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Rh-D hemolytic disease in Negro and white infants
474
The Journal o[ P E D I A T R I C S
Rh-D hemolytic disease in Negro and white infants A comparison
Hemolytic disease o[ the newborn due to Rh-D has had lower morbidity and mortality rates in Negro than in white in~ants delivered at Temple University Hospital [rom 1946 to 1962. Negro and white mothers have shown a similar incidence o[ R h sensitization and equal ability to produce anti-D antibody. Sixty per cent of affected Negro infants and 26.5 per cent of affected white infants did not require treatment. Neonatal mortality was 2 per cent for Negro, 8.5 per cent [or white infants. Fewer Negro mothers have had stillbirths due to hemolytic disease. ABO hemolytic disease has shown equal severity in Negro and white in/ants.
Lyndall Molthan, M.D., M.Se.* PHILADELPHIA~
PA.
I I-I a v ~ noticed, during an 8 year period at Temple University Hospital, that hemolytic disease of the newborn due to Rh-D is clinically quite different in Negro babies that it is in white babies. This hospital is a nonprofit, 1,000 bed general hospital located in North Philadelphia where approximately 25,000 live-born infants have been delivered between Jan. l, 1955, and Oct. 1, 1962. Nearly 60 per cent of live-born infants have been Negro, 40 per cent being white. Temple University Hospital has occasionally been a referral center for mothers with Rh problems, only once a referral center for affected infants born elsewhere. Sensitized From the Temple University Medical Center, Philadelphia, Pa. *Address, Director of the Blood Bank, Temple University Medical Center, Philadelphia, Pa.
mothers delivered at this hospital are usually routine prenatal patients who happen to be sensitized. In general, there are 3 areas where Rh sensitization in Negroes differs from that in whites. First, Negro babies affected by Rh-D hemolytic disease have had Iower morbidity and mortality rates than have white infants so affected. Second, Negro mothers have been less likely to produce stillborn infants due to Rh-D sensitization. Third, the prognosis for infants born to the Negro mother sensitized by transfusion prior to pregnancy is better than the prognosis for those born to white mothers so sensitized. CASE
MATERIAL
The case material varies somewhat depending upon the subject being analyzed.
Volume 62 Number 4
R h - D hemolytic disease
A total of 108 Sensitized white mothers and 81 sensitized Negro mothers are included, as are their 143 white and 117 Negro infants, respectively. Routine R h typing of prenatal patients and of all infants born to Rh-D-negative mothers has been carried out since 1947; the direct Coombs test of cord blood from infants born to R h - D negative mothers has been performed routinely since 1949. Screening of sera for atypical antibodies in all Rh-negative prenatal patients was begun in May, 1958. Positive identification of the atypical antibody as anti-D (or anti-CD) has been established in each sensitized mother through the use of cell panels. As controls, 1,942 Rhnegative, unsensitized mothers were used. Table I shows the incidence of R h - D sensitization in consecutive R h - D - and DLUnegative prenatal patients tested between Jan. 1, 1955, and Oct. 15, 1962. The total includes women pregnant for the first time and those whose husbands are known to be Rh-D negative. Thirteen (13 per cent) of the 98 sensitized white mothers were sensitized by transfusion or intramuscular injection of blood prior to pregnancy. Sixteen (20 per cent) of the Negro mothers were so sensitized. Only 2 of the white mothers sensitized by transfusion had received their Rh-positive transfusion since 1950, 10 of the 16 Negro mothers had received theirs since 1950. RESULTS
Table I I evaluates the clinical status of each Rh-D-sensitized mother's first, second, third, and fourth (on up) affected infants. Only those infants delivered at this hospital and completely supervised by its pediatric staff are included. Two hundred and eighteen Rh-positive-affected babies are evaluated; 3 were born between 1946 and 1949,
4 75
25 between 1950 and 1954, and 190 between 1955 and Oct. 15, 1962. Criteria for managing sensitized mothers and criteria for exchange transfusion of affected infants have undergone some modification since 1950; however, over the years, similar criteria have been applied to each case regardless of race. Definitions. 1. Clinically normal describes the infant with neither clinical jaundice nor a total serum bilirubin above 12 mg.% during the first 5 days of life. The direct Coombs test is positive and the hemoglobin normal or slightly reduced. 2. Mild disease describes the infant with either clinical jaundice or a total serum bilirubin above 12 rag.% during the first 5 days of life but not requiring exchange transfusion by the usual criteria. Infants with progressive anemia requiring simple transfusion at 1 to 4 weeks have been classified as mild cases. 3. Exchanged with recovery refers to infants with clinical and laboratory criteria which establish the need for exchange transfusion. 4. Neonatal death refers to infants who were live born but who died as a result of hemolytic disease with or without treatment. Deaths occurring in premature infants where the prematurity was due to an obstetric complication such as placenta previa are not included. Deaths occurring 1 week or more after successful exchange where the cause of death was an infection, possibly, but never proved to be a result of exchange, have not been included. 5. Stillborn refers to the infant stillborn as a result of Rh-D hemolytic disease. Stillbirths due to other causes occurring in Rh-D-sensitlzed mothers have not been included.
