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author:("vor, Betty R.")
1.  Elevated Temperature and 6-7 Year Outcome of Neonatal Encephalopathy 
Annals of neurology  2013;73(4):520-528.
Determine if higher temperature after hypoxia-ischemia is associated with death or IQ < 70 at 6-7 yr among infants treated with intensive care without hypothermia.
Control infants (non-cooled, n=106) of the NICHD Neonatal Research Network hypothermia trial had serial esophageal and skin temperatures over 72hrs. Each infant's temperature was ranked to derive an average of the upper and lower quartile, and median of each site. Temperatures were used in logistic regressions to determine adjusted associations with death or IQ < 70 at 6-7yrs. Secondary outcomes were death, IQ < 70, and moderate/severe CP. IQ and motor function were assessed with Wechsler Scales for Children and Gross Motor Function Classification System. Results are odds ratio (OR, per °C increment within the quartile or median) and 95% confidence interval (CI).
Primary outcome was available for 89 infants. At 6-7yrs death or IQ < 70 occurred in 54 infants (37 deaths, 17 survivors with IQ < 70) and moderate/severe CP in 15 infants. Death or IQ < 70 was associated with the upper quartile average of esophageal (OR 7.3, 95% CI 2.0-26.3) and skin temperature (OR 3.5, 95% 1.2-10.4). CP was associated with the upper quartile average of esophageal (OR 12.5, 95% CI 1.02-155) and skin temperature (OR 10.3, 95% 1.3-80.2).
Among non-cooled infants of a randomized trial, elevated temperatures during the first post-natal days are associated with increase odds of a worse outcome at 6-7yrs.
PMCID: PMC3720800  PMID: 23595408
encephalopathy; hypoxia-ischemia; hyperthermia; cerebral palsy
2.  Early Predictors of Hypertension in Prematurely Born Adolescents 
Acta paediatrica (Oslo, Norway : 1992)  2010;99(12):1812-1818.
To assess the blood pressure of former preterm and term matched adolescent controls, and identify risk factors associated with blood pressure at 16 years.
Observational cohort study. Secondary analysis of a randomized clinical trial.
Three academic centers participating in the Multicenter Indomethacin IVH Prevention Trial.
296 children born in 1989–1992 with birth weights 600- <1250g who participated in the Multicenter Indomethacin IVH Prevention Trial and 95 term controls were evaluated at 16 years.
Main Outcome Measures
Blood pressure and predictors of blood pressure.
The adjusted mean difference in blood pressure for preterm adolescents was 5.1 mm Hg; p=0.002 for systolic and 2.1 mm Hg; p=0.027 for diastolic blood pressure. Among preterms, the primary predictors of increased systolic blood pressure were weight gain velocity between birth and 36 months (b=8.54, p<.001), preeclampsia (b=5.67, p=0.020), non-white race (b=3.77, p=0.04) and male gender (b=5.09). Predictors of diastolic blood pressure were weight gain velocity between birth and 36 months, (b=4.69, p=0.001, brain injury (b=6.51, p=0.002 and male gender (b=−2.4, p=0.02).
Early programming secondary to increased early weight gain velocity, intrauterine stress and neonatal brain injury may all contribute to risk of increased blood pressure among former preterm adolescents.
PMCID: PMC2970763  PMID: 20586997
brain injury; hypertension; preterm; weight gain velocity
3.  Characteristics of extremely low birth weight infant survivors with unimpaired outcomes at 30 months of age 
To evaluate characteristics of unimpaired outcome in ELBW survivors.
Study Design
ELBW infants (n=714) with 30 months’ assessments were analyzed. Logistic regression was used to develop a model for the binary outcome of unimpaired versus impaired outcome.
Thirty-three percent of infants had an unimpaired outcome. 17% of ELBW survivors had a Bayley II Mental Developmental Index score of ≥101 and 2% had a score of ≥116. Female gender, use of antenatal steroids, maternal education ≥ high school and absence of major neonatal morbidities were independent predictors of unimpaired outcome. The likelihood of an unimpaired outcome in presence of major neonatal morbidities was higher in infants exposed to antenatal steroids.
The majority of unimpaired ELBW survivors had cognitive scores shifted towards the lower end of the normal distribution. Exposure to antenatal steroids was associated with higher likelihood of an unimpaired outcome in infants with major neonatal morbidities.
PMCID: PMC3903461  PMID: 23807719
extremely low birth weight; unimpaired outcome; outcome; antenatal steroids; cerebral palsy
4.  A left cerebellar pathway mediates language in prematurely-born young adults 
NeuroImage  2012;64:371-378.
