Journal of Perinatology (2015), 1–5 © 2015 Nature America, Inc. All rights reserved 0743-8346/15 www.nature.com/jp
ORIGINAL ARTICLE
Impact of intraventricular hemorrhage on cognitive and behavioral outcomes at 18 years of age in low birth weight preterm infants P Ann Wy, M Rettiganti, J Li, V Yap, K Barrett, L Whiteside-Mansell and P Casey OBJECTIVE: Although high-grade intraventricular hemorrhage (IVH; grades III–IV) in preterm and low birth weight infants are clearly associated with increased risk of long-term adverse neurodevelopmental sequelae, the impact of low-grade IVH (grades I–II) has been less clear. Some studies have followed these infants through early school age and have shown some conflicting results regarding cognitive outcome. Such studies that assess children at younger ages may not accurately predict outcomes in later childhood, as it is known that fluid and crystallized intelligence peak at age 26 years. There is paucity of data in current medical literature, which correlates low-grade IVH with outcomes in early adulthood. To determine the link between the occurrence of lowgrade IVH in low birth weight (birth weight ⩽ 2500 g) infants born prematurely (gestational age o 37 weeks) and intellectual function, academic achievement, and behavioral problems to the age of 18 years. STUDY DESIGN: This study is an analysis of data derived from the Infant Health and Development Program (IHDP), a multisite national collaborative study and a randomized controlled trial of education intervention for low birth weight infants from birth until 3 years of age with follow-up through 18 years of age. A total of 985 infants were enrolled in the IHDP. Of the 462 infants tested for IVH, 99 demonstrated sonographic evidence of low-grade IVH, whereas 291 showed no sonographic evidence of IVH. Several outcomes were compared between these two groups. Intelligence was assessed using Stanford–Binet Intelligence scales at age 3 years, Wechsler Intelligence Scale for Children (WISC-III) at age 8 years, Wechsler Abbreviated Scale of Intelligence (WASI) at age 18 years and Woodcock Johnson Tests of Achievement at age 8 and 18 years. Behavior was measured using the Achenbach Behavior Checklist at age 3 years and Child Behavior Checklist (CBCL) at age 8 and 18 years. Outcomes were compared between the IVHpositive and IVH-negative groups using analysis of covariance after adjusting for the presence or absence of intervention, birth weight, gestational age, gender, severity of neonatal course, race and maternal education. RESULTS: No statistically significant difference in intelligence as measured by Stanford–Binet Intelligence scales, WISC-III, WASI and Woodcock–Johnson Tests of Achievement could be appreciated between IVH-positive patients and controls at any age group (36 months, 8 years and 18 years of age). In addition, there was no significant difference in problem behavior as assessed by the Achenbach Behavior Checklist and Child Behavior Checklist (CBCL) comparing IVH patients with controls. CONCLUSION: Low-grade IVH was not demonstrated in our study to be an independent risk factor associated with lower outcomes in intelligence, academic achievement or problem behavior at age 3, 8 and 18 years. Journal of Perinatology advance online publication, 5 February 2015; doi:10.1038/jp.2014.244
INTRODUCTION Approximately twelve thousand infants are born annually with intraventricular hemorrhage (IVH) in the United States alone.1 The largest proportion of these cases occur in preterm infants with a birth weight of o 1500 g, with an incidence as high as 20%.2 The consequences of grade I or II IVH remains a matter of considerable debate.3 Some studies have demonstrated IVH to be an independent risk factor for the development of lasting neurodevelopmental sequelae, inclusive of cerebral palsy and poorer cognitive development, with the severity of impairments being proportional to IVH grade.4,5 These sequelae have been demonstrated in studies with longer term follow-up to translate into increased use of school services at age 12 years.6 On the other hand, there have also been a number of studies that have demonstrated minimal whether any observable adverse sequelae in cases of low-grade
IVH.4,7–9 In both cases, although, follow-up data were obtained at relatively young ages. Limited data exist regarding cognitive and behavioral outcomes in these patients in early adulthood, at which time the peak of capacity for both fluid intelligence and crystallized intelligence occurs.10 It has been demonstrated in several studies that sociodemographic factors have a greater role in determining long-term outcomes compared with biological factors in the absence of profound physical handicaps.11–13 Because of the paucity of studies with long-term follow-up in such patients, it is unclear whether cognitive and behavioral problems, when observed, persist in later life. Furthermore, questions remain about the potential of neuroplasticity to overcome early brain injury.14,15 The objective of this study was to determine whether the presence of low-grade IVH in low birth weight preterm infants
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Correspondence: Dr P Ann Wy, Department of Pediatrics, University of Arkansas for Medical Sciences, 1301 Wolfe Street, Little Rock, AR 72202, USA. E-mail: [email protected] Received 23 September 2014; accepted 23 December 2014
Impact of IVH on preterm infants P Ann Wy et al
2 represents an independent risk factor for poorer intellectual and behavioral function and lower academic achievement at age 18 years.
being reflective of more problem behaviors. A T score of 470 is considered clinically significant for problem behavior.
Academic achievement at ages 8 and 18 years METHODS Subject population Data were derived from the Infant Health and Development Program (IHDP) study. The IHDP study was a national collaborative, multisite, randomized controlled trial of education intervention for low birth weight premature infants initiated in the 1980s to determine the impact of early intervention on long-term cognitive and developmental outcomes. The study assessed patients from birth until 3 years of age with follow-up through 18 years of age. Details of the protocol have been described elsewhere.16–20 Nine hundred and eighty-five (primary analysis group) low birth weight premature infants from eight different sites were randomly assigned to an early-intervention group (n = 377) or a follow-up only group (n = 608) using a 2:1 adaptive randomization scheme. Among the primary analysis group, 390 subjects had either no IVH or grade 1 or 2 IVH and formed the initial sample for this study. Twenty-four of these subjects did not participate in any of the 3-, 8- or 18-year assessments either due to inability to locate or re-establish contact after multiple attempts from site teams or repeated missed appointments. These subjects (n = 24) were removed, resulting in 366 subjects in the final analytic sample.
Identification of subjects with IVH The presence or absence of IVH was assessed by cranial ultrasound. The decision whether or not to perform cranial ultrasound was at the discretion of the treating physician. No criteria were set at the onset of the study for performance of cranial ultrasound as a screening tool for IVH. Five hundred and ninety-five subjects had no cranial ultrasound performed; as we were not able to determine the presence or absence of IVH in these subjects, they were not included in the analyses.
Academic achievement was assessed using the Woodcock–Johnson Tests of Achievement-Revised.28 These tests assessed letter–word identification, passage comprehension, calculation and applied problems subtests of the standard scores. Two scores were calculated, the Woodcock–Johnson Tests of Achievement in reading and in mathematics, referenced to a mean of 100 and an s.d. of 15. Higher scores are indicative of better achievement.
