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A. Syndrome

  1. Edema - due to Right Sided heart failure
  2. Hemolysis (with extramedullary hematopoiesis)
    1. Circulatory Failure
    2. Ascites (Hypertension and Hypoalbuminemia)
  3. Jaundice (Hyperbilirubinemia)

B. Causes

  1. RhD Disease ~90%
  2. ABO Incompatibility ~1%
  3. Autoimmune (targets are other RBC Antigens)
    1. Anti-Kell (anti-K1) Abs account for ~10% of cases of Ab mediated severe fetal anemia
    2. Possible relation to parvovirus B19 infection
  4. Non-Immune Hydrops

C. Pathophysiology

  1. Mother is sensitized (IgM) to an Ag (usually Rh-D)
    1. The antigen is present on fetus' RBC but not on mother's
    2. The primary response is generally a maternal IgM anti-RBC response
  2. On secondary exposure, mother produces IgG Abs which can cross the placenta
  3. Anti-Fetal RBC Abs cause destruction of fetal RBC
    1. This is a Coombs' Positive Process
    2. Destruction is most likely mediated by complement and macrophages
    3. Jaundice is frequently seen due to increased bilirubin production
  4. Fetal Hematocrit drops leading to compensatory increase in cardiac output
  5. High cardiac output by the fetal heart leads to heart failure over time
  6. Result is Right sided and Left sided congestive heart failure
    1. Signs include edema and ascites
    2. Circulatory failure with fetal death in utero
  7. Summary of Key Points
    1. Development of this disease requires TWO exposures to sensitizing antigen
    2. Triad of Signs is due to hemolysis, hyperbilirubinemia and heart failure
  8. Most common Antigens are discussed below

D. Rh Incompatibility

  1. Most common cause of Hydrops fetalis
  2. Mother is Rh-, Father is Rh+, Fetus is Rh+
  3. Mother is sensitized to Rh
    1. Previous Pregnancy (including maternal-fetal blood mixing)
    2. Previous Abortion (spontaneous, missed, therapeutic)
    3. First timester bleeding
    4. Trauma
    5. Blood Transfusion (rare)
  4. Prophylaxis
    1. Rh Gamma-Globulin (RhoGam®) - 2 doses im at Week 28 (and post-delivery) or anytime
    2. Rh Immune globulin, given intravenously, is now available [2]
    3. These anti-Rh IgGs bind to Rh on fetal cells and in fetal blood
    4. The IgG coated Rh Antigen does not sensitize the mother

E. Incompatibility of ABO Type

  1. ~20% of pregnancies are ABO incompatible
  2. However, only 5% of these (overall 1% of hydrops cases) lead to Hydrops
  3. Mother is nearly always O+ (with antibodies to A, B, or both)
  4. Fetus is A,B, or AB

F. Other Antigens

  1. Other antigens on the RBC have been described which can sensitize the mother
    1. Initial sensitizations usually occur with blood transfusion
    2. Less commonly, such sensitizations are associated with a previous fetus
  2. Most common are "Public Antigens"
    1. Lewis - Benign ("Lewis Lives)
    2. Kell - mild to severe hydrops ("Kell Kills")
    3. Duffy - mild to severe hydrops ("Duffy Dies")
  3. Private Antigens (large numbers)
  4. Kell Antigens [2]
    1. Major antigenic systems in human red blood cells
    2. 23 known antigens reside on one 93K transmembrane protein (chr 7q33)
    3. Antigen is expressed on erythroid progenitor cells and mature erythroid cells
    4. Antibodies to Kell specifically inhibit progenitor cells as well as causing RBC lysis
    5. These anti-Kell Abs lead to reduced reticulocytes and hemolytic anemia

G. Diagnosis

  1. Rh Testing in all pregnancies
    1. All mothers must be tested; Fathers are tested if mother is Rh-
    2. Father may not be available for, or may refuse, testing
    3. Rh Status can be detected by molecular analysis of maternal plasma in >80% of cases [4]
  2. Suspicion for Disease
    1. Cord Blood for hemolysis, hematocrit
    2. Amniocentesis for bilirubin
  3. Specific Testing for Abs in women with previous pregnancy loss (high risk group)
  4. Doppler Ultrasonography [5]
    1. Used to measure peak velocity of systolic blood flow in fetusus
    2. Fetuses with anemia develop increased peak systolic blood flow velocity
    3. Doppler detection of increased systolic velocity is 100% sensitive for fetal anemia
    4. The specificity of the doppler was 88% for absence of anemia

H. Therapy

  1. Goals
    1. Prevent sensitization who Rhogam® or Rh Immune globulin
    2. If sensitization of mother reaction occurs, then prevent fetal heart failure
  2. All Rh- mothers are given Rh g-Globulin at 28 Weeks
    1. Rh Globulin (Rhogam®) 1-2 ampules or Intravenous Rh Immune Globulin [3]
    2. Should always be given to pregnant women with trauma whose Rh Status is unknown
  3. Fetal Transfusion - cordocentesis
  4. Induction of Labor
  5. Intensive care unit placement for preterm babies
  6. Post-partum fetal transfusion

References

  1. Winkelstein A and Kiss JE. 1997. JAMA. 278(22):1982 abstract
  2. Vaughan JI, Manning M, Warwick RM, et al. 1998. NEJM. 338(12):798 abstract
  3. Rh Immune Globulin. 1996. Med Let. 38(966):6 abstract
  4. Lo YMD, Hjelm NM, Fidler C, et al. 1998. NEJM. 339(24):1734 abstract
  5. Mari G et al. 2000. NEJM. 342(1):9 abstract