LONG-TERM EFFECTS OF NEONATAL JAUNDICE ON BRAIN FUNCTION IN CHILDREN OF LOW BIRTH WEIGHT

Full text

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(Received June 7; revision accepted for publication September 1, 1971.) This study was supported by National Health Grant 609-7-115, Canada.

ADDRESS FOR REPRINTS: (J.U.C.) Department of Paediatrics, University of British Columbia, 715

West 12th Avenue, Vancouver 9, B.C., Canada.

PEDIATRICS, Vol. 49, No. 5, May 1972

LONG-TERM

EFFECTS

OF

NEONATAL

JAUNDICE

ON

BRAIN

FUNCTION

IN CHILDREN

OF

LOW

BIRTH

WEIGHT

John U. Crichton, M.B., F.R.C.P.(E), Henry G. Dunn, M.B., M.R.C.P.,

Annetta Karaa McBurney, Ph.D., Ann-Marie Robertson, M.D.,

and Enid Tredger, M.D.

From the Section of Neurology, Department of Paediatrics, and the Department of Psychology,

University of British Columbia, B.C., Canada

ABSTRACT. The remote effects of neonatal jaun-dice were studied prospectively in three matched groups of 30 children of low birth weight with varying maximal neonatal levels of serum bilirubin.

After 4 to 11 years, mean IQ scores were slightly

lower in the most severely jaundiced group than in the others, and this group had a significant excess of mentally retarded children. (IQ < 70), mostly boys. However, the differences between the mean

IQ scores of the three matched groups were not

significant, particularly when cases with hemolytic disease of the newborn were excluded. Analysis of the discrepancy between verbal and performance scores and of various special test scores also failed to demonstrate significant differences. Subsequent

clectroencephalographic abnormalities were slightly

more frequent according to neonatal levels of

serum bilirubin, but differences were not signifi-cant. Within the most severely jaundiced group, 13 infants without hemolytic disease who received an exchange transfusion, on the average regained their birth weight significantly sooner than 14 similar in-fants who did not have a transfusion; the ultimate mean IQ of the former group was also considerably higher than that of the latter, but the difference was not significant. Large scale studies are consid-ered necessary to elucidate these sequelae.

Pediat-ric.c, 49:656, 1972, LOW BIRTH WEIGHT,

HYPERBIL-IRUBINEMIA, INTELLIGENCE, DEVELOPMENT, ERYTH-ROBLASTOSIS FETALIS.

I

T is well recognized that neonatal ker-nicterus may not be fatal but may leave serious neurological sequelae, particularly extrapyramidal forms of cerebral palsy,1 intellectual deficit,3’#{176}8 senori-neural hearing loss,23,69-fl pareses of upward gaze,2 and autonomic dysfunction.5 A continuum of damage ranging from such serious sequelae to minor intellectual impairment has been postulated.12 There is also considerable evi-dence that sequelae of neonatal jaundice tend to occur particularly in hemolytic dis-ease of the newborn when the serum bili-rubin level has risen to very high values.13

While the aftereffects of jaundice and their prevention by replacement transfusion are now fairly well established in hemolytic disease of the newborn, the situation is more controversial in nonhemolytic jaun-dice, as in the so-called jaundice of prema-turity. On the one hand, this type of jaun-dice is free from two mechanisms which

may make the jaundice of hemolytic disease

especially dangerous, namely the coating of

red cells with antibody (which impairs oxy-gen transport) and the excess of circulating hematin-like pigment (which is toxic by

it-self and can displace bilirubin from pro-tein) 17 On the other hand, kernicterus may

evidenfly occur at quite low levels of serum bilirubin in infants of short gestation.182#{176}

Accordingly, there has been considerable discussion in the literature whether jaundice contributes signfficantly to brain damage in children of low birth weight, whether it should be treated with replacement

transfu-sions, and if so, at what level of serum

bili-rubin.1831

In one prospective follow-up study of

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Case

Nurn-ber

Name Sex

Birth Weight

(gm)

Gesta-tional Lenh

(weeks)

