HYPOGLYCEMIA AND RH ERYTHROBLASTOSIS FETALIS

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(Received June 27; revision accepted for publication December 27, 1966.) ADDRESS: 1800 SW. 152nd Street, Seattle 66, Washington.

HYPOGLYCEMIA

AND

RH

ERYTHROBLASTOSIS

FETALIS

Frederick

G. Hazeltine,

M.D.

Department

of

Pediatrics, University of Washington, School of Medicine, Seattle, Washington

T

HE following report concerns two

in-fants with severe erythroblastosis due

to

Rh

incompatibility

who

also

had

severe

neonatal

hypoglycemia.

The

first

baby

(E.I.)

was born at Burien General Hospital,

Seattle, Washington, where he expired at

26 hours

of

age.

The

second

baby

(C.S.)

was

born

at

Riverton

General

Hospital,

Seattle, Washington, and was subsequently

transferred

to

the

Children’s

Orthopedic

Hospital,

Seattle,

Washington,

for

evalua-tion

and

treatment.

CASE I, E.l.

The patient’s mother was 32 years old, white, para IV, gravida V, blood type A, Rh-negative. She entered the hospital in active labor 1 week from her expected date of confinement. The

preg-nancy was uncomplicated by any illness, except

for evidence of Rh isoimmunization. Antibodies to anti-D in the second month of pregnancy were

1:128 dilution, at 7 months 1:256, and at term

1:4000. There had been a weight gain of only 5.9 kg

(13 lb) with this pregnancy, and there were no signs

of toxemia.

The 9-hour labor was complicated by a large

amount of bleeding, 10 minutes prior to delivery,

because of an abruptio placentae. The fetal heart

tones remained normal, however, and the baby

was delivered vaginally with the umbilical cord

wrapped twice around the neck and one true knot

in the cord. Although the infant was given an

immediate Apgar rating of 8, he became apneic, was resuscitated, and was given 5 ml of 73i%

sodium bicarbonate into the umbilical vein.

Examination at 1 hour of age revealed a flaccid,

2,410 gm (5 lb,

5 oz)

male

infant with gasping

respirations, 40 per minute, and no cry or spon-taneous movements. The skin was pale and there

was scattered purpura over the face and torso. The

lungs were clear to percussion and auscultation

and there was good air exchange. The heart rate

was 80 per minute with normal sinus rhythm; no

heart murmurs were heard. The liver was palpable 5 cm below the right costal margin. The spleen

descended 2 cm below the left costal margin.

Initial Laboratory Work

The infant was type A, Rh-positive; Coombs

test was

4+;

hematocrit was 32%; hemoglobin

was 11 gm/100 ml; white count was 32,400/umt’

when corrected for nucleated red blood cells. The

differential was 7 polymorphonuclear leukocytes,

2 stab cells, 80 lymphocytes, 2 monocytes, and 4

eosinophiles, and 159 nucleated red cells per 100

white cells. Pre-exchange bilirubin was 4.2 mgI

100 ml with 0.4 mg/100 ml direct.

An exchange transfusion with type 0,

Rh-nega-tive ACD donor blood was begun at 23i hours of

age. The venous pressure at the onset of the

ex-change was 10 cm H20. The baby sustained a spell of apnea and cardiac arrest in the first 20

minutes of the exchange transfusion. Artificial respiration and external cardiac massage were

given and the heart beat was restored. It was

be-lieved that no more than 2 minutes elapsed in

which there was no spontaneous heart beat. He

was given another 5 ml of 7i% sodium bicarbonate

intravenously and the trachea was intubated

for

better ventilation.

The exchange transfusion was resumed 30

mm-utes later, and the baby’s condition began to

improve. A total of 615 ml of whole blood was

removed from the baby, and a total of 595 ml of

donor blood was infused. Following each 100 ml

of whole blood infused, 1 ml of 10% calcium

gin-conate was given intravenously. The venous

pres-sure, measured frequently, never exceeded 11 cm

H20. At the end of this exchange transfusion he

was alert, crying, moving about, and sucking on

his fist.

