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Evaluation of the Coombs test in congenitalhemolytic disease of the newborn infant
E V A L U A T I O N ()1~' T H E COOMBS T E S T IN C ( ) N G E N I T A I ~ H E M O L Y T I C I ) I S E A S E OF T t I E N E W B O R N I N F A N T ISADORE R()THSTE[N,
L~'[.I)., A N D C H A R L E S
T. FRIED, ~.I).
N~,~,w YORK, N. Y. N 1945 Coombs, Mourant, and Race ~ describcd a new method for the detection hh antibodies by the use of a sermn p r e p a r e d f r o m rabbits immunized with h u m a n serum or its globulin fraction. This serum is used to denmnstrate the presence of a f o r m of l{h antibody which a p p a r e n t l y is adsorbed on the surface of erythroeytes. Wtten the test is positive, visible ehtmping of the affected red blood eells occurs, aud this reaction has been referred to as the Coombs test or developing test. ~ The test is of considerable practical value in congenital hemolytic disease of the newborn infant, or erythroblastosis fetalis, in wlhich condition it has been used to detect a type of m a t e r n a l Rh antibody and to examine the erythrocytes of the newborn infant for adsorbed antibodies. The test is not specific :for Rh antibodies as it is also positive in eases of acquired hemolytic anemia not due to Rh sensitization, a The purpose of this p a p e r is to indicate the value of the Coombs (developing) test in the diagnosis and management oi congenitM hemolytic disease of the newborn infant,
I ot
,
)
Since 1948 several h u n d r e d Coombs tests have been p e r f o r m e d in the labo r a t o r y of this hospital on the Mood of newborn infants in order to rule out congenital hemolytic disease of the newborn infant. The usual indications for the performance of the test were (1) early onset of jaundice in a newborn infant, (2) infants born of Rh negative mothers in whom there m a y or m a y not have been a previous examination for Rh antibodies and (3) eases of congenital hemolytic disease and related conditions requiring differential diagnosis. T w e n t y cases have been selected f r o m this latter group as illustrative of the value of the Coombs test as an aid in the diagnosis and m a n a g e m e n t of congenital hemolytic disease. (See Table I.)
Case if, Death of Er'ythroblastotic Infant Prior to Use of Exchange Trans]%sions.--This gh-posit~ve i n f a n t was born jaundi:eed of an g b - n e g a t i v e mother, The Rh antibody status of the mother was not known at the time of deIivery but was later found to be positive for blocking antibodies in a titer of 1:16. The jaundice was progressive and marked. A t no time was there a n y appreciable anemia or erythroblastemia. Therefore, simple transfusions were withheld. On the fourth day of life the jaundice was deeper and convulsions occurred. B]ood was sent elsewhere for a Coombs test which was reported as 4 plus a few hours before death. The necropsy showed kernicterus. This ease exemplifies l~rom t h e D e p a r t m e n t of P a t h o l o g y a.nd t h e D e p a r t m e n t of P e d i a t r i c s , The Bronx Hosp i t a l , :New Y o r k , :N. Y. A c k n o w l e d g m e n t is g r a . t e f u l l y m a d e to Dr. J o s e p h F e l s e n , D i r e c t o r of L a b o r a t o r i e s a n d R e s e a r c h , f o r s u g g e s t i o n s m a d e in t h e p r e p a r a n o n of t h i s p a p e r , a n d to l ) r . P h i l i p L e v i n e a n d Dr. P e t e r V o g e l f o r s o m e of t h e l a b o r a t o r y d a t a i n c l u d e d h e r e i n .
