Adolescents born prematurely with isolated grade 2 haemorrhage in the early 1990s face increased risks of learning challenges.

AIM: To compare the impact of low-grade haemorrhage on neurocognitive function in 16-year-old adolescents born preterm, by grade of intraventricular haemorrhage, and term controls. METHODS: We evaluated 338 preterm adolescents (birth weight 600-1250 g) for intelligence, executive function and memory tasks. Eleven had grade 3-4 haemorrhage, 44 had grade 2, 31 had grade 1, and 251 had no haemorrhage. Group comparisons were made with 102 term age-matched controls, and regression models used to identify the risk that low-grade haemorrhage posed for cognitive, executive function and memory deficits. RESULTS: Preterm adolescents with grade 2 haemorrhage had higher deficit rates of verbal intelligence, receptive vocabulary, phonemic fluency, cognitive flexibility and phonological fluency than preterm adolescents with grade 1 or no haemorrhage, compared with term controls. After excluding preterm adolescents with both grade 2 haemorrhage and cystic periventricular leukomalacia, those with isolated grade 2 haemorrhage remained at greater risk of cognitive and executive function deficits than term controls and of cognitive deficits than preterm adolescents with no haemorrhage. CONCLUSION: Our findings suggest that preterm adolescents born in the early 1990s with isolated grade 2 haemorrhage are at increased risk of learning challenges, including cognitive and executive function deficits.

Early predictors of hypertension in prematurely born adolescents.

OBJECTIVE: To assess the blood pressure of former preterm and term matched adolescent controls and to identify risk factors associated with blood pressure at 16 years. DESIGN: Observational cohort study. Secondary analysis of a randomized clinical trial. SETTING: Three academic centres participating in the Multicenter Indomethacin IVH Prevention Trial. PARTICIPANTS: A total of 296 children born in 1989-1992 with birth weights 600 to <1250 g 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. RESULTS: 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<0.001), pre-eclampsia (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). CONCLUSIONS: 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.

Maternal obesity and markers of inflammation in pregnancy.

OBJECTIVES: To evaluate whether obesity is associated with changes in pro-inflammatory and immunomodulatory cytokines in pregnancy. METHODS: We performed a cross-sectional study using maternal serum from the early second trimester to examine biomarkers associated with inflammation in relation to maternal body mass index (n=80 total). RESULTS: Leptin and high sensitivity C-reactive protein were significantly different between groups and increased with increasing body mass index. MCP-1 was significantly increased in the morbidly obese mothers. Interleukin-2 exhibited a U-shaped relationship with body mass index; transforming growth factor-beta1 demonstrated a nonsignificant negative trend with body mass index; and the levels of hepatocyte growth factor and tumor necrosis factor-alpha did not differ appreciably between groups. CONCLUSIONS: Maternal obesity in pregnancy is associated with changes in cytokines, protein hormones and acute phase proteins in the second trimester, with an increase in MCP-1 in the morbid obesity category, and an increase in Leptin and hsCRP with increasing BMI category.

Seizures, syncope, or breath-holding presenting to the pediatric neurologist--when is the etiology a life-threatening arrhythmia?

Using case reports from their own experience and in the literature the authors illustrate the difficulty in distinguishing non-life threatening causes, including epilepsy, from a serious cardiac arrythmia when evaluating children with paroxysmal events. Focusing on long QT syndrome, they suggest an approach for the pediatric neurologist that utilizes the electrocardiogram recorded during the electroencephalogram--direct measurement of the corrected QT interval. This approach requires knowledge of the distribution of the corrected QT interval in long QT syndrome.

Neonatal intensive care neurology.

The pediatric neurologist's role in the neonatal intensive care unit is described in four clinical settings: (1) assessment of outcome in neonatal encephalopathy, (2) treatment of seizures in full-term infants, (3) assessment and treatment of intraventricular hemorrhage with posthemorrhagic hydrocephalus, and (4) assessment of outcome in preterm infants. Emphasis is placed on the evidenced-based information available in these settings and on new therapies on the horizon. Using evidence-based information, the pediatric neurologist can accurately assess prognosis in the neonatal period, and this can provide the basis for a rational assessment of newer therapies in neonatal intensive care.

