The choice of the subtitle "A Selected Retrospective" denotes two considerations which I was forced to make in preparing this text. First, the topic of neonatal jaundice is a vast one and an exhaustive review of its ancient and modern history could not be performed without the devotion of many years-perhaps a good subject for post-chairmanship recuperation. Thus, the title "selective." I have tried, however, to include those publications which are generally held by modern investigators in the field to have influenced thinking over the past 100 years.
As for the second consideration in the subtitle-" retrospective,"-when I entered medical school in 1954, knowledge of bilirubin chemistry and metabolism was on the very threshold of what we currently hold to be the "truth," but the door had not yet been opened. The textbooks that I read during my courses in physiology, biochemistry and pathology were written prior to the revelation of the chemical difference between direct and indirect-reacting bilirubin by Billing, Cole, and Lathe, Schmid and Talafant in 1956 and 1957. Thus, I recall reading in a monograph by Arnold Rich, a great teacher and scientist, and my pathology professor, a labored and unconvincing attempt to explain the differences between the two forms of bilirubin, direct and indirect. When, in 1959, 1 began to read the new bilirubin literature, the memory of that exposition by Arnold Rich came back. It has stuck with me and forced me to the realization that what we now hold to be "truth" may, in a matter of a few months be made to seem naive, if not foolish. History can only be written with sufficient perspective. In this case, my perspective requires at least a 20 year gap. While I will make passing reference to a few of the highly significant points of modern bilirubin history after 1959, the major view will be backwards.
It seems to me there arc two ways to examine medical history, one by citing the major advances in knowledge as defined by their appearance in periodical publications. The second is to examine the textbooks of the period in an attempt to garner an understanding of the thinking of our leading teachers. I will attempt to do both. The textbooks which I have chosen to use for this purpose are those 19th and early 20th century books which f have in my own collection.
Jaundice in newborn infants has been recognized for many centuries. Indeed, ancient Talmudic analysis devotes space to this issue because of its relevance to the requirement to delay circumcision of the newborn male if jaundice is present. Until the early 19th century, only the more severe forms of neonatal jaundice were generally recognized. This failure to appreciate the milder forms of jaundice may have resulted from the extraordinarily high neonatal death rates of that era. Also, neonatal illness, regardless of etiology, was probably frequently associated with exaggerated jaundice due to starvation, dehydration, generalized infection and even attempts at therapy. Thus, Dewees writes in his 1825 American textbook (as quoted by Thomas Cone),' jaundice in the newborn infant "is but too often fatal, with whatever propriety or energy we may attempt to relieve it." Since Dewees then went on to recommend intensive purging with castor oil and calomel as treatment for neonatal jaundice, the modern pediatrician may well not be surprised at the high mortality associated with jaundice. Two hundred years earlier, Stafford in 1643 advised, for the treatment of jaundice, that one should "boyle a quart of sweet Milke, dissolve therein as much bay-salt or fine Saltpeter, as shall make it brackish in taste and putting Saffron in a fine linen clout, rubb it into the Milke, until the Milke be very yellow; and give it the patient to drink."
There were those, however, even in the 18th century who made the attempt to separate benign from more severe forms of neonatal jaundice. Thus, Juncker, in 1724, speaks on the one hand of "true jaundice" and, on the other hand, "the icteric tinge which may be observed in infants, immediately after birth." The latter, he says, is of no account and disappears spontaneously after the meconium has been passed.
A quote from Bracken's 1737 textbook entitled "The Midwives Companion" gives a perspective on the 18th Century view of neonatal jaundice:
This distemper for the most part seizes infants presently after birth; very often they are born infected with it and therefore it may be supposed they contain the cause of it within themselves without being infected by the nurse; and it is probable that it owes its origin to a glutinous and sizy Humour, insomuch that it may often happen without any obstruction of the biliary duct, although this obstruction is the cause of the jaundice in adult or full-aged persons. . . . I do not remember many practical authors. . . . who have taken notice of the jaundice in infants; nevertheless, many die of it for want of proper and seasonable helps; and most nurses are so stupidly ignorant that they imagine because the poor child grows yellow-consequently it must die, and therefore they will not look out for help.
