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FOLLOW-UP STUDY OF EXCHANGE TRANSFUSION FOR HYPERBILIRUBINEMIA IN INFANTS IN JAPAN

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FOLLOW-UP

STUDY

OF

EXCHANGE

TRANSFUSION

FOR

HYPERBILIRUBINEMIA

IN

INFANTS

IN

JAPAN

Toru Ose, M.D., Tsuneo Tsuruhara, M.D., Masayoshi Araki, M.D.,

Toshiyuki Hanaoka, M.D., and Ovid B. Bush, Jr., M.D.

From the Department of Pediatrics, Yodogawa Chrtstian hospital, and till’

Osaka Rehabilitation Center, Osaka, Japan

(Received June 13, 1966; revision accepted for publication March 6, 1967.)

ADDRESS: (TO.) Yodogawa Christian Hospital, 57 Awaji Honmachi 1-Chome, Higashiodogawa-Ku,

Osaka, Japan.

PEDIATRICS, Vol. 40, No. 2, August 1967

196

EXCHANGE TRANSFUSIONS have saved a

large number of infants from cerebral

palsy or death due to erythroblastosis fetalis

since their use was first reported in 1946.’

There have been conflicting reports as to

the bilirubin level at which exchange trans-fusion is indicated2 and the relative risk of

sequelae at various bilirubin levels.’ A

crit-ical evaluation of these factors must be made in every case of severe jaundice of the newborn, weighing the danger of ker-nicterus against the hazards of exchange transfusion itself. The following study was

undertaken to determine the incidence of

brain damage among 157 consecutive in-fants who had 251 exchange transfusions at the Yodogawa Christian Hospital and to re-late the brain damage, if possible, to the

bi-lirubin level.

MATERIALS AND METHODS

The Yodogawa Christian Hospital is a general hospital which has about 700

dcliv-cries a year. From December 1957 to Dc-cember 1965 there were 277 infants with hyperbilirubinemia treated by 475 cx-change transfusions. A follow-up study of

157 of these infants who received exchange

transfusions before 1964 was carried out in

April and May of 1964. The examination

was repeated in June of 1965 on 10 infants who were less than 6 months old at the time of the first examination.

The criteria for exchange transfusion in

our hospital are either one or both of the

following:

1. Bilirubin* level-over 6 mg/100 ml 6

hours after birth; over 10 mg/100 ml 12

hours after birth; over 20 mg/100 ml at any

time; an hourly increase of more than 0.25

mg/100 ml, reaching a total of 17/100 ml.

2. Rh incompatibility

(

if present

)-posi-tive Coomb’s test; anti Rh

(

D

)

antibody

titer over 1:64 in the maternal serum.

A questionnaire was sent to the parents of each infant who had an exchange

trans-fusion and survived to be discharged

(

154).

The questionnaire requested that the child’s

status be reported and that the child be

brought to the hospital for examination.

This examination included a routine

physi-cal, ABO and Rh typing, hemoglobin

deter-mination, special neurological and

orthope-die evaluation, and the Enjoji-Yanai

analyt-ical development test.6 (This test nieasures

six categories of development : locomotor,

manual activity, language, emotional

sta-tus, intelligence, and social behavior.)

RESU LTS

There were 153 questionnaires completed. Seventeen (10.8%) had died and 9 (5.7%)

children were not examined (Table I). One

hundred thirty-one

(

83.4%

)

of the original

0 The term bilirubin refers to the total serum

bilirubin concentration, expressed in mg/100 ml.

To insure accuracy and reproducibility of results, Dade’s “moni-trol” I and II (normal and abnormal controls) were used.

Method of bilirubin determination: Mallov and Evelyn; Ducci and Watson per “Manual of Clinical

Methods” for the Coleman Junior

Spectrophotom-eter. The 19 mm cuvette was used and reading

made at 550 mu.

