Maternal Isoimmunisation

Maternal Isoimmunisation
MATERNAL ALLOIMMUNIZATION, ALSO KNOWN

AS ISOIMMUNIZATION, OCCURS WHEN A WOMAN’S
IMMUNE SYSTEM IS SENSITIZED TO FOREIGN
ERYTHROCYTE SURFACE ANTIGENS, STIMULATING
THE PRODUCTION OF IMMUNOGLOBULIN G (IGG)
ANTIBODIES
•Causes of Maternal Isoimmunisation.
•Causes of Rh Isoimmunisation
•Biochemistery of Rh Antigen
• Genetic of Rh Antigen.
•Mechanis of Rh Isoimmunisation
•Pathogeneisis of Fetal Rh Diseaes.
•History Management of Rh Disease.
•Prevention of Rh Isoimmunisation.
•Treatement of cases of Rh isoimmunisation.
•Other cases of meternal Isoimmunisation
Among the antigens capable of causing maternal alloimm-

unization and fetal hemolytic disease, the Rh blood group
system is the most common. In particular, the D antigen of
the Rh blood group system (Rh D) causes the most cases
of severe hemolytic disease.
Because anti-D Ig prophylaxis has reduced the risk of sensitization to

less than 1% of susceptible pregnancies, other alloantibodies have
increased in relative importance. These include:
-antibodies to other antigens of the Rh blood group system (c, C, e,
and E),
-as well as other atypical antigens known to cause severe anemia,
such as anti-Kell (K, k), anti-Duffy (Fya), and anti-Kidd (Jka, Jkb).
• Biochemsitery and Genetic Rh Antigen.
•Causes of Rh Isoimmunisation.
Rh-Isoimmunization- Biochemical Aspect of Rh Antigen
The Rh antigen is a complex of three components:

C, D, and E antigen. It is distributed on the cell membrane in a
non-random fashion.
Two of these antigens (C and E) have alleles that can be

identified immunologically (by antisera).
The third one (D) antigen has no antigenic allele I.e. no

specific antisera for a “d” antigen.
The presence of “D” antigen implies an Rh-positive blood.

Rh-Isoimmunisation- Genetics of Rh Antigen
RH antigen is a genetically determined protein produced during

Red Cells formation. It appears as early as the 38 days after
fertilization.
The Rh “gene complex” reside on the distal end of the short

arm of chromosome one.
Three genetic loci, each with two possible alleles determine the
Rh antigen (Rh blood group)
Genotype Phenotype
eCd/EcD D positive
Antigenicity of the Rh surface
protein:
genetic expression of the D
eCd allele.
Number of specific Rh
antigen sites.
Ec D Interaction of components of
the Rh gene complex.
Exposure of the D antigen
on the surface of the red cell
Rates of Rh Negativity Among Ethnic Groups
Frequency
Race/Ethnicity
(%)
Caucasian 15-16
African American 8
African 4
Basque* 30-35
Asian <1
Asian American 1
Native
1-2
American/Inuit
Eurasian 2-4
•*Region of France/Spain
Table 2. Rh Gene Frequencies in 2000 Unrelated Caucasian
Adults
Gene Frequency
Complex (%)
CDe 41
c(d)e 39
cDE 16
cDe 2.2
C(d)e 1.1
c(d)E 0.6
CDE 0.08
C(d)E 0.00
The D antigen is the most immunogenic. Three pairs of Rh

antigens exist with varying gene frequencies and possible
combinations
•Causes of Maternal Isoimmunization.
•Genetic and Biochemistry of Rh Antigen.
•Natural History of Rh Isoimmunization
•Causes of Rh Isoimmunization.
•Mechanism of Rh Isoimmunization
•Pathogenesis of Fetal Rh Disease.
•Prevention of Rh Isoimmunization.
•Treatment of cases of Rh isoimmunization.
•Other cases of maternal Isoimmunization
Natural History of Rh-Isoimmunization:
If no preventive measures are taken:

