TRANSIENT NEUROLOGICAL ABNORMALITIES: EARLY SCHOOL OUTCOMES IN EXTREMELY PREMATURE INFANTS HEIDI HARMON, M.D. Master of Science

Transcription

1 TRANSIENT NEUROLOGICAL ABNORMALITIES: EARLY SCHOOL OUTCOMES IN EXTREMELY PREMATURE INFANTS by HEIDI HARMON, M.D. Submitted in partial fulfillment of the requirements for the degree of Master of Science Clinical Research Scholars Program School of Medicine CASE WESTERN RESERVE UNIVERSITY May 2014

2 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Heidi Harmon, MD candidate for the degree of Master of Science *. Committee Chair Douglas Einstadter, M.D Committee Member H. Gerry Taylor, Ph.D. Committee Member Deanna Wilson-Costello, MD Date of Defense March 26, 2014 *We also certify that written approval has been obtained for any proprietary material contained therein.

3 TABLE OF CONTENTS List of Tables. iv List of Figures.... v Acknowledgements vi List of Abbreviations..... vii Abstract.. ix Background and Significance 1 Hypotheses and Specific Aims.. 4 Methods. 5 Study Population 5 Data Collection...7 Data Analysis. 8 Results 11 Aim Aim Aim Discussion.. 34 Bibliography.. 42 iii

4 LIST OF TABLES Table 1: Social Demographic and Clinical Characteristics of Study Population.. 12 Table 2: Maternal Sociodemographic Characteristics Table 3: Infant and Toddler Developmental Testing and al Exam.. 14 Table 4: Characteristics of Each Assessment.15 Table 5: Woodcock Johnson Tests of Cognitive Abilities.17 Table 6: Woodcock Johnson Tests of Academic Abilities 18 Table 7: Motor Testing.. 19 Table 8: Child Behavior Checklist. 20 Table 9: Longitudinal Growth Trajectories for Cognitive Outcomes 21 Table 10: Longitudinal Growth Trajectories for Academic Outcomes. 23 Table 11: Longitudinal Growth Trajectories for Motor Outcomes Table 12: Longitudinal Trajectories for Behavior Problems. 30 iv

5 LIST OF FIGURES Figure 1: Consort Diagram... 6 Figure 2: Classification Diagram of al Exam.. 11 Figure 3: Longitudinal Growth of IQ by Exam Group Figure 4: Longitudinal Growth of Verbal Comprehension Skills by Exam Group Figure 5: Longitudinal Growth of Concept Formation Skills by Exam Group Figure 6: Longitudinal Growth of Visual Matching Skills by Exam Group. 25 Figure 7: Longitudinal Growth of Spatial Relations Skills by Exam Group 26 Figure 8: Longitudinal Growth of Letter Word Identification by Exam Group 26 Figure 9: Longitudinal Growth of Spelling Skills by Exam Group Figure 10: Longitudinal Growth of Math Skills by Exam Group..27 Figure 11: Longitudinal Growth of Motor Skills by Exam Group 29 Figure 12: Longitudinal Growth of Visual Motor Integration by Exam Group 30 Figure 13: Internalizing Behavior Problems over Time 32 Figure 14: Externalizing Behavior Problems over Time Figure 15: Total Behavior Problems over Time 33 Figure 16: Attention Problems over Time v

6 ACKNOWLEDGEMENTS My sincere appreciation and thanks go to all my mentors, past and present, who have supported me in my career. I would like to thank H. Gerry Taylor, PhD, for all his mentorship and access to his tremendous dataset. I would also like to thank Dr. Maureen Hack, for her assistance in the concept design of this project. Special thanks go to Dr. Dee Wilson for her constant encouragement and assistance with study refinement. I would also like to give thanks to Nori Minich, MS, for all her assistance in statistical analysis and project design. I would also like to thank Douglas Einstadter, PhD, for his assistance with the completion of this thesis. I would also like to thank Dr. Richard Martin for the opportunity to participate in the CRSP program with the help of the division of neonatology T32 program. My most heartfelt thanks go to my husband, Devon Harmon, for his patience and support throughout fellowship and this master s program. Lastly, I would like to thank all the families and children who agreed to participate in this study. FUNDING SUPPORT A special thanks to the Rainbow Babies & Children s Foundation for their funding support through the Fellowship Research Award Program (FRAP). vi

7 This educational program and thesis were supported by Grant Number T32 - NIH 5-T32-HD Its content are solely the responsibility of the author and do not necessarily represent the official views of NIH. vii

8 LIST OF ABBREVIATIONS AB ally Abnormal Group AIC Akaike s Information Criterion ANOVA Analysis of Variance ANCOVA Analysis of Covariance BIA Brief Intellectual Ability BOT2 Bruininks-Oseretsky Test of Motor Proficiency BSID-2 Bayley Scales of Infant Development, 2 nd Edition CBCL Child Behavior Checklist CP Cerebral Palsy EP Extremely Premature g Grams IVH Intraventricular Hemorrhage MDI Mental Development Index MRI Magnetic Resonance Imaging NN ally Normal Group PDI Physical Development Index viii

9 PVL Periventricular Leukomalacia PMA Postmenstrual Age SES Socioeconomic Status SD Standard Deviation TNA Transient al Abnormalities VLBW Very Low Birth Weight VMI Visual Motor Integration ix