Two hours later, at approximately 6 hours of

age, the baby had an apneic spell which responded

to artificial respiration. The pulse was then 160

with slapping heart tones and a systolic gallop was

heard. The liver was now only 2 cm below the

costal margin. The muscle tone was fair,

but

the

baby continued to have a dusky pallor.

Except for irritability, this infant’s condition

remained fairly good until 20 hours of age when

he had a generalized seizure. This was followed by

several more apneic spells and seizures of short

duration which terminated spontaneously. After

resuscitation from a cardiac arrest at 23 hours, a

second exchange transfusion, with packed cells,

was performed.

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TABLE I

LABORATORY DATA OF E.I.

ARTICLES

697

Blood drawn at 22 hours was then reported

(3 hours later) as having less than 5 mg sugar

1100 ml and calcium 3.6 mEq/l; therefore, the

baby

was

given an additional 1 ml of 10% calcium gluconate and 4 ml of 50% glucose in distilled water intravenously. In spite of this an(l continua-tion of intravenous 10 glucose in water, apneic

spells and seizures contnued until death at 26

hours of age. Autopsy revealed marked

extra-medullary hematopoiesis, cardiac dilatation and

hypertrophy, hyperplastic and hvpertrophic islets

of Langerhans, and hepatic glvcogen depletion. Other organs, including the brain, were not

markable.

Comment

This

infant

was

in

obvious

distress

from

birth. His initial cardiac arrest may have

been

precipitated

by

acidosis

from

unbuffered

citrated

ACD

blood

used

for

his

exchange

transfusion.12

Although

he had

cy-anosis,

irritability,

and

apnea,

hypogly-cemia

was

not

suspected

until

his

first

seiz-tire

at

20 hours

of

age.

Hypocalcemia,

also

not

diagnosed

until

20 hours

of

age,

has

been

found

to

occur

in

other

infants

with

neonatal hypoglycemia.3

CASE 2, C.S.

The patient’s mother was 28 years old, white,

para

II, gravida V. She entered the hospital 6 days from her expected date of confinement. This preg-nancy was uneventful with 5.9 kg (13 Ib) weight

gain

and

no

sign of toxemia or diabetes. The baby,

born after a normal, 5-hour labor, cried and

breathed spontaneously, and weighed 3,770 gm

(8 Ib, 5 oz).

Physical examination showed a pale, inactive,

female infant

with

perioral

cyanosis

and

edema

of

the eyelids. The pulse was 100, flush blood

pres-sure was 60 mm/Hg systolic, and a grade 11/6

systolic murmur was heard at the left sternal

border. Respiration was 60 per minute with no retractions, although moist rales were heard in

both lungs. The liver was palpable 7 cm below

the right costal margin. Muscle tone was poor.

Initial Laboratory Data

The mother was Rh-negative with anti-D anti-bodies in her serum. The baby was type

0,

Rh-positive, and the Coombs

test

was strongly

posi-tive. Initial blood count was: hemoglobin 7.Z

gm/

100 ml; hematocrit 31%, white count 212,000/

mm’ uncorrected and 26,500/mm’ corrected for

nucleated

red

cells.

The white cell differential was

.lge in Hours 1 4 6 10 2.1

Ilemoglobingm,’tOOmI ii FL 11.5 8.

Ilematocrit % 32 36.3 30.5 8

Biliruhin tot,1 mg/

100 ml 4.2 2.6

Biliruhin direct mg’

lOOmI 0.8 0.4

Sodium mEqi’l 153 135

Potassium mEq’l 4.7 5.1

Bicarbonate mE1/1 13.5 17

Calcium mEq/I 3.6

Phosphorus mEq/l II .5

Blood urea nitrogen

mg/lOOml 21

BlOOd sugar mg/100 ml 5

37 polymorphonuclear leucocytes, 7 stab

cells,

41

lymphocytes, 2 monocytes, 4 eosinophiles, 2

bas-ophiles, 4 myelocytes, and 750 nucleated

red

cells!