Standard Curve-as calibrated for the Coleman

J unior Spectrophotometer by the Coleman

(2)

TABLE I

FOLLOW-UP STUDY OF 157 CASE.S OF

HYPERBILIRUBINEMIA

DECEMBER 1957 TO DECEMBER 1963

B/OOd

Incompatibility

(‘anses

Rh (D)

0 A (Mature) 0 A (Premature)

0 B (Mature)

0 B (Premature) A AR

B AR AR B A E

Subtotal

Number

17

37 5 34 3

3

3

2 a

109 “C

10.8

23.6 3.2 21.6

1.9

1.3

1.9 1.9 1.3

1.3

0.6 69.4

Total 157 100.0

157 children were brought to the hospital for examination. Including the 17 infants

who died

(

10.8%), there was a follow-up of

148 children (94.2%).

Causes of Hyperbilirubinemia

Blood typing of the mother and infant

demonstrated maternal-infant

incompatibil-ity in 109 instances (69.4%). As might be

expected in Japan, where only about 0.5%

of the Japanese are Rh negative,’ this

factor is relatively infrequently associated

with severe jaundice. Three of the 17 Rh

negative patients in our series were

non-J

apanese. One very rare case was due to

gene deletion; the mother had no C or E

subgroup factor.8 No incompatibility or

other cause of hyperbilirubinemia could be

demonstrated in 48

(

30.6%

)

of our patients

(

Table II

)

. In this “compatible” group there

was a much larger percentage of

prema-ture infants (birth weight under 2,500 gm),

1 1 (23%), than in the incompatible group

where only 8

(

7.3%

)

were premature.

There was a mortality rate of 17.3% (15)

of 87 infants brought into our hospital as

compared to a 2.8%

(

2

)

mortality rate of

the 70 infants born in our hospital. There

were no deaths during any of the exchange

transfusions.

Total Cases 157 #{182}:;

Number examined 131 (83.42)

Number of deaths 17 (10.8) ‘

Not examined 9 S .7

129 who could be tested fell below a score

of 90 (Table IV). This means that 11.6% of

the infants who received an exchange

trans-fusion had a score which would place them

in the lower developmental group.

According to the Educational Ministry,0

4.25% of the normal pre-school population

of Japan would be in the lower mental

abil-ity group.

Relation of Height of Bilirubin Level

and Developmental Retardation

There were nine

(

23.1%) children in the

compatible group who were in the lower

developmental score group

(

Table V

)

and

six

(

10.9%) in the incompatible group who

TABLE II

Cerebral Palsy

CAUSES OF HYPERBILIRUBINEMIA

Among the 131 children who received

cx-change transfusions and were examined, 93

(

71.0%) were normal to all tests and 17

(

13.0%

)

had cerebral palsy

(

Table III).

In 11 of the 17 the disease was definitely

due to kernicterus. In the other six,

who were in the lower bilirubin

(

less

than 20 mg/100 ml) level group, the disease

was probably due to kernicterus but there

was also the possibility of a birth injury.

There were 21 children with retarded

func-tional development and/or poor

communi-eating ability

(

16.0%).

Results of Developmental Testing

Two patients could not cooperate for the

analytic development testing, but 15 of the

Compatibility

Mature infant Premature infant

37

I 1

23.6

7.0

(3)

RESULTS OF DEVELOPMENTAL TESTING (ENJOJI TEST6)

19 OF 131 CHILDREN WERE CHECXED*

20 mg/lOt) 1111

and above

Compatible

20 mg/lOt) ml

5 3 4

8 a

* Two patients could not cooperate for this test. TABLE III

DIAGNosIs OF CEREBRAL PALSY

Diagnosis Number

Total in study

Number of children examined

Cerebral palsy (C.P.)

c_P. due to kernicterus

c_P. with pathological reflexes

Spastic monoplegia with birth injury

Mild quadriplegia

157 131 17

8 3 Q 4

130% 8 4’7

Retardation

Physical-functional retardation and

retardation of communication Physical-functional retardation

Retardation of communication

Q1

9 6 6

16-0%

Normal 93 710%

were in the lower developmental score

group. All of the infants with

developmen-tal retardation had a serum bilirubin level

of 20 mg/100 ml or more at the time of the

exchange.