Table I. Incidence of Rh-D sensitization in consecutive Rh-D-negative prenatal patients from Jan. 1, 1955, to Oct. 15, 1962
Race
White Negro
Total Rh-negatire patients
No.
No. sensitized I %
1,000 670
98 80
9.8 11.9
No. sensitized by pregnancy No. I %
85 64
8.5 9.8
4 7 6
April 1963
Molthan
T a b l e II. Clinical status of R h - D - a f f e c t e d infants delivered at T e m p l e U n i v e r s i t y Hospital from 1946 to Oct. 15, 1962 Total infants
Clinically normal
Mild disease
Exchanged with recovery
Neonatal death
Stillborn
White Negro
63 57
t2 31
15 12
31 14
2 0
3 0
First affected infants
White Negro
30 25
1 I0
2 2
21 10
2 0
4 3
Second affected infants
White Negro
14 14
0 4
0 1
10 6
2 1
2 2
Third affected infants
White Negro
10 5
0 1
1 0
4 2
4 1
1 1
Fourth to sixth affected infants
Total white
117
13
18
66
10
10
(Plus 26 Rh neg. infants )
Total Negro
101
46
15
32
2
6
(Plus 16 Rh neg. infants)
Race
T a b l e I I I . I n f a n t s b o r n to mothers after sensitization by intravenous or i n t r a m u s c u l a r blood, delivered at T e m p l e University Hospital from 1946 to Oct. I5, 1962 Rh-positive infants Exchanged, ~ Race
Rh-negative infants
White Negro
10 5
Total
Clinically normal
Mild disease
recovered
8 21
0 8
0 2
4 8
Stillborn death and neonatal % No. I I
4 3
50 14
T a b l e IV. Stillbirths due to R h - D sensitization
Race
Total mothers interviewed
White Negro
108 82
. Mothers with history of stillbirth No. 1 %
19 7
No. of stillbirths
Mothers sensitized by I.V. or I.M. blood
31 14
5 3
18 8.5
T a b l e V. I n f a n t s born subsequent to stillbirth Rh-positive infants Race
Rh-negative infants
Total
Clinically normal
Mild disease
Exchanged, recovered
Stillborn and neonatal death
White Negro
9 0
28 8
0 0
0 0
7 1
21 7
T a b l e I I I shows the outcome of p r e g n a n cies following i n t r a v e n o u s or i n t r a m u s c u l a r R h - D sensitization o f R h - n e g a t i v e mothers. O n l y infants delivered at this hospital have been included. Tables I V a n d V show the incidence of stillbirths due to R h - D sensitization a n d the outcome of pregnancies occurring subse-
q u e n t to stillbirth. While m a t e r n a l histories have been used as the basis for these figures, the fact that R h sensitization was responsible for each stillbirth has been confirmed. T h e prognosis for Rh-positive infants born subseq u e n t to stillbirth has been quite bad for both races. T a b l e V I summarizes the few cases of
Volume 62
Number 4
Rh-D
T a b l e V I . H e m o l y t i c disease of the n e w b o r n due to antigens o t h e r t h a n R h - D a n d the A B O system. I n f a n t s delivered at T e m p l e U n i v e r s i t y H o s p i t a l 1955 to 1962
normal
Cases
Race
White
Rh-g 5 Kell 1
Negro
Rh-E I Rh-E 3 Rh-f 1
Mild dis-
'hanget with
geo-
recouerfl
mortality
eas~
2
natal
2 1
1 3 1
T a b l e V I I A. H e i g h t of m a t e r n a l indirect C o o m b s - a c t i v e a n t i - D titers; m a x i m u m titer p e r m o t h e r d u r i n g p r e g n a n c y 1:4 to 1:32
1:64 to 1:256
1:512 to 1:4096 No. I %
Race
No.
