Abstract
Whether intraventricular hemorrhage increases the risk of adverse developmental outcome among premature infants is controversial. Using brain ultrasound, we identified IVH and white matter abnormalities among 1064 infants born before 28 weeks gestation. We identified adverse developmental outcomes at 24 months of age using a standardized neurological examination and the Bayley Scales of Infant Development Mental and Motor Scales. In logistic regression models that adjusted for gestational age, sex, and public insurance, isolated intraventricular hemorrhage was associated with visual fixation difficulty (odds ratio: 2.5 (95% confidence limits: 1.2, 5.1)) but no other adverse outcome. Infants who had a white matter lesion unaccompanied by intraventricular hemorrhage were at increased risk of cerebral palsy, low Mental and Motor Scores, and visual and hearing impairments. Except when accompanied or followed by a white matter lesion, intraventricular hemorrhage is associated with no more than a mild increase (and possibly no increase) in the risk of adverse developmental outcome during infancy.
Keywords: cerebral palsy, vision impairment, developmental delay, developmental disability, prematurity, Bayley Scales of Infant Development, neurodevelopmental outcome
Introduction
Among the many studies describing an association between intraventricular hemorrhage and developmental impairments,1 few have masked the ultrasound readers or individuals who assessed developmental outcome, and few included methods to increase inter-rater agreement about ultrasound findings or developmental outcomes. Some studies have failed to control potential confounders. Most studies have used samples selected on birth weight (rather than gestational age), which increases the potential for confounding due to fetal growth restriction. 2 Finally, studies based on ultrasonography performed in the first weeks of life would not have identified a substantial proportion of infants with white matter lesions. 3
To address limitations of existing studies of developmental outcome after intraventricular hemorrhage, we analyzed data from the Extremely Low Gestational Age Newborn Study. In this study, participants were eligible on the basis of gestational age (< 28 weeks), masked assessments were made of ultrasound images and infant development, standardized procedures were used to enhance inter-rater reliability,4 infants were scanned both in the first two postnatal weeks and again after that age, and confounding variables were considered.
Methods
The Extremely Low Gestational Age Newborn Study
The Extremely Low Gestational Age Newborn Study was designed to identify characteristics and exposures that increase the risk of structural and functional neurological disorders in children born before 28 weeks gestation.4 During the years 2002-2004, we invited the participation of women who delivered before 28 weeks gestation at any of 14 participating institutions; 1249 mothers of 1506 infants consented. The study was approved by the Institutional Review Board at each site.
For this report, we limited the sample to the 949 infants who had both an early cranial ultrasound scan (protocol 1 or 2 scan; described below) and a late scan (protocol 3 scan; described below) and were evaluated at about 24 months adjusted age [Table 1].
Table 1.
Sample derivation
| Yes | No | |
|---|---|---|
| Enrolled | 1506 | |
| Had the 3rd (“late”) protocol head ultrasound scan | 1260 | 241 |
| Had the 1st &/or 2nd protocol head ultrasound scan | 1171 | 89 |
| Survived to 2 years | 1064 | 107 |
| Had one or more of the 4 evaluations below* | 949 | 115 |
| Had a neurologic exam (CP diagnosis) at 2 years | 937 | 12 |
| Had a Bayley assessment (MDI and PDI) at 2 years | 904 | 15 |
| Had a head circumference measurement at 2 years** | 824 | 125 |
| Information about visual dysfunction available at 2 years | 939 | 10 |
All numbers below are subtracted from 949
And had a birth head circumference Z-score > -2
Abbreviations: CP – cerebral palsy; MDI – Mental Development Index; PDI – Psychomotor Development Index
Neonatal and maternal data
After delivery, a trained research nurse interviewed each mother in her native language using a structured data collection form and following procedures described in a manual. The mother's report of her own characteristics and exposures, as well as the sequence of events leading to preterm delivery were used, even when the medical record provided discrepant information. The gestational age estimates were based on a hierarchy of the quality of available information. Most desirable were estimates based on the dates of embryo retrieval or intrauterine insemination or fetal ultrasound before the 14th week (62%). When these were not available, we used (in order of preference) fetal ultrasound at 14 or more weeks (29%), last menstrual period without fetal ultrasound (7%), and gestational age recorded in the log of the neonatal intensive care unit (1%). The neonate's sex was ascertained from the medical record.
Ultrasound protocol scans
Routine scans were performed by technicians at all of the hospitals using digitized high frequency transducers (7.5 and 10 MHz). Ultrasound studies always included the six standard quasi-coronal views and five sagittal views using the anterior fontanel as the sonographic window.5
Of 1506 infants enrolled, 1064 had both an “early” (i.e., before 15 days) and a “late” (i.e., after 15 days) ultrasound and survived to 24 months adjusted age. Eight-nine percent of these infants (n=949) had one or more of the four evaluations on which this study is focused. The three sets of protocol ultrasound scans were defined by the postnatal day on which they were obtained. Protocol 1 scans were obtained between the first and fourth day (N=726); protocol 2 scans were obtained between the fifth and fourteenth day (N=890), and protocol 3 scans were obtained between the fifteenth day and the 40th week (N=949).