456
ROTHSTEIN AND FRIED: COOMBS TEST, CONGENITAL HEMOLYTIC DISEASE 437 the importance of performing tile Coombs test immediately upon ttle birth of every jaundiced infant. Cases 2, 3, 4, 5, 6, an,d 7, Exchange Transfusion Group.---These infants all showed 3 to 4 plus Coombs reactions and were given exchange transfusions within a few hours of the time of birth. One infant died forty-eight hours later, from either cardiac failure or kernicterus. Permission for necropsy was not granted. All of the remaining infants were well six months to one year later with no sequelae. However, a much longer follow-up period is advisable for adequate appraisal of results from the standpoint of possible mental or neurological disturbances. The mothers showed marked variability in their Rh sensitization. The mother in Case 7 showed no agglutinating or blocking antibodies but 2 plus " c r y p t a g g l u t i n o i d s " 3 were found in her blood with the aid of Coombs serum. The presence of strongly sensitized red blood cells in any newborn infant as demonstl'ated by a 3 to 4 plus Coombs test performed at birth was eonsidered an immediate indication for an exchange transfusion regardless of the presence or absence of clinical symptoms. Exchange transfusions were done as soon after birth as arrangements could be made, usually within the first few hours. I n three of the cases a Coombs test was done on the day following the transfusion and showed a reversal to negative in each instance, indicating fairly complete removal of sensitized red blood cells. Two infants required additional small simple transfusions to overcome the anemia due to con-. tinued hemolysis of the remaining sensitized erythrocytes which replacement transfusion failed to remove.
Cases 8, 9, 10, 1l, and 12, Group in Which Exchange Transj'usion Was Not Performed.--Cases 8, 9, and J0 were similar in that jaundice was noted within twenty-four hours of birth and the Coombs test was negative. The impression was early icterus neonatorum rather than mild hemolytic disease. Case 11 deve]oped slight jaundice at 24 hours but no anemia or erythroblastemia. Because of the 2 plus Coombs test, it was felt that this child could be followed expectantly. The infant recovered without specific treatment. Case 12 showed slight jaundice at 6 to 12 hours but no anemia or erythroblastemia. Inasmuch as the jaundice (lid not increase, exchange transfusion was not done although the child h a d a 3 plus Coombs test. Only one simple transfusion was needed to overcome a mild anemia which appeared later. Cases 13, 14, 15, 16, and 17, Group With O-A-B lncompatibility.--A negative Coombs test was obtained in all of these infants. Treatment was conserwJtire and recovery was the rule. Case 17 required no transfusions, whereas Case 15 was given more t h a n one simple transfusion with group-specific A and B substances added. F o u r of the cases occurred in primigravida. Cases 18, 19, and 20, Miscdlaneous.--In the first two cases the Coombs test was of value in the differential diagnosis. Case 18 was an infant born jaundiced about the face, groin, and umbilical cord. Moderate anemia was present. The probable etiology was hemorrhage from premature separation of the placenta. Erythroblastosis was considered unlikely when the Coombs test was reported negative and there was no group or Rh incompatibility. Case 19 ~ showed ictevus neonatorum on the f o u r t h day and a routine blood count revealed 21 pet' ee~t
i])~ iii
ii
ii
iii
ii
ii
vi
iii
ii
ii
xo. 1
2
3
4
5
6
7
8
9
10
i
[
i
i
ii
iv
i
ii
ii
i
i
O
--
--
A
A
A
O
AB
]PAPA ] TYPE ii AB
C~AV-I
]
neg.
pos.
neg.
neg.
neg.
neg.
neg.
neg.
aH neg.
~{OTtIER
neg.
eryptagglutinins 2 plus
1-1,000
1-64
14
1-8
1-256
A~TI-R~ 1-16
JAUN-
-
-
-
-
-
-
I
--
--
3 plus in 18 hours 1 plus in 10 hours 1 plus in 24 hours
3 plus at, birth 2 plus in 12 hours i plus in 3 hours
1 plus
3 plus in 5 hours 3 plus in 12 hours
AN~I-B DICE -at birth
o~
ANTI-A
130
122
132
88
84-
124 100 82
60
NOR-
4.8
6.15
5.5
3.94
3.9
P
56,000
53~000 13,500
44J00
750
1,600
21,000
38,000
2,500
3,500
11,000 13,600
12~500
24,000
--
A
A
0
O
A
O
A
neg.
pos.
pos.
pos.
pos.
pos.
pos.
pos.
transfusion
Exchange
neg.
neg.
