ALLOIMMUNIZATION IN PREGNANCY BY DR. ELIOBA J. RAIMON 2023

ALLOIMMUNIZATION
IN PREGNANCY
DR. ELIOBA J. RAIMON
Third Year Resident – Obstetrics & Gynecology
Kampala International University Western Campus
9/1/2023 Alloimmunization In Pregnancy BY Dr. Elioba J. Raimon 1

PRESENTATION OUTLINE
Introduction to alloimmunization
Blood group systems
Epidemiology
Pathogenesis of CDE (Rh) Alloimmunization
Effects of Alloimmunization in pregnancy
Management of unsensitized pregnant women
Management of sensitized pregnant women

INTRODUCTION
“CDE blood group was formerly termed
Rh or Rhesus, due to a misconception that
red cells from Rhesus monkeys expressed
these human antigens. In transfusion
medicine, “Rhesus” is no longer used”
(Sandler, 2017).

A fetus receives half of its genetic components from its mother and
half from its father
Therefore, the fetus may have red blood cell (RBC) antigens different
from those of its mother.
Some blood groups may act as antigens in individuals not possessing
those blood groups.
The antigens reside on red blood cells. If enough fetal cells cross into
the maternal blood, a maternal antibody response may be provoked
INTRODUCTION CONT’D

If these maternal antibodies cross the placenta, they then can
enter the fetal circulation and destroy the fetal erythrocytes,
causing haemolytic anemia.
Several blood groups are capable of producing fetal risk, but those
in the CDE (Rh) group have caused the overwhelming majority of
cases of Erythroblastosis fetalis.
Therefore, the CDE (Rh) group is used as an example
INTRODUCTION CONT’D

DEFINITIONS OF TERMS
ALLOIMMUNIZATION
Development of antibodies in response to antigens from a non-
self protein
RHESUS ALLOIMMUNIZATION
The development of antibodies against Rhesus antigen on the
red blood cells of a Rhesus positive person
A preventable disease
Formerly termed as isoimmunization.

BLOOD GROUP SYSTEMS
Currently, 36 blood group systems and 360 erythrocytes antigens
are recognized by the International Society of Blood transfusion,
namely ABO system, Rhesus system, Duff, Kell, MNSs, P, Lewis,
Diego, etc.
These blood group systems have been found to be associated with
hemolytic diseases.
Most cases of severe fetal anemia requiring antenatal transfusion
are attributable to anti-D, anti-Kell, anti-c, or anti-E
alloimmunization.
However ABO & Rh account for 98%

ABO BLOOD GROUP SYSTEM

RHESUS BLOOD GROUP SYSTEM

RHESUS BLOOD GROUP SYSTEM
The Rhesus antigens are transmembrane glycoproteins
found on the RBC membranes
Currently, 50 antigens have been described in the Rhesus
group system.
However D, C, c, E and e antigens are the most important.
The two responsible genes (RHD and RHCE) are located on
the short arm of chromosome 1 and are inherited together.

Persons having the D gene are termed as Rhesus positive (85%).
Rhesus positive individuals can be homozygous (DD) 45%, or
heterozygous (Dd) 55%.
When the D gene is absent from both chromosomes the individual
is Rhesus negative (15%) denoted as (dd) and always
homozygous.
D - antigen is by far the most immunogenic in the Rh system
RHESUS BLOOD GROUP SYSTEM CONT’D

Immunogenicity follows this order D > c > E > C > e
D’ antigen has no natural antibody while C & E have the
corresponding natural antibodies, though weak & found
infrequently.
A single transfusion of Rh positive (+ ve )blood to an Rh
negative ( - ve ) person has a 50% chance of forming anti Rh D
antibodies (IgG)

Alloimmunization is uncommon for the following reasons:
1. Low prevalence of incompatible erythrocyte antigens
2. Insufficient trans-placental passage of fetal antigens
and maternal antibodies
3. Maternal-fetal ABO incompatibility, which leads to
rapid clearance of fetal erythrocytes before they elicit
an immune response
4. Variable antigenicity
5. Variable maternal immune response to the antigen.