10 Transient al Abnormalities: Early School Outcomes in Extremely Premature Infants Abstract by HEIDI HARMON, MD Extremely premature infants often have transient neurological abnormalities (TNA) during infancy and the implications of TNA for school age functioning are unclear. The aim of this study was to determine if the neurological exam at 8 and 20 months predicts cognitive, behavioral, and motor outcomes in early elementary school. A cohort of 124 infants, admitted in , were examined in early childhood and then yearly between kindergarten and 2 nd grade. Analysis with cross-sectional study methods and mixed modeling, demonstrated an increased risk of cognitive problems, academic problems, and motor problems in children with TNA and persistent neurological abnormalities (AB) compared to those in the neurologically normal (NN) group. There is not an accelerated rate of skill acquisition in the TNA group or AB group to allow for catch-up growth compared to the NN group. Children with TNA represent a commonly unrecognized group with high risk of difficulties at school entry. x

11 Background and Significance Extremely premature (EP) infants, defined as those born prior to 28 weeks gestational age, are at an elevated risk of developmental delays and neurological injury. While survival of extremely premature infants has increased and neurosensory impairment has decreased, the burden of cognitive, learning and behavior problems is still substantial and may affect more than 50% of this population. 1,2 Unfortunately, developmental assessments in early childhood generally have poor validity in predicting which children are most likely to exhibit these problems at school age. 3 With the tightening of governmental budgets and current expenditures toward special education for children who were premature exceeding $1.5 billion annually 4, it is important to direct resources in a thoughtful manner to those most likely to benefit. Further research on early childhood characteristics associated with school-age outcomes is needed to better target interventions to the children in greatest need before school entry. For some EP infants, signs of cerebral palsy (CP) will appear during the first year of their life with abnormal muscle tone and/or delayed motor milestones. Most of these infants will go on to have the diagnosis of CP in early childhood and have lifelong physical challenges. There is a poorly studied subgroup of premature infants who exhibit these same neurological signs as those that develop cerebral palsy in infancy, but this subgroup appears to outgrow these impairments. This syndrome has previously been referred to as transient neurological abnormalities (TNA). 5 TNA affects an estimated 11%-60% of very low birth weight (VLBW), infants and an unknown number of term and larger preterm infants. 6,7 The first to recognize this pattern of transient abnormal neurological signs was C. Drillien in She described a syndrome of abnormalities in 1

12 muscle tone, posture, and primitive reflexes which resolved by 12 months corrected age. 6 Following a cohort of VLBW infants until 6-7 years of age, Drillien found that those children with TNA in infancy went on to have normal IQ but had increased learning difficulties. 8 Subsequent studies have revealed an inconsistent relationship between TNA and later motor, cognitive, and behavioral problems. Some studies have found no association of TNA with later outcomes. Sommerfelt, et al. 9 followed 93 VLBW infants born until five years of age and found no difference in cognitive, neuromotor, or behavior problems. Brandt, et al. 10 followed VLBW infants as part of the Bonn Longitudinal Study( ) into adulthood and found that the adult IQs were similar between those that had had TNA and those with a normal neurological exam in infancy. D Eugenio et. al. 11 followed infants of gestational age of weeks born until four years of age found no difference in the rates of cognitive impairment. However, other studies have reported residual difficulties later in childhood. PeBenito, et al. 13 followed a group of preterm and full-term infants with transient hypertonia in the first year of life and found frequent learning disabilities and behavior problems at five years of age. Chaudhari, et al. 14 followed a cohort of high risk infants (term and preterm) in India until five years of age and found isolated increased difficulties with language skills. Interpreting these studies is difficult because they often included heterogeneous cohorts of preterm and term infants born prior to the 1990s. The results of these studies may not reflect the outcomes for extremely low gestational age newborns managed with current neonatology practice. 2

13 To further complicate matters, there has been no evaluation of the rate of skill acquisition for children with TNA. These children, by definition, have motor delays in early childhood and it is unclear if and when they catch-up in these skills. The trajectory of cognitive growth and motor development in premature infants is poorly understood and has never been previously assessed in children with TNA. While it has been well established that VLBW are at increased risk of cognitive, motor, and behavior problems, 2,15 there have been relatively few true longitudinal studies with similar repeated measures. It is still unclear whether the deficits in early childhood will be stable over time, increase with increasingly complex tasks, or show improvement and whether the trajectory is modifiable with educational or environmental interventions. A limited number of studies in premature infants have assessed the pattern of change in cognitive testing through growth modeling or mixed modeling. Taylor, et al. 16 found a slower rate of growth in some cognitive skills for premature infants (<1,500g) compared to term infants from 7 to 14 years of age. The infants with a birth weight less than 750 grams showed stable skill acquisition overall with slower growth in perceptual-motor and executive function skills while the children 750-1,499 g had accelerated catch-up growth in some areas. Epsy, et al. 17 demonstrated differences in rate of math skill acquisition based on birth weight and medical morbidities in the same longitudinal cohort of VLBW infants between 7 to 16 years of age. Luu, et al. 18,19 found catch-up growth in language between 3 to 16 years of life in a cohort of infants with birth weight less than 1,250 g. They also found that the rate of skill acquisition varied by race, maternal education, and presence of neurosensory problems. Koller, et al. 20 and Liaw, et al. 21 both followed premature infants from infancy to preschool or early school age and found distinct 3