Gesta-tionat

Age-Weight Category

Outcome

IQ Social

Class Continents

la Kin. I%i i,98 84 P N 96 4

b Jer. M 2,041 34 P N 116 4

c Cro. M 1,957 35 P MCD 114 1 RDS

a Bar. F 1,588 30 P N 111 4

b Barn. F 1,446 8 P N 104 4

C Gre. F 1,503 33 P N 96 4 RDS

3a Smi. F 1,871 35 SFD MCD 89 4

b Fro. F 1,928 87 SFD N 105 4

c Rob. F 1,814 38 SFD N 76 4

4a Wra. M 1,871 35 SFD MCD 101 5 lIDS

b Fan. M 1,786 35 SFD N 125 1

-c Sli. M 1,956 36 SFD N 97 5

-5a Orw. F 1 ,814 33 P N 107 4

-bFar. F 1,814 8 P CP 85 4

-c Tje. F 1 ,848 83 P N 102 5 neonatal pneumonia

6a Moo. F ,OlS 36 SFD N 105 5

-b Won. F 1,98 37 SFD N 77 4

-C Par. F 1,984 37 SFD N 115 2

-7a Kas. F 1,848 81 P N 101 4

-b Hoo.(A)* F 1,786 31 P N 88 5

-c Wit. F 1,701 31 P N 99 5

-8a Hur. M 1,956 35 P MIt 60 4

-b Del. M 2,O13 38 P N 115 4

-c Sig. M 1,928 34 P N 107 4

-9a LeB. M 1,474 30 P MR 56 5 lIDS

b San. M 1,446 31 P MCD 100 4

c Bea. F 1,417 80 P N 105 4 CHD

IOa Mau. M 1,98 34 P MCD 98 4

-b Owe. M 1,98 ‘35 P MCD 112 4

-c Tow. M 1,899 S P N 87 4

-ha Her. F i,98 8Z P N 91 5

-b Pic.(A) F 1,871 54 P N

-

5

-c Ver.(B) F ,O41 34 P N 88 5

-1aLum. F ,O18 33 P N 92 5

-b Moor. F 1,958 35 P N 98 8

-c War.(B) F ,126 33 P N 86 5

-iSa Yan. F ,O13 36 SFD N 104 5

-b Day. F ,O13 37 SFD N 109 4

-c Pas. F 1 ,871 36 SFD CD 74 5 multiple congenital defects

TABLE I

DATA OF INDIVIDUAL CASES AND CONTROLS

a

(A), (B), (C) refer to ordinal rank in multiple birth. CD =cerebral dysfunction (more than minimal) CHD =congenital heart disease

CP=cerebral palsy

HDN’=hemolytic disease of the newborn MCD =minimal cerebral dysfunction

MR=mental retardation (IQ<70)

N = normal

P= “true premature” i.e. preterm and within 11-89th percentile of expected weight43 RDS=respiratory distress syndrome.

SFD =small-for-dates i.e. at and below 10th percentile of expected weight for duration of gestation,”

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TABLE I (Continued)

Gesta-

(Liesia-Case Birth

.

tional

tional Social

Num- Name Sex Weight Age- Outcome IQ Comments

Length

.

Class

ber (gin) Weight (weeks)

Category

14a list. M 1,503 ? ? MCD 88 5

b Smit. M 1,588 35 SFD Deaf 86 3 RDS

c Cox.(A) M 1,446 28 P N 103 3 RDS

iSa Fid. M 1,956 32 P MR 50 4

b Cm. M 1,956 32 P CP, MR 62 5

Hod.(A) M 1,984 35 P MCD 85 5

-16a Tho. M 1,474 29 P MR 3() 5 significantly small head

b Mal. M 1,559 29 P CP 62 5

-cMac. M 1,446 Si P N 103 4

-17a Pri.(B) M 1,474 33 P MCD 90 5 hypoglycemia

b Ber. M 1,446 30 P CP 106 5

-cSan. F 1,588 32 P N 105 5

-18a Mol. F 1,701 33 P N 115 5

-b Haa. F 1,644 31 P N 104 5 RDS

c Pic.(B) F 1,871 34 P N

-

5

19a Bur. M 1,701 36 SFD N 115 5

b Bow. M 1,843 35 SFD N 97 4

c Bed. ‘SI 1,871 37 SFD MCD 120 5

20a Mar. M 1,389 30 P CP,MR 61 5

b She. M 1,389 31 P N 101 3 RDS

c Jen. M 1,417 ? ? MCD 88 4

21a Pen. M 1,871 33 P N 120 1

bLam. M 1,899 33 P N 117 4

c War.(A) M 1,843 33 P CD 85 5

22a Die. F 1,899 33 P N 112 3

b Fre. F 1,871 33 P N 104 3

c Hie. F 1,879 36 P N 82 4

23a Ham. M 1,361 30 P N 86 5

b Par.(A) M 1,389 29 P Blind 88 3 RDS

c Town. F 1,361 31 P N 101 4

24a Sco. M 2,041 35 P N 107 3

b Sim. M 1,928 33 P N 121 4 RDS

c Pat.(B) M 2,070 35 P N 92 4

25a Bur. F 1,588 32 P N 97 4

b Bri. F 1,588 32 P CP 80 5

c Lan.(A) F 1,446 32 P MCD 80 5

26a Laj. M 1,644 31 P N 127 5 lIDS

b Nag. M 1,559 31 P N 90 5 RDS

c Ske. M 1,474 31 P N 120 S

* (A), (B), (C) refer to ordinal rank in multiple birth.

CD = cerebral dysfunction (more than minimal)

CHI) = congenital heart disease

CP = cerebral palsy

HDN = hemolytic disease ofthe newborn MCD = minimal cerebral dysfunction

MR = mental retardation (IQ<70) N=norznal

P= “true premature” i.e. preterm and within 11-89th percentile of expected weight’3 RDS = respiratory distress syndrome.

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Case

Num-ber

Name Sex

.

Birth Weight

(pm)

Gesta-.

tional Length

(weeks)

Gesta.

.

tional Age-Weight

Category

Outcome IQ

.