Statistical analysis All statistical analyses were generated using SAS/STAT software, Version 9.4 (SAS Institute Inc., Cary, NC, USA) of the SAS System for Windows 7, Copyright © 2002–2012 SAS Institute Inc. All tests were two-sided and a P-value of 0.05 or lower was assumed to indicate statistical significance. Descriptive statistics such as mean and s.d. for continuous variables and frequency and percent for categorical variables are presented for all demographic variables of interest and outcomes at 3, 8, and 18 years. Categorical variables were compared between two independent groups using a χ2-test of association, whereas continuous variables were compared using a two-sample t-test. Cognitive and behavioral outcomes such as standardized IQ score, test scores and CBCL were compared between low-grade IVH and no IVH groups using an analysis of covariance (ANCOVA) method at ages 3, 8 and 18 years. The ANCOVA model included the following confounding variables to reduce bias: intervention, gestational age, birth weight, maternal education, maternal race and gender. Furthermore, Neonatal Health Index, which serves as a composite score factoring in birth weight, and length of stay in the hospital, was also used to denote severity of the neonatal course.29 Mean differences in continuous outcome measures were summarized using differences in least square means from the ANCOVA model and 95% confidence intervals.
Outcomes Outcomes assessed in this study include cognitive functioning at ages 3, 8 and 18 years, as well as problem behavior and academic achievement at ages 8 and 18 years. Cognitive, behavioral and academic achievement evaluations were performed by trained assessors, who were blinded to the child’s treatment group in the original IHDP study.16
Cognitive assessment at ages 3, 8 and 18 years The Stanford–Binet Intelligence Scale, forms L-M,21 and The Peabody Picture Vocabulary Test-Revised (PPVT-R)22 were used to assess cognitive development at 36 months. The Stanford–Binet Intelligence Scale functions as an age scale, which assesses basal age, ceiling age and deviation intelligent quotient (IQ). It has a normative mean standard score of 100 and an s.d. of 15. PPVT-R is a measure of receptive language and is referenced to a mean of 100 and an s.d. of 15. The PPVT-R22 and the Wechsler Intelligence Scale for Children (WISCIII)23 were used to evaluate cognitive development at age 8 years. The WISC-III provides four indices (verbal comprehension, perceptual organization, freedom from distractibility and processing speed) and can generate a verbal IQ and performance IQ, as well as a full IQ score. Both tests are referenced to a mean of 100 and an s.d. of 15. The Peabody Picture Vocabulary Test-version III24 and the Wechsler Abbreviated Scale of Intelligence (WASI)25 were used to evaluate cognitive development at age 18 years. PPVT-III, like PPVT-R is used as a measure of receptive language. The Wechsler Abbreviated Scale of Intelligence provides four subscales (vocabulary, block design, similarities and matrix reasoning) and can generate a verbal IQ and performance IQ, as well as a full IQ score. Both tests, like the WISC-III and PPVT-R, are referenced to a mean of 100 and an s.d. of 15.
Behavioral assessment at ages 8 and 18 years Problem behavior was measured by maternal report using the Child Behavior Checklist (CBCL)26 for ages 2–3 years for subjects at age 3 years. Child Behavior Checklist for ages 3–18 years27 was used to evaluate problem behavior in subjects at ages 8 and 18 years. Results were interpreted based on Total Problem Raw Score or T score with higher values Journal of Perinatology (2015), 1 – 5
Table 1. Summary statistics and comparison of baseline demographics between the No IVH and IVH groups Variables
No IVH (N = 273)
IVH (N = 93)
Treatment group—no. (%) Follow-up Intervention
178 (65%) 63 (68%) 95 (35%) 30 (32%)
Birth weight group—no. (%) High Low
28 (10%) 6 (6%) 245 (90%) 87 (94%)
Maternal education—no. (%) o9th grade 9th–12th grade High school graduate Completed some college College degree or more
7 91 78 57 40
Maternal race—no. (%) White Black Hispanic Other/unknown
104 (38%) 30 (32%) 130 (48%) 51 (55%) 29 (11%) 10 (11%) 10 (4%) 2 (2%)
Gender—no. (%) Male Female
142 (52%) 50 (54%) 131 (48%) 43 (46%)
Gestational age (weeks)—mean (s.d.) Birth weight (kg)—mean (s.d.) Neonatal health index—mean (s.d.)
P 0.66
0.28
0.58 (3%) (33%) (29%) (21%) (15%)
3 35 25 13 17
(3%) (38%) (27%) (14%) (18%) 0.60
0.77
31 (2.2) 1.5 (0.4) 96 (16)
30 (2.4) o.0001 1.3 (0.4) o.0001 94 (19) 0.46
Abbreviation: IVH, intraventricular hemorrhage. P-values correspond to χ2-test for categorical variables and two-sample t-test for continuous variables.
© 2015 Nature America, Inc.
Impact of IVH on preterm infants P Ann Wy et al
3 Table 2.
Comparison of outcomes at 3, 8 and 18 years between subjects with and without IVH (LSMean and s.e.)
Outcomes
No IVH
IVH
Diff (95% CI)
P
N
Mean (s.e.)
N
Mean (s.e.)
3 years Achenbach Total Prob. Sum Score at 36 months Child's PPVT-R at 36 months Stanford–Binet IQ (corrected age) at 36 months
263 240 270
49.1 (2.1) 85.7 (1.6) 88.0 (1.8)
88 75 93
49.4 (2.8) 82.6 (2.2) 85.4 (2.3)
− 0.34 (−5.27, 4.59) 3.14 (−0.73, 7.00) 2.59 (−1.51, 6.69)
0.89 0.11 0.21
8 years CBCL: internalizing 8-year score CBCL: externalizing 8-year score CBCL: total raw 8-year score PPVT-R standard score: 8 year W–J letter–word ID standard score: 8 years W–J passage comprehension standard score: 8 years W–J broad reading standard score: 8 years W–J broad math standard score: 8 years WISC-III Vb IQ: 8 year WISC-III Pf IQ: 8 year WISC-III Total IQ: 8 year
261 261 262 261 260 260 256 262 263 264 263
10.3 13.0 36.9 84.7 96.2 98.0 95.7 94.1 92.9 91.3 91.4
(0.8) (0.9) (2.3) (2.2) (2.3) (2.1) (2.3) (2.6) (1.7) (1.7) (1.7)
88 88 88 87 88 86 86 88 88 89 88
9.4 13.2 36.4 80.9 95.1 96.3 95.3 91.5 90.1 88.8 88.5
(1.0) (1.2) (3.0) (2.9) (2.9) (2.7) (2.9) (3.3) (2.2) (2.2) (2.2)
0.91 − 0.14 0.56 3.82 1.18 1.73 0.46 2.62 2.79 2.47 2.88
(−0.76, (−2.19, (−4.60, (−1.12, (−3.80, (−3.01, (−4.62, (−3.03, (−1.07, (−1.31, (−0.93,
2.58) 1.90) 5.72) 8.75) 6.16) 6.46) 5.53) 8.27) 6.66) 6.25) 6.69)
0.29 0.89 0.83 0.13 0.64 0.47 0.86 0.36 0.16 0.20 0.14
18 years CBCL aggressive behavior scale CBCL attention problems scale CBCL delinquent behavior scale Total, CBCL scales PPVT-III, standard score W–J, letter–word ID, standard score W–J, comprehension, standard score W–J, calculation, standard score W–J, broad reading, standard score W–J, broad math, standard score WASI, full scale, IQ WASI, performance, IQ WASI, verbal, IQ WASI, verbal, sum of T scores
179 180 178 176 177 177 177 177 176 177 178 178 178 178
4.9 2.7 2.0 9.7 96.8 102 92.3 89.8 94.3 88.7 92.1 91.9 93.3 90.9
(0.6) (0.4) (0.3) (1.1) (2.4) (8.5) (3.0) (2.9) (3.2) (2.6) (2.0) (2.1) (2.0) (2.7)
70 71 69 68 71 70 72 72 70 71 72 72 72 72
5.0 2.8 2.2 9.8 94.8 92.4 91.8 85.1 93.4 86.1 90.4 91.1 91.8 88.4
(0.7) (0.5) (0.3) (1.4) (2.9) (10.5) (3.7) (3.5) (4.0) (3.2) (2.4) (2.5) (2.5) (3.3)
− 0.05 − 0.06 − 0.26 −0.11 2.02 9.37 0.45 4.75 0.88 2.54 1.69 0.84 1.52 2.48
(−1.25, (−0.93, (−0.86, (−2.48, (−2.93, (−8.56, (−5.85, (−1.23, (−5.99, (−2.93, (−2.44, (−3.47, (−2.68, (−3.17,
1.15) 0.80) 0.33) 2.27) 6.98) 27.3) 6.75) 10.73) 7.75) 8.01) 5.83) 5.14) 5.71) 8.14)
0.93 0.89 0.38 0.93 0.42 0.30 0.89 0.12 0.80 0.36 0.42 0.70 0.48 0.39
Abbreviations: CBCL, Child Behavior Checklist; ID, identification; IQ, intelligent quotient; IVH, intraventricular hemorrhage; PPVT, Peabody Picture Vocabulary Test; WASI Wechsler Abbreviated Scale of Intelligence; WISC, Wechsler Intelligence Scale for Children; W–J, Woodcock–Johnson.