During the past 100 years, five major themes have dominated thinking about the pathogenesis and treatment of neonatal jaundice. The first of these is the achievement of an understanding of' the chemical basis of jaundice or identification of' the substance causing jaundice as bilirubin. The second theme involves the conceptualization of the biochemical pathways of bilirubin metabolism and transport, both in liver and in blood. The third theme concerns the development of an understanding of erythroblastosis fetalis, especially Rh disease, the major, although not sole, cause of' the severe form of neonatal jaundice known for many years as icterus gravis to distinguish it from physiologic jaundice. The fourth theme and the one still least understood, is that of kernicterus. Finally, the fifth area of concern is the separation of what we now recognize as the unconjugated hyperbilirubinemias from the conjugated or direct-reacting hyperbilirubinemias and a delineation of their diverse etiologies.
Let me now turn to a consideration of the history of each of these issues. Although it was not until 1937 that the chemical structure of bilirubin was defined by Fischer and Orth as that of a tetrapyrrol closely related to hemoglobin, 90 years earlier, in 1847, Virchow isolated bilirubin crystals from hematomas and suggested that bilirubin was derived from blood. Many intervening studies gradually tied that link tighter and tighter, until London and his associates in 1950, using isotopically labelled glycine, definitively demonstrated that heme is the source of bilirubin.
In 1913, Yllpo demonstrated that the newborn had an elevated serum bilirubin concentration, but, of even greater importance in the chemical delineation of neonatal jaundice was the development by Ilymans van den Bergh, in 1916, of the definitive test for measurement of bilirubin and its separation into two chemically distinct compounds labeled by van den Bergh as direct and indirect-reacting bilirubin, terms which dominate all clinical and investigative thinking in the field. It is this conception which, of course, in 1956 and 1957 led to the definitive discovery independently and simultaneously by three groups that direct-reacting bilirubin is the diglucuronide conjugate of bilirubin.[1,2,3] Many elaborations on the nature of the conjugates of' bilirubin and their significance in the newborn have since followed, but they will not be discussed since they fall into the wrong end of my retrospectoscope. Almost immediately after these landmark discoveries came the reports by Lathe and Walker in 1957 and Brown and Zuelzer in 1958 that the newborn was deficient in glucuronyl transferase, the hepatic enzyme responsible for the formation of the glucuronide conjugate of bilirubin. From these observations came the assumption that this single enzyme deficiency was responsible for physiologic jaundice of the newborn; a point still under investigation.
Lathe and Walker were also responsible for another critical observation in our understanding of neonatal jaundice; that was the demonstration that glucuronyl transferase activity was absent in the congenitally jaundiced Gunn rat. It is, of course, to Dr. Gunn, an animal geneticist and fox breeder in Canada, that we owe a special word of appreciation, for it was the availability of this remarkable animal model which has permitted us to learn so much about the nature of bilirubin metabolism and its toxicity to the brain. Dr. Gunn reported his finding, the subject of his Ph.D. thesis, in 1938. The mutant strain of rat was not further studied until the mid 1950's when, through the efforts of Dr. Gerald Lucey, a small colony of the animals was found living in Boston, having been bred throughout that period by Dr. Castle. They now reside in virtually every bilirubin laboratory in the world and have been the subject of many hundreds of papers.
It is an interesting sidelight to this story that Dr. Gunn was unaware of the significance of his discovery, until sometime in the late 1960's when he wrote to Dr. Lucey to inquire whether the animals had ever been found. Dr. Lucey, rather than simply writing back to him, assembled all of the published work which utilized the Gunn rat and sent him a bound volume of these publications.
For the history of erythroblastosis fetalis, to which I now wish to turn, I acknowledge the assistance I received from a 1957 monograph by G. Fulton Robert and an equally scholarly paper on the subject by Drs. Radel and Schorr in 1965.
Erythroblastosis fetalis may well have been described as early as 1609 in France. The report by a midwife named Bourgeois, describes an hydropic infant girl who died 15 minutes after birth with severe jaundice of the placenta and blood. The infant's twin brother also died but was noted to have only respiratory difficulty. The etiology was said to be the mother's excessive ingestion of water and a "heated liver."
In 1654, Panaroli reported another apparent case of hemolytic disease of the newborn in what may be the shortest paper on the subject-a mere 19 words. Ah, that we could be so terse today!
It was in the early 19th century that a perspective on neonatal jaundice began to emerge in which icterus gravis neonatorum was distinguished from the more benign or physiologic jaundice of the newborn." For the most part, the etiology of icterus gravis was thought to be related to obstruction of the bile duct either by glutinous bile, as suggested a century earlier, or by meconium, which had made its way up the duct. Congenital absence of the bile duct or obliteration is also mentioned, obviously confusing two now distinct entities -biliary atresia and erythroblastosis fetalis. Some authors, however, recognized the familial nature of icterus gravis and noted patency of the bile duct at autopsy.