The prevalence of red cell alloimmunization in pregnancy
approximates 1%
In mothers who do not receive prophylaxis with anti-D
immunoglobulin, the overall risk of alloimmunization is
approximately 16% after delivery of Rh-positive baby.
2% will become sensitized by the time of delivery, 7% by 6 months
postpartum, and the remaining 7% will be “sensibilized” (producing
detectable antibodies only in a subsequent pregnancy)
EPIDEMIOLOGY

In mothers who receive prophylaxis with anti-D immunoglobulin
administered both antepartum and postpartum, the risk of
alloimmunization is reduced to 0.1 %.
If there is ABO incompatibility, the D-alloimmunization risk
decreases to 2% because erythrocyte destruction of incompatible
cells limits sensitization
D-sensitization may also occur following first-trimester pregnancy
complications, prenatal diagnostic procedures, and maternal
trauma
EPIDEMIOLOGY CONT’D

EPIDEMIOLOGY CONT’D
Incidence of CDE (Rh) negative varies in different races:(Moise, K,
Uptodate-2014)
Basques - 30 to 35%
Caucasians in North America and Europe -15%
African Americans – 8%
Africa - 4 to 6%
India – 5%
Native Americans and Inuit Eskimos - 1 to 2%
Japan - 0.5%
Thailand & China - 0.3%
Mongoloids- Nil

PATHOGENESIS
RHESUS NEGATIVE WOMAN CARRYING A RHESUS POSITIVE FETUS
FMH (Delivery, Trauma, APH, Abortion,
Ectopic pregnancy, ECV, Amniocentesis etc.)
Fetal RBCs with Rhesus positive antigen enter maternal circulation
Mother produces Antibodies against fetal RBCs
Haemolysis of fetal RBCs
HDFN
Icterus Gravis Neonatorum
Fetal Anemia
Hyperbilirubinemia
Hydrops Fetalis Congenital Anemia
Kernicterus

FETOMATERNAL HEMORRHAGE
Occur in as many as 75% of
pregnancies
The incidence increases as
gestation advances
1. 3% in the first trimester
2. 12% in second trimester
3. 47% of the patients by
the end of the third
trimester
FMH can occur during:-
1. Delivery (most cases)
2. Obstetric events
 APH
 External cephalic version
 Operative delivery
 Invasive in-utero procedures
 Amniocentesis
 CVS
 Cordocentesis
 Evacuation
3. Abortion, Ectopic pregnancy, Molar
4. Fetal death
5. Abdominal trauma
6. Occult or silent hemorrhage

THE GRANDMOTHER EFFECT
In some pregnancies, small amount of maternal blood enter the
fetal circulation.
Thus, a D-negative female fetus exposed to maternal D-positive
red cells might develop sensitization, and later might produce anti-
D antibodies before or during pregnancy
This mechanism is called the grandmother effect because the
fetus in the current pregnancy is jeopardized by maternal
antibodies that were initially provoked by his or her
grandmother’s erythrocytes

BLOOD GROUPING + RHESUS FACTOR OF ALL WOMEN DURING FIRST ANC CONTACT
If Mother Rhesus Negative, Check Paternal Rh (D) type
For paternal Rhesus positive, determine zygosity
Determine fetal Rh (D) type if paternal RhD is heterozygous AffDNA, cffDNA
If fetus Rhesus Positive, Do indirect combs test on the mother
MANAGEMENT OF UNSENSITIZED PREGNANT WOMAN

Repeat biweekly
Positive, Do anti-D Titres
Negative
≤ 1:16 > 1:16 (Critical Titres)
Repeat Titres 4weeky till 24
weeks, then 2 weekly till term
Fetal MCA Doppler
≤ 1.5 MoM
>1.5 MoM
1. Cordocentesis
2. Amniotic spectrophotometry
INDIRECT COMBS TEST
 Repeat test every 4 weeks
 Give Anti-D Prophylaxis at 28WOA, and
within 72 hours postpartumly

Anti-D Titers

ANTI-D IMMUNE GLOBULIN
300 mcg at 28 WOG and 300 mcg within 72 hours after delivery (suppress
15mls of Rh+ fetal RBCs)
Partial protection is afforded within 13 days of the birth, and some experts
recommend giving it as late as 28 days after delivery
MOA
1. RBC clearance before recognition by the immune system
2. Prevent B cell activation (elicit inhibitory signal)
3. Blocks B-cell epitopes on the Rh +ve RBC
Route - Intramuscular and intravenous are equally effective.

TESTING FOR FETOMATERNAL HEMORRHAGE
ROSETTE TEST
Qualitative, yet sensitive,
test for fetomaternal
hemorrhage.
Negative result when the
amount of fetomaternal
hemorrhage is small (<2
mL or 0.04% fetal cells),
give standard dose of
Anti-D
KLEIHAUER-BETKE TEST
Recommended when the rosette test
is positive
To determine the percentage of fetal
red blood cells in the maternal blood.

