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1.  Death or Neurodevelopmental Impairment at 18 To 22 Months in a Randomized Trial of Early Dexamethasone to Prevent Death or Chronic Lung Disease in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2013;164(1):34-39.e2.
To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18 to 22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants.
Evaluation of infants at 18 to 22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI). NDI was defined as moderate or severe cerebral palsy, MDI or PDI less than 70, blindness, or hearing impairment.
Death or NDI at 18 to 22 months corrected age was similar in the dexamethasone and placebo groups (65 vs 66 percent, p= 0.99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50 vs 41 percent, p=0.42 for weight less than 10th percentile). Forty nine percent of infants in the placebo group received treatment with corticosteroid compared to 32% in the dexamethasone group (p=0.02).
The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.
PMCID: PMC4120744  PMID: 23992673
neurodevelopmental outcome; growth; bronchopulmonary dysplasia; cerebral palsy; neonatal follow-up
2.  The investment case for preventing NICU-associated infections 
American journal of perinatology  2012;30(3):179-184.
Nosocomial (hospital-associated or NICU-associated) infections occur in as many as 10–36% of very low birth weight infants cared for in newborn intensive care units (NICU).
To determine the potentially avoidable, incremental costs of care associated with NICU-associated bloodstream infections.
Study Design
This is a retrospective study that included all NICU admissions of infants 401–1500 grams birth weight in the greater Cincinnati region from January 1, 2005 through December 31, 2007. Non-physician costs of care were compared between infants who developed at least one bacterial bloodstream infection prior to NICU discharge or death and infants who did not. Costs were adjusted for clinical and demographic characteristics that are present in the first three days of life and are known associates of infection.
Among 900 study infants with no congenital anomaly and no major surgery, 82 (9.1%) developed at least one bacterial bloodstream infection. On average, the cost of NICU care was $16,800 greater per infant who experienced NICU-associated bloodstream infection.
Potentially avoidable costs of care associated with bloodstream infection can be used to justify investments in the reliable implementation of evidence-based interventions designed to prevent these infections.
PMCID: PMC3789586  PMID: 22836823
quality improvement; investment case; nosocomial infection
3.  Brain injury following trial of hypothermia for neonatal hypoxic–ischaemic encephalopathy 
The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic–ischaemic encephalopathy treated with hypothermia.
Design and patients
Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18–22 months of age.
Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability.
Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18–22 months following hypothermia for neonatal encephalopathy.
PMCID: PMC3722585  PMID: 23080477
4.  Using Improvement Science to Increase Accuracy and Reliability of Gestational Age Documentation 
American journal of perinatology  2011;29(3):217-224.
Our aim was to improve the reliability of recording gestational age (GA) in the mother’s obstetric record, as this record is used for clinical management, research databases, and eventual transmission to the Ohio Department of Health birth certificates. We performed a prospective cohort study, including all hospital births. We began quality improvement interventions in October 2009. Improvement test cycles were targeted to four working groups, including nursing staff, community obstetric providers, and the process itself. Test cycle results were evaluated to determine which successful interventions could spread further. Rates of process outcome measurements were compared by statistical process control and univariate analysis pre- and postintervention. During the preintervention period, the median daily GA reliability was 25%. To date, over 30 small sample size tests of change have been completed. Of 8795 births studied, significant improvement in GA accuracy/completeness was detected (median postintervention =78%, p <0.01). Increased communication of and completion of the prenatal record, in addition to GA recording in high-risk groups, such as premature infants, were also achieved (all p <0.01). GA reliability can be increased using standardized improvement science methods. Better communication of GA will enable better clinical decisions and foster population-based perinatal research.
PMCID: PMC3615548  PMID: 21809263
Gestational age; electronic medical record; birth certificate; vital statistics; quality improvement
5.  In their own words: Adolescent views on ADHD and their evolving role managing medication 
Academic Pediatrics  2011;12(1):53-61.
Up to 90% of adolescents with ADHD remain functionally impaired, yet less than half continue to take medication. The objective of this study was to gain a detailed understanding of how adolescents with ADHD contribute to medication treatment decisions.
44 adolescents with ADHD aged 13 to 18 years old participated in 1 of 7 focus groups. An experienced facilitator used a semi-structured focus group guide to prompt discussion which was audio-recorded and transcribed verbatim. We coded transcripts using an inductive approach. Thematic saturation was reached after the seventh focus group.
Adolescents assumed increased responsibility for managing medication as they matured and developed insight into the functional impact of ADHD and medication on their lives. Insights were often formed by contrasting time spent on and off medication. ADHD impacted functioning in the following domains: academics, social interactions and relationships, creativity, and driving skills. Select domains were relevant for some adolescents but not others. Adolescents described different roles that they played in managing medication as well as strategies they employed to exert autonomy over medication use. Side effects were common and contributed to negative feelings toward medication. Some adolescents had begun to use medication selectively. Many expressed uncertainty about future use of medication.
