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History of Alloimmunization and Treatment Options

Before the development of modern medicine, infant mortality was high, often due to unknown causes. On one occasion, during a twin birth, one neonate was grossly swollen and stillborn, while the other developed severe jaundice and died a few days later. We now understand the swelling as hydrops, and the severe jaundice as kernicterus; both of which are components of Hemolytic Disease of the Fetus and Newborn (HDFN). In those days there was nothing to be done, no hope for infants with HDFN.

It wasn’t until the 20th century that there was any notable progress with HDFN. In 1911 the discovery of the ABO blood group led to huge medical advancements. Patients needing transfusions were matched to donors using a new system of testing for ABO compatibility. The transfusion mortality rate went down, and scientists started studying blood types more and more. In 1921, Unger reported on strange incompatibilities between patients with the same blood type. When the blood of a patient and a donor was mixed in vitro, it clumped, or agglutinated. Unger didn’t know it yet, but he had just discovered the cause of HDFN, a deadly disease resulting from maternal alloimmunization. As a result of his findings, Unger recommended that the blood of the patient and donor be mixed before transfusion to be certain they were compatible. In 1932 Diamond and colleagues described the neonatal disease and proposed the term erythroblastosis fetalis based on the finding of circulating erythroblasts (nucleated red blood cells). However, 30% of fetuses continued to die in utero. Premature delivery was attempted to prevent these cases however a clinical trial in England failed to find that this resulted in improved neonatal outcome as prematurity itself was often associated with neonatal death.

Investigation  into blood types continued and in 1940 Landsteiner and Weiner did an experiment involving Rhesus monkeys. They discovered what is now known as the Rhesus factor (Rh), leading to the Rhesus factor being added to a person’s blood type. This set the stage for Robert Coombs. Around 1945, he created both the Indirect Agglutination Test (IAT), also called the Indirect Coombs Test, and the Direct Agglutination Test (DAT), also called the Direct Coombs Test, both of which are invaluable to the detection of HDFN. After the introduction of the IAT, there was a rapid increase in identifying alloantibodies. Around this time approximately 245 blood cell antigens were discovered and classified into 29 blood group systems. New antigens are still being discovered today. By 1950, though alloimmunization could be identified and tested for, there was still no prenatal intervention or hope available for HDFN.

The 1950s and 1960s saw the greatest advancement for treatment of HDFN. In 1958, Bevis performed the first analysis of amniotic fluid and found bilirubin. Around the same time, Cremer created the first artificial phototherapy unit to help infants with jaundice, the first non-invasive treatment option for the other major side effect of HDFN. Bevis’ discovery of bilirubin in amniotic fluid led to Liley’s extensive work in the 1960s where he created a chart for normal and high bilirubin in amniotic fluid. In the early 1960s, it was too risky to directly test the fetus, so the amniotic fluid was tested instead. As fetal blood cells die, they produce bilirubin, which is then excreted into the amniotic fluid. Liley was able to use the bilirubin measurements to determine if a fetus was anemic. In 1963 Liley conducted the first intraperitoneal intrauterine transfusion, the first maternal Intrauterine Transfusion (IUT) by injecting donor blood directly into the fetus’ abdomen. The fetal position was first determined using palpation of the pregnant woman’s abdomen. Liley then taped paper clips on the mother’s belly and then took an Xray. He then blindly placed a needle into the pregnant uterus and into the fetal abdomen! This procedure was fraught with difficulties and risks, but was the only treatment option available for HDFN at the time and offered alloimmunized women a glimpse of hope.

In 1965 Rewald and Suringar reported the first use of Intravenous Immune Globulin (IVIG), an infusion therapy whereby donor antibodies from the plasma of non-alloimmunized individuals are introduced to the maternal bloodstream to prevent stillbirth due to HDFN. IVIG works in one of these three ways: by reducing the amount of antibodies in the maternal circulation, by restricting the antibodies from crossing the placenta, or by making the fetus mitigate the effects of the antibodies. This drug is still used today, though it is not a consistently used treatment. IVIG has been used in hundreds of case reports to successfully reduce effects of HDFN. IVIG is also used after birth in cases of high bilirubin and anemia.

Just three years later the first preventation for alloimmunization was discovered; a drug called Rhesus immune globulin (RhoGAM©). This breakthrough helped pregnant women who were Rh- to carry an Rh+ fetuses without becoming alloimmunized to the D antigen. The sensitization rates for anti-D plummeted as RhoGAM© became well studied and more widely available. In the mid-1980’s, many countries added a second dose of RhoGAM© to be administered at 7 months into the pregnancy to further reduce the risk of D alloimmunization. Unfortunately no preventative measures are available for the rest of the 245+ antigens that have been discovered. The number of D alloimmunized pregnancies began to decline , but advancements in care were still desperately needed. In addition, no preventative medications are available to prevent alloimmunization to the remaining 245+ red cell antigens that have been discovered – so alloimmunization to come of these antigens continues to this day.