%
No. I %
White Negro
23 18
23 23
50 45
51 58
25 15
4 77
affected infants were in the u n t r e a t e d category, few (7 p e r cent) white second and t h i r d affected infants could do well without exchange transfusions. I n the infants of mothers sensitized by intravenous or intram u s c u l a r blood, 48 p e r cent of the Negro babies, b u t none of the white babies, were in the u n t r e a t e d category. T h e r e was a neon a t a l m o r t a l i t y rate of 8.5 per cent for white infants, 2 per cent for N e g r o infants. N e o n a t a l mortality, at this time, requires f u r t h e r analysis. O n e of the N e g r o infants died as a result of an air embolus inadvertently i n t r o d u c e d at the end of an exchange transfusion. This i n f a n t was n o t severely affected a n d could h a v e been expected to do well with the one exchange. T h e other Negro infant was an u n a n t i c i p a t e d liveborn infant of a m o t h e r w h o h a d delivered 3 consecutive stillborn infants. T h i s b a b y arrived at night on a holiday, a n d died at 2 hours of age w i t h o u t benefit of t r e a t m e n t ; however, he p r o b a b l y w o u l d have died even with p r o m p t t r e a t m e n t since he was r a t h e r severely affected. T e n white infants are listed as n e o n a t a l deaths, 5 delivered between 30 a n d 36 weeks' gestation, 5 between 37 a n d 40 weeks' gestation. Six died within 1 hour of birth, only 1 of these d u r i n g exchange transfusion; 4 h a d an exchange p e r f o r m e d b u t died a t 2 hours, 12 hours, 36 hours, and 48 hours, respectively. All these infants were severely affected. It is possible t h a t 3 infants born at 39 to 40 weeks m i g h t have been salvaged h a d early induction of l a b o r been in vogue locally at the time (1955 a n d 1956). K e r n i e t e r u s with cerebral palsy has not been e n c o u n t e r e d in infants delivered at this hospital since at
Ex-
Clinically
h e m o l y t i c disease
26 18
hemolytic disease due to antigens other t h a n R h - D a n d the A B O system. These cases seem to parallel the R h - D cases in clinical manifestations. DISCUSSION I t is a p p a r e n t f r o m the results in Tables I I a n d I I I that P~h-D h e m o l y t i c disease of the n e w b o r n has lower m o r b i d i t y and mortality rates in the N e g r o infants t h a n in the white infants in this series. Sixty per cent of N e g r o affected infants c o m p a r e d with 26.5 p e r cent of white affected i n f a n t s did not require t r e a t m e n t . A high percentage (44 p e r cent) of N e g r o second a n d t h i r d
T a b l e V I I B. Correlation between m a x i m u m a n t i - D titer a n d outcome of pregnancy Rh-positive infants Maternal titer
Total in{ants
Rh-negative infants
Clinically normal and mild disease
White
1:4 to 1:32 1:64 to 1:256 1:512 to 1:4096
29 61 26
7 8 1
18 9 1
3 34 18
1 10 6
Negro
1:4 to 1:32 1:64 to 1:256 1:512 to 1:4096
25 57 17
6 4 1
17 30 4
2 20 8
0 3 4.