None
None
4 plus E x c h a n g e transfusion and 1 transfusmn 3 plus E x c h a n g e transfusion 3plus Exchange transfusion 3 plus E x c h a n g e transfusion 3 plus E x c h a n g e transfusion and 2 transfusions neg. None
4 plus
WBC 3/~BL } T Y P E ! R H C00MBS [ TI~EATNfENT 18,000 1/100 B pos. 4 plus None WBC
I
5.25 3.6 2 1 , 5 0 0 7,000 3.75 41,000 10,000
3.44
2.26
5.0
130
60
RBC
KGB
T A B L E I*
REI~fARKS
Recovered without treatment Recovered without treatment Recovered without treatment
Recovered
Recovered
l~eeovered
Recovered
Recovered
Died on f o u r t h day with kernieterus Died in 48 hours
OO
ii
i
i
i
i
iii
i
iii
ii
12
13
14
15
16
17
18
19
20
i
ii
0
i
0
0
0
0
i
ii
O
O
O
O
O
0
O
O
O
O
pos.
pos.
pos.
neg.
pos.
pos.
CDf
neg.
neg.
neg.
--
neg,
neg.
--
--
Anti-A 1-512
Anti-A 1-6r Anti-A 1-320 knti-A 1-512
--
--
Anti-J3 1-1024 --
--
neg.
--
--
neg.
1~8
1-8
none
day
Fourth
1 p l u s in 3 hours 2 plus at birth
4 plus in 6 hours
3 plusin 12 h o u r s 1 plus in 6 hours 1 plus in 4 hours
1 plus in 24 hours 1 plusin 6~12 hours
118
lg0
80
104
80
140
108
124
220
118
5.1
6.5
3.9
4.2
3.5
6.6
3.9
4.0
5.0
5.2
3,500
1 000
1,500
5~000
4/100 WBC
WBC
3/100
3,500
16,800 none
11~500
32,000
23,000 12,000
25~400
17;600
36,000 11,000
23,000
19~500
13,500
*A f e w o m i s s i o n s of p e r t i n e n t d a t a w e r e d u e to c i r c u m s t a n c e s b e y o n d o u r c o n t r o l . -~Normbl : n o r m o b l a s t s . C D : l~h s u b t y p e . A & B s u b s t , z A a n d B g r o u D specific s u b s t a n c e s .
iii
11
O
O
O
I~
A
A
A
A
O
--
pos.
pos.
pos.
pos.
pos.
pos.
CDf
pos.
pos.
pos.
neg.
neg.
neg.
neg.
neg.
neg.
neg.
neg.
3 plus
2 plus
None
None
None
None
1 transfusion i transfusion 2 transfusions w. A & B subst, f 1 transfusion w. A & B subst.t
I transfusion
None
action tIemolytie anemia pregnancy ; :Baby not affected
centa 21% m y e l o b l a s t s . Leucemoid re-
Recovered without treatment Anemia due to premature separ a t i o n of pla-
Recovered with one transfusion
Recovered with one transfusion t~ecovered with one transfusion Igeeovered with two transfusions
Recovered without treatment Recovered with one transfusion
O
9
" c~ o o
m z >
9
440
T!IE ,IOURNAL OF 1?E1)IATRICS
mye[oblasts. M a n y ad(:litiomll Moo(I counts all demonstrated at leueocyiosis with about the same n u m b e r oli primitive cells. B y the third month, tire i n f a n t ' s blood picture returned to normal and the episode was thought to be a leueemoid reaction. Hemolytic disease was excluded by a negative Coombs test on the infant, a negative Rh antibody titer in the mother, and no incompatibility of blood types. Case 20 is that of a normal infant delivered of a mother who had an acquired chronic hemolytic anemia of pregnancy. The m o t h e r ' s blood showed no Rh antibodies and no circulating hemolysins by the technique of Dameshek and Schwartz, ~ but her washed erythrocytes showed 3 plus clumping with Coombs serum. Tire newborn i n f a n t was normal in every respect and the Coombs test was negative. The hemolytic disease in the mother disappeared soon a f t e r delivery. The positive Coombs test in the mother indicated that a hemolytic antibody of some kind existed in her blood. A p p a r e n t l y it had not been t r a n s m i t t e d to the infant. DISCUSSION
