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Icterus precox
ICTERUS PRECOK FURTHER ~TUDIES ON ITS FREQUENCY, ETIOLOGY, PROGNOSIS AND THE BLOOD CHEMISTRY OF THE CORD BLOOD I. HALBRECHT, M . D . I~ADERA, ISRAEL
N 1944, we described 1 the clinical of a mild f o r m of the hemolytic disease of newborn babies, characterized by an especially intense icterus which a p p e a r e d during the first twenty-four hours a f t e r birth. We called it " i c t e r u s p r e c o x " in order to distinguish it f r o m the grave f o r m of the same disease, icterus gravis. The existence of the syndrome was confirmed and the name suggested by us was accepted by most observers. 2, 3, 4,_ ~, 6, 7, s There is very little to add to the original clinical description of this syndrome as published in 1944.
pregnancies (incompatibility of t h e blood-grouping system ABO between mother and child). I n a second series of t h i r t y additional cases we f o u n d two that were not caused by a heterospecific p r e g n a n c y but by an iso-immunization of the mother against the Rh factor of the baby. I n both cases the mother as well as the b a b y belonged to the same blood group of the A B 0 system. However, both mothers were Rh negative a n d both babies were Rh positive. I n the blood of both mothers Rh-blocking antibodies were found.
I syndrome
TABLE
I Mother
Infant No cases
ABO INCOMPATIBILITY O
A 66
O
B 15
A
B 2
I
I
RH INCOMPATIBILITY
I
NO INCOMPATIBILITY
Rh Negative Rh Positive 2
B
A 2
The purpose of this p a p e r is to report our clinical experiences with regard to the etiology, prognosis in future pregnancies, and the mental development of ninety babies who de: veloped icterus precox, and the results of o u r studies of the blood chemistry of the cord blood of some of these babies.
A O 3 FREQUENCY
Among approximately 16,000 babies delivered we have found to date 90 cases of ieterus precox, which gives an incidence of one case of icterus precox in 180 births. The number of heterospecific cases among the same number of deliveries was 1,250, which gives an incidence of one case of icterus precox in 25 heterospecific pregnancies.
ETIOLOGY
About 95 per cent of the first group of sixty cases of icterus precox reported by us belonged to heterospecific
ICTERUS PRECOX IN PRIMIGRAVIDAS
I n contrast to erythroblastosis fetalis, icterus precox occurs frequently
From the Maternity Hospital.
185
186
THE JOURNAL OF PEDIATRICS
in first pregnancies. Of our 90 cases, 30 were first babies. HEMOLYTIC DISEASES IN THE SIBLINGS OF SUBSEQUENT PREGNANCIES
In only a relatively small n u m b e r of cases could information be obtained about the fate of children born subsequently to the babies with icterus precox. The following case, observed by us, of a family whose first child had icterus precox, while the second child died of kernicterus five days a f t e r birth, is instructive. Mrs. M. N., 29 years old, blood group O-Rh negative. The husband was A-Rh positive. The first pregnancy terminated in an abortion in the f o u r t h month. The second pregnancy terminated in a nonviable baby at the end of the sixth month. The third pregnancy, two years l a t e r , was brought to an end by delivery of a baby weighing 3,100 grams, w h i c h showed an intensive icterus the first day of life. The child's blood group was A-Rh positive. No hepatosplenomegaly was present and, no nucleated red blood corpuscles were f o u n d in the peripheral blood. Hemoglobin was 90 per cent, erythrocytes 3,900,000. Diagnosis : icterus precox. This baby left the hospital on the ninth day in good general condition without need of any special treatment. He has been developing since (three years) into a physically and mentally normal child. The f o u r t h pregnancy started fifteen months after the birth of the first viable child. Beginning with the third month of pregnancy, we examined m o n t h 1 y the iso-antibodies (anti-A, anti-B, anti-Rh) in the blood of the prospective mother. At the beginning of the sixth month an increased titer of the anti-A, also of the anti-B but to a lesser degree, was noted. A t the end of the pregnancy the titers of the iso-antibodies were as follows : Anti-A agglutinins (dilution with saline)
1:128
Anti-& conglutinins (dilution with plasma) Anti-B agglutinins Anti-B conglutinins Rh-antibodies
1:1,024 1:64 1:512 0
