Early-onset intraventricular hemorrhage in preterm neonates: Incidence of neurodevelopmental handicap

Early-Onset Intraventricular Hemorrhage in Preterm Neonates: Incidence of Neurodevelopmental Handicap Betty Vohr, Walter C. Allan, David T. Scott, Karol H. Katz, Karen C. Schneider, Robert W. Makuch, and Laura R. Ment

The neurodevelopmental outcome of very low birth weight infants experiencing early-onset intraventricular hemorrhage (IVH) occurring within the first 6 postnatal hours was compared with that of their peers without early-onset IVH at 3 years corrected age. The 440 surviving preterm infants (birth weight 600 to 1,250 g) who had been enrolled in a multicenter, prospectively randomized, controlled trial evaluating the efficacy of postnatal indomethacin to prevent IVH were evaluated with the Stanford-Binet Intelligence Scale and neurological examinations at 3 years corrected age. All study infants had echoencephalography between 5 and 11 hours of life, and testing is reported for all children residing in English monolingual households at 3 years corrected age (ie, from the obstetric due date). Fifty five of the 73 (75%) infants with IVH within the first 5 to 11 hours survived to 3 years of age, compared with 385 of the 432 (89%) children without early-onset hemorrhage who were alive at 3 years corrected age (P < .001). Eleven of the 29 (38%) English monolingual children with early-onset IVH had Stanford-Binet intelligence quotient scores of less than 70, compared with 47 of the 249 (19%) children without early IVH (P = .03). Similarly, 7 of 28 (25%) early IVH children were found to have cerebral palsy, compared with 20 of 241 (8%) children without early IVH (P = .01). These data suggest that infants who experience the early onset of IVH are at high risk for both cognitive and motor handicaps at 3 years corrected age.

Copyright 9 1999 by W.B. Saunders Company 'ntraventricular h e m o r r h a g e (IVH) or hemorrhage into the germinal matrix tissues of the developing brain remains a major problem of p r e t e r m infants. IVH is m o r e c o m m o n in those infants of lowest gestational age, a group for whom survival data have most markedly improved during the past several years. 1,2 Thus, reports suggesting high incidences of cranial ultrasonographic abnormalities, neonatal mortal-

l

From the Department of Pediatrics, Brown University School of Medicine, Providence, RI; the Departments of Pediatrics and Neurology, Maine Medical Center, Portland, Maine; the Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington; and the Departments of Pediatrics, Neurology, Neuroscience, Obstetrics and Gynecology, Surgery and Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT. Supported by NS 27116 and NS 35476 of the National Institute of Neurological Disorders and Stroke and RR 06022 of the National Center of Research Resources. Address reprint requests to Betty Vohr, MD, Women & Infants Hospital of Rhode Island, 101 Dudley St, Providence, RI 02905-2499. Copyright 9 1999 by W.B. Saunders Company 0146-0005/99/2303-0002510. 00/0

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ity, and neurodevelopmental handicap among the very low birth weight survivors o f perinatal intensive care have p r o m p t e d multiple postnatal pharmacological IVH prevention trials. 4-7 Recent studies suggest that the incidence of IVH in preterm infants of less than 1,500 g ranges from 20% t o 4 0 % , 2,6,8 and data from several centers over the past decade indicate that approximately 50% of all IVHs in preterm infants occur within the first 6 to 8 postnatal hours. 5,8,9 Infants with the earliest onset of IVH have been noted to have p r o l o n g e d significant depression of cerebral blood flow during the first postnatal week, TMand extension of IVH and neonatal death are also more c o m m o n in those patients with the earliest onset of hemorrhage.S,10,11 Therefore, we h)zpothesized that those infants with the earliest onset of IVH would be at highest risk for neurodevelopmental handicap. This article documents the neurodevelopmental outcome of those infants with IVH present within the first 11 postnatal hours (ie, early IVH) in 505 p r e t e r m infants (birth weight 600 to 1,250 g)

Seminars in Perinatology, Vol 23, No 3 (June), 1999: pp 212-217

Early-Onset Intraventricular Hemorrhage

enrolled in a multicenter trial evaluating the efficacy of postnatal indomethacin to prevent IVH.

