Rh disease
Encyclopedia
Rh disease is one of the causes of hemolytic disease of the newborn
(HDN). The disease ranges from mild to severe, and typically occurs only in some second or subsequent pregnancies of Rh negative women where the fetus's father is Rh positive,leading to a Rh+ pregnancy. During birth, the mother may be exposed to the infant's blood, and this causes the development of antibodies, which may affect the health of subsequent Rh+ pregnancies. In mild cases, the fetus may have mild anaemia with reticulocytosis
. In moderate or severe cases the fetus may have a more marked anaemia and erythroblastosis (erythroblastosis fetalis). When the disease is very severe it may cause HDN, hydrops fetalis
, or stillbirth
.
Rh disease is generally preventable by treating the mother during pregnancy or soon after delivery with an intramuscular injection
of anti-RhD immunoglobulin (Rho(D) immune globulin
). The RhD protein is coded for by the RHD
gene.
can enter the mother's circulation. If the mother is Rh negative and the baby is Rh positive, the mother produces antibodies
(including IgG) against the Rhesus D
antigen
on her baby's red blood cell
s. During this and subsequent pregnancies the IgG is able to pass through the placenta
into the fetus
and if the level of it is sufficient, it will cause destruction of Rhesus D positive fetal red blood cells leading to the development of Rh disease. It may thus be regarded as insufficient immune tolerance in pregnancy
. Generally Rhesus disease becomes worse with each additional Rhesus incompatible pregnancy.
The main and most frequent sensitizing event is child birth (about 86% of sensitized cases), but fetal blood may pass into the maternal circulation earlier during the pregnancy (about 14% of sensitized cases). Sensitizing events during pregnancy include miscarriage
, therapeutic abortion
, amniocentesis
, ectopic pregnancy
, abdominal trauma and external cephalic version
. However, in many cases there was no apparent sensitizing event.
The incidence of Rh disease in a population depends on the proportion that are rhesus negative. Many non-caucasian peoples have a very low proportion who are Rhesus negative, so the incidence of Rh disease is very low in these populations. In Caucasian populations about 1 in 10 of all pregnancies are of a Rhesus negative woman with a Rhesus positive baby. It is very rare for the first Rhesus positive baby of a Rhesus negative woman to be affected by Rh disease. The first pregnancy with a Rhesus positive baby is significant for a rhesus negative woman because she can be sensitized to the Rh positive antigen. In Caucasian populations about 13% of Rhesus negative mothers are sensitized by their first pregnancy with a rhesus positive baby. If it were not for modern prevention and treatment, about 5% of the second Rhesus positive infants of Rhesus negative woman, would result in stillbirths or extremely sick babies and many babies who managed to survive would be severely ill. Even higher disease rates would occur in the 3rd and subsequent Rhesus positive infants of rhesus negative woman. By using anti-RhD immunoglobulin (Rho(D) Immune Globulin) the incidence is massively reduced.
Rh disease sensitization is about 10 times more likely to occur if the fetus is ABO compatible with the mother than if the mother and fetus are ABO incompatible.
), sold under the brand name RhoGAM. This is done so that the fetal Rhesus D positive erythrocytes are destroyed before her immune system can discover them. This is passive immunity and the effect of the immunity will wear off after about 4 to 6 weeks (or longer depending on injected dose) as the anti-Rh antibodies gradually decline to zero in the maternal blood.
It is part of modern antenatal care to give all Rhesus D negative pregnant women an anti-RhD IgG immunoglobulin injection at about 28 weeks gestation (with or without a booster at 34 weeks gestation). This reduces the effect of the vast majority of sensitizing events which mostly occur after 28 weeks gestation. Anti-RhD immunoglobulin is also given to non-sensitized Rhesus negative women immediately (within 72 hours - the sooner the better) after potentially sensitizing events that occur earlier in pregnancy.
Fetal blood (or umbilical cord blood)
Postnatal
and Alexander S. Wiener
.
