Obstetric Medicine

Rhesus Disease (Rh-isoimmunization in pregnancy)

Dr.Amina Zakaria Al-tutunji M.B.Ch.B, MD
Fig.1 ABO blood group system
ABO System
There are 4 basic blood types
A (surface antigen A)
B (surface antigen B)
AB (surface antigen AB)
O (neither A nor B antigens)
Plasma will contain naturally-occurring antibodies to the missing antigen. See Fig.1

ABO iso-immunization
It may occur when the mother's blood group is O and the baby's blood group is A or B.
ABO incompatibility may occur in a first pregnancy.
It not require prior sensitization in order to be produced because of anti-A & anti-B antibodies are
present in the maternal circulation naturally. Anti A or anti B antibodies may pass to fetal
circulation, causing fetal hemolysis and anemia (most anti A & anti B are mainly IgM & do not
cross the placenta, however, IgG class antibodies are also present especially in type O individuals).
Therefore, ABO incompatibility generally causes mild hemolytic disease of the baby but some
time explains unexpected jaundice in other healthy term infant.
Rhesus blood group system
The Rhesus blood group consists of five major antigens, D, C, c, E, e. The most important & the
most common Rh antigens is D antigen which is strongly immunogenic.
Rh iso-immunization
Iso-immunization: Production of antibodies in response to an antigen derived from another
individual of the same species. Incidence 2-16%
Rh isoimmunization: Maternal antibody production in response to fetal RBC rh antigen. It
occurs mostly in pregnant Rh-ve women carrying an Rh+ve fetus resulting in a serious
complication affecting the fetus/or neonate ranging from mild neonatal jaundice to intrauterine
loss or neonatal death

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The possibilities:
Rh + ve and Rh -ve →no problem

Rh -ve and Rh -ve →no problem

Rh -ve and Rh +ve →Rh -ve baby →no problem

Rh -ve and Rh +ve →Rh +ve baby →Problem may arise.

Etiology & pathophysiology
In classical Rh disease, the mother is Rh -ve & the fetus Rh +ve
Rh iso-immunization is caused by maternal antibodies production in response to exposure to fetal
RBC antigens. When Rh-negative patients are exposed to Rh antigen, they may become sensitized
(antibodies in maternal circulation).
The initial response to exposure to Rh antigen is the production of IgM antibodies for a short
period of time (6wks- 6 months), followed by the production of IgG antibodies that are capable
of crossing the placenta (Fig.2). If the fetus of next pregnancy has the Rh antigen, these antibodies
will cross the placenta to the fetal circulation coating the fetal RBCs & cause hemolysis. The
concentration of antibody appears to be the most important factor in determining the severity of
the disease.
Once a mother is sensitized to a fetal RBC antigen, the sensitization can′t be lost and the response
will magnify in subsequent pregnancies.

Maternal immune system exposure to Rh +ve RBCs can occur as a result of several mechanisms:
1- Feto-maternal hemorrhage during pregnancy. An amount of 0.1 ml of fetal blood is sufficient
to cause the initial sensitization to Rh D antigen
2- Inadvertent transfusion of Rh +ve blood
3- Injection with needles contaminated by Rh +ve blood
Feto-maternal haemorrhage (sensitizing events) can occur in the following situations:
1-APH
2-Abortion, molar pregnancy& ectopic pregnancy
3-Invasive pre-natal testing (chorionic villous sampling (CVS) & amniocentesis)
4-External cephalic version (ECV)
5-Delivery
6-Manual removal of placenta
7-Abdominal trauma
8- IUFD

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Fig.2 pathophysiology of iso-immunization