Tim p r i m a r y ob,jeetive for the effective m a n a g e m e n t of congenital hemolytic disease of the newborn infant is to rid tire involved i n f a n t of immunologically altered erythrocytes a n d circulating foreign antibody as soon as possible a f t e r birth. Immediate replacement or' exchange transfusion serves these purposes. W h e t h e r exchange transfusion has a n y effect on antibody which is already fixed in tissue cells is still debatable. However, f u r t h e r tissue damage is minimized by early removal of foreign circulating antibody. The problem in the past has, therefore, been the p r o p e r selection of cases of congenital heinolytie disease for exchange transfusion. The height of the m o t h e r ' s Rh antibody titer is not always correlated with the severity of the disease in the infant. This is shown by out' series of eases. However, m a n y infants are born with no evidence, either clinical or hematologie, of erythroblastosis, and develop signs of the disease r a p i d l y after several hours or even days. I n our limited experienee, which is in agreement with that of others, '~ the Coombs test is best correlated with the degree of the disease process in the Rh-sensitized infant. I t has fulfilled the requirement for a rapid, simple, and reliable test which ean be employed at birth on cord or i n f a n t ' s blood :for tire diagnosis of congenital hemolytic disease and for eonsideration of p r o p e r therapy. Until mnre is known about the prevention of residua of erythroblastosis, it seems advisable to use exchange transfusions in borderline as well as in manifest eases. Some infants with strongly positive Coombs tests have recovered without such transfusions, as i n Case 12, but the wisdom of this procedure cannot be estimated until there has been a long period of follow-up for sequelae. The results of the Coombs test in erythroblastotie infants with O-A-B incompatibility bears emphasis. The test was negative in all of our eases, which is the opposite of what one finds in Rh sensitization. This fact has helped differentiate eases of suspected sensitization to both O-A-B and Rh factors. None of our eases of ieterus neonatorum gave a positive Coombs test. Even when there was a fall in hemoglobin to below 100 per cent in the newborn in-
I~.OTt-[STE[N ANI) FRIED:
(JOOMBS TFST~ CON(}ENITAI~ HESIOLYTIC DISFASE
44[
rant this was regarded as an exaggeration of the normal neonatal processes of blood destruction and not hemolytic disease due to Rh incompatibility, provided that O-A-B incompatibility could be excluded. CONCLUSIONS
1. In a series of twenty selected eases, the Coombs (developing) test has proved to be of great value in the diagnosis and management of congenital hemolytic disease of tile newborn infant: 2. The results of the test appear to be more closely correlated with the severity of the disease in cases of Rh sensitization than any other finding. 3. The test is very helpful in the proper selection of cases for exchange transfusion. REFERENCES I. Coombs, R. R. A., Mourant, A. E., and Race, R . R . : A New Test for the Detection of W e a k and " I n c o m p l e t e " Rh Agglutlnlns, Brit. J. Exper. Path. 24: 255, 1945. 2. Hill, J. M., Ha.berman, S., and Jones, F.: Hemolytic Rh Immune Globulins: Evidence for a Possible Third Order of Antibodies I n c a p a b l e of A g g l u t i n a t i o n or Blocking, in ttill, J. ~v[., and b a m e s h e k , William: The Rh F a c t o r in the Clinic and the L a b o r a t o r y , New York, 1948, Grune and Stratton~ p. 80. 3. Boorman, K. E., Dodd, B. E., and Loutit, J . F . : l-Ielno]ytic Icterus (Acholuric Jaundice) Congenital and Acquired, Lancet I 250: 812, 1946. 4. Ill p r e p a r a t i o n . 5. Dameshek, W., and Schwartz, S. O.: The Presence of Hemolysins in Acute Hemolytic Anemia, New England J. Ned. 218: 75, ]938. 6. Sturgeon~ P.: Immuno-hematologic Observations on E r y t h r o b l a s t o t i c I n f a n t s , Pediatrics 3: 318, 1949.
