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author:("Das, abik")
1.  Immunogenicity of Haemophilus influenzae Type b Protein Conjugate Vaccines in Very Low Birth Weight Infants 
doi:10.1097/01.inf.0000437263.04493.7c
PMCID: PMC3960569  PMID: 24569312
Infant; premature; infant; very low birth weight; Haemophilus influenzae vacines; immunization; vaccines
2.  Cerebral Palsy and Growth Failure at 6 to 7 Years 
Pediatrics  2013;132(4):e905-e914.
OBJECTIVE:
To evaluate the association between severity of cerebral palsy (CP) and growth to 6 to 7 years of age among children with moderate to severe (Mod/Sev) hypoxic ischemic encephalopathy (HIE). It was hypothesized that children with Mod/Sev CP would have poorer growth, lower cognitive scores, and increased rehospitalization rates compared with children with no CP (No CP).
METHODS:
Among 115 of 122 surviving children followed in the hypothermia trial for neonatal HIE, growth parameters and neurodevelopmental status at 18 to 22 months and 6 to 7 years were available. Group comparisons (Mod/Sev CP and No CP) with unadjusted and adjusted analyses for growth <10th percentile and z scores by using Fisher’s exact tests and regression modeling were conducted.
RESULTS:
Children with Mod/Sev CP had high rates of slow growth and cognitive and motor impairment and rehospitalizations at 18 to 22 months and 6 to 7 years. At 6 to 7 years of age, children with Mod/Sev CP had increased rates of growth parameters <10th percentile compared with those with No CP (weight, 57% vs 3%; height, 70% vs 2%; and head circumference, 82% vs 13%; P < .0001). Increasing severity of slow growth was associated with increasing age (P < .04 for weight, P < .001 for length, and P < .0001 for head circumference). Gastrostomy feeds were associated with better growth.
CONCLUSIONS:
Term children with HIE who develop Mod/Sev CP have high and increasing rates of growth <10th percentile by 6 to 7 years of age. These findings support the need for close medical and nutrition management of children with HIE who develop CP.
doi:10.1542/peds.2012-3915
PMCID: PMC3784290  PMID: 24019415
encephalopathy; hypoxia-ischemia; hypothermia; cerebral palsy; growth
3.  Neurodevelopmental Outcome of Extremely Low Birth Weight Infants with Candida Infection 
The Journal of pediatrics  2013;163(4):961-967.e3.
Objective
Candida remains an important cause of late-onset infection in preterm infants. Mortality and neurodevelopmental outcome of extremely low birthweight (ELBW) infants enrolled in the Candida study was evaluated based on infection status.
Study design
ELBW infants born at NICHD Neonatal Research Network (NRN) centers between March 2004 and July 2007 screened for suspected sepsis were eligible for inclusion in the Candida study. Primary outcome data for neurodevelopmental impairment (NDI) or death were available for 1317/1515 (90%) of the infants enrolled in the Candida study. The Bayley Scales of Infant Development (BSID)-II or the BSID-III was administered at 18 months adjusted age. A secondary comparison with 864 infants registered with NRN enrolled during the same cohort never screened for sepsis and therefore not eligible for the Candida study was performed.
Results
Among ELBW infants enrolled in the Candida study, 31% with Candida and 31% with late-onset non-Candida sepsis had NDI at 18 months. Infants with Candida sepsis and/or meningitis had an increased risk of death and were more likely to have the composite outcome of death and/or NDI compared with uninfected infants in adjusted analysis. Compared with infants in the NRN registry never screened for sepsis, overall risk for death were similar but those with Candida infection were more likely to have NDI (OR 1.83 (1.01,3.33, p=0.047).
Conclusion
In this cohort of ELBW infants, those with infection and/or meningitis were at increased risk for death and/or NDI. This risk was highest among those with Candida sepsis and/or meningitis.
doi:10.1016/j.jpeds.2013.04.034
PMCID: PMC3786056  PMID: 23726546
Candida; Neonatal sepsis; Neurodevelopmental and Prematurity
4.  Neurodevelopmental Outcomes in the Early CPAP and Pulse Oximetry Trial 
The New England journal of medicine  2012;367(26):2495-2504.
BACKGROUND
Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses.
METHODS
Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age.
RESULTS
The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P = 0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P = 0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P = 0.046).
CONCLUSIONS
We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.)
doi:10.1056/NEJMoa1208506
PMCID: PMC4140695  PMID: 23268664
5.  Elevated Temperature and 6-7 Year Outcome of Neonatal Encephalopathy 
Annals of neurology  2013;73(4):520-528.
OBJECTIVE
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.
DESIGN/METHODS
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).
RESULTS
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).
CONCLUSIONS
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.
doi:10.1002/ana.23843
PMCID: PMC3720800  PMID: 23595408
encephalopathy; hypoxia-ischemia; hyperthermia; cerebral palsy
6.  Characteristics of extremely low birth weight infant survivors with unimpaired outcomes at 30 months of age 
Objective
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.
Results
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.
Conclusions
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.
doi:10.1038/jp.2013.71
PMCID: PMC3903461  PMID: 23807719
extremely low birth weight; unimpaired outcome; outcome; antenatal steroids; cerebral palsy
7.  Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants 
Objective
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.
Results
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.