The increase of the anti-A conglutinins at the end of the pregnancy led to the prediction that the expected baby would suffer from a hemolytic disease. We expected to find an icterns precox in view of the increased anti-A-B conglutinins and the complete absence of Rh antibodies in the mother's blood. The woman was delivered at term of a male baby weighing 3,200 grams who showed, on the first day of life, an icterus which became more and more intensive. The peripheral blood had only a few erythroblasts. Hemoglobin was 90 per cent, red b 1 o o d cells 4,000,000. Hepatosplenomegaly was pronounced. The general condition at the start was satisfactory but became worse on the f o u r t h day, and the baby expired on the fifth day. Autopsy proved the case to be one of kernicterus. This case, as well as the report by Broncato, 9 of icterus precox and erythroblastosis fetalis in two children of the same family, permits some conclusions concerning the relationship between icterus precox and the other forms of hemolytic disease of the newborn, namely, that (1) icterus precox is only a mild form of hemolytic disease of the newborn. I t may occur alternately in a more severe form of the disease in different children of the same family. (2) The possibility that after an icterus precox a more severe form of hemolytic disease may occur in the same family makes it imperative to investigate systematically and repeatedly t h e iso-antibodies in the mother in all pregnancies subsequent to an icterus precox in order to be able to foretell an eventual occurrence of a hemolytic disease in subsequent children.
HALBRECHT : ICTERUS PRECOX
I t should be emphasized, however, that neither the titer n o r the kind of antibodies (anti-A, anti-B, or anti-Rh) is capable of giving us a definite clue as to the intensity of the expected hemolytic disease in t h a t baby. HEMOLYTIC DISEASE IN SIBLINGS PRECEDING THE ICTERUS PRECOX In two cases there were stillbirths preceding the i c t e r u s precox. We were not able to establish definitely the cause of the stillbirths. I n three more cases in which we observed an icterus precox, each time in the t h i r d child, the mothers volunteered the information t h a t the first babies also showed an intensive icterus the first d a y a f t e r birth. I t is possible, therefore, t h a t the first children of these three families had icterus precox. The repeated occurrence of icterus precox in the same family as well as the occurrence of icterus precox a f t e r one of the more severe f o r m s of hemolytic disease (icterus gravis, hydrops) should be taken into account when considering the indication of the preventive exchange transfusion. CORD BLOOD C H E M I S T R Y
IN
ICTERUS PRECOX
The cord blood chemistry of twelve babies suffering f r o m icterus precox was studied. T h e s e investigations seem to allow us to draw some conclusions as to the hepatic function of these babies. Of p a r t i c u l a r interest is a comparison of these results with those obtained by examining the blood chemistry of nonicteric babies as published in a previous article. 1~ As can be seen in Tables I I and I I I , the studies did not show any significant differences between icterie and nonicteric babies, with the exception of
:18T
a p a r t i c u l a r l y high bflirubin content in the blood of the icterus precox babies. I n all but one case the bilirubin content was over 1 rag. per cent, and in nine of the twelve cases the direct van den Bergh test was positive. The average value of total bilirubin in the serum of the cord blood was 3.57 rag. per cent for the icterus precox in contrast to a total of 0.94 to 1.34 mg. per cent in various groups of nonicteric babies ( p r e m a t u r e , full t e r m and p o s t m a t u r e ) . The total cholesterin in the serum of the cord blood showed an average of 88.4 mg. per cent which is about 20 mg. per cent less t h a n in normal full term, and 3.7 rag. per cent more t h a n in p o s t m a t u r e nonicteric babies. The total protein was 5.57 Gm. and the albumin-globulin ratio showed an average of 1.78 which is about what we found in nonicteric babies. The cepha~in-cholesterol flocculation test was positive in nine of the twelve cases (mostly 4 plus). The thymol turbidity test showed low values in all twelve cases of icterus precox similar to the findings in normal newborn infants (average 1.6 U.). I n all cases of icterus precox a mild left deviation of the Weltman coagulation band occurred. Thus chemistry of the cord blood of newborn babies with the icterus precox syndrome does not differ substantially f r o m that of nonicteric babies, with the exception of an elevated bilirubin content in the blood of icteric newborn infants. PROGNOSIS
The of the icterus babies
immediate prognosis in the case newborn b a b y suffering f r o m precox is always good. These need no special treatment, and
~188
'tHE JOURNAL OF PEDIATRICS TABLE I I AVERAGE VALUES TOTAL BILIRUBIN CI-IOLESTEROL lY[G, ~PER, MG. PEI~ ~100 C.C. 100 C.C.