In 1939 Philip Levine
and Rufus E. Stetson published their findings about a family who had a stillborn
baby who died of hemolytic disease of the newborn
. The mother was aged 25 and it was her second pregnancy
and she suffered blood loss at the delivery. Both parents were blood group O and the husband's blood was used to give the mother a blood transfusion
, but the mother suffered a severe transfusion reaction. They investigated this transfusion reaction. Since the mother and the father were both blood group O, they concluded that there must be a previously undiscovered blood group antigen
that was present on the husband's RBCs but was not present on the mother's RBCs and that the mother had formed antibodies against the new blood group antigen. This suggested for the first time that a mother could make blood group antibodies because of immune sensitization to her fetus
's RBCs. They did not name this blood group antigen, but it was subsequently found to be the Rhesus factor.
The first treatment for Rh disease was an exchange transfusion
, which was invented by Dr. Alexander S. Wiener
. That procedure was further refined by Dr, Harry Wallerstein, a transfusionist. Although the most effective method of treating the problem at the time, it was only partially ameliorative in cases where damage to the neonate had already been done. Children with severe motor damage and/or retardation could result. However, it is estimated that in the two decades it was used approximately 200,000 lives were saved, and the great majority were not brain damaged.
Ronald Finn
, in Liverpool
, England applied a microscopic technique for detecting fetal cells in the mother's blood. It led him to propose that the disease might be prevented by injecting the at-risk mother with an antibody against fetal red blood cells. He proposed this for the first time to the public on February 18, 1960. A few months later, he proposed at a meeting of the British Genetical Society that the antibody be anti-RhD.
Nearly simultaneously with him, William Pollack, then of Ortho Pharmaceutical Corporation, and researchers John Gorman and Vincent Freda of New York City's Columbia-Presbyterian Medical Center, having come to the same realization, set out to prove it by injecting a group of male prisoners at Sing Sing Correctional Facility with antibody provided by Ortho, obtained by a fractionation technique developed by Dr Pollack (who also provided Dr. Finn with several vials of antibody during a visit by Dr. Finn to Ortho).
Animal studies had previously been conducted by William Pollack, using a rabbit model of Rh. This model, named the rabbit HgA-F system, was a perfect animal model of human Rh, and enabled Dr. Pollack's team to gain experience in preventing hemolytic disease in rabbits by giving specific HgA antibody, as was later done with Rh-negative mothers. One of the needs was a dosing experiment that could be used to determine the level of circulating Rh-positive cells in an Rh-negative pregnant female derived from her Rh-positive fetus. This was first done in the rabbit system, but subsequent human tests at the University of Manitoba conducted under Dr. Pollack's direction confirmed that this result matched the human dosing perfectly. The dose is 20 µG of antibody for 1mL of Rh-positive red cells.
Sir William Liley
performed the first successful intrauterine transfusion in 1963.
Dr. Gorman's sister-in-law was the first at risk woman to receive a prophylactic injection on January 31, 1964. Clinical trials set up by Dr. Pollack in 42 clinical centers in the US, Great Britain, Germany, Sweden, Italy, and Australia confirmed their hypothesis, and the vaccine was finally approved in England and the United States in 1968. The FDA approved the drug under the name RhoGAM, with a fixed dose of 300 µG, to be given within three days postpartum. There being no known harm done by delaying the dosage for a week or more after birth, Ortho asked the FDA to grant permission for it to be given without a postpartum time restriction. In addition, Dr. John M. Bowman, one of the researchers at the University of Manitoba, and Dr Freda pushed to allow antepartum use. All of this was subsequently granted. Within a year or so, the antibody had been injected with great success into more than 500,000 women. Time magazine picked it as one of the top ten medical achievements of the 1960s. By 1973, it was estimated that in the US alone, over 50,000 babies' lives had been saved. The use of Rh immune globulin to prevent the disease in babies of Rh negative mothers has become standard practice, and the disease, which used to claim the lives of 10,000 babies each year in the US alone, has been virtually eradicated in the developed world. The achievement was made almost entirely without support from the NIH, who rejected the New York group's proposal twice. The group got instead only a small grant ($329,765 over 10 years) from the City of New York. The total cost of the effort was only a couple of million dollars, which is about the cost of the life-time care of a half-dozen irreparably brain-damaged children. In 1980, Prof Cyril Clarke
, Dr Ronald Finn
, Dr John Gorman, Dr Vincent Freda, and Dr William Pollack each received an Albert Lasker Award for Clinical Medical Research for their work on Rhesus blood types and the prevention of Rh disease.
