‫بسم هللا الرحمن الرحيم‬
Management of Rh
alloimmunization
CDE (Rhesus) System
• Includes c, C, D, e, E
• D negativity defined as absence of
D antigen
Antibodies Associated
with
• Anti-c, Anti-D, Anti-E, and AntiKell
• Anti-D-immunoglobulin
prophylaxis reduced the hemolytic
disease caused by anti-D, but not
the others
Minor RBC Antigens causes
hemolyisis
• Kell is most common of minor
• Responsible for 10% of cases of
severe antibody-mediated anemia
**Transfuse women with Kell(-) blood**
Inert Antibodies
• Antigens such as A, P, Le (a), M, I,
IH, and Sd (a) are innocuous
• Mostly are IgM
• Lewis antibodies is the commonest
one detected
Sensitization rate
• 16 percent without prophylaxis
• 2 percent with routine postpartum
administration
• 0.1 percent with routine antenatal
administration
Causes of Rh isoimmunization
•
•
•
•
•
•
•
Delivery
Induced abortion
Spontaneous abortion
Ectopic pregnancy
Partial molar pregnancy
Chorionic villus sampling
Cordocentesis
• Amniocentesis
• External cephalic version
• Abruptio placenta
• Antenatal hemorrhage
• Maternal abdominal trauma
• Spontaneous
• Needles
• Blood and blood product
Clinical Management
 Routine booking blood group
&Antibodies screen
Rh –v Ab –v
Determine father’s RhBC status if
-v No risk

If the father is +ve for-D-antigen, fetus is at RISK
- Repeat Antibodies screen at 28 weeks for Rh-ve
women prior to receiving Anti-D immunoglobulin
-Determine father’s RBC antigen status and zygosity
Clinical Management
 If Antibody screen is +ve, identify
antibody type
• Identify the risk factors for
alloimmunization (past pregnancies,
transfusions, shared needles)
Clinical Management
Obtain antibody titer from the
mother if the past history is not
significant for an affected
pregnancy.
**Titers less reliable after a
sensitized pregnancy**
Consider invasive testing at titer of
1:16 or greater by indirect Coombs
•
Clinical Management
• If Antibodies titer remains below
critical titer- invasive testing is not
indicated and the patient can be
followed up by serial Antibodies
titter
• Serial titers before 18-20 weeks not
necessary
If Antibodies titer is above the
critical level or the past history is
positive regardless of the antibodies
titer - invasive testing is indicated
Clinical Management
• Amniocentesis for amniocytes at
15 weeks by (PCR) to determine
fetal blood type if father is
heterozygous.
• Free fetal DNA in maternal
circulation.
Fetal antigenic determination
Amniocentesis, CVS, cordocentesis samples can be used
to determine fetal antigen status by DNA typing
100% accuracy in 390 samples
Bennett et al. 1993
Molecular analysis of maternal plasma: fetal DNA for RhD
100% accuracy in 45 fetuses second/third trimester
Lo et al. N Engl J Med 1998;339:1734-8.
PCR from cell free DNA in maternal serum
100% accuracy in 137 fetuses (including 21 female fetuses)
Finning et al. Transfusion 2002;42:1079-85.
Possible utility in embryo selection for sensitized
mothers
Clinical Management
• Serial amnio to measure delta
OD450 and plot values on Liley or
Queenan graph
Delta OD450
• Spectral analysis of amniotic fluid
at 450 nm proposed in 1961 by
Liley- measures change in OD
• Measures the level of bilirubin and
predicts severity of hemolytic
disease after 27 weeks
• Delivery or intrauterine transfusion
if delta OD450 falls into zone III
or upper zone II
Queenan Curve
• Proposed another method of using
delta OD450
• Suggested four zones and extended
the gestational age to 14 weeks
Limitations of
Amniocentesis
May give a falsely elevated
bilirubin level in presence of mec
or blood
May be low after exposure to light
or in Kell alloimmunization
Cordocentesis
• Gold standard for detection of fetal
anemia
• Complications!