KLEIHAUER CALCULATIONS
Percentage of Fetal RBCs = Fetal cells counted*100/Maternal cells counted
Fetal blood Volume = (% fetal RBCs * MBV* Maternal Hct)/Fetal Hct
Vials Required = Volume of fetal blood/30
RhoGAM Dose
300 mcg per 30ml fetal whole blood or 15ml fetal RBCs
Calculating Maternal Blood Volume (ml)
 (Pre-pregnant weight in kg) x 70 ml/kg x (1.0 + (0.5 x weeks
gestation/36)) - Estimated Blood loss (ml) at time of test
MANAGEMENT OF UNSENSITIZED PATIENT CONT’D

EXAMPLE:
Maternal Blood Volume = 5000mls
Maternal Hct = 35%
Percentage of fetal RBCs = 1.7%
Fetal Hct = 50%
Fetal blood volume = (0.017*5000*0.35)/0.5 = 60mls
Vials Required = 60mls/30mls = 2 = 600mcg or 3000 IU
MANAGEMENT OF UNSENSITIZED PATIENT CONT’D

MANAGEMENT OF UNSENSITIZED PREGNANT WOMAN CONT’D
PROPHYLACTIC FAILURE OF ANTI-D
1. Inadequate dosage
2. Dose too late
3. Patient already immunized but antibody titer too low for
laboratory recognition/ Unrecognized FMH)
4. Defective immune globulin

SPECIAL FETOMATERNAL RISK STATES
ABORTION
Sensitization will occur in 2% of
spontaneous abortions and 4-5%
of induced abortions.
In the first trimester, because of
the small amount of fetal blood, 50
μg of RhigG is sufficient to prevent
sensitization.
However, because the cost of
RhlgG has dropped, a full 300-μg
dose is usually given.
Amniocentesis, CVS, Cordocentesis
If the placenta is traversed by the
needle,
There is up to an 11 % chance of
sensitization. Therefore,
Administration of 300 μg of
RhigG is recommended when
these procedures are performed
in the unsensitized patient

ANTEPARTUM BLEEDING
Administration of 300 μg of
RhlgG is recommended.
If the pregnancy is carried >
12 weeks from the time of
RhlgG administration, a repeat
prophylactic dose is
recommended.
EXTERNAL CEPHALIC VERSION
Fetomaternal haemorrhage
occurs in 2-6% of patients who
undergo ECV.
Whether failed or successful;
therefore, these patients
should receive 300 μg of
RhlgG.
SPECIAL FETOMATERNAL RISK STATES CONT’D

MANAGEMENT OF UNSENSITIZED PREGNANT WOMAN CONT’D
Continuous EFM
No stripping of membranes
No Fundal pushing in 2nd stage of
labour
No fundal message
For PPH, Oxytocin preferred over
ergometrine
Avoid episiotomy
No contraindication to delay cord
clamping
Allow placental side to drain out
Avoid manual removal of the placenta
LABOR AND DELIVERY CONSIDERATIONS

MANAGEMENT OF SENSITIZED PATIENT
No Hx of previously affected baby
RH-NEGATIVE PATIENT WITH ANTI-D ALLOIMMUNIZATION
< 1:16
Antibodies titres
≥ 1:16
PSV ≤1.5 MoM PSV >1.5 MoM
MCA Doppler
Repeat Titres 4weeky till 24 weeks,
then 2 weekly till term
Hx of previously affected baby

MANAGEMENT OF SENSITIZED PATIENT
RESULTS OF MCA DOPPLER
POG ≥ 35 weeks
Mildly/moderately affected fetus
PSV ≤1.5 MoM
PSV >1.5 MoM
Severely affected fetus
Repeat MCA doppler every 2 weeks
Delivery at term or near term
Enhance fetal lung maturity maybe considered
Cordocentesis
POG < 35 weeks
Deliver
Fetal Hb <8g/dl or HCT < 30
Intrauterine transfusion

REFERENCES
1. Williams obstetrics 26th edition, F. Gary Cunningham et al (2022),
pages 352 -359
2. Obstetrics normal and problem pregnancies, 7th edition, Gabbe et al
(2017), pages 770-785
3. Current diagnosis and treatment in obstetrics and gynecology, 12th
edition, Alan H et al (2019), pages 261-264
4. Alloimmunization in pregnancy, Epidemiology, Clinical features,
pathogenesis and management, Kenneth J Moise et al, Up-to-date, 27
Jun 2022
5. ACOG – Prevention of Rhesus Alloimmunization August 2017

SHUKRAN
LIL’IISTIMAE
THE END
(ALNIHAYA)

ALLOIMMUNIZATION IN PREGNANCY BY DR. ELIOBA J. RAIMON 2023

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