~ o n i c t e r i c ~nfants Premature Full term Postmature I c t e r u s precox
0.94 1.16 1.34 3.57
TOTAL PROTEINS G~V[. PER 100 C.C.
95.1 108.3 84.7 88.4
ALBUMINGLOBULIN RATIO
5.36 5.70 5.57 5.57
2.52 1.61 1.62 1.78
TABLE I I I BILIRUBIN MC~. PER 100 C.C.
PROTEINS a}a. PER 100 c.e.
TESTS
D~
.el
Do
0.8
Neg
~.~
1.5 1.4 :1.0 7.0 1.0 5.5 4.5 5.6 5.8 3.5 2.8
1.0 9.0 Neg 2.3 Neg 3.0 3.0 1.0 0.7 0.5 0.9
).~ ).~ :.( i.i L.( ~.~ [.,~ L( i.: L( [2
90 78 92 104 99 92 113 64 79 75 86
o~
Z~ ~
1 2 3 4 5 6 7 8 9 10 II 12
E~
6o
o
.56
',.50
.50 .65 .60 .60 .40 .95 .70 .70 .50 .20 .50
;.80 1.70 :.55 2.10 ;.60 2.00 .10 2.50 K30 2.10 L30 1.65 t-.00 1.70 L50 2.20 L40 2.10 ').10 2 . ] 0 1.20 2.30
~
2_06 ~.~
they develop without p a r t i c u l a r difficulties in spite of the mild anemia present at birth and which m a y even increase during the following weeks and months. The f u t u r e prognosis of icterus precox is favorable, in contrast to t h a t of icterus gravis. I n 10 patients with icterus precox observed up to the t h i r d year of life we could detect no sign of mental deficiency nor of neurologie symptoms, as are so often seen in babies surviving icterus gravis. DISCUSSION
Icterus precox is a mild f o r m of hemolytic disease of the newborn. I t was, until recently, and is sometimes
2.23 1.66 1.80 1.48 1.55 2.0(] 2.3,5 1.62 1.60 1.47 1.39
+++ Neg Neg Neg +++ +++ +++ +++ +++ +++ +++ +++
~Te Ne Ne Ne Ne Ne Ne Ne Ne Ne Ne Ne
v~ l'~eg.
~Teg. Pos. Neg. Neg. Neg. Neg. lq'eg. Neg. Neg. Neg.
