated to NEC. The incidence of NEC and NEC-related surgery were tracked using statistical process control methodology. RESULTS: The baseline NEC rate in 2010 was 8% (27 NEC cases in 335 VLBW infants). After initiation of early human-milk feeding and conservative feeds during blood transfusions guidelines in November 2011, only 3.1% (19 of 606 VLBW infants) had developed NEC through December 2013 (P = .001). Special cause variation was noted in June 2012 establishing a new centerline at 3.1%. NEC-related mortality decreased from a 2010 baseline mean of 2.7% to a new baseline mean of 0.9% from January 2011 to December 2013. CONCLUSIONS: Implementation of QI initiatives decreased the NEC rate from 8.0% to

The Centers for Disease Control and Prevention estimates that >2 million people in the United States become ill every year due to antibiotic-resistant infections, and at least 23 000 die as a result.1 In India, newborn infants develop bacterial infections that are resistant to most known antibiotics; such infections led to the deaths of 58 000 infants in 2013.2 These problems seem distant to your typical NICU here in the United States. However, in this month’s issue of Pediatrics , Schulman et al3 demonstrate that there is fertile ground for the United States to also experience such a disaster. Our understanding of the negative effects of antibiotic exposure is expanding. New techniques for studying the human microbiome, as well as traditional epidemiologic studies, raise concerns about the negative effects antibiotics may have by altering healthy bacterial colonization.4 Connections have been made between antibiotic exposure and risk of necrotizing enterocolitis and nosocomial infection in neonates,5 as well as an understanding that alterations in the gut microbiome may be linked to longer term outcomes such … Address correspondence to Roger F. Soll, MD, Department of Pediatrics, University of Vermont Medical Center, 111 Colchester Ave, Burlington, VT 05401. E-mail: roger.soll{at}uvmhealth.org

BACKGROUND AND OBJECTIVE: Premature infants are often given glycerin enemas or suppositories to facilitate meconium evacuation and transition to enteral feeding. The purpose of this study was to assess the available evidence for this treatment strategy. METHODS: We conducted a systematic search of Medline, Embase, Central, and trial registries for randomized controlled trials of premature infants treated with glycerin enemas or suppositories. Data were extracted in duplicate and meta-analyzed using a random effects model. RESULTS: We identified 185 premature infants treated prophylactically with glycerin enemas in one trial (n = 81) and suppositories in two other trials (n = 104). All infants were less than 32 weeks gestation and had no congenital malformations. Treatment was associated with earlier initiation of stooling in one trial (2 vs 4 days, P = .02) and a trend towards earlier meconium evacuation in another (6.5 vs 9 days, P = .11). Meta-analysis demonstrated no effect on transition to enteral feeding (0.7 days faster, P = .43) or mortality (P = 0.50). There were no reports of rectal bleeding or perforation but there was a trend towards increased risk of necrotizing enterocolitis with glycerin enemas or suppositories (risk ratio = 2.72, P = .13). These three trials are underpowered and affected by one or more major methodological issues. As a result, the quality of evidence is low to very low. Three other trials are underway. CONCLUSIONS: The evidence for the use glycerin enemas or suppositories in premature infants in inconclusive. Meta-analyzed data suggest that treatment may be associated with increased risk of necrotizing enterocolitis. Careful monitoring of ongoing trials is required.

BACKGROUND AND OBJECTIVES: Infant mortality is an indicator of overall societal health, and a significant proportion of infant deaths occur in NICUs. The objectives were to identify causes of death and to define potentially preventable factors associated with death as areas for quality improvement efforts in the NICU. METHODS: In a prospectively defined study, the principal investigator in 46 level III NICUs agreed to review health care records of infants who died. For each infant, the principal investigator reviewed the medical record to identify the primary cause of death and to look for preventable factors associated with the infant’s death. Infants born at ≥22 weeks estimated gestational age who were born alive were included. Stillborn infants were excluded. RESULTS: Data were collected on 641 infants who died. At lower gestational ages, mortality was most commonly due to extreme prematurity and the complications of premature birth (respiratory distress progressing to respiratory failure, intraventricular hemorrhage, necrotizing enterocolitis, and sepsis). With increasing gestational age, the etiology of mortality shifted to hypoxic–ischemic encephalopathy and genetic or structural anomalies. Reviewers of clinical care identified 197 (31%) infants with potentially modifiable factors that may have contributed to their deaths. CONCLUSIONS: The factors associated with death in infants admitted for intensive care are multifactorial and diverse, and they change with gestational age. In 31% of the deaths, potentially modifiable factors were identified, and these factors suggest important targets for reducing infant mortality.

Necrotizing enterocolitis (NEC) is an inflammatory disease of the intestine primarily affecting preterm infants. Currently, the diagnosis of NEC is based on a constellation of non-specific clinical symptoms and signs, radiologic findings, and laboratory data (Bell's staging criteria). However, a definitive diagnosis of NEC is difficult because of its similarity in presentation to other clinical conditions. Biomarkers measured in stool samples will better reflect inflammation and pathology specific to the intestine. Certain stool markers are able to identify inflammatory bowel disease in pediatric and …