Rh disease

Rh disease (also known as Rh (D) disease, Rhesus disease, RhD Hemolytic Disease of the Newborn, Rhesus D Hemolytic Disease of the Newborn or RhD HDN) is one of the causes of hemolytic disease of the newborn (also known as HDN). The disease ranges from mild to severe. When the disease is mild the fetus may have mild anaemia with reticulocytosis. When the disease is moderate or severe the fetus can have a more marked anaemia and erythroblastosis (erythroblastosis fetalis). When the disease is very severe it can cause morbus haemolyticus neonatorum, hydrops fetalis, or stillbirth.

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Serology

During any pregnancy a small amount of the baby's blood 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 antigens on her baby's red blood cells. 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 a Rhesus D positive fetus to develop Rh disease. The mechanism is maternal anti-D IgG passing through the placenta to the fetus causing destruction of fetal red blood cells. 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)^[1]. Sensitizing events during pregnancy include miscarriage, therapeutic abortion, amniocentesis, ectopic pregnancy, abdominal trauma and external cephalic version.

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 still births 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 Globulin), 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 immunoglogbulin 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 test or flow cytometry on a postnatal maternal blood sample can confirm that foetal 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 anemia.

• Full blood count - the hemoglobin level and platelet count are important

• Bilirubin (total and indirect)

Management

Antenatal

• Ultrasound - to detect and monitor hydrops fetalis
• 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 vein - This is more modern 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 jaundice in mild disease
• Exchange transfusion 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 Landsteiner 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. Severely retarded children 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, a group of researchers from New York City Columbia-Presbyterian Medical Center, John Gorman, Vince Freda, and William Pollack came to the same realization, and set out to prove it by injecting a group of male prisoners at Sing Sing Correctional Facility with anti-body provided by the Ortho Pharmaceutical Corporation, obtained by a fractionation technique developed by Dr Pollack. Dr. Gorman's daughter-in-law was the first at risk woman to receive a prophylactic injection on January 31, 1964. Clinical trials by the two rival groups (Prof Clarke & Dr Finn in Liverpool and Dr Gorman's team in New York), and others quickly confirmed their hypothesis, and the vaccine was finally approved in England and the United States in 1968. Within a year or so, it 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 1960's. By 1973, it was estimated that in the US alone, over 50,000 babies' lives had been saved.

But it was two Canadian researchers from the University of Manitoba, Dr. Bruce Chown and Dr. John M. Bowman, who discovered and licensed the vaccine now used around the world. The Canadian Medical Hall of Fame reports that Chown and Bowman worked to understand Rh disease and how to treat it during pregnancy and they developed a vaccine, Rh gamma globulin -- purified and isolated human antibodies -- in 1968. The vaccine is now known as WinRho SD, was licensed in 1980, and has saved thousands of lives since. Indeed, 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.

References

• David R. Zimmerman, Rh: The Intimate History of a Disease and Its Conquest Macmillan (1973) ISBN 0-02-633530-1.
• Landsteiner K and Weiner A (1940). An agglutinable factor in human blood recognized by immune sera for rhesus blood. Proceedings of the Society for Experimental Biology and Medicine, 43,223.

• Levine P, Katzin E and Burnham L (1941). Isoimmunization in pregnancy: its possible bearing on the aetiology of erythroblastosis fetalis. Journal of the American Medical Association, 116, 825-7

• Clarke C, Donohoe W, McConnell R, Woodrow J, Finn R, Krevans J et al (1963) Further experimental studies in the prevention of Rh-haemolytic disease. BMJ 979-984

• Freda V, Gorman j, and Pollack W (1964) Successful prevention of experimental Rh sensitization in man with an anti-Rh Gamma 2-globulin antibody preparation: a preliminary report. Transfusion, 4, 26-32

• Wallerstein H (1946). Treatment of severe erythroblastosis by simultaneous removal and replacement of blood of the newborn. Science, 103, 583-4

• Harman C, Bowmanj, Menticoglou S and ManningF (1988). Profound fetal thrombocytopenia in Rhesus diseas: Serious hazard at intravascular transfusion. Lancet 2,741-2

• Clarke CA, Whitfield AGW and Mollison PL (1987) Deaths from Rh haemolytic disease in England and Wales in 1984 and 1985. BMJ 294, 1001

• Levine P and Stetson R E: Intra-group agglutination. J Am Med Assoc, 113: 126,1939

See also

• Hemolytic disease of the newborn
• Coombs test
• Hemolytic anemia
• Hematology