Social

(lass Comments

27a Rat. ISI 1,559 30 P N 90 4

b Kuy. M 1,701 30 P N 100 4

c lIut.(B) F 1,758 34 P N

-

1

28a And. M 1,446 ? ? MR 30 5

b Sto. ‘SI 1,219 28 P N 107 4

c Pyw.(A) F 1,219 29 P N 75 5

29a Kab. M 2,183 35 P MCD 99 3

b Bal. M 1,984 35 P MCD 82 4

c Warn.(B) M 2,014 34 P N 87 4

SOa Sor. F 1,616 31 P CP,MR 31 5

b Jun. F 1,899 84 P CP 72 5

c Hut.(C) F 1,843 34 P N - 1

IIDN, retrolental

fibro-plasia, blindness

HDN

HDN HDN

TABLE I (Continued)

* (A), (B), (C) refer to ordinal rank in multiple birth. CD =cerebral dysfunction (more than minimal) CHD = congenital heart disease

CP = cerebral palsy

HDN = hemolytic disease of the newborn MCD =minirnal cerebral dysfunction

MR =mental retardation (IQ<70)

N = normal

P=”true premature” i.e. preterm and within 11-89th percentile of expected weight43 RDS = respiratory distress syndrome.

SFD =small-for-dates i.e. at and below 10th percentile of expected weight for duration of gestation,’3 in-cluding preterm infants

shown that 94 children whose serum biliru-bin level had never risen above 12.9 mgI 100 ml obtained a better mean score with regard to gross motor development than 39 children whose serum bilirubin level had

risen above 15 mg/100 ml. This difference

persisted at 1 year, but was significant only among the males. On the other hand, Shil-ler and Silverman25 examined 110 prema-ture infants with a birth weight of less than 2,000 gm who had reached the age of 3 years, and when children with neonatal se-rum bilirubin levels above and below 18 mg

I100 ml were compared, there was no sig-nificant difference in the incidence of neu-rological deficits. Hugh-Jones, et al.26 ob-tained similar negative results with regard to 20 developmentally retarded infants of low birth weight at 1 year. In a discussion

concerning the diverging results of these studies, Day’7 commented that in Shiller

and Silverman’s25 series the babies with high bilirubin levels were mostly inferior to

the others, though the differences failed to

reach conventional levels of significance. In another prospective study, Koch21 examined 68 prematurely born children at 7 years and found that 6 of 27 whose serum bilirubin level had risen above 20 mgllOO ml had brain damage in which hyperbilirubinemia might have been a factor, but there was no apparent linear correlation between

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* One child in Group B and three children in Group C were not available for later psychological testing.

TABLE II

ANALYSIS OF MATCHED GROUPS

Data Group A Group B Group C

Maximal neonatal

serum bilirubin level (mg. ,) 20 11-19.9 <11 Total number of children studied 30 (27) 30 (27) 30 (27)

Socioeconomic class I 1 1 3 (2)

II 0 0 1

III 3 5(4) 2

IV 10(9) 15(13) 11

V 16(14) 9 13(11)

Neonatal abnormalities:

Respiratory distress syndrome 3 6 S

Pneumonia 0 0 1

Hypoglycemia 1 0 0

Congenital malformation of heart 0 0 1

Other congenital defects 1 0 1

(e.g. hepatic fibrosis)

Total 5 6 6

Numbers in parentheses are residual after exclusion of cases of hemolytic disease of the newborn and their matched controls.

and neurological examinations. Zero corre-lations were computed between all nine

variables for each sex and for the entire group. Recently Culley, et al.3’ reported on the reassessment of 371 children in the sixth

year of life. At 1 year, an abbreviated Grif-fiths32 type of developmental test had sug-gested that neonatal jaundice had an effect on the progress of these infants, even at se-rum bilirubin levels of 12 to 16 mgI 100 ml. In the sixth year neurological handicap was

concentrated among the 207 children of low

birth weight (LBW), but was not related to jaundice apart from one case of athetoid cerebral palsy with deafness. However, these authors had used replacement trans-fusions to keep the serum bilirubin level below 20 mgIlOO ml, and their sixth-year

group included only 34 LBW children with

a neonatal serum bilirubin level of 12 to 16

mg/ 100 ml and 16 LBW children with a

level above 16 mgilOO ml.

In all such studies, the role of other pathogenetic factors in jaundiced neonates

must be considered. The incidence of

kern-icterus is known to be increased not only

by low birth weight and marked prematur-ity, but also by anemia,33 birth asphyxia,3

and low body temperature.2’ The effect of large doses of Vitamin K in the production

of kernicterus is well established, and while the effect of drugs on bilirubin metabolism is complex, it is now thought that not only

sulflsoxazole36 but also sodium benzoate

and other drug components37 may

predis-pose to kernicterus by displacing bilirubin

from its binding on albumin. In addition, hypoxia, acidosis,38 and hypoglycemia in the first few days of life may contribute to brain damage in jaundiced infants. In all

such studies of intellectual development, it

TABLE III

LATER INTELLIGENCE OF LBW CHILDREN WITH VARYING LEVELS OF NEONATAL SERUM BILIRUBIN WITH AND WITHOUT HDN

Data

Group

A B C B+C

Maximal neonatal serum bilirubin

level (mg.%) 20 1119.9 <11 <20

Total children studied (N = 86)* n=30 n =29 n =27 11=56

Mean IQ 88.47 97.03 95.07 96.07

Statistical significance of difference

from Group A P .09 (N.S.) pN.S. p .73 (N.S.)

