• No results found

Neurodevelopment of Preterm Infants: Neonatal Neurosonographic and Serum Bilirubin Studies

N/A
N/A
Protected

Academic year: 2020

Share "Neurodevelopment of Preterm Infants: Neonatal Neurosonographic and Serum Bilirubin Studies"

Copied!
8
0
0

Loading.... (view fulltext now)

Full text

(1)

Neurodevelopment

of Preterm

Infants:

Neonatal

Neurosonographic

and

Serum

Bilirubin

Studies

Leonard

J.

Graziani, MD; Donald C. Mitchell, MD;

Michael Kornhauser, MD; Frank S. Pidcock, MD; Daniel A. Merton;

Christian Stanley, RN, MSN; and Linda McKee, MHS

ABSTRACT. In this study of 249 preterm infants of less

than 34 weeks’ gestation, the relationships between

maximal serum total bilirubin concentrations during the

neonatal period, neonatal cranial ultrasonographic

abnormalities, and severe neurodevelopmental sequelae

are described. The subjects, who were selected on the

basis of serial cranial ultrasonographic findings, had

repeated neurologic and developmental examinations

during late infancy and early childhood that established

the presence (n 45) or absence (n 204) of spastic forms

of cerebral palsy. Of the 204 subjects without cerebral

palsy, 23 scored abnormally low on standardized

devel-opmental testing during early childhood. All but seven

of the subjects with cerebral palsy had grade ffl/!V

intracranial hemorrhage or moderate to severe

periven-tricular echogenicity or both, ultrasonographic

abnor-malities that probably reflect a disruption in the

blood-brain barrier as well as extravasation of blood into brain

tissue; however,

analysis

of the data did not suggest that

these cranial ultrasonographic abnormalities increased

either the maximum serum bilirubin concentration

dur-ing the neonatal period or the susceptibility of the

subjects to neurologic damage from hyperbilirubinemia.

Also, there was no evidence to suggest that bilirubinemia

in the range studied (2.3 to 22.5 mg/100 mL total serum

biirubin) was causally related to cerebral palsy, early

developmental delay, or the development of

periventric-ular cysts in this population of preterm infants.

Uni-variate

analyses

revealed that Apgar scores were

signif-icantly lower, while grade ffl/IV intracranial

hemor-rhage, large periventricular cysts, moderate to severe

periventricular echodensity, ventriculomegaly, assisted

ventilation, and bronchopulmonary dysplasia occurred

significantly more often in infants with cerebral palsy

than in those without cerebral palsy; however, a stepwise

logistic regression revealed that of these clinical

van-ables only large periventricular cysts, moderate to severe

periventricular echodensity, and the need for assisted

ventilation were associated with the occurrence of

cere-bral palsy at a statistically significant level. Apgar scores

and average birth weight were significantly lower, and

duration of assisted ventilation was significantly longer,

but neurosonographic findings did not differ in the 23

developmentally delayed infants compared with the

nor-mal group. Pediatrics 1992;89:229-234; preterm infants,

bilirubine,nia, cerebral palsy, cranial ultrasonographic

abnormalities, periventricular leukomalacia, intracran#{252}d

hemorrhage.

From the Departments of Pediatrics, Neurology, and Radiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.

Received for publication Aug 8, 1990; accepted Apr 8, 1991.

Reprint requests to (LJG.) Dept of Pediatrics, Jefferson Medical College of ThomasJefferson University, Philadelphia, PA 19107.

PEDIATRICS (ISSN 0031 4005). Copyright © 1992 by the American Acad-emy of Pediatrics,

A causal relationship between maximal serum total

bilirubin concentrations and early

neurodevelopmen-tal outcome in a large population of preterm infants

was recently reported; cerebral palsy was the

predom-inant major neurologic sequelae of

hyperbilirubine-mia,

although neonatal intracranial hemorrhage,

cer-ebral ventriculomegaly, and bronchopulmonary

dys-plasia also contributed significantly to an adverse

outcome.1 A later study of the same subjects at age 5

years, however, found the association between the

risk of handicap and maximal serum total bilirubin

concentration only in those children who had

neo-natal intracranial hemorrhage.2 In another clinical and

neurosonographic study of preterm infants, the

pos-sible role of bilirubin toxicity in the development of

periventricular leukomalacia and neurologic deficits

is described.3

We reported in a previous study that neonatal

neurosonographic examinations disclosed intracranial

hemorrhage in the majority and penventricular

echodensity in all of the infants in whom cerebral

palsy eventually developed.4 Intracranial hemorrhage

results in little or no increase in serum bilirubin

levels5’6 but theoretically may increase the

suscepti-bility of the immature brain to the potentially

damag-ing effects of bilirubin-as may the lesion underlying

periventricular echodensity-by disrupting the

blood-brain barrier.7 However, whether acute brain

abnormalities detected in preterm infants by neonatal

cranial ultrasonography increase the risk or extent of

damage from serum bilirubin has not been reported.