even today, f r e q u e n t l y mistaken for either the physiologic icterus or the icterus gravis. The occurrence of icterus precox and one of the more severe forms of hemolytic disease of the newborn in the same family based upon the same etiological factor permits the conclusion t h a t we are dealing, not with a disease different f r o m the other f o r m s of the same syndrome, but, for reasons yet unknown, one child is afflicted with a mild f o r m a n d another child of the same family is afflicted with a severe f o r m of the same disease. We have not been able to detect a special order or serial r e g u l a r i t y in which the various f o r m s of hemolytic
FIALBRECHT
:
disease occur in the same family. I n only one instance kernieterus followed icterus precox in the same family. I n two eases we had reason to assume that severe erythroblastosis (hydrops) preceded the icterus precox, and in three eases icterus p r o b a b l y occurred twice in the same family. The m a r k e d frequency of occurrence of ieterus preeox in heterospecifie pregnancies (AB incompatibilities) and its relative r a r i t y in eases of Rh incompatibility seems to point toward a certain connection between the etiology of ieterus precox and the anti-A and anti-B antibodies. However, we cannot accept the explanation suggested by Wiener that the cause of the milder f o r m of hemolytic disease in eases of ABO incompatibilities is due to a selective permeability of the placenta for the Rhblocking antibodies and a relative impermeability for the anti-A-B agglutinins, f o r the following reasons: 1. I n 40 per cent of all newborn babies anti-A-B agglutinins and conglutinins were found in the cord blood that disappeared f r o m the peripheral blood of the newborn infant by the eighth day. They must have, therefore, originated in the blood of the mother. 2. The iso-immunization of the mother caused by the A or B agglutinogen of the child not only produces an increase in the anti-A-B agglutinins but also causes the a p p e a r a n c e of anti-A-B immuno-iso-antibodies (eonglutinins) which can be seen only in a dilution with plasma or p r o t e i n - - a s is the ease with the Rh-blocking antib o d i e s - - a n d therefore is bound to have passed the placenta as the latter does. 3. Icterus preeox occurs not less frequently t h a n the other forms of hemolytic disease, and it occurs in the
ICTERUS
189
PRECOX
same proportion of one in twenty-five to t h i r t y heterospecific pregnancies, corresponding to one erythroblastosis feta]is in twenty-five to t h i r t y cases of Rh incompatibilities. We are of the opinion, therefore, that we are not dealing with a r a r e r f o r m as would be expected according to W i e n e r ' s theory of selective permeability of the placenta but only with an attenuation of symptoms of the hemolytic diseases of newborn infantsl for reasons as yet unknown. Neither is the theory of the competition of antigens as an explanation for the occurrence of icterus preeox applicable in all eases. I n two of the eases observed by us in which there was an Rh incompatibility, both mother and child belonged to the same group of the ABO system. I n conclusion, we still do not have a plausible explanation of the fact t h a t in certain eases of incompatibility of blood groups between mother and child, ieterus precox develops. SUMMARY
1. To date, we have diagnosed ninety cases of icterus precox among 16,000 births. Almost all of them were caused by an autoimmunization of the mother through the antigen A, B of the children. Only two cases were due to an Rh incompatibility. 2. The blood chemistry of the cord blood in these eases is not materially different f r o m that in nonicterie children. 3. The immediate and future prognosis of the children suffering f r o m ieterus preeox is favorable. 4. The occurrence of ieterus gravis (kernieterus) a f t e r icterus precox in the same family makes special attention and precaution imperative in
190
THE JOURNAL OF PEDIATRICS
pregnancies following one in which ieterus precox was present. 5. The theories o f competition of antigens, and of selective permeability of the placenta to various isoantibodies, do not satisfactorily explain the occurrence of icterus preeox in certain cases of isoimmunization of the mother against the blood group antigen of her child. REFERENCES 1. ttalbrecht, I.: 248, 1944.
Am. J. Dis. Child. 68:
2. Wiener, A.: Am. J. Dis. Child. 71: 24, 1946. 3. Tortora, M." Arch. obstet, e ginee. 52" 436, 1948. 4. Broncato, G . J . : Am. J. Dis. Child. 80: 287, 1950. 5. Boorman, K. E,, Daley, D., and Dodd, B. E.: J. Obst. & Gynaec. Brit. Emp. 56" 281. 6. Grumbach, A., and Gasser, C.: ttelvet. paediat, actu 3: 447, 1948. 7. Grundorfer, J . : Am. J. 0bst. & Gynec. 58: 574, 1949. 8. Gurevitch, J., Polisiuk, Z., and I-Ierman, D.: Am. J. Clin. Path. 16: 574, 1946. 9. Broncato, G. J.: Am. J. Dis. Child. 77; 351, 1949. 1O. Halbrecht, I.: Am. J. Dis. Child. 79. 988, 1950.
