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BACKGROUND: Despite the standardization of care, formula feeding varied across sites of the Ohio Perinatal Quality Collaborative (OPQC). We used orchestrated testing (OT) to learn from this variation and improve nonpharmacologic care of infants with neonatal abstinence syndrome (NAS) requiring pharmacologic treatment in Ohio. METHODS: To test the impact of formula on length of stay (LOS), treatment failure, and weight loss among infants hospitalized with NAS, we compared caloric content (high versus standard) and lactose content (low versus standard) using a 22 factorial design. During October 2015 to June 2016, OPQC sites joined 1 of 4 OT groups. We used response plots to examine the effect of each factor and control charts to track formula use and LOS. We used the OT results to revise the nonpharmacologic bundle and implemented it during 2017. RESULTS: Forty-seven sites caring for 546 NAS infants self-selected into the 4 OT groups. Response plots revealed the benefit of high-calorie formula (HCF) on weight loss, treatment failure, and LOS. The nonpharmacologic treatment bundle was updated to recommend HCF when breastfeeding was not possible. During implementation, HCF use increased, and LOS decreased from 17.1 to 16.4 days across the OPQC. CONCLUSIONS: OT revealed that HCF was associated with shorter LOS in OPQC sites. Implementation of a revised nonpharmacologic care bundle was followed by additional LOS improvement in Ohio. Despite some challenges in the implementation of OT, our findings support its usefulness for learning in improvement networks.

OBJECTIVES: Neonatal abstinence syndrome (NAS) after an infant’s in-utero exposure to opioids has increased dramatically in incidence. No treatment standards exist, leading to substantial variations in practice, degree of opioid exposure, and hospital length of stay. METHODS: The Ohio Perinatal Quality Collaborative conducted an extensive multi-modal quality improvement initiative with the goal to (1) standardize identification, nonpharmacologic and pharmacologic treatment in level-2 and 3 NICUs in Ohio, (2) reduce the use of and length of treatment with opioids, and (3) reduce hospital length of stay in pharmacologically treated newborns with NAS. RESULTS: Fifty-two of 54 (96%) Ohio NICUs participated in the collaborative. Compliance with the nonpharmacologic bundle improved from 37% to 59%, and the pharmacologic bundle improved from 59% to 68%. Forty-eight percent of the 3266 opioid-exposed infants received pharmacologic treatment of symptoms of NAS, and this rate did not change significantly across the time period. Regardless of the opioid used to pharmacologically treat infants with NAS, the length of treatment decreased from 13.4 to 12.0 days, and length of stay decreased from 18.3 to 17 days. CONCLUSIONS: Standardized approaches to the identification and nonpharmacologic and pharmacologic care were associated with a reduced length of opioid exposure and hospital stay in a large statewide collaborative. Other states and institutions treating opioid-exposed infants may benefit from the adoption of these practices.

BACKGROUND: Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months’ corrected age. METHODS: Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants RESULTS: Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3–6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8–35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes. CONCLUSIONS: Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.

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.