Furthermore, others have noted that reported

associ-ations between neonatal hyperbiirubinemia and

neu-rologic sequelae have not been consistent.8

In the current study of preterm infants of less than

34 weeks’ gestation, we describe the

interrelation-ships of maximal total serum bilirubm concentrations,

neonatal cranial ultrasonographic abnormalities, and

the occurrence of cerebral palsy and developmental

delay.

Subjects

METHODS

Between August 1, 1981, and May 31, 1989, all 497 surviving infants with a birth weight of less than 1501 g or gestational age of less than 34 weeks who were admitted to Thomas Jefferson

University Hospital had, during their nursery course, serial cranial

ultrasonography utilizing high-resolution sector scanners. The 249 subjects of this report include the following: (1) 134 surviving infants who had neurosonographic evidence of moderate to severe

penventricular echodensity, grade III/IV intracranial hemorrhage,

at Viet Nam:AAP Sponsored on September 1, 2020

www.aappublications.org/news

(2)

or periventricular cysts, alone or in combination, at any time during their nursery course and whose parents consented to follow-up

evaluations; an additional 6 infants in this ultrasound category

were not followed because the parents declined; (2) a sample of I 15 of the remaining 357 infants whose neonatal ultrasonographic

studies revealed no abnormalities or only grade I/I! hemorrhage or

mild periventricular echodensity and whose parents consented to

follow-uj evaluations; a sample was selected because our previous

studies4- -‘#{176}disclosed that spastic forms of cerebral palsy do not

occur in this group of relatively low risk survivors. The 249 subjects were followed up until repeated examinations established the pres-ence (n = 45) or absence (n = 204) of cerebral palsy.

The following clinical features were recorded for each infant:

gestational age, birth weight, Apgar scores at 1 and 5 minutes, days

of phototherapy, maximal total and direct reacting serum bilirubin

concentrations, mechanical ventilation, and bronchopulmonary dysplasia (defined as supplementary oxygen dependency for more than 28 days).

Cranial Ultrasonographic Studies

Cranial ultrasonographic examinations of all infants were ob-tamed within 1 week of birth, at least weekly until 1 month of age, and then every 2 to 4 weeks until discharge. Subjects were studied

with either the AlL Mark 100 Unit or the Ultramark 4 Unit

(Advanced Technologies Lab, Bellevue, WA), equipped with 5- and 7.5-MHz sector scanner. Scans were performed through the

ante-nor fontanelle in the coronal and parasagittal planes. Coronal

images were obtained from as far forward as the frontal lobes to

the plane posterior and superior to the atria or trigones. Parasagittal views were obtained at increments from the midline to the area lateral to the lateral ventricles.

All images were reviewed by two of the authors (D.G.M. and

DAM.) who did not have knowledge of the subjects’ clinical

course; their interpretations were compared and when in accord were classified as previously reported.4 Periventricular echodensity was graded as none, mild, moderate, or severe. Cysts were recorded

as none, small (2 mm in diameter or less), or large (3 mm in

diameter or larger); large areas of multiple and contiguous small cysts were classified as large. Intracranial hemorrhage was graded

as none, grade I/I!, grade III, or grade IV. Ventricular size was measured and ventricular ratios were calculated for each subject at

approximately 36 weeks postconceptional age as previously

de-scribed.5#{176} The maximum grade of each ultrasonographic

abnor-mality noted during an infant’s nursery course was used in the

data analysis. Images that were interpreted differently by the two examiners were re-reviewed; all disagreements involved images that were ultimately classified as normal or as mild periventricular

echogenicity.

Bilirubin Measures

Serum total bilirubin concentrations were obtained in all infants

within 72 hours of birth and were obtained again as indicated by

the nursery course and laboratory results. Direct reacting bilirubin concentrations were obtained at least once, near or at the time of the maximal total bilirubin concentrations. Total and direct reacting bilirubin measurements were performed with the Advanced

Bill-rubin Stat Analyzer(Advanced Instruments Inc. Needham Heights,

MA). Phototherapy was used and exchange transfusions were

performed according to published guidelines” which were occa-sionally modified for clinical reasons. All but nine infants required phototherapy (mean number of days, 7.0 ± 4.8), and nine infants

required at least one exchange transfusion.

Twenty-four infants had direct reacting bilirubin levels above 4 mg/100 mL; results of statistical analyses were not changed by elimination of these subjects and all subjects are included in the analyses presented.