Throughout the nineteenth century and for almost a third of the way into the twentieth century, hydrops fetalis and icterus gravis neonatorum were not recognized as having a common etiology or being different expressions of the same disease. Buhrman and Sanford made this link in 1931 as did Diamond, Blackfan and Baty in 1932. The first use of the term "Erythroblastosis fetalis" was by Rautmann in 1912, in reference to an hydropic stillborn. During the 1920's, understanding of the pathophysiology of this disorder advanced exceedingly rapidly with the recognition that erythroblastosis has its onset in utero and that hemolysis is its underlying mechanism. Although Halban in 1900 suggested the idea that isoimmunization of the mother could be the basis for erythroblastosis, and Ottenberg in 1923 proposed that feto-maternal transfusion was etiologically responsible, it was the work of Levine and colleagues in 1941 which definitively demonstrated the role of Rh antibodies in the etiology of erythroblastosis fetalis. Of course, their work was built on the landmark discoveries of the Rh factor by Landsteiner and Wiener[30,31] during the previous year. Shortly after the end of World War II, Coombs and colleagues described the now standard test for detection of antibody coated erythrocytes. Just prior to this, in 1944, Halbrecht reported the first recognition of ABO hemolytic disease of the newborn.
For approximately the next 20 years the major efforts in erythroblastosis were directed to the introduction and refinement of exchange transfusion. This period and, in fact, the next 20 years beyond must be looked upon as the age of treatment-a remarkable period of 40 years in which therapy markedly reduced mortality and morbidity and, then, ultimately almost entirely eliminated the disorder through prophylaxis with anti-D immune globulin.
The first exchange transfusion in a newborn was performed in 1925 by Hart for the treatment of erythroblastosis fetalis. It was successful, but was ignored for the next two decades. Wiener, Wexler and Gamrin, in 1944, again tried to perform an exchange transfusion, but failed. (Perhaps there were too many cooks in the treatment room). Two years later,. in 1946, Wallerstein reported the successful exchange transfusion of three infants with erythroblastosis fetalis. His technique utilized the saggital sinus for blood withdrawal and a peripheral vein for infusion. Subsequent practitioners of the art of exchange transfusion used the radial artery for exsanguination and a peripheral vein for infusion, apparently fearing to enter the saggital sinus. Wallerstein, however, had considerable success with his technique and prepared a teaching movie which he took around the country instructing pediatricians in the new method. Within one year, however, Diamond introduced umbilical vein intubation for exchange transfusion, establishing the definitive technique which is still in general use.
The next major therapeutic era begain in 1958 with the report of Cremer and colleagues on the efficacy of light in reducing serum bilirubin concentrations in newborns. The subsequent impact of that observation on the management of neonatal jaundice is covered elsewhere in this book.
Now let me turn to the not-so-ancient history of kernicterus.
The first recorded recognition of yellow staining of the basal ganglia of the brain was by Hervieux in his 1847 doctoral thesis on neonatal jaundice. It was Orth, however, in 1875 who identified the crystals of bilirubin in the basal ganglia of an infant with severe jaundice. Schmorl, in turn, labeled the lesion "kernicterus" in 1903 and described the pathology of the brain, also noting that 5% of the brains of infants dying with severe jaundice were stained with bilirubin. The clinical manifestations of the lesion were described by Esch, five years later.
The pathogenesis of the basal ganglia lesions has been actively debated in the literature throughout the twentieth century and is likely to continue to be debated well into the twenty-first century. Orth attributed the lesion to a primary necrosis of brain cells with secondary staining by bilirubin. Schmorl believed the primary cell injury was vascular in nature with either a toxin such as bile or vascular thrombosis as the etiology. He too believed the bile staining to be secondary. Several authors suggested that bacterial infection injured the cells sufficiently to permit entry of bilirubin along with lipid, while others implicated toxins, shock, bile salts and even trauma. It is fair to say that to this very day, we do not yet know the true biochemical pathology of kernicterus, nor can we attribute to bilirubin alone the responsibility. Yet, the occurrence of kernicterus in the Gunn rat and especially in the genetically identical Crigler-Najjar Syndrome described in 1951 by the investigators whose syndrome bears their names, and in which there are no apparent defects other than severe unconjugated hyperbilirubinemia, strongly argues for the primacy of unconjugated bilirubin in the etiology of kernicterus.