RESULTS There was no association between the presence of IVH and the randomized intervention assignment (P = 0.66). In Table 1, 32% (30/93) of patients in the IVH group had intervention, whereas 35% (95/273) in the no IVH group had intervention. Birth weight category (P = 0.28), maternal education (P = 0.58), maternal race (P = 0.60), gender (P = 0.77) and neonatal health index (P = 0.46) were not significantly different between the IVH and no IVH groups. However, mean (s.d.) gestational age was 30 (2.4) weeks in the IVH group and 31 (2.2) weeks in the no IVH group, which was significantly different (P o .0001). Also, mean birth weight of 1.3 (0.4) kg in the IVH group was significantly lower than the mean of 1.5 (0.4) in the no IVH group (P o.0001). None of the outcome measures were significantly different between the two groups after adjusting for demographics and confounding variables at 3, 8 and 18 years (Table 2). At 3 years, mean PPVT-R at 36 months was lower in the IVH group than in the no IVH group (85.7 in non-IVH group vs 82.6 in IVH; mean difference = 3.14, 95% confidence interval − 0.73 to 7; P = 0.11). Mean Stanford–Binet IQ at 36 months was not significantly lower in IVH compared with no IVH group (85.4 in IVH group vs 88 in no IVH group; mean difference = 2.59, 95% confidence interval − 1.59 to 6.69; P = 0.21). Mean W–J letter–word identification standard score was 92.4 (10.5) in the IVH group while it was 102 (8.5) in the non-IVH group but this difference was not statistically significant © 2015 Nature America, Inc.
(mean difference = 9.37, 95% confidence interval − 8.56 to 27.3; P = 0.30). Few subjects had missing information on all outcomes at 3 (3 missing) and 8 years (13 missing). However, at age 18, 105 of the 366 subjects (28.7%) were lost to follow-up. Baseline demographics were not significantly different between participants who were in the study and those who dropped out at 18 years (results not shown) suggesting that participants who dropped out were not systematically different than those who did not in terms of their demographic characteristics. We also investigated whether participants who dropped out at 18 years had significantly worse outcomes at 3 and 8 years in the IVH group than in the non-IVH group (results not shown). None of the outcomes at 3 and 8 years were significantly different between the IVH and non-IVH groups among patients who dropped out of the study. This suggests that participants’ drop out from the study was at random rather than being systematically related to study outcomes. DISCUSSION Our study demonstrates that grade I and II IVH are not independent risk factors for adverse neurobehavioral sequelae as measured by indices of problem behavior, intelligence scores and academic achievement at age 3, 8 and 18 years of age. Bolisetty30 recently found that grade I or II IVH in extremely preterm infants, even with no white matter injury or other late Journal of Perinatology (2015), 1 – 5
Impact of IVH on preterm infants P Ann Wy et al
4 ultrasound abnormalities, was associated with adverse neurodevelopment outcomes. However, in their study, outcomes were collected at an early age of 2–3 years and there was no control of demographic characteristics of his sample. The latter is important as early developmental progress of preterm infants is significantly influenced by social characteristics of their families. Our results, on the other hand, are similar to outcomes in prior studies, which have earlier follow-up time. Sherlock et al.4 demonstrated little whether any sequelae observed in grade I and II IVH at age 8 years with adverse neurodevelopmental sequelae being most pronounced in grade III and grade IV IVH. Similar results were also observed by Roland et al.,7 as well as by Vassilyadi et al.,8 with the greatest impact seen in the setting of post-hemorrhagic hydrocephalus. Furthermore, Vohr et al. 9 observed little difference neurologically in ages 2, 7 and 14 days in cases of mild IVH compared with controls and normal neurologic function in 93% of grade I–II IVH at age 24 months. Such findings suggest neurologic plasticity with the prospect of early recovery, even in later age, as noted by McCormick et al.20 Conflicting findings among different studies have invoked differing theories regarding both neuroplasticity, mechanisms of repair in the setting of early brain insults and even regarding mechanism of initial injury in the setting of low-grade IVH. It has been further postulated that the mechanism of injury in grade I–II IVH stems from impaired cortical development, especially in pathways associated with integration, fine motor coordination and processing skills. Recovery from early brain insult has been described in the literature as a continuum between two opposing schools of thought—early vulnerability versus early plasticity. These models have been well studied and described in the context of visual pathway and motor development. However, there have been few conclusive studies examining neurobehavioral development following such insults.14 Among the limitations of earlier studies, inherent in the early age of follow-up and end point of the study period, is that the full spectrum of neurodevelopmental and behavioral sequelae could not be observed and that there may have been an inaccurate estimation of impairment. The advantage of a longer follow-up period is that it has enabled us to observe academic achievement and development beyond what has previously been considered to be critical ages of development. In addition, the final age of assessment at age 18 years is a closer approximation to peak of capacity for both fluid and crystallized intelligence, which occurs in early adulthood.10 There are several limitations in our study. The lack of standardized indications for cranial ultrasound across different sites makes it impossible for us to know whether those infants in the sample who did not undergo ultrasound did or did not suffer from IVH. We lack a measure of interobserver reliability among radiologists in interpretation of cranial ultrasound. In addition, the infants in our study were born before several advancements that were made in neonatal care such as administration of antenatal steroids and surfactant, which have markedly improved neonatal morbidity and mortality. Furthermore, the final age of assessment at 18 years may preclude other economically important outcomes such as performance in higher education, occupation and income. Cranial ultrasound itself has been demonstrated to be a useful screening tool for IVH but its sensitivity and specificity is inferior to brain magnetic resonance imaging. In addition, although none of the outcome measures in our study demonstrated a statistically significant difference between the IVH cases and non-IVH controls, W–J letter–word identification standard score at age 18 years showed a mean difference of greater than five points, which may be clinically significant. If this observed difference is considered clinically meaningful, a future larger study would be needed to minimize the risk of potentially failing to detect a significant difference. Journal of Perinatology (2015), 1 – 5