Effect on fetus& the newborn
If the hemolysis is mild, the fetus can compensate by increasing the rate of erythropoiesis to
maintain its red cell mass. If the hemolysis is severe, Erythropoiesis stimulated in the fetal liver,
which enlarges but eventually unable to meet the increased demand. The infant may be born with
one or more of the following:
1-Hemolytic anemia
2- Progressive anemia which may leads to congestive HF
3-Hydrops fetalis
4-Neonatal jaundice develops rapidly with in the first 24 hours of life. (Hyper-bilirubinemia in
utero; the excess bilirubin in fetal circulation is removed across the placenta to the maternal
circulation but following delivery the bilirubin accumulates & so the infant becomes jaundiced).
5-Kernicterus, unconjucated bilirubin crosses the BBB & damage the basal ganglia causing
lethargy, hyper-tonicity, cerebral palsy & learning disability)
Screening & Diagnosis
History can help to predict the sensitization. Detailed history should include:
1-Maternal, paternal blood groups & Rh
2-History of anti-D administration in previous pregnancy
3-Previous episodes of possible sensitization such as history of ectopic pregnancy, abortion,
previous blood transfusions with Rh +ve blood, previous delivery of an Rh +ve infant.

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Examination:
General for any sign of pre-eclampsia & abdominal examination for poly-hydromnios &
gestational age detection
Investigations
1-Antibody screening
All Rh -ve pregnant women should have antibody screen at the first prenatal visit & should be
repeated every 2-4 weeks from booking. Antibody levels can be described using the titer or by
using IU (international unit) Maternal serum antibody titer is a guide to disease severity. Anti-D
level <4 IU/ml, HDFN (hemolytic disease of fetus & newborn) unlikely…4-15 IU/ml, moderate
risk of HDFN….>15 IU/ml, high risk of hydrops fetalis
2-Kleihauer-Betke test
It determines the proportions of fetal RBCs present in maternal sample (relying on ability of fetal
RBCs to resist denaturation by alcohol or acid). RBCs containing fetal Hb are more resistant to
acid than those containing adult Hb. When a sample of maternal blood is exposed to acid, the
maternal Hb washes away while the fetal Hb remains intact in which the fetal RBCs will be red
& easy to see while the maternal RBC will look pale. The number of fetal RBC then counted to
estimate the total volume of fetal blood.
3-USG to evaluate fetal heart size, edema, pericardial effusion, ascites & AFI
4-Doppler ultrasound of middle cerebral artery of the fetus to determine the middle cerebral
artery peak systolic velocity (MCA-PSV) is being used to detect high output HF& fetal anemia.
The sensitivity is reported at 100% with false positive of 12%

Management
1-Rh-ve non sensitized patient (prevention of Rh iso-immunization)
Management aimed to prevent process of sensitization. UK guidelines suggest that all Rh –ve
pregnant women who have not previously sensitized should be offered routine antenatal
prophylaxis with anti-D either with a single dose regimen at around 28 weeks or a two-dose
regimen given at 28 & 34 weeks gestation. Once a woman is sensitized to the D rhesus antigen,
no amount of anti-D will ever turn back the clock and no rule for giving anti-D.
After delivery, determine blood group of the newborn baby& antibody screening. If the newborn
is Rh –ve, no further treatment is needed. If newborn is Rh +ve & antibody screen is –ve, provide
anti-D within 72 hrs. If newborn is Rh +ve & antibody screen is +ve, monitor the newborn for
hemolysis & manage next pregnancy as sensitized.