Race
Exchanged with recovery
Stillborn and neonatal death
478
Molthan
least 1950. The ten white stillborn infants were of from 24 to 37 weeks' gestation at the time of intrauterine death; the six Negro stillborn infants were of from 25 to 38 weeks' gestation. In only 3 infants, 1 white infant of 37 weeks' gestation (1954), 1 Negro infant of 38 weeks' gestation (1957), and 1 Negro infant of 38 weeks' gestation (1959 --unregistered patient) could early induction have been carried out, but it is questionable whether a more favorable course could have been effected. Each of these mothers had had a previous stillborn infant of much shorter gestation. I have no explanation as to why Rh-D hemolytic disease is milder in the Negro babies in this series. It has been suggested that perhaps this is a local phenomenon, limited not only to this city, but more specifically to this institution. Analysis of similar data from other institutions which "have a biracial clientele is obviously needed. Some possible explanations of the racial difference include the strength of the R h - D antigen of the Negro infants' red blood cells, the strength of the direct Coombs test on his cells, and perhaps less antibody production on the part of the Negro mother. With respect to the Negro D antigen, there has been no difference between results of routine Rh-D typing done on Negro and white infants' cord cells. Only 1 Negro affected infant has been considered to be a true D u, the others have been classified as Rh-D. The direct Coombs reactions have varied somewhat depending upon the maternal titer of anti-D at the time of delivery, being weaker in both races with titers in the 1:4 to 1:32 range. Twenty-seven per cent of Negro infants and 21 per cent of white infants have had 1-plus or 2-plus reactions to direct Coombs' testing of cord cells. Weaker reactions (1-plus or 2-plus) were, with the exception of 1 white infant, seen in infants who required no treatment. Strong reactions (3-plus or 4-plus) in white infants were found in 5 infants with mild disease, in 32 infants who required exchange, in 1 baby who died, and in 1 stillborn infant. Strong reactions (3-plus to 4-plus)
April 1963
Table V I I I . ABO.hemolytic disease of the newborn; infants born at Temple University Hospital from Jan. 1, 1955, to Oct. 15, 1962
Race White Negro
Tota[ affected in[ants 100 116
Infants exchanged No. 1 % 44 44 55 47
Infants with multiple exchanges No. 1 % 12 12 23 20
were found in 13 Negro babies who were clinically normal, in 5 who had mild disease, and in 14 in whom exchange transfusion occurred. The production of' anti-D antibody by Negro and white mothers is summarized in Table VII. Titers have been carried out without change in technique since 1954. Sera are diluted by the use of a clean dry pipette for each dilution; test cells are obtained from a single Group O, Rh-D-positive random donor. Aliquots of sera have been retained in the frozen state for carrying out serial titrations. Titers of saline-active, albumin-active, and indirect Coombs-active antibodies have been performed routinely. The indirect Coombs-active antibody, in our hands, has had the more prognostic value, and it is this antibody that is analyzed in Table VII. The results show that Negro mothers are as capable of producing anti-D as are white mothers. Table V I I also attempts to correlate m a x i m u m titer with outcome of pregnancy. Higher morbidity and mortality rates occur with higher titers in both races. Cord bilirubin values have reflected clinical status in every case. The highest cord total bilirubin in a Negro infant was 6.9 mg. per cent while 10 white infants had values between 7.0 and 10.0 mg. per cent. Only 23 per cent of Negro affected infants have had cord total bilirubin values above 3.0 mg. per cent, 62 per cent of white infants have had values above 3.0 mg. per cent. ABO
HEMOLYTIC
DISEASE
The apparent "immunity" of Negro babies against anti-D has not been paralleled by
Volume 62 Number 4
any "immunity" against anti-A and anti-B in ABO hemolytic disease. The incidence of ABO hemolytic disease in Negro ABOincompatible infants is approximately 4.5 per cent in this hospital; that for white ABOincompatible infants is 5 per cent. Table V I I I summarizes the cases of ABO hemolytic disease from Jan. 1, 1955, to Oct. 15, 1962. With the use of the incidence of exchange transfusion as the ~criterion of severity, there is no significant racial difference. In this disease, detection of clinical jaundice is usually effected earlier in white infants. Delay in detection of clinical jaundice in Negro infants is assumed to be the reason for the higher incidence of multiple exchanges in the Negro ABO-affected infants. There is no indication that the disease is more severe in Negroes. COMMENT
Since Rh-D hemolytic disease is milder in the majority of Negro infants delivered at Temple University Hospital, this fact has been taken into consideration in decisions made regarding the management of the
Rh-D hemolytic disease
479
sensitized prenatal patient and the management of her affected newborn infant. While care of each patient must be individualized, in general, there is less need for elective early termination of pregnancy in the Negro sensitized prenatal patient. Management of the affected newborn infant means if and when to carry out exchange transfusion. Criteria such as height and behavior of maternal antibody titer, history of a previously exchanged infant, and a 4-plus direct Coombs reaction on cord cells are very useful criteria in the management of both white and Negro infants. However, especially in the Negro infants, such criteria must be confirmed by the results of careful physical examination and confirmed hemoglobin and serial bilirubin values.
SUMMARY
Rh-D hemolytic disease of the newborn has been a milder disease in Negro than in white infants in this institution. ABO hemolytic disease of the newborn has been equally severe in Negro and white infants.