L~'[.I)., A N D C H A R L E S
T. FRIED, ~.I).
N~,~,w YORK, N. Y. N 1945 Coombs, Mourant, and Race ~ describcd a new method for the detection hh antibodies by the use of a sermn p r e p a r e d f r o m rabbits immunized with h u m a n serum or its globulin fraction. This serum is used to denmnstrate the presence of a f o r m of l{h antibody which a p p a r e n t l y is adsorbed on the surface of erythroeytes. Wtten the test is positive, visible ehtmping of the affected red blood eells occurs, aud this reaction has been referred to as the Coombs test or developing test. ~ The test is of considerable practical value in congenital hemolytic disease of the newborn infant, or erythroblastosis fetalis, in wlhich condition it has been used to detect a type of m a t e r n a l Rh antibody and to examine the erythrocytes of the newborn infant for adsorbed antibodies. The test is not specific :for Rh antibodies as it is also positive in eases of acquired hemolytic anemia not due to Rh sensitization, a The purpose of this p a p e r is to indicate the value of the Coombs (developing) test in the diagnosis and management oi congenitM hemolytic disease of the newborn infant,
I ot
,
)
Since 1948 several h u n d r e d Coombs tests have been p e r f o r m e d in the labo r a t o r y of this hospital on the Mood of newborn infants in order to rule out congenital hemolytic disease of the newborn infant. The usual indications for the performance of the test were (1) early onset of jaundice in a newborn infant, (2) infants born of Rh negative mothers in whom there m a y or m a y not have been a previous examination for Rh antibodies and (3) eases of congenital hemolytic disease and related conditions requiring differential diagnosis. T w e n t y cases have been selected f r o m this latter group as illustrative of the value of the Coombs test as an aid in the diagnosis and m a n a g e m e n t of congenital hemolytic disease. (See Table I.)
Case if, Death of Er'ythroblastotic Infant Prior to Use of Exchange Trans]%sions.--This gh-posit~ve i n f a n t was born jaundi:eed of an g b - n e g a t i v e mother, The Rh antibody status of the mother was not known at the time of deIivery but was later found to be positive for blocking antibodies in a titer of 1:16. The jaundice was progressive and marked. A t no time was there a n y appreciable anemia or erythroblastemia. Therefore, simple transfusions were withheld. On the fourth day of life the jaundice was deeper and convulsions occurred. B]ood was sent elsewhere for a Coombs test which was reported as 4 plus a few hours before death. The necropsy showed kernicterus. This ease exemplifies l~rom t h e D e p a r t m e n t of P a t h o l o g y a.nd t h e D e p a r t m e n t of P e d i a t r i c s , The Bronx Hosp i t a l , :New Y o r k , :N. Y. A c k n o w l e d g m e n t is g r a . t e f u l l y m a d e to Dr. J o s e p h F e l s e n , D i r e c t o r of L a b o r a t o r i e s a n d R e s e a r c h , f o r s u g g e s t i o n s m a d e in t h e p r e p a r a n o n of t h i s p a p e r , a n d to l ) r . P h i l i p L e v i n e a n d Dr. P e t e r V o g e l f o r s o m e of t h e l a b o r a t o r y d a t a i n c l u d e d h e r e i n .