Relation of Serum Bilirubin Levels

to Brain Damage

Nine of 10 infants (90%) who had a serum bilirubin level of 35 mg/100 ml or

more were either retarded or had cerebral

palsy. The term brain damage in Table VI

includes cerebral palsy, questionable

cere-bral palsy, and retardation. Twelve of 16

(75%) who had a serum bilirubin level of

between 30 and 34.9 mg/100 ml had

cere-bral palsy or brain damage. Among the 29

infants with a serum bilirubin level of less than 20 mg/100 ml at the time of exchange

transfusion, 2

(

7%

)

showed some mental

retardation and none had cerebral palsy. It

should be noted, however, that 17 (28.0%) of the 61 infants even in the 20 to 24.9

mg/100 ml level showed definite brain

damage.

Relation of Cause of Hyperbilirubinemia

to Brain Damage

Thirty

(

21%) in the incompatible group

and 20

(

14%) in the compatible group had

evidence of brain damage

(

Table VII ). In

the incompatible group there were 70

(

49%) normal infants regardless of the

height of the bilirubin; in the compatible

group there were only 23 (16%

)

in the nor-mal group.

COMMENT

Follow-up of patients who have had

cx-change transfusion has been carried out in

the West. However, the total number has

been relatively small, the duration of

fol-low-up was somewhat short, or only

spe-TABLE IV

Biliru&in

Level

Blood

Factor

A

o

BnlIiant

B

130

Very Good

C

110 Good

D

90 Average

E

70 Retarded

F

50 Dull

G

Very Dull

Rh 3 2 1

AB() 11 11 18 9 3 2 1

3 9 13

Rh 2 5 4

AIR) 2 3

(4)

TABLE V

RELATION OF IIEIGIIT OF BILIHUBIN LEVEL

AND DEVELOPMENTAL BETARDATION

TABLE VI

RELATION OF SERUM BILIRUBIN LEVELS TO BRAIN DAMAGE

cial groups were followed, i.e.,

prema-51

Until about 10 years ago it was thought

in Japan that erythroblastosis fetalis and its

severe complication, kernicterus, did not

occur. Although children died from

kernic-terus and cerebral palsy was known, little

work had been done to find the cause. This

is one reason a large number of our cases

were “brought in from the outside.” It does

give an opportunity, regrettable though it

is, to study very severe hyperbilirubinemia,

even with far advanced kernicterus.

Although there is clear recognition that

exchange transfusion done in time on

pa-tients with hyperbilirubinemia can be life

saving as ‘elI as prevent the complication

of kernicterus,12 there is as yet no

agree-ment on the level of total bilirubin at which

it should be done. Allen and Diamond1’

recommend a level of 20 mg/100 ml in the

incompatible type. Crosse’4 and Meyer1’

recommend that a level of 18 mg/l00 ml

should not be exceeded in premature

in-fants. Jablonski’ recommended a level of 25

mg/100 ml for full term and large

prema-tore infants. Koch, in his second follow-up

study,’ showed that no infant with a

biliru-bin level of less than 20 mg/100 ml

de-veloped major neurological abnormalities.

Up to the present time we have followed

the rule of 20 mg/100 ml in our hospital,

re-gardless of the cause of the

hyperbilirubine-mia. The usual maternity patient remains in

our hospital

7

days, and, as has been

re-ported by Cerrard,17 most cases of

hyperbili-rubinemia are evident by the fifth day of life.

Therefore, we feel confident that we have

been able to pick up practically all cases of

hyperbilirubinemia which have occurred

here.

Preisler and his co-workers” checked 109

children and found that 5 (11.1%) of 45

who had a bilirubin level of over 20 mgI

100 ml showed developmental retardation.

There were 3 (4.7%

)

of 64 patients with a

bilirubin level less than 20 mg/100 ml who

had developmental retardation. In our

se-ries of 129 patients there were 29 who had

bilirubin levels below 20 mg/100 ml and

incompatible

.

(ompat-Pat,ent.s --- .