Preterm (PT) subjects are at risk for developmental delay, and task-based studies suggest that developmental disorders may be due to alterations in neural connectivity. Since emerging data imply the importance of right cerebellar function for language acquisition in typical development, we hypothesized that PT subjects would have alternate areas of cerebellar connectivity, and that these areas would be responsible for differences in cognitive outcomes between PT subjects and term controls at age 20 years.
Nineteen PT and 19 term control young adults were prospectively studied using resting-state functional MRI (fMRI) to create voxel-based contrast maps reflecting the functional connectivity of each tissue element in the grey matter through analysis of the intrinsic connectivity contrast degree (ICC-d). Left cerebellar ICC-d differences between subjects identified a region of interest that was used for subsequent seed-based connectivity analyses. Subjects underwent standardized language testing, and correlations with cognitive outcomes were assessed.
There were no differences in gender, hand preference, maternal education, age at study, or Peabody Picture Vocabulary Test (PPVT) scores. Functional connectivity (FcMRI) demonstrated increased tissue connectivity in the biventer, simple and quadrangular lobules of the L cerebellum (p<0.05) in PTs compared to term controls; seed-based analyses from these regions demonstrated alterations in connectivity from L cerebellum to both R and L inferior frontal gyri (IFG) in PTs compared to term controls. For PTs but not term controls, there were significant positive correlations between these connections and PPVT scores (R IFG: r=0.555, p=0.01; L IFG: r=0.454, p=0.05), as well as Verbal Comprehension Index (VCI) scores (R IFG: r=0.472, p=0.04).
These data suggest the presence of a left cerebellar language circuit in PT subjects at young adulthood. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain.
PMCID: PMC3508203  PMID: 22982585
Preterm; cerebellum; language systems; functional MRI; resting state intrinsic connectivity contrast degree
5.  Trajectories of Receptive Language Development from 3 to 12 Years in Very Preterm Children 
Pediatrics  2009;124(1):333-341.
To examine whether indomethacin, gender, neonatal and sociodemographic factors predict patterns of receptive language development from 3–12 years of age in preterm children.
355 children born in 1989–1992 with birth weight 600–1250g were evaluated at 3, 4.5, 6, 8 and 12 years with the Peabody Picture Vocabulary Test - Revised (PPVT-R) as a measure of receptive language. Hierarchical growth-curve modeling was used to explore differences in language trajectories.
From 3 to 12 years corrected ages, preterm children displayed catch-up gains on the PPVT-R. Preterm children started with an average standard score of 84.1 at 3 years and gained 1.2 points per year across the age period studied. Growth-curve analyses on PPVT-R raw scores revealed an indomethacin-by-gender effect on initial scores at 3 years with preterm boys randomized to indomethacin scoring, on average, 4.2 points higher than placebo control boys. However, velocity of receptive vocabulary development from 3–12 years did not differ by treatment groups. Children with grade 3–4 intraventricular hemorrhage, periventricular leukomalacia or grade 2 and above ventriculomegaly demonstrated slower gains in skills over time than those who did not suffer severe brain injury. Significant differences in language trajectories were predicted by maternal education and minority status. Higher initial scores and faster language development were observed among children whose mothers had higher education levels and who had not identified themselves as a minority ethnic group.
Although indomethacin incurs an initial benefit in preterm boys, this pharmacologic intervention did not alter the developmental trajectory of PPVT-R scores in our study subjects. Severe brain injury leads to long-term sequelae on language development, whereas a socioeconomically advantaged environment supports better language development among preterm children.
PMCID: PMC2704989  PMID: 19564317
Very low birth weight; preterm birth; language development; preschool outcome; middle childhood development; indomethacin; intraventricular hemorrhage
6.  Improving the Neonatal Research Network Annual Certification for Neurologic Examination of the 18–22 month Child 
The Journal of pediatrics  2012;161(6):1041-1046.e2.
To describe the Neonatal Research Network’s (NRN) efforts to improve the certification process for the Follow-up Study neurologic exam and to evaluate inter-rater agreement before and after two annual training workshops.
Study design
The NRN Follow-up Study is a multi-center observational study that has examined more than 11,500 infants from 1998–2010 and born ≤ 26 weeks gestational age at 18 – 22 months corrected age for neurodevelopmental outcome. The percentages of examiners who agreed with the Gold Standard examiner on four neurodevelopmental outcomes on the initial training video and a test video were calculated. Consistency among examiners was assessed with the first-order agreement coefficient (AC1) statistic.
Improvements in agreement among examiners occurred between 2009 and 2010 and between initial training and test. Examiner agreement with the Gold Standard during the initial training was 83% – 91% in 2009 and 89% – 99% in 2010. Examiner agreement on the workshop test video increased from 2009 to 2010 with agreement reaching 100% for all four neurodevelopmental outcomes examined in 2010. AC1 values for the four neurodevelopmental outcomes on the training videos ranged from 0.64 – 0.82 in 2009 and 0.77 – 0.97 in 2010.