Conclusions
BSI was not associated with reduced odds of WHO-defined protective PCV7 responses in VLBWs.
doi:10.1038/jp.2013.5
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.
Objectives
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.
Results
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).
Conclusion
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.
doi:10.1016/j.jpeds.2012.01.057
PMCID: PMC3796892  PMID: 22421261
9.  Screening for Autism Spectrum Disorders in Extremely Preterm Infants 
Background
Extremely preterm (EP) infants screen positive for Autism Spectrum Disorders (ASD) at high rates. However it is not clear whether this is due to high rates of ASD in EPs or to high rates of false positive screens for ASD in children with a high rate of underlying neurodevelopmental impairments. Combining a parent questionnaire designed to distinguish developmental delay from ASD with direct observation of infant behavior may more accurately screen for ASD in EPs.
Objectives
To determine rates of positive screen for ASD at 18–22months(m) in EPs using three screens; to determine factors associated with a positive screen.
Methods
554 infants born <27 weeks were screened at 18–22m using the Pervasive Developmental Disorders Screening Test, 2nd edition, Stage 2 (PDDST-II) and the response to name and response to joint attention items from the Autism Diagnostic Observation Schedule. Infants with severe cerebral palsy, deafness and blindness were excluded. Associations between positive screen and neonatal/infant characteristics were determined.
Results
113/554 (20 %) had ≥1 positive screen. 10% had a positive PDDST-II, 6% response to name, 9% response to joint attention; in only 1% were all 3 screens positive. Positive screen was associated with male gender, more hospital days, white race, lower maternal education, abnormal behavioral scores, and cognitive/language delay.
Conclusions
The use of three screens for ASD in EPs results in higher screen positive rates than use of one screen alone. Diagnostic confirmation is needed before true rates of ASD in EPs are known.
doi:10.1097/DBP.0b013e31825fd0af
PMCID: PMC3434239  PMID: 22926660
Autism; Prematurity; Screening
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 
Background
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.
Design/Methods
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.
Results
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).
Conclusion
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.
doi:10.1136/archdischild-2011-300659
PMCID: PMC3753803  PMID: 22684157
extremely low birth weight infant; intestinal perforation; indometacin; cerebral palsy
11.  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.
Objective
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jpeds.2011.12.009
PMCID: PMC3343209  PMID: 22269248
development; prematurity; Bayley Scales; BSID
12.  Association of antenatal corticosteroids with mortality and neurodevelopmental outcomes among infants born at 22–25 weeks gestation 
Context
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.
Objective
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
RESULTS
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).
CONCLUSIONS
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.
doi:10.1001/jama.2011.1752
PMCID: PMC3565238  PMID: 22147379
prematurity; infant mortality; neonatal intensive care; neurodevelopmental impairment; lung maturation; limits of viability
13.  Childhood Outcomes after Hypothermia for Neonatal Encephalopathy 
The New England journal of medicine  2012;366(22):2085-2092.
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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; ClinicalTrials.gov number, NCT00005772.)
doi:10.1056/NEJMoa1112066
PMCID: PMC3459579  PMID: 22646631
14.  Neurodevelopmental Outcomes of Triplets or Higher-Order Extremely Low Birth Weight Infants 
Pediatrics  2011;127(3):e654-e660.
BACKGROUND:
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.
METHODS:
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.
RESULTS:
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]).
CONCLUSIONS:
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.
doi:10.1542/peds.2010-2646
PMCID: PMC3304548  PMID: 21357334
extremely low birth weight; triplets; neurodevelopmental outcomes
15.  Early-Childhood Neurodevelopmental Outcomes Are Not Improving for Infants Born at <25 Weeks' Gestational Age 
Pediatrics  2011;127(1):62-70.
OBJECTIVE:
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).
PATIENTS AND METHODS:
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.
RESULTS:
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).
CONCLUSIONS:
Early-childhood outcomes for infants born at <25 weeks' estimated gestational age were unchanged between the 2 periods.
doi:10.1542/peds.2010-1150
PMCID: PMC3375467  PMID: 21187312
extremely preterm; neurodevelopmental; outcome; cerebral palsy; Bayley Scales of Infant Development II
16.  HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE IMMUNOGENICITY IN VERY-LOW-BIRTH-WEIGHT, PREMATURE INFANTS 
Background
The heptavalent pneumococcal-CRM197 conjugate vaccine (PCV-7) has been incompletely studied in very-low-birth-weight (VLBW, ≤1500 grams) infants.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1097/INF.0b013e3181d264a6
PMCID: PMC2949965  PMID: 20234331
Infant, premature; infant, very low birth weight; pneumococcal vaccines; immunization; vaccines
17.  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 
Objectives
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.
Method
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.
Results
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.
Conclusions
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.
doi:10.1111/j.1651-2227.2010.01688.x
PMCID: PMC2875328  PMID: 20105142
Plasma bilirubin; unbound bilirubin; Extremely low birth weight infants; Neurodevelopmental outcomes
18.  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.
Objective
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.
Results
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.
Conclusions
Clinical models were better than head ultrasound models in predicting neurodevelopment.
doi:10.1016/j.jpeds.2007.04.013
PMCID: PMC2879162  PMID: 17961693
Logistic models; Predictive value of tests; ROC curve; Infant; premature; Intracerebral hemorrhage; Leukomalacia; periventricular
19.  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

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