Number of children studied without

1IDN (N=78) n=27 n=26 n=25 11=51

MeanIQ 92.37 98.15 96.2 97.

Statistical significance of difference

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must further be remembered that the ulti-mate 19 is highly dependent on parental

socioeconomic status’9’4#{176}and that males are affected more by neonatal jaundice than fe-males,” and twins or triplets more than sin-gletons.

In order to overcome these various

prob-lems in assessing the effects of neonatal jaundice on long-term neurological devel-opment, we have utilized the method of matched control groups which has served

us previously in studying the residual

effects of neonatal hypoglycemia and of

re-spiratory distress.41’42 We have examined the data acquired in the course of a long-term follow-up of low birth weight (LBW) infants in order to determine whether “hy-perbilirubinemia of prematurity” is related to subsequent impairment of intelligence, to other neurological or psychological Se-quelae, or to abnormalities of the

electroen-cephalogram (EEG).

MATERIAL AND METHODS

Five hundred and two infants weighing 2,183 gm or less at birth who were treated in the Intensive Care Nursery at the Van-couver General Hospital between 1958 and

1965 have been studied. Eighty-two have died, but so far 320 have been followed to 4 years and 274 to 6% years of age. These in-fants were all examined in the nursery, again on discharge, and then at 3 and 6 months and at 1, 1%, 2%, 4, and 6% years. The examinations had a neuropediatric empha-sis, and if abnormalities were discovered,

suitable consultations were obtained. De-velopmental testing according to the Griffiths’2 method was carried out at the early examinations, and psychological as-sessment was performed at 2%, 4, and 6% years of age. The psychological tests in-cluded the Stanford-Binet (Form L-M) and

Wechsler Intelligence Scale for Children (WISC) IQ scoring as well as the Vineland Social Maturity Scale, Graham-Ernhart Block Sort Test, Goodenough-Harris Draw-ing Test, Knox Cube, Vocal Encoding, and the Bender Gestalt Test. Since the children

remained under the care of their private

physicians, treatment was not standardized. Of these 502 infants, 30 had a maximum recorded serum bilirubin (SB) level of 20 mgi 100 ml or more in the nursery. These 30 infants (Group A) were matched with another 60 infants. Thirty of the latter had a maximum recorded SB of 11 to 19.9 mgI

100 ml (Group B ) and 30 had a maximum recorded SB of less than 11 mg/ 100 ml

(

Group C ) .The matching was carried out in respect of sex (except in five of the sets),

birth weight within 200 gm (except in

three of the sets), and categories (i.e., per-centile groupings) of gestational age-weight relationship (except in three of the

sets, where the gestational age of three

in-fants is unknown-see Table I). The cate-gories were defined by the use of data sup-plied by Babson, et al.” from a study of

40,000 singleton Caucasian infants born in Portland, Oregon. In the case of twins the data of Naeye, et al.” were used. No at-tempts at matching other variables were

made, because of the difficulties in doing so with the small numbers available. However,

socioeconomic circumstances were also ex-amined. As shown in Table II there was no

significant difference between the groups in this respect. Similarly cardiorespiratory

dis-ease or other complications affecting the child’s progress in the neonatal period

might be held to have an adverse influence, but all groups have about equal numbers of

such complications (Table II).

Hemolytic disease of the newborn (HDN) occurred in three cases in Group A (in sets 28, 29 and 30 of Table I) and also in one case in Group B (in set 30) but in

none of Group C. The three affected infants in Group A had replacement transfusions, as did 13 other children in Group A and one

each in Groups B and C.

The mean number of days required to re-gain birth weight was 19.5 in Group A, 19.0 in Group B, and 15.5 in Group C. The

dif-ference between Groups A and C in this re-spect is significant (t = -2.22, p =

.05).

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TABLE IV

SIGNIFICANCE OF DIFFERENCES IN IQ BETWEEN

MATChED SUBJECTS WIT!! VARYING LEVELS OF

NEONATAL SERUM BILIRUBIN, WITh AN!) %VITIIOLJT HDN (WILcoxoN

MATChED-P.iiis SIGNED-RANKS TT)

Wilcoxon Z=-l.45 Z=-.94

p=.O7 p=.l7

Z=-.65 Z=-.28 p=.25 p=.S9

‘A Maximum serum bilirubin level 20 mg/100 ml B Maximum serum bilirubin level 11-19.9 mg/I00 ml

C Maximum serum bilirubin level <11 mg/100 ml The remaining subjects were not available for psychological testing at the appropriate time.

662

.1 vs B’ lea

Total C’

Children Total Children

Test Children Studiedt n=9

Without IIDN n=26

Children Studiedt n=

J1’it hoot !IDN n=21

analysis of the results. A 360-67X IBM

Du-plex#{176}computer was used for multivariate contingency tabulations; selection of the most appropriate formulae was made for any pair of variables, and in some instances

consistent trends were found even in the absence of statistical significance.

