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).
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.
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.
brain injury; hypertension; preterm; weight gain velocity
To identify among extremely low birth weight (≤ 1000 grams) live births, the percent of infants who are unimpaired at 18–22 months corrected age.
Unimpaired outcome was defined as both Bayley-II MDI and PDI Scores ≥ 85, a normal neurological exam, normal vision, normal hearing and normal swallowing and ambulating. Outcomes at 18–22 months were determined for 5250 (86%) of 6090 ELBW inborn infants. Group comparisons were made and regression models were developed to identify factors associated with unimpaired outcome.
Of the 5250 infants whose outcome was known at 18 months, 850 (16%) were unimpaired, 1153 (22%) had mild impairments, 1147 (22%) had moderate to severe neurodevelopmental impairments and 2100 (40%) had died. Unimpaired survival rates varied by birth weight from <1% for infants ≤ 500 grams to 24% for infants 901–1000 grams for all live births. The regression model to predict unimpaired survival versus death or impairment for live births ( n=5250) identified that 25.3% of the variance was derived from infant factors present at birth including female gender, higher birth weight, singleton, and small for gestation, and less than 2% was explained either by maternal demographic factors or selected obstetric interventions. For the 3232 infants discharged from the NICU, the unimpaired survival rate was 26%. The regression model to predict unimpaired survival for discharged infants identified that most of the variance was derived from combined effects of major neonatal morbidities, neonatal interventions, and maternal demographics (15.7%) and only 8.5% was derived from infant factors present at birth.
Although <1% of ELBW live births ≤ 500 grams survive free of impairment at 18 months this increases to almost 24% for infants 901–1000 grams. Female gender, singleton, higher birth weight, absence of neonatal morbidities, private health insurance and White race increase the likelihood of unimpaired status.
Extremely low birth weight; outcomes; neurodevelopmental impairment
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.
Prospective evaluation of ELBW infants to quantify the relative risks of maternal age and multiple birth for death or adverse neurodevelopmental outcome.
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.
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.
outcomes; neurodevelopmental impairment; death
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.
Very low birth weight; preterm birth; language development; preschool outcome; middle childhood development; indomethacin; intraventricular hemorrhage
Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine.
To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low birth weight infants.
Retrospective cohort analysis of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998–2009 and evaluated at 18–22 months’ corrected age.
22 academic neonatal intensive care units.
Inclusion criteria were: birth weight 401–1500 g; survival to 12 hours; available for follow-up. Some conditions were excluded. 12 111 infants were included in analyses, 87% of those eligible.
Surgical procedures; surgery also classified by expected anesthesia type as major (general anesthesia) or minor surgery (non-general anesthesia).
MAIN OUTCOME MEASURES
Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted means of Bayley Scales of Infant Development, Second Edition, Mental Developmental Index and Psychomotor Developmental Index for patients born before 2006.
There were 2186 major, 784 minor and 9141 no surgery patients. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% confidence interval 1.08–1.55). For patients who had major surgery compared with those who had no surgery the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% confidence interval 1.24–1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery the adjusted odds ratio for neurodevelopmental impairment was 1.56 (95% confidence interval 1.26–1.93) and the adjusted mean Mental Developmental Index and mean Psychomotor Developmental Index values were lower.
CONCLUSIONS AND RELEVANCE
Major surgery in very low birth weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18–22 months’ corrected age. The role of general anesthesia is implicated but remains unproven.
To explore the early childhood pulmonary outcomes of infants who participated in the NICHD SUPPORT Trial, using a factorial design that randomized extremely preterm infants to lower vs. higher oxygen saturation targets and delivery room CPAP vs. intubation/surfactant, found no significant difference in the primary composite outcome of death or BPD.
The Breathing Outcomes Study, a prospective secondary to SUPPORT, assessed respiratory morbidity at 6 month intervals from hospital discharge to 18–22 months corrected age (CA). Two pre-specified primary outcomes, wheezing more than twice per week during the worst 2 week period and cough longer than 3 days without a cold were compared between each randomized intervention.
One or more interviews were completed for 918 of 922 eligible infants. The incidence of wheezing and cough were 47.9% and 31.0%, respectively, and did not differ between study arms of either randomized intervention. Infants randomized to lower vs. higher oxygen saturation targets had similar risks of death or respiratory morbidities (except for croup, treatment with oxygen or diuretics at home). Infants randomized to CPAP vs. intubation/surfactant had fewer episodes of wheezing without a cold (28.9% vs. 36.5%, p<0.05), respiratory illnesses diagnosed by a doctor (47.7% vs. 55.2%, p<0.05) and physician or emergency room visits for breathing problems (68.0% vs. 72.9%, p<0.05) by 18–22 months CA.
Treatment with early CPAP rather than intubation/surfactant is associated with less respiratory morbidity by 18–22 months CA. Longitudinal assessment of pulmonary morbidity is necessary to fully evaluate the potential benefits of respiratory interventions for neonates.
Bronchopulmonary Dysplasia; Infant, Newborn; Infant, Low Birth Weight; Infant, Extremely Low Birth Weight; Infant, Premature; Infant, Extremely Low Gestational Age; Infant mortality; Respiratory morbidity; Intensive care, neonatal; Hospital Readmission; Oximetry; Randomized controlled trial; Retinopathy of prematurity (ROP); Continuous Positive Airway Pressure; Intubation, endotracheal; Pulmonary surfactants/therapeutic use; Oxygen inhalation therapy/methods; Oxygen administration & dosage; Follow-up studies
To evaluate the incidence of death or neurodevelopmental impairment (NDI) at 18 to 22 months corrected age in subjects enrolled in a trial of early dexamethasone treatment to prevent death or chronic lung disease in extremely low birth weight infants.