Two of the Canadian researchers from the University of Manitoba
, Dr. Bruce Chown
and Dr. John M. Bowman, licensed a version of the vaccine, known as WinRho SD, in 1980. The drug is sold in 35 countries by the Manitoba-based research firm Cangene, listed on the Toronto Stock Exchange with worth of about $175 million. Cangene was purchased by the Winnipeg Rh Institute, a facility founded by Chown and Bowman and dedicated to conducting research into blood related diseases. Dr. Chown is honored by the Canadian Medical Hall of Fame
for his lifelong work with erythroblastosis fetalis.
Hemolytic disease of the newborn
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta...
(HDN). The disease ranges from mild to severe, and typically occurs only in some second or subsequent pregnancies of Rh negative women where the fetus's father is Rh positive,leading to a Rh+ pregnancy. During birth, the mother may be exposed to the infant's blood, and this causes the development of antibodies, which may affect the health of subsequent Rh+ pregnancies. In mild cases, the fetus may have mild anaemia with reticulocytosis
Reticulocytosis
Reticulocytosis is a condition where there is an increase in reticulocytes, immature red blood cell.It is commonly seen in Anemia. They are seen on blood films when the bone marrow is highly active in an attempt to replace red blood cell loss such as in haemolytic anaemia, haemorrhage.-External...
. In moderate or severe cases the fetus may have a more marked anaemia and erythroblastosis (erythroblastosis fetalis). When the disease is very severe it may cause HDN, hydrops fetalis
Hydrops fetalis
Hydrops fetalis is a condition in the fetus characterized by an accumulation of fluid, or edema, in at least two fetal compartments. By comparison, hydrops allantois or hydrops amnion are an accumulation of excessive fluid in the allantoic or amniotic space respectively.-Presentation:Locations can...
, or stillbirth
Stillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...
.
Rh disease is generally preventable by treating the mother during pregnancy or soon after delivery with an intramuscular injection
Intramuscular injection
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of several alternative methods for the administration of medications . It is used for particular forms of medication that are administered in small amounts...
of anti-RhD immunoglobulin (Rho(D) immune globulin
Rho(D) Immune Globulin
Rho Immune Globulin is a medicine given by intramuscular injection that is used to prevent the immunological condition known as Rhesus disease...
). The RhD protein is coded for by the RHD
RHD (gene)
Rh blood group, D antigen also known as Rh polypeptide 1 or cluster of differentiaion 240D is a protein that in humans is encoded by the RHD gene....
gene.
Serology
During any pregnancy a small amount of the baby's bloodBlood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
can enter the mother's circulation. If the mother is Rh negative and the baby is Rh positive, the mother produces antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
(including IgG) against the Rhesus D
Rhesus blood group system
The Rh blood group system is one of thirty current human blood group systems. Clinically, it is the most important blood group system after ABO. At Present, the Rh blood group system consists of 50 defined blood-group antigens, among which the 5 antigens D, C, c, E, and e are the most important...
antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
on her baby's red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s. During this and subsequent pregnancies the IgG is able to pass through the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
into the fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
and if the level of it is sufficient, it will cause destruction of Rhesus D positive fetal red blood cells leading to the development of Rh disease. It may thus be regarded as insufficient immune tolerance in pregnancy
Immune tolerance in pregnancy
Immune tolerance in pregnancy or gestational/maternal immune tolerance is the absence of a maternal immune response against the fetus and placenta, which thus may be viewed as unusually successful allografts, since they genetically differ from the mother. In the same way, many cases of spontaneous...
. Generally Rhesus disease becomes worse with each additional Rhesus incompatible pregnancy.