Neurologic and Developmental Measures

The presence or absence of cerebral palsy was determined in all subjects through repeated outpatient neurologic examinations

be-tween 6 months and 8 years of age by three of the authors (L.J.G.,

CS., and F.S.P.) who in some instances were aware of some

neonatal clinical and ultrasonographic findings. Cerebral palsy was

defined as spasticity of at least one lower extremity associated with

increased deep tendon reflexes, ankle clonus, and plantar extensor

responses in the affected lower limb and with markedly delayed

motor development or spastic gait or both. Cerebral palsy was

diagnosed when the characteristic abnormal neurologic findings

were noted independently by at least two of the examiners at a

minimum of three sequential examinations. Subjects who had nonspecific developmental delay without pathologic reflexes or

lower extremity spastidty, or who had transient dystonia of

prematurity’2 and eventually ambulated without a spastic gait, were not considered to have cerebral palsy. The diagnosis of spastic diparesis, hemiparesis, or quadriparesis was based on the

predom-inant pattern of extremity involvement.’3 If there was disagreement

among the examiners regarding the diagnosis, the subject was

reevaluated at I-to 3-month intervals until agreement was reached.

In the present study, the latest examination of the children with cerebral palsy was at an average age of 58.9 ± 24. 1 months (range,

21 months to 8 years).

Standard scores on the Mental and Psychomotor Indexes of the Bayley Scales of Infant Development’4 (in subjects younger than age 31 months) or the Mullen Scales of Early Learning’5 (in subjects older than 30 months) were obtained in 182 of the 204 subjects

without cerebral palsy at least once between the ages of 15 and 60 months by examiners who were unaware of the neonatal clinical and ultrasonographic findings. (Twenty-two children without

evi-dence of cerebral palsy when last evaluated neurologically did not have a standardized developmental test.) Standard scores were corrected for prematurity until age 24 months; subjects who scored

2 or more standard deviations below the mean for age on either of the Bayley indexes or any of the Mullen scales were classified as

developmentally delayed. Only the most recent standard scores

(average age 37.7 ± 13.6 months, range 15 to 72 months) were used to classify each subject as normal or developmentally delayed.

All 249 infants had ophthalmologic and hearing evaluations at the time of discharge and were reevaluated during the first year of

life.

Data Analysis

The relationship of maximal serum biirubin levels to penven-tricular cysts, cerebral palsy, and developmental delay was ana-lyzed by contingency tables, analysis of variance, Mantel-Haenszel

x2 test for trend, and logistic regression. Depending on whether

the data are continuous, ordinal, or categorical, univariate

corn-parisons of clinical neonatal variables in subjects with and without

cerebral palsy or developmental delay were analyzed by two-group ttest, Wilcoxon Rank Sum Test, and Fisher’s Exact Test. Stepwise

logistic regression was used to determine variables that significantly

predicted cerebral palsy. To evaluate the independent effect of elevated bilirubin levels on the risk of developing cerebral palsy, the significantly predictive variables were included in a logistic

model along with bilirubin level. A second model, to evaluate an increasing risk of cerebral palsy with increasing level of biirubin, was also developed using categorized levels of maximal serum

bilirubin. Finally, the data were analyzed by two-way analysis of

variance to determine whether the maximal serum total bilirubin

concentrations were increased by intracranial hemorrhage or

pen-ventricular echodensity.

All 249 subjects were included in the initial analyses of the

interrelationships between clinical neonatal features, ultrasono-graphic studies, and the occurrence of cerebral palsy (Table 1). All

subsequent analyses (Tables 2, 3, and 4) were restricted to the 134 higher risk subjects who had moderate to severe ultrasonographic

abnormalities, including grade III/IV intracranial hemorrhage,

moderate to severe penventricular echogenicity, and penventricular

cysts, alone or in combination.

RESULTS

A spastic form of cerebral palsy was diagnosed in

45 of the 249 subjects-32 with spastic diparesis, 9

with spastic quadriparesis, and 4 with spastic

hemi-paresis. Twelve of the children with cerebral palsy

were younger than age 3 years (range, 21 to 35

months) when last evaluated, at which time all had

persisting, marked spasticity with pathologic reflexes

in at least both lower extremities. The remaining 33

children with cerebral palsy, who were older than 36

(3)

absent ambulation with persisting spasticity and

path-ologic reflexes in at least two extremities. In all 45

children, cerebral palsy was initially diagnosed by age

22 months at the latest, and none were later

reclas-sified as normal, although 2 died. Seven had evidence

of at least unilateral mild sensorineural hearing loss,

but none had bilateral moderate to severe hearing

loss and none were blind. None of the 22 children

who

did

not have standardized developmental tests

disclosed neurologic signs of cerebral palsy when last

evaluated, at an average age of 27 ± 5 (SD) months

(range, 1 8 to 39 months).

