Rhesus Isoimmunization(HDFN)

Blood groups
• First, there is the ABO group, allowing four different
permutations of blood group (O, A, B, AB).
• Second, there is the rhesus system, which consists of C, D and
E antigens.
• Mismatch between the fetus and mother can mean that when
fetal red cells pass across to the maternal circulation
sensitization of the maternal immune system to these fetal
‘foreign’ red blood cells may occur and subsequently give rise
to haemolytic disease of the fetus and newborn (HDFN).
• The rhesus system is the one most commonly associated with
severe haemolytic disease.
Aetiology
• Occurrence of HDFN as a result of rhesus
isoimmunization involves three key stages
• Firstly, a rhesus-negative mother must conceive a
baby who has inherited the rhesus-positive
phenotype from the father.
• Secondly, fetal cells must gain access to the
maternal circulation in a sufficient volume to
provoke a maternal antibody response.
• Finally, maternal antibodies must cross the
placenta and cause immune destruction of red
cells in the fetus.
Aetiology
• Rhesus disease does not affect a first pregnancy
as the primary response is usually weak and
consists primarily of immunoglobulin (Ig) M
antibodies that do not cross the placenta.
• However, in a subsequent pregnancy with a
rhesus-positive baby, rhesus-positive red cells
pass from the baby to the maternal circulation
and cause maternal resensitization
Potential sensitizing events for
rhesus disease
• Miscarriage.
• Termination of pregnancy.
• Antepartum haemorrhage.
• Invasive prenatal testing (chorion villus sampling,
amniocentesis and cordocentesis).
• Delivery.
Prevalence of rhesus disease
• Rhesus disease is commonest in countries where anti-D
prophylaxis is not widespread, such as the Middle East and
Russia.
• The prevalence of D-rhesus negativity is 15% in the UK
Caucasian population, but lower in all other ethnic groups.
• Approximately 55% of UK Caucasian males are heterozygous
for the D antigen; therefore, around two-thirds of rhesus-
negative mothers would be expected to carry a rhesus-
positive fetus.
 Preventing rhesus isoimmunization
• The process of isoimmunization can be prevented by the
intramuscular administration of anti-D immunoglobulins to a
mother.
• Anti-D immunoglobulins ‘mop up’ any circulating rhesus-
positive cells before an immune response is excited in the
mother.
• It is normal practice to administer anti-D as soon as possible
after any potential sensitizing events that may cause feto-
maternal haemorrhage and preferably within 72 hours of
exposure to fetal red cells.
• However, if, exceptionally, this deadline cannot be met, some
protection may still be offered if anti-D Ig is given up to 10 days
after the sensitizing event.
Preventing rhesus isoimmunization
• Rhesus disease does not affect a first pregnancy as the
primary response is usually weak and consists primarily
of immunoglobulin (Ig) M antibodies that do not cross
the placenta.
• However, in a subsequent pregnancy with a rhesus-
positive baby, rhesus-positive red cells pass from the
baby to the maternal circulation and cause maternal
resensitization
 The management of sensitizing events in the
rhesusnegative pregnant woman
• In the first trimester of pregnancy, because the volume of fetal blood
is so small, it is unlikely that sensitization would occur, and anti-D is
only indicated following
• ectopic pregnancy,
• molar pregnancy,
• therapeutic termination of pregnancy
• and in cases of uterine bleeding where this is repeated, heavy or
associated with abdominal pain.
• The dose that should be given is 250 IU.
• For potentially sensitizing events between 12 and 20 weeks’
gestation, a minimum dose of 250 IU should be administered within
72 hours of the event and a Kleihauer test should be performed.
Further anti-D can be given if indicated by the Kleihauer test.
The management of sensitizing events in the
rhesusnegative pregnant woman
• For potentially sensitizing events after 20 weeks’ gestation, a
Kleihauer test is required and pending the result, a minimum
anti-D Ig dose of 500 IU should be administered within 72
hours of the event. Further anti-D can be given if indicated by
the Kleihauer test.
Signs of fetal anaemia
• Note: clinical and ultrasound features of fetal anaemia do not
usually become evident unless fetal haemoglobin is more than
5 g/dl less than the mean for gestation. Usually, features are
not obvious unless the fetal haemoglobin is less than 6 g/dl.
• Polyhydramnios.
• Enlarged fetal heart.
• Ascites and pericardial effusions.
• Hyperdynamic fetal circulation (can be detected by Doppler
ultrasound by measuring increased velocities in the middle
cerebral artery or aorta).
• Reduced fetal movements.
• Abnormal CTG with reduced variability, eventually a
‘sinusoidal’ trace.
 The management of rhesus disease in a
sensitized woman
• Once a woman who is D-rhesus negative has been sensitized to
the D-rhesus antigen, no amount of anti-D will ever turn the
clock back. In a subsequent pregnancy, close surveillance is
required.
• Rhesus disease gets worse with successive pregnancies, so it is
important to note the severity of the disease in previous
pregnancies.
• The father of the next baby is D-rhesus positive. He may be
heterozygous and in this situation determining the paternal
phenotype is useful in anticipating the likely fetal phenotype
and, thus, the potential for development of HDFN.
• In a sensitized woman, if the father is D-rhesus positive or
unknown, standard management involves monitoring
antibody levels every 2–4 weeks from booking.
• Antibody levels or quantity can be described using the titre or
by using IU (international units) as a standard quantification
method.
• The titre simply refers to the number of times a sample has
been diluted before the amount of antibody becomes
undetectable; titre of 2, 4, 8, 16, 32, 64, 128, etc.
• Each time a sample is tested it should be checked in parallel
with the previous sample to ensure the detection of significant
changes in the antibody level.
• Titrations of antiD do not correlate well with the development
of HDFN
• The standard quantification method (IU/ml) gives more
clinically relevant levels
Management
• If antibody levels rise, the baby should be examined for signs
of anaemia.
• In the past, the bilirubin concentration of amniotic fluid was
determined optically to give an indirect measure of fetal
haemolysis. This involved an invasive procedure with the
attendant risks of miscarriage/preterm labour and further
boosting of the alloimmune response.
• In the last decade, middle cerebral artery (MCA) Dopplers
(peak velocity measurement) have been shown to correlate
reliably with fetal anaemia
Fetal blood transfusion
• life saving in a
• severely anaemic fetus
• too premature for delivery to be contemplated.
• The aim is to restore haemoglobin levels, reversing or
preventing hydrops or death.
• A side-effect is that transfusion will also suppress fetal
erythropoiesis, which reduces the concentration of antigen-
positive cells available for haemolysis.
• Blood can be transfused into a fetus in various ways
depending on the gestation, the site of the cord insertion
Routes of fetal blood transfusion