456
ROTHSTEIN AND FRIED: COOMBS TEST, CONGENITAL HEMOLYTIC DISEASE 437 the importance of performing tile Coombs test immediately upon ttle birth of every jaundiced infant. Cases 2, 3, 4, 5, 6, an,d 7, Exchange Transfusion Group.---These infants all showed 3 to 4 plus Coombs reactions and were given exchange transfusions within a few hours of the time of birth. One infant died forty-eight hours later, from either cardiac failure or kernicterus. Permission for necropsy was not granted. All of the remaining infants were well six months to one year later with no sequelae. However, a much longer follow-up period is advisable for adequate appraisal of results from the standpoint of possible mental or neurological disturbances. The mothers showed marked variability in their Rh sensitization. The mother in Case 7 showed no agglutinating or blocking antibodies but 2 plus " c r y p t a g g l u t i n o i d s " 3 were found in her blood with the aid of Coombs serum. The presence of strongly sensitized red blood cells in any newborn infant as demonstl'ated by a 3 to 4 plus Coombs test performed at birth was eonsidered an immediate indication for an exchange transfusion regardless of the presence or absence of clinical symptoms. Exchange transfusions were done as soon after birth as arrangements could be made, usually within the first few hours. I n three of the cases a Coombs test was done on the day following the transfusion and showed a reversal to negative in each instance, indicating fairly complete removal of sensitized red blood cells. Two infants required additional small simple transfusions to overcome the anemia due to con-. tinued hemolysis of the remaining sensitized erythrocytes which replacement transfusion failed to remove.
Cases 8, 9, 10, 1l, and 12, Group in Which Exchange Transj'usion Was Not Performed.--Cases 8, 9, and J0 were similar in that jaundice was noted within twenty-four hours of birth and the Coombs test was negative. The impression was early icterus neonatorum rather than mild hemolytic disease. Case 11 deve]oped slight jaundice at 24 hours but no anemia or erythroblastemia. Because of the 2 plus Coombs test, it was felt that this child could be followed expectantly. The infant recovered without specific treatment. Case 12 showed slight jaundice at 6 to 12 hours but no anemia or erythroblastemia. Inasmuch as the jaundice (lid not increase, exchange transfusion was not done although the child h a d a 3 plus Coombs test. Only one simple transfusion was needed to overcome a mild anemia which appeared later. Cases 13, 14, 15, 16, and 17, Group With O-A-B lncompatibility.--A negative Coombs test was obtained in all of these infants. Treatment was conserwJtire and recovery was the rule. Case 17 required no transfusions, whereas Case 15 was given more t h a n one simple transfusion with group-specific A and B substances added. F o u r of the cases occurred in primigravida. Cases 18, 19, and 20, Miscdlaneous.--In the first two cases the Coombs test was of value in the differential diagnosis. Case 18 was an infant born jaundiced about the face, groin, and umbilical cord. Moderate anemia was present. The probable etiology was hemorrhage from premature separation of the placenta. Erythroblastosis was considered unlikely when the Coombs test was reported negative and there was no group or Rh incompatibility. Case 19 ~ showed ictevus neonatorum on the f o u r t h day and a routine blood count revealed 21 pet' ee~t
i])~ iii
ii
ii
iii
ii
ii
vi
iii
ii
ii
xo. 1
2
3
4
5
6
7
8
9
10
i
[
i
i
ii
iv
i
ii
ii
i
i
O
--
--
A
A
A
O
AB
]PAPA ] TYPE ii AB
C~AV-I
]
neg.
pos.
neg.
neg.
neg.
neg.
neg.
neg.
aH neg.
~{OTtIER
neg.
eryptagglutinins 2 plus
1-1,000
1-64
14
1-8
1-256
A~TI-R~ 1-16
JAUN-
-
-
-
-
-
-
I
--
--
3 plus in 18 hours 1 plus in 10 hours 1 plus in 24 hours
3 plus at, birth 2 plus in 12 hours i plus in 3 hours
1 plus
3 plus in 5 hours 3 plus in 12 hours
AN~I-B DICE -at birth
o~
ANTI-A
130
122
132
88
84-
124 100 82
60
NOR-
4.8
6.15
5.5
3.94
3.9
P
56,000
53~000 13,500
44J00
750
1,600
21,000
38,000
2,500
3,500
11,000 13,600
12~500
24,000
--
A
A
0
O
A
O
A
neg.
pos.
pos.
pos.
pos.
pos.
pos.
pos.
transfusion
Exchange
neg.
neg.