• 2.7% total risk of fetal loss
• Reserved for patients with
increased MCA-PSV or delta
OD450
MCA-PSV
• Velocity of blood flow in brain
increased with anemia
1. Increased cardiac output
2. Vasodilatation in the brain
3. Decreased blood viscosity
MCA & FETAL ANEMIA
The MCA PSV correlated well with hematocrit
and hemoglobin concentrations and is useful for
predicting the severity of fetal anemia
(Mari G. 1995)
The MCA PSV increases in fetuses with anemia
(Roberts AB. 2001)
FETAL ANEMIA
Fetal anemia
 blood viscosity
 Cardiac output
peripheral vasodilatation
 Blood flow to the Brain,
Heart and Adrenal gland
Bahauddin Sallout
Mari G. 1990
Many A. 1996
HecherK. 1995
Correct Technique for MCA
Doppler
• Fetus resting
• Circle of Willis imaged in axial
image using color Doppler
• Entire length of MCA
• Close to origin of internal carotid
artery
MCA LOCALIZATION
In a transverse axial view of the fetal head at a
slightly more caudal plane than the one used for
BPD
At this level, which
include the cerebral
peduncles, the MCA
can be seen as a major
lateral branch of the
Bahauddin Sallout
circle of Willis
30
MIDDLE CEREBRAL ARTERY
Transverse view of the fetal
head with color Doppler
showing the circle of Willis
Flow velocity waveforms
from the MCA at 32 wk
MIDDLE CEREBRAL ARTERY
• Normal flow in 1º trimester
• Normal flow in 2º & 3º trimester
MCA-PSV
MCA & FETAL ANEMIA
Fetal anemia due to maternal alloimmunization
Bahauddin Sallout
MCA ABSENT DIASTOLIC FLOW
Severe hydrops (kell antibody)
Bahauddin Sallout
Rh Alloimmunization
management
If using MCA-PSV, and initial is
less than 1.5 MoM, weekly testing
Cordocentesis or delivery depends
on the gestational age once the
MCA-PSV reaches 1.5 MoM
Mari et al. N Eng J Med
Advantages of MCA-PSV
• Non-invasive
• Mother not put at risk for
worsening alloimmunization
• Can be used with all antibodies
other than RhD, including anti-Kell
antibodies
Disadvantages of MCA-PSV
•
•
•
•
Need skill
Done weekly
Accuracy decreases after 35 weeks
False +ve results 12 percent
Current evidence supporting
MCA-PSV Doppler velocimetry
Initial prospective study of 16 fetuses: 14 anti-D, 2 anti-c
Mari et al. Ultrasound Obstet Gynecol 1995;5:400-5.
Since then several prospective and retrospective studies: over 200 additional cases
Rbc alloimmunization and parvovirus B19
1-Scott et al. Prenat Diagn 1998;18:1143-8.
2-Teixeira et al. Ultrasound Obstet Gynecol 2000;15:205-8.
3-Delle Chiaie et al. Ultrasound Obstet Gynecol 2001;18:232-6.
4-Mari et al. N Eng J Med 2000;342:9-14.
5-Zimmermann et al. Br J Obstet Gynecol 2002;109:746-52.
6-Mari et al. Ultrasound Obstet Gynecol 2002;99:589-93.
Current evidence supporting
MCA-PSV Doppler velocimetry
Sensitivity
87-90%
Specificity
88-100%
PPV
53-74%
NPV
98-100%
Data combined from 7 studies: rbc alloimmunization and parvovirus B19
Prediction of fetal anemia by MCA-PSV
Doppler compared to Amniocentesis
4 Comparative Studies
N = 28
Nishie EN, et al. Am J Obstet Gynecol
2003;188:214-9
N = 28
Pereira L et al. Am J Obstet Gynecol
2003;189:1002-6
N = 38
Bullock ,et al. Ultrasound Obstet Gynecol 2005
N = 165
Oepkes D, et al. N Engl J Med 2006;355:156-64.
Current evidence
MCA-PSV
Amniocentesis Doppler
Sensitivity
53-86
64-100
Specificity
71-78
81-91
PPV
44-100
47-75
NPV
95-96
97-100
N =259
Cumulative ranges from 4 trials
Conclusion
MCA-PSV accurately predicted moderate to
severe fetal anemia
Compared to conventional management, MCAPSV may have a better predictive accuracy for
moderate or severe anemia in alloimmunization
Management by MCA-PSV may eliminate the
need for amniocentesis and reduce the number of
PUBS performed in alloimmunized pregnancies
Potential Benefits of
Management by MCA-PSV
14,000 cases of alloimmunization per year in the U.S.
Avoid 24,500 amniocenteses and 900 PUBS
Avoid 1 pregnancy loss/preterm delivery for every
100 patients; 142 nationwide per year
Avoid worsening sensitization from procedure
related bleeding complications – TPH risk 2-10% following
amniocentesis, 50% following PUBS
Prevention of
Alloimmunization
Doses of ani-D-immuonoglubuline
for Rh-ve)
50 mcg dose protects against 2.5 ml of
Rh (+) RBC’s
300 mcg dose protects against 15 ml of
RBC’s or 30 ml of Rh (+) blood
20 mcg per ml RBC
Prevention
standard recommendations
 300 mcg dose within 72 hrs of
delivery to unsensitized Rh (-) women
(Rh positive infant) 13 days , 28 days
 300 mcg at 28 weeks UNLESS father
known to be Rh (-)
Repeat Antibody Screen before giving
the prophylactic dose?
Indications for administration of anti-(D) immune
globulin
•At 28 weeks of gestation
•Spontaneous abortion, threatened abortion, induced abortion
•Ectopic pregnancy
•Invasive procedures: genetic amniocentesis; chorionic
villus sampling; multi-fetal reduction; fetal blood sampling
•Hydatidiform mole
• Fetal death in the second or third trimester
• Blunt trauma to the abdomen
• Antepartum hemorrhage in the second or third
trimester (eg, placenta previa or abruption)
• External cephalic version
Prevention
• Test for excessive fetal-maternal
hemorrhage after blunt trauma,
abruption, cordocentesis, and bleeding
assoc. with previa
• Kleihauer Betke
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