Rhesus Isoimmunization

Dr Esgair Alzahra
MBBCH, DOG, ABOG
A . Prof.
Alfateh Medical Sciences
Faculty of medicine
Ob and gy department
Tripoli Libya
Consultant Obstetrician and
Gynecologist
Aljala teaching Hospital
Oumer Almokhtar Street
Tripoli Libya
1. A (surface antigen A)
2. B (surface antigen B)
3. AB (antigens A and B)
4. O (neither A nor B)
4 Basic Blood Types
ABO System & Pregnancy
hemolytic diseases of the newborn
may be due to ABO incompatibility
O + O = O,
O + A = O or A,
O + B = O or B,
O + AB = O or A B
Fetus inherits one gene from each parent.
Rhesus Blood Group System
First demonstrated in Rhesus
monkey
However the underlying biochemical genetics
is not well understood and the genotyping &
phenotyping remains little confused
Blood group are classified as
Rh negative or Rh positive
Rhesus Blood Group System
The genotype is determined by the inheritance
of 3 pairs of closely linked allelic genes
situated on chromosome 9 named as
D/d,
C/c,
E/e
.. (Fisher- Race theory)
Rhesus Blood Group System
The gene ( d ) is an amorph & has no antigenic
expression. So there are only five effective antigens
Weiner postulates a series of allelic genes at a
single locus Rh (D), Rh (C), Rh (E), Rh (c) & Rh (e)
The updated system of Rosenfield refers
these antigens as Rh1, Rh2, Rh3, Rh4, Rh5
Subsequently less common antigens
Cw, Du, Es have been found
Rhesus Blood Group System
The fetus inherits one gene from each group as a
haplotype such as sets of Cde, cde etc from each parent
12 sets of combinations & 78 genotypes are possible.
Most frequent genotypes are
Cde / cde (33%), Cde / cDe (18%), cde / cde
(15%),
Cde / cDE (12%) cDE / cde (11%),
cdE / cde (1%), Cde / cde (1%)
Rhesus Blood Group System
Incidence of Rh negative
varies in different races:
Mongoloids > 1,
Chinese & Japanese 1-2%,
Indians 5%,
Africans 5-8%,
Caucasians 15-17% &
Basques 30-35%.
Rhesus Isoimmunization
Rhesus Iso immunization is an immunologic disease
that occurs in pregnancy resulting in a serious
complication affecting the fetus / or the neonate
ranging from

mild neonatal jaundice

to intra uterine loss or neonatal death
Rhesus Isoimmunization
This immunologic disease occur when
a Rh negative patient carrying a Rh positive fetus

.. had a feto maternal blood transfusion

.. the mother immunological system is stimulated
to produce antibodies to the Rh antigen on the
fetal blood cell

.. This antibodies cross the placenta and destroy
fetal red blood cells leads to fetal anemia

. Usually the 1
st
fetus will not be affected if this is
the 1
st
time that the mother has been exposed to
the rhesus positive antigen
During pregnancy while the fetus still in the uterus
The bilirubin in the fetal blood will be removed by the
placenta to the maternal circulation and part of it go to
the liquor
The fetus will be anemic
.. If the degree of anemia is severe
fetus may die in utero because of heart failure
After delivery
The neonate will affected by
The degree of the anemia
The amount of bilirubin
Rh Negative Women Man Rh positive
(Homo/Hetero)

Fetus
Rh positive
Fetus


Rh+ve R.B.C.s enter
Maternal circulation

previously sensitized
2
nd
immune response

IgMIgG
antibodies

Non sensitized Mother
Primary immune
response

1
st
Baby usually
escapes. Mother gets
sensitized?

Fetus
Haemolysis

Pathogenesis Of Rh Iso - immunisation
Man Rh positive (Homo)
Rh Negative Women

Fetus
Rh Neg Fetus
No problem
Rh positive
Fetus



Rh+ve R.B.C.s enter
Maternal circulation

previously sensitized
2
nd
immune response

IgMIgG
antibodies

Non sensitized Mother
Primary immune
response

1
st
Baby usually
escapes. Mother gets
sensitized?