* Abbreviations: CE — : comparative effectiveness OHRP — : Office for Human Research Protection ROP — : retinopathy of prematurity SUPPORT — : Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments As emphasized by the Institute of Medicine,1 the effectiveness of more than half of therapies used in clinical practice is unclear. High priority should be given to promoting comparative effectiveness (CE) trials, trials of alternative therapies performed to facilitate better informed and more evidence-based decisions by clinicians, patients, third-party payers, and policy makers.2,3 In such trials, the effectiveness of different treatment options is assessed under usual clinical circumstances across a broad range of patients treated clinically with these therapies. CE trials provide essential information to improve outcomes in everyday clinical practice that cannot be obtained from trials performed to assess the efficacy of a new experimental therapy. Such trials are conducted in ideal or restricted circumstances; enroll a limited number of carefully selected, and often uncomplicated, patients; and thus generally yield an optimistic view of efficacy. In comparing alternative therapies already used in clinical practice, CE trials have no “experimental” arm and no “control” arm, and the potential risks of one treatment are the potential benefits of the other. Yet CE trials fall under the same regulatory requirements for trials of experimental interventions never previously administered to patients. The appropriate regulation of CE trials was a central issue in a public meeting in August 2013 held by the Office for Human Research Protection (OHRP) in response to heated controversy regarding the SUPPORT (Surfactant, Positive Pressure, and Oxgenation Randomized Trial) published in 2010 by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.4 This 20-center CE trial included 1316 infants 24 to 27 weeks’ gestation randomized to oxygen saturation goals of 85% to 89% or 91% to 95%, the upper and lower ends of the goal range (85%–95%) suggested by the American Academy of Pediatrics. Caregivers were blinded to the … Address correspondence to Jon E. Tyson, MD, MPH, University of Texas Health Science Center at Houston, 6431 Fannin St, MSB 2.106, Houston, Texas 77030. E-mail: jon.e.tyson{at}uth.tmc.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:Our aim was to examine the impact of a single enteral dose of vitamin E on serum tocopherol levels. The study was undertaken to see whether a single dose of vitamin E soon after birth can rapidly increase the low α-tocopherol levels seen in very preterm infants. If so, this intervention could be tested as a means of reducing the risk of intracranial hemorrhage.METHODS:Ninety-three infants RESULTS:Eighty-eight infants received the study drug and were included in the analyses. The α-tocopherol levels were similar between the groups at baseline but higher in the vitamin E group at 24 hours (median 0.63 mg/dL vs 0.42 mg/dL, P = .003) and 7 days (2.21 mg/dL vs 1.86 mg/dL, P = .04). There were no differences between groups in γ-tocopherol levels. At 24 hours, 30% of vitamin E infants and 62% of placebo infants had α-tocopherol levels CONCLUSIONS:A 50-IU/kg dose of vitamin E raised serum α-tocopherol levels, but to consistently achieve α-tocopherol levels >0.5 mg/dL, a higher dose or several doses of vitamin E may be needed.

OBJECTIVE:To examine factors affecting center differences in mortality for extremely low birth weight (ELBW) infants.METHODS:We analyzed data for 5418 ELBW infants born at 16 Neonatal Research Network centers during 2006–2009. The primary outcomes of early mortality (≤12 hours after birth) and in-hospital mortality were assessed by using multilevel hierarchical models. Models were developed to investigate associations of center rates of selected interventions with mortality while adjusting for patient-level risk factors. These analyses were performed for all gestational ages (GAs) and separately for GAs RESULTS:Early and in-hospital mortality rates among centers were 5% to 36% and 11% to 53% for all GAs, 13% to 73% and 28% to 90% for GAs CONCLUSIONS:Center intervention rates explain a portion of the center variation in mortality, especially for infants born at

OBJECTIVE: Methods are required to predict prognosis with changes in clinical course. Death or neurodevelopmental impairment in extremely premature neonates can be predicted at birth/admission to the ICU by considering gender, antenatal steroids, multiple birth, birth weight, and gestational age. Predictions may be improved by using additional information available later during the clinical course. Our objective was to develop serial predictions of outcome by using prognostic factors available over the course of NICU hospitalization. METHODS: Data on infants with birth weight ≤1.0 kg admitted to 18 large academic tertiary NICUs during 1998–2005 were used to develop multivariable regression models following stepwise variable selection. Models were developed by using all survivors at specific times during hospitalization (in delivery room [n = 8713], 7-day [n = 6996], 28-day [n = 6241], and 36-week postmenstrual age [n = 5118]) to predict death or death/neurodevelopmental impairment at 18 to 22 months. RESULTS: Prediction of death or neurodevelopmental impairment in extremely premature infants is improved by using information available later during the clinical course. The importance of birth weight declines, whereas the importance of respiratory illness severity increases with advancing postnatal age. The c-statistic in validation models ranged from 0.74 to 0.80 with misclassification rates ranging from 0.28 to 0.30. CONCLUSIONS: Dynamic models of the changing probability of individual outcome can improve outcome predictions in preterm infants. Various current and future scenarios can be modeled by input of different clinical possibilities to develop individual “outcome trajectories” and evaluate impact of possible morbidities on outcome.