The main and most frequent sensitizing event is child birth (about 86% of sensitized cases), but fetal blood may pass into the maternal circulation earlier during the pregnancy (about 14% of sensitized cases). Sensitizing events during pregnancy include miscarriage
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
, therapeutic abortion
Therapeutic abortion
Therapeutic abortion is abortion induced following a medical diagnosis. Many therapeutic abortions are performed today, with some degree of controversy regarding the quality of life, if there is a genetic condition in the embryo or fetus which is incompatible with life Therapeutic abortion is...
, amniocentesis
Amniocentesis
Amniocentesis is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections, in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
, ectopic pregnancy
Ectopic pregnancy
An ectopic pregnancy, or eccysis , is a complication of pregnancy in which the embryo implants outside the uterine cavity. With rare exceptions, ectopic pregnancies are not viable. Furthermore, they are dangerous for the parent, since internal haemorrhage is a life threatening complication...
, abdominal trauma and external cephalic version
External cephalic version
External cephalic version is a process by which a breech baby can sometimes be turned from buttocks or foot first to head first. It is usually performed after about 37 weeks...
. However, in many cases there was no apparent sensitizing event.
The incidence of Rh disease in a population depends on the proportion that are rhesus negative. Many non-caucasian peoples have a very low proportion who are Rhesus negative, so the incidence of Rh disease is very low in these populations. In Caucasian populations about 1 in 10 of all pregnancies are of a Rhesus negative woman with a Rhesus positive baby. It is very rare for the first Rhesus positive baby of a Rhesus negative woman to be affected by Rh disease. The first pregnancy with a Rhesus positive baby is significant for a rhesus negative woman because she can be sensitized to the Rh positive antigen. In Caucasian populations about 13% of Rhesus negative mothers are sensitized by their first pregnancy with a rhesus positive baby. If it were not for modern prevention and treatment, about 5% of the second Rhesus positive infants of Rhesus negative woman, would result in stillbirths or extremely sick babies and many babies who managed to survive would be severely ill. Even higher disease rates would occur in the 3rd and subsequent Rhesus positive infants of rhesus negative woman. By using anti-RhD immunoglobulin (Rho(D) Immune Globulin) the incidence is massively reduced.
Rh disease sensitization is about 10 times more likely to occur if the fetus is ABO compatible with the mother than if the mother and fetus are ABO incompatible.
Prevention
Most Rh disease can be prevented by treating the mother during pregnancy or promptly (within 72 hours) after childbirth. The mother has an intramuscular injection of anti-Rh antibodies (Rho(D) Immune GlobulinRho(D) Immune Globulin
Rho Immune Globulin is a medicine given by intramuscular injection that is used to prevent the immunological condition known as Rhesus disease...
), sold under the brand name RhoGAM. This is done so that the fetal Rhesus D positive erythrocytes are destroyed before her immune system can discover them. This is passive immunity and the effect of the immunity will wear off after about 4 to 6 weeks (or longer depending on injected dose) as the anti-Rh antibodies gradually decline to zero in the maternal blood.
It is part of modern antenatal care to give all Rhesus D negative pregnant women an anti-RhD IgG immunoglobulin injection at about 28 weeks gestation (with or without a booster at 34 weeks gestation). This reduces the effect of the vast majority of sensitizing events which mostly occur after 28 weeks gestation. Anti-RhD immunoglobulin is also given to non-sensitized Rhesus negative women immediately (within 72 hours - the sooner the better) after potentially sensitizing events that occur earlier in pregnancy.
Blood tests
Maternal blood- The Kleihauer-Betke testKleihauer-Betke testThe Kleihauer-Betke test, Kleihauer-Betke stain or Kleihauer test, is a blood test used to measure the amount of fetal hemoglobin transferred from a fetus to a mother's bloodstream...
or flow cytometryFlow cytometryFlow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
on a postnatal maternal blood sample can confirm that fetal blood has passed into the maternal circulation and can also be used to estimate the amount of fetal blood that has passed into the maternal circulation.
- The indirect Coombs test is used to screen blood from antenatal women for IgG antibodies that may pass through the placenta and cause hemolytic disease of the newborn.