Advancements continued and in 1980 Angela and Robinson used plasmapheresis (removing maternal blood and separating plasma before transfusing blood back into the mother) to reduce the amount of circulating antibodies. In 1981, Rodeck introduced the intravenous transfusion (IVT) by placing a needle into the umbilical vein of the fetus again, but this time with the aid of a fiberoptic fetoscope (a tiny telescope placed into the womb to find a blood vessel on the surface of the placenta). The intrauterine transfusion was still very difficult, but the procedure became much more successful. Around this time, ultrasound-guided fetal blood sampling began, and in 1982 ultrasound-guided Band described the first successful IVT following cordocentesis begins. This was the decade that in utero treatment for HDFN really evolved and became more commonplace. Higher procedure success rates meant that more women were giving birth to live babies, but these infants still suffered from jaundice and late onset anemia. 1987 saw Hara first use IVIG on an infant to help with late onset anemia. Five years later, Ohls used erythropoietin – a hormone given as an injection to make the bone marrow produce more red blood cells. This was used to treat infants with late onset anemia as well. Both practices are still in use today.

Since Liley’s work in the 1960s, amniocentesis was still the only way to check for fetal anemia. Unfortunately Liley’s original chart only worked after 27 weeks gestation. In 1993 Queenan developed his chart for assessing the severity of HDFN from 14-40 weeks gestation. This allowed for earlier fetal assessment and intrauterine transfusions. One problem still remained to be solved: amniocentesis raised the risk of developing additional antibodies and increasing maternal titers. In 1995, Mari et al conducted groundbreaking work which solved that problem and revolutionized the care of an alloimmunized pregnancy. Mari and colleagues used a specialized doppler ultrasound of the middle cerebral artery (MCA) in the fetal brain, to measure the peak systolic velocity of the blood. The faster the blood flows, the more anemic the fetus is. This revolutionized fetal monitoring for HDFN and eliminated the risks associated with the invasive amniocentesis procedure. Today, we no longer use serial amniocentesis as a way to check for anemia;  instead it has been replaced with MCA scans starting as early as 15 weeks.

The next big advancement came in the late 1990s. In 1997 fetal DNA was discovered in maternal plasma. Just one year later cell free fetal DNA was being used to check the RhD antigen status of the fetus. This meant that RhoGAM© could be avoided if an Rh- woman was found to be carrying an Rh- fetus. It also meant that a sensitized Rh- woman with an Rh+ fetus would be more closely monitored for signs of anemia. This advancement is still being developed today. Today some countries are able to test for the Kell, D, C/c, and E/e antigen status of the fetus simply by drawing the mother’s blood. While many testing facilities are located in Europe, blood may be drawn from anywhere in the world and shipped for testing.

In 2003, Trevett et al published material showing that the maternal administration of phenobarbital reduces the need for exchange transfusion in infants with HDFN. This drug can help mature the fetal liver so that the neonate is better able to process the higher levels of bilirubin. Just two years later, Kirplani reported the first use of IVIG on a fetus in utero for Rh disease. By the end of 2009, 400 years after the first suspected cases of HDFN were reported, we now have several methods to test for the disease, lower maternal titers, help the fetus in utero, and treat issues in the newborn.

2019 has brought the development of a new drug, Nipocalimab also known as M281. M281 is a monoclonal antibody that blocks antibodies from crossing the placenta. The U.S. Food and Drug Administration has fast tracked the drug as a treatment for HDFN. Studies on alloimmunized pregnant women who have previously given birth to a severely affected fetus are underwayhave begun. Today alloimmunization is no longer the death sentence it was years ago.Today women in developed countries have hope and an expectation for a successful pregnancy with the appropriate medical care. Though many consider Rh disease to be eradicated due to RhD prophylaxis (RhoGAM©), limited access to quality care, and alloimmunization to other red blood cell antigens remain a significant problem. Once a woman is alloimmunized, appropriate management of her affected pregnancies is essential. Unfortunately, a lack of standardized care and provider experience along with a lack of access to treatment options poses a significant threat to an alloimmunized woman’s child. Alloimmunization claims hundreds of thousands of lives around the globe each year in countries without the technology described above. We still have a long way to go before this dangerous disease is properly and consistently treated.


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