14 patterns of cognitive development (improvement, stable, decline) based on medical and sociodemographic factors. Neither Koller nor Liaw found any patterns of significant catch-up growth but did find the cognitive growth pattern could be predicted on maternal education, home environment, and medical factors. In addition, Koller found the neurological exam at one year of age (abnormal, suspicious, and normal) to be very predictive of cognitive growth patterns. These studies show that the rate of growth of skills for various populations can vary based on medical characteristics and social demographics. Discovering the trajectory of growth for children with TNA will provide important prognostic information for families and may provide additional information for modifiable areas of intervention. Specific Aims and Hypotheses Aim 1: To determine the current perinatal predictors of TNA for extremely preterm children. Hypothesis 1: The perinatal predictors of TNA will be similar to the risk factors of other types of motor problems in preterm infants including perinatal infections, abnormal cerebral imaging, respiratory morbidity, and postnatal steroid exposure. Aim 2: To assess and compare academic, cognitive, behavioral, and motor outcomes, in kindergarten through 2 nd grade for extremely preterm children with TNA, a normal neurological exam, or a persistently abnormal exam. Hypothesis 2: Children with TNA will have increased difficulties with academic, cognitive, motor testing, and more behavior problems in early elementary school 4

15 compared to children with a normal neurological exam in infancy. The level of impairment will increase with advancement in school as higher level tasks are required for school work. Aim 3: To assess and compare rate of skill acquisition in academic, cognitive, and motor domains between kindergarten and 2 nd grade for those that had TNA in infancy with those premature infants with normal neurological or a persistently abnormal exam. Hypothesis 3: Children with TNA will show a slower rate of skill acquisition compared to those with a normal neurological exam. Methods Study Population This was a prospective cohort study of 224 extremely preterm infants (<28 weeks gestation) admitted to the neonatal intensive care unit of Rainbow Babies & Children's Hospital in Cleveland, Ohio between January 1, 2001 and December 31, Fortyfour infants (20%) died prior to discharge and eight children with major malformations were excluded. Of the remaining 172 infants, 133 were recruited (77%). Of these 133 infants, 124 (72%) had a complete neurological exam at 8 and 20 months to allow for neurological classification (Figure 1). Of the 124 children evaluated at kindergarten there was an attrition of 10 children at first grade, and attrition of another four children by second grade. 5

16 Figure 1. Consort Diagram Total Births <28 weeks N=224 Major Congenital Abnormalities N=8 Non-recruitment 16-Lost to Follow-up 12-Moved Out of Area 5-Non-English Speaking or Amish 2-Families Declined 2-Missed Evaluation Visit 2-Custody Issues N=39 Eligible for Follow-up N=172 Recruitment for School Aged Follow-up N=133 School Aged Cohort at Kindergarten N=124 School Aged Cohort at 1st Grade N=114 School Aged Cohort at 2nd Grade N=110 Deaths N= 44 8 Month Exam Not Completed N=9 Attrition N=10 Attrition N=4 Neonatal and maternal data were collected as part of our ongoing neonatal followup program at the time of infant discharge. As part of routine high-risk follow-up, infants received physical and standardized Amiel-Tison neurological exams 5 at term, 4, 8, and 20 months corrected age. The Amiel-Tison exam evaluates active and passive muscle tone and allows for detection of abnormalities in motor development. The pathophysiological basis of the exam is evaluating the balance between the corticospinal and subcortical systems and the progression of postnatal myelination of the corticospinal system in a cephalocaudal pattern. 22 Children were classified at each visit based on the Amiel-Tison 6

17 exam as neurologically normal or abnormal. Children who had a normal exam at both 8 and 20 months were classified for the purpose of this study as neurologically normal. Children were classified as having transient neurological abnormalities if the exam was abnormal at 8 months and then was followed by a normal exam at 20 months. Children with an abnormal exam at 20 months were classified as abnormal regardless of the outcome of the 8 month exam. Infants also were assessed with the Bayley Scales of Infant Development, 2 nd Edition (BSID-2) assessment at 8 and 20 months corrected age. 23 Scores from the BSID-2 included both the Mental Development Index (MDI) and Psychomotor Developmental Index (PDI). A small number of children were untestable on the BSID-2 due to severe neurological impairment and were assigned a score of 50. Comparison of participants and non-participants on the basis of demographic factors, neurological risk factors, and maternal social risk factors showed no statistically significant differences. Data Collection Families were recruited for the school-age follow-up during their first year of kindergarten. Annually, between kindergarten and 2 nd grade, children were tested on areas of cognition, academic achievement, and motor function during a half-day session. Families completed questionnaires on the child s health, family demographics, and behavior. Cognitive skills were assessed through an age-standardized brief intelligence assessment from the Woodcock-Johnson III Tests of Cognitive Abilities, 3 rd edition. 24 School achievement was assessed with subtests of the Woodcock-Johnson III Tests of Achievement, 3 rd edition. 25 Achievement test results were standardized based on grade and time in school. Motor ability was assessed with the Bruininks-Oseretsky Test of 7