The now widely accepted contributory role of defective albumin binding in the pathogenesis of kernicterus was elaborated by Odell in 1959, just making it into my retrospective but also notable because as a medical student investigator in 1957 in that same laboratory but working on a different project, I watched Gerry Odell perform those now famous studies demonstrating the displacing effect of sulfisoxazole on albumin binding of bilirubin. The impetus for these studies came, of course, from the elegant, controlled clinical trial of William Silverman and colleagues, reported in 1956, showing an increased incidence of kernicterus in those premature infants assigned at random to an antibacterial regimen containing sulfisoxazole.
I would now like to take a brief glimpse at the textbook views of neonatal jaundice during the end of the nineteenth century and first half of the twentieth century.
In 1885, Murchison, in his textbook on diseases of the liver states, "In a large number of the cases of so-called jaundice of new-born children (icterus neonatorum), the yellow colour which appears on the third or fourth day after birth is not due to jaundice, but is merely the result of changes in the blood in the over-congested skin, the vivid redness of the new-born babe fading as bruises fade, through shades of yellow into the genuine flesh colour." However, Murchison's views on "real jaundice" in newborns, including his clinical and pathologic descriptions of biliary atresia are remarkably modern.
In the first edition of Holt's The Diseases of Infancy and Childhood published in 1897, and continuously since then, (now as Rudolph's Pediatrics with the 17th edition in press) the clinical description of physiologic jaundice is entirely compatible with modern concepts. However, the mechanism suggested by Holt to explain physiologic jaundice was that bile pigment is resorbed from the small bile ducts in the liver of the newborn, due to vascular congestion which obstructs the flow of bile. Filatov, in his Russian textbook of 1904, offered virtually the same explanation, although the additional suggestion was made that the intrahepatic bile ducts may also be obstructed by desquamated bilary epithelial cells.
Only five years later, in 1909, Keller, of Berlin, in Abraham Jacobi's textbook, Diseases of Children, discarded all previous suggestions as to the etiology of physiologic jaundice and attributed it to the "peculiar conditions of metabolism of the first days of life." He felt that these metabolic disorders were related to nutrition and that physiologic jaundice could be ameliorated by early and adequate milk feeding.
The tenth edition of Holt's textbook under the editorship of Holt Jr. and Bustin McIntosh, holds special interest for me because it was published in the year of my birth, 1933. By this time, the etiologic concepts are much more in tune with modern views. Thus, physiologic jaundice is ascribed to "increased blood destruction" coupled with "a limited capacity on the part of the liver cells to excrete bile pigment." In their discussion of differential diagnosis, Holt and McIntosh note that the van den Bergh reaction is indirect in physiologic jaundice. In the next paragraph, however, they speak of severe forms of "physiologic jaundice" in which there is direct-reacting bilirubin, "identical with" the findings in "obstructive hepatitis due to bile duct malformations or syphilis." Some of the old concepts die hard. They also note that physiologic jaundice may persist for two or even three months. Thus, it would appear in the light of present day concepts that there was much confusion in the use of the term "physiologic jaundice," in 1933, and a failure to fully comprehend the application of the van den Bergh reaction in the diagnosis of neonatal jaundice. It is also noteworthy that although passing mention is made of bilirubin staining of the basal ganglia in some infants who die, Holt and McIntosh do not refer to kernicterus anywhere in the textbook, nor do they describe the symptomatology associated with severe jaundice. This is rather surprising, considering that kernicterus had been well characterized in Europe more than 25 years earlier.
In the 12th edition of the same textbook, Holt and McIntosh devote more discussion to the importance of the van den Bergh reaction, but state that only physiologic jaundice and erythroblastosis need be considered in jaundice which has its onset in the first week of life. Kernicterus is now given its due, but is said to occur only in association with erythroblastosis and severe sepsis; the antigen-antibody reaction of Rh hemolytic disease and not bile pigment is stated as being responsible for nerve cell injury in kernicterus. With publication of the 13th edition in this series, now edited by Holt, McIntosh and Barnett, in 1962, virtually all of the current ideas are expressed.
After recognizing how embarrassing it can be to examine textbook statements from years back, I thought it best not to examine the statements contained in the 14th, 15th, and 16th editions of this textbook, since I am afraid that I must take personal responsibility for them. I will leave that critical role to future historians.