Fetal blood (or umbilical cord blood)
- The direct Coombs test is used to confirm that the fetus or neonate has an immune mediated hemolytic anemiaHemolytic anemiaHemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
.
- Full blood count - the hemoglobin level and plateletPlateletPlatelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
count are important
- BilirubinBilirubinBilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
(total and indirect)
Management
Antenatal- Serial Ultrasound and Doppler examinations- to detect signs of fetal anemia such as increased blood flow velocities and monitor hydrops fetalisHydrops fetalisHydrops fetalis is a condition in the fetus characterized by an accumulation of fluid, or edema, in at least two fetal compartments. By comparison, hydrops allantois or hydrops amnion are an accumulation of excessive fluid in the allantoic or amniotic space respectively.-Presentation:Locations can...
- Quantitative analysis of maternal anti-RhD antibodies - an increasing level is a sign of fetal Rh disease
- Intrauterine blood transfusion
- Intraperitoneal transfusion - blood transfused into fetal abdomen
- Intravascular transfusion - blood transfused into fetal umbilical veinUmbilical veinThe umbilical vein is a vein present during fetal development that carries oxygenated blood from the placenta to the growing fetus.The blood pressure inside the umbilical vein is approximately 20 mmHg.-Development:...
- This is the method of choice since the late 1980s, and more effective than intraperitoneal transfusion. A sample of fetal blood can be taken from the umbilical vein prior to the transfusion.
- Early delivery (usually after about 36 wks gestation)
Postnatal
- Phototherapy for neonatal jaundiceNeonatal jaundiceNeonatal jaundice or Neonatal hyperbilirubinemia is a yellowing of the skin and other tissues of a newborn infant. A bilirubin level of more than 85 umol/l manifests clinical jaundice in neonates whereas in adults a level of 34 umol/l would look icteric...
in mild disease - Exchange transfusionExchange transfusionAn exchange transfusion is a medical treatment in which apheresis is used to remove one person's red blood cells or platelets and replace them with transfused blood products...
if the neonate has moderate or severe disease (the blood for transfusion must be less than a week old, Rh negative, ABO compatible with both the fetus and the mother, and be cross matched against the mothers serum)
History of medical advances in Rh disease
The Rhesus blood type was first discovered in 1937 by Karl LandsteinerKarl Landsteiner
Karl Landsteiner , was an Austrian-born American biologist and physician of Jewish origin. He is noted for having first distinguished the main blood groups in 1900, having developed the modern system of classification of blood groups from his identification of the presence of agglutinins in the...
and Alexander S. Wiener
Alexander S. Wiener
Alexander Solomon Wiener , a lifelong resident of New York City, was recognized internationally for his contributions to medicine. He was an outstanding leader in the fields of forensic medicine, serology, and immunogenetics. His pioneer work led to discovery of the Rh factor in 1937, along with Dr...
.
In 1939 Philip Levine
Philip Levine (physician)
Philip Levine was an imuno-hematologist whose clinical research advanced knowledge on the Rhesus factor, Hemolytic disease of the newborn and blood transfusion.-Life and career :...
and Rufus E. Stetson published their findings about a family who had a stillborn
Stillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...
baby who died of hemolytic disease of the newborn
Hemolytic disease of the newborn
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta...
. The mother was aged 25 and it was her second pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
and she suffered blood loss at the delivery. Both parents were blood group O and the husband's blood was used to give the mother a blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
, but the mother suffered a severe transfusion reaction. They investigated this transfusion reaction. Since the mother and the father were both blood group O, they concluded that there must be a previously undiscovered blood group antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
that was present on the husband's RBCs but was not present on the mother's RBCs and that the mother had formed antibodies against the new blood group antigen. This suggested for the first time that a mother could make blood group antibodies because of immune sensitization to her fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
's RBCs. They did not name this blood group antigen, but it was subsequently found to be the Rhesus factor.
The first treatment for Rh disease was an exchange transfusion
Exchange transfusion
An exchange transfusion is a medical treatment in which apheresis is used to remove one person's red blood cells or platelets and replace them with transfused blood products...