After creation of a manual and data collection form, observer variability minimization efforts included conference calls discussing aspects of images prone to different interpretations.5 An ultrasound manual prepared before the study began defined gerrminal matrix hemorrhage as an echogenicity in the caudothalamic region or in any other periventricular location where germinal matrix is usually found. A diagnosis of intraventricular hemorrhage was made only when echogenic material was seen in the ventricular cavity or if a clot was adherent to the choroid plexus. The data collection forms required that information about hyperechoic and hypoechoic lesions be recorded for every one of 16 white matter zones on each side seen on coronal views. The data collection form did not require that a diagnosis accompany these lesions, nor were criteria provided for any diagnosis. Templates of multiple levels of ventriculomegaly were included in the manual.
All ultrasound scans were read by two independent readers who were not provided clinical information. Each set of scans was first read by one study sonologist at the institution of the infant's birth. The images, usually as electronic images on a CD imbedded in the software eFilm Workstation™ (Merge Healthcare/Merge eMed, Milwaukee, WI) were sent to a sonologist at another Extremely Low Gestational Age Newborn Study institution for a second reading. The eFilm program allowed the second reader to see what the first reader saw, and provided options to adjust and enhance the studies similar to the original reader, including the ability to zoom and alter gains.
When the two readers differed in their recognition of intraventricular hemorrhage, moderate/severe ventriculomegaly, hyperechoic lesion, or hypoechoic lesion, the films were sent to a third (tie-breaking) reader who did not know what the readers reported.
For the current analysis, we defined white matter injury as the presence of a parenchymal hyperechoic or hypoechoic lesion, or late ventriculomegaly.6 These findings are highly predictive of cerebral palsy7 and somewhat predictive of impaired early cognitive function.8
24-month developmental assessment
Bayley Scales of Infant Development – Second Edition9
Certified examiners administered and scored the Bayley Scales of Infant Development-II. All examiners were experienced users of the Bayley Scales of Infant Development-II and, specifically for the Extremely Low Gestational Age Newborn Study, attended a one-day workshop where published guidelines for test administration and videotaped examinations were reviewed. Examiners were aware of the child's enrollment in the Extremely Low Gestational Age Newborn Study and corrected age, but not the child's medical history.
When a child's visual or neurological impairments precluded assessment with the Bayley Scales of Infant Development-II, or more than 2 items were omitted or judged to be ‘unscorable,’ the child was classified as not testable on that scale. The Adaptive Behavioral Composite of the Vineland Adaptive Behavior Scales,10 obtained for 26 of 33 children who were considered not testable with the Bayley Scales of Infant Development-II Mental Scale (i.e., Mental Development Index), was used to approximate the Mental Scale score 10. Among infants not testable with the Bayley Scales of Infant Development-II Motor Scale (i.e., Psychomotor Development Index), 32 were assessed with the Vineland Adaptive Behavior Scales, and the Vineland Adaptive Behavior Scales Motor Skills Domain score was used to approximate the Motor Scale score.
The Bayley Scales of Infant Development-II manual classifies Mental or Motor Scale score below 70 (i.e., 2 standard deviations below the mean for the standardization sample) as “significantly delayed performance”.9 On the other hand, in very preterm infants, the predictive ability of a Mental Scale below 55 (i.e., more than three standard deviations below the mean for the standardization sample) is higher than that of a score below 70.11 Thus, we classified the Bayley Scales of Infant Development-II outcomes into 3 categories: Mental or Motor Scale below 55 (more than 3 standard deviations below the mean), 55-69 (between 2 and 3 standard deviations below the mean), and 70 or greater (within 2 standard deviations of the mean or higher).
Head circumference
The head circumference was measured as the largest possible occipital-frontal circumference. Measurements were rounded to the closest 0.1 centimeter when taken at birth, and when examined at 24-month corrected age. All head circumferences are presented as Z-scores because newborns were assessed at different gestational ages at birth (23-27 weeks) and at different approximations of 24 months corrected age (range: 16-44 months corrected age, with 68% assessed at 23-25 weeks corrected age). Birth Z-scores were based on standards from Oxford, England12 and Z-scores at the 24-month assessment were based on standards in the Centers for Disease Control data sets.13
Cerebral palsy
Those who performed the neurological examinations studied a manual, a data collection form and an instructional compact disc designed to minimize examiner variability, and demonstrated acceptably low variability.14 The topographic diagnosis of cerebral palsy (quadriparesis, diparesis, or hemiparesis) was based on an algorithm using data from the neurological examination.15 Children allocated to one cerebral palsy diagnosis differ from their peers with the two other cerebral palsy diagnoses in their score on the Gross Motor Functional Classification System,(v.i.) as well as in the frequency of microcephaly, cognitive impairment, and screening positive with the Modified Checklist for Autism in Toddlers. Only 4% of examiners indicated at the time of the examination that they had knowledge of the child's brain-imaging studies; in all other cases examiners were not aware of the results of these studies.
Vision impairment
Neurological examiners assessed fixation by observing how the child followed the examiner's hand as well as objects. Visual fields were assessed by confrontation. Strabismus was defined as dysconjugate eye postitions at rest and on movement. A parental questionnaire administered during child's 24-month follow-up visit asked about the child's prior use of an eye patch, history of disconjugate gaze (‘squint') or surgery, or diagnosis of monocular or binocular blindness. The nine children whose parent reported surgery and who had no abnormality evident on the two year exam were classified as having strabismus.
Data analysis
We evaluated two hypotheses. The first is that among children who had no sonographic evidence of white matter damage, those who had IVH were not at increased risk of having adverse neurodevelopmental outcomes or microcephaly. The second is that among children who had sonographic evidence of white matter damage, those who had IVH were not at increased risk of having adverse neurodevelopmental outcomes or microcephaly.
