David T. Scott

Early Intervention in Low Birth Weight Premature Infants: Results at 18 Years of Age for the Infant Health and Development Program

OBJECTIVE. To assess whether improvements in cognitive and behavioral development seen in preschool educational programs persist, we compared those in a multisite randomized trial of such a program over the first 3 years of life (INT) to those with follow-up only (FUO) at 18 months of age. METHODS. This was a prospective follow-up of the Infant Health and Development Program at 8 sites heterogeneous for sociodemographic characteristics. Originally 985 children were randomized to the INT (n = 377) or FUO (n = 608) groups within 2 birth weight strata: heavier low birth weight (HLBW; 2001–2499 g) and lighter low birth weight (LLBW; ≤2000 g). Primary outcome measures were the Peabody Picture Vocabulary Test (PPVT-III), reading and mathematics subscales of the Woodcock-Johnson Tests of Achievement, youth self-report on the Total Behavior Problem Index, and high-risk behaviors on the Youth Risk Behavior Surveillance System (YRBSS). Secondary outcomes included Weschler full-scale IQ, caregiver report on the Total Behavior Problem Index, and caregiver and youth self-reported physical health using the Medical Outcome Study measure. Assessors were masked as to study status. RESULTS. We assessed 636 youths at 18 years (64.6% of the 985, 72% of whom had not died or refused at prior assessments). After adjusting for cohort attrition, differences favoring the INT group were seen on the Woodcock-Johnson Tests of Achievement in math (5.1 points), YRBSS (−0.7 points), and the PPVT-III (3.8 points) in the HLBW youth. In the LLBW youth, the Woodcock-Johnson Tests of Achievement in reading was higher in the FUO than INT group (4.2). CONCLUSIONS. The findings in the HLBW INT group provide support for preschool education to make long-term changes in a diverse group of children who are at developmental risk. The lack of observable benefit in the LLBW group raises questions about the biological and educational factors that foster or inhibit sustained effects of early educational intervention.

Formula Supplementation With Long-chain Polyunsaturated Fatty Acids: Are There Developmental Benefits?

Objective. To evaluate the developmental outcomes of children who participated in an augmented randomized clinical trial of supplementing a standard infant formula with long-chain polyunsaturated fatty acids. Design. Randomized clinical trial, augmented with a nonrandomized human milk comparison group. There were three randomized formula groups: standard formula, standard formula containing docosahexaenoic acid (DHA), and standard formula containing DHA and arachidonic acid. Setting. Three clinical sites serving diverse populations: Kansas City, MO; Portland, OR; and Seattle, WA. Participants. A total of 274 healthy full-term infants were enrolled in the infant-feeding protocol; of these, 197 (72%) participated in assessments of developmental outcome. Formula Supplements. In the randomized trial, one group received a standard formula, another group received a formula that had been supplemented with DHA from fish oil, and a third group received a formula supplemented with both DHA and arachidonic acid from an egg phospholipid. Outcome Measures. Mental and Motor Scales of the Bayley Scales of Infant Development at 12 months of age; vocabulary and gesture communication scores from the MacArthur Communicative Development Inventories at 14 months of age. Results. There were no statistically significant differences for either the Bayley Mental Scale or the Bayley Motor Scale, neither when the analysis was restricted to the three randomized formula groups nor when the analysis included all four groups. However, the DHA formula group had significantly lower scores on two of the MacArthur scales: the DHA group scored lower than the nonrandomized human milk comparison group on the Vocabulary Comprehension Scale, and the DHA group scored lower than the randomized control formula group on the Vocabulary Production Scale. Moreover, additional analyses both in the formula groups and in the human milk comparison group found significant negative correlations between DHA levels and vocabulary outcomes. Conclusion. We believe that additional research should be undertaken before the introduction of these supplements into standard infant formulas.

Intraventricular hemorrhage in the preterm neonate: timing and cerebral blood flow changes

Serial cranial ultrasound studies, 133xenon inhalation cerebral blood flow determinations, and risk factor analyses were performed in 31 preterm neonates. Contrast echocardiographic studies were additionally performed in 16 of these 31 infants. Sixty-one percent were found to have germinal matrix or intraventricular hemorrhage. Seventy-four percent of all hemorrhages were detected by the thirtieth postnatal hour. The patients were divided into three groups: early GMH/IVH by the sixth postnatal hour (eight infants) interval GMH/IVH from 6 hours through 5 days (10), and no GMH/IVH (12). Cerebral blood flow values at 6 postnatal hours were significantly lower for the early GMH/IVH group than for the no GMH/IVH group (P less than 0.01). Progression of GMH/IVH was observed only in those infants with early hemorrhage, and these infants had a significantly higher incidence of neonatal mortality. Ventriculomegaly as determined by ultrasound studies was noted equally in infants with and without GMH/IVH (50%) and was not found to correlate with low cerebral blood flow. The patients with early hemorrhage were distinguishable by their need for more vigorous resuscitation at the time of birth and significantly higher ventilator settings during the first 36 postnatal hours, during which time they also had higher values of PCO2. An equal incidence of patent ductus arteriosus was found across all of the groups. We propose that early GMH/IVH may be related to perinatal events and that the significant decrease in cerebral blood flow found in infants with early GMH/IVH is secondary to the presence of the hemorrhage itself. Progression of early GMH/IVH and new interval GMH/IVH may be related to later neonatal events known to alter cerebral blood flow.