The strengths of our study include a relatively large sample of infants with low-grade IVH and long duration of follow-up. We employed a very broad array of outcomes including intellectual and behavior assessments along with academic achievement. We additionally controlled for maternal education, birth weight, race, gender, gestational age, mean neonatal health index and presence/absence of neurobehavioral intervention. In conclusion, our study has demonstrated that low-grade IVH does not represent an independent risk factor for the development of adverse neurodevelopmental sequelae even in early adulthood. Future studies into later adulthood may further delineate any differences observed with regard to problem behavior and academic achievement. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr Res 2010; 67(1): 1–8. 2 Bassan H, Feldman HA, Limperopoulos C, Benson CB, Ringer SA, Veracruz E et al. Periventricular Hemorrhagic Infarction: Risk Factors and Neonatal Outcome. Pediatr Neurol 2006; 35(2): 85–92. 3 Neubauer AP, Voss W, Kattner E. Outcome of extremely low birth weight survivors at school age: the influence of perinatal parameters on neurodevelopment. J Pediatr 2008; 167(1): 87–95. 4 Sherlock RL, Anderson PJ, Doyle LW. Victorian Infant Collaborative Study Group Neurodevelopmental sequelae of intraventricular haemorrhage at 8 years of age in a regional cohort of ELBW/very preterm infants. Early Hum Dev 2005; 81(11): 909–916. 5 Patra K, Wilson-Costello D, Taylor HG, Mercuri-Minich N, Hack M. Grades I-II intraventricular hemorrhage in extremely low birth weight infants: effects on neurodevelopment. J Pediatr 2006; 149(2): 169–173. 6 Luu TM, Ment LR, Schneider KC, Katz KH, Allan WC, Vohr BR. Lasting effects of preterm birth and neonatal brain hemorrhage at 12 years of age. Pediatrics 2009; 123(3): 1037–1044. 7 Roland EH, Hill A. Germinal matrix-intraventricular hemorrhage in the premature newborn; management and outcome. Neurol Clin 2003; 21: 833–851. 8 Vassilyadi M, Tataryn Z, Shamji MF, Ventureyra EC. Functional outcomes among premature infants with intraventricular hemorrhage. Pediatr Neurosurg 2009; 45(4): 247–255. 9 Vohr BR, Garcia-VColl C, Mayfield S, Brann B, Shaull P, Oh W. Neurologic and developmental status related to the evolution of visual-motor abnormalities from birth to 2 years of age in preterm infants with intraventricular hemorrhage. J Pediatr 1989; 115(2): 296–302. 10 McArdle JJ, Ferrer-Caja E, Hamagami F, Woodcock RW. "Comparative longitudinal structural analyses of the growth and decline of multiple intellectual abilities over the life span.". Dev Psychol 2002; 38(1): 115–142. 11 Hack M. Young adult outcomes of very-low-birth-weight children. Semin Fetal Neonatal Med 2006; 11(2): 127–137. 12 Werner EE. Journeys From Childhood to Midlife: Risk, Resilience, and Recovery. Pediatrics 2004; 114: 492. 13 Werner EE, Smith RS. Journeys From Childhood to Midlife: Risk, Resilience and Recovery. Cornell University Press: Ithaca, NY, USA, 2001. 14 Anderson V, Spencer-Smith M, Wood A. Do children really recover better? Neurobehavioural plasticity after early brain insult. Brain 2011; 134(Pt 8): 2197–2221. 15 Levin HS. Long-term intellectual outcome of traumatic brain injury in children: limits to neuroplasticity of the young brain? Pediatrics 2012; 129(2): e494–e495. 16 Enhancing the outcomes of low-birth-weight, premature infants: a multisite, randomized trial. The Infant Health and Development Program.JAMA 1990; 263: 3035–3042. 17 Brooks-Gunn J, McCarton CM, Casey PH et al. Early intervention in low-birthweight premature infants: results through age 5 years from the Infant Health and Development Program. JAMA 1994; 272: 1257–1262. 18 McCarton CM, Brooks-Gunn J, Wallace IF et al. Results at age 8 years of early intervention for low-birth-weight premature infants. The Infant Health and Development Program. JAMA 1997; 277: 126–132. 19 McCormick MC, McCarton C, Brooks-Gunn J et al. The Infant Health and Development Program: interim summary. J Dev Behav Pediatr 1998; 19: 359–370.
© 2015 Nature America, Inc.
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5 20 McCormick MC, Brooks-Gunn J, Buka SL, Goldman J, Yu J, Salganik M et al. Early intervention in low birth weight premature infants: results at 18 years of age for the Infant Health and Development Program. Pediatrics 2006; 117(3): 771–780. 21 Terman LM, Merrill MA. Stanford-Binet Intelligence Scale: Manual for the Third Revision, Form L-M (1972 table of norms by R.L. Thorndike). Houghton Mifflin Co.: Boston, MA, USA, 1973. 22 Dunn LM, Dunn LM. Examiner’s manual for the Peabody Picture Vocabulary Test Revised edition. American Guidance Service: Circle Pines, MN, USA, 1981. 23 Wechsler D. Wechsler Intelligence Scale for Children, 3rd edn, The Psychological Corporation: San Antonio, TX, USA, 1991. 24 Dunn LM, Dunn LM. Examiner’s manual for the Peabody Picture Vocabulary Test, 3rd edn, American Guidance Service: Circle Pines, MN, USA, 1997. 25 Wechsler D. Wechsler Abbreviated Scale of Intelligence. The Psychological Corporation: San Antonio, TX, USA, 1999.
© 2015 Nature America, Inc.
26 Achenbach TM, Edelbrock CS, Howell CT. Empirically based assessment of the behavioral/emotional problems of 2- and 3-year-old children. J Abnorm Child Psychol 1987; 15: 629–650. 27 Achenbach TM, Edelbrock C. Manual for the Child Behavior Checklist and Revised Child Behavior Profile. Queen City Printers: Burlington, VT, USA, 1983. 28 Woodcock RW, Johnson MB. Manual for the Woodcock-Johnson Tests of Achievement- Revised. RCL Enterprises: Allen, TX, USA, 1990. 29 Scott DT, Bauer CR, Kraemer HC, Tyson J. A neonatal health index for preterm infants. Pediatric Research 1989; 25(4): 263A. 30 Bolisetty S, Dhawan A, Abdel-Latif M, Bajuk B, Stack J, Lui K. New south wales and australian capital territory neonatal intensive care units' data collection. Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants. Pediatrics 2014; 133(1): 55–62.