Fetus
Haemolysis

Pathogenesis Of Rh Iso - immunisation
Man Rh positive
(Hetero)
Antigen-Antibody reaction on the RBCs
surface Hemolysis
IN UTERO
Anemia
Hepatic erythropoesis & dysfunction

Portal & Umbilical Vein Hypertension Heart
Failure
Erythroblastosis
fetalis

IUD


Polyhydramni
os
After birth

Anemia Jaundice
Kernicterus
Neonatal death
Hemolysis


Antigen-Antibody reaction on the RBCs surface
Management
of rhesus negative pregnant women
Management of non sensitized Pregnancy
Management of sensitized Pregnancy
Blood Group typing at 1st visit, If negative
Check husbands Blood Group typing.
If husband is also Rhesus negative then no rhesus
complication and manage as other pregnant women
If husband is Rh Positive then
Management of non sensitized Pregnancy
Non sensitized Rh Neg. mothers married to a Rh Pos. husband
Non sensitized Rh Neg. mothers married to a Rh Pos. husband
If husband is Rh Positive then
Check Husband being Homozygous or Heterozygous
.... Check for maternal antibodies
by indirect Comb's test ( ICT )
if antibodies detected treat as sensitized
If no antibodies Repeat ( ICT )
at 28 and 32 weeks provided that no bleeding.
If there is bleeding then ..
Management of non sensitized Pregnancy
Management of non sensitized Pregnancy
Bleeding before 20 weeks of gestation
.. Check for fetal red blood cells in
maternal circulation by Kleihauer test

.. Check for maternal antibodies ( ICT ) if negative

.. Give ( 250 IU / 50 mcg ) anti D to the mother within
72 hours from the bleeding
Management of non sensitized Pregnancy
Bleeding after 20 weeks of gestation
.. Check for fetal red blood cells in
maternal circulation by Kleihauer test
.. Check for maternal antibodies ( ICT ) if negative
.. Give ( 500 IU / 100 mcg ) anti D to the mother
within 72 hours from the bleeding
.. The dose should be doubled or tripled if fetal
RBCs are more than 80 cells in maternal circulation
Prophylactic Management of non sensitized Pregnancy
During antenatal period
Prophylactic (500 IU / 100 mcg ) Anti D
are recommended to be given to all
negative non sensitized mothers married to
Rh positive husband at
28weeks and 34 weeks to protect and
overcome any asymptomatic or un noticed
antenatal feto maternal blood transfusion
Prophylactic Management of non sensitized Pregnancy
Indications for prophylaxis

At 28weeks to a Rhesus ve non sensitized woman
whose husband is Rhesus +ve

Postpartum if the woman remains non sensitized and
delivers a Rhesus +ve fetus

Following amniocentesis or chorionic villus sampling
Following evacuation of a molar pregnancy or
termination of pregnancy

Following an ectopic pregnancy
Following abruptio placenta or
undiagnosed uterine bleeding
Prophylactic Management of non sensitized
Pregnancy
Failure of prophylaxis

Dose too small

Dose too late >72 hours

Patient already immunized but antibody
titer too low for laboratory recognition

Defective immune globulin given
Management of non sensitized Pregnancy
Precaution should be taken to prevent the
possibility of increased chance of feto - maternal
blood transfusion At birth
During labor
No fundal pushing in 1
st
or 2
nd
stage of labor
No uterine massage or uterine grasp and squeeze
in 3
rd
stage
Let the placenta to be delivered spontaneous
A void avulsions of the cord
Protect the vaginal and perineal wounds and laceration
from being exposed to the fetal blood spilled from cord
Management of non sensitized Pregnancy
During cesarean section

Use abdominal packs in the sides of the uterus
before opening the lower segment to prevent
spilled blood from the placenta to inter the
peritoneal cavity.