RESULTS

Intelligence Scores of Matched Groups

The mean scores were calculated on the basis of the latest IQ measurements of these children, i.e., mostly the Full Scale WISC IQ at or after 6% years, and in 14 of the 90

cases the Stanford-Binet (Form L-M) IQ at

4 years. In five cases specially modified test-ing was required since three children in

Group A were severely retarded, one child in Group B was blind, and one in Group B was deaf. Table III shows that the mean IQ of the three matched groups is thus found to be 88.5, 97, and 95.1, respectively, and when the two groups with the lower serum bilirubin levels are combined, the value is

96.1. It will be noted that the differences

are not significant, though the difference between Group A and Group B approaches

significance (p = .09).

When the three sets of children which

in-o International Business Machines, Boardman

Road, Poughkeepsie, New York.

elude cases of HDN are eliminated from the analysis, the mean IQ of the three groups becomes 92.4, 98.2 and 96.2, respec-tively, and the differences are farther from significance (Table III ). Instead of com-paring group means one may analyze the

IQ differences within each matched triple

set. If the Wilcoxon matched-pairs signed-ranks test is used in such comparisons, the

differences are still nonsignificant, but ap-proach significance even when the sets con-taming cases of HDN are excluded (Table

IV) . Similar but less striking results are ob-tamed if the t test or sign test are used for this comparison.

When the distribution of IQ scores is shown graphically (Figure 1), it becomes evident that the range and spread of scores

in Group C more nearly approximate a nor-mal distribution than in Group A,

consider-ing the small numbers of subjects involved. Another way of illustrating this finding is to analyze the incidence of mental retardation (IQ below 70). As shown in Table V this occurred seven times in Group A (five times after exclusion of cases with HDN), twice in Group B and not at all in Group C. The differences between Groups A, B, and C are statistically significant at the 0.01 level for all the children studied and are close to the 0.05 level for the children with-out HDN.

Incidentally, it is of interest that of the nine retarded children (with IQ below 70) eight are males, and the seven retarded children who did not have HDN are all males. In contrast, of the total series of 90

matched children, 49 are males. When the mean IQ of males and females in the whole series are compared, the females score slightly higher, but the difference is not sig-nificant. In each of the Groups A and C the

Mann Whitney U figure is only 4.5 and 3 points, respectively, short of significance.

It is also of interest to compare the devel-opment of the 13 children within Group A who received exchange transfusions for “jaundice of prematurity” (without

hemo-lytic disease of the newborn) with the

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I,

I I

#{149}

ii#{149}nII

III

I

Grp. A

Grp. B

Grp. C

-30

I

n

#{149}uiIl

.

I I I I I-- I I I

40 50 60 70 80 90 100 110 120 130

Group A .S.rum Bihirubin 20 mg% or more

Group B.Serum Bilirubin 11.19.9 mg% Group C.Serum Blirubin 11 mg%

-

I

.iilIi

#{149}

I

GLOBAL l.Q.

El

Children with hemolytic disease of the newborn (HDN)

#{149}Children without HDN

FIG. 1.Intelligence scores of LBW children after varying degrees of neonatal bilirubinemia.

have exchange transfusions. As shown in

Table VI, the former group, on the average, regained their birth weight significantly

sooner than the latter. The subsequent mean IQ of the transfused group was 99.2

and that of the nontransfused only 85.1, but this difference is not significant. It is true that the mean birth weight of the group who received exchange transfusions was slightly higher, but on the other hand, their mean maximal serum bilirubin level was

also slightly higher, so that the prognosis of the two groups might have been expected

to be similar.

Special Psychological Test Scores of

Matched Groups

An attempt was made to see whether the subsequent Verbal as compared to the

Per-formance scores on the WISC bore any re-lation to the neonatal serum bilirubin level. Preliminary analysis indicated that Group A contained a larger number of children

whose Verbal Scale IQ (VIQ) was 10 points or more greater than the

Perfor-mance Scale IQ (PIQ), and this might be taken as an indication of “cerebral

dysfunc-tion.” However, the numbers involved are very small (Table VII). The reverse

situa-tion (PIQ 10 points or more higher than

VIQ) occurred about equally in the three

groups. The standard deviation of the

dif-ference between PIQ and VIQ declines from Group A to B to C, but these differ-ences are not significant, particularly when

cases of HDN are excluded (Table VIII). The latest mean scores of the matched

groups in the Goodenough-Harris drawing

test, the Bender Visual-Motor Gestalt test, the Graham-Ernhart Block Sort Test, the

Knox Cube, and the Vocal Encoding sub-test (from the Illinois Test of

Psycholin-guistic Ability) were also analyzed but t

test comparisons showed that the mean

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TABLE V

INCIDENCE OF IQ<70 IN LBW CHILDREN WITh! VARYING DEGREES OF BILIRUBINEMIA

Group A

(n=30)

Group B

(n=B9)*

Group C

(n=27)*

Maximal Neonatal Serum

Bilirubin Level O mg/100 nil 11-19.9 ;ng/100 ml <11 mg/100 ml

Social

IQ Sex ClaJs

Social

JQ Sex Class

61 M 5

60 M 4

56 M 5

50 M 4

Sit F 5

SOt M 5

30 M 5

62 M 5

62 M 5

No cases

* The remaining subjects were not available for psychological testing at the appropriate time. t Children with HDN.

tamed a slightly lower score than Group B or Group C in the Goodenough-Harris drawing test, whereas the Bender Gestalt test indicated a slight trend in the opposite direction. It should be noted that these tests had only been applied to between 51 and 56 of the 90 children and in general not to those with an IQ below 80.