Journal of Perinatology (2015), 1 – 5
ORIGINAL ARTICLE
Impact of intraventricular hemorrhage on cognitive and behavioral outcomes at 18 years of age in low birth weight preterm infants P Ann Wy, M Rettiganti, J Li, V Yap, K Barrett, L Whiteside-Mansell and P Casey OBJECTIVE: Although high-grade intraventricular hemorrhage (IVH; grades III–IV) in preterm and low birth weight infants are clearly associated with increased risk of long-term adverse neurodevelopmental sequelae, the impact of low-grade IVH (grades I–II) has been less clear. Some studies have followed these infants through early school age and have shown some conflicting results regarding cognitive outcome. Such studies that assess children at younger ages may not accurately predict outcomes in later childhood, as it is known that fluid and crystallized intelligence peak at age 26 years. There is paucity of data in current medical literature, which correlates low-grade IVH with outcomes in early adulthood. To determine the link between the occurrence of lowgrade IVH in low birth weight (birth weight ⩽ 2500 g) infants born prematurely (gestational age o 37 weeks) and intellectual function, academic achievement, and behavioral problems to the age of 18 years. STUDY DESIGN: This study is an analysis of data derived from the Infant Health and Development Program (IHDP), a multisite national collaborative study and a randomized controlled trial of education intervention for low birth weight infants from birth until 3 years of age with follow-up through 18 years of age. A total of 985 infants were enrolled in the IHDP. Of the 462 infants tested for IVH, 99 demonstrated sonographic evidence of low-grade IVH, whereas 291 showed no sonographic evidence of IVH. Several outcomes were compared between these two groups. Intelligence was assessed using Stanford–Binet Intelligence scales at age 3 years, Wechsler Intelligence Scale for Children (WISC-III) at age 8 years, Wechsler Abbreviated Scale of Intelligence (WASI) at age 18 years and Woodcock Johnson Tests of Achievement at age 8 and 18 years. Behavior was measured using the Achenbach Behavior Checklist at age 3 years and Child Behavior Checklist (CBCL) at age 8 and 18 years. Outcomes were compared between the IVHpositive and IVH-negative groups using analysis of covariance after adjusting for the presence or absence of intervention, birth weight, gestational age, gender, severity of neonatal course, race and maternal education. RESULTS: No statistically significant difference in intelligence as measured by Stanford–Binet Intelligence scales, WISC-III, WASI and Woodcock–Johnson Tests of Achievement could be appreciated between IVH-positive patients and controls at any age group (36 months, 8 years and 18 years of age). In addition, there was no significant difference in problem behavior as assessed by the Achenbach Behavior Checklist and Child Behavior Checklist (CBCL) comparing IVH patients with controls. CONCLUSION: Low-grade IVH was not demonstrated in our study to be an independent risk factor associated with lower outcomes in intelligence, academic achievement or problem behavior at age 3, 8 and 18 years. Journal of Perinatology advance online publication, 5 February 2015; doi:10.1038/jp.2014.244
INTRODUCTION Approximately twelve thousand infants are born annually with intraventricular hemorrhage (IVH) in the United States alone.1 The largest proportion of these cases occur in preterm infants with a birth weight of o 1500 g, with an incidence as high as 20%.2 The consequences of grade I or II IVH remains a matter of considerable debate.3 Some studies have demonstrated IVH to be an independent risk factor for the development of lasting neurodevelopmental sequelae, inclusive of cerebral palsy and poorer cognitive development, with the severity of impairments being proportional to IVH grade.4,5 These sequelae have been demonstrated in studies with longer term follow-up to translate into increased use of school services at age 12 years.6 On the other hand, there have also been a number of studies that have demonstrated minimal whether any observable adverse sequelae in cases of low-grade
IVH.4,7–9 In both cases, although, follow-up data were obtained at relatively young ages. Limited data exist regarding cognitive and behavioral outcomes in these patients in early adulthood, at which time the peak of capacity for both fluid intelligence and crystallized intelligence occurs.10 It has been demonstrated in several studies that sociodemographic factors have a greater role in determining long-term outcomes compared with biological factors in the absence of profound physical handicaps.11–13 Because of the paucity of studies with long-term follow-up in such patients, it is unclear whether cognitive and behavioral problems, when observed, persist in later life. Furthermore, questions remain about the potential of neuroplasticity to overcome early brain injury.14,15 The objective of this study was to determine whether the presence of low-grade IVH in low birth weight preterm infants
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Correspondence: Dr P Ann Wy, Department of Pediatrics, University of Arkansas for Medical Sciences, 1301 Wolfe Street, Little Rock, AR 72202, USA. E-mail: [email protected] Received 23 September 2014; accepted 23 December 2014
Impact of IVH on preterm infants P Ann Wy et al
2 represents an independent risk factor for poorer intellectual and behavioral function and lower academic achievement at age 18 years.
being reflective of more problem behaviors. A T score of 470 is considered clinically significant for problem behavior.
Academic achievement at ages 8 and 18 years METHODS Subject population Data were derived from the Infant Health and Development Program (IHDP) study. The IHDP study was a national collaborative, multisite, randomized controlled trial of education intervention for low birth weight premature infants initiated in the 1980s to determine the impact of early intervention on long-term cognitive and developmental outcomes. The study assessed patients from birth until 3 years of age with follow-up through 18 years of age. Details of the protocol have been described elsewhere.16–20 Nine hundred and eighty-five (primary analysis group) low birth weight premature infants from eight different sites were randomly assigned to an early-intervention group (n = 377) or a follow-up only group (n = 608) using a 2:1 adaptive randomization scheme. Among the primary analysis group, 390 subjects had either no IVH or grade 1 or 2 IVH and formed the initial sample for this study. Twenty-four of these subjects did not participate in any of the 3-, 8- or 18-year assessments either due to inability to locate or re-establish contact after multiple attempts from site teams or repeated missed appointments. These subjects (n = 24) were removed, resulting in 366 subjects in the final analytic sample.
Identification of subjects with IVH The presence or absence of IVH was assessed by cranial ultrasound. The decision whether or not to perform cranial ultrasound was at the discretion of the treating physician. No criteria were set at the onset of the study for performance of cranial ultrasound as a screening tool for IVH. Five hundred and ninety-five subjects had no cranial ultrasound performed; as we were not able to determine the presence or absence of IVH in these subjects, they were not included in the analyses.
Academic achievement was assessed using the Woodcock–Johnson Tests of Achievement-Revised.28 These tests assessed letter–word identification, passage comprehension, calculation and applied problems subtests of the standard scores. Two scores were calculated, the Woodcock–Johnson Tests of Achievement in reading and in mathematics, referenced to a mean of 100 and an s.d. of 15. Higher scores are indicative of better achievement.