• Blood can be transfused into a fetus in various

ways depending on the gestation
• Into the umbilical vein at the point of the cord
insertion
• Into the intrahepatic vein.
• Into the peritoneal cavity (not as effective but
some blood is absorbed and this may be the only
option, for example in early gestations).
• Into the fetal heart.
Transfused blood is:
• RhD negative.
• Crossmatched with a maternal sample.
• Densely packed (haemoglobin usually around 30
g/l) so that small volumes are used.
• White cell depleted and irradiated.
• Screened for infection including cytomegalovirus
(CMV).
At delivery
• If the baby is known to be anaemic or has had multiple
transfusions, a neonatologist must be present at delivery
should exchange transfusion be required.
• Blood must therefore always be ready for the delivery.
• All babies born to rhesus negative women should have cord
blood taken at delivery for a blood count, blood group and
direct Coombs test.
 New developments
• When a fetus is at risk of HDFN in a sensitized rhesus-negative
mother, the genotype of the fetus is very important. When the father
is heterozygous for rhesus D, there is a 50% chance that the fetus will
be rhesus positive. In this situation it is important to establish the
fetal blood group to determine whether or not the baby is at risk. This
can now be done non-invasively by examining cell-free fetal DNA
(cffDNA) present in a maternal blood sample.
• Currently in the UK, all rhesus-negative pregnant women are offered
anti-D.
• Fetal blood group genotyping using cffDNA from maternal blood
samples taken between 16 and 20 weeks’ gestation have made it
possible to determine the fetal rhesus genotype type. Routine fetal
rhesus typing for all rhesus-negative pregnant women has been
introduced in Denmark and The Netherlands to allow selective use of
anti-D, though this has not yet been recommended in the UK.
References
• Obstetrics 20th edition by Ten Teachers
Thank
You