Perceptual organization based upon spatial relationships in Alzheimer's disease.

Alzheimer's disease (AD) is often accompanied by impaired object recognition, thereby reducing the ability to recognize common objects and familiar faces. Impaired recognition may stem from decreased efficacy in integrating visual information. Studies of perceptual abnormalities in AD indicate an impairment in organizing elements of the visual scene, thereby confusing components of individual forms. This type of impairment is consistent with the characteristics of neural loss, which impact cortical integration. To examine the extent to which perceptual organization is impaired in AD, psychophysical measurements were made of visual perceptual grouping based upon spatial relationships in a group of AD patients and demographically matched elderly control subjects. A comparison was also made between young and elderly control subjects to evaluate the effects of aging on these capacities. Deficits in perceptual organization were found for a subgroup of AD patients, which corresponded to impairment on facial recognition. A less profound functional decline was found for the elderly control group. The degree of impairment for AD subjects did not correlate to level of dementia, but instead appears to be idiosyncratic to individual patients. These results are consistent with impaired integrative function in AD, the degree of which reflects individual differences in the regional distribution of neuropathological changes.

Mid-gestational maternal free thyroxine concentration and offspring neurocognitive development at age two years.

CONTEXT: Lower neurocognitive development scores at age 2 yr have been reported in association with euthyroid hypothyroxinemia during early pregnancy. OBJECTIVE: The objective of this study was to further explore this association with euthyroid hypothyroxinemia during early pregnancy. DESIGN: This was an observational, nested case-control study. SETTING: The study was conducted at physician offices and prenatal clinics throughout Maine. STUDY SUBJECTS: Between May 2004 and March 2006, TSH was measured in 5734 women in conjunction with second-trimester Down syndrome screening. After completion of pregnancy, free T(4) was measured in stored second-trimester sera from euthyroid women (TSH 0.1-3.5 mIU/ml; n = 5560). Women with free T(4) at the third centile or less (n = 99) were matched with women whose free T(4) was at the 10th to the 90th centile (n = 99). INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: Bayley Scales of Infant Development (BSID III) were administered to the 198 offspring at age 2 yr. Scores for cognitive, language, and motor development were compared between matched pairs of offspring from the two groups before and after correcting for relevant variables. RESULTS: Unadjusted BSID-III scores (cognitive, language, and motor) were lower by about 3% at age 2 yr among offspring of 98 hypothyroxinemic women (cases), reaching borderline significance for cognitive and motor scores. After adjustment for gestational age, the child's age at testing, maternal weight, and education, all differences diminished and became nonsignificant. Scores less than 85 were more frequent among case children but did not reach statistical significance (P = 0.14). CONCLUSIONS: Isolated hypothyroxinemia during the second trimester is not associated with significantly lower BSID-III scores at age 2 yr, compared with scores for offspring of matched euthyroxinemic women.

Executive and memory function in adolescents born very preterm.

BACKGROUND: Many preterm children display school difficulties, which may be mediated by impairment in executive function and memory. OBJECTIVE: To evaluate executive and memory function among adolescents born preterm compared with term controls at 16 years. METHODS: A total of 337 of 437 (77%) adolescents born in 1989 to 1992 with a birth weight < 1250 g and 102 term controls were assessed with a battery of executive function and memory tasks. Multiple regression analyses were used to compare groups and to identify associations between selected factors and outcomes among preterm subjects. RESULTS: Adolescents born preterm, compared with term controls, showed deficits in executive function in the order of 0.4 to 0.6 SD on tasks of verbal fluency, inhibition, cognitive flexibility, planning/organization, and working memory as well as verbal and visuospatial memory. After exclusion of adolescents with neurosensory disabilities and full-scale IQ < 70, significant group differences persisted on most tests. Preterm subjects, compared with term controls, were at increased risk of exhibiting problems related to executive dysfunction, as measured with the Behavior Rating Inventory of Executive Function, on the Metacognition Index (odds ratio [OR]: 2.5 [95% confidence interval (CI): 1.2-5.1]) and the Global Executive Composite (OR: 4.2 [95% CI: 1.6-10.9]), but not on the Behavioral Regulation index (OR: 1.5 [95% CI: 0.7-3.5]). Among adolescents born preterm, severe brain injury on neonatal ultrasound and lower maternal education were the most consistent factors associated with poor outcomes. CONCLUSIONS: Even after exclusion of preterm subjects with significant disabilities, adolescents born preterm in the early 1990s were at increased risk of deficits in executive function and memory.