We demonstrate the importance of annual certification and the benefits of evaluation and revision of certification protocols to achieve high levels of confidence in neurodevelopmental study outcomes for multi-center networks.
PMCID: PMC3465479  PMID: 22748517
examiner training; neurodevelopmental outcome; inter-rater agreement
7.  Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants 
Sepsis in older children and adults modifies immune system function. We compared serotype-specific antibody responses to heptavalent pneumococcal conjugate vaccine (PCV7) in very low birth weight infants (<1500g,VLBW) with and without blood stream infection (BSI) during their birth hospitalization.
Patients and Methods
Retrospective analysis of prospectively collected data for the Neonatal Research Network study of PCV7 responses among VLBWs. Infants received PCV7 at 2, 4, and 6 months after birth with blood drawn 4–6 weeks after 3rd dose. Serotype antibodies were compared between infants with or without a history of BSI. Regression models were constructed with birth-weight groups and other confounding factors identified in the primary study.
244 infants completed the vaccine series and had serum antibody available; 82 had BSI. After adjustment, BSI was not associated with reduced odds of serum antibody ≥0.35μg/mL.
BSI was not associated with reduced odds of WHO-defined protective PCV7 responses in VLBWs.
PMCID: PMC3722279  PMID: 23370608
VLBW; immune response; vaccine; sepsis; blood stream infection
8.  Are Outcomes of Extremely Preterm Infants Improving? Impact of Bayley Assessment on Outcomes 
The Journal of pediatrics  2012;161(2):222-8.e3.
To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Development’s Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006–2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008–2011 (period 2).
Study design
Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates.
Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001).
Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.
PMCID: PMC3796892  PMID: 22421261
9.  An Initial Investigation of Baseline Respiratory Sinus Arrhythmia as a Moderator of Treatment Outcome for Young Children Born Premature with Externalizing Behavior Problems 
Behavior therapy  2012;43(3):652-665.
The aim of the current study was to examine the moderating effect of baseline respiratory sinus arrhythmia (RSA) on Parent-Child Interaction Therapy (PCIT), a behavioral parent-training intervention, for young children born premature. In this pilot randomized controlled trial, 28 young children (mean age of 37.79 months), who were born < 37 weeks gestation and presented with elevated externalizing behavior problems, were randomly assigned to an immediate treatment or waitlist control group. RSA, which provides an approximate marker of individual differences in cardiac vagal tone, was measured during a baseline period. Past research has generally shown that higher levels of baseline RSA correlate with various positive psychological states (e.g., empathy, sustained attention), whereas lower levels of baseline RSA correlate with less optimal psychological states (e.g., higher externalizing behavior problems). Results indicated that baseline RSA significantly interacted with treatment condition in predicting changes in child disruptive behavior. Specifically, low levels of baseline RSA were associated with greater improvements in child disruptive behavior following PCIT. While acknowledging the caveats of measuring and interpreting RSA and the need to include a sympathetic-linked cardiac measure in future research, these findings provide preliminary evidence that children with lower capacity for emotion regulation receive even greater treatment gains. Future research should also examine the moderating effect of RSA in larger samples and explore the potential mediating role of RSA on behavioral parenting interventions.
PMCID: PMC3475510  PMID: 22697452
respiratory sinus arrhythmia; emotion regulation; prematurity; behavior problems; behavioral parent training
10.  Spontaneous Intestinal Perforation in Extremely Low Birth Weight Infants: Association with Indometacin Therapy and Effects on Neurodevelopmental Outcomes at 18-22 months Corrected Age 
Spontaneous intestinal perforation (SIP) is associated with the use of postnatal glucocorticoids and indometacin in extremely low birth weight (ELBW) infants. We hypothesized: 1) an association of SIP with the use of antenatal steroids (ANS) and indometacin either as prophylaxis for IVH (P Indo) or for treatment of PDA (Indo/PDA) and 2) an increased risk of death or abnormal neurodevelopmental outcomes in infants with SIP at 18-22 months corrected age.
We retrospectively identified ELBW infants with SIP in the Neonatal Research Network’s generic database. Unadjusted analysis identified the differences in maternal, neonatal and clinical variables between infants with and without SIP. Logistic regression analysis identified the adjusted odds ratio for SIP with reference to ANS, P Indo and Indo/PDA. Neurodevelopmental outcomes were assessed among survivors at 18 to 22 months corrected age.
