From Tragedy to Triumph: Canadian Connections in the Management of Rhesus Hemolytic Disease of the Newborn

Abstract

J ohn Ballantyne (1861Ballantyne ( -1923 of Edinburgh wrote that the first record of fetal hydrops was given by Hippocrates in The Epidemics with a description of a "fleshy foetus" with "general foetal dropsy." 1 It is probable that the French midwife, Louise Bourgeois (1563-1636), gave the first account of hemolytic disease of the newborn in her 1609 midwifery text. 2 She reported the case of a multiparous woman who delivered twins; one was hydropic and died soon after birth, and the other developed jaundice and died on the fourth day. DEFINITION OF THE DISEASEUntil the 1930s the disease entity we now know as Rhesus (Rh) hemolytic disease of the newborn was not defined and was represented by four, at that time not necessarily related, disorders: hydrops, neonatal jaundice, anemia, and erythroblastosis. This constellation of disorders was first grouped as being from a single cause in 1930 by the Canadian-born John Ferguson (b. 1900) while working as a junior pathologist at Harvard University. 3 In his report of six neonatal deaths with erythroblastosis he concluded that hydrops, jaundice, and erythroblastosis "are probably representative of a definite disease entity of the newly born, and whatever the etiology may be, the underlying cause is undoubtedly the same in each instance." 3 The same conclusion was reached the following year by Diamond and colleagues, with the addition of neonatal anemia to the clinical picture. 4 It was also noted that the disease tended to recur from one pregnancy to the next, but never in the affected woman's first pregnancy. PATHOPHYSIOLOGYRuth Darrow (1895-1956) was a general practitioner in Chicago who worked from her medical office and clinic in the basement of her house and held staff privileges at the Women's and Children's Hospital. 5 In 1935, after two uneventful pregnancies, her third baby, a son, developed severe neonatal jaundice and died: the autopsy showed extensive erythroblastosis. While still in medical practice she dedicated the next 2 years to reviewing all the available literature on erythroblastosis fetalis. She concluded that the mother "poisoned" her own infant with some "toxic substance." Darrow eventually deduced that some fetal red cells must pass through the placenta into the maternal blood and initiate an immune reaction. As she put it: "An antigen-antibody reaction seems to explain best all aspects of these related disorders." 5 Thus, in her lonely one-woman review, she succeeded in accurately delineating the pathophysiological mechanism behind erythroblastosis fetalis that had taken the life of her son. However, she concluded, as had others, 4 that "This mechanism, incidentally, bears no relation to a difference in blood groups in mother and child." 5 The full explanation would await the discovery of the Rh blood antigen.

Hereditary thrombotic thrombocytopenic purpura: The risk for death at birth

“…Before treatment with plasma exchange treatment began a century ago, most infants with RhD alloimmunization died 7 . When immunization with Rho(D) immune globulin became available in 1968, severe hemolysis and hyperbilirubinemia in newborn infants became rare 8 . ABO alloimmunization may now be the most common cause neonatal hemolysis and hyperbilirubinemia, but it is rarely severe 9 .…”

“…7 When immunization with Rho(D) immune globulin became available in 1968, severe hemolysis and hyperbilirubinemia in newborn infants became rare. 8 ABO alloimmunization may now be the most common cause neonatal hemolysis and hyperbilirubinemia, but it is rarely severe. 9 When severe hemolysis with hyperbilirubinemia occurs soon after birth, it is often assumed that blood group alloimmunization is the cause.…”

The outstanding scientist, R.A. Fisher: his views on eugenics and race

“…An outcome of this work was Fisher's masterly analysis of the genetics of the Rhesus blood group system (Fisher 1947), which brought order to a chaos of data. Incompatibility between the Rhesus make-up of the mother and foetus is a major cause of haemolytic disease of the newborn; understanding the genetics of Rhesus has enabled this disease to be largely prevented (Baskett 2019).…”

Antenatal and postpartum prevention of Rh alloimmunization: A systematic review and GRADE analysis

“…Rhesus D (Rh D) alloimmunization leading to hemolytic disease in the fetus and newborn, a preventable condition, carries a global burden of infirmity, resulting in some 50,000 fetal deaths annually, primarily in low and middle income countries in Asia and Sub-Saharan Africa [1]. In the developed world, however, the introduction of Rh immunoprophylaxis (RhIg) in the 1960s into routine obstetrical care for Rh negative women at risk lead to a dramatic fall in the number of Rh affected babies and is considered an immunological success story in the conquest of hemolytic disease of the fetus and newborn in these countries [2]. Initial clinical trials of postpartum administration of RhIg by Freda and Gorman in the US demonstrated that sensitization to the Rh-D antigen of Rh negative women delivering Rh positive newborns could be reduced more than tenfold from 14% to approximately 1% when susceptible women were administered RhIg after delivery of these offspring [3].…”