100 white cells. The bilirubin on admission was

12.4 mg/100 ml total, with a direct bilirubin of

4.2 mg/100 ml. The blood sugar drawn upon

ad-mission was reported, “No blood sugar.” (The

author’s

impression

at the

time

was

that

the

de-termination had not been done; this report

ac-tually flleant the blood sugar was undetectable.)

A chest x-ray showed a wide heart shadow but no

lung abnormalities. An electrocardiogram was

normal.

At 9 hours of age, when the baby was being prepared for an exchange transfusion, her rectal temperature dropped to 36.5#{176}C,and she had a temporary spell of apnea. The blood sugar drawn at this time was also zero. Two hundred twenty

milliliters of the baby’s blood were replaced with

185 ml of sedimented packed cells, type 0, Rh-negative, and 1 ml of 10% calcium gluconate was

given twice. Opening venous pressure was 15 cm

H,O. Closing venous pressure was 8 cm H20.

Clinical improvement occurred with the exchange

transfusion until the baby became active, crying

and hungry. Following the exchange, she was

given 2 ml of 50% glucose intravenously,

con-tinued as 10l glucose 75 mI/kg/day. Oral

feed-ings were given, and Solu-cortef 10 mg

intra-muscularly every 6 hours was started.

At 36 hours of age, the baby was irritable and

“jittery,” and a possible seizure was noted. The

blood

sugar

drawn

at

40 hours of age was 19 mg/ 100 ml. A second exchange transfusion, with 680 ml of whole blood, was done for hyperbiirubi-nemia; following this the infant manifested no hypoglycemia. The hydrocortisone was discon-tinued at 1 week. At 1 year of

age,

this

baby

is

apparently normal neurologically with no signs of

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9 11 /6 .14 iC 4()

13.4

9. 14.0 ‘27

.5.’2 8.0

0 (1 30 99 80 19

698

Age in hours

Hemoglobin gm /100 ml

Ilematoerit

Bihirubin total nig/100 ml

Bihiruhin direct mg’lOO ml

Blood sugar mg ./100 ml

7.’2

31

1L4

0

TABLE II

LABORATORY DATA OF CS.

Comment

C.S.,

with

three

consecutive

blood

sugars

of

zero,

was

hypogiycemic

until

8 hours

of

age.

Her

clinical

condition

improved

markedly

after

a

packed

cell

exchange

transfusion

and

treatment

with

hydrocor-tisone

and

glucose.

Since the mother had none of the

compli-cations

frequently

associated

with

neonatal

hypoglycemia, such as diabetes or toxemia,

and

the

infant’s

birth

weigilt was normal

for

gestation,

it seems

probable

that

her

hy-poglycemia

as

indeed

part

of

her

syn-drome

of

erythroblastosis.

COMMENT

According

to

Coi-nblath,34

the

clinical

manifestations of neonatal symptomatic

hy-poglycemia

are

tremors

(“jitteriness”),

cy-anosis, convulsions, apnea, apathy, a

cry

which

is

weak

or

high-pitched,

limpness,

refusal

to

feed,

and

eye-rolling.

Under-grown

infants

are

prone

to

hypoglycemia

because

they

have

inadequate

glycogen

stores.

Infants

of

diabetic

mothers

are

prone to hypoglycemia because they have a

transient

state

of

functional

Ilyperinsulin-ism.35

The hyperplasia of tile islets of

Langerhans,

seen

in

infants

of

diabetic

mothers,

is

also

seen

in

the

pancreases

of

infants

with

Rh-erythroblastosis.#{176}’T

Dris-coIl and Steinke,8 found that,

when

com-pared

to

controls,

tile

pancreases

of

Rh-erythroblastotic

infants

had

a

significantly

elevated

insulin

content,

and

the

same

was

true

of infants

of diabetic

mothers.