N 1944, we described 1 the clinical of a mild f o r m of the hemolytic disease of newborn babies, characterized by an especially intense icterus which a p p e a r e d during the first twenty-four hours a f t e r birth. We called it " i c t e r u s p r e c o x " in order to distinguish it f r o m the grave f o r m of the same disease, icterus gravis. The existence of the syndrome was confirmed and the name suggested by us was accepted by most observers. 2, 3, 4,_ ~, 6, 7, s There is very little to add to the original clinical description of this syndrome as published in 1944.
pregnancies (incompatibility of t h e blood-grouping system ABO between mother and child). I n a second series of t h i r t y additional cases we f o u n d two that were not caused by a heterospecific p r e g n a n c y but by an iso-immunization of the mother against the Rh factor of the baby. I n both cases the mother as well as the b a b y belonged to the same blood group of the A B 0 system. However, both mothers were Rh negative a n d both babies were Rh positive. I n the blood of both mothers Rh-blocking antibodies were found.
I syndrome
TABLE
I Mother
Infant No cases
ABO INCOMPATIBILITY O
A 66
O
B 15
A
B 2
I
I
RH INCOMPATIBILITY
I
NO INCOMPATIBILITY
Rh Negative Rh Positive 2
B
A 2
The purpose of this p a p e r is to report our clinical experiences with regard to the etiology, prognosis in future pregnancies, and the mental development of ninety babies who de: veloped icterus precox, and the results of o u r studies of the blood chemistry of the cord blood of some of these babies.
A O 3 FREQUENCY
Among approximately 16,000 babies delivered we have found to date 90 cases of ieterus precox, which gives an incidence of one case of icterus precox in 180 births. The number of heterospecific cases among the same number of deliveries was 1,250, which gives an incidence of one case of icterus precox in 25 heterospecific pregnancies.
ETIOLOGY
About 95 per cent of the first group of sixty cases of icterus precox reported by us belonged to heterospecific
ICTERUS PRECOX IN PRIMIGRAVIDAS
I n contrast to erythroblastosis fetalis, icterus precox occurs frequently
From the Maternity Hospital.
185
186
THE JOURNAL OF PEDIATRICS
in first pregnancies. Of our 90 cases, 30 were first babies. HEMOLYTIC DISEASES IN THE SIBLINGS OF SUBSEQUENT PREGNANCIES
In only a relatively small n u m b e r of cases could information be obtained about the fate of children born subsequently to the babies with icterus precox. The following case, observed by us, of a family whose first child had icterus precox, while the second child died of kernicterus five days a f t e r birth, is instructive. Mrs. M. N., 29 years old, blood group O-Rh negative. The husband was A-Rh positive. The first pregnancy terminated in an abortion in the f o u r t h month. The second pregnancy terminated in a nonviable baby at the end of the sixth month. The third pregnancy, two years l a t e r , was brought to an end by delivery of a baby weighing 3,100 grams, w h i c h showed an intensive icterus the first day of life. The child's blood group was A-Rh positive. No hepatosplenomegaly was present and, no nucleated red blood corpuscles were f o u n d in the peripheral blood. Hemoglobin was 90 per cent, erythrocytes 3,900,000. Diagnosis : icterus precox. This baby left the hospital on the ninth day in good general condition without need of any special treatment. He has been developing since (three years) into a physically and mentally normal child. The f o u r t h pregnancy started fifteen months after the birth of the first viable child. Beginning with the third month of pregnancy, we examined m o n t h 1 y the iso-antibodies (anti-A, anti-B, anti-Rh) in the blood of the prospective mother. At the beginning of the sixth month an increased titer of the anti-A, also of the anti-B but to a lesser degree, was noted. A t the end of the pregnancy the titers of the iso-antibodies were as follows : Anti-A agglutinins (dilution with saline)
1:128
Anti-& conglutinins (dilution with plasma) Anti-B agglutinins Anti-B conglutinins Rh-antibodies
1:1,024 1:64 1:512 0