18 Motor Proficiency, 2 nd Edition (BOT2), 26 and visual-motor ability with the Beery Developmental Test of Visual-Motor Integration(VMI), 5 th edition. 27 Parent ratings of behavior problems were obtained using the Child Behavior Checklist (CBCL). 28 The CBCL scores considered in analysis were t-scores from the externalizing scale, internalizing scale, total behavior problem scales, and attention problems. Socioeconomic status (SES) 29 was defined as the mean of the sample z-scores for maternal education, caregiver occupation, 30 and census-based median family income. 31 University Hospitals Case Medical Center institutional review board reviewed and approved this study. Informed consent was obtained from parents and teachers and assent from the child participants seven years and older. Data Analysis Aim 1 and 2 Perinatal clinical and maternal demographic characteristics were summarized and compared between the three groups. Frequencies were calculated for categorical variables. Means and standard deviations were calculated for continuous variables and medians and the inter-quartile range for severely skewed variables. Normality for each variable was assessed by the Shapiro-Wilk test and homogeneity of variance by Levene s test. Multiple group comparisons were made using the analysis of variance (ANOVA) for continuous variables, Kruskal-Wallis tests for severely skewed continuous variables followed by the Wilcoxon rank sum test for exact p-values, and the Chi-square or Fisher s exact test for categorical variables. The BSID-2 scores were summarized with medians and inter-quartile range and group comparisons were completed with Kruskal- Wallis tests followed by the Wilcoxon rank sum test for post hoc analysis. 8

19 Analysis of covariance (ANCOVA) was conducted to compare the three groups on the kindergarten testing using socioeconomic status, race, and sex as covariates. Race and sex were removed on final analysis due to a lack of independence between sex and race with group membership and concerns with shared variance. 32 Female sex was associated with the neurological normal group and Caucasian race with the TNA group. Means were computed with standard errors and the ANCOVA analysis was followed by planned contrasts. To address the unequal variances created by small, unequal sample sizes, many of the standardized test results were transformed for ANCOVA analysis to improve normality and homogeneity of variance. The data presented in the tables is untransformed, rather than backward transformed data, to allow for easer clinical interpretation, but the p-values are a result of the analysis of the transformed data. The standardized data transformed by x 2 included the Woodcock-Johnson III Tests of Academic Achievement, many subtests with the Woodcock-Johnson III Tests of Cognitive Abilities (noted in table), and the Beery VMI. The Child Behavior Checklist Attention subtest was also transformed due to significant skew with the square root of standardized scores obtained. To include the fullest possible cohort of children for cognitive and academic testing, children who were too low functioning cognitively to complete testing were given the lowest possible raw score and for the Woodcock Johnson testing were assigned a 40. All statistical testing was conducted using two-sided alternatives. Most statistical analyses were performed with R (version ) 33 with the exception of ANVOA/ANCOVA which was completed with SAS (9.3) 34 software to allow for easier type III analysis of squares due to the unequal sample sizes. 9

20 Aim 3 To assess different rates of skill acquisition between the three groups, a fixed effects model was constructed for each individual test. Analysis was completed with the Proc Mixed package of SAS. 35 The use of this package facilitated the modeling of different patterns of growth and allowed the use of patients with incomplete data. The model was constructed using maximum likelihood estimation. Rather than the agestandardized scores or t-scores, the Rasch-scale scores for the Woodcock-Johnson test batteries 36 and raw scores (actual number of points achieved) for the other tests, were used in the longitudinal analysis. These scores should increase over time, rather than standardized scores, which remain relatively stable, and this should allow for longitudinal assessment of change over time. Raw scores and Rasch scores were assessed for normality and the CBCL were transformed with the square root function to improve normality and unequal variance. Covariates used in the model included the exam group, z-ses, race, sex, age of kindergarten testing (subsequent testing at 1 year intervals), time in kindergarten prior to the testing, and time between testing periods. Age at kindergarten testing was centered at 6 years to allow for easier interpretation of the intercept term. Initial model testing compared two models, one based on an interaction term between group and time and another based on an interaction term between visit and group that allowed for different slopes between visits. The two models were compared for each class of tests by evaluation of the goodness of fit measure of Akaike s information criterion (AIC) 37 and the better fitting model was selected. Variance structure was also compared between unstructured, compound, and autoregressive (1) 10

21 models by use of the AIC. Trajectories were plotted for the three groups for a prototypical individual using the estimates function. Results Aim 1 Group characteristics The neurological classification exam is presented in Figure 2. There were 17 children classified as TNA, 89 children classified as neurologically normal, and 18 children classified as having persistent neurologic abnormalities. Two children were initially classified as normal at 8 months but abnormal at 20 months and were classified at abnormal due to the 20 month exam being more definitive. Figure 2. Classification Diagram of al Exam Group demographic and neonatal characteristics are presented in Table 1 and 2. The TNA group and the neurologically normal group did not differ significantly in gestational age, birth weight, sex, or perinatal morbidities including infection, NEC, patent ductus 11