The Journal o[ P E D I A T R I C S
Rh-D hemolytic disease in Negro and white infants A comparison
Hemolytic disease o[ the newborn due to Rh-D has had lower morbidity and mortality rates in Negro than in white in~ants delivered at Temple University Hospital [rom 1946 to 1962. Negro and white mothers have shown a similar incidence o[ R h sensitization and equal ability to produce anti-D antibody. Sixty per cent of affected Negro infants and 26.5 per cent of affected white infants did not require treatment. Neonatal mortality was 2 per cent for Negro, 8.5 per cent [or white infants. Fewer Negro mothers have had stillbirths due to hemolytic disease. ABO hemolytic disease has shown equal severity in Negro and white in/ants.
Lyndall Molthan, M.D., M.Se.* PHILADELPHIA~
PA.
I I-I a v ~ noticed, during an 8 year period at Temple University Hospital, that hemolytic disease of the newborn due to Rh-D is clinically quite different in Negro babies that it is in white babies. This hospital is a nonprofit, 1,000 bed general hospital located in North Philadelphia where approximately 25,000 live-born infants have been delivered between Jan. l, 1955, and Oct. 1, 1962. Nearly 60 per cent of live-born infants have been Negro, 40 per cent being white. Temple University Hospital has occasionally been a referral center for mothers with Rh problems, only once a referral center for affected infants born elsewhere. Sensitized From the Temple University Medical Center, Philadelphia, Pa. *Address, Director of the Blood Bank, Temple University Medical Center, Philadelphia, Pa.
mothers delivered at this hospital are usually routine prenatal patients who happen to be sensitized. In general, there are 3 areas where Rh sensitization in Negroes differs from that in whites. First, Negro babies affected by Rh-D hemolytic disease have had Iower morbidity and mortality rates than have white infants so affected. Second, Negro mothers have been less likely to produce stillborn infants due to Rh-D sensitization. Third, the prognosis for infants born to the Negro mother sensitized by transfusion prior to pregnancy is better than the prognosis for those born to white mothers so sensitized. CASE
MATERIAL
The case material varies somewhat depending upon the subject being analyzed.
Volume 62 Number 4
R h - D hemolytic disease
A total of 108 Sensitized white mothers and 81 sensitized Negro mothers are included, as are their 143 white and 117 Negro infants, respectively. Routine R h typing of prenatal patients and of all infants born to Rh-D-negative mothers has been carried out since 1947; the direct Coombs test of cord blood from infants born to R h - D negative mothers has been performed routinely since 1949. Screening of sera for atypical antibodies in all Rh-negative prenatal patients was begun in May, 1958. Positive identification of the atypical antibody as anti-D (or anti-CD) has been established in each sensitized mother through the use of cell panels. As controls, 1,942 Rhnegative, unsensitized mothers were used. Table I shows the incidence of R h - D sensitization in consecutive R h - D - and DLUnegative prenatal patients tested between Jan. 1, 1955, and Oct. 15, 1962. The total includes women pregnant for the first time and those whose husbands are known to be Rh-D negative. Thirteen (13 per cent) of the 98 sensitized white mothers were sensitized by transfusion or intramuscular injection of blood prior to pregnancy. Sixteen (20 per cent) of the Negro mothers were so sensitized. Only 2 of the white mothers sensitized by transfusion had received their Rh-positive transfusion since 1950, 10 of the 16 Negro mothers had received theirs since 1950. RESULTS
Table I I evaluates the clinical status of each Rh-D-sensitized mother's first, second, third, and fourth (on up) affected infants. Only those infants delivered at this hospital and completely supervised by its pediatric staff are included. Two hundred and eighteen Rh-positive-affected babies are evaluated; 3 were born between 1946 and 1949,
4 75
25 between 1950 and 1954, and 190 between 1955 and Oct. 15, 1962. Criteria for managing sensitized mothers and criteria for exchange transfusion of affected infants have undergone some modification since 1950; however, over the years, similar criteria have been applied to each case regardless of race. Definitions. 1. Clinically normal describes the infant with neither clinical jaundice nor a total serum bilirubin above 12 mg.% during the first 5 days of life. The direct Coombs test is positive and the hemoglobin normal or slightly reduced. 2. Mild disease describes the infant with either clinical jaundice or a total serum bilirubin above 12 rag.% during the first 5 days of life but not requiring exchange transfusion by the usual criteria. Infants with progressive anemia requiring simple transfusion at 1 to 4 weeks have been classified as mild cases. 3. Exchanged with recovery refers to infants with clinical and laboratory criteria which establish the need for exchange transfusion. 4. Neonatal death refers to infants who were live born but who died as a result of hemolytic disease with or without treatment. Deaths occurring in premature infants where the prematurity was due to an obstetric complication such as placenta previa are not included. Deaths occurring 1 week or more after successful exchange where the cause of death was an infection, possibly, but never proved to be a result of exchange, have not been included. 5. Stillborn refers to the infant stillborn as a result of Rh-D hemolytic disease. Stillbirths due to other causes occurring in Rh-D-sensitlzed mothers have not been included.
