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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.
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.jpeds.2013.07.027
PMCID: PMC4120744  PMID: 23992673
neurodevelopmental outcome; growth; bronchopulmonary dysplasia; cerebral palsy; neonatal follow-up
2.  Is phototherapy exposure associated with better or worse outcomes in 501–1000 gram birth weight infants? 
Aim
To compare risk-adjusted outcomes at 18–22 months corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy.
Methods
Outcomes at 18–22 months corrected age included death, neurodevelopmental impairment (NDI), and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for center and other potentially confounding variables.
Results
Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501–1000 g BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI 0.60 –1.20), death, or adverse neurodevelopmental endpoints. However, among infants 501–750 g BW, the rate of significant developmental impairment with MDI<50 was significantly higher for NoPTx (29%) than PTx (12%) (p=0.004).
Conclusions
Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded due to bias from deaths before reaching conservative treatment threshold. The higher rate of MDI<50 in the 501–750g BW NoPTx group is concerning, and consistent with NRN Trial results.
doi:10.1111/j.1651-2227.2011.02175.x
PMCID: PMC3505994  PMID: 21272067
3.  Prenatal Cocaine Exposure and Small-for-Gestational-Age Status: Effects on Growth at 6 Years of age 
Neurotoxicology and teratology  2011;33(5):575-581.
OBJECTIVE
To evaluate the impact of prenatal cocaine exposure and small-for-gestational-age (SGA) status on childhood growth.
STUDY DESIGN
Cocaine exposure was defined by history or meconium metabolites. Hierarchical linear modeling was used to examine cocaine exposure and SGA status on growth, while controlling for exposure to other drugs and alcohol use.
RESULTS
At birth cocaine-exposed infants (n=364) had significantly lower growth parameters compared to non-exposed children (n=771). At 6 years, weight was similar between exposed and unexposed children. SGA infants continued to be growth impaired. There was a significant interaction between prenatal cocaine exposure and SGA status at 6 years. The negative effects of cocaine on weight and height were greater among non-SGA than SGA children (432 vs. 280 gm, and 0.7 and 0.5 cm, respectively) while negative effects of SGA status on weight and height were larger in non-cocaine exposed compared to the exposed children (2.3 kg vs.1.6 kg and 2.2 and 1.0 cm).
CONCLUSIONS
Children exposed to prenatal cocaine were similar in weight to non-exposed children at 6 years of age. Cocaine had an unexplained greater detrimental effect on non-SGA than SGA children. SGA status at birth has an independent detrimental effect on childhood growth.
doi:10.1016/j.ntt.2011.04.003
PMCID: PMC3183411  PMID: 21849244
Prenatal cocaine exposure; small for gestational age; childhood growth
4.  Predictive Value of an Early Amplitude Integrated Electroencephalogram and Neurologic Examination 
Pediatrics  2011;128(1):e112-e120.
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 <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months.
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.
doi:10.1542/peds.2010-2036
PMCID: PMC3124102  PMID: 21669899
neonatal hypoxic-ischemic encephalopathy; amplitude integrated EEG
5.  Effects of Delayed Cord Clamping in Very Low Birth Weight Infants 
Journal of Perinatology  2011;31(Suppl 1):S68-S71.
Background
Delayed cord clamping may be beneficial in very preterm and low birth weight infants.
Study Design
A randomized unmasked controlled trial
Setting
The study was performed in three centers of the NICHD Neonatal Research Network
Hypothesis
Delayed cord clamping in very preterm and very low birth weight infants will result in an increase in hematocrit at 4 hours of age.
Methods
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.
Results
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
Conclusion
A higher hematocrit is achieved by delayed cord clamping in very low birth weight infants suggesting effective placental transfusion.
doi:10.1038/jp.2010.186
PMCID: PMC3327157  PMID: 21448208
6.  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.
doi:10.1177/0883073810380915
PMCID: PMC3290332  PMID: 20921569
neonatal seizures; whole-body hypothermia; neurodevelopmental outcome; hypoxic-ischemic encephalopathy
7.  Twin Gestation and Neuro-developmental Outcome in Extremely Low Birth Weight Infants 
Pediatrics  2009;123(2):e220-e227.
