Rh Rhesus Isoimmunization

Chukwuma I. Onyeije, M.D.
Atlanta Perinatal Associates
Rh (Rhesus) Isoimmunization:Perinatal Implications and Management

A copy of this lecture can also be found at:http://onyeije.net/present/rhdis

Objectives
Review Terminology
Review Major Blood Group Antigens
Review Minor Blood group antigens
Overview of Clinical Management
Discuss Prevention Strategies
Q&A

Rh Disease
Alloimmunization
Isoimmunization
HDFN
ErythroblastosisFetalis
Confusing Terminology

Rh (Rhesus) Isoimmunization:

Red blood cell
antigens
and
antibodies.
Pathophysiology

INTRODUCTION:
Four blood types ( A, B, AB, and O)
Each blood type is additionally classified according to the presence or absence of the Rh factor

Rh Incompatibility
Occurs when there is a different Rh blood type between that of the pregnant mother (Rh negative) and that of the fetus (Rh positive)

Rh Incompatibility
Exposure to fetal ANTIGENS causes the mother to produce ANTIBODIES

The placenta usually acts as a barrier to fetal blood entering the maternal circulation.

Fetal cells can enter the maternal circulation through a “break” in the “placental barrier”.

Maternal production of Rhesus antibodies following introduction of Rhesus positive blood

Causes of RBC Transfer: “A break in the barrier”
Abortion/Ectopic Pregnancy
Partial molar pregnancy
Blighted ovum
Antepartumbleeding
Procedures (amniocentesis, cordocentesis, CVS)
External version
Platelet transfusion
Abdominal trauma
Inadvertent transfusion Rh+ blood
Postpartum (Rh+baby)

IMMUNIZED PREGNANCY
NON-IMMUNIZED PREGNANCY
Rh Incompatibility

Pathophysiology
After first antigenic exposure, memory B lymphocytes recognize appearance of RBC’s containing the antigen in subsequent pregnancies

Pathophysiology- Fetal Events
Maternal antibodies cross the placenta & attach to fetal RBC’s- leading to RBC destruction
Sequestration by macrophages in fetal spleen (extravascularhemolysis) produces fetal anemia

METABOLISM OF BILIRUBIN:

JAUNDICE DOES NOT OCCUR BEFORE DELIVERY:

* Hemolysis/Anemia is basis of MCA-PSV
** Increased Bilirubuin is basis of Delta OD-450
*
*

What’s harmless?
What’s dangerous?
Antigen Nomenclature

CDE (Rhesus) System
Clinically Important
Includes c, C, D, e, E
Rh negative status indicates the absence of D antigen
87% of Caucasians carry the D antigen

Other Antibodies
Antigens such as A, P, Le (a), M, I, IH, and Sd (a) are innocuous
Most are IgM
Lewis antibodies and cold agglutinins of I are prevalent but not clinically significant
“Lewis Lives”

Antibodies Associated with HDFN
Anti-c, Anti-D, Anti-E, and Anti-Kell

Antibodies Associated with HDFN
RhoGAM has decreased HDFN caused by anti-D
Anti-D antibody is still MOST COMMON CAUSE of red cell isoimmunization

Minor RBC Antigens
Kell is most common of minor
Responsible for 10% of cases of severe antibody-mediated anemia
Mechanism of anemia two-fold
1. Hemolysis
2. Suppression of erythropoiesis
**Transfuse women with Kell(-) blood**

Minor RBC Antigens
Duffy antigens Fy(a) and Fy(b)
Only anti-Fy(a) antibody associated with HDFN- may range from mild to severe
“Duffy Dies”
We treat sensitization to minor RBC antigens similar to those with Rhisoimmunization

Minor Antigens
MNS system = M, N, S, s, U antigens
Anti-M and anti-N naturally occurring- no clinical significance
Anti-S, anti-s, and anti-U antibodies ~ mild to severe HDFN

Clinical Management
Routine blood type screen
Repeat Ab screen at 24-28 weeks for Rhnegative women PRIOR to receiving RhoGAM
If Abscreen is (+), identify antibody and potential for HDFN

Clinical Management For Positive Antibody Screen
Determine risk factors for isoimmunization
Past pregnancies
Transfusions
Shared needles
Determine father’s RBC antigen status and zygosity
If paternity unknown or father is (+) for antigen, fetus is at RISK

Obtain antibody titer
Consider invasive testing at titer of 1:32 or greater by indirect Coombs (1:16 most often used)

If AB titer remains below critical titer…
Invasive testing can be deferred
Evaluate serial Ab titers
Serial titers are NOT necessary before 18-20 weeks
If critical titer noted at first visit, amnio for delta OD450 at 22-24 weeks

Clinical Management Fetal Testing
Obtain amniocytes to determine fetal blood type
When father is heterozygous for the antigen responsible for alloimmunization
When paternal status is unknown
MCA-PSV can be used as early as 18 weeks~ if greater than 1.5 MoM, consider fetal blood sampling

Normal and Abnormal MCA Dopplers

The Middle Cerebral Artery
Should be examined close to its origin in the internal carotid artery.
The angle of the ultrasound beam and the direction of blood flow should be zero degrees.
The risk of anemia is highest in fetuses with a peak systolic velocity of 1.5 times the median or higher.