Indo/PDA was associated with an increased risk of SIP (adjusted OR 1.61; 95% CI 1.25,2.08), while P Indo and ANS were not. SIP was independently associated with an increased risk of death or NDI (adjusted OR−1.85; 95% CI 1.32,2.60) and NDI among survivors (adjusted OR−1.75, 95% CI 1.20,2.55).
Indometacin used for IVH prophylaxis and ANS were not associated with the occurrence of SIP in ELBW infants. Indometacin used for treatment of symptomatic PDA was however associated with an increased risk of SIP. ELBW infants with SIP have an increased risk of poor neurodevelopmental outcomes.
PMCID: PMC3753803  PMID: 22684157
extremely low birth weight infant; intestinal perforation; indometacin; cerebral palsy
11.  Evidence-Based Intervention for Young Children Born Premature: Preliminary Evidence for Associated Changes in Physiological Regulation 
Infant behavior & development  2012;35(3):417-428.
The current study examined whether changes in maternal behaviors following an evidence-based treatment—Parent Child Interaction Therapy (PCIT)—was associated with improvements in cardiac vagal regulation in young children born premature. Participants included 28 young children (mean age = 37.79 months) that were born premature and presented with elevated externalizing behavior problems. To assess cardiac vagal regulation, resting measures of respiratory sinus arrhythmia (RSA) and RSA change (withdrawal or suppression) to a clean-up task were derived pre and post-treatment. Results indicated that an increase in behaviors mothers are taught to use during treatment (i.e., do skills—praise, reflection, and behavioral descriptions) were associated with an improvement in children’s post-treatment RSA suppression levels. The current study illustrates the important role of caregiver behavior in promoting physiological regulation in children born premature.
PMCID: PMC3409342  PMID: 22721742
cardiac vagal regulation; RSA suppression; emotion regulation; prematurity; child; parent training
12.  Effect of ethnicity and race on cognitive and language testing at 18 – 22 months in extremely preterm infants 
The Journal of Pediatrics  2012;160(6):966-971.e2.
To evaluate the relationship of race/ethnicity to cognitive and language scores on the Bayley Scales of Infant and Toddler Development 3rd edition (BSID-III) in extremely preterm toddlers (<28+0 weeks’ estimated gestational age).
Study design
Extremely preterm toddlers at NICHD Neonatal Research Network Centers evaluated at 18–22 months adjusted age from 3 race/ethnic groups (White, Black, and Hispanic-White) were included in this cohort study. Multivariable regression modeling was used to identify race/ethnic differences adjusting for medical and psychosocial factors.
Children included 369 Whites, 352 Blacks and 144 Hispanic-Whites. Cognitive scores differed between groups in unadjusted analysis (p=<0.001), but not after adjusting for medical and psychosocial factors (p=0.13). Language scores differed in adjusted and unadjusted analyses. Whites scored higher than Blacks or Hispanic-Whites, and Blacks scored higher than Hispanic-Whites.
A combination of medical variables and primary caretaker education accounted for differences in BSID-III cognitive scores between groups. Black and Hispanic-White toddlers had lower language scores than Whites, even after adjustment. Early intervention should be targeted to these identified risk factors. Assessment of early language development among minority groups may be warranted.
PMCID: PMC3343209  PMID: 22269248
development; prematurity; Bayley Scales; BSID
13.  Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22–25 weeks gestation 
Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24–34 weeks gestational age, but not before 24 weeks because of lack of data. However, many infants born before 24 weeks are provided intensive care now.
To determine if antenatal corticosteroids are associated with improvement in major outcomes in infants born at 22 and 23 weeks.
Design, Setting, Participants
Data for this cohort study were collected prospectively on 401–1000 gram inborn infants (N=10,541) of 22–25 weeks gestation born between 1993–2009 at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4,924 (86.5%) of the infants born in 1993–2008 who survived to 18–22 months. Logistic regression models generated adjusted odds ratios, controlling for maternal and neonatal variables.
Main Outcome Measures
Mortality and neurodevelopmental impairment at 18–22 months corrected age
Death or neurodevelopmental impairment at 18–22 months was lower for infants whose mothers received antenatal corticosteroids born at 23 weeks (antenatal corticosteroids, 83.4% vs no antenatal corticosteroids, 90.5%; adjusted odds ratio 0.58; 95% CI, 0.42–0.80), at 24 weeks (antenatal corticosteroids, 68.4% vs no antenatal corticosteroids, 80.3%; adjusted odds ratio 0.62; 95% CI, 0.49–0.78), and at 25 weeks (antenatal corticosteroids, 52.7% vs no antenatal corticosteroids, 67.9%; adjusted odds ratio 0.61; 95% CI, 0.50–0.74) but not at 22 weeks (antenatal corticosteroids, 90.2% vs no antenatal corticosteroids, 93.1%; adjusted odds ratio 0.80; 95% CI, 0.29–12.21). Death by 18–22 months, hospital death, death/intraventricular hemorrhage/periventricular leukomalacia, and death/necrotizing enterocolitis were significantly lower for infants born at 23, 24, and 25 weeks gestational age if the mothers had received antenatal corticosteroids but the only outcome significantly lower at 22 weeks was death/necrotizing enterocolitis (antenatal corticosteroids, 73.5% vs no antenatal corticosteroids, 84.5%; adjusted odds ratio 0.54; 95% CI, 0.30–0.97).