Evidence for catch-up in cognition and receptive vocabulary among adolescents born very preterm.

BACKGROUND: Very preterm adolescents display persistent deficits in neuropsychological functions. OBJECTIVE: To compare cognitive and language outcomes at 16 years and cognitive and receptive vocabulary trajectories throughout school years between very preterm and term children and to determine child and family factors associated with better developmental trajectories. DESIGN AND METHODS: At 8, 12, and 16 years, 322 very preterm children with birth weights of 1250 g or less and 41 term children had cognitive and language testing. Hierarchical growth-curve modeling was used to delineate the differences in cognitive and receptive vocabulary development between participants. Cluster analyses allowed for the characterization of very preterm children with different patterns of cognitive and receptive vocabulary development. RESULTS: At 16 years, very preterm adolescents had deficits in general cognition and higher-order language skills (phonological awareness and phonemic decoding) compared with term peers. Although the between-group difference in cognitive scores remained stable from 8 to 16 years, very preterm children demonstrated catch-up gains in receptive vocabulary during the same period. Moreover, subgroups of very preterm children displayed developmental trajectories in cognition similar to term children (55% on the vocabulary and 46% on the block-design subtests). These children had lower rates of neurosensory impairment and mothers with higher education and were from an ethnic nonminority. CONCLUSIONS: Significant catch-up in receptive vocabulary is observed by the age of 16 years among very preterm children compared to term peers. The absence of neurosensory impairment and residing in a favorable socioeconomic milieu are associated with the most optimal developmental trajectories.

Maternal obesity, gestational hypertension, and preterm delivery.

OBJECTIVE: To study maternal obesity as a risk factor for preterm delivery. METHODS: Maine State Birth Records Database from 1996 through 2006 was evaluated to investigate obese pregnant women compared with normal weight women regarding risk for preterm delivery. Multiple risk factors and outcomes were studied in univariable and multivariable models. RESULTS: Among 58,112 pregnant women, 8% (n = 4653) gave birth to preterm infants. Univariable analyses revealed a relationship between obesity and increased risk of prematurity. In multivariable regressions, the most important intermediate variable appears to be gestational hypertension/preeclampsia. CONCLUSIONS: As maternal body mass index increases in pregnancy, the risk of preterm delivery and other maternal complications increases. The obesity-prematurity relationship is complex, with hypertensive disorders of pregnancy playing a crucial role. More detailed analyses of causal pathways are warranted.

Lasting effects of preterm birth and neonatal brain hemorrhage at 12 years of age.

OBJECTIVES: Our goals were to compare cognitive, language, behavioral, and educational outcomes of preterm children to term controls and to evaluate the impact of neonatal brain injury, indomethacin, and environmental risk factors on intellectual function at 12 years of age. METHODS: A total of 375 children born in 1989-1992 with birth weights of 600 to 1250 g enrolled in the Indomethacin Intraventricular Hemorrhage Prevention Trial and 111 controls were evaluated. Neuropsychometric testing, neurologic examination, and interviews on educational needs were completed. Severe brain injury was defined as the presence of grade 3 to 4 indomethacin intraventricular hemorrhage, periventricular leukomalacia, or severe ventriculomegaly on cranial ultrasound. RESULTS: On the Wechsler Scales of Intelligence for Children, the preterm cohort obtained a full-scale IQ of 87.9 +/- 18.3, verbal IQ of 90.8 +/- 18.9, and performance IQ of 86.8 +/- 17.9. Preterm children obtained scores 6 to 14 points lower than term controls on all psychometric tests after adjustment for sociodemographic factors. On the Clinical Evaluation of Language Fundamentals (test of basic language skills), 22% to 24% of preterm children scored in the abnormal ranges (<70) as opposed to 2% to 4% of controls. Preterm children with and without brain injury required more school services (76% and 44% vs 16%), and support in reading (44% and 28% vs 9%), writing (44% and 20% vs 4%), and mathematics (47% and 30% vs 6%) compared with controls. Preterm children also displayed more behavior problems than their term counterparts. Severe neonatal brain injury was the strongest predictor of poor intelligence. Antenatal steroids, higher maternal education, and 2-parent family were associated with better cognition, whereas minority status incurred a disadvantage. Indomethacin did not affect intellectual function among preterm children. CONCLUSIONS: Preterm children born in the early 1990s, especially those with severe brain injury, demonstrate serious deficits in their neuropsychological profile, which translates into increased use of school services at 12 years.