We created logistic regression and multinomial logistic regression models to evaluate the contribution of intraventricular hemorrhage to developmental impairments, after adjustment for gestational age, sex, and public insurance, separately in subsamples defined by the presence/absence of sonographic evidence of white matter damage. These models allowed us to calculate odds ratios and 95% confidence intervals.
Because of the very low power comparing those with and without intraventricular hemorrhage in the white matter damage sample, we also created models for each developmental disorder that compared three groups with an ultrasound abnormality (i.e., intraventricular hemorrhage only, white matter damage only, and both intraventricular hemorrhage and white matter damage) to the common referent group of children who had no abnormality on their cranial ultrasound scans. Here, too, these models allowed estimation of odds ratios and 95% confidence intervals.
Results
Study participants
Twelve hundred and forty-nine mothers of 1506 infants consented to participate. Of the 1200 infants who survived to 24 months adjusted age, 1064 infants underwent scanning at least once in the first 15 postnatal days and at least once after that age. Of the infants who had both an early and late cranial ultrasound scan, 949 were evaluated at about 24 months adjusted age [Table 1].
Of the 949 infants who had one of more evaluation at 24 months adjusted age, 58 (6%) had late ventriculomegaly, 56 (6%) had a hyperechoic lesion, and 72 (8%) had a hypoechoic lesion. A hyperechoic lesion was identified on the first protocol scan (on postnatal day 1-4) in 52% of cases. In contrast, a hypoechoic lesion was not identified until the third protocol scan (postnatal day 15-40 weeks postmenstrual age) in 64% of case. Ventriculomegaly was first evident on the third protocol scan in 31% of cases (data not shown). In the remaining 69%, ventriculomegaly was first evident on an early scan but persisted on the late scan.
Intraventricular hemorrhage was strongly associated with white matter damage (odds ratio: 11.31; 95% confidence interval: 7.39, 17.31). Of the 180 infants with IVH, 41% also had white matter damage, and of the 108 infants with white matter damage, 69% also had IVH (data not shown). Fully 78% of infants with intraventricular hemorrhage also had germinal matrix hemorrhage and 5% (n=42) required a ventriculo-peritoneal shunt (data not shown). Because of the small number of infants with a shunt, we do not present analyses for this factor. In unadjusted analyses, odds ratios relating shunt to adverse outcomes ranged from 1.0 to 2.4 (data not shown).
In Tables 2-5, comparison of prevalence rates in the first two rows of the table provides information about the association of intraventricular hemorrhage and adverse outcomes in the absence of neonatal white matter damage. Comparison of prevalence rates in third and fourth rows of the table provides information about the association of intraventricular hemorrhage and adverse outcomes in the presence of neonatal white matter damage.
Table 2.
The percent of children who had each combination of ultrasound lesions listed on the left who developed the cerebral palsy type listed at the head of each column. These are row percents except for the column labeled “number of infants”.
| White matter lesion | Intraventricular hemorrhage | Cerebral palsy diagnosis | Number of infants | ||
|---|---|---|---|---|---|
| Quadriparesis | Diparesis | Hemiparesis | |||
| No | No | 3 | 3 | 1 | 713 |
| Yes | 4 | 6 | 1 | 106 | |
| Yes | No | 36 | 7 | 5 | 44 |
| Yes | 32 | 7 | 11 | 74 | |
| Column N | 62 | 32 | 18 | 937 | |
Table 5.
The percent of children who had each combination of ultrasound lesions listed on the left who had the sensory dysfunction listed at the top of each column. These are row percents.
| White matter lesion | Intraventricular hemorrhage | Strabismus | Visual Fields | Impaired Fixation | Hearing impairment | Row N for visual / hearing impairment |
|---|---|---|---|---|---|---|
| No | No | 13 | 4 | 4 | 1 | 714 / 741 |
| Yes | 15 | 6 | 12 | 3 | 106 / 109 | |
| Yes | No | 33 | 12 | 11 | 7 | 44 / 45 |
| Yes | 29 | 18 | 21 | 5 | 75/ 76 | |
| Column N | 141 | 55 | 66 | 19 | 939 / 971 |
Cerebral Palsy (Table 2)
Other than a statistically non-significant doubling of the risk of diplegia, no associations were observed between intraventricular hemorrhage and cerebral palsy diagnoses in children without white matter damage. Among children who had white matter damage, the doubling of hemiplegia risk associated with intraventricular hemorrhage was not statistically significant, perhaps because only 18 children had this diagnosis.
Bayley Scales of Infant Development (Table 3)
Table 3.
The percent of children who had each combination of ultrasound lesions listed on the left who developed the Bayley Scale Index listed at the head of each column. These are row percents.
| White matter lesion | Intraventricular hemorrhage | MDI | PDI | Row N | ||
|---|---|---|---|---|---|---|
| <55 | 55-69 | <55 | 55-69 | |||
| No | No | 12 | 11 | 11 | 14 | 690 |
| Yes | 18 | 16 | 19 | 19 | 102 | |
| Yes | No | 29 | 19 | 40 | 21 | 42 |
| Yes | 34 | 9 | 44 | 11 | 70 | |
| Column N | 138 | 104 | 146 | 133 | 904 | |
Abbreviations: MDI – Mental Development Index; PDI – Psychomotor Development Index
Among children without evident white matter damage, intraventricular hemorrhage was associated with small/modest increases (risk ratios ranging from 1.4 to 1.7) in risks of low scores on the Mental and Motor Scales. Among children who had evident white matter damage, intraventricular hemorrhage was not associated with an increased risk of low scores on either scale.