22 arteriosus, bronchopulmonary dysplasia, and abnormal cerebral ultrasound findings. However, the TNA group had a higher proportion of children who were Caucasian and had received postnatal steroid therapy than the neurologically normal group. Compared to the group with persistent neurologic abnormalities, the TNA group had a lower proportion of severely abnormal head ultrasounds, including grade III-IV periventricular hemorrhage. Table 1 Social Demographic and Clinical Characteristics of Study Participants Normal Transient Abnormalities Comparison of TNA vs Normal Persistent Abnormalities Comparison of TNA vs Persistent Abnormalities n=89 n=17 p value n=18 p value Gestational age (weeks), median (25th-75th %ile) 26 (25-26) 26 (25-27) (24-26).10 Birth weight (g) mean (SD) 796 ( ) 800 ( ) ( ).22 Small for gestational age, a n (%) 17 (19) 3 (18) (18) 1.00 Males, n (%) 36 (40) 10 (59) (50).60 African American Race, n(%) 60 (67) 6 (35) (67).09 Maternal antenatal steroids, n (%) 78 (88) 15 (88) (78).66 Chorioamnionitis, n (%) 12 (14) 1 (6) (6) 1.00 Maternal Hypertension, n (%) 16 (18) 2 (12) (28).40 Cesarean delivery, n (%) 51 (57) 6 (35) (44).58 5 minute Apgar <6, n (%) 30 (34) 7 (41) (47).73 Multiple birth, n (%) 18 (20) 3 (18) (33).44 Days of TPN, median (25th- 75th %ile) 29 (18-41) 33 (22-48) (39-69).03(NS) Ventilator days, median (25th-75th %ile) 20 (4-35) 30 (20-56) (14-77).34 Oxygen dependent at 36 wk PMA, n (%) 46 (52) 12 (71) (61).55 Duration of Oxygen, median (25th-75th %ile) 73 (37-95) 93 (56-110).05(NS) 106 (55-152).84 Postnatal steroids, n (%) 8 (9) 6 (35) (28).63 Retinopathy of Prematurity, n (%) 14 (16) 5 (29) (39).72 Symptomatic Patent Ductus Arteriosis, n (%) 49 (55) 11 (65) (72).63 12

23 Sepsis, meningitis, and/or NEC, n (%) b 33 (37) 9 (53) (56).91 Grade I/II IVH- without PVL, n (%) 12 (13) 4 (24) (6).18 Grade III/IV IVH and/or PVL, n (%) 5 (6) 1 (6) (50) <.01 PMA at Discharge, median (25th-75th %ile) 38.6 ( ) 39.7( ).05(NS) 41.8( ).37 Abbreviations: TNA Transient al Abnormality Exam Group, PMA postmenstrual age, IVH intraventricular hemorrhage, PVL periventricular leukomalacia, NEC Necrotizing Enterocolitis a. Birth weight > 2 SDs below expectation for gestational age based on Yudkin standards. Persistent neurologic abnormalities group had N=17 due to one child who could not be classified at <24 weeks. b. 1 case of meningitis in TNA group and 1 case in the persistent neurologic abnormalities group Table 2 Maternal Sociodemographic Characteristics Normal Transient Abnormalities Comparison of TNA vs Normal Persistent Abnormalities Comparison of TNA vs Persistent Abnormalitie s n=89 n=17 p value n=18 p value Married at Child's Birth, n (%) 37 (42) 9 (53) (44) 0.72 Educational level at Child's Birth, mean (SD) 13.0(2.6) 12.8 (2.1) (2.7) 0.98 Median Family Income at Kindergarten, mean (SD) a 56.2 (35.2) 61.6 (25.0) (24.6) 0.67 a. Family income in thousands of dollars based on neighborhood tract of family residence from 2000 US Census (Federal Financial Institutions Examinations Examination Council Geocoding System, 2010). Aim 2 Early Developmental and al Assessments The early childhood data is shown in Table 3. At 8 months corrected age the children with TNA had significantly lower scores on both the mental developmental index (MDI) and psychomotor developmental index (PDI) of the BSID-2 than the neurologically normal group. At 8 months of age, the TNA and persistent neurologic 13

24 abnormality groups did not differ significantly in PDI or findings from the neurological exam. At 20 months corrected age, the TNA group continued to have a significantly lower PDI than the neurologically normal group, whereas the groups did not differ significantly on the MDI. At the 20 months the mean PDI for persistent neurologic abnormality group and TNA group were not significantly different. Table 3. Infant and Toddler Developmental Testing and al Exam Standardized Score (SD) a Normal Transient Abnormalities Comparison of TNA vs Normal Persistent Abnormalities Comparison of TNA vs Persistent Abnormalities n=89 n=17 p value n=18 p value 8 Month Bayley II Psychomotor Development Index, median (25th-75th %ile) 100 (15) 89(79-97) 59(56-70) < (50-63).07 Mental Developmental Index, median (25th- 75th %ile) 100 (15) 98(94-101) 92(82-89) (61-88) Month Bayley II Psychomotor Development Index, median (25th-75th %ile) 100 (15) 86(76-93) 57(50-79) (50-55).054 Mental Developmental Index, median (25th- 75th %ile) 100 (15) 79(69-87) 71(56-88).23 57(50-71).12 Transient Abnormalities Persistent Abnormalities al Exam Results b 8 Month 20 month 8 month 20 month Hypertonia Hypotonia Hypertonia and Hypotonia Cerebral palsy Normal Data are presented as median (25-75%ile). Significant p value=.025(bonferroni correction) a. Standard scores represent the mean and SD for a normative sample b. Amiel-Tison exam 14