In 44 of the 45 children with cerebral palsy,

neo-natal neurosonographic studies disclosed moderate to

severe periventricular echodensity, periventricular

cysts, and grade 1111W intracranial hemorrhage, alone

or in combination. Of the 182 subjects without

cere-bral palsy who had standardized developmental tests,

23 had abnormally low Bayley or Mullen scores when

last evaluated (age 30 ± 13 months; range, 15 to 58

months) and were classified as developmentally

de-layed.

The 45 subjects with cerebral palsy had slightly but

significantly lower Apgar scores and were

signifi-cantly more likely to have severe ultrasonographic

abnormalities and to have required mechanical

yen-tilation than those in whom cerebral palsy

did

not

develop; other neonatal factors, including gestational

age, birth weight, phototherapy days, and maximum

serum bilirubin concentrations, did not differ

signifi-cantly in the two groups (Table 1).

When the significantly predictive clinical features

in Table 1 were simultaneously controlled by logistic

regression (in which only those 95% confidence limits

that do not include 1 are statistically significant),

maximal serum bilirubin concentration did not

in-crease the risk for cerebral palsy in the 134 infants

with the more severe cranial ultrasonographic

abnor-malities (Table 2). There was also no evidence of a

significant association between increasing

concentra-tions of maximal serum bilirubin and either cerebral

palsy (Table 3) or periventricular cysts (Table 4).

When maximal serum biirubin concentrations were

categorized using the incremental ranges of bilirubin

in Tables 3 and 4, logistic regressions adjusted for all

of the other neonatal clinical variables in Table 1

disclosed no increased risk for occurrence of cerebral

palsy, developmental delay, or penventricular cysts

at the higher biirubin ranges.

Excluding infants with 4 mg/100 mL or more of

direct reacting bilirubin, maximal serum total bilirubin

concentrations occurred at an average age of 6.4 ±

3.1 days.

x2

Analysis

did

not disclose a significant

relationship between maximal serum bilirubin

con-centrations and the preceding or subsequent

ultra-sonographic abnormalities; in addition, no effect of

intracranial hemorrhage or periventricular

echoden-sity or both on maximal serum bilirubin

concentra-tions was noted on two-way analysis of variance.

Of the 182 children without cerebral palsy who

had standardized developmental tests, 64 had

mod-erate to severe periventricular echodensities or grade

hilly intracranial hemorrhage or both which,

theo-retically, increased the risk of neurotoxic damage from

hyperbilirubinemia

by

disrupting

the blood-brain

barrier. Within this group of 64 subjects, the

two-group t test disclosed that the average maximal serum

total bilirubin concentration of 10.2 ± 1.9 mg/100 mL

in the 55 subjects classified as developmentally

nor-mal was not significantly different from the 9.6 ± 1.4

mg/100 mL (P = .37) in the 9 without cerebral palsy

but classified as developmentally delayed.

In a separate univanate analysis of the clinical

features in Table 1, the 23 subjects without cerebral

palsy who were developmentally delayed (at age 32

± 1 1 months) were compared with the 159 subjects

without cerebral palsy who scored within the normal

range (at age 34 ± 13 months); except for lower Apgar

scores at 1 and 5 minutes, lower average birth weight,

and longer duration of assisted ventilation in the

TABLE 1. Neonatal Clinical Features in Pre term Infants With and Without Cerebra I Palsy

Clinical Features Cerebral Palsy P

Yes (n = 45) No (n = 204) Gestational age, wk (mean ± SD)

Birth weight, g (mean ± SD)

Apgar score, median (range) 1 Minute

5Minute

Phototherapy, d (mean ± SD)

Ventilated, no. (%) If ventilated, d (mean ± SD)

BPD, no. (%)

PVE,t no. (%)

ICH4 no. (%)

Cysts, no. (%)

Ventricular ratiofi (mean ± SD)

Peak bilirubin,1 mg/dL (mean ± SD)

29.4 ± 2.2 30.0 ± 2.2 1271 ± 353 1318 ± 357

3 (0-8) 5 (0-9) 7 (4-9) 8 (2-10)

8.0 ± 4.6 6.8 ± 4.8

42 (93) 151 (74)

38.8 ± 50.0 34.2 ± 44.1

24 (53) 81 (40)

38 (84) 53 (26)

13 (29) 21 (10)

31 (69) 14 (7)

38.5 ± 9.0 33.0 ± 4.2 10.6 ± 2.9 10.1 ± 2.1

NS#

NS

CC CC

NS

CC

NS

CC CC CC CC CC NS CBronchopulmonary dysplasia; supplemental oxygen dependency for 28 days or more.

t Periventricular echodensity: moderate/severe.

IIntracranial hemorrhage: grade Ill/IV.