Statistical analysis All statistical analyses were generated using SAS/STAT software, Version 9.4 (SAS Institute Inc., Cary, NC, USA) of the SAS System for Windows 7, Copyright © 2002–2012 SAS Institute Inc. All tests were two-sided and a P-value of 0.05 or lower was assumed to indicate statistical significance. Descriptive statistics such as mean and s.d. for continuous variables and frequency and percent for categorical variables are presented for all demographic variables of interest and outcomes at 3, 8, and 18 years. Categorical variables were compared between two independent groups using a χ2-test of association, whereas continuous variables were compared using a two-sample t-test. Cognitive and behavioral outcomes such as standardized IQ score, test scores and CBCL were compared between low-grade IVH and no IVH groups using an analysis of covariance (ANCOVA) method at ages 3, 8 and 18 years. The ANCOVA model included the following confounding variables to reduce bias: intervention, gestational age, birth weight, maternal education, maternal race and gender. Furthermore, Neonatal Health Index, which serves as a composite score factoring in birth weight, and length of stay in the hospital, was also used to denote severity of the neonatal course.29 Mean differences in continuous outcome measures were summarized using differences in least square means from the ANCOVA model and 95% confidence intervals.
Outcomes Outcomes assessed in this study include cognitive functioning at ages 3, 8 and 18 years, as well as problem behavior and academic achievement at ages 8 and 18 years. Cognitive, behavioral and academic achievement evaluations were performed by trained assessors, who were blinded to the child’s treatment group in the original IHDP study.16
Cognitive assessment at ages 3, 8 and 18 years The Stanford–Binet Intelligence Scale, forms L-M,21 and The Peabody Picture Vocabulary Test-Revised (PPVT-R)22 were used to assess cognitive development at 36 months. The Stanford–Binet Intelligence Scale functions as an age scale, which assesses basal age, ceiling age and deviation intelligent quotient (IQ). It has a normative mean standard score of 100 and an s.d. of 15. PPVT-R is a measure of receptive language and is referenced to a mean of 100 and an s.d. of 15. The PPVT-R22 and the Wechsler Intelligence Scale for Children (WISCIII)23 were used to evaluate cognitive development at age 8 years. The WISC-III provides four indices (verbal comprehension, perceptual organization, freedom from distractibility and processing speed) and can generate a verbal IQ and performance IQ, as well as a full IQ score. Both tests are referenced to a mean of 100 and an s.d. of 15. The Peabody Picture Vocabulary Test-version III24 and the Wechsler Abbreviated Scale of Intelligence (WASI)25 were used to evaluate cognitive development at age 18 years. PPVT-III, like PPVT-R is used as a measure of receptive language. The Wechsler Abbreviated Scale of Intelligence provides four subscales (vocabulary, block design, similarities and matrix reasoning) and can generate a verbal IQ and performance IQ, as well as a full IQ score. Both tests, like the WISC-III and PPVT-R, are referenced to a mean of 100 and an s.d. of 15.
Behavioral assessment at ages 8 and 18 years Problem behavior was measured by maternal report using the Child Behavior Checklist (CBCL)26 for ages 2–3 years for subjects at age 3 years. Child Behavior Checklist for ages 3–18 years27 was used to evaluate problem behavior in subjects at ages 8 and 18 years. Results were interpreted based on Total Problem Raw Score or T score with higher values Journal of Perinatology (2015), 1 – 5
Table 1. Summary statistics and comparison of baseline demographics between the No IVH and IVH groups Variables
No IVH (N = 273)
IVH (N = 93)
Treatment group—no. (%) Follow-up Intervention
178 (65%) 63 (68%) 95 (35%) 30 (32%)
Birth weight group—no. (%) High Low
28 (10%) 6 (6%) 245 (90%) 87 (94%)
Maternal education—no. (%) o9th grade 9th–12th grade High school graduate Completed some college College degree or more
7 91 78 57 40
Maternal race—no. (%) White Black Hispanic Other/unknown
104 (38%) 30 (32%) 130 (48%) 51 (55%) 29 (11%) 10 (11%) 10 (4%) 2 (2%)
Gender—no. (%) Male Female
142 (52%) 50 (54%) 131 (48%) 43 (46%)
Gestational age (weeks)—mean (s.d.) Birth weight (kg)—mean (s.d.) Neonatal health index—mean (s.d.)
P 0.66
0.28
0.58 (3%) (33%) (29%) (21%) (15%)
3 35 25 13 17
(3%) (38%) (27%) (14%) (18%) 0.60
0.77
31 (2.2) 1.5 (0.4) 96 (16)
30 (2.4) o.0001 1.3 (0.4) o.0001 94 (19) 0.46
Abbreviation: IVH, intraventricular hemorrhage. P-values correspond to χ2-test for categorical variables and two-sample t-test for continuous variables.
© 2015 Nature America, Inc.
Impact of IVH on preterm infants P Ann Wy et al
3 Table 2.
Comparison of outcomes at 3, 8 and 18 years between subjects with and without IVH (LSMean and s.e.)
Outcomes
No IVH
IVH
Diff (95% CI)
P
N
Mean (s.e.)
N
Mean (s.e.)
3 years Achenbach Total Prob. Sum Score at 36 months Child's PPVT-R at 36 months Stanford–Binet IQ (corrected age) at 36 months
263 240 270
49.1 (2.1) 85.7 (1.6) 88.0 (1.8)
88 75 93
49.4 (2.8) 82.6 (2.2) 85.4 (2.3)
− 0.34 (−5.27, 4.59) 3.14 (−0.73, 7.00) 2.59 (−1.51, 6.69)
0.89 0.11 0.21
8 years CBCL: internalizing 8-year score CBCL: externalizing 8-year score CBCL: total raw 8-year score PPVT-R standard score: 8 year W–J letter–word ID standard score: 8 years W–J passage comprehension standard score: 8 years W–J broad reading standard score: 8 years W–J broad math standard score: 8 years WISC-III Vb IQ: 8 year WISC-III Pf IQ: 8 year WISC-III Total IQ: 8 year
261 261 262 261 260 260 256 262 263 264 263
10.3 13.0 36.9 84.7 96.2 98.0 95.7 94.1 92.9 91.3 91.4
(0.8) (0.9) (2.3) (2.2) (2.3) (2.1) (2.3) (2.6) (1.7) (1.7) (1.7)
88 88 88 87 88 86 86 88 88 89 88
9.4 13.2 36.4 80.9 95.1 96.3 95.3 91.5 90.1 88.8 88.5
(1.0) (1.2) (3.0) (2.9) (2.9) (2.7) (2.9) (3.3) (2.2) (2.2) (2.2)
0.91 − 0.14 0.56 3.82 1.18 1.73 0.46 2.62 2.79 2.47 2.88
(−0.76, (−2.19, (−4.60, (−1.12, (−3.80, (−3.01, (−4.62, (−3.03, (−1.07, (−1.31, (−0.93,
2.58) 1.90) 5.72) 8.75) 6.16) 6.46) 5.53) 8.27) 6.66) 6.25) 6.69)
0.29 0.89 0.83 0.13 0.64 0.47 0.86 0.36 0.16 0.20 0.14
18 years CBCL aggressive behavior scale CBCL attention problems scale CBCL delinquent behavior scale Total, CBCL scales PPVT-III, standard score W–J, letter–word ID, standard score W–J, comprehension, standard score W–J, calculation, standard score W–J, broad reading, standard score W–J, broad math, standard score WASI, full scale, IQ WASI, performance, IQ WASI, verbal, IQ WASI, verbal, sum of T scores
179 180 178 176 177 177 177 177 176 177 178 178 178 178
4.9 2.7 2.0 9.7 96.8 102 92.3 89.8 94.3 88.7 92.1 91.9 93.3 90.9
(0.6) (0.4) (0.3) (1.1) (2.4) (8.5) (3.0) (2.9) (3.2) (2.6) (2.0) (2.1) (2.0) (2.7)
70 71 69 68 71 70 72 72 70 71 72 72 72 72
5.0 2.8 2.2 9.8 94.8 92.4 91.8 85.1 93.4 86.1 90.4 91.1 91.8 88.4
(0.7) (0.5) (0.3) (1.4) (2.9) (10.5) (3.7) (3.5) (4.0) (3.2) (2.4) (2.5) (2.5) (3.3)
− 0.05 − 0.06 − 0.26 −0.11 2.02 9.37 0.45 4.75 0.88 2.54 1.69 0.84 1.52 2.48
(−1.25, (−0.93, (−0.86, (−2.48, (−2.93, (−8.56, (−5.85, (−1.23, (−5.99, (−2.93, (−2.44, (−3.47, (−2.68, (−3.17,
1.15) 0.80) 0.33) 2.27) 6.98) 27.3) 6.75) 10.73) 7.75) 8.01) 5.83) 5.14) 5.71) 8.14)
0.93 0.89 0.38 0.93 0.42 0.30 0.89 0.12 0.80 0.36 0.42 0.70 0.48 0.39
Abbreviations: CBCL, Child Behavior Checklist; ID, identification; IQ, intelligent quotient; IVH, intraventricular hemorrhage; PPVT, Peabody Picture Vocabulary Test; WASI Wechsler Abbreviated Scale of Intelligence; WISC, Wechsler Intelligence Scale for Children; W–J, Woodcock–Johnson.