Among infants born at 23–25 weeks gestation, use of antenatal corticosteroids compared to non-use was associated with a lower rate of death or neurodevelopmental impairment at 18–22 months.
PMCID: PMC3565238  PMID: 22147379
prematurity; infant mortality; neonatal intensive care; neurodevelopmental impairment; lung maturation; limits of viability
14.  Childhood Outcomes after Hypothermia for Neonatal Encephalopathy 
The New England journal of medicine  2012;366(22):2085-2092.
We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic–ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available.
In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70.
Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P = 0.06); death occurred in 27 (28%) and 41 (44%) (P = 0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P = 0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P = 0.87). Attention–executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P = 0.19), and visuospatial dysfunction occurred in 4% and 3% (P = 0.80).
The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; number, NCT00005772.)
PMCID: PMC3459579  PMID: 22646631
15.  Evidence for Catch-up in Cognition and Receptive Vocabulary Among Adolescents Born Very Preterm 
Pediatrics  2011;128(2):313-322.
Very preterm adolescents display persistent deficits in neuropsychological functions.
To compare cognitive and language outcomes at 16 years and cognitive and receptive vocabulary trajectories throughout school years between very preterm and term children and to determine child and family factors associated with better developmental trajectories.
At 8, 12, and 16 years, 322 very preterm children with birth weights of 1250 g or less and 41 term children had cognitive and language testing. Hierarchical growth-curve modeling was used to delineate the differences in cognitive and receptive vocabulary development between participants. Cluster analyses allowed for the characterization of very preterm children with different patterns of cognitive and receptive vocabulary development.
At 16 years, very preterm adolescents had deficits in general cognition and higher-order language skills (phonological awareness and phonemic decoding) compared with term peers. Although the between-group difference in cognitive scores remained stable from 8 to 16 years, very preterm children demonstrated catch-up gains in receptive vocabulary during the same period. Moreover, subgroups of very preterm children displayed developmental trajectories in cognition similar to term children (55% on the vocabulary and 46% on the block-design subtests). These children had lower rates of neurosensory impairment and mothers with higher education and were from an ethnic nonminority.
Significant catch-up in receptive vocabulary is observed by the age of 16 years among very preterm children compared to term peers. The absence of neurosensory impairment and residing in a favorable socioeconomic milieu are associated with the most optimal developmental trajectories.
PMCID: PMC3146356  PMID: 21768322
very low birth weight; prematurity; cognitive development; language
16.  Executive and Memory Function in Adolescents Born Very Preterm 
Pediatrics  2011;127(3):e639-e646.
Many preterm children display school difficulties, which may be mediated by impairment in executive function and memory.
To evaluate executive and memory function among adolescents born preterm compared with term controls at 16 years.
A total of 337 of 437 (77%) adolescents born in 1989 to 1992 with a birth weight < 1250 g and 102 term controls were assessed with a battery of executive function and memory tasks. Multiple regression analyses were used to compare groups and to identify associations between selected factors and outcomes among preterm subjects.
Adolescents born preterm, compared with term controls, showed deficits in executive function in the order of 0.4 to 0.6 SD on tasks of verbal fluency, inhibition, cognitive flexibility, planning/organization, and working memory as well as verbal and visuospatial memory. After exclusion of adolescents with neurosensory disabilities and full-scale IQ < 70, significant group differences persisted on most tests. Preterm subjects, compared with term controls, were at increased risk of exhibiting problems related to executive dysfunction, as measured with the Behavior Rating Inventory of Executive Function, on the Metacognition Index (odds ratio [OR]: 2.5 [95% confidence interval (CI): 1.2–5.1]) and the Global Executive Composite (OR: 4.2 [95% CI: 1.6–10.9]), but not on the Behavioral Regulation index (OR: 1.5 [95% CI: 0.7–3.5]). Among adolescents born preterm, severe brain injury on neonatal ultrasound and lower maternal education were the most consistent factors associated with poor outcomes.
Even after exclusion of preterm subjects with significant disabilities, adolescents born preterm in the early 1990s were at increased risk of deficits in executive function and memory.