None
None
4 plus E x c h a n g e transfusion and 1 transfusmn 3 plus E x c h a n g e transfusion 3plus Exchange transfusion 3 plus E x c h a n g e transfusion 3 plus E x c h a n g e transfusion and 2 transfusions neg. None
4 plus
WBC 3/~BL } T Y P E ! R H C00MBS [ TI~EATNfENT 18,000 1/100 B pos. 4 plus None WBC
I
5.25 3.6 2 1 , 5 0 0 7,000 3.75 41,000 10,000
3.44
2.26
5.0
130
60
RBC
KGB
T A B L E I*
REI~fARKS
Recovered without treatment Recovered without treatment Recovered without treatment
Recovered
Recovered
l~eeovered
Recovered
Recovered
Died on f o u r t h day with kernieterus Died in 48 hours
OO
ii
i
i
i
i
iii
i
iii
ii
12
13
14
15
16
17
18
19
20
i
ii
0
i
0
0
0
0
i
ii
O
O
O
O
O
0
O
O
O
O
pos.
pos.
pos.
neg.
pos.
pos.
CDf
neg.
neg.
neg.
--
neg,
neg.
--
--
Anti-A 1-512
Anti-A 1-6r Anti-A 1-320 knti-A 1-512
--
--
Anti-J3 1-1024 --
--
neg.
--
--
neg.
1~8
1-8
none
day
Fourth
1 p l u s in 3 hours 2 plus at birth
4 plus in 6 hours
3 plusin 12 h o u r s 1 plus in 6 hours 1 plus in 4 hours
1 plus in 24 hours 1 plusin 6~12 hours
118
lg0
80
104
80
140
108
124
220
118
5.1
6.5
3.9
4.2
3.5
6.6
3.9
4.0
5.0
5.2
3,500
1 000
1,500
5~000
4/100 WBC
WBC
3/100
3,500
16,800 none
11~500
32,000
23,000 12,000
25~400
17;600
36,000 11,000
23,000
19~500
13,500
*A f e w o m i s s i o n s of p e r t i n e n t d a t a w e r e d u e to c i r c u m s t a n c e s b e y o n d o u r c o n t r o l . -~Normbl : n o r m o b l a s t s . C D : l~h s u b t y p e . A & B s u b s t , z A a n d B g r o u D specific s u b s t a n c e s .
iii
11
O
O
O
I~
A
A
A
A
O
--
pos.
pos.
pos.
pos.
pos.
pos.
CDf
pos.
pos.
pos.
neg.
neg.
neg.
neg.
neg.
neg.
neg.
neg.
3 plus
2 plus
None
None
None
None
1 transfusion i transfusion 2 transfusions w. A & B subst, f 1 transfusion w. A & B subst.t
I transfusion
None
action tIemolytie anemia pregnancy ; :Baby not affected
centa 21% m y e l o b l a s t s . Leucemoid re-
Recovered without treatment Anemia due to premature separ a t i o n of pla-
Recovered with one transfusion
Recovered with one transfusion t~ecovered with one transfusion Igeeovered with two transfusions
Recovered without treatment Recovered with one transfusion
O
9
" c~ o o
m z >
9
440
T!IE ,IOURNAL OF 1?E1)IATRICS
mye[oblasts. M a n y ad(:litiomll Moo(I counts all demonstrated at leueocyiosis with about the same n u m b e r oli primitive cells. B y the third month, tire i n f a n t ' s blood picture returned to normal and the episode was thought to be a leueemoid reaction. Hemolytic disease was excluded by a negative Coombs test on the infant, a negative Rh antibody titer in the mother, and no incompatibility of blood types. Case 20 is that of a normal infant delivered of a mother who had an acquired chronic hemolytic anemia of pregnancy. The m o t h e r ' s blood showed no Rh antibodies and no circulating hemolysins by the technique of Dameshek and Schwartz, ~ but her washed erythrocytes showed 3 plus clumping with Coombs serum. Tire newborn i n f a n t was normal in every respect and the Coombs test was negative. The hemolytic disease in the mother disappeared soon a f t e r delivery. The positive Coombs test in the mother indicated that a hemolytic antibody of some kind existed in her blood. A p p a r e n t l y it had not been t r a n s m i t t e d to the infant. DISCUSSION
