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    Management of Rh Disease and Isoimmunization
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    The numerous antigens on the surface of red blood cells have been placed into groups. Many people are familiar with the Rhesus (Rh) group as it is the most clinically relevant. However the non-Rh groups such as Kell, MNS, and Kidd have assumed increasing importance as the incidence of Rh-D sensitization has decreased. Nonetheless sensitization  to Rh antigens (non-D ) is still responsible for the largest proportion of hemolytic disease  in the newborn (HMD)[1]. 

    According to the Fisher and Race theory of inheritance [2] :

    • The Rh alleles (D,Cc, Ee) are inherited as a complex of three loci .One set from each parent.
    • A person is Rh-positive if they possess the D allele and Rh negative if it is absent.
      • The hypothetical "d" allele has not been identified.
  • Schematic representation of the antigen D
  • Chromosomal organization of the RHCE and RHD genes

    •     Source: The Rhesus Site

    There are more than forty antigens in the Rh system including weak D (formerly called Du variant). Mothers typed as  weak D appear to be  Rh negative on blood screening.

    • The majority of  mothers with  weak D are Rh (D) positive. However, the presence of the C allele causes the D antigen to be weakly expressed [3].
      • Mothers or infants typed as  weak D are usually treated as Rh positive.
    • The true genetic Du variant is an incomplete form of D antigen and may rarely become D immunized.
    • The rare occurrence of a D immunized true genetic Du mother may be sufficient reason to treat a weak D mother with RhIg when the nature of the Du variant is in doubt[4].

    Incidence of the Rh Negative  Blood Group  in Various Populations[5]

    Population
    Incidence 
    Chinese and Japanese
    1%
    North American Indian and Inuit
    1 - 2%
    Indo-Eurasian
    2%
    African American
    4 - 8%
    Caucasian
    15 - 16%
    Basque
    30 - 35%

    Pathogenesis

    Blood production in the fetus begins at about 3 weeks' and  Rh antigen has been identifed in the red cell membrane bas early as 38 days after conception. [6]
    • The initial  response to D antigen is slow sometimes taking as long as 6 months to develop.
    • Re-exposure to the antigen produces a rapid immunological response usually measured in days.
    • The sensitized mother produces IgG anti-D (antibody) that crosses the placenta and coats D-positive fetal red cells which are then destroyed in the fetal spleen.
    • Mild to moderate hemolysis (red cell destruction) manifests as increased indirect bilirubin (red cell pigment).
    • Severe hemolysis leads to red blood cell production by the spleen and liver.
      • Subsequently, hepatic circulatory obstruction (portal hypertension) with placental edema interferes with placental perfusion and ascites develops.[5]
      • Hepatomegaly, increased placental thickness, and polyhydramnios often precede the development of hydrops (fetal heart failure).[5]
      • As liver damage progresses decreased albumin production results in the development of anasarca, and effusions.
    • Overall, 16% of Rh-negative women will become sensitized after their first pregnancy if not given Rhogam.
      • ABO incompatibility reduces this risk to 4-5%.[5]

        • The reduced risk of Rh sensitization with ABO incompatibility may result from the rapid clearance of incompatible red cells thus reducing the overall exposure to D antigen.

    Screening

    Initial blood type and screening for antibodies is part of routine prenatal care. The evaluation of a positive antibody screen  should include identification of the antibody and its titer. 

    Identification of  antibody [1,5,7 ]

    • There are several classes of antibodies. The two of interest are IgM and IgG. If the antibody can be identifed as an IgM then it does not cross the placenta and there is no risk of hemolysis to the fetus.
      • "Naturally occurring" IgM antibodies may result from antigenic stimulus such as bacteria, which have antigens on their surfaces chemically similar to blood group antigens. Anti-M antibodies are usually IgM , but IgG Anti-M does occur and is capable of causing hemolytic disease.
      • Anti-K, anti-D, anti-E, anti-Fya , anti-Jka, and antibodies directed against Rh antigens comprise the majority of antibodies resposible for hemolytic disease of the newborn .