§Periventricular cysts: 3 mm.

II

Average of the right and left ventricular ratios.

I Maximal serum total bilirubin concentrations.

# NS, not significant (P> .05).

(4)

TABLE 2. Neonatal Clinical Features and Adjusted Odds Ratios for Occurrence of Cerebral Palsy

(n = 44) in 134 Preterm Infants With Moderate to Severe Neurosonographic Abnormalities

Clinical Features Odds RatioC 95% Confidence

Limit

PVEt (none/mild, moderate/severe) 5.7 2.1-15.7

Cyst (none/small, large) 5.4 2.0-15.0

Ventilation (no, yes) 4.4 1.1-17.1

Peak bilirubin (continuous)% 1 .1 0.9-1.3

CAdjusted for all other variables in table and for gestational age.

tPeriventricular echodensity.

Periventricular cysts: small, 3 mm; large, 3 mm.

Maximal serum total bilirubin concentration as a continuous variable.

TABLE 3. Cerebral Palsy (n = 44) in Relationship to Maximal

Serum Total Bilirubin Concentrations in 134 Preterm Infants With Moderate to Severe Neurosonographic Abnormalities

Bilirubin, mg/dL Cerebral Palsfl No Cerebral Palsy

(n = 44), (n = 90), No. (%) No. (%)

8 6(13.6) 10(11.1)

8.0-10.9 20 (45.4) 49 (54.4)

11.0-12.9 12 (27.3) 20 (22.2)

13 6(13.6) 11 (12.2)

CGrade llI/IV intracranial hemorrhage, moderate to severe pen-ventricular echogenicity, or periventricular cysts.

t

Not significant; Mantel-Haenszel x2test for trend = .05; P= .81.

TABLE 4. Neonatal Periventricular Cysts in Relationship to

Maximal Serum Total Bilirubin Concentration in 134 Preterm

In-fants With Moderate to Severe Neurosonographic Abnormalities

Bilirubin, mg/dL Periventricular Cystst

No Cysts Small Cysts Large Cysts

(n = 42), (n = 47), (n = 45), No. (%) No. (%) No. (%)

8 2(4.8) 7(14.9) 7(15.6)

8.0-10.9 22 (52.4) 25 (53.2) 22 (48.9) 11.0-12.9 12 (28.6) 11 (23.4) 9 (20.0)

13 6(14.3) 4(8.5) 7(15.6)

CGrade III/IV intracranial hemorrhage, moderate to severe peri-ventricular echogenicity, or periventricular cysts.

t

Not significant; x2 4.4; P= .62.

delayed group (P < .05), no significant differences

between the two groups were found, although these

results should be considered preliminary. None of the

subjects without cerebral palsy had bilateral severe

retinopathy or hearing loss.

In summary, our data analysis disclosed that large

penventricular cysts, moderate to severe

periventric-ular echogenicity, and the need for but not the

dura-tion of mechanical ventilation significantly increased

the risk for the occurrence of cerebral palsy. Maximal

serum total biirubin levels were not associated with

a statistically significant increased risk for

periventric-ular cysts, cerebral palsy, or early developmental

de-lay.

DISCUSSION

Hyperbilirubinemia resulting in kernicterus

pro-duces widespread neuronal damage and neurologic

deficits, with the most common sites of staining and

destruction involving the hippocampus, basal ganglia,

and the brainstem nuclei in the floor of the fourth

ventricle, including the dorsal cochlear nucleus.’6

Au-topsy studies have noted histologic evidence of

ker-nicterus despite relatively low concentrations of

serum bilirubin in preterm asphyxic infants.17 The

neurologic deficits associated with kemicterus, at least

in full-term infants, include dyskinetic forms of

cer-ebral palsy with high-frequency hearing loss and

impaired vertical gaze.’8 In contrast, the

neuropath-ologic correlates of nonkernicteric brain injury in

pre-term infants predominantly involve penventricular

white matter; as a result, spasticity without

dys-kinesia, especially of the lower extremities, is

charact-eristic of prematurely born children with cerebral

palsy.’9 Whether hyperbilirubinemia is causally

re-lated to less severe neurologic and neuropathologic

abnormalities than observed in kernicterus is

uncer-tain,7’2#{176}although we previously reported that

hyper-bilirubinemia had an adverse effect on peripheral but

not central auditory pathways in studies of brainstem

auditory evoked potentials in high-risk preterm and

full-term neonates.21

In a study of 831 preterm infants, van de Bor et al1

suggested a causal relationship between maximal

bil-irubin concentrations and unspecified type of cerebral

palsy diagnosed at the corrected age of 2 years,

al-though Newman and Maisels8 noted that the strength

of the relationship may be weak; also, by age 5 years

the risk of handicap in relationship to

hyperbilirubi-nemia was found only in those children who had

neonatal intracranial hemorrhage.2 In another clinical

and cranial ultrasonographic study, Ikonen et al3

re-ported that neonatal bilirubin neurotoxicity in 5

pre-term infants was probably responsible for large

peri-ventricular cysts with ventriculomegaly and severe

neurologic sequelae including mental retardation and

spastic forms of cerebral palsy.