25 Based on the Amiel-Tison exam, the majority of children in the TNA group (13/17=76%) were hypotonic at the 8 month exam. In contrast, the majority of the persistent neurologic abnormality group (11/18=61%) had some form of hypertonic exam (hypertonia, mixed hypertonia/hypotonia) or suspected CP at 8 months. The majority of children with isolated hypotonia at 8 months (13/16=81%) had a normal exam by 20 months whereas the exam normalized for only a minority (4/17 = 23.5%) of children with any hypertonia or CP. School Outcomes The mean age of assessment in kindergarten was 6 years of age and subsequent exams were approximately spaced in 1 year intervals. (Table 4) The attrition rate over the course of study was similar between the three groups with 11-12% of children lost by the third year of the study. A small number of test scores were missing due to child noncompliance, missed testing, or equipment failure and the sample sizes are presented in the result tables. Table 4. Characteristics at Each Assessment Normal Transient Abnormalities Persistent Abnormalities Kindergarten N Mean age in Years 5.9 ± ± ±.4 First Grade N Mean age in 6.9 ± ± ±.4 15

26 Years Attrition Rate 7.9% 11.8% 11.1% Second Grade N Mean age in Years 7.9 ± ± ±.4 Attrition Rate 12.3% 11.8% 11.1% Cross Sectional Analysis of Woodcock Johnson Cognitive and Academic Testing (Table 5 and 6) Group comparisons revealed a consistent pattern of cognitive outcomes in which the TNA group performed poorer than the neurologically normal group but generally performed better than the persistent neurological abnormalities group. Looking at the test results over all three years, the standardized test scores appear to be consistent for each of the groups. The neurologically normal group generally scored around the standardized mean to 1 SD below. The children with TNA scored around 1 SD below the mean and those in the persistent neurological abnormalities groups scored 1-2 SD below the mean. In kindergarten, the mean test scores for the children with TNA were lower than the neurologically normal group in all areas but only significantly lower in spelling. By 2 nd grade, the TNA group scored significantly lower in IQ (BIA), verbal comprehension, visual matching, spelling, and letter word association than the neurologically normal group. The TNA group scored significantly better than the persistent neurologic abnormality group in most cognitive areas in kindergarten except for letter-word identification, spelling and spatial relations but were similar in all areas by 2 nd grade except concept formation with a trend in difference in math. 16

27 Table 5. Woodcock Johnson Tests of Cognitive Abilities Comparison of TNA vs Normal Comparison of TNA vs Persistent Abnormalities Standardized Score(SD) a Total IQ - BIA 100 (15) Normal Transient Abnormalities Persistent Abnormalities n Mean SE n Mean SE p value n Mean SE p value Kindergarten b b First Grade b b Second Grade b b Language - Verbal Comprehension 100 (15) Kindergarten First Grade Second Grade b b Visual Spatial Thinking- Spatial Relations 100 (15) Kindergarten c c First Grade c c Second Grade c c Visual Processing- Visual Matching 100 (15) Kindergarten b b First Grade b b Second Grade b b Reasoning Ability- Concept Formation 100 (15) Kindergarten First Grade Second Grade Abreviations: Abbreviations: BIA-Brief Intellectal Ability Data are presented as adjusted mean (SE). Means were adjusted z-ses. z-ses was the mean of the sample s z scores of maternal education in years, family occupation, and median income for the neighborhood of residence. a.standard scores represent the mean and SD for a normative sample b. p value obtained after transformation of raw data( x^2). c. p value obtained after transformation of raw data( x^3). 17

28 Comparison of TNA vs Normal Comparison of TNA vs Persistent Abnormalities Table 6. Woodcock Johnson Tests of Academic Abilities Standardized Score(SD) a Reading- Word-Letter Identification 100 (15) Normal Transient Abnormalities Persistent Abnormalities n Mean SE n Mean SE p value n Mean SE p value Kindergarten First Grade Second Grade Spelling 100 (15) Kindergarten < First Grade Second Grade Math- Applied Problems 100 (15) Kindergarten First Grade Second Grade Data are presented as adjusted mean (SE). p-values are obtained from x^2 transformation. Means were adjusted for z- SES. z-ses was the mean of the sample s z scores of maternal education in years, family occupation, and median income for the neighborhood of residence. a.standard scores represent the mean and SD for a normative sample Cross Sectional Analysis of Motor Testing All three groups showed impairment in motor scores at all 3 time points compared to standardized norms. Motor scores on the BOT2 were significantly lower for those with TNA versus the neurological normal group in kindergarten and at 1 st grade. The children with TNA had a trend toward lower scores in visual motor integration than the neurologically normal children but it was only significant in 1 st grade. There was a strong trend for the children with TNA to score better than the persistent neurologic abnormalities groups in both the motor scores on the BOT2 and the visual motor integration through all three years. 18

29 Comparison of TNA vs Normal Comparison of TNA vs Persistent Abnormalities Table 7. Motor Testing Standardized Score(SD) a Normal Transient Abnormalities p value Persistent Abnormalities n Mean SE n Mean SE n Mean SE p value Motor Proficiency (BOTS) 50 (10) Kindergarten First Grade Second Grade Visual Motor Integration (VMI) 100 (15) Kindergarten b b First Grade b b Second Grade b b Abreviations: Abbreviations: BOTS 2-Brunininks Oseretsky Test of Motor Profiency (2nd Edition), VMI-Beery Developmental Test of Visual-Motor Integration. Data are presented as adjusted mean (SE). BOTS scores represent t-scores. Means were adjusted for z-ses. z-ses was the mean of the sample s z scores of maternal education in years, family occupation (Hauser), and median income for the neighborhood of residence based on data from the 2000 US Census(FFIEC) a. Standard scores represent the mean and SD. b. p-values are obtained from x^2 transformation Cross Sectional Analysis of Behavior Testing The groups did not differ significantly on the internalizing, externalizing, or total behavior problem scales of the Child Behavior Checklist, with adjusted mean scores for all three groups falling well within normative standards for all three years. There was a trend on increased attention problems in TNA group compared to the other two groups and these differences were statistically significant by 2 nd grade. 19