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

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

OBJECTIVE: To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia. DESIGN: Neonates were eligible for this prospective study if moderate or severe HIE occurred at RESULTS: There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n = 12) or discontinuous normal voltage (n = 12), or abnormal, with burst suppression (n = 22), continuous low voltage (n = 26), or flat tracing (n = 36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P = .19). CONCLUSIONS: The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE.

BACKGROUND: Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen. OBJECTIVE: To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers. METHODS: Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ≤72 hours plus treatment with antibiotic therapy for ≥5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence. RESULTS: Among 396 586 LBs (2006–2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%). CONCLUSION: In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.

OBJECTIVE: We aimed to reduce late-onset bacterial infections in infants born at 22 to 29 weeks' gestation by using collaborative quality-improvement methods to implement evidence-based catheter care. We hypothesized that these methods would result in a 50% reduction in nosocomial infection. PATIENTS AND METHODS: We conducted an interrupted time-series study among 24 Ohio NICUs. The intervention began in September 2008 and continued through December 2009. Sites used the Institute for Healthcare Improvement Breakthrough Series quality-improvement model to facilitate implementation of evidence-based catheter care. Data were collected monthly for all catheter insertions and for at least 10 observations of indwelling catheter care. NICUs also submitted monthly data on catheter-days, patient-days, and episodes of infection. Data were analyzed by using statistical process control methods. RESULTS: During the intervention, NICUs submitted information on 1916 infants. Of the 242 infections reported, 69% were catheter associated. Compliance with catheter-insertion components was >90% by April 2009. Compliance with components of evidence-based indwelling catheter care reached 80.4% by December 2009. There was a significant reduction in the proportion of infants with at least 1 late-onset infection from a baseline of 18.2% to 14.3%. CONCLUSIONS: There was a 20% reduction in the incidence of late-onset infection after the intervention, but the magnitude was less than hypothesized, perhaps because compliance with components of evidence-based care of indwelling catheters remained

OBJECTIVE: Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low birth weight ( METHODS: The study involved a prospective observational cohort of infants ≤1000 g birth weight at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures were obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: (1) potentially modifiable risk factors; and (2) a clinical model at time of blood culture to predict candidiasis. RESULTS: Invasive candidiasis occurred in 137 of 1515 (9.0%) infants and was documented by positive culture from ≥1 of these sources: blood (n = 96); cerebrospinal fluid (n = 9); urine obtained by catheterization (n = 52); or other sterile body fluid (n = 10). Mortality rate was not different for infants who had positive blood culture compared with those with isolated positive urine culture. Incidence of candida varied from 2% to 28% at the 13 centers that enrolled ≥50 infants. Potentially modifiable risk factors included central catheter, broad-spectrum antibiotics (eg, third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model had an area under the receiver operating characteristic curve of 0.79 and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis. CONCLUSION: Previous antibiotics, presence of a central catheter or endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment.

OBJECTIVE. Postnatal steroid use decreases lung inflammation but increases impairment. We hypothesized that increased dose is associated with increased neurodevelopmental impairment, lower postmenstrual age at exposure increases impairment, and risk of bronchopulmonary dysplasia modifies the effect of postnatal corticosteroid.METHODS. Steroid dose and timing of exposure beyond 7 days was assessed among 2358 extremely low birth weight infants nested in a prospective trial, with 1667 (84%) survivors examined at 18 to 22 months' postmenstrual age. Logistic regression tested the relationship between impairment (Bayley Mental Developmental Index/Psychomotor Developmental Index of 0.5 as high risk, n = 2336 (99%) for days of life 4–7).RESULTS. Three hundred sixty-six (16%) neonates were steroid-treated (94% dexamethasone). Treated neonates were smaller and less mature; 72% of those treated were at high risk for bronchopulmonary dysplasia. Exposure was associated with neurodevelopmental impairment/death. Impairment increased with higher dose; 71% dead or impaired at highest dose tertile. Each 1 mg/kg dose was associated with a 2.0-point reduction on the Mental Developmental Index and a 40% risk increase for disabling cerebral palsy. Older age did not mitigate the harm. Treatment after 33 weeks' postmenstrual age was associated with greatest harm despite not receiving the highest dose. The relationship between steroid exposure and impairment was modified by the bronchopulmonary dysplasia risk, with those at highest risk experiencing less harm.CONCLUSIONS. Higher steroid dose was associated with increased neurodevelopmental impairment. There is no “safe” window for steroid use in extremely low birth weight infants. Neonates with low bronchopulmonary dysplasia risk should not be exposed. A randomized trial of steroid use in infants at highest risk is warranted.