Objective
To compare the risk-adjusted incidence of death or neuro-developmental impairment at 18–22 months corrected age, between twin and singleton extremely low birth weight infants.
Hypothesis
Twin gestation is independently associated with increased risk of death or adverse neuro-developmental outcomes at 18–22 months corrected age in extremely low birth weight infants.
Design/Methods
Retrospective study of inborn extremely low birth weight infants (BW 401– 1000g) admitted to NICHD Neonatal Research Network units between 1997 and 2005, who either died or had follow-up data available at 18–22 months corrected age. Neuro-developmental impairment (NDI), the primary outcome variable, was defined as the presence of any one of the following: moderate or severe cerebral palsy, severe bilateral hearing loss needing amplification, bilateral blindness, Bayley Mental Developmental Index or Psychomotor Developmental Index of less than 70. Death was included with NDI as a composite outcome since it is a competing variable. Results were compared for both twins, twin A, twin B, same sex twins, unlike sex twins and singleton infants. Logistic regression analysis was done to control for demographic and clinical factors that were different among the groups.
Results
The cohort of infants who either died or were assessed for NDI consisted of 7,630 singleton infants and 1,376 twins. Logistic regression adjusting for clinical and socio-demographic risk factors showed an increased risk of death or NDI for twins as a group when compared with the singletons (OR-1.39, 95% CI- 1.19–1.63). On analyzing twin A and B separately as well, risk of death or NDI was increased in both twin A (OR-1.32, 95% CI- 1.09–1.59) and for twin B (OR-1.47, 95% CI- 1.21–1.78), when compared with singleton infants.
Conclusions
Twin gestation in ELBW infants is associated with an independent increased risk of death or NDI at 18–22 months corrected age, compared to ELBW singleton gestation infants. Both first and second born twins are at increased risk of death or NDI when compared to singleton ELBW infants.
doi:10.1542/peds.2008-1126
PMCID: PMC2842087  PMID: 19139085
twins; neuro-developmental impairment; extremely low birth weight infants
8.  Maternal Age, Multiple Birth and Extremely Low Birth Weight Infants 
The Journal of pediatrics  2008;154(4):498-503.e2.
Objectives
To compare the rates of adverse neurodevelopmental outcome or death at 18 to 22 months among extremely low birth weight (ELBW) infants born to mothers ≥ 40 years to the corresponding rates among infants of younger mothers.
Study Design
Prospective evaluation of ELBW infants to quantify the relative risks of maternal age and multiple birth for death or adverse neurodevelopmental outcome.
Results
The sample consisted of 14,671 live ELBW births divided into maternal age groups: <20; 20–29; 30–39; and ≥ 40 years. Of infants born to mothers ≥ 40 years, 20% were multiples. Mothers ≥ 40 years had high rates of obstetrical interventions and medical morbidities compared to mothers < 40 years. ELBW live births of mothers ≥ 40 years were 22 % more likely to survive and had a 13% decreased risk of neurodevelopmental impairment or death compared to mothers< 20. Multiple birth, however, was associated with a 10 % greater risk or neurodevelopmental impairment or death.
Conclusion
Although mothers ≥ 40 years had high pregnancy related morbidities, we found no overall increased risk of the composite outcome of death or NDI. Multiple birth, however, was a predictor of all adverse outcomes examined, regardless of maternal age.
doi:10.1016/j.jpeds.2008.10.044
PMCID: PMC2834530  PMID: 19111322
outcomes; neurodevelopmental impairment; death
9.  Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight 
Background
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).
Methods
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.
Results
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.
Conclusions
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.)
doi:10.1056/NEJMoa0803024
PMCID: PMC2821221  PMID: 18971491
10.  Elevated Temperature after Hypoxic-Ischemic Encephalopathy: A Risk Factor for Adverse Outcome 
Pediatrics  2008;122(3):491-499.