RESULTS There was no association between the presence of IVH and the randomized intervention assignment (P = 0.66). In Table 1, 32% (30/93) of patients in the IVH group had intervention, whereas 35% (95/273) in the no IVH group had intervention. Birth weight category (P = 0.28), maternal education (P = 0.58), maternal race (P = 0.60), gender (P = 0.77) and neonatal health index (P = 0.46) were not significantly different between the IVH and no IVH groups. However, mean (s.d.) gestational age was 30 (2.4) weeks in the IVH group and 31 (2.2) weeks in the no IVH group, which was significantly different (P o .0001). Also, mean birth weight of 1.3 (0.4) kg in the IVH group was significantly lower than the mean of 1.5 (0.4) in the no IVH group (P o.0001). None of the outcome measures were significantly different between the two groups after adjusting for demographics and confounding variables at 3, 8 and 18 years (Table 2). At 3 years, mean PPVT-R at 36 months was lower in the IVH group than in the no IVH group (85.7 in non-IVH group vs 82.6 in IVH; mean difference = 3.14, 95% confidence interval − 0.73 to 7; P = 0.11). Mean Stanford–Binet IQ at 36 months was not significantly lower in IVH compared with no IVH group (85.4 in IVH group vs 88 in no IVH group; mean difference = 2.59, 95% confidence interval − 1.59 to 6.69; P = 0.21). Mean W–J letter–word identification standard score was 92.4 (10.5) in the IVH group while it was 102 (8.5) in the non-IVH group but this difference was not statistically significant © 2015 Nature America, Inc.
(mean difference = 9.37, 95% confidence interval − 8.56 to 27.3; P = 0.30). Few subjects had missing information on all outcomes at 3 (3 missing) and 8 years (13 missing). However, at age 18, 105 of the 366 subjects (28.7%) were lost to follow-up. Baseline demographics were not significantly different between participants who were in the study and those who dropped out at 18 years (results not shown) suggesting that participants who dropped out were not systematically different than those who did not in terms of their demographic characteristics. We also investigated whether participants who dropped out at 18 years had significantly worse outcomes at 3 and 8 years in the IVH group than in the non-IVH group (results not shown). None of the outcomes at 3 and 8 years were significantly different between the IVH and non-IVH groups among patients who dropped out of the study. This suggests that participants’ drop out from the study was at random rather than being systematically related to study outcomes. DISCUSSION Our study demonstrates that grade I and II IVH are not independent risk factors for adverse neurobehavioral sequelae as measured by indices of problem behavior, intelligence scores and academic achievement at age 3, 8 and 18 years of age. Bolisetty30 recently found that grade I or II IVH in extremely preterm infants, even with no white matter injury or other late Journal of Perinatology (2015), 1 – 5
Impact of IVH on preterm infants P Ann Wy et al
4 ultrasound abnormalities, was associated with adverse neurodevelopment outcomes. However, in their study, outcomes were collected at an early age of 2–3 years and there was no control of demographic characteristics of his sample. The latter is important as early developmental progress of preterm infants is significantly influenced by social characteristics of their families. Our results, on the other hand, are similar to outcomes in prior studies, which have earlier follow-up time. Sherlock et al.4 demonstrated little whether any sequelae observed in grade I and II IVH at age 8 years with adverse neurodevelopmental sequelae being most pronounced in grade III and grade IV IVH. Similar results were also observed by Roland et al.,7 as well as by Vassilyadi et al.,8 with the greatest impact seen in the setting of post-hemorrhagic hydrocephalus. Furthermore, Vohr et al. 9 observed little difference neurologically in ages 2, 7 and 14 days in cases of mild IVH compared with controls and normal neurologic function in 93% of grade I–II IVH at age 24 months. Such findings suggest neurologic plasticity with the prospect of early recovery, even in later age, as noted by McCormick et al.20 Conflicting findings among different studies have invoked differing theories regarding both neuroplasticity, mechanisms of repair in the setting of early brain insults and even regarding mechanism of initial injury in the setting of low-grade IVH. It has been further postulated that the mechanism of injury in grade I–II IVH stems from impaired cortical development, especially in pathways associated with integration, fine motor coordination and processing skills. Recovery from early brain insult has been described in the literature as a continuum between two opposing schools of thought—early vulnerability versus early plasticity. These models have been well studied and described in the context of visual pathway and motor development. However, there have been few conclusive studies examining neurobehavioral development following such insults.14 Among the limitations of earlier studies, inherent in the early age of follow-up and end point of the study period, is that the full spectrum of neurodevelopmental and behavioral sequelae could not be observed and that there may have been an inaccurate estimation of impairment. The advantage of a longer follow-up period is that it has enabled us to observe academic achievement and development beyond what has previously been considered to be critical ages of development. In addition, the final age of assessment at age 18 years is a closer approximation to peak of capacity for both fluid and crystallized intelligence, which occurs in early adulthood.10 There are several limitations in our study. The lack of standardized indications for cranial ultrasound across different sites makes it impossible for us to know whether those infants in the sample who did not undergo ultrasound did or did not suffer from IVH. We lack a measure of interobserver reliability among radiologists in interpretation of cranial ultrasound. In addition, the infants in our study were born before several advancements that were made in neonatal care such as administration of antenatal steroids and surfactant, which have markedly improved neonatal morbidity and mortality. Furthermore, the final age of assessment at 18 years may preclude other economically important outcomes such as performance in higher education, occupation and income. Cranial ultrasound itself has been demonstrated to be a useful screening tool for IVH but its sensitivity and specificity is inferior to brain magnetic resonance imaging. In addition, although none of the outcome measures in our study demonstrated a statistically significant difference between the IVH cases and non-IVH controls, W–J letter–word identification standard score at age 18 years showed a mean difference of greater than five points, which may be clinically significant. If this observed difference is considered clinically meaningful, a future larger study would be needed to minimize the risk of potentially failing to detect a significant difference. Journal of Perinatology (2015), 1 – 5