The increase of the anti-A conglutinins at the end of the pregnancy led to the prediction that the expected baby would suffer from a hemolytic disease. We expected to find an icterns precox in view of the increased anti-A-B conglutinins and the complete absence of Rh antibodies in the mother's blood. The woman was delivered at term of a male baby weighing 3,200 grams who showed, on the first day of life, an icterus which became more and more intensive. The peripheral blood had only a few erythroblasts. Hemoglobin was 90 per cent, red b 1 o o d cells 4,000,000. Hepatosplenomegaly was pronounced. The general condition at the start was satisfactory but became worse on the f o u r t h day, and the baby expired on the fifth day. Autopsy proved the case to be one of kernicterus. This case, as well as the report by Broncato, 9 of icterus precox and erythroblastosis fetalis in two children of the same family, permits some conclusions concerning the relationship between icterus precox and the other forms of hemolytic disease of the newborn, namely, that (1) icterus precox is only a mild form of hemolytic disease of the newborn. I t may occur alternately in a more severe form of the disease in different children of the same family. (2) The possibility that after an icterus precox a more severe form of hemolytic disease may occur in the same family makes it imperative to investigate systematically and repeatedly t h e iso-antibodies in the mother in all pregnancies subsequent to an icterus precox in order to be able to foretell an eventual occurrence of a hemolytic disease in subsequent children.
HALBRECHT : ICTERUS PRECOX
I t should be emphasized, however, that neither the titer n o r the kind of antibodies (anti-A, anti-B, or anti-Rh) is capable of giving us a definite clue as to the intensity of the expected hemolytic disease in t h a t baby. HEMOLYTIC DISEASE IN SIBLINGS PRECEDING THE ICTERUS PRECOX In two cases there were stillbirths preceding the i c t e r u s precox. We were not able to establish definitely the cause of the stillbirths. I n three more cases in which we observed an icterus precox, each time in the t h i r d child, the mothers volunteered the information t h a t the first babies also showed an intensive icterus the first d a y a f t e r birth. I t is possible, therefore, t h a t the first children of these three families had icterus precox. The repeated occurrence of icterus precox in the same family as well as the occurrence of icterus precox a f t e r one of the more severe f o r m s of hemolytic disease (icterus gravis, hydrops) should be taken into account when considering the indication of the preventive exchange transfusion. CORD BLOOD C H E M I S T R Y
IN
ICTERUS PRECOX
The cord blood chemistry of twelve babies suffering f r o m icterus precox was studied. T h e s e investigations seem to allow us to draw some conclusions as to the hepatic function of these babies. Of p a r t i c u l a r interest is a comparison of these results with those obtained by examining the blood chemistry of nonicteric babies as published in a previous article. 1~ As can be seen in Tables I I and I I I , the studies did not show any significant differences between icterie and nonicteric babies, with the exception of
:18T
a p a r t i c u l a r l y high bflirubin content in the blood of the icterus precox babies. I n all but one case the bilirubin content was over 1 rag. per cent, and in nine of the twelve cases the direct van den Bergh test was positive. The average value of total bilirubin in the serum of the cord blood was 3.57 rag. per cent for the icterus precox in contrast to a total of 0.94 to 1.34 mg. per cent in various groups of nonicteric babies ( p r e m a t u r e , full t e r m and p o s t m a t u r e ) . The total cholesterin in the serum of the cord blood showed an average of 88.4 mg. per cent which is about 20 mg. per cent less t h a n in normal full term, and 3.7 rag. per cent more t h a n in p o s t m a t u r e nonicteric babies. The total protein was 5.57 Gm. and the albumin-globulin ratio showed an average of 1.78 which is about what we found in nonicteric babies. The cepha~in-cholesterol flocculation test was positive in nine of the twelve cases (mostly 4 plus). The thymol turbidity test showed low values in all twelve cases of icterus precox similar to the findings in normal newborn infants (average 1.6 U.). I n all cases of icterus precox a mild left deviation of the Weltman coagulation band occurred. Thus chemistry of the cord blood of newborn babies with the icterus precox syndrome does not differ substantially f r o m that of nonicteric babies, with the exception of an elevated bilirubin content in the blood of icteric newborn infants. PROGNOSIS
The of the icterus babies
immediate prognosis in the case newborn b a b y suffering f r o m precox is always good. These need no special treatment, and
~188
'tHE JOURNAL OF PEDIATRICS TABLE I I AVERAGE VALUES TOTAL BILIRUBIN CI-IOLESTEROL lY[G, ~PER, MG. PEI~ ~100 C.C. 100 C.C.