In the present study, we were unable to

demon-strate a significant association between maximal

serum bilirubin levels and the subsequent occurrence

of neonatal neurosonographic abnormalities

(includ-ing

large periventricular cysts and ventriculomegaly),

cerebral palsy, or developmental delay. Van de Bor et

aP reported a much larger group (n = 831), including

50 infants (6%) with maximal total bilirubin levels

above 14.6 mg/100 mL, 5 of whom had ‘major

hand-icaps.’ By contrast, only 3 infants (1.2%) in our study

had levels above 14.6 mg/100 mL, 1 of whom

devel-oped cerebral palsy; the latter infant had a maximal

serum total bilirubin level of 22.5 mg/100 mL, 11

mg/dL of which, however, was direct reacting.

De-spite the differences in distribution of bilirubin

(5)

infants identified as having cerebral palsy are similar in the two studies.

We4 and others2224 previously reported that the

risk of developing cerebral palsy was increased in

preterm infants with the more severe grades of

intra-cranial hemorrhage or with moderate to severe

pen-ventricular echodensity and periventricular cysts.

Therefore, the relatively high incidence of cerebral

palsy (1 8. 1

%)

in the present study of 249 subjects

was due to the selection of virtually all infants with

severe neurosonographic abnormalities while

includ-ing only a representative sample (n = 1 15) from the

remaining 357 lower risk infants. Assuming complete

ascertainment, cerebral palsy occurred in 9. 1 % of the

497 surviving preterm infants, a sequelae rate

con-sistent with our previous report of 9% in a smaller

population4 but higher than the incidence of 5.4% of

“major handicap’ reported by van de Bor et al.’ The

incidence of neurologic sequelae may differ among

studies of preterm infants because of such factors as

age at diagnosis, gestational or pennatal variables

associated with etiologic mechanisms, and size of the

study population. Additionally, because of limitations

related to the upper range of bilirubin concentrations

in the present study, we were unable to determine

the risk of cerebral palsy associated with maximal

serum bilirubin levels above 14 mg/100 mL.

Intracranial hemorrhage may be difficult or

impos-sible to distinguish from severe periventricular

echo-density without serial ultrasonographic studies, and

stippling or bright specks within the echodensity may

represent petechial hemorrhages. However, we found

that neither periventricular echodensity nor

in-tracranal hemorrhage, regardless of severity, was

re-lated to increased maximal serum bilirubin

concentra-tions. In addition, the most severe grade of

intracra-nial hemorrhage occurred an average of 2 days after

the mean maximal total bilirubin concentration.

The neuropathology of nonkernicteric brain injury

in preterm infants was recently reviewed by Volpe,’9

who discussed the (theoretical) pathogenesis of

pen-ventricular leukomalacia and hemorrhagic infarction.

Periventricular echodensity and periventricular cysts,

readily detected by high-resolution sector scanners,

are the neurosonographic correlates of periventricular

leukomalacia and, in addition to grade IV intracranial

hemorrhage, are characteristically noted during the

nursery course of preterm infants in whom cerebral

palsy develops.4’9’2224 In the present study, we were

able to confirm the highly predictive value of these

relatively well-defined neonatal ultrasonographic

ab-normalities. We also noted, as did van de Bor et al,’

that the cerebral ventricles were significantly larger

and the incidence of both bronchopulmonary

dyspla-sia and intracranial hemorrhage was significantly

greater in subjects in whom cerebral palsy was later

diagnosed. Logistic regression analysis, however,

dis-closed that only moderate to severe periventricular

echodensity, large periventricular cysts, and the need

for mechanical ventilation were significantly

associ-ated with the occurrence of cerebral palsy. We found

no statistically significant evidence that either

intra-cranial hemorrhage or periventricular echodensity

in-creased the susceptibility of our subjects to the

puta-tive neurotoxic effects of serum bilirubin in

relation-ship to the subsequent development of penventricular

cysts, cerebral palsy, or early developmental delay. It

is possible, however, that some children in our study,

including

the 1 2 with a diagnosis of cerebral palsy

who were younger than age 36 months when last

evaluated, have been misclassified. Also, the absence

of a significant relationship between maximal total

serum bilirubin levels and abnormally low Bayley or

Mullen standard scores in 23 children without

cere-bral palsy must be considered a preliminary finding

because of the relatively small number of affected

children and the wide age range of those tested to

date.