In a newborn

infant

with

a sensitive

insu-lin

release

mecilanism,

it is possible

that

hy-poglycemia

may

be

induced

by

exchange

transfusion.

ACD

blood

has

1.54 gm

of

glu-cose added to each 500 ml unit. Thus,

dur-ing

the

exchange

transfusion,

hyperglyce-mia

may

occur.

With

abrupt

cessation

of

this glucose load, hypoglycemia may result

unless the infant is supported

with

oral

feedings

or

intravenous

glucose.

Subse-quent to the experience reported here,

re-peated blood sugar determinations have

been

made

ill two

infants

following

cx-change

transfusions

for

severe

Rh-erythro-blastosis,

and

in

both

infants

there

was a

blood

sugar

drop

to

hypoglycemic

levels

(less than 30 mg/100 ml) within 2 hours

after

the

exchange.#{176}’#{176}

On tile basis of this limited experience,

we

feel

that

some

infants

with

severe

Rh-erythroblastosis

behave

like

infants

of

dia-betic

mothers

and

should be so treated. It is

our

recommendation

that

all

infants

with

severe

erythroblastosis

fetalis

should

be

ob-served

and

tested

for

hypoglycemia,

and

that, following excilange transfusions, these

infants

should

receive

intravenous

glucose

until

oral

feedings

can

be

established.

SUMMARY

Severe

Rh-erythroblastosis

fetalis

was

as-sociated

with

hypoglycemia

in

two

new-born

infants;

one

died

at age

26 hours.

Pos-sible etiologic factors include transient

functional

hyperinsulinism

and

rebound

hy-poglycemia following exchange

transfu-sions

of ACD-preserved

blood.

REFERENCES

1. Calladine, NI., Gairdner, D., Naidoo, B. ‘F., and

Orwell, D. F!.: Acid base changes

fol-lowing exchange transfusion with citrated

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ARTICLES

2. Oliver T. K., Jr.: The use of THAM-buffered

ACD blood in high risk infants who require

exchange transfusion.

J.

Pediat., 67:951,

1965.

3. Cornblath, NI., Wybregt, S. ii., Baens, C. S.,

and Klein, R. I.: Symptomatic neonatal

hy-poglycemia: Studies of carbohydrate

metab-olism in the newborn infant VIII.

PEDI-ATRICS, 33:388, 1964.

4. Cornblath, NI., and Schwartz, R.: Disorders

of Carbohydrate Metabolism in Infancy.

Philadelphia: W. B. Saunders Co., pp.

57-104, 1966.

5. Wybryegt, S. H., Reisner, S. H., Patel, R. K.,

Heihaus, G., and Cornblath, M.: The

inci-dence of neonatal hypoglycemia in a

nur-sery for premature infants.

J.

Pediat., 64:

796, 1964.

6. Miller, H. C., and Johnson, B. D.: A

com-parison of newborn infants with

erythro-699

blastosis fetalis with those born to diabetic

mothers.

J.

Pediat., 24:603, 1944.

7. Brahler, H.

J.,

and Dellenbach-Hellweg, C.:

The islands of langerhans in fetal

erythro-blastosis. Virchows Arch. Path. Anat., 336:

544, 1963.

8. Driscoll, S. C., and Steinke,

J.:

Pancreatic

insulin content in severe erythroblastosis

fetalis. PEDIATRICS, 39:448, 1967.

9. Anderson,

J.:

Changes in the blood

concen-tration of glucose, alpha oxoglutamate

pyru-vate, and citrate during exchange

transfu-sion in hemolytic disease of the newborn.

Arch. Dis. Child., 38:481, 1963. 10. Oliver, T. K., Jr.: Personal communication.

Acknowledgment

I wish to thank Dr. Thomas K. Oliver, Jr. for his

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1967;39;696

Pediatrics

Frederick G. Hazeltine

HYPOGLYCEMIA AND RH ERYTHROBLASTOSIS FETALIS

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