~ o n i c t e r i c ~nfants Premature Full term Postmature I c t e r u s precox
0.94 1.16 1.34 3.57
TOTAL PROTEINS G~V[. PER 100 C.C.
95.1 108.3 84.7 88.4
ALBUMINGLOBULIN RATIO
5.36 5.70 5.57 5.57
2.52 1.61 1.62 1.78
TABLE I I I BILIRUBIN MC~. PER 100 C.C.
PROTEINS a}a. PER 100 c.e.
TESTS
D~
.el
Do
0.8
Neg
~.~
1.5 1.4 :1.0 7.0 1.0 5.5 4.5 5.6 5.8 3.5 2.8
1.0 9.0 Neg 2.3 Neg 3.0 3.0 1.0 0.7 0.5 0.9
).~ ).~ :.( i.i L.( ~.~ [.,~ L( i.: L( [2
90 78 92 104 99 92 113 64 79 75 86
o~
Z~ ~
1 2 3 4 5 6 7 8 9 10 II 12
E~
6o
o
.56
',.50
.50 .65 .60 .60 .40 .95 .70 .70 .50 .20 .50
;.80 1.70 :.55 2.10 ;.60 2.00 .10 2.50 K30 2.10 L30 1.65 t-.00 1.70 L50 2.20 L40 2.10 ').10 2 . ] 0 1.20 2.30
~
2_06 ~.~
they develop without p a r t i c u l a r difficulties in spite of the mild anemia present at birth and which m a y even increase during the following weeks and months. The f u t u r e prognosis of icterus precox is favorable, in contrast to t h a t of icterus gravis. I n 10 patients with icterus precox observed up to the t h i r d year of life we could detect no sign of mental deficiency nor of neurologie symptoms, as are so often seen in babies surviving icterus gravis. DISCUSSION
Icterus precox is a mild f o r m of hemolytic disease of the newborn. I t was, until recently, and is sometimes
2.23 1.66 1.80 1.48 1.55 2.0(] 2.3,5 1.62 1.60 1.47 1.39
+++ Neg Neg Neg +++ +++ +++ +++ +++ +++ +++ +++
~Te Ne Ne Ne Ne Ne Ne Ne Ne Ne Ne Ne
v~ l'~eg.
~Teg. Pos. Neg. Neg. Neg. Neg. lq'eg. Neg. Neg. Neg.