Tim p r i m a r y ob,jeetive for the effective m a n a g e m e n t of congenital hemolytic disease of the newborn infant is to rid tire involved i n f a n t of immunologically altered erythrocytes a n d circulating foreign antibody as soon as possible a f t e r birth. Immediate replacement or' exchange transfusion serves these purposes. W h e t h e r exchange transfusion has a n y effect on antibody which is already fixed in tissue cells is still debatable. However, f u r t h e r tissue damage is minimized by early removal of foreign circulating antibody. The problem in the past has, therefore, been the p r o p e r selection of cases of congenital heinolytie disease for exchange transfusion. The height of the m o t h e r ' s Rh antibody titer is not always correlated with the severity of the disease in the infant. This is shown by out' series of eases. However, m a n y infants are born with no evidence, either clinical or hematologie, of erythroblastosis, and develop signs of the disease r a p i d l y after several hours or even days. I n our limited experienee, which is in agreement with that of others, '~ the Coombs test is best correlated with the degree of the disease process in the Rh-sensitized infant. I t has fulfilled the requirement for a rapid, simple, and reliable test which ean be employed at birth on cord or i n f a n t ' s blood :for tire diagnosis of congenital hemolytic disease and for eonsideration of p r o p e r therapy. Until mnre is known about the prevention of residua of erythroblastosis, it seems advisable to use exchange transfusions in borderline as well as in manifest eases. Some infants with strongly positive Coombs tests have recovered without such transfusions, as i n Case 12, but the wisdom of this procedure cannot be estimated until there has been a long period of follow-up for sequelae. The results of the Coombs test in erythroblastotie infants with O-A-B incompatibility bears emphasis. The test was negative in all of our eases, which is the opposite of what one finds in Rh sensitization. This fact has helped differentiate eases of suspected sensitization to both O-A-B and Rh factors. None of our eases of ieterus neonatorum gave a positive Coombs test. Even when there was a fall in hemoglobin to below 100 per cent in the newborn in-
I~.OTt-[STE[N ANI) FRIED:
(JOOMBS TFST~ CON(}ENITAI~ HESIOLYTIC DISFASE
44[
rant this was regarded as an exaggeration of the normal neonatal processes of blood destruction and not hemolytic disease due to Rh incompatibility, provided that O-A-B incompatibility could be excluded. CONCLUSIONS
1. In a series of twenty selected eases, the Coombs (developing) test has proved to be of great value in the diagnosis and management of congenital hemolytic disease of tile newborn infant: 2. The results of the test appear to be more closely correlated with the severity of the disease in cases of Rh sensitization than any other finding. 3. The test is very helpful in the proper selection of cases for exchange transfusion. REFERENCES I. Coombs, R. R. A., Mourant, A. E., and Race, R . R . : A New Test for the Detection of W e a k and " I n c o m p l e t e " Rh Agglutlnlns, Brit. J. Exper. Path. 24: 255, 1945. 2. Hill, J. M., Ha.berman, S., and Jones, F.: Hemolytic Rh Immune Globulins: Evidence for a Possible Third Order of Antibodies I n c a p a b l e of A g g l u t i n a t i o n or Blocking, in ttill, J. ~v[., and b a m e s h e k , William: The Rh F a c t o r in the Clinic and the L a b o r a t o r y , New York, 1948, Grune and Stratton~ p. 80. 3. Boorman, K. E., Dodd, B. E., and Loutit, J . F . : l-Ielno]ytic Icterus (Acholuric Jaundice) Congenital and Acquired, Lancet I 250: 812, 1946. 4. Ill p r e p a r a t i o n . 5. Dameshek, W., and Schwartz, S. O.: The Presence of Hemolysins in Acute Hemolytic Anemia, New England J. Ned. 218: 75, ]938. 6. Sturgeon~ P.: Immuno-hematologic Observations on E r y t h r o b l a s t o t i c I n f a n t s , Pediatrics 3: 318, 1949.