Construction and validation of a quality of life questionnaire for neuromuscular disease (INQoL).

Background: Because there is no muscle disease specific measure of quality of life (QoL), we wanted to develop and validate an individualized muscle disease specific measure of QoL for adults suitable for both clinical and research use. Methods: A literature review exploring QoL and its measurement resulted in the development of a theoretical model of QoL. This was used alongside qualitative interviews (n = 41) and a postal survey (n = 252) to design a questionnaire. The psychometric properties, validity (n = 95), reliability (n = 40), and responsiveness (n = 25) of the scale were assessed. Results: The Individualized Neuromuscular Quality of Life questionnaire (INQoL) consists of 45 questions within 10 sections. Four of these focus on the impact of key muscle disease symptoms (weakness, locking [i.e., myotonia], pain, and fatigue), five look at the impact (degree and importance of impact) muscle disease has on particular areas of life, and one section asks about the positive and negative effects of treatment. The questionnaire is structured to allow for variations in the individual characteristics that influence quality of life. Psychometric evaluation established construct validity and test–retest reliability. A preliminary assessment of responsiveness was obtained. Conclusions: The Individualized Neuromuscular Quality of Life is a validated muscle disease specific measure of quality of life developed from the experiences of patients with muscle disease and can be used for individuals or large samples.

Randomized indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight infants.

We admitted 48 preterm neonates (600 to 1250 gm birth weight, normal 6-hour echoencephalograms) to a randomized prospective indomethacin or placebo trial for the prevention of neonatal intraventricular hemorrhage. Beginning at 6 postnatal hours, indomethacin or placebo was administered intravenously every 12 hours for a total of five doses. Cardiac ultrasound studies to assess the status of the ductus arteriosus were performed at 6 postnatal hours and on day 5. Urinary output, serum electrolytes, and renal and clotting functions were monitored. No differences in birth weight, gestational age, Apgar scores, or ventilatory needs were noted between the two groups. Six infants given indomethacin had intraventricular hemorrhage, compared to 14 control infants (P = 0.02). The indomethacin-treated group had significant decreases in serum prostaglandin values 30 hours after the initiation of therapy. The overall incidence of patent ductus arteriosus was 82% at 6 postnatal hours; 84% of the indomethacin-treated infants experienced closure of the ductus, compared to 60% of the placebo-treated patients. Closure of the ductus was not related to incidence of intraventricular hemorrhage. We speculate that indomethacin may provide some protection against neonatal intraventricular hemorrhage by acting on the cerebral microvasculature.

Low-dose indomethacin therapy and extension of intraventricular hemorrhage: a multicenter randomized trial.

We enrolled 61 neonates of 600 to 1250 gm birth weight with evidence of low-grade intraventricular hemorrhage at 6 to 11 hours of age in a prospective, randomized, placebo-controlled trial to test the hypothesis that indomethacin (0.1 mg/kg given intravenously at 6 to 12 postnatal hours and every 24 hours for two more doses) would prevent extension of intraventricular hemorrhage. Twenty-seven infants were assigned to receive indomethacin; 34 infants received saline placebo. There were no significant differences between the two groups in birth weight, gestational age, sex, Apgar scores, percentage of infants treated with surfactant, or distribution of hemorrhages at the time of the first cranial sonogram (echo-encephalogram). Within the first 5 days, 9 of 27 indomethacin-treated and 12 of 34 saline solution-treated infants had extension of their initial intraventricular hemorrhage (p = 1.00). Four indomethacin-treated and three saline solution-treated infants had parenchymal extension of the hemorrhage. Indomethacin was associated with closure of a patent ductus arteriosus by the fifth day of life (p = 0.003). There were no differences in adverse events attributed to indomethacin. We conclude that in very low birth weight infants with low grade intraventricular hemorrhage within the first 6 postnatal hours, prophylactic indomethacin therapy promotes closure of the patent ductus arteriosus and is not associated with adverse events, but does not affect the cascade of events leading to parenchymal involvement of intracranial hemorrhage.