Small head size (Table 4)
Table 4.
The percent of children who had each combination of ultrasound lesions listed on the left who had a small head at age two years. Children with a birth head circumference < -2 or whose head was not measured are excluded. These are row percents.
| White matter lesion | Intraventricular hemorrhage | Head circumference Z-score | Row N | |
|---|---|---|---|---|
| < -2 | ≥ -2, < -1 | |||
| No | No | 7 | 16 | 620 |
| Yes | 14 | 17 | 96 | |
| Yes | No | 15 | 24 | 41 |
| Yes | 22 | 25 | 67 | |
| Column N | 75 | 140 | 824 | |
Among children who had no evident white matter damage, intraventricular hemorrhage was associated with a doubling of the risk of microcephaly. Among children who had white matter damage, intraventricular hemorrhage was associated with a more modest increase in risk of microcephaly (risk ratio 1.5), but not of a head circumference Z-score ≥ -2 and < -1.
Visual and hearing dysfunction (Table 5)
Intraventricular hemorrhage was associated with impaired fixation both among children who did and did not have white matter damage. Intraventricular hemorrhage was also associated with visual fields limitations among children who had white matter damage (risk ratio 1.5).
Multivariate analyses (Tables 6 and 7)
Table 6.
Odds ratios and 95% confidence intervals of neurodevelopmental dysfunctions and reduced head circumference associated with IVH calculated separately among those with and without a sonographic white matter lesion. The models are adjusted for gestational age, sex, and public insurance. Early ventriculomegaly is not considered but children had to have a LATE SCAN (scan 3) to be included. Odds ratios in bold type are statistically significant at p < 0.05.
| Odds ratios associated with IVH | ||
|---|---|---|
| Sonographic white matter lesion | ||
| Outcome | No | Yes |
| Quadriplegia | 1.2 (0.4, 3.7) | 0.8 (0.3, 2.0) |
| Diplegia | 2.2 (0.8, 5.0) | 0.8 (0.1, 4.3) |
| Hemiplegia | 0.7 (0.1, 5.8) | 2.2 (0.2, 24) |
| MDI < 55 | 1.4 (0.8, 2.6) | 0.9 (0.3, 2.4) |
| MDI 55-69 | 1.7 (0.9, 3.2) | 0.2 (0.1, 0.9) |
| PDI < 55 | 1.8 (0.98, 3.1) | 0.9 (0.3, 2.5) |
| PDI 55-69 | 1.6 (0.8, 2.7) | 0.3 (0.1, 1.1) |
| HC Z-score < -2 | 1.8 (0.9, 3.7) | 2.2 (0.5, 8.8) |
| HC Z-score ≥ -2, < -1 | 1.1 (0.6, 2.0) | 0.9 (0.3, 2.7) |
| Strabismus | 0.9 (0.5, 1.7) | 0.7 (0.3, 1.8) |
| Visual field deficit | 1.1 (0.4, 2.8) | 1.5 (0.4, 5.0) |
| Impaired fixation | 2.5 (1.2, 5.1) | 1.8 (0.5, 6.0) |
| Hearing impairment | 2.5 (0.6, 10) | 0.7 (0.1, 3.7) |
Abbreviations: IVH – intraventricular hemorrhage; MDI – Mental Development Index; PDI – Psychomotor Development Index; HC – head circumference
Table 7.
Odds ratios and 95% confidence intervals of developmental disorders associated with intraventricular hemorrhage and a white matter lesion, alone and together. The models are adjusted for gestational age, sex, and public insurance. Early ventriculomegaly is not considered but child had to have a LATE SCAN (scan 3) to be included. Odds ratios in bold type are statistically significant at p < 0.05. The referent group is children without intraventricular hemorrhage or a white matter lesion.
| Outcome | IVH only | WML only | IVH + WML |
|---|---|---|---|
| Quadriplegia | 1.2 (0.4, 3.8) | 28 (12, 64) | 19 (9.2, 39) |
| Diplegia | 2.1 (0.8, 5.7) | 5.6 (1.5, 21) | 4.5 (1.5, 13) |
| Hemiplegia | 0.7 (0.1, 6) | 5.6 (0.6, 50) | 15 (4.9, 46) |
| MDI < 55 | 1.4 (0.8, 2.6) | 3.5 (1.6, 7.8) | 3.3 (1.8, 5.9) |
| MDI 55-69 | 1.6 (0.9, 3.0) | 2.8 (1.2, 6.6) | 1.0 (0.4, 2.6) |
| PDI < 55 | 1.8 (0.99, 3.1) | 7.5 (3.5, 16) | 5.9 (3.3, 11) |
| PDI 55-69 | 1.5 (0.9, 2.7) | 3.6 (1.5, 8.5) | 1.1 (0.5, 2.7) |
| HC Z-score < -2 | 1.8 (0.9, 3.7) | 2.6 (0.95, 7.2) | 3.5 (1.7, 7.5) |
| HC Z-score ≥ -2, < -1 | 1.1 (0.6, 1.9) | 2.0 (0.9, 4.5) | 2.0 (1.04, 4.5) |
| Strabismus | 1.0 (0.5, 1.8) | 3.4 (1.7, 6.9) | 2.0 (1.1, 3.6) |
| Visual field deficit | 1.2 (0.5, 3.0) | 3.5 (1.3, 9.7) | 3.9 (1.8, 8.3) |
| Impaired fixation | 2.4 (1.2, 4.9) | 2.9 (1.05, 8.0) | 4.3 (2.2, 8.5) |
| Hearing impairment | 2.4 (0.6, 9.3) | 6.7 (1.7, 27) | 4.2 (1.2, 15) |
Abbreviations: IVH – intraventricular hemorrhage; WML – white matter lesion; MDI – Mental Development Index; PDI – Psychomotor Development Index; HC – head circumference
In children who did not have white matter damage, intraventricular hemorrhage was associated only with an increased risk of impaired fixation [Table 6]. In those who had white matter damage, intraventricular hemorrhage was associated with a doubling of the risk of hemiplegic CP and microcephaly, but the confidence intervals are wide and include 1.0.