Table I. Incidence of Rh-D sensitization in consecutive Rh-D-negative prenatal patients from Jan. 1, 1955, to Oct. 15, 1962
Race
White Negro
Total Rh-negatire patients
No.
No. sensitized I %
1,000 670
98 80
9.8 11.9
No. sensitized by pregnancy No. I %
85 64
8.5 9.8
4 7 6
April 1963
Molthan
T a b l e II. Clinical status of R h - D - a f f e c t e d infants delivered at T e m p l e U n i v e r s i t y Hospital from 1946 to Oct. 15, 1962 Total infants
Clinically normal
Mild disease
Exchanged with recovery
Neonatal death
Stillborn
White Negro
63 57
t2 31
15 12
31 14
2 0
3 0
First affected infants
White Negro
30 25
1 I0
2 2
21 10
2 0
4 3
Second affected infants
White Negro
14 14
0 4
0 1
10 6
2 1
2 2
Third affected infants
White Negro
10 5
0 1
1 0
4 2
4 1
1 1
Fourth to sixth affected infants
Total white
117
13
18
66
10
10
(Plus 26 Rh neg. infants )
Total Negro
101
46
15
32
2
6
(Plus 16 Rh neg. infants)
Race
T a b l e I I I . I n f a n t s b o r n to mothers after sensitization by intravenous or i n t r a m u s c u l a r blood, delivered at T e m p l e University Hospital from 1946 to Oct. I5, 1962 Rh-positive infants Exchanged, ~ Race
Rh-negative infants
White Negro
10 5
Total
Clinically normal
Mild disease
recovered
8 21
0 8
0 2
4 8
Stillborn death and neonatal % No. I I
4 3
50 14
T a b l e IV. Stillbirths due to R h - D sensitization
Race
Total mothers interviewed
White Negro
108 82
. Mothers with history of stillbirth No. 1 %
19 7
No. of stillbirths
Mothers sensitized by I.V. or I.M. blood
31 14
5 3
18 8.5
T a b l e V. I n f a n t s born subsequent to stillbirth Rh-positive infants Race
Rh-negative infants
Total
Clinically normal
Mild disease
Exchanged, recovered
Stillborn and neonatal death
White Negro
9 0
28 8
0 0
0 0
7 1
21 7
T a b l e I I I shows the outcome of p r e g n a n cies following i n t r a v e n o u s or i n t r a m u s c u l a r R h - D sensitization o f R h - n e g a t i v e mothers. O n l y infants delivered at this hospital have been included. Tables I V a n d V show the incidence of stillbirths due to R h - D sensitization a n d the outcome of pregnancies occurring subse-
q u e n t to stillbirth. While m a t e r n a l histories have been used as the basis for these figures, the fact that R h sensitization was responsible for each stillbirth has been confirmed. T h e prognosis for Rh-positive infants born subseq u e n t to stillbirth has been quite bad for both races. T a b l e V I summarizes the few cases of
Volume 62
Number 4
Rh-D
T a b l e V I . H e m o l y t i c disease of the n e w b o r n due to antigens o t h e r t h a n R h - D a n d the A B O system. I n f a n t s delivered at T e m p l e U n i v e r s i t y H o s p i t a l 1955 to 1962
normal
Cases
Race
White
Rh-g 5 Kell 1
Negro
Rh-E I Rh-E 3 Rh-f 1
Mild dis-
'hanget with
geo-
recouerfl
mortality
eas~
2
natal
2 1
1 3 1
T a b l e V I I A. H e i g h t of m a t e r n a l indirect C o o m b s - a c t i v e a n t i - D titers; m a x i m u m titer p e r m o t h e r d u r i n g p r e g n a n c y 1:4 to 1:32
1:64 to 1:256
1:512 to 1:4096 No. I %
Race
No.