Objective
To determine if the risk of death or moderate/severe disability in term infants with hypoxic-ischemic encephalopathy increases with relatively high esophageal or skin temperature occurring between 6 and 78 hours following birth.
Patients and Methods
This is an observational secondary study within the NICHD Neonatal Research Network randomized trial comparing whole body cooling and usual care (control) for term infants with hypoxic-ischemic encephalopathy. Esophageal and skin temperatures were recorded serially for 72 hours. Each infant’s temperatures for each site were rank ordered. The high temperature was defined for each infant as the mean of all temperature measurements in the upper quartile. The low temperature was similarly defined as the mean of the lower quartile. Outcome was related to temperature in three logistic regressions for the high, median and low temperature at each temperature site for each group adjusting for level of encephalopathy, gender, gestational age and race.
Results
In control infants the mean esophageal temperature was 37.2±0.7°C over the 72 hours and 63, 22 and 8% of all temperatures were > 37, > 37.5 and > 38°C, respectively. For skin temperature the mean was 36.5±0.8°C and 12, 5 and 2% of all temperatures were > 37, > 37.5 and > 38°C, respectively. The odds of death or disability were increased 3.6–4 fold for each centigrade increase in the highest quartile of skin or esophageal temperature. There were no associations between temperature and outcome in the cooled group.
Conclusion
Relatively high temperatures during usual care following hypoxia-ischemia were associated with increased risk of adverse outcome. The results may reflect underlying brain injury and/or adverse effects of temperature on outcome.
doi:10.1542/peds.2007-1673
PMCID: PMC2782681  PMID: 18762517
11.  Predictors of Death or Bronchopulmonary Dysplasia in Preterm Infants with Respiratory Failure 
Objectives
To identify the variables that predict death/physiologic BPD in preterm infants with severe respiratory failure.
Study Design
The study was a secondary analysis of data from the NICHD Neonatal Research Network trial of inhaled nitric oxide (iNO) in preterm infants. Stepwise logistic regression models and Classification and Regression Tree (CART) models were developed for the outcome of death or physiologic BPD (O2 at 36 weeks’ postmenstrual age).
Results
Death and/or BPD was associated with lower birth weight, higher oxygen requirement, male gender, additional surfactant doses, higher oxygenation index, and outborn status, but not the magnitude of response in PaO2 to iNO. The positive predictive value of the CART model was 82% at 95% sensitivity.
Conclusions
The major factors associated with death/BPD were an increased severity of respiratory failure, lower birth weight, male gender, and outborn status, but not the magnitude of initial response to iNO.
doi:10.1038/jp.2008.18
PMCID: PMC2776028  PMID: 18337740
Logistic models; Predictive value of tests; ROC curve
12.  INTEROBSERVER RELIABILITY AND ACCURACY OF CRANIAL ULTRASOUND INTERPRETATION IN PREMATURE INFANTS 
The Journal of pediatrics  2007;150(6):592-596.e5.
Objective
To assess interobserver reliability between two central readers of cranial ultrasound (CUS) and accuracy of local compared with central interpretations.
Study design
A retrospective analysis of CUS data from the NICHD trial of inhaled nitric oxide for premature infants. Interobserver reliability of two central readers was assessed by kappa or weighted kappa. Accuracy of local compared with central interpretations was assessed by sensitivity and specificity.
Results
Cranial US from 326 infants had both central reader and local interpretations. Central reader agreement for grade 3/4 IVH, grade 3/4 IVH or PVL, grade of IVH, and degree of ventriculomegaly was very good (kappa=0.84, 0.81, 0.79, and 0.75, respectively). Agreement was poor for lower grade IVH and for PVL alone. Local interpretations were highly accurate for grade 3/4 IVH or PVL (sensitivity 87–90%, specificity 92–93%), but sensitivity was poor to fair for grade 1/2 IVH (48–68%) and PVL (20–44%).