    • The following antibodies ARE NOT associated with Hemolytic disease of the newborn (HMD):
       
      • Lewis:Lea, Leb
      • Lutheran:Lua , Lub
      • I 
      • Duffy: Fyb 
      • P
      • Jkb 
      		 Vw, Mur, Hil, Hut, Batty, Becker, Berrens, Evans, Gonzales,  Hunt, Jobbins, Rm, Ven, Wrightb ,Ytb, , Ge, Jra, Coa-b,Xga
    • The following antibodies ARE associated with HMD:

      •  
      Dia, Dib ,PP1Pk, Far, Good, Lan,LW, Mta, U ,Wr a, Zd


    Titer

    • A titer of > 1:4 is considered sensitized.
    • The method used should be stated as the titer will vary according to the method.
    • An albumin titer of 1:16 is equal to an indirect antiglobulin test (IAT) titer of 1:32 to 1:128.
    It is possible to encounter women with titers as high as 512 with fetuses that are negative for the antigen to which the antibody is directed. [8]

    Management[1,5,7 ]

    Rh-D  Negative  Unsensitized Patients
        For prevention of sensitization:
    • Rh-immune globulin(RhIgG)* 300 mcg (300 mcg covers 15 ml fetal cells) is given at 28 weeks' .
    • Postpartum if the antibody screen is negative a second dose of RhIgG is given if the infant is Rh-positive or Du-positive.

      •  
      *Rh-immune globulin is an antibody that will help to remove any Rh positive cells in the mother's blood. Rh-immune globulin must be given before the mother begins to produce her own antibody to the Rh factor.
    Antibody Sensitized Patient
    In general the priniciples used in the management of the Rh-D negative sensitized patient and the management of the patient with atypical blood antibodies do not differ.
  • However, the management of the Kell-sensitized pregnancy may require more intensive surveillance, since maternal titers and amniotic fluid bilirubin levels do not necessarily correlate with disease severity.  May involve marrow suppression.

    First Sensitized Pregnancy (no prior severely affected pregnancy).

  • If the father is Rh negative (or negative for the atypical antigen) then no further testing is necessary.
  • IAT titers of < 1:32 or less are managed noninvasively with repeat antibody titers every 2-4 weeks.
  • IAT > 64 amniocentesis q 2 to 3 weeks.
  • IAT titers of  > 1:32 with pregnancies at greater than 27 week are usually monitored with serial amniocentesis
  • If the father is heterozygous (Dd) or his blood is unavailable then PUBS or amniocentesis may be used to determine the fetal Rh (or atypical antigen) status if the IAT titer is > 1:32  or albumin titer  > 1:16.
  • Fetal DNA testing is available for:
    • RhD, RhE, Rhc, RhC, and Kell.

      • ( Send 5.0 ml of fluid in a unbreakable sterile plastic conical -bottom centrifuge tube. DO NOT FREEZE)
    • For RhE, Rhe, RhC, Rhc, Kell ,and Cellano (k) the parents' DNA should be tested concurrently (Send 5.0 ml of blood in a lavender-topped tube on each parent.  DO NOT FREEZE)
    • If the fetus is antigen negative then no further testing is necessary.
    • If the fetus is antigen positive then the pregnancy is followed with serial titers and ultrasound as long as titers remain below the "critical" value.

    Previously Affected Pregnancy
    For patients with a previously affected pregnancy, the timing of the initial procedure is determined by past clinical history. It is usually performed at least 4-8 weeks earlier than the prior gestational age at which significant morbidity occurred.

    Surveillance

    Serial Amniocentesis

    Fetuses affected by hemolytic disease secrete abnormally high levels of bilirubin into the amniotic fluid. The amount of bilirubin can be quantitated by spectrophotometrically measuring absorbance at the 450-nm wavelength in a specimen of amniotic fluid that has been shielded from light. Alternatively, percutaneous umbilical blood sampling (PUBS) may be used to determine all blood parameters directly.
    If amniocentesis is used to monitor the fetus, the results (delta 450) are plotted on a "Liley" curve.

