Rh sensitization in a primipara caused by intramuscular injection of human serum resulting in fatal erythroblastosis

Rh SENSITIZATION INJECTION J. THORNTON (From Island

IN A PRIMIPARA CAUSED BY INTRAMUSCULAR OF HUMAN SERUM RESULTING IN ‘FATAL ERYTHROBLASTOSIS

WALLACE, M.D., F.A.C.S., ALEXANFER WIENER, M.D., AND MARGARET H. DOYLE, M.D., BROOKLYN, N. Y.

the Depaartment of Obstetrics and College of Ye&tine and the Ofice

F.A.C.P.,

Gynecology of the Brooklyn Hospital and the Long the Chief Medical Ezambner of Nezcr Pork City.)

of

or even intramuscular injections of T IS now generally recognized that transfusions, Rh-positive blood are far more potent in sensitizing Rh-negative individuals than is pregI nancy with Rh-positive fetuses. Thus, while only one of about 25 Rh-negative women bearing Rh-positive babies becomes sensitized to the Rh factor, fully one-half of such individuals This difference is readily explained by can be sensitized by injections of Rh-positive blood.1 the difference in quantity of antigen injected. On the other hand, it has been generally believed up to now that such sensitization could not result from the injection of serum or plasma, which is presumably free of red cells. The purpose of this report is to present possibly that such sensitization can occur after intramuscular erythroblastosis even in a firstborn infant.

the first injection

case which of serum,

demonstrates cawing fatal

Case Report Mrs. B. G., aged 24 years, was first seen by oue of us (J.T.W.) on Jan. 30, 1947, in the fifth week of her pregnancy. Routine antenatal Rh test revealed that she was Rh Careful inquiry elicted no history of her having had negative, her husband Rh positive. either transfusions or injections of whole blood during infancy, childhood, or adult life. However, in discussing the matter with her father, who is a physician, he recalled that she had once had an intramuscular injection of pooled adult serum as a prophylactic measure against poliomyelitis. This had been given in October, 1931, when she was 8 years of age. The serum had been collected, prepared, and given by our own seroIogist as folIows: Twenty cubic centimeters of whole blood were drawn from each of six adult donors. * they were then centrifuged Each specimen was ‘ ( Wassermannized” individually to obtain the serums which were pooled. The pobled serum was diluted with normal saline to make a solution of 40 per cent serum. Ten cubic centimeters of this solution were injected intramuscularly into each buttock. Though it has been thought in the production of Rh antibodies in Rh-negative to a more complete study which showed the m00a

Prospective Prospective

0f

father mother

Group

past that individuals, following: M-N

Type &

*The M-N ty es are not important clinically, but ness. For a detal .f ed description of the Rh-Hr types Wiener.‘. 8 1163

serum alone she was

would not nevertheless Rh-Hr

Phenotype Rh,rh rh

cause the submitted

Tbpe* Genotype I&, RW or r”BQ Tr

are included for the sake of completeand their heredity see publications of

WALLACE,

1164 These husband Rh RS determined

results confirmed the original positive. Moreover, the husband by tests with anti-Hr” serum.*

These already serum.

tests

were

possible She was

in Table I. counter-immunization,

first

made

to demonstrate accordingly

Despite

TABLE --.-

the the I.

in

studied

of

of rose

OF Rh

that prembly

the

week

of

mother is heterozygous

ANTIBODY

Eh

pregnancy.

Rh antibodies during her

typhoid as shown

Am. J. Obst. % Gynec. December, 1948

DOYLE

and in

At

in the pregnancy

pertussis Table I.

TITRATION

negative for the that

time

her factor

it

prospective with results

vaccine

DURING

and Rh

was

mother’s recorded

for

purposes

of

PREGNANCY

.-_

-

l?;E

weeks weeks weeks weeks

Otherwise responded tilrie

her pregnancy better than

even the

obstetrician

pregnancy tl!r titer might. Clinically,

at of well

was

once the Rh

in the antibodies

be the the fetus

usual

pregnancy 2, long

labor

below,

cesarean

within

sulely in might fulther

so

transfusion data. because

minutes far at

affected infant. any further. a Group transfusion. At marked rrT)cirted, A.

A birth

the

a 5 of

the

showc,d

interests danmge

of

perfoirnr~l living ounces.

the

have

the

cesarean

apparent

urgent

problem

an of

anemia week.

which this

At

terminating

extreme probability

the

increase that

iu this

male

father that

was these

with

been

be

long,

Hr”

‘s postpartum

it was laboratory imlitatetl

stillborn

tightly

closed.

had

positive best

to

induction

was

from

without

immediately was begun course

the

noted

The and the

adverse

further

after on

delivery the babr

uneventful.

planned to proceed with exsanguination determinations or any other clinical that we were dealing with a severely pregnancy

therefore,

were

do

and

anesthesia

vigorously transfusion

500

except

hemoglobin red bloo,d

been

c.e.