Conclusions
Our findings demonstrate reliability and accuracy of highly unfavorable CUS findings, but suggest caution when interpreting mild to moderate IVH or white matter injury.
doi:10.1016/j.jpeds.2007.02.012
PMCID: PMC2757063  PMID: 17517240
intraventricular; hemorrhage; leukomalacia; central reader; neurodevelopmental; brain
13.  NEURODEVELOPMENTAL IMPAIRMENT: PREDICTORS OF ITS IMPACT ON THE FAMILIES OF EXTREMELY LOW BIRTH WEIGHT INFANTS AT 18 MONTHS 
Infant mental health journal  2008;29(6):570-587.
Effects on a family of a child with chronic illness have been described. The Impact on Family Scale (IOF) was developed to measure these effects. The impact of extremely low birth weight (ELBW) infants with neurodevelopmental impairment on families is unknown. This study determined IOF scores for families of ELBW infants with increasing degree of impairment at 18 months and identified factors that increase vulnerability to impact. A total of 3,849 ELBW infant survivors born at the 16 centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 1993 and February 2001 were assessed at 18 to 22 months. Infants were divided into four groups by degree of impairment. IOF scores were analyzed by impairment group. Multivariate analyses assessed effects of impairment, social/demographic factors, unmet service needs, and resource utilization on the IOF. A total of 1,624 (42.2%) infants had moderate/severe impairment. Increasing severity of impairment was associated with higher IOF scores. Severity of impairment contributed 6% of variance to the IOF scores. Twenty-one percent of variance was contributed by additional medical needs, low socioeconomic status (SES), and lack of social support. Although increasing severity of impairment impacts families of ELBW infants, significantly more impact is contributed by additional medical needs, low SES, and lack of social support.
doi:10.1002/imhj.20196
PMCID: PMC2749276  PMID: 19779585
14.  Community Supports After Surviving Extremely Low-Birth-Weight, Extremely Preterm Birth 
Objective
To determine special outpatient services (SOS) use, need, associated factors, and neurodevelopmental and functional outcomes among extremely preterm infants at 18 to 22 months’ corrected age.
Design
Retrospective analysis.
Setting
National Institute of Child Health and Human Development (NICHD) Neonatal Research Network.
Participants
Infants younger than 28 weeks’ gestational age who had been born weighing less than 1000 g at an NICHD Neonatal Research Network center from January 1, 1997, to December 31, 2000, and who were receiving follow-up at 18 to 22 months’ corrected age.
Interventions
Questionnaires were administered at the 18- to 22-month follow-up visit regarding SOS use since hospital discharge and the current need for SOS (social work, visiting nurse, medical specialty, early intervention, speech and language services, occupational therapy and physical therapy, and neurodevelopmental and behavioral services).
Main Outcome Measures
The use of and need for SOS were analyzed by gestational age. Logistic regression analysis identified factors independently associated with the use of more than 5 services and with the need for any services.
Results
Of 2315 infants, 54.7% used more than 3 SOS by 18 to 22 months, and 19.1% used 6 to 7 SOS. The need for any SOS was reported by approximately 37%. The following variables that were commonly associated with adverse neurodevelopmental outcomes were also associated with the use of more than 5 SOS: sepsis, birth weight, postnatal corticosteroid use, bronchopulmonary dysplasia, and cystic periventricular leukomalacia or grade 3 or 4 intraventricular hemorrhage. Male sex was associated with the need for any SOS. Although high SOS use was more likely among children with adverse neurodevelopmental outcomes, a reported need for SOS was common even among those with mild developmental impairment (39.7%) and mild cerebral palsy (42.2%).
Conclusions
High SOS use is common, has identifiable neonatal risk factors, and is associated with neurodevelopmental impairment. Extremely preterm survivors have substantial need for community supports regardless of their impairment level. Efforts to improve comprehensive delivery of family-centered community-based services are urgently needed.
doi:10.1001/archpedi.162.8.748
PMCID: PMC2748992  PMID: 18678807

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