Trajectories of receptive language development from 3 to 12 years of age for very preterm children.

OBJECTIVES: The goal was to examine whether indomethacin use, gender, neonatal, and sociodemographic factors predict patterns of receptive language development from 3 to 12 years of age in preterm children. METHODS: A total of 355 children born in 1989-1992 with birth weights of 600 to 1250 g were evaluated at 3, 4.5, 6, 8, and 12 years with the Peabody Picture Vocabulary Test-Revised. Hierarchical growth modeling was used to explore differences in language trajectories. RESULTS: From 3 to 12 years, preterm children displayed catch-up gains on the Peabody Picture Vocabulary Test-Revised. Preterm children started with an average standardized score of 84.1 at 3 years and gained 1.2 points per year across the age period studied. Growth-curve analyses of Peabody Picture Vocabulary Test-Revised raw scores revealed an indomethacin-gender effect on initial scores at 3 years, with preterm boys assigned randomly to receive indomethacin scoring, on average, 4.2 points higher than placebo-treated boys. However, the velocity of receptive vocabulary development from 3 to 12 years did not differ for the treatment groups. Children with severe brain injury demonstrated slower gains in skills over time, compared with those who did not suffer severe brain injury. Significant differences in language trajectories were predicted by maternal education and minority status. CONCLUSION: Although indomethacin yielded an initial benefit for preterm boys, this intervention did not alter the developmental trajectory of receptive language scores. Severe brain injury leads to long-term sequelae in language development, whereas a socioeconomically advantaged environment supports better language development among preterm children.

A functional magnetic resonance imaging study of the long-term influences of early indomethacin exposure on language processing in the brains of prematurely born children.

BACKGROUND: Previous studies have demonstrated that indomethacin lowers the incidence and decreases the severity of intraventricular hemorrhage, as well as improves the cognitive outcome, in prematurely born male infants. OBJECTIVE: The purpose of this work was to use functional magnetic resonance imaging to test the hypothesis that neonatal indomethacin treatment would differentially affect brain activation across genders in school-aged, prematurely born children during performance of a language task. METHODS: Forty-seven prematurely born children (600-1250-g birth weight) and 24 matched term control subjects were evaluated using a functional magnetic resonance imaging passive language task and neurodevelopmental assessments that included the Wechsler Intelligence Scale for Children-III and the Peabody Picture Vocabulary Test-Revised. Neural activity was assessed during both phonologic and semantic processing in the functional magnetic resonance imaging protocol. RESULTS: Neurodevelopmental assessments demonstrated significant differences in full-scale, verbal, and performance intelligence quotient, as well as Peabody Picture Vocabulary Test scores, between the preterm and term control subjects. Rates of perinatal complications did not differ significantly across preterm treatment groups, but male preterm subjects randomly assigned to saline tended to have lower Peabody Picture Vocabulary Test-Revised scores than did all of the other preterm groups. During phonological processing, a significant treatment-by-gender effect was demonstrated in 3 brain regions: the left inferior parietal lobule, the left inferior frontal gyrus (Broca's area), and the right dorsolateral prefrontal cortex. CONCLUSIONS: These data demonstrate a differential effect of indomethacin administration early in postnatal life on the subsequent development of neural systems that subserve language functioning in these male and female preterm infants.