30 Standardized t-scores Table 8. Child Behavior Checklist (SD) a Comparison of TNA vs Normal Comparison of TNA vs Persistent Abnormalities Internalizing Problems 50 (10) Normal Transient Abnormalities Persistent Abnormalities n Mean SE n Mean SE p value n Mean SE p value Kindergarten First Grade Second Grade Externalizing Problems 50 (10) Kindergarten First Grade Second Grade Total Problems 50 (10) Kindergarten First Grade Second Grade Attention Problems 50 (10) Kindergarten b b First Grade b b Second Grade b b Data are presented as adjusted mean (SE). Means were adjusted for z-ses. z-ses was the mean of the sample s z scores of maternal education in years, family occupation, and median income for the neighborhood of residence a. Standard scores represent mean t-score and SD for a normative sample. b. Non-parametic distribution- p-value provided from log of means score to normalize data. AIM 3 Model The results of the longitudinal analysis are summarized in Tables 9 through 13. The results in these tables were abbreviated from the full output for the most relevant covariates. The model fit was better for all measures except for the CBCL (behavior problems) with the inclusion of the interaction term of group x visit to account for 20

31 differences in slope between the three time points. The model fit was better for the CBCL with group x time. An unstructured covariance structure was used for all models. Longitudinal Analysis of Woodcock Johnson Cognitive and Academic Testing (Table 9 and 10) The neurological group classification was significant in all cognitive and academic testing areas. The neurologically normal group scored better than both the TNA and persistently abnormal group overall on all testing measures. There was not a significant difference between the TNA group and the persistently abnormal neurologic group. The interaction term for group x visit was not significant for any of the tests, with the possible exception of applied math problems, indicating that the rate of skill acquisition does not appear to vary by exam group. This difference in math skills needs to be judged cautiously based on the low number of children in the abnormal group able to complete testing. The z-ses term was significant for all testing areas except visual matching and spatial relations. Paralleling z-ses, race was significant in all cognitive and academic testing areas. Sex was only significant for verbal comprehension. Table 9. Longitudinal Growth Trajectories for Cognitive Outcomes Total IQ - BIA Effect Estimate SE p value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group z-ses sex race group x visit Verbal Comprehension Effect Estimate SE p value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group

32 Fixed Effects DF Den DF F Value p value group z-ses sex race <.0001 group x visit Concept Formation Effect Estimate SE p value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group z-ses sex race group x visit Visual Matching Effect Estimate SE p value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group <.0001 z-ses sex race group x visit Spatial Relation Effect Estimate SE p value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group z-ses sex race group x visit

33 Table 10. Longitudinal Growth Trajectories for Academic Outcomes Reading- Word- Letter Identification Effect Estimate SE p value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group z-ses sex race group x visit Spelling Effect Estimate SE p value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group <.0001 z-ses sex race group x visit Math- Applied Problems Effect Estimate SE p value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group <.0001 z-ses sex race group x visit Figures 3-10 show the trajectories of cognitive and academic skills growth. There is a more rapid growth of skills between kindergarten testing and 1 st grade in all testing areas except for concept formation. 23

34 Figure 3. Longitudinal Growth of IQ (BIA) by Exam Group Group Effects- F(2,117) = 8.12, p=.0005 Group x Visit - F(4,109)=1.22, p=.31 Figure 4. Longitudinal Growth of Verbal Comprehesion Skills by Exam Group Group Effects- F(2,121) = 6.94, p=.001 Group x Visit F(4,111)=1.92, p=.11 24

35 Figure 5. Longitudinal Growth of Concept Formation Skills by Exam Group Group Effects- F(2,119) = 7.55 p=.0008 Group x visit- F(4,112)=1.00 p=.41 Figure 6. Longitudinal Growth of Visual Matching Skills by Exam Group Group Effects- F(2,115) = p=<.0001 Group x Visit- F(4,108)=.48 p=.74 25

36 Figure 7. Longitudinal Growth of Spatial Relations Skills by Exam Group Group Effects- F(2,110) = 8.87 p=.0003 Group x Visit- F(4,96.6)=1.29 p=.28 Figure 8. Longitudinal Growth of Letter Word Identification by Exam Group Group Effects- F(2,118) = 9.23, p=.0002 Group x Visit- F(4,109)= 1.47, p=.27 26

37 Figure 9. Longitudinal Growth of Spelling Skills by Exam Group Group Effects- F(2,112) = 13.45, p=<.0001 Group x Visit- F(4,103)=1.98 p=.10 Figure 10. Longitudinal Growth of Math Skills by Exam Group Group Effects- F(2,120) = 11.59, p=<.0001 Group x Visit- F(4,104)=2.74, p=.03 27