, which was invented by Dr. Alexander S. Wiener
Alexander S. Wiener
Alexander Solomon Wiener , a lifelong resident of New York City, was recognized internationally for his contributions to medicine. He was an outstanding leader in the fields of forensic medicine, serology, and immunogenetics. His pioneer work led to discovery of the Rh factor in 1937, along with Dr...
. That procedure was further refined by Dr, Harry Wallerstein, a transfusionist. Although the most effective method of treating the problem at the time, it was only partially ameliorative in cases where damage to the neonate had already been done. Children with severe motor damage and/or retardation could result. However, it is estimated that in the two decades it was used approximately 200,000 lives were saved, and the great majority were not brain damaged.
Ronald Finn
Ronald Finn
Ronald Finn, was a medical researcher born in Liverpool, England. His research work contributed to advancing knowledge on the Rhesus factor...
, in Liverpool
Liverpool
Liverpool is a city and metropolitan borough of Merseyside, England, along the eastern side of the Mersey Estuary. It was founded as a borough in 1207 and was granted city status in 1880...
, England applied a microscopic technique for detecting fetal cells in the mother's blood. It led him to propose that the disease might be prevented by injecting the at-risk mother with an antibody against fetal red blood cells. He proposed this for the first time to the public on February 18, 1960. A few months later, he proposed at a meeting of the British Genetical Society that the antibody be anti-RhD.
Nearly simultaneously with him, William Pollack, then of Ortho Pharmaceutical Corporation, and researchers John Gorman and Vincent Freda of New York City's Columbia-Presbyterian Medical Center, having come to the same realization, set out to prove it by injecting a group of male prisoners at Sing Sing Correctional Facility with antibody provided by Ortho, obtained by a fractionation technique developed by Dr Pollack (who also provided Dr. Finn with several vials of antibody during a visit by Dr. Finn to Ortho).
Animal studies had previously been conducted by William Pollack, using a rabbit model of Rh. This model, named the rabbit HgA-F system, was a perfect animal model of human Rh, and enabled Dr. Pollack's team to gain experience in preventing hemolytic disease in rabbits by giving specific HgA antibody, as was later done with Rh-negative mothers. One of the needs was a dosing experiment that could be used to determine the level of circulating Rh-positive cells in an Rh-negative pregnant female derived from her Rh-positive fetus. This was first done in the rabbit system, but subsequent human tests at the University of Manitoba conducted under Dr. Pollack's direction confirmed that this result matched the human dosing perfectly. The dose is 20 µG of antibody for 1mL of Rh-positive red cells.
Sir William Liley
William Liley
Sir William Liley KCMG, FRSNZ , was a New Zealand surgeon, who worked primarily on techniques to improve the health of fetuses in utero.-Education and career:...
performed the first successful intrauterine transfusion in 1963.
Dr. Gorman's sister-in-law was the first at risk woman to receive a prophylactic injection on January 31, 1964. Clinical trials set up by Dr. Pollack in 42 clinical centers in the US, Great Britain, Germany, Sweden, Italy, and Australia confirmed their hypothesis, and the vaccine was finally approved in England and the United States in 1968. The FDA approved the drug under the name RhoGAM, with a fixed dose of 300 µG, to be given within three days postpartum. There being no known harm done by delaying the dosage for a week or more after birth, Ortho asked the FDA to grant permission for it to be given without a postpartum time restriction. In addition, Dr. John M. Bowman, one of the researchers at the University of Manitoba, and Dr Freda pushed to allow antepartum use. All of this was subsequently granted. Within a year or so, the antibody had been injected with great success into more than 500,000 women. Time magazine picked it as one of the top ten medical achievements of the 1960s. By 1973, it was estimated that in the US alone, over 50,000 babies' lives had been saved. The use of Rh immune globulin to prevent the disease in babies of Rh negative mothers has become standard practice, and the disease, which used to claim the lives of 10,000 babies each year in the US alone, has been virtually eradicated in the developed world. The achievement was made almost entirely without support from the NIH, who rejected the New York group's proposal twice. The group got instead only a small grant ($329,765 over 10 years) from the City of New York. The total cost of the effort was only a couple of million dollars, which is about the cost of the life-time care of a half-dozen irreparably brain-damaged children. In 1980, Prof Cyril Clarke
Cyril Clarke
Sir Cyril Astley Clarke KBE, FRCP, FRCOG, FRC Path, FRS was a British physician, geneticist and lepidopterist...