Clinical Sequelae (Table IX)

As mentioned above, mental retardation

(IQ less than 70) was found seven times in Group A, twice in Group B and not at all in Group C, so that it appeared significantly correlated with the neonatal level of serum bilirubin. Cerebral palsy was encountered twice in Group A and six times in Group B; it was not found at all in Group C; these differences are not statistically significant. Apart from two instances of extrapyramidal cerebral palsy (one in Group A and one in Group B), these were all cases of spastic

cerebral palsy. Minimal cerebral dysfunc-tion (as defined by Clements) occurred

six times in Group A, three times in Group

B, and five times in Group C. Other more

marked forms of cerebral dysfunction, e.g., central communication disorders, were found in two cases in Group C. Clinically

marked deafness was found only twice (one each in Groups A and B ). Sixty-three of these 90 children have been examined by audiometry at 6% years, and mild high-fre-quency hearing loss (exceeding 15 db) has been found in six cases, namely two each in Groups A, B, and C. Although the total number of known neurological disabilities

declines from Group A to B to C (18 to 14 to 9), the figures are clearly too small for further analysis. Similarly, among the 27 children in Group A who did not have he-molytic disease of the newborn, the 14 who

did not receive an exchange transfusion

ap-peared to have a higher incidence of

subse-quent mental retardation than the 13 who were given an exchange tranfusion (Table

VI), but again the numbers are too small to

be significant.

Electroencephalograms

The most recent electroencephalograms

(EEG) in the matched groups are

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trac-TABLE VI

COMPARISON OF INFANTS WITHoUT HDN WITHIN GROUP A Wiio DID OR DID NOT hAVE

REPLACEMENT TRANSFUSIONS

* Including one with epilepsy and one with cerebral palsy.

ARTICLES 665

ings to diminish from Group A to B to C.

The incidence of epileptiform abnormalities in these records similarly appears to decline in keeping with the neonatal serum

biliru-bin levels.

DISCUSSION

It is evident that many variables, occur-ring both in the newborn period and later, may affect cognitive and other brain func-lions at school age, but the method of

matched controls in the present study ap-pears to have equalized these variables which are exemplified by neonatal cardiore-spiratory disease and socioeconomic factors.

In relation to the degree of neonatal

jaun-dice in the three matched groups it must be

admitted that we can only rely on the maxi-mal recorded serum bilinibin levels; we

have no data concerning the saturation of serum proteins with bilirubin, which Odell,

et al.#{176}have shown to be an important

con-relate of brain damage. In hemolytic

dis-ease of the newborn, Day and Haines47 compared the subsequent intelligence of af-fected children with that of their siblings and found that the IQ was significantly de-pressed in relation to the severity of the jaundice and that replacement transfusion

appeared to protect the brain from the

effects of the disease. Similarly, Boggs, et

al.16 described a significant relationship be-tween neonatal bilirubin concentration and neurological impairment at 8 months of age

in a large collaborative series. However, several other studies have failed to show a

clear inverse relationship between neona-tal serum bilirubin level and subsequent IQ.46’485#{176}Odell, et al.46 suggest that the frac-tion of serum bilirubin which is dissociated from albumin and therefore free to diffuse into cells is of more importance in causing brain damage than the total serum bilirubin level. While such free bilinibin may cause kernicterus, the role of other pathogenetic

factors in jaundiced neonates is evidently complex; they may also damage the brain directly or may add to the toxicity of biliru-bin at the cellular level. Consequently, the serum bilirubin level per se is certainly a

Data

Exchange

.

Transfusion

.

Given

No Exchange

.

Transfusion

Number 13 14

Birth weight-gestation category:

True Premature 8 13

SFD 4 1

Uncertain 1

-Mean birth weight (gm) 1784 1719

Mean number of days to regain birth

weight

16.4 21. 6[t =2 1 1p=<.O5 Mean maximal serum bihirubin level 24.0 22.0

(mg/l0O ml)

MeanIQat4to6years 99.2 85.lJt=I.66

ip =N.S. Neurologcal abnormalities:

Mental retardation (IQ <70) 1 4’

Minimal cerebral dysfunction S 2

very rough index of the peril to which the infant’s brain is exposed.

Recent analyses have also shown that

de-tailed psychological testing may be more

TABLE VII

COMPARISON OF VERBAL (VIQ) AND PERFORMANCE

(PIQ) SCORES IN WISC

Group n VIQ>PIQ

VIQ 10 Points or more Higher than PIQ A B C 19(18) 25 (2) 22(22) 7(6) 7 (7) 5(5) 4(3) 1 (1) 1(1)

n PIQ> VIQ

PIQ 10 Points or More Higher than VIQ A B C 19(18) 23 (22) 22(22) 12(12) 16 (15) 16(16)t 8(8) 8 (7) 9(9) * The remaining children were not available for psy-chological testing at the appropriate time.

tIn Group C PIQ= VIQ for one subject.