Methods This study was conducted at the Women and Infants' Hospital in Providence, RI, Maine Medical Center in Portland, ME, and Yale New Haven Hospital in New Haven, CT, and has been previously described in detail. 5 The study was reviewed and approved by the Institutional Review Boards of the three participating institutions, and infants of 600 to 1,250 g birth weight were enrolled from September 5, 1989, to August 31, 1992. All infants underwent cranial ultrasonography echoencephalography (ECHO) between 5 and 11 postnatal hours, as previously reported. Images were recorded on videotape and still prints were also made; scans were interpreted first by the institutional radiologist and later, for data verification, by a central radiologist. Agreem e n t between the site and the central radiologist was achieved in 89% of all studies. In cases of disagreement, the data were reviewed by all participating radiologists and a group consensus was formulated. All participating radiologists were unaware of the infants' clinical conditions. Follow-up ECHO studies were performed on all infants on postnatal days 2, 3, 4, 5, 7, 14, and 21 and at 40 weeks' conceptional age. The grading system for hemorrhage was as follows: TM grade 1, blood in the periventricular germinal matrix regions or germinal matrix hemorrhage; grade 2, blood within the lateral ventricular system without ventricular dilation; grade 3, blood acutely distending the lateral ventricles; and grade 4, blood within the ventricular system and parenchymal involvement. In addition, all infants underwent gestational age assessment that included the use of a modification of the Ballard scale ]~ during the first postnatal day. Those infants with birth weights less than the 10% for gestational age were considered to be small for gestational age/4 Prenatal, perinatal, and neonatal data were obtained by maternal interviews and by prospective review of the maternal and neonatal charts. Tocolytic drugs and corticosteroids were administered at the discretion of the attending obstetrician and were not given by formal protocol.

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Neurodevelopmental Assessments At 36 months corrected age (CA; ie, age from the obstetric due date), each study child was tested with the Stanford-Binet Intelligence Scale (Form L-M, 3rd Edition)1~ and the Peabody Picture Vocabulary Test-Revised (PPVT-R). 16 The Stanford-Binet produces standardized scores that are deviation scores with a mean of 100 and a standard deviation of 16 points. Because the Stanford-Binet was standardized on Englishspeaking persons, all children being raised in bilingual or nonEnglish speaking homes were a priori excluded from the data analysis, although all study subjects were provided neurodevelopmental follow-up. All demographic data were obtained from the primary caregiver. Routine neurological examination was part of this assessment. Assignment of cerebral palsy into classical groups was based on the presence of hypertonicity, hyperreflexia, and dystonic or spastic movement quality in the affected limbs. These groups were spastic diplegia, tetraplegia, and hemiplegia. The risk factors for early-onset WH have previously been reported on these 505 neonates. 17 An a priori aim of our study was to test the hypothesis that those infants with early-onset IVH would fare worse at the time of neurodevelopmental testing that those infants with no evidence for IVH within the first 6 to 11 hours of life.

Statistical Methods Categorical data were analyzed by using the standard chi-square test, and continuous data were analyzed by using the nonparametric Wilcoxon rank-sum test for b e t w e e n / g r o u p comparisons. TM All Pvalues in this article are two sided.

Results Of the 505 neonates (87%) admitted to our study, 440 survived the first g years of life. Fiftyfive of the 73 (75%) infants with early-onset IVH present at the time of the first ECHO survived, compared with 385 of the 432 (89%) infants without early-onset IVH (P < .001). Of 440 survivors, 392 (88%), were seen for neurodevelopmental follow-up at 36 months CA. Forty eight children had early-onset IVH and 344 children did not. This review documents the outcome of

Vohr et al

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Table 1. Characteristics of the Study Population

Number Infant variables Birth weight (g) Gestational age (GA) (wk) Appropriate for GA Male gender Maternal variables Age (yr) Race Black Hispanic White Other Years of education

Early IVH (positive)

Early IVH (negative)

29

249

960.9 _+ 178 27.9 -- 2 28 (97%) 17 (59%)

965.5 -- 179 28 -+ 2 219 (88%) 140 (56%)