%
No. I %
White Negro
23 18
23 23
50 45
51 58
25 15
4 77
affected infants were in the u n t r e a t e d category, few (7 p e r cent) white second and t h i r d affected infants could do well without exchange transfusions. I n the infants of mothers sensitized by intravenous or intram u s c u l a r blood, 48 p e r cent of the Negro babies, b u t none of the white babies, were in the u n t r e a t e d category. T h e r e was a neon a t a l m o r t a l i t y rate of 8.5 per cent for white infants, 2 per cent for N e g r o infants. N e o n a t a l mortality, at this time, requires f u r t h e r analysis. O n e of the N e g r o infants died as a result of an air embolus inadvertently i n t r o d u c e d at the end of an exchange transfusion. This i n f a n t was n o t severely affected a n d could h a v e been expected to do well with the one exchange. T h e other Negro infant was an u n a n t i c i p a t e d liveborn infant of a m o t h e r w h o h a d delivered 3 consecutive stillborn infants. T h i s b a b y arrived at night on a holiday, a n d died at 2 hours of age w i t h o u t benefit of t r e a t m e n t ; however, he p r o b a b l y w o u l d have died even with p r o m p t t r e a t m e n t since he was r a t h e r severely affected. T e n white infants are listed as n e o n a t a l deaths, 5 delivered between 30 a n d 36 weeks' gestation, 5 between 37 a n d 40 weeks' gestation. Six died within 1 hour of birth, only 1 of these d u r i n g exchange transfusion; 4 h a d an exchange p e r f o r m e d b u t died a t 2 hours, 12 hours, 36 hours, and 48 hours, respectively. All these infants were severely affected. It is possible t h a t 3 infants born at 39 to 40 weeks m i g h t have been salvaged h a d early induction of l a b o r been in vogue locally at the time (1955 a n d 1956). K e r n i e t e r u s with cerebral palsy has not been e n c o u n t e r e d in infants delivered at this hospital since at
Ex-
Clinically
h e m o l y t i c disease
26 18
hemolytic disease due to antigens other t h a n R h - D a n d the A B O system. These cases seem to parallel the R h - D cases in clinical manifestations. DISCUSSION I t is a p p a r e n t f r o m the results in Tables I I a n d I I I that P~h-D h e m o l y t i c disease of the n e w b o r n has lower m o r b i d i t y and mortality rates in the N e g r o infants t h a n in the white infants in this series. Sixty per cent of N e g r o affected infants c o m p a r e d with 26.5 p e r cent of white affected i n f a n t s did not require t r e a t m e n t . A high percentage (44 p e r cent) of N e g r o second a n d t h i r d
T a b l e V I I B. Correlation between m a x i m u m a n t i - D titer a n d outcome of pregnancy Rh-positive infants Maternal titer
Total in{ants
Rh-negative infants
Clinically normal and mild disease
White
1:4 to 1:32 1:64 to 1:256 1:512 to 1:4096
29 61 26
7 8 1
18 9 1
3 34 18
1 10 6
Negro
1:4 to 1:32 1:64 to 1:256 1:512 to 1:4096
25 57 17
6 4 1
17 30 4
2 20 8
0 3 4.