Cortical recruitment patterns in children born prematurely compared with control subjects during a passive listening functional magnetic resonance imaging task.

OBJECTIVES: To use functional magnetic resonance imaging (fMRI) to test the hypothesis that subjects who were born prematurely develop alternative systems for processing language. STUDY DESIGN: Subjects who were born prematurely (n = 14; 600-1250 g birthweight) without neonatal brain injury and 10 matched term control subjects were examined with a fMRI passive listening task of language, the Clinical Evaluation of Language Fundamentals (CELF) and portions of the Comprehensive Test of Phonological Processing (CTOPP). The fMRI task was evaluated for both phonologic and semantic processing. RESULTS: Although there were differences in CELF scores between the subjects born prematurely and control subjects, there were no significant differences in the CTOPP measures in the 2 groups. fMRI studies demonstrated that the groups differentially engaged neural systems known to process language. Children born at term were significantly more likely to activate systems for the semantic processing of language, whereas subjects born prematurely preferentially engaged regions that subserve phonology. CONCLUSIONS: At 12 years of age, children born prematurely and children born at term activate neural systems for the auditory processing of language differently. Subjects born prematurely engage different networks for phonologic processing; this strategy is associated with phonologic language scores that are similar to those of control subjects. These biologically based developmental strategies may provide the substrate for the improving language skills noted in children who are born prematurely.

Telegenetics in Maine: Successful clinical and educational service delivery model developed from a 3-year pilot project.

PURPOSE: The goal of this 3-year pilot project was to increase accessibility to genetics educational and clinical services in Maine. METHODS: Southern Maine Genetics Services, Foundation for Blood Research in collaboration with Maine Telemedicine Services established telemedicine capacity to link with rural health care centers located in Northern, Central, and Southern Maine and public health nursing statewide for the provision of genetics clinical and educational services. Core partners included a rural family practice residency program, a rural pediatric practice in northern Maine, and public health nurses statewide. The telegenetics model created was based on development and implementation of a preventive and medical management technology solution, conducting a pilot study to collect data, and approaching insurance companies for reimbursement. Evaluation included surveys on the quality, acceptability, and usefulness of genetics services delivered via telemedicine, telephone interviews, and decision-making confidence evaluations. RESULTS: During the project period, 24 rural clinical sites participated. In total, 93 presentations were given, and 125 patients were evaluated. Sixty-four percent of patients evaluated were pediatric. Despite site coordinator efforts to complete satisfaction surveys, the provider and patient response level was low (18% and 25%, respectively). Of those evaluations received, provider and patient response to telegenetics was positive. Decision-making confidence for genetics and neurology consultants was high. Our experience contributes to the development of telegenetics models that can be used in other rural states.

An evidence-based approach to predicting low IQ in very preterm infants from the neurological examination: outcome data from the indomethacin Indomethacin Intraventricular Hemorrhage Prevention Trial.

We evaluated whether the degree of cerebral palsy (CP) at age 3 in very preterm children is predictive of full-scale intelligence quotient (FSIQ) <70 at age 8 by calculating likelihood ratios (LRs) for findings on the neurologic examination. Data from the follow-up phase of the Indomethacin Intraventricular Hemorrhage Prevention Trial, which includes periodic neurologic examination and neuropsychometric testing, were used. Information was available on 366 of 440 (83%) children with birth weight of 600 to 1250 g who survived. Neurologic examination at age 3 was grouped by presence and type of CP, and the Weschler Intelligence Scale for Children-Third Edition FSIQ at age 8 was grouped dichotomously (<70 or > or =70). CP was identified in 35 of 366 3-year-olds (9.5%). An FSIQ <70 was identified in 47 of 366 children at 8 years old (12.8%). FSIQ <70 occurred in 14 of 17 children with tri- or quadriplegia (82%), 8 of 18 children with di- or hemiplegia (44%), and 25 of 331 children without CP (7.5%). Useful LRs were calculated for tri- or quadriplegia (30), di- or hemiplegia (5.7), and children without CP (0.55). These LRs have greater impact on posttest odds for FSIQ <70 than those for birth weight <1000 g, history of bronchopulmonary dysplasia, and Stanford-Binet Intelligence Score <70 at age 3. We conclude that the neurologic examination at 3 years old predicts FSIQ <70 at age 8 with LRs that allow evidence-based parental counseling and intervention planning.