BACKGROUND. Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial. OBJECTIVE. Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age. DESIGN/METHODS. A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups. RESULTS. Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non–central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5°C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories. CONCLUSIONS. Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability.

OBJECTIVES: To evaluate the generalizability of stringent protocol-driven weaning in improving total duration of opioid treatment and length of inpatient hospital stay after treatment of neonatal abstinence syndrome (NAS). METHODS: We conducted a retrospective cohort analysis of 981 infants who completed pharmacologic treatment of NAS with methadone or morphine from January 2012 through August 2014. Before July 2013, 3 of 6 neonatology provider groups (representing Ohio’s 6 children’s hospitals) directed NAS nursery care by using group-specific treatment protocols containing explicit weaning guidelines. In July 2013, a standardized weaning protocol was adopted by all 6 groups. Statistical analysis was performed to identify effects of adoption of the multicenter weaning protocol on total duration of opioid treatment and length of hospital stay at the protocol-adopting sites and at the sites with preexisting protocol-driven weaning. RESULTS: After adoption of the multicenter protocol, infants treated by the 3 groups previously without stringent weaning guidelines experienced shorter duration of opioid treatment (23.0 vs 34.0 days, P < .001) and length of inpatient hospital stay (23.7 vs 31.6 days, P < .001). Protocol-adopting sites also experienced a lower rate of adjunctive drug therapy (5% vs 21%, P = .004). Outcomes were sustained by the 3 groups who initially had specific weaning guidelines after multicenter adoption (duration of treatment = 17.0 days and length of hospital stay = 23.3 days). CONCLUSIONS: Adoption of a stringent weaning protocol resulted in improved NAS outcomes, demonstrating generalizability of the protocol-driven weaning approach. Opportunity remains for additional protocol refinement.

OBJECTIVE. The goals were to identify predictor variables and to develop scoring systems and classification trees to predict death/disability or death in infants with hypoxic-ischemic encephalopathy.METHODS. Secondary analysis of data from the multicenter, randomized, controlled, National Institute of Child Health and Human Development Neonatal Research Network trial of hypothermia in hypoxic-ischemic encephalopathy was performed. Data for 205 neonates diagnosed as having hypoxic-ischemic encephalopathy were studied. Logistic regression analysis was performed by using clinical and laboratory variables available within 6 hours of birth, with death or moderate/severe disability at 18 to 22 months or death as the outcomes. By using the identified variables and odds ratios, scoring systems to predict death/disability or death were developed, weighting each predictor in proportion to its odds ratio. In addition, classification and regression tree analysis was performed, with recursive partitioning and automatic selection of optimal cutoff points for variables. Correct classification rates for the scoring systems, classification and regression tree models, and early neurologic examination were compared.RESULTS. Correct classification rates were 78% for death/disability and 71% for death with the scoring systems, 80% and 77%, respectively, with the classification and regression tree models, and 67% and 73% with severe encephalopathy in early neurologic examination. Correct classification rates were similar in the hypothermia and control groups.CONCLUSIONS. Among neonates diagnosed as having hypoxic-ischemic encephalopathy, the classification and regression tree model, but not the scoring system, was superior to early neurologic examination in predicting death/disability. The 3 models were comparable in predicting death. Only a few components of the early neurologic examination were associated with poor outcomes. These scoring systems and classification trees, if validated, may help in assessments of prognosis and may prove useful for risk-stratification of infants with hypoxic-ischemic encephalopathy for clinical trials.