0.7-1.8% of Rh negative women will become
isoimmunized antenatally, developing D antibody through
exposure to fetal blood.
8-17% will become isoimmunized at delivery.
3-6% after spontaneous or elective abortion.
2-5% after amniocentesis.
In subsequent D-positive pregnancies of isoimmunized women,

maternal D antibody will cross the placenta into the fetal
circulation and hemolyze red cells.
Without treatment:
25-30% of the offspring will have some degree of

hemolytic anemia and hyperbilirubinemia.
20-25% will be hydropic and often will die either in utero

or in the neonatal period.
Cases of hemolysis in the newborn that do not result in

fetal hydrops still can lead to kernicterus.
kernicterus
Is a neurological condition observed in infants with severe
hyperbilirubinemia and is due to the deposition of un-
conjugated bilirubin in the brain.
Causes of Neonatal Hyperbilirubinemia:

• Excessive destruction of RBCs.
• In the absence of placental clearance.
• And immature ability of conjugating fetal bilirubin.
Clinical Features of Kernicterus:

Symptoms that manifest several days after delivery include poor
feeding, inactivity, loss of the Moro reflex, a bulging fontanelle,
and seizures.
The 10% of infants who survive may develop spastic
choreoathetosis, deafness, and mental retardation.
•Genetic and Biochemistery of Rh Antigen.
•Natural History of Rh Isoimmunisaton.
•Factors that deterimine development of Rh Isommunisation
Approximately 10% of Caucasian pregnancies are Rh
incompatible.
However less than 20% of Rh D incompatible pregnancies

actually lead to maternal alloimmunization. In addition as many
as 30% of Rh D-negative individuals have been demonstrated
to not become alloimmunized even when challenged with
large volumes of Rh D-positive blood
Factors that affect the risk of development of alloimmunization

in a susceptible Rh D-negative woman:
(1) volume of fetomaternal hemorrhage.

(2) degree of maternal immune response (related to
antigenicity of fetal RBCs and type of IgG)
(3) concurrent ABO incompatibility
The Risk of development of Fetal Rh-diseaes is affected by:
• The Risk of development of Maternal isoimmunisation:

- the husband phenotype and genotype ( 40 % of Rh positive men are
homozygous and 60% are heterozygous).
- The antigen load and frequency of exposure.
- The classe of IgG.
- ABO incompatibility
• The Extend of Severity of Fetal Hemolytic Diseases:

- Degree of expression of genetic expression of the D allele.
- Number of specific Rh antigen sites.
- Interaction of other components of the Rh gene compelex.
- Degree of exposure of the D antigen on the surface of the red cell
Less than 20% of Rh D incompatible pregnancies actually
lead to maternal alloimmunization
• Role of ABO blood group status:
With an ABO-compatible fetus, the overall risk of

alloimmunization if not treated with anti-D Ig is approximately
16%. However, if ABO incompatibility exists, the risk is only 1.5-
2%.
The protective effect conferred by ABO incompatibility is believed to
be due to maternal destruction and subsequent clearance of the ABO-
incompatible fetal erythrocytes before Rh sensitization can occur.
• Role of Volume of Fetomaternal Hemorrhage:
Fifteen to 50% of births produce hemorrhage volumes sufficient

to cause alloimmunization (as little as 0.1 mL and in rare cases
can exceed 30 mL) depending on the maternal immune response
Causes of maternal alloimmunization
Blood transfusion
Fetomaternal hemorrhage
Antepartum
Intrapartum
Abortion
Therapeutic
Spontaneous
Ectopic pregnancy
Abruption
Abdominal trauma
Obstetric procedures
Amniocentesis
Chorionic villus sampling (CVS)
Percutaneous umbilical blood sampling (PUBS)
External cephalic version (ECV)
Manual removal of the placenta
Estimated Risk of Transplacental fetomaternal hemorrhage
Normal Pregnancy Risk TPH

First Trimester 6.7 %
Second Trimester 15.9 %
Third Trimester 28.9 %
Parturition 50 %
Spontaneous Abortion 2%
Therapeutic Abortion 4–5%
Amniocentesis 15- 25 %
In most cases FM hemorrhage is around 0.1 ml.