Rh .1110 ihle

Total

Number with bilirubin level of

0 mg/tOO ml and above 6 35 39 100 Number with developmental

retardation 0 6 9

Percent with developmental

retardation 0’;7 lO.S), eI.1%

Number with bilirubin level of

be1ow0mg/100ml 11 15 1 tO

Number with developmental

retardation 0 0 0

Percent with developmental

retardation 0% ()e 0e;3

there were no instances of developmental

retardation. However, there were 15

(

15%)

patients of the 100 with a bilirubin level of

20 mg/100 ml and above, who had

develop-mental retardation.

It is difficult to compare these results

cx-actly. Preisler and his coworkersh1 were

able to follow-up only 109 of 181 cases;

they found 35 ABO and 74 Rh incompati-bilities. In our study we found 19 Rh and

70 ABO incompatibilities and 40

compati-ble cases. However, even with these

differences, the results do not appear to be

too different.

There were no deaths during any of our

exchange transfusions and only three

deaths within the first 24 hours after

cx-change transfusion. This figure reflects a

-,erum Bilirubin mg/100 ml Brain Damage Num- ,. icrNormal., Num- ,,, bee ‘#{176}

Totals of Serie,

,

Num-ber -19.1) 0-4.9 5-9_9 30-34.9 35-. 17 10 12 9 7 8 37 75 90 27 44 17 4 1 93 7 63 5 10 Q9 61 7 16 10 0.3 42.9 18.9 11. 7.0

Total 50 33 93 65 113

(5)

TABLE VII

RELATION OF CAUSES OF HYPERBILIRUBINEMIA TO BISAIN DAMAGE

Serum

Bthrutnn

mg,’lOOml

Incompatible Otoup Compatible Group .Vormal

Num-ta % Retarded , 4’sum-bee #{176}#{176} Total Num-bee #{176} C.P. Nam-be #{176} R4arded Vum-ter #{176}

Total Incompatible Compatible

. ‘ .

.\un.

.\um-ber ber bee

-19.9 0-t4.9 5-9.9 30-34.9 0 6 S 5 0 9.9 3.7 31t 3 3 7 5.0 11.0 1.4 9 4 7 7 14.9 14.7 43.6 0 4 3 0 3Z 14.9 19 0 6 0 9.9 7.4 H.4 0 8 6 5 0 7 13.1 9 t.3 9 31.4 4 93 0 47.3 15 33.3 8 5.0 0 0 4.5 9.7 0 Total

-;:

i!

-i:-

--

-;:-:

-- -

i:-less severe disease in Japan, which is

possi-bly a result of the low incidence of Rh

neg-ative individuals.

One of the difficulties in comparing our

results with others is that there is no

world-wide standard to use in measuring

intelli-gence, physical development, description of

“good” or “bad” prognosis prior to exchange

transfusion, etc. We hope that those with

more experience than we have would

de-velop a standard form that could be used

all over the world in the follow-up of

chil-dren who have had exchange transfusion.

SUMMARY

A follow-up study of 157 consecutive

pa-tients who had hyperbilirubinemia was

un-dertaken by questionnaire. Parents of 153

patients answered the questionnaire.

Corn-plete examination was carried out on 131

(83.4%) patients and, if the 17 who died are

included, a 94.2% follow-up was made.

The relationship between the level of the

serum bilirubin and the development of

cc-rebral palsy showed that 90% of the

pa-tients who had a bilirubin level of 35

mg/100 ml and above either died or had

cerebral palsy or physical retardation. Of

the 131 cases followed up, there were 17

(

13.0%) patients who had definite cerebral

palsy, 21

(

16.0%) who were physically

re-tarded, and 93 (71.0%) who were normal.

In 129 infants checked for developmental retardation, no instances were found when

the serum bilirubin level was below 20

mg/100 ml. There was developmental

re-tardation in 15 patients who had a bilirubin

level of 20 mg/100 ml and above. It is felt

that this shows there is a definite relation

between the height of the bilirubin and the

development of cerebral palsy and/or de-velopmental retardation. In this series there

were 26 infants with bilirubin levels of 30

mg/100 ml and over. Based on our results,

we would suggest that the indication for

exchange transfusion should be a total

bi-lirubin level of 20 mg/100 ml for full-term,

incompatible infants and for all premature

infants; the level for full-term, compatible

infants should be 25 mg/100 ml.