The significant association between the need for

mechanical ventilation and increased risk for cerebral

palsy in preterm infants requires further study. In

addition, to determine whether neonatal

hyperbili-rubinemia and neurosonographic abnormalities are

related to the academic deficiencies reported to occur

at school age in 25% to 45% of prematurely born

children,’9 longer term studies are required.

ACKNOWLEDGMENTS

This research was supported by the National Institutes of Health,

grants HD2 1453 and NS27463.

We thank G. McCann for editing, P. Micou for data filing and compilation, and J. Lawrence, PhD, for review of the manuscript. We also thank the nursing staff of the Intensive Care Nursery of Thomas Jefferson University Hospital and A. R. Spitzer, MD, for

their help and support.

REFERENCES

I. van de Bor M, van Zeben-van der Aa TM, Verloove-Vanhorick SP,

Brand R, Ruys JH. Hyperbilirubinemia in preterm infants and

neurode-velopmental outcome at 2 years of age: results of a national collaborative survey. Pediatrics. 1989:83:915-920

2. van de Bor M, Veen S. Ens-Dokkum M, Schreuder AM, Brand R, Verloove-Vanhorick SP. Hyperbilirubinemia in preterm infants and

neurodevelopmental outcome at 5 years of age. Pediatr Res. 1990;27:259A

3. Ikonen RS, Kuusinen EJ, Janas MO, Koivikko MJ, Sorto AE. Possible etiological factors in extensive periventricular leukomalacia of preterm infants. Acta Paediatr Scand. 1988;77:489-495

4. Pidcock FS, Graziani U, Stanley C, Mitchell DC, Merton D.

Neuroson-ographic features of periventricular echodensities associated with cere-bral palsy in preterm infants. IPediatr. 1990116:417-422

5. Epstein MF, Leviton A, Kuban KCK, et al. Bilirubin, intraventricular

hemorrhage, and phenobarbital in very low birth weight babies.

Pedi-atrics. 1988;82:350-354

6. Amato M, Fauchere JC, von Muralt G. Relationship between periven-tricular hemorrhage and neonatal hyperbilirubinemia in very low birth

weight infants. Am JPerinatol. 1987;4:275-278

7. Hansen TWR, Bratlid D. Bilirubin and brain toxicity. Ada Paediatr Scand. 1986;75:513-522

8. Newman TB, Maisels MJ. Bilirubin and brain damage: what do we do

now? Pediatrics. 1989;83:1062-1065

9. Graziani U, Pasto M, Stanley C, et al. Neonatal neurosonographic correlates of cerebral palsy in preterm infants. Pediatrics. 1986;78:88-95

10. Graziani U, Pasto ME, Stanley C, et al. Cranial ultrasound and clinical

studies in preterm infants. I Pediatr. 1985;106:269-276

I I. Maisels MJ. Neonatal jaundice. In: Avery GB, ed. Neonatology. Philadel-phia, PA: JB Lippincott; 1975

12. Drillen CM. Abnormal neurologic signs in the first year of life in low birthweight infants: possible prognostic significance. Dcv Med Child

Neurol. 1972;14:575

13. Taft LT. Cerebral palsy. Pediatr Rev. 1984;6:35-45

14. Bayley N. Bayley Scales of Infant Development. New York, NY: Psycho-logical Corporation; 1979

at Viet Nam:AAP Sponsored on September 1, 2020

www.aappublications.org/news

(6)

15. Mullen E. Mullen Scales of Early Learning. East Providence, RI: TOTAL

Child mc; 1984

16. Friede RL. Developmental Neuropathology. New York, NY:

Springer-Verlag 1975

I 7. Ahdab-Barmada M, Moossy 1. The neuropathology of kernicterus in the premature neonate: diagnostic problems. I Neuropathol Exp Neurol. 1984;43:45-56

18. Hagberg B, Hagberg C, Olow I. The changing panorama of cerebral

palsy in Sweden 1954-1970: analysis of various syndromes. Ada

Paed-iatr Scand. 1975;64:193

19. Volpe JJ. Brain injury in the premature infant: is it preventable? Pediatr Res. 1990;27:S25-S33

20. Lucey JF. Bilirubin and brain damage: a real mess. Pediatrics.

1982;69:381-382

2 1. Streletz U, Graziani U, Branca PA, Desai HJ, Travis SF, Mikaelian DO. Brainstem auditory evoked potentials in fullterm and preterm newborns

with hyperbilirubinemia and hypoxemia. Neuropediatrics.