38 Longitudinal Analysis of Motor Testing (Table 11) The group classification was significant for both motor proficiency and visual motor integration (VMI). The group x visit interaction term was significant for visual motor integration but should be interpreted with caution given the variability in data at the 1 st grade point for TNA and persistent neurological abnormalities group. Sex and race were not significant for either measure. The z-ses term was significant for visual motor integration. Table 11. Longitudinal Growth Trajectories for Motor Outcomes Motor Proficiency- Effect Estimate SE p value BOTS 2 Intercept <.0001 Visual Motor Integration-VMI Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group <.0001 z-ses sex race group x visit Effect Estimate SE p value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group z-ses sex race group x visit Figures show the trajectories of motor skills and VMI. For motor skill acquisition there was more rapid growth between kindergarten and 1 st grade than between 1 st and 2 nd grade. It appears there may be some element of catch-up for the children with TNA. For 28

39 VMI, the neurologically normal children appear to have more growth between kindergarten and 1 st while the TNA children had more growth between 1 st and 2 nd grade. The persistent neurological group had a decline between 1 st and 2 nd grade but the data point at 1 st is inconsistent in the greater pattern. Figure 11. Longitudinal Growth of Motor Skills by Exam Group Group Effects- F(2,111) = 13.84, p=<.0001 Group x Visit- F(4,109)=1.03, p=.40 29

40 Figure 12. Longitudinal Growth of Visual Motor Integration by Exam Group Group Effects- F(2,114) = 7.53, p=.0008 Group x Visit- F(4,110)=3.45, p=.01 Longitudinal Analysis of Behavior Testing (Table 12) Group classification was not significantly associated with internalizing problems, externalizing problems, total problems, or attention problems. The interaction term of group x time was not significant for any of these problem areas either. Race was significant only for attention problems and sex was significant for externalizing problems. The z-ses term was not significant for any of these problem groups. Table 12. Longitudinal Trajectories for Behavior Problems Internalizing Problems Effect Estimate SE 30 p value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group

41 Externalizing Problems Total Problems Attention Problems z-ses sex race group x time p Effect Estimate SE value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group z-ses sex race group x time p Effect Estimate SE value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group z-ses sex race group x time p Effect Estimate SE value Intercept <.0001 Normal Neuro Group Abnormal Neuro Group Fixed Effects DF Den DF F Value p value group z-ses sex race group x time Scores estimates are the transformed values(sqrt of x). 31

42 The trajectories of the behavior problems reported by parents had very little change over the three years and are presented in Figures There is an upward trend in attention problems for the children with TNA but this is not statistically significant. Figure 13. Internalizing Behavior Problems over Time by Exam Group Group Effects- F(2,118) =.03, p=.97 Group x Time- F(4,107)=.06, p=.94 32

43 Figure 14. Externalizing Behavior Problems over Time by Exam Group Group Effects- F(2,121) =.31, p=.73 Group x Time- F(4,115)=.14, p=.87 Figure 15. Total Behavior Problems over Time by Exam Group Group Effects- F(2,118) =.48, p=.62 Group x Time- F(4,112)=.42, p=.66 33

44 Figure 16. Attention Problems over Time by Exam Group Group Effects- F(2,120) = 1.23, p=.30 Group x Time- F(4,115)=.86, p=.42 Discussion Extremely preterm newborns with TNA in infancy continued to show deficits in multiple developmental domains at school age compared to those without neurologic abnormalities. This is the first study to our knowledge to examine TNA in a preterm cohort of infants born since the routine introduction of antenatal steroids, surfactant, and reduction in postnatal steroid use. Children with persistent neurological abnormalities are usually excluded from follow-up studies and this is the first study including these children in investigation of TNA school-age outcomes. The inclusion of children with persistent neurological abnormalities allows for a deeper understanding of the full cohort of children and they provide comparison for the level of impairment in children with TNA. An additional strength of our study was the longitudinal nature of our data. The 34

45 serial testing over three years allows more reliable trends in the scores to emerge for children with TNA. The cross-sectional and longitudinal analyses both indicate that children with TNA have increased difficulty in early elementary school. The longitudinal analysis indicates that group status was predictive of outcomes in academic, cognitive, and motor testing but not in behavior problems. There were significant differences in scores between the TNA and neurological normal exam group in all these measures but there were no differences between the TNA and persistent neurological abnormalities group except for motor testing with BOT2. Because many children in the persistent neurological abnormalities group were unable to complete testing, only the highest functioning children from the persistent neurological abnormalities group are represented in the longitudinal modeling. This may have distorted the true differences in score between the TNA and persistent neurological abnormalities group. There do not appear to be significant differences in the rates of skill acquisition between the three groups. While it is positive that the TNA groups and persistent abnormalities groups are not gaining skills at a slower rate, it also indicates that neither group is catching-up with the neurologically normal group. On evaluation of the standardized scores, the mean scores for children with TNA in cognitive and motor testing fell around 1 SD below standards for age. By comparison, the children classified as neurologically normal at 8 months had mean scores on cognitive and motor tests that were all within 1 SD of normative scores. Children with persistent neurologic abnormalities scored consistently 1-2 SD below the standard scores in cognitive and academic testing while they were 2-3 SD below for the motor domain testing. The standardized scores in cognitive, academic, and motor 35