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Administration of anti -D
The exact dose is determined by:
1- Gestational age
2- Size of feto-maternal hemorrhage which determined by Kleihauer test.
Before 20 weeks gestation:
250 IU anti D given to non-sensitized Rh -ve pregnant women if indicated
After 20 weeks gestation:
500 IU of anti-D should be administered IM. Dose is enough to protect against maternal
sensitization from as much as 30 ml Rh +ve blood. Higher dose may be needed according to result
of Kleihauer test.
Ideally administration of anti-D immunoglobulin to a mother should be within 72 hours of
exposure to fetal RBCs.
Indications for anti-D administration
Anti-D should be given to un-sensitized Rh-ve women in;
1. Postpartum if women deliver Rh +ve baby.
2. Postpartum if women deliver dead baby and no sample can be obtained from the baby.
3. Prophylactically at 28 & /or 34 weeks of gestation of all non-sensitized Rh-ve pregnant women.
4. After accidental transfusion of Rh +ve blood to Rh -ve women.
5. Pregnant women with sensitizing events as amniocentesis, CVS, ECV, after evacuation of
molar pregnancy, abortion, ectopic pregnancy etc.)
Failure of anti-D prophylaxis
Although women receive anti-D, sensitization can occur due to:
1. Subclinical feto-maternal hemorrhage
2. Too small dose or too late given (>72hrs)
3. Disease caused by other rhesus type (mainly c and E).
4. Patient may already be immunized at time of giving anti D
2- Rh -ve sensitized patient
Further investigations are needed to recognize pregnancy at risk;
1- Maternal antibody titre monitoring every 2-4 weeks from booking is used to detect the
presence & the degree of iso-immunization by serial titers.
2- USG evaluation of the fetus, Serial ultrasound examination for: gestational age, amount of
liquor, hepato-splenomegaly, bowel wall edema, ascites, heart size (cardiomegaly& /or pericardial
effusion), sluggish fetal movement, placental hypertrophy, abnormal fetal posture (Buddha
position) & fetal HR changes have been noted with severe anemia
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3- Doppler study of middle cerebral artery of the fetus to determine MCA-PSV
4- Amniocentesis; beginning at 24-26 weeks to estimate the level of bilirubin in amniotic fluid as
an indirect indicator of fetal hemolysis, It is indicated when there is:
1-High antibody titer
2-Previous severely affected baby
Spectrophotometry of bilirubin contained amniotic fluid is done & plotting is done & optical
density of the fluid at wave length 450 nm (OD 450) is plotted in Liley′s curve. The deviation
bulge obtained is directly proportion to the severity of disease.
Zone 1: the fetus is unlikely to be affected at this time, or mildly affected. Repeated amniocentesis
in 10-14 days
Zone 2: the fetus experiencing mild-moderate hemolysis
Zone 3: the fetus is anemic with high probability of fetal death unless intervention occurs

Fig.3 Liley’s chart

5- Fetal blood sampling (cordocentesis) is a gold standard for detection of fetal anemia
Percutaneous umbilical blood sampling allows direct access to the fetal circulation to determine
severity of hemolytic process & the need for intrauterine transfusion.
Treatment of affected fetus: Either
1. Intrauterine transfusion for premature fetus
can be done by many routes; In to the umbilical ven at the point of cord insertion, into the intra
hepatic v, into the peritoneal cavity & into the fetal heart guided by USG using O-ve blood & it
can be started at 18 weeks, repeat at 1-3 weeks interval, it is lifesaving in a severely anemic fetus
that is too premature for delivery. The aim to restore Hb level, reversing or preventing hydrops
fetalis or death
2. Delivery; must be take place in a unit where adequate neonatal support is available & generally
delivery should not be before 36-37 weeks unless there is specific reasons such as difficult fetal
transfusion.
Check cord blood immediately after birth for blood group &Rh, bilirubin level & Hb.

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If the baby is known to be anemic or has had multiple transfusion, a neonatologist must be present
at delivery & the baby may require;
1- Exchange transfusion after delivery. Fig.4
2- Phototherapy after delivery. Fig.5
3. Top-up transfusion

Fig.4 Exchange transfusion Fig.5 Phototherapy

Hydrops fetalis
Is a serious fetal condition defined as the accumulation of fluid in more than two body cavities
including (pleural, pericardial, peritoneal, subcutaneous) with hepatosplenomegally,
placentomegaly & polyhydromnios
The 1st sign of fetal hydrops in early pregnancy (11-15 weeks) is often the presence of generalized
skin edema in the fetal head & neck area by USG
There is excessive destruction of fetal RBC lead to severe anemia & metabolic acidosis, this may
lead to damage to the liver leading to hypoprotenemia which responsible for generalized edema,
ascites & hydrothorax. Fetal death occurs due to heart failure.
It carries a high perinatal mortality.

Fig.6 hydrops fetalis

Key points
* Rhesus disease gets worse with successive pregnancies
* Anti-D is given only as prophylaxis & is useless once sensitization has occurred
* If the father of the fetus is Rh-ve, the fetus cannot be rhesus +ve