PMCID: PMC3065148  PMID: 21300680
very low birth weight; prematurity; executive function; memory
17.  Neurodevelopmental Outcomes of Triplets or Higher-Order Extremely Low Birth Weight Infants 
Pediatrics  2011;127(3):e654-e660.
Extremely low birth weight twins have a higher rate of death or neurodevelopmental impairment than singletons. Higher-order extremely low birth weight multiple births may have an even higher rate of death or neurodevelopmental impairment.
Extremely low birth weight (birth weight 401–1000 g) multiple births born in participating centers of the Neonatal Research Network between 1996 and 2005 were assessed for death or neurodevelopmental impairment at 18 to 22 months' corrected age. Neurodevelopmental impairment was defined by the presence of 1 or more of the following: moderate to severe cerebral palsy; mental developmental index score or psychomotor developmental index score less than 70; severe bilateral deafness; or blindness. Infants who died within 12 hours of birth were excluded. Maternal and infant demographic and clinical variables were compared among singleton, twin, and triplet or higher-order infants. Logistic regression analysis was performed to establish the association between singletons, twins, and triplet or higher-order multiples and death or neurodevelopmental impairment, controlling for confounding variables that may affect death or neurodevelopmental impairment.
Our cohort consisted of 8296 singleton, 2164 twin, and 521 triplet or higher-order infants. The risk of death or neurodevelopmental impairment was increased in triplets or higher-order multiples when compared with singletons (adjusted odds ratio: 1.7 [95% confidence interval: 1.29–2.24]), and there was a trend toward an increased risk when compared with twins (adjusted odds ratio: 1.27 [95% confidence: 0.95–1.71]).
Triplet or higher-order births are associated with an increased risk of death or neurodevelopmental impairment at 18 to 22 months' corrected age when compared with extremely low birth weight singleton infants, and there was a trend toward an increased risk when compared with twins.
PMCID: PMC3304548  PMID: 21357334
extremely low birth weight; triplets; neurodevelopmental outcomes
18.  Preterm Birth Results in Alterations in Neural Connectivity at Age 16 Years 
NeuroImage  2010;54(4):2563-2570.
Very low birth weight preterm (PT) children are at high risk for brain injury. Employing diffusion tensor imaging (DTI), we tested the hypothesis that PT adolescents would demonstrate microstructural white matter disorganization relative to term controls at 16 years of age. Forty-four PT subjects (600 - 1250 grams birth weight) without neonatal brain injury and 41 term controls were evaluated at age 16 years with DTI, the Wechsler Intelligence Scale for Children - III (WISC), the Peabody Picture Vocabulary Test - Revised (PPVT), and the Comprehensive Test of Phonological Processing (CTOPP).
PT subjects scored lower than term subjects on WISC full scale (p = 0.003), verbal (p = 0.043), and performance IQ tests (p = 0.001), as well as CTOPP phonological awareness (p = 0.004), but scored comparably to term subjects on PPVT and CTOPP Rapid Naming tests. PT subjects had lower fractional anisotropy (FA) values in multiple regions including bilateral uncinate fasciculi (left: p = 0.01; right: p = 0.004), bilateral external capsules (left: p < 0.001; right: p < 0.001), the splenium of the corpus callosum (p = 0.008), and white matter serving the inferior frontal gyrus bilaterally (left: p < 0.001; right: p = 0.011). FA values in both the left and right uncinate fasciculi correlated with PPVT scores (a semantic language task) in the PT subjects (left: r = 0.314, p = 0.038; right: r = 0.336, p = 0.026). FA values in the left and right arcuate fasciculi correlated with CTOPP Rapid Naming scores (a phonologic task) in the PT subjects (left: r = 0.424, p = 0.004; right: r = 0.301, p = 0.047).
These data support for the first time that dual pathways underlying language function are present in PT adolescents. The striking bilateral dorsal correlations for the PT group suggest that prematurely born subjects rely more heavily on the right hemisphere than typically developing adults for performance of phonological language tasks. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain.
PMCID: PMC3020252  PMID: 21073965
Preterm; adolescence; diffusion tensor imaging; dual language system
19.  Early-Childhood Neurodevelopmental Outcomes Are Not Improving for Infants Born at <25 Weeks' Gestational Age 
Pediatrics  2011;127(1):62-70.
We compared neurodevelopmental outcomes at 18 to 22 months' corrected age of infants born with extremely low birth weight at an estimated gestational age of <25 weeks during 2 periods: 1999–2001 (epoch 1) and 2002–2004 (epoch 2).
