Rh alloimmunization in pregnancy - PowerPoint PPT Presentation

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Rh alloimmunization in pregnancy

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Title: Rh alloimmunization in pregnancy


1
Rh Alloimmunization in Pregnancy
  • By
  • Dr. Hend M. Hamido

2
Epidemiology
  • Maternal Rh alloimmunization is a major cause of
    erythroblastosis fetalis and hemolytic disease of
    newborn.
  • In 2003 ,there were 6.8 cases of Rhesus
    alloimmunization per 1000 live births in the
    United States.

3
Epidemiology
  • Rh (D) negativity in various populations
  • Caucasians 15
  • Basques 30 to 35
  • Finnish 10 to 12
  • African Americans 8
  • Indo-Eurasians 2
  • Native Americans and Eskimos 1 to 2
  • 60 of Rh(D) ve individuals are homozygous, the
    remainder are heterozygous.

4
Pathogenesis
5
Rh ve father, Rh ve mother
6
  • Rh ve
  • Fetus

7
  • Fetal RBCs access
  • Maternal circulation,
  • Transplacental Feto-maternal
  • Hge, as in
  • Delivery
  • Induced abortion
  • Spontaneous abortion
  • Ectopic pregnancy
  • Partial molar pregnancy
  • Chorionic villus sampling
  • Cordocentesis
  • Percutaneous fetal procedures
  • (eg, fetoscopy)
  • Amniocentesis
  • External cephalic version
  • Abruptio placenta
  • Antenatal hemorrhage
  • Maternal abdominal trauma
  • Spontaneous

8
  • Anti-Rh-positive
  • antibodies are formed.
  • The mother is
  • Sensitized.

9
  • In subsequent pregnancies with an Rh-positive
    fetus, Rh-positive red blood cells are attacked
    by the
  • anti-Rh-positive maternal antibodies.

10
Resulting in
  • Hemolytic anemia
  • Numerous erythroblast in fetal circulation
  • Generalized edema (hydrops fetalis)
  • Enlargement of fetal liver spleen in its most
    severe form
  • Severity of the anemia resulted in cardiac
    failure, with widespread edema, ascites and
    pleural effusion.

11
Management
12
  • Paternal Rh type and zygosity If the father of
    the baby is Rh(D)ve, zygosity is determined.
    Homozygotes always pass the Rh(D) antigen to
    their offspring heterozygotes have a 50 percent
    chance of having Rh(D)-negative offspring.

13
  • Fetal Rh typing because Rh(D)-ve fetus is not at
    risk, thus further fetal and maternal monitoring
    in these cases is unwarranted.
  • Achieved by
  • Amniocentesis at 15 wks. Transplacental
    amniocentesis and villus biopsy should be avoided
    to prevent an increase in the maternal titer and
    worsening fetal anemia. The fetal blood genotype
    is determined by PCR (false negative 1.5 )
  • Cell free fetal DNA(ffDNA) in maternal plasma or
    serum.

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15
  • Maternal anti-D titers The indirect Coombs titer
    is used to detect the presence,and the degree, of
    alloimmunization.
  • Antibody titers is a screening test. A positive
    anti-D titer means that the fetus is at risk for
    hemolytic disease, not that it has occurred or
    will develop.
  • Critical titer refers to the titer associated
    with a risk for fetal hydrops. It varys among
    institutions and methodologies.
  • In most centers, an anti-D titer value between 8
    and 32 is used.
  • In Europe and the United Kingdom, the threshold
    for a critical titer is based upon comparison to
    an international standard invasive testing is
    recommended at 15 IU/mL

16
  • Assess severity of fetal anemia
  • Two-dimensional ultrasound should be employed
    early in the pregnancy to establish the correct
    gestational age, since this parameter is
    important in interpreting laboratory values.
  • Sonography is also essential for guiding invasive
    procedures and monitoring fetal growth and
    well-being.
  • It reliably detects fetal hydrops, when the fetal
    hemoglobin deficit is 7 g/dL below the mean for
    gestational age.
  • A variety of ultrasonographic parameters has been
    used to predict the presence of severe fetal
    anemia placental thickness, umbilical vein
    diameter, hepatic size, splenic size, and
    polyhydramnios, but none have proven to be
    sufficiently reliable for clinical practice.

