LAUSR

This paper seems rather odd, for an anniversary classic article, being rather short and without references. It was the final article of a group of six selected by the Editor-inChief, R.E. Rosenfield, from a symposium on the Immunologic Suppression of Primary Rh Antibody Formation held at the 20th AABB meeting in October 1967. Two papers described experiments on antibody suppression in rabbits and four on clinical experience with Rh immunoglobulin in post-partum women from trials in California, Liverpool, Edinburgh, and New York (the William Pollack article). These were summaries of trials showing remarkably effective prevention of primary immunization in Rh-negative mothers when they were given Rh antibody within 3 days of delivery of an Rh-positive infant. To achieve this wonderful result there was an extensive national and international collaboration, as can be seen from the Acknowledgements. In 1968, Rh immunoglobulin was approved for clinical use in the US and UK; other countries quickly followed. This enabled the start of routine prophylaxis to prevent hemolytic disease of the fetus and newborn (HDFN) – perhaps the most successful preventative medicine of the 20th century. This treatment was the result of many years of observations, experiments, and discoveries by obstetricians, pediatricians, pathologists, geneticists, blood group serologists, immunologists, and biochemists. It is quite a story! The earliest report of HDFN was written in 1609 by Louyse Bourgeois, the midwife to Marie de Medici in Paris. Twins were born, the first had hydrops (edema) and soon died, the other had rapidly worsening jaundice (icterus) and died on the third day. In 1938, Ruth Darrow (Chicago) reviewed many reports of “Icterus Gravis Neonatorum.” Infants with hydrops or severe jaundice rarely survived beyond a week. Kernicterus, caused by bilirubin toxicity of motor neurons in the brain, resulted in neonatal death or lifelong disability in survivors. Other symptoms were anemia, erythroblastosis, splenomegaly, hepatomegaly, and dark amniotic fluid. The disease occurred in families although the first child was usually unaffected. Darrow concluded that the mother was immunized against a component of fetal red blood cells (RBCs) when they gain access to placental sinuses, inducing antibodies that then passed through the placenta and milk to the fetus/ neonate. Because there was no relationship to the known blood group antigens (A, B, M, N, P), she thought antibodies to fetal hemoglobin, known to differ from adult hemoglobin, destroyed RBCs. She had identified the correct pathogenesis except for the antigen. What was the component of RBCs that caused maternal immunization? It took several years to find out. Karl Landsteiner, who had discovered the ABO blood group in 1900, and Alexander Wiener (New York, 1940) injected rabbits with blood from Rhesus monkeys. The antisera reacted moderately with 39 of 45 human blood samples. They designated the agglutinable factor “Rh.” At the time, human blood samples were typed by mixing anti-Rh with saline-diluted blood on a slide and waiting for 2 h to check agglutination. Patients with severe reactions after ABO-matched transfusion typed Rh-negative and donors Rh-positive. Infants with HDFNwere Rh-positive while most of their mothers typed Rh-negative (Philip Levine, 1941). However, anti-Rh agglutinins made by the patients and mothers were undetectable or only weak and transient. How could they cause fatalities? Wiener (1944) and Ruth Race (1944) simultaneously discovered that these hidden antibodies were “blocking” Received: 30 November 2021 Accepted: 30 November 2021