Among children who did not have white matter damage, intraventricular hemorrhage was associated only with an increased risk of impaired fixation [Table 6, left data column]. Among all children who had white matter damage, intraventricular hemorrhage was associated with a doubling of the risk of hemiplegic CP and microcephaly, but the confidence intervals are wide and include 1.0 [Table 6, right data column].
In the multinomial regression models, children who had intraventricular hemorrhage only, white matter damage only, and both intraventricular hemorrhage and white matter damage were compared to children who had neither intraventricular hemorrhage nor white matter damage (Table 7). Children who had a white matter lesion unaccompanied by intraventricular hemorrhage were at prominently increased risk of all three forms of cerebral palsy, Mental and Motor Scales less than 70, strabismus, visual field deficit, difficulty fixing gaze and a hearing impairment. Odds ratios for hemiparetic cerebral palsy, microcephaly, visual field reduction or impaired fixation were larger when both a white matter lesion and intraventricular hemorrhage were present than when white matter damage was unaccompanied by intraventricular hemorrhage; however, the odds ratios were not statistically significantly larger.
Discussion
Among infants without ultrasound evidence of white matter damage, intraventricular hemorrhage was associated with visual fixation difficulty, and, possibly, impaired early motor function, but no other developmental impairments. In contrast, white matter damage was associated with an increased risk of cerebral palsy, impaired early mental and motor development, and visual dysfunctions. Intraventricular hemorrhage was strongly associated with white matter damage. While intraventricular hemorrhage plus white matter damage was strongly associated with all of the developmental impairments that we studied, infants with both ultrasound abnormalities were not at greater risk for adverse outcome than infants who only had white matter damage.
Our findings suggest that infants with intraventricular hemorrhage not accompanied or followed by white matter damage have only a slight increase in the risks of major developmental impairments identifiable during infancy. We cannot exclude a relationship between intraventricular hemorrhage and developmental impairments that are best identified only after infancy, such as social and communication dysfunctions, attentional difficulties, and learning disabilties.
Ultrasound abnormalities were more strongly associated with cerebral palsy and impaired motor function (i.e., low Motor Scale) than with impaired early cognitive function (i.e., low Mental Scale). One explanation for this difference is the relatively greater importance of periventricular brain structures, such as corticospinal tracts, in control of motor function, and the better visualization of these structures as compared to cortical structures. 16
One proposed intermediate linking intraventricular hemorrhage and developmental impairment is post-hemorrhagic hydrocephalus, leading to placement of a ventricular shunt and, in a proportion of cases, shunt infection.17 In a large cohort of extremely low birth weight infants, those with Papile grade 3 intraventricular hemorrhage who required a shunt were at twice the risk of cerebral palsy compared to those who did not.18
A likely intermediate is white matter damage19 which was associated with intraventricular hemorrhage in the present study. To the extent that intraventricular hemorrhage is causally related to white matter damage, it very likely is an important antecedent of developmental impairments, particularly cerebral palsy.
A third possible intermediate linking intraventricular hemorrhage and developmental impairment is supression of neuronal and glial progenitor cell proliferation in the ganglionic eminence.20 This mechanism is relevant even to infants who have neither post-hemorrhagic hydrocephalus nor ultrasound-detectable white matter lesions, and might explain our observation that infants whose only ultrasound abnormality was IVH had a higher risk of impaired visual fixation.
Our findings agree with those from the first large study of developmental outcome in preterm infants with intraventricular hemorrhage.21 In that study, infants with and without intraventricular hemorrhage had almost identical rates of handicap, whereas intraventricular hemorrhage plus ventricular dilatation was associated with a more than 3-fold higher risk of handicap, and intraventricular hemorrhage plus parenchymal a hyperechoic lesion with a more than 7-fold increase. Similarly, in more recent studied cohorts, parenchymal pathology or ventricular enlargement on an infant's last ultrasound during hospitalization, but not intraventricular hemorrhage, was associated with cerebral palsy and low scores on the Bayley Motor Scale.22;23
On the other hand, in at least two large well designed studies, IVH was associated with an increased risk of developmental impairment. In one, the occurrence of germinal matrix or uncomplicated intraventricular hemorrhage (i.e., intraventricular hemorrhage without ventricular dilatation or white matter lesion) was associated with a 3.4-fold higher odds of cerebral palsy24 and a 4.6-fold higher odds of intellectual disability.25 However, one half of the study participants did not undergo ultrasound after the first postnatal week, when over 90% of white matter lesions are first detected in very preterm infants.3 Undetected white matter lesions might also explain the finding that at school age, children with germinal matrix or uncomplicated intraventricular hemorrhage had worse performance on measures of neuropsychological functioning and academic achievement, and had a higher risk of neurosensory disorder.26 On the other hand, even in a cohort of extremely low birth weight infants who were screened for white matter lesions with ultrasound screening in the first 10 postnatal days, at 30 days, and prior to discharge from the hospital, those with germinal matrix or uncomplicated intraventricular hemorrhage were twice as likely to have an Mental Scale < 70 and 2.6 times as likely to have a major neurological abnormality.27
Our study has at least three limitations. First, despite the large number of infants studied, the precision of odds ratios relating intraventricular hemorrhage and cerebral palsy was limited by the relatively small number of infants with this outcome and the relatively small number of infants with white matter lesions. Second, ultrasound fails to detect a substantial proportion of white matter lesions among extremely premature infants, even when scans are performed near discharge.1 Third, the measure of cognitive impairment used in this study, the Bayley Scales of Infant Development, is only moderately predictive of cognitive impairment at school age.11;28 The strengths include a relatively large cohort selected on the basis of gestational age, efforts taken to increase the reliability of interpretations of ultrasound and neurodevelopmental findings, and the masking of ultrasound readers and those who evaluated infants for neurodevelopmental outcomes.