I think there is no doubt that we have gone quite far down the yellow brick road, but even if we were to add the last 25 years of the history of neonatal jaundice, which I intentionally omitted, I think we can safely conclude that we have not yet reached the Land of Oz, which, as I recall, was green.
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2. Schmid R.: The identification of "direct reacting" bilirubin as bilirubin glucuronide. J. Biol. Chem. 229:881, 1957.
3. Talafant E.: Properties and composition of the bile pigments giving a direct diazo reaction. Nature 178:312, 1956.
4. Dewees W. P.: Treatise on the Physical and Medical Treatment of Children. First Edition. Philadelphia. Carey and Lea, 1825.
5. Cone T. E. Jr.: History of American Pediatrics. Little, Brown and Co. Boston, 1979. p. 191.
6. Stafford E.: From letter to John Winthrop, Sr. May 6, 1643.
7. Juncker D. L.: Conspectus Medicinae Theoreticopracticae. Halae Magdeburgeicae, p. 717, 1724.
8. Bracken H.: The Midwives Companion. Book 3, London, 1737.
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10. Virchow R.: Die Pathologischen pigmente. Arch. Pathol. Anat. 1:379, 1847.
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18. Roberts G. F.: Comparative Aspects of Haemolytic Disease of the Newborn. Heinemann Medical Books, Ltd., London, 1957.
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21. Panaroli D.: Iatrologismorum sive observationum medicinalium. Pentacostae quarta. obs. 44, p. 137, 1654.
22. Buhrman W. L., Sanford H. N.: Is familial jaundice of newborn infants erythroblastosis fetalis? Amer. J. Dis. Child. 41:225, 1931.
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24. Rautmann H.: Ueber blutbildung bei fotaler allgemeiner wassersuch. Beit. Z. Path. Anat. u. z. allg. Path. 54:332, 1912.
25. Hampson A. C.: Grave familial jaundice of newly-born. Lancet 1:429, 1929.
26. Damashek W., Greenwalt T. J., Tat, R. J.: Erythroblastosis fetalis (acute hemolytic anemia of the newborn). Amer. J. Dis. Child. 65:571, 1943.
27. Halban J.: Agglutinationsversuche mit muuterlichen and kinderlichen blute. Wien Klin. Woch. 13:545, 1900.
28. Ottenberg R.: The etiology of eclampsia: historical and critical notes. J. Amer. Med. Ass. 81:295, 1923.
29. Levine P., Burnham L., Katzin E. M. et al.: The role of isoimmunization in the pathogenesis of erythroblastosis fetalis. Amer. J. Obstet. & Gynec. 42:925, 1941.
30. Landsteiner K., Wiener A. J.: An agglutinable factor in human blood recognized by immune sera for rhesus blood. Proc. Soc. Exp. Biol. & Med. 43:223, 1940.
31. Landsteiner K., Wiener A. J.: Studies on an agglutinogen (Rh) in human blood recognizable by human sera for rhesus blood. J. Exp. Med. 74:309, 1941.
32. Coombs R. R. A., Mourant A. E., Race R. R.: A new test for detection of weak and `incomplete' Rh agglutinins. Brit. J. Exp. Path. 26:255, 1946.
33. Halbrecht L: Role of hemagglutinins anti-A and anti-B in pathogenesis of jaundice of newborn (icterus neonatorum precox). Amer. J. Dis. Child. 68:248, 1944.
34. Hart A. P.: Familial icterus gravis of the newborn and its treatment. Canad. Med. Assn. J. 15:1008, 1925.
35. Wiener A. S., Wexler I. B., Gamrin E.: Hemolytic disease of the fetus and the newborn infants with special reference to transfusion therapy and the use of the biological test for detecting Rh sensitivity. Amer. J. Dis. Child. 68:317, 1944.
36. Wallerstein H.: Treatment of severe erythroblastosis fetalis by simultaneous removal and replacement of the blood of the newborn infant. Science 103:583, 1946.
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44. Crigler J. F., Najjar V. A.: Congenital familial nonhemolytic jaundice with kernicterus. Pediatrics 10:169, 1952.
45. Odell G. B.: Studies in kernicterus. 1. The protein binding of bilirubin. J. Clin. Invest. 38:823, 1959.
46. Silverman W. A., Anderson D. H., Blank W. A. et al.: A difference in the mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics 18:614, 1956.
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