Let the placenta to be delivered spontaneous using
control cord traction without squeezing the uterus

A void avulsions of the cord
Management of non sensitized Pregnancy
At birth
. Maternal blood sample for
.. antibodies by indirect Comb's test ( ICT )
.. fetal red blood cells in maternal circulation
. Cord blood sample ( Neonatal blood sample ) for
.. antibodies by Direct Comb's test ( DCT )
.. Infant blood group
.. Infant bilirubin level
.. Infant Hb & Hct level
Management of non sensitized Pregnancy
. If fetal blood group is rhesus positive
. No antibodies detected
Dont give Anti D
. If fetal blood group is rhesus negative
. If Antibodies detected
Give full dose of Anti D ( 500 IU / 100 mcg )
to the mother within 72 hours after delivery
The dose should be corrected according to
the number of fetal red blood cells present
in the maternal circulation
Causes of sensitization
Misinterpretation of maternal Rh type
Rh positive blood transfusion
Unprotected pregnancy & labour
Inadequate dose Anti D on previous occasions
Sensitized Rh Negative mothers
Factors affecting immunization and severity
Influence of ABO group
Strength of the antigen ... antigenicity
Host factors .. Integrity of Maternal Immune Sys
Amount of Antigen ( amount of fetal RBCs)
ABO-incompatible Rh- positive cells will be
hemolysed before Rh antigen can be recognized by
the mothers immune system
Management of Sensitized Pregnancy
Check quantitative antibodies level @ 1st visit
Recheck the level every 2 weeks
Serial U/S Scan monitoring every 2 weeks
If antibodies level continuo at the same level
and no fetal compromise deliver at term
Sensitized Rh Negative mothers
Management of Sensitized Pregnancy
Sensitized Rh Negative mothers
If antibodies level start to increase
Arrange for amniocenteses
Spectrophotometer to study the optical density
of the amniotic fluid
( i.e. bilirubin level which reflect RBCs haemolysis )
U/S Scan evaluation of the fetal will beings
Use LILY s Curve to determine the fetal condition
Help in fetal monitoring and timing of first
intervention if anti-D level is 10 IU/mL

USS can detect
... Fetal Skin and scalp edema,
... Fetal Ascites,
... Fetal Pericardial or pleural effusion
.. Polyhydramnios
.. Fetal hepatosplenomegaly
.. Fetal Cardiomegaly
.. Placental hypertrophy and enlargements
.. Abnormal fetal posture (Buddha stance)
Ultrasound scan (USS)
Amniocentesis
Is an Indirect method to measure the degree of haemolysis of
the fetal red blood cells by measuring the Concentration of
bilirubin in the amniotic fluid.
Amniocentesis
Amniotic fluid sample taken and sent for Spectrophotometer
Where optic density of the fluid changes according
to the amount of the bilirubin concentration
Increasing of the OD as pregnancy advance shows
worsening of the fetal hemolytic disease
Amniocentesis
1
0
0