17
Hydrops Fetalis
18
  • Middle cerebral artery-peak systolic velocity 
  • Doppler assessment of the fetal middle
    cerebral artery (MCA) peak systolic velocity has
    emerged as the best tool for predicting fetal
    anemia.
  • It is based on the principle that the anemic
    fetus preserves oxygen delivery to the brain by
    increasing cerebral flow of low viscosity blood.
  • Sensitivity for prediction of moderate or severe
    anemia was 100 percent (95 CI 86-100), false
    positive rate of 12 , positive predictive value
    53 , and negative predictive value 98

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20
A moderate to severe anemia B mild anemia C
no anemia MCA middle cerebral artery MOM
multiples of the median.
21
  • Spectral analysis of amniotic fluid
  • In the absence of expertise in Doppler U/S of the
    MCA
  • Bilirubin present in amniotic fluid correlates
    with the degree of fetal hemolysis.
  • The analysis of the change in optical density of
    amniotic fluid at 450 nm on the spectral
    absorption curve (?OD450) is used to determine
    the degree of fetal anemia.
  • Data are plotted on a normative curve based upon
    gestational age. Two standardized curves are
    available for interpretation of results the
    original Liley curve and the curve subsequently
    introduced by Queenan.

22
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24
Prevention
25
  •  Prior to the development of anti-D immune
    globulin, approximately 16 of Rh(D)-ve women
    became alloimmunized after two deliveries of
    Rh(D)ve infants.
  • This rate fell to 2 with routine postpartum
    administration of a single dose of anti-D immune
    globulin and was
  • Further reduced to as low as 0.1 with the
    addition of routine antenatal administration in
    the third trimester.

26
ANTI-D IMMUNE GLOBULIN
27
  • Anti-D immune globulin is a sterile solution
    containing IgG anti-D (anti-Rh) manufactured from
    human plasma.
  • A single 300 microgram dose (1 microgram 5 IU)
    contains sufficient anti-D to suppress the immune
    response to 15 mL of Rh-positive red blood cells
    (30 mL Rh(D)-positive fetal whole blood).
  • A single 50 microgram dose contains sufficient
    anti-D to suppress the immune response to 2.5 mL
    of Rh-positive red blood cells.

28
  • Manufactured from pooled source plasma selected
    for high titers of antibodies to Rh( D)-positive
    erythrocytes.
  • Anti-D immune globulin prepared by Cohn cold
    ethanol fractionation followed by viral-clearance
    ultrafiltration (eg, HyperRho S/D, RhoGAM) must
    be administered intramuscularly because trace
    amounts of IgA and other plasma proteins in the
    product could cause anaphylaxis if they were
    given intravenously.
  • Anti-D immune globulin prepared by ion-exchange
    chromatography isolation (eg, Rhophylac, WinRho
    SDF) is purer and can be given intramuscularly
    or intravenously.

29
  • Peak serum levels are achieved faster after IV
    than IM injection, but the half-life is about the
    same for both preparations (mean 24 days).
  • After administration, low titer antibody (4 or
    less) can usually be detected in maternal serum
    for several weeks.

30
  • Once produced from the plasma of sensitized
    women, the decreasing prevalence of Rhesus
    disease has necessitated the use of male donors
    who undergo repeated injections of Rh(D)-positive
    red cells to develop high-titered polyclonal
    anti-D plasma.
  • This dwindling resource has led to a search for a
    synthetic anti-D immune globulin.

31
MECHANISM OF ACTION
  • The mechanism whereby anti-D immune globulin
    prevents alloimmunization remains unproven.
  • Possibilities include rapid macrophage mediated
    clearance of anti-D coated red blood cells.
  • And/or down-regulation of antigen-specific B
    cells before an immune response occurs.

32
GUIDELINES FOR USE OF ANTI-D IMMUNE GLOBULIN
  •  Anti-D immune globulin is not effective once
    alloimmunization to the Rh(D) antigen has
    occurred.
  • Therefore, it is essential that it be given to a
    Rh(D)-negative woman whose fetus is or may be
    Rh(D)-positive whenever there is a risk of
    fetomaternal hemorrhage.

33
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34
Antepartum
  • All Rh(D) -ve pregnant women should undergo an
    antibody screen at the first prenatal visit of
    each pregnancy.
  • Another antibody screen is obtained at 28 weeks
    of gestation to detect women who have become
    alloimmunized in the interval since the first
    screen.

35
Antepartum
  • Practice guidelines in the United States
    recommend that anti-D Ig be administered early in
    the third trimester, 300 micrograms at 28 weeks
    of gestation.
  • This practice reduces the incidence of antenatal
    alloimmunization from 2 to 0.1 percent.
  • In the United Kingdom, 100 micrograms of anti-D
    Ig is given at 28 and 34 weeks of gestation.
  • In Canada, 100 to 120 micrograms is administered
    at 28 and 34 weeks.

36
Antepartum 2nd dose
  • Some experts recommend a second dose of anti-D Ig
    be given if the patient has not delivered within
    12 and 3/7ths weeks of the previous dose, because
    of rare case reports of maternal sensitization
    from waning levels of antibody.
  • There is no consensus regarding routine
    administration of a repeat antepartum dose anti-D
    Ig at term in such women ACOG has left this
    decision to the physician's judgment, although in
    clinical practice a repeat dose is not often
    given.
  • 15 to 20 of patients who receive anti-D Ig at
    28 weeks will have a low titer (14) at term.