, Dr Ronald Finn
Ronald Finn
Ronald Finn, was a medical researcher born in Liverpool, England. His research work contributed to advancing knowledge on the Rhesus factor...
, Dr John Gorman, Dr Vincent Freda, and Dr William Pollack each received an Albert Lasker Award for Clinical Medical Research for their work on Rhesus blood types and the prevention of Rh disease.
Two of the Canadian researchers from the University of Manitoba
University of Manitoba
The University of Manitoba , in Winnipeg, Manitoba, Canada, is the largest university in the province of Manitoba. It is Manitoba's most comprehensive and only research-intensive post-secondary educational institution. It was founded in 1877, making it Western Canada’s first university. It placed...
, Dr. Bruce Chown
Bruce Chown
Bruce Chown, was a Canadian scientist who researched the blood factor known as the Rhesus factor and helped produced a Rh immune vaccine, Rh gamma globulin, which helps to prevent Erythroblastosis fetalis....
and Dr. John M. Bowman, licensed a version of the vaccine, known as WinRho SD, in 1980. The drug is sold in 35 countries by the Manitoba-based research firm Cangene, listed on the Toronto Stock Exchange with worth of about $175 million. Cangene was purchased by the Winnipeg Rh Institute, a facility founded by Chown and Bowman and dedicated to conducting research into blood related diseases. Dr. Chown is honored by the Canadian Medical Hall of Fame
Canadian Medical Hall of Fame
The Canadian Medical Hall of Fame is a Canadian charitable organization, founded in 1994, that honours Canadians who have contributed to the understanding of disease and improving the health of people. It has a museum in London, Ontario, and has an annual induction ceremony.-2012:*Terry Fox*John...
for his lifelong work with erythroblastosis fetalis.
See also
- Hemolytic disease of the newbornHemolytic disease of the newbornHemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta...
- Coombs testCoombs testCoombs test refers to two clinical blood tests used in immunohematology and immunology...
- Hemolytic anemiaHemolytic anemiaHemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
- HematologyHematologyHematology, also spelled haematology , is the branch of biology physiology, internal medicine, pathology, clinical laboratory work, and pediatrics that is concerned with the study of blood, the blood-forming organs, and blood diseases...
- Sperm donationSperm donationSperm donation is the provision by a man, , of his sperm, with the intention that it be used to impregnate a woman who is not usually the man's sexual partner, in order to produce a child....
- James HarrisonJames Harrison (blood donor)James Harrison, OAM, also known as the Man with the golden arm, is a blood donor from Australia. He holds the world record for blood donations by an individual, and his donations have saved over two million babies from Rhesus disease.-Biography:...
External links
- Green top guidelines for Rh disease prevention 2002 from the RCOG (UK)
- National institute of Clinical Excellence (NICE) Guidelines for the UK
- 1980 Lasker award for clinical advances in Rh disease
- 1980 Lasker award to Prof Cyril Clarke
- Medical References: Rh Disease
- Discovery Health :: All About Rh Disease
- High-Risk Pregnancy - Rh Disease
- RH Disease, What causes Rhesus Disease. RH Negative Factor Blood.
- A review of the clinical effectiveness and cost-effectiveness of routine anti-D prophylaxis for pregnant women who are rhesus-negative, from the National Health ServiceNational Health ServiceThe National Health Service is the shared name of three of the four publicly funded healthcare systems in the United Kingdom. They provide a comprehensive range of health services, the vast majority of which are free at the point of use to residents of the United Kingdom...
Technology Assessment Programme. - Intrauterine fetal blood transfusion for Rh disease