Hemolytic Disease of the Fetus and Newborn

Key points

Introduction

Hemolytic disease of the fetus and newborn (HDFN) is a potentially life-threatening illness of neonates, caused by maternal-fetal red blood cell antigen incompatibilities. The clinical presentation and natural history are heterogeneous, and range from mildly symptomatic neonates with self-limiting postnatal jaundice to hydrops fetalis and perinatal mortality, including stillbirth. Throughout the last century, there were a significant amount of resources and efforts to ensure the development and maintenance of programs to effectively treat and prevent a large proportion of the morbidity and mortality associated with this disease. However, this problem is far from obsolete.

The most recognized and often severe form of HDFN is that of rhesus (Rh) disease or Rh antigen D (RhD) HDFN (Rh-HDFN or Rh-HDN), caused by maternal antigens to RhD. Historically, Rh disease has caused most of the perinatal morbidity and mortality from HDFN. Thus, the discovery of a means to provide simple and effective prophylaxis against this condition revolutionized the perinatal outcomes and impact of this disease throughout the twentieth and into the twenty-first century. However, most cases of HDFN are not preventable in the same way and are not always able to be predicted. Therefore, careful antenatal and postnatal care and monitoring are required to manage such cases successfully. Effective perinatal care requires adequate education, knowledge, investigation, and management options, as well as access to therapy and resources, including transfusion and blood products.

HDFN remains a significant cause of worldwide perinatal morbidity as well as ongoing high rates of mortality in many parts of the world despite improvement in Rh-HDFN preventive measures (the most severe type of HDFN), to which there is inequitable access globally. HDFN continues to pose a large burden of disease to health care systems internationally. Ongoing focus on HDFN is required to maintain and improve prevention and mitigate poor outcomes. Health care providers in primary and specialty care have a valuable role to play in providing prompt, evidence-based diagnosis, prevention, investigation, and management to at-risk pregnancies and neonates.

History

A French midwife reported the first known documented case of HDFN in 1609, describing twins, 1 of whom died of hydrops on day 1 of life, and the other died on day 3 of life after developing severe jaundice and kernicterus. ¹ From then until the end of the nineteenth century, approximately 70 reports of similar descriptions were seen in the literature. ² It was not until 3 centuries after the first case was described that these symptoms and cases were linked together as part of the same disease process. In 1932, it was elucidated that severe hemolysis and extramedullary erythropoiesis lead to hydrops fetalis, postnatal jaundice, and consequent kernicterus; however, the cause was still not understood. ³ Further research led to the accurate theory that maternal antibodies to fetal red blood cells cross the placenta and cause hemolysis. ⁴ Initially, in 1938, the antibodies were inaccurately postulated to be toward fetal hemoglobin. ⁵

Soon after this, in 1940, the Rh blood group system was defined by Landsteiner and Wiener, ⁷ and the pathogenesis of HDFN became much clearer. ^6 , 7

There are suggestions that HDFN was at least vaguely identified a long time before any of these instances in the history of the English monarchy and that HDFN may have led to the events that triggered the English Reformation in the sixteenth century. ⁸ In 1509, Katherine of Aragon married Henry VIII, and subsequently they had 6 children, 5 of whom died in utero or in early infancy. ⁸ There was only 1 surviving girl, and, because of the perceived lack of ability of produce a live male heir, Henry VIII sought an annulment of the marriage. There were conflicts with the Pope over this request, and the marriage was annulled by the Archbishop of Canterbury, subsequently resulting in the English split from Rome. If the deaths of these offspring were caused by HDFN, as postulated by Rosse ⁹ , HDFN has significantly shaped English and Roman history, and thus the world today. ⁸

Some investigators even argue that the description of HDFN in the medical literature extends much earlier than these times. Hippocrates, often referred to as the Father of Medicine, described a condition called fetus carnosus, which is thought by medical historians to have represented fetal hydrops as early as 400 bc . ^10 , 11

It was not until 1940 that Karl Landsteiner, an Austrian physician and immunologist, and Alexander Wiener, an American immunohematologist, discovered and described the Rh blood group system, in addition to the previously described ABO system, by immunizing cells of guinea pigs and rabbits. ^6 , 7 In 1941, Philip Levine, another American immunohematologist, showed that the RhD antigen was the immune target to the immunoglobulin (Ig) G response seen in erythroblastosis fetalis and showed the ability of the antibody to cross the placenta. ^12 , 13 This work led to the understanding of Rh-HDFN but also the physiologic understanding of how all types of HDFN occur.

Levine continued his work in this area, and in 1956 he showed that the risk of sensitization to the RhD antigen is decreased if the fetus is also ABO incompatible to the mother and the mother has type O blood group. ¹⁴ Any fetal cells that enter the maternal circulation are rapidly hemolyzed by the potent and innate maternal anti-A and/or anti-B antibodies, thus reducing the likelihood of maternal exposure to the RhD antigen and subsequent sensitization. ^15 , 16

In 1961, Ronald Finn, an English medical researcher, made 2 important revelations. He showed that fetal red blood cells circulate in the maternal system in RhD-negative mothers; in fact, in all mothers. ¹⁷ He then went on to show that administration of passive anti-D immunoglobulin (Ig) G accelerated the clearance of RhD-positive red blood cells administered to RhD-negative male volunteers. In 1963, Vincent Freda, an American obstetrician, produced the first specific anti-D immunoglobulin preparation. ^18 , 19 In the same year, Schneider, ²⁰ a German physician, was able to show similar results in nonpregnant RhD-negative female volunteers who were given passive anti-D to protect against immunization after infusion of RhD-positive cells. ¹⁹ This work has formed the basis of the prevention of sensitization in pregnant women and has saved millions of lives around the world since this discovery.