even today, f r e q u e n t l y mistaken for either the physiologic icterus or the icterus gravis. The occurrence of icterus precox and one of the more severe forms of hemolytic disease of the newborn in the same family based upon the same etiological factor permits the conclusion t h a t we are dealing, not with a disease different f r o m the other f o r m s of the same syndrome, but, for reasons yet unknown, one child is afflicted with a mild f o r m a n d another child of the same family is afflicted with a severe f o r m of the same disease. We have not been able to detect a special order or serial r e g u l a r i t y in which the various f o r m s of hemolytic
FIALBRECHT
:
disease occur in the same family. I n only one instance kernieterus followed icterus precox in the same family. I n two eases we had reason to assume that severe erythroblastosis (hydrops) preceded the icterus precox, and in three eases icterus p r o b a b l y occurred twice in the same family. The m a r k e d frequency of occurrence of ieterus preeox in heterospecifie pregnancies (AB incompatibilities) and its relative r a r i t y in eases of Rh incompatibility seems to point toward a certain connection between the etiology of ieterus precox and the anti-A and anti-B antibodies. However, we cannot accept the explanation suggested by Wiener that the cause of the milder f o r m of hemolytic disease in eases of ABO incompatibilities is due to a selective permeability of the placenta for the Rhblocking antibodies and a relative impermeability for the anti-A-B agglutinins, f o r the following reasons: 1. I n 40 per cent of all newborn babies anti-A-B agglutinins and conglutinins were found in the cord blood that disappeared f r o m the peripheral blood of the newborn infant by the eighth day. They must have, therefore, originated in the blood of the mother. 2. The iso-immunization of the mother caused by the A or B agglutinogen of the child not only produces an increase in the anti-A-B agglutinins but also causes the a p p e a r a n c e of anti-A-B immuno-iso-antibodies (eonglutinins) which can be seen only in a dilution with plasma or p r o t e i n - - a s is the ease with the Rh-blocking antib o d i e s - - a n d therefore is bound to have passed the placenta as the latter does. 3. Icterus preeox occurs not less frequently t h a n the other forms of hemolytic disease, and it occurs in the
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same proportion of one in twenty-five to t h i r t y heterospecific pregnancies, corresponding to one erythroblastosis feta]is in twenty-five to t h i r t y cases of Rh incompatibilities. We are of the opinion, therefore, that we are not dealing with a r a r e r f o r m as would be expected according to W i e n e r ' s theory of selective permeability of the placenta but only with an attenuation of symptoms of the hemolytic diseases of newborn infantsl for reasons as yet unknown. Neither is the theory of the competition of antigens as an explanation for the occurrence of icterus preeox applicable in all eases. I n two of the eases observed by us in which there was an Rh incompatibility, both mother and child belonged to the same group of the ABO system. I n conclusion, we still do not have a plausible explanation of the fact t h a t in certain eases of incompatibility of blood groups between mother and child, ieterus precox develops. SUMMARY
1. To date, we have diagnosed ninety cases of icterus precox among 16,000 births. Almost all of them were caused by an autoimmunization of the mother through the antigen A, B of the children. Only two cases were due to an Rh incompatibility. 2. The blood chemistry of the cord blood in these eases is not materially different f r o m that in nonicterie children. 3. The immediate and future prognosis of the children suffering f r o m ieterus preeox is favorable. 4. The occurrence of ieterus gravis (kernieterus) a f t e r icterus precox in the same family makes special attention and precaution imperative in
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pregnancies following one in which ieterus precox was present. 5. The theories o f competition of antigens, and of selective permeability of the placenta to various isoantibodies, do not satisfactorily explain the occurrence of icterus preeox in certain cases of isoimmunization of the mother against the blood group antigen of her child. REFERENCES 1. ttalbrecht, I.: 248, 1944.
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2. Wiener, A.: Am. J. Dis. Child. 71: 24, 1946. 3. Tortora, M." Arch. obstet, e ginee. 52" 436, 1948. 4. Broncato, G . J . : Am. J. Dis. Child. 80: 287, 1950. 5. Boorman, K. E,, Daley, D., and Dodd, B. E.: J. Obst. & Gynaec. Brit. Emp. 56" 281. 6. Grumbach, A., and Gasser, C.: ttelvet. paediat, actu 3: 447, 1948. 7. Grundorfer, J . : Am. J. 0bst. & Gynec. 58: 574, 1949. 8. Gurevitch, J., Polisiuk, Z., and I-Ierman, D.: Am. J. Clin. Path. 16: 574, 1946. 9. Broncato, G. J.: Am. J. Dis. Child. 77; 351, 1949. 1O. Halbrecht, I.: Am. J. Dis. Child. 79. 988, 1950.