Despite improvements in neonatal care, bronchopulmonary dysplasia (BPD) continues to occur in approximately one third of newborns who have birth weights of

OBJECTIVES:To compare pharmacologic treatment strategies for neonatal abstinence syndrome (NAS) with respect to total duration of opioid treatment and length of inpatient hospital stay.METHODS:We conducted a cohort analysis of late preterm and term neonates who received inpatient pharmacologic treatment of NAS at one of 20 hospitals throughout 6 Ohio regions from January 2012 through July 2013. Physicians managed NAS using 1 of 6 regionally based strategies.RESULTS:Among 547 pharmacologically treated infants, we documented 417 infants managed using an established NAS weaning protocol and 130 patients managed without protocol-driven weaning. Regardless of the treatment opioid chosen, when we accounted for hospital variation, infants receiving protocol-based weans experienced a significantly shorter duration of opioid treatment (17.7 vs 32.1 days, P < .0001) and shorter hospital stay (22.7 vs 32.1 days, P = .004). Among infants receiving protocol-based weaning, there was no difference in the duration of opioid treatment or length of stay when we compared those treated with morphine with those treated with methadone. Additionally, infants treated with phenobarbital were treated with the drug for a longer duration among those following a morphine-based compared with methadone-based weaning protocol. (P ≤ .002).CONCLUSIONS:Use of a stringent protocol to treat NAS, regardless of the initial opioid chosen, reduces the duration of opioid exposure and length of hospital stay. Because the major driver of cost is length of hospitalization, the implications for a reduction in cost of care for NAS management could be substantial.

OBJECTIVE: Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care. METHODS: Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics. RESULTS: A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41–3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001). CONCLUSIONS: Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.

BACKGROUND. Postnatal corticosteroids were widely used in the 1990s in an attempt to reduce the incidence of bronchopulmonary dysplasia. However, high rates of short-term adverse effects and impaired neurodevelopmental outcomes were seen. In early 2002, a joint statement of the American Academy of Pediatrics and Canadian Paediatric Society called for limitation in the use of postnatal corticosteroids. The impact of this statement is not known. OBJECTIVES. The purpose of this work was to determine the frequency of postnatal corticosteroid use and mortality and morbidities over time, particularly before and after the joint statement. DESIGN/METHODS. We conducted a retrospective analysis of cohort data within 3 large network registries (the National Institute of Child Health and Development Neonatal Research Network [18 centers], the Vermont Oxford Network [444 centers], and the Canadian Neonatal Network [10 centers]) for the following 3 periods: prestatement (2001), statement (2002), and poststatement (2003) of very low birth-weight infants (501–1500 g). The National Institute of Child Health and Development Neonatal Research Network and the Vermont Oxford Network were also analyzed for longer-term trends from 1990 to 2003. Postnatal corticosteroid use, mortality at discharge, and neonatal morbidities (bronchopulmonary dysplasia at 36 weeks, late-onset infection >72 hours of age, necrotizing enterocolitis treated with surgery, and length of stay) between periods were compared. RESULTS. Mean birth weight (range: 1022–1060 g), postmenstrual age (28 weeks), and gender (51% male) were similar between the networks. Race differed with more black infants in the National Institute of Child Health and Development Neonatal Research Network than the Vermont Oxford Network (38% vs 24%). Antenatal steroid use was similar (range: 61%–75%). Postnatal corticosteroid use rose from 1990 (8%–16%), peaked in 1996–1998 (24%–28%), and began to decline in 1999. Use in 2003 was significantly less than in 2001. Mortality and major morbidities were similar. CONCLUSIONS. Postnatal corticosteroid use had decreased significantly in 3 large neonatal networks before the joint statement with further decreases after the statement with no apparent impact on mortality and short-term morbidity. Despite substantial decreases, ∼8% of very low birth-weight infants continue to be treated with postnatal corticosteroid.