    The Liley Curve


    The Liley curve is divided into three zones.
  •  A result in Zone I indicates mild or no disease. Fetuses in zone I are usually followed with amniocentesis every 3 weeks.
  • A result in zone II indicates intermediate disease. Fetuses in low Zone II are usually followed by amniocentesis every 1-2 weeks.
  • A result above the middle of Zone II may require transfusion or delivery. [11]

    Patients with results in zone I or low zone II can be allowed to proceed to term, at which point labor should be induced. In most cases, patients in the middle of zone II can progress to 36-38 weeks of gestation. Depending on gestational age, patients in zone III should either be delivered or should receive intrauterine fetal transfusion.

    Although serial determinations of Delta optical density at 450 nm and PUBs are the most common methods for the evaluation of fetal status, Doppler ultrasonography of the middle cerebral artery has also been used to identify fetuses at risk for moderate to severe hemolytic disease.

    Expected Peak Velocity of Systolic Blood Flow through MCA (calculator) [9, 10]

    Tranfusion Protocol (calculator)

    Lastly, in women with extremely high titers ( > 256), at less than 28 weeks, where the fetus does not demonstrate hydrops, and there is a documented history of fetal death due to hydrops intravenous immune serum globulin (IVIG) might be offered. The dose is 400 mg/kg per day for 5 days, with repeat infusions every 15 to 21 days. Specific contraindications to intravenous immunoglobulin use include a previous episode of intravenous immunoglobulin-induced anaphylaxis (rare) and selective IgA deficiency. [12, 13]

    REFERENCES
    1. American College of Obstetricians and Gynecologists. Management of Isoimmunization in Pregnancy ACOG Technical Bulletin 227. Washington, DC: ACOG, 1996

    2. Race RR. The Rh genotype and Fisher's theory. Blood (Special Issue No 2) 1948;3:27

    3. Masouredis SP:Realtionship between Rho(D) genotype and quantitiy of I131 anti-Rho(D) bound to red cells. J Clin Invest 39:1450,1960

    4. Lacey PA et al. Fatal hemolytic disease of the newborn due to anti-D in anRH positive Du variant mother. Transfusion 1983;23:91

    5. John M Bowman. Maternal Alloimmunization and Fetal Hemolytic Disease. In: Reece EA et al (eds), Medicine of the Fetus and Mother.Philadelphia ,J.B Lippincott, 1992. 

    6.Bergstrom H et al. :Demonstration of Rh antigens in a 38-day-old fetus. Am J Obstet Gynecol 99:130,1967.

    7.Michael L. Socol. Management of Blood Group Isoimmunization. In: Gleicher N et al (eds), Principles and Practice of Medical Therapy in Pregnancy.New York , Appleton & Lange, 1998. 

    8. Copel JA, Scioscia A, Grannum PA, Romero R, Reece EA, Hobbins JC. Related Articles Percutaneous umbilical blood sampling in the management of Kell isoimmunization. Obstet Gynecol. 1986 Feb;67(2):288-90.

    9. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med. 2000 Jan 6;342(1):9-14.

    10. Mari G, Adrignolo A, Abuhamad AZ, et al. Diagnosis of fetal anemia with Doppler ultrasound in the pregnancy complicated by maternal blood group immunization. Ultrasound Obstet Gynecol 1995;5:400-5.

    11. Liley AW. Liquor amnii analysis in management of pregnancy complicated by rhesus immunization. Am J Obstet Gynecol 1961;82:1359

    12. Margulies M, Voto LS, Mathet E, Margulies M. High-dose intravenous IgG for the treatment of severe rhesus alloimmunization. Vox
    Sang 1991;61:181-9.

    13. Porter TF, et al Intravenous immune globulin in the management of severe Rh D hemolytic disease.Obstet Gynecol Surv. 1997;52:193-7.


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    Archived: 2/14/2004