REFERENCES

1. Wallerstein, H. : Treatment of severe erythro-blastosis by simultaneous removal and

re-placement of blood of newborn infant.

Sci-ence, 103:583, 1946.

2. Mollison, P. L., and Cutbush, \l. : Hemolvtic

disease of newborn. In D. Gairdner, ed. :

Re-cent Advances in Pediatrics. New York: Blakiston, p. 112, 1954.

3. Killander, A., Muller-Eberhard, U., and Sjolin,

S.: Indications for exchange transfusion in newborn infants with hyperbilirubinemia

not related to Rh immunization. Acta

Paediat., Uppsala, 49:377, 1960.

4. Shiller, J. G., and Silverman, W. A. : Uncom-plicated hyperbilirubinaemia of prematurity:

Lack of association with neurologic deficit

at 3 years of age. Amer. J. Dis. Child., 101:

587, 1961.

5. Jablonski, W. J.: Risk associated with

cx-change transfusion. New Eng. J. Med., 266:

155, 1962.

(6)

development in infancy and childhood. (In

English.) Paediat. Jap., 4: May 1961. 7. Murakami, S., Stizuki, K., Matsuhashi, N., Ose,

T., Tsuruhara, T., Araki, M., and Ueno, N.: Rh bloodtvping. (In Japanese.) Tokyo: Mcd-ical-Dental-Pharmacological Co., Ltd.,

No-vember, p. 42, 1958.

8. Ose, T., Murakami, S., Suzuki, K., Matsuhashi,

N., Tsuruhara, T., Araki M., and Ueno, N.: Exchange transfusion in newborn infant. (In

Japanese.) J. Clin. Sci., 1:1105, 1965.

9. Special Education in Japan. Official

Informa-tion Material of Ministry’ of Education No.

18, March 1961.

10. Hugh-Jones, K., Slack, J., Simpson, K., Gross-man, A., and Hsia, D. Y. Y. : Clinical course

of hyperbilirubinemia in premature infants. New Eng. J. Med., 263:1223, 1960. 11. Preisler, 0., Gronau, M., and Horstmann, W.:

Hemolytic disease of the newborn and later development of the children. Deutsch. Med.

\Vschr., 88:1823, 1963.

12. Allen, F. H., Jr., Diamond, K. K., and Vaughn,

V. C., III: Erythroblastosis fetalis. VI.

Pre-vention of kernicterus. Amer. J. Dis. Child., 80:779, 1950.

13. Allen, F. H., Jr., and Diamond, L. K. : Eryth-roblastosis Fetalis. Boston: Little, Brown and Company, p. 56, 1957.

14. Crosse, V. M., Meyer, T. C., and Gerrard,

J. W. : Kernicterus and prematurity. Arch. Dis. Child., 30:501, 1955.

15. Meyer, T. C. : Study of serum bilirubin levels in relation to kernicterus and prematurity. Arch. Dis. Child., 31:75, 1956.

16. Koch, C. A.: Hyperbilirubinemia in premature infants. A follow up study II. J. Pediat., 65:

1, 1964.

17. Gerrard, J.: Kernicterus. Brain, 75:526, 1952.

Acknowledgment

The authors wish to express their thanks to the

members of the Social Service Department, to the laboratory staff of the Yodogawa Christian

Hospi-tal for their invaluable assistance, to Dr. Frank A.

Brown, Jr., for his helpful review of the material

(7)

1967;40;196

Pediatrics

Toru Ose, Tsuneo Tsuruhara, Masayoshi Araki, Toshiyuki Hanaoka and Ovid B. Bush, Jr.

HYPERBILIRUBINEMIA IN INFANTS IN JAPAN

FOLLOW-UP STUDY OF EXCHANGE TRANSFUSION FOR

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1967;40;196

Pediatrics

Toru Ose, Tsuneo Tsuruhara, Masayoshi Araki, Toshiyuki Hanaoka and Ovid B. Bush, Jr.

HYPERBILIRUBINEMIA IN INFANTS IN JAPAN

FOLLOW-UP STUDY OF EXCHANGE TRANSFUSION FOR

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