1986;17:66-71

22. Guzetta F, Shackelford GD, Volpe 5, Perlman JM, Volpe JJ. Periventric-ular intraparenchymal echodensities in the premature newborn: critical determinant of neurologic outcome. Pediatrics. 1986;78:995-1006 23. Graham M, Trounce JQ, Levene MI, et al. Prediction of cerebral palsy

in very low birthweight infants: prospective ultrasound study. Lancet.

1987;2:593-596

24. Bozynski MEA, Nelson MN, Genaze D, et al. Cranial ultrasonography

and the prediction of cerebral palsy in infants weighing less than 1200

grams at birth. Dcv Med Child Neurol. 1988;30:342-348

ANNOUNCEMENT

THE 1992 GENERAL PEDIATRICS CERTIFYING EXAMINATION OF THE

AMERICAN BOARD OF PEDIATRICS

The 1992 General Pediatrics Certifying Examination will be administered on

Tuesday and Wednesday, October 27 & 28 in various cities throughout the United

States and Canada.

NEW APPLICANTS

For new applicants, regular registration begins December 2, 1991 and extends

through March 2, 1992. The registration fee is $1,050. The registration fee must

accompany the completed application material and be postmarked by March 2, 1992.

On December 2, 1991 application material will be sent to qualified residents at their

training program address. However, any resident who does not receive the

material by mid-December should request the material directly from the

Amer-ican Board of Pediatrics (ABP). There will be a three-part partial payment plan for

new applicants only. The deadline for participation in that plan is January 13, 1992;

details will be included in the application material. Late registration begins March

3, 1992. The late registration fee is $1,250 (which includes a $200 nonrefundable

late fee). The final deadline for receipt of applications is May 1, 1992.

RE-REGISTRATION

In mid-February re-registration material will be mailed to those active candidates

who meet the examination requirements. Those who do not meet the examination

requirement of having a copy of their permanent, unrestricted license on file will

not be sent the re-registration material. Regular re-registration begins on February

17, 1992 and extends through April 17, 1992. Qualified individuals who do not

receive the material by March 2 should request the material directly from the ABP.

The re-registration fee is $950. The re-registration fee must accompany the

corn-pleted re-registration form and be postmarked by April 17, 1992. Late re-registration

begins April 18, 1992. The late re-registration fee is $1,150 (which includes a $200

nonrefundable late fee). The final deadline for receipt of re-registration material

is May 1, 1992.

SITE ASSIGNMENT

Site assignment is based on the date of receipt of the application or the

re-registration material. There may be limited seating at some sites so early registration

is suggested.

The American Board of Pediatrics

111 Silver Cedar Court

Chapel Hill, NC 27514-1651

(7)

1992;89;229

Pediatrics

Merton, Christian Stanley and Linda McKee

Leonard J. Graziani, Donald G. Mitchell, Michael Kornhauser, Frank S. Pidcock, Daniel A.

Bilirubin Studies

Neurodevelopment of Preterm Infants: Neonatal Neurosonographic and Serum

Services

Updated Information &

http://pediatrics.aappublications.org/content/89/2/229

including high resolution figures, can be found at:

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml

entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or in its

Reprints

http://www.aappublications.org/site/misc/reprints.xhtml

(8)

1992;89;229

Pediatrics

Merton, Christian Stanley and Linda McKee

Leonard J. Graziani, Donald G. Mitchell, Michael Kornhauser, Frank S. Pidcock, Daniel A.

Bilirubin Studies

Neurodevelopment of Preterm Infants: Neonatal Neurosonographic and Serum

http://pediatrics.aappublications.org/content/89/2/229

the World Wide Web at:

The online version of this article, along with updated information and services, is located on

American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

http://pediatrics.aappublications.org/content/89/2/229 http://www.aappublications.org/site/misc/Permissions.xhtml http://www.aappublications.org/site/misc/reprints.xhtml http://pediatrics.aappublications.org/content/89/2/229

References

Related documents

In an effort to provide surgeons with real-time biophotonic information to clearly define tumor margins and small foci of cancer cells, we recently developed a

Given these characteristics, we expect that the costs relating to the remuneration of directors in Canadian companies, subject to US regulations, be increased after

In order to examine the thermal effect of suitable powers for removing the smear layer and canal decontamination in primary teeth, among the different laser powers, 1 and

While the AEs documented in the studies included in the present systematic review (three acute-treatment trials and one maintenance RCT) were not life-threating ones, not

Therefore, human capital valuation, capitalization of human resource values in the books of account and the fair disclosure and presentation of such information

1) What is the relationship between technical feasibility of the project on managing credit risk in financial institutions?.. Licensed under Creative Common Page 180 2) What are

Prevalence of high blood pressure significantly associated with age, gender, family history of hypertension, physical activity, type of school and dietary habits6. Keywords:

Transition from real solution to complex turbulent solution is realized through infi nity of the right parts of ordinary differential equation system to which Navier –