We conducted a multicenter, retrospective analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Perinatal and neonatal variables and outcomes were compared between epochs. Neurodevelopmental outcomes at 18 to 22 months' corrected age were evaluated with neurologic exams and Bayley Scales of Infant Development II. Logistic regression analyses determined the independent risk of epoch for adverse outcomes.
Infant survival was similar between epochs (epoch 1, 35.4%, vs epoch 2, 32.3%; P = .09). A total of 411 of 452 surviving infants in epoch 1 and 405 of 438 surviving infants in epoch 2 were evaluated at 18 to 22 months' corrected age. Cesarean delivery (P = .03), surgery for patent ductus arteriosus (P = .004), and late sepsis (P = .01) were more common in epoch 2, but postnatal steroid use was dramatically reduced (63.5% vs 32.8%; P < .0001). Adverse outcomes at 18 to 22 months' corrected age were common in both epochs. Moderate-to-severe cerebral palsy was diagnosed in 11.1% of surviving infants in epoch 1 and 14.9% in epoch 2 (adjusted odds ratio [OR]: 1.52 [95% confidence interval (CI): 0.86–2.71]; P = .15), the Mental Developmental Index was <70 in 44.9% in epoch 1 and 51% in epoch 2 (OR: 1.30 [95% CI: 0.91–1.87]; P = .15), and neurodevelopmental impairment was diagnosed in 50.1% of surviving infants in epoch 1 and 58.7% in epoch 2 (OR: 1.4 [95% CI: 0.98–2.04]; P = .07).
Early-childhood outcomes for infants born at <25 weeks' estimated gestational age were unchanged between the 2 periods.
PMCID: PMC3375467  PMID: 21187312
extremely preterm; neurodevelopmental; outcome; cerebral palsy; Bayley Scales of Infant Development II
The heptavalent pneumococcal-CRM197 conjugate vaccine (PCV-7) has been incompletely studied in very-low-birth-weight (VLBW, ≤1500 grams) infants.
To assess PCV-7 immunogenicity in VLBW, premature infants. We hypothesized that the frequency of post-vaccine antibody concentrations ≥0.15 µg/mL would vary directly with birth weight.
This was a multi-center observational study. Infants 401–1500 grams birth weight and <32 0/7 weeks gestation, stratified by birth weight, were enrolled from 9 NICHD Neonatal Research Network centers. Infants received PCV-7 at 2, 4 and 6 months after birth and had blood drawn 4–6 weeks following the third dose. Antibodies against the 7 vaccine serotypes were measured by enzyme-linked immunosorbent assay.
Of 369 enrolled infants, 244 completed their primary vaccine series by 8 months and had serum obtained. Subjects were 27.8 ± 2.2 (mean ± standard deviation) weeks gestation and 1008 ± 282 grams birth weight. Twenty-six percent had bronchopulmonary dysplasia and 16% had received postnatal glucocorticoids. Infants 1001–1500 grams birth weight were more likely than those 401–1000 grams to achieve antibody concentrations ≥0.15 µg/mL against the least two immunogenic serotypes (6B: 96% v. 85%, P = 0.003 and 23F: 97% v. 88%, P = 0.009). In multiple logistic regression analysis, lower birth weight, postnatal glucocorticoid use, lower weight at blood draw and Caucasian race were each independently associated with antibody concentrations <0.35 µg/mL against serotypes 6B and/or 23F.
When compared with larger premature infants, infants weighing ≤1000 grams at birth have similar antibody responses to most, but not all, PCV-7 vaccine serotypes.
PMCID: PMC2949965  PMID: 20234331
Infant, premature; infant, very low birth weight; pneumococcal vaccines; immunization; vaccines
21.  Influence of Clinical Status on the Association Between Plasma Total and Unbound Bilirubin and Death or Adverse Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants.
Total plasma biirubin and unbound biirubin were measured in 1,101 extremely low birth weight infants at 5±1 day of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors.
Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants.
In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma and unbound bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.
PMCID: PMC2875328  PMID: 20105142
Plasma bilirubin; unbound bilirubin; Extremely low birth weight infants; Neurodevelopmental outcomes
22.  A Preliminary Study of Cortisol Reactivity and Behavior Problems in Young Children Born Premature 
Developmental psychobiology  2010;52(6):574-582.
The purpose of the present study was to examine the relation between cortisol reactivity and comorbid internalizing and externalizing behavior problems among children born premature. Children between the ages of 18 and 60 months who were born < 37 weeks gestation and presented with clinically significant externalizing behavior problems were included. Children were categorized based on those who mounted a cortisol response to a stressor and those who did not mount a cortisol response. Children demonstrating the cortisol response were reported to have more problems with attention, emotional reactivity, anxiety, and depression based on maternal report and displayed higher rates of negative verbalizations during a mother-child interaction than children without a cortisol response. These results extend the findings of the relation between cortisol reactivity and comorbid internalizing and externalizing behavior problems to a sample of children born premature.