MCA Doppler and Fetal Anemia
Fetuses with anemia show an increased peak velocity of systolic blood flow in the middle cerebral artery (MCA)
MCA Doppler is useful in the determination of fetal anemia in Rh-isoimmunizedpregnancies
MCA Doppler is also used to follow fetal response to intrauterine transfusion and to assist in timing subsequent transfusions.

MCA Doppler and Fetal Anemia
Method:
MCA closest to the maternal skin should be measured using a minimal angle of insonation
The Doppler gate is placed over the vessel as it bifurcates from the carotid siphon.
Serial MCA Doppler studies can be used to generate a curve that plots MCA peak systolic velocity as a function of gestational age.
After 35 weeks' gestation, accuracy in determining MCA PSV appears to decrease; therefore, at this gestational age amniocentesis for deltaOD450 is indicated.

Clinical Management (cont)
Perform serial amniocenteses to measure delta OD450
AND
Plot values on Liley Curve
“Belt and Suspenders” Approach

Delta OD450
Spectral analysis of amniotic fluid at 450 nm 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

RhIsoimmunized Pregnancy Worksheet

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

Advantages of MCA-PSV
Non-invasive
NO risk for worsening isoimmunization
Utility with alloantibodies other than Rh-D, including anti-Kell antibodies

Caution Regarding MCA-PSV
From: http://youtu.be/FGUFC39Bgu0

Review of Management for RhIsoimmunization
Monthly indirect coombs titer (in first sensitized pregnancy)
If critical titer reached, determine paternal and fetal antigen status
Amniocentesis and delta OD450 OR MCA-PSV
** For 2nd or greater sensitized pregnancy, initiate amnio or MCA at 18-20 weeks**

Prevention (cont)
Give 300 mcg dose within 72 hrs of delivery to unsensitizedRh (-) women (Rh positive infant)
ACOG: 300 mcg at 28 weeks UNLESS father known to be Rh(-)

Prevention
Test for excessive fetal-maternal hemorrhage after blunt trauma, abruption, cordocentesis, and bleeding assoc. with previa
KleihauerBetke
Give RhoGAM for partial molar pregnancy, SAB, TAB, ectopic, chorionic villus sampling, amniocentesis, external version

SUMMARY
Remember the instances in which to consider RhoGAM
SAB, TAB, threatened AB (controversial), ectopic, previa/bleeding, abruption, partial molar, CVS, blunt trauma, cordocentesis
Clinically important antibodies: Anti-c, Anti-D, Anti-E, and Anti-Kell, Rarely Anti-Duffy Fy(a)
Usually not associated with severe HDFN:
, ABO incompatibilities, Anti-Duffy(Fy-b) antibodies, (Duffy Fy-a causes mild to severe HDFN), Anti-A, Anti-P, Anti-M, Anti-I, Anti-IH, Anti-Sd(a)

SUMMARY
Anti-D still most common cause of red cell alloimmunization, despite RhoGAM
Kell = most common minorantigen
Critical titer most often used is 1:16 by indirect Coombs
Amnio with delta OD450 & MCA-PSV
Antibody screens and indications for RhoGAM

References
Gabbe Obstetrics – Normal and Problem Pregnancies, 4th edition.
Creasy R., Resnik R., Iams J., Maternal Fetal Medicine Principles and Practice, 5th edition.
ACOG Compendium 2005
Harkness U., Spinnato J., Prevention and Management of RhDisoimmunization. Clinics in Perinatology, Dec 2004 31:4.
Pereira L., Jenkins T., Conventional management of maternal red cell alloimmunization compared with management by Doppler assessment of MCA-PSV. American Journal of Obstetrics and Gynecology, Oct 2003 189:4.
Cohen D., Hemolytic disease of the newborn: RBC alloantibodies in pregnancy and associated serologic issues. Up to Date, Oct 2004.
Barss V., Moise K., Significance of minor red blood cell antibodies during pregnancy. Up to Date, Apr 2005.
Online resources:
www.austincc.edu/mlt/bb/bb_HDN.ppt
http://www.perinatology.com/Archive/Isoimmunization.htm
http://emedicine.medscape.com/article/273995-overview
http://www.nlm.nih.gov/medlineplus/ency/article/001600.htm

Kleihauer-Betke Test
% fetal RBC in maternal circulation
Fetal erythrocytes contain Hbg F which is more resistant to acid elution than HbgA so after exposure to acid, only fetal cells remain & can be identified with stain
1/1000 deliveries result in fetal hemorrhage > 30ml
Risk factors only identify 50%

Kleihauer Calculations
Fetal red cells = MBV X maternal Hct X % fetal cells in KB
newborn Hct
MBV – maternal blood volume (usually 5000ml)
Fetal cells X 2 = whole blood

Rh Rhesus Isoimmunization

by Chukwuma Onyeije

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