Race
Exchanged with recovery
Stillborn and neonatal death
478
Molthan
least 1950. The ten white stillborn infants were of from 24 to 37 weeks' gestation at the time of intrauterine death; the six Negro stillborn infants were of from 25 to 38 weeks' gestation. In only 3 infants, 1 white infant of 37 weeks' gestation (1954), 1 Negro infant of 38 weeks' gestation (1957), and 1 Negro infant of 38 weeks' gestation (1959 --unregistered patient) could early induction have been carried out, but it is questionable whether a more favorable course could have been effected. Each of these mothers had had a previous stillborn infant of much shorter gestation. I have no explanation as to why Rh-D hemolytic disease is milder in the Negro babies in this series. It has been suggested that perhaps this is a local phenomenon, limited not only to this city, but more specifically to this institution. Analysis of similar data from other institutions which "have a biracial clientele is obviously needed. Some possible explanations of the racial difference include the strength of the R h - D antigen of the Negro infants' red blood cells, the strength of the direct Coombs test on his cells, and perhaps less antibody production on the part of the Negro mother. With respect to the Negro D antigen, there has been no difference between results of routine Rh-D typing done on Negro and white infants' cord cells. Only 1 Negro affected infant has been considered to be a true D u, the others have been classified as Rh-D. The direct Coombs reactions have varied somewhat depending upon the maternal titer of anti-D at the time of delivery, being weaker in both races with titers in the 1:4 to 1:32 range. Twenty-seven per cent of Negro infants and 21 per cent of white infants have had 1-plus or 2-plus reactions to direct Coombs' testing of cord cells. Weaker reactions (1-plus or 2-plus) were, with the exception of 1 white infant, seen in infants who required no treatment. Strong reactions (3-plus or 4-plus) in white infants were found in 5 infants with mild disease, in 32 infants who required exchange, in 1 baby who died, and in 1 stillborn infant. Strong reactions (3-plus to 4-plus)
April 1963
Table V I I I . ABO.hemolytic disease of the newborn; infants born at Temple University Hospital from Jan. 1, 1955, to Oct. 15, 1962
Race White Negro
Tota[ affected in[ants 100 116
Infants exchanged No. 1 % 44 44 55 47
Infants with multiple exchanges No. 1 % 12 12 23 20
were found in 13 Negro babies who were clinically normal, in 5 who had mild disease, and in 14 in whom exchange transfusion occurred. The production of' anti-D antibody by Negro and white mothers is summarized in Table VII. Titers have been carried out without change in technique since 1954. Sera are diluted by the use of a clean dry pipette for each dilution; test cells are obtained from a single Group O, Rh-D-positive random donor. Aliquots of sera have been retained in the frozen state for carrying out serial titrations. Titers of saline-active, albumin-active, and indirect Coombs-active antibodies have been performed routinely. The indirect Coombs-active antibody, in our hands, has had the more prognostic value, and it is this antibody that is analyzed in Table VII. The results show that Negro mothers are as capable of producing anti-D as are white mothers. Table V I I also attempts to correlate m a x i m u m titer with outcome of pregnancy. Higher morbidity and mortality rates occur with higher titers in both races. Cord bilirubin values have reflected clinical status in every case. The highest cord total bilirubin in a Negro infant was 6.9 mg. per cent while 10 white infants had values between 7.0 and 10.0 mg. per cent. Only 23 per cent of Negro affected infants have had cord total bilirubin values above 3.0 mg. per cent, 62 per cent of white infants have had values above 3.0 mg. per cent. ABO
HEMOLYTIC
DISEASE
The apparent "immunity" of Negro babies against anti-D has not been paralleled by
Volume 62 Number 4
any "immunity" against anti-A and anti-B in ABO hemolytic disease. The incidence of ABO hemolytic disease in Negro ABOincompatible infants is approximately 4.5 per cent in this hospital; that for white ABOincompatible infants is 5 per cent. Table V I I I summarizes the cases of ABO hemolytic disease from Jan. 1, 1955, to Oct. 15, 1962. With the use of the incidence of exchange transfusion as the ~criterion of severity, there is no significant racial difference. In this disease, detection of clinical jaundice is usually effected earlier in white infants. Delay in detection of clinical jaundice in Negro infants is assumed to be the reason for the higher incidence of multiple exchanges in the Negro ABO-affected infants. There is no indication that the disease is more severe in Negroes. COMMENT
Since Rh-D hemolytic disease is milder in the majority of Negro infants delivered at Temple University Hospital, this fact has been taken into consideration in decisions made regarding the management of the
Rh-D hemolytic disease
479
sensitized prenatal patient and the management of her affected newborn infant. While care of each patient must be individualized, in general, there is less need for elective early termination of pregnancy in the Negro sensitized prenatal patient. Management of the affected newborn infant means if and when to carry out exchange transfusion. Criteria such as height and behavior of maternal antibody titer, history of a previously exchanged infant, and a 4-plus direct Coombs reaction on cord cells are very useful criteria in the management of both white and Negro infants. However, especially in the Negro infants, such criteria must be confirmed by the results of careful physical examination and confirmed hemoglobin and serial bilirubin values.
SUMMARY
Rh-D hemolytic disease of the newborn has been a milder disease in Negro than in white infants in this institution. ABO hemolytic disease of the newborn has been equally severe in Negro and white infants.