Change in cognitive function over time in very low-birth-weight infants.

CONTEXT: Preterm very low-birth-weight (VLBW) infants have a high prevalence of neurodevelopmental disability when evaluated during the first several years of life. However, recent experimental data suggest that the developing brain may recover from or compensate for injury. OBJECTIVE: To determine if there is cognitive improvement throughout early and middle childhood following VLBW birth. DESIGN, SETTING, AND PARTICIPANTS: Follow-up data of 296 infants born weighing 600 to 1250 g who participated in a prospective, randomized, placebo-controlled intraventricular hemorrhage (IVH) prevention study performed at 3 northeastern US hospitals between September 1989 and August 1992 and who were serially evaluated at 36, 54, 72, and 96 months of corrected age (CA). MAIN OUTCOME MEASURES: The age-normed Peabody Picture Vocabulary Test-Revised (PPVT-R) score and measures of intelligence. RESULTS: Overall, the median PPVT-R score increased from 88 at 36 months of CA to 99 at 96 months of CA; when data from 36 and 96 months of CA were compared, 45% of children gained 10 points or more and 12.5% showed a 5- to 9-point increase in test scores. Similar findings were noted for full-scale and verbal IQ scores. Multivariate analyses demonstrated that increasing age, residence in a 2-parent household, and higher levels of maternal education were all significantly associated with higher PPVT-R scores (for each, P<.001). In addition, early intervention led to greater increases over time in PPVT-R scores among children whose mothers had less than a high school education compared with those with a high school education level or greater (P =.03 by test for interaction). Although most children showed improvement in PPVT-R scores with increasing CA, children with early-onset IVH and subsequent significant central nervous system injury had the lowest PPVT-R scores initially and the scores declined over time (P =.009 by test for interaction). CONCLUSIONS: The majority of VLBW children had improvement in verbal and IQ test scores over time. Only children with early-onset IVH followed by significant central nervous system injury had low PPVT-R scores that declined over time.

School-age outcomes of very low birth weight infants in the indomethacin intraventricular hemorrhage prevention trial.

OBJECTIVE: The cohort consisted of 328 very low birth weight infants (600-1250 g birth weight) who were enrolled in the low-dose prophylactic indomethacin prevention trial and were intraventricular hemorrhage (IVH) negative at 6 postnatal hours. The objective was to determine the effects of both IVH and indomethacin on cognitive, language, and achievement performance at 8 years of age. METHODS: The cohort was divided into 4 subgroups for analysis: indomethacin plus IVH, indomethacin no IVH, saline plus IVH, and saline with no IVH. The children were evaluated prospectively at 8 years of age with a neurologic assessment, history of school performance, and a battery of cognitive, academic, behavioral, and functional assessments. RESULTS: Children in both IVH groups had more cerebral palsy; more hearing impairment; lower daily living skills scores; lower IQ, vocabulary, and reading and mathematics achievement test scores; and greater educational resource needs. With logistic regression analyses grade 3 to 4 IVH, periventricular leukomalacia and/or ventriculomegaly, male gender, maternal education, and language spoken in the home contributed to outcomes. No effects of indomethacin or gestational age were identified. CONCLUSIONS: Although biological factors including IVH, ventriculomegaly, and periventricular leukomalacia contribute significantly to school age outcomes among very low birth weight survivors at 8 years of age, social and environmental factors including maternal level of education and primary language spoken in the home are also important contributors to outcome.

Prevention of intraventricular hemorrhage by indomethacin in male preterm infants.

Our multicenter Indomethacin Intraventricular Hemorrhage (IVH) Prevention Trial demonstrated a reduction of IVH in preterm infants. Analysis of our cohort by sex showed indomethacin halved the incidence of IVH, eliminated parenchymal hemorrhage, and was associated with higher verbal scores at 3 to 8 years in boys.