BACKGROUND. Hypocarbia and hyperoxia are risk factors for periventricular leukomalacia in low birth weight infants. The association of a cumulative index of exposure to hypocarbia and hyperoxia and periventricular leukomalacia has not been evaluated.OBJECTIVE. Our goal was to examine the relationship between cumulative index of exposure to hypocarbia and hyperoxia and periventricular leukomalacia during the first 7 days of life in low birth weight infants.METHODS. Blood gas results were recorded in 6-hour intervals among low birth weight infants in a prospective data registry. Cumulative index of exposure to hypocarbia was calculated as the difference between arterial carbon dioxide level and 35 mmHg multiplied by the time interval in hours for each 6-hour block in a 24-hour day for the first 7 days of life. Cumulative index of exposure to hyperoxia was calculated in the same manner for arterial oxygen level >80 mm Hg. The relationship between exposure to hypocarbia, hyperoxia, and periventricular leukomalacia was examined in 778 infants with blood gas and cranial sonography data.RESULTS. Twenty-one infants had periventricular leukomalacia. Hypocarbia occurred in 489 infants and hyperoxia in 502 infants. Infants with periventricular leukomalacia were more likely to have a lower gestational age and to require delivery room resuscitation than those without periventricular leukomalacia. More infants in the highest quartile of exposure to hypocarbia had periventricular leukomalacia compared to those with no hypocarbia. Risk of periventricular leukomalacia was increased in infants with the highest quartile of exposure to hypocarbia after adjusting for maternal and neonatal variables, none to be associated with periventricular leukomalacia. Cumulative index exposure to hyperoxia was not related to periventricular leukomalacia.CONCLUSIONS. Cumulative exposure to hypocarbia and not hyperoxia was independently related to risk of periventricular leukomalacia in low birth weight infants.

Objective. A number of definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease, have been used. A June 2000 National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute Workshop proposed a severity-based definition of BPD for infants Methods. Data from 4866 infants (birth weight ≤1000 g, GA Results. A total of 77% of the neonates met the 28-days definition, and 44% met the 36-weeks definition. Using the consensus BPD definition, 77% of the infants had BPD, similar to the cohort identified by the 28-days definition. A total of 46% of the infants met the moderate (30%) or severe (16%) consensus definition criteria, identifying a similar cohort of infants as the 36-weeks definition. Of infants who met the 28-days definition and 36-weeks definition and were seen at follow-up at 18 to 22 months’ corrected age, 40% had been treated with pulmonary medications and 35% had been rehospitalized for pulmonary causes. In contrast, as the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up.Conclusion. The consensus BPD definition identifies a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy more accurately than other definitions.

Objective. Oxygen delivery through nasal cannulae to convalescent preterm infants is a common but largely unstudied practice. To learn more about current nasal cannula oxygen delivery practices, we examined the variations in oxygen delivery through nasal cannulae among the centers of the Neonatal Research Network, the frequency of prescription of low levels of oxygen, and the success of weaning to room air. We hypothesized that some infants treated with oxygen through nasal cannulae were receiving oxygen levels equivalent to those of room air.Methods. This was a descriptive, nested, cohort study of nasal cannula oxygen prescription among 187 infants with birth weights of Results. Fifty-two infants (27.8%) were receiving oxygen concentrations and flow rates through nasal cannulae that delivered an effective Fio2 of Conclusions. Prescription of oxygen with combinations of flow rates and oxygen concentrations that delivered a low effective Fio2 was common. We speculate that some of this, including the inadvertent prescription of an effective Fio2 equivalent to that of room air, is related to lack of knowledge of the effective Fio2. Routine calculation of effective Fio2 values may prompt earlier trials of room air and thus reduce unnecessary days of oxygen therapy.

Objective. This study was designed to test whether rotation of antibiotics can reduce colonization with resistant Gram-negative bacilli in a neonatal intensive care unit (NICU). Methods. A monthly rotation of gentamicin, piperacillin-tazobactam, and ceftazidime was compared with unrestricted antibiotic use in side-by-side NICU populations (rotation team vs control team). Pharyngeal and rectal samples were obtained 3 times a week and tested for Gram-negative bacilli resistant to each of the rotation antibiotics. Pulsed-field gel electrophoresis analysis determined the numbers of genetically discordant resistant organisms on each team. The association between colonization with a resistant bacillus (the primary outcome) and team assignment was tested. Results. A total of 1062 infants were studied during a 1-year period. A total of 10.7% infants on the rotation team versus 7.7% on the control team were colonized with a resistant bacillus. No interteam differences were distinguishable when the numbers of genetically discordant resistant organisms were normalized to the total number of team admissions. The incidence of nosocomial infection and mortality also were similar across teams. Conclusion. These data indicate that rotation of parenteral antibiotics according to the applied protocol has no detectable effect in decreasing the reservoir of resistant Gram-negative bacilli in a tertiary-care NICU.