wit.11 HI v.c. uf citrate was removed and replaced

babies

firm,

so spinal

crir11

mot,her

operation,

cord. Crm.)

very

conditions

fract-ional

which Exsanguination

The

to

pelvic inlet, and on the right an orbital ridge a brow presentation. Since termination of the and since even the time consumed in the baby7

baby?

abnormalities umbilical cent (6.4

cervix

uail~r

was concerned, waiting fur serologic: tests

moul
icterus of the was only 44 pt’r *The prospective E. Mourant. !‘We have found

with

except for thirty-second

the

the baby because of a sudden nmternnl strum, and the serious

the

tltc

type rh donor ant1 mixed Two-fifths of the plasma no

normally until

patient might ever hare of bearing a live baby. t,han would ordinarily be expected at this period of already be suffering from fetal hydrops. that it might utero aml from the size of the bones, it was felt that it The vertex appeared to be somewhat an hydropic one.

(lelivrry.

as the infant once without the antenat.al who Before

entirely therapy,

clown in the it essentially

was

baby wan 5 pounds,

fifteen In

i$

progressed to iron

suspicion fetus in

section

The weighed

CONGLUTINATION (IN ALBUMIN1 - PLASMA) 4 11 12 16 1,400

CONGLUTINATION ( (IN PLASMA)

only chance this appeared larger

part was well be felt, making

wss

0~

60

of

rather than exxminatiun

presenting eye could

METHOD

14 tir)

presented

was a ertcnded. The and

BY THE

BLOCKING (IN SALINE L MEDIA)

I )

interests in

the one

fetus Vaginal

(UNITS)

suddenly

gestation, arousing X-rag shobTed only large

TITER

AGGLUTINATION MEDIA) I( IN SALINE 0 0 I) 0 0

;ze;WT

17 .‘I’>. . 27 31

Dr.

seventh

presence at intervals

administration antibody titer

RESULTS

AND

report was

the

the

ANTIBODY

delay. and

WIENER,

of

blood

solution

in

mit,h

saline

for

xs

determined

with

if

fresh

rather

blood

pallor

concentration, cell count 1.21 serum than

allowed

to

were

proceed

drawn

from

preparation

for

the

solution.+ of

the

baby

as million

subsequently

kindly

provided

per

and

cu. mm. b>

bank blood is uSed for the exchange transfusion. Since the prospective mother belonged to Group A and the fwaBt~e&t$~ZrouP 0, we knew that a Group A donor wpuld be compatible even before the baby After experience with this and other similar cases we now use a~ much as l+g C.C. instead of 500 C.C. for replaCement transfusion in such severely affected infants.6 has proved more effective than the replacement of part of the donor’s plasma with saline.

Volume 56 Number 6

RH

SENSITIZATION

IN

1165

A PRIMIPARA

The baby was given oxygen. His tone and cry were good. As already mentioned, within fifteen minutes of delivery an exchange transfusion was started. During a t.wo-hour’ period 380 C.C. of blood were injected into the left saphenous vein at the ankle, while 345 C.C. of blood were withdrawn from the right radial artery. The infant withstood the procedure well and seemed in good condition at its termination. He was then transferred to the nursery where he received nen-born care and was placed in the incubator with continuous oxygen. The baby did not appear to be jaundiced. The liver and spleen were not palpable, and the hemoglobin concentration was now 80 per cent (11.6 grams). Three and one-half hours after transfusion, definite jaundice was noted. The liver The and spleen were palpable two and one-half fingerbreadths below the costal margin. baby continued to be lively and had a good cry. The hemoglobin concentration had risen to 85 per cent (12.3 Gm.) by the time the baby was eight hours old. Physical examination was essentially as noted above except that the respirations were somewhat shallow and rapid. Because of the appearance of rapidly increasing jaundice which, in similar cases, we had previously found to indicate impending nuclear jaundice, an attempt was made to prevent intravascular conglutination of the remaining 15 per cent of the infant’s blood cells, which had not been removed by the exchange transfusion, by instituting a continuous infusion of 15 C.C. of normal saline per hour. In addition 10 C.C. of blood were given each hour for five hours. This was effected through a ‘ L cutdown” in the right ankle vein.

A.

Fig.

l.-(a)

Section

B.

of lung showing small blood vessel of liver showing multiple islands

The baby voided in eighteen hours hfter

a scanty amount of whieh all feedings

Physical examination twenty-four with ‘a reddish tinge. The hemoglobin There was some edema of pams).

deep were

plugged with erythrocytes. of hematopoiesis.

yellow urine. refused.