The amount necessary to cause Isoimmunisation is not known.
Fetomaternal hemorrhages occurs in as many as 75% of pregn-
ancies. Its incidence increases as gestation advances and most
cases occurs during delivery.
Tests for detection and estimation of fetal blood in maternal

circulation
 Rosette screening test: is used to determine the
presence of a fetomaternal hemorrhage.
 The Kleihauer-Betke test: is employed to quantify the

volume of hemorrhage so that an appropriate dose of anti-D
Ig can be administered.
 FlowCytometery:
1. Cleared by
Macrophage Mother
2. Plasma Primary Response
stem cells
•6 wks to 6 M.
•IGM.
IGM antibodies
Placental
Fetal Anaemia
Macroph. antigen
Presenting cell Mother
T- helper cell Seocndary Response
•Small amount
B cell •Rapid
•IgG
IgG
Anti - D
Placental
Fetal Anaemia
Macroph. Antigen
Mother
Presenting Cell Group “O” Rh Negative
T-Hellper
Anti - A Anti - B
B-cell
Anti-D
Placenta
A Rh positive B Rh Positive
“O” Rh positive
Infant
Prevention of Maternal Alloimmunisation:
Exogenous administration of a dose of anti-D Ig sufficient

enough to suppress an immune response, is known as
antibody mediated immune suppression (AMIS).
The mechanism of AMIS: the most likely mechanism is via

central inhibition, wherein Rh Ig coats fetal erythrocytes,
which are then sequestered in the spleen and lymph nodes.
The local increase in antigen-antibody complexes interrupts
the commitment of B cells to plasma cell clones, thereby
suppressing the primary immune response. Additionally,
these antigen-antibody complexes stimulate the release of
cytokines by immune effector cells that inhibit the
proliferation of antigen-specific B cells
Because fetal Rh antigens are present as early as the 30th day
after conception, anti-D Ig is indicated with ectopic pregnancy as
well as therapeutic and spontaneous abortions. The risk of
alloimmunization in susceptible women undergoing therapeutic or
spontaneous abortion is 4–5% and 1.5–2%, respectively.
For pregnancies less than or equal to 12 weeks’ gestation, 50 mcg

of anti-D Ig sometimes is administered because the entire blood
volume of the fetus usually is less than 5 mL.
However, pregnancies exceeding 12 weeks’ gestation or

pregnancies in which gestational age is unknown should receive
the full 300-mcg dose
Dose of prophylactic Anti-D Ig:
10 mcg of anti-D Ig should be administered for every mL of fetal

blood in the maternal circulation.
Thus, the 300-mcg dose is more than adequate for a typical feto-
maternal hemorrhage and covers hemorrhage volumes up to 30
mL of whole fetal blood.
In the less than 1% of cases where the volume of fetomaternal

hemorrhage exceeds 30 mL, utilizing the Kleihauer-Betke test to
quantitate the volume of fetomaternal hemorrhage and admini-
stering the appropriate amount of anti-D Ig (10 mcg/mL fetal
blood) is necessary
•Factors that deterimine development of Rh
Isommunisation
Management of cases of Rh isoimmunisation
The goals in managing the alloimmunized pregnancy are 2-fold:
Initially detecting fetal anemia prior to the occurrence of

fetal compromise.
Minimize fetal morbidity and mortality by correcting this

anemia until fetal lung maturity and delivery can be achieved.
Past Obstetric History:
Although not reliably accurate in predicting severity

of fetal disease, past obstetrical history can be
somewhat prognostic
Antibody Titer in maternal blood
Titers greater than 1:4 should be considered Rh alloimmunized.

However, the threshold for invasive fetal testing varies at different
institutions and generally is 1:16 or greater because these titers
have been associated with fetal hydrops
spectrophotometric measurements of bilirubin in amniotic fluid
Because the wavelength at which bilirubin absorbs light is