Objectives. In the era before widespread use of inhaled nitric oxide, to determine the prevalence of persistent pulmonary hypertension (PPHN) in a multicenter cohort, demographic descriptors of the population, treatments used, the outcomes of those treatments, and variation in practice among centers. Study Design. A total of 385 neonates who received ≥50% inspired oxygen and/or mechanical ventilation and had documented evidence of PPHN (2D echocardiogram or preductal or postductal oxygen difference) were tracked from admission at 12 Level III neonatal intensive care units. Demographics, treatments, and outcomes were documented. Results. The prevalence of PPHN was 1.9 per 1000 live births (based on 71 558 inborns) with a wide variation observed among centers (.43–6.82 per 1000 live births). Neonates with PPHN were admitted to the Level III neonatal intensive care units at a mean of 12 hours of age (standard deviation: 19 hours). Wide variations in the use of all treatments studied were found at the centers. Hyperventilation was used in 65% overall but centers ranged from 33% to 92%, and continuous infusion of alkali was used in 75% overall, with a range of 27% to 93% of neonates. Other frequently used treatments included sedation (94%; range: 77%–100%), paralysis (73%; range: 33%–98%), and inotrope administration (84%; range: 46%–100%). Vasodilator drugs, primarily tolazoline, were used in 39% (range: 13%–81%) of neonates. Despite the wide variation in practice, there was no significant difference in mortality among centers. Mortality was 11% (range: 4%–33%). No specific therapy was clearly associated with a reduction in mortality. To determine whether the therapies were equivalent, neonates treated with hyperventilation were compared with those treated with alkali infusion. Hyperventilation reduced the risk of extracorporeal membrane oxygenation without increasing the use of oxygen at 28 days of age. In contrast, the use of alkali infusion was associated with increased use of extracorporeal membrane oxygenation (odds ratio: 5.03, compared with those treated with hyperventilation) and an increased use of oxygen at 28 days of age. Conclusions. Hyperventilation and alkali infusion are not equivalent in their outcomes in neonates with PPHN. Randomized trials are needed to evaluate the role of these common therapies.

In Reply .— We agree entirely with Dr Beckerman's concern that a 30-minute trial of room air should not be the basis for continued treatment of recovering very low birth weight infants with room air. The physiologic definition of bronchopulmonary dysplasia was developed to …

The long-term outcome of very low birth weight (VLBW) infants with necrotizing enterocolitis has been reported to be similar to that of other VLBW infants. To examine the influence of disease severity on outcome, the growth and neurodevelopment of survivors of necrotizing enterocolitis were evaluated when the babies were 20 months' corrected age. Between 1975 and 1983, 1506 VLBW infants were admitted to the hospital, and necrotizing enterocolitis developed in 84 (5.6%). Forty infants (48%) survived to be 20 months' corrected age, and complete follow-up data were available for 36. Survivors were classified by modified Bell's criteria into four groups by increasing severity of disease; 13 had mild necrotizing enterocolitis (stage IIA, IIB), and 23 had severe necrotizing enterocolitis (stage IIIA, IIIB). The 36 survivors were compared with 766 surviving VLBW infants without necrotizing enterocolitis. There were no perinatal or socioeconomic differences between groups. Compared with infants with stage II necrotizing enterocolitis at 20 months, infants with stage III necrotizing enterocolitis had a higher rate of subnormal body weight (39% vs 15%) and subnormal head circumference (30% vs 0%). Thirty-three percent of necrotizing enterocolitis survivors had significant neurodevelopmental impairment; the majority of impaired infants (10 of 12) were survivors of stage III necrotizing enterocolitis. These findings highlight the importance of continued evaluations for medical and neurodevelopmental sequelae.