Our findings imply that in the first 2 weeks of life, clinicians should offer only tentative statements about prognosis for infants diagnosed with an intraventricular hemorrhage, unless white matter lesions (ventricular enlargment, hypoechoic lesions, or hyperechoic lesions) are also present. More definitive ultrasound-based predictions about developmental prognosis should be postponed until follow up scans have been obtained.
What we found also has implications for researchers. Because of the strong association between intraventricular hemorrhage and white matter lesions, study is needed of whether brain MRI at term-age equivalent (a more sensitive test for white matter abnormality than ultrasound),1 might benefit infants whose early ultrasound showed intraventricular hemorrhage and late ultrasound showed no white matter abnormality. A second implication is that clinical trials powered to detect a reduced risk of intraventricular hemorrhage will not be sufficiently powered to detect a reduced risk of developmental impairment. Finally, more research is needed into the molecular mediators linking intraventricular hemorrhage to white matter lesions.
In conclusion, most of the association between intraventricular hemorrhage and developmental limitations appears to reflect the association between intraventricular hemorrhage and white matter damage, and the association between white matter damage and developmental limitations.
Acknowledgements
The authors gratefully acknowledge the contributions of the participants, and the participants’ families, as well as those of their colleagues. We are grateful to the following collaborators who made this report possible: Kristen Ecklund, Haim Bassan, Samantha Butler, Adré Duplessis, Cecil Hahn, Catherine Limperopoulos, Omar Khwaja, Janet S. Soul (Children's Hospital, Boston, MA); Bhavesh Shah. Frederick Hampf, Herbert Gilmore, Susan McQuiston (Baystate Medical Center, Springfield, MA); Camilia R. Martin, Jane Share (Beth Israel Deaconess Medical Center, Boston); Linda J. Van Marter, Sara Durfee (Brigham & Woman's Hospital, Boston); Robert M. Insoft (Massachusetts General Hospital, Boston); Cynthia Cole, John M. Fiascone, Roy McCauley, Paige T. Church, Cecelia Keller, Karen J. Miller (Floating Hospital for Children at Tufts Medical Center, Boston); Francis Bednarek, Jacqueline Wellman, Robin Adair, Richard Bream, Alice Miller, Albert Scheiner, Christy Stine (UMass Memorial Health Care, Worcester, MA); Richard Ehrenkranz, Cindy Miller, Nancy Close, Elaine Romano, Joanne Williams (Yale University School of Medicine, New Haven, CT); Barbara Specter, Deborah Allred, Robert Dillard, Don Goldstein, Deborah Hiatt, Gail Hounshell, Ellen Waldrep, Lisa Washburn, Cherrie D. Welch (Wake Forest University Baptist Medical Center and Forsyth Medical Center, Winston- Salem, NC); Stephen C. Engelke, Ira Adler, Sharon Buckwald, Rebecca Helms, Kathyrn Kerkering, Scott S. MacGilvray, Peter Resnik (University Health Systems of Eastern Carolina, Greenville, NC); Carl Bose, Lynn A. Fordham, Lisa Bostic, Diane Marshall, Kristi Milowic, Janice Wereszczak (North Carolina Children's Hospital, Chapel Hill, NC); Mariel Poortenga, Bradford W. Betz, Steven L. Bezinque, Joseph Junewick, Wendy Burdo-Hartman, Lynn Fagerman, Kim Lohr, Steve Pastyrnak, Dinah Sutton (Helen DeVos Children's Hospital, Grand Rapids, MI); Ellen Cavenagh, Victoria J. Caine, Nicholas Olomu, Joan Price (Sparrow Hospital, Lansing, MI); Nigel Paneth, Padmani Karna (Michigan State University, East Lansing); Michael D. Schreiber, Kate Feinstein, Leslie Caldarelli, Sunila E. O'Connor, Michael Msall, Susan Plesha-Troyke (University of ChicagoMedical Center, Chicago, IL); Daniel Batton, Karen Brooklier, Beth Kring, Melisa J. Oca, Katherine M. Solomon (William Beaumont Hospital, Royal Oak, MI); Joanna J. Seibert (Arkansas Children's Hospital); Robert Lorenzo (Children's Hospital of Atlanta, GA).