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Total Children Studied Children u’ithout HDN

A 19 12.11 23.85

B 22 -7.04 12.76

C 22 -7.54 11.38

.86 N.S.

.79 N.S.

18 -7.83 15.34

20 -6.85 13.39

20 -7.80 10.90

666

TABLE VIII

ANALYSIS OF DISchIEI’ANCIES IN VIQ AND PIQ* BETWEEN GROUPS OF LBW INFANTS WITH VARYING LEVELS OF NEONATAL SERUM BILIRUBIN, WITH AND WITHOUT HDN

Group means and standard deviations

Groups

According to

Level of Serum Bilirubin (see text)

n MeanJQ VIQ- Standard Deviatioti

1-Test for Statistical Significance of

Difference from

Group A

ii Mean1 ,IVIQ-PJQ Standard Deviation

t- Test for Statistical Significance of Difference from

Group A

p 1 p

.21 N.S.

.0! N.S.

‘l’he minus signs indicate that, for the total children studied and for the children without HDN, more subjects have a higher Performance thaI! Verbal IQ in each bilirubin group and combination of groups examined. The standard deviation of the difference between VIQ and PIQ falls with the serum bilirubin level hut not to a sig-nificant extent.

* The Verbal (VIQ) aIld Perforiiiauce (PIQ) scores on the WISC.

revealing than IQ measurements assessing overall cognitive ability. Odell, et al.46

pointed out that the hippocampus may be damaged in kernicterus and that this may affect learning, memory, and adaptive be-haviour. Such patchy impairment of cogni-tive functioning may not be reflected in the “global” IQ score and may not be

detect-able in the early years of life. Hyman, et al.15

did find lowered intelligence with atheto-sis in a 4-year follow-up study of infants with neonatal jaundice, but they also noted the possibility of auditory rote memory and visual perception being particularly im-paired. Stewart, et al.#{176}performed detailed psychological studies on 126 survivors of hemolytic disease of the newborn due to Rh

incompatibility; while overall cognitive functioning and motor development were not significantly affected, there was distinct impairment of visual-motor-perceptual

abilities, best shown by the Minnesota Per-cepto-Diagnostic Test. However, in our cases special psychological examinations like the Bender Gestalt and Graham-Em-hart Block Sort tests have not demonstrated

any more significant association with neo-natal serum bilirubin levels than more

com-prehensive IQ tests. There is a suggestion in our analysis that neonatal jaundice niay be associated with an unusually wide differ-ence between Verbal and Performance

scores in the WISC later and thus perhaps with “cerebral dysfunction,” but Table IX

shows that minimal cerebral dysfunction

(MCD) did not occur more frequently in

the severely jaundiced group, and the total number of MCD cases (14 of 90, i.e., 15.5%) is not high as compared to the ap-proximately 20% of cases in our survey of children with a birth weight below 2,183

gm who showed MCD at the corresponding

age. The results do suggest a slight

reduc-tion of mean IQ in the severely jaundiced

group, but it is evident that this is largely

due to a few, mostly male, retarded

chil-dren with an IQ below 70, who cause an abnormal distribution of IQ scores and lower the average. Hyman, et al.15 obtained somewhat similar findings.

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hyperbilimu-Maximum neonatal serum bilirubin level

(mg/lOOml) 20 11-19.9 <11

Number of children studied 30 30 30

Mental retardation (IQ <70) 7 2 0

Minimal cerebral dysfunction 6 3 .5

Cerebral palsy* 2 (1) 6 (1) 0

Cerebral dysfunction (more that! minimal) 0 0 2

Marked deafness 1 1 0

Mild high frequency loss 2 of 18 ‘2of 22 ‘2of 23

Total Neurological Disabilities

TABLE IX

INCIDENCE OF NEUROLOGICAL DISABILITIES IN LBW INFANTS WITII VARYING LE\-EIs OF NEONATAL SERUM BILIRUBIN

Data

Total Children Studied

A B C

Children Studied, without IIDN

A B C

20 11-19.9 <11

27 27 27

5 2 0

.5 2 5

I 5 0

0 0 2

1 1 0

2 of 17 0 of 20 2 of 23

18 14 9 14 10 9

* Number in parenthesis indicates cases of exhapyramidal cerebral palsy.

binemia into groups with and without

ex-change transfusion and found no differ-ences in the neurological status at 6 months

and 1 year. Comparison of the mean IQ at 4 to 6% years in those of our patients within Group A who did and did not receive ex-change transfusions, yields more

encourag-ing results in the transfused group.

How-ever, the number of subjects is small and the difference is not statistically significant.