Adolescents assume an increasing role in managing medication for ADHD. Well-structured and coordinated trials stopping medication and measuring outcomes relevant to adolescents, parents, teachers, doctors, and/or other stakeholders may help ensure a developmentally appropriate transition from family to self-management of ADHD.
PMCID: PMC3259217  PMID: 22133501
Adolescent; ADHD; Self-Management; Decision-Making; Transition
6.  Cytokines and Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2011;159(6):919-925.e3.
To determine if selected pro-inflammatory and anti-inflammatory cytokines/mediators of inflammation reported to be related to development of cerebral palsy predict neurodevelopmental outcome in extremely low birth weight infants.
Study design
Infants with birth weights ≤ 1000 g (n=1067) had blood samples collected at birth and on days 3±1, 7±1, 14±3, and 21±3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on five cytokines (IL-1β, IL-8, TNF-α, RANTES, and IL-2) reported to be most predictive of CP in term and late preterm infants.
IL-8 was higher on days 0–4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, TNF-β, SIL-rα, MIP-1β) were found to be altered on days 0–4 in infants who developed CP.
CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.
PMCID: PMC3215787  PMID: 21798559
7.  Predictive Value of an Early Amplitude Integrated Electroencephalogram and Neurologic Examination 
Pediatrics  2011;128(1):e112-e120.
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.
Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months.
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).
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.
PMCID: PMC3124102  PMID: 21669899
neonatal hypoxic-ischemic encephalopathy; amplitude integrated EEG
8.  Effects of Delayed Cord Clamping in Very Low Birth Weight Infants 
Journal of Perinatology  2011;31(Suppl 1):S68-S71.
Delayed cord clamping may be beneficial in very preterm and low birth weight infants.
Study Design
A randomized unmasked controlled trial
The study was performed in three centers of the NICHD Neonatal Research Network
Delayed cord clamping in very preterm and very low birth weight infants will result in an increase in hematocrit at 4 hours of age.
Infants with a gestational age of 24-28 weeks were randomized into early (< 10 seconds) or delayed (30-45 seconds) cord clamping. The primary outcome was venous hematocrit at 4 hours of age. Secondary outcomes included delivery room management, selected neonatal morbidities and the need for blood transfusion during the infants’ hospital stay.
Thirty three infants were randomized: 17 to the immediate cord clamping (ICC, cord clamped at 7.9 ± 5.2 seconds, m±SD) and 16 to the delayed cord clamping (DCC, cord clamped at 35.2 ± 10.1 seconds) group. The hematocrit was higher in the DCC group (45 ± 8 versus 40 ± 5%, p<0.05). The frequency of events during delivery room resuscitation was almost identical between the two groups. There was no difference in hourly mean arterial blood pressure during the first 12 hours of life, there was a trend in the difference in the incidence of selected neonatal morbidities, hematocrit at 2, 4 and 6 weeks as well as the need for transfusion, but none of the differences was statistically significant
A higher hematocrit is achieved by delayed cord clamping in very low birth weight infants suggesting effective placental transfusion.
PMCID: PMC3327157  PMID: 21448208
9.  Clinical Seizures in Neonatal Hypoxic-Ischemic Encephalopathy Have No Independent Impact on Neurodevelopmental Outcome: Secondary Analyses of Data from the Neonatal Research Network Hypothermia Trial 
Journal of Child Neurology  2010;26(3):322-328.
It remains controversial as to whether neonatal seizures have additional direct effects on the developing brain separate from the severity of the underlying encephalopathy. Using data collected from infants diagnosed with hypoxic-ischemic encephalopathy, and who were enrolled in an National Institute of Child Health and Human Development trial of hypothermia, we analyzed associations between neonatal clinical seizures and outcomes at 18 months of age. Of the 208 infants enrolled, 102 received whole body hypothermia and 106 were controls. Clinical seizures were generally noted during the first 4 days of life and rarely afterward. When adjustment was made for study treatment and severity of encephalopathy, seizures were not associated with death, or moderate or severe disability, or lower Bayley Mental Development Index scores at 18 months of life. Among infants diagnosed with hypoxic-ischemic encephalopathy, the mortality and morbidity often attributed to neonatal seizures can be better explained by the underlying severity of encephalopathy.