Following are the ELGAN Study participating institutions (site principal investigators and sonologists): Baystate Medical Center, Springfield, MA (Bhavesh Shah, Frederick Hampf); Beth Israel Deaconess Medical Center, Boston (Camilia R. Martin); Brigham & Women's Hospital, Boston (Linda J. Van Marter, Sara Durfee); Children's Hospital, Boston (Alan Leviton, Kirsten Ecklund); Massachusetts General Hospital, Boston (Robert Insoft); Floating Hospital for Children at TuftsMedical Center, Boston (Cynthia Cole/John Fiascone, Roy McCauley); University of Massachusetts Memorial Health Center, Worcester (Francis Bednarek, Jacqueline Wellman); Yale University School of Medicine, New Haven, CT (Richard Ehrenkranz, Cindy Miller); Forsyth Hospital, Baptist Medical Center, Winston-Salem, NC (T. Michael O'Shea, Barbara Specter); University Health Systems of Eastern Carolina, Greenville, NC (Stephen Engelke, Ira Adler); North Carolina Children's Hospital, Chapel Hill (Carl Bose, Lynn Fordham); DeVos Children's Hospital, Grand Rapids, MI (Mariel Portenga, BradfordW. Betz, Steven Bezinque, Joseph Junewick); Sparrow Hospital, Lansing, MI (Padmani Karna, Ellen Cavenagh); Michigan State University, East Lansing (Nigel Paneth); University of Chicago Hospital, Chicago, IL (Michael D. Schreiber, Kate Feinstein); William Beaumont Hospital, Royal Oak, MI (Daniel Batton). Sonologists not at participating sites were Robert Lorenzo, Joanna Sieber, and Jane Share.
Financial Disclosure/Funding
The authors disclosed receipt of the following financial support for the research and/or authorship of this article: This study was supported by a cooperative agreement with the National Institute of Neurological Diseases and Stroke (5U01NS040069-05) and a program project grant from the National Institute of Child Health and Human Development (5P30HD018655-28).
Abbreviations
- ELGAN
extremely low gestational age newborn
- BSID-II
Bayley Scales of Infant Development- 2nd Edition
- MDI
Mental Development Index
- PDI
Psychomotor Development Index
Footnotes
Author Contributions
TMO contributed to the design of the study, data acquisition, analysis, and interpretation. TMO compiled the first draft, contributed to rewriting and subsequent revisions, and approved the submitted version. ENA contributed to the design of the study, data analysis and interpretation, review and rewriting of the first draft and subsequent revisions, and approved the submitted version. KCKK contributed to the design of the study, data acquisition, data analysis and interpretation, review and rewriting of the first draft and subsequent revisions, and approved the submitted version. DH contributed to the design of the study, the review and rewriting of the first draft and subsequent revisions, and approved the submitted version. BS contributed to the design of the study, data acquisition, the review and rewriting of the first draft, and approved the submitted version. SD contributed to the design of the study, data acquisition, the review and rewriting of the first draft, and approved the submitted version. NP contributed to the design of the study, data acquisition, data analysis and interpretation, and the review and rewriting of the manuscript, and approved the submitted version. AL contributed to the design of the study, data analysis and interpretation, review and rewriting of the first draft and subsequent revisions, and approved the submitted version.
The authors have no conflicts of interests to disclose.
Reference List
- 1.O'Shea TM, Counsell SJ, Bartels DB, et al. Magnetic resonance and ultrasound brain imaging in preterm infants. Early Human Development. 2005;81(3):263–271. doi: 10.1016/j.earlhumdev.2005.01.004. [DOI] [PubMed] [Google Scholar]
- 2.Arnold CC, Kramer MS, Hobbs CA, et al. Very low birth weight: a problematic cohort for epidemiologic studies of very small or immature neonates. Am J Epidemiol. 1991;134:604–613. doi: 10.1093/oxfordjournals.aje.a116133. [DOI] [PubMed] [Google Scholar]
- 3.de Vries LS, Van Haastert ILC, Rademaker KJ, et al. Ultrasound abnormalities preceding cerebral palsy in high-risk preterm infants. Journal of Pediatrics. 2004;144(6):815–820. doi: 10.1016/j.jpeds.2004.03.034. [DOI] [PubMed] [Google Scholar]
- 4.O'Shea TM, Allred EN, Dammann O, et al. The ELGAN study of the brain and related disorders in extremely low gestational age newborns. Early Human Development. 2009;85(11):719–725. doi: 10.1016/j.earlhumdev.2009.08.060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kuban K, Adler I, Allred E, et al. Observer variabiity assessing US scans of the preterm brain: the ELGAN study. Pediatr Radiol. 2007;37:1201–1208. doi: 10.1007/s00247-007-0605-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Paneth N. Classifying brain damage in preterm infants. J Pediatr. 1999;134(5):527–529. doi: 10.1016/s0022-3476(99)70231-3. [DOI] [PubMed] [Google Scholar]