Evaluation of infants at 18 to 22 months corrected age included anthropomorphic measurements, a standard neurological examination, and the Bayley Scales of Infant Development-II, including the Mental Developmental Index (MDI) and the Psychomotor Developmental Index (PDI). NDI was defined as moderate or severe cerebral palsy, MDI or PDI less than 70, blindness, or hearing impairment.
Death or NDI at 18 to 22 months corrected age was similar in the dexamethasone and placebo groups (65 vs 66 percent, p= 0.99 among those with known outcome). The proportion of survivors with NDI was also similar, as were mean values for weight, length, and head circumference and the proportion of infants with poor growth (50 vs 41 percent, p=0.42 for weight less than 10th percentile). Forty nine percent of infants in the placebo group received treatment with corticosteroid compared to 32% in the dexamethasone group (p=0.02).
The risk of death or NDI and rate of poor growth were high but similar in the dexamethasone and placebo groups. The lack of a discernible effect of early dexamethasone on neurodevelopmental outcome may be due to frequent clinical corticosteroid use in the placebo group.
neurodevelopmental outcome; growth; bronchopulmonary dysplasia; cerebral palsy; neonatal follow-up
Infant; premature; infant; very low birth weight; Haemophilus influenzae vacines; immunization; vaccines
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).
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.
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.
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.
encephalopathy; hypoxia-ischemia; hypothermia; cerebral palsy; growth
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.
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.
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).
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.
Candida; Neonatal sepsis; Neurodevelopmental and Prematurity
To determine the association between 10 min Apgar scores and 6–7-year outcomes in children with perinatal hypoxic-ischaemic encephalopathy (HIE) enrolled in the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) whole body cooling randomised controlled trial (RCT).
Evaluations at 6–7 years included the Wechsler Preschool and Primary Scale of Intelligence III or Wechsler Intelligence Scale for Children IV and Gross Motor Functional Classification Scale. Primary outcome was death/moderate or severe disability. Logistic regression was used to examine the association between 10 min Apgar scores and outcomes after adjusting for birth weight, gestational age, gender, outborn status, hypothermia treatment and centre.
In the study cohort (n=174), 64/85 (75%) of those with 10 min Apgar score of 0–3 had death/disability compared with 40/89 (45%) of those with scores >3. Each point increase in 10 min Apgar scores was associated with a significantly lower adjusted risk of death/disability, death, death/IQ <70, death/cerebral palsy (CP) and disability, IQ<70 and CP among survivors (all p<0.05). Among the 24 children with a 10 min Apgar score of 0, five (20.8%) survived without disability. The risk-adjusted probabilities of death/disability were significantly lower in cooled infants with Apgar scores of 0–3; there was no significant interaction between cooling and Apgar scores (p=0.26).
Among children with perinatal HIE enrolled in the NICHD cooling RCT, 10 min Apgar scores were significantly associated with school-age outcomes. A fifth of infants with 10 min Apgar score of 0 survived without disability to school age, suggesting the need for caution in limiting resuscitation to a specified duration.
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.
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.
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).
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.)
To compare neurodevelopmental outcomes at 18–22 months corrected age for extremely low gestational age infants with low grade (Grade 1 or 2) periventricular-intraventricular hemorrhage to infants with either no hemorrhage or severe (Grade 3 or 4) hemorrhage on cranial ultrasound.
Longitudinal observational study
Sixteen centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
1472 infants born at <27 weeks gestational age between 2006–2008 with ultrasound results within the first 28 days of life and surviving to 18–22 months with complete follow-up assessments were eligible.
Low grade periventricular-intraventricular hemorrhage
Outcomes included cerebral palsy, gross motor functional limitation, Bayley III cognitive and language scores, and composite measures of neurodevelopmental impairment. Regression modeling evaluated the association of hemorrhage severity with adverse outcomes while controlling for potentially confounding variables and center differences.
Low grade hemorrhage was not associated with significant differences in unadjusted or adjusted risk of any adverse neurodevelopmental outcome compared to infants without hemorrhage. Compared with low grade hemorrhage, severe hemorrhage was associated with decrease in adjusted continuous cognitive (−3.91, [95% Confidence Interval [CI]: −6.41, −1.42]) and language (−3.19 [−6.19, −0.19]) scores as well as increased odds of each adjusted categorical outcome except severe cognitive impairment (OR: 1.46 [0.74, 2.88]) and mild language impairment (OR: 1.35 [0.88, 2.06]).
At 18–22 months, the neurodevelopmental outcomes of extremely low gestational age infants with low grade periventricular-intraventricular hemorrhage are not significantly different from those without hemorrhage.
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.
encephalopathy; hypoxia-ischemia; hyperthermia; cerebral palsy
To evaluate characteristics of unimpaired outcome in ELBW survivors.
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.
extremely low birth weight; unimpaired outcome; outcome; antenatal steroids; cerebral palsy
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.
Preterm; cerebellum; language systems; functional MRI; resting state intrinsic connectivity contrast degree
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.
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.
examiner training; neurodevelopmental outcome; inter-rater agreement
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.
VLBW; immune response; vaccine; sepsis; blood stream infection
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.
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.
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.
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.
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.
Autism; Prematurity; Screening
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.
respiratory sinus arrhythmia; emotion regulation; prematurity; behavior problems; behavioral parent training
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.
extremely low birth weight infant; intestinal perforation; indometacin; cerebral palsy
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.
cardiac vagal regulation; RSA suppression; emotion regulation; prematurity; child; parent training
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).
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.
development; prematurity; Bayley Scales; BSID
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.
prematurity; infant mortality; neonatal intensive care; neurodevelopmental impairment; lung maturation; limits of viability