Randomized low-dose indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates

We admitted 36 preterm neonates (600 to 1250 gm birth weight) with normal 6-hour echoencephalograms to a randomized, placebo-controlled prospective trial to determine whether a low dose of indomethacin would prevent germinal matrix or intraventricular hemorrhage and permit adequate urinary output. Between the sixth and tenth postnatal hours, indomethacin (0.1 mg/kg) or placebo was administered intravenously every 24 hours for a total of three doses. Cardiac ultrasound studies to assess the status of the ductus arteriosus were performed at 6 postnatal hours and on day 5. Urinary output, serum electrolytes, serum indomethacin levels, and renal and clotting functions were monitored. No differences in birth weight, gestational age, or Apgar scores were noted between the two groups of infants. Two indomethacin-treated infants and three infants given placebo had significant urinary output difficulties, requiring that the study medication be withheld. Of 19 infants given indomethacin, two had germinal matrix or intraventricular hemorrhage, in comparison with 8 of 17 infants given saline solution (p = 0.02). Of the infants who had a left-to-right patent ductus arteriosus shunt before treatment, 64% of the indomethacin-treated and 33% of the saline solution-treated infants no longer had a patent ductus arteriosus on day 5. Ductal status appeared unrelated to the development of germinal matrix or intraventricular hemorrhage.

Beagle puppy model of intraventricular hemorrhage Randomized indornethacin prevention trial

The newborn beagle puppy has been demonstrated to provide a good model for neonatal intraventricular hemorrhage (IVH). By randomized computerized design, indomethacin, a known inhibitor of prostaglandin synthetase, was administered to newborn beagle puppies, all of which underwent the experimental model of hemorrhagic hypotension followed by volume reexpansion for the production of IVH, to determine whether indomethacin can prevent intraventricular hemorrhage in this model. Nine percent of all pups receiving indomethacin experienced intraventricular hemorrhage, compared with 80% of animals who received the saline vehicle. In addition, significant alterations in the blood pressure responses to the hemorrhagic hypotension/volume reexpansion insult were noted in this group when compared with control animals.

Long-Term Perspective on Premature Infant Outcome and Contemporary Intervention Issues

Despite improvements in survival rates for low birthweight (LBW) infants, the prevalence among survivors of major neurodevelopmental impairment seems relatively stable. Cerebral palsy, the most common major impairment, can usually be ruled out by 18 months corrected age. Minor impairments such as learning disabilities cannot be ruled out until much later. The efficacy of interventional services in this population was addressed by a national randomized trial. The intervention produced large treatment effects for heavier LBW infants and moderate effects for lighter infants. Five years later, modest residual effects were found for heavier LBW infants, but not for the lighter, suggesting that 0 to 3 services alone are not sufficient to prevent scholastic disadvantage in this population.

Alcohol Intoxication Effects on Visual Perception: An fMRI Study

We examined the effects of two doses of alcohol (EtOH) on functional magnetic resonance imaging (fMRI) activation during a visual perception task. The Motor‐Free Visual Perception Test–Revised (MVPT‐R) provides measures of overall visual perceptual processing ability. It incorporates different cognitive elements including visual discrimination, spatial relationships, and mental rotation. We used the MVPT‐R to study brain activation patterns in healthy controls (1) sober, and (2) at two doses of alcohol intoxication with event‐related fMRI. The fMRI data were analyzed using a general linear model approach based upon a model of the time course and a hemodynamic response estimate. Additionally, a correlation analysis was performed to examine dose‐dependent amplitude changes. With regard to alcohol‐free task‐related brain activation, we replicate our previous finding in which SPM group analysis revealed robust activation in visual and visual association areas, frontal eye field (FEF)/dorsolateral prefrontal cortex (DLPFC), and the supplemental motor area (SMA). Consistent with a previous study of EtOH and visual stimulation, EtOH resulted in a dose‐dependent decrease in activation amplitude over much of the visual perception network and in a decrease in the maximum contrast‐to‐noise ratio (in the lingual gyrus). Despite only modest behavior changes (in the expected direction), significant dose‐dependent activation increases were observed in insula, DLPFC, and precentral regions, whereas dose‐dependent activation decreases were observed in anterior and posterior cingulate, precuneus, and middle frontal areas. Some areas (FEF/DLPFC/SMA) became more diffusely activated (i.e., increased in spatial extent) at the higher dose. Alcohol, thus, appears to have both global and local effects upon the neural correlates of the MVPT‐R task, some of which are dose dependent. Hum. Brain Mapping 21:15–26, 2004.