420-460 nm, the amount of shift in optical density from
linearity at 450 nm (D OD 450) in serial amniotic fluid
samples can be used to estimate the degree of fetal hemolysis.
Modification of the Liley curve to adjust for the relative

inaccuracy of D OD 450 readings in early-to-middle second
trimester and the use of serial measurements has improved its
accuracy.
Fetal Blood Sampling
The only definitive means of diagnosing fetal anemia and acidosis

is via fetal PUBS, also known as cordocentesis
Despite the wealth of information afforded by PUBS, routine

umbilical cord blood sampling is not universal due to concern for
fetal and maternal complications. These include fetomaternal
hemorrhage, fetal loss (0.5–2% per procedure), placental
abruption, acute refractory fetal distress, and amnionitis with
maternal adult respiratory distress syndrome.
the role of ultrasound
Ultrasound is primarily used to assess fetal well being;

diagnose hydrops; and guide amniocenteses, fetal blood
sampling, and IUTs. In this capacity, ultrasonography has
improved both the safety and success rate of invasive
procedures, as well as helping to minimize invasive testing.
Doppler blood flow measurment:
Doppler studies have not been successful in demonstrating

accurate prediction of fetal anemia.
Mari et al, 2000, purport that increases in peak velocity of systolic

blood flow in the middle cerebral artery can be used to detect
moderate and severe anemia in nonhydropic fetuses.
However, it does not identify milder cases of anemia consistently,
and results should therefore be interpreted with caution.
Doppler flow studies ultimately may be quite useful for cases of

non-D alloimmunization, such as those observed with the Kell
antigen, because in these patients the degree of fetal anemia
correlates poorly with the extent of erythrocyte destruction and
the D OD 450, rendering amniotic fluid studies ineffective
considerations for PUBS and possible IUT
A number of important considerations exist when preparing a patient

for PUBS and possible IUT; these include:
gestational age,
possibility of delivery,
fetal maturation with corticosteroids,
and likelihood of transfusion
The amount to be transfused can be calculated once the

hematocrit/hemoglobin results are returned. In general, 30-60
mL/kg of nonhydropic fetal weight is transfused
Current Indication of IPT
In the setting where repeat access cannot be gained or with a

posterior placenta in which intravascular access could not be
gained initially, performing an IPT is reasonable.
IPT require a greater volume of blood, roughly calculated as

the following:
(# of weeks’ gestation – 20) x 10 mL
Care should be taken to avoid the umbilical vessels and to
ensure that intraabdominal access is indeed intraperitoneal.
IVT vs. IUT
Benefits of IVT over IPT include:

Direct measurement of the fetal hemoglobin and acid-base
status.
Lower failure rate (particularly in the hydropic fetus).
Lower rates of procedure-related morbidity and mortality.
Better efficacy at earlier gestational ages.
The only benefit offered by IPT is the ability to drain off fetal
ascites during the procedure, but this is of minimal benefit in a
hydropic fetus
•Meternal Isoimmunisation to Rare antibodies.
Maternal Isoimmunisation to rare antibodies
Patients with serum antibody known to cause hemolysis in the

fetus, such as anti-c, anti-Kell and anti-E antibodies, these
patients are managed similarly to the patient who is Rh
sensitized.
Initial management involves following serial maternal antibody

titers, which leads to assessment of the fetus for hemolysis using
amniocentesis as indicated by rising antibody titers, ultrasound,
and possibly PUBS.
•Table 3. Association of Atypical Erythrocyte Antibodies and
Hemolytic Disease of the Newborn
•Disease
•Antibodies
Frequency
•Common •Kell, c, E
•Uncommo •e, C, cE, Ce, C , Kp , Kp , k, Jk , s, w a b a
n Wr , Fy a a
•Rare •Biles, Co , Di , Di , Do , En , Fy , Good,