He

retained

(B)

three

Section

feedings

hours after birth showed the jaudice to be deeper concentration at that time was 100 per cent (14.5 the thighs. The heart and lungs were normal. The

WALLACE,

WIENER,

AND

Am. J. Obst. & Gynec. December, 1948

DOYLE

spleen was smaller and the liver was not felt. The baby was apparently doing well, The intermittent periods when about one hour later he began having respiratory difficulties. of apnea and cyanosis were treated with carbogen, coramine, and art,ificial respiration. A small amount of blood was noted coming from the right nostril. Four hours later the infusion WaB discontinued, after a total volume of 180 C.C. of saline had been administered. The baby ‘B extremities and eyelids were edematous at this time. Shortly after this (one-half hour) the infant was pronounced dead. Subsequent tests confirmed the prediction that the baby was Rh positive (his complete As a matter of fact, the blood cells classification was Group A, Type M, Type Rh,). failed to clump in anti-Rho serum, but this was due to complete coating of the infant’s cells by the maternal Rh-blocking antibodies as proved by the anti-globulin technique of Coombs and associatess In addition, the cord serum contained free univalent Rh The icterus index antibodies of a titer of 400 units by the albumin-plasma technique.7 of the cord serum was 50 units by the acetone method, and the last sample obtained from the radial artery at the exchange transfusion had an ieterus index of 38 units and Rhantibody titer of 180 units. The fact that the icterus index and antibody titer did not decrease by 87 per cent in proportion to the replacement of red cells, can be explained, as pointed out in previous papers,9 by diffusion of bile and antibodies from the tissues inte the circulation during the transfusion. In view of these extreme serologic findings, a fatal outcome was to be expected in spite of the exchange transfusion.8 The most significant gross postmortem findings were the large size of the placenta ( 760 Gm. or about one-third the weight of the infant), edema of the skin, generalized passive congestion, hepatosplenomegaly and edema of the brain with nuclear jaundice. The significant microscopic findings were disorganization of the liver cords with numerous large islands of hematopoiesis and plugging of the smaller blood vessels in the lungs by masses of red cells together with some erythroblasts. the

Subsequently blood following results: Rlood Paternal l’aternal

was

obtained

from

the

parents

of

father

Rh-Hv.

Of

grandfather grandmother

the

0 0

M MN

Phenotype Rh;;hc

and

classified

with

Type Genotype R’R2 f r’R* or R’r” rr

These findings proved that the father of the patient, previously found to belong to type Rh2rh, is, Cth certainty, heterozygous. Repeat Rh-antibody titrations on the maternal serum two months post partum still showed a titer of about 1,000 units. Regarding Future pregnancies, therefore, the following prediction can be made. There is an equal chance of future infants being either Rh positive or Rh negative. If Rh negative, naturally the infant will not be erythroblastotic; if Rh positive in view of the high maternal Rhantibody titer it will be severely affected and so early in pregnancy that a stillbirth will bc inevitable. Experience in similar cases indicates that, it is unlikely that the Rh-antibody titer in this mother’s serum will drop low enough during her childbearing period to enable her to have a viable Rh-positive fetus Thus in fut,ure pregnancies we would be dealing with an all-or-none proposition with the outcome depending entirely on the Rh type of the fetus,

Summary

and Conclusions

aL ,:ase is repurted in which a young primigrarida is presumed to have been sensitized to the Rh factor by an in,jeetion of pooled humxu serum, given as a prophylactic measure against poliomyelitis during childhood, ant1 in n-hose baby fatal erythroblastosis developed. Accordingly, we should like to emphasize to clinicians that the injection of serum or plasma int,o Rh-negative women may create Rh sensitization. The hazard of such injections is at times as great as that accompanying the injection of Rh-positive whole blood, and may deprive even primiparas of the opportunity of having normal babies. Therefore, it is urgently recommended that in taking obstetric histories careful inquiry he made into whether or not

Volume Number

56 6

RH

SENSITIZATION

IN

A PRIMIPARA

1167

It is likewise recommended that all such injections have been received by the patient. physicians exercise utmost care and discretion in the u8e of these substances, Since the preparation of this report, our attention has been called by personal inquiry from a California physician, to a second ease of erythroblastosis in a firstborn baby whose mother may have been sensitised by injection of pooled serum as a prophylactic measure against poliomyelitis.

References 1. Wiener, 2. Wiener, 3. Wiener, 4. 5. 6, 7. 8. 9.

A. S., and Sonn-Gordon, E. B.: Am. J. Clin. Path. 17: 67-69, 1947. A. S.: Am. J. Clin. Path. 16: 477-497, 1946. A 8.: Dock and Snappers’ Advance8 111 Internal Medicine II, pp. 439-480, Interscience Press, N. Y., 1947. Wiener, A. S., and Wexler, I. B.: Anesthesiology 18: 141, 1948. Wiener, A. S., Wexler, I. B., and Shulman, A.: Am. J. Clin. Path. in press. Coombs, R. R. A., Mourant, A. E., and Race, R. R.: Brit. J. Exper. Path. 26: 255, 1945. Wiener, A. S., and Hurst, J. G.: Exp. Mea. & Surg. 5: 284-298, 1947. Wiener, A. S., and Gordon, E. B.: J. Lab, & Clin. Med. 33: 181, 1948. Wiener, A. S., Wexler, I. B., and Grundfast, T. H,: Bull. New York Acad. Med. 23: 207. 220,1947. SO HANSON

PLACE