The strengths of our study include a relatively large sample of infants with low-grade IVH and long duration of follow-up. We employed a very broad array of outcomes including intellectual and behavior assessments along with academic achievement. We additionally controlled for maternal education, birth weight, race, gender, gestational age, mean neonatal health index and presence/absence of neurobehavioral intervention. In conclusion, our study has demonstrated that low-grade IVH does not represent an independent risk factor for the development of adverse neurodevelopmental sequelae even in early adulthood. Future studies into later adulthood may further delineate any differences observed with regard to problem behavior and academic achievement. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 Ballabh P. Intraventricular hemorrhage in premature infants: mechanism of disease. Pediatr Res 2010; 67(1): 1–8. 2 Bassan H, Feldman HA, Limperopoulos C, Benson CB, Ringer SA, Veracruz E et al. Periventricular Hemorrhagic Infarction: Risk Factors and Neonatal Outcome. Pediatr Neurol 2006; 35(2): 85–92. 3 Neubauer AP, Voss W, Kattner E. Outcome of extremely low birth weight survivors at school age: the influence of perinatal parameters on neurodevelopment. J Pediatr 2008; 167(1): 87–95. 4 Sherlock RL, Anderson PJ, Doyle LW. Victorian Infant Collaborative Study Group Neurodevelopmental sequelae of intraventricular haemorrhage at 8 years of age in a regional cohort of ELBW/very preterm infants. Early Hum Dev 2005; 81(11): 909–916. 5 Patra K, Wilson-Costello D, Taylor HG, Mercuri-Minich N, Hack M. Grades I-II intraventricular hemorrhage in extremely low birth weight infants: effects on neurodevelopment. J Pediatr 2006; 149(2): 169–173. 6 Luu TM, Ment LR, Schneider KC, Katz KH, Allan WC, Vohr BR. Lasting effects of preterm birth and neonatal brain hemorrhage at 12 years of age. Pediatrics 2009; 123(3): 1037–1044. 7 Roland EH, Hill A. Germinal matrix-intraventricular hemorrhage in the premature newborn; management and outcome. Neurol Clin 2003; 21: 833–851. 8 Vassilyadi M, Tataryn Z, Shamji MF, Ventureyra EC. Functional outcomes among premature infants with intraventricular hemorrhage. Pediatr Neurosurg 2009; 45(4): 247–255. 9 Vohr BR, Garcia-VColl C, Mayfield S, Brann B, Shaull P, Oh W. Neurologic and developmental status related to the evolution of visual-motor abnormalities from birth to 2 years of age in preterm infants with intraventricular hemorrhage. J Pediatr 1989; 115(2): 296–302. 10 McArdle JJ, Ferrer-Caja E, Hamagami F, Woodcock RW. "Comparative longitudinal structural analyses of the growth and decline of multiple intellectual abilities over the life span.". Dev Psychol 2002; 38(1): 115–142. 11 Hack M. Young adult outcomes of very-low-birth-weight children. Semin Fetal Neonatal Med 2006; 11(2): 127–137. 12 Werner EE. Journeys From Childhood to Midlife: Risk, Resilience, and Recovery. Pediatrics 2004; 114: 492. 13 Werner EE, Smith RS. Journeys From Childhood to Midlife: Risk, Resilience and Recovery. Cornell University Press: Ithaca, NY, USA, 2001. 14 Anderson V, Spencer-Smith M, Wood A. Do children really recover better? Neurobehavioural plasticity after early brain insult. Brain 2011; 134(Pt 8): 2197–2221. 15 Levin HS. Long-term intellectual outcome of traumatic brain injury in children: limits to neuroplasticity of the young brain? Pediatrics 2012; 129(2): e494–e495. 16 Enhancing the outcomes of low-birth-weight, premature infants: a multisite, randomized trial. The Infant Health and Development Program.JAMA 1990; 263: 3035–3042. 17 Brooks-Gunn J, McCarton CM, Casey PH et al. Early intervention in low-birthweight premature infants: results through age 5 years from the Infant Health and Development Program. JAMA 1994; 272: 1257–1262. 18 McCarton CM, Brooks-Gunn J, Wallace IF et al. Results at age 8 years of early intervention for low-birth-weight premature infants. The Infant Health and Development Program. JAMA 1997; 277: 126–132. 19 McCormick MC, McCarton C, Brooks-Gunn J et al. The Infant Health and Development Program: interim summary. J Dev Behav Pediatr 1998; 19: 359–370.
© 2015 Nature America, Inc.
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5 20 McCormick MC, Brooks-Gunn J, Buka SL, Goldman J, Yu J, Salganik M et al. Early intervention in low birth weight premature infants: results at 18 years of age for the Infant Health and Development Program. Pediatrics 2006; 117(3): 771–780. 21 Terman LM, Merrill MA. Stanford-Binet Intelligence Scale: Manual for the Third Revision, Form L-M (1972 table of norms by R.L. Thorndike). Houghton Mifflin Co.: Boston, MA, USA, 1973. 22 Dunn LM, Dunn LM. Examiner’s manual for the Peabody Picture Vocabulary Test Revised edition. American Guidance Service: Circle Pines, MN, USA, 1981. 23 Wechsler D. Wechsler Intelligence Scale for Children, 3rd edn, The Psychological Corporation: San Antonio, TX, USA, 1991. 24 Dunn LM, Dunn LM. Examiner’s manual for the Peabody Picture Vocabulary Test, 3rd edn, American Guidance Service: Circle Pines, MN, USA, 1997. 25 Wechsler D. Wechsler Abbreviated Scale of Intelligence. The Psychological Corporation: San Antonio, TX, USA, 1999.
© 2015 Nature America, Inc.
26 Achenbach TM, Edelbrock CS, Howell CT. Empirically based assessment of the behavioral/emotional problems of 2- and 3-year-old children. J Abnorm Child Psychol 1987; 15: 629–650. 27 Achenbach TM, Edelbrock C. Manual for the Child Behavior Checklist and Revised Child Behavior Profile. Queen City Printers: Burlington, VT, USA, 1983. 28 Woodcock RW, Johnson MB. Manual for the Woodcock-Johnson Tests of Achievement- Revised. RCL Enterprises: Allen, TX, USA, 1990. 29 Scott DT, Bauer CR, Kraemer HC, Tyson J. A neonatal health index for preterm infants. Pediatric Research 1989; 25(4): 263A. 30 Bolisetty S, Dhawan A, Abdel-Latif M, Bajuk B, Stack J, Lui K. New south wales and australian capital territory neonatal intensive care units' data collection. Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants. Pediatrics 2014; 133(1): 55–62.
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