a a b a a b
Heibel, Jkb, Lua, Lub, M, Mia, Mta, N, Radin, S, U, Yta, Zd
•No
documente •Le , Le , P a b
d cases
•Two situations exist in which patients are not followed identically
to patients who are Rh sensitized. The first is that of
alloimmunization to the c, E, or C antigens. Some concern exists
that hemolysis may occur in these patients with a lower than 1:16
titer. Thus, if the initial titer is 1:4 and stable but increases at 26
weeks’ gestation to 1:8, assessing with amniocentesis for  OD
450 at that point is reasonable. If, however, the patient presents in
the first trimester with a 1:8 titer that remains stable at 1:8
throughout the second trimester, continued serial antibody titers
are indicated
•The second case in which patients should not be managed
identically to patients who are Rh sensitized is that of Kell
isoimmunization because several cases of severe fetal hemolysis
with anti-Kell antibodies have occurred in the setting of low  OD
450 values. The proposed etiology for this is that the anti-Kell
antibodies may attack and destroy erythroid precursors that have
low levels of hemoglobin. This leads to fetal anemia but not with
the concomitant rise in bilirubin breakdown products, thus leading
to relatively normal values of the  OD 450.
•This type of ABO incompatibility also can lead to mild fetal
hemolysis. Because most of the anti-A and anti-B antibodies are
immunoglobulin M (IgM), which does not cross the placenta, the
fetal hemolysis does not lead to severe anemia and hydrops.
However, even with mild anemia, the hemolysis may lead to
hyperbilirubinemia and even kernicterus, thus closely monitor
these patients postpartum for jaundice. No particular antepartum
management needs to be addressed in the setting of ABO
incompatibility.

Maternal Isoimmunisation

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Maternal Isoimmunisation

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Maternal Isoimmunisation

MATERNAL ALLOIMMUNIZATION, ALSO KNOWN

Among the antigens capable of causing maternal alloimm-

Because anti-D Ig prophylaxis has reduced the risk of sensitization to

The Rh antigen is a complex of three components:

Two of these antigens (C and E) have alleles that can be

The third one (D) antigen has no antigenic allele I.e. no

The presence of “D” antigen implies an Rh-positive blood.

RH antigen is a genetically determined protein produced during

The Rh “gene complex” reside on the distal end of the short

The D antigen is the most immunogenic. Three pairs of Rh

If no preventive measures are taken:

In subsequent D-positive pregnancies of isoimmunized women,

25-30% of the offspring will have some degree of

20-25% will be hydropic and often will die either in utero

Cases of hemolysis in the newborn that do not result in

Causes of Neonatal Hyperbilirubinemia:

Clinical Features of Kernicterus:

However less than 20% of Rh D incompatible pregnancies

Factors that affect the risk of development of alloimmunization

(1) volume of fetomaternal hemorrhage.

• The Risk of development of Maternal isoimmunisation:

• The Extend of Severity of Fetal Hemolytic Diseases:

With an ABO-compatible fetus, the overall risk of

• Role of Volume of Fetomaternal Hemorrhage:

Fifteen to 50% of births produce hemorrhage volumes sufficient

Normal Pregnancy Risk TPH

In most cases FM hemorrhage is around 0.1 ml.

Tests for detection and estimation of fetal blood in maternal

 The Kleihauer-Betke test: is employed to quantify the

Exogenous administration of a dose of anti-D Ig sufficient

The mechanism of AMIS: the most likely mechanism is via

For pregnancies less than or equal to 12 weeks’ gestation, 50 mcg

However, pregnancies exceeding 12 weeks’ gestation or

10 mcg of anti-D Ig should be administered for every mL of fetal

In the less than 1% of cases where the volume of fetomaternal

The goals in managing the alloimmunized pregnancy are 2-fold:

Initially detecting fetal anemia prior to the occurrence of

Minimize fetal morbidity and mortality by correcting this

Although not reliably accurate in predicting severity

Titers greater than 1:4 should be considered Rh alloimmunized.

Because the wavelength at which bilirubin absorbs light is

Modification of the Liley curve to adjust for the relative

The only definitive means of diagnosing fetal anemia and acidosis

Despite the wealth of information afforded by PUBS, routine

Ultrasound is primarily used to assess fetal well being;

Doppler studies have not been successful in demonstrating

Mari et al, 2000, purport that increases in peak velocity of systolic

Doppler flow studies ultimately may be quite useful for cases of

A number of important considerations exist when preparing a patient

The amount to be transfused can be calculated once the

In the setting where repeat access cannot be gained or with a

IPT require a greater volume of blood, roughly calculated as

Benefits of IVT over IPT include:

Patients with serum antibody known to cause hemolysis in the

Initial management involves following serial maternal antibody

•Rare •Biles, Co , Di , Di , Do , En , Fy , Good,

Heibel, Jkb, Lua, Lub, M, Mia, Mta, N, Radin, S, U, Yta, Zd

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