The high incidence of abnormal electro-encephalograms after neonatal jaundice has been documented in hemolytic disease of

the newbornl3 but again the incidence of

EEG abnormalities in our matched groups

of LBW children shows only a slight corre-lation with different degrees of neonatal

bi-lirubinemia (Table X), and the differences are not significant. If the continuum of brain damage postulated by Van Camp12 exists, one would expect to find some mildly

damaged children even at neonatal serum

bilirubin levels below 20 mg/100 ml when other risk factors are associated and may cause kernicterus.182#{176} However, one would still expect to find more brain damage in the more deeply jaundiced group. Our fig-tires are too small to prove this, though they

TABLE X

MOST RECENT ELECTROENCEPIIALOGIIAMS (EEG) IN MATCHED (inoucs VITIIOI’T UDY

Data Group A Group B Group (7

<11

Maximal neonatal serum bilirubin level (mg.%) 20 11-19.9

Number of children studied 27 27 27

EEG normal 12 15 15

EEG borderline 3 2 1

EEG abnormal 7 9 8

EEG not available 5 1 3

Incidence of borderline and abnormal EEGs among

those uvailable (%) 45.4% 42.3% 37.5% X2= 1.3 N.S.

EEGs-epileptiform abnormalities 5 4 3

Incidence of epileptiform abnormalities among

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668

tend to support that hypothesis. Frequently the statistical values are only slightly below the level at which significance is assumed. We therefore agree with Vuchovich, et al.#{176}

that the effect of nonhemolytic jaundice per

se on ultimate intelligence and neurological status in LBW infants without definite kern-icterus is probably small, but that the

ulti-mate answer to this problem will require pooling of data from several centres and applying appropriate complex analytic pro-cedures which will have to make allowance

for all the multiple risk factors. In this re-spect the situation is somewhat similar to

the assessment of the long-term effects of neonatal respiratory distress on brain

func-tion.42’51-53

SPECULATION

It is interesting that several previous studies have shown an effect of neonatal hyperbilirubinemia on developmental test scores in infancy,16’23’24’27 whereas later IQ

does not appear to be so clearly affec-ted.’5’25’31’’5#{176} In a previous study of devel-opmental and psychological test scores in LBW children, it was demonstrated that the effect of low birth weight per se tends to become overshadowed by the effect of

socioeconomic status from the age of 2% to 4 years onwards;#{176} the effect of neonatal hy-perbilirubinemia may similarly become less demonstrable with increasing age.

SUMMARY

Thirty children of low birth weight with maximum recorded neonatal serum biliru-bin levels above 20 mg/100 ml have been studied prospectively. Their subsequent

in-tellectual and neurological status and elec-troencephalograms have been analyzed and compared to those of two groups of 30 matched controls each, in whom the maxi-mal neonatal serum bilirubin level was 11 to 19.9 mg/100 ml and below 11 mg/100 ml, respectively. With a few exceptions, matching was carried out in respect of sex, birth weight (within 200 gm), and gesta-tional age at birth. Socioeconomic status and the incidence of other neonatal

abnor-malities were not significantly different in

these three matched groups.

After follow-up for periods of from 4 to 1 1 years, mean IQ scores were found to be lower in the more severely jaundiced group but the difference was not significant and

was further reduced when three cases of hemolytic disease of the newborn and their

matched partners were removed from the

analysis. When the triple sets of children

were studied by intrapair comparison of IQ, the differences approached significance on the Wilcoxon matched pairs signed ranks test.

The range and spread of IQ scores in the group who had had marked neonatal

hy-perbilirubinemia appeared abnormal, and this group had a significantly higher inci-dence of mental retardation (IQ below 70) than the other groups. Nearly all the re-tarded children were boys. Within this group with a neonatal serum bilirubin level above 20 mg/ 100 ml, the 13 infants who re-ceived an exchange transfusion without having hemolytic disease regained their

birth weight, on the average, significantly sooner than the 14 infants who had not had such a transfusion; the ultimate mean IQ of the former 13 children was also

considera-bly higher than that of the lafter 14, but the difference failed to reach significance.

The incidence of a discrepancy between

the Verbal and Performance scores on the WISC amounting to 10 or more points

ap-peared greater in the group with the high-est neonatal serum bilirubin levels, but the differences from the other groups were not statistically significant. The latest mean scores of the matched groups in the Goode-nough-Harris drawing test, the Bender

Vi-sual-Motor Gestalt test, the Graham-Ernhart Block Sort, Knox Cube, and Vocal Encod-ing tests also failed to demonstrate any sig-nificant differences.

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highest to that with the lowest neonatal

se-rum bilirubin level, but not significantly. It is concluded that the effect of nonhe-molytic jaundice per se on the ultimate in-telligence and neurological status of LBW infants without definite kernicterus is

prob-ably small, but our findings appear to indi-cate that large-scale studies of pooled data from several centres with complex analysis

of all associated risk factors are required to elucidate this problem.

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Acknowledgment

We wish to express our thanks to Dr. S. Israels

for encouragement and criticism, to the Depart-ment of Medical Illustration, University of British Columbia, for help with Figure 1, and to Mr. T. A.

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1972;49;656

Pediatrics

Enid Tredger

John U. Crichton, Henry G. Dunn, Annetta Karaa McBurney, Ann-Marie Robertson and

CHILDREN OF LOW BIRTH WEIGHT

LONG-TERM EFFECTS OF NEONATAL JAUNDICE ON BRAIN FUNCTION IN

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John U. Crichton, Henry G. Dunn, Annetta Karaa McBurney, Ann-Marie Robertson and

CHILDREN OF LOW BIRTH WEIGHT

LONG-TERM EFFECTS OF NEONATAL JAUNDICE ON BRAIN FUNCTION IN

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