37
Antepartum Additional indications
  • In USA, anti-D Ig is given to any Rh(D)-ve woman
    whose fetus is or may be Rh(D) ve and has
    Spontaneous or induced abortion.
  • By comparison, the RCOG has suggested that
    anti-D administration is unnecessary in cases of
    spontaneous abortions less than 12 weeks of
    gestation.
  • If surgical evacuation is undertaken, however, a
    250 IU (50 mcg) dose is recommended.
  • A dose of 50 mcg is effective through the 12th
    week of gestation due to the small volume of red
    cells in the fetoplacental circulation (mean red
    cell volume at 8 and 12 weeks is 0.33 mL and 1.5
    mL, respectively), although there is no harm in
    giving the standard 300 mcg dose, which is more
    readily available.

38
Antepartum Additional indications
  • In pregnancies complicated by fetal death, blunt
    abdominal trauma, or antepartum hemorrhage after
    20 weeks of gestation, 300 mcg of anti-D Ig
    should be given in association with testing for
    fetomaternal hemorrhage, because the prevalence
    of excessive fetomaternal bleeding is increased
    under these circumstances.
  • If excessive bleeding is detected, additional
    anti-D immune globulin is administered

39
Postpartum
  • Postpartum administration of Rh(D) Ig
    significantly reduces the risk of maternal
    alloimmunization.
  • This was illustrated in a Cochrane review of
    randomized trials comparing postpartum anti-D
    prophylaxis with no treatment/placebo .
  • Treatment within 72 hours of birth lowered the
    incidence of Rh(D) alloimmunization in a
    subsequent pregnancy relative risk 0.12, 95
  • CI 0. 07-0.23

Anti-D administration after childbirth for
preventing Rhesus alloimmunisation. AU Crowther
C, Middleton P SO Cochrane Database Syst Rev.
2000
40
Postpartum
  • Administration of 300 mcg of anti-D Ig within 72
    hours of delivery of a Rh(D) ve infant is
    recommended.
  • This dose of immune globulin is enough to
    protect against maternal sensitization from as
    much as 15 mL red blood cells (30 mL
    Rh(D)-positive fetal whole blood).
  • Approximately 1 in 1000 deliveries will be
    associated with excessive fetomaternal hemorrhage
    (greater than 15 mL red blood cells).
  • Therefore, routine testing of all women for
    excessive fetomaternal bleeding at the time of
    delivery should be performed.
  • Alternatively, a lower dose of anti-D immune
    globulin can be given postpartum (eg, 100 to 120
    mcg), with routine testing for fetomaternal
    hemorrhage and administration of more drug if
    more than 5 to 6 mL of fetal red blood cells are
    detected.

41
Testing for fetomaternal hemorrhage
  •  The rosette test is a qualitative, yet
    sensitive, test for fetomaternal hemorrhage.
  • It is performed as an initial evaluation.
  • A standard dose of anti-D Ig is given after a
    negative test.
  • A positive test for fetomaternal hemorrhage
    should be evaluated further.
  • A Kleihauer-Betke test or flow cytometry is
    recommended to determine the percentage of fetal
    red blood cells in the maternal blood.
  • The percentage of fetal red blood cells is
    multiplied by 50 to estimate the volume of the
    fetomaternal hemorrhage.

42
Rosette ve
43
Rosette -ve
44
KB ve
Fetal RBC
Maternal (ghost) RBCs
45
Management of fetomaternal hemorrhage
  • The American Association of Blood Banks
    standards recommend that at least one additional
    vial of anti-D Ig be administered over the
    calculated amount of 300 mcg per 15 mL fetal red
    blood cells.
  • No more than five 300 mcg doses should be
    administered intramuscularly in a 24-hour period.
  • However, large doses, if indicated, can be given
    using an intravenous preparation (WinRho SDF,
    Rhophylac).
  • In these cases, no more than 600 mcg should be
    given every eight hours intravenously until the
    total calculated dose is achieved.  

46
Additional considerations
  • If anti-D immune globulin is inadvertently
    omitted after delivery, it should be given as
    soon as possible after recognition of the
    omission. Partial protection is afforded with
    administration within 13 days of the birth.
  • A delivery that occurs less than 3 weeks from the
    administration of anti-D Ig for the usual
    indications does not require a repeat dose.
  • Inadvertent administration of anti(D) Ig to a
    Rh(D) ve woman is not harmful.

47
Thank You
  • REFERENCES
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    Gynecologists Practice Bulletin No 4 . American
    College of Obstetricians and Gynecologists,
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