PMCID: PMC3290332  PMID: 20921569
neonatal seizures; whole-body hypothermia; neurodevelopmental outcome; hypoxic-ischemic encephalopathy
10.  Association between Urinary Lactate to Creatinine Ratio and Neurodevelopmental Outcome in Term Infants with Hypoxic-Ischemic Encephalopathy 
The Journal of pediatrics  2008;153(3):375-378.
To assess the association between urinary lactate to creatinine ratio (ULCR) and neurodevelopmental outcome in term infants with hypoxic ischemic encephalopathy and examine the effect of hypothermia on the change in ULCR.
Study design
Spot urine samples were collected in 58 term infants (28 hypothermia, 30 control subjects) with hypoxic ischemic encephalopathy. Urinary lactate and creatinine were measured by using 1H nuclear magnetic resonance spectroscopy and expressed as ULCR. Survivors were examined at 18 months of age.
The ULCR was significantly higher in infants who died or had moderate/severe neurodevelopmental disability. Logistic regression analysis controlling for hypothermia and severity of encephalopathy confirmed the association (adjusted odds ratio, 5.52; 95% CI, 1.36, 22.42; P < .02). Considerable overlap in ULCR was observed between infants with normal/mild disability and those who died or survived with moderate/severe disability. ULCR fell significantly between 6 and 24 hours and 48 and 72 hours of age for all infants. The magnitude of decline did not differ between hypothermia and control groups.
High ULCR is associated with death or moderate/severe neurodevelopmental disability. Significant overlap in values between the normal/mild and moderate/severe disability groups limits predictive value of this measure. Whole-body hypothermia did not affect the decline in ULCR.
PMCID: PMC2953792  PMID: 18534246
11.  Epidemiology of Necrotizing Enterocolitis Temporal Clustering in Two Neonatology Practices 
The Journal of pediatrics  2008;154(5):656-661.
To develop a statistical method for defining clusters of necrotizing enterocolitis (NEC) cases in the neonatal intensive care unit (NICU).
Study design
2782 infants, between 1996–2004, weighing 401–1500 grams at birth were included. NEC was defined as Bell stage II or III. Two statistical methods used to define “disease clusters” were: (1) modified scan test; (2) comparison of observed and expected incidence density rates (IDR) of NEC at each NICU.
The proportion of infants with NEC was similar between NICUs (7.1% vs. 7.7%; p=0.6) as was the expected IDR of NEC (1.39/1000 patient-days vs. 1.32/1000 patient-days, p=0.72). Twelve temporal clusters of NEC were identified in the NICUs combined, comprising 18% of 203 total NEC cases during the study period. No seasonal/secular trends were noted for NEC rates or identified clusters. Potential NEC clusters of ≥3 cases at either NICU had >75% chance of being a true NEC cluster.
No operational definition of NEC cluster exists. This study introduced methods to be employed for prospective surveillance and guide studies to investigate etiologic relevance. Utilizing the proposed methods, statistically significant clusters (potential outbreaks) of NEC within NICUs can be identified early, providing early opportunity to implement cluster investigation protocols.
PMCID: PMC2700364  PMID: 19111317
disease clusters; outbreaks; neonatal intensive care unit; very low birth weight infants
12.  Use of a body proportionality index for growth assessment of preterm infants 
The Journal of pediatrics  2008;154(4):486-491.
We evaluated the utility of weight-for-length (defined as gm/cm3, “ponderal index”) as a complementary measure of growth in infants in neonatal intensive care units (NICUs).
Study design
Secondary analysis of infants (n=1214) 26-29 weeks at birth, included in a registry database (1991-2003), who had growth data at birth and discharge. Weight-for-age and weight-for-length were categorized as small (<10th percentile), appropriate or large (>90th percentile).
Statistical agreement between the weight-for-age and weight-for-length measures was poor (kappa=0.02 at birth, 0.10 at discharge, Bowker test for symmetry p<0.0001). From birth to discharge, the percent of small-for-age infants increased from 12% to 21%, and the percent of small-for-length infants decreased from 10% to 4%; the percent of large-for-age infants remained similar (<1%), and the percent of large-for-length infants increased from 5% to 17%. At discharge, 92% of small-for-age infants were appropriate or large-for-length, and 19% of appropriate-for-age infants were large-for-length.
Weight-for-age and weight-for-length are complementary measures. Weight-for-length or other measure of body proportionality should be considered for inclusion in routine growth monitoring of infants in the NICU.
PMCID: PMC2745983  PMID: 19041096
Growth status; growth; weight-for-age; weight/length3; ponderal index; weight/length ratio; obesity; overweight; underweight; small-for-gestational age; nutrition
13.  Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight 
It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).
We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.
Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 μmol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P = 0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.
Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials. gov number, NCT00114543.)
PMCID: PMC2821221  PMID: 18971491

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