27.4 -+ 6

27.3 -+ 6

6(21%) 1 (3%) 22 (76%) 0 12.8 + 2

50(020%)l 195 (78%)[ 4 (2%) J 13 + 2

P Value

.88 .89 .22 .85 1 .92 .87

NOTE. Values are mean _+ SD (standard deviation). the 278 children who were residing in English/ monolingual households. The d e m o g r a p h i c characteristics of the study population are f o u n d in Table 1 and show no differences between children with and without the early onset of IVH. The perinatal variables for the same groups are f o u n d in Table 2. At the

time of the first cranial ultrasound, 15 of the 29 (52%) infants with early-onset IVH were f o u n d to have grade 1 IVH and 11 of the 29 (37%) had grade 2 IVH. Only three children (10%) were f o u n d to have either grades 3 or 4 h e m o r r h a g e at the time of the first cranial ultrasound. Five of the 29 (17%) children with early-onset

Table 2. Perinatal Variables

Early IVH (positive)

Early 1VI-I (negative)

P Value

29 8 (28%) 12 (41%) 6 (21%)

249 84 (34%) 139 (56%) 82 (33%)

.68 .17 .21

5 (17%) 23 (79%) 1 (4%)

85 (34%) 140 (56%) 24 (10%)

.36

21 (72%) 8 (28%)

107 (43%)1 142 (57%)[

.003

Number Antenatal steroids Tocolytics Antenatal magnesium sulfate Mode of presentation Vertex Breech Transverse or unknown Mode of delivery Vaginal Cesarean Apgar score (medium) 1 minute 5 minute Grade IVH at first ECHO Grade 1 Grade 2 Grade 3 Grade 4 Grade V H on day 5 Grade 1 Grade 2 Grade 3 Grade 4 NOTE. Values are mean _+ SD (standard deviation).

4 6

5

15 11 1 2

0 0 0 0

12 11 1 5

7

19

.55 .17

.001

Early-Onset Intraventricular Hemorrhage

IVH progressed to a higher grade of V H and on postnatal day 5, 12 of the 29 (41%) had grade 1 IVH, 11 (38%) had grade 2 hemorrhage, and 6 (21%) infants had grades 3 to 4 hemorrhage. Thirty two of the 249 (13%) infants with no IVH at the time of the first cranial ultrasound developed hemorrhage by the fifth postnatal day. Six of these 32 (19%) children were found to have lower grade hemorrhages, which progressed during the study interval. On day 5, 9 of the 32 (28%) had grade 1 IVH, 19 (59%) had grade 2, and 4 (13%) children had grade 4 hemorrhage (P < .001 for early IVH v late IVM subjects). As shown in Table 3, the mean intelligence quotient (IQ) of the 29 children with early IVH was 78.7 - 25, compared with 87.5 -+ 20 for the 249 children without early WH (P = .09). In addition, 11 of the 29 (38%) early-onset IVH children had Stanford-Binet IQ scores less than 70, compared with 47 of the 249 (19%) children with no evidence for early IVH (P = .03). There were no significant differences in the Peabody Picture Vocabulary scores, although the late IVH group scored 10 points higher than the early IVH group. Finally, 7 of the 28 (25%) early IVH children for whom neurological examinations were available were found to have cerebral palsy, compared with 20 of the 241 (8%) children without early IVH (P = .01). Subgroup analysis comparing the 29 children with early-onset IVH, the 32 children with lateronset IVH after an early negative cranial ultrasound at 6 to 11 postnatal hours, and the 217 children with no evidence for IVH during the study protocol showed that 11 of 29 (38%) earlyonset IVH subjects, 11 of 32 (34%) late IVH children, and 36 of 217 (17%) no IVH subjects had Stanford-Binet IQ scores < 70 (P = .001). Finally, neurological examinations were available for 381 of the 392 total cohort of surviving children. Nine of the 47 (19%) children with early-onset IVH were found to have cerebral Table 3. Neurodevelopmental Outcome Variables

Number Binet IQ Binet IQ < 70 PPVT-R Cerebral Palsy

Early WH

No Early IVH

P

29 78.7 _+25 11 (38%) 76.6 +- 28 7/28 (25%)

249 87.5 -+ 20 47 (19%) 86 -+ 21 20/241 (8%)

.09 .03 .15 .01

NOTE. Valuesare mean _ SD (standarddeviation).