2
0
0

4
5
0

3
0
0

0.1
0.4
0.8
1
1.2
Lileys chart
Zone I
Zone II
Zone III
Lileys chart
Term pregnancy ( mild or Severely affected ) Deliver
Suitability of the place and its facility
Experience of the team
Type of Delivery
Extra uterine Blood exchange
Photo therapy
Medication
Management of Sensitized Pregnancy
Preterm fetus with
Zone I in ..
Cordocentesis blood sample Hb >
10g/dl
No U / S Scan evidence of Hydropic
changes
Consider conservative management with regular
follow up of fetal and maternal conditions till the
fetal lung maturity is assured . Then deliver
Regular cheek of the amniotic fluid bilirubin level by
repeated amniocentesis every 2 weeks until the lung
maturity reached
Regular cheek of the fetal Hb and Hct values if the
facilities available
Serial U / S Scan for fetal growth and amniotic fluid
Daily C T G
Biophysical Profile
Daily maternal clinical assessments
Fetal Movements Chart
Preterm fetus with
Zone II or III
Cordocentesis blood sample Hb less than 10g/dl
Ultrasound evidence of Hydropic changes Consider
Intra uterine therapy
Delivery + extra uterine mang.
Transfer to suitable place
Management of Sensitized Pregnancy
Dexamethazone to enhance lung maturity
Clinical assessments + C T G + U / S Scan + B P P
Lung maturity .. If certain deliver
Consider repeating the intrauterine blood transfusion
Management of Sensitized Pregnancy
Intra peritoneal blood transfusion
Through the umbilical vein Cordocentesis
80 % of packed cell o rhesus
negative Blood Cross matched
against maternal blood group
Free of infection
Fresh
Intra uterine therapy
Management of Sensitized Pregnancy
Thank you all
References
Background information
Contreras M. The prevention of Rh hemolytic disease of the newborn - general
background. BJOG 1998;105, s18:7-10
Lee D. Preventing RhD hemolytic disease of the newborn. 1998; 316:1611
NSW Health Rh D Immunoglobulin Policy Directive; avail at
http://www.health.nsw.gov.au/policies/pd/2006/pdf/PD2006_074.pdf; accessed 1 Nov
2008
ARCBS Guidelines for the use of Rh (D) Immunoglobulin (Anti-D), available at
http://manual.transfusion.com.au/Pregnancy-and-Anti-D/
Anti-D: mechanism of action, kinetics
Kumpel BM. On the immunologic basis of Rh immune globulin (anti-D) prophylaxis.
Transfusion 2006; 46:1652-1656
MacKenzie IZ, Roseman F, Findlay J, Thompson K, Jackson E, Scott J, Reed M. The
kinetics of routine antenatal prophylactic intramuscular injections of polyclonal anti-D
immunoglobulin. BJOG. 2006 Jan;113(1):97-101.
CSL Bioplasma Rh(D) Immunoglobulin VF Product Information; available at
http://www.csl.com.au/docs/603/830/CT36600198E.pdf; accessed 1 Nov 2008
Bichler J, Schndorfer G, Pabst G, Andresen I. Pharmacokinetics of anti-D IgG in
pregnant RhD-negative women. BJOG. 2003 Jan;110(1):39-45.
References contd
Serological testing
de Silva PM, Knight RC. Serological testing during pregnancy in women given routine
antenatal anti-D Ig prophylaxis. Transf Med. 1997 Dec;7(4):323-4.
Management of alloimmunization
Moise KJ. Red blood cell alloimmunization in pregnancy. Semin Hematol 2005;
42:169 178
Controversies
Jabara S, Barnhart KT. Is Rh immune globulin needed in early first-trimester
abortion? A review. AmJObGyn 2003; 188: 623-7
Weinberg L. Use of anti-D immunoglobulin in the treatment of threatened miscarriage
in the accident and emergency department. EmergMed J 2001; 18:444-447
Hannafin B, Lovecchio F, Blackburn P. Do Rh-negative women with first trimester
spontaneous abortions need Rh immune globulin? AmJEmergMed 2006; 24:487-489
Auguston B, Fong EA, Grey DE, Davies JI, Erber WN. Postpartum anti-D: can we
safely reduce the dose? MJA 2006; 184 (12): 611-613

Cordocentesis
Fetoscopy
The main and most frequent sensitizing event is child
birth (about 86% of sensitized cases),

but fetal blood may pass into the maternal circulation
earlier during the pregnancy (about 14% of sensitized
cases)
[1]
.
Sensitizing events during pregnancy include
miscarriage, therapeutic abortion, amniocentesis,
ectopic pregnancy, abdominal trauma and external
cephalic version.
The first pregnancy with a Rhesus positive baby is
significant for a rhesus negative woman because she
can be sensitized to the Rh positive antigen. about
13% of Rhesus negative mothers are sensitized by
their first pregnancy with a rhesus positive baby.
about 5% of the second Rhesus positive infants of
Rhesus negative woman, would result in still
births or extremely sick babies and many babies
who managed to survive would be severely ill
If no prevention measures were taken during antenatal
period
By using anti-RhD immunoglobulin (Rho(D) Immune
Globulin) the incidence is massively reduced .
Rh disease sensitization is about 10 times less likely to
occur if the fetus is ABO incompatible with the mother
than if the mother and fetus are ABO compatible.