PMCID: PMC2933079  PMID: 20806330
cortisol; prematurity; behavior problems; stress; assessment
23.  Seven Month Developmental Outcomes of Very Low Birth Weight Infants Enrolled in a Randomized Controlled Trial of Delayed versus Immediate Cord Clamping 
Results from our previous trial revealed that infants with delayed cord clamping (DCC) had significantly less intraventricular hemorrhage (IVH) and late onset sepsis (LOS) than infants with immediate cord clamping (ICC). A priori, we hypothesized that infants with DCC would have better motor function by 7 months CA.
Study Design
Infants between 24 and 316 weeks were randomized to ICC or DCC and follow-up evaluation was completed at 7 months corrected age.
We found no differences in the Bayley Scales of Infant Development (BSID) scores between the DCC and ICC groups. However, a regression model of effects of DCC on motor scores controlling for gestational age, IVH, bronchopulmonary dysplasia, sepsis, and male gender suggested higher motor scores of male infants with DCC.
Delayed cord clamping at birth appears to be protective of very low birth weight male infants against motor disability at 7 months corrected age.
PMCID: PMC2799542  PMID: 19847185
cord clamping; motor outcomes; very low birth weight infants; randomized controlled trial; gender
24.  Stability of Neuromotor Outcomes at 18 and 30 Months of Age After Extremely Low Birth Weight Status 
Pediatrics  2009;123(5):e887-e895.
Extremely low birth weight (≤1000 g) children have increased rates of cerebral palsy and other abnormal neurologic findings.
To investigate the stability of neuromotor findings between 18 and 30 months' adjusted age in extremely low birth weight infants.
Seven hundred nineteen extremely low birth weight infants with assessments at 18 and 30 months' adjusted age were included in this analysis. At each visit a neurologic examination, the modified gross motor function classification system, and the Bayley Scales of Infant Development II were administered. Logistic regression models were constructed to assess neonatal factors and neuromotor function at 18 months of age associated with stability in neuromotor function.
Eighty-four percent of the children had agreement in neurologic/motor function at both visits. However, classification changed from normal to abnormal in 6% and from abnormal to normal in 10%. Diagnosis of cerebral palsy was consistent for 91% of the children, and the gross motor function classification system score was consistent for 83%. In multivariate models, factors associated with decreased severity or absence of cerebral palsy diagnosis at 30 months of age were higher gestational age, no periventricular leukomalacia or severe intraventricular hemorrhage, and a gross motor function classification system score of 0 (normal) at the 18-month visit, whereas factors associated with a new cerebral palsy diagnosis at 30 months of age were postnatal steroid use, periventricular leukomalacia or severe intraventricular hemorrhage, a gross motor function classification system score of ≥1 at 18 months of age, and asymmetrical limb movement at 18 months of age.
Stability of neurologic diagnosis in 84% and cerebral palsy in 91% of the children is reassuring. However, for a significant percentage of children, the neurologic diagnosis changes between 18 and 30 months of age. The diagnosis of cerebral palsy may be delayed in some infants until an older adjusted age.
PMCID: PMC2879971  PMID: 19403482
neuromotor outcomes; extreme low birth weight; prematurity; cerebral palsy
25.  Clinical Data Predict Neurodevelopmental Outcome Better than Head Ultrasound in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2007;151(5):500-505.e2.
To determine the relative contribution of clinical data versus head ultrasound (HUS) in predicting neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants.
Study design
2103 ELBW infants (<1000g) admitted to a National Institute of Child Health and Human Development Neonatal Research Network center who had a HUS within the first 28 days, a repeat one around 36 weeks’ post-menstrual age, and neurodevelopmental assessment at 18–22 months corrected age were selected. Multivariate logistic regression models were developed using clinical and/or HUS variables. The primary outcome was the predictive abilities of the HUS done before 28 days after birth and closer to 36 weeks post-menstrual age, either alone or in combination with “Early” and “Late” clinical variables.
Models using clinical variables alone predicted NDI better than models with only HUS variables at both 28 days and 36 weeks (both p < 0.001), and addition of the HUS data did not improve prediction. NDI was absent in 30% and 28% of the infants with grade IV intracranial hemorrhage or periventricular leukomalacia, respectively, but was present in 39% of the infants with a normal head ultrasound.
Clinical models were better than head ultrasound models in predicting neurodevelopment.
PMCID: PMC2879162  PMID: 17961693
Logistic models; Predictive value of tests; ROC curve; Infant; premature; Intracerebral hemorrhage; Leukomalacia; periventricular

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