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palsy, compared with 27 of the 334 (8%) without early-onset hemorrhage (P = .03). Discussion

Although the development of sophisticated neonatal intensive care has led to a lower mortality rate and a reduction in major handicaps for infants weighing less than 1,500 g at birth, 1,7 the neurodevelopmental fate of very low birth weight infants is uncertain. 4,6 Depending on the birth weight of the patient cohort examined and the years in which they were born, the incidence of major neurodevelopmental handicap ranges from 6.7% to 32%, 19-21 and the prevalence of cerebral palsy is reported to be rising. ~2 In addition, these groups of very low birth weight infants have an increased incidence of more subtle intellectual behavioral problems at school age. 23,24 Because infants of less than 1,250 g birth weight now represent almost 2% of all live births in tertiary care centers in the United States, ~ examination of those factors that may affect developmental outcome is critical. Preterm infants with IVH are believed to be at significant risk for neurodevelopment handicap. 4,7 The high incidence of IVH increases as gestational age decreases, 8,29,26 and high grade hemorrhage is thought to be more common in the lowest birth weight infants.~6 Finally, many authors believe that the critical determinant of long-term neurodevelopmental outcome is the presence of cerebral parenchymal injury associated with high grade IVH,4,v and, in the 17 years since Krishnamoorthy~7 first reported that 2 of 3 surviving low birth weight infants with grade 4 IVH suffered mental retardation and spastic motor handicap, the incidence of major neurodevelopmental sequelae of this insult in very low birth weight infants has been reported to vary from 45% to 86%. 20,27"29 In addition, periventricular leukomalacia and posthemorrhagic hydrocephalus are all more frequent in infants with high-grade hemorrhage. 3~ To formulate strategies for the prevention of IVH, one must understand the pathophysiology of this injury, and several authors have speculated that the pathophysiology of early-onset IVH may differ from that of later-onset hemorrhage. 3~ The risk period for IVH for all preterm infants is the first 3 to 4 postnatal days. 8,1~ Over 50% of all hemorrhages are noted within

216

Vohr et al

the first 6 posmatal h o u r s , s,l~176 and the work o f Shaver s suggests that almost all o f these early h e m o r r h a g e s are, in fact, detectable within the first postnatal hour. Extension of IVH is twice as c o m m o n in those infants with the earliest onset o f IVH, and infants with early onset of h e m o r r h a g e are most likely to die in the neonatal period.S,1~ 11,25 We r e p o r t the neurodevelopmental o u t c o m e at 3 years CA for 278 very low birth weight infants who were ascertained for the presence of early-onset IVH within the first 6 t o 11 postnatal hours. Early IVH was detected in 29 o f the 278 (10%) survivors, and, although infants with early-onset IVH were at significantly higher risk for death in the newborn period, these 29 child r e n represent almost half of all the surviving children with hemorrhage. Although extension of h e m o r r h a g e o c c u r r e d with equal frequency in the early IVH and later IVH patients, o u r data show that children with early W H were more likely to develop high-grade h e m o r r h a g e than the infants with no evidence for early IVH (P < .001). In addition, they were two times more likely to have Stanford-Binet I Q scores less than 70 than the children without early IVH (38% v 19%; P = .03) and three times more likely to suffer cerebral palsy at 3 years CA (25% v 8%; P = .01). These findings may be secondary to p r o l o n g e d depression o f cerebral blood flow after early-onset IVH, the parenchymal echodensities, porencephalies, and hydrocephalus, which may accompany high-grade hemorrhage, or the failure o f plasticity of the developing brain. In summary, these data indicate that very low birth weight infants with early-onset IVH are at significantly increased risk of death, neurological sequelae and developmental handicap and strategies for preventing early-onset IVH in very low birth weight infants are of critical importance to us all.

Acknowledgment This study b e n e f i t e d greatly f r o m t h e assistance o f t h e following individuals: Yale University School o f Medicine: M a r j o r e n e Ainley, BS, Gail A n d e r s o n , MA, Sue DeLaney, MA, A r l e n T r e d e a u , RN, M i c h a e l Westerveld, PhD, J a n e W o m e r , MA, a n d T r i c i a n Zawacki, BA; B r o w n University: T e r r i Leach, CAES, Melissa Dingley, MA, Melissa Downey, MA, J e n n i f e r Gellert, BA, E l i z a b e t h Lurgio, MA, a n d A n d r i a n a Romos, BA;

M a i n e Medical C e n t e r : Alison Tito, RNC, a n d J u n e G a g n o n , MA. I n a d d i t i o n , t h e a u t h o r s t h a n k J o s e p h S. Drage, MD, G i o v a n n a M. Spinella, MD, a n d J o s e p h B. Warshaw, MD, for e x c e l l e n t scientific advice.

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Early-Onset Intraventricular Hemorrhage

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