- 7.Kuban K, Allred E, O'Shea TM, et al. Cranial ultrasound lesions in the NICU predict cerebral palsy at age 2 years in children who were born at extremely low gestational age. J Child Neurol. 2008;24:63–72. doi: 10.1177/0883073808321048. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.O'Shea TM, Kuban KCK, Allred EN, et al. Neonatal cranial ultrasound lesions and developmental delays at 2 years of age among extremely low gestational age children. Pediatrics. 2008;122(3):E662–E669. doi: 10.1542/peds.2008-0594. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Bayley N. Bayley Scales of Infant Development-Second Edition. Second ed. Psychological Corporation; 1993. [Google Scholar]
- 10.Sparrow SS, Balla DA, Cicchetti DV. Vineland Adaptive Behavioral Scales. American Guidance Service; Circle Pines, MN: 1984. [Google Scholar]
- 11.Roberts G, Anderson PJ, Doyle LW. The stability of the diagnosis of developmental disability between ages 2 and 8 in a geographic cohort of very preterm children born in 1997. Archives of Disease in Childhood 2010. 95(10):786–790. doi: 10.1136/adc.2009.160283. [DOI] [PubMed] [Google Scholar]
- 12.Yudkin PL, Aboualfa M, Eyre JA, et al. New Birth-Weight and Head Circumference Centiles for Gestational Ages 24 to 42 Weeks. Early Human Development. 1987;15(1):45–52. doi: 10.1016/0378-3782(87)90099-5. [DOI] [PubMed] [Google Scholar]
- 13.United States Centers for Disease Control CDC Growth Charts. 2011 http://www cdc gov/nchs/data/nhanes/growthcharts/zscore/zhcageinf xls. [Google Scholar]
- 14.Kuban KCK, O'Shea M, Allred E, et al. Video and CD-ROM as a training tool for performing neurologic examinations of 1-year-old children in a multicenter epidemiologic study. Journal of Child Neurology. 2005;20(10):829–831. doi: 10.1177/08830738050200101001. [DOI] [PubMed] [Google Scholar]
- 15.Kuban K, Allred E, O'Shea TM, et al. An algorithm for identifying and classifying cerebral palsy in young children. Journal of Pediatrics. 2008;153:466–472. doi: 10.1016/j.jpeds.2008.04.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Lee JD, Park HJ, Park ES, et al. Motor pathway injury in patients with periventricular leucomalacia and spastic diplegia. Brain. 2011;134:1199–1210. doi: 10.1093/brain/awr021. [DOI] [PubMed] [Google Scholar]
- 17.Whitelaw A, Cherian S, Thoresen M, et al. Posthaemorrhagic ventricular dilatation: new mechanisms and new treatment. Acta Paediatrica. 2004;93:11–14. doi: 10.1111/j.1651-2227.2004.tb03041.x. [DOI] [PubMed] [Google Scholar]
- 18.Adams-Chapman I, Hansen NI, Stoll BJ, et al. Neurodevelopmental outcome of extremely low birth weight infants with posthemorrhagic hydrocephalus requiring shunt insertion. Pediatrics. 2008;121(5):E1167–E1177. doi: 10.1542/peds.2007-0423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Kuban K, Sanocka U, Leviton A, et al. White matter disorders of prematurity: Association with intraventricular hemorrhage and ventriculomegaly. J Pediatr. 1999;134(539):546. doi: 10.1016/s0022-3476(99)70237-4. [DOI] [PubMed] [Google Scholar]
- 20.Bigio MR. Cell proliferation in human ganglionic eminence and suppression afterprematurity-associated haemorrhage. Brain. 2011;134(1344):1361. doi: 10.1093/brain/awr052. [DOI] [PubMed] [Google Scholar]
- 21.Papile LA, Munsickbruno G, Schaefer A. Relationship of Cerebral Intraventricular Hemorrhage and Early-Childhood Neurologic Handicaps. Journal of Pediatrics. 1983;103(2):273–277. doi: 10.1016/s0022-3476(83)80366-7. [DOI] [PubMed] [Google Scholar]
- 22.Stewart AL, Reynolds EO, Hope PL, et al. Probability of neurodevelopmental disorders estimated from ultrasound appearance of brains of very preterm infants. Dev Med Child Neurol. 1987;29(1):3–11. doi: 10.1111/j.1469-8749.1987.tb02101.x. [DOI] [PubMed] [Google Scholar]
- 23.Wood NS, Costeloe K, Gibson AT, et al. The EPICure study: associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2005;90(2):134–140. doi: 10.1136/adc.2004.052407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Pinto-Martin JA, Riolo S, Cnaan A, et al. Cranial ultrasound prediction of disabling and nondisabling cerebral palsy at age two in a low birth weight population. Pediatrics. 1995;95(2):249–254. [PubMed] [Google Scholar]
- 25.Whitaker AH, Feldman JF, VanRossem R, et al. Neonatal cranial ultrasound abnormalities in low birth weight infants: Relation to cognitive outcomes at six years of age. Pediatrics. 1996;98(4):719–729. [PubMed] [Google Scholar]
- 26.Taylor HG, Klein N, Drotar D, et al. Consequences and risks of < 1000-g birth weight for neuropsychological skills, achievement, and adaptive functioning. Journal of Developmental and Behavioral Pediatrics. 2006;27(6):459–469. doi: 10.1097/00004703-200612000-00002. [DOI] [PubMed] [Google Scholar]
- 27.Patra K, Wilson-Costello D, Taylor HG, et al. Grades I-II intraventricular hemorrhage in extremely low birth weight infants: Effects on neurodevelopment. Journal of Pediatrics. 2006;149(2):169–173. doi: 10.1016/j.jpeds.2006.04.002. [DOI] [PubMed] [Google Scholar]
- 28.Hack M, Taylor HG, Drotar D, et al. Poor predictive validity of the Bayley Scales of Infant Development for cognitive function of extremely low birth weight children at school age. Pediatrics. 2005;116(2):333–341. doi: 10.1542/peds.2005-0173. [DOI] [PubMed] [Google Scholar]